Benzamide preparation

Place 45 g (0.37 mol) of benzamide (prepared from benzoyl chloride, cf. Expt 5.154) and 80 g (0.56 mol) of phosphorus pentoxide in a 250-ml round-bottomed flask (for exact experimental details on the handling and weighing out of phosphoric oxide, see isobutyronitrile, Expt 5.160). Mix well. Fit the flask with a Claisen distillation head (Fig. 2.13(c)) and distil under reduced pressure using a water pump with an air leak in the system so that a pressure of about 100 mmHg is attained. Heat the flask with a free flame until no more liquid distils the nitrile will pass over at 126-130 °C/100 mmHg. Wash the distillate with a little sodium carbonate solution, then with water, and dry over anhydrous calcium chloride or magnesium sulphate. Distil under normal pressure from a 50-ml flask the benzonitrile passes over as a colourless liquid at 188-189 °C. The yield is 28 g (74%). The i.r. spectrum of benzonitrile is shown in Fig. 3.39. 

Fig. 5. Examples of substituted benzamides prepared by 3-fold sequential nucleophilic substitution on an insoluble support.

Prepared by the dehydration of benzamide. Hydrolysed by dilute acids and alkalis to benzoic acid. Good solvent. benzopheDone,C]3HioO,PhC(0)Ph. Colourless rhombic prisms, m.p. 49 C, b.p. 306°C. Characteristic smell. It is prepared by the action of benzoyl chloride upon benzene in the presence of aluminium chloride (Friedel-Crafts reaction) or by the oxidation of di-phenylmethane. It is much used in perfumery. Forms a kelyl with sodium. 

Prepared by stirring phthalimide with cold concentrated ammonia solution. Hydrolysed to phlhalic acid with dilute acids. Dehydration with ethanoic anhydride gives first n-cyano-benzamide and then phthalonitrile. 

Carry out this preparation in precisely the same way as the above preparation of oxamide, using 2 ml. (2-4 g.) of benzoyl chloride instead of the ethyl oxalate, and observing the same precautions. Considerably more heat is generated in this reaction therefore hold the cork very securely in position during the shaking. After vigorous shaking for 15 minutes, no trace of oily benzoyl chloride remains. Filter off the fine flakes of benzamide, wash with cold water, and then recrystallise from hot water yield, 1-5 g. Colourless crystals, m.p. 130°. 

Aromatic thioamides can be prepared as described in the literature by different ways, either by S -> O exchange between the corresponding benzamides and phosphorus pentasulfide in pyridine solution in the presence of triethylamine (65, 646) as strong base, or by action of H2S on the appropriate nitrile with pyridine and triethylamine solvents using the method of Fairfull et al. (34, 374, 503). In this reaction, thioacetamide in acidic medium can also be used as a H2S generator with dimethylform-amide as the solvent (485). 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

Glorius and colleagues [304] described a useful Cu -catalyzed preparation of 2-phenyl benzoxazoles 6/4-97 and related compounds from 1,2-dihaloaromatic substrates 6/4-95 and benzamide 6/4-96 (Scheme 6/4.23). 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

The intermolecular ruthenium enyne Alder-ene reaction has been extended to the stereoselective preparation of enamines (Equation (26)).39 The yields obtained for this reaction were high with allylacetamides, -benzamides,... 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Whether the dianion of azohenzene is able to deprotonate MeCN (pK 31.3) has been discussed [62, 64, 68]. However, on a preparative scale generation of CH2CN takes place at the potential of the second reduction of azohenzene, and reactions initiated by cyanomethylation of benzamide [108], carbonyl compounds (or their Schiff bases) or Q , 8-unsaturated nitriles either present in situ [69, 109] or added subsequently [110-112] have been studied. A mixture of products is normally obtained. 

An arylamidine found subsequently to have anti-arrythmic activity was actually synthesized in the hope of producing a hypoglycemic agent. Iminochloride 198 is prepared from the corresponding benzamide and the chlorine i displaced with n-amylpiperidine to... 

A series of benzamides as replacement for the zinc-binding hydrox-amic acid was also synthesized and investigated for HDAC inhibitory activity [62,63]. A clear SAR could be derived from the examples prepared (Fig. 10). 

A convenient route to 2-alkylthio-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives 176 is the reaction of A-alkyldithiocarbamates with a,/3-unsaturated ketones in the presence of boron trifluoride etherate at 0°C (Scheme 15) <2002HAC377>. The predominant diastereomer displayed a m-relationship between the hydroxyl group and the C-4 substituent. Subsequent dehydration led to two isomeric products 177 and 178 with an equilibrium mixture resulting in a ratio of 94 6 in the case of 2-benzylthio-4-hydroxy-4-methyl-5,6-dihydro-4/7-l,3-thiazine. 2-Phenyl-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives are similarly prepared by reacting thio-benzamide with o ,/3-unsaturated ketones at room temperature <2002EJP307>. 

Base-catalyzed cyclization of A -benzoyl-a-chloroacetamide is a classical method used to prepare 2-phenyl-4(5//)-oxazolone. Extension of this methodology to the A -aroylcinnamides 35 afforded a series of 5-arylidene analogues 37 albeit in unstated yield (Scheme 6.12). " Thus, acylation of the sodium salt of a benzamide with a cinnamoyl chloride gave the imides 35 that were converted to 36 via a bromination-dehydrobromination sequence. Cyclization to 37 was affected with sodium hydride in 1,2-dimethoxyethane (DME). The authors noted that catalytic reduction of 37 afforded the 5-(arylidene)oxazolidine from which 37 could be regenerated in the presence of air. 

Decarboxylation. Under certain experimental conditions dehydroamino acid derivatives can decarboxylate to produce unsaturated benzamides. In particular, N- [2-(p-hydroxyphenyl)ethyl] -p-chlorobenzamide " and A -( )-(4-methoxystyryl)-benzamide (alatamide) ° have been prepared in this manner. 

As reported, by polycondensation of dicarboxylic acids with diamines or by polycondensation of aminoacids in the presence of polyvinylpyrrolidone, polymers with very high molecular weight were obtained. The viscosities of poly(terephthalamides) prepared by template polymerization in the presence of polyvinylpyrrolidone from p-phenylenediamine and 4,4 -diaminodiphenylosulfone and of poly(m-benzamid) are very high. Also, polypeptides with molecular weight of 20-30 thousands were obtained by template polymerization in the presence of polyvinylpyrrolidone ... 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

Benzothiazepines of type (401) can be prepared by the Bischler-Napieralsky cycliz-ation of N- (arylthioethyl)benzamides and reactions of the same type have been used in the synthesis of dibenzo[6,/][ 1,4]thiazepines (70JHC409). 

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