Efficient synthesis of tetramethylsulfonylguanidines between a free sulfonamide group and HBTU

Article abstract of DOI:10.1016/j.tetlet.2006.06.094

The reaction of a sulfonamide moiety with HBTU (O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) during amide coupling, leading to the formation of tetramethylsulfonylguanidines, is described. Optimised conditions showed that HBT

Full text of DOI:10.1016/j.tetlet.2006.06.094

Tetrahedron Letters 47 (2006) 6087–6090
Efficient synthesis of tetramethylsulfonylguanidines between
a free sulfonamide group and HBTU
*
´
´
Sebastien Gluszok, Laurence Goossens, Patrick Depreux and Jean-Pierre Henichart
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite´ de Lille 2, EA 2692, IFR 114, 3, rue du Professeur Laguesse,
B.P. 83, F-59006 Lille, France
Received 12 April 2006; revised 15 June 2006; accepted 16 June 2006
Available online 10 July 2006
Abstract—The reaction of a sulfonamide moiety with HBTU (O-(1H-benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluoro-
phosphate) during amide coupling, leading to the formation of tetramethylsulfonylguanidines, is described. Optimised conditions
showed that HBTU was as a convenient agent for the synthesis of tetramethylsulfonylguanidines, in basic conditions. A panel of
diverse sulfonamides was used to demonstrate the scope of this procedure.
Ó 2006 Elsevier Ltd. All rights reserved.
The PI3K/Akt pathway plays a pivotal role in several
fundamental cellular functions, such as growth, survival
metabolism and motility.1,2 Mutations and constitutive
activation of this pathway observed in many cancer cell
lines made it particularly attractive for therapeutic strat-
egies. In the course of our continuing search for new
therapeutic agents potentially useful in prostate cancer
treatment,3–5 and in order to switch-off the constitutive
activation of this pathway, we focused our efforts
towards the design of new inhibitors of PDK-1.6 We also
attempted to design a new series of amide compounds
containing a heterocyclic scaffold and a sulfonamide
moiety. A large range of pharmaceutical compounds
are known to contain the sulfonamide group: many
drugs, such as celecoxib (cyclooxygenase-2 inhibitor),7
methazolamide (carbonic anhydrase inhibitor),8 bendro-
flumethiazide (thiazide diuretic),9 zonisamide (new anti-
epileptic drug)10 illustrate the importance of such a
functional group in medicinal chemistry (Fig. 1).
In this letter, we report an unexpected reaction between
the well known peptidic coupling agent HBTU and an
unprotected sulfonamide moiety during the amidifica-
tion reaction, leading to the formation of stable tetra-
methylsulfonylguanidines. Optimised reaction conditions
were studied, and provided a new simple method for the
synthesis of tetramethylsulfonylguanidines.
During the synthesis of pharmaceutical compounds, the
sulfonamide moiety often needs to be protected because
CF3
N
O
S
O
O
N
S
O
O
O
NH2
H2N
N
N
S
S
O
S
NH
O
N
S
NH2
N
O
F3C
N
H
O
O
O
NH2
Celecoxib
Methazolamide
Zonisamide
Bendroflumethiazide
Figure 1. Structure of pharmaceutical compounds containing the sulfonamide moiety.
Keywords: HBTU; Sulfonamide; Tetramethylsulfonylguanidines.
*
Corresponding author. Tel.: +33 320964379; fax: +33 320964906; e-mail: patrick.depreux@univ-lille2.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.094

6088
S. Gluszok et al. / Tetrahedron Letters 47 (2006) 6087–6090
Step (i)
Step (ii)
O
R
RNH2
N
A
H
O
O
O
S O
NH2
HOBt
HBTU
OH
OBt
A
+ HOBt
A
Desired products
O S
O
O
S O
NH2
O
RNH2
HOBt
NH2
R
N
A
H
O
S O
N
N
N
Isolated products
Scheme 1. Formation of tetramethylsulfonylguanidine (Central heterocycle (not detailed) is designed by the ring named A).
of the acidic character of protons. Nevertheless, there
are generally few examples of protecting groups for this
functionality. It is often protected with tert-butyl
group11 or N-benzyl moiety.12
tial. The DIEA is ordinarily used to convert carboxylic
acids into carboxylates and enhances nucleophilicity of
amines during the peptidic coupling. The suggested
mechanism probably involves a nucleophilic attack (en-
hanced by DIEA) of the tetramethyluronium by sulfon-
amide moiety; an intramolecular reaction gives the
guanidine and the by-product HOBt (Scheme 2).
To obtain the chemical diversity, an amide coupling
procedure was set up, using HOBt (N-hydroxybenzotri-
azole) as the coupling reagent.13 This method is a two
step procedure: (i) first the formation of activated ester
of carboxylic acid, using secondary coupling agent
HBTU; (ii) then the release of the target amide in solu-
tion, which is performed by treatment of an activated es-
ter with various amines. In our case, 1H NMR spectra of
the crude products isolated after reaction, indicated the
presence of an unexpected singlet (12 protons) at about
3 ppm. The mass spectra also showed a difference of 98
with the expected mass. As uronium salts are suspected
to be guanidinylation agents,13 we supposed that the
corresponding product could be a tetramethylsulfonyl-
guanidine (Scheme 1).
We were interested in applying this practical method to
a set of diverse sulfonamides in order to test the gener-
ality of the reaction conditions.
A few examples are described and a typical procedure of
the reaction is presented (Table 1). The common proce-
dure is the following: coupling reactions were performed
by addition of HBTU (1.0 equiv) to a solution of sulfon-
amide (1.0 equiv) and DIEA (3.0 equiv) in anhydrous
dichloromethane. The resulting solution is stirred at
room temperature for 1 h. The reaction taken up in
dichloromethane is washed with hydrochloric acid
(0.1 M), sodium bicarbonate (5%), and brine. The com-
bined organic layers are dried over sodium sulfate and
concentrated under vacuum. The residue is purified by
column chromatography or recrystallisation. Experi-
mental conditions and yields following purification are
summarised in Table 1. A set of derivatives differing in
their electronical nature, steric hindrance, aromatic or
In view of these results, we tried to understand the
mechanism of the reaction. Series of experiments have
also been carried out to explain the formation of such
tetramethylsulfonylguanidines. First we found that the
presence of a base (diisopropylethylamine, DIEA) was
necessary to afford the reaction, but HOBt is not essen-
PF6
O
S
O
S
H
N
N
N
R
R
H
H
N
N
N
O
O
O
N
N
S
O
O
O
O
R
N
N
N
PF6
N
N
N
R
SO2NH2
N
N
N
+
N
N
N
O
HBTU
N
N
N
HOBt
Scheme 2. Suggested mechanism for the formation of tetramethylsulfonylguanidines.

S. Gluszok et al. / Tetrahedron Letters 47 (2006) 6087–6090
Table 1. Synthesis of tetramethylsulfonylguanidines with HBTUa
6089
O
S
O
S
a
N
N
R1
NH2
R1
N
O
O
1 - 8
Entry
R1
Purification
Yieldb (%)
1
Recrystallisation (EtOH/H2O; 5/5)
78
90
O2N
O2N
2
Chromatography (CH2Cl2/MeOH; 5/5)
NO2
3
4
5
Recrystallisation EtOH
95
74
88
Chromatography (CH2Cl2/MeOH; 95/5)
Chromatography (CH2Cl2/MeOH; 9/1)
H2N
Cl
6
7
8
Chromatography (CH2Cl2/MeOH; 95/5)
Chromatography (CH2Cl2/MeOH; 95/5)
Chromatography (CH2Cl2/MeOH; 98/2)
92
69
81
H3C
H3CA
Cl
S
a The reaction is performed with 1 equiv of sulfonamide, 1 equiv of HBTU, 3 equiv of DIEA, in CH2Cl2 at room temperature for 1 h.
b Yields after purification.
non aromatic nature, were used. Yields are generally
high and not affected by the nature of the substituents.14
flexibility of the reaction (room temperature, short reac-
tion time, high yield). The use of derivatives of HBTU
with different kinds of guanidines such as benzotriazol-
yloxy-bis(pyrrolidino)-carbonium-hexa-fluorophosphate
(BCC another uronium reagent)13 provides a new
opportunity to design new substituted sulfonamides by
using our method.
Substituted sulfonamides are of great interest in medic-
inal chemistry,15,16 or as fluorescent chemosensors,17 for
example. Tetramethylsulfonylguanidines have been syn-
thesised from different ways: by condensation of acyl
chloride with 1,1,3,3-tetramethyl-guanidine,18 by reac-
tion of fluoroalkanesulfonyl azides with tetrakis(dimeth-
ylamino)ethylene accompanied by the release of N2.19
These tetramethylsulfonylguanidine derivatives are
actually poorly evaluated in pharmacology, but recent
preliminary published results showed their ability to
bind to biological targets of interest.18,20 They can be
considered as equivalent of guanidines with a variable
extra site.21
References and notes
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sulfonamide group and the HBTU in basic conditions
is described. We showed here the absolute necessity to
protect the sulfonamide moiety during amide bound
coupling with HBTU in basic conditions. We provided
an efficient synthesis method of tetramethylsulfonylguani-
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´
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