Larock indole synthesis internal alkynes

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. 

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... 

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. 

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [385, 386]. This excellent reaction, which is shown for the synthesis of indoles 303, involves oxidative addition of the aryl halide (usually iodide) to Pd(0),. vyw-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0). 

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. 

Roesch, K. R., Larock, R. C. Synthesis of lsoindolo[2,1-a]indoles by the Palladium-Catalyzed Annulation of Internal Alkynes. Org. Lett. 

Internal Alkynes. Several applications of the Larock synthesis of indoles have been published where heterocycles are used as substrate. f " In the Larock method for indol construction, Pd-catalyzed heteroannulation of internal alkynes using ort/to-iodoanilines are used. Similarly, Pd-catalyzed heteroannulation of internal alkynes using ortho-amino-iodopyridine substrates produces azaindoles (Scheme 103). The method provides a convenient access to a structurally diverse range of 5-, 6-, and 7-azaindoles, 304, 305, and... 

The scope and mechanism of palladium-catalyzed annulation of internal alkynes to give 2,3-disubstituted indoles, the effect of substituents on the aniline nitrogen or on the alkynes, as well as the effect of the salts such as LiCl or n-BuaNCl were studied by Larock and coworkers (1998 JOC7652). The mechanism they propose for indole synthesis proceeds as follows (a) reduction of the Pd(OAc)2 to Pd(0) (b) coordination of the chloride to form a chloride-Ugated zerovalent palladium species (c) oxidative addition of the aryl iodide to Pd(0) (d) coordination of the alkyne to the... 

In a reaction related to their indole synthesis (Scheme 19.55) [100], Larock et al. reported a convenient method for the preparation of benzofurans 252 using 2-halophenols 250 and internal alkynes 251 (Scheme 19.67) [121], The reaction tolerates various alkyne R /R substituents, such as butyl, ethoxycarbonyl, silyl, and hydroxymethyl groups. 

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