Diazomethane cyclopropanations with

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Most electrophilic carbene complexes with hydrogen at Cjj will undergo fast 1,2-proton migration with subsequent elimination of the metal and formation of an alkene. For this reason, transition metal-catalyzed cyclopropanations with non-acceptor-substituted diazoalkanes have mainly been limited to the use of diazomethane, aryl-, and diaryldiazomethanes (Tables 3.4 and 3.5). 

Cyclopropanations with diazomethane can proceed with surprisingly high diastereo-selectivities (Table 3.4) [643,662-664]. However, enantioselective cyclopropanations with diazomethane and enantiomerically pure, catalytically active transition metal complexes have so far furnished only low enantiomeric excesses [650,665] or racemic products [666]. These disappointing results are consistent with the results obtained in stoichiometric cyclopropanations with enantiomerically pure Cp(CO)(Ph3P)Fe=CH2 X , which also does not lead to high asymmetric induction (see Section 3.2.2.1). 

Table 3.4. Palladium- and copper-catalyzed cyclopropanations with diazomethane.

Fig. 4.20. Complexes for asymmetric cyclopropanation with acceptor-substituted diazomethanes. 1 [1372], 2 [1373], 3 [1033], Rh2(55-MEPY>4, Rh2(55-MPPIM)4 [1001,1074], For related rhodium-based catalysts, see, e.g., [997,1000,1002].

Chiral formylcyclopropanes.2 The oxazolidine (1), obtained by reaction of cinnamaldehyde with l>-( -)-ephedrine, reacts with diazomethane [Pd(OAc)2 catalysis] to give 2 in at least 90% ee. Hydrolysis of 2 to 3 is effected by moist SiO,. It is also possible to prepare cyclopropanes with three chiral centers, such as 5. 

The methylene generated from diazomethane reacts with alkenes to form cyclopropanes, but diazomethane is very toxic and explosive, and the methylene generated is so reactive that it forms many side products. A safer and more reliable way to make cyclopropanes is with the Simmons-Smith reagent. 

The ring expansion of the benzoxepinones 134 to benzoxocinones 136 involved a cyclopropanation with diazomethane in the presence of palladium acetate and a catalytic hydrogenation. The cleavage of the more labile internal bond in the cyclopropyl derivatives 135 leads to the eight-membered ketones 136 exclusively in excellent yields (90-95%). Reduction of ketones 136 with sodium borohydride affords the hydroxy derivatives 137 in a stereo-controlled manner (Scheme 34) <2002CC634>. 

Methylene ( CH2) generated photochemically or thermally from diazomethane is highly reactive and is prone to incur side reactions to a substantial extent. In order to avoid these undesirable complexities, the cyclopropanation of multiple bonds with diazomethane has usually been carried out under catalytic conditions The catalysts most frequently employed are copper salts and copper complexes as well as palladium acetate. The intermediate produced in the copper salt-catalyzed reactions behaves as a weak electrophile and exhibits a preference to attack an electron-rich double bond. It is also reactive enough to attack aromatic nuclei. In contrast, the palladium acetate-catalyzed decomposition of diazomethane cyclopropanates a,a- or a,jS-disubstituted a,jS-unsaturated carbonyl compounds in high yields (equation 47). The trisubstituted derivatives, however, do not react. The palladium acetate-catalyzed reaction has been applied also for the cyclopropanations of some strained cyclic alkenesstyrene derivatives and terminal double bondsHowever, the cyclopropanation of non-activated, internal double bonds occurs only with difficulty. The difference, thereby. 

Reaction of a cyclopropane with diazomethane or an azide generated cyclopropanes containing an azo function " a similar cycloaddition was reported for a nitri-limine. Cycloaddition of an ethandiylidene biscyclopropane and triazolinedione led to a hydrazine derivative Reactions of these types forming azo- or hydrazinocyclopro-panes are not subject of this review however, they could be of interest for aminocyclop-ropane synthesis by functional group interconversion (for the cycloaddition of cyclopropyl azide with a carbon-carbon double bond see Section II.E.3, equation 101). 

Cyclopropanation of coumarin derivatives with diazoalkanes (Scheme 47) is one of the general [2 + l]-annulations, but the product distribution depends on various factors substituents, the structures of their alkyl groups, reaction conditions, etc. [70JCS(C)897 76TL1227]. Diazomethane reacts with 3-nitrocoumarin 239 to give the cyclopropane derivative 240, but also... 

Highly strained cage compounds can also be prepared by the same method of simple cyclopropanation with diazomethane in the presence of palladium(II) acetate. This was applied to the fourfold bridged tricyclic heptacyclo[10.8.0.0 . 0 .0 . 0 .0 ]eicosa-l(12)16-diene (6), which reacted with diazomethane in the presence of catalytic amounts of palladium(II) acetate to afford a mixture of mono- and bis-adducts 7 and 8 in 68 and 3% yield, respectively. These were separated by column chromatography on silica gel. The monoene 7 was converted into the bis-adduct 8 by repeating the same cyclopropanation reaction. ... 

Interesting compounds, such as cyclopropylboronic acids and esters which are otherwise not easily accessible due to the apparent lack of convenient and versatile syntheses, can now be prepared by simple cyclopropanation with diazomethane. The carbene transfer to substituted and functionalized alkenes also takes place smoothly in the presence of palladium(II) acetate. Several 1-alkenylboronic acid esters 9 were converted to cyclopropylboronic acid esters 10 using this method. ... 

A chiral oxazolidine prepared from a,j6-unsaturated aldehydes and ( —)- or (-l-)-ephedrine efficiently induced asymmetric cyclopropanation with excess of diazomethane in the presence of palladium acetate, e.g. formation of 24 from ( —)-ephedrine and ( )-cinnamaldehyde 24 was cyclopropanated to give 25 and the auxiliary removed giving... 

Feist s acid, in its racemic and optically active forms, has been cyclopropanated with diazomethane affording access to nonracemic, chirally substituted spiropentanes, for example, cyclo-propanation of (-l-)-(7 ,7 )-29 gave spiropentane ( —)-(/ ,7 )-30 in 65% yield. ... 

With cyclohexene, the yields of fused cyclopropanes depend dramatically on the method of generation of the carbene, and on the substituents of the diazo derivatives. For a comparison, (diethoxyphosphoryl)(phenyl)diazomethane reacted with cyclohexene to give the cyclopropane adduct 3c in 54% yield in the presence of copper powder, and in 22% yield under photolytic conditions. With (dimethoxyphosphoryl)(methyl)diazomethane, formation of the cyclopropane derivative was not observed. ... 

Upon Simmons-Smith cyclopropanation (CH2I2, Zn/Ag " or Zn/Cu ) vinylidenecyclo-propane gave a mixture of bicyclopropylidene (7) and dispiro[2.1,2.0]heptane (8). - An analogous reaction took place when 7-methylenedispiroheptane (9) was reacted with diiodo-methane and zinc-silver couple to give the trispiro[2.0.2.0.2.0]nonane (10) in quantitative yield.Small quantities of dispiro[2.1.2.0]heptane were isolated from the palladium acetate catalyzed reaction of vinylidenecyclopropane and diazomethane together with a variety of methylene insertion products. 

Cyclopropanation with diazomethane was also briefly investigated but the reaction has not been developed into a practical method as yet (Scheme 7) [40,41 ]. 

Recently, Denmark and coworkers have confirmed that asymmetric cyclopropanation with chiral palladium complexes was not efficient [55]. They reported a systematic study toward the development of an enantioselective diazomethane-based cyclopropanation reagent derived from bis(oxazoline)palladium(II) complexes. In addition to the novel carbon-bound complexes, several simple palladium chelates were synthesized and evaluated in the cyclopropanation of various electron-deficient olefins (Fig. 2). Although all catalysts were effective at inducing the cyclopropanation, the products obtained were racemic in all the... 

Intramolecular cyclopropanations with unsaturated diazo ketones have also been reported. Furthermore, enantioselective cyclopropanation with diazomethane can be achieved in up to 75% ee. In detailed mechanistic discussions, a copper(I) species, complexed with only one semicorrin ligand, and formed by reduction and decomplcxation, is suggested as the catalytical-ly active species, cisjtrans Stereoselection and discrimination of enantiotopic alkene faces should take place within a copper-carbene-alkene complex25-54"56. According to these interpretations, cisjtrans selectivity is determined solely by the substituents of the alkene and of the diazo compound (especially the ester group in diazoacetates) and is independent of the chiral ligand structure (salicylaldimine or semicorrin)25. 

The 1,3-dipolar cycloaddition of diazomethane to bicyclic 2,/S-unsaturated /-lactams produces pyrazolidines which are transformed photolytically into cyclopropane derivatives80. The overall yields arc moderate to good while the diastereomeric ratio is at least 95 5. Reaction of the thiomethyl-substituted lactam with 2-diazopropane provides the corresponding geminal dimethyl-substituted cyclopropane with a d.r. of 95 5. These cyclopropane derivatives have been used for the synthesis of optically active cyclopropanecarboxylates and ethenylcyclopropanes80. 

A more efficient preparation of 7-(trimethylsilyl)bicyclo[4.1.0]heptane employs (trimethylsi-lyl)diazomethane under copper(I) chloride catalysis7. This method also allows the synthesis of l-phenyl-2-(trimethylsilyl)cyclopropane with good tram preference8. For silyl and related carbenes see Vol.E19b. pp 1410-1459 and for the synthetic uses of silyl-substituted cyclopropanes see reference 9. 

As with other diazoalkanes, diazomethane reacts with alkenes to form cyclopropane derivatives (sec. 13.9.C.i).272 Reaction with aromatic derivatives leads to ring expansion to cycloheptatriene derivatives.223 Both of these reactions (addition to an alkene or arene insertion) involve generation of an intermediate carbene and addition to a jt bond they will be discussed below. Many of the reactions of diazomethane tend to be ionic in nature and are, therefore, set aside from the other diazoalkane chemistry in this section. One of the commonest uses of diazomethane itself is esterification of small quantities of acids, especially acids that are precious for one reason or another. The reaction is quantitative and gives good yields of a single product, as in Tadano s conversion of 338 to the methyl ester of 339224 in a synthesis of (-)-verrucarol. 

Until the end of the 1970 s, interest in such reactions concentrated on catalysis by copper salts (review Burke and Grieco, 1979), obviously influenced by the long, broad, and successful experience with copper +- and copper-ions in aromatic diazo chemistry (Sandmeyer, Pschorr and Meerwein reactions, see Zollinger, 1994, Chapts. 8 and 10). A landmark was the discovery of Salomon and Kochi (1973), who found that cyclopropanations with diazomethane in the presence of copper(i) trifluoromethanesulfonate (triflate OTf) resulted in reduction of Cu + to Cu +, and that the rate of dediazoniation is inversely proportional to the alkene concentration. These results strongly indicate that formation of an alkene-Cu+ complex (8-47 2) precedes the complex formation with the diazoalkane. 

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