Ethyl formate, condensation with

Ethyl formate, condensation with 2-methylcydohexanone, 48, 41 purification of, 48, 42 Ethyl isocyanate, reaction with N,N-dimethy 1-1,3-propanediamine,... 

Explain why ethyl formate condenses with 2-methylcyclohexanone in the presence of base at the unsubstituted position ... 

A somewhat different route is used to prepare an analogue that bears additional oxygen. The sequence, in this case, starts by base-catalyzed formylation of the hydro-cinnamic acid derivative (40-1) with ethyl formate. Condensation of the product (40-2) with guanidine in this case leads to a pyrimidone (40-3), with the cyclization involving an ester-amide interchange between guanidine and the ester. Reaction of... 

Among other reactions proceeding through aldol-like intermediates, the formation of 2 hydroxymethylene-3-ketones (20) and similar derivatives deserves comment. The condensation occurs when ethyl formate reacts with the A2>4 enolate anion (ig), the product separating from non-polar solvents as an enolate salt (21) [xg6]. Similar condensations occur with ethyl oxalate [igy] 5a-3-Ketones naturally react at C 2>, through their stable enolates, but A -g-ketones and 5j5-3 ... 

The formation of ethyl acetoacetate is an example of a general reaction knowu as the acetoacetlc ester condensation in which an ester having hydrogen on the a-carbon atom condenses with a second molecule of the same ester or with another ester (which may or may not have hydrogen on the a-carbon atom) in the presence of a basic catalyst (sodium, sodium ethoxide, sodamide, sodium triphenylmethide) to form a p-keto-ester. The mechanism of the reaction may be illustrated by the condensation of ethyl acetate with another molecule of ethyl acetate by means of sodium ethoxide. ... 

Only esters containing two a-hydrogen atoms (ethyl acetate, propionate, n-butyrate, etc.) can be condensed with the aid of sodium alkoxides. For esters with one a-hydrogen atom, such as ethyl tsobutyrate, the more powerful base sodium triphenylmethide PhaC Na leads to condensation with the formation of ethyl a-tsobutyrylisobutyrate ... 

Hydrazinopyridazines are easily formylated with formic acid or ethyl formate and acety-lated with acetic anhydride. A-Pyridazinylthiosemicarbazides are obtained from thiocyanates or alkyl- and aryl-isothiocyanates. Hydrazinopyridazines condense with aliphatic and aromatic aldehydes and ketones to give hydrazones. 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

Indole has also been demonstrated to undergo a thermally induced condensation with trifluoroacetaldehyde ethyl hemiacetal to give a variety of products depending on the reaction conditions, e.g., the 6,12-dihydroindolo[3,2-f)]carbazole 172, which could be isolated in low yield from the mixture originating from the heating of equimolar amounts of the reactants in the absence of solvent. The formation of an intermediate indolenine species was suggested to account for the outcome (88JFC47). 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Reaction of ethyl formate with perhydroisoquinolone 54, in the presence of strong base leads to the (5-foimylketone 55 condensation of that product with hydrazine leads to the formation of a new pyrazole ring. This product, quinpirole (56), is an antihypertensive agent [11]. 

C. 2-Carbethoxycyclohexanone by Condensation with Ethyl Diethoxyphos-PHiNYL Formate... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a jS-diketone. The reaction works best when the ester component has no a hydrogens and thus can t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Technical ethyl formate was purified by washing with 3 per cent sodium carbonate solution, then with cold water, drying over anhydrous sodium sulfate, filtering, and fractionating. It is very important that all the materials used in the synthesis of acetol be anhydrous, as otherwise condensation products are formed. 

In a 3-I. round-bottom flask fitted with a 75-cm. Liebig condenser is placed 210 g. of potassium hydroxide (purified with alcohol) dissolved in 1500 cc. of anhydrous methyl alcohol. The solution is cooled to below 50° (Note 1), 300 g. of purified ethyl formate is added and the mixture is refluxed for two hours (Notes 2 and 3). 

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