ARTICLE https://doi.org/10.1038/s41467-020-19748-z OPEN Vicinal difunctionalization of carbon–carbon double bond for the platform synthesis of trifluoroalkyl amines ✉ Ferenc Béke1, Ádám Mészáros1, Ágnes Tóth1, Bence Béla Botlik1 & Zoltán Novák 1 Regioselective vicinal diamination of carbon–carbon double bonds with two different amines is a synthetic challenge under transition metal-free conditions, especially for the synthesis of 1234567890():,; trifluoromethylated amines. However, the synthesis of ethylene diamines and fluorinated amine compounds is demanded, especially in the pharmaceutical sector. Herein, we demonstrate that the controllable double nucleophilic functionalization of an activated alkene synthon, originated from a trifluoropropenyliodonium salt with two distinct nucleophiles, enables the selective synthesis of trifluoromethylated ethylene amines and diamines on broad scale with high efficiency under mild reaction conditions. Considering the chemical nature of the reactants, our synthetic approach brings forth an efficient methodology and provides versatile access to highly fluorinated amines. 1 ELTE “Lendület” Catalysis and Organic Synthesis Research Group, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/A, 1117 ✉ Budapest, Hungary. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:5924 | https://doi.org/10.1038/s41467-020-19748-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19748-z he vicinal diamine backbone is a prevalent motif in natural free conditions has been presented with bifunctional nucleophiles products, chelating agents, chiral ligands, and pharma- in an intramolecular manner to afford N,N- and N,O-heterocyclic T 1,2 ceuticals . Nature presents this structural motif in the systems using alkenyl-sulfonium salts with two adjacent electro- form of non-proteinogenic amino acids which constitute the philic centers29–32. However, the intermolecular difunctionaliza- skeleton of numerous peptide antibiotics3. (Fig. 1a) Along with tion of alkenes has not been performed by the utilization of two natural occurrence, the diamine moiety can be found in approved separate external nitrogen nucleophiles via metal-free vicinal drugs, such as Promethazine, Osimertinib, and Sunitinib which heterodiamination. Moreover, the major challenge of the present are placed among the most marketed pharmaceuticals4. (Fig. 1b) approach is the selective heterodiamination with two different Concurrently, many drug candidates that are investigated in the nitrogen nucleophiles due to the control of reactivity of the treatment of chronic pain and metastatic melanoma share the vic- nucleophiles and intermediates. diamine skeleton. Considering the importance of this moiety, the The presence of trifluoromethyl group could fine tune the phy- development of methods for the construction of vicinal diamines sical, biological, and chemical properties of organic molecules in is an important area of research in organic synthesis1,2. Among medicinal chemistry development33–35. Therefore, the incorporation the various synthetic possibilities of accessing the target diamine of this structure is an emerging field of synthetic methodology36–40. molecules, conceptually, the most straightforward way is the The presence of fluoroalkylamine group in several drug candidates, direct introduction of nitrogen atoms across a carbon–carbon such as Olinciguat, Cevipabulin, and Odanacatib (Fig. 1d) is double bond (Fig. 1c)1,5. Indeed, a diverse set of methodologies essential for high potency, and the bioisosteric relationships to have been developed to introduce nitrogen atoms attached the amide and amino acid moieties have been recognized in several same substituents onto carbon–carbon double bond, i.e., diazi- instances (Fig. 1e)41–44. In this respect, the syntheses of homo- and dation and homodiamination reactions in metal-assisted6,7, heterofunctionalized, α-trifluoromethyl vicinal diamines45–52 and metal-catalyzed8–13, organoselenium-catalyzed14, hypervalent other substituted trifluoropropylamines52–55 are demanding. iodine-assisted and -catalyzed15–19 photochemical20–23 and elec- In this work, we aim to design a versatile selective inter- trochemical24,25 fashions. molecular fluorous alkene difunctionalization strategy with the In general, the diamination reaction of alkenes requires radical utilization of different nucleophiles to afford valuable functiona- or oxidative conditions, which permit the introduction of N- lized trifluoromethylamines and diamines. atoms in form of azide, sulfonamide, urea, and amide function- alities, while easily oxidizable alkyl- and aryl-amines are intro- duced by transition metal-assisted and -catalyzed methods Results – limited to few examples1,26 28. Regarding the abundant N-atom Optimization and mechanistic studies. For the realization of our sources, nucleophilic difunctionalization of alkenes with simple goals on selective alkene difunctionalization to obtain tri- amines without the use of transition metals would be a corner- fluoropropyl amines, the presence of an efficient leaving group stone to improve structural diversity of diamine synthesis. This (LG) was necessary (Fig. 1f). A hypervalent iodonium moiety56–63 vicinal amination of the carbon–carbon double bond under metal could be an appropriate choice for LG, due to its super leaving R1 R1 ab N Me H H H Me Me H Et Et N O N O N N N O N Me HN COOH N R2 Me N N O N N N Me F H N H H S N Me O N Promethazine (R1= Me, R2= H) N N NH L-pyrazol-1-yl- R H alanine COOH rhinitis, allergy, antihistamine Propiomazine (R1= Me, R2= COEt) O N O N O H H H Antipsychotic, antihistamine Osimertinib Sunitinib 1 2 R = H; L-Dap Dexrazoxane Profenamine (R = Et, R = H) oncology oncology R = Me; Dab immunosuppressive Parkinson's disease, anticholinergic Tyrosine kinase inhibitor Tyrosine kinase inhibitor O c Alkene diamination d Cl NC e O F 1 1 Nu R H R H O N N N Nu O NH amide Nu HO NH N 2 F isostere Nu or H HN O CF3 1 R1 H R CF3 N N N Me N N F N N N Intramolecular N H CF3 CF difunctionalization 3 R1 H R1 H with N F Cevipabulin N N F Glycine different nucleophiles oncology isostere Olinciguat antineoplastic agent Odanacatib O CF3 Nu= N , NTs, urea-N, amide-N Sickle cell disease MeO S Osteoporosis 3 2 N N or other N, C, O, S soluble guanylate cyclase stimulator Catepshin K inhibitor R3 H R3 H f LG R1 R2 Intermolecular N R1 R2 R1 R2 R1 R2 diamination H N N N Fluorinated alkene CF3 / / and synthon with CF 3 CF3 CF3 H H suitable leaving group Amino difunctionalization N N N N 1 2 3 4 1 2 Nu R R / R R / Nu = X, O, S, P, C R R R3 R4 with different nucleophiles Fig. 1 General overview of ethylene diamines and trifluoromethyl amines. a Vicinal diamine backbones in natural products. b Pharmaceutical molecules with vicinal diamine motifs. c Alkene diamination and diazidation methodologies. d Fluoroalkylamine containing drug candidates. e Bioisosteric relations of fluoroalkylamine moiety. f This work: The intermolecular nucleophilic difunctionalization of a fluorinated alkene synthon provides a high degree of structural diversity of α-trifluoromethyl diamines and substituted trifluoropropylamines in one preparative step. 2 NATURE COMMUNICATIONS | (2020) 11:5924 | https://doi.org/10.1038/s41467-020-19748-z | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19748-z ARTICLE a Me R the operative mechanistic path, the reaction was monitored with N 19 H Me R Me R F-NMR spectroscopy and complete conversion was observed ArI OTf N N N N Conditions I within 15 s (Supplementary Fig. 1) in the presence of an excess or 19 CF3 CF3 CF3 CF3 CF3 amount (4 equiv.) of amine with only the F signal of the 1) N N N N diaminated product observed in the spectra. In contrast, utilizing Me R Me R Me R N one equivalent of amine led to the formation of a diastereomeric H mixture of the corresponding aziridinium ion intermediates70 123452) Pyrrolidine Conditions II (Fig. 2b and Supplementary Figs. 8–10). To prove the presence of this intermediate, we synthesized the putative aziridinium ion Ar= Conditions I: 90% --- 6 F in situ through an independent route from aziridine and Conditions II: nd (4%) 76% (96%) nd (0%) nd (0%) Independent route: nd {88%} ---MeOTf in d3-MeCN at 25 °C (Fig. 2b). Gratifyingly, we observed the complete consumption of aziridine 6 in 2.5 h and the R= 19 − b 4.0 equiv d3-MeCN appearance of a new signal in the F-NMR spectra at 63.65 Me R 25 °C X N ppm, which we assign to aziridinium intermediate (Supple- H < 1 min mentary Fig. 10). This peak was identical with the major Independent route ’ 1.0 equiv intermediate s signal observed in the diamination NMR experi- Me R MeOTf R ment (Supplementary Fig. 9), and this observation supports the ArI OTf N OTf Na2CO3 H N presence of an aziridinium ion as the key intermediate of this R CF3 d3-MeCN Me N d3-MeCN diamination process. We postulate that a minor intermediate also CF3 -20 °C CF3 25 °C observed is the other diastereomer which cannot be formed as 1 30 + 15 min 2.5 h 6 X easily in the N-alkylation route due to the stereoselective attack of the methyl triflate governed by the steric repulsion of Route B: Me R Aziridinium ion OTf N fl ArI ArI ArI Me R tri uoromethyl group. N In the second step of the mechanistic study, the aziridinium H CF CF3 CF3 CF3 3 X 6 H+ H intermediate generated from aziridine was reacted with 4 N OTf N OTf transfer N N Me R Me R Me R Me R equivalents of N-methyl-naphthylmethylamine (Fig. 2b), and H H immediate formation of the corresponding diamine 2 through Ylide formation Route A: Direct substitution ring opening was observed in the 19F-NMR spectrum (Supple- Fig. 2 Experimental mechanistic studies. a Optimized conditions of mentary Fig.