Carboxylates diazoalkanes

These complexes can be isolated in some cases in others they are generated in situ from appropriate precursors, of which diazo compounds are among the most important. These compounds, including CH2N2 and other diazoalkanes, react with metals or metal salts (copper, palladium, and rhodium are most commonly used) to give the carbene complexes that add CRR to double bonds. Ethyl a-diazoacetate reacts with styrene in the presence of bis(ferrocenyl) bis(imine), for example, to give ethyl 2-phenylcyclopropane-l-carboxylate. Optically active complexes have... 

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... 

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. 

Metallic groups as in case (c) lead to electrophilic or even carbocation-like carbene complexes. Typical examples are Fischer-type carbene complexes [e.g. (CO)5Cr=C(Ph)OMe] and the highly reactive carbene complexes resulting from the reaction of rhodium(II) and palladium(II) carboxylates with diazoalkanes. Also platinum ylides [1,2], resulting from the reaction of diazoalkanes with platinum(Il) complexes, have a strong Pt-C o bond but only a weak Pt-C 7t bond. In situation (d) the interaction between the metal and the carbene is very weak, and highly reactive complexes showing carbene-like behavior result. Similar to uncomplexed carbenes. 

The transition metal-catalyzed cyclopropanation of alkenes is one of the most efficient methods for the preparation of cyclopropanes. In 1959 Dull and Abend reported [617] their finding that treatment of ketene diethylacetal with diazomethane in the presence of catalytic amounts of copper(I) bromide leads to the formation of cyclopropanone diethylacetal. The same year Wittig described the cyclopropanation of cyclohexene with diazomethane and zinc(II) iodide [494]. Since then many variations and improvements of this reaction have been reported. Today a large number of transition metal complexes are known which react with diazoalkanes or other carbene precursors to yield intermediates capable of cyclopropanating olefins (Figure 3.32). However, from the commonly used catalysts of this type (rhodium(II) or palladium(II) carboxylates, copper salts) no carbene complexes have yet been identified spectroscopically. 

Because of the high nucleophilicity and reactivity of diazoalkanes, catalytic decomposition occurs readily, not only with a wide range of transition metal complexes but also with Brpnsted or Lewis acids. Well-established catalysts for diazodecomposition include zinc halides [638,639], palladium(II) acetate [640-642], rhodium(II) carboxylates [626,643] and copper(I) triflate [636]. Copper(II)... 

A broad range of compounds can be O-alkylated with carbene complexes, including primary, secondary, and tertiary alcohols, phenols, enols, hemiaminals, hydroxylamines, carboxylic acids, dialkyl phosphates, etc. When either strongly acidic substrates [1214] and/or sensitive carbene precursors are used (e.g. aliphatic diazoalkanes [1215] or diazoketones) etherification can occur spontaneously without the need for any catalyst, or upon catalysis by Lewis acids [1216]. 

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. One possible alternative is the use of alkyltriazenes as reactive alkylating agents.52 Alkyltriazenes are readily prepared from primary amines and aryldiazonium salts.53 The triazenes, on being protonated by the carboxylic acid, generate a reactive alkylating agent that is equivalent, if not identical, to the alkyldiazonium ions generated from diazoalkanes. 

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. 

The mechanism of this type of esterification reaction has been much studied in recent years, using diphenyldiazomethane. In alcoholic solvents the mechanism of the reaction involves a rate-determining proton transfer from the acid to the carbon atom of the diazoalkane, to form a benzhydryldiazonium-carboxylate ion-pair135, 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). 

We showed you the formation of a carbene from diazomethane to illustrate how this reaction was different from the (ionic) methylation of carboxylic acids. But this is not a very practical way of generating carbenes, not least because of the explosive nature of diazoalkanes. However, diazocarbonyl compounds are a different matter. 

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. 

By far the most useful method for making cyclopropanones has involved the addition of diazoalkanes to ketenes, a reaction which was first explored by Turro and Hammond and by de Boer and coworkers . The cyclopropanone formed (Scheme 1) is immediately trapped by the addition of a nucleophile such as water, an alcohol or carboxylic acid. Turro found that although cyclopropanone itself is not isolable, a dilute solution of this ketone (0.5-0.8 M) may be stored at — 78°C for several days. 

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... 

The Amdt-Eistert synthesis, usually carried out with diazomethane, is fairly general and tolerates a wide range of substituents on both the carboxylic acid and alcohol. An obvious limitation is the reactivity of other functional groups, such as carboxylic acids or phenols, with diazomethane. The use of the more stable trimethylsilyldiazomethane as a replacement for diazomethane has been reported. While the use of diazoalkanes other than diazomethane is fairly rare, it does offer the opportunity to introduce additional functionality. For example, when sulfonyldiazomethanes (7) are used, the result is an a-sulfo-nyl carboxylic ester (Scheme 3). ... 

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. 

---