Copper-Catalyzed Synthesis of 1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives by coupling of 2-Halobenzenesulfonamides with amidines

Article abstract of DOI:10.1002/adsc.200900101

We have developed a simple and practical copper-catalyzed method for the synthesis of 1,2,4-benzothiadiazine 1,1-dioxide derivatives via cascade reactions of substituted 2-halobenzenesulfonamides with amidines, and the method is of value for the construction of this kind of molecules with biological and medicinal activities.

Full text of DOI:10.1002/adsc.200900101

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DOI: 10.1002/adsc.200900101
Copper-Catalyzed Synthesis of 1,2,4-Benzothiadiazine 1,1-Dioxide
Derivatives by Coupling of 2-Halobenzenesulfonamides with
Amidines
Daoshan Yang,a,b Hongxia Liu,c Haijun Yang,a Hua Fu,a,* Liming Hu,b,*
Yuyang Jiang,a,c and Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+ 86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
College of Life Sciences and Bioengineering, Beijing University of Technology, Beijing 100124, Peopleꢀs Republic of
b
China
E-mail: huliming@bjut.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University,
c
Shenzhen 518057, Peopleꢀs Republic of China
Received: February 12, 2009; Revised: June 19, 2009; Published online: August 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900101.
Abstract: We have developed a simple and practical construction of this kind of molecules with biological
copper-catalyzed method for the synthesis of 1,2,4- and medicinal activities.
benzothiadiazine 1,1-dioxide derivatives via cascade
reactions of substituted 2-halobenzenesulfonamides Keywords:
1,2,4-benzothiadiazine
1,1-dioxides;
with amidines, and the method is of value for the copper; cyclization; ortho-substituent effect; synthet-
ic methods
Introduction
moval of AMPA receptor desensitization.[6] Some cy-
clothiazide derivatives exhibit physico-chemical char-
Benzothiadiazine 1,1-dioxide derivatives have been acteristics which should facilitate the crossing of the
used as ATP-sensitive potassium channel openers that blood-brain barrier and have potential application in
can activate channels (such as diazoxide in the treatment of attention disorders in children as
Figure 1),[1] and they have been shown to reduce the well as senile dementias. In addition, some of the ben-
AMPA receptor desensitization[2] and improve the im- zothiadiazine derivatives (such as A in Figure 1) have
paired synaptic transmission of functions, which are also been shown to possess antiviral activities[7] partic-
useful action in the treatment of early stages of Alz- ularly against human herpes virus 6 (HHV-6), human
heimer’s disease.[3] Cyclothiazid[4] and IDRA 21[5] cytomegalovirus (H-CMV) and Varicella-Zoster virus
have been demonstrated to be among the most potent (VVZ), and they have been also reported as heterocy-
compounds that enhance synaptic transmission by re- clic inhibitors of PDE7 with concurrent inhibitory ac-
tivity at PDE4 and PDE3.[8]
Although some methods have been developed for
synthesis of benzothiadiazine 1,1-dioxides deriva-
tives,[1b–e,7e,9] these routes are often troublesome and
some of the starting materials are not readily avail-
able (Scheme 1). It is highly desirable to develop
more convenient and efficient approaches. In the past
decade, copper-catalyzed Ullmann N-arylations have
made great progress,[10] and the N-arylation strategy
Figure 1. Examples of benzothiadiazine 1,1-dioxide deriva-
tives as ATP-sensitive potassium channel openers or HCV
has been used to make N-heterocycles.[11] Recently,
polymerase inhibitors.
we have developed some efficient copper catalyst sys-
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1999

Daoshan Yang et al.
FULL PAPERS
Scheme 1. Examples for synthesis of benzothiadiazine-1,1-dioxide derivatives.[9a,d]
tems for use in N-arylations,[12] and some of N-hetero- Table 1. Copper-catalyzed coupling of 2-bromobenzenesulfo-
namide with butyramidine hydrochloride: optimization of
cycles have been constructed via the Ullmann cou-
pling.[13] As a continuation of our research, herein, we
report a simple and efficient copper-catalyzed method
for synthesis of benzothiadiazine 1,1-dioxide deriva-
tives without addition of any ligand or additive.
conditions.[a]
Results and Discussion
Entry Catalyst Base
Solvent
Temp.
[8C]
Yield
[%][b]
2-Bromobenzenesulfonamide and butyramidine hy-
drochloride were initially chosen as the model sub-
strates to optimize reaction conditions including the
catalysts, bases and solvents under a nitrogen atmos-
phere. As shown in Table 1, reaction temperature was
investigated using CuI as the catalyst, Cs2CO3 as the
base and DMF as the solvent under a nitrogen atmos-
phere (entries 1–3), yield of the target product
reached a maximum when the temperature was raised
to 1108C (entry 3). Three copper catalysts were tested
at 1108C (entries 3–5), and CuBr showed the best ac-
tivity (entry 4). The reaction gave the same yield as
the result in entry 4 when proline was used as the
ligand (entry 6). Several bases, Cs2CO3, K3PO4 and
K2CO3, were screened, and Cs2CO3 proved to be most
effective (compare entries 4, 7 and 8). The effect of
solvents was also investigated (compare entries 4, 9–
11), and DMF was the best choice (entry 4).
1
2
3
4
5
6
7
8
CuI
CuI
CuI
Cs2CO3 DMF
50
80
50
70
77
80
75
80[c]
55
68
70
0
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
K3PO4 DMF
K2CO3 DMF
Cs2CO3 DMSO
Cs2CO3 toluene
Cs2CO3 1,4-diox-
ane
110
110
110
110
110
110
110
110
110
CuBr
CuCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
77
[a]
Reaction conditions: under nitrogen atmosphere, reaction
time (5 h). 2-Bromobenzenesulfonamide (1 mmol), butyr-
amidine hydrochloride (1.2 mmol), catalyst (0.1 mmol),
base (1.5 mmol), solvent (2 mL).
Isolated yield.
l-Proline (0.2 mmol) as the ligand was added.
[b]
[c]
We then investigated the scope of copper-catalyzed
couplings of the substituted 2-halobenzenesulfon-
ACHTUNGTRENNUNGamides with amidine hydrochlorides under the opti- worthwhile to note that the copper-catalyzed cou-
mized catalytic conditions determined above. As plings of the substituted 2-halobenzenesulfonamides
shown in Table 2, the substrates examined provided with amidines were performed in the absence of
good to excellent yields. For the substituted 2-halo- ligand and additive, this result also illustrates the
benzenesulfonamides, electron-withdrawing as well as ortho-substituent effect.
electron-donating substituents did not significantly
We also explored the formation mechanism of
affect the catalytic activity. Reactions of 2,5-dibromo- 1,2,4-benzothiadiazine 1,1-dioxide derivatives. Cou-
benzenesulfonamide with amidines only took place pling of benzenesulfonamide (4) with butyramidine
À
on the ortho-site C Br bond of the sulfonamide hydrochloride (2b) did not work under our standard
group, the 5-site C Br bond remained intact, and the condition (Scheme 2A), and reaction of 15N-labeled
À
result showed the ortho-substituent effect of the sulfon- 2-bromo-4-trifluoromethylbenzenesulfonamide
(1f)
ACHTUNGTRENNUNG
amide group during N-arylations (entries 13–15). It is with butyramidine hydrochloride (2b) led to fully 15N-
2000
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Copper-Catalyzed Synthesis of 1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives
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Table 2. Copper-catalyzed synthesis of benzothiadiazines-1,1-dioxides derivatives.[a]
Entry
1
1
2
Product
Yield [%][b]
77
1a
2a
3a
2
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
3b
3c
3d
3e
3f
3g
3h
3i
80
3
75
4
70[c]
65[c]
75[c]
81
5
6
7
8
78
9
80
10
11
12
3j
77[c]
75[c]
80[c]
3k
3l
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Daoshan Yang et al.
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Table 2. (Continued)
Entry
1
2
Product
Yield [%][b]
70[d]
13
1e
2a
3m
14
1e
1e
2b
2c
3n
3o
68[d]
65[d]
15
[a]
Reaction conditions: under nitrogen atmosphere, reaction temperature (1108C), reaction time (5 h). 1 (1 mmol), 2
(1.2 mmol), CuBr (0.1 mmol), Cs2CO3 (1.5 mmol), DMF (2 mL).
Isolated yield.
Reaction time (10 h).
Reaction time (12 h).
[b]
[c]
[d]
Scheme 2. Reaction of butyramidine hydrochloride with benzenesulfonamide (4) (A) or 15N-labeled 2-bromo-4-trifluoro-
methyl-benzenesulfonamide (1 f) (B) under the optimized catalytic conditions.
labeled
6-trifluoromethyl-3-propyl-2H-1,2,4-benzo- (Scheme 2B). The result implied that nucleophilic
thiadiazine 1,1-dioxide (3p) whose structure was eluci- attack of the amino group in the amidine to sulfoma-
1
dated by H, 13C, 15N NMR and high resolution mass mide was impossible. A possible formation mecha-
spectrometry
(see
Supporting
Information) nism for 1,2,4-benzothiadiazine 1,1-dioxide derivatives
is proposed in Scheme 3 on the basis of the results
above. Ullmann coupling of the substituted 2-halo-
benzenesulfonamide and the amidine produced inter-
mediate I and, in the presence of base (Cs2CO3), nu-
cleophilic attack of the amino group of the sulfona-
mide to the amidine in I affords the target product 3
while releasing ammonia.
Conclusions
We have developed an efficient method for the syn-
thesis of 1,2,4-benzothiadiazine 1,1-dioxide deriva-
tives. The couplings were performed using readily
available starting materials (substituted 2-halobenze-
Scheme 3. Possible formation mechanism of 1,2,4-benzothia-
diazine 1,1-dioxide derivatives.
2002
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Copper-Catalyzed Synthesis of 1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives
FULL PAPERS
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Experimental Section
General Procedure for Copper-Catalyzed Synthesis of
1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives (3a–p)
and 5
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 20672065, 20732004), the
Ministry of Science and Technology of China (Grant Nos.
2007AA02Z160, 2006DFA43030). Programs for New Centu-
ry Excellent Talents in University (NCET-05-0062) in China,
the Key Subject Foundation from Beijing Department of
Education (XK100030514) and the National Basic Research
Program of China (No. 2009CB930200).
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