A convenient catalytic procedure for the addition of trimethylsilyl cyanide to functionalised ketones, mediated by InBr3 - Insight into the reaction mechanism

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3243::AID-EJOC3243>3.0.CO;2-E

This paper describes a useful and practical methodology for the addition of trimethylsilyl cyanide (TMSCN) to a large variety of functionalised and unfunctionalised ketones in the presence of catalytic amounts of anhydrous InBr₃. The optimum pr

Full text of DOI:10.1002/1099-0690(200210)2002:19<3243::AID-EJOC3243>3.0.CO;2-E

FULL PAPER
A Convenient Catalytic Procedure for the Addition of Trimethylsilyl Cyanide
to Functionalised Ketones, Mediated by InBr ؊ Insight into the Reaction
3
Mechanism
[a]
[a]
[a]
[a]
Marco Bandini,* Pier Giorgio Cozzi, Andrea Garelli, Paolo Melchiorre, and
Achille Umani-Ronchi*[
a]
Dedicated to Prof. Gianfranco Cainelli on the occasion of his 70th birthday
Keywords: Catalysis / Cyanides / Indium / Ketones / Kinetics
This paper describes a useful and practical methodology for
the addition of trimethylsilyl cyanide (TMSCN) to a large
variety of functionalised and unfunctionalised ketones in the
isolated as their O-silyl ethers in good to excellent chemical
yields (up to 99%). Kinetic and spectroscopic studies suggest
that a catalytically active dimeric indium species is involved
3
presence of catalytic amounts of anhydrous InBr . The op- in the reaction mechanism.
timum procedure involves low catalyst loading (1 mol %) and
appears general in scope and applicability for aromatic and
aliphatic ketones. The desired cyanohydrins were typically
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
stoichiometric and in catalytic amount. Among these,
[
3]
[4]
[5]
[6]
Yb(CN) ,
Yb(OTf) ,
Cu(OTf) ,
ZnI2,
KCN/18-
3
[
3
2
7]
[8]
[9]
[10]
Cyanation is one of the most powerful procedures for the crown-6, LiClO4, R SnCl , and Zr(KPO4)2
ap-
2
2
synthesis of functionalised compounds containing the cy- peared to be the most effective. Nevertheless, the scope of
ano moiety, and has considerable synthetic potential in or- these procedures appears quite limited. In fact, only ZnI2
ganic synthesis (Figure 1).[1]
and KCN/18-crown-6 are known to be moderately active as
catalysts in the cyanation of heterosubstituted ketones. Low
chemical yields, the lack of broad tolerance of functional
groups and the high loading of catalyst required to perform
this transformation on substituted ketones were the factors
that prompted us to investigate a new catalytic system for
the addition of trimethylsilyl cyanide to functionalised ke-
tones.
Indium salts have some interesting features, namely their
low environmental impact, high chemoselectivity, and toler-
ance toward aqueous media. These characteristics make in-
dium salts unique in their group of the periodic table and
Figure 1. The versatility of the cyano group as a synthon in or-
ganic chemistry
Moreover, α-hydroxy nitriles or cyanohydrins are useful
starting materials for the synthesis of biologically active
compounds. For these reasons, cyanation methodologies
[11]
[12]
justify the growing employment of InCl ,
InBr3,
and
3
[13]
In(OTf)3
in organic synthesis. In this context, the low
[
2]
are attracting increasing interest in organic synthesis.
[14]
heterophilicity exhibited by indium salts (oxygen- and ni-
trogen-containing moieties) allows their employment in the
performance of chemoselective transformations of poly-
functionalised compounds.
Generally, in the absence of a catalyst, no reaction occurs
between TMSCN (a common cyano anion source) and car-
bonyl compounds. However, smooth reaction takes place
in the presence of several promoting agents used both in
We have recently reported a high-yield InBr -catalysed
3
cyanation of unfunctionalised and α-amino, α-thio, α-oxo,
[
a]
Dipartimento di Chimica ‘‘G. Ciamician’’
via Selmi 2, 40126 Bologna, Italy
[15]
and α-nitro ketones.
In this paper we report a full ac-
Fax: (internat.) ϩ 39-051/209-9456
count of our results, stressing the remarkable generality of
the procedure. Moreover, some example cyanation reactions
were carried out on enantiomerically pure ketones and N-
acyliminium ions, furnishing the corresponding cyano de-
E-mail: bandini@ciam.unibo.it
umani@ciam.unibo.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2002, 3243Ϫ3249  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3243 $ 20.00ϩ.50/0
3243

M. Bandini, P. G. Cozzi, A. Garelli, P. Melchiorre, A. Umani-Ronchi
In fact, weak Lewis acids such as NiCl , NiBr , AgF,
FULL PAPER
rivatives with moderate to excellent diastereoselectivity. Fi-
2
2
nally, experimental observations derived from detailed kin- FeCl , SbCl , and InF afforded the desired 3-methoxy-2-
2
3
3
etic and spectroscopic studies provided some information phenyl-2-(trimethylsilyloxy)propionitrile (2) only in traces
for the understanding of the reaction mechanism.
(Entries 3Ϫ6, 8Ϫ9). Contrary to a previously reported
study, the corresponding α-methoxy nitrile 2 was isolated
[
6]
in quantitative yield (97%, Entry 2) when ZnI was em-
2
Results and Discussion
ployed as the catalyst. Finally, the use of lanthanide salts
as catalysts afforded the products with poor levels of con-
The addition of cyanide to aldehydes in the presence version (Entries 15 and 16, Table 1).[3,18]
of organometallic catalysts, enzymes and biocatalytic sys-
Of particular interest were the results obtained with
tems is a well-known procedure.[1] The corresponding re-
action of the less reactive ketones, on the other hand,
has been much less exploited.[ Our ongoing interest in
the design and development of a new, mild, high-perform-
ance cyanation procedure prompted us to screen a large
variety of metal salts as catalysts for the addition of
TMSCN to the commercially available α-methoxyaceto-
phenone (1) (Scheme 1).
InBr . Despite the mild Lewis acid character usually dis-
3
played by indium salts, we were delighted to find that
16]
TMSCN reacted smoothly with 1 in the presence of 10
III
mol % of anhydrous In bromide. Moreover, the isolated
yields were excellent even at lower catalyst loadings (1
mol %, yield ϭ 99%; 0.1 mol %, yield 90%; 0.05 mol %,
[19]
yield ϭ 70%; Entries 3Ϫ5 Table 2).
3
Table 2. Anhydrous InBr -mediated catalytic addition of TMSCN
to 1
Entry[a]
Solvent
CH Cl
InBr
[mol %]
t [h]
Yield [%][b]
3
Scheme 1. Screening of different Lewis acids in the catalytic addi-
tion of TMSCN to 1
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
2
Ϫ
10
1
0.1
0 .05
10
10
10
10
10
48
0.5
0.5
3
72
3
3
3
3
3
7
99
99
90
70
7
CH
CH
CH
CH
Cl
Cl
Cl
Cl
The choice of an α-alkoxy ketone as the model substrate
was due to its known low reactivity toward Lewis acid me-
diated addition of trialkylsilyl cyanides.[6,17] The results ob-
tained with 10 mol % of catalyst are summarised in Table 1
Firstly, from analysis of the results it appears clear that a
narrow connection between yield and Lewis acidity of the
metal salts can be discerned.
[
[
c]
d]
THF
Et
n-pentane
CH CN
toluene
2
O
85
71
85
90
3
1
0
[
a]
[b]
All the reactions were carried out at room temperature. Isol-
ated yields after flash chromatography. [ For this reaction a solu-
tion of InBr
c]
Table 1. Screening of Lewis acids as catalysts for the addition reac-
[d]
3
(0.2 ) in dry CH
3
CN was used. For this reaction
tion of TMSCN to α-methoxyacetophenone (1)
a solution of InBr
3
(0.02 ) in dry CH CN was used.
3
Entry[a]
Lewis acid
t [h]
Yield [%][b]
It should be noted that, when the cyanation was per-
formed in the absence of the catalyst, the silyloxy nitrile was
isolated only in 7% yield after 48 h reaction time (Entry 1,
Table 2). To optimise the experimental conditions, the influ-
ence of the solvent on the effectiveness of the catalytic sys-
tem was briefly investigated. Several anhydrous solvents
1
2
3
4
5
6
7
8
9
ZnBr
ZnI
NiCl
NiBr
FeCl
SbCl
2
20
20
20
20
20
20
20
20
20
3
88
97
2
[
[
c]
c]
2
Ϫ
Ϫ
Ϫ
Ϫ
55[
Ϫ
19
90
99
60
91
93
15
18
2
2
3
c]
MgI
AgF
2
(
Et O, n-pentane, CH CN, THF, toluene) were examined
2 3
InF
InCl
InBr
MnBr
Sc(OTf)
Sn(OTf)
La(OTf)
Yb(OTf)
3
(Entries 6Ϫ10, Table 2), but the highest reaction rate was
10
11
12
13
14
15
16
3
[20]
obtained with the use of DCM as the reaction medium.
0.5[
20
20
20
20
20
d]
3
The optimised procedure was carried out with a large
variety of α-hetero-substituted ketones, showing the gener-
ality of the procedure, and the corresponding O-silyl cy-
anohydrins were isolated in excellent yields (Table 3). To the
best of our knowledge, this is the first significant example of
2
3
2
3
3
[
a]
2 2
All the reactions were carried out in anhydrous CH Cl
at room cyanation reaction carried out on amino-, thio- and halo-
temperature, with 10 mol % of catalyst. The uncatalysed reaction substituted ketones (Entries 6Ϫ9, Table 3). In fact, α-mor-
proceeded to 10% conversion after 48 h reaction time. [ The chem-
b]
pholinoacetophenone (13), α-(p-tolyl)acetophenone (15),
ical yields given are of the isolated product after chromatographic
[
c]
and α-bromoacetophenone (17) furnished the desired O-si-
lylated cyanohydrins 14, 16, and 18, respectively, in moder-
ate to superb isolated yields (71%, 95%, 85%; Table 3).
purification.
A large amount of silyl enol ether was observed
[
d]
as a side product.
of catalyst.
The reaction was carried out with 1 mol %
3244
Eur. J. Org. Chem. 2002, 3243Ϫ3249

Addition of Trimethylsilyl Cyanide to Functionalised Ketones
FULL PAPER
Table 3. Catalytic cyanation of α-substituted ketones with InBr
the Lewis acid
3
as
3
Table 4. Catalytic cyanation of unsubstituted ketones with InBr as
the Lewis acid
[
a]
[a]
[
a]
2 2
All the reactions were carried out in anhydrous CH Cl at room
temperature, with 1 mol % of catalyst. [ The given chemical yields
are of the isolated O-silylated product after chromatographic puri-
fication.
b]
[
a]
2 2
All the reactions were carried out in anhydrous CH Cl at room
temperature, with 10 mol % of catalyst. [ The given chemical
b]
yields are of the isolated O-silylated product after chromatographic
[
c]
purification. The cyanohydrin was isolated in a 61:39 diastereo- moderate diastereoisomeric ratios (drs) of 1.6:1 and 3.5:1,
1
isomeric ratio. The diastereoisomer ratio was determined from H
respectively (Entries 1Ϫ2, Table 5). The stereoselectivity ap-
NMR analysis of the crude product.
peared to be strongly correlated to the bulkiness in proxim-
ity to the carbonyl moiety. In fact, the chiral α-(S)-O-tert-
On the other hand, the α-hydroxy ketone 11 and α-(tert- butyldimethylsilyloxy ketones (Me)-37, (Bn)-39, and (Ph)-
[
22]
butyldimethylsilyloxy)acetophenone (9) are poor substrates 41 afforded, in the presence of InBr (10 mol %), the de-
3
for this procedure. As a matter of fact, while a complex sired 1,2-disilyloxy nitriles (40, 42, 44) with an increasing
mixture of undefined products was detected by GC analysis diastereoselectivity from 53:47 to 82:18 (Table 5, Entries
in the case of 12, the presence of a highly steric hindering 3Ϫ5).
group (TBDMS) in proximity to the carbonyl moiety of
The InBr was also able to catalyse the cyanation reaction
3
the substrate 9 effects the efficacy of the process strikingly. of 4-acetoxy-β-lactams. The (3R,4R,1ЈR)-4-acetoxy-3-[1-
Moreover, it should be mentioned that no product deriving (tert-butyldimethylsilyloxy)ethyl]azetedin-2-one (43) was
from enolisation of the ketones was detected during the easily converted into the (3S,4R,1ЈR)-4-cyano derivative 44
1
[21]
course of the reaction (checked by H NMR).
This indium catalytic system was also applied to aromatic Entry 6, Table 5).
and aliphatic unsubstituted ketones. The corresponding cy- A discriminating experiment between bidentate and mon-
in good yield (75%) and excellent diastereomeric ratio (98:2;
[
23]
anohydrins were obtained in high isolated yields (75Ϫ96%; odentate carbonyl substrates was carried out by treatment
see Table 4). In addition, it is important to stress the re- of an equimolar mixture of 21 and 25 with 10 mol % of
markable chemoselectivity observed for the α,β-unsaturated InBr in CH Cl at room temperature for 30 min, and sub-
3
2
2
ketone 31. In this case, in fact, only the product derived sequent addition of 1.05 equiv. of TMSCN (Scheme 2).
from 1,2-addition was obtained (Entry 6, Table 4). After a reaction time of 24 h, the competitive cyanation re-
Finally, several optically pure ketones were treated with action had given rise to an excess of the α-methoxy cy-
[
24]
TMSCN in the presence of InBr , and the results are col- anohydrin 26, accompanied by 22 in a 9:1 ratio.
3
lected in Table 5. Commercially available (S)-(Ϫ)-menthone
33) and (1R)-(ϩ)-camphor (35) afforded the corresponding chelating Lewis acids,[25] the result of the competition ex-
cyanohydrins 34 and 36 in good yields (85%, 88%) and periment could be a consequence of a preferred initial
Since the indium() salts are commonly identified as
(
Eur. J. Org. Chem. 2002, 3243Ϫ3249
3245

M. Bandini, P. G. Cozzi, A. Garelli, P. Melchiorre, A. Umani-Ronchi
Table 5. Stereoselectivity in the catalytic cyanation of optically act- ations of the signals of the carbonyl and methoxy carbon
FULL PAPER
[
a]
ive ketones
atoms indicate that indium bromide is involved in a two-
side-binding interaction with the heterosubstituted ketone.
Scheme 4
Reaction Mechanism
To make reactions available for kinetic studies requires
the identification of experimental conditions under which
the transformation rate is sufficiently slow. For our pur-
poses, α-morpholinoacetophenone (13) guaranteed feasible
monitoring of the initial reaction rates of the cyanation by
GC. A solution of naphthalene in dry CH Cl was used
2
2
as the internal standard. The reaction rates were measured
monitoring each run from 8% completion to 18Ϫ25% con-
version and all the cyanation reactions were monitored up
to at least 75% conversion.
The initial reaction rates calculated at different concen-
trations ([C] ) of InBr , 13, and TMSCN furnished the
0
3
overall kinetic equation of the cyanation process. An ex-
ample of such a study, directed towards exploration of the
rate order of the indium tribromide, is shown in Figure 2.
[
a]
All the reactions were carried out in anhydrous CH
2
Cl
2
with 10
[
b]
mol % of catalyst. The given chemical yields are of the isolated
[c]
O-silylated product after chromatographic purification. The dia-
stereoisomeric ratio was determined by GC and NMR analysis of
the crude mixture.
Scheme 2. The competitive experiment between mono- and bident-
ate carbonyl substrates
3 0
Figure 2. Degrees of conversion (%) versus time at different [InBr ]
formation of a pentacoordinate indium species[26] 45 with
respect to the unchelated adduct 46 (Scheme 3).
From the trends of the curves recorded at different in-
dium concentrations (2.5Ϫ37.5 m), it appears that the rate
of cyanation was strongly affected by the total concentra-
Scheme 3
To validate the former statement regarding chelate organ-
1
3
isation, a C NMR investigation of the reaction mixture
was performed (with CDCl as solvent). Scheme 4 shows
3
the more diagnostic chemical shifts of the complex 47
(
InBr /1, 1:1 ratio) in comparison with the signals of the
3
ketone 1. The recorded spectra displayed that a single spe-
cies is present in solution. Moreover, the chemical shift vari- centration of InBr
Figure 3. Determination of the order dependence on the total con-
3
3246
Eur. J. Org. Chem. 2002, 3243Ϫ3249

Addition of Trimethylsilyl Cyanide to Functionalised Ketones
FULL PAPER
tion of indium. The reaction orders with respect to all the reaction between InBr and TMSCN [Equation (1)][ was
30]
3
cyanation components were obtained by plotting log[rate] ruled out by spectroscopic investigations.
versus log[C] , and the case for InBr is reported in Fig-
0
3
ure 3.
With [InBr ] , [13] , and [TMSCN] indicating the initial
(
1)
3
0
0
0
concentrations of the pre-catalyst, α-morpholino ketone,
In fact, on monitoring of the reaction between TMSCN
and trimethylsilyl cyanide, respectively, the rate equation is
13
1
.4
1.0
0
[ C NMR (CD
2 2
Cl , TMS, 25 °C): δ ϭ 127.0, Ϫ1.8 ppm]
described as rate ϭ 2.3·[InBr3]0 ·[TMSCN]0 ·[13] . The
0
13
and InBr (1:1 ratio) in anhydrous CD Cl at 25 °C by
C
3
2
2
rate was first-order depending on the concentration of the
TMSCN and zero-order with respect to the concentration
of the carbonyl compound.
In the first step of the catalytic cycle, the Lewis acid is
assumed to coordinate the carbonyl compound 13. As pre-
viously reported, a fractional order (1.4) for a catalytic spe-
cies can be interpreted in terms of the presence of an equi-
librium between a mononuclear (A) and a dinuclear indium/
NMR, no formation of TMSBr (δ ϭ 4.2 ppm) was ob-
[
31]
served. On the other hand, the spectra showed the com-
plete disappearance of the TMSCN signals, and a new peak
[
32]
appeared at δ ϭ 1.9 ppm. This shifting to lower field, in
comparison to TMSCN, could indicate the presence of an
InǟNC species characterised by a dative interaction be-
tween the cyano group of the TMSCN and the indium
[
33]
metal centre.
In support of this hypothesis, we recorded
Cl ) of interacting InBr and
1
3 complex (B) in which the dimeric aggregate is the cata-
the 29Si NMR spectra (in CD
[27]
2
2
3
lytically active species (Figure 4). The hypothesis of a di-
bromo-bridged structure for the dimeric indium aggregate
is in agreement with several experimental data reported in
TMSCN (δ ϭ Ϫ11.1 ppm), and only one signal appeared
at δ ϭ 7.4 ppm. A tentative picture to account for the kin-
etic and spectroscopic investigations for the indium-medi-
ated cyanation is suggested in Figure 4.
[
28]
the literature.
Finally, the assumption that the rate-limiting step of the
process is the approach of the TMSCN and the further nu-
cleophilic addition could explain the independence of the
reaction rate of the concentration of the carbonyl com-
pound.
Conclusion
In conclusion, we have shown that InBr can be effec-
3
tively employed, at low catalytic loading, for promotion of
the chemoselective addition of TMSCN to variously substi-
tuted and unsubstituted ketones. Such a procedure allows
the isolation of the corresponding O-silylated cyanohydrins
in high yields. In this context, an investigation of the reac-
tion mechanism indicated the presence of an indium ag-
gregate as the catalytically active species. Thanks to the
mild experimental conditions required and due to its gener-
ality in scope and applicability, this procedure is probably
one of the most straightforward catalytic systems for the
synthesis of polyfunctionalised cyano compounds starting
from carbonyls.
Figure 4. Hypothetical InBr
3
-promoted cyanation reaction mech-
anism
To provide additional evidence for the presence of such
an equilibrium, we carried out some H NMR com-
plexation studies. InBr3 and 13 were mixed (1:1 ratio,
1
CD Cl ) and some NMR spectra were recorded at room
2
2
1
temp. and at Ϫ60 °C. While the H NMR spectra recorded
Experimental Section
at room temp. showed several sets of broad peaks, the 13
C
1
NMR spectra showed the existence of a single species in General Remarks: H NMR spectra were recorded with Varian Ge-
which the ketone seems to be coordinated by a bidentate mini 200 (200 MHz) or Varian INOVA 300 (300 MHz) spectro-
meters. Chemical shifts δ are given in ppm with respect to TMS,
interaction with the indium metal centre (see Supporting
Information).
[
29]
and coupling constants J are measured in Hz. Data are reported
as follows: chemical shifts, multiplicity (s ϭ singlet, d ϭ doublet,
t ϭ triplet, q ϭ quadruplet, br ϭ broad, m ϭ multiplet). 1 C NMR
spectra were recorded with Varian Gemini 200 (50 MHz) or Varian
INOVA 300 (75 MHz) spectrometers with complete proton decoup-
ling. Chemical shifts are reported in ppm from tetramethylsilane,
with the solvent as the internal standard (deuteriochloroform: δ ϭ
In order to explain the first-order dependence on the
TMSCN we suggest that the incoming nucleophile could
interact with the metal atom to furnish an aggregate in
which TMSCN and carbonyl compound are close to each
other (C). At present, the true nature of the InϪ[CN] inter-
3
2
9
action remains unclear. However, the hypothetical forma- 77.0 ppm; deuteriodimethyl sulfoxide: δ ϭ 39.0 ppm). Si NMR
tion of an indium cyanide species by a fast transmetallation spectra were recorded with a Varian Gemini 300 (51.6 MHz) spec-
Eur. J. Org. Chem. 2002, 3243Ϫ3249
3247

M. Bandini, P. G. Cozzi, A. Garelli, P. Melchiorre, A. Umani-Ronchi
FULL PAPER
trometer. Chemical shifts δ are reported in ppm from tetramethylsi-
lane as the external standard (TMS: δ ϭ 0.0 ppm). GC-MS spectra
were taken by EI ionization at 70 eV with a HewlettϪPackard 5971
with GC injection. They are reported as m/z (%). Flash column
chromatography was performed on 270Ϫ400 mesh silica gel. An-
shi, T. Busujima, S. Nagayama, Tetrahedron Lett. 1998, 39,
1
3
579Ϫ1582; T.-P. Loh, L.-L. Wei, Tetrahedron Lett. 1998, 39,
23Ϫ326. [
11c]
FriedelϪCrafts reaction: J. S. Yadav, S. Abra-
ham, B. V. S. Reddy, G. Sabitha, Synthesis 2001, 2165Ϫ2168.
[11d]
Aziridiation: S. Sengupta, S. Mondal, Tetrahedron Lett.
[11e]
2
000, 41, 6245Ϫ6248.
oue, M. Yasuda, A. Baba, Synlett 1997, 699Ϫ700.
reaction: B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem. 2000,
Allylation reaction: T. Miyai, K. In-
hydrous CH
were purchased from the Fluka and Co. and from Aldrich and used
as received. CDCl and CD Cl were dried over activated molecu-
2
Cl
2
, CH
3
CN, Et
2
O, THF, n-pentane, TMSCN, and 1
[11f]
Biginelli
65, 6270Ϫ6272. [
11g]
Azidolysis of epoxycarboxylic acids: F.
3
2
2
lar sieves. Elemental analyses were carried out with an EACE 1110
CHNOS analyser. IR analysis were performed with an FT-IR NIC-
OLET 205 spectrophotometer. IR spectra are expressed by wave-
Fringuelli, F. Pizzo, L. Vaccaro, J. Org. Chem. 2001, 66,
3554Ϫ3558. [
11h]
Y. Onishi, T. Ito, M. Yasuda, A. Baba, Eur. J.
[
11i]
Org. Chem. 2002, 1578Ϫ1581.
Sakurai reaction: P. H. Lee,
Ϫ1
K. Lee, S. Sung, S. Chang, J. Org. Chem. 2001, 66, 8646Ϫ8649.
K. Inoue, A. Sawada, I. Shibata, A. Baba, J. Am. Chem. Soc.
number in cm . All the commercially available ketones were
freshly distilled or crystallised before use. The azetedinone 43 was
crystallised from n-pentane before use. The substituted ketones
2
002, 124, 906Ϫ907.
[
12] [12a]
Dithioacetalization: M. A. Ceschi, L. de Araujo Felix, C.
[
15] [34a] [15]
[34b]
[15]
[15]
3,
5,
9, 11,
13, and 15 were prepared by literature
[12b]
Peppe, Tetrahedron Lett. 2000, 41, 9695Ϫ9699.
nucleophilic addition: M. Bandini, P. G. Cozzi, M. Giacomini,
Tandem
procedures. The ketone 25 was synthesised by methylation of the
commercially available ethyl (2-hydroxyphenyl) ketone (MeI/
P. Melchiorre, S. Selva, A. Umani-Ronchi, J. Org. Chem. 2002,
67, 3700Ϫ3704. [
12c]
Michael addition: M. Bandini, P. Mel-
K
2
CO
3
, H
2
O/acetone, yield 91%).
chiorre, A. [ Melloni, A. Umani-Ronchi, Synlett 2002,
12d]
General Procedure for the InBr
TMSCN to Ketones: Anhydrous CH
.03 mmol) and carbonyl compound (3 mmol) were placed, under
nitrogen, in a flame-dried two-necked flask. The mixture was
stirred until the indium tribromide was completely dissolved
3
-Mediated Catalytic Addition of
1110Ϫ1114.
Stereoselective ring-opening of epoxides: M.
2
Cl (2 mL), InBr (11 mg,
2
3
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[
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Cyclization: T.-P. Loh, Q.-Y. Hu, K.-T. Tan, H.-S. Cheng,
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13c]
Synthesis of tetrahydrofur-
dropwise by syringe. This clear solution was then stirred at room
temperature until the disappearance of the ketone (1Ϫ3 h, checked
by TLC). The reaction was then quenched with a saturated
1
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2000, 33, 16Ϫ22.
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2
4
[14c]
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3
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Acknowledgments
[
16]
This work was financially supported by the MURST, Rome (Pro-
getto Nazionale Stereoselezione in Sintesi Organica Ϫ Metodologie
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research topics). We are also grateful to Professor Antonio Arcelli
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3248
Eur. J. Org. Chem. 2002, 3243Ϫ3249

Addition of Trimethylsilyl Cyanide to Functionalised Ketones
FULL PAPER
in fact, it is possible that the active dimeric species is an equilib-
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[
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[
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Received May 20, 2002
[O02264]
29]
This result does not rule out the existence of a dimeric adduct;
Eur. J. Org. Chem. 2002, 3243Ϫ3249
3249