Thio acid/azide amidation: An improved route to N-acyl sulfonamides

Article abstract of DOI:10.1021/ol052671d

A one-pot procedure for the conversion of carboxylic acids to N-acyl sulfonamides, via thio acid/azide amidation, is presented. The method is compatible with acid- and base-sensitive amino acid protection. N-Acyl sulfonamide synthesis on solid support, pe

Full text of DOI:10.1021/ol052671d

ORGANIC
LETTERS
2006
Vol. 8, No. 5
823-826
Thio Acid/Azide Amidation: An
Improved Route to N-Acyl Sulfonamides
Kristin N. Barlett, Robert V. Kolakowski, Sreenivas Katukojvala, and
Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of
New Jersey, Piscataway, New Jersey 08854
ljw@rutchem.rutgers.edu
Received November 3, 2005
ABSTRACT
A one-pot procedure for the conversion of carboxylic acids to N-acyl sulfonamides, via thio acid/azide amidation, is presented. The method
is compatible with acid- and base-sensitive amino acid protection. N-Acyl sulfonamide synthesis on solid support, peptide thio acid/sulfonazide
coupling, and N-alkyl amide synthesis via selective cleavage of sulfonyl from an N-alkyl-N-acyl sulfonamide are also reported.
Sulfonyl azides react very rapidly with thio acids (Scheme
1) to give N-acyl sulfonamides,1 a product class useful in
Here we report our studies on an improved route to N-acyl
sulfonamides and related findings.
We have used trimethoxybenzyl (TMOB5) thio esters as
thio acid precursors;1 however, this approach is limited, as
illustrated in Scheme 2. TMOB-thio esters are readily
prepared6 from the corresponding carboxylic acid and
Scheme 1
(3) (a) Kenner, G. W. Chem. Commun. 1971, 636. (b) Backes, B. J.;
Ellman, J. A. J. Org. Chem. 1999, 64, 2322. (c) Shin, Y.; Winans, K. A.;
Backes, B. J.; Kent, S. B. H.; Ellman, J. A.; Bertozzi, C. R. J. Am. Chem.
Soc. 1999, 121, 11684. (d) Ingenito, R.; Dreznjak, D.; Guffler, S.; Wenschuh,
H. Org. Lett. 2002, 4, 1187. (e) Mclean, D.; Hale, R.; Chen, M. Org. Lett.
2001, 3, 2977.
(4) For ligation reactions, see: (a) Kemp, D. S. Biopolymers 1981, 20,
1793. (b) Tam, J. P.; Yu, Q.; Miao, Z. Biopolymers 1999, 51, 311. (c)
Coltart, D. M. Tetrahedron 2000, 56, 3449. (d) Prescher, J. A.; Bertozzi,
C. R. Nat. Chem. Biol. 2005, 1, 13. (e) Saxon, E.; Bertozzi, C. R. Science
2000, 287, 2007. (f) Kochendeoerfer, G. G.; Kent, S. B. H. Curr. Opin.
Chem. Biol. 1999, 3, 665. (g) Ko¨hn, M.; Wacker, R.; Peters, C.; Schro¨der,
H.; Soule`re, L.; Breinbauer, R.; Niemeyer, C. M.; Waldmann, H. Angew.
Chem., Int. Ed. 2003, 42, 5830. For a potential thio acid/sulfonazide
amidation strategy for ligation, see: (h) Merkx, R.; Brouwer, A. J.; Rijkers,
D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125.
medicinal chemistry,2 solid support linking strategies,3 and
for conjugation and ligation applications1,4 among others.
(1) (a) Method: Shangguan, N.; Katukojvala, S.; Greenberg, R.; Wil-
liams, L. J. J. Am. Chem. Soc. 2003, 125, 7754. (b) Mechanism:
Kolakowski, R. V.; Shangguan, N.; Wang, Z.; Sauers, R. R.; Williams, L.
J. Submitted.
(2) (a) Abbate, F.; Supuran, C. T.; Scozzafava, A.; Orioli, P.; Stubbs M.
T.; Klebe, G. A.; Jones, B. R. J. Med. Chem. 2002, 45, 3583. (b) Uehling,
D. E.; Donaldson, K. H.; Deaton, D. N.; Hyman, C. E.; Sugg, E. E.; Barrett,
D. G.; Hughes, R. G.; Reitter, B.; Adkison, K. K.; Lancaster, M. E.; Lee,
F.; Hart, R.; Paulik, M. A.; Sherman, B. W.; True, T.; Cowan, C. J. Med.
Chem. 2002, 45, 567. (c) Mader, M.; Shih, C.; Considine, E.; De Dios, A.;
Grossman, S.; Hipskind, P.; Lin, H.; Lobb, K.; Lopez, B.; Lopez, J.; et al.
Bioorg. Med. Chem. Lett. 2005, 15, 617. (d) Johansson, A.; Poliakov, A.;
Åkerblom, E.; Wiklund, K.; Lindeberg, G.; Winiwarter, S.; Danielson, U.;
Samuelsson, B.; Hallberg, A. Bioorg. Med. Chem. 2003, 11, 2551.
(5) Acronyms: Boc ) tert-butoxycarbonyl, DCC ) dicyclohexyl car-
bodiimide, DIC ) diisopropyl carbodiimide, DIEA ) ethyl diisopropyl-
amine, DMAP ) 4-dimethylamino pyridine, DMF ) N,N-dimethylforma-
mide, DMSO ) methyl sulfoxide, Fmoc ) 9-fluorenylmethoxycarbonyl,
IBCF ) isobutyl chloroformate, SES-N3 ) trimethylsilylethyl sulfonazide,
TBAF ) tetrabutylammonium fluoride, TLC ) thin-layer chromatography,
TMOB ) 2,4,6-trimethoxybenzyl.
(6) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
10.1021/ol052671d CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/09/2006

Scheme 2
Table 1.
TMOB-thiol.7 Conversion of protected threonine 5 to
TMOB-thio ester 6 and removal of the Fmoc protection
gave amine 7, and DCC-mediated coupling of 7 with
dipeptide 88 gave peptide thio ester 9 in excellent yield.9
TFA cleavage of both the TMOB and the tert-butyl groups
gave the crude peptide thio acid,10 which upon treatment with
trimethylsilylethyl sulfonazide (10)11 gave the peptide con-
jugate 11 in 92% yield. Similar treatment of 6 gave the
corresponding amide product 12. These experiments dem-
onstrate the ease with which thio acid/azide amidation can
be adapted to ligation/conjugation reactions. The major
limitations being that TMOB removal is slow, prolonged
exposure to TFA is required for good conversion, and
preparation of 11 by way of 6, while high yielding, is an
uneconomical route to simple amino acid-derived N-acyl
sulfonamides. Furthermore, this approach is not compatible
with acid-sensitive functional groups.
Our goal, therefore, was to develop an N-acyl sulfonamide
synthesis procedure compatible with acid- and base-sensitive
functionality. Scheme 3 summarizes the general approach,
and Table 1 provides several examples of the method.
Protected amino acids (13, Scheme 3) were transformed to
amino thio acids by exposure to isobutyl chloroformate,12
and then trimethylsilyl thiolate, followed by dilution with
methanol and then removal of volatiles under reduced
pressure. The N-acyl sulfonamide products (15) were formed
by dilution of the thio acid in mildly basic methanol, addition
of sulfonyl azide (14),13 stirring at room temperature,
followed by removal of solvent, and then silica gel chro-
matographic purification. Anhydrous trimethylsilyl thiolate
was prepared from bis(trimethylsilyl) sulfide14 upon treatment
with methyllithium.15
(7) Vetter, S. Synth. Commun. 1998, 28, 3219.
(8) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.; Williams, L. J. J. Am.
Chem. Soc. 2004, 126, 15348.
(9) No epimerization for this coupling was evident. For a closely related
coupling, see ref 8.
Scheme 3
(10) In dilute acid, the tert-butyl group is cleaved rapidly (<2 h), whereas
the TMOB group is cleaved slowly (>2 h).
(11) SES-N3 is readily prepared from (SES)2O. See: Weinreb, S. M.;
Chase, C. E.; Wipf, P.; Venkatraman, S. Organic Syntheses; Wiley &
Sons: New York; Collect. Vol. 10, p 707.
(12) Dudash, J.; Jiang, J.; Mayer, S. C.; Joullie, M. M. Synth. Commun.
1993, 23, 349.
(13) Sulfonyl azides are readily prepared in excellent yields from sulfonyl
chlorides or anhydrides and sodium azide. See: (a) Regitz, M.; Hocker, J.;
Liedhgener, A. Organic Syntheses; Wiley & Sons: New York, 1973;
Collect. Vol. 5, p 179. (b) Hazen, G. G.; Bollinger, F. W.; Roberts, F. E.;
Russ, W. K.; Seman, J. J.; Staskiewicz, S. Organic Syntheses; Wiley &
Sons: New York; Collect. Vol. 9, p 400.
824
Org. Lett., Vol. 8, No. 5, 2006

Presumably, the trimethylsilyl thioester generated from
addition of the thiolate to the mixed anhydride rearranges
to the trimethylsilyl thionoester under the reaction conditions.
Upon methanolysis, the thio acid is liberated. Subsequent
exposure to the azide leads to the amide according to the
mechanism outlined in Scheme 1.
trimethylsilyl thiolate formation step of entry 5, and the
overall yields were equally effective within experimental
error.
The ability to employ unprotected coupling partners, such
as 4-carboxy bezenesulfonazide (14a), enables direct sub-
sequent functionalization without having to implement a
protecting group strategy. For example, Fmoc-Ile-OH, was
converted to 15a (Table 1) and taken directly and im-
mobilized on the amine-functionalized Wang amide resin.
The same overall sequence, leading to an identically func-
tionalized resin, was achieved by formation of the N-acyl
sulfonamide on solid support (Scheme 4). Thus, Wang amide
This approach has many favorable qualities, including
reactant stoichiometry (near 1:1 for all reagents), volatility
of most reagents and reaction byproducts, reliably high
yields, and that the choice of solvent in the coupling reaction
can be determined by the solubility properties of the reactants
since the thio acid/azide amidation is effective in a range of
organic and aqueous solvents.1,16 Moreover, N-acyl sulfona-
mides often display significant water solubility. Avoidance
of aqueous workup and the lack of significant byproducts
and excess reagents, commonly used for other sulfonamide
couplings, also adds to the attractiveness of the method. In
generating the thio acid, the less convenient use of hydrogen
sulfide, sodium sulfide,15c-f or the less atom economical use
of thiols, such TMOB-thiol7 and related hydrogen sulfide
equivalents,15g,h is avoided by using bis(trimethylsilyl) sulfide.
The generation of trimethylsilyl thiolate from bis(trimeth-
ylsilyl) sulfide with methyllithium conveniently leads to
excellent overall yields of amide.15a Solutions of tetrabutyl-
ammonium fluoride in THF dried over activated molecular
sieves performed as well as methyllithium and gave yields
that were superior to those obtained with wet tetrabutylam-
monium fluoride;15b however, methyllithium reactions are
easier to monitor and are not contaminated by nonvolatile
tetrabutylammonium salts. In addition to the favorable qual-
ities mentioned above, this method is highly complementary
to other N-acyl sulfonamide syntheses. Direct amidation of
sulfonamides with active esters usually requires strong base
and/or highly active esters and excess reagents.3,17 The con-
ditions presented here are mildly basic and compatible with
a range of functionality, including acid- and base-sensitive
protecting groups as well as certain unprotected functionality.
Scheme 4
resin was coupled with commercial 14a18 and then exposed
to the crude Fmoc-Ile-SH (17) prepared according to our
method. The consumption of resin-bound azide was readily
monitored,19 and the only modification to the amidation
protocol was the use of excess 17 (2 equiv based on the
parent carboxylic acid) and methylene chloride instead of
methanol.20 Proof that we had indeed succeeded in effecting
thio acid/azide amidation on solid support was secured by
comparison of the spectral characteristics of the purified
cleavage products from the two resins, which were shown
to be identical. The overall isolated yield of the 18 was 72%
based on the loading capacity of the resin.
In Table 1, entries 4 and 5 employed trimethylsilylethyl
sulfonazide (SES-N3). We wondered if N-acyl sulfonamides
derived from the Weinreb SES group would offer the
opportunity of mild sulfonamide N-S bond cleavage (Scheme
5).21 Removal of the SES protecting group from an amine
usually requires high temperature and excess fluoride
reagent.22 These conditions are readily attributable to the poor
leaving group ability of the anionic amine. An N-acyl
sulfonamide represents a substrate with comparatively su-
For the entries in Table 1, the same procedure was
followed, modified only by the reaction time allowed for
the consumption of mixed anhydride by thiolate, a parameter
readily monitored by TLC. Coupling partners include base-
sensitive substrates (entries 1-3), acid-sensitive substrates
(entries 3-5), protected alcohol (entry 4), free alcohol (entry
5), and free carboxylic acid (14a, entries 1-3). Methyllithium
and dried tetrabutylammonium fluoride were used for the
(14) Caution: Bis(trimethylsilyl) sulfide hydrolyzes to hydrogen sulfide,
which is highly toxic. Although we have noted no problems with compounds
described in this report, azides may be explosive.
(15) For other methods to generate thio acids, see: (a) Kraus, G. A.;
Andersh, B. Tetrahedron Lett. 1991, 32, 2189. (b) Schwabacher, A. W.;
Maynard, T. L. Tetrahedron Lett. 1993, 34, 1269 and references therein.
(c) Yamashiro, D.; Blake, J. Int. J. Peptide Protein Res. 1981, 18, 383 and
references therein. (d) Pansare, S. V.; Vederas, J. C. J. Org. Chem. 1989,
54, 2311. (e) Hoeg-Jensen, T.; Holm, A.; Sorensen, H. Synthesis 1996, 383.
(f) Lee, A. H. F.; Chan, A. S. C.; Li, T. Tetrahedron 2003, 59, 833. (g)
Goldstein, A. S. Gleb, M. H. Tetrahedron Lett. 2000, 41, 2797. (h) Gartner,
H.; Villain, M.; Botti, P.; Canne, L. Tetrahedron Lett. 2004, 45, 2239.
(16) DMSO is an exception. We believe this is due to oxidation of the
thio acid. Selenocarboxylates appear to behave similarly. See: Wu, X.; Hu,
L.; Tetrahedron Lett. 2005, 46, 8401.
(18) Carboxybenzene sulfonazide was attached to amine functionalized
Wang amide resin. The reaction was monitored until completion as
determined by the Kaiser test: Kaiser, E.; Colescott, R. L.; Bossinger, C.
D.; Cook, P. I. Anal. Biochem. 1970, 34, 595. See Supporting Information.
(19) Punna, S.; Finn, M. G. Synlett 2004, 99.
(20) The thio acid/azide amidation is compatible with a wide range of
solvents (see also, ref 16).
(21) For other examples of mild N-acyl sulfonamide cleavage, see: (a)
Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (b) Fukuyama, T.;
Cheung, M.; Jow, C.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5931.
(c) Ahmed, N.; Tsang, W. Y.; Page, M. I. Org. Lett. 2004, 6, 595 and
references therein.
(22) Weinreb, S. M.; Demko, D. M.; Lessen, T. A., Demers, J. P.
Tetrahedron Lett. 1986, 27, 2099.
(17) Wieland, T.; Hennig, H. J. Chem. Ber. 1960, 93, 1236. For
alternatives applicable to solid support synthesis, see refs 2, 3d, and 3e.
Org. Lett., Vol. 8, No. 5, 2006
825

N-methyl N-isoleucyl SES amide 19 as expected. Upon brief,
room temperature treatment with TBAF, 19 was smoothly
converted to methyl amide 20 in excellent yield (85%). Thus,
the Weinreb SES group participated in the thio acid/azide
reaction to form an N-acyl sulfonamide, promoted smooth
N-alkylation, and was rapidly cleaved in this context under
mild conditions.
Scheme 5
This approach to effect mild N-S bond cleavage of
N-alkyl-N-acyl sulfonamides complements other methods and
avoids the high temperatures and/or strong reducing agents
required sometimes required.24 Demonstrated compatibility
with the Fmoc protecting group is especially attractive and
suggests good functional group compatibility.
This report offers a mild, chemoselective alternative to
the preparation of N-acyl sulfonamides from active esters
and sulfonamides that is compatible with acid- and base-
sensitive protecting groups and, in certain cases, unprotected
functionality. Generation of the thio acid from the parent
carboxylic acid followed by addition of sulfonyl azide gives
the desired product in excellent yield. The feasibility of
N-acyl sulfonamide synthesis with peptide segments and solid
support has also been demonstrated. Similarly, SES-N3 has
been shown to give N-acyl sulfonamides. Following N-
alkylation, the SES group is readily cleaved upon brief, room
temperature fluoride treatment. The generality of these
findings, including applications in target-oriented synthesis,
studies in chemical biology, and related amidations, will be
reported in due course.
perior leaving group ability. However, even weakly basic
reagents would generate the stable, anionic acyl sulfonamide
and would convert the acyl appendage to a very poor leaving
group.23 Moreover, N-alkyl-N-acyl sulfonamides usually react
with nucleophiles at the acyl center, effect cleavage of the
C-N bond, and give the substituted acyl product along with
the corresponding sulfonamide.3
Acknowledgment. Financial support by Merck & Co.,
Johnson & Johnson Innovative Research Award, the Petro-
leum Research Fund, administered by the ACS, and Rutgers,
The State University of New Jersey is gratefully acknowl-
edged.
In contrast to these established trends, we anticipated that
N-alkyl-N-acyl SES amides would react with fluoride to give
the N-alkyl amide with concomitant disintegration of the SES
moiety.22 Hence, the N-S bond would rupture by an
eliminative process initiated by fluoride at silicon, and the
normal mode of reactivity for N-alkyl-N-acyl sulfonamides
would be avoided (compare 1 with 2, Scheme 5). This
sequence of transformations, carboxylic acid f sulfonamide
f amide, would constitute a mild, chemoselective route to
N-alkyl amides that avoids amine intermediates. To dem-
onstrate the concept, we subjected 15d to methyl iodide in
the presence of ethyl diisopropylamine, which gave the crude
Supporting Information Available: Complete list of
authors for ref 2c. Experimental procedures and spectral data
for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL052671D
(24) (a) Knowles, H. S.; Parsons, A. F.; Pettiefer, R. M.; Rickling, S.
Tetrahedron 2000, 56, 979 and references therein. (b) Luo, J.; Huang, W.
Molecular DiVersity 2003, 6, 33.
(23) The pKa of acyl sulfonamides is ∼2.5. See ref 3a.
826
Org. Lett., Vol. 8, No. 5, 2006