AROMATIC ALDEHYDE SYNTHESES

C ( propyl) N phenylmtrone to N phenylmaleimide, 46, 96 semicarbazide hydrochloride to ami noacetone hydiochlonde, 46,1 tetraphenylcyclopentadienone to diphenyl acetylene, 46, 44 Alcohols, synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47, 1 /3-chloro a,0 unsaturated, from ke tones and dimethylformamide-phosphorus oxy chloride, 46, 20 from alky 1 halides, 47, 97 from oxidation of alcohols with dimethyl sulfoxide, dicyclohexyl carbodumide, and pyndimum tnfluoroacetate, 47, 27 Alkylation, of 2 carbomethoxycyclo pentanone with benzyl chloride 45,7... 

Alcohols, conversion to alkyl halides with triphcnylphosphine-halogen adducts, 48, 53 synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47, 1... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

A retrosynthetic analysis of a,/J-unsaturated ketones leading to various methods of synthesis is outlined in Section 5.18.2, p. 798. These methods are equally applicable to aromatic aldehydes. Aromatic aldehydes condense with aliphatic or mixed alkyl aryl ketones in the presence of aqueous alkali to form a,[i-unsaturated ketones (the Claisen-Schmidt reaction). 

Brown and Subba Rao found that addition of lithium tri-/-butoxyaluminum hydride in diglyme to a solution of an acid chloride at —78° provides a convenient synthesis of aldehydes. Aromatic acid chlorides with m- or p-substituents form aldehydes in yields of 60-90%. Substituent nitro-, cyano-, and carboethoxy groups are not affected. o-Substituents tend to reduce the yield. Yields are 5-10% lower at —40° than at—78°. 

The classical Biginelli synthesis is a one-pot condensation using P-dicarbonyl compounds with aldehydes (aromatic and aliphatic ones) and urea or thiourea in ethanol solution containing catalytic amounts of acid. Peng et al. for the first time reported a novel method for the synthesis of dihydropyrimidinones by three-component Biginelli condensations of aldehydes with 1,3-dicarbonyl compounds and urea using room temperature ionic liquids based on [bmim][BF ] or [bmim][PFJ as catalyst under solvent-free and neutral conditions (Fig. 12.15) [11]. 

Another possibility is the partial oxidation of methane to oxygen-containing compounds (methanol, higher alcohols, aldehydes) or synthesis gas and dehydrogenative coupling to give aromatic compounds. 

SFs-anilines, aldehydes, and arylacetylenes (15EJ01415). This method was inspired by the Fe(III)-catalyzed aerobically oxidative synthesis of quinoHnes developed by Tu and coworkers (09CEJ6332). Both 3- and 4-SF5-anihnes (39 and 11), various aldehydes—aromatic, heterocyclic, formaldehyde, trifluoroacetaldehyde ethyl glyoxylate, and aromatic alkynes can serve as reaction components to provide access to a series of 2-aryl substituted 6(7)-SF5-quinolines 104a—s (Scheme 26). Flowever, cyclization products were not observed when aliphatic alkynes were used under the reported conditions. 

Other catalysts, such as ZrCl [16] and cellulose sulfuric acid (CSA) [17], have been also reported to activate the Ugi-3CR. In this context, Khan et al. have described the nse of bromodimethylsulfonium bromide (9) (BDMS) as catalyst for the synthesis of a-amino amidines 10 by the reaction of aromatic aldehydes, aromatic amines, and isocyanides (Scheme 7.4) [18]. 

Synthesis of a-aminophosphonates. In 2012, Dar et reported a catalyst- and solvent-free rapid synthetie protocol for a-aminophosphonates at room temperature from the one-pot three-component condensation of aromatic aldehydes, aromatic amines, and triethyl-phosphite at room temperature under the influence of ultrasound irradiation with good to excellent yields and high selectivity (Scheme 35). 

Piperazinedione condenses easily with benzaldehyde in the presence of acetic anhydride/sodium acetate to yield 3,6-dibenzylidene-2,5-piperazinedione (343, 344). Analogous preparations have been conducted with heterocyclic and unsaturated aliphatic aldehydes (19), but not with saturated aliphatic aldehydes. The synthesis of alkylidenepiperazine-diones can be realized by condensation of N,N -diacetylpiperazine-diones with aliphatic aldehydes in the presence of potassium t-butoxide (138, 140), conditions also applicable to the synthesis of monoarylidene-piperazinediones. A second condensation is however only possible with aromatic aldehydes. 

Quinoline derivatives may be synthesised by heating aii aromatic amine with an aldehyde or a mixture of aldehydes in the presence of concentrated hydrochloric or sulphuric acid this synthesis is known as the Doebner - Miller reaction. Thus aniline and paraldehyde afford 2-methylquinohne or quinaldine. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

In a more elaborate and specific synthesis, the terpenoid indole skeleton found in haplaindole G, which is isolated from a blue-green alga, was constructed by addition of a nucleophilic formyl equivalent to enone 6.5A. Cyelization and aromatization to the indole 6.6B followed Hg -catalysed unmasking of the aldehyde group[6]. 

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

Aldehyde Synthesis. Formylation would be expected to take place when formyl chloride or formic anhydride reacts with an aromatic compound ia the presence of aluminum chloride or other Friedel-Crafts catalysts. However, the acid chloride and anhydride of formic acid are both too unstable to be of preparative iaterest. 

The Gattermann-Koch synthesis is suitable for the preparation of simple aromatic aldehydes from ben2ene and its substituted derivatives, as well as from polycychc aromatics. The para isomers are produced preferentially. Aromatics with meta-directing substituents cannot be formylated (108). 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

Aliphatic Aldehyde Syntheses. Friedel-Crafts-type aUphatic aldehyde syntheses are considerably rarer than those of aromatic aldehydes. However, the hydroformylation reaction of olefins (185) and the related oxo synthesis are effected by strong acid catalysts, eg, tetracarbonylhydrocobalt, HCo(CO)4 (see Oxo process). 

Synthesis and Properties. Polyquinolines are formed by the step-growth polymerization of o-aminophenyl (aryl) ketone monomers and ketone monomers with alpha hydrogens (mosdy acetophenone derivatives). Both AA—BB and AB-type polyquinolines are known as well as a number of copolymers. Polyquinolines have often been prepared by the Friedlander reaction (88), which involves either an acid- or a base-catalyzed condensation of an (9-amino aromatic aldehyde or ketone with a ketomethylene compound, producing quinoline. Surveys of monomers and their syntheses and properties have beenpubhshed (89—91). 

Aldehydes, Ketones, ndAcids. As with many aromatic compouads, the oxidatioa of methyl groups is an attractive synthetic route to both aldehydes and carboxyUc acids ia the quiaoliaes. The hydrolysis of dibromomethyl groups has also beea used for aldehydes and the hydrolysis of nitriles for carboxyhc acids. Detailed reviews of the synthesis of these compounds have appeared (4). 

A variation involves the reaction of benzylamines with glyoxal hemiacetal (168). Cyclization of the intermediate (35) with sulfuric acid produces the same isoquinoline as that obtained from the Schiff base derived from an aromatic aldehyde and aminoacetal. This method has proved especially useful for the synthesis of 1-substituted isoquinolines. 

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