Copper(I) iodide/boron trifluoride etherate-cocatalyzed aerobic dehydrogenative reactions applied in the synthesis of substituted heteroaromatic imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/adsc.201300333

Compared with the well-known palladium-catalyzed oxidative dehydrogenation coupling reactions, similar transforms initiated by copper/oxygen have attracted more and more attention. We have investigated a novel construction of heteroaromatic imidazo[1,2-a]

Full text of DOI:10.1002/adsc.201300333

UPDATES
DOI: 10.1002/adsc.201300333
Copper(I) Iodide/Boron Trifluoride Etherate-Cocatalyzed
Aerobic Dehydrogenative Reactions Applied in the Synthesis
of Substituted Heteroaromatic Imidazo[1,2-a]pyridines
AHCTUNGTRENNUNG
Zhong-Jian Cai,a Shun-Yi Wang,a,* and Shun-Jun Jia,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
E-mail: shunyi@suda.edu.cn or shunjun@suda.edu.cn
Received: April 19, 2013; Revised: June 30, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300333.
À
Abstract: Compared with the well-known palladi-
um-catalyzed oxidative dehydrogenation coupling
reactions, similar transforms initiated by copper/
oxygen have attracted more and more attention.
We have investigated a novel construction of heter-
the classical precious metal-catalyzed C H functional-
ization,[3] the copper-catalyzed dehydrogenative func-
À
tionalization, especially C H amination, have attract-
ed considerable attention due to its efficiency, inex-
pensiveness, readily available starting materials, insen-
sitivity to air, and easy handling advantages.[4] With
the advances in aerobic dehydrogenative reactions, O2
has been considered as the powerful and ideal oxidant
for its natural, inexpensive, and environmentally
friendly characteristics.[5] From both environmental
and economic points of view, it is a challenge to con-
struct heterocycles and drugs from simple and readily
oaromatic imidazoACTHNUGRTENUNG[1,2-a]pyridines through cop-
per(I) iodide/boron trifluoride etherate/oxygen-
mediated dehydrogenative reactions of aryl alkyl or
alkyl alkyl ketones with 2-aminopyridines. Four hy-
À
drogen atoms are removed and two new C N
bonds are formed in one step via the imine forma-
3
À
tion and oxidative C
N
accessible substrates using
a copper/O2 catalyst
system via direct C H amination. More recently, we
have reported the construction of substituted imida-
[6]
3
À
À
Keywords: C
G
hydrogenative coupling; imidazo
oxygen
À
zoles (Scheme 1) via aerobic oxidative C H amina-
tion under the CuI/BF3·Et2O/O2 catalyst system.[7] It
was found that the copper/O2 catalyst system could
activate the a-position of imines followed by other re-
actions such as cyclizations. In light of these consider-
À
The construction of N-heterocycles via direct C H ations, we reasoned that the CuI/BF3·Et2O/O2 catalyst
amination[1] is one of the most attractive and challeng- system could also activate the a-position of N-(aryl-
ing fields in organic chemistry. This strategy provides
a route without relying on prefunctionalization of the C H amination strategy for the construction of new
compounds to the corresponding organic halides and heterocyclic rings. To our delight, imidazo[1,2-a]pyri-
ACHTUNGTRENeNGNU thylidene)pyridin-2-amine via an aerobic oxidative
À
AHCTUNGTRENNUNG
features high bond-formation efficiencies and atom dine derivatives could be obtained by the reaction of
economy. Recently, several reports were focused on pyridin-2-amine with ketones under the action of the
the synthesis of, especially, pyrroles via the so-called CuI/BF3·Et2O/O2 catalyst system (Scheme 2).
“borrowing hydrogen” methodology.[2] Compared to
Scheme 1. Our previous work on the construction of substituted imidazoles.
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Zhong-Jian Cai et al.
UPDATES
Scheme 2. The strategy for the construction of imidazoACTHUNRTGNEUNG[1,2-a]pyridines.
The imidazoACTHNUTRGNEUNG
[1,2-a]pyridine ring system[8] is the core
structure of many commercially available drugs, some
of which show antibacterial,[9] antitumor,[10] and anti-
viral activities.[11] For example, the optically active
GSK812397 (Figure 1, I) is a drug for the treatment
of HIV infection.[12] Zolimidine, alpidem, zolpidem
(Figure 1, II, III, IV) are used as antiulcer, anxiolytic,
and hypnotic drugs, respectively.[13–15]
Numerous methods have been developed for the
formation of variously substituted imidazo
dines.[16] The traditional approach for the preparation
of substituted imidazo[1,2-a]pyridines is the condensa-
ACHTUNGTREN[NUNG 1,2-a]pyri-
AHCTUNGTRENNUNG
tion reaction of 2-aminopyridines with a-halocarbonyl
compounds which has found wide applications in me-
dicinal chemistry and drug synthesis [Scheme 3, Eq.
(1)].[17] Recently, Liang and co-workers have devel-
oped a copper-catalyzed method for the preparation
of imidazo
ACHTUNGTRENUN[NG 1,2-a]pyridines with aminopyridines and
Figure 1. Selected imidazoACTHUNTGRNEUNG[1,2-a]pyridines.
nitroolefins using air as oxidation [Scheme 3, Eq.
Scheme 3. The construction of imidazoACTHNUTRGNE[NUG 1,2-a]pyridines from 2-aminopyridines.
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Copper(I) Iodide/Boron Trifluoride Etherate-Cocatalyzed Aerobic Dehydrogenative Reactions
(2)].[18] A facile synthesis of imidazo
catalyzed by copper(II) and iron(III) has been report- showed higher catalytic reactivity than other copper
ed by Liuꢀs group [Scheme 3, Eq. (3)].[19] Leiꢀs group salts such as CuBr and Cu
(OTf)2 for this reaction
ACHTUNGTREN[NUNG 1,2-a]pyridines (Table 1, entries 3and 4). It was noted that CuI
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
reported that the reaction of 2-aminopyridines and (Table 1, entries 6–8). The N,N-ligands such as 1,10-
terminal alkynes catalyzed by 2.0 equiv. of Ag2CO3 phenanthroline, 2,2’-bipyridine and 4,4’-di-tert-butyl-
could form imidazo
Eq. (4)].[20] Meanwhile, Hajra and co-workers report- (GC yield) (Table 1, entries 9–11). To our delight, 3a
ed the synthesis of imidazo[1,2-a]pyridines by the could be obtained in 70% isolated yield (81% GC
iron(III)-catalyzed one-pot cascade reaction between yield) (Table 1, entry 2) under catalysis by CuI
ACHTUNGTRNE[NUNG 1,2-a]pyridines easily [Scheme 3, 2,2’-bipyridine could improve the yields up to 60%
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
nitroolefins and 2-aminopyridine [Scheme 3, Eq. (20 mol%) and BF3·Et2O (10 mol%) in the presecne
(5)].[21] However, efficient and straightforward strat- of O2 (O2 balloon, 1 atm) under neat conditions at
egies for constructing these scaffolds from simple, 408C, when the ratio of 1a and 2a was changed to
readly accessible and inexpensive materials are still 1:2.[24]
highly attractive topics. Herein, we report the update
study of CuI/BF3·Et2O/O2-mediated reactions utilizing investigated the scope of this protocol. As presented
ketones with 2-aminopyridines for the construction of in Table 2, a series of substituted imidazo[1,2-a]pyri-
heteroaromatic imidazo
[1,2-a]pyridines in one step.[22] dines could be prepared directly from different ke-
With the optimized conditions in hand, we further
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Our study was initiated by treating 1.0 equiv. aceto- tones and 2-aminopyridines in moderate to good
phenone 1a and 1.0 equiv. 4-methylpyridin-2-amine 2a yields. products 3b and 3c could be obtained in 51%
with CuI (20 mol%), BF3·Et2O (10 mol%) in the pre- and 52% yields, when 2-aminopyridine was reacted
secne of O2 (O2 balloon, 1 atm) under neat conditions with 1-(4-methoxyphenyl)ethanone 1b and 1-(p-tolyl)-
at 408C for 24 h. To our delight, 7-methyl-2-
ACHTUNGTRENeNGNU thanone 1c, respectively. Meanwhile, acetophenones
phenylimidazo[1,2-a]pyridine 3a was formed in 36% with methyl substituents at the ortho and meta posi-
ACHTUNGTRENNUNG
yield (GC yield). The structure of 3a was confirmed tions of the aromatic ring could react smoothly to
by spectroscopic analysis and further confirmed by afford the desired products 3d and 3e in moderate
a single-crystal X-ray analysis.[23] This interesting one- yields, respectively. The halogen-containing imidazo-
step transformation to the heteroaromatic imidazo-
ACHTUNGTREN[NUGN 1,2-a]pyridines (3g, 3h, 3i, 3j) could also be observed
ACHTUNGTRENNUNG[1,2-a]pyridines encouraged us to further screen dif- in good yields under the identical conditions, which
ferent proportions, copper salts, solvents (see the Sup- opens the possibility for further functionalization.
porting Information), reaction temperature as well as Moreover, when 1-[4-(trifluoromethyl)phenyl]ethan-
additives. By screening the temperature, it was found
ACHTUNGTRENoNGNU ne 1m bearing a strong electron-withdrawing group
that 3a could be produced in 54% and 80% (GC was subjected to this transformation, a good yield
yield) at room temperature and 608C, respectively (72%) of the desired product 3m was achieved as
Table 1. Optimization of the reaction conditions.
Entry
1a:2a
Catalyst (mol%)
Additive (mol%)
Temperature [oC]
Yield [%][a]
1
2
3
4
5
6
7
8
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (10)
CuBr (20)
CuBr2 (20)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
40
40
r.t.
60
40
40
40
40
40
40
40
36
81 (70)[b]
54
80
75
<5
n.r.
n.r.
60
Cu
N
9
10
11
CuI (20)
CuI (20)
CuI (20)
2,2’-bipyridyl (20)
1,10-phenanthroline (20)
4,4’-di-tert-butyl-2,2’-dipyridyl (20)
53
29
[a]
Reaction conditions: 1a (2 mmol), 2a (6 mmol), neat, O2 (1 atm); The yields were determined by GC analysis using bi-
phenyl as the internal standard.
Isolated yield.
[b]
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Table 2. Substrate scope for the reaction of ketones and 2-aminopyridines.[a]
[a]
Reaction conditions: 1 (2 mmol), 2 (6 mmol), CuI (20 mol%), BF3·Et2O (10 mol%), O2 (1 atm), 408C, 24 h.
well. However, the reaction with 1-(4-nitrophenyl)- nylethanone (5) instead of 1a was treated with 2a
ACHTUNGTRENNUNGethanone afforded the desired product 3f in a poor under the standard conditions, we could not isolate
yield. Notably, the reaction with propiophenone could the desired 3a, thus indicating that the 2,2-dihydroxy-
also proceed to furnish the desired product 3n in 38% 1-phenylethanone (5) should not be a plausible inter-
isolated yield. In addition, when methyl was sub- mediate for the reaction. Therefore, it would be an
stitued at the 5-position of 2-aminopyridine, the trans- important factor which leads to the result that our re-
formation resulted in a lower yield (28%) due to the action differs from that described by Wu and co-
effect of steric hindrance.
When the aliphatic ketone 3,3-dimethylbutan-2-one (pyridine-2-ylamino)imidazoAHCNUTGTRENNUNG
workers,[25] who reported the synthesis of 2-aryl-3-
[1,2-a]pyridines promot-
1q instead of 1a was subjected to the reaction with 2a ed by 1.5 equiv. I2. Moreover, no desired 3a was
under the optimized reaction conditions, the desired formed when the reaction of 1a and 2a was run under
imidazole derivative 3q could also be obtained in the modified conditions without CuI [Scheme 5, Eq.
35% yield [Scheme 4, Eq. (6b)]. However, when (11)]. Furthermore, the reaction of 1a with 2a under
thiazol-2-amine was applied to this reaction instead of anatmosphere of argon was also investigated, and it
2-aminopyridine, the corresponding 6-phenylimidazo- failed to give 3a [Scheme 5, Eq. (12)]. Interestingly,
ACHTUNGTRENNUNG[2,1-b]thiazole could be isolated in 10% yield only when 1.0 equiv. TEMPO was added to the reaction of
[Scheme 4, Eq. (7)]. By the way, when quinolin-2- 1a and 2a under the optimized conditions, it was
amine (2s) or quinolin-8-amine (2t) was treated with found that 3a could still be produced in 34% GC
acetophenone (1a), respectively, under the optimized yield [Scheme 5, Eq. (13)].
reaction conditions, we could not isolate any desired
product [Scheme 4, Eqs. (8) and (9)].
Based on the results of control experiments and the
works reported by Buchwald, Chiba, Hajra and
Meanwhile, some control experiments were carried others,[6,24] a plausible reaction mechanism for this
out in order to further understand the mechanism of transform is presented in Scheme 6. Enamine 4’ is
the reactions (Scheme 5). When 2,2-dihydroxy-1-phe- formed via tautomerization of imine 4 from the con-
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Copper(I) Iodide/Boron Trifluoride Etherate-Cocatalyzed Aerobic Dehydrogenative Reactions
Scheme 4. Expanding experiments.
Scheme 5. Control experiments.
densation reaction of 1a and 2a in the presence of
In summary, we have applied CuI/BF3·Et2O-cocata-
BF3·Et2O. In the process of oxidative addition cata- lyzed aerobic dehydrogenative reactions to synthesis
lyzed by copper/O2, enamine 4’ would be converted of imidazoACHTNUTRGNE[NUG 1,2-a]pyridines from readily available 2-
into B through the intermediate A. Finally, the de- aminopyridines and ketones through the oxidative
3
À
sired product 3a would be generated through the re-
ductive elimination of B.
C
G
Promoted only by copper species, diversified imidazo-
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Scheme 6. A plausible mechanism.
ACHTUNGTRENNUNG[1,2-a]pyridines are generated in moderate to good
References
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À
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Typical Procedure for the Synthesis of 7-methyl-2-
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À
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (No. 21042007, 21172162), the Young National Nat-
ural Science Foundation of China (No. 21202111), the Young
Natural Science Foundation of Jiangsu Province
(BK2012174), PAPD, and Soochow University for financial
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tained in 68% isolated yield, this is simliar to the result
of entry 2 (Table 1) which would confirm the activity of
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UPDATES
8 Copper(I) Iodide/Boron Trifluoride Etherate-Cocatalyzed
Aerobic Dehydrogenative Reactions Applied in the
Synthesis of Substituted Heteroaromatic ImidazoACTHUNTGRNEUNG[1,2-
a]pyridines
Adv. Synth. Catal. 2013, 355, 1 – 8
Zhong-Jian Cai, Shun-Yi Wang,* Shun-Jun Ji*
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!