Synthesis of new chiral benzylically substituted P,N-ligands and their applications in the asymmetric Heck reaction

Article abstract of DOI:10.1016/j.tetasy.2004.05.030

A series of new chiral P,N-ligands with substituents at the benzylic position has been prepared. Their high catalytic activity is shown in the Pd-catalyzed asymmetric Heck reaction and allylic substitution reaction.

Full text of DOI:10.1016/j.tetasy.2004.05.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2189–2191
Synthesis of new chiral benzylically substituted P,N-ligands and
their applications in the asymmetric Heck reaction
Xue-Long Hou,* Da Xuan Dong and Ke Yuan
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 30 April 2004; accepted 18May 2004
Available online 10 July 2004
Abstract—A series of new chiral P,N-ligands with substituents at the benzylic position has been prepared. Their high catalytic
activity is shown in the Pd-catalyzed asymmetric Heck reaction and allylic substitution reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
Chiral ligands play a crucial role in asymmetric catalysis
with a variety of ligands with different structural fea-
tures being synthesized and used in asymmetric cataly-
sis.1 Among them, the ligands with a type I structure,
which have both substituents at benzene ring-positions,
are common; one of the representatives is PHOX, which
allows effective asymmetric induction in a variety of
metal-catalyzed reactions (Scheme 1).2;3 However, only
a few reports on the synthesis and application of ligands
with type II, which have one of the substituent at the
benzylic position, have appeared although the structure
of type II ligands seems simple.4 During the course of
design, synthesis and application of chiral ligands in
asymmetric catalysis,5 we found that ligands 2 and 3,
which have a substituent at the benzylic position, show
higher catalytic activity.6 Based upon these findings,
other ligands with a substituent at the benzylic position
have been synthesized and used in asymmetric catalysis
to confirm if this phenomenon is general. Herein we
report the synthesis of P,N-ligands having the sub-
stituent at the benzylic position and their higher cata-
lytic activity in asymmetric Heck reaction.
The synthetic route to ligand 8 with an oxazoline ring as
the substituent at the benzylic position is depicted in
Scheme 2. Lithiation of o-bromotoluene 4 with BuLi
followed by quenching with PPh2Cl afforded phosphine
5. Acid 6 was prepared by direct benzylic-lithiation of
phosphine 5 and then quenching with CO2. Esterifica-
tion of acid 6 followed by treatment with amino alcohol
salts derived from the reaction with BuLi and ring-clo-
sure gave rise to ligands 8a–c.
X
X
Y
Y
Type I
Type II
With the ligands in hand, the Pd-catalyzed asymmetric
Heck reaction was used to test their efficiency.7 The
reaction of 2,3-dihydrofuran and PhOTf proceeded at
60 °C in THF using 1.5 mol % of [Pd2(dba3)dba] and
6 mol % ligand with the results summarized in Table 1. It
can be seen that all the reactions were complete in 20 h
to give the products in high regioselectivity; 4–5 days are
usually needed for completion when using PHOX as
ligands. The highest enantioselectivity (94% ee) with the
ratio of 70:1 for 9 and 10 was obtained using ligand (S)-
8b (entry 2), which was close to that using PHOX as the
ligand (97% ee).8 The ligands also proved suitable when
ArOTf was used as the reagent (entries 4 and 5).
O
O
R
R
O
N
N
SPh
N
PPh2
SPh
H
1
2
3
Scheme 1.
* Corresponding author. E-mail: xlhou@mail.sioc.ac.cn
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.030

2190
X.-L. Hou et al. / Tetrahedron: Asymmetry 15 (2004) 2189–2191
1. n-BuLi, TMEDA
1. nBuLi, -78 oC
0 oC,
COOH
PPh2
2. CO2, -78 oC
35%
Br
PPh2
2. ClPPh2
70%
5
6
4
1. n-BuLi, THF
0 oC
DCC, DMAP
MeOH
O
COOMe
PPh2
N
PPh2
2.
H2N
93%
OH
R
R
(S)-8
a: R = i-Pr;
b: R = t-Bu;
c: R = Ph;
7
3. MsCl, Et3N, CH2Cl2
Scheme 2.
Pd(dba)2 (3 mol%)
L* (6 mol%)
ArOTf
+
+
O
THF, 60 oC, (i-Pr)2NEt
O
O
10
ArOTf:
11
12
9
ð1Þ
OTf
OTf
OTf
MeO
a
b
c
Table 1. Pd-catalyzed asymmetric Heck reaction using ligand 8
Entry
Ligand
ArOTf
Time (h)
Yield %a
Ee% of 11b;c
Ratio of 11 and 12d
1
2
3
4
5
(S)-8a
(S)-8b
(S)-8c
(S)-8b
(S)-8b
10a
10a
10a
10b
10c
20
20
20
20
20
75
82
65
85
66
77.1 (R)
93.6 (R)
57.6 (R)
89.5e
15:1
70:1
65:1
59.2
a Isolated yield.
b Determined by chiral GC.5l
c The absolute configuration of the product was determined through comparison of the sign of specific rotations with literature data.8a
d Determined by GC.5l
e Determined by chiral HPLC.5l
Table 2. The influence of the amount of catalyst on the reaction of Eq. 1 using ligand (S)-8b
Entry
Pd(dba)2 (mol%)a
Time (h)
Yield %b
Ee% of 11c
Ratio of 11 and 12d
1
2
3
3
20
20
40
82
83
54
93.6 (R)
93.3 (R)
92.6 (R)
70:1
80:1
25:1
1.5
0.5
a Pd(dba)2:ligand ¼ 1:2.
b Isolated yield.
c Determined by chiral GC.5l
d Determined by GC.5l
When the amount of Pd(dba)2 was varied from 3 to
1.5 mol %, there was little change in ee values and yield
(Table 2, entry 1 vs entry 2). Even when the amount of
Pd(dba)2 was decreased to 0.5 mol %, high ee was still
obtained (Table 2, entry 3), although the yield was
slightly lower (54%) with 40 h needed for completion
(Table 2, entry 3). This result provides an example of
using less than 1 mol % catalyst in the asymmetric Heck
reaction. The high catalytic efficiency of the ligand was
also shown in the Pd-catalyzed allylic substitution
reaction (Eq. 2).9 Reaction product 14 was provided in
96.6% ee and 86% yield when the reaction proceeded in
2 h and 2.5 mol % of [Pd(C3H5)Cl]2 and 6 mol % of
ligand 8b were used as catalyst, while 94.4% ee and 88%
yield were also obtained for 14 when the amount of
[Pd(C3H5)Cl]2 and 8b was decreased to 0.25 and

X.-L. Hou et al. / Tetrahedron: Asymmetry 15 (2004) 2189–2191
2191
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Ph
Ph
*
Ph
Ph
CH2(COOMe)2, BAS
CH2Cl2, rt, 4 h
13
14
88% yield
94.4% ee
ð2Þ
In summary, several novel P,N-ligands with the sub-
stituent at the benzylic position have been prepared with
the high catalytic efficiency of them being shown in the
Pd-catalyzed asymmetric Heck reaction and allylic
substitution reaction. Further studies regarding their
applications in asymmetric catalysis and the reason why
the ligands give such high catalytic efficiency are in
progress.
Acknowledgements
Financial support from the National Natural Science
Foundation of China, the Major Basic Research
Development Program (Grant No G2000077506),
National Outstanding Youth Fund, Chinese Academy
of Sciences and Shanghai Committee of Science and
Technology.
References and notes
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