Efficient synthesis of sulfonyl azides from sulfonamides

Article abstract of DOI:10.1021/ol8011088

(Equation Presented) Triflyl azide serves as an efficient diazo transfer reagent in this first direct synthesis of sulfonyl azides from readily available and stable sulfonamides. The process is experimentally simple, mild, and high-yielding. Sulfonyl azid

Full text of DOI:10.1021/ol8011088

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3385-3388
Efficient Synthesis of Sulfonyl Azides
from Sulfonamides
Jessica Raushel, Suresh M. Pitram, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
fokin@scripps.edu
Received May 13, 2008
ABSTRACT
Triflyl azide serves as an efficient diazo transfer reagent in this first direct synthesis of sulfonyl azides from readily available and stable
sulfonamides. The process is experimentally simple, mild, and high-yielding. Sulfonyl azides participate in various catalytic transformations
providing rapid access to diversely functionalized sulfonamide derivatives in good yields.
Utility of sulfonyl azides in synthesis goes well beyond the
commonly used diazo1 and azide2 transfer reactions. Their
recent applications include a three-component copper(I)-
catalyzed coupling with alkynes and amines leading to
amidines described by Chang and co-workers,3 synthesis of
N-acylsulfonamides via reaction with either thio acids4 or
copper(I) acetylides,5 and facile preparation of azetidin-
imines.6 Unfortunately, the availability of sulfonyl azides has
been limited to those accessible from sulfonyl chlorides,
which are electrophilic and hydrolytically unstable, and hence
have limited functional group compatibility. Sulfonamides,
on the other hand, are moisture and air stable, are fairly
unreactive toward most functional groups, and are readily
available.7 Therefore, a direct method for the synthesis of
sulfonyl azides from sulfonamides would be a welcome
addition to the field.
To accomplish this transformation, we envisioned that a
sufficiently reactive diazo transfer reagent with a weakly
nucleophilic leaving group would favor formation of the
azide from the diazo donor reagent and the sulfonamide.
Herein, we report a convenient procedure for the direct
synthesis of sulfonyl azides from sulfonamides using tri-
fluoromethanesulfonyl (triflyl) azide.
In our initial studies, we subjected the test substrate 1 to
the modified diazo transfer conditions of Ernst and co-
workers8 (see Table 1), which uses a ternary mixture of
water, toluene, and methanol, obviating the use of dichlo-
romethane9 typically employed in other triflyl azide prepara-
tions.10 Although this procedure reliably afforded the desired
sulfonyl azide product 2, we found that seemingly identical
experiments exhibited disparate yields (entry 1), which we
attributed to the poor solubility of the sulfonamide 1.
Switching from methanol to isopropyl alcohol (entry 2) or
tert-butyl alcohol (entry 3) at the same volumetric ratio
improved the solubility of 1 and resulted in improved batch
to batch consistency. A scan of inorganic bases revealed that
4 equiv of either bicarbonate (entries 3 and 4) or carbonate
(entries 5 and 6) bases resulted in comparable conversions;
(1) Bollinger, F. W.; Tuma, L. D. Synlett 1996, 407–413.
(2) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud, P.;
Zigmantas, S. Chem.-Eur. J. 2004, 10, 3606–3614.
(3) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038–
2039.
(4) (a) Barlett, K. N.; Kolakowski, R. V.; Katukojvala, S.; Williams,
L. J. Org. Lett. 2006, 8, 823–826. (b) Merkx, R.; Brouwer, A. J.; Rijkers,
D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125–1128.
(5) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046–16047. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V.
Angew. Chem., Int. Ed. 2006, 45, 3154–3157.
(8) Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. Tetrahedron Lett. 2006,
47, 2383–2385.
(9) Use of dichloromethane as a solvent with sodium azide is avoided
to prevent inadvertent generation of the highly shock sensitive diazi-
domethane. See: Peet, N. P.; Weintraub, P. M. Chem. Eng. News 1993, 71,
4.
(6) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157–
3161.
(7) Compare 24 569 commericially available benzenesulfonamides
versus 1385 commercially available benzenesulfonyl chlorides. SciFinder,
version 2006, Chemical Abstracts Service: Columbus, OH, 2006. (as of
January 8, 2008).
(10) (a) Nyffler, P. T.; Liang, C. H.; Koeller, K. M.; Wong, C. H. J. Am.
Chem. Soc. 2002, 124, 10773–10778. (b) Liu, Q.; Tor, Y. Org. Lett. 2003,
5, 2571–2572.
10.1021/ol8011088 CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Table 2. Aryl Sulfonyl Azides via Diazo Transfer from TfN3 to
Sulfonamidesa
entry
base
ROH
1 consumed, %b yield of 2, %b
1
2
3
4
5
6
7
8
NaHCO3
NaHCO3
NaHCO3
KHCO3
Na2CO3
K2CO3
2,6-lutidine t-BuOH
Et3N
i-Pr2EtN
NaHCO3
NaHCO3
K2CO3
MeOH
92-97
92-94
90-99
98
>99
>99
9
37
79
97
>99
>99
79-95
92-93
85-98
91
95
92
ca. 1
10
65
97
>99
>99
i-PrOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
9
10c
11d
12e
a 0.1 mmol scale; TfN3 (ca. 1.0 equiv), CuSO4 (4 mol %), base (4.0
equiv), H2O/toluene/ROH 1/1.7/6.7. b As determined by LC/MS. See
Supporting Information for details. c Without CuSO4. d TfN3 (ca. 1.5 equiv).
e Imidazole-1-sulfonyl azide hydrochloride (1.2 equiv).
yet, amine bases (entries 7-9) were ineffectual. Although
the addition of copper(II) sulfate is not necessary for the
reaction to proceed (entry 10), its presence has been
demonstrated to mitigate variations in the quality of triflic
anhydride, eliminating the need for prior distillation.11
Despite the improvement achieved by altering the solvent,
the reaction still did not progress to completion, nor did it
produce the azide in consistently high yields across experi-
ments. Consequently, we increased the amount of triflyl azide
added (ca. 1.5 equiv, entry 11),12,13 which resulted in
virtually quantitative conversions and consistent performance
of the reaction.
Using these modified conditions, complete conversion was
typically observed after 15-42 h. If stirring was continued
for 72 h, degradation to the corresponding sulfonic acid
began to occur.
Although attempts to use tosyl azide, a less reactive diazo
transfer reagent, were unsuccessful, imidazole-1-sulfonyl
azide,14 the recently described alternative to triflyl azide,
a 1 mmol scale unless otherwise noted; TfN3 (ca. 1.5 equiv), NaHCO3
(4.0 equiv), CuSO4 (4 mol %), H2O/toluene/t-BuOH 1/1.7/6.7. b Isolated
yield. c 5 mmol scale. d 0.5 mmol scale. e Starting material (15%) was
recovered.
(11) Alper, P. B.; Hung, S. C.; Wong, C. H. Tetrahedron Lett. 1996,
37, 6029–6032.
(12) To a vigorously stirred ice-cold mixture of NaN3 (1.30 g, 20.0
mmol), water (5 mL), and toluene (3.3 mL) in a septum-fitted nitrogen
flushed scintillation vial, Tf2O (2.52 mL, 15.0 mmol) was added dropwise.
After stirring behind a blast shield for 2 h at 0 °C, the reaction was quenched
with saturated aq NaHCO3, and the organic layer was removed. The aqueous
layer was extracted with toluene (2 × 3.3 mL). The combined organic
extracts were used immediately. A conservative estimate of 50% yield was
exhibited similarly clean conversions (entry 12), with slight
procedural modifications.
The general procedure15 has been applied over a range of
sulfonamides, and Table 2 illustrates its broad scope. The
sulfonyl azide products were typically collected by filtration,
after removal of volatiles, or by extraction into ethyl acetate.
Both electron-deficient (entries 1 and 2) and electron-rich
(entries 3 and 4) sulfonamides were transformed into the
corresponding sulfonyl azides in good to excellent yield. The
heterocyclic substrates (entries 7-10) are particularly inter-
esting: their complexity would make syntheses of the
used for subsequent experiments. See ref 11
.
(13) CAUTION: These modifications increase the possibility of excess
TfN3 remaining at the end of the reaction. Before removing the volatiles
during the workup, xylenes are placed in the collection trap of the rotary
evaporator to prevent collection of neat TfN3. Before disposal of the solvent
in an appropriate fashion, copper powder is added to the xylenes to expedite
the degradation of TfN3
(14) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–
3800.
.
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Org. Lett., Vol. 10, No. 16, 2008

Scheme 1. Elaboration of Celecoxiba
Scheme 4. Further Transformations of Sulfonyl Azide 2a
aTol ) tolyl.
Scheme 2. C-Nucleophile Preference
a (a) 2 (1.0 equiv), tert-butyl prop-2-ynylcarbamate (1.0 equiv), NaHCO3
(1.0 equiv), CuSO4 (0.10 equiv), sodium ascorbate (0.20 equiv), 2:1 t-BuOH/
H2O; (b) 2 (1.2 equiv), phenylacetylene (1.0 equiv), diisopropylamine (1.2
equiv), CuI (0.10 equiv), THF; (c) 2 (1.2 equiv), phenylacetylene (1.0 equiv),
(4-bromophenyl)methanol (1.2 equiv), CuI (0.10 equiv), triethylamine (1.2
equiv), CHCl3; (d) 2 (1.0 equiv), malononitrile (1.0 equiv), NaOH (2.0
equiv), Et2O. NaAsc ) sodium ascorbate.
Scheme 3. One-Pot Synthesis of Sulfonyl Azides
nucleophilic enol R-carbon, leading to 25 (Scheme 2).
Although none of the desired sulfonyl azide was detected, a
trace amount of the doubly reacted material 26 was isolated.
corresponding sulfonyl chlorides challenging. This is readily
apparent when one compares two syntheses of the sulfonyl
azide 23, as shown in Scheme 1. Whereas the previous
preparation of this azide involved a four-step sequence
starting from the nitrobenzene derivative 2216 in 20% overall
yield, the improved procedure makes 23 available in a single
step from celecoxib (21, Celebrex), which is itself formed
from the fusion of 4,4,4-trifluoro-1-p-tolylbutane-1,3-dione
and 4-hydrazinylbenzenesulfonamide.17
Although the general procedure is more amenable to the
synthesis of libraries of sulfonyl azides, a one-pot synthesis
whereby a sulfonamide is added directly to the crude reaction
mixture of triflic anhydride and sodium azide can be
employed (Scheme 3).18 Omitting CuSO4,19 triflyl azide was
synthesized in situ from Tf2O and NaN3. In this example,
the conversion of sulfonamide 1 to sulfonyl azide 2 required
68 h instead of 18 h to reach completion.
Similarly to other sulfonyl azides, 2 undergoes a variety
of additional transformations, some of which are shown in
Scheme 4. Illustrating the three-component N-acylsulfona-
mide reaction,5 sulfonyl azide 2 was fused with tert-butyl
prop-2-ynylcarbamate in an aqueous solvent to form N-
acylsulfonamide 27.
As expected, sulfonamides containing carbon nucleophiles,
such as 24, preferentially undergo diazo transfer at the more
(15) To a mixture of sulfonamide 1 (1.43 g, 5.00 mmol), NaHCO3 (1.68.
g), water (6 mL), and 1 M aq CuSO4 (0.20 mL) in a 25 mL Erlenmeyer
flask was added a solution of freshly prepared TfN3 (10 mL, 0.75 M in
toluene, 7.5 mmol), followed by 40 mL of t-BuOH. The flask was loosely
capped, and the solution was stirred vigorously behind a blast shield for
18 h at room temperature. The reaction mixture was transferred to a larger
round-bottom flask, rinsing with water and toluene. With xylenes in the
collection flask, the volatiles were removed by a rotary evaporator, causing
precipitation. Filtration afforded 2 as a yellow powder (1.45 g, 93% yield):
mp 78.5-79.5 °C, Rf ) 0.46 (silica gel, hexanes:EtOAc 8:2); νmax(KBr
disc)/cm-1 2138 (N3), 1589, 1503, 1362 (SO2), 1185, 1161 (SO2), 1097,
1028; 1H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J ) 9.0 Hz, 2H) 7.93 (d,
J ) 9.0 Hz, 2H) 2.43 (s, 3H) 2.24 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 146.7, 144.2, 136.6, 135.2, 128.8, 124.0, 110.4, 11.1, 10.9. Anal.
calcd for C11H10ClN5O2S: C, 42.38; H, 3.23; N, 22.46. Found: C, 42.69;
H, 3.39; N, 22.23.
Analogously, 2 was reacted with in situ generated cop-
per(I) phenylacetylide and diisopropylamine or (4-bromophe-
(17) (a) Jenning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.;
Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins,
W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347–1350. (b) Gosselin, F.; O’Shea, P. D.; Webster, R. A.;
Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J. Synlett 2006, 3267–
3270.
(16) (a) Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem.
2003, 11, 5273–5280. (b) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med.
Chem. 2001, 44, 3039–3042. (c) Meerwein, H.; Dittmar, G.; Gollner, R.;
Hafner, K.; Mensch, F.; Steinfort, O. Chem. Ber. 1957, 90, 841–852.
(18) The authors would like to thank a reviewer for suggesting the
inclusion of this example.
(19) Wear, J. O. J. Chem. Educ. 1975, 52, A23–A25.
Org. Lett., Vol. 10, No. 16, 2008
3387

nyl)methanol, forming amidine3 28 and imidate20 29, re-
spectively. Additionally, sulfonyl azide 2 was reacted with
malononitrile under aqueous alkaline conditions to form a
5-amino-1-arylsulfonyl-1H-1,2,3-triazole-4-carbonitrile (not
shown), which under the reaction conditions undergoes a
Dimroth rearrangement21 to the corresponding NH-triazole
30.
The method for the synthesis of sulfonyl azides described
here is the first direct, mild, and facile route to sulfonyl azides
from readily available and stable sulfonamides. It subverts
the cross-reactivity inherent in the traditionally used sulfonyl
chlorides, which produce hydrochloric and sulfonic acids
upon contact with water, thus causing inadvertent formation
of toxic and shock-sensitive hydrazoic acid in the subsequent
azidation step. Further transformations of sulfonyl azides
illustrate their utility for rapid preparation of densely
substituted sulfonamide derivatives.
Acknowledgment. The authors thank Prof. K. B. Sharp-
less (TSRI) for valuable advice and stimulating discussions,
Drs. J. C. Tripp and J. E. Hein (TSRI) for a critical reading
of the manuscript, and Dr. A. V. Gontcharov (TSRI) for
research samples. Financial support from Novartis (JR
graduate fellowship) and the Skaggs Institute for Chemical
Biology is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006,
8, 1347–1350.
(21) (a) Mertz, R.; Van Assche, D.; Fleury, J. P.; Regitz, M. Bull. Soc.
Chim. Fr. 1973, 12, Pt. 2, 3442–3446. For reviews, see: (b) Gilchrist, T. L.;
Gymer, G. E. AdV. Heterocycl. Chem. 1974, 16, 33–85. (c) El Ashry,
E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H. AdV. Heterocycl. Chem.
1999, 75, 79–167.
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