Intramolecular Heck insertion

Another example of a tandem reaction, in this case an intramolecular Heck insertion followed by a r-allylpalladium displacement, comes from our opium alkaloid total synthesis project (Scheme 6-25) L53J. Treatment of diene aryl iodide 142 under forcing Heck cyclization conditions provided 143 in 56% yield in which the two final rings of the opium alkaloid skeleton are constructed in this one key step. 

Scheme 3-54). This transformation constitutes a cascade of an intramolecular Heck insertion and subsequent heterocyclization. The initially formed arylpalladium species attacks the bridgehead position of the diene functionality in 238 to foim a JT-allylpalladium complex which is trapped by the internal nucleophilic phenol moiety (cf. Scheme 3-26). Since the starting diene 238 can be prepared in both enantiomeric forms by asymmetric reduction of a ketone, this sequence allows the preparation of both the natural morphine and its unnatural enantiomer. 

In an imaginative construction of the angular triquinane ( )-hirsutene (158), Oppolzer and Robyr reported the carbonylative closure of allylic carbonate 155 to yield bicyclooctanes 156 and 157 (Scheme 6-27) [57]. In this multistep transformation, a alJylpalladium intermediate arising from the allylic carbonate 155 undergoes intramolecular Heck insertion of the pendant alkyne. Carbonylation of the resulting vinylpalladium intermediate, another Heck cyclization, and a second carbonylation then provide a mixture of acids, which after esterification yield esters 156 and 157 in good yield. 

In 2008, Ruck et al. developed a novel and efficient synthetic route to spiro-fused indance-oxindoles 9 by a palladium-catalyzed tandem Heck/C—H functionalization reaction [8] (Schone 6.2). Oxidative addition of the aryl bromide 8 to the palladium complex is followed by the intramolecular Heck insertion process through 5-exo-trig cycUzation to afford primary alkylpaUadium species 11. Reaction at the highlighted C—H bond provides six-monbered paUadacycle 12, and subsequent reductive elimination generates spiro-fused iudauce-oxindoles 9. 

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

Grigg s group synthesized a unique bicyclic P-lactam 108 via an intramolecular Heck reaction from 107 [87, 88]. The 7-membered ring was formed via an unusual insertion at C(3) of furan, an aromatic rc-system. 

All these protocols allow us to form a new carbocycle in a bimolecular process. The cyclization involving two different molecules besides CO has been realized, involving carbapalladation of norbornene, migratory insertion of CO, and subsequent intramolecular Heck-like attack at thiophene residue. Thallium acetate is required as electrophilic co-catalyst (Scheme 18). ... 

Transition metal catalyzed insertion reactions offer a convenient route for the preparation of five membered heterocyclic rings. Besides intramolecular Heck-couplings and CO insertion, examples of the intramolecular insertion of an acetylene derivative constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here. 

The seven membered core of iboga alkaloids has also been constructed in an intramolecular Heck reaction. Insertion of a pendant olefin into the indolylpalladium complex, formed from iodoindole, followed by / -hydride elimination gave the complex framework of the natural product (5.5.), Although the insertion step could have led to the formation of a six membered ring, the formed palladium complex would have contained a quaternary carbon center in the -position, blocking the closure of the catalytic cycle under the applied conditions.5... 

As discussed earlier, the generally accepted mechanism for the Heck reaction involves the steps of oxidative addition, coordination of the alkene, migratory insertion, and P-hydride elimination [2,3], With the intramolecular Heck reaction emerging as an important synthetic reaction over the past decade, the individual steps of this mechanism have come under closer scrutiny, and attention is beginning to be directed at determining the identity of the enantioselective step [41],... 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed intramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon. 

Another method for activating the versatile alkenyl halide moiety was the oxidative addition of a late transition metal species, which would then facilitate insertion of the C13-C14 double bond. The Rawal,7h Bonjosch,7e and Mori7b syntheses of 1 all employed a Pd-mediated intramolecular Heck reaction to build the F ring of the molecule.71 Our system, in as much as it contained additional unsaturation, was somewhat different from those in the literature and thus had the potential for displaying new chemistry. For example, in Rawal s approach (Scheme... 

The synthesis of selectively substituted benzoxepines from ortho-substituted aryl iodides and bromoenoates has been achieved by Lautens and coworkers by palladacycle alkylation followed by an intramolecular Heck reaction under the modified conditions reported in Eq. (8) for synthesis of l-(l-ethoxycarbonylmethy-lene)-9-methyl-4,5-dihydro-3-benzoxepine [8]. In the second example (Eq. 9) the palladium-bonded biphenylyl inserts diphenylacetylene to form 1,5-di-i-propyl-9,10-diphenylphenanthrene[9]. In the last case the synthesis of 4-methyl-5H-phenanthridin-6-one is achieved by palladium-catalyzed sequential C-C and C-N bond formation starting from o-iodotoluene and o-bromobenzamide [10]. 

Control over regioselectivity and stereoselectivity in the formation of new C-C a-bond is required to utilize the Heck reaction in complex molecule synthesis. For the intramolecular Heck reaction, the size of the ring formed in the insertion step controls the regiochemistry, with 5-exo and 6-exo cyclization favoured. A mixture of regioisomers is formed from Heck insertions of acyclic alkenes, whereas cyclic alkenes such as cycloalkenes as a Heck substrate produce a a-arkylpalladium(II) intermediate A, which has only one syn-P-hydrogen. Syn-elimination of the hydrogen provides only product B (Scheme 5.6). 

Intramolecular asymmetric Heck insertions of acyclic disubstituted alkenes are complicated by y8-hydride elimination to provide substitution products. In a potentially... 

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