Copper-Catalyzed Three-Component Tandem Cyclization for One-Pot Synthesis of 1,4-Benzothiazines

Article abstract of DOI:10.1021/acs.joc.6b01668

A copper-catalyzed three-component tandem reaction has been developed for the convenient and practical synthesis of 1,4-benzothiazines. A variety of terminal alkynes and 2-iodo/bromophenyl isothiocyanates underwent this one-pot cyclization with aqueous ammonia to afford 1,4-benzothiazines in moderate to good yields.

Full text of DOI:10.1021/acs.joc.6b01668

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Note
Copper-Catalyzed Three-Component Tandem
Cyclization for One-Pot Synthesis of 1,4-Benzothiazines
Jing-Jing Chu, Bo-Lun Hu, Zhi-Yong Liao, and Xing-Guo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01668 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 26, 2016
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The Journal of Organic Chemistry
Copper-Catalyzed Three-Component Tandem
Cyclization for One-Pot Synthesis of 1,4-
Benzothiazines
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JingꢀJing Chu, BoꢀLun Hu, ZhiꢀYong Liao and XingꢀGuo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
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zxg@wzu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
A copperꢀcatalyzed threeꢀcomponent tandem reaction has been developed for the convenient and
practical synthesis of 1,4ꢀbenzothiazines. A variety of terminal alkynes and 2ꢀiodo/bromophenyl
isothiocyanates underwent this oneꢀpot cyclization with aqueous ammonia to afford 1,4ꢀbenzothiazines
in moderate to good yields.
1,4ꢀBenzothiazine derivatives are important heterocyclics and widely exists in a great number of
natural products and biologically active molecules, which possess a broad spectrum of biological
activities such as antibacterial,1 antidiabetic,2 antiarrhythmic3 and antitumor.4 Therefore, sustainably
increasing attention has been directed toward their synthesis in synthetic and medicinal chemistry
areas.5
In the past decades, transitionꢀmetalꢀcatalyzed coupling reaction of aryl halides with thiol surrogates
has been developed for the synthesis of organosulfur compounds.6 For example, Paradies and coworkers
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reported the Pdꢀcatalyzed tandem reaction of aryl halides and thiourea for the synthesis of thioethers and
benzothiophenes.7 Aryl thioureas are also versatile sufuration reagents,8 and could be prepared from the
addition of aryl isothiocyanates and aqueous ammonia, which is one of the most abundant and low cost
nitrogen sources for the production of fertilizers and nitrogenꢀcontaining molecules.9 Meanwhile, oneꢀ
pot multiꢀstep tandem reaction has emerged as a powerful tool in the synthesis of complex organic
molecules, owing to their advantage in improving atom economy, saving time and efficient formation of
multiple bonds without separation.10 Therefore, the development of multifunctional catalytic system
which is compatible for several mechanistically diverse reactions in tandem reactions is still highly
desirable. Herein, we wish to report a copperꢀcatalyzed threeꢀcomponent tandem reaction of oꢀ
halophenyl isothiocyanates, terminal alkynes and aqueous ammonia for oneꢀpot synthesis of 1,4ꢀ
benzothiazines. The reaction pathway involves desulfhydrylation of aryl thioureas, double CꢀS bond
forming reaction and intramolecular hydroamination (Scheme 1).
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Scheme 1. Tandem cyclization for the synthesis of 1,4ꢀbenzothiazines
We began our study by exploring the reaction of 1ꢀiodoꢀ2ꢀisothiocyanatobenzene 1a11 with
ethynylbenzene 2a and aqueous ammonia to screen the reaction conditions, and the results are
summarized in Table 1. Firstly, a variety of copper catalysts were examined (entries 1ꢀ6), and moderate
yields were obtained in the presence of cupric or cuprous salts including CuCl, CuBr, CuI, Cu(OAc)2,
Cu(OTf)2 and copper(I) thiopheneꢀ2ꢀcarboxylate (CuTc). Treatment of substrate 1a with 2a, aqueous
ammonia, 10 mol % CuTc and 2 equiv of K2CO3 in MeCN afforded the desired product 3a in 69% yield
(entry 6). The reaction did not work in the absence of copper catalysts (entry 7). In order to improve the
reaction yields, we investigated some nitrogen ligands, such as tetramethyldiaminoethane (TMEDA), Lꢀ
proline, bipyridine and 1,10ꢀphenanthroline (1,10ꢀphen) (entries 8ꢀ11). The results disclosed that 1,10ꢀ
phenanthroline was the most effective ligand to give the product 3a in 85% yield (entry 11).
Subsequently, various bases were tested with aim of promoting CꢀS bond formation of aryl iodides
(entries 12ꢀ14). However, lower yields were obtained for K3PO4 and Cs2CO3, and only 24% yield was
observed when NEt3 was used as base (entry 14). During the screening of solvents, DMF, DMSO, THF
and H2O were found to be inferior to MeCN (entries 15ꢀ18). The yield was decreased to 57% when the
o
reaction was carried out at 80 C (entry 19), and 76% yield was obtained when the reaction was
performed under air atmosphere (entry 20).
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The Journal of Organic Chemistry
Table 1. Screening conditions
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Entry
1
Catalyst
CuCl
Ligand
ꢀ
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
NEt3
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Yield
52%
62%
66%
61%
62%
69%
0
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2
CuBr
CuI
ꢀ
3
ꢀ
4
Cu(OAc)2
Cu(OTf)2
CuTc
ꢀ
ꢀ
5
ꢀ
6
ꢀ
7
ꢀ
8
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
TMEDA
Lꢀproline
bipyridine
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
68%
66%
74%
85%
73%
70%
24%
75%
64%
43%
11%
57%
76%
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19b
20c
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
THF
H2O
CH3CN
CH3CN
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), aqueous ammonia
(1.0 mmol), copper salts (10 mol %), ligand (20 mol %) and base (2
o
b
o
c
equivalent) in solvent (2 mL) under N2 at 100 C for 12 h. At 80 C.
Under air.
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Table 2. Scope of the reaction
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CN
N
10 mol % CuTc
NCS
I/Br
R'
20 mol % 1,10-phen
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+
NH3 H2O
R'
+
R
R
2 equiv K2CO3
MeCN, 100 oC, N2
S
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a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), aqueous ammonia (1.0 mmol), CuTc (10
mol %), 1,10ꢀphenanthroline (20 mol %) and K2CO3 (0.4 mmol) in MeCN (2 mL) under N2 for
12 h, isolated yield. b oꢀbromophenyl isothiocyanate and 20 mol % CuTc were used.
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The Journal of Organic Chemistry
Under the optimal reaction conditions, we explored the scope of this threeꢀcomponent cyclization by
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examining a variety of terminal alkynes and isothiocyanates. As shown in table 2, both electronꢀ
withdrawing and electronꢀdonating groups were compatible for alkyne or isothiocyanate moiety, and the
corresponding products were obtained in moderate to good yields. It is noteworthy that oꢀbromophenyl
isothiocyanate was also suitable substrate to produce 3a in 47% yield by treatment with alkyne 2a in the
presence of 20 mol % CuTc. Similarly, a 40% yield was obtained when oꢀbromophenyl isothiocyanate
was reacted with 3ꢀfluorophenylethyne. Nevertheless, oꢀiodophenyl isothiocyanates provided better
results owing to the reactive CꢀI bond in coupling reaction. For example, the reactions of substrate 2a
with fluoride phenylethyne afforded products 3b ꢀ 3d in 65 ꢀ 81% yields. Chloride and bromide products
3e ꢀ 3g were isolated in 71 ꢀ 72% yields. Electronꢀpoor trifluoromethyl phenylethyne gave product 3h in
65% yield, and bulky methylꢀ2ꢀethynylbenzoate afforded product 3i in 43% yield. As expected,
phenylethynes bearing Me, Et, nꢀPr, nꢀBu, tꢀBu and OMe group underwent the cyclization smoothly to
afford the corresponding products 3j – 3p in 70 ꢀ 75% yields. Heteroaromatic 3ꢀethynylthiophene also
produced the corresponding product 3q in 62% yield. Interestingly, the reactions of aliphatic alkynes
were performed successfully under standard conditions. For instance, 1ꢀethynylcyclohexꢀ1ꢀene and decꢀ
1ꢀyne furnished product 3r and 3s in 67% and 70% yields, respectively. A 51% yield was also observed
when decꢀ1ꢀyne was conducted with oꢀbromophenyl isothiocyanate and aqueous ammonia.
Subsequently, substituents on oꢀiodophenyl isothiocyanate moiety were tested under the optimized
reaction conditions. Electronꢀdonating methyl and methoxy afforded product 3t and 3u in 74% and 75%
yields, while electronꢀwithdrawing trifluoromethyl gave product 3v in 40% yields. oꢀIodophenyl
isothiocyanate with a bromo or chloro group could also be transformed to benzothiazine 3w and 3x in
51% and 56% yields, respectively.
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To demonstrate the applicability of this reaction in the synthesis of diversely functionalized 1,4ꢀ
benzothiazines, further transformation of product 3a was explored as outlined in Scheme 2. The
hydration of cyano group was realized by treatment of 3a with 2 mol % Cu(OAc)2 and 3 equiv NEt2OH
in water, 1,4ꢀbenzothiazineꢀ4ꢀcarboxamide 4 was isolated in 73% yield.12 Furthermore, in the presence
of 10 mol % Ag2CO3 and 1 equiv K2S2O8, product 3a was oxidized to benzo[b][1,4]thiazine 1,1ꢀdioxide
5 in 92% yield, which has been reported to possess strong antimicrobial activity.13
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Scheme 2. Synthetic applications of 3a
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Scheme 3. Control experiment
In order to probe the mechanism and extend substrate scope of this oneꢀpot cyclization, the reaction
of oꢀchlorophenyl isothiocyanate 6 with phenylethyne 2a and aqueous ammonia was conducted under
standard conditions (Scheme 3, eq. 1). To our surprised, both the desired product 3a and addition
product 2ꢀchlorophenyl thioureas could not be observed, while Nꢀ(2ꢀchlorophenyl)cyanamide 7 was
isolated in 71% yield. These results suggested that elimination of 2ꢀchlorophenyl thioureas occurred to
generate cyanamide 7 and hydrogen sulfide, but the crossꢀcoupling reaction did not proceed due to the
less reactivity of aryl chloride. To further confirm the desulfhydrylation of aryl thioureas, phenyl
isothiocyanate 8 was treated with aqueous ammonia under standard conditions. As expected, Nꢀ
phenylcyanamide 9 was obtained in 75% yield (eq. 2).
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The Journal of Organic Chemistry
Scheme 4. Possible mechanism
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On the basis of the obtained results and previous reports,14 a plausible mechanistic pathway is
outlined in Scheme 4. Firstly, the addition of aqueous ammonia to oꢀiodophenyl isothiocyanate yields 2ꢀ
iodophenyl thioureas A. The desulfhydrylation of thioureas A and following CꢀS formation in the
presence of CuTc and K2CO3 occurs to produce cyanamide B, which undergoes another crossꢀcoupling
reaction with alkyne to afford intermediate C. Then, reductive elimination of intermediate C generates
alkynyl thioether D, the final copperꢀcatalyzed intramolecular hydroamination gives the cyclization
product 3a. However, the ring opening of 2ꢀaminobenzothiazoles pathway cannot be ruled out.5a
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In summary, we have developed a copperꢀcatalyzed threeꢀcomponent tandem reaction for the
convenient and practical synthesis of 1,4ꢀbenzothiazines from readily accessible starting materials. The
elimination of aryl thioureas generated in situ afforded dihydrosulfide surrogate, which triggered the
following double CꢀS formation and intramolecular hydroamination. A variety of terminal alkynes and
2ꢀiodo/bromophenyl isothiocyanates underwent this tandem cyclization with aqueous ammonia to give
1,4ꢀbenzothiazines in moderate to good yields. Moreover, the synthetic utility of this method was
investigated by the oxidation and hydration of the obtained product, and its derivative carboxamide and
sulfone could be prepared easily in good yields. The present process provided a valuable new approach
for the construction of 1,4ꢀbenzothiazine scaffold, which will be useful in the synthesis of heterocyclics.
Experimental Section
General Information:
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Chemicals were either purchased or purified by standard techniques. H NMR and C NMR spectra
were measured on a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz), using CDCl3 as the
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solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts are
given in δ relative to TMS, and the coupling constants J are given in hertz. Highꢀresolution mass spectra
were recorded on an ESIꢀQꢀTOF mass spectrometer. All reactions under nitrogen atmosphere were
conducted using standard Schlenk techniques. Melting point data are uncorrected. Column
chromatography was performed using EM silica gel 60 (300ꢀ400 mesh).
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General process for the synthesis of 1,4-benzothiazine:
2ꢀiodophenyl isothiocyanate 1a (0.2 mmol, 52.2 mg), phenylacetylene 2a (0.3 mmol, 30.6 mg),
aqueous ammonia (1.0 mmol, 125 mg, wt % = 28% ꢀ 30%), copper(І) thiopheneꢀ2ꢀcarboxylate (CuTc;
10 mol %, 3.8 mg), K2CO3 (0.4 mmol, 55.2 mg) and 1,10ꢀphenanthroline (20 mol %, 7.2 mg) in the
CH3CN (2.0 mL) were added in schlenk at 100 °C under N2. The solution was stirred for 12 h. Then the
removal of solvent, the product was purified by column chromatography (petroleum ether (PE) / ethyl
acetate (EA), v/v = 10:1).
3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3a)5b: Yellow solid (42.3 mg, 85%); m.p. 127ꢀ128
1
°C; H NMR (500 MHz, CDCl3) δ 7.43ꢀ7.42 (m, 5H), 7.38ꢀ7.36 (m, 1H), 7.29ꢀ7.26 (m, 1H), 7.17ꢀ7.14
(m, 1H), 7.11ꢀ7.09 (m, 1H), 5.76 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 137.5, 136.2, 132.3, 129.8,
128.9, 128.1, 127.2, 127.12, 127.10, 125.4, 118.5, 110.4, 106.2; LRMS (EI, 70 eV) m/z (%): 250 (M+,
100), 223 (20), 218 (11), 121 (9).
3ꢀ(3ꢀfluorophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3b): Yellow solid (43.3 mg, 81%); m.p.
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81ꢀ82 °C; H NMR (500 MHz, CDCl3) δ 7.34ꢀ7.31 (m, 1H), 7.29ꢀ7.27 (m, 1H), 7.22ꢀ7.19 (m, 1H),
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7.15ꢀ7.13 (m, 1H), 7.10ꢀ7.07 (m, 1H), 7.06ꢀ7.01 (m, 3H), 5.76 (s, 1H); C NMR (125 MHz, CDCl3) δ
162.8 (d, JCꢀF = 246.5 Hz), 136.0, 134.42, 134.35, 130.6, 128.2, 127.2 (d, JCꢀF = 20.1 Hz), 125.2, 122.8,
118.7, 116.8 (d, JCꢀF = 21.1 Hz), 114.3, 114.2, 110.2, 108.0; LRMS (EI, 70 eV) m/z (%): 268 (M+, 100),
241 (22), 236 (16); HRMS (ESI): Calcd for C15H10FN2S+ ([M + H]+): 269.0543, Found: 269.0556.
3ꢀ(4ꢀfluorophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3c): Yellow solid (40.7 mg, 76%); m.p.
1
118ꢀ119 °C; H NMR (500 MHz, CDCl3) δ 7.34ꢀ7.32 (m, 2H), 7.28ꢀ7.26 (m, 1H), 7.21ꢀ7.17 (m, 1H),
7.10ꢀ7.06 (m, 1H), 7.05ꢀ7.00 (m, 3H), 5.63 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 163.5 (d, JCꢀF
=
249.3 Hz), 136.5, 136.0, 129.2, 128.5, 128.1, 127.2, 127.1, 125.2, 118.5, 116.1 (d, JCꢀF = 21.9 Hz), 110.2,
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The Journal of Organic Chemistry
106.2; LRMS (EI, 70 eV) m/z (%): 268 (M+, 100), 241 (21), 236 (16); HRMS (ESI): Calcd for
C15H10FN2S+ ([M + H]+): 269.0543, Found: 269.0559.
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3ꢀ(2ꢀfluorophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3d): Yellow solid (34.7 mg, 65%); m.p.
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107ꢀ108 °C; H NMR (500 MHz, CDCl3) δ 7.36ꢀ7.29 (m, 2H), 7.26ꢀ7.25 (m, 1H), 7.22ꢀ7.18 (m, 1H),
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7.15ꢀ7.12 (m, 1H), 7.10ꢀ7.06 (m, 2H), 7.04ꢀ7.02 (m, 1H), 5.74 (s, 1H); C NMR (125 MHz, CDCl3) δ
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159.8 (d, JCꢀF = 249.8 Hz), 136.1, 132.3, 131.9, 131.8, 130.7, 128.2, 127.14, 127.08, 124.7, 120.4, 118.2,
116.4 (d, JCꢀF = 21.3 Hz), 109.9, 109.2; LRMS (EI, 70 eV) m/z (%): 268 (M+, 100), 241 (16), 121 (15);
HRMS (ESI): Calcd for C15H10FN2S+ ([M + H]+): 269.0543, Found: 269.0558.
3ꢀ(4ꢀchlorophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3e): Yellow solid (40.3 mg, 71%); m.p.
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123ꢀ124 °C; H NMR (500 MHz, CDCl3) δ 7.32ꢀ7.30 (m, 2H), 7.29ꢀ7.26 (m, 3H), 7.21ꢀ7.18 (m, 1H),
7.10ꢀ7.07 (m, 1H), 7.02ꢀ7.00 (m, 1H), 5.69 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 136.2, 136.0, 135.8,
130.8, 129.2, 128.4, 128.2, 127.3, 127.1, 125.1, 118.6, 110.2, 107.1; LRMS (EI, 70 eV) m/z (%): 284
(M+, 100), 286 (39), 249 (33), 222 (31); HRMS (ESI): Calcd for C15H10ClN2S+ ([M + H]+): 285.0248,
Found: 285.0249.
3ꢀ(3ꢀchlorophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3f): Yellow solid (41.1 mg, 72%); m.p.
1
114ꢀ115 °C; H NMR (500 MHz, CDCl3) δ 7.34 (s, 1H), 7.30ꢀ7.27 (m, 3H), 7.25ꢀ7.22 (m, 1H), 7.21ꢀ
7.18 (m, 1H), 7.11ꢀ7.08 (m, 1H), 7.03ꢀ7.01 (m, 1H), 5.75 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 136.0,
135.9, 135.0, 134.1, 130.2, 129.9, 128.3, 127.4, 127.3, 127.2, 125.2, 125.1, 118.7, 110.1, 108.0; LRMS
(EI, 70 eV) m/z (%): 284 (M+, 100), 286 (36), 249 (39); HRMS (ESI): Calcd for C15H10ClN2S+ ([M +
H]+): 285.0248, Found: 285.0254.
3ꢀ(4ꢀbromophenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3g): Yellow solid (46.9 mg, 71%); m.p.
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131ꢀ132 °C; H NMR (500 MHz, CDCl3) δ 7.56ꢀ7.54 (m, 2H), 7.36ꢀ7.34 (m, 1H), 7.30ꢀ7.26 (m, 3H),
7.18ꢀ7.15 (m, 1H), 7.10ꢀ7.08 (m, 1H), 5.78 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 136.2, 135.9, 132.1,
131.2, 128.6, 128.2, 127.3, 127.1, 125.1, 124.1, 118.6, 110.2, 107.2; LRMS (EI, 70 eV) m/z (%):
328/330 (M+, 100), 249 (51), 222 (56), 124 (18); HRMS (ESI): Calcd for C15H10BrN2S+ ([M + H]+):
328.9743, Found: 328.9750.
3ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3h): Yellow solid (41.2 mg,
65%); m.p. 108ꢀ109 °C; 1H NMR (500 MHz, CDCl3) δ 7.62ꢀ7.61 (m, 2H), 7.49ꢀ7.47 (m, 2H), 7.31ꢀ7.29
(m, 1H), 7.24ꢀ7.21 (m, 1H), 7.13ꢀ7.10 (m, 1H), 7.05ꢀ7.03 (m, 1H), 5.84 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 135.9, 135.82, 135.81, 135.78, 131.6 (q, JCꢀF = 32.6 Hz), 128.4, 127.4, 127.2, 126.0, 124.9,
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123.7 (q, JCꢀF = 270.8 Hz), 118.7, 110.1, 109.1; LRMS (EI, 70 eV) m/z (%): 318 (M+, 100), 286 (11),
249 (16), 121 (11); HRMS (ESI): Calcd for C16H10F3N2S+ ([M + H]+): 319.0511, Found: 319.0518.
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methyl 2ꢀ(4ꢀcyanoꢀ4Hꢀbenzo[b][1,4]thiazinꢀ3ꢀyl)benzoate (3i): Yellow solid (26.5 mg, 43%); m.p. 111ꢀ
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112 °C; H NMR (500 MHz, CDCl3) δ 8.09ꢀ8.07 (m, 1H), 7.60ꢀ7.57 (m, 1H), 7.54ꢀ7.51 (m, 1H), 7.44ꢀ
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7.42 (m, 1H), 7.26ꢀ7.23 (m, 1H), 7.20ꢀ7.19 (m, 1H), 7.15ꢀ7.12 (m, 1H), 7.09ꢀ7.08 (m, 1H), 5.47 (s, 1H),
3.71 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.9, 136.97, 136.94, 133.6, 132.70, 132.5, 131.2, 130.2,
129.9, 127.9, 127.0, 126.8, 122.9, 117.5, 109.7, 104.2, 52.4; LRMS (EI, 70 eV) m/z (%): 308 (M+, 100),
276 (47), 248 (58), 222 (15); HRMS (ESI): Calcd for C17H12N2NaO2S+ ([M + Na]+): 331.0512, Found:
331.0525.
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3ꢀ(pꢀtolyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3j)5a: Yellow solid (38.1 mg, 72%); m.p. 95ꢀ96 °C;
1H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.35 (m, 1H), 7.32ꢀ7.31 (m, 2H), 7.28ꢀ7.25 (m, 1H), 7.23ꢀ7.21 (m,
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2H), 7.17ꢀ7.13 (m, 1H), 7.10ꢀ7.08 (m, 1H), 5.69 (s, 1H), 2.37 (s, 3H); C NMR (125 MHz, CDCl3) δ
140.1, 137.7, 136.3, 129.6, 129.5, 128.0, 127.13, 127.10, 127.07, 125.5, 118.5, 110.5, 105.1, 21.3;
LRMS (EI, 70 eV) m/z (%): 264 (M+, 100), 249 (16), 232 (12).
3ꢀ(mꢀtolyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3k): Yellow solid (37.9 mg, 72%); m.p. 144ꢀ
145 °C; 1H NMR (500 MHz, CDCl3) δ 7.30ꢀ7.28 (m, 1H), 7.23ꢀ7.12 (m, 5H), 7.08ꢀ7.05 (m, 1H), 7.01ꢀ
7.00 (m, 1H), 5.64 (s, 1H), 2.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.6, 137.7, 136.4, 132.4,
130.7, 128.7, 128.0, 127.9, 127.08, 127.06, 125.4, 124.3, 118.5, 110.4, 105.9, 21.3; LRMS (EI, 70 eV)
m/z (%): 264 (M+, 100), 249 (21), 231 (12); HRMS (ESI): Calcd for C16H13N2S+ ([M + H]+): 265.0794,
Found: 265.0795.
3ꢀ(4ꢀethylphenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3l): Yellow solid (39.1 mg, 70%); m.p. 79ꢀ
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80 °C; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.33 (m, 3H), 7.28ꢀ7.24 (m, 3H), 7.16ꢀ7.13 (m, 1H), 7.10ꢀ
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7.08 (m, 1H), 5.70 (s, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); C NMR (125 MHz,
CDCl3) δ 146.3, 137.7, 136.3, 129.7, 128.4, 128.0, 127.2, 127.09, 127.06, 125.5, 118.5, 110.5, 105.2,
28.6, 15.2; LRMS (EI, 70 eV) m/z (%): 278 (M+, 100), 263 (50), 249 (19); HRMS (ESI): Calcd for
C17H15N2S+ ([M + H]+): 279.0950, Found: 279.0963.
3ꢀ(4ꢀpropylphenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3m): Yellow oil (43.8 mg, 75%); 1H NMR
(500 MHz, CDCl3) δ 7.38ꢀ7.33 (m, 3H), 7.29ꢀ7.28 (m, 1H), 7.24ꢀ7.22 (m, 2H), 7.18ꢀ7.15 (m, 1H), 7.11ꢀ
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7.10 (m, 1H), 5.72 (s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 1.68ꢀ1.62 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H); C
NMR (125 MHz, CDCl3) δ 144.8, 137.7, 136.4, 129.7, 128.9, 128.0, 127.07, 127.06, 127.05, 125.6,
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118.5, 110.5, 105.2, 37.8, 24.2, 13.8; LRMS (EI, 70 eV) m/z (%): 292 (M+, 100), 263 (89), 236 (15);
HRMS (ESI): Calcd for C18H17N2S+ ([M + H]+): 293.1107, Found: 293.1112.
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3ꢀ(4ꢀbutylphenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3n): Yellow oil (44.6 mg, 73%); H NMR
(500 MHz, CDCl3) δ 7.30ꢀ7.28 (m, 1H), 7.26ꢀ7.24 (m, 2H), 7.20ꢀ7.17 (m, 1H), 7.15ꢀ7.13 (m, 2H), 7.08ꢀ
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7.05 (m, 1H), 7.02ꢀ7.00 (m, 1H), 5.62 (s, 1H), 2.54 (t, J = 8.0 Hz, 2H), 1.56ꢀ1.49 (m, 2H), 1.30ꢀ1.26 (m,
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2H), 0.85 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) δ 145.0, 137.7, 136.4, 129.6, 128.9, 128.0,
127.09, 127.08, 127.05, 125.6, 118.5, 110.5, 105.2, 35.4, 33.2, 22.3, 13.9; LRMS (EI, 70 eV) m/z (%):
306 (M+, 100), 263 (85), 236 (15); HRMS (ESI): Calcd for C19H19N2S+ ([M + H]+): 307.1263, Found:
307.1267.
3ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3o): Yellow solid (44.0 mg, 72%);
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m.p. 125ꢀ126 °C; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.35 (m, 2H), 7.31ꢀ7.28 (m, 3H), 7.22ꢀ7.19 (m,
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1H), 7.10ꢀ7.07 (m, 1H), 7.04ꢀ7.02 (m, 1H), 5.65 (s, 1H), 1.25 (s, 9H); C NMR (125 MHz, CDCl3) δ
153.2, 137.7, 136.4, 129.4, 128.0, 127.1, 126.93, 126.92, 125.9, 125.6, 118.6, 110.6, 105.3, 34.8, 31.2;
LRMS (EI, 70 eV) m/z (%): 306 (M+, 100), 291 (81), 250 (30), 132 (24); HRMS (ESI): Calcd for
C19H19N2S+ ([M + H]+): 307.1263, Found: 307.1267.
3ꢀ(4ꢀmethoxyphenyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3p)5a: Yellow solid (41.5 mg, 74%); m.p.
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122ꢀ123 °C; H NMR (500 MHz, CDCl3) δ 7.36ꢀ7.35 (m, 3H), 7.27ꢀ7.24 (m, 1H), 7.16ꢀ7.13 (m, 1H),
7.09ꢀ7.08 (m, 1H), 6.94ꢀ6.92 (m, 2H), 5.62 (s, 1H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.8,
137.6, 136.3, 128.7, 127.9, 127.1, 127.0, 125.6, 124.6, 118.5, 114.3, 110.5, 104.1, 55.3; LRMS (EI, 70
eV) m/z (%): 280 (M+, 100), 265 (43), 237 (16).
3ꢀ(thiophenꢀ3ꢀyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3q): Yellow solid (31.6 mg, 62%); m.p. 96ꢀ
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97 °C; H NMR (500 MHz, CDCl3) δ 7.52ꢀ7.51 (m, 1H), 7.37ꢀ7.34 (m, 2H), 7.28ꢀ7.25 (m, 1H), 7.17ꢀ
7.14 (m, 2H), 7.10ꢀ7.09 (m, 1H), 5.82 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 136.2, 133.2, 132.8,
128.1, 127.2, 126.8, 126.0, 125.9, 125.5, 124.4, 118.8, 110.5, 105.8; LRMS (EI, 70 eV) m/z (%): 256
+
(M+, 100), 229 (33), 211 (16), 108 (9); HRMS (ESI): Calcd for C13H8N2NaS2 ([M + Na]+): 279.0021,
Found: 279.0034.
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3ꢀ(cyclohexꢀ1ꢀenꢀ1ꢀyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3r): Yellow oil (33.9 mg, 67%); H
NMR (500 MHz, CDCl3) δ 7.29ꢀ7.27 (m, 1H), 7.25ꢀ7.22 (m, 1H), 7.15ꢀ7.08 (m, 2H), 6.19 (t, J = 4.0 Hz,
1H), 5.67 (s, 1H), 2.23ꢀ2.20 (m, 2H), 2.18ꢀ2.15 (m, 2H), 1.75ꢀ1.70 (m, 2H), 1.65ꢀ1.62 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 139.1, 136.6, 130.3, 129.7, 127.9, 127.0, 126.90, 126.87, 119.2, 111.3, 105.2,
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26.2, 25.4, 22.2, 21.6; LRMS (EI, 70 eV) m/z (%): 254 (M+, 100), 239 (19), 221 (21); HRMS (ESI):
Calcd for C15H15N2S+ ([M + H]+): 255.0950, Found: 255.0951.
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3ꢀoctylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3s): Yellow oil (40.0 mg, 70%); H NMR (500 MHz,
CDCl3) δ 7.14ꢀ7.10 (m, 2H), 7.02ꢀ6.99 (m, 1H), 6.95ꢀ6.94 (m, 1H), 5.20 (s, 1H), 2.33 (t, J = 7.5 Hz, 2H),
1.49ꢀ1.45 (m, 2H), 1.27ꢀ1.17 (m, 10H), 0.79 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 135.5,
134.5, 126.7, 126.1, 125.6, 122.7, 116.4, 108.8, 100.0, 31.8, 30.7, 28.1, 28.0, 27.7, 26.1, 21.6, 13.0;
LRMS (EI, 70 eV) m/z (%): 286 (M+, 100), 188 (33), 155 (25); HRMS (ESI): Calcd for C17H23N2S+ ([M
+ H]+): 287.1576, Found: 287.1577.
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7ꢀmethylꢀ3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3t)5b: Yellow solid (38.9 mg, 74%); m.p.
119ꢀ120 °C; 1H NMR (500 MHz, CDCl3) δ 7.43ꢀ7.40 (m, 5H), 7.25 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.5
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Hz, 1H), 6.91 (s, 1H), 5.75 (s, 1H), 2.30 (s, 3H); C NMR (125 MHz, CDCl3) δ 137.5, 137.3, 133.7,
132.5, 129.8, 128.9, 128.7, 127.5, 127.2, 125.0, 118.4, 110.6, 106.1, 20.6; LRMS (EI, 70 eV) m/z (%):
264 (M+, 100), 236 (13), 231 (16).
7ꢀmethoxyꢀ3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3u)5b: Yellow solid (41.9 mg, 75%); m.p.
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126ꢀ127 °C; H NMR (500 MHz, CDCl3) δ 7.43ꢀ7.41 (m, 5H), 7.27 (d, J = 8.5 Hz, 1H), 6.80ꢀ6.77 (m,
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1H), 6.64 (d, J = 2.5 Hz, 1H), 5.76 (s, 1H), 3.78 (s, 3H); C NMR (125 MHz, CDCl3) δ 158.5, 137.9,
132.4, 129.8, 129.0, 128.9, 127.1, 126.9, 119.5, 113.3, 112.3, 110.8, 105.7, 55.7; LRMS (EI, 70 eV) m/z
(%): 280 (M+, 100), 236 (37), 134 (32).
3ꢀphenylꢀ7ꢀ(trifluoromethyl)ꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3v): Yellow solid (25.7 mg,
40%); m.p. 74ꢀ75 °C; 1H NMR (500 MHz, CDCl3) δ 7.54ꢀ7.52 (m, 1H), 7.46ꢀ7.41 (m, 6H), 7.35 (s, 1H),
5.72 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 139.5, 137.6, 131.9, 130.3, 129.7 (q, JCꢀF = 33.3 Hz), 129.0,
127.4, 126.7, 125.3, 124.3, 123.2 (q, JCꢀF = 267.8 Hz), 118.5, 109.5, 105.4; LRMS (EI, 70 eV) m/z (%):
318 (M+, 100), 298 (17), 291 (18), 217 (25); HRMS (ESI): Calcd for C16H10F3N2S+ ([M + H]+):
319.0511, Found: 319.0519.
7ꢀbromoꢀ3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3w): Yellow solid (33.4 mg, 51%); m.p.
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121ꢀ122 °C; H NMR (500 MHz, CDCl3) δ 7.36ꢀ7.33 (m, 5H), 7.31ꢀ7.29 (m, 1H), 7.16ꢀ7.14 (m, 2H),
5.64 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 137.8, 135.6, 132.0, 130.9, 130.1, 129.6, 129.0, 127.7,
127.3, 120.1, 119.7, 109.8, 105.5; LRMS (EI, 70 eV) m/z (%): 328/330 (M+, 100), 249 (69), 222 (52),
125 (25); HRMS (ESI): Calcd for C15H10BrN2S+ ([M + H]+): 328.9743, Found: 328.9746.
7ꢀchloroꢀ3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile (3x)5b: Yellow solid (31.9 mg, 56%); m.p.
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112ꢀ113 °C; H NMR (500 MHz, CDCl3) δ 7.35ꢀ7.33 (m, 5H), 7.22ꢀ7.20 (m, 1H), 7.17ꢀ7.14 (m, 1H),
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7.02ꢀ7.01 (m, 1H), 5.64 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 137.9, 135.0, 132.7, 132.0, 130.1, 129.0,
128.0, 127.4, 127.3, 126.8, 119.4, 109.9, 105.4; LRMS (EI, 70 eV) m/z (%): 284 (M+, 100), 249 (35),
222 (39), 125 (29).
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3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarboxamide (4): Pale yellow solid (39.0 mg, 73%); m.p. 170ꢀ171
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°C; H NMR (500 MHz, CDCl3) δ 7.55ꢀ7.53 (m, 1H), 7.48ꢀ7.47 (m, 2H), 7.31ꢀ7.21 (m, 5H), 7.14ꢀ7.11
(m, 1H), 6.75 (s, 1H), 5.00 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 155.3, 139.8, 137.9, 135.2, 133.6,
129.2, 128.8, 127.22, 127.19, 127.06, 126.5, 125.1, 118.2; LRMS (EI, 70 eV) m/z (%): 268 (M+, 23),
225 (100), 224 (45), 193 (21); HRMS (ESI): Calcd for C15H13ON2S+ ([M + H]+): 269.0743, Found:
269.0753.
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3ꢀphenylꢀ4Hꢀbenzo[b][1,4]thiazineꢀ4ꢀcarbonitrile 1,1ꢀdioxide (5)13: White solid (51.7mg, 92%); m.p.
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130ꢀ131 °C; H NMR (500 MHz, CDCl3) δ 8.15ꢀ8.13 (m, 1H), 7.80ꢀ7.79 (m, 2H), 7.65ꢀ7.61 (m, 4H),
7.58–7.55 (m, 2H), 6.31 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 144.7, 134.1, 133.8, 132.4, 130.7,
129.3, 128.9, 127.75, 127.65, 123.9, 117.9, 109.2, 106.0; LRMS (EI, 70 eV) m/z (%): 282 (M+, 40), 218
(100), 190 (14), 105 (13).
Nꢀ(2ꢀchlorophenyl)cyanamide (7)15: White solid (21.7mg, 71%); m.p. 103ꢀ104 °C; 1H NMR (500 MHz,
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CDCl3) δ 7.29ꢀ7.28 (m, 1H), 7.24ꢀ7.19(m, 2H), 6.98–6.95 (m, 1H), 6.53 (s, 1H); C NMR (125 MHz,
CDCl3) δ 134.0, 129.7, 128.3, 124.3, 120.2, 116.0, 109.8; LRMS (EI, 70 eV) m/z (%): 152 (M+, 100),
125 (36), 117 (21), 90 (22).
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Nꢀphenylcyanamide (9)15: White solid (17.8mg, 75%); m.p. 43ꢀ44 °C; H NMR (500 MHz, CDCl3) δ
7.32 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 137.3, 129.7, 123.5, 115.4, 111.5; LRMS (EI, 70 eV) m/z (%): 118 (M+, 100), 91 (90), 77 (25), 51
(19).
Acknowledgment. We thank the National Natural Science Foundation of China (No. 21272177 and
21276200) and Zhejiang Provincial Natural Science Foundation of China (No. LR15B020002) for
financial support.
Supporting Information Available: Copies of 1H and 13C NMR spectra for product 3aꢀ3x, 4, 5, 7 and
9. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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(1) (a) Cecchetti, V.; Fravolini, A.; Fringuelli, R.; Mascellani, G.; Pagella, P.; Palmioli, M.; Segre, G.;
Terni, P. J. Med. Chem. 1987, 30, 465. (b) Schiaffella, F.; Macchiarulo, A.; Milanese, L.; Vecchiarelli,
A.; Costantino, G.; Pietrella, D.; Fringuelli, R. J. Med. Chem. 2005, 48, 7658.
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(2) Tawada, H.; Sugiyama, Y.; Ikeda, H.; Yamamoto, Y.; Meguro, K. Chem. Pharm. Bull. 1990, 38,
1238.
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