Intermolecular Interception of α-Oxo Gold Carbenes of Nitroalkyne Cycloisomerization with 1,2-Benzo[ d]isoxazole: Synthesis of Functionalized Quinazoline 1-Oxides

Functionalized Quinazoline 1 ‑Oxides

Note

Intermolecular Interception of α‑Oxo Gold Carbenes of Nitroalkyne

Cycloisomerization with 1,2-Benzo[d]isoxazole: Synthesis of

Pawan S. Dhote, Kishor A. Pund, and Chepuri V. Ramana*

Cite This: J. Org. Chem. 2021, 86, 10874 −10882

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sı Supporting Information

ABSTRACT: The known nitrogen-transfer reagent 1,2-benzo[d]-

isoxazole has been used to trap the postulated α-oxo gold carbene

intermediate involved in the [Au]-catalyzed internal redox process of

-alkynylnitrobenzenes. This process led us to develop a general

convergent method for the synthesis of highly functionalized

quinazoline 1-oxides.

n recent years, homogeneous gold catalysis has taken a

nitroso group to quinomethide and deprotonation should lead

signiﬁcant place in organic synthesis, in general, and in

to the quinazoline 1-oxide 5. Quinazoline 1-oxides are

relatively unexplored in medicinal chemistry, which is quite

surprising, as the parent quinazoline is one of the privileged

skeletons in various drug discovery programs and is widely

heterocyclic synthesis, in particular. Speciﬁcally, the catalytic

processes involving the reactive α-imino or α-oxo gold carbene

intermediates represent an important advancement in this

domain because of the versatile transformations that these

found in various natural products/approved drugs. In

general, these quinazoline-1-oxides are synthesized by N-

oxidation, and there are no general methods documented for

intermediates undergo and the resulting product diversity. In

particular, the α-oxo gold carbene intermediates have attracted

much attention, as they are easy to generate by inter- or

intramolecular addition of nucleophilic oxygen donors to

their convergent synthesis. In this context, the development

of novel synthetic routes to access quinazoline-1-oxides is an

attractive task.

alkynes. The exploited oxygen donors in this context include

nitro compounds, nitrones, sulfoxides, pyridine N-oxides, and

epoxides.

Our initial experiments in this regard started with the

nitroalkyne 1a and benzo[d]isoxazole 4a as the substrates and

examined the gold and palladium complexes that are

commonly employed in the internal nitroalkyne redox process.

In general, the reactions were carried out employing 1 equiv of

In 2003, employing o-alkynylnitrobenzenes, Yamamoto’s

group revealed the inaugural entry on the gold-catalyzed

intramolecular oxygen atom transfer to alkyne that leads to

either isatogen 2 or anthranil 3. The possibility of an α-oxo

-(but-1-yn-1-yl)-2-nitrobenzene (1a) and 1.1 equiv of

metal carbene after the initial internal nitroalkyne redox

benzo[d]isoxazole 4a in suitable solvent at a given temperature

in the presence of 5 mol % of catalyst. Table 1 saliently

describes the exploratory experiments that were conducted in

cyclization has been proposed by Crabtree’s group in a similar

transformation mediated by IrH complexes. A similar

possibility in the gold-catalyzed internal nitroalkynes redox

this context. When AuBr was employed as a catalyst in

process has been speculated by Liu and our groups. The

possible inter/intramolecular trapping of these speculated gold

carbene intermediates with other nucleophiles that interrupt

the subsequent intramolecular process is challenging and has

toluene, it aﬀorded the self-cycloisomerization product

anthranil 3a, along with a trace amount of a new product

with an expected mass corresponding to the desired product

aa, while the reaction with Pd(CH CN) Cl complex in

7b,8

3 2 2

been attempted with limited success.

Recently, the carbene

7a,b

acetonitrile gave isatogen 2a exclusively. Next, AuCl₃was

transfer from the α-oxo gold carbene A has been realized

successfully by employing a benzo[c]isoxazole that resulted

initially in an imine, which subsequently underwent a Davis−

employed in 1,2-dichloroethane, which results in the formation

of anthranil 3a in trace amounts (entry 3). Gratifyingly, when

Beirut reaction giving highly functionalized indazoles.

Received: May 25, 2021

Published: July 27, 2021

In continuation, we speculated a similar carbene exchange

with the isomeric benzo[d]isoxazole 4 to synthesize the

quinazoline 1-oxides. As shown in Scheme 1, the postulated

[

Au] → N carbene exchange of intermediate A with

benzo[d]isoxazole 4 is expected to provide the imino-o-

quinomethide B. Subsequent nucleophilic addition of the

2021 American Chemical Society

J. Org. Chem. 2021, 86, 10874−10882

0874

The Journal of Organic Chemistry

Note

Scheme 1. Synthesis of Quinazoline 1-Oxides: Reported

Methods and the Proposed Method via the Trapping of the

Intermediate α-Oxo Gold Carbenes with 1,2-

Benzo[d]isoxazole

Table 1. Optimization of the Reaction Conditions.

yield (%)

entry

catalyst

solvent

PhMe

(%)

2a or 3a (%)

AuBr₃

Pd(CH CN) Cl

trace

64 (3a)

66 (2a)

trace (3a)

10 (3a)

CH CN

AuCl₃

(CH ) Cl

PhMe

CH CN

1,4 Dioxane

PhCF₃

PhCl

PhMe

13 (3a)

10 (3a)

32 (3a)

16 (3a)

19 (3a)

26 (3a)

18 (3a)

24 (3a)

6 (3a)

PPh AuCl/AgSbF₆

PicAuCl₂

JohnPhosAuCl/AgSbF₆

IPrAuCl/AgNTf₂

BrettPhosAuCl/AgNTf₂PhMe

PhMe

AuCl

PhMe

AuCl₃

trace (3a)

In general, the reactions were carried out with 0.2 mmol of 1a and

.22 mmol of 4a in 2 mL of solvent and 5 mol % of catalyst at rt with

a reaction time of 2−4 h. Isolated yield. Reaction was carried at 80

C. Addition of 1a to solution of 4a in solvent through a syringe

pump for 4 h. With 3 equiv (0.66 mmol) of 4a.

unit (1a−1i, 1o−1r) and also the phenyl-substituted one 1t by

placing diﬀerent substituents para to the alkyne group (1j−1n)

and also by changing the substituents on the 1,2-benzo[d]-

isoxazole counterpart (4a−4h). As shown in Scheme 2,

changing the length of the pendant alkyne unit did not alter

the reaction outcome (5aa−5ca), whereas steric hindrance on

the alkyne unit had an inﬂuence on the reaction outcome. For

example, with the isobutyl substituent, the yield of the desired

quinazoline 1-oxide was reduced to 60% (5da), and when a

benzyl (1o) and tert-butyl (1r) group was present, there was

no intermolecular interception and the intramolecular

cyclization leading to corresponding anthranils was the main

event. Similarly, when propargylic carbons bear an −I group

such as −OTHP (1p) or −NHBoc (1q) the reactions led to a

complex mixture from which a mixture of corresponding

anthranils and/or isatogens could be isolated in small amounts.

However, when the same groups are present on the

homopropargylic position, their reactions with 1,2-benzo[d]-

isoxazole 4a proceeded smoothly and provided the corre-

sponding quinazoline oxides in moderate to good yields. The

examined scope with these substrates revealed the tolerance for

various protecting group such as OAc, OTBS, OTHP, and

OBn on the alkyl chain under current conditions. In addition, a

gram-scale reaction was performed under the optimized

we switched to toluene as a solvent, it aﬀorded the desired

quinazoline 1-oxide 5aa (62%) as the major product along

with anthranil 3a (10% yield) (entry 4).

Encouraged by these results, we screened diﬀerent solvents.

However, there was no net increase in the yield of 5aa (entries

−8). The changing of gold catalyst and the addition of silver

salts did not improve the yields (entries 9−13). In all these

cases, the anthranil 3a was obtained in a major quantity along

with requisite 5aa obtained as a minor product. When AuCl

was employed as a catalyst, a mixture of 5aa and 3a was

obtained in equal proportions (entry 14). Heating the reaction

to 80 °C improved the yield of 5aa nominally (65%, entry 15).

The yield of 5aa was improved further to 73% when the

reaction was carried out by the slow addition of 1a to a

solution of 4a along with AuCl . In this case, the formation of

cycloisomerization product 3a was also minimized to trace

amounts (entry 16). At this stage, the reaction with excess 1,2-

benzo[d]isoxazole 4a (3 equiv) under these conditions was

tried. However, it did not improve the yield of the desired

product (entry 17). A control experiment conducted without

gold catalyst and by heating a mixture of 1a and 4a at 80 °C in

toluene revealed that both of the starting compounds were

intact as well as the essential role of the gold complex for the

internal oxygen transfer (entry 18).

conditions, and it was found that with 2 mol % of AuCl the

reactions proceeded well and provided the desired quinazoline

1-oxide 5ba in 69%. Next, we examined the reactions with the

substrates having electron withdrawing/donating groups such

as −CO Me (1m), −NO (1k), −F (1j), and −Me (1l) para

With the optimized conditions in hand, the scope of this

reaction has been expanded by employing nitroalkyne

substrates with varying substituents on the pendant alkyne

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The Journal of Organic Chemistry

Note

Scheme 2. Reaction Scope

employed in the current reaction to examine how the

electronic nature of the substituent para to the phenolic

oxygen would inﬂuence the reaction outcome. In general, the

reactions with these four 1,2-benzo[d]isoxazoles were found to

be smooth and provided the corresponding heterocyclic

products in moderate to good yields. In addition, the

benzo[d]isoxazole having 5,7-dichloro (4f) or −NO (4g)

were found to be incompatible, and the reactions with these

substrates resulted mainly in the anthranil formation. Some of

the synthesized N-oxide derivatives were subjected for N−O

bond reduction by using Zn dust in 30% aq NH Cl in THF to

aﬀord the corresponding quinazoline derivative in good yields

(

Scheme 3).

Scheme 3. Defunctionalization to Quinazoline Scaﬀolds

Reaction conditions: 5 (0.16 mmol), Zn dust (0.32 mmol), aq 30%

NH Cl/THF (1 mL, 1:1), rt, 1 h.

Having established the generality of the current reaction, we

next proceeded further to learn about the possible involve-

ment of the α-oxo gold carbene intermediate and carbene

transfer to a nitrogen center. With 2-phenyethynylnitroben-

zene 1t, there was no interception by the 1,2-benzo[d]-

isoxazoles and the reaction provided exclusively to isatogen (eq

, Scheme 4). When 3-methylbenzo[d]isoxazole 4h was used

along with 1b, the self-cycloisomerized product 3b was

obtained exclusively in 79% yield (eq 2, Scheme 4). This,

taken together with the fact that 3-methyl-1,2-benzo[d]-

isoxazole (4h) is not compatible in the current reaction,

provided an indirect support for the initial N−O transfer to the

alkyne. This ruled out the alternative possibility of the

competing addition of the benzoxazole nitrogen to the alkyne,

leading to an α-imino gold carbene and subsequent internal

For reaction conditions, see Table 1, entry 16. Isolated yields are

reported after column chromatography.

to the alkyne unit. Interestingly, with the substrate having the

−

CO Me, the best reaction outcome was seen. On the other

hand, with the substrate having the −NO group, the

10,18

intramolecular cyclization competed well and resulted in the

requisite quinazoline N-oxide (5ka) in 34% yield, along with

substantial amounts of anthranil/isatogen. With the substrates

oxygen transfer.

Similar unsuccessful attempts in interrupt-

ing or trapping of the intermediates of the nitroalkyne

cycloisomerization of 2-arylethynylnitrobenzenes such as 1t

reveal that the intermediate α-oxo gold carbene involved in this

process is relatively unstable and/or the subsequent 6π-

−

F or −Me, the corresponding quinazoline N-oxides 5ja

(

51%) and 5la (61%), respectively, were obtained in moderate

,8b,19

yields. Next, the 1,2-benzo[d]isoxazoles having substituents

such as −F (4b), −Cl (4c), −Br (4d), and −Me (4e) were

electrocyclization of this carbene is relatively faster.

Next,

competition experiments such as adding the nitroalkyne 1a to a

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Note

Scheme 4. Control and Competition Experiments

formation of α-imino vs α-oxo gold carbenes. It also revealed

the opportunities with 1,2-benzo[d]isoxazoles to participate in

the carbene transfer from the gold centers, apart from its

established addition to alkynes leading to α-imino gold

carbenes. Work in the direction of expanding the scope of

the reaction with other nitrogen transfer agents in this regard is

currently progressing in our lab.

EXPERIMENTAL SECTION

■

General Information. The reactions were carried out in

anhydrous solvents under argon atmosphere in oven-dried glassware.

All anhydrous solvents were distilled prior to use. Commercial

reagents were used without any puriﬁcation. Column chromatography

was carried out by using silica gel (60−120, 100−200, 230−400

mesh). H and C NMR chemical shifts are reported in relative to

chloroform-d (δ = 7.27) or TMS, and coupling constants (J) are

reported in hertz (Hz). The following abbreviations have been used to

designate signal multiplicity: s = singlet, d = doublet, t = triplet, q =

quartet, sxt = sextet, hept = septet, m = multiplet, b = broad. High-

resolution mass spectra (HRMS) were recorded on a Q Exactive

Hybrid Quadrupole Orbitrap mass spectrometer, where the mass

analyzer used for analysis is orbitrap and some compounds on

electrospray ionization time-of-ﬂight (ESI-TOF). Infrared (IR)

−

spectra were measured in cm using FT−IR spectrophotometer.

General Procedure for the Synthesis of Quianozoline 1-Oxide

Derivatives. In general, all reactions were carried out employing 50

mg of nitroalkyne 1. At rt, to a stirred solution of 1,2-benzo[d]-

isoxazole 4 (1.1 equiv) in anhydrous toluene (1 mL) were added

AuCl (5 mol %) and 4 Å molecular sieves (40 mg), and a solution of

nitroalkyne 1 (1 equiv) in anhydrous toluene (1 mL) was introduced

via syringe pump over a period of 2−4 h. The stirring was continued

until the complete disappearance of the starting nitroalkyne as

indicated by TLC. The reaction mixture was concentrated under

reduced pressure, and the resulting crude was puriﬁed by column

chromatography to aﬀord the products 5.

-(2-Hydroxyphenyl)-4-propionylquinazoline 1-oxide (5aa): R =

0.4 (20% EtOAc in petroleum ether); yield 61 mg (73%); orange

Conditions: (a) = AuCl (5 mol %), 4 Å MS, PhMe, rt, 4 h.

solid; IR (neat): ν 2975, 2930, 1699, 1530, 1468, 1314, 1252, 1159,

max

−

1 1

55 cm ; H NMR (500 MHz, CDCl ): δ 10.41 (s, 1H), 9.05 (dd, J

equimolar mixture of benzo[d]isoxazole 4a and its regioisomer

benzo[c]isoxazole 7a under the current conditions resulted

exclusively in quinazoline 1-oxide 5ba (71% yield) along with

the recovery of 7a, revealing that the N-centered nucleophile of

benzo[d]isoxazole is more reactive than the anthranil (eq 3,

= 0.7, 8.5 Hz, 1H), 8.87 (d, J = 8.7 Hz, 1H), 8.07−8.15 (m, 2H), 7.88

ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.58 (ddd, J = 1.7, 7.0, 8.4 Hz, 1H),

.09−7.22 (m, 2H), 3.42 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H),

(

ppm; C{ H} NMR (125 MHz, CDCl ) δ 202.3 (s), 160.3 (s), 152.1

(

s), 148.7 (s), 144.6 (s), 135.7 (d), 133.7 (d), 133.0 (d), 130.9 (d),

27.6 (d), 121.2 (s), 120.5 (d), 120.4 (s),120.1 (d), 119.3 (d), 33.2

t), 7.8 (q) ppm; HRMS (ESI) calcd for C H N O : 295.1077 [M +

Scheme 4). When deuterated (benzo[d]isoxazole-3-d) 4a-

17 15

was employed along with 1b, there was no incorporation

H] ; found: 295.1073.

of the deuterated hydrogen in product 5ba (eq 4, Scheme 4).

This indicated that the aromatization step involves the removal

of the hydrogen atom next to the imine. Finally, a control

experiment that included treating an equimolar mixture of o-

nitroalkyne 1b and the quinazoline N-oxide 5ba under the

optimized conditions (in the absence of benzo[d]isoxazole)

resulted exclusively in the cycloisomerized product anthranil

2-(2-Hydroxyphenyl)-4-propionylquinazoline 1-oxide (5ba): R =

0.4 (20% EtOAc in petroleum ether); yield 60 mg (74%); orange

solid; IR (neat) νmax 2975, 2930, 1699, 1530, 1468, 1314, 1252, 1159,

−1 1

(

55 cm ; H NMR (500 MHz, CDCl ) δ 10.41 (s, 1H), 9.03 (dd, J

0.7, 8.6 Hz, 1H), 8.06−8.16 (m, 2H), 8.84−8.92 (m, 1H), 7.88

ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.58 (ddd, J = 1.7, 7.0, 8.4 Hz, 1H),

.10−7.24 (m, 2H), 3.35 (t, J = 7.3 Hz, 2H), 1.79−1.91 (m, 2H),

.08 (t, J = 7.4 Hz, 3H) ppm; C{ H} NMR (125 MHz, CDCl ) δ

a (71%) with the recovery of N-oxide 5ba (eq 5, Scheme 4).

01.8 (s), 160.3 (s),152.0 (s), 148.9 (s), 144.6 (s), 135.7 (d), 133.7

d), 132.9 (d), 130.8 (d), 127.6 (d), 121.2 (s), 120.5 (d), 120.4 (s),

This result suggests that the obtained N-oxide products are

stable and that there is no oxygen transfer from these N-oxides

to the nitroalkyne that can potentially interrupt the initial

nitroalkyne redoxcyclization.

(

120.1 (d), 119.3 (d), 41.6 (t), 17.4 (t), 13.8 (q) ppm; HRMS (ESI)

calcd for C H N O : 309.1239 [M + H] ; found: 309.1248.

Procedure for 1 g Scale. At room temperature, to a solution of

,2-benzo[d]isoxazole 4a (632 mg, 5.81 mmol) in anhydrous toluene

(

To conclude, a novel methodology for the convergent

synthesis of functionalized quinazoline 1-oxides has been

developed. The overall process includes trapping of α-oxo gold

carbene with benzo[d]isoxazole with the orchestration of

sequential N−O bond cleavage and the formation of C−O and

C−N bonds in concert. The current example demonstrates ﬁne

competition between inter- vs intramolecular heteroatom

addition to alkynes interalia competition between the

20 mL) and 4 Å molecular sieves (800 mg) and AuCl (32 mg) was

added o-nitroalkyne 1b (1g, 5.29 mmol) in anhydrous toluene (20

mL) via syringe pump over 6 h. The reaction was stirred at room

tempreture until the completion as indicated by TLC. Usual workup

followed by puriﬁcation by column chromatography aﬀorded

compound 5ba (1.13 g, 69% yield) as yellow solid.

4-Hexanoyl-2-(2-hydroxyphenyl)quinazoline 1-oxide (5ca): R =

0.5 (15% EtOAc in petroleum ether); yield 53 mg (68%); yellow

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J. Org. Chem. 2021, 86, 10874−10882

The Journal of Organic Chemistry

Note

syrup; IR (neat) ν 2925, 2858, 1700, 1603, 1533, 1469, 1317, 1251,

8.85−8.90 (m, 1H), 8.07−8.15 (m, 2H), 7.88 (ddd, J = 1.2, 7.1, 8.5

Hz, 1H), 7.58 (ddd, J = 1.7, 7.0, 8.4 Hz, 1H), 7.17 (dd, J = 0.9, 8.3

Hz, 1H), 7.13 (ddd, J = 1.1, 7.1, 8.1 Hz, 1H), 4.57 (t, J = 3.4 Hz, 1H),

3.89 (dt, J = 6.3, 9.7 Hz, 1H), 3.82 (ddd, J = 3.0, 8.1, 11.1 Hz, 1H),

3.41−3.59 (m, 4H), 2.14 (quin, J = 6.6 Hz, 2H), 1.61−1.76 (m, 2H),

max

−

1 1

160, 759 cm ; H NMR (400 MHz, CDCl ) δ 10.42 (s, 1H), 9.02

(

d, J = 8.5 Hz, 1H), 8.87 (d, J = 8.7 Hz, 1H), 8.04−8.17 (m, 2H),

.83−7.94 (m, 1H), 7.51−7.65 (m, 1H), 7.08−7.22 (m, 2H), 3.36 (t,

J = 7.4 Hz, 2H), 1.82 (t, J = 7.3 Hz, 2H), 1.38−1.45 (m, 4H), 0.94 (t,

J = 7.1 Hz, 3H) ppm; C{ H} NMR (125 MHz, CDCl ) δ 202.0 (s),

1.53−1.61 (m, 2H), 1.43−1.49 (m, 2H) ppm; C{ H} NMR (100

(

60.3 (s), 152.0 (s), 148.9 (s), 144.6 (s), 135.7 (d), 133.7 (d), 132.9

d), 130.8 (d), 127.6 (d), 121.2 (s), 120.5 (d), 120.4 (s), 120.1 (d),

19.3 (d), 39.8 (t), 31.4 (t), 23.7 (t), 22.5 (t), 13.9 (q) ppm; HRMS

MHz, CDCl ) δ 201.5 (s), 160.3 (s), 152.0 (s), 148.7 (s), 144.6 (s),

135.6 (d), 133.7 (d), 133.0 (d), 130.8 (d), 127.7 (d), 121.2 (s), 120.5

(d), 120.4 (s), 120.1 (d), 119.2 (d), 98.9 (d), 66.5 (t), 62.4 (t), 36.8

(t), 30.6 (t), 25.4 (t), 24.4 (t), 19.6 (t) ppm; HRMS (ESI) calcd for:

(ESI) calcd for C H N O : 337.1547 [M + H] ; found: 337.1549.

20 21 2 3

-(2-Hydroxyphenyl)-4-(3-methylbutanoyl)quinazoline 1-oxide

C H N O : 409.1758 [M + H] ; found: 409.1757.

(

5da): R = 0.5 (10% EtOAc in petroleum ether); yield 48 mg

4-(4-(Benzyloxy)butanoyl)-2-(2-hydroxyphenyl)quinazoline 1-

(

60%); orange solid; IR (neat) ν 2958, 1700, 1603, 1534, 1320,

oxide (5ia): R = 0.4 (20% EtOAc in petroleum ether); yield 50 mg

max

−

1 1

253, 1163, 762 cm ; H NMR (400 MHz, CDCl ) δ 10.41 (s, 1H),

(71%); orange gummy solid; IR (neat) ν 2925, 2859, 1699, 1603,

max

−

1 1

.98−9.03 (m, 1H), 8.84−8.89 (m, 1H), 8.06−8.13 (m, 2H), 7.88

1533, 1363, 1104, 749, 693 cm ; H NMR (400 MHz, CDCl ) δ

(ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.59 (ddd, J = 1.7, 7.0, 8.4 Hz, 1H),

10.46 (s, 1H), 8.91−8.98 (m, 1H), 8.83 (dq, J = 0.6, 8.7 Hz, 1H),

8.11 (dd, J = 1.7, 8.1 Hz, 1H), 8.06 (ddd, J = 1.3, 7.1, 8.7 Hz, 1H),

7.76−7.82 (m, 1H), 7.58 (ddd, J = 1.7, 7.0, 8.4 Hz, 1H), 7.20−7.26

(m, 5H), 7.18 (dd, J = 0.9, 8.3 Hz, 1H), 7.10−7.15 (m, 1H), 4.43 (s,

2H), 3.62 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.9 Hz, 2H), 2.13−2.21 (m,

.12−7.21 (m, 2H), 3.23 (d, J = 6.9 Hz, 2H), 2.38 (dt, J = 6.7, 13.4

13 1

Hz, 1H), 1.08 (s, 3H), 1.06 (s, 3H) ppm; C{ H} NMR (100 MHz,

CDCl ) δ 201.7 (s), 160.3 (s), 152.0 (s), 149.1 (s), 144.6 (s), 135.7

(

d), 133.7 (d), 132.9 (d), 130.8 (d), 127.6 (d), 121.2 (s), 120.6 (d),

20.4 (s), 120.2 (d), 119.3 (d), 48.4 (t), 25.2 (d), 22.7 (q, 2C) ppm;

2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 201.4 (s), 160.3 (s),

HRMS (ESI) calcd for C H N O : 323.1390 [M + H] ; found:

151.9 (s), 148.9 (s), 144.5 (s), 138.1 (s), 135.5 (d), 133.7 (d), 133.0

(d), 130.7 (d), 128.3 (d, 2C), 127.8 (d), 127.7 (d), 127.5 (d, 2C),

121.2 (s), 120.5 (d), 120.4 (s), 120.1 (d), 119.1 (d), 72.9 (t), 69.3

(t), 36.8 (t), 24.7 (t) ppm; HRMS (ESI) calcd for: C H N O :

23.1388.

-(2-Hydroxyphenyl)-4-(3-phenylpropanoyl)quinazoline 1-oxide

5ea): R = 0.4 (15% EtOAc in petroleum ether); yield 46 mg (62%);

(

25 23

pale yellow solid; IR (neat) ν_m_a_x3016, 2922, 2859, 1699, 1601, 1532,

415.1652 [M + H] ; found: 415.1660.

4-Butyryl-7-ﬂuoro-2-(2-hydroxyphenyl)quinazoline 1-oxide

(5ja): R = 0.4 (15% EtOAc in petroleum ether); yield 40 mg

(51%); orange solid; IR (neat) νmax 2962, 1700, 1603, 1536, 1489,

−

1 1

488, 1318, 1251, 757, 698 cm ; H NMR (400 MHz, CDCl ) δ

0.32 (s, 1H), 9.00 (dd, J = 1.4, 8.7 Hz, 1H), 8.81−8.87 (m, 1H),

.08 (ddd, J = 1.1, 7.1, 8.7 Hz, 1H), 8.03 (dd, J = 1.8, 8.2 Hz, 1H),

.83−7.88 (m, 1H), 7.56 (ddd, J = 1.8, 7.1, 8.5 Hz, 1H), 7.28 (d, J =

.1 Hz, 3H), 7.25 (s, 1H), 7.18−7.22 (m, 1H), 7.15 (dd, J = 0.92, 8.2

−1 1

1322, 1252, 1159, 752 cm ; H NMR (400 MHz, CDCl ) δ 10.30 (s,

1H), 9.15 (dd, J = 5.6, 9.4 Hz, 1H), 8.51 (dd, J = 2.5, 9.3 Hz, 1H),

8.10 (dd, J = 1.5, 8.0 Hz, 1H), 7.57−7.65 (m, 2H), 7.12−7.20 (m,

2H), 3.35 (t, J = 7.2 Hz, 2H), 1.85 (sxt, J = 7.3 Hz, 2H), 1.07 (t, J =

Hz, 1H), 7.09−7.13 (m, 1H), 3.70 (t, J = 7.5 Hz, 2H), 3.14 (t, J = 7.5

Hz, 2H) ppm; ¹³C{ H} NMR (100 MHz, CDCl ) δ 200.8 (s), 160.2

(

s), 152.1 (s), 148.4 (s), 144.6 (s), 140.5 (s), 135.7 (d), 133.7 (d),

33.0 (d), 130.9 (d), 128.6 (d, 2C), 128.5 (d, 2C), 127.6 (d), 126.3

d), 121.1 (s), 120.5 (d), 120.3 (s), 120.2 (d), 119.2 (d), 41.3 (t),

0.1 (t) ppm; HRMS (ESI) calcd for C H N O : 371.1390 [M +

7.4 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 201.7 (s),

165.6 (ds, JC−F = 262.3 Hz), 160.4 (s), 153.0 (s), 148.1 (ds, JC−F = 1.4

Hz), 146.5 (ds, JC−F = 12.3 Hz), 134.1 (d), 133.0 (d), 131.2 (dd, JC−F

= 10.8 Hz), 121.0 (dd, JC−F = 24.7 Hz), 120.7 (d), 120.3 (d), 120.1

H] ; found: 371.1393.

-(4-Acetoxybutanoyl)-2-(2-hydroxyphenyl)quinazoline 1-oxide

5fa): R = 0.4 (20% EtOAc in petroleum ether); yield 49 mg (66%);

(s), 118.4 (s), 104.8 (dd, JC−F = 26.9 Hz), 41.5 (d), 17.4 (d), 13.8 (q)

ppm; HRMS (ESI) calcd for C18

found: 327.1141.

: 327.1139 [M + H] ;

(

yellow solid; IR (neat) ν

2954, 2928, 1726, 1530, 1468, 1239,

4-Butyryl-2-(2-hydroxyphenyl)-7-nitroquinazoline 1-oxide (5ka):

R_f= 0.3 (25% EtOAc in petroleum ether); yield 26 mg (34%); yellow

max

−

1 1

067, 873, 753 cm ; H NMR (400 MHz, CDCl ) δ 10.32 (s, 1H),

.07 (dd, J = 0.7, 8.5 Hz, 1H), 8.84−8.89 (m, 1H), 8.06−8.15 (m,

H), 7.89 (ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.59 (ddd, J = 1.7, 7.0, 8.4

solid; IR (neat) ν 2924, 2853, 1695, 1602, 1538, 1465, 1348, 1073,

max

−

1 1

746 cm ; H NMR (400 MHz, CDCl ) δ 9.71 (s, 1H), 9.66 (dd, J =

Hz, 1H), 7.12−7.21 (m, 2H), 4.24 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 7.1

0.5, 2.3 Hz, 1H), 9.35 (dd, J = 0.5, 9.2 Hz, 1H), 8.60 (dd, J = 2.3, 9.3

Hz, 1H), 8.09−8.14 (m, 1H), 7.60−7.66 (m, 1H), 7.15−7.22 (m,

2H), 3.38 (t, J = 7.2 Hz, 2H), 1.88 (sxt, J = 7.3 Hz, 2H), 1.09 (t, J =

Hz, 2H), 2.18 (quin, J = 6.7 Hz, 2H), 2.04 (s, 3H) ppm; C{ H}

NMR (100 MHz, CDCl ) δ 200.6 (s) 171.1 (s), 160.3 (s), 152.1 (s),

148.1 (s), 144.7 (s), 135.8 (d), 133.8 (d), 132.9 (d), 131.1 (d), 127.6

7.4 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 201.1 (s),

(

d), 121.2 (s), 120.6 (d), 120.3 (s), 120.2 (d), 119.3 (d), 63.5 (t),

160.5 (s), 153.5 (s), 151.4 (s), 147.5 (s), 145.0 (s), 134.6 (d), 132.9

(d), 130.6 (d), 124.2 (d), 123.6 (s), 120.9 (d), 120.6 (d), 119.5 (s),

115.8 (d), 41.4 (t), 17.4 (t), 13.8 (q) ppm; HRMS (ESI) calcd for

6.1 (t), 23.0 (t), 20.9 (q) ppm; HRMS (ESI) calcd for: C H N O :

20 19 2 5

67.1288 [M + H] ; found: 367.1284.

-(4-((tert-Butyldimethylsilyl)oxy)butanoyl)-2-(2-

C H N O : 354.1084 [M + H] ; found: 354.1090.

hydroxyphenyl)quinazoline 1-oxide (5ga): R = 0.4 (20% EtOAc in

petroleum ether); yield 37 mg (54%); dark yellow syrup; IR (neat)

4-Butyryl-2-(2-hydroxyphenyl)-7-methylquinazoline 1-oxide

(5la): R = 0.3 (20% EtOAc in petroleum ether); yield 48 mg

ν_m_a_x2929, 2860, 1699, 1602, 1531, 1469, 1315, 1252, 1103, 906, 760

(61%); yellow solid; IR (neat) ν 2961, 2929, 1702, 1605, 1523,

max

−

−1 1

cm ; H NMR (400 MHz, CDCl ) δ 10.42 (s, 1H), 9.03−9.09 (m,

1488, 1328, 1255, 1165, 756 cm ; H NMR (400 MHz, CDCl ) δ

H), 8.84−8.89 (m, 1H), 8.07−8.15 (m, 2H), 7.84−7.91 (m, 1H),

.54−7.61 (m, 1H), 7.16−7.19 (m, 1H), 7.10−7.15 (m, 1H), 3.78 (t,

10.57 (s, 1H), 8.91 (d, J = 8.7 Hz, 1H), 8.66 (s, 1H), 8.10 (dd, J = 1.6,

8.0 Hz, 1H), 7.69 (dd, J = 1.6, 8.7 Hz, 1H), 7.58 (ddd, J = 1.7, 7.0, 8.4

Hz, 1H), 7.10−7.20 (m, 2H), 3.34 (t, J = 7.2 Hz, 2H), 2.71 (s, 3H),

J = 6.1 Hz, 2H), 3.47 (t, J = 7.2 Hz, 2H), 2.05 (dt, J = 6.5, 13.4 Hz,

2H), 0.89 (s, 9H), 0.05 (s, 6H), ppm; C{ H} NMR (100 MHz,

1.85 (sxt, J = 7.3 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H) ppm; C{ H}

CDCl ) δ 201.6 (s) 160.3 (s), 152.1 (s), 148.6 (s), 144.6 (s), 135.7

NMR (100 MHz, CDCl ) δ 202.0 (s), 160.3 (s), 152.1 (s), 148.6 (s),

(

d), 133.7 (d), 133.0 (d), 130.8 (d), 127.7 (d), 121.2 (s), 120.5 (d),

20.4 (s), 120.1 (d), 119.3 (d), 62.1 (t), 36.4 (t), 27.0 (t), 25.9 (q,

147.9 (s), 144.7 (s), 133.6 (d), 132.9 (d, 2C), 127.3 (d), 120.6 (s),

120.5 (d), 120.1 (d), 119.4 (s), 118.3 (d), 41.6 (t), 22.7 (q), 17.4 (t),

13.8 (q) ppm; HRMS (ESI) calcd for C H N O : 500.2068 [M +

C), 18.3 (s), −5.4 (q, 2C) ppm; HRMS (ESI) calcd for:

C H N O Si: 439.2048 [M + H] ; found: 439.2055.

H] ; found: 500.2068.

-(2-Hydroxyphenyl)-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)-

2-(2-Hydroxyphenyl)-7-(methoxycarbonyl)-4-propionylquinazo-

butanoyl)quinazoline 1-oxide (5ha): R = 0.4 (20% EtOAc in

line 1-oxide (5ma): R = 0.4 (20% EtOAc in petroleum ether); yield

petroleum ether); yield 42 mg (59%); yellow solid; IR (neat) ν

58 mg (76%); yellow solid; IR (neat) ν 2939, 1720, 1605, 1529,

max

−1

−1 1

938, 2863, 1700, 1603, 1533, 1316, 1121, 1028, 756 cm ; H NMR

1447, 1281, 1177, 1051 754 cm ; H NMR (400 MHz, CDCl ) δ

(

400 MHz, CDCl ) δ 10.42 (s, 1H), 9.06 (dd, J = 0.7, 8.6 Hz, 1H),

10.14 (s, 1H), 9.42−9.46 (m, 1H), 9.14 (d, J = 8.9 Hz, 1H), 8.41−

0878

J. Org. Chem. 2021, 86, 10874−10882

The Journal of Organic Chemistry

Note

.46 (m, 1H), 8.10 (dd, J = 1.7, 8.1 Hz, 1H), 7.59 (td, J = 1.5, 7.7 Hz,

= 2.6, 8.9 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 3.42 (q, J = 7.1 Hz, 2H),

H), 7.41−7.51 (m, 1H), 7.12−7.19 (m, 2H), 6.94−7.00 (m, 1H),

1.31 (t, J = 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ

.07 (s, 3H), 3.42 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H) ppm;

202.1 (s), 158.9 (s), 150.8 (s), 149.0 (s), 144.6 (s), 135.9 (d), 133.6

(d), 131.8 (d), 131.2 (d), 127.7 (d), 125.0 (s), 122.0 (d), 121.5 (s),

C{ H} NMR (100 MHz, CDCl ) δ 201.9 (s), 165.0 (s), 160.2 (s),

52.6 (s), 148.1 (s), 144.6 (s), 136.3 (s), 134.1 (d), 133.0 (d), 130.4

68%); dark yellow gummy solid; IR (neat) ν_m_a_x2236, 1703, 1507,

(dt, J = 0.6, 8.5 Hz, 1H), 8.81−8.88 (m, 1H), 8.12 (ddd, J = 1.3, 7.1,

8.7 Hz, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.90 (ddd, J = 1.2, 7.1, 8.4 Hz,

1H), 7.51 (dd, J = 2.6, 8.9 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 3.22 (d,

J = 6.9 Hz, 2H), 2.38 (dt, J = 6.7, 13.4 Hz, 1H), 1.09 (s, 3H), 1.08 (s,

−

1 1

432, 1143, 750 cm ; H NMR (400 MHz, CDCl ) δ 10.13 (s, 1H),

.06 (d, J = 8.6 Hz, 1H), 8.86 (d, J = 8.9 Hz, 1H), 8.12 (td, J = 0.9,

.9 Hz, 1H), 7.86−7.96 (m, 1H), 7.78 (dd, J = 3.1, 9.6 Hz, 1H),

.28−7.34 (m, 1H), 7.12 (dd, J = 4.9, 9.0 Hz, 1H), 3.42 (q, J = 7.3

3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 201.5 (s), 158.9 (s),

150.7 (s), 149.3 (s), 144.6 (s), 135.9 (d), 133.6 (d), 131.9 (d), 131.2

(d), 127.7 (d), 125.0 (s), 122.0 (d), 121.5 (s), 121.3 (s), 119.3 (d),

48.5 (t), 25.3 (d), 22.7 (q, 2C) ppm; HRMS (ESI) calcd for:

Cl: 357.1000 [M + H] ; found: 357.1007.

2-(5-Chloro-2-hydroxyphenyl)-4-(3-phenylpropanoyl)-

quinazoline 1-oxide (5ec): R = 0.4 (20% EtOAc in petroleum ether);

yield 47 mg (58%); dark yellow solid; IR (neat) νmax³⁰¹⁸^,²⁹²⁵^,²⁸⁵⁹^,

-(5-Fluoro-2-hydroxyphenyl)-4-(3-methylbutanoyl)quinazoline

−1 1

-oxide (5db): R = 0.4 (20% EtOAc in petroleum ether); yield 49 mg

1703, 1606, 1318, 1251, 740, 689 cm ; H NMR (400 MHz, CDCl )

(

58%); yellow gummy solid; IR (neat) ν_m_a_x2958, 1699, 1535, 1477,

δ 10.33 (s, 1H), 8.99 (dt, J = 0.6, 8.5 Hz, 1H), 8.80−8.86 (m, 1H),

8.11 (ddd, J = 1.3, 7.1, 8.7 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.89

(ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.51 (dd, J = 2.6, 8.8 Hz, 1H), 7.30 (d,

J = 4.4 Hz, 4H), 7.19−7.23 (m, 1H), 7.10 (d, J = 8.9 Hz, 1H), 3.70 (t,

−

1 1

243, 754 cm ; H NMR (400 MHz, CDCl ) δ 10.14 (s, 1H), 9.01

(dt, J = 0.6, 8.5, Hz, 1H), 8.81−8.90 (m, 1H), 8.12 (ddd, J = 1.3, 7.1,

.7 Hz, 1H), 7.90 (ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.77 (dd, J = 3.1, 9.6

Hz, 1H), 7.31 (ddd, J = 3.1, 7.6, 9.1 Hz, 1H), 7.12 (dd, J = 4.9, 9.0

Hz, 1H), 3.23 (d, J = 6.9 Hz, 2H), 2.33−2.43 (m, 1H), 1.08 (s, 3H),

J = 7.4 Hz, 2H), 3.18 (t, J = 7.4 Hz, 2H) ppm; C{ H} NMR (100

MHz, CDCl ) δ 200.7 (s), 158.9 (s), 150.8 (s), 148.7 (s), 144.6 (s),

.07 (s, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 201.4 (s),

140.4 (s), 135.9 (d), 133.6 (d), 131.8 (d), 131.2 (d), 128.6 (d, 2C),

128.5 (d, 2C), 127.7 (d), 126.3 (d), 125.0 (s), 122.0 (d), 121.4 (s),

57.5 (s), 156.4 (ds, J_C₋_F= 1.5 Hz), 155.1 (s), 150.8 (ds, J_C₋_F= 3.0

Hz), 149.2 (s), 144.6 (s), 135.9 (d), 131.1 (d), 127.7 (d), 121.7 (dd,

J_C₋_F= 7.6 Hz), 121.3 (s), 121.0 (dd, J_C₋_F= 23.6 Hz), 119.3 (d), 117.6

121.3 (s), 119.2 (d), 41.3 (t), 30.3 (t) ppm; HRMS (ESI) calcd for:

Cl: 405.1000 [M + H] ; found: 405.1005.

(

dd, J_C₋_F= 25.2 Hz), 48.4 (t), 25.1 (d), 22.7 (q, 2C) ppm; HRMS

4-Butyryl-2-(5-chloro-2-hydroxyphenyl)-7-methylquinazoline 1-

oxide (5lc): R = 0.4 (20% EtOAc in petroleum ether); yield 52 mg

(59%); yellow gummy solid; IR (neat) νmax 2124, 1704, 1367, 1163,

ESI) calcd for: C H N O F: 341.1296 [M + H] ; found: 341.1300.

-(5-Fluoro-2-hydroxyphenyl)-4-(3-phenylpropanoyl)-

−

1 1

quinazoline 1-oxide (5eb): R = 0.4 (20% EtOAc in petroleum

742, 660 cm ; H NMR (400 MHz, CDCl ) δ 10.58 (s, 1H), 8.90

ether); yield 43 mg (56%); yellow solid; IR (neat) ν_m_a_x3016, 2958,

(d, J = 8.6 Hz, 1H), 8.62−8.69 (m, 1H), 8.05 (d, J = 2.6 Hz, 1H),

7.72 (dd, J = 1.4, 8.7 Hz, 1H), 7.50 (dd, J = 2.6, 8.9 Hz, 1H), 7.10 (d,

J = 8.9 Hz, 1H), 3.33 (t, J = 7.2 Hz, 2H), 2.72 (s, 3H), 1.81−1.91 (m,

−

1 1

699, 1601, 1532, 1488, 1318, 1251, 757, 698 cm ; H NMR (400

MHz, CDCl ) δ 10.05 (s, 1H), 9.01 (dd, J = 0.7, 8.6 Hz, 1H), 8.84 (d,

J = 8.4 Hz, 1H), 8.11 (ddd, J = 1.3, 7.1, 8.7 Hz, 1H), 7.89 (ddd, J =

2H), 1.09 (t, J = 7.4 Hz, 3H) ppm; C{ H} NMR (100 MHz,

.2, 7.1, 8.5 Hz, 1H), 7.72 (dd, J = 3.1, 9.6 Hz, 1H), 7.27−7.34 (m,

CDCl ) δ 201.8 (s), 158.9 (s), 150.9 (s), 149.0 (s), 148.2 (s), 144.6

(s), 133.5 (d), 133.3 (d), 131.9 (d), 127.4 (d), 124.9 (s), 122.0 (d),

H), 7.15−7.20 (m, 1H), 7.11 (dd, J = 4.8, 9.1 Hz, 1H), 3.71 (t, J =

.4 Hz, 2H), 3.17 (t, J = 7.4 Hz, 2H) ppm; C{ H} NMR (100 MHz,

121.7 (s), 119.5 (s), 118.2 (d), 41.7 (t), 22.7 (q), 17.4 (t), 13.8 (q)

CDCl ) δ 200.6 (s), 157.5 (s), 156.3 (ds, J

= 1.5 Hz), 155.1 (s),

ppm; HRMS (ESI) calcd for: C19

Cl: 357.1000 [M + H] ;

C−F

(

50.8 (s), 148.5 (s), 144.6 (s), 140.4 (s), 135.9 (d), 131.2 (d), 128.6

d, 2C), 128.5 (d, 2C), 127.7 (d), 126.3 (d), 121.7 (dd, J_C₋_F= 7.6

Hz), 121.3 (s), 121.0 (dd, J_C₋_F= 23.6 Hz), 119.2 (d), 117.6 (dd, J_C₋_F

25.2 Hz), 41.3 (t), 30.1 (t) ppm; HRMS (ESI) calcd for:

found: 357.1007.

2-(5-Bromo-2-hydroxyphenyl)-4-propionylquinazoline 1-oxide

(5ad): R = 0.4 (15% EtOAc in petroleum ether); yield 60 mg

(56%); orange solid; IR (neat) νmax 2926, 2855, 1690, 1601, 1534,

−1 1

C H N O F: 389.1296 [M + H] ; found: 389.1300.

1464, 1251, 1116, 759 cm ; H NMR (400 MHz, CDCl ) δ 10.46 (s,

-Butyryl-2-(5-ﬂuoro-2-hydroxyphenyl)-7-(methoxycarbonyl)-

1H), 9.04 (dd, J = 0.7, 8.6 Hz, 1H), 8.83−8.87 (m, 1H), 8.19 (d, J =

2.5 Hz, 1H), 8.12 (ddd, J = 1.3, 7.1, 8.6 Hz, 1H), 7.91 (ddd, J = 1.2,

7.1, 8.4 Hz, 1H), 7.64 (dd, J = 2.5, 8.9 Hz, 1H), 7.05 (d, J = 8.7 Hz,

quinazoline 1-oxide (5nb): R = 0.4 (20% EtOAc in petroleum

ether); yield 54 mg (69%); orange gummy solid; IR (neat) ν_m_a_x2959,

721, 1528, 1235, 1125, 748 cm ; H NMR (400 MHz, CDCl ) δ

.78 (s, 1H), 9.40−9.47 (m, 1H), 9.08−9.17 (m, 1H), 8.44 (dd, J =

.7, 8.8 Hz, 1H), 7.73−7.79 (m, 1H), 7.31 (ddd, J = 3.1, 7.5, 9.1 Hz,

H), 7.11 (dd, J = 4.8, 9.1 Hz, 1H), 4.08 (s, 3H), 3.35 (t, J = 7.2 Hz,

H), 1.82−1.90 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H) ppm; C{ H}

NMR (100 MHz, CDCl ) δ 201.3 (s), 164.9 (s), 157.6 (s), 156.4 (ds,

J_C₋_F= 1.5 Hz), 155.2 (s), 148.2 (s), 144.7 (s), 136.4 (s), 130.7 (d),

28.4 (d), 123.1 (s), 121.8 (dd, J_C₋_F= 8.4 Hz), 121.3 (dd, J_C₋_F= 23.6

−

1H), 3.42 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H) ppm; C{ H}

NMR (125 MHz, CDCl ) δ 202.0 (s) 159.4 (s), 150.7 (s), 149.1 (s),

144.6 (s), 136.4 (d), 135.9 (d), 134.8 (d), 131.2 (d), 127.7 (d), 122.4

(d), 122.0 (s), 121.3 (s), 119.2 (d), 112.0 (s), 33.3 (t), 7.7 (q) ppm;

HRMS (ESI) calcd for C H BrN O : 373.0182 [M + H] ; found:

373.0185.

2-(5-Bromo-2-hydroxyphenyl)-4-butyrylquinazoline 1-oxide

(5bd): R = 0.5 (15% EtOAc in petroleum ether); yield 63 mg

(62%); dark yellow solid; IR (neat) νmax 2925, 2866, 1699, 1600,

Hz), 121.1 (d), 120.4 (s), 117.6 (dd, J_C₋_F= 25.2 Hz), 53.2 (q), 41.5

t), 17.3 (t), 13.8 (q) ppm; HRMS (ESI) calcd for: C H N O F:

−

(

1531, 1466, 1323, 1246, 1155, 762 cm ; H NMR (400 MHz,

CDCl3): δ 10.46 (s, 1H), 8.99−9.05 (m, 1H), 8.82−8.89 (m, 1H),

8.20 (d, J = 2.5 Hz, 1H), 8.12 (ddd, J = 1.3, 7.1, 8.7 Hz, 1H), 7.91

(ddd, J = 1.2, 7.1, 8.5 Hz, 1H), 7.64 (dd, J = 2.5, 8.7 Hz, 1H), 7.06 (d,

J = 8.9 Hz, 1H), 3.34 (t, J = 7.2 Hz, 2H), 1.81−1.93 (m, 2H), 1.10 (t,

85.1194 [M + H] ; found: 385.1196.

-(5-Fluoro-2-hydroxyphenyl)-4-propionylquinazoline 1-oxide

5ac): R = 0.4 (20% EtOAc in petroleum ether); yield 59 mg

(

63%); dark yellow solid; IR (neat) ν 2932, 1706, 1603, 1532,

469, 1321, 763 cm ; H NMR (400 MHz, CDCl ) δ 10.42 (s, 1H)

.01−9.11 (m, 1H), 8.85 (d, J = 8.8 Hz, 1H), 8.12 (ddd, J = 1.2, 7.2,

.6 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.86−7.96 (m, 1H), 7.51 (dd, J

max

−

J = 7.4 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl : δ 201.6 (s),

159.4 (s), 150.7 (s), 149.2 (s), 144.6 (s), 136.4 (d), 135.9 (d), 134.9

(d), 131.2 (d), 127.7 (d), 122.0 (s), 121.3 (s), 119.3 (d), 112.0 (s),

0879

J. Org. Chem. 2021, 86, 10874−10882

The Journal of Organic Chemistry

Note

1.7 (t), 17.5 (t), 13.8 (q) ppm; HRMS (ESI) calcd for

2-(2-Hydroxy-5-methylphenyl)-4-propionylquinazoline 1-oxide

(5ae): R = 0.4 (20% EtOAc in petroleum ether); yield 55 mg

(62%); dark yellow gum; IR (neat) νmax2931, 1701, 1530, 1481, 1248,

C H BrN O : 387.0339 [M + H] ; found: 387.0344.

-(5-Bromo-2-hydroxyphenyl)-4-hexanoylquinazoline 1-oxide

−

1 1

(5cd): R = 0.4 (15% EtOAc in petroleum ether); yield 53 mg

823, 755 cm ; H NMR (400 MHz, CDCl ) δ 10.13 (s, 1H), 8.98−

(

56%); dark yellow solid; IR (neat) ν_m_a_x₋ 2927, 2862, 1694, 1600,

9.06 (m, 1H), 8.81−8.90 (m, 1H), 8.09 (ddd, J = 1.3, 7.1, 8.7 Hz,

1H), 7.81−7.91 (m, 2H), 7.39 (dd, J = 2.2, 8.4 Hz, 1H), 7.07 (d, J =

8.4 Hz, 1H), 3.42 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.32 (t, J = 7.2

530, 1469, 1251, 1079, 1022, 761 cm ; H NMR (400 MHz,

CDCl ) δ 10.47 (s, 1H), 9.02 (dd, J = 0.7, 8.6 Hz, 1H), 8.82−8.88

(m, 1H), 8.20 (d, J = 2.5 Hz, 1H), 8.12 (ddd, J = 1.1, 7.1, 8.7 Hz,

Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 202.3 (s), 158.1

H), 7.91 (ddd, J = 1.1, 7.1, 8.4 Hz, 1H), 7.64 (dd, J = 2.5, 8.7 Hz,

H), 7.06 (d, J = 8.9 Hz, 1H), 3.35 (t, J = 7.4 Hz, 2H), 1.84 (t, J = 7.4

(s), 152.1 (s), 148.6 (s), 144.6 (s), 135.6 (d), 134.8 (d), 132.6 (d),

130.7 (d), 129.3 (s), 127.6 (d), 121.1 (s), 120.3 (d), 120.0 (s), 119.3

Hz, 2H), 1.40−1.50 (m, 4H), 0.93−0.98 (m, 3H) ppm; C{ H}-

NMR (100 MHz, CDCl ) δ 201.8 (s), 159.4 (s), 150.7 (s), 149.2 (s),

(d), 33.2 (t), 20.7 (q), 7.8 (q) ppm; HRMS (ESI) calcd for:

C H N O : 309.1234 [M + H] ; found: 309.1238.

18 17

-(2-Hydroxy-5-methylphenyl)-4-(3-methylbutanoyl)quinazoline

144.6 (s), 136.4 (d), 135.9 (d), 134.9 (d), 131.2 (d), 127.7 (d), 122.4

-oxide (5de): R = 0.4 (20% EtOAc in petroleum ether); yield 50 mg

(

[

d), 122.0 (s), 121.3 (s), 112.0 (s), 39.9 (t), 31.4 (t), 23.9 (t), 22.5

t), 13.9 (q) ppm; HRMS (ESI) calcd for C H BrN O : 415.0652

M + H] ; found: 415.0654.

-(5-Bromo-2-hydroxyphenyl)-4-(3-methylbutanoyl)quinazoline

-oxide (5dd): R = 0.4 (15% EtOAc in petroleum ether); yield 55 mg

(

60%); yellow gummy solid; IR (neat) ν 2957, 1695, 1531, 1479,

max

−1 1

1161, 1067, 751 cm ; H NMR (400 MHz, CDCl ) δ 10.15 (s, 1H),

.00 (dd, J = 0.8, 8.5 Hz, 1H), 8.81−8.92 (m, 1H), 8.06−8.15 (m,

H), 7.84−7.90 (m, 2H), 7.37−7.42 (m, 1H), 7.08 (d, J = 8.4 Hz,

H), 3.23 (d, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.39 (dt, J = 13.5, 6.8 Hz,

(56%); orange solid; IR (neat) ν_m_a_x2958, 2874, 1696, 1599, 1531,

−

1H), 1.09 (s, 3 H),1.07 (s, 3H) ppm; C{ H} NMR (100 MHz,

1469, 1373, 1324, 1284, 1244, 1161, 762 cm ; H NMR (500 MHz,

CDCl ) δ 201.7 (s), 158.1 (s), 152.1 (s), 149.0 (s), 144.6 (s), 135.6

CDCl ) δ 10.48 (s, 1H), 9.01 (d, J = 7.6 Hz, 1H), 8.85 (d, J = 8.4 Hz,

(

d), 134.8 (d), 132.6 (d), 130.7 (d), 129.3 (s), 127.5 (d), 121.2 (s),

H), 8.19 (d, J = 3.05 Hz, 1H), 8.09−8.16 (m, 1H), 7.88−7.94 (m,

20.3 (d), 120.0 (s), 119.3 (d), 48.6 (t), 25.4 (q), 22.8 (q, 2C), 20.7

H), 7.64 (dd, J = 2.7, 8.8 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 3.22 (d,

(

d) ppm; HRMS (ESI) calcd for: C H N O : 337.1547 [M + H] ;

20 21 2 3

J = 6.9 Hz, 2H), 2.38 (dt, J = 6.6, 13.5 Hz, 1H), 1.10 (s, 3H), 1.08 (s,

_H₎_p_p_m_;₁3C{ H} NMR (125 MHz, CDCl ) δ 201.5 (s), 159.4 (s),

found: 337.1548.

General Procedure for N−O Bond Reduction. To a stirred

solution of 5 (1 equiv) in THF at room temperature was added Zn

50.6 (s), 149.4 (s), 144.6 (s), 136.4 (d), 135.9 (d), 134.9 (d), 131.2

(d), 127.7 (d), 122.4 (d), 122.0 (s), 121.3 (s), 119.3 (d), 112.0 (s),

dust (2 equiv) followed by 30% aq NH Cl solution. The reaction

8.6 (t), 25.4 (s), 22.7 (t, 2C) ppm; HRMS (ESI) calcd for

mixture was stirred until the disappearance of the starting material

shown by TLC (i.e., 1 h). Then the usual workup followed by

puriﬁcation by column chromatography aﬀorded compound 6.

C H BrN O : 401.0495 [M + H] ; found: 401.0497.

-(5-Bromo-2-hydroxyphenyl)-4-(3-phenylpropanoyl)-

quinazoline 1-oxide (5ed): R = 0.4 (20% EtOAc in petroleum

ether); yield 44 mg (47%); pale yellow solid; IR (neat) ν_m_a_x3016,

-(2-Hydroxyphenyl)-4-propionylquinazoline (6a). R = 0.5 (10%

EtOAc in petroleum ether); yield 41 mg (86%); dark yellow solid; IR

916, 2859, 1699, 1599, 1531, 1467, 1369, 1283, 1152, 758, 698

−

1 1

−

(neat) νmax 1703, 1547, 1471, 1254, 760 cm ; H NMR (400 MHz,

cm ; H NMR (400 MHz, CDCl ) δ 10.38 (s, 1H), 8.99 (dd, J = 0.7,

CDCl ) δ 13.50 (s, 1H), 8.59−8.72 (m, 2H), 8.05 (dq, J = 0.6, 8.5

.6 Hz, 1H), 8.81−8.87 (m, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.11 (ddd,

J = 1.3, 7.1, 8.7 Hz, 1H), 7.89 (ddd, J = 1.2, 7.1, 8.4 Hz, 1H), 7.64

dd, J = 2.5, 8.9 Hz, 1H), 7.31 (d, J = 4.4 Hz, 4H), 7.19−7.24 (m,

H), 7.05 (d, J = 8.7 Hz, 1H), 3.70 (t, J = 7.4 Hz, 2H), 3.18 (t, J = 7.4

Hz, 1H), 7.96 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H), 7.68 (ddd, J = 1.2, 6.9,

8.4 Hz, 1H), 7.46 (ddd, J = 1.8, 7.0, 8.4 Hz, 1H), 7.11 (dd, J = 0.9, 8.2

(

Hz, 1H), 7.04 (ddd, J = 1.2, 7.1, 8.1 Hz, 1H), 3.37 (t, J = 7.2 Hz, 2H),

1.83−1.95 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H) ppm; C{ H} NMR

Hz, 2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 200.7 (s), 159.4

(

100 MHz, CDCl ) δ 203.5 (s), 160.9 (s), 160.7 (s), 160.3 (s), 149.9

s), 135.0 (d), 133.5 (d), 129.6 (d), 128.8 (d), 127.3 (d), 126.7 (d),

(

s), 150.7 (s), 148.7 (s), 144.6 (s), 140.3 (s), 136.4 (d), 136.0 (d),

34.8 (d), 131.2 (d), 128.6 (d, 2C), 128.5 (d, 2C), 127.7 (d), 126.4

d), 122.4 (d), 122.0 (s), 121.3 (s), 119.2 (d), 112.0 (s), 41.3 (t),

0.3 (t) ppm; HRMS (ESI) calcd for C H BrN O : 449.0495 [M +

19.2 (d), 119.0 (s), 118.8 (s), 117.9 (d), 42.1 (t), 17.3 (t), 13.8 (q)

ppm; HRMS (ESI) calcd for: C H N O : 293.1290 [M + H] ;

found: 293.1292.

-(5-Fluoro-2-hydroxyphenyl)-4-(3-methylbutanoyl)quinazoline

6b): R = 0.5 (10% EtOAc in petroleum ether); yield 33 mg (69%);

H] ; found: 449.0504.

-(5-Bromo-2-hydroxyphenyl)-4-butyryl-7-methylquinazoline 1-

oxide (5ld): R = 0.4 (15% EtOAc in petroleum ether); yield 52 mg

(

dark yellow gummy solid; IR (neat) ν 1707, 1547, 1475, 1248, 760

max

(

53%); orange solid; IR (neat) ν_m_a_x₋2962, 2928, 2874, 1701, 1596,

−1 1

cm ; H NMR (400 MHz, CDCl ) δ 13.23 (s, 1H), 8.62−8.68 (m,

532, 1468, 1288, 1167, 823, 754 cm ; H NMR (400 MHz, CDCl )

(

H), 8.30 (dd, J = 3.2, 9.8 Hz, 1H), 8.03−8.09 (m, 1H), 7.98 (ddd, J

1.4, 6.9, 8.4 Hz, 1H), 7.71 (ddd, J = 1.2, 6.9, 8.4 Hz, 1H), 7.17

ddd, J = 3.2, 7.7, 9.0 Hz, 1H), 7.05 (dd, J = 4.7, 9.0 Hz, 1H), 3.25 (d,

J = 6.9 Hz, 2H), 2.40 (dt, J = 6.7, 13.4 Hz, 1H), 1.11 (s, 3H), 1.10 (s,

δ 10.62 (s, 1H), 8.83−8.95 (m, 1H), 8.65 (br. s., 1H), 8.17−8.22 (m,

H), 7.72 (d, J = 8.7 Hz, 1 H), 7.60−7.66 (m, H), 7.01−7.08 (m,

H), 3.30−3.37 (m, 2H), 2.72 (s, 3H), 1.82−1.91 (m, 2H), 1.06−

.12 (m, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 13.8 (q),

H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 203.1 (s), 160.7 (s),

7.5 (t), 22.7 (q), 41.7 (t), 111.9 (s), 118.3 (d), 119.6 (s), 122.2 (s),

22.4 (d), 127.4 (s), 133.3 (d), 134.9 (d), 136.3 (d), 144.6 (s), 148.3

59.8 (ds, J_C₋_F= 3.0 Hz), 156.9 (ds, J_C₋_F= 1.5 Hz), 154.6 (s), 149.8

(s), 135.2 (d), 129.2 (d), 127.4 (d), 126.7 (d), 120.5 (dd, J_C₋_F= 23.6

(s), 149.0 (s), 150.8 (s), 159.4 (s), 201.8 (s) ppm; HRMS (ESI) calcd

Hz), 119.1 (s), 119.0 (ds, J_C₋_F= 7.6 Hz), 118.9 (dd, J_C₋_F= 7.6 Hz),

for C H N O Br: 401.0495 [M + H] ; found: 401.0494.

114.7 (dd, J_C₋_F= 25.2 Hz), 49.0 (t), 24.9 (d), 22.8 (q, 2C) ppm;

-(5-Bromo-2-hydroxyphenyl)-4-butyryl-7-(methoxycarbonyl)-

HRMS (ESI) calcd for: C H N O F: 325.1352 [M + H] ; found:

quinazoline 1-oxide (5nd): R = 0.4 (20% EtOAc in petroleum

ether); yield 55 mg (61%); orange gummy solid; IR (neat) ν 2959,

25.1345.

-(5-Chloro-2-hydroxyphenyl)-4-(3-methylbutanoyl)quinazoline

6c). R = 0.5 (10% EtOAc in petroleum ether); yield 36 mg (75%);

max

−

1 1

680, 1723, 1567, 1435, 1235, 1132, 815, 755 cm ; H NMR (400

(

MHz, CDCl ) δ 10.11 (s, 1H), 9.45 (d, J = 1.1 Hz, 1H), 9.09−9.16

yellow gummy solid; IR (neat) ν_m_a_x1703, 1536, 1462, 1212, 819, 759

−

1 1

(

m, 1H), 8.44−8.49 (m, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.66 (dd, J =

cm ; H NMR (400 MHz, CDCl ) δ 13.45 (s, 1H), 8.64 (dt, J = 0.6,

.5, 8.7 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.08 (s, 3H), 3.35 (t, J =

.5 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.02−8.08 (m, 1H), 7.99 (dd, J

1.4, 6.9 Hz, 1H), 7.68−7.75 (m, 1H), 7.38 (dd, J = 2.7, 8.8 Hz, 1H),

7.05 (d, J = 8.7 Hz, 1H), 3.24 (d, J = 6.9 Hz, 2H), 2.41 (dt, J = 6.7,

.2 Hz, 2H), 1.82−1.94 (m, 2H), 1.10 (t, J = 7.38 Hz, 3H) ppm;

C{ H} NMR (100 MHz, CDCl ) δ 201.3 (s), 164.9 (s), 159.4 (s),

151.3 (s), 148.5 (s), 144.6 (s), 136.7 (d), 136.5 (s), 134.8 (d), 130.8

13.5 Hz, 1H), 1.12 (s, 3H), 1.10 (s, 3H) ppm; C{ H} NMR (100

(d), 128.4 (d), 123.2 (s), 122.5 (d), 121.7 (s), 121.1 (d), 112.2 (d),

MHz, CDCl ) δ 203.1 (s), 160.9 (s), 159.6 (s), 159.4 (s), 149.8 (s),

3.2 (q), 41.6 (t), 17.5 (t), 13.8 (q) ppm; HRMS (ESI) calcd for

135.3 (d), 133.3 (d), 129.2 (d), 128.9 (d), 127.4 (d), 126.7 (d), 124.0

(s), 119.7 (s), 119.5 (d), 119.2 (s), 49.0 (t), 25.0 (d), 22.8 (q, 2C)

C H BrN O : 445.0394 [M + H] ; found: 445.0399.

0880

J. Org. Chem. 2021, 86, 10874−10882

The Journal of Organic Chemistry

Note

ppm; HRMS (ESI) calcd for: C H N O Cl: 341.1057 [M + H] ;

REFERENCES

■

found: 341.1050.

-(2-Hydroxy-5-methylphenyl)-4-(3-methylbutanoyl)quinazoline

6d). R = 0.5 (10% EtOAc in petroleum ether); yield 37 mg (77%);

yellow gummy solid; IR (neat) ν_m_a_x1713, 1547, 1467, 1283, 810, 754

cm ; H NMR (400 MHz, CDCl ) δ 13.28 (s, 1H), 8.62 (dt, J = 0.7,

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ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01221.

Characterization data, H, C{ H}, DEPT NMR, and

HRMS spectra of all new compounds (PDF )

FAIR data, including the primary NMR FID ﬁles, for

compounds 5aa−5ia, 5ja−5ma, 5ab, 5db, 5eb, 5nb,

ac, 5dc , 5ec, 5lc, 5ad−5ed, 5ld, 5nd, 5ae, 5de, and

a−6d (ZIP )

Accession Codes

CCDC 2077663 contains the supplementary crystallographic

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 Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Catalysed oxidative cyclisation. Chem. Soc. Rev. 2016 , 45 , 4448 −4458.

e) Bhunia, S.; Ghosh, P.; Patra, S. Gold-Catalyzed Oxidative Alkyne

AUTHOR INFORMATION

Corresponding Author

Chepuri V. Ramana − Division of Organic Chemistry, CSIR-

National Chemical Laboratory, Pune 411 008, India;

Academy of Scientiﬁc and Innovative Research (AcSIR),

Ghaziabad 201002, India; orcid.org/0000-0001-5801-

■

Functionalization by N-O/S-O/C-O Bond Oxidants. Adv. Synth.

Catal. 2020, 362, 3664−3708. (f) Zheng, Z.; Ma, X.; Cheng, X.; Zhao,

K.; Gutman, K.; Li, T.; Zhang, L. Homogeneous Gold-Catalyzed

Oxidation Reactions. Chem. Rev. 2021, DOI: 10.1021/acs.chem-

rev.0c00774 .

11X ; Email: vr.chepuri@ncl.res.in

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o -(alkynyl)nitrobenzenes. Efficient synthesis of isatogens and

anthranils. Tetrahedron Lett. 2003, 44, 5675−5677.

Authors

Pawan S. Dhote − Division of Organic Chemistry, CSIR-

(5) Li, X.; Incarvito, C. D.; Vogel, T.; Crabtree, R. H. Intramolecular

National Chemical Laboratory, Pune 411 008, India;

Academy of Scientiﬁc and Innovative Research (AcSIR),

Ghaziabad 201002, India

Oxygen Transfer from Nitro Groups to C ≡C Bonds Mediated by

Iridium Hydrides. Organometallics 2005, 24, 3066−3073.

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[2 + 2 + 1] Cycloaddition Cascade of Nitroalkyne Substrates. J. Am.

Chem. Soc. 2011, 133, 1769−1771.

Kishor A. Pund − Division of Organic Chemistry, CSIR-

National Chemical Laboratory, Pune 411 008, India

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01221

(7) (a) Ramana, C. V.; Patel, P.; Vanka, K.; Miao, B.; Degterev, A. A

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The authors declare no competing ﬁnancial interest.

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ACKNOWLEDGMENTS

■

The authors acknowledge DST-SERB for funding this project

and DST-INSPIRE for a research fellowship to P.S.D. and Dr.

Srinu Tothadi (CSIR-National Chemical Laboratory) for

carrying out the single-crystal X-ray diﬀraction studies. This

work is dedicated to Professor Madhavarao Nagarajan on the

occasion of his 70th birthday.

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