Cyclization benzyl halides

In an alternate synthesis of the intermediate ketone, the benzylic halide, 69, is used to alkylate sodium phenoxide. Cyclization of the acid (70) obtained on hydrolysis of the ester by means of trifluoroacetic anhydride again gives 67... 

Applications of the aforementioned methodology are also found in the total synthesis of plagiochin D to link a 16-membered biaryl system [47], as well as to the intramolecular cyclization of di-benzyl halides [45, 48]. Additional examples include dithienothiophene (40) from dithienyl bromide 39 [49] and carbazole 42 from diarylbromide 41 [50]. 

The acid-catalyzed cyclization of salts (188 Scheme 101) prepared from 2-cyanopyridine by quaternization with a benzyl halide provides the only method yet developed for the synthesis of 11-aminoacridzinium salts (189). The prototype quaternary salt (188 R = H) was cyclized in sulfuric acid in an overall yield of 25% (73JOC4167). A better yield (59%) was obtained when the point of electrophilic attack was activated by a para methoxy group. 

When treated with a strong base such as butyllithium or potassium tert-butoxide, 2-isocyano-tV[(S)-l-phenylethyl]propanamide (1) forms an enolate 2 which is not alkylated at low temperatures. Instead it rearranges on warming and cyclizes to give the enolate of 3,5-dihydro-5-methyl-3-[(,3 )-1-phenylctbylJ-4//-imidazol-4-onc (3) which can be alkylated with benzylic halides with excellent diastereoselectivities4,13. 3-Halopropenes or haloalkanes give much lower diastereoselectivities. 

Benzylpalladation.11 Benzyl halides do not undergo usual radical cyclizations effected with organic halides, but do undergo Pd-catalyzed cyclization with alkenes and alkynes. A typical reaction is formulated in equation (I). The leaving group can also be Br, I, or OMs, but not OCOOCH3 or OCOCH3. Attempts to cyclize 1 with... 

The synthesis of N-alkylated dihydropteridinones 34 started with a displacement reaction of 4,6-dichloro-5-nitropyrimidine with a fluorous amino-ester (Scheme 23) [53]. The compounds formed 35 were then reacted with secondary amines to yield 36. The reduction of the nitro group of 36 was conducted by hydrogenation using Pd on charcoal as a catalyst. The cyclization reactions of 37 were promoted by microwave irradiation. The N-alkylation reaction of the cyclized products 38 with benzyl halides gave monobenzylated... 

In the case of benzyl halides, a lithium halogen exchange prevents the cyclization and the reaction gives only oligomers (equation 111)9,25. 

Scheme 6 The Leuchs Method for Preparation of a A -Carboxyanhydride Reaction of a A -Benzyloxycarbonyl-Protected Amino Acid with an Acid Halide Generating Agent (X-A) Followed by Cyclization To Give the NCA and a Benzyl Halide ...

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cychzations of266 and 267 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 266 and the TV-benzyl indole 268 [271]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 269, and they prepared a series of peripheral-type benzodiazepine receptors 270 using this chemistry. For example, 270 (n = 3, R = n-Pr) is obtained in 81% yield. 

There is one more way for conversion of ort/to-nitroarylacetonitriles into indoles. Alkylation of such nitriles with allyl or benzyl halides followed by treatment of the compounds obtained with basic agents results in a multistep transformation, which is likely to proceed via intermediate nitrosoarenes, to produce 1-hydroxyindoles. For instance, alkylation of ort/io-nitroarylacetonitriles with 3-phenylallyl bromide gives the compounds that in the presence of chlorotri-methylsilane and triethylamine undergo cyclization into 3-cyano-l-hydroxy-2-vinylindoles (Scheme 70) [188]. Presumably, this reaction proceeds via 0-silylation of the nitronate anion and 1,5-elimination of trimethylsilanol from the intermediate trimethylsilyl nitronate, followed by cyclization and a hydrogen shift. 

Wu, G., Lamaty, R and Negishi, E.-i. (1989) Palladium-catalyzed cyclization of benzyl halides and related electrophiles containing alkenes and alkynes as a novel route to carbocydes. J. Org. Chem., 54, 2507-8. 

In the reaction of aryl and alkenyl halides with 1,3-pentadiene (248), amine and alcohol capture the 7r-allylpalladium intermediate to form 249. In the reactions of o-iodoaniline (250) and o-iodobenzyl alcohol (253) with 1,3-dienes, the amine and benzyl alcohol capture the Tr-allylpalladium intermediates 251 and 254 to give 252 and 255[173-175]. The reaction of o-iodoaniline (250) with 1,4-pen tadiene (256) affords the cyclized product 260 via arylpalladiuni formation, addition to the diene 256 to form 257. palladium migration (elimination of Pd—H and readdition to give 258) to form the Tr-allylpalladium 259, and intramolecular displacement of Tr-allylpalladium with the amine to form 260[176], o-Iodophenol reacts similarly. 

Cobaloxime(I) generated by the electrochemical reductions of cobaloxime(III), the most simple model of vitamin Bi2, has been shown to catalyze radical cyclization of bromoacetals.307 Cobalt(I) species electrogenerated from [ConTPP] also catalyze the reductive cleavage of alkyl halides. This catalyst is much less stable than vitamin Bi2 derivatives.296 It has, however, been applied in the carboxylation of benzyl chloride and butyl halides with C02.308 Heterogeneous catalysis of organohalides reduction has also been studied at cobalt porphyrin-film modified electrodes,275,3 9-311 which have potential application in the electrochemical sensing of pollutants. 

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

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