An easy microwave-assisted synthesis of sulfonamides directly from sulfonic acids

Article abstract of DOI:10.1021/jo800424g

(Chemical Equation Presented) An easy and handy synthesis of sulfonamides directly from sulfonic acids or its sodium salts is reported. The reaction is performed under microwave irradiation, has shown a good functional group tolerance, and is high yielding.

Full text of DOI:10.1021/jo800424g

SCHEME 1. Sulfonamides from Sulfonic Acids
An Easy Microwave-Assisted Synthesis of
Sulfonamides Directly from Sulfonic Acids
Lidia De Luca* and Giampaolo Giacomelli
Dipartimento di Chimica, UniVersità degli Studi di Sassari,
Via Vienna 2, I-07100 Sassari, Italy
ldeluca@uniss.it
ReceiVed February 21, 2008
to long-term storage.7 Just a few of these compounds are
commercially available because of their instability. Caddick and
co-workers reported a suitable preparation of sulfonamides by
intermolecular radical addition to pentafluorophenyl vinylsul-
fonate and successive aminolysis.8 Katritzky and co-workers
proposed a general and efficient synthesis of sulfonamides by
the reaction between sulfonylbenzotriazoles (produced from
sulfinic acid salts with N-chlorobenzotriazole) and various
amines.9 Recently the synthesis of heteroaryl sulfonamides via
oxidation of thiols to sulfonyl chlorides or sulfonyl fluorides
has been reported that were then reacted with amines to give
the corresponding sulfonamides.10 The logical way to sulfon-
amides could be the direct synthesis from sulfonic acid. Even
if pharmaceutical compounds containing a sulfonamide group
have numerous significant therapeutic applications, at present
just two methodologies are reported to convert a sulfonic acid
directly to a sulfonamide. The first method permits the synthesis
of sulfonamides from the sulfonic acid pyridine or triethylamine
salts by the use of the activating agent triphenylphosphine
ditriflate.11 The second procedure considers the reaction of a
sulfonic acid with isocyanide at room temperature.12
Following our interest in the use of 2,4,6-trichloro-[1,3,5]-
triazine (TCT) and [1,3,5]-triazine derivatives in organic syn-
thesis,13 we report here a novel, easy, and convenient method
for the preparation of sulfonamides directly from easily available
sulfonic acid (Scheme 1) or its sodium salt (Scheme 2),
improved by microwave irradiation.
The procedure consists of the addition of 1 equiv of TCT to
a mixture of 1 equiv of sulfonic acid and 1 equiv of trieth-
ylamine in acetone. Even if the reaction can be conducted in
refluxing acetone (20 h), we have preferred to carry out the
reaction under microwave irradiation in a sealed tube (10-mL
An easy and handy synthesis of sulfonamides directly from
sulfonic acids or its sodium salts is reported. The reaction is
performed under microwave irradiation, has shown a good
functional group tolerance, and is high yielding.
Sulfonamides are an important category of pharmaceutical
compounds with a broad spectrum of biological activities.1
Sulfonamides drugs have broad applications in many areas
of clinical medicine, as good antibacterials, diuretics, anticon-
vulsants, hypoglycemics, and HIV protease inhibitors.2
In recent times, sulfonamides have been found to be powerful
carbonic anhydrase,3 COX-2,4 and caspase inhibitors.5 A series
of aromatic sulfonamides have been prepared and crystallized
as chiral crystals.6 Typically, sulfonamides were prepared by
the reaction of a sulfonyl chloride with ammonia or primary or
secondary amines. However, sulfonyl chlorides have some
disadvantages, as they are not handled easily and are not suitable
(1) For a review, see: Hansch, C.; Sammes, P. G.; Taylor, J. B. Compre-
hensiVe Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol. 2, Chapter
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Substances, Synthesis, Patents, Applications; Thieme: Stuggart, 1999. Guide,
2nd ed., available from Oxford Press.
(3) (a) Winum, J.-Y.; Dogné, J.-M.; Casini, A.; de Leval, X.; Montero,
J.-L.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C. T. J. Med. Chem.
2005, 48, 2121. (b) Nishimori, I.; Minakuchi, T.; Morimoto, K.; Sano, S.; Onishi,
S.; Takeuchi, H.; Vullo, D.; Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2006,
49, 2117. (c) Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.;
Vullo, C.; Supuran, C. T.; Poulsen, S.-A. J. Med. Chem. 2007, 50, 1651.
(4) (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang,
Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775. (b) Habeeb,
A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039. (c)
Almansa, C.; Bartrolí, J.; Belloc, J.; Cavalcanti, F. L.; Ferrando, R.; Gómez,
L. A.; Ramis, I.; Carceller, E.; Merlos, M.; García-Rafanell, J. J. Med. Chem.
2004, 47, 5579.
(7) (a) Caddick, S.; Wilden, J. D.; Wadman, S. J.; Bush, H. D.; Judd, D. B.
Org. Lett. 2002, 4, 2549. (b) Caddick, S.; Hamza, D.; Wadman, S.; Wilden,
J. D. Org. Lett. 2002, 4, 1775.
(8) Caddick, S.; Wilden, j. D.; Bush, H. d.; Wadman, S. N.; Judd, D. N.
Org. Lett. 2002, 4, 2549.
(9) Katritzky, A. R.; Rodriguez-Garcia, V.; Nair, S. K. J. Org. Chem. 2004,
69, 1849.
(10) Wright, S. W.; Hallstrom, K. N. J. Org. Chem. 2006, 71, 1080.
(11) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126,
1024.
(5) (a) Chu, W.; Zhang, J.; Zeng, C.; Rothfuss, J.; Tu, Z.; Chu, Y.; Reichert,
D. E.; Welch, M. J.; Mach, R. H. J. Med. Chem. 2005, 48, 7637. (b) Chu, W.;
Rothfuss, J.; d’Avignon, A.; Zeng, C.; Zhou, D.; Hotchkiss, R. S.; Mach, R. H.
J. Med. Chem. 2007, 50, 3751.
(12) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007,
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(13) (a) De Luca, L.; Giacomelli, G.; Niueddu, G. J. Org. Chem. 2007, 72,
3955. (b) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004,
2570. (c) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. Synlett 2004,
2299. (d) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67,
6272. (e) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553.
(6) Kato, T.; Okamoto, I.; Tanatani, A.; Hatano, T.; Uchiyama, M.;
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10.1021/jo800424g CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3967–3969 3967

TABLE 1. Sulfonic Acid and Amine Diversity in Sulfonamide
Synthesis
TABLE 2. Synthesis of Sulfonamides from Sulfonic Acid Sodium
Salts
TABLE 3. Comparison of Conventional and Microwave
Procedures for Sulfonamide Synthesis
% yield/puritya
microwave-assisted
entry
thermal reactionb
reactionc
4
9
80/86
71/85
95/95
88/98
a Yields determined at the end of both steps. Average purity
determined by NMR on the crude product. b Conditions: 20 h, refluxing
acetone, then 5 h, 50 °C. c Conditions: 20 min, 80 °C, 50 W then 10
min, 50 °C, 50 W.
the DCM extracts at reduced pressure. Following an easy
workup, the sulfonamide is obtained in a nearly quantitative
yield.
It has been demonstrated that sulfonic acids, treated with TCT,
in refluxing acetone for 20 h, are converted in the corresponding
sulfonyl chlorides, which are recovered pure by distillation.15
Even in our procedure the sulfonic acid (or its sodium salt) is
transformed in the corresponding sulfonyl chloride; however,
its isolation is not necessary as the sulfonyl chloride is directly
transformed in the corresponding sulfonamide in the presence
of an ammine.
As shown in Table 1, a selection of sulfamides were prepared
from an array of sulfonic acids and the yields were satisfactory
in all cases. The methodology is efficient and successful with
aromatic, aliphatic, and heterocyclic sulfonic acids. The reaction
is not limited to primary and secondary amines but works well
with hydrazines and amino acid derivatives. The optical rotation
value of the product 2g (from methyl ester of L-valine) is
comparable with that reported in the literature.16 Also, anilines
(entry 3) are applicable in the reaction.
SCHEME 2. Sulfonamides from Sulfonic Acid Sodium Salts
We should like to extend the applicability of the methodology
to sulfonic acid salts because the majority of sulfonic acids are
commercially available as sodium salts. By the addition of a
catalytic amount of 18-crown-6 to the reaction mixture, the
procedure allows the synthesis of sulfonamides directly from
sulfonic acids sodium salts (Scheme 2).
We chose to examine the reaction of benzenesulfonic acid
sodium salt with a number of common amines. As reported in
Table 2, the reaction is efficient with both primary and secondary
amines and yields are high in all cases.
pressure-rated reaction vial) in a self-tuning single mode
irradiating synthetizer, operating at 80 °C for 20 min, for
significantly shortening the reaction times and avoiding the
presence of byproducts. After cooling, the precipitate formed
is filtered off on Celite and the solution is added with 1.2 equiv
of NaOHaq, THF, and an amine. The reaction mixture is newly
exposed to microwave irradiation for 10 min at 50 °C in a sealed
tube.14 The reaction mixture is filtered on Celite to eliminate
the formed salts and then diluted with DCM and washed with
water, aqueous Na2CO3, diluted HCl, and brine. The target
product is obtained in pure form, simply by concentration of
A comparison between conventional heating (oil bath) and
microwave irradiation was carried out too, demonstrating a better
performance of the MW-assisted process (Table 3).
(14) The same reaction carried out by conventional heating required 5 h at
50 °C. The yields of the recovered products were lower than reactions carried
out under microwave irradiation.
(15) Blotny, G. Tetrahedron Lett. 2003, 44, 1499.
(16) Karrer, P.; Kehl, W. HelV. Chim. Acta 1924, 7, 740.
3968 J. Org. Chem. Vol. 73, No. 10, 2008

4b. The procedure for N-allyl-4-methylbenzenesulfonamide (Table
2, entry 15) is representative for all sulfonamides prepared from
sulfonic acid sodium salts. 2,4,6-Trichloro-[1,3,5]-triazine (0.09 g,
0.49 mmol) was added at room temperature to a solution of
benzenesulfonic acid sodium salt (0.09 g, 0.49 mmol) in acetone
dry (1 mL) and 18-crown-6 (0.01 g, 0.04 mmol). The resulting
mixture was irradiated to 80 °C (50 W of MW power) for 20 min
in a sealed tube (10 mL pressure-rated reaction vial) in a self-tuning
single mode irradiating synthesizer. The mixture was cooled rapidly
to room temperature by passing compressed air through the
microwave cavity for 1 min. After cooling to room temperature,
the precipitate formed was filtered off on Celite and to the solution
were added 0.3 mL of 2 M solution of NaOH, THF (0.25 mL),
and allylamine (0.04 mL, 0.49 mmol). The reaction mixture is
exposed to microwave irradiation for 10 min at 50 °C (50 W of
power) in a sealed tube. The reaction mixture is filtered on Celite
to eliminate the formed salts, then diluted with DCM and washed
with water, aqueous Na2CO3, diluted HCl, and brine. The desired
product is recovered in pure form (0.8 g, yield 89%), simply by
In conclusion, we think that the methodology described here
represents a new, convenient, and handy synthesis of sulfon-
amides even in large scale, as it uses friendly reaction conditions
and cheap and commercially available reagents. The methodo-
logy has shown a good functional group tolerance and is high
yielding.
Experimental Section
General Procedure for the Synthesis of Sulfonamides from
Sulfonic Acids (2a-o). N-Allyl-4-methylbenzene-sulfonamide
2e. The procedure for N-allyl-4-methyl-benzenesulfonamide (Table
1, entry 5) is representative for all sulfonamides prepared from
sulfonic acids (see Supporting Information). 2,4,6-Trichloro-[1,3,5]-
triazine (0.09 g, 0.49 mmol) was added at room temperature to a
solution of p-toluenesulfonic acid (0.08 g, 0.49 mmol) in acetone
dry (1 mL), followed by NEt3 (0.07 mL, 0.49 mmol) dropwise.
The resulting mixture was irradiated to 80 °C (50 W of MW power)
for 20 min in a sealed tube (10 mL pressure-rated reaction vial) in
a self-tuning single mode irradiating synthesizer. The mixture was
cooled rapidly to room temperature by passing compressed air
through the microwave cavity for 1 min. After cooling to room
temperature, the precipitate was filtered off on Celite and 0.3 mL
of a 2 M solution of NaOH, THF (0.25 mL), and allylamine (0.04
mL, 0.49 mmol) were added to the solution. The reaction mixture
is exposed to microwave irradiation for 10 min at 50 °C (50 W of
power) in a sealed tube and then filtered on Celite to eliminate the
formed salts, diluted with DCM, and washed with water, aqueous
Na2CO3, diluted HCl, and brine. The desired product is recovered
in pure form, simply by concentration of the DCM extracts at
reduced pressure (0.09 g, yield 85%). 1H NMR (300 MHz, CDCl3)
δ ) 7.77 (d, J ) 7.9 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H), 5.71 (m,
1H), 5.16 (d, J ) 17.1 Hz, 1H), 5.07 (d, J ) 10.2 Hz, 1H), 3.57
(m, 2H), 2.42 (s, 3H).9 13C NMR (75 MHz, CDCl3) δ ) 143.3,
136.7, 132.9, 129.6, 126.9, 117.4, 45.6, 21.4. 9 mp: 63–66 °C (lit.,9
63–66 °C).
1
concentration of the DCM extracts at reduced pressure. H NMR
(300 MHz, CDCl3) δ ) 7.89 (m, 2H), 7.56 (m, 3H), 5.61 (m, 1H),
5.13 (m, 2H), 4.67 (bs, 1H), 4.09 (d, J ) 7.1 Hz, 2H).17 13C NMR
(75 MHz, CDCl3) δ ) 140.1, 132.6, 132.4, 129.1, 127.2, 119.3,
49.5.14 mp: 39–42 °C (lit.,18 39.5–42.5 °C).
Acknowledgment. This work was financially supported by
the Univeristy of Sassari and MIUR (Rome) within the project
PRIN 2005.
Supporting Information Available: Characterization data
of the sulfonamides. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO800424G
(17) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J. Chem.
Soc. Perkin Trans. 1 1997, 9, 1411.
General Procedure for the Synthesis of Sulfonamides from
Sulfonic Acid Sodium Salts (4a-d). N-allylbenzenesulfonamide
(18) Gensler, W. J. J. Am. Chem. Soc. 1948, 70, 1843.
J. Org. Chem. Vol. 73, No. 10, 2008 3969