Esters from diazo ketones

A simple synthesis of a-amino ketones and esters 231 (R1 = EtO or Ph R2 = H or CO2EE R3 = Me or CH2C02Et R4 = PhCH2 or CH2C02Et) proceeds from diazo ketones and esters, respectively, tertiary amines and copper powder. The intermediate... 

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). 

This general method has been folldwed in the preparation of a few other ketoketenes from ethoxalylacetic ester and from acylacetic esters. The diazo ketones were prepared by nitrosation, reduction, and treatment with nitrous acid. The use of methyl acetoacetate is illustrative the ketene was isolated as the dimer. 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

To select between these two alternative structures it was necessary to synthesize a labeled analog. Three hydrogen atoms of the methyl moiety of the ester group were substituted for deuterium. One of the principal pathways of fragmentation of [M N2]+ ions involves the loss of CH3 radical. Since all R substitutes in diazo ketones 4-1 were also methyls it was important to detect what group exactly is eliminated from the [M N2]+ ion. The spectrum of deuterated sample has confirmed that the methyl radical of the ester moiety leaves the parent ion. As a result the cyclic structure 4-2 was selected as the most probable. The ketene structure 4-3 is hardly able to trigger this process, while for heterocyclic ion 4-2 it is highly favorable (Scheme 5.22). 

One of the earliest uses for rhodium(II)-catalyzed dipoles was demonstrated in Davies furan synthesis [22]. Isomiinchnones were also shown to produce substituted furans [115]. Additional furan syntheses have been described using silylacetates [116], unsaturated esters [117], and fluoroalkyl diazo acetates [118]. The synthesis of furofuranones and indenofuranones 35 from a-diazo ketones having pendant alkynes has also been reported (Eq. 6) [119]. Other fused heterocyclic systems include furo[3,4-c]furans [120, 121] furo[2,3-b]furans [122] as well as thiobenzofurans [123], and benzoxazoles[124] have also been synthesized with this methodology. 

The suitably protected amino acid is activated as the mixed anhydride and treated with diazomethane to produce the corresponding diazo ketone. Rearrangement in the presence of water furnishes the p-amino acid. Diazomethane contains varying amounts of water, which is able to hydrolyze the activated amino acid. This leads to subsequent methylation by diazomethane to form the methyl ester as a side product. This cannot easily be removed from the diazo ketone, but can be separated during work-up of the homologated amino acids. 

In recent work67, it has been demonstrated that simple a-diazo ketones and esters can, in fact, be induced to undergo 1,5-insertion in preparatively useful yields. It was already known51 that in the rhodium-catalyzed insertion process, methyl C-H is electronically less reactive than methylene C-H or methine C-H. It therefore seemed likely that competing -hydride elimination would be least likely with a diazoethyl ketone. Indeed, on cyclization of 2-diazo-3-tetrade-canone, only a trace of the enone product from /J-hydride elimination is observed. The predominant side reaction competing with 1,5-insertion is dimer formation. 

With the long chain a-diazo ketone. 6-diazo-7-tridecanone, 1,5-insertion could proceed with placement of the carbonyl outside the ring, or included in the ring. In fact, only the product 7, from the first of these two cyclization modes, is observed67. The alternative cyclopentane 9 is not formed. As with the a-diazo ester, the relative proportion of 1,2- and 1,5-products depends on the rhodium carboxylate employed. Throughout these studies, it has been observed that the olefin 8, obtained from 1,2-elimination, is cleanly Z-configured67 68. 

The system iV-halosuccinimide-hydrogen fluoride/pyridine can be used to prepare geminal chlorofluoro-, bromofluoro-, and fluoroiodo-substituted ketones and esters from the corresponding diazo compounds.35... 

The reaction of sodium azide with l-bromo-l-nitro-2-arylethenes takes place by a formal 1,3-cycloaddition Scheme leading to 4(5)-aryl-5(4)-nitro-l,2,3-triazoles [487-489], During the synthesis of nitrotriazoles the bromonitroarylethenes can be replaced successfully by the more readily obtainable l,2-dibromo-l-nitro-2-arylethanes [489], The intermediate product in the synthesis of 3-nitropyrazoles from 2,2-dinitroethanol and diazo ketones or diazoacetic ester is 1,1-dinitroethene [490,491] (Scheme 68). 

N-Nitrosation of oximes by nitrosyl halides or nitrite esters often results in the formation of N-nitrimines, R R C=NN02, these compounds being formed by rearrangement of the initial adducts. N-Amination of oximes by chloramine or by hydroxylamine-O-sulfonic acid can result in the formation of diazo compounds (Scheme 28). The reaction, known as the Forster reaction, has been used for the preparation of aryldiazoalkanes, although better methods are usually available. Diazo ketones of the general formula (49) have also been prepared by this method from the oximes. "... 

The method has been adapted to the formation of l)fs-diazoacetylalkanes from dibasic acid chlorides. Diazo ketones have been obtained from acyl chlorides containing a /Sj y-double bond, an ester group, and certain heterocyclic and aryl nuclei having alkyl, methoxyl, and nitro substituents. On the other hand, functional groups such as phenolic hydroxyl, arylamino, aldehyde, active methylene, and a,/S-unsaturated linkages may interfere. The method is ideal for application to complex molecules. 

MO calculations have been carried out on the isomerization of cyclopropane to propene, and the MNDO method has been used to study the reaction pathway and to optimize the structure of reactant, transition structure, and product of the ring opening reaction of bicyclo[1.1.0]butane. Various methods have been employed to estimate the rate constants for ring opening of the 2-cyclopropyl-2-propyl radical. 1-Acceptor-1-sulfenyl-substituted 2-vinylcyclopropanes of the type (430) have been found to afford 6-sulfenyl-a,jS y, -unsaturated carboxylic esters and nitriles (431) upon treatment with acid, by a process which involves C(l)—C(2) bond fission and a novel 1,5-sulfenyl rearrangement (see Scheme 110). It has been shown that the benzophenone-sensitized photolysis of vinyl norcaradiene derivatives, such as 5-(2-methylprop-l-enyl)-3-oxatricyclo[4.4.0.0 ]deca-7,9-dien-4-ones (432), results in the regioselective cleavage of only one of the cyclopropyl c-bonds to afford isochroman-3-one derivatives (433). It has been reported that the major product obtained from the reaction of structurally diverse a-diazo ketones with an electron-rich alkene in the... 

In the first step of the reaction sequence a methyl ester is formed via a Wolff rearrangement. The Wolff rearrangem ent provides acids, esters or amides from a-diazo ketones and is often used in a ring contractive way to form strained ring systems, which are not accessible by other sequences.It also occurs as the key step in the Arndt-Eistert homologation of carboxylic acids. ... 

This reaction sequence establishes the fifth cyclobutane ring of the ladderane core and is analogous to the reaction from 3 to 5. First P-formyl ketone 26 is formed, which undergoes deformylative diazo transfer in the second step yielding a-diazo ketone 27. The desired pentacyclic carboxylic acid ester 11 is built up via a light-induced IFb rearrangement. 

The original Regitz procedure for diazo transfer to a -keto ester (131) used p-toluenesulfonyl azide (132 equation 54). This reagent works well, and is easy to prepare from the corresponding sulfonyl chloride. A disadvantage of this reagent is that the p-toluenesulfonylamide coproduct (134), as well as any excess p-toluenesulfonyl azide, have to be removed from the product diazo ketone (133) before it can be used. 

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