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Rhodium-catalyzed asymmetric hydroamination of gem-difluoroallenes with anilines

  • Xiaowei Han
    Affiliations
    State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
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  • Yue Zhao
    Affiliations
    State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
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  • Author Footnotes
    1 Professor Zhuangzhi Shi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was assessed and the corresponding peer review managed by Dr Chaosheng Luo, a scientific editor working on Tetrahedron Chem.
    Zhuangzhi Shi
    Correspondence
    Corresponding author.
    Footnotes
    1 Professor Zhuangzhi Shi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was assessed and the corresponding peer review managed by Dr Chaosheng Luo, a scientific editor working on Tetrahedron Chem.
    Affiliations
    State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
    Search for articles by this author
  • Minyan Wang
    Correspondence
    Corresponding author.
    Affiliations
    State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
    Search for articles by this author
  • Author Footnotes
    1 Professor Zhuangzhi Shi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was assessed and the corresponding peer review managed by Dr Chaosheng Luo, a scientific editor working on Tetrahedron Chem.
Open AccessPublished:August 05, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100023

      Abstract

      A rhodium-catalyzed protocol has been established for the enantioselective hydroamination of gem-difluoroallenes with anilines. This strategy shows complete atom-efficiency to access a variety of enantioenriched gem-difluoroallylic amines in excellent branched selectivity (>99:1 for each case), which are important backbones in many biologically active compounds. Mechanistic studies suggest the generation of a gem-difluoro π-allyl rhodium intermediate by an exclusive hydrometalation pathway, which undergoes nucleophilic substitution of amines.

      Graphical abstract

      Keywords

      1. Introduction

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      Fig. 1
      Fig. 1State of the art in asymmetric hydroamination of gem-difluoroallenes and inspiration of the study.
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      2. Results and discussion

      We selected the reaction of gem-difluoroallene 1a and anilines (2a) as our model reaction for optimization (Table 1). Systematic screening revealed that using 2.5 ​mol% of [Rh(cod)Cl]2, 6 ​mol% of Josiphos L7, and 1.0 equiv. PPTS as an additive at 40 ​°C under an argon atmosphere in a mixed solvent (VDCM/VEtOH ​= ​5/1) provided the best results, affording product 3aa in 88% yield with 91% ee (entry 1). Among the tested ligands, Trost ligand L1 and BINAP (L2) showed much lower enantioselectivities (entries 2–3). Among the JOSIPHOS family, and the variation of substituents at two P atoms have great influence on the reaction outcome (entries 4–7). Besides rhodium complex, other transition metals such as iridium catalyst failed to work in this transformation (entry 8). The reaction efficacy was reduced without the addition of PPTS (entry 9) [
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      Table 1Reaction optimization.
      Standard conditions: [Rh(cod)Cl]2 (2.5 ​mol%), L7 (6 ​mol%), 1a (0.10 ​mmol), 2a (0.20 ​mmol), PPTS (0.1 ​mmol), 1.2 ​mL of DCM/EtOH (5/1), at 40 ​°C, under N2, 72 ​h.
      ..
      entryvariation from the standard conditionsyield of 3aa (%)
      Determined by GC analysis.
      ee of 3aa (%)
      Determined by chiral HPLC analysis.
      1none88 (80)
      Yield of isolated product. Bn = Benzyl. cod = (Z, Z)-1,5-Cyclooctadiene. PPTS = pyridin-1-ium 4-methylbenzenesulfonate. DCM = Dichloromethane.
      91
      2using L1 instead of L7125
      3using L2 instead of L73240
      4using L3 instead of L73642
      5using L4 instead of L7933
      6using L5 instead of L7177
      7using L6 instead of L76686
      8using [Ir(cod)Cl]2 as the catalyst0
      9without PPTS7889
      10at room temperature7093
      11only DCM1088
      12only EtOH4279
      a Standard conditions: [Rh(cod)Cl]2 (2.5 ​mol%), L7 (6 ​mol%), 1a (0.10 ​mmol), 2a (0.20 ​mmol), PPTS (0.1 ​mmol), 1.2 ​mL of DCM/EtOH (5/1), at 40 ​°C, under N2, 72 ​h.
      b Determined by GC analysis.
      c Determined by chiral HPLC analysis.
      d Yield of isolated product. Bn = Benzyl. cod = (Z, Z)-1,5-Cyclooctadiene. PPTS = pyridin-1-ium 4-methylbenzenesulfonate. DCM = Dichloromethane.
      With this protocol in hand, we first explored the hydroamination of gem-difluoroallene 1a with various anilines (Table 2). In all cases, the hydroamination reaction proceeded efficiently with excellent regioselectivity for the branched gem-difluoroallylic amines. Anilines with electron-neutral and -donating substituents including Me (2b), OMe (2c), OBn (2d), and SMe (2e) were transformed into allylic amines with excellent efficiency (3ab-ae). Among them, ortho-substituted anilines 2b and 2d worked well, suggesting that the increased steric congestion does not impair the reactivity. Notably, the reaction efficiency was not affected by halo substituents including F (2f), Cl (2g), Br (2h) and I (2i) on the anilines, highlighting the excellent chemoselectivity of this transformation. Anilines with electron-withdrawing groups such as trifluoromethoxy (2j), phenyldiazenyl (2k), benzoyl (2l), and methylsulfonyl (2m) were also well-tolerated in the present reaction conditions, affording the corresponding products 3aj-am in 43–63% yields and 86–92% ees. Furthermore, anilines 2n-s with multi-substituted groups were compatible with excellent enantioselectivities (90–93% ees). Fused aromatic amines including naphthalen-1-amine (2t) and pyren-1-amine (2u) also maintained good reactivity. Importantly, the reaction of anilines with heterocyclic aromatic motifs like carbazole (2v), indole (2w), benzo[d]thiazole (2x) and quinoxaline (2y) were also tolerable and afforded 3av-ay with 87–91% ees. In addition to primary amines, a number of secondary amines such as indoline (2z), 1,2,3,4-tetrahydroquinoline (2A) and N-methylaniline (2B) are suitable coupling partners for hydroamination.
      Table 2Substrate scope of anilines.[a] [a]Standard conditions: [Rh(cod)Cl]2 (2.5 ​mol%), L7 (6 ​mol%), 1a (0.10 ​mmol), 2a (0.20 ​mmol), PPTS (0.1 ​mmol), 1.2 ​mL of DCM/EtOH (5/1), at 40 ​°C, under N2, 72 ​h, yields of isolated products; Ee values determined by chiral HPLC..
      Table thumbnail fx2
      Next, we investigated the scope of gem-difluoroallenes with compound 2a (Table 3). The reaction conditions have proven effective for the hydroamination of gem-difluoroallenes containing diverse alkyl groups (1b-e) in excellent efficiencies. Importantly, the HCl salt of 3da was crystalized, and its absolute configuration was determined by X-ray diffraction [

      See Supporting Information for details. Deposition number 2072454 (3da·HCl) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge by the Cambridge Crystallographic Data Centre.

      ]. Versatile functional groups such as silyl ether (1f), phenoxy (1g), and ester (1h) were well tolerated with satisfactory enantioselectivities (91–94% ees). Gem-Difluoroallenes bearing naphthalene (1i) and heterocycles including furan (1j), thiophene (1k), and indole (1l) posed no problem during the hydroamination process. Under the current reaction conditions, tetrasubstituted allenes such as 1m exhibited a very low reactivity.
      Table 3Substrate scope of gem-difluoroallenes.[a] [a]Standard conditions: [Rh(cod)Cl]2 (2.5 ​mol%), L7 (6 ​mol%), 1a (0.10 ​mmol), 2a (0.20 ​mmol), PPTS (0.1 ​mmol), 1.2 ​mL of DCM/EtOH (5/1), at 40 ​°C, under N2, 72 ​h, yields of isolated products; Ee values determined by chiral HPLC. TBS ​= ​t-butyldimethylsilyl..
      Table thumbnail fx3
      To further demonstrate the functional breadth of this newly developed method, some challenging substrates were also investigated (Scheme 1). The reaction showed excellent selectivity with anilines with two competitive nucleophilic sites (Scheme 1a). For example, compound 4a with two amino groups, proceeded readily and selectively to produce product 5aa in 61% yield with 93% ee. Substrate 4b with one NH2 and one NHBz group, selectively produce the compound 5 ​ab in 67% yield with 90% ee. Complex aniline 4c with a NH group could also be tolerated (64% yield, 90% ee). With antiquated antibiotic sulfamethoxazole (4d), hydroamination was also preferred at the amino group over the sulfonimide N–H bond. The promising functional group compatibility and excellent site selectivity also prompted us evaluation of the gem-difluoroallenes derived from complex pharmaceuticals and biologically active molecules (Scheme 1b). The use of gem-difluoroallene 6a from α-linolenic acid bearing three cis double bonds was shown to be compatible with our system, affording the desired product 7aa in 57% yield with 90% ee. Derivatives of lithocholic acid (6b), diosgenin (6c), and oestrone (6d) bearing several chiral centers were also shown to be compatible with our reaction, providing the corresponding products 7ba-da with good de (diastereomeric excess) values determined by chiral HPLC.
      Scheme 1
      Scheme 1Further investigation of functional group compatibility.
      To showcase the practical utility of this reaction, a gram-scale transformation was first conducted to form 3aa in 80% yield and 91% ee (Scheme 2). The reaction of 3aa with allyl bromide was highly effective, delivering the product 9 in good yield. Furthermore, treatment of 3aa with Red Al® could produce an E-monofluoroalkene 10 as a major product. In addition, the use of copper-catalyzed hydrodefluorination, which was developed by our group [
      • Hu J.
      • Han X.
      • Yuan Y.
      • Shi Z.
      Stereoselective synthesis of Z fluoroalkenes through copper-catalyzed hydrodefluorination of gem-difluoroalkenes with water.
      ], could afford a Z-monofluoroalkene 11 in 75% yield without erosion of the ee.
      Scheme 2
      Scheme 2Gram-scale synthesis of compound 3aa and its downstream transformations.
      To probe the possible mechanism, isotopic labelling experiments were then conducted using D7-aniline (d-2a), D1-PPTS and deuterated ethanol (Scheme 3). Under the standard reaction conditions, D atom was only incorporated into the internal position of the product d-3aa. The results support the formation of a π-allyl Rh complex by an exclusive hydrometalation pathway. The use of D1-PPTS and EtOD showed much higher deuterium incorporation, indicating a direct H/D exchange between PPTS, EtOH and aniline.
      Scheme 3
      Scheme 3Isotopic labelling experiments.
      Density functional theory (DFT) calculations was further conducted to investigate the detailed mechanism of the reaction and the origin of the enantioselectivity. Initially, frontier molecular orbitals theory was used to illustrate the coordination selectivity (Fig. 2a). The cationic rhodium complex pre-A was generated from [Rh(cod)Cl]2 and L7, and its lowest unoccupied molecular (LUMO) orbital is derived from the Rh 4d orbital. The highest occupied molecular (HOMO) orbital of 2a is mainly contributed by the lone pair electrons of N atom. For the model substrate 1a, its HOMO-2 orbital is their gem-difluoroalkene π orbital and its HOMO-3 orbital is associated with the non-fluorinated double bond. The energy gap between the LUMO orbital of pre-A and HOMO orbital of 2a is 6.4 ​eV, which is much smaller than that of the LUMO-HOMO-2 and LUMO-HOMO-3 gaps between pre-A and 1a, illustrating that pre-A is more favorable to coordinate with amines 2a for subsequent reactions.
      Fig. 2
      Fig. 2Proposed mechanism. a) The analysis of the frontier molecular orbitals of model molecules. b) DFT-computed energy profile of the rhodium-catalyzed asymmetric hydroamination. c) DFT-computed free energies for the four competitive insertion pathways relative to intermediate B. d) DFT-computed free energies for the three competitive reductive elimination pathways relative to intermediate C-Z.
      Extensive studies on the amine-activation pathway has been proposed as shown in Fig. 2b involving π-allylmetal intermediate for allenes [
      • Ma S.
      Some typical advances in the synthetic applications of allenes.
      ,
      • Ma S.
      Electrophilic addition and cyclization reactions of allenes.
      ,
      • Soriano E.
      • Fernández I.
      Allenes and computational Chemistry: from bonding situations to reaction mechanisms.
      ,
      • Yang B.
      • Qiu Y.
      • Bäckvall J.-E.
      Control of selectivity in palladium(II)-Catalyzed oxidative transformations of allenes.
      ,
      • Liu L.
      • Ward R.M.
      • Schomaker J.M.
      Mechanistic aspects and synthetic applications of radical additions to allenes.
      ,
      • Blieck R.
      • Taillefer M.
      • Monnier F.
      Metal-catalyzed intermolecular hydrofunctionalization of allenes: easy access to allylic structures via the selective formation of C–N, C–C, and C–O bonds.
      ,
      • Alonso J.M.
      • Almendros P.
      Deciphering the chameleonic Chemistry of allenols: breaking the taboo of a onetime esoteric functionality.
      ]. The reaction is initiated with the in-situ formation of cationic rhodium complex A from pre-A and 2a, which further undergoes oxidative addition to N–H bond forming a Rh–H species B through transition state A-TS with a free energy of 29.9 ​kcal ​mol−1. Then, complex B inserts into allene 1a with different site-selectivity. Computational results suggest the insertion step with gem-difluoro double bond is energetically more favorable than that process with the nonfluorinated double bond, since the unique properties of the fluorine substituents can stabilize α carbocation by donating their lone pairs into the vacant p orbitals of the cationic centers (Fig. 2c). The transition state B-TS-Z forming intermediate C with Z configuration requires an activation free energy of 17.7 ​kcal ​mol−1 relative to intermediate B, which is stabilized by 3.8 ​kcal ​mol−1 as compared to the transition state B-TS-E (17.7 ​kcal ​mol−1 vs 21.5 ​kcal ​mol−1). In the reductive elimination process, there are three possible pathways involving three transition states (Fig. 2d). The energy in the pathway of direct reductive elimination leading to linear product via transition state D-TS-Z is 6.1 ​kcal ​mol−1 higher than an inner-sphere nucleophilic attack pathway through gem-difluoro π-allyl rhodium intermediate (32.9 ​kcal ​mol−1 vs 26.8 ​kcal ​mol−1). The transition state D-TS-S to the branched product 3aa with S configuration requires an activation free energy of 26.8 ​kcal ​mol−1 relative to C-Z, which is the enantioselectivity-determining step in the asymmetric hydroamination pathway, in agreement with our experimental observation.
      The catalytic cycle involving π-activation pathway [
      • Utsunomiya M.
      • Kuwano R.
      • Kawatsura M.
      • Hartwig J.F.
      Rhodium-catalyzed anti-markovnikov hydroamination of vinylarenes.
      ,
      • Takemiya A.
      • Hartwig J.F.
      Rhodium-catalyzed intramolecular, anti-markovnikov hydroamination. Synthesis of 3-arylpiperidines.
      ,
      • Liu Z.
      • Hartwig J.F.
      Mild, rhodium-catalyzed intramolecular hydroamination of unactivated terminal and internal alkenes with primary and secondary amines.
      ,
      • Julian L.D.
      • Hartwig J.F.
      Intramolecular hydroamination of unbiased and functionalized primary aminoalkenes catalyzed by a rhodium aminophosphine complex.
      ,
      • Shen X.
      • Buchwald S.L.
      Rhodium-catalyzed asymmetric intramolecular hydroamination of unactivated alkenes.
      ,
      • Liu Z.
      • Yamamichi H.
      • Madrahimov S.T.
      • Hartwig J.F.
      Rhodium phosphine-π-arene intermediates in the hydroamination of alkenes.
      ,
      • Strom A.E.
      • Balcells D.
      • Hartwig J.F.
      Synthetic and computational studies on the rhodium-catalyzed hydroamination of aminoalkenes.
      ,
      • Ickes A.R.
      • Ensign S.C.
      • Gupta A.K.
      • Hull K.L.
      Regio- and chemoselective intermolecular hydroamination of allyl imines for the synthesis of 1,2-diamines.
      ,
      • Vanable E.P.
      • Kennemur J.L.
      • Joyce L.A.
      • Ruck R.T.
      • Schultz D.M.
      • Hull K.L.
      Rhodium-catalyzed asymmetric hydroamination of allyl amines.
      ] from a cis-aminometalation mechanism was also investigated in Fig. 3. Deprotonation of rhodium–amine complex A via transition state E-TS reversibly generates intermediate E, releasing a molecular of HX (X ​= ​Cl). The generated HX species are more likely to undergo H/D exchange with the solvent and additive, such as EtOH and PPTS, leading to a dramatically reduce in the deuteration incorporation of 3aa when employing D7-aniline (Scheme 3). Subsequently, aminometalation of the non-fluorinated double bond of 1a might takes place. The transition states F-TS-S and F-TS-R require an overall barrier of 42.4 and 42.0 ​kcal ​mol−1, respectively, which is much higher than the above amine-activation mechanism (Fig. 3b). The subtle energy different between F-TS-S and F-TS-R is attributed to the loose Rh–N insertion transition state, resulting in the inability of the ligand center to control the generation of chiral carbons.
      Fig. 3
      Fig. 3Proposed mechanism. a) DFT-computed energy profile involving cis-aminometalation mechanism. b) DFT-computed transition states of the Rh–N insertion into difluoroallenes 1a.
      Alternatively, the trans-π-activation pathway is based on an outersphere nucleophilic attack mode (Fig. 4). In this pathway, Rh(I) species pre-A firstly coordinates with non-fluorinated double bond of 1a from different orientations to afford intermediate G-R and G-S, respectively. Next, the nucleophilic attack of amine to intermediates G occur to generate two different enantiomers H-R and H–S. The activation free energies of the transition states for this step was calculated to be 41.2 and 44.6 ​kcal ​mol−1, respectively, indicating that the outersphere nucleophilic attack is thermodynamically unfavorable in this transformation. These computational results well ruled out the possibility of the reported π-activation mechanism.
      Fig. 4
      Fig. 4DFT-computed energy profile involving π-activation mechanism.

      3. Conclusion

      In summary, we developed an enantioselective hydroamination of gem-difluoroallenes with primary and secondary anilines enabled by rhodium catalysis. The present strategy provided a facile and effective route to a large number of enantiopure gem-difluoroallylic amines under mild reaction conditions, exhibiting excellent functional groups compatibility and branched selectivity. Future studies will focus on the detailed mechanistic investigation and discovery of more examples on asymmetric hydrofunctionalization of gem-difluoroallenes via gem-difluoro π-allyl species.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We would like to thank the National Natural Science Foundation of China (Grants 22025104, 22171134, 21972064 and 21901111), the Fundamental Research Funds for the Central Universities (Grant 020514380254) for their financial support. The project was also supported by Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University. We are also grateful to the High-Performance Computing Center of Nanjing University for performing the numerical calculations in this paper on its blade cluster system.

      Appendix ASupplementary data

      The following are the Supplementary data to this article:

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      1. See Supporting Information for details. Deposition number 2072454 (3da·HCl) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge by the Cambridge Crystallographic Data Centre.

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