Quaternization and Alkylation

Alkylation and Quaternization.—4-Bromo-5-hydroxy-3-methylisothiazole is O-methylated by diazomethane in contrast, 3-hydroxy-5-phenylisothiazole is N-methylated, and equimolar mixtures of the O- and N-methyl derivatives are produced from 3-hydroxyisothiazoles. N-Methylation also prevails when 3-hydroxy-4,5-diphenylisothiazole is alkylated by dimethyl sulphate.  

Isothiazole-3(or 5)-carboxaldoxiine (31) (but not its 4-isomer) reacts with methyl tosylate, albeit with difficulty, affording 3(or 5)-hydroxyiminomethyl-2-methylisothiazolium tosylate (32) in low yield (8—9%).  

Nitration.—Isothiazole and its 3- and 5-methyl and 3,5-dimethyl homologues are nitrated exclusively in their 4-position. Quantitative experiments under standard conditions demonstrate the lower relative reactivities of isothiazoles compared with those of the corresponding thiazoles (see Table 1).  

A study of the nitration of 3-, 4-, and 5-phenylisothiazoles reveals a strong deactivation of the benzene nucleus by the heterocyclic ring. The calculated electron densities of the phenylisothiazoles are not in entire agreement with the observed orientation of the nitro-groups in the resulting mixtures of mono-nitro-derivatives.  

5-Amino-3-methylisothiazole has been converted, by way of the diazonium salt, into 3-methyl-5-nitroisothiazole. Treatment of 3,5-dichloro-isothiazole-4-carbonitrile with sodium or silver nitrite yields the 5-hydroxy-compound, presumably via an unstable nitrite ester a nitro-compound is not obtained.  

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Pyrrolidines and N-substituted pyrrolidines undergo reactions typical of secondary or tertiary alkylamines. They can be alkylated and quaternized NH-pyrrolidines can be acylated and nitrosated. The basicity and nucleophilicity of pyrrohdine is, however, greater than those of diethylamine (pyrrolidine pKa = 11.27, diethylamine pKa = 10.49). Because of these properties, pyrrolidine is an often used amine component for the conversion of carbonyl compounds into enamines ... 

The complex formation of partially alkylated PVP was reported by Kabanov et a 42 and by us5S. The K value fell by about two orders of magnitude with the degree of alkylation for the PVP derivatives that were alkylated or quaternized by methyl bromide42. This reduction of K was due to electrostatic repulsion on the quaternized PVP chain. On the other hand, Table 5 shows no effect of alkylation on the stability of the polymer chelate when benzyl chloride is used as the alkylating reagent, while the formation constant falls slightly for PVP alkylated by ethyl... 

Similar reactions involving intermolecular quaternization and quaternization/elimination of methyl bromide, using an appropriate alkyl bromide intermediate, led to the formation of the piroarsinolinium bromides (88) and (89) respectively, which were characterized as the iodides. In the case of (88), resolution into optical isomers was also achieved via the (-)-methoxyacetates to give the enantiomorphic iodides ([A/] 132° CHC13) <60JCS9>. 

Wittig reactions can also be performed with support-bound phosphorus ylides. Polystyrene-bound alkylphosphonium salts have been prepared from the corresponding alkyl mesylates or halides and trialkyl- or triarylphosphines (Figure 5.8 [60,80]). Because polystyrene is a hydrophobic support, salt formation does not proceed smoothly and quaternization of phosphines generally requires forcing conditions. The... 

Diphenyl-l,2,3-selenadiazole 138 and 3,5-diphenyl-l,2,4-selenadiazole 79 were alkylated with trimethylsilyl-methyl trifluoromethanesulfonate to give the salts 139 and 140 (Scheme 8) <2001J(P1)394>. Quaternizations occurred at N-3 and N-2, respectively. The structures and quaternization sites were confirmed by H, 13C, and 1SN NMR spectra and the subsequent reactions. The salts 139 and 140 were desilylated to generate transient selena-diazoliumylmethanide (ylide) intermediates. The transformation is described in Section 6.12.8. 

The preparation and characterization of the samples are described elsewhere [43]. The results are summarized in Tables 1 and 2. The number at the end of the sample code represents the contour length derived from the molar mass of the polymers. The PVP samples were quaternized with the respective alkyl and benzyl bromides in order to yield polypyridinium cations with... 

In order to improve cell and blood-brain-barrier permeability of the polar tetrahydropterins model studies were performed by applying the concepts of the Bodor system. 6-Mono- and 6,7-disubstituted 5,6,7,8-tetrahydropterins (172) have been acylated with nicotinoyl chloride at N-5 (173) followed by quaternization of the pyridine moiety by various alkyl and aralkyl halides (174), respectively (Scheme 27). Reduction of the pyridinium residue to its 1,4-dihydro stage afforded new types of potentially active conjugates (175) (Scheme 27) <90MI 718-07,91MI718-03). 

Thin layer chromatography and gas-liquid chromatography have been widely applied for the separation and for the identification of thiazoles in reaction mixtures. From systematic studies it appears that thiazole, alkyl- and aryl-thiazoles and benzothiazoles are best separated on stationary phase of low polarity in GLC and with eluents of low polarity in TLC. It has been possible to correlate, for these series of compounds, the RF of TLC or the specific volume of retention in GLC with the number of carbon atoms in the aliphatic side chain, and also with the rate constants of quaternization of the cyclic nitrogen atom. This last observation indicates a significant participation of the nitrogen atom in the chromatographic processes (67BSF846). 

Deady and Zoltewicz studied the influence of a larger set of substituents on the kinetics of quaternization of derivatives 20 and 21 including alkyl and functional groups R in position-2 and/or R-6 (72JOC603) (Scheme 15). As expected, the kinetic results are poorly correlated with pK values. Separate correlation lines were required for 2-substituted and 2,6-disubstituted pyridines. It was suggested that steric effects are superimposed on electronic effects, and that steric effects are nearly constant for ortho substituents like NH2, Me, Cl, Br, and CN, but are more important for Et, CH2Ph, 2-pyridyl, and C02Me. 

N-Oxidation can be formally considered a quaternization of a pyridine-type nitrogen atom by the HO+ cation, formed by heterolysis of OO bond in the peracid molecule. Indeed, common features exist between N-alkylation and... 

Imine formation in adenines is presumably a factor of some importance to reactivity towards electrophiles since in A -dialkylated derivatives where imine formation is not possible, further alkylation becomes more difficult. Thus 6-diethylamino-9-methylpurine required prolonged heating with methyl iodide to produce the quaternary salt (92) (65JOC3597) and similarly 6-dimethylamino-9-benzylpurine required 3 days boiling with benzyl bromide in acetonitrile to produce 3,9-dibenzyl-6-dimethylaminopurinium bromide (93) (66JOC2202). Under these circumstances it is clearly difficult to control the alkylation step and quaternization is the normal rule. 

Alkylation and arylation including quaternization are well explored, and acylation has also attracted much interest. The other classes of reactions to be considered here are addition reactions involving annular NH as the addend, A-halogenation and reactions involving metallic centres. 

Alkyl- and aryl-triazolium compounds are formed mostly by quaternization of preformed triazoles, more rarely by rearrangement of oxadiazoles proceeding through acylamidrazone intermediates. An unusual method (Scheme 136) is the addition of the alkoxydiazenium fluoroborate (312) to the Schiff base (313) to form the triazolium salt (314) through a mechanism that may involve a triazolidine intermediate (315) (69CB3176). 

The precursors of the macrocycles 745, that is the bis(iodoallyl)-TTFs 744, were prepared in a few steps from bis-protected TTF 742 via the sequence of cyanoethyl deprotection, alkylation of the resulting thiolates, the Finkelstein reaction, and quaternization of the 4,4 -bipyridyl with the iodides obtained (Scheme 110). Other singly and doubly tethered D-A systems 746-748 were synthesized in a similar way <1997JOC679, 2002CEJ4461>. 

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