Silver-catalyzed tandem ammonolysis-cyclization of 2-alkynylbenzenamines with tetraalkylthiuram disulfides to 4-methylene-4 h -benzo[ d ][1,3]thiazin-2-amines

Article abstract of DOI:10.1055/s-0029-1219828

In the presence of AgBF₄, the ammonolysis-cyclization tandem reactions of various 2-alkynylbenzenamines with tetraalkylthiuram disulfides afforded the corresponding 4-methylene-4H-benzo[d][1,3]thiazin-2-amines in moderate to good yields.

Full text of DOI:10.1055/s-0029-1219828

LETTER
1345
Silver-Catalyzed Tandem Ammonolysis–Cyclization of
2-Alkynylbenzenamines with Tetraalkylthiuram Disulfides to
4-Methylene-4H-benzo[d][1,3]thiazin-2-amines
M
ethylene-4
H
-
be
i
nzo[
d
]
-
[1,3]thia
Y
zin-2-amines uan Tang,a Pei-Song Luo,a Xing-Guo Zhang,a Ping Zhong,b Jin-Heng Li*a
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)88368607; E-mail: jhli@wzu.edu.cn
Oujiang College, Wenzhou University, Wenzhou 325035, P. R. of China
b
Received 18 January 2010
that AgBF4 was the most effective in terms of yield (en-
tries 9–13). It was interesting to find that the yield of 3
could be increased slightly to 91% at 80 °C after pro-
longed the reaction time (entry 14). Among the amounts
of catalyst examined, 10 mol% of AgBF4 gave the best re-
sults (entries 14 and 15). Although good yield was still
achieved in the presence of stoichiometric amount of
Abstract: In the presence of AgBF4, the ammonolysis–cyclization
tandem reactions of various 2-alkynylbenzenamines with tetraalkyl-
thiuram disulfides afforded the corresponding 4-methylene-4H-
benzo[d][1,3]thiazin-2-amines in moderate to good yields.
Key words: silver, tandem reaction, 2-alkynylbenzenamine, tetra-
alkylthiuram disulfide, 4-methylene-4H-benzo[d][1,3]thiazin-2-
amine
Table 1 Screening Optimal Conditionsa
The synthesis of sulfur-containing heterocycles is of con-
tinuing interest in the field of organic chemistry because
of their biological and pharmacological interest.1 Among
them, benzo[d][1,3]thiazines, a class of privileged frag-
ment, are found in many compounds with remarkably bi-
ological activities.2 Therefore, a number of efficient
methods for the synthesis of benzo[d][1,3]thiazines have
been developed. The most classical method is the conden-
sation of 2-aminobenzyl chloride with and thioamides or
thioureas.3 However, the unstable and inaccessible sub-
strates compelled organic chemists to search for new reac-
tion partners, particularly the sulfur sources. Recently,
two alternative sulfur sources have been developed: one
was the use of Lawesson’s reagent,4 the other involved
isothiocyanates.5 As a continuing interest in the construc-
tion of sulfur-containing heterocycles,6–7 we report here a
new, efficient tandem route to 4-methylene-4H-ben-
zo[d][1,3]thiazin-2-amines from 2-alkynylbenzenamines
using commercially available tetraalkylthiuram disulfides
as the sulfur source (Scheme 1).9
Ph
S
N
NMe2
S
NMe2
+
Me2N
S
S
NH2
1a
S
2a
3
Ph
Entry Catalyst
(mol%)
Solvent
Temp Time (h)Yield
(°C)
(%)b
1
2
AgOTf (10)
AgOTf (10)
NMP
60
48
48
48
48
48
36
24
24
24
24
24
24
24
36
36
36
26
toluene
MeCN
DCE
60
trace
trace
trace
63
3
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgBF4 (10)
AgSbF6 (10)
AgOAc (10)
Cu(OTf)2 (10)
Pd(OAc)2 (10)
AgBF4 (10)
AgBF4 (5)
60
4
60
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
6
80
80
7
100
120
100
100
100
100
100
80
81
8
72
Our study began with the reactions of 2-(phenyleth-
ynyl)aniline (1a) with tetramethylthiuram disulfide (2a)
and AgOTf in NMP at 60 °C for 48 hours, affording the
desired product 3 in 22% yield (entry 1, Table 1). Encour-
aged by the results, the effect of solvents was investigated
(entries 1–5). While toluene, MeCN and DCE, were less
effective (entries 2–4), DMSO enhanced the yield to 63%
(entry 5). To our delight, good yield of 3 were achieved at
either 80 or 100 °C (entries 6 and 7). However, the yield
was decreased slightly at 120 °C (entry 8). A series of oth-
er catalysts, such as AgBF4, AgSbF6, AgOAc, Cu(OTf)2,
and Pd(OAc)2, were evaluated, and the results revealed
9
88
10
11
12
13
14
15
16c
76
78
34
trace
91 (90:10)
83
80
AgBF4 (10)
80
76
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol) in solvent (1 mL).
b Isolated yield.
SYNLETT 2010, No. 9, pp 1345–1350
Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1219828; Art ID: W00810ST
x
x.
x
x.
2
0
1
0
c Conditions: 2a (0.25 mmol) was added.
© Georg Thieme Verlag Stuttgart · New York

1346
R.-Y. Tang et al.
LETTER
disulfide 2a (entry 16), excess amount of disulfide 2a substituted aryl groups at the terminal of 2-ethynylaniline
could improve the reaction (entry 14). The structure of 3 were investigated, and the results demonstrated that the
was unambiguously confirmed by the X-ray single-crystal electronic effect of these groups affected the reaction to
diffraction analysis (Figure 1).10
some extent (entries 3–9). We found that the electron-rich
aryl groups, such as 4-MeC6H4, 4-MeOC6H4, 2-MeC6H4,
2-BrC6H4, and 2-PhC6H4, provided good yields (entries 3,
4, and 6–8), whereas the electron-withdrawing acetyl- or
trifluoromethyl-substituted aryl groups lowered the yields
(entries 5 and 9). It was interesting to find that heteroaryl-
alkyne 1i was also a suitable substrate (entry 10). Howev-
er, aliphatic alkynes 1j and 1k displayed less activity
under the optimal conditions (entries 11 and 12). Finally,
substituents on the aryl moiety of 2-ethynylanilines were
also examined (entries 13–18). While substrates 1l–o with
a chloro group or a methyl group underwent the reaction
with disulfide 2a and AgBF4 in good yields (entries 13–
17), the reaction of substrate 1q, having an electron-
deficient NO2 group, was not successful (entry 18).
With the optimal reaction conditions in hand, various 2-
alkynylbenamines and tetraalkylthiuram disulfides were
explored for the AgBF4-catalyzed tandem reaction
(Table 2).11
Initially, treatment of substrate 1a with two other disul-
fides 2b or 2c in the presence of AgBF4 smoothly afforded
the desired products 4 and 5 in 53% and 88% yields, re-
spectively (entries 1 and 2). Subsequently, a number of
R2
R1
R3
NH2
N
N
1
+
R3
AgBF4
S
DMSO, 80 °C
S
R3
N
R1
R3
S
R3
R2
N
S
R3
S
2
Scheme 1
Ph
NH2
1r
Ph
AgBF4
+
S
DMSO, 80 °C
S
N
H
S
NMe2
NMe2
Me2N
S
23
S
2a
Figure 1 ORTEP diagram of the single-crystal X-ray structure of
Scheme 2
compound 3
S
S
NMe2
Me2N
S
Ph
S
Ph
2a
S
Ag+
NMe2
N
Ph
H
NH2
A
1
S
Ag+
NMe2
N
H
N
NMe2
B
S
H+
Ph
Ag+
Ph
N
NMe2
HS
S
NMe2
N
H+
Ag
Ph
C
D
Scheme 3 A possible mechanism
Synlett 2010, No. 9, 1345–1350 © Thieme Stuttgart · New York

LETTER
Methylene-4H-benzo[d][1,3]thiazin-2-amines
1347
To elucidate the mechanism, a controlled reaction was In summary, we have developed a novel and efficient tan-
carried out under the optimal conditions (Scheme 2). In dem method for the synthesis of 4-methylene-4H-ben-
the presence of AgBF4, only N-(2-styrylbenzyl)-thiourea zo[d][1,3]thiazin-2-amines. In the presence of AgBF4, a
23 was obtained in 30% yield from the ammonolysis reac- variety of 2-alkynylbenzenamines successfully under-
tion between 2-styrylbenzenamine 1r and disulfide 2a. went the tandem reaction with tetraalkylthiuram disul-
Notably, a similar product 22 was observed using the fides to selectively prepare the corresponding 4-
bulky tert-butyl-substituted alkyne 1k (entry 12 in methylene-4H-benzo[d][1,3]thiazin-2-amines in moder-
Table 2).
ate to good yields. Study of the detailed mechanism and
applying tetraalkylthiuram disulfides in new organic
transformations for the preparation of sulfur-containing
heterocycles are under way.
Consequently, a possible mechanism was proposed as
outlined in Scheme 3 on the basis of the present results
and the previous reported mechanism.5–7 The ammono-
lysis reaction of substrate 1 with disulfide 2 affords inter-
mediate A, followed by its complexation with Ag+ gives
intermediate B. Cyclization of the intermediate B takes
place to yield the desired product and regenerate the ac-
tive Ag+ catalyst.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Table 2 Silver-Catalyzed Tandem Reactions of 2-Alkynylbenzenamines (1) with Tetraalkylthiuram Disulfides 2a
R2
R3
N
S
R3
N
N
R3
AgBF4
R3
S
R1
+
N
R3
S
R3
DMSO, 80 °C
S
NH2
R1
S
S
S
1
2
R2
S
Bu
N
S
NMe2
S
N
Bu
S
Me2N
S
N
S
N
S
Bu
S
S
Bu
S
2a
2b
2c
Entry
1
Substrate 1
2
Product
Yield (%)b
53
2b
Ph
N
N
S
NH2
1a
1a
Ph
4
5
2
2c
88
Ph
Bu
N
N
Bu
S
NH2
Ph
R
N
NMe2
S
NH2
R
3
4
5
1b R = Me
2a
2a
2a
6 R = Me
85 (93:7)
88 (88:12)
63 (83:17)
1c R = MeO
1d R = MeCO
7 R = MeO
8 R = MeCO
Synlett 2010, No. 9, 1345–1350 © Thieme Stuttgart · New York

1348
R.-Y. Tang et al.
LETTER
Table 2 Silver-Catalyzed Tandem Reactions of 2-Alkynylbenzenamines (1) with Tetraalkylthiuram Disulfides 2a (continued)
R2
R3
N
S
R3
N
N
R3
AgBF4
R3
S
R1
+
N
R3
S
R3
DMSO, 80 °C
S
NH2
R1
S
S
S
1
2
R2
S
Bu
N
S
NMe2
S
N
Bu
S
Me2N
S
N
S
N
S
Bu
S
S
Bu
S
2a
2b
2c
Entry
Substrate 1
2
Product
Yield (%)b
N
NMe2
R
S
R
NH2
6
1e R = Me
1f R = Br
1g R = Ph
2a
2a
2a
2a
9 R = Me
10 R = Br
11 R = Ph
N
87 (97:3)
83 (94:6)
77 (>99:1)
38 (89:11)
7
8
9c
NMe2
S
CF3
CF3
NH2
1h
12
10
2a
86 (91:9)
N
NMe2
S
S
S
NH2
1i
1j
13
11
2a
2a
10
n-C8H17
N
NMe2
S
NH2
n-C8H17
14
12d
0
N
NMe2
S
NH2
1k
15
13
2a
82 (90:10)
Ph
N
NMe2
Cl
S
Cl
NH2
Ph
1l
16
Synlett 2010, No. 9, 1345–1350 © Thieme Stuttgart · New York

LETTER
Methylene-4H-benzo[d][1,3]thiazin-2-amines
1349
Table 2 Silver-Catalyzed Tandem Reactions of 2-Alkynylbenzenamines (1) with Tetraalkylthiuram Disulfides 2a (continued)
R2
R3
N
S
R3
N
N
R3
AgBF4
R3
S
R1
+
N
R3
S
R3
DMSO, 80 °C
S
NH2
R1
S
S
S
1
2
R2
S
Bu
N
S
NMe2
S
N
Bu
S
Me2N
S
N
S
N
S
Bu
S
S
Bu
S
2a
2b
2c
Entry
14
Substrate 1
2
Product
Yield (%)b
78 (93:7)
2a
MeO
NH2
N
NMe2
S
Cl
Cl
MeO
N
1m
17
15
2a
75 (81:19)
O
NMe2
S
Cl
Cl
O
NH2
1n
18
16
2a
85
S
N
NMe2
S
S
Cl
Cl
NH2
1o
19
20
17
18
2a
2a
79 (88:12)
Ph
N
NMe2
S
NH2
Ph
N
1p
trace
NMe2
Ph
O2N
S
O2N
NH2
Ph
1q
21
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), AgBF4 (0.05 mmol) in DMSO (1 ml) at 80 °C for 36 h.
b Isolated yield. The ratio of Z/E isomers determined by 1H NMR is given in parenthesis.
c At 100 °C for 5 d.
d Another product, 3-(2-tert-butylethynylphenyl)-1,1-dimethylthiourea (22), was isolated in 67% yield.
Acknowledgment
References and Notes
The authors thank the Zhejiang Provincial Natural Science Found-
ation of China (Nos. Y407116 and Y4080169), National Natural
Science Foundation of China (No 20872112), and Foundation of
Wenzhou University (2007L004) for financial support.
(1) (a) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R.
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6215.
Synlett 2010, No. 9, 1345–1350 © Thieme Stuttgart · New York

1350
R.-Y. Tang et al.
LETTER
(2) (a) Matysiak, J. Bioorg. Med. Chem. 2006, 14, 2613.
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98.
(10) The crystal structure of compound 3 has been deposited at
the Cambridge Crystallographic Data Centre and allocated
the deposition number CCDC 769763.
(11) General Procedure for the Silver-Catalyzed Tandem
Reaction
A flame-dried Schlenk tube with a magnetic stirring bar was
charged with 2-alkynylbenzenamine 1 (0.5 mmol),
tetraalkylthiuram disulfide 2 (0.5 mmol), AgBF4 (0.05
mmol), and DMSO (1 mL). The reaction mixture was stirred
at 80 °C for 36 h. After the reaction was finished, the mixture
was poured into EtOAc, washed with brine (3 × 10 mL), and
extracted with EtOAc. The combined organic layers were
dried by anhyd Na2SO4 and evaporated under vacuum. The
residue was purified by flash column chromatography
(hexane–EtOAc) to afford the desired product.
4-Benzylidene-N,N-dimethyl-4H-benzo[d][1,3]thiazin-2-
amine (3)
Z/E = 90:10; pale yellow solid, mp 68.9–72.6 °C
(uncorrected). 1H NMR (300 MHz, CDCl3): d = 7.51–7.46
(m, 3 H), 7.43–7.38 (m, 2 H), 7.29–7.25 (m, 2 H), 7.21–7.17
(m, 2 H), 7.08–7.07 (m, 2 H), 3.21 (s, 0.6 H), 3.16 (s, 5.4 H).
13C NMR (75 MHz, CDCl3): d = 153.3, 145.0, 136.0, 129.6,
129.4, 128.1 (2 C), 127.2, 126.0, 125.5, 124.2, 123.4, 120.0,
38.2. IR (KBr): 2924, 1560, 1187, 756 cm–1. LRMS (EI, 70
eV): m/z (%) = 280 (100) [M+], 236 (78). ESI-HRMS: m/z
calcd for C17H17N2S [M + H]+: 281.1107; found: 281.1104.
3-[2-(3,3-Dimethylbut-1-ynyl)phenyl]-1,1-dimethyl-
thiourea (22)
(4) (a) Nishio, T. Tetrahedron Lett. 1995, 36, 6113. (b) Nishio,
T. J. Org. Chem. 1997, 62, 1106. (c) Gimbert, C.;
Vallribera, A. Org. Lett. 2009, 11, 269.
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E. P. J. Heterocycl. Chem. 2001, 38, 343. (b) Dean, V. L.;
Lindamood, B. S.; Papadopoulos, E. P. Synthesis 1984, 68.
(c) Dean, W. D.; Papadopoulos, E. P. J. Heterocycl. Chem.
1982, 19, 1117. (d) Abaev, V. T.; Tsiunchik, F. A.; Gutnov,
A. V.; Butin, A. V. Tetrahedron Lett. 2006, 47, 4029.
(e) Butin, A. V.; Abaev, V. T.; Stroganova, T. A.; Gutnov,
A. V. Molecules 1997, 2, 62. (f) Tárraga, A.; Molina, P.;
López, J. L. Tetrahedron Lett. 2000, 41, 4895. (g) Hari, A.;
Miller, B. L. Org. Lett. 2000, 2, 3667. (h) Ding, Q.-P. W. J.
J. Comb. Chem. 2008, 10, 541.
(6) For recent reviews on Ag-catalyzed reactions, see:
(a) Álvarez-Corral, M.; Muñoz-Dorado, M.; Rodríguez-
García, I. Chem. Rev. 2008, 108, 3174. (b) Yamamoto, Y.
Chem. Rev. 2008, 108, 3199.
(7) Pi, S.-S.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H. Synthesis
2009, 3032.
(8) (a) Qiu, J.-W.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li,
J.-H. Adv. Synth. Catal. 2009, 351, 2319. (b) Guo, Y.-J.;
Tang, R.-Y.; Li, J.-H.; Zhong, P.; Zhang, X.-G. Adv. Synth.
Catal. 2009, 351, 2615. (c) Jiang, T.-S.; Zhang, X.-G.; Li,
J.-H. Synthesis 2009, 3029. (d) Du, H.-A.; Zhang, X.-G.;
Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2009, 74, 7844.
(e) Guo, Y.-J.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Tetrahedron
Lett. 2010, 51, 649.
Pale yellow solid, mp 88.1–89.3 °C (uncorrected). 1H NMR
(300 MHz, CDCl3): d = 8.34 (d, J = 8.3 Hz, 1 H), 7.77 (br, 1
H), 7.37 (d, J = 7.7 Hz, 1 H), 7.28–7.26 (m, 1 H), 7.05–7.02
(m, 1 H), 3.41 (s, 6 H), 1.34 (s, 9 H). 13C NMR (75 MHz,
CDCl3): d = 180.3, 140.3, 131.8, 127.8, 123.5, 121.9, 115.1,
105.7, 75.0, 41.2, 31.1, 28.3. IR (KBr): 3367, 2963, 1530,
1335, 755 cm–1. LRMS (EI, 70 eV): m/z (%) = 260 (29) [M+],
245 (37), 200(18), 88 (100), 88. ESI-HRMS: m/z calcd for
for C15H21N2S [M + H]+: 261.1420; found: 261.1419.
(E)-1,1-Dimethyl-3-(2-styrylphenyl)thiourea (23)
Pale yellow solid, mp 211.3–214.1 °C (uncorrected). 1H
NMR (300 MHz, CDCl3): d = 7.52–7.49 (m, 1 H), 7.35 (d,
J = 7.7 Hz, 2 H), 7.31–7.29 (m, 2 H), 7.28–7.25 (m, 4 H),
7.07–6.99 (m, 2 H), 3.30 (s, 6 H). 13C NMR (75 MHz,
CDCl3): d = 183.3, 137.6, 137.1, 133.2, 131.5, 128.7, 128.1,
128.0, 127.3, 126.8 (2 C), 126.4, 123.7, 41.8. IR (KBr):
2924, 1524, 1332, 758 cm–1. LRMS (EI, 70 eV): m/z (%) =
282 (100) [M+], 249 (27), 237 (100), 204 (32), 88 (78). ESI-
HRMS: m/z calcd for C17H19N2S [M + H]+: 283.1263; found:
283.1260.
(9) For selected papers on the synthesis of tetraalkylthiuram
disulfides, see: (a) Watanabe, Y.; Yuzurus Ishimura, Y.
J. Org. Chem. 1988, 53, 2120. (b) Karimi, B.; Hazarkhani,
H.; Zareyee, D. Synthesis 2002, 2513. (c) Liang, F.; Tan, J.;
Piao, C.; Liu, Q. Synthesis 2008, 3579.
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