Unsaturated carboxylic acids, cyclization

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

Reactants with internal nucleophiles are also subject to cyclization by electrophilic sulfur reagents, a reaction known as sulfenylcyclization.92 As for iodolactonization, unsaturated carboxylic acids give products that result from anti addition.93... 

CsF induces the ring-opening cyclization of the thus obtained l-[2-(trimethylsilylmethyl)cyclopropylcarbonyl] imidazole 154 with diethyl fumar-ate or diethyl maleate to give the cyclobutanone 155 [80], The facile ring fission of 154 also occurs in the presence of BF3OEt with the formation of the corresponding y,<5-unsaturated carboxylic acid. (Scheme 55)... 

Pyrazolones have been prepared by palladium promoted cyclization of a,/ -unsaturated carboxylic acid hydrazides but yields are only moderate (Scheme 91)15 6 and no attempt has been made to effect a catalytic conversion. 

Few other examples of such reaction sequences have been described to date. Oh has reported the palladium-catalyzed reductive cyclizations of 1,6-enynes in the presence of formic acid or triethylsilane via an alkylpalladium intermediate and its application to organic synthesis. Palladium complexes also catalyze the conversion of a range of enynes to cyclic 6,7-unsaturated carboxylic acids in the presence of CO.260... 

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

Unsaturated carboxylic acids can be de-carboxylated to alkyl radicals that undergo an intramolecular addition. The S-exo-trig-cyclization of fi-allyloxy radicals, generated from an appropriate carboxylic acid, combined with a final heterocoupling has been applied to synthesize a precursor of prostaglandine PGF2q (Fig. 47) [246] and a branched carbohydrate (ratio of diastereo-mers 1.8 1) (Fig. 48) [247]. A radical tandem cyclization of a doubly unsaturated monocyclic carbocyclic acid provides a... 

Gassman and co-workers have recently investigated the photoinduced cy-clization of y,5-unsaturated carboxylic acids to y-lactones [100]. 5-Methyl-4-hexenoic acid 51 is converted into the radical cation 52. The cyclization of 52 is expected to yield the distonic radical cations 53 and 54, which leads to the anti-Markonikow products 55 and 56 in ratio 5 1. Fine-tuning of the sensitizer improved combined yields up to 89% [101],... 

Phenol esters of a,(3-unsaturated carboxylic acids have an interesting reactivity due to the synthetic utility of the resulting hydroxychalcones (Scheme 19). This aspect will be illustrated in Section IV. However, from the basic point of view, it is worth mentioning that the cis or trans configuration of the olefinic part of the acyl moiety can have a marked influence on the photochemical reactivity of the ester. When para-methoxyphenyl fumarates are irradiated, the normal ortho-rearranged products are obtained. By contrast, irradiation of para-me-thoxyphenyl maleates does not lead to rearrangement. Instead, cyclization products are obtained (Scheme 20). 

Electrophilic selenium reagents are very effective in promoting cyclization of unsaturated molecules containing potentially nucleophilic substituents.72 Unsaturated carboxylic acids, for example, give selenolactones, and this reaction has been termed selenolactonization73 ... 

Treatment of aryl-substituted alkenes with hypervalent iodine compounds can lead to the formation of phenyliodinated intermediates, which can be stabilized by the aryl substituent via the formation of phenonium ions. Subsequent nucleophilic attack might then lead to rearranged products. This behavior can be nicely seen by comparing the unsaturated carboxylic acids 78 in their reaction with (diacetoxyiodo)benzene 3. The substrate 78a without the phenyl substituent is cyclized to the phenyliodinated intermediate 79, which is then attacked by the acetate under the formation of lactone 81 [142]. Substrate 78b is, however, then stabilized by the formation of an intermediate phenonium ion 80 and attack by the acetate is accompanied by a 1,2-phenyl migration and 82 is generated, Scheme 35 [143]. 

Intramolecular cohalogenation is a related process which leads to halogenation with cyclization. Recent examples are the polymer supported synthesis of 2,5-disubstituted tetrahydrofuran (equation 54)459 and the iodolactonization of co-unsaturated carboxylic acids (equation 55)460. 

Reactions between A -tosylpyrroles 394 and a-substituted unsaturated carboxylic acids in the presence of TFAA result in smooth 2-acylation of the pyrrole, followed by Nazarov cyclization to give 50-80% yields of 4,5-dihydrocy-clopenta[3]pyrrol-6(lf/)-ones 395 (Equation 93) <20060L163>. The presence of an a-substituent in the unsaturated acid appears to be mandatory. 

Oxyselenation ofalkeues, - Treatment of olefins with 1 or 2, water, and an acid catalyst (e.g., p-TsOH) in CH2CI2 affords j3-hydroxy selenides in excellent yield. Unsaturated carboxylic acids, phenols, alcohols, thioacetates, and urethanes react with 1 or 2 and an acid catalyst ( —78- 25°) to afford products of oxidative cyclization. These reagents are superior to benzeneselenenyl halides for selenium-induced ring closures. This reaction is also useful for synthesis of 14- and 16-membered lactones. Benzeneselenenyl halides and benzeneselenenic acid do not promote macrolide formation under similar conditions. 

A radical tandem cyclization, consisting of two radical additions and a heterocoupling reaction, has been achieved by coelectrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, such as... 

Intramolecular cyclization is a useful method for the preparation of lactones and cyclic ethers [34], The most common examples are iodolactonization and iodoetherification, the former using a carboxylic acid derivative as the nucleophile and the latter relying on a hydroxy group. Thus, butyrolactones are available from Y, -unsaturated carboxylic acid derivatives [1,35,36], while unsaturated alcohols lead to cyclic ethers [37-40], Lactones are also available from a wide variety of nucleophiles such as carbonates [41], orthoesters [42], or carbamates [43,44], which can all be used in place of a carboxylate anion [44,45],... 

Phenyl selenide transfer radical addition reactions can be limited by the lack of reactivity observed in some precursors. Simple alkyl phenyl selenides do not undergo inter- or intramolecular radical additions to olefins. Phenylselenotrichloromethane will add to olefins upon photolysis, and the products formed can be elaborated into a, ff-unsaturated carboxylic acids (Scheme 20) [57], Benzyl phenylselenides have been observed to undergo atom transfer cyclization (Scheme 20) [58]. 

Allylic oxidation. Allylic alcohc DMF. Allylic esters are obtained fn -nent with Pd(OAc)2-benzoquinone an Some unsaturated carboxylic acids und xidative cyclization leads to bicycitc t... 

Polhni, G.P, Barco, A. and De Giuli, G. (1972) Tetramethylguanidine-catalysed addition of nitromethane to a, P-unsaturated carboxylic acid esters. Synthesis, 44-45 Alvarez, F.S. and Wren, D. (1973) Synthesis of ( )-deoxyprostaglandin Ei, and Fip and its 15P-epimers by conjugate addition of nitromethane to 2-(6 -carbomethoxyhexyl)-2-cyclopenten-l-one. Tetrahedron Letters, 569-572 Hewson, A.T. and MacPherson, D.T. (1983) Conjugate addition to the ethylene ketal of 2-carbomethoxy-2-cyclopentenone a synthesis of sarkomycin. Tetrahedron Letters, 24, 647-648 Naito, T., Honda, Y, Bhavakul, V. et al. (1997) Radical cyclization in heterocycle synthesis. II. Total synthesis of ( )-anantine and ( )-isoanantine. Chemical Pharmaceutical Bulletin, 45, 1932-1939. 

Shin, C., K. Nanjo, M. Kato, and J. Yoshimura a,P Unsaturated Carboxylic Acid Derivatives. IX. The Cyclization of a-(N-Acyl-hydroxyamino) Acid Esters with Ammonia or Hydroxylamine. Bull. Chem. Soc. Japan 48, 2584 (1975). 

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