Synthesis of 4-methylene-4H-benzo[d][1,3]thiazines via a tandem reaction of 1-(2-alkynylphenyl)ketoximes with Lawesson's reagent

Article abstract of DOI:10.1039/c1cc12937f

1-(2-Alkynylphenyl)ketoximes react with Lawesson's reagent catalyzed by InCl₃ and cyanuric chloride leading to 4-methylene-4H-benzo[d][1,3] thiazines in good yields. This tandem reaction proceeds with high efficiency through Beckmann rearrangem

Full text of DOI:10.1039/c1cc12937f

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COMMUNICATION
Synthesis of 4-methylene-4H-benzo[d][1,3]thiazines via a tandem reaction
of 1-(2-alkynylphenyl)ketoximes with Lawesson’s reagentw
Guanyinsheng Qiu,a Yi Hu,a Qiuping Ding,a Yiyuan Peng,*a Xiangzheng Huc and Jie Wu*b
Received 19th May 2011, Accepted 14th July 2011
DOI: 10.1039/c1cc12937f
1-(2-Alkynylphenyl)ketoximes react with Lawesson’s reagent
catalyzed by InCl3 and cyanuric chloride leading to 4-methylene-
4H-benzo[d][1,3]thiazines in good yields. This tandem reaction
proceeds with high efficiency through Beckmann rearrangement,
thioamide formation, and intramolecular nucleophilic cyclization.
of 1-(2-alkynylphenyl)ketoxime.7a Inspired by the advancement
of the Beckmann rearrangement and our efforts toward
improved syntheses of nitrogen-containing heterocycles, we
envisioned that 1-(2-alkynylphenyl)ketoxime could be used as
a substrate for the generation of 4-methylene-4H-benzo[d]-
[1,3]thiazines. The proposed synthetic route is described in
Scheme 1. We anticipated that with a suitable catalyst, a
Beckmann rearrangement of 1-(2-alkynylphenyl)ketoxime 1
would occur first to form an amide intermediate A. It is well
known that benzamide can be easily transformed to benzothio-
amide in the presence of Lawesson’s reagent.9 Furthermore,
Lawesson’s reagent was employed in the formation of 2H-
thiopyrans in a regioselective one pot thionation–[4 + 2]-
cycloaddition sequence.9e Thus, intermediate A would react with
Lawesson’s reagent leading to thioamide B. In the presence of a
suitable metal catalyst, the triple bond would be activated. This
formed metal-complex renders the carbon–carbon unsaturated
bond moiety electrophilic, which triggers an intramolecular
attack by the sulfur nucleophile, giving rise to the desired
4-methylene-4H-benzo[d][1,3]thiazine 2. Accordingly, this
proposed pathway incorporating Beckmann rearrangement,
thioamide formation, and intramolecular cyclization in a one-
pot process for the formation of 4-methylene-4H-benzo[d][1,3]-
thiazines seemed feasible. To validate this hypothesis, we started to
explore the possibility of the transformation shown in Scheme 1.
We began by investigating the reaction of 1-(2-alkynyl-
phenyl)ketoxime 1a with Lawesson’s reagent (Table 1). Since
the Beckmann rearrangement works efficiently in the presence
of a catalytic amount of cyanuric chloride with an acid
co-catalyst,2h the initial studies were performed by using cyanuric
chloride (10 mol%) and InCl3 (10 mol%) as the co-catalyst.7a
The Beckmann rearrangement of ketoximes is a fundamental
synthetic transformation, which has been used as an efficient
tool for amide formation.1 To date, many catalysts including
metal salts and organocatalysts have been employed in this
transformation.2 For example, in 2005 Yamamoto and
co-workers described a Beckmann rearrangement under reflux
in acetonitrile or nitromethane using 2,4,6-trichloro-1,3,5-
triazine (cyanuric chloride) as an effective organocatalyst
(co-catalyzed by either HCl or ZnCl2).2h
The construction of heterocyclic systems is of continuing
interest in the field of organic chemistry, due to their impor-
tant place among biologically active natural products and
synthetic materials.3 The 4H-benzo[d][1,3]thiazine core can
be found in many compounds with promising biological
activities.4 Moreover, compounds with this subunit have
found application in electroluminescent devices.4 Among the
family of 4H-benzo[d][1,3]thiazines, 4-methylene-4H-benzo[d]-
[1,3]thiazine is particularly appealing since this kind of compound
could be further elaborated to form diverse 4H-benzo[d]-
[1,3]thiazines. In the past few years, we have been involved in
the preparation of natural product-like compounds via cascade
reactions,5 which are attractive approaches for the efficient
generation of complex molecules.6 During our studies, we were
convinced that 2-alkynylbenzaldoxime is a versatile substrate for
N-heterocycles generation.7,8 For instance, indole derivatives
could be generated via a multicatalytic one-pot Beckmann
rearrangement/intramolecular cyclization/halogenation reaction
a Key Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang, Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
c College of Science, Tianjin University of Science and Technology,
Tianjin 300222, China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of
compounds 2. CCDC 826316. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1cc12937f
Scheme 1 Synthesis of 4-methylene-4H-benzo[d][1,3]-thiazines via a cas-
cade reaction of 1-(2-alkynylphenyl)ketoxime with Lawesson’s reagent.
c
9708 Chem. Commun., 2011, 47, 9708–9710
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Table 1 Initial studies for the tandem reaction of 1-(2-alkynylphenyl)-
ketoxime 1a with Lawesson’s reagent
Table 2 Tandem reactions of 1-(2-alkynylphenyl)ketoximes with
Lawesson’s reagent
Entry Additive
Solvent
T/1C
Yielda (%)
Entry
1
Substrate
Product
Yielda (%)
1
2
3
CuI
AgOTf
PdCl2
MeCN
MeCN
MeCN
120
120
120
120
120
120
120
120
120
120
120
120
120
120
42
32
61
72
72
40
Trace
Complex
Trace
71
80 (2a)
4
PdCl2(MeCN)2 MeCN
5
6
7
8
—
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
THF
tBuOK
Cs2CO3
DBU
K3PO4
—
2
3
4
5
6
96 (2b)
73 (2c)
80 (2d)
71 (2e)
40 (2f)
9
10
11
12
13
14
15
16
—
—
—
—
—
—
34
24
Complex
Complex
1,4-Dioxane
EtOH
DMF
MeCN/tolueneb 80 to 120 80
MeCN/tolueneb rt
Trace
a
b
Isolated yield based on 1-(2-alkynylphenyl)ketoxime 1. MeCN/
toluene (v/v: 1 : 2).
At the outset, different metal salts were tested as additives since
a metal catalyst would be necessary to activate the triple bond
for subsequent intramolecular cyclization. To our delight, the
expected product 2a was isolated in 42% yield when the reaction
took place in MeCN at 120 1C in the presence of copper(I) iodide
as an additive (Table 1, entry 1). Silver(I) and palladium(II) salts
were examined in the meantime (Table 1, entries 2–4), and a
good yield was obtained when PdCl2(MeCN)2 was added to the
reaction system (72% yield). However, a blank experiment
without the addition of metal additive indicated that InCl3 was
an effective catalyst in the Beckmann rearrangement as well as in
the intramolecular cyclization process (Table 1, entry 5). No
further improvement was observed when organic or inorganic
bases were added (Table 1, entries 6–9). Further screening of
solvents showed that the reaction worked well in a mixed solvent
of MeCN and toluene, which gave rise to the corresponding
product 2a in 80% yield (Table 1, entry 15). However, only a
trace amount of product was detected when the reaction
occurred at room temperature (Table 1, entry 16). The reactivity
was diminished with lower yield and prolonged reaction time
when the catalytic amount of cyanuric chloride and InCl3 was
reduced to 5 mol% (data not shown in Table 1).
7
8
9
61 (2g)
50 (2h)
70 (2i)
10
11
12
64 (2j)
Next, we examined the scope of this tandem reaction under the
optimized conditions (10 mol% of cyanuric chloride, 10 mol% of
InCl3, MeCN/toluene). The results are shown in Table 2. Most
reactions proceeded smoothly to give rise to the corresponding
products in moderate to good yields. For instance, 1-(2-alkynyl-
phenyl)ketoxime 1b reacted with Lawesson’s reagent, leading to
the desired 4-methylene-4H-benzo[d][1,3]thiazine 2b in 96% yield
(Table 2, entry 2). Reactions of substrates with a 4-ethylphenyl,
4-chlorophenyl, or 4-fluorophenyl group attached to the triple
bond afforded the expected products in good yields as well
(Table 2, entries 3–5). A reasonable yield (61%) was obtained
when 1-(2-alkynylphenyl)ketoxime 1g with an alkyl group
66 (2k)
45 (2l)
13
—
Trace
a
Isolated yield based on 1-(2-alkynylphenyl)ketoxime 1.
c
This journal is The Royal Society of Chemistry 2011
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attached to the CRC triple bond was used as a reactant
(Table 2, entry 7). Other 1-(2-alkynylphenyl)ketoximes with a
chloro or methyl group attached to the aromatic ring were
examined in the meantime, and all reactions performed well to
afford the desired product 2 in moderate yield (Table 2, entries
8–12). Additionally, the structure of 4-methylene-4H-benzo[d]-
[1,3]thiazine 2j was unambiguously determined by X-ray crystallo-
graphy analysis (see the ESIw). However, no desired products
were observed when R3 was replaced by hydrogen (Table 2,
entry 13) or trimethylsilyl (data not shown in Table 2).
In conclusion, we have described a tandem reaction of
1-(2-alkynylphenyl)ketoxime with Lawesson’s reagent catalyzed
by InCl3 and cyanuric chloride, which leads to 4-methylene-4H-
benzo[d][1,3]thiazines in moderate to good yields. This cascade
process proceeds with high selectivity through Beckmann
rearrangement, thioamide formation, and intramolecular nucleo-
philic cyclization. Further exploration of other cascade reactions
using 1-(2-alkynylphenyl)ketoxime as a substrate is ongoing.
Financial support from the National Natural Science
Foundation of China (No. 20862009 and 20962010), the Science
& Technology Project of Tianjin (No. 10JCZDJC22500),
and the Natural Science Foundation of Jiangxi Province (No.
2008GQH0026) is gratefully acknowledged. We thank Dr Jason
Wong (Roche R&D Center, China) for English review.
(c) M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol and
P. Machado, Chem. Rev., 2009, 109, 4140; (d) M. Alvarez-Corral,
M. Munoz-Dorado and I. Rodrıguez-Garcıa, Chem. Rev., 2008,
108, 3174; (e) A. Minatti and K. Muniz, Chem. Soc. Rev., 2007,
36, 1142; (f) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644.
4 (a) M. Schmittel, A. Mahajan and J.-P. Steffen, Synthesis, 2004, 415;
(b) W.-C. Hsu, T.-M. Tao and K.-C. Liu, Chin. Pharm. J. (Taipei,
Taiwan), 2005, 57, 43; (c) W.-C. Hsu, T.-M. Tao, T.-C. Chou,
Y.-A. Ding and K.-C. Liu, Chin. Pharm. J. (Taipei, Taiwan), 2002,
54, 331; (d) O. Morgenstern, R. Schuster, M. Finke and
P. H. Richter, Pharmazie, 1996, 51, 458; (e) Y. Sato and
S. Maeda, Jpn. Kokai Tokkyo Koho, JP 05279662, 1993, 12;
(f) R. Hull, P. J. Van den Broek and M. L. Swain, J. Chem. Soc.,
Perkin Trans. 1, 1975, 922; (g) Q. Ding and J. Wu, J. Comb. Chem.,
2008, 10, 541.
5 For recent examples, see: (a) S. Li and J. Wu, Org. Lett., 2011,
13, 712; (b) Z. Chen, D. Zheng and J. Wu, Org. Lett., 2011, 13, 848;
(c) Y. Luo, X. Pan and J. Wu, Org. Lett., 2011, 13, 1150; (d) Y. Luo,
L. Hong and J. Wu, Chem. Commun., 2011, 47, 5298; (e) Z. Chen,
C. Ye, L. Gao and J. Wu, Chem. Commun., 2011, 47, 5623.
6 For selected examples, see: (a) J. Montgomery, Angew. Chem., Int.
Ed., 2004, 43, 3890; (b) E. Negishi, C. Coperet, S. Ma, S. Y. Liou
and F. Liu, Chem. Rev., 1996, 96, 365; (c) L. F. Tietze, Chem. Rev.,
1996, 96, 115; (d) R. Grigg and V. Sridharan, J. Organomet. Chem.,
1999, 576, 65; (e) T. Miura and M. Murakami, Chem. Commun.,
2007, 217; (f) M. Malacria, Chem. Rev., 1996, 96, 289;
(g) K. C. Nicolaou, T. Montagnon and S. A. Snyder, Chem.
Commun., 2003, 551; (h) K. C. Nicolaou, D. J. Edmonds and
P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134;
(i) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem.,
¨
Int. Ed., 2007, 46, 1570; (j) L. F. Tietze, G. Brasche and K. Gericke,
Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
Germany, 2006.
Notes and references
7 (a) G. Qiu, Q. Ding, H. Ren, Y. Peng and J. Wu, Org. Lett., 2010,
12, 3975; (b) H. Ren, Y. Luo, S. Ye and J. Wu, Org. Lett., 2011,
13, 2552; (c) S. Ye, H. Wang and J. Wu, ACS Comb. Sci., 2011,
13, 120; (d) S. Ye, K. Gao and J. Wu, Adv. Synth. Catal., 2010,
352, 1746; (e) S. Ye, H. Wang and J. Wu, Eur. J. Org. Chem., 2010,
6436; (f) Z. Chen, X. Yu, M. Su, X. Yang and J. Wu, Adv. Synth.
Catal., 2009, 351, 2702; (g) Q. Ding, Z. Wang and J. Wu, J. Org.
Chem., 2009, 74, 921; (h) Q. Ding, Z. Wang and J. Wu, Tetrahedron
Lett., 2009, 50, 198; (i) Q. Ding and J. Wu, Adv. Synth. Catal., 2008,
350, 1850.
8 (a) H.-S. Yeom, J.-E. Lee and S. Shin, Angew. Chem., Int. Ed., 2008,
47, 7040; (b) H.-S. Yeom, S. Kim and S. Shin, Synlett, 2008, 924;
(c) Z. Huo, H. Tomeba and Y. Yamamoto, Tetrahedron Lett., 2008,
49, 5531.
9 For selected examples, see: (a) D. Bernardi, L. A. Ba and G. Kirsch,
Synlett, 2007, 2121; (b) S. V. Rajender and K. Dalip, Org. Lett.,
1999, 1, 697; (c) G. Evindar and R. A. Batey, J. Org. Chem., 2006,
71, 1802; (d) Q. Ding, X. Huang and J. Wu, J. Comb. Chem., 2009,
11, 1047; (e) C. D. Gabbutt, J. D. Hepworth and B. M. Heron,
J. Chem. Soc., Perkin Trans. 1, 1992, 2603.
1 For reviews, see: (a) R. E. Gawly, Org. React., 1988, 35, 1 and
references therein; (b) M. B. Smith and J. March, Advanced
Organic Chemistry, John Wiley & Sons, New York, 5th edn 2001,
p. 1415 and references therein; (c) L. Kurti and B. Czako, Strategic
´
¨
Applications of Named Reactions in Organic Synthesis, Elsevier
Academic Press, 2005.
2 For selected examples, see: (a) M. Boero, T. Ikeshoji, C. C. Liew,
K. Terakura and M. Parrinello, J. Am. Chem. Soc., 2004, 126, 6280;
(b) L. De Luca, G. Giacomelli and A. Porcheddu, J. Org. Chem., 2002,
67, 6272; (c) A. Zicmanis, S. Katkevica and P. Mekss, Catal. Commun.,
2009, 10, 614; (d) H. J. Pi, J. D. Dong, N. An, W. T. Du and
W. P. Deng, Tetrahedron, 2009, 65, 7790; (e) M. Z. Zhu, C. T. Cha,
W. P. Deng and X. X. Shi, Tetrahedron Lett., 2006, 47, 4861;
(f) M. Hashimoto, Y. Obora, S. Sakaguchi and Y. Ishii, J. Org. Chem.,
2008, 73, 2894; (g) A. B. Fernandez, M. Boronat, T. Blasco and
A. Corna, Angew. Chem., Int. Ed., 2005, 44, 2370; (h) Y. Furuya,
K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 2005, 127, 11240.
3 Recent reviews for the synthesis of heterocycles: (a) A. Armstrong
and J. C. Collins, Angew. Chem., Int. Ed., 2010, 49, 2282;
(b) A. R. Katritzky and S. Rachwal, Chem. Rev., 2010, 110, 1564;
c
9710 Chem. Commun., 2011, 47, 9708–9710
This journal is The Royal Society of Chemistry 2011