Triflates intramolecular Heck reactions

Although the coupling of aiyl halides with alkenes (commonly referred to as the Heck reaction) was first reported more than 25 years ago [ 1 ], only in the past decade has its enormous synthetic potential been realized [2], Within that time, the reaction has been extended to many substrates, including vinyl iodides and bromides and enol triflates. Moreover, the intramolecular variant has become one of the more important reactions for the formation of carbon-carbon bonds and has emerged as a premier method for the construction of quaternary carbon centers. The ability of intramolecular Heck reactions to reliably fashion carbon-carbon bonds in polyfunctional molecules has led to wide application of this reaction at the strategy level for the synthesis of complex natural products [2g],... 

Construction of the B ring of the congested taxol molecule 101 has been carried out by the intramolecular Heck reaction of the enol triflate 100 [46],... 

By converting the enol triflate 41 to the spiro-tricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantio-selective formation of quaternary chiral carbon centers ean be carried out through an intramolecular Heck reaction. While the enantioselectiv-ities were only moderate at the beginning [ 16], the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclizalion of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. 

A palladium-catalyzed amination of triflate 111 with 2-bromoaniline 112, followed by an intramolecular Heck-reaction gave the P-carbolinone 113 <03OL4195>. 

Mizorokf and Heck reported independently in the early 1970s the first palladium-mediated coupling of an aryl or vinyl halide or triflate with an alkene. This reaction is generally referred to as the Heck reaction. From the first reports on asymmetric intramolecular Heck reactions by Overman and Shibasakf in 1989 the asymmetric Heck reaction has emerged as a reliable method for the stereoselective formation of tertiary and quaternary stereogenic centers by C-C bond formation in polyfunctionalized molecules. ... 

More common is use of intramolecular Heck reactions to fashion ckv-decalins. Several examples are found in our current program aimed at the total synthesis of complex cardenolides [14,15]. In a model study for a proposed synthesis of (-t-)-ouabagenin (48), trienyl triflate 45 was converted to pentacycle 47 in good yield (Scheme 6-8) [16]. The stereochemical outcome of this cyclization was rationalized by the preference for an eclipsed orientation of the two reacting bonds, which is readily achieved in a cyclization geometry (46), and led to the cis stereoisomer. This example also highlights the stability of... 

The naphth[3,2,l-cr/]indole ring system, e.g. 290, was constructed by Miki in very good yield via an intramolecular Heck reaction of triflate 289 [284]. The corresponding bromide furnished 290 in 74% yield. Interestingly, attempted radical cyclization of the bromide with BujSnH failed. 

Now the alkene must be moved yet one more time around the ring to prepare the way for another intramolecular Heck reaction. Hydroboration (chapter 17) of 153 is regioselective because of the large N-Boc group and Swem oxidation completes the insertion of the ketone 155. Reduction and elimination use another palladium-catalysed reaction. Conversion to the triflate 157 is followed by Pd-catalysed transfer hydrogenation, the H atom coming from formic acid HC02H. 

The intramolecular Fujiwara-Moritani/oxidative Heck reaction was applied to the synthesis of functionalized benzo[fe]furans and dihydrobenzo[h]furans in 50-80% yields, and 15 examples are given in the article <04AG(E)6144->. Ionic liquid ([bmimJBF4) was found to be an effective solvent for the PdCl -catalyzed intramolecular Heck reaction to realize benzofurans <04TL6235>. Another palladium-catalyzed intramolecular Heck reaction between vinyl triflate and benzo[(j]furan was utilized to construct the seven-membered ring based (-)-frondosin B <04T9675>. 

Cyclizations. A great number of substrates designed for cyclization have been studied, including those leading to l-sulfinylmethylene-2-methylenecycloalkanes and to pyrroles. - Intramolecular Heck reaction involving enol triflate and allylsilane moieties is useful for the synthesis of cyclic compounds. ... 

Kiely and Guiry reported an asymmetric version of the intramolecular Heck reaction of aryl triflate [36]. In this reaction. Proton Sponge (1) also greatly improved the reactivity. 

Table 8.11 Asymmetric intramolecular Heck reaction of aryl triflate...

In 2010, Weinreb and coworkers reported their synthesis of communesin F (17) [30]. The synthesis began with known enol triflate 37. A Suzuki-Miyaura crosscoupling with 0-nitrophenyl boronic acid (38) followed by a two-step reaction with iodoaniline 39, afforded amide 40. A one-pot displacement of the benzyl group with ethyl carbamate, amide nitrogen protection, and a subsequent intramolecular Heck reaction provided enamide 41 (Scheme 5). 

The Heck reaction, first disclosed independently by Mizoroki and Heck in the early 1970s, is the Pd-catalyzed coupling reaction of organohalides (or triflates) with olefins. In recent years, this transformation has become an indispensable tool for organic chemists. Inevitably, many applications to heterocyclic chemistry have been pursued and successfully executed. The greatest utility of the intramolecular Heck reaction was captured in Section 3.2 in this chapter. Intermolecular Heck reactions will be focused on this section. 

Tietze, L.F. and Modi, A. (2000) Regioselective sUane-terminated intramolecular Heck reaction with alkenyl triflates and alkenyl iodides. Eur. J. Org. Chem., 1959-64. 

The enormous potential of the intramolecular Heck reactions has been demonstrated impressively in elegant syntheses of even the most complicated natural product skeletons. The intramolecular Heck reaction on the achiral iodoalkenes 354 and the corresponding alkenyl triflates 357 with their pairs of enantiotopic double bonds in the cyclohexa-1,4-diene moieties, applying catalysts with chiral ligands, gave tetrahydronaphthalenes 359 or hydrindanes from precursors such as 354, 357 or corresponding precursors with one less carbon in the tether [204f], with excellent enantioselectivities. Complementary to the asymmetrically induced inter-molecular arylation with triflates (Scheme 8.72), reasonable asymmetric inductions in intramolecular reactions were also achieved with iodides on the addition of silver salts to promote the formation of cationic intermediates such as 356 (Scheme 8.73)... 

A convenient synthesis of 3-spiro-fused benzofuran-2(3//)-ones was reported via Pd-catalyzed chemoselective carbonylation of vinyl triflates in the presence of o-iodophe-nols, followed by a regioselective intramolecular Heck reaction (Scheme 20). ... 

Two Heck reactions, the first intramolecular in an exo- sense, the second intermolecular, were used to prepare an intermediate 5.105 for a prostaglandin receptor antagonist on a 2.17 kg scale (Scheme 5.32). An intramolecular Heck reaction of a vinyl triflate 5.106 with an cxo-ring closure was employed to form an eight-membered ring in a synthesis of taxol (Scheme 5.33). ... 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

Treatment of a benzyl-substituted and symmetrical bis-enol tri-flate with various aryl boronic acids in the presence of Pd(OAc)2 results in a Suzuki-Miyaura cross-coupling reaction, then an intramolecular Heck reaction between the remaining triflate residue and the benzyl group and so as to give the illustrated product (eq 96).i i... 

In a series of studies, Shibasaki examined the formation of chiral benzylic quaternary centers by using asymmetric intramolecular Heck reactions. The effect of double-bond stereochemistry was examined in the cyclization of aryl triflates 9.1 and 93 (Sdieme 8G.9) [22]. As is ctmunonly... 

Another sequence involving an anionic and a Pd-catalyzed step was described by the groups of Rossi and Arcadi [477]. These authors prepared substituted tetrahy-dro-2H-pyrrolo[3,2-c]pyrazolones 2-934 starting from hydrazones 2-932 and aryl-halides or alkenyl triflates 2-933 (Scheme 2.208). The first step is the formation of a pyrazolone. There follows cleavage of the urea moiety with piperidine and an inter-as well as an intramolecular Heck-type reaction with 2-933. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

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