Concise assembly of highly substituted furan-fused 1,4-thiazepines and their Diels-Alder reactions with benzynes

Article abstract of DOI:10.1021/jo702299m

(Chemical Equation Presented) A facile and highly efficient three-component reaction of thiazole or benzothiazole carbenes, disubstituted ketenes, and activated alkynes is disclosed. With this methodology, a poly substituted ring system containing furo[2,3-c]thiazepine core can be constructed from simple and readily accessible starting materials in good yields. The scope and limitation of this transformation were investigated in detail by using various thiazole carbene, ketene, and alkyne components. Furthermore, the synthetic utilities of these unique polyheterocyclic compounds were demonstrated via their Diels-Alder reactions with benzynes to furnish thiazepine-fused 7-oxanorbornadiene derivatives in excellent yields.

Full text of DOI:10.1021/jo702299m

Concise Assembly of Highly Substituted Furan-Fused
1,4-Thiazepines and Their Diels-Alder Reactions with Benzynes
Hanfeng Ding, Yiping Zhang, Ming Bian, Weijun Yao, and Cheng Ma*
Department of Chemistry, Zhejiang UniVersity, Hangzhou, 310027, China
mcorg@zju.edu.cn
ReceiVed October 24, 2007
A facile and highly efficient three-component reaction of thiazole or benzothiazole carbenes, disubstituted
ketenes, and activated alkynes is disclosed. With this methodology, a polysubstituted ring system containing
furo[2,3-c]thiazepine core can be constructed from simple and readily accessible starting materials in
good yields. The scope and limitation of this transformation were investigated in detail by using various
thiazole carbene, ketene, and alkyne components. Furthermore, the synthetic utilities of these unique
polyheterocyclic compounds were demonstrated via their Diels-Alder reactions with benzynes to furnish
thiazepine-fused 7-oxanorbornadiene derivatives in excellent yields.
SCHEME 1. Synthesis of Polysubstituted Furan-Fused
1,4-Thiazepine Derivatives
Introduction
The aryl- and heteroaryl-fused 1,4-thiazepines1 are an im-
portant group of compounds with interesting pharmacological
properties,2 such as antiarrhythmic, antispasmodic, angiogenic,
and CNS activities,3 and therefore represent promising synthetic
targets. The development of efficient synthetic strategies to the
* To whom correspondence should be addressed. Phone: +86-571-87953375.
Fax: +86-571-87953375.
(1) (a) Skiles, J. W.; Suh, J. T.; Williams, B. E.; Menard, P. R.; Barton,
J. N.; Love, B.; Jones, H.; Neiss, E. S.; Schwab, A.; Mann, W. S. J. Med.
Chem. 1986, 29, 784. (b) Umemiya, H.; Fukasawa, H.; Ebisawa, M.;
Eyrolles, L.; Kawachi, E.; Eisenmann, G.; Gronemeyer, H.; Hashimoto,
Y.; Shudo, K.; Kagechika, H. J. Med. Chem. 1997, 40, 4222. (c) Venkatesan,
A. M.; Gu, Y.; Dos Santos, O.; Abe, T.; Agarwal, A.; Yang, Y.; Petersen,
P. J.; Weiss, W. J.; Mansour, T. S.; Nukaga, M.; Hujer, A. M.; Bonomo,
R. A.; Knox, J. R. J. Med. Chem. 2004, 47, 6556.
(2) (a) Malli, R.; Frieden, M.; Trenker, M.; Graier, W. F. J. Biol. Chem.
2005, 280, 12114. (b) Neamati, N.; Turpin, J. A.; Winslow, H. E.;
Christensen, J. L.; Williamson, K.; Orr, A.; Rice, W. G.; Pommier, Y.;
Garofalo, A.; Brizzi, A.; Campiani, G. J. Med. Chem. 1999, 42, 3334. (c)
Maruenda, H.; Johnson, F. J. Med. Chem. 1995, 38, 2145.
(3) (a) Crescenza, A.; Botta, M.; Corelli, F.; Santini, A.; Tafi, A. J. Org.
Chem. 1999, 64, 3019. (b) Ilyn, A. P.; Loseva, M. V.; Vvedensky, V. Y.;
Putsykina, E. B.; Tkachenko, S. E.; Kravchenko, D. V.; Khvat, A. V.;
Krasavin, M. Y.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71, 2811. (c)
Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003, 68,
644.
related scaffolds may provide a valuable access to novel
physiologically active agents. On the other hand, polysubstituted
furan has been found as a key structural unit in many bioactive
natural products and pharmaceuticals,4 accordingly, various
annulated derivatives such as benzo-, thieno-, isoxazolo-, furo-,
pyridino-, pyridazino-, and indolofurans have been synthesized
and their properties investigated.5 However, to the best of our
knowledge, the furan-fused 1,4-thiazepine that combines furan
and thiazepine fragments in one molecule has scarcely been
demonstrated previously.
On the basis of the nucleophilicity of thiazole carbenes,6,7 in
a preliminary communication, we described a highly efficient
multicomponent domino synthesis of furo[2,3-c]thiazepine
(4) For reviews, see: (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b)
Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S.
Y. T.; Wong, H. N. C. Tetrahedron 1998, 54, 1955. (c) Kirsch, S. F. Org.
Biomol. Chem. 2006, 4, 2076. (d) Beay, B. A. Chem. Soc. ReV. 1999, 28,
209. (e) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (f) Brown, R. C.
D. Angew. Chem., Int. Ed. 2005, 44, 850.
(5) (a) Friedrichsen, W. In AdVances in Heterocyclic Chemistry; Katritz-
ky, A. R., Ed.; Academic Press: New York, 1999; Vol. 73, pp 1-96. (b)
For a recent report on furoquinolines synthesis by the multicomponent
domino process, see: Fayol, A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41,
3633.
10.1021/jo702299m CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/13/2007
578
J. Org. Chem. 2008, 73, 578-584

Assembly of Furan-Fused 1,4-Thiazepines
TABLE 1. Effects of Reaction Conditionsa
TABLE 2. Reactions of Thiazolium Salt 1a, Acetyl Chlorides 2,
and DMAD for the Synthesis of Furan-Fused 1,4-Thiazepines 3a-r
entry
base
i-Pr2NEt
i-Pr2NEt
solvent
T (°C)
t (h)b yield (%)c
entry
R1
R2
2
t (h)a
yield of 3 (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
-20 to 25
-78 to 25
-78 to 25
-78 to 25
-78 to 25
-78 to 25
-78 to 0
8
4
7
4
7
8
3
8
8
8
9
4
64
83
62
67e
25
<5d
<5
<5
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
4
5.5
7
9.5
8
3a, 83
3b, 85
3c, 84
3d, 59
3e, 74
3f, 72
3g, 81
3h, 77
3i, 83
3j, 28
3k, 91
3l, Ndc
3m, 76
3n, 84
3o, 88
3p, 81
3q, 85
i-Pr2NEt + NaHd CH2Cl2
4-MeOC6H4
4-MeC6H4
1-naphthyl
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-BrC6H4
3-ClC6H4
4-NO2C6H4
Ph
NaH
NEt3
DBU
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
CH3CN -40 to 25
DME
7
3.5
4.5
7
17
2.5
6
4
7
7
6
-78 to 25
-25 to 25
10
11
12f
45
0
84
-65 to 25
-78 to 25
CH2Cl2
i-Pr
Ph
Me
Me
4-ClC6H4
Ph
a General conditions: 1a (1.0 mmol), 2a (1.2 mmol), DMAD (1.5 mmol),
and base (2.5 mmol). b Reaction time for consuming all of the starting
materials. c Isolated yields. d i-Pr2NEt (1.2 mmol), NaH (1.3 mmol). e NaH
(1.2 mmol), phenyl(methyl)ketene was used instead of 2a. f Reaction
conditions: 1a (2.5 mmol), 2a (1.0 mmol), DMAD (2.5 mmol), and i-Pr2NEt
(4.0 mmol).
Me
Et
-(CH2)4-
-(CH2)5-
7
a Reaction time for consuming all of the starting materials. b Isolated
yields. c No product was detected.
TABLE 3. Formations of Products 3s-z by the Reactions of
Thiazolium Salts 1b-g, Acetyl Chloride 2, and DMAD
FIGURE 1. Structures of compounds 4a and 4b.
derivatives (3) from thiazolium salts (1), disubstituted ketenes
(2), and activated alkynes (Scheme 1).8 It is noteworthy that,
contrary to the typical reactivity of ketene,9-11 both of the double
bonds (CdC and CdO) in disubstituted ketene are used in the
assembly of the polysubstituted bicyclic compound 3. Although
this approach performed with high efficiency in constructing
the furo[2,3-c]thiazepine core, the implications from the ex-
entry
R1
R2
1
2
t (h)a
yield of 3 (%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Bn
Et
Bu
Bn
Me
Me
Me
Me
Me
H
1b
1b
1b
1c
1d
1e
1f
2a
2c
2e
2k
2c
2k
2k
2k
5.5
5
7
6
7
4.5
3
7
3s, 78
3t, 80
3u, 74
3v, 84
3w, 78
3x, 86
3y, 81
3z, 71
(6) For recent reviews of the reactions of N-heterocyclic carbenes, see:
(a) Cheng, Y.; Meth-Cohn, O. Chem. ReV. 2004, 104, 2507. (b) Nair, V.;
Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130. (c) Nair,
V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (d) Marion, N.; D´ıez-Gonza´lez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
(7) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) Breslow, R.;
Schmuck, C. Tetrahedron Lett. 1996, 37, 8241. (c) Lemal, D. M.; Lovaid,
R. A.; Kawano, K. I. J. Am. Chem. Soc. 1964, 86, 2518. (d) Castells, J.;
Lo´pez Calahorra, F.; Domingo, L. J. Org. Chem. 1988, 53, 4433. (e) Ma,
C.; Ding, H.; Wu, G.; Yang, Y. J. Org. Chem. 2005, 70, 8919. (f) Ma, C.;
Yang, Y. Org. Lett. 2005, 7, 1343.
(8) Ma, C.; Ding, H.; Zhang, Y.; Bian, M. Angew. Chem., Int. Ed. 2006,
45, 7793.
(9) For reviews, see: (a) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(b) Tidwell, T. T. Ketenes; John Wiley & Sons: New York, 1995. (c) Hyatt,
J.; Raynolds, R. W. Org. React. 1994, 45, 159. (d) Snider, B. E. Chem.
ReV. 1988, 88, 793.
H
H
AcO(CH2)2-
1g
a Reaction time for consuming all of the starting materials. b Isolated
yields.
perimental results are not fully apparent. Moreover, the scope
and limitation of this reaction such as the structures of each
component as well as the synthetic utilities of the unique bicyclic
product 3 clearly warranted further research. Herein, we report
the results of our detailed investigations on the multicomponent
reaction involving thiazole carbenes, ketenes, and activated
alkynes for the convergent synthesis of highly substituted furan-
fused 1,4-thiazepines and their Diels-Alder reactions with
benzynes resulting in 7-oxanorbornadienes derivatives.12
(10) For the cycloaddition through the CdO bond, see: (a) England, D.
C.; Krespan, C. G. J. Am. Chem. Soc. 1965, 87, 4019. (b) DoMinh, T.;
Strautz, O. P. J. Am. Chem. Soc. 1970, 92, 1766. (c) Yamabe, S.; Dai, T.;
Minato, T.; Machiguchi, T.; Hasegawa, T. J. Am. Chem. Soc. 1996, 118,
6518. (d) Machiguchi, T.; Okamoto, J.; Morita, Y.; Hasegawa, T.; Yamabe,
S.; Minato, T. J. Am. Chem. Soc. 2006, 128, 44.
Results and Discussion
(11) For our recent reports on the reactions of ketene, see: (a) Ding, H.;
Ma, C.; Yang, Y.; Wang, Y. Org. Lett. 2005, 7, 2125. (b) Ma, C.; Ding,
H.; Wang, Y. Org. Lett. 2006, 8, 3133.
The three-component reaction was carried out by dropping
the mixture of R-methyl phenylacetyl chloride (2a) and dimethyl
J. Org. Chem, Vol. 73, No. 2, 2008 579

Ding et al.
TABLE 4. Reactions of Thiazolium Salt 1a, 2, and Activated
NEt3 as the base, the yield of compound 3a decreased dramati-
cally due to the formation of dimethyl-(E)-2-diethylami-
nobutenoate 4a (61% yield, Figure 1) arising from the addition
of NEt3 onto DMAD (entry 5).13 The survey of solvents
demonstrated that CH2Cl2 was the choice of solvent, whereas
THF, toluene, CH3CN, or DME decreased the reaction efficiency
and resulted in poor yield of 3a (entries 2, 8-11). Furthermore,
it was observed that the temperature has a vital effect on this
reaction; only a trace amount of product was obtained when
the reaction temperature was maintained below 0 °C (entry 7).
Attempts to improve the transformation by using excess amounts
of 1a and DMAD were unsuccessful; a roughly equal yield of
3a was accessed aligned with a byproduct of 4b (comparing
entry 2 with entry 12).
Under the optimized reaction conditions, a variety of disub-
stituted acetyl chlorides 2 were submitted to the reaction with
thiazolium salt 1a and DMAD (Table 2). From R-methyl
arylacetyl chlorides 2a-k, the corresponding products 3a-k
were formed in good to excellent yields. Nevertheless, the
substrates with an electron-rich aromatic group (entries 2 and
3) performed better than their electron-poor counterparts (entries
5-9); especially in the case of R-methyl 4-nitrophenylacetyl
chloride 2j, the reaction was significantly sluggish and led to a
disappointing yield of the product 3j under the same conditions
(entry 10). The size of alkyl substitutes enclosed in R-alkyl
arylacetyl chlorides also played important roles in the tandem
reaction. The ethyl-substituted substrate 2k completed the
conversion within 2.5 h to produce 3k in a higher yield of 91%
than that of 2a, whereas the compound 2l bearing a bulky
isopropyl group did not undergo the similar reaction (comparing
entries 1, 11, and 12). One explanation for these results is that
the increased bulk may assist the ring-expansion step, but a very
crowded substitutent (e.g., isopropyl) inhibited the initial
formation of a spirocycle intermediate.14 Next, the transforma-
tions of dialkyl acetyl chlorides 2n-q were exploited under
the same conditions leading to the synthesis of furo[2,3-c]-
thiazepines 3n-q in 81-88% yields (entries 14-17). To our
delight, the tricyclic products 3p and 3q of more skeletal
complexity were easily and high efficiently constructed from
simple substrates.15
Alkynes 5a-e
entry
R1
Ph
Et
-(CH2)5-
R2
Ph
Ph
R
5
methoda
yield of 6 (%)b
1
2
3
4
OEt
5a
5a
5a
5b
A
A
A
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
6a, 78
6b, 83
6c, 81
6d, <5
6d, 81
6e, <5
6e, 83
6f, <5
6f, 87
6g, <5
6g, 85
6h, <5
6h, 38
6i, <5
6i, 32
6j, 55
6j, 46
6k, 58
6k, <5
6l, 62
6l, 26
6m, 46
6m, 18
OEt
OEt
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
6
Ph
Ph
Ph
Et
4-MePh
4-BrPh
t-Bu
5c
5d
5e
5d
5d
5d
5d
5c
5e
7
8
4-BrPh
4-BrPh
4-BrPh
4-BrPh
4-MePh
t-Bu
9
Me
10
11
12
13
-(CH2)5-
Me
Me
Et
Me
Me
Et
a Method A: 1a (1.0 mmol), acetyl chloride (1.2 mmol), alkyne (1.5
mmol), and i-Pr2NEt (2.5 mmol). Method B: 1a (1.0 mmol), ketene (1.2
mmol), alkyne (1.5 mmol), and NaH (1.2 mmol), then aqueous workup.
b Isolated yields.
We next turned our attention to test a set of thiazolium salts
1b-g from the commercially available thiazoles under previous
conditions in order to extend the molecular diversity of furo-
[2,3-c]thiazepines (Table 3). As a result, a range of furo[2,3-
c]thiazepines 3s-z with various substituents were obtained in
one step by simply mixing thiazolium salts, disubstituted acetyl
chlorides 2, and DMAD.
Encouraged by these results, the range of activated alkynes
was then probed to get a better insight into the generality of
this reaction (Table 4). In the presence of i-Pr2NEt, diethyl
acetylenedicarboxylate (5a) conducted the reaction smoothly to
provide 6a-c from corresponding substrates (entries 1-3). As
for 4-oxo-2-alkynoates 5b-e, two different experimental pro-
cedures were established for the transformations in the following
studies. The optimized results revealed that both aryl- and tert-
butyl-substituted alkynes 5b-e reacted with 1a and diphe-
FIGURE 2. Structures of compounds 7 and 8.
acetylenedicarboxylate (DMAD) to a suspension of thiazolium
salt 1a in CH2Cl2 in the presence of a base at -78 °C. Thus, a
thiazole carbene and a ketene were assumed to be initially
generated in situ from their corresponding precursors (1a and
2a) by the base, respectively. However, as the activated alkyne
(DMAD) is sensitive to some nucleophiles, the basicity and
nucleophilicity of the base may have critical effects on this
transformation. Accordingly, several typical bases including
NEt3, i-Pr2NEt, DBU, and NaH were investigated for this
reaction. As disclosed in Table 1, i-Pr2NEt proved to be the
optimum base among those tested (entries 1-6). Sodium hydride
afforded the desired product 3a in 67% yield with isolated
phenyl(methyl)ketene instead of 2a (entry 4). In contrast, using
(12) For reviews, see: (a) Kappe, C. O.; Murphree, S. S.; Padwa, A.
Tetrahedron 1997, 53, 14179. (b) Chiu, P.; Lautens, M. Topics in Current
Chemistry; Springer-Verlag: Berlin, Germany, 1997; Vol. 190, pp 1-85.
(c) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999, 55, 13521.
(d) Woo, S.; Keay, B. A. Synthesis 1996, 669. (e) Lautens, M.; Klute, W.;
Tam, W. Chem. ReV. 1996, 96, 49. (f) Lautens, M.; Fagnou, K.; Hiebert,
S. Acc. Chem. Res. 2003, 36, 48.
(13) For the reaction of NEt3 and alkynes in the presence of a proton
source, see: (a) Alaimo, R. J.; Farnum, D. G. Can. J. Chem. 1965, 43,
700. (b) Kandeel, K. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1
1987, 2023.
(14) See the proposed mechanism in Scheme 2.
(15) With dichloro acetyl chloride as the ketene precursor, the desired
product 3r was not detected.
580 J. Org. Chem., Vol. 73, No. 2, 2008

Assembly of Furan-Fused 1,4-Thiazepines
SCHEME 2. Proposed Mechanism
TABLE 5. Reactions of Benzothiazole Carbene, Diphenylketene,
and Activated Alkynesa
nylketene directly to provide 1,4-thiazepines 6d-g exclusively
in good yields via Method B, respectively (entries 4-7). In
contrast, only moderate yields of the target products were
obtained when R1 or R2 involved in the ketene component was
an alkyl group no matter by Method A or Method B (entries
8-13), presumably due to the instability of the related ketenes
and their reactivity toward 4-oxo-2-alkynoate 5 upon treatment
with i-Pr2NEt.16 In addition, when phenyl(ethyl)ketene was
enclosed in the reaction by using Method B, an AB2C-type
byproduct 717 (Figure 2) was isolated in 30% yield along with
the product 6h (entry 8, Table 4), while with phenyl(methyl)-
ketene instead, 3-ethyl-4,5-dimethylthiazole-2-one 8 was isolated
in 54% yield after aqueous workup, which was derived from
the unreacted thiazole carbene (entry 9).18
On the basis of the experimental results, a plausible mech-
anism that accounts for this novel three-component reaction is
devised as shown in Scheme 2. The in situ generated thiazole
carbene A from thiazolium salt 1 initially attacked the disub-
stituted ketene to give zwitterion B, which then underwent an
oxa-Michael addition to the activated alkyne and subsequently
converted into the spirocycle intermediate C through intramo-
lecular annulation. Next, two pathways were proposed for the
ring-transformation of spirocycle C, a concerted (path A) or a
stepwise (path B) pathway. In path A, the ring expansion of C
would proceed to directly afford the furothiazepine E, an
aromatic compound, via a [1,3]-sigmatropic sulfur shift.19 On
the other hand (path B), ring opening of C produced a reactive
thiolate D, which could subsequently undergo a 7-endo-trig
cyclization to produce thiazepine ring E.20
entry
R1
R2
yield of 10 (%)b
1
2
3
4
MeO
Ph
Me
MeO
EtO
EtO
EtO
10a, 56
10b, 65
10c, 58
10d, 52
t-Bu
a General conditions: 9 (1.0 mmol), diphenylketene (1.2 mmol), alkyne
(1.2 mmol), 80 °C for 12 h. b Isolated yields.
FIGURE 3. Structure of compound 11.
the current tentative mechanism, the reactivity of the benzothia-
zole carbene was further investigated for the synthesis of
annulated tricyclic derivatives. To our satisfaction, by using
cyano-benzothiazoline 9 as the precursor of carbene instead of
thiazolium salt 1, the corresponding furan-fused 1,4-benzothi-
azepines 10a-d were successfully formed from diphenylketene,
and activated alkynes in 52-65% yields under thermodynamic
conditions (Table 5). Similar to the previous results for the
thiazolium variant 1a (entry 12, Table 1), accompanied by the
formation of 10a, the byproduct 1122 was isolated in 32% yield
(entry 1, Table 5 and Figure 3).
The unique structure of furan-fused 1,4-thiazepines can be
of some potential synthetic utility, for instance, through Diels-
Alder reaction with arynes to form 1,4-thiazepine-fused 7-ox-
anorbornadienes,23 which may have interesting biological
activities and are also quite useful intermediates in the total
synthesis of natural products and analogues. As shown in Table
6, selected compounds 3, 6, and 10 reacted sufficiently with a
As tricyclic heterocycles, especially those azaheterocycles,
are important scaffolds in medicinal chemistry,21 according to
(16) For the examples in entries 4-9, Table 4, ketene was found to react
with the activated alkyne to form some volatile unidentified products.
(17) The structure of compound 7 was unambiguously confirmed by
single-crystal X-ray diffraction, see the Supporting Information.
(18) Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron 1993,
49, 4859.
(19) For rearrangements in the thizaole system, see: (a) Abbott, P. J.;
Acheson, R. M.; Eisner, U.; Watkin, D. J.; Carruthers, J. R. Chem. Commun.
1975, 155. (b) Potts, K. T.; Choudhury, D. R.; Westby, T. R. J. Org. Chem.
1976, 41, 187.
(20) For similar transformations in the convertion of â-lactamase
inhibitor, see: (a) Micetich, R. G.; Maiti, S. N.; Tanaka, M.; Yamazaki,
T.; Ogawa, K. J. Org. Chem. 1986, 51, 853. (b) Nukaga, M.; Abe, T.;
Venkatesan, A. M.; Mansour, T. S.; Bonomo, R. A.; Knox, J. R.
Biochemistry 2003, 42, 13152.
(21) Baldessarini, R. J. In Goodman and Gilman’s the Pharmacological
Basis of Therapeutics, 10th ed.; Hardman, J. G., Limbird, L. E., Eds.;
McGraw-Hill: New York, 2001; pp 447-483.
(22) The structure of compound 11 was unambiguously confirmed by
single-crystal X-ray diffraction; see the Supporting Information.
(23) For reviews on the Diels-Alder reaction, see: (a) Corey, E. J.
Angew. Chem., Int. Ed. 2002, 41, 1650. (b) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogian-nakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (c) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.
J. Org. Chem, Vol. 73, No. 2, 2008 581

Ding et al.
TABLE 6. Diels-Alder Reactions of Furan-Fused 1,4-Thiazepines
mmol) at -78 °C. After 10-15 min, a solution of acetyl chloride
2 (1.2 mmol) and DMAD (1.5 mmol) in CH2Cl2 (2 mL) was added
dropwise over 10 min and then stirred at this temperature for 30
min. The reaction temperature was raised slowly to room temper-
ature for an additional several hours. On completion of the reaction,
the solvent was removed under vacuum, and the residue was quickly
passed through a short pad of neutral Al2O3 column with a hexane-
ether mixture (5:1) as eluent; the crude obtained was recrystallized
from hexane to afford the desired products 3a-z.
with Benzynesa
entry
substrate
R6
R7
13
yield of 14 (%)b
Furan-fused 1,4-thiazepine 3a: white solid; mp 124-126 °C;
IR (film) V 3005, 2970, 1718, 1710, 1437, 1419, 1345, 1296, 828,
1
2
3
4
5
6
7
8
9
3b
3f
3g
3k
6f
6g
6h
6j
10a
10b
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13b
13c
14a, 95
14b, 93
14c, 96
14d, 95
14e, 95
14f, 95
14g, 94
14h, 95
1
767 cm-1; H NMR (500 MHz, d6-DMSO) δ 7.32 (t, J ) 7.5 Hz,
2H), 7.25 (t, J ) 7.0 Hz, 1H), 7.11 (d, J ) 7.5 Hz, 2H), 3.91 (s,
3H), 3.75 (s, 3H), 3.35-3.22 (m, 2H), 1.98 (s, 3H), 1.88 (s, 3H),
1.48 (s, 3H), 1.05 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, d6-
DMSO) δ 164.5, 157.8, 150.8, 147.2, 144.2, 136.5, 130.9, 128.6,
127.6, 126.7, 122.2, 118.4, 53.5, 52.7, 49.8, 44.3, 27.1, 22.8, 17.0,
14.7; HRMS (ESI) calcd for C22H25NO5SNa ([M + Na]+) 438.1346,
found 438.1325.
14i, 94
10
11
12
14j, 96
Ph
14k, 92 (1:1)c
14l, 88 + trace
Furan-fused 1,4-thiazepine 3d: pale yellow solid; mp 151-
153 °C; IR (film) V 2977, 2956, 1726, 1704, 1545, 1247, 962, 787
cm-1; 1H NMR (400 MHz, d6-acetone) δ 8.82 (d, J ) 8.4 Hz, 1H),
7.91-7.88 (m, 2H), 7.68 (s, 1H), 7.51 (t, J ) 8. Hz, 1H), 7.45-
7.35 (m, 2H), 3.93 (s, 3H), 3.63 (s, 3H), 3.56-3.41 (m, 2H), 2.18
(s, 3H), 2.06 (s, 3H), 1.97 (s, 3H), 1.31 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, d6-acetone) δ 164.3, 157.4, 150.3, 149.7, 136.9,
136.6, 134.9, 131.5, 129.6, 128.9, 128.5, 126.8, 125.4, 125.2, 125.1,
124.9, 122.2, 118.7, 52.4, 51.4, 49.6, 44.2, 22.9, 15.8, 14.5; HRMS
(ESI) calcd for C26H27NO5SNa ([M + Na]+) 488.1502, found
488.1482.
Furan-fused 1,4-thiazepine 3j: pale yellow solid; mp 152-
154 °C; IR (film) V 2977, 1735, 1715, 1654, 1518, 1347, 858, 794
cm-1; 1H NMR (400 MHz, d6-acetone) δ 8.20 (d, J ) 9.2 Hz, 2H),
7.45 (d, J ) 9.2 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.50-3.28
(m, 2H), 2.09 (s, 3H), 1.94 (d, J ) 1.2 Hz, 3H), 1.47 (d, J ) 1.2
Hz, 3H), 1.11 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, d6-acetone)
δ 165.1, 158.5, 153.1, 152.3, 147.9, 146.3, 138.0, 132.1, 128.6,
124.1, 122.9, 118.8, 53.2, 52.3, 50.2, 44.9, 26.8, 22.5, 17.1, 14.6;
HRMS (ESI) calcd for C22H24N2O7SNa ([M + Na]+) 483.1196,
found 483.1182.
6f
13
14
15
16
17
6f
6f
6f
6f
6f
F
Me
F
Me
13d
13e
13f
13g
13h
14m, 93
14n, 96
14o, 93
14p, 90
14q, 96
-(CH2)3-
-CH2OCH2-
a General conditions: furan 3, 6, or 10 (1.0 mmol), benzyne precursor
13 (1.5 mmol), CsF (3.0 mmol), 80 °C for 100 min. b Isolated yields. c Ratio
of isolated yields.
set of symmetric benzynes, no matter electron-rich, deficient,
or bulky ones, to furnish the corresponding 7-oxanorbornadienes
14 in excellent yields (entries 1-10 and 13-17). The structures
of compounds 14 were confirmed by NMR spectroscopic
analysis and further by single-crystal X-ray diffraction of 14e
(see the Supporting Information). On the other hand, the
reactions of 6f with unsymmetrical benzynes were also explored.
A 1:1 mixture of regioisomers of 14k was obtained in 92%
combined yield when 4-phenylbenzyne was employed (entry
11), while 1,2-didehydronaphthalene 13c gave a highly regi-
oselective product in 88% yield due to the steric hindrance (entry
12, Table 6).
Furan-fused 1,4-thiazepine 3z: white solid; mp 114-115 °C;
IR (film) V 2952, 1738, 1625, 1548, 1440, 1346, 980, 762 cm-1
;
1H NMR (500 MHz, d6-acetone) δ 7.28-7.21 (m, 3H), 7.08 (d, J
) 7.5 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.79-3.71 (m, 3H),
3.04 (s, 3H), 2.54-2.46 (m, 2H), 2.27-2.25 (m, 1H), 1.96 (s, 3H),
1.91 (s, 3H), 1.40-1.38 (m, 1H), 0.98 (t, J ) 7.2 Hz, 3H); 13C
NMR (125 MHz, d6-acetone) δ 169.9, 164.5, 157.7, 154.3, 145.4,
144.2, 136.7, 133.2, 127.9, 127.0, 126.7, 121.6, 115.3, 61.5, 55.6,
52.5, 51.6, 37.4, 34.4, 33.1, 19.9, 16.0, 9.8; HRMS (ESI) calcd for
C25H29NO7SNa ([M + Na]+) 510.1557, found 510.1564.
Conclusion
In conclusion, we have discovered a facile and efficient three-
component reaction of thiazole or benzothiazole carbenes,
disubstituted ketenes, and activated alkynes. A highly substituted
ring system containing furo[2,3-c]thiazepine core can be gener-
ated from simple and readily accessible starting materials via
this methodology. Furthermore, the Diels-Alder reactions of
the unique furo[2,3-c]thiazepines with benzynes were exploited
to give thiazepine-fused 7-oxanorbornadienes derivatives in
excellent yields. With high atom-economy and considerable
potential for synthetic and biological uses, we conceived that
this novel multicomponent reaction described herein will find
application in the synthesis of heterocyclic compounds and
natural products as well as in the exploration of some novel
bioactive molecules.
Dimethyl-(E)-2-diethylaminobutenoate 4a: pale yellow oil; IR
(film) V 3095, 2981, 2863, 1744, 1694, 1570, 1446, 1378, 1158,
1
973, 862, 790 cm-1; H NMR (400 MHz, CDCl3) δ 4.61 (s, 1H),
3.93 (s, 3H), 3.63 (s, 3H), 3.19 (q, J ) 6.8 Hz, 2H), 1.18 (t, J )
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 166.1, 153.7,
82.8, 52.8, 50.6, 44.8, 12.6; HRMS (ESI) calcd for C10H17NO4Na
([M + Na]+) 238.1050, found 238.1055.
General Procedure for the Synthesis of Furan-Fused 1,4-
Thiazepine Derivatives 6a-m. Method A: To a solution of
thiazolium salt 1a (1.0 mmol) in anhydrous CH2Cl2 (3 mL) was
added i-Pr2NEt (2.5 mmol) at -78 °C. After 10-15 min, a solution
of substituted acetyl chloride (1.2 mmol) and alkynes 5a-e (1.5
mmol) in CH2Cl2 (2 mL) was added dropwise over 10 min and
then the mixture was stirred at this temperature for 30 min. The
reaction temperature was raised slowly to room temperature for an
additional several hours. On completion of the reaction, The solvent
was removed under vacuum, and the residue was quickly passed
through a short pad of neutral Al2O3 column with a hexane-ether
mixture (5:1) as eluent; the crude obtained was recrystallized from
Experimental Section
General Procedure for the Synthesis of Furan-Fused 1,4-
Thiazepine Derivatives 3a-z. To a solution of thiazolium salt 1
(1.0 mmol) in anhydrous CH2Cl2 (3 mL) was added i-Pr2NEt (2.5
582 J. Org. Chem., Vol. 73, No. 2, 2008

Assembly of Furan-Fused 1,4-Thiazepines
hexane to afford the desired products 6a-m. Method B: To a
solution of thiazolium salt 1a (1.0 mmol) in anhydrous CH2Cl2 (3
mL) was added NaH (1.2 mmol) at -78 °C. After 10-15 min, a
solution of disubstituted ketene (1.2 mmol) and alkynes 5a-e (1.5
mmol) in CH2Cl2 (2 mL) was added dropwise over 10 min and
then the mixture was stirred at this temperature for 30 min. The
reaction temperature was then raised slowly to room temperature
for an additional several hours. On completion of the reaction, cold
water (1.5 mmol) was added with stirring and the solvent was
removed under vacuum. The residue was quickly passed through a
short pad of neutral Al2O3 column with a hexane-ether mixture
(5:1) as eluent; the crude obtained was recrystallized from hexane
to afford the desired products 6a-m.
(m, 1H), 1.63 (s, 1H), 1.57 (s, 3H), 1.33 (t, J ) 6.8 Hz, 3H), 1.26
(s, 9H), 1.08 (t, J ) 7.2 Hz, 3H), 0.95 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 210.1, 158.3, 149.1, 134.2, 130.6, 118.7,
61.0, 48.4, 46.6, 45.4, 27.0, 24.3, 18.7, 14.2, 13.8, 9.4; HRMS (ESI)
calcd for C22H33NO4SNa ([M + Na]+) 430.2023, found 430.2028.
4-(4-Bromophenyl)-2-[4,9-diethyl-2-methyl-3-methylene-8-
oxo-9-phenyl-6-(1-phenylpropylidene)-7-oxa-1-thia-4-aza-spiro-
[4.4]non-2-yl]-4-oxo-but-2-enoic acid ethyl ester 7: white solid;
mp 188-190 °C; IR (film) V 2976, 2930, 1738, 1712, 1542, 1125,
1
899, 702 cm-1; H NMR (400 MHz, CDCl3) δ 7.70 (d, J ) 2.0
Hz, 2H), 7.69-7.54 (m, 4H), 7.38-7.29 (m, 6H), 7.21 (d, J ) 6.8
Hz, 2H), 7.00 (s, 1H), 4.15-4.09 (m, 2H), 3.51 (d, J ) 2.0 Hz,
1H), 3.30 (d, J ) 1.6 Hz, 1H), 3.04-2.93 (m, 3H), 2.73-2.68 (m,
1H), 2.32-2.27 (m, 1H), 2.01-1.95 (m, 1H), 1.86 (s, 3H), 1.11-
1.05 (m, 6H), 0.88 (t, J ) 7.6 Hz, 3H), 0.78 (t, J ) 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 191.3, 173.4, 166.0, 148.4, 146.1,
142.0, 137.8, 135.4, 132.5, 132.0, 129.9, 129.1, 129.0, 128.6, 128.3,
128.2, 127.8, 127.3, 127.1, 85.1, 82.3, 61.7, 61.2, 58.9, 40.2, 31.6,
28.4, 23.9, 13.5, 12.0, 11.9, 8.7; HRMS (ESI) calcd for C39H40-
BrNO5SNa ([M + Na]+) 736.1703, found 736.1712.
Furan-fused 1,4-thiazepine 6a (Method A): white solid; mp
136-138 °C; IR (film) V 2986, 2936, 1738, 1722, 1548, 1370, 1179,
744, 697 cm-1; 1H NMR (500 MHz, d6-acetone) δ 7.35-7.26 (m,
10H), 4.41 (q, J ) 7.2 Hz, 2H), 4.18 (q, J ) 7.0 Hz, 2H), 3.45 (q,
J ) 7.0 Hz, 2H), 1.88 (s, 3H), 1.38 (t, J ) 7.0 Hz, 2H), 1.23-1.17
(m, 9H); 13C NMR (125 MHz, d6-acetone) δ 163.9, 157.1, 150.9,
145.3, 143.3, 137.0, 130.7, 129.1, 127.7, 127.3, 122.3, 118.5, 61.7,
60.8, 58.9, 44.4, 21.1, 16.3, 13.8, 13.5, 13.4; HRMS (ESI) calcd
for C29H31NO5SNa ([M + Na]+) 528.1815, found 528.1824.
Furan-fused 1,4-thiazepine 6d (Method B): yellow solid; mp
145-146 °C; IR (film) V 2980, 2931, 1729, 1705, 1537, 1247, 1185,
3-Ethyl-4,5-dimethylthiazole-2-one 8: colorless oil; IR (film)
1
V 2930, 2862, 1732, 1535, 1305, 1240, 1180, 851, 699 cm-1; H
NMR (400 MHz, CDCl3) δ 3.73 (t, J1 ) 7.6 Hz, J2 ) 6.4 Hz, 2H),
2.08 (s, 3H), 2.06 (s, 3H), 1.23 (t, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.3, 126.2, 106.3, 38.2, 14.4, 11.9, 11.2; HRMS
(ESI) calcd for C7H11NOSNa ([M + Na]+) 180.0459, found
180.0458.
1
954, 698 cm-1; H NMR (400 MHz, d6-acetone) δ 7.94 (d, J )
6.8 Hz, 2H), 7.66-7.53 (m, 3H), 7.34-7.25 (m, 10H), 3.90 (q, J
) 6.8 Hz, 2H), 3.10 (q, J ) 7.2 Hz, 2H), 1.68 (s, 3H), 1.19 (s,
3H), 1.01 (t, J ) 7.0 Hz, 3H), 0.80 (t, J ) 7.2 Hz, 3H); 13C NMR
(100 MHz, d6-acetone) δ 191.8, 158.0, 151.7, 146.6, 144.2, 138.2,
137.8, 134.7, 133.0, 130.1, 130.0, 129.7, 128.6, 128.6, 128.1, 119.4,
61.4, 59.7, 46.1, 22.0, 17.1, 14.4, 13.8; HRMS (ESI) calcd for
C33H31NO4SNa ([M + Na]+) 560.1866, found 560.1879.
Furan-fused 1,4-thiazepine 6h (Method B): white solid; mp
138-140 °C; IR (film) V 2975, 2928, 1736, 1702, 1539, 1188, 898,
699 cm-1; 1H NMR (400 MHz, d6-acetone) δ 7.98 (d, J ) 8.4 Hz,
2H), 7.83 (d, J ) 8.8 Hz), 7.31 (t, J ) 7.6 Hz, 2H), 7.24 (t, J )
7.2 Hz, 1H), 7.18 (d, J ) 8.0 Hz, 2H), 4.06 (q, J ) 7.2 Hz, 2H),
3.17-3.12 (m, 1H), 3.06-3.01 (m, 1H), 2.59-2.50 (m, 2H), 1.74
(s, 3H), 1.31 (s, 3H), 1.06 (t, J ) 7.6 Hz, 3H), 1.01-0.95 (m, 6H);
13C NMR (100 MHz, d6-acetone) δ 190.0, 157.2, 145.8, 149.5,
145.4, 136.8, 136.2, 133.7, 132.1, 130.9, 128.3, 127.8, 127.0, 126.7,
126.6, 118.4, 60.6, 55.2, 45.1, 32.8, 21.6, 16.3, 13.4, 13.0, 9.7;
HRMS (ESI) calcd for C29H30BrNO4SNa ([M + Na]+) 590.0971,
found 590.0978.
General Procedure for the Synthesis of Furan-Fused 1,4-
Benzothiazepine Derivatives 10a-d. At 80 °C, a solution of
cyano-benzothiazoline 9 (1.0 mmol) in DCE (3 mL) was added
dropwise to a solution of diphenylketene (1.2 mmol) and alkynes
(1.2 mmol) in DCE (5 mL) over 45 min; the mixture was then
stirred at this temperature overnight. On completion of the reaction,
The solvent was removed under vacuum, and the residue was
quickly passed through a short pad of neutral Al2O3 column with
a hexane-ether mixture (5:1) as eluent to afford the desired
products 10a-d.
Furan-fused 1,4-benzothiazepine 10a: white solid; mp 174-
176 °C; IR (film) V 2978, 2955, 1736, 1716, 1542, 1446, 740, 699
cm-1; 1H NMR (400 MHz, d6-acetone) δ 7.33-7.22 (m, 12H), 7.02
(d, J ) 7.6 Hz, 1H), 6.86-6.82 (m, 1H), 3.99 (s, 3H), 3.71 (s,
3H), 3.46 (s, 3H); 13C NMR (100 MHz, d6-acetone) δ 164.3, 157.1,
154.5, 144.1, 142.3, 137.1, 135.9, 131.2, 129.9, 128.6, 127.7, 127.3,
126.9, 124.3, 122.5, 121.8, 60.5, 52.3, 51.4, 40.6; HRMS (ESI)
calcd for C28H23NO5SNa ([M + Na]+) 508.1189, found 508.1196.
Furan-fused 1,4-benzothiazepine 10b: white solid; mp 183-
185 °C; IR (film) V 2974, 2952, 1735, 1712, 1540, 1443, 742, 699
cm-1; 1H NMR (400 MHz, d6-acetone) δ 8.05 (d, J ) 7.6 Hz, 2H),
7.72 (t, J ) 7.6 Hz, 1H), 7.60 (t, J ) 7.6 Hz, 2H), 7.32-7.26 (m,
8H), 7.24-7.20 (m, 3H), 7.06-7.01 (m, 2H), 6.83 (t, J ) 7.6 Hz,
1H), 3.94 (q, J ) 7.2 Hz, 2H), 3.21 (s, 3H), 0.84 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, d6-acetone) δ 191.0, 156.8, 154.7, 142.7,
137.7, 137.2, 136.0, 133.8, 132.7, 130.1, 129.2, 128.9, 127.9, 127.5,
127.5, 127.4, 124.6, 123.0, 60.6, 60.6, 42.3, 12.9; HRMS (ESI)
calcd for C34H27NO4SNa ([M + Na]+) 568.1553, found 568.1562.
Furan-fused 1,4-benzothiazepine 10c: white solid; mp 132-
134 °C; IR (film) V 2977, 2955, 1739, 1720, 1547, 1448, 746, 702
cm-1; 1H NMR (400 MHz, d6-acetone) δ 7.34-7.22 (m, 12H), 7.01
(q, J1 ) 1.6 Hz, J2 ) 6.4 Hz, 1H), 6.88-6.86 (m, 1H), 4.20 (q, J
) 7.2 Hz, 2H), 3.37 (s, 3H), 2.73 (s, 3H), 1.20 (t, J ) 7.2 Hz, 3H);
13C NMR (100 MHz, d6-acetone) δ 198.5, 157.3, 154.7, 145.4,
142.6, 136.0, 136.0, 131.7, 130.9, 130.2, 128.8, 128.0, 127.8, 127.4,
124.9, 123.9, 60.9, 60.5, 42.6, 32.1, 13.4; HRMS (ESI) calcd for
C29H25NO4SNa ([M + Na]+) 506.1397, found 506.1390.
Furan-fused 1,4-benzothiazepine 10d: white solid; mp 137-
139 °C; IR (film) V 2970, 2952, 1734, 1725, 1546, 1445, 744, 698
Furan-fused 1,4-thiazepine 6j (Method A): Pale yellow oil;
IR (film) V 2935, 2860, 1732, 1546, 1308, 1245, 1186, 856, 772
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.83 (d, J ) 8.4 Hz, 2H),
7.64 (d, J ) 8.8 Hz, 2H), 4.08 (q, J ) 7.2 Hz, 2H), 2.98 (q, J )
6.8 Hz, 2H), 2.22-2.14 (m, 2H), 2.02 (s, 3H), 1.95-1.91 (m, 2H),
1.79 (d, J ) 8.8 Hz, 6H), 1.63-1.60 (m, 2H), 1.40-1.36 (m, 1H),
1.00-0.94 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 191.0, 157.9,
151.0, 150.2, 136.0, 135.8, 132.0, 131.2, 130.8, 129.0, 127.1, 117.6,
61.0, 49.8, 45.5, 36.0, 25.5, 23.5, 21.5, 16.9, 14.1, 13.7; HRMS
(ESI) calcd for C26H30BrNO4SNa ([M + Na]+) 554.0971, found
554.0980.
Furan-fused 1,4-thiazepine 6l (Method A): pale yellow oil;
IR (film) V 2936, 2869, 1734, 1544, 1307, 1242, 1184, 856, 699
cm-1; 1H NMR (400 MHz, d6-acetone) δ 7.85 (d, J ) 8.4 Hz, 2H),
7.38 (d, J ) 8.0 Hz, 2H), 4.05 (q, J ) 7.2 Hz, 2H), 3.05 (q, J )
7.2 Hz, 2H), 2.43 (s, 3H), 2.06-2.02 (m, 4H), 1.92-1.86 (m, 1H),
1.80 (s, 3H), 1.60 (s, 3H), 1.02-0.94 (m, 9H); 13C NMR (100 MHz,
d6-acetone) δ 190.3, 157.3, 150.1, 149.5, 144.5, 136.0, 135.0, 131.2,
129.3, 129.2, 128.1, 117.2, 60.3, 48.4, 44.8, 34.1, 27.3, 23.1, 20.8,
16.3, 13.6, 13.1, 8.9; HRMS (ESI) calcd for C25H31NO4SNa ([M
+ Na]+) 464.1866, found 464.1874.
Furan-fused 1,4-thiazepine 6m (Method A): pale yellow oil;
IR (film) V 2932, 2863, 1735, 1540, 1308, 1240, 1183, 854, 702
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.33 (d, J ) 4.4 Hz, 2H),
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.30 (q, J ) 7.2 Hz, 2H),
7.22-7.18 (m, 10H), 6.99 (d, J ) 6.8 Hz, 1H), 6.87-6.83 (m,
1H), 4.18 (q, J ) 7.2 Hz, 2H), 3.29 (s, 3H), 1.38 (s, 9H), 1.21 (t,
3.26 (q, J ) 7.2 Hz, 2H), 2.05 (s, 3H), 1.91 (s, 3H), 1.89-1.85
J. Org. Chem, Vol. 73, No. 2, 2008 583

Ding et al.
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.6, 157.9,
154.0, 148.9, 142.1, 138.2, 136.7, 135.5, 132.2, 131.2, 130.4, 130.0,
128.9, 128.6, 128.6, 127.8, 127.3, 127.3, 126.7, 126.0, 61.1, 60.4,
45.5, 45.4, 27.2, 14.1; HRMS (ESI) calcd for C32H31NO4SNa ([M
+ Na]+) 548.1866, found 548.1870.
147.6, 143.1, 142.0, 141.8, 138.7, 131.8, 130.5, 130.4, 130.0, 129.5,
127.2, 127.0, 126.9, 126.8, 126.4, 125.5, 124.9, 124.2, 120.6, 119.4,
96.4, 88.2, 61.7, 58.5, 51.4, 22.9, 16.6, 13.8, 13.1; HRMS (ESI)
calcd for C39H34BrNO4SNa ([M + Na]+) 714.1284, found 714.1269.
1,4-Thiazepine-fused 7-oxanorbornadiene 14f: pale yellow
solid; mp 208-211 °C; IR (KBr) V 3055, 2998, 2948, 1752, 1701,
1561, 1201, 1142, 808, 754, 697 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.77 (d, J ) 8.0 Hz, 2H), 7.62 (d, J ) 7.6 Hz, 1H), 7.42 (d, J )
8.0 Hz, 2H), 7.38 (d, J ) 6.8 Hz, 1H), 7.19-7.08 (m, 6H), 6.83
(d, J ) 7.6 Hz, 1H), 6.74 (t, J ) 7.6 Hz, 1H), 4.33 (q, J ) 7.2 Hz,
2H), 3.16 (q, J ) 6.9 Hz, 1H), 2.62 (q, J ) 6.8 Hz, 1H), 1.79 (s,
3H), 1.35 (t, J ) 7.2 Hz, 3H), 1.28 (s, 9H), 1.21 (s, 3H), 0.51 (t,
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.5, 167.1,
159.6, 148.8, 147.8, 143.4, 143.3, 142.4, 131.7, 130.8, 130.5, 127.0,
126.8, 126.6, 126.1, 124.8, 124.7, 124.1, 119.8, 118.3, 95.8, 89.0,
61.8, 58.0, 50.0, 45.3, 27.0, 22.8, 17.3, 14.1, 13.7; HRMS (ESI)
calcd for C37H39NO4SNa ([M + Na]+) 616.2492, found 616.2493.
1,4-Thiazepine-fused 7-oxanorbornadiene 14l: white solid; mp
221-223 °C; IR (KBr) V 3052, 2973, 2895, 1745, 1583, 1456, 1270,
2,3-Bis(3-methyl-3H-benzothiazol-2-ylidene)succinic acid dim-
ethyl ester 11: white solid; mp 154-156 °C; IR (film) V 2954,
1
2935, 1735, 1718, 1540, 1437, 770 cm-1; H NMR (400 MHz,
CDCl3) δ 7.61-7.59 (m, 2H), 7.31-7.27 (m, 2H), 7.15-7.12 (m,
4H), 3.62 (s, 6H), 3.55 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
170.1, 159.0, 142.4, 127.0, 125.8, 122.3, 121.3, 109.7, 88.7, 51.6,
35.0; HRMS (ESI) calcd for C22H20N2O4S2Na ([M + Na]+)
463.0757, found 463.0763.
General Procedure for the Diels-Alder Reaction of Furan-
Fused 1,4-Thiazepine with Benzynes. To a solution of furan-fused
1,4-thiazpines 3, 6, or 10 (0.2 mmol) and benzyne precursors 13a-h
(0.3 mmol) in acetonitrile was added CsF (0.6 mmol). The mixture
was heated to reflux for 1.5 h. On completion of the reaction, the
solvent was removed under vacuum and diethyl ether was added
to precipitate the salt. The solid was filtered off through a short
pad of neutral Al2O3 column and the filtrate was concentrated. The
residue was then recrystallized from CH2Cl2/hexane to afford the
desired products 14a-q.
1,4-Thiazepine-fused 7-oxanorbornadiene 14a: pale yellow
solid; mp 205-207 °C; IR (KBr) V 3056, 2976, 2935, 1749, 1618,
1446, 1314, 1184, 1065, 852, 751, 699 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.01(d, J ) 7.2 Hz, 1H), 7.78 (d, J ) 7.2 Hz, 1H), 7.51
(d, J ) 9.2 Hz, 2H), 7.08-7.02 (m, 2H), 6.82 (d, J ) 8.8 Hz, 2H),
3.89 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.44 (q, J ) 6.8 Hz, 1H),
2.90 (q, J ) 6.8 Hz, 1H), 1.90 (s, 3H), 1.72 (s, 3H), 1.31 (s, 3H),
0.52 (t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.5,
167.5, 162.7, 157.8, 148.9, 148.6, 140.1, 134.2, 130.0, 125.8, 124.6,
122.1, 120.6, 119.9, 112.5, 97.1, 87.0, 55.1, 52.4, 50.1, 49.5, 31.4,
24.9, 23.1, 17.5, 14.0; HRMS (ESI) calcd for C29H31NO6SNa ([M
+ Na]+) 544.1764, found 544.1772.
1,4-Thiazepine-fused 7-oxanorbornadiene 14b: yellow solid;
mp 216-218 °C; IR (KBr) V 3059, 2978, 2936, 1754, 1619, 1448,
1316, 1186, 1066, 855, 754, 702 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.99 (d, J ) 7.2 Hz, 1H), 7.78 (d, J ) 7.2 Hz, 1H), 7.48 (d, J )
8.8 Hz, 2H), 7.40 (d, J ) 8.6 Hz, 2H), 7.11-7.00 (m, 2H), 3.90 (s,
3H), 3.72 (s, 3H), 3.47-3.40 (m, 1H), 2.91-2.85 (m, 1H), 1.90
(s, 3H), 1.73 (s, 3H), 1.33 (s, 3H), 0.51 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.9, 167.4, 162.7, 148.7, 148.4, 141.5,
140.5, 130.7, 130.3, 126.0, 124.6, 124.5, 121.4, 120.8, 120.5, 120.4,
96.8, 87.2, 52.6, 51.1, 49.9, 49.6, 24.8, 23.1, 17.6, 12.1; HRMS
(ESI) calcd for C28H28BrNO5SNa ([M + Na]+) 592.0764, found
592.0776.
1
1065, 1034, 855, 744, 698 cm-1; H NMR (400 MHz, CDCl3) δ
8.13 (d, J ) 8.8 Hz, 1H), 7.95 (d, J ) 8.4 Hz, 1H), 7.88 (d, J )
7.6 Hz, 2H), 7.82 (d, J ) 8.0 Hz, 2H), 7.67 (t, J ) 8.8 Hz, 3H),
7.54 (d, J ) 7.6 Hz, 2H), 7.45 (t, J ) 7.6 Hz, 1H), 7.36 (d, J ) 8.4
Hz, 2H), 7.21-7.11 (m, 6H), 4.39-4.33 (m, 2H), 2.69-2.64 (m,
1H), 2.29-2.24 (m, 1H), 1.56 (s, 3H), 1.22 (t, J ) 7.6 Hz, 6H),
0.41 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.1,
169.0, 166.9, 148.0, 146.8, 143.2, 142.2, 142.0, 138.4, 132.2, 132.0,
130.5, 130.5, 129.8, 128.1, 127.7, 127.3, 127.0, 126.8, 126.5, 126.3,
125.6, 125.5, 125.1, 124.9, 122.8, 119.4, 97.2, 90.8, 62.1, 58.3,
51.5, 22.9, 16.4, 13.9, 13.8; HRMS (ESI) calcd for C43H36BrNO4-
SNa ([M + Na]+) 764.1441, found 764.1453.
1,4-Thiazepine-fused 7-oxanorbornadiene 14q: yellow solid;
mp 215-217 °C; IR (KBr) V 3058, 2978, 2928, 1741, 1585, 1445,
1
1134, 1095, 754, 720, 699 cm-1; H NMR (400 MHz, CDCl3) δ
)9.21 (d, J ) 5.2 Hz, 1H), 8.62 (d, J ) 7.6 Hz, 1H), 8.53 (d, J )
8.4 Hz, 1H), 8.15 (d, J ) 5.6 Hz, 2H), 7.87 (s, 1H), 7.75 (s, 2H),
7.60 (s, 4H), 7.39-7.32 (m, 4H), 7.23-7.16 (m, 3H), 7.00 (d, J )
7.2 Hz, 2H), 6.95 (d, J ) 6.8 Hz, 1H), 4.46-4.23 (m, 2H), 2.77
(br, 1H), 2.36 (q, J ) 6.5 Hz, 1H), 1.61 (s, 3H), 1.21 (t, J ) 6.8
Hz, 3H), 1.16 (s, 3H), 0.27 (br, 3H); 13C NMR (100 MHz, CDCl3)
δ 193.9, 167.5, 147.5, 143.8, 141.4, 138.1, 132.0, 130.6, 130.2,
130.1, 129.8, 129.3, 128.8, 128.1, 127.3, 127.0, 127.0, 126.6, 126.5,
126.0, 125.8, 125.4, 125.4, 124.7, 124.6, 122.9, 122.5, 102.1, 102.1,
89.8, 62.5, 56.6, 49.1, 22.0, 15.6, 13.8, 13.8; HRMS (ESI) calcd
for C47H38BrNO4SNa ([M + Na]+) 814.1597, found 814.1587.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Grant Nos. 20672096 and
20772106) for financial support.
1,4-Thiazepine-fused 7-oxanorbornadiene 14e: yellow solid;
mp 213-215 °C; IR (KBr) V 3058, 2979, 2932, 1749, 1613, 1444,
1318, 1180, 1067, 850, 749, 698 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.73-7.62 (m, 8H), 7.46 (d, J ) 8.0 Hz, 2H), 7.25-7.10 (m,
6H), 6.93 (t, J ) 7.4 Hz, 1H), 6.79 (t, J ) 7.6 Hz, 1H), 4.19-4.13
(m, 2H), 2.85 (q, J ) 6.4 Hz, 2H), 2.42 (q, J ) 6.8 Hz, 2H), 1.61
(s, 3H), 1.24 (s, 3H), 1.19 (t, J ) 7.2 Hz, 3H), 0.52 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 189.7, 168.4, 166.6, 148.1,
Supporting Information Available: Crystallographic informa-
tion files (CIF) for compound 7, 11, and 14e, experimental
procedures and characterization data of all new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702299M
584 J. Org. Chem., Vol. 73, No. 2, 2008