Recyclable Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodoanilines with Acyl Chlorides in the Biomass-Derived Solvent 2-Methyltetrahydrofuran

Article abstract of DOI:10.1021/acs.joc.0c00887

A highly efficient, green palladium-catalyzed cyclocarbonylation of 2-iodoanilines with acyl chlorides has been developed that proceeds smoothly in a biomass-derived solvent 2-methyltetrahydrofuran with N,N-diisopropylethylamine as base at 100 °C under 20 bar of carbon monoxide using an 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as a heterogeneous catalyst, yielding a wide variety of 2-substituted 4H-3,1-benzoxazin-4-one derivatives in good to excellent yields. This supported palladium catalyst could be facilely obtained by a two-step procedure from easily available starting materials and readily recovered via a simple filtration process and recycled at least 8 times without any apparent decrease in catalytic efficiency. The developed methodology not only avoids the use of toxic solvents such as tetrahydrofuran and dimethylformamide but also solves the basic problem of expensive palladium catalyst recovery and reuse and prevents effectively palladium contamination of the desired product.

Full text of DOI:10.1021/acs.joc.0c00887

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Article
Recyclable Heterogeneous Palladium-Catalyzed
Cyclocarbonylation of 2-Iodoanilines with Acyl Chlorides
in the Biomass-Derived Solvent 2-Methyltetrahydrofuran
Wenyan Hao, Zhaotao Xu, Zebiao Zhou, and Mingzhong Cai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00887 • Publication Date (Web): 31 May 2020
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Recyclable Heterogeneous Palladium-Catalyzed Cyclo-
carbonylation of 2-Iodoanilines with Acyl Chlorides in the
Biomass-Derived Solvent 2-Methyltetrahydrofuran
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Wenyan Hao, Zhaotao Xu, Zebiao Zhou, and Mingzhong Cai*
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Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of
Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
E-mail: mzcai@jxnu.edu.cn
O
I
2N-MCM-41-Pd(OAc)2
(2 mol%)
O
O
R
+
R
R1
Cl
CO (20 bar), DiPEA,
2-MeTHF, 100 oC
NH2
R1
N
3
1
2
41 examples
up to 97% yield
Broad substrate scope
Good to excellent yields
High FG compatibility
Excellent atom economy
Eco-friendly solvent
Recyclable palladium catalyst
ABSTRACT: A highly efficient, green palladium-catalyzed cyclocarbonylation of
2-iodoanilines with acyl chlorides has been developed that proceeds smoothly in a
biomass-derived solvent 2-methyltetrahydrofuran (2-MeTHF) with N,N-diisopropyl-
ethylamine (DiPEA) as base at 100 ºC under 20 bar of carbon monoxide using an
2-aminoethylamino-modified MCM-41-anchored palladium acetate complex
[2N-MCM-41-Pd(OAc)2] as a heterogeneous catalyst, yielding a wide variety of
2-substituted 4H-3,1-benzoxazin-4-one derivatives in good to excellent yields. This
supported palladium catalyst could be facilely obtained by a two-step procedure from
easily available starting materials and readily recovered via a simple filtration process
and recycled at least 8 times without any apparent decrease in catalytic efficiency.
The developed methodology not only avoids the use of toxic solvents such as THF
and DMF, but also solves the basic problem of expensive palladium catalyst recovery
and reuse, and prevents effectively palladium contamination of the desired product.
INTRODUCTION
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4H-3,1-Benzoxazin-4-ones are a class of important N-heterocycles of considerable
interest and have found a wide range of applications in pharmaceutical research.1
Particularly, 2-substituted 4H-3,1-benzoxazin-4-ones exhibit a variety of biological
activities and can act as chymotrypsin inactivators, C1r protease inhibitors, HDL
elevators, and pancreatic lipase inhibitors.2 Moreover, 2-substituted 4H-3,1-benzo-
xazin-4-ones are also versatile and valuable synthetic intermediates for the synthesis
of bioactive N-substituted quinazolinone derivatives and their derived pharma-
ceuticals.3 Therefore, many methods have been developed for the construction of
4H-3,1-benzoxazin-4-ones over the past decades.4 The most popular methods for the
construction of 4H-3,1-benzoxazin-4-ones are the cyclization of anthranilic acid or its
derivatives, N-acylanthranilic acids, and isotoic anhydride.5 In order to improve the
yield and reduce the cost of the reaction, other notable synthetic pathways have also
been reported for the synthesis of 4H-3,1-benzoxazin-4-ones. These methods include
copper-catalyzed reactions such as cyclization of N-acyl-o-iodobenzamides,6
oxidative cyclization of N-TFA-protected 2-alkynylanilines7 or o-iodobenzoic acids
with benzyl amines,8 oxidation of 2-arylindoles,9 aza-Wittig reaction of 2-azido
phenyl anhydrides,10 palladium-catalyzed carbon-carbon triple bond cleavage of
2-azidoalkynylbenzenes,11 and CoCl2 or Ag2O-mediated intramolecular oxidative
cyclization.12 Besides, transition-metal-free syntheses of 4H-3,1-benzoxazin-4-ones
have also been developed through the oxidation of 2-arylindoles with oxone as the
sole oxidant, oxidative cyclization of 2-aminobenzoic acids with arylaldehydes or
2-aminobenzyl alcohols with aldehydes.13 Despite these significant progress made in
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their synthetic methodologies, the availability or scope of substrates and required
reaction conditions make these methods of limited synthetic utility.
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Palladium-catalyzed carbonylative transformations of readily available (hetero)aryl
halides with carbon monoxide have proven to be a general and straightforward route
for the construction of various benzoic acid derivatives.14 Combining such carbony-
lative reactions with subsequent intramolecular cyclization processes would allow for
a highly efficient synthesis of diverse heterocycles.15 Some papers have reported the
use of palladium-catalyzed carbonylation strategy for the construction of 2-substituted
4H-3,1-benzoxazin-4-ones.16 Larock and Fellows reported the first carbonylative
synthesis of 2-substituted 4H-3,1-benzoxazin-4-ones via a stoichiometric thallation
and subsequent palladium-catalyzed carbonylation of N-acetylaniline.16a Cacchi and
coworkers described Pd(0)-catalyzed carbonylation of o-iodoanilines with unsaturated
halides or triflates towards 2-substituted 4H-3,1-benzoxazin-4-ones.16b Palladium-
catalyzed cyclocarbonylation of o-iodoanilines with acid chlorides were reported by
the Alper group16c and the Petricci group.16d Recently, Wu and Beller have developed
palladium-catalyzed carbonylative coupling of 2-bromoanilines with aryl bromides,16e
acid anhydrides,16f or isocyanates,16g respectively. Palladium-catalyzed carbonylative
C‒H activation of benzanilides or aryl urea derivatives were independently reported
by the Yu group and the Lloyd-Jones and Booker-Milburn group for the synthesis of
4H-3,1-benzoxazin-4-ones.17 Besides, carbonylative cyclization of N-acyl-2-halo-
anilines under the catalysis of palladium using paraformaldehyde, phenyl formate, or
oxalyl chloride as CO surrogates has also been developed for the synthesis of
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2-substituted 4H-3,1-benzoxazin-4-ones.18
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Although the palladium-catalyzed carbonylation methodology is highly efficient for
the construction of 2-substituted 4H-3,1-benzoxazin-4-ones,16-18 these carbonylation
reactions are usually conducted using homogeneous palladium catalysts in toxic
solvents such as toluene, THF and DMF. Homogeneous palladium catalysis suffers
from difficult separation and non-recyclability of the expensive catalysts. What’s
more, homogeneous catalysis might cause unacceptable palladium contamination in
the desired isolated products owing to palladium leaching. The complete removal of
residual palladium is a great problem for pharmaceutical products where carryover of
palladium impurities may result in serious issues in the production of many
formulations.19 Thus, facile separation and recycle of expensive catalysts remain a
scientific challenge and represent one of the most important features in green organic
synthesis from economic and environmental viewpoints. In order to address these
issues, anchoring homogeneous palladium catalysts on various solid supports is a
promising option since the supported catalysts can be conveniently recovered via a
simple filtration process. Recently, there has been increasing interest in the
development of heterogeneous palladium catalytic systems that can be effectively
recycled whilst maintaining the inherent catalytic activity.20 Petricci and coworkers
reported Pd/C-catalyzed cyclocarbonylation of o-iodoanilines with acid chlorides in
DMF under microwave dielectric heating, but the catalytic activity of Pd/C was
obviously lower than that of Pd(OAc)2 and the catalyst can be recycled only two times
due to palladium leaching.16d
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Biomass solvents derived from renewable raw materials have recently attracted
significant interest because of exceedingly zero or negligible impact on the environ-
ment and health as well as the continuous increase in the price of petroleum.
2-Methyltetrahydrofuran (2-MeTHF) is definitely an eco-friendly solvent derived
from renewable resources like corn cobs and oat hulls, and has already a wide
application in organic synthesis and pharmaceutical industry due to its low toxicity
and high biodegradability.21 In continuation of our efforts to develop green and
sustainable catalytic systems for organic transformations,22 herein we wish to report a
highly efficient, green palladium-catalyzed cyclocarbonylation of 2-iodoanilines with
acyl chlorides in the bio-based solvent 2-MeTHF by using an 2-aminoethylamino-
modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as
a recyclable heterogeneous catalyst, yielding a wide variety of 2-substituted 4H-3,1-
benzoxazin-4-one derivatives in good to excellent yields from commercially easily
available starting materials (Scheme 1).
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Scheme 1. Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodo-
anilines with Acyl Chlorides in 2-MeTHF.
O
I
2N-MCM-41-Pd(OAc)2
(2 mol%)
O
O
R
+
CO +
R
R1
Cl
DiPEA, 2-MeTHF, 100 oC
NH2
R1
(20 bar)
N
2
3
1
OSiMe3
O
Si
N
NH2
OAc
2N-MCM-41-Pd(OAc)2 =
H
O
Pd
OEt
AcO
RESULTS AND DISCUSSION
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The 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex
[2N-MCM-41-Pd(OAc)2] was facilely prepared according to our previously reported
similar procedure, as shown in Scheme 2.22a The condensation reaction of mesoporous
MCM-41 with commercially available and inexpensive 3-(2-aminoethylamino)-
propyltrimethoxysilane at 100 ºC in toluene, followed by treating with Me3SiCl in
toluene at room temperature gave an 2-aminoethylamino-modified MCM-41 material
(2N-MCM-41). Subsequent coordination reaction of 2N-MCM-41 with Pd(OAc)2 in
acetone at reflux for 48 hours afforded the 2-aminoethylamino-modified MCM-41-
anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as a light yellow
powder with palladium content of 0.39 mmol/g based on ICP-AES analysis.
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Scheme 2. Preparation of the 2N-MCM-41-Pd(OAc)2 Complex.
OSiMe3
OH
OH
1. (MeO)3Si(CH2)3NH(CH2)2NH2
Toluene, 100 oC, 24 h
O
Si
N
NH2
O
OH
H
2. Me3SiCl, r.t., 24 h
OMe
2N-MCM-41
MCM-41
OSiMe3
O
Pd(OAc)2
Si
N
NH2
O
H
acetone, reflux, 48 h
OMe
Pd
AcO
OAc
2N-MCM-41-Pd(OAc)2
The 2N-MCM-41-Pd(OAc)2 complex was then employed as the catalyst for the
cyclocarbonylation reaction of 2-iodoanilines with acyl chlorides. Initial experiments,
with 2-iodoaniline 1a and benzoyl chloride 2a under 20 bar of carbon monoxide, were
conducted to determine the optimal reaction conditions, and the results are given in
Table 1. At first, the effect of various common solvents on the model reaction was
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evaluated in the presence of 2 mol% of 2N-MCM-41-Pd(OAc)2 with DiPEA as base
at 100 ºC, and a remarkable solvent effect was observed (entries 1-7). When DMF and
THF were used as solvents, the target product 3a was isolated in 84-95% yields and
THF gave the best result (entry 4), while other solvents such as NMP, DMSO,
dioxane, MeCN, and toluene were substantially less effective and afforded relatively
lower yields of 3a. To our delight, replacement of THF with the eco-friendly solvent
2-MeTHF afforded the desired 3a in a slightly higher yield of 97% (entry 8). So, the
use of 2-MeTHF as solvent in this reaction was the best choice. Our next studies
focused on the influence of base on the model reaction using 2-MeTHF as solvent
(entries 9-13). Performing the reaction using other organic bases such as Et3N,
n-Bu3N, DBU, and TMEDA provided the desired product 3a in 78-87% yields and
K2CO3 gave a low yield of 3a, thus, DiPEA was the most efficient base (entry 8).
Lowering reaction temperature to 90 ºC led to a decreased yield (entry 14), whilst
raising reaction temperature to 110 or 120 ºC also resulted in a slightly decreased
yield of 3a (entries 15 and 16), thus the reaction run at 100 ºC gave the best result
(entry 8). Finally, the palladium catalyst loadings were also screened. Reducing the
amount of the catalyst to 1 mol% provided the desired 3a in only 75% yield even after
36 h (entry 17), while increasing the amount of the catalyst to 4 mol% could shorten
the reaction time to 16 h, but did not improve the yield further (entry 18). When a
homogeneous Pd(OAc)2 (2 mol%) was used as catalyst, the desired product 3a was
also isolated in 96% yield (entry 19), indicating that the catalytic efficiency of
2N-MCM-41-Pd(OAc)2 was comparable to that of homogeneous Pd(OAc)2 catalyst.
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Therefore, the optimized reaction conditions for this cyclocarbonylation are the use of
2N-MCM-41-Pd(OAc)2 (2 mol%), DiPEA (3 equiv.) as base in 2-MeTHF as a green
solvent at 100 °C under 20 bar of CO for 24 h (Table 1, entry 8).
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Table 1. Optimization of the Reaction Conditions.a
O
O
I
O
2N-MCM-41-Pd(OAc)2
Solvent, base, temp.
Cl
+
CO
+
(20 bar)
NH2
N
3a
1a
2a
entry
solvent
base
temp. (ºC)
Pd loading (mol%) yield (%)b
1
2
NMP
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
100
100
100
100
100
100
100
100
100
100
100
100
100
90
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
4
2
73
84
62
95
71
56
69
97
78
84
87
81
43
67
93
89
75
97
96
DMF
3
DMSO
THF
4
5
dioxane
MeCN
Toluene
6
7
8
2-MeTHF DiPEA
2-MeTHF Et3N
9
10
11
12
13
14
15
16
17c
18d
19e
2-MeTHF n-Bu3N
2-MeTHF DBU
2-MeTHF TMEDA
2-MeTHF K2CO3
2-MeTHF DiPEA
2-MeTHF DiPEA
2-MeTHF DiPEA
2-MeTHF DiPEA
2-MeTHF DiPEA
2-MeTHF DiPEA
110
120
100
100
100
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), base (3.0 mmol), solvent (5 mL) under 20
bar of CO for 24 h. b Isolated yield. c For 36 h. d For 16 h. e 2 mol% of Pd(OAc)2 was used as the
catalyst.
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With the optimal reaction conditions in hand, we started to investigate the substrate
scope of this heterogeneous palladium-catalyzed cyclocarbonylation reaction by using
a wide variety of acyl chlorides and various o-iodoanilines as substrates. Firstly, the
substrate scope of acyl chlorides was studied by evaluating a variety of aromatic and
aliphatic acyl chlorides and the results are summarized in Table 2. para-Substituted
benzoyl chlorides 2b-g bearing either electron-donating or electron-withdrawing
groups could undergo the cyclocarbonylation with 2-iodoaniline 1a smoothly to give
the corresponding 2-substituted 4H-3,1-benzoxazin-4-ones 3b-g in good to excellent
yields. Electron-rich benzoyl chlorides 2b-c showed a higher reactivity than electron-
deficient ones 2d-g. Sterically hindered ortho-substituted benzoyl chlorides 2h-i were
also compatible with the standard conditions and furnished the desired products 3h-i
in good yields. Besides, bulky 1-naphthoyl chloride 2j proved to be a good substrate
and provided the target product 3j in 89% yield. Notably, heteroaroyl chlorides such
as 2-furoyl chloride 2k and thiophene-2-carbonyl chloride 2l also reacted well in this
transformation and delivered the expected 2-heteroaryl-4H-3,1-benzoxazin-4-ones 3k
and 3l in high yields. Subsequently, the cyclocarbonylation of 2-iodoaniline 1a with a
variety of aliphatic acid chlorides were investigated under the optimized conditions
and the results are also given in Table 2. To our delight, aliphatic acid chlorides
exhibited a similar reactivity with aromatic acid chlorides and afforded a wide variety
of 2-alkyl-substituted 4H-3,1-benzoxazin-4-ones in good to excellent yields. For
example, cyclocarbonylation of acetyl chloride 2m with 2-iodoaniline 1a proceeded
smoothly to give the desired product 3m in 94% yield. α-Monosubstituted acid
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chlorides 2n-p were compatible with the standard conditions and provided the
corresponding 2-alkyl-substituted 4H-3,1-benzoxazin-4-ones 3n-p in 62-70% yields.
Notably, α-di- or trisubstituted acid chlorides 2q-s exhibited a higher reactivity than
α-monosubstituted analogues and afforded the desired products 3q-s in excellent
yields. Interestingly, when (E)-cinnamoyl chloride 2t was employed for the palla-
dium-catalyzed cyclocarbonylation reaction with 2-iodoaniline 1a, (E)-2-styryl-4H-
3,1-benzoxazin-4-one 3t was obtained in 96% yield. A range of electron-donating or
electron-withdrawing functional groups such as alkyl, methoxy, chloro, ester, nitro,
and trifluoromethyl as well as bulky 1-naphthyl, t-butyl and heteroaryl were tolerated
well. The above results indicate the superiority of this methodology in comparison
with previously reported palladium-catalyzed carbonylative synthesis of 2-substi-
tuted 4H-3,1-benzoxazin-4-ones. For instance, 3i was isolated in 86% yield while the
yield of 3i was 29% by Pd(0)-catalyzed carbonylation of 2-methoxyiodobenzene with
2-iodoaniline 1a.16b Also 3t was obtained by the reaction described herein while the
yield of 3t was 47% by Pd(0)-catalyzed carbonylation of β-bromostyrene with 2-iodo-
aniline 1a.16b In addition, 3m was formed in 94% yield while 40 and 60% yields of
3m were obtained from the thallation/Pd-catalyzed carbonylation of N-acetylaniline16a
and Pd-catalyzed carbonylation of N-acetyl-2-iodoaniline,16b respectively.
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Table 2. Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodo-
aniline 1a with Various Acyl Chlorides.a,b
O
2N-MCM-41-Pd(OAc)2
(2 mol%)
I
O
O
+
CO
(20 bar)
+
Cl
NH2
R
DiPEA, 2-MeTHF
100 oC, 24 h
N
3a-t
1a
R
2
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O
N
O
O
N
O
N
O
O
O
O
N
3d
, 86%
3c
3a
3e
, 90%
, 97%
O
3b
, 93%
Cl
OMe
Me
O
O
O
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O
O
O
O
Cl
N
N
N
N
NO2
3g
3h
CO2Me
, 72%
, 78%
, 81%
O
3f
, 78%
O
CF3
O
O
O
O
N
O
O
OMe
N
N
N
S
O
3i
, 86%
3j
, 89%
3l
, 86%
3k
, 89%
O
O
N
O
O
N
Cl
O
O
O
O
Cl
N
, 94%
CH3
N
3o
3m
3n
, 62%
3p
, 68%
, 70%
Cl
O
O
O
O
O
O
O
O
N
Me
Me
Ph
Ph
N
N
N
, 91%
Ph
3r
, 94%
3q
3s
, 96%
Et
3t
, 96%
Me
Ph
a Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), DiPEA (3.0 mmol), 2N-MCM-41-Pd(OAc)2
(2 mol%), 2-MeTHF (5 mL) at 100 ºC under 20 bar of CO for 24 h. b Isolated yield.
Encouraged by the above promising results, we next examined the substrate scope
of 2-iodoanilines 1 under the optimal reaction conditions and the results are listed in
Table 3. To our delight, we found this heterogeneous palladium-catalyzed cyclo-
carbonylation reaction to be quite general for various substituted 2-iodoanilines. For
example, 2-iodo-4-methylaniline 1b could undergo the cyclocarbonylation reaction
smoothly with a variety of aromatic or aliphatic acid chlorides to give the corres-
ponding 2-substituted 4H-3,1-benzoxazin-4-ones 3u-y in 80-93% yields. Further-
more, 5- or 4-(fluoro or chloro)-substituted 2-iodoanilines 1c-e also showed good
reactivity and produced the desired 7- or 6-(fluoro or chloro)-substituted 2-aryl(alkyl)-
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4H-3,1-benzoxazin-4-ones 3z-f' in 87-95% yields. It is noteworthy that, 5- or
4-bromo-2-iodoanilines 1f and 1g could undergo this transformation chemoselectively
with various acid chlorides, affording the corresponding 7- or 6-bromo-substituted
2-aryl(alkyl)-4H-3,1-benzoxazin-4-ones 3g'-k' in 88-91% yields. However, 2-iodo-
anilines bearing strong electron-withdrawing groups such as 4-cyano-2-iodoaniline 1h
and 2-iodo-4-nitroaniline 1i displayed a relatively lower reactivity and led to the
expected products 3l'-n' in only 64-68% yields. Notably, 6-bromo-2-(4-tert-butyl-
phenyl)-4H-benzo[d][1,3]oxazin-4-one 3o', a high-density lipoprotein (HDL) elevator,
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2c
was prepared in 88% yield by the reaction of 4-bromo-2-iodoaniline 1g with
4-tert-butylbenzoyl chloride 2u under the standard conditions. In addition, we also
performed cyclocarbonylation reaction of 2-bromoanilines with acid chlorides,
unfortunately, no desired products were detected even at higher reaction temperatures
and under higher pressures of carbon monoxide since the oxidative addition reaction
of aryl bromides to a heterogeneous palladium(0) complex was too slow, hence, 7- or
6-bromo-substituted 2-aryl(alkyl)-4H-3,1-benzoxazin-4-ones 3g'-k' were selectively
formed in high yields. A range of functional groups such as methyl, fluoro, chloro,
bromo, cyano, and nitro on the phenyl ring of 2-iodoanilines were tolerated well. The
present method is applicable to a wide range of acyl chlorides and various
2-iodoanilines and provides a novel, highly efficient, green and practical procedure
for the construction of 2-substituted 4H-3,1-benzoxazin-4-ones from readily available
starting materials.
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Table 3. Heterogeneous Palladium-Catalyzed Cyclocarbonylation of Various
Substituted 2-Iodoanilines with Acyl Chlorides.a,b
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7
8
9
O
2N-MCM-41-Pd(OAc)2
(2 mol%)
I
O
R
+
CO
(20 bar)
+
O
R
R1
Cl
NH2
DiPEA, 2-MeTHF
100 oC, 24 h
R1
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N
3u-n'
1
2
O
O
O
O
Me
Me
Me
Me
O
O
O
O
Et
N
N
N
N
3x
, 92%
3v
3u
, 90%
O
3w
, 93%
, 89%
O
Ph
Me
O
O
O
N
Me
O
O
N
O
Ph
Et
O
N
N
, 80%
O
F
F
Cl
Cl
3y
3z
, 89%
3a'
, 87%
3b'
, 91%
Ph
O
O
O
Cl
O
O
N
O
N
O
Et
Et
Ph
Ph
Et
N
Cl
N
Cl
Br
Ph
3d'
, 87%
3e'
, 88%
3c'
3f'
, 94%
, 95%
Ph
Ph
O
O
O
O
Br
O
O
O
O
N
N
Br
Br
N
, 89%
O
N
Br
Ph
3j'
3h'
, 91%
3i'
3g'
, 88%
, 89%
O
O
O
O2N
O2N
NC
Cl
O
O
O
N
O
Et
Et
Et
N
N
N
, 90%
3m'
, 65%
3n'
, 68%
3k'
3l'
, 64%
Ph
Ph
Ph
O
Br
O
N
3o'
, 88%
a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), DiPEA (3.0 mmol), 2N-MCM-41-Pd(OAc)2 (2
mol%), 2-MeTHF (5 mL) at 100 ºC under 20 bar of CO for 24 h. b Isolated yield.
To ensure that the high activity of 2N-MCM-41-Pd(OAc)2 results from the
palladium sites on the channel inner walls of the MCM-41 support and not from the
leached Pd species from 2N-MCM-41-Pd(OAc)2, the heterogeneity of the 2N-MCM-
41-Pd(OAc)2 complex was investigated by hot filtration test.23 We focused on the
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cyclocarbonylation reaction of 2-iodoaniline 1a (2.0 mmol) and benzoyl chloride 2a
(2.0 mmol) in 2-MeTHF (10 mL) by using 2N-MCM-41-Pd(OAc)2 (103 mg, 0.04
mmol) as the catalyst and DiPEA (6.0 mmol) as the base. After the reaction was
conducted for 8 h, the reaction mixture was cooled to 80 ºC and excess CO was
released carefully. The palladium catalyst was then removed from the reaction
mixture by filtration at 80 ºC via a heat preserving glass funnel and the catalyst-free
filtrate was allowed to react further under identical conditions for 24 h. It was found
that no increase in conversion of 2-iodoaniline 1a was observed in the clear solution,
demonstrating that the observed high activity should not arise from the soluble Pd
species leached from 2N-MCM-41-Pd(OAc)2. In addition, no palladium species could
be detected in the filtrate based on ICP-AES analysis. The above results confirm the
fact that the 2N-MCM-41-Pd(OAc)2 catalyst is stable during the cyclocarbonylation
and supports heterogeneous nature of the cyclocarbonylation reaction.
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A possible mechanism for this heterogeneous Pd-catalyzed cyclocarbonylation
reaction of 2-iodoanilines with acyl chlorides is illustrated in Scheme 3. Firstly, the
2N-MCM-41-Pd(OAc)2 complex can be reduced to the 2N-MCM-41-Pd(0) in the
presence of carbon monoxide. Oxidative addition of amide intermediate (A) formed in
situ from the reaction of 2-iodoaniline (1) with acyl chloride (2) to 2N-MCM-41-Pd(0)
generates an MCM-41-anchored arylpalladium(II) complex intermediate (B), which is
followed by migratory insertion of CO furnishing an MCM-41-anchored acylpalla-
dium(II) complex intermediate (C). Then intermediate (C) undergoes intramolecular
cyclization by a deprotonation of the amide proton (or the proton of its enol tautomer)
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in the presence of DiPEA to give intermediate (D). Finally, reductive elimination of
intermediate (D) affords the desired 2-substituted 4H-3,1-benzoxazin-4-one (3) and
regenerates 2N-MCM-41-Pd(0) to complete the catalytic cycle.
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Scheme 3. Proposed Catalytic Cycle.
I
O
R
+
R1
Cl
NH2
2
( )
1
( )
L-Pd(OAc)2
CO
DiPEA
O
N
.
DiPEA HCl
O
I
R
O
R
A
( )
L-Pd(0)
R1
R1
N
H
3
( )
L = 2N-MCM-41
I
O
L
Pd
L
Pd
O
O
B
( )
R
D
( )
R
R1
N
H
R1
N
I
O
.
CO
DiPEA HI
Pd
L
O
R
C
( )
R1
N
H
(iPr)2NEt
For the practical application of a heterogeneous precious metal catalyst, its ease of
separation and the ability to recycle the catalyst are key factors that have to be
examined. The 2N-MCM-41-Pd(OAc)2 complex can be easily separated from the
product and recovered via a simple filtration process. We then investigated the recycle
of 2N-MCM-41-Pd(OAc)2 in the cyclocarbonylation reaction of 2-iodoaniline 1a and
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benzoyl chloride 2a. After the reaction was completed, the reaction mixture was
diluted with EtOAc and filtered. The palladium catalyst was washed with distilled
water and ethanol, and dried in vacuo at 100 ºC for 3 h. The recovered catalyst was
used in the next run with the same substrates under the identical reaction conditions.
As illustrated in Figure 1, the recovered 2N-MCM-41-Pd(OAc)2 catalyst can be
reused at least seven times without apparent decrease in catalytic activity and the
yield of 3a was above 94%. In addition, the Pd leaching in this supported catalyst was
also examined and the Pd content of the recovered 2N-MCM-41-Pd(OAc)2 catalyst
after eight consecutive cycles was found to be 0.38 mmol/g based on ICP-AES
analysis, showing a negligible Pd leaching.
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Figure 1. Recycle of the 2N-MCM-41-Pd(OAc)2 Complex.
CONCLUSIONS
In conclusion, we have developed a novel, efficient and green methodology for the
synthesis of 2-substituted 4H-3,1-benzoxazin-4-one derivatives from readily available
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2-iodoanilines and acyl chlorides through a heterogeneous palladium-catalyzed cyclo-
carbonylation reaction in the eco-friendly solvent 2-MeTHF. In contrast to classical
routes for the preparation of 2-substituted 4H-3,1-benzoxazin-4-ones, this hetero-
geneous cyclocarbonylation strategy displays many attractive features, including: (1)
the scope of both acyl chloride and 2-iodoaniline substrates are broad, and a variety of
aromatic or aliphatic acyl chlorides and various 2-iodoanilines are allowed; (2) the
cyclocarbonylation reaction afforded a wide variety of 2-aryl(heteroaryl) or alkyl-
substituted 4H-3,1-benzoxazin-4-ones in good to excellent yields; (3) the reaction can
tolerate a wide range of functional groups; (4) 2-MeTHF derived from renewable
resources can be employed as a highly efficient and green solvent; (5) this phosphine-
free heterogeneous palladium catalyst can be easily obtained via a simple two-step
procedure from commercially readily available materials and recovered by filtration,
and recycled up to eight times without apparent decrease in catalytic activity. Our
protocol not only avoids the use of toxic solvents such as THF and DMF, but also
solves the basic problem of expensive palladium catalyst recovery and reuse.
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EXPERIMENTAL SECTION
General Methods. 2-Iodoanilines 1a-i and acyl chlorides 2a-u were purchased from
different commercial suppliers (TCI and Aldrich) and were used without further
purification. THF and 2-MeTHF were distilled from sodium ketyl and stored under
argon and other solvents were also purified by drying and distillation. Mesoporous
MCM-41 material was prepared according to our previous method.22a Products were
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isolated by column chromatography on silica gel (100-200 mesh) with a mixture of
diethyl ether and light petroleum ether as eluent. The products were confirmed by the
comparison of their spectra and physical data with authentic samples. 1H and 13C{1H}
NMR spectra were recorded at 400 or 100 MHz with CDCl3 as the solvent and TMS
as an internal standard. Chemical shifts are reported in δ (ppm) relative to TMS.
HRMS spectra were recorded on a Q-Tof spectrometer with micromass MS software
using electrospray ionization (ESI). Melting points are uncorrected. The content of
palladium was measured by ICP-AES analysis.
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General Procedure for the Preparation of 2N-MCM-41-Pd(OAc)2 Complex
A mixture of 1.50 g of 3-(2-aminoethylamino)propyltrimethoxysilane and 2.1 g of the
MCM-41 in 160 mL of dry toluene was stirred at reflux (in an oil bath) for 24 h under
Ar. Then the product was filtered and washed by chloroform (30 mL), and dried in
vacuo at 120 °C for 6 h. The dried powdery product was then treated with 3.1 g of
Me3SiCl in 120 mL of dry toluene at room temperature for 24 h and filtered. The
product was washed with diethyl ether (3 × 20 mL) and dried in vacuo at 100 °C for 3
h to afford 3.35 g of 2-aminoethylamino-modified MCM-41 material (2N-MCM-41).
The nitrogen content was measured to be 1.86 mmol/g by elemental analysis.
A mixture of 2N-MCM-41(2.0 g) and 0.191 g (0.85 mmol) of Pd(OAc)2 in 50 mL
of dry acetone was stirred at reflux (in an oil bath) for 48 h under Ar. The solid
product was collected by filtration, washed with distilled water and acetone and dried
at 80 °C in vacuo under Ar for 6 h to deliver 2.09 g of a light yellow palladium
complex [2N-MCM-41-Pd(OAc)2]. The nitrogen and palladium contents were
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measured to be 1.71 mmol/g and 0.39 mmol/g, respectively.
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General Procedure for the Heterogeneous Palladium-Catalyzed Cyclocarbony-
lative Synthesis of 2-Substituted 4H-3,1-Benzoxazin-4-ones
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A mixture of o-iodoaniline 1 (1.0 mmol), acyl chloride 2 (1.0 mmol), 2N-MCM-41-
Pd(OAc)2 (2 mol%), DiPEA (3.0 mmol), and dry 2-MeTHF (5.0 mL) was reacted in
an autoclave at 20 bar of carbon monoxide at 100 ºC ( in a heating mantle) for 24 h.
Upon completion of the reaction, the reaction mixture was cooled to ambient
temperature and excess CO was released carefully. Ethyl acetate (15 mL) was then
added and the resulting mixture was filtered. The 2N-MCM-41-Pd(OAc)2 catalyst
was washed with distilled water (2 × 5 mL) and ethanol (2 × 5 mL), followed by
drying in vacuo at 100 ºC for 3 h and reused in the next run. The filtrate was washed
with water (10 mL) and dried over anhydrous Na2SO4 and concentrated by rotary
evaporation. The residue was purified by silica gel column chromatography (diethyl
ether–light petroleum ether = 1:1) to afford the desired products 3.
2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (3a).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a white
solid (216.5 mg, 97%). m.p. = 123-125 °C. 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J
= 7.2 Hz, 2H), 8.20 (d, J = 7.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.55 (t, J = 7.4 Hz, 1H), 7.51-7.45 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
159.5, 157.1, 147.0, 136.5, 132.6, 130.2, 128.7, 128.6, 128.3, 128.2, 127.2, 117.0.
2-(p-Tolyl)-4H-benzo[d][1,3]oxazin-4-one (3b).24 The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a white
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solid (220.7 mg, 93%). m.p. = 137-139 °C. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J
= 7.6 Hz, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.77-7.72 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H),
7
8
9
13
7.43 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H). C{1H} NMR (100
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MHz, CDCl3): δ 159.5, 157.2, 147.1, 143.3, 136.4, 129.4, 128.5, 128.3, 127.9, 127.4,
127.1, 116.9, 21.7.
2-(4-Methoxyphenyl)-4H-benzo[d][1,3]oxazin-4-one (3c).16e The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (227.9 mg, 90%). m.p. = 151-152 °C. 1H NMR (400 MHz, CDCl3): δ
8.22 (d, J = 8.8 Hz, 2H), 8.18 (dd, J = 8.0, 1.2 Hz, 1H), 7.80-7.75 (m, 1H), 7.61 (d, J
= 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.3, 159.7, 157.1, 147.3, 136.4, 130.3, 128.5, 127.7,
126.9, 122.5, 116.7, 114.1, 55.5.
2-(4-Chlorophenyl)-4H-benzo[d][1,3]oxazin-4-one (3d).24 The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
1
as a white solid (221.6 mg, 86%). m.p. = 190 °C. H NMR (400 MHz, CDCl3): δ
8.24-8.21 (m, 3H), 7.82 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.6
Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.2, 156.2,
146.8, 139.1, 136.6, 129.6, 129.1, 128.7, 128.6, 128.4, 127.2, 117.0.
2-(4-(Trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one (3e).16e The product
was isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1
1
(v/v)) as a white solid (235.8 mg, 81%). m.p. = 80-82 °C. H NMR (400 MHz,
CDCl3): δ 8.38 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.0 Hz, 1H), 7.85-7.80 (m, 1H), 7.73
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(d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ 158.9, 155.6, 146.4, 136.7, 133.9 (q, J = 32.6 Hz), 133.5, 128.9,
128.7, 128.6, 127.4, 125.7 (q, J = 3.7 Hz), 123.7 (q, J = 271.0 Hz), 117.1.
Methyl 4-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)benzoate (3f). The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (219.4 mg, 78%). m.p. = 166-167 °C. 1H NMR (400 MHz, CDCl3): δ
8.38 (d, J = 8.4 Hz, 2H), 8.26 (dd, J = 7.8, 1.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H),
7.87-7.83 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.59-7.54 (m, 1H), 3.97 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 166.3, 159.2, 156.2, 146.7, 136.7, 134.2, 133.6, 129.9,
128.8, 128.7, 128.3, 127.5, 117.2, 52.4. HRMS (ESI) m/z: [M]+ calcd for C16H11NO4,
281.0688; found, 281.0693.
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2-(4-Nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one (3g).13c The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
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yellow solid (193.1 mg, 72%). m.p. = 204-205 °C. H NMR (400 MHz, CDCl3): δ
8.51 (d, J = 9.2 Hz, 2H), 8.37 (d, J = 9.2 Hz, 2H), 8.28 (dd, J = 7.8, 1.4 Hz, 1H),
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7.92-7.87 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63-7.58 (m, 1H). C{1H} NMR (100
MHz, CDCl3): δ 158.5, 155.0, 150.2, 146.3, 136.9, 135.9, 129.3, 129.2, 128.9, 127.7,
123.9, 117.2.
2-(2-Chlorophenyl)-4H-benzo[d][1,3]oxazin-4-one (3h).12b The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (201.1 mg, 78%). m.p. = 137-139 °C. 1H NMR (400 MHz, CDCl3): δ
8.26 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 7.8, 1.4 Hz, 1H), 7.87-7.82 (m, 1H), 7.71 (d, J
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= 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.53-7.51 (m, 1H), 7.46 (td, J = 7.6, 1.6 Hz,
1H), 7.39 (td, J = 7.6, 1.2 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.2, 156.6,
146.4, 136.7, 133.5, 132.4, 131.5, 131.1, 130.3, 129.0, 128.6, 127.4, 126.9, 117.0.
2-(2-Methoxyphenyl)-4H-benzo[d][1,3]oxazin-4-one (3i).24 The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (217.8 mg, 86%).. m.p. = 150-152 °C. 1H NMR (400 MHz, CDCl3): δ
8.25 (dd, J = 8.0, 0.8 Hz, 1H), 7.88-7.80 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.55-7.48
(m, 2H), 7.09-7.02 (m, 2H), 3.93 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.9,
158.7, 157.8, 147.1, 136.4, 133.2, 131.3, 128.4, 128.3, 127.3, 120.6, 117.0, 112.2,
56.1.
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2-(Naphthalen-1-yl)-4H-benzo[d][1,3]oxazin-4-one (3j).25 The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (243.2 mg, 89%). m.p. = 138 °C. 1H NMR (400 MHz, CDCl3): δ 9.13
(d, J = 8.8 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.21 (dd, J = 8.0, 0.8 Hz, 1H), 7.97 (d, J
= 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.79-7.75 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H),
7.63-7.59 (m, 1H), 7.54-7.45 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.7,
157.5, 146.8, 136.5, 134.1, 133.2, 130.8, 130.1, 128.9, 128.6, 128.5, 127.9, 127.4,
126.9, 126.4, 125.9, 124.8, 117.0.
2-(Furan-2-yl)-4H-benzo[d][1,3]oxazin-4-one (3k).26 The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a yellow
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solid (189.7 mg, 89%). m.p. = 102 °C. H NMR (400 MHz, CDCl3): δ 8.19 (dd, J =
8.0, 0.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.70-7.67 (m, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.35
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(d, J = 3.6 Hz, 1H), 6.62 (dd, J = 3.6, 1.6 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3):
δ 158.5, 149.7, 147.1, 146.6, 144.4, 136.7, 128.7, 128.2, 127.1, 117.2, 116.9, 112.5.
2-(Thiophen-2-yl)-4H-benzo[d][1,3]oxazin-4-one (3l).25 The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
white solid (197.2 mg, 86%). m.p. = 133-135 °C. 1H NMR (400 MHz, CDCl3): δ 8.22
(dd, J = 7.8, 1.0 Hz, 1H), 7.97 (dd, J = 3.8, 1.0 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H),
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7.65-7.60 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.18 (dd, J = 5.0, 3.8 Hz, 1H). C{1H}
NMR (100 MHz, CDCl3): δ 159.1, 153.8, 147.1, 136.6, 134.3, 132.4, 131.8, 128.8,
128.3, 128.0, 126.9, 116.8.
2-Methyl-4H-benzo[d][1,3]oxazin-4-one (3m).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a white
solid (151.5 mg, 94%). m.p. = 81-82 °C. 1H NMR (400 MHz, CDCl3): δ 8.12 (dd, J =
8.0, 1.2 Hz, 1H), 7.75-7.70 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H),
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2.40 (s, 3H). C{1H} NMR (100 MHz, CDCl3): δ 160.3, 159.7, 146.4, 136.5, 128.4,
128.2, 126.4, 116.7, 21.3.
2-Benzyl-4H-benzo[d][1,3]oxazin-4-one (3n).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a yellow
solid (147.1 mg, 62%). m.p. = 86-88 °C. 1H NMR (400 MHz, CDCl3): δ 8.16 (dd, J =
7.6, 0.8 Hz, 1H), 7.79 (td, J = 8.2, 1.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (t, J =
7.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.30-7.25 (m, 1H),
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3.98 (s, 2H). C{1H} NMR (100 MHz, CDCl3): δ 161.2, 159.6, 146.4, 136.5, 134.2,
129.3, 128.8, 128.5, 128.4, 127.5, 126.8, 116.8, 41.6.
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2-(4-Chlorobenzyl)-4H-benzo[d][1,3]oxazin-4-one (3o).16c The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a yellow solid (184.7 mg, 68%). m.p. = 143-145 °C. 1H NMR (400 MHz, CDCl3):
δ 8.16 (d, J = 8.0 Hz, 1H), 7.79 (td, J = 8.4, 1.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H),
7.50 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.95 (s,
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2H). C{1H} NMR (100 MHz, CDCl3): δ 160.7, 159.4, 146.3, 136.6, 133.5, 132.6,
130.7, 129.0, 128.6, 128.5, 126.8, 116.8, 40.9.
2-(2,3-Dichlorobenzyl)-4H-benzo[d][1,3]oxazin-4-one (3p). The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a yellow solid (214.3 mg, 70%). m.p. = 125-127 °C. 1H NMR (400 MHz, CDCl3):
δ 8.18 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.33-7.30 (m, 1H), 7.21 (t, J =
13
7.8 Hz, 1H), 4.19 (s, 2H). C{1H} NMR (100 MHz, CDCl3): δ 159.5, 159.4, 146.2,
136.6, 134.6, 133.6, 133.1, 129.8, 129.7, 128.6, 128.5, 127.4, 126.9, 116.8, 39.8.
HRMS (ESI) m/z: [M]+ calcd for C15H9Cl2NO2, 305.0010; found, 305.0017.
2-Benzhydryl-4H-benzo[d][1,3]oxazin-4-one (3q).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a yellow
solid (285.1 mg, 91%). m.p. = 120-122 °C. 1H NMR (400 MHz, CDCl3): δ 8.02 (dd, J
= 7.8, 1.0 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35-7.27 (m,
13
5H), 7.24-7.19 (m, 4H), 7.18-7.13 (m, 2H), 5.27 (s, 1H). C{1H} NMR (100 MHz,
CDCl3): δ 162.3, 159.5, 146.4, 138.6, 136.5, 129.0, 128.8, 128.6, 128.5, 127.6, 127.2,
117.0, 57.1.
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2-(1-Phenylpropyl)-4H-benzo[d][1,3]oxazin-4-one (3r).16c The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a yellow solid (249.4 mg, 94%). m.p. = 135-136 °C. 1H NMR (400 MHz, CDCl3): δ
8.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.75 (td, J = 8.4, 1.6Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H),
7.47-7.42 (m, 3H), 7.35-7.30 (m, 2H), 7.27-7.23 (m, 1H), 3.78 (t, J = 7.8 Hz, 1H),
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2.37-2.30 (m, 1H), 2.06-2.01 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H). C{1H} NMR (100
MHz, CDCl3): δ 163.6, 159.7, 146.5, 139.2, 136.4, 128.8, 128.4, 128.2, 127.5, 126.9,
117.0, 53.3, 26.5, 12.2.
2-(tert-Butyl)-4H-benzo[d][1,3]oxazin-4-one (3s).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a green
solid (195.1 mg, 96%). m.p. = 117-118 °C. 1H NMR (400 MHz, CDCl3): δ 8.10-8.07
(m, 1H), 7.71-7.66 (m, 1H), 7.49 (dd, J = 8.0, 1.2 Hz, 1H), 7.42-7.37 (m, 1H), 1.32 (s,
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9H). C{1H} NMR (100 MHz, CDCl3): δ 168.2, 160.1, 146.6, 136.3, 128.3, 128.0,
126.9, 116.8, 37.9, 27.7.
(E)-2-Styryl-4H-benzo[d][1,3]oxazin-4-one (3t).16c The product was isolated via
column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a yellow
solid (239.3 mg, 96%). m.p. = 144-146 °C. 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J
= 8.0, 1.2 Hz, 1H), 7.83 (d, J = 16.4 Hz, 1H), 7.79 (t, J = 7.0 Hz, 1H), 7.61-7.55 (m,
3H), 7.51-7.47 (m, 1H), 7.42-7.36 (m, 3H), 6.77 (d, J = 16.0 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ 159.3, 157.3, 147.2, 142.0, 136.6, 134.7, 130.3, 129.0, 128.7,
128.2, 128.0, 127.0, 118.9, 117.0.
6-Methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (3u).27 The product was isolated
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via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
white solid (220.7 mg, 93%). m.p. = 114-115 °C. 1H NMR (400 MHz, CDCl3): δ 8.29
(d, J = 7.6 Hz, 2H), 8.03 (s, 1H), 7.64-7.48 (m, 5H), 2.48 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 159.8, 156.4, 144.9, 138.7, 137.8, 132.4, 130.4, 128.7, 128.2, 127.0,
116.7, 21.3.
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6-Methyl-2-(p-tolyl)-4H-benzo[d][1,3]oxazin-4-one (3v). The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
white solid (226.2 mg, 90%). m.p. = 165-167 °C. 1H NMR (400 MHz, CDCl3): δ 8.15
(d, J = 7.2 Hz, 2H), 7.99 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),
7.28 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 159.8, 156.6, 145.0, 143.1, 138.4, 137.7, 129.5, 128.2, 128.1, 127.6, 126.9, 116.6,
21.7, 21.3. HRMS (ESI) m/z: [M]+ calcd for C16H13NO2, 251.0946; found, 251.0938.
6-Methyl-2-(naphthalen-1-yl)-4H-benzo[d][1,3]oxazin-4-one (3w). The product
was isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1
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(v/v)) as a yellow solid (255.7 mg, 89%). m.p. = 112-114 °C. H NMR (400 MHz,
CDCl3): δ 9.05 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J =
8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.58-7.51 (m, 3H), 7.49-7.43 (m, 2H), 2.39 (s,
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3H). C{1H} NMR (100 MHz, CDCl3): δ 159.9, 156.9, 144.7, 139.1, 137.8, 134.1,
133.0, 130.8, 129.9, 128.8, 128.1, 127.8, 127.2, 127.1, 126.4, 125.9, 124.8, 116.7,
21.4. HRMS (ESI) m/z: [M+H]+ calcd for C19H14NO2, 288.1025; found, 288.1014.
6-Methyl-2-(1-phenylpropyl)-4H-benzo[d][1,3]oxazin-4-one (3x). The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
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as a yellow solid (256.9 mg, 92%). m.p. = 98-99 °C. H NMR (400 MHz, CDCl3): δ
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7.92 (s, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.2
Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 3.76 (t, J = 7.8 Hz, 1H),
2.42 (s, 3H), 2.35-2.29 (m, 1H), 2.08-2.01 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 162.8, 160.0, 144.3, 139.3, 138.6, 137.6, 128.7, 128.2,
128.0, 127.5, 126.7, 116.7, 53.2, 26.5, 21.2, 12.2. HRMS (ESI) m/z: [M]+ calcd for
C18H17NO2, 279.1259; found, 279.1257.
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2-Benzyl-6-methyl-4H-benzo[d][1,3]oxazin-4-one (3y).16c The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
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yellow solid (201.1 mg, 80%). m.p. = 187-189 °C. H NMR (400 MHz, CDCl3): δ
7.96 (s, 1H), 7.59 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.2
Hz, 2H), 7.36-7.32 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 3.97 (s, 2H), 2.45 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 159.9, 144.3, 138.8, 137.7, 134.4, 129.3,
128.8, 128.0, 127.4, 126.6, 116.5, 41.6, 21.2.
7-Fluoro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (3z). The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
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white solid (214.7 mg, 89%). m.p. = 132-134 °C. H NMR (400 MHz, CDCl3): δ
8.31-8.26 (m, 2H), 8.24 (dd, J = 8.8, 6.0 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.50 (t, J =
13
7.4 Hz, 2H), 7.33 (dd, J = 9.2, 2.4 Hz, 1H), 7.23-7.18 (m, 1H). C{1H} NMR (100
MHz, CDCl3): δ 167.8 (d, J = 256.4 Hz), 158.6, 158.4, 149.5 (d, J = 13.3 Hz), 133.0,
131.3 (d, J = 10.8 Hz), 129.9, 128.8, 128.5, 116.6 (d, J = 23.2 Hz), 113.6, 113.3 (d, J
= 22.4 Hz). HRMS (ESI) m/z: [M]+ calcd for C14H8FNO2, 241.0539; found, 241.0533.
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7-Fluoro-2-(1-phenylpropyl)-4H-benzo[d][1,3]oxazin-4-one (3a'). The product
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(v/v)) as a yellow solid (246.4 mg, 87%). m.p. = 90-92 °C. H NMR (400 MHz,
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CDCl3): δ 8.16 (dd, J = 8.8, 6.0 Hz, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz,
2H), 7.29-7.26 (m, 2H), 7.20-7.16 (m, 1H), 3.77 (t, J = 7.8 Hz, 1H), 2.35-2.28 (m,
1H), 2.08-2.00 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
167.7 (d, J = 256.3 Hz), 165.1, 158.8, 149.0 (d, J = 13.3 Hz), 138.9, 131.2 (d, J = 10.8
Hz), 128.8, 128.2, 127.7, 116.7 (d, J = 23.1 Hz), 113.6 (d, J = 2.3 Hz), 113.1 (d, J =
22.5 Hz), 53.3, 26.5, 12.2. HRMS (ESI) m/z: [M]+ calcd for C17H14FNO2, 283.1009;
found, 283.1014.
7-Chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (3b'). The product was isolated
via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v)) as a
white solid (234.5 mg, 91%). m.p. = 190-192 °C. 1H NMR (400 MHz, CDCl3): δ 8.28
(d, J = 7.6 Hz, 2H), 8.15 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.59 (t, J = 7.4
Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 (dd, J = 8.4, 2.0 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 158.8, 158.3, 148.1, 143.0, 133.0, 129.9, 129.8, 128.8, 128.7, 128.5,
127.0, 115.4. HRMS (ESI) m/z: [M]+ calcd for C14H8ClNO2, 257.0244; found,
257.0251.
7-Chloro-2-(1-phenylpropyl)-4H-benzo[d][1,3]oxazin-4-one (3c'). The product
was isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1
1
(v/v)) as a yellow solid (281.7 mg, 94%). m.p. = 150-151 °C. H NMR (400 MHz,
CDCl3): δ 8.03 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.43-7.36 (m, 3H), 7.32
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(t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 3.76 (t, J = 7.8 Hz, 1H), 2.35-2.27 (m,
1H), 2.07-1.99 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
165.1, 158.9, 147.5, 142.8, 138.9, 129.7, 128.8, 128.7, 128.2, 127.7, 126.8, 115.4,
53.2, 26.5, 12.2. HRMS (ESI) m/z: [M]+ calcd for C17H14ClNO2, 299.0713; found,
299.0716.
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2-Benzhydryl-7-chloro-4H-benzo[d][1,3]oxazin-4-one (3d'). The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (302.6 mg, 87%). m.p. = 167-169 °C. 1H NMR (400 MHz, CDCl3): δ
7.98 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H),
13
7.29-7.13 (m, 10H), 5.26 (s, 1H). C{1H} NMR (100 MHz, CDCl3): δ 162.7, 158.5,
144.8, 138.3, 136.8, 134.2, 129.0, 128.8, 127.8, 127.7, 118.1, 57.0. HRMS (ESI) m/z:
[M]+ calcd for C21H14ClNO2, 347.0713; found, 347.0708.
6-Chloro-2-(furan-2-yl)-4H-benzo[d][1,3]oxazin-4-one (3e'). The product was
isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1 (v/v))
as a white solid (217.9 mg, 88%). m.p. = 161-163 °C. 1H NMR (400 MHz, CDCl3): δ
8.13 (d, J = 8.4 Hz, 1H), 7.72-7.68 (m, 2H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.39 (d, J
13
= 3.2 Hz, 1H), 6.64 (dd, J = 2.8, 0.8 Hz, 1H). C{1H} NMR (100 MHz, CDCl3): δ
157.8, 150.8, 147.8, 147.5, 144.2, 143.2, 130.0, 128.8, 126.9, 118.0, 115.3, 112.7.
HRMS (ESI) m/z: [M]+ calcd for C12H6ClNO3, 247.0036; found, 247.0043.
6-Chloro-2-(1-phenylpropyl)-4H-benzo[d][1,3]oxazin-4-one (3f').16c The product
was isolated via column chromatography (eluent diethyl ether/petroleum ether = 1:1
1
(v/v)) as a yellow solid (284.8 mg, 95%). m.p. = 119-121 °C. H NMR (400 MHz,
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