Organocatalytic nucleophilic ring opening of cyclopropanecarbaldehydes by benzenethiols: Tandem synthesis of benzo[b]thiepines

Article abstract of DOI:10.1055/s-0029-1217370

An unprecedented nucleophilic ring opening of cyclopropanecarbaldehydes with benzenethiols proceeds regioselectively under the catalysis of 40 mol% proline to afford fair to good yields of 4-phenylthio-substituted butyraldehydes. If o-thiosalicylaldehydes

Full text of DOI:10.1055/s-0029-1217370

1830
LETTER
Organocatalytic Nucleophilic Ring Opening of Cyclopropanecarbaldehydes
by Benzenethiols: Tandem Synthesis of Benzo[b]thiepines
Tandem
S
ynthe
i
sis of
B
a
enzo[
b
]thi e
n
pine
s
gxi Li, Zhiming Li, Quanrui Wang*
Department of Chemistry, Fudan University, 200433 Shanghai, P. R. of China
Fax +86(21)65641740; E-mail: qrwang@fudan.edu.cn
Received 9 January 2009
Although organocatalyzed nucleophilic addition to a,b-
Abstract: An unprecedented nucleophilic ring opening of cyclo-
propanecarbaldehydes with benzenethiols proceeds regioselective-
ly under the catalysis of 40 mol% proline to afford fair to good
yields of 4-phenylthio-substituted butyraldehydes. If o-thiosalicyl-
unsaturated carbonyl systems has been thoroughly stud-
ied,10,11 as far as we are aware, a homoconjugate nucleo-
philic version to a cyclopropane ring under activation with
aldehydes are employed, a tandem homoconjugate addition–aldol organocatalysis remains untouched.12 Replacing a C=C
reaction occurs, which constitutes an expedient entry to pharmaceu-
tically valuable 2,3-dihydrobenzo[b]thiepine-4-carbaldehydes.
double bond with a cyclopropane ring, the reaction with
nucleophiles may provide an attractive entry into homo-
Key words: ring opening, tandem reactions, heterocycles, regio-
selectivity, aldol reactions
Michael addition products. In this letter, we wish to report
that cyclopropanecarbaldehydes can be activated by (S)-
proline to trigger an effective homoconjugate nucleo-
philic ring opening with benzenethiols. In the same way,
Cyclopropane-containing derivatives enjoy increasing using o-thiosalicylaldehydes as the nucleophile, the proto-
utilities in synthetic chemistry because of two main facts.1 col constitutes an unprecedented tandem homoconjugate
One is that the rapid development of carbene chemistry addition–aldol reaction affording benzo[b]thiepines,
has rendered cyclopropane derivatives easily accessible, which are of considerable biological significances.13
and the other is that the cyclopropane ring resembles a
In the domain of organocatalysis, secondary amines have
C=C double bond in many aspects to qualify it as a func-
been widely employed as iminium catalysts.10b For exam-
tional carbon group. Especially, the ring opening has been
ple, (S)-proline, being an inexpensive and nontoxic natu-
proved to be a very useful route to the myriad of function-
ral amino acid that is safe for use, has been found to
alized carbon skeletons.1g,2 The ring opening mostly relies
perform well in a number of transformations.10e We envi-
on activation with additional functional groups, and the
sioned that the formation of an iminium ion of the alde-
activations can be categorized into two classes.3 The first
hyde group in cyclopropanecarbaldehydes may render the
class includes the reactions of donor–acceptor cyclopro-
three-membered ring far more electrophilic to be attacked
panes.1f The second class features electrophilic reaction of
by a nucleophile and result in the formation of 1,4-difunc-
cyclopropanes, which are usually activated by cation-
tional compounds.
stabilizing groups or attached electron-withdrawing
We elected initially to treat 2-phenylcyclopropane-carb-
groups. Within the latter context, the most widely investi-
aldehyde (1a) with benzenethiol (2a) along with a second-
gated substrates have been those activated by two gem-
ary amine as the catalyst (Scheme 1). The required
substituted electron-accepting groups, for example, 1,1-
starting aldehyde 1a was easily prepared from ethyl cin-
cyclopropane dicarboxylic acid esters.4–6 In general, the
cyclopropane ring has to be further activated to achieve a
successful nucleophilic-induced ring opening. The well-
established methods employ a Lewis acid such as
Ni(ClO4)2·6H2O,3 BF3·OEt2,7 SnCl4,8 TMSOTf.9
–
namate by cyclopropanation using DMSY (Me2SO+CH2 )
in DMSO on the double bond followed by reduction with
LAH and oxidation with PCC in CH2Cl2.
A set of different reaction conditions including varying
solvents and acid additives was tested with emphasis on
the screening of amine catalyst. Several representative re-
sults are shown in Table 1. The reactions were performed
at room temperature with 1 mmol of 1a and 1.2 equiva-
lents of 2a in the presence of an amine catalyst along with
a small amount of 4 Å MS. To our delight, the use of 20
mol% of pyrrolidine 3a in combination of a stoichiomeric
amount of 2-nitrobenzoic acid could effectivelly promote
the expected homoconjugate addition with exclusive regio-
selectivity. After stirring for three days in toluene, the
reaction reached a maximal conversion (TLC) and the ad-
duct 4-phenyl-4-(phenylthio)butyraldehyde (4a) was iso-
lated in a low yield (Table 1, entry 1). We then turned to
the use of (S)-proline (3b) as the catalyst without additive,
As evidenced by an explosive growth in the number of
publications in recent years, organocatalysis has become
a rapidly evolving field.10 The use of organocatalytic
transformations implies a connotation of ecologically be-
nign and green chemistry. Numerous organocatalysts
have been developed to prompt a broad range of reactions,
some of which are either difficult to proceed or require ex-
pensive and toxic metal previously.
SYNLETT 2009, No. 11, pp 1830–1834
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217370; Art ID: W00809ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Tandem Synthesis of Benzo[b]thiepines
1831
R2
but with an increased dosage (40 mol%) in CH2Cl2 as the
solvent. Again, the reaction could also proceed to furnish
a slightly higher yield of 4a (Table 1, entry 2). Consider-
ing the poor solubility of 3b in CH2Cl2, the reaction medi-
um was switched to THF. The reaction could occur under
the catalyst of 20 mol% of 3b to afford 4a, but still in a
low yield (Table 1, entry 3). Increasing the amount of 3b
to 40 mol% could improve the yields (Table 1, entries 4
and 5). Further increase in the amount of the employed
catalyst 3b did not show beneficial efffects on improving
the yield. In addition, we found that addition of 4 Å MS
was also a vital point to promote this thia-homoconjugate
addition (Table 1, entry 7). Unexpectedly, when (S)-
diphenyl(pyrrolidin-2-yl)methanol (3c) was employed as
the catalyst, the reaction did not occur at all, and with (S)-
2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine (3d) as
the catalyst, the target compound could not be detected af-
ter stirring for three days (Table 1, entries 8 and 9). Thus,
the opmimized conditions were defined to be 40 mol% 3b
as catalyst in THF at room temperature with the addition
of 4 Å MS.
O
SH
5
–
CO2
N+
O
R1
R1
I
1
CO2H
N
O
R2
CO2H
H2O
N
II
R1
H
3b
S
–
CO2
N+
OH
R2
O
OH
R2
S
O
R1
III
R2
S
R1
With optimized conditions in hand, we next explored the
scope and generality of the protocol (Table 2). A range of
2-phenylcyclopropanecarbaldehydes 1 and benzenethiols
2 bearing different substituent at the para position on both
of the phenyl rings were investigated, respectively.14 As
indicated in Table 2, the reactions were applicable to a
wide variety of combinations of 1 and 2 (Table 2, entries
1–12). Both electron-donating groups and electron-
accepting groups can be tolerated. The results revealed
that an electron-withdrawing substituent, such as fluorine
atom, residing either on the phenyl ring of 1 or 2 or both
could appreciably facilitate the reaction. For instance, the
use of 1b carrying a strong electron-donating group pro-
vided generally lower yields than the use of 2-(4-fluo-
rophenyl)cyclopropanecarbaldehyde (1c,Table 2, entries
5–8 vs. 9–12, respectively). However, the substituent ef-
fects of benzenethiols 2 seemed to be less pronounced
than that of 1. In the pairing of 1c with 2d, where both sub-
strates bear a fluorine substituent, the reaction afforded
the highest yield of the homoconjugate addition product 4l
(Table 2, entry 12). We next became interested in exam-
ining the role of phenyl substituent in cyclopropane-
carbaldehydes 1. As shown in Table 2, although
cyclopropanecarbaldehyde 1d could also be employed to
produce the corresponding 4-phenylthio-substituted bu-
tyraldehydes 4, the yields were generally lower than the
phenyl-substituted analogues 1a–c (Table 2, entries 13–
16). In addition, when aliphatic thiols such as ethanethiol
were used as the nucleophilic reagents, the reaction only
delivered the trivial dithioacetals.
IV
S
R1
6
Scheme 1 The plausible mechanism of the tandem reaction
Table 1 Screening for the Optimal Reaction Conditions
O
O
SH
catalyst 3, additive,
4 Å MS, solvent
+
S
r.t., 3 d
1a
2a
4a
Ph
Ph
OH
Ph
Ph
OTMS
CO2H
N
N
N
N
H
H
H
H
3a
3b
3c
3d
Entry Cat. (equiv)Additive
Solvent
Time Yield
(d)
(%)a
25
27
28
45
55
50
0
1
2
3
4
5
6
7b
8
9
3a (0.2)
3b (0.4)
3b (0.2)
3b (0.4)
3b (0.4)
3b (0.8)
3b (0.4)
3c (0.2)
3d (0.2)
2-nitrobenzoic acid
toluene
CH2Cl2
THF
3
none
none
none
none
none
none
3
3
THF
2
THF
3
THF
3
THF
3
To further expand the scope of the proline-catalyzed
homoconjugate addition protocol, the reaction of 1 with o-
thiosalicylaldehydes 5 were investigated (Table 3).15
Recently, organocatalytic tandem Michael–aldol reaction
has been reported by two pioneer research groups, provid-
ing catalytic asymmetric synthesis of thiochromenes.16
Our work was directed to develop a tandem homoconju-
4-chlorobenzoic acid toluene
benzoic acid toluene
3
0
3
n.d.c
a Isolated by chromatography.
b Without addition of 4 Å MS.
c Not detected.
Synlett 2009, No. 11, 1830–1834 © Thieme Stuttgart · New York

1832
L. Li et al.
LETTER
Table 3 Tandem Reaction Leading to Benzo[b]thiepines
Table 2 Ring Opening of Cyclopropanes 1 by Nucleophilic Addi-
tion Using Benzenethiols 2
HS
O
R1
R2
O
3b, 4 Å MS
+
SH
R1
R2
THF, r.t., 3 d
R1
CHO
(S)-proline
S
R1
O
4 Å MS, THF
S
1
5
6
+
r.t., 3 d
CHO
Entry R1
1
R2
H
5
Product Yield (%)a
R2
R2
1
2
4
1
2
Ph
Ph
Ph
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
5a
5b
5c
5a
5b
5c
5a
5b
5c
5a
5b
6a
6b
6c
6d
6e
6f
40
35
45
41
56
40
50
44
34
39
37
Entry R1
1
R2
2
Product Yield
(%)a
Me
Cl
H
3
1
2
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
H
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
4a
4b
4c
4d
4e
4f
55
26
39
53
41
40
33
43
57
47
43
61
43
15
29
35
4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
4-FC6H4
H
Me
Cl
F
5
Me
Cl
H
3
6
4
7
6g
6h
6i
5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
H
H
8
Me
Cl
H
6
Me
Cl
F
9
7
4g
4h
4i
10
11
6j
8
H
Me
6k
9
H
a Isolated yield by chromatography.
10
11
12
13
14
15
16
Me
Cl
F
4j
of III produces the hydroxy aldehyde with regeneration of
the catalyst 3b. Then elimination of water occurs with as-
sistance of the added MS, furnishing the isolated 2,3-dihy-
drobenzo[b]thiepine-4-carbaldehydes 6. Perhaps because
the chiral center in intermediate I is too far away from the
initial reaction position of 1, no chiral induction has been
obtained in the present protocol.18
4k
4l
H
4m
4n
4o
4p
H
Me
Cl
F
H
The structure of 6 was unambiguously confirmed by an X-
ray crystal diffraction analysis for 2-(4-methoxyphenyl)-
7-methyl-2,3-dihydrobenzo[b]thiepine-4-carbaldehyde
(6e, Figure 1).19
H
a Isolated yield by chromatography.
gate addition–aldol sequence to provide an attractive
route to benzo[b]thiepines 6, which are of considerable
current biological significance.13 To our delight, the reac-
tion took place effectively and regioselectively to furnish
the expected 2,3-dihydrobenzo[b]thiepine-4-carbalde-
hydes 6 in fair to moderate yields (Table 3). In compari-
son to other ways for construction of such fused
heterocyclic core,13 this organocatalyzed domino method
is very straightforward, and the conditions avoid use of
any expensive reagents.17 A catalytic cycle to account for
the formation of 6 is postulated in Scheme 1.
The cyclopaopanecarboxaldehyde 1 reacts with (S)-pro-
line to form an iminium zwitterion I with loss of water,
whereby the carbonyl group is suitably activated. Nucleo-
philic attack at the C-2 position of the cyclopropane ring
results in the formation of ring-opened enamine interme-
diate II by the mercapto group of o-thiosalicylaldehyde.
Next, the enamine II undergoes an intramolecular 7-exo-
trig nucleophilic attack on the benzaldehyde moiety, lead-
ing to the initial hydroxyl iminium adduct III. Hydrolysis
Figure 1 ORTEP picture of compound 6e
Finally, the enantiomerically enriched cyclopropanealde-
hyde 1e was prepared according to a known procedure in
92% ee.20 The reaction of 1e with 5a as well as 5b was
performed under the similar conditions (Scheme 2). To
our delight, the reaction proceeded well to provide the op-
Synlett 2009, No. 11, 1830–1834 © Thieme Stuttgart · New York

LETTER
Tandem Synthesis of Benzo[b]thiepines
1833
(5) For the reaction of cyclopropane-1,1-dicarboxylic acid
diethyl ester with phenyl mercaptan to give homoconjugate
product (2-phenylsulfanyl-ethyl)-malonic acid diethyl ester,
see: Stewart, J. M.; Westberg, H. H. J. Org. Chem. 1965, 30,
1951.
(6) The homoconjugate addition reactions of activated
cyclopropane derivatives using b-keto esters as nucleophiles
have to be performed under catalysis of ytterbium(III)
trifluoromethanesulfonate at high pressures. See: Kotsuki,
H.; Arimura, K.; Maruzawa, R.; Ohshima, R. Synlett 1999,
650.
(7) Srinivasulu, M.; Reddy, V. L. N.; Reddy, S. M.; Ravikanth,
V.; Raju, T. V.; Ramakrishna, S.; Venkateswarlu, Y. Helv.
Chim. Acta 2005, 88, 2527.
(8) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709.
(9) Shi, M.; Tang, X.-Y.; Yang, Y.-H. J. Org. Chem. 2008, 73,
5311.
tically active benzo[b]thiepines (2R)-6k (88% ee) and, re-
spectively, (2R)-6l (81% ee).16,20 Mechanistically, the ring
opening step may be viewed as an SN2-type attack of the
mercapto group on the electrophilic 2R-carbon in 1e.
Thus, the chiral carbon is assumed to undergo inversion of
configuration, leading to the formation of 2R-configured
products 6.
O
O
R2
R2
3b, 4 Å MS
+
Ph
CHO
THF, r.t., 3 d
H
SH
S
Ph
H
5
(1R,2R)-1e
(2R)-6
92% ee
6k R2 = H 44%, 88% ee
6l R2 = Me 40%, 81% ee
(10) For recent reviews on organocatalysis, see: (a) Barbas, C. F.
III. Angew. Chem. Int. Ed. 2008, 47, 42. (b) List, B. Chem.
Rev. 2007, 107, 5413. (c) Erkkilä, A.; Majander, I.; Pihko,
P. M. Chem. Rev. 2007, 107, 5416. (d) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471. (e) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed.
2008, 47, 4638. (f) Dalko, P. I.; Moisan, L. Angew. Chem.
Int. Ed. 2004, 43, 5138. (g) Dalko, P. I.; Moisan, L. Angew.
Chem. Int. Ed. 2001, 40, 3726. (h) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007.
(11) For additional examples, see (a) Halland, N.; Hansen, T.;
Jøgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 4955.
(b) Prieto, A.; Halland, N.; Jøgensen, K. A. Org. Lett. 2005,
7, 3897. (c) Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V.
Chem. Commun. 2006, 66. (d) Deng, K.; Bensari-
Bouguerra, A.; Whetstone, J.; Cohen, T. J. Org. Chem. 2006,
71, 2360. (e) Dinér, P.; Nielsen, M.; Marigo, M.; Jøgensen,
K. A. Angew. Chem. Int. Ed. 2007, 46, 1983.
Scheme 2 Tandem reaction using (1R,2R)-2-phenylcyclopropane-
carbaldehyde 1e as substrate
In summary, we have presented the first proline-catalyzed
ring opening of cyclopropanecarbaldehydes by nucleo-
philic attack of benzenethiols. Using o-thiosalicylalde-
hydes as the nucleophiles, the protocol constitutes a novel
organocatalyzed homoconjugate addition–aldol domino
reaction. The reaction proceeds with complete regioselec-
tivity to furnish the biologically intetresting benzo[b]thi-
epines in moderate yields.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(12) Nucpeophilic ring opening of cyclopropyl ketones by
thiophenoxide anion has been known by Anand. See: Anand,
R. C.; Ranjan, H. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1985, 24, 673.
Acknowledgment
We thank Dr. Yue Zou for helpful discussions, and Mr. Peng Li for
performing the X-ray crystal structure analysis.
(13) For example, benzothiepine derivatives have been reported
to show activity as apical sodium-codependent bile acid
transporter for use in the treatment of hyperlipidemic
conditions and CCR5 antagonists as anti-HIV-1 agents.
See: (a) Tremont, S. J.; Lee, L. F.; Huang, H.-C.; Keller,
B. T.; Banerjee, S. C.; Both, S. R.; Carpenter, A. J.; Wang,
C.-C.; G arland, D. J.; Huang, W.; Jones, C.; Koeller, K. J.;
Kolodziej, S. A.; Li, J.; Manning, R. E.; Mahoney, M. W.;
Miller, R. E.; Mischke, D. A.; Rath, N. P.; Fletcher, T.;
Reinhard, E. J.; Tollefson, M. B.; Vernier, W. F.; Wagner,
G. M.; Rapp, S. R.; Beaudry, J.; Glenn, K.; Regina, K.;
Schuh, J. R.; Smith, M. E.; Trivedi, J. S.; Reitz, D. B. J. Med.
Chem. 2005, 48, 5837. (b) Seto, M.; Aramaki, Y.; Okawa,
T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.;
Iizawa, Y.; Baba, M.; Shiraishi, M. Chem. Pharm. Bull.
2004, 52, 577. (c) IkemotoT, ; Ito, T.; Nishiguchi, A.;
Tomimatsu, K. Tetrahedron 2004, 48, 10851.
References and Notes
(1) For reviews, see: (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-
W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989,
89, 165. (b) de Meijere, A.; Kozhushkov, S. I.; Khlebnikov,
A. F. Top. Curr. Chem. 2000, 207, 89. (c) Herndon, J. W.
Top. Curr. Chem. 2003, 7, 329. (d) Reissig, H.-U.; Zimmer,
R. Chem. Rev. 2003, 103, 1151. (e) Gnad, F.; Reiser, O.
Chem. Rev. 2003, 103, 1603. (f) Yu, M.; Pagenkopf, B. L.
Tetrahedron 2005, 61, 321. (g) Kulinkovich, O. G. Russ.
Chem. Rev. 1993, 62, 839.
(2) For recent examples, see (a) Lautens, M.; Ren, Y. J. Am.
Chem. Soc. 1996, 118, 9597. (b) Alper, P. B.; Meyers, C.;
Lerchner, A.; Siegel, D. R.; Carreira, E. M. Angew. Chem.
Int. Ed. 1999, 38, 3186. (c) Bertozzi, F.; Gustafsson, M.;
Olsson, R. Org. Lett. 2002, 4, 4333. (d) Lautens, M.; Han,
W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028.
(e) Rigo, B.; Gautret, P. Tetrahedron Lett. 2006, 47, 295.
(f) Huang, X.; Fu, W.; Miao, M. Tetrahedron Lett. 2008, 49,
2359.
(14) General Procedure for the Ring Opening of
Cyclopropanecarbaldehydes 1 by Nucleophilic Attack
with Benzenethiols 2
A mixture of cyclopropanecarbaldehyde 1 (1 mmol),
benzenethiol 2 (1.2 mmol), (S)-proline (46 mg, 0.4 mmol),
and 4 Å MS (500 mg) in THF (2 mL) was stirred at r.t. for 3
d, then H2O (5 mL) was added to quench the reaction. The
aqueous phase was extracted with Et2O (100 mL), and the
organic phase was dried over Na2SO4, filtrated, and
concentrated. The residue was purified by column
(3) Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809.
(4) For use in an annulation of 3-alkylindoles with 1,1-cyclo-
propanediesters, see: (a) Harrington, P.; Kerr, M. A.
Tetrahedron Lett. 1997, 38, 5949. (b) Kerr, M. A.; Keddy,
R. G. Tetrahedron Lett. 1999, 40, 5671.
Synlett 2009, No. 11, 1830–1834 © Thieme Stuttgart · New York

1834
L. Li et al.
LETTER
141.8, 137.5, 136.0, 135.2, 134.7, 134.5, 132.9, 130.9,
128.0, 114.2, 55.4, 52.6, 37.3, 21.0. ESI-HRMS: m/z calcd
for C19H18O2S: 310.1028; found: 310.1031.
chromatography (silica gel, PE–EtOAc) to afford 4a–p as
pale yellow oil. All new compounds have been isolated in
pure form and characterized by spectral data (1H NMR,
13C NMR, and MS).
(16) For remarkable examples, see: (a) Rios, R.; Sunden, H.;
Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Cordova, A.
Tetrahedron Lett. 2006, 47, 8547. (b) Wang, W.; Li, H.;
Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354.
(c) Ibrahem, I.; Sunden, H.; Rios, R.; Zhao, G.-L.; Cordova,
A. Chimia 2007, 61, 219.
(17) For comparision, we also conducted the tandem reaction
with the ‘best’ substrate 1c under Anand’s condition (ref.
12). After refuxing in EtOH for 3 h, the reaction afforded a
mixture of products, from which 6g was isolated in 13%
yield.
(18) Enantiomeric excess was determined chromatographically
as follows: Diacel CHIRALPAK AS-H, hexane–2-PrOH
(80:20), flow rate 0.6 mL/min, l = 254 nm.
(19) A single crystal of 6e suitable for X-ray diffraction analysis
was obtained by recrystallization from CH2Cl2–n-hexane.
Crystallographic data have been deposited with the
Cambridge Crystallographic Data Center as supplementary
publication number CCDC 726088.
Selected Data for Compounds 4
Compound 4a: yield 55%. 1H NMR (400 MHz, CDCl3):
d = 9.66 (1 H, s, CHO), 7.30–7.18 (10 H, m, ArH), 4.16 (1
H, dd, J = 6.9, 8.3 Hz, SCH), 2.48 (2 H, t, J = 7.3 Hz,
COCH2), 2.30–2.15 (2 H, m, H-3). 13C NMR (125 MHz,
CDCl3): d = 201.1, 141.0, 134.3, 132.4, 128.7, 128.5, 127.7,
127.4, 127.2, 52.6, 41.7, 28.5. GC-MS (EI): m/z = 256.1
[M]+.
(15) Typical procedure for the tandem synthesis of benzo[b]-
thiepines 6 was operated as described in ref. 14, except for
replacing benzenethiols 2 with o-salicylaldehydes 5. The
reaction gave 6 as off-white crystal solids. All new
compounds have been isolated in pure form and charac-
terized by spectral data (1H NMR, 13C NMR, and MS).
Selected Data for Compounds 6
Compound 6e: yield 56%; mp 120–121 °C. 1H NMR (400
MHz, CDCl3): d = 9.62 (1 H, s, CHO), 7.40–6.84 (8 H, m,
ArH, and CH=C), 4.26 (1 H, dd, J = 3.2, 11.4 Hz, SCH),
3.79 (3 H, s, OCH3), 3.26–3.02 (2 H, m, CH2), 2.37 (3 H, s,
CH3). 13C NMR (100 MHz, CDCl3): d = 194.9, 159.0, 150.4,
(20) Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985,
107, 8254.
Synlett 2009, No. 11, 1830–1834 © Thieme Stuttgart · New York