Larock indole synthesis

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles. This reaction involves 

The reaction can be regioselective with unsymmetrical alkynes, and this is particularly true with silylated alkynes wherein the silyl group always resides at the C-2 indole position in the product. This is noteworthy because silyl-substituted indoles are valuable substrates for other chemistry such as halogenation and Heck coupling. 7-Azaindoles were also prepared using a Larock indole synthesis.  

The Larock synthesis was used to synthesize Merck s rizatriptan (Maxalt, 5-(triazolylmethyl)tryptamine, MK-0462), a potent 5-HTid receptor agonist for the treatment of migraine. The reaction was carried out on a 25 kg scale. 

As shown in the next scheme, palladium-catalyzed coupling of iodoaniline with bis-triethylsilyl protected butynol in the presence of Na2C03 provided a mixture of indoles. This mixture was desilylated with aqueous HCl in MeOH to furnish the tryptophol in two steps. Protection of the alkyne prevented coupling at the terminal carbon of the alkyne and triethylsilyl (TES) was found to be optimal because it offered the correct balance between reactivity (rate of coupling) and stability. Notably, this palladium-catalyzed process does not require the use of triphenyl phospine, tetrabutyl ammonium chloride, or lithium chloride. The alcohol was converted into the mesylate and then treated directly with 40% dimethylamine to afford rizatriptan, which was purified via recrystallization after forming the benzoate salt. 

benzoic acid, /-PrOH, /-PrOAc, 96% rizatriptan benzoate (Maxalt) 

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A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

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 Larock indole synthesis was adapted to the solid phase both for the synthesis of 1,2,3-trisubstituted indole-5-carboxamides [396] and, as illustrated, for the "traceless" synthesis of 2,3-disubstituted indoles 308 [397], As seen earlier, the trimethylsilyl group is fastened to C-2 with complete regioselectivity. The TMS group is cleaved under the resin cleavage conditions. The original Larock conditions were not particularly successful. 

Substituting the benzene ring with a double bond, Pd-catalyzed intramolecular alkoxylation of alkyne 122 also proceeded via an alkenyl palladium complex to form furan 123 instead of a benzofurans [99, 100]. In addition, 3-hydroxyalkylbenzo[fc]furans was prepared by Bishop et al via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis, [101]. 

To make tryptophan analogs, Gronowitz and coworkers conducted a pyrrole annulation from an aminoiodopyrimidine utilizing the Larock indole synthesis conditions (see Section 1.10.) [80]. They prepared heterocondensed pyrrole 115 by treating 4-amino-5-iodopyrimidine 114 with trimethylsilyl propargyl alcohol under the influence of a palladium catalyst The regiochemical outcome was governed by steric effects. 

The total synthesis of (-)-fuchsiaefoline was accomplished in the laboratory of J.M. Cook using the Larock indole synthesis to prepare the key precursor 7-methoxy-D-tryptophan in enantiopure form. The propargyl-substituted Schollkopf chiral auxiliary was reacted with 2-iodo-6-methoxyaniline in the presence of 2 mol% Pd(OAc)2 to give the expected indole in good yield. Interestingly, the Bartoli indole synthesis gives /-substituted indoles only in moderate yield. 

T.F. Walsh and co-workers synthesized two (S)- 3-methyl-2-aryltryptamine based gonadotropin hormone antagonists via a consecutive Larock indole synthesis and Suzuki cross-coupling. The required (S)-P-methyltryptophol derivatives were prepared by coupling 4-substituted o-iodoanilines with optically active internal alkynes under standard conditions. The resulting 2-trialkylsilyl substituted indoles were then subjected to a silver-assisted iododesilylation reaction to afford the 2-iodo-substituted indoles that served as coupling partners for the Suzuki cross-coupling step. 

The preparation of diversely substituted azaindoles is fairly difficult, and there are no generally applicable strategies in the literature. Research by L. Xu et al. showed that 2-substituted-5-azaindoles could be synthesized by the Pd-catalyzed coupling of aminopyridyl iodides with terminal alkynes. The coupling reaction proceeded in good yield under the conditions originally developed by Larock. Therefore, this example can be considered an extension of the Larock indole synthesis. By stopping the reaction early it was shown that the intermediate was an internal alkyne. 

Larock indole synthesis Preparation of 2,3-disubstituted indoles from ortho-iodoanilines and disubstituted alkynes. 258... 

Related reactions Fischer indole synthesis, Larock indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis ... 

Related reactions Bartoli indole synthesis, Fischer Indole synthesis, Larock Indole synthesis, Nenitzescu Indole synthesis ... 

The current popularity and undisputed power of the Larock indole synthesis [371] is... 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

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