Pd-Catalyzed Versions

In 2007, the same group reported a second-generation catalytic system using 10mol% of Cul/phenanthroline and 3mol% Pd(acac)2 for the synthesis of unsymmetrical biaryls 

It then became clear that only certain ortl o-substituted or heterocyclic carboxylic acids undergo this reaction. To overcome this limitation, Goossen and coworkers [33] employed aryl sulfonates instead of aryl halides as the coupling partners in combination with a catalyst generated in situ from Pdl2, tolyl-2,2 -bis(diphenylphosphino)-l,l -binaphthyl (Tol-BINAP) or P(p-Tol)3, CUjO, and phenanthroline. The weakly coordinating triflate ions, released in the cross-coupling step, are unable 

Further improvement of the reaction conditions allowed extending the substrate scope to less expensive aryl tosylates, using Pd(acac)2, the sterically electron-rich XPhos ligand, CU2O, and 

In 2011, Goossen, Underwood, and coworkers [36] developed a practical protocol that allowed performing the decarboxylative cross-coupling reactions in continuous flow reactors. The advantage of this method was that the reaction time was reduced and the formation of side products was minimized. 

---

One of the most powerful methods for bicyclic ketone construction is the intramolecular Pauson-Khand reaction (14 ->15). Although catalytic methods for this transformation have been put forward, they are not always successful. Jihua Chen and Zhen Yang of Peking University have now found (Organic Lett. 2005, 7, 593) that the cyclization proceeds quickly and efficiently with 5 mol % of the commercial grade of Co,(CO), if it is run in the presence of the inexpensive tetramethylthiourea. The authors have also reported (Organic Lett. 2005, 7, 1657) that TMTU is beneficial to the Pd-catalyzed version of the reaction. These advances will make the Pauson-Khand cyclization a more generally practical procedure. 

Until recently, a-substitution of carbonyl compounds was largely restricted to those cases where alkyl groups, such as Me, allyl, and benzyl, were introduced via classical enolate alkylation. a-Aiylation of ketones with aryl halides can be effected using K in NH3 [120-123]. However, this reaction does not appear to be satisfactory for selective -alkenylation and a-alkynylation. -Arylation of ketones has also been catalyzed by Ni [124] and Pd [125,126]. The Pd-catalyzed version employed enolstannanes. This reaction has also been applied to a-alkenylation [127]. However, these reactions appear to be of very limited scope. Thus, the Pd-catalyzed procedures appear to be satisfactory mainly for a-substitution of methyl ketones. Furthermore, none of them addresses the critical question of how to control the regiochemistry of c-substitution, i.e., a vs. a. Critically needed from the viewpoint of selective synthesis were... 

Over the past two decades, Pd- or Ni-catalyzed cross-coupling, especially Pd-catalyzed version, has become one of the most common methods (possibly the most common method) for highly selective synthesis of arylated alkenes, conjugated dienes, conjugated enynes (Sect, in.2.8), and other related aUcene derivatives, hi addition to Mg, Zn, Al, and Zr used since the 1970s, several other metals including Sn,[2 ] [27] and Cu[2 ] [ i have been extensively employed since around 1980. 

In all cases presented above, annulation reactions were limited to intramolecular arrangements. There are also transformations involving two independent reaction partners. In 2005 a Cr-mediated synthesis of PAHs from halobiaryls was published [94]. The 2,2 -dihalobiaryl starting material 150 is first treated with BuLi before addition of the Cr reagent. Final treatment with an acetylenic reaction partner delivers the phenanthrene core 151 (Scheme 38). Recently, Wu and coworkers presented a Pd-catalyzed version starting from 2,2 -diiodobiphenyls to access substituted phenanthrenes [95]. 

The benzene derivative 409 is synthesized by the Pd-catalyzed reaction of the haloenyne 407 with alkynes. The intramolecular insertion of the internal alkyne, followed by the intermolecular coupling of the terminal alkyne using Pd(OAc)2, Ph3P, and Cul, affords the dienyne system 408, which cyclizes to the aromatic ring 409[281]. A similar cyclization of 410 with the terminal alkyne 411 to form benzene derivatives 412 and 413 without using Cul is explained by the successive intermolecular and intramolecuar insertions of the two triple bonds and the double bond[282]. The angularly bisannulated benzene derivative 415 is formed in one step by a totally intramolecular version of polycycli-zation of bromoenediyne 414[283,284],... 

Asymmetric nucleophilic allylic substitution has rarely been studied in its heterogeneous version, probably because of the difficulties encoimtered in properly stabilizing and recycling Pd(0) species. Nevertheless, some promising examples have been pubhshed. Lemaire et al. [143] studied the activity and enantioselectivity of various chiral C2-diamines for the asymmetric Pd-catalyzed transformation of various allyl acetates. The structures tested are represented in Scheme 58. 

The Pd-catalyzed amination of / -rm-butylphenyl bromide with pyrrole in the presence of Pd(OAc)2, dppf and one equivalent of NaOr-Bu led to the Af-arylation product 88. A simplified version of the mechanism commences with the oxidative addition of p-te/t-butylphenyl bromide to Pd(0), giving rise to the palladium complex 89. Ligand exchange with pyrrole followed by deprotonation by the base (NaOr-Bu) results in amido complex 90. Reductive elimination of 90 then gives the amination product 88 with concomitant regeneration of Pd(0) catalyst. If the amine had a (3-hydride in amido complex 90, a (3-hydride elimination would be a competing pathway, although reductive elimination is faster than P-hydride elimination in most cases. 

Miki effected Pd-catalyzed cross-coupling between dimethyl 7-bromoindole-2,3-dicarboxylate and both tributylvinyltin and tributyl-1-ethoxyvinyltin to yield the expected 7-vinylindoles [197]. Hydrolysis of the crude reaction product from using tributyl-1-ethoxyvinyltin gave the 7-acetylindole. Sakamoto used dibromide 192, which was prepared by acylation of 7-bromoindole, in a very concise and efficient synthesis of hippadine [36]. The overall yield from commercial materials is 39%. Somewhat earlier, Grigg employed the same strategy to craft hippadine from the diiodoindoline version of 192 using similar cyclization reaction conditions ((Me3Sn)2/Pd(OAc)2), followed by DDQ oxidation (90%) [198]. 

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

An asymmetric version of the Pd-catalyzed hydroboration of the enynes was reported in 1993(118]. The monodentate phosphine (S)-MeO-MOP was used as a chiral ligand for the palladium catalyst. Enantioselectivity of the asymmetric hydroboration was estimated from the enantiopurity of homopropargyl alcohols, which were obtained from the axially chiral allenylboranes and benzaldehyde via an SE pathway (Scheme 3.78). 

Organometallic methods, with the possible exception of those involving the stoichiometric generation of enolates and other stabilized carbanionic species 140], have seldom been used in carbohydrate chemistry for the synthesis of cyclohexane and cyclopentane derivatives. The present discussion will not cover these areas. The earliest of the examples using a catalytic transition metal appears in the work of Trost and Runge [41], who reported the Pd-catalyzed transformation of the mannose-derived intermediate 22 to the functionalized cyclopentane 23 in 98% yield (Scheme 10). Under a different set of conditions, the same substrate gives a cycloheptenone 24. Other related reactions are the catalytic versions of the Ferrier protocol for the conversion of methylene sugars to cyclohexanones (see Chap. 26) [40,42,43]. 

The transition metal-catalyzed addition of alcohols to unsaturated systems has not been widely investigated. Reports on addition of alcohols to 1,3-diene [24] or allene [25] have appeared but have very limited scope. We recently reported the palladium/benzoic acid-catalyzed inter- and intramolecular addition of alcohols to alkynes in which various acyclic and cyclic allylic ethers are produced [26], The Pd-catalyzed addition of alcohols to alkylidenecyclopropanes proceeds smoothly providing a powerful tool for synthesis of allylic ethers [27a]. An intramolecular version of the hydroalkoxylation has been demonstrated in which the phenol-tethered alkylidenecyclopropanes undergo facile cyclization to give exomethylene products [27b],... 

The synthesis of 1-substituted tetrahydroisoquinolines using an intramolecular Pd-catalyzed a-enolate arylation was described. Treatment of a-amino esters such as 71 and 73 with LiOr-Bu, Pd2(dba)3 and ligand 75 or 76 afforded the corresponding isoquinolines 72 and 74. Investigations to develop an asymmetric version of this reaction were reported to be ongoing <02JOC465>. 

Cyanosilylation of alkynes with Me3SiCN is effectively catalyzed by a PdCl2 complex.263 Its intramolecular version is valuable for the stereo-defined synthesis of tri- and tetrasubstituted alkenes.264 A Pd-catalyzed system effects an efficient three-component coupling of Me3SiCN, highly electron-deficient alkenes, and allyl chlorides (Equation (69))/ 3 The... 

---