C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric N-H Insertion of Amines with
the insertion reaction with aniline became very slow, and the
insertion product was obtained in a moderate yield with 94% ee
(entry 16). The reduced yield might be attributed to the steric
hindrance of R1. In the reaction of ethyl R-diazophenylacetate with
aniline, the insertion product was formed in high yield; however,
the enantioselectivity was only 8% ee (entry 17). Besides aniline
and substituted anilines, N-methylaniline and benzamide could also
react with the diazoester to afford insertion products, but no
enantioselectivity was measured (entries 18 and 19). The aliphatic
amine, cyclohexylamine, was completely inert under the identical
reaction conditions (entry 20).
In summary, we have developed the first highly enantioselective
catalytic insertion of R-diazoesters into N-H bonds. By using the
copper complexes of chiral spiro bisoxazoline ligands as catalysts,
the R-amino acid derivatives were produced in high yields and
excellent enantioselectivities (up to 98% ee). Further study on the
application of this novel reaction is ongoing in our laboratory.
Diazoestersa
yield
ee
entry
R1
R2
R3
R4
product
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18
19c
20
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
tBu
Et
Et
Et
Et
Et
Ph
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
94
94
96
92
95
92
95
96
95
86
95
89
91
78
93
51
85
93
55
NRd
98
91
85
98
98
96
97
98
98
98
88
98
98
96
96
94
8
p-MePh
p-MeOPh
p-ClPh
p-BrPh
m-MePh
m-ClPh
m-BrPh
o-MePh
o-MeOPh
o-ClPh
1-naphthyl
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Bz
c-C6H11
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
Acknowledgment. We thank the National Natural Science
Foundation of China, the Major Basic Research Development
Program (Grant No. 2006CB806106), and the “111” project
(B06005) of the Ministry of Education of China for financial
support.
Ph
Me
Me
Me
rac
rac
Supporting Information Available: Experimental procedures,
characterizations of ligands and products, and the analysis of ee values
of products (PDF). This material is available free of charge via the
a Reaction conditions were the same as those in Table 1, entry 5. For
the characterization and analysis of ee values of insertion products, see
Supporting Information. b Reaction time: 48 h. c Reaction time: 16 h. d No
reaction.
References
(1) For reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley:
New York, 1998; Chapters 3 and 8. (b) Ye, T.; Mckervey, M. A. Chem.
ReV. 1994, 94, 1091.
also compared in the reaction of 2a and aniline under the identical
reaction conditions. The insertion product was obtained in only 5%
ee (entry 14), which showed that the chiral spirobiindane structure
of ligands is essential for obtaining optimum enantioselectivity in
copper-catalyzed insertions of diazoesters into N-H bonds.
A broad range of aniline derivatives was examined in the copper-
catalyzed asymmetric insertion reaction with ethyl 2-diazopropi-
onate (2a) by using ligand (Sa,S,S)-1a (Table 2). All substituted
anilines underwent the insertion reaction with high reactivity, and
complete conversions were achieved within 2 h. The corresponding
insertion products were obtained in high yields regardless of the
nature and the position of the substituents of the aniline derivatives
(entries 1-11). For most substrates, the enantioselectivities were
excellent (96-98% ee). Introduction of an electron-donating group
in the para position (entries 2 and 3) or a halogen atom in the
ortho position (entry 11) of aniline slightly diminished the enan-
tioselectivities to 85-91% ee, but the reason for the negative effect
of these substituents is unclear. In addition to aniline and its
derivatives, naphthalen-1-amine and naphthalen-2-amine can also
react with R-diazoester 2a to afford the corresponding R-naphthyl-
aminoesters in 98% ee with high yield (entries 12 and 13). In order
to demonstrate the scope and potential of the present enantio-
selective insertion reaction, the influence of the structure of the
diazoester on the reactivity and enantioselectivity was examined.
The insertion reactions of methyl and tert-butyl 2-diazopropionates
yielded the corresponding products in 96% ee (entries 14 and 15),
showing that the size of the R2 group of the diazoester has a
negligible effect on the enantioselectivity of the reaction. When
the R1 group of the R-diazoester was changed from methyl to ethyl,
(2) For recent examples, see: (a) Bolm, C.; Kasyan, A.; Drauz, K.; Gunther,
K.; Raabe, G. Angew. Chem., Int. Ed. 2000, 39, 2288. (b) Morilla, M. E.;
D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.;
Pe´rez, P. J. Chem. Commun. 2002, 2998. (c) Burtoloso, A. C. B.; Correia,
C. R. D. Tetrahedron Lett. 2004, 45, 3355. (d) Davies, J. R.; Kane, P. D.;
Moody, C. J. Tetrahedron 2004, 60, 3967. (e) Matsushita, H.; Lee, S.-H.;
Yoshida, K.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. Org.
Lett. 2004, 6, 4627. (f) Davies, J. R.; Kane, P. D.; Moody, C. J. J. Org.
Chem. 2005, 70, 7305. (g) Aviv, I.; Gross, Z. Chem. Commun. 2006, 4477.
(3) For diastereoselective N-H insertion, see: (a) Nicoud, J.-F.; Kagan, H.
B. Tetrahedron Lett. 1971, 12, 2065. (b) Aller, E.; Buck, R. T.; Drysdale,
M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson, N. D.; Sanghera, J.
B. J. Chem. Soc., Perkin Trans. 1 1996, 2879. (c) Davis, F. A.; Fang, T.;
Goswami, R. Org. Lett. 2002, 4, 1599. For asymmetric C-H insertion,
see: (d) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103,
2861. For asymmetric O-H insertion, see: (e) Maier, T. C.; Fu, G. C. J.
Am. Chem. Soc. 2006, 128, 4594. For asymmetric Si-H insertion, see:
(f) Buck, R. T.; Doyle, M. P.; Drysdale, M. J.; Ferris, L.; Forbes, D. C.;
Haigh, D.; Moody, C. J.; Pearson, N. D.; Zhou, Q.-L. Tetrahedron Lett.
1996, 37, 7631. (g) Davies, H. M. L.; Hansen, T.; Rutberg, J.; Bruzinski,
P. R. Tetrahedron Lett. 1997, 38, 1741. (h) Dakin, L. A.; Schaus, S. E.;
Jacobsen, E. N.; Panek, J. S. Tetrahedron Lett. 1998, 39, 8947.
(4) Garc´ıa, C. F.; McKervey, M. A.; Ye, T. Chem. Commun. 1996, 1465.
(5) Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol. Chem. 2004,
2, 3044.
(6) Liu, B.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L. Tetrahedron: Asymmetry
2006, 17, 634.
(7) BARF- ) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
(8) For hydrogenation, see: (a) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.;
Hormann, E.; McIntyre, S.; Menges, F.; Schonleber, M.; Smidt, S. P.;
Wustenberg, B.; Zimmermann, N. AdV. Synth. Catal. 2003, 345, 33. (b)
Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S. J. Am. Chem. Soc. 2006, 128,
12886. For hydrovinylation, see: (c) Nomura, N.; Jin, J.; Park, H.;
RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 459. (d) Shi, W.-J.; Zhang,
Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou, Q.-L. J. Am. Chem. Soc.
2006, 128, 2780. For ring opening reaction, see: (e) Lautens, M.; Hiebert,
S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834.
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