Indium tribromide: A highly effective catalyst for the addition of trimethylsilyl cyanide to α-hetero-substituted ketones

Article abstract of DOI:10.1016/S0040-4039(01)00368-9

The catalytic addition of trimethylsilyl cyanide (TMSCN) to a large variety of hetero-substituted ketones promoted by anhydrous InBr₃ has been studied. The low catalytic loading (0.1-1 mol%) and the mild experimental conditions required represe

Full text of DOI:10.1016/S0040-4039(01)00368-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3041–3043
Indium tribromide: a highly effective catalyst for the addition of
trimethylsilyl cyanide to a-hetero-substituted ketones
Marco Bandini, Pier Giorgio Cozzi,* Paolo Melchiorre and Achille Umani-Ronchi*
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 12 January 2001; revised 12 February 2001; accepted 28 February 2001
Abstract—The catalytic addition of trimethylsilyl cyanide (TMSCN) to a large variety of hetero-substituted ketones promoted by
anhydrous InBr3 has been studied. The low catalytic loading (0.1–1 mol%) and the mild experimental conditions required
represent the key features of this novel catalytic system. © 2001 Elsevier Science Ltd. All rights reserved.
Cyanation reactions of carbonyl compounds is one of
the most powerful procedures for the synthesis of poly-
functionalized molecules. In fact, the cyano moiety has
considerable synthetic potential as a building block in
organic synthesis (Fig. 1).1 For this purpose, several
useful cyanating reagents were introduced.2 Among
them, trimethylsilyl cyanide (TMSCN) seems to be one
of the more effective and safe cyano anion sources for
nucleophilic addition to carbonyl compounds.
isolated yields of trimethylsilyloxy cyanohydrine 2 were
recorded employing ZnI2 (97%), InCl3 (90%), InBr3
(99%), Sc(OTf)3 (91%), Sn(OTf)2 (93%) as promoting
agents.
Particularly interesting are the results obtained with
InBr3. Despite the mild Lewis acid character usually
shown by indium salts, we found that anhydrous In(III)
bromide effectively promotes the addition of TMSCN7
to substituted ketones in CH2Cl2 and maintains its
performance even at lower catalytic loading (1 mol%,
yield=99%; 0.1 mol%, yield=90%; 0.05 mol%, yield=
70%; entries 3–5, Table 1). It should be noted that
performing the cyanation in the absence of the catalyst
gave the silyloxy nitrile in 7% yield after a reaction time
of 48 h (Table 1, entry 1).
Generally, in the absence of a catalyst, no reaction
occurs between TMSCN and carbonyl compounds.
Several additives and Lewis acids, both in stoichiomet-
ric and catalytic amounts, have been tested as promot-
ing agents for such reactions.3 The addition of TMSCN
to aldehydes4 and imines5 (Strecker reaction) has been
largely studied, whereas the cyanation reaction of less
reactive substituted and unsubstituted ketones has not
been extensively exploited.6
Our ongoing interest in the design and development of
new and high-performance mild cyanation procedures
prompted us to screen a large variety of Lewis acids as
catalysts (10 mol%) for the addition of TMSCN to the
commercially available a-methoxy acetophenone
(Scheme 1).
1
Figure 1. Cyanohydrins as intermediates in organic synthesis.
The choice of an a-alkoxy ketone as the model sub-
strate was due to its known low reactivity towards
Lewis acid-mediated addition reactions of trialkylsilyl
cyanides.3d Among all the reactions carried out, higher
O
TMSO
R
CN
R'
InBr3
X
+ TMSCN
X
R
CH2Cl2
R'
1: R=Ph, R'=H, X=OMe
Keywords: catalysis; cyanohydrins; indium; ketones.
* Corresponding authors. E-mail: pgcozzi@ciam.unibo.it; umani@
ciam.unibo.it
2
Scheme 1. Cyanation reaction of 1 mediated by Lewis acids.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00368-9

3042
M. Bandini et al. / Tetrahedron Letters 42 (2001) 3041–3043
Table 2. Catalytic cyanation of hetero-substituted and
Other reaction conditions were briefly considered. Dif-
ferent solvents were examined (Table 1, entries 6–10);
however, the highest reaction rate was obtained
employing CH2Cl2.8 It is noteworthy that when carry-
ing out the reaction in THF, cyanohydrin 2 was iso-
lated in only 7% yield. Such a low conversion is due to
a strong interaction between the highly oxophilic
indium tribromide and THF that decreases the Lewis
acidity of the indium salt.
unsubstituted ketones using InBr3 as a Lewis acida
Having optimized the reaction protocol (InBr3, 1
mol%), the indium-mediated cyanation of a wide range
of a-hetero-substituted ketones9 was investigated and
the results are given in Table 2.
To our knowledge, this is the first significant example
of a cyanation reaction carried out on amino-, thio-
and halo-substituted ketones (entries 5–7, Table 2). In
fact, a-morpholine acetophenone 7, a-p-tolyl acetophe-
none 8 and a-bromo acetophenone 9 furnished the
desired O-silylated cyanohydrins 16, 17 and 18, respec-
tively, in good to excellent yields (51, 95 and 85%,
respectively, Table 2). On the other hand, the a-t-
butyldimethylsilyloxy acetophenone 6 represents a limi-
tation for this procedure. As a matter of fact, the low
conversion in 15 was probably a function of the high
steric hindrance (O-TBDMS) of 6 in proximity to the
carbonyl moiety.
a
Finally, it is noteworthy that this cyanation reaction is
also able to convert unsubstituted ketones (10 and 11)
to the corresponding silyl cyanohydrins in excellent
yield (96%) with a low loading of InBr3 (0.1 mol%)
(entries 8 and 9, Table 2).
All the reactions were carried out in anhydrous CH2Cl2 at room
temperature, employing 1 mol% of catalyst.
The chemical yields are given on the isolated O-silyl product after
b
chromatographic purification.
c
The cyanohydrin was isolated in a diastereomeric ratio of 61:39 (1H
NMR of the crude product).
The reaction was carried out employing 1 mol% of InBr3.
d
In conclusion, we present a straightforward InBr3-medi-
ated cyanation methodology that allows the synthesis
of cyanohydrins from substituted and unsubstituted
ketones. The mild experimental conditions, the low
loading of catalyst and the general applicability repre-
sent the notable features of such a procedure. Studies
concerning the reaction mechanism, as well as the
application of the catalytic protocol in the synthesis of
biologically active compounds, are in progress.
Table 1. Catalytic addition of TMSCN to 1 mediated by
a
anhydrous InBr3
A typical procedure for the catalytic cyanation reaction
is as follows: To a flame-dried two-necked flask were
added 2 mL of dry CH2Cl2, anhydrous InBr3 (11 mg,
0.03 mmol) and 1 (460 mL, 3 mmol). After stirring for
10 min, TMSCN (560 mL, 4.5 mmol) was added by
syringe to the clear solution. The reaction was stirred at
room temperature until complete consumption of the
ketone had occurred (as evidenced by TLC, ca. 30 min)
and reaction was then quenched with a saturated solu-
tion of NaHCO3 (4 mL). After the usual work-up
(extraction with Et2O (3×5 mL), anhydrification with
Na2SO4 and evaporation of the solvent under reduced
pressure), the crude product was purified by flash chro-
matography (cyclohexane:Et2O 95:5) to afford the 3-
methoxy-2-phenyl-2-trimethylsilyl propionitrile 2 as a
pale yellow oil in 99% yield. 1H NMR (300 MHz,
CDCl3): l 0.18 (s, 9 H), 3.42 (s, 3 H), 3.57 (d, J=9.9
Hz, 1 H), 3.64 (d, J=9.9 Hz, 1 H), 7.35–7.72 (m, 3 H),
7.51–7.58 (m, 2 H). 13C NMR (75 MHz, CDCl3): l
1.01, 59.86, 75.23, 80.58, 119.93, 125.53, 128.47, 129.01,
Entry
Solvent
InBr3
(mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
–
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
90c
70d
7
85
71
85
90
Et2O
n-Pentane
CH3CN
Toluene
10
a All the reactions were carried out at room temperature.
b Isolated yields after flash chromatography.
c
For this reaction a solution of InBr3 (0.2 M) in dry CH3CN was
utilized.
d For this reaction a solution of InBr3 (0.02 M) in dry CH3CN was
utilized.

M. Bandini et al. / Tetrahedron Letters 42 (2001) 3041–3043
3043
138.18. GC–MS m/z (relative intensity): 59 (9), 73
(100), 91 (18), 103 (39), 135 (8), 147 (37), 193 (21), 207
(3), 277 (41), 292 (2). IR (neat): 3076, 2959, 2831, 2362,
2329, 1458, 1257, 854 cm−1.
Tetrahedron Lett. 1998, 39, 3823; (d) ZnI2: Gassman, P.
G.; Talley, J. J. Tetrahedron Lett. 1978, 19, 3773; (e)
KCN/18-crown-6: Greenlee, W. J.; Hangauer, D. G. Tetra-
hedron Lett. 1983, 24, 4559; (f) LiClO4: Jenner, G. Tetra-
hedron Lett. 1999, 40, 491; (g) R2SnCl2: Whitesell, J. K.;
Apodaca, R. Tetrahedron Lett. 1996, 37, 2525; (h)
Zr(KPO4)2: Curini, M.; Epifanio, F.; Marcotullio, M. C.;
Rosati, O.; Rossi, M. Synlett 1999, 315; (i) MgBr2·Et2O:
Ward, D. E.; Hrapchak, M. J.; Sales, M. Org. Lett. 2000,
2, 57.
2-Methyl-2-trimethylsilyloxy-octanenitrile 20: Pale yel-
1
low oil (96% yield). H NMR (200 MHz, CDCl3): l
0.24 (s, 9 H), 0.87–0.93 (m, 3 H), 1.30–1.36 (m, 4 H),
1.44–1.50 (m, 2 H), 1.57–1.58 (m, 4 H), 1.67–1.74 (m, 3
H). 13C NMR (50 MHz, CDCl3): l 1.37, 14.10, 22.59,
24.28, 29.01, 30.97, 31.65, 43.39, 69.68, 122.16. GC–MS
m/z (relative intensity): 55 (19), 69 (18), 73 (81), 75
(100), 100 (91), 115 (15), 127 (8), 142 (36), 185 (69), 212
(21), 227 (1). IR (neat): 2959, 2835, 2362, 2335, 1460,
1374, 1248, 837 cm−1.
4. Flores-Lope´z, L. Z.; Parra-Hake, M.; Somanathan, R.;
Walsh, P. J. Organometallics 2000, 19, 2153 and references
cited therein.
5. Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867 and
references cited therein.
6. (a) Garcia Ruano, J. L.; Martin Castro, A. M.; Rodriguez,
J. M. J. Org. Chem. 1992, 57, 7235; (b) Golinski, M.;
Brock, C. P.; Watt, D. S. J. Org. Chem. 1993, 58, 159. For
catalytic enantioselective addition of TMSCN to ketones,
see: Belokon´, Y. N.; Green, B.; Ikonnikov, N. S.; North,
M.; Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147;
Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 7412. However, no examples of functional-
ized ketones were reported.
7. Performing the reaction with (Bu)3SnCN as the cyanating
agent, the product was isolated in lower yield: 62%, reac-
tion time 72 h.
8. It is important to note that the success of this method
depends on the use of rigorously anhydrous solvents. In
fact, carrying out the cyanation of 1 in CH2Cl2 (99.6%,
ACS reagent) the chemical yield significantly dropped to
28% (reaction time 48 h, InBr3 10 mol%).
9. The substituted ketones 3 and 6 were synthesized from the
a-hydroxy acetophenone, see: (a) Zhu, G.; Casalnuovo, A.
L.; Zhang, X. J. Org. Chem. 1998, 63, 8100 [3: Ac2O/py/
CH2Cl2; 6: TBDMSCl/imidazole/DMF]. Ketone 4 was
prepared following a known procedure, see: (b) Ballini, R.;
Bartoli, G.; Bosica, G.; Marcantoni, E.; Vita, P. J. Org.
Chem. 2000, 65, 5854. Ketones 7 and 8 were obtained as
follows: 7: morpholine/Et3N/9 reflux in Et2O; 8: p-Tol-SH/
K2CO3/9 in EtOH.
Acknowledgements
The authors would like to thank CNR and MURST
(Progetto Nazionale ‘Stereoselezione in Sintesi Organ-
ica: Metodologie ed Applicazioni’) and Bologna Uni-
versity (funds for selected research topics) for financial
support of this research.
References
1. Gregory, R. H. J. Chem. Rev. 1999, 99, 3649.
2. (a) Hydrogen cyanide: Lapworth, A. J. Chem. Soc. 1903,
83, 995; (b) Alkali-metal cyanides: Kurtz, P. Ann. Chem.
1951, 23, 572; (c) Organosilicone cyanides: Groutas, W.
C.; Felker, D. Synthesis 1980, 861 and references cited
therein; Fujii, A.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2000, 65, 6209; (d) Acetone cyanohydrin: Kawasaki, Y.;
Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 1999, 64, 4214.
3. (a) Yb(CN)3: Matsubara, S.; Takai, T.; Utimoto, K.
Chem. Lett. 1991, 1447; (b) Yb(OTf)3: Yang, Y.; Wang, D.
Synlett 1997, 861; Yang, Y.; Wang, D. Synlett 1997, 1379;
(c) Cu(OTf)2: Saravanan, P.; Anand, R. V.; Singh, V. R.
.
.