Aryl amides, synthesis

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

Aryl amide anions are bidentate nucleophiles allowing C—C bond formation and the synthesis ofaminobiaryls. PhNH- gives low yields of substitution with Arl under irradiation, whereas 2-naphthylamide ions react by a photoinduced SRN1 process... 

The intramolecular ortho-arylation of aryl amide ions with aryl iodides has been recently applied to the synthesis of phenanthridines 25 in excellent yields (Scheme 10.49) [66], By applying the same procedure, N-(2-iodobenzyl) naphthalene-amine and N-(2-chlorobenzyl) naphthalen-1-amine yield benzo[a]- andbenzo[c] phenanthridines in 98% and 84% yields, respectively [66]. 

While often considered undesirable pathways in the past, radical hydrogen transfers have also been shown to constitute intriguing possibilities for organic synthesis. Curran has for instance defined the concept of protection and radical translocation (PRT) groups, fii this context, 2-0-(2-bromo-aryl)dimethylsilyl ethers, aryl amides and 2-bromo-4-methoxyphenyl ethers... 

Clemens, J. J., Davis, M. D., Lynch, K. R., Macdonald, T.L. Synthesis of para-alkyl aryl amide analogues of sphingosine-l-phosphate discovery of potent SIP receptor agonists. Bioorg Med Chem Lett 13 (2003) 3401-3404. 

Bt) group in organic synthesis and synthetic methodology. This group also adapted the methodology for a novel preparation of 5-(aroylamino)-2-aryloxazoles 587 (Scheme 1.160). Reaction of l,2-bis(17f-benzotriazol-l-yl)-l,2-ethanediol 583 with two equivalents of an aryl amide affords a l,2-(diaroylamino)-l,2-di(benzo-triazol-l-yl)ethane, 584 in excellent yield. Heating 584 with sodium hydride in... 

Rigby s studies on the synthesis of alkenylisocyanates fostered the preparation of a suitable substituted aryl enamide, which on photocyclization yielded the polysubstituted pentacyclic system. Key to the success of this process is the hydrogen bond between the phenolic OH and the carbonyl group, which restricts the rotation around the aryl-amide bond and directs the cyclization. Further functionalization allowed the total synthesis of pancratistatin (272) and narciclasine (68) (275) (Scheme 11). The [4-1-1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates was the key process in a recent synthesis of (+)-mesembrine (92) 274). 

The synthesis of N,N -disubstituted ureas has been achieved from arpmatic and also aliphatic nitro compounds using bromomagnesiurn alkyl and aryl-amides and FeCCOgCSPjs... 

Ackermann engineered a copper-catalyzed process to achieve the A-arylation/hydroamination synthesis of indoles (Scheme 4, equation 1) [35], In similar fashion, A-acylindoles and NH-indoles were made available using A-unsubstituted amides and carbamates in place of anilines. In these latter reactions, a vicinal diamine ligand improved the cyclizations. Miura and Hirano reported a... 

Remarkably, Beller s group developed several novel methodologies for the primary amides synthesis [135-139]. In the presence of palladium catalysts, aryl halides, phenyl triflates, benzyl chlorides and even phenols were transformed into the corresponding primary amides in good to excellent yields. Ammonia gas was used directly as an amine source and also as a base. These were the primary reports on using NH3 and CO for primary amides synthesis (Scheme 2.14). 

The potential of the the Meerwein-Eschenmoser Claisen rearrangement was exploited by Muxfeldt and co-workers in the course of their studies of crimine alkaloid total synthesis. Allylic alcohol 302 was treated with 265 in refluxing dioxane resulting in a single diastereomer of y9-aryl amide 304. ° ... 

Palladium catalysts again featured in cyclization reactions to yield ben-zazepines. Palladium and silver species were used to catalyze a ring-closure step in the total synthesis of clavicipitic acid (130L4528) while palladium was used to catalyze the annulation of an aryl amide onto an aryl bromide for the synthesis of a number of dibenzo[l>,e]azepin-6-ones (13CC7623). Annulation of aryl iodides onto aryl aldehydes to form dibenzo[fc,c]azepin-11-ones was also reported (13JOC8136). 

As already briefly mentioned earlier, simple propoxy aryl amides were known [39] but in our hands, proved to be poorly brain-penetrant Synthesis of a limited munber of cyclobutoxy analogs was straightforward and a quick amine scan was performed [57]. 

Moody reported the synthesis of 2-aryl-5-(trifluoromethyl)imidazole-4-carboxylate by the cyclization of the corresponding 0-ketoamides in the presence of NH4OH-ACOH in refluxing toluene (Scheme 41) [55], The prerequisite d-ketoamides were prepared, in turn, by N-H insertion of rhodium carbenoids to aryl amides. These ketoamides was isolated as their hydrates due to increased electrophilicity of trifluoromethyl ketones. The carbene 0-H insertion, followed by in situ cyclization, also produced the oxazolines as the by-products under these Rh-catalyzed conditions. 

Several name reactions are promoted by AICI3. For example, the Darzens-Nenitzescu reaction is simply the acylation of alkenes. The Ferrario reaction generates phenoxathiins from diphenyl ethers (eq 19) The rearrangement of acyloxy aromatic systems is known as the Fries rearrangement (eq 20). Aryl aldehydes are produced by the Gatterman aldehyde synthesis (eq 21). The initial step of the Haworth phenanthrene synthesis makes use of a Friedel-Crafts acylation. The acylation of phenolic cort tounds is called the Houben-Hoesch reaction (eq 22). The Leuckart amide s)oithesis generates aryl amides from isocyanates (eq 23). ... 

The synthesis of BIRT-377 (1) is outlined in Scheme 4. The commercially available (D)-iV-Boc-alanine (13) reacted with 3,5-dichloroaniline via a mixed anhydride intermediate (i-BuOCOCl, iV-methylmorpholine, -10 °C to rt, THF) to give amide 14. Deprotection of the crude amide 14 with trifluoroacetic acid in dichloromethane afforded amino iV aryl amide 15 in 92% yield over two steps. This crude product was pure enough to carry on for next step without any purification. 

SCHEME 64 Synthesis of acridines and acridones from aryl amides [89],... 

D.G. Pintori, M.F. Greaney, Insertion of benzene rings into the amide bond one-step synthesis of acridines and acridones from aryl amides, Org. Lett 12 (2010) 168-171. 

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