Alkynes oxidative annulation

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). 

Cu(OAc)2-oxidized annulations of (di)aryl- and (di)alkyl-substituted alkynes by various electron-rich and electron-deficient acrylamides using [RuCl2(p-cymeme)]2 as the catalyst in the presence of f-AmOH as a solvent result in the formation of 2-pyridones. The catalyst displayed a notable chemo- and regio-selectivity. °... 

Ruthenium-catalysed oxidative annulations of alkynes (55) to benzamides (54), involving the CH activation, has been developed as a new method for the synthesis of l(2//)-isoquinolones (56). Mechanistic studies provided strong evidence for a rate-limiting CH bond metallation, assisted by the orf/zo-amide group. 

Rhodium(lll)-catalyzed redox—neutral coupling of N-phenoxyacet-amides and alkynes led to benzo[l)]furan derivatives (13AGE6033). Furo[2,3-l)]pyran-6-one derivatives were prepared via rhodium(II)-catalyzed reactions of diazo compounds and ethynyl compounds (13T9294). Copper-mediated oxidative annulation of phenols and unactivated internal alkynes afforded benzo[l ]furan derivatives (13CS3706). E t-kaurane maoecrystalV was produced via C-H functionalization (13JA14552). Rhodium-catalyzed intramolecular C-H... 

In a different approach, Minakata and coworkers [94] developed a practical and high yielding PIDA-induced oxidative [4 + 2] annulation of o-phenylene diamines 122 and electron-deficient alkynes 126 for direct access to quinoxalines 127 bearing two electron-withdrawing groups (Scheme 31). The formation of quinoxalines 127 was proposed to occur via an initial generation of enamine 128, which was likely to undergo PIDA-mediated oxidative annulation and rearomatization. 

Abstract The selective catalytic activation/functionalization of sp C-H bonds is expected to improve synthesis methods by better step number and atom economy. This chapter describes the recent achievements of ruthenium(II) catalysed transformations of sp C-H bonds for cross-coupled C-C bond formation. First arylation and heteroarylation with aromatic halides of a variety of (hetero)arenes, that are directed at ortho position by heterocycle or imine groups, are presented. The role of carboxylate partners is shown for Ru(II) catalysts that are able to operate profitably in water and to selectively produce diarylated or monoarylated products. The alkylation of (hetero)arenes with primary and secondary alkylhalides, and by hydroarylation of alkene C=C bonds is presented. The recent access to functional alkenes via oxidative dehydrogenative functionalization of C-H bonds with alkenes first, and then with alkynes, is shown to be catalysed by a Ru(ll) species associated with a silver salt in the presence of an oxidant such as Cu(OAc)2. Finally the catalytic oxidative annulations with alkynes to rapidly form a variety of heterocycles are described by initial activation of C-H followed by that of N-H or O-H bonds and by formation of a second C-C bond on reaction with C=0, C=N, and sp C-H bonds. Most catalytic cycles leading from C-H to C-C bond are discussed. 

Oxidative annulations reaction of alkynes is one of the important methods to synthesize fused polycyclic heteroarenes [169-173]. Whereas the above examples show easy ruthenium catalysed insertions of alkynes into aromatic sp C-H bonds efforts have been made with related catalysts to perform the double insertion of alkynes into C-H and heteroatom-hydrogen bonds as a route to a variety of heterocycles. Chae S. Yi, has first shown, using ruthenium(ll) catalyst precursors [RuH(CO)(PCy3)2(NCMe)2]BF4 and preferably Ru3(CO)i2/NH4PF6, the alkenylation and double insertions of alkynes into C-H and N-H bonds for the transformation of indolines with terminal alkynes into quinoline derivatives [(Eq. 86)] [174, 175]. 

IH-pyrazoles appeared also suitable substrates for the oxidative annulation with aryl- and alkyl- alkynes with good chemo- and regioselectivities. This reaction was carried out using 5 mol% of [RuCl2(p-cymene)]2,20 mol% of AgSbFg, 1 equiv. of Cu(0Ac)2.H20 as the oxidant The H/D experiments indicate a reversible C-H bond metallation step with the Ru(II)/AgSbF6 catalytic system in DCE/D2O (9 1) [(Eq. 90)] [179]. 

Various pyrroles were synthesized through the ruthenium(II)-catalysed oxidative annulation of enamines with aryl- and alkyl-alkynes in r-AmOH with only 30 mol% of Cu(0Ac)2.H20 under ambient air conditions. Numerous functional groups including ester, vinyl, bromo, nitro substituents and heteroaromatic were tolerated in this catalytic system [(Eq. 96)] [184]. 

It is noteworthy that based on this reaction a-pyrone could be synthesized from the oxidative annulation with alkynes of acrylic acid derivative with [RuCl2(p-cymene)]2/KPF6 catalytic system [(Eq. 100)] [191]... 

The direct oxidative annulations with alkynes by Csp -H/Csp -H bond cleavage have not been developed yet only two examples were described in this area using nickel(O) by Hiyama [198] and rhodium(lll) by Wang [199]. With ruthenium (11) catalyst, Lam reported the first annulations with alkynes of 2-aryl-l,3-dicarbonyl compounds by Csp -H and Csp -H bond activation [200]. The reaction of 2-aryl-3-hydroxy-2-cyclohexenones and cyclic 2-aryl-l,3-dicarbonyl compounds with 2.5 mol% of [RuCl2(/ -cymene)]2 and 2.2 equiv. of Cu(OAc)2 was performed in 1,4-dioxane at 90°C, and led to spiroindene derivatives in 50-84%... 

A tremendous recent innovation brought by ruthenium(ll) catalysts deals with the oxidative annulations with alkynes and activation of both C-H and N-H or O-H bonds to form very easily a large variety of heterocycles. Ruthenium(II) activation of C-H bond in the presence of alkynes can be tamed to form two C-C bonds from C-H bond activation and, after alkyne insertion, on addition of C-Ru bond to a ketone or imine group. 

SCHEME 15 Ruthenium-catalyzed oxidative annulation of enamide with alkynes forming N-acylpyrrole-2-carboxylates. 

Scheme 3.15 Palladium-catalyzed oxidative annulation of phenols and alkynes.

In 2009, Fagnou et al. discovered a Rh(III)-catalyzed synthesis of substituted isoquinolines 45 by oxidative annulation between N-tBu aromatic aldimines and internal alkynes [28a]. The -Bu leaving group was eliminated as isobutene in the reaction process and avoided the generation of a mixture of isoquinolines. However, the substrate scope was limited to aldimines, and a stoichiometric amount of Cu(0Ac)2-H20 was used as an external oxidant. Mechanistic studies omitted the ort/zo-alkenylation/64 -electrocyclization/oxidation pathway, and intermediate H2 was crucial for the C-N reductive elimination to proceed (Eq. (5.44)). At the same time, Satoh and Miura groups also exploited a Rh(III)-catalyzed oxidative cyclization of N-H benzophenone imine and internal alkynes to give isoquinolines [28b]. Both aromatic and aliphatic alkynes were agreeable for this protocol, but a stoichiometric amount of the Cu(II) salt was required. 

There has been a considerable focus on the development of reliable conditions for Rh-catalyzed C-N bond formation in the absence of metal oxidants. The first example of Rh(III)-catalyzed oxidative annulation reactions of a, -unsaturated oximes and alkynes was described by Rovis in 2011 for the construction of pyridine derivatives (Eq. (5.90)) [49a]. Equations (5.91)-(5.96) illustrate subsequent modifications of these reactions for the synthesis of various substituted pyridines in good yields. Catalytic amounts of Rh, alkyne/alkene substrates, and a stoichiometric amount of a cooxidant, such as AgOAc or Cu(0Ac)2-H20, were required to facilitate catalyst turnover [49b-g]. 

The synthesis of naphtho[l,8- c]pyran derivatives and related compounds via the oxidative annulation of 1-naphthols with internal alkynes was first reported by the Miura group in 2010 (Scheme 6.15) [27]. A series ofnaphtho[l,8-hc]pyran derivatives was obtained in good yields with 1 mol% [RhCp Cl2]2 in the presence of o-xylene or DMF. 

Shortly after, the same group reported a Rh(III)-catalyzed oxidative annulation of benzyl alcohols with internal alkynes for the synthesis of isochromenes (Scheme 6.16a) [28]. Interestingly, a,a-dimethylallyl alcohol also underwent the oxidative annulation reaction to give the corresponding products in good yields... 

Scheme 6.16 Synthesis of isochromenes by oxidative annulation of benzyl alcohols with alkynes by Miura and Tanaka.

In 2013, the synthesis of phosphaisocoumarins is achieved by Miura and coworkers via Rh(III)-catalyzed oxidative annulation of phenylphosphonic acids with alkynes (Scheme 6.25a) [40]. Shortly after, Lee and coworkers reported a similar result using phenylphosphinic or alkenylphosphonic acids to afford phosphaisocoumarins in good yields (Scheme 6.25b) [41]. 

Hydroxyl group-directed oxidative annulations with alkynes for the production of fluorescent pyrans were reported (Eq. (7.7)) [12]. Not only naphthols but also 4-hydroxycoumarin and 4-hydroxy-substituted quinolin-2-one underwent this ruthenium(II)-catalyzed C-H/O-H bond functionalization process in a highly chemo- and regioselective manner. Competition reactions showed that electron-deficient alkynes are more reactive. Deuterium experiments also revealed a reversible C-H bond ruthenation step via carboxylate assistance. 

Recently, Ackermann and coworkers reported aliphatic hydroxyl-directed oxidative annulation reactions of benzyl alcohols with alkynes to form isochromene derivatives (Eq. (7.11)) [16]. This C-H/O-H functionalization process performed smoothly by using [RuCl2(/ -cymene)]2 (5 mol%)/AgPFg (20 mol%) as catalyst and Cu(OAc)2 H2O (20 mol%) as oxidant under an atmosphere of air. Various tertiary benzylic alcohols, a,a-dimethylallyl alcohol, and diverse internal alkynes are appropriate substrates for this transformation. The reaction occurred with moderate to high regioselectivity for unsymmetrical alkylarylacetylene, and an irreversible C-H metalation step is involved in the catalytic cycle. 

Lam and coworkers explored the direct C- bond alkenylation of 2-aryl-3-hydroxy-2-cyclohexenones (Eq. (7.14)) [20] after their studies on oxidative annulation of alkynes with these substrates [21]. The resulting benzopyrans were formed in the presence of [RuCl2(p-cymene)]2 (2.5 mol%), Cu(OAc)2 (2.1 equiv.), and K2CO3 (2.0 equiv.) in up to 78% yield via oxa-Michael-type addition of... 

Then until 2011, the Ackermann group reported a ruthenium(II)-catalyzed oxidative annulations of alkynes with benzamides (Eq. (7.22)) [29]. In this method, Cu(OAc)2 H2O was used as the terminal oxidant to regenerate the ruthenium(II) catalyst in the catalytic cycle. This cyclization reaction proceeded via cleavage of both ortho-C H and amide N-H bonds of benzamides to form isoquinolones in high chemo- and regioselectivity. The insertion of unsymmetrical alkylarylalkynes occurred with a connection of the electron-deficient alkyne carbon with nitrogen atom selectively. Moreover, electron-deficient alkynes exhibited higher reactivity in this transformation. 

Under conditions of C-H/N-H bond functionalization, aryl-, heteroaryl-, and alkenyl-substituted IH-pyrazoles underwent oxidative annulation with aryl and alkyl alkynes in high chemo- and regioselectivity in the presence of Ru(II)/AgSbFg catalyst (Eq. (7.28)) [36]. Aryl alkynes particularly bearing electron-donating substituents are more reactive in the present reaction system. A cationic ruthenium(II)-catalyzed reversible C-H bond metalation step was observed in the H/D exchange experiments. 

Scheme 7.9 Proposed mechanism for ruthenium-catalyzed oxidative annulations of isoquinolones with alkynes.

Under similar reaction conditions, a regioselective oxidative annulation of quinazolones with alkynes was reported by Peng and coworkers (Eq. (7.31)) [39]. A series of fused polycyclic heteroarenes were formed in moderate to high yields with a broad substrate scope. The substrates bearing electron-donating... 

Oxidative annulation of enamides with alkynes via ruthenium(II)-catalyzed cleavage of C(sp )-H/N-H bonds was described by Li and Wang (Eq. (7.36)) [45]. The Af-acetyl-substituted pyrroles were produced in high yield in the presence of 5 mol% of [RuCl2(p-cymene)]2 catalyst and 0.5 equiv. of Cu(OAc)2 HjO in DCE at 100 °C for 12 h. Interestingly, this process can afford M-unsubstituted pyrroles... 

A wide variety of heterocycles can be readily prepared by the heteroannulation of alkynes. For example, the palladium-catalyzed annulation of internal alkynes by 2-iodoanilines provides easy access to 2,3-disubstituted indoles by a process that involves initial reduction of Pd(OAc)2 to Pd(0), oxidative addition of the aryl halide to Pd(0), c/s-addition of the arylpalladium... 

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