One-pot, three-component synthesis of novel δ-sultam scaffolds via N-sulfonylation - Intramolecular Michael sequences

Article abstract of DOI:10.1016/j.tetlet.2011.09.146

The synthesis of novel δ-sultam scaffolds utilizing one-pot, three-component reactions of 1,3-dicarbonyl compounds, primary aliphatic amines and substituted styrenesulfonyl chlorides is reported. A variety of six-membered sultams are obtained in moderate

Full text of DOI:10.1016/j.tetlet.2011.09.146

Tetrahedron Letters 52 (2011) 6613–6615
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot, three-component synthesis of novel d-sultam scaffolds via
N-sulfonylation—intramolecular Michael sequences
Mehdi Ghandi a, , Seyed Hadi Nazari a, Abolfazl Hasani Bozcheloei a, Masoud Sadeghzadeh a, Reza Kia b,c
⇑
a School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran
b X-ray Crystallography Laboratory, Plasma Physics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
c Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 May 2011
Revised 21 September 2011
Accepted 30 September 2011
Available online 6 October 2011
The synthesis of novel d-sultam scaffolds utilizing one-pot, three-component reactions of 1,3-dicarbonyl
compounds, primary aliphatic amines and substituted styrenesulfonyl chlorides is reported. A variety of
six-membered sultams are obtained in moderate to good yields presumably via N-sulfonylation
—intramolecular Michael addition sequences.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
d-Sultams
Enaminones
N-Sulfonylation
Styrenesulfonyl chlorides
Sulfonamides have a rich chemical and biological history and
are an important class of compounds in drug discovery due to their
extensive chemical and biological activities.1 Significant interest
has been directed toward cyclic sulfonamides, also known as sul-
tams. Although not found in nature, these compounds demonstrate
a wide spectrum of activitiy.2 Examples include the antiepileptic
agent sulthiame,3 the COX-2 inhibitor ampiroxicam,4 and benzodi-
thiazine dioxides displaying anti-HIV-1 activity5 (Fig. 1). As chem-
ically important materials, sultams have been utilized as efficient
chiral auxiliaries and reagents.6
C2H5O2CO
O
O
Cl
S
S
N
R4
N
H
N
N
R1
R3
N
O
S
R2
O
O
O
ampiroxicam (COX-2)
benzodithiazine dioxides (anti-HIV-1)
Sultams have traditionally been synthesized via cyclization pro-
tocols such as the Pictet–Spengler,2a and methods including Fri-
edel–Crafts,7 dianion alkylation,8 cyclization of aminosulfonyl
chlorides,9 [3+2] cycloadditions,10 and Diels–Alder reactions.11 Re-
cently, a number of transition metal catalyzed approaches to sul-
tams have been reported, including the use of Pd,12 Au,13 Cu,14
and Rh.15
H2NO2S
N
S
O
O
sulthiame
Figure 1. Biologically active six-membered sultams.
Herein, we report the one-pot, three-component synthesis of
novel d-sultams via reaction of commercially available primary ali-
phatic amines and 1,3-dicarbonyl compounds with readily pre-
pared substituted styrenesulfonyl chlorides.16
In a model experiment enaminone 3a, obtained from the reac-
tion of primary amine 1a with b-ketoester 2a, was treated with
styrenesulfonyl chloride (4a) in CH2Cl2 at room temperature. The
reaction proceeded smoothly and was complete within 12 h,
affording the sultam 5a in 76% yield (Scheme 1a).
Further studies revealed that 5a could be prepared via a one-pot
reaction. This involved successive addition of amine 1a and sty-
renesulfonyl chloride (4a) to a solution of b-ketoester 2a in CH2Cl2
at room temperature (Scheme 1b).17 Therefore, enaminone 3a may
be implicated in this three-component reaction. The structure of 5a
was confirmed on the basis of analytical data.18
⇑
Corresponding author.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.146

6614
M. Ghandi et al. / Tetrahedron Letters 52 (2011) 6613–6615
were obtained with branched amines (entries 3 and 4, Table 1).
(a)
Me
SO2Cl
Compared to linear amines, sec-butylamine, and cyclohexylamine
with increased steric crowding about the nitrogen atom would
be expected to react more slowly with styrenesulfonyl chloride
(4a).
To further explore the scope of this reaction, several 1,3-dicar-
bonyl compounds 2a–c and substituted styrenesulfonyl chlorides
4a–c were examined (Scheme 2, Table 2). The analytical data
including IR, 1H NMR, and 13C NMR spectra of the products 5f–o
were in agreement with the proposed structures.19 Confirmation
of the product structure was obtained by single crystal X-ray dif-
fraction of d-sultam 5m (Fig. 2).20
The results shown in Table 2 reveal that dicarbonyl compounds
either in the form of b-ketoesters or 1,3-diketones, and unsubsti-
tuted or substituted styrenesulfonyl chlorides with electron-with-
drawing groups were tolerated.
In conclusion, a variety of sultams 5a–o were synthesized in
moderate to good yields via one-pot, three-component reactions
of 1,3-dicarbonyl compounds, amines and substituted
H
N
Me
O
+
Me
O
O
O
Me
S
N
CH2Cl2
RT
3a
4a
4a
(b)
Me
Me
SO2Cl
O
O
O
NH2
+
O +
Me
O
Me
5a
Me
1a
2a
Scheme 1. Synthesis of sultam 5a from: (a) the two-component reaction of 3a and
4a, and (b) the three-component reaction of 1a, 2a, and 4a.
O
O
SO2Cl
R1
S
Me
N
We next examined several primary amines 1a–e, in the
coupling of b-ketoester 2a with styrenesulfonyl chloride (4a) using
our one-pot method (Table 1). Whereas linear amines afforded the
sultams in good yields (entries 1, 2 and 5, Table 1), lower yields
O
O
CH2Cl2
RT
R1 NH2
Me
+
O
R2
R3
R2
R3
4a-c
Table 1
Reactions of amines 1a–e, b-ketoester 2a and styrenesulfonyl chloride (4a) to afford
d-sultams 5a–e
1a-e
2a-c
5f-o
Me
Scheme 2. Synthesis of sultams 5f–o via the condensation of various amines, 1,3-
dicarbonyl compounds and styrenesulfonyl chlorides.
O
O
SO2Cl
CH2Cl2
O
O
R1
S
N
R1
+
NH2
Me
Table 2
O
RT
Reactions of various amines 1a–e, 1,3-dicarbonyl compounds 2a–c and styrenesulfo-
nyl chlorides 4a–c to afford sultams 5f–o
O
O
Me
Entry
R1
R2
R3
Time (h)
Product
Yield (%)
Me
5a-e
1
2
3
4
5
6
7
8
9
Propyl
Butyl
sec-Butyl
Cyclohexyl
Benzyl
H
H
Propyl
Butyl
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Me
Cl
Cl
Cl
Cl
Cl
H
Cl
Br
H
12
12
24
24
12
24
24
12
12
12
5f
83
67
36
37
78
86
42
77
66
62
1a-e
2a
R1
4a
5g
5h
5i
5j
5k
5l
5m
5n
5o
Entry
Time (h)
Product
Yield (%)
1
2
3
4
5
Propyl
Butyl
sec-Butyl
Cyclohexyl
Benzyl
12
12
24
24
16
5a
5b
5c
5d
5e
76
72
42
35
73
Me
Me
10
Butyl
Cl
Figure 2. ORTEP diagram of compound 5m.

M. Ghandi et al. / Tetrahedron Letters 52 (2011) 6613–6615
6615
16. Culbertson, B. M.; Dietz, S. J. Chem. Soc. C 1968, 992–993.
styrenesulfonyl chlorides. The six-membered sultams were pre-
sumably obtained via N-sulfonylation—intramolecular Michael
addition sequences.
17. General procedure for the synthesis of sultam 5a. To a stirred solution of b-
ketoester 2a (1 mmol, 0.126 mL) was added amine 1a (1 mmol, 0.082 mL)
dropwise. Styrenesulfonyl chloride (4a) (1 mmol, 0.202 g) dissolved in CH2Cl2
(7 mL) was subsequently added and the mixture stirred for 12 h. After
completion of the reaction, the solvent was evaporated under reduced
pressure and the residue purified by column chromatography on silica gel
(230–400 mesh; Merck), using hexane–EtOAc (9:1) as eluent to give sultam 5a.
Acknowledgment
18. Ethyl
1,1-dioxide (5a).White solid, (258 mg, 76%), mp: 79–81 °C; IR (KBr)
(CO), 1323 (SO2), 1125 (SO2) cmÀ1 1H NMR (500 MHz, CDCl3)
3-methyl-5-phenyl-2-propyl-5,6-dihydro-2H-1,2-thiazine-4-carboxylate
: 1708
0.83 (t,
The authors acknowledge the University of Tehran for the finan-
cial support of this research.
m
.
d
J = 7.0 Hz, 3H, CH3CH2CH2N), 0.99 (t, J = 7.5 Hz, 3H, CH3CH2O), 1.73–1.75 (m,
2H, CH3CH2CH2N), 2.29 (d, J = 1.5 Hz, 3H, CH3C@C), 2.96 (dd, J = 13.2, 12.5 Hz,
1H, SO2CHHCHPh), 3.48–3.51 (m, 1H, SO2CHHCHPh), 3.52–3.54 (m, 1H,
CH3CH2CHHN), 3.72–3.77 (m, 1H, CH3CH2CHHN), 3.80 (q, J = 7.5, 2H,
CH3CH2O), 4.44–4.48 (m, 1H, SO2CH2CHPh), 7.21–7.33 (m, 5H, Ph); 13C NMR
(125 MHz, CDCl3) d 11.5 (CH3CH2CH2N), 13.9 (CH3CH2O), 19.3 (CH3C@C), 23.4
(CH3CH2CH2N), 44.2 (SO2CH2CHPh), 48.3 (CH3CH2CH2N), 53.8 (CH3CH2O), 60.8
(SO2CH2CHPh), 116.2 (NC@C), 144.53 (NC@C), 127.9, 127.9, 129.3, 141.0 (Ph),
167.4 (OC@O); MS (EI, 70 eV) m/z 337 (49, M+), 292 (21), 272 (17), 244 (76), 43
(100%); Anal. calcd for C17H23NO4S: C, 60.51; H, 6.87; N, 4.15. Found: C, 60.29;
H, 6.49; N, 4.25.
References and notes
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19. (a) Ethyl 2-benzyl-3-methyl-5-phenyl-5,6-dihydro-2H-1,2-thiazine-4-carboxylate
1,1-dioxide (5e). White solid (281 mg, 73%); mp: 108–110 °C; IR (KBr)
m
: 1715
(CO), 1346 (SO2); 1158 (SO2) cmÀ1 1H NMR (500 MHz, CDCl3)
;
d 0.86 (t,
J = 7.0 Hz, 3H, CH3CH2O), 2.39 (d, J = 2.0 Hz, 3H, CH3C@C), 2.59 (dd, J = 13.3,
12.5 Hz, 1H, SO2CHHCHPh), 3.37–3.41 (m, 1H, SO2CHHCHPh), 3.85 (q,
J = 7.0 Hz, 2H, CH3CH2O), 4.38–4.42 (m, 1H, SO2CH2CHPh), 4.79 (d,
J = 16.0 Hz, 1H, PhCHHN), 5.01 (d, J = 16.0 Hz, 1H, PhCHHN), 6.91–7.47 (m,
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10H); 13C NMR (125 MHz,CDCl3)
d 13.9 (CH3CH2O), 20.0 (CH3C@C), 44.1
(SO2CH2CHPh), 50.3 (PhCH2N), 53.5 (CH3CH2O), 60.9 (SO2CH2CHPh), 118.6
(NC@C), 144.1 (NC@C), 127.8, 127.9, 128.8, 128.9, 129.2, 129.4, 135.7, 140.5,
167.1 (OC@O); MS (EI, 70 eV) m/z 385 (4, M+), 351 (27), 258 (55), 214 (43), 91
(100%). Anal. calcd for C21H23NO4S: C, 65.43; H, 6.01; N, 3.63. Found: C, 65.12;
H, 6.23; N, 3.86; (b) 1-[5-(4-bromophenyl)-3-methyl-2-propyl-5,6-dihydro-2H-
1,2-thiazin-4-yl]ethanone 1,1-dioxide (5m). Cream solid, (296 mg, 77%); mp:
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105–108 °C; IR (KBr)
m
1725 (CO), 1346 (SO2); 1146 (SO2) cmÀ1
;
1H NMR
(500 MHz, CDCl3)
d
0.98 (t, J = 7.3 Hz, 3H, CH3CH2CH2N), 1.71–1.78 (m,
J = 7.6 Hz, 2H, CH3CH2CH2N), 1.98 (s, 3H, CH3C@C), 2.13 (s, 3H, CH3CO), 2.92
(t, J = 12.7 Hz, 1H, SO2CHHCHPh), 3.46–3.50 (m, 1H, SO2CHHCHPh), 3.51–3.54
(m, 1H, CH3CH2CHHN), 3.69–3.73 (m, 1H, CH3CH2CHHN), 4.43–4.47 (m, 1H,
SO2CH2CHPh), 7.10 (d, J = 8.2 Hz, 2H, Ph), 7.40 (d, J = 8.2 Hz, 2H, Ph); 13C NMR
(125 MHz,CDCl3) d 11.5 (CH3CH2CH2N), 19.6 (CH3C@C), 23.4 (CH3CH2CH2N),
30.8 (CH3CO), 43.7 (SO2CH2CHPh), 48.4 (CH3CH2CH2N), 53.8 (SO2CH2CHPh),
122.4 (NC@C), 141.2 (NC@C), 129.9, 133.0, 133.2, 138.7, 201.8 (C@O); MS (EI,
11. (a) Metz, P.; Seng, D.; Fröhlich, R. Synlett 1996, 741–742; (b) Plietker, B.; Seng,
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70 eV) m/z 387 [20, M+ 81Br)], 385 [52, M+ 79Br)], 329 (61), 250 (55), 236 (94),
( (
41 (100%). Anal. calcd for C16H20BrNO3S: C, 49.75; H, 5.22; N, 3.63. Found: C,
50.12; H, 5.18; N, 3.43.
20. Crystallographic data for 5m have been deposited at the Cambridge
Crystallographic Data Centre with the deposition number CCDC 844991.
Copies of these data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax:
+44 1223 336 033; or e-mail:deposit@ccdc.cam.ac.uk).