Larock conditions

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. 

Employing Jefferey s ligandless conditions, Larock and Babu (87TL5291) synthesized quinolines and other nitrogen-containing heterocycles via the intramolcular Heck reaction strategy as exemplified by reaction 144 145. This reaction is similar to the Mori-Ban indole... 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

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. 

Microwave-promoted palladium-catalysed processes have found wide general application (see Chapter 2). A Larock-type heteroannulation of an iodoaniline and an internal alkyne has been employed in the synthesis of substituted indoles9 (Scheme 3.7). The microwave conditions were carefully optimised using a focused microwave reactor. Application of microwave heating provided clear advantages in reaction rate and yield over conventional thermal conditions. It is interesting to note that fixed microwave power input provided improved yields over constant temperature conditions (variable microwave power input). This chemistry was successfully extended to a solid-phase format (Rink amide resin)10. 

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 modified Saegusa oxidation conditions were utilized in the total synthesis of ( )-8,14-cedranoxide by M. lhara et al. The main strategy was to apply an intramolecular double Michael addition reaction to assemble the tricyclic cedranoid skeleton. The precursor five-membered enone was prepared in high yield from the corresponding substituted cyclopentanone in two steps. 

T. Jeffery, Tetrahedron Lett., 1985, 26, 2667 J. Chem. Soc., Chem. Common., 1984, 1287 and R. Larock and B. E. Baker, Tetrahedron Lett., 1988, 29, 905. These reaction parameters are sometimes referred to as Jeffery s ligandless conditions. ... 

Larock has described the reaction of diphenylacetylene with iodosulfonamides 260 to give alkylidene dihydropyrroles 261 [159]. This ring-forming reaction is similar to the large number of related indole syntheses we will see in the next chapter. For example, 262 affords 263 under these conditions. 

Larock and Kuo [68] investigated the Pd-catalyzed coupling of allylic alcohols and o-iodoaniline which provided a convenient, one-step synthesis of quinolines as represented by the reaction between o-iodoaniline and alkenol 156 to give quinoline 157. The optimal conditions for this reaction were found to be 5 mol% IklCk. 5 mol% PPh3, 3 equivalents NaHCO3, 1.5 equivalents alkenol and 10 mL of HMPA per mmol of o-iodoaniline at 140°C for 1 day under N2. The reaction was found to be fairly versatile and the use of a range... 

In 2009, Djakovitch et al. described the first heterogeneous ligand- and salt-free Larock indole synthesis [43]. For instance, indole 22 was assembled in high yield under these conditions compared to the traditional homogeneous Larock indole synthesis conditions. 

Under the Larock s reaction conditions, where bases like pyridine A7-oxide and cesium fluoride are in deficient proportions, transformafiMi of the intermediate A into... 

Another structure mentioned several times in the literature as a suitable substrate for 6- xo-cyclizations is substructure G (Figure 6.4) [108, 109]. Larock and Babu [110] prepared 4-methylisoquinoline (143) from A-(but-3-enyl)-2-iodoaniline (142) under very mild conditions in nearly quantitative yield (Scheme 6.40). The cyclized compound completely isomerizes to the aromatic isoquinoline no xo-cyclic product could be detected. It is worth mentioning that the reaction proceeds cleanly without a protecting group on the secondary amine, a group which has been known to cause problems during intramolecular cyclizations if left unprotected [8]. 

The Larock indolization was applied to solid-phase indole synthesis (Smith) [32], to phosphine-free (Guo [33], Djakovitch [34]) and salt-free (Djakovitch [34]) conditions, to 2-chloroanilines (Senanayake [35], Ackermann... 

By employing o-(trimethylsilyl)phenyl triflate derivatives (11) as the aryne precursors, Larock and coworkers have developed a facile transition metal-free N-arylation method for amines, sulfonamides and carbamates under very mild reaction conditions (Scheme 12.4) [11]. Aromatic and aliphatic, as well as primary and secondary amines, react well, afTording good to excellent yields of the desired products. Secondary amines generally react faster than primary amines in... 

A similar process has been developed simultaneously by the Larock group (Scheme 12.55) [104]. Both, 1-arylindazoles 194 and IH-indazoles 195 are readily produced in fair to good yields by simply adjusting the stoichiometry of the reagents and the reaction conditions. When dicarbonyl-containing diazo com-... 

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