Intramolecular Heck-type cyclization

Fu et al. recently presented their results on carbene-catalyzed intramolecular Heck-type cyclizations [68]. The N-heterocyclic carbene generated in situ from the triazolium salt 83 catalyzed cyclization of the substrates 84 to form the cycloalkanes 85 (Scheme 9.25). The lowest yields were obtained when the reaction products were cyclobutanes. These authors assumed that the carbene initially reacted with the Michael acceptor site of the substrate to the intermediate 86, which subsequently cyclized via 86 to the final products 85. 

Drastic changes in regioselectivities were observed when intramolecular Heck-type cyclization was performed in an aqueous medium using Pd (OAc)2/tppts as the catalyst the selective formation of the e do-cyclized compound was observed instead of the exo compound obtained in a usual organic medium [Eq. (16)] [105]. 

Scheme 39. Intramolecular Heck-type cyclization reactions of aryl halides with arenes a) Pd(OAc)2, DMF, K2C03, Bu4NBr, 140°C, 36 h [132b] b) Pd(OAc)2, DMF, K2C03, ttBu4NHS04,120°C, 51 h,X = Cl (3.2%),X = H (5.6%) [133]...

Cobalt catalysts were studied by Oshima and co-workers in cyclization reactions in 2002. By using the cobalt complex [CoCl2(dppb)] as the catalyst and assisted by Me3SiCH2MgCl, the intramolecular Heck-type cyclization reactions of 6-halo-l-hexenes proceeded via a radical process to provide the corresponding tetrahydrofurans in good yields. Allyl-o-halogenophenols were tested under identical conditions and gave the desired dihy-drobenzofurans in low to excellent yields (Scheme 2.41). 

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. 

An interesting sequence of two consecutive Heck-type cyclizations and a subsequent Diels-Alder addition was observed when the methoxycarbonyl-substituted 2-bromo-trideca-1,1 l-dien-6-yne ( /Z)-63 was treated with the typical palladium catalyst (Scheme 3-20) [172]. The cyclization of dienyne 63 at 80 °C gave two diastereomeric trienes ( /Z)-64. At higher temperature (130 °C), an intramolecular Diels-Alder reaction of only the ( J)-isomer ( )-64 occurred to give the tetracyclic 65, whereas (Z)-64 remained as such, probably due to steric interference of the methoxy group. 

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]. 

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 45 Synthesis of carbazoles 32 by Buchwald-Hartwig amination and subsequent cyclization by intramolecular Heck-type coupling of the intermediate diarylamines 197...

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. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

The catalytic system proved not only applicable to alkyl hahdes, but also allowed for the intramolecular conversion of aryl halides. Interestingly, the corresponding Mizoroki-Heck-type cyclization products were formed selectively, without traces of reduced side-products (Scheme 10.27) [55]. Therefore, a radical reaction via a single electron-transfer process was generally disregarded for cobalt-catalysed Mizoroki-Heck-type reactions of aromatic hahdes. Instead, a mechanism based on oxidative addition to yield an aryl-cobalt complex was suggested [51]. 

More recently, a study on intramolecular carbonickelation of alkenes vwis published. The authors show that the NiBr2bipy complex can be used to catalyze an intramolecular Heck-type reaction in the absence of any additional base and without the need of a glove box. By using 20 mol% of NiBrabipy and Mn (2 equiv.) in DMF at 50 °C, the desired dihy-drobenzofurans or indoles were formed in moderate yields from allylic ethers and allylic amines via 5-exo-trig cyclization (Scheme 2.39). 

The Sasai research group found an intramolecular Heck-type approach to simple 3-pyrrolin-2-ones (Scheme 50 2010CC9064). For example, treatment of P,y-unsaturated amide 218 with palladium acetate in the presence of the isoxazoline ligand 219 and p-benzoquinone gives 3-pyrroUn-2-one 220 via a S-endo-trig cyclization. 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

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>. 

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