Novel uncatalyzed hydrocyanation of ketones utlizing tetrachlorosilane- potassium cyanide reagent

Article abstract of DOI:10.1080/00397910701226897

A combination of tetrachlorosilane and potassium cyanide (in situ trichlorosilyl cyanide) was found to work efficiently for hydrocyanation of ketones to afford the corresponding cyanohydrins in high yield under mild conditions. Copyright Taylor & Francis Group, LLC.

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Novel Uncatalyzed Hydrocyanation of
Ketones utlizing Tetrachlorosilane–Potassium
Cyanide Reagent
Tarek A. Salama a , Saad S. Elmorsy a , Abdel‐Galel M. Khalil a , Margret M.
Girges a & Abdel‐Aziz S. El‐Ahl a
a Department of Chemistry, Faculty of Science , Mansoura University ,
Mansoura, Egypt
Published online: 12 Apr 2007.
To cite this article: Tarek A. Salama , Saad S. Elmorsy , Abdel‐Galel M. Khalil , Margret M. Girges &
Abdel‐Aziz S. El‐Ahl (2007) Novel Uncatalyzed Hydrocyanation of Ketones utlizing Tetrachlorosilane–Potassium
Cyanide Reagent, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:8, 1313-1319, DOI: 10.1080/00397910701226897
To link to this article: http://dx.doi.org/10.1080/00397910701226897
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Synthetic Communicationsw, 37: 1313–1319, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701226897
Novel Uncatalyzed Hydrocyanation of
Ketones utlizing Tetrachlorosilane–
Potassium Cyanide Reagent
Tarek A. Salama, Saad S. Elmorsy, Abdel-Galel M. Khalil,
Margret M. Girges, and Abdel-Aziz S. El-Ahl
Department of Chemistry, Faculty of Science, Mansoura University,
Mansoura, Egypt
Abstract: A combination of tetrachlorosilane and potassium cyanide (in situ trichlor-
osilyl cyanide) was found to work efficiently for hydrocyanation of ketones to afford
the corresponding cyanohydrins in high yield under mild conditions.
INTRODUCTION
Cyanohydrins are key building blocks for the one-step synthesis of many bio-
logically active compounds that are otherwise obtained only with difficulty,
such as a-hydroxy aldehydes, a-aminoalcohols, a-azidonitriles, b-hydroxy-
a-aminoacids, and a-hydroxyacids.[1] The formation of cyanohydrins is
generally considered to be a reaction that is achieved under equilibrating con-
ditions.[2] One of the most convenient preparative methods for cyanohydrins is
the addition reaction of trimethylsilyl cyanide (TMSCN) to carbonyl
compounds under catalysis by a plethora of reagents including Lewis
acids,[3] Lewis bases,[4] inorganic/organic salts,[5] metal complexes,[6] and
organic catalysts[7] followed by acid hydrolysis in a subsequent step. Only a
few reports for uncatalyzed cyanation reaction of aldehydes have
appeared,[8] but cyanation of keto compounds has not been hitherto
Received in Poland June 12, 2006
Address correspondence to Tarek A. Salama, Natural Products Synthesis and
Bioorganic Chemistry Laboratory, National Center for Scientific Research “NCSR
Demokritos,” 15310 Ag. Paraskevi, P. O. Box 60228, Athenes, Greece. E-mail:
tasalama@yahoo.com
1313

1314
T. A. Salama et al.
observed in the absence of catalyst. In conjunction with our interest[9] in
exploring the utility of in situ reagents based on tetrachlorosilane (TCS)[10]
in organic synthesis, we report here a facile and comparably safe practical
route for cyanation of ketones using the inexpensive and readily available
TCS and potassium cyanide (in situ trichlorosilyl cyanide)[9c] without
further addition of any catalyst.
RESULTS
Stirring a mixture of ketone (1 equiv) with a combination of TCS (2 equiv) and
potassium cyanide (2 equiv) at 60–708C in acetonitrile affords the corre-
sponding cyanohydrins in high yields in one-pot process after a simple
aqueous workup (Scheme 1, Table 1).
The results summarized in Table 1 show that the cyanohydrin formation
was applied for aryl methyl ketones and tolerated a variety of functional
groups on the phenyl ring regardless of whether they had electron-donating
or electron-withdrawing character. Thus, chloro-, bromo-, methyl-, and
nitro-containing aromatic ketones underwent this transformation in good to
excellent yields (entries 2, 3, 4, 6).
Identification of cyanohydrins was carried out by their spectroscopic
analyses as well as by comparing their properties to those reported. Each
product exhibited the characteristic IR signals at 2237–2247 and 3375–
3442 cm21 for the -CN and -OH groups respectively. Absence of the -CO-
stretching bands indicate that the starting material was consumed in each
1
case. The H NMR spectra showed broad singlet peaks at 2.96–3.5 ppm
attributed to the OH group which disappeared with D2O exchange, as well
as the characteristic singlet peaks at 1.87–1.93 ppm for the methyl group.
In addition, 13CNMR of 2f, for example, showed two characteristic peaks at
120.5 and 69.97, corresponding to CN and C-2 respectively.[11]
In contrast to the electronic factor, which seems to have no observable
effect on the reaction path, it seems that the steric factor is so important in
this reaction that actually no reaction was observed with the sterically
hindered ketones. Stirring a mixture of benzophenone in acetonitrile even in
the presence of an excess of TCS/KCN under gentle reflux conditions for a
relatively long time led to the recovery of the starting material after usual
Scheme 1.

Uncatalyzed Hydrocyanation of Ketones
1315
Table 1. Cyanation of ketones with SiCl4/KCN
Entry
1
Substrate
Time (h)
5
Product
Yielda (%)
82
2
3
4
5
6
7
8
6
7
79
77
86
95
91
68
—
5
6
14
6
22
none
aIsolated yield.
aqueous workup (entry 8). On the other hand, the TCS/KCN system is
highly reactive toward alicyclic ketones. For example, the reaction of TCS/
KCN with cyclohexanone under the same conditions led to the formation of
respective cyanohydrin in relatively good yield (entry 7, Table 1).

1316
T. A. Salama et al.
In contrast to the substrate sensitivity of HCN–carbonyl addition
reactions, the addition of the present reagent to ketones is a general and
high-yield process. Apparently this is a consequence of the alteration in the
DH for the carbonyl addition reaction when changing from proton to
silicon. From thermodynamic calculations of the bond energy values of
Si-CN and H-C, it was suggested that the addition of silyl cyanides to
carbonyl groups should be energetically more favorable than the correspond-
ing addition reactions of HCN (DHSi–DHH value of –31 to –41 Kcal/
mol).[12] A plausible mechanism for the present reaction may agree with
that depicted in Scheme 2.
In conclusion, we have developed TCS/KCN (in situ trichlorosilyl
cyanide) as a new reagent for the cyanation of ketones in high yields
without the need for further catalyst. It is relatively cheap compared with
TMSCN, and it is safer comparable to the volatile and highly toxic HCN.
Moreover, it does not involve equilibrating conditions.
EXPERIMENTAL
General
Melting points were recorded using a Griffin capillary Melt-Temp apparatus
1
and are uncorrected. H NMR and 13C NMR spectra were obtained on a
Varian þ300 spectrometer; chemical shifts (d) are in ppm relative to TMS,
and coupling constants (J ) are in Hertz. TCS was used as obtained from
Aldrich. Acetonitrile was dried by refluxing over P2O5 followed by distilla-
tion. All reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.2-mm silica-gel aluminum sheets Merck, (60 F-254) using
UV light and heat for visualization. Merck silica gel 60 F-245 (230–400
mesh) was used for column chromatography.
General Procedure for Synthesis of Cyanohydrins
TCS (1.2 mL, 10 mmol) was added under anhydrous conditions to a mixture
of ketone (5 mmol) and KCN (1.3 g, 10 mmol) in 15 mL of acetonitrile. The
Scheme 2. Regents and conditions: a) MeCN, 60–708C and b) aq. NAHCO3.

Uncatalyzed Hydrocyanation of Ketones
1317
mixture was stirred under gentle heating (60–708C) until TLC showed the
disappearance of the starting material. The reaction mixture was allowed to
cool to room temperature, quenched with a cold NaHCO3 solution, and
extracted with 2 ꢀ 50 mL of diethyl ether. The combined ether was washed
with water and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure. The crude products were purified either
by recrystallization from pet. ether (2b–d) or from pet. ether–diethyl ether
(3:1) (2e,f) or by column chromatography using a mixture of pet. ether–
ethyl acetate (10:1) for 2a,g.
Data
Acetophenone cyanohydrin (2a): Yield 82%; TLC; Rf ¼ 0.34 (pet. ether–
ethyl acetate ¼ 6:1); IR (neat) y ¼ 3420 (-OH), 2243 (CN); 1H NMR
(CDCl3) d 7.86 (d, J ¼ 8 Hz, 2H, Ar-H,), 7.55 (t, 2H, Ar-H), 7.44 (t, 1H,
Ar-H), 3.22 (br s, 1H, -OH), 1.89 (s, 3H, CH3).
4-Chloroacetophenone cyanohydrin (2b): Yield 79%; mp 90–918C (lit.[3b]
91.5–92.58C); TLC; Rf ¼ 0.35 (pet. ether–ethyl acetate ¼ 6:1); IR (KBr,
1
cm21) 3381 (-OH), 2247 (CN); H NMR (CDCl3) d 7.51 (d, J ¼ 8.4 Hz,
2H, Ar-H), 7.39 (d, J ¼ 8.4 Hz, 2H, Ar-H), 3.26 (br s, 1H, -OH), 1.87
(s, 3H, CH3).
4-Bromoacetophenone cyanohydrin (2c): Yield 77%; mp 96–988C (the
compound is mentioned in the literature[13] but no data are available); TLC;
Rf ¼ 0.34 (pet. ether–ethyl acetate ¼ 6:1); IR (KBr, cm21) 3383 (-OH),
2249 (CN); 1H NMR (CDCl3) d 7.65 (d, J ¼ 8.2 Hz, 2H, Ar-H), 7.32
(d, J ¼ 8.2 Hz, 2H, Ar-H), 3.22 (br s, 1H, -OH), 1.90 (s, 3H, CH3).
4-Methylacetophenone cyanohydrin (2d): Yield 86%; mp 78–808C (lit.[3b]
79.5–808C); TLC; Rf ¼ 0.38 (pet. ether–ethyl acetate ¼ 6:1); IR (KBr,
1
cm21) 3383 (-OH), 2249 (CN); H NMR (CDCl3) d 7.47 (d, J ¼ 7.8 Hz,
2H, Ar-H), 7.23 (d, J ¼ 7.8 Hz, 2H, Ar-H), 2.96 (s, 1H, -OH), 2.39 (s, 3H,
Ar-CH3), 1.91 (s, 3H, CH3).
4-Acetylbiphenyl cyanohydrin (2e): Yield 95%; mp 1368C (the compound is
mentioned in the literature[2b] but no data are available); TLC; Rf ¼ 0.35 (pet.
ether–ethyl acetate ¼ 6:1); IR (KBr, cm21) 3408 (-OH), 2242 (CN); 1H NMR
(CDCl3) d 7.55–7.52 (m, 4H, Ar-H), 7.41–7.23 (m, 5H, Ar-H), 3.17 (br s,
1H, -OH), 1.92 (s, 3H, CH3).
4-Nitroacetophenone cyanohydrin (2f): Yield 91%; mp 1148C (lit.[3b] 112–
1138C); TLC; Rf ¼ 0.33 (pet. ether–ethyl acetate ¼ 3:1); IR (KBr, cm21
)
1
3375 (-OH), 2247 (CN), 1522, 1347 (-NO2) cm21; H NMR (CDCl3) d 8.29

1318
T. A. Salama et al.
(d, J ¼ 9 Hz, 2H, Ar-H), 7.79 (d, J ¼ 9.3 Hz, 2H, Ar-H), 3.5 (brs, 1H, -OH)
exchanged with D2O, 1.93 (s, 3H, CH3); 13C NMR (CDCl3) d 148.23,
147.16, 125.74, 124.19, 120.5 (CN), 69.97 (C-2), 31.43 (CH3).
Cyclohexanone cyanohydrin (2g): Yield 68%; mp 32–338C (lit.[14] 358C);
IR (neat, cm21) 3590 (-OH), 2943, 2864 (CH), 2240 (-CN), 1450, 1345,
1158, 1094, 977, 932.
ACKNOWLEDGMENT
We are indebted to M. A. Ismail for NMR spectroscopic assistance.
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