Carbopalladation domino reactions

A domino Heck carbopalladation/cyclization reaction of (Z)-3-(2-(but-2-ynyloxy)phenyl)prop-2-en-l-ol 453 with aryl iodides furnishes chroman derivatives 454 in good yield (Equation 185) <2004AGE5997>. 

The fate of this Tj -aUcyne-organopalladium intermediate has been found to depend on a number of reaction variables. For example, in the presence of a nucleophile close to the carbon-carbon triple bond, it can enter the carbopalladation-f f oxypalladation,- " or aminopalladation-f t reductive elimination domino reaction path or, when the reaction is carried out with a terminal alkyne, it can produce coupling products. ... 

The remainder of this section will focus on the different ways carbopalladation has been used to consuuct natural products. First, Sect. B will consider intermolecular cases. Then, Sect. C will discuss innamolecular carbopalladation showing the potential of the reaction to create small, medium, or large rings. Finally, domino reactions, cycloiso-merizations of enynes, and asymmetric reactions will be highlighted. 

Intramolecular carbopalladation has widely been used to assemble the polycyclic frameworks of natural products. The majority of these carbopalladations are intramolecular Heck reactions and examples of 5-exo, 6-exo, 1-exo, -exo, 6-endo, S-endo, and macro-cyclic ring closures will be presented (Scheme 12). Examples fall into two basic categories vinylic substitution (75- 76) and quaternary center construction (77- 78). Investigation of domino reactions like polyene cyclizations (79- 80) and asynunetric Heck reactions (81 82) has been fruitful. 

Several other types of domino reactions have been employed in the synthesis of natural products. Diastereoselective conversion of allylic carbonate 173 into enone 174 was one key transformation in a total synthesis of (+)-3-isorauniticine 175 (Scheme 27).Treatment of allylic sulfonamide 173 with a palladium catalyst re-gioselectively forms a 7r-allylpalladium intermediate by carbonate displacement. Carbopalladation of the pendant alkene, carbonylation, a second intramolecular alkene insertion, and /3-hydride elimination delivers a 67 22 11 mixture of stereoisomers of which enone 174 is the major product (isolated in 45-53% yield). Carbopalladation products can also undergo anion capture reactions. For instance, during the synthesis... 

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. 

Metal-catalyzed domino reactions are characterized by organometallic specimens that are regenerated in multiple insertion events and yield after an elimination step the complex, often polycyclic organic product. Predominantly in palladium chemistry, unimolecular reactions proceeding in an intramolecular fashion, for example, by cyclic carbopalladation [5], furnish complex polycyclic structures starting from linear polyunsaturated substrates. 

Carbopalladation of dienes yields 7r-allylpalladium intennediates capable of capturing nucleophiles. An example of this type of reaction in natural product synthesis is the conversion of the aryl iodide 168 into pentacycle 169. After 6-exo carbopalladation the free phenol is captured by the resultant Tr-allylpaUadium intermediate to yield aUyUc ether 169 en route to (-)-morphine 120. The domino reaction closes a srx-membered ring, forges a quaternary center, and forms a five-membered furan ring. The reaction sequence has also been effectively reversed in a construction of (+)-y-lycorane 172. Treatment of aUylic benzoate 170 with a palladium catalyst in the presence of sodium hydride triggers tt-allylpalladium formation and intramolecular amide capture. rr-Allylpalladium formation occurs with inversion, as does reaction with the pendant amide, resulting in a net retentive 1,3-transposition of stereochemical information. Subsequent addition of base and thermolysis induces 6-exo intramolecular carbopalladation to yield alkene 171. 

Consult Ref [37] compare Ref [38], where a similar reaction principle is reported. (3-Alkylidene) THFs with a CH2CH=0 side chain in 4-position were obtained in anelegant PdCl2-catalyzed Heck carbopalladation/cyclization domino reaction of... 

A concise route to oxygen-containing helical tetrasubstituted alkenes via a palladium-catalyzed domino reaction with Sonogashira coupling/ carbopalladation/C-H functionalization sequence has been developed by Tietze and coworkers (Scheme 3.12) [30].lnthiswork, the in s/fM-generated vinyl palladium intermediate from alkyne plays a vital role in the C—H activation. The reaction is efficient, and a mixture ofZ- and -isomers of the helical alkenes was afforded under the typical condition (44—96% yields, ElZ =1.5 1 to 1 1.6). 

A cascade carbopalladation-carbonylation sequence for substrates possessing P-hydrogens was explored by Seashore-Ludlow and Somfai [19] (Scheme 6.10). This allows for the construction of complex architectures with vicinal stereocenters in a concise and rapid fashion via the stereocontrolled formation of two carbon-carbon bonds. An integral aspect of this domino reaction is the ability to control P-hydride elimination of the organopalladium intermediate and instead form the carbonylation product. 

In 2005, Ohno et al. reported a cascade intramolecular carbopalladation/aromatic C-H bond activation for the synthesis of tri- or tetracyclic heterocycles 174 in the presence of palladium species [70] (Scheme 6.48). The authors proposed that this domino reaction might proceed through the oxidative addition of bromoenyne 173 to Pd(0), insertion of the alkyne into the C-Pd bond of intermediate 175, followed by C-H bond functionalization of the aromatic ring. Not only benzene-substituted substrates but also heteroaromatic rings such as benzofuran and indole, could be introduced efficiently to this reaction. Similar work was reported by Chernyak and Gevorgyan [71]. 

Double and even triple Heck-Diels-Alder domino reactions involving bicyclopropylidene and 1,4-diiodobenzene or 1,3,5-triiodobenzene, respectively, have been accomplished. In these sequences, the carbopalladation across the highly strained alkene is followed by a cyclopropylmethyl to homoallyl rearrangement with concomitant P-hydride elimination to yield an allylidenecyclopropane that subsequently undergoes a smooth [4+2] cycloaddition to furnish the spiro[5.2]octene moiety (Scheme 5-24). ... 

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. 

Intramolecular version can be extended to polycyclization as a one-pot reaction. In the so-called Pd-catalysed domino carbopalladation of trienediyne 178, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion generates 179. One alkyne and two alkene insertions are followed. The last step is the elimination of /f-hydrogen. In this way, the steroid skeleton 180 is constructed from the linear trienediyne 178 [78]. 

For the Heck reaction as discussed in Section III.2.1 the final position of the olefi-nic double bond of the products must not necessarily be the same as in the starting materials (for example Schemes 8, 9, and 10 of Section III.2.1) [1], The selectivity is often driven by stereochemical requirements, because the /1-hydrogen elimination step which forms the double bond proceeds exclusively in a syn manner (if a trans /3-hydrogen is eliminated, one should suspect major deviations from the general mechanism of the Heck reaction, for example electrophilic substitution instead of carbopalladation). An impressive example of a double bond migration is depicted in Scheme 1 - instead of olefins the coupling reaction of iodobenzene 1 with the olefmic alcohol 2 results in the isomeric aldehydes 3 and 4 as final products [2], Reactions of this type have emerged as valuable tools for the synthesis of carbonyl compounds and also as crucial steps in domino processes. 

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