The asymmetric addition of trimethylsilylcyanide to aldehydes catalysed by anionic chiral nucleophiles. Part 2

Article abstract of DOI:10.1016/S0040-4039(00)01276-4

Studies have been carried out on the addition of trimethylsilylcyanide to aldehydes using highly active chiral lithium phenolate catalysts. The screening of a number of chiral phenolates has resulted in a system which gives the TMS ethers of cyanohydrins

Full text of DOI:10.1016/S0040-4039(00)01276-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7457–7460
The asymmetric addition of trimethylsilylcyanide to
aldehydes catalysed by anionic chiral nucleophiles. Part 2
Ian P. Holmes and Henri B. Kagan*
Laboratoire de Synthe`se Asyme´trique, associe´ au CNRS, ICMO, Universite´ Paris-Sud, 91405 Orsay, France
Received 21 July 2000; accepted 24 July 2000
Abstract
Studies have been carried out on the addition of trimethylsilylcyanide to aldehydes using highly active
chiral lithium phenolate catalysts. The screening of a number of chiral phenolates has resulted in a system
which gives the TMS ethers of cyanohydrins in excellent chemical yields with enantiomeric excesses of up
to 97%. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric addition; trimethylsilylcyanide; aldehydes; chiral nucleophiles; hypervalent silicon.
In our previous communication we detailed studies on the addition of trimethylsilylcyanide
(TMSCN) to aldehydes catalysed by the monolithium salt of (S)-(−)-1,1%-bi-2-naphthol 1
(S)-(−)-BINOL).1 These reactions are believed to proceed through hypervalent silicon intermedi-
ates.2,3 In order to investigate the possibility of obtaining higher enantioselectivities for the
transfer of the cyanide group, the addition of TMSCN to aldehydes catalysed by lithium salts
of other chiral phenols and related compounds has been studied.
Initially several analogues of BINOL 1 were screened (Fig. 1).4–10 These compounds were
tested for activity using benzaldehyde as a model aldehyde under the conditions that were found
to be optimal for BINOL (Scheme 1).1 Results were disappointing. Whilst all compounds
showed excellent catalytic activity, giving high yields of the desired TMS ether of 2-hydroxy-2-
phenylacetonitrile 10, the enantioselectivity never exceeded 5%.
* Corresponding author. Fax: 33 1 69 15 46 80; e-mail: kagan@icmo.u-psud.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01276-4

7458
Figure 1.
Scheme 1.
Thus, a range of chiral phenols derived from Schiff’s bases were investigated (Fig. 2).11–14
Testing these compounds using the same conditions described above we were pleased to obtain
TMS ether 10 in an isolated chemical yield of 94%, with 70% ee15 (configuration R)16 using the
monolithium salt of (R,R)-(−)-N,N%-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine 13
(R,R)-(−)-SALEN). The closely related compounds 11 and 12 gave poor enantioselectivity. With
these results in hand optimal conditions for the reaction catalysed by 13 were investigated.
Figure 2.
Firstly, the effect of catalyst loading was studied at room temperature. Thus, benzaldehyde 9
was treated with the mono lithium salt of 13 in a range of solvents, with varying catalyst
loadings. As a general trend, as for BINOL, in all the solvents studied, (THF, ether, toluene and
dichloromethane) starting from a catalyst loading of 30 mol% decreasing the amount of catalyst
led to an increase in the rate of reaction to an optimal value of 1 mol%. Using 1 mol% of
catalyst a rapid and exothermic reaction yielded, essentially quantitatively, the racemic TMS
cyanohydrin 10 on completion of the addition of TMSCN. The (R,R)-(−)-SALEN was
recovered unchanged from the reaction mixture.

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It was observed that as the temperature of reaction was lowered the enantioselectivity
improved. The choice of solvent was found to strongly influence the degree of enantioselectivity,
the rate and the yield of the reaction. Poor results were obtained with all solvents other than
ether that were investigated: toluene (96% yield, 0% ee), dichloromethane (95% yield, 0% ee) and
THF (96% yield, 0% ee). The mono lithium salt of (R,R)-SALEN was found to be superior to
the dilithium salt, as already noted for BINOL catalysed TMSCN additions.1 Again the
dilithium salt was shown to be a good catalyst for the reaction, a nearly identical chemical yield
was obtained, though the enantioselectivity was severely reduced (18% ee). Changing the cation
to Na, K or Mg gave a good catalyst, but cyanohydrin 10 was isolated as a racemic mixture.
Finally, the effects of concentration were investigated. Here, a marked difference was found
between the SALEN and BINOL systems. The SALEN system proved to be quite tolerant of
dilution, whereas the BINOL system rapidly lost enantioselectivity. Optimum conditions found
were concentrations of 0.28 M for SALEN compared with 1.18 M for BINOL. Under these
optimised conditions 10 was obtained in 98% yield with an ee of 86%.
With these results in hand, the addition of TMSCN to other aldehydes was studied using the
optimal reaction conditions for benzaldehyde detailed above. A summary of the results obtained
is presented below (Table 1).
Table 1
Asymmetric TMSCN addition to aldehydes catalysed by the monolithium salt of (R,R)-SALEN 13
Entry
Starting aldehyde17
% Isolated yielda
% eeb
Abs. config.16
Rxn time
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Benzaldehyde
p-Tolualdehyde
m-Tolualdehyde
o-Tolualdehyde
p-Anisaldehyde
m-Anisaldehyde
o-Anisaldehyde
o-Anisaldehyde
p-Chlorobenzaldehyde
p-CF3 benzaldehyde
2-Naphthaldehyde
4-Ethylbenzaldehyde
4-Isopropylbenzaldehyde
4-t-Butylbenzaldehyde
98
96
88
96
93
96
86
96
85
88
64
99
99
99
86
93
97
45
2
77
6
40
64
0
R
R
R
R
R
R
R
R
R
–
15 min
45 min
20 min
40 min
11 days
45 min
9 days
c
4 h
2 h 20 min
2 h
2 h
40 min
1 h 20 min
6
S
61
82
53
R
R
R
a TMS cyanohydrins were purified by column chromatography on silica gel.18
b Enantiomeric excess were determined by HPLC analysis15 of either the O-TMS cyanohydrin (entries 1–5 and
8–10) or O-acetyl cyanohydrin derivatives (entries 1–7 and 11–14).
c The reaction medium was stirred at −78°C for 3 h, then allowed to warm slowly to room temperature,
concentration of aldehyde 0.39 M.
It should be noted that the ee values obtained are strongly dependent on the aldehyde used,
i.e. the nature of the substrate strongly influences the reaction. Furthermore, studies have
revealed that the reaction mechanism is complex and probably differs from that occurring for
BINOL.

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To conclude, we have formed a number of highly enantiomerically enriched cyanohydrins in
up to 97% ee. The enantioselectivity and rate of reactions are very substrate specific. Investiga-
tions are currently underway to try to discover the nature of the reaction mechanism and to
check the applicability of such catalyst systems in the asymmetric transfer of other groups to
aldehydes and ketones.
Acknowledgements
We acknowledge the EU INCO-COPERNICUS scheme (Contract Number IC15 CT96-722)
for financial support and for a postdoctoral fellowship to one of us (I.P.H.). We also thank the
CNRS, Universite´ Paris-Sud and the Institut Universitaire de France for additional funding. We
also wish to acknowledge Professor Y. Belokon and F. Lagasse for useful discussions.
References
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17. All aldehydes used were distilled and stored under argon.
18. All data obtained was in accordance with literature values.16a–c
.