Highly enantioselective insertion of carbenoids into NH bonds catalyzed by copper(I) complexes of binol derivatives

Article abstract of DOI:10.1002/anie.201001686

Figure Persentation Secondary amines do It tool Catalytic asymmetric insertion of a-diazoesters in the N-H bond of differently substituted amines has been successfully achieved (see scheme; M.S.=molecular sieves). For a wide substrate scope, excellent enantioselectivities (up to 98% ee) and high yields (up to 99%) were obtained under mild reaction conditions.

Full text of DOI:10.1002/anie.201001686

Angewandte
Chemie
DOI: 10.1002/anie.201001686
Asymmetric Catalysis
À
Highly Enantioselective Insertion of Carbenoids into N H Bonds
Catalyzed by Copper(I) Complexes of Binol Derivatives**
Zongrui Hou, Jun Wang, Peng He, Jing Wang, Bo Qin, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*
The catalytic asymmetric insertion reaction of a-diazocar-
ee values (up to 94%).[9] Despite these achievements, in view
À
À
bonyl compounds into X H bonds (X = C, N, P, O, S, etc.) has
attracted much attention because it provides an efficient way
of the great utility of this N H insertion reaction, the
exploration of alternative efficient catalytic systems is still
highly desirable. Herein, we describe a novel and readily
available copper(I) catalyst generated from the (R)-binol
derivative 2b and CuCl, from which a series of enantioen-
riched substituted a-amino acetates were prepared in excel-
lent yields and ee values.
to construct versatile and useful building blocks.[1] In contrast
À
to the extensive and fruitful studies on asymmetric C H
insertion,[2] the investigation of enantioselective insertion of
a-diazocarbonyl compounds into heteroatom–hydrogen
bonds (X H) is still limited. This may result from the
presence of the highly reactive polar X H bonds, which form
the ylide intermediates upon attack of the electrophilic metal
carbene to the lone pair of electrons on the heteroatom, thus
leading to a more intricate complexion.[4] Moreover, the
Lewis basic nitrogen atoms in the starting amine and in the
products tend to strongly coordinate to the central metal atom
in the catalyst, which may result in the deactivation of the
catalyst.[5] Among the insertion reactions, metal-catalyzed
[3]
À
À
Recently, our research group reported a novel axially
chiral N,N’-dioxide 1, which was demonstrated to be a highly
efficient organocatalyst for the enantioselective Strecker
reaction of N-Ts-protected ketimines (Ts = 4-toluenesul-
fonyl; Scheme 1).[10] To find further uses for this compound,
À
carbenoid N H insertions are of great importance, because
they lead to the formation of various bioactive molecules such
as a-amino ketones, a-amino acid derivatives, and pharma-
ceutically useful compounds.[6] In a pioneering study, Jørgen-
sen and co-workers reported the first asymmetric intermo-
À
lecular N H insertion reactions by means of chiral copper(I)/
silver(I) bisoxazoline complexes. Although only low to
moderate yields and ee values were obtained, this study has
À
actually opened the doors to asymmetric versions of N H
insertion reactions.[7] No further breakthrough was made until
Zhou and co-workers reported excellent ee values (98%) and
yields (94%) using a catalytic system consisting of a
spirobisoxazoline ligand, CuCl, and NaBARF (BARF =
[B[3,5-(CF3)2C6H3]4]À).[8] Later, Lee and Fu disclosed another
À
highly enantioselective N H insertion reaction with a-aryl
diazoesters and carbamates (Boc-NH2 and Cbz-NH2; Boc =
tert-butoxycarbonyl, Cbz = benzyloxycarbonyl) as substrates,
which leads to useful arylglycine derivatives with excellent
[*] Z. R. Hou, Dr. J. Wang, P. He, J. Wang, Dr. B. Qin, Dr. X. H. Liu,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Scheme 1. Ligands used in this study.
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University Chengdu 610064 (China)
Fax: (+86)28-8541-8249
À
we employed it as a chiral ligand in N H insertion reactions.
However, almost racemic product was obtained in moderate
yield for the reaction of aniline (6a) with three equivalents of
the diazo compound 7a using the complex of 1 with CuCl in
CH2Cl2 (Table 1, entry 1).
E-mail: xmfeng@scu.edu.cn
[**] We acknowledge the National Natural Science Foundation of China
(Nos. 20702033 and 20732003), the PCSIRT (No. IRT0846), and the
National Basic Research Program of China (973 Program)
Interestingly, when 2a (the precursor of 1) was used both
the yield and the ee value were slightly improved, thus
suggesting that the N-oxide moieties in 1 were not necessary
for the present reaction (Table 1, entry 2). From the observa-
tion that several chiral elements co-existed in ligand 2a, it was
(No. 2010CB833300) for financial support. We also thank the
Sichuan University Analytical & Testing Center for NMR analysis
and the State Key Laboratory of Biotherapy for HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001686.
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4763

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À
Table 1: Catalytic asymmetric insertion of diazopropionate into the N H
bond of aniline.
Entry[a] L/M
Solvent Additive (M.S.) Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1/CuCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
62
85
96
99
trace
86
12
trace
90
trace
22
NR
NR
76
trace
trace
trace
92
98
93
96
99
À8
À17
85
67
0
8
0
À6
À5
3
8
–
–
38
0
À28
66
86
88
87
2a/CuCl
2b/CuCl
2c/CuCl
2d/CuCl
3/CuCl
4a/CuCl
4b/CuCl
binol/CuCl CH2Cl2
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
22[e]
23[e,f]
24[e,g]
5a/CuCl
5b/CuCl
2b/CuCl2
CH2Cl2
CH2Cl2
CH2Cl2
Figure 1. ORTEP plot of 2b with ellipsoids drawn at 30% probability.
2b/CuClO4 CH2Cl2
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
2b/CuCl
CHCl3
toluene
THF
CH3CN
CH2Cl2 3 ꢀ
CH2Cl2 4 ꢀ
CH2Cl2 5 ꢀ
CH2Cl2 4 ꢀ
CH2Cl2 4 ꢀ
CH2Cl2 4 ꢀ
CH2Cl2 4 ꢀ
led to a lower ee value (Table 1, entry 4), thus indicating that a
suitable dihedral angle was crucial in the chiral induction step
of the catalytic process. When two hydroxy groups of 2b were
replaced by two methoxymethoxy groups (2d), traces of
racemic product were obtained, which showed that the
hydroxy groups in ligand 2b were essential to the formation
of a complex with CuI (Table 1, entry 5). When the axially
chiral binaphthyl skeleton was replaced by an achiral benzene
ring to afford ligand 3, the enantioselectivity was drastically
decreased (Table 1, entry 6). Moreover, binol-derived bisoxa-
zolines 4a and 4b were also synthesized for ligand screening.
However, nearly no enantiodiscrimination, and very low
yields were given under identical reaction conditions (Table 1,
entries 7 and 8). Other ligands such as (S)-binol and binol-
derived tertiary amines 5a and 5b were also examined.
However, only very poor results were obtained (Table 1,
entries 9–11).
86 (S)
93
85
91
88
99
[a] All the reactions were carried out with 6a (0.2 mmol), 7a (3 equiv) in
2 mL solution with 10 mol% of catalyst at 08C in a dry test tube under an
inert atmosphere and reactions were stirred for 8 hours unless otherwise
specified. [b] Yield of isolated product. [c] Determined by HPLC on a
chiral stationary phase. [d] 7b was used instead of 7a. [e] For details, see
the Experimental Section. [f] 2 mol% of catalyst was used. [g] 20 mol%
of catalyst was used.
reasonable to speculate that the chirally matched properties
might have a significant impact on the reaction outcome. As
expected, when the configuration of the binaphthyl unit was
switched from S (2a) to R (2b) while other structural moieties
were kept constant, a high yield (96%) and a greatly
enhanced enantioselectivity (85% ee) were observed
(Table 1, entry 3). It should be noted that to the newly
formed chiral center in ligand 1 (or 2a) derived from (S)-binol
and l-proliamide was assigned the R configuration based on
the observation of a strong NOE interaction between H1 and
H2.[10] However, for the ligand 2b derived from (R)-binol and
l-proliamide, nearly no NOE interaction was observed, thus
suggesting that the corresponding H1 and H2 are in the
anti positions. This assumption was further confirmed by the
single-crystal X-ray analysis of 2b, and the configuration of
the new stereogenic center was assigned as S (Figure 1).[11]
Based on the above findings, it was concluded that the
configuration of the new chiral center was predominantly
controlled by the axial chirality of the binol ligand rather than
by l-proliamide.
With 2b as the optimal ligand, other copper sources
including CuCl2 and CuClO4 were tested. However, nearly no
reaction was observed (Table 1, entries 12 and 13). Besides
CH2Cl2, other solvents were investigated. When CHCl3 was
used, low ee values and moderate yields were obtained
(Table 1, entry 14) while use of toluene, led to the formation
of the product in a trace amount (Table 1, entry 15). Other
coordinating solvents such as THF and CH3CN were also
tested, however, the reactions were very slow and the
ee values were dramatically decreased (Table 1, entries 16
and 17). Additive screening showed that molecular sieves
(M.S.) have a slight positive effect on the enantioselectivity
(Table 1, entries 18–20). Among the tested molecular sieves,
4 ꢀ M.S. gave the best ee value (Table 1, entry 19). However,
when the R group in the diazopropionate 7 was changed from
tert-butyl to ethyl, a lower ee value (86%) was obtained with a
yield of 96% (Table 1, entry 21).
To further improve the outcome of our reaction, different
kinds of operational procedures were tried and compared.
Intriguingly, it was found that better results could be achieved
by allowing the reaction mixture to stay without continuous
stirring after the full addition of the reactants to the solution
Next, the dihedral angle of the binaphthyl unit was
investigated. However, the ligand 2c derived from H8-binol
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Angewandte
Chemie
containing the catalyst. However, the reaction mixture should
be kept homodisperse by shaking the reaction tube for several
seconds every 2 hours during the initial 6 hours of the reaction
at the reaction temperature. We reasoned that under such
conditions, the reaction rate was effectively lowered. As a
result, the non-enantioselective background reaction was to
some extent suppressed and more products were formed
through the desired enantioselective route (Table 1, entry 22).
Some other catalyst loadings (such as 2 mol% and 20 mol%)
were also tried, but improved results were not achieved
(Table 1, entries 23 and 24).
and 22). To our knowledge, these are the best results for the
reaction of a-diazoester with secondary amines.
In summary, a novel and readily available binol-derivative
copper(I) catalyst was developed for the highly enantioselec-
À
tive catalytic insertion reaction of a-diazoesters into N H
bonds of the amines under mild reaction conditions. In
addition to the excellent ee values and yields observed for
primary amines, the reaction with secondary amine also led to
moderate to good results. A variety of useful chiral a-amino
esters with different N-substituted groups could be facilely
prepared in excellent yields and enantiomeric excesses.
À
Under the optimized reaction conditions, a broad range of
substituted anilines were examined with tert-butyl 2-diazo-
propionate (7a). As shown in Table 2, regardless of the
position and the nature of the substituents, various substituted
anilines could be smoothly converted into the corresponding
Further studies on the efficient catalytic N H insertion of
secondary amine with diazoesters as well as mechanistic
studies are in progress.
products in high yields (92–99%) with excellent ee values Experimental SectionÀ
Typical procedure for the N H insertion reaction: CH2Cl2 (2.0 mL)
(87–98%; Table 2, entries 1–18). In addition, 1-naphthyl
amine was also treated with 7a to afford a-amino ester in
93% ee with 90% yield (Table 2, entry 19).
Moreover, besides primary amines, the secondary amine
N-methylaniline was also examined under the same reaction
conditions. The desired product was obtained in high yield
although with only 25% ee (Table 2, entry 20). When methyl
and ethyl a-diazophenylacetate were treated with N-methyl-
aniline, improved ee values were observed (Table 2, entries 21
was added under an inert atmosphere to a dry test tube charged with
2b (0.02 mmol), CuCl (0.02 mmol), and M.S.(4 ꢀ, 50 mg). The tube
was well sealed with a septum and the mixture was stirred at 308C for
1 h. After cooling to 08C, amine (0.2 mmol) and a-diazoester
(0.6 mmol) were introduced successively by syringes. Subsequently,
the reaction mixture was carefully shaken for several seconds. During
the next 6 h, the mixture was shaken for several seconds every 2 h to
ensure homodispersity and then allowed to stay without stirring for
further 12 h at 08C. The reaction mixture was directly upload onto a
column of silica gel and eluted with petroleum ether/ethyl acetate =
10:1.
Table 2: copper(I)-catalyzed asymmetric insertion of diazoesters into the
Received: March 21, 2010
Published online: June 8, 2010
À
N H bond of amine.
Keywords: a-amino acids · asymmetric catalysis · binol ·
.
À
carbenoids · N H insertion
Entry[a]
Aniline 6
Diazo 7 Product Yield [%][b] ee [%][c]
R1
R2
R3
R4
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Catalytic Methods for Organic Synthesis with Diazo Compounds,
Wiley, New York, 1998, Chapters 3 and 8; b) T. Ye, M. A.
Mckervey, Chem. Rev. 1994, 94, 1091; c) Z. H. Zhang, J. B. Wang,
Tetrahedron 2008, 64, 6577; Y. Zhang, J. B. Wang, Chem.
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1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me tBu 8a
Me tBu 8b
Me tBu 8c
Me tBu 8d
Me tBu 8e
Me tBu 8 f
Me tBu 8g
Me tBu 8h
Me tBu 8i
Me tBu 8j
Me tBu 8k
Me tBu 8l
Me tBu 8m
Me tBu 8n
Me tBu 8o
Me tBu 8p
Me tBu 8q
Me tBu 8r
Me tBu 8s
99
99
98
99
99
99
99
97
98
98
92
95
92
93
98
92
99
98
90
98
82
88
93
94
97
93
96
98
96
94
95
96
90
94
87
95
93
90
97
95
93
25
67
70
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-MeC6H4
3-NO2C6H4
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
2-CF3OC6H4
3-CF3OC6H4
4-CF3OC6H4
1-naphthyl
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Me Me tBu 8t
Me Ph Me 8u
Me Ph Et
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Ph
Ph
8v
[a] All the reactions were carried out with 6 (0.2 mmol), 7 (3 equiv) in
2 mL CH2Cl2 with 10 mol% catalyst and M.S. (4 ꢀ, 50 mg) at 08C in a dry
test tube under an inert atmosphere for 18 h. [b] yield of isolated
product. [c] Determined by HPLC on a chiral stationary phase.
Angew. Chem. Int. Ed. 2010, 49, 4763 –4766
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Communications
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