Copper(I)-catalyzed one-pot synthesis of 2H-1,4-benzoxazin-3-(4H)-ones from o-halophenols and 2-chloroacetamides

Article abstract of DOI:10.1021/jo802818s

We developed an efficient and convenient method for preparing N-substituted 2H-1,4-benzoxazin-3-(4H)-ones from 2-halophenols via a nueleophilic substitution with 2-chlo-roacetamides followed by a Cul-catalyzed coupling cyclization. A broad spectrum of substrates can be effectively employed to afford the desired products in good yields. Since this method involves simple reaction conditions, a short reaction time, and a broad substrate scope, it is particularly attractive for the efficient preparation of biologically and medicinally interesting molecules.

Full text of DOI:10.1021/jo802818s

myocardial necrosis, and arrhythmia.4 Compound 6 is a potential
agent for treating anxiety and depression.5 The 2-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid derivative 7
was found to be a potent immunostimulant.6 It is known that
2H-1,4-benzoxazin-3-(4H)-ones bearing a carboxylate and a
benzamidine side chain are fibrinogen receptor antagonists,7 and
compound 8 exhibits a dual antithrombotic action, exhibiting
both thrombin inhibitory and fibrinogen receptor antagonistic
activities.8 Similar biologically active derivatives have been
briefly described in a broader-context review.9
Copper(I)-Catalyzed One-Pot Synthesis of
2H-1,4-Benzoxazin-3-(4H)-ones from
o-Halophenols and 2-Chloroacetamides
Enguang Feng,† He Huang,† Yu Zhou,† Deju Ye,†
Hualiang Jiang,†,‡ and Hong Liu*,†
The Center for Drug DiscoVery and Design, State Key
Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, Shanghai, 201203, China, and School
of Pharmacy, East China UniVersity of Science and
Technology, Shanghai, 200237, China
hliu@mail.shcnc.ac.cn
ReceiVed December 29, 2008
FIGURE 1. Structures of 2H-1,4-benzoxazin-3-(4H)-one and some
biologically important derivatives.
We developed an efficient and convenient method for
preparing N-substituted 2H-1,4-benzoxazin-3-(4H)-ones from
2-halophenols via a nucleophilic substitution with 2-chlo-
roacetamides followed by a CuI-catalyzed coupling cycliza-
tion. A broad spectrum of substrates can be effectively
employed to afford the desired products in good yields. Since
this method involves simple reaction conditions, a short
reaction time, and a broad substrate scope, it is particularly
attractive for the efficient preparation of biologically and
medicinally interesting molecules.
Most of the available literature indicates that 2-aminophenols
or substituted 2-nitrophenols are common building blocks for
the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones.10 Recently,
Zuo and co-workers11 used 2-chlorophenols to synthesize
diverse 2H-1,4-benzoxazin-3-(4H)-ones via Smiles rearrang-
ment.12 Although this method is encouraging, its disadvantage
(5) Bertani, B.; Borriello, M.; Bozzoli, A.; Bromidge, S. M.; Granci, E.;
Leslie, C.; Serafinowska, H.; Stasi, L.; Vong, A.; Zucchelli, V.; Serafinowska,
H. G.; Stasi, L. G.; Serfinowska, H. WO2004046124-A1.
(6) Kikelj, D.; Suhadolc, E.; Rutar, A.; Pecar, S.; Puncuh, A.; Urleb, U.;
Leskovsek, V.; Marc, G.; Sollner, M.; Krbavcic, A.; Sersa, G.; Novakovic, S.;
Povsic, L.; Stalc, A. EP695308-A; WO9424152-A.
(7) Stefanic, P.; Simoncic, Z.; Breznik, M.; Plavec, J.; Anderluh, M.; Addicks,
E.; Giannis, A.; Kikelj, D. Org. Biomol. Chem. 2004, 2, 1511.
(8) Stefanic Anderluh, P.; Anderluh, M.; Ilas, J.; Mravljak, J.; Sollner Dolenc,
M.; Stegnar, M.; Kikelj, D. J. Med. Chem. 2005, 48, 3110.
The 2H-1,4-benzoxazin-3-(4H)-ones scaffold has been studied
extensively as an important heterocyclic system for building
natural1 and synthetic compounds.2 Its derivatives are now
known to possess useful biological and medicinal activities
(Figure 1). For example, compound 4, a novel antibacterial
agent, is an inhibitor of bacterial histidine protein kinase.3
Compound 5 is a potential drug for treating heart disease,
(9) Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett 2004,
2449.
(10) For selected examples, see: (a) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron
2006, 62, 4635. (b) Hashimoto, Y.; Ishizaki, T.; Shudo, K. Tetrahedron 1991,
47, 1837. (c) Wu, J.; Nie, L.; Luo, J.; Dai, W.-M. Synlett 2007, 17, 2728. (d)
Xing, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron 2006, 62, 6774. (e) Dai,
W.-M.; Wang, X.; Ma, C. Tetrahedron 2005, 61, 6879. (f) Feng, G.; Wu, J.;
Dai, W.-M. Tetrahedron Lett. 2007, 48, 401. (g) Yuan, Y.; Liu, G.; Li, L.; Wang,
Z.; Wang, L. J. Comb. Chem. 2007, 9, 158. (h) Rybczynski, P. J.; Zeck, R. E.;
Combs, D. W.; Turchi, I.; Burris, T. P.; Xu, J. Z.; Yang, M.; Demarest, K. T.
Bioorg. Med. Chem. Lett. 2003, 13, 235. (i) Matsumoto, Y.; Uchida, A.;
Nakahara, H.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Chem. Pharm. Bull.
2000, 48, 428.
† Chinese Academy of Sciences.
‡ East China University of Science and Technology.
(1) (a) Zhen, Y. S.; Ming, X. Y.; Yu, B.; Otani, T.; Saito, H.; Yamada, Y.
J. Antibiot. 1989, 42, 1294. (b) Sugimoto, Y.; Otani, T.; Oie, S.; Wierzba, K.;
Yamada, Y. J. Antibiot. 1990, 43, 417.
(2) For a representative review, see: Ilas, J.; Anderluh, P. S.; Dolenc, M. S.;
Kikelj, D. Tetrahedron 2005, 61, 7325–7348.
(3) (a) Frechette, R.; Beach, M. WO9728167-A. (b) Frechette, R.; Weidner-
Wells, M. A.; Weidnerwells, M. A. WO9717333-A.
(4) Hori, M.; Watanabe, I.; Ohtaka, H.; Harada, K.; Maruo, J.; Morita, T.;
Yamamoto, T.; Tsutsui, H. EP719766-A.
(11) Zuo, H.; Meng, L.; Ghate, M.; Hwang, K.-H.; Kweon Cho, Y.;
Chandrasekhar, S.; Raji Reddy, C.; Shin, D.-S. Tetrahedron Lett. 2008, 49, 3827.
(12) (a) Baker, W. R. J. Org. Chem. 1983, 48, 5140. (b) Coutts, I. G. C.;
Southcott, M. R. J. Chem. Soc., Perkin. Trans. 1990, 1, 767.
2846 J. Org. Chem. 2009, 74, 2846–2849
10.1021/jo802818s CCC: $40.75 2009 American Chemical Society
Published on Web 03/03/2009

TABLE 1. Optimization for the Synthesis of
SCHEME 1. Copper-Catalyzed Synthesis of
N-Substituted-2H-1,4-benzoxazin-3-(4H)-ones
4-Phenyl-2H-1,4-benzooxazin-3-(4H)-onea
ratio
(1a/2a)
time
is that only a limited number of substrates can be employed.
For example, it is problematic for the synthesis of N-aryl-2H-
1,4-benzoxazin-3-(4H)-ones. Up to now, no protocols for the
construction of N-substituted-2H-1,4-benzoxazin-3-(4H)-ones
based on coupling reactions have been reported. Apparently,
the development of an alternative and improved procedure with
wide applications still remains a formidable task.
entry
catalyst
CuI
CuI
CuI
ligand
DBU
DBU
DBU
DBU
base
(min) yield (%)
1
2
3
4
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
10
20
10
10
10
20
30
10
10
10
10
10
10
10
10
210
8
NaOH
39
59
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
5
CuI
CuI
CuI
CuI
trace
35
61
85/81c
84
65
70
15
12
75
25
75
6b
7
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
As a part of our continuing effort to assemble heterocycles
by copper-catalyzed cross-coupling reactions,13,14 we aimed to
develop a novel protocol for synthesizing N-substituted-2H-1,4-
benzoxazin-3-(4H)-ones via copper(I)-catalyzed intramolecular
cyclization of 2-iodophenols 1 and 2-chlor-acetamides 2, which
can be readily prepared in high yields from commercially
available amines with 2-chloroacetyl chloride. The studies
undertaken are presented in Scheme 1. In comparison with
existing methods, the present approach offers the following
advantages: (i) it is the first highly efficient and practical protocol
based on coupling reactions for the construction of N-substituted-
2H-1,4-benzoxazin-3-(4H)-ones; (ii) it uses inexpensive CuI/
DBU (1,8-diazabicyclo[5.4.0 undec-7-ene) without requiring any
other additives; (iii) it proceeds rapidly and affords good to
excellent yields within minutes under microwave heating; and
(iv) it encompasses a much broader substrate scope, both N-aryl-
and N-alkyl-2H-1,4-benzoxazin-3-(4H)-ones, as well as
N-heterocyclic substituted ones, can be employed in this
protocol.
8
9
CuI
10
11
12
13
14f
15g
16h
CuCl
Cu2O
Cu(OAc)2
d
e
CuSO4
CuI
CuI
CuI
DMEDA
L-proline
DBU
a Reaction conditions: catalyst (0.2 equiv), base (1.6 equiv), DBU (1.5
equiv), DMSO (2 mL), MW, 130 °C. b MW, 120 °C. c A subsequential
procedure was conducted. d Cu(OAc)2 (0.5 equiv). e CuSO4 (0.5 equiv).
f DMEDA (N,N′-dimethylethylenediamine) (0.4 equiv), Cs2CO3 (2.0
equiv). L-Proline (0.4 equiv), Cs2CO3 (2.0 equiv). h The general
g
method without microwave heating was adopted, 130 °C, CuI (0.5
equiv).
However, no target compound was generated in the absence of
the catalyst or ligand, indicating that both are crucial for the
intermolecular nucleophilic substitution and intramolecular
cyclization (Table 1, entries 4 and 5). When the temperature
was reduced to 120 °C, the starting materials were not consumed
completely within 20 min (Table 1, entry 6). The yields failed
to improve any further when the reaction time was prolonged
to 30 min (Table 1, entries 3 and 7). Thin-layer chromatography
(TLC) analysis showed that 1a was not fully converted, thus
inspiring us to further investigate the molar ratios of the building
blocks. As anticipated, the best yield of the target compound
was obtained when 1.5 equiv of 2-chloro-N-phenylacetamide
2a was added (Table 1, entries 3, 8, and 9).
Both CuCl and Cu2O were found to be effective catalysts
for this coupling reaction (Table 1, entries 10 and 11); however,
the bivalent copper salts, Cu(OAc)2 and CuSO4, were not as
effective as CuI even though the intramolecular cyclization could
proceed to some extent (Table 1, entries 12 and 13). The use of
other ligands such as DMEDA or L-proline gave somewhat
lower yields (Table 1, entries 14 and 15). Subsequently, we
investigated the solvent effect, which revealed that DMSO was
superior to dioxane, toluene, and DMF.17 Finally, we found that
when the reaction was performed without microwave heating,
it afforded a 75% yield after refluxing at 130 °C for 3.5 h (Table
1, entry 16). We also tried a two-step procedure during our
original research (Scheme 2). A mixture of 1a (1.0 mmol), 2a
(1.0 mmol), and DBU (1.2 mmol) in DMSO (2.0 mL) was
treated at 100 °C with microwave heating for 5 min without
any catalyst and additive. The mixture was purified by flash
column chromatography (petroleum ether/ethyl acetate ) 10/
2-Iodophenol 1a and 2-chloro-N-phenylacetamide 2a were
used as the model substrates to optimize the reaction conditions
in terms of bases, solvents, reaction time, and catalyst-loading.
The results are summarized in Table 1.
We initially employed the conditions used in our previously
published studies13,15 on the copper-catalyzed C-N bond
formation from halides and amines. Almost no coupling
occurred in the absence of the base, while the addition of 1.6
equiv of NaOH resulted in the formation of the desired coupling
product in 39% yield after 20 min of irradiation at 130 °C in
the presence of DBU (Table 2, entries 1 and 2). The nature of
the base was found to have a pronounced impact on the process,
and Cs2CO3 was proven to be more effective than NaOH,
K2CO3, K3PO4, and DABCO.16 A moderate amount of the
expected product 3a was obtained when using CuI (0.2 equiv)
as the catalyst, DMSO (dimethyl sulfoxide) as the solvent,
Cs2CO3 as the base, and DBU as the ligand (Table 1, entry 3).
(13) For some of our group studies on the synthesis of N-heterocycles, see:
(a) Li, Z.; Sun, H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263. (b) Li, Z.;
Huang, H.; Sun, H.; Jiang, H.; Liu, H. J. Comb. Chem. 2008, 10, 484.
(14) For recent studies on the synthesis of N-heterocycles through Ullmann-
type couplings from other groups, see: (a) Evindar, G.; Batey, R. A. Org. Lett.
2003, 5, 133. (b) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L.
J. Am. Chem. Soc. 2004, 126, 3529. (c) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.;
Zhao, Y. Org. Lett. 2005, 7, 4781. (d) Evindar, G.; Batey, R. A. J. Org. Chem.
2006, 71, 1802. (e) Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (f)
Martin, R.; Rodriguez Rivero, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006,
45, 7079. (g) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291.
(15) (a) Huang, H.; Yan, X.; Zhu, W.; Liu, H.; Jiang, H.; Chen, K. J. Comb.
Chem. 2008, 10, 617. (b) Chen, S.; Huang, H.; Liu, X.; Shen, J.; Jiang, H.; Liu,
H. J. Comb. Chem. 2008, 10, 358.
(16) Yields of the desired product for the screening reactions with other bases:
K2CO3 (20%), K3PO4 (0%), DABCO (trace).
(17) Yields of the desired product for the screening reactions with other
solvents: toluene (trace), DMF (30%), dioxane (15%).
J. Org. Chem. Vol. 74, No. 7, 2009 2847

TABLE 2. Synthesis of N-Substituted-2H-1,4-benzoxazin-3-(4H)-ones
TABLE 3. Synthesis of Various Substituted
2H-1,4-Benzoxazin-3-(4H)-ones
a Reaction conditions: X ) I, CuI (0.2 equiv), Cs2CO3 (1.6 equiv),
DBU (1.5 equiv), DMSO (2 mL), MW, 130 °C, 10 min. b X ) Br,
MW, 130 °C, 20 min.
SCHEME 2. Two-Step Synthesis of
2H-1,4-Benzoxazin-3-(4H)-one via Intermolecular
Nucleophilic Substitution (Path A)/Intramolecular C-N
Coupling (Path B)
a Reaction conditions: X ) I, 1 (0.5 mmol), 2 (0.75 mmol), CuI (0.1
mmol), DBU (0.75 mmol), Cs2CO3 (0.9 mmol), MW, 130 °C, 10 min.
b X ) Br, MW, 130 °C, 20 min.
After determining the optimized conditions, we proceeded
to examine the generality of the process. As summarized in
Table 2, the reaction was compatible with various 2-chloroac-
etamides to afford different N-substituted-2H-1,4-benzoxazin-
3-(4H)-ones. Aryl, alkyl, and heterocyclic substituents are well
tolerated. The ortho-, meta-, and para-substituents on the
acetamide component had no significant steric effects (Table
2, entries 2-7). Moreover, the electron-donating and electron-
withdrawing substituents had no perceptible effect on the yields
(Table 2, entries 5, 8, and 9). Furthermore, several functional
groups were employed in this copper-catalyzed process. It was
observed that the N-(4-bromophenyl) and N-(4-ethoxycarbon-
yl)phenyl, which are sensitive to bases or acids, were all
tolerated in the cyclization process (Table 2, entries 8 and 10).
Reaction involving the N-heterocyclic group such as pyridine-
3-yl proceeded smoothly to afford the desired product in a good
yield (Table 2, entry 11). In addition to N-aryl substituents,
several N-alkyl ones were also obtained in moderate to high
yields (Table 2, entries 12-14).
1) to yield the intermediate compound 9. Then compound 9
(0.5 mmol), CuI (0.1 mmol), Cs2CO3 (0.9 mmol), and DBU
(0.15 mmol) in DMSO (2.0 mL) were treated at 130 °C with
microwave heating for 10 min. The desired product 3a was
isolated in 81% total yield (Table 1, entry 8). We used 1.2 equiv
of DBU as the base for the first intermolecular nucleophilic
substitution, and the other DBU for purely ligand purpose.
Comparing the two methods, the former is superior for its
concise single-step manipulation and better yield. Apparently,
microwave irradiation in one pot had a significant effect on the
increase in the yield and the decrease in the reaction time.
Therefore, microwave heating was adopted in the following
investigation. Briefly, the optimum results were obtained when
2-chloroacetamide (1.5 equiv) and 2-iodophenol (1.0 equiv) were
treated with CuI (0.2 equiv), Cs2CO3 (1.6 equiv), and DBU (1.5
equiv) in DMSO at 130 °C with microwave heating for 10 min.
2848 J. Org. Chem. Vol. 74, No. 7, 2009

mmol) in CH2Cl2 (5 mL) at -5 °C was added 2-chloroacetyl
chloride (0.6 mmol) dropwise. After 10 min, the reaction mixture
was allowed to warm to room temperature. When the starting
materials were consumed monitored with TLC, the solution was
diluted with CH2Cl2 (20 mL), washed with water and brine, and
dried over anhydrous Na2SO4. On evaporation of the solvent, the
desired N-substituted-2-chloroacetamides 2 were obtained in high
yields and purity without further purification.
Subsequently, we investigated the application of the devel-
oped protocol to 2-bromophenol. Unfortunately, the desired
product 3b was obtained in a low yield under the optimized
conditions. When the reaction time was prolonged to 20 min,
there was a moderate improvement in the yield (Table 2, entries
2, 6, and 7). As compared to iodides, bromides exhibited lower
reactivity. These results indicated that the reactivity order of
aryl halides was iodides > bromides, which was consistent with
the order reported previously.15
Finally, we focused on employing different 2-chloroaceta-
mides and 2-halophenols. Fortunately, as shown in Table 3, the
method was applicable to a broad range of substrates including
both 2-chloroacetamides and 2-halophenols. First, this new
process was applied to 2-methyl-2-chloroacetamides. The ortho-,
meta-, and para-substituents on the acetamide component had
no significant steric effects, and the electronic effects on the
reactions were also limited (Table 3, entries 1-5). Second,
4-tert-butyl-2-iodophenol, 4-methyl-2-bromophenol, and 6-methyl-
2-iodopyridin-3-ol were investigated, and the corresponding
N-substituted-2H-1,4-benzoxazin-3-(4H)-ones were obtained in
moderate to excellent yields (Table 3, entries 6-18). Therefore,
our method is an alternative approach for the synthesis of these
heterocyclic molecules. The product 3x was recrystallized from
methanol and was characterized crystallographically.
General Procedure for Synthesis of 2H-1,4-Benzooxazin-3-
(4H)-ones 3. To a solution of 2-halophenol (0.5 mmol) and 2 (0.75
mmol) in DMSO (2 mL) were added CuI (0.1 mmol), Cs2CO3 (0.9
mmol), and DBU (0.75 mmol). The vial was sealed and the mixture
was then irradiated for 10 min at 130 °C. The cold mixture was
diluted with CH2Cl2 (20 mL), washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuum. The residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate ) 10/1) to yield the expected product. Selected example,
1
compound 3a: H NMR (300 MHz, CDCl3, ppm) δ 4.78 (s, 2H),
6.43 (dd, J ) 1.5, 6 Hz, 1H), 6.83-6.88 (m, 1H), 6.96-7.07 (m,
2H), 7.28-7.31 (m, 2H), 7.44-7.57 (m, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 68.2, 116.9, 167.0, 122.6, 124.1, 128.8, 128.9, 130.0,
135.8, 145.0, 164.3; EI-MS m/z (M+) 225; EI-HRMS calcd for
C14H11NO2 (M+) 225.0790, found 225.0790. (For details, please
see the Supporting Information.)
In conclusion, we have developed a novel protocol for the
elaboration of 2H-1,4-benzoxazin-3-(4H)-ones via a cascade
reaction with a nucleophilic substitution followed by a CuI/
DBU-catalyzed coupling cyclization. This method enables the
use of a wide range of 2-halophenols and 2-chloroacetamides
to assemble various products in moderate to good yields. In
this regard, this approach would be particularly attractive for
the efficient preparation of biologically and medicinally interest-
ing molecules.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of China
(Grants 20721003 and 20872153), international collaboration
projects (Grants 2007DFB30370/20061334 and 20720102040),
and the 863 Hi-Tech Program of China (Grants 2006AA020602).
Supporting Information Available: Detailed experimental
1
procedures, characterization data, copies of H and 13C NMR
spectra for all products, and crystallographic information files
(CIF) of 3x. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experiment Section
General Procedure for Synthesis of 2-Chloroacetamides 2.
To a solution of amine (0.5 mmol) and triethylamine (TEA) (0.5
JO802818S
J. Org. Chem. Vol. 74, No. 7, 2009 2849