Enantioselective N-H insertion reaction of α-aryl α-diazoketones: An efficient route to chiral α-aminoketones

Article abstract of DOI:10.1002/anie.201400236

A highly enantioselective N-H insertion reaction of α-diazoketones was developed by using cooperative catalysis by dirhodium(II) carboxylates and chiral spiro phosphoric acids. The insertion reaction provides a new access route to diverse chiral α-aminoketones, which are versatile building blocks in organic synthesis, with fast reaction rates, good yields and high enantioselectivity under mild and neutral conditions. Spiro inspiration: A highly enantioselective N-H insertion reaction of α-diazoketones was developed by using cooperative catalysis by dirhodium(II) carboxylates and chiral spiro phosphoric acids. The insertion reaction provides a new access route to diverse chiral α-aminoketones, which are versatile building blocks in the organic synthesis, with fast reaction rates, good yields and high enantioselectivity under mild and neutral conditions.

Full text of DOI:10.1002/anie.201400236

Angewandte
Chemie
DOI: 10.1002/anie.201400236
Asymmetric Catalysis Very Important Paper
À
Enantioselective N H Insertion Reaction of a-Aryl a-Diazoketones:
An Efficient Route to Chiral a-Aminoketones**
Bin Xu, Shou-Fei Zhu,* Xiao-Dong Zuo, Zhi-Chao Zhang, and Qi-Lin Zhou*
À
Abstract: A highly enantioselective N H insertion reaction of
a-diazoketones was developed by using cooperative catalysis
by dirhodium(II) carboxylates and chiral spiro phosphoric
acids. The insertion reaction provides a new access route to
diverse chiral a-aminoketones, which are versatile building
blocks in organic synthesis, with fast reaction rates, good yields
and high enantioselectivity under mild and neutral conditions.
À
T
he construction of carbon–heteroatom bonds (C X) is
a central task for studies in organic synthesis.[1] C X bonds
can be formed directly by transition-metal-catalyzed insertion
À
À
of carbenes into heteroatom–hydrogen bonds (X H, where
X = N, O, S, etc.).[2] Recently, significant progress in catalytic
À
asymmetric X H insertion reactions has been made, for
example, high enantioselectivities have been achieved with
Figure 1. The catalysts and ligands used in this study.
À
À
À
carbene insertions into N H, O H, and S H bonds, which all
contain heteroatoms with lone-pair electrons.[3] However, a-
diazoesters are the only carbene precursors that have been
À
into X H bonds in which X has lone-pair electrons is that the
À
used for these asymmetric X H insertion reactions, which
strongly electron-withdrawing carbonyl group promotes the
formation of free ylide III[2,6] or enol IV,[7] and chiral catalyst
is thus not present during the chirality-determining proton-
transfer step (Scheme 1).
produce chiral a-heteroatom-substituted esters. Therefore,
the potential applications of these reactions are severely
limited. a-Diazoketones, another readily available carbene
precursor, have been used in a few rhodium-catalyzed
À
À
asymmetric cyclopropanation reactions, in C H and Si H
insertion reactions, and in tandem reactions involving
ylides.[2,4] X H insertion reactions of a-diazoketones produce
À
a-heteroatom-substituted ketones, which are useful building
blocks for organic synthesis. However, when we used 1-diazo-
1-phenylpropan-2-one (2a) in the asymmetric insertion
reaction with tert-butyl carbamate (BocNH2) catalyzed by
[Rh2(R-DOSP)4], [Rh2(S-PTAD)4], or a chiral copper com-
plex with a spirobisoxazoline ligand (4; Figure 1), no enan-
tioselectivity was observed (Table 1, entries 1–3).[5] The
problem with the asymmetric insertion of a-diazoketones
[*] B. Xu, Prof. S.-F. Zhu, X.-D. Zuo, Z.-C. Zhang, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin 300071 (China)
and
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
À
Scheme 1. Proposed pathway of X H insertions of a-diazoketones.
E-mail: sfzhu@nankai.edu.cn
qlzhou@nankai.edu.cn
Homepage: http://zhou.nankai.edu.cn/
À
Herein, we report a highly enantioselective N H insertion
[**] We thank the National Natural Science Foundation of China and the
National Basic Research Program of China (2012CB821600), the
“111” project (B06005) of the Ministry of Education of China, and
the Program for New Century Excellent Talents in University (NCET-
10-0516) for financial support.
reaction of a-diazoketones co-catalyzed by dirhodium(II)
carboxylates and chiral spiro phosphoric acids (SPAs, 1), in
which chiral induction was achieved in the proton-transfer
step.[8] The mild, neutral conditions bring special advantages
for the preparation of synthetically important chiral a-
aminoketones,[9] which can epimerize under harsh conditions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400236.
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À
À
Table 2: Enantioselective N H insertion reaction of a-diazoketones:
substrate scope.
Initially, we performed the N H insertion reaction of a-
diazoketone 2a with BocNH2 by using 1 mol% [Rh2(OAc)4]
and 1 mol% SPA 1 as the catalysts (Table 1). SPAs with
various substituents at the 6 and 6’ positions were evaluated
(Table 1, entries 4–11), and the 6,6’-di-(4-PhC6H4)-substituted
SPA 1c afforded the highest enantioselectivity (52% ee;
Table 1, entry 6). The type of dirhodium(II) complex strongly
Entry R1
R2
Product Yield [%] ee [%][11]
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
Me
3a
3b
3c
3d
3e
3 f
3g
3h
3i
80
79
82
78
80
82
75
86
95
85
78
96(R)
94
93
93
95
96
90
86
97
4-MeC6H4
4-BrC6H4
4-FC6H4
À
Table 1: Enantioselective N H insertion reaction of a-diazoketone 2a:
optimization of the reaction conditions.
3-MeOC6H4 Me
3-MeC6H4
3-FC6H4
2-FC6H4
2-Naph
C6H5
Me
Me
Me
Me
Et
9
10
11
Entry[a]
[M]
SPA
Yield [%][b]
ee [%][c]
3j
3k
97(R)
98(R)
1[d]
2
3
4
5
6
7
8
CuI/4
none
none
none
1a
1b
1c
1d
1e
1 f
1g
1h
1c
78
70
72
79
76
85
84
88
75
85
76
75
89
87
85
80
–
0
1
1
14
50
52
25
37
17
8
C6H5
nBu
[Rh2(R-DOSP)4]
[Rh2(S-PTAD)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(oct)4]
[Rh2(piv)4]
[Rh2(TPA)4]
[Rh2(TFA)4]
[Rh2(TFA)4]
none
12
13
C6H5
C6H5
3l
82
46
96(R)
95(R)
3m
14
15
C6H5
C6H5
3n
3o
56
85
92
95(R)
16
17
18
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-FC6H4
3p
3q
3r
85
89
78
96(R)
98
96
9
10
11
12
13
14
15
16[e]
17[f]
4
47
58
67
93
96
–
19
C6H5
3s
79
94
1c
1c
1c
1c
The reaction conditions and analysis method were the same as those
described for Table 1, entry 16. All of the reactions had run to completion
within 1 min after the addition of diazo compound 2.
1c
[a] Reaction conditions: [Rh]/SPA/2a/BocNH2 =0.002:0.002:0.21:0.2
(mmol) in 2 mL of CHCl3 at 258C. [b] Yield of isolated product.
[c] Determined by HPLC. [d] With 5 mol% catalyst, 4 h. [e] A mixed
solution of two substrates was added over 5 min by a pump. [f] No
insertion product was detected and 2a was recovered in 93% yield.
diazoketones[10] (Table 2). All of the tested a-aryl-a-diazo-
acetones (2a–2i) reacted completely in 1 min to afford the
corresponding chiral a-aminoketones 3a–3i in good yields
with high enantioselectivity (Table 2, entries 1–9). The elec-
tronic properties of the substituent at the para or meta
position of the phenyl ring of the diazoketone affected the
yields and enantioselectivity only slightly, whereas an ortho-
fluoro substituent lowered the enantioselectivity slightly
(86% ee; Table 2, entry 8). We also studied the effect of the
R2 substituent. Excellent enantioselectivity (92–98% ee) was
obtained when R2 was either an alkyl group (2j–2o; Table 2,
entries 10–15) or an aryl group (2p–2s; Table 2, entries 16–
19). The insertion reaction tolerated a range of functional
groups, such as alkenyl, methoxy, silyloxy, and N-methyl
pyrrole (Table 2, entries 13–15 and 19). In the reactions of
2m, which has a terminal olefin, and 2n, which has a methoxy
group, the occurrence of side reactions (intramolecular
affected the enantioselectivity of the reaction (Table 1,
entries 12–15). Specifically, when we used dirhodium(II)
carboxylates, including [Rh2(TPA)4], which gives the best
results in the N H insertion reaction of a-diazoesters,[8a] only
À
moderate enantioselectivity was obtained. In sharp contrast,
dirhodium(II) trifluoroacetate, a strong Lewis acid, signifi-
cantly increased the enantioselectivity to 93% ee (Table 1,
entry 15). The enantioselectivity was further improved to
96% ee by addition of the mixed solution of 2a and BocNH2
with a syringe pump over the course of 5 min (Table 1,
entry 16). A control experiment showed that the SPA did not
catalyze the insertion reaction in the absence of a dirhodium
complex (Table 1, entry 17). Although the reaction afforded
comparable enantioselectivity (93% ee) when it was per-
À
cyclopropanation and C H insertion) decreased the yields
(Table 2, entries 13 and 14).
À
À
formed without argon protection, the yield of desired N H
To demonstrate the utility of this asymmetric N H
insertion product markedly decreased to 32%. The lower
yield is attributed to significant dimerization of a-diazoke-
tones.
insertion reaction of a-diazoketones, we carried out various
reactions with the chiral a-aminoketone products (Scheme 2).
Ketone 3p could be reduced with NaBH4 to chiral a-amino
alcohol 5a in quantitative yield with high stereoselectivity
(anti/syn > 20:1, 97% ee; Scheme 2A).[12] Upon addition of
Using the optimal reaction conditions, we investigated the
substrate scope of the asymmetric N H insertion reaction of
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chromatography on silica gel (petroleum ether/ethyl acetate = 8:1) to
give 3a as a white solid.
Received: January 9, 2014
Published online: March 5, 2014
Keywords: asymmetric catalysis · carbenes ·
.
chiral proton shuttle · chiral a-aminoketones · diazo compounds
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À
In conclusion, we have described the first asymmetric N
H insertion reaction of a-diazoketones, which was achieved
by cooperative catalysis by achiral dirhodium(II) carboxy-
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and straightforward route to synthetically important chiral a-
aminoketones with good yields and high enantioselectivity.
À
This study markedly broadens the scope of asymmetric X H
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À
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Experimental Section
The [Rh2(F3CCO2)4] (1.3 mg, 0.002 mmol, 1 mol%) and (R)-1c
(1.2 mg, 0.002 mmol, 1 mol%) were introduced into an oven-dried
Schlenk tube in an argon-filled glovebox. After 2 mL CHCl3 was
injected into the Schlenk tube, the mixture was stirred at 258C. A
solution of 1-diazo-1-phenylpropan-2-one 2a (33.6 mg, 0.21 mmol)
and BocNH2 (23.4 mg, 0.2 mmol) in 1 mL CHCl3 was introduced into
the mixture by a syringe pump over 5 min. The color of the diazo
compound disappeared immediately after the addition. TLC showed
that the reaction ran to completion as soon as the addition finished.
The reaction mixture was then concentrated and purified by flash
À
[5] An N H insertion of a-diazoketones catalyzed by a chiral iron
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ccdc.cam.ac.uk/data_request/cif.
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