A -Acetylindoles

For instance, when A-acetylindole (153) is irradiated, the three rearranged products are 3 -acetylindole (154) (65%), 6-acetylindole (155) (20%), and 4-acetylindole (156) (8%). From this and other experiments, it has been claimed that the order of reactivity toward photo-Fries rearrangement in the indolyl system is 3 > 6 > 4. 

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give A -acetylindole and 7V-acetyl-2-methylindole each in 45% yield [387], In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 338 and 339 [388], The regioselectivity was excellent with unsymmetrical alkynes. 

Regiochemical dependency in the oxidative coupling of A-acetylindole with arenes on the added oxidant [AgOAc vs. Cu(OAc)2] is a remarkable phenomenon. ... 

Indole only reacts with acetic anhydride at an appreciable rate above HO C, giving 1,3-diacetylindole predominantly, together with smaller amounts of N-and 3-acetylindoles 3-acetylindole is prepared by alkaline hydrolysis of product mixtures.That P-attack occurs first is shown by the resistance of 1-acetylin-dole to C-acetylation, but the easy conversion of the 3-acetylindole into 1,3-diacetylindole. In contrast, acetylation in the presence of sodium acetate, or 4-dimethylaminopyridine, affords exclusively A-acetylindole, probably via the indolyl anion (section 17.4). Trifluoroacetic anhydride, being much more reactive, acylates at room temperature, in DMF at C-3, but in dichloromethane at nitrogen. ... 

Pd(CF3CO)2 catalyses the decarboxylation of electron-rich aromatic acids (e.g. with OMe groups) in DMSO/DMF at 70-90° (1 to 24 hours) in high yields and is not affected by steric hinderance [Dickstein et al. Org Lett 9 2441 2007], and (in the presence of Cu(OAc)2 with Cesium pivalate + 3-nitropyridine as additives at 110-140° in a microwave) it catalysed direct cross-coupling between unactivated arenes and A-acetylindoles with coupling mostly at C3 of indoles but with no homo-coupling [Stuart Fangou Science 316 1172 2007]. 

Enamides can also be efficiently hydrogenated with chiral Rh-complexes. The Rh complexes of Ph-BPE,f > BICP, TangPhos, SIPHOS,f and others have been shown to catalyze the hydrogenation of a mixture of (E) and (Z) P-methyl-a-phenylenamides 161 with excellent enantioselectivities. The hydrogenation of 2- and 3-substituted A -acetylindoles with the Ph-TRAP-Rh system was also possible with high ee. (R,S,S,R)-D10P was shown to be an excellent catalyst system for a variety of aromatic enamides. ... 

Palladium(II)-mediated oxidative coupling reactions involving the indole nucleus have been studied extensively in the literature. Fujiwara et al. [8b] reported that the reaction of A-acetylindole (8) with methyl acrylate (4b) gives (ii)-methyl 3-(l-acetyl-l//-indol-2-yl)acrylate (9, 4%) and ( )-methyl 3-(l-acetyl-l//-indol-3-yl)acrylate (10, 20%), along with A-acetyl-2,3-bis(methoxycarbonyl)carbazole (12,9%) which was believed to be generated by an electrocyclization and subsequent dehydrogenation of a 2,3-dialkenylated indole intermediate (11, Scheme 9.1). 

Itahara et al. [9] found that A-2,6-dichlorobenzoylindole (13) was oxidatively coupled with methyl acrylate (4b) in the presence of stoichiometric Pd(OAc)2 in acetic acid, affording the 3-alkenylated product 14 in 25% yield. Similarly, A-tosylindole (15) reacted with ethyl acrylate (4c) to generate the 3-alkenylated indole 16 in 48% yield (Scheme 9.2) [10]. Unlike what Fujiwara et al. [8b] had observed in the reaction with A-acetylindole (8) and methyl acrylate (4b), both cases did not produce any 2-alkenylated indoles, presumably due to the steric hindrance of the relatively bulky 2,6-dichlorobenzoyl and tosyl groups. 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

In a series of papers, Itahara established the utility of Pd(OAc)2 in the oxidative cyclization of C- and A-benzoylindoles, and two examples are shown [61-63], Itahara also found that the cyclization of 3-benzoyl-1,2-dimethylindole proceeds to the C-4 position (31% yield) [61]. Under similar conditions, both 1-acetylindole and l-acetyl-3-methylindole are surprisingly intermolecularly arylated at the C-2 position by benzene and xylene (22-48% yield) [64,65],... 

Miki effected Pd-catalyzed cross-coupling between dimethyl 7-bromoindole-2,3-dicarboxylate and both tributylvinyltin and tributyl-1-ethoxyvinyltin to yield the expected 7-vinylindoles [197]. Hydrolysis of the crude reaction product from using tributyl-1-ethoxyvinyltin gave the 7-acetylindole. Sakamoto used dibromide 192, which was prepared by acylation of 7-bromoindole, in a very concise and efficient synthesis of hippadine [36]. The overall yield from commercial materials is 39%. Somewhat earlier, Grigg employed the same strategy to craft hippadine from the diiodoindoline version of 192 using similar cyclization reaction conditions ((Me3Sn)2/Pd(OAc)2), followed by DDQ oxidation (90%) [198]. 

Sakamoto described similar reactions of o-bromoaniline derivatives with (Z)-tributyl-2-ethoxyvinyltin and subsequent cyclization of the coupled product with TsOH to yield, for example, N-acetylindole (29% yield overall) [185], This research group also used this methodology to synthesize a series of azaindoles, an example of which is illustrated below [204]. Halonitropyridines were particularly attractive as coupling partners with tributyl-2-ethoxyvinyltin and precursors to azaindoles. Although the (Z)-isomer of 202 is obtained initially, it isomerizes to the ( )-isomer which is the thermodynamic product. This strategy represents a powerful method for the synthesis of all four azaindoles (l//-pyrrolopyridines). In fact, this method, starting with 2,6-dibromoaniline, is one of the best ways to synthesize 7-bromoindole (96% overall yield) [36]. 

Dienes can undergo 1,2- and/or 1,4-addition [65]. 1,3-Bisnucleophiles, as 1,3-dimethylurea, favor 1,2-addition due to the formation of a five-membered ring (Eq. 15) [90]. Furan and its derivatives undergo a clean 1,4-addition, which is mediated by NH4Br[91] and has been also used for a technical scale conversion [92]. Af-Acetylindole reacts in a 1,2-bisacetoxylation because the phenyl ring wants to regain aromaticity [93]. 

A diazo transfer to N-Boc-3-acetylindole (674) provided the corresponding a-diazo ketone 675. Irradiation of a 1,2-dichloroethane solution of 675 and... 

Indole reacts with dimethylacetylene dicarboxylate giving tetramethylcar-bazol-l,2,3,4-tetracarboxylate as a major product,formed via 384 (R = H, and/or geometric isomer) and then Diels-Alder addition and dehydrogenation. /V-Acetylindole undergoes an extraordinary double condensation and cyclization with methyl acrylate in the presence of palladium(II) acetate in acetic acid giving 9% of the dimethyl 9-acetylcarbazole-2,3-dicar-boxylate 393 as well as 394 and 395, the products of monosubstitution at the indole a and S-positions. ... 

SYNTHESIS (from indoleacetone) To a solution of 1.55 g NaOAc in 5 mL acetic anhydride there was added 2.0 g 3-indoleacetic acid and the mixture was heated at 135-140 °C for 18 h. Removal of all volatiles on the rotary evaporator under vacuum produced a pale yellow residue that was the 1-acetylindole-3-acetone. This was dissolved in MeOH to which 0.93 g MeONa was added, and the solution held a reflux several hours. After removal of the solvent under vacuum, the residue was suspended in H20 and extracted with several portions of Et20. These extracts were pooled, and removal of the solvent under vacuum gave 0.41 g (21%) indole-3-acetone as a white solid, mp 115-117 °C. MS (in m/z) indolemethylene+ 130 (100%) parent ion 173 (16%). IR (in cm-1) 691,753,761,780. 1017, 1110, 1172, and a broad C=0 at 1710. 

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