Ethyl diazoacetate, 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. 

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. 

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. 

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... 

For purposes of classification the 4-aminopyrazoles are considered to be 4-imino-2-pyrazolines and analogs of 2-pyrazolin-4-ones. These compounds are listed in Table XL. Such compounds can be prepared by direct cyclization using ethyl diazoacetate and ethyl cyanoacetate.92 This is the same as eq. 243, except that the malonic ester is replaced by ethyl cyanoacetate. Purines can be hydrolyzed to 4-imino-2-pyrazolines by using strong acid.1210 1846 By far the most frequently used preparation is reduction of appropriately substituted pyrazoles, such as 4-nitro,368,812,819,1015,1019,1049 4-nitroso1165 or 4-aryl-azo.671 974,995 The hydrolysis of the carbethoxy 4-imino-2-pyrazolines derived from ethyl cyanoacetate and ethyl diazoacetate forms 4-imino-2-pyrazolin-3-carboxylic acid which is readily decarboxylated to the parent compound.92... 

Reaction with trialkyIhoranes.14 Ethyl diazoacetate reacts with trialkylboranes with loss of nitrogen to give, after hydrolysis, the homologated ethyl ester ... 

Preparation of cycloheptane-1,3-dione. Indian chemists19 have prepared this dione from dihydroresorcinol (1) by conversion into the monoethylene ketal (2) followed by reaction with ethyl diazoacetate catalyzed by anhydrous zinc chloride. They note that the quality of zinc chloride is important consistently good yields were obtained with material supplied by Riedel-de Haen. The product (3) is converted into the dione (4) by hydrolysis and decarboxylation with aqueous potassium hydroxide. 

Ring expansion (1, 369-370 6, 252-253). The ring expansion of ketones to the next higher homolog with ethyl diazoacetate requires hydrolysis and decarboxylation of the intermediate 8-keto ester, a step that is sometimes troublesome. Baldwin and Landmesser have used benzyl diazoacetate and allyl diazoacetate as alternative reagents. The benzyl jS-keto esters are cleaved and decarboxylated on hydrogenation both benzyl and allyl keto esters are reduced by sodium in liquid ammonia to ketones. 

Follow-up chemistry of azetidyl ylide 94, which was obtained by hydrolysis of ylide 84, led to various pyrrolidines and pyrazoles [68]. The reaction with methyl oxalyl chloride gave a 4-triphenylphosphoranyhdene-pyrrolidine-2,3,5-trione 95, while treatment with ethyl diazoacetate afforded 4-anilido-3-triphenylphosphoran-ylidene-pyrazole-5-carboxylic acid ethyl ester 96 (Scheme 20). 

The total synthesis started with a Birch reduction of p-methoxytoluene (382) to obtain the dihydro compound 383, which was treated with p-toluenesulfonic acid to obtain acetal 384. CyclopropanatiOTi with ethyl diazoacetate and transaceta-lization led to compound 385, which reacted to the unsaturated keto ester 386 on treatment with base. In the next step, the keto ester 386 was methylated with methylmagnesium chloride, and it reacted selectively at the 2-positon to yield 387. Lactonization with further methylation with methyl iodide afforded homo-lactone 389, which reacted with lithium salt 390 to alkyne 391 and was reduced with sodium borohydride to diol 392. Partial reductiOTi of the triple bond to the double bond was obtained with sodium in ammonia and further treatment with acid led to hydrolysis of the acetal, which subsequently cychzed to 394 (Scheme 8.1). 

We have already seen (pp. 164-171) that in the hydrolysis of many aliphatic diazo-compounds, notably ethyl diazoacetate, there is good evidence for a pre-equilibrium of the type... 

Since Theodor Curtius reported the synthesis of ethyl diazoacetate in 1883, Buchner had investigated its reactions with carbonyl compounds, alkenes, alkynes, and aromatic compounds for more than 30 years.His extensive contributions in this area resulted in two reactions named in his honor the Buchner-Curtius-Schlotterbeck reaction (formation of ketones from aldehydes and aliphatic diazo compounds) and the Buchner reaction. The prototypical example of the latter involves the thermal or photochemical reaction of ethyl diazoacetate with benzene to give (via norcaradiene 7) a mixture of four isomeric cycloheptatrienes 8-11. Initially, Buchner believed that a single norcaradiene product 7 was generated from this reaction, but later, he realized that the hydrolysis of the product afforded a mixture of four isomeric carboxylix acids. The norcaradiene formulation persisted until 1956 when Doering reinvestigated this reaction. ... 

The addition of ethyl diazoacetate and diphenyldiazomethane to dibutyl vinyl-boronate was first reported over forty years ago [87]. This initial study was completed later to establish the scope and limitations of these reactions and the exact nature of the intermediates involved [88]. The regioselective cydoaddition step was immediately followed by a spontaneous 1,3-migration of boron to give a N-boronyl 2-pyrazo-line, which can be trapped, after hydrolysis, with phenylisocyanate (Scheme 9.41). 

Triacetylenic boranes are derived from lithium acetylides and boron trifluoride etherate in THF at —20 °C. They react with ethyl diazoacetate to give homologated propargyl esters (7) after hydrolysis. Hydration of these iSy-acetylenic esters using mercuric ion is regiospecific only y-keto-esters (8)... 

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-... 

Hydrolysis of diazoacetate ion Hydrolysis of 3-diazo-2-butanone Hydrolysis of ethyl 2-diazopropionate Hydrolysis of p-nitrophenyldiazomethane 0.49 ... 

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