Heterocyclic benzamides

The normal reagent used in the von Braun reaction [e.g. 1320b] with heterocyclic benzamides is PBr ... 

A dimerisation reaction of N-methylanabasine (17) has been reported and a modification of the useful dealkylation reaction for tertiary amines has been used in a partial degradation (17) -> (18). The harsh conditions necessary for the von Braun reaction of heterocyclic benzamides with phosphorous penta-bromide has generally precluded its application to structural determination. It has now been found that carbonyl bromide is a useful reagent for this reaction... 

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]. 

Benzamides e.g. MS-275 8 are one of the more common hydroxamic acid alternatives but are often less potent. Recent exceptions to this pattern include substituted pyridyl [29] and thiazolyl [30] benzamides, such as 9 and 10 with HDAC1 enzyme IC50s of 19nM and 29 nM, respectively and series of benzamides substituted with other heterocycles, such as indazoles [31] and benzo [l,2,4]thiadiazines [32], many with HDAC2 IC50s of <50 nM. The addition of... 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

Benzamides are heterocyclic neuroleptics. These include the gastroenterologic agents metoclopramide and cisapride, which have antiserotonergic as well as anti-D2 receptor dopaminergic actions and also the antipsychotic agents sulpiride and tiapride. Tachyarrhythmias have resulted in the withdrawal of cisapride from general use. 

A one-step construction of both of heterocyclic rings of the title compounds (415 and 416) was accomplished when anthranilamides reacted with 5-oxoalkanoic acids (68JOC2402 69USP3441566 75USP3883524) or when anthranilic acids reacted with l-cyano-4-haloalkanes (79KGS1427), respectively. Cyclization of 2-(2-carboxyethylamino)benzamide (417) with ethyl chloroformylacetate gave 4-ethoxycarbonyl-I,2-dihydropyrido[I,2-a]quinazoline-3,6-dione (419) (83CPB2234). 

The use of transition-metal arene complexes to facilitate nucleophilic aromatic substitution features in a route to derivatives of thiosalicylic acid and hence to thioxanthone. The cyclopentadienyl iron complex of 2-chlorobenzoic acid is converted into the benzamide prior to displacement of the chloride by thiophenoxide. Photolytic decom-plexation followed by directed remote metallation of the diaryl sulfide yielded the heterocycle (Scheme 207) <2000SL975>. 

BTIB can be utilized in conjunction with trifluoroacetic acid(TFA) for interrupted Pummerer reactions leading to heterocyclic products. This is illustrated in Scheme 27 with BTIB-induced conversions of the benzylsulfanylalkenamides and -benzamides 89 and 91 to the isothiazolones 90 and 92 via N-S bond formation (01MI3, 01H1231). Similar treatment of the l-(2-alkylthiophenyl)pyrroles 93 affords the pyrrolo[2,l-Z>]benzothiazoles 94, in this case by C-S bond formation (Scheme 28) (99H1437). 

Heterocycles. This thallation-olefination sequence is widely applicable to synthesis of oxygen and nitrogen heterocycles. Thus it is applicable to tolylacctic acids, benzamides, and acetanilides. 

Snieckus, V. Heterocycles via ortho-lithiated benzamides. Heterocycles 980, 14,1649-1676. 

Snieckus, V. New directions in heterocyclic synthesis using metalated benzamides. Lect. Heterocycl. Chem. 1984, 7, 95-106. 

Directed metalation. orf/io-Metalation of benzamides has been used for a one-pol route to polycyclic anthraquinones and heterocyclic benzoquinones.1 Example ... 

Benzisothiazole-3(2 H)-ones.1 A novel route to these heterocycles involves cyclization of 2-(methylsulfinyl)benzamides with thionyl chloride (equation I). 

An elegant safety-catch linker fhat is activated by derivatization of a benzamide with a Boc group has been reported. The compounds can then be released by various nucleophiles, which, in turn, lead to different heterocyclic systems [195]. This linker was developed in connection with an Ugi four-component condensation, for which the starting isonitrile was formed directly on the sohd support 174 (Scheme 80). 

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). 

Pyridine iV-benzoylimine decomposes at, 180°-200° to pyridine and phenyl isocyanate [Eq. (18)].73-128 Similarly quinoline and isoquinoline N-benzoylimines yield the heterocyclic base together with benzanilide, diphenylurea, and benzamide.1281,2,4-Triazole N-acylimines also decompose on heating but do not yield isocyanates.147... 

Heterocyclization. Participation of an imino group to form five-membered -eterocyclic products or intermediates thereof is observed during PhSeBr-induced jnctionalization of alkenes. Likewise, the cyclofunctionalization of allylic benzimi-lates and benzamides can be achieved. ... 

Hence the heterocycle can be used for the conversion of phenols into the corresponding primary arylamines [164], i.e. Ar-OH —> Ar-NH2. The chloroquinazoline 30 is obtained from anthranilic acid and benzamide ... 

Following this activity, we set out to prepare a series of heterocyclic derivatives of the benzamide to explore a range of physical properties including the pyridine, pyrimidine, and pyrazoles of formula D4-D8. Based on the emerging structure-activity trends, we also examined phenyl pyrazoles of formula D9-D10 (Figure 3). 

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