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

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4 J. E. R. Sadig, M. C. Willis REVIEW BnO 13 + (HO) 2B MeO O Scheme 5 N Scheme 6 Br NH2 S Br Pd(OAc) 2 (1 mol%) SPhos (2 mol%) S N H Ph NH Me Me N 86% 73% 77% 15, 86% (2 mol% Pd) Br NH Bn Br + N H MeO (HO) 2B Ph K3PO . 4 H2O toluene, 90 °C regioisomeric 5- and 4-azaindoles was more challenging and required the use of N-oxide substrates. Thienopyrroles could also be prepared starting from the corresponding thiophene-derived substrates. The same gem-dihalovinylaniline substrates have been utilized in a number of different tandem processes. For example, as Scheme 7 illustrates, the initial intramolecular amination reactions have been partnered with a number of alternative reactions, including Heck olefinations (16 → 17), 31e carbonylations (16 → 18) 34 and Sonogashira couplings (16 → 19), 31f to deliver acrylate-, ester- and alkynesubstituted indoles, respectively. Bisseret and co-workers used the same substrates in tandem palladium-catalyzed amination/phosphonation sequences to deliver 2-phosphonate-substituted indoles. 33 Tethered substrates were used in the Heck chemistry to provide polycyclic products via an intramolecular second step. 31e Related tethered substrates, invoking a second intramolecular amination reaction, 31g or an intramolecular direct arylation reaction, 31h were also developed to access alternative polycyclic scaffolds. It is interesting to note that the double amination processes were achieved using copper catalysis. Lautens and co-workers also demonstrated that the reactivity of gem-dibromovinylanilines can be controlled to allow access to 2-bromoindoles by a single (as opposed to a tandem) palladium-catalyzed intramolecular amination reaction. 31i The Willis research group has developed cascade catalytic amination strategies to access a range of indole deriva- Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York N Me Pd(OAc) 2 (3 mol%) SPhos (14) (6 mol%) K3PO . 4 H2O toluene, 100 °C N H Me 86% (dichloro substrate) Cy2P OMe MeO SPhos (14) N N Bn 74% Ph t-BuO 2C Scheme 7 Br NH 16 R SiMe 3 Pd(OAc) 2 (4 mol%) Me4NCl (100 mol%) K3PO4 . H2O, Et3N toluene, reflux Br PdCl2(PPh3) 2 Ph3P (10 mol%) CO (10 atm) DIPEA, THF MeOH, 110 °C P(p-MeOC6H4)3 (8 mol%) Pd/C (2 mol%) CuI (4 mol%) i-Pr2NH, toluene, 100 °C tives. They focused on the use of 2-(2-haloalkenyl)aryl halides, together with the corresponding alkenyl triflates, as indole substrates. 35a,b Scheme 8 shows examples of both the aryl halide/alkenyl triflate (20) and the aryl halide/alkenyl halide (21) substrates in palladium-catalyzed indole-forming reactions. Both reactions feature an initial intermolecular amination reaction followed by an intramolecular amination as the second step of the cascade, to deliver N-functionalized indole products. The authors noted that it was possible to employ either Z- or E-configured alkene isomers in the process, a consequence of the initial amination reaction taking place at the alkenyl halide and generating a configurationally unstable enamine intermediate. Reactions employing the triflate substrates were best achieved using DPEPhos (22) or XantPhos (2) ligands, while the dihalide substrates delivered best yields with the Buchwald diphenyl ligands, such as SPhos (14). By selecting the appropriate class of substrate it was possible to access a number of indole substitution patterns. Significant variation of the nitrogen coupling partner was possible, with examples of aniline, amine, amide, hydrazine and sulfonamide nucleophiles all being reported. Sterically demanding nitrogen nucleophiles, such as tertbutylamine, could also be introduced; 35c the ability to access indoles bearing bulky N-substituents was exploited in a synthesis of the natural product demethylasterriquinone A, in which N-(reverse prenyl)indole 23 was utilized as a key intermediate. A recent extension of the chemistry has seen trihalogenated substrates employed, allowing access to 4-, 5-, 6- and 7-chloroindoles. 35d The Li research group has adapted the method to encompass trifluoromethyl-substituted substrates in order to prepare a series of N-aryl-2-trifluoromethyl-substituted indoles. 36 A related intramolecular amination reaction between an aniline and an alkenyl triflate was employed by Smith and co-workers in their synthesis of the nodulisporic acids tetracycle. 37 The Willis research group also demonstrated that similar palladium-catalyzed cascade processes can be achieved using pyridine-derived substrates to provide access to the corresponding azaindole products. 35e For example, reaction of dihalopyridine substrate 24 with p-anisidine, using a DPEPhos-derived catalyst, delivered the corresponding N Bn 17, 79% CO2t-Bu CO2Me N 18, 70% Bn N H SiMe3 19, 57%
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 5 Br OTf Cl + 20 H2N N 71% Ph Scheme 8 7-azaindole in good yield (Scheme 9). The process was shown to work well for 7-azaindoles; however, access to the remaining regioisomers was less successful. Scheme 9 The 2-(2-haloalkenyl)aryl halide substrates have also been shown to undergo cascade copper-catalyzed amination reactions to deliver N-functionalized indoles. 35f An example featuring a carbamate coupling partner is shown in Scheme 10. Although some overlap in scope with the palladium-catalyzed version of the process was established, there were also significant differences in reactivity. In general, the copper-catalyzed variant was more limited, with chloro-substituted substrates performing poorly; however, greater success was achieved with amide nucleophiles, relative to the palladium system. Scheme 10 Pd2(dba)3 (2.5 mol%) DPEPhos (6 mol%) Cs2CO3 toluene, 100 °C Br Cl Ph 21, E/Z 2:7 + H2N Ph Pd2(dba)3 (2.5 mol%) SPhos (14) (7.5 mol%) NaOt-Bu toluene, 80 °C N Cl Br + O OEt 24 H2N OMe O PPh2 PPh2 DPEPhos (22) N Ph 81% OMe Pd2(dba) 3 (5 mol%) DPEPhos (22) (12 mol%) Cs2CO3 toluene, 110 °C Br Br 25 MeO CuOAc (10 mol%) MeO MeO H2N + Ot-Bu (20 mol%) Cs2CO3 toluene, 110 °C MeO O MeN NMe H H 25 75% 94% N N Ph N 23, 77% Me Me N 83% N t-BuO 82% OEt O OMe N O Cl Ackermann and co-workers developed efficient indole syntheses based on a cascade amination process starting from o-alkynylhaloarenes. 38 In his original report, Ackermann described both palladium- and copper-catalyzed variants of the process (Scheme 11). 38a For example, the combination of o-alkynylchloroarene 26 with benzylamine under the action of an NHC-derived palladium catalyst delivered indole 27 in 66% yield. The original copper-catalyzed protocol simply employed copper(I) iodide to combine o-alkynylchoroarenes with anilines furnishing the corresponding N-arylindoles in good yields. The reactions proceed via initial intermolecular N-arylation, followed by cyclization onto the alkyne. The two different metal systems were shown to display differing, and complementary, reactivities; for example, the palladium-catalyzed methods were effective for N-alkyl and Naryl nucleophiles, while the copper system tolerated Naryl and N-acyl substrates. 38b The N-acyl systems required the use of diamine ligand 25. Scheme 11 shows several examples of products obtained using the copper methodology, including an N-acyl indole, as well as an azaindole. An indole corresponding to the Chek1/KDR kinase inhibitor pharmacophore was also prepared. The palladiumcatalyzed version of the chemistry was shown to be effective for the preparation of indoles bearing sterically demanding substituents; for example, the adamantylsubstituted indole 28 was obtained in 94% yield. 38c,d The Hu 39 and Sanz 40 research groups have reported related indole-forming chemistries. F3C Scheme 11 29 26 Hex Pd(OAc)2 (5 mol%) (5 mol%) + H2N Cl Ph K3PO4 toluene, 105 °C Bu i-Pr i-Pr Cl + N N – F 3C N 27, 66% Bn Hex H2N Cl + OMe CuI (10 mol%) KOt-Bu toluene, 105 °C N Bu OMe 69% t-BuO 61% N O S N N t-BuO 86% O i-Pr i-Pr 29 Ph Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York N 28, 94% F
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