Asymmetric organocatalysis of the addition of acetone to 2-nitrostyrene using N-diphenylphosphinyl-1,2-diphenylethane-1,2-diamine (PODPEN)

Article abstract of DOI:10.1016/j.tetlet.2009.10.131

The highly enantioselective addition of acetone to 2-nitrostyrene, using N-diphenylphosphinyl-trans-1,2-diphenylethane-1,2-diamine (PODPEN) as a catalyst, is described.

Full text of DOI:10.1016/j.tetlet.2009.10.131

Tetrahedron Letters 51 (2010) 209–212
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Tetrahedron Letters
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Asymmetric organocatalysis of the addition of acetone to 2-nitrostyrene using
N-diphenylphosphinyl-1,2-diphenylethane-1,2-diamine (PODPEN)
David J. Morris a, A. Simon Partridge a, Charles V. Manville a, Daugidas T. Racys a, Gary Woodward b,
Gordon Docherty b, Martin Wills a,
*
a Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
b New Products and Phosphine Development, Rhodia Consumer Specialities Ltd, PO Box 80, Trinity Street, Oldbury, W. Midlands B69 4LN, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly enantioselective addition of acetone to 2-nitrostyrene, using N-diphenylphosphinyl-trans-1,2-
diphenylethane-1,2-diamine (PODPEN) as a catalyst, is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 September 2009
Revised 16 October 2009
Accepted 28 October 2009
Available online 31 October 2009
The use of enantiomerically pure amines in organocatalysis has
enjoyed a period of rapid recent development.1–3 Several of these
reactions involve the formation of an active species (iminium or
enamide) by a reversible condensation reaction between the amine
catalyst and the carbonyl group in one of the reagents. In a large
proportion of examples of amine-catalysed reactions, a second
functional group in the catalyst serves to activate and direct the
reaction. In the case of proline, the carboxylic acid may act in this
capacity.2 The asymmetric addition of acetone to 2-nitrostyrene
(Fig. 1) may be catalysed by a number of amine derivatives includ-
ing thiourea derivatives of S,S-1,2-diphenyl-1,2-ethylenediamine
(DPEN) and R,R-1,2-diaminocyclohexane (DACH).4 Examples in-
clude ureas 1 and 2, which give products 3 in up to 91%4a and
99% ee,4b respectively (Scheme 1).
In addition, closely related pyrrolidine derivatives have been
employed,7–16 including the triflate 4, which catalyses additions of
aldehydes and ketones in up to 99% ee.7 Good results were also
obtained using the 3,5-bis(trifluoromethane)phenylsulfonyl deriva-
tive.8 Closely related 2-aminomethylpyrrolidines have also been
studied in the nitrostyrene addition reaction (up to 92% ee).9 Proline
supported on hydrotalcite clays has been used as a heterogeneous
catalyst.10 Diamines derived from cinchona alkaloids have been
applied to the addition of 1,3-diketones to nitrostyrenes.11
O
H
Ph
Ph
Ph
Ph
N
NHTf
P
P
O
P
O
N
H
Ph
Ph
N
H
N
H
N
H
O
4
6
5
7
Ph
Ph
HN
(S,S,R )
In a recent report, published during the course of our studies,
phosphine oxide 5 was described as an excellent organocatalyst
for the asymmetric addition of cyclic ketones to nitrostyrenes, fur-
nishing products in >99% ee and high diastereoselectivity.12 Oxide
5, as well as the related compounds 6,13 and 7,14 have been applied
to asymmetric aldol reactions. In previous reports on the use of
pyrrolidine-based catalysts, cyclic ketones gave the best results.
In contrast, the addition of acetone is less enantioselective.
S
S
H2N
HN
H2N
tBu
NMeBn
Me
HN
HN
(R,R,S )
2
1
O
The mechanism of the amine-catalysed addition reaction is
believed to proceed via the enamine, whilst the urea engages the
nitro group in a hydrogen bond (Fig. 1).1d
Other derivatives of C2-symmetric diamines have been applied to
the nitrostyrene addition reaction. These include the mono N-triflu-
oromethylsulfonate (Tf) derivative of DACH5 and a series of sulfa-
mides, which promoted the addition of aldehydes in up to 99% ee.6
Ph
Ph
Ph
Ph
S
S
H
R
R
H
N
H
N
H
N
N
H
N
H
N
O
N
2
NO2
O
Ph
Ph
H
H
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
Figure 1. Secondary directing effect of urea.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.131

210
D. J. Morris et al. / Tetrahedron Letters 51 (2010) 209–212
requirement for a basic amine. Secondary amine derivatives 12–
O
1518 also proved to be essentially inactive, possibly for reasons of
steric hindrance. All the DPEN derivatives tested gave the same
product enantiomer relative to the diamine, that is, (R,R)-DPEN
derivatives gave the S-configured product. The ee did not change
with conversion (samples were taken at regular 1–2 h intervals)
in the reaction catalysed by 10 and did not deteriorate when the
reaction was allowed to stand after completion (up to 4 days), sug-
gesting that the addition is essentially irreversible. These results
indicate that the phosphinamide group plays an activating role in
the reaction, and contributes to the enantiocontrol, possibly in an
analogous mechanism to that shown in Figure 1.
acetone, AcOH, H2O
10-15% ligand
S
NO2
NO2
1,2, 8-15
3 X=H; up to 97% ee
16 X=OMe; 93% ee
17 X=Cl; 96% ee
X
See Table 1
X
Scheme 1. Asymmetric addition of acetone to nitrostyrene.
Given a long standing interest in phosphinamide catalysts,17 we
wished to establish whether other functional groups, and particu-
larly those based on P@O directing groups, could be applied to cat-
alytic reactions. Phosphinamides have been used as catalysts in
other reactions which may be described as organocatalytic (no
metals are present in the catalyst).17,18 These include the catalysis
of the asymmetric reduction of ketones using borane, and the addi-
tion of trichloroallylsilanes and silyl enol ethers to aldehydes.
Phosphinamide 10 has been reported as a chiral directing group
in a Rh-catalysed asymmetric Michael addition reaction.19 Phosph-
inylated compounds closely related in structure to 10 have been
formed in nucleophilic addition reactions to N-diphenylphosphinyl
ketimines, but were not used as asymmetric catalysts.20 The at-
tempted use of a phosphinamide in an indium-catalysed addition
to a hydrazone was reported, but this gave a product with low ee.21
A series of homochiral DPEN derivatives were prepared and
screened as organocatalysts in nitrostyrene addition (Scheme 1,
Table 1). DPEN alone proved to be capable of high enantioinduction
(78% ee), as previously reported,4a but did not furnish a product in
high yield. Of its derivatives, N-tosylated amine TsDPEN 8 gave a
product of high ee but the reaction was slow. TsDPEN 8 has been
successfully used in a closely related addition to nitrostyrene.22
N-Benzoyl amide 9 gave a good result in terms of ee (82% conver-
sion after 96 h, 89% ee) however, the best catalyst, of those tested,
proved to be the phosphinamide 1023 (100% conversion after 7 h,
96% ee). The bis-phosphorylated DPEN derivative 1124 was, how-
ever, ineffective as a catalyst, thus confirming the expected
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
NH2
NH
NH2
(R,R)-DPEN
H2N
TsHN
NH2
(R,R)-8
(S,S)-9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
P
NH2
P
HN P
NH
NH
O
O
O
(S,S)-11
(S,S)-10
Ph
BnHN
Ph
12 R=Bn
13 R=cHex
14 R=(CH2)2Ph
Ph
TsHN
Ph
NHBn
15
NHR
Further studies revealed that added acetic acid and water are
important to the reaction. The conversion dropped to just 15% in
96 h when both AcOH and water were omitted from the reaction,
and to 75% in 18 h when only AcOH, but not water, was added.
Benzoic acid may be used in the place of acetic acid, but gives low-
er reaction rates. The importance of water in such reactions has
been investigated in detail,25 whilst the acid presumably catalyses
the formation and decomposition of the intermediate enamine and
iminium species. Excess water (>1 equiv/relative to nitrostyrene) is
Table 1
Use of DPEN derivatives in nitrostyrene additionsa
Catalyst
Product
Loading (%)
Added water
Time (h)
Conv (%)
eeh (R/S)
b
b
b
b
b
b
b
b
b
(R,R)-DPEN
(R,R)-8
(S,S)-9
3
3
3
3
3
3
3
3
15
15
15
15
15
15
15
15
15
15
10
10
10
10
10
10
10
10
10
10
10
96
96
96
7
96
96
96
96
96
96
5
5
3
5
18
18
18
18
18
24
24
46
68
82
100
0
0
0
0
0
16
65
100
62
41
96
89
96
84
75
100
100
78 (S)
91 (S)
89 (R)
96 (R)
—
—
—
—
—
(S,S)-10
(S,S)-11
(R,R)-12
(R,R)-13
(R,R)-14
(S,S)-15
(S,S)-10
(R,R)-10
(R,R)-10d
(R,R)-10e
(R,R)-10f
(R,R)-10
(R,R)-10
(R,R)-10
(R,R)-10
(R,R)-10
(R,R)-10
(R,R)-10
3
3g
3
(0)c
—
b
95 (S)
93 (S)
88 (S)
94 (S)
94 (S)
92 (S)
94 (S)
97 (S)
95 (S)
93 (S)
96 (S)
b
b
b
3
3
3
3
3
3
3
3
(0.75)c
(0.50)c
(0.25)c
(0.10)c
(0)c
b
16
17
b
a
b
c
See Scheme 1, all reactions were carried out at rt in toluene unless otherwise stated.
Technical grade acetone was used; ca. 6.7% H2O by volume and 2% H2O by mass.
Reagent grade acetone was used, level of water relative to the catalyst in parentheses.
At 40 °C.
At 60 °C.
At 0 °C.
No AcOH added.
d
e
f
g
h
ee was determined by chiral HPLC, configuration by optical rotation.

D. J. Morris et al. / Tetrahedron Letters 51 (2010) 209–212
211
The successful synthesis of 18 was achieved starting from a pro-
tected proline derivative 21a, following a related method reported
in the literature.26 We favoured the use of 21a because we feared
that the acidic conditions required for tBoc removal would also re-
sult in loss of the phosphinamide. In the event, 21a was success-
fully converted into 18 through the sequence shown in Scheme
2, however, the last step gave a very poor yield of product. A search
of the literature yielded an example of a method for the removal of
a tBoc group in the presence of a phosphinamide.21 The conversion
of 21b to 25b followed the previous sequence,26 and the subse-
quent conversion into 18 was successful, although the work-up re-
quired the use of triethylamine21 to avoid a highly basic solution
being formed. A better yield was obtained using a combination of
isopropylsilane and TFA, but this remained low due to concomitant
cleavage of the phosphinamide group.27
Conversion vs catalyst (10) loading (in hexane)
100
90
80
70
60
50
40
30
20
10
0
10%
5%
3%
1%
0
5
10
15
20
Time, h
H
N
H
N
Ph
Ph
Ph
Ph
NH2
Figure 2. Effect of catalyst 10 loading on reaction rate.
P
O
N
P
P
O
N
H
19
N
H
Ph
Ph
18
O
not beneficial; a series of tests on pure acetone revealed that the
level of water in the technical grade is close to optimal (see Supple-
mentary data). In hexane, the catalyst loading can be reduced to
10%, which gives full reaction in 24 h at rt or 5 h at 40 °C (with a
drop in the ee to 93%) but at <5 mol % catalyst loading the reaction
requires unacceptable (>72 h) times for completion (Fig. 2). Of a
series of solvents tested, the nonpolar solvents hexane (94% ee)
and toluene (96% ee) gave the fastest rates, whilst reactions in
CH2Cl2, THF, EtOAc and acetone were much slower.
Although catalyst 10 worked well in the specific addition of ace-
tone to nitrostyrenes, poor results were obtained in attempts to
use both cyclohexanone and ethanal, with <5% formation of prod-
ucts in each case. In view of the known value of pyrrolidine deriv-
atives in the nitrostyrene addition reaction, but mindful of their
only moderate reported enantioselectivities for the acetone addi-
tion reaction,7–16 proline derivative 18 represented an attractive
candidate for evaluation.7–15 An attempt to prepare 18 by direct
phosphinylation of homochiral diamine 19 resulted in formation
of 20, which was not an active catalyst (Table 2).
20
Compound 18 proved to be an efficient, but not highly enantio-
selective, catalyst for the nitrostyrene addition reaction (Table 2).
The 16% ee of the product was similar to that of the unprotected
diamine 19, suggesting that its mechanism of action may be re-
lated. This low ee with pyrrolidine derivatives mirrors those ob-
tained in the same reaction using related pyrrolidine-based
organocatalysts.7–16 The use of 18 in other applications is currently
being studied.
In conclusion, we have described the promising results of a
study directed at establishing the ability of the phosphinamide
group to direct asymmetric organocatalytic additions to nitrosty-
rene. To the best of our knowledge, the phosphinamide group
has not been studied in this capacity before and this therefore rep-
resents a novel subject for investigation. We are currently examin-
ing further applications of this system.
Acknowledgements
Table 2
Use of pyrrolidine derivatives in nitrostyrene additionsa
We thank the EPSRC for funding (postdoctoral grant EP/
D031168/1 to DJM) and Rhodia Consumer Specialities Ltd for sup-
porting CVM through a Collaborative Training Account student-
ship. The EPSRC National MS service (Swansea) is thanked for
HRMS analyses as is the EPSRC Chemical Database Service.28
Catalyst
Product
Loading (%)
Time (h)
Conv (%)
eeb (R/S)
(S)-18
(S)-19
(S)-20
3
3
3
10
15
15
96
3/23
96
100
50/100
0
16 (R)
17 (R)
—
a
See Scheme 1, all reactions were carried out at rt in toluene unless otherwise
Supplementary data
stated, with technical grade acetone; ca. 6.7% H2O by volume and 2% H2O by mass.
b
ee was determined by chiral HPLC, configuration by optical rotation.
General experimental details, graphs of experimental results,
and 1H and 13C NMR of all new compounds are available. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.10.131.
TsCl,
BH3.DMS, THF
OH
OH
OTs
X=Z, 55%
N
X
N
X
N
X
X=Z, 85%
X=tBoc, 78%
O
X=tBoc, 89%
23a
23b
22a
22b
References and notes
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21b (X=tBoc)
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