Indole transition metal-catalyzed

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

AT-acetyltryptamines could be obtained via microwave-assisted transition-metal-catalyzed reactions on resin bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide. While acceptable reaction conditions for the application of microwave irradiation have been identified for Stille heteroaryla-tion reactions, the related Suzuki protocol on the same substrate gave poor results, since at a constant power of 60 W, no full conversion (50-60%) of resin-bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide could be obtained even when two consecutive cross-coupling reaction cycles (involving complete removal of reagents and by-products by washing off the resin) were used (Scheme 36). Also under conventional heating at 110 °C, and otherwise identical conditions, the Suzuki reactions proved to be difficult since two cross-coupling reaction cycles of 24 h had to be used to achieve full conversion. 

Transition metal catalyzed decomposition of diazoester 64b, which is available from 64a with TsNj/base, results in the formation of furo[3,4-b]indole 65. This intermediate is trapped intramolecularly in situ to give 66. Furo[3,4-b]indoles of type 67 can be prepared similarly... 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

The cationic imidazolium rhodium complex (56) has been found to catalyze the intramolecular hydroamination of alkynes in refluxing THF. In the case of 2-ethynylaniline, indole is formed in 100% yield over 9h at 55 °C (Scheme 38).173 One of the earliest examples of late transition metal-catalyzed hydroamination involved the use of the iridium(I) complex [Ir(PEt3)2(C2H4)Cl] as... 

Scheme 7.23 Transition metal-catalyzed indole formation on a solid phase.

One of the most frequently studied transition metal catalyzed transformations of azoles and indole is their participation in cross-coupling reactions. Due to the abundance of examples in this field we only present some representative examples of the different reaction classes. In this chapter reactions where a halogenated azole is used to introduce the five membered ring onto the palladium in the oxidative addition and processes,... 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

Other variations involve transition metal-catalyzed generation of the required hydrazones . In a representative example, the iodoarene derivative 49 was converted to the intermediate 50, which was thereafter subjected to Fischer conditions rendering the indole 51 in a good overall yield (Scheme 30) <2004JOC3336>. 

Yet another transition metal-catalyzed route to indoles involves the use of aminoalcohol precursors, for instance 94, which could be efficiently converted to 6-chloroindole 95 (Equation 24). A plausible mechanism seems to feature an oxidation of the alcohol to an aldehyde functionality, which undergoes intramolecular condensation with the amino group <20020L2691>. 

Transition-metal catalyzed reactions are now common and attractive routes to exotic indoles with substitution patterns which are otherwise difficult to realize. Using an intramolecular Heck reaction, the precursors 94 were converted to a number of 3-aryl-3-alkenyl oxindoles 95 in good yield and with good ee. The requisite compounds 94 are available in three steps from IV-benzylbenzoxazolin-2-one using palladium-based chemistry <03JA6261>. 

Metal-catalyzed cross-coupling reactions have emerged as an important advancement in organic chemistry during the last few decades. Meanwhile, due to the importance of indoles in medicinal chemistry and many other fields, metal-catalyzed crosscoupling reactions have been extensively applied in the field of indole synthesis. While many books and reviews [1-3] have been published in the field, a book by the authors is solely dedicated to Palladium in Heterocyclic Chemistry [4]. In this chapter, we will cover applications of palladium- and other transition metal-catalyzed cross-coupling reactions in indole synthesis and reactimis. 

An excellent review by Djakovitch on transition metal-catalyzed, direct and site-selective Nl, C2-, or C3-arylation of indole nucleus was published in 2009 [205]. 

The reductive cyclization of 6>-nitrostryene (i.e., the Cadogan-Sundberg indole synthesis) has been improved by the transition metal catalyzation, selenium-based reductive cyclization, or hydrogen/Raney nickel reduced cyclizationJ... 

After that, the same group also reported catalytie, enantioselective hydroacylations of AT-allylindole-2-carboxaldehyes and N-allylpyrrole-2-car-boxaldehydes (Scheme 8.12)/ These hydroacylations occur smoothly to form dihydropyridoindolones and dihydroindolizinones in moderate to high yields and excellent enantioselectivity from a variety of indole and pyrrole substrates and represent the first example of highly enantioselective, transition metal-catalyzed hydroacylation reactions to form six-membered-rings in the absence of chelation assistance. 

Under rhodium-catalyzed conditions, hydrazine 137 undergoes oxidative annulation with alkyne 135 to furnish 1,2,3-tri-substituted indole 138 in moderate to excellent yield. The 1-aminoindole products can be substituted at C2 and C3 with aryl, heteroaryl, alkyl, and alkynyl groups (free hydroxyls and alkyl chlorides are also tolerated). 1,3-Dinitrobenzene acts as the stoichiometric oxidant and this is believed to be the first report of its use as such in a transition metal-catalyzed C-H activation (140L6176). 

Synthesis of pyrroles, indoles, and carbazoles through transition-metal-catalyzed C—H functionalization 13AJ0466. 

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. 

Yamamoto was first to report that orfho-alkynylanilines, which are fully substituted at the N-site, could undergo a transition metal-catalyzed cycloisomerization reaction to give indoles via a formal 1,3-migration of a suitable migrating group from the... 

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