Acetophenone: acylation reduction

A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27 the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 5J. 

Ruoho and Rong have descnbed a shorter route to salmeterol (Scheme 4). Friedel-Crafts acylation of salicylaldehyde (16) with bromoacetyl bromide in the presence of aluminum chloride gave the acetophenone 17. Alkylation of amine 18 with bromoacetyl 17 in refluxing acetonitrile gave the ketone 19. Reduction of 19 with sodium borohydride in methanol followed by catalytic hydrogenolysis of the benzyl group over 10% Pd/C gave salmeterol (2). 

Recalling that arylamines are normally prepared by reduction of nitroarenes, we see that ethyl m-nitrophenyl ketone is a pivotal synthetic intermediate. It is prepared by nitration of ethyl phenyl ketone, which is analogous to nitration of acetophenone, shown in Section 12.16. The preparation of ethyl phenyl ketone by Friedel-Crafts acylation of benzene is shown in Section 12.7. 

For a preparation of alkaloids 35 configurated beyond all doubt, synthetic pathways from the ehiral pool were also elaborated (71). The C3N unit destined to represent the crucial chiral center at C-3 turned out to be the amino acid alanine, in its natural L-form 118, which should easily be incorporated into the isoquinoline framework by reductive amination with the acetophenone 119 and subsequent intramolecular acylation, as outlined in Scheme 29. The practical realization of such a non-biomimetic synthesis (see Scheme 30), however, differs from this very simple concept in three ways ... 

Reductions. In contrast to hydrosilylation reactions catalyzed by metal chlorides, aldehydes and ketones are rapidly reduced at rt by Triethylsilane and BF3-OEt2, primarily to symmetrical ethers and borate esters, respectively. Aryl ketones like acetophenone and benzophenone are converted to ethylbenzene and diphenyl-methane, respectively. Friedel-Crafts acylation-silane reduction reactions can also occur in one step using these reagents thus Benzoyl Chloride reacts with benzene, triethylsilane, and BF3-OEt2 to give diphenyhnethane in 30% yield. ... 

Acetophenone is readily available (and if it were not, it s simple to make by a Friedel-Crafts acylation reaction), and it is readily nitrated to weta-nitroacetophenone. For the reduction of the ketone to a hydrocarbon. I ve chosen a new reaction, the Wolff-Kishner reduction, which we... 

---