Oxidative annulation

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... 

A vigorous reaction occurs when 1,2,5-thia- and selena-diazole A -oxides annulated onto pyrimidine rings are treated with 10-30% hydrogen peroxide resulting in the formation of 6-amino-5-nitrouracils (Scheme 25) <2000CHE1359>. 

By using an olefin embedded into the parent molecule Stoltz developed the oxidative annulation of indoles. The optimal catalyst consisted of palladium acetate and ethyl nicotinate, and molecular oxygen was used as the oxidant in the process. The reaction proceeded equally well irrespective of the attachment point of the alkyl chain bearing the pendant olefin bond on the five membered ring, and the formation of five and six membered rings were both effective (6.95.),127... 

D. P. Curran and P. B. Jacobs, Combination Claisen-nitrile oxide annulation. A strategy for ring construction with rigid stereocontrol dictated by an allylic hydroxyl group, Tetrahedron Lett. 26 2031 (1985). 

Alkyl enol ethers and vinyl sulfides may also be oxidatively annulated onto electron-rich aromatic rings (Scheme 71)168. 

Examples of nitrogen-containing heterocycle syntheses based on condensation reactions continue to be forthcoming. Examples include a tandem oxidation-annulation of propargyl alcohols in a one-pot synthesis of pyridines (Equation 148) <2003SL1443>, trifluoromethyl-substituted pyridines (Scheme 94) <2003S1531>, and standard malononitrile additions to a,/3-unsaturated ketones <1995JCM392>. 

Manganese(m)-mediated oxidative annulation of methylenecyclopropanes with 1,3-dicarbonyl compounds produces spirocyclopropane 2,3-dihydrofuran derivatives in moderate to good yields under mild conditions (Equation 63) <2005JOC3859>. 

Tandem oxidation-annulations of propargylic alcohols yield pyridines via a one-pot synthesis <03SL1443>. 

Radical-mediated oxidative annulation of heteroaromatic compounds 03S803. 

The fragment corresponding to C-9 to C-13 was then constructed by a Raney-nickel desulfurization and debenzylation to afford an intermediate alcohol, which was dehydrated and oxidatively cleaved to afford 167 in an overall yield of 80%. Ketone 168, the C-3 to C-8 segment, was produced in 85% yield from 166 via acid deprotection of the MOM group followed by oxidation. Annulation of the... 

Scheme 7.111 NHC-catal) ed oxidative annulation of enals with p-diketones reported by Studer.

Scheme 7.112 NHC-catalyzed oxidative annulations of enals with indolin-3-ones reported by Du and Lu.

Scheme 7.113 NHC-catalyzed oxidative annulations of a,p,P -trisubstituted enals with cyclic sulfonylimines reported by Bode.

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). 

The choice of solvent also proved to be important in these indole annulations. In standard solvents and in the absence of catalyst, the annulated indole products were susceptible to oxidative decomposition. After a thorough analysis of solvent and catalyst effects, it was found that the products were stabilized in the presence of the Pd(OAc)2/ethyl nicotinate catalyst in a 4 1 mixture of tert-amyl alcohol/AcOH as the solvent. Since the oxidative decomposition of indoles is generally initiated by addition at C(3), it was hypothesized that the catalyst and/or AcOH can act as a competitive inhibitor. With this carefully optimized system, the oxidatively annulated indoles could be accessed in good to excellent yields. 

Figure 9.6 The palladium-catalysed oxidative annulation of indoles.

Ferreira, E.M. and Stoltz, B.M. (2003) Catalytic C-H bond functionalization with paUadium(II) aerobic oxidative annulations of indoles. J. Am. Chem. Soc., 125, 9578-9. 

Shortly afterwards, Stoltz et al. (5- and 6-exo-trig cyclizations) [129] and Beccalli et al. (6-exo-trig cyclization) [135] simultaneously reported palladium] I)-catalyzed oxidative annulations of indoles. The observation that an electronically modified pyridine ligand increases chemical yields emerged from the systematic survey by Stoltz et al. [vide supra) [129]. Under an atmosphere of dioxygen, a number of indoles cyclized in moderate to good yields (218 221 and 219 222 Scheme 7.53). As a quaternary carbon is formed upon cyclization of the C—Pd" onto C-1... 

Sol 4. (a) Oxidative annulation of alkenols to form six-membered rings may be accomplished with mildly acidic oxidant pyridinium chlorochromate (PCC). This process is postulated to occur via initial oxidation of the citronellol (I) to... 

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... 

Ruthenium(II)-mediated oxidative annulation reaction of benzoic acids and cyclopropylarylethynes furnishes a mixture of 3- and 4-cyclopropyl substituted isocoumarins (130BC142).A facile one-pot synthesis of4-aryl-isocoumarins involves an acidic hydrolysis of ( -2-(l-aryl-2-methoxy-ethenyl)benzaldehydes with HBr and subsequent oxidation with PCC (13HCA2173). 

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. 

Ferreira EM, Stoltz BM (2003) Catalytic C-H bond fimctimialization with palladium(II) aerobic oxidative annulation of indoles. J Am Chem Soc 125 9578-9579... 

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]. 

---