Synthesis of Cyclic Sulfonamides through Intramolecular Diels-Alder Reactions

Article abstract of DOI:10.1021/ol006863e

(Matrix Presented) Substituted 2,3,3a,4,5,7a-hexahydrobenzo[d]isothiazole 1,1-dioxides and 3,4,4a,5,6,8a-hexahydro-2H-benzo[e][1,2]thiazine 1,1-dioxides, novel cyclic sulfonamides, were synthesized by the thermal Diels-Alder reaction of triene derivatives

Full text of DOI:10.1021/ol006863e

ORGANIC
LETTERS
2001
Vol. 3, No. 3
369-371
Synthesis of Cyclic Sulfonamides
through Intramolecular Diels−Alder
Reactions
Ian R. Greig, Matthew J. Tozer,* and Paul T. Wright
James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, UK
matthew.tozer@kcl.ac.uk
Received November 13, 2000
ABSTRACT
Substituted 2,3,3a,4,5,7a-hexahydrobenzo[d]isothiazole 1,1-dioxides and 3,4,4a,5,6,8a-hexahydro-2H-benzo[e][1,2]thiazine 1,1-dioxides, novel
cyclic sulfonamides, were synthesized by the thermal Diels−Alder reaction of triene derivatives of buta-1,3-diene-1-sulfonic acid amide. The
stereochemical outcome of the reaction was determined by NMR spectroscopy and X-ray crystallographic analysis. This chemistry has been
used for the synthesis of 2-(4-chlorobenzyl)-5-(1H-imidazol-4-yl)-2,3,3a,4,5,7a-hexahydrobenzo[d]isothiazole 1,1-dioxide, a histamine H receptor
3
antagonist.
The sulfonamide group is ubiquitous in bioorganic and
medicinal chemistry, providing a key polar alternative to the
amide group for which it is frequently used as a bioisosteric
replacement. Through several series of histamine H3 receptor
antagonists,1-4 we have made particular use of the contrasting
properties of sulfonamides, finding that the in vitro profiles
were superior to the amide equivalents. As part of this
program, we developed methodology for the synthesis of
vinyl sulfonamides.5 This also allowed access to the rarely
encountered dienes 2, which we hoped would form the basis
of conformationally constrained equivalents of our relatively
flexible compounds. Growing interest in cyclic sulfonamides
is evident in the development of new synthetic approaches
utilizing a variety of intramolecular reactions including the
cyclization of R-methylsulfonamidyl radicals6 and carban-
ions,7 radical cyclization based on hypervalent iodine spe-
cies,8 the transition metal catalyzed insertion of nitrenes,9
and ring-closing metathesis.10 Intramolecular Diels-Alder
reactions are an attractive option for constructing rigid cyclic
systems, and sulfonamides have been incorporated in the
dienophile component as vinyl sulfonamides.11 However, we
have found the inverse electron demand counterpart to be a
valuable new route to cyclic sulfonamides, and we report,
herein, our findings on the thermal Diels-Alder reactions
of trienes 3 and 4.
1,3-Butadiene sulfonamides 2 were prepared by the base-
mediated condensation of N-Boc-methanesulfonamides 1
with a series of aldehydes (a 67%, b 69%, c 99%, d 51%),
using the previously reported one-pot version of this reac-
tion.5 N-Alkylation of 2 to give trienes 3 (a 69%, b 76%, c
82%, d 59%) and 4 (a 29%, b 47%, c 44%, d 27%) was
(6) Leit, S. M.; Paquette, L. A. J. Org. Chem. 1999, 64, 9225.
(7) Marco, J. L.; Ingate, S. T.; Jaime, C.; Bea´, I. Tetrahedron 2000, 56,
2523
(8) Togo, H.; Harada, Y.; Yokoyama, M. J. Org. Chem. 2000, 65, 926.
(9) Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327.
(10) (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M.
Tetrahedron Lett. 1999, 40, 4761. (b) Brown, R. C. D.; Castro, J. L.;
Moriggi, J.-D. Tetrahedron Lett. 2000, 41, 3681. (c) Long, D. D.; Termin,
A. P. Tetrahedron Lett. 2000, 41, 6743.
(1) Tozer, M. J.; Harper, E. A.; Kalindjian, S. B.; Pether, M. J.; Shankley,
N. P.; Watt, G. F. Bioorg. Med. Chem. Lett. 1999, 9, 1825.
(2) Tozer, M. J.; Buck, I. M.; Cooke, T.; Kalindjian, S. B.; McDonald,
I. M.; Pether, M. J.; Steel, K. I. M. Bioorg. Med. Chem. Lett. 1999, 9,
3103.
(3) James Black Foundation patent publication number WO 9942458,
1999.
(4) Linney, I. D.; Buck, I. M.; Harper, E. A.; Kalindjian, S. B.; Pether,
M. J.; Shankley, N. P.; Watt, G. F.; Wright, P. T. J. Med. Chem. 2000, 43,
2362.
(11) Plietker, B.; Seng, D.; Fro¨lich, R.; Metz, P. Tetrahedron 2000, 56,
873. For an example of an intermolecular Diels-Alder reaction involving
a vinylsulfonamide see: Abou-Gharbia, M.; Moyer, J. A.; Patel, U.; Webb,
M.; Schiehser, G.; Andree, T.; Haskins, J. T. J. Med. Chem. 1989, 32, 1024.
(5) Tozer, M. J.; Woolford, A. J. A.; Linney, I. D. Synlett 1998, 186.
10.1021/ol006863e CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

achieved by reacting the sodium salts with either allyl or
homoallyl bromide in tetrahydrofuran at reflux. While
generally good yields were obtained in the former case, the
lower yields in the latter can be offset against the degree of
recovery of the starting diene (Scheme 1). Where studied,
Table 1. Thermal Intramolecular Diels-Alder Reactions of
Trienes 3a-d and 4a-d
triene
R1
R2
product (ratio)a,b
yield (%)c
3a
3b
3c
3d
4a
4b
4c
4d
H
4-Cl-C6H4CH2
4-Cl-C6H4CH2
4-Cl-C6H4CH2
n-Bu
4-Cl-C6H4CH2
4-Cl-C6H4CH2
4-Cl-C6H4CH2
n-Bu
5a , 6a (6:1)
5b, 6b (6:1)
5c, 6c (3:1)
5d , 6d (3:1)
7a , 8a (5:1)
7b, 8b (6:1)
7c, 8c (4:1)
7d , 8d (4:1)
76
71
92
87
66
74
92
80
Me
Ph
Ph
H
Me
Ph
Ph
Scheme 1
a Ratio estimated from integral values of discernible peaks of common
1
protons in the H NMR spectrum. The crude reaction mixtures were used
1
for this analysis. b Compounds 5, 7, and 8c were characterized by H and
13C NMR spectroscopy techniques, including 2D correlation experiments
for peak assignment. Satisfactory data from microanalysis and mass
spectrometery were also obtained. c Combined yields (5 and 6 or 7 and 8)
after flash column chromatography.
the use of cesium carbonate and dimethylformamide for the
alkylation did not afford any improvement.
The intramolecular Diels-Alder reactions of compounds
3 and 4 were performed at 145 °C in toluene, in a sealed
screw-cap vessel under argon (Scheme 2).12 Under these
amides, although an exact comparison of substituent effects
and reaction conditions is not possible at present. Within
the limits of experimental measurement and the scope of this
study, it seems that the nature of the substituents R1 and R2
were not determinants in the stereoselectivity. From examples
in the amide series, it could be suggested that a monosub-
stituted sulfonamide nitrogen (R2 ) H) might be deleterious
to cyclization.14b However, the stereoelectronic demands of
sulfonamides and amides differ. The exploration of these and
the other steric and stereoelectronic factors14a that contribute
to the stereoselectivity of the reaction will be the concern of
future studies.
Scheme 2
With a practical route to the novel cyclic sulfonamides in
hand, we applied our findings to the synthesis of the
imidazole analogue 9, a racemic mixture of cis- and trans-
fused products. Compound 9 was conceived as a conforma-
conditions, the [4.3.0] products 5 and 6 and the [4.4.0]
products 7 and 8 were obtained in good yields (Table 1).
Lower temperatures, such as toluene at reflux, were not
adequate, although the effects of elevated pressures have not
been investigated. The two products in each case differed in
the geometry about the newly formed ring junction, with
the cis-fused compounds 5 and 7 predominating. For some
product mixtures, such as 7c and 8c, separation of the
individual components was possible by flash column chro-
matography,12 and for others, such as 5c and 6c, enrichment
in the major component was achieved by recrystallization.
The relative stereochemistries of 5c, 6c, and 7c were
confirmed by X-ray crystallography (Figure 1)13 and the
1
measurement of nuclear Overhauser effects using H NMR
spectroscopy. 1H NMR spectroscopy thence became an
invaluable tool in analyzing the other product mixtures.
The amide equivalent of this reaction has been the subject
of several reports,14 and from the results disclosed here a
similarity between the two systems is apparent. Selectivity
for cis-fused products was generally higher for the sulfon-
Figure 1. X-ray crystallographic structures of the cis-fused
compounds 5c and 7c, rendered in Chem3D. For the purposes of
clarity, only protons attached to stereogenic centers are shown.
370
Org. Lett., Vol. 3, No. 3, 2001

tionally restricted variant of existing histamine H3 receptor
antagonists,2,3 and affinity levels in the micromolar range
were measured in two standard in vitro assays (Figure 2).15
A further discussion of the chemistry reported here and its
use in the histamine H3 area will appear in due course.
(12) The preparation of 2-(4-chlorobenzyl)-6-phenyl-3,4,4a,5,6,8a-
hexahydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (7c and 8c) is given as an
illustration of the general procedure for the intramolecular Diels-Alder
reactions. A solution of 4c (393 mg, 1.01 mmol) in dry toluene (5 mL), in
a screw-cap vessel with a septum, was degassed in vacuo three times and
sealed under an atmosphere of argon. The solution was heated at 145 °C,
with stirring, for 60 h. The mixture was adsorbed onto silica gel and purifed
by column chromatography (silica, 20% EtOAc/hexane). Thus, in addition
to a mixture of 7c and 8c (207 mg, 53%, 7c:8c ) 10:1), 7c was isolated as
a colorless oil (90 mg, 23%) and 8c as a colorless solid (63 mg, 16%). 7c
1H NMR (300 MHz; CDCl3) δ 7.35-7.23 (9H, m, Ar), 6.21 (1H, d, J 9.9
Hz, H-7), 6.06 (1H, m, H-8), 4.44 (1H, d, J 14.4 Hz, NCHH′Ar), 4.27 (1H,
d, J 14.7 Hz, NCHH′Ar), 3.86 (1H, m, H-8a), 3.52 (2H, m, H-3, 6), 2.94
(1H, dt, J 14.1, 3.3 Hz, H-3′), 2.57 (2H, m, H-4a, 5), 2.09 (1H, m, H-4),
1.75 (1H, m, H-5), 1.47 (1H, d, J 14.7, H-4′); 13C NMR (75 MHz; CDCl3)
δ 145.1, 140.3 (C-7), 135.4, 134.4, 130.4, 129.5, 129.3, 128.4, 127.3, 118.3
(C-8), 58.7 (C-8a), 50.2 (NCH2Ar), 44.8 (C-3), 43.9 (C-6), 35.4 (C-4a),
32.6 (C-5), 28.3 (C-4). 8c 1H NMR (300 MHz; CDCl3) δ 7.35-7.25 (9H,
m, Ar), 6.25 (1H, d, J 10.2 Hz, H-8), 6.13 (1H, m, H-7), 4.41 (1H, d, J
14.4 Hz, NCHH′Ar), 4.22 (1H, d, J 14.7 Hz, NCHH′Ar), 3.61 (1H, m,
H-6), 3.54 (1H, ddd, J 10.8, 4.2, 2.4 Hz, H-8a), 3.36 (1H, dt, J 13.2, 3.0
Hz, H-3), 2.98 (1H, ddd, J 13.8, 4.2, 2.4 Hz, H-3′), 2.36 (1H, m, H-4a),
1.94 (1H, dt, J 13.0, 6.5 Hz, H-5), 1.77 (1H, dt, J 13.0, 1.5 Hz, H-5′), 1.52
(1H, m, H-4), 1.39 (1H, m, H-4′); 13C NMR (75 MHz; CDCl3) δ 143.7,
135.1, 134.9 (C-7), 134.1, 130.2, 129.2, 129.0, 128.8, 127.0, 119.2 (C-8),
63.8 (C-8a), 50.3 (NCH2Ar), 48.1 (C-3), 40.3 (C-6), 36.6 (C-5), 32.4 (C-
4a), 30.0 (C-4).
Figure 2. Histamine H3 antagonist with affinities from the guinea
pig isolated ileum assay (pKB) and a radioligand binding assay using
guinea pig cerebral cortex membranes (pKi).15
Acknowledgment. We thank Kevin McCullough, Heriot-
Watt University, Edinburgh, UK, for the X-ray crystal-
lographic analyses. We also thank Barret Kalindjian for his
support and encouragement throughout this work.
Supporting Information Available: Details, data, and
illustrations for the X-ray crystal structures of compounds
5c (with 6c) and 7c. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) See Supporting Information for full details of the X-ray crystal
structures of compounds 5c (with 6c) and 7c.
(14) (a) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J.
Org. Chem. 1983, 48, 5170. (b) Brettle, R.; Jafri, I. A. J. Chem. Soc., Perkin
Trans. 1 1983, 387. (c) Guy, A.; Lemaire, M.; Negre, M.; Guette, J. P.
Tetrahedron Lett. 1985, 26, 3575. (d) Hauser, A.; Gru¨ndemann, E.;
Preuschhof, H.; Schmitz, E.; Kuban, R.-J. J. Prakt. Chem. 1986, 328, 488.
(e) Fra´ter, G. Tetrahedron Lett. 1976, 4517.
OL006863E
(15) For a discussion of these assays refer to ref 1 and other papers cited
therein.
Org. Lett., Vol. 3, No. 3, 2001
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