Asymmetric allylic alkylation using a palladium complex of chiral 2- (phosphinoaryl)pyridine ligands

Article abstract of DOI:10.1055/s-1999-2916

A palladium complex of newly designed chiral 2-(phosphinoaryl)pyridine (4b) was found to be an effective catalyst for asymmetric allylic alkylation. High enantioselectivity was achieved in the reactions of both 1,3-diphenyl-2- propen-1-yl acetate (98% ee) and (2E)-1-methyl-2-butenyl phenyl carbonate (93% ee) with dimethyl malonate.

Full text of DOI:10.1055/s-1999-2916

LETTER
1563
Asymmetric Allylic Alkylation Using a Palladium Complex of Chiral 2-
(Phosphinoaryl)pyridine Ligands
Katsuji Ito,a* Risa Kashiwagi,a Kazunori Iwasaki,a Tsutomu Katsukib*
a Department of Chemistry, Fukuoka University of Education, Akama, Munakata, Fukuoka 811-4192, Japan
b Department of Molecular Chemistry, Graduate School of Science, Kyushu University 33, Hakozaki, Higashi-ku, Fukuoka 812-8581,
Japan
Fax +81-92-642-2607
Received 22 July 1999
Abstract: A palladium complex of newly designed chiral 2-(phos-
phinoaryl)pyridine (4b) was found to be an effective catalyst for
asymmetric allylic alkylation. High enantioselectivity was achieved
in the reactions of both 1,3-diphenyl-2-propen-1-yl acetate (98%
ee) and (2E)-1-methyl-2-butenyl phenyl carbonate (93% ee) with
dimethyl malonate.
N
O
O
N
PPh2
PPh2
N
PPh2
R
Key words: asymmetric allylic alkylations, asymmetric catalysis,
palladium, chiral P,N-ligands
3
1
2
Palladium-catalyzed allylic alkylation is one of the most
useful carbon-carbon bond forming reactions, because the
reaction proceeds smoothly under mild conditions to give
b-functionalized alkenes that are useful building blocks in
synthetic organic chemistry.1 In particular, asymmetric al-
lylic alkylation catalyzed by chiral palladium complex has
attracted the attention of synthetic organic chemists.2 In
the early stage of this area of chemistry, C2-symmetric
diphosphine and dinitrogen ligands were extensively used
as chiral sources. To achieve high enantioselectivity in al-
lylic alkylation, two factors, the orientation of the allyl
moiety in the intermediary p-allyl complexes and regiose-
lection in nucleophilic attack to the complex, have to be
controlled strictly. Use of C2-symmetric ligand removes
the first issue but the regiocontrol remains as a difficult
problem.2 Only a few C2-symmetric diphosphine ligands
show high enantioselectivity in the reaction of a wide
range of substrates.3,4 Recently, however, non-symmetric
heterobidentate ligands were found to be efficient chiral
sources for asymmetric allylic substitution. These new
N
PPh2
N
PPh2
R
R
4
5
lates the orientation of the allyl moiety but the regulation
is not sufficient for the latter reaction. Following these pi-
oneering studies, various second generation heterobiden-
tate ligands have been introduced and the scope of
asymmetric allylic alkylation has been extended.5e-t,6
Quite recently, Helmchen et al reported that highly enan-
tioselective allylic alkylation of 1,3-dimethyl-substituted
allyl substrates using new type of 2-(phosphinoaryl)ox-
azolines 3 (up to 89.5% ee).5p,7
Several years ago, we found that chiral bipyridine ligands
showed high enantioselectivity in cyclopropanation and
ring-enlargement reactions.8 Therefore we were intrigued
ligands regulate the above two factors through their steric by the heterobidentate ligands 4 and 5 bearing chiral pyri-
and ligand effects. In particular, the coordination of the
ligand atoms of the different rows in periodic table affects
the susceptibility of the p-allyl terminal carbons trans to
the atoms, to nucleophiles in a different way (trans-effect)
and results in high regioselectivity in the nucleophilic at-
tack.5,6 Some successful examples in this class of ligands
are 2-(phosphinoaryl)oxazolines 15a-c and (phosphinon-
aphthyl)isoquinoline (QUINAP) ligand 2.5d
dine ligands as chiral auxiliaries, in which the substituent
at the chiral center was fixed to direct toward the allyl-pal-
ladium moiety and therefore expected to efficiently con-
trol the orientation of the allyl moiety.5p Here we wish to
report our preliminary results on the synthesis of 2-(phos-
phinoaryl)pyridine ligands and their application to palla-
dium-catalyzed asymmetric allylic alkylation.
The synthesis of chiral 2-(phosphinoaryl)pyridines 4 and
5 started with the corresponding chiral chloropyridines 6,
which are key intermediates for the chiral bipyridine syn-
thesis (Scheme 1).8c Suzuki cross-coupling of the chloro-
pyridines 6 with 2-hydroxyphenylboronic acid gave
pyridylphenols 7. Pyridylphenols 7 were converted into
the desired 2-(phosphinoaryl)pyridines 4 and 5, respec-
tively, in a conventional manner.9
These first generation heterobidentate ligands showed
high enantioselectivity in the allylic alkylation of 1,3-
diphenyl-substituted allyl (i.e. a,g-diphenylallyl) sub-
strates, but they gained a limited success in the reaction of
1,3-dimethyl-substituted allyl (i.e. a,g-dimethylallyl) or
cyclic allyl substrates. It is clear that the chiral coordina-
tion sphere constructed by heterobidentate ligands regu-
Synlett 1999, No. 10, 1563–1566 ISSN 0936-5214 © Thieme Stuttgart · New York

1564
K. Ito et al.
LETTER
OH
B(OH)2
( )n
N
N
Cl
( )
Pd(PPh3)4
Na2CO3
1,4-dioxane / H20 6:1
n
OH
R
R
6
7
HSiCl3, NEt3
toluene
1) Tf20, 2,6-lutidine
O
N
( )
2)
n
PPh2
H
PPh2
R
O
Pd(OAc)2, dppb
i-Pr2NEt, DMSO
8
N
PPh2
R
( )
n
4 (n= 1) a (R= Ph)
b
c
a
b
c
(R= i-Pr)
(R= CMe2OSiMe2(t-Bu))
(R= Ph)
(R= i-Pr)
(R= CMe2OSiMe2(t-Bu))
5 (n= 2)
We next examined the reaction of 3-penten-2-yl acetate
which is an unmanageable substrate among 1,3-dialkyl-
substituted allyl acetates, using 4b as the chiral source
(Table 2). Reaction in dichloromethane using BSA as the
base proceeded smoothly but the enantioselectivity was
moderate (entry 1). It is well-known that the enantioselec-
tivity of allylic alkylation was affected by the base used in
many cases.2 Thus, we next examined the effect of the
base on enantioselectivity. Rapid reaction was observed
by using sodium hydride as the base in THF, but the enan-
tioselectivity was decreased to a considerable extent (en-
try 2).11 In contrast, the reaction in acetonitrile using
sodium hydride in the presence of 15-crown-55d showed
the greatly improved enantioselectivity of 82% ee (entry
3). The reaction at 0 °C otherwise under the same condi-
tions further improved the enantioselectivity to 86% ee
(entry 5). Although enantioselectivity was improved to
88% ee by further depressing the temperature (-15 °C), the
reaction rate became slow (entry 6). Except for the last
run, the starting material was completely consumed in
these reactions but the chemical yields of the desired
product were unsatisfactory (entries 2-5).12 This indicated
that elimination of acetic acid occurred competitively dur-
ing the reaction. To suppress this undesired side-reaction,
we examined the reaction of the substrates bearing alkyl
carbonyloxy groups1a,3b that are less potent leaving groups
than acetoxy group. The reactions of these substrates pro-
ceeded smoothly with better chemical yields (entries 7-9)
and an equal level of enantioselectivity was observed
when the phenyl carbonate was used as a substrate (entry
9). Enantioselectivity increased as reaction temperature
was decreased and high enantioselectivity of 93% ee as
well as good chemical yield of 85% were achieved when
the reaction was performed at -25 °C (entry 11).13
Scheme 1
With chiral 2-(phosphinoaryl)pyridines 4 and 5 in hand,
we first examined the allylic alkylation of 1,3-diphenyl-2-
propen-1-yl acetate with dimethyl malonate in the pres-
ence of the palladium complex of 4 or 5 in dichlo-
romethane using N,O-bis(trimethylsilyl)acetamide (BSA)
and potassium acetate as the base (Table 1).10 The catalyt-
ic activity of the palladium complexes and their asymmet-
ric induction depended on the ligands used. Although all
the reactions completed to give the product in quantitative
yield at room temperature, the reaction time varied with
the ligands. The reaction using ligand 4c or 5c having a
bulky substituent at the stereogenic carbon was slow and
required longer reaction times (entries 3 and 6). When 5c
was used as the ligand, the enantioselectivity also suf-
fered. As expected, however, the other new ligands served
as efficient chiral auxiliaries and high enantioselectivity
greater than 90% ee was attained. The most effective one
was 4b, the Pd complex of which showed the best enanti-
oselectivity of 97% ee together with high catalytic activity
(entry 2). Ligand 5a was almost equally effective to 4b.
Absolute configuration of all the products was determined
to be S by chiroptical comparison with the published val-
ue.3b,4 This sense of asymmetric induction by these ligands
was identical with that by chiral 2-(phosphinoaryl)oxazo-
lines 1, suggesting the present reaction proceeds through
a similar transition state proposed by Helmchen et al.5b
Cl
Pd Pd
(1mol%)
Cl
MeOOC
Ph
COOMe
Ph
Under the conditions using sodium hydride as the base in
the presence of 15-crown-5, we re-examined the allylic
alkylation of 1,3-diphenyl-2-propen-1-yl acetate with
OAc
Ph
chiral ligand (2.5 mol%)
Ph
CH2(COOMe)2 (3eq)
racemic
BSA (3eq), cat. AcOK
Synlett 1999, No. 10, 1563–1566 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Allylic Alkylation Using a Palladium Complex
1565
(3) a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116,
4089. b) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano,
J. J. Am. Chem. Soc. 1996, 118, 6520. The best
dimethyl malonate and found that high enantioselectivity
of 98% ee and quantitative yield were realized (Table 1,
entry 7).
enantioselectivity (92% ee) in the so far reported allylic
alkylations of 1,3-dimethyl-substituted allyl substrates
reaction has been achieved by using
cyclohexanediamidodiphosphine-Pd complex as a catalyst.
However, the catalyst can not be successfully applied to 1,3-
diphenyl-substituted allyl substrate.
Cl
Pd Pd
O
(1mol%)
Cl
MeOOC
Me
COOMe
Me
O
R'
chiral ligand (2.5 mol%)
-CH(COOMe)2
(4) Dierkes, P.; Ramdeehul, S.; Barloy, L.; De Cian, A.; Fischer,
J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Osborn, J. A.;
Angew. Chem. Int. Ed. Engl. 1998, 37, 3116.
Me
Me
racemic
(5) Some recent examples of asymmetric allylic substitution of
1,3-disubstituted allyl substrates using P,N-chelate ligands:
a) von Matt, P.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1993,
32, 566. b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993,
34, 1769. c) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.;
Coote, S. J. Tetrahedron Lett. 1993, 34, 3149. d) Brown, J. M.;
Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50, 4493.
e) Kubota, H.; Koga, K. Tetrahedron Lett. 1994, 36, 6689.
f) Wimmer, P.; Widhalm, M. Tetrahedron: Asymmetry 1995,
6, 657. g) Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin,
P. S.; Salzmann, R.; J. Am. Chem. Soc. 1996, 118, 1031.
h) Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37,
9143. i) Saitoh, A.; Morimoto, T.; Achiwa, K. Tetrahedron:
Asymmetry 1997, 8, 3567. j) Brunel, J. -M.; Constantieux, T.;
Labande, A.; Lubatti, F.; Buono, G. Tetrahedron Lett. 1997,
38, 5971. k) Bourghida, M.; Widhalm, M. Tetrahedron:
Asymmetry 1998, 9, 1073. l) Ogasawara, M.; Yoshida, K.;
Kamei, H.; Kato, K.; Uozumi, Y.; Hayashi, T. Tetrahedron:
Asymmetry 1998, 9, 1779. m) Zhang, W.; Yoneda, Y.; Kida,
T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron: Asymmetry 1998, 9,
3371. n) Cahill, J. P.; Guiry, P. J. Tetrahedron: Asymmetry
1998, 9, 4301. o) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji, Y.;
Ikeda, I. Tetrahedron Lett. 1998, 39, 4343. p) Wiese, B.;
Helmchen, G. Tetrahedron Lett. 1998, 39, 5727. q) Yonehara,
K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. Chem.
Commun. 1999, 415. r) Saitoh, A.; Misawa, M.; Morimoto, T.
Synlett, 1999, 483. s) Hiroi, K.; Suzuki, Y.; Abe, I.
Tetrahedron: Asymmetry 1999, 10, 1173. t) Suzuki, Y.; Ogata,
Y.; Hiroi, K. Tetrahedron: Asymmetry 1999, 10, 1219. See
also reference 2b.
(6) Efficient regio- and enantioselective allylic alkylation of 1-
and 3-aryl-2-propenyl acetates has been reported with chiral
palladium catalysts: a) Pretoto, R.; Pfaltz, A. Angew. Chem.
Int. Ed. Engl. 1998, 37, 323. b) Pretot, R.; Lloyd-Jones, G. C.;
Pfaltz, A. Pure Appl. Chem. 1998, 70, 1035. For regio- and
enantioselective allylic alkylation using the catalysts other
than palladium catalysts, see: c) Lloyd-Jones, G. C.; Pfaltz, A.
Angew. Chem. Int. Ed. Engl. 1995, 34, 462. d) Janssen, J. P.;
Helmchen, G. Tetrahedron Lett. 1997, 38, 8025. e) Bartels,
B.; Helmchen, G. Chem. Commun. 1999, 741. See also
reference 6b.
In conclusion, we were able to disclose that the newly de-
signed 2-(phosphinoaryl)pyridines were promising chiral
ligands for palladium-catalyzed asymmetric allylic alkyl-
ation. Further studies on the optimization of the ligands
and application to other asymmetric reactions are in
progress in our laboratory.
Acknowledgment
Financial support from a Grant-in-Aid for Scientific Research
(10740338) from the Ministry of Education, Science, Sports and
Culture, Japan is gratefully acknowledged.
(7) Highly enantioselective allylic alkylation of cyclic allyl
substrates using P,N-chelate ligands has also been reported:
Kudis, S.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 1998,
37, 3047.
(8) a) Ito, K.; Katsuki, T. Tetrahedron Lett. 1993, 34, 2661.
b) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857. c) Ito, K.;
Yoshitake, M.; Katsuki, T. Tetrahedron 1996, 52, 3905.
d) Ito, K.; Yoshitake, M.; Katsuki, T. Heterocycles, 1996, 42,
305.
(9) a) Uozumi, Y.; Suzuki, N.; Ogiwara, A.; Hayashi, T.
Tetrahedron 1994, 50, 4293. b) Valk, J. -M.; Claridge, T. D.
W.; Brown, J. M. Tetrahedron: Asymmetry 1995, 6, 2597.
(10) Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143.
References and Notes
(1) Reviews: a) Tsuji, J. Tetrahedron 1986, 42, 4361. b) Trost, B.
M.; Verhoeven, T. R. In Comprehensive Organometallic
Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds;
Pergamon Press: Oxford, 1982, Vol. 8, pp. 799.
(2) Reviews: a) Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993, pp.325. b) Trost, B.
M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395.
Synlett 1999, No. 10, 1563–1566 ISSN 0936-5214 © Thieme Stuttgart · New York

1566
K. Ito et al.
LETTER
(11) In contrary to our results, Helmchen et al reported that high
enantioselectivity was observed using sodium hydride as the
base in THF with their new phosphinooxazoline-palladium
complex (reference 5p).
(12) The formation of the corresponding (Z) product was not
detected spectroscopically.
added to the mixture and the resulting solution was used for
allylic alkylation.
Asymmetric allylic alkylation: To the above malonate
solution (1.5 ml) was added (2E)-1-methyl-2-butenyl phenyl
carbonate (43.6 mg, 0.21 mmol) and cooled to -25 °C. To this
mixture was added the solution of palladium catalyst (168 µl)
and further stirred at the temperature for 48 h. The mixture
was quenched with saturated aqueous NH4Cl, allowed to
warm to room temperature, and extracted with ethyl acetate.
The extract was dried over anhydrous MgSO4 and
concentrated. Silica gel chromatography of the residue
(hexane-ethyl acetate = 9:1) gave the desired product (36.1
mg, 85%) as an oil. Enantiomeric excess of the product was
determined to be 93% by 1H NMR analysis in the presence of
chiral shift reagent Eu(hfc)3.
(13) Typical experimental procedure:
Preparation of a solution of palladium catalyst: To a
solution of allylpalladium chloride dimer (2.7 mg, 7.4 µmol)
in acetonitrile (0.6 ml) was added ligand 4b (7.8 mg, 18.5
µmol) under argon. After being stirred for 1h at room
temperature, the resulting orange solution was used for allylic
alkylation.
Preparation of a malonate solution: Sodium hydride (40
mg, 60% in mineral oil, 1 mmol) was placed in flask under
nitrogen, washed three times with acetonitrile and suspended
in acetonitrile (3.7 ml). To this suspension was added
dimethyl malonate (117 µl, 1 mmol). After being stirred for 30
min at room temperature, 15-crown-5 (200 µl, 1 mmol) was
Article Identifier:
1437-2096,E;1999,0,10,1563,1566,ftx,en;Y14699ST.pdf
Synlett 1999, No. 10, 1563–1566 ISSN 0936-5214 © Thieme Stuttgart · New York