Trimethylsilyl cyanide preparation

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

Another useful reagent for the preparation of alkynyl lodonium Inflates is [cyano(trifluoromethylsulfonyloxy)(phenyl)]iodine [/i7, 138, 139, 140] prepared from iodosobenzene, trimethylsilyl tnflate, and trimethylsilyl cyanide (equation 71). This reagent reacts with various stannylacetylenes under very mild conditions to form the corresponding alkynyl iodonium salts in high yields [139] (equation 72)... 

A completely different way of preparing isocyanides involves the reaction of epoxides or oxetanes with trimethylsilyl cyanide and zinc iodide, for example, ... 

Thus removal of water from classical rather inactive fluoride reagents such as tetrabutylammonium fluoride di- or trihydrate by silylation, e.g. in THF, is a prerequisite to the generation of such reactive benzyl, allyl, or trimethylsilyl anions. The complete or partial dehydration of tetrabutylammonium fluoride di- or trihydrate is especially simple in silylation-amination, silylation-cyanation, or analogous reactions in the presence of HMDS 2 or trimethylsilyl cyanide 18, which effect the simultaneous dehydration and activation of the employed hydrated fluoride reagent (cf, also, discussion of the dehydration of such fluoride salts in Section 13.1). For discussion and preparative applications of these and other anhydrous fluoride reagents, for example tetrabutylammonium triphenyldifluorosilicate or Zn(Bp4)2, see Section 12.4. Finally, the volatile trimethylsilyl fluoride 71 (b.p. 17 °C) will react with nucleophiles such as aqueous alkali to give trimethylsilanol 4, HMDSO 7, and alkali fluoride or with alkaline methanol to afford methoxytri-methylsilane 13 a and alkali fluoride. 

The efficiency of the amination methodology of enolates with 0-phoshinylhydroxyl-amine-type reagents was further demonstrated by Boche and Schrodt in the high-yield amination of 0-(trimethylsilyl)cyanohydrin anions with 4c (Scheme 44)". 0-(Trimethyl-silyl)cyanohydrins prepared by treatment of aryl, hetaryl and conjugated aldehydes with trimethylsilyl cyanide were lithiated to the eniminates. This is a practical method that enables the easy conversion of aldehydes to iV,Ai-dimethylamides under mild conditions. 

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

The formation of Reissert derivatives of the antineoplastic agent ellipticine (225) (Scheme 29) and their reactions have been extensively studied by Popp and co-workers 39,49-51). The ellipticine Reissert compound 226 could be prepared either with benzoyl chloride and potassium cyanide in a dichloromethane-water system or, better, with benzoyl chloride and trimethylsilyl cyanide in dichloromethane. In similar manner 9-methoxyellipticine and a number of 6-substituted ellipticines have also been converted to the corresponding Reissert compounds. 

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of haIides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsilyl cyanide in EtjN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

Some organosilieon compounds undergo transmetallation. The allylic cyanide 461 was prepared by the reaction of an allylic carbonate with trimethylsi-lyl cyanide[298]. The ortho esters and acetals of the a. uJ-unsaturated carbonyl compounds 462 undergo cyanation with trimethylsilyl cyanide[95]. 

Trimethylsilyl cyanide was prepared shortly before use according to the procedure of Livinghouse, T, Org. Synth. 1980, SO, 126-132. The checkers used trimethylsilyl cyanide as supplied from Aldrich Chemical Company, Inc. 

The cyanide ion is an ambident nucleophile and isocyanides may be side products. If the preparation of isocyanides is desired, they can be made the main products by the use of silver or copper(I) cyanide1577 (p. 368). Vinylic bromides can be converted to vinylic cyanides with CuCN,1578 with KCN, a crown ether, and a Pd(0) complex,1579 with KCN and a Ni(0) catalyst,15 1 or with K4Ni2(CN)6.1581 Tertiary halides can be converted to the corresponding nitriles by treatment with trimethylsilyl cyanide in the presence of catalytic amounts of SnCl4 RjCCl + Me3SiCN — R3CCN.1582... 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

In 1987 Kunz [32] reported the use of 2,3,4,6-tetra-0-pivaloyl-/ -D-galactopyrano-sylamine 27 as chiral auxiliary in the preparation of a-aminoacid derivatives via the Strecker reaction with aldehydes and trimethylsilyl cyanide. One year later he reported [33, 34] the use of the same chiral auxiliary in the Ugi reaction, where trimethylsilyl cyanide was replaced by an isocyamde and a carboxylic acid (Scheme 1.12). 

Trimethylsilyl cyanide (0.54 ml, 4 mmol) was added to a stirred suspension of iodosyl triflate (0.58 g, 2 mmol) in dichloromethane (15 ml) at — 78°C under nitrogen. The mixture was allowed to warm to — 20°C and stirred at this temperature for 15 min until the formation of a clear solution. The solution was cooled to — 78°C and transferred to a cold stirred solution of the appropriate tributyltin heterocycle (4 mmol) in dichloromethane (15 ml). The mixture was brought to room temperature and crystallized by the addition of dry hexane (20-30 ml). The precipitated iodonium salt was filtered under nitrogen, washed with dry ether (30 ml) and dried in vacuo. Mono or bis hetaryl iodonium salts prepared by these and related methods also involved groups coming from selenophene [23], pyrazoles [24], benzothiophene [21], etc. 

A related salt, 0-COOH-C6H4I+ CN MeSOj, was obtained from a cyclic precursor and trimethylsilyl cyanide [13]. Another potentially useful compound, ethyl diazoacetato phenyliodonium triflate, was prepared from DIB, ethyl diazoacetate and trimethylsilyl triflate [14] ... 

Fig (16) The enone (131), prepared from (130) is alkylated with iodide (133) to obtain the product (134). It reacts with trimethylsilyl cyanide and zinc iodide. The resulting product (135) is converted to tricyclic compound (136) by heating with hydrochloric acid and ethanol. 

Reduction of oxonitriles (Method D) may afford either phenethylamines or phenylethanolamines, depending on the reaction conditions (311, 312). Alternative methods for the synthesis of phenylethanolamines are exemplified by reduction of 2-aminoacetophenones (Method E) (313) or by reduction of cyano-hydrines (Method F) (314). Octopamine has been recently synthesized in high yield via a BH3 THF-catalyzed reduction of a trimethylsilyl cyanide adduct (Method G) (315). Two other amino alcohols were synthesized in similar yields, suggesting that this method is of general value for the preparation of this class of compounds. 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

Reissert compounds have been prepared from compounds (21) and (23) using either trimethylsilyl cyanide or potassium cyanide as the cyanating agents. Yields ranged from 57% to 71 % <84JHCl 119, 86JHC545). The N-oxides of some thieno[2,3-6]pyridine derivatives, as shown in Equation (8), have been used in the Reissert-Henze reaction to produce cyano-substituted products <83JHC213>. 

Trimethylsilyl)benzophenone cyanohydrin has been prepared previously by the addition of trimethylsilyl cyanide to benzophenone using an aluminum chloride catalyst.4 The preparation of cyanohydrin silyl ethers described in the synthesis is based on... 

Trimethylsilyl cyanide is a useful reagent for the preparation of /8-amino alcohols,2 a-amino nitriles,3 and a-trimethylsiloxyacrylo-nitriles4 from the corresponding ketones, imines, and ketenes. The reagent adds rapidly to the carbonyl of aldehydes at 25°C,2 and the resulting adducts have proven useful precursors for the preparation of carbonyl anion synthons.5 Enones give exclusively the products derived from 1,2-addition.2... 

Trimethylsilyl cyanide has been prepared in modest yield by the action of hexamethyldisilazane on hydrogen cyanide8 and the reaction of silver cyanide with trimethylchlorosilane.6,7 It has been prepared in good yield by the treatment of preformed lithium cyanide (from LiH and HCN) with trimethylchlorosilane in ether.7 The procedure described here not only affords trimethylsilyl cyanide in good yield, but also avoids the use of hydrogen cyanide and the need for Schlenk ware. 

Phenylquinazoline-2-carbonitrile (mpl27 129°C) is prepared in good yields from 4-phenylquinazoline 1-oxide by treatment with trimethylsilyl cyanide in the presence of 1,8-diaza-bicycio[5.4.0]undec-7-ene or triethylamine as a base. ... 

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