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

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8 J. E. R. Sadig, M. C. Willis REVIEW 2.3 Benzimidazoles and Benzimidazolones A host of approaches to benzimidazoles and related derivatives, featuring inter- and intramolecular and cascade reactions, as well as both palladium and copper catalysts, have been reported. Ma and co-workers developed a number of copper-catalyzed routes to these important heterocycles. 52 In 2007, they demonstrated that o-haloacetanilides could be combined with primary amines to deliver benzimidazoles (Scheme 18). For example, a copper(I) iodide/proline catalyst system was effective for the union of aryl iodide 44 with allylamine, to furnish benzimidazole 45 in 94% yield. 52a When more sterically demanding amines, or less activated aryl units, were employed it was necessary to use either heat or an acid/heat combination to achieve cyclization to the aromatic system; for example, the formation of cyclohexyl-substituted benzimidazole 46 required the addition of acid. A broad range of amines and aryl units, including pyridine derivatives, could be included in the method, delivering benzimidazoles in good to excellent yields. Although Scheme 18 shows only aryl iodide substrates, aryl bromides were also used. When the starting substrates were changed to o-iodoarylcarbamates, the same reaction system was used to access benzimidazolones (47 → 48). 52b Aqueous ammonia could also be employed as the nitrogen nucleophile in both reaction pathways, leading to the corresponding N–H derivatives. 52c 44 + H2N + H2N 47 + H2N H N Scheme 18 I H N I H N I O O O CF3 O OMe N Boc CuI (10 mol%) L-proline (20 mol%) K 2CO 3, DMSO, r.t. i) CuI (10 mol%) L-proline (20 mol%) K2CO3, DMSO, 40 °C ii) AcOH, 140 °C CuI (10 mol%) L-proline (20 mol%) K 2CO 3, DMSO 50 °C then 130 °C OH N H H O L-proline N 45, 94% 46, 73% 48, 74% Buchwald and co-workers developed a related palladiumcatalyzed route to aryl-substituted benzimidazoles. For example, the coupling of o-bromacetanilide 49 with otoluamine using an XPhos-derived catalyst provided the corresponding N-arylbenzimidazole in 94% yield Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York N N N H N N N CF3 O Boc O (Scheme 19). 53a A good range of anilines and aryl substrates (both Br and Cl) were described; Scheme 19 also shows an aza-example, derived from the corresponding pyridine substrate, as well as a cyclopropyl-substituted product. Some variation of ligand between XPhos (32) and RuPhos (50) was needed for certain substrates. In 2006, Scott reported a palladium-catalyzed synthesis of imidazopyridinones (aza-benzimadazolones) in a process analogous to the conversion of 47 into 48 shown in Scheme 18. 54 Me N H2N Me Scheme 19 Buchwald and Zheng also described a complementary copper-catalyzed protocol, based on aryl halide amidation (as opposed to amination), for benzimidazole synthesis. 53b The basic process is shown in Scheme 20; copper(I) iodide/diamine-catalyzed coupling of hexamide with oiodo-N-alkylaniline 51, followed by base-promoted cyclization, delivered the desired N-alkylbenzimidazole 52 in 87% yield. Alkyl, alkenyl and aryl amides could all be incorporated effectively. Scheme 20 N N (from ArCl using ligand 50) F 3C 49 Br H N Me Pd2(dba) 3 (1 mol%) + O Br XPhos (32) (8 mol%) K3PO4 t-BuOH, 110 °C 88% H2N 51 + O H N I Pent N Me Me Me N Me Me 83% (using ligand 50) i) CuI (5 mol%) 25 (20 mol%) Cs2CO3, dioxane, 90 °C ii) K3PO4 t-BuOH, 110 °C F3C 94% Intramolecular aryl amidation using urea substrates has been achieved using both palladium and copper catalysis and provides a further route to benzimidazolones (Scheme 21). The cyclization of urea 53, using a palladium(II) acetate/XPhos catalyst system, was described by the process group at Merck. 55 Chloro-, bromo- and iodoaryl derivatives could all be employed as substrates, as could chloropyridines. Copper-catalyzed variants of similar cyclizations have also been reported, 56 including a polymer-supported example; 57 the second reaction shown in Scheme 21, reported by SanMartin, Domínguez and co- Me Br N N Cy 2P Oi-Pr i-PrO RuPhos (50) 52, 87% N N Pent Me Me Me
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 9 MeO Scheme 21 workers, 58 illustrates a copper(I) iodide catalyzed cyclization using water as the solvent. Intramolecular reactions to access benzimidazoles can be achieved using amidines as substrates. An example, reported by Brain et al., 59 is shown in Scheme 22 in which amidine 54 was converted into the corresponding benzimidazole under the action of a Pd2(dba) 3/triphenylphosphine catalyst. The authors were also able to show that use of a ‘catch-and-release’ purification strategy, 59b involving Amberlyst resin, allowed the benzimidazoles to be obtained in pure form without recourse to chromatography. Related cyclizations in which the amidine is embedded within a heterocycle have also been described. 60,61 De Meijere and Lygin reported that amidines, generated in situ from an isocyanide and a primary amine, can also be cyclized using copper(I) conditions to access N-alkylbenzimidazoles. 62 Me 53 54 Scheme 22 PMB PMB Pd(OAc) 2 (1 mol%) N O XPhos (32) (3 mol%) N NH2 Cl Bn N O NH2 Br NaHCO3 i-PrOH, 83 °C CuI (8.5 mol%) TMEDA (3.5 equiv) H 2O, 120 °C MeO 92% 92% Batey and Evindar used related cyclizations employing guanidine substrates to access 2-aminobenzimidazoles. 63 Efficient reactions were achieved using either palladium or copper catalysis; Scheme 23 gives an example of the reaction conditions needed for each metal. In general, the copper conditions were found to be superior, providing higher yields and more selective reactions. Both aryl iodides and aryl bromides could be employed as substrates, allowing a broad range of 2-aminobenzimidazoles to be Me Br HN Bn N Scheme 23 N N Me NHMe Br Pd2(dba)3, (1.5 mol%) Ph3P (12 mol%) NaOH, H 2O–DME 160 °C, MW Pd(PPh3)4 (10 mol%) Cs2CO3, DME, 80 °C or CuI (5 mol%) 1,10-Phen (10 mol%) Cs2CO3, DME, 80 °C Me Me 82% N N Bn N Pd: 66% Cu: 90% N N N H Bn N N H Me O O Me prepared in good yields. Szczepankiewicz et al. applied this type of copper-catalyzed cyclization to substrates based on uracil templates to prepare purine and related fused imidazole systems. 64 2-Mercaptobenzimidazoles can similarly be accessed using copper-catalyzed cyclization of in situ generated isothioureas. 65 The research groups of both Zhang66and Wu67 showed that o-halophenylimidoyl chlorides are effective substrates for copper-catalyzed benzimidazole synthesis. Scheme 24 presents an example from the Zhang group, and shows how imidoyl chloride 55 can be combined with benzylamine using a copper(I) iodide catalyst, to deliver the expected benzimidazole in excellent yield. Both alkyland arylamines could be employed. In both reports it was necessary to include an electron-withdrawing substituent on the imidoyl chloride substrate; for example, the trifluoromethyl substituent on imidoyl chloride 55. N Scheme 24 Maes and co-workers explored a range of cascade amination strategies to access a variety of benzo-fused benzimidazole systems. 68 In their lead publication, they were able to combine 2-chloro-3-iodopyridine with 2-picoline to generate dipyridoimidazole 56 in 96% yield (Scheme 25). The example shown employs a palladium(II) acetate/ BINAP catalyst, although XantPhos (2) was also shown to be an effective ligand. 68a The chemistry has been extended to the preparation of a number of benzo-fused and aza analogues, 68a–c,69 and in an interesting application a temperature/halide dependent regioselectivity switch was developed. 68d Scheme 25 I H2N Ph N 55 + I Cl + CF3 Cl N NH 2 CuI (10 mol%) TMEDA (20 mol%) Cs 2CO 3 toluene, 110 °C Pd(OAc) 2 (3 mol%) BINAP (3) (3 mol%) Cs2CO3 toluene, reflux 98% Batey and co-workers described a copper-catalyzed cascade route to benzimidazoles from the combination of a 1,2-dihalobenzene with an amidine, although only a single example was reported. 70 Deng et al. reported a related cascade in which amidines were exchanged for guanidines, leading to the synthesis of 2-aminobenzimidazoles (Scheme 26). The majority of examples delivered N–H products, although N-substitution could also be introduced. 71 Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York N N N CF3 Ph N N 56, 96%
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