Sulfonamide synthesis using N-hydroxybenzotriazole sulfonate: An alternative to pentafluorophenyl (PFP) and trichlorophenyl (TCP) esters of sulfonic acids

Article abstract of DOI:10.1016/j.tetlet.2011.10.107

The N-hydroxybenzotriazole (HOBt) sulfonate esters undergo amidation under ambient conditions in the presence of di-isopropylethyl amine. This method can be applied to varieties of amines including sterically hindered amino acid esters in less time with reasonably good yields. HOBt ester of sulfonic acids can be a replacement for pentafluorophenyl and trichlorophenyl ester as well as chloride moiety of sulfonyl chloride for amidation.

Full text of DOI:10.1016/j.tetlet.2011.10.107

Tetrahedron Letters 52 (2011) 7132–7134
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Tetrahedron Letters
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Sulfonamide synthesis using N-hydroxybenzotriazole sulfonate: an
alternative to pentafluorophenyl (PFP) and trichlorophenyl (TCP) esters
of sulfonic acids
⇑
Nani Babu Palakurthy, Bhubaneswar Mandal
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The N-hydroxybenzotriazole (HOBt) sulfonate esters undergo amidation under ambient conditions in the
presence of di-isopropylethyl amine. This method can be applied to varieties of amines including steri-
cally hindered amino acid esters in less time with reasonably good yields.
HOBt ester of sulfonic acids can be a replacement for pentafluorophenyl and trichlorophenyl ester as
well as chloride moiety of sulfonyl chloride for amidation.
Received 6 August 2011
Revised 18 October 2011
Accepted 19 October 2011
Available online 26 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-Hydroxybenzotriazole sulfonate
Sulfonamide
Aminolysis
Di-isopropyl ethyl amine
Sulfonamide unit has drawn attention of synthetic organic chem-
ists because of its diversified applications in medicinal chemistry1 as
anticancer, antiinflammatory, antimicrobial, anticonvulsant, and
antiviral agents.2 Another important property of sulfonamides is
its crystalline nature, which renders easier handling, purification,
and characterization. Furthermore, sulfonamides are very impor-
tant catalysts in asymmetric synthesis.3 Moreover, tosylated
derivatives are the reactive intermediates to synthesize various
molecules including heterocycles containing N, O atoms.4 Therefore,
finding out novel routes for their synthesis is important.
Although, there are many protocols for the synthesis of sulfon-
amides from sulfonyl chlorides,5 these methods are associated
with many drawbacks, as sulfonyl chlorides are very reactive and
difficult to handle. Therefore, it is important to develop a method
in which sulfonic acids are activated by a better leaving group so
that amidation is facilitated under ambient conditions. In this con-
nection, Stephen group has contributed remarkably in replacing
sulfonyl chlorides by activating sulfonic acids as corresponding
pentaflurophenyl sulfonates6 and trichlorophenyl sulfonates.7
However, green chemistry practice restricts not to use polyhalo-
genated compounds, since they are perceived to be toxic and
expensive. Moreover, said methods are associated with bases such
as DBU, LHMDS, and NMP along with heating condition. In another
report, benzotriazole (Bt) activation is described in which long
reaction time and heating conditions are necessary.8
Our group is interested in converting amino acid esters into sul-
fonamides under milder conditions. Therefore, we wanted to find
out an alternative to pentaflurophenyl sulfonates and trichlorophe-
nyl sulfonates for synthesizing sulfonamides at ambient conditions
without using any strong bases in order to address the limitations
of earlier reported methods while retaining the benefits of acti-
vated sulfonate esters. We chose N-hydroxybenzotriazole (HOBt)
ester of p-toluene sulfonic acid which is also as stable as pentaflur-
ophenyl sulfonates and trichlorophenyl sulfonates. HOBt is largely
used in peptide synthesis 9 as it acts as racemization suppressant.10
Moreover ÀOBt group acts as a better leaving group for aminolysis.
Preparation of HOBt ester of sulfonic acid (3) was achieved by
the reaction of sulfonyl chloride and HOBt, in the presence of DI-
PEA (Scheme 1) following a reported protocol.11 Resulting white
crystalline stable product in high yield inspired us for further
investigation on aminolysis of this ester.
N
N
N
O
O
O
O
S
X
S
X
N
N
O
Cl
DIPEA
N
+
R1
R1
DCM, N2, 0 o
C
HO
a) R1 = CH3, X = H
b) R1 = NO2, X = H
c) R1 = H, X = NO2
d) R1 = H, X = H
3
1
2
⇑
Corresponding author. Tel.: +91 0361 2582319.
E-mail address: bmandal@iitg.ernet.in (B. Mandal).
Scheme 1. Synthesis of various sulfonate esters.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.107

N. B. Palakurthy, B. Mandal / Tetrahedron Letters 52 (2011) 7132–7134
7133
Table 1
Synthesis of sulfonamides from N-hydroxybenzotriazole esters of sulfonic acids
Entry
1
Sulfonate ester
Amine
Timeb (h)
1.5
Isolated yielda (%)
R1 = CH3
X = H
Benzylamine
75
60
84
91
80
84
90
—
2
R
1 = CH3
n-Butyl amine
2.5
2
X = H
3
R
1 = CH3
a-Methyl benzyl amine
X = H
4
R
1 = CH3
Piperidine
2
X = H
5
R
1 = CH3
Cyclohexyl amine
Cyclohexyl amine
Cyclohexyl amine
NH2-Phe-OMe
NH2-Phe-OMe
NH2-Phe-OMec
NH2-Gly-OMe
NH2-Gly-OMe
NH2-Gly-OMe
NH2-Ala-OMe
NH2-Ala-OMe
NH2-Ala-OMe
2.5
1
X = H
6
R
1 = H
X = H
7
R
1 = NO2
1
X = H
8
R
1 = CH3
—
X = H
9
R
1 = H
7
34
47
71
82
79
65
76
67
X = H
10
11
12
13
14
15
16
R
1 = NO2
2.5
2
X = H
R
1 = CH3
X = H
R
1 = NO2
1.5
1.5
2.5
2.5
2.5
X = H
R
1 = H
X = NO2
1 = CH3
X = H
R
R
1 = NO2
X = H
R
1 = H
X = NO2
a Yield after purification by passing through a short silica gel column.
b TLC is checked for every 30 min.
c Conversion was 60% only and few unidentified products were noticed.
N
at para position of 3. When electron donating methyl group was
present the reaction was slower (2.5 h, entry 5), the reaction time
was reduced to 1 h when methyl group was removed (entry 6) and
an electron withdrawing group was inserted (entry 7). Sequential
increment of the reaction yield was also observed (entry 5–7). Such
substituent effect also can be observed by comparing the percent-
age yield in entries 11 versus 12, and 14 versus 15, although the
differences are not much but consistent. Variation of the position
of the nitro group also influences the reaction yield which is clear
from the comparison of the same in the entries 12 versus 13 and 15
versus 16. Therefore, in general, the scheme is influenced by the
electronic factors on benzene ring of the sulfonate esters of
N-hydroxy benzotriazole (3).
N
N
O
O
O
O
S
X
S
X
R2
N
N
O
N
DIPEA
R2NH2
N
H
+
+
R1
R1
DCM, rt.
HO
5
3
4
2
) R1 = CH3, X = H
a
b) R1 = NO2, X = H
c) R1 = H, X = NO2
d) R1 = H, X = H
Scheme 2. Synthesis of sulfonamides from TsOBt.
We noticed that when TsOBt was treated with benzyl amine at
All the products that were new were characterized by 1H NMR,
13C NMR, IR, and ESI-MS and the reported products and activated
esters were characterized by 1H NMR, IR, and ESI-MS. The data is
matched with reported data. TsOBt (3a) is also characterized by
room temperature in the presence of 1 equiv of DIPEA, N-benzyl
sulfonamide of p-toluene sulfonic acid (entry 1, Table 1) was pro-
duced in good yield (Scheme 2), as white crystalline solid after
usual acid base work-up and column chromatography. The present
method is compatible with primary (entries 1–3 and 5–7), and sec-
ondary amines (entry 4) with comparable efficiency to that dem-
onstrated in the previously reported methods.6,7 All the reactions
went to completion within 1–2.5 h except for entry 9.
Amino acid esters also showed similar reactivity except for ste-
rically hindered methyl ester of phenylalanine. Reaction of 3a with
methyl ester of phenylalanine did not progress at all (entry 8).
However, removal of the electron donating methyl group on ben-
zene ring of the sulfonyl chloride showed better reactivity by yield-
ing at least 34% although the reaction took longer time (7 h, entry
9). On the other hand, insertion of an electron withdrawing group
increases the yield further (47%) and reduces the reaction time as
well (2.5 h, entry 10). Difference in reactivity was also observed
when cyclohexyl amine was used with variation of the substitution
Figure 1. ORTEP diagram of TsOBt with 50% ellipsoid (CCDC # 834974).

7134
N. B. Palakurthy, B. Mandal / Tetrahedron Letters 52 (2011) 7132–7134
single crystal XRD (Fig. 1, characterization data of all the reaction
products including crystallographic data are provided in the
Supplementary data in detail).
References and notes
1. (a) Navia, M. A. Science 2000, 288, 2132; (b) Hansch, C.; Sammaes, P. G.; Taylor,
J. B. In Comprehensive Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol.
2, Chapter 7.1; (c) Yan, L.; Bertarelli, D. C.; Hayallah, A. M.; Meyer, H.; Klotz, K.
N.; Müller, C. E. J. Med. Chem. 2006, 49, 4384.
2. (a) Roush, W. R.; Gwaltney, S. L.; Cheng, J.; Scheidt, K. A.; McKerrow, J. H.;
Hansell, E. J. Am. Chem. Soc. 1998, 120, 10994; (b) Yoshino, H.; Ueda, N.; Niijima,
J.; Sugumi, H.; Kotake, Y.; Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe,
T.; Nagaau, T.; Tsukahara, K.; Iijima, A.; Kitoh, K. J. Med. Chem. 1992, 35, 2496;
(c) Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 5, 535; (d)
Scozzafava, A.; Owa, T.; Mostrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003,
10, 925.
3. (a) Feng, Y.; Xiaomin, S.; Zhichao, J.; Shiganag, W.; Xinmiao, L.; Jinxing, Y. Chem.
Commun. 2010, 4589; (b) Wei, J.; Xinxheng, L.; Yongbo, H.; Fan, W.; Boshun, W.
Chem. Eur. J. 2010, 16, 8259.
4. (a) Yuan, W.; Fearon, K.; Gelb, M. H. J. Org. Chem. 1989, 54, 906; (b) Kabalka, G.
W.; Varma, M.; Varma, R. S. J. Org. Chem. 1986, 51, 2386.
5. Sulfonamide synthesis from tosyl chlorides using catalysts: (a) Sridhar, B.;
Srinivas, B.; Pavan, K. V.; Narender, M.; Rama, R. K. Adv. Synth. Catal. 2007, 349,
1873; (b) Joong-Gon, K.; Doo, O. J. Synlett 2007, 2501; (c) Meshram, G. A.;
Vishvanath, D. P. Tetrahedron Lett. 2009, 50, 1117; Using base: (d) Xiaohu, D.;
Neelakandha, S. M. Green. Chem. 2006, 8, 835; Directly from thiols: Kiumars, B.;
Mohammad, M. K.; Mehdi, S. J. Org. Chem. 2009, 74, 9287.
6. (a) Stephen, C.; Jonathan, D. W.; Duncan, B. J. J. Am. Chem. Soc. 2004, 126, 1024;
(b) Stephen, C.; Jonathan, D.; Hanna, D.; Sjoerd, N.; Duncan, B. J. Org. Lett. 2002,
4, 2549.
7. Jonathan, D. W.; Lynsey, G.; Chieh, C. L.; Duncan, B. J.; Stephen, C. Chem.
Commun. 2007, 1074.
8. Katritzky, A. R.; Rodriguez-Garcia, V.; Satheesh, K. N. J. Org. Chem. 2004, 69,
1849.
In terms of reactivity, these activated HOBt esters undergo ami-
dation at ambient conditions as it works for sulfonyl chlorides. This
methodology eliminates the use of expensive solvents; rather DCM
was used in most of the cases. However, sometimes sonication and
addition of DMF were necessary for better solubility. This method
offers many advantages over the existing methods for the synthe-
sis of sulfonamides: (a) the harsh bases, for example, NMM, DBU
were replaced with milder DIPEA, (b) long reaction times were re-
duced to 1–3 h, and (c) required reaction temperature was reduced
to the ambient temperature. Moreover, the current method is free
from the production of HCl, which enables it to be applicable to
those substrates in which acid labile groups such as, Boc are pres-
ent. Furthermore, as the base being used is milder, it can also be
applied to those substrates in which base labile groups like Fmoc
are present. In addition to the above advantages, N-hydroxy benzo-
triazole can be easily removed from the reaction mixture at the end
by mere washing with water.
Thus, in this letter we have shown that N-hydroxy benzotria-
zole sulfonate motif is a potential replacement for the chloride unit
of sulfonyl chloride for the synthesis of sulfonamides. Unlike the
previous activation methods in which pentaflurophenyl and tri-
chlorophenyl esters of sulfonic acids were used, current activation
undergoes amidation quite easily without the use of solvents like
NMP, high temperatures and harsh bases, retaining decent yields
even in case of complicated amines, such as, hindered amino acid
esters. Regarding the issue of cost, N-hydroxybenzotriazole is
cheaper than pentafluorophenol, while comparable to trichloro-
phenol. Therefore, these properties enable N-hydroxy benzotria-
zole sulfonate to be a good synthetic auxiliary for sulfonamide
synthesis.
9. Rich, D. H.; Singh, J. In The Peptides. Analysis, Synthesis, Biology; Gross, E.,
Meienhofer, J., Eds.; Academic Press: New York, 1979; Vol. 1, p 250.
10. Carpino, L. A.; Xia, J.; Zhang, Ch.; El-Faham, A. J. Org. Chem. 2004, 69, 62.
11. The procedure for N-benzyl-4-methylbenzene sulfonamide (Table 1, entry 1)
synthesis is described below as a representative procedure for the preparation
of sulfonamides from TsOBt and other HOBt sulfonates (see Supplementary
data): TsOBt (1 mmol, 1 equiv) is dissolved in a 1 mL DCM in an oven dried
25 mL round bottom flask which is charged with magnetic stir bar. To this,
benzyl amine (1 mmol, 1 equiv) was added followed by the addition of DIPEA
(1 mmol, 1 equiv) with 0.5 mL of DCM (for amino acid esters DCM and DMF
mixture in 1:3). Then stirring was continued at room temperature while being
monitored by TLC. After completion of the reaction, the reaction mixture was
diluted with 10 mL of DCM and washed with 5% HCl (2 Â 10 mL), 5% NaHCO3
(2 Â 10 mL), and brine solution (2 Â 10 mL). Organic fraction was dried under
CaCl2, filtered and evaporated to dryness. Then purified by column
chromatography. Rf product 0.58 (EtoAc/Hexane, 1:4) yield 75%, white solid,
Acknowledgments
mp 87–89 °C. IR (KBr, m
/cmÀ1) 3262, 3027, 1594, 1492, 1450, 1320, 1156.1H
NMR (400 MHz, CDCl3) d ppm 7.38–7.48 (m, 3H, ArH), 7.77–7.75 (d, 2H,
J = 8.4 Hz, 2 Â ArH), 7.31–7.18 (m, 7H, 7 Â ArH), 4.74 (br s, 1H, NH), 4.11(s, 2H,
CH2), 2.43 (s, 3H, CH3). LRMS (ESI) m/z 261 [M+H]+.
We are thankful to DST for XRD facility; CIF, IITG for NMR, ESI-
MS facility; DST SERC for research grant (Sanction No. SR/FT/CS-
011/2008, FAST TRACK SCHEME). PNB thanks IITG for fellowship.
Supplementary data
Supplementary data (General procedures.) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.10.107.