Diazoalkanes reactions with carboxylic acids

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. 

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. 

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... 

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]. 

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... 

Fig. 7. Triazenes as versatile polymer-supported diazoalkane analogues (resins 10) were obtained from polymeric diazonium salts (resins 9) and releasing carbenium ions upon acidic activation. The reaction can be employed for the alkylation of carboxylic acids with a reaction half life of ca. 5 min.

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

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. 

The evidence for diazonium-ion formation in neutral or basic solutions is strong. Nonetheless, a number of serious problems remain. One difficulty is the high reactivity that must be attributed to the diazocompounds. Although aliphatic diazoalkanes can be expected to be particularly reactive towards protonation, the difference between, on the one hand, diazomethane, which requires the presence of a carboxylic acid for the observation of proton exchange at room temperature (van der Merwe et al., 1964) and, on the other hand, diazobutane, which undergoes protonation in methanolic sodium methoxide at —64° (Kirmse and Rinkler, 1962) is somewhat surprising. One would wish to see the acidic character of the solvent catalysis corroborated by a Bronsted relation within which the rate constant for the solvent reaction is compared with that for other molecular acids. 

The reactions illustrated in equations (62-64) are each catalyzed by rhodium acetate. Diazo compounds, especially diazoalkanes, can also react by a simple ionic mechanism. The esterification of a carboxylic acid with diazomethane is a familiar example. The ionic pathway is especially likely when the intermediate carbocation would be stabilized. Thus, diazine (158) couples smoothly with phenols, presumably by thermal rearrangement to the corresponding diazo sugar, followed by acid-catalyzed N2 loss... 

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. 

Monohalo or dihalo alkanes, carboxylic acids, or ketones are obtained on treating diazoalkanes,1167 diazocarboxylic esters,1168 or diazo ketones with hydrogen halides or halogens. The reaction usually occurs at room temperature or below. However, preparative importance attaches only to the formation of the halo ketones from diazo ketones they are obtained free from isomers (cf. page 189). 

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,... 

The esterification of carboxylic acids with diazoalkanes has become a classical method. The success of the reaction stems from the interaction of two rather hard species which are simultaneously generated by proton transfer... 

The metallocarbene intermediates are most often formed from thermal, photolytic, or metal-catalyzed deconposition of diazocarbonyl compounds, with concomitant loss of dinitrogen. Under transition metal catalysis, the initially formed species is a metallocarbene rather than a free carbene, and this is usually desirable due to the moderated reactivity (and, hence, fewer undesired side reactions) of the metal-complexed carbene. The two most common methods for introduction of the diazo group are acylation of diazoalkanes with suitably activated carboxylic acid derivatives and diazo transfer reactions in the case of more acidic active methylene substrates fScheme 16.12T... 

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