Palladium- and Copper-Catalyzed Aryl Halide Amination ...

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2 J. E. R. Sadig, M. C. Willis REVIEW 2 Carbon–Nitrogen Bond Formation 2.1 Indoles A number of new indole syntheses based on aryl halide amination have been developed; however, one of the first heterocycle syntheses to be reported using palladiumcatalyzed amination chemistry was concerned with intercepting reaction intermediates from a very well established route to indoles. 24 In 1998 Buchwald demonstrated that a variety of aryl halides could be combined with benzophenone hydrazone using intermolecular palladiumcatalyzed amination reactions to generate the corresponding N-arylhydrazones (1, Scheme 1). 25 A palladium(II) acetate/XantPhos (2) catalyst system, in combination with sodium tert-butoxide, was found to be optimal. The Narylhydrazones could either be isolated or, after simple filtration through a silica plug, treated directly with an enolizable ketone under acid hydrolysis conditions. The ensuing Fischer cyclization provided the corresponding indoles in good to excellent yields. Variations to access either N-alkyl- or N-arylindoles were also developed, although in these cases functionalization of the isolated Narylhydrazones was necessary. A limitation of the benzophenone hydrazone methodology is the difficulty in removing benzophenone from the final indole products, particularly in large-scale applications. Cho and Lim reported a related procedure, in which N-Boc arylhydrazines were employed in Fischer cyclizations. 26 The required N-Boc arylhydrazines were prepared using palladium-catalyzed amination chemistry, but in these cases were isolated before indole formation. The use of intramolecular carbon–nitrogen bond formation onto an aryl halide has proved to be a popular method to achieve indole synthesis. In one of the first routes based Biographical Sketches Jessie Sadig received her MChem degree from the University of Oxford in July 2008, where she carried out her final year project under Michael Willis received his undergraduate education at Imperial College London, and his PhD from the University of Cambridge working with Prof. Steven V. Ley, FRS. After a postdoctoral stay with Prof. David A. Evans at Harvard University, as a NATO/Royal Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York on this approach, Watanabe et al. demonstrated that N,Ndimethylhydrazones derived from o-chloroarylacetaldehydes (4) underwent cyclization under the action of palladium catalysis to provide the corresponding N-aminoindoles (Scheme 2). 27 Tri(tert-butyl)phosphine and the ferrocene derivative 5 were found to be the optimal ligands. The authors went on to demonstrate that if an appropriately functionalized substrate was employed, then a second palladium-catalyzed transformation could be achieved in the reactions. For example, dichloride 6 could N Ph Ph NH2 + MeO MeO Scheme 1 65% Br Me N H Me Me PPh 2 the supervision of Dr. Jeremy Robertson. She then joined the Willis group and is currently working towards her DPhil degree. Her Society Research Fellow, he was appointed to a lectureship at the University of Bath in November 1997. In January 2007 he moved to the University of Oxford, where he is a University Lecturer and Fellow of Lincoln College. He was awarded an EPSRC Ad- O i) Pd(OAc) 2 (0.1 mol%) XantPhos (0.11 mol%) NaOt-Bu, toluene, 80 °C ii) TsOH. H2O, EtOH reflux O Me Me Pent Ph Ph N HN Me 1 PPh 2 N H Ph Ph 79% Pent N H Pent N H Me Me 70% 70% (BINAP used as ligand) XantPhos (2) (rac)-BINAP (3) PPh2 PPh2 research focuses on palladium- and copper-catalyzed cascade processes for heterocycle synthesis. vanced Research Fellowship in 2005 and the 2008 AstraZeneca Research Award for Organic Chemistry. His group’s research interests are based on the development and application of new catalytic processes for organic synthesis.
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 3 be reacted under the standard conditions but with the addition of phenyl boronic acid, to provide 4-phenylindole 7, resulting from tandem carbon–carbon and carbon– nitrogen bond formation. In addition to aryl boronic acids being introduced by Suzuki couplings, a range of azoles and amines could also be effectively incorporated via a second carbon–nitrogen bond-forming process. F Cl 4 6 Scheme 2 Doye and co-workers demonstrated that N-alkyl imines corresponding to hydrazones 4 can also be effectively cyclized under the action of palladium catalysis to provide N-alkylindoles. 28 In their approach, the imine substrates were prepared from the corresponding alkynes using a titanium-catalyzed hydroamination process. In this onepot protocol, the imines were then subjected to palladium catalysis to deliver the indole products. Scheme 3 shows an example in which alkyne 8 was converted in a one-pot process into indole 9. N-Heterocyclic carbene (NHC) ligand 10 was most effective. Substrates containing a tethered amine nucleophile could also be included, leading to the formation of N–C2 annulated indoles. Scheme 3 H N Cl NMe2 H N Cl NMe2 Pd(dba) 2 (3 mol%) 5 (4.5 mol%) NaOt-Bu o-xylene, 120 °C PhB(OH) 2 Pd(dba)2 (5 mol%) 5 (7.5 mol%) Cs 2CO 3 o-xylene, 120 °C Fe NMe2 Pt-Bu2 5 N 60% NMe2 N NMe2 7, 56% 10 8 MeO Pr i) [Cp2TiMe2] (5 mol%) toluene 110 °C, 24 h MeO + H2N Me ii) Pd2(dba)3 (5 mol%) Cl Me Me (10 mol%) KOt-Bu, dioxane 9, 65% N Pr Me 110 °C Me Me Me Me Isolated dehydrohalophenylalinate derivatives have been converted into indoles using related cyclizations. For example, Brown was the first to report the cyclization of enamines such as 11 (Scheme 4) into the corresponding indole-2-carboxylates. In this report from 2000, a simple dppf-derived catalyst was employed in combination with F Ph Me Me Me Cl N N Me – 10 + potassium acetate as base. 29 Kondo and co-workers subsequently showed that polymer-supported substrates corresponding to 11 can also be cyclized effectively. 30 O 2N Scheme 4 11 HN I Br CO2Et PdCl 2(dppf) (5 mol%) KOAc, DMF 90 °C PPh 2 Fe dppf (12) PPh2 O2N 83% Br Lautens and co-workers established gem-dihalovinylanilines as versatile substrates for indole synthesis based on a series of tandem metal-catalyzed processes. The substrates were readily accessed from the relevant o-nitrobenzaldehyde derivatives via Ramirez olefinations followed by reduction of the nitro group. The early chemistry focused on tandem palladium-catalyzed intramolecular amination reactions and intermolecular Suzuki couplings to deliver a series of variously substituted indoles. 31a,b For example, reaction of gem-dibromoaniline 13 with thienyl-3-boronic acid delivered the expected indole in 86% yield (Scheme 5). The electron-rich biphenyl-based phosphine SPhos (14), developed by Buchwald, proved to be optimal. Significant variation in the substitution pattern of the substrates and in the type of organoboron coupling partner was possible. For example, it was possible to prepare indoles with individual substituents at positions C2–C7; N-aryl substrates could also be employed. Aryl, alkenyl and alkyl boron reagents were all used successfully. For many of the examples it was possible to use palladium loadings of only 1 mol%. Although no reaction intermediates were detected, a brief mechanistic investigation suggested that the intramolecular amination reaction preceded the intermolecular Suzuki coupling. It is interesting to note that the amination reactions took place on alkenyl halides, 32 as opposed to the usual aryl halide substrates. To demonstrate the synthetic utility of the method, indole 15, prepared in 86% yield from the corresponding gem-dibromovinylaniline and 2methoxyquinoline boronic acid, was utilized in a short synthesis of KDR kinase inhibitors. 31c Bisseret and coworkers also reported a single example of the synthesis of a 2-arylindole using a similar strategy. 33 In an elegant extension of this chemistry the same group was able to demonstrate that the corresponding pyridinederived substrates could be utilized to access azaindoles. 31d The example shown in Scheme 6 illustrates the preparation of a 7-azaindole using reaction conditions almost identical to those for the parent indole series. An important modification from the parent system, needed to achieve high yields, was the use of a nitrogen-protecting group. It was also possible to extend the chemistry to the preparation of 6-azaindoles; however, the synthesis of the Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York N CO2Et
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