Cyanotrimethylsilane1

Me3SiCN

[7677-24-9]  · C4H9NSi  · Cyanotrimethylsilane  · (MW 99.21)

(agent for the cyanosilylation of saturated and unsaturated aldehydes and ketones;2 powerful silylating agent;3 reagent for carbonyl umpolung4)

Alternate Name: trimethylsilyl cyanide.

Physical Data: mp 11-12 °C; bp 118-119 °C; d 0.744 g cm-3.

Solubility: sol organic solvents (CH2Cl2, CHCl3); reacts rapidly with water and protic solvents.

Form Supplied in: colorless liquid; available commercially. Can also be prepared.1e

Handling, Storage, and Precautions: flammable liquid which must be stored in the absence of moisture and used in an inert atmosphere. Reagent is highly toxic: contact with water produces hydrogen cyanide.

Introduction.

Cyanotrimethylsilane is a highly versatile reagent that reacts with a multitude of functional groups to yield an array of products and/or highly valuable synthetic intermediates.

Cyanohydrin Trimethylsilyl Ethers and Derivatives.

Aldehydes and ketones are readily transformed into the corresponding cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of Lewis acids (eq 1),5,6 triethylamine,7 or solid bases such as CaF2 or hydroxyapatite.8 The products can be readily hydrolyzed to the corresponding cyanohydrins. The cyanosilylation of aromatic aldehydes can be achieved with high enantioselectivity in the presence of catalytic amounts of a modified Sharpless catalyst consisting of Titanium Tetraisopropoxide and L-(+)-diisopropyl tartrate (eq 2).9 Catalysis with chiral titanium reagents yields aliphatic and aromatic cyanohydrins in high chemical and optical yields (eq 3).10 Cyanohydrins can be subsequently transformed into a variety of useful synthetic intermediates (eq 4).11,12

Conjugate Additions.

Cyanotrimethylsilane reacts with a,b-unsaturated ketones in the presence of Lewis acids (Aluminum Chloride, Tin(II) Chloride, Triethylaluminum) to yield, upon hydrolysis, the corresponding 1,4-addition products (eqs 5 and 6).13 This methodology is superior to other procedures.14 By controlling the reaction conditions and the stoichiometry of the reaction, the kinetically controlled 1,2-addition products can also be obtained in high yields (eq 7).13,15

Regioselective cyanosilylation of unsaturated ketones can also be effected efficiently using a solid acid or solid base support.16 1,4-Adducts are obtained when a strong solid acid such as Fe3+- or Sn4+-montmorillonite is used (see Iron(III) Nitrate-K10 Montmorillonite Clay), while 1,2-adducts are obtained in the presence of solid bases such as CaO and MgO.

Reactions with Oxiranes, Oxetanes, and Aziridines.

Lewis acids, lanthanide salts, and titanium tetraisopropoxide or Aluminum Isopropoxide catalyze the reactions of cyanotrimethylsilane with oxiranes, oxetanes, and aziridines, yielding ring-opened products. The nature of the products and the regioselectivity of the reaction are primarily dependent on the nature of the Lewis acid, the substitution pattern in the substrate, and the reaction conditions. Monosubstituted oxiranes undergo regiospecific cleavage to form 3-(trimethylsiloxy)nitriles when refluxed with a slight excess of cyanotrimethylsilane in the presence of a catalytic amount of Potassium Cyanide-18-Crown-6 complex (eqs 8-10).17 The addition of cyanide occurs exclusively at the least-substituted carbon.

Good yields of 3-(trimethylsiloxy)nitriles are also obtained from the reactions of oxiranes with cyanotrimethylsilane in the presence of lanthanide salts,18 or when the reaction is catalyzed by AlCl3 or Diethylaluminum Chloride (eq 11).19 Ring opening of chiral glycidyl derivatives by Me3SiCN catalyzed by Ti(O-i-Pr)4 or Al(O-i-Pr)3 occurs in a regiospecific and highly stereoselective manner (eq 12).20

Oxetanes give rise to 4-(trimethylsiloxy)propionitriles (eq 13).19 Similar observations have been made in the reactions of N-tosylaziridines and cyanotrimethylsilane catalyzed by lanthanum salts (eq 14).21

The ambident nature of cyanotrimethylsilane22 can lead to the formation of nitriles or isocyanides, depending on the nature of the catalyst. For example, cyanotrimethylsilane reactions with epoxides and oxetanes catalyzed by soft Lewis acids give rise to 2-(trimethylsiloxy) isocyanides arising by attack on the more substituted carbon (eqs 15 and 16).23-25 Milder reaction conditions and better yields of isocyanides can be realized when the reaction of cyanotrimethylsilane with oxiranes is carried out in the presence of Pd(CN)2, SnCl2, or Me3Ga (eq 17).26 Isocyanides are useful precursors for the synthesis of b-amino alcohols and oxazolines.

Carbonyl Umpolung.

When deprotonated with a strong base, O-(trimethylsilyl) cyanohydrins can function as effective acyl anion equivalents that can be used to convert aldehydes to ketones,27 and in the synthesis of 1,4-diketones,28 tricyclic ketones,29 and the highly sensitive a,b-epoxy ketone functionality (eq 18).30

Miscellaneous Transformations.

Cyanotrimethylsilane effects the transformation of acyl chlorides to acyl cyanides,31 a-chloro ethers and a-chloro thioethers to a-cyano ethers32 and a-cyano thioethers (eq 19),33 t-butyl chlorides to nitriles (eqs 20 and 21),34 1,3,5-trisubstituted hexahydro-1,3,5-triazines to aminoacetonitriles,35 the cyanation of allylic carbonates and acetates (eqs 22 and 23),36 and the formation of aryl thiocyanates from aryl sulfonyl chlorides and sulfinates.37 The reagent has been used effectively in peptide synthesis38 and in a range of other synthetic applications.39-46

Related Reagents.

t-Butyldimethylsilyl Cyanide; Hydrogen Cyanide.


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William C. Groutas

Wichita State University, KS, USA



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