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Palladium-Catalyzed Oxidative Allylic Alkylation of N-Hydroxy- Imides

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Palladium-Catalyzed Oxidative Allylic Alkylation of N-Hydroxy- Imides SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2020, 31, 87–91 letter 87 en Syn lett N. Ayyagari et al. Letter Palladium-Catalyzed Oxidative Allylic Alkylation of N-Hydroxy- imides Narasimham Ayyagari◊ ◊ open air O Sunil Kumar Sunnam H O N Milind M. Ahire O R + HO N R Minxi Yang Pd O Kevin Ngo R = alkyl, halide, O C–H activation 20 examples up to 85% yield Jitendra D. Belani* 0000-0003-4876-0044 ether, ester, ketone, nitrile up to 1 gram scale Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, 901 Walnut St, Ste. 919, Philadelphia, PA 19107, USA [email protected] ◊ The authors contributed equally to the project Received: 13.09.2019 Previous work Accepted after revision: 13.11.2019 Published online: 29.11.2019 Intermolecular allylic alkylation DOI: 10.1055/s-0039-1691508; Art ID: st-2019-r0489-l C–C bond nitro alkanes, aryl boronic R1 C (1) Abstract A palladium-catalyzed oxidative C–H allylic alkylation of acids, active methylenes, N-hydroxyimides has been developed. This transformation provided ylides, allenes Pd valuable N-allyloxypyrrolidinediones in moderate to excellent yields us- R1 C–N bond R1 N (2) ing operationally simple, ligand free, and mild reaction conditions. The amides, anilines, amines reaction tolerated broad and variable substituents on allylarenes and R = alkyl or aryl C–O bond 1 N-hydroxyimides. R O (3) acids, alcohols, phenols Key words allylic C–H activation, palladium, N-hydroxyimides, C–O Intramolecular allylic alkylation bond formation X Y Pd X Y (4) 2 3 3 3 3 R Construction of Csp –oxygen, Csp –Csp , and Csp –nitro- R2 gen bond can be efficiently achieved using the classic palla- X, Y = O, N 1 dium-catalyzed Tsuji–Trost allylic alkylation. The reaction This work involves a Pd-η3--allyl complex, which undergoes attack O O H by various nucleophiles. The reaction, however, requires Pd N (5) allylic substrates to be pre-oxidized. Transition-metal- Ar + HO N Ar O O catalyzed oxidative allylic alkylation is a privileged synthet- O ic transformation, which provides strategic advantages in Scheme 1 Palladium-catalyzed allylic alkylation access of C–C and C–X (carbon–heteroatom) bonds with This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. minimum prefunctionalization.2 Direct oxidation or func- 3 7 tionalization of allylic Csp –H bonds was first introduced by try. They have been used in peptide synthesis and in radi- the White group in 2004 using sulfoxide-promoted, catalyt- cal and electrocatalytic reactions.8 It was thus envisioned ic Pd(OAc)2/benzoquinone (BQ)/AcOH -olefin allylic oxida- that nucleophiles such as N-hydroxysuccinimide (NHS, 3a 9a 9b tion systems. This chemo- and regioselective transforma- pKa = 6.1) and N-hydroxyphthalimide (NHPI, pKa = 7.0) tion proceeds via a serial ligand catalysis mechanism.3b The have low basicity to allow their use in allylic substitutions. reaction has now been expanded for the construction of C–C Such oxygenation of allylic substrates has been reported bond (Scheme 1, eq. 1),4 C–N bond (Scheme 1, eq. 2 and 4),5 previously on allylic acetates using NHS and NHPI.10 Sepa- and C–O bond (Scheme 1, eq. 3 and 4)6 to provide function- rately benzylic and allylic hydrocarbons have been reported alized products. to undergo radical-mediated oxygenation specifically with We have sought to extend the scope of oxidative allylic NHPI.11 This work expands on the previous reports and C–H alkylation reaction using oxygen nucleophiles that presents an alternative method utilizing nonradical process have heteroatoms directly attached to it. N-Hydroxyimides that uses unfunctionalized allylic substrates. The N-allyl- are strategically very important reagents in organic chemis- oxypyrrolidinedione products obtained in this reaction can © 2020. Thieme. All rights reserved. Synlett 2020, 31, 87–91 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 88 Syn lett N. Ayyagari et al. Letter serve as convenient synthons for terminal oxygenation11a or oxidant3a in 1,4-dioxane did not work (entry 1). A quick 12 the installation of the –ONH2 group, which is an import- survey of solvents using the above conditions proved that ant moiety in biologically active molecules. Hydroxylamine acetonitrile was better than 1,4-dioxane and dichlo- derivatives obtained easily from these pyrrolidinediones roethane (entries 2–4). To our delight, the desired product exhibit important anticancer, antibacterial, and antimalari- 3a was isolated in 23% yield using acetonitrile as the solvent al activities.13 Separately, their structural features allow at 40 °C (entry 4). Increasing the reaction temperature to them to be used as excellent directing groups in transition- 75 °C improved the yields to 40% (entry 5). Commercially metal-catalyzed C–H activation reactions14a as well as ami- available White catalyst in the presence of BQ provided a nating reagents in C–H activation reagents.14b low yield (entry 6). At this point, we wished to screen palla- Toward the goal of identifying suitable reaction condi- dium catalysts and oxidants for the reaction. Four addition- 15a 15b tions for the transformation, preliminary evaluation was al oxidants were screened including O2, PhI(OAc)2, 15c 15d conducted on commercially available 4-allyl anisole (1a) as Cu(OAc)2 , and Cu(OTf)2. The reaction works with oxy- the allylic substrate (Table 1). A trial reaction with 1a (0.2 gen as the terminal oxidant in 46% yield (entry 7). PhI(OAc)2 mmol scale) and N-hydroxysuccinimide (NHS, 2a, 2 equiv) was found to be less efficient oxidant providing the desired as the nucleophilic partner in the presence of Pd(OAc)2 (0.1 product in only 29% yield (entry 8). Stoichiometric Cu(OAc)2 equiv) as the catalyst and benzoquinone (BQ, 2 equiv) as the and Cu(OTf)2 were both tried with catalytic Pd(OTf)2 for the Table 1 Optimization of Allylic Functionalization O H O catalyst (10 mol%) oxidant N O OAc N OH + O + MeO solvent MeO MeO O temperature time 1a 2a 3a 4a Entrya Catalyst Oxidant (equiv) NHS (equiv) Solvent Temp (°C)b Yield (%)c 1 Pd(OAc)2 BQ (2) 2 1,4-dioxane 40 NR 2 Pd(OAc)2 BQ (2) 2 DMSO/1,4-dioxane (1:1) 40 NR 3 Pd(OAc)2 BQ (2) 2 DCE 40 16 4 Pd(OAc)2 BQ (2) 2 MeCN 40 23 5 Pd(OAc)2 BQ (2) 2 MeCN 75 40 6 White catalyst BQ (2) 2 MeCN 75 15 7 Pd(OAc)2 O2 (1 atm) 2 MeCN 75 46 8 Pd(OAc)2 PhI(OAc)2 (2) 2 MeCN 75 29 9 Pd(OTf)2 Cu(OAc)2 (1) 2 MeCN 75 50 10 Pd(OTf)2 Cu(OTf)2 (1) 2 MeCN 75 NR 11 Pd(OAc)2 Cu(OAc)2 (1) 2 MeCN 75 62 12 PdCl2 Cu(OAc)2 (1) 2 MeCN 75 NR This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 13 Pd(OAc)2 Cu(OAc)2 (1) 2 MeCN 75 52 TEMPO (1 equiv) 14 – Cu(OAc)2 (1) 2 MeCN 75 NR d 15 Pd(OAc)2 Cu(OAc)2 (1) 3 MeCN 75 70 without AcOH d 16 Pd(OAc)2 Cu(OAc)2 (1) 3 MeCN 75 84 AcOH (0.5 equiv) e 17 Pd(OAc)2 Cu(OAc)2 (1) 3 MeCN 75 27 AcOH (0.5 equiv) a The reactions were carried out at a concentration of 0.1 M and heated for 24–28 h, 1a (0.05 mmol, 1 equiv), 2a (2 equiv), Pd catalyst (10 mol%). Abbreviations: MeCN: acetonitrile; BQ: benzoquinone; DMSO: dimethylsulfoxide; TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl radical; DCE: dichloroethane; NR: no reaction observed by TLC. b Temperature refers to inside temperature. c Isolated yield. d Conditions: 1a (0.05 mmol, 1 equiv), 2a (3 equiv), Pd(OAc)2 (10 mol%), Cu(OAc)2 (1 equiv), 75 °C. e Reaction under strict anaerobic conditions. © 2020. Thieme. All rights reserved. Synlett 2020, 31, 87–91 89 Syn lett N. Ayyagari et al. Letter reaction. When Cu(OAc)2 was used as the oxidant, the de- proved after the equivalents of NHS (2a) were increased to sired product was isolated in 50% yield (entry 9). No C–H 3.0 ( entry 15). Additionally, slight improvement in the activation product was isolated when Cu(OTf)2 was the oxi- yield of 3a was observed after addition of acetic acid (entry 5d dant in presence of catalytic Pd(OTf)2 (entry 10). Stoichio- 16). All reactions were conducted under aerobic condi- metric copper(II) acetate was found to be the best oxidant tions, and no special precautions were taken to remove dis- in the presence of Pd(OAc)2 providing 3a in 62% yield (entry solved oxygen from the solvent. When dissolved oxygen 11). Amongst the palladium catalysts, the more expensive was completely removed using freeze-thaw cycles and the Pd(OTf)2 provided yields similar to Pd(OAc)2 when Cu(OAc)2 reaction was conducted under strict anaerobic conditions, was the oxidant [entry 9 (50%) and entry 11 (62%)]. Catalyt- the reaction yield fell to 27% percent (entry 17). It is note- ic PdCl2 did not work for the reaction (entry 12). Addition- worthy to mention that the Z-isomer was not observed. Fi- ally, we conducted a reaction in the presence of TEMPO (1 nally, the linear E-allylic acetate 4a (10–12%) was the only equiv) to investigate the reaction mechanism. The desired byproduct formed and was characterized by 1H NMR and product 3a was obtained in 52% yield confirming that the 13C NMR spectroscopy.
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