Alkynes Larock indole synthesis

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]. 

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... 

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]. 

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 greatest application of the Sonogashira coupling is of course the Larock indole synthesis, which is reviewed in Section 3.3 in this chapter. A Sonogashira coupling was carried out between protected phenyliodide and alkyne. With JV-methanesulfonyl protection, the coupling product spontaneously cyclized to the indole, which was converted into an indole-based insulin mimic. 

This reaction was first reported by Larock et al. in 1991. It is a palladium-catalyzed chemoselective and ligandless heteroannulation between ort/io-iodoanilines and disub-stituted alkynes to form substituted indole derivatives. Therefore, this reaction is generally known as the Larock heteroannulation or Larock indole synthesis. ... 

The Larock indole synthesis, also known as the Larock heteroannulation, is a one-pot palladium-catalyzed heteroannulation of o-iodoaniline and internal alkynes for the synthesis of 2,3-disubstituted indoles. The original Larock reaction was performed with Pd(OAc)2 using carbonate or acetate bases with or without catalytic amounts of triphenyl phosphine and K-BU4NCI. However, it was subsequently observed that Li Cl is often more effective and reproducible (Scheme 1 1991JA6689). The reaction... 

The Larock indole synthesis is the internal alkyne version of the Yamanaka-Sakamoto-Sonogashira indole synthesis presented in Chapter 75. Also known as the Larock heter-oannulation, it affords 2,3-disubstituted indoles, in contrast to 2-snbstituted indoles from the Sonogashira reaction (Scheme 1, eqnations 1-3) [1-12], Like the Sonogashira, the Larock reaction has been of enormous utility in indole synthesis. With unsymmetrical alkynes, the regiochemistry is such that the more bulky group (e.g., t-butyl relative to... 

Larock indole synthesis, also known as Larock heteroannulation, is the one-pot palladium-catalyzed heteroannulation of ort/ro-iodoaniline and its derivatives 1 and internal alkynes 2 for the synthesis of 2,3-disubstituted... 

As mentioned early in the chapter, one of the general features of Larock indole synthesis is that the reaction gave exclusively 2-silyl indoles when a silyl-substituted alkyne was present, and the corresponding 2-silyl indoles can be further functionalized. In this respect, Denmark and Baird recently reported a sequential Larock heteroannulation and silicon-based... 

When the coupling partner alkynes in the Larock indole synthesis were replaced with substituted allenes 37, the corresponding 3-methyleneindolines 38 were obtained in 94—95% yields and 80 82% enantiomeric pure in the presence a chiral bisoxazoline ligand 39. ... 

Similarly, the 4-methoxytryptamine derivatives 83 and 84 were prepared via the Larock indole synthesis of iodoaniline 85 and alkynes 86 and 87, respectively. ... 

Larock indole synthesis was also employed to prepare substituted tryptophans 88 via annulation of silylated alkyne 89 with o-iodoanilines 90. ... 

Two (5)-P-methyl-2-aryltryptamine-based gonadotropin-releasing hormone antagonists 95 and 96 were synthesized via a consecutive Larock indole synthesis and Suzuki cross-coupling reaction." The key transformation involved the Larock heteroannulation of o-iodoaniline 97 with chiral silyl alkyne 98 in the presence of Pd(OAc)2, PPha, 1 equiv of LiCl, and 2.5 equiv of K2CO3 in DMF at 100 °C to give 99 in 72% yield. 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Larock Indole Synthesis of Internal Alkynes with o-Iodoaniline 2,3-Di-/i-propylindole (130) ... 

Since it was first reported in 1991, the Larock indole synthesis has become one of the most attractive and practical methods for the preparation of 2,3-disubstituted indoles (Scheme 24.46, disconnection D-1). In the seminal publication, Larock and Yum described the palladium-catalyzed heteroannulation of internal alkynes such as 71 with o-iodoanilines to generate substituted indoles such as 73 in excellent yield (Scheme 24.47) [149]. Unsymmetrical alkynes could be regioselectively incorporated, with the more sterically hindered group of the alkyne resulting at the 2-position of the indole. Trimethylsilyl-substituted alkynes were found to be particularly effective, affording the corresponding 2-silylated products such as 73 in exemplary yields. 

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 (V-acetylindole and N-acetyl-2-methylindole each in 45% yield [409]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 313 and 314 [410]. The regioselectivity was excellent with unsymmetrical alkynes. 

The 5-, 6-, and 7-azaindoles were synthesized via the Pd-catalyzed heteroannulation of internal alkynes using orf/w-aminopyridine derivatives in an extention of Larock s indole synthesis [169], LiCl was found to be an essential component in order to obtain regioselectivity, reproducibility and improved yields. 

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