A convenient synthesis of N-alkyl-(E)-1-alkenesulfonamides

Article abstract of DOI:10.1055/s-1998-1609

A series of vinylsulfonamides 3 has been synthesised through a condensation of N-Boc-methanesulfonamides 1 and aldehydes 2. O-Boc-2-hydroxyalkanesulfonamides were identified as intermediates, arising from N-O transfer of the Boc group. Elimination of OBoc gave the vinylsulfonamides.

Full text of DOI:10.1055/s-1998-1609

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A Convenient Synthesis of N-Alkyl-(E)-1-alkenesulfonamides
Matthew J. Tozer,* Alison J. A. Woolford and Ian D. Linney
James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, UK
Fax: 0171 274 9687; e-mail: m.tozer@kcl.ac.uk
Received 7 November 1997
Abstract: A series of vinylsulfonamides 3 has been synthesised through
a condensation of N-Boc-methanesulfonamides 1 and aldehydes 2. O-
Boc-2-hydroxyalkanesulfonamides were identified as intermediates,
arising from N–O transfer of the Boc group. Elimination of OBoc gave
the vinylsulfonamides.
Scheme 1
The sulfonamide group has found wide usage in medicinal chemistry as
For its ease of preparation, the derivative of 4-chlorobenzylamine, 1a,
was used for much of the initial work and the results of its reaction with
a series of aldehydes are set out in the Table (entries 1–14). The anion of
1a was generated at -78°C with one equivalent of potassium t-butoxide
(t-BuOK) and allowed to react with arylaldehydes 2a-i to give
vinylsulfonamides 3a-i, respectively, in good yields and excellent trans-
stereoselectivity. The reaction was not sensitive to the nature and
position of the aryl substituents of the aldehydes.
a
metabolically stable polar group. 1-Alkenesulfonamides
(vinylsulfonamides), however, have received relatively little attention.
A noteworthy example of their use in bioorganic chemistry and a
pointer
to
their
potential
is
Gennari’s
“vinylogous
1
sulfonamidopeptides.” Sulfonamides have classically been prepared by
the reaction of sulfonyl chlorides and amines. As part of a broad
medicinal chemistry programme, targeted towards the synthesis of
sulfonamides, an alternative disconnection strategy was sought. In order
to avoid the synthesis of sulfonyl chlorides, which frequently requires
harsh conditions, and to provide ready access to N-substituted
None of the anticipated 2-hydroxyalkanesulfonamides were observed
and the absence of the Boc group was marked. However, when the
reaction was attempted with decylaldehyde 2l a mixture (3:1) of the
vinylsulfonamide 3l and the O-Boc-2-hydroxyalkanesulfonamide 4
(Scheme 2) was obtained. From analysis of the reaction by thin layer
chromatography it appeared that 4 was formed initially and during the
vinylsulfonamides, the introduction of the sulfonamide as
a
prefabricated unit was considered. To this end, the illustrated
disconnection was explored (Figure).
9
course of the reaction underwent elimination to give 3l. It seemed,
therefore, that the condensation of the aldehyde and sulfonamide
fragments was followed by a rapid intramolecular N–O transfer of the
Boc group.
Figure
Realisation of this strategy has been achieved on few occasions.
Aldehydes have been used in the Peterson reaction of α-
2
silylsulfonamides
and the Wittig–Horner reaction of N,N-
3
dimethyl(diethoxy)methylsulfonamide. Both approaches were limited
to N,N-dimethylsulfonamides and the former suffered variable
stereoselectivity. Styrenesulfonamides have also been prepared by a
Knoevenagel-type condensation and the base mediated reaction of α-
halosulfonamides with benzyl halides. Thompson has reported the C-
4
5
alkylation of N-alkanesulfonamide dianions with
a variety of
6
electrophiles. The utility of this approach has been duly recognised in
7
the subsequent literature, in particular the reaction with aldehydes to
8
produce 2-hydroxyalkanesulfonamides.
In the case of two
arylaldehydes Thompson reported the conversion of the 2-
hydroxyalkanesulfonamides to the corresponding styrenesulfonamides
6
by mesylation and base induced elimination. We would like to report
It was found that products 3l and 4 could be prepared selectively by
varying the reaction conditions: the use of a second equivalent of t-
BuOK facilitated vinylsulfonamide synthesis, with an efficiency
herein
a complementary method that achieves vinylsulfonamide
synthesis in a single step through the condensation of aldehydes and
methanesulfonamides.
10
comparable to that of the arylaldehydes (Table, entry 12); and the
reaction was halted at the intermediate product 4 by reducing the
11
Having experienced somewhat variable returns from Thompson's two
step dianion route, we investigated the possibility of N-protection using
the t-butoxycarbonyl (Boc) group. The N-Boc-methanesulfonamides 1
of a variety of alkylamines were readily prepared, in high yields, from
the corresponding methanesulfonamides by reaction with di-t-butyl
dicarbonate in the presence of catalytic 4-dimethylaminopyridine
(DMAP) (Scheme 1).
reaction time (Scheme 2). The intermediacy of 4 was further
suggested through its ready conversion to 3l under basic conditions,
with cesium carbonate in anhydrous methanol being of particular
practical value (Scheme 2).
Using two equivalents of t-BuOK, several other non-arylaldehydes
underwent the single step conversion to vinylsulfonamides (Table,
entries 10–14). Increasing steric bulk of the aldehyde did not have a
deleterious effect as judged by cyclohexylcarboxaldehyde 2m and
pivaldehyde 2n (entries 13 and 14). It is worth noting that potentially

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SYNLETT
187
In conclusion, the synthesis of vinylsulfonamides has been
demonstrated for range of aldehydes and N-Boc-
a
methanesulfonamides. O-Boc-2-hydroxyalkanesulfonamides were
shown to be intermediates that underwent elimination either in situ or as
a separate reaction. Thus, the N–O transfer of the Boc group was
identified as the key step en route to vinylsulfonamides. Reduction of
1a
the double bond of vinylsulfonamides has been demonstrated, so this
route may be additionally provide access to alkanesulfonamides. The
wider application of this approach will be reported in due course.
Acknowledgement. We would like to thank Barret Kalindjian and
Tracey Cooke for their help and support during this project.
References and Notes
1.
(a) Gennari, C.; Salom, B.; Potenza, D.; Williams, A. Angew.
Chem. Int. Ed. Engl. 1994, 33, 2067. (b) Gennari, C.; Nestler, H.
P.; Salom, B.; Still, W. C. Angew. Chem. Int. Ed. Engl. 1995, 34,
1763. (c) Gennari, C.; Nestler, H. P.; Salom, B.; Still, W. C.
Angew. Chem. Int. Ed. Engl. 1995, 34, 1765. (d) Gennari, C.;
Salom, B.; Potenza, D.; Longari, C.; Fioravazo, E.; Carugo, O.;
Sardone, N. Chem. Eur. J. 1996, 2, 644.
2.
3.
Mladenova, M.; Gaudemar-Bardone, F. Phosphorus, Sulfur, and
Silicon 1991, 62, 257.
El Hadri, A.; Maldivi, P.; Leclerc, G.; Rocher, J.-P. Bioorg. Med.
Chem. 1995, 3, 1183.
4.
5.
Oliver J. E.; DeMilo, A. B. Synthesis 1975, 321.
(a) Golinski, J.; Makosza, M. Synthesis 1978, 823. (b) Briene, M.-
J.; Varech, D.; Leclercq, M.; Jacques, J.; Radembino, N.;
Dessalles, M.-C.; Mahuzier, G.; Gueyouche, C.; Bories, C.;
Loiseau, P.; Gayral, P. J. Med. Chem. 1987, 30, 2232.
6.
7.
Thompson, M. E. J. Org. Chem. 1984, 49, 1700.
An example being: Roth, B. D.; Roark, W. H.; Picard, J. A.;
Stanfield, R. L.; Bousley, R. F.; Anderson, M. K.; Hamelehle, K.
L.; Homan, R.; Krause, B. R. Bioorg. Med. Chem. Lett. 1995, 5,
2367.
12
useful 1,3-butadiene-1-sulfonamides 3j and 3k were easily prepared
8.
Examples of 2-hydroxyalkanesulfonamide synthesis based on
Thompson's method: (a) Grunder-Klotz, E.; Ehrhardt, J.-D.
Synlett 1991, 800. (b) Poss, M. A.; Reid, J. A. Tetrahedron Lett.
1992, 33, 7291. (c) Poss, M. A.; Reid, J. A.; Free, C. A.; Rogers,
W. L.; Weber, H.; Ryono, D. E.; Dejneka, T.; DeForrest, J. M.;
Waldron, T. L.; Brittain, R. J.; Weller, H. N.; Cimarusti, M. P.;
Petrillo, E. W. Bioorg. Med. Chem. Lett. 1993, 3, 2739. (d) Davis,
F. A.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1993, 58, 4890.
(e) Tsuge, H.; Takumi, K.; Nagai, T.; Okano, T.; Eguchi, S.;
Kimoto, H. Tetrahedron 1997, 53, 823.
from acrolein 2j and trans-cinnamaldehyde 2k, respectively (entries 10
and 11).
The reaction was not limited to benzylamine derivatives. It was applied
successfully to the n-butylamine compound 1b (entries 15 and 16) and
the cyclohexylamine compound 1c (entries 17 and 18) for both alkyl-
and arylaldehydes. The reaction in the majority of cases showed a high
selectivity for the trans-double bond. A small amount of a (Z)-
vinylsulfonamide was observed for the least sterically demanding
combination of substrates, the two straight chain alkyl components 1b
and 2l.
9.
There is precedent for OBoc behaving as a leaving group in
similar circumstances, with a lactam rather than a sulfonamide:
Schmidt, U.; Riedl, B.; Haas, G.; Griesser, H.; Vetter, A.;
Weinbrenner, S. Synthesis 1993, 216.
The choice of t-BuOK followed an extensive study of alternative bases,
from which it was concluded that this base was much to be preferred for
the one-pot reaction. Lithium diisopropylamide can be used in its place
for the synthesis of intermediate 4 and compounds of its like. As an
indication of the scope and limitations of this approach, it is worth
noting that the anion of 1a was stable at -78°C, but at room temperature,
in the absence of an electrophile, the methanesulfonyl group was
eliminated to give N-Boc-4-chlorobenzylamine. In preliminary
investigations, it was found that this was a competing pathway for less
reactive electrophiles such as ketones.
10. The procedure is exemplified by vinylsulfonamide 3l (refer to the
table for the number of equivalents of t-BuOK used in other
examples): To
a solution of N-(tert-butoxycarbonyl)-N-(4-
chlorobenzyl)-methanesulfonamide 1a (480mg, 1.50mmol) in
THF (5ml), cooled under argon to -78°C, was added 1M
potassium t-butoxide in THF (3.00ml, 3.00mmol) (Fluka
Chemicals). The mixture was stirred at this temperature for 1h and
a solution of decylaldehyde 2l (234mg, 1.50mmol) in THF (5ml)
was added by means of cannula. The mixture was allowed to
warm to room temperature, with stirring, over 18h and partitioned

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SYNLETT
between ethyl acetate (20ml) and saturated ammonium chloride
(20ml). The aqueous phase was extracted twice with ethyl acetate
(20ml). The combined organic phases were washed with water
and brine and dried over magnesium sulfate. Filtration and
evaporation of the filtrate afforded the crude product mixture,
which was purified by column chromatography (silica; 65%
11. The procedure for the preparation of compound 4 was as for
vinylsulfonamide 3l with the following modifications: one
equivalent of t-BuOK was used; the cold bath was removed as
soon as the aldehyde had been added; and the mixture was stirred
1
for 1h. H NMR (300MHz, CDCl ): 7.34(4H, m); 5.00(1H, m);
3
4.28(2H, d, J 6.3Hz); 3.28(1H, dd, J 14.9, 8.6Hz); 3.01(1H, dd, J
dichloromethane/toluene). The vinylsulfonamide 3l was isolated
14.9, 3.1Hz); 1.65(1H, m); 1.54(1H, m); 1.48(9H, s); 1.27(14H,
s); 0.89(3H, t, J 6.8Hz). Anal. Calcd. for C H ClNO S: C
18 28 2
1
as a colourless solid (359mg, 67%). H NMR (300MHz, CDCl ):
3
7.32(2H, m); 7.26(2H, m); 6.77(1H, dt, J 15, 6.9Hz); 6.13(1H, dt,
J 15, 1.5Hz); 4.49(1H, t, J 6.3Hz); 4.17(2H, d, J 6.9Hz); 2.21(1H,
dt, J 6.9, 1.5Hz); 2.19(1H, dt, J 6.9, 1.5Hz); 1.43(2H, m);
60.40, H 7.89, N 3.91%; Found: C 60.64, H 7.74, N 3.91%.
12. For a perspective of the area: Lee, Y. S.; Ryu, E. K.; Yun, K.-Y.;
Kim, Y. H. Synlett 1996, 247. Table. The Synthesis of
Vinylsulfonamides.
1.28(12H, br s); 0.89(3H, t,
J 6.8Hz). Anal. Calcd. for
C
H
ClNO S: C 58.03, H 8.05, N 2.94%; Found: C 58.05, H
23 38
5
8.26, N 3.04%.