A General and Efficient Synthesis of Sulfonylbenzotriazoles from N-Chlorobenzotriazole and Sulfinic Acid Salts

Article abstract of DOI:10.1021/jo035515y

One-pot reactions of sulfinic acid salts (produced from organometallic reagents with SO₂) with N-chlorobenzotriazole gave the corresponding N-alkane-, N-arene-, and N-heteroenesulfonylbenzotriazoles 3a-j in 41-93% yields. Reagents 3a-j are effi

Full text of DOI:10.1021/jo035515y

A Gen er a l a n d Efficien t Syn th esis of Su lfon ylben zotr ia zoles fr om
N-Ch lor oben zotr ia zole a n d Su lfin ic Acid Sa lts
Alan R. Katritzky,* Valerie Rodriguez-Garcia, and Satheesh K. Nair
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received October 14, 2003
One-pot reactions of sulfinic acid salts (produced from organometallic reagents with SO2) with
N-chlorobenzotriazole gave the corresponding N-alkane-, N-arene-, and N-heteroenesulfonylben-
zotriazoles 3a -j in 41-93% yields. Reagents 3a -j are efficient sulfonylating agents, reacting at
20-80 °C with various primary and secondary aliphatic amines to yield the corresponding
sulfonamides in 64-100% yields.
In tr od u ction
fer reagent,8 (v) by the radical addition of organo halides
to pentafluorophenyl vinylsulfonate9 followed by substi-
tution of the pentafluorophenyl moiety by amines, and
(vi) by the sulfamoylation of aromatics using sulfamoyl
chloride.10 Alkyl/arylsulfonylimidazoles, prepared from
sulfonyl halides and 1H-imidazole or 1-trimethylsilylimi-
dazole, have also been used as sulfonyl transfer reagents
in the preparation of sulfonamides (vii in Scheme 1).11
However, the imidazole ring requires activation as its
3-methylimidazolium triflate to act as a leaving group
in its reactions with N- and O-nucleophiles.
Although these additional synthetic technologies have
proven to be of great utility for specific substrate classes,
there remains a need for straightforward and general
methods toward accessing sulfonamides. It would be
highly desirable to have a sulfonating reagent that would
react under mild conditions in the absence of a strong
base or competing nucleophile.
We have reported earlier the synthesis and utility of
1-phenylsulfonylbenzotriazole 3,12 which was shown to
react with primary and secondary amines and with
alcohols to give the corresponding sulfonamides and
sulfonates, respectively12 (Scheme 2), in good yields and
under mild conditions (stirring in THF at rt). Thus, the
sulfonylbenzotriazolyl motif is a practical replacement for
the highly reactive, frequently labile, and often difficult
to access sulfonyl halide unit. Other than its use as a
benzenesulfonating agent, 3 and its analogues have also
been widely used in the preparation of (i) N-acylbenzo-
triazoles (well-known synthetic equivalents to acyl ha-
lides;13) and (ii) N-imidoylbenzotriazoles14 and (iii) for the
benzotriazolylalkylation of aromatic compounds.15
Compounds containing sulfonyl groups have long been
a research focus as a result of their biological importance
and chemical applications. Sulfonamides occupy a unique
position in the drug industry with their antibacterial and
antimicrobial properties.1 Sulfonamides are also diuretics
and hypoglycemic agents as well as protease inhibitors.2
Arylsulfonyl substituents have been used as protecting
groups for oxygen and nitrogen functionalities.3 Sulfona-
mide derivatives of azo dyes achieve improved light
stability, water solubility, and fixation to fiber.1
Reactions of ammonia, or primary or secondary amines,
with sulfonyl halides in the presence of a base are the
usual routes for the formation of sulfonamides.4 This
approach requires the availability of the sulfonyl halide,
some of which can be hard to prepare and difficult to store
or handle. Also, side reactions are possible due to the
presence of the base or the liberated chloride nucleophile,
particularly under harsh conditions with relatively non-
nucleophilic substrates. Moreover, the corresponding
disulfonimide is stated4 to be a byproduct in reactions of
sulfonyl halides with primary amines or ammonia.
These issues have led to the development of several
alternative protocols for sulfonamide synthesis (Scheme
1). Thus, sulfonamides are formed (i) by reaction of
sulfinic acid salts with hydroxylamine-O-sulfonic acid,5
(ii) by reduction of arylsulfonyl azides,6 (iii) from aromatic
and aliphatic sulfinic acid salts using bis(2,2,2-trichlo-
roethyl)azodicarboxylate as an electrophilic nitrogen
source,7 (iv) from alkyl or aryl halides by means of sodium
3-methoxy-3-oxopropane-1-sulfinate as a sulfinate trans-
However, to prepare aryl/alkylsulfonylbenzotriazoles12
from the corresponding sulfonyl halides by reactions with
(1) Hansch, C.; Sammes, P. G.; Taylor, J . B. Comprehensive Me-
dicinal Chemistry; Pergamon Press: Oxford, 1990; Vol. 2, Chapter 7.1.
(2) Roush, W. R.; Gwaltney, S. L., II; Cheng, J .; Scheidt, K. A.;
McKerrow, J . H.; Hansell, E. J . Am. Chem. Soc. 1998, 120, 10994.
(3) O’Connel, J . F.; Rapoport, H. J . Org. Chem. 1992, 57, 4775.
(4) Andersen, K. K. In Comprehensive Organic Chemistry; J ones,
D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3.
(8) Baskin, J . M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479.
(9) Caddick, S.; Wilden, J . D.; Bush, H. D.; Wadman, S. N.; J udd,
D. B. Org. Lett. 2002, 4, 2549.
(5) Graham, S. L.; Scholz, T. H. Synthesis 1986, 1031.
(10) Frost, C. G.; Hartely, J . P.; Griffin, D. Synlett 2002, 1928.
(11) O’Connell, J . F.; Rapoport, H. J . Org. Chem. 1992, 57, 4775.
(12) Katritzky, A. R.; Zhang, G.; Wu, J . Synth. Commun. 1994, 24,
205.
(6) (a) Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J . S. Synlett
1997, 1253; (b) Iyer, S.; Sattar, A. K. Synth. Commun. 1998, 28, 1721.
(7) Chan, W. Y.; Berthelette, C. Tetrahedron Lett. 2002, 43, 4537.
10.1021/jo035515y CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/18/2004
J . Org. Chem. 2004, 69, 1849-1852
1849

Katritzky et al.
SCHEME 1
TABLE 1. Alk yl/a r ylsu lfon ylben zotr ia zoles 3
SCHEME 2
yield
(%)
mp
(°C)
3
R
M
a
b
c
d
e
f
g
h
i
n-butyl
cyclohexyl
isobutyl
p-CH3C6H5
2-pyridyl
3-pyridyl
2-furyl
2-thienyl
1-methyl-2-indolyl
1-methylimidazolyl
Li
65
71
75
93
71
41
83
82
20
80
oil
117-119
oil
MgCl
MgBr
MgBr
Li
Li
Li
Li
Li
Li
133-134a
132-135
128-129
107-109
143-144
131-132
147-150
j
a
Reference 20 gives mp 134-135; all other compounds are
novel.
reaction of sulfinic acids and chloramines to produce a
ca. 50:50 mixture of sulfonamide and sulfonyl chloride.
We now show that addition of N-chlorobenzotriazole to
an intermediate sulfinic acid salt gives the corresponding
sulfonylbenzotriazole. For example, the reaction of p-
tolylmagnesium bromide and sulfur dioxide21 followed by
treating the intermediate sulfinic acid salt with chlo-
robenzotriazole proceeded smoothly at 20 °C, giving the
p-tolylsulfonylbenzotriazole in 68% yield (Scheme 2)
along with traces of p-toluenesulfonyl chloride. Use of 1
equiv of triethylamine with the N-chlorobenzotriazole
made a significant improvement: p-tolylsulfonylbenzo-
triazole was isolated in 93% yield under this modified
condition. The mechanism may involve nucleophilic
counterattack of the benzotriazolyl anion on an interme-
diate sulfonyl chloride (Scheme 2). The effect of triethy-
lamine may be to coordinate with the magnesium cation.
Other organomagnesium reagents also afforded the cor-
responding sulfonylbenzotriazoles in good to excellent
yields, as shown in Table 1.
either 1H-benzotriazole or 1-trimethylsilylbenzotriazoles
limits their application to the synthesis of sulfonamides.
Therefore, a general method to prepare sulfonylbenzo-
triazoles starting from easily available materials would
be useful. We herein report such an approach starting
from aryl/alkyllithiums or Grignard reagents by reacting
successively with SO2 and N-chlorobenzotriazole.
Resu lts a n d Discu ssion
P r ep a r a tion of ben zotr ia zole Rea gen ts 3. Conver-
sion of organometallic reagents to sulfinic acid salts by
reaction with sulfur dioxide has been discussed by Pinnic
and co-workers.16 Furukawa17 was the first to report the
(13) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J . Org. Chem. 2000,
65, 8210; (b) Katritzky, A. R.; Shobana, N.; Pernak, J .; Afridi, A. S.;
Fan, W.-Q. Tetrahedron 1992, 48, 7817.
(14) Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. O. Org. Lett.
1999, 1, 577.
Arylorganolithiums can also be used in the preparation
of arylsulfonylbenzotriazoles. Thus, thiophene was lithi-
(15) Katritzky, A. R.; Gupta, V.; Garot, C.; Stevens, C. V.; Gordeev,
M. F. Heterocycles 1994, 38, 345.
(16) Pinnick, H. W.; Reynold, M. A. J . Org. Chem. 1979, 44, 160.
(17) Nishikawa, M.; Inaba, Y.; Furukawa, M. Chem. Pharm. Bull.
1983, 31, 1374.
1850 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Sulfonylbenzotriazoles
TABLE 2. Su lfon a m id es 7 P r ep a r ed Usin g Rea gen ts 3
ated at C2, and the lithium reagent was allowed to react
with SO2 and N-chlorobenzotriazole under the conditions
described above. Thiophene-2-sulfonylbenzotriazole was
isolated in 82% yield (Table 1, 3h ). We have used a
variety of alkyl- and arylorganometallic reagents to check
the general applicability and functional group tolerance
of this method. The respective sulfonylbenzotriazoles
were isolated in good yields (41-93%, Table 1). In the
case of 1-methylindole, the expected 2-sulfonylated prod-
uct was isolated in 20% yield along with 11% of 2-ben-
zotriazolyl-1-methylindole, which might have formed by
the addition of 2-lithio-1-methylindole to N-chlorobenzo-
triazole.
Syn th esis of Su lfon a m id es Usin g Rea gen ts 3. The
benzotriazolylsulfonamides 3a -j reacted as expected
with diverse amines to generate novel sulfonamides. On
the basis of our previous experience,12 we tried the
reaction in THF at rt in the absence of a base. Thus, when
3a was treated with cyclohexylamine, the corresponding
sulfonamide 7a was obtained in 89% yield (Table 1).
Sulfonylbenzotriazoles 3c and 3h also reacted under the
same conditions with N-methylbenzylamine and piperi-
dine, yielding the resultant sulfonamides in 72% and 85%
yields, respectively. However, for reagents 3f, 3g, 3j, and
3i the smooth displacement of benzotriazole took place
Attempts to react prop-2-enesulfinic acid salt, formed
from the reaction of allylmagnesium bromide and SO2,
with N-chlorobenzotriazole to make allylsulfonylbenzo-
triazole gave only unidentifiable byproducts and benzo-
triazole. Prop-2-enesulfinic acids are known to be very
unstable and to undergo acid-catalyzed decomposition to
SO2 and the olefin.18 Similar unsatisfactory results were
also obtained with acetylenic Grignard reagents.
(18) Masilamani, D.; Rogic, M. M. J . Am. Chem. Soc. 1978, 100,
4634.
(19) (a) Biellmann, J .-F.; Ducep, J .-B. Organic Reactions; J ohn Wiley
& Sons: New York, 1982; Vol. 27, Chapter 1. (b) Gschwend, H. W.;
Rodriguez, H. R. Organic Reactions; J ohn Wiley & Sons: New York,
1982; Vol. 26, Chapter 1.
(20) Katritzky, A. R.; Kurz, T.; Zhang, S.; Voronkov, M.; Steel, P. J .
Heterocycles 2001, 55, 1703.
(21) Sulfur dioxide is
a gas, which may cause eye, skin, and
respiratory irritation. Handle with care.
J . Org. Chem, Vol. 69, No. 6, 2004 1851

Katritzky et al.
0.88 (t, J ) 7.4 Hz, 3H), 1.35-1.48 (m, 2H), 1.69-1.79 (m, 2H),
3.62 (t, J ) 8.0 Hz, 2H), 7.54 (t, J ) 8.1 Hz, 1H), 7.68 (t, J )
7.2 Hz, 1H), 8.02 (d, J ) 8.4 Hz, 1H), 8.17 (d, J ) 8.4 Hz, 1H).
13C NMR: δ 13.1, 20.9, 24.6, 55.3, 111.8, 120.4, 125.8, 130.3,
132.1, 145.0. Anal. Calcd For C10H13N3O2S: C, 50.19; H, 5.48;
N, 17.56. Found: C, 50.41; H, 5.39; N, 17.89.
with aliphatic amines (Table 2) in DMF at 80 °C but not
in refluxing THF or acetonitrile.
In summary, N-chlorobenzotriazole is a useful reagent
for converting sulfinate salts to sulfonylbenzotriazoles,
which offer access to a wide variety of sulfonamides
where the corresponding sulfonyl halide is not readily
available. In addition, the approach obviates the forma-
tion of disulfonimides that can arise during the am-
monolysis of sulfonyl halides.4 The particular usefulness
of the method lies in the ease with which the benzotria-
zole group can be replaced by N-nucleophiles. The easy
accessibility of sulfinic acid salts from SO2 and organo-
metallics and the preparative ease of N-chlorobenzotria-
zole should give the approach substantial utility.
N-Cycloh exyl-1-bu ta n esu lfon a m id e (7). 7 was purified
by column chromatography with CHCl3 as eluent and obtained
1
as colorless prisms (89%), mp 64-65 °C. H NMR: δ 0.95 (t,
J ) 7.2 Hz, 3H), 1.14-1.49 (m, 7H), 1.56-1.84 (m, 5H), 1.95-
1.99 (m, 2H), 3.01 (t, J ) 8.0 Hz, 2H), 3.20-3.33 (m, 1H), 4.31
(d, J ) 6.6 Hz, 1H). 13C NMR: δ 13.6, 21.5, 24.8, 25.1, 25.8,
34.7, 52.7, 53.9. Anal. Calcd For C10H21NO2S: C, 54.76; H, 9.65;
N, 6.39. Found: C, 54.77; H, 9.67; N, 6.34.
Su p p or tin g In for m a tion Ava ila ble: Procedures, experi-
mental details, and structural data for all new compounds not
described in the text (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Exp er im en ta l Section
1-(Bu ta n e-l-su lfon yl)-1H-1,2,3-ben zotr ia zole (3a ). 3a
was purified by column chromatography with hexanes/EtOAc
(4:1) as eluent and obtained as a brown oil (65%). 1H NMR: δ
J O035515Y
1852 J . Org. Chem., Vol. 69, No. 6, 2004