Indole 2,3-disubstituted

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-f-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or A"-methoxy-At-melhyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyelization product to acid[4]. Use of CO as the electrophile generates oxindoles. 

In a related procedure A -melhyl-o-loluidine can be A-lithiated, carboxylated and C-lithiated by sequential addition of n-butyllithium, CO2, and n-butyl-lithium[5]. The resulting dilithiated intermediate reacts with esters to give 1.2-disubstituted indoles. 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Table 11.1 lists some of the reaction conditions which have given prepara-tively useful yields of 3-alkylation. Entries 1-3 are typical alkylations using a magnesium salt and an alkyl halide. Even 2,3-disubstituted indoles are alkylated at C3 under these conditions (Entry 7). Entry 5 represents a more recently developed method in which an allylic alcohol and indole react in the... 

Oxidation. As a 7t-excessive heterocycle, indole is susceptible to oxidation a variety of oxidation intermediates and products have been observed. With oxygen as the oxidant, the key intermediate is normally a 3-hydroperoxy-3ff-indole. These intermediates ate observable for 2,3-disubstituted indoles but are unstable for less substituted derivatives. Figure 1 indicates typical reactivity patterns toward oxygen. 

Although there are a wide variety of indole ring syntheses (25), most of the more useful examples fall within a small number of groups. Indole syntheses usually start with an aromatic compound, either monosubstituted or ortho-disubstituted. Those which begin with a monosubstituted starting material must at some point effect a substitution of the benzene ring. 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

The 1-azirines obtained from the vapor phase pyrolysis of 4,5-disubstituted 1-phthalimido-1,2,3-triazoles (157) have been found to undergo further thermal reactions (71CC1S18). Those azirines which contain a methyl group in the 2-position of the ring are cleaved to nitriles and phthalimidocarbenes, whereas those azirines which possess a phenyl substituent in the 2-position rearrange to indoles. 

Beckmann rearrangement, 4, 292 pyrolysis, 4, 202 synthesis, 4, 223 Wittig reaction, 4, 294 Wolff-Kishner reduction, 4, 291 Indole, 1-acyl-2,3-disubstituted photoisomerization, 4, 204 photo-Fries rearrangement, 4, 204 photoisomerization, 4, 42 synthesis, 4, 82 Indole, 2-acyl acidity, 4, 297 synthesis, 4, 337, 360 Indole, 3-acyl-acidity, 4, 297 cleavage, 4, 289 reduction, 4, 289 synthesis, 4, 360 Indole, 7-acyl-synthesis, 4, 246... 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Nucleophilic attack at a carbon atom, followed by a mesomeric shift to make a nitrogen atom quaternary, has been known for many years. The best example is the formation of 1,3,3-trisubstituted 3 -indole salts by the action of alkyl halides on 1,3-disubstituted indoles. 

During studies on the acid-induced formation of the alkaloid yuehchukene and related structures from pienylindoles, it was discovered that treatment of indole 173 with p-toluenesulfonic acid and silica gel leads to the formation of indolo-[3,2-b]carbazole 174 and the indole derivative 175 (Scheme 21). Similarly, the disubstituted product 176 could be isolated after TFA treatment of the substrate 177. Detailed mechanistic explanations have also been provided in this work (96T9455). 

A wide variety of heterocycles can be readily prepared by the heteroannulation of alkynes. For example, the palladium-catalyzed annulation of internal alkynes by 2-iodoanilines provides easy access to 2,3-disubstituted indoles by a process that involves initial reduction of Pd(OAc)2 to Pd(0), oxidative addition of the aryl halide to Pd(0), c/s-addition of the arylpalladium... 

Again, using a Pd-catalyzed amidation as the first step, Edmondson and coworkers [162] developed a synthesis of 2,3-disubstituted indoles 6/1-340 by reaction of 6/1-337 and 6/1-338 with catalytic amounts of Pd2(dba)3 and the ligand 6/1-341. On order to achieve good results, a second charge of Pd had to be added after 12 h. In the first step the enaminone 6/1-339 is formed, which then cydizes in a Heck-... 

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

Indoles can be formed by metal-catalyzed cyclizations of azobenzenes on disubstituted alkynes (Equation (106)). 

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