Cascade carbopalladation

An inter-intra-intramolecular carbopalladation cascade, initiated by the alkenylpalladium bromide intermediate from /3-bromostyrene 74 inserting into one of the triple bonds of the diyne 73, yields the ring-annelated fulvene derivative 75 (Scheme 22). ... 

Scheme 22 Alkyne relays in inter-intramolecular carbopalladation cascades leading to ring-annelated alkylidenecyclopenta-dienes and cyclopentenes. ...

Scheme 23 Highly convergent assembly of calcitriol 83 employing an alkyne-relayed inter-intramolecular carbopalladation cascade.

Scheme 24 Two alkyne relays in sequence in intra-intramolecular carbopalladation cascades. ...

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). ... 

Since hydroxy groups do not interfere with palladium catalysts, the termination of carbopalladation cascades by oxygen nucleophiles has been employed in various cases. As... 

As hydroxy groups do not interfere with palladium catalysts, the termination of carbopalladation cascades by oxygen nucleophiles has been employed in various cases. As discussed earlier, the palladium-catalyzed couphngs of alkenyl halides with alkenes can give rise to the formation of it-allylpaUadium complexes, which can then be attacked by internal nucleophiles including hydroxy groups to yield various oxacychc systems (Scheme 8.38) [343]. 

Scheme 8.38 Intramolecular termination of carbopalladation cascades by oxygen nucleophiles [343].

Scheme 8.39 Termination of a two-step 5-exo-trig carbopalladation cascade by reductive elimination from an alkylpalladium iodide intermediate [344].

Some representative examples of the application of the halopalladation-cyclic carbopalladation cascade to the synthesis of natural products are shown in Table 3. 

In fact, the preferential cyclic carbopalladation even in the presence of large excesses of CO and MeOH has been exploited in developing cyclic carbopalladation cascades terminated by carbonylative esterification, as discussed in Sect. IV.3.3. More recent attempts... 

Many different combinations of carbopalladation and/or acylpalladation processes are conceivable for devising cascading di- and multicyclization processes. Those consisting only of straightforward carbopalladation processes have been systematically investigated by a number of chemists since around 1988, as detailed in Sect IV.3. Aside from these carbopalladation cascades and those allylpalladation-acylpalladation cascades discussed above, only a small number of scattered examples are known, as shown below, and this area needs to be explored further. 

As shown in Scheme 6.37, some transition-metal-assisted ring-closure reactions of 1,2-diethynylbenzenes afford dibenzopentalene derivatives unexpectedly. Diederich s group designed a carbopalladation cascade reaction of easily accessible ew-dibromoolefins 286 and alkynes to furnish monobenzo-287 and mononaphthopentalenes 288 (Scheme 6.72). This successful methodology allows the preparation of asymmetrically substituted pentalene derivatives with only one fused aromatic system [167]. 

Whereas the carbopalladation cascade as the key reaction did not cause any difficulties, several other transformations proved to be rather challenging. In a very first step, compounds of type 32 had to be synthesized (not shown). For this purpose, two different silylalkynyl groups were installed to appropriate benzylic iodides. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

The alkyne relay, in particular, has frequently been used for cascade carbopaliadations with ring formation, because a carbon-carbon triple bond is more reactive toward carbopalladation than a carbon-carbon double bond. Thus, methyl -iodocinnamate 70 reacts with diphenylacetylene 71 to yield the methylenediphenylindene derivative 72 (Scheme 22). ... 

Tricyclic skeletons such as 85, 87, 89 with a central benzene ring are formed in the fully intramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-//,w-diynes 84, 86, 88 and analogs (Scheme 24). This process involves two alkyne relays in a row and a final 67r-electrocyclization or 6-endo-trig carbopalladation with ensuing / -dehydropalladation. 

Cascade carbopalladation sequences after attack on an alkene are most commonly terminated by dehydropallada-tion, if a / -hydride is available in a yy//-orientation. The intramolecular carbopalladation starting from the monocyclic diene 122 with a geminally disubstituted alkene terminator leads to a neopentylpalladium intermediate 123, which cannot undergo /J-dehydropalladation, but continue the cascade by a carbopalladation to eventually form the... 

For such cascades with intramolecular carbopalladations, smaller ring sizes (5 and 6) are preferred due to the entropic term thus, 1,1-disubstituted alkenes suitably located in the substrate preferably serve as the relay without formation of the larger ring size resulting from insertion into the terminal alkene moiety. 

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 ... 

Termination of cascade carbopalladation sequences by arylation can play a major role in systems that form a reasonably long-lived palladium intermediate and contain a suitably functionalized arene moiety in the vicinity of the organopalladium function. In particular, neopentylpalladium intermediates have been found to intramolecularly attack an adjacent arene moiety. For example, iodoarenes 149 with electron-withdrawing substituents in the... 

With its (9r/ (9-(cu-phenylalkynyl) group, the iodoarene 156 in the presence of a palladium catalyst initiates the cascade process with an intramolecular carbopalladation this is followed by an intermolecular insertion, for example, into the double bond of the 3-azanorborn-5-en-l-one 157 and terminated by ortho-2XX,2Jz of the norbornyl-type cr-palladium intermediate on the previously terminal aryl group to yield the two regioisomeric hexacyclic systems 158 and 159 in a ratio of 1 1 (Scheme 39). ... 

Scheme 37 Two cascade cyclizations involving inter- or intramolecular carbopalladations of allenes.

In their pioneering work on the catalytic carbopalladation reaction of 1,2-heptadiene with phenyl iodide in the presence of a suitable base, Shimizu and Tsuji observed the formation of the corresponding substituted 1,3-dienes 62 via a / -hydride elimination from the 7z>allyl intermediate 61 [61]. Based on these observations, a three-component Heck-Diels-Alder cascade process has been developed by Grigg and co-workers [73]. A wide variety of aryl and heteroaryl iodides were used for the intermolecular reaction with dimethylallene to afford the corresponding 1,3-dienes. These subsequently react in situ with N-methylmaleimide to give the bicyclic adducts 63 (Scheme 8.30). 

When the carbopalladation of the bicyclopropylidene is performed in the presence of methyl acrylate, the reaction takes a different course (Scheme 8.34) [79]. The 1,3-diene intermediate 75 reacts in situ with the dienophile to give the spiro[2.5]octane derivative 76. An extension of this cascade Heck-Diels-Alder reaction involving l,3-dicyclopropyl-l,2-propadiene as the alkene partner, an alkenyl or aryl halide and a dienophile has been reported [80]. 

The final option available to a u-alkylpalladium intermediate from Heck alkylation occurs if another alkene or alkyne function is situated properly to participate in a further Heck-type carbopalladation (equation 161)318,319. In properly constructed systems, more than one further carbopalladation is feasible, and many examples of these cascade car-bopalladations have been reported. Several have been quite spectacular (equation 162)320. Fused, spirocyclic and bridged bicyclic ring systems have been prepared in this manner. The process may also create as many as five rings in one step, with five-,six- and three-membered rings321 being the most suitable for preparation (equation 163). Alternatively, the proper orientation of double and triple bonds allows cyclotrimerization to highly functionalized arenes or fulvenes (equation 164)322,279. 

Patterns of cyclic carbopalladation. As discussed above, the fundamentally stoichiometric and living nature of carbopalladation imposes various difficulties to be overcome. Carbopalladation can, in principle, be either a single-stage process or double- or multiple-stage processes. Double-and multiple-stage carbopalladation reactions have often been called either domino or cascade carbopalladation reactions. In some cases, two-stage carbopalladation reactions have also been called tandem carbopalladation reactions. None of these three words is a chemical term, and choice between them is a matter of taste. In this chapter, the term cascade will be used for both double- and multiple-stage carbopalladation processes. 

As discussed in conjunction with the intermolecular cascade carbopalladation reaction shown in Scheme 4, it has been very difficult to satisfactorily control both queuing or pair -selectivity and regioselectivity of intermolecular cascade carbopalladation processes. Consequently, essentially all of the cascade carbopalladation reactions discussed here are at least partially intramolecular. The currently known cyclic cascade carbopalladation processes can be classified into a few to several types shown in Scheme 6. 

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