Palladium/sulfoxide-phosphine-catalyzed highly enantioselective allylic etherification and amination

Article abstract of DOI:10.1039/c4cc03920c

The Pd/sulfoxide-phosphine-catalyzed highly enantioselective allylic etherification and amination with a wide range of O- and N-nucleophiles have been developed (up to 97% yield, 98.5% ee). The products can also be conveniently transformed into biologically active chiral heterocycles. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03920c

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Palladium/sulfoxide–phosphine-catalyzed highly
enantioselective allylic etherification and amination†
Cite this: Chem. Commun., 2014,
50, 9550
Bin Feng,‡ab Hong-Gang Cheng,‡ab Jia-Rong Chen,*ab Qiao-Hui Deng,ab
Liang-Qiu Luab and Wen-Jing Xiao*ab
Received 22nd May 2014,
Accepted 4th July 2014
DOI: 10.1039/c4cc03920c
www.rsc.org/chemcomm
The Pd/sulfoxide–phosphine-catalyzed highly enantioselective allylic
etherification and amination with a wide range of O- and N-nucleo-
philes have been developed (up to 97% yield, 98.5% ee). The products
can also be conveniently transformed into biologically active chiral
heterocycles.
Transition-metal catalyzed asymmetric allylic substitution reaction
with C-, N-, O-, S- and P-nucleophiles represents one of the most
powerful and versatile approaches to the formation of C–C and
C–heteroatom bonds, and has attracted a great of attention from
the chemical community.1 Over the past decades, however,
Scheme 1 Asymmetric allylic substitution and sulfoxide–phosphine ligands.
this field has been mainly dominated by enantioselective allylic combination of two privileged backbones into one molecule.10,11 And,
alkylation. Recently, the catalytic asymmetric allylic etherification we have recently documented a new family of chiral sulfoxide–
with a diverse set of O-nucleophiles has become the focus of many phosphine ligands (Scheme 1), which demonstrated excellent
research groups because of the biological and synthetic significance activities and enantioselectivities in Pd-catalyzed asymmetric allylic
of the resulting chiral allylic ethers and related derivatives.2 In this alkylation reaction.11b Notably, the scaffold can be easily prepared
field, many powerful Pd-, Ir-, and Ru-based catalytic systems have from chiral sulfoxide-amino and aryl phosphine units, and such
been elegantly developed for enantioselective allylic etherification modular features offer great potential for finely tuning the steric
reaction by the use of phenols/alcohols,3 aryloxides/alkoxides,4 and electronic properties of these ligands for each particular
carboxylic acids/carboxylates,5 bicarbonate,6 oximes,7 silanolates,8 chemical reaction. To fully explore the potential of these ligands,
and water9 as O-nucleophiles. These studies have also resulted in we recently extended the scope of nucleophiles to aliphatic alcohols
the identification of several privileged dienes, P–P, P–N, and P–S and amines in Pd-catalyzed asymmetric allylic substitution reaction
ligands, which exhibited a broad substrate scope and high functional (Scheme 1). Herein, we wish to report our efforts in this subject,
group tolerance. Despite these impressive advances, it is still highly and the application of the methodology to the practical synthesis
desirable to develop more efficient catalytic systems for enantio- of biologically important enantioenriched oxygen and nitrogen
selective allylic etherification by directly utilizing relatively hard heterocycles.
aliphatic alcohols as nucleophiles.
Based on our previous studies,11b we initially screened a
We have been investigating the design and applications of representative set of chiral sulfoxide–phosphine ligands 1 in the
sulfoxide-containing chiral ligands based on the strategy of rational model reaction between racemic (E)-1,3-diphenylallyl acetate 2a and
benzyl alcohol 3a using K2CO3 and Cs2CO3 as bases in CH2Cl2 at
40 1C (Table 1).12 To our delight, all the sulfoxide–phosphine ligands
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
proved to be suitable for the reaction, giving the desired product 4aa
in generally good yields with excellent enantioselectivities (64–99%
yields, 93.7–97.7% ee) (Table 1, entries 1–7). Among them, ligand 1a
provided superior results over others and was chosen for further
optimization study. A simple examination of commonly used solvents
with ligand 1a confirmed toluene to be the best of choice in terms of
efficiency and enantioselectivity (Table 1, entries 8–11).13
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China. E-mail: chenjiarong@mail.ccnu.edu.cn,
wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041; Tel: +86 27 67862041
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03920c
‡ These authors contributed equally to this work.
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Table 1 Condition optimizationa
Table 2 Substrate scope of asymmetric allylic etherificationa
Entry
Ligand
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1a
1a
1a
1a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
24
24
24
24
24
24
24
24
4
99
97
99
84
99
99
64
87
99
85
74
97.7
95.3
93.7
94.3
96.7
96.3
96.5
97.7
98.2
97.7
97.1
Entry
2
3
Product
Yieldb (%)
eec (%)
9
10
11
Toluene
THF
CH3CN
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
90
82
84
87
97
85
87
83
82
87
81
74
89
87
84
80
82
81
80
64
98.2
98.1
97.2
96.3
93.8
95.9
96.9
96.1
96.1
96.9
95.5
95.5
95.1
97.5
95.3
94.4
93.3
96.9
96.8
52.0
24
24
a
Unless otherwise noted, reactions were carried out with 2a (0.2 mmol), 3a
(0.6 mmol), [Pd(C3H5)Cl]2 (3.0 mol%), ligand 1 (6.0 mol%), K2CO3
(0.3 mmol) and Cs2CO3 (0.3 mmol) in solvent (2.0 mL) at 40 1C. b Deter-
c
mined by GC using biphenyl as internal standard. Determined by chiral
HPLC, the absolute configuration was established as R by comparison with
literature data.
9
10
11
12
13
14
15
16d
17
18
19
20
3j
3k
3l
4aj
4ak
4al
3m
3n
3o
3p
3q
3a
3a
3a
4am
4an
4ao
4ap
4aq
4ba
4ca
4da
With the optimized reaction conditions in hand, we then
explored the substrate scope of the Pd-catalyzed asymmetric allylic
etherification (Table 2). In contrast to Chan’s catalytic system,4c it was
found that the electronic and steric natures of aromatic rings of
benzylic alcohols have no obvious effect on the results. For example, a
wide variety of benzylic alcohols 3a–3h bearing electron-donating
(MeO, Me) or electron-withdrawing (Br, Cl) groups at ortho-, meta-, or
para-positions were well tolerated, and afforded the corresponding
products 4aa–4ah in consistently good yields with excellent enantio-
selectivities (Table 2, entries 1–8, 82–97% yields, 93.8–98.2% ee). In
addition to benzylic alcohols, the potentially problematic hetero-
cycle-substituted alcohols also proved to be suitable as O-nucleo-
a
Unless otherwise noted, reactions were carried out with 2 (0.2 mmol), 3
(0.6 mmol), [Pd(C3H5)Cl]2 (3 mol%), ligand 1a (6 mol%), K2CO3 (0.3 mmol)
and Cs2CO3 (0.3 mmol) in toluene (2.0 mL) at 40 1C for 5 h. b Isolated yield.
c
Determined by chiral HPLC, the absolute configuration was established as
R by comparison with literature data. d 3q (0.24 mmol).
philes. For instance, 2-pyridinyl, 2-thiophenyl and 2-furanyl (ligands, bases, and reaction media) resulted in the optimal system:
methanols reacted well to give the corresponding allylic ethers 3 mol% of [Pd(C3H5)Cl]2 and 6 mol% of ligand 1a in the presence of
4ai–4ak in a range of 81–87% yields with excellent enantio- Cs2CO3 (3.0 equiv.) as base in CH2Cl2 at 40 1C.12,13 And allylic amine 6a
selectivities (Table 2, entries 9–11, 95.5–96.9% ee). Moreover, was obtained in 83% yield with 97.1% ee (Table 3, entry 1). In addition
simple aliphatic alcohols, such as cinnamyl alcohol, allyl alcohol, to neutral benzyl amine, MeO- and CF3-substituted benzyl amines 5b
methanol and ethanol, also participated in the reaction smoothly to and 5c also reacted smoothly with 2a, affording the corresponding
give products 4al–4ao in a highly enantioselective manner (Table 2, products 6b and 6c in high yields (83–97%) with excellent enantio-
entries 12–15). Importantly, the catalytic system could also be selectivities (97.0–98.5% ee) (Table 3, entries 2 and 3). Notably, both
successfully applied to secondary alcohol 3p and oxime7 3q to phenyl amine 5d and p-toluenesulfonamide 5e proved to be suitable for
provide good yields of the corresponding products 4ap and 4aq the reaction and excellent results were also obtained. It is noteworthy
with 80% yield and 94.4% ee, 82% yield and 93.3% ee, respectively that products 6f and 6g, formed by the reaction between allylic amines
(Table 2, entries 16 and 17). As for racemic (E)-1,3-diphenylallyl (5f and 5g) and 2a with high enantiopurity, would allow for further
acetate components, both Br and Cl could be incorporated into the elaborations for the synthesis of biologically interesting heterocycles
aromatic ring without any deleterious effect on the yields or (Table 3, entries 6 and 7). The reaction was also successfully
enantioselectivities (Table 2, entries 18 and 19, 80–81% yields, extended to secondary amines, such as phthalimide (5h),
96.8–96.9% ee). The reaction with (E)-4-phenylbut-3-en-2-yl acetate morpholine (5i), and tetrahydroisoquinoline (5j), with satisfactory
2d also proceeded smoothly to give the corresponding product 4da results (Table 3, entries 8–10).
in 64% yield, albeit with 52% ee (Table 2, entry 20).
To demonstrate the synthetic potential of the method, we
Encouraged by the excellent results achieved in the asymmetric applied the products to the convenient synthesis of biologically
allylic etherification, we next turned our attention to the enantioselective important oxygen and nitrogen heterocycles.14 For example,
allylic amination by the use of a Pd/sulfoxide–phosphine catalytic product 4am underwent a ring-closing metathesis smoothly to
system. As for the model reaction of racemic (E)-1,3-diphenylallyl acetate give the corresponding chiral dihydrofuran 7 in good yield with
2a with benzyl amine 5a, a brief investigation of reaction parameters no loss of enantiopurity (eqn (1)). After protection of product 6f with
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Table 3 Substrate scope of asymmetric allylic aminationa
Scheme 2 Proposed transition state.
In summary, we have developed Pd/sulfoxide–phosphine-catalyzed
highly enantioselective allylic etherification and amination with
a wide range of O- and N-nucleophiles. Successful transformations
of the allylic substitution products into the corresponding chiral
dihydrofuran and dihydropyrrole derivatives also highlighted the
synthetic potential of these sulfoxide–phosphine ligands. Further
applications of these ligands to other transition-metal catalyzed
asymmetric reactions for the construction of carbon–heteroatom
bonds are currently in progress in our laboratory.
Entry
5
Product
Yieldb (%)
eec (%)
1
2
3
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
83
97
83
90
87
72
81
80
80
84
97.1
98.5
97.0
97.3
93.9
98.3
89.9
98.3
95.3
85.1
4
5d
6
7e
8
9
10 f
5j
6j
We are grateful to the National Science Foundation of China
(No. 21272087, 21202053, and 21232003) and the National
Basic Research Program of China (2011CB808603) for support
of this research.
a
Unless otherwise noted, reactions were carried out with 2a (0.2 mmol),
5 (0.6 mmol), [Pd(C3H5)Cl]2 (3 mol%), 1a (6 mol%), Cs2CO3 (0.6 mmol)
b
c
in CH2Cl2 (2.0 mL) at 40 1C for 4 h. Isolated yield. Determined by
chiral HPLC, the absolute configuration was established as R by
comparison with literature data. Reaction was conducted at room
d
e
f
temperature, 12 h. Na2CO3 (0.6 mmol) instead of Cs2CO3, 24 h. 10 h.
Notes and references
an easily removable Boc group, a further Grubbs II catalyst-promoted
ring-closing metathesis afforded dihydropyrrole derivative 8 in 72%
overall yield with 98.3% ee (eqn (2)). Moreover, a direct ring-closing
metathesis reaction of 6g also furnished a good yield of dihydro-
pyrrole 9 with 89.7% ee (eqn (3)).
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