A novel synthetic approach towards 2-guanidinomethyl-4(5)- sulfamoylimidazoles

Article abstract of DOI:10.1016/j.tetlet.2004.05.143

A library of 2-guanidinomethyl-4(5)-sulfamoylimidazoles was synthesised in a convergent manner by introducing a sulfonyl chloride group via a trianion electrophilic sulfinylation of suitably protected 2-guanidinomethyl imidazoles.

Full text of DOI:10.1016/j.tetlet.2004.05.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5581–5583
A novel synthetic approach towards
2-guanidinomethyl-4(5)-sulfamoylimidazoles
Steve Price,a,* Richard Bull,a Sue Cramp,a Sophie Gardan,a Marco van den Heuvel,a
David Neighbour,a Susan E.Osbourn, a Iwan J.P.de Esch b and Christoph L.Buenemann b
aArgenta Discovery Ltd, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex, CM19 5TR, UK
bDe Novo Pharmaceuticals Ltd, Compass House, Vision Park, Histon, Cambridge CB4 9ZR, UK
Received 7 May 2004; accepted 27 May 2004
Abstract—A library of 2-guanidinomethyl-4(5)-sulfamoylimidazoles was synthesised in a convergent manner by introducing a
sulfonyl chloride group via a trianion electrophilic sulfinylation of suitably protected 2-guanidinomethyl imidazoles.
Ó 2004 Elsevier Ltd.All rights reserved.
As part of a collaborative effort to discover new inhib-
itors of certain serine proteases, an in silico design
exercise has been carried out using the bespoke SKEL-
To synthesise a library of such sulfonamides 1 in an
efficient fashion it was desirable to use a convergent
approach and introduce the diversity at the latest pos-
sible stage to avoid multiple synthetic repetitions.It was
envisaged that the best way to achieve this would be
condensation of suitably protected 2-guanidinomethyl-
5-sulfonyl chlorides with a number of diverse amines.
â
GEN software1 to design molecules that should interact
competitively at the target enzyme active sites.The
â
nature of the SKELGEN derived molecules was a
combination of an imidazole template, a guanidine
warhead and a sulfamoyl substituent suitable for
diversity creation, which presented novel challenges to
the synthetic chemist.Thus, whereas 4(5)-sulfamoylimid-
azoles have been reported on a limited number of
occasions, when combined with substitution at the 2-
position few examples have been described.2 Herein, we
can now describe the synthesis of a library of 2-guan-
idinomethyl-4(5)-sulfamoylimidazoles 1 in quantities
and purities suitable for biological evaluation against
the target enzymes.
It was also envisaged that the sulfonyl chlorides would
be synthesised from 2-guanidinomethylimidazoles, but
that the ring nitrogen and exocyclic guanidine nitrogens
would require protection.The protecting group selected
for the guanidine nitrogens was tert-butoxycarbonyl
(Boc).3 2-(Trimethylsilyl)ethoxymethyl (SEM)4 was se-
lected as a protecting group for the imidazole ring
nitrogen when required.These were chosen primarily
due to their expected ease of removal under mild acidic
conditions as a final synthetic stage.
R1
N
O
O
NH
Conventional approaches for the introduction of a sul-
fonyl chloride group at the 4- or 5-position of an imid-
azole have involved the use of strongly acidic conditions,
with chlorosulfonic acid being the reagent of choice.2;5
Evidently, this methodology would not be compatible
with either Boc or SEM protecting groups.An alterna-
tive method for the introduction of a sulfonyl chloride
group into aryl and heteroaryl systems involves the
reaction of a suitable Grignard reagent or lithium
reagent with a suitable electrophile, such as sulfuryl chlo-
ride or sulfur dioxide followed by chlorination.6;7 The use
of lithium anion chemistry has been previously described
H
N
R3
S
N
NH2
R2
N
1
Keywords: Electrophilic sulfinylation; Imidazole; Trianion; Guanidine;
Sulfonamides.
* Corresponding author.Tel:. +44-1279-645622; fax: +44-1279-645-
646; e-mail: steve.price@argentadiscovery.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd.All rights reserved.
doi:10.1016/j.tetlet.2004.05.143

5582
S. Price et al. / Tetrahedron Letters 45 (2004) 5581–5583
to capture electrophiles at the 5-position of N-substituted
imidazoles, albeit only on simplified systems.8 Thus it
was decided to determine whether a trianion 2a (which
might be in equilibrium with 2b) could be generated and
captured by a suitable electrophile6;7 at the 5-position of
the N-substituted 2-(bis(Boc)-guanidino)methylimid-
azoles to provide the desired sulfonyl chlorides.
These (unoptimised) reaction conditions were then ap-
plied to the suitably protected imidazoles 4a,b with
sulfur dioxide as the final electrophile, to generate the
lithium salts of the respective 5-sulfinic acids.These
sulfinic acids were oxidised in situ using sulfuryl chloride
to give the desired sulfonyl chlorides, which were puri-
fied by silica gel column chromatography, thus provi-
ding the desired sulfonyl chlorides 6a and 6b in
unoptimised yields (7% and 10%, respectively).
R1
N
NBoc
NBoc
R1
N
NBoc
NBoc
Li
Li
Li
With the sulfonyl chlorides 6a,b in hand, synthesis of the
final library products was completed using the appro-
priate amines in the presence of triethylamine to give the
desired protected sulfonamides.
N
N
N
N
Li
Li Li
2a
2b
Deprotection of the protected sulfonamides using
hydrogen chloride in dioxane (4 M solution) gave the
final products 1 as their corresponding HCl salts
(Scheme 2).Table 1 shows yields and purities over the
two final steps.
Synthesis of suitably protected 2-guanidinomethyl imid-
azoles commenced from the known 2-formyl imid-
azoles 3a,b (Scheme 1).4a;9 Reaction of 3a,b with
hydroxylamine hydrochloride and pyridine in ethanol
(v/v 85%), followed by reduction of the resultant oximes
(which could be effected by reducing agents such as
Raney Ni, H2 or Zn in acetic acid) gave the desired
amines (80–90%).These were subsequently reacted with
N,N0-bis(tert-butoxycarbonyl)-S-methylisothiourea10 to
give the protected 2-guanidinomethylimidazoles 4a,b
(40–45%).Treatment of the protected 2-guanidino-
methylimidazole 4a with 3 equiv of n-butyllithium was
expected to provide the trianion 2a and/or 2b.Unfor-
tunately, quenching with the electrophile dimethyl
disulfide yielded the undesired regioisomer 5a (27%)
showing that the obtained trianion had, in fact, a
structure better depicted as 2b.
In summary, novel trianions of suitably protected 2-
guanidinomethylimidazoles have been generated.These
undergo electrophilic sulfinylation at the 5-position.
These trianions have a trimethylsilyl group at the
methylene position to prevent regioisomeric electrophile
capture.The desired 5-sulfinic acids generated have been
oxidised in situ to the corresponding sulfonyl chlorides.
A
library of 2-guanidinomethyl-4(5)-sulfamoylimid-
azoles, prospective serine protease inhibitors, has been
synthesised.
To prevent the capture of an electrophile at the methyl-
ene position, trimethylsilyl chloride (TMSCl) was added
as a sacrificial electrophile to block derivatisation at this
position.8b;11 Thus, treatment of 4a with n-butyllithium
(3.5 equiv) followed by TMSCl (1 equiv), addition of
sec-butyllithium,8c;11 (1 equiv to deprotonate at the 5-
position of the imidazole), and finally introduction of
dimethyl disulfide to the desired trianion indeed gave
the 5-substituted protected 2-guanidinomethylimidazole
6c (20%).
R1
N
NBoc
R1
N
NH
O
O
O O
R3
S
H
N
H
N
S
a, b
N
Cl
NHBoc
NH2
R2
N
N
6a R = SEM
6b R = Me
1
Scheme 2. Reagents and conditions: (a) R2R3NH2, Et3N, THF; (b)
HCl, dioxane.
SEM
N
NBoc
H
N
NHBoc
SMe
R1
N
R1
N
d
NBoc
N
H
N
5a
O
a, b, c
NHBoc
R1
NBoc
R1
N
e
Li
NBoc
H
N
N
N
Li
E
N
N
NBoc
Li
NHBoc
3a R= SEM
3b R= Me
4a R= SEM
4b R= Me
N
N
TMS
6a R= SEM, E= SO2Cl
6b R= Me, E= SO2Cl
6c R= SEM, E= SMe
Scheme 1. Reagents and conditions: (a) Py, NH2OH, EtOH, 50 °C; (b) Zn, AcOH or Raney Ni, H2, EtOH; (c) MSC(@NBoc)NHBoc, THF; (d) (i)
3 equiv n-BuLi, THF, (ii) MeSSMe; (e) (i) 3.5 equiv n-BuLi, THF, (ii) 1 equiv TMSCl, (iii) 1 equiv sec-BuLi, THF, (iv) MeSSMe or SO2/H2O, (v)
SO2Cl2.

S. Price et al. / Tetrahedron Letters 45 (2004) 5581–5583
Table 1. 2-Guanidinomethyl-4-sulfamoylimidazoles 1
5583
Entry
R1
R2
R3
Purity (%)
Yielda
1a
1b
H
H
H
Me
Me
Me
95
95
46
30
1c
1d
1e
H
H
H
Me
H
85
95
90
15
51
51
BnO
EtO
O
N
H
1f
H
H
H
H
H
85
90
90
38
34
19
b
1g
1h
HO
b
1i
H
90
45
HO
F3C
1j
Me
Me
H
H
80
95
4
CF3
1k
13
BnO
a Yields calculated assuming the products to be trihydrochloride salts.
b Structural integrity confirmed by HMBC and HMQC NMR experiments.
Vaccaro, W.; Huff, B. Tetrahedron Lett. 1986, 35, 4095–
4098.
Acknowledgements
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We would like to thank the analytical department at
Argenta Discovery for NMR and LCMS analysis, and
Drs.Chris Newton and Hazel Hunt for their help with
the preparation of this manuscript.
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