Preparation of γ-oxo esters by Staudinger reduction of β-azidocyclopropane esters

Article abstract of DOI:10.1016/j.tetlet.2013.07.019

An efficient and practiced procedure for the preparation of γ-oxo esters from the β-azidocyclopropane esters has been developed. Ph ₃P was proven to be a good promoter in THF/H₂O, and 11 γ-oxo esters were prepared in 73-99% yields under mild and neutral conditions.

Full text of DOI:10.1016/j.tetlet.2013.07.019

Tetrahedron Letters 54 (2013) 4957–4959
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of
c
-oxo esters by Staudinger reduction
of b-azidocyclopropane esters
a
Peiming Gu a, , Xiu-Ping Wu , Yan Su a,b, Ping Xue a, Xue-Qiang Li a, Bo-Lin Gong a, Rui Li a,
⇑
⇑
a Key Laboratory of Energy Sources & Engineering, Department of Chemistry, Ningxia University, Yinchuan 750021, China
b State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practiced procedure for the preparation of
esters has been developed. Ph3P was proven to be a good promoter in THF/H2O, and 11
prepared in 73–99% yields under mild and neutral conditions.
c
-oxo esters from the b-azidocyclopropane
Received 4 April 2013
Revised 25 June 2013
Accepted 3 July 2013
Available online 10 July 2013
c-oxo esters were
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Staudinger reaction
b-Azidocyclopropane esters
c
-Oxo esters
Ring opening
Reduction
1,4-Dicarbonyl moieties exist in many natural products1 and
alyst.7 Theoretically, reduction of the azido group and removal of
are employed as synthetically useful intermediates for many
important medicinal compounds.2 The general method for their
preparation is based on the Stetter reaction,3,4 in which the cya-
nides or thiazoliums are used to promote the 1,4-addition of an
the benzyl group from ester 1a can be achieved in one operation
under hydrogenation conditions, however only
c-oxo ester 2a
was separated as the major product in 30–40% yield. We thought
that ester 2a was derived from b-amino cyclopropane ester, as
the cyclopropane ring proved to be very susceptible to ring open-
ing (Scheme 2).
acyl anion to an
a,b-unsaturated carbonyl compound. However
the use of toxic or basic reagents would limit its application. Ring
opening of donor–acceptor-substituted cyclopropanes affords an
alternative way to address the motifs5 (Scheme 1). To promote ring
opening of the cyclopropane esters with a b-donor substituent in
the form of the protected hydroxyl group or the amino group, var-
iable acids or fluoride reagents were used. Though the desired 1,4-
dicarbonyl compounds could be obtained in moderate to good
The low yield might be due to the excessive reaction of benzyl
ester. To obtain c-oxo ester 2a in better yield, the Staudinger con-
ditions8 were employed. The reduction of azido cyclopropane ester
1a with Ph3P in THF/H2O gave
c
-oxo ester 2a9 in 93% yield at room
yields, the development of an efficient preparation of c-oxo esters
previous reports
from ring opening of cyclopropane esters under more mild and
neutral conditions is still in urgent demand. Following our research
on the reactions of organic azide,6 here we report the preparation
O
O O
R1
O
Acids or fluoride reagents
X
O
R3
R3
of
c-oxo esters by the Ph3P-mediated reduction of b-azidocyclo-
R1
R2
R2
propane esters.
To pursue the conformationally restricted b-peptide, we had
developed an efficient preparation of cis-b-azidocyclopropane ester
1 in good control of relative and absolute configuration.6a However
the attempt to convert b-azidocyclopropane ester 1a to the corre-
sponding b-amino cyclopropane carboxylic acid 3a (b-ACC), a
promised building block for b-peptide, failed with Pd/C as the cat-
X = OH, OSiR3, OR or NR2
this work
neutral conditions
Ph3P
O O
O
R1
O
N3
R1
O
R3
R3
R2
R2
⇑
Corresponding authors. Tel.: +86 (951) 206 2274; fax: +86 (951) 206 2323.
E-mail addresses: gupm@nxu.edu.cn (P. Gu), ruili@nxu.edu.cn (R. Li).
Scheme 1. Preparation of c-oxo esters from b-functionalized cyclopropane esters.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.019

4958
P. Gu et al. / Tetrahedron Letters 54 (2013) 4957–4959
O
O
O
O
Ph3P, THF/H2O
R1
O
H2N
Ph
O
N3
R1
O
R3
H
R3
O
H2, Pd/C
Ph
R2
R2
N3
Ph
O
Bn
3a
O O
2
1
PPh3
- N2
Ph
1a
- NH3
H2O
Ph
O
H
Bn
O
N
O
Ph3P
2a Ph
R1
O
N
O
R3
R3
a: Intramolecular proton transfer
b: intermolecular protonation
Scheme 2. Attempt to convert cis-b-azidocyclopropane ester 1a to cis-b-ACC 3a.
R1
H2O
R2
R2
b
H
O
8
4
H
a or b
- Ph3P=O
O
a or b
temperature (Table 1, entry 1). With the above conditions, the
analogues of cyclopropanes (1b–1k) were investigated for the ring
H
H
H
O
N
O
opening. In all cases,
to excellent yield. First, the conversions of ethyl ester 1b and 4-
methoxybenzyl ester 1c to -oxo esters could be afforded in com-
c-oxo esters (2b–2k) were obtained in good
N
a
H2N
R1
O
R3
H
R1
O
R1
O
b
a
R3
R3
H
c
R2
R2
R2
O
6
parable or even higher yields to that of cyclopropane ester 1a (en-
tries 2 and 3). Introduction of the p-methoxyl group on the
aromatic ring of R2 had very little influence on the transformation
(entries 4 vs 1). The aromatic rings of R1 in cyclopropanes 1e–1g
were substituted with electronic withdrawing groups, and the
yields of their reduction were slightly dropped (entries 5–7). When
5
7
H
Scheme 3. Mechanistic proposal for Ph3P-promoted ring opening of b-azidocyclo-
propane ester.
R3 was substituted with bromine (1g, 1i, and 1k), the
c-oxo esters
could be obtained, though the yields were not excellent (entries 7,
9, 11 vs entry 1). One exception was the reaction of substrate 1h,
which was attached with a CN group on R1 and a bromine group
on R3 (entry 8). The conversions of naphthyl analogues 1j and 1k
to the corresponding esters could also be achieved in acceptable
yields (entries 10 and 11).
It should be noted there was a stereo-center neighboring to the
ester group in the product. Then further attempt on the control of
the stereochemistry was initiated. The enantio-enriched b-azido-
cyclopropane ester 1a (89% ee) was used, however the ee value
intramolecular proton transfer will take place, and imino ester 8
is afforded (path a). Another possible way to imino ester 8 could
be addressed from the intermolecular protonation of intermediate
6 or 7 by H2O (path b). Finally aqueous work up of the imino ester
leads to the
In conclusion, we have developed a practiced and efficient pro-
cedure for the preparation of the -oxo esters from the b-azidocy-
clopropane esters. Ph3P was proven to be an efficient promoter in
THF/H2O, and 11 -oxo esters were prepared in good to excellent
c-oxo ester 2.
c
c
yields under the mild and neutral conditions. Currently, further
investigation of the reduction of cyclopropane esters and applica-
tion of the c-oxo esters in total synthesis of natural products are
underway in our laboratory.
(<2%) of the
analysis.
c-oxo ester 2a was almost lost upon the chiral HPLC
From the above experiments and previous literatures, a pro-
posed mechanism is outlined above (Scheme 3): Staudinger con-
version of b-azidocyclopropane ester
1 with Ph3P forms an
Acknowledgments
iminophosphorane 4 after losing N2, amine 5 will be obtained from
the aqueous conditions. Then the unstable donor–acceptor-
substituted cyclopropane ester 5 proceeds ring opening to afford
zwitterionic intermediate 6 or its resonance structure 7. The
This work was supported by the National Natural Science Foun-
dation of China (No. 21262024, 21062014 and 21064005), the Key
Table 1
Scope of the conversiona
O O
O
Ph3P, THF/H2O, rt
R1
O
N3
R1
O
R3
R3
R2
R2
1
2
Entry
Cyclopropane
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1a R1 = R2 = Ph; R3 = Bn
1b R1 = R2 = Ph; R3 = Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
20
17
24
35
43
24
48
43
52
37
24
93
92
99
89
80
79
80
95
73
77
79
1c R1 = R2 = Ph; R3 = 4-OMe-Bn
1d R1 = Ph; R2 = 4-OMe-C6H4; R3 = Bn
1e R1 = 4-Br-C6H4; R2 = Ph; R3 = Bn
1f R1 = 4-F-C6H4; R2 = Ph; R3 = Bn
1g R1 = R2 = 4-Br-C6H4; R3 = 4-Br-Bn
1h R1 = 4-CN-C6H4; R2 = 4-Br-C6H4; R3 = 4-Br-Bn
1i R1 = 4-OMe-C6H4; R2 = 4-Br-C6H4; R3 = 4-Br-Bn
1j R1 = Naphth; R2 = Ph; R3 = Bn
9
10
11
2j
2k
1k R1 = Naphth; R2 = 4-Br-C6H4; R3 = 4-Br-Bn
a
Reduction of the cyclopropane in the presence of Ph3P (2.0 equiv) in THF/H2O (10:1) at room temperature.
Isolated yield.
b

P. Gu et al. / Tetrahedron Letters 54 (2013) 4957–4959
4959
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