Heck reaction 8-endo cyclizations

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]. 

Intramolecular Heck reactions have frequently been used for the synthesis of cyclopen-tanoid structures. In nearly all cases reported so far, the ring closure occurs as a 5-exo process (for an exception, see Table 4, entry 6), for which 2-halo-l,6-heptadienes and related compounds are the appropriate starting materials. In some cases, however, these substrates cyclize by a 6-endo mode to give cyclohexane derivatives (see Sect. IV.2.2.1.B.V). 

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. 

According to Baldwin s rules [4], 5-endo-tiig cyclizations are normally disfavoured nevertheless, this reaction mode can be realized by Mizoroki-Heck reactions. Although they were outshone by the many 5- and 6-exo-type transformations, quite a number of examples following this cyclization mode were reported. This was mostly for the construction of five-membered heteroaromatic compounds (Chapter 6), but in these cases an alternative mechanistic scenario sometimes seems likely [39]. However, a few syntheses of carbocycles via (formal) 5-o Mizoroki-Heck cyclization were disclosed as well. 

It is interesting to note that the substitution pattern of nonactivated alkene functions also has only minor influence on the 5-endo- ng Mizoroki-Heck cyclization (Scheme 5.15). The Mizoroki-Heck reaction of alkene 71 without terminal substitution proceeded well and provided indanone 72 in 65% yield (71 72) [40]. Furthermore, terminal substitution is tolerated -configured 73 was cyclized in moderate yield (52%) (73 74) [31], while... 

Scheme 5.16 presents two conceptually interesting examples of Mizoroki-Heck reactions. In the first one, Ma and Negishi [41] showed that allenes are also suitable for intramolecular Mizoroki-Heck reactions 75a was cyclized in a 5-endo- g mode, providing benzofulvene (76a) in 69% yield (75a 76a, Scheme 5.16). Its cognate, 75b,...

Intramolecular Mizoroki-Heck reactions following a (formal) 6-endo-tiig pathway are, as with the 5-endo-tiig cyclizations (see above), not very common this circumstance is usually rationalized by Baldwin s rules [4]. Apart from occasional side-reactions of 5-cxo-trig-type cyclizations (see Section 5.2, Scheme 5.2), there were also several selective transformations reported. 

Vital, P, Norrby, P.-O. and Tanner, D. (2006) An intramolecular Heck reaction that prefers a 5-endo- to a 6-exo-trig cyclization pathway. Synlett, 3140-4. 

Besides the different mechanistic pathways mainly depending on the substrate types, the Mizoroki-Heck reaction can also be run under several conditions with diverse additives which affect the outcome. A major achievement in this field was the discovery of the so-called Jeffery conditions [25-28]. Mizoroki-Heck reactions are indeed greatly accelerated by the use of inorganic bases in combination with a phase-transfer agent which allows lowered reaction temperatures. In some cases, Jeffery conditions can even lead to the endo-cyclizod product, whereas standard conditions give the exo-cyclized compound [8]. 

Dankwardt, J.W. and Fhpprn, L.A. (1995) Palladium-mediated 6-endo-XA% intramolecular cyclization of N-acryloyl-7-hromoindolines. A regiochemical variant of the intramolecular Heck reaction. J. Org. Chem., 60, 2312-3. 

In 2006, Lu and coworkers [53] described a method for the synthesis of carbazoles using the palladium(ll)-catalysed oxidative Heck reaction (Scheme 9.25). Indole 177 was subjected to catalytic Pd(OAc)2 and 2.1equiv of benzoquinone to afford carbazole 178 in 88% yield. Because the alkene is 1,1-disubstituted, a 5-exo cyclization mode (as seen in Ferreira and Stoltz s [48] indole annulation) is unproductive, and a 6-endo cyclization ultimately occurs. The putative intermediate is then believed to be oxidized to the aromatic carbazole by the excess benzoquinone. When indole 179, featuring a terminal alkene, was treated with these oxidative conditions, a mixture of products from 6-endo cyclization (180) and 5-exo cyclization (and subsequent isomerization and [3+2] cycloaddition, 181) was observed. A variety of substituted carbazoles were obtained by this palladium(n)-catalysed oxidative cyclization. 

The use of hydrophilic sulfonated phosphines TPPMS and particularly TPPTSf allowed development of a very mild procedure for Heck reactions of iodoarenes and iodoalkenes, though this protocol requires a large amount of expensive catalyst, which makes this scheme unsuitable for large-scale reactions. The method showed unusual selectivity trends for example, in the reactions with cycloalkenes no migration of double bond was reported. "" Also, a very rare endo-trig-mode of cyclization is favored in the aqueous phosphine-assisted method compared to the normal exo-trig-mode observed in nonaqueous methods (Scheme 35). "" " ... 

Scheme 33. Examples of 1-exo and i-endo Heck cyclization reactions...

Treatment of hydrazonium salt 4 with palladium(0) led to the formation of p3UTole 5 via 5-exo-trig amino-Heck cyclization <05H(65)273>. The reaction presumably proceeds by the oxidative addition of palladium(O) into an A-Abond. An oxidative addition into the A-O bond of benzoyloximes was the key step in the 5-endo-trig amino-Heck cyclization leading to 5-fluoro-3A-pyrroles <05CC4684>. 

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. 

Compared to Figure 1, the substructures of Figure 3 have side chains elongated by one carbon atom. Heck-type cyclization of substrates that match these substructures should lead to six-membered heterocycles because the intramolecular carbopalladation in the sense of a 6-exo-trig reaction should clearly be favored against the 1-endo-trig pathway. 

When investigating the first syntheses of five-membered carbocycles (Section 5.2), Grigg et al. [8, 9] at the same time also revealed Mizoroki-Heck cyclizations forming the structurally related six-membered ring systems. Cyclization of 2-bromo-l,7-octadiene 79 gave 80 with a 4 1 ratio of exocyclic to endocyclic double-bond isomers in 86% yield, and without any 7-endo-ttig product (79 80, Scheme 5.17). Reaction of 81 was less successful, only providing 66% yield and a 2.5 1 ratio of double-bond isomers (81 82). Both products 80 and 82 were later successfully employed in Diels-Alder... 

However, a straightforward 6-endo-ttig cyclization is at least sometimes in question or might even be ruled out. As demonstrated by Negishi and coworkers [13] in the reactions of 163 and 165 (Scheme 5.30), Mizoroki-Heck cyclization of 163 proceeded well, forming... 

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