2-Aminopyridines as an α-Bromination Shuttle in a Transition Metal-Free One-Pot Synthesis of Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/adsc.201501012

A wide range of imidazo[1,2-a]pyridines are accessible from cheap and readily available 2-aminopyridines and 1,3-dicarbonyl compounds using a unique CBrCl₃/2-aminopyridine system for bromination at the α-carbon. 2-Aminopyridine is not only the substrate but also acts as a bromination shuttle, transferring the bromine atom from CBrCl₃ to the α-carbon of the 1,3-dicarbonyl. The reaction mechanism involves a series of reversible steps, including an addition reaction with cyclic transition state, to form a bromo-hemiaminal intermediate. Isolated yields of up to 97% were obtained under mild conditions and at short reaction times in this transition metal-free, one-pot synthesis.

Full text of DOI:10.1002/adsc.201501012

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DOI: 10.1002/adsc.201501012
2-Aminopyridines as an a-Bromination Shuttle in a Transition
Metal-Free One-Pot Synthesis of Imidazo[1,2-a]pyridines
Irwan Iskandar Roslan,a Kian-Hong Ng,a Gaik-Khuan Chuah,a,*
and Stephan Jaenickea,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Fax: (+65)-6779-1691; phone: (+65)-6516-2918; e-mail: chmcgk@nus.edu.sg or chmsj@nus.edu.sg
Received: November 4, 2015; Revised: November 17, 2015; Published online: January 18, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501012.
Abstract: A wide range of imidazo[1,2-a]pyridines
are accessible from cheap and readily available 2-
aminopyridines and 1,3-dicarbonyl compounds
using a unique CBrCl3/2-aminopyridine system for
bromination at the a-carbon. 2-Aminopyridine is
not only the substrate but also acts as a bromination
shuttle, transferring the bromine atom from CBrCl3
to the a-carbon of the 1,3-dicarbonyl. The reaction
mechanism involves a series of reversible steps, in-
cluding an addition reaction with cyclic transition
state, to form a bromo-hemiaminal intermediate.
Isolated yields of up to 97% were obtained under
mild conditions and at short reaction times in this
transition metal-free, one-pot synthesis.
field of materials science.[5] Thus, the synthesis of imi-
dazo[1,2-a]pyridines has become an attractive target
for chemists over the last decade.[6] Many synthetic
routes have been explored that involve the condensa-
tion of a-halo ketones, 1-bromo-2-phenylacetylenes,
a-diazo ketones or nitroolefins with 2-aminopyri-
dine.[7] Multicomponent reactions have also been de-
veloped involving 2-aminopyridine and aldehydes, to-
gether with isonitriles, alkyne or nitroalkanes.[8] More
recently, oxidative coupling has been employed to
connect 2-aminopyridines with alkenes, alkynes or ke-
tones, which utilizes readily available substrates and
catalysts to achieve the transformation.[9] The reaction
between 2-aminopyridines, a-halo carbonyl and 1,3-
dicarbonyl compounds is a practical method with
wide applications in medicinal chemistry and drug
synthesis.[10] However, most of these a-halo-substitut-
ed compounds are either expensive or not commer-
cially available and thus require additional steps for
their synthesis.
À
À
Keywords: bromination; C H activation; C N
bond formation; cyclization; fused ring systems
Here, we report a one-pot, transition metal-free
Imidazo[1,2-a]pyridines are an important class of synthesis of imidazo[1,2-a]pyridines from easily avail-
fused heterocyclic compounds which represent a privi- able 2-aminopyridines and 1,3-dicarbonyls. Yu et al.
leged scaffold that fulfils Lipinskiꢀs rule of fives for had pioneered a protocol using these substrates with
drugs with good oral bioavailability.[1] This scaffold is bis(acetyloxy)(phenyl)-l3-iodane as an oxidant and
present in compounds with a wide spectrum of biolog- BF3·Et2O as a catalyst.[11] It is proposed that the reac-
ical activities including antifungal, antiproliferative, tion proceeds via an in-situ generated a-iodinated in-
anti-inflammatory, antiulcer, antiapoptotic and antivi- termediate. The group also disclosed another synthet-
ral properties.[2]
ic route using TBHP as the oxidant and a different
Several drugs containing the imidazo[1,2-a]pyridine catalyst, TBAI-BF3·Et2O.[12] However, these protocols
framework have indeed been developed including zol- suffer from long reaction times (9 to 48 h), and isolat-
pidem (insomnia treatment), alpidem and saripidem ed yields were less than 83%. Furthermore, the use of
(anxiolytic agents), olprinone (acute heart failure toxic BF3·Et2O or the highly reactive TBHP makes
treatment), zolimidine (treatment of peptic ulcers), the reactions unsuitable for large-scale synthesis.
and miroprofen (antiplatelet aggregation).[3] Imida-
In contrast to these methodologies, we have devised
zo[1,2-a]pyridines are known to be highly potent res- a simple oxidant-free strategy using CBrCl3 as cosol-
piratory syncytial virus fusion inhibitors, mitotic kine- vent and source of Br with 2-aminopyridine as an a-
sin inhibitors, and have been developed as a GABAA bromination shuttle (Scheme 1). CBrCl3 has a relative-
receptor positive allosteric modulator.[4] In addition, ly low boiling point, thus allowing easy separation. To
imidazo[1,2-a]pyridines have found applications in the the best of our knowledge, this is the first example
364
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2-Aminopyridines as an a-Bromination Shuttle
between methyl acetoacetate 1a and 1.5 equivalents
of 2-aminopyridine 2a using NaHCO3 as a base at
808C for 8 h (Table 1, entries 1–6). Two products were
formed: the desired 3aa was the major product with
amide 4 as a minor product. While 3aa was obtained
in aprotic solvents, non-polar solvents proved unsuita-
ble for this reaction. The best yield of 3aa was 92%.
Without NaHCO3, the yield of 3aa dropped signifi-
cantly (Table 1, entry 7) due to a competing reaction
forming the side product 4H-pyrido[1,2-a]pyrimidin-4-
one. We have previously shown that the coupling of
1a with 2a to form 4H-pyrido[1,2-a]pyrimidin-4-ones,
is acid-catalyzed.[13] Thus, by adding a base such as
NaHCO3, the liberated HBr is neutralized, preventing
the formation of this heterocyclic side product.
A number of basic salts were screened during the
optimization process keeping a constant reaction time
of 5 h (Table 1, entries 8–11). Interestingly, KHCO3
gave much higher yields than NaHCO3. Similarly,
K2HPO4 performed better than the corresponding
Na+ salt, although the yield was significantly lower
than with the bicarbonates (Table 1, entries 10 and
11). It appears that the nature of the cation signifi-
cantly affects the yield of 3aa. We were delighted to
Scheme 1. Comparison of the coupling reaction developed
by Yu et al.[12] and that used in the present work.
where the substrate is used as a Br shuttle, transfer- find that reducing the excess of 2-aminopyridine from
ring the Br atom to another substrate molecule 1.5 to 1 with respect to 1a did not affect the yield
before initiating a domino reaction which ultimately (Table 1, entries 12 and 13). Hence, high yields of 3aa
forms the cyclized product.
can be obtained after 5 h at 808C using 1 mmol each
Several solvent combinations always containing of 1a and 2a, with 1.1 mmol of KHCO3 in 2 mL 1/9
10% v/v of CBrCl3 were first tested for the reaction (v/v) CBrCl3/MeCN as solvent system.
Table 1. Optimization parameters for synthesis of imidazo[1,2-a]pyridines.[a]
Entry
Solvent
Base
Time [h]
Conversion [%][b]
Yield of 3aa [%][c]
Yield of 4a [%]
1
2
3
4
5
6
7
8
DME
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
–
NaHCO3
KHCO3
Na2HPO4
K2HPO4
KHCO3
KHCO3
8
8
8
8
8
8
8
5
5
5
5
5
5
38
58
94
85
8
35 (15)
45 (29)
92 (85)
83 (73)
8
3
13
2
2
0
0
0
0
0
0
0
0
0
NO2Me
MeCN
DMF
dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
0
98
77
98
36
62
99
97
63 (39)
77 (71)
98 (93)
36 (14)
62 (47)
99 (95)
97 (93)
9
10
11
12[d]
13[e]
[a]
Reaction conditions: 1a (1.0 mmol), 2a (1.5 equiv) and base (1.1 mmol) in 2 mL of 1:9 (v/v) CBrCl3/solvent mixture (con-
taining 2.0 mmol CBrCl3).
[b]
[c]
[d]
[e]
Conversion (from GC) with respect to 1a.
Isolated yields in parenthesis.
1.25 equiv. of 2a were used.
1.0 equiv. of 2a was used.
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Irwan Iskandar Roslan et al.
Table 2. Scope of reaction.[a]
The scope of the reaction was tested using the opti-
mized conditions (Table 2). The reactions proceeded
with excellent yields when various b-keto esters, in-
cluding alkyl, cyclic and methoxyethyl esters, were re-
acted with 2 (Table 2, 3aa– 3ga). Good to excellent
yields were obtained with various types of b-keto
amides (Table 2, 3ha–3ja). b-Keto esters with more
sterically demanding tert-butyl and phenyl groups also
reacted smoothly, but required longer reaction times
of 7–10 h (Table 2, 3ka–3oa). Good to excellent yields
were also obtained with 1,3-diketones and 1,3-cyclo-
hexanedione (Table 2, 3pa and 3qa).
Various substituted 2-aminopyridines were reacted
with 1a using the optimized condition. Excellent
yields were obtained with substrates bearing a methyl
group at C-3, C-4, C-5 or C-6 of the 2-aminopyridine
structural motif. Likewise, ethyl- or dimethyl-substi-
tuted 2-aminopyridines reacted smoothly (Table 2,
3ab–3ag). Electron-donating OMe and various elec-
tron-withdrawing substituents, including Cl, Br, and
CO2Me were well tolerated, but longer reaction times
were needed when the aminopyridine contained an
electron-withdrawing substituent (Table 2, 3ah–3ak).
We were elated to see that reactions with 2-aminoqui-
nolines and 1-aminoisoquinolines proceeded to give
excellent yields of 3al and 3am under the optimized
conditions.
To gain some insight into the reaction mechanism,
a mechanistic study was performed (Scheme 2). There
is some ambiguity about the nature of the a-bromina-
tion of 1,3-dicarbonyls and their derivatives with
CBrCl3 as brominating reagent. Meyers et al. reported
that the bromination proceeded via a base-initiated
(KOH-t-BuOH) radical anion–radical pair (RARP)
mechanism.[14] On the other hand, an ionic mechanism
has also been proposed.[15] To determine whether the
reaction proceeds via a radical or an ionic pathway,
a radical scavenger 2,2,6,6-tetramethylpiperidine 1-
oxyl (TEMPO) was added into a typical reaction
using the optimized conditions (Scheme 2, reaction A,
i and ii). With 1 equivalent of TEMPO, the yield was
reduced to 52%. The yield dropped further to only
11% when 2 equivalents of TEMPO were added.
These results provide strong support that the reaction
proceeds via a radical pathway, involving CCl3C and
BrC.
We next investigated the a-bromination reaction
with CBrCl3. Hori and co-workers reported that 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) mediates the
bromination of 1,3-dicarbonyl compounds with
[16]
CBrCl3 whereas Sasson et al. found that quaternary
[a]
Reaction conditions: 1 (1.0 mmol), 2 (1.0 equiv.) and
KHCO3 (1.1 equiv.) in 2 mL of 1:9 (v/v) CBrCl3/MeCN
mixture (2.0 mmol with rerspect to CBrCl3). Percentage
isolated yield.
After 7 h.
ammonium fluoride salts were good catalysts for the
bromination of similar functionalities.[17] Only the
weak bases KHCO3 and 2-aminopyridine were pres-
ent in our reaction; the latter is also a substrate in the
reaction. To establish whether these bases could cata-
lyze the bromination of 1a at the a-position, three
[b]
[c]
After 10 h.
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2-Aminopyridines as an a-Bromination Shuttle
is stabilized by intramolecular H-bonding. As MeCN
is polar, it can potentially disrupt the intramolecular
H-bonding since it is present in a large excess. Na+
and K+ reduce this disruption via ion-dipole interac-
tion with MeCN and thus promote the enol form. The
interaction is stronger with the more electropositive
K+ ion, which could explain the increase in reactivity
compared to that of Na+ (Table 1, entries 7 and 8).
The enol then undergoes an addition reaction with B
which involves a cyclic 6p-transition state to form the
bromo-hemiaminal intermediate C. A similar inter-
mediate has been proposed by Lee et al. in the one-
pot synthesis of 3-arylimidazo[1,2-a]pyridines using
NIS as the a-iodination source.[18] The 2-aminopyri-
dine thus acts as a shuttle for the a-bromination,
transferring Br from CBrCl3 to the enol tautomer of
1a through a series of reversible steps. Dehydration
results in the a-bromo imine intermediate D, followed
by a ring-closing nucleophilic attack at the a-carbon
À
to form E. Deprotonation by HCO3 then yields 3aa.
The role of KHCO3 in removing HBr with release of
CO2 provides the driving force to shift the equilibri-
um forward. Indeed, substituting KHCO3 with phos-
phate dibasic salts gave lower yields of 3aa as no CO2
was evolved (Table 1, entries 7–10). The competing
formation of the N-acylated product is proposed to
proceed following mechanism B in Figure 1. The NH2
group undergoes a nucleophilic addition at the ketone
functionality of the b-keto ester, forming hemiaminal
intermediate F. This undergoes a 1,5-H shift, forming
the N-acylated product 4 and releasing methyl acetate
in the process. The small amount of 4 compared to
3aa (Table 1, entry 8) shows that a nucleophilic attack
on the ketone moiety of 1a is less likely compared to
the bromination step. With 2-aminopyridine, the for-
mation of a 6-membered ring transition state facili-
tates the bromine transfer. In contrast, 3-aminopyri-
dine and 4-aminopyridine cannot form such a transi-
Scheme 2. Mechanistic studies to (A) distinguish between
a radical or ionic pathway and to determine the role of (B)
KHCO3 and (C) 3/4-aminopyridines as a base.
sets of experiments were conducted where KHCO3 tion state and instead the N-acylated products 4’ and
was used alone and in combination with 3-aminopyri- 4’’, are formed instead.
dine and 4-aminopyridine (Scheme 2, reactions B and
Another possible mechanism for the formation of
C). No monobrominated products were observed in hemiaminal intermediate C is via a direct nucleophilic
any of these experiments, ruling out KHCO3 and 3- addition of NH2 of 2a to the ketone moiety of 1a,
or 4-aminopyridine as bases for the a-bromination of forming intermediate F followed by bromination at its
1a. It is interesting that, with 3- and 4-aminopyridines, a-carbon (Scheme 3 in the Supporting Information).
1
the N-acylated side products 4’ and 4’’ were formed, To investigate this, H and 13C NMR measurements
albeit in low yields (<35%), whereas 2-aminopyri- were conducted on a reaction mixture of 0.5 mmol 1a
dines gave only traces of 4 (Table 1, entry 8). With with 0.5 mmol 2a in CD3CN at 508C after 2 h (Sup-
the NH2 group adjacent to the pyridine N-atom, the porting Information, pages S44–S46). Only the physi-
competing N-acylation reaction is apparently effec- cal mixture of 1a and 2a was detected without any ob-
tively suppressed.
servable changes, showing that the reaction did not
Based on these results, we propose a plausible occur via an initial nucleophilic addition of 2a to 1a.
mechanism for the reaction (Figure 1, mechanism A). This lends support to the hypothesis that 2-aminopyri-
Bromination of 2a at the NH2 group occurs via a radi- dine acts as an a-bromination shuttle.
cal reaction forming intermediate A which rearranges
In summary, we have developed a new a-bromina-
to form B containing a brominated pyridine N atom. tion system CBrCl3/2-aminopyridine for the one-pot
À
The tautomerization of 1a gives the enol form which synthesis of imidazo[1,2-a]pyridines via a direct C N
Adv. Synth. Catal. 2016, 358, 364 – 369
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Irwan Iskandar Roslan et al.
Figure 1. Proposed mechanisms for the formation of 3aa (Mechanism A) and the competing reaction for formation of 4/4’/4’’
(Mechanism B).
and the residue was purified by column chromatography
using ethyl acetate and hexane (v/v=2/1) as eluent to afford
3aa; yield: 95%.
coupling of 2-aminopyridines and 1,3-dicarbonyls. The
2-aminopyridine is not only a reaction partner but is
also essential as an a-bromination shuttle, transferring
the Br atom from CBrCl3 to the enol form of the 1,3-
dicarbonyl via a series of reversible steps, involving
Methyl
2-methylimidazo[1,2-a]pyridine-3-carboxylate
(3aa): 1H NMR (300 MHz, CDCl3): d=9.02 (d, J=6.9 Hz,
1H), 7.38 (d, J=8.7 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.73
(t, J=6.9 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H); 13C NMR
(300 MHz, CDCl3): d=161.2, 152.3, 146.4, 127.4, 127.2,
116.1, 113.2, 112.0, 50.9, 16.1; HR-MS (ESI): m/z=191.0814,
calcd. for C10H11N2O2 [MÀH]+: 191.0815.
a
bromo-hemiaminal intermediate. Starting from
cheap commercially available starting materials and
reagents, the reaction occurs under mild conditions to
give isolated yields of 83–97% in a short time.
Experimental Section
Acknowledgements
Typical Procedure for the Formation of Imidazo[1,2-
Financial support from the Ministry of Education ARC Tier
1 Grant numbers R-143-000-603-112 and R-143-000-550-112
is gratefully acknowledged. I. I. Roslan thanks NUS for the
award of an NUS-PGF Scholarship.
a]pyridines
A 10-mL round-bottomed flask was charged with methyl
acetoacetate 1a (107.9 mL, 1 mmol), 2-aminopyridine 2a
(94.1 mg, 1 mmol) and KHCO3 (110 mg, 1.1 mmol) and
2 mL of CBrCl3/MeCN solvent mixture (1/9 v/v) (2.0 mmol
CBrCl3). The reaction mixture was stirred at 808C for 5–
10 h. The mixture was then diluted with H2O and extracted References
with EtOAc (15 mL”5). The combined organic layer was
washed with brine and dried with anhydrous Na2SO4. After
filtration, the solvent was removed by rotary evaporation
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