Halides, alkyl intramolecular reactions with

Thioamides exhibit a pronounced nucleophilic character due to their nitrogen atom. Alkyl halides often react at room temperature to give thioimi-doester salts which may be subsequently used. This reaction was applied [134] to the preparation of an enaminoketone, the cyclohexenone ring being formed by base treatment of a ketone and intramolecular reaction with the iminium salt. A similar sequence [135] was mentioned in Scheme 28. 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Electron-rich carbyne complexes can react at the carbyne carbon atom with electrophiles to yield carbene complexes. Numerous examples of such reactions, mostly protonations, have been reported [519]. Depending on the nucleophilicity of the carbyne complex, such reactions will occur more or less readily. The protonation of weakly nucleophilic carbyne complexes requires the use of strong acids, such as triflic [533], tetrafluoroboric [534] or hydrochloric acid [535,536]. More electron-rich carbyne complexes can, however, even react with phenols [537,538], water [393,539], amines [418,540,541], alkyl halides, or intramolecularly with arenes (cyclometallation, [542]) to yield the corresponding carbene complexes. A selection of illustrative examples is shown in Figure 3.25. 

In order to strengthen evidence in favour of the proposition that concerted inplane 5n2 displacement reactions can occur at vinylic carbon the kinetics of reactions of some /3-alkyl-substituted vinyliodonium salts (17) with chloride ion have been studied. Substitution and elimination reactions with formation of (21) and (22), respectively, compete following initial formation of a chloro-A, -iodane reaction intermediate (18). Both (17) and (18) undergo bimolecular substitution by chloride ion while (18) also undergoes a unimolecular (intramolecular) jS-elimination of iodoben-zene and HCl. The [21]/[22] ratios for reactions of (18a-b) increase with halide ion concentration, and there is no evidence for formation of the -isomer of (Z)-alkene (21) iodonium ion (17d) forms only the products of elimination, (22d) and (23). 

Alkyl halides with (3-hydrogens generally undergo only elimination reactions under the conditions of the vinyl substitution (100 C in the presence of an amine or other base). Exceptions are known only in cases where intramolecular reactions are favorable. Even alkyl halides without (3-hydrogens appear not to participate in the intermolecular alkene substitution since no examples have been reported, with the exception of reactions with benzyl chloride and perfluoroalkyl iodides. 

Intramolecular attack of the acetylide j8 carbon on a pendant terminal alkyl halide chain gives cyclic vinylidene complexes (78). Reaction of 6-chlorohex-l-yne with 1 leads to the intermediate vinylidene complex 72, which on passing down an alumina column converts to the cyclic vinylidene complex 73 [Eq. (70)]. The similar reaction with 5-chloropent-l-yne, however, yields the stable chloroacetylide complex 74. Presumably, the steric constraints that would arise from forming a four-membered ring prevent cyclization [Eq. (71)]. 

Nickel catalysts have been used in the reaction of aryl halides with A-alkyl aniline derivatives. Nickel catalyst also allow the conversion of aryl halides to A-arylamines via reaction with aliphatic amines. An intramolecular reaction of a... 

Wurtz reaction The coupling of two alkyl halides, RX, with sodium metal to give the R-R compound. Usually of almost no synthetic value as there are many side reactions. However, the intramolecular reaction of l-bromo-3-chlorocyclobutane with sodium gives bicyclobutane in about 95% yield. 

Other similar methods which involve cyclization of iV-substituted diaminoalkenes or -alkanes include the preparation of 2-alkyl- and 2-acyl-l-methylimidazole-4-carboxylates from methyl (Z)-j -dimethylamino-a-isocyanoacrylate (191) in reaction with an alkyl or acyl halide <82LA2093>, the preparation of perfluorinated 3-imidazolines (192) <83S169>, the high yield synthesis of 2-imidazolines by decay of phosphaza compounds (193) in a version of the intramolecular Staudinger reaction <85T793>, and the formation of 1,3-diaroylimidazolidines (34-71%) when bis-alkylidene-or -arylidene-ethylenediamines react with acid chlorides in polar solvents (Scheme 129)... 

Reaction of (50) with alkyl halides gives exclusive a-alkylation. With aldehydes and ketones, a-addi-tion again takes place to give (52) via intramolecular silyl transfer with concomitant loss of lithium cyanide (c/. 25 Scheme 30). Treatment of (52) with p-Ts0H H20 gives the cyclopentenone annelation product. The allylic cyanohydrin anion (53) also gives a-adducts upon treatment with aldehydes and ketones at -78 °C, whereas reaction with electrophiles at 0 C affords -y-adducts (c/. 25). 

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