Enantioselective cyanosilylation of ketones catalyzed by a nitrogen-containing bifunctional catalyst

Article abstract of DOI:10.1002/adsc.200505418

An efficient and optically active, bifunctional tetraaza ligand (2S)-N-{(1R,2R)-2-[(S)-pyrrolidine-2-carboxamido]-1,2-diphenylethyl} pyrrolidine-2-carboxamide has been developed for the addition of trimethylsilyl cyanide (TMSCN) to ketones. The bifunctional catalyst system based on a monometallic titanium complex was found to be a highly enantioselective catalyst to provide O-TMS cyanohydrins with up to 94% ee. A possible transition state has been proposed to explain the origin of the activation and asymmetric inductivity.

Full text of DOI:10.1002/adsc.200505418

FULL PAPERS
DOI: 10.1002/adsc.200505418
Enantioselective Cyanosilylation of Ketones Catalyzed by a
Nitrogen-Containing Bifunctional Catalyst
Yan Xiong,a Xiao Huang,a Shaohua Gou,a Jinglun Huang,a Yuehong Wen,a
Xiaoming Fenga, b,*
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Peopleꢀs Republic of
b
China, Fax: þ86-28-8541-8249, e-mail: xmfeng@scu.edu.cn
Received: October 24, 2005; Accepted: December 30, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient and optically active, bifunction- catalyst to provide O-TMS cyanohydrins with up to
al tetraaza ligand (2S)-N-{(1R,2R)-2-[(S)-pyrrolidine- 94% ee. A possible transition state has been proposed
2-carboxamido]-1,2-diphenylethyl}pyrrolidine-2-car-
to explain the origin of the activation and asymmetric
boxamide has been developed for the addition of tri- inductivity.
methylsilyl cyanide (TMSCN) to ketones. The bifunc-
tional catalyst system based on a monometallic titani- Keywords: amides; bifunctional catalysts; cyanosilyla-
um complex was found to be a highly enantioselective tion; hypervalent silicon; ketones; titanium
Introduction
natural glucose as the chiral scaffolds. Particularly, the
catalysts with a phosphine oxide moiety were very effi-
The addition of TMSCN to ketones is one of the most cient for the asymmetric cyanosilylation of aldehydes,[5]
popular strategies to afford versatile cyanohydrin trime- imines,[6] and ketones,[3b,c] as well as the addition of cya-
[1,2]
thylsilyl ether intermediates in organicsynthesis,
nide to quinoline or isoquinoline derivatives.[7] Other ni-
which can be conveniently converted into various im- trogen-containing bifunctional catalysts (A and B) have
portant polyfunctionalized building blocks, including also been discovered (Figure 1),[8] which could be used
a-hydroxy carbonyl compounds and b-amino alcohols for the efficient enantioselective cyanosilylation of alde-
for the synthesis of many natural products and bioactive hydes by basicamines simultaneously aticvating
molecules.[2a] In recent years, avarietyofLewis acids and TMSCN. Recently we reported that chiral N-oxides
Lewis bases have been employed successfully as pro- can effectively catalyze the asymmetric cyanosilylation
moters in the cyanosilylation of carbonyl compounds of imines[9] and aldehydes[10] by activating TMSCN and
and significant advances in this area have been made.[3] chiral N-oxide titanium complexes can also effectively
As methodologies for promoting the catalytic cyanosily- and dually catalyze the cyanosilylation of ketones.[3e,f,g,i]
lation of ketones, Snapper and Hoveydaꢀs peptide-Al
catalysis,[3d] Jacobsenꢀs thiourea catalysis,[3n] and Fengꢀs
double-activation and amino acid salt catalysis[3j,o] pro-
vided particular and efficient synthetic strategies for
the construction of chiral quaternary carbon centers.
In searching for new methodology, a lot of chiral bi-
functional catalysts that tried to imitate natural enzy-
maticprocesses have been designed in asymmetricsyn-
thesis.[4] At least, these catalysts must contain an acid
center and a basic functional group capable of simulta-
neously binding a basic substrate and an acidic reactant
in a proper manner. Shibasaki et al. have reported a ser-
ies of bifunctional catalysts derived from BINOL and lysts.
Figure 1. Structures of nitrogen-containing bifunctional cata-
538
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Enantioselective Cyanosilylation of Ketones
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Inspired by this pioneering work and our early results lower yield (Table 1, entry 8). Thus Ti(O-i-Pr)4 was chos-
on asymmetric cyanosilylation using chiral bifunctional en to assess the following ligands.
catalysts and in order to developing new catalyst systems
The different diamine derivatives (1a–h and 2a–e)
for the addition of cyanide to ketones, we initiated a (Figure 2) were examined, with the results listed in Ta-
study to synthesize an efficient asymmetric amine-tita- ble 2. The data suggested that the face selectivities of re-
nium complex C, structurally similar to complex A and actions depended on the configuration of the chiral di-
B, as a bifunctional catalyst. It is well known that, com- amine moiety X, R, S of X corresponding to S and R of
pared to aldehydes, the lower reactivity and greater ster- products, respectively (Table 2, entries 1–6). The ligand
ichindrance of ketones delay the asymmetricsynthesis
containing a thiazolidine ring (2a) or substituted at the
of tertiary cyanohydrins.[11] Moreover, the bifunctional 4’- and 5’-positions of the pyrrolidine ring (2b) had a neg-
ligand 1a only required a two-step synthesis to give a ative effect on the ee value (Table 2, entries 9 and 10).
higher yield from commercially available materials. Ligands 2c, 2d and 2e which contain piperidine rings
Herein, we report its simple synthesis and its successful or primary amine gave poor enantioselectivities (Ta-
application in cyanohydrin synthesis.
ble 2, entries 11, 12 and 13). The ligand 1a containing a
simple pyrrolidine ring was beneficial to the enantiose-
lectivity (Table 2, entry 1).
Results and Discussion
Optimization of the Catalyst
Building on the understanding of chiral tetraaza ligands
in asymmetriccatalysis, [12] complexes of different metals
with 1a were used to catalyze the cyanosilylation of ace-
tophenone as the model reaction. The results are sum-
marized in Table 1. Ti(O-i-Pr)4 gave better enantioselec-
tive inductivity than other Lewis acids. Although YbCl3 ·
6 H2O exhibited excellent chemical efficiency, the enan-
tioselectivity was poor (Table 1, entry 2). Ti(O-n-Bu)4
could attain almost equal enantioselectivity but with
Table 1. Asymmetric cyanosilylation of acetophenone cata-
lyzed by Lewis acids.
Entry[a]
Lewis acids
t [h]
Yield [%][b]
74
(69)
92
48
41
Trace
33
–
ee [%][c]
1
Ti(O-i-Pr)4
60
51 (S)
(38)[d]
1 (S)
1 (S)
6 (S)
10 (S)
8 (S)
–
[d]
2
3
4
5
6
7
8
YbCl3 ·6 H2O
AlEt3
AlEt2Cl
Al(O-i-Pr)3
Zr(O-i-Pr)4
TiCl4
60
60
60
60
60
60
60
Ti(O-n-Bu)4
18
49 (S)
[a]
All reactions were carried out at 08C under the following
condition: 0.2 M acetophenone, 20 mol % 1a·indicated
metal complex, 1.5 equivs. TMSCN in CH2Cl2.
Isolated yield of O-TMS cyanohydrin was determined
after column chromatography on silica gel.
Determined by GC analysis on Chirasil DEX CB. The ab-
solute configuration was established as S by comparison of
the sign of the optical rotation value with that in the litera-
ture (ref.[3b]).
[b]
[c]
[d]
After the mixture of ligand 1a and Ti(O-i-Pr)4 in CH2Cl2
which had been stirred for 40 min at room temperature,
the solvent was not removed under vacuum.
Figure 2. Ligands evaluated in this study.
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539

Yan Xiong et al.
FULL PAPERS
Table 2. Effect of the ligand structure on the yield and enan-
tioselectivity.
transformation proceeded with comparable enantiose-
lectivities, but the reaction rate was higher in CH2Cl2
(Table 3, entries 4 and 8). The reactions in toluene and
under solvent-free conditions gave higher yields, but
the ee values were lower (Table 3, entries 1 and 5). No
reaction was observed in the protic solvent CH3OH (Ta-
ble 3, entry 6). Temperature clearly affected the enan-
tioselectivity. The optimum enantioselectivity of 80%
ee was obtained on decreasing the temperature from
20 to À458C (Table 3, entries 7–10). Further decreasing
the reaction temperature increased the enantioselectiv-
ity up to 90% ee, but the yield was greatly reduced (Ta-
ble 3, entry 16). The catalyst loading dramatically influ-
enced the enantioselectivity: 30 mol % of catalyst load-
ing was superior to lower loading in terms of catalyst ef-
ficiency (Table 3, entry 13 vs. 11 and 12). The further in-
creasing catalyst loading to 40 mol % gave lower ee
values (Table 3, entry 15). The practical level of catalyst
loading for this reaction was 30 mol %. The lower isolat-
ed yield could be overcome to some extent by prolong-
ing the reaction time and increasing the amount of
TMSCN and fortunately the enantioselectivity was re-
tained (Table 3, entry 14 vs. 13).
Entry[a]
Ligand
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
2e
60
60
60
60
60
60
60
60
60
60
60
60
60
74
46
81
74
34
47
26
61
9
23
25
32
27
51 (S)
30 (R)
50 (S)
49 (R)
16 (S)
33 (R)
30 (S)
6 (S)
19 (S)
35 (S)
17 (S)
31 (S)
21 (S)
[a]
All reactions were carried out at 08C under the following
condition: 0.2 M acetophenone, 20 mol % indicated li-
gand·Ti(O-i-Pr)4 complex, 1.5 equivs. TMSCN in CH2Cl2.
Isolated yield of O-TMS cyanohydrin was determined
after column chromatography on silica gel.
Determined by GC analysis on Chirasil DEX CB. The ab-
solute configuration was established as S by comparison of
the sign of the optical rotation value with that in the litera-
ture (ref.[3b]).
[b]
[c]
Substrate Generality
To obtain the optimal reaction conditions, solvent ef-
fect, reaction temperature and the catalyst loading were After establishing the optimal reaction conditions, we
studied, with the results summarized in Table 3. The use investigated a wide range of ketones. As depicted in Ta-
of polar solvents such as Et2O and THF reduced the ble 4, aromatic, bulky cyclic, heterocyclic, a,b-unsatu-
enantioselectivities (Table 3, entries 2 and 3). In moder- rated and aliphatic ketones were converted into the cor-
ately polar solvents, CH2Cl2 and CH2ClCH2Cl, this responding O-TMS ethers of cyanohydrins with up to
Table 3. Asymmetric cyanosilylation of acetophenone catalyzed by 1a·Ti(O-i-Pr)4 complex under various conditions.
Entry
Solvent
T [ 8C]
t [h]
TMSCN
[equivs.]
Concentration of
acetophenone
[mol/L]
Catalyst
loading
[mol %]
Yield
[%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
None
Et2O
THF
0
0
0
0
0
0
20
0
À20
À45
À45
À45
À45
À45
À45
À78
60
60
60
60
60
60
60
60
60
60
60
60
60
100
60
60
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.5
2.5
1.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
2.0
2.0
2.0
2.0
2.0
0.2
20
20
20
20
20
20
20
20
20
20
10
20
30
30
40
20
86
46
65
65
78
–
59
74
50
45
15
62
56
77
48
9
31 (S)
12 (R)
19 (S)
48 (S)
37 (S)
–
12 (S)
51 (S)
68 (S)
80 (S)
81 (S)
82 (S)
92 (S)
92 (S)
76 (S)
90 (S)
CH2ClCH2Cl
toluene
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[a]
Isolated yield of O-TMS cyanohydrin was determined after column chromatography on silica gel.
[b]
Determined by GC analysis on Chirasil DEX CB. The absolute configuration was established as S by comparison of the sign
of the optical rotation value with that in the literature (ref.[3b]).
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Enantioselective Cyanosilylation of Ketones
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Table 4. Enantioselectivity cyanosilylation of ketones catalyzed by 1a·Ti(O-i-Pr)4 complex.
Entry[a]
Ketone
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Acetophenone
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
77
60
48
72
66
63
82
90
61
87
56
65
89
84
92[d]
90
4’-Methylacetophenone
4’-Methoxyacetophenone
b-Acetonaphthone
1-Indanone
94[e]
88[f]
92
a-Tetralone
87
74
61
83
4’-Chloroacetophenone
3’-Chloroacetophenone
4’-Fluoroacetophenone
3’-Fluoroacetophenone
2-Acetylthiophene
trans-4-Phenyl-3-buten-2-one
2-Heptanone
66
88
64[g]
51[d]
51
Benzylacetone
[a]
Conditions: 1a·Ti(O-i-Pr)4 complex (1: 1, 30 mol %), 100 h, TMSCN (2.5 equivs.), À458C, [ketone]¼2.0 M in CH2Cl2.
Isolated yield of O-TMS cyanohydrin was determined after column chromatography on silica gel.
Determined by GC analysis on Chirasil DEX CB.
[b]
[c]
[d]
[e]
[f]
The absolute configurations were established as S by comparison the reported value of optical rotation (ref.[3b]).
The absolute configuration was established as S by comparison with the reported value of optical rotation (ref.[3 m]).
Determined by HPLC analysis on Chiralpak OJ.
[g]
Determined by HPLC analysis on Chiralpak OD.
90% yield and up to 94% ee. Introducing electron-do- here that in the presence of an equivalent amount of ti-
nating groups on the para-position of acetophenone tanium tetraisopropoxide two nitrogen atoms on amide
À
led to lower yields but similar enantioselectivities to ace- groups probably formed N Ti bonds with Ti(O-i-Pr)4.
tophenone (Table 4, entries 2 and 3). Aromaticand ster-
Thus, a possible dual activation mechanism was pro-
ic cyclic ketones such as b-acetonaphthone, 1-indanone posed (Figure 4), in which the acidic titanium activated
and a-tetralone afforded moderate yields and excellent the ketone as a Lewis acid and the basic nitrogen atom of
enantioselectivities (Table 4, entries 4–6). The chloro- one of the pyrrolidinyl groups activated TMSCN as a
substituted ketones gave higher yields and moderate Lewis base, respectively. Hypervalent silicon,[14] formed
enantioselectivities, and the fluoro-substituted ones from an interaction between the amine group and
also provided moderate ee values (Table 4, entries 7– TMSCN, was assumed to be an active cyanation inter-
10). The reaction of 1-(thiophen-2-yl)ethanone pro- mediate which readily reacts with acetophenone to pro-
ceeded in moderate yield and high enantioselectivity duce 4a since the nucleophilicity of the cyano group was
(Table 4, entry 11). The a,b-unsaturated ketone gave enhanced by the electron donation from the hypervalent
the corresponding product with moderate chemical silicon.
yield and ee value (Table 4, entry 12). The aliphaticke-
On the basis of the observed absolute configuration of
tones provided relatively low enantioselectivities with 2-phenyl-2-trimethylsilanyloxypropionitrile (Table 4,
good yields (Table 4, entries 13 and 14). Of practical entry 1), we proposed a possible asymmetricinductivity
relevance, the chiral ligand 1a could be partly recovered pathway including transition state 5. In transition state 5,
in 62% yield, after column chromatography to give O- the Re face of the carbonyl of acetophenone is much
TMS cyanohydrins, by simple aqueous acid/base work-
up on silica gel and reused (see Experimental Section).
Mechanism
Because of the similarity between 1a and the N,N’-
[(1R,2R)-cyclohexane-1,2-diyl]bis(trifluoromethane-
Figure 3. The complex of N,N’-[(1R,2R)-cyclohexane-1,2-
sulfonamide) reported[13] (see Figure 3) we considered diyl]bis(trifluoromethanesulfonamide) and Ti(O-i-Pr)4.
Adv. Synth. Catal. 2006, 348, 538 – 544
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Yan Xiong et al.
FULL PAPERS
step synthesis to give an excellent yield and its starting
materials are commercially available. Using the bifunc-
tional catalyst 1a·Ti(O-i-Pr)4 complex, we have carried
out a logical development process to obtain a highly
enantioselective cyanosilylation of ketones with up to
94% ee. This contribution should provide a simple and
practical synthetic strategy for the construction of chiral
quaternary carbon centers. Further efforts should be de-
voted to the optimization of the catalyst to enhance
enantioselectivity and reactivity, and clarify the mecha-
nism of this reaction.
Experimental Section
General Remarks
NMR data were obtained for 1H at 300, 400 and 600 MHz, and
for 13C at 75 and 100 MHz. Chemical shifts are reported in ppm
from tetramethylsilane with the solvent resonance as the inter-
nal standard in CDCl3 solution. Data are reported as follows:
chemical shift (d), multiplicity (s¼singlet, d¼doublet, t¼trip-
let, m¼multiplet), coupling constants (J) in Hz, integration
and assignment. HR-MS were recorded on a Bruker Apex-2.
In each case, enantiomer ratios were determined by chiral
GC analysis or chiral HPLC analysis on Chiralcel OD or OJ
in comparison with authentic racemates. Optical rotation
data were examined in CH2Cl2 solutions. Amino acids and di-
amines obtained from commercial sources were used directly
without further purification. All ketones, TMSCN, Ti(O-i-
Pr)4 and solvents were purified by usual methods.
Figure 4. The proposed working model.
more accessible to a nucleophilic group CN than the Si
face since the interaction of the Si face and the attacking
group CN will strongly increase the repulsion between
phenyl subunits as in transition state 6. S-Proline is
also vital to enantioselective inductivity, which causes
a fit concave to define the position of the coordinated
ketone at the Re face syn to the Lewis basicamine group
of pyrrolidine. The activated nucleophile will attack the
Preparation of Tetraaza Ligands
¼
highly polarized C O of acetophenone at the carbon
atom from a less stereohindered direction (Re) to give
the S-configuration product.
The ligands 1a–h and 2a–e listed in Figure 2 were prepared ac-
cording to similar procedures (Scheme 1).
Meanwhile, preliminary studies in which the 1a·Ti(O-
i-Pr)4 complex showed relatively low enantioselectivi-
ties for aliphaticketones (Table 4, entries 13, 14) sug-
gested that the existence of a weak p-p stacking interac-
tion[15] between the aromaticketones and (1 R,2R)-1,2-
diphenylethane-1,2-diamine moiety should play a key
role in the transition state of cyanation. Taking advant-
age of the detailed studies on the hypervalent silicon in-
termediate, we found that transition state 6 is less favor-
able because of steric repulsion and low overlap of p-p
stacking resulting from the larger dihedral angle be-
tween the bulky phenyl groups. On the other hand, 5
avoids this repulsion and shows adequate p-p interac-
tion to eventually give (S)-4a
Scheme 1. The two-step synthesis of the ligand 1a.
Conclusion
[C24H30N4O2] (1a)
In summary, the new development here is that the bi-
functional catalyst used in this work is more easily acces-
(1) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxylic acid (430.5 mg, 2.0 mmol) in CH2Cl2, triethylamine
sible. The optimal ligand 1a only requires a simple two- (0.31 mL, 2.2 mmol) and isobutyl carbonochloridate (0.26 mL,
542
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Enantioselective Cyanosilylation of Ketones
FULL PAPERS
2.0 mmol) were added at 08C under stirring. After 15 min,
(1R,2R)-1,2-diphenylethane-1,2-diamine (212.3 mg, 1 mmol)
was added. The mixture was allowed to warm to room temper-
ature and stirred for 4 h. The mixture was washed with 1 M
KHSO4, saturated NaHCO3 and brine, dried over anhydrous
Na2SO4 and concentrated.
(2) To the residue in CH2Cl2, TFA (2.0 mL) was added and
stirring was continued for an hour. Then the solution was con-
centrated under vacuum to leave a glutinous phase to which
H2O (4 mL) was added. The pH of the mixture was brought
into the range of ~12 by the addition of 2 M NaOH. The aque-
ous phase was extracted with ethyl acetate. The ethyl acetate
extracts were pooled, washed with brine, dried over anhydrous
Na2SO4 and evaporated under vacuum. The residue was puri-
fied by flash chromatography using MeOH/EtOAc (1:2, v/v)
as eluent to afford (2S)-N-{(1R,2R)-2-[(S)-pyrrolidine-2-car-
boxamido]-1,2-diphenylethyl}pyrrolidine-2-carboxamide (1a)
as a white solid; yield: 374.0 mg (92%).
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Optically Active Cyanohydrin Trimethylsilyl Ethers 4;
Typical forthe Addition of TMSCN to Acetopheone
To a solution of 1a (24.4 mg, 0.06 mmol) in CH2Cl2 (0.6 mL)
was added Ti(O-i-Pr)4 (1 M in toluene, 60 mL, 0.06 mmol) at
room temperature under an N2 atmosphere. After the mixture
had been stirred for 40 min, the solvent was removed under
vacuum. This catalyst was then dissolved in CH2Cl2 (0.1 mL).
To this solution, acetophenone (24.2 mL, 0.2 mmol) was added
at À458C, followed by the addition of TMSCN (68.2 mL,
0.5 mmol). The reaction was monitored by TLC. After 100 h,
the mixture was concentrated and then purified by flash silica
gel chromatography using diethyl ether/petroleum ether
(1:100 v/v) as the eluent to obtain the corresponding cyanohy-
drin trimethylsilyl ether 4a; yield: 77%; 92% ee.
To recover the chiral ligand, the silica gel in the column was
transferred to a flask equipped with a stirrer. Water (10 mL)
and 1 M HCl (2 mL) were added, stirring was continued for
about 30 min and the mixture filtered. A solution of 2 M
NaOH was added dropwise to the filtrate, cooled in an ice-wa-
ter bath, until pH~ 12. The mixture was extracted with ethyl
acetate. The ethyl acetate extracts were pooled, washed with
brine, dried over anhydrous Na2SO4 and evaporated under vac-
uum to afford chemically and optically pure 1a (15.1 mg, 62%
recovered).
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Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20225206, 20390055 and 20372050), the Ministry of Edu-
cation, P. R. China (Nos. 104209 and others) and Sichuan Uni-
versity (No. 2004CF07) for financial support.
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