Triple cyclizations

Triple and quadruple cyclizations. A wide variety of triple and even quadruple [49, 50] cyclizations can be carried out with multiply unsaturated 1,3-dicarbonyl compounds. Oxidative triple cyclization of 82 affords 70% of 83 since the cyclo-pentanemethyl radical is oxidized to a double bond by Cu(II) (Scheme 26) [47]. Similar cyclization of 84 provides 43% of 85 (Scheme 27) [49]. Oxidative cyclization... 

Although most attention has focussed on a cationic mechanism in the oxidative cyclization of squalene [20]. Breslow was concerned with the possibility that nature utilizes a free-radical pathway [21]. and studied the addition of benzoyloxy radical to trans, trani-famesyl acetate [22]. The benzoyloxy radicals generated by CuCl-catalyzed thermal decomposition and copper(II) benzoate was added to provide a termination mechanism. Excluding any intervention of a carbocationic process, Breslow obtained a tran -decalin compound (20 30% yield) bearing an exomethylene moiety. As pointed out by Breslow, despite a limited biochemical interest , this work evidenced a new synthetic reaction of considerable potential . An application shortly followed with the first example of a triple cyclization by Julia [23]. Triene isomers 40 were treated by benzoylperoxide in benzene and alforded after saponification alcohol 41 in 12% yield as a single diastereomer (relative stereochemistry confirmed by an X-ray analysis) with a similar tra 5-decalin system (A and B rings. Scheme 14). 

Applications included a related triple cyclization from lactone 74, which opened a route to spongian-16-one [37] and an approach to azasteroids involving an enamine double bond (75) as a final radical acceptor (Scheme 22) [38]. Moreover, spectacular tetracyclizations from acyclic 76 and 77 have also been accomplished to provide the corresponding aW-trans tetracyclic ketones [36], both of them consisting of ring D methyl epimers (Scheme 23). 

The 2-bromododeca-l,ll-dien-6-yne derivative 461 undergoes a triple cyclization, followed by rearrangement, under the influence of a palladium catalyst to yield 462. Cross-coupling of the iodo compound 463 with ( )-l-hexen-l-ylzinc chloride in the presence of tetrakis(triphenylphosphine)palladium yields 68% of the indane 464 and 19% of the uncyclized product 465 ". ... 

Diacetylene 365, possessing o-bromothienyl subunits at both ends, underwent an intramolecular triple cyclization, resulting in pentathienoacene 367 in 22% yield (Scheme 91) [140, 141]. 

Two different approaches could be envisioned to attach binding groups to the CTV derivatives. The usually low yield of the triple cyclization reaction may be placed at the end of the synthesis or at the beginning of the synthesis, as represented in Figure 4. 

Truxene derivative 57, which was easily prepared by alkylation of trianion of trux-ene with l-bromo-2-(bromomethyl)benzene, underwent triple cyclization followed by dehydrogenation in the presence of Pd(OAc)2, BnMesNBr, and K2CO3 upon heating in DMA, giving rise to 58 in 79% yield (Scheme 22.13) [28]. 

In 2010, Lian and Ma combined one molecule of 1,5-bisallene 381 with two molecules of 2,3-aUenoic acids 346 and developed an unexpected sandwich type of triple cyclization with excellent stereoselectivity. A possible mechanism involving sequential highly stereoselective anh-oxopalladation, intermolecular carbopalladation, cyclic... 

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

The benzene derivative 409 is synthesized by the Pd-catalyzed reaction of the haloenyne 407 with alkynes. The intramolecular insertion of the internal alkyne, followed by the intermolecular coupling of the terminal alkyne using Pd(OAc)2, Ph3P, and Cul, affords the dienyne system 408, which cyclizes to the aromatic ring 409[281]. A similar cyclization of 410 with the terminal alkyne 411 to form benzene derivatives 412 and 413 without using Cul is explained by the successive intermolecular and intramolecuar insertions of the two triple bonds and the double bond[282]. The angularly bisannulated benzene derivative 415 is formed in one step by a totally intramolecular version of polycycli-zation of bromoenediyne 414[283,284],... 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

Recently, a one-pot method for preparation of 2-aryl-1,5-benzotelluroazepines 60 has been developed based on the reaction of sodium 2-aminophenyltellurolate [from di(o-aminophenyl) ditelluride) with arylpropargyl aldehydes (99MI1). Considering the high affinity of supemucleophilic aryltellurolate anions to a triple bond, one may assume that at the first stage of this reaction arylvinyl tellurides 61 are formed. Cyclization of 61 spontaneously or on silica gel in a chromatographic column forms the heterocycles 60. 

It was assumed that the failure of cyclization of 3-amino- and 5-amino-4-acetylenylpyrazole derivatives is due both to the decreased nucleophilicity of the amino groups in the acceptor positions 3 and 5 of the pyrazole ring and to the low electrophilicity of the triple bond carbons in position 4 of the ring. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

The reaction of disubstituted diacetylenes with hydrazine hydrate was reported by Darbinyan et al. (70AKZ640). In the first stage the addition of hydrazine to the terminal carbon atom of the diacetylene system is analogous to that of primary amines to diacetylene (69ZC108 69ZC110). With monosubstituted diacetylenes (R = H), hydrazine adds to the terminal triple bond. This leads to the formation of vinylacetylenic hydrazine 22 which cyclizes to dihydropyrazole 23 subjected to further isomerization to the pyrazole 25. It is possible that hydrazine 22 undergoes hydration to the ketone 24 which can easily be cyclized to the pyrazole 25... 

AKZ640). Although some data (00UK642) support a ready hydration of the activated triple bond in a weakly basic medium, the latter route seems less probable, since the cyclization of hydrazine 22 is a monomolecular process (70AKZ640) and the hydrazine group is much more nucleophilic than water. 

The reaction seems to involve double addition of ammonia to the ketone 102 (at the methoxyethenyl group and the triple bond) to form the diamine 104 which further undergoes cyclization to aminopyridine 103 by elimination of water and methanol. 

Of great importance for the Bergman cyclization is the distance between the triple bonds. The reaction cannot occur at moderate temperatures if the distance is too large. Optimal reactivity at physiological temperatures is obtained by fitting the enediyne element into a ten-membered ring." ... 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

A versatile approach to the 5-ary ldibenzo[7>,/]oxcpin system is the electrophilic ring-closure reaction of 2-phenoxy-substituted diphenylacetylenes or 1-bromostilbenes. Cyclization of the alkynes 4 occurs after addition of a suitable electrophile such as H +, PhS+, Br+, or I+ to give products 5.100-101 Addition across the triple bond gives stilbenes as byproducts. 

Radical cyclization to triple bonds is used as the key step for the synthesis of oxygen heterocycles. This methodology can benefit from a Lewis acid, such as aluminum fns(2,6-diphenyl phenoxide) (ATPH), which forms a complex with the... 

The reverse reaction (that is, the oxidation of a vinyl radical by Fe to the corresponding vinyl cation) may be involved in the reaction of the dimethyl ester of acetylenedicarboxyUc acid 261 with Fenton s reagent [Fe —H2O2, (217)] (216). When 261 was treated with Fe —H2O2 and the reaction mixture was extracted with ether, a small amount of furan 262 was isolated. A possible mechanism (216) for its formation may be addition of hydroxyl radical to the triple bond of 261, followed by addition of the intermediate vinyl radical to a second molecule of 261 and oxidation of the resulting radical with Fe to the corresponding vinyl cation, followed by cyclization to 262, as shown in Scheme XX. 

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