Dibrominative Spirocyclization of 2-Butynolyl Anilides: Synthesis of gem-Dibromospirocyclic Benzo[ d][1,3]oxazines and Their Application in the Synthesis of 4 H-Furo[3,2- b]indoles

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Dibrominative Spirocyclization of 2‑Butynolyl Anilides: Synthesis of

gem-Dibromospirocyclic Benzo[d][1,3]oxazines and Their

Application in the Synthesis of 4H‑Furo[3,2‑b]indoles

Nattawadee Chaisan, Sureeporn Ruengsangtongkul, Jumreang Tummatorn, Somsak Ruchirawat,

Kittipong Chainok, and Charnsak Thongsornkleeb *

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ABSTRACT: The combination of catalytic aqueous hydrochloric

acid (HCl) and N-bromosuccinimide (NBS) generated electro-

philic bromine monochloride (BrCl), which readily induced

spiroannulation of 2-alkynolyl anilides (n = 1−3) to form gem-

dibromospirocyclic benzo[d][1,3]oxazines in up to 92% yield. The

reaction occurred under mild and metal-free conditions using

EtOAc as a green solvent. The resulted spirocyclic products

contained benzo[d][1,3]oxazine, which was useful both as a

pharmacophore and synthetic precursor. In addition, the current

protocol allowed to eﬀortlessly introduce the sp³-gem-dibromide

carbon adjacent to the sterically demanding spiroketal center.

These spiroheterocycles (n = 1) were shown to be synthetically

versatile and conveniently maneuvered. Base-promoted debromi-

native aromatization of these spirocycles unmasked rare and synthetically useful 2-aryl-3-bromofurans in mostly excellent yields.

These 3-bromofurans were well-suited substrates for intramolecular Ullmann C−N bond coupling to construct diﬃcult-to-prepare

4H-furo[3,2-b]indoles. Additionally, the current protocol was ﬂexible and adaptable to preparing the gem-dichloride variants.

of halogen can often improve bioactivities and other desired

drug-like properties of these compounds.⁷The sp³-carbon-

centered geminal dihalides, or gem-dihalides, comprise a

subclass of halogenated functional groups holding special

status as useful synthons, especially of carbenes,^8a−cand as

precursors for cross-coupling reactions,^8dthus making the

development of methods for their preparation remain a topic

of interest among synthetic chemists. However, most published

methods for preparing sp³-gem-dihalides involved carbonyl

compounds as precursors undergoing complicated and lengthy

reactions,⁹whereas alkynes were much less utilized due to

several challenging issues, including the regioselectivity of

hydrohalogenation and the competing elimination of HX to

form vinyl halides as side products.

INTRODUCTION

■

Alkyne serves as an excellent functional group for various

notable transformations.¹Its excellent ability to be activated by

Brønsted and Lewis acids led to various useful annulation

reactions for constructing functionalized cyclic structures.²Our

own work demonstrated that halogen and interhalogen species

generated in situ^3acould be utilized in a number of

electrophilic halogen-induced annulation processes leading to

a variety of carbocyclic and heterocyclic scaﬀolds.^3b−dIn these

works, TMSCl was employed, which, upon hydrolysis, led to

the generation of HCl in the reaction that served as a crucial

source of the chloride ion to react with N-halosuccinimide

(NXS) under acidic conditions to form interhalogen species

(X−Cl). It was shown that Cl₂, BrCl, and ICl could be

prepared as a solution from the reaction of TMSCl and the

corresponding NXS. Among numerous cyclic skeletons, both

of natural and synthetic origins, spirocyclic structures represent

a class of fascinating molecules with intricate architectures. The

spiro centers in these molecules add three-dimensionality,

spatial complexity, and spatial diversity that frequently exerted

increased medicinal values.⁴These special properties of

spirocyclic systems garnered much interest in the development

of preparative methods.⁵Additionally, halogenated compounds

are well-documented for their bioactivities, as observed in

many natural products.⁶In medicinal chemistry, the presence

Building on our previous work, the in situ generation of the

electrophilic halogen and its synthetic utilities in other

reactions continued to be a main theme of our research.

Received: January 12, 2021

Published: March 10, 2021

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

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Scheme 1. Features of the Current Work

Relating to the important facets of spirocycles and gem-

dihalides discussed thus far, novel uses of these electrophilic

halogens were intended for gem-dihalogenative spiroannulation

(Scheme 1). The electrophilic XCl could induce the

spiroannulation of the 2-alkynolyl anilide to form gem-

dihalospirocyclic benzo[d][1,3]oxazines (n = 1−3). In

addition to the assembly of the pharmacologically useful

benzoxazine nucleus,¹⁰the embedded sp³-centered gem-

dihalide moiety in these compounds was anticipated to serve

as a useful synthetic handle for the synthesis of other

heterocyclic systems (Scheme 1). A transformation of,

especially, gem-dibromospirocyclic benzo[d][1,3]oxazines (n

= 1) could unveil N-(2-(3-bromofuran-2-yl)-phenyl)amides

which in turn was a suitable substrate for conversion to 4H-

furo[3,2-b]indoles. In fact, this type of indolofuran nucleus is

present in several bioactive compounds with bioactivities

including analgesic, anti-inﬂammatory, and anticancer proper-

ties.¹¹There are few existing preparative methods of this

indolofuran and related core structures, and they involved

lengthy procedures, needs for harsh conditions, expensive or

diﬃcult-to-access chemicals, and special equipment.^11a,b,12At

the same time, these indolofuran core structures have been

shown to be synthetically useful for several notable trans-

formations, particularly for preparing various indole-containing

heterocycles.¹³

electrophilic bromination with another molecule of BrCl to

form oxocarbenium ion intermediate C, which could then be

intercepted intramolecularly by the nucleophilic oxygen of the

anilide to form gem-dibromospirocyclic benzo[d][1,3]oxazine

2Br. Pathway II, however, could not be discounted. The

nucleophilic oxygen of the anilide could potentially add to

bromonium ion D in a favorable 6-exo-trig fashion to generate

benzoxazine intermediate E. Electron delocalization from the

benzoxazine oxygen to abstract another bromine atom resulted

in oxonium intermediate F, which could be intercepted by the

remaining hydroxyl group in a favorable 5-exo-trig cyclization

to give the spirocyclic benzoxazines (2Br) as the product.

Spirocycles 2Br could serve as a novel and versatile

precursor for sequential transformations to compounds 3Br

and 4. The placement of gem-dibromide in spirocycle 2Br was

crucial for its conversion to 3-bromofuran 3Br. This could be

conceivably aﬀected through a bromine atom abstraction by a

bulky nucleophile to aﬀect fragmentation which would lead to

intermediate G. This intermediate then would readily undergo

aerobic aromatization to result in the formation of 3-

bromofuran 3Br. Due to scarce records in literature for the

synthesis of compounds 3Br, a successful conversion from 2Br

would add value to the current work to ensure eﬀective and

reliable access to these compounds and to enable the

exploration of their relatively unknown synthetic potentials.

One foreseeable synthetic utility of compounds 3Br was the

conversion to indolofurans 4 via intramolecular C−N bond

formation between the anilide nitrogen and the Br-bearing

carbon at the 3-position of the furan ring.

As shown in Scheme 2, we hypothesized that, when 2-

butynolyl anilide 1 was treated with NBS and HCl, which

generated BrCl,^3aboth Pathways I and II were possible. In

Pathway I, a favorable 5-endo-trig cyclization of the hydroxyl

group onto bromonium ion A led to bromodihydrofuran

intermediate B. This intermediate could undergo another

Herein, we reported a successful development of a practical

and eﬃcient method for the simultaneous construction of sp³-

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Scheme 2. Proposed Mechanisms for the Synthesis of gem-Dibromospirocycle 2Br and Its Sequential Transformations to 3Br

and 4

gem-dibromide embedded within benzoxazine spirocycles

(2Br). We also demonstrated that compounds 2Br could be

sequentially converted to 3-bromofurans 3Br and indolofurans

4. Furthermore, the developed method was shown to be

applicable to preparing 6- and 7-membered spirocyclic ether

systems as well as gem-dichloride variants.

deionized water. In addition, solvents used in these studies

were of AR grade unless speciﬁed. The results of these studies

were summarized in Table 1.

The optimization started with using 1.0 M of HCl solution

prepared in dry 1,4-dioxane. The initial reaction also employed

dry dioxane as the solvent with the concentration of substrate

1a maintained at 0.2 M, and the reaction was conducted at 0

°C. As shown in entries 1 and 2, the reactions gratifyingly

provided the desired product (2aBr) as expected from the

mechanism (Scheme 2). The reaction employing 2.0 equiv of

HCl was found to aﬀord product 2aBr in lower yield (77%)

than 0.5 equiv (86%) while requiring the same amount of time.

A commercial solution of 4.0 M HCl in 1,4-dioxane was next

investigated (entry 3) using dry dioxane as the solvent. The

reaction went to completion within 30 min at 0 °C giving

product 2aBr in a slightly lower yield (82%). It was expected

that adventitious water present in 1,4-dioxane did not

negatively aﬀect the reaction. Therefore, a more practical 1.0

M aqueous HCl solution was prepared and evaluated in the

optimization. The reaction optimization was further conducted

in AR-grade 1,4-dioxane using aqueous HCl solution.

RESULTS AND DISCUSSION

■

In order to realize the proposed transformations, starting

material 1a was prepared in two steps in an excellent overall

yield and employed as the screening substrate in search of

optimal conditions. According to the proposed mechanism in

Scheme 2, 2.0 equiv of NBS was required; therefore, all

reactions were optimized with this amount of NBS. As

discussed above, a source of chloride and acidic proton was

crucial for the generation of BrCl with NBS. With this

requirement, hydrochloric acid (HCl) solution was appropriate

for the reaction and was used as the Brønsted acid catalyst for

the optimization. Unless noted otherwise, the stock HCl

solution employed in the optimization was a 1.0 M aqueous

solution prepared by diluting concentrated (∼12 M) HCl with

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employing 0.5 equiv of aq HCl and 0.2 M concentration of 1a,

the reaction smoothly went to completion at room temper-

ature within 15 min to give the desired product in an 87% yield

(entry 13). Under the same conditions, except for reducing the

concentration of 1a to 0.05 M, the reaction still went to

completion within 15 min at room temperature to aﬀord the

product in practically identical yield (86% yield, entry 14).

However, when the reaction was conducted with a lower equiv

of HCl (0.25 equiv, entry 15), the reaction was very sluggish,

and only 17% of the desired product was aﬀorded along with

an inseparable and unidentiﬁable mixture after 22 h. As our

previous work^3aemployed TMSCl and NBS to generate BrCl,

we attempted the reaction using TMSCl (0.5 equiv), instead of

HCl (entry 16). In this case, the reaction conducted at room

temperature was very slow, and the reaction was allowed to stir

overnight. Upon complete consumption of the substrate, the

reaction was observed by TLC to be a complex mixture of

products, and the desired product (2aBr) was isolated in only

8% yield. These results suggested that HCl was most

appropriate for the current spiroannulation reaction. The

conditions in entry 13, employing EtOAc, which is considered

a green solvent,¹⁴were deemed practical and eﬃcient and

were, therefore, adopted as the optimal conditions to study the

scope of the reaction.

Table 1. Reaction Optimization for Conversion of 1a to

2aBr

equiv of

HCl

conc of 1a temp

time

(min)

yield

a

entry

solvent

(M)

(°C)

(%)

b

d

1

2

3

4

5

6

7

8

2.0

1,4-dioxane

acetone

EtOH

MTBE

DCM

0.2

0.1

0.2

0.1

0.2

0.05

0.2

0

20

30

10

80

35

15

10

80

10

15

22 h

o/n

77

86

82

b

0.5

c

0.5

g

0.5

0.25

rt

0

rt

63

47

52

57

64

86

80

82

87

86

9

10

11

12

13

14

15

16

DCE

EtOAc

The reaction of anilides 1 was studied with the results

presented in Table 2. Although EtOAc was the main solvent

used for these substrates, it was also found that 1,4-dioxane

could perform better in some cases, and the results were noted

accordingly in the table.

e

17

f

e

n/a

EtOAc

8

a

b

Isolated yields. 1.0 M stock solution prepared from conc HCl in dry

c

1,4-dioxane was used. Commercial 4.0 M solution in 1,4-dioxane was

d

e

f

used. Dry 1,4-dioxane was used. Complex mixture. 0.5 equiv of

TMSCl was used instead of the aqueous HCl solution. MTBE =

methyl t-butyl ether. DCM = dichloromethane. DCE = 1,2-

dichloroethane. n/a = not applicable. o/n = overnight.

The reactions generally proceeded smoothly and rapidly

(complete within 5−15 min in most cases) with NBS to

generate compounds 2Br. For compound 1a, the reaction

proceeded slightly more eﬃciently in EtOAc than in 1,4-

dioxane, giving the desired 2aBr in 87% yield (86% in

dioxane). The structure of 2aBr was conﬁrmed by X-ray

crystallographic analysis. Next, with R²= Ph, substituents R¹

were varied. The reaction of 1b (R¹= 6-Me) provided 2bBr in

82% yield, while the same reaction in 1,4-dioxane provided

2bBr in a better yield (88%), although this diﬀerence was

negligible. When R¹= 7-F (1c), product 2cBr was obtained in

a satisfactory yield (70%) while the reaction of 1d (R¹= 6-F)

furnished product 2dBr in 87%. These results seemed to

suggest that the electron-withdrawing property of ﬂuorine

exerted no eﬀect on the reaction. However, its diﬀerent

positions on the anilide ring imposed a signiﬁcant diﬀerence in

results with a more detrimental eﬀect at C-7 (para- to the

alkyne) than at C-6 (para- to the amide). The same trend was

echoed as observed in substrates 1e (R¹= 7-Cl) and 1f (R¹=

6-Cl). For 1e, the reaction aﬀorded 2eBr in 74% yield while

2fBr was obtained in 87% yield from 1f. These results of 1c−f

were decisive in concluding that an electron-withdrawing

group was more damaging to the reaction outcome when

located para- to the alkyne (2cBr and 2eBr) than para- to the

amide (2dBr and 2fBr). Nevertheless, the reactions were still

adequately eﬃcient, providing the corresponding products in

good to excellent yields in all cases. Reactions were well-

tolerated to other electron-withdrawing substituents at C-6 as

seen in compounds 1g (R¹= 6-CF₃) and 1h (R¹= 6-CN) as

they provided the desired products in good to excellent yields

(81% for 2gBr and 79% for 2hBr). However, for the strongly

electron-withdrawing NO₂group in substrate 1i (R¹= 6-NO₂),

the reaction furnished the corresponding product (2iBr) in a

However, the reaction was attempted at room temperature

(entry 4) to ﬁnd that the reaction went to completion within

10 min while the yield dropped to 63% with a more complex

mixture observed. Although a lower yield was obtained, this

result showed that the reaction was largely feasible at room

temperature, which was more practical. We continued to

explore the reaction optimization at room temperature with

other solvents. When the solvent was switched to acetone

(entry 5), the reaction required 80 min to complete and could

furnish only a 47% yield of 2aBr. Keeping everything else

identical to entry 5 while reducing the concentration of the

substrate to 0.1 M gave an identical yield of the product (entry

6). Ethanol was next studied in entries 7−9 with diﬀerent

concentrations of 1a and temperatures. By using 0.5 equiv of

aq HCl at 0 °C, the reaction aﬀorded a 52% yield of 2aBr after

35 min (entry 7). When the reaction was conducted at room

temperature, it went to completion within 15 min and 57% of

2aBr was obtained (entry 8). When the substrate concen-

tration was reduced to 0.1 M, yield of the product improved

slightly to 64% (entry 9). The reaction was next investigated in

methyl t-butyl ether (MTBE) as the solvent (entry 10). At 0.1

M of 1a and 0.5 equiv of aq HCl at room temperature, the

reaction became more sluggish (80 min) and furnished the

desired product in 86% yield. The reactions were next

attempted in DCM and DCE (entries 11 and 12). Both

reactions in DCM and DCE at 0.2 M of 1a at room

temperature displayed fast conversion (10−15 min) to aﬀord

2aBr in comparable yields (80% and 82% yield, respectively).

The reaction was next assessed in EtOAc (entries 13−16). By

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a

Table 2. Scope of Dibrominative Spirocyclization of 1 to Form 2Br

a

b

c

d

Isolated yields. NCS (X = Cl) or NBS (X = Br) was used. Reaction was performed in 1,4-dioxane. Reaction required 30 min to complete.

e

f

Reactions were attempted in several solvents; see text for discussion. Crystals of 2aBr and 2yBr were grown from a solution in MeOH with the

nucleation induced by a small addition of hexane into the solution. Once crystal was formed, the solvent mixture was allowed to slowly evaporate at

room temperature to allow the crystal to grow slowly.

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low yield (37%) in EtOAc and a lower but comparable yield

(31%) in 1,4-dioxane.

compound 2xBr (Table 2). The diastereoselectivity observed

for this compound probably stemmed from the same reason as

stated above. The formation of 2yBr was also attempted in

EtOAc at 0 °C which produced the desired product in a better

yield (47%). However, yield became poorer when the reaction

was conducted in DCM at room temperature, which aﬀorded

2yBr in only 25% yield. Finally, the reaction proceeded most

optimally for 1y in 1,4-dioxane at room temperature. In this

solvent, the product (2yBr) was obtained in 58% yield.

N-Chlorosuccinimide (NCS) was also eﬀective in the

reactions of 1 to give gem-dichlorospirocyclic benzo[d][1,3]-

oxazine derivatives 2Cl, although the reactions were less

eﬃcient than those with NBS. As shown in Table 2, the

reaction of 1a in EtOAc only aﬀorded the corresponding 2aCl

in 19% yield. However, when 1,4-dioxane was used as the

solvent, the yield of 2aCl was improved to 53%. Reactions of

1b and 1c with NCS, performed in dioxane, gave 2bCl and

2cCl in 48% and 33% yields, respectively. The trend of results

observed for 2aCl−2cCl similarly paralleled that of 2aBr−

2cBr and was probably due to the same reasons as described

previously (vide supra). In contrast, attempts to synthesize the

gem-diiodide variants employing N-iodosuccinimide (NIS)

were proven fruitless as only decompositions were observed in

these reactions.

We then investigated the conversion of 2Br to 3Br as

proposed in Scheme 3. The optimal conditions were identiﬁed

after a brief optimization¹⁵using 2aBr; the reaction proceeded

most optimally to furnish product 3aBr in 98% yield using 2.0

equiv of t-BuOK in N-methyl-2-pyrrolidone (NMP) at room

temperature. The scope of the reaction was studied with all

compounds 2Br prepared previously, as displayed in Table 3.

Conversion of 2Br to 3Br was generally well-behaved. For

compounds 2aBr−2iBr where R²= Ph and R¹were varied, the

reactions consistently produced compounds 3Br in more than

80% yields, except for 2gBr (R¹= 6-CF₃) and 2iBr (R¹= 6-

NO₂), which produced the corresponding 3gBr and 3iBr in

satisfactory yields of 70% and 79%, respectively. With

compounds 2jBr-2wBr (R¹= H, varying R²), the reactions

proceeded very well in most cases, giving the corresponding

3Br products in good to excellent yields. For R²as substituted

aryl groups, the conversions of these substrates provided

products in excellent yields (86−99%), except for 2kBr (R²=

2-OMe-Ph), 2tBr (R²= 4-CN-Ph), and 2uBr (R²= 4-NO₂−

Ph). For 2kBr, steric hindrance of the 2-OMe substituent may

have negatively aﬀected the yield of the product (3kBr, 75%),

while, for 2tBr and 2uBr, the yields seemed to be negatively

aﬀected by the strong electron-withdrawing eﬀect of the

substituents (74% yields for both 3tBr and 3uBr). For

substrates with nonaryl R²groups as in 2vBr (R²= Cy) and

2wBr (R²= t-Bu), the conversions proceeded reasonably well,

although giving lower yields than those with aryl R²groups;

3vBr and 3wBr were obtained in 61% and 78% yields,

respectively. As for substrates 2xBr and 2yBr, both reactions

proceeded excellently to provide 3xBr and 3yBr in 93% and

99% yields, respectively. As expected from the mechanisms

(Scheme 2), an aryl substituent on the spirocyclic ether ring

did not cause any problem for the transformation of these

compounds. The reaction was proven to be very robust for

preparing compounds 3Br with full control of substitution

patterns on any portions of the molecules starting from

properly prefunctionalized substrates.

Substrates 1 with a variation of R²(R¹= H) were next

examined. The reaction of 1j (R²= 4-Me-Ph) proceeded

excellently to give desired product 2jBr in 86% yield. The

reaction of substrate 1k with the strongly electron-donating

group R²= 2-OMe-Ph was less satisfactory (2kBr, 41%), which

may be largely attributed to the steric bulkiness of the methoxy

group at the ortho-position. This rationale was supported when

the methoxy substituent was placed further away from the

amide functional group as demonstrated with substrates 1l−m,

whose reactions provided corresponding products 2lBr and

2mBr in 83% and 82% yields, respectively. The reaction of

substrate 1n (R²= 3,4,5-(OMe)₃-Ph) furnished the corre-

sponding product 2nBr in a slightly lower but comparable

yield (78%). Conversion of 1o (R²= 4-OCF₃−Ph) proceeded

smoothly to aﬀord product 2oBr in 84% yield. Substrates with

R²as halogenated aryl groups were next examined. These

substrates were well-tolerated under the reaction conditions.

Both compounds 1p (R²= 4-F-Ph) and 1q (R²= 4-Cl-Ph)

were converted eﬃciently to furnish corresponding products

2pBr and 2qBr in 81% and 79% yields, respectively. However,

the reaction was slightly less eﬃcient for 1r (R²= 2-Br-Ph),

which gave desired product 2rBr in 75% yield. The eﬃciency

of the reaction was reduced further for substrate 1s (R²= 2-F-

4-Br-Ph) which aﬀorded product 2sBr in moderate yield

(69%). For these two latter cases, the steric hindrance of

halogen atoms at the 2-position of the aryl rings was suspected

as a probable cause of lower yields. The more strongly

electron-withdrawing substituents were next evaluated with

substrates 1t (R²= 4-CN-Ph) and 1u (R²= 4-NO₂-Ph). The

reaction became more eﬃcient with 1t that desired product

2tBr was obtained in 92% yield while the reaction of 1u was

less eﬃcient; nevertheless, product 2uBr could still be obtained

in 74% yield. In these cases of 1t−u, however, the reactions

were slightly more sluggish, requiring up to 30 min to

complete. R²alkyl groups were next studied with compounds

1v (R²= Cy) and 1w (R²= t-Bu). The reaction proceeded

moderately well with 1v to give the desired product (2vBr) in

72% yield while the reaction of 1w was far less eﬃcient and

product 2wBr was obtained in a low yield of 36%. These two

latter cases repetitively suggested the sensitivity of the reaction

toward the steric hindrance of the group attached to the amide.

These cases showed that the bulkier tert-butyl group exerted a

more negative eﬀect on the reaction yield than the less bulky

cyclohexyl group.

Substrates containing a secondary hydroxyl group 1x and 1y

were next studied. For substrate 1x substituted with a phenyl

group, the reaction proceeded moderately well to give the

corresponding product (2xBr) in 57% as a single diastereomer

as an amorphous solid. The yield was, however, inferior for the

reaction of substrate 1y, containing 4-OMe-Ph group, which

was conducted in EtOAc at room temperature and resulted in

only 36% of the product (2yBr). In this case, several

unidentiﬁable side-products were observed. Although low

yield, product 2yBr was obtained as a single diastereomer in

the crystalline form, the structure of which was conﬁrmed by

X-ray crystallographic analysis with the relative stereochemistry

shown. This diastereomer was assumed to be lower in energy

because the bulky 4-OMe-Ph group was projected to the less

1

hindered side of the cyclic ether. With a similar pattern in H

NMR spectra of 2xBr to 2yBr, it was reasonable to suggest the

same relative stereochemistry for the single diastereomer of

Compound 3aBr was used to study the conversion to

indolofurans 4a. The reaction was successfully optimized¹⁵

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a

Table 3. Scope of the Transformations of Spirocycles 2Br to 3-Bromofurans 3Br

a

b

Isolated yield. 3.0 equiv of t-BuOK was required. NMP = N-methyl-2-pyrrolidone.

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a

Table 4. Scope of Conversions of 3-Bromofurans 3Br to Indolofurans 4

a

b

c

Isolated yield. Reaction time was 23 h. Starting material was recovered. CuTC = copper(I) thiophene-2-carboxylate. DMEDA = N,N′-

dimethylethylenediamine. NR = no reaction.

under modiﬁed Ullmann^16a−cconditions based on a published

procedure.^16dThe most optimal conditions utilized 5 mol % of

copper(I) thiophene-2-carboxylate, or CuTC, 0.5 equiv of

N,N′-dimethylethylenediamine (DMEDA) as the ligand and

1.0 equiv of Cs₂CO₃in reﬂuxing anhydrous 1,4-dioxane under

an argon atmosphere. Under such conditions, 3aBr was

converted within 3 h to give the desired indolofuran (4a) in a

quantitative yield. This sequence of reactions was also carried

out with substrate 1a in a 1.84 mmol scale, which could

prepare product 4a in 60% yield over three steps, showcasing

the practicality of the current procedure. All compounds 3Br

prepared from the previous step were subjected to the optimal

conditions with results summarized in Table 4.

Most reactions produced the corresponding products in

good to excellent yields with the exception of a few cases.

Compounds 3bBr−3iBr (varying R,¹R²= Ph) were converted

to the corresponding products in good to excellent yields in

almost all cases (76−95% yields), except for 3iBr (R¹= 6-

NO₂). The reaction of 3iBr required 23 h to complete to

aﬀord indolofuran 4i in 31% yield along with N-debenzoylated

indolofuran 4i′ in 19% yield, making the overall conversion

moderately eﬃcient (50% combined yields). The strong

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a

Table 5. Scope of Dibrominative Spirocyclization of 5 to Form 6Br

a

b

c

d

Isolated yields. NCS (X = Cl) or NBS (X = Br) was used. Reaction required 30 min to complete. Reaction was performed in 1,4-dioxane.

e

f

Reaction was performed in DCM. Crystal of 6aBr was grown from a solution in MeOH with the nucleation induced by a small addition of hexane

into the solution. Once crystal was formed, the solvent mixture was allowed to slowly evaporate at room temperature to allow the crystal to grow

g

slowly. Reaction required 3.5 h to complete.

electron-withdrawing eﬀect of the NO₂group present in 3iBr

noticeably reduced the eﬃciencies of the C−N bond

formation. For the next series of substrates where R¹= H

and R²= aryl groups (3jBr−3uBr), the outcomes seemed to

be more adversely aﬀected by the steric eﬀect of substituents

on R²than their electronic properties. In most cases, products

4 were obtained in good to excellent yields (72−96%)

regardless of the electronic properties of the substituents

with only one exception in substrate 3pBr (R²= 4-F-Ph). The

presence of the 4-F substituent resulted in the production of

product 4p in 55% yield. The larger adversity imposed on

these reactions by the steric eﬀect was clearly illustrated in

substrates 3kBr, 3rBr, and 3sBr containing 2-substituents on

the R²groups. Products were obtained in low to modest yields

4k (R²= 2-OMe-Ph), 29%; 4r (R²= 2-Br-Ph), 30%; and 4s

(R²= 2-F-4-Br-Ph), 45%. In contrast, reactions of 3vBr (R²=

Cy) and 3wBr (R²= t-Bu) did not fare as well as those with R²

as substituted aryl rings. In these latter cases, only 25% of 4v

was obtained along with the recovered starting material

(3vBr), while the reaction of 3wBr failed to yield 4w

completely, and the starting compound was fully recovered.

Finally, compounds 3xBr and 3yBr, both containing 2,5-diaryl-

3-bromofuran systems, were uneventfully converted under the

standard conditions to give the corresponding products, 4x and

4y, in 94% and 73% yields, respectively. With these examples,

the synthetic sequence was shown to be robust and eﬀective

for preparing indolofurans 4 with desired substituents and

substitution patterns in the molecules starting with appropri-

ately assembled substrates 1.

The versatility of the reaction was further evaluated with

substrates having longer pentynolyl pendant (5) with a focus

on the formation of the gem-dibromospirocycles. The reaction

of 5a (0.2 M) with NBS proceeded rapidly (typically 5−15

min) to furnish the corresponding product 6aBr in 80% yield

in EtOAc and 72% yield in 1,4-dioxane. The structure of this

crystalline product was unambiguously conﬁrmed by X-ray

crystallographic analysis. A brief scope of the reaction was next

studied (Table 5).

The reaction of compound 5b (R¹= 6-Me) proceeded

uneventfully to give the corresponding product (6bBr) in 82%.

Substrates with R¹as a halogen atom were next assessed. Both

compounds 5e (R¹= 7-Cl) and 5f (R¹= 6-Cl) were

successfully converted to corresponding products 6eBr and

6fBr in 73% and 75% yields, respectively. The diﬀerence in

yields between 6eBr and 6fBr (73% vs 75%) was smaller than

that between 2eBr and 2fBr (74% vs 87%), suggesting the less

imposing electronic eﬀects of substituent R¹in the formation

of the 6-membered spirocyclic ether ring. However, the

electronic eﬀect was more pronounced for compound 5g (R¹=

6-CF₃) as the reaction produced the corresponding product

(6gBr) in a moderate yield (60%). For substrates with

variations only on R²(R¹= H), all reactions underwent

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a

Table 6. Scope of Dibrominative Spirocyclization of 7 to Form 8Br

a

b

c

d

e

f

Isolated yields. Reaction was conducted in DCM. Reaction time was 3 h. Reaction time was 2 h. Reaction time was 40 min. Contaminated by

inseparable impurities.

smooth conversions to the desired products in good to

excellent yields 6mBr (R²= 4-OMe-Ph), 82%; 6tBr (R²= 4-

CN-Ph), 80%; and 6vBr (R²= Cy), 72%. Among these, a

larger steric hindrance of the cyclohexyl group (5v) seemed to

somewhat deteriorate the reaction eﬃciency as observed with a

slight drop in yield of 6vBr. In addition, the reaction of 5v was

also attempted in DCM for comparison to ﬁnd that the yield of

6vBr was lower (62%) in this case, although the reaction was

comparably rapid. The reaction was next attempted with

substrate 5x containing a phenyl substituent on the secondary

hydroxyl group. The reaction led to the formation of the

desired product (6xBr) in 67% combined yield as inseparable

and unassignable diastereomers in a 37:63 ratio as determined

Me, R²= Ph) was subjected to the optimal conditions in

EtOAc, product 8bBr was obtained in 38% yield while the

reaction carried out in DCM resulted in an improved yield

(54%) although reaction also took longer to complete. The

reactions of 7e (R¹= 7-Cl, R²= Ph) and 7f (R¹= 6-Cl, R²=

Ph) gave products 8eBr and 8fBr in poor but comparable

yields (29% and 22%, respectively). In addition, these reactions

required longer reaction times to complete, even in EtOAc (2

h). The reaction of compound 7g (R¹= 6-CF₃, R²= Ph)

resulted in a complex mixture, both in EtOAc and DCM, and

provided less than 10% of impure 8gBr in both cases. When R¹

= H and R²were varied to 4-OMe-Ph (7m) and 4-CN-Ph

(7t), the reactions provided the desired products in low yields

8mBr, 36% (in EtOAc); and 8tBr, 20% (in EtOAc). However,

when the reaction of 7t was conducted in DCM, the yield of

8tBr was improved to 39%, although the reaction took longer

(2 h) to complete. Additionally, the reaction of 7v (R²= Cy)

aﬀorded product 8vBr in 30% yield in EtOAc while the

reaction performed in DCM rapidly (15 min) furnished

product 8vBr in 65% yield. From these results, the formation

of 7-membered spirocycles seemed to proceed better in DCM

than in EtOAc. Furthermore, when compared to other

arylamide substrates, the cyclohexanecarboxamide substrate

(7v) was more readily converted to the corresponding

spirocyclic product, with the exception of 7a, resulting in

both a faster conversion and a better yield.

1

by the H NMR spectrum of the mixture.

The reaction was also applicable to using NCS to form 6Cl

as demonstrated with 5a, whose reaction with NCS in EtOAc

furnished 6aCl in 39% yield, while the reaction in 1,4-dioxane

provided the same product in 24% yield. Conversion of 5 to

6Cl was less eﬃcient than to 6Br, reﬂecting the same general

trend as those in Table 2 between the conversions of 1 to 2Br

and of 1 to 2Cl.

Dibrominative spiroannulation was also studied with

substrates 7 possessing hexynolyl pendant (Table 6). The

reaction of 7a (0.01 M in EtOAc) proceeded to give the

corresponding 7-membered spirocyclic product (8aBr) in only

33% yield. However, the yield of 8aBr could be improved to

77% when the reaction was conducted in DCM, although the

reaction took longer (3 h). Regardless, reactions were less

eﬃcient when compared to the formation of 5-membered

(2Br) and 6-membered (6Br) products even with a lower

concentration of the substrate. This, however, was not totally

unexpected as the formation of 7-membered rings is

intrinsically less favorable compared to those of 5-membered

and 6-membered rings.¹⁷

CONCLUSIONS

■

In conclusion, a simple and convenient protocol to prepare

various gem-dibromospirocyclic benzo[d][1,3]oxazine deriva-

tives via dibrominative spirocyclization of 2-alkynolyl anilides

was disclosed. The reaction was induced by electrophilic BrCl

generated in situ from catalytic aqueous HCl and 2.0 equiv of

NBS and could be performed over a wide range of substrates to

form the desired spirocyclic products of 5- to 7-membered

Nevertheless, this reaction remained useful for the formation

of the 7-membered spirocycles. When compound 7b (R¹= 6-

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Preparation of Compound 1d). A 25 mL round-bottomed ﬂask

containing a magnetic stir bar was charged sequentially with 4-ﬂuoro-

2-iodoaniline (318.4 mg, 1.343 mmol, 1.00 equiv), PdCl₂(PPh₃)₂

(19.6 mg, 0.0279 mmol, 0.02 equiv), CuI (11.0 mg, 0.0578 mmol,

0.04 equiv), and 4 mL of Et₃N. The resulted yellow heterogeneous

mixture was degassed by a steady stream of argon for 15 min. After

degassing was complete, the mixture was added with homopropargyl

alcohol (0.10 mL, 92.6 mg, 1.321 mmol, 0.98 equiv) via syringe. The

reaction mixture immediately turned dark brown and was allowed to

stir at room temperature under argon overnight (16 h). Upon

completion, the reaction mixture was diluted with saturated aqueous

NH₄Cl, and the separated aqueous layer was extracted with EtOAc.

Combined organic phases were washed with saturated aqueous NaCl,

dried over anhydrous Na₂SO₄, ﬁltered, and concentrated under

reduced pressure to give the crude product. The crude material was

puriﬁed by SiO₂column chromatography eluting 50% EtOAc/hexane

to furnish 218.2 mg (91%) of the desired product as a yellow solid.

A 25 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with 2-butynolylaniline (343.5 mg, 1.960 mmol, 1.34 equiv)

obtained from the previous step, followed by 5 mL of DCM. The

resulted clear solution was added with benzoyl chloride (0.17 mL,

205.7 mg, 1.463 mmol, 1.00 equiv) via syringe, and the resulted

reaction mixture was allowed to stir at room temperature overnight

(18 h). Upon completion, the mixture was diluted with water, and the

separated aqueous layer was extracted with DCM. Combined organic

phases were washed with saturated aqueous NaCl, dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated on a rotary evaporator

to give the crude product. The crude material was puriﬁed by SiO₂

column chromatography, eluting 30% EtOAc/hexane to provide

461.9 mg (≥99%) of the desired product (1d) as a beige solid.

Procedure for Preparing Compounds 1x,y (Representative

Case: Preparation of Compound 1x). A 25 mL round-bottomed

ﬂask was charged with benzaldehyde (572.6 mg, 5.396 mmol, 1.00

equiv) followed by 10 mL of dry THF to give a clear solution. The

solution under an argon atmosphere was then added sequentially with

zinc dust (1.895 g, 28.98 mmol, 5.37 equiv), diiodomethane (1.542 g,

5.470 mmol, 1.01 equiv), and propargyl bromide (0.53 mL, 887.4 mg,

7.040 mmol, 1.30 equiv). The reaction mixture was sonicated in a

sonication bath for 2.5 h to complete the reaction. Upon completion,

the reaction mixture was diluted with water, and the separated

aqueous phase was extracted with EtOAc. Combined organic phases

were washed with saturated aqueous NaCl, dried over anhydrous

Na₂SO₄, ﬁltered, and concentrated in vacuo to give the crude product

as a yellow oil. The crude product was puriﬁed by SiO₂column

chromatography eluting 2−5% EtOAc/hexane to furnish 548.4 mg

(70%) of the desired benzylic alcohol as a clear yellow oil.

A 25 mL round-bottomed ﬂask containing a magnetic stir bar and

the benzylic alcohol obtained from the previous step (249.5 mg, 1.707

mmol, 1.00 equiv) was added with PdCl₂(PPh₃)₂(24.7 mg, 0.035

mmol, 0.02 equiv), followed by N-benzoyl-2-iodoaniline (615.2 mg,

1.904 mmol, 1.12 equiv) and Et₃N (5 mL), to give a yellow reaction

mixture. The reaction mixture was degassed by passing through a

steady stream of argon for 15 min. A slurry of CuI (13.7 mg, 0.072

mmol, 0.04 equiv) in 1 mL of Et₃N was added into the reaction ﬂask

by syringe followed by a 1 mL Et₃N rinse. The reaction mixture

immediately turned dark brown, and it was allowed to stir at room

temperature under argon overnight (17 h). Upon completion, the

reaction mixture was diluted with saturated aqueous NH₄Cl, and the

separated aqueous phase was extracted with EtOAc. Combined

organic phases were washed with saturated aqueous NaCl, dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated under a vacuum to give

the crude product as a brown oil. The crude material was puriﬁed by

SiO₂column chromatography, eluting 5−20% EtOAc/hexane to

furnish 320.6 mg (55%) of the desired product (1x) as a brown solid.

Procedure for Preparing Compound 5x. A 25 mL round-

bottomed ﬂask containing a magnetic stir bar was charged with ethyl

benzoylacetate (524.9 mg, 2.731 mmol, 1.00 equiv), followed by 13

mL of THF. The resulted clear solution was added sequentially with

propargyl bromide (0.20 mL, 316.0 mg, 2.656 mmol, 0.97 equiv),

K₂CO₃(566.2 mg, 4.097 mmol, 1.50 equiv), and NaI (102.0 mg,

rings in good to excellent yields in most cases. Furthermore,

the 5-membered gem-dibromospirocyclic products 2Br were

shown to be a useful building block in the conversion to 3-

bromofuran 3Br, mostly in good to excellent yields. In

addition, most 3-bromofurans 3Br were suitable substrates for

conversion via intramolecular modiﬁed Ullmann coupling to

yield indolofurans 4 in moderate to excellent eﬃciencies.

These sequential reactions provided straightforward, scalable,

and ﬂexible access to indolofuran derivatives 4 in three steps

from compounds 1, making this procedure one of the only few

methods available for preparing this fused indolofuran system.

Many more synthetic potentials from this methodology could

be realized and foreseen in the near future.

EXPERIMENTAL SECTION

■

General Procedure. Commercial grade chemicals were used

without further puriﬁcation, unless otherwise indicated. All solvents

were used as received. Oven-dried glassware (110 °C at least for 2 h)

was used in all reactions. Crude reaction mixtures were concentrated

under reduced pressure on a rotary evaporator. Column chromatog-

raphy was performed using silica gel 60 (particle size 0.06−0.2 mm;

70−230 mesh ASTM). Analytical thin-layer chromatography (TLC)

was performed with silica gel 60 F254 aluminum sheets. Nuclear

magnetic resonance (NMR) spectra were recorded in deuteriochloro-

form (CDCl₃) with 300 and 400 MHz spectrometers, unless stated

1

otherwise. Chemical shifts for H NMR and ¹³C NMR spectra are

reported in parts per million (ppm, δ), relative to tetramethylsilane

(TMS) as the internal reference. Chemical shifts for ¹⁹F NMR spectra

are reported in parts per million (ppm, δ) using hexaﬂuorobenzene as

the internal reference (δ = −164.9 ppm). Coupling constants (J) are

reported in hertz (Hz). Infrared spectra were measured using an FT-

IR spectrometer and are reported in cm⁻¹. High-resolution mass

spectra (HRMS) were obtained using a time-of-ﬂight (TOF)

instrument.

Procedure for Preparing Compounds 1a−c, 1e−p, 1r−w,

5a,b, 5e−g, 5m, 5t, 5v, 7a,b, 7e−g, 7m, 7t, 7v (Acylation

before Sonogashira Coupling) (Representative procedure:

Preparation of Compound 1a). A 25 mL round-bottomed ﬂask

containing a magnetic stir bar was charged with 2-iodoaniline (1.034

g, 4.720 mmol, 1.00 equiv), followed by dry THF (10 mL), to give a

clear solution. The reaction mixture was then added with benzoyl

chloride (0.60 mL, 726.0 mg, 5.165 mmol, 1.09 equiv) and Et₃N

(0.35 mL, 254.1 mg, 2.511 mmol, 0.53 equiv). The resulted mixture

was allowed to stir at room temperature under argon overnight (17−

18 h). Upon completion, the solvent was removed from the reaction

mixture under reduced pressure, and the remaining crude material

was puriﬁed by SiO₂column chromatography, eluting 5% EtOAc/

hexane to yield 1.283 g (84%) of the corresponding N-benzoyl-2-

iodoaniline product as a white solid.

A 25 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with N-benzoyl-2-iodoaniline (1.047 g, 3.240 mmol, 1.00

equiv), followed by PdCl₂(PPh₃)₂(44.5 mg, 0.0634 mmol, 0.02

equiv), and CuI (16.7 mg, 0.0877 mmol, 0.03 equiv), 3 mL of MeCN,

and 4 mL of Et₃N. The resulted yellow mixture was degassed by a

steady stream of argon for 15 min. After degassing was complete,

homopropargyl alcohol (0.26 mL, 240.8 mg, 3.436 mmol, 1.06 equiv)

was added into the reaction via syringe, and the reaction mixture

immediately turned dark brown. The mixture was allowed to stir at

room temperature under argon overnight (17 h). Upon completion,

the reaction was diluted with saturated aqueous NH₄Cl, and the

separated aqueous layer was extracted with EtOAc. Combined organic

phases were washed with saturated aqueous NaCl, dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated on a rotary evaporator

to give the crude product. The crude material was puriﬁed by SiO₂

column chromatography, eluting 30% EtOAc/hexane to furnish 805.3

mg (89%) of product 1a as a brown solid.

Procedure for Preparing Compounds 1d and 1q (Sonoga-

shira Coupling before Acylation) (Representative Case:

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0.681 mmol, 0.25 equiv). The reaction mixture immediately turned

from a clear yellow solution to an orange heterogeneous mixture. This

mixture was allowed to stir vigorously at room temperature overnight

(23 h). Upon completion, the reaction mixture was diluted with

water, and the separated aqueous phase was extracted with EtOAc.

Combined organic phases were washed with saturated aqueous NaCl,

dried over anhydrous Na₂SO₄, ﬁltered, and concentrated under a

vacuum to a crude material, which was puriﬁed by SiO₂column

chromatography, eluting 5−20% EtOAc/hexane to give 402.1 mg

(64%) of pure 2-propargylated 1,3-ketoester.

The 1,3-ketoester (351.9 mg, 1.528 mmol, 1.00 equiv) obtained

from the previous step was taken up in a 1:1 mixture of MeOH/H₂O

(8 mL total) in a 25 mL round-bottomed ﬂask with a magnetic stir

bar. The resulted reaction mixture was added with KOH (229.9 mg,

4.097 mmol, 2.68 equiv) and was allowed to stir at room temperature

for 3 h. Upon completion, the reaction mixture was diluted with

water, and the separated aqueous phase was extracted with EtOAc.

Combined organic phases were washed with saturated aqueous NaCl,

dried over anhydrous Na₂SO₄, ﬁltered, and concentrated under

reduced pressure to give the crude decarboxylated product, which was

further puriﬁed by SiO₂column chromatography, eluting 5% EtOAc/

hexane to aﬀord 103.0 mg (43%) of the desired alkynone as a white

solid.

The alkynone (93.9 mg, 0.594 mmol, 1.00 equiv) obtained from

the previous step was dissolved in 1 mL of EtOH and was added with

5 drops of MeOH. The reaction mixture was added with NaBH₄(23.2

mg, 0.613 mmol, 1.03 equiv) in one portion, and the resulted mixture

was allowed to stir at room temperature for 1 h. Upon completion, the

reaction mixture was diluted with water, and the separated aqueous

phase was extracted with EtOAc. Combined organic phases were

washed with saturated aqueous NaCl, dried over anhydrous Na₂SO₄,

ﬁltered, and concentrated under reduced pressure to give the crude

product as a colorless oil. This crude material was puriﬁed by SiO₂

column chromatography, eluting 5% EtOAc/hexane to yield 84.3 mg

(89%) of the desired alkynol as a colorless oil.

A 25 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with the alkynol obtained from the previous step (74.2 mg,

0.463 mmol, 1.00 equiv), N-benzoyl-2-iodoaniline (180.4 mg, 0.558

mmol, 1.21 equiv), PdCl₂(PPh₃)₂(6.8 mg, 0.010 mmol, 0.02 equiv),

and 3 mL of MeCN. The resulted mixture was stirred and degassed by

passing through a steady stream of argon for 25 min. Then a slurry of

CuI (4.1 mg, 0.022 mmol, 0.05 equiv) in 1.0 mL of Et₃N was added

into the reaction ﬂask via syringe, followed by a 1 mL Et₃N rinse. The

reaction mixture immediately turned from yellow to dark brown, and

it was allowed to stir at room temperature overnight (16 h). Upon

completion, the reaction was diluted with saturated aqueous NH₄Cl,

and the separated aqueous phase was extracted with EtOAc.

Combined organic phases were washed with saturated aqueous

NaCl, dried over anhydrous Na₂SO₄, ﬁltered, and concentrated in

vacuo to give the crude product. The crude material was puriﬁed by

SiO₂column chromatography eluting 20% EtOAc/hexane to give

132.5 mg (67%) of desired product 5x as a brown solid.

20.3; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₄H₁₂INNaO

359.9856, found 359.9850.

N-(5-Fluoro-2-iodophenyl)benzamide: 673.1 mg (63%, white

solid, puriﬁed by SiO₂column chromatography eluting 2−5%

EtOAc/hexane); mp 107.9−108.4 °C; IR (neat) ν_max3264, 1686,

1

1651, 759, 708 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.41 (dd, J =

11.2, 3.2 Hz, 1H), 8.36 (br s, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.75 (dd,

J = 8.4, 6.4 Hz, 1H), 7.63−7.59 (m, 1H), 7.56−7.52 (m, 2H), 6.68

(td, J = 8.4, 2.8 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.3,

1

3

163.3 (d, C−F, J_C−F= 245 Hz), 139.5 (d, C−F, J_C−F= 12 Hz),

139.1 (d, C−F, ³J_C−F= 9 Hz), 134.1, 132.4, 129.0, 127.1 113.1 (d, C−

F, ²J_C−F= 22 Hz), 109.1 (d, C−F, ²J_C−F= 29 Hz), 82.3 (d, C−F, ³J_C−F

= 3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ − 113.37 to −113.44 (m);

HRMS (ESI-TOF) m/z [M − H]⁻calcd for C₁₃H₈FINO 339.9629,

found 339.9639.

N-(5-Chloro-2-iodophenyl)benzamide: 449.1 mg (≥99%, white

solid, puriﬁed by SiO₂column chromatography eluting 5% EtOAc/

hexane); mp 144.0−145.3 °C; IR (neat) ν_max3264, 2924, 1651, 1517,

1400, 1019, 713 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J = 2.4

Hz, 1H), 8.29 (br s, 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 8.4 Hz,

1H), 7.63−7.51 (m, 3H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 165.2, 139.2, 139.1, 135.5, 134.1, 132.4,

129.0, 127.1, 125.9, 121.5, 86.8; HRMS (ESI-TOF) m/z [M + Na]⁺

calcd for C₁₃H₉³⁵ClINNaO 379.9310, found 379.9307.

N-(4-Chloro-2-iodophenyl)benzamide: 468.6 mg (≥99% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 128.4−129.4 °C; IR (neat) ν_max3264, 1686,

1651, 759, 708 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.39 (d, J = 9.0

Hz, 1H), 8.25 (br s, 1H), 7.96−7.93 (m, 2H), 7.78 (d, J = 2.4 Hz,

1H), 7.61−7.49 (m, 3H), 7.37 (dd, J = 8.9, 2.1 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 165.2, 137.8, 137.1, 134.1, 132.3, 129.9,

129.4, 129.0, 127.1, 122.1, 89.9; HRMS (ESI-TOF) m/z [M + Na]⁺

calcd for C₁₃H₉³⁵ClINNaO 379.9310, found 379.9314.

N-(2-Iodo-4-(triﬂuoromethyl)phenyl)benzamide: 322.7 mg (67%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

5−10% EtOAc/hexane); mp 137.0−137.5 °C; IR (neat) ν_max3285,

1

1651, 1524, 1319, 1117, 706 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.66 (d, J = 8.4 Hz, 1H), 8.46 (br s, 1H), 8.059−8.055 (m, 1H),

7.99−7.96 (m, 2H), 7.68−7.52 (m, 4H); ¹³C{¹H} NMR (75 MHz,

3

CDCl₃) δ 165.4, 141.4, 135.7 (q, C−F, J_C−F= 4 Hz), 134.0, 132.6,

129.1, 127.4 (q, C−F, ²J_C−F= 33 Hz), 127.2, 126.6 (q, C−F, ³J_C−F= 4

1

Hz), 122.9 (q, C−F, J_C−F= 270 Hz), 120.7, 88.9; ¹⁹F NMR (376

MHz, CDCl₃) δ − 65.4 (s); HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₄H₁₀F₃INO 391.9754, found 391.9745.

N-(4-Cyano-2-iodophenyl)benzamide: 355.1 mg (≥99% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 10%

EtOAc/hexane); mp 147.2−148.0 °C; IR (neat) ν_max3264, 2925,

2233, 1718, 1655, 1508, 1305, 1114, 715 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.70 (d, J = 8.7 Hz, 1H), 8.52 (br s, 1H), 8.09 (d, J = 1.8

Hz, 1H), 7.98−7.95 (m, 2H), 7.69 (dd, J = 8.7, 1.8 Hz, 1H), 7.67−

7.61 (m, 1H), 7.58−7.53 (m, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃)

δ 165.3, 142.3, 142.0, 133.7, 133.4, 132.8, 129.2 127.2, 120.5, 117.1,

108.8, 88.6; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₄H₁₀ON₂I

348.9832, found 348.9825.

N-(2-Iodo-4-nitrophenyl)benzamide: 200.0 mg (45% yield, yellow

solid, puriﬁed by recrystallization from DCM/hexane mixture); mp

172.2−172.5 °C; IR (neat) ν_max3271, 3080, 1655, 1501, 712 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, J = 9.2 Hz, 1H), 8.69 (d, J =

2.0 Hz, 1H), 8.62 (br s, 1H), 8.29 (dd, J = 9.0, 2.0 Hz, 1H), 7.98 (d, J

= 8.0 Hz, 2H), 7.66−7.63 (m, 1H), 7.59−7.55 (m, 2H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 165.3, 143.9, 143.5, 134.2, 133.6, 132.9,

129.2, 127.3, 125.1, 119.6, 87.8; HRMS (ESI-TOF) m/z [M - H]⁻

calcd for C₁₃H₈O₃N₂I 366.9574, found 366.9582.

N-(2-Iodophenyl)benzamide: 1283 mg (84%, white solid, puriﬁed

by SiO₂column chromatography eluting 5% EtOAc/hexane); mp

129.7−130.5 °C; IR (neat) ν_max3265, 3058, 1650, 1527, 749 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 8.45 (dd, J = 8.1, 1.5 Hz, 1H), 8.29

(br s, 1H), 7.99−7.95 (m, 2H), 7.81 (dd, J = 8.0, 1.2 Hz, 1H), 7.61−

7.49 (m, 3H), 7.42−7.36 (m, 1H), 6.87 (td, J = 7.7, 1.5 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.3 138.8, 138.3, 134.5, 132.2,

129.4, 129.0, 127.2, 126.1, 121.8, 90.3; HRMS (ESI-TOF) m/z [M +

H]⁺calcd for C₁₃H₁₁ONI 323.9880, found 323.9875.

N-(2-Iodo-4-methylphenyl)benzamide: 474.1 mg (≥99%, yellow

solid, puriﬁed by SiO₂column chromatography eluting 5−10%

EtOAc/hexane); mp 161.5−162.3 °C; IR (neat) ν_max3247, 1647,

N-(2-Iodophenyl)-4-methylbenzamide: 384.0 mg (99% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−

10% EtOAc/hexane); mp 122.1−122.9 °C; IR (neat) ν_max3230,

1

1513, 1486, 1301, 818, 711 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

1

2921, 1650, 1522, 1304, 753 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.29 (d, J = 8.1 Hz, 1H), 8.20 (br s, 1H), 7.96 (dd, J = 8.0, 1.2 Hz,

2H), 7.651−7.647 (m, 1H), 7.61−7.49 (m, 3H), 7.21 (dd, J = 8.4, 1.2

Hz, 1H), 2.31 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2,

139.0, 136.1, 135.8, 134.6, 132.1, 130.0, 128.9, 127.1, 121.6, 90.3,

8.46 (dd, J = 8.4, 1.5 Hz, 1H), 8.27 (br s, 1H), 7.87 (d, J = 8.1 Hz,

2H), 7.81 (dd, J = 8.0, 1.5 Hz, 1H), 7.43−7.37 (m, 1H), 7.32 (d, J =

8.1 Hz, 2H), 6.87 (td, J = 7.5, 1.5 Hz, 1H), 2.44 (s, 3H); ¹³C{¹H}

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J. Org. Chem. 2021, 86, 4671−4698

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1

NMR (75 MHz, CDCl₃) δ 165.3, 142.8, 138.8, 138.4, 131.7, 129.6,

129.4, 127.2, 125.9, 121.7, 90.1, 21.5; HRMS (ESI-TOF) m/z [M +

Na]⁺calcd for C₁₄H₁₂INNaO 359.9856, found 359.9855.

3023, 1655, 1518, 1306, 748 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.39 (d, J = 7.8 Hz, 1H), 7.94 (br s, 1H), 7.81 (dd, J = 8.0, 1.5 Hz,

1H), 7.66 (d, J = 7.8 Hz, 2H), 7.45−7.31 (m, 3H), 6.90 (td, J = 8.1,

1.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.6, 139.0, 138.0,

137.5, 133.7, 131.8, 129.4, 129.3, 127.7, 126.5, 122.3, 119.4, 90.2;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₃H₉⁷⁹BrINNaO

423.8804, found 423.8797.

N-(2-Iodophenyl)-2-methoxybenzamide: 521.3 mg (95% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 10−20%

EtOAc/hexane); mp 136.7−137.4 °C; IR (neat) ν_max3291, 2964,

1

1657, 1599, 1302, 742 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 10.18

(br s, 1H), 8.50 (dd, J = 8.1, 1.5 Hz, 1H), 8.30 (dd, J = 7.8, 1.8 Hz,

1H), 7.81 (dd, J = 8.1, 1.5 Hz, 1H), 7.52−7.46 (m, 1H), 7.39−7.34

(m, 1H), 7.11 (td, J = 7.5, 0.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.83

(td, J = 7.5, 1.5 Hz, 1H), 4.08 (s, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 163.4, 157.2, 139.8, 139.0, 133.4, 132.6, 128.9, 125.5, 122.8,

121.3, 111.4, 89.5, 56.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₄H₁₃O₂NI 353.9986, found 353.9971.

N-(2-Iodophenyl)-3-methoxybenzamide: 708.8 mg (66% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 10−20%

EtOAc/hexane); mp 89.7−90.0 °C; IR (neat) ν_max3267, 2832, 1650,

1037, 757 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.45 (dd, J = 8.1, 1.5

Hz, 1H), 8.28 (br s, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.53−7.50

(m, 2H), 7.43−7.37 (m, 2H), 7.14−7.10 (m, 1H), 6.88 (td, J = 7.7,

1.5 Hz, 1H), 3.89 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.1,

160.1, 138.8, 138.3, 136.0, 129.9, 129.4, 126.0, 121.7, 118.8, 118.4,

112.5, 90.2, 55.5; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₄H₁₃O₂NI 353.9986, found 353.9982.

4-Bromo-2-ﬂuoro-N-(2-iodophenyl)benzamide: 704.6 mg (≥99%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

2−5% EtOAc/hexane); mp 119.5−119.9 °C; IR (neat) ν_max3392,

1

3072, 1677, 1526, 1431, 1301, 901, 740 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ, 8.75 (d, J = 14.1 Hz, 1H), 8.38 (dd, J = 8.4, 1.2 Hz, 1H),

8.08 (t, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.50−7.37 (m,

3H), 6.90 (td, J = 7.8, 1.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃)

3

1

δ 160.5 (d, C−F, J_C−F= 4 Hz), 159.9 (d, C−F, J_C−F= 251 Hz),

3

139.1, 138.5, 133.5 (d, C−F, J_C−F= 3 Hz), 129.2, 128.7 (d, C−F,

³J_C−F= 3 Hz), 127.3 (d, C−F, J_C−F= 10 Hz), 126.5, 122.8, 120.2,

3

2

119.9 (d, C−F, J_C−F= 28 Hz), 90.2; HRMS (ESI-TOF) m/z [M +

H]⁺calcd for C₁₃H₉⁷⁹BrFINO 419.8891, found 419.8881.

4-Cyano-N-(2-iodophenyl)benzamide: 519.1 mg (98% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 50%

DCM/hexane); mp 154.1−154.4 °C; IR (neat) ν_max3248, 3058,

1

2230, 1661, 1524, 1308, 747 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.32−8.29 (m, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.82−7.77 (m, 3H),

7.39 (t, J = 8.1 Hz, 1H), 6.92 (td, J = 7.7, 1.2 Hz, 1H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 163.4, 138.8, 138.1, 137.5, 132.6, 129.3, 127.7

126.7, 122.2, 117.7, 115.5, 90.8; ¹⁹F NMR (376 MHz, CDCl₃) δ −

112.0 to −112.1 (m); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₄H₁₀IN₂O 348.9832, found 348.9836.

N-(2-Iodophenyl)-4-nitrobenzamide: 373.9 mg (40% yield, white

solid, puriﬁed by SiO₂column chromatography eluting 30−50%

DCM/hexane); mp 148.3−148.6 °C; IR (neat) ν_max3284, 2931,

1655, 1344, 776 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.42−8.37 (m,

3H), 8.29 (br s, 1H), 8.15−8.12 (m, 2H), 7.85 (dd, J = 8.1, 1.2 Hz,

1H), 7.46−7.41 (m, 1H), 6.97−6.92 (m, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 163.2, 150.0, 140.0, 138.9, 137.6, 129.6, 128.4, 126.8,

124.2, 122.0, 90.5; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₃H₁₀O₃N₂I 368.9731, found 368.9731.

N-(2-Iodophenyl)-4-methoxybenzamide: 569.3 mg (97% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 30−50%

EtOAc/hexane); mp 151.8−152.4 °C; IR (neat) ν_max3263, 2840,

1

1644, 1505, 1254, 1016, 750 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.44 (dd, J = 8.3, 1.5 Hz, 1H), 8.22 (br s, 1H), 7.96−6.98 (m, 2H),

7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.41−7.36 (m, 1H), 7.00 (dt, J = 9.0,

2.7 Hz, 2H), 6.89−6.83 (m, 1H), 3.88 (s, 3H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 164.8, 162.7, 138.7, 138.4, 129.3, 129.0, 126.7, 125.7,

121.6, 114.1, 90.1, 55.5; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₄H₁₂INNaO₂375.9805, found 375.9810.

N-(2-Iodophenyl)-3,4,5-trimethoxybenzamide: 411.8 mg (74%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

5% EtOAc/DCM); mp 164.4−165.2 °C; IR (neat) ν_max3270, 2943,

1

1651, 1126, 760 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.45 (dd, J =

8.3, 1.2 Hz, 1H), 8.24 (br s, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H),

7.44−7.39 (m, 1H), 7.21 (s, 2H), 6.89 (td, J = 7.5, 1.5 Hz, 1H), 3.96

(s, 6H), 3.93 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.0,

153.4, 141.5, 138.8, 138.2, 129.9, 129.5, 126.0, 121.5, 104.6, 90.1,

61.0, 56.3; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₆H₁₆INNaO₄436.0016, found 436.0021.

N-(2-Iodophenyl)cyclohexanecarboxamide: 599.9 mg (≥99%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

5% EtOAc/hexane); mp 135.7−136.2 °C; IR (neat) ν_max3266, 2925,

2852, 1709, 1655, 1524, 1017, 747 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.24 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 8.0, 1.5 Hz, 1H),

7.52 (br s, 1H), 7.35−7.30 (m, 1H), 6.82 (td, J = 7.7, 1.5 Hz, 1H),

2.32 (tt, J = 11.4, 3.6 Hz, 1H), 2.07−2.02 (m, 2H), 1.89−1.84 (m,

2H), 1.74−1.71 (m, 1H), 1.56 (qd, J = 12.0, 3.0 Hz, 2H), 1.43−1.19

(m, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 174.2, 138.6, 138.2,

129.2, 125.7, 122.0, 90.0, 46.5, 29.7, 25.7, 25.6; HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₁₃H₁₆INNaO 352.0169, found 352.0168.

N-(2-Iodophenyl)pivalamide: 598.2 mg (76% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 0−2% EtOAc/

hexane); mp 65.6−66.9 °C; IR (neat) ν_max3264, 2964, 1637, 1468,

N-(2-Iodophenyl)-4-(triﬂuoromethoxy)benzamide: 638.5 mg

(≥99% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 10% DCM/hexane); mp 119.2−119.5 °C; IR (neat) ν_max

3269, 1648, 1528, 1266, 1166, 747 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.39 (dd, J = 8.3, 0.9 Hz, 1H), 8.25 (br s, 1H), 8.01 (d, J =

8.7 Hz, 2H), 7.81 (dd, J = 8.0, 0.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H),

7.35 (d, J = 8.7 Hz, 2H), 6.89 (td, J = 7.7, 1.2 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 163.9, 152.0, 138.8, 138.0, 132.9, 129.4,

129.1, 126.3, 121.9, 120.9, 120.3 (q, C−F, ¹J_C−F= 257 Hz), 90.4; ¹⁹

F

1

739 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.27 (dd, J = 8.1, 1.5 Hz,

NMR (376 MHz, CDCl₃) δ − 60.9 (s); HRMS (ESI-TOF) m/z [M

1H), 7.80 (br s, 1H), 7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.35−7.29 (m,

1H), 6.81 (td, J = 7.5, 1.5 Hz, 1H), 1.36 (s, 9H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 176.6, 138.5, 138.2, 129.1, 125.6, 121.6, 90.1, 40.0,

27.6; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₁H₁₅INO

304.0193, found 304.0182.

+ H]⁺calcd for C₁₄H₁₀F₃INO₂407.9703, found 407.9697.

4-Fluoro-N-(2-iodophenyl)benzamide: 564.9 mg (>99% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 2−5%

EtOAc/hexane); mp 135.9−136.6 °C; IR (neat) ν_max3268, 1913,

1

1649, 1501, 747 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.40 (dd, J =

1-Phenylbut-3-yn-1-ol: 548.4 mg (70% yield, pale yellow oil,

puriﬁed by SiO₂column chromatography eluting 5−20% EtOAc/

hexane); IR (neat) ν_max3386, 3293, 3032, 1953, 1455, 1047, 756, 700

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.39−7.24 (m, 5H), 4.83 (t, J =

6.3 Hz, 1H), 2.62 (dd, J = 3.2, 0.4 Hz, 1H), 2.60 (dd, J = 3.2, 0.4 Hz,

1H), 2.05 (td, J = 2.7, 0.3 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃)

δ 142.4, 128.4, 127.9, 125.7, 80.7, 72.2, 70.9, 29.3; HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₁₀H₁₀NaO 169.0624, found 169.0625.

1-(4-Methoxyphenyl)but-3-yn-1-ol: 736.5 mg (84% yield, white

solid, puriﬁed by SiO₂column chromatography eluting 10−20%

EtOAc/hexane); mp 38.8−39.1 °C; IR (neat) ν_max3407, 3289, 2838,

8.3, 1.2 Hz, 1H), 8.21 (br s, 1H), 8.01−7.95 (m, 2H), 7.81 (dd, J =

8.0, 1.5 Hz, 1H), 7.42−7.36 (m, 1H), 7.23−7.16 (m, 2H), 6.91−6.86

(m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.1 (d, C−F, ¹J_C−F

=

252 Hz), 164.2, 138.8, 138.1, 130.7 (d, C−F, ³J_C−F= 3 Hz), 129.5 (d,

3

2

C−F, J_C−F= 9 Hz), 129.4, 126.1, 121.8, 116.0 (d, C−F, J_C−F= 23

Hz), 90.3; ¹⁹F NMR (376 MHz, CDCl₃) δ − 110.0 to −110.1 (m);

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₃H₁₀FINO 341.9786,

found 341.9782.

2-Bromo-N-(2-iodophenyl)benzamide: 560.9 mg (96% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 2−

10% EtOAc/hexane); mp 158.4−159.4 °C; IR (neat) ν_max3249,

1

2120, 1513, 1244, 1031, 831 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

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7.34−7.31 (m, 2H), 6.92−6.88 (m, 2H), 4.86−4.82 (m, 1H), 3.81 (s,

3H), 2.65−2.62 (m, 2H), 2.34 (d, J = 3.2 Hz, 1H), 2.07 (t, J = 2.8 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3, 134.6, 127.0, 113.8,

80.8, 72.0, 70.8, 55.3, 29.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd

for C₁₁H₁₂NaO₂199.0730, found 199.0731.

Ethyl 2-Benzoylpent-4-ynoate: 402.1 mg (64% yield, colorless oil,

puriﬁed by SiO₂column chromatography eluting 2−5% EtOAc/

hexane); IR (neat) ν_max3293, 2983, 1735, 1685, 1234, 688 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 8.05−8.03 (m, 2H), 7.62−7.59 (m, 1H),

7.51−7.47 (m, 2H), 4.58 (t, J = 7.6 Hz, 1H), 4.16 (qd, J = 7.2, 1.2 Hz,

2H), 2.94 (ddd, J = 17.2, 9.4, 2.8 Hz, 1H), 2.85 (ddd, J = 17.0, 7.0, 2.4

Hz, 1H), 2.00 (t, J = 2.4 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 193.2, 168.1, 135.7, 133.7, 128.7, 128.6,

80.4, 70.3, 61.7, 53.0, 18.2, 13.8; HRMS (ESI-TOF) m/z [M + Na]⁺

calcd for C₁₄H₁₄NaO₃253.0835, found 253.0841.

= 6.0 Hz, 2H), 2.27 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.3, 139.1, 134.7, 131.9, 131.6, 129.3, 128.8, 127.1, 123.4, 119.2,

112.6, 94.7, 77.5, 60.9, 23.8; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₇H₁₆NO₂266.1176, found 266.1173.

N-(2-(4-Hydroxybut-1-yn-1-yl)-4-methylphenyl)benzamide (1b):

297.2 mg (≥99% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 119.7−120.2 °C;

IR (neat) ν_max3390, 2920, 1659, 1519, 705, 577 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.76 (br s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.84 (dd, J

= 8.0, 1.2 Hz, 2H), 7.49−7.38 (m, 3H), 7.17 (s, 1H), 7.09 (d, J = 8.4

Hz, 1H), 3.80 (t, J = 6.0 Hz, 2H), 3.02 (br s, 1H), 2.24 (s, 3H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.1, 136.5 134.5, 133.0, 131.8,

131.7, 129.8, 128.6, 126.9, 119.1, 112.7, 94.4, 77.4, 60.8, 23.7, 20.5;

HRMS (ESI-TOF) m/z [M - H]⁻calcd for C₁₈H₁₆NO₂278.1176,

found 278.1186.

1-Phenylpent-4-yn-1-one: 103.0 mg (43% yield, white crystal,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 66.0−66.5 °C; IR (neat) ν_max3268, 1678, 1205, 741, 685 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 7.98−7.96 (m, 2H), 7.60−7.56 (m,

1H), 7.49−7.46 (m, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.64 (td, J = 7.6,

2.8 Hz, 2H), 1.99 (t, J = 2.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 197.6, 136.4, 133.3, 128.6, 128.0, 83.3, 68.7, 37.5, 13.2;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₁H₁₀NaO 181.0624,

found 181.0630.

N-(5-Fluoro-2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1c):

78.2 mg (≥99% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 50% EtOAc/hexane); mp 103.9−104.2 °C;

1

IR (neat) ν_max3394, 2947, 1671, 1527, 701 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 8.89 (br s, 1H), 8.37 (dd, J = 11.2, 2.4 Hz, 1H), 7.91

(d, J = 7.6 Hz, 2H), 7.55−7.52 (m, 1H), 7.49−7.45 (m, 2H), 7.37−

7.33 (m, 1H), 6.74 (td, J = 18.4, 2.4 Hz, 1H), 3.86 (t, J = 6.0 Hz, 2H),

2.77 (t, J = 6.0 Hz, 2H), 2.29 (br s, 1H); ¹³C{¹H} NMR (100 MHz,

1

CDCl₃) δ 165.3, 162.6 (d, C−F, J_C−F= 246 Hz), 140.6 (d, C−F,

3

³J_C−F= 12 Hz), 134.3, 132.7 (d, C−F, J_C−F= 10 Hz), 132.2, 128.8,

1-Phenylpent-4-yn-1-ol: 84.3 mg (89% yield, colorless oil, puriﬁed

by SiO₂column chromatography eluting 5% EtOAc/hexane); IR

127.1, 110.5 (d, C−F, ²J_C−F= 23 Hz), 108.3 (d, C−F, ³J_C−F= 3 Hz),

106.8 (d, C−F, ²J_C−F= 29 Hz), 94.6, 76.6, 60.9, 23.8; ¹⁹F NMR (376

MHz, CDCl₃) δ − 110.58 to −110.65 (m); HRMS (ESI-TOF) m/z

[M - H]⁻calcd for C₁₇H₁₃O₂NF 282.0925, found 282.0935.

1

(neat) ν_max3381, 3295, 2924, 2115, 1454, 1060, 763, 700 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 7.35−7.31 (m, 4H), 7.29−7.23 (m, 1H),

4.78 (dd, J = 8.0, 5.2 Hz, 1H), 2.47 (br s, 1H), 2.34−2.15 (m, 2H),

1.99−1.97 (m, 1H), 1.96−1.92 (m, 1H), 1.90−1.81 (m, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 143.9, 128.4, 127.6, 125.7, 83.9,

72.9, 68.9, 37.3, 15.0; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₁H₁₂NaO 183.0780, found 183.0781.

4-(2-Aminophenyl)but-3-yn-1-ol: 694.1 mg (82% yield, brown oil,

puriﬁed by SiO₂column chromatography eluting 10−40% EtOAc/

hexane); IR (neat) ν_max3346, 2884, 1612, 1491, 1041, 746 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 7.23 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6

Hz, 1H), 6.66−6.62 (m, 2H), 4.22 (br s, 2H), 3.73 (t, J = 6.0 Hz,

2H), 2.64 (t, J = 6.4 Hz, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

147.6, 131.8, 129.0, 117.8, 114.3, 108.3, 92.3, 78.4, 60.8, 23.6; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₀H₁₂ON 162.0913, found

162.0911.

N-(4-Fluoro-2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1d):

461.9 mg (≥99% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 94.9−95.3

°C; IR (neat) ν_max3399, 1719, 1523, 1270, 709 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.74 (br s, 1H), 8.51 (dd, J = 9.0, 5.1 Hz, 1H), 7.93

(d, J = 6.9 Hz, 2H), 7.58−7.46 (m, 3H), 7.13−7.03 (m, 2H), 3.86 (t,

J = 6.0 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 1.86 (br s, 1H); ¹³C{¹H}

1

NMR (75 MHz, CDCl₃) δ 165.2, 158.2 (d, C−F, J_C−F= 242 Hz),

135.6 (d, C−F, ³J_C−F= 2 Hz), 134.7, 132.0, 128.8 127.1, 120.9 (d, C−

F, ³J_C−F= 8 Hz), 118.0 (d, C−F, ²J_C−F= 24 Hz), 116.3 (d, C−F, ²J_C−F

= 22 Hz), 114.2 (d, C−F, ³J_C−F= 9 Hz), 95.7, 76.8 (d, C−F, ³J_C−F= 2

Hz), 60.8, 23.8; ¹⁹F NMR (376 MHz, CDCl₃) δ − 121.69 to −121.73

(m); HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₅O₂NF

284.1081, found 284.1072.

4-(2-Amino-5-ﬂuorophenyl)but-3-yn-1-ol: 218.2 mg (91% yield,

yellow solid, puriﬁed by SiO₂column chromatography eluting 50%

EtOAc/hexane); mp 81.5−82.0 °C; IR (neat) ν_max3379, 3172, 2867,

N-(5-Chloro-2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1e):

260.6 mg (≥99% yield, pale orange solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 116.8−117.3

°C; IR (neat) ν_max3433, 3388, 2880, 2220, 1671, 1570, 701 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 8.83 (br s, 1H), 8.64 (d, J = 2.1 Hz, 1H),

7.92−7.89 (m, 2H), 7.57−7.44 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H),

7.00 (dd, J = 8.4, 2.1 Hz, 1H), 3.89−3.84 (m, 2H), 2.78 (t, J = 6.3 Hz,

2H), 2.18−2.14 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2,

140.0, 135.1, 134.3, 132.22, 132.21, 128.8, 127.1, 123.6, 119.2, 110.9

95.8, 76.6, 60.8 23.8; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₇H₁₄³⁵ClNNaO₂322.0605, found 322.0597.

N-(4-Chloro-2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1f):

221.4 mg (≥99% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 116.8−117.3

°C; IR (neat) ν_max3392, 2943, 1663, 1516, 1403, 1310, 703 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 8.78 (br s, 1H), 8.46 (d, J = 9.0 Hz, 1H),

7.89 (d, J = 7.2 Hz, 2H), 7.54−7.42 (m, 3H), 7.34 (d, J = 2.4 Hz,

1H), 7.28−7.24 (m, 1H), 3.85−3.83 (m, 2H), 2.76 (t, J = 6.0 Hz,

2H), 2.49 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2,

137.7, 134.3, 132.1, 131.1, 129.2, 128.8, 128.3, 127.1, 120.3, 114.2,

96.2, 76.3, 60.7, 23.8; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₅³⁵ClNO₂300.0786, found 300.0790.

1

2224, 1495, 863 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.95 (dd, J =

9.0, 2.7 Hz, 1H), 6.82 (td, J = 8.6, 3.0 Hz, 1H), 6.61 (dd, J = 9.0, 4.8

Hz, 1H), 4.06 (br s, 2H), 3.82 (t, J = 6.3 Hz, 2H), 2.36 (br s, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 155.2 (d, C−F, ¹J_C−F= 234 Hz),

2

144.2, 117.8, (d, C−F, J_C−F= 23 Hz), 116.3 (d, C−F, J_C−F= 23

3

Hz), 115.3 (d, C−F, J_C−F= 8 Hz), 109.1 (d, C−F, J_C−F= 9 Hz),

92.9, 78.1 (d, C−F, ³J_C−F= 3 Hz), 61.0, 23.9; HRMS (ESI-TOF) m/z

[M + H]⁺calcd for C₁₀H₁₁ONF 180.0819, found 180.0821.

N-(2-(3-Hydroxyprop-1-yn-1-yl)phenyl)benzamide: 90.2 mg

(57% yield, yellow solid, puriﬁed by SiO₂column chromatography

eluting 20−30% EtOAc/hexane); mp 92.1−92.7 °C; IR (neat) ν_max

3392, 2924, 1663, 1524, 1450, 756 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.76 (br s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.90−7.88 (m,

2H), 7.52−7.40 (m, 3H), 7.37−7.32 (m, 2H), 7.06−7.01 (m, 1H),

4.55 (s, 2H), 2.78 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.3, 139.1, 134.4, 132.0, 131.6, 129.9, 128.8, 127.0, 123.5, 119.3,

111.8, 95.4, 80.8, 51.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₆H₁₃NNaO₂274.0839, found 274.0833.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)benzamide (1a): 805.3 mg

(89% yield, brown solid, puriﬁed by SiO₂column chromatography

eluting 5−30% EtOAc/hexane); mp 77.1−78.1 °C; IR (neat) ν_max

3388, 2882, 1662, 1521, 755, 705 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 8.84 (br s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.94−7.91 (m, 2H), 7.56−

7.44 (m, 3H), 7.40 (dd, J = 7.7, 1.5 Hz, 1H), 7.34 (td, J = 7.7, 1.5 Hz,

1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 3.85 (t, J = 6.3 Hz, 1H), 2.77 (t, J

N-(2-(4-Hydroxybut-1-yn-1-yl)-4-(triﬂuoromethyl)phenyl)-

benzamide (1g): 237.9 mg (98% yield, yellow solid, puriﬁed by SiO₂

column chromatography eluting 30% EtOAc/hexane); mp 87.7−88.4

°C; IR (neat) ν_max3387, 2941, 2227, 1675, 1527, 1333, 1121, 706

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.97 (br s, 1H), 8.68 (d, J = 8.7

4684

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Hz, 1H), 7.94−7.91 (m, 2H), 7.65 (s, 1H), 7.57−7.45 (m, 4H), 3.88

(t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.28 (br s, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 165.5, 141.8, 134.1, 132.4, 128.9, 128.6 (q,

6.96 (d, J = 8.8 Hz, 2H), 3.89−3.86 (m, 5H), 2.80 (t, J = 6.1 Hz, 2H),

2.07 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 164.8, 162.6,

139.4, 131.6, 129.3, 129.0, 127.0, 123.2, 119.1, 114.0, 112.4, 94.6,

77.7, 61.0, 55.4, 23.9; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₈H₁₈O₃N 296.1281, found 296.1282.

3

C−F, J_C−F= 4 Hz), 127.2, 126.1 (q, C−F, J_C−F= 4 Hz), 125.4 (q,

2

1

C−F, J_C−F= 33 Hz), 123.7 (q, C−F, J_C−F= 270 Hz), 118.9, 112.9,

96.5, 76.2, 60.7, 23.8; ¹⁹F NMR (376 MHz, CDCl₃) δ − 65.5 (s);

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₈H₁₄F₃NNaO₂

356.0869, found 356.0867.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-3,4,5-trimethoxybenza-

mide (1n): 206.1 mg (73% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 50% EtOAc/hexane); mp 126.9−127.7 °C;

1

IR (neat) ν_max3467, 2939, 1642, 1502, 1333, 1230, 753 cm⁻¹; H

N-(4-Cyano-2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1h):

263.8 mg (≥99% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 50−70% DCM/hexane); mp 159.2−159.9

°C; IR (neat) ν_max3488, 3382, 2946, 2229, 1673, 1518, 700 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 9.04 (br s, 1H), 8.74 (d, J = 8.7 Hz, 1H),

7.98−7.94 (m, 2H), 7.68 (d, J = 1.7 Hz, 1H), 7.63−7.57 (m, 2H),

7.54−7.49 (m, 2H), 3.89 (q, J = 6.0 Hz, 2H), 2.82 (t, J = 6.1 Hz, 2H),

1.88 (t, J = 5.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.5,

142.8, 135.2, 134.0, 133.0, 132.6, 129.0, 127.3, 119.2, 118.2, 113.4,

106.6, 97.4, 75.5, 60.7, 23.7; HRMS (ESI-TOF) m/z [M + Na]⁺calcd

for C₁₈H₁₄N₂NaO₂313.0948, found 313.0948.

N-(2-(4-Hydroxybut-1-yn-1-yl)-4-nitrophenyl)benzamide (1i):

117.2 mg (70% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 20−50% EtOAc/hexane); mp 140.9−141.4

°C; IR (neat) ν_max3397, 2908, 2227, 1691, 1246, 701 cm⁻¹; ¹H NMR

(300 MHz, DMSO-d₆) δ 9.83 (br s, 1H), 8.41−8.37 (m, 1H), 8.37−

8.26 (m, 2H), 8.02 (d, J = 7.5 Hz, 2H), 7.67−7.64 (m, 1H), 7.60−

7.55 (m, 2H), 5.06 (t, J = 5.4 Hz, 1H), 3.64 (q, J = 6.3 Hz, 2H), 2.69

(t, J = 6.6 Hz, 2H); ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 165.2,

144.5, 143.0, 133.4, 132.6, 128.9, 127.7, 126.8, 124.2, 121.6, 115.9,

98.4, 75.3 59.3, 23.6; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₅O₄N₂311.1026, found 311.1025.

NMR (300 MHz, CDCl₃) δ 8.73 (br s, 1H), 8.53 (d, J = 8.3 Hz, 1H),

7.43 (dd, J = 7.6, 1.2 Hz, 1H), 7.40−7.35 (m, 1H), 7.18 (s, 2H), 7.07

(td, J = 7.5, 0.9 Hz, 1H), 3.95 (s, 6H), 3.92 (s, 3H), 3.85 (t, J = 6.0

Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 1.85 (br s, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.0, 153.4, 141.7, 139.2, 131.7, 130.3, 129.5, 123.5,

119.2, 112.4, 105.0, 94.5, 77.8, 61.0, 60.9, 56.6, 23.8; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₂₀H₂₂NO₅356.1493, found

356.1503.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-4-(triﬂuoromethoxy)-

benzamide (1o): 378.5 mg (≥99% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 20−30% EtOAc/hexane); mp 93.6−

94.1 °C; IR (neat) ν_max3389, 2928, 1665, 1505, 1252, 1054, 756

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.82 (br s, 1H), 8.52 (d, J = 8.4

Hz, 1H), 8.04−8.00 (m, 2H), 7.41 (td, J = 7.7, 1.5 Hz, 1H), 7.36−

7.30 (m, 3H), 7.07 (td, J = 7.7, 1.2 Hz, 1H), 3.87 (q, J = 6.0 Hz, 2H),

2.79 (t, J = 6.0 Hz, 2H), 1.95 (t, J = 5.4 Hz, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 163.9, 151.8, 138.9, 133.1, 131.6, 129.4, 129.1, 123.7,

120.7, 120.3 (q, C−F, ¹J_C−F= 257 Hz), 119.2, 112.7, 94.9, 77.5, 60.9,

23.9; ¹⁹F NMR (376 MHz, CDCl₃) δ − 60.8 (s); HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₁₈H₁₄F₃NNaO₃372.0818, found 372.0821.

4-Fluoro-N-(2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1p):

389.9 mg (87% yield, orange solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 100.3−100.6

°C; IR (neat) ν_max3437, 3390, 2916, 1655, 1501, 751, 583 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 8.78 (br s, 1H), 8.45 (d, J = 8.4 Hz,1H),

7.96−7.90 (m, 2H), 7.38 (dd, J = 7.7, 1.2 Hz, 1H), 7.34−7.28 (m,

1H), 7.14−7.07 (m, 2H), 7.02 (td, J = 7.7, 1.2 Hz, 1H), 3.83 (t, J =

6.0 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.62 (br s, 1H); ¹³C{¹H} NMR

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-4-methylbenzamide (1j):

311.0 mg (≥99% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 100.8−101.6 °C;

1

IR (neat) ν_max3391, 2879, 1661, 1525, 1448, 1308, 755 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 8.81 (br s, 1H), 8.54 (d, J = 8.4 Hz, 1H),

7.83 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 7.8, 1.2 Hz, 1H), 7.37−7.32

(m, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.04 (td, J = 7.7, 1.2 Hz, 1H), 3.86

(t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.3 Hz, 2H), 2.40 (s, 3H), 2.11 (br s,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2, 142.5, 139.3, 132.0,

131.6, 129.5, 129.3, 127.1, 123.3, 119.1, 112.5, 94.6, 77.7, 61.0, 23.9,

21.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₈H₁₇NNaO₂

302.1152, found 302.1149.

1

(75 MHz, CDCl₃) δ 164.9 (d, C−F, J_C−F= 251 Hz), 164.2, 138.9,

3

131.5, 130.7 (d, C−F, J_C−F= 3 Hz), 129.5 (d, C−F, J_C−F= 9 Hz),

129.2, 123.6, 119.2, 115.8 (d, C−F, ²J_C−F= 22 Hz), 112.8, 95.0, 77.3,

60.8, 23.8; ¹⁹F NMR (376 MHz, CDCl₃) δ − 110.4 to −110.5 (m);

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₅O₂NF 284.1081,

found 284.1082.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-2-methoxybenzamide

(1k): 412.9 mg (≥99% yield, pale yellow oil, puriﬁed by SiO₂column

chromatography eluting 30−50% EtOAc/hexane); IR (neat) ν_max

3315, 2932, 1650, 1527, 1040, 755 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 10.32 (br s, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.23 (dd, J = 7.8,

1.8 Hz, 1H), 7.50−7.39 (m, 2H), 7.35−7.29 (m, 1H), 7.13−7.08 (m,

1H), 7.04−6.99 (m, 2H), 4.00 (s, 3H), 3.81 (t, J = 6.4 Hz, 2H), 2.75

(t, J = 6.4 Hz, 2H), 2.60 (br s, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 163.5, 157.3, 139.6, 133.3, 132.4, 132.3, 129.0, 123.3, 122.0,

121.6, 120.5, 113.1, 111.9, 92.7, 61.0, 56.3, 24.1; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₈H₁₈O₃N 296.1281, found 296.1279.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-3-methoxybenzamide

(1l): 368.4 mg (58% yield, orange solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 109.0−109.4 °C;

4-Chloro-N-(2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1q);

222.6 mg (68% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 109.0−109.4

°C; IR (neat) ν_max3379, 2891, 1653, 1527, 752 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.79 (br s, 1H), 8.40 (d, J = 8.3 Hz, 1H), 7.82 (d, J =

8.5 Hz, 2H), 7.37−7.33 (m, 3H), 7.31−7.25 (m, 1H), 7.01 (td, J =

7.6, 0.8 Hz, 1H), 3.82 (t, J = 5.9 Hz, 2H), 2.96 (br s, 1H), 2.73 (t, J =

6.0 Hz, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 164.2, 138.6, 138.2,

132.7, 131.5, 129.1, 128.9, 128.5, 123.6, 119.1, 112.9, 95.2, 77.1, 60.7,

23.8; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₅O₂N³⁵Cl

300.0786, found 300.0788.

2-Bromo-N-(2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1r):

312.7 mg (98% yield, yellow oil, puriﬁed by SiO₂column

chromatography eluting 20−40% EtOAc/hexane); IR (neat) ν_max

3369, 2936, 2234, 1667, 1518, 1310, 1041, 755 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.68 (br s, 1H), 8.44 (d, J = 8.4 Hz,1H), 7.61−7.56

(m, 2H), 7.39−7.21 (m, 4H), 7.03 (td, J = 7.5, 0.9 Hz, 1H), 3.64 (t, J

= 6.3 Hz, 2H), 2.93 (br s, 1H), 2.59 (t, J = 6.3 Hz, 2H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 165.5, 138.4, 137.4, 133.3, 131.5, 129.5,

128.8, 127.5, 123.8, 119.5, 119.0, 113.1, 94.7, 77.1, 60.4, 23.5; HRMS

(ESI-TOF) m/z [M + Na]⁺calcd for C₁₇H₁₄⁷⁹BrNNaO₂366.0100,

found 366.0094.

1

IR (neat) ν_max3441, 2943, 2233, 1656, 1577, 750 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 8.84 (br s, 1H), 8.51−8.46 (m, 1H), 7.47−7.44

(m, 2H), 7.38−7.26 (m, 3H), 7.05−6.99 (m, 2H), 3.83−3.81 (m,

5H), 2.91 (br s, 1H), 2.77−2.72 (m, 2H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 165.0, 159.7, 138.9, 135.95, 135.89, 131.4, 129.7, 129.0,

123.4, 119.0, 118.8, 117.6, 112.7, 95.0, 77.2, 60.7, 55.3, 23.6; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₈O₃N 296.1281, found

296.1280.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-4-methoxybenzamide

(1m): 411.8 mg (96% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 178.5−179.0

°C; IR (neat) ν_max3428, 2958, 2231, 1611, 1024, 757, 608 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 8.77 (br s, 1H), 8.53 (d, J = 8.3 Hz, 1H),

7.91 (d, J = 8.8 Hz, 2H), 7.41−7.32 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H),

4-Bromo-2-ﬂuoro-N-(2-(4-hydroxybut-1-yn-1-yl)phenyl)-

benzamide (1s): 372.1 mg (≥99% yield, yellow solid, puriﬁed by SiO₂

column chromatography eluting 30% EtOAc/hexane); mp 117.1−

118.2 °C; IR (neat) ν_max3454, 3389, 2888, 2224, 1678, 1579, 1537,

1314, 758 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 9.31 (d, J = 15.0 Hz,

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1H), 8.53 (d, J = 8.4 Hz, 1H), 8.06 (t, J = 8.7 Hz, 1H), 7.45−7.30 (m,

4H), 7.04 (td, J = 7.8, 0.9 Hz, 1H), 3.87 (t, J = 6.3 Hz, 2H), 2.79 (t, J

= 6.3 Hz, 2H), 2.31 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

160.1 (d, C−F, ³J_C−F= 4 Hz), 159.7 (d, C−F, ¹J_C−F= 250 Hz), 139.1,

133.4 (d, C−F, ³J_C−F= 3 Hz), 131.7, 129.2, 128.6 (d, C−F, ³J_C−F= 3

Hz), 127.0 (d, C−F, ³J_C−F= 10 Hz), 123.8, 120.2 (d, C−F, ³J_C−F= 12

Hz), 119.74, 119.66 (d, C−F, ²J_C−F= 28 Hz), 112.9, 94.6, 77.2, 60.9,

23.9; ¹⁹F NMR (376 MHz, CDCl₃) δ − 114.05 to −114.15 (m);

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₇H₁₃⁷⁹BrFNNaO₂

384.0006, found 383.9997.

93.5−94.0 °C; IR (neat) ν_max3386, 2906, 1662, 1513, 1246, 1033,

756, 706 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.80 (br s, 1H), 8.55

(d, J = 8.4 Hz, 1H), 7.88−7.86 (m, 2H), 7.55−7.52 (m, 1H), 7.47−

7.44 (m, 2H), 7.41−7.38 (m, 1H), 7.37−7.33 (m, 1H), 7.32−7.30

(m, 2H), 7.04 (td, J = 7.4, 0.8 Hz, 1H), 6.85−6.83 (m, 2H), 4.93−

4.90 (m, 1H), 3.74 (s, 3H), 2.96 (dd, J = 16.8, 6.9 Hz, 1H), 2.91 (dd,

J = 16.8, 5.6 Hz, 1H), 2.34 (br d, J = 2.6 Hz, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 165.3, 159.4, 139.3, 134.84, 134.78, 131.9,

131.6 129.3, 128.7, 127.2, 126.9, 123.4, 119.1, 113.9, 112.5, 94.3, 78.1,

72.3, 55.2, 30.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₂₄H₂₁NNaO₃394.1414, found 394.1414.

4-Cyano-N-(2-(4-hydroxybut-1-yn-1-yl)phenyl)benzamide (1t):

349.4 mg (≥99% yield, pale yellow solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 134.6−135.3 °C;

N-(2-(5-Hydroxypent-1-yn-1-yl)phenyl)benzamide (5a): 267.4

mg (98% yield, orange solid, puriﬁed by SiO₂column chromatog-

raphy eluting 20−30% EtOAc/hexane); mp 81.5−82.0 °C; IR (neat)

1

IR (neat) ν_max3385, 2891, 2231, 1663, 1526, 1447, 760 cm⁻¹; H

1

ν_max3391, 2945, 2222, 1665, 1520, 754, 704 cm⁻¹; H NMR (400

NMR (300 MHz, CDCl₃) δ 8.90 (br s, 1H), 8.46 (d, J = 8.4 Hz, 1H),

8.06 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 7.8,

1.2 Hz, 1H), 7.38−7.32 (m, 1H), 7.08 (td, J = 7.7, 0.9 Hz, 1H), 3.86

(q, J = 5.7 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 5.4 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 16.3.4, 138.5, 138.4, 132.5, 131.6,

129.3, 127.9, 124.1, 119.2, 117.9, 115.3, 112.9, 95.5, 77.1, 60.7, 23.8;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₈H₁₄N₂NaO₂

313.0948, found 313.0950.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)-4-nitrobenzamide (1u):

351.3 mg (≥99% yield, brown solid, analytically pure after aqueous

workup); mp 171.2−171.3 °C; IR (neat) ν_max3381, 2949, 1524,

1044, 759 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.93 (br s, 1H), 8.52

(d, J = 8.4 Hz, 1H), 8.34−8.31 (m, 2H), 8.16−8.13 (m, 1H), 7.44

(dd, J = 7.7, 1.5 Hz, 1H), 7.41−7.35 (m, 1H), 7.10 (td, J = 7.7, 0.9

Hz, 1H), 3.89 (t, J = 5.7 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 1.93 (br s,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 163.1, 149.8, 140.2, 138.6,

131.6, 129.4, 128.5, 124.2, 124.0, 119.3, 112.9, 95.4, 77.3, 60.9, 23.8;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₅O₄N₂311.1026,

found 311.1017.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)cyclohexanecarboxamide

(1v): 323.7 mg (95% yield, pale yellow solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 92.6−93.2 °C;

IR (neat) ν_max3387, 2929, 2855, 1671, 1519, 1447, 1056, 755 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J = 8.4 Hz, 1H), 8.17 (br s,

MHz, CDCl₃) δ 8.81 (br s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.88 (d, J =

7.2 Hz, 2H), 7.52−7.43 (m, 3H), 7.36 (d, J = 7.6 Hz, 1H), 7.31 (t, J =

8.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 2.61 (t,

J = 7.2 Hz, 2H), 2.56 (br s, 1H), 1.88−1.82 (m, 2H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 165.2, 138.8, 134.7, 131.9, 131.4, 128.9, 128.7,

126.8, 123.4, 118.9, 112.9, 97.5, 76.2, 61.0, 31.3, 16.0; HRMS (ESI-

TOF) m/z [M + Na]⁺calcd for C₁₈H₁₇NNaO₂302.1152, found

302.1151.

N-(2-(5-Hydroxypent-1-yn-1-yl)-4-methylphenyl)benzamide

(5b): 233.0 mg (95% yield, yellow solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 79.9−80.5 °C; IR

(neat) ν_max3393, 2934, 2224, 1661, 1517, 1308, 704 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.73 (br s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.89−

7.87 (m, 2H), 7.54−7.43 (m, 3H), 7.19 (br s, 1H), 7.13 (dd, J = 8.4,

1.5 Hz, 1H), 3.76 (t, J = 5.7 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.27 (s,

3H), 2.12−2.06 (m, 1H), 1.91−1.82 (m, 2H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.2, 136.6, 135.0, 133.1, 131.9, 129.8, 128.8, 127.0,

119.1, 112.9, 97.1, 76.5, 61.3, 31.5, 20.7, 16.1; HRMS (ESI-TOF) m/

z [M + Na]⁺calcd for C₁₉H₁₉NNaO₂316.1308, found 316.1304.

N-(5-Chloro-2-(5-hydroxypent-1-yn-1-yl)phenyl)benzamide (5e):

190.1 mg (98% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 103.8−105.1 °C;

1

IR (neat) ν_max3389, 2937, 2215, 1569, 1516, 1415, 705 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 8.81 (br s, 1H), 8.65 (d, J = 2.1 Hz, 1H),

7.90 (d, J = 6.9 Hz, 2H), 7.60−7.48 (m, 3H), 7.31 (d, J = 8.4 Hz,

1H), 7.02 (dd, J = 8.3, 2.1 Hz, 1H), 3.81−3.77 (m, 2H), 2.67 (t, J =

6.9 Hz, 2H), 1.94−1.85 (m, 2H), 1.57 (br s, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.2, 140.0, 134.9, 134.5, 132.2, 128.9, 127.0, 123.6,

119.2, 111.1, 98.3, 75.6, 61.4, 31.3, 16.2; HRMS (ESI-TOF) m/z [M

+ H]⁺calcd for C₁₈H₁₇³⁵ClNO₂314.0942, found 314.0948.

N-(4-Chloro-2-(5-hydroxypent-1-yn-1-yl)phenyl)benzamide (5f):

352.5 mg (96% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 88.7−88.3 °C;

IR (neat) ν_max3392, 2947, 2223, 1667, 1510, 1308, 822, 703 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 8.75 (br s, 1H), 8.48 (d, J = 8.7 Hz,

1H), 7.87 (d, J = 6.9 Hz, 2H), 7.57−7.45 (m, 3H), 7.34−7.33 (m,

1H), 7.27 (dd, J = 9.0, 2.4 Hz, 1H), 3.76 (t, J = 5.7 Hz, 2H), 2.64 (t, J

= 7.2 Hz, 2H), 2.10 (br s, 1H), 1.91−1.82 (m, 2H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 165.1, 137.5, 134.5, 132.1, 131.0, 129.0, 128.8,

128.2, 126.9, 120.1, 114.4, 98.7, 75.2, 61.1, 31.2, 16.1; HRMS (ESI-

TOF) m/z [M + Na]⁺calcd for C₁₈H₁₆³⁵ClNNaO₂336.0762, found

336.0761.

1H), 7.35 (dd, J = 7.7, 1.5 Hz, 1H), 7.30−7.24 (m, 1H), 6.98 (td, J =

7.8, 0.6 Hz, 1H), 3.85 (br s, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.59 (br s,

1H), 2.31 (tt, J = 11.7, 3.3 Hz, 1H), 2.02−1.97 (m, 2H), 1.85−1.80

(m, 2H), 1.71−1.68 (m, 1H), 1.52 (qd, J = 12.0, 2.7 Hz, 2H), 1.39−

1.16 (m, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 174.6, 139.2,

131.3, 129.1, 123.0, 119.2, 112.3, 94.3, 77.5, 60.9, 46.4, 29.6, 25.7,

25.6, 23.8; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₂₂NO₂

272.1645, found 272.1641.

N-(2-(4-Hydroxybut-1-yn-1-yl)phenyl)pivalamide (1w): 427.9 mg

(94% yield, brown oil, puriﬁed by SiO₂column chromatography

eluting 30% EtOAc/hexane); IR (neat) ν_max3400, 2961, 1669, 1519,

1447, 761, 753 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J = 8.4

Hz, 1H), 8.36 (br s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 8.1 Hz,

1H), 7.00 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 6.3

Hz, 2H), 1.34 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 176.7,

139.2, 131.5, 129.3, 123.1, 119.0, 112.2, 94.0, 77.6, 61.0, 40.1, 27.6,

23.8; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₅H₁₉NNaO₂

268.1308, found 268.1305.

N-(2-(4-Hydroxy-4-phenylbut-1-yn-1-yl)phenyl)benzamide (1x):

320.6 mg (55% yield, brown solid, puriﬁed by SiO₂column

chromatography eluting 5−20% EtOAc/hexane); mp 98.9−99.0 °C;

IR (neat) ν_max3386, 2925, 1676, 1521, 1449, 1308, 1057, 754, 698

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.78 (br s, 1H), 8.55 (d, J = 8.4

Hz, 1H), 7.89−7.85 (m, 2H), 7.56−7.22 (m, 10H), 7.04 (td, J = 7.7,

0.9 Hz, 1H), 4.97 (td, J = 6.0, 3.3 Hz, 1H), 2.95 (d, J = 6.3 Hz, 2H),

2.39 (d, J = 3.6 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.4,

142.7, 139.3, 134.8, 131.9, 131.6, 129.4, 128.7, 128.6, 128.2, 127.2,

125.6, 123.4, 119.2, 112.5, 94.1, 78.2, 72.6, 30.4; HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₂₃H₁₉NNaO₂364.1308, found 364.1313.

N-(2-(4-Hydroxy-4-(4-methoxyphenyl)but-1-yn-1-yl)phenyl)-

benzamide (1y): 377.4 mg (≥99% yield, brown solid, puriﬁed by

SiO₂column chromatography eluting 30% EtOAc/hexane); mp

N-(2-(5-Hydroxypent-1-yn-1-yl)-4-(triﬂuoromethyl)phenyl)-

benzamide (5g): 161.9 mg (84% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 30% EtOAc/hexane); mp 108.5−

109.0 °C; IR (neat) ν_max3316, 2951, 2229, 1660, 1533, 1334, 1116,

707 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.94 (br s, 1H), 8.71 (d, J

= 8.7 Hz, 1H), 7.94−7.91 (m, 2H), 7.66 (br s, 1H), 7.62−7.50 (m,

4H), 3.81 (t, J = 5.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 1.96−1.87 (m,

2H), 1.48 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.4,

141.7, 134.5, 132.4, 129.0, 128.6 (q, C−F, ³J_C−F= 4 Hz), 127.1, 126.0

3

1

(q, C−F, J_C−F= 4 Hz), 125.6 (q, C−F, J_C−F= 278 Hz), 125.4 (q,

C−F, J_C−F= 33 Hz), 118.8, 113.1, 99.0, 75.3, 61.3, 31.2, 16.1; ¹⁹F

2

NMR (376 MHz, CDCl₃) δ − 65.5 (s); HRMS (ESI-TOF) m/z [M

+ H]⁺calcd for C₁₉H₁₇F₃NO₂348.1206, found 348.1206.

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N-(2-(5-Hydroxypent-1-yn-1-yl)phenyl)-4-methoxybenzamide

(5m): 342.3 mg (93% yield, yellow solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 65.2−65.3 °C; IR

(neat) ν_max3394, 2935, 2220, 1660, 1505, 1247, 1028, 759 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 8.73 (br s, 1H), 8.49 (d, J = 8.4 Hz, 1H),

7.85−7.82 (m, 2H), 7.37−7.28 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H),

6.95−6.92 (m, 2H), 3.79 (s, 3H), 3.77−3.75 (m, 2H), 2.64 (t, J = 7.2

Hz, 2H), 2.52 (br s, 1H), 1.92−1.83 (m, 2H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 164.8, 162.5, 139.0, 131.4, 128.9, 128.8, 126.8, 123.1,

118.9, 113.9, 112.7, 97.3, 76.3, 61.1, 55.3, 31.3, 16.0; HRMS (ESI-

TOF) m/z [M + Na]⁺calcd for C₁₉H₁₉NNaO₃332.1257, found

332.1257.

(ESI-TOF) m/z [M + Na]⁺calcd for C₂₀H₂₁NNaO₂330.1465, found

330.1465.

N-(5-Chloro-2-(6-hydroxyhex-1-yn-1-yl)phenyl)benzamide (7e):

157.9 mg (92% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 102.5−102.9 °C;

IR (neat) ν_max3485, 3378, 2939, 2215, 1664, 1569, 1516, 1416, 708

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.79 (br s, 1H), 8.66 (d, J = 1.8

Hz, 1H), 7.91−7.88 (m, 2H), 7.60−7.48 (m, 3H), 7.31 (d, J = 8.4 Hz,

1H), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 3.67 (br s, 2H), 2.58 (t, J = 6.6

Hz, 2H), 1.78−1.67 (m, 4H), 1.44 (br s, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.1, 139.8, 134.9, 134.6, 132.2, 128.9, 127.0, 123.6,

119.1, 111.2, 98.7, 75.6, 62.1, 31.9, 25.1, 19.4; HRMS (ESI-TOF) m/

z [M + Na]⁺calcd for C₁₉H₁₈³⁵ClNNaO₂350.0918, found 350.0912.

N-(4-Chloro-2-(6-hydroxyhex-1-yn-1-yl)phenyl)benzamide (7f):

382.1 mg (97% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 90.6−90.9 °C;

4-Cyano-N-(2-(5-hydroxypent-1-yn-1-yl)phenyl)benzamide (5t):

245.0 mg (93% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 109.1−109.6 °C;

1

IR (neat) ν_max3401, 2934, 2229, 1653, 1532, 1449, 756 cm⁻¹; H

1

IR (neat) ν_max3261, 2931, 2222, 1684, 1512 1304, 700 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 8.83 (br s, 1H), 8.50 (d, J = 8.4 Hz, 1H),

8.03 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.6 Hz,

1H), 7.37 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.81 (q, J = 5.6

Hz, 2H), 2.68 (t, J = 6.8 Hz, 2H), 1.92−1.86 (m, 2H), 1.61 (br s,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.3, 138.7, 138.4, 132.7

131.7, 129.2, 127.7, 124.1, 119.2, 117.9, 115.5, 113.1, 97.8, 76.3, 61.4,

31.3, 16.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₁₇N₂O₂

305.1285, found 305.1282.

NMR (300 MHz, CDCl₃) δ 8.74 (br s, 1H), 8.51 (d, J = 9.0 Hz, 1H),

7.89 (d, J = 6.9 Hz, 2H), 7.59−7.48 (m, 3H), 7.37−7.36 (m, 1H),

7.29 (dd, J = 9.0, 2.4 Hz, 1H), 3.66 (br s, 2H), 2.57 (t, J = 6.3 Hz,

2H), 1.80−1.65 (m, 4H), 1.58 (br s, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 165.1, 137.5, 134.6, 132.1, 131.1, 129.0, 128.9, 128.2, 127.0,

120.1, 114.5, 99.1, 75.3, 62.1, 31.8, 25.1, 19.4; HRMS (ESI-TOF) m/

z [M + Na]⁺calcd for C₁₉H₁₈³⁵ClNNaO₂350.0918, found 350.0918.

N-(2-(6-Hydroxyhex-1-yn-1-yl)-4-(triﬂuoromethyl)phenyl)-

benzamide (7g): 159.6 mg (84% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 30% EtOAc/hexane); mp 100.7−

101.3 °C; IR (neat) ν_max3394, 3303, 2937, 2227, 1684, 1528, 1331,

1116, 704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (br s, 1H), 8.70

(d, J = 8.7 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.66 (s, 1H), 7.61−7.50

(m, 4H), 3.68 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 1.82−1.71

(m, 4H), 1.61 (br s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.3,

141.6, 134.4, 132.4, 129.0, 128.6 (q, J_C−F= 4 Hz), 127.0, 125.9 (q,

J_C−F= 4 Hz), 125.4 (q, J_C−F= 33 Hz), 123.7 (q, J_C−F= 270 Hz),

118.8, 113.2, 99.4, 75.2, 62.1, 31.8, 25.1, 19.4; ¹⁹F NMR (376 MHz,

CDCl₃) δ − 65.5 (s); HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₂₀H₁₈F₃NNaO₂348.1182, found 348.1173.

N-(2-(6-Hydroxyhex-1-yn-1-yl)phenyl)-4-methoxybenzamide

(7m): 347.5 mg (90% yield, pale orange solid, puriﬁed by SiO₂

column chromatography eluting 30% EtOAc/hexane); mp 77.1−77.5

°C; IR (neat) ν_max3433, 3387, 2939, 1652, 1508, 1255, 1064, 752

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.74 (br s, 1H), 8.52 (d, J = 8.4

Hz, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.33 (t, J

= 8.1 Hz, 1H), 7.05−6.96 (m, 3H), 3.85 (m, 3H), 3.67 (br s, 2H),

2.59−2.54 (m, 2H), 1.80−1.72 (m, 5H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 164.7, 162.5, 139.1, 131.5, 129.0, 128.8, 127.1, 123.1, 118.9,

114.0, 112.8, 97.7, 76.4, 62.1, 55.4, 31.9, 25.2, 19.4; HRMS (ESI-

TOF) m/z [M + Na]⁺calcd for C₂₀H₂₁NNaO₃346.1414, found

346.1411.

N-(2-(5-Hydroxypent-1-yn-1-yl)phenyl)cyclohexanecarboxamide

(5v): 263.8 mg (97% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 99.9−100.2 °C; IR

1

(neat) ν_max3293, 2928, 1655, 1521, 1446, 754 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 8.39 (d, J = 8.4 Hz, 1H), 8.09 (br s, 1H), 7.35 (d, J =

7.6 Hz, 1H), 7.30−7.27 (m, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.86−3.85

(m, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.31 (tt, J = 11.6, 3.2 Hz, 1H), 2.02

(d, J = 12.4 Hz, 2H), 1.94−1.83 (m, 4H), 1.73−1.64 (m, 2H), 1.54

(qd, J = 12.0, 3.0 Hz, 2H), 1.39−1.21 (m, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 174.2, 139.1, 131.5, 129.0, 123.0, 119.1, 112.4, 96.4,

76.5, 61.6, 46.6, 31.4, 29.7, 25.73, 25.63, 16.2; HRMS (ESI-TOF) m/

z [M + H]⁺calcd for C₁₈H₂₄NO₂286.1802, found 286.1800.

N-(2-(5-Hydroxy-5-phenylpent-1-yn-1-yl)phenyl)benzamide

(5x): 132.5 mg (67% yield, brown solid, puriﬁed by SiO₂column

chromatography eluting 20% EtOAc/hexane); mp 92.4−93.2 °C; IR

1

(neat) ν_max3390, 3062, 1665, 1521, 1310, 755, 699 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 8.82 (br s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.88−

7.86 (m, 2H), 7.51−7.47 (m, 1H), 7.41−7.39 (m, 2H), 7.37−7.36

(m, 1H), 7.34−7.25 (m, 6H), 7.05 (t, J = 7.6 Hz, 1H), 4.83 (dd, J =

8.0, 4.8 Hz, 1H), 2.72−2.56 (m, 2H), 2.27 (br s, 1H), 2.15−2.06 (m,

1H), 2.04−1.95 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2,

143.9, 139.0, 135.0, 131.9, 131.5, 129.1, 128.8, 128.6, 127.8, 127.0,

125.7, 123.4, 119.0, 112.9, 97.6, 76.6, 73.2, 37.8, 16.3; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₂₄H₂₂NO₂356.1645, found

356.1642.

N-(2-(6-Hydroxyhex-1-yn-1-yl)phenyl)benzamide (7a): 263.8 mg

(99% yield, yellow solid, puriﬁed by SiO₂column chromatography

eluting 30% EtOAc/hexane); mp 63.0−63.3 °C; IR (neat) ν_max3390,

4-Cyano-N-(2-(6-hydroxyhex-1-yn-1-yl)phenyl)benzamide (7t):

313.1 mg (96% yield, pale yellow solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 118.6−119.4 °C;

1

2937, 1676, 1521, 1310, 755 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

1

IR (neat) ν_max3368, 2944, 2233, 1686, 1523, 1447, 767 cm⁻¹; H

8.81 (br s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.93−7.90 (m, 2H), 7.59−

7.48 (m, 3H), 7.42−7.33 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 3.66 (t, J

= 6.0 Hz, 2H), 2.57 (t, J = 6.3 Hz, 2H), 1.81−1.66 (m, 5H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 165.2, 139.0, 135.1, 131.9, 131.5, 129.1,

128.8, 127.0, 123.4, 119.0, 112.9, 97.8, 76.4, 62.2, 31.9, 25.2, 19.4;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₉H₁₉NNaO₂

316.1308, found 316.1310.

NMR (300 MHz, CDCl₃) δ 8.79 (br s, 1H), 8.49 (d, J = 8.1 Hz, 1H),

8.01 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 7.8,

1.2 Hz, 1H), 7.39−7.33 (m, 1H), 7.09 (td, J = 7.5, 0.9 Hz, 1H), 3.70−

3.69 (m, 2H), 2.57 (t, J = 6.6 Hz, 2H), 1.78−1.70 (m, 4H), 1.68 (br s,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 163.3, 138.8, 138.2, 132.7,

131.7, 129.1, 127.6, 124.1, 119.1, 117.8, 115.4, 113.2, 98.2, 76.1, 62.0,

31.7, 25.2, 19.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₂₀H₁₈N₂NaO₂341.1260, found 341.1258.

N-(2-(6-Hydroxyhex-1-yn-1-yl)-4-methylphenyl)benzamide (7b):

306.5 mg (96% yield, pale orange solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 87.7−88.3 °C; IR

N-(2-(6-Hydroxyhex-1-yn-1-yl)phenyl)cyclohexanecarboxamide

(7v): 336.5 mg (89% yield, orange solid, puriﬁed by SiO₂column

chromatography eluting 30% EtOAc/hexane); mp 78.1−78.8 °C; IR

1

(neat) ν_max3338, 2922, 1653, 1310, 1057, 707 cm⁻¹; H NMR (300

1

MHz, CDCl₃) δ 8.73 (br s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.92−7.89

(m, 2H), 7.58−7.47 (m, 3H), 7.22 (s, 1H), 7.15 (dd, J = 8.4, 1.8 Hz,

1H), 3.65 (t, J = 5.4 Hz, 2H), 2.56 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H),

1.79−1.66 (m, 4H), 1.47 (br s, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 165.1, 136.6, 135.2, 133.1, 131.88, 131.86, 129.8, 128.8,

127.0, 119.0, 112.9, 97.3, 76.6, 62.2, 31.9, 25.2, 20.7, 19.4; HRMS

(neat) ν_max3389, 2929, 1673, 1517, 1447, 755 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 8.38 (d, J = 8.4 Hz, 1H), 8.08 (br s, 1H), 7.35 (dd, J

= 7.6, 1.6 Hz, 1H), 7.29−7.25 (m, 1H), 6.99 (td, J = 7.6, 0.8 Hz, 1H),

3.73−3.70 (m, 2H), 2.57−2.54 (m, 2H), 2.29 (tt, J = 11.6, 3.6 Hz,

1H), 2.03−2.00 (m, 3H), 1.86−1.82 (m, 2H), 1.79−1.70 (m, 5H),

1.53 (qd, J = 12.0, 2.8 Hz, 2H), 1.39−1.19 (m, 3H); ¹³C{¹H} NMR

4687

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(100 MHz, CDCl₃) δ 174.2, 138.8, 131.4, 128.9 123.0, 119.0, 112.5,

97.3, 76.3, 62.0, 46.6, 31.8, 29.7, 25.7, 25.6, 25.1, 19.3; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₁₉H₂₆NO₂300.1958, found

300.1963.

MHz, CDCl₃) δ − 117.6 to −117.7 (m); HRMS (ESI-TOF) m/z [M

+ H]⁺calcd for C₁₇H₁₃O₂N⁷⁹Br₂F 439.9292, found 439.9279.

3′,3′-Dibromo-7-chloro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2eBr): 162.5 mg (74% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 164.3−165.0 °C; IR (neat) ν_max2930, 2853, 2155, 1642, 931, 769

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.13 (d, J = 7.5 Hz, 1H), 7.71

(d, J = 8.1 Hz, 1H), 7.58−7.46 (m, 4H), 7.32−7.28 (m, 1H), 4.53−

4.42 (m, 2H), 3.73−3.62 (m, 1H), 3.18 (dd, J = 13.7, 4.8 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 156.4, 143.1, 137.0, 131.9, 131.3,

Procedure for Spiroannulation of Substrates 1 to Spiro-

cycles 2X (Representative Case: Synthesis of Spirocycle 2aBr).

A 5 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with substrate 1a (49.7 mg, 0.178 mmol, 1.00 equiv) and

EtOAc (1.0 mL). The reaction mixture was added to a solution of 1

M aqueous HCl (0.09 mL, 0.09 mmol, 0.51 equiv) (eﬀective

concentration of 1a ≈ 0.2 M), followed by NBS (64.2 mg, 0.361

mmol, 2.02 equiv). The reaction mixture was allowed to stir at room

temperature until judged complete by TLC (typically 5−15 min).

Upon completion, the mixture was diluted with water, and the

separated aqueous phase was extracted with EtOAc. Combined

organic phases were washed with saturated aqueous NaCl, dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated in vacuo to give the

crude spirocyclic product, which was puriﬁed by SiO₂column

chromatography, eluting 5% EtOAc/hexane to give 65.6 mg (87%) of

the pure desired product (2aBr) as a white crystalline solid.

The reaction of 1a at a larger scale (514.3 mg, 1.841 mmol) was

conducted employing the same procedure to aﬀord 654.9 mg (84%)

of 2aBr as a white crystalline solid.

3′,3′-Dibromo-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo[d][1,3]-

oxazine-4,2′-furan] (2aBr): 65.6 mg (87% yield, white crystalline

solid, puriﬁed by SiO₂column chromatography eluting 15% EtOAc/

hexane); mp 128.9−129.3 °C; IR (neat) ν_max2922, 1629, 816, 764

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.13−8.10 (m, 2H), 7.76 (dd, J

= 7.8, 0.9 Hz, 1H), 7.54−7.42 (m, 5H), 7.34−7.42 (m, 1H), 4.52−

4.40 (m, 2H), 3.67 (dt, J = 13.5, 9.6 Hz, 1H), 3.11 (ddd, J = 13.8, 6.0,

1.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 155.3, 141.7, 131.7,

131.5, 131.3, 128.7, 128.3, 128.0, 125.9, 125.1, 117.3, 109.2, 66.6,

66.4, 45.0; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₄O₂N⁷⁹Br₂421.9386, found 421.9376.

130.0, 128.4, 128.2, 125.9, 125.0, 115.8, 109.2, 66.8, 66.1, 44.9;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₃⁷⁹Br₂³⁵ClNO₂

455.8996, found 455.8999.

3′,3′-Dibromo-6-chloro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2fBr): 141.4 mg (87% yield, pale yellow

solid, puriﬁed by SiO₂column chromatography eluting 5% EtOAc/

hexane); mp 144.4−145.6 °C; IR (neat) ν_max2907, 1626, 1252, 1056,

1

935, 691 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.10 (d, J = 7.2 Hz,

2H), 7.74 (d, J = 2.4 Hz, 1H), 7.53−7.42 (m, 4H), 7.35 (d, J = 8.4

Hz, 1H), 4.49−4.37 (m, 2H), 3.63 (dt, J = 13.5, 9.6 Hz, 1H), 3.13

(ddd, J = 10.5, 5.9, 1.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

155.7, 140.4, 131.8, 131.4, 131.1, 128.7, 128.4, 128.1, 126.5, 118.8,

108.8, 66.9 65.6, 45.0; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₃⁷⁹Br₂³⁵ClNO₂455.8996, found 455.8988.

3′,3′-Dibromo-2-phenyl-6-(triﬂuoromethyl)-4′,5′-dihydro-3′H-

spiro[benzo[d][1,3]oxazine-4,2′-furan] (2gBr): 152.4 mg (81% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 96.3−96.9 °C; IR (neat) ν_max2977, 1606, 1264,

1079, 692 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.15−8.12 (m, 2H),

8.02 (br s, 1H), 7.76−7.73 (m, 1H), 7.56−7.44 (m, 4H), 4.54−4.41

(m, 2H), 3.66 (dt, J = 18.3, 9.3 Hz, 1H), 3.16 (ddd, J = 14.4, 6.0, 1.1

Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 157.1, 144.7, 132.2,

131.2, 128.44, 128.36, 128.2 (q, C−F, ³J_C−F= 4 Hz), 127.6 (q, C−F,

²J_C−F= 33 Hz), 126.4 (q, C−F, ³J_C−F= 4 Hz), 125.5, 124.0 (q, C−F,

3′,3′-Dibromo-6-methyl-2-phenyl-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2bBr): 179.5 mg (82% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 20%

EtOAc/hexane); mp 73.4−73.7 °C; IR (neat) ν_max2904, 1631, 1287,

1084, 936, 690 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 6.8

Hz, 2H), 7.57 (s, 1H), 7.54−7.43 (m, 3H), 7.34−7.30 (m, 2H),

4.49−4.40 (m, 2H), 3.71−3.63 (m, 1H), 3.14 (ddd, J = 13.8, 6.2, 1.4

Hz, 1H), 2.42 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.7,

139.4, 135.9,132.1, 131.9, 131.4, 129.0, 128.3, 128.0, 125.0, 117.0,

109.2, 66.6, 66.2, 45.1, 21.4; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₈H₁₆O₂N⁷⁹Br₂435.9542, found 435.9540.

¹J_C−F= 270 Hz), 117.9, 109.0, 67.0, 65.8, 44.9; ¹⁹F NMR (376 MHz,

CDCl₃) δ − 65.5 (s); HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₈H₁₃⁷⁹Br₂F₃NO₂489.9260, found 489.9268.

3′,3′-Dibromo-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo[d][1,3]-

oxazine-4,2′-furan]-6-carbonitrile (2hBr): 136.4 mg (79% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 163.0−163.9 °C; IR (neat) ν_max2909, 2226,

1

1596, 1259, 1058, 694 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.14−

8.11 (m, 2H), 8.033−8.027 (m, 1H), 7.73 (dd, J = 8.1, 1.8 Hz, 1H),

7.58−7.53 (m, 1H), 7.47 (t, J = 7.5 Hz, 3H), 4.52−4.41 (m, 2H),

3.64 (dt, J = 13.8, 9.3 Hz, 1H), 3.17 (ddd, J = 13.7, 5.7, 1.8 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 157.8, 145.5, 134.7, 133.2, 132.5,

3′,3′-Dibromo-7-ﬂuoro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2cBr): 133.1 mg (70% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 162.3−162.6 °C; IR (neat) ν_max2907, 1600, 1493, 1057, 929, 690

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J = 7.2 Hz, 2H), 7.75−

7.70 (m, 1H), 7.54−7.43 (m, 3H), 7.12 (dd, J = 9.8, 2.1 Hz, 1H), 7.00

(td, J = 8.4, 2.1 Hz, 1H), 4.49−4.37 (m, 2H), 3.69−3.59 (m, 1H),

3.14 (dd, J = 13.5, 4.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

130.8, 128.5, 128.4, 125.8, 118.5, 108.9, 108.6, 67.2, 65.5, 44.7;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₃⁷⁹Br₂N₂O₂

446.9338, found 446.9337.

3′,3′-Dibromo-6-nitro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2iBr): 176.8 mg (37% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 153.4−154.2 °C; IR (neat) ν_max2922, 1607, 1569, 1339, 693

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.61 (br s, 1H), 8.33−8.30 (m,

1H), 8.14 (d, J = 8.1 Hz, 2H), 7.59−7.46 (m, 4H), 4.51−4.41 (m,

2H), 3.70−3.59 (m, 1H), 3.19 (dd, J = 13.8, 6.0 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 158.3, 147.2, 144.9, 132.6, 130.7, 128.52,

128.47, 126.4, 125.8, 125.1, 118.2, 108.8, 67.3, 65.5, 44.7; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₃O₄N₂⁷⁹Br₂466.9237,

found 466.9236.

3′,3′-Dibromo-2-(p-tolyl)-4′,5′-dihydro-3′H-spiro[benzo[d][1,3]-

oxazine-4,2′-furan] (2jBr): 305.0 mg (86% yield, white solid, puriﬁed

by SiO₂column chromatography eluting 5% EtOAc/hexane); mp

130.0−130.7 °C; IR (neat) ν_max2922, 1596, 1251, 1057, 935, 766

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J = 8.1 Hz, 2H), 7.75

(dd, J = 7.8, 1.2 Hz, 1H), 7.51−7.40 (m, 2H), 7.30−7.23 (m, 3H),

4.48−4.36 (m, 2H), 3.64 (dt, J = 13.8, 9.3 Hz, 1H), 3.11 (ddd, J =

13.7, 6.0, 1.8 Hz, 1H), 2.39 (s, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 155.5, 142.0, 141.8, 131.2, 129.1, 129.0, 128.7, 128.3, 125.6,

1

3

164.5 (d, C−F, J_C−F= 248 Hz), 156.4, 143.9 (d, C−F, J_C−F= 12

Hz), 131.9, 131.4, 130.6 (d, C−F, ²J_C−F= 20 Hz), 128.4, 128.2, 113.3

(d, C−F, ³J_C−F= 3 Hz), 113.0 (d, C−F, ²J_C−F= 22 Hz), 111.7 (d, C−

F, J_C−F= 23 Hz), 109.3, 66.7, 66.4, 44.9; ¹⁹F NMR (376 MHz,

2

CDCl₃) δ − 112.9 to −113.0 (m); HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₁₇H₁₃⁷⁹Br₂FNO₂439.9292, found 439.9300.

3′,3′-Dibromo-6-ﬂuoro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2dBr): 148.9 mg (87% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 147.7−148.9 °C; IR (neat) ν_max2923, 1632, 1494, 1054, 795, 735

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 6.0 Hz, 2H), 7.49−

7.38 (m, 5H), 7.24−7.17 (m, 1H), 4.47−4.37 (m, 2H), 3.67−3.59

(m, 1H), 3.12 (dd, J = 10.5, 4.5 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

1

CDCl₃) δ 160.4 (d, C−F, J_C−F= 244 Hz), 154.8, 138.1 (d, C−F,

3

³J_C−F= 3 Hz), 131.6, 131.5, 128.3, 128.0, 126.7 (d, C−F, J_C−F= 8

3

2

Hz), 118.9 (d, C−F, J_C−F= 9 Hz), 118.4 (d, C−F, J_C−F= 22 Hz),

115.6 (d, C−F, ²J_C−F= 25 Hz) 108.7, 66.8, 65.6, 44.9; ¹⁹F NMR (376

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125.0, 117.3, 109.1, 66.6, 66.4, 45.0, 21.6; HRMS (ESI-TOF) m/z [M

+ H]⁺calcd for C₁₈H₁₆⁷⁹Br₂NO₂435.9542, found 435.9545.

3′,3′-Dibromo-2-(2-methoxyphenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2kBr): 210.0 mg (41% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−10%

EtOAc/hexane); mp 104.6−104.9 °C; IR (neat) ν_max2906, 1598,

1247, 925, 749 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J = 7.2

Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.52−7.40 (m, 3H), 7.30 (t, J = 7.5

Hz, 1H), 7.03−6.96 (m, 2H), 4.46−4.38 (m, 1H), 4.35−4.29 (m,

1H), 3.88 (s, 3H), 3.70 (dt, J = 13.5, 9.3 Hz, 1H), 3.05 (dd, J = 13.2,

6.0 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 158.7, 155.8, 141.9,

132.4, 131.9, 131.2, 128.5, 125.8, 125.1, 121.4, 120.4, 116.8, 112.2,

109.1, 66.7, 55.9, 44.3; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₈H₁₆⁷⁹Br₂NO₃451.9492, found 451.9494.

3′,3′-Dibromo-2-(3-methoxyphenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2lBr): 136.5 mg (83% yield, white

solid, puriﬁed by SiO₂column chromatography eluting 5% EtOAc/

hexane); mp 104.1−105.1 °C; IR (neat) ν_max2906, 1629, 1577, 1285,

1035, 927, 768 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.76 (d, J = 7.8

Hz, 1H), 7.70−7.67 (m, 2H), 7.53−7.48 (m, 1H), 7.44−7.42 (m,

1H), 7.38−7.28 (m, 2H), 7.07−7.03 (m, 1H), 4.49−4.38 (m, 2H),

3.87 (s, 3H), 3.70−3.59 (m, 1H), 3.16−3.10 (m, 1H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 159.5, 155.2, 141.6, 133.1, 129.3, 128.7, 125.9,

125.2, 120.5, 117.6, 117.4, 113.1, 109.2, 66.7, 66.3, 55.4, 45.0; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₆O₃N⁷⁹Br₂451.9492,

found 451.9479.

3′,3′-Dibromo-2-(4-methoxyphenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2mBr): 336.6 mg (82% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−10%

EtOAc/hexane); mp 164.5−164.8 °C; IR (neat) ν_max2928, 1596,

1170, 793, 765 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J = 8.7

Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.40 d, J =

7.2 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.48−

4.36 (m, 2H), 3.83 (s, 3H), 3.69−3.58 (m, 1H), 3.12 (dd, J = 13.8,

4.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.4, 155.2, 142.0,

131.2, 129.8, 128.6, 125.4, 124.8, 124.1, 117.2, 113.7, 109.0, 66.6,

66.4, 55.3, 45.0; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₈H₁₆ON⁷⁹Br₂451.9492, found 451.9488.

3′,3′-Dibromo-2-(3,4,5-trimethoxyphenyl)-4′,5′-dihydro-3′H-

spiro[benzo[d][1,3]oxazine-4,2′-furan] (2nBr): 163.0 mg (78% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−20%

EtOAc/hexane); mp 134.2−134.9 °C; IR (neat) ν_max2939, 1583,

1348, 1125, 930, 768 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.75 (d, J

= 7.8 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44−7.41 (m, 1H), 7.38 (s,

2H), 7.33−7.26 (m, 1H), 4.52−4.40 (m, 2H), 3.95 (s, 6H), 3.91 (s,

3H), 3.65−3.54 (m, 1H), 3.17 (dd, J = 13.5, 5.1 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 155.0, 152.9, 141.6, 141.3, 131.3, 128.7,

127.0, 125.8, 125.0, 117.2, 109.3, 105.5, 66.7, 66.2, 60.9, 56.3, 45.2;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₀H₂₀Br₂NO₅511.9703,

found 511.9690.

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 164.9 (d, C−F, ¹J_C−F= 251 Hz),

3

154.5, 141.6, 131.4, 130.3 (d, C−F, J_C−F= 9 Hz), 128.8, 128.0 (d,

3

2

C−F, J_C−F= 3 Hz), 125.9, 125.1, 117.3, 115.5 (d, C−F, J_C−F= 22

Hz), 109.3, 66.7, 66.3, 45.1; ¹⁹F NMR (376 MHz, CDCl₃) δ − 111.1

to −111.2 (m); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₃O₂N⁷⁹Br₂F 439.9292, found 439.9290.

3′,3′-Dibromo-2-(4-chlorophenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2qBr): 68.9 mg (79% yield, white

solid, puriﬁed by SiO₂column chromatography eluting 5−10%

EtOAc/hexane); mp 149.2−149.5 °C; IR (neat) ν_max2920, 1631,

1107, 768 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J = 8.6 Hz,

2H), 7.74 (dd, J = 7.7, 1.1 Hz, 1H), 7.49 (td, J = 7.8, 1.5 Hz, 1H),

7.42−7.39 (m, 3H), 7.30 (td, J = 15.0, 1.3 Hz, 1H), 4.47−4.35 (m,

2H), 3.59 (dt, J = 13.8, 9.3 Hz, 1H), 3.11 (ddd, J = 13.7, 6.1, 1.6 Hz,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 154.4, 141.4, 137.7, 131.3,

130.3, 129.3, 128.7, 128.6, 126.1, 125.1, 117.3, 109.3, 66.7, 66.2, 45.0;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₃O₂N⁷⁹Br₂³⁵Cl

455.8996, found 455.8996.

3′,3′-Dibromo-2-(2-bromophenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2rBr): 207.0 mg (75% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 104.8−106.1 °C; IR (neat) ν_max2972, 2905,

1640, 1064, 921, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J

= 7.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H),

7.54−7.25 (m, 5H), 4.46−4.31 (m, 2H), 3.61−3.50 (m, 1H), 3.10−

3.04 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 155.1, 141.1,

134.2, 133.5, 131.5 131.4, 128.8, 127.1, 126.4, 125.3, 121.4, 116.6,

109.5, 66.8, 66.5, 44.7; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₃⁷⁹Br₃NO₂499.8491, found 499.8500.

3′,3′-Dibromo-2-(4-bromo-2-ﬂuorophenyl)-4′,5′-dihydro-3′H-

spiro[benzo[d][1,3]oxazine-4,2′-furan] (2sBr): 138.8 mg (69% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 2%

EtOAc/hexane); 106.6−107.0 °C; IR (neat) ν_max2973, 2906, 1626,

1599, 1483, 923, 767 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (t, J

= 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H),

7.41−7.32 (m, 4H), 4.48−4.34 (m, 2H), 3.73−3.62 (m, 1H), 3.12−

3.05 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.1 (d, C−F,

¹J_C−F= 261 Hz), 153.3 (d, C−F, ³J_C−F= 4 Hz), 141.2, 132.6 (d, C−F,

3

³J_C−F= 2 Hz), 131.4, 128.8, 127.6 (d, C−F, J_C−F= 4 Hz), 126.4,

126.2 (d, C−F, ³J_C−F= 10 Hz), 125.2, 120.6 (d, C−F, ²J_C−F= 26 Hz),

119.1 (d, C−F, ³J_C−F= 9 Hz), 117.2, 109.5, 66.9, 66.3, 44.6 (d, C−F,

³J_C−F= 2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ − 111.1 (dd, J = 10.5,

8.3 Hz); HRMS (ESI-TOF) m/z [M

+

H]⁺calcd for

C₁₇H₁₂⁷⁹Br₃FNO₂517.8397, found 517.8389.

4-(3′,3′-Dibromo-4′,5′-dihydro-3′H-spiro[benzo[d][1,3]oxazine-

4,2′-furan]-2-yl)benzonitrile (2tBr): 156.6 mg (92% yield, yellow

solid, puriﬁed by SiO₂column chromatography eluting 5−15%

EtOAc/hexane); mp 223.4−224.4 °C; IR (neat) ν_max2923, 2226,

1

1630, 1311, 1059, 915, 769 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.21 (d, J = 8.1 Hz, 2H), 7.77−7.72 (m, 3H), 7.53 (td, J = 7.8 Hz,

1H), 7.42 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.52−4.40 (m

2H), 3.61 (dt, J = 13.8, 9.6 Hz, 1H), 3.16 (dd, J = 13.8, 5.1 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.5, 141.0, 135.9, 132.1, 131.5,

128.8 128.4, 126.7, 125.5, 118.3, 117.4, 114.7, 109.6, 66.9, 66.1, 45.0;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₃Br₂N₂O₂

446.9338, found 466.9338.

3′,3′-Dibromo-2-(4-(triﬂuoromethoxy)phenyl)-4′,5′-dihydro-

3′H-spiro[benzo[d][1,3]oxazine-4,2′-furan] (2oBr): 143.5 mg (84%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

5% EtOAc/hexane); mp 122.3−122.6 °C; IR (neat) ν_max2920, 1629,

1

1603, 1248, 1152, 927, 767 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.18−8.13 (m, 2H), 7.77−7.74 (m, 1H), 7.54−7.49 (m, 1H), 7.43−

7.40 (m, 1H), 7.35−7.27 (m, 3H), 4.52−4.39 (m, 2H), 3.63 (dt, J =

14.1, 9.6 Hz, 1H), 3.16 (ddd, J = 13.8, 6.3, 1.5 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 154.2, 151.6, 141.5, 131.4, 130.3, 129.8,

128.8, 126.2, 125.2, 120.39, 120.36 (q, C−F, ¹J_C−F= 257 Hz), 117.3,

109.5, 66.8, 66.2, 45.1; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₈H₁₃⁷⁹Br₂F₃NO₃505.9209, found 505.9204.

3′,3′-Dibromo-2-(4-ﬂuorophenyl)-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2pBr): 450.6 mg (81% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−20%

EtOAc/hexane); mp 126.7−127.1 °C; IR (neat) ν_max2905, 1632,

1506, 1082, 930 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.14−8.10 (m,

2H), 7.75 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 7.5

Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 8.4 Hz, 2H), 4.51−4.39

(m, 2H), 3.63 (dt, J = 13.8, 9.3 Hz, 1H), 3.19−3.12 (m, 1H);

3′,3′-Dibromo-2-(4-nitrophenyl)-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2uBr): 117.8 mg (74% yield, yellow

solid, puriﬁed by SiO₂column chromatography eluting 5% EtOAc/

hexane); mp 156.9−157.4 °C; IR (neat) ν_max3073, 2982, 1595, 1518,

1

1345, 715 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.28 (s, 4H), 7.77

(d, J = 7.8 Hz, 1H), 7.54 (td, J = 7.8, 1.2 Hz, 1H), 7.45−7.43 (m,

1H), 7.36 (td, J = 7.5, 0.9 Hz, 1H), 4.54−4.42 (m, 2H), 3.62 (dt, J =

13.8, 9.3 Hz, 1H), 3.17 (ddd, J = 13.7, 6.3, 1.5 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 153.3, 149.5, 141.0, 137.6, 131.5, 128.9,

128.8, 126.9, 125.6, 123.5, 117.4, 109.7, 67.0, 66.1, 45.0; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₁₇H₁₃O₄N₂Br₂466.9237, found

466.9229.

3′,3′-Dibromo-2-cyclohexyl-4′,5′-dihydro-3′H-spiro[benzo[d]-

[1,3]oxazine-4,2′-furan] (2vBr): 210.5 mg (72% yield, yellow oil,

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puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

IR (neat) ν_max2922, 1627, 1594, 1057, 931, 692 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 7.70 (dd, J = 7.8, 1.2 Hz, 1H), 7.46−7.41 (m, 1H),

7.28−7.21 (m, 2H), 4.41−4.24 (m, 2H), 3.53−3.42 (m, 1H), 3.03

(dd, J = 13.5, 6.3 Hz, 1H), 2.41 (tt, J = 11.7, 3.4 Hz, 1H), 2.11−2.07

(m, 1H), 2.03−1.98 (m, 1H), 1.84−1.80 (m, 2H), 1.71−1.68 (m,

1H), 1.60−1.42 (m, 2H), 1.39−1.15 (m, 3H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 163.4, 141.4, 131.1, 128.5, 125.3, 124.5, 116.6, 108.3,

66.7, 66.4, 44.6, 43.5, 30.0, 29.9, 25.8; HRMS (ESI-TOF) m/z [M +

H]⁺calcd for C₁₇H₂₀⁷⁹Br₂NO₂427.9855, found 427.9861.

3′,3′-Dibromo-2-(tert-butyl)-4′,5′-dihydro-3′H-spiro[benzo[d]-

[1,3]oxazine-4,2′-furan] (2wBr): 67.2 mg (36% yield, yellow oil,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

IR (neat) ν_max3362, 2969, 1619, 1233, 928, 780 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ, 7.75 (dd, J = 7.7, 1.5 Hz, 1H), 7.47 (td, J = 7.7, 1.2

Hz, 1H), 7.34−7.32 (m, 1H), 7.30−7.25 (m, 1H), 4.45−4.37 (m,

1H), 4.31 (t, J = 9.3 Hz, 1H), 3.50 (dt, J = 13.5, 9.3 Hz, 1H), 3.11−

3.05 (m, 1H), 1.34 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.6, 141.6, 131.1, 128.4, 125.4, 124.8, 116.2, 108.4, 66.6, 66.3, 44.6,

37.3, 28.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₅H₁₈⁷⁹Br₂NO₂401.9699, found 401.9704.

3′,3′-Dibromo-2,5′-diphenyl-4′,5′-dihydro-3′H-spiro[benzo[d]-

[1,3]oxazine-4,2′-furan] (2xBr): 173.2 mg (57% yield, white

amorphous solid, puriﬁed by SiO₂column chromatography eluting

2−5% EtOAc/hexane); mp 115.1−115.9 °C; IR (neat) ν_max3064,

1631, 1254, 1065, 935, 766, 691 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 8.14−8.11 (m, 2H), 7.84 (dd, J = 7.8, 0.9 Hz, 1H), 7.61−7.58 (m,

2H), 7.56−7.30 (m, 9H), 5.71 (dd, J = 9.9, 6.0 Hz, 1H), 3.55 (dd, J =

13.8, 9.9 Hz, 1H), 3.44 (dd, J = 13.8, 6.0 Hz, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 155.4, 141.7, 139.3, 131.8, 131.6, 131.4, 129.0,

128.8, 128.43, 128.40, 128.1, 126.2, 125.9, 125.2, 117.6, 109.6, 81.6,

66.7, 53.6; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₂₃H₁₈⁷⁹Br₂NO₂497.9699, found 497.9700.

puriﬁed by SiO₂column chromatography eluting 20% EtOAc/

hexane); mp 156.2−156.7 °C; IR (neat) ν_max2910, 1598, 1059, 954

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.13−8.09 (m, 2H), 7.62 (dd, J

= 8.7, 8.0 Hz, 1H), 7.56−7.43 (m, 3H), 7.12 (dd, J = 9.5, 2.7 Hz, 1H),

7.00 (td, J = 8.4, 2.7 Hz, 1H), 4.52 (td, J = 8.6, 1.5 Hz, 1H), 4.46−

4.38 (m, 1H), 3.38 (dt, J = 13.5, 9.6 Hz, 1H), 3.00 (ddd, J = 13.4, 6.6,

1.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 164.6 (d, C−F,

¹J_C−F= 248 Hz), 156.3, 143.8 (d, C−F, ³J_C−F= 12 Hz), 131.9, 131.4,

130.3 (d, C−F, ³J_C−F= 10 Hz), 128.4, 128.1, 113.2 (d, C−F, ²J_C−F

=

3

2

22 Hz), 112.9, (d, C−F, J_C−F= 3 Hz), 111.8 (d, C−F, J_C−F= 23

Hz) 109.2, 90.9, 66.3, 42.5; ¹⁹F NMR (376 MHz, CDCl₃) δ − 112.96

to −113.02 (m); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₃O₂N³⁵Cl₂F 352.0302, found 352.0297.

Procedure for Spiroannulation of Substrates 5 to Spiro-

cycles 6X (Representative Case: Synthesis of Spirocycle 6aBr).

A 10 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with substrate 5a (161.8 mg, 0.579 mmol, 1.00 equiv), 2.9

mL of EtOAc (eﬀective concentration of 5a ≈ 0.2 M), and 0.29 mL of

a solution of 1.0 M aqueous HCl (0.29 mmol, 0.5 equiv). The

resulted solution was then added with NBS (208.9 mg, 1.174 mmol,

2.03 equiv) and was allowed to stir at room temperature. Upon

completion as judged by TLC (typically 5−15 min), the reaction

mixture was diluted with water. The separated aqueous phase was

extracted with EtOAc, and the combined organic phases were washed

with saturated aqueous NaCl, dried over anhydrous Na₂SO₄, ﬁltered,

and concentrated in vacuo to give the crude spirocyclic product. The

crude material was puriﬁed by SiO₂column chromatography, eluting

5% EtOAc/hexane to give 203.3 mg (80%) of pure compound 6aBr

as a white solid.

3′,3′-Dibromo-2-phenyl-3′,4′,5′,6′-tetrahydrospiro[benzo[d]-

[1,3]oxazine-4,2′-pyran] (6aBr): 203.3 mg (80% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 20% EtOAc/

hexane); mp 125.8−126.0 °C; IR (neat) ν_max2966, 1633, 956, 763

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.18−8.15 (m, 2H), 7.90 (dd, J

= 7.8, 1.2 Hz, 1H), 7.55−7.44 (m, 4H), 7.38 (dd, J = 7.8, 1.2 Hz, 1H),

7.30 (td, J = 7.5, 1.5 Hz, 1H), 4.53−4.44 (m, 1H), 4.01 (dd, J = 11.7,

5.7 Hz, 1H), 3.47−3.37 (m, 1H), 2.75 (d, J = 14.4 Hz, 1H), 2.69−

2.54 (m, 1H), 1.70 (dd, J = 14.0, 3.1 Hz, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 154.3, 140.1, 132.0, 131.6, 130.8, 128.9, 128.5, 127.7,

126.0, 125.0, 120.4, 100.3, 71.8, 61.2, 41.4, 24.4; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₈H₁₆O₂N⁷⁹Br 435.9542, found 435.9540.

3′,3′-Dibromo-6-methyl-2-phenyl-3′,4′,5′,6′-tetrahydrospiro-

[benzo[d][1,3]oxazine-4,2′-pyran] (6bBr): 134.0 mg (82% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 152.3−152.8 °C; IR (neat) ν_max2961, 2103,

3′,3′-dibromo-5′-(4-methoxyphenyl)-2-phenyl-4′,5′-dihydro-

3′H-spiro[benzo[d][1,3]oxazine-4,2′-furan] (2yBr): 44.0 mg (36%

yield, white crystalline solid, puriﬁed by SiO₂column chromatography

eluting 2−5% EtOAc/hexane); mp 127.9−128.2 °C; IR (neat) ν_max

1

2931, 1630, 1514, 1250, 1033, 930, 830, 767, 692 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 8.16−8.13 (m, 2H), 7.82 (dd, J = 7.6, 1.2 Hz,

1H), 7.54−7.50 (m, 4H), 7.49−7.45 (m, 3H), 7.32 (td, J = 7.2, 1.2

Hz, 1H), 6.95−6.91 (m, 2H), 5.66 (dd, J = 10.2, 5.6 Hz, 1H), 3.81 (s,

3H), 3.54 (dd, J = 13.6, 10.0 Hz, 1H), 3.39 (dd, J = 14.0, 5.6 Hz, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.7, 155.5, 141.7, 131.8,

131.6, 131.4, 131.0, 129.0, 128.5, 128.2, 127.8, 125.9, 125.2, 117.7,

114.2, 109.5, 81.5, 66.8, 55.3, 53.6; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₂₄H₂₀⁷⁹Br₂NO₃527.9804, found 527.9804.

1

1634, 1251, 1066, 1021, 688 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.15 (dd, 2H, J = 7.8, 1.2 Hz), 7.72 (br s, 1H), 7.55−7.45 (m, 3H),

7.28−7.26 (m, 2H), 4.56−4.46 (m, 1H), 4.04 (dd, J = 11.7, 5.7 Hz,

1H), 3.44 (td, J = 13.7, 3.9 Hz, 1H), 2.79−2.55 (m, 2H), 2.43 (s,

3H), 1.76−1.71 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.7,

137.8, 136.1, 132.1, 131.7, 131.4, 129.2, 128.5, 127.7, 124.9, 120.1,

100.3, 71.8, 61.3, 41.5, 24.4, 21.5; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₁₉H₁₈⁷⁹Br₂NO₂449.9699, found 449.9705.

3′,3′-Dibromo-7-chloro-2-phenyl-3′,4′,5′,6′-tetrahydrospiro-

[benzo[d][1,3]oxazine-4,2′-pyran] (6eBr): 203.3 mg (73% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 132.5−133.0 °C; IR (neat) ν_max2963, 1632,

1594, 1091, 962, 690 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.17 (d, J

= 7.2 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.58−7.49 (m, 3H), 7.400−

7.395 (m, 1H), 7.30−7.27 (m, 1H), 4.53−4.46 (m, 1H), 4.03 (dd, J =

11.6, 5.6 Hz, 1H), 3.42 (td, J = 13.6, 4.0 Hz, 1H), 2.78 (d, J = 14.4

Hz, 1H), 2.68−2.56 (m, 1H), 1.75 (dd, J = 14.0, 2.8 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 156.2, 142.5, 137.5, 132.9, 132.4,

131.1, 129.5, 128.8, 127.0 125.7, 119.8, 101.3, 72.5, 62.3, 42.2, 25.2;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₅⁷⁹Br₂³⁵ClNO₂

469.9153, found 469.9157.

3′,3′-Dibromo-6-chloro-2-phenyl-3′,4′,5′,6′-tetrahydrospiro-

[benzo[d][1,3]oxazine-4,2′-pyran] (6fBr): 178.5 mg (75% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 166.0−166.4 °C; IR (neat) ν_max2964, 1632,

3′,3′-Dichloro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo[d][1,3]-

oxazine-4,2′-furan] (2aCl): 26.0 mg (19% yield, white crystal,

puriﬁed by SiO₂column chromatography eluting 10% EtOAc/

hexane); mp 133.9−134.2 °C; IR (neat) ν_max3060, 1628, 767, 689

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 8.4 Hz, 2H), 7.61

(d, J = 7.6 Hz, 1H), 7.46−7.37 (m, 5H), 7.25 (t, J = 7.6 Hz, 1H), 4.46

(t, J = 8.8 Hz, 1H), 4.40−4.34 (m, 1H), 3.38−3.30 (m, 1H) 2.96−

2.91 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 155.2, 141.6,

131.7, 131.6, 131.3, 128.4, 128.3, 128.0, 126.0, 125.1, 116.9, 109.1,

90.9, 66.2, 42.6; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₄O₂N³⁵Cl₂334.0396, found 334.0390.

3′,3′-Dichloro-6-methyl-2-phenyl-4′,5′-dihydro-3′H-spiro-

[benzo[d][1,3]oxazine-4,2′-furan] (2bCl): 31.3 mg (48% yield, white

solid, puriﬁed by SiO₂column chromatography eluting 20% EtOAc/

hexane); mp 164.5−165.0 °C; IR (neat) ν_max3271, 2908, 1629, 1061,

832, 687 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (dd, J = 8.0, 1.5

Hz, 2H), 7.52−7.41 (m, 4H), 7.34−7.28 (m, 2H), 4.52 (td, J = 8.4,

1.5 Hz, 1H), 4.47−4.38 (m, 1H), 3.40 (dt, J = 13.5, 9.6 Hz, 1H), 2.99

(ddd, J = 13.2, 6.6, 1.5 Hz, 1H), 2.41 (s, 3H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 154.6, 139.3, 136.0, 132.1, 131.9, 131.4, 128.7, 128.3,

127.9, 125.0, 116.6, 109.1, 90.8, 66.2, 42.6, 21.4; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₈H₁₆O₂N³⁵Cl₂348.0553, found 348.0548.

3′,3′-Dichloro-7-ﬂuoro-2-phenyl-4′,5′-dihydro-3′H-spiro[benzo-

[d][1,3]oxazine-4,2′-furan] (2cCl): 19.9 mg (33% yield, white solid,

4690

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

1475, 1252, 1064, 759, 691 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

(t, J = 6.0 Hz, 1H), 3.54 (ddd, J = 17.1, 12.9, 3.9 Hz, 0.61H, minor),

3.45 (ddd, J = 15.0, 7.2, 5.4 Hz, 1H, major), 3.15 (ddd, J = 15.0, 7.5,

5.7 Hz, 1H, major), 2.83 (dt, J = 14.4, 3.9 Hz, 0.60H, minor), 2.90−

2.47 (m, 2.72H, major+minor), 2.02 (dq, J = 14.1, 3.0 Hz, 0.57H,

minor); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 154.7, 154.3, 140.8,

140.3, 140.1, 132.0, 131.64, 131.60, 131.3, 130.9, 130.7, 129.1, 128.53,

128.50, 128.3, 128.2, 128.1, 127.9, 127.8, 127.5, 126.1, 126.0, 125.7,

125.6, 125.0, 120.9, 120.4, 101.1, 101.0, 73.6, 73.2, 71.5, 70.1, 41.6,

41.4, 32.6, 28.0; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₂₄H₂₀⁷⁹Br₂NO₂511.9855, found 511.9851.

3′,3′-Dichloro-2-phenyl-3′,4′,5′,6′-tetrahydrospiro[benzo[d]-

[1,3]oxazine-4,2′-pyran] (6aCl): 50.4 mg (39% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 10% EtOAc/

hexane); mp 124.2−124.9 °C; IR (neat) ν_max2973, 1632, 769 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 8.18−8.15 (m, 2H), 7.80 (dd, J = 7.8,

0.9 Hz, 1H), 7.55−7.44 (m, 4H), 7.39 (dd, J = 7.8, 1.2 Hz, 1H), 7.30

(td, J = 7.5, 1.5 Hz, 1H), 4.51−4.41 (m, 1H), 3.99 (dd, J = 11.9, 5.4

Hz, 1H), 3.15 (td, J = 13.7, 3.9 Hz, 1H), 2.61−2.43 (m, 2H), 1.85−

1.78 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 154.1, 140.2,

132.0, 131.6, 130.9, 128.6, 128.5, 127.7, 126.2, 125.0, 119.6, 100.9,

90.8, 61.3, 38.7, 23.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₈H₁₆O₂N³⁵Cl₂348.0553, found 348.0545.

Procedure for Spiroannulation of Substrates 7 to Spiro-

cycles 8X (Representative Case: Synthesis of Spirocycle 8aBr).

A 250 mL round-bottomed ﬂask containing a magnetic stir bar was

charged with substrate 7a (504.5 mg, 1.720 mmol, 1.00 equiv) and

DCM (172 mL, eﬀective concentration of 7a ≈ 0.01 M). The resulted

solution was then added with a solution of 1 M aqueous HCl (0.86

mL, 0.86 mmol, 0.50 equiv), followed by NBS (613.1 mg, 3.445

mmol, 2.00 equiv). The reaction mixture was allowed to stir at room

temperature for 3 h. Upon completion, the reaction mixture was

diluted with water, and the biphasic mixture was extracted with DCM.

Combined organic phases were washed with saturated aqueous NaCl,

dried over anhydrous Na₂SO₄, ﬁltered, and concentrated in vacuo to

give the crude spirocyclic product. The crude material was puriﬁed by

SiO₂column chromatography, eluting 5% EtOAc/hexane to give

598.7 mg (77%) of pure product 8aBr as a white solid.

3′,3′-Dibromo-2-phenylspiro[benzo[d][1,3]oxazine-4,2′-oxe-

pane] (8aBr): 598.7 mg (77% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 2% EtOAc/hexane); mp 177.0−

178.0 °C; IR (neat) ν_max2953, 1635, 1248, 764, 690 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.18 (dd, J = 8.1, 1.2 Hz, 2H), 8.04 (dd, J = 7.8,

0.9 Hz, 1H), 7.57−7.43 (m, 4H), 7.38−7.29 (m, 2H), 4.32−4.25 (m,

1H), 3.99−3.89 (m, 1H), 3.25−3.15 (m, 1H), 2.91−2.84 (m, 1H),

2.22−2.03 (m, 3H), 1.95−1.86 (m, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 154.1, 139.0, 131.8, 131.6, 130.4, 128.5, 128.3, 127.8, 126.4,

125.0, 123.4, 103.3, 77.9, 64.3, 46.7, 29.0, 24.2; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₉H₁₈⁷⁹Br₂NO₂449.9699, found 449.9692.

3′,3′-Dibromo-6-methyl-2-phenylspiro[benzo[d][1,3]oxazine-

4,2′-oxepane] (8bBr): 83.9 mg (54% yield, white solid, puriﬁed by

SiO₂column chromatography eluting 5% EtOAc/hexane); mp

144.1−144.6 °C; IR (neat) ν_max2923, 1638, 1250, 1068, 691 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 8.17−8.14 (m, 2H), 7.85 (br s, 1H),

7.55−7.45 (m, 3H), 7.26−7.24 (m, 2H), 4.31−4.24 (m, 1H), 3.97−

3.88 (m, 1H), 3.23−3.13 (m, 1H), 2.90−2.82 (m, 1H), 2.44 (s, 3H),

2.25−2.01 (m, 3H), 1.93−1.84 (m, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 153.4, 136.7, 136.3, 131.9, 131.4, 131.2, 128.6, 128.5, 127.6,

124.8, 123.0, 103.2, 78.0, 64.3, 46.7, 29.0, 24.2, 21.6; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₂₀H₁₉⁷⁹Br₂NO₂463.9855, found

463.9855.

8.17−8.13 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.57−7.46 (m, 3H),

7.43 (dd, J = 8.4, 2.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.53−4.44

(m, 1H), 4.07−4.01 (m, 1H), 3.46−3.36 (m, 1H), 2.79−2.74 (m,

1H), 2.71−2.54 (m, 1H), 1.77−1.71 (m, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 154.6, 138.9, 131.8, 131.7, 131.3, 131.0, 129.0, 128.5,

127.8, 126.3, 121.7, 100.0, 71.0, 61.4, 41.3, 24.3; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₈H₁₅⁷⁹Br₂³⁵ClNO₂469.9153, found

469.9157.

3′,3′-Dibromo-2-phenyl-6-(triﬂuoromethyl)-3′,4′,5′,6′-

tetrahydrospiro[benzo[d][1,3]oxazine-4,2′-pyran] (6gBr): 91.1 mg

(60% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 5% EtOAc/hexane); mp 165.2−165.5 °C; IR (neat) ν_max

1

2931, 1606, 1258, 1090, 692 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.19−8.17 (m, 3H), 7.71 (dd, J = 8.4, 1.5 Hz, 1H), 7.59−7.45 (m,

4H), 4.53−4.44 (m, 1H), 4.05 (dd, J = 11.7, 5.7 Hz, 1H), 3.41 (td, J =

13.8, 4.2 Hz, 1H), 2.80−2.75 (m, 1H), 2.71−2.54 (m, 1H), 1.74 (dd,

J = 14.1, 3.0 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 156.1,

2

143.1, 132.2, 131.4, 128.6, 128.1, 127.8 (q, C−F, J_C−F= 33 Hz),

3

127.7 (q, C−F, J_C−F= 4 Hz), 126.7 (q, C−F, J_C−F= 4 Hz), 125.3,

1

124.0 (q, C−F, J_C−F= 270 Hz), 120.7, 100.2, 71.0, 61.5, 41.2, 24.3;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₁₅⁷⁹Br₂F₃NO₂

503.9416, found 503.9419.

3′,3′-Dibromo-2-(4-methoxyphenyl)-3′,4′,5′,6′-tetrahydrospiro-

[benzo[d][1,3]oxazine-4,2′-pyran] (6mBr): 127.6 mg (82% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5%

EtOAc/hexane); mp 184.2−184.7 °C; IR (neat) ν_max2919, 1625,

1254, 1068, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.12 (d, J = 8.7

Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.35 (d, J

= 7.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H),

4.53−4.44 (m, 1H), 4.04−3.99 (m, 1H), 3.87 (s, 3H), 3.42 (td, J =

13.5, 4.5 Hz, 1H), 2.78−2.73 (m, 1H), 2.70−2.53 (m, 1H), 1.74−

1.70 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.4, 154.2,

140.4, 130.8, 130.0, 128.8, 125.6, 124.7, 124.3, 120.2, 113.9, 100.2,

71.9, 61.2, 55.4, 41.4, 24.4; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₉H₁₈⁷⁹Br₂F₃NO₃465.9648, found 465.9655.

4-(3′,3′-Dibromo-3′,4′,5′,6′-tetrahydrospiro[benzo[d][1,3]-

oxazine-4,2′-pyran]-2-yl)benzonitrile (6tBr): 126.7 mg (80% yield,

white solid, puriﬁed by SiO₂column chromatography eluting 5−10%

EtOAc/hexane); mp 192.6−193.0 °C; IR (neat) ν_max2952, 2229,

1

1633, 1255, 1066, 978, 764 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.27 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.1 Hz,

2H), 7.53−7.48 (m, 1H), 7.40−7.34 (m, 2H), 4.51−4.43 (m, 1H),

4.09−4.03 (m, 1H), 3.36 (td, J = 13.8, 3.6 Hz, 1H), 2.81−2.73 (m,

1H), 2.71−2.58 (m, 1H), 1.76 (d, J = 12.6 Hz, 1H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 152.5, 139.5, 136.2 132.3, 131.1, 129.1, 128.2,

127.0, 125.3, 120.4, 118.3, 114.8, 100.8, 71.3, 61.4, 41.4 24.3; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₁₅⁷⁹Br₂N₂O₂460.9495,

found 460.9491.

3′,3′-Dibromo-2-cyclohexyl-3′,4′,5′,6′-tetrahydrospiro[benzo[d]-

[1,3]oxazine-4,2′-pyran] (6vBr): 126.5 mg (72% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 5% EtOAc/hexane);

mp 109.5−110.1 °C; IR (neat) ν_max2930, 1650, 1078, 967, 763 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.84 (dd, J = 7.8, 1.2 Hz, 1H), 7.41

(td, J = 7.7, 1.5 Hz, 1H), 7.27−7.20 (m, 2H), 4.37−4.28 (m, 1H),

3.93 (dd, J = 11.4, 5.7 Hz, 1H), 3.28 (td, J = 13.4, 4.2 Hz, 1H), 2.71−

2.66 (m, 1H), 2.62−2.44 (m, 2H), 2.16−2.03 (m, 2H), 1.87−1.83

(m, 2H), 1.74−1.72 (m, 1H), 1.65−1.51 (m, 3H), 1.41−1.19 (m,

3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.2, 139.8, 130.7, 128.7,

125.6, 124.4, 120.0, 99.5, 72.3, 61.0, 43.9, 41.3, 30.1, 30.0, 25.8, 24.4;

HRMS (ESI-TOF) m/z [M

+

H]⁺(Br−79) calcd for

3′,3′-Dibromo-7-chloro-2-phenylspiro[benzo[d][1,3]oxazine-

4,2′-oxepane] (8eBr): 65.6 mg (29% yield, white solid, puriﬁed by

SiO₂column chromatography eluting 5% EtOAc/hexane); mp

115.8−116.5 °C; IR (neat) ν_max2919, 1634, 1593, 1234, 1067, 734,

C₁₈H₂₂⁷⁹Br₂NO₂442.0012, found 442.0011.

3′,3′-Dibromo-2,6′-diphenyl-3′,4′,5′,6′-tetrahydrospiro[benzo-

[d][1,3]oxazine-4,2′-pyran] (6xBr): 116.2 mg (67% yield, white solid,

puriﬁed by SiO₂column chromatography eluting 2% EtOAc/hexane);

(63:37); mp 181.6−182.1 °C; IR (neat) ν_max3063, 2929, 1635, 1252,

1063, 766, 693 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.23−8.20 (m,

1.07H, minor), 8.01 (dd, J = 7.8, 1.5 Hz, 0.53H, minor), 7.92 (dd, J =

8.1, 1.2 Hz, 1H, major), 7.76−7.73 (m, 2H, major), 7.57−7.15 (m,

17H, major+minor), 5.53 (dd, J = 12.6, 3.3 Hz, 0.56H, minor), 5.24

1

689 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.18−8.14 (m, 2H), 7.96

(d, J = 8.4 Hz, 1H), 7.59−7.47 (m, 3H), 7.40 (d, J = 2.1 Hz, 1H),

7.28 (dd, J = 8.6, 2.1 Hz, 1H), 4.31−4.24 (m, 1H), 3.99−3.89 (m,

1H), 3.23−3.13 (m, 1H), 2.91−2.83 (m, 1H), 2.22−2.13 (m, 2H),

2.11−2.00 (m, 1H), 1.97−1.86 (m, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 155.2, 140.5, 136.0, 131.9, 131.4, 129.6, 128.6, 127.9, 126.3,

4691

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

124.8, 121.9, 103.3, 77.6, 64.6, 46.5, 28.9, 24.2; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₉H₁₇⁷⁹Br₂³⁵ClNO₂483.9309, found

483.9311.

1675, 1520, 759 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.67 (br s,

1H), 8.51 (dd, J = 8.4, 0.8 Hz, 1H), 7.83−7.80 (m, 2H), 7.63 (dd, J =

8.1, 1.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.54−7.43 (m, 4H), 7.22

(td, J = 7.7, 1.2 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.2, 148.2, 142.7, 135.9, 134.9, 131.8, 130.3, 130.1,

128.8, 126.9, 124.0, 122.1, 119.2, 115.9, 99.2; HRMS (ESI−TOF) m/

z [M + H]⁺calcd for C₁₇H₁₃⁷⁹Br N O₂342.0124, found 342.0125.

N-(2-(3-Bromofuran-2-yl)-4-methylphenyl)benzamide (3bBr):

137.5 mg (94% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5−20% EtOAc/hexane); mp 139.6−139.9

°C; IR (neat) ν_max3246, 1642, 1530, 1318, 713 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.55 (br s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.82−7.79

(m, 2H), 7.55−7.43 (m, 5H), 7.29 (dd, J = 8.4, 1.5 Hz, 1H), 2.39 (s,

3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.1, 148.3, 142.7, 135.0,

133.8, 133.4, 131.7, 131.0, 130.4, 128.4, 126.9, 122.3, 119.3, 115.8,

99.0, 20.8; HRMS (ESI−TOF) m/z [M + H]⁺calcd for

C₁₈H₁₅⁷⁹BrNO₂356.0281, found 356.0272.

3′,3′-Dibromo-6-chloro-2-phenylspiro[benzo[d][1,3]oxazine-

4,2′-oxepane] (8fBr): 67.6 mg (22% yield, white solid, puriﬁed by

SiO₂column chromatography eluting 5% EtOAc/hexane); mp

1

161.3−161.6 °C; IR (neat) ν_max2925, 1640, 1248, 690 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 8.16 (d, 2H, J = 6.0 Hz), 8.030−8.025

(m, 1H), 7.57−7.49 (m, 3H), 7.43−7.40 (m, 1H), 7.32−7.26 (m,

1H), 4.31−4.26 (m, 1H), 3.99−3.93 (m, 1H), 3.21−3.14 (m, 1H),

2.89−2.85 (m, 1H), 2.19−2.13 (m, 2H), 2.10−1.91 (m, 2H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.4, 137.7, 131.8, 131.6,

131.5, 130.5, 128.6, 128.5, 127.8, 126.2, 124.6, 103.0, 77.2, 64.7, 46.5,

28.9, 24.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₉H₁₇⁷⁹Br₂³⁵ClNO₂483.9309, found 483.9311.

3′,3′-Dibromo-2-(4-methoxyphenyl)spiro[benzo[d][1,3]oxazine-

4,2′-oxepane] (8mBr): 62.8 mg (36% yield, white solid, puriﬁed by

SiO₂column chromatography eluting 5% EtOAc/hexane); mp

164.2−164.5 °C; IR (neat) ν_max2921, 1635, 1935, 1598, 1246,

1030, 764 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.13 (d, J = 8.7 Hz,

2H), 8.02 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.35−7.26 (m,

2H), 7.00 (d, J = 9.0 Hz, 2H), 4.30−4.23 (m, 1H), 3.97−3.90 (m,

1H), 3.87 (s, 3H), 3.22−3.13 (m, 1H), 2.90−2.83 (m, 1H), 2.20−

2.01 (m, 3H), 1.93−1.88 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃)

δ 162.4, 154.0, 139.2, 130.3, 129.6, 128.2, 125.9, 124.7, 124.2, 123.2,

113.9, 103.1, 78.1, 64.2, 55.4, 46.7, 29.0, 24.2; HRMS (ESI-TOF) m/

z [M + H]⁺calcd for C₂₀H₂₀⁷⁹Br₂NO₃479.9804, found 479.9810.

4-(3′,3′-Dibromospiro[benzo[d][1,3]oxazine-4,2′-oxepan]-2-yl)-

benzonitrile (8tBr): 58.9 mg (39% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 5% EtOAc/hexane); mp 177.0−

178.0 °C; IR (neat) ν_max2924, 1637, 1250, 1073, 736 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.28 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 7.2 Hz,

1H), 7.78 (d, J = 8.1 Hz, 2H), 7.50−7.45 (m, 1H), 7.39−7.34 (m,

2H), 4.32−4.25 (m, 1H), 4.01−3.92 (m, 1H), 3.18−3.09 (m, 1H),

2.91−2.86 (m, 1H), 2.18−2.05 (m, 3H), 1.94−1.89 (m, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 152.3, 138.4, 136.0, 132.3, 130.6,

N-(2-(3-Bromofuran-2-yl)-5-ﬂuorophenyl)benzamide (3cBr):

93.8 mg (97% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5−10% EtOAc/hexane); mp 132.3−133.0

°C; IR (neat) ν_max3454, 3110, 1684, 1545, 1256, 697 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.74 (br s, 1H), 8.42 (dd, J = 11.3, 2.4 Hz, 1H),

7.79 (d, J = 7.2 Hz, 2H), 7.61−7.44 (m, 5H), 6.91 (td, J = 7.8, 2.4 Hz,

1H), 6.64 (d, J = 1.5 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.1, 163.4 (d, C−F, ¹J_C−F= 247 Hz), 147.3, 142.8, 137.8 (d, C−F,

³J_C−F= 13 Hz), 134.5, 132.1, 131.6 (d, C−F, J_C−F= 10 Hz), 128.8,

3

126.9, 115.9, 114.6 (d, C−F, ³J_C−F= 3 Hz), 110.9 (d, C−F, ²J_C−F= 22

Hz), 109.0 (d, C−F, J_C−F= 28 Hz), 99.3; ¹⁹F NMR (376 MHz,

2

CDCl₃) δ − 111.1 to −111.2 (m); HRMS (ESI−TOF) m/z (M

+Na)⁺calcd for C₁₇H₁₁⁷⁹BrFNNaO₂381.9849, found 381.9844.

N-(2-(3-Bromofuran-2-yl)-4-ﬂuorophenyl)benzamide (3dBr):

217.1 mg (92% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 20% EtOAc/hexane); mp 103.8−104.1 °C;

IR (neat) ν_max3441, 3307, 1670, 1522, 867, 707 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.63 (br s, 1H), 8.42 (dd, J = 9.0, 3.0 Hz, 1H), 7.81

(d, J = 7.2 Hz, 2H), 7.56−7.52 (m, 2H), 7.49−7.44 (m, 2H), 7.38

(dd, J = 9.2, 2.7 Hz, 1H), 7.17 (td, J = 8.3, 3.0 Hz, 1H), 6.64 (d, J =

1.9 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.2, 158.7 (d, C−

F, ¹J_C−F= 243 Hz), 146.9 (d, C−F, ³J_C−F= 2 Hz), 143.0, 134.7, 131.9,

128.8, 126.9, 124.4 (d, C−F, ³J_C−F= 8 Hz), 121.1 (d, C−F, ³J_C−F= 8

Hz), 116.9 (d, C−F, ²J_C−F= 22 Hz), 116.4 (d, C−F, ²J_C−F= 24 Hz),

116.1, 99.8; ¹⁹F NMR (376 MHz, CDCl₃) δ − 120.6 to −120.7 (m);

HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₂⁷⁹BrFNO₂

360.0030, found 360.0032.

128.4, 128.2, 127.2, 125.3, 123.4, 118.3, 114.8, 103.8, 77.4, 64.6, 46.5,

29.0, 24.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₂₀H₁₇⁷⁹Br₂N₂O₂474.9651, found 474.9654.

2′,2′-Dibromo-2-cyclohexylspiro[benzo[d][1,3]oxazine-4,1′-cy-

cloheptane] (8vBr): 262.3 mg (65% yield, white solid, puriﬁed by

SiO₂column chromatography eluting 5% EtOAc/hexane); mp

1

127.4−127.8 °C; IR (neat) ν_max2928, 1655, 1119, 768 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 7.97 (dd, J = 7.8, 1.2 Hz, 1H), 7.38 (td, J

= 7.5, 1.2 Hz, 1H), 7.25 (td, J = 7.5, 1.5 Hz, 1H), 7.21−7.18 (m, 1H),

4.16−4.09 (m, 1H), 3.89−3.79 (m, 1H), 3.09−3.00 (m, 1H), 2.86−

2.79 (m, 1H), 2.49 (td, J = 11.7, 3.3 Hz, 1H), 2.14−1.93 (m, 5H),

1.87−1.72 (m, 4H), 1.66−1.50 (m, 2H), 1.42−1.18 (m, 3H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.7, 138.6, 130.2, 128.1, 125.9,

N-(2-(3-Bromofuran-2-yl)-5-chlorophenyl)benzamide (3eBr):

81.0 mg (91% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 1% EtOAc/DCM); mp 137.6−138.0 °C;

IR (neat) ν_max3430, 2923, 2361, 1676, 705 cm⁻¹; H NMR (300

1

MHz, CDCl₃) δ 8.73 (br s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 7.81−7.79

(m, 2H), 7.58−7.45 (m, 5H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 6.65 (d,

J = 2.0 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.1, 147.3,

143.0, 137.0, 136.2, 134.5, 132.2, 131.0, 128.9, 126.9, 124.1, 121.9,

117.2, 116.1, 99.6; HRMS (ESI−TOF) m/z [M + H]⁺calcd for

C₁₇H₁₂⁷⁹Br³⁵ClNO₂375.9735, found 375.9733.

124.3 123.0, 102.4, 78.3, 64.2, 47.1, 44.2, 30.1, 29.8, 29.1, 25.9, 25.8,

23.9; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₂₄⁷⁹Br₂NO₂

456.0168, found 456.0167.

Procedure for Conversion of Spirocycles 2Br to 3-

Bromofurans 3Br (Representative Case: Synthesis of 3-

Bromofuran 3aBr). To 10 mL round-bottomed ﬂask containing a

magnetic stir bar was added compound 2aBr (472.4 mg, 1.117 mmol,

1.00 equiv), followed by 5.0 mL of NMP. The resulted clear colorless

solution was then added with t-BuOK (175.0 mg, 1.559 mmol, 1.40

equiv), which immediately turned the reaction mixture to dark purple.

The mixture was allowed to stir at room temperature for 10 min.

Upon completion (judged by TLC), the reaction mixture was diluted

with 1 M aqueous HCl and water. The separated aqueous layer was

extracted with EtOAc. Combined organic phases were washed with

saturated aqueous NaCl, dried over anhydrous Na₂SO₄, ﬁltered, and

concentrated in vacuo to yield a crude brown material. This material

was puriﬁed by SiO₂column chromatography eluting 10% EtOAc/

hexane to furnish 375.3 mg (98%) of product 3aBr as a brown solid.

N-(2-(3-Bromofuran-2-yl)phenyl)benzamide (3aBr): 375.3 mg

(98% yield, brown solid, puriﬁed by SiO₂column chromatography

eluting 5% EtOAc/hexane); mp 91.2−91.8 °C; IR (neat) ν_max3325,

N-(2-(3-Bromofuran-2-yl)-4-chlorophenyl)benzamide (3fBr):

153.2 mg (84% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 137.1−137.5 °C;

IR (neat) ν_max3430, 2923, 2361, 1676, 705 cm⁻¹; H NMR (400

1

MHz, CDCl₃) δ 8.66 (br s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.81 (d, J =

7.2 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.58−7.53 (m, 2H), 7.50−7.42

(m, 3H), 6.65 (d, J = 1.6 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 165.2, 146.7, 143.2, 134.6, 134.5, 132.1, 130.1, 129.6, 129.1,

128.9, 127.0, 123.4, 120.5, 116.1, 99.9; HRMS (ESI−TOF) m/z [M +

H]⁺calcd for C₁₇H₁₂⁷⁹Br³⁵ClNO₂375.9734, found 375.9731.

N-(2-(3-Bromofuran-2-yl)-4-(triﬂuoromethyl)phenyl)benzamide

(3gBr): 211.0 mg (70% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 2−10% EtOAc/hexane); mp 96.0−96.3 °C;

IR (neat) ν_max3439, 3067, 1687, 1522, 1329, 1122, 703 cm⁻¹; H

1

NMR (300 MHz, CDCl₃) δ 8.85 (br s, 1H), 8.73 (d, J = 8.7 Hz, 1H),

7.91 (s, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.60−

4692

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

7.59 (m, 1H), 7.56−7.54 (m, 1H), 7.50−7.45 (m, 2H), 6.67 (d, J =

1.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 165.3, 146.7, 143.3,

7.49−7.44 (m, 1H), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 6.97−6.92 (m,

2H), 6.63 (d, J = 2.0 Hz, 1H), 3.85 (s, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 164.7, 162.5, 148.2, 142.7, 136.1, 130.2, 130.1, 128.8, 127.1,

123.7, 122.1, 119.0, 115.9, 114.0, 99.1, 55.4; HRMS (ESI−TOF) m/z

[M + H]⁺calcd for C₁₈H₁₅⁷⁹BrNO₃372.0230, found 372.0226.

N-(2-(3-Bromofuran-2-yl)phenyl)-3,4,5-trimethoxybenzamide

(3nBr): 291.6 mg (66% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 20−30% EtOAc/hexane); mp 104.5−105.3

°C; IR (neat) ν_max3312, 2922, 2361, 1500, 1126, 759 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.56 (br s, 1H), 8.48 (d, J = 8.1 Hz, 1H), 7.60−

7.45 (m, 3H), 7.21 (t, J = 7.2 Hz, 1H), 7.04 (br s, 2H), 6.62 (br s,

1H), 3.89 (br s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 164.7,

153.1, 148.1, 142.8, 141.0, 135.9, 130.3, 130.1, 130.0, 123.9, 121.7,

119.0, 115.6, 104.2, 99.1, 60.8, 56.1; HRMS (ESI−TOF) m/z [M +

H]⁺calcd for C₂₀H₁₉⁷⁹BrNO₅432.0441, found 432.0440.

3

138.9, 134.3, 132.3, 128.9, 127.2 (q, C−F, J_C−F= 4 Hz), 127.1 (q,

3

1

C−F, J_C−F= 4 Hz), 126.9, 126.0, 123.8 (q, C−F, J_C−F= 269 Hz),

121.8, 118.9, 116.2, 100.3; ¹⁹F NMR (376 MHz, CDCl₃) δ − 65.5

(s); HRMS (ESI−TOF) m/z (M+Na)⁺calcd for

C₁₈H₁₁⁷⁹BrF₃NNaO₂431.9817, found 431.9813.

N-(2-(3-Bromofuran-2-yl)-4-cyanophenyl)benzamide (3hBr):

207.7 mg (89% yield, yellow solid, puriﬁed by SiO₂column

chromatography eluting 1% EtOAc/DCM); mp 182.4−182.7 °C;

1

IR (neat) ν_max3428, 3128, 2224 1698, 1512, 1303 701 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 8.91 (br s, 1H), 8.80 (d, J = 9.0 Hz, 1H),

7.95 (d, J = 1.8 Hz, 1H), 7.83−7.80 (m, 2H), 7.76 (dd, J = 8.7, 2.1

Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.59−7.56 (m, 1H), 7.53−7.48 (m,

2H), 6.71 (d, J = 1.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.3, 145.9, 143.6, 139.9, 134.1, 133.92, 133.86, 132.5, 129.0, 127.0,

121.8, 119.1, 118.3, 116.4, 107.2, 100.8; HRMS (ESI−TOF) m/z [M

+ H]⁺calcd for C₁₈H₁₂⁷⁹BrN₂O₂367.0077, found 367.0077.

N-(2-(3-Bromofuran-2-yl)-4-nitrophenyl)benzamide (3iBr): 58.7

mg (79% yield, yellow solid, puriﬁed by SiO₂column chromatography

eluting 5−10% EtOAc/hexane); mp 186.3−186.6 °C; IR (neat) ν_max

3440, 2922, 1698, 1506, 1342, 693 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 9.03 (br s, 1H), 8.88 (d, J = 6.9 Hz, 1H), 8.60 (d, J = 1.8

Hz, 1H), 8.34 (dd, J = 6.9, 2.1 Hz, 1H), 7.84 (d, J = 5.7 Hz, 2H), 7.65

(d, J = 1.5 Hz, 1H), 7.60 (t, J = 5.4 Hz, 1H), 7.52 (t, J = 5.7 Hz, 2H),

6.73 (d, J = 1.2 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.3,

145.8, 143.7, 143.0, 141.5, 134.1, 132.6, 129.1, 127.0, 125.7, 125.6,

121.2, 118.7, 116.5, 101.1; HRMS (ESI−TOF) m/z [M + H]⁺calcd

for C₁₇H₁₂⁷⁹BrN₂O₄386.9975, found 386.9976.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-(triﬂuoromethoxy)-

benzamide (3oBr): 119.5 mg (96% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 5% EtOAc/hexane); mp 137.7−

138.3 °C; IR (neat) ν_max3301, 2925, 1652, 1266, 762 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.62 (br s, 1H), 8.44 (d, J = 8.1 Hz, 1H), 7.86

(d, J = 8.4 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H),

7.48 (t, J = 7.5 Hz, 1H), 7.31−7.21 (m, 3H), 6.64 (d, J = 1.2 Hz, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 163.9, 151.7, 148.0, 142.8, 135.5,

133.3, 130.3, 130.2, 128.8, 124.3, 122.3, 120.7, 120.3 (q, C−F, ¹J_C−F

=

258 Hz), 119.4, 116.0, 99.2; HRMS (ESI−TOF) m/z [M + H]⁺calcd

for C₁₈H₁₂⁷⁹BrF₃NO₃425.9947, found 425.9946.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-ﬂuorobenzamide (3pBr):

80.7 mg (87% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5−10% EtOAc/hexane); mp 126.1−126.3

°C; IR (neat) ν_max3458, 3104, 1616, 1237, 751 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.58 (br s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.86−7.79

(m, 2H), 7.64 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H),

7.51−7.46 (m, 1H), 7.22 (dd, J = 7.5, 1.2 Hz, 1H), 7.18−7.11 (m,

2H), 6.64 (dd, J = 2.1, 0.9 Hz, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 164.8 (d, J_C−F= 251 Hz), 164.1, 148.1, 142.7, 135.7, 131.0

(d, J_C−F= 3 Hz), 130.2 (d, J_C−F= 8 Hz), 129.3 (d, J_C−F= 9 Hz), 124.2,

122.3, 119.3, 115.93, 115.90, 115.6, 99.1; ¹⁹F NMR (376 MHz,

CDCl₃) δ − 110.5 to −110.6 (m); HRMS (ESI−TOF) m/z [M +

H]⁺calcd for C₁₇H₁₂⁷⁹BrFNO₂360.0030, found 360.0026.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-methylbenzamide (3jBr):

80.5 mg (93% yield, orange solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 94.2−94.6 °C; IR

1

(neat) ν_max3442, 2923, 1675, 1304, 945, 758 cm⁻¹; H NMR (300

MHz, CDCl₃) δ 8.70 (br s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.74 (d, J =

8.1 Hz, 2H), 7.65 (dd, J = 7.8, 1.2 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H),

7.52−7.47 (m, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.5 Hz,

1H), 6.64 (d, J = 1.8 Hz, 1H), 2.42 (s, 3H) ; ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.1, 148.1, 142.7, 142.3, 136.0, 132.0, 130.1, 130.0,

129.4, 126.8, 123.8, 122.1, 119.0, 115.8, 99.0, 21.4; HRMS (ESI−

TOF) m/z (M+Na)⁺calcd for C₁₈H₁₄⁷⁹BrNNaO 378.0100, found

378.0095.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-chlorobenzamide (3qBr):

56.2 mg (86% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 136.9−137.1 °C;

N-(2-(3-Bromofuran-2-yl)phenyl)-2-methoxybenzamide (3kBr):

47.4 mg (75% yield, yellow oil, puriﬁed by SiO₂column

chromatography eluting 1% EtOAc/DCM); IR (neat) ν_max3335,

1

IR (neat) ν_max2922, 2852, 1681, 756 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 8.60 (br s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.76−7.73 (m,

2H), 7.63 (dd, J = 7.8, 1.5 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.50−

7.42 (m, 3H), 7.26−7.20 (m, 1H), 6.63 (d, J = 2.1 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 164.2, 148.1, 142.8, 138.1, 135.6, 133.3,

130.3, 130.2, 129.0, 128.3, 124.3, 122.2, 119.3, 116.0, 99.2; HRMS

(ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₂⁷⁹Br³⁵ClNO₂375.9735,

found 375.9726.

1

1664, 1525, 1308, 753 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 10.03

(br s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 7.8, 1.8 Hz, 1H),

7.53 (d, J = 1.8 Hz, 1H), 7.50−7.43 (m, 3H), 7.19 (t, J = 7.5 Hz, 1H),

7.11 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 1.8 Hz,

1H), 3.76 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 163.3, 157.3,

148.5, 143.0, 137.0, 133.2, 132.6, 130.6, 130.3, 123.6, 122.5, 121.8,

121.4, 119.5, 115.3, 111.3, 99.4, 55.9; HRMS (ESI−TOF) m/z (M

+Na)⁺calcd for C₁₈H₁₄⁷⁹BrNNaO₃394.0049, found 394.0054.

N-(2-(3-Bromofuran-2-yl)phenyl)-3-methoxybenzamide (3lBr):

442.5 mg (98% yield, yellow oil, puriﬁed by SiO₂column

chromatography eluting 10% EtOAc/hexane); IR (neat) ν_max3433,

2-Bromo-N-(2-(3-bromofuran-2-yl)phenyl)benzamide (3rBr):

144.0 mg (96% yield, yellow oil, puriﬁed by SiO₂column

chromatography eluting 2−10% EtOAc/hexane); IR (neat) ν_max

3411, 3062, 1679, 1517, 1306, 946, 758 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.47 (d, J = 8.4 Hz, 1H), 8.37 (br s, 1H), 7.63−7.57

(m, 3H), 7.50−7.44 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.30−7.21 (m,

2H), 6.55 (d, J = 2.1 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.4, 147.7, 142.8 137.6, 135.3, 133.5, 131.5, 130.2, 130.1, 129.6,

127.6, 124.4, 122.4, 119.5, 119.1, 115.6, 99.2; HRMS (ESI−TOF) m/

z [M + H]⁺calcd for C₁₇H₁₂⁷⁹Br₂NO₂419.9229, found 419.9228.

4-Bromo-N-(2-(3-bromofuran-2-yl)phenyl)-2-ﬂuorobenzamide

(3sBr): 160.7 mg (88% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 1% EtOAc/hexane); IR (neat) ν_max3430,

2923, 1680, 1538, 1448, 1306, 760 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 9.13 (d, J = 14.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.05 (t,

J = 8.4 Hz, 1H), 7.61 (dd, J = 7.5 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H),

7.49−7.41 (m, 2H), 7.31 (dd, J = 11.7, 1.5 Hz, 1H), 7.25−7.20 (m,

1H), 6.61 (d, J = 2.1 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

160.2 (d, C−F, ³J_C−F= 4 Hz), 159.8 (d, C−F, ¹J_C−F= 250 Hz), 147.6,

1

3320 1676, 1582, 1521, 1307, 1046, 759 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 8.67 (br s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 7.7,

1.5 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.50−7.44 (m, 1H), 7.41−7.40

(m, 1H), 7.38−7.30 (m, 2H), 7.22 (td, J = 7.7, 1.2 Hz, 1H), 7.08−

7.04 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 165.0, 159.9, 148.1, 142.8, 136.4, 135.9, 130.3,

130.1, 129.7, 124.0, 122.1, 119.2, 118.6, 118.2, 115.9, 112.3, 99.2,

55.4; HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₈H₁₅⁷⁹BrNO₃

372.0230, found 372.0223.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-methoxybenzamide (3mBr):

84.9 mg (≥99% yield, yellow solid, puriﬁed by SiO₂column

chromatography eluting 20% EtOAc/hexane); mp 90.2−90.4 °C;

1

IR (neat) ν_max3440, 2925, 1527, 1246, 758 cm⁻¹; H NMR (300

MHz, CDCl₃) δ 8.59 (br s, 1H), 8.49 (dd, J = 8.3, 0.8 Hz, 1H), 7.80−

7.75 (m, 2H), 7.62 (dd, J = 7.8, 1.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H),

3

142.8, 135.7, 133.5 (d, C−F, J_C−F= 3 Hz), 130.2, 130.1, 128.5 (d,

4693

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

3

C−F, J_C−F= 3 Hz), 126.9 (d, C−F, J_C−F= 10 Hz), 124.4, 122.7,

130.0, 129.9, 128.6, 127.0, 125.4, 123.9, 122.0, 121.9, 119.1, 114.3,

109.2, 101.0, 55.3; HRMS (ESI−TOF) m/z [M + Na]⁺calcd for

C₂₄H₁₈⁷⁹BrNNaO₃470.0362, found 470.0359.

3

2

120.4 (d, C−F, J_C−F= 11 Hz), 119.64, 119.63 (d, C−F, J_C−F= 28

Hz), 115.6, 99.2; ¹⁹F NMR (376 MHz, CDCl₃) δ − 114.5 to −114.6

(m); HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₁⁷⁹Br₂FNO₂

437.9135, found 437.9135.

Procedure for Intramolecular Ullmann Coupling of 3-

Bromofurans 3Br to Indolofurans 4 (Representative Case:

Synthesis of Indolofuran 4a). A 10 mL round-bottomed ﬂask

containing a magnetic stir bar was charged with substrate 3aBr (101.7

mg, 0.297 mmol, 1.00 equiv), CuTC (2.9 mg, 0.015 mmol, 0.05

equiv), Cs₂CO₃(97.8 mg, 0.300 mmol, 1.01 equiv), DMEDA (13 μL,

10.7 mg, 0.121 mmol, 0.41 equiv), and 2 mL of dry 1,4-dioxane. The

resulted mixture was heated in an oil bath at reﬂux under argon for 3

h. Upon completion (judged by TLC), the reaction was cooled down

to room temperature, and the mixture was diluted with saturated

aqueous NH₄Cl. The separated aqueous phase was extracted with

EtOAc. Combined organic phases were washed with saturated

aqueous NaCl, dried over anhydrous Na₂SO₄, ﬁltered, and

concentrated under a vacuum to give the crude material. The crude

product was puriﬁed by SiO₂column chromatography eluting 10%

EtOAc/hexane to give 69.7 mg (≥99%) of the desired product (4a)

as a white solid.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-cyanobenzamide (3tBr):

550.5 mg (74% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/DCM); mp 170.7−171.7 °C;

IR (neat) ν_max3386, 2959, 1677, 1518, 1310, 1039, 749 cm⁻¹; H

1

NMR (300 MHz, CDCl₃) δ 8.63 (br s, 1H), 8.43 (d, J = 8.4 Hz, 1H),

7.91 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 7.5,

0.2 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.53−7.47 (m, 1H), 7.27 (t, J =

7.5 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 163.4, 147.9, 142.9, 138.8, 135.2, 132.6, 130.4, 130.3, 127.6,

124.8, 122.3, 119.5, 117.8, 116.1, 115.5, 99.4; HRMS (ESI−TOF) m/

z [M + H]⁺calcd for C₁₈H₁₂⁷⁹BrN₂O₃367.0077, found 367.0083.

N-(2-(3-Bromofuran-2-yl)phenyl)-4-nitrobenzamide (3uBr):

368.2 mg (74% yield, yellow solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/DCM); mp 182.5−183.4 °C;

IR (neat) ν_max3323, 2921, 1655, 1516, 1345, 712 cm⁻¹; H NMR

1

The reaction of 3aBr at a larger scale (374.6 mg, 1.095 mmol) was

conducted, employing the same procedure to aﬀord 267.7 mg (94%)

of 4a as a white solid.

(300 MHz, CDCl₃) δ 8.67 (br s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.32

(d, J = 8.7 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.67 (dd, J = 7.8, 1.5 Hz,

1H), 7.57 (d, J = 1.8 Hz, 1H), 7.53−7.48 (m, 1H), 7.30−7.25 (m,

1H), 6.66 (d, J = 2.1 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

163.2, 149.8, 147.9, 142.9, 140.5, 135.1, 130.4, 130.3, 128.1, 124.8,

124.0, 122.4, 119.6, 116.1, 99.4; HRMS (ESI−TOF) m/z [M + H]⁺

calcd for C₁₇H₁₂⁷⁹BrN₂O₄386.9975, found 386.9973.

N-(2-(3-Bromofuran-2-yl)phenyl)cyclohexanecarboxamide

(3vBr): 104.6 mg (61% yield, brown solid, puriﬁed by SiO₂column

chromatography eluting 1% EtOAc/DCM); mp 102.7−103.1 °C; IR

(neat) ν_max3222, 2924, 2854, 1651, 1535, 1450, 760 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.34 (d, J = 8.1 Hz, 1H), 7.83 (br s, 1H), 7.57−

7.54 (m, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.63

(d, J = 1.8 Hz, 1H), 2.19 (tt, J = 11.7, 3.3 Hz, 1H), 1.95−1.91 (m,

2H), 1.82−1.79 (m, 2H), 1.70−1.62 (m, 1H), 1.51−1.40 (m, 2H),

1.36−1.20 (m, 3H) ; ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 174.1,

148.2, 142.7, 136.0, 130.2, 130.1, 123.7, 122.1, 118.9, 115.7, 99.0,

46.6, 29.5, 25.7, 25.6; HRMS (ESI−TOF) m/z [M + H]⁺calcd for

C₁₇H₁₉⁷⁹BrNO₂348.0594, found 348.0593.

N-(2-(3-Bromofuran-2-yl)phenyl)pivalamide (3wBr): 193.3 mg

(78% yield, yellow oil, puriﬁed by SiO₂column chromatography

eluting 1% EtOAc/DCM); IR (neat) ν_max3451, 2964, 1686, 1510,

1300, 1158, 947, 761 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J

= 8.4 Hz, 1H), 8.17 (br s, 1H), 7.57 (dd, J = 7.7, 1.8 Hz, 1H), 7.53 (d,

J = 1.8 Hz, 1H), 7.45−7.39 (m, 1H), 7.16 (td, J = 7.5, 0.6 Hz, 1H),

6.63 (d, J = 2.1 Hz, 1H), 1.24 (s, 9H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 176.5, 148.3, 142.5, 136.2, 130.2, 130.0, 123.6, 121.9, 118.8,

115.8, 99.0, 39.8, 27.4; HRMS (ESI−TOF) m/z [M + H]⁺calcd for

C₁₅H₁₇⁷⁹BrNO₂322.0437, found 322.0441.

N-(2-(3-Bromo-5-phenylfuran-2-yl)phenyl)benzamide (3xBr):

114.4 mg (93% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 10% EtOAc/hexane); mp 117.6−117.8 °C;

IR (neat) ν_max3438, 2924, 1650, 1581, 1525, 1450, 1340, 958, 759,

700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (br s, 1H), 8.56 (d, J

= 8.4 Hz, 1H), 7.80−7.77 (m, 2H), 7.73 (dd, J = 8.4, 1.2 Hz, 1H),

7.62−7.59 (m, 2H), 7.51−7.48 (m, 1H), 7.46−7.43 (m, 1H), 7.41−

7.33 (m, 3H), 7.30−7.21 (m, 3H), 6.85 (s, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 165.2, 153.9, 147.3, 135.9, 134.7, 131.8, 130.2, 130.0,

129.0, 128.9, 128.65, 128.59, 127.0, 124.0, 123.9, 122.1, 119.0, 110.7,

(4H-Furo[3,2-b]indol-4-yl)(phenyl)methanone (4a): 69.7 mg

(≥99% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 10% EtOAc/hexane); mp 97.9−98.7 °C; IR (neat) ν_max3125,

1676, 1354, 751 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.47−8.43 (m,

1H), 7.73−7.70 (m, 2H), 7.69−7.60 (m, 2H), 7.56−7.51 (m, 2H),

7.38−7.31 (m, 3H), 5.61 (d, J = 1.8 Hz, 1H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 168.2, 145.2, 144.3, 139.9, 135.2, 131.8, 130.1, 128.6,

128.4, 124.5, 124.3, 118.6, 117.8, 116.3, 103.0; HRMS (ESI−TOF)

m/z [M + H]⁺calcd for C₁₇H₁₂NO₂262.0863, found 262.0864.

(7-Methyl-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4b):

53.1 mg (87% yield, yellow oil, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); IR (neat) ν_max2923,

1683, 1354, 695 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J = 8.7

Hz, 1H), 7.72−7.69 (m, 2H), 7.65−7.60 (m, 1H), 7.53 (t, J = 7.8 Hz,

2H), 7.47 (s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.15 (d J = 8.4 Hz, 1H),

5.59 (d, J = 1.8 Hz, 1H), 2.48 (s, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 168.0, 145.0, 144.2, 138.1, 135.3, 134.0, 131.6, 130.2, 128.5,

128.3, 125.6, 118.7, 117.4, 116.4, 102.9, 21.4; HRMS (ESI−TOF) m/

z (M+Na)⁺calcd for C₁₈H₁₃NNaO₂298.0839, found 298.0834.

(6-Fluoro-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4c): 44.8

mg (94% yield, yellow oil, puriﬁed by SiO₂column chromatography

eluting 2% EtOAc/hexane); IR (neat) ν_max3129, 1686, 1354, 700

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.25 (dd, J = 10.5, 2.1 Hz, 1H),

7.73−7.70 (m, 2H), 7.67−7.61 (m, 1H), 7.60−7.52 (m, 3H), 7.29 (d,

J = 2.1 Hz, 1H), 7.10 (td, J = 8.7, 2.4 Hz, 1H), 5.59 (d, J = 1.8 Hz,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 168.2, 160.5 (d, C−F, ¹J_C−F

= 240 Hz), 144.9 (d, C−F, ³J_C−F= 1 Hz), 143.7, 140.0 (d, C−F, ³J_C−F

3

= 12 Hz), 134.7, 132.0, 130.3 (d, C−F, J_C−F= 3 Hz), 128.6, 128.4,

116.7 (d, C−F, ³J_C−F= 10 Hz), 115.2 (d, C−F, ³J_C−F= 2 Hz), 112.1

2

(d, C−F, J_C−F= 24 Hz), 105.7 (d, C−F, J_C−F= 29 Hz), 103.0; ¹⁹F

NMR (376 MHz, CDCl₃) δ − 119.25 to −119.32 (m); HRMS (ESI−

TOF) m/z [M + H]⁺calcd for C₁₇H₁₁FNO₂280.0768, found

280.0768.

(7-Fluoro-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4d): 75.9

mg (95% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 5% EtOAc/hexane); mp 125.1−125.5 °C; IR (neat) ν_max

1

2926, 1687, 1438, 1351, 1135, 860, 695 cm⁻¹; H NMR (300 MHz,

101.0; HRMS (ESI−TOF) m/z [M

+

Na]⁺calcd for

C₂₃H₁₆⁷⁹BrNNaO₂440.0257, found 440.0264.

CDCl₃) δ 8.42 (dd, J = 9.3, 4.8 Hz, 1H), 7.71−7.69 (m, 2H), 7.66−

7.61 (m, 1H), 7.56−7.51 (m, 2H), 7.32−7.28 (m, 2H), 7.03 (td, J =

9.2, 2.4 Hz, 1H), 5.57 (d, J = 1.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 159.8 (d, C−F, ¹J_C−F= 240 Hz), 158.2, 145.8, 143.5 (d, C−

N-(2-(3-Bromo-5-(4-methoxyphenyl)furan-2-yl)phenyl)-

benzamide (3yBr): 58.8 mg (99% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 5% EtOAc/hexane); mp 139.1−

139.4 °C; IR (neat) ν_max3439, 1677, 1498, 1250, 1027, 958, 832, 758,

706 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (br s, 1H), 8.56 (d, J

= 8.4 Hz, 1H), 7.80−7.77 (m, 2H), 7.72 (dd, J = 7.8, 1.2 Hz, 1H),

7.53 (d, J = 8.7 Hz, 2H), 7.50−7.41 (m, 2H), 7.30−7.20 (m, 3H),

6.89 (d, J = 9.0 Hz, 2H), 6.70 (s, 1H), 3.83 (s, 3H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 165.1, 159.9, 154.0, 146.5, 135.8, 134.8, 131.7,

3

F, J_C−F= 4 Hz), 136.0 (d, C−F, J_C−F= 1 Hz), 134.9, 131.9, 131.5

128.6, 128.3, 119.3 (d, C−F, ³J_C−F= 11 Hz), 118.4 (d, C−F, ³J_C−F= 9

Hz), 111.6 (d, C−F, ²J_C−F= 25 Hz), 102.9, 102.6 (d, C−F, ²J_C−F= 26

Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ − 120.7 to −120.8 (m); HRMS

(ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₁FNO₂280.0768, found

280.0775.

4694

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(6-Chloro-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4e):

50.9 mg (84% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 138.6−139.1 °C;

(4H-Furo[3,2-b]indol-4-yl)(2-methoxyphenyl)methanone (4k):

11.0 mg (29% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5−10% EtOAc/hexane); mp 125.0−125.4

°C; IR (neat) ν_max2933, 1685, 1359, 1021, 752 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 8.60 (br s, 1H), 7.67−7.65 (m, 1H), 7.55 (t, J = 7.6

Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.35−7.28 (m, 3H), 7.12 (t, J = 7.6

Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.31 (br s, 1H), 3.73 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.5, 156.5, 145.3, 144.4,

139.4, 132.1, 129.9 128.4, 125.6, 124.6, 124.3, 120.9, 118.7, 117.9,

116.2, 111.4, 102.1, 55.7; HRMS (ESI−TOF) m/z (M+Na)⁺calcd

for C₁₈H₁₃NNaO₃314.0788, found 314.0790.

1

IR (neat) ν_max2924, 1687, 1349, 1295, 698 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 8.53 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.66−7.62 (m,

1H), 7.56−7.52 (m, 3H), 7.32−7.30 (m, 2H), 5.56 (d, J = 1.6 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.1, 145.5, 143.5, 139.9,

134.6, 132.0, 130.6, 130.2, 128.6, 128.3, 124.6, 118.1, 116.9, 116.7,

102.9; HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₁³⁵ClNO₂

296.0473, found 296.0471.

(7-Chloro-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4f): 61.3

mg (92% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 2−10% EtOAc/hexane); mp 126.6−126.9 °C; IR (neat) ν_max

(4H-Furo[3,2-b]indol-4-yl)(3-methoxyphenyl)methanone (4l):

292.3 mg (87% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 65.8−66.2 °C; IR

1

3130, 1684, 1349, 1304, 699 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

1

(neat) ν_max2939, 1683, 1307, 1040, 748 cm⁻¹; H NMR (300 MHz,

8.39 (d, J = 8.9 Hz, 1H), 7.73−7.71 (m, 2H), 7.67−7.63 (m, 2H),

7.55 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.9,

2.1 Hz, 1H), 5.60 (d, J = 1.9 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 168.1, 145.9, 143.0, 138.1, 134.7, 132.0, 131.3, 129.9, 128.7,

128.4, 124.4, 119.5, 118.8, 116.1, 102.9; HRMS (ESI−TOF) m/z [M

+ H]⁺calcd for C₁₇H₁₁³⁵ClNO₂296.0473, found 296.0469.

CDCl₃) δ 8.46−8.44 (m, 1H), 7.68−7.65 (m, 1H), 7.43 (t, J = 7.8

Hz, 1H), 7.37−7.32 (m, 3H), 7.29−7.26 (m, 1H), 7.24−7.23 (m,

1H), 7.15 (dd, J = 8.3, 2.4 Hz, 1H), 5.67 (d, J = 1.8 Hz, 1H), 3.84 (s,

3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 168.0, 159.6, 145.2, 144.3,

139.8, 136.3, 130.1, 129.7, 124.5, 124.2, 120.5, 118.6, 118.0, 117.8,

116.3, 113.1, 103.0, 55.5; HRMS (ESI−TOF) m/z [M + H]⁺calcd

for C₁₈H₁₄NO₃292.0968, found 292.0963.

(4H-Furo[3,2-b]indol-4-yl)(4-methoxyphenyl)methanone (4m):

53.3 mg (86% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 10−20% EtOAc/hexane); mp 100.6−101.0

°C; IR (neat) ν_max2989, 1670, 1300, 732 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.42−8.36 (m, 1H), 7.76−7.71 (m, 2H), 7.69−7.64 (m,

1H), 7.35−7.29 (m, 3H), 7.04−6.99 (m, 2H), 5.86 (d, J = 2.1 Hz,

1H), 3.90 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 167.8, 162.7,

145.1, 144.1, 139.9, 131.0, 130.4, 127.0, 124.3, 123.9, 118.4, 117.6,

116.2, 113.8, 103.1, 55.5; HRMS (ESI−TOF) m/z [M + H]⁺calcd

for C₁₈H₁₄NO₃292.096, found 292.0966.

Phenyl(7-(triﬂuoromethyl)-4H-furo[3,2-b]indol-4-yl)methanone

(4g): 126.8 mg (76% yield, beige solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 92.9−93.2 °C; IR

1

(neat) ν_max1689, 1354, 1303, 1116, 697 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 8.50 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.73−7.62 (m, 3H),

7.56−7.51 (m, 3H), 7.34 (d, J = 1.8 Hz, 1H), 5.63 (d, J = 1.8 Hz,

1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 168.1, 146.2, 143.2, 141.1,

2

134.4, 132.2, 131.7, 128.7, 128.5, 126.3 (q, C−F, J_C−F= 32 Hz),

124.4 (q, C−F, ¹J_C−F= 270 Hz), 121.0 (q, C−F, ³J_C−F= 4 Hz), 118.0,

3

117.8, 113.5 (q, C−F, J_C−F= 4 Hz), 102.9; ¹⁹F NMR (376 MHz,

CDCl₃) δ − 64.6 (s); HRMS (ESI−TOF) m/z [M + H]⁺calcd for

C₁₈H₁₁F₃NO₂330.0736, found 330.0735.

4-Benzoyl-4H-furo[3,2-b]indole-7-carbonitrile (4h): 104.6 mg

(89% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 70% DCM/hexane); mp 184.7−185.0 °C; IR (neat) ν_max

(4H-Furo[3,2-b]indol-4-yl)(3,4,5-trimethoxyphenyl)methanone

(4n): 65.4 mg (81% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 10% EtOAc/hexane); mp 102.6−103.7 °C;

1

2924, 2227, 1683, 1355, 728 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

1

IR (neat) ν_max2940, 1682, 1584, 1353, 1124, 754 cm⁻¹; H NMR

8.52 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.74−7.73 (m,

2H), 7.71−7.67 (m, 1H), 7.59−7.54 (m, 3H), 7.41 (d, J = 2.0 Hz,

1H), 5.66 (d, J = 2.0 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

168.0, 146.7, 142.4, 141.1, 134.0, 132.5, 132.1, 128.7, 128.5, 127.4

120.4, 119.1, 118.23, 118.16, 107.4, 102.8; HRMS (ESI−TOF) m/z

[M + H]⁺calcd for C₁₈H₁₁N₂O₂287.0815, found 287.0822.

(300 MHz, CDCl₃) δ 8.44−8.41 (m, 1H), 7.71−7.68 (m, 1H), 7.38−

7.32 (m, 3H), 6.99 (s, 2H), 5.86 (d, J = 2.1 Hz, 1H), 3.97 (s, 3H),

3.87 (s, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 167.6, 153.2, 145.2,

144.3, 141.1, 139.8, 130.1 129.9, 124.5, 124.2, 118.5, 117.7, 116.3,

106.0, 103.1, 61.1, 56.3; HRMS (ESI−TOF) m/z (M+Na)⁺calcd for

C₂₀H₁₇NNaO₅374.0999, found 374.0990.

(7-Nitro-4H-furo[3,2-b]indol-4-yl)(phenyl)methanone (4i): 12.4

mg (31% yield, yellow solid, puriﬁed by SiO₂column chromatography

eluting 10−20% EtOAc/hexane); mp 158.9−159.4 °C; IR (neat) ν_max

(4H-Furo[3,2-b]indol-4-yl)(4-(triﬂuoromethoxy)phenyl)-

methanone (4o): 58.5 mg (93% yield, white solid, puriﬁed by SiO₂

column chromatography eluting 5% EtOAc/hexane); mp 76.4−77.4

°C; IR (neat) ν_max2928, 1685, 1388, 1258, 753 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.45−8.42 (m, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.70−

7.67 (m, 1H), 7.40−7.32 (m, 5H), 5.66 (d, J = 1.5 Hz, 1H); ¹³C{¹H}

1

3136, 1692, 1516, 1344, 723 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

8.58−8.55 (m, 2H), 8.23 (dd, J = 9.2, 2.4 Hz, 1H), 7.76 (d, J = 7.6

Hz, 2H), 7.70 (t, J = 6.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.44 (d, J =

2.0 Hz, 1H), 5.69 (d, J = 1.6 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 168.1, 146.9, 144.3, 142.9, 142.4, 133.9, 132.9, 132.7, 128.8,

128.6, 119.5, 118.2, 117.7, 112.3, 103.0; HRMS (ESI−TOF) m/z [M

+ H]⁺calcd for C₁₇H₁₁⁷⁹BrN₂O₄307.0713, found 307.0706.

3

NMR (75 MHz, CDCl₃) δ 166.8, 151.7 (q, C−F, J_C−F= 2 Hz),

145.4, 144.6, 139.9, 133.5, 130.5, 129.7, 124.7, 124.5, 120.7, 120.3 (q,

1

C−F, J_C−F= 257 Hz), 118.6, 117.8, 116.4, 102.7; HRMS (ESI−

TOF) m/z (M+Na)⁺calcd for C₁₈H₁₀F₃NNaO₃368.0505, found

368.0495.

7-Nitro-4H-furo[3,2-b]indole (4i′): 5.1 mg (19% yield, orange

solid, puriﬁed by SiO₂column chromatography eluting 10−20%

EtOAc/hexane); mp 210.0−210.3 °C; IR (neat) ν_max3320, 1499,

(4-Fluorophenyl)(4H-furo[3,2-b]indol-4-yl)methanone (4p): 51.5

mg (55% yield, colorless crystal, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 98.9−99.8 °C; IR

(neat) ν_max3071, 1687, 1307, 749 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 8.41−8.39 (m, 1H), 7.77−7.73 (m, 2H), 7.67−7.65 (m,

1H), 7.36−7.31 (m, 3H), 7.21 (t, J = 8.8 Hz, 2H), 5.70 (d, J = 2.0 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.0, 164.8 (d, C−F,

¹J_C−F= 252 Hz), 145.3, 144.4, 139.8, 131.2, 131.1, 131.0, 129.9, 124.4

1

1308, 738, 698 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.83 (s, 1H),

8.22 (br s, 1H), 8.13 (dd, J = 9.0, 1.2 Hz, 1H), 7.65 (s, 1H), 7.45 (d, J

= 9.2 Hz, 1H), 6.67 (s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

148.4, 143.09, 143.07, 142.5, 133.5, 118.1, 114.4, 114.1, 112.7, 100.4;

HRMS (ESI−TOF) m/z (M+Na)⁺calcd for C₁₀H₆N₂NaO₃

225.0271, found 225.0274.

(4H-Furo[3,2-b]indol-4-yl)(p-tolyl)methanone (4j): 38.6 mg (91%

yield, white solid, puriﬁed by SiO₂column chromatography eluting

5−15% EtOAc/hexane); mp 142.7−143.1 °C; IR (neat) ν_max2925,

(d, C−F, ²J_C−F= 24 Hz), 118.5, 117.7, 116.3, 115.8 (d, C−F, ²J_C−F

=

22 Hz), 102.8; ¹⁹F NMR (376 MHz, CDCl₃) δ − 109.45 to −109.52

(m); HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₁FNO₂

280.0768, found 280.0775.

1

1595, 1305, 1030, 751, 692 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.44−8.41 (m, 1H), 7.68−7.61 (m, 3H), 7.36−7.31 (m, 5H), 5.72 (d,

J = 2.1 Hz, 1H), 2.47 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

168.3, 145.1, 144.2, 142.5, 139.9, 132.2, 130.3, 129.2, 128.7, 124.4,

124.1, 118.5, 117.7, 116.2, 103.1, 21.7; HRMS (ESI−TOF) m/z (M

+Na)⁺calcd for C₁₈H₁₃NNaO₂298.0839, found 298.0839.

(4-Chlorophenyl)(4H-furo[3,2-b]indol-4-yl)methanone (4q): 57.9

mg (96% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 5% EtOAc/hexane); mp 130.6−130.8 °C; IR (neat) ν_max

3110, 1684, 1354, 1310, 1089, 748 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 8.42−8.39 (m, 1H), 7.68−7.64 (m, 3H), 7.52−7.49 (m,

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Article

2H), 7.36−7.30 (m, 3H), 5.70 (d, J = 1.8 Hz, 1H); ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ 167.0, 145.3, 144.4, 139.8, 138.2, 133.4, 130.0,

129.7, 128.9, 124.6, 124.4, 118.5, 117.7, 116.3, 102.8; HRMS (ESI−

TOF) m/z [M + H]⁺calcd for C₁₇H₁₁ClNO₂296.0473, found

296.0475.

(2-Bromophenyl)(4H-furo[3,2-b]indol-4-yl)methanone (4r): 24.3

mg (30% yield, brown solid, puriﬁed by SiO₂column chromatography

eluting 5−10% EtOAc/hexane); mp 159.9−160.2 °C; IR (neat) ν_max

3128, 1682, 1367, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (br

s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68−7.66 (m, 1H), 7.54−7.44 (m,

3H), 7.38−7.29 (m, 3H), 5.02 (br s, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 165.9, 145.7, 144.8, 139.4, 137.8, 133.2, 131.8, 129.3, 128.4,

127.9, 124.9, 124.8, 119.6, 119.0, 118.3, 116.4, 101.8; HRMS (ESI−

TOF) m/z [M + H]⁺calcd for C₁₇H₁₁⁷⁵BrNO₂339.9968, found

339.9968.

column chromatography eluting 5% EtOAc/hexane); mp 176.0−

176.5 °C; IR (neat) ν_max2925, 1683, 1255, 1023, 798 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.42−8.39 (m, 1H), 7.77−7.74 (m, 2H), 7.69−

7.64 (m, 2H), 7.58−7.50 (m, 4H), 7.38−7.27 (m, 2H), 6.91−6.86

(m, 2H), 5.72 (s, 1H), 3.81 (s, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 168.2, 159.5, 156.9, 143.2, 139.4, 135.2, 131.9, 131.8, 128.6,

128.5, 125.3, 124.3, 124.1, 123.7, 118.6, 117.6, 116.0, 114.2, 96.2,

55.3; HRMS (ESI−TOF) m/z [M + Na]⁺calcd for C₂₄H₁₇NNaO₃

390.1101, found 390.1096.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00086.

(4-Bromo-2-ﬂuorophenyl)(4H-furo[3,2-b]indol-4-yl)methanone

(4s): 31.2 mg (45% yield, white solid, puriﬁed by SiO₂column

chromatography eluting 5% EtOAc/hexane); mp 174.8−175.3 °C; IR

Optimization studies for the conversions of compounds

1

2aBr to 3aBr and 3aBr to 4a, copies of H, ¹³C{¹H},

and ¹⁹F NMR spectra, copies of high-resolution mass

spectra of all compounds, and X-ray diﬀraction

parameters and thermal ellipsoid plots (PDF)

1

(neat) ν_max3085, 2853, 1675, 1604, 1371, 753 cm⁻¹; H NMR (300

MHz, CDCl₃) δ 8.52 (br s, 1H), 7.71−7.68 (m, 1H), 7.55−7.48 (m,

3H), 7.43−7.36 (m, 3H), 5.61 (br s, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 162.6, 159.0 (d, C−F, ¹J_C−F= 255 Hz), 145.7, 144.9, 139.5,

Accession Codes

3

130.5 (d, C−F, J_C−F= 4 Hz), 129.1, 128.2 (d, C−F, J_C−F= 4 Hz),

CCDC 2057692−2057694 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

3

126.0 (d, C−F, J_C−F= 9 Hz), 124.9 (d, C−F, J_C−F= 6 Hz), 123.2

(d, C−F, ²J_C−F= 17 Hz), 120.4, 120.1, 118.9, 117.8, 116.5, 101.9; ¹⁹

F

NMR (376 MHz, CDCl₃) δ − 114.26 to −114.30 (m); HRMS (ESI−

TOF) m/z [M + H]⁺calcd for C₁₇H₁₀⁷⁹BrFNO₂357.9873, found

357.9881.

4-(4H-Furo[3,2-b]indole-4-carbonyl)benzonitrile (4t): 56.5 mg

(72% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 50% DCM/hexane to 20% EtOAc/hexane); mp 171.3−171.7

°C; IR (neat) ν_max3352, 2976, 1647, 1045, 879 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 8.44−8.41 (m, 1H), 7.88−7.82 (m, 4H), 7.72−7.67

(m, 1H), 7.42−7.34 (m, 3H), 5.56 (d, J = 0.9 Hz, 1H); ¹³C{¹H}

NMR (75 MHz, CDCl₃) δ 166.1, 145.6, 144.9, 139.8, 139.1, 132.5,

129.3, 129.0, 125.0, 124.9, 118.8, 117.8, 117.7, 116.6, 115.5, 102.5;

HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₈H₁₁N₂O₂287.0815,

found 287.0818.

AUTHOR INFORMATION

Corresponding Author

■

Charnsak Thongsornkleeb − Laboratory of Organic

Synthesis, Chulabhorn Research Institute, Bangkok 10210,

Thailand; Program on Chemical Biology, Chulabhorn

Graduate Institute, Center of Excellence on Environmental

Health and Toxicology (EHT), Ministry of Education,

Bangkok 10210, Thailand; orcid.org/0000-0003-2653-

5137; Email: charnsak@cri.or.th

(4H-Furo[3,2-b]indol-4-yl)(4-nitrophenyl)methanone (4u): 68.3

mg (84% yield, yellow solid, puriﬁed by SiO₂column chromatography

eluting 30−50% DCM/hexane); mp 147.9−148.4 °C; IR (neat) ν_max

1

3077, 1685, 1525, 1308, 754 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

Authors

8.40−8.37 (m, 3H), 7.90−7.87 (m, 2H), 7.68−7.66 (m, 1H), 7.37−

7.34 (m, 3H), 5.56 (s, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

165.8, 149.6, 145.6, 144.9, 140.8, 139.7, 129.4, 129.2, 125.0, 124.9,

123.9, 118.8, 117.8, 116.6 102.5; HRMS (ESI−TOF) m/z [M + H]⁺

calcd for C₁₇H₁₁N₂O₄307.0713, found 307.0718.

Cyclohexyl(4H-furo[3,2-b]indol-4-yl)methanone (4v): 16.0 mg

(25% yield, yellow oil, puriﬁed by SiO₂column chromatography

eluting 5% EtOAc/hexane); IR (neat) ν_max2931, 1699, 1268, 753

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.65−8.63 (m, 1H), 7.67−7.64

(m, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.35−7.29 (m, 2H), 6.67 (d, J =

1.8 Hz, 1H), 3.04 (tt, J = 11.4, 3.3 Hz, 1H), 2.08−2.04 (m, 2H),

1.97−1.92 (m, 2H), 1.82−1.64 (m, 3H), 1.51−1.25 (m, 3H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 174.7, 145.8, 144.6, 139.6, 128.0,

124.8, 123.9, 118.3, 118.0, 116.1, 102.8, 44.4, 29.0, 25.75, 25.71;

HRMS (ESI−TOF) m/z [M + H]⁺calcd for C₁₇H₁₈NO₂268.1332,

found 268.1339.

Nattawadee Chaisan − Program on Chemical Biology,

Chulabhorn Graduate Institute, Center of Excellence on

Environmental Health and Toxicology (EHT), Ministry of

Education, Bangkok 10210, Thailand

Sureeporn Ruengsangtongkul − Laboratory of Medicinal

Chemistry, Chulabhorn Research Institute, Bangkok 10210,

Thailand

Jumreang Tummatorn − Laboratory of Medicinal Chemistry,

Chulabhorn Research Institute, Bangkok 10210, Thailand;

Program on Chemical Biology, Chulabhorn Graduate

Institute, Center of Excellence on Environmental Health and

Toxicology (EHT), Ministry of Education, Bangkok 10210,

Thailand; orcid.org/0000-0002-1662-151X

Somsak Ruchirawat − Laboratory of Medicinal Chemistry,

Chulabhorn Research Institute, Bangkok 10210, Thailand;

Program on Chemical Biology, Chulabhorn Graduate

Institute, Center of Excellence on Environmental Health and

Toxicology (EHT), Ministry of Education, Bangkok 10210,

Thailand

Phenyl(2-phenyl-4H-furo[3,2-b]indol-4-yl)methanone (4x): 49.7

mg (94% yield, white solid, puriﬁed by SiO₂column chromatography

eluting 5−10% EtOAc/hexane); mp 169.5−169.8 °C; IR (neat) ν_max

1

2923, 1679, 1442, 1367, 758 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

8.42−8.40 (m, 1H), 7.76−7.74 (m, 2H), 7.71−7.64 (m, 2H), 7.60−

7.54 (m, 4H), 7.37−7.30 (m, 4H), 7.27−7.22 (m, 1H), 5.85 (s, 1H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 168.1, 156.7, 143.8, 139.7, 135.1,

131.9, 131.7, 130.7, 128.7, 128.6, 128.5, 127.9, 124.5, 124.4 123.8,

118.5, 117.7, 116.2, 97.6; HRMS (ESI−TOF) m/z [M + H]⁺calcd

for C₂₃H₁₆NO₂338.1176, found 338.1175.

Kittipong Chainok − Thammasat University Research Unit in

Multifunctional Crystalline Materials and Applications (TU-

MCMA), Faculty of Science and Technology, Thammasat

University, Pathum Thani 12121, Thailand

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00086

(2-(4-Methoxyphenyl)-4H-furo[3,2-b]indol-4-yl)(phenyl)-

methanone (4y): 30.5 mg (73% yield, yellow solid, puriﬁed by SiO₂

4696

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J. Org. Chem. 2021, 86, 4671−4698

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pubs.acs.org/joc

Article

S.; Ghosez, L. Discovery of a subnanomolar and selective spirocyclic

agonist of the glucocorticoid receptor. Eur. J. Med. Chem. 2019, 161,

354−363. (c) García, M.; Virgili, M.; Alonso, M.; Alegret, C.;

Fernández, B.; Port, A.; Pascual, R.; Monroy, X.; Vidal-Torres, A.;

Serafini, M.-T.; Vela, J. M.; Almansa, C. 4-Aryl-1-oxa-4,9-diazaspiro-

[5.5]undecane Derivatives as Dual μ -Opioid Receptor Agonists and

σ₁Receptor Antagonists for the Treatment of Pain. J. Med. Chem.

2020, 63, 2434−2454. (d) Yuan, X.; Bu, H.; Zhou, J.; Yang, C.-Y.;

Zhang, H. Recent Advances of SHP2 Inhibitors in Cancer Therapy:

Current Development and Clinical Application. J. Med. Chem. 2020,

63, 11368−11396.

(6) (a) Laus, G. Biological Activities of Natural Halogen

Compounds. In Studies in Natural Products Chemistry; Atta-ur-

Rahman, Ed.; Elsevier Science B. V.: Amsterdam, The Netherlands,

2001; Vol. 25, pp 757−809. (b) La Barre, S.; Potin, P.; Leblanc, C.;

Delage, L. The Halogenated Metabolism of Brown Algae

(Phaeophyta), Its Biological Importance and Its Environmental

Significance. Mar. Drugs 2010, 8, 988−1010. (c) Cabrita, M. T.;

Vale, C.; Rauter, A. P. Halogenated Compounds from Marine Algae.

Mar. Drugs 2010, 8, 2301−2317. (d) Gribble, G. W. Biological

Activity of Recently Discovered Halogenated Marine Natural

Products. Mar. Drugs 2015, 13, 4044−4136.

(7) (a) Hernandes, M.; Cavalcanti, S. M.; Moreira, D. R.; de

Azevedo Junior, W.; Leite, A. C. Halogen Atoms in the Modern

Medicinal Chemistry: Hints for the Drug Design. Curr. Drug Targets

2010, 11, 303−314. (b) Wilcken, R.; Zimmermann, M. O.; Lange, A.;

Joerger, A. C.; Boeckler, F. M. Principles and Applications of Halogen

Bonding in Medicinal Chemistry and Chemical Biology. J. Med. Chem.

2013, 56, 1363−1388. (c) Jiang, S.; Zhang, L.; Cui, D.; Yao, Z.; Gao,

B.; Lin, J.; Wei, D. The Important Role of Halogen Bond in Substrate

Selectivity of Enzymatic Catalysis. Sci. Rep. 2016, 6, 34750. (d) Ho, P.

S. Halogen bonding in medicinal chemistry: from observation to

prediction. Future Med. Chem. 2017, 9, 637−640.

(8) (a) Kropp, P. J.; Pienta, N. J. Photochemistry of Alkyl Halides. 9.

Geminal Dihalides. J. Org. Chem. 1983, 48, 2084−2090. (b) Ashby, E.

C.; Deshpande, A. K. Mechanism of Reaction of Geminal Dihalides

with Lithium Aluminum Hydride. Evidence for Single Electron

Transfer as the Major Reaction Pathway. J. Org. Chem. 1994, 59,

3798−3805. (c) Ashby, E. C.; Deshpande, A. K. Electron Transfer in

the Reactions of Geminal Dihalides with Ph₂P⁻. Evidence for the

Formation of a Carbene Intermediate from a Radical Precursor. J. Org.

Chem. 1995, 60, 7117−7124. (d) Liang, Y.; Fu, G. C. G. C. Catalytic

Asymmetric Synthesis of Tertiary Alkyl Fluorides: Negishi Cross-

Couplings of Racemic α ,α -Dihaloketones. J. Am. Chem. Soc. 2014,

136, 5520−5524.

(9) (a) Buysch, H.-J.; Scholz, K.-H. Process for Preparing Geminal

Dihalides. U.S. Patent 4,044,060, August 23, 1977. (b) Furrow, M. E.;

Myers, A. G. Practical Procedures for the Preparation of N -tert -

Butyldimethylsilylhydrazones and Their Use in Modified Wolff-

Kishner Reductions and in the Synthesis of Vinyl Halides and gem -

Dihalides. J. Am. Chem. Soc. 2004, 126, 5436−5445. (c) Cloarec, J.-

M.; Charette, A. B. Highly Efficient Two-Step Synthesis of C-sp³-

Centered Geminal Diiodides. Org. Lett. 2004, 6, 4731−4734.

(d) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. A

Mild Synthesis of Vinyl Halides and gem -Dihalides Using Triphenyl

Phosphite −Halogen-Based Reagents. J. Org. Chem. 2007, 72, 2216−

2219.

(10) Zinad, D. S.; Mahal, A.; Mohapatra, R. K.; Sarangi, A. K.;

Pratama, M. R. F. Medicinal chemistry of oxazines as promising

agents in drug discovery. Chem. Biol. Drug Des. 2020, 95, 16−47.

(11) (a) Nakashima, Y.; Kawashima, Y.; Amanuma, F.; Sota, K.;

Tanaka, A.; Kameyama, T. Furo[3,2-b ]indole Derivatives I. Synthesis

and Analgesic and Anti-inflammatory Activities of 4,5-Disubstituted-

furo[3,2-b ]indole-2-carboxamide Derivatives. Chem. Pharm. Bull.

1984, 32, 4271−4280. (b) Nakashima, Y.; Kawashima, Y.; Sato, M.;

Okuyama, S.; Amanuma, F.; Sota, K.; Kameyama, T. Furo[3,2-

b ]indole Derivatives II. Synthesis and Analgesic and Anti-inflamma-

tory Activities of 4-Alkoxycarbonyl-2-morpholinocarbonylfuro[3,2-

b ]indole Derivatives. Chem. Pharm. Bull. 1985, 33, 5250−5257.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research work was supported in part by grants from

Chulabhorn Research Institute (CRI), Chulabhorn Graduate

Institute (CGI), Mahidol University, the Center of Excellence

on Environmental Health and Toxicology, Science &

Technology Postgraduate Education and Research Develop-

ment Oﬃce (PERDO), Ministry of Education, and The

Thailand Research Fund (TRF) Grant (RSA6180045). N.C.

was also grateful for the support from the Royal Golden Jubilee

(RGJ) scholarship program (PHD/0139/2560).

REFERENCES

■

(1) (a) Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene

Chemistry. Chemistry, Biology and Material Science; Wiley-VCH:

Weinheim, Germany, 2005. (b) Trost, B. M.; Tracy, J. S. Organic

Synthesis. Use of Alkynes as a Key to Innovation in Designing

Structure for Function. Isr. J. Chem. 2018, 58, 18−27. (c) Voronin, V.

V.; Ledovskaya, M. S.; Bogachenkov, A. S.; Rodygin, K. S.; Ananikov,

V. P. Acetylene in Organic Synthesis: Recent Progress and New Uses.

Molecules 2018, 23, 2442.

(2) (a) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of

Alkynes for the Construction of Molecular Complexity. Chem. Rev.

2015, 115, 9028−9072. (b) Gupta, A.; Flynn, B. L. Electrophilic

Activation of P-Alkynes in the Synthesis of P-Substituted and P-

Centered Heterocycles. J. Org. Chem. 2016, 81, 4012−4019.

(c) Takeda, Y.; Kajihara, R.; Kobayashi, N.; Noguchi, K.; Saito, A.

Molecular-Iodine-Catalyzed Cyclization of 2-Alkynylanilines via

Iodocyclization −Protodeiodination Sequence. Org. Lett. 2017, 19,

6744−6747. (d) Garkhedkar, A. M.; Gore, B. S.; Hu, W.-P.; Wang, J.-

J. Lewis Acid Catalyzed Atom-Economic Synthesis of C2-Substituted

Indoles from o -Amido Alkynols. Org. Lett. 2020, 22, 3531−3536.

(3) (a) Maibunkaew, T.; Thongsornkleeb, C.; Tummatorn, J.;

Bunrit, A.; Ruchirawat, S. Practical and Metal-Free Electrophilic

Aromatic Halogenation by Interhalogen Compounds Generated In

Situ from N -Halosuccinimide and Catalytic TMSCl. Synlett 2014, 25,

1769−1775. (b) Kaewsri, W.; Thongsornkleeb, C.; Tummatorn, J.;

Ruchirawat, S. Isomerizable (E/Z )-alkynyl-O -methyl oximes employ-

ing TMSCl −NCS in chlorinative cyclization for the direct synthesis of

4-chloroisoxazoles. RSC Adv. 2016, 6, 48666−48675. (c) Kaewsri, W.;

Norseeda, K.; Ruengsangtongkul, S.; Chaisan, N.; Thongsornkleeb,

C.; Tummatorn, J.; Ruchirawat, S. Synthesis of 2-Cyclohexenone-2-

carboxylate and 4-Chloro2-cyclohexenone-2-carboxylate Derivatives

by Cyclization of Alkyne-Tethered 1,3-Ketoesters. Asian J. Org. Chem.

2018, 7, 203−211. (d) Norseeda, K.; Chaisan, N.; Thongsornkleeb,

C.; Tummatorn, J.; Ruchirawat, S. Metal-Free Synthesis of 4-

Chloroisocoumarins by TMSCl-Catalyzed NCS-Induced Chlorinative

Annulation of 2-Alkynylaryloate Esters. J. Org. Chem. 2019, 84,

16222−16236.

(4) (a) Zheng, Y.; Tice, C. M.; Singh, S. B. The use of spirocyclic

scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 2014, 24, 3673−

3682. (b) Zheng, Y.-J.; Tice, C. M. The utilization of spirocyclic

scaffolds in novel drug discovery. Expert Opin. Drug Discovery 2016,

11, 831−834. (c) Muller, G.; Berkenbosch, T.; Benningshof, J. C. J.;

Stumpfe, D.; Bajorath, J. Charting Biologically Relevant Spirocyclic

Compound Space. Chem. - Eur. J. 2017, 23, 703−710. (d) Chupakhin,

E.; Babich, O.; Prosekov, A.; Asyakina, L.; Krasavin, M. Spirocyclic

Motifs in Natural Products. Molecules 2019, 24, 4165.

(5) (a) Thaler, F.; Varasi, M.; Abate, A.; Carenzi, G.; Colombo, A.;

Bigogno, C.; Boggio, R.; Zuffo, R. D.; Rapetti, D.; Resconi, A.;

Regalia, N.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.;

Mercurio, C. Synthesis and biological characterization of spiro[2 H -

(1,3)-benzoxazine-2,4 ’-piperidine] based histone deacetylase inhib-

itors. Eur. J. Med. Chem. 2013, 64, 273−284. (b) Badarau, E.; Robert,

F.; Massip, S.; Jakob, F.; Lucas, S.; Friebe, D.; Hennen, S.; Frormann,

4697

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(c) Kawashima, Y.; Sato, M.; Hatada, Y.; Okuyama, S.; Amanuma, F.;

Nakashima, Y.; Sota, K.; Moriguchi, I. Furo[3,2-b ]indole Derivatives

III. Structure-Activity Studies of 4,6-Disubstituted N -(3-

Piperidinopropyl)furo[3,2-b ]indole-2-carboxamide Derivatives for

Analgesic and Antiinflammatory Activities. Chem. Pharm. Bull. 1986,

34, 3267−3272. (d) Kawashima, Y.; Amanuma, F.; Sato, M.;

Okuyama, S.; Nakashima, Y.; Sota, K.; Moriguchi, I. Structure-

Activity Studies of 4,6-Disubstituted 2-(Morpholinocarbonyl)furo-

[3,2-b ]indole Derivatives with Analgesic and Antiinflammatory

Activities. J. Med. Chem. 1986, 29, 2284−2290. (e) Zhuang, S.-H.;

Lin, Y.-C.; Chou, L.-C.; Hsu, M.-H.; Lin, H.-Y.; Huang, C.-H.; Lien,

J.-C.; Kuo, S.-C.; Huang, L.-J. Synthesis and anticancer activity of 2,4-

disubstituted furo[3,2-b ]indole derivatives. Eur. J. Med. Chem. 2013,

66, 466−479.

(12) (a) Tanaka, A.; Yakushijin, K.; Yoshina, S. Synthesis of 4 H -

Furo[3,2-b ]indole Derivatives. A New Heterocyclic Ring System. J.

Heterocycl. Chem. 1977, 14, 975−979. (b) Tanaka, A.; Yakushijin, K.;

Yoshina, S. Synthesis of 4 H -Furo[3,2-b ]indoles. (II). Bromination,

Acylation and Nitration of 4 H - and 4-Benzoylfuro[3,2-b ]indoles. J.

Heterocycl. Chem. 1978, 15, 123−125. (c) Tanaka, A.; Yakushijin, K.;

Yoshina, S. Synthesis of 4 H -Furo[3,2-b ]indole Derivatives. III.

Preparation of 4 H -Furo[3,2-b ]indole-2-carboxylic Acid Derivatives.

J. Heterocycl. Chem. 1979, 16, 785−788. (d) Pudlo, M.; Csanyi, D.;

Moreau, F.; Hajos, G.; Riedl, Z.; Sapi, J. First Suzuki-Miyaura type

cross-coupling of ortho -azidobromobenzene with arylboronic acids

and its application to the synthesis of fused aromatic indole-

heterocycles. Tetrahedron 2007, 63, 10320−10329. (e) Zhang, Z.;

Fang, S.; Liu, Q.; Zhang, G. Microwave-Assisted Facile Synthesis of

Furo[3,2-b ]indole Derivatives via Silver(I)-Mediated [3 + 2]

Cycloaddition. Adv. Synth. Catal. 2012, 354, 927−932.

(17) (a) Illuminati, G.; Mandolini, L.; Masci, B. Ring-closure

reactions. V. Kinetics of five- to ten-membered ring formation from

o-.omega.-bromoalkylphenoxides. Influence of the O-heteroatom. J.

Am. Chem. Soc. 1975, 97, 4960−4966. (b) Illuminati, G.; Mandolini,

L. Ring Closure Reactions of Bifunctional Chain Molecules. Acc.

Chem. Res. 1981, 14, 95−102. (c) Casadei, M. A.; Galli, C.;

Mandolini, L. Ring-Closure Reactions. 22. Kinetics of Cyclization of

Diethyl (ω -Bromoalky1)malonates in the Range of 4- to 21-

Membered Rings. Role of Ring Strain. J. Am. Chem. Soc. 1984, 106,

1051−1056. (d) Di Martino, A.; Galli, C.; Gargano, P.; Mandolini, L.

Ring-closure Reactions. Part 23. Kinetics of Formation of Three- to

Seven-membered-ring N -Tosylazacycloalkanes. The Role of Ring

Strain in Small- and Common-sized-ring Formation. J. Chem. Soc.,

Perkin Trans. 2 1985, 2, 1345−1349. (e) Galli, C.; Mandolini, L. The

Role of Ring Strain on the Ease of Ring Closure of Bifunctional Chain

Molecules. Eur. J. Org. Chem. 2000, 2000, 3117−3125.

(13) (a) Pirovano, V.; Brambilla, E.; Rizzato, S.; Abbiati, G.; Bozzi,

M.; Rossi, E. Gold-Catalyzed Cascade Reactions of 4 H -Furo[3,2-

b ]indoles with Allenamides: Synthesis of Indolin-3-one Derivatives. J.

Org. Chem. 2019, 84, 5150−5166. (b) Brambilla, E.; Pirovano, V.;

Giannangeli, M.; Abbiati, G.; Caselli, A.; Rossi, E. Gold-catalyzed

cascade reactions of 4 H -furo[3,2-b ]indoles with propargyl esters:

synthesis of 2-alkenylidene-3-oxoindolines. Org. Chem. Front. 2019, 6,

3078−3084. (c) Pirovano, V.; Caselli, A.; Colombo, A.; Dragonetti,

C.; Giannangeli, M.; Rossi, E.; Brambilla, E. Synthesis of 2-

alkenylidene-3-oxoindolines: cascade reactions of 4 H -furo[3,2-b ]-

indoles with diazoacetates catalyzed by a Cu(I) macrocyclic

pyridine-containing ligand (PcL) complex. ChemCatChem 2020, 12,

5250−5255. (d) Pirovano, V.; Brambilla, E.; Moretti, A.; Rizzato, S.;

Abbiati, G.; Nava, D.; Rossi, E. Synthesis of Cyclohepta[b ]indoles by

(4 + 3) Cycloaddition of 2-Vinylindoles or 4 H -Furo[3,2-b ]indoles

with Oxyallyl Cations. J. Org. Chem. 2020, 85, 3265−3276.

(14) (a) Nelson, W. M. Green Solvents for Chemistry: Perspectives and

Practice; Oxford University Press: New York, USA, 2003. (b) Capello,

̈

C.; Fischer, U.; Hungerbuhler, K. What is a green solvent? A

comprehensive framework for the environmental assessment of

solvents. Green Chem. 2007, 9, 927−934. (c) Prat, D.; Hayler, J.;

Wells, A. A survey of solvent selection guides. Green Chem. 2014, 16,

4546−4551. (d) Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H. M.;

Clark, J. H.; Farmer, T. J.; Hunt, A. J.; Robert McElroy, C.; Sherwood,

J. Tools and techniques for solvent selection: green solvent selection

guides. Sustainable Chem. Processes. [Online] 2016, 4, DOI: 10.1186/

s40508-016-0051-z (accessed September 19, 2020).

(15) See Supporting Information for details of these optimization

studies.

(16) (a) Shaughnessy, K. H.; Ciganek, E.; DeVasher, R. B. Copper-

Catalyzed Amination of Aryl and Alkenyl Electrophiles; Wiley:

Hoboken, New Jersey, 2017. (b) Strieter, E. R.; Bhayana, B.;

Buchwald, S. L. Mechanistic Studies on the Copper-Catalyzed N-

Arylation of Amides. J. Am. Chem. Soc. 2009, 131, 78−88. (c) Lin, H.;

Sun, D. Recent Synthetic Developments and Applications of the

Ullmann Reaction. A Review. Org. Prep. Proced. Int. 2013, 45, 341−

394. (d) Hu, T.; Li, C. Synthesis of Lactams via Copper-Catalyzed

Intramolecular Vinylation of Amides. Org. Lett. 2005, 7, 2035−2038.

4698

https://dx.doi.org/10.1021/acs.joc.1c00086

J. Org. Chem. 2021, 86, 4671−4698

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Dibrominative Spirocyclization of 2-Butynolyl Anilides: Synthesis of gem-Dibromospirocyclic Benzo[ d][1,3]oxazines and Their Application in the Synthesis of 4 H-Furo[3,2- b]indoles

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