Preparation of nitriles

SECTION 183 Nitriles from Alcohols and Thiol3 No Additional Examples SECTION 184 Nitriles from Aldehydes 

SECTION 185 Nitriles from Alkyls, Methylenes, and Aryls 

SECTION 189 Nitriles from Ethers, Epoxides, and Thioethers 

Conjugate reductions and Michael alkylations of olefinic nitriles are found in Section 74D (Alkyls from Olefins). 

SECTION 185 NITRILES FROM ALKYLS, METHYLENES, AND ARYLS 

Conjugate reductions and Michael alkylations of alkene nitriles are given in Sections 74D and 74E (Conjugate Reductions and Alkylations of a, 3-Unsaturated Carbonyl Compounds and Nitriles, respectively). 

Miyazawa,E. Sakamoto, T. Kikusawa. Y. Synth. Commun.2002, 32, 3871. 

SECTION 189 NITRILES FROM ETHERS, EPOXIDES AND THIOETHERS 

Mukaiyama, T. Takenosbita, H. Yamada, M. Soga, T. Chem. Lett., 1990,229 (Z product]. 

Preparations of nitriles from oximes and bydrazones, which are ketone derivatives, are found in Section 195, 

Rearrangement proceeds with retention of configuration at the migrating group. 

Isocyanates are intermediates. When the reaction of an amide with bromine is carried out in methanol containing sodium methoxide instead of in aqueous base, the product that is isolated is a carbamate. 

Carbamates are esters of carbamic acid (H2NCOH). Carbamates are also known as urethans. They are relatively stable and are formed by addition of alcohols to 

Carbamic acid itself (H2NCOH) and iV-substituted derivatives of carbamic acid are unstable they decompose spontaneously to carbon dioxide and ammonia or an amine. Thus in aqueous solution, an isocyanate intermediate yields an amine via the corresponding carbamic acid in methanol, an isocyanate is converted to an isolable methyl carbamate. If desired, the carbamate can be isolated, purified, and converted to an amine in a separate hydrolysis operation. 

Although the Hofmann rearrangement is complicated with respect to mechanism, it is easy to carry out and gives amines that are sometimes difficult to prepare by other 

We have already discussed two procedures by which nitriles are prepared, namely, nucleophilic substitution of alkyl halides by cyanide and conversion of aldehydes and ketones to cyanohydrins. Table 19.6 reviews aspects of these reactions. Neither of the reactions in Table 19.6 is suitable for aryl nitriles (ArC=N) these compounds are normally prepared by a reaction to be discussed in Section 21.17. 

Both alkyl and aryl nitriles are accessible by dehydration of amides. 

Nucleophilic substitution by cyanide ion (see Sections 8.1, 8.10) Cyanide ion is a good nucleophile and reacts with alkyl halides to give nitriles. The reaction is of the Sn2 type and is limited to primary and secondary alkyl halides. Tertiary alkyl halides undergo elimination aryl and vinyl halides do not react. 

Cyanohydrin formation (see Section 17.7) Hydrogen cyanide adds to the carbonyl group of aldehydes and kefones. 

MMPP = magnesium monoperoxyphthalate Fem dez, R. Gasch, C. Lassalwtta. J-M. Llera, J-M. V izquez, J. 

Compendium of Organic Synthetic Methods, Volume 9. Michael B. Smith Copyright 2001 by John Wiley Sons, Inc. ISBNs 0-471-14579-3 (Hardback) 0-471-22822-2 (Electronic) 

NH4HCO3, aq KOH, MeCN, 15 h (Bu4N)2S2Q,, Cu(HC02)Ni(C02H 2 

PyBOP = benzotriazol-l-yloxylris(pyjTolidino)phosphoniumhexafliMrophosphate Bose. D.S. Narsaiah, A.V. Synthesis, 2001, 373. 

Sivakumar, M. Senthilkumar, P. Pandit. A.B. Synth. Commun., 2001, 31, 2583. NHa Cl3C-CH20a)Cl 

EEO= l-(3-dimethylaminopropyl)-3-ethyl-B-carbodiimide hydrochloride Bose. n.S.-. Sunder, K.S. Synth. Commun., 1999, 29, 4235. 

Deoxo-Fluor, 0°C to rt, Ih Kangani, C.O. Day, B.W. Kelley, D.E. Tetrahedron Lett. 2007, 48, 5933. P2lj.NH4C03,rt 

Chiampanichayakul, S. Pohmakotr, M. Reutrakul, V. Jaipetch, T. Kuhakam, C. Synthesis 2008, 2045. 

Vaccari, D. Davoli, P. Spaggiari, A. Prati, F. Synlett 2008, 1317. 2.5 IBX, TEAB, MeCN 

phosphine ligand Schareina, T. Zapf, A. MSgerlein, W. MUller, N. Seller, M. Tetrahedron Lett. 2007, 48, 1087. 

Sharghi.H. Sarvari, MU. Tetrahedron 2002,58,10323. phCHo NH2OH, H-Y-zeolite, microwaves 

Ramnauth, J. Bhardwaj,N. Renton,P. Rakhit, S. Maddaford. S.P. Synlett 2003, 2237. 

Taeawa. Y. Higuchi, Y. Yamagata, K. Shibata, K. Teshima, D. Heterocycles2004,63,2859. 

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The Sandmeyer reaction may also be applied to the preparation of nitriles. The solution of the diazonium salt is added to a solution of cuprous cyanide in excess of sodium or potassium cyanide solution (sometimes improved yields are obtained by substituting nickel cyanide for cuprous cyanide), for example CH3 CH, CH3... 

Nitdles may be prepared by several methods (1). The first nitrile to be prepared was propionitdle, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelou2e reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl hahdes with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide appHcabiUty ... 

Nitriles. Nitriles can be prepared by a number of methods, including ( /) the reaction of alkyl haHdes with alkaH metal cyanides, (2) addition of hydrogen cyanide to a carbon—carbon, carbon—oxygen, or carbon—nitrogen multiple bond, (2) reaction of hydrogen cyanide with a carboxyHc acid over a dehydration catalyst, and (4) ammoxidation of hydrocarbons containing an activated methyl group. For reviews on the preparation of nitriles see references 14 and 15. 

The gold is then recovered from solution by precipitation with zinc dust, electro deposit, or absorption on carbon. Sodium cyanide is used extensively in organic syntheses, especially in the preparation of nitriles (qv). 

Preparation of nitriles (Section 20.7) (a) S sj2 reaction of alkyl halides... 

Drivers for Performing Preparation of Nitriles in Micro Reactors... 

Beneficial Micro Reactor Properties for Preparation of Nitriles... 

Preparation of Nitriles Investigated in Micro Reactors Organic synthesis 4 [OS 4] Nitrile synthesis from a-bromotoluene... 

Thioamides have been transformed into the corresponding nitriles. Treatment of primary thioamides by tellurium tetrachloride or selenium tetrachloride in combination with triethylamine affords nitriles.66 Treatment of primary amides and thioamides with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) gives nitriles.67 Reactions of thioamides with metal carboxylates in organic solvents enables the selective preparation of nitriles, imides or amides depending on the substitution pattern of the starting material (Scheme 33).68... 

In the case of the oximes of the aldose sugars, the situation is more complicated because of the possibility of both open-chain and cyclic structures. That aldose oximes can react in the open-chain form follows from the formation of the nitriles and from the isolation of acylated open-chain aldose oximes as secondary products in preparation of nitriles. For example, Wolfrom and Thompson, by the action of sodium acetate-acetic anhydride on n-glucose oxime, not only obtained pentaacetyl-D-glucononitrile, in 40% yield, but also isolated a small amount of hexaacetyl-oWeAydo-D-glucose oxime (V) identical with that prepared by mild acetylation of pentaacetyl-aWe%do-D-glucose oxime (IV) whose structure was assured by its formation from pentaacetyl-aldehydo-D-glucoae (III). 

Preparation of nitrile acetates from oximes with sodium acetate and acetic anhydride. Pentaacetyl-v-glucononitrile. If only the nitrile is needed, isolation of the oxime can be avoided. One hundred grams of anhydijous n-glucose was dissolved in 50 ml. of warm water, and maintaining the temperature at 60°, a solution of 28 g. of hydro-xylamine in 700 ml. of ethanol was added sufficiently slowly that no precipitation took place. After one hour at 65°, the reaction mixture was concentrated under reduced pressure to a thick sirup. The residue was mixed with absolute ethanol, the ethanol evaporated and the operation repeated in order to eliminate all water. One hundred and twenty grams of anhydrous sodium acetate and 700 ml. of acetic anhydride were added to the sirup, and the mixture was slowly and cautiously warmed in a water bath to 95°. It was advisable to agitate the flask continuously and to watch the... 

Another methodology for the in situ preparation of nitrile oxide is the dehydro-halogenation of hydroxymoyl chlorides vrith triethylamine. Hydroxymoyl chlorides are accessible by the reaction of aldoximes vrith chlorinating agents such as NCS (N-chlorosuccinimide). Isoxazolines of C50 and C70 [293-295] with R = Ph, alkyl, 4-C5H4OCH3 4-C5H4CHO, amino acid [305], dialkoxyphosphoryl [296, 297] or ferrocene [298] have been synthesized in ca. 20 0% yields. The latter reaction is slower than the dehydration of nitroalkanes and requires one equivalent of hydroxymoyl chloride whereas excess nitroalkane is necessary for an optimum reaction [293]. 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

Preparation of nitriles Cyanide ion (CN ) is a good nucleophile, and can displace leaving groups from 1° and 2° alkyl halides. Nitriles are prepared hy the treatment of alkyl halides with NaCN or KCN in dimethyl sulphoxide (DMSO). The reaction occurs rapidly at room temperature. 

Further purification of this intermediate is unnecessary for the preparation of nitriles. 

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