Regioselective synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/S0040-4039(02)02278-5

A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines 3 is described. A halogen-metal exchange study on building block 1 showed that use of i-propyl magnesium chloride is most effective for chemoselective functionalization at position

Full text of DOI:10.1016/S0040-4039(02)02278-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9051–9054
Regioselective synthesis of
3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines
Carlos Jaramillo,a,* Juan Carlos Carretero,c J. Eugenio de Diego,a Miriam del Prado,a
Chafiq Hamdouchi,b Jose´ Luis Rolda´nc and Concha Sa´nchez-Mart´ıneza
aCentro de Investigacio´n Lilly, Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
bLilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46385, USA
cDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad Auto´noma de Madrid, 28049 Madrid, Spain
Received 27 September 2002; revised 11 October 2002; accepted 14 October 2002
Abstract—A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines 3 is described. A halogen–metal exchange
study on building block 1 showed that use of i-propyl magnesium chloride is most effective for chemoselective functionalization
at position 6. Further regiospecific metalation at position 3, followed by quenching with different electrophiles, afforded target
compounds. © 2002 Elsevier Science Ltd. All rights reserved.
Imidazo[1,2-a]pyridines have demonstrated significant
potential in the search of new drugs.1 The amine group
at position 2 confers special properties to this nucleus,
which have been used to prepare 2-aminoimidazo[1,2-
a]pyridines as antirhinovirus agents.2 This class of com-
pounds, as well as the related imidazo[1,2-a]pyrazines,
imidazo[1,2-a]pyridazines, and imidazo[1,2-a]pyrimi-
dines, are currently object of a renewed interest in the
pharmaceutical field.3 They can be found in pharmaco-
logically active compounds such as benzodiazepine
receptor agonists, anti-inflammatory agents, inhibitors
of gastric acid secretion, calcium channel blockers and
antibacterials.
of molecules, which has served to perform a broad
structure–activity relationship study at positions 3 and
6. In this paper, we describe a convenient method for
preparation of 3,6-disubstituted-2-aminoimidazo[1,2-a]-
pyridines from 6-iodo-2-trifluoroacetamidoimidazo-
[1,2-a]pyridine 1, by sequential regioselective introduc-
tion of substituents at the desired positions. This conve-
nient starting material can be prepared in four steps
from 2-aminopyridine in 40% overall yield.7
We envisaged (Scheme 2) the chemoselective introduc-
tion of substituents at position 6 by halogen–metal
exchange and further addition of electrophiles, which
would afford the desired monosubstituted intermediate
2. Subsequent a-directed metalation at position 3, facil-
itated by vicinal trifluoroacetamide, followed again by
electrophilic quench, would then render target molecule
3.
The main approach for the synthesis of imidazo[1,2-
a]pyridines is based on the reaction of 2-aminopyridine
with a-halocarbonyl compounds.1h,i,4,5 However, this
method is not useful for the corresponding 2-amino
analogs. We have recently described (Scheme 1) other
approaches for this kind of molecule, from N-tosyl-2-
aminopyridines6,7 or 2-chloropyridines.8,9
Although these methods afford 3,6-disubstituted-2-
aminoimidazo[1,2-a]pyridines, their main disadvantage
is the use of building blocks (2-iodoacetamides, 2-
haloacetophenones) which are usually commercially
unavailable, and must therefore be prepared. For this
reason, we have developed a new synthesis for this kind
Scheme 1. Synthesis of 2-aminoimidazo[1,2-a]pyridines.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02278-5

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C. Jaramillo et al. / Tetrahedron Letters 43 (2002) 9051–9054
Scheme 2. Synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines.
We then turned our attention to the regioselective
A study on the halogen–metal exchange of 1 followed
by deuteration was first performed. The goal was to
find out the best conditions for a chemoselective reac-
tion, which would give the corresponding derivative
regioselectively deuterated at position 6, 4a. Acidic
amide proton should be abstracted prior to halogen–
metal exchange and, even so, metalation at position 3
or 5 could be also a competing process leading to 4b or
4c, respectively (Scheme 3).
functionalization of 1 by halogen–metal exchange and
further addition of different electrophiles (Scheme 4,
Table 2), providing 6-substituted derivatives 2a–l. Trap-
ping of anion was attained in conversions similar to
deuteration, except for the less reactive MeI (entry 8).
The reaction was optimized11 with 2,6-dihaloaryl alde-
hydes (entries 1–3), affording the corresponding
carbinols in 76–79% yields.
We were interested in the preparation of 6-benzoyl
derivatives such as 2e. To compare the efficacy of the
direct introduction of this kind of substituent with
reaction with an aldehyde and subsequent oxidation,
we studied the reactivity of the magnesium anion
derived from 1 with different benzoyl containing elec-
trophiles. The best results were obtained when benzoyl
chloride was used (entry 5), affording desired 2e in 43%
yield.
The results of this study using different bases are
summarized in Table 1. The best conditions were
obtained by the use of 2 equiv. of i-PrMgCl10 as base
(entry 1), affording 4a as the only deuterated regioiso-
mer. Experiments directed to lower the amount of
protonation (which leads to 4d) were tried (reaction
with NaH or LHMDS prior to i-PrMgCl addition, with
4 equiv. of base, or with inverse addition of the base),
but gave similar results (4a:4d ratio was 79:21, 80:20
and 74:26, respectively).
Introduction of a second substituent at position 3 of the
heterocyclic nucleus was next investigated. a-Metala-
tion on 2e was attempted, but either no reaction, or
addition of the base to the carbonyl group, was
obtained. However, this intermediate is still useful for
the introduction of sulfur containing electrophiles, as
we have previously reported.7
Conditions for regioselective deprotonation at other
positions of heterocyclic nucleus were also found. PhLi/
t-BuLi promoted a-lithiation at position 3 (entry 2),
leading to 4b as major product (55%), whereas the use
of LDA (entry 3), or more effectively, LiTMP (entry 4)
resulted in deprotonation at position 5, affording 4c
selectively (43 and 54%, respectively).
With these results in hand, we undertook an alternative
preparation of 3-substituted-6-benzoyl derivatives by
a-metalation of carbinols 2a–c, as exemplified in
Scheme 5.12
The hydroxyl group was protected as t-butyldimethylsi-
lyl ether, and proton at position 3 was abstracted with
n-BuLi. Reaction of the corresponding carbanion with
2,6-difluorobenzoyl chloride gave 6. Finally, deprotec-
tion of hydroxyl group, oxidation,13 and nitrogen
deprotection, afforded target compound 7 in 56% over-
all yield from 1.
Scheme 3. Chemoselective functionalization on 6-iodo-2-tri-
fluoroacetamidoimidazo[1,2-a]pyridine 1 at position 6.
Table 1. Deuteration study of 1. Relative ratios of 4a–d
1
were calculated from H NMR spectra of crude mixtures
Entry
Base 1, Base 2
1
4a
4b
4c
4d
1
2
3
4
i-PrMgCl
PhLi, t-BuLi
LDA
81
19
13
55
13
28
32
43
54
44
17
LiTMP
1
Scheme 4. Regioselective functionalization of 6-iodo-2-tri-
fluoroacetamidoimidazo[1,2-a]pyridine 1.

C. Jaramillo et al. / Tetrahedron Letters 43 (2002) 9051–9054
9053
Table 2. Regioselective functionalization of 6-iodo-2-trifluoroacetamidoimidazo[1,2-a]pyridine 1 at position 6. Ratios 2/4d
1
were calculated from H NMR spectra of crude mixtures
Entry
Electrophile
Equiv.
Temp. (°C)
Time (min)
2, yield (%)
2/4d
1
2
3
4
5
6
7
8
2,6-Di-F-C6H3CHO
2,6-Di-Cl-C6H3CHO
2-Cl-6-F-C6H3CHO
C6H5CHO
ClCOPh
DMF
ClCO2Et
MeI
(2,6-Di-Cl-C6H3S)2
BrCN
Bu3SnCl
3
3
3
3
3
3
3
3
−40
−40
−40
−40
45
5
10
45
45
300
300
960
180
180
120
180
2a, 76
2b, 77
2c, 79
2d, 51
2e, 43
2f, 32
2g, n.i.*
2h, n.i.
2i, 40
80:20
87:13
80:20
60:40
50:50
65:35
56:44
10:90
72:18
83:17
80:20
79:21
−40
−40 to 10
−40 to 10
−40 to rt
−40 to rt
−40 to 0
−40 to rt
−40 to rt
9
2
10
11
12
1.5
1.5
1.5
2j, 38
2k, 75
2l, 32
B(Oi-Pr)3
* n.i., not isolated.
Scheme 5. Synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridine.
In summary, we have found a convenient method for
the synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]-
pyridines from 6-iodo-2-trifluoroacetamidoimidazo-
[1,2-a]pyridine 1, by sequential regioselective introduc-
tion of substituents at the desired positions. A variety
of functional groups can also be introduced by use of
other electrophiles.
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12. All new compounds showed satisfactory physical proper-
1
ties. Selected data: 2a: H NMR (d6-acetone, 200 MHz):
l 10.89 (bs, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 7.48–7.34 (m,
2H), 7.18 (d, 1H, J=9.4 Hz), 7.01 (dd, 2H, J=8.4, 8.5
Hz), 6.31 (s, 1H), 5.49 (bs, 1H); Ms (Es+) (M++H): 372.1.
2e: 1H NMR (d6-acetone, 200 MHz): l 11.25 (bs, 1H),
9.07 (dd, 1H, J=1.7, 0.9 Hz), 8.41 (s, 1H), 7.90–7.85 (m,
2H), 7.78–7.54 (m, 5 H); Ms (Es+) (M++H): 334.1. 2f: H
1
NMR (d6-acetone, 200 MHz): l 11.15 (bs, 1H), 10.0 (s,
1H), 9.25 (s, 1H), 8.40 (s, 1H), 7.70 (d, 1H, J=9.3 Hz),
7.56 (d, 1H, J=9.2 Hz); Ms (Es+) (M++H): 258.1. 2i: H
1
NMR (d6-acetone, 200 MHz): l 8.60 (dd, 1H, J=1.8, 1.0
Hz), 8.18 (s, 1H), 7.56–7.40 (m, 4H), 7.16 (dd, 1H,
J=9.5, 1.8 Hz); Ms (Es+) (M++H): 406.0. 2j: H NMR
1
(d6-acetone, 200 MHz): l 11.76 (bs, 1H), 9.27 (dd, 1H,
J=1.8, 1.0), 8.72 (s, 1H), 7.91 (dd, 1H, J=9.5, 1.0 Hz),
7.84 (dd, 1H, J=9.5, 1.8 Hz); Ms (Es+) (M++H): 308.0.
1
7: H NMR (d6-acetone, 300 MHz): l 10.14 (s, 1H), 8.09
(m, 2H), 7.70–7.00 (m, 6 H), 5.60 (bs, 2H); Ms (Es+)
(M++H): 429.5.
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