Esters, formate

Kinetic results for the decompositions of formate esters are shown in Table 5. The reported Arrhenius parameters are supposed to apply to the ordinary uni-molecular elimination reactions 

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The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

This reaction occurs readily ia the presence of sulfuric or hydrofluoric acid. In the absence of such strong acids, formic acid reacts readily with olefins to give formate esters (21). 

Formic acid is used as an intermediate in the production of a number of dmgs, dyes, flavors, and perfume components. It is used, for example, in the synthesis of aspartame and in the manufacture of formate esters for flavor and fragrance appHcations. 

Uses ndReactions. Dihydromyrcene is used primarily for manufacture of dihydromyrcenol (25), but there are no known uses for the pseudocitroneUene. Dihydromyrcene can be catalyticaUy hydrated to dihydromyrcenol by a variety of methods (103). Reaction takes place at the more reactive tri-substituted double bond. Reaction of dihydromyrcene with formic acid gives a mixture of the alcohol and the formate ester and hydrolysis of the mixture with base yields dihydromyrcenol (104). The mixture of the alcohol and its formate ester is also a commercially avaUable product known as Dimyrcetol. Sulfuric acid is reported to have advantages over formic acid and hydrogen chloride in that it is less compUcated and gives a higher yield of dihydromyrcenol (105). 

When dihydromyrcene is treated with formic acid at higher temperatures (50°C) than that required to produce dihydromyrcenol and its formate, an unexpected rearrangement occurs to produce a,3,3-trimethylcyclohexane methanol and its formate (106). The product is formed by cyclization of dihydromyrcene to the cycloheptyl carbonium ion, which rearranges to give the more stable cyclohexyl compound (107). The formate ester, a,3,3-trimethylcyclohexane methanol formate [25225-08-5] (57) is a commercially avaUable product known as Aphermate. 

Reaction of acetic acid and a catalytic amount of sulfuric acid at reflux temperatures for 6—8 hours with dihydromyrcene can cause rearrangement of the dihydromyrcenyl acetate to give a mixture of the cycHc acetates analogous to the cycHc formate esters (108). The stereochemistry has also been explained for this rearrangement, depending on whether (+)- or (—)-dihydromyrcene is used (109). The cycHc acetates are also commercially avaUable products known as Rosamusk and CyclocitroneUene Acetate. 

Formic anhydride is not stable. However, formate esters of alcohols and phenoHcs can be prepared using formic—acetic anhydride (69,70). Anhydrides can also be incorporated into polystyrene backbones which can then be treated with alcohols to afford the corresponding esters and carboxypolystyrene for recycle (71). 

Formate esters generally become less toxic as the alcohol moiety increases up to C. With this increase in alkyl si2e, the LD q (oral, rabbit) increases from 1.62 g/kg for methyl formate to 3.0 g/kg for isoamyl formate [110-45-2]. In comparison, both aHyl and vinyl formates are more toxic than their saturated analogues. 

A formate ester can be cleaved selectively in the presence of an acetate [(MeOH, 1 eflux) ordil. NH3 (formate is 100 times faster than an acetate) ] or benzoate ester (dil. NHg). ... 

KOH, MeOH, 72% yield. A formate ester was not hydrolyzed under these conditions. 

Formate Ester 3. Acetate Ester 6. Trichloroacetate Ester 10. Phenoxyacetate Ester 19. Isobutyrate Ester... 

Formate Esters Methyl formate Ethyl formate Propyl formate Isopropyl formate Butyl formate Isobutyl formate... 

Azides can use enamines as dipolarophiles for ],3 cycloadditions to form triazolines. These azides can be formate ester azides (186), phenyl azides (187-195), arylsulfony] azides (191-193,196), or benzoylazides (197,198). For example, the reaction between phenyl azide (138) and the piperidine enamine of propionaldehyde (139) gives 1 -phenyl-4-methy l-5-( 1 -piperidino)-4,5-dihydro-l,2,3-triazole (140), exclusively, in a 53% yield (190). None of the isomeric l-phenyl-5-methyl product was formed. This indicates that the... 

The formate ester of phenol is rarely formed, but can be prepared from the phenol, formic acid, and DCC, 94-99% yield. The formate ester is not very stable to basic conditions or to other good nucleophiles. ... 

The mandelic acid formate ester obtained as a syrup as described above Is stirred for 2 hours with 2.9 kg ( 1.75 ) of thionyl chlorideat a temperature of about 70°C. The excess thionyI chloride is removed by evaporation and the residual green solution is vacuum distilled. The product, 0-formyl mandeloyl chloride, distills over at 127°C to 130°C (15 mm) or at 108°C to 112°C (7 mm). 

For 49, the reaction was highly successful in that a 3-O-formate ester (127) was indeed formed in a reaction period of 1 to 2 hours at room temperature with 121 followed by usual processing. Refluxing the solution for 3 to 4 hours afforded a chlorodeoxy sugar in 69-71% yield which proved to be 120 rather than the expected 3-chloro derivative (d-alio). 

The superiority of extractive hydrolysis over acid hydrolysis with respect to its productivity, yield, raw materials, and waste streams, for the transformation of drug intermediates (e.g. for Primaxin) in formate ester form to the corresponding alcohol, has been effectively demonstrated by King et al. (1985). They carried out the hydrolysis of the relevant formate ester with simultaneous extraction of the desired product from the undesired impurities by two-phase reaction/extraction with a base. 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

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). 

Scheme 10.1 gives some representative examples of laboratory syntheses involving polyene cyclization. The cyclization in Entry 1 is done in anhydrous formic acid and involves the formation of a symmetric tertiary allylic carbocation. The cyclization forms a six-membered ring by attack at the terminal carbon of the vinyl group. The bicyclic cation is captured as the formate ester. Entry 2 also involves initiation by a symmetric allylic cation. In this case, the triene unit cyclizes to a tricyclic ring system. Entry 3 results in the formation of the steroidal skeleton with termination by capture of the alkynyl group and formation of a ketone. The cyclization in Entry 4 is initiated by epoxide opening. 

The formation esters 99 by irradiation of 3-pyrazolidone azomethinimines 100 is the result of cyclization to diaziridines 101 followed by addition of methanol.82... 

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2 1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a P-hydrogen elimination. 

The production of formate esters in periodate work will be considered subsequently (see p. 34). 

If a representative formula (X) for this type of structure is examined, it may readily be seen that, if the formate ester on the (originally reducing) end of the oxidation product (XI) remains intact, each end will give rise to one molecule of formic acid per mole. But, if the formate ester is broken,... 

One of the more difficult problems encountered in obtaining a valid assay of formic acid is that of formate ester formation. The formate is derived from the cyclic, hemi-acetal structure which is an equilibrium form of many free sugars in solution. For example, the oxidation of one of the cyclic forms of D-glucose can readily be seen to give a formate ester (as well as a C-formyl group) on the atom originally denoted as C5. It... 

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