Microwave-assisted sequential one-pot protocol to benzothiadiazin-3-one-1,1-dioxides via a copper-catalyzed N-arylation strategy

Article abstract of DOI:10.1016/j.tetlet.2009.09.090

A microwave-assisted, sequential, one-pot protocol has been developed for the synthesis of a variety of benzothiadiazin-3-one-1,1-dioxides. This protocol utilizes a copper-catalyzed N-arylation of α-bromobenzenesulfonamides with a number of amines to gene

Full text of DOI:10.1016/j.tetlet.2009.09.090

Tetrahedron Letters 50 (2009) 6935–6937
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted sequential one-pot protocol to benzothiadiazin-3-one-
1,1-dioxides via a copper-catalyzed N-arylation strategy
*
Alan Rolfe, Paul R. Hanson
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
KU Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 1501 Wakarusa Drive, Lawrence, KS 66047, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2009
Revised 17 September 2009
Accepted 17 September 2009
Available online 25 September 2009
A microwave-assisted, sequential, one-pot protocol has been developed for the synthesis of a variety of
benzothiadiazin-3-one-1,1-dioxides. This protocol utilizes a copper-catalyzed N-arylation of
a-bromo-
benzenesulfonamides with a number of amines to generate the corresponding 2-aminobenzenesulfona-
mides, which undergo cyclization to the desired sultams using carbonyl diimidazole (CDI). A range of
conditions was evaluated for the key C–N bond formation step with tolerance toward functionalized
amines.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Traditionally, sultams have been synthesized using a number of
classical cyclization protocols such as Friedel–Crafts, [3+2] cyc-
The development of protocols for the synthesis of skeletally di-
verse heterocyclic scaffolds is a critical step in the drug discovery
process. The growing demand for libraries of small molecules as
potential small molecule therapeutic agents for high-throughput
screening presents challenging opportunities in this field. One-
pot strategies are highly efficient pathways to rapidly synthesize
complex heterocyclic molecules from simple substrates.1 When
coupled with transition metal-catalyzed processes, one-pot pro-
cesses enable the generation of complex heterocyclic scaffolds
loadditions, Diels–Alder reactions, and recently the application of
oxa- and aza-Michael reactions.4 Notably, there have been a num-
ber of transition metal-catalyzed protocols reported for the gener-
ation of diverse sultams.3,5
In addition to their inherent chemical properties, sultams have
emerged as important targets for drug discovery due to their po-
tent biological activities. In particular, benzothiadiazin-3-one-1,1-
dioxides and their derivatives have shown promising activity,
including hypoglycemic,6 anti-HIV,7 RSV inhibitory activity,8 as
well asand serving as selective antagonists of CXR2 (Fig. 1).9
from simple building blocks. In this regard,
a-haloarylsulfona-
mides represent an attractive building block for the production
of benzofused sultams.2,3
Sultams and their sulfonamide precursors possess a number of
advantageous chemical properties making them ideal building
blocks for the titled process, the most prominent of these include:
O
O
O
O
Cl
S
S
NH
NH
Anti HIV activity
N
H
O
N
H
O
(i) click coupling between starting
rides and amines under mild conditions, (ii) the
be utilized in transition metal-catalyzed cross coupling (iii) the
-halo group enhances the acidity of the aryl sulfonamide N–H en-
a
-halobenzenesulfonyl chlo-
a-halo group can
Hypoglycemic agent
O
O
a
S
N
Bn
O
O
O
HIV-1 Specific
Non-Nucleoside reverse
Transcriptase inhibitor
N
S
N
abling Mitsunobu and conventional alkylation reactions to occur
under mild conditions, and (iv) the commercial availability of a
variety of substituted a-halo benzenesulfonyl chlorides. Taken col-
S
N
O
lectively, these attributes have guided our efforts to develop a
microwave-assisted, sequential one-pot protocol for the synthesis
of benzothiazdiazin-3-one-1,1-dioxides based on a pivotal cop-
per-catalyzed N-arylation strategy.
O
O
Cl
S
(CH2)4F
N
N
N
N
H
N
H
OH
RSV Inhibitors
Selective CXR2 antagonists
* Corresponding author. Tel.: +1 785 864 3094; fax: +1 785 864 5396.
E-mail address: phanson@ku.edu (P.R. Hanson).
Figure 1. Biologically active benzofuzed sultams.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.090

6936
A. Rolfe, P. R. Hanson / Tetrahedron Letters 50 (2009) 6935–6937
Table 2
2. Results and discussion
Catalytic N-arylation of a
-bromobenzene sulfonamides16
Since the observation of copper-catalyzed coupling of a arylbr-
omide with an acetanilide by Goldberg in 1907,10 copper-catalyzed
N-arylation represents an effective reaction for the formation of C–
N and C–O bonds.11 Early reports classically required harsh reac-
tion conditions and stoichiometric quantities of copper. Seminal
work by Buchwald, Hartwig and Ley reported notable advances
in both ligands and reduced reaction temperatures for copper-cat-
alyzed couplings.12
Traditionally, benzothiadiazin-3-one-1,1-dioxides have been
synthesized in a number of linear protocols.6–9,13 Envisioning a
copper-catalyzed approach to benzothiadiazin-3-one-1,1-dioxides,
a variety of conditions were evaluated to probe and subsequently
optimize the N-arylation of allyl amine with N-allyl-2-bromo-4-
fluorobenzenesulfonamide 1 to yield N-allyl-2-(allylamino)-4-flu-
orobenzenesulfonamide 2 (Scheme 1, Table 1).14 An array of cop-
per sources (Table 1, entries 1–3) and ligands (Table 1, entries 4–
7) were initially evaluated followed by a survey of reaction solvent.
Under conventional heating, the desired sulfonamide 2, could be
isolated in 92% yield after 6 h.
Entrya
R1
R2
R3
R4–NH2
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Bn
Bn
Bn
Bn
Bn
4-MeOBn
Cp
Allyl
n-Butyl
Allyl
(CH2)2Bn
Allyl
4-MeOBnNH2
4-ClBnNH2
Octylamine
Phenethylamine
Allylamine
Cyclopentylamine
4-MeOBnNH2
Allyl NH2
90
89
94
91
96
90
96
94
92
95
69
80
H
F
BnNH2
10
11
12
CF3
CF3
H
H
H
F
n-Butyl amine
Propargyl amine
EtC(O)NH2
a
Reaction conditions: sulfonamide (0.17 mmol), amine (0.2 mmol), CuI
(0.017 mmol), 1,10-phenanthroline (0.034 mmol), Cs2CO3 (0.34 mmol) in dry DMSO
(0.5 M) in microwave for 11 min at 150 °C.
With an array of 2-aminobenzenesulonfamides in hand, cycliza-
tion to the corresponding benzothiadiazin-3-one-1,1-dioxides
with carbonyl diimidazole (CDI) was achieved in excellent yields
under thermal conditions (Scheme 3, Table 3).13b,17
Finally with both protocols in hand, a sequential, two-step, one-
pot approach was achieved whereby microwave irradiation affor-
ded the desired benzothiadiazin-3-one-1,1-dioxides in good yield
(Scheme 4).18 To achieve this, the CDI cyclization was conducted
under microwave irradiation following the initial copper-catalyzed
step in the same microwave vial. This required a change of solvent
to DMF which was the optimum compatible solvent for both the N-
arylation and CDI cyclization steps while maintaining good yields.
Further optimization was achieved using microwave irradia-
tion, which reduced reaction times to 11 min at 150 °C with com-
parable yields (Table 1, entry 8 vs 11).15 With these results in hand,
a number of 2-aminobenzenesulfonamide derivatives were syn-
thesized to demonstrate the versatility of the protocol with a vari-
ety of amines, amides, and sulfonamide starting materials (Scheme
2, Table 2).
O
O
O
O
CuX (10 mol%)
Ligand (20 mol%)
S
S
N
N
H
H
Cs2CO3
O
O
O
O
F
N
H
F
Br
CDI (4 eq.)
Et3N, DMF
R1
R2
S
R3
R1
R2
S
N
R3
O
1
2
N
N
H
Scheme 1.
100 ºC
NH
R4
R4
Table 1
Scheme 3. CDI cyclization to benzothiadiazin-3-one-1,1-dioxides.
Screening conditions for reaction optimization
Entrya,d
[Cu] cat.
Ligand
Solvent
Yield (%)
Table 3
Entrya
1
2
3
CuI
DMSO
DMSO
DMSO
65
55
10
L
L
L
-Proline
-Proline
-Proline
CuBr
Cu2O
R1
R2
R3
R4–NH2
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
CF3
H
H
H
H
F
H
H
H
H
F
Bn
Bn
4-MeOBnNH2
Octylamine
Allylamine
Phenethylamine
n-Butylamine
Cyclopentylamine
4-MeOBnNH2
BnNH2
96
96
98
94
97
92
93
97
4
5
6
7
8
9
10
11
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
(CH2OH)2
1,10-Phenanthroline
DBU
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
DMF
DMF
78
94
50
72
92
Allyl
Bn
Allyl
4-MeOBn
Cp
(CH2NHMe)2
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
84
96b
94c
H
n-Butyl
a
Reaction conditions: sulfonamide (0.17 mmol), CDI (0.69 mmol), Et3N
(0.34 mmol) in dry DMF (0.2 M) at 100 °C for 6 h.
a
Reaction conditions: 1 (0.17 mmol), allylamine (0.2 mmol), CuX (0.017 mmol),
ligand (0.034 mmol), Cs2CO3 (0.34 mmol) in solvent (0.5 M) at 100 °C for 6 h.
b
Microwave irradiation for 22 min at 140 °C.
Microwave irradiation for 11 min at 150 °C.
Other bases were also investigated (DBU, K2CO3, Et3N) but Cs2CO3 was
c
d
preferred.
O
O
O
O
O
O
CDI
Et3N
Cu cat.
N-Arylation
R2
O
R2
S
R2
S
N
S
N
N
N
H
H
O
O
O O
Mw
DMF, Mw
R4-NH2 (1.2 eq)
CuI (10 mol%)
R1
Br
R1
R1
NH
R3
R1
R2
S
R3
R1
R2
S
R3
N
N
R3
H
H
R1 = H, R2 = Allyl, R3 = Allyl, 72%
R1 = F, R2= 4-MeOBn, R3 = Octyl, 68%
1 = H, R2= Allyl, R3 = OBn, 73%
1,10-Phenanthroline (20 mol%)
DMSO, Cs2CO3
Br
NH
R4
11min, 100 ºC, Mw
R
Scheme 2.
Scheme 4. Sequential one-pot synthesis of benzothiadiazin-3-one-1,1-dioxides.

A. Rolfe, P. R. Hanson / Tetrahedron Letters 50 (2009) 6935–6937
6937
9. Wang, Y.; Busch-Petersen, J.; Wang, F.; Ma, L.; Fu, W.; Kerns, J. K.; Jin, J.;
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G. E.; Sarau, H. M.; Widdowson, K. L. Bioorg. Med. Chem. Lett. 2007, 17, 3864–
3867.
In conclusion, we have developed a microwave-assisted, cop-
per-catalyzed, sequential, one-pot synthesis of benzothiadiazin-
3-one-1,1-dioxides. A variety of derivatives of benzothiadiazin-3-
one-1,1-dioxides can be rapidly accessed by combining a copper-
mediated N-arylation followed by cyclization with CDI. Further ef-
forts toward employment of this method in library production will
be published in due course.
10. Golberg, I. Ber. Dtsch. Chem. Ges. 1907, 40, 4541.
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Acknowledgments
This publication was made possible by the Pilot-Scale Libraries
Program (P41 GM076302), the National Institutes of General Med-
ical Sciences (KU Chemical Methodologies and Library Develop-
ment Center of Excellence P50 GM069663) and by Grant Number
P20 RR015563 from the National Center for Research Resources,
a component of the National Institutes of Health, and the State of
Kansas. Its contents are solely the responsibility of the authors
and do not necessarily represent the official view of the NCRR or
NIH.
15. While final yields obtained with DMSO, using DMF gave results within 5%
experimental error. However it was found that under microwave conditions at
150 °C,
a small amount of by-product was formed from the addition of
dimethylamine into the 4-F position of the benzene ring in a SNAr mechanism.
It is proposed that a small amount of dimethylamine is produced from the
decomposition of DMF under these conditions and hence DMSO is a better
solvent for such substrates.
Supplementary data
Supplementary data associated with this article Letter can be
found, in the online version, at doi:10.1016/j.tetlet.2009.09.090.
16. General procedure for the N-arylation of
a-bromobenzenesulfonamides: Into a
microwave reaction vial was added sulfonamide (0.17 mmol, 1 equiv), CuI
(0.017 mmol. 0.1 equiv), 1,10-phenanthroline (0.034 mmol, 0.2 equiv), Cs2CO3
(0.34 mmol, 2 equiv), dry DMSO or DMF (0.5 M), and amine (0.2 mmol,
1.2 equiv). The reaction was heated in the microwave (Biotage initiator,
www.biotage.com) at 150 °C for 11 min. After such time, the crude reaction
was purified by flash chromatography [hexane/EtOAc, 8:2] to afford the
desired product as a solid. Table 2, entry 8. FTIR (neat): 3400, 1579, 1301, 1149,
547 cmÀ1; mp 178–181 °C: 1H NMR (400 MHz, CDCl3) d 7.73 (dd, J = 8.5, 6.6 Hz,
1H), 6.42 (ddd, J = 13.5, 9.7, 2.0 Hz, 2H), 6.19 (s, 1H), 5.98–5.83 (m, 1H), 5.67
(qt, J = 15.0, 7.5 Hz, 1H), 5.25 (dd, J = 19.5, 13.8 Hz, 2H), 5.12 (dd, J = 25.7,
13.7 Hz, 2H), 4.67 (t, J = 5.6 Hz, 1H), 3.88–3.74 (m, 2H), 3.52 (t, J = 5.8 Hz, 2H);
13C NMR (126 MHz, CDCl3) d 167.8, 165.8, 147.9 (d, JC–F = 13.1 Hz), 133.2, 132.7,
117.8, 116.9, 103.5, 103.3, 99.6, 99.4, 46.1; HRMS calcd for C12H16FN2O2S
(M+H)+ 271.0917; found 271.0923.
References and notes
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2239–2258; (b) Jiménez-Hopkins, M.; Hanson, P. R. Org. Lett. 2008, 10, 2951–
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17. General procedure for the synthesis of benzothiadiazin-3-one-1,1-dioxides via CDI
cyclization: To a round-bottomed flask was added sulfonamide (0.17 mmol,
1 equiv), dry DMF (0.2 M), Et3N (0.34 mmol, 2 equiv) and CDI (0.69 mmol,
4 equiv). The reaction mixture was heated at 100 °C for 6 h, cooled to rt and
concentrated under reduced pressure. The crude oil was diluted in CH2Cl2,
washed with 1 M HCl (aq, 5 mL), water (5 mL), and dried (MgSO4). Subsequent
filtration and concentration yielded a crude oil which was purified by flash
chromatography [hexane/EtOAc, 7:3] to afford the desired product as clear oil.
(Table 3, entry 3). FTIR (neat): 3400, 1575, 1310, 1149 cmÀ1
;
1H NMR
(500 MHz, CDCl3) d 7.92–7.83 (m, 1H), 7.03–6.94 (m, 2H), 6.04–5.88 (m, 2H),
5.39–5.30 (m, 2H), 5.29–5.19 (m, 2H), 4.69–4.59 (m, 2H), 4.52–4.46 (m, 2H);
13C NMR (126 MHz, CDCl3) d 166.7, 164.6, 150.2, 138.8 (dd, JC–F = 10.8 Hz),
131.6, 130.7, 125.3, 119.2, 118.0, 111.1, 104.7, 104.4, 48.5, 44.8; HRMS calcd for
C13H13FN2O2S (M+H)+ 297.0709; found 297.0712.
18. General one-pot procedure for the synthesis of benzothiadiazin-3-one-1,1-
dioxides: Into a microwave reaction vial (0.5–2.0 ml) was added sulfonamide
(0.17 mmol, 1 equiv), CuI (0.017 mmol. 0.1 equiv), 1,10-phenanthroline
(0.034 mmol, 0.2 equiv), Cs2CO3 (0.34 mmol, 2 equiv), dry solvent (0.5 M),
and amine (0.2 mmol, 1.2 equiv). The reaction was heated in the microwave
(Biotage initiator, www.biotage.com) at 150 °C for 11 min. After such time Et3N
(0.34 mmol, 2 equiv) and CDI (0.69 mmol, 4 equiv) was added directly to the
microwave vial. The reaction mixture was heated at 150 °C for 11 min, cooled
to rt and concentrated under reduced pressure. The crude oil was diluted in
CH2Cl2, washed with 1 M HCl (aq, 5 mL), water (5 mL) and dried (MgSO4).
Subsequent filtration and concentration yielded a crude oil, which was purified
by flash chromatography [hexane/EtOAc, 7:3] to afford the desired product.