Cu(I)-catalyzed transannulation of N -heteroaryl aldehydes or ketones with alkylamines via C(sp3)-H amination

Article abstract of DOI:10.1021/ol503165b

A copper(I)-catalyzed direct transannulation of N-heteroaryl aldehydes or ketones with alkylamines via C_sp³-H amination has been achieved using molecular oxygen as a sole oxidant. N-Heteroarenes are employed as the amine source. This transformation provides a rapid and concise access to multifunctional imidazo[1,5-a]pyridines.

Full text of DOI:10.1021/ol503165b

Letter
pubs.acs.org/OrgLett
Cu(I)-Catalyzed Transannulation of N‑Heteroaryl Aldehydes or
Ketones with Alkylamines via C(sp3)−H Amination
Mingyang Li,† Ying Xie,† Yong Ye,*,† Yong Zou,‡ Huanfeng Jiang,† and Wei Zeng*,†
†School of Chemistry and Chemical Engineering, South China University of Technolgy, Guangzhou 510641, China
‡School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: A copper(I)-catalyzed direct transannulation of
3
N-heteroaryl aldehydes or ketones with alkylamines via Csp −H
amination has been achieved using molecular oxygen as a sole
oxidant. N-Heteroarenes are employed as the amine source. This
transformation provides a rapid and concise access to multi-
functional imidazo[1,5-a]pyridines.
a
transition-metal-catalyzed direct C−H amination strategy
Table 1. Optimization of the Reaction Parameters
A
has attracted extensive attention due to its atom and step
economy.1 Recently, remarkable progress has been achieved
based on C(sp2)−H bond activation/amination to form
C(sp2)−N bonds.2 Meanwhile, more challenging metal-
catalyzed unactivated C(sp3)−H aminations via nitrene
insertion,3 as well as a C(sp3)−H activation/C−N coupling pro-
cess,4 pioneer another unique access to site-selectively construct
b
entry
pyridines
Cu salts
oxidant
solvent
yield (%)
c
1
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
CuOAc
CuOAc
CuOAc
CuCl
air
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2a, nr
3
C−N bonds on a Csp atom. In this regard, several major amino
sources including arylamines and aliphatic amines,4b amides,4a,c,5
azides,4d,6 haloamines, etc.7 have been extensively investigated
for constructing the C(sp3)−N bond using transition-metal
catalysts. However, employing N-heteroarenes as amino sources
to couple with the C(sp3) atom via metal-catalyzed C(sp3)−H
amination is rarely reported,8 although this strategy poten-
tially results in the rapid assembly of structurally diverse
N-heterocycles which commonly occur in synthetic molecules.
Imidazo[1,5-a]pyridine nuclei belong to an important class of
building blocks in both material chemistry and pharmaceutical
industry.9 Based on the traditional Vilsmeier-type protocol,10
alternative synthetic methods have been successfully developed
to construct imidazo[1,5-a] N-heterocycles in which an ex-
cess amount of activating reagents such as iodine, S8, etc. were
employed.11 Therefore, the development of an atom-economic
synthetic method for these N-heteroarenes is in strong demand.
Recently, Zhu reported that a Cu(II)-catalyzed direct intra-
molecular C−N formation reaction of N-aryl-2-aminopyridines
via C(sp2)−H activation/amination could efficiently construct
pyrido[1,2-a]benzimidazoles using N-heterarenes as amino
sources.2b Inspired by this work, and in combination with our
continuing efforts to explore efficient reactions starting from
imines to rapidly construct N-heterocycles,12 we expect that a
2
air
2a, trace
2b, 8
3
air
4
air
2b, 28
2b, 47
2b, 25
2b, 25
5
CuBr
air
6
CuI
air
7
CuCN
Cu(OAc)2
CuBr2
CuBr
air
c
8
air
2b, nr
c
9
air
2b, nr
10
11
12
13
14
15
16
17
18
19
20
O2
Ar
2b, 64
c
CuBr
2b, nr
c
CuBr
MnO2
AgOAc
BQ
air
2b, nr
c
CuBr
2b, nr
CuBr
2b, <5
2b, 22
2b, 75
CuBr
CuBr
air
cd
,
CuBr
air
2b, nr
e
CuBr
air
2b, 31
2b, 56
2b, 81
f
CuBr
air
g
CuBr
air
a
Unless otherwise noted, all the reactions were carried out using
pyridines (1) (0.10 mmol) and oxidant (0.20 mmol) with a Cu catalyst
(20 mol %) in solvent (2.0 mL) at 80 °C for 12 h in a sealed reaction
tube, followed by flash chromatography on SiO2. Isolated yield. nr =
b
c
d
e
no reaction. 60 °C of reaction temperature. 100 °C of reaction
f
g
temperature. 10 mol % of CuBr was used. 1c was generated in situ by
using 0.1 mmol of n-BuNH2 and 0.1 mmol of 2-formylpyridine as
starting material under standard conditions.
3
Scheme 1. Cu(I)-Catalyzed Direct Csp −H Amination
Received: October 30, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503165b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Cu(I)-Catalyzed Sequential One-Pot Synthesis of Imidazo[1,5-a]pyridines via C(sp3)−H Amination
a
All the reactions were carried out using aldehyde (3) (0.10 mmol) and amine (4) (0.10 mmol) with the CuBr catalyst (10 mol %) in CH3CN
b
c
(2.0 mL) at 80 °C for 24 h under air in a sealed reaction tube, followed by flash chromatography on SiO2. Isolated yield. nr = no reaction.
metallcyclic species (B) could be possibly formed via alkyl
C(sp3)−H activation using pyridine derivative A as starting
material and also could be oxidized to the high oxidation state of
species B which will result in the formation of heterocycles C
through reductive elimination if additional coupling partners
such as alkynes, arylboronic acids, etc. are avoided in reaction
systems (Scheme 1).12c To identify this hypothesis, herein we
describe a novel Cu(I)-catalyzed C(sp3)−H amination using
N-heteroarenes as an amino source to construct an imidazo[1,5-a]
N-heterocyclic skeleton under atmospheric oxygen.
under an air atmosphere (Table 1, entries 1−3), and we quickly
found butyl-pyridin-2-ylmethylene amine 1c could afford an 8%
yield of the desired imidazo[1,5-a]pyridine 2b (entry 3).
Although the yield of 2b is too low, this positive result stimulated
us to further optimize the reaction conditions for achieving
satisfying yields. Then, we employed 1c as a model substrate
to investigate the effect of various copper salts on this trans-
formation. Among the tested copper catalysts (entries 3−9),
Cu(I) salts, especially CuBr, afforded an improved 2b yield
(entry 5, 47% yield). In contrast, Cu(II) salts such as Cu(OAc)2
and CuBr2 could not provide the desired target product 2b.
Subsequently, the reaction conditions were further optimized by
screening a series of oxidants and various solvents, and we found
the CuBr/air/CH3CN reaction system could afford a 75% yield
of 2b at 80 °C for 12 h (entries 10−16). Notably, poorer
Initially, we tried to design and synthesize 2-substituted
pyridines including 1a, 1b, and 1c which contain various linking
spacers X (X = CONH, CH2NH, and CHN) to investigate the
effect of substrate type on the CuOAc-catalyzed intramolecular
3
Csp −H amination in ethyl acetate (2.0 mL) at 80 °C for 12 h
B
dx.doi.org/10.1021/ol503165b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conversions of 2b were observed when lowering and increasing
the reaction temperature to 60 and 100 °C, respectively (com-
pare entries 17 and 18 with 16), and employing 10 mol % of the
CuBr catalyst also resulted in a lower yield (56% yield; compare
entry 19 with 16). Finally, the best yield (81% yield of 2b) was
obtained by directly using 0.1 mmol of n-BuNH2 and 0.1 mmol of
2-formylpyridine as starting material which led to the in situ
formation of 1c under optimized conditions (compare entry 20
with 16).
Scheme 2. Preliminary Mechanistic Studies
On the basis of these promising screening results, we next
investigated the scope of the current procedure by testing various
pyridine derivatives and amines via the Cu(I)-catalyzed one-pot
C(sp3)−H amination/cyclization. First, different substitutions
at the 5-position of 2-formylpyridine 3 was examined in the
C(sp3)−H amination reaction with benzylamine 4a. As sum-
marized in Table 2, electron-donating groups such as a 5-methyl
group facilitated the reaction and led to an 80−85% yield of the
imidazo[1,5-a]pyridine (entries 1 and 2). In contrast, changing
the substituted groups from 5-methyl to the electron-with-
drawing 5-CO2Et, 5-Cl, and 5-Br group resulted in an ∼15%
decrease in yield (compare entries 3−5 with 2). In addition,
other N-heteroaryl aledhydes such as 2-quinolinecarbaldehyde 3f
and 2-formylpyrimidine 3i also exhibited excellent reactivity and
could furnish quinoline derivatives 2g and 2j in excellent yields
(entries 6 and 9). Gratifyingly, when we attempted to use the
2-pyridyl ketones as substrates under our reaction conditions, we
found this transformation tolerated phenyl-pyridin-2-yl-meth-
anone (3g), which could be smoothly converted to the corre-
sponding 1,3-disubstituted imidazo[1,5-a]pyridines 2h in 42%
yield (entry 7).
(eq 2). Next, addition of 1.0 equiv of TEMPO to the CuBr/air
reaction system remarkably inhibited the intramolecular
C(sp3)−H amination of 1d (eq 3), revealing that radical inter-
mediates were possibly involved in this reaction. Finally, the
intramolecular isotope effect (KH/KD = 1.10) further indicated
that the C(sp3)−H bond breaking was not the rate-limiting step
of the reaction (eq 4). Based on the above observations and
relevant reactions regarding the Cu(I)−dioxygen catalytic
system,13 we depict a plausible catalytic cycle in Scheme 3. The
Scheme 3. Proposed Catalytic Cycle
Subsequently, we further examined the scope of amines that
participate in this C(sp3)−H amination with 2-formylpyridine
3a. The results in Table 2 show that this protocol tolerated
a variety of electron-rich and -poor benzylamines (4a−4f);
common functional groups on the benzene rings including an
alkyl, hydroxyl, halogen, and trifluoromethyl group were all
compatible with this transformation and gave moderate to good
yields of the desired imidazo[1,5-a]pyridines (entries 9−13).
Moreover, various aliphatic amines also allowed for this transfor-
mation and afforded the corresponding 3-alkyl-imidazo[1,5-a]-
pyridines in good yields (71−83% yield, entries 14−17),
regardless of whether the steric hindrance of the alkyl groups
[such as Ph(CH2)3, isobutyl, etc.] is large or not (compare
entries 14 and 17 with 16). Most importantly, the present
C(sp3)−H amination method could be successfully applied to a
wide range of heteroarylmethylene amines (4m, 4n, and 4o)
which could be readily employed to construct the corresponding
3-(2-pyridyl), 3-(2-furyl), and 3-(2-thienyl)-substituted imidazo-
[1,5-a]pyridines (2t, 42% yield; 2u, 56% yield; 2v, 62% yield) in
moderate yields (entries 19−21). Unfortunately, the reactivity of
the electron-deficient cyanomethylene amine 4l was observed to
be very low and did not produce the desired N-heteroarene 2s
(entry 18).
To further investigate the primary mechanism of the present
Cu(I)-catalyzed C(sp3)−H amination, several controlled re-
actions were carried out. First, employing deuterated pyridine
derivative d-1d as starting material under our reaction conditions
only furnished an 83% yield of 2a; no deuterated d-2a was
observed by 1 H NMR and GC-MS methods (Scheme 2, eq 1).
This fact ruled out the possibility that imine d-1d could be
isomerized to d-1f via 1,3-H shift under CuBr/air/CH3CN
system, and then Cu(I) salts enhanced this transformation via a
Lewis acid catalyzed nucleophilic addition/oxidation cascade
transformation is first triggered by the coordination of the Cu(I)
ion with the pyridine N-atom and imine N-atom from A, which
could enable the [Cu(II)−O−O·] C formation from Cu(I) B
under an oxygen atmosphere.14 Subsequently, the corresponding
Cu(II)-superoxo radical C would abstract the intramolecular H
atom from the coordinated imine to produce Cu(II) inter-
mediate D,13c which could be further led to the formation of a six-
membered Cu(III) species E via isomerization/oxidation pro-
cesses. Finally, the reductive elimination of Cu(III) intermediate
E led to the formation of imidazo[1,5-a]pyridine F with regen-
eration of the Cu(I) catalyst.15
In conclusion, we have developed the first Cu(I)-catalyzed
3
direct Csp −H amination of 2-acylpyridines with aliphatic amines
to construct multifunctional imidazo[1,5-a]pyridines16 via a one-
pot tandem process employing aerial oxygen as the green oxidant, in
which N-heteroarenes were used as amine sources. This trans-
formation is compatible with electron-rich or -poor 2-acylpyridines
and aliphatic amines. More detailed mechanistic studies and further
applications of this transformation in the synthesis of complex mole-
cules are currently underway in our laboratory.
C
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Organic Letters
Letter
V.; Yakimansky, A. V.; Goikhman, M. Y.; Podeshvo, I. V. Electrochim.
Acta 2009, 54, 1444.
(14) (a) Toh, K. K.; Wang, Y. F.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc.
2011, 133, 13942. (b) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.;
Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678. (c) Zhang, C.; Feng, P.;
Jiao, N. J. Am. Chem. Soc. 2013, 135, 15257.
ASSOCIATED CONTENT
* Supporting Information
Analytical data for all isolated compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(15) (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(b) Huber, S. M.; Ertem, M. Z.; Aquilant, F.; Gaqliard, L.; Tolman, W.
B.; Cramer, C. J. Chem.Eur. J. 2009, 15, 4886.
AUTHOR INFORMATION
Corresponding Authors
■
(16) An efficient approach to imidazo [1,5-a] pyridines via Rh(II)-
catalyzed NH insertion was just reported; see: Shi, Y.; Gulevich, A. V.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2014, 53, DOI: 10.1002/
anie.201408335.
*E-mail: yeyong@scut.edu.cn.
*E-mail: zengwei@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NSFC (No. 21372085) and the GNSF
(No. 10351064101000000) for financial support.
REFERENCES
■
(1) (a) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (b) Godula,
K.; Same, D. Science 2006, 312, 67.
(2) (a) Kim, H.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2014, 136, 5904.
(b) Wang, H.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132,
2
13217. For recent reviews about transition-metal-catalyzed Csp −H
amination: (c) Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43,
901 and references therein.
(3) For selected reviews, see: (a) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem.
Soc. Rev. 2012, 41, 931. (b) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc.
Rev. 2011, 40, 1926 and references therein.
(4) (a) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc.
2012, 134, 3. (b) Pan, J.; Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 8647. (c) He, G.; Zhang, Y.; Nack, W. A.; Li, Q.; Chen, G.
Angew. Chem., Int. Ed. 2013, 52, 11124. (d) Kang, T.; Kim, Y.; Lee, D.;
Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136, 4141.
(5) (a) Bess, E. N.; Deluca, R. J.; Tindall, D. J.; Oderinde, M. S.; Roizen,
J. L.; Bois, J. D.; Sigman, M. S. J. Am. Chem. Soc. 2014, 136, 5783.
(b) Liang, C.; Robert-Peillard, F.; Fruit, C.; Muller, P.; Dodd, R. H.;
Dauban, P. Angew. Chem., Int. Ed. 2006, 45, 4641.
(6) (a) Lu, H.; Jiang, H.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int. Ed.
2010, 49, 10192. (b) Ichinose, M.; Suematsu, H.; Yasutomi, Y.;
Nishioka, Y.; Uchida, T.; Katsuki, T. Angew. Chem., Int. Ed. 2011, 50,
9884.
(7) (a) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.;
Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51, 1244.
(8) For the selected examples: (a) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu,
H. Org. Lett. 2011, 13, 3694. (b) Liang, D.; He, Y.; Liu, L.; Zhu, Q. Org.
Lett. 2013, 15, 3476.
(9) For selected examples, see: (a) Nakamura, H.; Yamamoto, H. PCT
Int. Appl. WO 2005043630; Chem. Abstr. 2005, 142, 440277.
(b) Cappelli, A.; Giuliani, G.; Anzini, M.; Riitano, D.; Giorgi, G.;
Vomero, S. Bioorg. Med. Chem. 2008, 16, 6850.
(10) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2823.
(11) For selected examples: (a) Wang, Q.; Zhang, S.; Guo, F.; Zhang,
B.; Hu, P.; Wang, Z. J. Org. Chem. 2012, 77, 11161. (b) Shibahara, F.;
Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006, 8, 5621. (c) Yan,
Y.; Zhang, Y.; Zha, Z.; Wang, Z. Org. Lett. 2013, 15, 2274. (d) Shibahara,
F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.; Murai, T. J. Org. Chem.
2009, 74, 3566. (e) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 15,
2290. (f) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27, 3713.
(12) (a) Luo, Y. T.; Lu, X. X.; Ye, Y.; Guo, Y.; Jiang, H. F.; Zeng, W.
Org. Lett. 2012, 14, 5640. (b) Dang, L.; Liang, L. B.; Qian, C.; Fu, M. Q.;
Ma, T. M.; Xu, D. G.; Jiang, H. F.; Zeng, W. J. Org. Chem. 2014, 79, 769.
(c) Xie, Y.; Chen, T.; Fu, S.; Li, X. S.; Deng, Y.; Zeng, W. Chem.
Commun. 2014, 50, 10699.
(13) For selected examples, see: (a) Mandal, S.; Macikenas, D.;
Protasiewicz, J. D.; Sayre, L. M. J. Org. Chem. 2000, 65, 4804. (b) Du, F.
T.; Ji, J. X. Chem. Sci. 2012, 3, 460. (c) Magdesieva, T. V.; Dolganov, A.
D
dx.doi.org/10.1021/ol503165b | Org. Lett. XXXX, XXX, XXX−XXX