TBAI-catalyzed oxidative coupling of aminopyridines with β-keto esters and 1,3-diones - Synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c1cc13568f

TBAI could catalyze the direct oxidative C-N coupling of 2-aminopyridines with β-keto esters and 1,3-diones, which affords imidazo[1,2-a]pyridines as the products. The reaction was realized under metal-free conditions by using tert-butyl hydroperoxide (TB

Full text of DOI:10.1039/c1cc13568f

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COMMUNICATION
TBAI-catalyzed oxidative coupling of aminopyridines with b-keto esters
and 1,3-diones—synthesis of imidazo[1,2-a]pyridinesw
Lijuan Ma, Xianpei Wang, Wei Yu* and Bing Han*
Received 16th June 2011, Accepted 17th August 2011
DOI: 10.1039/c1cc13568f
TBAI could catalyze the direct oxidative C–N coupling of
2-aminopyridines with b-keto esters and 1,3-diones, which
affords imidazo[1,2-a]pyridines as the products. The reaction
was realized under metal-free conditions by using tert-butyl
hydroperoxide (TBHP) as the oxidant.
carbonyl compounds, and by using the chiral quaternary
ammonium iodides, the enantioselective intramolecular oxida-
tive C–O coupling was realized. The reaction was proposed to
be effected by the quaternary ammonium (hypo)iodite salts
generated in situ from the oxidation of quaternary ammonium
iodides by TBHP or H2O2. In another study, Wan et al.
employed the reagent combination of tetrabutyl ammonium
iodide (TBAI) and TBHP to realize the intermolecular C–O
coupling of carboxylic acids and ethers.8 Encouraged by these
results, we envisioned that this methodology might also be
applied to the intra- and intermolecular oxidative C–N
coupling.9 As a preliminary study toward this end, we found
that imidazo[1,2-a]pyridines could be prepared from 2-amino-
pyridines with b-keto esters and 1,3-diones via the TBAI-
catalyzed oxidative coupling.
The imidazo[1,2-a]pyridine ring system constitutes the core
structure of many pharmacologically important compounds.
Several synthetic strategies have been developed to gain access
to the variously substituted imidazo[1,2-a]pyridine rings.1,2
The coupling reaction of 2-aminopyridines with a-halocarbonyl
compounds provides a practical method which has found wide
applications in medicinal chemistry and drug synthesis.3 Very
recently, we developed a new protocol for the synthesis
of imidazo[1,2-a]pyridine rings which employs the PIDA-
mediated oxidative coupling of 2-aminopyridines with b-keto
esters or 1,3-diones.4 This method is advantageous in terms
of high efficiency and easy operation, and obviates the pre-
functionalization of the 1,3-dicarbonyl compounds.
We commenced our study by subjecting compounds
2-aminopyridine 1a and ethyl 2-benzoylacetate 2a to 2.0 equiv.
of 30% H2O2 or TBHP (70% in water) in the presence of
0.1 equiv. of TBAI under various conditions. Our previous
work demonstrates that a catalyic amount of BF3ꢀEt2O can
catalyze the PhI(OAc)2-mediated coupling reaction between
2-aminopyridines and 1,3-dicarbonyl compounds.4 Therefore,
BF3ꢀEt2O was used here too to promote the reaction (eqn (1)).
Initial attempt showed that the reaction did not take place at
room temperature. So the reaction was performed at elevated
From both environmental and economical points of view, it
is highly desirable to develop oxidizing systems where only a
catalytic amount of hypervalent iodine reagent is required. The
hypervalent iodine reagent can be generated in situ and recycled
by using another cheap and nontoxic terminal oxidant.5 So far
the most investigated catalytic system based on this notion
involves the use of ArI as the catalyst and mCPBA or urea–
H2O2 as the stoichiometric oxidant. Other systems are much
less explored. Recently, Ishihara et al. revealed the synthetic
potential of a novel oxidizing system which features the use of
quaternary ammonium iodide as the catalyst and 30% H2O2 or
tert-butyl hydroperoxide (TBHP) as the stoichiometric
oxidant.6 This system was first employed by Kirihara et al. to
realize the oxidative homocoupling of thiols to disulfides.7 The
studies by Ishihara et al. showed that quaternary ammonium
iodides could efficiently catalyze the a-oxy functionalization of
Table 1 Screening of the conditions for the TBAI-catalyzed reaction
between 1a and 2aa
Equiv.
Oxidant
Equiv. of Reaction Yield of
3ab (%)
Entry 1a/2a of TBAI (2 equiv.) BF3ꢀEt2O time/h
1
2
3
4
5
6
7
8
1 : 1
1 : 1
1 : 1
0.1
0.1
None
30% H2O2 0.2
16
16
16
12
23
12
35
12
12
16
35
47
53
0
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
0.2
0.2
0.2
0.2
0.2
0.2
None
1.0
0.2
1 : 1.5 0.1
1.2 : 1 0.1
1.5 : 1 0.1
1.5 : 1 0.05
1.5 : 1 0.1
1.5 : 1 0.1
1.5 : 1 1.0
1.5 : 1 0.1
30
71
81
76
48
44
10
64
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, P. R. China. E-mail: yuwei@lzu.edu.cn,
hanb@lzu.edu.cn; Fax: +86-931-8912582; Tel: +86-931-8912500
w Electronic supplementary information (ESI) available: General
experimental procedures, detailed information on the optimization
of reaction conditions, control experiments, characterization data,
1H NMR and 13C NMR spectra of compounds 3a–3z. CCDC
824738. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc13568f
9
10
11
30% H2O2 0.2
a
The reaction was performed at 80 1C with 2.0 mmol of 30% H2O2 or
TBHP (70% in water) as the oxidant. 5 mL CH3CN was used as the
b
solvent unless otherwise indicated. Isolated yield based on the
compound used in fewer amount.
c
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Chem. Commun., 2011, 47, 11333–11335 11333

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temperatures next. We found that the expected reaction took
place at 80 1C, and when CH3CN was used as the solvent, 3a
was obtained in yields of 47% and 53%, respectively, with
30% H2O2 and TBHP as the oxidants (Table 1, entries 1
and 2). The yield was improved by raising the amount of 1a
(Table 1, entries 5, 6 and 11). On the other hand, adjusting
the ratio of 1a and 2a to 1 : 1.5 led to inferior results
(Table 1, entry 4). Besides CH3CN, several other solvents
were also used, but the results were less satisfactory.10
ð1Þ
Table 2 Synthesis of imidazo[1,2-a]pyridines 3 via the TBAI-catalyzed reactions between 1 and 2a
Entry
Reaction time/h
Product
Yieldb (%)
Entry
14
Reaction time/h
Product
Yieldb (%)
1
2
12
12
81
82
11
11
57
52
15
3
4
10
16
83
82
16
17
24
48
45
21
5
6
7
8
36
36
12
10
23
37
66
70
18
19
20
21
48
9
18
65
55
54
11
11
9
14
65
22
9
54
10
11
12
11
11
78
68
23
24
10
12
12
63
45c
17
24
73
58
25
26
39c
61
13
10
a
b
c
The reaction was performed with 1.5 mmol of 1 and 1.0 mmol of 2 unless otherwise specified. Isolated yield based on 2. 1.0 mmol of 1 and
1.1 mmol of 2 were used for the convenience of product purification and the yield was based on 1.
c
11334 Chem. Commun., 2011, 47, 11333–11335
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Control experiments showed that TBAI played the key role in
the reaction (Table 1, entry 3). It is noteworthy that while
using a catalytic amount of TBAI ensures a good result,
too much TBAI has negative effect on the reaction (Table 1,
entry 10). The reaction also took place in the absence of
BF3ꢀEt2O, but the yield of 3a was lower (Table 1, entry 8).
On the other hand, using 1.0 equiv. of BF3ꢀEt2O was less
favorable for the reaction, consistent with our previous
findings (Table 1, entry 9).4 Besides TBAI, NaI and KI were
also capable of catalyzing the reaction, indicating that an
ammonium counterion was not necessary during the reaction.10
To examine the scope of this protocol, the optimized condi-
tions (Table 1, entry 6) were then applied to the synthesis of a
variety of substituted imidazo[1,2-a]pyridines 3 from 2-amino-
pyridines 1 and 1,3-dicarbonyl compounds 2.z The results are
listed in Table 2. 2-Phenyl-imidazo[1,2-a]pyridine-3-carboxy-
lates were prepared in good yields except for the chloro-
substituted 3e and 3f, in which cases the reaction was not
complete even after prolonged reaction time (Table 2, entries 5–6).
The structure of 3d was confirmed by X-ray crystallographic
analysis.11 The reaction can also be used to prepare 2-alkyl
substituted imidazo[1,2-a]pyridine-3-carboxylates (3m–3v),
and 2-alkyl-3-acyl imidazo[1,2-a]pyridines (3w–3z). Compounds
3 are useful intermediates for the synthesis of pharmaceutically
important compounds.12
likely the working mechanism. Another alternative mecha-
nism, which involves firstly the condensation between 1 and 2,
and then the oxidation of thus formed enamine ester, is not
possible as the condensation of 1a and 2a cannot take place in
refluxing acetonitrile.10
In summary, this work demonstrates that the direct oxida-
tive C–N coupling between 2-aminopyridines and b-keto esters
or 1,3-diones can be effected by using TBAI as the catalyst and
TBHP as the terminal oxidant. The reaction constitutes a
simple and economical protocol for the synthesis of
imidazo[1,2-a]pyridines.
The authors thank the National Natural Science Foundation
of China (No. 20772053) for financial support.
Notes and references
z General procedure for the synthesis of substituted imidazo-
[1,2-a]pyridines (3) from 2-aminopyridines (1) and b-keto esters and
acetylacetone (2): a mixture of 1.0 mmol of 2, 1.5 mmol of 1, 0.1 mmol
of TBAI, 2.0 mmol of TBHP (70% in water) and 26 mL of BF3ꢀEt2O
(0.2 mmol) in 5 mL of CH3CN was stirred in a 15 mL Pyrex screw-cap
pressure tube at 80 1C for the indicated period of time shown in
Table 2. After the reaction finished as indicated by TLC, the reaction
mixture was cooled to room temperature, and then poured into 15 mL
saturated Na2SO3 solution. The product was extracted with EtOAc
(20 mL ꢂ 3). The combined organic layer was washed with brine and
dried with anhydrous Na2SO4. After filtration, the solvent was
removed under reduced pressure, and the residue was treated with
silica gel chromatography to give product 3.
To account for the reaction process described above, a
mechanism (Scheme 1, path a) was proposed based on
Ishihara’s study6 and our experiments. In this mechanism,
MI is firstly oxidized by TBHP to M+[IO2]ꢁ (A), and the latter
reacts with 2 to give intermediate C. Nucleophilic attack of C
by 1 affords E, from which product 3 is generated. The
released M+[IO]ꢁ (B) is reoxidized to A by TBHP. Catalytic
amount of BF3ꢀEt2O has beneficial effect on the reaction,
probably because it can enhance the electrophilicity of A as
well as facilitate the removal of B from C. On the other hand,
using 1 equiv. BF3ꢀEt2O hampers the function of 1 as the
nucleophile, thus resulting in lowering of the yield.4 It is also
possible that the active oxidant was B, which reacted with 2 to
generate D (Scheme 1, path b). However, control experiments
showed that the reaction of 1a with ethyl 2-iodo-3-oxo-3-
phenylpropanoate only affords 3a in low yield. Besides, we
failed to obtain D when 2a was treated with TBAI and TBHP
in the presence of BF3ꢀEt2O. Therefore, path b seems less
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9 After submission of this paper, a work dealing with TBAI-
catalyzed C–N oxidative coupling with TBHP as the oxidant was
published. See: T. Froehr, C. P. Sindlinger, U. Kloeckner,
P. Finkbeiner and B. J. Nachtsheim, Org. Lett., 2011, 13, 3754.
10 Please see ESIw for more details.
11 CCDC 824738.
12 (a) P. George and C. Giron, Patent Application US 4,650,796,
1987; (b) G. Trapani, M. Franco, L. Ricciardi, A. Latrofa,
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Scheme 1
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11333–11335 11335