Construction of quaternary carbon stereocentres: Catalytic enantioselective allylation assisted by a bimetallic catalytic system

Article abstract of DOI:10.1016/j.tetasy.2005.02.009

The asymmetric allylic alkylation of prochiral aryl cyano esters has been carried out in the presence of a bi-component catalytic system containing a palladium and a rhodium complex modified by phosphorus containing chiral auxiliaries. The allyl derivativ

Full text of DOI:10.1016/j.tetasy.2005.02.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1295–1298
Construction of quaternary carbon stereocentres:
catalytic enantioselective allylation assisted by a bimetallic
catalytic system
*
´
Audrey Nowicki, Andre Mortreux and Francine Agbossou-Niedercorn
Laboratoire de Catalyse de Lille, UMR CNRS 8010, ENSCL, BP 108, 59652 Villeneuve d’Ascq Cedex, France
Received 28 December 2004; accepted 8 February 2005
Abstract—The asymmetric allylic alkylation of prochiral aryl cyano esters has been carried out in the presence of a bi-component
catalytic system containing a palladium and a rhodium complex modified by phosphorus containing chiral auxiliaries. The allyl
derivatives were isolated in up to 63% ee. The chiral pocket ligands of Trost appear the most appropriate to produce the desired
chiral derivatives.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In order to prepare highly functionalised chiral quater-
nary centres for further transformation, we sought to
explore the allylation of cyano ester substrates. To the
best of our knowledge, only one report has so far
described the palladium assisted allylation of closely
related substrates, that is, a-isocyanocarboxylates.4
Another report on the use of a bimetallic Pd/Rh cata-
lytic system for the allylation of a-cyanopropionates
has also been described.8 In the latter case, the two
catalysts activate the two substrates. As such, the cyano-
propionate is activated by the rhodium complex and the
allyl derivative by the palladium catalyst.8,9 In a previ-
ous study, we explored the enantioselective allylation
at the benzylic position of aryl cyano esters.10 Very high
levels of enantioselectivity are difficult to reach in the
presence of palladium catalysts bearing Trost-type chiral
auxiliaries. This fact is most certainly related to the non-
cyclic nature of the enolate nucleophile. Thus, we
thought to explore the allylation of the same substrate
in the presence of a bimetallic catalytic system in order
to improve the selectivity of the transformation. Herein,
we report on the results of the allylation of 3,4-dichloro-
phenyl cyano ester derivatives assisted by a catalytic
mixture containing palladium and rhodium complexes
modified by various chiral auxiliaries.
The generation of quaternary stereocentres including
catalytic asymmetric allylation, has been the subject of
investigations in recent years.1 Indeed, although many
examples describe the successful introduction of chiral-
ity into a prochiral allylic substrate,2 the enantioselective
nucleophilic addition of stabilised prochiral carbon
nucleophiles to a p-allylpalladium(II) complex has been
fairly less explored and is quite difficult to control.3
Nonetheless, such a reaction has proven to be a valuable
tool for the construction of tetrasubstituted stereocen-
tres.1 Efficient catalytic systems, which are able to in-
duce high enantiodifferentiation in the preparation of
quaternary centres, have been described for specific sub-
strates. In many cases, in order to enable a better trans-
mission of the chiral information, the chiral auxiliary
presents specific features. For example, chiral ferrocen-
ylphosphines, which bear a functional group able to
interact with the prochiral enolate while approaching
the p-allyl carbon of the p-allyl palladium intermediate,4
have been synthesised and applied successfully to the
allylation of b-diketones. As another example, the chiral
pocket ligands of Trost have been used successfully in
the allylation of b-ketoesters,5 b-diketones6 and non-sta-
bilised ketone enolates.7
2. Results and discussion
*
The substrate cyano-(3,4-dichloro-phenyl)-acetic acid
methyl ester 1 has been synthesised quantitatively, as
Corresponding author. Tel.: +33 3 20 434927; fax: +33 3 20
436585; e-mail: francine.agbossou@ensc-lille.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.009

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A. Nowicki et al. / Tetrahedron: Asymmetry 16 (2005) 1295–1298
previously described, through the reaction of 3,4-di-
chloro benzonitrile with dimethyl carbonate in toluene
in the presence of sodium malonate.10 The correspond-
ing isopropyl ester 2 was prepared quantitatively
through a transesterification of 1 performed in isopropyl
alcohol under reflux (Scheme 1).
rhodium and palladium complexes (entries 1 and 2).
The reaction was performed in THF and no external
base was introduced. The cyano ester was activated as
an ester enolate coordinated to the rhodium complex
through the cyano nitrogen atom [trans-[RhNCC(Ar)-
(COOMe)(CO)(PhTRAP)]].8 This nucleophile adds to
the electrophilic p-allyl-palladium(II)–PhTRAP result-
ing from the reaction of allyl acetate with the palla-
dium(0)–PhTRAP complex. The reaction proved very
slow. An allyl carbonate, allyl hexafluoroisopropyl car-
bonate, was also used as the allyl source. The latter,
which gives the advantage of releasing an anion
(CF3)2CHOꢀ with a lower basicity than CH3COꢀ2 , has
been used successfully by Sawamura et al.8 Thus, the
allyl-palladium species was obtained by the decarboxyl-
ative oxidative addition of allyl hexafluoroisopropyl
carbonate to the palladium(0)–PhTRAP complex. This
reaction was also very slow. Even though the cyano sub-
strate is activated and able to undergo the allylation
reaction (see below), in the presence of the trans chelat-
ing PhTRAP ligand, the overall crowding is certainly
too important to allow the addition of the rhodium–
PhTRAP complexed cyano ester to the allyl-palla-
dium–PhTRAP species.
These substrates were then subjected to allylation in the
presence of allyl acetate catalysed by a system composed
by the mixture obtained from the reaction of the two
precursors [Pd(allyl)Cl]2 and Rh(acac)(CO)2 with vari-
ous phosphorus containing auxiliaries (Schemes 2 and
3).11 The catalytic results are summarised in Table 1.
Initial experiments were carried out in the presence of
the PhTRAP ligand (Scheme 3), which has already been
reported as efficient in an allylic alkylation reaction of a
closely related non-aryl substrate.8 The PhTRAP ligand
has been synthesised following the reported proce-
dure.8,12 First, allyl acetate was used as the reagent for
the allylation of 1 in the presence of the two-component
catalytic system obtained from the reaction of
Rh(acac)(CO)2 (1 mol%) and [Pd(allyl)Cl]2 (1 mol% in
Pd) and (S,S)-(R,R)-PhTRAP as the ligand for both
Me
CO
2
NC
NC
NC
CO iPr
2
OC(OMe)
i PrOH
reflux
2
NaOMe
toluene
reflux
Cl
Cl
Cl
Cl
Cl
Cl
1
2
Scheme 1.
R
O
*
O
O
NC
R
O
CN
1. Rh(acac)(CO) / Chiral Ligand (1mol%)
2
2. [Pd(allyl)Cl] / Chiral ligand (1mol%)
2
OAc
THF
Cl
Cl
Cl
Cl
1 : R = Me
3 : R = Me
i
i
2 : R = Pr
4 : R = Pr
Scheme 2.
PPh
2
Me
O
O
HN
NH
PPh
2
Fe
Fe
PPh
2
Ph P
PPh
Me
(S,S)-(R,R)-PhTRAP
2
2
Ph P
2
(R)-BINAP
TROST
Scheme 3.

A. Nowicki et al. / Tetrahedron: Asymmetry 16 (2005) 1295–1298
1297
Table 1. Asymmetric allylic alkylationa
Entry
Substrate
Ligand (Pd)b
Ligand (Rh)c
Based
Temp. (ꢁC)
Time (h)e
Conv. (%)f
Ee (%)g
1
1
(R,R)-(S,S)-TRAP
(R,R)-(S,S)-TRAP
(R,R)-(S,S)-TRAP
(R,R)-(S,S)-TRAP
Trost
(R,R)-(S,S)-TRAP
(R,R)-(S,S)-TRAP
dppb
ꢀ78
0
2
6
5
ndh
nd
32
10
32
60
63
52
51
45
50
51
2i
2
3
rt
2
100
100
100
100
55
4
(R)-BINAP
Trost
Trost
rt
2
5
rt
0.5
0.5
1.5
0.5
0.5
1
6
7j
Trost
Trost
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
Trost
Trost
8
9j
Trost
Trost
(ꢀ)-Sparteine
n-BuLi
LDA
100
100
89
Trost
Trost
10k
11
12
13
14
15
16
Trost
Trost
dppb
dppb
Trost
0.5
0.5
2
100
100
0
PhTRAP
Trost
Trost
1
80
45
43
53
2
0.5
0.5
100
100
Trost
Trost
a The catalytic reactions were carried out in THF with ligand(Pd)/Pd/ligand(Rh)/Rh/substrate ratio 1/1/1/1/100 and in the presence of allyl acetate
(1.5 equiv) in the experimental conditions mentioned unless otherwise stated.
b The ligand was used as 1 equiv with respect to Pd. [Pd(allyl)Cl]2 introduced.
c The ligand was used as 1 equiv with respect to Rh. Rh(acac)(CO)2 introduced.
d Base as 1.2 equiv/substrate.
e The time is not optimised.
f Conversions were determined by 1H NMR on the crude reaction mixture.
g Determined by 13C NMR in the presence of [Eu(hfc)] shift reagent. The absolute configuration has not been determined. The sign of the specific
rotation is (ꢀ).
h Not determined.
i The allyl hexafluoroisopropyl carbonate was used as the allylation agent.
j (ꢀ)-Sparteine was used. Sparteine/substrate: 1.2.
k ZnCl2 was used. ZnCl2/substrate: 2.
As demonstrated by Sawamura et al.,8 when a catalytic
system composed by Rh–PhTRAP and Pd–dppb was
used in the allylation of the closely related cyano ester
substrate instead of the mixture Rh–PhTRAP/Pd–
PhTRAP, the selectivity remained very high. We applied
the same system composed by Rh–PhTRAP and Pd–
dppb (entry 3) and another one composed by Rh–
PhTRAP and Pd-BINAP (entry 4). In both cases, the
conversions went to completion in THF within 2 h at
room temperature. The enantiomeric excesses were
low, 32% and 10% ee, respectively. The fact that the
reaction went to completion proves that the crowding
present while using a PhTRAP ligand on both metals,
inhibits the addition reaction. Also, this result shows
the importance of the chiral rhodium species in the ori-
gin of the enantioselectivity of the process. Associating
(S,S)-(R,R)-PhTRAP and (R)-BINAP provided allyl
derivative 3 with 10% ee. We did not check the influence
of the other BINAP enantiomer but rather turned our
attention to the use of Trost-type ligands.
reaction conditions (entry 7), a small increase in the ee
was observed (63% ee). However, the reaction slowed
down significantly as only 55% conversion was obtained
in 1.5 h as compared to a total conversion reached with-
in the non-optimised 30 min. We also examined the
effect of a base associated to additives (entries 8–10).
Even if the enantioselectivity decreased under such
conditions (45–51% ee), the conversions were still very
high.
When the reaction was carried out in the presence of
either the mixture Rh–dppb/Pd–Trost ligand or Rh–
Trost/Pd–dppb the enantioselectivity dropped to ca.
50% ee (entries 11 and 12) although the reaction still
went to completion in 0.5 h. On the other side, the con-
trol reaction performed in the presence of only the pal-
ladium–Trost ligand catalyst proceeded in an analogous
manner but with a lower rate and a lower selectivity
(45% ee) (entry 14). It is noteworthy that when an iden-
tical reaction was carried out in the presence of the Pd–
PhTRAP catalyst alone, no addition reaction was ob-
served. First, these results prove that the acetate released
during the catalytic process from the allyl acetate is able
to generate the enolate via deprotonation of the cyano
ester. Second, the addition of the benzylic cyano enolate
to a chiral allyl-palladium–Trost ligand complex is pos-
sible with moderate asymmetric induction. Also, the
conclusion made by Sawamura considering that the rho-
dium catalyst bearing the chiral auxiliary is at the origin
of the enantioselectivity of the process is verified here.
Indeed, when the chiral auxiliary is introduced either
When applying the Trost ligand in association with the
bi-component catalytic system Rh/Pd in the allylation
of 1, at room temperature, within non-optimised
30 min, the reaction went to completion and the enan-
tiomeric purity measured for the isolated allyl derivative
3 was 32% ee (entry 5). Lowering the temperature to
ꢀ78 ꢁC led to an improvement in the selectivity of up
to 60% ee (entry 6). The conversion was still complete
at this temperature. When the allyl hexafluoroisopropyl
carbonate was used instead of allyl acetate in the same

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A. Nowicki et al. / Tetrahedron: Asymmetry 16 (2005) 1295–1298
(f) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed.
2003, 42, 2580.
via the Pd complex or via the rhodium species, the
enantioselectivity remained the same. Thus, there is a
redistribution of the ligands between the Pd and Rh
complexes. However, it is difficult to conclude that the
chiral ligand is exclusively coordinated to the rhodium
species, the palladium bearing only dppb after equilibra-
tion. Yet, it appears clearly that the bi-component cata-
lytic system accelerates the reaction compared to a
palladium catalyst alone and provides the allyl deriva-
tive with a higher enantioselectivity. The properties
exhibited by PhTRAP and the Trost ligand are different
in the reaction studied here. Also, the PhTRAP has only
been studied earlier in the allylation of non-aryl cyano
esters. Finally, when using isopropyl ester substrate 2 in-
stead of the methyl ester 1, no improvement in the selec-
tivity of the allylation reaction was obtained (entries 15
and 16).
3. Fiaud, J. C.; Hibon de Gournay, A.; Larcheveque, M.;
Kagan, H. J. Organomet. Chem. 1978, 154, 175.
4. (a) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M.
J. Org. Chem. 1988, 53, 113; (b) Sawamura, M.; Nagata,
H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114,
2586.
5. Trost, B. M.; Radinov, R.; Grenzer, E. J. Am. Chem. Soc.
1997, 119, 7879.
6. Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121,
10727.
7. (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc.
1999, 121, 6759; (b) Trost, B. M.; Schroeder, G. M.;
Kristensen, J. Angew. Chem., Int. Ed. 2002, 41, 3492.
8. Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 3309.
9. Murahashi, S.; Naota, T.; Taki, H.; Mizuno, M.; Takaya,
H.; Komiya, S.; Mizuho, Y.; Oyasoto, N.; Hiraoka, M.;
Hirano, M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117,
12436.
3. Conclusion
10. Nowicki, A.; Mortreux, A.; Agbossou-Niedercorn, F.
Tetrahedron Lett. 2005, 46, 1617.
In conclusion, we have shown that the aryl cyano esters
can be allylated efficiently in the presence of a bi-compo-
nent Rh/Pd catalytic system with a moderate enantiose-
lectivity. The overall balance of the steric features of the
rhodium-complexed enolate nucleophile and the allyl-
palladium electrophile is a crucial factor affecting the
rate and enantioselectivity of the addition process. Also,
the Trost-type ligand appears appropriate in association
with both Pd and Rh to assist efficiently in the allylation
of aryl cyano ester enolates and behave quite differently
compared to PhTRAP. Further research is currently in
progress in order to study the scope of the process.
11. Representative experimental procedure for the allylation
reaction: in a Schlenk tube equipped with a stirrer bar,
Rh(acac)(CO)2 (2.6 mg, 0.01 mmol) and the chiral auxil-
iary (0.021 mmol) were introduced with THF (2 mL). The
resulting mixture was stirred for 5 min. The latter was then
added to the cyano ester substrate (1 mmol) and dissolved
in freshly distilled THF (4 mL). In a second Schlenk tube
equipped with a stirrer bar, the palladium complex
[Pd(allyl)Cl]2 (3.7 mg, 0.01 mmol) and chiral auxiliary
(0.021 mmol) were dissolved in THF (2 mL) followed by
the allyl reactant (1.5 mmol). This mixture was stirred for
15 min at room temperature and then transferred via
cannula onto the solution containing the substrate. The
catalytic medium was stirred at the indicated temperature
and the evolution of the reaction was followed by GC
analysis of aliquots taken from the reaction mixture. At
the end of the reaction, a saturated solution of NH4Cl
(5 mL) was added and the medium stirred for 5 min before
addition of water (10 mL). The allyl product was extracted
with ethyl acetate (3 · 15 mL). The combined organic
layers were washed with saturated NaHCO3 (25 mL),
dried over MgSO4 and concentrated under reduced
pressure. If necessary, the isolated product was purified
through silica gel chromatography. Compound 3: Rf = 0.8
Acknowledgments
We thank Sanofi-Chimie (grant to A.N.) for financial
support and Pr Bertrand Castro for very stimulating
discussions.
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