Intermolecular arylation with triflates

Fagnou et al. reported the synthesis of mukonine (11) starting from methyl vanillate (644). This synthesis uses both a palladium(0)-catalyzed intermolecular direct arylation and an intramolecular cyclization reaction. Triflation of methyl vanillate (644) afforded the aryl triflate 645. Using a Buchwald-Flartwig amination protocol, the latter was subjected to direct arylation with 2-chloroaniline (646) to furnish the corresponding diarylamine 647. Finally, intramolecular cyclization of 647 afforded mukonine (11). To date, this is the best synthesis (three steps, 75% overall yield) available for mukonine based on commercially available methyl vanillate (644) (582) (Scheme 5.45). 

Although the Heck reaction may be efficiently employed for synthesis, it has its limits that should not go unmentioned the Heck reaction can not—at least not intermolecularly—couple alkenyl triflates (-bromides, -iodides) or aryl triflates (-bromides, -iodides) with metal-free aromatic compounds in the same way as it is possible with the same substrates and metal-free alkenes. The reason is step 4 of the mechanism in Figure 16.35 (part II). If an aromatic compound instead of an alkene was the coupling partner the aromaticity with this carbopallada-tion of a C=C double bond would have to be sacrificed in step 4. Typically, Heck reactions can only be run at a temperature of 100 °C even if they proceed without any such energetic effort. This is why this additional energetically demanding loss of aromaticity is not feasible. 

B.xiv.c. Intermolecular Heck Reactions on Polymeric Support. Combinatorial chemistry has initiated a reappraisal and consequent renaissance in synthesis of compounds attached to polymeric supports. Therefore, it comes as no surprise that Pd-catalyzed reactions are among the most widely explored reactions for the generation of combinatorial libraries on solid phase. The first example of the intermolecular Heck reaction on solid phase was reported in 1994. In this article, 4-vinylbenzoic acid was attached to Wang resin and coupled with aryl halides/triflates under catalysis with Pd(OAc)2 (Scheme 45). Similar... 

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 phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

The Pd-catalyzed intermolecular C—O bond formation has also been achieved, and is also most effective with bulky, electi on-rich phosphines [91b, 95]. In addition, Buchwald has shown that these types of ligands facilitate the Pd-catalyzed diaryl ether formation [96]. When 2-(di-/ 7-butylphosphino)biphenyl (95) was used as the ligand, the coupling of triflate 93 and phenol 94 afforded diaryl ether 96 in the presence of PdtOAcfj and K,PO, . The methodology also worked for electron-poor, neutral, and electron-rich aryl halides. 

Hydrazonyl chlorides have been employed in the synthesis of 1,2,4-triazoles. Intermolecular cyclization of hydrazonyl chlorides 166 with nitriles catalyzed by ytterbium(I) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 167 in good yields <05SC1435>. Dipolar cycloadditions between hydrazonyl chlorides 168 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the syndesis of l-aryl-5-substituted-... 

The first example of the intermolecular AHR was reported by Hayashi et al. and involved the asymmetric arylation of 2,3-dihydrofurans using aryl triflates [18]. Although little or no enantiomeric excess was obtained when aryl iodide/silver salt combinations were used, the use of triflates along with the familiar Pd(OAc)2/ BINAP catalyst system resulted in the formation of the 2-aryl-2,3-dihydrofuran product 54, together with minor amounts of the 2, 5-dihydrofuran isomer 55. The rationale proposed by the authors for this outcome is shown in Scheme 12 it is hypothesized that addition of the catalytic complex to either face of the sub-... 

The report assumes that the key step involves an intermolecular transmetalation of the vinyl triflate to form a vinyltin that undergoes intramolecular cyclization with the aryl bromide. 

C.i.a. Four-Centered Processes. The carbopalladation of a C,C multiple bond with a carbon-palladium single bonds is the key step in the catalytic cycle of the standard Heck reaction, the intermolecular version of which has been used extensively since its discovery for the functionalization and derivatization of aryl and alkenyl halides, as well as alkenyl triflates or the more reactive nonafiates, which are readily available from the corresponding ketones (Scheme 2) (Sect. IV.2.1.2). 

The first example of the asymmetric intermolecular Mizoroki-Heck reaction was reported by Hayashi and coworkers [8] in 1991. This involved the asymmetric arylation of 2,3-dihydrofuran (1) with aryl triflates using a palladium/(7 )-BINAP (BINAP = 2,2 -bis(diphenylphosphino)-l,F-binaphthyl) catalytic system (Scheme 11.4). 

While 2,3-dihydrofuran (1) was the initial test substrate of choice for the intermolecular asymmetric Mizoroki-Heck reaction, the reaction was also applied to 2,3-dihydropyrrole 12, which shows similar patterns of both regio- and stereoselectivity to 2,3-dihydrofuran (1) [16], The intermolecular Mizoroki-Heck reaction with substituted 2,3-dihydropynole 12 and aryl triflates 13 gave mixtures of the 2-aryl-2,3-dihyropym)les 14 and the 2-aryl-2,5-dihydropyrroles 15, with the 2,3-product being the major product formed with a 74% ee (Scheme 11.9). 

Shibasaki and coworkers [18] carried out the intermolecular asymmetric Mizoroki-Heck reaction with dihydrodioxepines 20 using the palladium-(50-BlNAP catalytic system (Scheme 11.11). The product 21 was obtained in yields up of to 86% and with up to 75% ee. When the aryl group on the triflate 13 was changed, the enantioselectivity was not found to vary appreciably. 

As described in Sect. 2.1.2, the a-functi(Mialization (tosylation, triflation) of ketones with hypervalent iodine, followed by nucleophilic attack by diverse nucleophiles in an intramolecular fashion offers a convenient entry to various heterocycles [6]. Such a transformation can also be realized in an intermolecular fashion. Along these lines, Togo and coworkers [97] reported an elegant one-pot synthesis of 2,4,5-trisubstituted oxazoles 142 from alkyl aryl ketones 140 and nitriles 141 via an iodoarene-catalyzed oxidation reaction (Scheme 35). In this reaction sequence, reactive aryliodonium species were generated in situ by the reaction of aryl iodide with mCPBA and trifluoromethanesulfonic acid (TfOH). Afterwards, aryliodOTiium species reacted with alkyl aryl ketone to form a fi-keto aryliodonium species. 

In the same year, Durbin and Willis showed that potassium enolates of a variety of oxindole derivatives undergo efficient C3-arylation using Pd(dba)j and the bulky electron-rich phosphane ligand XPhos. Significant variation of the aryl coupling partner was possible, with both electron-rich and electron-poor substituents. Aryl bromides, chlorides, and triflates were all viable substrates in this intermolecular reaction (Scheme 8.48) [87],... 

Pt(PPh3)4 reacts with iodobenzene derivatives having OGH2SnBu3 or OGH2SiMe3 substituents at the 2-position to form the 3-oxa-platinacycle 399 (Scheme 55). Oxidative addition of a G-I bond to Pt(0) is followed by intramolecular transmetallation via activation of the G-Sn or G-Si bonds. The reactions proceed smoothly without additives, although intermolecular cross-coupling of aryl triflate with vinyl(tributyl)stannane promoted by the Pt complex requires addition of a base such as K2GO3. 

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