2-Bromoacetophenone, reaction with amines

Recently Cosford and co-workers used a one-step continuous flow Hantzsch synthesis to prepare a series of A -substituted pyrrole-3-carboxylic acids as part of their ongoing efforts to develop efficient and high-yielding flow chemistry methods for multistep transformations. Reaction of /-butyl acetoacetate 32 and a-bromoacetophenone 34 with amines 33,36,38,40,42, and 44 using diisopropylethyl amine (DIPEA) and DMF at 200 "C in a continuous flow reactor gave the corresponding A-substituted pyrroles in modest yields (40-62%). The authors found the optimal reaetion conditions were 2.2 equiv of /-butyl acetoacetate, 1 equiv of amine and 0.5 equiv of DIPEA in a 0.5M solution of a-bromoacetophenone predissolved in DMF. In addition, the authors noted that the HBr produced as a byproduct of the reaction simultaneously hydrolyzed the ester to give the free acid. Several additional P-ketoesters and a-bromoketones were explored in their report with similar success. 

The synthesis of 1,3-selenazoles from A -phenylimidoyl isoselenocyanates has been reported. N-phenylimidoyl isoselenocyanates 94 are prepared from N-phenylbenzamides 92. Treatment of 92 with thionyl chloride affords N-phenylbenzimidoyl chlorides 93, which yield imidoyl isoselenocyanates 94 on reaction with potassium isoselenocyanate. The imidoyl isoselenocyanates 94 were transformed into selenoureas 95 with either ammonia or primary or secondary amines. Reaction of 95 with an activated bromomethylene compound such as bromoacetophenone in the prescence of a base gave the 1,3-selenazole 97 via the salt 96 <00HCA1576>. 

The solid-phase synthetic route for the preparation of thiazolo[4,5-6]pyridines uses appropriate 2-bromoacetophenones, ketones, and amines as key building blocks and diversity elements. The sequence began on the basis of successful solution-phase synthetic conditions. The known thiazole resin 16 with R diversity element was reacted under optimized Friedlander reaction conditions (AICI3 and MW irradiation) with ketones (R CHaCOR ). This process efficiently produced the thiazolo[4,5-6] pyridine resin 21 and introduced the second potential diversity elements R and R. Treatment of resin 21 with mCPBA in CH2CI2 provided the resin-bound sulfone intermediate 22 (Scheme 10.2). 

It was possible to effect lOOC reaction leading to six-membered rings, e.g., 220 in low yield (ca. 20%) by heating the reaction mixture at 110 °C (Eq. 22) [59]. In fact, Oppolzer and Keller [60] had previously reported the lOOC reaction of 219 to 220 in 20% yield by heating at 110 °C. Furthermore, the scope of these oxime-olefin cycloadditions has been extended to ketoximes, e.g., 221. The latter was prepared by amination of a-bromoacetophenone with allylamine 214a. Heating of 221 at 110 °C for 8 h led to cycloaddition with formation of the fused pyrrolidine 222 in 88% yield. As in Scheme 25, only one... 

The synthons of oxiranes have also been used in this respect. For example, the reaction of C02 with a-bromoacylophenones in the presence of aliphatic primary amines, in methanol, afforded 3-alkyl-4-hydroxyoxazolidin-2-one derivatives under mild conditions [83a]. However, neither oc-bromoacetophenone nor a-chloroacetophenone afforded any carbamate product, and no urethanes were obtained with aromatic or aliphatic secondary amines. The proposed mechanism involved, as the first step, the formation of a 3-alkyl-2-methoxy-2-phenyloxirane intermediate, which reacted with alkylammonium carbamate to give the oxazo-lidone product (Scheme 6.16). This synthetic protocol was successfully applied to the synthesis of bis(oxazolidin-2-one) derivatives by reactions of 2-methoxy-3,3-dimethyl-2-phenyloxirane or a-bromoisobutyrophenone with C02 and aliphatic a,G)-diamines [83b],... 

Reactions of such chloro compounds with ammonia also produce some secondary amines. Thus Gabriel (166) examined the reaction of co-bromoacetophenone... 

The reaction of4-bromoacetophenone with N-mefhylanilme in water using NaOH as the base and the aforementioned catalyst afforded the tertiary amine in 36% yield. By adding co-solvents, such as methanol, the yield can be increased to 91%. In conclusion, the advantages are the facile catalyst/product separation, the reusability of the water-soluble palladium catalyst, and the use of NaOH instead of the expensive NaOBu as the base. 

The Bischler-Mohlau indole synthesis, also known as the Bischler indole synthesis, is the formation of a 2-arylindole from an a-bromoacetophenone and excess aniline.Although not widely used in making indoles, one of the syntheses of fluvastatin sodium (Lescol) took advantage of the Bischler-Mohlau indole synthesis to assemble its indole core. As shown below, reaction of a-chloroketone with A-/-Pr-aniline at elevated temperature generated the tertiary amine. The resulting A-/-Pr-aniline underwent a ZnCb-mediated Bischler-Mohlau indole synthesis also at an elevated temperature to afford the indole core structure of fluvastatin. ... 

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