β-cyclodextrin-catalyzed monosulfonylation of amines and amino acids in water

Article abstract of DOI:10.1002/adsc.200600652

A mild and efficient procedure has been developed for the first time under biomimetic conditions for the monosulfonylation of various amines and amino acids catalyzed by β-cyclodextrin in water at room temperature to afford the corresponding sulfonamides in high yields.

Full text of DOI:10.1002/adsc.200600652

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DOI: 10.1002/adsc.200600652
b-Cyclodextrin-Catalyzed Monosulfonylation of Amines and
Amino Acids in Water
R. Sridhar,a B. Srinivas,a V. Pavan Kumar,a M. Narender,a and K. Rama Raoa,*
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad – 500007, India
Fax : (+91)-40-2716-0757; e-mail: ramaraok@iict.res.in
Received: December 29, 2006; Revised: July 2, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A mild and efficient procedure has been
developed for the first time under biomimetic con-
ditions for the monosulfonylation of various amines
and amino acids catalyzed by b-cyclodextrin in
water at room temperature to afford the corre-
sponding sulfonamides in high yields.
Therefore, there is a clear need for the develop-
ment of a generally applicable, environmentally
benign and mild methodology for the synthesis of sul-
fonamides in water. Organic reactions in aqueous
media have recently become the focus in organic syn-
thesis since they overcome the harmful effects of or-
ganic solvents and are environmentally benign.[8]
These aqueous reactions can be made more sophisti-
cated if they can be performed under supramolecular
catalysis. In continuation of our interest in the use of
cyclodextrins as mild and efficient biomimetic cata-
lysts in promoting various transformations,[9] we have
attempted the sulfonylation of amines in water in the
Keywords: amines; amino acids; b-cyclodextrin; sul-
fonamides; sulfonyl chlorides; water
Sulfonamides are diverse group of medicinally impor- presence of cyclodextrin.
tant compounds widely used as anticancer, antibacte-
Cyclodextrins (CDs) are cyclic oligosaccharides
rial, anticonvulsants, HIV protease inhibitors, anti-in- possessing hydrophobic cavities, which bind substrates
flammatory, antitumor and antiviral agents.[1,2] Phar- selectively and catalyze chemical reactions with high
maceutically important examples include the protease selectivity. They promote reactions by supramolecular
inhibitor amprenavir, the analgesic celecoxib, sildena- catalysis involving reversible formation of host-guest
fil for erectile dysfunction and the antimigraine agent complexes by non-covalent bonding as seen in en-
sumatriptan.[3]
zymes. We describe herein the remarkable catalytic
Although many efforts have been made towards activity of b-cyclodextrin in the reaction of various
the development of novel sulfonamides,[4] the conven- amines and amino acids with p-toluenesulfonyl chlo-
tional synthesis involves the reaction of amino com- ride and methanesulfonyl chloride, to give exclusively
pounds with sulfonyl chlorides.[5] However, these pro- the monosulfonamides (Scheme 1 and Scheme 2).
cedures involve the use of organic solvents, base and
In general, the reactions were carried out by dis-
elevated temperatures, especially for less reactive ani- solving b-cyclodextrin in water and then adding the
line substrates. For sterically hindered primary amines
with electron-withdrawing substituents, bis-sulfonyla-
tion is a common side reaction which requires further
monodesulfonylation.[6] Although Diang and Mani re-
cently reported[7] a synthesis of sulfonamides in water,
it requires dynamic pH control with Na2CO3 and iso-
lation of the products involves acidification up to
Scheme 1.
pH 2 with HCl. This methodology has some draw-
backs such as the limitation of utilizing mostly water-
soluble amines like aminobenzoic acids and sluggish
reactions with insoluble amines like aniline with
yields only up to 30% of the desired product even
after three days.
Scheme 2.
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R. Sridhar et al.
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Table 1. Sulfonamide synthesis in water/in buffer catalyzed
by b-cyclodextrin.
Table 1. (Continued)
[a]
All products were identified by IR, NMR and mass spec-
troscopy.
Yields of products isolated after column chromatography.
[b]
amine followed by the addition of p-toluenesulfonyl
chloride or methanesulfonyl chloride at room temper-
ature to get the corresponding sulfonamides in high
yields (76–95%,). The reactions were rapid with all
the amines studied (25–60 min). This method was also
compatible with various types of primary and secon-
dary amines. No bis-sulfonylated product formation
was observed even with sterically hindered and elec-
tron-deficient anilines (entries 13–16, Table 1). High
enantioselectivity was also observed in the case of
amino alcohols (entries 19–22, Table 1). b-CD can be
recovered and reused. All the products were isolated
1
and characterized by H NMR, mass and IR spectros-
copy and by comparison with the known com-
pounds.[4–6,10]
The successful monosulfonylation of amino com-
pounds with TsCl and MsCl prompted us to attempt
this reaction with amino acids. These reactions were
attempted at pH 8 using a mild carbonate buffer
(0.1M) with b-cyclodextrin as the catalyst. Surprising-
ly, the reactions with TsCl were complete in 45–
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b-Cyclodextrin-Catalyzed Monosulfonylation of Amines and Amino Acids
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Figure 1. 1H NMR spectra (200 MHz, DMSO-d6) of a) b-CD, b) aniline:b-CD complex and c) aniline.
55 min at room temperature giving yields of 85–88%, Table 2. 200 MHz (DMSO-d6) 1H NMR chemical shifts of
aniline and b-CD protons in free and complexed states.[a]
whereas no product formation was observed with
MsCl due to rapid hydrolysis. No racemization was
observed during these reactions.
The catalytic activity of cyclodextrin for this sulfo-
nylation of amines and amino acids is established by
the fact that no reaction was observed in the absence
of cyclodextrin. Evidence for complexation between
1
the amine and cyclodextrin is supported by H NMR
spectroscopy. Although all these reactions were car-
ried out with a catalytic amount of b-CD, these stud-
ies were undertaken with b-CD-aniline (1:1) complex
as a representative example, as cylcodextrins catalyze
reactions by supramolecular catalysis involving rever-
sible formation of host-guest complexes. A compari-
1
son of H NMR spectra of aniline, b-CD and the b-
CD-aniline complex was undertaken. All aromatic
and NH2 protons of aniline are shifted upfield due to
the inclusion of aniline inside of b-CD cavity
(Figure 1, Table 2).[11] There is also a clear upfield
[a]
Chemical shifts are expressed in Hertz with reference to
shift of H-3 (0.03 ppm) and H-5 (0.05 ppm) of cyclo-
DMSO-d6 signal.
dextrin in the b-CD-aniline complex in comparison to
b-CD indicating the formation of an inclusion com-
plex of aniline with b-CD (Figure 1, Table 2).[11] For-
mation of hydrogen bonding between the hydroxy molecular hydrogen bonding with the guest to pro-
groups of the top torus in the b-CD molecule and ani- mote the reaction.
line was already established by molecular dynamics
In conclusion, we have presented an elegant and
studies.[12] Here, b-CD not only forms the inclusion simple methodology for the monosulfonylation of var-
complex with the amine but is also involved in inter- ious amines and amino acids in the presence of b-cy-
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R. Sridhar et al.
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clodextrin in water. This straightforward methodology Acknowledgements
may find widespread applications in organic and me-
dicinal chemistry.
V.P.K. and M.N.R. thank CSIR, New Delhi, India, forthe
award of research fellowships
Experimental Section
References
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b-Cyclodextrin (0.1 mmol) was dissolved in water (15 mL)
at room temperature and the amine (1 mmol) dissolved in
acetone (1 mL) was added dropwise with stirring. To this
suspension p-toluenesulfonyl chloride (1.2 mmol) or meth-
anesulfonyl chloride (1.5 mmol) was added and the mixture
stirred at room temperature until the reaction was complete
(Table 1). The reaction mixture was extracted with ethyl
acetate, dried over Na2SO4 and concentrated under reduced
pressure and the resulting product was further purified by
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General Procedure for Synthesis of N-(p-
Toluenesulfonyl)amino Acids
b-Cyclodextrin (0.1 mmol) was dissolved in 0.1M carbonate
buffer (pH 8) (10 mL) at room temperature, then the amino
acid (1 mmol) was added and the mixture stirred for 5 min.
Then TsCl (1.2 mmol) was added and stirring was continued
at room temperature until the reaction was complete
(Table 1). The reaction mixture was extracted with ethyl
acetate, the organic layer was dried over anhydrous Na2SO4
and the solvent was removed under vacuum to yield the
product. These products were purified by silica gel chroma-
tography.
Preparation of b-CD-Aniline Inclusion Complex
b-CD (1 mmol) was dissolved in water (15 mL) by warming
to 608C until a clear solution was formed, and then aniline
(1 mmol) dissolved in acetone (1 mL) was added dropwise
and the mixture was allowed to come to room temperature.
It was cooled to 158C for 5 h and the white solid precipitate
was filtered and dried.
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Adv. Synth. Catal. 2007, 349, 1873 – 1876