Butenolide complexes

When complexes 37a,b reacted in pentane solution at — 78°C under an atmosphere of CO with dmad (Scheme 8), the butenolide complexes 38a,b were formed in clean reactions and could be isolated in 85 and 65% yields, i.e. the reaction proceeded with complete chemoselectivity for the Fe-0=C fragment. When the same reaction was performed at — 50 °C and — 30°C, respectively, with methyl propynoate (mp) as dipolarophile, the butenolide complexes 39a,b with the hydrogen next to the inserted carbonyl group were formed with complete chemo- and regio-selectivity. Complexes that had incorporated two moles of the alkyne (40a,b) were observed as minor side-products. In the absence of CO, and with two equivalents of mp, the tricyclic complexes 40a,b were formed exclusively in moderate yields. Complexes 40a,b can also be prepared in almost quantitative yields by irradiation of the corresponding complexes 39a,b in the presence of an excess of mp at room temperature, an observation that strongly supports the pathway indieated in Scheme 8. X-Ray structural analysis of 40b has confirmed that, of the possible regioisomers, only the one shown in Scheme 8 is formed. 

In the absence of nucleophilic solvents, (RC2H)Co2(Cp)6 compounds are carbonylated to produce butenolide complexes (XIV) in variable yields (Sternberg et al, 1959 Sauer et al, 1959 Mills and Robinson, 1967 Guthrie et al, 1975 Pdlyi et al, 1975). Complexes of internal alkynes generally fail to... 

Triethylammonium formate is another reducing agent for q, /3-unsaturated carbonyl compounds. Pd on carbon is better catalyst than Pd-phosphine complex, and citral (49) is reduced to citronellal (50) smoothly[55]. However, the trisubstituted butenolide 60 is reduced to the saturated lactone with potassium formate using Pd(OAc)2. Triethylammonium formate is not effective. Enones are also reduced with potassium formate[56]. Sodium hypophosphite (61) is used for the reduction of double bonds catalyzed by Pd on charcoal[57]. 

Carbonylation of alkynes is a convenient method to synthesize various carbonyl compounds. Alper et al. found that carbonylation of terminal alkynes could be carried out in aqueous media in the presence of 1 atm CO by a cobalt catalyst, affording 2-butenolide products. This reaction can also be catalyzed by a cobalt complex and a ruthenium complex to give y-keto acids (Scheme 4.8).92... 

The bisfunctionalization of alkynes by both C02 and another electrophile can also be achieved, as shown in Scheme 9.17,17a The titanium-carbon bond in the titanacycle complex 31, which was formed by reaction of C02 with the titanacyclopropene 30, can be substituted with various electrophiles. For example, its reaction with NBS or I2 afforded the synthetically useful vinyl bromide or iodide 32, respectively, while the reaction with D20 yielded the /3-deuterated a,/ -unsaturated carboxylic acid. When an aldehyde such as PhCHO was used as an electrophile, butenolide 33 was produced after acidic workup. 

The reaction of an allene with an aryl- or vinylpalladium(II) species is a widely used way of forming a Jt-allyl complex. Subsequent nucleophilic attack on this intermediate gives the product and palladium(O) (Scheme 17.1). Oxidative addition of palladium ) to an aryl or vinyl halide closes the catalytic cycle that does not involve an overall oxidation. a-Allenyl acids 27, however, react with palladium(II) instead of with palladium(O) to afford cr-vinylpalladium(II) intermediates 28 (Scheme 17.12). These cr-complexes than react with either an allenyl ketone [11] or with another alle-nyl acid [12] to form 4-(3 -furanyl)butenolides 30 or -dibutenolides 32, respectively. 

Amino-3-cyanofurans (307) are obtained by base catalyzed condensation of the acyloins (306) with malonodinitrile, and on acid hydrolysis yield the butenolides (308) (Scheme 80) (66CB1002). Diketene and an isocyanide react to give the lactone (309) in the presence of a tertiary base (73GEP2222405). When diphenylketene is treated with bis(cycloocta-l,5-diene)nickel and pyridine, the complex Ni(py)2(Ph2C=CO)2 is formed which is converted into compound (310) by carbon monoxide (78JOM(l52)C29). 

If the halide and the hydroxy group are present in the same molecule, reaction (107) leads to the synthesis of lactones.484 With complex (102) as catalyst a series of butenolides were prepared in good yields from vinyl iodides (equation 110). Four- and six-membered ring lactones and a-methylene lactones were prepared. 5,486 The mechanism proposed was analogous to that of Scheme 37. This cyclization has been used in the synthesis of the natural product zearalenone.487 PdCl2 was the catalyst. 

In certain other systems, there is compelling evidence for the insertion into a metal-caiboxylate complex (equation 37). For example, in the synthesis of a-methylene-y-lactones from alkynic alcohols,70,71 no double bond rearrangement to a butenolide occurs, a reaction shown to take place in the presence of transition metal hydrides. The source of the vinyl proton (deuterium) on the a-methylene group is indeed the alcohol function. Finally, palladium carboxylate complexes containing alkynic (equation 40) or vinyl tails (equation 41) can be isolated and the corresponding insertion reaction can be observed. 

Butenolides,1 Addition of the Schwartz reagent to a protected propargylic alcohol (2) followed by carbonylation provides an acyl zirconocene complex (3). This is not isolated but treated in situ with iodine to provide an intermediate (a) that cyclizes to a 3,5-disubstituted butenolide (4). Optically active substrates undergo this sequence with no loss of optical purity. 

In addition to its impact on the biologically active form, the tautomeric process has profound implications for formulation of drug candidates, as illustrated in some recent further development work on compound 3.62 While it is easy to synthesize and isolate water-soluble salts of the keto-acids, once they are placed in aqueous solution the tautomeric equilibrium determines how much of each form is present. Indeed, if the closed butenolide tautomer is sufficiently water insoluble, it can precipitate out of solution and the equilibrium can drive the complete precipitation of the compound. While 3 has good oral activity, its intravenous use is limited by the insolubility of the closed-form butenolide tautomer without the use of a specific and complex buffered formulation. Thus, in recent work Patt et al.62 developed a series of water-soluble butenolides to overcome this limitation for parenteral uses. This culminated in the development of 4 (Table 2), currently in preclinical evaluation. 

The efficiency of this method was demonstrated in a total synthesis of the antibiotic (-r)-tetrahy-drocerulenin 28 (Scheme 8) and (-h)-cerulenin [11]. Irradiation of complex 22 in the presence of the chiral iV-vinyl-oxazolidinone 24, which is easily prepared from the amino carbene complex 23 [12], leads to the cyclobutanone 25 with high diastereoselectivity. Regioselective Baeyer-Villiger oxidation followed by base-induced elimination of the chiral carbamate yields the butenolide 26 in high enantiomeric purity. This is finally converted, using Nozoe s protocol [13], to the target molecule 28 by diastereo-selective epoxidation (- 27) and subsequent aminolysis. 

Vinylogous Mukaiyama-Michael additions of 2-trimethylsilyloxyfuran to 3-alkenoyl-2-oxazolidinones to provide 7-butenolides were shown to be /7-selective. The reaction could be rendered enantioselective in the presence of a (T symmetric copper-bisoxazoline complex <1997T17015, 1997SL568> or a l,T-binaphthyl-2,2 -diamine-nickel(ii) complex as catalyst, as depicted in Equation (16) <2004CC1414>. 

Trimethylsilyloxyfuran reacted stereoselectively with chiral tungsten carbene complexes in a Mukaiyama-Michael addition fashion to provide -products, as shown in Equation (18) <2005AGE6583>. The metal carbene in the butenolide product serves as a useful functional group for further transformations. 

A concise synthesis of highly substituted furans, pyrroles, butenolides, and 2-butene-4-lactam esters starts from alkynyl adducts of a Fischer carbene complex 21 (Scheme 27) < 1998JOC3164>. Incorporation of an aldehyde yields a reactive vinyl tungstencarbonyl complex 22 that can be oxidatively transformed to an ester group, furnishing the furan carboxylic ester 23. 

Silylated propargylmolybdenum species, which are obtained from addition of an alkynyllithium to a silyl-sub-stituted carbene complex, exhibit a unique chemical behavior in their reaction with carbon dioxide to afford 7-silylsubstituted A -butenolides after mild acidic workup, in decent isolated yields (Scheme 46) <2006AGE6874>. 

Building on their earlier research into S-endo cyclisations of Sml2-generated ketyl-type radicals, Molander and co-workers [107,108] developed this process as a key step in the syntheses of several naturally occurring lignans of the dibenzocyclooctadiene type. For example, they prepared the biaryl-chromium tricarbonyl complex 128 containing orffio-formyl and butenolide... 

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