Alkylation with 1-butyl chloride

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCU-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with iV-bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-raethylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine,only the 5-isomer (besides some side-chain bromination) is obtained in fhe bromination of alkyltiiiophenes with A "-bromosuccinimide. However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chloro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with fhiocyanog or chloiination with sulfuryl chloride. 2-Methyl- and 2-ethyI-thio-phene give, somewhat unexpectedly, upon alkylation with <-butyl chloride in the presence of FeCls, only 6-f-butyl monosubstituted and... 

The other method results directly from the piperidine-2-carboxylic acid chloride, which is reacted with 2,6-dimethylaniline. The resulting amide (2.2.8) is further alkylated with butyl bromide to bupivacaine [17-19]. 

Silica gel is an effective catalyst for the /-butylation of thiophene and benzo[ ]thiophene using /-butyl bromide. 2,5-Di-/-butylthiophene and 3-/-butylbenzo[A]thiophene can be prepared easily by this procedure. Alkylation of thiophene with /-butyl chloride, isopropyl chloride, or ethyl chloride at 70 C in the presence of AICI3 produced -complexes under kinetic control. On thermal equilibration, migration of alkyl from C(3) to C(2), as well as disproportionation to dialkyl and trialkyl thiophenes can occur. 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

Under similar conditions, ethyl chloride gave only low yields of diethyltin dichloride, and attempts to alkylate tin, either in a sealed tube or under these flow conditions, with butyl chloride, butyl bromide, or bromobenzene were unsuccessful. 

Insight into another mode of formation of these by-products is furnished by the observation that l-chloro-3,3-dimethylpentane and 1-chloro-3,3-dimethylbutane are by-products of the condensation of ethylene with <-butyl chloride and <-amyl chloride, respectively, in the presence of aluminum chloride (Schmerling, 16). Partial conversion of either <-alkyl chloride into the other presumably occurs under the reaction conditions. It is apparent, then, that the alkyl chloride formed as indicated in step 3 of the three step chain mechanism may be converted into a chloride of higher or lower molecular weight before undergoing the condensation of... 

Arata and Hino found that better catalysts could be obtained by calcining Fe(OH)3 at 573 — 873 K. The hydroxide was prepared by hydrolyzing FeCls or Fe(N03)3 9H20. The alkylation reactions were carried out at room temperature with 50 cm of toluene solution (0.5 mol 1 ) of benzyl chloride, t-butyl chloride or acetyl chloride and 0.1 g (for benzylation or t-butylation) or 0.5g (for acetylation) of catalyst. Benzylation and t-butylation was completed within 2 min and 10 min, respectively. For acetylation with acetyl chloride, the reaction was slow, the conversion being 28% after 6 h of reaction. The reaction with acetyl bromide is slighdy faster conversion of 30% was obtained after 4 h.The isomer distribution of alkyltoluenes was 42% ortho, 6% meta and 52% para for benzylation and 3% meta and 97% para for butylation with /-butyl chloride. It was presumed that iron chloride formed on the surface of amorphous iron oxide by its reaction with hydrogen chloride is a catalytically active species for alkylation. 

Alkylation of pyrrole magnesium bromide and chloride with y-chloro-butyronitrile gives 2- and 3-cyanopropylpyrrole (2 >3). The isomer distribution is similar to those observed in reactions with butyl chloride, heptyl chloride and 8-methoxybutyl chloride. It is concluded that the constitution of pyrrole magnesium chloride is the same in tetrahydrofuran as in ether s. 

The direct reaction of other alkyl chlorides, such as butyl chloride, results in unacceptably low overall product yields along with the by-product butene resulting from dehydrochlorination. AH alkyl haHdes having a hydrogen atom in a P- position to the chlorine atom are subject to this complication. 

There are only few reactions known introducing substituents to the H-bearing nitrogen of oxaziridines. (V-Alkylation of l-oxa-2-azaspiro[2.5]octane (3,3-pentamethylene-oxaziridine 52) with r-butyl chloride to give (53) was carried out for structure proof of (52). This reaction is of no preparative importance, since N-alkylated oxaziridines are easily obtained by ring synthesis. 

Phenylacetonitrile is alkylated with secondary butyl bromide and the resultant nitrile is hydrolyzed to 3-methyl-2-phenylvaleric acid. The acid is converted to the acid chioride with thionyl chloride and the acid chloride is in turn reacted with 1-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. 

The method described is successfully used for the alkylation and aralkylation of ethyl and /-butyl phenylacetate.3 The alkylation of ethyl phenylacetate with methyl iodide, M-butyl bromide, benzyl chloride, and a-phenylethyl chloride affords the corresponding pure monoalkylation products in 69%, 91%, 85%, and 70% (erythro isomer) yields, respectively. The alkylation of /-butyl phenylacetate with methyl iodide, M-butyl bromide, a-phenylethyl chloride, and /3-phenylethyl bromide gives the corresponding pure monoalkylated products in 83%, 86%, 72-73%, and 76% yields, respectively. 

Certain of the monoalkylated ethyl phenylacetates have been further alkylated with alkyl and aralkyl halides to produce the corresponding disuhstituted phenylacetic esters.4 Ethyl 2-phenyl-propanoate has been alkylated by methyl iodide to give pure ethyl 2-methyl-2-pheny]propanoate in 81% yield. Similarly, the alkylations of ethyl 2-phenylhexanoate with methyl iodide, M-butyl bromide, and benzyl chloride gave the corresponding pure dialkylated products in 73%, 92%, and 72% yields, respectively. 

For example /-butyl phenyl ether with aluminium chloride forms para-t-butyl phenol155. Often the de-alkylated phenol is also formed in considerable quantity. The reaction formally resembles the Fries and Claisen rearrangements. Like the Fries rearrangement the question of inter- or intramolecularity has not been settled, although may experiments based on cross-over studies156, the use of optically active ethers157 and comparison with product distribution from Friedel-Crafts alkylation of phenols158 have been carried out with this purpose in view. 

There is direct evidence, from IR and NMR spectra, that the re/T-butyl cation is quantitatively formed when tert-butyl chloride reacts with AICI3 in anhydrous liquid HCl. In the case of alkenes, Markovnikov s rule (p. 984) is followed. Carbocation formation is particularly easy from some reagents, because of the stability of the cations. Triphenyhnethyl chloride and 1-chloroadamantane alkylate activated... 

Schrauzer and co-workers have studied the kinetics of alkylation of Co(I) complexes by organic halides (RX) and have examined the effect of changing R, X, the equatorial, and axial ligands 148, 147). Some of their rate constants are given in Table II. They show that the rates vary with X in the order Cl < Br < I and with R in the order methyl > other primary alkyls > secondary alkyls. Moreover, the rate can be enhanced by substituents such as Ph, CN, and OMe. tert-Butyl chloride will also react slowly with [Co (DMG)2py] to give isobutylene and the Co(II) complex, presumably via the intermediate formation of the unstable (ert-butyl complex. In the case of Co(I) cobalamin, the Co(II) complex is formed in the reaction with isopropyl iodide as well as tert-butyl chloride. Solvent has only a slight effect on the rate, e.g., the rate of reaction of Co(I) cobalamin... 

Notes on the preparation of secondary alkylarylamines. The preparation of -propyl-, ijopropyl- and -butyl-anilines can be conveniently carried out by heating the alkyl bromide with an excess (2-5-4mols) of aniline for 6-12 hours. The tendency for the alkyl halide to yield the corresponding tertiary amine is thus repressed and the product consists almost entirely of the secondary amine and the excess of primary amine combined with the hydrogen bromide liberated in the reaction. The separation of the primary and secondary amines is easily accomplished by the addition of an excess of per cent, zinc chloride solution aniline and its homologues form sparingly soluble additive compounds of the type B ZnCl whereas the alkylanilines do not react with sine chloride in the presence of water. The excess of primary amine can be readily recovered by decomposing the zincichloride with sodium hydroxide solution followed by steam distillation or solvent extraction. The yield of secondary amine is about 70 per cent, of the theoretical. 

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