Intramolecular Heck cyclization reaction

B.M. Trost and co-workers conducted studies toward the total synthesis of saponaceolide B, an antitumor agent active against 60 human cancer cell lines. " One of the challenging structural features of this compound was the cis 2,4-disubstituted 1-methylene-3,3-dimethylcyclohexane ring. The key steps to construct this highly substituted cyclohexane ring were a diastereoselective Barbier reaction to install a vinyl bromide moiety followed by an intramolecular Heck cyclization reaction. 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

In total syntheses of (+)-codeine and (-)-galanthamine, the bcnzo /> I uran core of both molecules was built up by intramolecular Heck cyclization, as shown below <07SL2859 07OL1867>. The Heck reaction was applied to make several bcnzo b furan-bascd benzazepin cores from their corresponding ap-unsaturated amides <07OBC655>. In addition,... 

Starting from 1-methyl-17/-pyrrole-2-carboxylic acid, the tricyclic fused quinolin-4-one and naphthyridin-4-one derivatives 441 were prepared, in only three steps, by an intramolecular Heck cyclization of derivative 440 (Scheme 94) <2005EJ02091>. This reaction was performed in DMA as solvent, with potassium acetate as base and Pd(PPh3)4 as catalyst. The use of microwave irradiation, in some cases, gives better yields of cyclized products. 

Whereas inter- and intramolecular Diels-Alder reactions normally require electron-deficient dienophiles, the 67r-electrocyclization proceeds with a large vaiiety of substituents on a hexatriene. In one such approach, the intramolecular Heck-type reaction of a 2-bromo-1 -en-(ft> — l)-yne 66 is used as a trigger to initiate an intermolecular Heck coupling with an alkene to form the conjugated 1,3,5-hexatriene 67 which eventually cyclizes in a 67T-electrocyclic process (Scheme 3-21) [173]. In many cases, aromatization of the cyclohexadiene 68 formed primarily occurs to yield carbo- and heterobicyclic compounds of type 70 [173a,b]. But with alkyl ethenyl ethers the cyclohexadienes 69 can be obtained in moderate yields [173b]. 

The intramolecular Heck cyclizations highlighted in this chapter were typically conducted with 5-20 mol% of a palladium catalyst. In few, if any, of these studies were catalyst loadings and cyclization conditions carefully optimized. As a result, we have not included catalyst loadings in the schemes in this chapter. Only recently has serious attention been directed to optimizing catalyst turnover in Heck reactions and to the development of more robust catalyst systems. It seems likely that in the future many Heck cyclizations will be accomplished with catalyst loads of 1 % or lower [76]. 

An intramolecular variation of the Heck reaction was used in the construction of the monoterpene alkaloid ( )-oxerime 395 [138]. Nucleophilic addition to 392 of an allyl anion equivalent produced 393, a precursor to an intramolecular Heck cyclization. Palladium-catalyzed ring closure afforded 394, an intermediate in the synthesis of the natural product 395. 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(ll) species. Pleixats and coworkers treated iodophenylsulfide 276, obtained from o-iodoaniline and crotyl bromide in two steps, with Pd(Ph,P)4 and EtjN in refluxing acetonitrile to form the intramolecular Heck cychzation product 277 [175]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 27). In another case, the intramolecular Heck cyclization of enamidone 278 with a pendant thienylbromide moiety furnished the 6-endo-trig product, indolizine 279, in 63% yield, along with the debrominated enamidone 280 in 37% yield [179]. 

Coordinating the triply sulfonated analog, TPPTS, to palladium has led to improvements in CCBF reactions. For example, Genet previously reported the selective intramolecular Heck-type reaction of various substrates to produce the cyclized product in good yield (Eq. 5) intramolecular Heck coupling [18]. One of the most important features of the Pd(TPPTS)3 catalyst involves the regioselectivity associated with the reaction. For these types of reactions, carried out in organic media, the exo product is usually favored. However, with the use of this catalyst, the endo species was the predominant product. 

Intramolecular Heck substitution reactions have been key steps in several recent synthetic endeavors directed toward Strychnos alkaloids (Scheme 6-11). In 1993, Rawal and coworkers reported a short stereocontrolled total synthesis of ( )-dehydrotubifoline (62) in which vinyl iodide 61 was converted to pentacycle 62 in good yield using Jeffery s cyclization conditions [22]. Of note in this construction of the core pentacyclic skeleton of... 

Heck reactions involving nonaromatic components are particularly versatile synthetic processes. For example, 1,2,4-trienes and l,2-dien-4-ynes are readily prepared from propargyl carbonates." Intramolecular Heck cyclization followed by Diels-Alder or nucleophilic attackleads to bicyclic products. Substituted pyrrolidines and piperidines are formed by coupling of alkenyl sulfonamides with vinylic halides. ... 

Moreover, several resveratrol-derived natural products can be synthesized by a palladium-catalyzed cascade reaction of bromostilbene derivative 121 and tolane 122 (Scheme 60) (110). In this cascade reaction, intermolecular Heck reaction proceeds first, followed by intramolecular Heck cyclization to give the desired carbon framework of dimeric resveratrol natural products. 

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