Enantioselective Cyanosilylation of α,α-Dialkoxy Ketones by Using Phosphine-Thiourea Dual-Reagent Catalysis

Article abstract of DOI:10.1002/ejoc.201800459

The first highly enantioselective cyanosilylation of α,α-dialkoxy ketones enabled by a dual-reagent catalysis has been developed. With the combination of a chiral bifunctional phosphine-thiourea and methyl acrylate, the key organophosphorus zwitterion intermediate was generated in situ as a novel Lewis base, which catalyzed the enantioselective cyanosilylation reaction in excellent yields (up to 99 %) with good-to-excellent enantioselectivities (up to 94 % ee).

Full text of DOI:10.1002/ejoc.201800459

A Journal of
Accepted Article
Title: Enantioselective Cyanosilylation of α,α-Dialkoxy Ketones
Catalyzed by Phosphine-Thiourea Dual-Reagent Catalysis
Authors: Qi-Wen Yu, Lu-Ping Wu, Tian-Chen Kang, Jin Xie, Feng Sha,
and Xin-Yan Wu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800459
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800459
Supported by

10.1002/ejoc.201800459
European Journal of Organic Chemistry
FULL PAPER
Enantioselective Cyanosilylation of α,α-Dialkoxy Ketones
Catalyzed by Phosphine-Thiourea Dual-Reagent Catalysis
Qi-Wen Yu, Lu-Ping Wu, Tian-Chen Kang, Jin Xie, Feng Sha, and Xin-Yan Wu*[a]
Abstract: The first highly enantioselective cyanosilylation of α,α-
dialkoxy ketones enabled by a dual-reagent catalysis has been
developed. With the combination of a chiral bifunctional phosphine-
thiourea and methyl acrylate, the key organophosphorus zwitterion
intermediate was generated in situ as a novel Lewis base, which
catalyzed the enantioselective cyanosilylation reaction in excellent
yields (up to 99%) with good-to-excellent enantioselectivities (up to
94% ee).
Figure 1. The activation mode of the dual-reagent catalysis
Introduction
works on cyanohydrin syntheses were generally carried out with
In the past two decades, chiral phosphine organocatalysis has
hydrogen cyanide as the cyanide source,[11] while the applications
emerged as a powerful strategy for the enantioselective synthesis
were limited due to its volatility and extreme toxicity. By far the
of various useful compounds.[1] Typically, the catalytic cycle is
most universal cyanide source, however, is trimethylsilyl cyanide
initiated by the addition of a phosphine as the Lewis base to an
(TMSCN).[12] In recent years, a couple of chiral organocatalysts
activated alkene/allene reactant, and then the resulting
have been explored for the asymmetric cyanation reactions of
intermediate reacts with activated electrophilic partners.[2] This
aldehydes, ketones and imines, with TMSCN as the cyanide
category includes (aza)-Morita-Baylis-Hillman reactions,[3]
source. The catalytic systems involve chiral oxazaborolidinium
Rauhut-Currier reactions,[4] phosphine-catalyzed annulation
ions,[13] cinchona-derived organic chiral Lewis bases,[14]
reactions[5] and other reactions.[6] However, the catalytic mode is
bifunctional tertiary amines,[15] N,N’-dioxide compounds,[16]
limited to the reactions involving electron-deficient alkenes,
allenes or alkynes. Recently, Lu[7a] and Zhao[8] developed an in
sulfonamides,[17] amino acid salts,[18] dual-reagent catalysts[10]
and so on.[19] In spite of these achievement, asymmetric cyanation
situ generated phosphonium resulted from
a bifunctional
of ketones are very limited.[14a,15a,16b,18] To the best of our
knowledge, metal-free chiral phosphine-catalyzed cyanosilylation
of carbonyl compounds is still vacant.[20] In 2010, Tian and co-
phosphine and an acrylate. This so-called “asymmetric dual-
reagent catalysis” mode has been successfully applied to the
asymmetric conjugate addition,[7] Mannich-type reactions,[9] and
Strecker reactions.[10] In this strategy, a catalytic amount of an
activated alkene was cooperated with the chiral phosphine, which
formed the key zwitterion as an in situ generated chiral Brønsted
base (pathway A, Figure 1) or chiral Lewis base (pathway B,
Figure 1) during the enantioselective reactions.
Catalytic asymmetric cyanation of prochiral compounds could
afford versatile building blocks for pharmaceuticals,
agrochemicals and specialty materials, providing an immense
opportunity for the synthesis of various chiral compounds.[11] Early
workers[21] reported
a
racemic dual-reagent catalyzed
cyanosilylation of carbonyl compounds, using triphenylphosphine
and methyl acrylate as an efficient nucleophilic catalyst.
Encouraged by Tian’s report and with our continuing interest in
enantioselective phosphine catalysis, herein, we report an
asymmetric cyanosilylation reaction between TMSCN and α,α-
dialkoxy ketones with a dual-reagent catalysis system, which
consists of a chiral phosphine-thiourea organocatalyst and methyl
acrylate.
Results and Discussion
Initially, the enantioselective cyanosilylation reaction between
TMSCN and acetophenone 1a was selected as the model
reaction. The reactions were performed with different bifunctional
organophosphine catalysts (Figure 2) in CH2Cl2 at -30 oC, and the
results were summarized in Table 1. Firstly, the chiral
cyclohexane-based bifunctional phosphines with different
Brønsted acid group were investigated.[22] The results indicated
that the H-bonding donator in the bifunctional phosphines affected
the enantioselective reaction, and thiourea catalyst C4 provided
[a]
Q.-W. Yu, L.-P. Wu, T.-C. Kang, J. Xie, Prof. Dr. F. Sha, Prof. Dr. X.-
Y. Wu
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals
School of Chemistry & Molecular Engineering
East China University of Science and Technology
Shanghai 200237 (P. R. China)
E-mail: xinyanwu@ecust.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800459
European Journal of Organic Chemistry
FULL PAPER
better yield and enantioselectivity than squaramide C1, amide C2
and C3 (entries 1-4). To improve the stereoselectivity, variant
phosphine-thioureas were evaluated. In general, the phosphine-
thioureas containing aromatic scaffolds provided higher
enantioselectivities than the aliphatic analogues (entry 4-11). The
highest enantioselectivity was obtained using chiral catalyst C7
(62% ee, entry 7).
4, Table 1). Incorporation of a carbohydrate motif to the chiral
thiourea catalysts might improve the enantioselectivity.[24] As
predicted, the stereoselectivity of the cyanosilylation reaction was
controlled by the chiral cyclohexane backbone, and gratifyingly,
78% ee enantioselectivity was achieved with catalyst C15 (entries
12-17). These results indicated the (S,S)-configuration of 2-
amino-1-(diphenylphosphino)cyclohexane matched well with β-D-
galactose to enhance the stereochemical control.
Table 1. Screening of the chiral bifunctional phosphine organocatalysts[a]
Entry
Catalyst
Time (h)
Yield (%)[b]
Ee (%)[c]
1
C1
3
1
1
1
3
1
1
1
1
1
1
1
1
1
1
1
1
96
90
87
99
88
99
99
98
92
97
89
97
99
90
99
94
96
4
2
C2
7
3
C3
8
4
C4
46
48
55
62
59
59
54
53
33
-72
3
5
C5
6
C6
7
C7
8
C8
9
C9
10
11
12
13
14
15
16
17
C10
C11
C12
C13
C14
C15
C16
C17
Figure 2. Structure of the chiral phosphines screened.
Subsequently, the optimization of reaction conditions was carried
out with chiral phosphine C15 (Table 2). In all the solvents
examined except Et2O, product 2a was obtained in excellent
yields (entry 1-7). Only a trace amount of product was detected
with Et2O as the solvent, probably due to the poor solubility of
catalyst C15 in Et2O (entry 4). Compared with other solvents,
MTBE turns out to be the most suitable one, which afforded
product 2a in the highest yield and enantioselectivity (1.5 h, 97%
yield and 81% ee, entry 5). In the absence of methyl acrylate, no
product was detected. The result strongly supported our
hypothesis that the zwitterion generated in situ acted as the “real”
catalyst for the enantioselective cyanosilylation reaction (entry 8).
The enantioselectivity could not be improved using other
acrylates, such as phenyl acrylate and butyl acrylate (entry 9-10)[8].
Lowering the reaction temperature to -78 oC enhanced the
enantioselectivity significantly to give a 91% ee, in spite of a
slightly lower yield of 92% and a prolonged reaction time of 24 h
(entry 12). Furthermore, reducing the catalyst loading from 10
mol% to 5 mol% led to a loss of yield and enantioselectivity (entry
-78
60
-54
[a] The reactions were performed with TMSCN (0.2 mmol), ketone 1a (0.1
mmol), Catalyst (0.01 mmol) and methyl acrylate (0.01 mmol) in CH2Cl2 (0.5
mL). [b] Isolated yields. [c] The ee values were determined by HPLC using
a
Chiralpak AD-H column. The absolute configurations of 2a were
determined by comparison of the optical rotation values reported.[14a]
In our previous work on Morita-Baylis-Hillman reaction, the
phosphine-thiourea with an additional chiral group could enhance
the enantioselectivity, and there was a chirality match between
the chiral backbone and the additional chiral group.[23] The same
effects were observed when the diastereomer C5 and C6 were
used as catalyst for the model reaction (entries 5 and 6 vs entry
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10.1002/ejoc.201800459
European Journal of Organic Chemistry
FULL PAPER
13 vs entry 12). Therefore, the optimal reaction conditions have
been identified as follows: α,α-dialkoxy ketone 1 and TMSCN in
MTBE (0.1 M) at -78 oC, with 10 mol% of galactose-based
phosphine-thiourea C15 and 10 mol% methyl acrylate as the
chiral catalyst.
Table 3. Substrate scope of the acetal ketones [a]
Entry
Ar1
Temp
(oC)
Time
(h)
Yield (%)[b]
Ee
(%)[c]
Table 2. Optimization of the reaction conditions[a]
1
4-ClC6H4
C6H5
-78
-78
-60
-60
-78
-60
-60
-50
-50
-78
-78
-78
-60
-50
-60
-60
-50
20
20
16
6
2a, 89
2b, 89
2c, 96
2d, 99
2e, 92
2f, 89
2g, 80
2h, 88
2i, 95
91
92
88
87
75
88
79
86
87
94
88
85
91
83
88
90
66
2
3
4-FC6H4
Entry
R
Solvent
Temp
(oC)
Time
(h)
Yield
(%)[b]
Ee
(%)[c]
4
4-BrC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-MeC6H4
3-NO2C6H4
3-ClC6H4
2-FC6H4
1
Me
Me
Me
Me
Me
Me
Me
-
Toluene
CH2Cl2
CHCl3
Et2O
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-60
-78
-78
1
82
75
78
79
nd[d]
81
76
71
nd
79
80
88
91
86
5
16
20
48
12
12
20
24
24
24
24
24
48
72
2
1
99
6
3
1
90
7
4
120
1.5
2
trace
97
8
5
MTBE
THF
9
6
86
10
11
12
13
14
15
16
17
2j, 86
7
CH3CN
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
1
95
2k, 93
2l, 97
8[e]
9
120
6
trace
94
2-ClC6H4
2-MeC6H4
2,4-Me2C6H3
3,5-Cl2C6H3
2-naphthyl
2-furyl
t-Bu
Ph
Me
Me
Me
2m, 92
2n, 86
2o, 81
2p, 88
2q, 98
10
11
12
13[f]
1.5
6.5
24
24
97
96
92
87
[a] Unless stated otherwise, the reactions were performed with TMSCN (0.2
mmol), ketone 1a (0.1 mmol), catalyst C15 (0.01 mmol) and acrylate (0.01
mmol) in solvent (0.5 mL). [b] Isolated yields. [c] The ee values were
determined by HPLC using a Chiralpak AD-H column. [d] Referred to not
detected. [e] In the absence of methyl acrylates. [f] Using 5 mol% (0.005
mmol) C15 and methyl acrylate.
[a] The reactions were performed with TMSCN (0.2 mmol), ketone 1 (0.1
mmol), catalyst C15 (0.01 mmol) and methyl acrylate (0.01 mmol) in MTBE
(0.5 mL). [b] Isolated yields. [c] The ee values were determined by chiral
HPLC analysis.
Alkyl acetal ketones were also tolerated for the cyanosilylation
reaction (Scheme 1). Notably, compound 4a was achieved in 91%
ee with 20 mol% C15 and methyl acrylate, which could be
converted to analogues of the Bisorbicillinoids.[25] According to the
optical rotation values reported[14a], the absolute configuration of
product 4b was assigned as S-configuration.
Under the established optimal reaction conditions, the substrate
scope of the cyanosilylation reaction was investigated (Table 3).
In general, the catalytic system showed excellent efficiency for all
the substrates examined, providing good-to-excellent yields and
high enantioselectivities. However, the acetal ketones with a
strong electron-withdrawing group such as 4-NO2, as well as the
heterocyclic ketones exhibited relatively low enantioselectivity
(entries 5 and 17), probably due to a hydrogen-bond interaction
with the chiral catalyst. A certain number of acetal ketones were
inert under the gelid temperature of -78 oC, and therefore the
reaction temperature was raised to -60 oC or -50 oC (entries 3, 4,
6-9 and 13-17).
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10.1002/ejoc.201800459
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To demonstrate the practical application of this methodology, a
gram-scale synthesis of product 6c was performed (Scheme 3).
The desired product was achieved in 1.78 grams with excellent
yield and enantioselectivity (91% yield, 92% ee).
To study the mechanism of the dual-reagent catalytic system, 31
P
NMR spectroscopy was used to explore the reaction process
(Figure 3). The catalyst C15 alone showed a 31P resonance signal
at -8.94 ppm. No change was observed when TMSCN was mixed
with catalyst C15 in 1:1 mole ratio. When compound C15 was
mixed with methyl acrylate in a mole ratio of 1:1, a new chemical
shift of the in situ generated zwitterion appeared at 35.81 ppm.
Moreover, in a mixture of catalyst C15, TMSCN and methyl
acrylate (1:1:1 mole ratio), another new chemical shift was
observed at 48.19 ppm, which suggested the efficient interaction
between TMSCN and the zwitterion intermediate. The result also
revealed the in situ generated zwitterion was the active species
for the catalytic reaction..
Scheme 1. The enantioselective cyanosilylation reaction between TMSCN and
alkyl acetal ketones 3
When α,β-unsaturated acetal ketone 5a was used as substrate
under the typical reaction conditions mentioned above, only 44%
ee was obtained, which suggested that phosphine-thiourea C15
might not be a suitable catalyst for the cyanosilylation of substrate
5a. After screening a series of chiral bifunctional phosphine
catalysts, compound C12 was proved to be the optimal one for
the enantioselective cyanosilylation reaction between TMSCN
and α,β-unsaturated ketones (See Table S1 and S2 in the
Supporting Information). Generally, the enantioselective
cyanosilylation reaction of α,β-unsaturated acetal ketones and
TMSCN proceeded with high 1,2-regioselectivity to afford the
corresponding products 6a-6e in high yields and good
enantioselectivities (Scheme 2).
Scheme 2. The enantioselective cyanosilylation reaction between TMSCN and
α,β-unsaturated acetal ketones 5.
Figure 3. a) 31P NMR spectrum of catalyst C15 in CDCl3. b) 31P NMR spectrum
of C15 and TMSCN in CDCl3. c) 31P NMR spectrum of C15 and methyl acrylate
in CDCl3 d) 31P NMR spectrum of C15, methyl acrylate and TMSCN in CDCl3.
Conclusions
Scheme 3. Gram scale reaction between TMSCN and ketone 5c
In conclusion, we have developed an efficient dual-reagent
catalyst system for the enantioselective cyanosilylation reaction
of α,α-dialkoxy ketones. In the presence of bifunctional
phosphine-thiourea C12 or C15 with methyl acrylate, the
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10.1002/ejoc.201800459
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Further studies on enantioselective organophosphine catalysis
and other potential applications of the dual-reagent catalytic
system are currently underway in our group.
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Experimental Section
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of
Shanghai
Municipality
(15ZR1409200).
Keywords: asymmetric catalysis • organocatalysis • dual-
reagent catalysis • chiral phosphine • cyanosilylation reaction
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Entry for the Table of Contents
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Qi-Wen Yu, Lu-Ping Wu, Tian-Chen
Kang, Jin Xie, Feng Sha, and Xin-Yan
Wu*
Chem. Eur. J. Year, Volume, Page No. –
Page No.
Enantioselective Cyanosilylation of α,α-
Dialkoxy Ketones Catalyzed by
Phosphine-Thiourea Dual-Reagent
Catalysis
An organophosphine-catalyzed enantioselective cyanosilylation of carbonyl
compounds has been disclosed for the first time. This process, the dual-reagent
catalysis serves as a powerful tool, affording the desired cyanohydrin trimethylsilyl
ethers in excellent yields (up to 99%) and good-to-excellent enantioselectivities (up
to 94% ee).
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