Nitriles condensation

If the initial temperature of the oil bath is below 140°, the nitrile distils too slowly (with consequent lowering of yield) if the temperature is above 140°, the nitrile comes over too fast. In the latter case, some nitrile condenses in the rubber tubes leading to the pump, thus clogging the line. 

Active methylene nitriles condense with o-substituted aryl and heteroaryl azides in a two-step process to give tricyclic triazolopyrimidines without isolation of the triazole intermediates <85BSB441, 87BSB587). 5-Azido-4-formyltriazoles (758) condense with dimethyl 3-oxopentanedioate and tri-ethylamine in ethanol to give 5-(triazol-l-yl)-4-formyltriazoles (759), which undergo cyclization to... 

Carboxylic acids (511) and their chlorides, anhydrides, amides, esters and nitriles, condense with o-aminothiophenols (507) or their zinc salts, affording 2-substituted benzothiazoles (513), the only exception being acetic acid. The intermediate o -acylaminothioph-enols (512) could be isolated and readily cyclized. The activation of carboxylic acids in... 

Tetrachloropyrimidine is formed in quantitative yield by the cyclization (with FeCla, at 200 °C) of perchloro-l-cyano-3-azabutadiene (Cl2C=N—CC1=CC1CN), itself formed by successive treatment of cyanoethyl)formamide with phosphorus pentachloride and chlorine. j8-Iminoyl-enamines (222), prepared by the reaction of the appropriate anils with nitriles, condense with ethyl chloroformate and carbon disulphide to give excellent yields of 2-oxo- and 2-thioxo-pyrimidines (223 X = O or S). Aldehydes, acetals, and ketals (but not ketones) also react with these enamines (222) to give 1,2-dihydropyrimidines (224) (70—93%). In similar fashion, malondiamidines condense with a large variety of aromatic aldehydes to give 2-aryl-5-arylmethyl-4,6-diaminopyrimidines. °... 

Nitriles condense with malonyl chloride to give 2-chloro4,6-dihydroxypyii-dines (MI-174) in 23 to 63% yield and/or the pyrimidones (XII-17S) or chloropyranooxazines (Section I.5.C.) depending on conditions. 5-Bromo-3-carbethoxy-2-chloro-4,6-dihydroxypyridine (XII-176, R = CO2C2H5) is prepared either by bromination of MI-174 (R = C02Et) or by cyclization of bromomalonyl chloride and ethyl cyanoacetate. Methylmalonyl chloride did not react with propionitrile. The product from acetonitrile and malonyl chloride, first described as 2-chloro-4,6-dihydroxypyridine (MI-174,R = H), is6-chloro-2-methyl-4-pyrimidone (XI-175, R = H). ... 

Claisen condensation Condensation of an ester with another ester, a ketone or a nitrile in the presence of sodium ethoxide, sodium or sodamidc, with the elimination of an alcohol. The result is the formation of a / -ketonic ester, ketone, or nitrile respectively, e.g. 

Hoesch synthesis A variation of the Gattermann synthesis of hydroxy-aldehydes, this reaction has been widely applied to the synthesis of anthocyanidins. It consists of the condensation of polyhydric phenols with nitriles by the action of hydrochloric acid (with or without ZnCl2 as a catalyst). This gives an iminehydrochloride which on hydrolysis with water gives the hydroxy-ketone. 

The crude acetonitrile contains as impurity chiefly acetic acid, arising from the action of phosphoric acid on the acetamide. Therefore add to the nitrile about half its volume of water, and then add powdered dry potassium carbonate until the well-shaken mixture is saturated. The potassium carbonate neutralises any acetic acid present, and at the same time salts out the otherwise water-soluble nitrile as a separate upper layer. Allow to stand for 20 minutes with further occasional shaking. Now decant the mixed liquids into a separating-funnel, run off the lower carbonate layer as completely as possible, and then pour off the acetonitrile into a 25 ml, distilling-flask into which about 3-4 g. of phosphorus pentoxide have been placed immediately before. Fit a thermometer and water-condenser to the flask and distil the acetonitrile slowly, collecting the fraction of b.p. 79-82°. Yield 9 5 g. (12 ml.). 

Boil 5 ml. (5-1 g.) of benzonitrile and 75 ml. of 10% aqueous sodium hydroxide in a 200 ml. flask under a reflux water condenser until no more oily drops of unchanged nitrile run down from the condenser (usually about 40 minutes). Th detach the condenser and boil the solution in the open flask for a few minutes to remove free ammonia, Cool the liquid, and add concentrated hydrochloric acid cautiously until precipitation of benzoic acid is complete. Cool the mixture again thoroughly, filter off the benzoic acid at the pump, and wash well with cold water. Yield, 5 8 g. (almost theoretical). Confirm the identity of the benzoic acid by the tests given on p. 347. The benzoic acid obtained in this way should be pure and have m.p. 121 a portion may if desired be recrystallised from hot water. 

If during the steam-distillation the />-tolunitrile tends to crystallise in the condenser, it is usually sufficient to increase the amount of steam momentarily in order to melt and dislodge the nitrile alternatively... 

Hydrolysis of />-Tolunitrile. As in the case of benzonitrile, alkaline h> drolysis is preferable to hydrolysis by 70% sulphuric acid. Boil a mixture of 5 g. of p-tolunitrile, 75 ml. of 10% aqueous sodium hydroxide solution and 15 ml. of ethanol under a reflux water-condenser. The ethanol is added partly to increase the speed of the hydrolysis, but in particular to prevent the nitrile (which volatilises in the steam) from actually crystallising in the condenser. The solution becomes clear after about i hour s heating, but the boiling should be continued for a total period of 1-5 hours to ensure complete hydrolysis. Then precipitate and isolate the p-toluic acid, CH3CgH4COOH, in precisely the same way as the benzoic acid in the above hydrolysis of benzonitrile. Yield 5 5 g. (almost theoretical). The p-toluic acid has m.p. 178°, and may be recrystallised from a mixture of equal volumes of water and rectified spirit. 

This Reaction should be carefully distinguished from the Claisen Conden-tation, which is the condensation of an ester, under the influence of sodium ethoxide, with (i) another ester, (ii) a ketone, or (iii) a nitrile, with the elimination of alcohol. For details of this condensation, see Ethyl Acetoacetate, p. 264. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

Place together in a 50 ml. conical flask about 1 g. of the substance and 10 ml. of 10% NaOH solution (or use apparatus in Fig. 38, p. 63)-Add a few pieces of unglazed porcelain, fit a reflux water- condenser, and boil gently for about 20 minutes. Nitriles require longer heating than amides, usually about 30 minutes. The completion of the hydrolysis of an insoluble nitrile ( .g., benzonitrile) is indicated by the disappearance of oily drops in the liquid. Cool the flask, add an excess of dil. H2SO4 and cool thoroughly. 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

By the condensation of a nitrile with a phenol or phenol ether in the presence of zinc chloride and hydrogen chloride a hydroxyaryl- or alkoxyaryl-ketone is produced. The procedure is termed the Hoesch reaction and is clearly an extension of the Gattermann aldehyde reaction (Section IV,121). The reaction gives the best results with polyhydric phenols and their ethers with simple monohydric phenols the imino ester hydrochloride is frequently the sole product for example ... 

Preparation of benzyl cyanide. Place 100 g. of powdered, technical sodium cyanide (97-98 per cent. NaCN) (CAUTION) and 90 ml. of water in a 1 litre round-bottomed flask provided with a reflux condenser. Warm on a water bath until the sodium cyanide dissolves. Add, by means of a separatory funnel fitted into the top of the condenser with a grooved cork, a solution of 200 g. (181-5 ml.) of benzyl chloride (Section IV.22) in 200 g. of rectified spirit during 30-45 minutes. Heat the mixture in a water bath for 4 hours, cool, and filter off the precipitated sodium chloride with suction wash with a little alcohol. Distil off as much as possible of the alcohol on a water bath (wrap the flask in a cloth) (Fig. II, 13, 3). Cool the residual liquid, filter if necessary, and separate the layer of crude benzyl cyanide. (Sometimes it is advantageous to extract the nitrile with ether or benzene.) Dry over a little anhydrous magnesium sulphate, and distil under diminished pressure from a Claisen flask, preferably with a fractionating side arm (Figs. II, 24, 2-5). Collect the benzyl cyanide at 102-103°/10 mm. The yield is 160 g. 

Phthalonitrile. In a 1 litre round-bottomed flask, provided with a reflux condenser, place 100 g. of phthalamide and 350 ml. of acetic anhydride. Reflux for 5-6 hours. Add the reaction product whilst still hot cautiously to 700 ml. of boiling water this decomposes the excess of acetic anhydride. Cool in ice, and then render the reaction mixture alkaline with sodium hydroxide solution. Filter ofiF the precipitated crystals at the pump, wash with water, and dry at 100°. The yield of the crude nitrile is 70 g. After one or two recrystallisations from benzene, the m.p. should be 141°—that of pure phthalonitrile. It is usually best to distil the crude nitrile under reduced pressure (Figs. II, 19, 3-4) the distillate has m.p. 137-138°, and the m.p. is raised to 141° after one recrystallisation from benzene. 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Thus a second method was envisaged, the reaction of a nitrile, hydrogen selenide, and an a-halogenated ketone in the presence of a condensation catalyst, which can be POCl, or POCI3 with a Lewis acid such as PCI3 or anhydrous ZnCl. The use of fresh AICI3 leads to the formation of tarry side-products. 

The reaction of phosphorus pentasulfide with a-acylamino carbonyl compounds of type Ilia also yields thiazoles. Even more commonly, a mercaptoketone is condensed with a nitrile of type IVa or a-mercaptoacids or their esters with Schiff bases. This ring closure is limited to the thiazolidines. In the Va ring-closure type, /3-mercaptoalkylamines serve as the principal starting materials, and ethylformate is the reactant that supplies the carbon at the 2-position of the ring. These syntheses constitute the most important route for the preparation of many thiazolidines and 2-thiazohnes. In the Vb t3fpe of synthesis, one of the reactant supplies only the carbon at the 5-position of the resultant thiazole. Then in these latter years new modern synthetic methods of thiazole ring have been developed (see Section 7 also Refs. 515, 758, 807, 812, 822). 

Just as most other aldehydes do, furfural condenses with compounds possessing active methylene groups such as aUphatic carboxyUc esters and anhydrides, ketones, aldehydes, nitriles, and nitroparaffins. 

Nitrile Synthesis. Cyanogen bromide [506-68-3] condenses with toluene in the presence of aluminum chloride to give -tolunittile (129). 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Amin omethyl-3,5,5-trimethyl cyclohexyl amine (21), commonly called isophoronediamine (IPD) (51), is made by hydrocyanation of (17) (52), (53) followed by transformation of the ketone (19) to an imine (20) by dehydrative condensation of ammonia (54), then concomitant hydrogenation of the imine and nitrile functions at 15—16 MPa (- 2200 psi) system pressure and 120 °C using methanol diluent in addition to YL NH. Integrated imine formation and nitrile reduction by reductive amination of the ketone leads to alcohol by-product. There are two geometric isomers of IPD the major product is ds-(22) [71954-30-5] and the minor, tram-(25) [71954-29-5] (55). 

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