An efficient approach for the construction of benzazepine and benzoxepine derivatives

Article abstract of DOI:10.1002/asia.201200636

A novel and facile synthetic protocol for the construction of benzazepine and benzoxepine derivatives through a copper(I)-catalyzed reaction of 2-(2-ethynylphenyl)-1-tosylaziridine or 2-(2-ethynylphenyl)oxirane with sulfonyl azides is disclosed. A ketenimine is the key intermediate during the reaction process. Copper on the beat: An efficient and facile synthetic protocol for the construction of benzazepine and benzoxepine derivatives through a copper(I)-catalyzed reaction of 2-(2-ethynylphenyl)-1-tosylaziridine or 2-(2-ethynylphenyl)oxirane with sulfonyl azides is disclosed. Copyright

Full text of DOI:10.1002/asia.201200636

DOI: 10.1002/asia.201200636
An Efficient Approach for the Construction of Benzazepine and
Benzoxepine Derivatives
Shaoyu Li,[a] Shaowu Zou,[b] and Jie Wu*[a, c]
Abstract: A novel and facile synthetic protocol for the construction of benzazepine
Keywords: benzazepine · benzoxe-
pine · copper · cyclization · homo-
geneous catalysis
and benzoxepine derivatives through a copper(I)-catalyzed reaction of 2-(2-ethy-
nylphenyl)-1-tosylaziridine or 2-(2-ethynylphenyl)oxirane with sulfonyl azides is
disclosed. A ketenimine is the key intermediate during the reaction process.
Introduction
Tandem reactions have been recognized as an efficient ap-
proach for the generation of N-heterocycles.[1] As part of
our ongoing research program for the preparation of natural
product-like compounds in different biological evaluations,
we are interested in the development of tandem reactions
for the generation of N-heterocycles with privileged scaf-
folds.[2] As pioneered by the research groups of Chang and
Wang, the ketenimine intermediate generated from the cop-
per(I)-catalyzed reaction of terminal alkynes with sulfonyl
azides has been extensively used for the construction of het-
erocycles.[3–5] A number of nucleophilic reagents such as
amines and alcohols have been successfully employed in the
transformations. We are also involved in ketenimine chemis-
try. For example, a three-component reaction of (E)-2-ethy-
nylphenylchalcone, sulfonyl azide, and amine catalyzed by
copper(I) chloride in the presence of triethylamine delivered
Scheme 1. Tandem reaction of 2-(2-ethynylphenyl)aziridine or 2-(2-ethy-
nylphenyl)oxirane with sulfonyl azide.
aziridine or 2-(2-ethynylphenyl)oxirane as the starting mate-
rial in the reaction of sulfonyl azide with amine.
the 1,2-dihydroisoquinolin-3
(4H)-imines in good to excel-
Results and Discussion
lent yields (Scheme 1).[4n] Prompted by this result, we envi-
sioned that the alkenyl moiety of (E)-2-ethynylphenylchal-
cone could be replaced by other electrophiles, such as aziri-
dine and epoxide (Scheme 1). Therefore, we started to ex-
plore the related transformation using 2-(2-ethynylphenyl)-
We chose 2-(2-ethynylphenyl)-1-tosylaziridine (1a), 4-meth-
ylbenzenesulfonyl azide (2a), and aniline as the substrates
to commence our studies. Initially, the reaction was cata-
lyzed by copper(I) iodide (10 mol%) in the presence of trie-
thylamine as a base in 1,4-dioxane at room temperature. To
our surprise, we found that the reaction afforded a complex
mixture, and a small amount of product was obtained. After
structural elucidation by X-ray diffraction analysis, the prod-
uct was identified as compound 3a (see the Supporting In-
formation).[6] From this result, it seemed that aniline did not
take part in the reaction. Therefore, a control experiment
was performed without the addition of aniline. As expected,
compound 3a was obtained in 52% isolated yield (Table 1,
entry 1). This result and the attractiveness of the benzaze-
pine scaffold encouraged us to further investigate. So far,
significant efforts have been made to construct seven-mem-
bered heterocyclic skeletons owing to their abundance in
a large number of bioactive natural products and pharma-
ceutical molecules. Among these compounds, benzazepine
and benzoxepine derivatives are of great importance. Some
commercial drugs such as galantamine contain the benzaze-
[a] S. Li,+ Prof. Dr. J. Wu
Department of Chemistry
Fudan University
220 Handan Road, Shanghai 200433 (China)
Fax : (+86) 21 6564 1740
E-mail: jie_wu@fudan.edu.cn
[b] Dr. S. Zou+
Department of Hepatobiliary and Pancreatic Surgery
10th Peopleꢀs Hospital
Tongji University
301 Yangchang Middle Road, Shanghai 200072 (China)
[c] Prof. Dr. J. Wu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200636.
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Table 1. Initial studies for the copper(I)-catalyzed reaction of 2-(2-ethy-
nylphenyl)-1-tosylaziridine 1a with 4-methylbenzenesulfonyl azide 2a.
used as the solvent (Table 1, entry 9). No improvement in
the results is observed when other solvents were tested
(Table 1, entries 10–13).
Under the optimized reaction conditions (Table 1,
entry 9), we next set out to explore the substrate scope of
this copper(I)-catalyzed reaction of 2-(2-ethynylphenyl)-1-
tosylaziridines 1 with sulfonyl azides 2 (Table 2). All reac-
tions proceeded smoothly to afford the expected products 3
in good yields. Different substituents including fluoro,
chloro, methyl, methoxy, bromo, and nitro groups were com-
patible under the standard reaction conditions. Interestingly,
isomerized products were isolated in moderate yields when
R2 was changed to an alkyl or aryl group (Table 2, com-
pound 3k–3m). The deuteroxide exchange experiment of
compound 3k identified the existence of an active hydrogen
atom.
With the above results in hand, we proposed a possible
process, which is illustrated in Scheme 2. We reasoned that
2-(2-ethynylphenyl)-1-tosylaziridine 1 would react with sul-
fonyl azide 2 catalyzed by the copper(I) salt, thereby afford-
ing the triazole intermediate A, which is then transferred
into the reactive ketenimine B after the release of molecular
Entry
[Cu]
Base
Solvent
Yield [%][a]
1
2
3
CuI
Et3N
Et3N
Et3N
Et3N
iPr2NEt
Pyridine
K2CO3
K3PO4
Et3N
Et3N
Et3N
Et3N
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
ACHTUGNRTNE(NUNG CH2Cl)2
THF
MeCN
Toluene
DMSO
52
78
72
73
65
38
29
35
85
70
28
77
ND
CuBr
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
4[b]
5
6
7
8
9
10
11
12
13
[a] Yield of isolated product based on 2-(2-ethynylphenyl)-1-tosylaziri-
dine 1a. [b] In the presence of 5 mol% CuBr.
pine framework,[7] and a recent research indicates
that many compounds containing this moiety
Table 2. Scope investigation for the copper(I)-catalyzed reaction of 2-(2-ethynylphen-
appear to be novel and prominent dopamine D1/
D5 receptor antagonists.[8] Meanwhile, several ben-
zoxepines are found to possess antibiotic activities[9]
and potentially considered as bronchodilators and
antihypertensives.[9d] Despite their prominent im-
portance, less attention has been paid to the synthe-
sis of benzazepine and benzoxepine derivatives.
The general method to access these scaffolds usual-
ly involves a 7-endo heterocyclization of aromatic
ynamines and alkynols. For example, Liu and co-
workers reported a strategy for the synthesis of 3-
yl)-1-tosylaziridine 1 with sulfonyl azide 2.
benzazepinones by a AuACHTNUGTRENUNG(PPh3)Cl/AgSbF6-catalyzed
intramolecular hydroamidation of 2-(1-alkynyl)phe-
nylacetamides.[10] However, the poor substrate sus-
tainability and high temperatures restricted the
prospects of this methodology. Recently, Saꢂ and
co-workers disclosed an osmium-catalyzed 7-endo
heterocyclization of aromatic alkynols into benzox-
epines, which was only suitable for the terminal al-
kynes.[11] Therefore, the development of an efficient
strategy toward the preparation of benzazepine and
benzoxepine derivatives is highly desirable.
[a] Yield of isolated product based on 2-(2-ethynylphenyl)-1-tosylaziridine 1.
As aniline was not involved in the reaction, we
re-investigated the reaction of 2-(2-ethynylphenyl)-1-tosyla-
ziridine 1a with 4-methylbenzenesulfonyl azide 2a (Table 1).
Screening of the copper(I) salt revealed that copper(I) bro-
mide was the best choice, thus affording the corresponding
product 3a in 78% yield (Table 1, entry 2). A lower yield
was obtained when 5 mol% of copper(I) bromide was used
(Table 1, entry 4). Inferior results were observed when other
bases such as iPr2NEt, pyridine, K2CO3, and K3PO4 were
employed in the transformation (Table 1, entries 5–8). The
yield was improved to 85% when 1,2-dichloroethane was
nitrogen. An intramolecular nucleophilic attack of tosylaziri-
dine to the ketenimine would furnish the intermediate C,
which would undergo a rearrangement to produce the corre-
sponding product 3.
Based on the above results, we then shifted our focus to
2-(2-ethynylphenyl)oxiranes, with the aim of synthesizing 3-
benzoxepine derivatives. The reaction of 2-(2-ethynylphen-
yl)-3-propyloxirane 4a with 4-methylbenzenesulfonyl azide
2a catalyzed by copper(I) bromide was performed in the
presence of triethylamine in 1,4-dioxane at room tempera-
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Benzazepine and Benzoxepine Derivatives
Table 4. Scope investigation for the copper(I)-catalyzed reaction of 2-(2-
ethynylphenyl)oxirane 4 with 4-methylbenzenesulfonyl azide 2a.
Scheme 2. A possible route for the copper(I)-catalyzed reaction of 2-(2-
ethynylphenyl)-1-tosylaziridine 1 with sulfonyl azide 2.
ture, the desired 3-benzoxepine derivative 5a was produced
in 61% yield (Table 3, entry 1). The structure of compound
5a was further verified by X-ray diffraction analysis (see the
Supporting Information).[6] With this promising result in
[a] Yield of isolated product based on 2-(2-ethynylphenyl)oxirane 4.
This was mainly due to the stability issue of the methoxy-
substituted product 5i, as it decomposed extremely quickly
during the process of purification. Interestingly, compared
with the results obtained from the reactions of 2-(2-ethynyl-
phenyl)-1-tosylaziridines 1 with sulfonyl azides 2 (Table 2),
no isomerized products were found in the reactions. The
presence of a tosyl group on the nitrogen atom of the aziri-
dine might force the subsequent isomerization, thus result-
ing in a different outcome.
Table 3. Optimization studies for the reaction of 2-(2-ethynylphenyl)-3-
propyloxirane 4a with 4-methylbenzenesulfonyl azide 2a.
Entry
[Cu]
Base
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
CuBr
CuI
Et3N
Et3N
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
61
45
70
83
60
35
38
33
47
25
51
16
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
iPr2NEt
Pyridine
K2CO3
K3PO4
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
Conclusions
In conclusion, we have described a novel and efficient ap-
proach for the concise synthesis of benzazepine and benzox-
epine derivatives through a copper-catalyzed reaction of (2-
ethynylphenyl)-1-tosylaziridine or 2-(2-ethynylphenyl)oxir-
ane with sulfonyl azide. The mild reaction conditions and
short reaction time enable the protocol to be attractive for
further library construction. Applications of ketenimine
chemistry for the formation of other heterocycles are ongo-
ing.
9
ACHTUGNRTNE(NUNG CH2Cl)2
10
11
12
MeCN
Toluene
DMSO
[a] Yield of isolated product based on 2-(2-ethynylphenyl)-3-propyloxir-
ane 4a.
hand, we continued to screen for optimal reaction condi-
tions. After an extensive investigation of catalysts, bases,
and solvents (Table 3, entries 2–12), we found the reaction
worked efficiently when the reaction was catalyzed by
10 mol% of CuCl in the presence of diisopropylethylamine
as the base in 1,4-dioxane, thus leading to the corresponding
product 5a in 83% yield (Table 3, entry 4).
After establishing the optimal reaction conditions, the
scope and generality of this copper(I)-catalyzed reaction of
2-(2-ethynylphenyl)oxirane 4 with 4-methylbenzenesulfonyl
azide 2 were explored (Table 4). It was found that various 2-
(2-ethynylphenyl)oxiranes 4 participated successfully in the
reaction and generated good results, except for the me-
thoxy-substituted substrate.
Experimental Section
General experimental procedure for the copper(I)-catalyzed reaction of 2-
(2-ethynylphenyl)-1-tosylaziridine 1 with sulfonyl azide 2
Triethylamine (45 mg, 0.45 mmol) was added to a solution of 2-(2-ethy-
nylphenyl)-1-tosylaziridine 1 (0.3 mmol), sulfonyl azide 2 (0.36 mmol),
and copper(I) bromide (4.2 mg, 0.03 mmol) in 1,2-dichloroethane
(3.0 mL). The resulting mixture was stirred at room temperature under
N2 atmosphere. After completion of the reaction as indicated by TLC,
the mixture was diluted with CH2Cl2 (10 mL) and filtered through a thin
layer of silica gel. The solvent was evaporated and the residue was puri-
fied by column chromatography on silica gel (eluted with petroleum
ether (b.p. 60/90)/EtOAc=4:1) to provide products 3.
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Jie Wu et al.
FULL PAPER
4-Methyl-N-(3-tosyl-1H-benzo[d]azepin-2
(3H)-
4-Bromo-N-(3-tosyl-1H-benzo[d]azepin-2
ACHTUNGTNER(NUNG 3H)-
ylidene)benzenesulfonamide (3a)
ylidene)benzenesulfonamide (3g)
Yield: 85%; White solid; M.p.: 152.3–153.38C; 1H NMR (400 MHz,
CDCl3): d=2.27 (s, 3H), 2.45 (s, 3H), 4.09 (s, 2H), 6.63 (d, J=9.6 Hz,
1H), 6.89 (d, J=8.0 Hz, 2H), 7.25–7.37 (m, 8H), 7.57 (d, J=7.2 Hz, 1H),
7.74 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.7, 38.9,
120.4, 122.6, 127.0, 127.6, 128.1, 128.8, 129.2, 129.3, 129.9, 130.0, 131.2,
133.0, 134.7, 138.7, 143.4, 145.3 ppm; IR: n˜ =3061, 1631, 1593, 1492, 1303,
1188 cmÀ1; HRMS (ESI) calcd for C24H22N2O4S2: 467.1094 [M+H+];
found: 467.1108.
Yield: 87%; White solid; M.p.: 180.2–180.98C; 1H NMR (400 MHz,
CDCl3): d=2.30 (s, 3H), 4.17 (s, 2H), 6.68 (d, J=9.6 Hz, 1H), 6.92 (d,
J=7.2 Hz, 2H), 7.26–7.39 (m, 6H), 7.57 (d, J=6.8 Hz, 1H), 7.64–
7.71 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=21.7, 39.1, 120.8,
122.6, 127.5, 127.6, 128.2, 128.5, 128.6, 129.3, 130.0, 130.1, 130.1, 132.0,
132.9, 134.7, 140.6, 145.5, 160.1 ppm; IR: n˜ =3055, 2911, 1637, 1592, 1365,
1148 cmÀ1; HRMS (ESI) calcd for C23H19BrN2O4S2: 531.0042 [M+H+];
found: 531.0066.
N-(7-Fluoro-3-tosyl-1H-benzo[d]azepin-2
methylbenzenesulfonamide (3b)
ACHTUNGTREN(NUGN 3H)-ylidene)-4-
4-Methoxy-N-(3-tosyl-1H-benzo[d]azepin-2
ylidene)benzenesulfonamide (3h)
ACHTUNGTNER(NUNG 3H)-
Yield: 78%; White solid; M.p.: 168.5–169.58C; 1H NMR (400 MHz,
CDCl3): d=2.29 (s, 3H), 2.47 (s, 3H), 4.09 (s, 2H), 6.55 (d, J=9.6 Hz,
1H), 6.90–6.97 (m, 3H), 7.05–7.09 (m, 1H), 7.29–7.34 (m, 5H), 7.54–7.57
(m, 1H), 7.74 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
21.7, 21.7, 38.1, 113.7 (d, 2JCF =22.0 Hz), 117.1 (d, 2JCF =21.9 Hz), 119.2,
Yield: 80%; White solid; M.p.: 149.8–150.88C; 1H NMR (400 MHz,
CDCl3): d=2.28 (s, 3H), 3.88 (s, 3H), 4.17 (s, 2H), 6.63 (d, J=9.6 Hz,
1H), 6.93 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 7.25–7.37 (m, 6H),
7.58 (d, J=7.2 Hz, 1H), 7.79 ppm (d, J=8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=21.7, 38.8, 55.7, 113.8, 120.3, 122.7, 127.6, 128.1,
128.8, 129.1, 129.2, 129.9, 130.0, 131.2, 133.1, 133.5, 134.8, 145.3, 159.7,
163.0 ppm; IR: n˜ =3080, 2916, 1627, 1593, 1493 cmÀ1; HRMS (ESI) calcd
for C24H22N2O5S2: 483.1043 [M+H+]; found: 483.1046.
3
123.7, 126.9, 127.0, 127.0, 128.8, 129.2, 131.8 (d, JCF =7.7 Hz), 134.5, 134.7
1
(d, 3JCF =8.6 Hz), 138.5, 143.6, 145.4, 159.5, 162.3 ppm (d, JCF
=
245.0 Hz); IR: n˜ =1632, 1595, 1152 cmÀ1
C24H21FN2O4S2: 485.1000 [M+H+]; found: 485.1011.
; HRMS (ESI) calcd for
4-Nitro-N-(3-tosyl-1H-benzo[d]azepin-2ACTHUNTGRNEUNG(3H)-ylidene)benzenesulfonamide
(3i)
N-(7-Chloro-3-tosyl-1H-benzo[d]azepin-2(3H)-ylidene)-4-
methylbenzenesulfonamid (3c)
ACHTUNGTRENNUNG
Yield: 61%; Yellow solid; M.p.: 209.0–210.08C; 1H NMR (400 MHz,
[D6]DMSO): d=2.26 (s, 3H), 4.10 (s, 2H), 6.96 (d, J=9.2 Hz, 1H), 7.11
(d, J=8.0 Hz, 2H), 7.25 (d, J=9.2 Hz, 1H), 7.36–7.43 (m, 6H), 7.88 (d,
J=7.6 Hz, 2H), 8.41 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz,
[D6]DMSO): d=21.7, 38.9, 122.3, 123.4, 125.1, 128.3, 128.4, 128.8, 129.9,
130.1, 130.4, 131.5, 133.3, 134.5, 146.2, 146.3, 150.4, 161.6 ppm; IR: n˜ =
3065, 2926, 1632, 1593, 1529 cmÀ1; HRMS (ESI) calcd for C23H19N3O6S2:
498.0788 [M+H+]; found: 498.0814.
Yield: 75%; White solid; M.p.: 169.9–170.98C; 1H NMR (400 MHz,
CDCl3): d=2.29 (s, 3H), 2.47 (s, 3H), 4.10 (s, 2H), 6.53 (d, J=10.6 Hz,
1H), 6.91 (d, J=7.6 Hz, 2H), 7.25 (s, 1H), 7.32–7.34 (m, 6H), 7.52 (d, J=
8.4 Hz, 1H), 7.73 ppm (d, J=7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=21.7, 38.3, 118.8, 123.8, 127.0, 127.2, 127.2, 128.9, 129.3, 129.4, 129.5,
129.9, 131.4, 134.0, 134.5, 134.5, 138.5, 143.6, 145.5, 159.2 ppm; IR: n˜ =
2923, 1627, 1594 cmÀ1; HRMS (ESI) calcd for C24H21ClN2O4S2: 501.0704
[M+H+]; found: 501.0707.
N-(3-tosyl-1H-benzo[d]azepin-2ACTHNUTRGNE(NUG 3H)-ylidene)benzenesulfonamide (3j)
4-Methyl-N-(7-methyl-3-tosyl-1H-benzo[d]azepin-2ACHTUNTRGNEUNG(3H)-
White solid; M.p.: 169.5–170.58C; 1H NMR (400 MHz, [D6]DMSO): d=
2.27 (s, 3H), 4.12 (s, 2H), 6.65 (d, J=9.6 Hz, 1H), 6.88 (d, J=7.2 Hz,
2H), 7.27–7.40 (m, 6H), 7.52–7.54 (m, 2H), 7.58–7.63 (m, 2H), 7.86 ppm
(d, J=7.6 Hz, 2H); 13C NMR (100 MHz, [D6]DMSO): d=21.7, 39.1,
120.5, 122.7, 127.0, 127.6, 128.1, 128.7, 128.8, 129.2, 130.0, 130.0, 131.1,
132.7, 133.0, 134.7, 141.5, 145.4, 160.0 ppm; IR: n˜ =3060, 2921, 1627,
1592, 1447 cmÀ1; HRMS (ESI) calcd for C23H20N2O4S2: 453.0937 [M+H+
], found: 453.0947.
ylidene)benzenesulfonamide (3d)
Yield: 90%; White solid; M.p.: 153.8–154.88C; 1H NMR (400 MHz,
CDCl3): d=2.28 (s, 3H), 2.32 (s, 3H), 2.46 (s, 3H), 4.09 (s, 2H), 6.59 (d,
J=10.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 2H), 7.07 (s, 1H), 7.18 (d, J=7.6 Hz,
1H), 7.24 (d, J=9.6 Hz, 1H), 7.30–7.33 (m, 4H), 7.46 (d, J=9.6 Hz, 1H),
7.74 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.1, 21.7,
38.6, 120.4, 122.5, 127.0, 127.9, 128.0, 128.4, 128.8, 129.2, 129.4, 129.8,
130.9, 132.9, 134.7, 137.9, 138.8, 143.4, 145.2, 159.9 ppm; IR: n˜ =2968,
1616, 1323, 1158 cmÀ1; HRMS (ESI) calcd for C25H24N2O4S2: 481.1250
[M+H+]; found: 481.1253.
4-Methyl-N-(4-methyl-3-tosyl-3H-benzo[d]azepin-2-
yl)benzenesulfonamide (3k)
Yield: 75%; White solid; M.p.: 164.0–165.08C; 1H NMR (400 MHz,
CDCl3): d=1.66 (s, 3H), 2.06 (s, 3H), 2.44 (s, 3H), 6.24 (s, 1H), 6.63 (d,
J=7.2 Hz, 2H), 6.77–6.79 (m, 3H), 6.87 (s, 1H), 6.93–6.95 (m, 2H), 7.17
(d, J=7.2 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.73 ppm (d, J=7.2 Hz, 2H);
1H NMR (400 MHz, CDCl3+D2O): d=1.66 (s, 3H), 2.06 (s, 3H), 2.44 (s,
3H), 6.24 (s, 1H), 6.63 (d, J=7.2 Hz, 2H), 6.77–6.79 (m, 3H), 6.93–6.95
(m, 2H), 7.17 (d, J=7.6 Hz, 2H), 7.29 (d, J=7.2 Hz, 2H), 7.73 ppm (d,
J=7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.2, 21.6, 24.1, 121.2,
126.3, 126.5, 127.2, 127.4, 127.8, 128.5, 129.3, 129.7, 129.7, 130.3, 132.0,
133.2, 134.5, 136.4, 138.7, 143.9, 144.4 ppm; IR: n˜ =3264, 3060, 1597,
1353, 1165 cmÀ1; HRMS (ESI) calcd for C25H24N2O4S2: 481.1250 [M+H+
]; found: 481.1249.
N-(8-Methoxy-3-tosyl-1H-benzo[d]azepin-2
methylbenzenesulfonamide (3e)
ACHTUNGTREN(NUGN 3H)-ylidene)-4-
Yield: 79%; White solid; M.p.: 163.7–164.78C; 1H NMR (400 MHz,
CDCl3): d=2.28 (s, 3H), 2.46 (s, 3H), 3.80 (s, 3H), 4.10 (s, 2H), 6.58 (d,
J=9.6 Hz, 1H), 6.85–6.87 (m, 1H), 6.91 (d, J=8.0 Hz, 2H), 7.10–7.13 (m,
1H), 7.15–7.18 (m, 2H), 7.32–7.34 (m, 4H), 7.75 ppm (d, J=8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=21.7, 21.7, 39.2, 55.5, 113.8, 115.5, 120.2,
120.8, 125.9, 127.0, 128.8, 128.9, 129.2, 129.3, 132.6, 134.7, 138.8, 143.4,
145.2, 159.2, 161.2 ppm; IR: n˜ =2952, 1607, 1594, 1499, 1174 cmÀ1; HRMS
(ESI) calcd for C25H24N2O5S2: 497.1199 [M+H+]; found: 497.1195.
N-(3-Tosyl-1H-benzo[d]azepin-2ACTHNUTRGNE(NUG 3H)-ylidene)methanesulfonamide (3 f)
Yield: 76%; White solid; M.p.: 173.8–174.78C; 1H NMR (400 MHz,
CDCl3): d=2.37 (s, 3H), 2.93 (s, 3H), 4.01 (s, 2H), 6.66 (d, J=9.6 Hz,
1H), 7.23–7.35 (m, 6H), 7.50 (d, J=9.2 Hz, 1H), 7.70 ppm (d, J=7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=21.8, 38.8, 42.8, 120.6, 122.6, 127.6,
128.2, 128.5, 129.6, 129.9, 131.1, 132.9, 135.3, 145.8, 160.2 ppm; IR: n˜ =
4-Methyl-N-(4-propyl-3-tosyl-3H-benzo[d]azepin-2-
yl)benzenesulfonamide (3l)
Yield: 57%; White solid; M.p.: 167.7–168.78C; 1H NMR (400 MHz,
CDCl3): d=0.82 (t, J=6.4 Hz, 3H), 1.28–1.30 (m, 2H), 1.77–1.84 (m,
1H), 2.04 (s, 3H), 2.35–2.42 (m, 4H), 6.21 (s, 1H), 6.58 (d, J=6.8 Hz,
2H), 6.71–6.73 (m, 2H), 6.81 (s, 1H), 6.91–6.93 (m, 3H), 7.06 (d, J=
6.4 Hz, 2H), 7.29 (d, J=6.8 Hz, 2H), 7.76 ppm (d, J=6.8 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=13.6, 20.6, 21.2, 21.6, 39.9, 117.8, 126.2,
127.5, 127.5, 127.9, 128.2, 128.5, 129.6, 129.6, 129.7, 130.1, 132.2, 133.1,
2926, 1595, 1368, 1136 cmÀ1
391.0781 [M+H+]; found: 391.0805.
; HRMS (ESI) calcd for C18H18N2O4S2:
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Benzazepine and Benzoxepine Derivatives
134.5, 136.4, 142.7, 143.8, 144.4 ppm; IR: n˜ =3268, 3049, 1591, 1354,
1164 cmÀ1; HRMS (ESI) calcd for C27H28N2O4S2: 509.1563 [M+H+];
found: 509.1565.
4-Methyl-N-(4-phenylbenzo[d]oxepin-2ACTHUGNETRNNU(G 1H)-ylidene)benzenesulfonamide
(5e)
Yield: 53%; White solid; M.p.: 160.1–161.18C; 1H NMR (400 MHz,
CDCl3): d=2.39 (s, 3H), 3.70 (s, 2H), 7.06 (s, 1H), 7.21–7.28 (m, 3H),
7.35–7.44 (m, 6H), 7.74–7.82 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=21.6, 40.7, 111.4, 125.5, 127.1, 128.6, 128.9, 129.4, 129.6, 129.7, 130.3,
130.4, 132.5, 133.2, 138.4, 143.5, 149.6, 160.7 ppm; IR: n˜ =2922, 1655,
4-Methyl-N-(4-phenyl-3-tosyl-3H-benzo[d]azepin-2-
yl)benzenesulfonamide (3m)
Yield: 62%; White solid; M.p.: 162.6–162.98C; 1H NMR (400 MHz,
CDCl3): d=2.07 (s, 3H), 2.10 (s, 3H), 6.64 (d, J=7.6 Hz, 2H), 6.79–6.83
(m, 3H), 6.97–6.99 (m, 2H), 7.04–7.05 (m, 2H), 7.10 (s, 1H), 7.19–7.21
(m, 5H), 7.34 (s, 1H), 7.44–7.47 ppm (m, 4H); 13C NMR (100 MHz,
CDCl3): d=21.2, 21.5, 121.4, 125.3, 126.0, 126.7, 127.1, 127.2, 127.5, 127.8,
127.9, 128.2, 128.6, 129.3, 130.4, 130.7, 132.6, 133.4, 134.7, 135.8, 136.6,
138.0, 144.0 ppm; IR: n˜ =3269, 3057, 1597, 1354, 1164 cmÀ1; HRMS (ESI)
calcd for C30H26N2O4S2: 543.1407 [M+H+]; found: 543.1408.
1448 cmÀ1 HRMS (ESI) calcd for C23H19NO3S: 390.1158 [M+H+];
;
found: 390.1171.
N-(7-Fluoro-4-propylbenzo[d]oxepin-2ACHTNUTRGNEUNG(1H)-ylidene)-4-
methylbenzenesulfonamide (5 f)
Yield: 70%; Brown solid; M.p.: 145.0–146.08C; 1H NMR (400 MHz,
CDCl3): d=0.94 (t, J=7.2 Hz, 3H), 1.50–1.56 (m, 2H), 2.33–2.35 (m,
2H), 2.39 (s, 3H), 3.53 (s, 2H), 6.17 (s, 1H), 6.87–7.26 (m, 5H), 7.78 ppm
(d, J=6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.5, 20.4, 21.6,
General experimental procedure for the copper(I)-catalyzed reaction of 2-
(2-ethynylphenyl)oxirane 4 with sulfonyl azide 2
37.0, 39.9, 110.7, 116.0 (d, 2JCF =22.0 Hz), 116.3 (d, 2JCF =20.9 Hz), 126.0,
Diisopropylethylamine (58 mg, 0.45 mmol) was added to a solution of 2-
(2-ethynylphenyl)oxirane 4 (0.3 mmol), 4-methylbenzenesulfonyl azide
2a (71 mg, 0.36 mmol), and copper(I) chloride (3 mg, 0.03 mmol) in 1,4-
dioxane (3.0 mL). The resulting mixture was stirred at room temperature
under N2 atmosphere. After completion of the reaction as indicated by
TLC, the mixture was diluted with CH2Cl2 (10 mL) and filtered through
a thin layer of silica gel. The solvent was evaporated and the residue was
purified by column chromatography on silica gel (eluted with petroleum
ether (b.p. 60/90)/EtOAc=4:1) to provide the products 5.
1
127.0, 127.3, 129.2, 129.5, 130.4, 134.3, 138.3, 143.6, 153.9, 162.5 (d, JCF
=
246.0 Hz), 164.3 ppm; IR: n˜ =2962, 1615, 1495, 1322, 1158 cmÀ1; HRMS
(ESI) calcd for C20H20FNO3S: 374.1221 [M+H+]; found: 374.1240.
N-(7-Chloro-4-propylbenzo[d]oxepin-2ACHTUNGTREN(NGNU 1H)-ylidene)-4-
methylbenzenesulfonamide (5g)
Yield: 71%; Brown solid; M.p.: 101.2–102.28C; 1H NMR (400 MHz,
CDCl3): d=0.95 (t, J=6.8 Hz, 3H), 1.53–1.61 (m, 2H), 2.35–2.43 (m,
5H), 3.54 (s, 2H), 6.15 (s, 1H), 7.18–7.27 (m, 5H), 7.79 ppm (d, J=
7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.5, 20.4, 21.6, 37.0, 40.1,
110.6, 127.3, 127.6, 128.6, 128.8, 129.2, 129.5, 134.1, 138.2, 143.7, 154.0,
164.2 ppm; IR: n˜ =2962, 1616, 1485, 1323, 1162 cmÀ1; HRMS (ESI) calcd
for C20H20ClNO3S: 390.0925 [M+H+]; found: 390.0947.
4-Methyl-N-(4-propylbenzo[d]oxepin-2ACTHNUGTRNEUNG(1H)-ylidene)benzenesulfonamide
(5a)
Yield: 83%; White solid; M.p.: 158.0–159.08C; 1H NMR (400 MHz,
CDCl3): d=0.93 (t, J=6.4 Hz, 3H), 1.46–1.58 (m, 2H), 2.31–2.37 (m,
5H), 3.55 (s, 2H), 6.23 (s, 1H), 7.17–7.30 (m, 6H), 7.78 ppm (d, J=
7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.5, 20.5, 21.6, 37.0, 40.7,
111.7, 127.3, 127.8, 128.3, 128.9, 129.1, 129.3, 130.1, 132.4, 138.5, 143.5,
152.9, 164.8 ppm; IR: n˜ =2962, 1648, 1602, 1501 cmÀ1; HRMS (ESI) calcd
for C20H21NO3S: 356.1315 [M+H+]; found: 356.1314.
4-Methyl-N-(7-methyl-4-propylbenzo[d]oxepin-2ACHTUNTRGNEUNG(1H)-
ylidene)benzenesulfonamide (5h)
Yield: 77%; White solid; M.p.: 100.5–101.58C; 1H NMR (400 MHz,
CDCl3): d=0.94 (t, J=7.6 Hz, 3H), 1.49–1.53 (m, 2H), 2.30–2.41 (m,
2H), 2.33 (s, 3H), 2.39 (s, 3H), 3.52 (s, 2H), 6.18 (s, 1H), 6.98–7.25 (m,
5H), 7.79 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.5,
20.5, 21.1, 21.6, 37.0, 40.3, 111.7, 127.3, 128.2, 128.8, 129.3, 130.0, 132.2,
N-(benzo[d]oxepin-2ACHTUNGTRENNUNG(1H)-ylidene)-4-methylbenzenesulfonamide (5b)
Yield: 57%; White solid; M.p.: 83.5–84.58C; 1H NMR (400 MHz,
CDCl3): d=2.38 (s, 3H), 3.61 (s, 2H), 6.39 (d, J=6.0 Hz, 1H), 6.70 (d,
J=6.0 Hz, 1H), 7.23–7.25 (m, 4H), 7.34–7.36 (m, 2H), 7.79 ppm (d, J=
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.6, 40.9, 115.6, 127.2,
127.3, 128.4, 128.5, 129.3, 129.5, 129.9, 138.2, 143.6, 151.4, 164.6 ppm; IR:
n˜ =2961, 1610, 1321 cmÀ1; HRMS (ESI) calcd for C17H15NO3S: 314.0845
[M+H+]; found: 314.0863.
138.1, 138.5, 143.4, 152.7, 164.9 ppm; IR: n˜ =2961, 1613, 1450, 1303 cmÀ1
;
HRMS (ESI) calcd for C21H23FNO3S: 370.1471 [M+H+]; found:
370.1492.
Acknowledgements
4-Methyl-N-(4-methylbenzo[d]oxepin-2ACTHNUGTRNEUNG(1H)-ylidene)benzenesulfonamide
Financial support from the National Natural Science Foundation of
China (Nos. 21032007, 21172038) is gratefully acknowledged.
(5c)
Yield: 83%; White solid; M.p.: 156.7–157.78C; 1H NMR (400 MHz,
CDCl3): d=2.11 (s, 3H), 2.39 (s, 3H), 3.57 (s, 2H), 6.23 (d, J=6.0 Hz,
1H), 7.16–7.31 (m, 6H), 7.79 ppm (d, J=8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=21.0, 21.6, 40.7, 112.1, 127.5, 127.6, 128.2, 128.5,
129.2, 129.3, 129.4, 132.4, 138.3, 143.6, 149.2, 164.4 ppm; IR: n˜ =2961,
1610, 1154 cmÀ1; HRMS (ESI) calcd for C18H17NO3S: 328.1002 [M+H+];
found: 328.1032.
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methylbenzenesulfonamide (5d)
Yield: 91%; White solid; M.p.: 114.0–115.08C; 1H NMR (400 MHz,
CDCl3): d=1.21 (d, J=6.4 Hz, 6H), 2.39 (s, 3H), 2.63–2.67 (m, 1H), 3.55
(s, 2H), 6.26 (s, 1H), 7.22–7.33 (m, 6H), 7.79 ppm (d, J=7.2 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=18.2, 20.6, 21.6, 33.9, 40.6, 109.4, 127.1,
128.1, 128.3, 128.5, 128.8, 129.1, 129.3, 138.5, 143.4, 158.4, 165.4 ppm; IR:
n˜ =2967, 1653, 1616, 1565 cmÀ1; HRMS (ESI) calcd for C20H21NO3S:
356.1315 [M+H+]; found: 356.1337.
Chem. Asian J. 2012, 00, 0 – 0
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Jie Wu et al.
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Received: July 16, 2012
Published online: && &&, 0000
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FULL PAPER
Tandem Cyclizations
Shaoyu Li, Shaowu Zou,
Jie Wu*
&&&& — &&&&
An Efficient Approach for the
Construction of Benzazepine and
Benzoxepine Derivatives
Copper on the beat: An efficient and
facile synthetic protocol for the con-
struction of benzazepine and benzoxe-
pine derivatives through a copper(I)-
catalyzed reaction of 2-(2-ethynyl-
phenyl)-1-tosylaziridine or 2-(2-ethy-
nylphenyl)oxirane with sulfonyl azides
is disclosed.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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