Formic acid condensation with esters

Gnnamaldehyde, by reduction of, cinnamonitrile with Raney nickel alloy in formic acid, 51, 23 ester-mesylate, 51,16 Gnnamic acid, 50,18 CINNAMONITRILE, 50,18 Condensation, of p-acetylbenzene-diazonium bromide with acrylic acid, 51,1... 

The reactivity of the a-methylene group in lactams allows Claisen condensation with esters of formic, oxalic, and arylcarboxylic acids. Treatment of ethyl formate with A-methylpiperidone, followed by acidification, yields a salt of 1 -methyl- J2-piperideine, whereas in an alkaline medium its dimer was isolated.34- 158 With oxalic acid ester as the condensing reagent, 1-methyl-J2-pyrroline-2-carboxylic acid159 and l-methyl-d2-piperideine-2-carboxylic acid160 were obtained (Scheme 4). 

A. Ethyl N- p-tolylsulfonylmethyl)carhamate,[Carbamic acid, (4 -methyl-phenylsulfonylmethyl)-, ethyl ester]. A solution of 178 g. (1.0 mole) of sodium p-toluenesulfinate (Note 1) in 1 1. of water is placed in a 3-1., three-necked daak, equipped with a condenser, an efficient mechanical stirrer, and a thermometer. After addition of 100 ml. (108 g.) of a 34—37% solution of formaldehyde ca. 1.2-1.4 moles) (Note 2), 107 g. (1.2 moles) of ethyl carbamate (Note 3), and 250 ml. of formic acid (Note 4), the stirred solution is heated to 70°. Soon after this temperature is reached, the reaction mixture becomes turbid by separation of the... 

Carboxylic esters can be treated with ketones to give p-diketones in a reaction that is essentially the same as 10-118. The reaction is so similar that it is sometimes also called the Claisen condensation, though this usage is unfortunate. A fairly strong base, such as sodium amide or sodium hydride, is required. Yields can be increased by the catalytic addition of crown ethers. Esters of formic acid (R H) give P-keto aldehydes. Ethyl carbonate gives P-keto esters. 

Ordinarily, p-toluenesulfonic acid has been used as the catalyst. Although p-toluenesulfonic acid has high activity, its use results in the formation of by-products such as methylbenzyl-p-toluenesulfonates, high molecular weight condensates, and esters. We found that formic acid is a better catalyst for this reaction and gives almost quantitatively the mixture of HexMeDPM in a pure state without any contamination due to undesirable by-products. Formic acid also serves as a solvent. From this study, it was found that benzyl alcohols react easily with arenes to form asym DAMs, and formic acid is the most favorable catalyst for the benzylation reaction. 

Alkyl or 1-arylbiguanides (jS97) react analogously 1-Arylbiguanides condense slowly with esters other than those of formic acid (226), but metal alkoxide-catalysts 475) or caustic alkalis (477) have again been employed (475) to good effect. The synthesis has been widely used (19, 127, 204, 221, 417, 593, 599, 601, 602, 677, 701). 

The C=0 double bond of esters is usually not electrophilic enough to be olefinated by P ylides. Only formic acid esters can undergo condensation with Ph3P -CH2 and then they give enol ethers of the structure H—C(=CH2)—OR. a,/3-Unsaturated esters can sometimes react with P ylides, but this then results in a cyclopropanation ... 

Figure 13.50 outlines how esters in general (not shown) and especially lactones (shown) can be prepared for a one-step aldol condensation with an aldehyde they are exposed to a mixed ( crossed ) Claisen condensation with formic acid methyl ester (cf. Figure 13.59, first line). Like all Claisen condensations (Section 13.5.1), this also first leads to the formation of the enolate of the acylated ester. Unlike other Claisen condensations, this enolate is isolated. 

A 2- or 6-hydroxy-substituted purine can be prepared from the corresponding 4,5-diamino-pyrimidinol by cyclization with an acid, ester, ortho ester, or amide. If the ring closure is performed with reagents such as urea, alkyl chloroformates, urethanes, phosgene, and alkyl isocyanates, the 8-hydroxypurines are formed. Various xanthine and uric acid derivatives have been prepared by the condensation of 5,6-diaminopyrimidine-2,4-diols with formic acid. Purin-2-ol (1) was prepared by this route from 4,5-diaminopyrimidin-2-ol and ethyl orthoformate. ... 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

A. 2-exo-Norbornyl formate. Approximately 800 g. (17.4 moles) of 98-100% formic acid (Note 1) is added to 400 g. (4.25 moles) of norbornene (Note 2) in a 2-1. round-bottomed flask equipped with a condenser, and the mixture is boiled under reflux for 4 hours (Note 3). The dark solution is cooled and the flask arranged for distillation using a 30-cm. Vigreux column. The excess formic acid is removed under reduced pressure (b.p. 26-30°/21-30 mm.). Distillation of the residue then gives a forerun of about 100 ml. of a mixture of formic acid and ester followed by about 485 g. of 2-em-norbornyl formate, a colorless oil, b.p. 65-67°/14-16 mm., 1.4594—1.4597. Another 55-65 g. of ester is obtained by adding water to the forerun, extracting with 30-60° petroleum ether, washing the extracts with dilute sodium carbonate solution, dry-... 

Pathway A has already been discussed (2-23). In the reaction sequence C, introduction of the formyl group by a Claisen ester condensation with a formic acid ester is followed by treatment with 4-toluenesulfonyl azide, i. e., by a diazo transfer reaction (Regitz and Menz, 1968 see Sect. 2.6). Mn04 is also frequently used for the synthesis of bis- and tetradiazo compounds from the corresponding bis- and tetrahydrazones (Teki et al., 1986 Hannemann et al., 1988 and references therein). 

Reaction between two moles of wj-chloroaniline and a mole of formic acid yields an imidine which on treatment with ethyl malonate at 100° undergoes exchange and results into a diester. This further imdergoes cyclization through condensation to yield the corresponding ethyl ester of 7-chloro-4-hydroxy-quinoline-3-carboxylie acid which on hydrolysis gives 7-chloro-4-hydroxy quinoline. Finally, on chlorination with either phosphorus oxychloride or thionyl chloride yields the nueleus 4, 7-diehloro quinoline. 

The known 7-e carboxylic acid 506, obtained by the condensation of acrylic acid with furan, was used as a substrate for synthesis of validamine, (510) a component of validamycin antibiotics. The treatment of 506 with hydrogen peroxide in formic acid gave the tricyclic compound 507, which after reduction and hydrolysis afforded cyclitol. Treatment of 508 with 2,2-dimethoxy-propane in the presence of an acid gave a mixture of diisopropylidene derivatives in which compound 509 was predominant. Introduction of an amino group, by way of a tosyl ester and azide displacement, followed by hydrogenation and hydrolysis, completed the synthesis of DL-val-... 

Shafer and Molinski reported an efficient synthesis of the parent heterocycle 1, which they required as a starting material to prepare substituted analogs as shown in Scheme 1.110. Condensation of ethyl isocyanoacetate with formic acid and l,l -carbonyldiimidazole gave 4-oxazolecarboxylic acid ethyl ester 408. Hydrolysis and decarboxylation with CuO and quinoline afforded oxazole 1 in 24-33% yield from ethyl isocyanoacetate. The authors noted this route was amenable to scale up. 

Condensation of the bis(2-aminoethyl)arsonous acid ester (126) with acetylacetone in the presence of a trace of formic acid gave (127) in 58% yield <87CZ273>. 

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