activation is still rare and is limited to a benzylic or allylic
position.8,9
amides with alkynes.2d We next focused on the use of
cationic Ir complex as an effective catalyst in the activation
of the sp3 CÀH bond of 2-(methylamino)pyridine (R = H).11
The reaction with styrene (2 equiv) proceeded efficiently to
give alkylated product in a high NMR yield of 91% under
the previous reaction conditions (Scheme 2).12 We further
examined the reaction of 2-(ethylamino)pyridine with
styrene (8 equiv): to our delight, secondary sp3 CÀH bond
activation proceeded, and the alkylated product 3a with a
chiral center was obtained,12 albeit in moderate yield even
after a longer reaction time. We were then ready to study
the enantioselective reaction initiated by secondary sp3
CÀH bond cleavage.
In this communication, we describe an enantioselective
secondary sp3 CÀH bond activation of 2-(alkylamino)-
pyridine using a chiral cationic Ir(I) catalyst, for which
the enantiomeric excess was as high as 90%. Jun re-
ported pioneering work of a Ru-catalyzed reaction of
2-(benzylamino)pyridine with alkenes, which was initiated
by secondary sp3 CÀH bond cleavage at the benzylic
position (Scheme 1).7b,10 Murai also reported a Ru-
catalyzed reaction of 2-(N-pyrrolidinyl)pyridine with alkenes.
In contrast, we realized an enantioselective cleavage
of secondary sp3 CÀH bond adjacent to nitrogen of
2-(alkylamino)pyridine at relatively lower temperature by
using a chiral Ir catalyst.
Scheme 2. Reaction of 2-Aminopyridines with Styrene under the
Previous Reaction Conditions
Scheme 1. Examples of Secondary sp3 CÀH Bond Cleavage
Adjacent to Nitrogen of 2-Aminopyridine Derivatives
When (S)-BINAP was used, chiral amine 3a was ob-
tained with good enantioselectivity (Table 1, entry 1). We
further screened the reaction conditions. Initially, several
chiral diphosphine ligands were examined (entries 2À5).
The enantiomeric excess of 3a reached 80% with the use of
(S)-tolBINAP. More bulky xylylBINAP gave a higher
yield, but with low ee. H8ÀBINAP derivatives facilitated
the reaction to give 3a in high yield but with moderate ee.
Therefore, we decided upon tolBINAP as the best chiral
ligand, and next tuned the counteranion of the iridium
complex (entries 6À8). However, the results did not exceed
those with BF4. When 1,2-dimethoxyethane (DME) was
used as a solvent in place of chlorobenzene, the reaction
proceeded efficiently even at 75 °C; the enantioselectivity
was improved to ca. 90% and the yield was increased
(entry 9). Three equivalent amounts of styrene were suffi-
cient to achieve good yield and high ee at a slightly higher
reaction temperature (entry 10).
We previously reported that a cationic Ir-rac-BINAP
complex catalyzed the sp3 CÀH bond alkenylation of
(8) For enantioselective sp3 CÀH oxidation/CÀC bond formation:
(a) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (b) Li, Z.; Macleod, P. D.; Li,
C.-J. Tetrahedron: Asymmetry 2006, 17, 590. (c) Shi, B.-F.; Maugel, N.;
Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882.
(d) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi, P. G.
Chem. Commun. 2009, 5919. (e) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z.
Angew. Chem., Int. Ed. 2010, 49, 5558.
(9) For enantioselective hydride transfer/CÀC bond formation, see:
(a) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 13226. (b) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc.
2010, 132, 11847. (c) Li, Q.; Yu, Z.-X. Angew. Chem., Int. Ed. 2011, 50,
2144.
Subsequently, the scope of alkene was examined for the
present enantioselective reaction with 2-(ethylamino)-
pyridine using two reaction conditions (methods A and B)
(Table 2). 4-Methoxy- and methyl-substituted styrenes 2b
and 2c led to the corresponding products 3b and 3c in
good yields with high enantiomeric excesses (entries 1À4).
(10) For sp2 CÀH bond activation adjacent to the nitrogen atom of
2-aminopyridine: (a) Chatani, N.; Ishii, Y.; Ie, Y.; Kakiuchi, F.; Murai,
S. J. Org. Chem. 1998, 63, 5129. (b) Matsuura, Y.; Tamura, M.; Kochi,
T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129,
9858. (c) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.; Miura, M.
Chem. Lett. 2009, 38, 118. (d) Gao, K.; Lee., P.-S.; Fujita, T.; Yoshikai,
N. J. Am. Chem. Soc. 2010, 132, 12249.
(11) From an organometallic aspect, CÀH bond cleavage of
2-(dimethylamino)- and 2-(diethylamino)pyridine by using Ir(III)-dihy-
dride complex was reported, where Ir-carbene complexes were obtained:
(a) Lee, D.-H.; Chen, J.; Faller, J. W.; Crabtree, R. H. Chem. Commun.
2001, 213. (b) Clot, E.; Chen, J.; Lee, D.-H.; Sung, S. Y.; Appelhans,
L. N.; Faller, J. W.; Crabtree, R. H.; Eisenstein, O. J. Am. Chem. Soc.
2004, 126, 8795.
(12) When the reaction of 2-(dimethylamino)pyridine with styrene
was examined under the same reaction conditions, the monoalkylated
product was obtained in low yield (10%).
(13) In the last two years, an enantioselective hydroaminoalkylation
of amines to substituted alkenes was reported by using chiral Ta and Nb
catalysts. Primary sp3 CÀH bond activation of methylaniline derivatives
realized moderate to high enantioselectivities. (a) Eisenberger, P.;
Ayinla, R. O.; Lauzon, J. M. P.; Schafer, L. L. Angew. Chem., Int. Ed.
2009, 48, 8361. (b) Zi, G.; Zhang, F.; Song, H. Chem. Commun. 2010, 46,
6296. (c) Reznichenko, A. L.; Emge, T. J.; Audorsch, S.; Klauber, E. G.;
Hultzsch, K. C.; Schmidt, B. Organometallics 2011, 30, 921.
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