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Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions in the Synthesis of Pharmaceutical Compounds

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Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions in the Synthesis of Pharmaceutical Compounds http://dx.doi.org/10.5935/0103-5053.20140255 J. Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014. Printed in Brazil - ©2014 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Review Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions in the Synthesis of Pharmaceutical Compounds André F. P. Biajoli, Cristiane S. Schwalm, Jones Limberger, Thiago S. Claudino and Adriano L. Monteiro* Laboratory of Molecular Catalysis, Institute of Chemistry, UFRGS, Av. Bento Gonçalves, 9500, 91501-970 Porto Alegre-RS, Brazil A grande capacidade do paládio de formar ligações carbono-carbono entre substratos apropriadamente funcionalizados permitiu que os químicos orgânicos efetuassem transformações antes impossíveis ou alcançáveis somente através de rotas muito longas. Neste contexto, uma das mais elegantes e importantes aplicações das reações de acoplamento cruzado catalisadas por paládio é a síntese de compostos de interesse farmacêutico. A presente revisão tem por objetivo apresentar uma visão geral do uso de acoplamentos cruzados na síntese de componentes de medicamentos (ou de candidatos a medicamentos), independentemente da escala, compreendendo o período de 2011 até o final de julho de 2014. The impressive ability of palladium to assemble C-C bonds between appropriately functionalized substrates has allowed synthetic organic chemists to perform transformations that were previously impossible or only possible using multi-step approaches. In this context, one of the most important and elegant applications of the Pd-catalyzed C-C coupling reactions currently is the synthesis of pharmaceuticals. This review is intended to give a picture of the applications of Pd-catalyzed C-C cross-coupling reactions for the synthesis of drug components or drug candidates regardless of the scale from 2011 through to the end of July, 2014. Keywords: cross-coupling reactions, Heck reactions, palladium, pharmaceuticals 1. Introduction for their remarkable contributions for the Pd-catalyzed cross-couplings in organic synthesis.11 Palladium-catalyzed cross-coupling reactions comprise The generally accepted mechanisms for Pd-catalyzed one of the most efficient methods for the construction C-C cross-coupling reactions are summarized in Scheme 1. of carbon-carbon bonds.1-3 The impressive ability of All reactions start with a Pd zerovalent species preformed palladium to assemble C-C bonds between appropriately or formed in situ from Pd divalent catalyst precursors. functionalized substrates has allowed synthetic organic The first step is common for all reactions, consisting chemists to perform transformations that were previously of the oxidative addition reaction of organic halide (or impossible or only possible using multi-step approaches. pseudohalide) to the Pd zerovalent species affording the Therefore, these cross-coupling methodologies have R1-Pd-X intermediate. In the case of coupling reactions revolutionized the way of thinking regarding synthetic involving an organometallic partner (R2M), the R1-Pd-R2 organic chemistry, having found widespread use in organic intermediate is formed by a transmetalation step. Finally, synthesis and material science, as well playing an important reductive elimination provides the R1-R2 coupling product, role in pharmaceutical, agrochemical and fine chemical and regenerates the Pd zerovalent species. The Sonogashira industries.4-8 In this scenario, the award of the Nobel Prize reaction involves the coupling between organic halides and in Chemistry in 2010 was a deserved recognition, rewarding alkynes. When copper salts are used as the co-catalyst, jointly Richard F. Heck, Ei-ichi Negishi9 and Akira Suzuki10 copper acetylides are formed in situ and are involved in the transmetalation step. A different catalytic cycle is involved *e-mail: [email protected] in the Heck-Mizoroki reaction. In this case, the alkene is This article is dedicated to the memory of Prof Roberto F. de Souza coordinated to the common R1-Pd-X intermediate. Then, Vol. 25, No. 12, 2014 Biajoli et al. 2187 a syn migratory insertion occurs and the organopalladium of phosphodiesterase 4 (PDE4), an enzyme related to species formed undergoes β-hydride elimination to form the inflammatory and respiratory diseases. The first synthesis alkene product. Finally, a base-assisted elimination of HX of 1 involved six steps, with one Suzuki reaction step, regenerate the Pd(0) catalyst.12-17 When an aryldiazonium with an overall yield of 8%.25 By using the benzyl aryl salt is used in place of an aryl halide, the reaction is known dibromide 2 as starting material, the synthesis of 1 was as Heck-Matsuda reaction.18-21 The difference in terms of shortened to two-steps with an overall yield of 47% on the mechanism is that the oxidative addition of aryldiazonium gram scale (Scheme 2). salts to the Pd zerovalent species generates a cationic The more reactive benzyl bromide moiety of dibromide [R1-Pd]+ intermediate. 2 was coupled with a pinacol arylboronic ester, providing In our opinion, the most important and elegant diarylmethane 3 in 66% yield. Activation of the remaining application of the coupling reactions is the synthesis of bromide in 3 was carried out using the same conditions, pharmaceuticals. In this context, there is an excellent only changing the temperature and reaction time, and review about the applications of Pd-catalyzed coupling furnishing 1 at a yield of 71%. The optimal conditions reactions. This review covers the period from 2001 to 2008, displayed in Scheme 2 were established after a screening of and highlights examples that have been performed on at Pd sources [Pd(PPh3)4, PdCl2(PPh3)2 and Pd(OAc)2/PPh3], least a kilogram scale in the chemical and pharmaceutical solvents [dimethoxyethane/EtOH/H2O, dioxane/H2O and 5 industries. In addition, Pfizer researchers have reviewed dimethylformamide (DMF)] and bases (K3PO4, K2CO3, the large-scale applications of transition metal-catalyzed Na2CO3 and Cs2CO3). It is worth noting that a reduction coupling reactions for the manufacture of drug components of the amount of catalyst increased the conversion in some in the pharmaceutical industry through to the end of cases, while higher amounts generally increased the level August, 2010.4 This review is intended to give a picture of impurities and difficult purification. This process was of the applications of Pd-catalyzed C-C cross-coupling applied to the synthesis of two new PDE4D partial allosteric reactions for the synthesis of drug components or drug modulators, D159404 (4) and D159153 (5) (Figure 1), with candidates, regardless of scale, from 2011 through to the overall yields of around 26% for the two Suzuki reactions. end of July, 2014. Thiel et al. described the preparation of several inhibitors of p38 mitogen-activated protein (MAP) kinases, 2. Suzuki-Miyaura Reactions which are enzymes that positively regulate the production of pro-inflammatory mediators (TNF-a and IL-1).26 These The transition metal-catalyzed reaction between an mediators are involved in rheumatoid arthritis, Crohn’s organoboron compound and a halide or pseudohalide is disease and psoriasis. The original synthetic route27 known as Suzuki-Miyaura cross-coupling.22 This important presented some challenges for scaling-up, most notably the reaction is well-known for the assembly of biphenyl employment of toxic carbon tetrachloride, silver salts and motifs.23 For example, Dalby et al.24 reported a concise microwave irradiation. Therefore, the authors optimized the synthesis of D159687 (1), a partial allosteric modulator route, on a kilogram scale, employing the aryl chloride 6 R-R1 R2 R reductive HX elimination R2 R base 0 XPdIILn LnPd R H R-X syn β-hydride elimination II oxidative LnPd addition IIPdL X R R1 R n II LnPd R2 H X syn mi gratoryinsertion M-X R1-M R2 transmetalation Negishi(M=ZnR) Heck-Mizoroki II + Suzuki-Miyaura[M=B(OH)2 or B(OR)2] Heck-Matsuda(with[LnPd R] afteroxidative Stille (M =SnR3) addition) Sonogashira (M =CuI) Scheme 1. General catalytic cycles for the Pd-catalysed reactions. 2188 Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions J. Braz. Chem. Soc. O O B Pd(PPh ) (8 mol%) Br 3 4 O + K3PO4 (2 equiv.) MeO MeO N NH2 DME/EtOH/H2O H Br HN O 65 ºC,3h Br 2 3 (1.06equiv.) NH2 (66%) O (HO)2B Cl (1.5 equiv.) MeONNH2 H Pd(PPh3)4 (8 mol%) K3PO4 (2 equiv.) DME/EtOH/H2O Cl 80 ºC,16h D159687 1 (71%) Scheme 2. Sequential Suzuki reactions in the synthesis of D159687 (1). O 1,1-carbonyldiimidazole (CDI) and cyclopropylamine in MeONF NH2 H ethyl acetate leading to the desired product in 70% yield after two steps. The authors believe that any significant R amount of palladium present as an impurity in intermediate 8 was removed quantitatively with the aid of imidazole R=Cl (4) R=NO2 (5) employed in the carbonyl activation step. Figure 1. PDE4D allosteric modulators D159404 (4) and D159153 (5). It is worth noting that the large scale synthesis of 10, another inhibitor of p38 MAP kinases, demanded as starting material and avoiding the use of toxic solvents a completely different catalytic system for the Suzuki (Scheme 3). For activation of the less reactive C-Cl bond, reaction. While the original medicinal chemistry route ligand screening was necessary, and MePhos (7) was employed Pd(PPh3)4 for the coupling of 11 with a boron identified as the most effective. Thus, this ligand combined pinacolate derivative, on a large scale, the authors were with a mixture of ethanol/aqueous sodium hydroxide was capable of reducing the catalyst loading (albeit no amounts employed with Pd2(dba)3, where dba = dibenzalacetone, as were disclosed in the text) by using PdCl2(APhos) (12), pre-catalyst to provide 8 in yields between 70 and 81%. allowing a very clean reaction to be performed due to the In contrast to the medicinal chemistry route, the final step high activity of this catalyst (Scheme 4).26 Thus, the Suzuki did not employ a palladium-catalyzed reaction, allowing product 13 was obtained in 93% yield by treating 11 with easier removal of this metal: the synthesis of 9 employed the appropriate arylboronic acid in the presence of 12 and PCy2 Me O O N N (HO)2B CO2H MePhos (7) + N N Pd (dba) NaOH (aq), Me 2 3, N CO H N EtOH,reflux 2 Cl Me 68(70-81%) O N 1.
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