Magnesium complexes as highly effective catalysts for conjugate cyanation of α,β-unsaturated amides and ketones

Article abstract of DOI:10.1002/chem.201304835

Asymmetric cyanation of trimethylsilyl cyanide (TMSCN) with α,β-unsaturated amides and ketones, respectively, catalyzed by bifunctional mononuclear 1,1-bi-2-naphthol (BINOL)-Mg and binuclear bis(prophenol)-Mg catalysts was realized. A series of synthetica

Full text of DOI:10.1002/chem.201304835

DOI: 10.1002/chem.201304835
Communication
&
Asymmetric Synthesis
Magnesium Complexes as Highly Effective Catalysts for Conjugate
Cyanation of a,b-Unsaturated Amides and Ketones
Jinlong Zhang, Xihong Liu, and Rui Wang*[a]
alcohols or phenol ligands, such as BINOL derivatives[8] and
Abstract: Asymmetric cyanation of trimethylsilyl cyanide
bis(prophenol) ligands[9] are used, magnesium base[10] can de-
(TMSCN) with a,b-unsaturated amides and ketones, re-
protonate the hydroxyl moiety of the ligand to form a rigid
spectively, catalyzed by bifunctional mononuclear 1,1’-bi-
chiral complex, in which the particularly low electronegativity
2-naphthol (BINOL)–Mg and binuclear bis(prophenol)–Mg
of the metal center usually results in stronger Brøsted basicity
catalysts was realized. A series of synthetically important
of the oxygen atoms. Both the Lewis acidity of the magnesium
1,4-cyano products were obtained with good to high
and Brøsted basicity of the oxygen atom are very important
enantioselectivities (up to 97% ee).
for the chemical activity and selectivity of the bifunctional
acid–base magnesium catalyst, which simultaneously activates
both a substrate and an acidic pronucleophile. Until now, only
The asymmetric conjugate cyanide addition is certainly one of
the most efficient and practical methods to afford optically
active b-cyano adducts, which can be readily converted into
important compounds, including g-aminobutyric acids (GABA
analogues) and 1,2-dicarboxylic acids.[1] As a result of the im-
portance of these enantioenriched derivatives, particularly in
biological and pharmaceutical chemistry, the asymmetric con-
jugate cyanation of a,b-unsaturated carbonyl compounds has
attracted much attention from biological and synthetic chem-
ists.[2] In 2003, Jacobsen and co-workers reported the first
chiral Salen–Al[3] catalytic system for the enantioselective con-
jugate cyanation between a,b-unsaturated imides and tri-
methylsilyl cyanide (TMSCN). Since then, a varied of elegant
works on those reactions have been disclosed. Generally
speaking, chiral organic–metal complexes involving Ti, Al, Gd,
and Sr,[4] phase-transfer catalysts,[5] or organocatalysts[6] have
been developed for this kind of reaction. It is undoubted that
further advances in practical methods are still desirable. In this
context, we are interested in the development of readily acces-
sible magnesium catalysts for catalyzing the 1,4-addition of tri-
methylsilyl cyanide in high enantioselectivity.
a few catalytic methods for the asymmetric phenol–Mg cataly-
sis have been developed and most of these reaction processes
are restricted to the additions of phosphorus nucleophiles,[8a]
a- or g-positions of carbonyl compounds[8b,c] to electrophilic
acceptors. The conjugate cyanation of a,b-unsaturated com-
pounds catalyzed by magnesium has never been reported. As
part of our ongoing work on the magnesium catalysis, we ex-
plored the viability of this method for the conjugate cyanation
reaction. Gratifyingly, the reaction proceeded smoothly to
afford the desired 1,4-cyano adducts with good to excellent re-
sults catalyzed by mononuclear catalyst La and dinuclear cata-
lyst Lb by using TMSCN as the cyanide source (Scheme 1).
The alkaline earth metal is among the most common ele-
ments on earth, and in contrast to the transition metals it is
vastly abundant and relatively nontoxic. However, applications
of these catalysts to catalyze chemical transformations, espe-
cially the asymmetric synthetic reactions, have been rarely re-
vealed. Thus, we turned our attention to the alkaline earth
metal magnesium as an easy to handle catalyst.[7] When chiral
Scheme 1. Asymmetric conjugate cyanation with mononuclear or dinuclear
magnesium salts.
The initial investigation began with the reaction between b-
phenyl-substituted pyrazole 1a and TMSCN in CH2Cl2 at room
temperature with a 20 mol% catalyst loading (Scheme 2). Al-
though chiral alcohol and phenol ligands have been widely
used in asymmetric catalysis, their application for chiral modifi-
cation of magnesium was less investigated. It should be noted
that these types of metal salts could be easily obtained, a diva-
lent magnesium center firmly bonded to both oxygen atoms,
forming an effective chiral acid–base catalyst. We examined
a series of phenol–Mg derivatives with 4 ꢀ molecular sieves in
the model reaction, and an excellent result in terms of both
[a] J. Zhang,+ X. Liu,+ Prof. R. Wang
Key Laboratory of Preclinical Study for New Drugs
of Gansu Province, School of Basic Medical Science and
Institute of Biochemistry and Molecular Biology School of Life Science
Lanzhou University, Lanzhou, 730000 (P. R. China)
E-mail: wangrui@lzu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304835.
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Table 2. Substrate scope for the asymmetric conjugate cyanation of a,b-
unsaturated amides.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
Ph (1a)
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
61
65
68
71
68
63
58
75
79
71
76
69
62
88
76
75
70
74
70
82
40
72
76
60
64
50
37
48
2-MeC6H4 (1b)
3-MeC6H4 (1c)
4-MeC6H4 (1d)
4-ClPhC6H4 (1e)
2,4-2ClC6H3 (1 f)
4-BrC6H4 (1g)
4-CF3C6H4 (1h)
4-CNC6H4 (1i)
4-MeOC6H4 (1j)
2-naphthyl (1k)
PhCH=CH (1l)
Me (1m)
9
10
11
12
13
14[e]
Scheme 2. Magnesium catalysts for the model reaction: The reactions were
carried out with 1a (0.1 mmol), TMSCN (0.3 mmol, 3.0 equiv) and L/Bu2Mg
(20 mol%) in 1.0 mL CH2Cl2 for 24 h. For La, La1–La6, and Lc, L/Bu2Mg=1:1;
for Lb and Lb1, L/Bu2Mg=1:2.
3-N-Methylindol (1n)
[a] Unless otherwise specified, the reaction was performed on 0.1 mmol
scale with (1.0 equiv), TMSCN (3.0 equiv), and catalyst La/Bu2Mg
the enantioselectivity and yield was observed under the cataly-
sis of catalyst La. Surprisingly, no cyanide adduct was detected
in the presence of protic additives, such as phenol, alcohol, or
water. Structural information of the substrate suggested that
the use of 3,5-dimethylpyrazole as an achiral auxiliary leads to
an interaction between the trimethylsilane and acetylpyrazole
group, and the chelating capacity was relatively weak to un-
dergo rapid catalyst exchange.
1
(20 mol%) in CH2Cl2 (1.0 mL) at 108C for 30 h. [b] Isolated yields. [c] De-
termined by HPLC analysis on a chiral stationary phase. [d] The absolute
configuration of 2a was determined to be R by comparison with litera-
ture data. For details, see the Supporting Information. [e] The reaction
time was 72 h.
ing decreased to 10 mol% or no molecular sieves were added,
low selectivity and yield were observed (entries 9–10).
On the basis of the experimental results, we then tried to
optimize the cyanation reaction with La/Mg by changing other
variables including temperature and solvent (Table 1). A signifi-
With the optimal reaction conditions as indicated in entry 3
of Table 1, we further examined the substrate scope (Table 2).
A series of a,b-unsaturated N-acylimides with either electron-
withdrawing or -donating groups on the aromatic ring were
proved to be amenable and gave the corresponding cyanide
adducts in high yields, and good to high enantioselectivities
(except for 2g, which was only obtained with 40% ee, 2a–k).
The use of diolefin substrate also afforded the product in 69%
yield and with 50% ee (entry 12, 2l). With aliphatic-substituted
substrates, the enantioselectivity decreased to 37% (entry 13,
2m). Because of the medicinal properties of many natural and
non-natural compounds that contain an indole backbone, an
indole heterocycle-substituted olefin was tested in this process
and the corresponding adduct was obtained in 92% yield, al-
though with 48% ee (entry 14, 2n). The pyrazole motif is
a good leaving group and these products can be easily con-
verted into carboxylic acid derivatives.
Table 1. Reaction condition optimization of the model reaction.[a]
Entry
Solvent
T [oC]
Additive
T [h][b]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et2O
toluene
CCl4
RT
30
10
0
10
10
10
10
10
10
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
–
24
24
30
>72
n.d.
>72
>72
48
66
52
76
80
n.d.
34
45
24
68
50
9[d]
10
CH2Cl2
CH2Cl2
>72
>72
[a] Unless otherwise specified, the reaction was performed on a 0.1 mmol
scale in 1.0 mL of the solvent with a 1a/TMSCN/L/Bu2Mg molar ratio of
1:3:0.2. [b] Determined by TLC analysis. [c] Determined by HPLC analysis
on a chiral stationary phase. [d] The reaction was performed at 10 mol%
catalyst loading.
Encouraged by the successful synthesis of cyanide adducts
of a,b-unsaturated N-acylimides catalyzed by mononuclear
BINOL–Mg complex as described above, we attempted to
extend the substrate scope of a,b-unsaturated amides to a,b-
unsaturated ketones. The model reaction was performed be-
tween chalcone 3a and TMSCN at the optimized reaction con-
ditions. Unfortunately, catalyst La was not a good choice be-
cause of the very poor catalytic activity and low stereoselectiv-
ity. The ESI-MS analysis suggested that a dimeric chiral com-
plex might exist as a mixture of La and TMSCN (1:5 molar ratio)
in CH2Cl2. We observed a peak at m/z: 743.42, which could be
cant influence of reaction temperature on the yield and enan-
tioselectivity was found. The reaction proceeded at 108C and
resulted in a higher enantioselectivity without an obvious sac-
rifice of reaction rate (Table 1, entries 1–4). Further screening of
the solvents revealed that CH2Cl2 appeared to be the most
suitable reaction media (entries 5–8). When the catalyst load-
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identified as [2BINOL–Mg+TMSCN+HCN+H]+. Although other
oligomeric candidates can still be considered, we proposed
that the presence of a,b-unsaturated amides could promote
the dissociation of dimeric complexes into highly active mono-
meric species under our reaction conditions. For the a,b-unsat-
urated N-acylimide with pyrazole as a achiral auxiliary,[11] ste-
reocontrol would be much more favorable as illustrated in
complex A (Figure 1).[12] While the rotatable monochelated
Table 3. Substrate scope for the asymmetric conjugate cyanation of a,b-
unsaturated ketones.[a]
Entry
R6, Ar1
Product
Yield[b] [%]
ee[c] [%]
1[d]
2
3
4
5
6
7
8
Ph, Ph (3a)
4a
4b
4c
4d
4e
4 f
4g
4h
4i
95
89
93
91
82
85
91
89
90
92
90
94
88
92
85
93
94
95
2-MeC6H4, Ph (3b)
4-MeC6H4, Ph (3c)
4-ClPhC6H4, Ph (3d)
2-BrC6H4, Ph (3e)
4-BrC6H4, Ph (3 f)
2-MeOC6H4, Ph (3g)
3-MeOC6H4, Ph (3h)
4-MeOC6H4, Ph (3i)
9
10
, Ph (3j)
4j
92
97
11
12
13
14
15
16
17
18
19
2-naphthyl, Ph (3k)
2-furanyl, Ph (3l)
PhCH=CH, Ph (3m)
Hex, Ph (3n)
Ph, 4-MeC6H4 (3o)
Ph, 2-ClC6H4 (3p)
Ph, 3-ClC6H4 (3q)
Ph, 4-ClC6H4 (3r)
Ph, 4-MeOC6H4 (3s)
4k
4l
83
79
75
85
93
84
87
90
92
94
88
79
82
95
77
89
90
94
Figure 1. Proposed complexes A and B.
4m
4n
4o
4p
4q
4r
bond between the ketones and catalyst generated in the cyan-
ation process might reduce the chemical enantioselectivity. In
this case, a dinuclear catalyst might theoretically provide an ef-
fective asymmetric environment around the two metal atoms
and the dual-mode coordination in complex B enabled the cy-
anation to undergo stereospecific addition.[13] To validate our
hypothesis, a bis(prophenol)–Mg catalyst was synthesized. To
our delight, compared to La, the catalyst Lb gave the 1,4-
adduct as the only detectable product with a much higher
enantioselectivity and moderate yield. Afterward, 2,6-di-tert-bu-
tylphenol was added as a protic additive and both yield and
enantioselectivity were dramatically enhanced (92% ee). Grati-
fyingly, the peak (m/z: 711.40) corresponding to [bis(prophe-
nol)–Mg+HCN+H]+ was observed by ESI-MS analysis of a mix-
ture between bis(prophenol)–Mg and TMSCN (1:5 molar ratio)
in THF, which led us to propose the hypothesis that the bis-
(prophenol)–Mg/CN complex was a more possible reaction in-
termediate. Thus, the combined use of catalyst Lb and protic
additive 2,6-di-tert-butylphenol worked in a highly effective
manner to give the cyanide addition products of a,b-unsatu-
rated ketones in THF at 308C (for details, see the Supporting
Information).
4s
[a] Unless otherwise specified, the reaction was performed on 0.1 mmol
scale with (1.0 equiv), TMSCN (2.0 equiv), 2,4-di-tert-butylphenol
3
(1.5 equiv), and catalyst Lb/Bu2Mg (20 mol%) in THF (1.0 mL) at 308C for
10 h. [b] Isolated yields. [c] Determined by HPLC analysis on a chiral sta-
tionary phase. [d] The absolute configuration of 2a was determined to be
R by comparison with literature data and the other products were as-
signed by analogy.
Table 4. Cyanation of chalcone 3a with TBDMSCN or HCN as cyanide
source.
Entry
Cyanide
Additive
Yield [mol%]
ee [%]
1[a]
2[a]
3[b]
TMSCN
TBDMSCN
HCN
dibutylphenol
dibutylphenol
–
95
64
93
92
93
92
Evaluation of the reaction scope revealed that high yield
and enantioinduction could be obtained for a range of enone
substrates with the dinuclear catalyst Lb. Various aromatic
enones possessing both electron-donating and -withdrawing
groups afforded the corresponding products in 70–97% yields
with enantiomeric excesses up to 97% ee (Table 3, 4a–s). In ad-
dition, b-heteroaromatic-substituted substrate was also tolerat-
ed and gave the desired product in high yield and ee value
(entry 12, 4l). It was worth noting that the b-aliphatic enone
was also applicable to the present catalytic system (entry 14,
4n).
[a] The reaction was performed on 0.1 mmol scale with 3a (1.0 equiv), cy-
anide (2.0 equiv), 2,4-di-tert-butylphenol (1.5 equiv), and catalyst Lb/
Bu2Mg (20 mol%) in THF (1.0 mL) at 308C for 10 h. [b] The HCN solution
was generated from equimolar amounts of TMSCN and MeOH at RT, and
the reaction proceeded without addition of 2,4-di-tert-butylphenol. The
product was isolated and the ee value was determined by HPLC analysis
on a chiral stationary phase.
to give 4a with high enantioselectivity from moderate to high
yield (Table 4, entries 2–3).
Next, we examined the cyanation of chalcone 3a with the
use of tert-butyldimethylsilanecarbonitrile (TBDMSCN) or HCN
as the cyanide source. To our delight, both cyanide com-
pounds were amenable and the reaction proceeded smoothly
Catalyst La could also be used in the conjugate addition of
trimethylsilylazide to b-methyl a,b-unsaturated N-acylimide,
providing the azide compound with 5% ee (Scheme 3).[14] The
synthetic utility of cyanation product 2a was demonstrated in
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in THF (0.2 mL), the resulting reaction mixture was stirred for 10 h
at 308C until the reaction was accomplished (monitored by TLC
analysis). The cyanide adducts 4 obtained by the following workup
as above.
Acknowledgements
Scheme 3. Conjugate addition of trimethylsilylazide to a,b-unsaturated
amide 1n.
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (Nos. 91213302 and 21272102), the
Key National S&T Program “Major New Drug Development” of
the Ministry of Science and Technology of China
(2012ZX09504001–003) and the Program for Changjiang Schol-
ars and Innovative Research Team in University (PCSIRT:
IRT1137).
Scheme 4. Transformation of 2a to pyrrolidin-2-one 2aa.
Keywords: asymmetric catalysis · cyanation · magnesium ·
synthetic methods · unsaturated ketones
the intramolecular cyclization to give product pyrrolidin-2-one
2aa as a useful building block (Scheme 4).[15]
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In summary, we have developed the asymmetric cyanation
of TMSCN with a,b-unsaturated carboxylic compounds cata-
lyzed by the bifunctional acid–base mononuclear BINOL–Mg
and dinuclear bis(prophenol)–Mg salts, respectively. A series of
synthetically important 1,4-cyano products were obtained with
good to high enantioselectivities (up to 97% ee). Several note-
worthy features of the magnesium catalyst include its vast
abundance and relative nontoxicity should render this enantio-
selective chemical transformation a potentially very valuable
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Experimental Section
Typical procedure for the cyanation of a,b-unsaturated
amides 1
Bu2Mg (0.5m in heptane, 40 mL, 0.02 mmol) was added to a stirred
solution of La (5.9 mg, 0.02 mmol) and well-dried 4 ꢀ molecular
sieves (20 mg) in CH2Cl2 (0.8 mL), under an argon atmosphere at
08C. The mixture was then stirred at 08C for 2 h to generate the
bifunctional La–Mg catalyst. After the addition of amides
1 (0.1 mmol) and TMSCN (3.0 equiv) in CH2Cl2 (0.2 mL), the result-
ing reaction mixture was stirred for 30 h at 108C until the reaction
was accomplished (monitored by TLC analysis). The reaction was
quenched by water and extracted with CH2Cl2 (10 mLꢂ3). The mix-
ture was washed by brine (10 mL) and dried over Na2SO4, and then
concentrated under vacuum. The crude product was purified by
silica gel column chromatography to give the desired product 2.
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Typical procedure for the cyanation of a,b-unsaturated ke-
tones 3
Bu2Mg (80 mL, 0.04 mmol) was added to a stirred solution of Lb
(12.8 mg, 0.02 mmol) and well-dried 4 ꢀ molecular sieves (20 mg)
in THF (0.8 mL) under an argon atmosphere at 08C. The mixture
was then stirred at 08C for 2 h to generate the bifunctional dinu-
clear Lb–Mg catalyst. After the addition of ketones 3 (0.1 mmol),
additive 2,4-di-tert-butylphenol (1.5 equiv) and TMSCN (2.0 equiv)
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Received: December 10, 2013
Revised: January 24, 2014
Published online on March 18, 2014
Chem. Eur. J. 2014, 20, 4911 – 4915
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