Intermediates palladium

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

Ketones can be prepared by trapping (transmetallation) the acyl palladium intermediate 402 with organometallic reagents. The allylic chloride 400 is car-bonylated to give the mixed diallylic ketone 403 in the presence of allyltri-butylstannane (401) in moderate yields[256]. Alkenyl- and arylstannanes are also used for ketone synthesis from allylic chlorides[257,258]. Total syntheses of dendrolasin (404)f258] and manoalide[259] have been carried out employing this reaction. Similarly, formation of the ketone 406 takes place with the alkylzinc reagent 405[260],... 

Another protecting group of amines is 1-isopropylallyloxycarbonyl, which can be deprotected by decarboxylation and a /3-elimination reaction of the (tt-l-isopropylallyl)palladium intermediate under neutral conditions, generating CO2 and 4-methyl-1,3-pentadiene. The method can be applied to the amino acid 674 and peptides without racemization[437]. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

R H) then the palladium intermediate can be induced to undergo a variety of other reactions 80JA3583). The catalytic cyclization of 5-tosylamidoalkenes to dihydropyrroles has been achieved similarly (Scheme 7b) 82JA2444). 

The Stille coupling of an aryl triflate normally calls for the addition of at least one equivalent of LiCl. Presumably, the transmetallation is facilitated by replacing triflate with CP at the palladium intermediate generated from oxidative addition. As Stille demonstrated in 1988, 4-quinolinyl triflate 100 was coupled with phenylstannane 101 in the presence of Pd(Ph3P)4 and LiCl in refluxing 1,4-dioxane to furnish biaryl 102, which was used as an intermediate for the first total synthesis of antibiotic amphimedine (88JA4051). 

The poor regioselectivity of alkyne insertion in our polycychc aromatic hydrocarbon synthesis (Scheme 17) suggested to us that perhaps the palladium intermediate in that process was actually undergoing migration from one aromatic ring to the other, perhaps by a Pd(IV) hydride intermediate, to establish an equilibrium mixture of two regioisomeric arylpalladium intermediates under our reaction conditions (Scheme 18). This, indeed, appears to be true as... 

This chemistry becomes synthetically useful when one of the isomeric palladium intermediates can react with a neighboring substituent and the other isomer cannot. Thus, we have taken advantage of this effect to synthesize a range of polycyclic aromatic hydrocarbons by Pd migration and subsequent arylation (Scheme 24).21 This provides a unique way to form new carbon-carbon bonds in a location remote from the original functionality. 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

In 1971, Brown and Davidson reported that 1,3-cyclohexadiene undergoes a palladium-catalyzed 1,4-diacetoxylation of unspecified stereochemistry28. The oxidant employed was p-benzoquinone. They were uncertain about the mechanism at the time but later work has shown that the reaction proceeds via a (jr-allyl)palladium intermediate and subsequent nucleophilic attack by acetate6,7. 

A unique bis-silylation system, in which a bis(silyl)palladium intermediate is generated via recombination of two Si-Si bonds, has been developed.8,97 A bis(disilanyl)dithiane reacts with alkynes in the presence of a palladium/ isocyanide catalyst, giving five-membered ring bis-silylation products in high yield with elimination of hexamethyl-disilane (Scheme 14). The recombination, that is, bond metathesis, is so efficient that no product derived from direct insertion of acetylene into the Si-Si bonds of the bis(silyl)dithiane is formed at all. 

A proposed mechanism of the bis(allene) cyclization involves the formation of the allyl(stannyl)palladium species 6, which undergoes carbocyclization to give vinyl(stannyl)palladium intermediate 7 (Scheme 36). Reductive elimination and cr-bond metathesis may lead to the formation of the m-pentane derivative and the bicyclic product, respectively. The cyclization of allenic aldehydes catalyzed by a palladium complex was also reported.163... 

Both enantiomers of racemic 2-propenyl acetate can be formed from meso-type 7r-alkyl palladium intermediates by oxidative addition. 7r-Allylpalladium complexes with two alkyl substituents at the 1- and 3-positons are known to... 

Grigg extended this alkyne cyclization to trapping with stannanes to give 3-exo-dienes [347], alkynes to afford tetracycles [338, 348], and alkenes leading to cyclopropanes [349], an example of which is illustrated. In his studies Grigg and co-workers have found that thallium and silver salts suppress direct capture of these palladium intermediates prior to capture [350]. 

Vinyl- [64] and aryl triflates [65] as pseudo organic halides readily couple with stannylpyridines as long as more than one equivalent of LiCl is present in the reaction mixture. Presumably, the transmetalation is facilitated by replacing triflate with Cl at the palladium intermediate generated from oxidative addition. For example, 2-(benzopyran-4-yl)pyridine 80 was obtained from treatment of vinyl triflate 79 with 2-trimethylstannylpyridine in the presence of Pd2(dba)3(CHCl3)-Ph3P and LiCl [64],... 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

Cyanohydrin diethyl phosphates 87, easily accessible from propargyl aldehydes or ketones of type 86, reacted with lithium dialkylcuprates or similar reagents via an Sn2 process to give cyanoallenes in moderate to good yields [135]. The transformations 80 —> 81 and 84 —> 85 are only formally also SN2 reactions. Thus, plausible catalytic cycles, which include different short-lived palladium intermediates, have been postulated to explain these nucleophilic substitution reactions [127, 134],... 

Substituted propargylic alcohols were found to undergo direct carbonylation to the corresponding butenolides in 67-98% yield (Eq. 9.120) [86]. This reaction requires a catalytic amount of Pd2(dba)3-CHC13 (4%) and l,4-bis(diphenylphosphi-no)butane (8%) in CH2C12 under an atmosphere of CO (600 psi) and H2 (200 psi) at 95 °C for 36 h. The cyclocarbonylation reaction is believed to proceed via an allenyl-palladium intermediate, which is formed by initial insertion of Pd(0) into the C-O bond of the alkynol followed by rearrangement (Scheme 9.25). 

A single reaction has been described in which a palladium-catalyzed reaction was employed to form an alkyne [45], Thus, attempted alkylation of carbonate 145 with dimethyl malonate in the presence of Pd(PPh3)4 gave a mixture of enyne 87 and the alkylation product 86 in a 15 1 ratio (Scheme 14.37). Methoxide caused an elimination in (jT-allyl)palladium intermediate 146, which is apparently faster under these conditions than a reaction with the nucleophile (cf. Eq. 14.9). The synthetic importance of this process seems to be limited. 

In some examples 1,3-dienes 201 were formed. This is good evidence for a hydrido-palladium intermediate, at least for the formation of 201. On the other hand, this does not necessarily mean that the same reaction pathway is responsible for the formation of the normal product 200 (Scheme 15.64) [130],... 

Palladium(II) is one of the most important transition metals in catalytic oxidations of allenes [1], Scheme 17.1 shows the most common reactions. Transformations involving oxidative addition of palladium(O) to aryl and vinyl halides do not afford an oxidized product and are discussed in previous chapters. The mechanistically very similar reactions, initiated by nucleophilic attack by bromide ion on a (jt-allene)pal-ladium(II) complex, do afford products with higher oxidation state and are discussed below. These reactions proceed via a fairly stable (jt-allyl)palladium intermediate. Mechanistically, the reaction involves three discrete steps (1) generation of the jt-allyl complex from allene, halide ion and palladium(II) [2] (2) occasional isomeriza-... 

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