Synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives via intramolecular C–H activation reactions of trichloroacetamidine and benzenesulfonyl chloride

Article abstract of DOI:10.1016/j.tetlet.2018.04.038

The synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives was achieved through a novel three-component intramolecular C–H activation reaction of trichloroacetonitrile, benzenesulfonyl chloride, and various primary amines. This reaction was performed in the presence of catalytic copper(I) and L-proline as the ligand in tetrahydrofuran at room temperature.

Full text of DOI:10.1016/j.tetlet.2018.04.038

Accepted Manuscript
Synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives via intra-
molecular C-H activation reactions of trichloroacetamidine and benzenesulfonyl
chloride
Manijeh Nematpour, Elham Rezaee, Mehdi Jahani, Sayyed Abbas Tabatabai
PII:
S0040-4039(18)30495-7
https://doi.org/10.1016/j.tetlet.2018.04.038
TETL 49901
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 February 2018
9 April 2018
16 April 2018
Please cite this article as: Nematpour, M., Rezaee, E., Jahani, M., Tabatabai, S.A., Synthesis of functionalized
benzothiadiazine 1,1-dioxide derivatives via intramolecular C-H activation reactions of trichloroacetamidine and
benzenesulfonyl chloride, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.038
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Page 1 of 10
Synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives via intramolecular C-H
activation reactions of trichloroacetamidine and benzenesulfonyl chloride
Manijeh Nematpour1, Elham Rezaee1, Mehdi Jahani2 and Sayyed Abbas Tabatabai1*
1
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran. e-mail address: sa_tabatabai@sbmu.ac.ir.
2
Department of Chemistry, Sharif University of Technology, Tehran, Iran.
ABSTRACT
The synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives was achieved through a
novel three-component intramolecular C-H activation reaction of trichloroacetonitrile,
benzenesulfonyl chloride, and various primary amines. This reaction was performed in the
presence of catalytic copper(I) and L-proline as the ligand in tetrahydrofuran at room
temperature.
Keywords:
C-H Activation
Copper-catalyzed
Benzothiadiazine 1,1-dioxide
Benzenesulfonyl chloride
Trichloroacetonitrile
Primary amine
* Corresponding author. e-mail address: sa_tabatabai@sbmu.ac.ir (Sayyed Abbas Tabatabai).
1

Page 2 of 10
Benzothiadiazine 1,1-dioxide derivatives are the key structural motifs in various
biologically active molecules.1 They have shown antiviral activities against Hepatitis C virus
(HCV) (Fig. 1), human herpes virus 6 (HHV-6) and Varicella-Zoster virus (VZV).2-4 Moreover,
benzothiadiazine 1,1-dioxide derivatives have revealed excellent biological activity in the
treatment of cancer5 and the early stages of Alzheimer disease,6 and have also been used as
potassium channel openers (PCOs) that can activate KATP channels7 (Fig. 1).
Figure 1. Representative examples of benzothiadiazine 1,1-dioxide derivatives as HCV polymerase inhibitors (A)
and ATP-sensitive potassium channel openers (Diazoxide).
Recently, many methods have been developed for the synthesis of benzothiadiazines.8
These methods often require toxic reagents, harsh reaction conditions, expensive catalysts,
inconvenient multi-step processes, high temperatures, long reaction times and also produce
undesirable by-products. Therefore, the development of an efficient and practical method for the
synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives under mild conditions is
desirable.
An immense effort has been made to develop efficient strategies for the direct
functionalization of C-H bonds using transition-metal catalysis. The intramolecular
heterofunctionalization of C-H bonds is an ideal, truly atom-economical approach for the
construction of new heterocyclic architectures. A rapidly growing number of different types of
2

Page 3 of 10
heterocycles, especially those containing nitrogen, have been constructed by applying this novel
strategy in recent years.9 Recently, we reported that quinazoline derivatives could be formed by
intramolecular C-H bond functionalization.10 We were eager to extend our approach to the
synthesis of other classes of heterocycles, such as benzothiadiazine 1,1-dioxide derivatives, by
copper-catalyzed C-H activation reactions which are of remarkable importance in medicinal
chemistry.
Herein, we report a novel, simple and efficient protocol for the synthesis of various
functionalized benzothiadiazine 1,1-dioxide derivatives via the copper-catalyzed C-H activation
reactions of trichloroacetamidines11 and benzenesulfonyl chlorides (see Scheme 1). Compared
with conventional methods, this method has considerable advantages such as mild conditions,
easy work-up, uses readily-available starting materials including the catalyst, and results in
highly pure products in good yields.
Scheme 1. Synthesis of various benzothiadiazine 1,1-dioxide derivatives via the Cu-catalyzed intramolecular C-H
activation reactions of trichloroacetamidines and benzenesulfonyl chlorides.
Benzylamine, trichloroacetonitrile and benzenesulfonyl chloride were initially chosen as
model substrates to optimize the reaction conditions, including the catalyst, base and solvent, at
room temperature. As shown in Table 1, the copper salts CuI, CuBr, CuCl, Cu(OAc)2 and CuSO4
(10 mol% amount) were tested. CuI was found to be the most effective catalyst. Also THF was
3

Page 4 of 10
the best solvent for the reaction; K2CO3 proved to be most effective among several bases tested,
Cs2CO3, KOH, KOt-Bu, K2CO3 and NaOH. Combining these parameters resulted in the use of
THF, 10 mol% of CuI as the catalyst, 2.0 mmol of K2CO3 as the base, 20 mol% of L-proline as
the ligand, 1.5 mmol of benzenesulfonyl chloride, 1.0 mmol of trichloroacetonitrile and 1.0
mmol of benzylamine (Table 1, entry 1).
Table 1. Optimization of reaction conditions for the formation of product 5a (R1 = Bn, R2 = H) from 1.5 mmol of
benzenesulfonyl chloride, 1.0 mmol of trichloroacetonitrile, 1.0 mmol of benzylamine, 10 mol% of copper salt as
the catalyst, 2.0 mmol of base, and 20 mol% of L-proline as the ligand at room temperature.
Entry
Catalyst
Solvent
Base
Yield 5a
(%)a
80
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
CuI
CuI
CuI
CuCl
CuCl
CuBr
CuBr
CuBr
THF
MeCN
DMF
THF
MeCN
THF
MeCN
DMF
DMF
MeCN
DMF
MeCN
THF
K2CO3
KOt-Bu
NaOH
Cs2CO3
KOH
K2CO3
Cs2CO3
K2CO3
NaOH
Cs2CO3
KOt-Bu
K2CO3
K2CO3
Cs2CO3
K2CO3
63
19
70
38
64
59
62
25
31
20
36
29
15
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuSO4
CuSO4
CuSO4
DMF
MeCN
a
Reaction time 8 h.
b 5 mol% catalyst, reaction time was 12 h.
Using the optimized conditions described above, various benzothiadiazine 1,1-dioxide
derivatives were then synthesized from trichloroacetonitrile, benzenesulfonyl chlorides and
primary amines with various electron-withdrawing or electron-donating substituents on the
aromatic rings (see Table 2).
4

Page 5 of 10
Table 2. Synthesis of various benzothiadiazine 1,1-dioxide derivatives.
Compound
R1
R2
Yield 5 (%)
Bn
H
H
80
84
78
83
81
86
76
75
70
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-Me-CH2C6H4
4-Br-CH2C6H4
4-MeO-CH2C6H4
Ph
Me
Me
Me
NO2
NO2
NO2
H
4-Me-C6H4
4-Cl-C6H4
4-Br-C6H4
2-Cl-C6H4
1
The structures of compounds 5a-i were assigned by IR, H NMR, 13C NMR and mass
1
spectral data. The H NMR spectrum of 5a exhibited one singlet for the CH2 group (δ = 4.61
ppm) along with characteristic multiplets for the phenyl protons. The 13C NMR spectrum of 5a
displayed 12 signals in agreement with the proposed structure. The NMR spectra of other
compounds were similar to those of 5a, except for the substituents, and showed characteristic
signals in the appropriate regions of the spectra. The mass spectrum of 5a displayed the
molecular ion peak at m/z = 389.
A possible reaction mechanism is shown in Scheme 2. It is proposed that
trichloroacetamidine derivative 3 formed from benzylamine 1 and trichloroacetonitrile 2,
undergoes nucleophilic substitution by benzenesulfonyl chloride 4 to give N-sulfonyl
trichloroacetamidine 6. Reaction of CuI with L-proline produced a five-membered chelate A.
5

Page 6 of 10
Oxidative addition of the chelated Cu(I) with compound 6 in the presence of K2CO3 led to
intermediate B stabilized by the amidine nitrogen atom which may coordinate to Cu. Reductive
elimination of B afforded product 5 regenerating the catalyst chelate A. Since
trichloroacetamidine derivative 3 possesses two nucleophilic sites, formation of an alternative
product, namely 2-benzyl-3-(trichloromethyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 7, is
also possible. Structure 7, can be ruled out by studying the HMBC 2D NMR spectrum of the
products. The presence of a cross peak through the CH2 at δH = 4.88 ppm with the C-4a group at
140.0 ppm (in HMBC) confirmed structure 5. Such a connection should not be present in
structure 7. Key HMBC connectivity is also shown in the ESI.
Scheme 2. Possible mechanism for the formation of compound 5.
In conclusion, a novel protocol for the one-pot synthesis of various benzothiadiazine 1,1-
dioxide derivatives via the three-component, intramolecular C-H activation reaction of
6

Page 7 of 10
benzenesulfonyl chlorides and trichloroacetamidines catalyzed by copper(I) iodide in THF at
room temperature is described. Readily, available starting materials, including the catalyst, the
use of mild conditions and the ease of purification resulting in high yields makes this reaction a
suitable method for the synthesis of various benzothiadiazine 1,1-dioxide derivatives.
Acknowledgements
This work was supported by the Research Council of Shahid Beheshti University of
Medical Sciences.
References and Notes
[1] Yang, D.; Liu, H.; Yang, H.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2009, 351,
1999.
[2] Castro, S.; Peromingo, M. T.; Naesens, L.; Andrei, G.; Snoeck, R.; Balzarini, J.; Velazquez,
S.; Camarasa, M. J. J. Med. Chem. 2008, 51, 5823.
[3] Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Comb. Chem. 2009, 11, 653.
[4] a) Castro, A.; Abasolo, M. I.; Gil, C.; Segarra, V.; Martienz, A. Eur. J. Med. Chem. 2001, 36,
333; b) Martinez, A.; Castro, A.; Gil, C.; Miralpiex, M.; Segarra, V.; Domenech, T.; Beleta, J.;
Palacios, J. M.; Ryder, H.; Miro, X.; Bonet, C.; Casacuberta, J. M.; Azorin, F.; Pina, B.;
Puigdomenech, P. J. Med. Chem. 2000, 43, 683.
[5] a) Arranz, M. I.; Diaz, J. A.; Ingate, S. T.; Witrrouw, M.; Pannecouque, C.; Balzarini, J.; De
Clercq, E.; Vega, S. Bioorg. Med. Chem. 1999, 7, 2811; b) Martinez, A.; Gil, C.; Abasolo, M. I.;
Casto, A.; Bruno, A. M.; Perez, C.; Preto, C.; Otero, J. J. Med. Chem. 2000, 43, 3218.
[6] Bliss, T. V. P.; Collingridge, G. L. Nature. 1993, 361, 31.
7

Page 8 of 10
[7] Boverie, S.; Antoine, M. H.; Somers, F.; Becker, B.; Sebille, S.; Ouedraogo, R.; Counerotte,
S.; Pirotte, B.; Lebrun, P.; Tullio, P. J. Med. Chem. 2005, 48, 3492.
[8] a) Rolfe, A.; Hanson, P. R. Tetrahedron. Lett. 2009, 50, 6935; b) Kim, J.; Lee, S. Y.; Lee, J.;
Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454; c) Cherepakha, A.; Kovtunenko, V. O.;
Tolmachev, A.; Lukin, O.; Nazarenko, K. G. Synth. Commun. 2011, 41, 1977; d) Zhao, D.;
Zhou, Y. R.; Shen, Q.; Li, J. X. RSC Adv. 2014, 4, 6486; e) Coghlan, M. J.; Carroll, W. A.;
Gopalakrishnan, M. J. Med. Chem. 2001, 44, 1627; f) de Tullio, P.; Boverie, S.; Becker, B.;
Antoine, M. H.; Nguyen, Q. A.; Francotte, P.; Counerotte, S.; Sebille, S.; Pirotte, B.; Lebrun, P.
J. Med. Chem. 2005, 48, 4990; g) Khazi, A.; Jung, Y. S. Lett. Org. Chem. 2007, 4, 423; h)
Kumar, C. V.; Gopidas, K. R.; Bhattacharyya, K.; Das, P. K.; George, M. V. J. Org. Chem.
1986, 51, 1967.
[9] For recent reviews of C-H functionalization using transition metals, see: a) Godula, K.;
Sames, D. Science 2006, 312, 67; b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174; c) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077; d) Ritleng, V.; Sirlin,
C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
[10] Nematpour, M.; Rezaee, E.; Tabatabai, S. A.; Jahani, M. Synlett 2017, 12, 1441.
[11] Yavari, I.; Nematpour, M.; Sodagar, E. Synlett 2013, 24, 161.
8

Page 9 of 10
Highlights
•Novel synthesis of benzothiadiazine 1,1-dioxide.
•CuI catalyzed the efficient synthesis of benzothiadiazine 1,1-dioxide.
•Intramolecular C-H activation reactions of benzenesulfonylchlorides and trichloroacetamidines.
9

Page 10 of 10
Graphical Abstract
Synthesis of functionalized benzothiadiazine 1,1-dioxide derivatives via intramolecular C-H
activation reactions of trichloroacetamidines and benzenesulfonylchloride
Manijeh Nematpour1, Elham Rezaee1, Mehdi Jahani2 and Sayyed Abbas Tabatabai1*
1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran. e-mail address: sa_tabatabai@sbmu.ac.ir.
2 Department of Chemistry, Sharif University of Technology, Tehran, Iran.
10