Re-evaluation of the outcome of a multiple component reaction - 2- and 3-amino-imidazo[1,2-a]pyrimidines?

Article abstract of DOI:10.1016/S0040-4039(02)00709-8

Multi-component reactions between aldehydes, isonitriles and 2-aminoazines do not always give the expected products.

Full text of DOI:10.1016/S0040-4039(02)00709-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4267–4269
Re-evaluation of the outcome of a multiple component
reaction—2- and 3-amino-imidazo[1,2-a]pyrimidines?
Gurjit S. Mandair, Mark Light, Andrea Russell, Mike Hursthouse and Mark Bradley*
Combinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ, UK
Received 12 February 2002; revised 25 March 2002; accepted 11 April 2002
Abstract—Multi-component reactions between aldehydes, isonitriles and 2-aminoazines do not always give the expected products.
© 2002 Elsevier Science Ltd. All rights reserved.
There are now large numbers of multi-component-
reactions (MCRs) known in the literature. Passerini
developed one of the first in 1921, with the treatment
of an isonitrile with a carboxylic acid and an aldehyde
or ketone to give a-acyloxy amides (Scheme 1a).1 This
reaction was later expanded by Ugi in 1961, to give
bis-amides, by the introduction of ammonia (or an
amine component) giving the four component MCR
so well known today (Scheme 1b).2
pared both in solution and on the solid phase,3,7 where
one entity of the MCR is used to ‘capture’ the desired
final product on the resin, with the Rink amine linker
often proving to be the linker of choice for the provi-
sion of the amine component.
During the synthesis of a library of imidazo[1,2-a]-
pyrimidines, while seeking to evaluate the performance
of different catalysts (Sc(OTf)3, AcOH, and HClO4) in
a model reaction using 2-aminopyrimidine as the
amine component with five different aldehydes and
Recently, a new variant of this reaction was described
by Blackburn,3 Bienayme´4 and Groebke,5 which
enabled the ready synthesis of imidazo[1,2-a]azines by
the acid-catalysed condensation of an aldehyde, an
isonitrile and a 2-aminoazine to give 3-alkyl-amino-2-
substituted-imidazo[1,2-a]azines 1a (Scheme 2). Since
imidazo[1,2-a]azines have emerged as versatile drug
templates in broad areas of medicinal chemistry, rang-
ing from cardiac stimulating, anti-inflammatory, anti-
ulcer, and anti-viral based therapies6,
a
parallel
Scheme 2. Model multi-component imidazo[1,2-a]azine syn-
thesis (from Ref. 3). All reagents 0.1 M, 48 h, catalysed with
either (i) 0.05 equiv. Sc(OTf)3, MeOH/DCM (1:4), (ii) 2.0
equiv. glacial AcOH, MeOH, or (iii) 1 M HClO4, MeOH.
synthesis to these compounds is dramatically enhanced
by a route comprising an efficient one-pot MCR. Sub-
sequently, imidazo[1,2-a]azine libraries have been pre-
Scheme 1. (a) Passerini and (b) Ugi reactions.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00709-8

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G. S. Mandair et al. / Tetrahedron Letters 43 (2002) 4267–4269
two different isonitrile components, it became clear that
the products isolated were not only those which had
been reported previously.3,4
The rationale for the formation of these two products is
shown in Scheme 3. Thus the initial iminium species
can be generated by addition of either the 2-amino
group or the ring nitrogen to the aldehyde. The
iminium species is then attacked by the isonitrile in the
accepted manner followed by intramolecular cyclisation
and aromatisation. In the latter case the expected 3-
amino substituted product is formed, while in the for-
mer the mechanism proposed gives the 2-amino
derivatised product. The question then arises as to
which product is favoured in which case.
The initial condensation reaction of 2-aminopyrimidine
2, methyl-4-formyl-benzoate 3, and 1,1,3,3-tetramethyl-
butylisonitrile 4 (Scheme 2) was initially catalysed with
0.05 equiv. of Sc(OTf)3 to give a yellow solid in 33%
yield which on the basis of MS and NMR evidence we
assumed was the expected 3CC product, namely the
3-alkylamino-2-substituted-imidazo[1,2-a]pyrimidine
1a. According to several publications the low product
yield could be attributed to the incomplete consump-
tion of the amine component. However, closer scrutiny
indicated that all the amine component had been con-
sumed and a more polar second adduct had in fact been
formed in 23% yield, which exhibited an Rf value very
similar to the starting 2-aminopyrimidine 2. Interest-
In the case of 2-aminopyrimidine, the symmetry of the
starting material might be expected to enhance the yield
of the 2-alkylamino product that might be obtained
compared to other aminoazines. The relative nucle-
ophilicity of the amines is another consideration. To the
best of our knowledge, this is the first reported synthe-
sis of 2-alkyl-amino-3-substituted-imidazo[1,2-a]pyrimi-
dine derivatives 1b using MCR protocols.
1
ingly this compound had H NMR and MS data that
were essentially identical to those obtained for the
suspected product 1a. To allow the exact assignment of
the two structures, the two samples were crystallised
and subjected to X-ray analysis resulting in the two
structures shown in Fig. 1.
A series of reactions was carried out to look for trends
in the formation of the two products 1a,b varying the
Figure 1. X-Ray structures of the two isolated substituted imidazo[1,2-a]pyrimidines 1a (left) and 1b (right).
Scheme 3. Mechanistic rationale for the formation of the 2- and 3-amino-imidazo[1,2-a]pyrimidines.

G. S. Mandair et al. / Tetrahedron Letters 43 (2002) 4267–4269
4269
Table 1. Substituted imidazo[1,2-a]pyrimidines prepared by multi-component condensation
Entry no.
Temp. (°C)
Catalyst
Aldehyde
Isonitrile
1a (Yield%)
1b (Yield%)
1
2
3
4
5
6
7
8
9
20
20
20
20
20
50
50
50
50
50
Sc(OTf)3
Sc(OTf)3
AcOH
ArCHO
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNCMe2CH2But
CNBut
28
33
15
11
34
40
36
34
65
20
37
23
0
11
33
35
32
26
13
32
pCHOArCO2Me
pCHOArCO2Me
pCHOArCO2Me
ArCH2CH2CHO
ArCHO
pCHOArCO2Me
pCHOArOMe
2-C4H3S-CHO
ArCHO
HClO4
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
10
Acknowledgements
aldehyde and the isonitrile components. Overall there
was little variation with the choice of the catalyst
being the dominant feature. This side reaction might
well explain the low yields reported by others4 when
using pyrimidines in these MCRs (Table 1).
Work in the Combinatorial Centre of Excellence is
funded by GSK, AstraZeneca, Pfizer, Roche, Eli-Lilly,
Organon, NovaBiochem/Merck, Amersham/Nycomed
Amersham and through the JIF initiative (EPSRC).
Another novel product was also isolated. It is well
known that the iminium cation shown in Scheme 4
can be trapped with methanol to give the by-product
5. However, the bis(aminopyrimidine) derivative 6 was
also observed here (although in low yield (5%)), gener-
ated by trapping of the iminium species by the azine.
The structure of this derivative was also confirmed by
1H and 13C NMR, and X-ray crystallography.
References
1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
2. Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229–2233.
3. (a) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41,
1495–1500; (b) Blackburn, C. Tetrahedron Lett. 1998, 39,
5469–5472; (c) Blackburn, C.; Guan, B.; Fleming, P.;
Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635–3638.
4. Bienayme´, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37,
2234–2237.
5. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–663.
6. (a) Sablayrolles, C.; Cros, G. H.; Milhavet, J. C.; Rechenq,
E.; Chapat, J. P.; Boucard, M.; Serrano, J. J.; McNeill, J.
H. J. Med. Chem. 1984, 27, 206–212; (b) Maruyma, Y.;
Anami, K.; Terasawa, M.; Goto, K.; Imayoshi, T.; Kadobe,
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(c) Hamdouchi, C.; Ezquerra, J.; Vega, J. A.; Vanquero, J.
J.; Alvarez-Builla, J.; Heinz, B. A. Bioorg. Med. Chem. Lett.
1999, 9, 1391–1394; (d) Bonnet, P. A.; Michel, A.; Laurent,
F.; Sablayrolles, C.; Rechencq, E.; Mani, J. C.; Boucard, M.;
Chapat, J. P. J. Med. Chem. 1992, 35, 3353–3358; (e) Starrett,
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R1
R1
R1
H
N
N
H
H
NH
OMe
HN
H
N
+
H
N
Nu
N
N
N
N
N
N
6
5
Scheme 4. By-products isolated and characterised during
aminoimidazo[1,2-a]pyrimidine synthesis.
In conclusion, these results suggest that a certain
amount of reflection on the presumed structures from
a MCR library is warranted. In this series of experi-
ments a new series of MCR products have been iden-
tified which provide a novel scaffold for biological
screening.
7. Chen, J. J.; Golebiowski, A.; McClenaghan, J.; Klopfenstein,
S. R.; West, L. Tetrahedron Lett. 2001, 42, 2269–2271.