Carboxamides, dehydration

Thiazolecarboxylic acids, esters or acid chlorides react readily with ammonia or various amines, affording the corresponding carboxamides. Dehydration of the amides with phosphorus pentoxide or phosphoryl chloride occurs readily and gives the corresponding nitriles (Scheme 99). Thiazolecarboxylic acid hydrazides are obtained in a similar way, using hydrazine or substituted hydrazines instead of ammonia or amines. The Raney nickel reduction of cyanothiazoles leads to the corresponding amino compounds, the 4-cyano derivative being the isomer most readily reduced. 

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-f-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or A"-methoxy-At-melhyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyelization product to acid[4]. Use of CO as the electrophile generates oxindoles. 

Thiazole carboxamides are readily dehydrated to nitriles in good yields by heating with phosphorus oxychloride (91), phosphorus pentoxide (87, 71), or phosphoryl chloride (16) (Scheme 19). 

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

Pyrimidine-5-carboxamide, 4-amino-purine synthesis from, 5, 582 Pyrimidine-5-carboxamide, 4-amino- N- pheny synthesis, 3, 122 Pyrimidinecarboxamides Curtius degradation, 3, 82 dehydration, 3, 82 Hofmann degradation, 3, 82 hydrolysis, 3, 81 reactions, 3, 81 synthesis, 3, 127 Pyrimidinecarboxamides, thio-synthesis, 3, 128... 

Indole-3-carbonitrile has been prepared by the dehydration of indole-3-carboxaldehyde oxime,8 5 indole-3-glyoxalic acid oxime,58 or indole-3-carboxamide 8 by the action of cyanogen... 

Dehydration of carboxamides Sulphatcd Zr catalyst Nitriles Fine chemicals... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Aliphatic and aromatic carboxamides, with the exception of p-nitrobenzamide, are dehydrated in this way in high yield. Acid-labile protective groups such as tetra-hydropyranyl and tert-butyldimethylsilyl ether and base-sensitive compounds are not attacked. A,A -Sulfinyldi-1,2,4-triazole, easily prepared from thionylchloride and triazole [THF, (C2H5)3N, 0 °C, 1 h] in 85-95% yield, was used without further purification. 

DEHYDRATION OF CARBOXAMIDE GROUPS TO CYANO GROUPS DURING ACTIVATION... 

The action of gaseous ammonia on diethyl chromone-2,6-dicarboxylate (478) is a good example of the different reactivity between identical substituents in the same molecule. The 2-carboxylate function is more reactive even than an ester group in a side chain such as —0CH2C02Et, which is unaffected by ammonia. This is consistent with the low electron density of C-2.2-Carboxamides, such as (479), need drastic conditions for their dehydration... 

DEHYDRATION UF CARBOXAMIDES TO NITRILES USING SULPHATED ZIRCONIA CATALYST... 

The dehydration of carboxamide is believed to proceed through its enol form (ref.11). On a Lewis acid catalyst the reaction is likely to follow the following mechanism. 

The present study demonstrates suitability of sulphated zirconia for dehydration of carboxamides. It needs to be emphasised that the common inorganic acid catalysts are not sufficiently acidic to catalyst the reaction below 400°C while the strongly acidic resin catalysts are not structurally stable at temperature at which the reaction would occur at appreciable rate. Thus the sulphated zirconia appears to be a unique catalyst for this application. 

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