Nitriles imidate synthesis

Electron-deficient nitriles, such as for instance trichloroacetonitrile and trifluoroacetonitrile (A=B A = N B = CCC13, CCF3), are known to undergo direct and reversible, base-catalyzed addition of alcohols providing O-alkyl trichloroacetimidates (1,50). This imidate synthesis has the advantage that the free imidates can be isolated as stable adducts, which are less sensitive to hydrolysis than their corresponding salts. 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

The method described for the preparation of 4-methoxycarbonyl-2-methyl-1,3-oxazole is that of Cornforth, and is widely applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates. The appropriate imidate hydrochloride required for step A is obtained from the reaction of a nitrile with an alcohol in the presence of hydrochloric add (eq. 1 ). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-catalyzed heterocycloaddition of a diazomalonate to a nitrile has been described in Organic Syntheses by Helquist, but appears to be less general than the present route. 

The addition of dry HCI to a mixture of a nitrile and an alcohol in the absence of water leads to the hydrochloride salt of an imino ester (imino esters are also called imidates and imino ethers). This reaction is called the Pinner synthesis.103 The salt can be converted to the free imino ester by treatment with a weak base such as sodium bicarbonate, or it can be hydrolyzed with water and an acid catalyst to the corresponding carboxylic ester. If the latter is desired, water may be present from the beginning, in which case aqueous HCI can be used and the need for gaseous HCI is eliminated. Imino esters can also be prepared from nitriles with basic catalysts.104... 

Aminohydrazines (640) are useful intermediates for the synthesis of reduced 1,2,4-triazines. With nitriles, carboxylic acids, imidates, thioimidates or orthocarboxylates, they form l,4,5,6-tetrahydro-l,2,4-triazines (641) (78HC(33)189, p. 629), with carbon disulfide they give the 3-thiones (642) <78HC(33)189, p.648), and with aldehydes or ketones hexahydro-1,2,4-triazines (643) are formed <78HC(33)189, p. 657). 

A variety of imino derivatives has been used in the synthesis of 1,3,5-triazine (Scheme 85) (B-61MI22000, p. 680). The trimerization of the imidates is the most valuable of these routes to 1,3,5-triazine. Imidates can be considered as activated nitriles, and cyclotrimerize more readily than do the corresponding nitriles. The symmetrical 2,4,6-trialkyl-l,3,5-triazines are easily formed (Table 15), although large alkyl substituents may give rise to steric hindrance (61JOC2778). The mechanism is shown in Scheme 86. 

Synthesis of /i-Keto Acids, Esters, Amides, Imides and Nitriles and Decarboxylation... 

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