Indoles, palladium-catalyzed synthesis

More recently, Dong s group developed a palladium-catalyzed synthesis of indoles from nitroalkenes [43]. This was the first report on transition metal-catalyzed transformation of conjugated nitroalkenes into indoles. Under mild reaction conditions (1 bar carbon monoxide, 110 °C), palladium catalyzes the reductive cyclization of nitroalkenes to form a putative nitrosoalkene intermediate, which then rearranges to provide 3-arylindoles in high yields (Table 9.5). Notably, this novel C-H bond amination takes advantage of carbon monoxide as an inexpensive stoichiometric reductant and produces carbon dioxide as the major byproduct. 

Indoles. A soln. of N-allyl-o-iodoaniline, 2.5 eqs. Na2C03, 1 eq. Bu4N CL, and a little Pd(OAc)2 in DMF stirred at 25° for 1 day - 3-methylindole. Y 97%. Quinolines and isoquinolines are also obtainable under these conditions. F.e. inch indolines and oxindoles, and bases. (NaOAc, EtjN), s. R.C. Larock, S. Babu, Tetrahedron Letters 28, 5291-4 (1987) review of palladium-catalyzed synthesis of condensed heteroarenes s. T. Sakamoto et al.. Heterocycles 27, 2225-49 (1988). 

Scheme 2.97 Palladium-catalyzed synthesis of indoles from 2-chloroanilines and internal alkynes.

Rowland DA, Taylor JB (1979) Neue pyrrolochinoxaline, vtrfahren zu deren herstellung und pharmazeutische zusammensetzungen. JB Patent Ger Offen 2816109, 26 Oct 1978 Rudisill DE, Stille JK (1989) Palladium-catalyzed synthesis of 2-substituted indoles. J Org Chem 54 5856-5866. doi 10.1021/jo00286a014... 

The palladium-catalyzed synthesis of functionalized indoles through intramolecular nitrogen-carbon(sp ) bond formation has been reported (Scheme 3.55) [61], This was an oxidative cycloisomerization process, and the authors found that molecular oxygen (1 atm) was an effective oxidant for the process. The substrate scope for this reaction was quite... 

A cascade reaction including oxidative functionalization of the indole intermediates at the C3 position is shown in Scheme 19.87. The Zhu group reported a palladium-catalyzed synthesis of tetracyclic indoles 328 by intramolecular diamina-tion of alkynylanilines 327 bearing a benzamide moiety [160]. The reaction would be initiated by the coordination of both alkyne and amide, followed by deprotonation to form the intermediate 329. An anti addition of the dimethylamino group of 329... 

Movassaghi, M. and A.E. Ondrus. 2005. Palladium-catalyzed synthesis of N-vinylpyrroles and indoles. J Org Chem 70 8638-8641. 

Rizatriptan (Maxalt ) A 5-HTm Receptor Agonist 4.1.2.2 Palladium-Catalyzed Indole Synthesis... 

Thus far, we have discovered and demonstrated a new and effident method for the synthesis of indoles from various carbonyl compounds. This, in conjunction with the use of alkyries in the palladium-catalyzed indolization, widens the spectrum of indoles that can be prepared by these means. The simple procedure, mild reaction conditions, and ready availability of the starting materials render these methods valuable additions to indole chemistry. We next extended this method to the synthesis of the indole core of a PGD2 receptor antagonist, laropiprant 3. 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719-721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from CIS- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from... 

General procedures for the synthesis of 10f/-[l]benzothieno[3,2- ]indoles 359a-c <2003T3737> and 2,4-dimethylpyrrolo[3,2-, ]indole 360 <1997J(P1)2843> using palladium-catalyzed intramolecular cyclization of the appropriate o-bromodiarylamines and palladium-catalyzed arylation of a cyano group, respectively, were described. 

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