Heterocycles alkylation

The heterocyclic alkyl quaternary salts used for preparing spiropyrans are usually obtained by N-alkylating the heterocyclic bases by standard methods. The common bases having an active methyl group of the indolenine, benzothiazole, benzoxazole, and quinoline series some of their substitution products, and a few of their quaternary salts are commercially available. The pyrylium, thiopyrylium, 2-azaazulenium and bcnz[c,d]indolenium salts needed for potentially infrared-absorbing spiropyrans are not (as of the time of writing). 

As for the amine moiety, the rearrangement has been demonstrated (although not unequivocally in all cases) for mono-A -substituted glycosyl-amines derived from aromatic amines and aralkyl- and alkyl-amines and for di-A-substituted glycosylamines containing dialkyl, alkyl-aryl, aralkyl, isocyclic, and heterocyclic alkyl radicals. The rearrangement has been reported for A-glucosyl derivatives of amino acids, but not as yet... 

Alkylation, Acylation, and Carbalkoxylation of Nitrogen Heterocycles Alkylation or Alkyl-de-hydrogenation, and so on... 

The scope of the organotin hydride mediated process encompasses the formation of six-mem-bered ring heterocycles. Alkylation of methyl 4-oxotetrahydrothiophene-3-carboxylate (35) with chloromethyl phenyl selenide afforded the 3-(phenylselanylmethyl) derivative 36 which rearranged to methyl 5-oxotetrahydrothiopyran-3-carboxylate (37) in good yield when treated with 1.1 equivalents of tributyltin hydride a higher proportion of the tin hydride was deliteri-ous. ... 

Diary] and triaryl or naphthyl carbamates exhibit low herbicidal activity. The substitution of the aryl radical for a heterocyclic radical gives heterocyclic alkyl and dialkyl ureas, of which many examples have been prepared in recent years. The herbicidal activity of urea derivatives containing a heterocyclic radical, such as benzthiazole, thiazole, thiadiazole, oxadiazole and pyridine, is favourable if one or two methyl groups are substituted at the N -nitrogen. The carrier of total or selective action in these derivatives is presumably the heterocyclic part of the molecule. More recently several new groups of compounds have become known, mainly in the patent literature, for which the structure-activity on relationships are still to be elucidated. 

Heterocycles alkylated by allylic carbonates are shown in Scheme 37. The reactive atom is in bold type. The following general preferences are observed when both atoms are connected C > N, C> O, N > O. For pyrimidine bases N-1 > N-3 unless N-1 is sterically hindered, as in 6-methyluracil (N-3 preferred). 

The same Rh/[HPCy3]Cl catalyst system was found to facilitate alkylation reactions on notoriously challenging heterocycles such as electron-deficient pyridines and quinolines, thereby displaying its broad utility. Although the exact mechanism for intra- and inter-molecular heterocycle alkylation still remains unclear, activation is thought to proceed via a mechanistically distinct pathway that involves formation of a Rh(I)-Af-heterocyclic carbene complex. 

A wide class of aiyl-based quaternary surfactants derives from heterocycles such as pyridine and quinoline. The Aralkyl pyridinium halides are easily synthesized from alkyl halides, and the paraquat family, based upon the 4, 4 -bipyridine species, provides many interesting surface active species widely studied in electron donor-acceptor processes. Cationic surfactants are not particularly useful as cleansing agents, but they play a widespread role as charge control (antistatic) agents in detergency and in many coating and thin film related products. 

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 ... 

In readily available (see p. 22f.) cyclic imidoesters (e.g. 2-oxazolines) the ot-carbon atom, is metallated by LDA or butyllithium. The heterocycle may be regarded as a masked formyl or carboxyl group (see p. 22f.), and the alkyl substituent represents the carbon chain. The lithium ion is mainly localized on the nitrogen. Suitable chiral oxazolines form chiral chelates with the lithium ion, which are stable at —78°C (A.I. Meyers, 1976 see p. 22f.). 

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. 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

Tertiary amines may be obtained from alkaline alkylation of secondary amines (46), but mixtures are obtained (see Section III.l.B) hence heterocyclization and ammonolysis of 2-halothiazoles are to be preferred. 

The nature of the substituent on the exocyclic nitrogen also influences the ambident activity of anion 48 in DMF (Scheme 35) when R is an heterocyclic ring, nitrogen alkylation predominates (189) when R is a methylamino group, a mixture of the two isomers is reported (190) when... 

The general pattern of alkylation of 2-acylaininothiazoles parallels that of 2-aminothia2ole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161. 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an acid-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

Reaction of 2-aminothiazoles with alkyl isocyanates yields 2-thiazolylureas (256) (Scheme 153) (479-483). This reaction is general and works with acyl isocyanates (484. 485). These heterocyclic ureas are also prepared by the reaction of H2O on 2-thia2olylcyanamide (486) or by action of HjOj on the corresponding thiourea (303, 481). 

The reaction of 2-aminothiazoles with alkyl isothiocyanates yields 2-thiazolylthioureas (30.3, 490), otherwise usually obtained by direct heterocyclization (Chapter II. Section II.4). Other synthetic methods... 

The infrared spectra of a set of 2-thiazolylthioureas are reported in Ref. 486. The ultraviolet spectra of l-aryl-3-(2-thiazolyl)thioureas are characterized by two bands of approximate equal intensity around 282 and 332 nm (492). For l-alkyl-3-(2-thiazolyl)thioureas these bands are shifted to 255 and 291 nm, respectively (492). The shape of the spectrum is modified further when l.l -dialkyl-3-(2-thiazolyl)thioureas are considered (491). Fragmentation patterns of various 2-thiazolylthioureas have been investigated (100, 493), some of which are shown in Scheme 158. Paper and thin-layer chromatography provide an effective tool for the analysis of these heterocyclic thioureas (494. 495). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

Quaternarj salts are obtained by alkylation of selenazole bases, the heterocyclic nitrogen atom playing the role of nucleophile with regard to the electrophilic carbon of the alkylating, agent. 

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). 

The quatemization reaction of the thiazole nitrogen has been used to evaluate the steric effect of substituents in heterocyclic compounds since thiazole and its alkyl derivatives are good models for such study. In fact, substituents in the 2- and 4-positions of the ring only interact through their steric effects (inductive and resonance effects were constant in the studied series). The thiazole ring is planar, and the geometries of the ground and transition states are identical. Finally, the 2- and 4-positions have been shown to be different (259. 260). 

The effect of alkyl groups in the 5-position on the reactivity of the thiazole nitrogen is analogous to that found for 3-alkylpyridines, in other words, a simple inductive effect. In passing from the unsubstituted heterocycle to the methyl derivative, the rate constant doubles a further increase in substitution produces a much less pronounced variation. 

It is well known that in nitrogen-containing heterocyclic compounds the reactivity of alkyl groups is enhanced. In the thiazole series, alkyl groups in the 2-position are reactive towards carbonyl compounds and condensations may be realized. 

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