Diazomalonate

Solubility sol ether, THF, halocarbon and hydrocarbon solvents. Form Supplied in not commercially available. 

Preparative Methods diazomalonates are generally prepared by diazo transfer reaction of malonates and sulfonyl azides. A recent modification employs polystyrene-supported trialkylam-monium azide (generated in situ) under phase-transfer catalysis conditions and allows for facile isolation.  

Handling, Storage, and Precautions dimethyl diazomalonate has been utilized more extensively than has diethyl diazomalonate due to the explosion hazard of the latter. Nonetheless, care should be taken in preparation and handling of dimethyl diazomalonate. Storage at low temperature is recommended. The decomposition of dimethyl diazomalonate evolves nitrogen and can result in high pressures. 

Cyclopropanation. Decomposition of dimethyl diazomalonate by direct photolysis or by transition metal catalysis in the presence of alkenes leads to cyclopropanation (eq 1). The use of alkynes to trap the carbenoid species affords cyclopropenes (eq 2). Rhodium(II) acetate-catalyzed reaction with allenes allows ready access to methylenecyclopropanes, which form the basis for a methylenecyclopentane annulation protocol (eq 3).  

In contrast to the direct photolytic cyclopropanation of alkynes with dimethyl diazomalonate, benzophenone-sensitized photolysis in the presence of alkynes affords furans as the major products in moderate yields (eq 5).  

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Geminal difluorination ot diethyl diazomalonate can be effected with molecu lar fluorine (10% in nitrogen) to give diethyl difluoromalonate m 70% yield [90] (equation 27)... 

Pyridinium ylide is considered to be the adduct car-bene to the lone pair of nitrogen in pyridine. The validity of this assumption was confirmed by Tozume et al. [12J. They obtained pyridinium bis-(methoxycarbonyl) meth-ylide by the photolysis of dimethyl diazomalonate in pyridine. Matsuyama et al. [13] reported that the pyridinium ylide was produced quantitatively by the transylidalion of sulfonium ylide with pyridine in the presence of some sulfides. However, in their method it was not easy to separate the end products. Kondo and his coworkers [14] noticed that this disadvantage was overcome by the use of carbon disulfide as a catalyst. Therefore, they used this reaction to prepare poly[4-vinylpyridinium bis-(methoxycarbonyl) methylide (Scheme 12) by stirring a solution of poly(4-vinylpyridine), methylphenylsulfo-nium bis-(methoxycarbonyl)methylide, and carbon disulfide in chloroform for 2 days at room temperature. 

Kondo maintained his interest in this area, and with his collaborators [62] he recently made detailed investigations on the polymerization and preparation of methyl-4-vinylphenyl-sulfonium bis-(methoxycarbonyl) meth-ylide (Scheme 27) as a new kind of stable vinyl monomer containing the sulfonium ylide structure. It was prepared by heating a solution of 4-methylthiostyrene, dimethyl-diazomalonate, and /-butyl catechol in chlorobenzene at 90°C for 10 h in the presence of anhydride cupric sulfate, and Scheme 27 was polymerized by using a, a -azobisi-sobutyronitrile (AIBN) as the initiator and dimethylsulf-oxide as the solvent at 60°C. The structure of the polymer was confirmed by IR and NMR spectra and elemental analysis. In addition, this monomeric ylide was copolymerized with vinyl monomers such as methyl methacrylate (MMA) and styrene. 

The carbenoid displacement reaction (see Section 1.4.5.2.1.4.) of the optically active acetoxy sulfide derivative 19 (or the corresponding methoxymethyl ether) with diazomalonate in the presence of a catalytic amount of rhodium acetate in refluxing benzene affords the tram-alkylation productl22. 

A solution of 1.93 g (6.91 mmol) of methyl 4-nitrobenzyl diazomalonate in 100 mL of dry benzene is added dropwise over 1 h to a refluxing solution of 1.79 (4.48 mmol) of (4S,5R/S )-4-acetoxy-l-(2-benzoyl-oxyethyl)-5-phenylthio-2-pyrrolidinone in 100 mL of dry benzene in the presence of a catalytic amount of rhodium acetate. The mixture is stirred under reflux for an additional hour after which the solvent is removed. The residue is chromatographed (silica gel, benzene/ethyl acetate 8 2) to furnish an oil yield 2.32 g (85%). 

Diazocarbonyl compounds are especially useful in these reactions because of their ease of formation, relative stability, and controlled reactivity in catalytic reactions [ 1,11 ]. As outlined in Scheme 1, a wide diversity of methodologies are available for this synthesis, with access dependent on the nature of Z. Vinyl- and aryldiazoacetates are accessible by other pathways [2]. The order of reactivity toward diazo decomposition has diazoketones and diazoacetates much more reactive than diazoacetoacetates or diazomalonates. However, the influence of electronic effects on reactivities is more pronounced with phenyl- and vinyl-diazoacetates than with diazoacetoacetates and, especially, diazoacetates [12]. 

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

Much of the early work into the rhodium(II)-catalysed formation of oxazoles from diazocarbonyl compounds was pioneered by the group of Helquist. They first reported, in 1986, the rhodium(II) acetate catalysed reaction of dimethyl diazomalonate with nitriles.<86TL5559, 93T5445, 960S(74)229> A range of nitriles was screened, including aromatic, alkyl and vinyl derivatives with unsaturated nitriles, cyclopropanation was found to be a competing reaction (Table 3). 

Helquist s work on the use of diazomalonate in the synthesis of oxazoles has been extended to other diazocarbonyl compounds in our own laboratory.<92TL7769, 94T3761> Thus it was found that sulfonyl-, phosphonyl- and cyano-substituted diazoesters gave the corresponding 4-functionalised oxazoles 30 in acceptable yield (Scheme 20). In many cases the yield of oxazole was significantly improved by the use of rhodium(II) trifluoroacetamide as catalyst. The 4-cyano-oxazole 30 (R = Me, Z = CN) proved interesting in that it allowed the formation of a bis-oxazole 31 by a second rhodium catalysed reaction (Scheme 20). 

DIAZO TRANSFER BY MEANS OF PHASE-TRANSFER CATALYSIS DI-tert-BUTYL DIAZOMALONATE... 

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. 

A gas ehromatographic analysis on the produet by the submitter, using an 0.3 x 80 cm. column packed with 10% silicone rubber (SE-30) supported on acid-washed, 60-80 mesh Chromasorb P at 80°, exhibited a single peak. The retention times of di-ter(-butyl malonate, di-fert-butyl diazomalonate, and p-toluenesulfonyl azide were 2, 6, and 9 minutes, respectively. The purity of the product obtained by the checkers was estimated from proton magnetic resonance spectra to be ca. 94%, the remainder being di-tert-butyl malonate. 

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)... 

Copper-catalyzed reactions are particularly effective with a-diazo-P-dicarbonyl compounds such as diethyl diazomalonate. 

Thorough investigations with dimethyl diazomalonate and catalysts of the type (RO)3P CuX have revealed that the efficiency of competing reaction paths, the synjanti or EjZ selectivity in cyclopropane formation as well as the cis/trans ratio of carbene dimers depend not only on catalyst concentration and temperature but also on the nature of R58) and of the halide anion X 57 6". Furthermore, the cyclopropane yield can be augmented in many cases at the expense of carbene dimer... 

The preference for the less substituted double bond also determines the outcome of the copper-catalyzed cyclopropanation of isotetraline with dimethyl diazomalonate which gives 27 and its dehydrogenated relative 2883) the same behavior of the carbenoid derived from ethyl diazoacetate has been reported 84). 

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,... 

Alkyl diazoacetates undergo little or no allylic C/H insertion when decomposed catalytically in the presence of appropriate olefins 6,13,I4). In contrast, such insertions occur with diazomalonates or ot-diazoketones. From the available facts, the conclusion can be drawn that different pathways may lead to what finally looks like the direct or rearranged allylic insertion product, but convincing evidence for one or the other mechanism is available only in a few cases. As Scheme 22 shows, the C/H insertion products 98-100 may arise from one of three major sources ... 

C/H-insertions have been reported to occur in copper-catalyzed reactions between diazomalonates and cyclohexene as well as some alkylated derivatives 9,57. Some acyclic alkenes behave similarly9, but not so 1,1-dicyclopropylethylene150), An abstraction/recombination mechanism via intermediates of type 103 has been proposed53 which would account not only for the three insertion products 104-106... 

The question as to whether enol ether 72, the insertion product derived from diethyl diazomalonate and 1-methoxycyclohexene, has a similar origin or arises from a dipolar intermediate of type 102, has already been discussed (Sect. 2.3.1). Interestingly enough, only one formal C/H insertion product was reported in that case, rather than three as in the reaction with 1-methylcyclohexene. 

In contrast to ethyl diazoacetate, diethyl diazomalonate reacts with allyl bromide in the presence of Rh2(OAc)4 to give the ylide-derived diester favored by far over the cyclopropane (at 60 °C 93 7 ratio). This finding bespeaks the greater electrophilic selectivity of the carbenoid derived from ethyl diazomalonate. For reasons unknown, this property is not expressed, however, in the reaction with allyl chloride, as the carbenoids from both ethyl diazoacetate and diethyl diazomalonate exhibit a similarly high preference for cyclopropanation. 

Allyl acetals154). Allyl ethers give no or only trace amounts of ylide-derived products in the Rh2(OAc)4-catalyzed reaction with ethyl diazoacetate, thus paralleling the reactivity of allyl chloride. In contrast, cyclopropanation must give way to the ylide route when allyl acetals are the substrates and ethyl diazoacetate or dimethyl diazomalonate the carbenoid precursors. 

In addition to cyclopropane 145 and the expected [2,3] rearrangement product 143 of an intermediary oxonium ylide, a formal [1,2] rearrangement product 144 and small amounts of ethyl alkoxyacetate 146 are obtained in certain cases. Comparable results were obtained when starting with dimethyl diazomalonate. Rh2(CF3COO)4 displayed an efficiency similar to Rh2(OAc)4, whereas reduced yields did not recommend the use of Rh6(CO)16 and several copper catalysts. Raising the reaction temperature had a deleterious effect on total product yield, as had... 

Olefins analogous to 158 and 159 were also isolated from the CuS04-catalyzed decomposition of ethyl diazoacetate in the presence of 2-isopropenyl-2-methyl-1,3-dithiane (total yield 56%, E Z — 4 1) a butadiene was absent from the reaction mixture 161). With dimethyl diazomalonate instead of ethyl diazoacetate, only the Z-olefin resulting from a [2,3]-sigmatropic rearrangement of the corresponding sulfur ylide was obtained in 36 % yield 161). When the same procedure was applied to... 

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