Synthesis of 5-bromo-6-methyl imidazopyrazine, 5-bromo and 5-chloro-6-methyl imidazopyridine using electron density surface maps to guide synthetic strategy

Article abstract of DOI:10.1016/j.tet.2011.08.090

Small heteroaromatic rings are valuable monomers in drug discovery that can enable rapid access to novel and desirable chemical space. Installation of a synthetic handle on a heteroaromatic core may be difficult if steric and electronic factors are not in alignment with the desired transformation. Described are practical routes for the construction of 5-bromo-6-methyl imidazopyrazine (1) as well as 5-bromo and 5-chloro-6-methyl imidazopyridines (2a and 2b), which were developed using electron density surface maps encoded with ionization potential to guide synthetic strategy.

Full text of DOI:10.1016/j.tet.2011.08.090

Tetrahedron 67 (2011) 9063e9066
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 5-bromo-6-methyl imidazopyrazine, 5-bromo and 5-chloro-6-methyl
imidazopyridine using electron density surface maps to guide synthetic strategy
Anthony R. Harris a, Deane M. Nason a, Elizabeth M. Collantes a, Wenjian Xu a, Yushi Chi b, Zhihan Wang b,
,
Bingzhi Zhang b, Qingjian Zhang b, David L. Graya, Jennifer E. Davoren a
*
a Neuroscience Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Pfizer Department, WuXi AppTec, Fute Zhong Road, Pudong New District, Shanghai 200131, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2011
Received in revised form 26 August 2011
Accepted 29 August 2011
Available online 3 September 2011
Small heteroaromatic rings are valuable monomers in drug discovery that can enable rapid access to
novel and desirable chemical space. Installation of a synthetic handle on a heteroaromatic core may be
difficult if steric and electronic factors are not in alignment with the desired transformation. Described
are practical routes for the construction of 5-bromo-6-methyl imidazopyrazine (1) as well as 5-bromo
and 5-chloro-6-methyl imidazopyridines (2a and 2b), which were developed using electron density
surface maps encoded with ionization potential to guide synthetic strategy.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Electron density surface maps
Electrophilic aromatic substitution
Imidazopyrazine
Imidazopyridine
1. Introduction
2. Results and Discussion
Small halogenated heteroaromatic ring systems are valuable
monomers because of their ability to participate in established
cross-couplings including the Heck, Stille, and Suzuki reactions.1 As
part of a chemistry initiative to increase the diversity of our avail-
able low molecular weight heteroaryl monomer set, we were in-
terested in developing a practical construction of the novel
heterocycles imidazopyrazine 1 and imidazopyridines 2a and 2b
(Eq. 1). Formation of the fused imidazole ring was planned by re-
action of chloroacetaldehyde with a 2-amino pyrazine or pyridine,
such as in 5 or 6. One anticipated challenge with this approach was
regioselective installation of the requisite halogen handle at the
sterically and electronically disfavored C(5) position.
Brominating reagents, such as N-bromosuccinimide (NBS) and
bromine, react with heterocycles via electrophilic aromatic halo-
genation (EAH) at the site of greatest electron density.2 The elec-
tronic properties of a ring system are dictated by the heteroatom
substitution pattern and pendant electron donating or withdraw-
ing functionality. Protonated or hydrogen-bonded heterocycles can
have vastly different charge distributions and orbital energies rel-
ative to their neutral counterparts. Imidazo[1,2-a]pyrazine 7 is an
interesting example of this phenomenon (Fig. 1).3 The electron
density surface map encoded with ionization potential predicts
that neutral reactant 7 will preferentially undergo electrophilic
attack at C(3) while its protonated counterpart 8 would likely
substitute at C(5).4
1
N
8
The calculations on this system are in agreement with published
experimental data which we have reproduced in our laboratories.
H2N
N
X
X
X
2
or
N
N
N
6
When
7 is treated with NBS under neutral conditions 3-
3
5
bromoimidazo[1,2-a]pyrazine 9 is obtained exclusively,5 while
treatment with bromine provides 5-bromoimidazo[1,2-a]pyrazine
10 as the major adduct (Eqs. 2 and 3).6 We believe in the latter case
that the HBr generated during the course of the reaction protonates
the parent heterocycle at N(1) and is responsible for the altered
reactivity, although we stipulate that hydrogen bonding to ethanol
might also be responsible.
Br
Br
: X N
3: X N
5
1: X N
=
=
=
4 X CH
2a: X CH
:
6: X
H
C
=
=
=
Equation 1.
The electronic properties of related 6-methylimidazo[1,2-a]
pyrazine 11 are predicted to be similar to 7 (Fig. 2) with C(3) being
* Corresponding author. Fax: þ1 (860) 686 7444; e-mail address: jennifer.e.
davoren@pfizer.com (J.E. Davoren).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.090

9064
A.R. Harris et al. / Tetrahedron 67 (2011) 9063e9066
species (Eqs. 4 and 5). GCeMS of the crude reaction mixture
identified two major dibrominated products. 1H NMR data suggests
that one of the dibromo species was brominated on the 6-methyl
group while the other had only aromatic bromides. In addition,
a minor amount of 13 (ca. 10%), but no 1, was present. Taken to-
gether, we conclude that the two major products from this reaction
were 14a and either 14b or 14c. With the steric effect of the methyl
group apparently overriding any electronic bias for bromination at
C(5), an alternate approach to 5-bromo-6-methyl imidazopyrazine
1 was investigated.
Our second approach to 5-bromo-6-methyl imidazopyrazine 1
commenced with commercial 2-amino-5-methyl pyrazine 15
(Scheme 1). Due to the strong directing effect of the amino sub-
stituent, EAH of 15 with either Br2 or NBS exclusively led to the for-
mation of undesired regioisomer 17b. The key to at least partially
mitigating the amine’s directing effect was to form the HBr salt of 15
prior to bromination (Fig. 3).7 With C(3) sufficiently deactivated,
bromination of 15 ortho to the weakly activating methyl group at C(6)
was accomplished in moderate yield and selectivity (w3:2). We
noted that when the crude reaction mixture was heated to 50 ꢀC, the
undesired isomer 17b wasconverted to a highly polar material, which
simplified the purification of 17a by silica gel chromatography. Cy-
clization of 17a with aqueous chloroacetaldehyde furnished the tar-
get 5-bromo-6-methylimidazo[1,2-a]pyrazine 1 in moderate to good
yield8 making the overall efficiency ꢁ22% over the two steps.
Fig. 1. Electrophilic frontier density map for 7 and 8.
N
N
NBS CH
3C
N
,
N
N
N
N
86
%
Br
7
9
Equation 2.
,
t
E H
O
Br2
N
N
N
N
N
N
95
%
7
10
Br
Equation 3.
Scheme 1.
Fig. 2. Electrophilic frontier density map for 11 and 12.
Fig. 3. Electrophilic frontier density map for 15 and 16.
the preferential site of electrophilic attack on the neutral reactant
and C(5) on its protonated form. As expected bromination of 11
with NBS exclusively furnished the C(3) brominated adduct 13 in
80% yield. Treatment with bromine, however, under conditions
identical to those used on 7 yielded a mixture of brominated
Although it would have been convenient to prepare 5-bromo-6-
methylimidazo[1,2-a]pyridine 2 via an analogous route, direct bromi-
nation of commercial 2-amino-5-methyl pyridine 18 under the de-
scribed acidic conditions led exclusively to 3-bromo-5-methylpyridin-
2-amine 20 (Eq. 6). This is not surprising since as a pyridine,18, is more
polarized than pyrazine 15. Protonation of 18 should predominately
occur on the more basic pyridine nitrogen 19, further deactivating the
ortho-position towards electrophilic attack (Fig. 4).
N
NB
,
H
N
S C 3C
N
N
N
N
N
80%
Br
11
13
Facing this combination of electronic and steric factors, we
focused our attention on work done by Wachi and Terada.9
Equation 4.
Br
N
N
N
N
N
N
e
)
t
H
O
Br2 1.5 q , E
N
N
(
N
H2N
HBr in CH3CO2H,
then Br
H2N
or
Br
N
+
N
N
CHCl3,
53
2
N
N
Br
Br
Br
14a
Br
14c
Br
%
11
14b
18
20
Equation 5.
Equation 6.

A.R. Harris et al. / Tetrahedron 67 (2011) 9063e9066
9065
DMSO-d6 as the solvent. Chemical shifts are reported in parts per
million (ppm) relative to solvent (CDCl3: 7.27 and 77.0 ppm;
DMSO-d6: 2.50 and 39.51 ppm; CD3OD: 3.31 and 49.2 ppm in 1H
and 13C NMR, respectively). IR spectra were recorded on an FT-IR
type Nicolet 380 spectrometer and are reported in cmꢂ1. Mass
spectra were recorded using the ESIþ method on an Agilent
G1969A LC/MSD TOF mass spectrometer. Melting points were
measured on a WRS-2A apparatus and are uncorrected. Petro-
leum ether (PE) used refers to the fraction boiling in the range
30e60 ꢀC.
3.1.1. 3-Bromo-6-methylimidazo[1,2-a]pyrazine (13). NBS (26 mg,
0.15 mmol) was added to a solution of 6-methylimidazo[1,2-a]
pyrazine (11) (20 mg, 0.15 mmol) in anhydrous acetonitrile at 0 ꢀC.
The ice bath was removed and after 1.5 h the reaction was con-
centrated under reduced pressure. The residue was purified by
preparative TLC eluting with petroleum ether/EtOAc (1:2) to give
3-bromo-6-methylimidazo[1,2-a]pyrazine (13) (25 mg, 80%) as
a yellow solid. mp 80e83 ꢀC; IR (KBr): 3430, 2923, 1618, 1502,
Fig. 4. Electrophilic frontier density map for 18 and 19.
Accordingly, when N-oxide 2110 was refluxed with benzoxazine 22,11
the intermediate addition product cyclized to an oxadiazolidine and
eliminated HCl to give a mixture (1:1) of bromo- and chloro-pyr-
idinium oxazines 23a and 23b in moderate yield (Scheme 2).
The ratio of 23a to 23b could be determined by 1H NMR. We believe
that the bromide is extremely labile to displacement by chloride
generated during the reaction. Hydrolysis of the mixture with con-
centrated HCl furnished 2-aminopyridines 24a and 24b (1:1). For-
mation of the imidazole ring was accomplished by refluxing the
mixture with 2-chloroacetaldehyde in ethanol to give 5-bromo and
5-chloro-6-methylimidazo[1,2-a]pyridines 2a and 2b in high yield
but with further erosion of the bromo/chloro ratio in some batches.
The individual bromo- and chloro components could either be
1436, 1320, 923 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼8.99 (s, 1H),
7.88 (s, 1H), 7.74 (s, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼142.7, 140.4, 139.5, 135.6, 113.6, 100.0, 20.9; HRMS-ESI: calcd for
C7H7BrN3 (MþH)þ: 211.9823 and 213.9803; found: 211.9818 and
213.9794.
3.1.2. 6-Bromo-5-methylpyrazin-2-amine (17a) and 3-bromo-5-
methylpyrazin-2-amine (17b). A solution of HBr/CH3CO2H (360 g
(260 mL), 1.50 mol, 33% HBr in CH3CO2H) in anhydrous CHCl3
(300 mL) was added over 15 min to a solution of 5-methylpyrazin-
2-amine 15 (42 g, 0.38 mmol) in CHCl3 (1 L). The reaction flask was
wrapped in aluminum foil and heated to 50 ꢀC for 30 min in the
dark whereupon a solution of Br2 (68 g, 0.42 mmol) in CHCl3
(500 mL) was added dropwise over 3 h during which time the in-
ternal temperature of the reaction never exceeded 55 ꢀC. After 18 h
at 55 ꢀC the solvent was evaporated under reduced pressure. The
crude mixture was diluted with water (200 mL) and the pH was
adjusted to pH¼9 by the addition of solid Na2CO3. The suspension
was filtered under vacuum and the filtrate was extracted with
EtOAc (1 Lꢃ5). The combined organic extracts were concentrated
under reduced pressure and purified by flash silica gel chroma-
tography eluting with petroleum ether/EtOAc (5:1/1:1) to give
compound 6-bromo-5-methylpyrazin-2-amine 17a (36 g, 50%) as
a light orange solid; mp 154e157 ꢀC; IR (KBr): 3315, 3188, 1744,
1638,1575,1482,1375,1308,1051 cmꢂ1; 1H NMR (400 MHz, CDCl3):
separated by HPLC or used as
a mixture. Although chlor-
oimidazopyrazine 2b is presumably less reactive than its bromo-
substituted counterpart 2a, we found no practical disadvantage to
using a mixture of these halogenated heterocycles in subsequent
Suzuki couplings.
d
¼7.84 (s, 1H), 4.55 (br s, 2H), 2.52 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼152.2, 141.8, 138.4, 129.2, 22.2; HRMS-ESI: calcd for
C5H7BrN3 (MþH)þ: 187.9823 and 189.9803; found: 187.9816 and
189.9796. An analytical sample of 3-bromo-5-methylpyrazin-2-
amine (17b) was also isolated for spectroscopic analysis; mp
Scheme 2.
56e57 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼7.80 (s, 1H), 4.95 (br s, 2H),
In summary, described herein is a practical and scalable route for
the synthesis of previously unknown heterocycles 5-bromo-6-methyl
imidazopyrazine 1, 5-bromo- and 5-chloro-6-methyl imidazopyr-
idines 2a and 2b. The challenge in constructing these architectures
was the regioselective installation of the bromine or chlorine func-
tionality at the sterically and electronically disfavored C(5) position.
Electron density surface maps encoded with ionizationpotential were
used to guide synthetic strategy. In our hands, both heterocycles
readily underwent Suzuki reactions in a parallel format with a diverse
set of boronic esters with average yields ranging from 50 to 80%.
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼150.6, 142.8, 139.9,
125.2, 19.7; HRMS-ESI: calcd for C5H7BrN3 (MþH)þ: 187.9823 and
189.9803; found: 187.9817 and 189.9796.
3.1.3. 5-Bromo-6-methylimidazo[1,2-a]pyrazine (1). A mixture of
compound 15a (100 g, 0.53 mol) and ClCH2CHO (500 g (400 mL),
3.20 mol, 50 wt % aqueous solution) in H2O (600 mL) was refluxed
for 5 h. The reaction mixture was concentrated to remove
ClCH2CHO then extracted with EtOAc (600 mLꢃ3). The combined
organic layers were concentrated and recrystallized from EtOAc
and petroleum ether. The mother liquor was purified by column
chromatography eluted with petroleum ether/EtOAc (2:1/1:1) to
give 5-bromo-6-methylimidazo[1,2-a]pyrazine 1 (50 g, 44%) as
a yellow solid; mp 145e148 ꢀC; IR (KBr): 3100, 1495, 1324, 1295,
3. Experimental
3.1. General
NMR spectra were recorded on a Bruker Avance II spectrometer
(1H: 400 MHz, 13C: 100 MHz) at 25 ꢀC, using CDCl3, CD3OD or
1145, 771 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼8.99 (s, 1H),
7.87e7.84 (m, 2H), 7.69 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼140.0

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A.R. Harris et al. / Tetrahedron 67 (2011) 9063e9066
(2C), 139.0, 134.8, 115.0, 110.4, 22; HRMS-ESI: calcd for C7H7BrN3
61 mmol, 50% aqueous solution) was added to a solution of 23a and
23b (2.3 g, w14 mmol) in EtOH (50 mL). The mixture was heated to
reflux for 4 h whereupon the solution was cooled to rt and con-
centrated under reduced pressure. The crude residue was purified
by flash silica gel chromatography eluting with CH2Cl2/MeOH
(100:0/95:5) to give a mixture (1:1) of 2a and 2b (1.8 g,
w9.6 mmol, 68%). A sample was separated by HPLC and the in-
dividual heterocycles were characterized as follows: for 2a: IR
(MþH)þ: 211.9823 and 213.9803; found: 211.9817 and 213.9797.
3.1.4. 3-(6-Bromo-5-methylpyridin-2-yl)-2,2-dimethyl-2H-benzo[e]
[1,3]oxazin-4(3H)-one (23a) and 3-(6-chloro-5-methylpyridin-2-yl)-
2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (23b). A solution of
2-bromo-3-methylpyridine 1-oxide 21 (10 g, 54 mmol) and 4-
chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine 22 (5.3 g, 27 mmol)
in anhydrous CH2Cl2 (250 mL) was refluxed for 18 h under an inert
atmosphere. The reaction was cooled to rt, then concentrated under
reduced pressure. The crude residue was purified by flash silica gel
chromatography eluting with CH2Cl2/heptane (1:1/1:0) to give
a mixture (1:1) of 23a and 23b (5.4 g, w17 mmol, 62%) as a yellow
solid. A sample was separated by HPLC and the individual hetero-
cycles were characterized as follows: for 23a: mp 106e109 ꢀC; IR
(KBr): 1672, 1469, 1342, 1067, 765 cmꢂ1; 1H NMR (400 MHz, CDCl3):
(KBr): 3154, 1482, 1289, 1142, 801, 602 cmꢂ1 1H NMR (400 MHz,
;
CDCl3)
d
¼7.79 (s, 1H), 7.65 (d, J¼1.2 Hz, 1H), 7.54 (d, J¼9.2 Hz, 1H),
7.10 (d, J¼9.2 Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼144.9, 132.9, 127.7, 122.8, 115.7, 114.4, 113.7, 20.5; HRMS-ESI:
calcd for C8H8BrN2 (MþH)þ: 210.9871 and 212.9850; found:
210.9865 and 212.9845. For 2b: IR (KBr): 3377, 1488, 1288, 1146,
800, 700 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d¼7.68 (s, 1H), 7.61 (d,
J¼1.2 Hz, 1H), 7.46 (d, J¼9.0 Hz, 1H), 7.04 (d, J¼9.0 Hz, 1H), 2.34 (s,
d
¼7.98 (d, J¼6.8 Hz, 1H), 7.60 (d, J¼7.6 Hz, 1H), 7.50 (t, J¼7.8 Hz, 1H),
7.23 (d, J¼7.6 Hz, 1H), 7.10 (t, J¼7.4 Hz, 1H), 6.97 (d, J¼8.4 Hz, 1H),
2.42 (s, 3H), 1.78 (s, 6H); 13C NMR (100 MHz, CDCl3):
3H); 13C NMR (100 MHz, CDCl3):
d
¼145.2, 133.4, 127.7, 123.9, 119.3,
115.2, 111.3, 17.7. HRMS-ESI: calcd for C8H8ClN2 (MþH)þ: 167.0376;
d¼161.8, 155.5,
found: 166.0298.
148.8, 142.1, 139.9, 134.8, 134.2, 128.4, 123.3, 122.1, 117.6, 117.1, 93.1,
26.8, 21.5; HRMS-ESI: calcd for C16H16BrN2O2 (MþH)þ: 347.0395
and 349.0375; found: 347.0390 and 349.0371. Foꢂr1 23b: mp
;
1H NMR
Acknowledgements
99e103 ꢀC; IR (KBr): 1672, 1453, 1345, 1073, 766 cm
We would like to acknowledge Professors Justin Dubois and
Andy Myers, colleagues: Heather Frost, Bruce Rogers, Jinhua Yang,
Jinlong Wang as well as all other members of Team Cobra (Past and
Present) for their helpful discussions.
(400 MHz, CDCl3):
d
¼7.98 (dd, J¼7.6, 1.6 Hz, 1H), 7.64 (d, J¼8.0 Hz,
1H), 7.50 (td, J¼8.0, 1.2 Hz, 1H), 7.20 (d, J¼7.6 Hz, 1H), 7.11 (td, J¼7.6,
1.2 Hz, 1H), 6.98 (d, J¼8.0 Hz, 1H), 2.42 (s, 3H), 1.77 (s, 6H); 13C NMR
(100 MHz, CDCl3):
d
¼161.9, 155.5, 149.7, 148.7, 140.6, 134.8, 131.6,
128.3, 123.1, 122.1, 117.6, 117.1, 93.0, 26.8, 19.2; HRMS-ESI: calcd for
C16H16ClN2O2 (MþH)þ: 303.0900; found: 303.0890.
References and notes
3.1.5. 6-Bromo-5-methylpyridin-2-amine (24a) and 6-chloro-5-
methylpyridin-2-amine (24b). A solution of 20a and 20b (5.4 g,
w17 mmol) in concentrated HCl (35 mL) was refluxed for 45 h
whereupon it was concentrated under reduced pressure. The resi-
due was adjusted to pH 8 by the addition of satd aqueous NaHCO3
and extracted with CH2Cl2 (3ꢃ80 mL). The combined organic ex-
tracts were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure to give a mixture (1:1) of 24a and 25b
(2.5 g, w15 mmol, 92%) as a white solid. A sample was separated by
HPLC and the individual heterocycles were characterized as fol-
lows: for 24a: mp 96e98 ꢀC; IR (KBr): 3364, 3200, 1600, 1475, 1373,
1. Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998.
2. Bernard, P.; De la Mare, D. Electrophilic Halogenation. Reaction Pathways In-
volving Attack by Electrophilic Halogens on Unsaturated Compounds; Cambridge
University Press: 1976; ISBN-10: 0521209684, ISBN-13: 978-0521209687. p 231.
3. In color map figures the HOMO is mapped onto an electron density isosurface.
Colors toward red predict where electrophilic attack would likely occur.
4. All computational studies were performed using the Density Functional
Theory (DFT) methods implemented in the Jaguar version 7.7 suite of pro-
grams. Molecular geometries were optimized using the 6-31G** basis set. The
electronic properties calculated from these structures were the HOMO and
LUMO energies. The distribution of the electron density in the HOMO is
highlighted as the principal factor governing the selective behavior of sub-
strate to reagent.
5. (a) Bradac, J.; Furek, Z.; Janezic, D.; Molan, S.; Smerkolj, I.; Stanovnik, B.; Tisler,
M.; Vercek, B. J. Org. Chem. 1977, 42, 4197e4201; (b) DePompei, M. F.; Paudler,
W. W. J. Heterocycl. Chem. 1975, 12, 861e863.
6. Sablayrolles, C.; Milhavet, J. C.; Rechenq, E.; Chapat, J. P.; Cros, G. H.; Boucard,
M.; Serrano, J. J.; McNeill, J. H. J. Med. Chem. 1984, 27, 206e212.
7. Sato, N. J. Heterocycl. Chem. 1980, 17, 143e147.
8. Yields >70% were routinely obtained on <5 g scale. Upon scale up the yields
dropped to 40e50% with the balance of material being a highly colored in-
tractable mixture of polar products.
9. Wachi, K.; Terada, A. Chem. Pharm. Bull. 1980, 28, 465e472.
10. Ando, M.; Sato, N.; Nagase, T.; Nagai, K.; Ishikawa, S.; Takahashi, H.; Ohtake, N.;
Ito, J.; Hirayama, M.; Mitobe, Y.; Iwaasa, H.; Gomori, A.; Matsushita, H.; Tadano,
K.; Fujino, N.; Tanaka, S.; Ohe, T.; Ishihara, A.; Kanatani, A.; Fukami, T. Bioorg.
Med. Chem. 2009, 17, 6106e6122.
819 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼7.25 (d, J¼8.0 Hz, 1H), 6.38
(d, J¼8.0 Hz, 1H), 4.48 (br s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼156.4, 141.7, 140.5, 123.3, 107.3, 20.7; HRMS-ESI: calcd for
C6H8BrN2 (MþH)þ: 186.9871 and 188.9850; found: 186.9865 and
188.9845. For 24b: mp 90e92 ꢀC; IR (KBr): 3362, 1639, 1479, 1378,
820 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼7.29 (d, J¼8.0 Hz, 1H), 6.36
(d, J¼8.0 Hz, 1H), 4.41 (br s, 2H), 2.23 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼156.4, 148.8, 141.2, 120.7, 106.9, 18.3; HRMS-ESI: calcd for
C6H8ClN2 (MþH)þ: 143.0376; found:143.0371.
3.1.6. 5-Bromo-6-methylimidazo[1,2-a]pyridine (2a) and 5-chloro-6-
methylimidazo[1,2-a]pyridine (2b). 2-Chloroacetaldehyde (9.5 g,
11. Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441e6445.