Synthesis of 2,3-dihydro-1H-2-benzazepin-1-ones and 3H-2-benzoxepin-1-ones by isocyanide-based multicomponent reaction/Wittig sequence starting from phosphonium salt precursors

Article abstract of DOI:10.1021/jo502275f

A one-pot synthesis of multisubstituted 2,3-dihydro-1H-2-benzazepin-1-ones and 3H-2-benzoxepin-1-ones by an I-MCR/Wittig sequence was developed. The reaction of phosphonium salt 3, arylglyoxals 4, amine 5 (or without), and isocyanide 6 produced the 2,3-di

Full text of DOI:10.1021/jo502275f

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Note
Synthesis of 2,3-Dihydro-1H-2-benzazepin-1-ones and 3H-2-
Benzoxepin-1-ones by Isocyanide-based Multicomponent Reaction/
Wittig Sequence Starting from Phosphonium Salt Precursors
Long Wang, Zhi-Lin Ren, and Ming-Wu Ding
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502275f • Publication Date (Web): 03 Dec 2014
Downloaded from http://pubs.acs.org on December 10, 2014
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Synthesis of 2,3-Dihydro-1H-2-benzazepin-1-ones and
3H-2-Benzoxepin-1-ones by Isocyanide-based Multicomponent
Reaction/Wittig Sequence Starting from Phosphonium Salt Precursors
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Long Wang, ZhiꢀLin Ren, and MingꢀWu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal
University, Wuhan 430079, P. R. China
Eꢀmail: mwding@mail.ccnu.edu.cn
O
R1
COOH
R1
X
IMCR/Wittig
one-pot
CONHR3
CH2P+Ph3 Br-
Ar
X = NR2, O
28 examples
52-87% overall yields
ABSTRACT: A oneꢀpot synthesis of multisubstituted 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones and
3Hꢀ2ꢀbenzoxepinꢀ1ꢀones by an IꢀMCR/Wittig Sequence was developed. The reaction of phosphonium
salt 3, arylglyoxals 4, amine
5
(or without), and isocyanide
6
produced the
2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones 8 or 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones 10 in good yields via a sequential
Ugi or Passerini condensation and intramolecular Wittig reaction in the presence of NEt3.
Key words: 1Hꢀ2ꢀbenzazepinꢀ1ꢀone; 3Hꢀ2ꢀbenzoxepinꢀ1ꢀone; Ugi reaction; Passerini reaction;
intramolecular Wittig reaction; isocyanide
Multicomponent reactions (MCRs) have become an essential tool in organic and medicinal
chemistry because they are oneꢀpot processes bringing together three or more components and show
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high efficiency for rapid access to natural product and druglike small molecules with diverse molecular
structures. The isocyanide based multicomponent reactions (IꢀMCRs), mainly Ugi and Passerini
reaction, are extremely useful tools for synthesis of combinatorial libraries of compounds.1 The
sequences of Ugi and Passerini reactions, followed by postꢀcondensation transformations, constitute
extremely powerful synthetic tools for the preparation of structurally diverse complex molecules,
among them are heterocyclic compounds with elaborate substitution patterns.2 For example, some
sequential IꢀMCRs and DielsꢀAlder, PictetꢀSpengler, Heck, SmilesꢀMetathesis, SN2 reaction have been
utilized in preparation of various heterocycles.3
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The Wittig reaction of phosphorus ylide with carbonyl compound provides a powerful method for
construction of C=C double bond via interꢀ or intramolecular fashion under mild reaction condition.4
Intramolecular Wittig reaction has become a useful tool in preparation of various five, six, seven and
large membered heterocycles through intramolecular cyclization.5 Thus, it is envisioned that combining
the efficiency of the IꢀMCRs with a postꢀcondensation Wittig reaction would facilitate access to a series
of biologically useful heterocycles. Indeed, the sequence of IꢀMCRs/Horner reaction has been used in
preparation of butenolides, pyrrolidinones and pyridones.6 However, the sequence of IꢀMCRs starting
from phosphonium salt precursors, followed by postcondensation of intramolecular Wittig reaction,
was not previously reported.
The synthesis of 2ꢀbenzazepines has been the focus of continuing interest because these ring systems
lie at the heart of a great number of polyꢀ and diversely functionalized compounds, that have shown
broad spectrum of biological properties. For example, some of the 2ꢀbenzazepines have been found to
be potent analgesic or anticonvulsant agents,7 phenylethanolamine Nꢀmethyltransferase inhibitors,8
2,4ꢀdiaminopyrimidine cꢀMet inhibitors,9 melaninꢀconcentrating hormone receptor 1 antagonists,10 and
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NꢀmethylꢀDꢀaspartate receptor antagonists.11 The range of biological activities and characteristic
chemical structures have made synthetic studies of 2ꢀbenzazepines very attractive.12 However, the
corresponding 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones and 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones were seldom
reported in the literature. Recently we have been interested in the synthesis of various heterocycles via
azaꢀWittig or multicomponent reactions.13 Herein we wish to report a new efficient synthesis of
multisubstituted 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones and 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones by an
IꢀMCR/Wittig sequence starting from phosphonium salt precursors.
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The phosphonium salt precursors 3 (Scheme 1) were synthesized according to standard protocols.14
Bromination of 2ꢀmethylꢀbenzoic acid derivatives 1 with the NBS led to 2ꢀbromomethylꢀbenzoic acid
derivatives 2, which were converted to the corresponding phosphonium salts 3 via reaction with
triphenylphosphine.
R1
COOH
CH2Br
R1
COOH
CH3
NBS
85-92%
1
2
R1
COOH
CH2P+Ph3 Br-
PPh3
87-91%
3
Scheme 1. Preparation of phosphonium salt precursors 3
Initially, we selected the phosphonium salt 3a, 4ꢀchlorophenylglyoxal 4a, benzylamine 5a and
tꢀbutylisocyanide 6a as the reactants (Scheme 2). When the phosphonium salt 3a,
4ꢀchlorophenylglyoxal 4a, benzylamine 5a and tꢀbutylisocyanide 6a was stirred in methanol at room
temperature for 24 h, the Ugi product 7a was often obtained as semiꢀsolid or oil which was difficult to
be purified. So after washed by ether/petroleum ether (V/V = 1:1), the crude phosphonium salt 7a was
used directly without further purification for intramolecular Wittig reaction. The solvent and base used
had remarkable effect on this reaction. In case that the solid K2CO3 was used as base at 60 °C,
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moderate to good yields of the product 8a were obtained when THF or toluene were utilized as solvents
(52ꢀ71%, Table 1, entry 1ꢀ2). However, no product was got as K2CO3/MeOH was utilized (Table 1,
entry 3), probably due to decomposition of the intermediate 7a under the more polar solvent condition.
Relatively lower yields were obtained when K2CO3/toluene system was used at room or refluxing
temperature (45ꢀ56%, Table 1, entry 4ꢀ5). Utilizing the more basic NaOH also resulted in lower yield
of the product (35%, Table 1, entry 6). The best result was obtained (87%, Table 1, entry 7ꢀ9) when
NEt3 was used as base at toluene refluxing temperature.
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COOH
Cl
PhCH2NH2
CH2P+Ph3 Br-
3a
O
5a
HN
+
O
MeOH
N
O
CH2Ph
Cl
COCHO
NC
CH2P+Ph3 Br-
6a
4a
7a
Ph
O
N
O
Base
HN
solvent
Cl
8a
Scheme 2. Optimization of the reaction condition
Table 1. Screening reactions conditions for intramolecular Wittig reaction
Yielda
entry
solvent
Condition
base
(%)
52
1
2
3
4
5
6
7
8
9
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
NEt3
60 °C /2 h
60 °C/2 h
60 °C /2 h
rt/24 h
toluene
MeOH
toluene
toluene
toluene
toluene
toluene
MeOH
71
0
56
45
35
61
87
72
reflux/1 h
60°C/1 h
60°C/12 h
reflux/2 h
reflux/12 h
NEt3
NEt3
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a Isolated yields.
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With the optimized condition, various phosphonium salt 3, arylglyoxals 4, amine 5 and isocyanide 6
were employed for the reaction (Scheme 3). All of the reactions were carried out smoothly to give the
corresponding 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones 8 in toluene at reflux temperature, and moderate to
satisfactory yields were obtained with various substituents on the reactants (Table 2). Various amines
can be used in above oneꢀpot cyclization to prepare 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones 8. As
aromatic amine substituted by ester group (compounds 8s and 8t, R2 = 2ꢀMeOOCC6H4) was used,
moderate yields (51ꢀ55%) of the products were obtained, however, no products were reached when
other amines with strong electronꢀwithdrawing group (R2 = 4ꢀMeCOC6H4, 4ꢀNCC6H4 and 4ꢀNO2C6H4)
were utilized. Better yields (62ꢀ87%) were obtained as various aliphatic and aromatic amines
(compounds 8a-r, R2 = alkyl, 4ꢀMeC6H4, 2ꢀMeC6H4 and 4ꢀClC6H4) were applied. The investigated
functional groups (NO2, COOEt, Cl, Br) are all tolerant for the oneꢀpot method due to the mild reaction
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condition.
R1
COOH
O
R3HN
O
Ar
O
R2NH2
CH2P+Ph3 Br-
R1
N
5
R2
+
MeOH
3
CH2P+Ph3 Br-
R3NC
ArCOCHO
4
6
7
O
R2
R1
N
O
NEt3
toluene
refluxing
NHR3
Ar
8
Scheme 3. Preparation of 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones 8
Table 2. Preparation of 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones 8
yieldb
R1
H
R2
Ar
R3
(%)
87
8a
PhCH2
4ꢀClC6H4
tꢀBu
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8b
8c
8d
8e
8f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
Ph
iꢀPr
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀCH3C6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀNO2C6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀCH3C6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀCH3C6H4
4ꢀCH3C6H4
4ꢀClC6H4
tꢀBu
tꢀBu
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73
85
87
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75
78
81
62
85
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82
67
83
74
75
52
56
nꢀPr
tꢀBu
PhCH2
tꢀBu
4ꢀClC6H4
PhCH2
tꢀBu
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8g
8h
8i
tꢀBu
nꢀBu
tꢀBu
Et
tꢀBu
8j
4ꢀCH3C6H4
PhCH2
tꢀBu
8k
8l
tꢀBu
PhCH2
cꢀC6H11
tꢀBu
8m
8n
8o
8p
8q
8r
8s
Me
nꢀPr
cꢀC6H11
tꢀBu
nꢀPr
4ꢀCH3C6H4
2ꢀCH3C6H4
PhCH2
cꢀC6H11
tꢀBu
tꢀBu
2ꢀMeOOCC6H4
2ꢀMeOOCC6H4
tꢀBu
8t
tꢀBu
aIsolated yields.
The Passerini reaction of phosphonium salt 3, arylglyoxals 4 and isocyanide 6 also took place
smoothly to give phosphonium intermediate 9. In the presence of triethylamine,
3Hꢀ2ꢀbenzoxepinꢀ1ꢀones 10 were obtained in good yields (70ꢀ86%, Table 3) via intramolecular Wittig
reaction of 9 (Scheme 4). Various arylglyoxals can be used in above oneꢀpot cyclization to prepare
3Hꢀ2ꢀbenzoxepinꢀ1ꢀones 10 and good yields were reached regardless of the Ar group with substituents
(Cl, Br, CH3) on the benzene ring. A single crystal of 10a was obtained from the CH2Cl2 solution, and
Xꢀray structure analysis verified the proposed structure (Figure 1).
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O
ArCOCHO
R3HN
O
Ar
O
COOH
4
+
O
CH2P+Ph3 Br-
MeOH
R3NC
CH2P+Ph3 Br-
3
6
9
O
10
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O
O
NEt3
toluene
refluxing
NHR3
Ar
10
Scheme 4. Preparation of 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones 10
Table 3. Preparation of 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones 10
Yielda
Ar
R3
10a
10b
4ꢀClC6H4
4ꢀClC6H4
tꢀBu
84
76
cꢀC6H11
10c
10d
10e
4ꢀBrC6H4
4ꢀBrC6H4
Ph
tꢀBu
cꢀC6H11
tꢀBu
85
82
78
86
72
70
10f 4ꢀCH3C6H4
tꢀBu
10g 4ꢀCH3C6H4 cꢀC6H11
10h 4ꢀBrC6H4 nꢀBu
aIsolated yields.
In conclusion, the first example of IꢀMCR/Wittig sequence starting from phosphonium salt
precursors for preparing heterocycles is reported. The method was adapted to the synthesis of various
multisubstituted 2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones and 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones in oneꢀpot fashion.
The used phosphonium salt acids, arylglyoxals, amines, and isocyanides can be varied broadly,
producing products with multiple potential points of diversity, in combination to the easy availability of
the synthetic approach and the large scope of the reaction makes it useful in synthetic and medicinal
chemistry.
Experimental Section
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Preparation of 2,3-dihydro-1H-2-benzazepin-1-ones 8
5
6
7
8
9
A mixture of phosphonium salt 3 (1 mmol), amine 5 (1 mmol), isocyanide 6 (1 mmol), and arylglyoxal
4 (1 mmol) was stirred in methanol (5 mL) at room temperature for 24ꢀ48 h, and then the solvent was
evaporated under reduced pressure, NEt3 (0.20 g, 2 mmol) with toluene (5 mL) was added to the
reaction system and the reaction mixture was stirred at 110 oC for 2 h. The solvent was removed under
reduced pressure and the residue was purified by flash chromatography on silica gel (ether/petroleum
ether = 1 : 4, V/V) to give 8.
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2-benzyl-N-(tert-butyl)-4-(4-chlorophenyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8a) White solid (yield 0.40 g, 87%), mp 184ꢀ186 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.04 (d, J =
7.8 Hz, 1H), 7.48ꢀ7.39 (m, 2H), 7.31ꢀ7.16 (m, 10H), 6.90 (s, 1H), 5.35 (s, 1H), 4.94 (d, J = 14.4 Hz,
1H), 4.86 (d, J = 13.8 Hz, 1H), 4.75 (s, 1H), 0.81 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.0,
166.5, 142.3, 138.8, 136.8, 133.9, 133.8, 133.7, 130.9, 129.4, 128.9, 128.8, 128.7, 128.6, 128.1, 127.8,
127.3, 127.1, 62.8, 53.6, 51.1, 27.8; MS (EI, 70 eV): m/z (%) = 458 (7) [M+], 358 (55), 268 (25), 91
(100). Anal. Calcd for C28H27ClN2O2: C, 73.27; H, 5.93; N, 6.10. Found: C, 73.38; H, 5.67; N, 6.34.
N-(tert-butyl)-4-(4-chlorophenyl)-2-phenyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8b) Light yellow solid (yield 0.35 g, 79%), mp 166ꢀ168 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.08
(d, J = 7.8 Hz, 1H), 7.52ꢀ7.28 (m, 12H), 7.10 (s, 1H), 5.65 (s, 1H), 5.10 (s, 1H), 0.95 (s, 9H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 167.7, 166.3, 144.4, 142.0, 138.3, 134.5, 134.3, 133.8, 130.4, 129.6, 129.5,
129.3, 129.3, 128.8, 127.5, 127.2, 127.1, 126.7, 67.1, 51.6, 28.1; MS (EI, 70 eV): m/z (%) = 444 (18)
[M+], 344 (100), 316 (11), 242 (17), 178 (19), 104 (55). Anal. Calcd for C27H25ClN2O2: C, 72.88; H,
5.66; N, 6.30. Found: C, 72.92; H, 5.41; N, 6.57.
N-(tert-butyl)-4-(4-chlorophenyl)-2-isopropyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
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(8c) White solid (yield 0.30 g, 73%), mp 235ꢀ237 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d, J =
7.8 Hz, 1H), 7.47ꢀ7.24 (m, 7H), 6.91 (s, 1H), 5.64 (s, 1H), 5.15ꢀ5.10 (m, 1H), 4.73 (s, 1H), 1.25 (d, J =
6.6 Hz, 3H), 0.93 (s, 9H), 0.83 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.6, 167.3,
143.1, 138.9, 134.6, 134.1, 133.7, 131.1, 130.7, 130.0, 129.1, 129.0, 128.3, 127.4, 57.5, 51.4, 46.2,
27.9, 21.9, 20.0; MS (EI, 70 eV): m/z (%) = 410 (14) [M+], 310 (90), 268 (100), 241 (17), 178 (18).
Anal. Calcd for C24H27ClN2O2: C, 70.15; H, 6.62; N, 6.82. Found: C, 69.92; H, 6.52; N, 6.98.
N-(tert-butyl)-4-(4-chlorophenyl)-2-propyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8d) White solid (yield 0.35 g, 85%), mp 155ꢀ158 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d, J =
7.8 Hz, 1H), 7.47ꢀ7.26 (m, 7H), 6.94 (s, 1H), 5.64 (s, 1H), 4.72 (s, 1H), 3.91ꢀ3.41 (m, 2H), 1.52ꢀ1.45
(m, 2H), 0.95 (s, 9H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.8, 166.7,
142.3, 139.0, 134.2, 134.1, 133.7, 131. 0, 130.7, 129.8, 129.0, 128.9, 128.2, 127.3, 64.1, 52.3, 51.3,
27.8, 21.8, 11.0; MS (EI, 70 eV): m/z (%) = 410 (10) [M+], 310 (100), 268 (24). Anal. Calcd for
C24H27ClN2O2: C, 70.15; H, 6.62; N, 6.82. Found: C, 70.33; H, 6.42; N, 6.89.
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2-benzyl-N-(tert-butyl)-4-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide (8e) White
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solid (yield 0.38 g, 87%), mp 115ꢀ117 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.05 (d, J = 7.8 Hz,
1H), 7.45ꢀ7.11 (m, 12H), 6.93 (s, 1H), 5.32 (s, 1H), 4.92 (s, 2H), 4.81 (s, 1H), 2.36 (s, 3H), 0.80 (s,
9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.2, 166.7, 143.2, 138.1, 137.4, 136.9, 134.4, 133.9,
131.3, 130.7, 129.4, 128.8, 128.7, 128.6, 127.8, 127.7, 125.7, 62.9, 53.6, 51.1, 27.7, 21.1; MS (EI, 70
eV): m/z (%) = 438 (12) [M+], 338 (100), 248 (25), 91 (98). Anal. Calcd for C29H30N2O2: C, 79.42; H,
6.89; N, 6.39. Found: C, 79.69; H, 6.87; N, 6.58.
N-(tert-butyl)-2,4-bis(4-chlorophenyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8f)
White solid (yield 0.37 g, 77%), mp 115ꢀ117 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.07 (d, J = 7.8
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Hz, 1H), 7.53ꢀ7.31 (m, 11H), 7.12 (s, 1H), 5.55 (s, 1H), 5.04 (s, 1H), 0.93 (s, 9H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 167.6, 166.0, 143.0, 141.5, 137.9, 134.7, 134.0, 133.9, 133.0, 131.9, 131.2, 130.5,
129.5, 129.4, 128.8, 128.7, 128.3, 127.0, 66.9, 51.6, 27.9; MS (EI, 70 eV): m/z (%) = 478 (13) [M+],
378 (100), 241 (34), 178 (30), 138 (64). Anal. Calcd for C27H24Cl2N2O2: C, 67.65; H, 5.05; N, 5.84.
Found: C, 67.84; H, 4.94; N, 5.89.
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2-benzyl-4-(4-bromophenyl)-N-(tert-butyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8g) White solid (yield 0.36 g, 72%), mp 190ꢀ191 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.04 (d, J =
7.2 Hz, 1H), 7.46ꢀ7.09 (m, 12H), 6.90 (s, 1H), 5.35 (s, 1H), 4.95 (d, J = 13.8 Hz, 1H), 4.85 (d, J = 14.4
Hz, 1H), 4.74 (s, 1H), 0.81 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.0, 166.5, 142.4, 139.3,
136.8, 134.0, 133.8, 131.7, 131.2, 130.9, 129.6, 129.0, 128.9, 128.2, 128.0, 127.5, 122.1, 62.7, 53.5,
51.1, 27.7; MS (EI, 70 eV): m/z (%) = 502 (4) [M+], 402 (36), 312 (14), 91 (100). Anal. Calcd for
C28H27BrN2O2: C, 66.80; H, 5.41; N, 5.56. Found: C, 66.87; H, 5.21; N, 5.79.
N-(tert-butyl)-2-butyl-4-(4-chlorophenyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8h) White solid (yield 0.32 g, 75%), mp 101ꢀ103 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d, J =
7.8 Hz, 1H), 7.47ꢀ7.26 (m, 7H), 6.94 (s, 1H), 5.64 (s, 1H), 4.72 (s, 1H), 3.97ꢀ3.43 (m, 2H), 1.43ꢀ1.26
(m, 4H), 0.94 (s, 9H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.8, 166.7,
142.4, 139.0, 134.3, 134.2, 133.7, 131.0, 130.7, 129.8, 129.0, 128.9, 128.3, 127.3, 64.1, 51.4, 50.4,
30.6, 27.8, 19.7, 13.6; MS (EI, 70 eV): m/z (%) = 424 (9) [M+], 324 (100), 268 (28). Anal. Calcd for
C25H29ClN2O2: C, 70.66; H, 6.88; N, 6.59. Found: C, 70.88; H, 6.65; N, 6.74.
N-(tert-butyl)-4-(4-chlorophenyl)-2-ethyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide (8i)
White solid (yield 0.31 g, 78%), mp 181ꢀ182 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d, J = 7.2
Hz, 1H), 7.47ꢀ7.26 (m, 7H), 6.94 (s, 1H), 5.64 (s, 1H), 4.73 (s, 1H), 3.91ꢀ3.58 (m, 2H), 1.13 (t, J = 7.2
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Hz, 3H), 0.94 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.5, 166.7, 142.4, 138.9, 134.2, 133.7,
130.9, 130.7, 129.7, 129.1, 128.9, 128.3, 127.4, 64.0, 51.4, 45.7, 27.9, 13.9; MS (EI, 70 eV): m/z (%) =
396 (11) [M+], 296 (100), 268 (20). Anal. Calcd for C23H25ClN2O2: C, 69.60; H, 6.35; N, 7.06. Found:
C, 69.88; H, 6.25; N, 7.12.
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N-(tert-butyl)-4-(4-chlorophenyl)-2-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8j) White solid (yield 0.37 g, 81%), mp 181ꢀ183 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.07 (d, J =
7.2 Hz, 1H), 7.50ꢀ7.18 (m, 11H), 7.09 (s, 1H), 5.66 (s, 1H), 5.07 (s, 1H), 2.35 (s, 3H), 0.95 (s, 9H); 13
C
NMR (CDCl3, 150 MHz) δ (ppm) 167.7, 166.4, 142.0, 141.9, 138.3, 137.3, 134.4, 134.3, 133.8, 131.6,
131.0, 130.1, 130.0, 129.2, 128.7, 128.5, 127.1, 126.4, 67.1, 51.5, 27.9, 21.0; MS (EI, 70 eV): m/z (%)
= 458 (16) [M+], 358 (100), 330 (10), 242 (13), 178 (19), 118 (46). Anal. Calcd for C28H27ClN2O2: C,
73.27; H, 5.93; N, 6.10. Found: C, 73.13; H, 5.75; N, 6.36.
2-benzyl-N-(tert-butyl)-4-(4-nitrophenyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8k) Yellow solid (yield 0.29 g, 62%), mp 212ꢀ213 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.14 (d, J
= 8.4 Hz, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.50ꢀ7.17 (m, 10H), 6.99 (s, 1H), 5.43 (s, 1H), 5.02 (d, J = 14.4
Hz, 1H), 4.78 (d, J = 13.8 Hz, 1H), 4.77 (s, 1H), 0.85 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm)
168.0, 166.3, 147.0, 146.7, 141.9, 136.8, 133.8, 133.4, 132.0, 131.2, 131.1, 129.4, 129.0, 128.9, 128.8,
128.2, 126.8, 123.9, 62.6, 53.4, 51.4, 27.8; MS (EI, 70 eV): m/z (%) = 469 (7) [M+], 369 (42), 279 (51),
91 (100). Anal. Calcd for C28H27N3O4: C, 71.62; H, 5.80; N, 8.95. Found: C, 71.91; H, 5.87; N, 9.16.
2-benzyl-4-(4-chlorophenyl)-N-cyclohexyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8l) White solid (yield 0.41 g, 85%), mp 237ꢀ239 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.04 (d, J =
8.4 Hz, 1H), 7.45ꢀ7.14 (m, 12H), 6.91 (s, 1H), 5.40 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 14.4 Hz, 1H), 4.84
(d, J = 13.8 Hz, 1H), 4.79 (s, 1H), 3.33ꢀ3.29 (m, 1H), 1.57ꢀ0.50 (m, 10H); 13C NMR (CDCl3, 150
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MHz) δ (ppm) 168.2, 166.5, 141.9, 138.8, 136.8, 134.0, 133.5, 131.4, 131.1, 129.9, 129.1, 129.0, 128.9,
128.8, 128.3, 128.1, 127.1, 62.3, 53.5, 48.1, 32.3, 25.2, 24.5; MS (EI, 70 eV): m/z (%) = 484 (10) [M+],
358 (98), 268 (32), 91 (100). Anal. Calcd for C30H29ClN2O2: C, 74.29; H, 6.03; N, 5.78. Found: C,
74.56; H, 6.17; N, 5.86.
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N-(tert-butyl)-4-(4-chlorophenyl)-2-methyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8m) White solid (yield 0.31 g, 81%), mp 208ꢀ209 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.00 (d, J
= 7.8 Hz, 1H), 7.47ꢀ7.26 (m, 7H), 6.97 (s, 1H), 5.55 (s, 1H), 4.74 (s, 1H), 3.36 (s, 3H,), 0.92 (s, 9H);
13C NMR (CDCl3, 150 MHz) δ (ppm) 168.2, 166.5, 141.7, 139.0, 134.4, 134.1, 133.7, 131.1, 130.8,
129.9, 129.2, 128.8, 128.4, 127.2, 65.8, 51.4, 39.1, 27.9; MS (EI, 70 eV): m/z (%) = 382 (11) [M+], 282
(100), 254 (15), 241 (20), 178 (20). Anal. Calcd for C22H23ClN2O2: C, 69.01; H, 6.05; N, 7.32. Found:
C, 69.07; H, 5.81; N, 7.36.
4-(4-chlorophenyl)-N-cyclohexyl-2-propyl-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8n) White solid (yield 0.36 g, 82%), mp 111ꢀ112 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d, J =
7.8 Hz, 1H), 7.46ꢀ7.24 (m, 7H), 6.95 (s, 1H,), 5.68 (d, J = 7.8 Hz, 1H), 4.76 (s, 1H), 3.92ꢀ3.87 (m, 1H),
3.49ꢀ3.43 (m, 2H), 1.51ꢀ0.71 (m, 15H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.8, 166.6, 141.8,
139.0, 134.2, 133.9, 133.6, 131.1, 130.8, 130.1, 129.1, 129.0, 128.3, 127.3, 63.7, 52.3, 48.3, 32.3, 25.2,
24.6, 21.9, 11.1; MS (EI, 70 eV): m/z (%) = 436 (10) [M+], 310 (100), 268 (22), 241 (10), 178 (10).
Anal. Calcd for C26H29ClN2O2: C, 71.46; H, 6.69; N, 6.41. Found: C, 71.74; H, 6.74; N, 6.56.
N-(tert-butyl)-2-propyl-4-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8o)
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Yellow oil (yield 0.26 g, 67%), H NMR (CDCl3, 600 MHz) δ (ppm) 8.00 (d, J = 7.8 Hz, 1H),
7.43ꢀ7.23 (m, 7H), 6.95 (s, 1H), 5.61 (s, 1H), 4.78 (s, 1H), 3.86ꢀ3.4 (m, 2H), 2.41 (s, 3H), 1.52ꢀ1.48 (m,
2H), 0.91 (s, 9H), 0.84 (t, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.9, 167.0, 143.1,
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138.5, 137.5, 134.5, 134.1, 131.3, 130.6, 129.7, 128.9, 128.7, 128.0, 125.7, 64.3, 52.5, 51.3, 27.9, 21.8,
21.2, 11.1; MS (EI, 70 eV): m/z (%) = 390 (12) [M+], 290 (100), 248 (16). Anal. Calcd for C25H30N2O2:
C, 76.89; H, 7.74; N, 7.17. Found: C, 77.06; H, 7.53; N, 7.43.
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4-(4-chlorophenyl)-N-cyclohexyl-2-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8p) White solid (yield 0.40 g, 83%), mp 196ꢀ197 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.06 (d, J =
7.2 Hz, 1H), 7.48ꢀ7.18 (m, 11H), 7.10 (s, 1H), 5.70 (d, J = 6.6 Hz, 1H), 5.12 (s, 1H), 3.50ꢀ3.45 (m, 1H),
2.35 (s, 3H), 1.54ꢀ0.62 (m, 10H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.9, 166.5, 142.0, 141.5,
138.5, 137.4, 134.5, 134.1, 133.7, 131.7, 131.1, 130.4, 130.1, 129.3, 128.9, 128.7, 127.1, 126.4, 66.8,
48.4, 32.4, 25.2, 24.5, 21.1; MS (EI, 70 eV): m/z (%) = 484 (13) [M+], 358 (100), 330 (9), 242 (10),
178 (17). Anal. Calcd for C30H29ClN2O2: C, 74.29; H, 6.03; N, 5.78. Found: C, 74.36; H, 6.21; N, 5.64.
N-(tert-butyl)-4-(4-chlorophenyl)-2-(o-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8q) Light yellow solid (yield 0.34 g, 74%), mp 231ꢀ233 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.11
(d, J = 7.2 Hz, 0.7H), 8.02 (d, J = 7.2 Hz, 0.3H), 7.68ꢀ7.21 (m, 11H), 7.12 (s, 1H), 5.79 (s, 0.3H), 5.63
(s, 0.7H), 5.01 (s, 0.3H), 4.96 (s, 0.7H), 2.61 (s, 0.9H), 2.07 (s, 2.1H), 0.95 (s, 9H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 166.9, 166.3, 143.8, 142.1, 138.3, 135.2, 134.5, 134.2, 133.7, 131.9, 131.1, 130.6,
130.1, 129.3, 128.7, 128.6, 127.9, 127.6, 127.1, 126.9, 67.1, 51.5, 27.8, 18.1; MS (EI, 70 eV): m/z (%)
= 458 (15) [M+], 358 (100), 330 (9), 242 (18), 178 (22). Anal. Calcd for C28H27ClN2O2: C, 73.27; H,
5.93; N, 6.10. Found: C, 73.54; H, 5.87; N, 6.32.
2-benzyl-8-bromo-N-(tert-butyl)-4-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-carboxamide
(8r) Light yellow solid (yield 0.39 g, 75%), mp 231ꢀ233 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.18
(s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.34ꢀ7.11 (m, 10H), 6.85 (s, 1H), 5.24 (s, 1H), 5.01 (d, J = 14.4 Hz,
1H), 4.82 (s, 1H), 4.77 (d, J = 14.4 Hz, 1H), 2.37 (s, 3H), 1.31 (s, 1H), 0.83 (s, 8H); 13C NMR (CDCl3,
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150 MHz) δ (ppm) 166.9, 166.3, 143.8, 138.4, 137.2, 136.7, 135.5, 134.0, 133.7, 133.3, 130.4, 129.5,
128.9, 128.0, 127.5, 125.7, 121.7, 62.8, 53.6, 51.2, 27.8, 21.1; MS (EI, 70 eV): m/z (%) = 516 (8) [M+],
418 (74), 326 (28), 189 (11), 91 (100). Anal. Calcd for C29H29BrN2O2: C, 67.31; H, 5.65; N, 5.41.
Found: C, 67.18; H, 5.75; N, 5.20.
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N-(tert-butyl)-2-(2-methoxycarbonylphenyl)-4-(p-tolyl)-2,3-dihydro-1H-2-benzazepin-1-one-3-car
boxamide (8s) White solid (yield 0.25 g, 52%), mp 223ꢀ224 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm)
8.64 (s, 1H), 7.88ꢀ7.23 (m, 11H), 6.99 (s, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.33 (s, 1H), 3.99 (s, 3H), 2.41
(s, 3H), 1.03 (s, 8H), 0.93 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.7, 167.5, 166.8, 145.0,
143.1, 137.9, 137.8, 134.2, 134.0, 133.4, 130.7, 130.3, 129.6, 129.5, 128.9, 128.4, 128.0, 127.6, 126.7,
126.5, 126.4, 66.8, 52.7, 51.1, 27.9, 21.3; MS (EI, 70 eV): m/z (%) = 482 (2) [M+], 382 (100), 351 (98),
322 (17), 221 (14), 162 (45), 130 (22). Anal. Calcd for C30H30N2O4: C, 74.67; H, 6.27; N, 5.81. Found:
C, 74.84; H, 6.16; N, 5.66.
N-(tert-butyl)-4-(4-chlorophenyl)-2-(2-methoxycarbonylphenyl)-2,3-dihydro-1H-2-benzazepin-1-
one-3-carboxamide (8t) White solid (yield 0.28 g, 56%), mp 235ꢀ237 °C; 1H NMR (CDCl3, 600 MHz)
δ (ppm) 8.68 (s, 1H), 7.90ꢀ7.29 (m, 11H), 7.00 (s, 1H), 6.76 (d, J = 6.6 Hz, 1H), 5.27 (s, 1H), 3.99 (s,
2.6H), 3.61 (s, 0.4H), 1.03 (s, 7.7H), 0.94 (s, 1.3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.5,
167.4, 166.6, 143.9, 143.0, 139.3, 134.0, 133.7, 133.5, 130.8, 130.4, 129.8, 129.0, 128.9, 128.0, 127.9,
126.9, 126.3, 66.7, 52.7, 51.2, 27.8; MS (EI, 70 eV): m/z (%) = 502 (1) [M+], 403 (100), 371 (89), 342
(21), 241 (14), 162 (61), 130 (34). Anal. Calcd for C29H27ClN2O4: C, 69.25; H, 5.41; N, 5.57. Found: C,
69.01; H, 5.43; N, 5.46.
Preparation of 3H-2-benzoxepin-1-ones 10
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A mixture of phosphonium salt 3 (1 mmol), isocyanide 6 (1 mmol), and arylglyoxal 4 (1 mmol) was
stirred in methanol (5 mL) at room temperature for 48 h, and then the solvent was evaporated under
reduced pressure, NEt3 (0.20 g, 2 mmol) with toluene (5 mL) was added to the reaction system and the
reaction mixture was stirred at 110 °C for 1ꢀ2 h. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography on silica gel (ether/petroleum ether = 1 : 4, V/V) to
give 10.
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N-(tert-butyl)-4-(4-chlorophenyl)-3H-2-benzoxepin-1-one-3-carboxamide (10a) White solid (yield
0.31 g, 84%), mp 163ꢀ164 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.96 (d, J = 7.8 Hz, 1H), 7.60ꢀ7.27
(m, 8H), 6.02 (s, 1H), 5.38 (s, 1H), 1.22 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 168.4, 165.1,
140.2, 135.2, 134.3, 133.9, 133.0, 132.5, 132.2, 131.0, 129.7, 129.3, 128.4, 127.4, 74.5, 51.7, 28.3; MS
(EI, 70 eV): m/z (%) = 369 (4) [M+], 270 (24), 230 (38), 174 (39), 157 (100). Anal. Calcd for
C21H20ClNO3: C, 68.20; H, 5.45; N, 3.79. Found: C, 68.49; H, 5.42; N, 3.90.
4-(4-chlorophenyl)-N-cyclohexyl-3H-2-benzoxepin-1-one-3-carboxamide (10b) White solid (yield
0.30 g, 76%), mp 209ꢀ212 oC; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.93 (d, J = 7.8 Hz, 1H), 7.56ꢀ7.24
(m, 8H), 6.08 (s, 1H), 5.62 (d, J = 7.2 Hz, 1H), 3.75ꢀ3.69 (m, 1H), 1.88ꢀ0.93 (m, 10H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 168.5, 164.8, 139.4, 135.7, 134.3, 134.0, 133.0, 132.6, 131.1, 129.5, 128.6,
128.4, 127.4, 127.3, 74.5, 48.6, 32.6, 25.2, 24.6; MS (EI, 70 eV): m/z (%) = 395 (13) [M+], 270 (31),
256 (100). Anal. Calcd for C23H22ClNO3: C, 69.78; H, 5.60; N, 3.54. Found: C, 69.59; H, 5.43; N, 3.50.
4-(4-bromophenyl)-N-(tert-butyl)-3H-2-benzoxepin-1-one-3-carboxamide (10c) White solid (yield
0.35 g, 85%), mp 149ꢀ151 oC; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.94 (d, J = 7.8 Hz, 1H), 7.57ꢀ7.25
(m, 8H), 6.00 (s, 1H), 5.48 (s, 1H), 1.23 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.5, 165.0,
140.1, 135.5, 134.9, 133.0, 132.6, 131.5, 131.4, 131.0, 129.7, 127.7, 127.6, 122.2, 74.5, 51.8, 28.2; MS
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(EI, 70 eV): m/z (%) = 413 (1) [M+], 371 (6), 314 (100). Anal. Calcd for C21H20BrNO3: C, 60.88; H,
4.87; N, 3.38. Found: C, 60.83; H, 4.79; N, 3.64.
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4-(4-bromophenyl)-N-cyclohexyl-3H-2-benzoxepin-1-one-3-carboxamide (10d) White solid (yield
0.36 g, 82%), mp 222ꢀ224 oC; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.93 (d, J = 7.8 Hz, 1H), 7.57ꢀ7.23
(m, 8H), 6.06 (s, 1H), 5.57 (d, J = 7.2 Hz, 1H), 3.73ꢀ3.69 (m, 1H), 1.88ꢀ0.92 (m, 10H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 168.5, 164.8, 139.4, 135.9, 134.8, 132.9, 132.6, 131.5, 131.4, 131.1, 129.8,
127.7, 127.6, 122.2, 74.5, 48.7, 32.6, 25.3, 24.7; MS (EI, 70 eV): m/z (%) = 439 (11) [M+], 314 (19),
299 (15), 256 (100). Anal. Calcd for C23H22BrNO3: C, 62.74; H, 5.04; N, 3.18. Found: C, 62.84; H,
4.91; N, 3.35.
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N-(tert-butyl)-4-phenyl-3H-2-benzoxepin-1-one-3-carboxamide (10e) White solid (yield 0.26 g,
o
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78%), mp 167ꢀ169 C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.96 (d, J = 7.8 Hz, 1H), 7.58ꢀ7.28 (m,
9H), 6.04 (s, 1H), 5.36 (s, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.7, 164.4, 140.4,
136.9, 136.6, 135.8, 133.4, 132.4, 132.3, 130.0, 128.8, 128.6, 125.9, 125.6, 75.0, 51.6, 28.3; MS (EI, 70
eV): m/z (%) = 335 (4) [M+], 236 (32), 230 (42), 174 (45), 157 (100). Anal. Calcd for C21H21NO3: C,
75.20; H, 6.31; N, 4.18. Found: C, 75.49; H, 6.20; N, 4.17.
N-(tert-butyl)-4-(p-tolyl)-3H-2-benzoxepin-1-one-3-carboxamide (10f) White solid (yield 0.30 g,
o
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86%), mp 136ꢀ138 C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.96 (d, J = 6.0 Hz, 1H), 7.58ꢀ7.13 (m,
8H), 6.00 (s, 1H), 5.35 (s, 1H), 2.31 (s, 3H), 1.15 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 168.7,
164.4, 140.4, 138.2, 136.7, 133.5, 132.7, 132.4, 132.3, 131.2, 129.9, 129.4, 129.3, 125.8, 75.0, 51.6,
28.2, 21.0; MS (EI, 70 eV): m/z (%) = 349 (11) [M+], 276 (15), 250 (32), 230 (46), 174 (52) 157 (100),
119 (47). Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63; N, 4.01. Found: C, 75.55; H, 6.41; N, 4.27.
N-cyclohexyl-4-(p-tolyl)-3H-2-benzoxepin-1-one-3-carboxamide (10g) White solid (yield 0.27 g,
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72%), mp 128ꢀ130 C; H NMR (CDCl3, 400 MHz) δ (ppm) 7.94 (d, J = 7.6 Hz, 1H), 7.54 (s, 2H),
7.54ꢀ7.09 (m, 8H), 6.07 (s, 1H), 5.64 (d, J = 6.8 Hz, 1H), 3.70ꢀ3.66 (m, 1H), 2.29 (s, 3H), 1.93ꢀ0.81 (m,
10H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 168.8, 164.4, 139.6, 138.2, 136.9, 133.4, 132.6, 132.4,
132.3, 131.3, 129.9, 129.4, 129.3, 125.8, 75.0, 48.5, 32.3, 25.3, 24.6, 21.0; MS (EI, 70 eV): m/z (%) =
375 (48) [M+], 292 (24), 276 (31), 250 (47), 233 (100). Anal. Calcd for C24H25NO3: C, 76.77; H, 6.71;
N, 3.73. Found: C, 76.94; H, 6.45; N, 3.93.
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4-(4-bromophenyl)-N-butyl-3H-2-benzoxepin-1-one-3-carboxamide (10h) White solid (yield 0.29 g,
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70%), mp 176ꢀ178 C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.04 (d, J = 7.8 Hz, 1H), 7.66ꢀ7.27 (m,
7H), 6.99 (s, 1H), 6.90 (s, 1H), 5.31 (s, 1H), 3.32ꢀ3.11 (m, 2H), 1.43ꢀ1.25 (m, 4H), 0.90 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 167.9, 165.7, 141.5, 136.6, 135.0, 134.1, 132.9, 132.4,
131.5, 129.6, 129.5, 128.9, 128.6, 122.5, 75.4, 39.0, 31.3, 19.9, 13.6; MS (EI, 70 eV): m/z (%) = 413 (1)
[M+], 371 (13), 314 (100), 286 (44). Anal. Calcd for C21H20BrNO3: C, 60.88; H, 4.87; N, 3.38. Found:
C, 60.94; H, 4.78; N, 3.60.
Isolation of phosphonium intermediate 7e
A mixture of phosphonium salt 3a (0.48 g, 1 mmol), benzylamine (0.12 g, 1.1 mmol), tꢀbutylisocyanide
(0.09 g, 1.1 mmol), and pꢀtolylglyoxal (0.16 g, 1.1 mmol) was stirred in methanol (5 mL) at room
temperature for 48 h, and then the solvent was evaporated under reduced pressure. The residue was
washed three times with ether/petroleum ether (1:1, 10 mL×3) and then recrystallized from
methanol/ether (1:2) to give the phosphonium intermediate 7e as white solid (yield 0.41 g, 51%), mp
1
191ꢀ193 °C; H NMR (DMSOꢀd6, 400 MHz) δ (ppm) 8.42 (s, 1H), 7.91ꢀ7.01 (m, 28H), 6.10 (s, 1H),
5.22 (d, J = 14.4 Hz, 2H), 4.00ꢀ3.94 (m, 2H), 2.40 (s, 3H), 0.98 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
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(ppm) 191.9, 170.4, 163.6, 144.0, 136.9, 136.4, 135.6, 135.2, 134.1, 132.7, 130.6, 130.2, 130.1, 129.9,
129.2, 128.5, 128.3, 127.8, 127.3, 127.1, 126.1, 125.9, 118.5, 117.7, 65.3, 50.7, 39.5, 27.5, 21.2; MS
(EI, 70 eV): m/z (%) = 717 (37) [M+ꢀBrꢀ], 381 (86), 322 (63), 256 (100), 211 (64), 120 (72). Anal.
Calcd for C47H46BrN2O3P: C, 70.76; H, 5.81; N, 3.51. Found: C, 70.53; H, 5.69; N, 3.60.
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Isolation of phosphonium intermediate 9a
A mixture of phosphonium salt 3a (0.48 g, 1 mmol), tꢀbutylisocyanide (0.09 g, 1.1 mmol), and
4ꢀchlorophenylglyoxal (0.19 g, 1.1 mmol) was stirred in methanol (5 mL) at room temperature for 48 h,
and then the solvent was evaporated under reduced pressure. The residue was washed three times with
ether/petroleum ether (1:1, 10 mL×3) and then recrystallized from methanol/ether (1:2) to give the
phosphonium intermediate 9a as white solid (yield 0.31 g, 43%), mp 178ꢀ179 °C; 1H NMR (DMSOꢀd6,
600 MHz) δ (ppm) 8.36 (s, 1H), 8.03ꢀ7.18 (m, 23H), 6.27 (s, 1H), 5.63ꢀ5.49 (m, 2H), 1.22 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 189.5, 164.7, 162.1, 139.0, 135.0, 133.9, 133.8, 132.3, 130.5, 130.1,
130.0, 129.8, 129.2, 129.1, 128.9, 128.8, 128.1, 125.2, 117.8, 116.9, 77.6, 51.1, 39.5, 27.7; MS (EI, 70
eV): m/z (%) = 727 (13) [M+], 370 (8), 278 (100), 238 (40), 174 (37), 139 (26). Anal. Calcd for
C39H36BrClNO4P: C, 64.25; H, 4.98; N, 1.92. Found: C, 64.45; H, 4.76; N, 1.97.
Acknowledgments
We gratefully acknowledge financial support of this work by the National Natural Science Foundation
of China (No. 21172085, 21032001).
Supporting Information
1H and 13C NMR spectra of compounds 8, 7e, 9a and 10, Xꢀray crystallographic data (CIF file) of
compound 10a, This material is available free of charge via the Internet at http://pubs.acs.org.
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