Diazoalkanes reaction with carboxylates

The sites of alkylation are the oxygen atoms of the hydroxyl, carbonyl, and carboxyl groups in lignin. Reactions a and b are selective with diazoalkanes (a) reacting under anhydrous conditions to alkylate, chiefly, the slightly acidic hydroxyl groups (98) of the phenolic, enolic(99-102), and carboxylic (103-107) units to form ethers. The diazoalkane reaction with carboxylic acids only occurs in solvents in which the acid is deprotonated to an enolate anion. The RN reactions are shown in Equation 2. 

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

One other type of esterification process which formally involves the carboxylic acid is the Reaction with diazoalkanes. Diazomethane in particular is widely used for the synthesis of methyl esters, viz. 

A practicable strategy to provide access to chiral pyrazolidine-3-carboxylic acid (16) makes use of asymmetric dipolar cycloaddition of diazoalkanes to u,p-unsaturated carboxylic acid derivatives. For this purpose a chiral auxiliary of the alkene component is used, e.g. Op-polzer s1166 1671 (lf )-2,10-camphorsultam.t164l As shown in Scheme 7, by reaction of (tri-methylsilyl)diazomethane (41) with /V-( aery I oy I )cam p h ors u 11 am (42), the AL(4,5-dihy-dropyrazoline-5-carbonyl)camphorsultam (43) is obtained. Reduction of 44 with sodium cyanoborohydride leads to A-(pyrazolidine-3-carbonyl)camphorsultam (45) as the 35-dia-stereoisomer (ee 9 1) in 65 to 80% yields.[164] The camphorsultam 45 is then converted into the methyl ester 46 by reaction with magnesium methylate without racemizationj1641... 

Just as most other diazoalkanes, ADM can readily react with carboxylic acids under mild conditions (in the absence of the catalysts, at or below room temperature and at low concentrations of the reacting compounds) forming the corresponding esters. The reactions between carboxycontaining polymers and ADM can be separated into three groups 1) reactions carried out under homogeneous conditions, 2) reactions proceeding at the liquid-liquid interface and 3) reactions at the liquid-solid interface. 

The nature of the solvent plays an important role in the reactions between carboxy-containing compounds and diazoalkanes. Protic solvents of the R-OH type can react with diazoalkanes in the presence of carboxylic acids to form the corresponding ethers Hence, in reactions with polymers dissolved in alcohols or alcohol-containing mixtures (poly(acrylic and methacrylic acids) etc.) the yield of the main reaction can decrease to 30—50% (with respect to ADM) 1 Consequently, when polymers soluble in aprotic solvents undergo anthryhnethylation, the reaction should be carried out in such solvents as benzene or toluene. 

One of the more commonly applied chain extension reactions for carboxylic acids utilizes die unique reactivity of diazoalkanes. This sequence, generally referred to as the Amdt-Eistert synthesis, is a two-step process which, in the first step, involves the formation of an a-diazo ketone by reaction of the corresponding acyl chloride with an excess of diazoalkane (Scheme In the second stage of the... 

Reaction with diazoalkanes. Catalytic amounts of nickel carbonyl decompose diazoalkanes to products evidently formed from an intermediate carbene. Use of a large excess of reagent in the presence of ethanol leads to formation of carboxylic acid esters in yields of 20-25%. 

The first step in the decomposition of nitrosoamides 123) is formation of the diazo ester 125) which fragments to a diazonium ion pair (128)129 The ion pairs thus produced differ from those obtained in the reaction of diazoalkanes with acids. The ratio of ester to ether formed in the decomposition of rV-nitroso-fV-benzhydrylbenz-amides in alcohol is lower than that found in the reaction of diphenyldiazomethane 132) with acids, and in the solvolysis of benzhydryl benzoate (I35)135,136 This effect has been attributed to the intervention of trans-diazo ester in the decomposition of 125) which leads to a greater distance between carbocation and carbox-ylate anion. In the diazoalkane reaction attack of the acid occurs at the electron-rich carbon atom to generate the carboxylate in the immediate vicinity of the incipient carbocation. 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

Whenever other methods of esterification fail for any reason, e.g., because of the sensitivity of the acid, or when small amounts of valuable carboxylic acids are to be esterified, the reaction can be carried out by use of a diazoalkane. Esterification with these reagents occurs in an inert medium, in ether,... 

Esters by reaction of carboxylic acids with halides and sulfonates 276-277 Esters by reaction of carboxylic acids with diazoalkanes and... 

Reaction of Diazoalkanes with Carboxylic Acids (Method G)... 

Formation of esters by reaction of diazoalkanes with carboxylic acids is a mild and often quantitative procedure. It is particularly useful for the preparation of methyl and ethyl [4], benzyl [3, 58], and benzhydryl esters [45, 59, 60], although not on a large scale. The reaction is initiated by proton transfer from the carboxyl group and 0-alkylation is a competing reaction with phenolic acids. Diazoalkanes may also add to carbonyl [61] and olefinic linkages [62]. Thus the shikimic acid derivative (16) with a limited amount of diazomethane at low temperature gives the methyl ester (17) but with an excess of the reagent forms the isomeric pyrazolines (18 and 19) [63, 64]. 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl bromides, iodides or tosylates. The carboxylate anion is not a particularly reactive nucleophile so reaction proceeds best in polar aprotic solvents or with crown ether catalysis. Acetone has also been found to be a good solvent for reactions with alkyl iodides. Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters which can be relatively difficult to prepare by the acid-catalyzed esterification reactions to be discussed in Section 3.4. Sections F and G of Scheme 3.2 give some specific examples of ester alkylation by both diazoalkanes and other alkylating agents. 

Despite the fragmentary results known to date, the dediazotation of diazoalkanes coupled with the carbene-carbon monoxide trapping reaction seems to be a promising synthetic path for the preparation of various carboxylic acid derivatives through the ketene intermediate product. Especially the highly effective and selective cobalt-catalyzed examples of the reactions are worth to explore in more detail. 

Diazoalkanes alkylate acidic and enolic groups rapidly and other groups with replaceable hydrogens slowly. Carboxylic and sulfonic acids, phenols and enols are alkylated virtually instantaneously when treated with this reagent. Lewis acid catalysts (e.g., BF3.Et20) are used to promote the reaction of... 

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