A new approach to the synthesis of 2-aminoimidazo[1,2-a]pyridine derivatives through rapid parallel synthesis

Article abstract of DOI:10.1055/s-2002-33539

Different substituted 6-(2,6-difluorobenzoyl)-imidazopyridines 3 have been prepared using rapid parallel synthesis. Key cyanamide intermediate 4 was prepared from chloropyridine 1, and alkylated at the endocyclic nitrogen with different bromoacetophenones (prepared also in rapid parallel synthesis fashion). Subsequent cyclization was performed in situ with EtOAc/H₂O to give target molecules.

Full text of DOI:10.1055/s-2002-33539

1544
LETTER
A New Approach to the Synthesis of 2-Aminoimidazo[1,2-a]pyridine
Derivatives Through Rapid Parallel Synthesis
A
N
ew Approach
a
to the Syn
r
thesis of
l
2-Ami
o
noimidazo[1
s
,2-
a
]
pyridine De
J
r
ivatives aramillo,*a J. Eugenio de Diego,a Chafiq Hamdouchib
a
Centro de Investigación Lilly, Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
Fax +34(916)6233591; E-mail: c.jaramillo@lilly.com
b
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, 46385, USA
Received 7 June 2002
Abstract: Different substituted 6-(2,6-difluorobenzoyl)-imida-
zopyridines 3 have been prepared using rapid parallel synthesis.
Key cyanamide intermediate 4 was prepared from chloropyridine 1,
and alkylated at the endocyclic nitrogen with different bromoace-
tophenones (prepared also in rapid parallel synthesis fashion). Sub-
sequent cyclization was performed in situ with EtOAc/H2O to give
target molecules.
Key words: rapid parallel synthesis, imidazopyridine, antiviral
agents, heterocycle, cyclization
Imidazopyridines have demonstrated significant potential
as new drugs.1 The amine group at position 2 confers spe-
cial properties to this nucleus, which has been used to
prepare antirhinovirus agents.2
Scheme 1 Synthesis of 2-amino-imidazo[1,2-a]pyridines
In the original procedure, the imidazopyridine nucleus
was built (Scheme 2) by treatment of 2-chloropyridines 1
with haloacetophenones to give intermediate salts 2, and
further reaction with cyanamide, followed by in situ cy-
clization, which gave the desired 3-benzoyl-imidazo-
pyridines 3. However, this method was unpractical, giving
low yields, and purification problems. We have now
found that changing the reaction sequence (i.e., addition
of cyanamide to 1 to give intermediate cyanimide 4, fol-
lowed by reaction with haloacetophenones), resulted in
much better yields and cleaner reactions.
The main synthetic pathway towards imidazo[1,2-a]pyr-
idines is based on the reaction of 2-aminopyridine with
-halocarbonyl compounds.3 However, this method is not
useful for the corresponding 2-amino analogs. We have
recently described (Scheme 1) the synthesis of this kind of
molecules, from 2-chloropyridines,4 or N-tosyl-2-ami-
nopyridines.5
We were interested in the rapid parallel synthesis prepara-
tion of analogs bearing benzoyl substituents at C-3 of the
imidazopyridine nucleus. For this purpose, we have mod-
ified our previous method.4
Scheme 2 Alternative pathways for the synthesis of 2-amino-imidazo[1,2-a]pyridines
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1544,1546,ftx,en;G15902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
A New Approach to the Synthesis of 2-Aminoimidazo[1,2-a]pyridine Derivatives
1545
The new conditions were optimized (Scheme 3) using 2- The optimized procedure6 was then applied in rapid paral-
chloropyridine 5. Substitution of the chlorine atom of the lel synthesis fashion (Figure 1), yielding the final products
pyridine nucleus with cyanamide was best achieved with 8 in 4–20% overall yield using the automated purification.
KO-t-Bu as base in DMSO, giving cyanimide 6. Further All compounds were >95% pure by HPLC. Interestingly,
alkylation at the endocyclic nitrogen with bromoace- we also found that bromoacetophenone could be replaced
tophenone 7a was next investigated. Rapid parallel syn- by chloroacetophenone and a catalytic amount of NaI in
thesis was used for the screening of conditions (20 the alkylation step.
experiments were carried out), varying the amounts of
The preparation of the bromoacetophenones 7 was also
bromoacetophenone (2.0, 4.0, 4.5 or 6.0 equiv) and base
performed by rapid parallel synthesis, using the corre-
(i-Pr2NEt, 3.0 or 6.0 equiv; K2CO3, 2.0 or 4.0 equiv).
sponding acetophenones7 9 and DMAP HBr3 complex
The best results were obtained using i-Pr2NEt in DMF. Fi- (Scheme 4). No purification step was performed at this
nally, addition of EtOAc and H2O was enough to promote stage, and crude compounds were used.
8
the cyclization to target molecule 8a. In the end, we were
In summary, we have presented a simple and versatile
able to carry out all three steps in one-pot. Using only one
novel method for the preparation of the 2-aminoimida-
purification step, 8a was obtained in 36% overall yield af-
zopyridine nucleus. The use of rapid parallel synthesis
ter flash chromatography (62% conversion was observed
allows the introduction of different benzoyl derivatives at
by HPLC). Alternatively, purification by automated
3 position, and only one purification step, which can be
HPLC-MS gave 28% yield.
automated, is required.
Scheme 3 Rapid parallel synthesis of 2-amino-imidazo[1,2-a]pyridines
O
O
O
O
O
F
O
O
Cl
7j (18%)
(28%)
7g
(15%)
7a
7d (8%)
F
O
F
O
O
F
O
F
F
O2N
F
F
F
O
7k (12%)
7h (8%)
7b (14%)
7e (18%)
F
O
O
F
O
O
F
O
F
OAc
7i (4%)
7l (20%)
7f (14%)
7c (17%)
Figure 1 Bromoacetophenones used in rapid parallel synthesis of 2-amino-imidazo[1,2-a]pyridines (isolated yields shown in parenthesis)
Synlett 2002, No. 9, 1544–1546 ISSN 0936-5214 © Thieme Stuttgart · New York

1546
C. Jaramillo et al.
LETTER
slowly added at 0 ºC and the resulting mixture was stirred at
r.t. for 2.5 h. After this time, methanol (20 mL) was slowly
added at 0 ºC and the suspension was filtered through a pad
of SiO2 (ethyl acetate:ethyl acetate/methanol 1:1) to give
cyanimide 6, which was used without further purification.
To a solution of 6 (0.87 M in DMF, 1 mmol scale) was added
a solution of 7 (3.1 M in DMF, 2.5 equiv) and diisopropyl-
ethylamine (6 equiv), and the mixture was vigorously stirred
at r.t. for 4 h. Then, H2O (4 mL/mmol) and EtOAc (4 mL/
mmol) were successively added, and the stirring was
continued at r.t. for 18 h. The mixture was then diluted with
H2O (15 mL/mmol) and extracted with EtOAc (3 15 mL/
mmol), and the combined organic layers were washed with
H2O (10 mL/mmol) and concentrated under vacuum. The
residue was purified by automated HPLC-MS to give 8 (4–
28% overall yield, >95% purity). Compound 8a: 1H NMR
(d6-acetone, 500 MHz): = 9.43 (br s, 1 H, CH), 8.00 (dd,
J = 1.9 Hz, 9.1 Hz, 1 H, CH), 7.70 (ddd, J = 6.6 Hz, 8.2 Hz,
8.5 Hz, 1 H, CH), 7.60 (m, 2 H, 2 CH), 7.52 (m, 3 H, 3 CH),
7.47 (d, J = 9.4 Hz, CH), 7.21 (dd, J = 7.8 Hz, 8.2 Hz, 2 H,
2 CH), and 5.85 (br s, 2 H, NH2) ppm. 13C NMR (d6-acetone,
125 MHz): = 185.7, 184.0, 161.0, 160.3, 149.7, 141.1,
134.6, 134.0, 132.0, 130.0,128.9, 127.8, 124.1, 116.9, 115.1,
113.2, 108.2 ppm.
O
O
Br
DMAP·HBr3
AcOH
R
R
7
9
Scheme 4 Rapid parallel synthesis of bromoacetophenones (>95%
conversion by 1H NMR analysis of the crude mixtures)
References
(1) Bonnet, P. A.; Michael, A.; Laurent, F.; Sablayrolles, C.;
Rechencq, E.; Mani, J. C.; Boucard, M.; Chapat, J. P. J. Med.
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(3) Montgomery, J. A.; Secrist, A. A. In Comprehensive
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Oxford, 1984, Chap. 4.10, 607; and references cited therein.
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(5) (a) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.;
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(6) General Procedure: A solution of cyanamide (1.89 g, 45
mmol, 1.5 equiv) in DMF (50 mL) was treated with NaH
(60% mineral oil, 3.84 g, 96 mmol, 3.2 equiv) at 0 ºC, and
the suspension was stirred at r.t. for 45 min. A solution of
chloropyridine 5 (7.6 g, 30 mmol) in DMF (75 mL) was then
(7) (a) The acetophenones not commercially available were
prepared by condensation of an aryllithium derivative with
acetaldehyde. See, for example: Soll, R. M.; Guinosso, C.;
Asselin, A. J. Org. Chem. 1988, 53, 2844; and further
oxidation with tetra-n-propylammonium perruthenate
–
(Pr4N+RuO4 ). (b) For a review, see: Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
(8) Arrieta, A.; Ganboa, I.; Palomo, C. Synth. Commun. 1984,
14, 939.
Synlett 2002, No. 9, 1544–1546 ISSN 0936-5214 © Thieme Stuttgart · New York