A dramatic switch of enantioselectivity in asymmetric heck reaction by benzylic substituents of ligands

Article abstract of DOI:10.1021/ja7104174

A series of benzylic substituted P,N-ligands 1 and 2 have been synthesized. The Pd-complexes of these ligands show high catalytic activity and enantioselectivity in catalyzing the asymmetric Heck reaction. A dramatic switch in enantioselectivity is realized using ligands with and without substituents at the benzylic position of the ligand. Ligands 1 with H as the substituents offer products in (R)-configuration while ligands 2 with the methyl as substituents result in (S)-configuration products. In most cases high enantioselectivities are achieved. Density functional theory calculations on the reaction mechanism as well as X-ray analysis of 1a-PdCl₂ and 2a-PdCl₂ complexes provide a rational explanation for the above observations.

Full text of DOI:10.1021/ja7104174

Published on Web 07/01/2008
A Dramatic Switch of Enantioselectivity in Asymmetric Heck
Reaction by Benzylic Substituents of Ligands
Wen-Qiong Wu,‡ Qian Peng,‡ Da-Xuan Dong,† Xue-Long Hou,*,†,‡ and
Yun-Dong Wu*,‡,§
State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint Laboratory in
Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Feng Lin Road, Shanghai, 200032, China, and Department of Chemistry, The Hong Kong
UniVersity of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
Received November 18, 2007; E-mail: xlhou@mail.sioc.ac.cn
Abstract: A series of benzylic substituted P,N-ligands 1 and 2 have been synthesized. The Pd-complexes
of these ligands show high catalytic activity and enantioselectivity in catalyzing the asymmetric Heck reaction.
A dramatic switch in enantioselectivity is realized using ligands with and without substituents at the benzylic
position of the ligand. Ligands 1 with H as the substituents offer products in (R)-configuration while ligands
2 with the methyl as substituents result in (S)-configuration products. In most cases high enantioselectivities
are achieved. Density functional theory calculations on the reaction mechanism as well as X-ray analysis
of 1a-PdCl2 and 2a-PdCl2 complexes provide a rational explanation for the above observations.
backbone simply by modifying some groups of the ligands6
or using other approaches.7 Recently, an excellent example
Introduction
Both enantiomers of a chiral compound may often be
demanded in organic synthesis, medicinal and biological
chemistry, and the pharmaceutical industry. Usually, they can
be obtained by using chiral ligands with opposite configurations
in asymmetric catalysis.1 However, the antipodes of ligands are
not always easily available. Thus, many strategies have been
developed to realize the tuning of enantioselectivity of reactions2
using single ligands with different transition metals,3 solvents,4
or temperatures.5There are also some examples of the reversal
of enantioselectivity using ligands with a single chiral
of a hydrogen-bond-directed reversal of enantioselectivity was
also reported.8
In the course of studying reaction selectivity control,9 we
observed that ligands with substituents at the benzylic position
showed higher catalytic activities in a Pd-catalyzed asymmetric
Heck reaction and an allylic alkylation reaction.10 Further
structural modification of ligands revealed that the substituent
(6) (a) Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brien, E. M.; Spinelli,
E. M. Org. Lett. 2003, 5, 595. (b) Busacca, C. A. J. Org. Chem. 2004,
69, 5187. (c) Hoarau, O.; A¨ıt-Haddou, H.; Daran, J. C.; Cramaile´re,
D.; Balavoine, G. G. A. Organometallics 1999, 18, 4718. (d) A¨ıt-
Haddou, H.; Hoarau, O.; Cramaile`re, D.; Pezet, F.; Daran, J. C.;
Balavoine, G. G. A. Chem.sEur. J. 2004, 10, 699. (e) Clyne, D. S.;
Mermet-Bouvier, Y. C.; Nomura, N.; RajanBabu, T. V. J. Org. Chem.
1999, 64, 7601.
† State Key Laboratory of Organometallic Chemistry.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
§ The Hong Kong University of Science and Technology.
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Asymmetric Catalysis; Springer: Heidelberg, 1999.
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(b) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E.
Chem. Soc. ReV. 2003, 32, 115.
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T. J. Org. Chem. 2006, 71, 2524. (b) Lutz, F.; Igarashi, T.; Kawasaki,
T.; Soai, K. J. Am. Chem. Soc. 2005, 127, 12206. (c) Mao, J.; Wan,
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J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J.
J. Am. Chem. Soc. 1999, 121, 669. (g) Ashimori, A.; Overman, L. E.
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K.; Uemura, S. Chem. Commun. 1996, 847. (b) Nishibayashi, Y.;
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Chem. Soc. 2004, 126, 5585. (d) Sibi, M. P.; Gorikunti, U.; Liu, M.
Tetrahedron 2002, 58, 8357.
9
10.1021/ja7104174 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 9717–9725 9717

A R T I C L E S
Wu et al.
Scheme 1. Synthesis of Ligands 1
Scheme 2. Synthesis of Ligands 2
Table 1. Pd-Catalyzed Asymmetric Heck Reaction of 11 Using
Ligands 1 and 2a
at the benzylic position had great impact on the stereoselectivity
of the reactions. The configuration of products was switchable
when ligands 1 (R1 ) H) and 2 (R1 ) Me) were used in Pd-
catalyzed asymmetric Heck reactions. Here, we report our results
on the application of these ligands in Pd-catalyzed asymmetric
intermolecular Heck reactions of 2,3-dihydrofuran and N-car-
bomethoxy-2,3-dihydropyrrole as well as a detailed computa-
tional study for the rationalization of the observed stereo-
chemistry.10d
entry
ligand
12
yield, %b
13/14c
ee, % (13)d
1
2
3
4
5
6
7
8
1a
1b
1c
2a
2b
1b
2a
1b
2a
1b
2a
1b
2a
1b
2a
12a
12a
12a
12a
12a
12b
12b
12c
12c
12d
12d
12e
12e
12f
62
79
93
86
78
89
quant.
77e
90f
66
80/1
80/1
50/1
50/1
50/1
18/1
18/1
n.d.g
n.d.g
70/1
1/0
78 (R)
93 (R)
61 (R)
81 (S)
10 (S)
86 (R)
39 (S)
82 (R)
82 (S)
87 (R)
87 (S)
89 (R)
84 (S)
95 (R)
65 (S)
9
Results and Discussion
10
11
12
13
14
15
83
82
78
69
The preparation of ligands 1 is depicted in Scheme 1.
Lithiation of o-bromotoluene 3 with n-BuLi followed by
quenching with PPh2Cl gave phosphine 4.11 Direct benzylic-
lithiation of 4 and quenching with CO2 provided acid 5.12
Esterification of acid 5 followed by treatment with n-BuLi and
amino alcohols afforded amides 7, and ring-closure of 7 gave
rise to ligands 1a-c.
The synthesis of ligands 2 is outlined in Scheme 2. Reaction
of compound 813 with SOCl2 and then with corresponding amino
alcohols provided amides 9, from which oxazolines 10 were
prepared according to the literature procedure.14 Lithiation of
10 with n-BuLi at -78 °C followed by quenching with PPh2Cl
resulted in ligands 2.
100/1
100/1
40/1
100/1
12f
quant.
a Reaction conditions: 11 (0.5 mmol), 12 (2 mmol), Pd(dba)2 (3 mol
%), ligand (6 mol %), i-Pr2NEt (1 mol), solvent (2.5 mL, THF for
entries 1-5, benzene for entries 6-15). b Isolated yields of 13 and 14.
c Determined by GC. d Determined by GC or HPLC using chiral
columns. The absolute configuration of products was assigned according
to the reference method.9f e Pd(OAc)2 was used as the palladium source.
Isolated yield of 13c after 40 h. f Yield of 13c and Pd(OAc)2 was used.
g Not determined.
With these ligands in hand, we applied them to the Pd-
catalyzed asymmetric intermolecular Heck reaction of 2,3-
dihydrofuran 11 with aryl triflates 12a-e and cyclohexenyl
triflate 12f using 3 mol % of Pd(dba)2 and 6 mol % of ligands
with i-Pr2NEt as a base in THF at 60 °C (eq 1).15,10c The results
are shown in Table 1.
(10) (a) Hou, X. L.; Wu, X. W.; Dai, L. X.; Cao, B. X.; Sun, J. Chem.
Commun. 2000, 1195. (b) Wu, H.; Wu, X. W.; Hou, X. L.; Dai, L. X.;
Wang, Q. R. Chin. J. Chem. 2002, 20, 816. (c) Hou, X. L.; Dong,
D. X.; Yuan, K. Tetrahedron: Asymmetry 2004, 15, 2189. (d)
Preliminary results on the application of ligands 1 in Pd-catalyzed
asymmetric Heck reaction of 2,3-dihydrofuran have been reported;
see ref 10c.
(11) Tanner, D.; Wyatt, P.; Johansson, F.; Bertilsson, S. K.; Andersson,
P. G. Acta Chem. Scand. 1999, 53, 263.
(12) Hingst, M.; Tepper, M.; Stelzer, O. Eur. J. Inorg. Chem. 1998, 73.
(13) Beak, P.; Kerrick, S. T.; Gallagher, D. J. J. Am. Chem. Soc. 1993,
115, 10628.
(14) Vorbru¨ggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471.
(15) For some recent reviews, see: (a) Tietze, L. T.; Ila, H.; Bell, H. P.
Chem. ReV. 2004, 104, 3453. (b) Shibasaki, M.; Vogl, E. M.; Ohshima,
T. AdV. Synth. Catal. 2004, 346, 1533. (c) Tietze, L. F.; Lotz, F. In
Asymmetric Synthesis; Christmann, M.; Braese, S., Eds.; Wiley-VCH:
Weinheim, 2007, p 147. (d) Shibasaki, M.; Vogl, E. M. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., ; Pfaltz, A., ;
Yamamoto, H., Eds.; Springer: Berlin and Heidelberg, 1999; p 458.
For some examples of intermolecular asymmetric Heck reactions: (e)
Ozawa, F.;; Kubo, A.;; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417. (f) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 200. (g) Tietze, L. F.; Thede, K.; Sannicolo`, F. Chem.
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40. (i) Mata, Y.; Pa`mies, O.; Die´guez, M. Chem.sEur. J. 2007, 13,
3296.
The ligands appeared to be more active in the intermolecular
Heck reaction than other reported ligands did.15 All the reactions
completed in 20 h monitored by TLC, providing 2-substituted-
2,5-dihydrofuran 13 predominantly. It is intriguing that 13 was
obtained as an (R)-enantiomer when ligands 1a-c were used
(entries 1-3, 6, 8, 12, 14), while (S)-13 was afforded when
ligands were 2a-b (entries 4, 5, 7, 9, 11, 13, 15). 1 and 2 have
the same configuration. Thus, the dimethyl groups at the
9
9718 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Switch of Enantioselectivity in Asymmetric Heck Reaction
A R T I C L E S
That is, (1) the coordination of dihydrofuran can be either cis
or trans with respect to ligand oxazoline N; (2) the seven-
membered ring formed by the ligand coordination with Pd can
be in either the syn or anti conformation according to the
orientation of the benzylic substituents and the phenyl group
on phosphorus; (3) the addition of Ph can be on either the Re
or Si face of dihydrofuran. Overall, eight transition states are
possible. Six of the possible transition states for the reactions
of 1a-Pd and 2a-Pd with 2,3-dihydrofuran 11 were fully
optimized with the density functional theory method of B3LYP/
6-31G*(Lanl2DZ for Pd and P).19 The relative energies and
some selected bond lengths of the six transition states along
with those of the corresponding precursor complexes (CP2) are
given in Table 2. The other two possible transition states, cis-
anti-Si and cis-anti-Re, were not calculated because of expected
high instabilities (see below).
Figure 1. Three modes in the asymmetric phenyl insertion reaction.
benzylic position of the ligand have a significant impact on the
stereochemistry of the reactions.16
Trans versus Cis. The calculations indicate that, for complex
CP2, the cis mode is apparently more stable than the trans mode,
but the trans mode of the transition states (TS1) is much more
stable than the cis mode with both ligands 1a and 2a. These
results can be rationalized by ligand-ligand interactions. CP2
and TS1 structures are all in a square-planar geometry.20,21 As
shown in Figure 2, the dihydrofuran coordinates to Pd in a
perpendicular geometry to facilitate a π-back-donation. Since
P is a more powerful σ-donor and π-acceptor than N,22 it has
a larger trans-influence. That is, the bond anti to P is more
weakened. This is clearly indicated by the calculated bond
distances as shown in Table 2 and in Figure 2: the Pd(1)-C(2)
distance is 2.010 Å in the cis-syn-Re structure and is increased
to 2.019 Å in the trans-syn-Re structure, which is the main cause
of destabilization for the trans-syn-Re structure. This effect is
The enantioselectivity is also affected by the R group on the
oxazoline ring. In the case of ligands 1, (R)-2-phenyl-2,5-
dihydrofuran 13a in 93% ee was obtained when ligand 1b with
a tert-butyl group on the oxazoline ring was used while the ee
value of 13a decreased to 78% and 61% if 1a and 1c with an
iso-propyl and a phenyl group on the oxazoline ring was the
ligand, respectively (entry 2 vs entries 1 and 3). For ligands 2
with two methyl groups at the benzylic position, better ee of
(S)-13a was obtained by using ligand 2a with iso-propyl as the
substituent on the oxazoline ring than by using 2b with tert-
butyl as the substituent (entry 4 vs entry 5). It is interesting
that higher enantioselectivity is obtained with more bulky R2
for ligands 1 while it is the opposite for ligands 2.
In order to verify further the reversal of the enantioselectivity
using these ligands, Heck reactions of N-carbomethoxy-2,3-
dihydropyrrole 15 with some aryl triflates were carried out (eq
2).17,18 Still, ligand 1b yielded products 16 as (R)-enantiomers
while ligand 2a led to (S)-enantiomers. Ligand 2a demonstrated
better activities than ligand 1b did.
(19) The calculations were performed with Gaussian 03 program: Frisch,
M. J. et al. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford,
CT, 2004.
(20) For selected papers on the calculation of Heck reaction, see: (a) Dotta,
P.; Magistrato, A.; Rothlisberger, U.; Pregosin, P. S.; Albinati, A.
Organometallics 2002, 21, 3033. (b) von Schenck, H.; Åkermark, B.;
Svensson, M. J. Am. Chem. Soc. 2003, 125, 3503. (c) Deeth, R. J.;
Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144. (d) Lin,
B. L.; Liu, L.; Fu, Y.; Luo, S. W.; Chen, Q.; Guo, Q. X. Organome-
tallics 2004, 23, 2114. (e) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert,
J. J. Am. Chem. Soc. 2005, 127, 7171. (f) Tabares-Mendoza, C.;
Guadarrama, P. J. Organomet. Chem. 2006, 691, 2978. (g) Cui, X.;
Li, Z.; Tao, C. Z.; Xu, Y.; Li, J.; Liu, L.; Guo, Q. X. Org. Lett. 2006,
8, 2467. (h) Datta, G. K.; von Schenck, H.; Hallberg, A.; Larhed, M.
J. Org. Chem. 2006, 71, 3896. (i) Lee, M. T.; Lee, H. M.; Hu, C. H.
Organometallics 2007, 26, 1317.
(21) For selected papers on the calculation of oxidative addition: (a)
Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Chem. Commun.
2004, 2141. (b) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W.
Organometallics 2005, 24, 2398. (c) Goossen, L. J.; Koley, D.;
Hermann, H. L.; Thiel, W. J. Am. Chem. Soc. 2005, 127, 11102. (d)
Fazaeli, R.; Ariafard, A.; Jamshidi, S.; Tabatabaie, E. S.; Pishro, K. A.
J. Organomet. Chem. 2007, 692, 3984. (e) Fairlamb, I. J. S.; Lee,
A. F. Organometallics 2007, 26, 4087. (f) Lam, K. C.; Marder, T. B.;
Lin, Z. Y. Organometallics 2007, 26, 758. (g) Kozuch, S.; Amatore,
C.; Jutand, A.; Shaik, S. Organometallics 2005, 24, 2319. (h) Ariafard,
A.; Lin, Z. Y. Organometallics 2006, 25, 4030.
To reveal the effect of the geminal dimethyl groups at the
benzylic position of the ligand and rationalize the reversal of
the enantioselectivity, density functional theory (DFT) calcula-
tions were used to model the asymmetric insertion step of the
Heck reaction (Scheme 3). Three different modes in the
asymmetric insertion need to be studied, as shown in Figure 1.
(16) There have been many examples of geminal alkyl group effect on
reactivity and stereochemistry. For reviews, see: Jung, M. E.; Piizzi,
G. Chem. ReV. 2005, 105, 1735.
(22) For selected papers, see: (a) Goldfuss, B. J. Organomet. Chem. 2006,
4508. (b) Goldfuss, B.; Lo¨schmann, T.; Rominger, F. Chem.sEur. J.
2004, 10, 5422. (c) Tu, T.; Zhou, Y. G.; Hou, X. L.; Dai, L. X.; Dong,
X. C.; Yu, Y. H.; Sun, J. Organometallics 2003, 22, 1255. (d) Kollmar,
M.; Steinhagen, H.; Janssen, J. P.; Goldfuss, B.; Malinovskaya, S. A.;
Va´zquez, J.; Rominger, F.; Helmchen, G. Chem.sEur. J. 2002, 8,
3103. (e) Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2108. (f) Togni, A.; Burckhardt, U.; Gramlich,
V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem. Soc. 1996, 118, 1031.
(g) Lin, Z. Y.; Hall, M. B. Inorg. Chem. 1991, 30, 646. (h) Keith,
J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard,
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11876.
(17) (a) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267. (b)
Tietze, L. F.; Thede, K. Synlett 2000, 1470. (c) Loiseleur, O.; Hayashi,
M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338. (d) Tu, T.; Hou,
X. L.; Dai, L. X. Org. Lett. 2003, 5, 3651.
(18) The reaction was carried out with a 0.5 mmol scale (12/15 ) 1/4) in
the presence of Pd(dba)2 (3 mol %) and the ligand (6 mol %) with
i-Pr2NEt (200 mol%) as a base in 2.5 mL of toluene under an argon
atmosphere for 4 days. The ee value of 16 was determined by chiral
HPLC. Absolute configuration of products was assigned according to
ref 17a.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9719

A R T I C L E S
Wu et al.
Table 2. Selected Bond Lengths (Å) and Relative Free Energies (kcal/mol) of Calculated Complexes and Transition States in the Insertion
Reaction Step (Scheme 3)a
1a
2a
CP2
TS1
CP2
TS1
∆G333K
g/s
∆G′333K
g/s
∆G333K ∆G′333K
g/s g/s
∆G333K
g/s
∆G′333K
g/s
∆G333K ∆G′333K
g/s g/s
structure
Pd1-C2
Pd1-C2 C2-C3
Pd1-C2
Pd1-C2 C2-C3
cis-syn-Si
cis-syn-Re
trans-syn-Si
2.010 -2.5 /-3.6 -2.7/-3.7 2.158 2.027 3.6/2.5 3.9/2.8 2.011
2.010 -2.8/-4.6 -2.9/-4.6 2.160 2.006 6.3/5.1 6.7/5.7 2.010
0.1/-1.7 -0.2/-2.1 2.160 2.029 5.2/4.1 5.3/3.8
0.2/-1.8 -0.1/-2.1 2.162 2.000 8.3/6.2 8.6/6.7
2.021
0.0/0.0
0.0/0.0
2.152 2.127 0.0/0.0 0.0/0.0 2.022
2.7/1.9
1.9/1.0
2.5/1.7
2.0/1.1
2.156 2.131 1.9/1.6 1.6/1.2
2.150 2.125 2.8/1.9 2.9/1.9
trans-syn-Re 2.019 -0.5/-0.9 -0.2/-0.6 2.146 2.124 0.7/0.5 0.9/0.7 2.023
trans-anti-Si 2.016
trans-anti-Re 2.014
0.7/-0.1
0.8/-0.4
0.8/0.0
2.147 2.124 2.5/2.0 2.6/2.0 2.019 -0.5/-0.5 -0.3/-0.3 2.147 2.117 0.8/0.6 1.0/0.7
0.7/-0.5 2.147 2.137 1.8/1.6 1.8/1.2 2.019
0.0/0.0 0.0/0.0 2.149 2.134 0.0/0.0 0.0/0.0
a g/s: the gas phase/with solvation effects; G333K: relative free energies with 6-31G. G′333K: relative free energies with single-point energies
(6-311+G** basis set for H, C, N, and O) and frequency calculation with the 6-31G* basis set for H, C, N, and O).
Figure 2. Calculated complex structures (CP2 in Scheme 3) mediated by Pd-1a. For clarity, most hydrogen atoms are omitted.
Scheme 3. Asymmetric Insertion Step of the Heck Reaction
structures, and there is not a big difference in the rotation energy
between the trans and the cis modes of coordination. Therefore,
it cannot be a major factor for the higher reactivity of the trans
mode.
Syn versus Anti. When ligand 1a or 2a coordinates with Pd,
two conformations (syn and anti) are possible for the seven-
membered-ring. If we use the plane of the bridging benzene
ring as a reference, both the P-Pd and CR-C(oxazoline) bonds
have to be out of the plane. If the P-Pd is below the plane, the
CR-C(oxazoline) bond can be either below or above the plane
to form syn and anti conformations, respectively. The two
phenyl groups on P arrange in axial (above the plane) and
transferred to the transition state as the trans-effect; that is, the
PdsPh bond is more activated in the trans mode, and it is more
equatorial (below the plane) positions, respectively. Calculations
indicate that the syn conformation is more stable than the anti
reactive toward the C-C coupling reaction. In addition, the
(by 1-2 kcal/mol, Table 2) both in the CP2 and in the TS1
CdC bond in the trans-syn-Re is better activated as indicated
with ligand 1a. The anti conformation is less stable because of
by its longer C(3)-C(4) bond length (1.386 Å) than that in the
a larger ring strain. The PdsNdC(oxazoline)sCR dihedral angle
cis-syn-Re structure (1.376 Å). Therefore, the trans-Ph group
is about 10°-13° in the syn structures, but it is about 33°-36°
can proceed with the addition to the 2,3-dihydrofuran double
in the anti structures. As a result, the N-Pd binding is stronger
bond with an earlier transition state (longer forming C(2)sC(3)
in the syn than in the anti structures, as indicated by the
bond distance and shorter Pd(1)-C(2) bond distance) and a
lower activation energy (see Table 2).
Another possibility for the higher reactivity of the trans mode
calculated Pd-N distances (∼2.210 Å in syn and ∼2.260 Å in
anti). On the other hand, ligand 2a with two methyl groups at
the benzylic position favors forming the anti-conformation of
CP2 and TS1 (by 1-2 kcal/mol, Table 2). If the benzylic group
is H (1a), the syn structure does not suffer from the steric
interaction between the benzylic group H and the axial phenyl
group on the phosphine; the shortest HsH distance is 2.795 Å.
However, when the benzylic groups are methyl, the syn
might be that it takes less energy to rotate the CdC double
bond from the perpendicular conformation in CP2 to a coplanar
conformation, which is required for the transition state. Indeed,
we were able to locate the coplanar complexes. As given in
Supporting Information (Table S2), these structures are all about
4 kcal/mol with respect to their corresponding perpendicular
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9720 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Switch of Enantioselectivity in Asymmetric Heck Reaction
A R T I C L E S
Figure 3. ORTEP drawings of X-ray crystal structures of PdCl2-1a and PdCl2-2a complexes.
Figure 4. Calculated transition states TS1 and the dihedral angles for the phenyl insertion reaction step (the number of the atom, see Scheme 3) mediated
by Pd-1a, in which the phenyl group is trans to the P ligand. For clarity, the bridging benzyl group of the ligand and most hydrogen atoms are omitted.
conformation suffers from a significant steric interaction between
the axial Me and axial Ph groups, as indicated in Scheme 3.
The above predictions prompted us to obtain crystal structures
of the complexes of PdCl2 with ligands 1a and 2a. As shown
in Figure 3, X-ray analyses of the two complexes indeed indicate
that PdCl2-1a is in a syn conformation and PdCl2-2a is in an
anti conformation.
Re versus Si. As shown in Table 2, no matter whether the
ligand is 1a or 2a, the trans-syn-Si transition state is more stable
than the trans-syn-Re transition state by 0.7-0.9 kcal/mol. On
the other hand, the trans-anti-Si transition state is less stable
than the trans-anti-Re transition state by 0.7-1.0 kcal/mol. Since
trans-syn is more stable than trans-anti for ligand 1a, the (R)-
product is predicted to be the major product when the ligand is
1a. In contract, trans-anti is more stable than trans-syn for ligand
2a, and the (S)-product is predicted to be the major product
when the ligand is 2a. These predictions are in qualitative
agreement with experimental observations (Table 1).
Figure 4 shows the four phenyl insertion transition states (TS1
in Scheme 3) of Pd-1a-(phenyl)(2,3-dihydrofuran) with the
bridging benzyl group of the ligand deleted for clarity. In these
structures, the phenyl group is trans to the P atom of the 1a
ligand. The structures are arranged in such a way that P-Pd-N
is in the plane perpendicular to the paper. The two favorable
transition structures for the syn and anti conformations, trans-
syn-Si and trans-anti-Re, have a nearly perfect square-planar
Pd center (the dihedral angels of N-P-C4-C2 are nearly 0°,
Figure 4). On the other hand, the two less favorable transition
structures, trans-syn-Re and trans-anti-Si, have the Pd center
distorted away from a square-planar geometry. This situation
is exactly the same for the corresponding four transition
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A R T I C L E S
Wu et al.
Figure 5. Side view of the syn conformation of Pd-1a and the anti conformation of Pd-2a and schematic models for the prediction of enantioselectivity with
the two ligands 1a and 2a.
structures with 2a as ligand (see Supporting Information,
coordinates of calculated structures in Table S1).
preference for the products of trans-syn-Si and trans-anti-Re
over the products of trans-syn-Re and trans-anti-Si is about 2.4
and 1.8 kcal/mol, respectively (Figure 6, CP3).
A closer inspection of the transition structures indicates that
the distortions in trans-syn-Re and trans-anti-Si are not caused
by the steric interaction between the Pd-bound phenyl group
and the oxazoline. The only close contact is between the
hydrogen of the isopropyl group and the phenyl group. However,
the steric interaction should be about the same for Si and Re
structures without the distortion. Figure 5 shows the side view
of the syn conformation of Pd-1a and the anti conformation of
Pd-2a. Due to the constraint of the seven-membered-ring, the
two phenyl groups on P atom create an unsymmetrical environ-
ment around the Pd metal center. As shown more clearly by
ChemDraw schematic pictures (Figure 5B), in the syn confor-
mation, the axial phenyl group is closer to the Pd center (the
bond length of C5-C4 is shorter than the one of C6-C4). Thus,
it is more crowded above the square-planar Pd plane and less
crowded below the Pd plane in the syn transition state. On the
other hand, in the anti conformation, the equatorial phenyl group
is closer to the Pd center (the bond length of C6-C4 is shorter)
and causes more steric crowding below the Pd plane in the anti
transition state. This explains why the trans-syn-Si and trans-
anti-Re transition states, which do not need distortion, are more
favorable than the trans-syn-Re and trans-anti-Si transition
states, which have to be distorted, respectively. As expected,
differences in steric interaction in the products should be even
more significant. This is indeed the case. The calculated
The above results also allow us to rationalize the opposite
effect of t-Bu of ligands 1b and 2b on the enantioselectivity
that is observed experimentally (Table 1). Both ligands 1a and
1b should favor the syn conformation. Because of the geo-
metrical distortion in the trans-syn-Re, the replacement of the
i-Pr group by the t-Bu group causes more steric interaction to
the trans-syn-Re than to the trans-syn-Si, resulting in increased
enantioselectivity. On the other hand, both ligands 2a and 2b
favor the anti conformation. The replacement of the i-Pr by the
t-Bu group introduces more steric interaction to the trans-anti-
Re than to the trans-anti-Si, resulting in decreased enantiose-
lectivity. These qualitative analyses are supported by calculation
results. With ligand 2b, the trans-anti-Si transition state is less
stable than the trans-anti-Re transition state by only 0.4 kcal/
mol. The trans-syn-Si transition state is much more stable than
the trans-syn-Re transition state by 1.9 kcal/mol when ligand
1b is used.
Summary
A series of benzylic substituted P,N-ligands 1 and 2 with H
and Me as substituents at the benzylic position, respectively,
have been synthesized. The palladium complexes of these
ligands show high catalytic activity and enantioselectivity in
catalyzing the asymmetric Heck reaction. A dramatic switch in
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9722 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Switch of Enantioselectivity in Asymmetric Heck Reaction
A R T I C L E S
Figure 6. Calculated free energy (∆G′333K, 6-311+G**) profiles relevant to the Re-attack and Si-attack in the insertion reaction.
to external 85% H3PO4. Optical rotation was measured with a
enantioselectivity is realized using ligands with and without
substituents at the benzylic position of the ligands. Ligands 1
with R1 ) H offer products in the (R)-configuration while
ligands 2 with R1 ) Me result in (S)-configuration products. In
most cases high enantioselectivities are achieved. Density
functional theory calculations on the reaction mechanism as well
as X-ray analysis of PdCl2-1a and PdCl2-2a complexes provide
a rational explanation for the above observations: (1) Ligands
1 and 2 coordinate with Pd in syn and anti seven-membered-
ring conformations, respectively; (2) due to the stronger trans
effect of P over N, the Pd-bound phenyl group prefers trans to
P in the transition state so that it is more activated with a lower
barrier for addition to Pd-coordinated 2,3-dihydrofuran substrate;
(3) because of the unsymmetrical environment caused by the
two phenyl groups on P (Figure 5), the trans-syn-Si and the
trans-anti-Re transition states are more favorable than trans-
syn-Re and trans-anti-Si transition states, respectively, which
require a geometrical distortion away from the square-planar
Pd center. Further applications of these ligands in asymmetric
catalysis are in progress.
thermally jacketed 10 cm cell at 20 °C (concentration C given as
g/100 mL). IR spectra were recorded in KBr and measured in cm-1
.
Melting points are uncorrected. Diphenyl(o-tolyl)phosphine (4),11
2-[2-(diphenylphosphino)phenyl]acetic acid (5),12 and 2-(2-bro-
mophenyl)-2-methylpropanoic acid 813 were prepared using the
literature procedure. Asymmetric Heck reactions proceeded ac-
cording to the known procedures, and the ee values of products
were determined using GC or HPLC with a chiral column.
Preparation of Methyl 2-[2-(diphenylphosphino)phenyl]ac-
etate (6). At 0 °C, 5 (4.363 g, 13.6 mmol), DCC (3.330 g, 16.0
mmol), and DMAP (60 mg) were mixed in MeOH (6 mL). The
mixture was stirred at room temperature until the reaction was
completed monitored by TLC. The reaction mixture was filtered
through a silica gel pad and washed with CH2Cl2. After removal
of the solvent, the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate ) 20) to afford 6 as a
white solid (4.586 g, 13.6 mmol, quant.). Mp: 66-68 °C; IR (KBr,
cm-1): 3058, 1737, 751, 699; 1H NMR (300 MHz, CDCl3): δ 3.43
(s, 3H), 3.96 (s, 2H), 6.91-6.95 (m, 1H), 7.11-7.40 (m, 13H);
31P NMR (121 MHz, CDCl3): δ -14.31; 13C NMR (75 MHz,
CDCl3): δ 39.7 (d, JPC ) 23 Hz), 51.7, 127.4, 128.4 (d, JPC ) 6.8
Hz), 128.5 (d, JPC ) 20.5 Hz), 129.1, 130.5 (d, JPC ) 4.6 Hz),
133.8 (d, JPC ) 19.5 Hz), 133.9, 136.1 (d, JPC ) 9.2 Hz), 136.5 (d,
JPC ) 12.6 Hz), 138.9 (d, JPC ) 26.9 Hz), 171.5; MS (EI) m/z (%):
334 (M+, 3.67), 319 (100). Anal. Calcd for C21H19O2P: C, 75.44;
H, 5.73. Found: C, 75.46; H, 5.66.
Experimental Section
General Information. All reactions were performed under a dry
argon atmosphere. The commercially available reagents were used
without further purification. The solvents were treated by using
standard methods. Unless otherwise stated, all 1H NMR spectra
were recorded in CDCl3 and the chemical shifts were referenced
to CHCl3 (δ ) 7.27 ppm) or TMS (δ ) 0 ppm). The chemical
shifts for 13C NMR spectra were referenced to CDCl3 (δ ) 77.0
ppm). The chemical shifts for 31P NMR spectra were referenced
Preparation of (S)-2-[2-(Diphenylphosphino)benzyl]-4-iso-
propyl-4,5-dihydrooxazole (1a). To a solution of L-valinol (514
mg, 5.0 mmol) in THF (40 mL) was added n-BuLi (1.6 M in
hexane, 6.3 mL, 10.0 mmol) dropwise within 20 min at 0 °C. After
the mixture was stirred at room temperature for 1 h, a solution of
6 (1.670 g, 5.0 mmol) in THF (10 mL) was added. The reaction
mixture was refluxed for 27 h. The reaction mixture was cooled to
room temperature, and 20 mL of saturated NH4Cl aqua solution
were added. The organic phase was separated, and the water phase
was extracted with EtOAc (20 mL × 3). The combined organic
phases were dried over Na2SO4. After evaporation of the organic
solvents, the mixture was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate ) 2) to give 7a as a white solid
(1.306 g, 3.2 mmol, 64%).
(23) Yuan, K.; Zhang, T. K.; Hou, X. L. J. Org. Chem. 2005, 70, 6085.
(24) (a) Becke, A. D. Phys. ReV. 1988, A38, 3098. (b) Becke, A. D. J. Chem.
Phys. 1993, 98, 1372. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV.
1988, B37, 785.
(25) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
(26) (a) Cance`s, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997,
107, 3032. (b) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106,
5151. (c) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem.
Phys. 2002, 117, 43.
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A R T I C L E S
Wu et al.
MsCl (160 mg, 1.40 mmol) was added dropwise over 10 min
into a solution of 7a (567 mg, 1.4 mmol) and Et3N (1 mL, 7.0
mmol) in CH2Cl2 (7 mL) at 0 °C. The reaction mixture was warmed
to room temperature and stirred overnight and quenched with H2O
(7 mL). Usual workup gave 1a as a colorless oil (389 mg, 1.0 mmol,
72%). [R]D20 -36.0 (c 0.56, CHCl3); IR (KBr, cm-1): 2960, 2873,
7.15-7.21 (m, 1H), 7.35-7.41 (m, 1H), 7.51-7.54 (m, 1H),
7.61-7.64 (m, 1H); MS (EI) m/z (%): 328 (M + 1+, 100).
Preparation of (S)-2-(2-Bromophenyl)-N-(1-hydroxy-3,3-di-
methylbutan-2-yl)-2-methylpropanamide (9b). 9b was prepared
as a white solid (93%) using the same procedure as that for 9a.
Mp: 105-107 °C; IR (KBr, cm-1): 3370, 2958, 2866, 1651, 1504,
1437, 767, 757; 1H NMR (300 MHz, CDCl3): δ 0.82 (s, 9H),
1.69-1.71 (m, 6H), 2.98-3.02 (m, 1H), 3.50-3.57 (m, 1H),
3.68-3.74 (m, 1H), 3.79-3.87 (m, 1H), 7.16-7.22 (m, 1H),
7.37-7.42 (m, 1H), 7.53-7.56 (m, 1H), 7.62-7.65 (m, 1H); 13C
NMR (75 MHz, CDCl3): δ 26.4, 26.8, 26.9, 33.4, 48.8, 60.4, 63.4,
124.0, 127.9, 128.1, 129.0, 135.0, 142.9, 177.8; MS (EI) m/z (%):
286 (M-tBu+, 21.81), 284 (M-tBu+, 23.53), 199 (95.81), 197
(100.00); Anal. Calcd for C16H24BrNO2: C, 56.15; H, 7.07; N, 4.09.
Found: C, 56.30; H, 6.85; N, 3.98.
Preparation of (S)-2-[2-(2-Bromophenyl)propan-2-yl]-4-iso-
propyl-4,5-dihydrooxazole (10a).23 To a solution of amide 9a
(1.140 g, 3.5 mmol) in MeCN (8 mL) were added PPh3 (2.911 g,
11.1 mmol), Et3N (2.33 mL, 16.7 mmol), and CCl4 (3.22 mL, 33.3
mmol). The reaction mixture was stirred overnight at room
temperature. After completion of the reaction (monitored by TLC),
water (10 mL) was added and the resulting mixture was extracted
with CH2Cl2 (10 mL × 3). The combined organic phase was dried
over Na2SO4. The solvent was removed under reduced pressure,
and the crude product was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate ) 10) to give 10a as a
colorless oil (1.020 g, 3.3 mmol, 94%). 1H NMR (300 MHz,
CDCl3): δ 0.88 (d, J ) 7.0 Hz, 3H), 0.97 (d, J ) 7.0 Hz,
3H), 1.71-1.72 (m, 6H), 1.80-1.93 (m, 1H), 3.93-4.01 (m, 2H),
4.18-4.27 (m, 1H), 7.07-7.12 (m, 1H), 7.27-7.33 (m, 1H),
7.42-7.46 (m, 1H), 7.55-7.58(m, 1H); 13C NMR (75 MHz,
CDCl3): δ 17.9, 19.1, 27.2, 27.7, 32.3, 42.4, 70.3, 72.0, 123.8, 127.3,
127.4, 128.2, 134.6, 143.6, 171.7.
1
1699, 1435, 745, 697; H NMR (300 MHz, CDCl3): δ 0.82 (d, J
) 6.6 Hz, 3H), 0.91 (d, J ) 6.6 Hz, 3H), 1.59-1.71 (m, 1H),
3.69-3.82 (m, 2H), 3.88-4.05 (m, 3H), 6.88-6.92 (m, 1H),
7.14-7.38 (m, 13H); 31P NMR (121 MHz, CDCl3): δ -14.44; 13
C
NMR (75 MHz, CDCl3): δ 17.9, 18.8, 32.2, 33.1 (d, JPC ) 23 Hz),
69.8, 71.8, 127.0, 128.26 (d, JPC ) 6.8 Hz), 128.32 (d, JPC ) 16.6
Hz), 128.9, 129.3 (d, JPC ) 4.6 Hz), 133.63 (d, JPC ) 20.0 Hz),
133.65 (d, JPC ) 19.4 Hz), 133.72, 136.1 (d, JPC ) 13.1 Hz), 136.2
(d, JPC ) 10.3 Hz), 140.0 (d, JPC ) 26.8 Hz), 165.1; MS (EI) m/z
(%): 387 (M+, 2.33), 344 (2.25), 316 (100). Anal. Calcd for
C25H26NOP: C, 77.50; H, 6.76; N, 3.62. Found: C, 77.38; H, 6.80;
N, 3.52.
Preparation of (S)-2-[2-(Diphenylphosphino)benzyl]-4-tert-
butyl-4,5-dihydrooxazole (1b). 1b was prepared as a white solid
(43%, two steps) using the same procedure as that for 1a. Mp:
20
49-51 °C; [R]D -37.2 (c 1.00, CHCl3); IR (KBr, cm-1): 2960,
1666, 1471, 1433, 744, 695; 1H NMR (300 MHz, CDCl3): δ 0.85
(s, 9H), 3.69-3.76 (m, 1H), 3.87-4.02 (m, 4H), 6.87-6.92 (m,
1H), 7.12-7.40 (m, 13H); 31P NMR (121 MHz, CDCl3): δ -14.36;
13C NMR (75 MHz, CDCl3): δ 25.5, 32.8 (d, JPC ) 24 Hz), 33.1,
68.2, 75.2, 126.8, 128.13 (d, JPC ) 6.9 Hz), 128.15 (d, JPC ) 6.8
Hz), 128.2 (d, JPC ) 17.2 Hz), 128.7, 129.0 (d, JPC ) 4.6 Hz),
133.48 (d, JPC ) 19.4 Hz), 133.52, 135.9 (d, JPC ) 13.2 Hz) 136.0
(d, JPC ) 10.3 Hz), 136.1 (d, JPC ) 10.3 Hz), 139.8 (d, JPC ) 26.4
Hz), 165.0 (d, JPC ) 1.2 Hz); MS (EI) m/z (%): 401 (M+, 6.86),
316 (100). Anal. Calcd for C26H28NOP: C, 77.78; H, 7.03; N, 3.49.
Found: C, 77.45; H, 7.05; N, 3.28.
Preparation of (S)-2-[2-(2-Bromophenyl)propan-2-yl]-4-tert-
butyl-4,5-dihydrooxazole (10b). 10b was prepared as an oil (99%)
using the same procedure as that for 10a. IR (KBr, cm-1): 2976,
2955, 2903, 2869, 1664, 1471, 756; 1H NMR (300 MHz, CDCl3):
δ 0.92 (s, 9H), 1.72-1.74 (m, 6H), 3.89-3.95 (m, 1H), 4.01-4.07
(m, 1H), 4.15-4.21 (m, 1H), 7.07-7.13 (m, 1H), 7.28-7.33 (m,
1H), 7.42-7.45 (d, J ) 8.1 Hz, 1H), 7.55-7.58 (d, J ) 8.1 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 26.0, 27.2, 28.0, 34.0, 42.5,
69.1, 75.6, 123.7, 127.3, 127.4, 128.2, 134.6, 143.7, 171.7; MS
(EI) m/z (%): 324 (M+, 0.52), 244 (100); 268 (30.85), 266 (32.06).
Anal. Calcd for C16H22BrNO: C, 59.27; H, 6.84; N, 4.32. Found:
C, 59.30; H, 6.89; N, 4.14.
Preparation of (S)-2-[2-(Diphenylphosphino)benzyl]-4-phe-
nyl-4,5-dihydrooxazole (1c). 1c was prepared as a white solid
(48%, two steps) using the same procedure as that for 1a. Mp:
109-111 °C; [R]D20 -43.0 (c 1.15, CHCl3); IR (KBr, cm-1): 1662,
1432, 989, 752, 745, 698; 1H NMR (300 MHz, CDCl3): δ
3.90-3.98 (m, 1H), 4.05 (dd, J ) 15.5, 24 Hz, 2H), 4.36-4.44
(m, 2H), 6.91-6.96 (m, 1H), 7.16-7.48 (m, 18H); 31P NMR (121
MHz, CDCl3): δ -14.44; 13C NMR (75 MHz, CDCl3): δ 33.2 (d,
JPC ) 22.9 Hz), 69.5, 74.6, 126.6, 127.27, 127.34, 128.36, 128.46,
128.6, 129.2, 129.8 (d, JPC ) 4.6 Hz), 133.6, 133.7, 133.89, 133.95,
136.18, 136.24, 136.30, 136.37, 136.44, 139.9 (d, JPC ) 26.3 Hz),
142.3, 166.8 (observed complexity due to P-C splitting; definitive
assignments have not yet been made); MS (ESI) m/z: 422 (M +
1+). Anal. Calcd for C28H24NOP: C, 79.79; H, 5.74; N, 3.32. Found:
C, 79.62; H, 5.74, N, 3.10.
Preparation of (S)-2-{2-[2-(Diphenylphosphino)phenyl]pro-
pan-2-yl}-4-iso-propyl-4,5-dihydrooxazole (2a). To a solution of
10a (997 mg, 3.2 mmol) in THF (15 mL) at -78 °C was added
n-BuLi (1.6 M in hexane, 2.3 mL, 3.7 mmol) dropwise over 5 min.
The reaction mixture was stirred for 1 h at that temperature, and
then PPh2Cl (0.67 mL, 3.7 mmol) was added dropwise over 5 min
to the solution at -78 °C. The reaction mixture was warmed to
room temperature, stirred overnight, and quenched with a saturated
NH4Cl solution (15 mL). The water phase was extracted with Et2O
(15 mL × 3). The combined organic phases were dried over
Na2SO4. Evaporation of the organic solvents gave a residue, which
was purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate ) 10) to give 2a as a white solid (766 mg, 1.8 mmol,
Preparation of (S)-2-(2-Bromophenyl)-N-(1-hydroxy-3-me-
thylbutan-2-yl)-2-methylpropanamide (9a).23 2-(2-Bromophenyl)-
2-methylpropanoic acid 8 (983 mg, 4.0 mmol) was added to thionyl
chloride (8 mL). The reaction mixture was refluxed for 3 h, and
the excess SOCl2 was removed in vacuo. Dry CH2Cl2 (2 mL) was
then added, and the mixture was concentrated in vacuo to remove
any remaining SOCl2 and this was repeated three times. Dry CH2Cl2
(8 mL) was then added to the acid chloride. Under an argon
atmosphere, L-valinol (500 mg, 4.8 mmol) and Et3N (0.9 mL, 6.4
mmol) were dissolved in dry CH2Cl2 (8 mL) and cooled to 0 °C.
The above acyl chloride solution was added dropwise over a period
of 0.5 h. The reaction mixture was allowed to warm up to room
temperature and stirred overnight. The resulting solution was
washed with water (10 mL) and dried over Na2SO4. The solvent
was removed under reduced pressure, and the crude product was
purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate ) 2) to give 9a as an oil (1.140 g, 3.5 mmol,
87%). 1H NMR (300 MHz, CDCl3): δ 0.79 (d, J ) 6.6 Hz,
3H), 0.87 (d, J ) 6.6 Hz, 3H), 1.62-1.72 (m, 6H), 1.72-1.82 (m,
1H), 2.76-2.80 (m, 1H), 3.58-3.79 (m, 3H), 5.25-5.27 (br d, 1H),
20
57%). Mp: 95-97 °C; [R]D -48.5 (c 0.935, CHCl3); IR (KBr,
cm-1): 3051, 2982, 2953, 2873, 1652, 1478, 747, 737, 695; 1H
NMR (300 MHz, CDCl3): δ 0.76 (d, J ) 7.0 Hz, 3H), 0.84 (d, J
) 7.0 Hz, 3H), 1.73-1.79 (m, 1H), 1.77 (s, 3H), 1.84 (s, 3H),
3.60-3.70 (m, 3H), 7.15-7.40 (m, 13H), 7.51-7.55 (m, 1H); 13
C
NMR (75 MHz, CDCl3): δ 17.4, 19.1, 29.9 (d, JPC ) 5.7 Hz), 30.1
(d, JPC ) 7.4 Hz), 31.8, 42.2 (d, JPC ) 6.9 Hz), 69.4, 71.8, 125.4,
125.5, 126.8, 127.9, 128.0, 128.1, 128.17, 128.24, 129.6, 133.1 (d,
JPC ) 18.9 Hz), 135.6, 135.9, 138.2, 138.3, 138.40, 138.44, 151.4,
(d, JPC ) 26 Hz), 173.0 (observed complexity due to P-C splitting;
definitive assignments have not yet been made); 31P NMR (121
9
9724 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Switch of Enantioselectivity in Asymmetric Heck Reaction
A R T I C L E S
MHz, CDCl3): δ -14.52; MS (ESI) m/z: 416 (M + 1+); Anal.
Calcd for C27H30NOP: C, 78.05; H, 7.28; N, 3.37. Found: C, 77.98;
H, 7.34; N, 3.27.
fully optimized with the density functional theory method of
B3LYP24 without any symmetry constraint. The effective core
potentials (ECPs) of Hay and Wadt with a double-ꢀ basis set
(LanL2DZ) were used for Pd and P,25 and the 6-31G* basis set
was used for H, C, N, and O. The energies were further estimated
using a larger basis set (6-311+G** basis set for H, C, N, and O)
by single-point calculations. Solvent effects was estimated by the
integral equation formulation of the polarized continuum model
(IEFPCM).26 THF was used as solvent with a dielectric constant
value of 7.58 and using UAHF (United Atom Hartree-Fock) radii
for the respective (Pd, H, C, N, O, P) in the IEFPCM calculations.
The nature of the extrema (local minima or transition states) was
checked by analytical frequency calculations. The energies given
throughout the paper are Gibbs free energy values G computed
with Gaussian 03 at 298 K (entropy revise at the reaction
temperature of 60 °C) and P ) 1 atm.
Preparation of (S)-2-{2-[2-(Diphenylphosphino)phenyl]pro-
pan-2-yl}-4-tert-butyl-4,5-dihydrooxazole (2b). 2b was prepared
as a white solid (32%) using the same procedure as that for 2a.
Mp: 124-126 °C; [R]D20 -44.5 (c 0.70, CHCl3); IR (KBr, cm-1):
3054, 2983, 2947, 2899, 2865, 1657, 1478, 1432, 746, 696; 1H
NMR (300 MHz, CDCl3): δ 0.80 (s, 9H), 1.76 (s, 3H), 1.87 (s,
3H), 3.43 (dd, J ) 8.1, 9.9 Hz, 1H), 3.53-3.58 (m, 1H), 3.73-3.78
(m, 1H), 7.13-7.39 (m, 13H), 7.49-7.54 (m, 1H); 13C NMR (75
MHz, CDCl3): δ 25.9, 29.9 (d, JPC ) 4.6 Hz), 30.3 (d, JPC ) 8.6
Hz), 33.8, 42.3 (d, JPC ) 6.9 Hz), 68.4, 75.5, 125.4, 125.5, 126.8,
127.8, 127.97, 128.04, 128.1, 128.2, 129.54, 133.07 (d, JPC ) 18.3
Hz), 133.12 (d, JPC ) 18.9 Hz), 135.7, 136.0, 138.1, 138.3, 138.39,
138.42, 138.6, 151.4 (d, JPC ) 26 Hz), 172.7 (observed complexity
due to P-C splitting; definitive assignments have not yet been made);
31P NMR (121 MHz, CDCl3): δ -14.44; MS (ESI) m/z (%): 430
(M+1+). Anal. Calcd for C28H32NOP: C, 78.29; H, 7.51; N, 3.26.
Found: C, 78.02; H, 7.48; N, 3.09.
General Experimental Procedure of the Asymmetric Heck
Reaction. Pd(dba)2 (8.6 mg, 0.015 mmol), ligand (0.03 mmol), and
solvent (2.5 mL) were placed under an argon atmosphere in a
Schlenk tube with a magnetic stirring bar. After the mixture stirred
for 30 min, phenyl triflate (112 mg, 0.5 mmol) was added, followed
by the addition of 2,3-dihydrofuran (0.15 mL, 2 mmol) and i-Pr2NEt
(0.17 mL, 1 mmol). The mixture was stirred at 60 °C for about
20 h until the reaction was completed monitored by TLC. The
reaction mixture was quenched with additional EtOAc (2 mL), and
the resulting suspension was filtered through a short silica gel
column to removed the palladium black. The solvent was removed
under reduced pressure, and the mixture was purified by flash
chromatography on silica gel to afford a mixture of 13 and 14 as
a colorless oil. The ratio of 13 and 14 was determined by GC. The
ee value of 13 was determined by chiral GC or HPLC.9f
Acknowledgment. This work was supported by National
Natural Science Foundation of China, the Major Basic Research
Development Program (2006CB806106), Chinese Academy of
Sciences, Science and Technology Commission of Shanghai
Municipality, and the Croucher Foundation of Hong Kong. W.Q.W.
and Q.P. gratefully acknowledge the Croucher Foundation of Hong
Kong for a studentship.
Supporting Information Available: Spectral data for 1a-c,
2a, b, 6, 9b, and 10b; X-ray analysis data of [PdCl2(1a)] and
[PdCl2(2a)] (cif file). The coordinates of calculated structures,
the relative free energies (kcal/mol) of calculated complexes
and transition states in the CdC double bond rotating from the
perpendicular conformation in CP2 to coplanar conformation
and optimized energies (hartree) from B3LYP calculations.
Complete refs 6b and 19. This material is available free of
charge via the Internet at http://pubs.acs.org.
Computational Details. All calculations were carried out with
the Gaussion 03 program package.19 Molecular geometries were
JA7104174
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J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9725