Development of chiral terminal-alkene-phosphine hybrid ligands for palladium-catalyzed asymmetric allylic substitutions

Article abstract of DOI:10.1021/ol101069y

A variety of novel chiral terminal-alkene-phosphine hybrid ligands were successfully developed from diethyl l-tartrate for palladium-catalyzed asymmetric allylic alkylations, etherifications, and amination to give the desired products in excellent yields and ees.

Full text of DOI:10.1021/ol101069y

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3054-3057
Development of Chiral
Terminal-Alkene-Phosphine Hybrid
Ligands for Palladium-Catalyzed
Asymmetric Allylic Substitutions
Zhaoqun Liu and Haifeng Du*
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
haifengdu@iccas.ac.cn
Received May 11, 2010
ABSTRACT
A variety of novel chiral terminal-alkene-phosphine hybrid ligands were successfully developed from diethyl L-tartrate for palladium-catalyzed
asymmetric allylic alkylations, etherifications, and amination to give the desired products in excellent yields and ee’s.
Chiral alkenes as one novel type of ligands have attracted
intensive attention since Hayashi and Carreira reported the
development of chiral bicyclic dienes as steering ligands
independently in 2003 and 2004.1,2 Generally, due to the
relatively weak coordination ability of simple alkenes to
transition metals, chelating alkene ligands are often necessary
to ensure the generated catalysts maintain enough stability
for asymmetric catalysis reactions.3 The phosphorus atom
usually displays higher coordination ability to transition
metals; therefore, the combination of alkenes and phosphorus
atoms allows the advantages of each class to be united which
provides good opportunities to find highly efficient hybrid
ligands.1d,4 In 2004, Gru¨tzmacher reported enantiomerically
pure ligand 1 (Figure 1) based on the 5-phosphanyl-5H-
dibenzo[a,d]cycloheptene framework for iridium-catalyzed
hydrogenation of an imine to achieve up to 86% ee.5
Concurrently, Hayashi and co-workers reported chiral
phosphine-alkene ligands 2 based on a norbornene frame-
(3) For recent leading references on chiral diene ligands, see: (a) Wang,
Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129,
5336. (b) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S.
Angew. Chem., Int. Ed. 2008, 47, 7669. (c) Mahoney, S. J.; Dumas, A. M.;
Fillion, E. Org. Lett. 2009, 11, 5346. (d) Fournier, P.; Fiammengo, R.;
Ja¨schke, A. Angew. Chem., Int. Ed. 2009, 48, 4426. (e) Brown, M. K.;
Corey, E. J. Org. Lett. 2010, 12, 172. (f) Luo, Y.; Carnell, A. J. Angew.
Chem., Int. Ed. 2010, 49, 2750. (g) Shintani, R.; Isobe, S.; Takeda, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3795. (h) Shintani, R.; Takeda,
M.; Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969.
(4) For leading references on amine-alkene hybrid ligands, see: (a)
Marie, P.; Breher, F.; Scho¨nberg, H.; Gru¨tzmacher, H. Organometallics
2005, 24, 3207. (b) Hahn, B. T.; Tewes, F.; Fro¨hlich, R.; Glorius, F. Angew.
(1) For reviews on chiral alkene ligands, see: (a) Glorius, F. Angew.
Chem., Int. Ed. 2004, 43, 3364. (b) Johnson, J. B.; Rovis, T. Angew. Chem.,
Int. Ed. 2008, 47, 840. (c) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2008, 47, 4482. (d) Shintani, R.; Hayashi, T.
Aldrichim. Acta 2009, 42, 31
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(2) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (b) Fisher, C.; Defieber, C.; Suzuki, T.;
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10.1021/ol101069y  2010 American Chemical Society
Published on Web 06/10/2010

suitable chiral backbones may provide a practical strategy
for developing novel phosphine-alkene hybrid ligand 10
(Figure 2). Herein, we report our efforts on the development
of highly efficient terminal-alkene-phosphine hybrid ligands
derived from diethyl L-tartrate for palladium-catalyzed allylic
alkylations, etherifications, and aminations as well.
At first, a variety of terminal-alkene-phosphine hybrid
ligands 10a-f were synthesized in reasonable yields from
known compounds 11 which were obtained with diethyl
L-tartrate as a starting material according to the reported
procedures (Scheme 1).14,15 With these ligands in hand, the
initial studies were carried out with 10a as ligand (5.0 mol
Figure 1. Representative phosphinoalkene hybrid ligands.
work.6 Subsequently, Widhalm7 and Carreira8 developed
binaphthyl-based phosphinoalkene ligands 3 and 4. Steˇka
Scheme 1.
Synthesis of Terminal-Alkene-Phosphine Ligands10
c
9
ˇ
and Bolm10 reported planar chiral phosphine-alkene hybrid
ligands 5 and 6. Very recently, Boysen and co-workers
reported an phosphinite-alkene hybrid ligand 7 derived from
D-glucose.11 Among them, ligands 2,6b 5,9 and 711 were
employed in palladium-catalyzed asymmetric allylic alky-
lations,12 and 96%, 43%, and 61% ee’s were achieved,
respectively.
We are interested in the development of chiral alkene
ligands for asymmetric catalysis. We previously reported that
flexible acyclic dienes 8 and 9 containing two terminal
alkenes as coordinating moieties can be used as effective
ligands for rhodium-catalyzed asymmetric 1,4-additions with
promising activity and selectivity (Figure 2).13 However, the
enantioselectivity still cannot reach very high levels, which
%, 1:1 molar ratio to Pd(II)) for palladium-catalyzed allylic
alkylation of racemic 1,3-diphenyl-2-propenyl acetate (12a)
with dimethyl malonate (13a) at 35 °C in CH2Cl2, and the
reaction proceeded smoothly to afford 14a in quantitative
conversion with 74% ee for the R-isomer (Scheme 2). We
are curious for whether alkene moieties in ligand 10a are
Scheme 2. Pd-Catalyzed Asymmetric Allylic Alkylation
Figure 2. Chiral ligands containing terminal alkenes.
may be partially attributed to the weak coordination between
flexible dienes and transition metals. We envisioned that
installing the terminal alkene and phosphine moieties on
involved in the coordination with palladium. Hence, mono-
phosphine ligand 15 bearing ethyl instead of vinyl group was
subjected to this reaction,16 and it was interesting to find
that 42% ee for the contrary configuration was obtained,
(5) (a) Deblon, S.; Gru¨tzmacher, H.; Scho¨nberg, H. WO 03/048175 A1,
2003. (b) Marie, P.; Delbon, S.; Breher, F.; Geier, J.; Bo¨hler, C.; Ru¨egger,
H.; Scho¨nberg, H.; Gru¨tzmacher, H. Chem.sEur. J. 2004, 10, 4198. (c)
Piras, E.; La¨ng, F.; Ru¨egger, H.; Stein, D.; Wo¨rle, M.; Gru¨tzmacher, H.
Chem.sEur. J. 2006, 12, 15849.
(6) (a) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T.
Angew. Chem., Int. Ed. 2005, 44, 4611. (b) Shintani, R.; Duan, W.-L.;
Okamoto, K.; Hayashi, T. Tetrahedron: Asymmetry 2005, 16, 3400. (c)
Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 2130.
(12) For leading reviews on asymmetric allylic alkylations, see: (a) Trost,
B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(13) (a) Hu, X.; Zhuang, M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744.
(b) Hu, X.; Cao, Z.; Liu, Z.; Wang, Y.; Du, H. AdV. Synth. Catal. 2010,
342, 651.
(7) Kasa´k, P.; Arion, V. B.; Widhalm, M. Tetrahedron: Asymmetry 2006,
17, 3084.
(8) (a) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew.
Chem., Int. Ed. 2007, 46, 3139. (b) Mariz, R.; Bricen˜o, A.; Dorta, R.
Organometallics 2008, 27, 6605.
(14) (a) Wershofen, S.; Scharf, H.-G. Synthesis 1988, 854. (b) Bell,
T. W.; Ciaccio, J. A. J. Org. Chem. 1993, 58, 5153. (c) Mukai, C.; Kim,
J. S.; Sonobe, H.; Hanaoka, M. J. Org. Chem. 1999, 64, 6822. (d) Pandey,
G.; Kapur, M. Org. Lett. 2002, 4, 3883. (e) Pandey, G.; Kapur, M.; Khan,
M. I.; Gaikwad, S. M. Org. Biomol. Chem. 2003, 1, 3321. (f) Horva´th, A.;
Benner, J.; Ba¨ckvall, J.-E. Eur. J. Org. Chem. 2004, 3240.
(15) Lee, S.-g.; Zhang, Y. J.; Song, C. E.; Lee, J. K.; Choi, J. H. Angew.
Chem., Int. Ed. 2002, 41, 847.
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(9) (a) Steˇpnicˇka, P.; C´ısaˇrova´, I. Inorg. Chem. 2006, 45, 8758. (b)
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Steˇpnicˇka, P.; Lamacˇ, M.; C´ısarˇova, I. J. Organomet. Chem. 2008, 693,
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Org. Lett., Vol. 12, No. 13, 2010
3055

which suggests that the active catalyst species generated from
palladium between ligands 10a and 15 are completely
different and vinyl group in ligand 10a plays a very important
role in the asymmetric induction.
can be formed efficiently and cleanly with [PdCl(C3H5)]2 (0.5
equiv) and 10c (1.0 equiv) (Pd/10c ) 1:1), which can be kept
at room temperature for at least 12 h without changes. The 31P
resonance for coordinated ligand 10c was shifted obviously from
-23.9 ppm to 17.4 ppm as a singlet. However, the signals for
the protons on vinyl groups in the formed complexes had few
changes compared to free ligand 10c. Tuning the ratio of
palladium and 10c from 1:1 to 1:3 afforded messy spectra,
which indicated that more than one species were formed.
Subsequently, the impacts on the ratios of palladium and ligand
10c were studied. It was found that only 57% conversion and
80% ee were obtained at the ratio of 1:2 (Table 1, entry 10).
Alteration of the ratio to 1:3 led to a low conversion and 36%
ee for the contrary configuration, which was consistent with
the aforementioned results catalyzed by monophosphine ligand
15 (Table 1, entry 11 vs Scheme 2). According to these results,
it was proposed that ligand 10c acted as an alkene-phosphine
hybrid ligand at a ratio of 1:1, and there may involve a very
rapid coordination and dissociation process between alkene and
palladium which accounted for the observed no changes for
Table 1. Evaluation of Ligands and Optimization of Reaction
Conditions for Palladium-Catalyzed Alkylation of Allylic
Acetate 12a with 13aa
cat.
temp
convnb
(%)
eec, d
(%)
entry
ligand
10a
(mol %) (°C) additive
1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0.5
0.1
0.5
0.5
0.5
-40 KOAc
-40 KOAc
-40 KOAc
-40 KOAc
-40 KOAc
-40 KOAc
-20 LiOAc
-20 LiOAc
-20 LiOAc
-20 LiOAc
-20 LiOAc
-20 LiOAc
>99
>99
>99
>99
>99
>99
>99
>99
79
83 (R)
85 (R)
90 (R)
86 (R)
85 (R)
83 (R)
95 (R)
95 (R)
93 (R)
80 (R)
36 (S)
19 (S)
2
3
4
5
6
7
8
10b
10c
10d
10e
10f
10c
10c
10c
10c
10c
9e
10f
11g
12
1
57
15
>99
proton signals of vinyl group in H NMR study. With the
increasing amount of 10c, some of them were supposed to act
as monophosphine ligands to generate different active species
with palladium giving the contrary configuration products which
still awaits further studies.
Encouraged by the results obtained with phosphine-alkene
ligand 10c, asymmetric alkylation of several allylic acetates
12 with different malonates 13 were subsequently investi-
gated. As shown in Table 2, all the reactions can proceed
efficiently to give the desired products in excellent yields
and ee’s. In particular, when malonates 13b were employed
as nucleophiles, >99% ee’s were successfully achieved (Table
2, entries 2, 6, and 9).
(-)-DIOP
a All of the reactions were carried out with Pd/ligand ) 1/1 (molar
ratio) for 12 h unless otherwise stated. b The conversion was determined
by crude H NMR. c The ee was determined by chiral HPLC (Chiralpak
1
AD-H column). d The absolute configuration was determined by comparing
the optical rotation with the reported one. e The reaction time was 24 h.
f Pd/10c ) 1/2 (molar ratio). g Pd/10c ) 1/3 (molar ratio).
Screening ligands and optimizing reaction conditions were
subsequently carried out to search for more effective ligands.
Some of the results are summarized in Table 1. When the
temperature was decreased to -40 °C, under the catalysis of
10a/Pd complex, the reaction of 1,3-diphenyl-2-propenyl acetate
(12a) and dimethyl malonate (13a) still went efficiently to give
the desired product 14a in 83% ee (Table 1, entry 1). Under
the same conditions, ligands 10b-f were examined, and it was
found that the substituents on phosphorus atoms have slightly
impacts on the enantioselectivities (Table 1, entries 2-6). We
were pleased to find that employing 10c as ligand achieved up
to 90% ee with quantitative conversion (Table 1, entry 3).
Further studies on additives using 10c as ligand showed that
lithium acetate was a more effective additive for this reaction,
and up to 95% ee with quantitative conversion was achieved
at -20 °C with the catalyst loading as low as 0.5 mol % (Table
1, entry 8). Promising results were also obtained when the
catalyst loading was reduced to 0.1 mol % (Table 1, entry 9),
while the bisphosphine ligand (-)-DIOP17 containing the same
chiral framework only gave 19% ee for the S-isomer (Table 1,
entry 12).
Table 2. Asymmetric Alkylations Catalyzed by Pd/10ca
Pd/10c
entry (mol %)
yieldb
(%)
eec
(%)
14
Ar/R/R′
1
2
3
4
5
6
7
8
9
0.5
3.0
3.0
3.0
3.0
1.0
3.0
3.0
3.0
14a Ph/H/Me
14b Ph/Me/Et
98
98
99
99
93
88
95
96
95
95 (R)d
>99 (S)d
93
98
91
>99
98
92
14c
Ph/Ph/Et
14d Ph/Bn/Et
14e 4-ClC6H4/H/Me
14f
4-ClC6H4/Me/Et
The excellent reactivity and enantioselectivity encouraged us
to have better insight for the catalyst generated from
[PdCl(C3H5)]2 and phosphine-alkene hybrid ligand 10c. NMR
studies (see the Supporting Information) in CD2Cl2 were
conducted, and it was observed that the complexes of Pd/10c
14g 4-ClC6H4/Bn/Et
14h 4-CH3C6H4/H/Me
14i
4-CH3C6H4/Me/Et
>99
a All of the reactions were carried out with Pd/ligand )1/1 (molar ratio)
for 12 h unless otherwise stated; for entry 1, the reaction time was 10 h.
b Isolated yield. c The enantiomeric excess was determined by chiral HPLC
(Chiralpak AD-H column). d The absolute configuration was determined
by comparing the optical rotation with the reported one.
(16) Studies on 15/Pd complexes at ratios of 1:1 and 2:1 for the
asymmetric alkylation reactions afforded the same ee’s and conversions.
(17) Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 92, 6429.
3056
Org. Lett., Vol. 12, No. 13, 2010

In contrast to the intensive studies on palladium-catalyzed
allylic substitutions with carbon nucleophiles, only a few
examples of palladium-catalyzed enantioselective allylic
substitutions with relatively hard oxygen nucleophiles have
been reported.18 In particular, to the best of our knowledge,
few chiral alkene ligands have ever been applied for this
type of reactions.2b With terminal-alkene-phosphine ligands
in hand, asymmetric allylic substitutions of 1,3-diphenyl-2-
propenyl acetate 12a with aliphatic alcohols were also
studied. As shown in Scheme 3, the reaction of allylic acetate
12a and benzyl alcohol (16a) using 10a as ligand in the
been achieved (Table 3, entries 5-7). Terminal-alkene-
phosphine hybrid ligand 10a was also effective for Pd-
catalyzed allylic substitution with morpholine as a nu-
cleophile to give the desired product in high yield and ee
(Scheme 4).19
Scheme 4. Pd/10a-Catalyzed Asymmetric Amination
Scheme 3. Pd-Catalyzed Asymmetric Etherification of 12a
In summary, a variety of terminal-alkene-phosphine
hybrid ligands have been successfully developed for pal-
ladium-catalyzed enantioselective allylic alkylations, etheri-
fications with aliphatic alcohols, and amination as well,
giving the desired products in good yields with high
enantioselectivities. Interestingly, these ligands are also
possible to partially act as monophosphine ligands in some
cases to give the contrary configuration products which still
awaits further study in detail. Further searching for more
effective terminal-alkene-phosphine hybrid ligands as well
as expansion of their applications in asymmetric catalysis
are currently underway.
presence of cesium carbonate as base gave the desired
product in 77% ee for the (+)-isomer, while using mono-
phosphine 15 as ligand afforded 17a in the opposite
configuration. It was found that the enantioselectivity can
be improved to 91% when the temperature was decreased
to -40 °C (Table 3, entry 1). Ligand 10c and (-)-DIOP
were also examined under the same conditions. It was found
that ligand 10c gave a slightly higher ee, while (-)-DIOP
afforded almost racemic product (Table 3, entries 2 and 4).
Alcohols 16b-d as nucleophiles were subsequently inves-
tigated, and high yields (95-97%) and ee’s (90-93%) have
Acknowledgment. We are grateful for the generous
financial support from the National Science Foundation of
China (20802079), the Scientific Research Foundation for
the Returned Overseas Chinese Scholars, State Education
Ministry, Ministry of Science and Technology (2009ZX09501-
018), and the National Basic Research Program of China
(973 Program, 2010CB833300).
Table 3. Asymmetric Etherifications Catalyzed by Pd/10ca
Supporting Information Available: Procedures for the
synthesis of ligands, allylic substitutions, characterization,
and data for the determination of ee’s along with NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101069Y
(18) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815.
(b) Haight, A. R.; Stoner, E. J.; Peterson, M. J.; Grover, V. K. J. Org.
Chem. 2003, 68, 8092. (c) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet,
J.-P. J. Am. Chem. Soc. 2003, 125, 9276. (d) Tietze, L. F.; Lohmann, J. K.;
Stadler, C. Synlett 2004, 6, 1113. (e) Uozumi, Y.; Kimura, M. Tetrahedron:
Asymmetry 2006, 17, 161. (f) Lam, F. L.; Au-Yeung, T. T.-L.; Kwong,
F. Y.; Zhou, Z.; Wong, K. Y.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008,
47, 1280. (g) Kato, M.; Nakamura, T.; Ogata, K.; Fukuzawa, S.-i Eur. J.
Org. Chem. 2009, 5232. (h) Caldentey, X.; Perica`s, M. A. J. Org. Chem.
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a All of the reactions were carried out with 1,3-diphenyl-2-propenyl
acetate (12a) (0.33 mmol), alcohol (1.0 mmol), [PdCl(C3H5)]2 (0.005 mmol),
ligand (0.010 mmol), and cesium carbonate (1.0 mmol) in toluene (1.0 mL)
for 12 h; for entries 1 and 2, the reaction temperature was -40 °C; for
entries 3-7, the reaction temperature was -20 °C. b Isolated yield. c The
ee was determined by chiral HPLC (Chiralcel OJ-H column).
(19) When benzylamine was used as a nucleophile for this reaction at
35 °C, a lower ee (55%) was obtained which may be partially due to its
relatively strong coordination ability with palladium.
Org. Lett., Vol. 12, No. 13, 2010
3057