Cyclization oxypalladation

As an example, formation of cyclic alkenyl ethers 2 and 3 from acetylenic aldehyde 1 is catalyzed by Pd(OAc)2,. Also, 2-alkynylbenzaldehyde 7 was converted to the cyclic alkenyl ether 8 in high yield in the presence of Pd(OAc)2 (5 mol%) in MeOH. In these reactions, Pd(OAc)2 as a Lewis acid, coordinates to the carbonyl group to facilitate the formation of the hemiacetals as shown by 5, Then either 5-exo or 6-endo cyclization (oxypalladation of triple bond) occurs to give 6 or 6a. Finally, protonolysis of 6 and 6a affords the cyclized products 2 and 3 with regeneration of Pd(OAc>2.. In this reaction, Pd(OAc>2 exhibits dual roles [1]. 

Phenolic oxygen participates in facile oxypalladation. The intramolecular reaction of 2-hydroxychalcone (105) produces the flavone 106[127]. The ben-zofuran 107 is formed from 2-allyIphenol by exo cyclization with Pd(OAc)2, but benzopyran 108 is obtained by endo cyclization with PdChf S], Normal cyclization takes place to form the furan 109 from 2-(l-phenylethenyl)phe-nol[129]. Benzofuran formation by this method has been utilized in the synthesis of aklavinione (110)[130]. 

The mechanism of the rearrangement catalyzed by Pd(fl), typically by PdCl2(RCN)2, is explained by the oxypalladation of an alkene to form 810 as an intermediate, or cyclization-induced rearrangement. As a limitation, no rearrangement takes place when the allylie ester 812 is substituted at the C-2 position of the allyl group, while a smooth rearrangement of 811 takes place[500]. 

A deuterium-labeling study of a reaction of this type demonstrated syn stereoselectivity in both the oxypalladation and P-elimination, which indicates that the cyclization occurs by internal migration, rather than by an anti nucleophilic capture.113 This particular system also gives products from double-bond migration that occurs by reversible Pd(II)-D addition-elimination. 

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. 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

The phenolic oxygen on 2-allyl-4-bromophenol (7) readily underwent oxypalladation using a catalytic amount of PdCl2 and three equivalents of Cu(OAc)2, to give the corresponding benzofuran 8. This process, akin to the Wacker oxidation, was catalytic in terms of palladium, and Cu(OAc)2 served as oxidant [17]. Benzofuran 10, a key intermediate in Kishi s total synthesis of aklavinone [18], was synthesized via the oxidative cyclization of phenol 9 using stoichiometric amounts of a Pd(II) salt. 

Successive intramolecular oxypalladation of dihydroxyalkynes has been used for the synthesis of spirocyclic and bridged acetals. Equations (78) to (80) show the syntheses of some insect pheromones by this method.198 The results from several diols suggest that preferred modes for initial cyclization are 5-endo > 5-exo > 6-endo. A related conversion of 8-hydroxyoct-4-ynoic acid to an oxaspirolactone with mercury(II) oxide has been reported.199... 

Cyclization of a variety of y-allenic alcohols with silver nitrate proceeds by 5-exo cyclization to form 2-alkenyltetrahydrofurans (equation 87).205c 206 Little stereoselectivity is seen in cyclizations of secondary alcohols. Cyclization by intramolecular oxypalladation/methoxycarbonylation or oxymercuration followed by transmetallation and methoxycarbonylation also showed no stereoselectivity (equation 88 and Table 24, entries 1 and 2).50 207 However, cyclization of the corresponding r-butyldimethylsilyl ether derivatives with mercury(II) trifluoroacetate followed by transmetallation/methoxycarbonylation pro-... 

The formation of spirolactams 47-49 could be rationalized in terms of a sequence domino cyclization of a-allenols-cross coupling reactions. A palladium (Il)-catalyzed mechanism for the domino sequence leading to spiranic adducts 47-49 is proposed in Scheme 17. It could be presumed that the initially formed allenepalladium complex 50 undergoes an intramolecular attack by the hydroxyl group (oxypalladation), giving rise to the spirocyclic vinylic palladium species 51. 

A phenolic oxygen participates in facile oxypalladation. 2-Allylphenol (55) undergoes clean cyclization to 2H-l-benzopyran (56) in DMSO under air with a catalytic amount of Pd(OAc)2 without a reoxidant. 2-Methylbenzofuran (57) is obtained when PdCl2 is used [50]. But different chemoselectivity with the Pd(II) salts was also reported [51]. Catalytic asymmetric cyclization of the tetrasubstituted 2-allylic phenol 58 using the binaphthyl-type chiral ligand 60, called (.S, .S )-ip-borax, afforded the furan 59 with 96% ee. Use of Pd(CF3 002)2 as a catalyst is essential in the presence of benzoquinone [52]. Formation of the benzofuran 62 from 61 has been utilized in the synthesis of aklavinione [53]. The intramolecular reaction of 2-hydroxychalcone (63) produces the flavone 64 [54]. 

Cyclization of a-propargyl-/3-ketoesters can be combined with cross-coupling of aryl halides or triflates in an oxypalladation-reductive elimination reaction to yield arylfurylmethanes (Equation 12) <2003X4661 >. 

Consider the first oxidative cyclization shown to produce A. It was proposed originally that the cyclization proceeded through if-allyl-Pd intermediate B. Treatment of C, however, which was predicted to form B under the same reaction conditions, led to A in less than 5% yield, even after 21 hours of reaction time. The researchers involved were forced to come up with another mechanism. Propose an alternate catalytic pathway that involves complexation of the phenolic oxygen and side chain C=C bond to Pd and then oxypalladation of the C=C bond.213... 

Arai et al. reported that asymmetric tandem cyclization of the dialkenyl alcohol 182 in the presence of Pd(II)— spiro bis(isoxazoline) catalyst gave the bicyclic heterocycle 183 in 89% yield with 82% ee (Scheme 61).132d The reaction proceeds through Wack-er-type oxypalladation, formation of the palladacycle 185 by carbopalladation of the resulting alkylpalla-dium intermediate 184, elimination of HX, and subsequent reductive elimination of Pd(0) to give the product 183. 

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... 

Intramolecular cyclization of alcohols to 1,3-dienes can lead to fused tetrahydrofurans and tetrahydropyrans. In this reaction, using 5 mol% Pd(0Ac)2, the first step involves a trans oxypalladation to form the heterocyclic ring and a jr-allyl palladium complex. In the presence of 0.2 equiv. of LiCl, AcO adds trans to the r-allyl, leading to a net cA-l,4 addition of oxygen nucleophiles to the diene. When LiCl is omitted, the AcO adds to the same face of the r-allyl as the palladium, giving net tra/ 5-1,4-addition of oxygen groups to the diene (Scheme 41). 

A phenolic oxygen participates in facile oxypalladation [16], Different chemos-electivity is observed depending on the catalytic species. The 2H-l-benzopyran 66 was formed cleanly from 2-allylphenol (65) by endo cyclization with Pd2(dba)3 or... 

Asymmetric domino cyclization of the unsaturated alcohol 71 proceeded smoothly to give the bicyclic compound 72 with 82% ee in 89% yield as a single diastereomer using a spiro bis(oxazoline) ligand which has a chiral spiro skeleton and two oxazoline rings. The reaction proceeds via the formation of 73 and 74 as oxypalladation products. BQ was used as a reoxidant [36],... 

PdCl2-catalyzed oxypalladation of 4-pentynoic acid generates the y-lactonic alkenylpalladium 266, and its protonolysis affords the y-methylene-y-lactone 267 with regeneration of Pd(II) [113]. A palladium cluster is a very active catalyst of the cyclization, and the S-methylene-S-lactone 268 was obtained from 5-hexynoic acid in high yield at 40°C in a few minutes [114]. 

Treatment of (Z)-pent-2-en-4-yn-l-ol 284 with Pdl2 and KI afforded furan 286 via oxypalladation, followed by protonolysis to give 285 and regeneration of Pdl2. KI is added to make Pdl2 soluble [119]. The corresponding thiol 287 undergoes a similar cyclization to form the thiophene 288 [120],... 

A similar experiment with an unsaturated alcohol reported by Stoltz also implies that syn oxypalladation occurs. Again, the observation of deuterium in the product implies that the alkoxyalkylpalladium intermediate contains the palladium cis to the alkoxo group and trans to the deuterium label. The stereochemical outcome of catalytic cyclizations reported by Wolfe also imply that cis oxypalladation occurs during certain transformations, as shown in Equation 9.82. 

A combination of Pd(dba)2 catalyst and KHCO3 in aqueous DMSO under air results in the 6-endo cyclization to give chromenes (2H-l-benzopyrans). Using this system, a wide variety of chromenes have been cleanly synthesized from 2-allylphenols (Scheme although the reaction time is rather long (3 days). The reaction could be accounted for by oxypalladation followed by Pd—H elimination. Alternatively, the allylic moiety may directly be converted into a 7r-allylpalladium intermediate formed in situ, and subsequently the oxygen nucleophile attacks at the remote end of the allylic system to give the chromene. 

Bicyclic acetals are obtained in the cyclization of alkenyl diols as shown in Scheme 31, where the attack of OH group toward an internal alkene formed after the oxypalladation process takes place.f " " Thus, optically active natural (5)-(-)-frontaUnt" m43] prepared from (5)-6,7-dihydroxy-6-methyl-l-heptene. Amberketal and its homologue are able to be similarly synthesized,... 

Cyclization of homoallylic alcohols bearing an OH group at the allylic position gives an oxypalladation intermediate in which the OH group is in the adjacent position of Pd—C bond. In such cases, elimination of Pd—OH predominates to give dihydrofurans as shown in Scheme 34.The same type of cyclization and elimination occurs with /3-diketones bearing allylic alcohol moiety. The cyclization proceeds via keto-enol tautomerism (Scheme 35). 

Unlike the cases of alkenes, Wacker-type intermolecular oxypalladation reactions of alkynes have not been extensively investigated, although their intramolecular cyclization reactions have been developed into synthetically useful procedures (Sects. V3.2). In principle, they can proceed by a few alternative paths shown for the cases of terminal alkynes in Scheme 14. In reality, however, alkynyl C—H activation by Pd to give alkynylpalladium derivatives shown in Scheme 3 may well be the dominant path, as suggested by the carbonylative oxidation of terminal alkynes to give alkynoic acid esters shown in Scheme 15. Oxidative dimerization of alkynes is a potentially serious side reaction. Further systematic investigation of this fundamentally important process appears to be highly desirable. 

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