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

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14 J. E. R. Sadig, M. C. Willis REVIEW 2.9 Quinazolines, Quinazolinones and Quinazolindiones In 2006 Willis and co-workers reported the palladiumcatalyzed coupling of o-bromobenzoate esters with monosubstituted ureas as a route to 3-alkylated quinazolinediones. 96 The reactions proceeded via initial intermolecular carbon–nitrogen bond formation followed by intramolecular, base-promoted, amidation. A XantPhosderived catalyst in combination with cesium carbonate allowed efficient and regioselective processes; for example, bromobenzoate 91 was combined with N-butyl urea to provide quinazolinedione 92 in 77% yield as a single regioisomer (Scheme 43). A variety of substituents were tolerated on both the aryl bromide and urea coupling partners. The observed regiocontrol originates from the initial aryl carbon–nitrogen bond formation taking place at the least hindered nitrogen of the urea nucleophile. Cl 91 Scheme 43 O OMe Br + Bu N H O Pd 2(dba) 3 (2.5 mol%) XantPhos (2) (5 mol%) NH2 Cs 2CO 3 dioxane, 100 °C N H 92, 77% The Fu research group reported a related strategy for the synthesis of quinazolinones and quinazolines. In their original report, they exploited a copper-catalyzed coupling of amidines with o-bromobenzoic acids to access quinazolinones. For example, acid 93 was combined with acetimidamide 94 to provide quinazolinone 95 in 81% yield (Scheme 44). 97a The reaction conditions consisted of copper(I) iodide without any added ligand, in N,N-dimethylformamide at room temperature. The ability to use such low-temperature conditions was attributed to the formation of a chelated intermediate involving the oxygen atom of the ortho-positioned carboxylic acid. The reaction was applicable to a broad range of amidines and benzoic acids. The researchers next extended the chemistry to include guanidines as the nitrogen nucleophiles, resulting in the formation of 3-aminoquinazolinone products such as 96. 97b The carboxylic acid substrates could also be replaced; the use of the related ketones in combination with guanidines resulted in the synthesis of 3-aminoquinazolines such as 97. Ding and co-workers reported an alternative copper-catalyzed route to quinazolinones based on the use of o-iodobenzamide substrates. 98 A typical reaction is shown in Scheme 44: coupling of benzamide 98 with formimidamide, using copper(I) iodide as catalyst, provided quinazolinone 99 in 77% yield. The method was shown to tolerate reasonable variation of both reaction components. Li and co-workers reported a cascade process involving in situ amidine formation followed by palladium-catalyzed Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York Cl O N Bu O O 93 95, 81% 94 OH CuI (20 mol%) NH + H2N Br NH.HCl Cs2CO3 DMF, r.t. N Me Me 75% O N cyclization as an entry into ring-fused quinazolinone derivatives. The key amidine intermediates were generated from intramolecular amide addition to a nitrile; the nitrile group also being introduced by a palladium-catalyzed process. 99 Scheme 45 outlines the overall conversion, with aryl iodide 100 being transformed into quinazolinone 101 in 91% yield. A DPEPhos-derived catalyst was effective for both the initial cyanation reaction to generate nitrile 102, and then to achieve the final ring closure from the proposed amidine intermediate to give quinazolinone 101. Using a bromoquinoline-derived substrate, the authors were able to apply the methodology to a synthesis of the natural product luotonin (103). Scheme 45 NH 2.10 Phenazines O N 96, 81% NH The Kamikawa and Beifuss groups have both reported intramolecular palladium-catalyzed aryl-amination routes to phenazines. Both explored the ring-closure of 2-amino- 2¢-bromodiphenylamines to access the target systems. Scheme 46 shows an example from Beifuss and co-workers, in which a JohnPhos-derived catalyst was used to convert aniline 104 into phenazine 105 in 76% yield. 100 The Kamikawa research group utilized BINAP-derived cata- N O O Ph N 97, 56% 98 O O I Scheme 44 Ph N H + H2N NH AcOH CuI (10 mol%) K2CO3 DMF, 80 °C N 99, 77% N Ph O NH Pd(OAc)2 (5 mol%) DPEPhos (22) (10 mol%) O I Br + KCN dioxane, reflux then dppf (10 mol%) K2CO3 N N 100 101, 91% N H O CN Br 102 N N O N N 91% luotonin (103) N
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 15 MeO Scheme 46 lysts. 101 In both cases the phenazine ring system was isolated directly from the amination reactions. 2.11 Cinnolines An intermolecular copper-catalyzed aryl amination was used by Nishida and co-workers to access cinnoline derivatives. In the example shown in Scheme 47, hydrazonesubstituted aryl iodide 107 was converted into N-acyldihydrocinnoline 108 using a copper(I) iodide/diamine catalyst. 102 The use of superstoichiometric amounts of catalyst led to mixtures of N-acyl product 108 together with smaller amounts (up to 40%) of the aromatic cinnoline being obtained. Cyclization of hydrazines derived from hydrazone 107 allowed access to 1-aminoindoles. I NH2 107 Scheme 47 H N Br 104 OTBS CO2t-Bu HN Ac N 3 Carbon–Oxygen Bond Formation Initially, the development of catalytic carbon–oxygen bond-forming processes using aryl halide substrates lagged behind the corresponding carbon–nitrogen forming reactions; however, efficient methods, using both palladium and copper catalysts, are now well established. 3.1 Benzofurans Pd 2(dba) 3 (3 mol%) JohnPhos (6 mol%) NaOt-Bu toluene, 100 °C MeO P(t-Bu)2 JohnPhos (106) CuI (10 mol%) 25 (10 mol%) Cs 2CO 3 DMSO, r.t. N N Ac 108, 89% Few examples of benzofuran syntheses that proceed via a metal-catalyzed intermolecular (aryl)carbon–oxygen bond-forming reaction exist. In one example, Buchwald and co-workers were able to apply their palladium-catalyzed phenol synthesis to the preparation of benzofurans. 103 The chemistry was based on the use of potassium hydroxide as a nucleophile in the palladiumcatalyzed hydroxylation of aryl halides to provide phenols. When applied to benzofuran synthesis, o-chloroarylalkyne substrates reacted with potassium hydroxide in the presence of t-Bu-XPhos as catalyst, to give o-hydroxyalkynylarenes, which, as previously shown, 104 undergo N N 105, 76% OTBS CO2t-Bu cyclization to the required benzofurans (109 → 110, Scheme 48). You’s research group went on to develop a copper-catalyzed version of the hydroxylation reaction and also demonstrated its use in benzofuran synthesis, in this case from an o-iodoarylalkyne to generate benzofuran 112. 105 F 3C Cl 109 Scheme 48 A greater number of research groups have utilized intramolecular carbon–oxygen bond formation as the key step in benzofuran syntheses. In 2004 Willis et al. demonstrated the use of a-(o-haloaryl) ketones as precursors to the required oxygen heterocycles via an enolization/palladium-catalyzed intramolecular O-arylation reaction, with a Pd 2(dba) 3/DPEPhos catalyst system proving optimum for the process (Scheme 49). 106 The starting ketones were themselves formed by a palladium-catalyzed ketone arylation; however, attempts to achieve a one-pot combination of these processes was not straightforward, and after optimization only a single high-yielding example of the cascade could be achieved. Kotschy and co-workers showed that the same cyclization of o-bromobenzyl ketones, which they accessed from aromatic aldehydes and 2-bromobenzyl bromide using dithiane chemistry, is possible using a palladium–NHC catalyst system. 107 O Scheme 49 Cl I O Br Me 86% (NaOt-Bu) Ph S KOH F3C Pd2(dba) 3 (2 mol%) t-BuXPhos (8 mol%) H2O, dioxane 100 °C KOH Ph CuI (10 mol%) 1,10-phenathroline (20 mol%) H 2O, DMSO 100 °C t-Bu2P i-Pr i-Pr t-BuXPhos (111) Cs2CO3 toluene, 100 °C Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York Cl i-Pr Pd 2(dba) 3 (2.5 mol%) DPEPhos (22) (6 mol%) N O 86% (NaOt-Bu) (chloro substrate) F O 110, 87% O 112, 86% O 95% O 74% (NaOt-Bu) Ph S
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