Synthesis of Disubstituted 3-Phenylimidazo[1,2-a]pyridines via a 2-Aminopyridine/CBrCl3 α-Bromination Shuttle

Article abstract of DOI:10.1021/acs.joc.6b01714

A versatile protocol for the synthesis of disubstituted 3-phenylimidazo[1,2-a]pyridines by coupling 2-aminopyridine with phenylacetophenones, phenylacetones, or β-tetralone has been developed. Isolated yields of up to 97% were obtained at 80 °C within 5 h

Full text of DOI:10.1021/acs.joc.6b01714

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Article
Synthesis of Di-Substituted 3-Phenylimidazo[1,2-a]pyridines
via a 2-Aminopyridine/CBrCl3 alpha-Bromination Shuttle
Irwan Iskandar Roslan, Kian-Hong Ng, Ji'en Wu, Gaik-Khuan Chuah, and Stephan Jaenicke
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01714 • Publication Date (Web): 08 Sep 2016
Downloaded from http://pubs.acs.org on September 9, 2016
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Synthesis of Di-Substituted 3-Phenylimidazo[1,2-a]pyridines via a 2-
Aminopyridine/CBrCl α-Bromination Shuttle
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Irwan Iskandar Roslan, KianꢀHong Ng, Ji’ꢀEn Wu, GaikꢀKhuan Chuah*, Stephan Jaenicke*
*Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore
117543. [Fax: (+65)ꢀ6779ꢀ1691; phone: (+65)ꢀ6516ꢀ2918; email: chmsj@nus.edu.sg,
chmcgk@nus.edu.sg]
ABSTRACT
A versatile protocol for the synthesis of diꢀsubstituted 3ꢀphenylimidazo[1,2ꢀa]pyridines by
coupling 2ꢀaminopyridine with phenylacetophenones, phenylacetones or βꢀtetralone has been
developed. Isolated yields of up to 97 % were obtained at 80 °C within 5 h. The 2ꢀ
aminopyridine/CBrCl system acts as an αꢀbromination shuttle by transferring Br from CBrCl to
3
3
the αꢀcarbon of the carbonyl moiety. This triggers a series of steps with double CꢀN/CꢀN bond
formation to the final product. The distinct advantages of this protocol include the use of
commercially available inexpensive substrates, simplicity of a metalꢀfree oneꢀpot synthesis, and
ease of scaleꢀup to multiꢀgram quantities.
1
R = Me (phenylacetones)
1
R = Ar (phenylacetophenones)
2
R = Alkyl, halides, esters, OMe
Br shuttle
Stop 1
Stop 2
.....
Br
KHCO
3
.
....
Br
23 examples
75 - 97 % yield
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INTRODUCTION
The regioselective αꢀbromination of 1,3ꢀdicarbonyls and related 1,3ꢀdiactivated derivatives, such
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as phenylacetones and phenylacetophenones is an important transformation in organic synthesis.
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These αꢀbrominated products serve as important synthetic intermediates to construct more
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complex molecules. A large variety of brominating reagents have been utilized for αꢀ
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,8
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bromination,
including
Br2,
NBS,
bromodimethylsulfonium
bromide,
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tetraethylammonium bromide, CuBr2, NaOBr and CBrCl3.
The reaction normally
requires catalytic or stoichiometric amounts of reagents including Lewis and Brønsted acids,
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inorganic or organic bases, oxidants and transition metal complexes.
Recently, the inꢀsitu αꢀ
halogenation of acetophenones or 1,3ꢀdicarbonyls and their derivatives has been exploited for the
construction of heteroaromatics, with an emphasis on step economy. In these transformations, αꢀ
halogenation of the 1,3ꢀdicarbonyl is the first step of a cascade reaction that leads to the
heteroaromatic structures. Inꢀsitu αꢀiodination and bromination has been utilized in constructing
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various heteroaromatic backbones including oxazoles,
thiazoles
and benzothiazoles,
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quinoxalines, pyrido[1,2ꢀa] benzimidazoles and imidazo[1,2ꢀa]pyridines.
Most of these
methods use highly energetic species like NBS and NIS as the halogenating reagent and/or
require overstoichiometric amounts of peroxide oxidants such as TBHP or corrosive Brønsted
acids like pꢀtoluenesulfonic acid (PTSA). Therefore, these reactions face challenging safety
concerns for scaleꢀups.
In a recent communication, we employed an inꢀsitu αꢀbromination strategy to synthesize
3
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imidazo[1,2ꢀa]pyridines in high yields from 2ꢀaminopyridines and 1,3ꢀdicarbonyls.
Bromotrichloromethane, CBrCl , was used as brominating reagent. The low toxicity and
3
exothermicity of CBrCl and its low boiling point which allows for easy removal via rotary
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evaporation are distinct advantages. The reaction follows a unique αꢀBr shuttle mechanism
where 2ꢀaminopyridine is not only the substrate but also transfers the Br from CBrCl to the αꢀ
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carbon of the 1,3ꢀdicarbonyl. This then initiates a cascade reaction that forms the imidazo[1,2ꢀ
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a]pyridine structure. The study draws inspiration on the synthesis of oxazoles via inꢀsitu αꢀ
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iodination by Zhu’s group. In contrast to the direct αꢀhalogenation hypothesis, they proposed
that the iodine atom is transferred to the αꢀcarbon with the help of TBHP reagent. The concept of
the Nꢀbrominated 2ꢀaminopyridine as a shuttle was drawn from the work of Antonchick’s group
on pyrido[1,2ꢀa]benzimidazole, where in the mechanism, an Nꢀiodinated form of 2ꢀ
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aminopyridine was introduced.
Particular advantages of our methodology are that it is a oneꢀpot synthesis, does not require
any oxidants or prefunctionalization of the substrates and employ commercially available and
inexpensive substrates and reagents. The transition metalꢀfree nature makes it suitable for
applications in the pharmaceutical industry, for example, to synthesize libraries of
physiologically active compounds. Hence, we investigated the feasibility of extending it to other
1
,3ꢀdiactivated derivatives, including phenylacetones, phenylacetophenones and βꢀtetralones
Scheme 1). This would give ready access to a large diversity of disubstituted 3ꢀ
phenylimidazo[1,2ꢀa]pyridines, which are less reported in the literature. The reported reactions
(
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couple 2ꢀaminopyridines with αꢀbromo phenylacetaldehyde, αꢀbromoacetophenones,
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alkynylꢀiodonium salts and (bromoethynyl)benzene.
Shortcomings of these reactions include
the need to prefunctionalize the substrate with a halide which requires additional steps, high
reaction temperatures and low to moderate yields of up to 80 % only. Hence, an efficient oneꢀpot
synthesis of 3ꢀphenylimidazo[1,2ꢀa]pyridines with inꢀsitu halogenation is highly desirable. In
this work, substitutions at Cꢀ2 and Cꢀ3 position of the imidazo[1,2ꢀa]pyridines backbone are
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explored. This structural motif is prevalent in psychoactive drugs known as nonbenzodiazepines,
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which includes Zolpidem, Zolimidine, TPꢀ003 and Miroprofen.
Scheme 1. Coupling reaction with 2ꢀaminopyridine as an αꢀbromination shuttle.
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RESULTS AND DISCUSSION
The reaction between 2ꢀaminopyridine 1a and 4ꢀmethoxyphenylacetone 2a was tested at 80 °C
using various solvents containing 10 % v/v of CBrCl (Table 1). After 5 h, the yield of 3a was
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8 % in MeCN while slightly lower yields were obtained in DMAc, DMF, and NO Me (Table 1,
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entries 1ꢀ4). No conversion was observed with DMSO which could be due to its radical
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8
quenching ability (Table 1, entry 5). Toluene, a nonꢀpolar solvent, was not suitable for the
reaction (Table 1, entry 6). Without a base like KHCO , the yield of 3a dropped significantly
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(Table 1, entry 7). Hence, several bases were screened for the reaction (Table 1, entries 8 ꢀ 11).
No 3a was formed with KOtBu which may be due to the fact that its conjugate acid, tertꢀbutanol,
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is a radical scavenger and could quench any radicals formed in the reaction. Both NaHCO and
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K CO gave lower yields than KHCO , whereas with CsHCO , the yield of 3a was slightly
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higher, 84 %. However, as CsHCO is more expensive than KHCO , we used KHCO for
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subsequent reactions.
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a
Table 1. Reaction optimization.
N
MeO
+
O
Base
CBrCl /Solvent
N
N
NH2
3
80 °C, 5 h
OMe
1a
2a
3a
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Entry
Solvent
Base
Yield 3a
b,c
(%)
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2
3
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5
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8
9
MeCN
DMAc
KHCO
3
78 (72)
70 (57)
KHCO3
DMF
KHCO3
69 (58)
55 (44)
0
NO Me
KHCO3
2
DMSO
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
KHCO3
KHCO3
ꢀ
0
45 (29)
0
KOtBu
K CO
49 (33)
65 (60)
84 (79)
67 (54)
93 (91)
94 (91)
80 (77)
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2
3
NaHCO3
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CsHCO3
d
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KHCO3
e
13
KHCO3
KHCO3
KHCO3
KHCO3
f
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e,g
h
1
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a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol) and base (1.0 mmol) in 2 mL of 1:9 (v/v)
b
CBrCl /solvent mixture (2.0 equiv. wrt 1a) at 80 °C for 5 h. Yield from GC with respect to 2a.
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d
e
f
Isolated yields in parenthesis. 1.25 equiv. of 1a was used 1.1 equiv. of 2a was used. 1.25
g
h
equiv. of 2a used. Ratio of CBrCl /MeCN changed to 1:18 (v/v). Reaction at 50 °C.
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To further optimize the yield of 3a, the amounts of 1a, 2a and CBrCl were varied.
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Increasing 4ꢀmethoxyphenylacetone 2a to 1.25 equivalents decreased the yield of 3a to 67 %
(Table 1, entry 12). On the other hand, 93 – 94 % of 3a was obtained when 1a was increased to
overꢀstoichiometric 1.1 and 1.25 equivalents (Table 1, entries 13 and 14). Decreasing CBrCl3
from 2 to 1 equivalent and reducing the reaction temperature to 50 °C caused significant drops in
yield (Table 1, entries 15 and 16). Hence, the highest 3a yield was obtained using 1 mmol of 4ꢀ
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methoxyphenylacetone 2a together with 1.1 equivalents of 2ꢀaminopyridine 1a and 1 equivalent
of KHCO in a solvent system of CBrCl /MeCN (1:9 v/v) at 80 °C for 5 h.
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Using the optimized conditions, various phenylacetones were tested as substrates (Table 2).
Methoxyphenylacetones with OMe substituents at the para, meta, or ortho position and even
disubstituted derivatives were well tolerated (Table 2, 3a ‒ 3d). Good yields were achieved with
phenylacetone and its pꢀCl and pꢀBr derivatives (Table 2, 3e ‒ 3g). Interestingly, the cyclic
phenylacetone derivative, βꢀtetralone, also reacted smoothly with 2ꢀaminopyridine to form the
multiplyꢀfused ring product 3h with 89 % isolated yield.
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Table 2. Scope of reaction (1,3ꢀdiactivated compounds).
R3
N
R1
R2
O
KHCO
3
N
+
R2
N
NH
2
CBrCl /MeCN
3
8
0 °C, 5 h
1a
2
3
R1
N
N
N
N
N
N
N
N
OMe
OMe
OMe
OMe
OMe
91% 3a
88% 3b
90% 3c
86% 3d
N
N
N
N
N
N
N
N
Cl
Br
85% 3e
81% 3f
85% 3g
89% 3h
N
N
N
N
N
N
Cl
Br
N
N
a
Reaction conditions: 1a (1.1 equiv), 2 (1.0 mmol), and KHCO (1.0 equiv) in 2 mL of 1:9 (v/v)
3
b
CBrCl /MeCN mixture (2.0 equiv. wrt 2) at 80 °C for 5 h. Percentage isolated yields. 1 equiv.
of phenylacetophenone derivative used. Reaction time of 4 h.
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Phenylacetophenones were more reactive substrates than phenylacetones and a shorter
reaction time of 4 h was sufficient for adequate yields. Excellent yields of 95 % 3i and 97 % 3j
were obtained with phenylacetophenone and 4ꢀmethylbenzyl phenyl ketone, respectively.
However, as observed with 3a, using a lower stoichiometric ratio of 1 equivalent of
phenylacetophenone decreased the yields of 3i and 3j significantly. The reaction also proceeded
well with substituents at the other phenyl ring. Hence, 4’ꢀchloroꢀ2ꢀphenylacetophenones and 4’ꢀ
bromoꢀ2ꢀphenylacetophenones formed 3k and 3l with yields of 91 % and 93 %, respectively.
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Next, we investigated the scope of 2ꢀaminopyridines and their heteroaromatic analogues for
the reaction with derivatives of phenylacetone and phenylacetophenone (Table 3). 2ꢀ
Aminopicolines with methyl or ethyl substituent at the Cꢀ3, Cꢀ4 and Cꢀ5 position reacted
smoothly with both phenylacetone and phenylacetophenone derivatives to give excellent yields
(Table 3, 4a ꢀ 4c and 4f). Interestingly, 2ꢀaminoꢀ6ꢀmethylpyridine was unreactive with
phenylacetone and phenylacetophenone derivatives. Even after extending the reaction time to
10 h, only traces of the product was formed (Table 3, 4d). This did not improve when the
stronger base CsHCO was used. This surprising trend was also observed with 2ꢀaminoꢀ4,6ꢀ
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dimethylpyridine which likewise has a methyl group at the Cꢀ6 position (Table 3, 4e). This is in
sharp contrast to our previous observation that 2ꢀaminoꢀ6ꢀmethylpyridine was an excellent
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substrate to methyl acetoacetate (Table 3, 4d’). The results show that the reaction with
phenylacetone or phenylacetophenone derivatives is sensitive to the presence of a substituent at
the carbon adjacent to the Nꢀatom of the pyridine ring, in contrast to methyl acetoacetate. The
sluggish reaction rate for Cꢀ6 methylꢀsubstituted aminopyridines in the synthesis of 3ꢀ
phenylimidazo[1,2ꢀa]pyridine derivatives has been reported in literature and was attributed to
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a
Table 3. Scope of reaction (2ꢀaminopyridine derivatives).
R3
R3
N
O
R2
R1
KHCO3
CBrCl /MeCN
N
+
R2
N
NH2
R1
3
80 °C, 5 h
0
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Phenylacetones: R = Ar, R = Me
Phenylacetophenones: R , R = Ar
1
2
N
N
N
N
N
N
N
N
N
N
2
CO Me
OMe
OMe
OMe
94% 4bb
trace 4dc,e
MeO C
2
92% 4d'f
89% 4a
90% 4c
MeO
N
N
N
N
N
N
N
N
OMe
trace 4ec,e
92% 4fb
94% 4gb
92% 4h
N
N
S
N
Cl
Cl
N
N
N
Cl
Br
7
5% 4i
79% 4j
79 % 4k
N
N
N
N
85% 4l
92% 4m
a
Reaction conditions: 1 (1.1 equiv. with 2), 2 (1.0 mmol), and KHCO (1.0 equiv. with 2) in 2
3
mL of 1:9 (v/v) CBrCl /MeCN mixture (2.0 equiv. wrt 2) at 80 °C for 5 h. Percentage isolated
3
b
c
yields. After 4 h. Additional experiments with CsHCO and with 4ꢀmethylbenzyl phenyl ketone
3
d
. e
f
also gave trace amounts of products. 7 h reaction time 10 h reaction time. Isolated yield of 4d’
3
7
from previous work for comparison with 4d.
Both electronꢀdonating and electronꢀwithdrawing substituents, including OMe, Cl, Br, and
CO Me, on the 2ꢀaminopyridine substrate were well tolerated when coupled to various
2
derivatives of phenylacetophenones, with good to excellent yields of 75 – 95 % (Table 3, 4g ꢀ 4j).
Heteroaromatic derivatives, including 2ꢀaminothiazole, 2ꢀaminoquinoline and 1ꢀaminoisoꢀ
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quinolines, also reacted smoothly with these derivatives to give their respective desired products
with isolated yields of up to 92 % (Table 3, 4k ꢀ 4m).
The formation of imidazo[1,2ꢀa]pyridines from 2ꢀaminopyridine and 1,3ꢀdicarbonyl was
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shown to occur via a radical pathway rather than an ionic one. The reaction was severely
inhibited by the addition of the radical scavenger 2,2,6,6ꢀtetramethyl piperidinoxyl (TEMPO).
Hence, we anticipate that the reaction should be able to proceed under UV irradiation. As CBrCl3
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absorbs in the UV range with maxima at ~240 and 280 nm,
homolytic fission to CCl • and
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Br• is possible. A reaction mixture of 2ꢀaminopyridine and methyl acetoacetate in CBrCl /MeCN
3
was irradiated with UV light (30 W, UVC) at room temperature. Gratifyingly, when the reaction
mixture was worked up after 10 h, 4a was obtained in 78 % isolated yield. (Scheme 2a). The
possibility to use UV light instead of heat for the reaction is useful for substrates that are
thermally labile. We also investigated if direct αꢀbromination of methyl acetoacetate 2a’ can
occur under UV irradiation (Scheme 2b). However, this can be discounted as no monoꢀ
brominated products were observed after 5 h.
Scheme 2. Reactions under UV irradiation.
a)
UV irradiation
.1 equiv. KHCO3
N
O
O
1
+
NH2
N
N
OMe
4
mL CBrCl /MeCN
3
CO Me
4a
78% Isolated yield
2
r.t., 10 h
1
a
2a'
(1 mmol)
(
1.25 mmol)
b)
O
O
O
O
UV irradiation
OMe
OMe
4 mL CBrCl /MeCN
3
Br
2a''
Not observed
2
a'
r.t. 5 h
(
1 mmol)
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Based on these observations, the proposed mechanism is as follows (Figure 1). Upon UV
irradiation or thermal activation, chain initiation occurs with cleavage of the CꢀBr bond in
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CBrCl , forming CCl • and Br• (see Supporting Information). The CCl • removes a H• from
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the NH moiety of 2ꢀaminopyridine to form C H NH• and CHCl . The C H NH• abstracts a Br•
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6
5
from another CBrCl molecule to form the intermediate A. Intermediate A then couples to the
3
enol form of the dielectrophile 2 via an addition reaction to form the bromoꢀhemiaminal
intermediate B. A similar intermediate has been postulated in the oneꢀpot synthesis of 3ꢀ
3
2
arylimidazo[1,2ꢀa]pyridines employing NIS as the αꢀiodination source. The 2ꢀaminopyridine
a thus functions as an αꢀbromination shuttle, transferring Br from CBrCl to the enol tautomer
1
3
of 2. Dehydration of B leads to the αꢀbromo imine intermediate C which undergoes
intramolecular cyclization to form the ionic salt D. This step involves an S 2ꢀtype nucleophilic
N
attack at the αꢀcarbon. The trace amounts of products obtained with the coupling of 2ꢀamino 6ꢀ
methylpyridine with phenylacetones or phenylacetophenones can be explained by the close
Figure 1. Proposed mechanism.
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proximity of the phenyl H to the CH moiety of 2ꢀamino 6ꢀmethylpyridine which prevents the
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pyridine N atom from attacking the αꢀcarbon (Figure 2). In contrast, this steric effect is absent
when the phenyl group is replaced by an ester moiety, hence, high product yields are obtained
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ꢀ
with methyl acetoacetate. Deprotonation by HCO affords the desired product.
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Figure 2. Steric interactions during intramolecular cyclization of C.
1
Support for the mechanism comes from inꢀsitu H NMR studies (Figure 3). As proposed,
CHCl should be formed in the initial bromination of 1a to intermediate A. A mixture of 0.5
3
mmol each of 2ꢀaminopyridine and methyl acetoacetate together with 3 equivalents of CBrCl3
were added into 0.65 mL of CD CN in an NMR tube and a spectrum recorded at room
3
temperature (Run 1). A very small chloroform peak at 7.62 ppm could be observed which is due
to trace amounts of CHCl in the CBrCl solvent. The chemical shift of the CHCl peak in
3
3
3
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9
CD CN agrees with reported literature. The temperature was raised to 50 °C and the spectrum
3
measured again (Run 2). The chloroform peak became more pronounced indicating the
formation of additional CHCl . The chemical shift of ~ 0.006 ppm is due to the higher
3
temperature. To confirm that this peak was indeed that of CHCl , the reaction mixture was
3
spiked with chloroform (Run 3). The area of the peak at 7.61 ppm increased significantly,
showing unambiguously that CHCl was indeed formed as postulated.
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.75
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.5
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ppm
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Figure 3. Inꢀsitu H kinetic study using 0.5 mmol 1a, 0.5 mmol 2a’, 3 equiv. CBrCl in 0.65 mL
CD CN. Run 1 at room temperature, Run 2 at 50 °C and Run 3 at 50 °C spiked with CHCl .
3
3
3
Inset: chloroform peak.
To demonstrate the practicality and versatility of this methodology, a scaledꢀup synthesis of
3
i was conducted (Scheme 3). Using 15 mmol of phenylacetophenone and 16.5 mmol of 2ꢀ
aminopyridine, 2,3ꢀdiphenylimidazo[1,2ꢀa]pyridine, 3i, was obtained as a light yellow solid
with an isolated yield of 88 % (3.55 g) after workꢀup, purification via column chromatography
and recrystallization from ethanol.
Scheme 3. Scaledꢀup synthesis of 3ꢀphenylimidazo[1,2ꢀa]pyridine 3i
In comparison, reported protocols for the synthesis of 3i require Cu(I) or Pd(II) catalysts for
6
0−62
the coupling of bromo or iodobenzene with 2ꢀphenylimidazo[1,2ꢀa]pyridine.
Another
protocol uses Pd(II)ꢀcatalyzed Suzuki coupling of phenylboronic acid and bromoꢀ or 3ꢀiodoꢀ2ꢀ
63−65
phenylimidazo[1,2ꢀa]pyridine.
The phenylimidazo[1,2ꢀa]pyridines substrates in these
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protocols are not commercially available and need to be presynthesized. In comparison, the
present protocol using commercially available inexpensive reagents without requiring any
transition metals is straightforward and offers a much greener alternative with comparable yields
to previous methodologies found in the literature. The ease of scale up together with the wide
scope of substrates it useful for applications in the industry. However, one limitation is that it
cannot be extended to the use of 2ꢀaminopyridines with a substituent at the Cꢀ6 position due to
steric hindrance.
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CONCLUSION
In conclusion, we have demonstrated a novel and efficient protocol employing a unique αꢀ
bromination system of 2ꢀaminopyridine/CBrCl to synthesize disubstituted 3ꢀphenylimidazo[1,2ꢀ
3
a]pyridines by CꢀN/CꢀN bond formation. 2ꢀAminopyridines and phenylacetones,
phenylacetophenones or βꢀtetralones are coupled in this oneꢀpot synthesis to give good to
excellent yields at a relatively low temperature of 80 °C. Being radicalꢀbased, the reaction can
also proceed under UV radiation at room temperature. The 2ꢀaminopyridine acts both as the
substrate and an αꢀbromination shuttle, transferring a Br atom to the αꢀcarbon of its coupling
partner for inꢀsitu bromination. The synthesis was successfully scaled up to gram quantity with
88 % yield of 3i as an example. Hence, this protocol offers a practical and economical
alternative to the syntheses disclosed in earlier literature
.
EXPERIMENTAL SECTION
General information: Thin layer chromatography (TLC) was performed using TLC silica gel 60
1
F254 glass plates. Silica gel 60 (230 – 400 mesh) was used for column chromatography. The H
1
3
NMR and C NMR of samples in CDCl , DMSOꢀd or CD CN were measured using a
3
6
3
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00 MHz or 500 MHz spectrometer with tetramethylsilane (TMS) as an internal standard. For H
NMR spectra, chemical shifts were reported in ppm (δ), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet) and coupling constant (Hz). Detection and analysis of
compounds by gas chromatography and gas chromatography mass spectrometry were performed.
Mass spectra measurements were recorded on TOFQ under electrospray ionization (ESI) mode.
Melting points were recorded with samples in capillary tubes using an automated melting point
system. The following chemicals were purchased and used as received: CBrCl , KHCO ,
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3
CsHCO , MeCN, and derivatives of phenylacetones, phenylacetophenones and 2ꢀaminopyridine.
3
Representative procedure for formation of 3-phenylimidazo[1,2-a]pyridines: A 10 mL
roundꢀbottomed flask was charged with 2ꢀaminopyridine 1a (104 mg, 1.1 mmol), 4ꢀ
methoxyphenylacetone 2a (107.9 µL, 1 mmol) and KHCO (100 mg, 1.0 mmol in 2 mL of
3
CBrCl /MeCN solvent mixture (1/9 v/v). The reaction mixture was stirred at 80 °C for 5 h.
3
Thereafter, the reaction was diluted with H O and extracted with EtOAc (15 mL × 5). The
2
combined organic layers were washed with brine and dried with anhydrous Na SO . After
2
4
filtration, the solvent was removed by rotary evaporation and the residue was cleaned up by
column chromatography using ethyl acetate and hexane (v/v = 4/1) as eluent to afford 3a in 91 %
yield.
Scaled-up synthesis for compound 3i: A 100 mL roundꢀbottomed flask was charged with 2ꢀ
aminopyridine 1a (1.55 g, 16.5 mmol), 2ꢀphenylacetophenone (2.94, 15.0 mmol) and KHCO3
(1.50 g, 15.0 mmol) in 300 mL of CBrCl /MeCN solvent mixture (1/9 v/v). The reaction mixture
3
was stirred at 80 °C for 5 h. Thereafter, the reaction was diluted with H O and extracted with
2
EtOAc (200 mL × 5). The combined organic layers were washed with brine and dried with
anhydrous Na SO . After filtration, the solvent was removed by rotary evaporation and the
2
4
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residue was cleaned up by column chromatography using hexane and ethyl acetate (v/v = 4/1) as
eluent. Further recrystallization with ethanol afforded 3i in 88 % yield.
3-(4-Methoxyphenyl)-2-methylimidazo[1,2-a]pyridine (3a): Obtained as
a
brown
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14
15
16
17
18
19
20
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22
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24
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27
28
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1
amorphous solid; yield: 216 mg (91 %). H NMR (300 MHz, CDCl ) δ 8.00 (d, J = 6.9 Hz, 1H),
3
7
2
1
.53 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.7 Hz,
1
3
H), 6.68 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 2.43 (s, 3H); C NMR (300 MHz, CDCl ) δ 159.4,
3
44.2, 140.5, 130.9, 123.8, 123.0, 121.5, 121.1, 116.8, 114.6, 111.7, 55.3, 13.7. HRMS (ESI)
+
calcd for C H N O [M+H] : 239.1179; found 239.1181.
15 15
2
3-(3-Methoxyphenyl)-2-methylimidazo[1,2-a]pyridine (3b): Obtained as
a
brown
1
amorphous solid; yield: 210 mg (88 %). H NMR (300 MHz, CDCl ) δ 8.07 (d, J = 6.9 Hz, 1H),
3
7
.51 (d, J = 9.0 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.5 Hz,
1
3
1
H), 6.96ꢀ6.89 (m, 2H), 6.65 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 2.45 (s, 3H); C NMR (300 MHz,
CDCl ) δ 160.0, 144.3, 140.8, 130.6, 130.1, 123.9, 123.0, 121.5, 121.1, 116.8, 115.0, 113.2,
3
+
111.7, 55.2, 13.8. HRMS (ESI) calcd for C H N O [M+H] : 239.1179; found 239.1182.
1
5
15
2
3
-(2-Methoxyphenyl)-2-methylimidazo[1,2-a]pyridine (3c): Obtained as
a
brown
1
amorphous solid; yield: 215 mg (90 %). H NMR (300 MHz, CDCl ) δ 7.62 (d, J = 6.6 Hz, 1H),
3
7.53 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.12ꢀ6.99 (m, 3H),
13
6
.63 (t, J = 6.8 Hz, 1H), 3.72 (s, 3H), 2.40 (s, 3H); C NMR (300 MHz, CDCl ) δ 157.4, 144.5,
3
1
41.2, 132.3, 130.0, 124.5, 123.5, 120.8, 118.6, 117.8, 116.4, 111.1, 110.9, 55.2, 13.8. HRMS
+
(ESI) calcd for C H N O [M+H] : 239.1179; found 239.1181.
1
5
15
2
3
-(3,4-diMethoxyphenyl)-2-methylimidazo[1,2-a]pyridine (3d): Obtained as a brown
1
amorphous solid; yield: 231 mg (86 %). H NMR (300 MHz, CDCl ) δ 8.03 (d, J = 6.9 Hz, 1H),
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.53 (d, J = 9.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 2H), 7.00 (s, 2H), 7.00 (s, 2H), 6.92 (s, 1H), 6.70 (t,
1
3
J = 6.8 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 2.45 (s, 3H); C NMR (300 MHz, CDCl ) δ 149.4,
3
149.0, 144.0, 140.3, 124.0, 123.0, 122.4, 121.6, 121.3, 116.7, 112.6, 111.9, 111.7, 56.0, 55.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
13.7. HRMS (ESI) calcd for C H N O [M+H] : 269.1285; found 269.1286.
1
6
17
2
2
6
6
2
-Methyl-3-phenylimidazo[1,2-a]pyridine (3e): Obtained as a brown oil; yield: 177 mg
1
(85 %). H NMR (300 MHz, CDCl ) δ 8.07 (d, J = 6.9 Hz, 1H), 7.57ꢀ7.47 (m, 3H), 7.46ꢀ7.36 (m,
3
1
3
3H), 7.12 (t, J = 7.8 Hz, 1H), 6.68 (t, J = 6.9 Hz, 1H), 2.46 (s, 3H); C NMR (300 MHz, CDCl )
3
δ 144.3, 140.8, 129.4, 129.3, 129.1, 128.0, 124.0, 122.9, 121.4, 116.8, 111.8, 13.8. HRMS (ESI)
+
calcd for C H N [M+H] : 209.1073; found 209.1075.
1
4
13
2
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3
-(4-Chlorophenyl)-2-methylimidazo[1,2-a]pyridine (3f): Obtained as a brown amorphous
1
solid; yield: 196 mg (81 %). H NMR (300 MHz, CDCl ) δ 8.03 (d, J = 6.9 Hz, 1H), 7.58 (d, J =
3
9.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 6.74 (t, J
1
3
=
6.9 Hz, 1H), 2.46 (s, 3H); C NMR (300 MHz, CDCl ) δ 144.5, 141.1, 134.1, 130.7, 129.5,
3
+
1
27.8, 124.5, 122.8, 120.3, 117.0, 112.2, 13.8. HRMS (ESI) calcd for C H ClN [M+H] :
14
12
2
243.0684; found 243.0682.
3-(4-Bromophenyl)-2-methylimidazo[1,2-a]pyridine (3g): Obtained as a brown solid; yield:
1
245 mg (85 %). H NMR (300 MHz, CDCl ) δ 7.99 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H),
3
7.51 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 6.68 (t, J = 6.8 Hz,
1
3
1H), 2.41 (s, 3H); C NMR (300 MHz, CDCl ) δ 144.5, 141.1, 132.3, 130.8, 128.2, 124.2, 122.7,
3
+
122.0, 120.1, 116.9, 112.0, 13.7. HRMS (ESI) calcd for C H ClN [M+H] : 243.0684; found
1
4
12
2
243.0682.
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,3-Dihydronaphthylimidazo[1,2-a]pyridine (3h): Obtained as a yellowishꢀbrown
1
amorphous solid; yield: 196 mg (89 %). H NMR (300 MHz, CDCl ) δ 8.55 (d, J = 6.9 Hz, 1H),
3
7
.62 (d, J = 9.0 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.15 (q, J = 6.6 Hz, 2H), 6.87 (t, J = 6.9 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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41
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1
H), 3.05 (s, 4H); C NMR (300 MHz, CDCl ) δ 146.6, 145.9, 135.3, 128.8, 128.1, 126.7, 124.0,
3
+
123.5, 119.5, 118.6, 117.6, 112.7, 30.1, 23.9. HRMS (ESI) calcd for C H N [M+H] :
1
5
13
2
2
21.1073; found 221.1072.
5
0
2,3-Diphenylimidazo[1,2-a]pyridine (3i): Obtained as a light yellow solid; yield: 257 mg
1
(
95 %). H NMR (300 MHz, CDCl ) δ 7.83 (d, J = 6.3 Hz, 1H), 7.71ꢀ7.57 (m, 3H), 7.43ꢀ7.29 (m,
3
1
3
5
H), 7.25ꢀ7.13 (m, 3H), 7.06 (t, J = 7.8 Hz, 1H), 6.57 (t, J = 6.5 Hz, 1H); C NMR (300 MHz,
CDCl ) δ 144.4, 142.0, 133.9, 130.2, 129.4, 129.1, 128.5, 127.9, 127.7, 127.1, 124.2, 122.8,
3
+
1
20.6, 117.0, 111.8. HRMS (ESI) calcd for C H N [M+H] : 271.1230; found 271.1229.
1
9
15
2
6
1
2-Phenyl-3-p-tolylimidazo[1,2-a]pyridine (3j): Obtained as a light yellow solid; yield: 275
1
mg (97 %). H NMR (300 MHz, CDCl ) δ 7.87 (d, J = 6.9 Hz, 1H), 7.70 (d, J = 6.9 Hz, 2H),
3
7
.64 (d, J = 9.0 Hz, 1H), 7.30ꢀ7.18 (m, 7H), 7.10 (t, J = 7.8 Hz, 1H), 6.61 (t, J = 6.9 Hz, 1H)
1
3
2.40 (s, 3H); C NMR (300 MHz, CDCl ) δ 144.4, 141.9, 138.5, 134.1, 130.3, 130.0, 128.0,
3
1
27.8, 127.1, 126.5, 124.2, 123.0, 120.9, 117.2, 111.9, 21.2. HRMS (ESI) calcd for C H N
20 17 2
+
[
M+H] : 285.1386; found 285.1384.
66
2
-(4-Chlorophenyl)-3-phenylimidazo[1,2-a]pyridine (3k): Obtained as a light yellow
1
solid; yield: 276 mg (91 %). H NMR (300 MHz, CDCl ) δ 7.65 (d, J = 6.6 Hz, 1H), 7.47ꢀ7.39
3
(m, 3H), 7.30ꢀ7.11 (m, 5H), 7.01 (d, J = 8.1 Hz, 2H), 6.90 (t, J = 7.7 Hz, 1H), 6.40 (t, J = 6.5 Hz,
13
1
H); C NMR (300 MHz, CDCl ) δ 144.1, 140.5, 132.6, 132.3, 129.9, 129.0, 128.8, 128.6,
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
5
5
5
5
6
+
1
28.4, 127.8, 124.2, 122.5, 120.5, 116.7, 111.7. HRMS (ESI) calcd for C H Cl N [M+H] :
19 14 2
3
05.0840; found 305.0843.
67
2
-(4-Bromophenyl)-3-phenylimidazo[1,2-a]pyridine (3l): Obtained as a yellow solid;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield: 321 mg (92 %). H NMR (300 MHz, CDCl ) δ 7.91 (d, J = 6.9 Hz, 1H), 7.65 (d, J = 9.0
3
Hz, 1H), 7.55ꢀ7.46 (m, 5H), 7.43ꢀ7.35 (m, 4H), 7.18 (t, J = 7.4 Hz, 1H), 6.71 (t, J = 6.8 Hz, 1H);
13
C NMR (300 MHz, CDCl ) δ 144.1, 141.0, 133.1, 131.3, 130.5, 129.6, 129.5, 129.4, 129.0,
3
+
128.7, 124.9, 123.2, 121.5, 117.4, 112.4. HRMS (ESI) calcd for C H Br N [M+H] : 349.0335;
1
9
14
2
found 349.0338.
3
-(4-Methoxyphenyl)-2,8-dimethylimidazo[1,2-a]pyridine (4a): Obtained as a brown
1
amorphous solid; yield: 226 mg (89 %). H NMR (300 MHz, CDCl ) 7.81 (d, J = 6.6 Hz, 1H),
3
7
.28 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 6.6 Hz, 1H), 6.53 (t, J = 6.8 Hz,
1
3
1H), 3.79 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H); C NMR (300 MHz, CDCl ) δ 159.2, 144.3, 139.4,
3
1
30.7, 129.4, 126.2, 122.7, 121.5, 120.7, 114.4, 111.6, 55.1, 16.9, 13.5. HRMS (ESI) calcd for
+
C H N O [M+H] : 253.1335; found 253.1337.
16
17
2
7
-Methyl-2-phenyl-3-p-tolylimidazo[1,2-a]pyridine (4b): Obtained as a light yellow solid;
1
yield: 281 mg (94 %); m.p. 150 ꢀ 152 °C. H NMR (300 MHz, CDCl ) δ 7.74 (d, J = 6.9 Hz, 1H),
3
7.68 (d, J = 6.9 Hz, 2H), 7.39 (s, 1H), 7.27ꢀ7.15 (m, 7H), 6.44 (d, J = 6.9 Hz, 1H), 2.38 (s, 3H),
13
2
.32 (s, 3H); C NMR (300 MHz, CDCl ) δ 144.9, 141.5, 138.3, 135.2, 134.2, 130.2, 129.9,
3
1
27.9, 127.7, 126.9, 126.7, 122.2, 120.3, 115.5, 114.5, 21.1, 21.0. HRMS (ESI) calcd for
+
C H N [M+H] : 299.1543; found 299.1545.
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-(4-Mehoxyphenyl)-2,6-dimethylimidazo[1,2-a]pyridine (4c): Obtained as a brown
1
amorphous solid; yield: 227 mg (90 %). H NMR (300 MHz, CDCl ) δ 7.89 (d, J = 6.9 Hz, 1H),
3
7
.37ꢀ7.27 (m, 3H), 7.04 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 6.9 Hz, 1H), 3.87 (s, 3H), 2.41 (s, 3H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2
.37 (s, 3H); C NMR (300 MHz, CDCl ) δ 159.3, 144.4, 139.6, 135.1, 130.8, 122.3, 121.6,
3
+
120.6, 115.1, 114.6, 114.5, 55.3, 21.2, 13.6. HRMS (ESI) calcd for C H N O [M+H] :
16
17
2
2
53.1335; found 253.1333.
7-Ethyl-2-phenyl-3-p-tolylimidazo[1,2-a]pyridine (4f): Obtained as a light yellow solid;
1
yield: 288 mg (92 %). H NMR (300 MHz, CDCl ) δ 7.78 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 6.9 Hz,
3
2
H), 7.44 (s, 1H), 7.28ꢀ7.17 (m, 7H), 6.51 (d, J = 7.2 Hz, 1H), 2.64 (q, J = 7.5 Hz, 2H), 2.39 (s,
1
3
3H), 1.24 (t, J = 7.5 Hz, 3H); C NMR (300 MHz, CDCl ) δ 145.2, 141.8, 141.5, 138.5, 134.4,
3
1
30.5, 130.1, 128.1, 127.9, 127.1, 126.9, 122.6, 120.5, 114.3, 113.7, 28.3, 21.4, 14.4. HRMS
+
(
ESI) calcd for C H N [M+H] : 313.1699; found 313.1703.
2
2
21
2
7
-Methoxy-2-phenyl-3-p-tolylimidazo[1,2-a]pyridine (4g): Obtained as a yellow solid;
1
yield: 297 mg (94 %); m.p. 149 ꢀ 151 °C. H NMR (300 MHz, CDCl ) δ 7.67ꢀ7.59 (m, 3H),
3
1
3
7.23ꢀ7.10 (m, 7H), 6.86 (s, 1H), 6.30 (d, J = 7.5 Hz, 1H), 3.74 (s, 3H), 2.33 (s, 3H); C NMR
(
300 MHz, CDCl ) δ 157.6, 145.7, 141.0, 138.2, 134.1, 130.2, 129.8, 127.8, 127.4, 126.8, 126.5,
3
+
1
23.4, 119.7, 106.7, 94.1, 55.0, 21.0. HRMS (ESI) calcd for C H N O [M+H] : 315.1492;
21 19
2
found 315.1494.
Methyl 2-phenyl-3-p-tolylimidazo[1,2-a]pyridine-7-carboxylate (4h): Obtained as a light
1
yellow solid; yield: 315 mg (92 %). H NMR (300 MHz, CDCl ) δ 8.34 (s, 1H), 7.89 (d, J = 7.2
3
13
Hz, 1H), 7.64 (d, J = 6.9 Hz, 2H), 7.29ꢀ7.19 (m, 8H), 3.88 (s, 3H), 2.40 (s, 3H); C NMR (300
MHz, CDCl ) δ 165.4, 144.6, 143.3, 139.1, 133.5, 130.2, 130.1, 128.1, 127.9, 127.6, 125.8,
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5
5
5
5
5
5
5
5
6
+
1
25.4, 122.6, 122.5, 119.9, 111.2, 52.2, 21.2. HRMS (ESI) calcd for C H N O [M+H] :
22 19 2 2
3
43.1441; found 343.1444.
6
-Chloro-2-(4-chlorophenyl)-3-phenylimidazo[1,2-a]pyridine (4i): Obtained as a light
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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6
7
8
9
0
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yellow solid; yield: 254 mg (75 %); m.p. 187 ꢀ 189 °C. H NMR (300 MHz, CDCl ) δ 7.91 (s,
3
1
H), 7.63ꢀ7.50 (m, 6H), 7.42 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 9.6 Hz,
13
1
H); C NMR (300 MHz, CDCl ) δ 143.1, 142.2, 133.6, 132.2, 130.5, 129.8, 129.5, 129.2,
3
+
128.9, 128.5, 126.2, 121.7, 121.1, 120.8, 117.9. HRMS (ESI) calcd for C H Cl N [M+H] :
19
13
2
2
3
39.0450; found 339.0451.
6
-Bromo-2-phenyl-3-p-tolylimidazo[1,2-a]pyridine (4j): Obtained as a yellow solid; yield:
1
2
88 mg (79 %); m.p. 214 ꢀ 216 °C. H NMR (300 MHz, CDCl ) δ 8.03 (s, 1H), 7.67 (d, J = 7.8
3
13
Hz, 2H), 7.55 (d, J = 9.3 Hz, 1H), 7.33ꢀ7.19 (m, 8H), 2.45 (s, 3H); C NMR (300 MHz, CDCl )
3
δ 142.9, 142.9, 139.2, 133.7, 130.3, 128.2, 127.8, 127.7, 127.6, 126.0, 123.2, 121.4, 118.0, 106.9,
+
21.4. HRMS (ESI) calcd for C H BrN [M+H] : 363.0491; found 363.0494.
2
0
16
2
6-(4-chlorophenyl)-5-phenylimidazo[2,1-b]thiazole (4k): Obtained as a yellow solid; yield:
1
2
46 mg (79 %). H NMR (300 MHz, CDCl ) δ 7.53 (d, J = 8.7 Hz, 2H), 7.45ꢀ7.37 (m, 5H), 7.32
3
1
3
(
d, J = 4.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 4.5 Hz, 1H); C NMR (300 MHz,
CDCl ) δ 149.0, 142.1, 132.8, 132.8, 130.0, 129.2, 129.0, 128.6, 128.5, 128.3, 122.9, 117.3,
3
+
1
12.7. HRMS (ESI) calcd for C H ClN S [M+H] : 311.0404; found 311.0407.
1
7
12
2
2-Phenyl-1-p-tolylimidazo[1,2-a]quinoline (4l): Obtained as a yellow solid; yield: 284 mg
1
(
85 %); m.p. 182 ꢀ 184 °C. H NMR (300 MHz, CDCl ) δ 8.79 (d, J = 8.4 Hz, 1H), 7.58 (d, J =
3
6
.9 Hz, 2H), 7.49ꢀ7.41 (m, 3H), 7.38ꢀ7.26 (m, 5H), 7.23 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.1 Hz,
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H), 6.79 (d, J = 9.6 Hz, 1H), 2.33 (s, 3H); C NMR (300 MHz, CDCl ) δ 181.2, 155.5, 140.1,
3
38.1, 137.6, 137.0, 134.8, 130.9, 129.3, 129.2, 128.5, 128.4, 127.8, 127.3, 127.2, 125.3, 122.3,
+
18.7, 115.8, 21.0. HRMS (ESI) calcd for C H N [M+H] : 335.1543; found 335.1545.
2
4
19
2
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
25
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53
54
55
56
57
58
59
60
2
-Phenyl-3-p-tolylimidazo[2,1-a]isoquinoline (4m): Obtained as a yellow solid; yield: 306
1
mg (92 %); m.p. 138 ꢀ 140 °C. H NMR (300 MHz, CDCl ) δ 8.83 (d, J = 7.5 Hz, 1H), 7.79 (d, J
3
=
6.9 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.1 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.39ꢀ
1
3
7.25 (m, 7H), 6.93 (d, J = 7.5 Hz, 1H), 2.47 (s, 3H); C NMR (300 MHz, CDCl ) δ 142.2, 140.2,
3
1
38.7, 134.5, 130.6, 130.1, 129.5, 128.2, 128.0, 127.9, 127.8, 127.0, 126.7, 126.7, 123.8, 123.4,
+
1
23.0, 121.0, 112.6, 21.4. HRMS (ESI) calcd for C H N [M+H] : 335.1543; found 335.1545.
24
19
2
Acknowledgements
Financial support from the Ministry of Education ARC Tier 1 Grant numbers Rꢀ143ꢀ000ꢀ603ꢀ
12 and Rꢀ143ꢀ000ꢀ550ꢀ112 is gratefully acknowledged. I. I. Roslan thanks NUS for the award
1
of an NUSꢀPGF Scholarship.
Supporting Information
1
13
H, C NMR and HSQC spectra and a proposed reaction mechanism for the initial bromination
are given in the Supporting Information.
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