Endo cyclization intramolecular Heck reaction

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. 

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. 

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. 

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. 

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. 

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. 

An interesting case of 6-endo- versus 5- j o-cylization has been studied by Bombrun and Sageot [129], who investigated intramolecular Mizoroki-Heck cycUzation of enamides in a thiophene series (Scheme 6.50). If the reaction was carried out under Jeffery conditions, then it proceeded nearly exclusively via the 6- iio-cychzation mode however, when run under reductive Mizoroki-Heck conditions (e.g. in the presence of a hydride source), a 5-exo-cyclization is mostly achieved and the lack of a /3-hydrogen in this case leads to product 179. 

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