Pd-catalyzed oxidation Cyclization

Ohta has developed a facile and efficient synthesis of pyrroles 42 that involves the Pd-catalyzed oxidative cyclization of hydroxy enamines such as 41 [41]. Fused pyrroles 43 and 44 were also synthesized in similar fashion. 

A Pd-catalyzed oxidative cyclization of phenols with oxygen as stoichiometric oxidant in the noncoordinating solvent toluene has been developed for the synthesis of dihydrobenzo[ ]furans (Equation 136). Asymmetric variants of this Wacker-type cyclization have been reported by Hayashi and co-workers employing cationic palladium/2,2 -bis(oxazolin-2-yl)-l,l -binaphthyl (boxax) complexes <1998JOC5071>. Stoltz and co-workers have reported ee s of up to 90% when (—)-sparteine is used as a chiral base instead of pyridine <2003AGE2892, 2005JA17778>. Attempts to effect such a heteroatom cyclization with primary alcohols as substrates, on the other hand, led to product mixtures contaminated with aldehydes and alkene isomers, which is in contrast to the reactions with the Pd(ii)/02 system in DMSO <1995TL7749>. 

Sasai s group [13] developed a series of bisnitrogen ligands with fused hetero spiro cyclic backbones, including spiro bis(isoxazoline) 11 and 12, spiro isoxazole-isoxazoline 13, spiro bis(oxazoline) 14, spiro bis(pyrazole) 15, and spiro bis(isoxazole) 16 (Figure 3). Ligands 11 [14] and 13 [15] exhibited excellent reactivity and enantioselectivity in the Pd-catalyzed oxidative cyclization reactions. 

Table 3 Pd-catalyzed oxidative cyclization of aryl amines, aryl ethers, and benzanilidc ...

An important variation of the Mori-Ban-Heck indole synthesis is Pd-catalyzed oxidative cyclization of A/-aryl enaminones and enamines, as largely developed by Glorius (Scheme 4, equations 1 and 2) [44-46]. The C-2 substituent was easily varied, and the method was extended to imine cyclization (equation 2). Related Pd-catalyzed oxidative cyclizations were described by Li (carbazolones) [47],... 

Guan (1,3-disubstituted indoles) [48], Rueping (photoredox catalysis) [49], and Jiao (/V-alkynylaniline hydroamination) [50]. Before Glorius, Lee and colleagues employed Pd-catalyzed oxidative cyclization in a synthesis of duocarmy-cin SA analogues [51]. Some additional examples of this oxidative cyclization to give indoles are in later chapters. 

In a multitude of publications, Knolker and coworkers have parlayed the twin Pd-catalyzed oxidative cyclizations to give carbazoles or carbazole-l,4-quinones into an impressive collection of natural-product syntheses [8-12] some recent examples are illustrated in Scheme 2 and include syntheses of glycozoline (equation 1) [13], isokoeniginequi-none A (equation 2) [14], and mukonine (equation 3) [15]. Knolker and colleagues were able to isolate and crystallize the palladium complex 2 from the Pd-catalyzed reaction of diaryl amine 1 to give four isomeric carbazoles, from which an x-ray crystal structure was obtained [16]. 

Intramolecular alkoxycarbonylation of alkynols is parallel to what has been described for alkenols except that functionalization of the triplebond produces a double bond. No lactone formation is observed in the Pd(II)-catalyzed oxidative cyclization-carbonylation of alkynes. Instead [(methoxycarbonyl)methylene]tetrahydrofurans are selectively formed [134, 135]. Moreover, starting from an enynol, furan-2-acetic ester is obtained resulting from a final aromatization step [136]. 

Palladium-catalyzed oxidative cyclization of aryl homoallyl ethers affords 4-methyl-2//-chromenes in moderate yield. The reaction is proposed to proceed via activation of the alkene by coordination to Pd(ll) followed by intramolecular nucleophilic attack by the arene. Subsequent [1-hydride elimination and isomerization then affords 4-methyl-27/-chromenes (Scheme 13). Electron-rich aryl homoallyl ethers give the best yield and good regio-selectivity is observed for the reaction of unsymmetrical arenes <2005OL3355>. 

An intramolecular double nitrile oxide cycloaddition with alkyne and olefin moieties was exploited in the synthesis of novel unsymmetrical hybrid spiro (isoxazole-isoxazoline) ligands 14 which were effective in promoting a Pd-catalyzed tandem cyclization <07TA919>. 

Z)-Enynols can also be employed as substrates when ruthenium or iridium catalysts are used <2006ASC1671>. Furan-2-acetic esters are obtained by a Pd(n)-catalyzed oxidative cyclization-alkoxycarbonylation of (Z)-enynols <1999JOC7693>. In analogy, 2-furan-2-ylacetamides are obtained in an aminocarbonylation with secondary amines (Equation 22) <2006S4247>. 

A convenient method for the synthesis of benzofurans proceeds via Pd(ll)-catalyzed oxidative cyclization of o-allylphenols (Equation 112) <1998JOM(560)163>. Dimethylformamide (DMF) accelerates the reaction to completion within minutes and the addition of LiCl allows the reaction be run at room temperature. 

In 2011, Yoshikai and Liu developed a Pd(ii)-catalyzed oxidative cyclization reaction of a 2-arylphenol to dibenzofuran derivatives respectively (Scheme 2.27). ° The catalytic system features a simple combination of a palladium(ii) salt and a pyridine ligand and the use of pero g benzoate as an inexpensive and convenient oxidant. In their mechanistic experiments, they showed that the reaction involves Pd(ii)-mediated C-H bond cleavage as the rate-limiting step, which is followed by oxidation to a high-oxidation-state palladium species and subsequent C-O bond-forming reductive elimination. 

Later on, Hamed s group explored another desymmetrization method based on a Pd-catalyzed acetoxylation-cyclization of 45 -type alkyne-tethered cyclohexa-2,5-dienones 75, which were generated by a DIB- or BTI-mediated dearomatization of para-substituted phenols 51 in the presence of propargyl alcohol or but-2-yn-l-ol as solvent (Fig. 20). The control of stereoselectivity of the Pd-catalyzed cycUzatiOTi event was brought by the use of the pinene-derived bipyridine ligand 76, but enantiomeric excesses of only up to 62% could be obtained for the formation of the bicycles 77 [68]. An extension of this exploratory work was later reported by Sasai and co-workers, who used their SPRIX ligand 78 under oxidative conditions to generate a-acetoxylated variants of 77 (i.e., 79) with ee values up to 82% (Fig. 20) [69]. 

Bisalkoxycarbonylation of olefins commonly uses this Pd(II)-Cu(I) bimetallic catalysis some additives, such as phosphine sulfides and thiourea-based ligands, are known to facilitate the conversion. Recently Pd(II)-Cu(l)-catalyzed oxidative cyclization has been reported in the preparation of dihydrop3Ta-nones and furanones (eq 25). ... 

Gabriele, B., Salerno, G. and Cassoni, S. (2005) Heteroqfdic derivative syntheses by palladium-catalyzed oxidative cyclization-alkoxycarbonylation of substituted y-oxoalkynes. The Journal of Organic Chemistry, 70, 4971 979. no Gabriele, B., Salerno, G., Fazio, A. and Campana, F.B. (2002) Unprecedented carbon dioxide effect on a Pd-catalysed oxidative carbonylation reaction a new synthesis of pyrrole-2-acetic esters. Journal of the Chemical Society, Chemical Communications, 1408-1409. m Gabriele, B., Salerno, G., Fazio, A. and Veltri, L (2006) Versatile synthesis of pyrrole-2-acetic esters and (pyridine-... 

Besides six-membered heterocycles, the construction of five-membered analogs by C-H olefination of phenol derivatives has also been reported. In 2011, Wang and coworkers reported a palladium-catalyzed oxidative cyclization of 3-phenoxy acrylates to construct benzofurans via an intramolecular aromatic C-H olefination (Scheme 3.13) [31]. In the presence of 5 mol% Pd(OAc)2/PPh3 and 2.0 equiv. of CF3C02Ag, benzofurans were obtained in good yields in... 

Inspired by the synthesis of tetrahydrofurans that are imbedded in natural products, a number of groups have examined the metal-catalyzed oxidative cyclization of 1,5-dienes and/or hydroxyolefins where the alkenes in both instances are inactivated. Metals that have been shown to be capable of carrying out these transformations include Mn, Ru, Pd, Os, and Co. As is outlined in this section, these reactions have several significant advantages over other tetrahydrofuran-... 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Pd-cataly2ed reactions of butadiene are different from those catalyzed by other transition metal complexes. Unlike Ni(0) catalysts, neither the well known cyclodimerization nor cyclotrimerization to form COD or CDT[1,2] takes place with Pd(0) catalysts. Pd(0) complexes catalyze two important reactions of conjugated dienes[3,4]. The first type is linear dimerization. The most characteristic and useful reaction of butadiene catalyzed by Pd(0) is dimerization with incorporation of nucleophiles. The bis-rr-allylpalladium complex 3 is believed to be an intermediate of 1,3,7-octatriene (7j and telomers 5 and 6[5,6]. The complex 3 is the resonance form of 2,5-divinylpalladacyclopentane (1) and pallada-3,7-cyclononadiene (2) formed by the oxidative cyclization of butadiene. The second reaction characteristic of Pd is the co-cyclization of butadiene with C = 0 bonds of aldehydes[7-9] and CO jlO] and C = N bonds of Schiff bases[ll] and isocyanate[12] to form the six-membered heterocyclic compounds 9 with two vinyl groups. The cyclization is explained by the insertion of these unsaturated bonds into the complex 1 to generate 8 and its reductive elimination to give 9. 

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

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