Intramolecular reaction double 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]. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

At the very beginning of polymerization, there is a very small concentration of macromolecules dissolved in the monomers. For this reason, the probability of the active center meeting a pendant double bond of another primary chain is close to zero and most of the pendant double bonds participate in intramolecular reactions. Spatial correlations increase the effective reactivity of pendant double bonds and explain the occurrence of intramolecular cyclization at the beginning of the reaction. 

Titanocene(n) species promote the conversion of unsaturated thioacetals to cyclic compounds. This cyclization proceeds with the loss of the terminal alkene carbon. Treatment of the thioacetal 83 with the low-valent titanium species Cp2Ti[P(OEt)3]2 (3 equiv) in refluxing THF afforded benzoxocines 86 and 87 (by isomerization of 86) in 61% yield (Scheme 14) <1999SL354>. Using 4 equiv of the titanocene(n), the yield is higher (70%) but the selectivity is lower (the ratio 86 87 becomes 82 18). The mechanism or the reaction probably involves the formation of the titanium carbene complex 84, its intramolecular reaction with the double bond to form titanocyclobutane 85, and the subsequent elimination of methylidenetitanocene <1999SL354>. 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

Intramolecular allene alkyne cyclizations using cobalt complexes are nonspecific and both double bonds of the allene participate in the reaction affording [4.3.0] and [3.3.0]ring systems (Scheme 260). Both inter- and intramolecnlar Pauson - Khand-type reactions have been reported using... 

Figure 4.2 Intramolecular reaction between carbonium ions and double bond, cyclization...

Production of carbonium ions gives the possibility to produce different hydrocarbons molecules, e.g. cycloparaffins and aromatics by cyclization and dehydrogenation reactions (Figure 4.2). In the first step presumably intramolecular reactions between carbonium ions and double bonds take place. 

Intramolecular reaction of an allylsilane and an aldehyde was performed to prepare cyclic compounds as illustrated in Eq. (90) [233], which shows a high diastereoselec-tivity. The cyclization of optically active allylsilane proceeds stereoselectively in a manner consistent with the antiS l mechanism (Eq. 91) [234]. Development of a new reagent with a bis-allylsilane moiety effected tandem inter- and intramolecular cyclizations to give cyclic compounds as exemplified in Eqs (92) [235] and (93) [236-238]. In Eq. (92), the double addition product initially formed underwent a pinacol-type rearrangement under the influence of TiCU to give, eventually, the methyl cyclopentyl ketone. Further examples of intramolecular cyclization of allylsilanes are summarized in Table 8. 

Intramolecular reactions of allylic acetates with conjugated dienes catalyzed by Pd(0) lead to a 1,4-addition of a carbon and an oxygen nucleophile to the diene. The reaction, which is formally an isomerization, involves tw different yr-allyl complexes (Scheme 8-4) [44]. Reaction of 22 in the presence of the Pd(0) catalyst Pd2(dba)3-CHCl3 (dba = dibenzyl-ideneacetone) and LiOAc/HOAc in acetonitrile at reflux produces the cyclized isomer 25 in 62% yield. The double bond was exclusively of E stereochemistry, while the ring stereochemistry was a mixture of cis and tram isomers. Oxidative addition of the Pd(0) to the allylic acetate gives the intermediate jr-allyl complex 23. Subsequent insertion of a diene double bond into the allyl-palladium bond produces another jr-allyl intermediate (24), which is subsequendy attacked by acetate to give the product 25. 

Intramolecular cyclization is a general reaction in the anodic oxidation of substituted amino alkenes. Thus, the already mentioned A-methyl-A-phenyl-1,2,2-triphe-nylvinylamine leads to a new 3/7-indole by anodic oxidation in the presence of 2,6-lutidine [149,150]. The corresponding enediamine undergoes an electrolytic double cyclization to form an indolooxazolidine [149]. The formation of isoquinolines, benzaze-pines, and tetrahydrocarbazoles may also be obtained by anodically initiated intramolecular cyclization of A-benzyl, A- S-phenethyl, and anilino enaminones [Eq. (30)] [158]. 

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