DOI: 10.1002/chem.201101195
Mild and Efficient Trimethylsilylcyanation of Ketones Catalysed by PNP
Chloride
Marie-Agnꢀs Lacour, Nicolas J. Rahier, and Marc Taillefer*[a]
Cyanohydrins are versatile intermediates in organic syn-
thesis due to the presence of hydroxyl and nitrile functional-
ities, and are able to undergo transformation into a wide va-
riety of building blocks, including a-hydroxy acids,[1] a-hy-
droxy esters,[2] a-hydroxy ketones,[3] b-amino alcohols,[4] a-
amino nitriles,[5] acylnitriles,[6] a-ketoesters[7] or a-amino
acids.[8] The most common way to prepare cyanohydrins in-
volves the catalysed cyanosilylation of carbonyl compounds
in the presence of a cyanide source, such as trimethylsilyl cy-
anide (TMSCN), a safe and easily handled reagent com-
pared to the highly toxic HCN. Since the pioneering work of
Evans et al.,[9] which first described the zinc-catalysed cya-
nosilylation of aldehydes and ketones, multiple catalytic sys-
tems allowing this reaction have been described. Thus, inor-
ganic, organometallic or organic Lewis acids[10–15] or Lewis
bases,[16–30] used alone or as bifunctional[31–33] or double acti-
vating systems,[34–37] are known to promote the cyanosilyla-
tion of carbonyl compounds. Among them, organocatalysts
containing nitrogen or phosphorus atoms, such as phospha-
zanes,[24,25] guanidines,[26] N-heterocyclic carbenes[27–29] or
phosphoniums,[37,38] have been described. Because they
avoid the use of transition metal catalysts, they are particu-
larly suitable in the field of green chemistry.
The catalytic activity of 1 was first tested in the reaction
of TMSCN with benzaldehyde, a highly reactive substrate,
in solvent-free conditions. Only 15% yield of silylated cya-
nohydrin was obtained from the blank experiment per-
formed in the absence of any catalyst (Table 1, entry 1).
Table 1. Cyanosilylation of benzaldehyde in the presence of various
amounts of PNPCl catalyst.[a]
PNPCl (1) [mol%]
Yield 3 [%][b]
1 h
3 h
1
2
3
4
–
7
22
88
15
31
100
–
0.001
0.01
0.1
100
[a] Benzaldehyde (1.74 mmol), TMSCN (1.2 equiv, 2.09 mmol), PNPCl
(1; 0.001–0.1 mol%). [b] GC yield.
Under similar conditions but with 0.001 mol% PNPCl, the
yield although two-times better, was disappointing (Table 1,
entry 2). However, we were pleased to observe the full and
selective formation of silylated cyanohydrin (3) with, respec-
tively, 0.01 mol% of catalyst in 3 h and 0.1 mol% of catalyst
in less than 1 h (Table 1, entries 3 and 4).
We recently reported that bis(triphenylphosphoranyli-
dene) ammonium chloride (PNPCl) and derivatives are effi-
cient organocatalysts for the halogen exchange reaction
(Halex reaction).[39] We present here a new application for
PNPCl (1), which was found to be an excellent catalyst for
the cyanosilylation reaction.
With these promising conditions in hand, we tried to con-
vert the more challenging ketones into their corresponding
silylated cyanohydrins 5. The former are indeed often de-
scribed as less reactive substrates than aldehydes, because of
their steric hindrance. We, thus, investigated the cyanosilyla-
tion of a wide variety of cyclic, aliphatic, aromatic and a,b-
unsaturated ketones, always working without any solvent,
which is an obvious advantage for a green and sustainable
chemistry. For the first tests we chose three different catalyst
concentrations (Figure 1). In the presence of 0.1 mol%
PNPCl, cyclohexanone (4a) and p-nitroacetophenone (4h)
were fully converted in 24 h into their corresponding cyano-
hydrins (5a and 5h). The formation of product was also sat-
isfying for less hindered aliphatic substrates, such as pinaco-
lone (4e, 78%) and diisopropylketone (4 f, 62%). For the
other ketones tested, often strained and/or hindered, the
yields were disappointing. In the presence of a higher cata-
lyst loading (0.5 mol%) ketones were converted with good
[a] Dr. M.-A. Lacour, Dr. N. J. Rahier, Dr. M. Taillefer
Institut Charles Gerhardt Montpellier ENSCM
8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5 (France)
Fax : (+33)467-144-319
Supporting information for this article is available on the WWW
12276
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12276 – 12279