Regioselective two step synthesis of 3-substituted 2-aminoimidazo[1,2-a]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2006.11.181

A two step procedure for the regioselective synthesis of 3-substituted-2-aminoimidazo[1,2-a]pyrimidines is described. The key step is a Dimroth rearrangement of a mixture of 2 and 3-substituted aminoimidazo[1,2-a]pyrimidines that yields quantitatively one

Full text of DOI:10.1016/j.tetlet.2006.11.181

Tetrahedron Letters 48 (2007) 2041–2045
Regioselective two step synthesis of 3-substituted
2-aminoimidazo[1,2-a]pyrimidines
Santiago Carballares,a,* Marta M. Cifuentesa and Gregory A. Stephensonb
aDepartamento de Investigacio´n, Lilly, S.A. Avda. de la Industria, 30, 28108 Alcobendas, Madrid, Spain
bX-ray Crystallography, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 22 September 2006; revised 23 November 2006; accepted 29 November 2006
Available online 13 January 2007
Abstract—A two step procedure for the regioselective synthesis of 3-substituted-2-aminoimidazo[1,2-a]pyrimidines is described. The
key step is a Dimroth rearrangement of a mixture of 2 and 3-substituted aminoimidazo[1,2-a]pyrimidines that yields quantitatively
one regioisomer. Reaction screening for the rearrangement step is reported. A multicomponent isocyanide based reaction is chosen
as the preferred way for the synthesis of the precursors. Elucidation of regiochemistry has been done by X-ray determination of
some representative compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
During the recent years an increasing number of papers
have been published for the synthesis or further trans-
formations of fused [5,6] ring systems. Among them,
great interest has been focused on imidazo[1,2-a]pyri-
dines and pyrimidines (Fig. 1). They represent a class
of molecules capable of binding to multiple receptors
with a high affinity giving useful biological activities
(e.g., antifungal, antibacterial, local anesthetic activity,
etc.).1
heterocycle and subsequent reduction,3 multicomponent
reaction between 2-aminopyridines, aldehydes and iso-
nitriles4 or preparation from pyridiniumfluorides,5
Strecker-type reaction between a 2-aminoazine, cyanide
ion and a limited number of aldehydes,6 or by use of
benzotriazoles as auxiliary groups,7 the introduction of
an alkyl/aryl amino side chain at C-2 has remained more
challenging. The most common synthetic route for the
preparation of these compounds involves the condensa-
tion of 2-aminoazine or N-tosyl 2-aminoazines with a-
amino carboxamides.8 These methods involve three or
more sequential synthetic steps, use harsh reaction con-
ditions that give a low yield and frequently obtain mix-
tures of regioisomers when 2-aminopyrimidine is used.9
There are several methods reported in the literature to
prepare 2-substituted or 3-substituted imidazo[1,2-a]-
pyridines, the majority relying on the condensation of
2-aminopyridine or 2-aminopyrimidine with a-bromo-
ketones to form the five member cyclic system.2 Particu-
larly interesting are those structures that contain amino
groups at C-2 or C-3. While there are well established
methods for the preparation of 3-amino substituted
products; by nitration at C-3 of the already formed
As part of our continuing interest in the chemistry of
fused [5,6] ring systems, we were aware of the formation
of 2-aminoimidazopyrimidines as a by product from an
isocyanide based multicomponent reaction.10 Given the
ease of synthesis of these heterocycles in a combinatorial
way, we envisioned the possibility of getting selectivity
in the synthesis of these 2-amino imidazopyrimidines
by changing the reaction medium. Unfortunately the
driving force of this condensation reaction makes the
formation of 3-amino derivatives easier, as demon-
strated by Krasavin and co-workers.11 We turned our
attention to obtaining regioselectivity by Dimroth rear-
rangement of the system. While the Dimroth rearrange-
ment is typically a reversible process,12 in some systems
substitution at the 2-position with an aryl group is
thermodynamically favoured to substitution at the
R2
R2
3
6
N
N
R1
R1
N
N
N
1
I
II
Figure 1.
*
Corresponding author. Tel.: +34 916233574; fax: +34 916233591;
e-mail: carballares@lilly.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.181

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S. Carballares et al. / Tetrahedron Letters 48 (2007) 2041–2045
Table 1.
Cl
H
HN
N
Base, Solvent
N
N
N
H
Cl
Cl
N
+
N
N
N
N
N
N
1a
1a
1b
Entry
Base
Solvent
T
1a/1b (1 h)
1a/1b (3 h)
1a/1b (24 h)
1
2
4
5
6
7
8
9
1% NaOH
5% NaOH
2.5% NaOH
KOH/MeOH 1M
5% LiOH
5% KOH
H2O
H2O
H2O/MeOH 1:4
—
H2O/MeOH 1:4
H2O/MeOH 1:4
H2O/MeOH 1:4
H2O/MeOH 1:4
H2O/MeOH 1:4
100
100
80
80
80
80
80
80
—
—
1:1
97:2
66:33
25:75
40:60
5:95
0:100
—
—
5:95
—
95:5
95:5
0:100
7:3a
1% NaOH
5% NaOH
1:1
0:100
—
—
—
—
10
10% NaOH
80
Ratio a/b determined by the integration of peaks at HPLC 300 nm. No other peaks detected.
a For entry 5 by products can be detected in LCMS in a high quantity.
3-position. There is, however, no literature references
for the successful rearrangement of disubstituted sys-
tems containing an amino side chain at C-2 or C-3.
of the two possible regioisomers, depending mainly
upon the pattern of substitution. In a first attempt, com-
pound 1a13 was treated in NaOH/H2O 100 °C for 24 h
yielding a mixture 95/5 of both regioisomers. The reac-
tion was very clean and by products were not detected
by LCMS and 1H NMR; but the insolubility of the
The Dimroth rearrangement is usually performed under
acidic or basic conditions, and usually yields a mixture
Table 2.
R2
N+
H
R2
N
R1
R1
C
N
N
ii
N
i
N
H
R1
N
+
N
N
NH2
OHC R1
N
N
R2
N
N
R2
N
N
isomer-b
(minor)
isomer-a
(major)
isomer-b
(only regioisomer)
i: MeOH/DCM 1:4 (0.3M); Sc(OTf)3 0.05 eq., 65ºC; ii: NaOH 5% H2O/MeOH 1:4, 80ºC
Entry
1
R1
R2
Ratio a/b
(first step)
Starting material used
for second step
T (°C)/time (h)
Ratio a/b
(second step)
Yield of
isomer b (%)
Cl
3:2
1a
1b
80 (3)
80 (3)
0:100
0:100
94
95
Cl
2
3
4
9:1
1:1
2a
80 (3)
80 (4)
80 (3)
0:100
0:100
0:100
92
95
91
3a/3b (1:1)
4a/4b (95:5)
N
95:5
5
6
1:4
1:1
5a
6a
80 (3)
80 (3)
0:100
5:95
99
94

S. Carballares et al. / Tetrahedron Letters 48 (2007) 2041–2045
2043
Table 2 (continued)
Entry
R1
R2
Ratio a/b
(first step)
Starting material used
for second step
T (°C)/time (h)
Ratio a/b
(second step)
Yield of
isomer b (%)
7
4:1
3:1
1:1
3:1
7a/7b (4:1)
80 (3)
0:100
1:99
92
F
F
8
8a
80 (3)
80 (3)
98
62
73
9
9a/9b (1:1)
10a/10b (3:1)
0:100
21:79
10
100 (4)
Yield based in isolated compound for the rearrangement step. For entries 9 and 10 the yield was calculated by integration of the peaks by HPLC.
For entries 1, 3 and 4, the first step was also performed with NH4Cl, Toluene, 120 °C, 48 h, yielding only isomer a.
Yield for first step is generally above 70% except for entries 5, 6, 9, 10 (25–50%).
For entry 6, the experiment was done with NaOH 10% in MeOH/H2O 3:1, heating overnight.
OH
H
O
R1
O
R1
R1
R1
N
N
N
N
N
N
N
N
N
H
N
N
H
N
Ia
Ia
O
N
N
R1
R1
N
N
N
N
H
Ib
Scheme 1. Proposed mechanism for Dimroth rearrangement of imidazopyrimidines.
products in the reaction medium could be masking the
results. We decided to explore broadly the reaction con-
ditions by changing the bases, mixtures of solvents, tem-
perature and reaction times. The use of a mixture H2O/
MeOH prompts an increase of the ratio b/a, while
changes in the base did not afford any better result.
The reaction is very clean and no purification was
needed. If the concentration of base is increased, the
reaction time can be reduced up to 1 h; however, we
wanted to use mild conditions in order to avoid possible
decomposition of intermediates when the reaction is
applied to other substrates.12b
of several groups at C-2 and C-3. We used the known
Groebke multicomponent reaction to synthesize a mixture
of the two regioisomers, since the method is straightfor-
ward and the variety of the products formed can be
almost unlimited. The ratio a/b obtained in the first step
is quite dependent on the substituents, when protic con-
dition are used, and in general a mixture of both regio-
isomers is obtained. The reaction works cleanly and
fast with MeOH/DCM and Sc(OTf)3, heating for 3 h
The experimental conditions listed in Table 1 were
applied to a variety of products to study the influence
NH2
i
>95%
N
N
NH2
N
N
N
N
11a
11b
Scheme 2. Reagents and conditions: (i): NaOH 5% H2O/MeOH 1:4,
80 °C, 1 h.
Figure 2. X-ray crystallographic structure of compound 1b.

2044
S. Carballares et al. / Tetrahedron Letters 48 (2007) 2041–2045
H
R2
N
R1
R2
N+
N
ii
i
N
N
H
+
NH2
R1
N
C
N
N
N
ref 11
R2
N
N
OHC R1
Scheme 3. Reagents and conditions: (i) toluene, NH4Cl, 120 °C, 24–48 h; (ii) (a) MeOH/DCM 1:4 (0.3 M), Sc(OTf)3 0.05 equiv, 65 °C; (b) NaOH 5%
H2O/MeOH 1:4, 80 °C.
at 65 °C.14 A crude mixture is treated with NaOH/
hedron 2002, 58, 4445; (e) Lee, Y. S.; Lee, K-J. Bull.
Korean Chem. Soc. 2002, 23, 1845; (f) Nadipuram, A.;
MeOH/H2O at 80 °C for 3 h to yield, in most cases, only
Kerwin, S. Tetrahedron 2006, 62, 3798; (g) Kolar, P.;
regioisomer b in yields higher than 90% usually with-
Pizzioli, A.; Tisler, M. J. Heterocycl. Chem. 1996, 33,
out requiring purification.15 In some cases, pure starting
639.
materials were used for the rearrangement step (Table
3. For some examples of nitration at C-3 see: Roubaud, C.;
2).
Vanelle, P.; Maldonado, J.; Crozet, M. P. Tetrahedron
1995, 51, 9643; Yveline, R.; Gerard, G.; Georges, M.
Chem. Pharm. Bull. 1992, 40, 1170.
4. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661;
Interestingly, the reaction can be expanded to com-
pounds bearing a free –NH2 group. When the commer-
cially available compound 11a is treated under the
same conditions, 11b is formed as the only regio-
isomer quantitatively. It seems that the selectivity in
the cyclization step (see Scheme 1) is not only driven
by the steric effects, but also by the different electronic
pattern of the imidazole intermediate due the presence
of an amino group at C-3 (Scheme 2). The correct iden-
tity of compound as 2-amino imidazo[1,2-a]pyrimidines
´
(b) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998,
37, 2234; (c) Blackburn, C.; Guan, B.; Fleming, P.;
Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635.
5. Kiselyov, A. Tetrahedron Lett. 2005, 46, 4487.
6. (a) Bristow, N. W.; Charlton, P. T.; Peak, D. A.; Short, W.
F. J. Chem. Soc. 1954, 616–629; (b) Tadeka, K.; Shudo,
K.; Okamoto, T.; Kousuge, T. Chem. Pharm. Bull. 1978,
26, 2924; (c) Knott, E. B. J. Chem. Soc. 1956, 1360; (d)
Sugiura, S.; Akoi, H. K.; Inouf, S.; Goto, T. Yakukagaku
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Zousi, C. J. Heterocycl. Chem. 1981, 18, 1565–1570; (f)
Ohta, M.; Masaki, M. Bull. Chem. Soc. Jpn. 1960, 37,
1392.
1
was confirmed by LCMS analysis, H NMR, by com-
parison with those compounds already characterized
by Krasavin and co-workers11 and finally, by the X-ray
structure of some representative products (1b, Fig. 2).
7. Katritzky, A.; Xu, Y.; Tu, H. J. Org. Chem. 2003, 68,
4935.
In summary, we have developed a new way to prepare 2-
aminoimidazopyrimidines by a selective rearrangement.
The process has been tested in a great variety of prod-
ucts including free amino groups, which indicates the
broad scope of the reaction. The process can be coupled
to an isocyanide MCR affording a very versatile process
for the rapid synthesis of 2-aminoimidazopyrimidines
(Scheme 3).
8. (a) Bochis, R.; Olen, L.; Fisher, M. H.; Reaner, R. A. J.
Med. Chem. 1981, 24, 1483; (b) Hamdouchi, C.; Zhong,
B.; Mendoza, J.; Collins, E.; Jaramillo, C.; de Diego, J. E.;
Robertson, D.; Spencer, C. D.; Anderson, B.; Watkins, S.
A.; Zhang, F.; Brooks, H. Bioorg. Med. Chem. Lett. 2005,
15, 1943; (c) Jaramillo, C.; Carretero, J. C.; de Diego, J.
E.; del Prado, M.; Hamdouchi, C.; Roldan, J. L.; Sanchez-
Martinez, C. Tetrahedron Lett. 2002, 43, 9051; (d) Acero-
Alarcon, A.; Armero-Alart, T.; Jorda-Gregori, J. M.;
Rojas-Arguo, C.; Zaballos-Garcia, E.; Server-Carrio, J.;
Ahjyaje, F. Z.; Sepu´lveda-Arques, J. Synthesis 1999, 12,
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erra, J. Synthesis 1998, 867; (g) Hamdouchi, C.; de Blas, J.;
Ezquerra, J. Tetrahedron 1999, 55, 541.
9. N-Alkylation of 2-halopyridines have been also used for
the preparation of 2-aminoimidazo[1,2-a]pyridines, but it
has not been applied successfully in the case of pyrimi-
dines: (a) Vega, J.; Vaquero, J.; Alvarez-Builla, J.;
Ezquerra, J.; Hamdouchi, C. Tetrahedron 1999, 55, 2317;
(b) Jaramillo, C.; de Diego, J. E.; Hamdouchi, C. Synlett
2002, 1544.
10. Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.;
Bradley, M. Tetrahedron Lett. 2002, 43, 4267.
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vchenko, D.; Krasavin, M. Tetrahedron Lett. 2006, 47,
947.
12. (a) Jacquier, R.; Lopez, H.; Mary, G. J. Heterocycl. Chem.
1973, 755; (b) Guerret, P.; Jacquier, R.; Maury, G. J.
Heterocycl. Chem. 1971, 643; (c) Jensen, M. S.; Hoerrner,
R. S.; Li, W.; Nelson, D. P.; Javadi, G. J.; Dormer, P. G.;
Cai, D.; Larsen, D. R. J. Org. Chem. 2005, 70, 6034; (d)
Chezal, J. M.; Moreau, E.; Delmas, G.; Gueiffier, A.;
References and notes
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Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson,
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Evrard, G. H.; Durant, F. V.; George, P.; Wick, A. Eur. J.
Med. Chem. 1993, 28, 323.
2. For less common methods of synthesis of imidazopyri-
dines see: (a) Moutou, J.; Schmitt, M.; Collot, V.;
Bourguignon, J. Tetrahedron Lett. 1996, 37, 1787; (b)
Knolker, H.; Hitzemann, R. Tetrahedron Lett. 1994, 35,
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13. During this work, notation of the products as ‘a’ is used
for aminosubstituted isomer at C-3 of imidazopyrimidine
and notation as ‘b’ is used for isomer at C-2.
support. Thus, the basic product was adsorbed on cation
exchange resin and excess of aldehyde, isonitrile and
neutral impurities were removed by a solvent wash.
Treatment of the resin (SCX) with 2 N methanolic
ammonia eluted a mixture of 7a/7b (8:2) very clean. The
mixture of regioisomers can be either isolated previously
to Dimroth rearrangement (purification in normal phase
with DCM/MeOH) or treated directly with NaOH/MeOH
5% and later on purified if needed. Compound 7a placed
in a screw capped glass tube under nitrogen was dissolved
in deoxygenated NaOH 5% MeOH/H2O (4:1) (0.1 M) and
heated 3 h at 80 °C affording 7b (92%). The reaction
mixture was diluted with DCM and extracted with water,
and the organic solvent was evaporated under vacuum. 1H
NMR (7b) (DMSO-d6, 300 MHz) d 8.65 (dd, J = 2.0,
7.0 Hz, 1H), 8.19 (dd, J = 1.8, 4.3 Hz, 1H), 7.62–7.18 (m,
10H), 6.88 (dd, J = 4.4, 11.1 Hz, 1H), 6.57 (t, J = 6.41 Hz,
1H), 4.57 (d, J = 4.5 Hz, 2H) ppm.
14. (a) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41,
1495; (b) Ireland, S.; Tye, H.; Whittaker, M. Tetrahedron
Lett. 2003, 44, 4369; (c) Blackburn, C.; Guan, B.; Fleming,
P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39,
3635.
15. Experimental procedure: To a solution of 300 mg of 2-
aminopyrimidine (3.15 mmol, 1 equiv) dissolved in 5 ml of
DCM/MeOH (3:1) placed in a screw capped glass tube
was added Sc(OTf)3 (0.13 mmol, 0.05 equiv), benzalde-
hyde (4.1 mmol, l.3 equiv) and benzylisocyanide
(4.1 mmol, 1.3 equiv). The reaction mixture was heated
overnight at 65 °C. Isolation of pure product from the
reaction mixture was achieved by capture on a solid