N-Alkylation heterocycles

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

Mercaptothiazoles with heterocyclic substituents in the 4-position have also been prepared (292, 508, 602). For example, N-alkyl-2-benzimidazolyl chloromethylketones (169) give the corresponding 2-mercaptothiazole derivatives (170) with R, = H, Me, CHjPh, Ac, COPh and R2==H, Me, 5,6-dichloro (Scheme 86) (602). 

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

The mesomeric effect of the C=S linkage is very pronounced and is responsible for the facile quaternization of heterocyclic N-alkylated thiones (159) this effect is operative even when such a shift does not increase the aromaticity of the ring. Thione derivatives of pyridazine, benzothiazole, quinazoline, 1,3-thiazine, triazole,and isoindole are examples of compounds which readily form quaternary salts. 

Palladium(II)-catalyzed cyclization of N-alkylation of allyl alcohols by ure-tanes and its application to the synthesis of natural saturated heterocycles 98YGK34. 

Certain reagents promote ring opening and subsequent cyclization to give other heterocycles. For example, di-tert-butyl dicarbonate induces the stereoselective ring transformation of N-alkyl aziridines 159 into oxazolidin-2-ones 160 <96TET2097>. 

Moncrief summarized the work of Cohn and the information in the early literature. As early as 1923, it was known that rupture of the heterocyclic ring, as well as substitution of the imino hydrogen atom, results in the loss of sweetness. Thus, o-carboxybenzenesulfonamide and N-alkyl derivatives of saccharin are tasteless. This loss of sweetness would be expected, as the NH group is the only proton-donor function available in the molecule. 

A variety of related microwave-promoted N-alkylations involving more elaborate heterocyclic scaffolds are summarized in Scheme 6.116 [230-234]. Additional examples concerning the synthesis of ionic liquids can be found in Section 4.3.3.2. 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

N-alkyl- and N-aryl-substituted acyclic or cyclic imines and the subsequent cycliza-tions providing the heterocyclic target compounds [74, 79]. ... 

T. Deligeorgiev, A. Vasilev and K.-H. Drexhage, Synthesis of novel intermediates for cyanine by the quaternization of V-heterocycles with acrylamide and N-alkyl acrylamides. Dyes Pigm., 67 (2005) 21-26. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Scheme 2.64 The clean and efficient N-alkylation of heterocyclic compounds.

Singh and Han [60] have reported the preparation of another dihydropyrrole by using a N-Cbz derivative obtained by decarboxylative amidation (Scheme 9.27, results line 1) as starting material. N-Alkylation with allyl bromide followed by RCM (Grubbs II catalyst) furnished the dihydropyrrole in excellent yield (95%). Lee et al. have similarly transformed the amination product (Table 9.2, entry 21) into a variety of N-heterocycles [54]. 

Aromatic N-containing heterocycles (pyridine, imidazole etc.,) and their alkyl derivatives represent an important group of products and they have received considerable attention because of their various applications. For instance, methyl pyridines (picolines) and dimethyl pyridines (lutidines) are a class of industrially valuable compounds for the production of dyes and fine chemicals [108]. Sreekumar et al [109] reported pyridine methylation to 3-picolines over Zni xCoxFe204 spinel systems at reaction temperature between 325 and 425°C. The... 

Treatment of 7-chloroamine 363 with potassium /i t/-butoxide in refluxing THE gave rise to a mixture of (Z-tert-butyl)-5,5-dimethyl-5,6-dihydro-4f/-l,3-oxazine 366 and 1-pivaloylazetidine 367 (Scheme 67). The heterocycles 366 and 367 were formed through generation of the Favorskii intermediate 364 by dehydrocyanation, which was followed by opening of the cyclopropylideneamine by /r-rt-butoxide with the subsequent loss of isobutene and a subsequent intramolecular N-alkylation or O-alkylation of the amide anion 365 <1999EJ0239>. 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

Numerous modifications of this procedure have been used. The synthesis of ben-zimidazolone monomers (12), dimers (13) and trimers demonstrate this versatile, simple approach to bridged heterocycles (76TL79). N-Alkylated products (e.g. 14) are in many cases the result of side reactions caused by a competitive transmetallation process (78MI52202) polymerization is also a common reaction course. 

A7-Acyl derivatives of heterocycles can often be quatemized by hard alkylating agents, such as trialkyloxonium fluoroborates406 or methyl fluorosulfonate.364 The quaternary salt is not usually isolated, but N-alkylated derivatives are obtained whose structures are generally different from those obtained by alkylation of anions (Sections IV,C,2). This method, due to Olofson and Kendall,406 has been used with success in azapentalenes [Eqs. (34) and (35)1, where the products 384 and 385 are different from those obtained by alkylation of the anions 361 and 364, respectively (Scheme 16). 

Plots of Aae against the percentage of lone-pair axial conformer (estimated by dipole-moment measurements) for some monocyclic heterocyclic compounds with differing N-alkyl substitution showed no correlation.44 This is to be expected because the nature of the N-alkyl substituent also affects A,e40 Table III). 

A general problem in alkylation of nitrogen heterocycles is the regio-chemistry of the corresponding anions. The ratio of N- versus C-alkylation usually depends on reaction conditions PTC strongly favors N-alkylation. 

Wang et al.122 have described methylation and alkylation of pyrrole and obtained mono-N-alkylation products with yields of 30-85%. An increase in the ratio of N- versus C-alkylation of pyrrole (and of other heterocyclic compounds bearing an acidic hydrogen atom) has been observed by Guida and Mathre,124 who carried out the reaction with t-BuOK, 18-crown-6 (10%), and diethyl ether. 

In general, alkylation of ambident S,N-nucleophilic heterocycles gives predominantly, if not exclusively, S-alkylated products. In some cases, however, N-alkylation follows S-alkylation to give N,S-dialkylated compounds. 

Quaternary ammonium salts of heterocyclic compounds have been used in liquid-liquid phase-transfer syntheses. When these compounds are achiral, they show a behavior very similar to that of other quaternary ammonium salts. For example, 2-dialkylamino-l-alkylpyridinium tetrafluoroborates have been used by Tanaka and Mukayama282 in the alkylation of active methylene compounds PhCH2CN, PhCH(Et)CN, and PhCH(Me)COPh. However, comparative studies of the efficiency of the catalysts show that alkylpyridinium bromides283 or N-alkyl-Af-benzyl-piperidinium chloride284 have a smaller catalytic activity compared to tetraalkylammonium halides. McIntosh285 has described the preparation of azapropellane salts 186 as potential chiral phase transfer catalysts. 

N-Oxidation may be formally considered as quatemization of pyridine-like nitrogen atom by the HO+ cation, formed by heterolysis of 0-0 bond in the peracid molecule. Indeed, common features exist between N-alkylation and N-oxidation both reactions are second order (first order at each reagent). The reaction constant, p, for oxidation of 3- and 4-substituted pyridines by PhC03H in aqueous dioxane is -2.35, Close to the p value for N-alkylation (Chem. of the Heterocyclic N-oxides, N-Y, Acad. Press, 197l). 

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