Chiral-at-Metal Rh(III) Complex Catalyzed Asymmetric Conjugate Addition of Unactivated Alkenes with α,β-Unsaturated 2-Acyl Imidazoles

Article abstract of DOI:10.1021/acs.orglett.7b01456

A newly prepared chiral-at-metal Rh(III) complex catalyzed highly efficient asymmetric conjugate addition of para-vinylanilines with α,β-unsaturated 2-acyl imidazoles is developed, affording the corresponding adducts in 67-95% yields with 86-95% ee. Remarkably, employing as low as 0.05 mol % of Rh(III) complex as catalyst, a gram-scale reaction still affords the desired product in 81% yield with 92% ee.

Full text of DOI:10.1021/acs.orglett.7b01456

Letter
pubs.acs.org/OrgLett
Chiral-at-Metal Rh(III) Complex Catalyzed Asymmetric Conjugate
Addition of Unactivated Alkenes with α,β-Unsaturated 2‑Acyl
Imidazoles
Kuan Li,†,‡ Qian Wan,‡ and Qiang Kang*,‡
†College of Chemistry, Fuzhou University, Fuzhou 350108, China
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002, China
S
* Supporting Information
ABSTRACT: A newly prepared chiral-at-metal Rh(III) complex catalyzed highly efficient asymmetric conjugate addition of
para-vinylanilines with α,β-unsaturated 2-acyl imidazoles is developed, affording the corresponding adducts in 67−95% yields
with 86−95% ee. Remarkably, employing as low as 0.05 mol % of Rh(III) complex as catalyst, a gram-scale reaction still affords
the desired product in 81% yield with 92% ee.
symmetric Michael addition of vinyl anion synthons
(alkenyl nucleophiles) to Michael acceptors is a powerful
Scheme 1. Catalytic Asymmetric Conjugate Addition of
Nucloephilic Alkene
A
synthetic protocol that allows for construction of enantiomeri-
cally enriched chiral centers adjacent to an alkenyl moiety.1
Despite the great synthetic value of this kind of double bond,2 the
catalytic asymmetric addition of alkenyl nucleophiles remains
insufficiently explored. Typical protocols to install a vinyl group
onto α,β-unsaturated carbonyl compounds require stoichiomet-
ric vinyl organometallic reagents, such as alkenyl boronic acids3
or boronates,4 alkenylaluminums,5 alkenylsilanes,6 alkenylzirco-
niums,7 alkenylstannanes,8 and alkenyl Grignard reagents9
(Scheme 1a). Simple alkenes have rarely been utilized in
asymmetric conjugate addition reactions due to the low
nucleophilicity and uncontrolled side reactions.10 Recently,
only the Luo group realized the first example of the asymmetric
conjugate addition of para-vinylanilines11 to enones catalyzed by
chiral primary amines (Scheme 1b).12 Despite these impressive
advances,13 development of efficient and highly enantioselective
protocols for conjugate addition of unactivated alkenyl
nucleophiles is still in great demand. We envisioned combining
simple alkenes and chiral-at-metal rhodium complex in
asymmetric conjugate addition reaction. Herein, we report an
enantioselective addition of para-vinylanilines with α,β-unsatu-
rated 2-acyl imidazoles catalzyed by chiral-at-metal Rh(III)
complexes (Scheme 1c).14,15
50 °C, the reaction gave the conjugate addition product 3a in
93% yield with 75% ee (entry 1). Encouraged by these promising
results, we examined different chiral Rh(III) complexes Λ-
Rh2,15k Λ-Rh3, and Λ-Rh415m in the title reaction. Gratifyingly,
Λ-Rh3 was the best one in terms of enantioselectivity, resulting
in 3a in 92% yield with 88% ee (entry 3). In the absence of
catalyst, the reaction could not afford any product, which showed
that the presence of Λ-Rh3 is mandatory (entry 5). Various
solvents such as CHCl3, CH2Cl2, toluene, THF, and MeCN were
Our studies were initiated by an exploration of the reaction of
α,β-unsaturated 2-acyl imidazole16 1a with para-vinylaniline 2a
catalyzed by chiral-at-metal Rh(III) complexes (Table 1). In the
presence of 2 mol % of Λ-Rh115a in 1,2-dichloroethane (DCE) at
Received: May 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope: α,β-Unsaturated 2-Acyl Imidazoles
b
c
entry
R1
R2
time (h) product yield (%) ee (%)
1
2
Me
iPr
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
iPr
iPr
C6H5
C6H5
C6H5
4
5
4
2
3
5
2
2
3
2
2
2
2
3
2
9
5
6
3a
3b
3c
3d
3e
3f
87
93
90
95
94
80
95
86
92
95
95
82
92
90
82
80
84
67
92
95
86
93
90
87
93
94
94
94
93
88
88
88
95
95
95
93
3
4
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
3-Br-C6H4
4-Cl-C6H4
3-Cl-C6H4
2-Me-C6H4
1-naphyl
2-furyl
5
6
7
3g
3h
3i
b
c
temp
(°C)
time
(h)
yield
ee
8
entry
Λ-Rh (x)
solvent
(%)
(%)
9
1
2
Λ-Rh1 (2)
Λ-Rh2 (2)
Λ-Rh3 (2)
Λ-Rh4 (2)
DCE
50
50
50
50
50
30
30
30
30
30
30
30
1
3
93
92
92
91
trace
87
90
93
84
95
89
87
75
76
88
85
10
11
12
13
14
15
16
17
18
3j
DCE
3k
3l
3
DCE
1
4
DCE
1
3m
3n
3o
3p
3q
3r
5
DCE
12
6
2-thienyl
Me
6
Λ-Rh3 (2)
Λ-Rh3 (2)
Λ-Rh3 (2)
Λ-Rh3 (2)
Λ-Rh3 (2)
Λ-Rh3 (2)
Λ-Rh3 (1)
CHCl3
toluene
THF
75
34
83
87
91
92
92
7
9
Et
iPr
8
5
9
MeCN
DCM
DCE
5
CO2Et
10
11
12
4
a
2
Reaction conditions: 1 (0.25 mmol), 2a (0.3 mmol), Λ-Rh3 (1 mol
b
%) in DCE (0.5 mL) at 30 °C under argon atmosphere. Isolated
yields. Determined by chiral HPLC analysis.
DCE
4
c
a
Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), Λ-Rh (x mol
b
%), solvent (0.5 mL) under argon atmosphere. Isolated yields.
c
conditions to give desired products in good yields with slightly
decreased enantioselecvivities (entries 13 and 14).
Determined by chiral HPLC analysis.
In addition to aromatic substituents, the aliphatic variants of
α,β-unsaturated 2-acyl imidazoles (Me, Et, iPr, CO2Et) were also
examined, affording the corresponding vinylated adducts 3o−3r
in 67−84% yields with 93−95% ee (entries 15−18). The
absolute configuration of product 3k was determined and
confirmed by a single-crystal X-ray analysis (Figure 1; for details,
see the Supporting Information).17
screened at 30 °C (entries 6−11). This investigation led to the
finding that DCE is optimal for the process in terms of reactivity
and enantioselectivity, delivering desired adduct 3a in 89% yield
with 92% ee within 2 h (entry 11). Further decreasing the catalyst
loading to 1 mol % under similar reaction conditions exhibited
significant reactivity without decreasing enantioslectivity, afford-
ing 3a in 87% yield with 92% ee (entry 12).
With the optimized reaction conditions in hand (entry 12,
Table 1), the substrate scope of the enantioselective conjugate
addition of para-vinylaniline 2a with α,β-unsaturated 2-acyl
imidazoles 1 was investigated, and the results are summarized in
Table 2. The bulkiness of the substituent on the imidazole ring
(R1) had a slight influence on enantioselecivity as the sterically
hindered isopropyl-substituted imidazole delivered the corre-
sponding adduct 3b in 95% ee (entry 2, Table 2). The α,β-
unsaturated 2-acyl imidazoles bearing electron-donating groups
on the phenyl ring had little impact on the outcome, leading to
the corresponding products 3d−3f with good to excellent
enantioselectivies (entries 4−6). Substrates with electron-
withdrawing groups, such as Br or Cl, on the phenyl ring were
also tolerable, affording the desired products with comparable
enantioselectivities (entries 7−10). The ortho-substituted
substrate 1k was also compatible to afford the desired product
3k in 95% yield with 93% ee (entry 11). Sterically hindered
substrate such as 1-naphyl-substituted 2-acyl imidazole was
tolerated in the optimal reaction conditions, resulting in the
corresponding adduct 3l in 82% yield with 88% ee (entry 12).
Moreover, heterocycle-substituted α,β-unsaturated 2-acyl imida-
zoles (1m, 1n) worked smoothly in the optimal reaction
Figure 1. X-ray derived ORTEP of 3k with thermal ellipsoids shown at
the 35% probability level.
Then we evaluated the scope of nucleophilic alkenes (Scheme
2). In general, replacing the N,N-dimethyl with N,N-diethyl or
piperidinyl of alkenes had no influence on enantioselectivities.
The corresponding adducts were obtained in good yields with
95% ee (3s and 3t, Scheme 2). However, methoxyl-substituted
alkene 1u and other alkyl-substituted alkenes19 could not give
any conjugate addition product in the optimal reaction
B
DOI: 10.1021/acs.orglett.7b01456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope: Alkenes 2
a
Reaction conditions: 0.25 mmol of 1o, 0.3 mmol of 2, and 1 mol % of
Λ-Rh3 in DCE (0.5 mL) at 30 °C under an argon atmosphere. Yields
of isolated products 3 are shown. Enantiomeric excesses were
determined via HPLC analysis on a chiral stationary phase.
conditions, probably due to low nucleophilicity of these
substrates.
To demonstrate the practicality of the current methodology, a
gram-scale reaction of α,β-unsaturated 2-acyl imidazole 1k (0.89
g, 3.5 mmol) with para-vinylaniline 2a (1.12 g, 4.2 mmol) was
conducted under the optimal reaction conditions, affording 3k in
88% yield with 92% ee within 4 h.18 Notably, when as low as 0.05
mol % of Λ-Rh3 (2.3 mg) was used, the asymmetric conjugate
addition of 1k on 3.93 mmol scale (1.0 g) with 2a (1.2 equiv)
could deliver the desired product 3k in 81% yield (1620 catalyst
turnovers) with 92% ee (Scheme 3, eq 1). In addition, the alkenyl
Figure 2. Proposed mechanism.
affording the corresponding adducts in good yields with excellent
enantioselectivities. This protocol features wide substrate scope,
mild reaction conditions, and an operationally simple procedure.
Moreover, this process exhibits remarkable reactivity and
enantioselectivity, given the fact that the title reaction can be
conducted on a gram scale using as low as 0.05 mol % of Λ-Rh3
as catalyst with comparable enantioselectivity. Further research
on the new design type of chiral Rh(III) complexes and its
application in asymmetric synthesis is ongoing in our laboratory.
Scheme 3. Gram-Scale Experiments and Synthetic
Transformation of Product 3k
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01456.
X-ray data for compound 3k, experimental procedures,
1
characterization data, and copies of H and 13C NMR
spectra and HPLC chromatograms for obtained com-
pounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kangq@fjirsm.ac.cn.
ORCID
moiety of product 3k (>99% ee) could be easily hydrogenated to
afford saturated product 4 in 86% yield without loss in
enantiomeric excess (Scheme 3, eq 2).
Qiang Kang: 0000-0002-9939-0875
Notes
The proposed mechanism for this reaction is depicted in
Figure 2. The 2-acyl imidazole substrate 1b is activated by the
Rh(III) complex through bidentate N,O-coordination to form
intermediate A. Excellent shielding of the Si face of A by the bulky
tBu group of achiral ligand leads to Re facial nucleophilic attack by
2a, resulting in the iminium cation (intermediate B) with
dearomatization of the phenyl ring. The driving force of
rearomatization helps to lose the proton of B to form
intermediate C with α-carbanion, which undergoes subsequent
protonation to generate vinylated intermediate D. Finally,
desired product 3b is released from the coordinated intermediate
D by ligand exchange with 1b.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Daqiang Yuan (Fujian Institute of Research on
the Structure of Matter, Chinese Academy of Sciences) for his
kind help with X-ray analysis. This work was supported by the
Strategic Priority Research Program of the Chinese Academy of
Sciences, Grant No. XDB20000000, and 100 Talents Pro-
gramme of the Chinese Academy of Sciences.
REFERENCES
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