A’-Acylindole

This amide is readily prepared from the acid chloride (Pyr, rt, 1 h, 77-86% yield) or the acid (DCC, DMAP, CH2CI2, rt, 1 h, 88% yield). Treatment of the amide with camphorsulfonic acid forms an A-acylindole. The acid can be regenerated from the A-acylindole by Li0H/H202/THF/H20 or NaOH/MeOH. Alternatively, it can be transesterified with MeOH/TEA, converted to an amide, by heating with an amine or converted to an aldehyde by DIB AH (62-85% yield). ... 

The double bonds in certain heterocyclic compounds, such as furans, Af-acylpyrroles and A-acylindoles are also susceptible to photoaddition of carbonyl compounds to form oxetanes (equation 106) (77JHC1777). A wide range of carbonyl compounds can be used, including quinones, a-diketones, acyl cyanides, perfluorinated aldehydes and ketones and esters. A remarkable case of asymmetric induction in oxetane formation has been reported from optically active menthyl phenylglyoxylate and 2,3-dimethyl-2-butene the oxetane product obtained after hydrolysis of the ester group had an optical purity of 53% (79AG(E)868). 

Several new variations of methods for preparation of indoles by Pd-mediated cyclization were reported. Vinylene carbonate was found to be a satisfactory C2-C3 precursor for synthesis of N-acylindolin-2-ols and A-acylindoles from o-iodoacetanilides under Heck conditions. <95H(41)1627>... 

Melinonine B is formulated as C2oH2 N20+ on the basis of analyses of the chloride, iodide, and perchlorate the chloride, mp 311° (dec.), has [a]D —14.8° (methanol-water) (54). The alkaloid has one A-methyl group but no methoxyl or (7-methyl groups. Its UV-spectrum is that of a 2,3-disubstituted indole and its IR-spectrum exhibits both hydroxyl (3.05 /x) and N—H (3.20 /x) absorption. Acetylation of melinonine B gives a crystalline 0,A-diacetyl derivative which results from attack at the indolic Na, since the UV-spectrum of this derivative is that of an A-acylindole and its IR-spectrum has both ester and amide bands. 

The hypofluorination of benzofuran and of A -acylindoles with trifluoromethy] hypofluorite gives isomers 14A and ... 

The syn addition of iodine azide has been observed with a strained cyclobutene derivative29. Anomalous products were obtained from (i )-cyclooctenes and bicyclic (-E -cyclooctenes30,3I, e.g., 5-7. From 1,5-cyclononadiene and 1,5- and 1,6-cyclodecadiene, stereoselective transannu-lar cyclization occurred, involving acetonitrile (solvent) as the nucleophile to give 8--1032. From 1,3-dienes, benzofuran and A-acylindoles were obtained 1,2- or 1,4-diazides via the corresponding iodo azides (Section 7.2.2.4.). 

When the A -acylindoles 177 and 178 were heated in dimethyl sulfoxide at 80-90°C in the presence of DBU, acetylene derivatives 179 were produced (74JAP(K)72248). 

Adam, W. Ahrweiler, M. Peters, K. Schmiedeskamp, B. Oxidation of A-acylindoles by dimethyldioxirane and singlet oxygen substituent effects on thermally persistent indole epoxides and dioxetanes. J. Org. Chem. 1994, 59, 2733-2739. 

Oxosilicine (163), a new alkaloid of a Malagasy plant, Hazunta silicicola Pichon, has an a-acylindole structure related to 20-epiervatamine. Although details of the isolation are still not available, the synthesis of (163) has already been announced (Scheme 19) this constitutes the first total synthesis of an alkaloid of the dihydrovobasine-ervatamine group. The major feature of the route adopted is that the acylindole linkage is formed at the outset, and the bond to C-7 (indole jS -position) formed much later. This route may well be applicable to the synthesis of other 2-acylindole alkaloids. 

DCC as condensation agent. Such amides are stable under basic conditions, but converted to A-acylindoles readily. 

A-Acylindoles are much more readily hydrolysed that ordinary amides, aqueous sodium hydroxide at room temperature being sufficient this lability is due in part to a much weaker mesomeric interaction of the nitrogen and carbonyl groups, making the latter more electrophilic, and in part to the relative stability of the indolyl anion, which makes it a better leaving group than amide anion. 

Under the influence of light, A-methylindoles add dimethyl acetylenedicarbox-ylate, generating cyclobuteno-fused products, and even simple alkenes add in an apparent 2 + 2 fashion to A-acylindoles, but the mechanism probably involves radical intermediates. Other photochemical additions to form A-benzoylindolines fused to four-membered rings include addition to the carbonyl group in benzophenone, and the double bond in methyl acrylate. ... 

Intramolecular Diels-Alder reactions have been reported for a series of iV-(hexa-2,4-dienyl) carbamoylindoles, which yield useful tetracyclic systems. Similar cyclizations occur for the related A -acylindoles (CHj replacing NPh), but not for the alkoxycarbonyl analogs (O replacing NPh)... 

Ultraviolet light irradiation of A-acylindoles in the presence of alkenes gives cyclobutane ring formation. In intermolecular examples the major pathway involves bond formation of the indole... 

The regiochemical and stereochemical courses of the photocycloaddition of A-acylindoles with monosubstituted olefins such as methyl acrylate and vinyl acetate, as well as the possible mechanistic pathways for these reactions, have been the subject of several reports. In one of the earliest examples, the photocycloaddition of 1 -benzoylindole (8) and methyl acrylate (9) produced the compound 10, which was then converted via a short synthetic sequence to a variety of 2a,7b-dihydrocyclobut[h]indole derivatives 11 (Scheme 2). These compounds were in turn converted to the corresponding l//-l-benzazepines 12, through silver ion-catalyzed thermolysis reactions at 100-160°C [14, 15]. 

Indole reacts readily with mercuric acetate at room temperature to give a 1,3-disubstituted product. Even A -acylindoles are substituted under mild conditions the 3-mercurated compounds thus produced are useful in palladium-catalysed couplings. ... 

The reagent MoO. HMPA, known as MoOPH , in methanol, brings about addition of the elements of methyl hydrogen peroxide to an A -acylindole, and these adducts in turn can be utilised one application is to induce loss of methanol, and thus the overall transformation of an indole into an indoxyl. ... 

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... 

The direct coupling of diarylamines and aUcenes (e.g., styrenes) with Pd(OAc)j was described by Maiti and colleagues (Scheme 4, equation 1) [39], and Wu and coworkers reported a one-pot sequential Beckmann rearrangement, cycUzation, and indole C-3 chlorination to afford A-acylindoles (equation 2) [40]. Gong, Wu, and colleagues synthesized 2-trifluoromethyl-3-vinylindoles via a domino carbopalladation C-H activation protocol... 

Diastereoselective U-4CR of chiral y-keto acid 10s with 6i and lx in 2,2,2-trifluoroethanol at room temperature provides y-lactam 205 in a 78% yield as a single diastereomer. The diastereoselectivity is believed to arise from the exclusive axial approach of small nucleophiles onto the carbonyl group of l,3-dioxan-4-ones [82]. Deprotection of the acetonide with catalytic amount of CSA in MeOH followed by protection of the diol to the corresponding diacetate and further treatment with catalytic amount of CSA in benzene provides the A-acylindole 206. The A-acylindole... 

Kreye and coworkers have utilized CIC lx in their U-4CR for the synthesis of a,fi)-diene monomer 213 (Scheme 7.72) [85]. Employing an acyclic diene metathesis polymerization strategy, the monomers were subsequently polymerized using the second-generation Hoveyda-Gmbbs catalyst in the presence of 1,4-benzoquinone (1,4-BQ) as an additive to obtain compound 214. Hydrogenation followed by the treatment with pyridiniump-toluenesulfonate provided the A -acylindole intermediate 215. Under various conditions, 215 provided polymers containing amide and acid (216,217, and 218) functionalities that can be useful for further modification of the side chain. This method clearly exemplifies that judicious application of IMCRs can lead to a new era in polymer synthesis. 

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