A mild and efficient cyanosilylation of ketones using in situ generated n-oxides-ti(iPrO)4 complexes as catalysts

Article abstract of DOI:10.1055/s-2002-25370

The addition of TMSCN to ketones catalyzed by complex of racemic N-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide (rac-1) or N-benzyl-N,N-dihydroxyethylamine N-oxide and Ti(iPrO)₄ affords the racemic O-TMS cyanohydrins in good to excellent isolated yields (up to 97%) under mild reaction conditions.

Full text of DOI:10.1055/s-2002-25370

LETTER
793
A Mild and Efficient Cyanosilylation of Ketones Using In Situ Generated
N-oxides-Ti(iPrO) Complexes as Catalysts
4
b
a
a
c
b
M
Y
ildand Efficient
o
Cyanosilyla
n
tionof Keton
g
e
s
cun Shen, Xiaoming Feng,* Yan Li, Guolin Zhang, Yaozhong Jiang*
a
Sichuan Key Laboratory of Green Chemistry and Technology, The Faculty of Chemistry, Sichuan University, Chengdu 610064, China
Fax +86(28)5412907; E-mail: xmfeng@pridns.scn.edu.cn
b
c
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
Received 12 February 2002
Ph
Ph
Abstract: The addition of TMSCN to ketones catalyzed by com-
plex of racemic N-(2 -pyridylmethyl)-2-diphenylhydroxymethyl-
pyrrolidine N-oxide (rac-1) or N-benzyl-N,N-dihydroxyethylamine
Ph
Ph
O
OH
OH
N
N
N
OH
OH
Bn
O
N-oxide and Ti(iPrO) affords the racemic O-TMS cyanohydrins in
4
N
good to excellent isolated yields (up to 97%) under mild reaction
conditions.
N
Key words: catalysis, cyanosilylation, ketones, N-oxides, complex
rac-3
rac-1
Figure
N-oxide 2
Cyanation reaction of carbonyl compounds is one of the
most powerful procedures for the synthesis of polyfunc-
tionalized molecules. In fact, cyanohydrins are highly ver-
satile synthetic intermediates, which can easily be
converted to various important building blocks including
We have recently reported that chiral N-oxides are highly5
effective catalysts for enantioselective Strecker reaction,
which prompted an investigation of addition of TMSCN
to ketones employing chiral N-oxides, however, no cy-
anosilylation adduct was obtained with (+)-S-3,3 -dime-
thyl-2,2 -biquinoline-N,N -dioxide. This could be due to
the poor activities of ketones. Although (+)-S-3,3 -dime-
thyl-2,2 -biquinoline- N,N -dioxide can activate TMSCN,
it is still difficult for addition of TMSCN to ketones. We
envisaged that compounds with N-oxide moiety and avail-
able multiple coordination sites to metal ion, coordinating
with metal, would catalyze cyanosilylation reaction of ke-
tones. For testing this assumption, a series of racemic N-
-
hydroxy carbonyl derivatives and -aminoalcohols.1
The addition of TMSCN to ketones catalyzed by Lewis
acids or Lewis bases is the most used strategy for the syn-
2
thesis of cyanohydrins. Generally, in the absence of cat-
alyst, no reaction occurs between TMSCN and carbonyl
compounds. Additives and Lewis acids have been exam-
ined as promoters for such reactions. A variety of Lewis
acids and Lewis bases have been employed successfully
2
as promoters in cyanosilylation of ketones. However, the
number of methods for effecting catalytic cyanosilylation
of ketones remains quite limited, and to the best of our
knowledge, although chiral amine N-oxides were used in
6
oxides were synthesized. With N-oxides in hand, and ac-
etophenone as a test substrate, a rac-1-Ti(iPrO) complex
4
system was found to be the most promising catalyst for
3
asymmetric synthesis, such as allylation of aldehydes and
7
this reaction. In CH Cl at 0 °C, 20 mol% rac-1-Ti(iPrO)
2
2
4
4
reduction of ketones and addition of ZnEt to aldehydes,
2
(
2:1 ratio) complex used as catalyst, acetophenone gave
racemic O-TMS cyanohydrin in 82% isolated yield
Table 1, entry 1). Further studies showed that there was
there is no report about the application of N-oxides in nu-
cleophilic addition of cyanide to ketones. Herein, we wish
to report the first example about cyanosilylation reaction
(
no difference in catalytic activities between two
of ketones using N-oxides-Ti(iPrO) complexes as pro-
8
4
diastereoisomer and several factors were important for
moters (Scheme 1) to afford racemic O-TMS cyanohy-
drins in high isolated yields (up to 97%).
isolated yield. The best results were obtained when 2
equiv. of rac-1 (Figure) were used per Ti and concentra-
tion of substrates was 0.34 M. A solvent study showed
N-oxides-Ti(OiPr)4
9
that CH Cl provided the best results (Table 1). It is note-
2
2
O
(2:1 ratio)
CN
R2
TMSO
R1
worthy that, when the reaction was carried out in CH CN,
3
+
TMSCN
R1
R2
CH Cl2
product was found to be trace. Such a low conversion is
probably due to a strong coordination interaction between
2
Scheme 1
Ti and CH CN. This result was different from that report-
3
ed by Saravanan, using Cu(OTf) as catalyst for the addi-
2
2
e
tion of TMSCN to carbonyl compounds.
Investigation of the scope of substrates was conducted un-
der the optimized conditions as outlined above, the results
were given in Table 1. The aromatic, conjugated and ali-
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
437-2096,E;2002,0,05,0793,0795,ftx,en;Y01502ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
1
©

7
94
Y. Shen et al.
LETTER
phatic ketones afforded the corresponding products in
good to excellent isolated yields (Table 1, entries 1–10).
The experimental results indicated that substituents on ar-
omatic ring had slight influence on conversion. Especial-
ly, less reactive ketone such as 2-acetylthiophen gave the
product in moderate isolated yield (Table 1, entry 12) by
our procedure, this is the first example of cyanosilylation
of 2-acetylthiophen. As a matter of fact, the low conver-
sion of 2-acetylthiophen (Table 1, entry 12) was probably
due to coordination between sulfur atom on the thiophen
ring and titanium, which restricted the coordination be-
tween carbonyl group and titanium.
BnBr/K CO
2
3
HN(CH CH OH)
2
BnN(CH CH
2 2
OH)
2
2
2
DMF
O
mCPBA/K CO
2
3
BnN(CH CH OH)
2 2 2
CH Cl
2
2
Scheme 2
at 0 °C in CH Cl , after 76 h, no product was obtained. It
2
2
showed that, although catalyst could activate the ketone,
the reaction still proceeded difficultly. It revealed that N-
oxide moiety played an important role in this reaction. On
the other hand, bases can catalyze the addition of TMSCN
1
2
Table 1 Cyanosilylation of Ketones (R COR ) Catalyzed by rac-1-
a
Ti (iPrO) (2:1 ratio) Complex
4
Entry R1
R2
Time (h)
Isolatedyield
12
to carbonyl compounds. However, in the absence of
b
(
%)
Ti(iPrO) , 20 mol% rac-1 was used as catalyst for this re-
4
action, after 70 h, no product was found. This result sug-
1
2
3
4
5
6
7
8
9
0
1
2
Ph
CH3
CH3
CH3
CH3
62
68
68
96
72
92
98
80
96
51
98
76
82
85
84
93
87
79
79
86
80
97
54
42
gested that Ti(iPrO) was also necessary for this reaction.
4
2-FC H4
Although the mechanistic details of 20 mol% rac-1-Ti(iP-
6
rO) (2:1 ratio) complex catalyst accelerating cyanosilyla-
4
4-FC H4
6
tion process of ketones are uncertain, from experimental
results obtained, it could be postulated that Ti as a Lewis
acid and N-oxide moiety as a Lewis base work coopera-
tively to activate the ketones and TMSCN, respectively.
Therefore, rac-1-Ti(iPrO) and N-oxide 2-Ti(iPrO) com-
C H (CH )
6
5
2 2
C H
C H
6
5
2
5
4-CH C H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4
4
3
6
4
plexes are probably the Lewis acid and Lewis base bifunc-
tional catalysts.
-naphthyl
4-NO C H
4
2
6
1
2
Table 2 Cyanosilylation of Ketones (R COR ) Catalyzed by N-Ox-
(2:1 ratio) Complexa
C H CH=CH
ide (2)-Ti (iPrO)
4
6
5
1
1
n-C H
Entry R1
R2
Time (h)
Isolated Yield
5
11
b
(
% )
4-NH C H
4
2
6
1
2
3
4
Ph
CH3
CH3
C H
68
68
80
96
80
80
84
87
93
76
1
2-thiophenyl
4-FC H
6
4
a
All the reactions were carried out according to experimental proce-
dure.
The isolated yields are given on the isolated O-TMS cyanohydrins
10
C H
6
5
5
2
5
b
1
after chromatographic purification, satisfactory spectral data ( H
C
6
H
(CH
2
)
2
CH
3
NMR, 13C NMR, IR) and elemental analysis were obtained for the
new compounds.
5
4-NO C H
CH3
2
6
4
a
All the reactions were carried out according to experimental proce-
10
dure, but rac-1 was replaced by N-oxide 2.
Although rac-1 was easily synthesized, Grignard reaction
conditions are severe in process of preparation. We at-
tempted to employ more easily prepared N-oxide instead
b
The isolated yields are given on the isolated O-TMS cyanohydrins
1
after chromatographic purification, satisfactory spectral data ( H
NMR, C NMR, IR) and elemental analysis were obtained for the
13
of rac-1. For this purpose, N-oxide 2 (Figure) was synthe- new compounds.
1
1
sized (Scheme 2) and employed for cyanosilylation of
ketones according to procedure described above, the re-
sults of representative substrates were shown in Table 2.
Gratifyingly, the results indicated that catalytic activity of
In conclusion, we have developed a new, mild and highly
efficient protocol for the synthesis of racemic O-TMS cy-
anohydrins from ketones and TMSCN catalyzed by N-ox-
ides–titanium complexes generated in situ. The reported
procedure clearly demonstrated that N-oxides–titanium
complexes are good catalysts for the preparation of race-
mic O-TMS cyanohydrins. It compares favorably and rep-
resents a valid alternative to the existing methods. The
important features of our method are: mild reaction condi-
tions, simple work-up, inexpensive catalyst employed and
N-oxide 2-Ti(iPrO) is similar to that of rac-1-Ti(iPrO)4
4
for this reaction. So N-oxide 2 as more inexpensive ligand
could be employed in this procedure, and make this pro-
cedure more practical.
To glean mechanistic insight into the cyanosilylation re-
action of ketones and understand the role of N-oxide moi-
ety, 20 mol% rac-3-Ti(iPrO) (2:1 ratio) complex was
4
used to catalyze cyanosilylation reaction of acetophenone
Synlett 2002, No. 5, 793–795 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Mild and Efficient Cyanosilylation of Ketones
795
wide substrate scope. Further efforts will be directed at
understanding the catalytic mechanism, catalyst structure
of this reaction and study of asymmetric cyanosilylation
of ketones catalyzed by chiral N-oxide-metal complex.13
(4) Derdau, V.; Laschat, S.; Hupe, E.; König, W. A.; Dix, I.;
Jones, P. G. Eur. J. Inorg. Chem. 1999, 2001.
(
(
(
5) Liu, B.; Feng, X. M.; Chen, F. X.; Zhang, G. L.; Cui, X.;
Jiang, Y. Z. Synlett 2001, 1551.
6) O’Neil, I. A.; Miller, N. D.; Barkley, J. V.; Low, C. M. R.;
Kalindjian, S. B. Synlett 1995, 617.
7) N-(3’-Pyridylmethyl), N-(2 -methoxyphenylmethyl) and N-
phenylmethyl-2- diphenylhydroxymethyl-pyrrolidine N-
oxides were screened.
Acknowledgement
The authors are grateful to the National Science Foundation of
China for the financial support (No. 29832020 and 20072037)
(8) With 20 mol% rac-1-Ti(iPrO) (1:1.2 ratio) complex used as
4
catalyst, acetophenone gave O-TMS cyanohydrin in 0% ee,
but with 20 mol% (S)-1-Ti(iPrO) (1:1.2 ratio) complex used
as catalyst, acetophenone gave O-TMS cyanohydrin in
4
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(
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2
2
2
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(
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2
4
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(
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(
Synlett 2002, No. 5, 793–795 ISSN 0936-5214 © Thieme Stuttgart · New York