Mild metal-free sequential dual oxidative amination of C(sp3)-H bonds: Efficient synthesis of imidazo[1,5-a]pyridines

Article abstract of DOI:10.1021/ol4008487

A metal-free sequential dual oxidative amination of C(sp³)-H bonds under ambient conditions was the first developed, affording imidazo[1,5-a]pyridines in good to excellent yields. The reaction was involved in two oxidative C-N couplings and one oxidative dehydrogenation process with six hydrogen atoms removed.

Full text of DOI:10.1021/ol4008487

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Mild Metal-Free Sequential Dual Oxidative
Amination of C(sp3)ꢀH bonds: Efficient
Synthesis of Imidazo[1,5‑a]pyridines
Yizhe Yan, Yonghui Zhang, Zhenggen Zha, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of
Soft Matter Chemistry and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, P. R. China
zwang3@ustc.edu.cn
Received March 28, 2013
ABSTRACT
A metal-free sequential dual oxidative amination of C(sp3)ꢀH bonds under ambient conditions was the first developed, affording imidazo[1,5-a]-
pyridines in good to excellent yields. The reaction was involved in two oxidative CꢀN couplings and one oxidative dehydrogenation process with
six hydrogen atoms removed.
Imidazo[1,5-a]pyridines have drawn much attention for
their potential photophysical and biological activities.1
However, only a few synthetic routes are available for
these compounds so far.2 The process of these reported
methods mainly relied on traditional Vilsmeier-type cycli-
zations of N-2-pyridylmethylamides. Therefore, develop-
ing more practical and efficient synthetic approaches for
imidazo[1,5-a] pyridines is highly desirable.
Transition-metal-catalyzed intermolecular or intramo-
lecular direct oxidative aminations of the C(sp3)ꢀH bond
have emerged as important methods for CꢀN bond forma-
tions because of economical advantages over the present
procedures by employing prefunctionalized substrates.3ꢀ5
However, using expensive transition metals and the substate
scope limited their applications in organic synthesis. Re-
cently, Chang6 and Muniz7 have, respectively, developed
interesting metal-free benzylic and allylic CꢀH aminations
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Black-
well Science: Oxford, U.K., 2000; Chapter 25. (b) Katritzky, A. R. Compre-
hensive Heterocyclic Chemistry III; Elsevier: Oxford, U.K., 2008; Vol. 11.
(c) Kakehi, S. H.; Okumura, Y.; Itoh, K.; Kobayashi, K.; Aikawa, Y.;
Misawa, K. Chem. Pharm. Bull. 2010, 58, 1502. (d) Ge, Y. Q.; Hao, B. Q.;
Duan, G. Y.; Wang, J. W. J. Lumin. 2011, 131, 1070.
(2) (a) Bower, J. D.; Ramage, C. R. J. Chem. Soc. 1955, 2834. (b)
Winterfeld, K.; Franzke, H. Angew. Chem. 1963, 75, 1101. (c) Shibahara,
F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006, 8, 5621. (d)
Arvapalli, V. S.; Chen, G. W.; Kosarev, S.; Tan, M. F. E.; Xie, D. J.; Yet,
L. Tetrahedron Lett. 2010, 51, 284. (e) Pineiro, M.; Pinho, E.; Melo, T.
M. V. D. Eur. J. Org. Chem. 2009, 5287. (f) Adrio, J.; Carretero, J. C.
Chem. Commun. 2011, 47, 6784.
(3) For recent reviews on CꢀH amination, see: (a) Armstrong, A.;
Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282. (b) Thansandote, P.;
Lautens, M. Chem.;Eur. J. 2009, 15, 5874. (c) Collet, F.; Dodd, R. H.;
Dauban, P. Chem. Commun. 2009, 45, 5061. (d) Davies, H. M. L.;
Manning, J. R. Nature 2008, 451, 417. (e) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439. (f) Davies, H. M. L.; Long, M. S. Angew.
Chem., Int. Ed. 2005, 44, 3518. (g) Muller, P.; Fruit, C. Chem. Rev. 2003,
103, 2905. (h) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011,
40, 1926. (i) Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2010, 292, 347.
(4) For selected examples of oxidative amination of activated sp3
CꢀH bonds including allylic and benzylic CꢀH bonds and CꢀH bonds
having heteroatoms or electron-withdrawing substituents on the carbon
atom; see: (a) Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.;
Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2003, 125, 12078. (b)
Fructos, M. R.; Trofimenko, S.; Diaz-Requejo, M. M.; Perez, P. J.
J. Am. Chem. Soc. 2006, 128, 11784. (c) Bhuyan, R.; Nicholas, K. M.
Org. Lett. 2007, 9, 3957. (d) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8,
6031. (e) Liang, J. L.; Yuan, S. X.; Huang, J. S.; Yu, W. Y.; Che, C. M.
Angew. Chem., Int. Ed. 2002, 41, 3465. (f) Liang, J. L.; Yuan, S. X.;
Huang, J. S.; Che, C. M. J. Org. Chem. 2004, 69, 3610. (g) Espino, C. G.;
Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378.
(h) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562. (i) Zhang,
Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813. (j) Wang, Z.;
Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2008, 10, 1863. (k)
Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47,
6825. (l) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129,
7274. (m) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
(n) Liu, G. S.; Yin, G. Y.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733.
(o) Gephart, R. T., III; Huang, D. L.; Aguila, M. J.; Schmidt, G.; Shahu,
A.; Warren, T. H. Angew. Chem., Int. Ed. 2012, 51, 6488.
r
10.1021/ol4008487
XXXX American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Scheme 1. Initial Hypothesis Pathway for Dual Oxidative
C(sp3)ꢀH Aminations
entry
XI
oxidant
solvent
yieldb (%)
1
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
O2(1 atm)
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
THF
85
nd
99
31
49
nd
6
2
none
NIS
Bu4NI
KI
3
4
5
6
PhI
7
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
with sulfonamides in the presence of stoichiometric hyperva-
lent iodine(III) reagents. However, large amounts of iodo-
benzene were generated as waste, and the substrates remained
limited to sulfonamides in the absence of transition metal.
Therefore, the development of an efficient, and environmen-
tally friendly catalytic system for oxidative C(sp3)ꢀH amina-
tion with primary amine remains challenging.
8
13
16
10
99
31
46
23
58
21
69
28
9
10
11
12
13
14
15
16
17c
18d
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CH3CN
EtOH
H2O
Recently, our group8 and other groups9 have developed
iodine-catalyzed intramolecular and intermolecular oxda-
tive C(sp3)ꢀH amination for the synthesis of heterocycles.
As a continuous study on this field, we hypothesized that
multisubstituted imidazo[1,5-a]pyridine could be synthe-
sized from ethyl 2-(pyridin-2-yl)acetate and benzylamine
via iodine-catalyzed C(sp3)ꢀH aminations. The reaction
was involved in two oxidative CꢀN couplings and one
oxidative dehydrogenation process with six hydrogen atoms
removed (Scheme 1). The reaction could be carried out
under metal-free conditions with only water and tert-butyl
alcohol as waste. To the best of our knowledge, this protocol
has been not reported to date.
Initially, we began our study with the reaction of 1 equiv
of ethyl 2-(pyridin-2-yl)acetate (1a) and 2 equiv of benzyl-
amine (2a) in the presence of 3 equiv of tert-butyl hydro-
peroxide (TBHP, 70% in aqueous) as the oxidant and
1 equiv of molecular iodine as the catalyst. When the
reaction mixture was stirred in 1 mL of N,N-dimethylforma-
mide (DMF) in air at room temperature for 12 h, ethyl
3-phenylimidazo[1,5-a]pyridine-1-carboxylate (3aa) was ob-
tained in 85% isolated yield (Table 1, entry 1). In the absence
Tol.
DMA
DMA
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), XI (0.3 mmol),
oxidant (0.9 mmol), solvent (1 mL), rt, 12 h. b Isolated yield. c 0.5 equiv of
NIS was used. d 0.2 equiv of NIS was used.
of iodine, no desired 3aa was detected, which indicated that
iodine was essential to this reaction (Table 1, entry 2). When
various iodine reagents were used, N-iodosuccinimide (NIS)
gave 3aa in the highest yield (Table 1, entries 3ꢀ6). Among
the examination of various oxidants, such as di-tert-butyl
peroxide (DTBP), potassium peroxydisulfate (K2S2O8), and
oxygen, TBHP gave 3aa in the highest yield (Table 1, entries
7ꢀ9). In the absence of extra oxidant (or only in air), only
10% of 3aa was detected (Table 1, entry 10). Moreover,
various solvents were also examined, and DMA proved to
be the best choice (Table 1, entries 11ꢀ16). In addition, the
amount of NIS was also optimized. Reducing the amount of
NIS to 50 or 20 mol % decreased the yield of 3aa (Table 1,
entries 17 and 18). Therefore, the optimal conditions are
those described in entry11.
Under the optimal reaction conditions, we investigated
the substrate scope of oxidative CꢀN coupling. First, when
various aromatic benzylamines (2aꢀk) were employed in
this reaction, the corresponding products (3aaꢀak) could
be obtained in 80ꢀ99% yields (Table 2, entries 1ꢀ11). It is
noted that benzylamines bearing electron-donating groups
(4-Me or 4-OMe) gave the desired products in higher yields
than electron-withdrawing groups (4-CF3 or 4-Cl) on the
phenyl ring (Table 2, entries 5, 7, 8, and 11). However, no
steric hindrance was observed in the reaction. For example,
benzylamines bearing a p-methyl or p-chlorophenol group
on the phenyl ring, respectively, gave the corresponding
products in the same yields as that of benzylamine bearing
an o-methyl or o-chlorophenol group (Table 2, entries 5, 6,
8, and 10). Moreover, ring-fused (2l) and heterocyclic
(5) For selected examples of oxidative amination of unactivated sp3
CꢀH bonds, see: (a) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem.
Soc. 2006, 128, 9048. (b) Neumann, J.; Rakshit, S.; Droge, T.; Glorius,
F. Angew. Chem., Int. Ed. 2009, 48, 6892. (c) Pan, J.; Su, M.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2011, 50, 8647. (d) He, G.; Zhao, Y.; Zhang,
S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (e) Nadres, E. T.;
Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7.
(6) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011,
133, 16382.
(7) Souto, J. A.; Zian, D.; Muniz, K. J. Am. Chem. Soc. 2012, 134,
7242.
(8) (a) Zhang, J. T.; Zhu, D. P.; Yu, C. M.; Wan, C. F.; Wang, Z. Y.
Org. Lett. 2010, 12, 2841. (b) Yan, Y. Z.; Zhang, Y. H.; Feng, C. T.; Zha,
Z. G.; Wang, Z. Y. Angew. Chem., Int. Ed. 2012, 51, 8077. (c) Zhang,
B. Q.; Wan, C. F.; Wang, Q.; Zhang, S.; Zha, Z. G.; Wang, Z. Y. Acta
Chim. Sin. 2012, 70, 2408.
(9) (a) Ma, L. J.; Wang, X. P.; Yu, W.; Han, B. Chem. Commun. 2011,
47, 11333. (b) Lamani, M.; Prabhu, K. R. Chem.;Eur. J. 2012, 18,
14638.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Substrate Scope of Benzylaminesa
Scheme 2. Scope of Substrate 1a
entry
R1
Ph (2a)
product
yieldb (%)
1
3aa
3ab
3ac
3ad
3ae
3af
99
93
94
94
90
90
80
96
96
95
92
99
70
81
ndc
2
4-F-Ph (2b)
3
3-F-Ph (2c)
4
2-F-Ph (2d)
5
4-Cl-Ph (2e)
2-Cl-Ph (2f)
4-CF3Ph (2g)
4-Me-Ph (2h)
3-Me-Ph (2i)
2-Me-Ph (2j)
4-OMe-Ph (2k)
1-naphthyl (2l)
2-furyl (2m)
2-thienyl (2n)
2-pyridyl (2o)
6
7
3ag
3ah
3ai
8
9
10
11
12
13
14
15
3aj
3ak
3al
3am
3an
3ao
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), NIS (0.3 mmol),
TBHP (70% aq, 0.9 mmol), DMA (1 mL), rt, 12 h. Isolated yields are
given.
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), NIS (0.3 mmol),
oxidant (0.9 mmol), solvent (1 mL), rt, 12 h. b Isolated yield. c Unknown
complex mixture.
(2m and 2n) benzylamines also gave the corresponding
products in good yields (Table 2, entries 12ꢀ14).
Scheme 3. Synthesis of Imidazo[1,5-a]pyridine from Amino
Acids
Subsequently, various substrates1bꢀh replacing1awere
also employed in this reaction, giving the desired products
3baꢀha in good yields (Scheme 2). For example, when R2
were various ester groups such as COOMe or COOtBu,
90% of 3ba and 85% of 3ca were obtained, respectively.
When R2 was a benzoyl group, the product 3da was
obtained in 80% yield. Similarly, substrates 1e or 1f also
gave the desired products 3ea or 3fa with 85% or 82%
yields, respectively. However, when R2 was a cyano group,
an unknown complex mixture was obtained. In addition,
ethyl 2-(quinolin-2-yl)acetate (1h) also gave 3ha with an
almost quantitive yield.
product was obtained because the existence of the methyl
group restrained the first amination process (Scheme 4a).
Furthermore, when the reaction of 1a with 1-phenylethana-
mine (2p) was carried out under standard conditions, a new
product 5ap was obtained in 53% yield. The reason for the
generation of 5ap is probably that the existence of a methyl
group in 1-phenylethanamine prevented the second amina-
tion process (Scheme 4b). Moreover, when stoichiometric
hypervalent iodine reagents, such as PhI(OAc)2 or IBX, were
employed instead of our catalytic system, no desired product
was obtained. This result indicated that the reaction pathway
may be not followed in catalysis involving in situ generated
hypervalent iodine (III or V) reagents (Scheme 4c). Final-
ly, radical trapping experiments were also carried out.
Recently, our group has also developed some novel
methods for the synthesis of heterocycles using amino acids
as nitrogen motifs via decarboxylative amination.10 There-
fore, we expected to use amino acids as nitrogen motifs
instead of benzylamines for the synthesis of imidazo[1,5-a]-
pyridines. To our delight, imidazo[1,5-a]pyridines could be
obtained in moderate yields from 1a and amino acids 4
under standard conditions (Scheme 3).
To gain insight into the mechanism, several control
experiments were carried out. First, 1a under standard
conditions in the absence of 2a did not produce the
expected iodo intermediate, suggesting that the reaction
does not proceed through an R-iodointermediate. When
the reaction of ethyl 2-(pyridin-2-yl)propanoate (1i) with 2a
was carried out under standard conditions, no amination
(11) For reviews on the CDC reaction, see: (a) Li, C.-J. Acc. Chem.
Res. 2009, 42, 335. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (c) Zhang, C.; Tang, C. H.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(12) For the benzylic cation intermediate, see: Sun, C. L.; Li, B. J.;
Shi, Z.-J. Chem. Rev. 2011, 111, 129.
(10) (a) Yan, Y. Z.; Wang, Z. Y. Chem. Commun. 2011, 47, 9513. (b)
Wang, Q.; Zhang, S.; Guo, F. F.; Zhang, B. Q.; Hu, P.; Wang, Z. Y.
J. Org. Chem. 2012, 77, 11161.
(13) For the imine ion intermediate, see: (a) Li, Z. P.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810. (b) Li, Z. P.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 3672.
Org. Lett., Vol. XX, No. XX, XXXX
C

or 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 4d).
This observation implied that the reaction presumably un-
derwent a radical pathway.
Scheme 4. Control Experiments for Mechanism
On the basis of the results described above and in
previous reports,8,11ꢀ13 a plausible mechanism was pro-
posed (Scheme 5). Initially, 1a is presumably involved a
hydrogen abstraction from benzylic CꢀH bond to give a
carbon radical A, which generates a benzylic cation B via a
single-electron-transfer process in the presence of Iþ.6,12
The nucleophilic substitution of 2a to B provides an inter-
mediate C. A oxidative dehydrogenation in C gives inter-
mediate D. Finally, D provides the intermediate E via a
similar radical process to the first amination, which could be
further converted to 3aa by removing a hydrogen ion and
rearrangement.8,13 Overall, the I2ꢀIþ redox process8b,10a
plays a key role in the CꢀN bond formations by promoting
reductive cleavage of OꢀO bond in the peroxide and the
oxidation of the benzylic radical to a benzylic cation or the
N-bound carbon radical to an imine ion.
In summary, we have developed a metal-free sequential
dual oxidative amination of C(sp3)ꢀH bonds for the synthe-
sis of imidazo[1,5-a]pyridines under mild conditions. Nota-
bly, this novel protocol is distinguished by (1) the lack of any
expensive transition metals; (2) operational simplicity; (3)
room temperature; (4) the fact that an inert atmosphere or
dry solvents are not required; (5) a broad substrate scope;
and (6) the production of alcohol and water as the only
waste. Iodine-catalyzed oxidative CꢀH aminations for the
synthesis of other heterocycles are ongoing in our laboratory.
Scheme 5. Mechanism for Synthesis of Imidazo[1,5-a]pyridine
via Dual Oxidative C(sp3)ꢀH Aminations
Acknowledgment. We are grateful to the Natural
Science Foundation of China (20932002, 207721118, and
20972144), the Ministry of Science & Technology of China
(2010CB912103), and the Chinese Academy of Sciences.
Supporting Information Available. General procedure
for the reaction and characterization data for products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We observed that the reaction was obviously inhibited in the
presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX