Ortho acylation

The Sugasawa reaction (ortho-acylation of aniline) was optimized for this route using a combination of BCl3/GaCl3. 

In 1978, Sugasawa et al., at Shionogi Pharmaceutical Co. reported ortho-selective Friedel-Craft acylation with free anilines with nitrile derivatives [4]. Sugasawa reported that the reaction requires two different Lewis acids (BC13 and A1C13) and does not proceed when N,N-dialkyl anilines are used. He proposed that boron bridging between nitriles and anilines led to exclusive ortho-acylation but a conclusive mechanism was not elucidated. The report did not offer any reason why two different Lewis acids were required and why the reaction did not progress with N,N-dialkyl anilines. Therefore, we initiated mechanistic studies. 

Rossi and co-workers <66AC(R)728> also showed that ortho-acyl methanesulfanilides 41 carrying an electron-withdrawing group at the a position of the sulfonyl group can readily... 

The rearrangement of aryl and naphthyl acetates has been reported to be catalyzed by Bi(0Tf)3xH20 (Scheme 9) [68, 69]. As previously reported, only ortho-Fries products (l-hydroxy-2-acylaromatics) were produced from substrates for which ortho acylation was possible. In the case of 2,6-dimethoxyphenyl acetate, only the 3,5-dimethoxy-2-hydroxy acetophenone was produced, indicating that in this case the mechanism involves an intermolecular acyl-group transfer. As in other reactions, the nature of the true catalyst is still unclear since triflic acid also catalyzes this reaction. 

As expected, the para-acylated ketone 3 is the major reaction product, with only minor yields of the ortho-acylated product formed. Reaction is very rapid and complete conversions are obtained. Catalyst TOP numbers are >19000h under these conditions. Enolisation and further reaction with the anhydride results in formation of the vinyl ester. Minor amounts of diacile and side products are formed. Similar performances are observed with both supported and nonsupported ST A (at equivalent ST A loading in reactor). Use of nonsupported ST A resulted in agglomeration and deposition of the material onto the reactor wall, whereas the silica supported material could be readily removed by filtration. 

Central intermediates in our strategy were the known ortho-acylated hydroxy)... 

C-Acylation imidazoles in, 1, 463 ortho-Acylation 2-alkylpyridines, 1, 436 Acylimines... 

Benzo[/]annelated naphtho[bc]thiepine-4-one derivatives 482 are obtained by cyclization of 8-arylmercapto-1 -naphthoic or 1-naphthylmercap-tosalicylic acids 480 and 481 (38M440 75CCC1604 84JHC1737). In the latter case, in order to avoid ortho-acylation, the ortho-position (towards the sulfur atom) of the naphthalene nucleus is blocked by a substituent. 

The electrophilic cyclization of /3-(arylchalcogeno)propenoic acids 62 and acyl chlorides 63 may occur in two different ways. Whereas ortho acylation involving formation of the intermediate 64 gives rise to the six-membered heterocycles, chalcogenachromones (flavones) 65, ipso acylation is accompanied by formation of the typical c-complex 66, which transforms to the five-membered heterocycle, 1,2-oxachalcogenolium chloride 67. 

Substrates of Friedel-Crafts acylations are benzene and naphthalene, as well as their halogen, alkyl, aryl, alkoxy, or acylamino derivatives. Acceptor-substituted aromatic compounds are inert. Because Friedel-Crafts acylations introduce an acceptor into the aromatic substrate, no multiple substitutions take place. This distinguishes them from Friedel-Crafts alkylations. Free OH and NH2 groups in the aromatic compound prevent Friedel-Crafts acylations because they themselves are acylated. However, the O-acylphenols available in this way can later be rearranged with A1C13 into ortho-acylated isomers (Fries rearrangement). 

The borane 1 can also be used for ortho-acylation of anilines by reaction wdth nitriles. The yields in this reaction are considerably improved by addition of aluminum chloride, but other Lewis acids are ineffective. This reaction is also successful for primary anilines. No other metal halides are effective in these two substitution reactions. 

Indoles have been prepared form ortho-acyl amides with Ti(powder) and MesSiCl or with TiCl3—Benzofurans have been prepared by a closely related reaction. 

V. Snieckus and co-workers developed a new carbamoyl Baker-Venkataraman rearrangement, which allowed a general synthesis of substituted 4-hydroxycoumarins in moderate to good overall yields. The intermediate arylketones were efficiently prepared from arylcarbamates via directed ortho metallation and Negishi cross coupling. The overall sequence provided a regiospecific anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and coumarins. 

The Fries rearrangement proceeds via ionic intermediates but the exact mechanistic pathway (whether it is inter- or intramolecular) is still under debate. There are many reports in the literature that present evidence to support either of the pathways, but it appears that the exact route depends on the structure of the substrates and the reaction conditions. The scheme depicts the formation of an ortho-acylated phenol from a substituted phenolic ester in the presence of aluminum trihalide catalyst. The photo-Fries rearrangement proceeds via radical intermediates. ... 

The first atropo-enantioselective total synthesis of a phenylanthraquinone natural product (Af)-knipholone was reported by G. Bringmann et al. In the late stages of the synthesis, an acetyl group had to be introduced under mild conditions. The advanced substituted anthraquinone intermediate was first deprotected with TiCU and then acylated with AC2O in the presence of TiCU. A spontaneous Fries-rearrangement took place to afford the ortho-acylated product in high yield. The natural product was obtained by a mono O-demethylation at C6 with AIBrs. 

Research in the laboratory of P. Magnus showed that the macrocyclic skeleton of diazonamide could be synthesized with the use of macroiactonization followed by a photo-Fries rearrangement. First, the aromatic carboxylic acid and the phenol were coupled with EDCI to form the macrolactone (phenolic ester), which was then exposed to light at high-dilution to cleanly afford the macrocyclic ortho-acylated phenol skeleton of diazonamide. 

The Fries reaction can also be metal-promoted to afford, under the proper reaction conditions, good yields of specific ortho acyl migration products. For instance, o-bromophenyl pivaloate (248) has been treated at —95 °C with s-butyllithium to afford o-hydroxypivalophenone (249) in 76% yield (equation 178) . Similarly, benzoate 250 gave o-hydroxyketone 251 in 82% yield by treatment with n-butyllithium (equation 179) °. 

The Hf(OTf)4, is also effective in the ortho-acylation of phenols using carboxylic acids instead of the acid chlorides, although somewhat lower yields are obtained and larger amounts of the catalyst are required (equations 42 and 43). ... 

Fig. 4 Structure of ortho-acyl-/V-phenol amine MC1863...

Quinolines from ortho-Acyl-Arylamines and Carbonyl Compounds ortfto-Acyl-arylamines react with ketones having an a-methylene to give quinolines. 

From ortho-Acyl-Anilides The Furstner Synthesis ... 

In a similar fashion, as carboxylic acids or their esters, certain carboxamides possessing an ortho acyl group tnay also cyclocondense with hydrazine. Thus, Ar,/V-dicthyl-3-(2-pyridy car-bonyl)pyridine-2-carboxamide gives the corresponding pyrido[2,3-(i]pyridazin-H(7//)-one 15 in 89% yield, whereas, in contrast, 3-benzoyl-A, Ar-diisopropylpyridine-2-carboxamide and hydrazine give jV,2V-diisopropyl-5-phenylpyrido[2,3-d]pyridazin-8-amine (16) in 42% yield.50... 

The production of aromatic hydroxyketones can also be performed by the Fries rearrangement in this case, the mode of para-acylation is probably different from that of ortho-acylation. Indeed, the ortho-isomer is a primary product, whereas the para-isomer seems to be a secondary product. Of course, other methods for... 

The metal-template effect is also exploited as a powerful instrument to achieve highly selective ortho-acylation of the phenol ring in the... 

Unusual Friedel-Crafts reactions, IX. One-step ortho-acylation of phenols with a,(3-unsaturated acyl chlorides. Synthesis of 2 -hydroxychalcones and sorbicillin analogues. Tetrahedron 40 4081-4084. 

Sartori, G., Casnati, G., Bigi, R, and Bonini, G. 1988. Metal template ortho acylation of phenols direct synthesis of salicylic acid chlorides and derivatives. Synthesis 763-766. 

There have been several reports of ortho-acylations using palladium catalysis. Orthoacylation of acetanilides with aldehydes is catalysed by palladium trifluoroacetate in the presence of f-butylhydroperoxide. A likely pathway involves the formation of a cyclopalladated intermediate (57), which reacts with an acyl radical to give (58) followed by carbon—carbon bond formation through reductive elimination. A similar methodology has been used in the preparation of a range of ort/io-acylacetanilides. ... 

Ortho acylation of anilines by nitriles in the presence of BCI3 and an auxiliary Lewis acid ... 

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