A-Arylamino-ketone

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Treatment of 2-benzylideneamino-l-phenylvinyl benzoate (47) with sodium methoxide produced one major product which was assigned as 2,5-dibenzoyI-3,6-diphenyl-1,4-dihydropyrazine (48) (1585). Dimerization of a series of a-arylamino ketones (49) in toluene with p-toluenesulfonic acid gave the symmetrical 1,4-diaryl-1,4-dihydropyrazine (50), not the corresponding l,4-diaryl-l,4-dihydropyrazines (51) or l-aryl-l,2-dihydropyrazines (52). Thus w-(4-chloroanilino)acetophenone gave 1,4-bis(p-chlorophenyl)-2,6-diphenyl-1,4-dihydropyrazine (1546). 

An a-arylamino-ketone is cyclised by electrophilic attack onto the aromatic ring. 

In the original method, the Bischler synthesis, harsh acidic treatment of a-ary-laminoketones (produced from the 2-haloketone and an arylamine) was used to bring about electrophilic cyclisation onto the aromatic ring these conditions often resulted in mixtures of products via rearrangements. It is now known that A-acylated a-arylamino ketones can be cyclised under much more controlled conditions and, in contrast to early work, this approach to indoles can even be used to produce hetero-ring-unsubstituted indoles. ... 

In 1981, Nordlander demonstrated that acetals 22 can be used as reactants in the Bischler-Mdhlau indole synthesis, providing 2,3-unsubstituted indoles in good yield. Subsequent modification was made by Sundberg in 1984. From 1998 to 2002, Moody and co-workers developed a modified Bischler indole synthesis by using rhodium(II) acetate to catalyze the reaction of N-methylanilines with a-diazo-P-ketoesters via an N-H insertion reaction of a rhodium carbenoid. The resulting a-(A -arylamino)ketones cyclize to give indoles upon treatment with BF3 or an acidic ion exchange resin. ... 

The syntheses of a-alkylamino-acetals and the corresponding a-alkylamino-ketones from a-halogeno-ketimines, a-amino-ketones from benzilmonoamines, 3-arylamino-ketones from 3-carbamyloxy-ketones by decarboxylation, and chiral N- and iV,A( -substituted diamines and diamino-alcohols from amino-acids have also been reported. 

The method has been adapted to the formation of l)fs-diazoacetylalkanes from dibasic acid chlorides. Diazo ketones have been obtained from acyl chlorides containing a /Sj y-double bond, an ester group, and certain heterocyclic and aryl nuclei having alkyl, methoxyl, and nitro substituents. On the other hand, functional groups such as phenolic hydroxyl, arylamino, aldehyde, active methylene, and a,/S-unsaturated linkages may interfere. The method is ideal for application to complex molecules. 

Various 4-, 5-, or 4,5-disubstituted 2-arylamino thiazoles (124), R, = CfiH R with R= 0-, m-, or p-Me, HO C, Cl, Br, H N, NHAc, NR, OH, OR, or OjN, were obtained by condensing the corresponding N-arylthiourea with chloroacetone (81, 86, 423), dichloroacetone (510, 618), phenacylchloride or its p-substituted methyl, t-butyl, n-dodecyl or undecyl (653), or 2-chlorocyclohexanone (653) (Method A) or with 2-butanone (423), acetophenone or its p-substituted derivatives (399, 439), ethyl acetate (400), ethyl acetyl propionate (621), a- or /3-unsaturated ketones (691), benzylidene acetone, furfurylidene acetone, and mesityl oxide in the presence of Bt2 or I2 as condensing agent (Method B) (Table 11-17). 

Intramolecular Friedel-Crafts reaction Worthy of mention is the case of intramolecular Friedel-Crafts-type reaction affording 4(lH)-quinolone derivatives [443]. Thus, after extensive investigations, the authors prepared a solid-supported Meldrum s acid derivative by alkylation of a Merrifield resin with ethyl acetoacetate, decarboxylation, and subsequent ketalization of the resulting supported ketone with malonic acid (638). Treatment with triethyl orthoformate and various arylamines (639) afforded immobilized arylamino-methylene derivatives of Meldrum s acid (640). Upon thermal cyclization, these intermediates afforded 4(lH)-quinolone derivatives with simultaneous release from the resin (641). Highly pure final compounds were obtained in moderate to good yields. The resin was recovered in the form of the precursor of (638), i.e., the ketone (642), and thus could be potentially reused (Scheme 133). 

If a compound contains an arylamino group at the multiple bond, heating this compound with TiCl4 leads to six-membered heterocyclic compounds (93TL7737). jd-Ethoxyvinyl trifluoromethyl ketone reacts with cyclohexyl isocyanide, forming... 

Arylamino-3-bromo-l-aza-1,3-butadienes (281 R = Br), prepared by the action of A-bromo-succinimide on the 1-azadienes (281 R = H), on treatment with thionyl chloride in cold pyridine furnish the 4-bromo-l,2,6-thiadiazine 1-oxides (282) in high yields (72-82%) (Equation (39)) <83JCS(Pl)2273>. In contrast, the 3-chloro-azabutadiene (281 R =C1) remains unchanged with thionyl chloride at room temperature, whereas at 70°C the enamino ketone (281 0=0 in place of C=NH) is formed rather than the chlorothiadiazine 1-oxide. At higher temperatures (100°C) the bromo- and chloro-1-azadienes yield 4-chloropyrazoles by thermal extrusion of sulfur monoxide from the initially formed 1,2,6-thiadiazine 1-oxides (Section 6.16.6.1). 

Gems, I.I. Rropachev, L.V. Gorbunova, M.G. Ilchenko, A.Y. Kukhar, V.R Synthesis of trifluoromethyl-containing quinohnes from beta-(Al-arylamino)vinyltrifluoromethyl ketones. Ukr. Khim. 2h. 1993, 59(4), 408-411. 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to inprove the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the s)fnthesis of Al-aryl-3-arylamino acids from a three-component reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisuhstituted oxazoles, or 4-cyanooxazoles, and the three-component Biginelli reaction (eq 92) and Biginelli-like Mannich reaction of carhamates, aldehydes, and ketones. 

---