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State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
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.
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
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
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.
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.
Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor.
Experimental and theoretical studies on rhodium-catalyzed coupling of benzamides with 2,2-difluorovinyl tosylate: diverse synthesis of fluorinated heterocycles.
Experimental and computational studies of the iron-catalyzed selective and controllable defluorosilylation of unactivated aliphatic gem-difluoroalkenes.
]. Among them, gem-difluoroallylic amine scaffolds bearing a chiral C–N bond have been examined for potential applications for isostere-based drug design and enzyme inhibitors (Fig. 1a) [
Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor.
]. The preparation of these molecules traditionally relies on multistep organic synthesis through installation of fluorine-containing functional groups [
A remarkably efficient fluoroalkylation of cyclic sulfates and sulfamidates with PhSO2CF2H: facile entry into β-difluoromethylated or β-difluoromethylenated alcohols and amines.
Synthesis of (S)-3-Amino-4-(difluoromethylenyl)-cyclopent-1-ene-1-carboxylic acid (OV329), a potent inactivator of γ-aminobutyric acid aminotransferase.
]. It has been reported by Breit et al. that allenes can provide completely atom-efficient path to allylmetal intermediates for asymmetric hydrofunctionalization reactions [
]. In this context, Hartwig and co-workers first described an iridium-catalyzed enantioselective allylic substitution of 3,3-difluoropropenes with carbon nucleophiles via monofluoro π-allyl species using F atom as a leaving group (Fig. 1c) [
Regiospecific synthesis of bicyclo- and heterobicyclo-gem-difluorocyclobutenes using functionalized fluoroallenes and a novel Mo-catalyzed intramolecular [2 + 2] cycloaddition reaction.
Because the introduction of two F atoms at the allenic terminus can strongly influence allene reactivity, catalytic asymmetric reaction of gem-difluoroallenes remains difficult to achieve [
The Nucleophilic 5-Endo-Trig Cyclization of 1,1-Difluoro-1-Alkenes: Ring-Fluorinated Hetero- and Carbocycle Synthesis and Remarkable Effect of the Vinylic Fluorines on the Disfavored Process.
]. Herein, we report a catalytic enantioselective hydroamination of gem-difluoroallenes with anilines to access a diverse of enantiopure gem-difluoroallylic amines (Fig. 1d). The combination of a rhodium catalyst with a chiral ligand and using 2.0 equiv. Of anilines as nucleophiles can form branched amination products through gem-difluoro π-allyl complex, with regio- and enantiocontrol.
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) [
]. The enantioselectivity could be further improved at room temperature, but with relatively lower conversion (entry 10). Finally, control experiments run either just using DCM or EtOH as solvent, the reaction outcome dramatically decreased (entries 11–12).
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 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..
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 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..
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 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 [
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.
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. 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.
Metal-catalyzed intermolecular hydrofunctionalization of allenes: easy access to allylic structures via the selective formation of C–N, C–C, and C–O bonds.
]. 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 [
] from a cis-aminometalation mechanism was also investigated in Fig. 3. Deprotonation of rhodium–amine complex Avia 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. 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. 4DFT-computed energy profile involving π-activation mechanism.
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:
Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor.
Experimental and theoretical studies on rhodium-catalyzed coupling of benzamides with 2,2-difluorovinyl tosylate: diverse synthesis of fluorinated heterocycles.
Experimental and computational studies of the iron-catalyzed selective and controllable defluorosilylation of unactivated aliphatic gem-difluoroalkenes.
Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor.
A remarkably efficient fluoroalkylation of cyclic sulfates and sulfamidates with PhSO2CF2H: facile entry into β-difluoromethylated or β-difluoromethylenated alcohols and amines.
Synthesis of (S)-3-Amino-4-(difluoromethylenyl)-cyclopent-1-ene-1-carboxylic acid (OV329), a potent inactivator of γ-aminobutyric acid aminotransferase.
Regiospecific synthesis of bicyclo- and heterobicyclo-gem-difluorocyclobutenes using functionalized fluoroallenes and a novel Mo-catalyzed intramolecular [2 + 2] cycloaddition reaction.
The Nucleophilic 5-Endo-Trig Cyclization of 1,1-Difluoro-1-Alkenes: Ring-Fluorinated Hetero- and Carbocycle Synthesis and Remarkable Effect of the Vinylic Fluorines on the Disfavored Process.
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.
Metal-catalyzed intermolecular hydrofunctionalization of allenes: easy access to allylic structures via the selective formation of C–N, C–C, and C–O bonds.
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