Intramolecular oxypalladation

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

Utimoto et al. synthesized substituted furans using a Pd-catalyzed rearrangement of easily accessible P/y-acetylenic ketones [103]. One plausible pathway is illustrated here using the transformation of p,y-acetylenic ketone 127 to 2,5-disubstituted furan 128. Enolization of 127 is followed by an intramolecular oxypalladation of the resulting enol 129 to form furylpalladium(II) species 130, which is subsequently treated with acid to give furan 128. 

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-... 

Cyclic ethers and amines can be formed if the nucleophile is an intramolecular alcohol or amine. Stoichiometric palladium can be avoided by using benzoquinone as the stoichiometric oxidant with a catalytic amount of palladium. In this example intramolecular oxypalladation of a diene is followed by attack of an external nucleophile on a TC-allyl complex. 

Allenols behaved similarly affording 5,6-dihydro-2H-pyrans 19 (Scheme 4). No expected product was found for the 3,4-allenols with R =R =R =H. Through control experiments with Ti-allylic Pd complexes it is believed that the reaction proceeded via the sequential intramolecular oxypalladation-intermolecular carbopalladation-p-dehalopalladation process (pathway 4, Scheme 1). 

In 1997, Hashmi et al. observed the Pd-catalyzed homodimerization of 1,2-allenyl ketones affording2-substituted4-(4 -oxo-2 -alken-2 -yl)furans (Scheme 31) [23]. The reaction may proceed via intramolecular oxypalladation involving the carbonyl oxygen, leading to the formation of furanylpalladium intermediate 69, followed by intermolecular carbopalladation with a second molecule of 1,2-allenyl ketone. Protonation of the C-Pd bond in 70 afforded the product 66 and regenerated Pd(II) (Scheme 32). 

Intramolecular oxypalladation of the allenyl aldehyde 249 generates the intermediary alkenylpalladium complex 250, and subsequent carbonylation affords the unsaturated ester 251 in 88 % yield. Propylene oxide is added as a scavenger of HCl [107]. 

Intramolecular oxypalladation of 5,6-dienoic acid 252 is followed by acrolein insertion to generate 254, which undergoes protonolysis to produce the aldehyde 253 without giving elimination product as a Heck-type reaction. The reaction proceeds with a catalytic amount of Pd(OAc>2 in the presence of LiBr, which plays an important role in inhibiting j6-H elimination in 254 [108]. Reaction of 252 in the presence of Pd(OAc>2, Cu(OAc), LiBr and O2 in MeCN provided alkenyl bromide 255 [109]. 

Intramolecular path b-type reaction of (Z)-alk-2-en-4-yn-l-ols 322, catalyzed by Pdl2 and KI, produced the furan-2-acetic ester 325 by efficient oxidative carbony-lation. The reaction is explained by intramolecular oxypalladation of the triple bond to generate 323, followed by CO insertion to give 324 and double bond isomerization [129]. 

Different regioselectivities were observed in the reaction of 3,4-pentadien-l-ols 387 with aryl iodides. The expected products 390 and 391 from the tt-allylpalladium intermediates 389 were not formed [151]. Exclusive formation of the dihydrofuran 388 is explained by concerted inter- and intramolecular exo-oxypalladation as shown by 392 to give 7r-allylpalladium 393, and reductive elimination gives rise to the dihydrofuran 394, showing that the intramolecular oxypalladation is faster than the intermolecular carbopalladation with Ar-Pd-I. 

Compared to intramolecular oxypalladation of alkyne with RCOOH or ROH (Sect. V.3.2.1), examples of its intramolecular version are rare. Recently, heterometallic Pd... 

V.3.2 Intramolecular Oxypalladation and Related Reactions Involving Other Group 16 Atom Nucleophiles... 

B. INTRAMOLECULAR OXYPALLADATION OF ALKENES CONTAINING PHENOLIC GROUP... 

In summary, the intramolecular oxypalladation followed by Pd—elimination is undoubtedly useful for synthesizing 0-heterocycles. In addition, some reactions of this type serve as useful probes for developing novel catalyst systems of paUadium(II). A highly enantioselective oxypalladation has been developed by incorporation of chiral hgands in the catalyst systan. However, it does not appear that the catalyst system applies to a broad range of substrates. Efforts focusing on the control of chirality are expected to continue in this field. 

Another prototypical example of the application of intermolecular oxypalladation to the synthesis of natural products and related compounds is shown in Scheme 3. Unlike the Wacker oxidation of alkenes to give ketones, the conversion of alkynes to ketones is a net nonredox process involving hydration of the triple bond. It should also be clearly noted that the observed high regioselectivity can most readily be explained in terms of intramolecular oxypalladation involving anchimeric participation by the cyclopentanone moiety followed by hydrolysis. 

More genuine examples of intramolecular oxypalladation applied to the natural product synthesis involve conversion of alkenediols into cyclic acetals, as exemplified by the synthesis of brevicomint t and frontalint t shown in Scheme 4. The brevicomin synthesis reported in 1976 may well be the first reported example of the application of intramolecular oxypalladation to the synthesis of natural products. 

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