Process for the preparation of optically pure enantiomers of cyclic iminium salts and their use as catalysts - Patents.com

Abstract

The present invention relates to a process for the preparation of optically pure (+) or (-) enantiomers of iminium salts having formula (I), the process comprising the steps of: a) a reduction step of an iminium salt having formula (II), said salt being in the form of a racemic mixture, to give a compound having formula (III), also in the form of a racemic mixture; b) a chiral HPLC separation step of the compound of formula (III) in the form of a racemic mixture to obtain optically pure (+) or (-) enantiomer compounds having formula (IV); c) oxidation of a compound of formula (IV) to obtain a compound of formula (I); The present invention relates to a method comprising the steps of: JPEG2024533172000104.jpg95128

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of optically pure enantiomers of cyclic iminium salts, and to the corresponding optically pure enantiomers of cyclic iminium salts. [Background technology]

[0002] Since their discovery in the early 1960s, N-heterocyclic carbenes (NHCs) have become essential ligands in transition metal (TM)-catalyzed transformations in both academic and industrial research environments (N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools (Eds.: S. Diez-Gonzalez), RSC Catalysis series, RSC Publishing: Cambridge, 2011). In part, this growing popularity is due to their remarkable suitability in generating more stable, yet highly reactive, catalysts. Not surprisingly, chiral forms of diaminocarbene emerged spontaneously in the early 1990s and, thanks to their unique and highly modular steric environment, they also found success in enantioselective catalysis and quickly became particularly favored stereodirecting ligands ((a) Wang, F.; Liu, L.-J.; Wang, W.; Li, S; Shi, M. Chiral NHC-Metal-Based Asymmetric Catalysis. Coord. Chem. Rev. 2012, 256, 804-853. (b) Janssen-Muller, D.; Schlepphorst, C.; Glorius, F. Privileged Chiral N-Heterocyclic Carbene Ligands for Asymmetric Transition-Metal Catalysis. Chem. Soc. Rev., 2017, 46, 4845-4854).

[0003] Recently, however, a new class of chiral carbenes, namely, chiral cyclic (alkyl)(amino)carbenes (CAACs), have emerged as competitors to the NHC-dominated domain for carbene-driven enantioselective catalysis. ((a) Lavallo, V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2005, 44, 5705-5709. CAACs. For recent reviews, see (b) Soleilhavoup, M.; Bertrand, G. Acc. Chem. Res. 2015, 48, 256-266; (c) Melaimi, M., Jazzar, R., Soleilhavoup, M., Bertrand, G. Angew. Chem. Int. Ed., 2017, 56, 10056; d) Morvan, J; Mauduit, M; Bertrand, G; Jazzar, R. ACS Catal., 2021, 11, 1714. CAAC ligands have been shown in recent years by various research groups to provide robust and well-defined CAAC-metal transition complexes. The latter have demonstrated that their unique electronic (more sigma donating and pi accepting than NHCs) and steric properties allow for improvements of known catalytic methods (Ru: see, e.g., (a) Marx, VM; Sullivan, AH; Melaimi, M.; Virgil, SC; Keitz, BK; Weinberger, DS; Bertrand, G.; Grubbs, RH Angew. Chem., Int. Ed. 2015, 54, 1919. (b) Zhang, J.; Song, S.; Wang, X.; Jiao, J.; Shi, M. Chem. Commun. 2013, 49, 9491. (c) Anderson, DR; Lavallo, V.; O'Leary, DJ; Bertrand, G.; Grubbs, RH Angew. Chem., Int. Ed. 2007, 46, 7262).According to (a) V. Lavallo, Y. Canac, C. Prasang, B. Donnadieu and G. Bertrand, Angew. Chem., Int. Ed., 2005, 44, 5705; G. Bertrand, J. Am. Chem. Soc., 2018, 140, 9255. (a) MPWiesenfeldt, Z. Nairoukh, W. Li and https: / / doi.org / 10.1103 / PhysRevLett.137.9250;(b) Y. Wei, B. Rao, X. Cong, and X. Zeng, J. Am. Chem. Soc., 2015, 137,9250; F.Glorius,Nat.Chem.,2019,11,264 and promoting novel reactions with coinage metals G. Bertrand, Chem.Sci.,2017,8,165; G. Bertrand, J. Am. Chem. Soc., 2016, 138, 7884. (a) Hu, D. Martin, M. Melaimi and J. Am.Chem.Soc., 2014,136,13594;(b)R.Kinjo,B.Donnadieu and G.Bertrand,Angew.Chem.,Int.Ed.,2011,50,5560; G.Bertrand,Angew.Chem.,Int.Ed.,2014,53,9059;

[0004] Surprisingly, as recently pointed out by Glorius and co-workers (D. Janssen-Mueller, C. Schlepphortst and F. Glorius, Chem. Soc. Rev., 2017, 46, 4845), despite the existence of various stable heterocyclic carbenes, only diaminocarbenes have been intensively used as ligands for enantioselective transformations. Indeed, with regard to chiral CAAC ligands, only two applications have been reported in the literature ((a) Pichon, D.; Soleilhavoup, M.; Morvan, J.; Junor, GP; Vives, T.; Crevisy, C.; Lavallo, V.; Campagne, J.-M.; Mauduit, M.; Jazzar, R.; Bertrand, G. The Debut of Cyclic (Alkyl) (Amino) Carbenes (CAACs) in Enantioselective Synthesis, 1999, 14, 1111-1121, 1999). Catalysis.Chem.Sci.2019,10,7807;(b)Morvan,J.;Vermersch,F.;Zhang,Z.;Falivene,L.;Vives,T.;Dorc et,V.;Roisnel,T.;Crevisy,C.;Cavallo,L.;Vanthuyne,N.;Bertrand,G.;Jazzar,R.;Mauduit,M.Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene(CAAC)Ruthenium-Complexes for Asymmetric Olefin Metathesis.J.Am.Chem.Soc.2020,142,19895).

[0005] Nevertheless, the main drawback is that these optically pure CAAC ligands were obtained following lengthy procedures with low yields and very often only one of the two enantiomers was prepared. Summary of the Invention

[0006] It is therefore an object of the present invention to provide novel optically pure enantiomers of iminium salts as precursors of optically pure cyclic (alkyl)(amino)carbene (CAAC) ligands for use in asymmetric catalysis.

[0007] Another object of the present invention is to provide novel optically pure enantiomers of iminium salts that can be prepared by a process that does not require any optically pure or enantiomerically enriched starting materials, in other words, that does not require the use of chiral chemical compounds.

[0008] Another object of the present invention is to provide a process for the preparation of novel optically pure enantiomers of iminium salts which is more economical and faster as compared to the prior art processes. [Brief description of the drawings]

[0009] [Figure 1] As a preliminary photophysical and chiral-optical characterization, the unpolarized (black solid line) and circularly polarized luminescence (CPL) of the high enantiomeric purity copper complexes ((R) and (S), blue and red solid lines, respectively, with an average glum value of 10-3) were measured using a CPL spectrofluorometer. The samples were excited with a xenon ozone-free lamp 150W LS using a 90° geometry. The following parameters were used: emission slit width ≈ 2 mm, integration time = 4 s, scan speed = 50 nm / min, accumulation = 5. The concentration of all samples was about 10-5 M. Excitation of the samples was performed at 320 nm. The corresponding results are shown in Figure 1. [Diagram 2]As a preliminary photophysical and chiral-optical characterization, the unpolarized (black solid line) and circularly polarized luminescence (CPL) of the high enantiomeric purity copper complexes ((R) and (S), blue and red solid lines, respectively, with an average glum value of 10-3) were measured using a CPL spectrofluorometer. The samples were excited with a xenon ozone-free lamp 150W LS using a 90° geometry. The following parameters were used: emission slit width ≈ 2 mm, integration time = 4 s, scan speed = 50 nm / min, accumulation = 5. The concentration of all samples was about 10-5 M. Excitation of the samples was performed at 320 nm. The corresponding results are shown in Figure 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Accordingly, the present invention relates to a process for the preparation of optically pure (+) or (-) enantiomers of iminium salts having the following formula (I): [ka] [In the formula, R 1 is (C6-C 14 ) aryl group, (C1-C6) alkyl group or (C8-C 20 ) cycloalkyl group, the aryl group optionally being selected from halogen, (C6-C 10 ) aryl groups and (C1-C6) alkyl groups, the alkyl groups being optionally substituted with one or more phenyl groups; Or R 1 '-NR' a R' b R' is a a and R' b are each independently H, (C1-C6) alkyl and (C6-C 10 aryl; or R ’ a and R ’ b together with the nitrogen atom that carries them form N(CH2) 2+mforming a heterocyclyl ring, and m is 0 or an integer of 1 to 6; R 2 H, (C6-C 10 ) an aryl group or a (C1-C6) alkyl group; R 3 is a (C1-C6) alkyl group; or R 2 and R 3 may together with the carbon atoms which carry them form a (C3-C6)cycloalkyl; R 5 The following groups: (C6-C 20 )Aryl, (C1-C 10 ) alkyl and (C3-C 12 ) cycloalkyl groups; The alkyl group is optionally selected from the group consisting of (C6-C 10 ) aryl groups; The aryl group is a (C1-C6) alkyl, (C6-C 10 )aryl(C1-C6)alkyl, and in particular (C6-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl, optionally substituted with one or more substituents selected from the group consisting of (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl. 10 ) aryl; R 6 The following groups: (C6-C 20 )Aryl, (C1-C 10 )Alkyl, (C3-C 12 )Cycloalkyl, heteroaryl, (C6-C 10 ) aryl(C1-C6)alkyl and heteroaryl(C1-C6)alkyl; The aryl group is a (C1-C6) alkyl, (C6-C 10)aryl(C1-C6)alkyl, and in particular (C6-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl, optionally substituted with one or more substituents selected from the group consisting of (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl. 10 ) aryl; However, R 6 is R 5 Unlike; Or R 5 and R 6 together with the carbon atoms to which they are attached form a 5-, 6-, or 10-membered cycloalkyl or heterocyclyl ring; R 4 is H or a (C1-C6) alkyl group; n is an integer from 1 to 3; Or R 3 and R 5 together with the carbon atom to which they are attached form a 6-, 7-, or 8-membered cycloalkyl ring; X - is the counter anion, The salts are in the form of optically pure (+) or (-) enantiomers. The method comprises the steps of: a) reduction of an iminium salt having the following formula (II), said salt being in the form of a racemic mixture: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and X - is as defined above in formula (I), to obtain a compound having the formula (III), [ka] (In the formula, R 1 , R 2 , R3 , R 4 , R 5 , R 6 and n is as defined above in formula (I), a reduction step, wherein the compound of formula (III) is in the form of a racemic mixture; b) a chiral HPLC separation step of the compound of formula (III) in the form of a racemic mixture to obtain optically pure (+) or (-) enantiomer compounds having formula (IV), [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n is as defined above in formula (I), a chiral HPLC separation step in which the compound of formula (IV) is in the form of an optically pure (+) or (-) enantiomer; c) oxidation of a compound of formula (IV) to obtain a compound of formula (I); d) optionally a counter anion exchange step; The present invention relates to a method comprising the steps of:

[0011] The present invention also relates to optically pure (+) or (-) enantiomers of iminium salts having the following formula (I): [ka] [In the formula, R 1 is (C6-C 14 ) aryl group, (C1-C6) alkyl group or (C8-C 20 ) cycloalkyl group, the aryl group optionally being selected from halogen, (C6-C 10 ) aryl groups and (C1-C6) alkyl groups, the alkyl groups being optionally substituted with one or more phenyl groups; Or R 1 '-NR'a R' b R' is a a and R' b are each independently H, (C1-C6) alkyl and (C6-C 10 aryl; or R ’ a and R ’ b together with the nitrogen atom that carries them form N(CH2) 2+m forming a heterocyclyl ring, and m is 0 or an integer of 1 to 6; R 2 H, (C6-C 10 ) an aryl group or a (C1-C6) alkyl group; R 3 is a (C1-C6) alkyl group; or R 2 and R 3 may together with the carbon atoms which carry them form a (C3-C6)cycloalkyl; R 5 The following groups: (C6-C 20 )Aryl, (C1-C 10 ) alkyl and (C3-C 12 ) cycloalkyl groups; The alkyl group is optionally selected from the group consisting of (C6-C 10 ) aryl groups; The aryl group is a (C1-C6) alkyl, (C6-C 10 )aryl(C1-C6)alkyl, and in particular (C6-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl, optionally substituted with one or more substituents selected from the group consisting of (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl. 10 ) aryl; R 6 The following groups: (C6-C 20 )Aryl, (C1-C 10 )Alkyl, (C3-C 12)Cycloalkyl, heteroaryl, (C6-C 10 ) aryl(C1-C6)alkyl and heteroaryl(C1-C6)alkyl; The aryl group is a (C1-C6) alkyl, (C6-C 10 )aryl(C1-C6)alkyl, and in particular (C6-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl, optionally substituted with one or more substituents selected from the group consisting of (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy and (C1-C6)alkyl. 10 ) aryl; However, R 6 is R 5 Unlike; Or R 5 and R 6 together with the carbon atoms to which they are attached form a 5-, 6-, or 10-membered cycloalkyl or heterocyclyl ring; R 4 is H or a (C1-C6) alkyl group; n is an integer from 1 to 3; Or R 3 and R 5 together with the carbon atom to which they are attached form a 6-, 7-, or 8-membered cycloalkyl ring; X - is the counter anion, The salts are in the form of optically pure (+) or (-) enantiomers.

[0012] A preferred family of optically pure (+) or (-) enantiomers of iminium salts according to the present invention consists of salts having the following formula (I-1): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X- is as defined in formula (I).

[0013] The salt of formula (I-1) corresponds to the salt of formula (I) where n=0.

[0014] Preferably, in formula (I-1), R 4 is H.

[0015] The present invention therefore also relates to said salts and to a process for the preparation of said salts as defined above, starting from a compound having formula (II) where n=0.

[0016] A preferred family of optically pure (+) or (-) enantiomers of iminium salts according to the invention consists of salts having the following formula (I) as defined above, wherein n is an integer from 1 to 3, preferably 1.

[0017] A preferred family of optically pure (+) or (-) enantiomers of iminium salts according to the present invention consists of salts having the following formula (I-2): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X - is as defined in formula (I).

[0018] The salt of formula (I-2) corresponds to the salt of formula (I) where n=1.

[0019] The present invention therefore also relates to said salts and to a process for the preparation of said salts as defined above, starting from a compound having formula (II) where n=1.

[0020] A preferred family of optically pure (+) or (-) enantiomers of iminium salts according to the present invention consists of salts having the following formula (I-3): [ka] [In the formula, R 1 , R 2 , R 4 , R 6 and X - is as defined in formula (I).

[0021] Preferably, in formula (I-3), R 2 is a (C1-C6) alkyl group such as methyl.

[0022] Preferably, in formula (I-3), R 6 is a (C1-C6) alkyl group, such as a methyl, ethyl or propyl group, optionally substituted with a phenyl group.

[0023] Preferably, in formula (I-3), R 4 is a (C1-C6) alkyl group.

[0024] According to one embodiment, in formulae (I), (I-1), (I-2) and (I-3), R 1 is a substituted phenyl group. Preferably, in formulae (I), (I-1), (I-2) and (I-3), R 1 is a phenyl group substituted with at least one or two substituents selected from (C1-C6) alkyl groups such as methyl, ethyl or isopropyl.

[0025] Preferably, in formulae (I), (I-1), (I-2) and (I-3), R 1 is a phenyl group substituted at the ortho position with two substituents which may be the same or different.

[0026] Preferably, in formulae (I), (I-1), (I-2) and (I-3), R 1is a phenyl group substituted at the ortho position with two substituents which may be the same or different, and which are preferably (C1-C6) alkyl groups such as methyl, ethyl or isopropyl.

[0027] Preferred R 1 The group may include a phenyl group having two alkyl groups in the ortho positions, especially two identical alkyl groups, such as ethyl or isopropyl.

[0028] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 1 is a (C6-C) alkyl group substituted with at least one substituent selected from the group consisting of (C1-C6) alkyl groups; 10 ) an aryl group, preferably a phenyl group substituted with two alkyl groups, such as methyl, isopropyl or ethyl groups, and / or R 2 is a (C1-C6) alkyl group, such as a methyl group.

[0029] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 2 and R 3 are the same and are preferably methyl groups.

[0030] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 2 and R 3 are different, R 2 is preferably a (C1-C6) alkyl group such as a methyl group, and R 3 is preferably H or (C6-C 10 ) an aryl group.

[0031] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 4 is H.

[0032] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 6 is an alkyl group as defined above, preferably a methyl group, and R 5 is an aryl group as defined above. Preferably, the aryl group is substituted with at least one, in particular one, two or three, substituents (C6-C 10 )aryl groups, for example naphthyl or phenyl groups, and the substituents are (C1-C6)alkyl groups such as methyl or isopropyl, (C1-C6)alkylamino groups, di(C1-C6)alkylamino groups, (C1-C6)alkoxy groups, (C6-C6)aryl groups such as phenyl, 10 ) an aryl group, and -CH(Ar)2, such as -CH(Ph)2, where Ar is an aryl group. Preferably, R 5 is a phenyl group substituted in the meta position with two substituents which are the same or different, preferably the same, for example methyl, isopropyl or tert-butyl.

[0033] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 5 is a cyclohexyl group.

[0034] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 4 is an aryl group as defined above, and R is an alkyl group as defined above, preferably a methyl group. Preferably, the aryl group is a naphthyl group or a substituted group with at least one, in particular one, two or three, substituents (C6-C 10 )aryl groups, for example phenyl groups, the substituents being (C1-C6)alkyl groups such as methyl or isopropyl, (C1-C6)alkylamino groups, di(C1-C6)alkylamino groups, (C1-C6)alkoxy groups, (C6-C6)aryl groups such as phenyl, 10 ) an aryl group, and -CH(Ar)2, such as -CH(Ph)2, where Ar is an aryl group. Preferably, R6 is a phenyl group substituted in the meta position with two substituents which are the same or different, preferably the same, for example methyl, isopropyl or tert-butyl.

[0035] R 6 or R 5 Preferred aryl groups include the following: [ka] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 6 is an aryl group as defined above, which is optionally substituted with at least one substituent as defined below; R 5 is an alkyl group as defined above, preferably a methyl group.

[0036] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 5 is an aryl group as defined above, which is optionally substituted with at least one substituent as defined below; R 6 is an alkyl group as defined above, preferably a methyl group.

[0037] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 6 is an alkyl group as defined above, preferably a methyl group, and R 5 is a (C1-C 10 ) alkyl, and (C3-C 12 ) cycloalkyl groups.

[0038] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 5 is an alkyl group as defined above, preferably a methyl group, and R 6is a (C1-C 10 ) alkyl, and (C3-C 12 ) cycloalkyl groups.

[0039] R + (or R 5 Preferred cycloalkyl groups for ) include the following: [ka]

[0040] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 6 is an alkyl group as defined above, preferably a methyl group, and R 5 is an aryl group as defined above, preferably a phenyl group.

[0041] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 5 is an alkyl group as defined above, preferably a methyl group, and R 6 is an aryl group as defined above, preferably a phenyl group.

[0042] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), R 5 and R 6 are different and include the following groups: (C6-C 10 ) aryl, (C1-C6) alkyl, such as methyl, and (C3-C6) cycloalkyl, such as cyclohexyl, the aryl group being optionally substituted with two substituents selected from a (C1-C6) alkyl group.

[0043] According to one embodiment, in formula (I) or also in formula (I-1), (I-2) or (I-3), X - is a counter anion, preferably BF - , I- , Cl - , OTF - , Br - , PF6 - , SbF6 - and B(Ar)4 - Ar is an aryl group, e.g., BPh4 - The counter anion is: MX n - , e.g. CuCl2 - , AuBr2 - , [Pd(η3-cis)Cl2] - , FeCl4 - (See Ekaterina A. Martynova, Nikolaos V. Tzouras, Gianmarco Pisano, Catherine SJCazin and Steven P. Nolan (Chemical Communications, 32, 2021)), or [NiCl4 2- ](Mickael Henrion, Sonia Duarte Barroso, Ana M. Martins, Vincent Ritleng, Michael J. Chetcuti (Polyhedron, volume 87, February 2015, p. 398-402) or Yan-Chao Xu, Jie Zhang, Hong-Mei Sun, Qi Shen and Yong Zhang (Dalton Transactions, 23, 2013).

[0044] Any counter anion known to those skilled in the art can be used. Other examples can be found, for example, in Han Vinh Huynh, Truc Tien Lam and Huyen TTLuong (RSC Advances, issue 61, 2018).

[0045] According to a preferred embodiment, X - is BF4 - It is.

[0046] In the context of the present invention, "C t -Cz " means a carbon-based chain that can have t to z carbon atoms, for example C1-C3 means a carbon-based chain that can have 1 to 3 carbon atoms.

[0047] According to the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0048] According to the invention, the term "alkyl group" means, unless otherwise stated, a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 12 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups. According to the present invention, the term "cycloalkyl group" means a cyclic carbon-based group containing 3 to 12 carbon atoms, unless otherwise specified. By way of example, mention may be made of groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl. According to the present invention, the term "alkoxy group" means an -O-alkyl group, the alkyl group being as defined above. By way of example, mention may be made of -O-(C1-C4) alkyl groups, in particular -O-methyl, -O-ethyl, as -O-C3 alkyl groups -O-propyl, -O-isopropyl, as -O-C4 alkyl groups -O-butyl, -O-isobutyl or -O-tert-butyl.

[0049] According to the invention, the term "aryl group" means a cyclic aromatic group containing 6 to 10 carbon atoms. Examples of aryl groups include phenyl or naphthyl groups.

[0050] According to the present invention, the term "heteroaryl" refers to a 5-10 membered aromatic monocyclic or bicyclic group containing 1-4 heteroatoms selected from O, S or N. Examples include imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl and isoquinolinyl groups.

[0051] As heteroaryl containing 5 to 6 atoms, including 1 to 4 nitrogen atoms, there may be mentioned in particular the following representative groups: pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and 1,2,3-triazinyl.

[0052] Heteroaryl includes thiophenyl, oxazolyl, furazanyl, 1,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzazaindole, 1,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl, and also the corresponding groups resulting from the fusion or condensation of these with a phenyl nucleus.

[0053] According to the present invention, the term "heterocycloalkyl" means a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic group containing 1-3 heteroatoms selected from O, S or N, the heterocycloalkyl group may be attached to the remainder of the molecule via a carbon atom or via a heteroatom, and the term bicyclic heterocycloalkyl includes fused bicyclic and spiro-type rings.

[0054] Examples of saturated heterocycloalkyl containing 5 to 6 atoms include oxetanyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, azepinyl, oxazepinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, and isoxazolidinyl.

[0055] If a heterocycloalkyl is substituted, the substitutions may be on one (or several) carbon atoms and / or heteroatoms. If a heterocycloalkyl comprises several substituents, they may be carried by one and the same atom or by different atoms.

[0056] The above-mentioned "alkyl", "cycloalkyl", "aryl", "heteroaryl" and "heterocycloalkyl" groups may be substituted with one or more substituents, among which the following groups may be mentioned: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy or carboxyalkyl.

[0057] According to the present invention, the term "alkylthio" means an --S-alkyl group, wherein the alkyl group is as defined above.

[0058] According to the present invention, the term "arylthio" means the group --S-aryl, wherein the aryl group is as defined above.

[0059] According to the present invention, the term "alkylamino" means a -NH-alkyl group, wherein the alkyl group is as defined above.

[0060] According to the present invention, the term "cycloalkyloxy" means an --O-cycloalkyl group, wherein cycloalkyl group is as defined above.

[0061] According to the present invention, the term "aryloxy" means an --O-aryl group, the aryl group being as defined above.

[0062] According to the present invention, the term "(hetero)arylalkoxy" means a (hetero)aryl-alkoxy group, wherein the (hetero)aryl and alkoxy groups are as defined above.

[0063] According to the present invention, the term "alkylcarbonyl" means a -CO-alkyl group, the alkyl group being as defined above.

[0064] According to the present invention, the term "alkoxylcarbonyl" means a -CO-O-alkyl group, the alkyl group being as defined above.

[0065] According to the present invention, the term "arylcarbonyl" means a -CO-aryl group, the aryl group being as defined above.

[0066] According to the present invention, the term "aryloxycarbonyl" means a -CO-aryloxy group, the aryloxy group being as defined above.

[0067] According to the present invention, the term "alkylsulfonyl" means a -SO2-alkyl group, the alkyl group being as defined above.

[0068] According to the present invention, the term "arylsulfonyl" means a -SO2-aryl group, the aryl group being as defined above.

[0069] According to the present invention, the term "alkylsulfinyl" means a -SO-alkyl group, wherein the alkyl group is as defined above.

[0070] According to the present invention, the term "arylsulfinyl" means a -SO-aryl group, the aryl group being as defined above.

[0071] According to the invention, the term "carboxyalkyl" denotes an HOOC-alkyl group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may be made in particular of carboxymethyl or carboxyethyl.

[0072] According to the present invention, the term "carboxyl" means a -COOH group.

[0073] According to the present invention, the term "oxo" means "=O".

[0074] When an alkyl group is substituted with an aryl group, the term "arylalkyl" or "aralkyl" group is used. An "arylalkyl" or "aralkyl" group is an aryl-alkyl group, in which the aryl and alkyl groups are as defined above. Among the arylalkyl groups, particular mention may be made of benzyl or phenethyl groups.

[0075] Preferred salts according to the invention include the following: [ka] Preferred salts according to the invention include the following: [ka] As mentioned above, the process according to the invention comprises a first step consisting of a reduction step of the iminium salt of formula (II), said salt being in the form of a racemic mixture, which gives the compound of formula (III), also in the form of a racemic mixture.

[0076] Formulae (II) and (III) are as defined above. In these formulae, n, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above in formula (I), (I-1), (I-2) or (I-3).

[0077] The reduction step of the method of the present invention is carried out in particular with a reducing agent. For reducing agents, see Reductions by the Alumino and Borohydrides in Organic Synthesis, 2nd edition (Seyden-Penne, Jacqueline), Chapter 3.3.1 Imines and Iminium Salts, page 122, or further Hitchhiker's Guide to Reductive Amination (Evgeniya Podyacheva, Oleg I. Afanasyev, Alexey A. Tsygankov, Maria Makarova, Denis Chusov) in Synthesis 2019; 51 (13): 2667-2677).

[0078] According to one embodiment, the reducing agent is selected from the group consisting of LiAlH4, NaBH4, diisobutylaluminum hydride (DIBAL), lithium triethylborohydride (LiTEBH), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and cyanoborohydride.

[0079] Preferably, the reduction step is carried out in a solvent, in particular THF. According to one embodiment, the reduction step is carried out at a temperature between 0° C. and room temperature (20-24° C.).

[0080] According to one embodiment, the reduction step can be carried out using an HPLC column.

[0081] The process of the present invention also comprises a chiral HPLC separation step of the compound of formula (III) in the form of a racemic mixture to obtain the optically pure (+) or (-) enantiomer compound of formula (IV), said compound of formula (IV) being in the form of the optically pure (+) or (-) enantiomer.

[0082] Formula (IV) is as defined above. In this formula, n, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above in formula (I), (I-1), (I-2) or (I-3).

[0083] Preferably, this step of chiral HPLC separation is carried out using an HPLC column, which in particular comprises chloro-phenylcarbamate substituted cellulose as chiral stationary phase.

[0084] HPLC columns can include Lux® columns, such as Lux-Cellulose-3 (cellulose tris(4-methylbenzoate)) or Lux-Cellulose-4 (cellulose tris(4-chloro-3-methylphenylcarbamate)).

[0085] According to one embodiment, ethanol or heptane is used as the mobile phase.

[0086] The process of the present invention also comprises a step of oxidation of the compound of formula (IV) to obtain a salt of formula (I), said salt of formula (I) being in the form of an optically pure (+) or (−) enantiomer.

[0087] The oxidation step of the present invention is carried out in particular with the aid of an oxidizing agent, which according to one embodiment is selected from the group consisting of Br2, N-bromosuccinimide, I2, N-iodosuccinimide, copper(II) compounds (particularly CuX2 (X is, for example, Cl, Br, I or OTf), more particularly CuCl2), Cl2, hypervalent iodine compounds such as 2-iodoxybenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetra-N-butylammonium iodide (TBAI) and tert-butyl hydroperoxide (TBHP).

[0088] Other examples of oxidizing agents can be found in Yan Qin, Lihui Zhu and Sanzhong Luo, "Organocatalysis in Inert CH Bond Functionalization" (Chem. Rev. 2017, 117, 13, 9433-9520).

[0089] Preferably, the oxidation step is carried out in a solvent, in particular dichloromethane. According to one embodiment, the oxidation step is carried out at a temperature between 0° C. and room temperature (20-24° C.).

[0090] The method of the invention may also comprise a further step consisting of a counteranion exchange.

[0091] Such steps are carried out by means well known to those skilled in the art. For example, it makes it possible to obtain salts of formula (I) in which X is BF44 or PF6. See, for example, Han Vinh Huynh, Truc Tien Lam and Huyen TT Luong, "Anion influences on reactivity and NMR spectroscopic features of NHC precursors" (RSC Advances, issue 61, 2018), or Ekaterina A. Martynova, Nikolaos V. Tzouras, Gianmarco Pisano, Catherine SJ Cazin and Steven P. Nolan (Chemical Communications, 32, 2021).

[0092] Methods for this process include: Extraction with a saturated solution of salt, or Use of resin, or and the use of silver salts (e.g., AgNO3) for salt metathesis, taking advantage of the insolubility of silver.

[0093] The present invention also relates to the use of a compound of formula (I), or of formula (I-1), (I-2) or (I-3) as defined above, optionally in combination with a transition metal, as a catalyst, preferably as a catalyst in asymmetric olefin metathesis.

[0094] The present invention also relates to the use of a compound of formula (I), or of formula (I-1), (I-2) or (I-3) as defined above, as a catalyst.

[0095] The present invention also relates to the use of a compound of formula (I), or of formula (I-1), (I-2) or (I-3) as defined above, as a catalyst in combination with a transition metal other than ruthenium.

[0096] The present invention also relates to the use of a compound of formula (I), or of formula (I-1), (I-2) or (I-3) as defined above, as a catalyst in combination with a transition metal selected from the group consisting of gold, copper and rhodium.

[0097] The present invention also relates to the use of a compound of formula (I), or of formula (I-1), (I-2) or (I-3) as defined above, in combination with a transition metal, in an organic light-emitting diode.

[0098] The present invention also relates to the use of a compound of formula (I) or of formula (I-1), (I-2) or (I-3) as defined above in combination with a transition metal in an organic light-emitting diode, wherein the transition metal is selected from the group consisting of gold, copper and rhodium.

[0099] The present invention also relates to an organic light emitting device (OLED), comprising an anode, a cathode and an organic layer disposed between the anode and the cathode, the organic layer comprising a compound of formula (I) as defined above in combination with a transition metal selected from the group consisting of Ru, Os, Ir, Pd, Pt, Cu, Ag and Au, and capable of binding other ligands. EXAMPLES

[0100] Preparation of the Compounds of the Invention General Information All reactions and subsequent manipulations were carried out under an argon atmosphere in an MBraun glove box or using standard Schlenk techniques unless otherwise noted. 1 H and 13 C{ 1 H}NMR spectra were recorded on a Varian 400 or a Bruker Avance 400 at 25 °C. 1 H NMR chemical shifts are reported relative to TMS (δ ppm units) and referenced via the residual proton resonances of the corresponding deuterated solvents (CHCl: 7.26 ppm; CDH: 7.16 ppm). 13 C{ 1H} NMR spectra were reported relative to TMS using the naturally occurring carbon resonances (CDCl3: 77.16 ppm; C6D6: 128.0 ppm). Coupling constants are given in Hertz.

[0101] CAAC salt reduction to form the H2 adduct (corresponding to step a) of the process according to the invention for the preparation of the compound of formula (III) according to the invention General procedure: In a Schlenk tube under argon, lithium aluminum hydride (2 equiv.) was slowly added to a solution of iminium salt (1.0 equiv.) in THF at 0° C., and the resulting suspension was further stirred at room temperature overnight. The reaction mixture was then quenched with a mixture of hydrated MgSO4 and silica, and then passed through a short pad of silica, which was further washed with Et2O. The combined organic fractions were evaporated to give the desired CAAC-H2 adduct as a white sticky solid in a typical yield of 90%.

[0102] Analytical data: compound 1 [ka] 1 H NMR (400MHz, 25℃, CDCl3): δ=7.41-7.31(m,4H),7.28-7.20(m,2H),7.16(ddd,J=17.0,7. 5,2.0Hz,2H),4.01(d,J=8.4Hz,1H),3.91(p,J=6.9Hz,1H),3.50(d,J=8.6Hz,1H),3.37( p,J=6.8Hz,1H),2.54(d,J=12.7Hz,1H),2.30(dd,J=12.7,0.8Hz,1H),1.63(s,3H),1.30 (d,J=6.9Hz,3H),1.26(s,3H),1.16(t,J=6.8Hz,6H),1.08(d,J=6.8Hz,3H),1.05(s,3H).

[0103] 13 C{ 1H}NMR (100MHz, 25℃, CDCl3): δ=152.3,152.3,150.7,138.4,128.2,126.5,126.0,125.6,1 24.1,123.8,65.8,62.7,54.4,45.1,32.2,29.7,29.4,28.4,28.2,26.7,26.6,23.1,22.8.

[0104] Compound 2

change

[0105] 13 C{ 1 H}NMR (100MHz, 25℃, CDCl3): δ=152.3,152.3,147.9,138.5,133.4,131.8,127.9,127.9,127.5,126.6,125.9,1 25.5,125.3,124.1,123.8,123.6,65.9,62.9,54.6,45.3,32.0,29.7,29.5,28.4,28.3,26.8,26.7,23.2,22.9.

[0106] Compound 3

change

[0107] 13 C{ 1 1H}NMR (100 MHz, 25 °C, CDCl3): δ =.2, 152.1, 146.6, 138.7, 134.9, 131.5, 129.5, 127.2, 126.6, 126.2, 125.2, 125.0, 124.9, 124.2, 123.8, 123.6, 67.2, 62.4, 56.1, 46.0, 31.2, 29.7, 28.8, 28.6, 28.2, 26.7, 26.3, 23.3, 22.9.

[0108] Compound 4

Chem.

[0109] 13 C{ 1 13C{1H} NMR (100 MHz, 25 °C, CDCl3): δ = 152.3, 152.3, 150.9, 138.5, 137.6, 127.3, 126.5, 124.1, 123.8, 123.7, 65.9, 62.7, 54.3, 44.9, 32.3, 29.8, 29.5, 28.5, 28.1, 26.8, 26.6, 23.2, 22.8, 21.6.

[0110] Compound 5

Chem.

[0111] 13 C{ 1H}NMR(100MHz,25℃,CDCl3):δ=δ152.4,152.1,138.9,126.3,123.9,123.7,66.6,62.6,55.2,4 9.9,43.5,29.7,29.2,28.8,28.7,28.5,27.9,27.2,27.1,26.9,26.6,26.6,23.2,22.9,22.1.

[0112] compound 6 [ka] The diastereoisomeric ratio of the starting iminium salts ranges from 90 / 10 to 75 / 25 and is the same in the product.

[0113] Analytical data is obtained for the major diastereomer. 1 H NMR(400MHz,25℃,CDCl3):δ=7.25-7.19(m,2H),7.18-7.12(m,2H),7.09(m,3H),7.00(dd,J=7.5,2.0Hz,1H),3.67 (hept,J=6.9Hz,1H),3.21(dd,J=8.8,2.8Hz,1H),2.99(hept,J=6.8Hz,1H),2.79(q,J=7.3Hz,1H),2.50(dd,J=8.7 ,1.7Hz,1H),2.30-2.15(m,1H),2.05(dd,J=12.6,10.9Hz,1H),1.92-1.83(m,2H),1.81-1.71(m,2H),1.75-1.56(m ,1H),1.30(d,J=7.2Hz,3H),1.28-1.21(m,6H,overlapping signal),1.09(d,J=6.9Hz,3H),0.64(s,3H),0.63(d,J=6.8Hz,3H).

[0114] 13 C{ 11H NMR (100 MHz, 25 °C, CDCl3): δ = 151.8, 151.5, 143.9, 143.0, 129.4, 127.6, 126.2, 126.1, 124.1, 123.5, 55.7, 51.3, 47.9, 42.5, 38.7, 35.5, 31.2, 28.5, 27.6, 26.4, 25.7, 24.8, 24.6, 24.5, 23.6, 17.3, 14.1.

[0115] Compound 7

Chem.

[0116] 13 13C{ 1H}NMR (100MHz, 25℃, CDCl3): δ=152.3,151.9,151.2,150.8,150.1,146.2,146.0,14 0.1,138.8,128.5,128.3,127.8,127.6,126.7,126.7,126.6,126.1,126.0,125.9, 125.8,125.7,124.2,123.9,123.7,123.6,68.0,67.9,65.9,52.0,45.3,33.8,32.9,30.6,29.2,28.8,28.2,28.0,26.8,26.8,26.7,26.2,25.6,23.7,23.0,21.5,21.1.

[0117] Compound 8

change

[0118] 13 C{ 1H}NMR (100MHz, 25℃, CDCl3): δ=.2,151.0,150.5,150.2,150.2,149.9,140.6, 139.7,128.3,128.2,126.5,126.4,126.0,125.9,125.7,125.7,124.6,124.0, 123.7,123.5,66.9,66.8,58.1,57.0,49.1,46.8,45.9,45.3,31.8,30.5,27.9,27.8,27.5,27.4,25.6,25.5,24.8,24.7,24.2,24.2,23.9,23.6,22.3,20.5.

[0119] Compound 9

change

[0120] 13 C{ 1 H}NMR (100MHz, 25℃, CDCl3): δ=150.7,147.6,147.5,140.3,128.2,127.1,126.6,12 6.0,125.9,125.6,65.3,63.4,54.5,45.2,32.2,29.9,29.2,25.5,25.4,16.3,16.2.

[0121] Compound 10

change

[0122] 13 C{ 1 13C{1H} NMR (100 MHz, 25 °C, CDCl3): δ = 148.0, 147.7, 147.6, 140.5, 133.5, 131.9, 128.0, 128.0, 127.6, 127.2, 126.8, 126.2, 126.1, 125.6, 125.5, 123.8, 65.5, 63.6, 54.8, 45.5, 32.1, 29.9, 29.4, 25.7, 16.5.

[0123] Compound 11

Chem.

[0124] 13 C{ 1 1H}NMR (100 MHz, 25 °C, CDCl3): δ = 147.7, 147.4, 146.9, 140.6, 135.0, 131.6, 129.6, 127.4, 127.3, 126.8, 126.4, 126.2, 125.4, 125.2, 125.0, 123.8, 66.8, 63.0, 56.2, 46.2, 31.3, 30.0, 28.8, 25.7, 25.6, 16.4, 16.3.

[0125] Compound 12

Chem.

[0126] 13 C{ 1 H}NMR (100MHz, 25℃, CDCl3): δ=147.9,147.5,140.9,127.1,126.6,125.9,66.3,63.4,5 5.3,50.1,43.7,30.3,29.1,28.8,28.6,27.3,27.2,27.0,25.8,25.3,22.3,16.4,16.3.

[0127] Compound 13

change

[0128] 13 C{ 1 H}NMR (100MHz, 25℃, CDCl3): δ=147.7,147.4,146.5,140.7,137.2,130.4,126.9,126.8,1 26.0,65.6,63.6,54.8,48.2,41.7,33.8,29.6,29.3,27.5,25.6,25.5,24.2,16.4,16.4.

[0129] Compound 14

change

[0130] 13 C{ 1 H}NMR(100MHz,25℃,CDCl3):δ=150.9,141.3,140.9,139.6,135.0,130.2,129.7, 128.3,126.1,125.7,64.1,63.9,54.6,45.0,32.3,30.1,29.5,21.1,20.9,20.9.

[0131] compound 15 [ka] The diastereoisomeric ratio of the starting iminium salt is 1 / 1, but the product is obtained as a 4 / 1 mixture.

[0132] Analytical data is obtained for the major diastereomer. 1 H NMR (400MHz, 25℃, CDCl3): δ=7.48-7.41(m,2H),7.40-7.33(m,3H),7.32-7.26(m,2H),7.26-7.20(m,3H),7.04(s,1H),7.02(s,1H),4.25(d,J=8. 3Hz,1H),3.55(d,J=8.3Hz,1H),2.37(s,3H),2.35(s,3H),2.30(d,J=12. 6Hz, 1H), 1.97 (d, J=12.6Hz, 1H), 1.45 (s, 3H), 1.00 (s, 3H), 0.60 (s, 3H).

[0133] 13 C{ 1H}NMR (100MHz, 25℃, CDCl3): δ=151.5,146.2,144.1,140.9,138.5,135.0,132.2,130.4,130. 3,128.4,127.5,126.3,125.9,125.7,65.1,64.4,54.1,45.09,32.4,30.5,28,5,21.7,20.9.

[0134] Chiral resolution: analytical chiral HPLC separation data (corresponding to step b) of the process according to the invention for the preparation of the compound of formula (IV) according to the invention) Analytical chiral HPLC separation of compound 1 [ka] The sample is dissolved in hexane and injected into the chiral column, and detected with a UV detector at 220 nm and a circular dichroism detector at 254 nm at a flow rate of 1 mL / min. [Table 1] [Table 2]

[0135] Semi-preparative isolation of compound 1: Sample preparation: Approximately 160 mg of compound 1 is dissolved in 1.8 mL of hexane.

[0136] Chromatographic conditions: Lux-Cellulose-4 (250 × 10 mm), hexane as mobile phase, flow rate = 5 mL / min, UV detection at 254 nm.

[0137] Injections (stack): 45 injections of 40 μL, every 2.8 min.

[0138] First fraction: 72 mg (45% yield) of the first eluted enantiomer with ee>99.5%. [Table 3]

[0139] Second fraction: 72 mg (45% yield) of the second eluted enantiomer with ee>96%. [Table 4]

[0140] Middle fraction: 12mg optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578 and 546 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 5]

[0141] Preparative isolation of compound 1: Sample preparation: Approximately 2.54 g of compound 2 is dissolved in 30 mL of hexane.

[0142] Chromatographic conditions: Lux-CelluloseCellulose-2 (250 × 10 mm), thermostated in an oven at 30 °C, hexane / 2-PrOH (99.9 / 0.1) as mobile phase, flow rate = 5 mL / min, UV detection at 254 nm. Injections (stack): 600 50 mL injections, 1.5 min each, collecting 2 fractions.

[0143] The first fraction (er98 / 2) was dissolved in 16 mL of hexane and purified again. Injection (stack): 64 250 mL injections, 2.5 min each, giving 1.09 g of the first eluted enantiomer ((+)-(R)-compound 1) with ee>99.5%. [Table 6] The second fraction (er7 / 93) was dissolved in 14 mL of hexane and purified again. Injection (stack): 700 20 mL injections, 1.5 min each, giving 1.22 g of the second eluted enantiomer ((-)-(S)-compound 1) with ee>98.5%. [Table 7]

[0144] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder.

[0145] The structures of (+)-(R)-Compound 1 (from the first fraction) and (-)-(S)-Compound 1 (from the second fraction) were determined by single crystal X-ray diffraction.

[0146] Analytical chiral HPLC separation of compound 2 [ka] The sample is dissolved in ethanol and injected onto the chiral column and detected at 254 nm using a UV detector at a flow rate of 0.5 mL / min. [Table 8] [Table 9]

[0147] Preparative separation of compound 2 Sample preparation: Approximately 360 mg of compound 2 is dissolved in 150 mL of ethanol.

[0148] Chromatographic conditions: Lux-Cellulose-3 (250 × 10 mm), ethanol as mobile phase, flow rate = 2 mL / min, UV detection at 310 nm.

[0149] Injections (stack): 185 injections of 800 μL, every 8 min.

[0150] First fraction: 160 mg of first eluted enantiomer ((+)-R-compound 2) with ee>99%, 44% yield. [Table 10] Second fraction: 160 mg of second eluted enantiomer ((-)-S-compound 2) with ee>99%, 44% yield. [Table 11] Impurities: 12mg

[0151] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 12]

[0152] Analytical chiral HPLC separation of compound 3 [ka] The sample is dissolved in ethanol and injected onto the chiral column and detected at 254 nm using a UV detector at a flow rate of 0.5 mL / min. [Table 13] [Table 14]

[0153] Preparative separation of compound 3 Sample preparation: Approximately 320 mg of compound 3 is dissolved in 15 mL of ethanol.

[0154] Chromatographic conditions: Lux-Cellulose-3 (250 × 10 mm), ethanol as mobile phase, flow rate = 2 mL / min, UV detection at 310 nm.

[0155] Injections (stack): 60 injections of 250 μL, every 6 min.

[0156] After collection and evaporation of the first intermediate fraction: 28 times 250 μL, 5 min each.

[0157] After evaporation of the second intermediate fraction: 20 times 250 μL, 5 min each. First fraction: 152 mg of first eluted enantiomer ((-)-S-compound 3) with ee>99%, 48% yield. [Table 15] Second fraction: 152 mg of second eluted enantiomer ((+)-R-compound 3) with ee>98.5%, yield 48%. [Table 16] Impurities: 15mg

[0158] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 17]

[0159] Analytical chiral HPLC separation of compound 4 [ka] The sample is dissolved in ethanol and injected onto the chiral column and detected with a UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow rate is 1 mL / min. [Table 18] [Table 19]

[0160] Semi-preparative isolation of compound 4: Sample preparation: Approximately 234 mg of compound 4 is dissolved in 3.6 mL of hexane.

[0161] Chromatography: Lux-Cellulose-2 (250 × 10 mm), hexane / 2-PrOH 99.9 / 0.1 as mobile phase, flow rate = 5 mL / min, 30 °C, UV detection at 290 nm.

[0162] Injections (stack): 90 injections of 40 μL, every 2.4 min.

[0163] First fraction: 108 mg of the first eluted enantiomer ((+)-(R)-compound 4) with ee>99.5%. [Table 20] The second fraction (127 mg, er7 / 93) was dissolved in 2 mL of hexane and purified again: Injection (stack): 50 40 μL injections, 2.4 min each, giving 106 mg of the second eluted enantiomer ((-)-(S)-compound 4) with ee>98%. [Table 21]

[0164] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 22]

[0165] Analytical chiral HPLC separation of compound 6 [ka] Analytical chiral HPLC separation of compound 6 The sample was dissolved in heptane / 2-PrOH and injected onto a chiral column Lux-Cellulose-2, and detected with a UV detector at 230 nm and a circular dichroism detector at 254 nm at a flow rate of 1 mL / min. [Table 23]

[0166] Preparative separation of compound 6 Sample preparation: Approximately 100 mg of compound 6 is dissolved in 10 mL of hexane.

[0167] Chromatographic conditions: Lux-Cellulose-2 (250 × 10 mm), hexane / 2-PrOH (99.9 / 0.1) as mobile phase, flow rate = 5 mL / min, UV detection at 290 nm.

[0168] Injection (stack): 200 x 50L, every 5 minutes.

[0169] First fraction: ee>99.5% and 25 mg ("main" 1) [Table 24] Second fraction: 14 mg (the "smaller" fraction) [Table 25] Third fraction: ee>99.5% and 28 mg ("main" 2). [Table 26] Intermediate fraction: 17mg

[0170] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 27]

[0171] Analytical chiral HPLC separation of compound 9 [ka] The sample is dissolved in ethanol and injected onto the chiral column and detected with a UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow rate is 0.5 mL / min. [Table 28] [Table 29]

[0172] Semi-preparative isolation of compound 9: Sample preparation: Approximately 160 mg of compound 9 is dissolved in 2 mL of ethanol.

[0173] Chromatographic conditions: Lux-Cellulose-3 (250 × 10 mm), ethanol as mobile phase, flow rate = 2 mL / min, UV detection at 254 nm.

[0174] Injections (stack): 25 80 μL injections, every 4 min.

[0175] First fraction: 69 mg (43% yield) of the first eluted enantiomer ((+)-(R)-compound 9) with ee>99.5%. [Table 30] Second fraction: 76 mg (48% yield) of the second eluted enantiomer ((-)-(S)-compound 9) with ee>97%. [Table 31] Middle fraction: 14mg

[0176] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 32]

[0177] Analytical chiral HPLC separation of compound 13 [ka] The sample is dissolved in ethanol and injected into the chiral column Lux-3 and detected at 254 nm using a UV detector. The flow rate is 0.5 mL / min. [Table 33]

[0178] Preparative isolation of compound 13 Sample preparation: Approximately 182 mg of compound 13 is dissolved in 7 mL of ethanol.

[0179] Chromatographic conditions: Lux-Cellulose-3 (250 × 10 mm), methanol as mobile phase, flow rate = 3 mL / min, UV detection at 254 nm.

[0180] Injection (stack): 35 200L injections, every 8 minutes.

[0181] First fraction: 83 mg of first eluted enantiomer with ee>99.5% [Table 34] Second fraction: 81 mg of second eluted enantiomer with ee>99.5% [Table 35] Intermediate fraction: 11mg

[0182] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 36]

[0183] Analytical chiral HPLC separation of compound 14 [ka] The sample is dissolved in heptane / 2-PrOH and injected onto a chiral column Lux-Cellulose-2, and detected by a UV detector at 230 nm and a polarimetric detector. The flow rate is 1 mL / min. [Table 37]

[0184] Preparative isolation of compound 14 Sample preparation: Approximately 127 mg of compound 14 is dissolved in 8 mL of hexane. Chromatographic conditions: Lux-Cellulose-2 (250 × 10 mm), hexane / 2-PrOH (99.9 / 0.1) as mobile phase, flow rate = 5 mL / min, UV detection at 290 nm.

[0185] Injections (stack): 45 injections of 180 μL, every 5.25 min.

[0186] First fraction: 54 mg with ee>99.5% [Table 38] Second fraction: ee>99.5% and 53 mg [Table 39]

[0187] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 40]

[0188] Analytical chiral HPLC separation of compound 15 [ka] The sample is dissolved in heptane / 2-PrOH and injected onto a chiral column Lux-Cellulose-2, and detected by a UV detector at 230 nm and a polarimetric detector. The flow rate is 1 mL / min. [Table 41]

[0189] Preparative isolation of compound 15 Sample preparation: Approximately 80 mg of compound 15 is dissolved in 10 mL of hexane.

[0190] Chromatographic conditions: Lux-Cellulose-2 (250 × 10 mm), hexane / 2-PrOH (99.9 / 0.1) as mobile phase, flow rate = 5 mL / min, UV detection at 290 nm.

[0191] Injection (stack): 67 150L injections, every 9 minutes.

[0192] First fraction: ee>99.5% and 38 mg [Table 42] Second fraction: ee>99.5% and 41 mg [Table 43]

[0193] optical rotation Optical rotations were measured on a Jasco P-2000 polarimeter equipped with halogen lamps (589, 578, 546, 436, 405 and 365 nm) in a 10 cm cell thermostated at 25° C. using a Peltier controlled cell holder. [Table 44]

[0194] Oxidation of the CAAC-H2 adduct to obtain the CAAC-BF4 iminium salt (corresponding to step c) of the process according to the invention for the preparation of the compound of formula (I) according to the invention) General procedure: In a Schlenk tube under argon, the enantiomerically pure CAAC-H2 adduct was dissolved in dry DCM. The resulting solution was then cooled to 0° C. in an ice bath and bromine (3 equiv.) was added dropwise. The reaction mixture was then allowed to reach room temperature and stirred overnight. An aqueous solution of KBF4 (6 equiv.) and Na2S2O3 (3 equiv.) was then added and the resulting biphasic mixture was stirred for 1 h. The phases were then separated and the aqueous phase was further washed with additional DCM. The combined organic phase was dried over anhydrous MgSO4 and filtered. The remaining solution was then reduced to approximately 5 mL and excess Et2O was added to cause the precipitation of a white solid. After filtration and thorough washing of the precipitate with Et2O and pentane, the cyclic iminium salt BF4 was obtained as a white solid in a typical yield of 85%.

[0195] The structure of a compound that was isolated and analyzed by NMR, where examination of a single crystal by X-ray diffraction allowed the determination of the absolute configuration.

[0196] compound 16 [ka] (-)-(R)-Compound 16 (obtained from (+)-(R)-Compound 1) and its enantiomer (+)-(S)-Compound 16 (obtained from (-)-(S)-Compound 1) have identical spectra. 11H NMR (500 MHz, 25 °C, CD3CN): δ: 9.26 (s, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 3.10 (d, J = 14.0 Hz, 1H), 2.82 (d, J = 14.0 Hz, 1H), 2.79 (sept, J = 7.0 Hz, 1H), 2.55 (sept, J = 7.0 Hz, 1H), 1.93 (s, 3H), 1.58 (s, 3H), 1.40 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H).

[0197] 13 13C NMR (125 MHz, CD3CN): δ: 189.8, 145.7, 145.4, 142.0, 133.2, 130.8, 130.0, 129.6, 126.7, 126.6, 126.6, 85.3, 55.7, 48.6, 29.9, 29.7, 27.2, 26.8, 26.8, 25.6, 25.5, 21.5, 21.4.

[0198] 11 11B NMR (128 MHz, CDCl3): δ: -0.98.

[0199] 19 19F NMR (376 MHz, CDCl3): δ: -151.0 (minor), 151.1. The compound has opposite [α] D = (-)-(R)-Compound 16 (T = 25 °C, c = 0.110 g / mL, L = 10 cm, CHCl3) = -22.0 (+)-(S)-Compound 16 (T = 25 °C, c = 0.110 g / mL, L = 10 cm, CHCl3) = +22.1 and has.

[0200] Compound 17

Chemical Structure

[0201] 1 H NMR(300MHz,CD3CN)δ:(ppm)9.72(s,1H),8.06(dJ=8.1Hz,1H),7.89-7.97(m,3H),7.58-7.6 6(m,4H),7.51(dJ=8.1Hz,1HHz),7.47(dJ=8.1Hz,1H),3.22(dJ=14.1Hz,1H),2.88(dJ=14.1 Hz,1H),2.83(septJ=6.6Hz,1H),2.60(septJ=6.6Hz,1H),2.01(s,3H),1.60(s,3H),1.41(d J=6.6Hz,3H),1.40(s,3H),1.21(dJ=6.6Hz,3H),1.19(dJ=6.6Hz,3H),1.15(dJ=6.6Hz,3H). 13 C NMR(125MHz,CD3CN)δ:190.4,145.7,145.4,139.7,134.2,133.7,133.1,130.8,130.1,128.9,128.7,128.2 ,128.1,126.7,126.5,125.6,124.4,85.3,55.9,48.5,29.9,29.7,27.4,26.9,26.9,25.7,25.6,21.6,21.5.

[0202] 11 B NMR(128MHz, CDCl3)δ:-0.91.

[0203] 19 F NMR (376MHz, CDCl3): δ: -150.9 (small), -151.0.

[0204] The compound has the opposite [α] D = (-)-(S)-Compound 16 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=-239.2 (+)-(R)-Compound 16 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=+241.8 has.

[0205] compound 18 [ka] (+)-(R)-Compound 18 (obtained from (+)-(R)-Compound 3) and its enantiomer (-)-(S)-Compound 18 (obtained from (-)-(S)-Compound 3) have identical spectra. 1 H NMR(400MHz,CDCl3)δ:9.89(s,1H),8.03(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.80(d,J=8.0Hz ,1H),7.61(t,J=7.5Hz,1H),7.52-7.55(m,2H),7.33-7.38(m,4H),3.30(d,J=14.0Hz,1H),3.19(d, J=14.0Hz,1H),2.70(sept,J=6.5Hz,1H),2.69(sept,J=6.5Hz,1H),2.15(s,3H),1.54(s,3H),1.37 (d,J=6.5Hz,3H),1.31(d,J=6.5Hz,3H),1.25(s,3H),1.23(d,J=6.5Hz,3H),1.20(d,J=6.5Hz,3H).

[0206] 13 C NMR(125MHz,CDCl3)δ:191.6,145.3,144.3,138.3,135.8,132.6,130.5,130.1,129.3,129.3,127.2,126.6 ,126.0,126.0,125.6,124.8,123.5,84.0,55.8,50.0,30.0,29.4,28.1,26.9,26.9,25.9,25.6,22.3,22.0.

[0207] 11 B NMR(128MHz, CDCl3)δ:-0.91.

[0208] 19F NMR (376MHz, CDCl3)δ:ppm) -150.9 (small), -151.0.

[0209] The compound has the opposite [α] D = (-)-(S)-Compound 18 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=-21.3 (+)-(R)-Compound 18 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=+22.2 has.

[0210] compound 19 [ka] (-)-(R)-Compound 19 (obtained from (+)-(R)-Compound 4) and its enantiomer (+)-(S)-Compound 19 (obtained from (-)-(S)-Compound 4) have identical spectra. 1 H NMR(500MHz,CDCl3)δ:9.59(s,1H),7.51(t,J=7.5Hz,1H),7.34(d,J=7.5Hz,1H),7.29(d,J=7 .5Hz,1H),7.06(s,2H),6.97(s,1H),3.16(d,J=14.0Hz,1H),2.67(sept,J=6.5Hz,1H),2.66( d,J=14.0Hz,1H),2.39(sept,J=6.5Hz,1H),2.31(s,6H),1.87(s,3H),1.52(s,3H),1.35(d,J =6.5Hz,3H),1.31(s,3H),1.18(d,J=6.5Hz,3H),1.16(d,J=6.5Hz,3H),1.12(d,J=6.5Hz,3H).

[0211] 13 C NMR(125MHz,CDCl3)δ:191.0,145.2,144.6,141.2,140.1,132.4,130.5,129.3,125.8 ,123.6,83.6,55.3,48.5,30.0,29.1,28.7,27.0,26.4,25.9,25.7,22.2,21.9,21.2.

[0212] 11 B NMR(128MHz, CDCl3)δ:-0.99.

[0213] 19 F NMR (376MHz, CDCl3): δ: (ppm) -151.2 (small), -151.3.

[0214] The compound has the opposite [α] D = (-)-(S)-Compound 19 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=-71.4 (+)-(R)-Compound 19 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=+71.5 has.

[0215] compound 20 [ka] (-)-(R)-Compound 20 (obtained from (+)-(R)-Compound 9) and its enantiomer (+)-(S)-Compound 20 (obtained from (-)-(S)-Compound 9) have identical spectra. 1 1H NMR(500MHz,CDCl3)δ:9.55(s,1H),7.47(tJ=7.5Hz,2H),7.44(dJ=7.5Hz,2H),7.42(dJ=7 .5Hz,1H),7.33(tJ=7.5Hz,1H),7.31(dJ=7.5Hz,1H),7.24(dJ=7.5Hz,1H),3.16(dJ=14.0 Hz,1H),2.67(dJ=14.0Hz,1H),2.55(qJ=7.5Hz,2H),2.33(dtJ=7.5Hz,1H),2.16(dtJ=7.5 Hz,1H), 1.91(s,3H), 1.52(s,3H), 1.31(s,3H), 1.26(tJ=7.5Hz,3H),1.09(tJ=7.5Hz,3H).

[0216] 13C NMR(125MHz,CDCl3)δ:190.5,141.0,140.2,139.7,131.8,131.0,130.3,128.9, 128.3,128.1,126.0,83.8,55.5,48.3,28.9,26.9,26.6,24.8,24.6,15.3,14.5.

[0217] 11 B NMR(128MHz, CDCl3)δ:-0.98.

[0218] 19 F NMR (376MHz, CDCl3): δ: -151.0 (small), -151.1. The compound has the opposite [α] D = (-)-(S)-Compound 20 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=-59.7 (+)-(R)-Compound 20 (T=25℃, c=0.110g / mL, L=10cm, CHCl3)=+60.3 has. The structures of (+)-(R)-Compound 16, (+)-S-Compound 16, (-)-(R)-Compound 17, (+)-S-Compound 18, (-)-R-Compound 18, (-)-(R)-Compound 19, and (-)-(R)-Compound 20 were determined by single crystal X-ray diffraction.

[0219] Structures of compounds isolated and analyzed by NMR, with enantiomers assigned as (+) or (-) based on the sign of their optical rotation.

[0220] compound 21 [ka] (+)-Compound 21 and (−)-Compound 21 were obtained from (+) or (−)-Compound 6. 1H NMR (400MHz, 25℃, アセトン-d6): δ=8.82(s,1H),7.48(t,J=7.8Hz,1H),7.42-7.29(m,5H),7.27-7. 22(m,1H),7.18(dd,J=7.8,1.5Hz,1H),3.77(q,J=7.2Hz,1H),3.47(q,J=7.0Hz,1H),2.93-2.7 9(m,2H),2.72(m,1H),2.67-2.60(m,1H),2.51-2.40(m,1H),1.76-1.58(m,5H),1.47(d,J=7.2 Hz,3H),1.38(d,J=6.8Hz,3H),1.24(d,J=6.7Hz,3H),1.22-1.18(m,7H),0.34(d,J=6.8Hz,3H).

[0221] 13 C{ 1 H}NMR (100MHz, 25℃, アセトン-d6): δ=190.6,143.7,143.5,141.0,135.7,132.1,129.7,129.3,128.0,125.7,125. 7,70.5,66.0,51.9,44.0,39.0,35.9,33.0,30.2,28.9,25.6,25.4,24.1,23.4,22.6,21.7,20.5,15.4,13.5.

[0222] 11 B NMR (128MHz, CDCl3) δ: -0.90.

[0223] 19 F NMR (376MHz, CDCl3): δ: -152.7 (small), -152.8. (-)-Compound 21 (T=25°C, c=0.101g / mL, L=10cm, アセトニトリル)=-87.4. (+)-Compound 21 (T = 25° C., c = 0.103 g / mL, L = 10 cm, アセトニトリル) = +87.1.

[0224] Compound 22

change

[0225] 1 1H NMR (400MHz, 25℃, CDCl3): δ=9.38(s,1H),7.45(t,J=7.7Hz,1H),7.35-7.29(m,3H),7.27-7 .21(m,3H),3.75(d,J=14.0Hz,1H),2.93(sept,J=6.9Hz,1H),2.86(d,J=14.0Hz,1H),2.72( d,J=13.7Hz,1H),2.51(q,J=7.5Hz,2H),2.27(d,J=13.7Hz,1H),1.89-1.78(m,5H),1.45(s, 3H),1.32(d,J=7.4Hz,3H),1.26(dd,J=6.9,1.8Hz,6H),1.11(t,J=7.5Hz,3H),0.98(s,3H).

[0226] 13 C{ 1 H}NMR (100MHz, 25℃, CDCl3): δ=192.5,148.4,139.8,139.4,133.4,131.2,130.5,130.4(2C),127.6( 2C),127.2(2C),83.0,54.5,44.4,43.6,33.8,28.1,27.9,27.4,24.7,24.4,24.0,24.0,15.3,14.9.

[0227] 11 B NMR (128MHz, CDCl3) δ: -0.89.

[0228] 19 F NMR (376MHz, CDCl3): δ: -151.1 (small), 151.2.

[0229] (-)-Compound 22 (T=25°C, c=0.120 g / mL, L=10 cm, CHCl3)=-65.7. (+)-Compound 22 (T=25°C, c=0.110 g / mL, L=10 cm, CHCl3)=+64.8.

[0230] Compound 23 [ka] (+)-Compound 23 and (−)-Compound 23 were obtained from (+) or (−)-Compound 14.

[0231] 1 H NMR (400MHz, 25℃, acetone-d6): δ=9.71(s,1H),7.65(m,2H),7.50(m,2H),7.44-7.35(m,1H),7.18(s,1H),7.14(s,1H),3.23(d,J =13.9Hz,1H),2.94(d,J=14.1Hz,1H),2.37(s,3H),2.31(s,3H),2.17(s,3H),2.01(s,3H,overlapping with acetone),1.70(s,3H),1.52(s,3H).

[0232] 13 C{ 1 H}NMR (100 MHz, 25 °C, acetone-d6): δ = 190.8, 142.4, 134.8, 134.4, 131.2, 131.1, 130.5, 129.1, 126.7, 85.6, 56.1, 49.1, 28.6, 27.7, 27.4, 20.7, 19.4.

[0233] 11 B NMR (128 MHz, acetone-d6) δ: −0.93.

[0234] 19 F NMR (376 MHz, acetone-d6) δ: -151.2 (small), -151.3. (-)-Compound 23 (T = 25 °C, c = 0.120 g / mL, L = 10 cm, acetonitrile) = -67.5. (+)-Compound 23 (T = 25 °C, c = 0.122 g / mL, L = 10 cm, acetonitrile) = +68.3.

[0235] compound 24 [ka] (+)-Compound 24 and (−)-Compound 24 were obtained from (+) or (−)-Compound 15.

[0236] The diastereomeric ratio of the starting amines is 4 / 1 and the iminium salts are obtained in the same ratio. 1 H NMR (400 MHz, 25 °C, CDCl3): δ = 9.85 (s, 1H), 7.53 (m, 2H), 7.47-7.28 (m, 7H), 7.20-6.95 (m, 3H), 2.96 (d, J = 13.9 Hz, 1H), 2.36 (s, 3H), 2.09 (s, 3H), 2.06 (d, J = 13.9 Hz, 1H), 1.76 (s, 3H), 1.23 (s, 3H), 0.81 (s, 3H) (analytical data is shown for the major isomer, the aromatic region is difficult to identify due to overlapping signals of the two diastereomers).

[0237] 13 C{ 1 H}NMR (100MHz, 25℃, acetone-d6): δ = 191.5, 191.4, 142.7, 142.6, 141.9, 141.2, 139.4, 139.3, 139.1, 138.7, 135.7, 135.5, 132.9, 132.9, 131.9, 131.8, 131.1, 130.7, 130.7, 1 30.6, 130.1, 129.7, 129.4, 129.4, 127.3, 126.9, 85.9, 85.7, 56.3, 56.1, 49.3, 48.8, 29.0, 28.7, 27.9, 27.6, 27.3, 27.1, 21.0, 19.5, 19.5 (analytical data obtained for the mixture of diastereomers). 11 B NMR (128 MHz, acetone-d6) δ: −0.89. 19 F NMR (376 MHz, acetone-d6): δ: -151.2 (small), -151.3. (-)-Compound 24 (T = 25 °C, c = 0.141 g / mL, L = 10 cm, acetonitrile) = -40.1. (+)-Compound 24 (T = 25 °C, c = 0.136 g / mL, L = 10 cm, acetonitrile) = +39.3.

[0238] Complexation of CAAC iminium salts to demonstrate ee preservation. [ka] Procedure for (-)-(S)-Ru complex: In a glove box, (+)-(S)-compound 19 (2.5 equiv.) was dissolved in dry degassed toluene (0.5 mL). KHMDS (0.5 M in toluene, 2.5 equiv.) was added. The mixture was stirred at 40° C. for 1 min. Then M10 catalyst (1 equiv.) and toluene (0.5 mL) were added. The mixture was stirred at 40° C. for 5 min. CuCl (4.5 equiv.), styrenyl ether (1.6 equiv.) and toluene (0.5 mL) were added. The mixture was removed from the box and stirred at 80° C. for 30 min. The volatiles were removed under vacuum and the product was purified by column chromatography (eluent: toluene). The green fraction was washed with pentane.

[0239] The desired complex is obtained as a green solid (61% yield) as a mixture of rotamers (in CDCl3 1 Ratio determined by 1 H NMR: 76:24). [ka]

[0240] 1 H NMR(400MHz,,CDCl3):δ17.78(s,0.23H),16.45(s,0.77H),8.45(d,J=9.1Hz ,1H),8.23(s,1H),7.75-7.38(m,8H),6.98(d,J=9.0Hz,1H),5.15-4.97(m,1H ),3.30-3.07(m,1H),2.86-2.64(m,2H),2.63-2.48(m,2H),2.48-2.24(m,4H) ,1.69-1.50(m,6H),1.50-1.28(m,8H),1.19-1.01(m,3H),0.98-0.74(m,3H).

[0241] 13C NMR(101MHz,CDCl3):δ:295.1,260.6,156.5,143.5,143.2,142.6,138.2,132.1,129.5,129.4,128.7,128.6 ,127.6,127.4,127.1,125.4,118.2,113.2,78.4,63.2,48.4,31.1,29.7,27.6,25.6,24.2,22.2,14.8,14.3.

[0242] [α D ] = (-)-(S)-ruthenium complex (T = 25 °C, c = 0.110 g / mL, L = 10 cm, CH2Cl2) = -565.

[0243] The analytical data for this compound were consistent with previously reported data.

[0244] Chiral HPLC for the Analysis of (-)-(S)-Ru Complexes The sample is dissolved in dichloromethane and injected onto a chiral column Chiralpak IE and detected with a UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow rate is 1 mL / min, heptane / ethanol / dichloromethane (60 / 20 / 20). ee decision: 98%. [Table 45] [ka]

[0245] Procedure for preparation of Au and Cu complexes: In a glove box, a 100 mL Schlenk tube equipped with a magnetic stir bar and a septum was charged with (+)-(R)-compound 14 (100.0 mg, 0.23 mmol, 1.0 equiv.), copper(I) chloride (25.0 mg, 0.25 mmol, 1.1 equiv.) and sodium acetate (56.5 mg, 0.69 mmol, 3.0 equiv.). Toluene (11 mL) was added and the reaction vessel was taken out of the glove box. The septum was then replaced with a glass stopcock using a metal clipper and the reaction mixture was stirred overnight at 110 °C in a closed system. After cooling to room temperature, the suspension was exposed to air and filtered through a silica gel column and washed with dichloromethane. The pure (+)-(R)-copper complex (86.7 mg, 0.2 mmol) was obtained as a white powder (isolated mass = 86.7 mg, yield = 87%). 1 H NMR(400MHz,CDCl3)δ:7.57-7.46(m,2H),7.46-7.31(m,3H),7.31-7.19(m,3H),2.86(m 2H), 2.58(d,J=13.4Hz,1H),2.32(d,J=13.4Hz,1H),1.82(s,3H),1.38-1.30(m,12H),1.26(d,J=6.7Hz,3H),1.21(s,3H).

[0246] 13 C NMR (101 MHz, CDCl3): δ: 13 C NMR(101MHz,CDCl3)δ246.8,145.9,145.1,144.8,134.5,129.9,129.0,127.2,126 .3,124.9,124.9,81.2,60.9,51.4,29.2,29.2,28.2,28.1,27.2,27.2,22.5,22.4.

[0247] [α D ]=(+)-(R)-copper complex (T=25℃, c=0.110g / mL, L=10cm, CH2Cl2)=+20.

[0248] Chiral HPLC for the Analysis of Cu Complexes ee determination: the sample is dissolved in dichloromethane and injected into a chiral column Chiralpak IG, and detected by UV detector at 254 nm and circular dichroism detector at 254 nm. The flow rate is 1 mL / min, heptane / isopropanol / dichloromethane (80 / 10 / 10), 1 mL / min. ee>99.5%. [Table 46] In a glove box, a Schlenk was charged with (R)-copper complex (23.6 mg, 0.055 mmol, 1.0 equiv), [(SMe2)AuCl] (24.2 mg, 0.082 mmol, 1.5 equiv), and THF (0.5 mL). The mixture was then heated at 40° C. for 4 h. The solvent was removed under reduced pressure and the crude was purified by column chromatography (dichloromethane). The resulting solid was filtered through packed Celite to remove the nanoparticles. The (R)-gold complex (19.9 mg, 0.035 mmol) was obtained as a white solid (19.9 mg, 64% yield).

[0249] 1 1H NMR(400MHzCD2Cl2)δ:7.59-7.53(m,2H),7.51(dJ=7.7Hz,1H),7.48-7.39(m,2H ),7.39-7.29(m,3H),2.96(heptJ=6.8Hz,1H),2.84(heptJ=6.7Hz,1H),2.65(dJ= 13.4Hz,1H),2.45(dJ=13.4Hz,1H),1.92(s,3H),1.46(dJ=2.4Hz,3H),1.45(dJ= 2.4Hz, 3H), 1.42 (s, 3H), 1.36 (dJ=6.7Hz, 3H), 1.33 (dJ=6.8Hz, 3H), 1.29 (s, 3H).

[0250] 13 C NMR(101MHz,CD2Cl2)δ:234.6,145.8,145.6,145.3,134.7,130.5,129.3,127.7,126.9 ,125.6,125.4,81.1,61.4,52.4,29.8,29.6,28.9,28.6,28.5,27.1,26.9,23.1,22.8.

[0251] [α D ] = (+)-(R)-gold complex (T = 25 °C, c = 0.153 g / mL, L = 10 cm, acetonitrile) = +24. Preliminary photophysical and chiral-optical characterization of the copper complexes of high enantiomeric purity ((R) and (S), solid blue and red lines, respectively, mean g lum Value 10 -3 The unpolarized (black solid line) and circularly polarized (CPL) emission of 100 nm of 10-150 nm fluorescein was measured using a CPL spectrofluorometer. Samples were excited with a xenon ozone-free lamp 150W LS using a 90° geometry. The following parameters were used: emission slit width ≈ 2 mm, integration time = 4 s, scan speed = 50 nm / min, accumulation = 5. All samples had a concentration of approximately 10 -5 The excitation of the sample was at 320 nm. The corresponding results are shown in Figures 1 and 2.

[0252] Chiral HPLC for the Analysis of Au Complexes ee determination: the sample is dissolved in dichloromethane and injected into a chiral column Chiralpak IG, detected by UV detector at 254 nm and circular dichroism detector at 254 nm. The flow rate is 1 mL / min, heptane / isopropanol / dichloromethane (80 / 10 / 10), 1 mL / min. ee>98%. [Table 47] [ka]

[0253] Procedure for (+)-(S)-Rh complex: [Rh(COD)Cl]2 (36.3 mg, 0.074 mmol, 0.5 equiv), (-)-(S)-compound 14 (75 mg, 0.172 mmol, 1.2 equiv) and KHMDS (39.2 mg, 0.197 mmol, 1.3 equiv) were added to a Schlenk tube in a glove box. Removed from the box under Ar atmosphere, dry and degassed THF (3 mL) was added dropwise to the solid at -78 °C over 10 min. The suspension was stirred at -78 °C for 10 min, after which the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 16 h, the volatiles were removed under vacuum. The product was purified by column chromatography (pentane / diethyl ether = 9:1) to give a yellow-orange solid of the (+)-(S)-Rh complex (44.9 mg, 51% yield). 1 H NMR(400MHz, CDCl3):7.99(d,J=7.3Hz,2H),7.41(dt,J=17.2,7.6Hz,4H),7.29(d,J=7.2Hz,1H),7.11(d d,J=7.5,1.8Hz,1H),5.32(m,1H),4.52(m,1H),3.87(m,1H),2.86(d,J=13.3Hz,1H),2.65(m,2H),2.51-2 .40(m,1H),2.38(s,3H),2.07(d,J=13.2Hz,1H),1.91(m,1H),1.75(d,J=6.4Hz,3H),1.66(s,3H),1.66-1 .49(m,3H),1.48-1.38(m,2H),1.35(s,3H),1.29(2 pairs of d overlap,6H),1.24-1.07(m,2H),0.72(d,J=6.7Hz,3H).

[0254] 13C NMR(101MHz,CDCl3):269.23(d,J=46.7Hz),147.98,146.11,145.89,136.57, 129.00,128.50,128.11,126.59,126.53,124.15,101.81(d,J=5.8Hz),98.00( d,J=6.4Hz),78.67,78.65,72.11(d,J=14.6Hz),66.37(d,J=14.0Hz),49.03, 35.16,33.29,31.28,30.16,28.84,28.58,28.56,26.27,25.52,25.28,24.58.

[0255] [α] D =(+)-(S)-Rhodium complex (T=25°C, c=0.110g / mL, L=10cm, CH2Cl2) = +5

[0256] Chiral HPLC for the Analysis of Rh Complexes ee determination: the sample is dissolved in dichloromethane and injected into a chiral column Chiralpak IB N-5, and detected by UV detector at 254 nm and circular dichroism detector at 254 nm. The flow rate is 1 mL / min. ee>99%. [Table 48]

Claims

1. A method for preparing an optically pure (+) or (−) enantiomer of an iminium salt having the following formula (I), 【Chemical 1】 wherein, R １ is a (C ６ -C １４ ) aryl group, a (C １ -C ６ ) alkyl group or a (C ８ -C ２０ ) cycloalkyl group, wherein the aryl group is optionally substituted with at least one substituent selected from the group consisting of halogen, a (C ６ -C １０ ) aryl group and a (C １ -C ６ ) alkyl group, and the alkyl group is optionally substituted with one or more phenyl groups; or R １ is -NR' ａ R' ｂ is a group, R' ａ and R' ｂ are independently of each other, H, (C １ -C ６ )alkyl and (C ６ -C １０ )aryl, or R ’ ａ and R ’ ｂ together with the nitrogen atom carrying them form an N(CH ２ ) ２＋ｍ heterocyclic ring, and m is 0 or an integer from 1 to 6; R ２ is H, (C ６ -C １０ -aryl group or (C １ -C ６ -alkyl group; R ３ is an (C １ -C ６ )alkyl group; or, R ２ and R ３ together with the carbon atoms carrying them, may form a (C ３ -C ６ )cycloalkyl; R ５ is selected from the following groups: (C ６ -C ２０ )aryl, (C １ -C １０ )alkyl and (C ３ -C １２ )cycloalkyl groups, The alkyl group is optionally substituted with at least one substituent selected from (C ６ -C １０ ) aryl groups, The aryl group is optionally substituted with one or more phenyl groups (C １ -C ６ ), alkyl, (C ６ -C １０ ), aryl (C １ -C ６ ), alkyl, and in particular (C １ -C ６ ), alkylamino, di(C １ -C ６ ), alkylamino, (C １ -C ６ ), alkoxy, and (C １ -C ６ ), alkyl, and is optionally substituted with one or more substituents selected from the group consisting of (C ６ -C １０ ), aryl, and is substituted with at least one substituent selected from the group consisting of; R ６ is selected from the following groups: (C ６ -C ２０ )aryl, (C １ -C １０ )alkyl, (C ３ -C １２ )cycloalkyl, heteroaryl, (C ６ -C １０ )aryl(C １ -C ６ )alkyl and heteroaryl(C １ -C ６ )alkyl, The aryl group is optionally substituted with one or more phenyl groups (C １ -C ６ ), alkyl, (C ６ -C １０ ), aryl (C １ -C ６ ), alkyl, and especially (C １ -C ６ ), alkylamino, di(C １ -C ６ ), alkylamino, (C １ -C ６ ), alkoxy, and (C １ -C ６ ), alkyl, and is optionally substituted with one or more substituents selected from the group consisting of (C ６ -C １０ ), aryl, and is substituted with at least one substituent selected from the group consisting of; However, R ６ is different from R ５ ; or R ５ and R ６ together with the carbon atom(s) to which they are attached form a 5-, 6- or 10-membered cycloalkyl or heterocyclyl ring; R ４ is H or a (C １ -C ６ ) alkyl group; n is an integer from 1 to 3; or R ３ and R ５ together with the carbon atom(s) to which they are attached form a 6-, 7- or 8-membered cycloalkyl ring; X － is a counter anion, the salt is in the form of an optically pure (+) or (−) enantiomer], the method comprises the following steps: a) A reduction step of an iminium salt having the following formula (II), wherein the salt is in the form of a racemic mixture, 【Chemical 2】 (wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n and X － are as defined above in formula (I)), to obtain a compound having formula (III), 【Chemical Formula 3】 (wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ and n are as defined above in formula (I)), the compound of formula (III) is in the form of a racemic mixture, the reduction step; b) A chiral HPLC separation step of the compound of formula (III) in the form of a racemic mixture to obtain an optically pure (+) or (−) enantiomer compound having formula (IV), 【Chemical Formula 4】 (wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ and n are as defined above in formula (I)), the compound of formula (IV) is in the form of an optically pure (+) or (−) enantiomer, the chiral HPLC separation step; c) An oxidation step of the compound of formula (IV) to obtain the compound of formula (I); d) Optionally, a counteranion exchange step; A method comprising.

2. The reduction step is carried out using a reducing agent selected from the group consisting of LiAlH ４ , NaBH ４ , diisobutylaluminum hydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, and cyanoborohydride, according to the method of claim 1.

3. The oxidation step is carried out using an oxidizing agent selected from the group consisting of Br ２ , N-bromosuccinimide, I ２ , N-iodosuccinimide, Cl ２ , a copper (II) compound, a hypervalent iodine compound such as 2-iodoxybenzoic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetra-N-butylammonium iodide, and tert-butyl hydroperoxide, the method according to claim 1 or 2.

4. R １ is a (C １ -C ６ ) aryl group substituted with at least one substituent selected from (C ６ -C １０ ) alkyl groups, preferably a phenyl group substituted with two alkyl groups such as methyl, isopropyl or ethyl groups, and / or R ２ is a (C １ -C ６ ) alkyl group such as a methyl group, the method according to claim 1 or 2.

5. R ２ and R ３ are the same and are preferably a methyl group, the method according to claim 1 or 2.

6. R ２ and R ３ are different, R ２ is preferably a (C １ -C ６ ) alkyl group such as a methyl group, and R ３ is preferably H, or a (C ６ -C １０ ) aryl group such as a phenyl group, the method according to claim 1 or 2.

7. R ４ The method according to claim 1 or 2, wherein R is H.

8. R ５ and R ６ are different and are selected from the following groups: (C ６ -C １０ ) aryl such as phenyl or naphthyl, (C １ -C ６ ) alkyl such as methyl, and (C ３ -C ６ ) cycloalkyl such as cyclohexyl, and the aryl group is optionally substituted with two substituents selected from (C １ -C ６ ) alkyl groups, the method according to claim 1 or 2.

9. An optically pure (+) or (−) enantiomer of an iminium salt having the following formula (I) [Chemical Formula 5] wherein, R １ (C ６ -C １４ ) an aryl group, (C １ -C ６ ) alkyl group or (C ８ -C ２０ ) cycloalkyl group, the aryl group optionally being selected from halogen, (C ６ -C １０ ) an aryl group and (C １ -C ６ ) alkyl groups, said alkyl groups being optionally substituted with one or more phenyl groups; or, R １ is -NR' ａ R' ｂ is a group, and R' ａ and R' ｂ are each independently selected from the group consisting of H, (C １ -C ６ )alkyl and (C ６ -C １０ )aryl, or, R ’ ａ and R ’ ｂ together with the nitrogen atom bearing them form an N(CH ２ ) ２＋ｍ heterocyclic ring, and m is 0 or an integer from 1 to 6; R ２ is H, (C ６ -C １０ )aryl group or (C １ )alkyl group; ６ ​ R ３ is an (C １ -C ６ ) alkyl group; or R ２ and R ３ together with the carbon atoms carrying them may form a (C ３ -C ６ ) cycloalkyl; R ５ is selected from the following groups: (C ６ -C ２０ )aryl, (C １ -C １０ )alkyl and (C ３ -C １２ )cycloalkyl group, The alkyl group is optionally substituted with at least one substituent selected from (C ６ -C １０ ) aryl groups, The aryl group is optionally substituted with one or more phenyl groups (C １ -C ６ ), alkyl, (C ６ -C １０ ), aryl(C １ -C ６ ), alkyl, and in particular (C １ -C ６ ), alkylamino, di(C １ -C ６ ), alkylamino, (C １ -C ６ ), alkoxy and (C １ -C ６ ), alkyl, and is optionally substituted with one or more substituents selected from the group consisting of (C ６ -C １０ ), aryl, and is substituted with at least one substituent selected from the group consisting of; R ６ is selected from the following groups: (C ６ -C ２０ )aryl, (C １ -C １０ )alkyl, (C ３ -C １２ )cycloalkyl, heteroaryl, (C ６ -C １０ )aryl(C １ -C ６ )alkyl and heteroaryl(C １ -C ６ )alkyl, The aryl group is optionally substituted with one or more phenyl groups (C １ -C ６ ), alkyl optionally substituted with one or more substituents selected from the group consisting of (C ６ -C １０ ), aryl (C １ -C ６ ), alkyl, and in particular (C １ -C ６ ), alkylamino, di(C １ -C ６ ), alkylamino, (C １ -C ６ ), alkoxy and (C １ -C ６ ), aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, and is substituted with at least one substituent selected from the group consisting of (C ６ -C １０ ), aryl; However, R ６ is different from R ５ ; or R ５ and R ６ together with the carbon atom(s) to which they are attached form a 5-, 6- or 10-membered cycloalkyl or heterocyclyl ring; R ４ is H, or a (C １ -C ６ ) alkyl group; n is 0 or an integer from 1 to 3, preferably 1; or, R ３ and R ５ together with the carbon atoms to which they are attached form a 6-, 7- or 8-membered cycloalkyl ring; X － is a counter anion, the salt is in the form of an optically pure (+) or (−) enantiomer].

10. Use of a compound of formula (I) as defined in any one of Claims 1, 2 or 9 as a catalyst.

11. Use of a compound of formula (I) as defined in any one of Claims 1, 2 or 9 as a catalyst in combination with a transition metal other than ruthenium.

12. Use of a compound of formula (I) as defined in any one of Claims 1, 2 or 9 as a catalyst in combination with a transition metal selected from the group consisting of gold, copper and rhodium.

13. Use of a compound of formula (I) as defined in any one of Claims 1, 2 or 9 in combination with a transition metal in an organic light-emitting diode.

14. The use according to Claim 13, wherein the transition metal is selected from the group consisting of gold, copper and rhodium.

15. An organic light-emitting device (OLED) comprising an anode, a cathode, and an organic layer disposed between the anode and the cathode, the organic layer comprising a compound of formula (I) as defined in any one of claims 1, 2 or 9, combined with a transition metal selected from the group consisting of Ru, Os, Ir, Pd, Pt, Cu, Ag and Au, and capable of binding to other ligands.

Images