Acid chlorides ketone synthesis

A reaction that does work with simple diazoalkanes is the acylation with acid chlorides. This synthesis of diazo ketones was found by Staudinger et al. (1916 b), but its broad applicability and the optimization of the reaction conditions is mainly due to the work of Arndt and Eistert (Arndt et al., 1927 Arndt and Amende, 1928). Eistert proposed mechanism 9-6 for this reaction in 1935 and it was corroborated later in many respects. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The alkynyl ketones 840 can be prepared by the reaction of acyi chlorides with terminal alkynes, Cul in the presence of Et3N is the cocatalyst[719]. (1-Alkynyl)tributylstannanes are also used for the alkynyl ketone synthesis[720]. The a,. 3-alkynic dithio and thiono esters 842 can be prepared by the reaction of the corresponding acid chloride 841 with terminal alkynes[721,722]. 

Ketone Synthesis. In the Friedel-Crafts ketone synthesis, an acyl group is iatroduced iato the aromatic nucleus by an acylating agent such as an acyl haUde, acid anhydride, ester, or the acid itself. Ketenes, amides, and nittiles also may be used aluminum chloride and boron ttitiuotide are the most common catalysts (see Ketones). 

For use of other organocopper reagents in converting carboxylic acid chlorides to ketones, see G. H. Posner and C. E. Whitten, Tetrahedron Lett., 1815 (1973) G. H. Posner, C. E. Whitten, and P. E. McFarland, J. Amer. Chem. Soc., 94, 5106 (1972). For a recent report on direct and convenient preparation of lithium phenylthio (alkyl)-cuprate reagents, see G H Posner, D J Brunelle, and L. Sinoway, Synthesis, 662 (1974). 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

Buron et al, published the synthesis of botryllazine derivatives containing a pyrazine core [84]. Scheme 42 describes the synthesis of these compounds. Chloropyrazine 160 was employed as the starting material for the synthesis of the pyrazine chalcone analog 161. 2-Chloro-3-tributylstannylpyrazine 162 was the key intermediate and was coupled with acid chloride 163 to produce the ketone 164. Following protection and subsequent reaction with 165, pyrazine 166 was generated. Oxidation, deprotection, and demetallation produced the pyrazine of interest 161. 

The preparation of acetylenic ketones from soluble silver acetylenides and acid chlorides was reported in 1956 (Scheme 108).512 Analogously to that report, the reaction of silver acetylenides with acylpyridinium salts was reported to proceed effectively.513 This chemistry was applied to the synthesis of cotarnine derivatives, as exemplified in Scheme lQ9.514 514a... 

Methyl isovalerate, azeotropic mixtures with butyl alcohols, 4 395t Methyl ketones, acetic anhydride used in synthesis, 1 148 Methyllithium, 14 249 15 147 Methylmagnesium chloride, 16 319 (R)-(—)-Methylmandelic acid chloride, chiral derivatizing reagent, 6 76t Methyl mercaptan production, 15 17 3-Methylmercaptopropionaldehyde (MMP), intermediate in methionine synthesis, 1 268, 269, 276... 

The intramolecular ketone synthesis from the chloride of hydro-cinnamic acid ... 

Oxidation is the first step for producing molecules with a very wide range of functional groups because oxygenated compounds are precursors to many other products. For example, alcohols may be converted to ethers, esters, alkenes, and, via nucleophilic substitution, to halogenated or amine products. Ketones and aldehydes may be used in condensation reactions to form new C-C double bonds, epoxides may be ring opened to form diols and polymers, and, finally, carboxylic acids are routinely converted to esters, amides, acid chlorides and acid anhydrides. Oxidation reactions are some of the largest scale industrial processes in synthetic chemistry, and the production of alcohols, ketones, aldehydes, epoxides and carboxylic acids is performed on a mammoth scale. For example, world production of ethylene oxide is estimated at 58 million tonnes, 2 million tonnes of adipic acid are made, mainly as a precursor in the synthesis of nylons, and 8 million tonnes of terephthalic acid are produced each year, mainly for the production of polyethylene terephthalate) [1]. 

The reactions of dimethyl phenylphosphonite with acid chlorides, a-halogeno-ketones, and iV-(bromomethyl)phthalimide have been used to prepare acyl phos-phinates, /3-keto-alkylphosphinates, and phthalimidomethylphosphinates as intermediates in the synthesis of a-diazophosphinic esters.39 a-Amino-phosphonates have also been prepared by the addition of secondary phosphites to nitriles40 and to isocyanides.41... 

The reaction between zinc-copper reagents and acid chlorides is very general and provides a useful synthesis of ketones [7, 34, 41, 42], This acylation has also been used to prepare various indoles substituted in position 2 (Scheme 2.42) [88],... 

Arndt, F. Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. Fritz Arndt (1885—1969) was bom in Hamburg, Germany. He discovered the Arndt—Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902-1978), bom in Ohlau, Silesia, was Arndt s Ph.D. student. Eistert later joined I. G. Earbenindustrie, which became BASE after the Allies broke the conglomerate up after WWII. 

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