Intramolecular "aryl-Heck" cyclization

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthe-... 

Scheme 43. An intramolecular aryl-Heck cyclization in the total synthesis of hippadine...

One of the latest additions to the impressive repertoire of indole alkaloid total syntheses using intramolecular Heck strategy is the total synthesis of hippadine (18a) [109]. As depicted in Scheme 43, an intramolecular aryl-Heck cyclization of substrate 241 under normal Heck conditions gave Ihe cyclized product 242, which was transformed into hippadine (18a) upon further manipulations. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

Ishar and coworkers discovered a spectacular indole synthesis involving a Diels-Alder reaction between aza-dienes and a silyl enol ether, followed by an aryl-Heck cyclization (Scheme 6, equation 1) [56]. Jiao s team developed a Pd-catalyzed intramolecular amination and C-H functionalization to give 2,3-dihydropyrrolo[l,2-a]indoles (equation 2) [57]. 

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 Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki-Heck ring closure <06JOC5340>. 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cyclizations of 254 and 255 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 254 and the IV-benzylindole 256 [271,272]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 257, and they prepared a series of peripheral-type benzodiazepine receptors 258 using this chemistry. For example, 258 (n = 3, R = n-Pr) is obtained in 81% yield. 

Intramolecular arylation of alkenes. The intramolecular palladium-catalyzed condensation of aryl halides with an alkene group (Heck arylation5) can actually proceed more readily than the original bimolecular version. These intramolecular cyclizations typically proceed in acetonitrile at room temperature, particularly when catalyzed by Ag2C03, which also inhibits isomerization of the double bond of the product. They can be used to obtain spiro, bridged, and fused systems. Even tetrasubstituted alkenes can participate, with formation of quaternary centers.6... 

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

The Heck reaction may also proceed in an intramolecular fashion if the aryl halide is covalently bound to the allyl substrate. In this case the sequential allylic substitution-Heck-cyclization with Pd acetate as a catalyst takes place very smoothly as an unimolecular process and furnishes the polycon-densed pyrrolidones 91 in excellent yields (Scheme 29). 

A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <20040L4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of... 

When the Heck cyclization is carried out under oxidative conditions (intramolecular Fujiwara-Moritani arylation), spirocyclic dihydrobenzofurans are formed in good yields directly from aryl ethers (Equation 139) <2004AGE6144>. 

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. 

Preliminary results on the synthesis of oxindoles by intramolecular Heck cyclization followed by tandem arylation have been outlined. <94JHC631>... 

By the reaction of a,-unsaturated carbonyl compounds with the dibromide 55, cyclization occurs by a-arylation, followed by intramolecular Mizoroki-Heck reaction. For example, reaction of verbenone (61) with 55 using PPh3 generates 62 by y-arylation of 61, and subsequent intramolecular Mizoroki-Heck reaction affords the indane 63. The benzocyclobutane 67 was obtained unexpectedly... 

In contrast to intramolecular carbonylative Mizoroki-Heck cyclizations, the intermolecular carbonylative reaction of aryl halides with alkenes has been much less explored. Figure 3.10 depicts one of these rare examples using a carbon monoxide pressure of 5 atm [62], Small... 

Zhang, H., Ferreira, E.M. and Stoltz, B.M. (2004) Direct oxidative Heck cyclizations intramolecular Fujiwara-Moritani arylations for the synthesis of functionalized benzofurans and dihydrobenzofurans. Angew. Chem. Int. Ed., 43, 6144-8. 

In contrast to the substrate-type presented in Scheme 5.6, intramolecular Mizoroki-Heck reactions with cychc alkene moieties are quite common. Negishi and coworkers [21, 29] screened numerous substrates with different substitution patterns, out of which four are shown in Scheme 5.7. Cychzation of aryl iodide 35 proceeded well and furnished tricyclic 36 in good yield, including 10% of a double-bond isomer (not shown) (35 36). Mizoroki-Heck reactions of cyclohexenones 37 and 39 provided 68% and 82% yields respectively and, probably, due to conjugation with the carbonyl group in isomerically pure form (37,39 38,40). The two analogous cyclohexenone derivatives of aryl iodide 35 (not shown) cyclized under identical conditions in 50% and 71% yields respectively. Substrate 41a even allowed for formation of spirocyclic 42a in good yield, yet with poor... 

Cyclopentadiene 68 was formed in 63% yield by the Mizoroki-Heck cyclization of open-chain vinyl iodide 67 under classic reaction conditions (67 68, Scheme 5.14) [22], The analogous unsubstituted aryl iodide (not shown) provided a comparable yield (65%). Reaction in the /3-position of the a,/3-unsaturated carbonyl or carboxyl compound is not mandatory, as intramolecular Mizoroki-Heck reaction of 69 also proceeded well, forming tricyclic ketone 70 in 68% yield (69 70). 

Kiindig, E.P., Ratni, H., Crousse, B. and Bernardinelli, G. (2001) Intramolecular Pd-catalyzed carbocyclization, Heck reactions, and aryl-radical cyclizations with planar chiral arene tricarbonyl chromium complexes. J. Org. Chem., 66,1852-60. 

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