Microwave-assisted multi-component synthesis of fused 3-aminoimidazoles

Article abstract of DOI:10.1016/S0040-4039(03)00941-9

A variety of fused 3-aminoimidazoles have been synthesised by a microwave assisted Ugi three-component coupling (3cc) reaction catalysed by scandium triflate in methanol as solvent. Yields of 33-93% have been achieved after just 10 min of microwave irradiation using a simple one-stage procedure. The methodology described is suitable for the rapid and efficient synthesis of a range of fused heterocycles of pharmacological interest.

Full text of DOI:10.1016/S0040-4039(03)00941-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4369–4371
Microwave-assisted multi-component synthesis of fused
3-aminoimidazoles
Sarah M. Ireland, Heather Tye* and Mark Whittaker
Evotec OAI, 151 Milton Park, Abingdon, Oxfordshire OX14 4SD, UK
Received 3 March 2003; revised 31 March 2003; accepted 10 April 2003
Abstract—A variety of fused 3-aminoimidazoles have been synthesised by a microwave assisted Ugi three-component coupling
(3cc) reaction catalysed by scandium triflate in methanol as solvent. Yields of 33–93% have been achieved after just 10 min of
microwave irradiation using a simple one-stage procedure. The methodology described is suitable for the rapid and efficient
synthesis of a range of fused heterocycles of pharmacological interest. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
up to 72 h were required. The use of microwaves, to
accelerate reactions, offers an attractive means of
extending the utility of this reaction for use in high
throughput library synthesis. An example of a solvent
free microwave accelerated version of this Ugi 3cc
reaction has been reported by Varma and Kumar.5
Encouraged by their results we have investigated the
potential of microwaves to accelerate the scandium
triflate catalysed reaction in solution.6
The advent of single mode microwave reactors, which
enable precise control of reaction conditions, has
opened the way for the exploration of microwave
assisted synthetic methods in combinatorial and parallel
synthesis.1 As part of an ongoing programme of
research, we decided to investigate the possibility of
using microwaves to accelerate the synthesis of a range
of fused 3-aminoimidazoles via a three-component Ugi
reaction (Scheme 1).
The reaction of heterocyclic amidines with aldehydes
and isocyanides under acid catalysed conditions was
first reported in 1998.2,3 The reaction is considered to
proceed via formation of an iminium species followed
by a [4+1] cycloaddition with the isocyanide. A varia-
tion of this methodology, using scandium triflate as a
Lewis acid catalyst, was reported by Blackburn et al.4
In all cases the yields of the desired fused 3-aminoimi-
dazoles were good, however extended reaction times of
2. Results and discussion
The reaction of 2-amino-5-methylpyridine with 2-naph-
thaldehyde and benzylisocyanide using scandium tri-
flate as catalyst was carried out in methanol as solvent
(Scheme 2). Pre-formation of the imine intermediate
was found to be unnecessary and immediate addition of
the isocyanide followed by microwave irradiation† in a
sealed 10 ml vial (200 W, 160°C, 10 min) gave the best
Scheme 1. Ugi 3cc reaction to form fused 3-aminoimidazoles.
Keywords: Ugi; multi-component reaction; microwave; scandium triflate; heterocycle; imidazole.
* Corresponding author. Fax: +44-(0)1235-441509; e-mail: heather.tye@evotecoai.com
† Microwave reactions carried out using a CEM Discover Synthesis Unit (CEM Corp. Matthews, NC). For further information see:
http://www.cem.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00941-9

4370
S. M. Ireland et al. / Tetrahedron Letters 44 (2003) 4369–4371
Table 1. One-stage Ugi 3cc reaction of an aldehyde, amidine and isocyanide

S. M. Ireland et al. / Tetrahedron Letters 44 (2003) 4369–4371
4371
Scheme 2. Microwave assisted Ugi 3cc reaction of 2-amino-5-methylpyridine with benzylisocyanide and 2-naphthaldehyde.
results. It is noteworthy that in the absence of scandium
triflate only a 25% conversion was achieved after 2 h in
the microwave at 160°C.
reviewed in the recently published text: Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Wein-
heim, 2002.
2. Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998,
37, 2234–2237.
3. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–
663.
4. Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.;
Tsai, S. Tetrahedron Lett. 1998, 39, 3635–3638.
5. Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40,
7665–7669.
6. Lindstrom, P.; Westman, J.; Lewis, A. Comb. Chem.
High Throughput Screening 2002, 5, 441–458. This review
refers to a manuscript in preparation regarding an inves-
tigation of microwave assisted, perchloric acid catalysed
Ugi 3cc reactions of a similar nature.
This optimised method7 was then applied to a number
of reactions where the heterocyclic amidine, aldehyde and
isocyanide were varied (Table 1). The more reactive,
electron rich, amidines in combination with benzyliso-
cyanide gave high yields (65–93%) in all cases. Less
reactive amidines such as aminopyrazine and aminothi-
azole gave reduced conversion to product and some side
product formation was observed particularly in the case
of aminothiazole. Bienayme et al. have postulated that
unreactive amidines of this type suffer from a competing
reaction of MeOH with the imine intermediate leading
to poorer conversion to the Ugi product.2 They have
reported that the use of a less nucleophilic reaction solvent
such as trifluoroethanol helps to prevent this side reaction
leading to improved yields in the Ugi reaction. An
investigation into similar solvent effects in our reaction
is currently underway and the results will be presented
in due course. Use of ethyl isocyanoacetate as the
isocyanide gave slightly reduced yields compared to
benzylisocyanide and in these cases it was necessary to
use ethanol as solvent to avoid problems with partial
transesterification.
7. Typical procedure: 2-Amino-5-methylpyridine (0.23
mmol) was dissolved in methanol (1 ml) and scandium
triflate (0.01 mmol) added with stirring at room temper-
ature. 2-Naphthaldehyde (0.23 mmol) was added fol-
lowed by benzylisocyanide (0.23 mmol) and the vessel
sealed with
a
pressure cap and irradiated with
microwaves (200 W) maintaining a temperature of 160°C
for 10 min. The mixture was allowed to cool, then
diluted with DCM (2 ml) and water (1 ml). The organic
phase was separated and the aqueous phase extracted
with DCM (2×5 ml). The combined organics were dried
over sodium sulfate, filtered and the solvent evaporated.
Purification by column chromatography on silica gel
eluted with 2% MeOH–DCM gave the product isolated
as a white solid (78 mg, 93%). 1H NMR (CDCl3, 400
MHz): l 2.26 (3H, s), 3.55 (1H, bt, J 6 Hz), 4.20 (2H,
d, J 6.2 Hz), 6.95 (1H, dd, J 9.2, 1.7 Hz), 7.25–7.38
(5H, m), 7.43–7.50 (3H, m), 7.68 (1H, s), 7.79–7.89 (3H,
m), 8.14 (1H, dd, J 8.6, 1.7 Hz), 8.40 (1H, s); 13C NMR
3. Conclusion
We have developed a rapid and efficient microwave
assisted method for the synthesis of a range of fused
3-aminoimidazoles in moderate to good yields via an Ugi
3cc reaction. This methodology should prove useful for
the synthesisof libraries ofsuchderivatives with improved
efficiency using high throughput synthesis methods.
(CDCl3, 100 MHz):
l 18.38, 52.49, 116.56, 120.07,
121.50, 124.99, 125.56, 125.75, 125.86, 126.12, 127.56,
127.63, 127.67, 128.15, 128.30, 128.71, 131.51, 132.68,
133.63, 135.52, 139.1, 140.61; MS (ES+) 364 (MH+,
100%).
References
1. The use of microwaves in organic synthesis is extensively