Diazoacetates, hydrolysis

The kinetics of acid catalyzed hydrolysis of ethyl diazoacetate in aqueous solution was studied for the first time by Bredig and Fraenkel [195] in 1905, and the decomposition kinetics of diphenyldiazomethane in aprotic solvents was investigated by Staudinger and Gaule [196] in 1916. Reinvestigations of the ethyl diazoacetate hydrolysis were carried out by Bronsted et al. [197] and Moelwyn-Hughes and Johnson [198], The reaction was followed by gas volumetric measurement of the evolved nitrogen. Ultraviolet spectrophotometric [199] and thermometric [200] methods were applied in more recent studies which were concerned with a variety of different diazo compounds. A review article [201] was published in 1967 even more new material is available today. 

Using previously described techniques, catalytic coefficients, have been evaluated for the catalysis of diazoacetate hydrolysis (7) by four phenols, seven carboxylic acids, water, and the aquated proton—all at 25°, in aqueous solution, at an ionic strength ofO.105. The mechanism of this reaction involves several steps, and the rate law is somewhat complicated, but it is possible to... 

The copper-catalyzed decomposition of diazoacetic ester in the presence of pyrrole was first described in 1899 and later investigated in more detail by Nenitzescu and Solomonica. Ethyl pyrrole-2-acetate (13), the normal product of electrophilic substitution, was obtained in 50% yield and was degraded to 2-methylpyrrole. Similarly iV -methylpyrrole with two moles of diazoacetic ester gave, after hydrolysis, the 2,5-diacetic acid (14) while 2,3,5-trimethylpyrrole gave, after degradation, 2,3,4,5-tetramethylpyrrole by substitution of ethoxycarbonylcarbene at the less favored )3-position. Nenitzescu and Solomonica also successfully treated pyrroles with phenyl-... 

Jackson and Manske described the decomposition of diazoacetic ester with indoles to give, after hydrolysis, the 3-acetic acid and some 1,3-diacetic acid no product of 2-substitution was found (see also ref. 49). Diazoacetone and diazopyruvic ester similarly gave the 3-sub-stituted indoles.Badger et al. have also examined the reaction of iV -methylindole, as well as of indole, with diazoacetic ester. Again only the 3-substituted product resulted and no evidence was obtained for addition. 

The specific rate of the hydrolysis of diazoacetic ester N2CHC00C2H5 + H20 => H0CH2C00C2H5 + N2 varies with the hydrogen ion concentration as follows ... 

Hydrazine salts have been prepared by the action of hypochlorites on ammonia1 or urea 2 by the hydrolysis of salts of sulfohydrazimethylene disulfonic acid 3 by the hydrolysis of triazoacetic acid 4 by the reduction of diazoacetic ester 5 by the reduction of nitroguanidine followed by hydrolysis 6 by the reduction of the nitroso derivatives of hexamethylene tetramine 7 by the reduction of nitrates or nitrites with zinc in neutral solution 8 by the action of sodium bisulfite on hyponitrous acid... 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

Indolizine-l-acetic acid has been prepared by reaction of 3-benzoylindolizine with diazoacetic ester followed by basic hydrolysis <68AC(R)1206). 

The methods of preparation of i. ost cyclojro-par.e acids involve first the preparation of tAie cyclic ester and subsequent hydrolysis to the free acid. That such hydrolysis did not change tne cyclic structure has been seen to be true ir. all tne cases tnus iar examined i o exceptions to tnis rule will now be studied,ior tney are botn 1,1,2,3 compounds. Aconitic ester and diazoacetic ester give by the usual reactions a cyclopropane ester as follows ... 

A shorter method has been used to prepare indolizine-1-acetic acid (88) by reaction with diazoacetic ester followed by base hydrolysis and acidification.139... 

According to Scheme 1 methyl 2-siloxycyclopropanecarboxylates should also be available from donor-acceptor-substituted olefins like 100, which are easily synthesized by silylation of the corresponding 1,3-dicarbonyl compounds. Cyclopropanation of 100 with methyl diazoacetate or diazomethane could be realized in the presence of Cu(II)-catalysts, but due to the relatively low reactivity of the olefins a large excess of diazoalkanes had to be employed. This makes the isolation of 101 troublesome and therefore direct hydrolysis with acid to give 1,4-dicarbonyl compounds 102 is advantageous (Eq. 32) 66). 

Considerable work has been invested in the experimental verification of Marcus theory. Kreevoy and Konasewich (1971) have studied the hydrolysis of the diazoacetate ion catalysed by a series of phenols and carboxylic acids (20). Proton transfer takes place in the... 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

According to the findings of kinetic and mechanistic studies of the hydrolysis reaction, the aliphatic diazo compounds may be divided into the following three groups (a) ethyl diazoacetate, primary diazoketones, primary diazosulfones, 2,2,2-trifluorodiazoethane (b) diaryldiazo-methanes, 9-diazofluorene and ring substituted derivatives, p-nitrophenyl-... 

The kinetics of hydrolysis of ethyl diazoacetate has been studied most thoroughly. The equation... 

Equation (47) was suggested for the first time by Bredig and Ripley [202]. In order to establish it unambiguously, it is necessary to carry out experiments at a constant ionic strength since feH and kHX are influenced by salt effects. Studies in the presence of halides at a constant ionic strength have never been done. Other approaches have been used instead. Albery and Bell [200] measured hydrolysis rates of ethyl diazoacetate in moderately concentrated perchloric acid and hydrochloric acid solutions. Rates in hydrochloric acid were faster than those in perchloric acid at the same stoichiometric concentration. In order to verify the dependence on the chloride ion concentration, it was assumed that rates of the reaction without participation of chloride (first term in eqn. (47)) are the same in perchloric acid and hydrochloric acid if the H0 values are equal. Activity coefficients were introduced in eqn. (47) as follows ... 

The solvent isotope effect for the acid catalyzed hydrolysis of ethyl diazoacetate (without halide ions) is much smaller than 1 (Table 19, p. 63) as expected for a pre-equilibrium proton transfer mechanism. Furthermore, according to the findings of Roberts et al. [205] the products of ethanolysis of ethyl diazoacetate in C2HsOD solution are C2HS OCHDCOOEt as well as C2 H5 OCD2 COOEt which indicates that H exchange is faster than ethanolysis. 

Rate coefficients of acid catalyzed hydrolysis of ethyl diazoacetate, primary diazoketones [206, 207] and primary diazosulfones [208, 209] are collected in Tables 17 and 18. 

It is interesting to compare reactivities of various diazo compounds (Tables 17 and 18). The substrates with the highest hydrolysis rate coefficients are diazoacetate ion and ethyl diazoacetate. The rate coefficients, kH, of diazoacetone and diazoacetophenone are 1.5 powers of ten lower and those of the diazosulfones are 2 to 3.5 powers of ten lower than the value for ethyl diazoacetate. Substituent effects on the hydrolysis rates of diazoacetophenone [212, 213] and phenylsulfonyl-diazomethane [208] follow Hammett s rule with p values of ca. —1 (Table 20) which is a little less negative than expected for substituent effects on the protonation equilibria. 

Rates of hydrolysis of diazoacetate ion in the presence of sodium acetate (plus a very small amount of acetic acid) or phenol—sodium phenoxide buffers are increased in comparison to rates without buffers at the same pH. The experimental data do not obey the simple equation... 

The value of fef1 for the hydrolysis of diazoacetate ion is five powers of ten higher than that for the hydrolysis of 3-diazo-2-butanone (Table 17). Proton transfer is rate-determining in both cases. Part of the rate... 

It is estimated that fe i is 1 to 2 powers of ten lower for diazoacetate ion in comparison to ethyl diazoacetate. This is not sufficient to explain the change from fe i/kn > lOfor ethyl diazoacetate to fc5[/feu = 4.6 x 10" 3 for diazoacetate ion. It appears that fen must be higher in the hydrolysis of diazoacetate ion. The computed value of fepfen/fe-i for diazoacetate ion is 7.3 powers of ten higher than the experimental feH for ethyl diazoacetate. Since the increase of the protonation equilibrium constant 1 /Ksh (when going from ethyl diazoacetate to diazoacetate ion) amounts to 5 to 6 powers of ten at most it is obvious that fen must be ca. 1.3 to 2.5 powers of ten higher for the hydrolysis of diazoacetate ion. 

The mechanism of hydrolysis of diazo compounds has been well studied [51] and like the examples in Sect. 2.2.3 involves protonation of an unsaturated carbon atom. Essentially two different mechanisms operate depending upon the diazo compound involved. The first mechanism is shown in eqns. (30) for the hydrolysis of ethyl diazoacetate in... 

Fig. 8. Bronsted plot for the trialkylammonium ion catalysed hydrolysis of diazoacetate ion. Catalytic coefficients log10 ha/p are plotted against the catalyst acidity log io %a9/P where p and q are the number of equivalent acid and base sites in the catalyst (HA) and its conjugate base. Redrawn with permission from M. M. Kreevoy and S.-W. Oh, J. Am. Chem. Soc., 95 (1973) 4805. Copyright by the American Chemical Society.

The reaction is carried out at ambient temperature and nearly complete enantioselectivity (>99%) is observed for mono- and 1,1-disubstituted olefins with diazoacetates. With all copper catalysts, the transkis selectivities in the cyclopropanation of mono-substituted olefins are only moderate. The transkis ratio depends, in this case, mainly on the structure of the diazo ester rather than the chiral ligand (eq 2). It increases with the steric bulk of the ester group of the diazo compound. With the BHT ester, the more stable trans isomer is formed with selectivities up to >10 1. The steric hindrance usually prevents ester hydrolysis, but the BHT group can be removed by reduction with LiAlHj. The trans isomer is even enriched by the reduction procedure because the cis isomer reacts more slowly. 

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