Quaternary synthesis

The cyclization to form very congested quaternary carbon centers involving the intramolecular insertion of di-, tri-, and tetrasubstituted alkenes is particularly useful for natural products synthesis[l36-138], In the total synthesis of gelsemine, the cyclization of 166 has been carried out, in which very severe steric hindrance is e.xpected. Interestingly, one stereoisomer 167... 

Recently, a new synthesis of 2-aminothiazo es has been proposed it involves the reaction between quaternary salts of 2-aikylthiothiazo es and the appropriate amine (1566). 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

In 1923, Mills introduced thiazole for the first time in the synthesis of methine dyes through a somewhat indirect route. In order to demonstrate the 2,4 -cyanine mechanism of formation by quinoline and quinaldine quaternary salts reacting together, Mills used other pairs of quaternary salts as 2-methylthiazolium with either quinolinium or benzothiazolium (42, 43). 

The first reported synthesis of acrylonitrile [107-13-1] (qv) and polyacrylonitrile [25014-41-9] (PAN) was in 1894. The polymer received Htde attention for a number of years, until shortly before World War II, because there were no known solvents and the polymer decomposes before reaching its melting point. The first breakthrough in developing solvents for PAN occurred at I. G. Farbenindustrie where fibers made from the polymer were dissolved in aqueous solutions of quaternary ammonium compounds, such as ben2ylpyridinium chloride, or of metal salts, such as lithium bromide, sodium thiocyanate, and aluminum perchlorate. Early interest in acrylonitrile polymers (qv), however, was based primarily on its use in synthetic mbber (see Elastomers, synthetic). 

Strong Base Anion Exchangers. As ia the synthesis of weak base anion exchangers, strong base resias are manufactured from styrenic as well as acryhc copolymers. Those based on copolymers of styrene and divinylben2ene are chloromethylated and then aminated. These reactions are the same as for the styrenic weakbase resias. The esseatial differeace is the amine used for amination. Trimethyl amine [75-50-3] N(CH2)3, and /V, /V- dim ethyl eth a n ol amine [108-01 -0] (CH2)2NCH2CH20H, are most commonly used. Both form quaternary ammonium functional groups similar to (8). 

Synthesis and Manufacture of Amines. The chemical and busiaess segments of amines (qv) and quaternaries are so closely linked that it is difficult to consider these separately. The majority of commercially produced amines origiaate from three amine raw materials natural fats and oils, a-olefins, and fatty alcohols. Most large commercial manufacturers of quaternary ammonium compounds are fully back-iategrated to at least one of these three sources of amines. The amines are then used to produce a wide array of commercially available quaternary ammonium compounds. Some iadividual quaternary ammonium compounds can be produced by more than one synthetic route. 

Pha.se-Tra.nsfer Ca.ta.lysts, Many quaternaries have been used as phase-transfer catalysts. A phase-transfer catalyst (PTC) increases the rate of reaction between reactants in different solvent phases. Usually, water is one phase and a water-iminiscible organic solvent is the other. An extensive amount has been pubHshed on the subject of phase-transfer catalysts (233). Both the industrial appHcations in commercial manufacturing processes (243) and their synthesis (244) have been reviewed. Common quaternaries employed as phase-transfer agents include benzyltriethylammonium chloride [56-37-17, tetrabutylammonium bromide [1643-19-2] tributylmethylammonium chloride [56375-79-2] and hexadecylpyridinium chloride [123-03-5]. 

Quaternary ammonium alkyl ethers are prepared similarly an alkaline starch is reacted with a quaternary ammonium salt containing a 3-chloto-2-hydtoxyptopyl or 2,3-epoxyptopyl radical. Alternatively, such derivatives can be prepared by simple quaternization of tertiary aminoalkyl ethers by reaction with methyl iodide. Sulfonium (107) and phosphonium (108) starch salts have also been prepared and investigated. Further work has explained the synthesis of diethyl aminoethyl starch (109) as well as the production of cationic starches from the reaction of alkaline starch with... 

Synthesis of P-Methylheptenone from Petrochemical Sources. p-MethyUieptenone (1) is an important intermediate in the total synthesis of terpenes. Continuous hydrochlorination of isoprene [78-79-5] produces prenyl chloride [505-60-6] which then reacts with acetone with a quaternary ammonium catalyst and sodium hydroxide to give P-methyUieptenone (6-methyIhept-5-en-2-one [110-93-0]) (eq. 1) (16—19). 

Quaternary bismuth compounds have not found extensive use ia industry or ia organic synthesis. In manifold studies of organobismuth(V) compounds as oxidi2ing and arylating agents, such quaternary bismuth compounds as (CgH )4Bi02CCH2, (CgH )4Bi02SCgH4CH2-4, and... 

Electrolyte. The ideal electrolyte, ie, the fluid part of the cell, for organic synthesis would give high solubiHty to the organic, possess good conductivity, have low cost, contain easy recovery and purification, and be noncorrosive. Quaternary ammonium salts provide many of the above criteria ia aqueous systems. A coacise compilation of solveats and salts used ia electroorganic chemistry is available (40). 

Pyrazole, C-formyl-conformation, 5, 209 Pyrazole, fluoro-reactions, 5, 263, 267 Pyrazole, 4-fluoro-5-hydroxy-tautomerism, 5, 214 Pyrazole, 1-germyl-synthesis, 5, 236 Pyrazole, halo-halogenation by, 5, 54 reactions, 5, 104, 105, 266 reduction, S, 105, 106, 266 Pyrazole, 3-halo-1-phenyl-quaternary salts... 

Quaternary ammonium compounds biocidal activity mechanism, 1, 401 toxicity, 1, 124 Quaternization heterocyclic compounds reviews, 1, 73 ( )-Quebrach amine synthesis, 1, 490 Queen substance synthesis, 1, 439 4, 777 Quercetin occurrence, 3, 878 pentamethyl ether photolysis, 3, 696 photooxidation, 3, 695 Quercetrin hydrolysis, 3, 878 Quinacetol sulfate as fungicide, 2, 514 Quinacridone, 2,9-dimethyl-, 1, 336 Quinacridone pigments, 1, 335-336 Quinacrine... 

A relative of the latter class of compounds are the macrotricyclic quaternary ammonium salts which have been reported by Schmidtchen. The bridges may contain either methylenes or ethyleneoxy units and the nitrogens are quaternarized. The underlying principle is to provide a cavity suitable for solvating or at least trapping anions. Schmidtchen presents evidence which suggests the formation of halide inclusion complexes. The synthesis of these molecules is accomplished along more or less traditional lines Such a species is illustrated above as compound 19. 

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

Roylance showed that pilocarpidine on -methylation yielded two products, pilocarpine and neopilocarpine (see below), thus confirming Hamack s suggestion that pilocarpidine is the imino-base corresponding to pilocarpine, Spath and Kunz showed that pilocarpidine, on treatment with alcoholic sodium ethoxide, is converted into isopilocarpidine (nitrate, m.p. 109-111°), which, on quaternary methylation, yields isopilocarpine metho-salts (methopicrate, m.p. 119-120°). The confirmation of these observations by the synthesis of pilocarpidine and isopilocarpidine and their conversion into pilocarpine and isopilocarpine has been described already. 

Quaternary salts of the substances represented by tliese formulae have been prepared by Kogl, Veldstra and van der Laan as well as of the next lower homologues, the substituted butyraldehydes, and the methyl ethers of both series. Their pharmacological activities were negligible in comparison with that of muscarine, but as six stereoisomeric forms may be produced in each synthesis, the inactivity may be due to stereoisomerism, just as in the case of threonine (a-amino-)3-hydroxy-butyric acid) where West and Carter found that only the d —) form is... 

The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

Partial hydrogenation of the quaternary pyridinium salts in the presence of triethylamine on palladium in methanol has been used for the synthesis of a large number of alkaloids. The tetrahydropyridine derivatives thus formed undergo various cyclization reactions in acidic media (89). 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

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