Enantioselective conjugate addition of cyanide to chalcones catalyzed by a magnesium-Py-BINMOL complex

Article abstract of DOI:10.1039/c5cy01056j

An enantioselective magnesium-catalyzed conjugate addition of trimethylsilyl cyanide to chalcones in the presence of Py-BINMOL with multiple stereogenic centers, through dual activation of substrates, has been successfully developed with moderate to good enantioselectivities and in good yields.

Full text of DOI:10.1039/c5cy01056j

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Ca Pt al el ya ss ies d So c ni eo nt ca ed j&u s Tt emc ah rng oi nl os gy
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DOI: 10.1039/C5CY01056J
Journal Name
COMMUNICATION
Enantioselective Conjugate Addition of Cyanide to Chalcones
Catalyzed by Magnesium-Py-BINMOL Complex
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a,b
a
a
a,b
Cheng Dong , Tao Song , Xing-Feng Bai , Yu-Ming Cui , Zheng Xu , and Li-Wen Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
10
An enantioselective magnesium-catalyzed conjugate addition of BINOL-derived organocatalysts, and chiral ProPhenol-magnesium
11
trimethylsilyl cyanide to chalcones in the presence of Py-BINMOL complexes. In this context, we are interested in the development
with multiple stereogenic centers, through dual activation of of readily accessible alkaline earth metal–promoted conjugate
substrates, has been successfully developed with moderate to hydrocyanantion of chalcone-type aromatic enones with TMSCN by
good enantioselectivities and good yields.
using of readily available Ar-BINMOL (1,1’-binaphthalene-2--
arylmethanol-2'-ol) ligands.
We recently reported the synthesis and application of Ar-BINMOL
1
2
Nitriles are undoubtedly important functional compounds in
organic chemistry, and it is one of the most useful building blocks
for the synthesis of amines, acids or amides, natural products, and
(
1,1’-binaphthalene-2--arylmethanol-2'-ol) ligands in various
12
organic transformations.
Especially, the Ar-BINMOL-derived
1
pharmaceuticals. Therefore, numerous efforts have been
functional molecule has been recognized as an efficient ligand or
catalyst in the enantioselective 1,2-addition of organometallic
dedicated to the development of enantioselective methods for
introducing cyano groups into carbonyl compounds. Despite the
2
12
reagents to aldehydes with high level of enantioselectivity.
asymmetric 1,2-addition of cyanide to aldehydes or ketones has
been established well, the stereoselective synthesis of -cyano
adducts by the 1,4-conjugate addition of cyanide to ,-
unsaturated carbonyl compounds is less well explored and only a
limited number has been reported involving enantioselective
conjugate hydrocyanation of ,-unsaturated carbonyl compounds.
As a result, the asymmetric 1,4-conjugate cyanation of ,-
unsaturated carbonyl compounds has attracted much attention in
from synthetic chemists in the past decade. In 2003, Jacobsen et.
Notably, the attractive features of the Ar-BINMOLs and its
analogues, including their salient structure with axial and sp
3
central chirality as well as the easily achieving from commercially
available 1,1'-bi-2-naphthol (BINOL), render these ligands very
1
3
attractive in catalytic asymmetric transformations. In this regard,
Yus and coworkers also reported the privileged role of Ar-BINMOL
14
ligands in the asymmetric catalysis. On the basis of previous work
on the successful application of Ar-BINMOLs ligands with multiple
stereogenic centers in asymmetric catalysis, we expected that the
multifunctional Ar-BINMOLs ligands (L1-L4) capable of introduction
of alkaline earth metal centers would not only accelerate the
catalytic asymmetric conjugate addition of cyanide to chalcones in
good stereoselectivity.
3
al. reported the first example of asymmetric catalysis of salen-
Al(III)-catalyzed 1,4-conjugate addition with cyanide and ,-
unsaturated imides. Subsequently, a varied of elegant works on
enantioselective conjugate hydrocyanation of ,-unsaturated
carbonyl compounds and nitroolefins have been disclosed by
Initially, we hypothesized that the Ar-BINMOLs bearing pyridine
moiety would be effective in the enantioselective conjugate
addition of cyanide to chalcone 1a because of its multifunctional
4
-11
several groups,
generally involving binuclear or bimetallic salen-
4
5
Al(III) complexes, gadolinium catalyst, Sr catalyst derived from
Sr(OiPr)2 and new chiral alcohol ligand, ruthenium-lithium
combined catalysts, phase-transfer catalysts, titanium complexes,
6
11,15
N,O-groups similarly to the Trost ligand (ProPhenol).
In addition,
7
8
9
magnesium is not only an environmentally benign and abundant
metal but is also inexpensive and readily available. Thus our work
commenced with a preliminary survey of the solvent effect using
a.
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry
14d
chalcone (1a) as the model substrate in the Py-BINMOL (L1)
-
of Education, and College of Material, Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou 310012, P. R. China. Fax: 86 2886 5135;
Tel: 86 2886 5135; E-mail: liwenxu@hznu.edu.cn.
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, P.
R. China. E-mail: licpxulw@yahoo.com
promoted magnesium-catalyzed conjugate addition of cyanide. As
shown in Table S1 (See Supporting Information), a series of solvent
were screened in this reaction. It was found that the diethyl ether
was suitable solvent in term of good yield and promising
enantioselectivity (48% ee), while as the other solvents, such as
DCM, toluene, THF, 1,4-dioxane, and toluene, were exhibited to be
b.
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Ca Pt al el ya ss ies d So c ni eo nt ca ed j&u s Tt emc ah rng oi nl os gy
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Journal Name
inferior media for both the conversion and enantioselectivity in investigation on the effect of temperature in this reaction,
View Article Online
DOI: 10.1039/C5CY01056J
comparison to that of Et O. Next, chiral BINOL and other Ar- summarized in Table 1 (Entries 15-18), establishing the optimized
BINMOL-derived ligands (L2-L5, Scheme 1)
2
1
3d-e,14d
with reaction conditions (As depicted in Table 1, entries 11-21). However,
multifunctional diols were exploited in this reaction. These studies the effect of the phenolic additive on enantioselectivity strongly
indicated that in the presence of chiral BINOL and ligand L2-L5, depends on the temperature was unclear. It might be arisen from
enantioselective conjugate addition of cyanide to chalcone 1a leads the stability and activity of multifunctional catalyst system at a
to the formation of -cyano ketone 2a with low enantioselectivities reasonable temperature.
16
(
0-38% ee). In addition, representative amino alcohols L6-L7 with
Table 1. Further optimization of the reaction conditions by use of additive.
multiple stereogenic centers were proved to be no enantioselective
induction in this reaction. Thus of the ligands evaluated in this
reaction, Py-BINMOL (L1) exhibited the best enantioselectivity and
yield among these ligands.
TMSCN (2 eq.)
MgBu2 (20 mol%)
additive
=
O
CN
O
L1 (20 mol%)
OH
R
additive (1.5 eq.)
1a
Et2O, 0 o
2a
C
TMSCN (2.0 eq.)
MgBu2 (20 mol%)
Ligand (20 mol%)
O
CN O
a
o
b
c
Entry
T ( C)
Additive (R)
H
Yield (%)
82
ee (%)
50
30
45
10
62
49
37
72
82
77
21
16
24
44
34
90
90
35
75
84
39
69
62
40
o
Solvent, T ( C)
1
2
3
4
5
6
7
8
9
0
0
1
a
2a
2,4-tert-Bu
2,6-tert-Bu
p-tert-Bu
o-tert-Bu
78
N
0
75
N
0
86
OH
OH
OH
OH
OH
OH
OH
OH
0
77
0
m-NH
2
71
0
p-Me
83
(
R)-BINOL
(S)-BINOL
2% yield, -11% ee
L1 (Py-BINMOL)
L2
68% yield, 38% ee
8
1% yield, 21% ee
9
81% yield, 48% ee
0
m-OMe
84
R
0
p-NO
2
83
1
0
1
0
m-OH
86
R
d
1
0
o-tert-Bu
76
NH
H
OH
OH
TMS
d
OH
OH
OH
OH
N
12
0
m-OH
77
H
Ar-BINMOLs
L3 (R = H)
L4 (R = OMe)
d
2
1
3
0
p-NO
77
PPh2
d
14
0
(R)-BINOL
81
L5 (Tao-Phos)
L6 (BBAA)
L7
52% yield, 0% ee
d
L3: 72% yield, 25% ee
L4: 91% yield, 0% ee
1
1
5
6
0
(S)-BINOL
p-NO
88
40% yield, 15% ee
71% yield, 0% ee
-5
-5
-5
-10
-10
-10
0
2
89
Scheme 1. Catalytic asymmetric conjugate hydrocyanation of chalcone with TMSCN
17
(R)-BINOL
(S)-BINOL
88
1
1
2
2
2
2
2
8
9
0
1
2
3
4
91
p-NO
2
70
Subsequently, it was found that the enantioselectivity could be
improved to 50%ee in the presence of phenol (Table 1, entry 1),
which suggested the positive activation of phenolic additive in this
reaction. As a result, further investigation on the effect of various
phenols on the enantioselectivity of catalytic asymmetric conjugate
hydrocyanation of chalcone with TMSCN was carried out. As shown
in Table 1, the effect of phenolic additives on the enantioselectivity
of hydrocyanation reaction is quite obvious, and phenols bearing
electron-deficient groups exhibited enhanced enantioselectivity
(R)-BINOL
(S)-BINOL
MeOH
77
87
88
0
EtOH
71
0
CF
3
CH
2
OH
56
a
Note: Reaction conditions: 20 mol% of MgBu
2
, 20 mol% of ligand (L1),
b
chalcone 1a (0.25 mmol), TMSCN (2 eq.), and additive (1.5 eq.). Isolated yields.
The ee value or e.r. was determined by chiral HPLC. 20 mol% of additive was
used in this case.
c
d
(
Entries 8-10). Notably, L1 promoted the enantioselective Mg-
catalyzed conjugate addition of cyanide to chalcone 1a, giving rise
to enantioenriched -cyano ketone 2a in good enantioselectivity
(
Entry 9, 83% yield and 82% ee) in the presence of para-nitrophenol.
However, the use of alcohols, ortho-substituted phenols, and
methyl-, tert-butyl, amino-substituted phenols, as additives,
resulted in decreased enantioselectivity in the Py-BINMOL-Mg
complex -promoted conjugate hydrocyanation (Entries 2-4, 6, 7,
and 22-24). In addition, 20 mol% of phenol additives gave poor
enantioselective induction (Entries 11-14). Also interestingly, the
use of chiral binaphthol {(R)-BINOL or (S)-BINOL} as an additive
resulted into no enhancement of enantioselectivity in comparison
to that of para-nitrophenol (Entries 15, 16, and 19). Unexpectedly,
the (S)-BINOL gave strong negative effect on the catalytic
asymmetric conjugate addition of TMSCN to chalcone 1a, in which
the formation of BINOL-involved magnesium complex could be
CN
O
OH
2a
O2N
Figure 1. The effect of para-nitrophenol (PNP) on the catalytic asymmetric conjugate
responsible for the change of enantioselectivity. Further addition of cyanide to chalcone 1a.
2
| J. Name., 2012, 00, 1-3
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Ca Pt al el ya ss ies d So c ni eo nt ca ed j&u s Tt emc ah rng oi nl os gy
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On the basis of the above findings, we continued to investigate the possible supramolecular catalyst with unique functionViaelwitAyr.ticTlehuOsnlianes
effect of para-nitrophenol (PNP) on the catalytic asymmetric shown in Scheme 2, Py-BINMOL (L1) contaiDniOnIg: 1t0w.1o03d9i/fCfe5rCeYn0t10ty5p6eJ
conjugate addiction. The experimental results confirmed the use of of H-donors might result in dimer with unique functionality due to
PNP was the best choice for enantioselective conjugate the intramolecular hydrogen bonding interaction between alcohol
hydrocyanation in term of yield and enantioselectivity. As shown in and pyridine, which gave the dimeric magnesium complex (Ia) in
Figure 1, it implied that the use of 1.2 equivalents of PNP provided the presence of MgBu2.
higher enantioselectivity in this reaction (92% ee).
CN
O
R2
Table 2. Substrate scope of the catalytic asymmetric conjugate addition of cyanide to
chalcones
N
R1
N
MgBu2
O
2
OH
OH
O
Mg
TMSCN (2 eq.)
MgBu2 (20 mol%)
Py-BINMOL (20 mol%)
O
CN O
R2
R2
Ib
R1
R1
para-nitrophenol (1.2 eq.)
N
Et2O, -5 o
C
2
1
O
H
Si
Mg
Ar
O
Mg
H
O
Si
CN H O Ar'
CN
O
O
a
1
2
b
c
Entry
R
R
Yield (%)
2a: 89
2b: 71
2c: 81
2d: 70
2e: 84
2f: 72
ee (%)
N
Ar
1
2
3
4
5
6
7
8
9
H
H
H
4-F
4-F
H
92
45
72
64
79
70
80
51
79
59
56
82
58
79
82
50
(III)
(Ia)
O
H-O-Ar'
CN
Mg
Si
4-F
4-Cl
H
Ar
Ar
N
Si
CN
CN
4-Cl
4-Cl
4-Br
H
Si
Si
O
H
O
NC
O
H
Mg
O
4-Cl
4-Br
4-Me
N
2g: 77
2h: 67
2i: 90
Si CN
(
II)
4-CF
3
H
Scheme 2. Proposed mechanism for Py-BINMOL-Mg catalysed hydrocyanation
1
0
1
2
3
4
5
4-Ph
H
2j: 71
1
1
1
1
1
2-OMe
3-OMe
4-OMe
H
2k: 76
2l: 85
To gain the support for the characteristics of supramolecular dimers,
we made use of electrospray ionization mass spectrometry (ESI-
MS). In the cationic ESI-MS spectra of the mixture of Py-BINMOL
H
H
2m: 72
2n: 91
2o: 90
2p: 88
1
8
4-CF
3
4-F
4-Me
with MgBu , we “fished” the important intermediate signal for the
4-F
4-F
2
d
d
1
6
Pyridine
dimeric magnesium complex (Figure S1, see Supporting
Information), for intermediate Ia, m/z = 776.6 (the theoretical
molecular weight of Mg-Py-BINMOL, m/z = 776.2526). In addition,
a
Note: Reaction conditions: 20 mol% of MgBu
2
, 20 mol% of ligand (L1),
chalcone 1 (0.25 mmol), TMSCN (2 eq.), and para-nitrophenol (1.2 eq.), in
1
9
o
b
c
diethyl ether, at -5 C, for 12 hs. Isolated yields. The ee value was determined by the experimental result of the nonlinear study by variation of the
d
chiral HPLC. The enone is 3-(4-fluoro-phenyl)-1-pyridin-2-yl-propenone.
optical purity of the Py-BINMOL L1, graphically depicted in Table S2
and Figure S1 (See ESI) clearly demonstrated that no spectacular
NLE was presented. In this case, slight negative nonlinear effect can
be exhibited in the presence of Mg-Py-BIMNOL system, in which a
possible complex with one Mg-center is preferentially involved in
With the optimized conditions in hand, the substrate scope of the
Py-BINMOL-Mg for the synthesis of aromatic -cyano ketones 2 was
investigated. In general, various chalcones bearing electron-rich and
electron-deficient substituents exhibited good yields (up to 91%
yield) and moderate to good enantioselectivities (up to 92% ee). As
shown in Table 2, the presence of methyl, halide, methoxyl,
trifluoromethyl, and phenyl groups in the chalcones allowed the
the stereochemical rate-determining step of the stereoselective
,4-conjugate addition reaction. Notably, on the basis of DFT
17
1
20
calculation (Figure S5 and Figure S6 of ESI), the formation of
intermediate Ia was more possibly than that of intermediate Ib.
Therefore, we can conclude that the magnesium complex would be
probably generated from two molecules of chiral ligand L1 and
magnesium based on the experimental results. And then the
TMSCN could be activated by the para-nitrophenol and magnesium
complex. The proposed intermediate (II) is believed to involve the
hypervalent coordination between silicon and functional N,O-
1
,4-conugate addition of cyanide to the exclusive formation of
aromatic -cyano ketone in good yields. However, the
2
introduction of nitro-group on chalcones led to significant erosion
of yield or no reaction, which revealed the negative effect of nitro
group in the bifunctional Py-BINMOL-Mg complex -catalysed
conjugate addition of TMSCN to chalcones because of the
competing coordination of nitro and carbonyl group of enone
during the activation of substrate with catalyst.
21
group, in which it could be a vital factor in assisting the Si-C bond
cleavage (TMS-CN) with aid of para-nitrophenol. In fact, we also
observed a major peak at m/z = 920.5 (Figure S1, see ESI), which
could be identified as the silylated magnesium complex came from
On the basis of the experimental results, a plausible catalytic
activity for this conjugate addition is depicted in Scheme 2. Similarly
+
the cation [2Py-BINOL + Mg + 2TMS] (m/z = 920.3). Although other
17
to the previous report, we assumed that the chiral ligand, Py-
BINMOL, exhibited the strong non-covalent interaction similarly to
that of Ar-BINMOLs, leading to the existence of dimeric
supramolecular structure. The dimer of Py-BINMOL would act as a
oligomeric intermediates could still be probably effective in this
reaction, we suggested the activated model (III) derived from the
magnesium complex and substrate (chalcone) might be reasonable.
In this case, the dimeric Py-BINMOL-magnesium complex might
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7
8
a) N. Kurono, N. Nii, Y. Sakaguchi, M. Uemura, T. Ohkuma,
provide an asymmetric environment around the substrate to give a
promising enantioselectivity.
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2
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3
13
Py-BINMOL bearing both axial and sp -central chirality as chiral
ligand, in which the corresponding aromatic -cyano ketones were
obtained in moderate to good enantioselectivities (up to 92% ee)
and good yields (up to 91% yield). In comparison to previous work,
a noteworthy feature of the new catalyst system is the dual-mode
coordination in the possibly diverse supramolecular structure,
which enabled the transition-metal-free hydrocyanation to undergo
stereospecific addition by dual action of TMSCN and chalcone
respectively. Although the results were not perfect in term of
enantioselectivity, the new finding regarded to the multifunctional
ligand and main group element as catalyst is very useful for the
development of biomimetic catalysis and environmentally benign
process with non-toxic catalyst.
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7
Notes and references
2
‡
Footnotes relating to the main text should appear here. These
4
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
2
,
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Catalysis Science & Technology
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DOI: 10.1039/C5CY01056J
Graphical Abstract
Enantioselective Conjugate Addition of Cyanide to Chalcones
Catalyzed by Magnesium-Py-BINMOL Complex
Cheng Dong, Tao Song, Xing-Feng Bai, Yu-Ming Cui, Zheng Xu, and Li-Wen Xu*
TMSCN (1.2 eq.)
MgBu (20 mol%)
Py-BINMOL (20 mol%)
An efficient asymmetric conjugate addition of
trimethylsilyl cyanide (TMSCN) to chalcones,
catalyzed by bifunctional Py-BINMOL-Mg
complex, with moderate to good
O
CN
O
R2
2
R2
R1
R
1
nitrophenol (1.2 eq.)
Et
2
O, -5 oC, 12 h
up to 92% ee
up to 91% yield
N
Si
CN
enantioselectivities and good yields, has been
realized in this work.
Mg
Ar
OH
OH
Si
H
Ar'
CN
O
O
Ar
Py-BINMOL