Synthesis of Benzamides

Jacoby (187) and the Hamilton group (188-191) suggested that bis- or tris-aromatic residues could serve as scaffolds for helical mimetics. Che et al. have examined a variety of aromatic-based scaffolds as potential helix mimetics (192). Rebek and coworkers have suggested a central pyridazine ring (193) as well as a heterocyclic piperazine-based scaffold (194). Ahn and Han developed a facile synthesis of benzamides as potential helix mimetics (195). 

Wang reported an example of a water soluble, ionic scavenger for the sequestration of excess acid chlorides in the synthesis of benzamides and sulfonamides [76]. 

The first palladium-catalyzed carbonylations of aryl halides were published in 1974 and 1975 (Equation 17.59). ° Heck first reported the synthesis of benzoates by the reaction of an aryl iodide, carbon monoxide, and an alcohol in the presence of a tertiary amine and catalytic amoimts of the combination of palladium acetate and triphenylphosphine. Concurrently, he reported the synthesis of benzamides from an aryl iodide, carbon monoxide, a primary amine, and a tertiary amine as base catalyzed by the same type of palladium complex. The related reactions of vinyl halides were also reported, and these reactions occurred with retention of the olefin geometry. ... 

Scheme 3.16 Synthesis of benzamides from benzylic primary alcohols...

Sharif M, Chen J, Langer P, Beller M, Wu X-F (2014) TBAl-catalyzed oxidative synthesis of benzamides from acetophenones and caibinols. Oig Biomol Chem 12(33) 6359-6362... 

Peng H-g XuL, Wu H, Zhang K, Wu P (2013) One-pot synthesis of benzamide over a robust tandem catalyst based on center radially fibrous silica encapsulated TS-1. Chem Common 49 (26) 2709-2711... 

ENANTIOSELECTIVE SYNTHESIS OF AXIALLY CHIRAL ANILIDES AND BEZAMIDES 277 9.5 Synthesis of Benzamides... 

The synthesis of a benzamide with a somewhat more complex side chain starts by condensation of acid 144 with racemic cis-aminopiperidine 152. Removal of the benzyl group of 153 by hydrogenolysis gives the secondary amine 154. Alkylation on nitrogen with the halide 155 gives finally the dopamine antagonist, cisapride (156) [38,39]. 

Poly(arylene thioether)s, 363-364 Poly(arylene thioether sulfone)s, 364 Poly(aryl sulfone) derivatives, 354 Poly(p-benzamide), synthesis of, 188-189 Polybenzimidazoles (PBIs), 265 ferrocene-containing, 315 synthesis of, 313... 

Fig. 13 Synthesis of oxazoles on JandaJel. Reagents and conditions a toluene, alkyl acetoacetate (R0(C0)CH2C0R R =t-Bu), reflux, 6h or alkyl acetoacetate (R = Me, Et), toluene, LiC104, reflux, 6h fc dodecylbenzenesulfonyl azide, EtsN, toluene, rt, 16 h c benzamide, Rh2(oct)4, toluene, 65 °C, Ih rf Burgess reagent, pyridine, chlorobenzene, MW 100 °C, 15 min (or 80 °C, 4 h with conventional heating) e AICI3, piperidine, CH2CI2, rt, 16 h...

Luke GP, Holt DA. Synthesis of (S)-5-(l-aminoethyl)-2-(cyclohexylmethoxy) benzamide. Tetrahedron Asymmetry 1999 10 4393-4403. 

The 1,4- addition of an ortho-] i th iated benzamide to 1-nitrocyclohexene has been used for synthesis of pancratistatin models (Eq. 4.75).95... 

V-bromo-benzamide is a useful method for the synthesis of the side chain of paclitaxel (taxol) from isopropyl cinnamate.219... 

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>. 

Scheme 1.1 Hydrolysis of benzamide. The first published example (1986) of microwave-assisted organic synthesis.

A simple two-step synthesis of 5H-alkyl-2-phenyloxazol-4-ones has been reported by Trost and coworkers (Scheme 6.209) [377]. a-Bromo acid halides were condensed with benzamide in the presence of pyridine base at 60 °C to form the corresponding imides. Microwave irradiation of the imide intermediates in N,N-dimethylacetamide (DMA) containing sodium fluoride at 180 °C for 10 min provided the desired 5H-alkyl-2-phenyloxazol-4-ones (oxalactims) in yields of 44—82%. This class of heterocycles served as excellent precursors for the asymmetric synthesis of a-hydroxycar-boxylic acid derivatives [377]. 

In other somewhat related work, the synthesis of pyrano[2,3-c]azepines (and pyrido[2,3-c]azepines has been described. Reaction of hydrazoic with iV-(5,6,7.8-tetrahydro-2,5-dioxo-2W-l-benzopyran-3-yl)benzamide (or 8-hydrazono) derivatives afforded pyrano[2,3-c]azepines, which in turn can be transformed to pyrido[2,3-c]azepines <00H(53)1111>. 

Polyazo dyes, 9 363—361 Polybenzamide, 15 109-110 Poly(p-benzamide) (PBA), 10 212 19 714 crystal lattice parameters of, 19 728t laboratory synthesis of, 19 719 Polybenzimidazole (PBI), asbestos substitute, 3 3141 Polybenzimidazole (PBI) fibers,... 

Further divergence from classical benzamide structure is represented by the synthesis of ondansetron (GRF 38032F, (33)), a potent 5-HT3 receptor antagonist where the basic nitrogen atom is part of an imidazole ring and the aromatic ring is part of tetrahydrocarbazolone ring system [27],... 

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). 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

The classical Harley-Mason cyclization was utilized en route to (—)-aspidospermidine 84. 9 The synthesis of 84 required 12 steps from the chiral benzamide 12 (X = SiMcs) and was carried out with an overall yield of 19%. 

Fully aromatic polyamides are synthesized by interfacial polycondensation of diamines and dicarboxylic acid dichlorides or by solution condensation at low temperature. For the synthesis of poly(p-benzamide)s the low-temperature polycondensation of 4-aminobenzoyl chloride hydrochloride is applicable in a mixture of N-methylpyrrolidone and calcium chloride as solvent. The rate of the reaction and molecular weight are influenced by many factors, like the purity of monomers and solvents, the mode of monomer addition, temperature, stirring velocity, and chain terminators. Also, the type and amount of the neutralization agents which react with the hydrochloric acid from the condensation reaction, play an important role. Suitable are, e.g., calcium hydroxide or calcium oxide. 

As a prelude to the use of olefination reactions to introduce the fluoroolefin amide isostere, the synthesis of fluoroolefin analogs of CGP 49823 is described where a nonpeptidic amide bond was replaced with a fluoroolefin [55]. Comparison of the binding affinities of these analogs for the NK1 receptor enabled determination of the active conformation of the amide containing compound CGP 49823. It was otherwise not easy to establish that the syn orientation of the aromatic ring of the benzamide towards the 2-benzyl substituent was the active conformation (Scheme 10). 

Mathias and Moore (30-33) described a new synthesis of isomiinchnones 55 via the thermal cyclization of A-(chloroacetyl)lactams (54) (Scheme 10.7). These isomiinchnones can be captured by NPM to give fused 2-pyridones in moderate yields. Cycloadducts from the reaction with DMAD are produced in much lower yields (<17%), and other olefinic dipolarophiles (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of 7/-(chloroacetyl)benzamide (57) in the presence of NPM gave 58 in low yield. 

However, racemization has been reported. For example, during the total synthesis of mycestericin, Node and co-workers reported that treatment of en-antiomerically pure fhreo-benzamide 11 with SOCI2 unexpectedly gave a 1 1 trans- and cis-mixture of oxazolines 13a and 13b. Consistent with this configurational assignment, further reaction with an electrophile would result in a racemic... 

A very popular route to piperid-4-ones is by a Dieckmann or Thorpe cyclization of appropriate diesters or dinitriles. In most cases the nitrogen atom is tertiary, to avoid the formation of amides as by-products. A simple example is provided by the synthesis of the piperidone ester (129) which, after hydrolysis and decarboxylation, gives the piperid-4-one (130) (45JOC277). The diesters are available by addition of amines to acrylates and so the two ester fragments can be different. For the production of AT-benzoylpiperid-4-one (132) the whole operation from benzamide and ethyl acrylate to the ester (131) can be achieved... 

As mentioned earlier, the synthesis of primary amides is rather challenging due to technical difficulty in handling gaseous ammonia. Thus, the use of ammonia substitutes such as HMDS and formamide has been studied (see Schemes 21 and 22). With the use of microwave irradiation, however, it has been shown that it is possible to generate both CO and ammonia at the same time for the synthesis of primary amides from aryl bromides. This protocol is very useful for laboratory organic syntheses, especially combinatorial syntheses. As Scheme 29 illustrates, the Pd-catalyzed aminocarbonylation of aryl bromides 200 with formamide (33.5 equiv.) in the presence of KOBu (1.5 equiv.) and imidazole (1 equiv.) with microwave irradiation for 400 s (6.7 min) gave the corresponding benzamides... 

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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