Bemthsen reaction

It was later determined that acridine and proflavine are potent DNA intercalators. The ability to intercalate DNA has been proposed as a basis for the carcinogenicity seen with several acridine analogues. In the early 20th century, acridines played a major role in the understanding of how small molecules interact in biological systems. The Bemthsen reaction was one of the work horse reactions necessary to generate those acridines. 

Although investigations into the reaction mechanism are limited it is believed to proceed through an acylation ortho to the aniline followed by acid catalyzed cyclization and dehydration of the resulting ketone. The observation of 4 and 4 acyldiphenyl amine side products in many Bemthsen reactions support this mechanism. 

A more recent article used the Bemthsen reaction to generate a potent but not selective DYRK2 kinase inhibitor 19. It is interesting that the authors chose to use InCla as the Lewis acid in this sequence. They also took... 

Several groups have used the Bemthsen reaction to access acridines tethered to other molecues to take advantage of photo-physical, electron-transfer or DNA intercalating propensity... 

Acridines have continued to be of interest but the Bemthsen reaction has generally been replaced by a stepwise cyclization using transition metal catalyzed amination of aryl ketones or acids followed by acid catalyzed cyclization to form the acridine ring system. ... 

Seijas et al. [115] suggested microwave-assisted synthesis of Bemthsen reaction in the presence of Lewis acid catalyst ZnCl2 with shortened reaction time and increased yield (Scheme 11.57). The yield was 57-98% within 2.5-11 min. R was taken as alkyl or aiyl group. 

The Bemthsen reaction is an example of a type C ring closure. A short summary on the characteristic features of the Bemthsen reaction and recent applications have appeared recently (201IMI). The classical Bemthsen... 

A modification of the Bemthsen reaction uses polyphosphoric acid instead of zinc chloride however, the conditions are also quite vigorous with respect to the temperature (200 °C 15 min) in addition, the yields of 9-substituted acridines were low (1962JOC2658). In 2002, two synthetic procedures have been published, which use microwave conditions and zinc chloride as catalyst to prepare 125 from 124 (2002SC729 2002MI390 Scheme 44). Reaction conditions for the synthesis of 9-substituted acridines have been optimized for microwave conditions in the presence of 2,2-dime-thoxypropane as water scavenger very recendy (2014H(89) 1877). 

Various other potential catalysts of the Bemthsen reaction have been tested imder thermal as well as microwave conditions, among those are basic AI2O3 and ceric ammonium nitrate (CAN). Best results were achieved with p-toluenesulfonic acid under microwave conditions. Scheme 45. Other potential catalysts such as zirconium oxychloride octahydrate, potassium dichromate, or alumium chloride failed (2011MI131). 

Diarylamines will also usually require strong acylating agents to undergo acylation. If Lewis acids such as ZnCl2 are used as catalysts the formation of an acridine can compete with N-acylation (Bemthsen acridine synthesis last reaction, Scheme 7.10). 

Baker-Venkataraman rearrangement 338 Balaban synthesis (pyrylium ion) 302 Bamberger-Hughes-Ingold rearrangement 350 Barton-Zard synthesis (pyrrole) 120 Batcho-Leimgruber synthesis (indole) 136 Baylis-Hillman reaction 452 Beirut reaction 254, 500 Bemthsen synthesis... 

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