A,j8-Unsaturated esters

Rando and von E. Doering have investigated the synthetic utility of double bond positional isomerization in the photolysis of a,j8-unsaturated esters,<106)... 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

Fig. 11.7. trans-Selective Wittig olefination of aldehydes I—Preparation of a trans-configured a,j8-unsaturated ester (preparation of the starting material Figure 17.24). 

Horner-Wadsworth-Emmons reactions are C—C-forming condensation reactions between the Li, Na, or K salt of a /J-keto- or an -(alkoxycarbonyl)phosphonic acid dialkyl ester and a carbonyl compound (cf. Figure 4.41). These reactions furnish a,f)-unsaturated ketones or a j8-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced fraus-selectively or in the case of olefins with trisubstituted C—C double bonds -selectively. 

There is one type of ester —> alcohol reduction for which one always employs DIBAL (in a polar solvent) rather than LiAlH4 (in ether of THF). This reduction is the reduction of a,j8-unsaturated esters to allyl alcohols (example in Figure 14.54). The reaction of this kind of substrate with LiAlH4 sometimes results in a partial reduction of the C=C double bond to a C—C single bond in addition to the desired transformation —C(=Q)OR -> —CH2OH. 

Dibutyl tellurium induced cyclopropanation of a,j8-unsaturated esters, ketones, and nitriles with dibromomalonic acid derivatives. Bis[4-methoxyphenyl] tellurium hardly promoted these reaction even at 150°... 

Another route to a,j8-unsaturated esters involves reaction of an aldehyde or ketone with ethoxyacetylene in the presence of boron fluoride etherate. ... 

The combination of diethylzinc and chloroiodomethane was employed in the synthesis of carbo-cyclic cyclopropyl nucleosides projected for biological evaluation. Attempts to cyclopropanate the intermediate a,j8-unsaturated ester, methyl (Z)-4,5-(isopropylidenedioxy)pent-2-enoate, gave a low yield (10%) of the desired cyclopropyl product. However, hydroxy-directed cyclo-propanation vide infra) of the reduced allyl alcohol 21 with diethylzinc/chloroiodomethane at 0°C afforded the cyclopropane derivative 22 in 54% yield. 

Cyclopropanes 5 were obtained when hexafluorobut-2-yne, carbon disulfide, and alkoxyalkenes were heated in a sealed tube. When a,j8-unsaturated esters were used, no cyclopropanes were formed. A 2 1 adduct 4 of the alkyne and carbon disulfide is assumed to be an intermediate in this reaction which behaves as an electrophilic carbene. 

Thus, allyl telluronium ylides generated in situ from the corresponding telluronium salts in the presence of Li salts react with a,j8-unsaturated esters and amides to afford trans-2-vinyl-lrani -3-substituted cyclopropyl compounds in high yieds. 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,j8-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and j3-keto and a-alkynic nitriles with hydroxylamine (62HC(17)1, pp. 3,7). 

The reaction of ketones with diethylaminosulfur trifluoride or related aminosulfur trifluorides in the presence of fuming sulfuric acid affords vinyl fluorides66 72 74 (see Vol. F.lOa, p 415). Certain / -oxo esters and pcntanc-2.4-dione react with diethylaminosulfur trifluoride to give a,/i-difluoro-a.j8-unsaturated esters and 3,4-difluoropent-3-cn-2-one, respectively.75 In the reaction of y-oxocarboxylic acids with diethylaminosulfur trifluoride cyclization leads to y-fluorobutyrolactones.76... 

With the exception of the chelation-controlled reduction of the 1,2-dioxy-substituted radical (Scheme 5) and the radical reactions of ketones with Sml2, most of the radicals illustrated so far were generated from the homolytic cleavage of a carbon-halide or carbon-selenide bond. Radicals can also be generated by other chemical means, such as by the addition of radicals to an a,j8-unsaturated ester as Sato and Nagano have shown (Scheme 8). 

Attempted correlation of the alkaloid with demethoxydihydrocory-nantheine alcohol (VII), obtained by Karrer and co-workers during his degradation studies on corynantheine, resulted in failure. Although lithium aluminum hydride reduction of the a,j8-unsaturated ester cited above gave a mixture of products which seemed to contain a small amount of the alcohol VII, the major substance formed on such reduction was a... 

In the next two MCRs, two heterocyclic rings are constructed in the same reaction step. The first example is a rather complicated synthesis of pyrido[2,3-d] pyrimidine scaffolds 49 via a one-pot MW-assisted condensation of a a,j8-unsaturated ester, malononitrile or cyanoacetate, and an amidine (Scheme 17.36) [90]. 

It should be pointed out that manganese dioxide is a mild oxidant that usually converts primary allylic alcohols into conjugated aldehydes without significant further oxidation to carboxylic acids." However, in the presence of HCN and cyanide, the a, -unsaturated aldehydes could be converted into cyanohydrins, which are susceptible to the oxidation of Mn02 to acyl cyanides. In the presence of an alcohol, the a,j8-unsaturated esters are obtained. It should be emphasized that this reaction works only for a,j8-unsaturated aldehydes and will not cause any cis-trans isomerization for the a,/3-unsaturated double bond. For example, benzaldehyde (> 95%), cinnamaldehyde (> 95%), furfural (> 95%), geranial (85-95%), and farnesal (> 95%) have all been transformed into the corresponding methyl esters. ... 

Scheme 12 Diastereoselective intermolecular cathodic coupling of a,j8-unsaturated esters yields 70-98%, de 0 to >95%.

A one pot Ramberg-Backlund process, by treatment of 2-ethoxycarbonyl-sulphones with sodium hydride, leads to a,j8-unsaturated esters. ... 

N-Protected a, 8-dehydroamino-acids and a,j8-dehydroamino-esters can be coupled simply by formation of the acid chloride of the former using PClg. " Dehydropeptides can also be prepared by reaction of a-amino-acid chlorides with adducts of a-azido-a,j8-unsaturated esters and triethyl phosphite. " Peptides can be cyclized using diphenylphosphoryl azide, on a large scale if necessary, in 40—50% yields in favourable cases. ... 

The presence of a trialkylsilyl group in the cyclopent-2-enone (27) improves the yield and selectivity of the photoaddition to 2-methylpropene and the adduct (28) is easily desilylated by fluoride ions. Intramolecular photocycloadditions of a,j8-unsaturated esters are less common than those of enones, but Pearlman has... 

Hirama has reviewed the application of intramolecular conjugate additions of y- and fi-carbamoyloxy-a,j8-unsaturated esters fc.f , Vol.21, p.89) in the synthesis of a variety of aminodeoxy-sugars." Further anomalously coupled nucleosides, e.a.. isonucleosides (46), have been obtained by Michael-type addition of purines to unsaturated aldehydes (Scheme 13). complex amino-disaccharides have been synthesized by employing the cycloadducts... 

The history of 1,3-dipoles began in the nineteenth century, when Curtius reported on the diazoacetic ester. A few years later, Buchner et al successfully performed the first 1,3-dipolar cycloaddition of the diazoacetic ester with a,j8-unsaturated esters. Despite the fact that, over the subsequent years, different 1,3-dipoles have been discovered, only a few have been generally effective in organic synthesis, e.g. the well-known Diels-Alder reaction. ... 

All of the mixed organocopper reagents shown in Scheme 6.6 react with a,/3-unsaturated ketones. The efficiency of the reaction can be promoted by the addition of trialkylphosphines. a,/0-Unsaturated esters are borderline in terms of reactivity toward simple cuprates. Unsubstituted and monosubstituted acrylates generally are reactive but more extensively substituted acrylates are not. The R-Cu-BFs reagents are more reactive than simple cuprates toward a,j8-unsaturated esters and also react with a,/3-unsaturated nitriles. Boron trifluoride has been found to catalyze addition of dimethylcuprate to very hindered a,)0-unsaturated ketones.Conjugated acetylenic esters react readily with cuprate reagents, with syn addition being the kinetically preferred mode of addition. ... 

Reactions of a-sUylalkyl halides with carbonyl compounds using activated zinc have been reported. Reactions of ethyl bromo(trimethylsilyl)acetate with aldehydes and ketones in the presence of zinc/silver-graphite rapidly afford the corresponding a,j8-unsaturated esters (Scheme 2.32) [87]. In this case, the Reformatsky-Peterson reaction sequence proceeds under the mild conditions. 

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