Highly enantioselective insertion of carbenoids into N-H bonds catalyzed by copper complexes of chiral spiro bisoxazolines

Article abstract of DOI:10.1021/ja0711765

A highly efficient copper-catalyzed asymmetric insertion of α-diazoesters into N-H bonds has been realized by using chiral spiro bisoxazoline ligands, affording α-amino acid derivatives in high yields with excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja0711765

Published on Web 04/12/2007
Highly Enantioselective Insertion of Carbenoids into N-H Bonds Catalyzed
by Copper Complexes of Chiral Spiro Bisoxazolines
Bin Liu, Shou-Fei Zhu, Wei Zhang, Chao Chen, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received February 17, 2007; E-mail: qlzhou@nankai.edu.cn
Scheme 1
The catalytic insertion of R-diazocarbonyl compounds, which
are easily prepared from readily accessible precursors and have a
long history of useful applications in organic synthesis, into X-H
(X ) C, N, O, S) bonds is a very powerful organic transformation
for preparing highly versatile building blocks.1 Among these
reactions, the insertion of N-H bonds was proven to be an efficient
method for preparing R-amino ketones, R-amino esters, and
nitrogen-containing heterocycles and has received considerable
attention.2 The concept of metal-carbenoid insertions into N-H
bonds has been known for more than three decades, but surprisingly,
Table 1. Cu-Catalyzed Asymmetric Insertion of Ethyl
only two catalytic asymmetric versions of this topic have been
documented, and the enantioselectivities were very low.3 In 1996,
2-Diazopropionate into the N-H Bond of Anilinea
McKervey and co-workers4 reported the first asymmetric intra-
molecular N-H bond insertion reaction catalyzed by chiral rhod-
ium(II) carboxylates leading to pipecolic acid derivatives with up
to 45% ee. Very recently, Jørgensen et al.5 disclosed the copper-
time
yield
(%)b
ee
(%)c
and silver-catalyzed asymmetric intermolecular insertion of R-di-
entry
ligand
[Cu]
solvent
(h)
azoesters into N-H bonds in the presence of chiral nitrogen ligands,
including Evans bisoxazoline, resulting in R-amino acid derivatives
with up to 48% ee. The highly enantioselective catalytic N-H
insertion reaction remains a great challenge to organic chemists.
Recently, we have developed a new class of chiral bisoxazoline
ligands (SpiroBOX, 1) based on the spirobiindane scaffold (Scheme
1) and proved they were efficient for copper-catalyzed asymmetric
cyclopropanation and allylic oxidation.6 Here we report a copper-
catalyzed asymmetric insertion of R-diazoesters into N-H bonds
of aromatic amines in the presence of chiral spiro bisoxazoline
ligands 1, providing R-amino acid derivatives in high yields with
excellent enantioselectivities (up to 98% ee).
1
2
3
(Sa,S,S)-1a
(Ra,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1b
(Sa,S,S)-1c
(Sa,S,S)-1d
CuPF6(MeCN)4
CuPF6(MeCN)4
CuOTf(Tol)1/2
CuCl
CuCl/NaBARF
CuCl/NaBARF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
24
2
2
2
2
6
72
2
78
95
83
15
94
90
80
89
80
45
83
90
75
66
43
5
5
4
rac
98
95
85
98
85
rac
61
79
85
5
5
6d
7
CuCl2/NaBARF CH2Cl2
8
9
CuCl/NaBARF
CuCl/NaBARF
CuCl/NaBARF
CuCl/NaBARF
CuCl/NaBARF
CuCl/NaBARF
CHCl3
C6H6
10
11
12
13
14
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
(S,S)-Ph-Box CuCl/NaBARF
In our study, the insertion of ethyl 2-diazopropionate (2a) into
the N-H bond of aniline (3a) was initially performed in dichlo-
romethane at 25 °C with the catalyst generated in situ from 5 mol
% of CuPF6(MeCN)4 and 6 mol % of (Sa,S,S)-1a. The insertion
product, ethyl R-phenylaminopropionate, was obtained in 78% yield
with 43% ee (Table 1, entry 1). Comparison of the two diastere-
omers of ligand 1a clearly revealed that the (Sa,S,S)-1a has a
matched combination of chiralities in terms of enantioselectivity
(entries 1 and 2). Various copper catalyst precursors, including
CuOTf and CuCl, were tested in the reaction with ligand (Sa,S,S)-
1a. The nature of the counterions of the catalysts significantly
influenced the enantioselectivity and reactivity of the catalyst. The
CuOTf gave the insertion product in only 5% ee, which showed
that the smaller and stronger coordinating OTf- ion is evidently
inferior to the PF6- ion in the enantiocontrol of the reaction (entries
1 and 3). The use of the neutral copper catalyst precursor CuCl
gave an extremely low yield and no asymmetric induction (entry
4). To improve the enantioselectivity of the reaction, we further
investigated a copper catalyst with the larger and non-coordinating
ion BARF-,7 which has been successfully applied in a range of
catalytic asymmetric transformations for modifying the reactivity
and enantioselectivity of catalysts.8 The catalyst [Cu((Sa,S,S)-
a Reaction conditions: [Cu] (0.01 mmol), ligand (0.012 mmol), and
NaBARF (0.012 mmol) (entries 5-14) were mixed in solvent (2 mL) for
2 h at 25 °C, then aniline (0.2 mmol) and ethyl 2-diazopropionate (0.2
mmol) were introduced and stirred at 25 °C. b Isolated yield. c Determined
by chiral HPLC using a Chiralpak AS column. d With 1 mol % of catalyst,
refluxing.
1a)]+BARF- was prepared by mixing CuCl, ligand (Sa,S,S)-1a, and
NaBARF. As we expected, the catalyst [Cu((Sa,S,S)-1a)]+BARF-
dramatically increased the ee value of the insertion products 4a to
98% and afforded a high yield (entry 5). The catalyst with the
BARF- anion also has a high activity, which permitted reduction
of catalyst loading to 1 mol % (entry 6). Besides CuCl, CuCl2 could
be used as a catalyst precursor, although the enantioselectivity was
slightly lower than that obtained by using CuCl. In addition to CH2-
Cl2, CHCl3 and C6H6 are suitable solvents for the insertion reaction
with good to excellent enantioselectivities (entries 8 and 9).
However, the reaction became very slow and non-enantioselective
in the polar coordinating solvent MeCN (entry 10). In contrast to
the ligand (Sa,S,S)-1a, other spiro bisoxazolines containing different
aliphatic substituents on the oxazoline rings gave lower enantio-
selectivities (entries 11-13). The Evans ligand (S,S)-Ph-Box was
9
5834
J. AM. CHEM. SOC. 2007, 129, 5834-5835
10.1021/ja0711765 CCC: $37.00 © 2007 American Chemical Society

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
Internet at http://pubs.acs.org.
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
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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.
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