Indole triflates

Mdrour studied the reaction of indole triflates with diamines to afford pyrazino[2,3-fc]indoles 374 and indolo[2,3-fejquinoxalines [467]. In the absence of palladium the yield of 374 is only 31% after 15 h. In some cases spiroindoxyls are formed. 

Indole triflates have proven to be very compatible with Pd-catalyzed methodologies,... 

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]. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

Direct 3-silylation of A -substituted indoles has been ellected by reaction of the indoles with trimethylsilyl triflate in the presence of triethylamine[12]. The trimethylsilyl group has also been introduced via 3-lithio-l-(phenylsulfonyl)-indole[13]. 

Indoles with carbocyclic halogen or triflate substituents are potential starting materials for vinylation, arylation and acylation via palladium-catalysed pro-cesses[l]. Indolylstannanes. indolylzinc halides and indolylboronic acids are also potential reactants. The principal type of substitution which is excluded from such coupling reactions is alkylation, since saturated alkyl groups tend to give elimination products in Pd-catalysed processes. 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

Other examples of nucleophilic attack on the oxirane ring include the formation of (3-halohydrins with silica-gel supported lithium halides <96TL1845>, the addition of amines catalyzed by lithium triflate, an ersatz for lithium perchlorate <96TL7715>, and the addition of pyrroles, indoles and imidazoles under high pressure i.e., 91 —> 93) <96JOC984>. 

Feldman reported a route to dihydropyrroles, pyrroles, and indoles via the reaction of sulfonamide anions with alkynyliodonium triflates <96JOC5440>. Thus, upon nucleophilic addition of the anion of 91 to the p-carbon of the alkynyliodonium salt, the alkylidene carbene 92 is generated which can the undergo C-H insertion to the desired product 93. 

Instead of Bronsted acids, lanthanide triflates can be used to catalyze the reaction of indole with benzaldehyde (Eq. 7.7). The use of an ethanol/water system was found to be the best in terms of both yield and product isolation. The use of organic solvent such as chloroform resulted in oxidized byproducts.17... 

Soderberg and coworkers have developed a palladium-phosphine-catalyzed reductive iV-het-eroannulation of 2-nitrostyrenes forming indoles in good yields.85 For example, reaction of 6-bromo-2-nitrostyrene with carbon monoxide in the presence of a catalytic amount of palladium diacetate (6 mol%) and triphenylphosphine (24 mol%) in acetonitrile at 70 °C, gives 4-bromoindole in 86% yield (Eq. 10.62). Several functional groups, such as esters, ethers, bromides, triflates, and additional nitro groups, have been shown to be compatible with the reaction conditions. 

In terms of methodologies for the preparation of A-arylindoles 140, Buchwald reported improved conditions for the palladium-catalyzed coupling of aryl chlorides, bromides, iodides and triflates 138 with a variety of 2-, 7- and polysubstituted indoles 139 utilizing novel electron-rich biaryl(dialkyl)phosphine ligands in combination with Pd2(dba)3 <00OL1403>. Alternatively, Watanabe reports similar A-arylations of pyrrole, indole and carbazoles with aryl bromides and chlorides using Pd(OAc)2/P(f-Bu)3 in xylene at 120°C <00TL481>. 

Edstrom has utilized the carbonylation variation to engineer new routes to 3-substituted 4-hydroxyindoles, indolequinones, and mitosene analogs [113, 114]. For example, triflate 155 is converted to methyl ester 156 in high yield [114]. Subsequent oxidation affords indole 157. 

Boronic acids 96 and 97 couple very well with vinyl triflates 98 and 99 under typical Suzuki conditions (Pd(PPh3)4/Na2C03/LiCl/DME) to give indoles 100 and 101, respectively, in 76-92% yield [115, 116]. Enol triflates 98 and 99 were prepared in good yield (73-86%) from N-substituted 3-piperidones, wherein the direction of enolization (LDA/THF/-78 °C PhNTf2) is dictated by the tf-substituent. 

Indolyltriflates have been used in Suzuki couplings by Mdrour [138, 139]. Thus, the readily available l-(phenylsulfonyl)indol-2-yl triflate (131) smoothly couples with arylboronic acids in 65-91% yield. Similarly, Pd-catalyzed cross-coupling of phenylboronic acid with l-benzyl-2-carbomethoxyindol-3-yl triflate affords the 3-phenyl derivative (62% yield) [139]. 

Doi and Mori made excellent use of dihydroindole triflate 189 in Pd-catalyzed cross-coupling reactions. This compound was discussed earlier in the Suzuki section, and it also undergoes Stille couplings as illustrated below [140]. A final dehydrogenation completes the sequence to indoles. 

Triflates also undergo Heck reactions and Gribble and Conway reported several such couplings of l-(phenylsulfonyl)indol-3-yl triflate (34) to afford 3-vinylindoles 224 [183]. Cyclohexene, allyl bromide, and methyl propiolate failed to react under these conditions, but triphenylphosphine afforded 225 in excellent yield (93%), and divinyl carbinol yielded the rearranged enal 226 (82% yield). 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

Na2CC>3), 25 °C, 24 h. Larock extended his work in several ways [302-305], particularly with regard to Pd-catalyzed cross-coupling of o-allylic and o-vinylic anilides with vinyl halides and triflates to produce 2-vinylindoles [303-305], an example of which is shown [305]. The related "Larock indole synthesis" is discussed separately in the next section. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

In conclusion, the fantastically diverse chemistry of indole has been significantly enriched by palladium-catalyzed reactions. The accessibility of all of the possible halogenated indoles and several indolyl triflates has resulted in a wealth of synthetic applications as witnessed by the length of this chapter. In addition to the standard Pd-catalyzed reactions such as Negishi, Suzuki, Heck, Stille and Sonogashira, which have had great success in indole chemistry, oxidative coupling and cyclization are powerful routes to a variety of carbazoles, carbolines, indolocarbazoles, and other fused indoles. 

Both vinyl- and aryl triflates have been cross-coupled with 2-furylzinc chloride [26-28]. Since vinyl triflates are easily obtained from the corresponding ketones, they are useful substrates in Pd-catalyzed reactions. In the following example, a Negishi coupling of 2-furylzinc chloride and indol-5-yl triflate (22) provided an expeditious entry to 2-(5 -indolyl)furan (23). Protection of the NH in the indole ring was not required. A similar reaction was successful with pyridyl- and quinolinyl triflates. 

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