Kinetics and mechanism of the racemic addition of trimethylsilyl cyanide to aldehydes catalysed by Lewis bases

Article abstract of DOI:10.1039/c2ob25188d

The mechanism by which four Lewis bases, triethylamine, tetrabutylammonium thiocyanate, tetrabutylammonium azide and tetrabutylammonium cyanide, catalyse the addition of trimethylsilyl cyanide to aldehydes is studied by a combination of kinetic and spectr

Full text of DOI:10.1039/c2ob25188d

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PAPER
Kinetics and mechanism of the racemic addition of trimethylsilyl cyanide to
aldehydes catalysed by Lewis bases†
Michael North,* Marta Omedes-Pujol and Carl Young
Received 25th January 2012, Accepted 18th April 2012
DOI: 10.1039/c2ob25188d
The mechanism by which four Lewis bases, triethylamine, tetrabutylammonium thiocyanate,
tetrabutylammonium azide and tetrabutylammonium cyanide, catalyse the addition of trimethylsilyl
cyanide to aldehydes is studied by a combination of kinetic and spectroscopic methods. The reactions can
exhibit first or second order kinetics corresponding to three different reaction mechanisms. Spectroscopic
evidence for the formation of hypervalent silicon species is obtained for reaction between all of the
tetrabutylammonium salts and trimethylsilyl cyanide. The reactions are accelerated by the presence of
water in the reaction mixture, an effect which is due to a change in the reaction mechanism from Lewis to
Brønsted base catalysis. Tetrabutylammonium thiocyanate is shown to be an excellent catalyst for the
synthesis of cyanohydrin trimethylsilyl ethers on a preparative scale.
reactions between ketones and trimethylsilyl cyanide,6 and
Denmark and Chung had studied the use of various amines and
Introduction
Cyanohydrin synthesis achieved by the base-catalysed addition
of cyanide to aldehydes was one of the first reactions to be
mechanistically studied1 and remains one of the fundamental
carbon–carbon bond forming reactions used in organic syn-
thesis.2 However, whilst cyanide salts are still used in cyanohy-
drin synthesis,3 other cyanide sources are now often used to
avoid potential side reactions,4 render cyanohydrin synthesis ir-
reversible and directly produce protected cyanohydrins suitable
for further manipulation. Examples of these cyanide sources
include trimethylsilyl cyanide,5–12 ethyl cyanoformate,12,13
diethyl cyanophosphonates12,14,15 and acyl cyanides.12,16
Another advantage of these cyanide sources is that, when used
with a suitable chiral catalyst, they permit the asymmetric syn-
thesis of cyanohydrin derivatives.17 We have developed metal
(salen) complexes as highly effective catalysts for asymmetric
cyanohydrin synthesis18 and have also studied the mechanism of
asymmetric cyanohydrin synthesis using trimethylsilyl cyanide
as the cyanide source.19,20 During this work, we became aware
that surprisingly little work had been done on the kinetics and
mechanism of racemic cyanohydrin synthesis using cyanide
sources other than alkali metal cyanides. Thus, Umani-Ronchi
and co-workers had studied the indium tribromide catalysed
phosphines as Lewis base catalysts for the reaction between alde-
hydes and trimethylsilyl cyanide.7 Therefore, we undertook a
project to investigate the mechanism of cyanohydrin trimethylsi-
lyl ether formation using trimethylsilyl cyanide as the cyanide
source and dichloromethane as solvent (Scheme 1), in order to
allow comparison of the results with our previous work on the
kinetics of asymmetric cyanohydrin synthesis.19,20
The addition of trimethylsilyl cyanide to aldehydes is known
to be catalysed by both Lewis acids5,6 and Lewis bases.7–12
However, preliminary attempts to study the kinetics of cyanohy-
drin trimethylsilyl ether formation catalysed by a range of Lewis
acids (titanium isopropoxide, aluminium triflate, zinc iodide)
were unsuccessful as in all cases catalyst decomposition occurred
during the reaction. In contrast, Lewis bases were found to be
kinetically well-behaved catalysts and in this manuscript we
present the results obtained using four Lewis bases in dichloro-
methane solution and discuss how the differing kinetic data
obtained correspond to three different mechanisms for cyano-
hydrin trimethylsilyl ether formation.
Results and discussion
Four Lewis base catalysts were selected for this study. Triethyl-
amine 1 has been shown to be an effective catalyst for the
School of Chemistry and University Research Centre in Catalysis and
Intensified Processing, Bedson Building, University of Newcastle,
Newcastle upon Tyne, UK, NE1 7RU. E-mail: michael.north@ncl.ac.uk;
Fax: +44 191 222 6929; Tel: +44 191 2227128
†Electronic supplementary information (ESI) available: Kinetic data for
reactions catalysed by Lewis bases 1–4, 1H NMR spectra of cyanohydrin
trimethylsilyl ethers and NMR spectra showing the formation of hyper-
valent silicon species. See DOI: 10.1039/c2ob25188d
Scheme 1 Synthesis of cyanohydrin trimethylsilyl ethers.
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Fig. 1 Plot of [catalyst] against kobs for each of catalysts 1–4. kobs is
the average of two experiments carried out at the same catalyst concen-
tration. Solid line and filled diamonds = 1 (m = 3, n = 4) (y = 0.7194x −
0.0937; R2 = 0.993); short dashed line and empty squares = 2 (m = n =
4) (y = 0.6659x − 0.1304; R2 = 0.9995); dotted line and filled triangles
= 3 (m = 4, n = 2) (y = 1.9527x + 0.1756; R2 = 0.994); long dashed line
Scheme 2 Possible mechanisms for the addition of trimethylsilyl
cyanide to aldehydes.
and empty circles = 4 (m = 5, n = 3) (y = 0.4411x + 0.0109; R2
=
addition of many cyanide sources including trimethylsilyl
cyanide to aldehydes12 and the kinetics of the addition of tri-
methylsilyl cyanide to aldehydes catalysed by triethylamine have
previously been reported.7 The relatively large size of triethyl-
amine suggested that the reaction mechanism was most likely to
be that shown in Scheme 2A. Tetrabutylammonium thiocyanate
2 and tetrabutylammonium azide 3 were selected as both these
anions are known to catalyse the addition of trimethylsilyl
cyanide to aldehydes10 and isothiocyanate was found to be the
most effective of a series of ligands (X) in VO(salen)X-catalysed
asymmetric cyanohydrin synthesis.20 The small, linear nature of
thiocyanate and azide would facilitate the formation of hyper-
valent silicon intermediates,21 so that the reaction mechanism
could be that shown in Scheme 2A or B.‡ Finally, tetrabutyl-
ammonium cyanide 4 was selected as an organic solvent soluble
source of cyanide, since it9 and other species which contain
cyanide anions10,15 are also known to catalyse the addition of tri-
methylsilyl cyanide and other cyanide reagents to aldehydes.
Mechanistically, the cyanide anions could form a hypervalent
silicon complex (Scheme 2B) as previously proposed9,22 or
could directly add to the aldehyde (Scheme 2C). It was antici-
pated that a thorough analysis of the reaction kinetics of the
addition of trimethylsilyl cyanide to a range of aromatic alde-
hydes catalysed by each of these four catalysts would allow the
reaction mechanisms to be determined.
0.989).
intervals. All of the reactions carried out under these conditions
were kinetically well behaved and could be followed to >90%
conversion.
Differences between catalysts 1–4 were immediately apparent
from this study. Thus, whilst reactions catalysed by 1 and 4 were
found to follow first order kinetics, reactions catalysed by tetra-
butylammonium salts 2 and 3 were found to follow second order
kinetics.† Reactions were then carried out at various initial con-
centrations of benzaldehyde and trimethylsilyl cyanide to deter-
mine the order with respect to each reactant.† These experiments
showed that reactions catalysed by triethylamine 1 or tetrabutyl-
ammonium cyanide 4 gave reactions which were first order in
benzaldehyde concentration, but zero order in trimethylsilyl
cyanide concentration. Reactions catalysed by tetrabutylammo-
nium salts 2 and 3 were found to be first order in both benz-
aldehyde and trimethylsilyl cyanide concentration.
To complete the determination of the rate equations, reactions
were carried out at different catalyst concentrations to allow the
order with respect to catalyst 1–4 to be determined.†
Fig. 1 shows that in each case the reactions were first order in
catalyst concentration. As a result, the rate equations for reac-
tions catalysed by complexes 1–4 were found to be:
Initial kinetic studies using catalysts 1–4 were carried out at
0 °C in dichloromethane using benzaldehyde as substrate with
initial concentrations of benzaldehyde and trimethylsilyl cyanide
of 0.53 M and 0.56 M respectively. The catalyst concentration
(0.01 M for triethylamine, 9.4 × 10−3 M for tetrabutylammo-
nium thiocyanate and 2.3 × 10−3 M for both tetrabutylammo-
nium azide and tetrabutylammonium cyanide) was adjusted so as
to give a convenient reaction rate to allow the reactions to be
monitored by UV analysis of samples withdrawn at regular
•
•
•
•
Rate = 0.072( 0.017)[1][PhCHO]
Rate = 0.67( 0.01)[2][Me3SiCN][PhCHO]
Rate = 195( 4)[3][Me3SiCN][PhCHO]
Rate = 441( 11)[4][PhCHO]
The rate equation for cyanohydrin trimethylsilyl ether syn-
thesis catalysed by triethylamine 1 is identical to that previously
determined by Denmark and Chung under slightly different con-
ditions.7 It is consistent with the mechanism shown in
Scheme 2A provided that the second step of the mechanism is
rate determining and that the first step is irreversible or has an
equilibrium which favours formation of free cyanide.7 Similarly,
the rate equation for reactions catalysed by tetrabutylammonium
‡It is also possible that azide and thiocyanate will undergo addition to
the aldehyde under the reaction conditions. This has been shown to
occur for azide addition,32 however, under our reaction conditions we
were unable to detect any such species by mass spectrometry, NMR
spectroscopy or UV spectroscopy. Thus, whilst we cannot fully discount
this possibility we have no evidence to support it.
cyanide
4 is consistent with the mechanism shown in
Scheme 2C, again provided that the first step is rate determining.
In this case, the first step of Scheme 2A would be a degenerate
process and it therefore becomes equivalent to Scheme 2C, so
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Table 2 Rate data for the addition of trimethylsilyl cyanide to
substituted benzaldehydes catalysed by tetrabutylammonium thiocyanate
2a
Aldehyde
σ
k (M−1 s−1 b
)
3,5-F2C6H3CHO
4-F3CC6H4CHO
3-ClC6H4CHO
3-FC6H4CHO
4-ClC6H4CHO
4-FC6H4CHO
0.68
0.53
0.37
0.34
0.23
0.06
0
0.28 0.04
0.097 0.007
0.035 0.002
Scheme 3 Synthesis of cyanohydrin trimethylsilyl ethers from substi-
tuted benzaldehydes.
0.00299 0.00006
0.0083 0.0002
0.00052 0.00005
0.00064 0.00002
0.00077 0.00001
0.00034 0.00001
0.00066 0.00002
0.00010 0.00001
0.00014 0.00001
Table 1 Rate data for the addition of trimethylsilyl cyanide to
substituted benzaldehydes catalysed by triethylamine 1a
PhCHO
4-MeSC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3,4-Me2C6H3CHO
4-MeOC6H4CHO
0
Aldehyde
σ
k (s−1 b
)
−0.06
−0.14
−0.24
−0.27
3-ClC6H4CHO
3-FC6H4CHO
4-ClC6H4CHO
4-FC6H4CHO
PhCHO
4-MeSC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3,4-Me2C6H3CHO
4-MeOC6H4CHO
0.37
0.34
0.23
0.06
0
0.00139 0.00008
0.00122 0.00008
0.00072 0.00004
0.00098 0.00008
0.00065 0.00007
0.00078 0.00008
0.00056 0.00007
0.00092 0.00007
0.00042 0.00001
0.00055 0.00005
a All reactions carried out at 0 °C with [aldehyde]0 = 0.49 M,
[Me3SiCN]0 = 0.56 M and [2] = 9.4 × 10−3 M. b Average of two
experiments.
0
−0.06
−0.14
−0.24
−0.27
Table 3 Rate data for the addition of trimethylsilyl cyanide to
substituted benzaldehydes catalysed by tetrabutylammonium azide 3a
a All reactions carried out at 0 °C with [aldehyde]0 = 0.49 M,
[Me3SiCN]0
experiments.
= 0.56 M and [1] =
0.001 M. b Average of two
Aldehyde
σ
k (M−1 s−1 b
)
4-ClC6H4CHO
4-FC6H4CHO
PhCHO
4-MeSC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3,4-Me2C6H3CHO
4-MeOC6H4CHO
0.23
0.06
0
0.204 0.007
0.058 0.008
0.057 0.001
0.070 0.008
0.029 0.002
0.030 0.008
0.0051 0.0004
0.0088 0.0001
0
that the two mechanisms have identical kinetic features. The rate
equations for catalysts 2 and 3 could however be interpreted as
being consistent with the mechanism shown in Scheme 2A or B,
provided that the first step of the mechanism is not rate limiting.
However, as azide and thiocyanate are both small linear species,
the large difference in rate constant (almost a factor of 300)
between reactions catalysed by 2 and 3, is suggestive of either a
change in mechanism between the two catalysts, or both reac-
tions proceeding by the mechanism shown in Scheme 2B. In the
mechanism shown in Scheme 2B, the anion is coordinated to the
hypervalent silicon during the cyanide transfer step and so can
influence the rate of this step both sterically and electronically. In
contrast, in the mechanism shown in Scheme 2A, the anion is
dissociated from the tetravalent silicon and so would be expected
to have only a small influence on the rate of cyanide transfer.
To investigate the extent of charge transfer to the aldehyde in
the rate determining step of the mechanism, a Hammett analysis
of the reaction using various meta- and/or para-substituted ben-
zaldehydes was undertaken with each of catalysts 1–4
(Scheme 3). Each of these kinetic experiments was carried out in
duplicate† and Tables 1–4 detail the resulting rate data. In all
cases, each of the substituted benzaldehydes was found to give a
good fit to the same reaction order determined for reactions
−0.06
−0.14
−0.24
−0.27
a All reactions carried out at 0 °C with [aldehyde]0 = 0.49 M,
[Me3SiCN]0 = 0.56 M and [3] = 2.3 × 10−3 M. b Average of two
experiments.
Table 4 Rate data for the addition of trimethylsilyl cyanide to
substituted benzaldehydes catalysed by tetrabutylammonium cyanide 4a
Aldehyde
σ
k (s−1 b
)
3-ClC6H4CHO
3-FC6H4CHO
4-ClC6H4CHO
4-FC6H4CHO
PhCHO
4-MeSC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3,4-Me2C6H3CHO
4-MeOC6H4CHO
0.37
0.34
0.23
0.06
0
0.0323 0.0007
0.0113 0.0005
0.0093 0.0006
0.0018 0.0001
0.00132 0.00009
0.00097 0.00005
0.00040 0.00002
0.00033 0.00001
0.00024 0.00001
0.00013 0.00001
0
−0.06
−0.14
−0.24
−0.27
a All reactions carried out at 0 °C with [aldehyde]0 = 0.49 M,
[Me3SiCN]0 = 0.56 M and [4] = 2.3 × 10−4 M. b Average of two
experiments.
using benzaldehyde. The average of the two rate constants (kavg
)
was used to construct the Hammett plot. In the case of reactions
catalysed by triethylamine 1, no correlation between the substitu-
ent constants and the rate of reaction was observed,† but for cata-
lysts 2–4 there was a clear correlation as shown in Fig. 2.
All of the data given in Tables 1–4 was obtained by manual
sampling of reactions carried out at 0 °C. However, reactions cat-
alysed by tetrabutylammonium thiocyanate 2 and involving the
less electron-rich aromatic aldehydes were also fast enough to be
monitored in situ in a stopped-flow kinetics system.† These
reactions were carried out at 17 °C and also gave a Hammett plot
with a large positive slope (2.7), thus providing further evidence
of the robustness of the kinetic data used to construct the
Hammett plots.
It is apparent from Fig. 2 that reactions catalysed by catalysts
2–4 all have large positive reaction constants (+3.0 to +3.6)
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Fig. 4 Eyring plots for reactions catalysed by 1–4. Solid line and filled
triangles = 1 (y = −6.13x + 9.80; R2 = 0.96). Short dashed line and
empty circles = 2 (y = −3.96x + 3.02; R2 = 1.00). Long dashed line and
filled squares = 3 (y = −4.56x + 8.22; R2 = 1.00). Long and short
dashed line and empty diamonds = 4 (y = −4.18x + 3.29; R2 = 0.99).
Fig. 2 Hammett plots for reactions catalysed by catalysts 2–4. Short
dashed line and empty squares = 2 (y = 3.58x + 0.1; R2 = 0.93). Solid
line and filled triangles = 3 (y = 2.98x − 0.07; R2 = 0.91). Long dashed
line and empty circles = 4 (y = 3.50x − 0.07; R2 = 0.97).
Table 5 Activation parameters for reactions catalysed by catalysts 2–4
Catalyst
ΔH‡a (kJ mol−1
)
ΔS‡a (J mol−1 K−1
)
ΔG‡a,b (kJ mol−1
)
1
2
3
4
53.2 5.0
33.0 6.8
38.1 5.3
35.9 2.5
−68 18
−128 24
−78 20
71.8 9.9
68.0 13.3
59.4 10.8
62.1 5.0
70.4 7.1
−96
9
Fig. 3 Possible modes of Lewis acid activation of aldehydes by tetra-
or pentavalent silicon species.
1 + H2O 15.2 3.6
−202 13
a For details of the error analysis see the ESI.† b At 0 °C.
which implies that there is a significant movement of negative
charge towards the benzylic carbon atom of the aldehyde in the
rate-determining transition state. This is consistent with nucleo-
philic addition of cyanide to the carbonyl being the rate-deter-
mining step for reactions catalysed by catalysts 2–4. Tetra- or
pentavalent silicon species are known to possess Lewis acidity23
and hence could activate the aldehyde as illustrated in Fig. 3.
However, this would result in a decrease in electron density at
the benzylic carbon atom of the coordinated aldehyde and hence
would be expected to decrease the magnitude of the reaction
constant. The large magnitude of the observed reaction constants
for reactions catalysed by tetrabutylammonium salts 2–4
suggests that any such activation of the aldehyde by silicon-
based Lewis acids is of at most minor importance and the reac-
tions are dominated by Lewis base activation of the trimethyl-
silyl cyanide. In contrast, the absence of a Hammett correlation
for reactions catalysed by triethylamine, even though the alde-
hyde is involved in the rate-determining step of the mechanism,
could be explained by the initial coordination of the aldehyde to
the trimethylsilyl cyanide, which would withdraw electron
density from the benzylic carbon atom and offset the subsequent
increase in electron density at this carbon atom during the
nucleophilic addition of cyanide (cf. Fig. 3D).
in having a significantly larger enthalpy of activation. This is
consistent with the other kinetic data and in particular with reac-
tions catalysed by triethylamine following the reaction shown in
Scheme 2A requiring the complete cleavage of the Si–CN bond,
prior to nucleophilic addition of cyanide to the carbonyl; whilst
reactions catalysed by tetrabutylammonium salts 2–4 follow the
mechanisms shown in Scheme 2B/C in which this bond has to
be (at most) partially broken prior to the cyanohydrin-forming
transition state.
The ΔS‡ data has to be interpreted with care as it is well
known that the extrapolation of the data shown in Fig. 4 to 1000/
T = 0, necessary to obtain the entropies of activation, results in
relatively large errors being associated with the calculated entro-
pies.24 Nevertheless, it is notable that the reaction catalysed by
triethylamine has the least negative entropy of activation and this
is significantly less negative than the entropy of activation for
the reaction catalysed by tetrabutylammonium thiocyanate 2.
This is consistent with the triethylamine and tetrabutylammo-
nium thiocyanate catalysed reactions occurring by the mechan-
isms shown in Scheme 2A and B respectively, as the latter,
involving a hypervalent silicon species, will have a much more
ordered transition state. The less negative entropy of activation
observed for reactions catalysed by tetrabutylammonium azide 3
compared to tetrabutylammonium thiocyanate 2 may be related
to the symmetrical nature of the azide group, which makes its
coordination to silicon through either terminal nitrogen degener-
ate and hence results in an increase in the disorder of the tran-
sition state relative to that for tetrabutylammonium thiocyanate
2. The entropy of activation for the reaction catalysed by
To allow the activation parameters (ΔH‡, ΔS‡ and ΔG‡) for
reactions catalysed by 1–4 to be determined and compared, a
variable-temperature kinetics study was carried out using each of
the catalysts with benzaldehyde as substrate.† The resulting
Eyring plot is shown in Fig. 4 and the derived activation par-
ameters are given in Table 5.
It is apparent from the ΔH‡ data in Table 5 that triethylamine
1 differs from the three tetrabutylammonium-based catalysts 2–4
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Table 6 NMR data for hypervalent silicon cyanide complexes
that 10–14% of the trimethylsilyl cyanide had been converted
into a hypervalent silicon species. However, trimethylsilyl cya-
nation reactions involving Lewis bases 2–4 are carried out at a
trimethylsilyl cyanide to Lewis base ratio of between 60 and
2400 : 1. Therefore, even if all of the Lewis base forms a hyper-
valent silicon species, then for virtually all of the reaction there
will be far more trimethylsilyl cyanide than hypervalent species
present. Thus, if the hypervalent silicon species is to be the cata-
lytically active form of trimethylsilyl cyanide for cyanohydrin
synthesis, then it will have to have a rate constant 2–3 orders of
magnitude greater than that of trimethylsilyl cyanide to compen-
sate for its lower concentration.
Entry
Compound
δH
δC
1
2
3
4
5
6
7
8
Me3SiCNa
+0.31
+0.08
+0.28
+0.07
−0.02
−1.88
+2.15
−0.93
+2.07
+1.89
+1.93
+1.91
−1.88
+1.80
+1.64
+1.79
Me3SiNCSa
a
Me3SiN3
(Me3Si)2Oa
PNP+ [Me3SiCl(NC)]− a,b
Li+ [Me3SiCl(NC)]− c
Li+ [Me3Si(NC)2]− c
Me3SiCN + Et3Na
+0.31
−0.01
+0.01
+0.04
9
10
11
Me3SiCN + Bu4NSCNa,d
a,d
Me3SiCN + Bu4NN3
Me3SiCN + Bu4NCNa,d
The combination of the kinetic and spectroscopic data indicate
that triethylamine does not form a hypervalent silicon species
with trimethylsilyl cyanide and that it therefore catalyses the for-
mation of cyanohydrin trimethylsilyl ethers through the mechan-
ism shown in Scheme 2A with the nucleophilic addition of
cyanide to the carbonyl being rate determining. This does
require that during the reaction, [Me3SiNEt3]+ CN− should
accumulate and this species was not detected by 1H or 13C NMR
spectroscopy of an equimolar amount of trimethylsilyl cyanide
and triethylamine. However, the kinetics experiments were
carried out using just 2 mol% of triethylamine, so a 50-fold
excess of trimethylsilyl cyanide is present which will shift the
first equilibrium in Scheme 2A in favour of formation of
[Me3SiNEt3]+ CN−.
In contrast, tetrabutylammonium salts 2–4 do form hyper-
valent silicon species with trimethylsilyl cyanide and in the case
of catalysts 2 and 3 these are the most reactive cyanide-contain-
ing species present in solution, so cyanohydrin trimethylsilyl
ether synthesis follows the mechanism shown in Scheme 2B. For
reactions catalysed by tetrabutylammonium cyanide 4, although
a hypervalent silicon species is formed in situ, cyanide ions are
also present and the kinetics suggest that these rather than the
hypervalent silicon species attack the carbonyl compound, thus
giving the mechanism shown in Scheme 2C with the first step
rate determining.
During the course of this work, it became apparent that reac-
tions catalysed by 1–4 were sensitive to the presence of water.
This was particularly notable for the hygroscopic tetrabutylam-
monium salts 3 and 4. The reactions were greatly accelerated by
the presence of water and the rate equation also changed. Fig. 5
shows the progress of the addition of trimethylsilyl cyanide to
3,4-dimethylbenzaldehyde catalysed by tetrabutylammonium
azide 3. In this case, the reaction in the presence of water is an
order of magnitude faster than that under anhydrous condition,
reaching 86% conversion after 124 rather than 1813 seconds.
The presence of water was also found to change the rate equation
from second order to first order.†
a In CDCl3. b PNP = bis(triphenylphosphoranylidene)ammonium. Data
taken from ref. 25b. c In thf-d8. Data taken from ref. 25a. d Signals due
to Me3SiCN were also present.
tetrabutylammonium cyanide 4 is less negative than that for the
tetrabutylammonium thiocyanate catalysed reaction and is con-
sistent with the mechanism shown in Scheme 2C.
The ΔG‡ data also has quite large errors associated with it.
However, the Gibbs free energies of activation for reactions cata-
lysed by 1 and 2 appear to be similar and higher than those of
reactions catalysed by 3 and 4 which are also similar. This is
consistent with the rate constants determined for reactions cata-
lysed by 1–4, as those for reactions catalysed by 1 and 2 were
around three orders of magnitude lower than those for reactions
catalysed by tetrabutylammonium salts 3 and 4.
To investigate the formation of hypervalent silicon complexes
from trimethylsilyl cyanide and Lewis bases 1–4, NMR studies
1
were carried out. H and 13C NMR data of hypervalent silicon
species obtained by treatment of trimethylsilyl cyanide with
chloride or cyanide have been reported in the literature and
formed the basis of our study.25 Table 6 presents the literature
data for relevant four- and five-coordinate silicon species and the
data we have observed when equimolar amounts of trimethylsilyl
cyanide and Lewis bases 1–4 were mixed in CDCl3. Entries
1–4 give the NMR data of tetravalent silicon species that could
be formed in situ from mixtures of trimethylsilyl cyanide and
Lewis bases 2–4 and entries 5–7 give the literature data reported
for hypervalent silicon complexes derived from trimethylsilyl
cyanide. When the NMR spectrum of a 1 : 1 mixture of tri-
methylsilyl cyanide and triethylamine was recorded (entry 8), no
change in the spectrum relative to that of trimethylsilyl cyanide
was observed and in particular, there was no evidence for the for-
mation of hypervalent silicon species.
1
In contrast, the H and 13C NMR spectra of 1 : 1 mixtures of
trimethylsilyl cyanide and Lewis bases 2–4 (entries 9–11)
showed clear evidence of hypervalent silicon species being
formed in situ. The H NMR spectra all showed a new peak at
The effect of water on reactions catalysed by triethylamine
and tetrabutylammonium thiocyanate was studied quantitatively.
Fig. 6 shows the effect of adding 2 or 10 mol% of water (relative
to benzaldehyde) to reactions catalysed by triethylamine. The
significant rate enhancement due to the water is again apparent
in Fig. 6. In this case, the reactions followed first order overall
kinetics under both anhydrous and hydrated reaction conditions
and were first order in benzaldehyde concentration and zero
order in trimethylsilyl cyanide concentration. Reactions carried
out at various concentrations of triethylamine showed that in the
1
−0.01 to +0.04 ppm consistent with the literature data of
−0.02 ppm for a closely related hypervalent silicon species
(Table 6, entries 5 and 9–11) and the 13C NMR spectra showed
a new signal at +1.64 to +1.80 ppm consistent with the literature
data of +1.89 to +1.93 ppm for related hypervalent silicon
species (Table 6, entries 5–7 and 9–11). Integration of the tri-
methylsilyl signals for trimethylsilyl cyanide and the hypervalent
1
silicon species in the H NMR spectra of the mixtures indicated
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Fig. 7 Second order kinetics plots for the reaction between benzal-
dehyde and Me3SiCN catalysed by tetrabutylammonium thiocyanate 2
under anhydrous reaction conditions (empty squares and solid line) (y =
0.0029x − 0.0504; R2 = 0.994); in the presence of 1 mol% water (filled
triangles and short dashed line) (y = 0.003x + 0.3075; R2 = 0.993); in
the presence of 5 mol% water (empty circles and long dashed line) (y =
0.0051x − 0.2043; R2 = 0.997); and in the presence of 10 mol% water
(filled diamonds and long and short dashed line) (y = 0.0072x − 0.4646;
R2 = 0.998). The units for the vertical scale are: ln[(B0At)/(BtA0)]/(A0 −
B0) where: A = [PhCHO], B = [Me3SiCN] and the subscripts 0 and t
refer to initial concentrations and concentrations at time t, respectively,
and the concentration of benzaldehyde was monitored during the
reactions.
Fig. 5 Comparison of the rate of reaction between 3,4-dimethylbenzal-
dehyde and Me3SiCN under anhydrous reaction conditions (filled dia-
monds and solid line) and in the presence of water (empty squares and
broken line).
accelerated in the presence of water. In this case, the reactions
followed second order kinetics under both anhydrous conditions
and in the presence of 1–10 mol% of water (relative to benzal-
dehyde). As shown in Fig. 7, the rate enhancement due to water
was much more modest in this case and the time required for the
reaction to reach 70% conversion decreased by just a factor of
two from 1200 seconds under anhydrous conditions to 600
seconds in the presence of 10 mol% water.
Fig. 6 First order kinetics plots for the reaction between benzaldehyde
and Me3SiCN catalysed by triethylamine 1 under anhydrous reaction
conditions (empty squares and solid line). (y = −0.0006x − 0.7041; R2 =
0.997); in the presence of 2 mol% water (filled triangles and short
dashed line) (y = −0.0059x − 0.5916; R2 = 0.997); and in the presence
of 10 mol% water (empty circles and long dashed line) (y = −0.01x −
0.65; R2 = 0.999).
Water and other protic additives are known to react rapidly
with trimethylsilyl cyanide to form hydrogen cyanide,26 which
can be the cyanide source in asymmetric cyanohydrin syn-
thesis.27 In the presence of a Brønsted base (X− or Et3N), hydro-
gen cyanide will add to aldehydes to form a cyanohydrin which
can then be silylated by trimethylsilyl cyanide reforming
cyanide. This alternative reaction pathway appears to account for
the kinetic behaviour observed for triethylamine catalysed reac-
tions in the presence of water. In particular, if the reaction
between trimethylsilyl cyanide and water is fast, then the reac-
tion would be expected to show first order kinetics in benzal-
dehyde and triethylamine concentrations and to be independent
of the trimethylsilyl cyanide concentration. The activation par-
ameters will be totally different to those observed under anhy-
drous conditions as they correspond to the transition state for a
different reaction. Thus, in the presence of water, the reaction
mechanism reverts to that established by Lapworth over a
century ago.1 Reactions catalysed by tetrabutylammonium thio-
cyanate 2 show a much lower rate acceleration in the presence of
water than those catalysed by compounds 1, 3 or 4. This is con-
sistent with the pKa values for the conjugate acids of the bases
since, in water, thiocyanic acid (HSCN) has a much lower pKa
presence of water, the reactions still exhibited first order kinetics
with respect to triethylamine concentration.†
A Hammett analysis was also carried out using wet triethyl-
amine as catalyst and, as for the analysis carried out using anhy-
drous triethylamine as catalyst, no correlation between the
substituent constant and relative rate of reaction was apparent.†
Finally, a variable temperature kinetics study was carried out using
wet triethylamine as catalyst.† The results of this study are
included in Table 5 and it is apparent that the activation parameters
in the presence of water are very different to those of triethylamine
(or catalysts 2–4) under anhydrous conditions. In particular, the
enthalpy of activation is much lower and there is a much more
negative entropy of activation in the presence of water.
The addition of trimethylsilyl cyanide to benzaldehyde cata-
lysed by 1 mol% of tetrabutylammonium thiocyanate 2 was also
4294 | Org. Biomol. Chem., 2012, 10, 4289–4298
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Table 7 Comparison of Lewis acids for the addition of Me3SiCN to
Table 8 Comparison of Al(OTf)3 and Bu4NNCS as catalysts for the
benzaldehydea
addition of Me3SiCN to aldehydesa
Catalyst
Conversionb (%)
Conversionb (%)
AlCl3
73
98
88
20
28
83
Aldehyde
Al(OTf)3
Bu4NNCS
Al(OTf)3
FeCl3
PhCHO
81
93
96
77
84
62
64
63
68
72
58
55
50
41
—
94
Ti(OiPr)4
ZnBr2
ZnI2
3,5-F2C6H3CHO
3,4-Cl2C6H3CHO
4-F3CC6H4CHO
3-ClC6H4CHO
3-FC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
4-FC6H4CHO
4-MeSC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3,4-Me2C6H3CHO
4-MeOC6H4CHO
4-tBuOC6H4CHO
100
100
100
100
100
100
100
91
88
80
87
76
a Reactions carried out at room temperature in CH2Cl2 for one hour,
using 10 mol% of catalyst and 1.2 equivalents of Me3SiCN.
b Determined by 1H NMR spectroscopy.
(−1.1)28 than those of hydrazoic acid (HN3, pKa 4.7),29 hydro-
gen cyanide (HCN, pKa 9.0)30 or triethylammonium (Et3NH+,
pKa 10.8).31 Thus, thiocyanate is the weakest Brønsted base
amongst the catalysts studied and hence would be expected to be
the least effective catalyst for the addition of hydrogen cyanide
to aldehydes.
66
72
a Reactions carried out at room temperature in CH2Cl2 for two hours,
using 5 mol% of catalyst and 1.2 equivalents of Me3SiCN. b Determined
by 1H NMR spectroscopy.
Previous work has shown that triethylamine, tetrabutylammo-
nium azide and tetrabutylammonium cyanide are all effective
catalysts for the preparation of cyanohydrins.10,12 However, the
preparative utility of tetrabutylammonium thiocyanate 2 had not
previously been investigated. Therefore, since the mechanistic
studies had shown tetrabutylammonium thiocyanate to be such
an effective catalyst and one which was much less affected by
moisture present in the reaction mixture than the other tetrabutyl-
ammonium salts, a preparative study of the utility of catalyst 2
was undertaken. To allow the catalytic efficiency of tetrabuty-
lammonium thiocyanate to be compared with other catalysts, the
effectiveness of six Lewis acids as catalysts for the addition of
trimethylsilyl cyanide to benzaldehyde was investigated. Table 7
compares the results obtained using 10 mol% of each catalyst for
one hour at room temperature and clearly shows that aluminium
triflate is the most effective of these Lewis acidic catalysts.
Therefore, aluminium triflate and tetrabutylammonium thio-
cyanate were both used as catalysts for the addition of trimethyl-
silyl cyanide to a range of aromatic and aliphatic aldehydes. For
this study the catalyst loading was reduced to 5 mol% and the
reaction time extended to two hours, giving the results shown in
Table 8. In every case, tetrabutylammonium thiocyanate was
found to be a more effective catalyst than aluminium triflate and
for the more electron-deficient aldehydes, total conversion was
obtained in the tetrabutylammonium thiocyanate catalysed reac-
tions under these conditions. This provided a very convenient
and high yielding synthesis of pure cyanohydrin trimethylsilyl
ethers.
salts 2 and 3 it is the hypervalent silicon complex which reacts
with the aldehyde. Tetrabutylammonium cyanide 4 can directly
provide cyanide anions to add to the aldehyde.
Reactions involving catalysts 1–4 are accelerated by the pres-
ence of water and this appears to be due to a change in mechan-
ism from Lewis base-catalysed trimethylsilyl cyanide addition to
Brønsted base-catalysed hydrogen cyanide addition. Tetrabutyl-
ammonium thiocyanate was shown to be a particularly effective
catalyst for the synthesis of cyanohydrin trimethylsilyl ethers
from a range of aldehydes.
Experimental
Aldehyde concentrations were calculated by measuring UV
absorbance maxima at the appropriate wavelength using a Bio-
chrom Libra S12 UV-visible spectrophotometer. Stopped flow
experiments were carried out using an Applied Photophysics SX
stopped flow spectrometer used in absorbance mode with the
monochromator set at the appropriate wavelength for the alde-
hyde being used. NMR spectra were recorded on a Bruker
Avance 300 spectrometer operating at 300 MHz for 1H and
75 MHz for 13C. Infrared spectra were recorded using a Varian
800 FT-IR Scimitar series spectrometer fitted with an ATR
attachment. Positive ion electrospray mass-spectra were recorded
on a Waters LCT Premier LCMS spectrometer.
Conclusions
General procedure for kinetic experiments with manual
sampling
Lewis bases 1–4 catalyse the addition of trimethylsilyl cyanide
to aldehydes by three distinct mechanisms. The formation of
hypervalent silicon species could be detected for the reaction
between trimethylsilyl cyanide and tetrabutylammonium salts
2–4, but not triethylamine 1. Thus triethylamine appears to react
with trimethylsilyl cyanide to generate cyanide anions which
then add to the aldehyde. In contrast, for tetrabutylammonium
A solution of the appropriate catalyst in CH2Cl2 was added to a
5 mL round bottomed flask fitted with a Suba Seal stopper.
CH2Cl2 was added to dilute the solution to the desired volume.
An aliquot (0.5 μL) was taken via a microsyringe and diluted
into CH2Cl2 (3 mL); this sample provided the reference for UV
measurements. Aldehyde (0.94 mmol) was then added and
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another aliquot (0.5 μL) taken to calculate the concentration at
time = 0. Me3SiCN (0.14 mL, 1.03 mmol) was added and simul-
taneously a timer was started. Samples (0.5 μL) were taken and
diluted into CH2Cl2 (3 mL) at appropriate intervals and the UV
absorbance measured to determine the concentration of the
remaining aldehyde. The amount of CH2Cl2 used to dissolve the
catalyst in a particular reaction was varied to ensure that the total
initial reaction volume (CH2Cl2 + aldehyde + Me3SiCN) was
kept constant at 2.0 mL.
(CHAr), 133.3 (CAr), 133.7 (CAr), 136.3 (CAr); MS (ESI, pos.)
m/z 296 (M + Na+).
2-Trimethylsilyloxy-(4-trifluoromethylphenyl)acetonitrile.19e
IR: 2981, 2350, 1584, 1515 cm−1; 1H NMR (300 MHz, CDCl3):
δ 0.27 (s, 9H, Si(CH3)3), 5.55 (s, 1H, CHO), 7.61 (d, 2H, 3J(H,H)
3
= 8.1 Hz, CHAr), 7.70 (d, 2H, J(H,H) = 8.1 Hz, CHAr);
13C NMR (75 MHz, CDCl3): δ −0.3 (Si(CH3)3), 63.0 (CHO),
118.5 (CN), 122.4 (CHAr), 126.0 (q, 2J(C,F) = 4 Hz, ArC), 126.6
1
(CHAr), 131.55 (q, J(C,F) = 33 Hz, CF3), 140.0 (ArC); MS
(ESI, pos.) m/z 296 (M + Na+).
2-Trimethylsilyloxy-(3-chlorophenyl)acetonitrile.19e IR: 2971,
General procedure for stopped-flow kinetic experiments
1
2884, 2355, 1636, 1596 cm−1; H NMR (300 MHz, CDCl3):
Solutions of aldehyde (1.96 mol L−1) and Me3SiCN (1.12 mol
δ 0.26 (s, 9H, Si(CH3)3), 5.44 (s, 1H, CHO), 7.3–7.4 (m, 2H,
CHAr), 7.4–7.5 (m, 2H, CHAr); 13C NMR (75 MHz, CDCl3): δ
−0.3 (Si(CH3)3), 62.9 (CHO), 118.6 (CN), 124.3 (CHAr), 126.4
(CHAr), 129.5 (CHAr), 130.2 (CHAr), 134.9 (CAr), 138.1
(CAr); MS (ESI, pos.) m/z 280 (M + Na+ + H2O), 240 (MH+).
L
−1) in CH2Cl2 were prepared. The aldehyde solution was com-
bined with an equal volume of CH2Cl2 solution containing
Bu4NNCS (4 mmol L−1). The combined aldehyde and catalyst
solution was placed into one of the syringes on the stopped flow
unit and the Me3SiCN solution placed into the other. On mixing
the reagents, data was collected automatically over a time period
of between 10 seconds and 60 minutes depending on the
aldehyde.
2-Trimethylsilyloxy-(3-fluorophenyl)acetonitrile.19e IR: 3078,
2976, 2360, 1592 cm−1; 1H NMR (300 MHz, CDCl3): δ 0.25 (s,
9H, Si(CH3)3), 5.49 (s, 1H, CHO), 7.0–7.1 (m, 1H, CHAr),
7.1–7.2 (m, 1H, CHAr), 7.2–7.3 (m, 1H, CHAr), 7.3–7.4 (m,
1H, CHAr); 13C NMR (75 MHz, CDCl3): δ −0.3 (Si(CH3)3),
2
2
General procedure for Bu4NNCS-catalysed cyanohydrin
trimethylsilyl ether synthesis
62.9 (CHO), 113.5 (d, J(C,F) = 23 Hz), 116.4 (d, J(C,F) = 21
4
Hz), 118.8 (CN), 121.9 (d, J(C,F) = 3 Hz, CHAr), 130.7 (d,
3J(C,F) = 8 Hz, CHAr), 138.7 (d, J(C,F) = 7 Hz, CAr) 163.0 (d,
3
An aldehyde (1.0 mmol) was added to a solution of Bu4NNCS
(15 mg, 0.05 mmol) in dry CH2Cl2 (1.75 mL). To this solution,
Me3SiCN (119 mg, 1.2 mmol) was added and the reaction was
stirred for 2 hours at room temperature. The solution was then
passed through a short silica plug, eluting with CH2Cl2 and the
solvent was evaporated in vacuo. All the cyanohydrin trimethyl-
silyl ethers had spectroscopic data identical to those reported
previously.19e
1J(C,F) = 246 Hz, CF); MS (ESI, pos.) m/z 224 (MH+).
2-Trimethylsilyloxy-(4-chlorophenyl)acetonitrile.19e IR: 2971,
1
2352, 1595 cm−1; H NMR (300 MHz, CDCl3): δ 0.24 (s, 9H,
Si(CH3)3), 5.46 (s, 1H, CHO), 7.3–7.5 (m, 4H, CHAr); 13C
NMR (75 MHz, CDCl3): δ −0.2 (Si(CH3)3), 63.0 (CHO), 118.8
(CN), 127.7 (CHAr), 129.2 (CHAr), 134.8 (CAr), 135.3 (CAr);
MS (ESI, pos.) m/z 280 (M + Na+ + H2O).
2-Trimethylsilyloxy-(4-bromophenyl)acetonitrile.19e IR: 2970,
2-Trimethylsilyloxy-phenylacetonitrile.19e IR: 3092, 2972,
1
2230, 1590 cm−1; H NMR (300 MHz, CDCl3): δ 0.24 (s, 9H,
1
2243, 1592 cm−1; H NMR (300 MHz, CDCl3): δ 0.24 (s, 9H,
3
Si(CH3)3), 5.50 (s, 1H, CHO), 7.3–7.5 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3): δ −0.3 (Si(CH3)3), 63.6 (CHO), 119.2 (CN),
126.3 (CHAr), 128.9 (CHAr), 129.3 (CHAr), 136.2 (CAr); MS
(ESI, pos.) m/z 206 (MH+).
Si(CH3)3), 5.45 (s, 1H, CHO), 7.35 (d, 2H, J(H,H) = 8.3 Hz),
3
7.55 (d, 2H, J(H,H) = 8.3 Hz); 13C NMR (75 MHz, CDCl3):
δ −0.3 (Si(CH3)3), 63.0 (CHO), 118.7 (CN), 123.5 (CHAr),
127.9 (CHAr), 132.1 (CAr), 135.3 (CAr); MS (ESI, pos.) m/z
324 and 326 (M + Na+ + H2O), 284 and 286 (MH+).
2-Trimethylsilyloxy-(3,5-difluorophenyl)acetonitrile.19e IR:
3096, 2962, 2903, 2243, 1626, 1602 cm−1; 1H NMR (300 MHz,
CDCl3): δ 0.27 (s, 9H, Si(CH3)3), 5.50 (s, 1H, CHO), 6.84 (tt,
2-Trimethylsilyloxy-(4-fluorophenyl)acetonitrile.19e IR: 2972,
2330, 1596, 1507 cm−1; 1H NMR (300 MHz, CDCl3): δ 0.24 (s,
3
3
9H, Si(CH3)3), 5.47 (s, 1H, CHO), 7.09 (t, 2H, J(H,H) = J(H,F)
3
4
1H, J(H,F) = 8.8 Hz, J(H,H) = 2.4 Hz, CHAr), 6.9–7.1 (2H, m,
3
4
= 6.3 Hz), 7.42 (dd, 2H, J(H,H) = 6.3 Hz, J(H,F) = 3.9 Hz); 13C
NMR (75 MHz, CDCl3): δ −0.3 (Si(CH3)3), 63.0 (CHO), 116.1
(d, 2J(C,F) = 22 Hz, CHAr), 119.1 (CN), 128.4 (d, 3J(C,F) = 9 Hz,
CHAr); 13C NMR (75 MHz, CDCl3): δ −0.4 (Si(CH3)3),
2
62.4 (CHO), 104.8 (t, J(C,F) = 25.1 Hz, CHAr), 109.3 (d,
3
2J(C,F) = 26.9 Hz, CHAr), 118.2 (CN), 140.0 (t, J(C,F) = 9.1 Hz,
4
1
CHAr), 132.3 (d, J(C,F) = 3 Hz, CAr), 163.2 (d, J(C,F) = 247
1
3
CAr), 163.2 (dd, J(CF) = 249.4 Hz, J(C,F) = 12.4 Hz, CAr); MS
Hz, CF); MS (ESI, pos.) m/z 224 (MH+).
(ESI, pos.) m/z 259 (M + H2O)+.
2-Trimethylsilyloxy-(4-thiomethylphenyl)acetonitrile.19e IR:
2970, 2920, 2834, 2240, 1590, 1560 cm−1; 1H NMR (300 MHz,
CDCl3): δ 0.23 (s, 9H, Si(CH3)3), 2.50 (s, 3H, SCH3), 5.45 (1H,
2-Trimethylsilyloxy-(3,4-dichlorophenyl)acetonitrile.19e IR:
3094, 3025, 2961, 2901, 2242, 1595, 1568 cm−1 1H NMR
;
3
(300 MHz, CDCl3): δ 0.26 (s, 9H, Si(CH3)3), 5.44 (s, 1H,
s, CHO), 7.27 (d, 2H, J(H,H) = 7.6 Hz, CHAr), 7.38 (d, 2H,
3
4
CHO), 7.31 (dd, 1H, J(H,H) = 8.4 Hz, J(H,H) = 2.0 Hz, CHAr),
3J(H,H) = 7.7 Hz, CHAr); 13C NMR (75 MHz, CDCl3): δ −0.3
(Si(CH3)3), 15.4 (SCH3), 63.3 (CHO), 119.1 (CN), 126.5
(CHAr), 126.8 (CHAr), 127.1 (CAr), 139.4 (CAr); MS (ESI,
pos.) m/z 292 (M + Na+ + H2O), 252 (MH+).
7.50 (d, 1H, 3J(H,H) = 8.4 Hz, CHAr), 7.57 ppm (d, 1H, 4J(H,H)
=
2.0 Hz, CHAr); 13C NMR (75 MHz, CDCl3): δ −0.3 (Si(CH3)3),
62.4 (CHO), 118.4 (CN), 125.4 (CHAr), 128.3 (CHAr), 131.0
4296 | Org. Biomol. Chem., 2012, 10, 4289–4298
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2-Trimethylsilyloxy-(3-methylphenyl)acetonitrile.19e IR: 3052,
5179; (c) C. J. Peterson, R. Tsao and J. R. Coates, Pest Manage. Sci.,
2000, 56, 615–617; (d) N. Thasana, V. Prachyawarakorn, S. Tontoolarug
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A.-A. S. El-Ahl, Synth. Commun., 2007, 37, 1313–1319; (f) F.
L. Cabirol, A. E. C. Lim, U. Hanefeld, R. A. Sheldon and I.
1
2971, 2882, 2358, 1606 cm−1; H NMR (300 MHz, CDCl3): δ
0.23 (s, 9H, Si(CH3)3), 2.39 (s, 3H, ArCH3), 5.45 (1H, s, CHO),
7.1–7.2 (m, 1H, CHAr), 7.2–7.3 (m, 3H, CHAr); 13C NMR
(75 MHz, CDCl3): δ −0.3 (Si(CH3)3), 21.4 (ArCH3), 63.7
(CHO), 119.3 (CN), 123.5 (CHAr), 127.0 (CHAr), 129.9
(CHAr), 130.1 (CHAr), 136.1 (CAr), 138.8 (CAr); MS (ESI,
pos.) m/z 260 (M + Na+ + H2O).
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2-Trimethylsilyloxy-(4-methylphenyl)acetonitrile.19e IR: 3020,
1
2968, 2820, 2352, 1604 cm−1; H NMR (300 MHz, CDCl3): δ
0.22 (s, 9H, Si(CH3)3), 2.37 (s, 3H, ArCH3), 5.45 (1H, s, CHO),
3
3
7.22 (d, 2H, J(H,H) = 7.9 Hz), 7.35 (d, 2H, J(H,H) = 7.9 Hz);
13C NMR (75 MHz, CDCl3): δ −0.2 (Si(CH3)3), 21.2 (ArCH3),
63.6 (CHO), 119.3 (CN), 126.4 (CHAr), 129.6 (CHAr), 133.4
(CAr), 139.4 (CAr); MS (ESI, pos.) m/z 260 (M + Na+ + H2O).
2-Trimethylsilyloxy-(3,4-dimethylphenyl)acetonitrile.19e IR:
1
3017, 2960, 2924, 2239 cm−1; H NMR (300 MHz, CDCl3): δ
0.21 (s, 9H, Si(CH3)3), 2.26 (s, 3H, ArCH3), 2.28 (s, 3H,
ArCH3), 5.41 (1H, s, CHO), 7.1–7.3 (m, 3H, CHAr); 13C NMR
(75 MHz, CDCl3): δ −0.2 (Si(CH3)3), 19.6 (ArCH3), 19.8
(ArCH3), 63.6 (CHO), 119.4 (CN), 123.9 (CHAr), 127.6
(CHAr), 130.1 (CHAr), 133.7 (CAr), 137.4 (CAr), 138.0 (CAr);
MS 274 (M + Na+ + H2O).
6 M. Bandini, P. G. Cozzi, A. Garelli, P. Melchiorre and A. Umani-Ronchi,
Eur. J. Org. Chem., 2002, 3243–3249.
2-Trimethylsilyloxy-(4-methoxyphenyl)acetonitrile.19e IR: 3002,
2960, 2840, 2742, 2270, 1596, 1577 cm−1; 1H NMR (300 MHz,
CDCl3): δ 0.21 (s, 9H, Si(CH3)3), 3.83 (s, 3H, OCH3), 5.44
7 S. E. Denmark and W. Chung, J. Org. Chem., 2006, 71, 4002–4005.
8 For representative examples see: (a) H. Kawabata and M. Hayashi, Tetra-
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3
(1H, s, CHO), 6.93 (d, 2H, J(H,H) = 8.5 Hz), 7.39 (d, 2H,
3J(H,H) = 8.5 Hz); 13C NMR (75 MHz, CDCl3): δ −0.2
(Si(CH3)3), 55.3 (OCH3), 63.3 (CHO), 114.3 (CAr), 119.3 (CN),
127.9 (CHAr), 128.5 (CHAr), 160.3 (CAr); MS (ESI, pos.) m/z
236 (MH+).
2-Trimethylsilyloxy-(4-tert-butoxyphenyl)acetonitrile.19e IR:
3063, 3036, 2978, 2904, 2240, 1608, 1508 cm−1 1H NMR
;
(300 MHz, CDCl3): δ 0.22 (s, 9H, Si(CH3)3), 1.36 (s, 9H, OC
3
(CH3)3), 5.46 (1H, s, CHO), 7.02 (d, 2H, J(H,H) = 8.4 Hz,
3
CHAr), 7.36 (d, 2H, J(H,H) = 8.4 Hz, CHAr); 13C NMR
(75 MHz, CDCl3): δ −0.2 (Si(CH3)3), 28.8 (C(CH3)3), 63.4
(CHO), 79.0 (OCMe3), 119.3 (CN), 124.2 (CAr), 127.2 (CHAr),
130.9 (CHAr), 156.4 (CAr); MS (ESI, pos.) m/z 278 (M + H).
9 (a) R. Córdoba, A. G. Csákÿ and J. Plumet, ARKIVOC, 2004, vi, 94–99;
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