Diazomalonic ester

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. 

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. ... 

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. 

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). 

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. 

A detailed analysis of the reaction of diazoalkanes and a-diazocarbonyl compounds with thiophene has revealed that the formation of stable ylids is observed only with diazomalonic esters (79JCS(P 1)2624). Other a-diazocarbonyl compounds, such as diazoacetic esters, Meldrum s diazo, or ethyl diazoacetoacetate, do not generally give rise to stable ylids. However, with tetrachlorothiophene under favorable conditions, the corresponding ylids may be isolated (84CC190). 

Bisalkoxycarbonylcarbenes have been generated from several different sources. In the photochemical reaction of diazomalonic esters, the adducts to alkenes have been obtained with substantial retention of stereochemistry when the singlet species is allowed to react. On the other hand, an almost complete loss of olefin stereochemistry is observed in the reaction of triplet species Under the catalytic conditions, the cyclopropanation occurs stereospecifically. The major side reactions in these cyclopropanations are allylic C-H... 

Copper powder, copper bronze, copper(I) oxide, copper(II) oxide, copper(Il) sulfate, and cop-per(I) halides, typically applied as a suspension in refluxing solvent or alkene, are used extensively for intermolecular cyclopropanation with diazoacetic esters or diazomalonic esters, and for intramolecular cyclopropanation of unsaturated diazocarbonyl compounds. Bis(acetylacetonato)copper(Il) [Cu(acac)2], a more recently introduced catalyst, is only sparingly soluble in the typical solvents and alkenes which are used and is therefore applied under the same conditions. Catalysts such as trialkyl phosphite and triaryl phosphite complexes of copper(I) halides and salicylaldimatocopper(II) chelates [e.g. 1 (R = (R)-a-phenylethyl, R = /ert-butyl ) and 2 ] are soluble in many organic solvents and liquid alkenes. 

Under the conditions of homogeneous catalysis, decomposition temperatures are normally significantly lower than with the heterogeneous catalysts mentioned above, and cyclopropane yields in general are higher. However, catalysts of type 2 must first be converted into the active form [presumably a copper(I) monochelate] by brief heating or by in situ reduction (see Table 10). Another soluble catalyst, copper(I) triflate, even decomposes diazoacetic esters and diazomalonic esters at temperatures below 0 °C and sterically more encumbered diazocarbonyl compounds (e.g. a-diazo-a-trialkylsilyl acetic esters " ) still at room temperature, and has shown its effectiveness in a number of cyclopropanation reactions. Since copper(I) triflate is... 

Catalytic cyclopropanation of alkenes with diazomalonates is sometimes carried out with copper powder, but it appears that copper(I) halide/trialkyl phosphite complexes (for a procedure see Houben-Weyl Vol. E19b, p 1113), bis(acetylacetonato)copper(II), " ° and tet-raacetatodirhodium can be employed more advantageously (Table 13, entries 7-9). For the cyclopropanation of styrene with dicyclohexyl diazomalonate, however, copper(I) triflate was the catalyst of choice, while intramolecular C —H insertion at the cyclohexyl ring took place in the presence of tetraacetatodirhodium. A detailed comparison of copper catalysts for the cyclopropanation of cyclohexene, 1-methyl- and 1,2-dimethylcyclohexene, (Z)- and ( )-hept-2-ene with dimethyl diazomalonate, including competitive reaction pathways such as allylic C-H insertion and carbene dimer formation, is available. The catalyzed interaction between diazomalonic esters and enol ethers leads to cyclopropanes in some cases (e.g. ethoxymethylenecyclohexane to dimethyl 2-ethoxyspiro[2.5]octane-l,l-dicarboxylate ) and to different products in other cases (e.g. 1-methoxycyclohexene, 2-methoxy-3,4-dihydro-2/7-pyran ). This behavior is attributed to the occurence of stabilized dipolar intermediates in these reactions. 

In contrast to diazoacetic esters, a-diazo ketones yield only a-(2-thienyl) ketones in the car-benoid reaction, and methyl 2-diazo-3-oxobutanoate provides methyl 6-acetyl-2-thiabicyclo[3.1.0]hex-3-ene-6-carboxylate (13%) and methyl 2-(2-thienyl)-3-oxobutanoate (67%). Diazomalonic esters yield sulfur ylides that are stable at room temperature and rearrange to products other than cyclopropanes on heating the formation of a 2-thiabicyclo[3.1.0]hex-3-ene derivative 46 is an exception. 

Copper powder, copper bronze, Cu O, CuO, CuSO, CuCl and CuBr were the first catalysts which were used routinely for cyclopropanation of olefins as well as of aromatic and heteroaromatic compounds with diazoketones and diazoacetates. Competing insertion of a ketocarbene unit into a C—H bond of the substrate or solvent remained an excpetion in contrast to the much more frequent intramolecular C—H insertion reactions of appropriately substituted a-diazoketones or diazoacetates Reviews dealing with the cyclopropanation chemistry of diazo-acetic esters (including consideration of the efficiency of the copper catalysts mentioned above) and diazomalonic esters as well as with intramolecular cyclopropanation reactions of diazoketones have appeared. 

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 Rh lOAc) -catalyzed reaction with dimethyl diazomalonate but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated carbenoid reactions. Fonnation of a diazomalonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to... 

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