Heck polycyclization

Heck polycyclization of dienynes. Treatment of dienyne 1 bearing a vinyl bromide group with catalytic amounts of Pd(OAc)2 and P(Q,H5)3 and 2 cquiv. of silver carbonate in CH,CN at 80° results in the tricyclic cyclohexadicne 2 in 60% yield. A similar reaction occurs if the dicnync group is attached to a cyclohexane ring (3 — 4, equation I). 

Polycyclic aromatic hydrocarbons such as fluoranthrene or Cso-fullerene are structures of great interest A straightforward entrance to analogues and partial structure, respectively, has now been developed by de Meijere and coworkers [89], using a combination of a Suzuki and a Heck-type coupling. Thus, reaction of 1,8-dibromophenanthrene 6/1-166 and obromphenylboronic acid 6/1-167 employing 20 mol% of the Pd° catalyst led to 6/1-168 and 6/1-169 in 54% yield as a Id-mixture (Scheme 6/1.45). 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

Whereas Hegedus [335] and Danishefsky [336] were the first to discover a tandem Heck reaction from o-allyl-A -acryloylanilines leading to tricyclic pyrrolo[l,2-a]indoles or pyridino[l,2-a]indoles [336], it has been the fantastic work of Grigg to unleash the enormous potential of this chemistry. Grigg and his co-workers parlayed their Pd-catalyzed tandem polycyclization-anion capture sequence into a treasure trove of syntheses starting with IV-allyl-o-haloanilines [337-345], Diels-Alder and olefin metathesis reactions can be interwoven into the sequence or can serve as the culmination step, as can a wide variety of nucleophiles. An example of the transformation of 289 to 290 is shown below in which indole is the terminating nucleophile [340],... 

This intramolecular Heck cyclization can be extended to diunsaturated aryl iodides, which can undergo two consecutive cyclizations to form polycyclic systems.7 Examples ... 

Intramolecular Heck reactions.6 Heck intramolecular coupling of alkenyl or aryl iodides substituted by 3-cycloalkenyl group is an attractive route to fused, spiro, and bridged polycyclic products. Coupling is achieved with a Pd-phosphine catalyst such as Pd[P(QH5),]4 in combination with a base, N(C2H5)3 or NaOAc. The coupling tends to produce a mixture of two isomeric alkenes, in which the newly formed bond is allylic or homoallylic to the ring juncture. 

Similar intramolecular Heck reactions with Pd(OAc)2 and a base (KOAc) or a phosphine have been reported by two other groups.78 These conditions also result in two isomeric polycyclic alkenes. 

The arylation shown in Figure 5.3 is a rare example of a palladium-mediated hydro-arylation of an alkene. Because of the polycyclic structure of the alkene, the intermediate formed by insertion of the alkene into the Pd-Ar bond does not undergo 13-elimination (to yield the product of a normal Heck reaction), but remains unchanged. Reduction of this stable alkylpalladium intermediate with formic acid furnishes the formally hydrogenated Heck product [38],... 

An intriguing showcase for polycyclizations based upon hetero-domino reactions is outlined in Scheme 30, where the catalyst 89 gives rise to the formation of a mixture of indolone skeletons 92-94 with a preference for the generation of tetracycle 94 as a result of an intramolecular allylic substitution-Heck sequence. 

Scheme 30 Polycycles by sequential intramolecular allylic substitution-Heck reaction [82]...

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

For the construction of highly condensed polycyclic skeletons, the cascade consisting of two intramolecular Heck-type reactions and a 67r-electrocyclization as performed with the... 

Both S-endo and 8-exo Heck cyclizations have been described. In an early example, Sundberg and Cherney reported an S-endo cyclization of 88 to the homoibogamine analog 89 (Scheme 6-15) [30]. Among the most striking examples of the application of intramolecular Heck cyclizations to assemble complex polycyclic products, Danishefsky, Masters, and co-workers have reported several S-exo cyclizations during investigations that culminated in a total synthesis of baccatin III (96) [32]. In an early example, exposure of... 

Scheme 1 shows the desired Heck reaction of alkoxy-DSB 1 with 2. The formation of 3 is accompanied by two destructive pathways the reductive debromination of 1 to 4 as a side reaction and the protodesilylation to 5 as a subsequent reaction. Particularly the latter limits the reaction conditions in terms of time and temperature. The phosphine is a decisive factor in this system consisting of three reactions a fine-tuning of the reaction conditions is possible via electronic and steric effects of the substituents in the phosphine electron-rich trialkylphosphines 6 and 7 strongly favor the reduction. Fast coupling reactions were observed with tris-o-tolylphosphine 8, the chelating diphosphine dppe 9 being even more efficient in terms of turnover, yield, and suppression of side reactions. Compared with Heck reactions of polycyclic or electron-deficient arenes with 2 [21, 22], the yield of 3 is only moderate. The reactivity of bromo-distyrylbenzenes 1 and 12 -14 in the coupling reaction is controlled by the substituents on the opposite side of the n-system (Fig. 1, Table 2) a compensation for the electron-donating alkoxy groups by a cyanide (13) or exchange of donors with electronically neutral alkyl side chains strongly improves the yields.

The intramolecular Heck reaction to construct the polycyclic benzofuran skeleton in morphine was reported by Overman [21] in their synthesis of (+)- and (-)-dihydroisocodeine in 1993, and after that, the Heck cyclization has been extensively studied by Cheng [22], Hsin [23, 24], Hudlicky [25] (see Sect. 2.2.3), Trost (see Sect. 2.2.1), and Guillou (see Sect. 2.1.2). In Fukuyama s synthesis, the Heck reaction of 11 works well and successfully provided the A-C-E tricyclic ring system 13 in 87% yield after deprotection of the TBS group in the intermediary enol ether 12. 

Intramolecular Heck reactions are useful for synthesizing cyclic compounds. When the reaction is performed with polyolefins, successive insertion of olefins into a Pd—C bond takes place, leading to polycyclic compounds (eq (63)) [91]. 

The first successful case was reported by Overman et al. in 1989 [66], a pioneering strategy, which opened the way for the development of AHRs leading to quaternary centers. Furthermore it was outlined that polycyclizations are well within the scope of the Heck reaction. According to Scheme 20 it can be expected that contrary to the case of polycyclizations of carbocations and free radicals, cy-... 

Scheme 19 Polycyclic heterocycles synthesized via intramolecular o/t/jo-alkylation/Mizoroki— Heck coupling...

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

The first detailed study of alkyl to aryl palladium migrations, reported in 2004, involved homobenzylic to phenyl migration (Table 5) [58], The process was demonstrated using aryl iodides tethered to an olefin. An additional hap, either intramolecular arylation or intermolecular Heck olefination, was used to hap the migrated palladium. The reaction gives high yields of the desired polycyclic products. 

Polycyclization of dienynes.9 Treatment of the cnyne 1 with Pd(OAc)2/ triphenylphosphine and a base (Heck conditions) results in cyclization to a mixture of cis-and rrans-tricnes 2. At 130° and with K COj, only trans-2 undergoes an intramolecular Diels-Alder reaction to 3. 

---