Rh(I)/Bisoxazolinephosphine-Catalyzed Regio- And Enantioselective Allylic Substitutions

Article abstract of DOI:10.1021/acscatal.0c00712

Rhodium(I)/bisoxazolinephosphine combination has been developed as a general catalyst to achieve the dynamic kinetic asymmetric allylation of a variety of nitrogen, carbon, oxygen, and sulfur pronucleophiles from branched racemic allylic carbonates. Exclusive branch-selectivity and up to 99% enantiomeric excess could be obtained under neutral conditions. Linear allylic substrates (both Z and E) could be converted to the same chiral branched products with excellent regio- and enantioselectivities as well. Chiral π-allyl-Rh(III)/NPN intermediate was isolated and characterized to understand the origin of the high selectivities.

Full text of DOI:10.1021/acscatal.0c00712

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Letter
Rh(I)/Bisoxazolinephosphine-Catalyzed Regio-
and Enantioselective Allylic Substitutions
Wen-Bin Xu, SAMIR GHORAI, Wenyu Huang, and Changkun Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00712 • Publication Date (Web): 23 Mar 2020
Downloaded from pubs.acs.org on March 24, 2020
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ACS Catalysis
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Rh(I)/Bisoxazolinephosphine-Catalyzed Regio- and Enantioselective
Allylic Substitutions
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Wen-Bin Xu, Samir Ghorai, Wenyu Huang, Changkun Li*
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering,
Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, China
coordination atom. Herein, we report that bisoxazolinephosphines
were identified as powerful ligands to control the expected
ABSTRACT: Rhodium(I)/bisoxazolinephosphine combination
has been developed as a general catalyst to achieve the dynamic
selectivities. Rh(I)/bisoxazolinephosphine is able to catalyze the
kinetic asymmetric allylation of a variety of nitrogen, carbon,
exclusively branch-selective asymmetric allylation with different
oxygen and sulfur pronucleophiles from branched racemic allylic
nitrogen, carbon, oxygen and sulfur pronucleophiles in excellent
carbonates. Exclusively branch-selectivity and up to 99%
enantioselectivities. Importantly, either racemic branched or linear
enantiomeric excess could be obtained under neutral conditions.
(both Z and E) allylic substrates could be used as substrates
Linear allylic substrates (both Z and E) could be converted to the
(Scheme 1, c). An Rh/allyl/bisoxazolinephosphine complex was
same chiral branched products with excellent regio- and
enantioselectivities as well. Chiral -allyl-Rh(III)/NPN
intermediate was isolated and characterized to understand the
isolated and characterized by X-ray diffraction analysis, which
could be used to interpret the high regio- and enantioselectivities.
origin of the high selectivities.
Scheme
1.
Rh-Catalyzed
Asymmetric
Allylic
Substitutions
Keywords: Rhodium, allylic substitution, bisoxazolinephosphine,
asymmetric catalysis, -allyl-rhodium complex
a)
Stereospecific allylic substitution, achiral ligand
Lg
LnRhIII
R
Nu
P(OR)
Rh/
3
Transition-metal-catalyzed asymmetric allylic substitution has
become a powerful method to construct chiral building blocks with
olefin functions.1 Compared to frequently used Pd, Ir and Cu, Rh-
catalyzed asymmetric allylic substitution is underexplored,
although challenging aliphatic group substituted allylic compounds
could be prepared by Rh.2 The pioneering reports from Evans
demonstrate that chiral branched allylic substrates could be
converted to chiral products in a stereospecific manner with
Rh/P(OR)3 catalysts, in which a (+-allyl-Rh intermediate was
proposed (Scheme 1, a).3 The dynamic kinetic asymmetric
allylation from racemic allylic precursors is more attractive for the
easily accessible substrates and higher reactivities (Scheme 1, b).
Hayashi’s report on Rh/Phox-catalyzed selective carbon-carbon
bond construction from malonates and racemic allylic esters
indicates that this challenging process could be realized when
suitable ligands and reaction conditions were selected.4 The groups
of Vrieze,5 Nguyen,6 Breit,7 Guo8 and You9 developed the
asymmetric allylation of several nucleophiles with chiral
diphosphine, diene, or (P, olefin) ligands respectively. Nevertheless,
the scope of allylic substrates and nucleophiles is still very limited.
Moreover, extensive ligand screening is usually necessary when a
new reaction is explored. A ligand which could be used in a general
Rh-catalyzed highly enantioselective allylation for different
nucleophiles is highly desired.
Nu-
R
R
 Rh-enyl complex proposed
chiral substrates
b)
Dynamic kinetic asymmetric allylic alkylaltion, chiral ligand
L*
=
Phox
diphosphine
diene
Lg
Nu
L*
Rh/
Nu-
R
R
(P, olefin)
racemic substrates
lack of general ligands; ligand screening for each reaction
Problem:
c
)
This work
: Rh(I)/Bisoxazolinephosphines as general catalysts
R
OCO2Me
OCO2Me
Nu
NPN*
Rh(I)/
or
R
or
R
NuH
R
OCO2Me
branched
racemic
R = Ar or alkyl
Nu = N, C, O and S
linear (Z or E)
General for N, C, O and S nucleophiles
Exclusively branched, up to 99% ee
High temperature tolerance
High reactivities for branched
and linear substrates
Neutral reaction conditions
OTf-
R'
O
P
P
iPr
N
O
N
O
N
N
O
iPr
Rh
Me
NPN*
Bisoxazolinephosphine
R'' R''
Cl
NPN-
[
Rh(MeC3H4)Cl]OTf
To develop a dynamic kinetic asymmetric allylation, a rapid --
 isomerization before the new bond formation is mandatory.
Inspired by our recently report on cobalt-catalyzed regio- and
enantioselective allylic amination with bisoxazolinephosphine
ligands,10 we assume that the applying of tridentate ligand may help
generate the -allyl-Rh intermediate and accelerate the
interconversion of the chiral intermediates because of the third
isolation of Rh/allyl intermediate
We began our study by using racemic allylic carbonate 1a and
aniline 2a in a 1 : 1 ratio as model substrates (Table 1). When the
reaction was conducted with Rh(cod)2BF4 and L1 in acetonitrile at
60 oC, excellent yield, exclusively branched regioselectivity and 99%
ee were achieved (entry 1). Comparable yield and selectivity were
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obtained with electron-richer and bulkier L2 (entry 2). L3 with the
worthwhile to mention that more challenging allylic carbonate with
t-butyl group could also be used in this reaction to prepare 3l.
Phenyl-substituted racemic allyl carbonate reacts to provide the
branched 3m selectively when L2 was used.
1
2
3
4
5
6
7
8
flexible linkers is also a suitable ligand with rhodium (90% yield,
entry 3). However, only 10% ee was observed, which implies the
rigid phenyl skeleton is crucial for the enantioselective process.
Reactions with Phox L4 and Pybox L5 were not efficient (entries
4 and 5). The counter anion effect was also examined. Similar result
was obtained when [Rh(cod)Cl]2 was used (entry 6), while
relatively lower conversion and ee were observed with
Rh(cod)2OTf (entry 7). The reaction could also be conducted at
room temperature and 50% of 3a was isolated (entry 8). Finally,
the reactivity of [Ir(cod)Cl]2 and Ir(cod)2BF4 were checked under
otherwise the identical condition.11 However, much lower
conversion and enantioselectivities were obtained (entries 9 and
10), which demonstrates the different reactivities of the metals.
Acetonitrile is the best among solvents examined probably due to
the coordination effect. Reactions from allylic acetate or phosphate
lead to lower ees, probably due to the  or  complexation mode
change caused by bidentate leaving groups (see SI).
Table 2. Reaction Scope of Anilinesa
2.5 mol% Rh(cod)2BF4
R2
R1
Ar
OCO2Me
H
N
L1
2.5 mol%
+
N
R2
R1
Ar
CH3CN, 60 oC, 12 h
R2 = H or Me
2b-2g
1a-1g
3b-3m
racemic
HN
9
10
11
12
13
14
15
16
17
18
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22
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60
CN
OMe
Me
HN
Me
HN
n-C3H7
HN
n-C3H7
O
n-C3H7
n-C3H7
3b
3c
3d
3e
, 93% yield
, 89% yield
, 94% yield
, 90% yield
96% ee
98% ee
99% ee
96% ee
MeO2C
HN
OMe
OMe
Table 1. Optimization of Rhodium-Catalyzed Asymmetric
Allylic Substitutionsa
Me
N
HN
Me
HN
iPr
3i
n-C3H7
2.5 mol% Rh(I)
n-C3H7
OCO2Me
NHPh
L
2.5 mol%
+
PhNH2
n-C3H7
3f
3g
3h
, 79% yield
99% ee
, 93% yield
98% ee
, 94% yield
, 99% yield
99% ee
n-C3H7
CH3CN, 60 oC, 12 h
3a
2a
1a
rac-
98% ee
OMe
OMe
R1
OMe
OMe
Ph
P
PPh2
P
O
N
O
HN
N
HN
HN
HN
O
N
N
O
N
N
O
O
N
O
N
tBu
3l
Ph
3m
Cy
3k
iPr
iPr
iPr
iPr
iPr
iPr
iPr
b
b
b
3j
, 83% yield
, 99% yield
, 99%yield
, 92% yield
99% ee
, R1 = Ph
, R1 = 4-OMe-3,5-tBu2C6H2
L3
L4
, Phox
L5
, Pybox
92% ee
97% ee
99% ee
L1
L2
aConditions: 1a (0.4 mmol, 1.0 equiv), 2a (0.4 mmol, 1.0 equiv), Rh(I)
(0.01 mmol, 0.025 equiv), L1 (0.01 mmol, 0.025 equiv), CH3CN (2
mL). b[Rh(cod)Cl]2(0.0125 equiv) and L2 (0.025 equiv) were used.
entry
1
metal salts
ligand
L1
yield (%)b
ee of 3a (%)c
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
[Rh(cod)Cl]2
Rh(cod)2OTf
Rh(cod)2BF4
[Ir(cod)Cl]2
Ir(cod)2BF4
99
99
90
< 5
27
92
83
50
39
16
99
99
10
-
Having established the efficient asymmetric allylation of anilines,
we turned our attention to other nucleophiles (Table 3). Benzyl
amine 4a react smoothly to afford 5a in high yield under the
identical condition as anilines. Heterocycles could be tolerated to
deliver secondary amines 5b to 5e in high selectivities. Carbon-
carbon double and triple bonds were introduced in 5f and 5g, which
allows further ring constructions. High diastereomeric ratios in 5h
and 5i were obtained when chiral amines were used. Although
sterically more hindered, morpholine and dibenzyl amine were
successfully utilized to prepare tertiary amines 5j and 5k.
Benzophenone imine could also be used as a nucleophile and
primary amine with 99% ee was prepared after subsequent
hydrolysis. To demonstrate the practicality of this transformation,
a reaction at 10 mmol scale was conducted with 1.0 mol% catalyst.
83% of 5l with 98% ee could be obtained after 48 hours.
Tosylamide, benzimidazole, phthalimide and N-Boc-benzamide
could also react to give the allylation products in high yields and
ees under the same condition (5m to 5p). The absolute
configuration of these compounds were assigned to be R by
comparing with literature (see SI). Different from the basic
aromatic and aliphatic amines, these acidic nitrogen containing
molecules are more likely to react as good nucleophiles after
deprotonation by the released carbonate or methoxide anion.
Finally, not only aliphatic allylic carbonates, phenyl substituted
allylic carbonate could also be used to produce chiral allylic amines
5q to 5s in highly efficiency.
2
L2
3
L3
4
L4
5
L5
5
6d
L1
99
95
99
16
7
7
L1
8e
9d
10
L1
L1
L1
aConditions: 1a (0.4 mmol, 1.0 equiv), 2a (0.4 mmol, 1.0 equiv), Rh(I)
(0.01 mmol, 0.025 equiv), ligand (0.01 mmol, 0.025 equiv), CH3CN (2
b
c
mL). Isolated yield. The enantiomeric excess of 3a was determined
by HPLC with a chiral column. d1.25 mol% of catalyst precursor dimer
was used. eReaction was run at room temperature.
Under the optimized reaction condition (Table 1, entry 1), the
substrate scope was examined by varying the substituents on
anilines and the allylic carbonates (Table 2). Anilines containing
electron-donating and electron-withdrawing functional groups
react smoothly with completely branched selectivities and excellent
enantioselectivities (3b to 3d). ortho-Substituted anilines are also
reactive in this transformation (3e and 3f). Sterically more hindered
N-methyl aniline was allylated to give 3g efficiently with Rh. This
protocol was amenable to a set of allylic carbonates bearing simple
alkyl groups. Allylic amine 3g with -methyl was prepared with 98%
ee and 94% yield. Allylic carbonates with -branched isopropyl,
cyclopropyl and cyclohexyl groups underwent the amination
reaction to deliver 3i to 3k in excellent yields and ees. It is
Encouraged by the successful formation of 5m to 5p, we further
examined the reactions of weakly acidic carbon, oxygen and sulfur
pronucleophiles (Table 4). Under the neutral condition,
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product formation under the catalysis of Ir.12 However, the ee of
3 a d r o p s t o 8 6 % . T o o u r
Table 3. Scope of Other Nitrogen Nucleophilesa
1
2
3
2.5 mol% Rh(cod)2BF4
R2
R1
R3
OCO2Me
H
N
L1
2.5 mol%
+
N
Table 4. Scope of Carbon, Oxygen and Sulfur Nucleophilesa
R2
R3
R1
CH3CN, 60 oC, 12 h
4
5
6
7
8
9
1a, 1g
1h
and
5a-5s
racemic
4a-4p
2.5 mol% Rh(cod)2BF4
OCO2Me
L1
Nu
2.5 mol%
+
NuH
O
CH3CN, 60 oC, 12 h
R
R
O
S
NHBn
HN
HN
n-C3H7
5b
O
HN
1a
1h
and
6 and 7
8
racemic
Ph
Ph
n-C3H7
Bn
PhO2S
n-C3H7
SO2Ph
NC
CN
PhO2S
n-C3H7
CN
NC
CN
5a
5c
5d
, 84% yield
99% ee
, 87% yield
99% ee
, 99% yield
, 96% yield
99% ee
99% ee
10
11
12
13
14
15
16
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60
n-C3H7
Ph
N
8a
8b
, 98% yield
99% ee
8c
8d
, 99% yield, dr = 4 : 1
96% ee, 99% ee
, 98% yield
99% ee
, 71% yield
98% ee
BnN
HN
HN
HN
NH
n-C3H7
Ph
5f
O2N
O2N
Ph
5g
n-C3H7
5h
, 86% yield
NC
CO2Me
b
b
CN
CO2Et
5e
, 92% yield
> 99% ee
, 99% yield
, 87% yield
> 20 : 1 dr
99% ee
O
96% ee
Ph
n-C3H7
n-C3H7
HO
Ph
8e
, 98% yield, dr = 1.6 : 1
97% ee (major diastereomer)
8f
8g
, 95% yield, dr = 1: 1
99% ee, 98% ee
, 98% yield, dr = 1.4 : 1
Bn
Bn
N
Ph
N
N
99% ee, 99% ee
Bn
n-C3H7
NH
Me
n-C3H7
Ph
5j
Ph
5k
CF3
c,d
5i
, 88% yield
> 20 : 1 dr
5l
, 99% yield
98% ee
, 77% yield
, 90% yield (83% yield)
O
O
CF3
O2S
98% ee
99% ee (98% ee)
Ph
n-C3H7
n-C3H7
b
c,d
8h
8i
8j
, 89% yield
, 89% yield
, 87% yield
N
N
96% ee
94% ee
96% ee
Boc
Bz
O
N
O
NHTs
N
n-C3H7
n-C3H7
n-C3H7
n-C3H7
aConditions: 1 (0.4 mmol, 1.0 equiv), 4 (0.4 mmol, 1.0 equiv), Rh(I)
(0.01 mmol, 0.025 equiv), L1 (0.01 mmol, 0.025 equiv). b7b (0.6 mmol,
1.5 equiv) was used. c[Rh(cod)Cl]2 (0.0125 equiv) and L2 (0.025 equiv)
were used. dThe thio-ether was oxidized to sulfone to avoid the linear
product formation and measure the ee.
b
b
b
5m
, 90% yield
5n
5o
5p
, 99% yield
, 99% yield
99% ee
, 95% yield
99% ee
99% ee
99% ee
O
Ph
NHBn
N
N
Ph
Ph
Ph
Ph
b,c
5q
, 99% yield
98% ee
5r
5s
, 99% yield
, 86% yield
surprise, the ee could be improved to 98% by simply increasing the
reaction temperature to 100 oC, which indicates that a higher
reaction barrier to reach the same intermediate from 10 may exist.
Under the optimized conditions for both 9 and 10, different
nucleophiles were examined. Aniline, benzyl amine,
benzophenone imine, bis(phenylsulfonyl)methane, substituted
malononitrile, and phenol all reacted to produce the allylation
products 3a, 5t, 5l, 8b, 8c and8h regio- and enantioselectively.
97% ee
99% ee
aConditions: 1 (0.4 mmol, 1.0 equiv), 4 (0.4 mmol, 1.0 equiv), Rh(I)
(0.01 mmol, 0.025 equiv), L1 (0.01 mmol, 0.025 equiv), CH3CN (2
b
mL). [Rh(cod)Cl]2 (0.0125 equiv) and L2 (0.025 equiv) were used.
cThe imine was hydrolyzed and protected as an amide. The ee was
d
determined with the amide. Data in brackets is for 10 mmol scale
reaction and 1 mol% Rh catalyst was used.
Table 5. Scope of Linear Allylic carbonatesa
malononitrile and bis(phenylsulfonyl)methane react smoothly to
produce 8a and 8b with excellent yields and ees. Substituted
malononitrile could also be used to give 8c with a quaternary
carbon. 1 : 1 to 1.4 : 1 drs were obtained with unsymmetrical carbon
nucleophiles which contain ester and ketone groups, while the
regio- and enantioselectivities remain excellent (8d to 8g). Acidic
phenol, hexafluoropropan-2-ol and and 4-toluenethiol react to form
8h, 8i and 8j in this base-free condition, which further extends the
scope of this reaction to oxygen and sulfur pronucleophiles.
Et3N·3HF does not react under the same condition, probably due to
its low acidity.
2.5 mol% Rh(cod)2BF4
n-C3H7
n-C3H7
OCO2Me 9, E
or
Nu
L1
2.5 mol%
+
NuH
CH3CN, 60 or 100 oC, 12 h
n-C3H7
10
, Z
OCO2Me
condition : from , 60 oC
condition : from , 100 oC
A
9
B
10
Ph
NHPh
NHBn
N
Ph
n-C3H7
n-C3H7
n-C3H7
b
5l
,
A
B
3a
,
A
B
5t
,
A
B
: 99% yield, 99% ee
: 90% yield, 98% ee
: 90% yield, 98% ee
: 88% yield, 97% ee
: 74% yield, 97% ee
: 99% yield, 99% ee
The previously-reported rhodium-catalyzed allylic substitution
predominantly takes place predominantly at the position where
the leaving group leaves. The dynamic kinetic asymmetric
allylation performance for the rhodium/bisoxazolinephosphine
catalyst inspires us to examine whether the Rh-catalyzed
regiospecific allylation is also ligand dependent. As shown in
Table 5, when E-linear allylic carbonate 9 was subjected to the
reaction condition as above (60 oC), the same level of yield, regio-
and enantioselectivity for 3a were obtained. Reaction of Z-linear
allylic carbonate 10 under the identical condition leads to the
formation of 3a as well, which is different from the Z-linear
Bn
PhO2S
n-C3H7
SO2Ph
NC
CN
O
n-C3H7
n-C3H7
8b
,
A
8c
,
A
B
8h A
,
: 91% yield, 99% ee
: 79% yield, 99% ee
: 78% yield, 99% ee
: 61% yield, 99% ee
: 99% yield, 96% ee
B
: 99% yield, 96% ee
B
aConditions: 9 or 10 (0.4 mmol, 1.0 equiv), 4 (0.4 mmol, 1.0 equiv),
Rh(I) (0.01 mmol, 0.025 equiv), L1 (0.01 mmol, 0.025 equiv), CH3CN
(2 mL). bThe imine was hydrolyzed and protected as an amide.
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Racemic tertiary allylic carbonate 1i could also react with aniline
complex. [L1-Rh(MeC3H4)Cl]OTf adopts a distorted six-
1
2
3
4
5
6
7
8
2c to give 3n with a tetrasubstituted carbon under the catalysis of
the same rhodium complexes. The yield of 3n was relatively lower
and small amount of 1,3-dienes by elimination reaction could be
observed. Two possible reasons may lead to the lower
enantioselectivity of 3n: 1) The slower interconversion between the
two diastereomers of the -allyl/Rh complex; 2) The difference of
methyl group and CH2R group becomes smaller than that of methyl
group and hydrogen, which makes the face-selection be more
difficult. Modification of the ligand to improve the
enantioselectivity of tetrasubstituted carbons is under investigation.
coordinate octahedral geometry, with the chloride located trans to
the phosphorus atom in the axial direction. The two allyl termini
carbons are oriented trans to one nitrogen atom on the oxazolines
respectively. The Rh-C3 bond is longer than the Rh-C1 bond by
0.108 Å. The relatively weaker Rh-C3 bond and shielding effect at
C1 by the isopropyl group at the right oxazoline ring may account
for the excellent branch-selectivity. The excellent exo face-
selectivity of the syn-methylallyl moiety could be interpreted by
the size effect of the chloride anion on the rhodium. The steric
repulsion between the methyl or C2-H and the chloride could make
the endo--allyl-Rh(III) intermediate be less stable.16 The role of
the chloride could be replaced by the carbonate anion or methoxide
when Rh(cod)2BF4 was used as the catalyst precursor, in which case
no chloride exists. The formation of [L1-Rh(MeC3H4)Cl]OTf from
both 11 and 12 as the most stable reaction intermediate is consistent
with the observed facts that both branched
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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OMe
OMe
2.5 mol% Rh(cod)2BF4
Me
Me OBoc
L1 L2
or
2.5 mol%
+
Me
MeCN, 100 oC, 16 h
HN Me
Me
eq 1
Me
NH2
1i
2c
3n
racemic
L1
with , 65% yield, 70% ee
Scheme 3. Synthesis of [L1-Rh(MeC3H4)Cl]OTf and
Reactivity
L2
with , 50% yield, 73% ee
To better understand the role of bisoxazolinephosphine ligand,
characterization of Rh/ligand complex was conducted (scheme 2).
By simply mixing Rh(cod)2BF4 or Rh(cod)2OTf with L1 in
benzene at room temperature, [L1-Rh(cod)]BF4 and [L1-
Rh(cod)]OTf were synthesized in high yields (eqs 2 and 3). A set
of doublet peak at 30.2 ppm in 31P NMR indicates only one
rhodium complex formed. Recrystallization of [L1-Rh(cod)]OTf in
pentane and acetone affords a crystal suitable for single crystal X-
ray diffraction analysis. Solid-state
OTf-
Cl
O
iPr
11
, racemic
P
iPr
Me
Me
N
benzene
60 oC, 24 h
O
N
Rh(cod)2OTf
or
L1
+
+
Rh
Me
Cl
Rh(MeC3H4)Cl]OTf
12
Cl
L1-
[
trans and cis mixture
1.0 equiv
11
12
Yieid: 61% from
68% from
1.0 equiv
1.0 equiv
Scheme 2. Synthesis of [L1-Rh(cod)]OTf, [L1-Rh(cod)]BF4
and Their Reactivities
o
selected bond lengths: A
2
1
Me
3
Rh-C1: 2.148
Rh-C3: 2.256
C1-C2: 1.418
C2-C3: 1.397
o
o
2.148A
2.256
A
Rh
Cl
Ph
- cod
P
benzene
Rh(cod)2OTf
+
eq 2
O
N
N
O
rt, 5 h
NH2
OMe
88% yield
iPr
iPr
L1
L1-
+
[
Rh(MeC3H4)Cl]OTf
HN
Me
L1-
[ Rh(cod)]OTf
eq 5
eq 6
CH3CN, 60 oC, 12 h
P-N bidentate complex
2c
1.0 equiv
- cod
OMe
benzene
3h
, 71%, 88% ee
eq 3
eq 4
Rh(cod)2BF4
[L1-Rh(cod)]BF4
+
L1
rt, 5 h
85% yield
OCO2Me
L1-
2.5 mol% [ Rh(MeC3H4)Cl]OTf
+
2c
3h
, 98%, 88% ee
CH3CN, 60 oC, 12 h
Me
L1
2.5 mol% -Rh(cod)BF4
1b
, 1.0 equiv
1.0 equiv
NHPh
L1
or -Rh(cod)OTf
3a
1a
rac-
2a
+
CH3CN, 60 oC, 12 h
n-C3H7
racemic and linear (Z and E) allylic carbonates lead to the same
enantiomer of product.
[L1
[L1
from
from
-Rh(cod)]BF4: 99%, 99% ee
-Rh(cod)]OTf: 99%, 96% ee
structure reveals that L1 coordinates with Rh(I) as only a P-N
bidentate ligand, and one cod is still on the metal.13 The rhodium
complex adopts a distorted square planar geometry. The reactivities
of these two complexes match with the in-situ generated catalysts
(eq 4) (Table 1, entries 1 and 7).
The stoichiometric reaction of [L1-Rh(MeC3H4)Cl]OTf was
studied (eq 5). 3h with 88% ee was isolated in 71% yield after
heating the complex with 2c in acetonitrile for 12 hours.17 The
complex was also efficient in the catalytic reaction (eq 6), and the
same 88% ee was obtained, which indicates that [L1-
Rh(MeC3H4)Cl]OTf is involved as reaction intermediate of the
catalysis. The absolute R-configuration of 3h supports an outer-
sphere attack on allyl carbon by nucleophiles opposite to the metal
center. This possible mechanism could also explain the fact that the
same level of enantioselectivities were obtained from sterically
quite different nitrogen, carbon, oxygen and sulfur pronucleophiles.
To get more insight about the high selectities controlled by the
bisoxazolinephosphine ligand, we further focused on the Rh(III)-
allyl complex synthesis. After the unsuccessful attempts starting
from either branched or linear allylic carbonates, we turned our
attention to the allylic chloride. Both racemic 3-chlorobut-1-ene 11
and crotyl chloride 12 react with Rh(cod)2OTf and L1 to form the
same yellow solid (Scheme 3). The doublet peak at 40.5 ppm in
31P-NMR indicates a new rhodium complex was generated and
only one isomer exists in solution. Different from -allyl-Ir-cod
complex, no cyclooctadiene peaks could be found in this rhodium
complex.14,15 A crystal suitable for X-ray diffraction was obtained
by slow diffusion of pentane into the acetone solution of the
In summary, we have developed
a highly regio- and
enantioselective allylic substitution based on rhodium and
bisoxazolinephosphine ligands. This catalyst system provides a
general reaction platform for different nitrogen, carbon and oxygen
pronucleophiles. In contrast to the previous reported rhodium-
catalyzed regiospecific allylic substitution, both challenging
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(4) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. High
branched racemic and linear (Z and E) allylic substrates bearing
simple alkyl groups could be converted to the same chiral products.
-Allyl-Rh(III) intermediate was isolated to understand the origin
of the high regio- and enantioselectivities. The modular synthesis
of bisoxazolinephosphine ligands enables the fine tuning of the
steric and electronic properties of the ligands, which is expected to
broaden the scope of the nucleophiles and the allylic substrates in
the future.
Enantioselectivity in Rhodium-Catalyzed Allylic Alkylation of 1-
Substituted 2-Propenyl Acetates. Org. Lett. 2003, 5, 1713-1715.
(5) Vrieze, D. C.; Hoge, G. S.; Hoerter, P. Z.; Van Haitsma, J. T.;
Samas, B. M. A Highly Enantioselective Allylic Amination Reaction
Using a Commercially Available Chiral Rhodium Catalyst: Resolution
of Racemic Allylic Carbonates. Org. Lett. 2009, 11, 3140-3142.
(6) (a) Arnold, J. S.; Nguyen, H. M. Rhodium-Catalyzed Dynamic
Kinetic Asymmetric Transformations of Racemic Tertiary Allylic
Trichloroacetimidates with Anilines. J. Am. Chem. Soc. 2012, 134,
8380-8383. (b) Arnold, J. S.; Cizio, G. T.; Heitz, D. R.; Nguyen, H. M.
Rhodium-catalyzed regio- and enantioselective amination of racemic
secondary allylic trichloroacetimidates with N-methyl anilines. Chem.
Commun. 2012, 48, 11531-11533. (c) Arnold, J. S.; Mwenda, E. T.;
Nguyen, H. M. Rhodium-Catalyzed Sequential Allylic Amination and
Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven-
Membered Nitrogen Heterocycles. Angew. Chem. Int. Ed. 2014, 53,
3688-3692.
(7) (a) Li, C.; Breit, B. Rhodium-Catalyzed Dynamic Kinetic
Asymmetric Allylation of Phenols and 2-Hydroxypyridines. Chem. Eur.
J. 2016, 22, 14655-14663. (b) Zhou, Y.; Breit, B. Rhodium-Catalyzed
Asymmetric N-H Functionalization of Quinazolinones with Allenes
and Allylic Carbonates: The First Enantioselective Formal Total
Synthesis of (-)-Chaetominine. Chem. Eur. J. 2017, 23, 18156-18160.
(8) Liang, L.; Xie, M.-S.; Qin, T.; Zhu, M.; Qu, G.-R.; Guo, H.-M.
Regio- and Enantioselective Synthesis of Chiral Pyrimidine Acyclic
Nucleosides via Rhodium-Catalyzed Asymmetric Allylation of
Pyrimidines. Org. Lett. 2017, 19, 5212-5215.
1
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ASSOCIATED CONTENT
9
Supporting Information. Detailed experimental procedures,
characterization data, copies of 1H, 13C NMR spectra, HPLC
spectra and X-ray crystal structure of [L1-Rh(cod)]OTf and [L1-
Rh(MeC3H4)Cl]OTf. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: chkli@sjtu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(9) Tang, S.-B.; Zhang, X.; Tu, H.-F.; You, S.-L. Regio- and
Enantioselective Rhodium-Catalyzed Allylic Alkylation of Racemic
Allylic Alcohols with 1,3-Diketones. J. Am. Chem. Soc. 2018, 140,
7737-7742.
(10) Ghorai, S.; Chirke, S. S.; Xu, W.-B.; Chen, J.-F.; Li, C. Cobalt-
Catalyzed Regio- and Enantioselective Allylic Amination. J. Am.
Chem. Soc. 2019, 141, 11430-11434.
This work is supported National Natural Science Foundation of
China (NSFC) (Grant 21602130) and Shanghai Jiao Tong
University. We thank Prof. Yong Jian Zhang for the helpful
discussion.
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(14) For recent examples of achiral rhodium/allyl complex X-ray
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(Phosphoramidite,Olefin)-Catalyzed
Enantioselective
Allylic
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A Combined
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14843 -14852.
(16) exo and endo: the C2-H bond of the allyl ligand points towards
phosphorus or chloride respectively.
(17) Relatively lower 88% ee might be caused by the weak
coordinating OTf as a bidentate anion, which may turn the -Rh-allyl
complexation mode to -Rh-allyl as shown in ref. 14b. 3a with a n-
propyl group could be obtained in 96% ee with [L1-
Rh(MeC3H4)Cl]OTf, which indicates that the smaller methyl group in
3h is another reason for the lower 88% ee
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R
OCO2Me
OCO2Me
OCO2Me
Nu
exclusively branched
NPN*
Rh/
or
R
or
up to 99% ee
R
R
NuH
branched
racemic
R = alkyl or Ar
Nu = N, C, O, S
linear (Z or E)
OTf-
R'
P
O
P
iPr
N
O
N
N
O
O
N
Rh
iPr
Me
iPr
iPr
NPN*
Cl
isolation of Rh/allyl intermediate
Bisoxazolinephosphine
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