Oxidative Cross-Coupling of sp3- and sp2-Hybridized C-H Bonds: Vanadium-Catalyzed Aminomethylation of Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1021/acs.orglett.5b02539

The vanadium-catalyzed oxidative coupling of substituted 2-arylimidiazo[1,2-a]pyridines to N-methylmorpholine oxide, which acts as both a coupling partner and an oxidant, has been achieved. This reaction was applied to various substituted imidiazo[1,2-a]pyridine and indole substrates, resulting in yields as high as 90%. Mechanistic investigations indicate that the reaction may proceed via a Mannich-type process. This work demonstrates how oxidative aminomethylation can be used as a useful method to introduce tertiary amines into heterocycles, thus providing an alternative method for conventional Mannich-type reactions.

Full text of DOI:10.1021/acs.orglett.5b02539

Letter
pubs.acs.org/OrgLett
Oxidative Cross-Coupling of sp3- and sp2‑Hybridized C−H Bonds:
Vanadium-Catalyzed Aminomethylation of Imidazo[1,2‑a]pyridines
Pinku Kaswan,†,§ Ashley Porter,‡,§ Kasiviswanadharaju Pericherla,†,⊥ Marissa Simone,‡,⊥ Sean Peters,‡
Anil Kumar,*,† and Brenton DeBoef*,‡
†Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India
‡Department of Chemistry, University of Rhode Island, 51 Lower College Road, Kingston, Rhode Island 02881, United States
S
* Supporting Information
ABSTRACT: The vanadium-catalyzed oxidative coupling of
substituted 2-arylimidiazo[1,2-a]pyridines to N-methylmor-
pholine oxide, which acts as both a coupling partner and an
oxidant, has been achieved. This reaction was applied to
various substituted imidiazo[1,2-a]pyridine and indole sub-
strates, resulting in yields as high as 90%. Mechanistic
investigations indicate that the reaction may proceed via a
Mannich-type process. This work demonstrates how oxidative aminomethylation can be used as a useful method to introduce
tertiary amines into heterocycles, thus providing an alternative method for conventional Mannich-type reactions.
ncorporating new carbon−carbon and carbon−nitrogen
Ibonds into organic molecules is an apparent need in
modern chemical industry. There have been many recent
advances in this field, most using metal catalysis; however, these
methods require prefunctionalization steps, thus diminishing
the overall atom economy of the process.1 The ability to
Figure 1. Pharmaceuticals with imidazo[1,2-a]pyridine backbone.
oxidatively couple two carbon−hydrogen (C−H) bonds to
form a carbon−carbon (C−C) bond with no prefunctionaliza-
tion would be ideal.2 The same is true for the synthesis of
coupling of sp3- and sp2-hybridized C−H bonds is much less
carbon−nitrogen (C−N) bonds from the coupling of C−H and
common, as sp3-hybridized C−H bonds are generally less
nitrogen−hydrogen (N−H) bonds. One can envision the
reactive.4 In fact, in order to achieve sp3 C−H bond activation,
incorporation of new C−N bonds via cross-dehydrogenative
directing groups are often needed.3 In the absence of such a
coupling through either oxidative amination or oxidative
directing group, and occasionally even when these groups are
employed, β-hydride elimination, as opposed to cross-coupling,
aminomethylation (Scheme 1). The former process, direct
oxidative amination, has been reported numerous times, though
is often observed during the C(sp3)−H activation step.4
much work remains to be done.3 In contrast, aminomethylation
Despite these challenges, we sought to develop a novel
is a rare4−7 but attractive bond disconnection for the synthesis
aminomethlation via the oxidative coupling of sp3- and sp2-
of tertiary amines. Two notable examples have been reported to
hybridized C−H bonds.
date: Hwang and Uang achieved the regioselective amino-
Specifically, we sought to find a method for the amino-
methylation of naphthols,6 and a team at Eli Lilly used an
methylation of imidiazo[1,2-a]pyridine substrates. Neuroactive
pharmaceuticals such as necopidem, saripidem, and zolpidem
contain a substituted imidazo[1,2-a]pyridine backbone (Figure
oxidative aminomethylation in the large-scale synthesis of an
active pharmaceutical ingredient for the treatment of
myeloproliferative disorders.8
1).9 Providing a way to oxidatively couple the 3-position of 2-
arylimidazo[1,2-a]pyridine with alkylamines would be a useful
tool for the synthesis of derivatives of these nonbenzodiazepine
GABA potentiators. Herein, we disclose the discovery of a
vanadium-catalyzed oxidative coupling of imidiazo[1,2-a]-
pyridines with N-methylmorpholine oxide (NMO), which
serves as both the sp3-hybridized coupling partner and the
oxidant.
There are numerous methods to oxidatively couple two sp2-
hybridized C−H bonds in high yields;2 however, the cross-
Scheme 1. Oxidative Amination versus Aminomethylation
Received: September 3, 2015
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization of the Oxidative Aminomethylation
Conditions
Scheme 2. Substrate Scope for Oxidative Aminomethylation
of Imidazo[1,2-a]pyridines
a
yield (%)
VO(acac)2
(mol %)
NMO
time
(h)
entry
1
(equiv)
solvent
DCM
3a
4
VO(acac)2
(25)
10
10
10
10
10
10
5
18
18
18
18
18
18
6
70
(59 )
4
c
2
3
4
5
6
7
VO(acac)2
(20)
DCM
DCM
ethanol
toluene
THF
65
3
b
VO(acac)2
(10)
62
33
30
57
88
VO(acac)2
(20)
2
VO(acac)2
(20)
29
1
VO(acac)2
(20)
VO(acac)2
(10)
DCM
6
c
c
8
9
V2O5 (20)
10
10
DCM
1,4-
6
58
80
0
0
VO(acac)2
(20)
12
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
c
10 VO(acac)2
(20)
5
3
1
12
12
12
80
0
0
7
c
11
VO(acac)2
(20)
69
c
12
VO(acac)2
(20)
36
a
b
Product yield determined by NMR. Traces of 4 were observed.
c
Isolated yield.
Based on the previous work of Hwang and Uang,6 we chose
to commence our studies using vanadyl acetylacetonate,
VO(acac)2, as the catalyst for the oxidative aminomethylation
shown in Table 1. We systematically studied the effect of
solvent, catalyst loading, time, and NMO loading. Ethanol,
toluene, and tetrahydrofuran were initially tested (Table 1
entries 4−6), but none had yields comparable to those with
methylene chloride (DCM). To our surprise, the amino-
methylation reactions consistently formed the acetylacetonate
byproduct 4, which was very difficult to remove from the
desired product 3a by flash chromatography. The loading of
VO(acac)2 was varied from 25% to 10%, showing that lower
catalyst loading provided lower yields but also lower impurities
(entries 1−3). Performing a careful study of the reaction over
time gave further insight into the reaction’s profile (see the
Supporting Information). This study indicated that the optimal
yield of 3a could be achieved using 10 mol % VO(acac)2 and 5
equiv of NMO for 6 h in methylene chloride (entry 7), but as
previously mentioned, the product 3a was nearly impossible to
purify from the byproduct 4. Consequently, we chose to study a
vanadyl catalyst that did not contain organic ligands, V2O5
(entry 8), but the yield of 3a was lower.. Finally, we found that
changing the solvent to 1,4-dioxane and increasing the catalyst
loading of VO(acac)2 to 20 mol % allowed for the facile
synthesis of 3a in 80% yield in high purity. Decreasing the
Scheme 3. Oxidative Aminomethylation of Indoles
Scheme 4. Conventional Mannich Conditions
amount of NMO below 5 equiv decreased the yield of 3a, and
when it became 1 equiv the yield of the unwanted byproduct 4
increased to 7% (Table 1, entries 10−12).
Once the optimal conditions were obtained, the oxidative
aminomethylation was performed on a wide variety of
substrates (Scheme 2). 2-Arylimidazo[1,2-a]pyridines contain-
ing electron-withdrawing groups on the para position of the
B
DOI: 10.1021/acs.orglett.5b02539
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a proton from 1 which then attacks the iminium ion, forming 3.
The elimination of water from vanadium regenerates the
catalyst. We believe 4 is formed when the iminium ion reacts
with one of the ligands from the vanadium catalyst, thus
formally incorporating the acac ligand and the methyl from the
NMO in the observed byproduct.
Scheme 5. Proposed mechanism of formation of both
product 3 and byproduct 4
In summary, the vanadium-catalyzed oxidative coupling of
substituted imidazo[1,2-a]pyridines to N-methylmorpholine
was achieved in yields up to 90%. Despite the ability to
produce this product using conventional Mannich conditions,
we believe this is a useful, orthogonal method to synthesize
tertiary amines.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02539.
Experimental procedures as well as characterization of
previously unknown compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: anilkadian@gmail.com.
*E-mail: bdeboef@chm.uri.edu.
Author Contributions
aryl substituent resulted in diminished yields, while electron-
donating groups in the para position generally led to higher
yields. For example, 3r, which contains a nitro substituent in
the para position, could not be formed, while 3s, with a methyl
ether substituent in the same position, was easily synthesized in
84% yield. The addition of a second electron-donating
substituent at the meta position did not improve the yield of
the reaction; rather, it produced a slightly lower yield (compare
3d and 3f). Changing the position of an electron-donating
methyl group on the imidazo[1,2-a]pyridine ring from the C6-
position (entry 3f) to the C8-position (entry 3g) did not appear
to significantly effect the reaction. Importantly, halogens could
be tolerated by the reactions, indicating that subsequent
coupling reactions could be performed on the aminomethylated
products.
§P.K. and A.P. contributed equally.
Author Contributions
⊥K.P. and M.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER 0847222) and the National Institutes of Health
(NIGMS, 1R15GM097708-01). B.D. is the recipient of a Pfizer
Green Chemistry Award. P.K. and K.P. are thankful to CSIR,
New Delhi, and UGC, New Delhi, respectively, for senior
research fellowships. The majority of the data shown in Table 1
and Scheme 4 was obtained at URI, while the majority of the
data shown in Schemes 2 and 3 was obtained at BITS Pilani.
In addition to imidazo[1,2-a]pyridines, 2-substituted indoles
could also be aminomethylated. As shown in Scheme 3, both 2-
phenyl and 2-methylindole were oxidatively aminomethylated
in 60% and 73% yields (6a and 6b).
REFERENCES
■
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(Scheme 5). This was determined by running a conventional
Mannich reaction using 1, formaldehyde, and morpholine to
make the imminium ion in situ, resulting in 3a in a 98% yield
(Scheme 4). Performing the aminomethyation for the synthesis
of 3a using our optimal reaction conditions in the presence of
TEMPO, a radical inhibitor, did not prevent product formation,
further indicating that the reaction is likely not radical
mediated.
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