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ChemComm
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Journal Name
COMMUNICATION
different electronic substituents on the EMDQ. Various functional Cu(OTf)2/amine synergistic catalytic system VaiellwoAwrteicdle Ontlihnee
DOI: 10.1039/C5CC03314D
groups including benzyl ether (1b), carboxylate (1e), bromide (1f), nucleophilic addition of diverse functionalized aldehydes to a wide
and chloride (1g and 1h) were compatible with the mild catalysis range of electronically varied N-acyl quinoliniums in good yields
system, which will be beneficial for further diversification.
with excellent enantiocontrol. The synergistic catalytic system was
also effective for N-acyl dihydroisoquinoliniums and β-carboliniums,
demonstrating the general applicability of the protocol in the
enantioselective alkylation of diverse N-acyl hemiaminals.
We gratefully acknowledge the National Science
Foundation of China (21202093, 21472112), the Program for
New Century Excellent Talents in University (NCET-13-0346),
and the Shandong Science Fund for Distinguished Young
Scholars (JQ201404), Young Scientist Foundation Grant of
Shandong Province (BS2013YY001), and the Fundamental
Research Funds of Shandong University (2014JC005,
2015JC035) for financial support.
OH
ClCO2Me (1.1 equiv)
EtOH (5 equiv)
standard
condition
N
OEt
N
NaHCO3 (2 equiv)
toluene
N
C3H7
MeO
O
MeO
O
5a
3a
1a
(72%, syn/anti = 63:37)
(90% ee/ 66% ee)
Scheme 2 One‐Pot Alkylation of the Quinoline.
Given that quinolines are precursors for the preparation of
EMDQs, developing a one-pot protocol directly using quinolines as
the starting point would be highly desired. Treatment of quinoline 5a
with methyl chloroformate, EtOH, and NaHCO3, followed by
exposure to the standard coupling condition, delivered 3a with
moderate diastereoselectivity (syn/anti
enantioselectivity (90%/66% ee) in 72% yield (Scheme 2).
=
63:37) and good
Notes and references
1
(a) J. P. Michael, Nat. Prod. Rep. 1995, 12, 77; (b) J. Fotie, M.
Kaiser, D. A. Delfin, J. Manley, C. S. Reid, J.‐M. Paris, T.
Wenzler, L. Maes, K. V. Mahasenan, C. Li and K. A. Werbovetz,
J. Med. Chem. 2010, 53, 966.
E
2g
(3 equiv)
1) (20 mol %),
Cu(OTf)2 (10 mol %)
EtOH (1 equiv), Et2O, rt
N
O
N
O
2) NaBH4, EtOH
OMe
2
(
a
) M. Nakamura, A. Hirai and E. Nakamura, J. Am. Chem. Soc.
1996, 118, 8489; ( ) M. S. Taylor, N. Tokunaga and E. N.
Jacobsen, Angew. Chem., Int. Ed. 2005, 44, 6700; ( ) N.
Sasamoto, C. Dubs, Y. Hamashima and M. Sodeoka, J. Am.
Chem. Soc. 2006, 128, 14010; ( ) T. Hashimoto, M. Omote
Bn
7a
(< 5%)
OEt OMe
6a
b
OH
c
d
N
O
N
O
and K. Maruoka, Angew. Chem., Int. Ed. 2011, 50, 8952; (e)
same as above
+
N
O
W. Lin, T. Cao, W. Fan, Y. Han, J. Kuang, H. Luo, B. Miao, X.
OMe
OMe
Bn
Bn
Tang, Q. Yu, W. Yuan, J. Zhang, C. Zhu and S. Ma, Angew.
OEt OMe
OH
OH
Chem., Int. Ed. 2014, 53, 277; (
and P. G. Cozzi, Chem. Sci. 2014,
Landa, S. Saaby and K. A. Jørgensen, Angew. Chem., Int. Ed
2005, 44, 6058. ( ) J. Zhang, B. Tiwari, C. Xing, X. Chen and Y.
R. Chi, Angew. Chem., Int. Ed. 2012, 51, 3649; ( ) G. Zhang, Y.
Zhang and R. Wang, Angew. Chem., Int. Ed. 2011, 50, 10429;
) G. Zhang, Y. Ma, S. Wang, Y. Zhang and R. Wang, J. Am.
Chem. Soc. 2012, 134, 12334; ( ) G. Zhang, Y. Ma, S. Wang,
W. Kong and R. Wang, Chem. Sci. 2013, , 2645; ( ) A. J. Neel,
J. P. Hehn, P. F. Tripet and F. D. Toste, J. Am. Chem. Soc. 2013,
135, 14044; ( ) G. Bergonzini, C. S. Schindler, C.‐J. Wallentin,
E. N. Jacobsen and Stephenson, C. R. J. Chem. Sci. 2014,
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Meng, C. Li, H. Lou and L. Liu, Angew. Chem., Int. Ed 2015
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) M. Takamura, K. Funabashi, M. Kanai and M. Shibasaki, J.
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Y. Yamaoka, H. Miyabe, Y. Takemoto, J. Am. Chem. Soc. 2007,
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f
) L. Mengozzi, A. Gualandi
6b
7b
(68%, anti:syn = 60:40)
(94% ee/ 84% ee)
5
, 3915; ( ) K. Frisch, A.
g
.
h
E
2a
(3 equiv)
1) (20 mol %),
Cu(OTf)2 (10 mol %)
O
i
N
O
EtOH (1 equiv), Et2O, rt
N
N
H
OEt
(
j
2) NaBH4, EtOH
N
H
OEt
H7C3
OEt
OH
k
7c
6c
4
l
(77%, dr = 64:36)
(95% ee/ 93% ee)
m
Scheme 3 One‐Pot Alkylation of the Quinoline.
5
,
n
6
o
While the previously reported alkylations of isoquinoliniums
with aldehydes displayed excellent enantiocontrol, functionality-
containing aldehydes were not well tolerated due to the
incompatibility of the Hayashi-Jørgensen catalyst with the acyl
chloride, and the low stability of the isoquinolinium ion.2f The
success of the synergistic catalytic system on the alkylation of
quinoliniums prompted us to apply the concept to the reaction of
isoquinoliniums. In light of the low yield (9%) for the known
protocol with 3-phenylpropanal 2g, the aldehyde was selected as the
coupling partner for preliminary study. While isoquinoline-based
.
,
p
q
,
r
s
t
u
v
w
hemiaminal
6a
was
not
a
suitable
component,
3
(a
tetrahydroisoquinoline-derived 6b proved to be a competent partner
with 2g, affording 7b in 68% yield with high enantiocontrol
(94%/84% ee).11 Additionally, the alkylation of tetrahydro-β-
carboline-based 6c gave 7c in 77% yield with excellent
enantioselectivities (95%/93% ee), demonstrating the general
applicability of the synergistic catalytic system in the alkylation of
diverse N-acyl hemiaminals.
,
b
,
4
5
6
,
,
T. Kodama, P. N. Moquist and S. E. Schaus, Org. Lett. 2011,
13, 6316.
In conclusion, the first catalytic asymmetric alkylation of N-acyl
hemiaminals with aldehydes has been described. The
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