Orthoformic amides

Many other reactions of ethylene oxide are only of laboratory significance. These iaclude nucleophilic additions of amides, alkaU metal organic compounds, and pyridinyl alcohols (93), and electrophilic reactions with orthoformates, acetals, titanium tetrachloride, sulfenyl chlorides, halo-silanes, and dinitrogen tetroxide (94). 

There is also the possibility of removing the 2-oxo group by ring cleavage and subsequent recyclization. Lumazine can be hydrolyzed by strong alkali to 2-aminopyrazine-3-carboxylic acid (153) which is converted first into the amide (154) and then cyclized by ethyl orthoformate into pteridine-4-one (155 equation 47) (51JCS474). 

In cases where decarboxylation is anticipated, the quinazolinone could be obtained by heating ammonium o-formamidobenzoate or o-forra ami do benz amide for several hours. This ring closure could be effected more conveniently by boiling the o-formamidobenzamide with 3% aqueous sodium hydroxide for a few minutes, o-Amino-benzamides have also been converted to quinazolinones by refluxing with ethyl orthoformate alone or preferably in the presence of acetic anhydride. ... 

Evodiamine (113) was synthesized by a Bischler-Napieralski type reaction from the amide 112 and ethyl orthoformate. 

The secondary amine group of the thiadiazole 103 was acylated when heated in the presence of acetic anhydride and ethyl orthoformate to afford the amide 104 in 88% yield (Equation 30) <2002CHE852>. 

Acetals have been used in the presence of Lewis acids, particularly zinc chloride and ferric chloride, for the addition of phosphorus-halogen species to prepare 1-alkoxyphosphonic dichlorides and dialkyl 1-alkoxyphosphonates (from phosphorus trichloride and dialkyl phosphinous chlorides, respectively).143-145 It should be noted that good yields of these types of products have also been reported in the absence of catalysts.146 147 Other types of substrates have also been used in these types of processes. These include acylals,148 amidals,149 orthoformates,150 and orthoacetates.151... 

The unsubstituted 1,2,4-oxadiazole has been prepared from formamidoxime and the mixed anhydride of acetic and formic acid, or formamide <67BSB92>. 5-Unsubstituted 1,2,4-oxadiazoles are formed by heating the condensation products of amide oximes with formic acid <63CI(M)1238>. Alternatively, amidoximes are treated with triethyl orthoformate in the presence or absence of... 

Aryl-substituted amides 39, when treated with triethyl orthoformate, give the corresponding N-arylated pyrimidine-fused rings 40 (Scheme 4) <2000PS(164)299> as well as one example of the triazine 41 <2000PS(164)299>. 

Incorporation of a piperazine function on the heterocyclic ring leads to a compound in which bronchodilator activity predominates. Treatment of the amino-amide (73-1) with trimethyl orthoformate provides the additional carbon atom for the formation of the quinazolone ring in (73-2). Reaction with phosphoms oxychloride in effect converts the ring to its aromatic form (73-3) by locking in the former amide as an enol chloride. Displacement of the halogen with the isobutyryl urethane (73-4) from piperazine affords piquizil (73-5) [82]. 

A general route39b to meso-ionic l,3-diazol-4-ones (91) involves the reaction of amino amides (R NHCOCH2NHR3) either with triethyl orthoformate or with JV-phenylbenzimidoyl chloride. 

The condensation of 2-aminopyridine derivatives 64 with ethyl cya-noacetate gave amides 65, which were cyclized to 2//-pyrido[l,2-a] pyrimidin-2-ones 66 by the treatment of triethyl orthoformate and acetic anhydride (90IZV229). 

Brief reference has already been made to the work of Cragoe and his colleagues on the preparation of amino-A-amidinopyrazinecarbox-amides which has led to the development of clinically useful diuretics (see Section V, B 254-260). Aminocarboxamides of type 120 give 4-pteridones (121) on ring closure with triethyl orthoformate in boiling acetic anhydride.330... 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

Clavier et al. used the amino acid (L)-valine to synthesise a C-chiral imdazolidinium salt for chiral molecular recognition studies [65]. The synthetic route utilises the C-terminus to form an amide. Subsequent reduction to the diamine and ring closure with trimethyl-orthoformate yields the chiral imdazolidinium salt (see Figure 6.25). 

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