Wacker-type cyclization

Early mechanistic studies have indicated that the oxypalladation step in the Wacker process proceeds through an <37z/z-pathway,399 although recent deuterium-labeling experiments have shown the viability of a yy/z-mechanism involving insertion of a metal-coordinated oxygen into the alkene.400,401 For example, with excess chloride ion present, the Wacker-type cyclization of a deuterated phenol system occurred in a primarily //-pathway, whereas the oxypalladation step favored a yy/z-mode in the absence of excess chloride ion (Scheme 16). Thus, either mechanism may be operative under a given set of experimental conditions. 

Asymmetric induction has also been achieved in the cyclization of aliphatic alcohol substrates where the catalyst derived from a spirocyclic ligand differentiates enantiotopic alcohols and alkenes (Equation (114)).416 The catalyst system derived from Pd(TFA)2 and (—)-sparteine has recently been reported for a similar cyclization process (Equation (115)).417 In contrast to the previous cases, molecular oxygen was used as the stoichiometric oxidant, thereby eliminating the reliance on other co-oxidants such as GuCl or/>-benzoquinone. Additional aerobic Wacker-type cyclizations have also been reported employing a Pd(n) system supported by A-heterocyclic carbene (NHC) ligands.401,418... 

Wacker cyclization has proved to be one of the most versatile methods for functionalization of olefins.58,59 However, asymmetric oxidative reaction with palladium(II) species has received only scant attention. Using chiral ligand 1,1 -binaphthyl-2,2 -bis(oxazoline)-coordinated Pd(II) as the catalyst, high enantioselectivity (up to 97% ee) has been attained in the Wacker-type cyclization of o-alkylphenols (66a-f) (Scheme 8-24). 

A palladium-mediated Wacker-type cyclization process was applied in an efficient single-step synthesis of furofur-ans and furopyrroles 489 from propargyl alcohols (or amines) 487 and arylidene (or alkylidene) /3-ketosulfones 488 <2000JOC3223>. 

Scheme 12.23. Synthesis of burseran using a three-component conjugate addition/Wacker-type cyclization, by Balme and co-workers [79]. DMSO = dimethylsulfoxide, THF = tetrahydrofuran, Ra-Ni = Raney nickel.

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>. 

The stereochemical course of Wacker-type cyclization, when the Exercise 12-5... 

Uozumi developed polymer-supported 2,2 -bis(oxazolin-2-yl)-l,l -binaphthyls 252 as chiral ligands for the asymmetric Wacker-type cyclization reaction (Scheme 3.81) [152]. In the presence ofthe polymeric catalyst derived from [Pd(MeCN)4](BF4)2] and 252 o-allylphenol, 253 was asymmetrically cychzed to give 254 in 46% yield with 95% ee. 

In 2003, Stoltz at CalTech described a palladium-catalyzed oxidative Wacker cyclization of o-allylphenols such as 55 in nonpolar organic solvents with molecular oxygen to afford dihydrobenzofurans such as 56.44 Interestingly, when (-)-sparteine was used in place of pyridine, dihydrobenzofuran 56 was produced asymmetrically. The ee reached 90% when Ca(OH)2 was added as an additive. Stoltz considered it a stepping stone to asymmetric aerobic cyclizations. In 2004, Mufiiz carried out aerobic, intramolecular Wacker-type cyclization reactions similar to 55—>56 using palladium-carbene catalysts.45 Hiyashi et al. investigated the stereochemistry at the oxypalladation step in the Wacker-type oxidative cyclization of an o-allylphenol. Like o-allylphenol, o-allylbenzoic acid 57 underwent the Wacker-type oxidative cyclization to afford lactone 58.47... 

One of the exciting developments of the Wacker-type oxidation is the asymmetric synthesis of the reaction. For instance, using a new chiral bis(oxazoline) ligand L = 3,3 -Disubstituted 2,2 -bis(oxazolyl)-l,r-binaphthyls (boxax), a catalytic asymmetric Wacker -type cyclization converted allyl-phenol 55 to dihydrofuran 74 with 67% ee.ss... 

Binaphthyl-bisoxazoline ligands (the so-called boxax) [165,166] have also been immobilized on various polymer supports [167]. A palladium complex of polymeric boxax 116 catalyzed the Wacker-type cyclization [168, 169] of al-lylphenol 117 with up to 96% ee (Scheme 38) [170]. 

Complexes 24, 25, and 26 aU possess two neutral and two anionic ligands, respectively, and they are included in this section although they do not have halide ligands. Each of C2-symmetric bisoxazoline complexes 24 and 25 has two tiifluoroacetate ligands and is a good catalyst for asymmetric Wacker-type cyclization. Complex 26, applied to the asymmetric Fujiwara-Moritani reaction, is a rare example of having anionic chelate... 

Allylpalladium complexes with BOX-type ligands and glucopyrano-oxazoline-palladium catalysts were used as catalysts for enantioselective allylic substitution (277). A chiral bisoxazoline ligand (BOXBZ) developed by Pfaltz has been used for asymmetric carbo- and heteroannulation reactions (278). An axial binaphthyl-based ligand possessing oxazolyl substituents (BOXAX) was developed by Hayashi and co-workers and successfully applied for the asymmetric Wacker-type cyclization (279). 

A significant experimental problem in Wacker-type cyclization consists in the nature of the reoxidant Traditional reoxidants such as benzoquinone or copper] 11) dichloride have the disadvantage of difficult separation and sometimes the occurrence of product contamination. A way to overcome this problem lies in the exclusive use of dioxygen as the reoxidant however, the activation barrier for reoxidation of simple palladium salts is usually too high. A significant observation was made by Larock [26] and Hiemstra [27] that dimethyl sulfoxide (DMSO) as solvent markedly enhanced the aerobic reoxidation [28]. 

For example, under such aerobic conditions, Stoltz et al. [32] accomplished clean Wacker-type cyclization of 2-allyl phenols 5, demonstrating the superiority of the aerobic system. 

Scheme 100 Wacker-type cyclization for the synthesis of spiroacetals...

Uozumi Y, Kato K, Hayashi T. Catalytic asymmetric Wacker-type cyclization. 7. Am. Chem. Soc. 1997 119 5063-5064. 

Wang F, Zhang YJ, Yang G, Zhang W. Highly enantioselec-tive Pd(II)-catalyzed Wacker-type cyclization of 2-allyl-phenols by use of bisoxazoline ligands with axis-unfixed biphenyl backbone. Tetrahedron Lett. 2007 48 4179-4182. 

Aral MA, Kuraishi M, Aral T, Sasai H. A New asymmetric Wacker-type cyclization and tandem cyclization promoted by Pd(II)-spiro bis(isoxazoline) catalyst. J. Am. Chem. Soc. 2001 123 2907-2908. 

The asymmetric Wacker-type cyclization of phenolic olefins (93) using the chiral tetraoxazoline ligand (95) has been developed the resulting pyran derivatives (94) were obtained in <92% ee. ... 

Uemura s discovery also opened the door to direct 02-coupled asymmetric catalytic oxidative kinetic resolution (OKR) of alcohols with catalytic amounts of chiral ligands. Simultaneously both Stoltz and Sigman reported the aerobic OKR of secondary alcohols using catalytic Pd[(-)-sparteine]Q2 with the addition of catalytic (-)sparteine, 36 (Scheme 5.18E) [66]. Mechanistic studies on this system performed by Sigman and coworkers have found the chiral amine to have a dual role as a hgand and an exogenous base [66e,hj. This system has been further apphed to asymmetric Wacker-type cyclizations [2 c, 22a,bj. 

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