A highly efficient kinetic resolution of Morita-Baylis-Hillman adducts achieved by N-Ar axially chiral Pd-complexes catalyzed asymmetric allylation

Article abstract of DOI:10.1039/c1cc15543a

Palladium complexes with an axially chiral N-Ar framework have been developed. These complexes showed high stereoselectivities in asymmetric allylic arylation to achieve the kinetic resolution of Morita-Baylis-Hillman adducts, affording up to 99% ee of (E

Full text of DOI:10.1039/c1cc15543a

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COMMUNICATION
A highly efficient kinetic resolution of Morita–Baylis–Hillman adducts
achieved by N–Ar axially chiral Pd-complexes catalyzed asymmetric
allylationw
Feijun Wang,*a Shengke Li,a Mingliang Qu,a Mei-Xin Zhao,a Lian-Jun Liua and Min Shi*ab
Received 7th September 2011, Accepted 12th October 2011
DOI: 10.1039/c1cc15543a
Palladium complexes with an axially chiral N–Ar framework have
been developed. These complexes showed high stereoselectivities in
asymmetric allylic arylation to achieve the kinetic resolution of
Morita–Baylis–Hillman adducts, affording up to 99% ee of
(E)-allylation products and 92% ee of recovered Morita–Baylis–Hillman
adducts.
It is a challenging task to develop highly active catalysts for
this transformation.10
During our ongoing studies on the development of axially
chiral bis(N-heterocyclic carbene)–metal complexes (metal =
Pd, Ir, Cu, Au, Pt, etc.) with a biaryl framework as well as
their applications in asymmetric catalysis,11 we found that
complex 6a can promote asymmetric 1,4-conjugate addition of
arylboronic acids to cyclic enones, affording the corresponding
addition products in up to 99% yield and 97% ee.11 Considering
the formation of palladium enolate or p-palladium complex in
the 1,4-conjugate addition12 and the feasibility of elimination
of b-OH–Pd to generate a CQC moiety,13 we envisioned that
Morita–Baylis–Hillman (MBH) adducts 3 with an allylic
alcohol motif could be directly used as allylation agents in
AA. More importantly, kinetic resolution (KR)14 of racemic 3
by Pd-catalyzed AA could be also envisioned to furnish
enriched 3 which are valuable chiral reagents in organic
synthesis.15 Herein, we wish to report Pd-complexes (aS,S)-2
with an axially chiral N–Ar framework catalyzed highly
enantioselective allylic arylation to achieve the kinetic resolution
of MBH adducts 3 (Scheme 1).
Design and synthesis of axially chiral ligands have played a
significant role in the development of asymmetric catalysis,
and have attracted a great deal of attention from both
academia and industry.1 Although many successful examples
using axially chiral ligands with a biaryl framework2 have been
disclosed, there are still a considerable amount of reactions in
which these ligands are not efficient. The search for new well-
designed axially chiral ligands is therefore still a remarkably
challenging subject in the field of asymmetric catalysis.
Like the atropisomerism resulting from restricted rotation
around the biaryl axis produced by ortho-substituents,3 certain
properly substituted N-aryl compounds also showed this similar
isomerism.4 Since this atropisomeric framework was firstly
introduced into the design of axially chiral ligands,5 a variety
of axially chiral ligands has been disclosed by several groups.6
However, the development of axially chiral bidentate ligands 1
with sterically bulky groups (R1 and R2) along with coordination
groups (L1 and L2) on the ortho-site of the N–Ar axis has
received less attention.7 The development of ligands 1 will
undoubtedly enrich the design strategy of axially chiral ligands.
On the other hand, compared with the well-established
catalytic asymmetric allylation (AA) using allylic derivatives
such as halides and carboxylates,8 the successful examples with
the direct use of allylic alcohols as the ideal allylation agents
are rare because the hydroxyl group is a poor leaving group.9
Using methyl 1-hydroxy-2-naphthoate as the starting material,
stable axially chiral Pd-complexes, (aS,S)-2, were synthesized in
eight steps and easily isolated by silica gel column chromatography
(see the ESIw). The structure of complex (aS,S)-2a was further
confirmed by single-crystal X-ray diffraction (see the ESIw).
Due to the steric repulsion between the substituents on the
oxazoline ring and Pd salt, the Pd(II)-complex with R-geometry
of the chiral N-naphthyl axis failed to be prepared.16
With complexes (aS,S)-2 in hand, the Pd-catalyzed AA of
arylboronic acids with MBH adducts was examined. Racemic
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 MeiLong Road, Shanghai 200237, P. R. China.
E-mail: feijunwang@ecust.edu.cn
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: Mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of new compounds, and chiral
HPLC analysis of allylation products and recovered MBH adducts.
CCDC 798781 and 822886. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c1cc15543a
Scheme 1 Design of N–Ar axially chiral Pd-complexes and their
applications in asymmetric catalysis.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12813–12815 12813

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Table 1 Screening of chiral Pd-complexesa
5aa
Recovered 3a
Yieldc [%]
E : Zb
eed [%]
Yieldc [%]
eee [%]
f
Entry
Pd complex
Conv.b [%]
krel
1
2
(aS,S)-2a, R = Me
(aS,S)-2b, R = Et
(aS,S)-2c, R =i-Pr
(aS,S)-2a, R = Me
(aS,S)-2a, R = Me
23
21
17
36
39
22
20
17
35
38
90 : 10
91 : 9
90 : 10
90 : 10
90 : 10
98
95
96
98
98
76
77
81
62
58
13
12
8
32
38
2.9
3.0
2.5
4.9
5.9
3
4g
5h
a
b
Reaction conditions: 1.0 mL CH3CN, 0.1 mmol 3a, 0.2 mmol 4a, 3 mol% Pd complex, 3 mol% AgOTf, 0.05 mmol NEt3, RT, 24 h. Determined
by crude 1H NMR spectra. Isolated yields. The enantioselectivity of (E)-5aa was determined by chiral HPLC analysis. Determined by chiral
c
d
e
f
g
HPLC analysis. krel = ln[(1 À C)(1 À ee)]/ln[(1 – C)(1 + ee)]/ln[(1 – C)(1 + ee)], C: Conversion of 3a, ee: % ee of recovered 3a. 10 mol% Pd
h
complex, 10 mol% AgOTf. 15 mol% Pd complex, 15 mol% AgOTf.
MBH adduct 3a derived from the MBH reaction of cyclohexenone
with benzaldehyde was used as a model substrate. The reaction of
3a with phenylboronic acid 4a was carried out in the presence of
complex (aS,S)-2a (3 mol%), AgOTf (3 mol%), and NEt3
(50 mol%), affording the trisubstituted alkene 5aa in 22% yield
along with a 90 : 10 E/Z ratio determined by crude 1H NMR
spectrum, in which the (E)-5aa was formed in 98% ee value
(Table 1, entry 1). Moreover, to our delight, recovered 3a was
obtained in 13% ee with a krel value of 2.9. Complexes (aS,S)-2b
and (aS,S)-2c were also tested in this reaction, giving similar results
along with slightly lower ee-values of (E)-5aa and recovered 3a
(Table 1, entries 2 and 3). Increasing the employed amount of
(aS,S)-2a to 10 mol% and 15 mol%, the ee-values of recovered
alcohol 3a could be significantly improved to 32% ee and 38% ee,
respectively. While using other axially chiral Pd(II)-complexes in
this KR (see ESIw), none of the allylation product 5aa was formed.
In order to investigate the substrate scope of arylboronic acid in
this interesting AA as well as further optimise this KR of MBH
adduct 3a, various arylboronic acids 4b–i were next examined in
the presence of 15 mol% (aS,S)-2a. It was found that the
(E)-allylation products 5ab–ai were obtained in excellent enantio-
selectivities with up to 99% ee (Table 2, entries 1–8). However,
arylboronic acids 4 with different substitution patterns and
electronic properties of substituents showed a significant influence
on the reaction outcome. Arylboronic acids with para-substituted
electron withdrawing groups were good resolution reagents for
this AA of MBH adducts. Using 4f gave recovered 3a in 60% ee
along with krel = 10.5 (Table 2, entry 5).
along with 51% conv. was observed, giving 5hf in 50% yield
with 99% ee of (E)-5hf and recovered 3h in 47% yield with
90% ee (Table 2, entry 15).
Compared to the sterically bulky aromatic moieties in alcohols
3b–g, MBH adducts 3i and 3j derived from the corresponding
aliphatic aldehydes were also tested in this catalytic reaction
(Table 2, entries 16 and 17). To our delight, 450% yields of
allylation products 5ia17 (57% yield and 99% ee for (E)-5i) and 5ja
(61% yield and 99% ee for (E)-5j) were obtained. Moreover, 91%
ee of recovered 3i and 92% ee of recovered 3j were, respectively,
obtained along with krel values of 14.9 and 11.1. The absolute
configurations of allylation products 5 and MBH adducts 3 were
determined by comparing the sign of optical rotation with that of
(R)-5hf which is determined by X-ray diffraction (see the ESIw)
and those of literature values,18 respectively.
With up to 61% yields of enantiomerically pure allylation products
5 (up to 99% ee for (E)-5), this KR was not a standard KR which is
limited to a maximum yield of 50% of the enriched product, and also
was not a dynamic kinetic resolution as a-substituted allylation
products were not found in all cases from the analysis of their crude
1H NMR spectra. The KR method might proceed with the genera-
tion of new stereogenic centers with the same (R)-geometry under the
control of chiral catalyst (aS,S)-2 via a Pd-catalyzed 1,4-addition19
and the subsequent elimination of the original chiral center via a
Pd–OH elimination mechanism (see the ESIw).20
In summary, we have developed a novel type of palladium
complexes (aS,S)-2 with an axially chiral N–Ar framework. These
Pd complexes are quite effective catalysts in the kinetic resolution
of MBH adducts 3 by Pd-catalyzed asymmetric allylic alkylation
between arylboronic acids and racemic MBH adducts 3 under
mild reactions, affording allylation products 5 in 8–61% yields
with 93–99% ee and the recovered 3 in 37–90% yields with
5–92% ee. Further studies focusing on the development of axially
chiral metal catalysts with an N–Ar framework as well as their
applications in asymmetric catalysis are undergoing.
Subsequently, KR of various MBH adducts 4b–g was also
investigated under the standard conditions. All reactions proceeded
smoothly to deliver the corresponding (E)-allylation products
5ba–ga in 98–99% ee (Table 2, entries 9–14). Similarly,
different substitution patterns and the electronic property of
substituents on aromatic rings of 3b–g also played a key role in
this reaction. Substrate 3b with a cyano group at the 4-position
of the phenyl ring was an excellent substrate (krel = 17.6),
giving product 5ba in 45% yield and recovered 3b in 52% yield
with 70% ee (Table 2, entry 9). Combining the influence of
arylboronic acid and MBH adducts on the reaction outcome
of this catalytic reaction, the reaction of 3h with 4f was also
carried out. It is noteworthy that up to 42.2 of the krel value
Financial support from the National Natural Science Foundation
of China (21072206, 20902019, 20472096, 20872162,
20672127, 20821002 and 20732008), the National Basic
Research Program of China (973)-2010CB833302, and the
Fundamental Research Funds for the Central Universities
(WJ1014034 and WK1013004) is gratefully acknowledged.
c
12814 Chem. Commun., 2011, 47, 12813–12815
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Table 2 Substrate suitability for the Pd-catalyzed asymmetric allylic arylationa
Alkylation product
Recovered alcohol
Yieldc [%]
E/Zb
eed [%]
3
Yieldc [%]
eee [%]
f
Entry
R
Ar
Conv.b [%]
krel
5
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-CNPh
p-CH3Ph
p-MeOPh
m-ClPh
o-ClPh
2,4-diClPh
p-NO2Ph
CH3
o-CH3Ph
m-CH3Ph
p-CH3Ph
m-ClPh
p-ClPh
o-CH3Oph
2-Naph
p-C6H5Ph
Ph
Ph
Ph
Ph
Ph
8
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
5ba
5ca
5da
5ea
5fa
5ga
5hf
5ia
8
98 : 2
94 : 6
96 : 4
90 : 10
90 : 10
94 : 6
90 : 10
93 : 7
93 : 7
90 : 10
99 : 1
94 : 6
99 : 1
95 : 5
98 : 2
99 : 1
94 : 6
93
95
95
97
98
94
98
99
99
99
98
99
98
99
99
99
99
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
90
76
63
63
51
74
61
50
52
63
70
55
62
56
47
41
37
5
22
38
26
60
15
38
61
70
36
32
48
30
34
90
91
92
3.9
6.9
7.4
3.5
10.5
4.3
7.4
9.9
17.6
7.1
11.2
6.6
5.0
3.8
24
36
36
46
23
36
46
47
35
29
44
34
42
51
58
62
23
36
35
45
22
34
45
45
34
28
44
33
40
50
57
61
9
10
11
12
13
14
15
16
17
Ph
3g
3h
3i
p-ClPh
Ph
Ph
42.2
14.9
11.1
Cyclohexyl
5ja
3j
18
Ph
22
5ka
21
94 : 6
62
3k
76
13
3.1
a
b
Reaction conditions: 1.0 mL CH3CN, 0.1 mmol 3, 0.2 mmol 4, 15 mol% (aS,S)-2a, 15 mol% AgOTf, 0.05 mmol NEt3. Determined by crude
1H NMR spectra. Isolated yields. The enantioselectivity of (E)-5 was determined by chiral HPLC analysis. Determined by chiral HPLC
c
d
e
f
analysis. krel = ln[(1 – C)(1 À ee)]/ln[(1 – C)(1 + ee)], C: Conversion of 3, ee: % ee of recovered 3.
M. L. Crawley, Chem. Rev., 2003, 103, 2921; (e) Z. Lu and S. Ma,
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12813–12815 12815