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Reductive Cyanation of Organic Chlorides Using CO2 and NH3 Via Triphosâ

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Reductive Cyanation of Organic Chlorides Using CO2 and NH3 Via Triphosâ ARTICLE https://doi.org/10.1038/s41467-020-17939-2 OPEN Reductive cyanation of organic chlorides using CO2 and NH3 via Triphos–Ni(I) species ✉ Yanan Dong1,2, Peiju Yang1, Shizhen Zhao3 & Yuehui Li 1 Cyano-containing compounds constitute important pharmaceuticals, agrochemicals and organic materials. Traditional cyanation methods often rely on the use of toxic metal cyanides which have serious disposal, storage and transportation issues. Therefore, there is an fi 1234567890():,; increasing need to develop general and ef cient catalytic methods for cyanide-free produc- tion of nitriles. Here we report the reductive cyanation of organic chlorides using CO2/NH3 as the electrophilic CN source. The use of tridentate phosphine ligand Triphos allows for the nickel-catalyzed cyanation of a broad array of aryl and aliphatic chlorides to produce the desired nitrile products in good yields, and with excellent functional group tolerance. Cheap and bench-stable urea was also shown as suitable CN source, suggesting promising appli- cation potential. Mechanistic studies imply that Triphos-Ni(I) species are responsible for the reductive C-C coupling approach involving isocyanate intermediates. This method expands the application potential of reductive cyanation in the synthesis of functionalized nitrile compounds under cyanide-free conditions, which is valuable for safe synthesis of (isotope- labeled) drugs. 1 State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, 730000 Lanzhou, P. R. China. 2 University of Chinese Academy of Sciences, 100049 Beijing, P. R. China. 3 Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, 475001 ✉ Kaifeng, P. R. China. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:4096 | https://doi.org/10.1038/s41467-020-17939-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17939-2 itriles are key intermediates in production of pharma- increasing need to develop general methods for cyanide-free ceuticals, agrochemicals, organic materials, and functional cyanation of organic chlorides. N 1,2 materials . Moreover, nitrile group serves as a versatile In order to synthesize nitriles through reductive cyanation motif for the synthesis of aldehydes, ketones, carboxylic acids, pathway, the use of higher oxidation state CO2 as the carbon alcohols, amides, amines, and heterocycles3. Significant progress source is ideal for charge balance purpose. Accordingly, there are has been made in transition-metal-catalyzed cyanation in the past challenges to be overcome: (1) suppressing reductive dehalo- century, among which cyanation of aryl (pseudo)halides is the genation; (2) suppressing the undesired CO2 reduction; 3) con- most commonly used approach for selective synthesis of aryl quering possible formation of stable urea, and (4) generation of nitriles4–7. active electrophile ready for C–C bond formation and C–N triple Careful selection of cyanating reagents is usually required. In bond construction (Fig. 2). Accordingly, the choice of metal this regard, the direct use of metal/silyl cyanides or the precursors and ligands is crucial to suppress the above mentioned in situ generation of cyanide ion is often involved (Fig. 1a, b: side-reactions. 8–14 15 16,17 K4[Fe(CN)6] ,K3[Fe(CN)6] , ethyl cyanoacetate , acetone The discovery of cyanation reagents with operational simplicity cyanohydrin18–20, butyronitrile21, 4-cyanopyridine N-oxide22, and economic viability is a sought-after goal in organic synthesis. 23 +24–26 formamide , DMF/NH4 , etc). These reactions proceed In this respect, CN source from sustainable C1 and N1 feedstocks through Rosenmund-von Braun reaction mechanism and suffer is a natural line of enquiries. The fixation and transformation of 36–40 from limited catalytic efficiency and/or substrate scope due to carbon dioxide (CO2) has attracted considerable attention . strong coordination ability and poisoning of cyanide ion. Carbon dioxide is the most abundant carbon source, and is thus Meanwhile, elegant development of cyanide-free methods regarded as the most promising nontoxic C1 feedstock41–46. involving diverse mechanisms to circumvent this challenge Recently, we developed the Cu-catalyzed reductive cyanation of β 47 has been achieved including -H elimination-facilitated aryl iodides with CO2/NH3 as cyano (CN) source . Herein, we 27,28 cyanation , electrophilic cyanation with N-cyano-N-phenyl-p- report the reductive cyanation of organic chlorides using CO2/ 29 methylbenzenesulfonamide , oxidative cyanation with tert-butyl NH3 or urea as either gaseous or solid forms of carbon and isocyanide30,31 or hexamethylenetetramine32 etc. Besides, the nitrogen, respectively (Fig. 1c). recently emerging cyanation under reductive conditions as well undergoes different mechanisms, and in principle offers a com- Results plementary synthesis protocol for nitriles. Pioneering work by Reaction discovery. Our study began by investigating catalytic Cheng and co-workers used Pd/Ni-phosphine complexes for the cyanation of chlorobenzene with ambient CO2 and NH3 in the catalytic cyanation of aryl halides with acetonitrile in the presence presence of PhSiH3 and KF (Table 1). The model reaction was of zinc powder at 160 °C33. Also using Zn as reductant, Rous- firstly tested with different metal catalysts (also see Supplemen- seaux and co-workers applied electrophilic cyanating reagent 2- tary Table 1). Among a wide range of catalysts examined, only methyl-2-phenyl malononitrile for the cyanation of aryl halides34. nickel salts provided the desired product (Table 1, entries 1–5). Very recently, Tsurugi and Mashima et al. developed the use of Further reaction optimization indicated that Ni(acac)2 was a acetonitrile as cyano source using N-silylated dihydropyrazines as superior choice (entry 6). The addition of Zn powder as co- reductant35. However, to the best of our knowledge none of these reductant promoted the reaction significantly raising the yield to systems are suitable for general cyanation of the least expensive 37% (Table 1, entry 7). Gratifyingly, evaluation of ligands showed and most widely available organic chlorides having the relatively − remarkable performance of Triphos for this transformation to inert C(sp2)-Cl bond (ca. 96 kcal mol 1). Therefore, there is an produce 2a in 81% yield (Table 1, entries 8–13). Screening of solvents and silane reductants were carried out. Other high boiling point polar solvents like DMI were found less suitable Previous works: (Table 1, entry 14). Notably, the choice of silanes also appeared to be crucial for the reaction with PMHS giving poor reactivity a metal cyano source (Table 1, entry 15). cat. Ar X + K4[Fe(CN)6] Ar C N a reductive dehalogenation II b organic cyano source M0 [H] II M M cat. Ar Cl Ar Cl Ar H – Cl– Ar H Ar X + "CN" Ar C N via Ar M CN b reduction of CO2 and waste of reductant HO CN n HCONH , [H] "CN" : CH3CN, BuCN, 2 CO Me Me , etc. 2 HCO2H, HCHO, CH3OH, CH4 This work: c generation of highly stable urea CN source for complex nitriles c O CO2/NH3 dead end? Ni(acac) (12 mol%) – H O 2 2 H2N NH2 Triphos (12 mol%) hard to activate RCl + CO2/NH3 R C N (1/1 atm) silane, Zn, KF d CO2/NH3 as the electrophile: formation of C-C and CN aryl and aliphatic chlorides many functional groups tolerated active Ar Cl CO /NH Ar C N safe and cyanide-free cheap and abundant CO2/NH3 2 3 electrophile Fig. 1 Catalytic cyanations with different cyano sources. a The use of Fig. 2 Challenges for reductive cyanation strategy. a Reductive metal cyanides, b organic cyano compounds, and c CO2/NH3 as the CN dehalogenation. b reduction of CO2. c The generation of stable urea. d The source. challenging generation of active electrophiles. 2 NATURE COMMUNICATIONS | (2020) 11:4096 | https://doi.org/10.1038/s41467-020-17939-2 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17939-2 ARTICLE Table 1 Optimization of the reaction conditionsa. Cat. (12 mol%) Cl CN ligand (12 mol%) + CO2/NH3 PhSiH3 (6 equiv.) 1a KF (1 equiv.), NMP, 140 °C 2a Entry Cat. Ligand Yield (%) b 1 Pd(OAc)2 dppp n.d. 2 Cu(OAc)2 dppp n.d. 3 Co(acac)2 dppp n.d. 4 Ni(COD)2 dppp 2 5 NiBr2 dppp 17 6 Ni(acac)2 dppp 20 c 7 Ni(acac)2 dppp 37 c 8 Ni(acac)2 dppe 4 c 9 Ni(acac)2 dppb 5 c 10 Ni(acac)2 dppf 10 c 11 Ni(acac)2 PPh3 n.d. c 12 Ni(acac)2 Tripod 64 c 13 Ni(acac)2 Triphos 81 c,d 14 Ni(acac)2 Triphos 16 c,e 15 Ni(acac)2 Triphos 5 NMP 1-methyl-2-pyrrolidinone, DMI 1,3-dimethyl-2-imidazolidinone, acac acetylacetonate, COD 1,5-cyclooctadiene, dppp 1,3-bis(diphenylphosphino)propane, dppe 1,2-bis(diphenylphosphino)ethane, dppb 1,4-bis(diphenylphosphino)butane, dppf 1,1’-bis(diphenylphosphino)ferrocene, Tripod 1,1,1-Tris(diphenylphosphinomethyl)ethane, Triphos bis(2-diphenylphosphinoethyl)phenylphosphine, PMHS poly (methylhydrosiloxane), n.d. not detected. a Reaction conditions: 1a (0.125 mmol), CO2/NH3 (1/1 atm), NMP (0.5 mL), 20 h; GC yield. b 5 mol% Pd(OAc)2. cWith 1.0 equiv. of Zn powder. dDMI as solvent. e PMHS was used instead of PhSiH3. Cyanation using CO2/NH3 and the synthetic application. compounds 2ad and 2ae showed moderate antiproliferative Encouraged by the results above, we then investigated the utility activities against these cell lines with IC50 values ranging and scope of this method. An array of aryl chlorides bearing from 5.91 to 23.54 μM, while compounds 2ad’ and 2ae’ showed various substituents were well-tolerated to afford the desired no activities toward tumor cell lines MCF-7 and Hela with 13 μ nitrile products in moderate to high yields (Fig.
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