Oxypalladation acetalization

The intramolecular oxidative earbonylation has wide synthetie applieation. The 7-lactone 247 is prepared by intramolecular oxycarbonylation of the alke-nediol 244 with a stoichiometric amount of Pd(OAc)2 under atmospheric pres-sure[223]. The intermediate 245 is formed by oxypalladation, and subsequent CO insertion gives the acylpalladium 246. The oxycarbonylation of alkenols and alkanediols can be carried out with a catalytic amount of PdCl2 and a stoichiometric amount of CuCb, and has been applied to the synthesis of frenolicin(224] and frendicin B (249) from 248[225]. The carbonylation of the 4-penten-l,3-diol 250, catalyzed by PdCl2 and CuCl2, afforded in the c -3-hydroxytetrahydrofuran-2-aeetie acid lactone 251[226J. The cyclic acetal 253 is prepared from the dienone 252 in the presence of trimethyl orthoformate as an accepter of water formed by the oxidative reaction[227]. 

The isoflavone 406 is prepared by the indirect a-phenylation of a ketone by reaction of phenylmercury(II) chloride with the enol acetate 405, prepared from 4-chromanone[371]. A simple synthesis of pterocarpin (409) has been achieved based on the oxypalladation of the oriho-mercurated phenol derivative 408 with the cyclic alkene 407[372,373]. 

The unsaturated c.vo-enol lactone 17 is obtained by the coupling of propargylic acetate with 4-pentynoic acid in the presence of KBr using tri(2-furyl)-phosphine (TFP) as a ligand. The reaction is explained by the oxypalladation of the triple bond of 4-pentynoic acid with the ailenyipailadium and the carbox-ylate as shown by 16, followed by reductive elimination to afford the lactone 17. The ( -alkene bond is formed because the oxypalladation is tnins addition[8]. 

Chromene acetals 39 are accessible from 2-vinyl-substituted phenols via the allylic acetals 38 through oxypalladation of benzyloxypropa- 1,2-diene and a subsequent Ru-catalysed RCM. 2-Substituted chromenes can be derived from the acetals 39 by conversion into the 1-benzopyrylium salts which are then trapped by nucleophiles (Scheme 26) <00TL5979>. In a like manner, 2-aIkoxychromans have been converted into various 2-substituted chromans by sequential treatment with SnCl4 and a silyl enol ether <00TL7203>. 

The Pd-catalyzed coupling reaction of the propargyl acetate 53 and 4-pentynoic acid (54) in the presence of potassium bromide produced the unsaturated exo-enol lactone 55 [66], The reaction proceeded via oxypalladation of the triple bond of 54 with an allenylpalladium intermediate, which was formed from Pd(0) and 53 and the carboxylate as shown in Scheme 3.30. 

The oxypalladation method mentioned above was introduced as a crucial step in the synthesis of several natural products. As shown in Scheme 8.51, Metz and coworkers used this strategy in an enantioselective synthesis of ricciocarpin A [122], Other impressive applications including the acetalization-RCM sequence have been employed in the synthesis of the AB ring of ciguatoxin [123] and of the Q-C fragment of laulimalide [124] (Scheme 8.52). 

The oxypalladation reaction of I takes place partly in the anti-Markovnikov direction (Reaction 9) leading to 2-hexen-l-yl acetate via Reaction 10. Subsequently an allylic shift (19) can generate l-hexen-3-yl acetate. 

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... 

The conditions for allylic acyloxylation of internal olefins are, for reasons which are not clear, unsuitable for terminal olefins. They undergo Wacker oxidation (Markovnikov oxypalladation//) - h yd ride elimination) to yield mixtures of vinyl acetates and methyl ketones [37a]. A combination of Pd(OAc)2/BQ with air as cooxidant in a mixture of DMSO/AcOH (1 1) enables conversion of a broad range of functionalized terminal olefins to the corresponding linear allylic acetates in acceptable yields (Scheme 5) [41]. 

An example of catalytic oxypalladation is the rearrangement of allylic acetates with Pd ll). The reaction starts with oxypalladation of the alkene and it is the acetate already present in the molecule that provides the nucleophile to attack... 

Cyclic acetals, oxypalladation of alkenes in the synthesis of 90ACR49. 

Thus far we have considered oxidations in which the initial step is addition of acetate or methoxide (oxypalladation). Now we shall consider oxidations in which the first step is addition of Pd(II)-carbon bonds. 

In an analogous reaction the acetoxypalladation adduct of 1,5-cyclo-octadiene reacted in acetic acid, containing traces of chloride in the presence of Pb(OAc)4, to give 2,6-cwinsertion into the second double bond, and trans elimination of Pd(II) with OAc ... 

However, if in nonaqueous solutions (discussed next) the oxidations also proceed through oxypalladation adducts, then the two mechanisms of decomposition of the oxypalladation adducts would predict diflFerent products. First, let us consider the mechanism of Jira, Sedlmeier, and Smidt (Reactions 50-53). In this case OH in II (Reaction 52) is replaced by OR. Decomposition via Reaction 55 is impossible, so II must decompose by solvolysis. This would give 1,1-disubstituted ethanes from ethylene oxidation. On the other hand, the first suggestion (Reaction 48) would probably be more consistent with formation of the vinyl compounds since hydride elimination should be completed if a rapid rearrangement of electrons to give acetaldehyde cannot occur. Evidence exists that 1,1-disubstituted ethanes are the initial products in methanol, and in acetic acid it is claimed that both vinyl acetate and 1,1-diace-toxyethane are initial products this suggests that in this solvent competition exists between palladium (II) hydride elimination and acetate attack. However, until now there have been no detailed studies of the oxidation under conditions where 1,1-disubstituted products are formed. More work is needed before the course of the reaction under these conditions is completely understood. 

A recent study (30) of the oxidation of several straight-chain olefins reported product distributions which could be explained only by preferential Markovnikov oxypalladation, followed by HPdOAc elimination, preferentially by abstracting hydrogen from the carbon not containing the acetate. The products obtained with 1- and 2-butene can be used as an example. 

The reagent oxidizes a A -olefin to give the enol acetate as the main product, and the predominant product from a A -olefin is the allylic acetate. The reactions are considered to involve oxypalladation followed by loss of the elements of HPdOAc. 

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]. 

Buchwald described an oxypalladation reaction, followed by a C-H functionalization. This entirely intramolecular reaction is initiated through a 5-exo Wacker-type cychzation of 84. The resulting a-alkyl-paUadium intermediate M provides subsequent C-H activation at the neighboring arene, which allows a paUadium(II) intermediate N bearing a-alkyl and o-aryl substituents, respectively. Reductive elimination provides the C-C bond installation of 85 with the concomitant release of a paUadium(O) catalyst state. Reoxidation imder aerobic conditions, most probably through a palladium(II) -peroxo complex and protonolysis with the acetic add hber-ated in the previous steps, regenerates the original paUadium(II) diacetate catalyst. 

The use of other oxygen nncleophiles such as acetic acid or alcohols also results in oxypalladation. Subsequent 8-Pd-H elimination produces vinyl acetates or vinyl ethers. However, these are not necessarily the final products. When acetic acid is used as the nucleophile, ally lie acetates often become the major product. In the case of alcohols, another alcohol reacts with the resulting vinyl ether to give an acetal (Scheme 2). Focusing on such product compositions, the oxypalladation of alkenes with carboxylic acids and alcohols followed by dehydropalladation is described here. 

The reaction of methyl (a-hydroxymethyl)acrylate with MeOH does not give the corresponding acetal however, interestingly exclusive elimination of /3-Pd—OH takes place from the oxypalladation intermediate shown in Scheme 29 to give methyl (a-methoxymethyl)acrylate. ... 

Oxygen nucleophiles such as water, alcohols, and acetic acid react with alkenes coordinated to PdXj (X = Cl, OAc, etc.) to give oxypalladation adducts. In general, a subsequent pathway is /3-Pd—elimination from the intermediate as shown in Scheme 1. 

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,... 

As shown in Scheme 32, when allylilc alcohols are allowed to react with vinyl ethers, the resulting a--bond in oxypalladation intermediate adds intramolecularly to the C=C bond of allylic moiety.f Subsequent (3-Pd—elimination leads to cyclic acetals. With this method, albeit stoichiometric in palladium(II), a unique approach to the synthesis of prostaglandins was attained by Larock and Lee as shown in Scheme 33.1 ... 

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. 

Alkylidenetetrahydrofurans can be prepared via intramolecular oxypalladation and subsequent coupling by treatment of aryl or alkyl alkynic alcohols with butyllithium followed hy palladium acetate and triphenylphosphine. The reaction proceeds to yield furans in moderate yields. ... 

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