N-heterocyclic carbene-catalyzed cascade annulation reaction of o-vinylarylaldehydes with nitrosoarenes: One-step assembly of functionalized 2,3-benzoxazin-4-ones

Article abstract of DOI:10.1039/c2ob25137j

The NHC-catalyzed reactions of ortho electron-deficient vinyl substituted arylaldehydes with nitrosoarenes were studied. The reactions produced multifunctional 2,3-benzoxazin-4-ones in good to excellent yields via a cascade aza-benzoin reaction between aldehyde and nitroso groups followed by an intramolecular oxo-Michael addition. The resulting 1-acetate substituted 2,3-benzoxazinones were transformed into a new type of β-hydroxycarboxylate derivatives or 3-oxo-1-isobenzofuranacetates, respectively, under different reductive conditions. This work not only provides a simple and efficient method for the construction of multifunctional 2,3-benzoxazin-4-ones of potential pharmacological interest, but also expands the application of NHC-catalyzed cascade reactions in the formation of carbon-heteroatom and heteroatom- heteroatom bonds.

Full text of DOI:10.1039/c2ob25137j

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PAPER
N-Heterocyclic carbene-catalyzed cascade annulation reaction of
o-vinylarylaldehydes with nitrosoarenes: one-step assembly of functionalized
2,3-benzoxazin-4-ones†
Zhong-Xin Sun and Ying Cheng*
Received 18th January 2012, Accepted 19th March 2012
DOI: 10.1039/c2ob25137j
The NHC-catalyzed reactions of ortho electron-deficient vinyl substituted arylaldehydes with
nitrosoarenes were studied. The reactions produced multifunctional 2,3-benzoxazin-4-ones in good to
excellent yields via a cascade aza-benzoin reaction between aldehyde and nitroso groups followed by an
intramolecular oxo-Michael addition. The resulting 1-acetate substituted 2,3-benzoxazinones were
transformed into a new type of β-hydroxycarboxylate derivatives or 3-oxo-1-isobenzofuranacetates,
respectively, under different reductive conditions. This work not only provides a simple and efficient
method for the construction of multifunctional 2,3-benzoxazin-4-ones of potential pharmacological
interest, but also expands the application of NHC-catalyzed cascade reactions in the formation of
carbon–heteroatom and heteroatom–heteroatom bonds.
1,1-diesters with indole-2-carbaldehydes or salicylaldehydes
Introduction
leads to pyrrolo[1,2-a]indoles or coumarin.6 Although various
Since the discovery of umpolung reactivity of carbonyls trig-
gered by N-heterocyclic carbenes (NHC), NHC-catalyzed
carbon–carbon bond forming reactions have become a very
intense area of organic chemistry.1 In recent years, the cascade
processes promoted by N-heterocyclic carbenes have received
great attentions due to the rapid generation of complexity of pro-
ducts.2 Most of the NHC-catalyzed cascade reactions are
initiated by the interaction of umpolung carbonyls with carbon
electrophiles to form carbon–carbon bonds and to produce cyclic
compounds. For example, in the presence of NHC catalysts, the
cascade reactions of aldehydes with (1,2-phenylene)bis(2-prope-
nones),3a (2-formylphenyl)acrylates with imines,3b phthalalde-
hydes with 1,4-diarylbutene-1,4-diones,3c imines,3d or
o-vinylarylaldehydes,3e,f and the dimerization of o-vinylarylalde-
hydes3e,f or phthalaldehydes,3g afford various indene, indanone
or spiro-indene derivatives. While the NHC-catalyzed cascade
[4 + 2] cycloaddition of α,β-unsaturated acid fluorides with silyl
dienol ethers forms 1,3-cyclohexadienes,4 the reactions of 2-pro-
pargyloxy-1-arylaldehydes with aldehydes produce chroman-4-
one or benzofuran-3-one derivatives under different conditions.5
The NHC-catalyzed cascade reactions of formylcyclopropane
cascade reactions promoted by N-heterocyclic carbenes have
been reported, the NHC-catalyzed cascade carbon–heteroatom
and heteroatom–heteroatom bonds formations are still largely
unexplored.
Only a few examples of NHC-catalyzed reactions of carbonyl
compounds with nitrosoarenes have been documented in litera-
ture, which constitute an efficient method for the formation of
carbon–nitrogen bonds.7–9 Under the catalysis of NHC, the reac-
tion of aldehydes with nitrosoarenes has led to direct amidation
of aldehydes to provide N-arylhydroxamic acids,7 while in the
reactions of α,β-unsaturated aldehydes with nitroso compounds,
isoxazolidin-5-ones intermediates or products were formed, and
could further convert into isoxazol-5-ones, β-amino acid esters
or benzo[b][1,4]oxazepin-2-ones.8 The NHC-catalyzed reaction
between ketenes and nitrosoarenes has been reported to proceed
via a formal [2 + 2] cycloaddition to form oxazetidinones.9 We
envisioned that, if an aldehyde is linked with a Michael acceptor,
the reaction between the aldehyde and a nitroso compound
would probably proceed via cascade carbon–nitrogen and
carbon–oxygen bond formation to produce highly functionalized
2,3-benzoxazine derivatives, which represent a bioactive scaf-
fold.10 We report herein the study on the reactions of ortho elec-
tron-deficient vinyl substituted arylaldehydes with nitrosoarenes.
College of Chemistry, Beijing Normal University, Beijing 100875,
China. E-mail: ycheng2@bnu.edu.cn; Fax: +861058805558;
Tel: +861058805558
†Electronic supplementary information (ESI) available: The copies of
1H NMR and 13C NMR spectra of products 4, 6, 10 and 11 are available.
CCDC 862111. For ESI and crystallographic data in CIF or other elec-
tronic format see 10.1039/c2ob25137j
Results and discussion
We began our study with the examination of the reaction
between o-formylcinnamate 1a and nitrosobenzene 2a
4088 | Org. Biomol. Chem., 2012, 10, 4088–4094
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Table 1 Optimization of reaction conditions
Table 2 The reaction of o-formylcinnamates 1 and nitrosoarenes 2
under optimized conditions
Entry
1
X, Y
2
Z
T (h)
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1a
1a
1a
1a
H, H
2a
2a
2a
2a
2a
2b
2c
2d
2f
H
H
H
H
10
15
—
3
4a: 71
4b: 63
4c: —
4d: 80
4e: 77
4f: 76
4g: 78
4h: 69
4i: —
Me, Me
OMe, OMe
Br, Br
NO2, H
H, H
H, H
H, H
Reaction conditionsa
Yield of
T (°C) T (h) 4a (%)
Entry 3 mol% of 3 Base
Sol.
H
2
Me
OMe
Cl
12
18
10
—
1
2
3
4
5
6
7
8
3a 20
3b 20
3c 20
3d 20
3d 10
3d 20
3d 20
3d 20
3d 20
3d 20
3d 20
3d 20
3d 20
3d 20
3d 20
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
t-BuOK
NaH
CHCl3 25–30 18
CHCl3 25–30 18
CHCl3 25–30 18
CHCl3 25–30 9
CHCl3 25–30 16
CHCl3
CHCl3 Reflux 9
THF 25–30 10
60
38
14
71
46
36
53
60
64
44
51
58
17
14
11
H, H
NO2
0
17
produce corresponding products 4 in 63–80%, whereas the more
electron-rich 4,5-dimethoxy-2-formylcinnamate 1c was inert in
this reaction (Table 2, entries 1–5). On the other hand, the reac-
tions of 2-formylcinnamate 1a with nitrosobenzenes 2 that are
substituted by methyl, methoxy and chlorine groups all produced
2,3-benzoxazin-4-ones 4 in good yields (Table 2, entries 6–8).
However, no expected product was obtained from the reaction of
2-formylcinnamate 1a with 1-nitro-4-nitrosobenzene 2f. The
inertness of 4,5-dimethoxy-2-formylcinnamate 1c in the reaction
with nitrosobenzene 2a was most probably due to the electron-
donating effect of methoxy groups that deactivates the aldehyde
towards nucleophilic carbene. In contrast, the inactivity of 2-for-
mylcinnamate 1a toward 1-nitro-4-nitrosobenzene 2f in the pres-
ence of triazole carbene and DBU was most likely attributable to
the instability of 1-nitro-4-nitrosobenzene under reaction
conditions.
The generality of the cascade annulation reaction was further
expanded to the reactions of nitrosoarenes with o-formylchal-
cones and their analogues (Table 3). It was found that the NHC-
catalyzed reactions of o-(3-aryl (or alkyl)-3-oxo-1-propenyl)ben-
zaldehydes 5a–5h and 3-(3-oxo-3-phenylprop-1-enyl)-2-
naphthaldehyde 5i with nitrosoarenes 2 were more efficient than
those of o-formylcinnamates 1 with 2. As indicated in Table 3,
the reaction showed good tolerance to the substituents of both
aldehydes 5 and nitrosoarenes 2. For example, when o-formyl-
chalcone 5a reacted with nitrosobenzene, and methyl, methoxy,
chlorine substituted nitrosobenzenes 2a–2d, all reactions
produced 1-(2-oxo-2-phenylethyl)-2,3-benzoxazin-4-ones 6a–6d
in good yields. On the other hand, various benzaldehydes
bearing an ortho vinyl ketone moiety and 2-naphthaldehyde
5 reacted efficiently with nitrosobenzene 2a to afford 2,3-ben-
zoxazin-4-ones 6e–6l in good to excellent yields (Table 3).
The higher reactivity of o-formylchalcones 5 than o-formylcin-
namates 1 in the reaction with nitrosobenzenes 2 is best
explained by the stronger electron-withdrawing effect of
ketone carbonyl than ester carbonyl, which facilitates the intra-
molecular nucleophilic addition during the formation of oxazi-
none rings.
9
CH3CN 25–30 12
Benzene 25–30 12
Dioxane 25–30 12
10
11
12
13
14
15
DCEb
25–30 12
CHCl3 25–30 10
CHCl3 25–30 10
CHCl3 25–30 10
Et3N
a 1a : 2a = 1 : 1.5. b DCE = ClCH2CH2Cl.
employing a catalytic amount of different N-heterocyclic carbene
catalysts 3. The N-heterocyclic carbenes 3 were generated from
deprotonation of azolium salts by DBU. At 25–30 °C and in
chloroform, the reaction of o-formylcinnamate 1a with nitroso-
benzene 2a (1a : 2a = 1 : 1.5) in the presence of 20 mol% of N,
N-dibenzyl-1,2,4-triazole, -imidazole, or -thiazole carbene pro-
duced 2-(4-oxo-3-phenyl-2,3-benzoxazin-1-yl)acetate 4a in
60%, 38%, or 14% yield, respectively (Table 1, entries 1–3. X-
ray crystal structure of 4a was shown in ESI†).11 The yield of 4a
was improved to 71% yield, when N,N-dibenzyltriazole carbene
3a was replaced by N,N-dimethyltriazole carbene 3d (Table 1,
entry 4). Decreasing of catalyst loading of 3d to 10 mol% led to
the formation of 4a in lower yield (46%) (Table 1, entry 5).
Under the catalysis of dimethyltriazole carbene 3d (20 mol%),
the reaction conditions were further optimized by varying temp-
erature, solvents and bases that were used to generate carbene
catalyst. Unfortunately, however, the use of other solvents
including THF, acetonitrile, benzene, 1,4-dioxane and 1,1,2-tri-
chloroethane, or other bases like t-BuOK, NaH and Et3N, or at
higher and lower temperature, all diminished the yield of product
(Table 1, entries 6–15).
Under the optimized conditions, we tested the reaction scope
by using a variety of substituted o-formylcinnamates 1 and nitro-
soarenes 2. As shown in Table 2, the substituents on formylcin-
namates 1 have influence on the reaction efficiency. For
example, 2-formylcinnamate 1a, 4,5-dimethyl-2-formylcinna-
mate 1b, 4,5-dibromo-2-formylcinnamate 1d and 4-nitro-2-for-
mylcinnamate 1e reacted efficiently with nitrosobenzene 2a to
Mechanistically, we proposed that the reaction would
commence with the addition of NHC to aldehydes of
This journal is © The Royal Society of Chemistry 2012
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Table 3 The reaction of 2-(3-oxo-1-propenyl)benzaldehydes 5 and nitrosoarenes 2 under optimized conditions
Entry
5
X, Y
R
2
Z
T (h)
Yield of 6 (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5c
5d
5e
5f
H, H
H, H
H, H
H, H
Me, Me
Br, Br
H, H
H, H
H, H
Ph
Ph
Ph
Ph
Ph
Ph
Me
PhCH2CH2
p-MeOPh
p-BrPh
p-NO2Ph
Ph
2a
2b
2c
2d
2a
2a
2d
2f
2a
2a
2a
2b
H
4
4
5
5
11
2
5
8
11
4
6a: 81
6b: 83
6c: 86
6d: 78
6e: 79
6f: 92
6g: 88
6h: 84
6i: 77
6j: 82
6k: 88
6l: 85
Me
OMe
Cl
H
H
H
H
H
H
H
9
10
11
12
5g
5h
5i
H, H
H, H
(CHvCH)2
2
6
Me
Scheme 2 Reductive transformations of 2,3-benzoxazinones 4.
Conclusions
In summary, we have shown that the NHC-catalyzed reactions of
o-formylcinnamates, o-formylchalcones and their analogues with
nitrosoarenes proceeded via a cascade aza-benzoin and oxo-
Michael addition to produce multifunctional 2,3-benzoxazinones
in good to excellent yields. The reductive transformations of the
acetate substituted 2,3-benzoxazinones 4 under different con-
ditions led to the formation of a new type of β-hydroxycarboxy-
late derivatives and 3-oxo-1-isobenzofuranacetates, respectively.
This work not only provides a simple and efficient method for
the construction of 2,3-benzoxazinones that represent a bioactive
scaffold,10 but also expands the application of NHC-catalyzed
cascade reactions in the carbon–heteroatom and heteroatom–
heteroatom bond formation.
Scheme 1 Proposed mechanism.
o-formylcinnamates 1 or o-formylchalcones 5 to form the Breslow
intermediates 7. Nucleophilic addition of the resulting enols 7 to
the nitroso group of 2 followed by elimination of carbene moiety
forms N-hydroxybenzamide anions 9. Intramolecular oxo-Michael
addition of oxygen anions to α,β-unsaturated esters or ketones of
9 affords 2,3-benzoxazin-4-ones 4 or 6 (Scheme 1).
Experimental section
The resulting 2,3-benzoxazin-4-ones are useful in organic syn-
thesis. To demonstrate their synthetic utility, we conducted their
reductive transformation. Under the catalysis of Pd–C in THF,
hydrogenation of 4a and 4f produced 3-(N-arylcarbamoyl)-
phenyl-3-hydroxypropanoates 10a and 10f in 90% and 96%
yields. Instead of Pd-catalyzed hydrogenation, the reduction of
2,3-benzoxazin-4-ones 4 using Zn/HCl in ethyl ether afforded
directly 3-oxo-1-isobenzofuranacetate 11 in 90–93% yields
(Scheme 2).
1. General procedure for the reaction of o-formylcinnamates 1,
o-formylchalcones and their analogues 5 with nitrosoarenes 2
Under nitrogen atmosphere and at 25–30 °C, a mixture of N,N-
dimethyl-1,2,4-triazolium salt (0.2 mmol) and DBU (0.3 mmol)
in dry chloroform (10 mL) was stirred for 10 min, and then a sol-
ution of o-formylcinnamates 112 (1 mmol), or o-(3-oxo-1-prope-
nyl)benzaldehydes 513 (1 mmol), and nitrosoarenes 214
(1.5 mmol) in chloroform (10 mL) was added. The reaction
4090 | Org. Biomol. Chem., 2012, 10, 4088–4094
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mixture was stirred at 25–30 °C until the aldehydes 1 or 5 were
consumed. The solvent was removed under vacuum and the
residue was chromatographed on a silica gel column eluting with
a mixture of petroleum ether and ethyl acetate (6 : 1) to afford
2,3-benzoxazin-4-ones 4 or 6, respectively.
J = 16.2, 4.7 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 170.1, 161.5, 138.8, 136.9, 135.7, 132.9,
129.2, 128.7, 128.4, 126.8, 122.8, 120.8, 77.2, 52.1, 37.2, 21.0;
MS (EI): 105 (100), 311 (M+, 26%); Anal. Calcd for
C18H17NO4: C 69.44; H 5.50; N 4.50; Found: C 69.26, H 5.41,
N 4.40.
Methyl 2-(4-oxo-3-phenyl-3,4-benzoxazin-1-yl)acetate 4a.
1
White solid, 71%, mp 66–67 °C; IR ν (cm−1) 1741, 1660; H
Methyl
2-(3-(p-methoxyphenyl)-4-oxo-3,4-benzoxazin-1-yl)
NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 7.7 Hz, 1H),
7.77 (d, J = 7.7 Hz, 2H), 7.57 (td, J = 7.5, 1.3 Hz, 1H), 7.51 (t,
J = 7.0 Hz, 1H), 7.40 (t, J = 8.4 Hz, 2H), 7.21 (t, J = 7.5 Hz,
2H), 5.81 (dd, J = 8.9, 4.7 Hz, 1H), 3.69 (s, 3H), 3.12 (dd, J =
16.2, 8.9 Hz, 1H), 2.99 (dd, J = 16.2, 4.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 170.1, 161.6, 139.5, 138.8, 133.0,
128.7, 128.6, 128.5, 126.8, 125.7, 122.8, 120.3, 77.3, 52.1,
37.2; MS (EI): 91 (100), 297 (M+, 47%); Anal. Calcd for
C17H15NO4: C 68.68; H 5.09; N 4.71; Found: C 68.68, H 5.12,
N 4.65.
acetate 4g. White solid, 78%, mp 88–89 °C; IR ν (cm−1) 1739,
1662; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d, J = 7.7 Hz,
1H), 7.64 (d, J = 9.1 Hz, 2H), 7.56 (td, J = 7.4, 1.2 Hz, 1H),
7.50 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.93 (d, J =
9.1 Hz, 2H), 5.78 (dd, J = 8.9, 4.6 Hz, 1H), 3.83 (s, 3H), 3.70
(s, 3H), 3.14 (dd, J = 16.2, 9.0 Hz, 1H), 2.98 (dd, J = 16.2, 4.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.1, 161.6,
157.8, 138.7, 132.8, 132.3, 128.6, 128.3, 126.6, 123.5, 122.8,
113.9, 77.2, 55.5, 52.2, 37.3; MS (EI): 121 (100), 327 (M+,
18%); Anal. Calcd for C18H17NO5: C 66.05; H 5.23; N 4.28;
Found: C 65.8, H 5.01, N 4.27.
Methyl 2-(6,7-dimethyl-4-oxo-3-phenyl-3,4-benzoxazin-1-yl)-
acetate 4b. White solid, 63%, mp 88–89 °C; IR ν (cm−1) 1737,
1
Methyl
2-(3-(p-chlorophenyl)-4-oxo-3,4-benzoxazin-1-yl)-
1662; H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (s, 1H), 7.76
acetate 4h. White solid, 69%, mp 114–115 °C; IR ν (cm−1
)
(d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.4 Hz,
1H), 6.95 (s, 1H), 5.72 (dd, J = 9.0, 4.6 Hz, 1H), 3.68 (s, 3H),
3.07 (dd, J = 16.2, 9.0 Hz, 1H), 2.94 (dd, J = 16.2, 4.6 Hz, 1H),
2.34 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.2,
162.0, 142.6, 139.7, 137.4, 136.5, 129.3, 128.6, 125.4, 124.2,
123.9, 120.2, 77.2, 52.1, 37.4, 20.3, 19.6; HRMS (ESI): [M +
H]+ calcd for C19H20NO4: 326.1392; found: 326.1419.
1
1737, 1657; H NMR (400 MHz, CDCl3) δ (ppm) 8.19 (d, J =
7.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.58 (td, J = 7.5, 1.3 Hz,
1H), 7.51 (t, J = 6.9 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 7.21 (d,
J = 7.5, 1H), 5.80 (dd, J = 9.0, 4.6 Hz, 1H), 3.71 (s, 3H), 3.09
(dd, J = 16.3, 9.1 Hz, 1H), 2.98 (dd, J = 16.3, 4.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 170.0, 161.6, 138.7, 138.1,
133.2, 130.7, 128.8, 128.7, 128.5, 126.5, 122.8, 121.1, 77.4,
52.1, 37.0; MS (EI): 125 (100), 331 (M+, 81%); Anal. Calcd for
C17H14ClNO4: C 61.55; H 4.25; N 4.22; Found: C 61.45, H
4.32, N 3.97.
Methyl 2-(6,7-dibromo-4-oxo-3-phenyl-3,4-benzoxazin-1-yl)-
acetate 4d. White solid, 80%, mp 128–129 °C; IR ν (cm−1
)
1
1722, 1667; H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (s, 1H),
7.72 (d, J = 7.8 Hz, 2H), 7.52 (s, 1H), 7.41 (t, J = 7.6 Hz, 2H),
7.23 (t, J = 7.4 Hz, 1H), 5.72 (dd, J = 8.4, 5.1 Hz, 1H), 3.70 (s,
3H), 3.10 (dd, J = 16.4, 8.5 Hz, 1H), 2.97 (dd, J = 16.4, 5.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 169.5, 159.8, 139.0,
138.9, 133.6, 130.1, 128.8, 128.5, 127.9, 126.2, 125.5, 120.4,
76.5, 52.3, 36.9; MS (EI): 91 (100), 452 (M+, 7%)/454 (M+2,
16%); Anal. Calcd for C17H13Br2NO4: C 44.87; H 2.88; N 3.08;
Found: C 44.55, H 2.82, N2.93.
1-(2-Oxo-2-phenylethyl)-3-phenyl-3,4-benzoxazin-4-one
6a.
White solid, 81%, mp 105–106 °C; IR ν (cm−1) 1683, 1667,
1651; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.21 (d, J = 7.5 Hz,
1H), 7.91 (dd, J = 7.2, 1.2 Hz, 2H), 7.75 (d, J = 7.8, 2H), 7.56
(tt, J = 7.6, 1.8 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 8.0
Hz, 2H), 7.33 (t, J = 8.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.14
(t, J = 7.6 Hz, 1H), 6.10 (dd, J = 7.4, 5.1 Hz, 1H), 3.89 (dd, J =
17.4, 7.5 Hz, 1H), 3.51 (dd, J = 17.4, 5.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 196.0, 161.8, 139.7, 139.5, 136.4,
133.7, 133.0, 128.7, 128.6, 128.5, 128.4, 128.2, 126.8, 125.5,
123.1, 120.0, 76.7, 40.9; HRMS (ESI): [M + H]+ calcd for
C22H18NO3: 344.1287; found: 344.1289.
Methyl 2-(6-nitro-4-oxo-3-phenyl-3,4-benzoxazin-1-yl)acetate
4e. White solid, 77%, mp 156–157 °C; IR ν (cm−1) 1743, 1665;
1H NMR (400 MHz, CDCl3) δ (ppm) 9.03 (d, J = 2.3 Hz, 1H),
8.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.76 (dd, J = 8.8, 1.0 Hz, 2H),
7.47 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 8.5 Hz, 2H), 7.26 (t, J =
7.7 Hz, 1H), 5.88 (dd, J = 8.2, 5.3 Hz, 1H), 3.71 (s, 3H), 3.17
(dd, J = 16.5, 8.2 Hz, 1H), 3.05 (dd, J = 16.5, 5.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 169.5, 159.5, 148.4, 144.8,
138.8, 128.9, 128.7, 127.3, 126.4, 124.8, 123.8, 120.3, 77.0,
52.4, 36.8; MS (EI): 91 (100), 342 (M+, 16%); Anal. Calcd for
C17H14N2O6: C 59.65; H 4.12; N 8.18; Found: C 59.64, H 4.37,
N 8.45.
1-(2-Oxo-2-phenylethyl)-3-(p-tolyl)-3,4-benzoxazin-4-one 6b.
1
White solid, 84%, mp 89–90 °C; IR ν (cm−1) 1687, 1658; H
NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 7.7 Hz, 1H),
7.92 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.55 (td, J =
7.6, 1.3 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz,
2H), 7.28 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 6.09
(dd, J = 7.3, 5.2 Hz, 1H), 3.88 (dd, J = 17.2, 7.4 Hz, 1H), 3.51
(dd, J = 17.4, 5.1 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 196.0, 161.7, 139.7, 137.0, 136.5, 135.5,
133.7, 132.8, 129.2, 128.7, 128.5, 128.3, 128.2, 126.9, 123.1,
120.5, 77.2, 41.0, 20.9; MS (EI): 105 (100), 357 (M+, 20%);
Anal. Calcd for C23H19NO3: C 77.29; H 5.36; N 3.92; Found: C
77.14, H 5.56, N 3.51.
Methyl 2-(4-oxo-3-(p-tolyl)-3,4-benzoxazin-1-yl)acetate 4f.
1
White solid, 76%, mp 96–97 °C; IR ν (cm−1) 1738, 1657; H
NMR (400 MHz, CDCl3) δ (ppm) 8.19 (d, J = 7.7 Hz, 1H),
7.64 (d, J = 8.5 Hz, 2H), 7.56 (td, J = 7.5, 1.2 Hz, 1H), 7.50 (t,
J = 7.5 Hz, 1H), 7.21 (d, J = 8.2 Hz, 3H), 5.78 (dd, J = 8.8, 4.7
Hz, 1H), 3.70 (s, 3H), 3.12 (dd, J = 16.2, 8.9 Hz, 1H), 2.99 (dd,
This journal is © The Royal Society of Chemistry 2012
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3.01 (dd, J = 17.5, 4.7 Hz, 1H), 2,15 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 204.3, 161.7, 139.6, 139.4, 132.9,
128.7, 128.5, 128.4, 126.8, 125.6, 122.9, 120.0, 76.4, 45.5,
30.9; MS (EI): 91 (100), 281 (M+, 51%); Anal. Calcd for
C17H15NO3: C 72.58; H 5.37; N 4.98; Found: C 72.57, H 5.42,
N 4.78.
1-(2-Oxo-2-phenylethyl)-3-(p-methoxyphenyl)-3,4-benzoxazin-
4-one 6c. White solid, 86%, mp 112–113 °C; IR ν (cm−1) 1693,
1655; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 7.5 Hz,
1H), 7.93 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 9.1 Hz, 2H),
7.53–7.60 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz,
2H), 7.27 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 9.1 Hz, 2H), 6.08
(dd, J = 7.4, 5.0 Hz, 1H), 3.89 (dd, J = 17.4, 7.5 Hz, 1H), 3.78
(s, 3H), 3.52 (dd, J = 17.4, 5.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 196.0, 161.7, 157.6, 139.6, 136.5, 133.7,
132.8, 132.5, 128.8, 128.5, 128.3, 128.2, 126.8, 123.1, 123.0,
113.9, 77.3, 55.4, 40.9; MS (EI): 121 (100), 373 (M+, 37%);
Anal. Calcd for C23H19NO4: C 73.98; H 5.13; N 3.75; Found: C
73.63, H 5.01, N 3.69.
1-(2-Oxo-4-phenylbutyl)-3-phenyl-3,4-benzoxazin-4-one
6h.
1
White solid, 83%, mp 77–78 °C; IR ν (cm−1) 1716, 1653; H
NMR (400 MHz, CDCl3) δ (ppm) 8.18 (dd, J = 7.4, 1.2 Hz,
1H), 7.75 (d, J = 7.8 Hz, 2H), 7.53 (td, J = 7.4, 1.4 Hz, 1H),
7.48 (td, J = 7.6, 1.2 Hz, 1H), 7.39 (t, J = 8.5 Hz, 2H), 7.24 (d,
J = 7.6 Hz, 2H), 7.20 (t, J = 8.6 Hz, 2H), 7.14 (t, J = 7.4 Hz,
1H), 7.08 (d, J = 7.1 Hz, 2H), 5.87 (dd, J = 8.0, 4.4 Hz, 1H),
3.25 (dd, J = 17.2, 8.0 Hz, 1H), 2.91 (dd, J = 17.2, 4.4 Hz, 1H),
2.83–2.88 (m, 2H), 2.66–2.71 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 205.7, 161.6, 140.4, 139.6, 139.4, 132.9,
128.7, 128.5, 128.4, 128.3, 126.7, 126.2, 125.6, 122.9, 120.0,
76.5, 45.3, 44.9, 29.4; MS (EI): 91 (100), 371 (M+, 88%), Anal.
Calcd for C24H21NO3: C 77.61; H 5.70; N 3.77; Found: C
77.68, H 5.42, N 3.46.
1-(2-Oxo-2-phenylethyl)-3-(p-chlorophenyl)-3,4-benzoxazin-4-
one 6d. White solid, 78%, mp 99–100 °C; IR ν (cm−1) 1679,
1663; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 7.6 Hz,
1H), 7.91 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H),
7.56–7.61 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.45(t, J = 7.6 Hz,
2H), 7.27 (d, J = 9.6 Hz, 2H), 7.29 (d, J = 6.8 Hz, 1H), 6.09
(dd, J = 7.9, 4.6 Hz, 1H), 3.87 (dd, J = 17.4, 8.0 Hz, 1H), 3.47
(dd, J = 17.4, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 195.8, 161.7, 139.6, 138.1, 136.4, 133.8, 133.1, 130.4,
128.8, 128.6, 128.5, 128.2, 126.6, 123.7, 120.9, 77.0, 40.7; MS
(EI): 105 (100), 377 (M+, 37%); Anal. Calcd for C22H16ClNO3:
C 69.94; H 4.27; N 3.71; Found: C 69.88, H 4.43, N 3.55.
1-(2-(4-Methoxyphenyl)-2-oxoethyl)-3-phenyl-3,4-benzoxazin-
4-one 6i. White solid, 61%, mp 126–127 °C; IR ν (cm−1
)
1680, 1652; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.20
(d, J = 7.5 Hz, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 8.0,
2H), 7.55 (td, J = 7.4, 1.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H),
7.33 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.14
(t, J = 7.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.09 (dd, J = 7.3,
5.2 Hz, 1H), 3.85 (s, 3H), 3.84 (dd, J = 17.0, 7.1 Hz, 1H), 3.44
(dd, J = 17.1, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 194.4, 164.0, 161.8, 140.0, 139.6, 132.9, 130.6, 129.6,
128.6, 128.5, 128.3, 126.9, 125.4, 123.2, 120.0, 113.9, 77.2,
55.5, 40.5; MS (EI): 135 (100), 373 (M+, 11%); Anal. Calcd
for C22H17NO3: C 73.98; H 5.13; N 3.75; Found: C 73.87,
H 5.25, N 3.37.
6,7-Dimethyl-1-(2-oxo-2-phenylethyl)-3-phenyl-3,4-benzoxa-
zin-4-one 6e. White solid, 79%, mp 123–124 °C; IR ν (cm−1
)
1
1696, 1661; H NMR (400 MHz, CDCl3) δ (ppm) 7.96 (s, 1H),
7.91 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.8, 2H), 7.56 (t, J = 7.4
Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.12
(t, J = 7.4 Hz, 1H), 7.02 (s, 1H), 6.03 (dd, J = 7.6, 4.8 Hz, 1H),
3.86 (dd, J = 17.3, 7.7 Hz, 1H), 3.45 (dd, J = 17.3, 4.8 Hz, 1H),
2.34 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 196.2, 162.2, 142.5, 139.8, 137.4, 137.2, 136.6, 133.6,
129.2, 128.7, 128.6, 128.2, 125.2, 124.4, 124.2, 120.0, 77.3,
41.1, 20.2, 19.5; MS (EI): 105 (100), 371 (M+, 9%), Anal.
Calcd for C24H21NO3: C 77.61; H 5.70; N 3.77; Found: C
77.58, H 5.76, N 3.67.
1-(2-(4-Bromophenyl)-2-oxoethyl)-3-phenyl-3,4-benzoxazin-4-
one 6j. White solid, 77%, mp 116–117 °C; IR ν (cm−1) 1678,
1
1662; H NMR (400 MHz, CDCl3) δ (ppm) 8.21 (dd, J = 7.5,
1.1 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 7.7 Hz, 2H),
7.57 (t, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.51 (t, J =
7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H),
7.15 (t, J = 7.4 Hz, 1H), 6.07 (dd, J = 7.6, 4.8 Hz, 1H), 3.86
(dd, J = 17.3, 7.8 Hz, 1H), 3.43 (dd, J = 17.3, 4.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 195.1, 161.7, 139.50, 139.46,
135.2, 132.1, 129.7, 129.0, 128.6, 128.5, 126.8, 125.5, 123.1,
120.0, 77.2, 40.8; MS (ESI): 422 [M + H]+; Anal. Calcd for
C22H16BrNO3: C 62.57; H 3.82; N 3.32; Found: C 62.41, H
3.84, N 3.10.
6,7-Dibromo-1-(2-oxo-2-phenylethyl)-3-phenyl-3,4-benzoxazin-
4-one 6f. White solid, 92%, mp 144–145 °C; IR ν (cm−1) 1677,
1
1661; H NMR (400 MHz, CDCl3) δ (ppm) 8.42 (s, 1H), 7.92
(d, J = 7.2 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.61 (s, 1H), 7.59
(t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 8.5 Hz,
2H), 7.18 (t, J = 7.4 Hz, 1H), 6.03 (t, J = 6.4 Hz, 1H), 3.86 (dd,
J = 17.6, 7.0 Hz, 1H), 3.51 (dd, J = 17.6, 5.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 195.3, 160.0, 139.9, 139.1,
136.2, 133.9, 133.5, 130.0, 128.8, 128.8, 128.2, 127.4, 126.0,
125.3, 120.1, 76.1, 40.7; MS (EI): 105 (100), 499 (M+, 5%)/501
(11%); Anal. Calcd for C22H15Br2NO3: C 52.72; H 3.02; N
2.79; Found: C 52.73, H 2.88, N 2.65.
1-(2-(4-Nitrophenyl)-2-oxoethyl)-3-phenyl-3,4-benzoxazin-4-
one 6k. White solid, 87%, mp 98–99 °C; IR ν (cm−1) 1697,
1667; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.24 (d, J = 8.7 Hz,
2H), 8.22 (d, J = 6.1 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.69 (d,
J = 8.2, 2H), 7.59 (td, J = 7.5, 1.2 Hz, 1H), 7.53 (t, J = 7.4 Hz,
1H), 7.27–7.34 (m, 3H), 7.13 (t, J = 7.4 Hz, 1H), 6.08 (dd, J =
8.0, 4.6 Hz, 1H), 3.96 (dd, J = 17.3, 8.0 Hz, 1H), 3.47 (dd, J =
17.3, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.8,
161.7, 150.6, 140.8, 139.5, 139.1, 133.1, 129.2, 128.8, 128.7,
1-(2-Oxopropyl)-3-phenyl-3,4-benzoxazin-4-one
6g. White
solid, 88%, mp 82–83 °C; IR ν (cm−1) 1724, 1656; H NMR
(400 MHz, CDCl3) δ (ppm) 8.19 (dd, J = 7.7, 1.0 Hz, 1H), 7.78
(dd, J = 8.8, 1.1 Hz, 2H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.49 (t,
J = 7.4 Hz, 1H), 7.41 (t, J = 8.5 Hz, 2H), 7.18–7.22 (m, 2H),
5.87 (dd, J = 8.0, 4.7 Hz, 1H), 3.29 (dd, J = 17.4, 8.1 Hz, 1H),
1
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128.6, 126.8, 125.6, 123.9, 123.1, 119.9, 77.3, 41.3; HRMS
(ESI): [M + H]+ calcd for C22H16N2O5: 389.1059; found:
389.1169.
then HCl gas was bubbled into the solution of reactants 4 with
stirring for 2 h. After removal of solvent, the residue was neutral-
ized with saturated aqueous NaHCO3 solution. The aqueous sol-
ution was extracted with ethyl acetate (50 × 3 mL), and the
combined extraction was dried and evaporated. The residue was
chromatographed on a silica gel column eluting with a mixture
of petroleum ether and ethyl acetate (5 : 1) to give product 11 in
90–93% yields.
1-(2-Oxo-2-phenylethyl)-3-phenyl-3,4-naphthoxazin-4-one 6l.
1
White solid, 85%, mp 152–153 °C; IR ν (cm−1) 1675, 1658; H
NMR (400 MHz, CDCl3) δ (ppm) 8.78 (s, 1H), 8.02 (d, J = 8.0
Hz, 1H), 7.97 (d, J = 7.3 Hz, 2H), 7.87 (d, J = 8.0, 1H), 7.81 (d,
J = 7.8 Hz, 2H), 7.70 (s, 1H), 7.55–7.63 (m, 3H), 7.46 (t, J =
7.6 Hz, 2H), 7.36 (t, J = 8.4 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H),
6.26 (dd, J = 7.0, 5.3 Hz, 1H), 3.94 (dd, J = 17.4, 7.4 Hz, 1H),
3.66 (dd, J = 17.4, 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 196.0, 162.0, 139.5, 136.5, 135.7, 135.0, 133.7, 132.5,
130.1, 129.5, 128.8, 128.6, 128.2, 127.8, 127.0, 125.5, 124.7,
122.0, 120.1, 77.4, 41.1; HRMS (ESI): [M + H]+ calcd for
C26H19NO3: 394.1443; found: 394.1448.
Methyl 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)acetate 11.15
White solid, 90% from 4a and 93% from 4f, mp 64–65 °C (bp15
175 °C/0.3 mmHg). IR ν (cm−1) 1753, 1736; 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.85 (d, J = 7.6 Hz, 1H), 7.62 (t, J
= 7.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H),
5.82 (t, J = 6.6 Hz, 1H), 3.70 (s, 3H), 2.78–2.91 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 169.8, 169.7, 148.7, 134.3,
129.6, 125.94, 125.85, 122.1, 77.1, 52.2, 39.4; HRMS (ESI):
[M + H]+ calcd for C11H11O4: 207.0657; found: 207.0663.
2. Pd-catalyzed hydrogenation of 2-(3-aryl-4-oxo-3,4-dihydro-
3,4-benzoxazin-1-yl)acetates 4a and 4f
Acknowledgements
At ambient temperature, 2,3-benzoxazinone 4a or 4f (0.5 mmol)
was mixed with Pd–C (8 mg, 10% w/w) in THF. The air in flask
was sucked by an oil pump and hydrogen gas was then bubbled
into the solution of reactant 4. The reaction mixture was stirred
at room temperature for 2–5 h. After removal of THF under
vacuum, the residue was dissolved in dichloromethane and
washed with saturated NaCl aqueous solution. The organic layer
was dried and evaporated, and the product 3-(N-arylcarbamoyl)
phenyl-3-hydroxypropanoate 10a or 10f, was isolated by chrom-
atography on a silica gel column eluting with a mixture of pet-
roleum ether and ethyl acetate (4 : 1).
This work was supported by the National Natural Science Foun-
dation of China (No. 21172021 and 20832006), Beijing Munici-
pal Commission of Education and the Fundamental Research
Funds for the Central Universities (2009SC-1).
Notes and references
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5606–5655; (b) N. Marion, S. Diez-Gonzalez and S. P. Nolan, Angew.
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Methyl 3-hydroxy-3-(2-(phenylcarbamoyl)phenyl)propanoate
10a. White solid, 90%, mp 55–57 °C; IR ν (cm−1) 3473, 3417,
1
1727, 1637; H NMR (400 MHz, CDCl3) δ (ppm) 8.34 (s, 1H),
7.62 (t, J = 8.3 Hz, 3H), 7.55 (d, J = 7.6 Hz, 1H), 7.50 (t, J =
7.6 Hz, 1H), 7.36–7.41 (m, 3H), 7.17 (t, J = 7.4 Hz, 1H), 5.37
(t, J = 6.7 Hz, 1H), 4.30 (s, 1H), 3.68 (s, 3H), 2.95 (d, J = 6.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 172.6, 168.3,
140.6, 138.0, 135.3, 131.0, 129.0, 128.1, 127.3, 124.7, 120.5,
68.3, 51.9, 41.4; HRMS (ESI): [M
C17H17NO4Na: 322.1055; found: 322.1049.
+
Na]+ calcd for
2 A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314–
325.
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4 S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc., 2011, 133,
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Methyl 3-hydroxy-3-(2-(p-tolylcarbamoyl)phenyl)propanoate
10f. White solid, 96%, mp 47–48 °C; IR ν (cm−1) 3434, 3315,
1727, 1646; H NMR (400 MHz, CDCl3) δ (ppm) 8.27 (s, 1H),
1
7.58 (d, J = 7.6 Hz, 1H), 7.47–7.55 (m, 4H), 7.38 (t, J = 7.3 Hz,
1H), 7.17 (d, J = 8.1 Hz, 2H), 5.35 (t, J = 6.7 Hz, 1H), 4.40 (s,
1H), 3.67 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 2.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 172.8, 167.9, 140.6, 135.6,
135.2, 134.6, 131.1, 129.6, 128.2, 127.8, 127.4, 120.4, 68.5,
51.9, 41.2, 20.9; HRMS (ESI): [M
C18H19NO4Na: 336.1212; found: 336.1220.
+
Na]+ calcd for
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3. Reduction of 2-(3-aryl-4-oxo-3,4-dihydro-3,4-benzoxazin-1-yl)-
acetates 4a and 4f using Zn/HCl
At ambient temperature, 2,3-benzoxazinones 4 (0.5 mmol) were
mixed with Zn powder (10 mmol) in ethyl ether (10 mL) and
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4088–4094 | 4093

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9 T. Wang, X.-L. Huang and S. Ye, Org. Biomol. Chem., 2010, 8, 5007–
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11 CCDC 862111 [4a] contains the supplementary crystallographic data for
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