Alkylation, intramolecular, forming

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

In intramolecular reactions, direct interaction with the thiophene ring is possible by appropriate positioning of the tether as shown for the 3-substituted thiophene (229), which resulted in alkylation to form (230) and (231) (equation 46).)6la In contrast, the rhodium(II) acetate catalyzed decomposition of the 2-... 

When 5- and 8-hydroxyquinolines and 5-hydroxyisoquinoline are used as alkylating agents (see Section 5.2.7) the primary alkylation products undergo a second, intramolecular alkylation to form methano-bridged compounds in low yields, which is due to the reversibility of the reactions294,295 [Eq. (5.133)]. 

Ito and coworkers [122] found that allylsulfides can be alkylated intramolecularly by epoxides in the presence of a proper base to form macrocycles. Tsuji and... 

The classical (Grignard-like) mechanism for Barbier reactions involves the primary formation of an Sm-alkyl species via halogen abstraction and subsequent reduction of the alkyl radical formed after the first electron transfer. Be that as it may, the Barbier reaction can be used to construct complex polycyclic target molecules, e.g. the synthesis of tetraquinanes from diquinane precursors by two independent intramolecular cyclization steps (Scheme 24) [83]. 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

Synthesis of polycyclic compounds. 2,2 -Bisbramomethyldiphenyl (1) reacts with 1 mole of triphenylphosphine to give the phosphonium salt (2), which is converted into the ylide (3) on treatment with base (sodium methoxide). The ylide (3) is not isolated but undergoes intramolecular C-alkylation to form the phosphonium salt (4). This salt on treatment with phenyllithium gives the ylide (5). This ylide is readily transformed into phenanthrene or 9-substituted phenanthrenes.3... 

Fast intramolecular palladation to VII iii) Oxidative addition of alkyl halide forms Pd(IV) complex IV... 

Desoxoprosophylline (224) and (-)-desoxoprosopinine (225) were synthesized from a D-glucose-derived percursor via a palladium (O)-catalyzed intramolecular /V-alkylation to form the piperidine ring in a key step [501]. 

Cyclopropyl ketones While normal selenenylchlorination occurs when y,8-unsaturated ketones are treated with PhSeCl, subsequent reaction of the adducts with a base (e.g., NaH) effects an intramolecular alkylation to form cyclopropane derivatives. 

Synthetic Routes to Chromanes Chromanes are important structural motifs in organic synthesis and have been found as core structural elements commonly present in many bioactive compounds. J0rgensen et al. [32] have developed a tandem reaction that involves a Lewis acid-catalyzed oxa-Michael addition of phenols 208 to p,y-unsaturated a-ketoesters 209, followed by an intramolecular FC alkylation to form chromanes 211 (Scheme 2.29). The reaction proceeds under the influence of a Mg-BOX (210) catalyst to give diastereomerically pure chromanes with enanti-oselectivities up to 81% and excellent yields. The best results were obtained with m-methoxyphenol, while m-A(Al-dimethylaminophenol afforded the corresponding chromane as single diastereomer in excellent yield but with low enantioselectivity (<20% ee). 

Alkylation to form substrates which undergo intramolecular Diels-Alder reaction is controlled by choice of metal (Pd, Mo, W) template . [MoCp(cyclohexadiene) (CO)2 J" " may be used to control functionalisation of the 6-membered ring in particular a novel stereocontrolled lactone synthesis O effects of m- or p-... 

The formation of silane is consistent with a reaction pathway in which the silicon-stabilized cationic intermediate resulting from l,6-ad(fition by the allylsilane undergoes intramolecular alkylation to form a cyclobutane ring. This analysis complements House s observations that signficant quantities of cyclobutyl silane 75 are produced when 22 reacts with an enone and TiCU at elevated temperatures (Eq. 3).ll... 

P-Alkyl elimination is much less common than hydride elimination. This is because it is difficult to have an alkyl group form an intramolecular interaction with the metal, as is required prior to the elimination, and the reaction is now sometimes endothermic because an M-C and a C-H bond are traded for another M-C bond and a C-C -it bond. However, P-alkyl elimination can occur. For example, Eq. 12.36 shows an example involving Lu, where... 

Problem 18.13 Intramolecular reactions are also observed in Friedel-Crafts alkylation. Draw the intramolecular alkylation product formed from each of the following reactants. (Watch out for rearrangements )... 

The product obtained from an intramolecular reaction can undergo further reactions, making it possible to synthesize many different compounds. For example, the cyclic alkyl bromide formed as the product of the next reaction could undergo an elimination reaction, or it could undergo substitution with a wide variety of nucleophiles, or it could be converted to a Grignard reagent that could react with many different electrophiles. 

The small and mobile "OH can readily abstract hydrogen from a nearby polymer chain, creating a secondary or tertiary macroalkyl radical. The tertiary alkoxy radical can abstract hydrogen intramolecularly, forming a primary alkyl radical as in Eq. (41). 

Takeo Kawabata of Kyoto University found (J. Am. Chem. Soc. 2008, 130, 4153) that intramolecular alkylation to form four, five and six-membered rings from amino esters such as 21 proceeded with remarkable enantioretention. 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

Gumylphenol. -Cumylphenol (PGP) or 4-(1-methyl-l-phenylethyl)phenol is produced by the alkylation of phenol with a-methylstyrene under acid catalysis. a-Methylstyrene is a by-product from the production of phenol via the cumene oxidation process. The principal by-products from the production of 4-cumylphenol result from the dimerization and intramolecular alkylation of a-methylstyrene to yield substituted indanes. 4-Cumylphenol [599-64-4] is purified by either fractional distillation or crystallization from a suitable solvent. Purification by crystallization results in the easy separation of the substituted indanes from the product and yields a soHd material which is packaged in plastic or paper bags (20 kg net weight). Purification of 4-cumylphenol by fractional distillation yields a product which is almost totally free of any dicumylphenol. The molten product resulting from purification by distillation can be flaked to yield a soHd form however, the soHd form of 4-cumylphenol sinters severely over time. PGP is best stored and transported as a molten material. 

An interesting case of ipso intramolecular alkylation has been observed in the case of the acid-promoted cyclization of the amino alcohols (61). With trifluoroacetic acid the major product was the rearranged thienopyridine (62), whereas with polyphosphoric acid the product formed exclusively was the non-rearranged thienopyridine (63) (82CC793). 

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