Cyclopropanation diazomalonate

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). 

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. ... 

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). 

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... 

It is notable that Table 11 contains examples of intramolecular cyclopropanation of an acrylate. It was found that Cu(acac)2 was not an efficient catalyst for this transformation cosiderable improvement was achieved by using catalytic amounts of Cu(acac)2 and excess CuS04 186). A similar observation was made with (2,4-pentadien-l-yl)diazoacetates or diazomalonates t91). 

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. 

Intramolecular cyclopropanations are also well documented in the literature. It has been shown by Koskinen and co-workers that the cyclopropanation of diazomalonate 57, illustrated in Figure 9.18, using benzyl bis(oxazoline) 40 and copper(I) triflate afforded lactone 58 in 73% yield and 32% ee. Nishiyama and coworkers showed that cyclopropanations of diazoacetates 59a-c proceeded in yields ranging from 79-93% and 24-86% ee (Table 9.6, Fig. 9.18, p. 544). ... 

Beyond these systems, challenges in stereocontrol remain for both inter- and intramolecular cyclopropanation reactions with diazoketones, diazoketoesters (18), diazomalonates, and diazomethane. Although some progress has been made in intramolecular reactions of diazoketones, with selected examples having high % ee values,enantiocontrol is generally low to moderate for these systems. 

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). 

Examples are known where intermolecular carbenoid transformations between diazomalonates or certain diazoketones and appropriate olefins result in competition between formation of cyclopropane and products derived from allylic C—H insertion2-4. For example, catalytic decomposition of ethyl diazopyruvate in the presence of cyclohexene gave the 7-ejco-substituted norcarane 93 together with a small amount of the allylic C—H insertion product 94 (equation 95)142 143. In some cases, e.g. rhodium(II) decomposition of a-diazo-j8-ketoester 95, the major pathway afforded C—H insertion products 96 and 97 with only a small amount of the cyclopropane derivative 98. In contrast, however, when a copper catalyst was employed for this carbenoid transformation, cyclopropane 98 was the dominant product (equation 96)144. The choice of the rhodium(II) catalyst s ligand can also markedly influence the chemoselectivity between cyclopropanation and C—H... 

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and <5-lactones, respectively (equations 137 and 138)198 205. The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of E-alkenes in bicyclic y-lactone formation198. Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enandoselectivity in intramolecular cyclopropanation (equation 139)194. On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations201. In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140)206. 

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 production of buta-1,3-dienes (37) by reaction of 1,2-diarylcyclopropenes with dihalocarbenes is thought to involve electrophilic attack of the carbene to give a dipolar intermediate (38).51 The addition of carbene to CO and H2C=0 has been studied by MNDO calculations.52 Photolysis of diethyl diazomalonate in a CO matrix at low temperature gave rise to ketenes by immediate trapping of the postulated carbene (39).53 The major products of reaction between dichlorocarbene and cyclone were CO and the gem-dichloro species (40).54 The predominance of this pathway over formation of the dichlorooxirane or the cyclopropane is attributed to the aromatic nature of the carbonyl ylide and its twist geometry. 

Only a limited number of examples have been reported. The reactivity of sulfonium ylide 98a, prepared by the reaction of thiepine 96 and dimethyl diazomalonate (Section 13.03.6.1), was examined <20060BC2218>. The reactivity of the stabilized sulfonium ylide 98a was restricted to the highly reactive Michael acceptor, tetracya-noethylene 152 (the ylide failed to react with benzaldehyde or dicyanoethylene). Reaction of ylide 98a with tetracyanoethylene 152 led to the consumption of the ylide 98a (Equation 22). Thiepine 96 was produced in the reaction and the formation of cyclopropane 153 was suggested. 

Copper-catalyzed cyclopropanation of 4,7-dihydro-l,3-dioxepin 46a with ethyl diazoacetate gave cyclopropanodiox-epane 49, as the only product. The product formation of cyclopropanation with dimethyl diazomalonate (dmdm) catalyzed by copper(n) acetylacetonate depends on the substitution pattern of the dioxepin (Scheme 3) <2000HCA966>. 

Dimethyl diazomalonate undergoes reaction with nitriles in the presence of rhodium(II) acetate to give 2-substituted-4-carbomethoxy-l,3-oxazoles (255). The reaction proceeds with a wide range of nitriles,133-139 although cyclopropanation is a competing process in the case of unsaturated nitriles.129... 

Reaction of the enol ether 58 with dimethyl diazomalonate provides the spiro compound 59 in high yield. Reduction and acid catalyzed cyclopropane cleavage gives the unsaturated y-lactol 60 which can be oxidized to p-methylene y-butyro-lactone 61 20). 

Deoxygenation of epoxides.1 In the presence of rhodium(II) acetate, dimethyl diazomalonate converts epoxides into the corresponding alkenes with formation of dimethyl oxomuionate. Alkene isomerization or cyclopropanation is not observed. Yields are generally >80%. 

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