Intermolecular carbopalladation

Because of their high reactivity and their low steric demand, alkynes are highly versatile partners. The resulting vinylmetal species are also important reactive entities. Accordingly, the intermolecular carbopalladation of alkynes has attracted the interest of organic chemists for years.42-45... 

Recently, synthesis of aryl ketones by a combination of palladium-catalyzed C-H activation of arenes and intermolecular carbopalladation of nitriles has been reported (Equation (119)).474... 

Grigg and Xu have developed a variety of so-called queuing cascades involving allenes. The intra-intermolecular carbopalladation sequence of the <9-iodo-A-methyl-A -(methylallyl)aniline 142 and 1,1-dimethylallene 143 with subsequent / -dehydropalladation leads to the 1,3-dienyl-substituted indole derivative 144, which is immediately trapped by an added dienophile (e.g., A-methylmaleimide) in a Diels-Alder reaction to yield 145 (Scheme 37)7 ... 

Under palladium catalysis, the < -iodoallenylbenzene 146 first undergoes an intermolecular carbopalladation of the double bond in the added norbornene 116, and only then follows an intramolecular carbopalladation of the allene moiety in 146 ensuing /3-hydride elimination finally provides the tricyclic compound 147 (Scheme 37)7 ... 

Scheme 31 Cyclopentannelation succeeding intermolecular carbopalladation of an alkene double bond/...

The intermolecular carbopalladation of a triple bond can be faster than that of an intramolecular double bond as, for example, in the (9-iodo(l-methylallyl)benzene 152. The arylpalladium iodide initially formed from 152 and a palladium(O) species intermolecularly carbopalladates diphenylacetylene 71, and only the thus formed alkenylpalla-dium intermediate 153 undergoes insertion into the internal double bond to furnish the neopentylpalladium species 154 which, by <9r/ (9-attack on the adjacent phenyl group, finally forms the tetracyclic system 155. ... 

Ma and co-workers have reported the selective synthesis of pyrrolidine derivatives through a three-component reaction based on a conceptually related strategy (Scheme 8.29) [72], Beginning with the catalytic intermolecular carbopalladation of y-allenic malonate 57 in the presence of a base, they succeeded in intercepting the internal carbonucleophile 58 with an imine such as the N-benzylidene p-toluenesulfonamide 59. The attack of the newly formed heteronucleophile on the 7r-allyl palladium intermediate affords the functionalized pyrrolidine 60 with high... 

There are at least two issues to be addressed regarding the Type lie circular cascade process shown in Scheme 42. One is the regioselectivity in the initial intermolecular carbopalladation. Since it is not very difficult to differentiate the two terminal positions of a. j-diyncs, this is not a serious problem in most cases. A more serious problem is the exclusive formation of fulvene derivatives observed in a couple of cases [124] (Scheme 45). It is not very clear what the scope of the fulvene formation is and whether the course of the reaction could be altered to give benzene derivatives. 

A palladium(II)-catalyzed three component coupling reaction was established by Lu, who performed the intermolecular carbopalladation involving propargyl alcohols and alkenes, and this was followed consecutively by allylic chloride insertion to the C-Pd bond and its quenching by p-heteroatom elimination in the presence of an excess of chloride ions. An example is shown below <03TL467>. 

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). 

With as H, the expected product was not formed. Based on these experimental observations, a Pd(II)-catalyzed intramolecular azapalladation-intermolecular carbopalladation of the C=C bond in allylic halides (or car-bonates)-p-deheteroatom palladation was proposed (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). 

Numerous carbo- and heterocyclic compounds of various sizes have been prepared by HR-type monocyclization. Cyclopropanes are formed only when neopentylpalladium intermediates are formed in the absence of anions. Intramolecular carbopalladation of the alkenyl triflate 201 generates the neopentylpalladium 202, and its 3-exo cyclization and jd-H elimination afford the cyclopropane 203 [95]. Intermolecular carbopalladation of the alkyne 204 generates 205. Its 5-exo cyclization provides the neopentylpalladium 206, which undergoes 3-exo cyclization to construct the three-membered ring 207. Finally y3-H elimination gives rise to the cyclopropane 208 [96]. 

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. 

As a typical intermolecular carbopalladation and termination, hydroarylation of alkynes are carried out extensively in the presence of HCO2H as a hydride source. Formation of regioisomers is observed in the reaction of asymmetric alkynes, and ratios depend on the nature of the substituents. High regioselectivity was observed in the reaction of the tertiary propargylic alcohol 14 to give 15 as a major product [5]. The (Z)-2-arylcinnamates 17, rather than 3-arylcinnamate 18, was obtained by the hydroarylation of methyl phenylpropiolate (16) [6]. 3-Substituled quinoline 21 was prepared by the regioselective hydroarylation of 19, followed by treatment of 20 with an acid without isolation [6]. 

Two types of reactions are summarized in this section (i) the intermolecular carbopalladation leads to a Pd functionality such as alkyl-, alkenyl-, or allylpalladium complexes, which is intramolecularly trapped by a heteroatom (again Wacker-type processes are mechanistic alternatives) (ii) the palladium catalyst is not directly involved in the hetero-cyclization step, but the carbopalladation builds up a suitable functionality or changes bond angles so that the heterocyclization can take place. 

In contrast to the diverse insertion chemistry of vinylpalladium intermediates discussed in Sects. IV.3 and IV.5, the reactions of vinylpalladium complexes with electrophiles had not been reported until recently. Although a single report on the annulation of the o-mer-curio benzaldehyde with diphenylacetylene into the corresponding indenols and inde-nones catalytic in palladium and stoichiometric in copper had been communicated in 1992, the more synthetically useful protocol for the catalytic version of this type of transformation remained unknown until 1999. In this section the intermolecular carbopalladation of alkynes with aryl halides followed by the intramolecular trapping of the formed vinylpalladium species with ketones, aldehydes, and nitriles will be discussed. 

Cascade intermolecular carbopalladations of alkynes followed by intramolecular trapping with electrophiles represent not only a novel type of organic transformation involving vinylpalladium intermediates, but also provide synthetically useful routes toward differently substituted indenols, indanones, indenones, and naphthy-lamines." Although these protocols are restricted to the intramolecular trapping with electrophiles, a wide application of this methodology toward the synthesis of various types of complex carbocychc compounds may be anticipated in the near future. 

Norbomene can serve as an excellent external relay, for example, for the alkenylpalla-dium species first formed by intramolecular carbopalladation of an ort/to-alkynyl-substituted arylpalladium halide. The 2-alkenylnorbonylpalladium halide formed by intermolecular carbopalladation then undergoes another intramolecular carbopalladation, this one in a 3-exo-trig mode, and subsequent /3-hydride elimination terminates the cascade process to yield a cyclopropanated norbomene derivative (Scheme... 

When the ort/io-alkynyl tether on the iodoarene bears a terminal aryl group the cascade process after the intra-intermolecular carbopalladation sequence may be terminated by an ortho attack of the norbomylpaUadium intermediate on the previously terminal aryl group (cf. Scheme 10) to yield an oligocyclic system (Scheme... 

The inter-intermolecular carbopalladation cascade, starting with the palladium intermediate from /3-halostyrene derivatives and two molecules of an alkyne, does not yield a benzene, but highly substituted fulvene derivatives, albeit in moderate yields only (Scheme 47, Eqs. 1 and Fulvene derivatives are also formed from 1-haloalkenes and 1,6-diynes (Schemed , Eq. 3). ... 

The relative rates of carbopalladation and CO insertion represent a very delicate issue, which is, to a considerable extent, dependent on the reaction conditions. The reaction of Phi with even 1 attn of CO in the presence of 1-octyne and MeOH under the influence of 5 mol % of Cl2Pd(PPh3)2 gives only methyl benzoate (73%) without the sign of either intermolecular carbopalladation or acylpalladation. One may conclude that inter-molecular C—Pd and Ac—Pd processes are, in general, decidedly slower than the CO insertion-methanolysis tandem process. 

As in the cases of termination by lactonization and lactamization, some specially structured alkenes, such as norbomene and related alkenes, can participate in intermolecular carbopalladation-carbonylative ketonization tandem processes. In the reactions shown in Scheme 22, the acylpalladium intermediates undergo intramolecular acylpalladation with arenes to provide ketones. ... 

B. INTERMOLECULAR CARBOPALLADATION OF ALLENES FOLLOWED BY /8-HYDRIDE ELIMINATION REACTION... 

In Sect. B, the intermolecular carbopalladations of aUenes are followed by a /S-hydride elimination to afford a 1,3-diene. However, in the presence of a nucleophile, a Tsuji-Trost-type nucleophilic substitution of the intermediate Tr-allylpaUadium spedes has been fuUy established (Scheme 6). 

In these cases the interactions between and play the major role to determine the stereochemical outcome of the sequence of an intermolecular carbopalladation and an in-termolecular nucleophilic trapping. Some typical results are listed in Scheme 12. In the case of 29, the methyl group at the 2-position of the alkenyl bromide clearly shifts the equilibrium between anti-26 and syn-16 exclusively to anti-26 (Scheme 2)P ... 

As outlined in Sect. B and C, catalytic intermolecular carbopalladations of allenes followed by either /3-hydride elimination or intermolecular nucleophilic trapping provide 1,3-dienes or allyl derivatives bearing the nucleophile moiety, respectively, while an intermolecular carbopalladation followed by intramolecular trapping sequential reaction provides cyclic skeletons (Scheme 27). In Type I, the nucleophilic moiety is connected with the C—X bond, and in lype II it is attached to the allene moiety. 

An analogous ring expansion was observed upon an intermolecular carbopalladation of the 1-propadienylcyclobutanol 149 with PhPdX formed from phenyl iodide or phenyl triflate (Scheme 48). i... 

The intermolecular carbopalladation of aUenes has been shown to fonn 7r-allyl-palladium intermediates. 

An example of the use of an intermolecular carbopalladation in complex molecule synthesis is the preparation of a PAF (platelet activating factor) antagonist (Scheme 11). In the key step, an intermolecular Heck reaction of 2-naphthyl triflate with 2,3-dihydrofuran 71 yields 2-naphthyl-2,3-dihydrofuran 72 in 52% yield with excellent enantioselectivity. The reaction presumably occurs via the cationic manifold and the alkene is isomerized by a hy-dropalladation/dehydropalladation reaction. The minor product 2,5-dihydrofuran 73 is obtained in 26% yield with modest enantioselectivity favoring the opposite absolute configuration at the key center. Critical to the reaction is the use of the sterically demanding and highly basic proton sponge [l,8-bis(dimethylamino)naphthalene] as the base. It is... 

Zhu and coworkers [12] reported the synthesis of unsymmetrically substituted 3-(diarylmethylenyljindolinones via a palladium-catalyzed domino reaction involving intermolecular carbopalladation and C-H activation. For example, the reaction between propiolamide 31 and aryl iodide 32 afforded the oxindole product 33 in 82% yield as a single stereoisomer (Scheme 3.8). The h-configuration of the tetrasubstituted double bond was confirmed by X-ray analysis. 

Subsequent C-H activation generates the five-membered paUadacycle 65, which undergoes intermolecular carbopalladation with aryne 66 to give seven-membered paUadacycle 67. FinaUy, reductive ehmination furnishes the product 62 and regenerates the palladium catalyst. Overall, three C-C bonds are constructed in this reaction sequence. In an earher report, Tanaka and coworkers [23] had observed similar domino reactions with bromoenynes to synthesize benzoisoindoles in the absence of external benzyne acceptors. 

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