Palladium-Catalyzed Divergent Imidoylative Cyclization of Multifunctionalized Isocyanides: Tunable Access to Oxazol-5(4 H)-ones and Cyclic Ketoimines

(4 H )‑ones and Cyclic Ketoimines

Article

Palladium-Catalyzed Divergent Imidoylative Cyclization of

Multifunctionalized Isocyanides: Tunable Access to Oxazol-

Jian Wang,* Ling Zhong, Shi Tang, Yuan Liu, Shumin Ding, Lianjie Li, Haixia Zhao, Chen Chen,

and Yongjia Shang *

Cite This: https://dx.doi.org/10.1021/acs.joc.0c00672

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sı Supporting Information

ABSTRACT: A palladium-catalyzed tunable imidoylative cycliza-

tion of multifunctionalized isocyanides to construct diverse imine-

containing heterocycles has been developed. Oxazol-5(4H)-one

derivatives were obtained exclusively when allyl-2-benzyl(or allyl)-

-isocyanoacetates were used in the reaction with aryl triﬂates as

electrophiles, whereas cyclic ketoimines were generated in the

presence of aryl iodides with the allyl ester group remaining

unreacted. The reactions proceeded smoothly under mild

conditions with a wide functional group tolerance.

INTRODUCTION

were introduced to the formed cycle, demonstrating the

advantage over carbon monoxide-participated carbonylation

■

Selective catalytic transformation of organic molecules is one

of the most challenging tasks in modern synthetic chemistry.

reactions. For instance, camptothecins, indoles, oxazoles,

phenanthridines, β-carbolines, tetrasubstituted imidazo-

The construction and modiﬁcation of nitrogen-containing

heterocycles are of vital importance, which are ubiquitous in

natural products, pharmaceutical chemistry, and material

sciences. In this regard, divergent heterocycles could be

accessed by conditions-controlled selective reactions from the

same molecules, which could facilitate the assembly of complex

lones, and cyclic imines were successfully prepared by

applying this approach. In 2017, the Zhu group developed the

ﬁrst enantioselective palladium-catalyzed C−H bond imidoy-

lation reaction via a desymmetrization strategy (Scheme

a). Later on, a site-selective imidoylative cyclization was

reported by the same group (Scheme 1b). The selectivity of

18a

compounds. For example, a solvent-controlled site-selective

(

2/3 position) alkenylation reaction of indoles was developed

the formation of six- or ﬁve-membered ketoimines was tuned

by the Gaunt group in 2005. Tunable cyclization of 2-aryl

cyclic 1,3-dicarbonyl compounds with alkynes and alkenes

leading to fused or spiro N-heterocycles was reported by the

Lam group using palladium or ruthenium catalysis,, respec-

by using bulky Ad PnBu or bidentate DPPB as the ligands.

However, to the best of our knowledge, selective and tunable

cyclization of isocyanides bearing diﬀerent functional groups,

which could oﬀer divergent access to diﬀerent types of

heterocycles, remains unprecedented. Herein, we developed

the ﬁrst palladium-catalyzed imidoylative cyclization of multi-

functionalized isocyanides, aﬀording diverse imine-containing

heterocycles. Oxazol-5(4H)-one derivatives were obtained

exclusively when allyl-2-benzyl(allyl)-2-isocyanoacetates were

conducted in the reaction with aryl triﬂates as electrophiles.

When aryl iodides were used as the coupling partner, cyclic

ketoimines were generated selectively with the allyl ester group

remaining unreacted. A wide range of functional groups were

tively. Very recently, Fan and co-workers reported an elegant

annulation reaction of 2-arylindazoles with maleimides for the

divergent synthesis of indazo-lo[2,3-a]pyrrolo[3,4-c]-

quinolinones or spiroindolo[1,2-b]indazole-11,3′-pyrrolidi-

nones, which could be simply switched by resorting to

5a−d

diﬀerent additives.

In the past decades, isocyanide was widely investigated in

transition-metal-catalyzed insertion reactions, multicompo-

nent reactions, cycloaddition reactions, and even biorthog-

onal reactions because of its diverse reactivities. As an

equivalent of carbon monoxide (CO), C1 insertion reactions

of isocyanide under palladium catalysis have been applied in

the construction of numerous N-containing compounds.

Received: March 14, 2020

Published: May 6, 2020

Because of the adjustable R group of isocyanides, an eﬃcient

access to N-heterocycles by the strategy of functionalized

isocyanide was successfully developed, in which multiple atoms

(

including both nitrogen and carbon atoms of isocyanide)

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 1. Selective Palladium-Catalyzed Imidoylative Cyclization of Functionalized Isocyanides; (a) Enantioselective

Imidoylative Cyclization; (b) Site-Selective Imidoylative Cyclization

tolerated under mild conditions and the reactions featured an

exclusive selectivity.

Table 1. Optimization of the Reaction Conditions

RESULTS AND DISCUSSION

■

The study was started with allyl 2-benzyl-2-isocyano-3-

phenylpropanoate (1a) and naphthalen-2-yl triﬂuoromethane-

sulfonate (2a) as model substrates in the presence of

Pd(OAc) , PPh , Cs CO , and PivOH. An unexpected product

,4-dibenzyl-2-(naphthalen-2-yl)oxazol-5(4H)-one (3a) was

generated in 89% yield, whereas the initial designed

imidoylative-Heck type product 3a′ was not detected when

entry

change from the “standard conditions”

yield (%)

a was added via a syringe pump in 1 h (Table 1, entry 1). In

none

this transformation, the allyl group was released and the

DMSO as solvent

dioxane as solvent

with 1.0 equiv of PivOH

with 0.3 equiv of PivOH

without PivOH

C(sp )−H bonds remained unreacted, which diﬀered from the

previously reported C−H bond imidoylation reaction. Other

solvents such as dimethyl sulfoxide (DMSO) and dioxane

reduced the eﬃciency of this transformation (entries 2−3).

The product was obtained in 89 and 81% yields, respectively,

using 1.0 or 0.3 equiv of PivOH (entries 4−5). The yield

decreased sharply in the absence of PivOH (entry 6). The

product 3a was generated in 85 and 52% yield when the

reaction was conducted at 70 and 60 °C, respectively (entries

70 °C

60 °C

the addition time was 0.5 h

the addition time was 1.5 h

Standard reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol),

Pd(OAc) (0.01 mmol), PPh (0.02 mmol), Cs CO (0.1 mmol),

−8). When the addition time of 1a was reduced to 0.5 h, 3a

was obtained in only 56% yield and the eﬃciency of the

PivOH (0.06 mmol), toluene, 80 °C, Ar, A solution of 1a in toluene

(1 mL) was added slowly via a syringe pump within 1 h. Isolated

yields.

reaction was not improved by prolonging the time to 1.5 h

(

entries 9−10).

With the optimized conditions in hand, we ﬁrst screened the

scope of isocyanides with 2a as the reaction partner (Scheme

). Both electron-donating and -withdrawing groups on the

benzylic ring were well tolerated under the reaction conditions

and the products were generated in good to excellent yields

changing one of the benzyl groups to alkyl ones such as Et, Pr,

and Bu. C2-Phenylated oxazol-5(4H)-one 3m could be

prepared smoothly as well using phenyl triﬂates as the

electrophilic coupling partner of 1a under slightly modiﬁed

conditions. Substituents on the phenyl ring such as Me, OMe,

(

3a−3i). It should be pointed out that the C−Br bond, which

could facilitate further transformations, remained stable in this

F, Cl, Br, and CF were well tolerated under the reaction

reaction (3e). Tetrasubstituted product 3h was generated in

conditions and the corresponding products 3n−3t were

generated in 67−83% yields. However, alkenyl triﬂates were

not able to participate in the cyclization reaction. When

6% yield, showing that the reaction was not very sensitive to

steric hindrance. 4-Benzyl-4-alkyloxazol-5(4H)-ones 3j−3l

were aﬀorded in 70, 72, and 86% yields, respectively, when

changing the R group to H, no desired product was generated

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

Scheme 2. Synthesis of Multisubstituted Oxazol-5(4H)-ones

and 3,4-Dihydroisoquinolines Using Aryl Triﬂates

Scheme 3. Synthesis of 3,4-Dihydroisoquinolines from Allyl

2-Benzyl-2-isocyano-3-phenylpropanoates

Reaction Conditions. 1a (0.1 mmol), 4 (0.15 mmol), Pd(OAc)₂

(

0.01 mmol), PPh (0.02 mmol), Cs CO (0.1 mmol), PivOH (0.06

3 2 3

mmol), toluene, 80 °C, Ar. A solution of 1a in toluene (1 mL) was

added slowly via a syringe pump within 1 h. Isolated yields.

Then, the reactivity of isocyanide bearing three functional

groups (6) under the optimized conditions was investigated

(

Scheme 4). When iodobenzene was used as the electrophile,

the reaction proceeded via an imidoylative-Heck pathway,

leading to 4-methylene-3,4-dihydro-2H-pyrrole derivative 7a,

with the allyl ester and benzyl group remaining unreacted,

revealing that the alkene group could trap the imidoyl-

palladium intermediate prior to C(sp )−H bonds. Tetrasub-

stituted oxazol-5(4H)-one 7b was aﬀorded in 74% yield when

^R^e^a^c^tⁱ^oⁿ^C^oⁿ^dⁱ^tⁱ^oⁿ^s^.¹⁽⁰^.¹^m^m^o^l⁾^,²⁽⁰^.¹⁵^/⁰^.³^m^m^o^l⁾^,^P^d⁽^O^A^c⁾2

(

0.01 mmol), PPh (0.02 mmol), Cs CO (0.1 mmol), PivOH (0.06

mmol), toluene, 80 °C, Ar. A solution of 1 in toluene (1 mL) was

3 2 3

2-naphthyl triﬂate was applied as the coupling partner, which

added slowly via a syringe pump within 1 h. Isolated yields.

was in accordance with the results shown in Scheme 2.

To further demonstrate the practicality of the trans-

formation, tandem reactions were conducted with 9a′ and

9b′ as the reaction partner of 1a respectively. However, a

mixture of 3,4-dihydroisoquinoline and oxazol-5(4H)-one was

generated (not shown). By changing the benzyl groups to ethyl

ones, C1-tethered oxindole-oxazolone biheterocycle scaﬀold 9a

was obtained in 81% yield and a tandem alkyne insertion

cascade was realized as well, aﬀording 9b in 58% yield

(Scheme 5).

Gram-scale preparation of oxazol-5(4H)-one 3a was carried

out in 54% yield (Scheme 6). The oxazol-5(4H)-one ring

could be disclosed using methanol and allyl alcohol as

nucleophiles, aﬀording amide products 10a and 10b in 99

and 44% yields, respectively.

using 2-naphthyl triﬂate as the coupling partner. Interestingly,

the eater group remained unreacted when the allyl moiety of

the substrate 1 was changed to ethyl or benzyl groups. 3,4-

Dihydroisoquinoline products 3u−3z were aﬀorded exclusively

through a C−H bond activation pathway in 65−86% yields,

which demonstrated the essential role of the allyl group in the

formation of oxazol-5(4H)-one scaﬀolds.

Next, we moved our attention to the study of the reactivity

of functionalized isocyanide 1a with aryl iodides 4 (Scheme 3).

To our surprise, 3,4-dihydroquinolines were generated

exclusively under the standard conditions with the allyl ester

group remaining unreacted. Oxazol-5(4H)-one derivatives

were not detected in this transformation. Substituents such

as Ph, OMe, F, and Cl survived the reaction conditions

smoothly and the products 5a−5g were generated in 65−92%

yields.

To gain further insight into the mechanism of the formation

of oxazol-5(4H)-ones, a series of control experiments were

conducted. The desired product 3a was generated in excellent

J. Org. Chem. XXXX, XXX, XXX−XXX

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Scheme 4. Cyclization Reactions of Allyl 2-Benzyl-2-isocyano-3-phenylpropanoates

Reaction Conditions. 6 (0.1 mmol), iodobenzene/2-naphthyl triﬂate (0.15 mmol), Pd(OAc) (0.01 mmol), PPh (0.02 mmol), Cs CO (0.1

mmol), PivOH (0.06 mmol), toluene, 80 °C, Ar. A solution of 6 in toluene (1 mL) was added slowly via a syringe pump within 1 h. Isolated yields.

Scheme 5. Tandem Annulation for the Synthesis of Oxindole-oxazol-5(4H)-one Biheterocyclies

Reaction Conditions. 8 (0.1 mmol), 9a/9a′ (0.15 mmol), Pd(OAc) (0.01 mmol), PPh (0.02 mmol), Cs CO (0.1 mmol), PivOH (0.06 mmol),

toluene, 80 °C, Ar. A solution of 8 in toluene (1 mL) was added slowly via a syringe pump within 1 h. Isolated yields.

Scheme 6. Gram-Scale Preparation and Transformations of 3a

yields when one equivalent of KI or Bu NI was added under

the subsequent reductive elimination aﬀorded the cyclic

standard conditions (Scheme 7a). Additionally, if AgOTf or

ketoimine product 5 with Pd(0) being released to complete

the catalytic cycle. When aryl triﬂate was applied in the

reaction, the Pd(II) intermediate III was considered to be

more ionic, which featured the potential to be attacked by an

intramolecular nucleophile (path a). Intermediate IV was

formed, followed by the release of the allyl group with the

AgBF was added in the reaction for the formation of 5a, the

title product was obtained in 42 and 39% yields, respectively,

in which the corresponding oxazol-5(4H)-one compounds

were not detected (Scheme 7b). These results suggested that

the exchange of the counteranion of imidoyl-palladium

intermediate was very slow. No product 3a was detected

with 92% of 10b being recovered by submitting 10b into the

catalytic system under standard conditions (Scheme 7c),

suggesting that the possibility of the generation of 10b

followed by intramolecular condensation annulation could be

ruled out. Next, 1.0 equiv of H₂¹⁸O was added in the standard

reaction with anhydrous solvent (Scheme 7b). The desired

product 3a was generated in 56% yield and the isotope labeling

ratio was 0%, revealing that the oxygen atoms of 3a were

totally from the ester group of 1a.

assistance of a nucleophile such as H O from the reaction

system. The product 3m was given from six-membered

palladacycle intermediate V, along with the regeneration of

Pd(0). However, the possibility that 3m was delivered from a

Pd(IV) intermediate, which was generated via an intra-

molecular oxidative addition of species III, could not be

ruled out at this stage. The allyl group was revealed to be

essential for the formation of oxazol-5(4H)-ones. The pivalic

acid might play the role of assisting the release of the allyl

group.

Based on the experiments, a possible mechanism of the

reactions was depicted in Scheme 8. Oxidative addition of the

in situ-generated Pd(0) species to electrophiles aﬀorded aryl-

Pd(II) intermediate II, followed by isocyanide coordination

and migratory insertion to deliver the imidoyl-Pd(II)

intermediate III. When the coupled anion was iodide, seven-

membered palladacycle intermediate (VI) was generated and

CONCLUSIONS

■

In summary, we have developed an eﬃcient and practical

method for the tunable preparation of oxazol-5(4H)-ones and

cyclic ketoimines via a palladium-catalyzed selective imidoyla-

tive cyclization of multifunctionalized isocyanides. Oxazol-

5(4H)-one derivatives were obtained exclusively when allyl-2-

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

Scheme 7. Mechanistic Studies

on a 400 or 500 MHz spectrometer. Chemical shifts were reported in

Scheme 8. Proposed Mechanism

units (ppm) by assigning TMS resonance in the H spectrum as 0.00

ppm, CDCl₃resonance in the C spectrum as 77.16 ppm. All

coupling constants (J values) were reported in Hertz (Hz). NMR

analysis was carried out at 298 K unless noted otherwise. High-

resolution mass spectrometry (HRMS) was obtained on an ESI-LC−

MS/MS or APCI-LC−MS/MS spectrometer.

General Procedure for the Synthesis of Multisubstituted

Oxazol-5(4H)-ones. Synthesis of 3a−3l. An oven-dried 25 mL

Schlenk tube charged with Pd(OAc) (0.01 mmol, 2.24 mg, 10 mol

), PPh (0.02 mmol, 10.8 mg, 20 mol %), and Cs CO (0.1 mmol,

32.6 mg, 1.0 equiv) was reﬁlled with Ar three times. Then, a solution

of 2 (0.15 mmol, 1.5 equiv), PivOH (0.06 mmol, 6.1 mg, 0.6 equiv) in

.5 mL of toluene was added by syringe and the tube was placed in an

0 °C oil-bath. A solution of 1 (0.1 mmol, 1.0 equiv) in 1.0 mL of

toluene was added dropwise with a syringe pump to the reaction

mixture within 1 h. The crude reaction mixture was extracted with EA

(20 mL × 3) and washed with brine (20 mL). The organic phase was

concentrated in vacuo and the residue was puriﬁed by silica gel ﬂash

column chromatography to aﬀord the corresponding products.

Synthesis of 3m−3t. An oven-dried 25 mL Schlenk tube charged

with Pd(OAc) (0.01 mmol, 2.24 mg, 10 mol %), PPh (0.02 mmol,

benzyl(or allyl)-2-isocyanoacetates were used in the reaction

with aryl triﬂates as electrophiles. Mechanistic studies

suggested that the allyl eater group may play the role of an

intramolecular nucleophile to trap the imidoyl-Pd(II) inter-

mediate. Cyclic ketoimines were generated in the presence of

aryl iodides with the allyl ester group remaining unreacted.

Furthermore, tandem annulation reactions were realized,

oﬀering an eﬃcient approach to oxindole-oxazolone biheter-

ocyclic systems.

10.8 mg, 20 mol %), and Cs CO (0.1 mmol, 32.6 mg, 1.0 equiv) was

reﬁlled with Ar three times. Then, a solution of 2 (0.3 mmol, 1.5

equiv), PivOH (0.06 mmol, 6.1 mg, 0.6 equiv) in 0.5 mL of toluene

was added by syringe and the tube was placed in an 80 °C oil-bath. A

solution of 1 (0.1 mmol, 1.0 equiv) in 1.0 mL of toluene was added

dropwise with a syringe pump to the reaction mixture within 1 h. The

crude reaction mixture was extracted with EA (20 mL × 3) and

washed with brine (20 mL). The organic phase was concentrated in

vacuo and the residue was puriﬁed by silica gel ﬂash column

chromatography to aﬀord the corresponding products.

EXPERIMENTAL SECTION

■

Gram-Scale Preparation of 3a. An oven-dried round-bottom ﬂask

General Information. Reactions were monitored by using thin-

charged with Pd(OAc)

(0.98 mmol, 220 mg, 10 mol %), PPh (1.96

2 3

layer chromatography (TLC) on commercial silica gel plates (GF

mmol, 1.06 g, 20 mol %), and Cs CO (9.8 mmol, 3.2 g, 1.0 equiv)

54). Visualization of the developed plates was performed under UV

was reﬁlled with Ar three times. Then, a solution of 2a (14.7 mmol,

4.06 g, 1.5 equiv), PivOH (5.88 mmol, 598 mg, 0.6 equiv) in 49 mL

of toluene was added by syringe and the tube was placed in an 80 °C

lights (GF 254 nm). Flash column chromatography was performed on

silica gel (200−300 mesh). H and C NMR spectra were recorded

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

oil-bath. A solution of 1a (9.8 mmol, 3.0 g, 1.0 equiv) in 98 mL of

toluene was added dropwise with a syringe pump to the reaction

mixture within 1 h. The crude reaction mixture was extracted with EA

5.70−5.62 (m, 1H), 5.20−5.11 (m, 2H), 4.48 (dt, J = 6.0, 1.5 Hz,

13 1

2H), 3.32 (d, J = 13.5 Hz, 2H), 3.03 (d, J = 14.0 Hz, 2H); C{ H}

NMR (125 MHz, CDCl ): δ 167.3, 162.1, 134.2, 131.8, 131.7, 130.4,

(

200 mL × 3) and washed with brine (200 mL). The organic phase

128.9, 119.7, 70.1, 67.2, 44.2. HRMS (ESI) m/z: [M + H] calcd for

was concentrated in vacuo and the residue was puriﬁed by silica gel

ﬂash column chromatography to aﬀord the compound 3a in 54% yield

C H Cl NO , 374.0709; found, 374.0705.

Allyl 2-(4-Bromobenzyl)-3-(4-bromophenyl)-2-isocyanopropa-

noate (1e). This compound was prepared similarly to 1a. Eluent:

(

2.06 g).

Substrates 1a−1i Were Prepared by the Following

petroleum ether/ethyl acetate (8:1). White solid, 82% yield. mp =

Procedures. Compound 1a was prepared according to the similar

61−63 °C. H NMR (400 MHz, CDCl ): δ 7.40−7.32 (m, 4H),

18,20,21

route of literature-reported methods.

i)To a solution of ethyl isocyanoacetate A (4.0 g, 35 mmol) in

tetrahydrofuran (THF) (20 mL) was added a solution of KOH

85%, 2.0 g, 35 mmol) in H O (5.0 mL) at room temperature.

7.06−7.03 (m, 4H), 5.62−5.52 (m, 1H), 5.11−5.01 (m, 2H), 4.40

dt, J = 5.6, 1.2 Hz, 2H), 3.22 (d, J = 13.6 Hz, 2H), 2.92 (d, J = 13.6

Hz, 2H); C{ H} NMR (100 MHz, CDCl ): δ 167.2, 162.0, 132.2,

(

31.9, 131.7, 130.3, 122.3, 119.7, 69.9, 67.1, 44.1. HRMS (ESI) m/z:

(

[M + H] calcd for C H Br NO , 461.9699; found, 461.9696.

20 18 2 2

The mixture was stirred for 5 h and concentrated in vacuo to

give a crude. The crude was pulverized in a mortar, washed

Allyl 2-Isocyano-2-(4-(triﬂuoromethyl)benzyl)-3-(4-

triﬂuoromethyl)phenyl)propanoate (1f). This compound was

prepared similarly to 1a. Eluent: petroleum ether/ethyl acetate

(

with Et O (50 mL), and dried in vacuo to give B (4.29 g, 99%)

as pale yellow solids.

(

8:1). White solid, 68% yield. mp = 67−68 °C. H NMR (400 MHz,

(

ii)To a suspension of potassium isocyanoacetate B (2.46 g, 20

CDCl ): δ 7.60 (d, J = 8.0 Hz, 4H), 7.40 (d, J = 8.0 Hz, 4H), 5.65−

mmol) in 15 mL of dimethylformamide (DMF), allyl bromide

5.55 (m, 1H), 5.15−5.04 (m, 2H), 4.47 (dt, J = 5.6, 1.2 Hz, 2H), 3.45

(

2.42 g, 20 mmol) were added and stirred at 55−60 °C for 3 h.

(d, J = 13.6 Hz, 2H), 3.14 (d, J = 13.6 Hz, 2H); C{ H} NMR (100

DMF was evaporated and the residue was diluted in 40 mL of

ethyl acetate and washed with water (3 × 15 mL). The organic

layer was separated and dried over Mg SO and concentrated.

MHz, CDCl ) 167.1, 162.8, 137.2, 130.8, 130.6 (q, J = 32.5) 130.2,

125.7 (q, J = 3.7 Hz), 124.1 (q, J = 270.5 Hz), 119.9, 69.8, 67.4, 44.7.

HRMS (ESI) m/z: [M + H] calcd for C H F NO , 442.1236;

22 18

The product was puriﬁed by column chromatography to give

.482 g (60%) of a colorless oil.

iii)To a solution of allyl 2-isocyanoacetate C (5 mmol) in

acetonitrile (20 mL) were added K CO (3.0 g, 22 mmol),

TBAHS (1.0 mmol), and (bromomethyl)benzene (10 mmol).

The mixture was heated at 70 °C until the reaction was

completed, monitoring with TLC. Then, the mixture was

cooled and the solvent was removed under reduced pressure.

found, 442.1239.

Dimethyl 4,4′-(2-((Allyloxy)carbonyl)-2-isocyanopropane-1,3-

diyl)dibenzoate (1g). This compound was prepared similarly to 1a.

(

Eluent: petroleum ether/ethyl acetate (6:1). White solid, 78% yield.

mp = 138−139 °C. H NMR (400 MHz, CDCl ): δ 8.00 (d, J = 8.4

Hz, 4H), 7.34 (d, J = 8.0 Hz, 4H),5.69−5.59 (m, 1H), 5.17−5.11 (m,

H), 4.47 (dt, J = 6.0, 1.2 Hz, 2H), 3.91 (s, 6H), 3.44 (d, J = 13.6 Hz,

H), 3.13 (d, J = 13.6 Hz, 2H); C{ H} NMR (100 MHz, CDCl ): δ

67.3, 166.9, 162.6, 138.4, 130.5, 130.4, 130.1, 129.9, 119.9, 69.8,

7.3, 52.3, 44.8. HRMS (ESI) m/z: [M + H] calcd for C H NO ,

42.1598; found, 442.1601.

Allyl 2-(2,6-Diﬂuorobenzyl)-3-(2,6-diﬂuorophenyl)-2-isocyano-

H O (20 mL) and ethyl acetate (20 mL) were added into the

mixture. The organic phase was separated and the aqueous

24 24

phase was extracted with ethyl acetate (20.0 mL × 3). The

combined organic phase was washed with H O and brine, and

propanoate (1h). This compound was prepared similarly to 1a.

dried over Na SO . The solvent was removed under reduced

Eluent: petroleum ether/ethyl acetate (8:1). White solid, 72% yield.

pressure and the residue was puriﬁed by column chromatog-

raphy to aﬀord the product 1a as a colorless oil in 80% yield

mp = 93−95 °C. H NMR (400 MHz, CDCl ): δ 7.26−7.18 (m, 2H),

.89−6.82 (m, 4H), 5.87−5.77 (m, 1H), 5.27−5.17 (m, 2H), 4.61

(new compound).

13 1

(

dt, J = 6.0, 1.2 Hz, 2H), 3.44−3.34 (m, 4H); C{ H} NMR (100

Allyl 2-Benzyl-2-isocyano-3-phenylpropanoate (1a). Eluent:

MHz, CDCl ): δ 167.2, 162.6, 162.0 (dd, J = 247.8, 7.4 Hz), 130.9,

petroleum ether/ethyl acetate (8:1). H NMR (500 MHz, CDCl ):

130.2 (t, J = 10.2 Hz), 119.6, 111.6 (dd, J = 19.4, 6.0 Hz) 110.1 (t, J =

19.4 Hz), 67.9, 67.0, 31.2. HRMS (ESI) m/z: [M + H] calcd for

δ 7.34−7.24 (m, 10H), 5.68−5.60 (m, 1H), 5.14−5.09 (m, 2H), 4.47

(

dt, J = 5.5, 1.5 Hz, 2H), 3.36 (d, J = 13.5 Hz, 2H), 3.07 (d, J = 13.5

C H F NO , 378.1112; found, 378.1120.

Hz, 2H); C{ H} NMR (125 MHz, CDCl ): δ 167.7, 161.5, 133.5,

Allyl 2-(2-Chlorobenzyl)-3-(2-chlorophenyl)-2-isocyanopropa-

noate (1i). This compound was prepared similarly to 1a. Eluent:

petroleum ether/ethyl acetate (8:1). Colorless oil, 75% yield. H

[

30.7, 130.4, 128.6, 128.0, 119.3, 70.4, 67.0, 45.0. HRMS (ESI) m/z:

M + H] calcd for C H NO , 306.1489; found, 306.1482.

Allyl 2-Isocyano-2-(4-methylbenzyl)-3-(p-tolyl)propanoate (1b).

NMR (500 MHz, CDCl ): δ 7.40−7.37 (m, 4H), 7.24−7.22 (m, 4H),

This compound was prepared similarly to 1a. Eluent: petroleum

5.81−5.73 (m, 1H), 5.26−5.19 (m, 2H), 4.62 (dt, J = 6.0, 1.5 Hz,

ether/ethyl acetate (8:1). Colorless oil, 79% yield. H NMR (400

2H), 3.55−3.48 (m, 4H); C{ H} NMR (125 MHz, CDCl ): δ

MHz, CDCl ): δ 7.16−7.10 (m, 8H), 5.74−5.64 (m, 1H), 5.17−5.11

167.67 163.0, 135.4, 131.9, 131.8, 130.6, 130.0, 129.3, 127.0, 119.5,

68.5, 67.5, 40.3. HRMS (ESI) m/z: [M + H]⁺calcd for

C H Cl NO , 374.0709; found, 374.0710.

(

m, 2H), 4.49 (dt, J = 5.6, 1.2 Hz, 2H), 3.31 (d, J = 13.6 Hz, 2H),

.03 (d, J = 13.6 Hz, 2H), 2.32 (s, 6H); C{ H} NMR (100 MHz,

CDCl ): δ 167.9, 161.2, 137.7, 130.9, 130.6, 130.3, 129.3, 119.3, 70.7,

Substrates 1j−1l & 6 Were Prepared by the Following

7.0, 44.6, 21.2. HRMS (ESI) m/z: [M + H] calcd for C H NO ,

42.1802; found, 342.1810.

Procedures. Compound 1j was prepared according to a route similar

22 23 2

to the methods reported in literature:

Allyl 2-(4-Fluorobenzyl)-3-(4-ﬂuorophenyl)-2-isocyanopropa-

(

i) A 100 mL round bottom ﬂask charged with 30 mL of

noate (1c). This compound was prepared similarly to 1a. Eluent:

CH(OMe) (solvent) and D (10 mmol, 1.95 g) was heated at

petroleum ether/ethyl acetate (8:1). Colorless oil, 84% yield. H

10 °C for 5 h. The solvent was removed under reduced

NMR (500 MHz, CDCl ): δ 7.26−7.22 (m, 4H), 7.04−6.99 (m, 4H),

pressure to aﬀord the crude product E for the next step

without further puriﬁcation.

.69−5.61 (m, 1H), 5.18−5.10 (m, 2H), 4.47 (dt, J = 6.0, 1.5 Hz,

13 1

H), 3.34 (d, J = 14.0 Hz, 2H), 3.04 (d, J = 13.5 Hz, 2H); C{ H}

(

ii)To a solution of crude E (10 mmol, 1.0 equiv) and Et N (4

NMR (125 MHz, CDCl ): δ 167.5 162.8 (d, J = 245.4 Hz) 161.9

equiv) in 30 mL of dry DCM was added POCl (1.2 equiv)

32.0 (d, J = 8.1 Hz) 130.5 129.2 (d, J = 3.0 Hz) 119.6 115.6 (d, J =

dropwise in 30 min at −20 °C. The reaction mixture was

1.3 Hz) 70.5 67.1 44.1. HRMS (ESI) m/z: [M + H] calcd for

stirred for 4 h. Then, 10 mL of H O was added slowly to the

C H F NO , 342.1300; found, 342.1307.

reaction mixture at −20 °C. The crude reaction mixture was

extracted with DCM (100 mL × 3) and washed with brine

(100 mL). The organic phase was concentrated in vacuo and

the residue was puriﬁed by silica gel ﬂash column

Allyl 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-2-isocyanopropa-

noate (1d). This compound was prepared similarly to 1a. Eluent:

petroleum ether/ethyl acetate (8:1). Colorless oil, 85% yield. H

NMR (500 MHz, CDCl ): δ 7.32−7.28 (m, 4H), 7.22−7.18 (m, 4H),

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

chromatography (petroleum ether/EtOAc = 6:1) to aﬀord the

product F as a yellow oil in 90% yield for two steps.

Substrates 1m & 1n Were Prepared by the Following

18a

Procedure.

(

iii)To a solution of ethyl isocyanoacetate F (7.10 g, 35 mmol)

(i)Compound 1m was prepared according to the route of

methods reported in the literature.

18a

in THF (20 mL) was added a solution of KOH (85%, 2.0 g, 35

mmol) in H O (5.0 mL) at room temperature. The mixture

was stirred for 5 h and concentrated in vacuo to give a crude.

(ii) To a solution of 1m (2.93 g, 10 mmol) in THF (6 mL) was

added a solution of KOH (85%, 0.56 g, 10 mmol) in H O (1.4

The crude was pulverized in a mortar, washed with Et O (50

mL) at room temperature. The mixture was stirred for 5 h and

concentrated in vacuo to give a crude. The crude was

mL), and dried in vacuo to give G (6.70 g, 90%) as a white

solid.

pulverized in a mortar, washed with Et O (50 mL), and

(

iv) To a suspension of potassium isocyanoacetate G (4.26 g, 20

mmol) in 15 mL of DMF, allyl bromide (2.42 g, 20 mmol)

were added and stirred at 55−60 °C for 3 h. DMF was

evaporated and the residue was diluted in 40 mL of ethyl

acetate and washed with water (3 × 15 mL). The organic layer

was separated and dried over Mg SO and concentrated. The

dried in vacuo to give I (2.73 g, 90%) as a white solid.

(

iii) To a suspension of I (3.03 g, 10 mmol) in 5 mL of MeCN,

BnBr (1.71 g, 10 mmol) was added and stirred at 80 °C for 4

h. MeCN was evaporated, the residue was diluted in 40 mL of

ethyl acetate, and washed with water (3 × 15 mL). The organic

layer was separated and dried over Mg SO and concentrated.

product was puriﬁed by distillation (p:1,2 mbar, T(oil bath) 91

C, T 58−60 °C) to give H (2.67 g,62%) as a colorless oil.

The product was puriﬁed by column chromatography [eluent:

petroleum ether/ethyl acetate (8:1)]. to give 1n (2.87 g,78%)

as a colorless oil.

(

v) An oven-dried 100 mL round bottom ﬂask charged with a stir-

bar and NaH (60%) (15 mmol, 1.5 equiv) was vacuumed and

reﬁlled with Ar three times. A mixture solution of DMSO (2

Benzyl 2-Benzyl-2-isocyano-3-phenylpropanoate (1n). H NMR

(

500 MHz): δ 7.30−7.25 (m, 9H), 7.23−7.20 (m, 4H), 7.09−7.07

m, 2H), 5.02 (s, 2H), 3.37 (d, J = 13.5 Hz), 3.08 (d, J = 14.0 Hz);

mL) and Et O (50 mL) was added to the ﬂask using a syringe.

(

Then, 10 mmol of H with a syringe and the reaction mixture

was stirred for 30 min. Two equivalents of bromoethane was

added with a syringe and the reaction mixture was stirred for

C{ H} NMR (125 MHz, CDCl ): δ 167.9, 161.6, 134.5, 133.5,

30.4, 128.7, 128.6, 128.6, 128.4, 128.0, 70.5, 68.2, 45.0. HRMS (ESI)

m/z: [M + H] calcd for C H NO , 356.1645; found, 356.1637.

0 min. Then, 2 mL of H O was added dropwise to the

Allyl 2-Benzyl-2-isocyanopent-4-enoate (6). This compound was

reaction mixture carefully at room temperature. The crude

reaction mixture was extracted with DCM (20 mL × 3) and

washed with brine (20 mL). The organic phase was

concentrated in vacuo and the residue was puriﬁed by silica

gel ﬂash column chromatography (petroleum ether/EtOAc =

prepared similarly to 1j. Eluent: petroleum ether/ethyl acetate (10:1).

Colorless oil, 90% yield. H NMR (400 MHz, CDCl ): δ 7.33−7.23

(

m, 5H), 5.87−5.74 (m, 2H), 5.29−5.21 (m, 4H), 4.58 (dt, J = 6.0,

.6 Hz, 2H), 3.23 (d, J = 13.6 Hz, 1H), 3.05 (d, J = 13.6 Hz, 1H),

.77 (dd, J = 13.6, 7.2 Hz, 1H), 2.57 (dd, J = 13.6, 7.2 Hz, 1H);

6:1) to aﬀord the product 1j as a colorless liquid in 70% yield

C{ H} NMR (100 MHz, CDCl ): δ 167.6, 160.7, 133.5, 130.8,

(new compound).

(

30.3, 123.0, 128.5, 127.9, 121.4, 119.5, 69.0, 67.0, 44.3, 43.2. HRMS

Allyl 2-Isocyano-3-phenylpropanoate (H). Colorless oil. H NMR

APCI) m/z: [M + H] calcd for C H NO , 256.1332; found,

(

400 MHz, CDCl ): δ 7.33−7.22 (m, 5H), 5.89−5.79 (m, 1H),

256.1329.

.33−5.23 (m, 2H), 4.63 (dt, J = 6.0, 1.6 Hz, 2H), 4.48−4.42 (m,

Substrates 8 Was Prepared by the Following Procedure.

An oven-dried 100 mL round bottom ﬂask charged with a stir-bar and

NaH (60%) (15 mmol, 3 equiv) was vacuumed and reﬁlled with Ar

H), 3.23 (dd, J = 14.0, 5.2 Hz, 1H), 3.11 (dd, J = 14.0, 8.4 Hz, 1H);

C{ H} NMR (100 MHz, CDCl ): δ 165.6, 160.8, 134.3, 130.6,

29.2, 128.6, 127.7, 119.5, 66.9, 57.9, 38.6. HRMS (APCI) m/z: [M +

three times. A mixture solution of DMSO (2 mL) and Et O (50 mL)

H] calcd for C H NO , 216.1019; found, 216.1023.

was added to the ﬂask using a syringe. Then, 5 mmol of C (1.0 equiv)

was added to the mixture dropwise in 10 min at room temperature

and the reaction mixture was stirred for 30 min. Three equivalents of

bromoethane was added with a syringe and the reaction mixture was

Allyl 2-Benzyl-2-isocyanobutanoate (1j). Eluent: petroleum

ether/ethyl acetate (10:1). Colorless oil, 80% yield. H NMR (400

MHz, CDCl ): δ 7.32−7.28 (m, 3H),7.26−7.23 (m, 2H), 5.86−5.76

(

m, 1H), 5.30−5.21 (m, 2H), 4.61−4.58 (m, 2H), 3.22 (d, J = 13.6

stirred for 30 min. Then, 2 mL of H O was added dropwise to the

Hz, 1H), 3.04 (d, J = 13.6 Hz, 1H),2.14−2.05 (m, 1H), 1.91−1.82

reaction mixture carefully at room temperature. The crude reaction

mixture was extracted with DCM (20 mL × 3) and washed with brine

(20 mL). The organic phase was concentrated in vacuo and the

residue was puriﬁed by silica gel ﬂash column chromatography

(petroleum ether/EtOAc = 16:1) to aﬀord the product 8 as a

colorless liquid in 86% yield (new compound).

(

m, 1H), 1.05 (t, J = 7.4 Hz, 3H); ¹³C{ H} NMR (100 MHz,

CDCl ): δ 168.1, 160.2, 133.7, 130.9, 130.3, 128.5, 127.9, 119.5, 70.2,

6.9, 44.6, 32.5, 8.6. HRMS (APCI) m/z: [M + H] calcd for

C H NO , 244.1332; found, 244.1338.

Allyl 2-Benzyl-2-isocyanobutanoate (1k). This compound was

prepared similarly to 1j. Eluent: petroleum ether/ethyl acetate (10:1).

Allyl 2-Ethyl-2-isocyanobutanoate (8). Eluent: petroleum ether/

Colorless oil, 75% yield. H NMR (400 MHz, CDCl ): δ 7.31−7.27

ethyl acetate (10:1). Colorless oil. H NMR (400 MHz, CDCl ): δ

(

m, 3H), 7.25−7.22 (m, 2H), 5.84−5.74 (m, 1H), 5.29−5.27 (m,

H), 4.58−4.56 (m, 2H), 3.21 (d, J = 13.6 Hz, 1H), 3.02 (d, J = 13.6

Hz, 1H), 2.07−1.93 (m, 1H), 1.82−1.75 (m, 1H), 1.69−1.57 (m,

.98−5.88 (m, 1H), 5.43−5.29 (m, 2H), 4.70 (dt, J = 5.6, 1.6 Hz,

H), 2.02−1.93 (m, 2H), 1.89−1.80 (m, 2H), 1.03 (t, J = 7.2 Hz,

H); C NMR (100 MHz, CDCl ): δ 168.7, 159.0, 131.2, 119.6,

(

H), 1.38−1.25 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); C{ H} NMR

0.1, 66.9, 32.3, 8.6. HRMS (APCI) m/z: [M + H] calcd for

100 MHz, CDCl ): δ 168.1, 160.2, 133.6, 130.8, 130.2, 128.4, 127.8,

C H NO , 182.1176; found, 182.1174.

19.3, 69.3, 66.7, 44.8, 41.0, 17.5, 13.5. HRMS (APCI) m/z: [M +

,4-Dibenzyl-2-(naphthalen-2-yl)oxazol-5(4H)-one (3a). Eluent:

H] calcd for C H NO , 258.1489; found, 258.1492.

petroleum ether/ethyl acetate (16:1). White solid (35 mg, 89%

Allyl 2-Benzyl-2-isocyano-4-methylpentanoate (1l). This com-

pound was prepared similarly to 1j. Eluent: petroleum ether/ethyl

acetate (10:1). Colorless oil, 72% yield. H NMR (400 MHz,

yield.). mp = 100−102 °C. H NMR (500 MHz, CDCl ): δ 8.08 (s,

H), 7.88−7.86 (m, 1H), 7.83−7.78 (m, 3H),7.55−7.47 (m, 2H),

.24−7.22 (m, 4H), 7.17−7.14 (m, 4H), 7.11−7.09 (m, 2H), 3.37−

3.31 (m, 4H); C{ H} NMR (125 MHz, CDCl ): δ 179.1, 159.9,

CDCl ): δ 7.31−7.28 (m, 3H), 7.24−7.21 (m, 2H), 5.81−5.72 (m,

H), 5.29−5.17 (m, 2H),4.56−4.49 (m, 2H), 3.18 (d, J = 13.6 Hz,

35.2, 134.5, 132.5, 130.3, 129.2, 129.1, 128.6, 128.3, 128.3, 127.9,

27.4, 127.0, 123.5, 122.9, 76.2, 43.8. HRMS (ESI) m/z: [M + H]⁺

H), 2.98 (d, J = 13.6 Hz, 1H), 2.04−1.87 (m, 2H), 1.81 (dd, J =

3.6, 4.8 Hz, 1H), 1.01 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H);

calcd for C H NO , 392.1645; found, 392.1642.

C{ H} NMR (100 MHz, CDCl ): δ 168.4, 160.8, 133.4, 130.7,

30.2, 128.3, 127.8, 119.4, 68.5, 66.8, 46.9, 46.3, 25.0, 23.6, 22.1.

HRMS (APCI) m/z: [M + H] calcd for C H NO , 272.1645;

found, 272.1647.

4,4-Bis(4-methylbenzyl)-2-(naphthalen-2-yl)oxazol-5(4H)-one

(3b). Eluent: petroleum ether/ethyl acetate (16:1). Colorless oil. (37

mg, 89% yield.). H NMR (400 MHz, CDCl ): δ 8.04 (s, 1H), 7.85−

7.82 (m, 1H), 7.79−7.73 (m, 3H), 7.50−7.41 (m, 2H), 7.04−7.02

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(

m, 4H), 6.89−6.88 (m, 4H), 3.26−3.18 (m, 4H). 2.11 (s, 6H);

127.0, 126.7, 123.7, 122.9, 75.6, 39.5. HRMS (ESI) m/z: [M + H]⁺

C{ H} NMR (100 MHz, CDCl ): δ 179.1, 159.8, 136.8, 135.2,

calcd for C H Cl NO , 460.0866; found, 460.0862.

27 20

32.5, 131.4, 130.2, 129.2, 129.0, 128.6, 128.3, 127.9, 127.0, 123.6,

23.0, 76.4, 43.3, 21.1. HRMS (ESI) m/z: [M + H] calcd for

4-Benzyl-4-ethyl-2-(naphthalen-2-yl)oxazol-5(4H)-one (3j). Elu-

ent: petroleum ether/ethyl acetate (16:1). Colorless oil (23 mg, 70%

C H NO , 420.1958; found, 420.1955.

yield.). H NMR (400 MHz, CDCl

): δ 8.31 (s, 1H), 7.98 (dd, J =

-(3-Fluorobenzyl)-4-(4-ﬂuorobenzyl)-2-(naphthalen-2-yl)-

8.6, 1.5 Hz, 1H), 7.90−7.86 (m, 3H), 7.60−7.52 (m, 2H), 7.22−7.10

oxazol-5(4H)-one (3c). Eluent: petroleum ether/ethyl acetate (16:1).

(m, 5H), 3.26 (d, J = 13.4 Hz, 1H), 3.18 (d, J = 13.4 Hz, 1H), 2.15−

White solid (22 mg, 52% yield.) mp = 116−118 °C. H NMR (500

2.05 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); C{ H} NMR (100 MHz,

MHz, CDCl ): δ 8.11 (s, 1H), 7.79−7.82 (m, 4H), 7.58−7.50 (m,

CDCl ): δ 179.9, 160.2, 135.3, 134.7, 132.6, 130.3, 129.3, 129.2,

H), 7.21−7.16 (m, 4H), 6.87−6.83 (m, 4H), 3.32−3.26 (m, 4H);

128.8, 128.4, 128.3, 128.0, 127.3, 127.1, 123.6, 123.0, 75.7, 43.7, 30.8,

C{ H} NMR (125 MHz, CDCl ): δ 178.9, 162.2 (d, J = 244.4 Hz),

8.6. HRMS (APCI) m/z: [M + H] calcd for C H NO , 330.1489;

22 20

60.2, 135.4, 132.6, 131.9 (d, J = 7.9 Hz), 130.2, 130.1, 129.2(d, J =

found, 330.1485.

5-4-Benzyl-2-(naphthalen-2-yl)-4-propyloxazol-5(4H)-one (3k).

.3 Hz), 128.8, 128.5, 128.0, 127.1, 123.3, 122.5, 115.3(d, J = 21.1

Hz), 76.2, 42.8. HRMS (ESI) m/z: [M + H] calcd for C H F NO ,

Eluent: petroleum ether/ethyl acetate (16:1). Colorless oil (25 mg,

28.1457; found, 428.1452.

,4-Bis(4-chlorobenzyl)-2-(naphthalen-2-yl)oxazol-5(4H)-one

3d). Eluent: petroleum ether/ethyl acetate (16:1). White solid (42

72% yield.). H NMR (400 MHz, CDCl ): δ 8.30 (s, 1H), 7.97 (dd, J

= 8.4, 1.6 Hz, 1H), 7.90−7.85 (m, 3H), 7.60−7.51 (m, 2H), 7.21−

(

.11 (m, 5H), 3.27−3.16 (m, 2H), 2.06−2.01 (m, 2H), 1.41−1.30

13 1

mg, 91% yield.) mp = 149−151 °C. H NMR (400 MHz, CDCl ): δ

(m, 1H), 0.93 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz,

.06 (s, 1H), 7.83−7.76 (m, 4H), 7.53−7.44 (m, 2H), 7.10−7.05 (m,

CDCl ): δ 180.0, 160.1, 135.3, 134.6, 132.6, 130.3, 129.3, 129.2,

H), 3.25−3.17 (m, 4H); C{ H} NMR (100 MHz, CDCl ): δ

128.8, 128.4, 128.3, 128.0, 127.3, 127.1, 123.5, 123.0, 75.2, 44.0, 39.7,

78.7, 160.4, 135.4, 133.5, 132.8, 132.5, 131.6, 129.4, 129.3, 128.9,

7.7, 14.1. HRMS (APCI) m/z: [M + H] calcd for C H NO ,

28.6, 128.0, 127.1, 123.3, 122.4, 75.9, 42.9. HRMS (ESI) m/z: [M +

44.1645; found, 344.1639.

4-Benzyl-4-isobutyl-2-(naphthalen-2-yl)oxazol-5(4H)-one (3l).

Eluent: petroleum ether/ethyl acetate (16:1). Colorless oil (31 mg,

H] calcd for C H Cl NO , 460.0866; found, 460.0859.

,4-Bis(4-bromobenzyl)-2-(naphthalen-2-yl)oxazol-5(4H)-one

(

3e). Eluent: petroleum ether/ethyl acetate (16:1). White solid (40

6% yield.). H NMR (400 MHz, CDCl ): δ 8.28 (s, 1H), 7.97 (dd, J

mg, 73% yield.) mp = 149−151 °C. H NMR (500 MHz, CDCl ): δ

= 8.6, 1.6 Hz, 1H), 7.90−7.85 (m, 3H), 7.60−7.51 (m, 2H), 7.28−

.07 (s, 1H), 7.82−7.78 (m, 4H), 7.53−7.45 (m, 2H), 7.24−7.19 (m,

.09 (m, 5H), 3.25−3.14 (m, 2H), 2.14−1.98 (m, 2H), 1.76−1.66 (m

13 1

H), 7.03−7.01 (m, 4H), 3.23−3.16 (m, 4H); C{ H} NMR (125

13 1

H), 0.94 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); C{ H}

MHz, CDCl ): δ 178.6, 160.4, 135.5, 133.3, 132.6, 132.0, 131.5,

NMR (100 MHz, CDCl ): δ 180.4, 159.8, 135.3, 134.2, 132.7, 130.4,

29.5, 129.3, 128.9, 128.6, 128.0, 127.2, 123.3, 121.7, 75.6, 43.0.

29.2, 128.8, 128.4, 128.2, 128.0, 127.4, 127.1, 123.5, 123.1, 74.7,

6.4, 45.2, 25.4, 24.2, 23.2. HRMS (APCI) m/z: [M + H] calcd for

HRMS (APCI) m/z: [M + H] calcd for C H Br NO , 547.9855;

found, 547.9850.

-(Naphthalen-2-yl)-4,4-bis(4-(triﬂuoromethyl)benzyl)oxazol-

(4H)-one (3f). Eluent: petroleum ether/ethyl acetate (16:1). White

C H NO , 358.1802; found, 358.1806.

,4-Dibenzyl-2-phenyloxazol-5(4H)-one (3m). Eluent: petroleum

ether/ethyl acetate (16:1). Colorless oil (25 mg, 72% yield.) H NMR

solid (35 mg, 66% yield.) mp = 116−118 °C. H NMR (400 MHz,

(

400 MHz, CDCl ): δ 7.69−7.67 (m, 2H), 7.49−7.45 (m, 1H),

CDCl ): δ 8.04 (s, 1H), 7.80−7.75 (m, 4H), 7.53−7.42 (m, 2H),

.38−7.33 (m, 2H), 7.22−7.12 (m, 10H), 3.33−3.26 (m, 4H);

.39−7.37 (m, 4H), 7.29−7.27 (m, 4H), 3.35−3.27 (m, 4H);

C{ H} NMR (100 MHz, CDCl

): δ 179.2, 159.9, 134.5, 132.5,

C{ H} NMR (100 MHz, CDCl ): δ 178.5, 160.6, 138.3, 135.5,

30.4, 128.7, 128.3, 127.8, 127.3, 125.8, 76.1, 43.7. HRMS (ESI) m/z:

32.5, 130.7, 129.8 (q, J = 32.4 Hz), 129.5, 129.3, 128.9, 128.7, 128.0,

[M + H] calcd for C H NO , 342.1489; found, 342.1486.

23 20 2

27.2, 125.4 (q, J = 3.7 Hz), 124.1 (q, J = 270.4 Hz), 123.2, 122.2,

4,4-Dibenzyl-2-(p-tolyl)oxazol-5(4H)-one (3n). Eluent: petroleum

5.4, 43.3. HRMS (ESI) m/z: [M + H] calcd for C H F NO ,

ether/ethyl acetate (16:1). White solid (29 mg, 81% yield.) mp = 64−

28.1393; found, 528.1399.

Methyl 3-((4-(4-(Methoxycarbonyl)benzyl)-2-(naphthalen-2-yl)-

-oxo-4,5-dihydrooxazol-4-yl)methyl)benzoate (3g). Eluent: petro-

5 °C. H NMR (400 MHz, CDCl ): δ 7.57 (d, J = 8.4 Hz, 2H),

13 1

.23−7.10 (m, 12H), 3.32−3.25 (m, 4H), 2.35 (s, 3H); C{ H}

NMR (100 MHz, CDCl ): δ 179.3, 159.9, 143.2, 134.6, 130.3, 129.4,

leum ether/ethyl acetate (12:1). White solid (33 mg, 65% yield.) mp

128.3, 127.8, 127.3, 123.0, 76.0, 43.7, 21.8. HRMS (ESI) m/z: [M +

149−151 °C. H NMR (500 MHz, CDCl ): δ 8.08 (s, 1H), 7.86−

H] calcd for C H NO , 356.1645; found, 356.1652.

.80 (m, 8H), 7.58−7.55 (m, 1H), 7.53−7.51 (m, 1H), 7.31−7.29

24 22

4,4-Dibenzyl-2-(4-methoxyphenyl)oxazol-5(4H)-one (3o). Elu-

ent: petroleum ether/ethyl acetate (16:1). White solid (27 mg, 74%

(

m, 4H), 3.81 (s, 6H), 3.41−3.56 (m, 4H); C{ H} NMR (125

MHz, CDCl ): δ 178.6, 166.9, 160.4, 139.6, 135.5, 132.5, 130.4,

yield.) mp = 75−76 °C. H NMR (400 MHz, CDCl ): δ 7.58−7.54

29.7, 129.4, 129.4, 128.9, 128.5, 128.0, 127.1, 123.3, 122.3, 75.6,

₂_.₁_,₄₃_.₆_._H_R_M_S₍_E_S_I₎_m_/_z_:_[_M₊_H_]+ calcd for C H NO ,

(m, 2H), 7.14−7.04 (m, 10H), 6.79−6.75 (m, 2H), 3.74 (s, 3H),

.24−3.17 (m, 4H); C{ H} NMR (100 MHz, CDCl ): δ 179.3,

08.1755; found, 508.1759.

,4-Bis(2,6-diﬂuorobenzyl)-2-(naphthalen-2-yl)oxazol-5(4H)-one

3h). Eluent: petroleum ether/ethyl acetate (16:1). White solid (31

63.0, 159.5, 134.7, 130.4, 129.6, 128.3, 127.3, 118.1, 114.1, 75.9,

(

55.5, 43.7. HRMS (ESI) m/z: [M + H] calcd for C24

372.1594; found, 372.1603.

4,4-Dibenzyl-2-(4-ﬂuorophenyl)oxazol-5(4H)-one (3p). Eluent:

H22NO

mg, 66% yield.) mp = 165−167 °C. H NMR (500 MHz, CDCl ): δ

.18 (s, 1H), 7.85 (dd, J = 8.5, 2.0 Hz, 1H), 7.80−7.76 (m, 3H),

.51−7.43 (m, 2H), 7.09−7.03 (m, 2H), 6.76−6.71 (m, 4H), 3.43−

petroleum ether/ethyl acetate (16:1). Colorless oil (26 mg, 72%

.36 (m, 4H); ¹³C{ H} NMR (125 MHz, CDCl ): δ 178.1, 161.9

yield.) H NMR (400 MHz, CDCl

): δ 7.70−7.67 (m, 2H), 7.20−

(dd, J = 248.1, 7.9 Hz), 160.4, 135.4, 132.6, 129.50 (t, J = 10.3 Hz),

7.12 (m, 10H), 7.05−7.01 (m, 2H), 3.32−3.25 (m, 4H); C{ H}

NMR (100 MHz, CDCl ): δ 178.9, 165.4 (d, J = 252.6 Hz), 158.9,

29.4, 129.2, 128.7, 128.4, 128.0, 127.0, 123.7, 123.0, 111.3 (dd, J =

06.3, 4.8 Hz), 110.8,(t, J = 19.9 Hz), 73.2, 30.2. HRMS (ESI) m/z:

134.5, 130.3, 130.1 (d, J = 8.8 Hz), 128.3, 127.3, 121.9 (d, J = 2.9₊

[

M + H] calcd for C H F NO , 464.1268; found, 464.1271.

Hz), 116.0 (d, J = 22.3 Hz). 76.1, 43.7. HRMS (ESI) m/z: [M + H]

,4-Bis(2-chlorobenzyl)-2-(naphthalen-2-yl)oxazol-5(4H)-one

calcd for C23H19FNO , 360.1394; found, 360.1390.

4,4-Dibenzyl-2-(4-chlorophenyl)oxazol-5(4H)-one (3q). Eluent:

(3i). Eluent: petroleum ether/ethyl acetate (16:1). White solid (37

mg, 81% yield.) mp = 105−107 °C. H NMR (500 MHz, CDCl ): δ

petroleum ether/ethyl acetate (16:1). Yellow oil (29 mg, 78%

.11−8.10 (m, 1H), 7.89−7.87 (m, 1H), 7.79−7.76 (m, 3H), 7.51−

.43 (m, 2H), 7.30−7.26 (m, 2H), 7.24−7.19 (m, 2H), 7.04−6.99

yield.). H NMR (400 MHz, CDCl ): δ 7.63−7.59 (m, 2H), 7.34−

7.31 (m, 2H), 7.19−7.13 (m, 10H), 3.29 (s, 4H); C{ H} NMR

(m, 4H), 3.57 (d, J = 13.5 Hz, 2H), 3.45 (d, J = 14.0 Hz, 2H);

(100 MHz, CDCl ): δ 178.8, 159.0, 138.9, 134.4, 130.3, 129.1, 129.0,

C{ H} NMR (125 MHz, CDCl ): δ 179.1, 159.7, 135.4, 135.3,

128.3, 127.4, 124.2, 76.2, 43.6. HRMS (ESI) m/z: [M + H] calcd for

132.7, 132.6, 132.1, 129.9, 129.3, 129.2, 128.8, 128.7, 128.4, 128.0,

C H ClNO , 376.1099; found, 376.1106.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

,4-Dibenzyl-2-(4-bromophenyl)oxazol-5(4H)-one (3r). Eluent:

Hz, 3H); ¹³C{ H} NMR (100 MHz, CDCl ): δ 173.2, 165.5, 150.5,

petroleum ether/ethyl acetate (16:1). White solid (31 mg, 74%

139.1, 136.7, 136.5, 131.8, 131.4, 130.5, 128.7, 128.2, 127.9, 127.9,

127.2, 126.9, 121.3, 67.2, 61.3, 42.7, 33.0, 14.1.

yield.) mp = 91−92 °C. H NMR (400 MHz, CDCl ): δ 7.79−7.76

(

m, 2H), 7.27−7.25 (m, 2H), 7.19−7.16 (m, 10H), 3.31 (s, 4H);

Benzyl 3-Benzyl-1-(naphthalen-2-yl)-3,4-dihydroisoquinoline-3-

C{ H} NMR (100 MHz, CDCl ): δ 178.5, 158.3, 152.1, 134.3,

carboxylate (3z). Eluent: petroleum ether/ethyl acetate (12:1).

Colorless oil (38 mg, 78% yield.) H NMR (500 MHz, CDCl ): δ

30.3, 129.9, 128.4, 127.5, 126.0, 121.9, 76.4, 43.6. HRMS (ESI) m/z:

.10 (s, 1H), 7.91−7.86 (m, 3H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H),

.53−7.51 (m, 2H), 7.41−7.38 (m, 1H), 7.31−7.29 (m, 1H), 7.27−

.25 (m, 4H), 7.24−7.19 (m, 4H), 7.17−7.12 (m, 4H), 5.05 (s, 2H),

.40 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 13.0

[

M + H] calcd for C H BrNO , 420.0594; found, 420.0590.

23 19 2

,4-Dibenzyl-2-(4-(triﬂuoromethyl)phenyl)oxazol-5(4H)-one (3s).

Eluent: petroleum ether/ethyl acetate (16:1). White solid (27 mg,

7% yield.) mp = 96−98 °C. H NMR (400 MHz, CDCl ): δ 7.79 (d,

Hz, 1H), 2.98 (d, J = 16.0 Hz, 1H); C{ H} NMR (125 MHz,

J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.20−7.13 (m, 10H), 3.35−

.28 (m, 4H); ¹³C{ H} NMR (100 MHz, CDCl ): δ 178.6, 158.7,

CDCl ): δ 173.4, 167.2, 136.7, 136.6, 136.1, 135.8, 134.1, 133.0,

31.4, 130.6, 129.2, 128.8, 128.6, 128.5, 128.5, 128.5, 128.2, 128.2,

34.3, 134.0 (q, J = 32.5 Hz), 130.3, 129.0, 128.4, 128.1, 127.5, 125.8

28.1, 127.9, 127.8, 127.1, 126.9, 126.8, 126.8, 126.4, 67.4, 66.9, 43.2,

3.0. HRMS (ESI) m/z: [M + H] calcd for C H NO , 482.2115;

(

q, J = 38.0 Hz), 123.6 (q, J = 271.0 Hz), 76.4, 43.6. HRMS (ESI) m/

z: [M + H] calcd for C H F NO , 410.1362; found, 410.1363.

34 27

found, 482.2110.

,4-Dibenzyl-2-(m-tolyl)oxazol-5(4H)-one (3t). Eluent: petroleum

Allyl 3-Benzyl-1-phenyl-3,4-dihydroisoquinoline-3-carboxylate

ether/ethyl acetate (16:1). Pale yellow solid (30 mg, 83% yield.) mp

(5a). Eluent: petroleum ether/ethyl acetate (14:1). Colorless oil

57−59 °C. H NMR (400 MHz, CDCl ): δ 7.50−7.47 (m, 2H),

13 1

(28 mg, 72% yield.). H NMR (400 MHz, CDCl ): δ 7.59−7.56 (m,

.28−7.12 (m, 12H), 3.33−3.27 (m, 4H), 2.32 (s, 3H); C{ H}

NMR (100 MHz, CDCl ): δ 179.1, 160.0, 138.5, 134.5, 133.4, 130.3,

H), 7.39−7.31 (m, 4H), 7.21−7.10 (m, 8H), 5.72−5.63 (m, 1H),

.11−5.03 (m, 2H), 4.43 (dt, J = 5.6, 1.6 Hz, 2H), 3.27 (d, J = 13.2

Hz, 1H), 3.19 (d, J = 16.0 Hz, 1H), 2.96 (d, J = 13.2 Hz, 1H);

28.6, 128.3, 128.2, 127.3, 125.6, 125.0, 76.0, 43.7, 21.3. HRMS (ESI)

m/z: [M + H] calcd for C H NO , 356.1645; found, 356.1652.

C{ H} NMR (100 MHz, CDCl ): δ 173.2, 167.1, 138.7, 136.6,

Ethyl 3-Benzyl-1-(naphthalen-2-yl)-3,4-dihydroisoquinoline-3-

carboxylate (3u).

(Known compound) eluent: petroleum ether/

136.6, 132.0, 131.4, 130.5, 129.7, 129.3, 128.5, 128.5, 128.4, 128.3,

ethyl acetate (12:1). Colorless oil (33 mg, 78% yield.). H NMR (400

128.2, 127.0, 126.8, 118.2, 67.3, 65.8, 42.7, 32.8. HRMS (ESI) m/z:

MHz, CDCl ): δ 8.13 (s, 1H), 7.92−7.88 (m, 3H), 7.80 (dd, J = 8.4,

[M + H] calcd for C26

24NO

, 382.1802; found, 382.1801.

.6 Hz, 1H), 7.53−7.50 (m, 2H), 7.43−7.39 (m, 1H), 7.33−7.21 (m,

H), 4.07 (q, J = 7.2 Hz, 2H), 3.37 (d, J = 13.2 Hz, 1H), 3.28 (d, J =

6.0 Hz, 1H), 3.10 (d, J = 13.2 Hz, 1H), 2.97 (d, J = 16.0 Hz, 1H),

Allyl 1-([1,1′-Biphenyl]-4-yl)-3-benzyl-3,4-dihydroisoquinoline-3-

carboxylate (5b). Eluent: petroleum ether/ethyl acetate (14:1).

Colorless oil (42 mg, 92% yield.). H NMR (400 MHz, CDCl ): δ

.77−7.74 (m, 2H), 7.69−7.64 (m, 4H), 7.49−7.44 (m, 3H), 7.44−

.35 (m, 3H), 7.30−7.27 (m, 2H),7.23−7.19 (m, 4H), 5.81−5.71 (m,

H), 5.19−5.11 (m, 2H), 4.51 (dt, J = 5.6, 1.6 Hz, 2H), 3.36 (d, J =

3.3 Hz, 1H), 3.28 (d, J = 16.0 Hz, 1H), 3.06 (d, J = 13.4 Hz, 1H),

.11 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 173.5,

67.1, 136.8, 136.8, 136.2, 134.1, 133.0, 131.3, 130.6, 129.1, 128.8,

28.7, 128.5, 128.4, 128.1, 127.9, 127.8, 127.0, 126.9, 126.8, 126.8,

26.4, 67.2, 61.2, 42.9, 33.0, 14.1.

Ethyl 3-Benzyl-1-phenyl-3,4-dihydroisoquinoline-3-carboxylate

2.97 (d, J = 16.0 Hz, 1H); C{ H} NMR (100 MHz, CDCl ): δ

(

3v).

(Known compound) eluent: petroleum ether/ethyl acetate

173.2, 166.8, 142.6, 140.9, 137.7, 136.7, 136.7, 132.0, 131.4, 130.6,

130.6, 129.9, 129.0, 128.6, 128.5, 128.4, 128.2, 127.7, 127.3, 127.1,

126.9, 118.2, 67.4, 65.8, 42.8, 33.0. HRMS (ESI) m/z: [M + H]⁺

(

12:1). Colorless oil (30 mg, 81% yield.). H NMR (400 MHz,

CDCl ): δ 7.66−7.63 (m, 2H), 7.47−7.38 (m, 4H), 7.28−7.19 (m,

H), 4.05 (q, J = 7.2 Hz, 2H), 3.33 (d, J = 13.2 Hz, 1H), 3.25 (d, J =

calcd for C32H28NO , 458.2115; found, 458.2112.

6.0 Hz, 1H), 3.04 (d, J = 13.2 Hz, 1H), 2.94 (d, J = 16.0 Hz, 1H),

Allyl 3-Benzyl-1-(3-methoxyphenyl)-3,4-dihydroisoquinoline-3-

.09 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 173.5,

carboxylate (5c). Eluent: petroleum ether/ethyl acetate (14:1).

67.1, 138.9, 136.8, 136.7, 131.3, 130.6, 129.6, 129.4, 128.6, 128.5,

28.4, 128.3, 128.1, 127.0, 126.8, 67.1, 61.2, 42.9, 33.0, 14.1.

Ethyl 3-Benzyl-1-(p-tolyl)-3,4-dihydroisoquinoline-3-carboxylate

Colorless oil (27 mg, 65% yield.). H NMR (400 MHz, CDCl

): δ

7.35−7.11 (m, 12H), 6.96−6.93 (m, 1H), 5.73−5.63 (m, 1H), 5.11−

5.03 (m, 2H), 4.43 (dt, J = 5.6, 1.6 Hz, 2H), 3.78 (s, 3H), 3.26 (d, J =

13.2 Hz, 1H), 3.20 (d, J = 15.6 Hz, 1H), 2.97 (d, J = 13.6 Hz, 1H),

(3w). Eluent: petroleum ether/ethyl acetate (12:1). Colorless oil (33

mg, 86% yield.). H NMR (500 MHz, CDCl ): δ 7.56 (d, J = 8.0 Hz,

2.88 (d, J = 16.0 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) 173.2,

H), 7.40−7.37 (m, 1H), 7.29−7.19 (m, 10H), 4.06−4.01 (m, 2H),

166.9, 159.6, 140.1, 136.6, 136.6, 132.0, 131.4, 130.6, 129.3, 128.5,

128.4, 128.3, 128.1, 127.1, 126.9, 121.9, 118.2, 115.8, 114.4, 67.3,

65.8, 55.5, 42.7, 32.8. HRMS (ESI) m/z: [M + H]⁺calcd for

C H NO , 412.1907; found, 412.1904.

3.32 (d, J = 13.0 Hz, 1H), 3.23 (d, J = 16.0 Hz, 1H), 3.02 (d, J = 13.5

Hz, 1H), 2.92 (d, J = 16.0 Hz, 1H), 2.42 (s, 3H), 1.08 (t, J = 7.5 Hz,

H); ¹³C{ H} NMR (125 MHz, CDCl ): δ 173.6, 166.9, 139.7,

27 26

36.8, 136.8, 136.0, 131.2, 130.6, 129.3, 128.9, 128.6, 128.4, 128.4,

Allyl 3-Benzyl-1-(4-ﬂuorophenyl)-3,4-dihydroisoquinoline-3-car-

28.1, 126.9, 126.6, 67.0, 61.1, 42.8, 32.9, 21.5, 14.1. HRMS (ESI) m/

boxylate (5d). Eluent: petroleum ether/ethyl acetate (14:1). Yellow

z: [M + H] calcd for C H NO , 384.1958; found, 384.1964.

oil (32 mg, 81% yield.) H NMR (400 MHz, CDCl

): δ 7.61−7.57

Ethyl 3-Benzyl-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline-3-

(m, 2H), 7.37−7.32 (m, 1H), 7.22−7.14 (m, 6H), 7.12−7.04 (m,

4H), 5.71−5.64 (m, 1H), 5.10−5.04 (m, 2H), 4.43 (dt, J = 5.6, 1.6

Hz, 2H), 3.24 (d, J = 13.3 Hz, 1H), 3.19 (d, J = 16.0 Hz, 1H), 2.95

carboxylate (3x). Eluent: petroleum ether/ethyl acetate (8:1).

Colorless oil (26 mg, 65% yield.). H NMR (500 MHz, CDCl ): δ

.63 (d, J = 8.5 Hz, 2H), 7.41−7.38 (m, 1H), 7.31 (d, J = 7.5 Hz,

H), 7.27−7.19 (m, 7H), 6.96 (d, J = 8.5 Hz, 2H), 4.05−4.01 (m,

H), 3.86 (s, 3H), 3.31 (d, J = 13.0 Hz, 1H), 3.22 (d, J = 16.0 Hz,

H), 3.01 (d, J = 13.5 Hz, 1H), 2.92 (d, J = 16.0 Hz, 1H), 1.08 (t, J =

(d, J = 13.3 Hz, 1H), 2.88 (d, J = 16.0 Hz, 1H); C{ H} NMR (100

MHz, CDCl ): δ 173.1, 166.1, 163.9 (d, J = 247.6 Hz) 136.7, 136.5,

134.8, 131.9, 131.5, 131.4, 131.3, 130.5, 128.6, 128.3, 128.2 (d, J = 2.9

Hz), 127.1, 126.9, 118.3, 115.3(d, J = 21.2 Hz), 67.3, 65.8, 42.7, 32.9.

.0 Hz, 3H); ¹³C{ H} NMR (125 MHz, CDCl ): δ 173.6, 166.3,

HRMS (ESI) m/z: [M + H] calcd for C H FNO , 400.1707;

26 23

61.0, 136.9, 136.8, 131.3, 131.1, 130.9, 130.5, 128.7, 128.5, 128.3,

28.1, 126.9, 126.7, 113.6, 67.0, 61.1, 55.5, 42.8, 33.1, 14.1. HRMS

found, 400.1699.

Allyl 3-Benzyl-1-(4-chlorophenyl)-3,4-dihydroisoquinoline-3-car-

(

ESI) m/z: [M + H]⁺calcd for C H NO , 400.1907; found,

boxylate (5e). Eluent: petroleum ether/ethyl acetate (14:1). Yellow

00.1912.

oil (31 mg, 76% yield.). H NMR (400 MHz, CDCl

): δ 7.55−7.52

Ethyl 3-Benzyl-1-(4-bromophenyl)-3,4-dihydroisoquinoline-3-

(m, 2H), 7.36−7.32 (m, 3H), 7.21−7.13 (m, 6H), 7.11−7.08 (m,

2H), 5.70−5.61 (m, 1H), 5.09−5.03 (m, 2H), 4.42 (dt, J = 5.6, 1.6

Hz, 2H), 3.23 (d, J = 13.2 Hz, 1H),.3.18 (d, J = 16.0 Hz) 2.96 (d, J =

carboxylate (3y).

ethyl acetate (12:1). Colorless oil (37 mg, 81% yield.) H NMR (400

(Known compound) eluent: petroleum ether/

MHz, CDCl ): δ 7.69 (d, J = 8.4Hz, 2H), 7.38−7.34 (m, 1H), 7.30−

13.2 Hz, 1H), 2.87 (d, J = 16.0 Hz, 1H); C{ H} NMR (100 MHz,

.27 (m, 2H), 7.23−7.09 (m, 8H), 4.01−3.95 (m, 2H), 3.20 (m, 2H),

.98 (d, J = 13.2 Hz, 1H), 2.88 (d, J = 16.0 Hz, 1H), 1.02 (t, J = 7.2

CDCl ): δ 173.0, 166.1, 137.1, 136.6, 136.4, 135.8, 131.9, 131.6,

130.7, 130.5, 128.6, 128.5, 128.2, 128.1, 128.1, 127.1, 126.9, 118.3,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c00672.

Article

7.3, 65.8, 42.7, 32.8. HRMS (ESI) m/z: [M + H]⁺calcd for

C H ClNO , 416.1412; found, 416.1403.

Allyl 3-Benzyl-1-(naphthalen-2-yl)-3,4-dihydroisoquinoline-3-

that the solvent was removed under reduced pressure, and the crude

material was puriﬁed by ﬂash column chromatography on silica gel to

aﬀord the product 10a.

carboxylate (5f). Eluent: petroleum ether/ethyl acetate (14:1).

Colorless oil (34 mg, 79% yield.). H NMR (400 MHz, CDCl ): δ

Methyl 2-(2-naphthamido)-2-benzyl-3-phenylpropanoate (10a).

Eluent: petroleum ether/ethyl acetate (10:1). White solid (42 mg,

.13 (s, 1H), 7.93−7.89 (m, 3H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H),

.55−7.52 (m, 2H), 7.43−7.41 (m, 1H), 7.34−7.28 (m, 3H), 7.25−

.20 (m, 5H), 5.81−5.72 (m, 1H), 5.20−5.11 (m, 2H), 4.53 (dt, J =

.6, 1.6 Hz, 2H), 3.38 (d, J = 13.2 Hz, 1H), 3.30 (d, J = 16.0 Hz, 1H),

99% yield.) mp = 110−112 °C. H NMR (400 MHz, CDCl ): δ

8.08−8.07 (m, 1H), 7.87−7.85 (m, 3H), 7.70−7.67 (m, 1H), 7.58−

7.50 (m, 2H), 7.22−7.09 (m, 10H), 6.98 (s, 1H), 4.24 (d, J = 13.6

Hz, 2H), 3.87 (s, 1H),3.35 (d, J = 13.2 Hz, 2H); C{ H} NMR (100

.10 (d, J = 13.2 Hz, 1H), 2.98 (d, J = 16.0 Hz, 1H); C{ H} NMR

MHz, CDCl ): δ 173.2, 167.7, 136.4, 134.9, 132.8, 129.8, 129.1,

(

100 MHz, CDCl ): δ 173.3, 167.1, 136.8, 136.7, 136.2, 134.1, 133.1,

32.0, 131.4, 130.7, 129.2, 128.8, 128.7, 128.6, 128.5, 128.2, 128.0,

27.9, 127.1, 126.9, 126.8, 126.4, 118.2, 67.4, 65.8, 42.9, 32.9. HRMS

128.7, 128.5, 127.9, 127.8, 127.4, 127.2, 126.9, 123.6, 68.3, 52.8, 40.9.

(

HRMS (ESI) m/z: [M + H] calcd for C H NO , 424.1907; found,

424.1908.

ESI) m/z: [M + H]⁺calcd for C H NO , 432.1958; found,

Allyl 2-(2-Naphthamido)-2-benzyl-3-phenylpropanoate (10b).

This compound was prepared similarly to 13a. Eluent: petroleum

32.1957.

Allyl 5-Chloro-3-(2-chlorobenzyl)-1-phenyl-3,4-dihydroisoquino-

line-3-carboxylate (5g). Eluent: petroleum ether/ethyl acetate

ether/ethyl acetate (10:1). White solid (20 mg, 44% yield.) mp =

130−132 °C. H NMR (400 MHz, CDCl ): δ 8.09 (s, 1H), 7.86 (d, J

(

14:1). Colorless oil (35 mg, 77% yield.). H NMR (400 MHz,

= 9.2 Hz, 3H),7.71−7.69 (m, 1H), 7.56−7.52 (m, 2H), 7.31−7.28

(m, 1H), 7.18−7.11 (m, 10H), 6.98 (s, 1H), 6.11−6.01 (m, 1H),

5.52−5.41 (m, 2H), 4.70−4.68 (m, 2H), 4.27 (d, J = 13.6 Hz, 2H),

CDCl ): δ 7.61−7.59 (m, 2H), 7.47−7.40 (m, 5H), 7.31−7.29 (m,

H), 7.14−7.11 (m, 4H), 5.81−5.71 (m, 1H), 5.20−5.11 (m, 2H),

.55−4.53 (m, 2H), 3.63 (d, J = 14.0 Hz, 1H), 3.52 (d, J = 16.4 Hz,

3.37 (d, J = 13.6 Hz, 2H); C{ H} NMR (100 MHz, CDCl ): δ

H), 3.47 (d, J = 14.0 Hz, 1H), 3.06 (d, J = 16.4 Hz, 1H); C{ H}

172.5, 167.6, 136.4, 134.9, 132.9, 132.8, 131.3, 129.9, 129.1, 128.7,

NMR (100 MHz, CDCl ): δ 172.8, 167.1, 138.4, 135.3, 134.6, 133.9,

128.4, 127.9, 127.8, 127.4, 127.2, 126.9, 123.6, 120.3, 68.2, 67.0, 41.0.

32.7, 132.0, 131.8, 130.1, 129.8, 129.5, 129.3, 128.3, 128.2, 127.5,

HRMS (ESI) m/z: [M + H] calcd for C30

28NO

, 450.2064; found,

26.8, 126.5, 118.3, 66.9, 66.0, 40.2, 30.4. HRMS (ESI) m/z: [M +

450.2067.

H] calcd for C H Cl NO , 450.1022; found, 450.1020.

Allyl 2-Benzyl-4-methylene-5-phenyl-3,4-dihydro-2H-pyrrole-2-

ASSOCIATED CONTENT

sı Supporting Information

■

carboxylate (7a). Eluent: petroleum ether/ethyl acetate (12:1).

Yellow oil (23 mg, 72% yield.) H NMR (400 MHz, CDCl ): δ 7.60−

The Supporting Information is available free of charge at

(

.57 (m, 2H), 7.45−7.39 (m, 3H), 7.23−7.19 (m, 5H), 5.99−5.89

m, 1H), 5.36−5.30 (m, 1H), 5.25−5.19 (m, 3H), 4.70−4.68 (m,

¹H and ¹³C{ H} NMR spectra of starting materials and

H), 3.38−3.30 (m, 2H), 3.20−3.15 (m, 1H), 2.88−2.82 (m, 1H);

C{ H} NMR (100 MHz, CDCl ): δ 173.7, 173.2, 147.8, 135.9,

products (PDF )

33.2, 132.1, 131.0, 130.2, 128.8, 128.5, 128.1, 126.8, 118.7, 112.8,

9.8, 66.2, 43.8, 38.4. HRMS (APCI) m/z: [M + H] calcd for

AUTHOR INFORMATION

Corresponding Authors

C H NO , 332.1645; found, 322.1646.

■

-Allyl-4-Benzyl-2-(naphthalen-2-yl)oxazol-5(4H)-one (7b). Elu-

ent: petroleum ether/ethyl acetate (10:1). Colorless oil (25 mg, 74%

Jian Wang − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China; orcid.org/

yield.). H NMR (400 MHz, CDCl ): δ 8.29 (s, 1H), 7.97 (dd, J =

(

.4, 1.6 Hz, 1H), 7.89−7.85 (m, 3H), 7.60−7.51 (m, 2H), 7.22−7.10

m, 5H), 5.77−5.67 (m, 1H), 5.26−5.21 (m, 1H), 5.15−5.12 (m,

H), 3.29−3.18 (m, 2H), 2.83−2.72 (m, 2H); C{ H} NMR (100

000-0003-0806-9590 ; Email: wang_jian989@163.com

MHz, CDCl ): δ 179.2, 160.2, 135.3, 134.4, 132.6, 130.92, 130.3,

Yongjia Shang − Key Laboratory of Functional Molecular

Solids, Ministry of Education, Anhui Laboratory of Molecule-

Based Materials, College of Chemistry and Materials Science,

Anhui Normal University, Wuhu 241000, P. R. China;

orcid.org/0000-0001-9873-9150; Email: shyj@

mail.ahnu.edu.cn

29.4, 129.2, 128.7, 128.4, 128.3, 128.0, 127.4, 127.1, 123.6, 122.9,

20.8, 75.1, 43.4, 41.7. HRMS (APCI) m/z: [M + H] calcd for

C H NO , 342.1489; found, 342.1496.

-((1,3-Dimethyl-2-oxoindolin-3-yl)methyl)-4,4-diethyloxazol-

(4H)-one (9a). Eluent: petroleum ether/ethyl acetate (5:1). White

solid (25 mg, 81% yield.) mp = 94−96 °C. H NMR (400 MHz,

CDCl ): δ 7.27−7.23 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.82 (d, J =

.4 Hz, 1H), 3.26−3.22 (m, 4H), 2.96 (d, J = 15.6 Hz, 1H), 1.53−

.51 (m, 4H), 1.47 (s, 3H), 0.46 (t, J = 7.2 Hz, 3H), 0.37 (t, J = 7.2

Authors

Ling Zhong − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Shi Tang − Department of Pharmacy, School of Life and

Pharmaceutical Sciences, Hainan University, Haikou 570228,

P. R. China

Yuan Liu − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Shumin Ding − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Hz, 3H). C{ H} NMR (101 MHz, CDCl ): δ 180.2, 179.2, 160.3,

43.9, 131.9, 128.6, 123.0, 122.7, 108.4, 73.8, 46.0, 36.9, 29.8, 29.6,

6.6, 24.6, 7.7, 7.6. HRMS (ESI) m/z: [M + H] calcd for

C H N O , 315.1703; found, 315.1703.

,4-Diethyl-2-((1-methyl-2-oxoindolin-3-ylidene) (phenyl)-

methyl)oxazol-5(4H)-one (9b). Eluent: petroleum ether/ethyl acetate

(

4:1). Yellow solid (22 mg, 58% yield.) mp = 89−91 °C. H NMR

400 MHz, CDCl ): δ 7.56−7.52 (m, 2H), 7.51−7.49 (m, 3H),

.28−7.23 (m, 1H), 6.78−6.66 (m, 3H), 3.23 (s, 3H), 1.93 (q, J = 7.6

13 1

Hz, 4H), 0.91 (t, J = 7.6 Hz, 6H); C{ H} NMR (100 MHz,

CDCl ): δ 180.5, 165.6, 160.4, 145.0, 135.3, 134.3, 131.4, 131.1,

30.2, 129.4, 128.6, 124.3, 122.1, 120.8, 108.4, 74.1, 29.4, 26.2, 8.3.

HRMS (ESI) m/z: [M + H] calcd for C H N O , 375.1703; found,

75.1709.

Compounds 10a and 10b Were Prepared by the Following

Procedure. To a solution of 3a (0.1 mmol) in MeOH (0.5 mL, 5

mL/mmol), two drops of triﬂic acid were added and the solution was

stirred at room temperature until completion of reaction (1 h). After

Lianjie Li − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

(5) (a) Guo, C.; Li, B.; Liu, H.; Zhang, X.; Zhang, X.; Fan, X.

Article

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Haixia Zhao − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Chen Chen − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, College of Chemistry and Materials Science, Anhui

Normal University, Wuhu 241000, P. R. China

Cyclic 1,3-Dicarbonyl Compounds with Alkynes and Alkenes. J. Am.

Chem. Soc. 2013, 135, 10829.

Synthesis of Fused or Spiro Polyheterocyclic Compounds via the

Dehydrogenative Annulation Reactions of 2-Arylindazoles with

Maleimides. Org. Lett. 2019 , 21 , 7189. (b) Guo, S.; Liu, Y.; Zhao,

L.; Zhang, X.; Fan, X. Rhodium-Catalyzed Selective Oxidative

(Spiro)annulation of 2-Arylindoles by Using Benzoquinone as a C2

or C1 Synthon. Org. Lett. 2019 , 21 , 6437. (c) Chen, X.; Wang, M.;

Zhang, X.; Fan, X. Rh(III)-Catalyzed Cascade Reactions of

Sulfoxonium Ylides with α -Diazocarbonyl Compounds: An Access

to Highly Functionalized Naphthalenones. Org. Lett. 2019 , 21 , 2541.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c00672

d) He, Y.; Feng, T.; Fan, X. Synthesis of Functionalized Indole-1-

oxide Derivatives via Cascade Reactions of Allenynes and BuONO.

Org. Lett. 2019, 21, 3918.

Notes

(6) (a) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A.

The authors declare no competing ﬁnancial interest.

Palladium-Catalyzed Migratory Insertion of Isocyanides: An Emerg-

ing Platform in Cross-Coupling Chemistry. Angew. Chem., Int. Ed.

2013 , 52 , 7084. (b) Lang, S. Unravelling the labyrinth of palladium-

catalysed reactions involving isocyanides. Chem. Soc. Rev. 2013 , 42 ,

ACKNOWLEDGMENTS

■

This work was supported by the National Natural Science

Foundation of China (21702003, 21772001) and the Natural

Science Foundation of Anhui Province (1808085QB31)

867. (c) Qiu, G.; Ding, Q.; Wu, J. Recent advances in isocyanide

insertion chemistry. Chem. Soc. Rev. 2013, 42, 5257.

7) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Versuche mit

isonitrilen. Angew. Chem. 1959 , 71 , 386. (b) Ramon, D. J.; Yus, M.

Asymmetric Multicomponent Reactions (AMCRs): The New

Frontier. Angew. Chem., Int. Ed. 2005 , 44 , 1602. (c) Domling, A.

(

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