Highly efficient asymmetric Michael addition of diaryl phosphine oxides to α,β-unsaturated N-acylated oxazolidin-2-ones

Article abstract of DOI:10.1002/asia.201200025

A highly efficient asymmetric Michael reaction of diaryl phosphine oxides with α,β-unsaturated N-acylated oxazolidinones has been developed. Excellent enantioselectivities (up to >99 % ee) and chemical yields (up to 99 %) were achieved with a broad substrate scope of the oxazolidinones. The bidentate property of oxazolidinones was found to be critical for high enantioselectivities.

Full text of DOI:10.1002/asia.201200025

DOI: 10.1002/asia.201200025
Highly Efficient Asymmetric Michael Addition of Diaryl Phosphine Oxides
to a,b-Unsaturated N-Acylated Oxazolidin-2-ones
Depeng Zhao, Linqing Wang, Dongxu Yang, Yixin Zhang, and Rui Wang*[a]
Table 1. Optimization of the phospha-Michael reaction
Organophosphorus compounds are an important class of
compounds, which have been studied for more than 180
years. In recent years, organophosphorus chemistry has ach-
ieved its rapid development owing to its wide application in
medical chemistry, agriculture, and industry.[1] Especially, the
[2]
À
catalytic asymmetric construction of P C bonds is an in-
tensively studied area in the past years and numerous stud-
ies have focused on asymmetric addition of nucleophiles
Entry[a]
X
L
Solvent
Yield [%][b]
ee [%][c]
such as dialkyl phosphites,[3] secondary phosphines,[4] and
secondary phosphine oxides[5] to form P C bonds with adja-
À
1
2
L1
L1
THF
THF
90
85
0
2
cent chiral centers. The conjugate addition of diaryl phos-
phine oxides to a,b-unsaturated carboxylic acid derivatives
is one of the most practical approaches for asymmetric con-
OMe 3
3[d]
L1
THF
72
–
À
struction of P C bonds. Nonetheless, present successful ex-
amples including asymmetric addition of diaryl phosphine
oxides to a,b-unsaturated ketones[6] and aldehydes[7] are not
efficent and require long reaction times of usually >12 h or
several days. Therefore, there is still great demand to devel-
op a new efficient approach towards these compounds.
Herein, we report a highly efficient asymmetric reaction of
diaryl phosphine oxides with a,b-unsaturated N-acylated ox-
azolidin-2-ones.
In connection with our continuous interest in phosphorus-
containing nucleophiles[8] and previous success in asymmet-
ric reactions of dialkyl phosphine oxides with enones,[9] we
decided to investigate the reaction of diaryl phosphine
oxides with a,b-unsaturated carboxylic acid derivatives. The
preliminary attempts were unsuccessful, the reaction of a,b-
unsaturated N-acylpyrrole 2 and diphenyl phosphine oxide
1a gave only racemic products in the presence of the dinu-
clear catalyst[10] L1/Et2Zn and pyridine (Table 1, entry 1).
Considering the effect of the background reaction, the sig-
nificantly less reactive a,b-unsaturated ester 3 was then em-
ployed as the acceptor. The low ee of the ester adduct sug-
gested the origin of poor enantioselectivities was due to the
4
L1
THF
78
86
5
L1
THF
96
90
6
7
8
9
10
11
6a
6a
6a
6a
6a
6a
L2
L1
L1
L1
L1
L1
THF
THF
DCM
diethyl ether
PhCF3
toluene
97
84
82
95
96
96
75
60[e]
89
90
89
99[f]
[a] Unless otherwise noted, all reactions were carried out with 1a
(0.75 mmol, 1.5 equiv), L/Et2Zn (10 mol%), a,b-unsaturated carbonyl
compounds (0.5 mmol), and pyridine (0.5 mmol, 1 equiv) in solvent
(5 mL) at RT for 12 h. [b] Yield of isolated product. [c] The enantiomeric
excess was determined by chiral HPLC analysis. [d] Only the phospha-
Brook rearrangement product was observed. [e] The reaction was per-
formed without pyridine. [f] The reaction was completed within 10 min.
THF=tetrahydrofuran.
steric hindrance imparted by diphenyl phosphine oxide
(Table 1, entry 2).
Having failed to use these monodentate substrates in the
asymmetric hydrophosphinylation reaction of diaryl phos-
phine oxides, we then tried some bidentate substrates, as we
expected that these substrates might be helpful because the
double binding could change the spatial conformation of the
a,b-unsaturated carbonyl compounds. Interestingly, the use
of ketoester 4 as the electrophile only led to 1,2-addition
[a] Dr. D. Zhao, L. Wang, D. Yang, Y. Zhang, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu Prov-
ince
School of Basic Medical Sciences and Institute of Biochemistry and
Molecular Biology
School of Life Sciences
Lanzhou University
Lanzhou, 730000 (P. R. China)
followed by
a phospha-Brook rearrangement (Table 1,
entry 3). Surprisingly, when pyrrolidinone 5 was employed
as the electrophile, the enantioselectivity increased signifi-
cantly to 86% (Table 1, entry 4). Further investigations sug-
gest that oxazolidinone 6a is a more advantageous substrate
E-mail: wangrui@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200025.
Chem. Asian J. 2012, 7, 881 – 883
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
881

COMMUNICATION
than 5 in terms of both yield and enantioselectivity (96%,
90% ee; Table 1, entry 5). In contrast, the phenyl ligand L2
gave only 75% ee under the same reaction conditions. Then,
the solvent test suggested that toluene was the best solvent
and the reaction could be completed within 10 min (Table 1,
entry 11).
The absolute configuration of the Michael adduct 7e was
determined to be S by X-ray crystallographic analysis
(Figure 1).[11] According to this result, a plausible transition
With optimized reaction conditions, we then screened
a series of analogues 6a–q, which bear various b-substitu-
ents. As shown in Table 2, oxazolidinones 6a–q were well
Table 2. Substrate scope of the phospha-Michael reaction.
Figure 1. X-ray crystal structure of 7e and proposed reaction mechanism.
state that explains the absolute stereochemistry of the prod-
ucts can be proposed. As shown in Figure 1, the diaryl phos-
phine oxides can be readily deprontonated by the zinc com-
plex, and the bidentate oxazolidinones are believed to bind
to one zinc atom of the catalyst. The mechanism is similar
to the reaction of dialkyl phosphine oxides with enones.[9b]
However, in the current case, the spatial conformation of
the a,b-unsaturated carbonyl compounds was changed by
the bindings of the two carbonyl groups, thus making the
chiral pocket more compatible with more sterically hindered
diaryl phosphine oxides.
In summary, we have developed a highly efficient asym-
metric Michael reaction of diaryl phosphine oxides with a,b-
unsaturated N-acylated oxazolidinones. This is a significant
improvement over previous methods in which long reaction
times are required, typically >12 hours or more. Excellent
enantioselectivities (up to >99% ee) and chemical yields
(up to 99%) were achieved with a broad substrate scope of
the oxazolidinones. The bidentate property of oxazolidi-
nones was found to be critical for high enantioselectivities.
We have found that the precipitation of the products from
the reaction solution greatly accelerated the reaction rate.
Further investigations of the detailed mechanism and appli-
cations of the products are in progress.
Entry[a]
R
1
7
t [min]
Yield [%][b]
ee [%][c]
1
2
3
Ph
1a
1a
1a
7a
7b
7c
10
15
30
96
95
98
99
4-MeC6H4
4-MeOC6H4
>99
>99[e]
4
1a
7d
60
95
96
5
6
7
8
4-ClC6H4
4-BrC6H4
4-FC6H4
2-FC6H4
3-ClC6H4
4-CF3C6H4
2-furyl
2-thienyl
2-naphthyl
Me
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
15
15
15
90
30
15
90
90
45
30
90
15
60
60
30
98
99
93
94
97
97
92
96
95
98
97
95
98
95
99
99[d]
98
94
90[e]
94
9
10
11
12
13
14
15
16
17
18
19
93
95
99
98
99
iPr
iBu
nHex
Ph
96[e]
93
99[e]
93[e]
95[e]
Ph
[a] Unless otherwise noted, reactions were carried out with 1 (0.75 mmol,
1.5 equiv), (0.5 mmol), L1/Et2Zn (10 mol%), and pyridine (0.5 mmol,
1 equiv) in toluene (5 mL) at RT. [b] Yield of isolated product. [c] The enan-
tiomeric excess was determined by chiral HPLC analysis. [d] The absolute
configuration of 7e was determined as S by X-ray analysis. [e] 15 mol% of
the catalyst was employed.
6
applicable to the present catalysis; the products can be effi-
ciently synthesized in high yield and high enantioselectivi-
ties. In comparison, the rate of the reaction was lower for
electron-rich substrate 7c (R=para-methoxyphenyl) and
ortho-substituted substrate 7h and higher catalyst loading
was required to achieve good results (Table 2, entries 3 and
8). Interestingly, we found, in many cases, the products
formed in the reaction were poorly soluble in toluene and
precipitated from the solution. As a result, the reaction
rates of the reactions with insoluble products such as 7a and
7b are much faster than those dissolved in the solution such
as 7k and 7l (Table 2, entries 1, 2, 11, and 12). In addition,
two other diaryl phosphine oxides 1b and 1c bearing elec-
tron-withdrawing substituents or electron-donating substitu-
ents were also tested and proved to be excellent substrates
for the present method (Table 2, entries 18 and 19).
Acknowledgements
We are grateful for the grants from the National Natural Science Founda-
tion of China (Nos. 90813012 and 20932003), the Key National S&T Pro-
gram “Major New Drug Development” of the Ministry of Science and
Technology (2012ZX09504001-003), and Scholarship Award for Distin-
guished Doctoral Candidates of Lanzhou University.
À
Keywords: asymmetric catalysis · C P bonds · Michael
addition · phosphine oxides · synthetic methods
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Received: January 8, 2012
Published online: March 13, 2012
Chem. Asian J. 2012, 7, 881 – 883
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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883