Preparation of sulfonamides from N-silylamines

Article abstract of DOI:10.1016/j.tetlet.2013.08.034

Sulfonamides have been prepared in high yields by the reactions of N-silylamines with sulfonyl chlorides and fluorides. In a competition experiment, the sulfonyl chlorides were found to be far more reactive than sulfonyl fluorides. The chemistry may be used to prepare aliphatic, aromatic, tertiary, secondary, and primary sulfonamides. It may also be done in the absence of solvent and the byproduct trimethylsilyl chloride recovered in good yield. Primary sulfonamides were synthesized from the sulfonyl chloride with aminotriphenyl silane (Ph₃SiNH₂), a conversion demonstrated with the synthesis of the carbonic anhydrase inhibitor, acetazolamide.

Full text of DOI:10.1016/j.tetlet.2013.08.034

Accepted Manuscript
Preparation of sulfonamides from N-silylamines
Rajasekhar Reddy Naredla, Douglas A. Klumpp
PII:
S0040-4039(13)01387-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.034
TETL 43396
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 July 2013
8 August 2013
10 August 2013
Please cite this article as: Naredla, R.R., Klumpp, D.A., Preparation of sulfonamides from N-silylamines,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.034
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Preparation of sulfonamides from N-silylamines.
Rajasekhar Reddy Naredla and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115
Phone 815-753-1959; FAX 815-753-4208; Email: dklumpp@niu.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Sulfonamides have been prepared in high yields by the reactions of N-silylamines with
sulfonyl chlorides and fluorides. In a competition experiment, the sulfonyl chlorides were
found to be far more reactive than sulfonyl fluorides. The chemistry may be used to prepare
aliphatic, aromatic, tertiary, secondary, and primary sulfonamides. It may also be done in the
absence of solvent and the byproduct trimethylsilyl chloride recovered in good yield.
Primary sulfonamides were synthesized from the sulfonyl chloride with aminotriphenyl
silane (Ph3SiNH2), a conversion demonstrated with the synthesis of the carbonic anhydrase
inhibitor, acetazolamide.
Available online
Keywords:
Keyword_1
Keyword_2
Keyword_3
Keyword_4
Keyword_5
Keywords: Sulfonamides, sulfonyl transfer, N-silylamine, substitution
2009 Elsevier Ltd. All rights reserved.
Introduction
The sulfonamide functional group is a structure with broad
importance, as it is found in numerous medicinal agents,
dyes/pigments, polymers, and other structures.1 For example, the
anti-cholesterol drug Crestor and anti-arthritic drug Celebrex
both contain the sulfonamide functional group. Sulfonamides are
studied and the expected sulfonamide products (5,7) were
obtained in fair to good yields (eqs 2-3). Even with added
fluoride (20 mol %, Bu4NF), the sulfonyl fluorides exhibited
sluggish reactivities. However, the same reactions with
analogous sulfonyl chlorides (4b,6b) provide the sulfonamides
(5,7) in quantitative yields. The greater reactivity of the sulfonyl
chlorides was also observed in a competition experiment. One
equivalent of 4a and 4b were reacted with one equivalent of N-
often prepared by the reactions of sulfonyl chlorides with amines,
accompanied by the release of HCl.2 Given the importance of the
sulfonamide functional group, convenient methods of preparing
this structure are highly desirable. In this manuscript, we report
the efficient preparation of sulfonamides from N-silylamines and
sulfonyl halides. Our results indicate that sulfonyl chlorides are
superior to sulfonyl fluorides in the reaction.
(trimethylsilyl)morpholine (1) and product
5 was formed
Results and Discussion
exclusively by reaction of the sulfonyl chloride (4b). Unreacted
sulfonyl fluoride (4a) could be recovered quantitatively. These
results were somewhat surprising as the formation of the
trimethylsilylfluoride – and the strong fluorine-silicon bond – is
evidently not the most important factor in determining reaction
rates or yields (vide infra).
In our initial studies, we sought to react sulfonyl fluorides and
N-silylamines. With formation of the sulfonamide, the byproduct
of the reaction should be the silyl fluoride. We reasoned that the
formation of the fluorine-silicon bond could be a good driving
force for the conversion. Our initial experiment involved a
reaction between N-(trimethylsilyl)morpholine (1) and the
perfluorinated sulfonyl fluoride (2, eq 1). Although the expected
sulfonamide (3) was isolated, the yield of the conversion was
somewhat disappointing. Other sulfonyl fluorides (4a,6a) were
The N-silylamines 1 and 12 were shown to react with a variety
of sulfonyl chlorides to give the respective sulfonamide products
(8-11, 13-17; Table 1). Heterocyclic, aromatic, and carbocyclic

2
Tetrahedron Letters
Table 1. Sulfonamide products (8-17) and yields from N-silyl-
Table 2. Sulfonamide products (23-27) and yields from tosyl
amines 1 and 12.
chloride and N-silylamines (18-22).
measured to be around 103 to 105 in reactions with
benzenesulfonyl halide (acetonitrile/water).5
As noted by
Maccarone, these results are clearly related to the relative sulfur-
halogen bond strengths,6 where the S-F and S-Cl bonds are
respectively 82 and 66 kcal•mol-1.7,8 Previous studies with
sulfonyl transfer reactions have suggested a two-step addition-
elimination process, SAN, for the substitution mechanism
involving nitrogen nulceophiles and sulfonyl halides.6 Other
studies have also suggested a one-step, SN2 mechanism for
sulfonyl transfer reactions.5
sulfonamides have all been prepared in quantitative yields. In the
optimized reaction conditions, equimolar quantities of N-
silylamine and sulfonyl chloride are combined in acetonitrile and
the mixture is stirred at reflux for one hour. Removal of the
solvent and silyl chloride provides the sulfonamide.
Our own theoretical calculations9 (B3LYP 6-311G(d, p) level)
showed the sulfonyl fluoride reaction to be more highly
exothermic compared to the same conversion with the sulfonyl
chloride (Figure 1). This is likely due to the strong Si-F bond
formed in the product mixture. This suggests that sulfonamide
formation is a kinetically controlled process involving N-
silylamine attack at the sulfur with subsequent elimination of the
silyl halide. Assuming the SAN mechanism is operating, the
sulfonyl halide (4a,b) reacts with the N-silylamine to give the
adduct 30. The reverse reaction is more important with X = F,
while the forward reaction is favored with X = Cl. Elimination
of the silyl halide gives the sulfonamide 5. Rather than a
concerted elimination process, the halide may also dissociate
from the sulfur and directly attack the silyl group. This process
could occur from the adduct 30, or alternatively, by the SN2-type
mechanism where 30 would represent a transition state. Other
mechanistic proposals are conceivable, for example a catalytic
cycle with halide anion reacting directly with the N-silylamine.
Such a pathway is not likely, given that added fluoride does not
improve the reaction yields/rates for the conversions involving
sulfonyl fluorides.
Other N-silylamines were reacted with p-toluenesulfonyl
chloride to provide varied sulfonamides (Table 2). The N-
silylamines include those from a secondary alkyl amine (18),
allyl amine (19), and the imine (20). Primary sulfonamides have
found significant use in drug design. In order to prepare the
primary sulfonamide (26), aminotriphenylsilane (21) was
utilized. The silane 21 itself was prepared from triphenylsilyl
chloride and ammonia.3 In the case of sulfonamide 27, this
conversion was accomplished without the use of solvent. Thus,
the byproduct trimethylsilyl chloride can be distilled off directly
and recovered in greater then 75% yield.
As an application of the chemistry, aminotriphenylsilane
(Ph3SiNH2, 21) was also used in the synthesis of the carbonic
anhydrase inhibitor, acetazolamide (29; eq 4). Starting from the
Conclusions
In summary, we have found a convenient procedure for the
synthesis of sulfonamides from N-silylamines and sulfonyl
chlorides.10 A “solvent-free” example of the conversion has been
demonstrated. Our studies also show that the conversions to
sulfonamides may be done with sulfonyl fluorides, although the
chemistry is less efficient. A mechanism is proposed involving
an addition-elimination process. The methodology compliments
an earlier report describing the synthesis of amides with acid
chlorides and N-silylamines.11
commercially available 5-amino-1,3,4-thiadiazole-2-thiol, the
sulfonyl chloride (28) is prepared in two steps by acetylation of
the amino group and oxidation of the thiol group.4 A subsequent
reaction between the sulfonyl chloride 28 and Ph3SiNH2 provides
acetazolamide (29) in 74% yield.
Regarding the relative reactivities of the sulfonyl fluorides and
chlorides in the reactions above, it is known that sulfonyl transfer
reactions are considerably faster with sulfonyl chlorides versus
sulfonyl fluorides.5 For nitrogen nucleophiles, kCl/kF has been

3
Figure 1. Calculated energies of reactants, products, and the conversion (B3LYP 6-311G (d,p) level), as well as the proposed
mechanism of formation for sulfonamide 5.
A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.;Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
Acknowledgments
T.; Honda, Y.; Kitao, O.; Nakai,H.; Vreven, T.; Montgomery, Jr.,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand,J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.;Rega, N.; Millam, J. M.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.;Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.;Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,Ö.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian,
Wallingford, CT, 2009.
We gratefully acknowledge the support of the NIH-National
Institute of General Medical Sciences (GM085736-01A1) and the
Northern Illinois University for Great Journeys Fellowship
(R.R.N.). This manuscript is dedicated to Rachel A. Klumpp on
the occasion of her tenth birthday.
References and notes
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Med. Chem. 2003, 10, 925. d. The Chemistry of the Functional
Groups: Sulfonic Acids and their Derivatives, Patai, S.;
Rappoport, Z., eds.; Wiley: New York, 1991.
10. Typical procedure: The sulfonyl chloride (1 mmol) is dissolved
in 15 ml acetonitrile and then silylamine (1 mmol) is slowly
added. The reaction mixture is refluxed for 1 hour and
concentrated with rotary evaporator. If necessary, the product may
be further purified by silica gel chromatography (hexane: ethyl
acetate).
11. a. Bowser, J. R.; Williams, P. J.; Kura, K. J. Org. Chem. 1983,
48, 4111. b. For a related preparation of an N-silylated
sulfonamide, see: Roy, A. K. J. Am. Chem. Soc. 1993, 115, 2598.
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Supplementary Material
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Rajasekhar Reddy Naredla and Douglas A. Klumpp*