Ruthenium indole synthesis

Metathesis of N-tosylated ene-amides and yne-amides has been less extensively investigated. An example of the RCM of ene-amides is a new indole synthesis developed by Nishida [79] metathesis precursor 96 (prepared by ruthenium-catalyzed isomerization of the corresponding allyl amide) is cy-clized to indole 97 in the presence of 56d (Eq. 13). 

Jones and co-workers reported the ruthenium-catalyzed synthesis of indol derivatives in a single step starting from di-o,o -substituted aromatic isonitriles a representative example is shown in Scheme 77 366>366a... 

For indole synthesis, the best additive both for yield and regioselectivity was found to be the anilinium hydrochloride (PhNH2- HCl). The formation of the indole product can be explained by the isomerization of the hydroamination product, in which it has been clearly shown that the ruthenium catalyst is not involved. 

As with several indole-ring syntheses to be discussed, transition metals have been adapted to the Sundberg azide indole-carbazole synthesis. These include rhodium, ruthenium, palladium, and iron. Rather than discuss these elegant methods in the present chapter, 1 have relegated them to the respective chapters on metal-promoted indole synthesis. Two excellent reviews discuss the synthesis of nitrogen heterocycles via azides [59] and nitrenes [60]. 

Although Zamyshlyaeva and her colleagues in 1970 described a low yield of indole (6%-7%) by the catalytic cyclization of A-(p-hydroxyethyl)aniline with ThO and Al Oj at 300-380 °C [6, 7], it was Watanabe who elevated this reaction to a bona fide indole synthesis (Scheme 2, equations 1-4) [3, 5], Indoles are also obtained from 2-nitrophenethyl alcohols using this ruthenium catalyst (equation 4). A mechanism proposed by Watanabe involves hydroxyl coordinating to the Ru center, oxidation to the corresponding aldehyde (loss of H ), and cyclodehydration to indole [5]. For a detailed mechanistic discussion see Watanabe et al [1]. 

Mori and Sato [17], Rasmussen [18], and Shuto and Arisawa [19, 20] have each exploited the synthetic power of these ruthenium catalysts in indole synthesis (Scheme 3,... 

Table 2.1 lists some of the mechanistic studies of organic and organometallic reactions reported in the literature by ESI-MS. All sorts of reactions have been successfully explored in the gas phase, such as the Baylis-Hillman reaction [211-213], C-H or N-H activation [214—219], cydopropanation reaction [220], Diels-Alder reactions [221], displacement reactions [222], electrophilic fluorination [223, 224], Fischer indole synthesis [225], Gilman reaction [226, 227], Grubbs metathesis reaction [228-231], Heck reaction [194], methylenation [232], oxidation [233, 234], Petasis olefination reaction [235], Raney Nickel-catalyzed coupling [236], ruthenium... 

SCHEME 3.63 Ruthenium-catalyzed synthesis of functionalized indoles [69]. 

Scheme 7.1 Proposed mechanism for ruthenium-catalyzed indole synthesis from 2,6-xylylisocyanides.

The2-aminophenethyl alcohols resulting from condensation of orr/ici-nitrotoliienes are good precursors for preparation of indoles. Watanabe and co workers have developed ruthenium-catalyzed dehydrogenadveiV-heterocyclizadon for synthesis of indoles and other hereto cycles from 2-aminophenethyl alcohols or 2-nitrophenylethyl alcohols fEq. 10.52. The oxidadve cycli-zadon of 2-aminophenethyl alcohols are also catalyzed by Pd-based catalysts. ... 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

Another type of unique coupling reaction was reported by Jones and coworkers [87]. The low-valent ruthenium phosphine complexRuH2(dmpe)2 catalyzed intramolecular insertion of isocyanide into the benzyl C-H bond of 2,6-xy-lylisonitrile under thermal conditions (Eq. 59). Their finding provided a new route to the synthesis of indoles. 

The same differential behavior can be observed with amine nucleophiles. For example, calcium triflate promotes the aminolysis of propene oxide 84 with benzylamine to give 1-(A -benzyl)amino-2-propanol 85, the result of attack at the less substituted site <03T2435>, and which is also seen in the solventless reaction of epoxides with heterocyclic amines under the catalysis of ytterbium(III) triflate <03SC2989>. Conversely, zinc chloride directs the attack of aniline on styrene oxide 34 at the more substituted carbon center <03TL6026>. A ruthenium catalyst in the presence of tin chloride also results in an SNl-type substitution behavior with aniline derivatives (e.g., 88), but further provides for subsequent cyclization of the intermediate amino alcohol, thus representing an interesting synthesis of 2-substituted indoles (e.g., 89) <03TL2975>. 

Recently, we found that Af-allyl-o-vinylaniline 44 gave 1,2-dihydroquinoline 45 by normal RCM and developed silyl enol ether-ene metathesis for the novel synthesis of 4-siloxy-l,2-dihydroquinoline and demonstrated a convenient entry to quinolines and 1,2,3,4-tetrahydroquinoline [13], We also have found a novel selective isomerization of terminal olefin to give the corresponding enamide 46 using ruthenium carbene catalyst [Ru] and silyl enol ether [14], which represented a new synthetic route to a series of substituted indoles 47 [12], We also succeeded an unambiguous characterization of ruthenium hydride complex [RuH] with A -heterocyclic carbene... 

Grant and Krische have described a racemic protocol for the synthesis of allcarbon C3 quaternary centers from 3-hydroxy-3-tert-prenyloxindole 76 that was accessed via ruthenium catalyzed addition of 1,1-dimethylallene 75 to isatin 74 [45]. As outlined in Scheme 21, 76 was converted to the electrophilic 3-chloro derivative, which was trapped with indole under basic conditions to afford 78 in 60% yield. A mechanism has been proposed for the C-C bond-forming event that involved first-order irmizatirHi of chloride irm assisted by delocaUzatiOTi of oxindole... 

This chapter on nitrene cyclization is a segue to the following several chapters that employ this tactic in powerful and widely used indole ring syntheses. The use of metals, such as palladium, rhodium, and ruthenium, to generate nitrenes or their equivalent and effect indole ring construction is discussed in later chapters. Soderberg has reviewed the synthesis of heterocycles via the generation... 

Following their discovery of the ruthenium-catalyzed A -alkylation of anilines with alcohols to give secondary and tertiary amines (Scheme 1, equation 1) [1], Watanabe and his colleagues adapted their chemistry to a synthesis of indoles as shown in equations 2 and 3 12-5], The reaction of Af-methylaniline with propylene glycol under typical conditions affords 1,2-dimethylindole and 1,3-dimethylin-dole in a 1 1 ratio (50% yield), whereas aniline plus styrene glycol gives only 2-phenyUndole (43% yield) [4], The best yield was 89% for the preparation of 5-chloro-2,3-dimeth-ylindole (equation 2). 

The use of metals as catalysts to constract the indole ring has revolutionized this area of organic synthesis. In the following chapters we present the role of copper, palladium, rhodium, ruthenium, titanium, zirconium, gold, and other metals to prepare indoles. 

Shimura, S., Miura, H., Wada, K., Hosokawa, S., Yamazoe, S. and Inoue, M. 2011. Ceria-supported ruthenium catalysts for the synthesis of indole via dehydrogenative N-heterocyclizatio. Catal. Sci. Technol. 1(8) 1340-1346. 

Borylated pyrrole 88 was prepared by Oestreich by treatment of the corresponding pyrrole with pinacolborane and a ruthenium(II) thiolate complex. The direct synthesis of 88 promises to find wide utility in medicinal chemistry and was applied to a variety of substituted indoles (13JA10978). N-Methylpyrrole was directly arylated at room temperature by photoredox catalysis with diaryliodonium salts to furnish 89 in 84% yield (13SL507). 

This reaction appears to be more difficult than the insertion into a vinylic C-H bond, which occurs in the synthesis of indoles from 2-nitrostyrenes (see paragraph 5.3.). The known chemical inertness of aromatic C-H bonds towards nitrene insertion [13] and the stabilisation of the intermediate aryl nitrene triply bridged in the ruthenium cluster are probably responsible for the poor yield of the heterocyclic product. 

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