Diazo esters formation

Thermolysis of 58a in butanol affords, together with 17% of 60a (R = C4H9) which evidences the intermediacy of the thiophosphene 59 a, a variety of partly atypical products which seriously impede the desired rearrangement38. Photolysis of 58b in methanol is also found to give only 18 % 1,2-P/C shift to form the heterocumulene 59b, from which the thiophosphinic rater 60b (R = CH3) results 39). As already mentioned in connection with the photolysis of diazo compounds of type 36 (see Sect. 2.2), Wolff rearrangement (9%) and O/H insertion (6%) once again compete with thiophosphinic ester formation. Moreover, solvolysis of the P(S)/C(N2) bond 391 prevents a greater contribution of carbene products to the overall yield. 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

Although the present procedure illustrates the formation of the diazoacetic ester without isolation of the intermediate ester of glyoxylic acid />-toluenesulfonylhydrazone, the two geometric isomers of this hydrazone can be isolated if only one molar equivalent of triethylamine is used in the reaction of the acid chloride with the alcohol. The extremely mild conditions required for the further conversion of these hydrazones to the diazo esters should be noted. Other methods for decomposing arylsulfonyl-hydrazones to form diazocarbonyl compounds have included aqueous sodium hydroxide, sodium hydride in dimethoxyethane at 60°, and aluminum oxide in methylene chloride or ethyl acetate." Although the latter method competes in mildness and convenience with the procedure described here, it was found not to be applicable to the preparation of aliphatic diazoesters such as ethyl 2-diazopropionate. Hence the conditions used in the present procedure may offer a useful complement to the last-mentioned method when the appropriate arylsulfonylhydrazone is available. 

For the cyclization of diazo ester 32 there are four competing diastereomeric chair transition states leading to CH2 insertion products. In the transition state, the Rh-C bond is aligned with the target C-H bond leading to C-C bond formation. The two most stable of these transition states are depicted in Scheme 16.8. The actual product from cyclization is determined as the intermediate carbenoid commits to a particular diastereomeric transition state. If the C-C distance is short at the point of commitment (tight transition state), there will be a substantial steric interaction between the arene and the ester, and 32 b will be disfavored. If the C-C distance is longer, this interaction will not be as severe and more of 32 a will be formed. Thus, it seems reasonable that the ratio of 3 a to 36b is a measure of the C-C bond distance at the point of commitment of the rhodium carbenoid. 

Carbonyl ylides possess versatile reactivities, among which the 1,3-dipolar cycloaddition is the most common and important reaction. The reaction sequence of ylide formation and then 1,3-dipolar cycloaddition can occur in either inter- or intramolecular manner. When the reaction occurs intermolecularly, the overall reaction is a one-pot three-eomponent process leading to oxygen-containing five-membered cyclic compounds, as demonstrated by the example shown in Scheme 8. A mixture of diazo ester 64, benzaldehyde, and dimethyl maleate, upon heating to reflux in CH2CI2 in the presence of 1 mol% rhodium(ii) perfluorobutyrate [Rh2(pfb)4], yields tetrahedrofuran derivative 65 in 49% yield as single diastereomer. " ... 

The present procedure uses sodium methoxide in methanol for generation of the tosylhydrazone salt. This procedure gives the highest reported yield and, unlike other procedures, also gives pure diazo compounds free from solvents. This vacuum pyrolysis method appears applicable to the formation of relatively volatile aryldiazomethanes from aromatic aldehydes. Table I gives yields of diazo compounds produced by this vacuum pyrolysis method. The yields have not been optimized. The relatively volatile diazo esters, ethyl a-... 

A neutral diazo compound can be considered as both a nucleophile and an electrophile. Thus, it can be substituted by the combination of an electrophilic moiety and a nucleophilic moiety (X+ Nu ") (Scheme 8). In practice, the diazomethyl group is transformed to the fluoromethyl group by treatment with hydrogen fluoride/pyridine mixture (70 30 w/w) (X = H Nu = F), or to the halofluoromethyl group by addition of A-halosuccinimide in the same medium (X = Cl, Br, I Nu = F), e.g. formation of l.16 The reaction can be performed on secondary diazo alkanes, diazo ketones or diazo esters.16 90 316... 

This diazo ester is formed because loss of N2 from the diazonium ion results in formation of a quite unfavorable carbocation. 

Diazocarbonyl compounds, especially diazo ketones and diazo esters [19], are the most suitable substrates for metal carbene transformations catalyzed by Cu or Rh compounds. Diazoalkanes are less useful owing to more pronounced carbene dimer formation that competes with, for example, cyclopropanation [7]. This competing reaction occurs by electrophilic addition of the metal-stabilized carbocation to the diazo compound followed by dinitrogen loss and formation of the alkene product that occurs with regeneration of the catalytically active metal complex (Eq. 5.5) [201. 

As with the Aratani catalysts, enantioselectivities for cyclopropane formation with 4 and 5 are responsive to the steric bulk of the diazo ester, are higher for the trans isomer than for the cis form, and are influenced by the absolute configuration of a chiral diazo ester (d- and 1-menthyl diazoacetate), although not to the same degree as reported for 2 in Tables 5.1 and 5.2. 1,3-Butadiene and 4-methyl- 1,3-pentadiene, whose higher reactivities for metal carbene addition result in higher product yields than do terminal alkenes, form cyclopropane products with 97% ee in reactions with d-men thy 1 diazoacetate (Eq. 5.8). Regiocontrol is complete, but diastereocontrol (trans cis selectivity) is only moderate. 

Scheme 148). The tosyl group induces ring opening, in preference to hydroxide elimination, to give a triazole. Numerous diazo esters and ketones have been prepared by diazo transfer reactions441 447 4S1 and improved yields obtained using phase-transfer catalysis.452 Diazoalkane formation via retro-1,3-cycloadditions may also be considered as diazo transfer reactions.12... 

The decomposition of a-diazo esters by a ruthenium porphyrin catalyst has been used by Che and co-workers in a multicomponent strategy directed toward functionalized pyrrolidines 172. The first step involves the formation of a ruthenium... 

Carbene insertion into the O-H bond of alcohols is especially versatile for the formation of ethers. Diazomethane has been used, but other diazo compounds have also been used even those with fluorine in the carbene species. Rhodium acetate seems to be the catalyst of choice for the decomposition of a-diazo esters. Different alcohols 21 react with compound 22 to give fluorinated ethers 23 in good yield. ... 

Benzaimulated products are obtained via thermolysis of a-diazo ester-substituted complexes. For example, formation of diazo ketone complex (103) via a tosyl hydrazone followed by thermolysis gave (104) (Scheme 167). ... 

The chemistry of aliphatic diazo compounds of the general formula RCHNj, among which are the important diazo ketones RCOCHN, and diazo esters NjCRCOjR, has been reviewed. " In addition, the formation of aromatic diazonium salts, ArN CF, has been extensively studied and fully described in several monographs. For this reason, only the most pertinent points are included here along with key references. 

Further studies on a-diazo ketones with a second more remote carbonyl group have appeared and formation of a carbonyl ylide and its addition to an added aldehyde yields bicyclic dioxolanes 199 (Scheme 19) <2004TL6485, 2005ARK(xi)146>. A rearrangement is clearly involved in the more complex reaction of a silyl diazo ester to give a dioxolan-4-one (Equation 66) <20020L4631>. 

Photolytic and catalytic decomposition of a-diazo esters produces )8-lactones, which are formed via intramolecular C—H insertion of a carbene or carbenoids. Tertiary alkyl esters of diazomalonic acid are decomposed by rhodium acetate with exclusive formation of the four-membered ring 211. This suggests a smooth insertion into the C—H bond activated by the adjacent oxygen atom (90TL1023). jS-Lactone 212 was obtained by photolysis of diazo malonic ester 213 (71CC577). 

Intramolecular cyclopropanation of olefinic a-diazo ketones and a-diazo esters has been widely used in organic synthesis. When a carbenoid center and the double bond are separated by a chain of three atoms, one of which is oxygen, a five-membered O-containing heterocycle is formed. Intermolecular cyclopropanations of olefins are known to allow stereospecific formation of desired products. Thus, decomposition of substituted allyl diazomalonates 265 in the presence of copper salts gives rise to bicyclic... 

The intramolecular reaction of the carbene from diazo ester 280, which contains a 1,3-diene moiety in the ester group and a double bond adjacent to the carbene center, leads to the formation of a substituted 1,2-divinyl-cyclopropane, whose CIS isomer then undergoes a Cope rearrangement to give substituted cycloheptadiene. In such a way, bicyclic 281 and tricyclic 282 y-lactones with a neighboring seven-membered carbocycle have been obtained (89JOC930). 

The reaction of dichlorocarbene with ketones and diamines results in near quantitative formation of a mixture piperazinones 584 and 585 (80JOC754). As shown in Section III,C,2, piperazine 78 [R = H, R + R = (CH2)s], the minor product of the Rh2(OAc)4-catalyzed decomposition of diazo ester 73, is the result of the dimerization of the intermediate ylide 76 (84JOC113). Tetrahydropyrazines were synthesized through ring expansion of imidazolidines. Thermolysis or photolysis of diazo compounds... 

Rhodium(II) acetate-catalyzed decomposition of diazo ester 677 gives oxacepham 678 via the formation of oxonium ylide 679 and its subsequent fragmentation (91CC1235). 

The first step in the decomposition of nitrosoamides 123) is formation of the diazo ester 125) which fragments to a diazonium ion pair (128)129 The ion pairs thus produced differ from those obtained in the reaction of diazoalkanes with acids. The ratio of ester to ether formed in the decomposition of rV-nitroso-fV-benzhydrylbenz-amides in alcohol is lower than that found in the reaction of diphenyldiazomethane 132) with acids, and in the solvolysis of benzhydryl benzoate (I35)135,136 This effect has been attributed to the intervention of trans-diazo ester in the decomposition of 125) which leads to a greater distance between carbocation and carbox-ylate anion. In the diazoalkane reaction attack of the acid occurs at the electron-rich carbon atom to generate the carboxylate in the immediate vicinity of the incipient carbocation. 

Due to the high reaction temperature and long reaction times, this method is less suited for the synthesis of thermally labile cyclopropanes. In such cases, the corresponding diazo esters are a better source of alkoxycarbonyl(chloro)carbene and alkoxycarbonyl(bromo)car-bene (see Section 1.2.1.2.4.2.6.2.). However, no alternative exists for transfer of alkoxycarbo-nyl(fluoro)carbenes here, [bromo(ethoxycarbonyl)fluoromethyl]phenylmercury is a more reactive precursor than [chloro(ethoxycarbonyl)fluoromethyl]phenylmercury. Typical examples are shown for the formation of 1, 2, and 3. Further examples are given in Houben-Weyl, Vol.E19b, pl044ff. 

When dienes or trienes were cyclopropanated according to these procedures, a monocyclo-propanation product was obtained almost exclusively or exclusively. Twofold cyclopropanation predominated, however, when an excess of diazo ester was employed and the two C-C double bonds have a similar nucleophilicity, e.g. formation of 13. ... 

The thermally induced cyclopropanation of alkenes with silyldiazoacetates is virtually unknown. Silylated diazo esters are thermally rather stable and do not readily decompose to give a carbene under standard laboratory conditions. The only known cyclopropanation of this type, i.e. synthesis of 2 from ethyl diazo(trimethylsilyl)acetate and ethyl acrylate (formation of E- and Z-isomers, no yield given), probably occurs via a pyrazoline intermediate. 

Catalytic cyclopropanation reactions with disubstituted diazo esters are discussed in the following sections, R1C( = N2)C02R2 R1 = CF3 Section 1.2.1.2.4.1., R1 = R3CO, this section R1 = SiRl, Section 1.2.1.10. R1 = N02, Section I.2.I.8.3. R1 = P(0)Ri Section 1.2.1.9, Some examples of catalytic cyclopropanation reactions with diazo acetamides are given in Table 14. In reactions with a-diazo-A,A-dimethylacetamide catalyzed by tetraacetatodirhodium, cyclopropane yields decrease with decreasing alkene reactivity (ethoxyethene, 82% styrene, 47% cyclohexene, 21%),164,258 Furthermore, with A-alkyl substituents larger than methyl, intramolecular carbenoid C-H insertion is in competition with alkene addition, e.g, formation of 4.164,259... 

With 1 as catalyst, alkene bonds which have oxidation potentials less than 1.6 V (vs standard calomel electrode) are considered potentially susceptible to this transformation. With the stronger oxidant 2, the scope of the reaction can be extended to include, for example, tetraalkyl-substituted double bonds, but obviously not disubstituted alkenes such as cyclohexene. On the other hand, electron-rich alkenes such as enol ethers and vinyl sulfides cannot be cyclo-propanated by this method. In order to suppress cyclodimer formation from the alkene and its radical cation, the diazo ester is sometimes applied in a four- to fivefold amount with respect to the alkene. 

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