Ester diazomalonates

Caution Diazomalonic esters are toxic and potentially explosive. They must be handled with care. This preparation should be carried out in a well-ventilated hood, and the distillation of di-tcit-butyl diazomalonate should be conducted behind a safety shield. 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

Although the hazardous properties of di-tert-butyl diazomalo-nate are not known with certainty, it is reasonable to assume that they are similar to those of diazoacetic esters, which are considered to be moderate explosion hazards when heated. Contact with rough or metallic surfaces should be avoided. The submitter has routinely distilled 10-g. quantities of di-ferf-butyl diazomalonate under argon with no sign of decomposition. 

Diazomalonic esters serve as intermediates for the synthesis of a wide variety of compounds including cyclopropanes, cyclo-propenes, cycloheptatrienes, sulfur ylides, lactones, and substituted malonates. ... 

Di-fcr(-butyl diazomalonate Malonic acid, diazo-, di-(erf-butyl ester (8) Propanedioic acid, diazo-, bis(l,l-dimethylethyl)ester (9) (35207-75-1)... 

Diazomalonic esters, in their behavior towards enol ethers, fit neither into the general reactivity pattern of 2-diazo-l,3-dicarbonyl compounds nor into that of alkyl diazoacetates. With the enol ethers in Scheme 17, no dihydrofurans are obtained as was the case with 2-diazo-l,3-dicarbonyl compounds. Rather, copper-induced cyclo-propanation yielding 70 occurs with ethoxymethylene cyclohexane u4). However,... 

The view has been expressed that a primarily formed ylide may be responsible for both the insertion and the cyclopropanation products 230 246,249). In fact, ylide 263 rearranges intramolecularly to the 2-thienylmalonate at the temperature applied for the Cul P(OEt)3 catalyzed reaction between thiophene and the diazomalonic ester 250) this readily accounts for the different outcome of the latter reaction and the Rh2(OAc)4-catalyzed reaction at room temperature. Alternatively, it was found that 2,5-dichlorothiophenium bis(methoxycarbonyl)methanide, in the presence of copper or rhodium catalysts, undergoes typical carben(oid) reactions intermole-cularly 251,252) whether this has any bearing on the formation of 262 or 265, is not known, however. 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

Rh2(OAc)4 has become the catalyst of choice for insertion of carbene moieties into the N—H bond of (3-lactams. Two cases of intermolecular reaction have been reported. The carbene unit derived from alkyl aryldiazoacetates 322 seems to be inserted only into the ring N—H bond of 323 246). Similarly, N-malonyl- 3-lactams 327 are available from diazomalonic esters 325 and (3-lactams 326 297). If, however, the acetate function in 326 is replaced by an alkylthio or arylthio group, C/S insertion rather than N/H insertion takes place (see Sect. 7.2). Reaction of ethyl diazoacetoacetate 57b with 328 also yields an N/H insertion product (329) 298>, rather than ethyl l-aza-4-oxa-3-methyl-7-oxabicyclo[3.2.0]hex-2-ene-2-earboxylate, as had been claimed before 299). 

Reactions of carbenoids with 4-thio-substituted 2-azetidinones have attracted much interest recently. Insertion of the carbene unit derived from diazomalonic esters 297-34°> or ethyl diazo(diethoxyphosphoryl)acetate 340 into the C4—S bond of simple P-lactams 353 and 354 took place irrespective of whether a N—H or a N—R... 

No S-ylide derived product at all was obtained from the Rh2(0Ac)4-catalyzed decomposition of diazomalonic ester amide 362 rather, a compound was isolated to which the structure of the Wolff rearrangement product 363 was tentatively assigned344. The desired C/S insertion product 364 was accessible, however, by photochemical decomposition of 362. 

The sulfonium ylide derived chemistry of penicillins continues to meet the interest of several research groups. It is well known that intermolecular carbenoid attack at the sulfur atom generates a sulfonium ylide which undergoes spontaneous opening of the thiazolidine ring to furnish a l,2-sm>-penicillin 326). Novel examples of this reaction type were found upon Rb2(0Ac)4-catalyzed decomposition of diazomalonic esters in the presence of various penicillins this transformation constituted the opening step of a synthetic sequence directed towards 2-alkoxycarbonyl-cephems 345 a) or modified penicillins 345 b). Similar to its reaction with 4-thio-2-azetidinone... 

Wulfman, D.S., van Thinh, N., McDaniel, R.S., Pierce, B.W., Heitsch, C.W., and Jones, M.T., Metal salt-catalyzed carbenoids. IX. Catalysts in trialkyl phosphite-copper(I) complex catalyzed decomposition of diazomalonic esters in cycloalkenes, ]. Chem. Soc., Dalton Trans., 522, 1975. 

Thiophenium bis(alkoxycarbonyl)methylides (44) are obtained in high yield by rhodium(II) carboxylate-catalyzed reaction of diazomalonate esters with thiophene derivatives (88JCS(P1)1023). Likewise, ylides from benzo[b]thiophene and dibenzothiophene (e.g. 45) have also been reported by tram-ylidation using phenyliodonium bis(phenylsulfonyl)methylide (88JHC1599). 

The comparison of thiophene with thioethers on the one hand and with enol thioethers on the other, in regard to its behaviour towards conventional electrophiles, has been made in Section 3.02.2.3. Attack on carbon is the predominant mode of reaction (Section 3.14.2.4) reaction at sulfur is relatively rare (Section 3.14.2.5). Carbenes are known to act as electrophiles attack at both carbon and sulfur of thiophene has been reported. The carbene generated from diazomalonic ester by rhodium(II) catalysis attacks the sulfur atom of thiophene, resulting in an ylide. It has also been shown that the carbenoid species derived by thermolysis of such an ylide functions as an electrophile, attacking the a-carbon of a second molecule of thiophene (Section 3.14.2.9). Singlet nitrene is electrophilic. However, in contrast to carbenes, it invariably attacks only the carbon atom (Section 3.14.2.9). 

Cyclopropanated products from thiophene can undergo further transformations. For instance, irradiation of tetraphenyldiazocyclopentadiene in the presence of 2,5-dimethyl-thiophene gives the product (248) by rearrangement of the cyclopropane (247) (72CC1257). With thiophene as the substrate the ylide (249) was also obtained. Likewise, ylide (15) is formed by photolysis of diazomalonic ester in the presence of thiophene (77JOC3365). 

The reaction of N-alkylated pyrroles with carbenoids leads exclusively to substitution products. Due to the pharmaceutical importance of certain pyrrolylacetates, the reaction with alkyl diazoacetates (Scheme 45) has been systematically studied using about 50 different catalysts.13 Both the 2- and 3-alkylated products (216) and (217) could be formed and the ratio was dependent on the size of the JV-alkyl group and ester and also on the type of catalyst used. This has been interpreted as evidence that transient cyclopropane intermediates were not involved because if this were the case, the catalyst should not have influenced the isomer distribution. Instead, the reaction was believed to proceed by dipolar intermediates, whereby product control is determined by the position of electrophilic attack by the carbenoid. Similar alkylations with dimethyl diazomalonate gave greater selectivity and yields.164... 

The diazo compound (181a), prepared from the nitrosamine, cyclized to a pyrrolopyrazoline in 80% yield.98 The diazo compound (181b), prepared from diethyl diazomalonate and allylamine, cyclized similarly but at a much more rapid rate. This is consistent with the lowered LUMO of the dipole of (181b), substituted with an ester group here the dipole LUMO-dipolarophile HOMO is the likely dominant interaction. The N—N double bond of the pyrrolopyrazoline products was readily isomerized to afford A2-isomers. 

Thep-nitrophenyl ester of diazomalonic acid has been made. While this derivative proved useful for acylating the serine residues at the active sites of trypsin and chymotrypsin (e.g. Vaughan and Westheimer, 1969a,b ... 

Fig. 15.39. Rate constants of 1,3-dipolar cycloadditions of diazomalonic ester as a function of the HOMO or LUMO energies, respectively, of the dipoLarophile.

Fig. 15.42. Preparation of diazomalonic ester via diazo group transfer via the Regitz procedure.

Diazomalonic ester is another important 1,3-dipole for synthesis. We saw the kinetics of 1,3-dipolar cycloadditions of diazomalonic ester earlier, in the discussion of Figure 15.39. The preparation of this 1,3-dipole is accomplished most conveniently with the procedure shown in Figure 15.42. 

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