Patent Application
20240368079
The present invention concerns a process for the preparation of optically pure enantiomers of cyclic iminium salts, as well as the corresponding optically pure enantiomers of cyclic iminium salts.
Since their discovery in early 1960s, N-heterocyclic carbenes (NHCs) have become inescapable 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. Díez-González), RSC Catalysis series, RSC Publishing: Cambridge, 2011). In part, this growing popularity has been attributed to their remarkable aptitude in generating more stable, yet very reactive catalysts. Not surprisingly, chiral variants of diaminocarbenes naturally emerged in early 1990s, and thanks to their unique and highly modular steric environment, they also rapidly became privileged stereo-directing ligands with resounding successes in enantioselective catalysis ((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-Müller, D.; Schlepphorst, C.; Glorius, F. Privileged Chiral N-Heterocyclic Carbene Ligands for Asymmetric Transition-Metal Catalysis. Chem. Soc. Rev., 2017, 46, 4845-4854).
Recently however, a new class of chiral carbenes namely chiral cyclic (alkyl) (amino) carbenes (CAACs) arose as a contender to NHCs dominion over carbene driven enantioselective catalysis ((a) Lavallo, V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2005, 44, 5705-5709. For recent reviews on CAACs, 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). In recent years, CAAC ligands have been shown by various research groups to afford robust and well-defined CAAC-metal transition complexes. The latter demonstrated that their unique electronic (more sigma-donating and pi-accepting than NHCs) and steric properties allow for the improvement of known catalytic processes (Ru: see for instance: (a) Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.; Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R. H. 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, D. R.; Lavallo, V.; O'Leary, D. J.; Bertrand, G.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 7262; For Pd, see: (a) V. Lavallo, Y. Canac, C. Präsang, B. Donnadieu and G. Bertrand, Angew. Chem., Int. Ed., 2005, 44, 5705; (b) C. M. Weinstein, G. P. Junor, D. R. Tolentino, R. Jazzar, M. Melaimi and G. Bertrand, J. Am. Chem. Soc., 2018, 140, 9255. For Rh, see: (a) M. P. Wiesenfeldt, Z. Nairoukh, W. Li and F. Glorius, Science, 2017, 357, 908; (b) Y. Wei, B. Rao, X. Cong and X. Zeng, J. Am. Chem. Soc., 2015, 137, 9250; (c) Z. Nairoukh, M. Wollenburg, C. Schlepphorst, K. Bergander and F. Glorius, Nat. Chem., 2019, 11, 264) as well as promoting novel reactions with coinage metals (For Cu, see: (a) E. A. Romero, R. Jazzar and G. Bertrand, Chem. Sci., 2017, 8, 165; (b) J. Chu, D. Munz, R. Jazzar, M. Melaimi and G. Bertrand, J. Am. Chem. Soc., 2016, 138, 7884. For Au, see: (a) X. Hu, D. Martin, M. Melaimi and G. Bertrand, J. Am. Chem. Soc., 2014, 136, 13594; (b) R. Kinjo, B. Donnadieu and G. Bertrand, Angew. Chem., Int. Ed., 2011, 50, 5560; (b) L. Jin, D. S. Weinberger, M. Melaimi, C. E. Moore, A. L. Rheingold and G. Bertrand, Angew. Chem., Int. Ed., 2014, 53, 9059).
Surprisingly, as recently noted by Glorius and co-workers (D. Janssen-Mueller, C. Schlepphortst and F. Glorius, Chem. Soc. Rev., 2017, 46, 4845) despite the existence of a variety of stable heterocyclic carbenes, only diaminocarbenes have been intensively used as ligands for enantioselective transformations. Indeed, regarding chiral CAAC ligands, only two applications were reported in the literature ((a) Pichon, D.; Soleilhavoup, M.; Morvan, J.; Junor, G. P.; 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 Catalysis. Chem. Sci. 2019, 10, 7807; (b) Morvan, J.; Vermersch, F.; Zhang, Z.; Falivene, L.; Vives, T.; Dorcet, 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).
Nevertheless, as a major drawback, these optically pure CAAC ligands were obtained following tedious low yielding procedures, and very often only one of the two enantiomers was prepared.
The aim of the present invention is thus to provide new optically pure enantiomers of iminium salts as precursors of optically pure cyclic (alkyl)(amino) carbenes (CAACs) ligands used for asymmetric catalysis.
Another aim of the present invention is to provide new optically pure enantiomers of iminium salts that could be prepared by a process that does not require any optically pure or enantioenriched raw materials, and, in other words, that does not require the use of chiral chemical compounds.
Another aim of the present invention is to provide a process for the preparation of new optically pure enantiomers of iminium salts that is more economic and faster in comparison with the prior art processes.
Therefore, the present invention relates to a process for the preparation of an optically pure (+) or (−) enantiomer of an iminium salt having the following formula (I):
The present invention also relates to an optically pure (+) or (−) enantiomer of an iminium salt having the following formula (I):
A preferred family of optically pure (+) or (−) enantiomers of iminium salt according to the invention consists of salts having the following formula (I-1):
Salts of formula (I-1) correspond to salts of formula (I) wherein n=0.
Preferably, in formula (I-1), R4 is H.
Thus, the present invention also relates to said salts, and to the process for the preparation of said salts as defined above, starting from compounds having the formula (II) wherein n=0.
A preferred family of optically pure (+) or (−) enantiomers of iminium salt according to the invention consists of salts having the following formula (I) as defined above wherein n is an integer comprised between 1 and 3, and is preferably 1.
A preferred family of optically pure (+) or (−) enantiomers of iminium salt according to the invention consists of salts having the following formula (I-2):
wherein R1, R2, R3, R4, R5, R6 and X− are as defined in formula (I).
Salts of formula (I-2) correspond to salts of formula (I) wherein n=1.
Thus, the present invention also relates to said salts, and to the process for the preparation of said salts as defined above, starting from compounds having the formula (II) wherein n=1.
A preferred family of optically pure (+) or (−) enantiomers of iminium salt according to the invention consists of salts having the following formula (I-3):
wherein R1, R2, R4, R6 and X− are as defined in formula (I).
Preferably, in formula (I-3), R2 is a (C1-C6)alkyl group, such as methyl.
Preferably, in formula (I-3), R6 is a (C1-C6)alkyl group, such as methyl, ethyl, or propyl groups, optionally substituted by a phenyl group.
Preferably, in formula (I-3), R4 is a (C1-C6)alkyl group.
According to an embodiment, in formulae (I), (I-1), (I-2), and (I-3), R1 is a substituted phenyl group. Preferably, in formulae (I), (I-1), (I-2), and (I-3), R1 is a phenyl group being substituted with at least one or two substituent(s), said substituents being selected from the (C1-C6)alkyl groups, such as methyl, ethyl or isopropyl.
Preferably, in formulae (I), (I-1), (I-2), and (I-3), R1 is a phenyl group being substituted with two substituent(s) in ortho position, said substituents being identical or different.
Preferably, in formulae (I), (I-1), (I-2), and (I-3), R1 is a phenyl group being substituted with two substituents in ortho position, said substituents being identical or different, said substituents being preferably (C1-C6)alkyl groups, such as methyl, ethyl or isopropyl.
As preferred R1 groups, one may cite phenyl groups with two alkyl groups, in particular two identical alkyl groups, such as ethyl or isopropyl, in ortho position.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R1 is a (C6-C10)aryl group substituted with at least one substituent chosen from the (C1-C6)alkyl groups, preferably a phenyl group substituted with two alkyl groups, such as methyl, isopropyl or ethyl groups, and/or wherein R2 is a (C1-C6)alkyl group such as a methyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R2 and R3 are identical, and are preferably a methyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R2 and R3 are different, R2 being preferably a (C1-C6)alkyl group such as a methyl group and R3 being preferably H or a (C6-C10)aryl group such as a phenyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R4 is H.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R6 is an alkyl group as defined above, preferably a methyl group, and R5 is an aryl group as defined above. Preferably, said aryl group is a (C6-C10)aryl group, such as a naphthyl group or a phenyl group, being substituted with at least one, in particular one, two or three, substituent(s), said substituent(s) being selected from the group consisting of: (C1-C6)alkyl groups, such as methyl or isopropyl, (C1-C6)alkylamino groups, di(C1-C6)alkylamino groups, (C1-C6)alkoxy groups, (C6-C10)aryl groups such as phenyl, and —CH(Ar)2, such as —CH(Ph)2, Ar being an aryl group. Preferably, R5 is a phenyl group being substituted with two substituents in meta position, said substituents being identical or different, preferably identical, such as methyl, isopropyl or tertiobutyl.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R5 is a cyclohexyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R4 is an aryl group as defined above and R5 is an alkyl group as defined above, preferably a methyl group. Preferably, said aryl group is a naphthyl radical or a (C6-C10)aryl group, such as a phenyl group, being substituted with at least one, in particular one, two or three, substituent(s), said substituent(s) being selected from the group consisting of: (C1-C6)alkyl groups, such as methyl or isopropyl, (C1-C6)alkylamino groups, di(C1-C6)alkylamino groups, (C1-C6)alkoxy groups, (C6-C10)aryl groups such as phenyl, and —CH(Ar)2, such as —CH(Ph)2, Ar being an aryl group. Preferably, R6 is a phenyl group being substituted with two substituents in meta position, said substituents being identical or different, preferably identical, such as methyl, isopropyl or tertiobutyl.
As preferred aryl groups for R6 (or R5), the followings may be mentioned:
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R6 is an aryl group as defined above, said aryl group being optionally substituted with at least one substituent as defined hereafter, and R5 is an alkyl group as defined above, preferably a methyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R5 is an aryl group as defined above, said aryl group being optionally substituted with at least one substituent as defined hereafter, and R6 is an alkyl group as defined above, preferably a methyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R6 is an alkyl group as defined above, preferably a methyl group, and R5 is selected from the group consisting of: (C1-C10)alkyl, such as tertio-butyl group, and (C3-C12)cycloalkyl groups.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R5 is an alkyl group as defined above, preferably a methyl group, and R6 is selected from the group consisting of: (C1-C10)alkyl, such as tertio-butyl group, and (C3-C12)cycloalkyl groups.
As preferred cycloakyl groups for R+ (or R5), the followings may be mentioned:
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R6 is an alkyl group as defined above, preferably a methyl group, and R5 is an aryl group as defined above, preferably a phenyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R5 is an alkyl group as defined above, preferably a methyl group, and R6 is an aryl group as defined above, preferably a phenyl group.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), R5 and R6 are different and selected from the following groups: (C6-C10)aryl such as phenyl or naphthyl, (C1-C6)alkyl such as methyl, and (C3-C6)cycloalkyl such as cyclohexyl, said aryl group being optionally substituted with two substituents selected from the (C1-C6)alkyl groups.
According to an embodiment, in formula (I) or also in formulae (I-1), (I-2) or (I-3), X− is a counteranion, preferably selected from the group consisting of: BF4−, I−, Cl−, OTf−, Br−, PF6−, SbF6−, and B(Ar)4−, Ar representing an aryl group, such as BPh4−. As counteranions the followings may also be mentioned: MXn− e.g. CuCl2−, AuBr2−, [Pd(η3-cin)Cl2]−, FeCl4− (see Ekaterina A. Martynova, Nikolaos V. Tzouras, Gianmarco Pisanò, Catherine S. J. Cazin and Steven P. Nolan (Chemical Communications, 32, 2021)) or [NiCl42−] (see Mickaël 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)).
Any counteranion known from the skilled person may be used. Other examples may be found for example Han Vinh Huynh, Truc Tien Lam and Huyen T. T. Luong (RSC Advances, issue 61, 2018).
According to a preferred embodiment, X− is BF4−.
In the context of the present invention, the expression “Ct-Cz” means a carbon-based chain which can have from t to z carbon atoms, for example C1-C3 means a carbon-based chain which can have from 1 to 3 carbon atoms.
According to the invention, the term “halogen” means: a fluorine, a chlorine, a bromine or an iodine.
According to the invention, the term “alkyl group” means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 12 carbon atoms. By way of examples, mention may be made of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups;
According to the invention, the term “cycloalkyl group” means: a cyclic carbon-based group comprising, unless otherwise mentioned, from 3 to 12 carbon atoms. By way of examples, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl etc. groups;
According to the invention, the term “alkoxy group” means: an —O-alkyl radical where the alkyl group is as previously defined. By way of examples, mention may be made of —O—(C1-C4)alkyl groups, and in particular the —O-methyl group, the —O-ethyl group as —O—C3alkyl group, the —O-propyl group, the —O-isopropyl group, and as —O—C4alkyl group, the —O-butyl, —O-isobutyl or —O-tert-butyl group.
According to the invention, the term “aryl group” means: a cyclic aromatic group comprising between 6 and 10 carbon atoms. By way of examples of aryl groups, mention may be made of phenyl or naphthyl groups.
According to the invention, the term “heteroaryl” means: a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N. By way of examples, mention may be made of 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.
By way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms, mention may in particular be made of the following representative groups: pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and 1,2,3-triazinyl.
Mention may also be made, by way of heteroaryl, of 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, benzoazaindole, 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 their fusion or from fusion with the phenyl nucleus.
According to the invention, the term “heterocycloalkyl” means: a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic group comprising from one to three heteroatoms selected from O, S or N; the heterocycloalkyl group may be attached to the rest of the molecule via a carbon atom or via a heteroatom; the term bicyclic heterocycloalkyl includes fused bicycles and spiro-type rings.
By way of saturated heterocycloalkyl comprising from 5 to 6 atoms, mention may be made of oxetanyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, azepinyl, oxazepinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl or isoxazolidinyl.
When the heterocycloalkyl is substituted, the substitution(s) may be on one (or more) carbon atom(s) and/or on the heteroatom(s). When the heterocycloalkyl comprises several substituents, they may be borne by one and the same atom or different atoms.
The abovementioned “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” and “heterocycloalkyl” radicals can be substituted with one or more substituents. Among these substituents, mention may be made of the following groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy or carboxyalkyl.
According to the invention, the term “alkylthio” means: an —S-alkyl group, the alkyl group being as defined above.
According to the invention, the term “arylthio” means: an —S-aryl group, the aryl group being as defined above.
According to the invention, the term “alkylamino” means: an —NH-alkyl group, the alkyl group being as defined above.
According to the invention, the term “cycloalkyloxy” means: an —O-cycloalkyl group, the cycloalkyl group being as defined above.
According to the invention, the term “aryloxy” means: an —O-aryl group, the aryl group being as defined above.
According to the invention, the term “(hetero)arylalkoxy” means: a (hetero)aryl-alkoxy-group, the (hetero)aryl and alkoxy groups being as defined above.
According to the invention, the term “alkylcarbonyl” means a —CO-alkyl group, the alkyl group being as defined above.
According to the invention, the term “alkoxylcarbonyl” means a —CO—O-alkyl group, the alkyl group being as defined above.
According to the invention, the term “arylcarbonyl” means a —CO-aryl group, the aryl group being as defined above.
According to the invention, the term “aryloxycarbonyl” means a —CO-aryloxy group, the aryloxy group being as defined above.
According to the invention, the term “alkylsulfonyl” means a —SO2-alkyl group, the alkyl group being as defined above.
According to the invention, the term “arylsulfonyl” means a —SO2-aryl group, the aryl group being as defined above.
According to the invention, the term “alkylsulfinyl” means a —SO-alkyl group, the alkyl group being as defined above.
According to the invention, the term “arylsulfinyl” means a —SO-aryl group, the aryl group being as defined above.
According to the invention, the term “carboxyalkyl” means: an HOOC-alkyl-group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may in particular be made of carboxymethyl or carboxyethyl.
According to the invention, the term “carboxyl” means: a COOH group.
According to the invention, the term “oxo” means: “═O”.
When an alkyl radical is substituted with an aryl group, the term “arylalkyl” or “aralkyl” radical is used. The “arylalkyl” or “aralkyl” radicals are aryl-alkyl-radicals, the aryl and alkyl groups being as defined above. Among the arylalkyl radicals, mention may in particular be made of the benzyl or phenethyl radicals.
As preferred salts according to the invention, the followings may be mentioned:
As preferred salts according to the invention, the followings may be mentioned:
As mentioned above, the process according to the invention comprises a first step consisting in a reduction step of an iminium salt of formula (II), said salt being in the form of a racemic mixture, and said step giving a compound of formula (III) also in the form of a racemic mixture.
Formulae (II) and (III) are as defined above. In these formulae, n, R1, R2, R3, R4, R5, and R6 are as defined above in formulae (I), (I-1), (I-2) or (I-3).
The reduction step of the process of the invention is carried out in particular with a reduction agent. Concerning the reduction agent, 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 also 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).
According to an embodiment, the reduction agent is selected from the group consisting of: LiAlH4, NaBH4, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LITEBH), sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al), and cyanoborohydrides.
Preferably, the reduction step is carried out in a solvent, said solvent being in particular THF. According to an embodiment, the reduction step is carried out at a temperature comprised between 0° C. and room temperature (20-24° C.).
According to an embodiment, the reduction step may be carried out with a HPLC column.
The process of the invention also comprises a step of chiral HPLC separation of the compound of formula (III) in the form of a racemic mixture, for obtaining an optically pure (+) or (−) enantiomer compound of formula (IV), said compound of formula (IV) being in the form of an optically pure (+) or (−) enantiomer.
Formula (IV) is as defined above. In this formula, n, R1, R2, R3, R4, R5, and R6 are as defined above in formulae (I), (I-1), (I-2) or (I-3).
Preferably, said step of chiral HPLC separation is carried out with a HPLC column comprising cellulose, in particular substituted with chloro-phenylcarbamate as chiral stationary phase.
As HPLC columns, the Lux® columns may be mentioned such as Lux-Cellulose-3 (Cellulose tris(4-methylbenzoate)) or Lux-Cellulose-4 (Cellulose tris(4-chloro-3-methylphenylcarbamate)).
According to an embodiment, ethanol or heptane is used as mobile phase.
The process of the invention also comprises an oxidation step of the compound of formula (IV) for obtaining the salt of formula (I), said salt of formula (I) being in the form of an optically pure (+) or (−) enantiomer.
The oxidation step of the invention is in particular carried out with an oxidation agent. According to an embodiment, the oxidation agent is selected from the group consisting of: Br2, N-bromosuccinimide, I2, N-iodosuccinimide, a copper (II) compound in particular CuX2 (X being for example Cl, Br, I or OTf), and more particularly CuCl2, Cl2, a hypervalent iodine compound 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).
Other examples of oxidant agents may be found in “Organocatalysis in Inert C—H Bond Functionalization” of Yan Qin, Lihui Zhu, and Sanzhong Luo (Chem. Rev. 2017, 117, 13, 9433-9520).
Preferably, the oxidation step is carried out in a solvent, said solvent being in particular dichloromethane. According to an embodiment, the oxidation step is carried out at a temperature comprised between 0° C. and room temperature (20-24° C.).
The process of the invention may also comprise a further step consisting in a counteranion exchange.
Such step is carried out by means well-known from the skilled person. It allows for example to obtain the salts of formula (I) wherein X is BF4 or PF6. See for example “Anion influences on reactivity and NMR spectroscopic features of NHC precursors” of Han Vinh Huynh, Truc Tien Lam and Huyen T. T. Luong (RSC Advances, issue 61, 2018) or see Ekaterina A. Martynova, Nikolaos V. Tzouras, Gianmarco Pisanò, Catherine S. J. Cazin and Steven P. Nolan (Chemical Communications, 32, 2021).
As methods for this step, the followings may be mentioned:
The present invention also relates to the use of the compound of formula (I), or formulae (I-1), (I-2) or (I-3), as defined above as a catalyst, preferably as a catalyst in asymmetric olefin metathesis, optionally in combination with a transition metal.
The present invention also relates to the use of the compound of formula (I), or formulae (I-1), (I-2) or (I-3), as defined above as a catalyst.
The present invention also relates to the use of the compound of formula (I), or formulae (I-1), (I-2) or (I-3), as defined above as a catalyst, in combination with a transition metal other than ruthenium.
The present invention also relates to the use of the compound of formula (I), or formulae (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.
The present invention also relates to the use of the compound of formula (I), or formulae (I-1), (I-2) or (I-3), as defined above, in combination with a transition metal, in an organic light-emitting diode.
The present invention also relates to the use of the compound of formula (I), or formulae (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.
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, wherein the organic layer comprises 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 can be bonded to other ligands.
All reactions and subsequent manipulations were performed under an argon atmosphere in an MBraun glovebox or using standard Schlenk techniques, if not stated otherwise. 1H and 13C{1H} NMR spectra were recorded on a Varian 400 or Bruker Avance 400 at 25° C. 1H NMR chemical shifts are reported relative to TMS (0 in ppm) and were referenced via residual proton resonances of the corresponding deuterated solvent (CHCl3: 7.26 ppm; C6D5H: 7.16 ppm) whereas 13C{1H} NMR spectra are reported relative to TMS using the natural-abundance carbon resonances (CDCl3: 77.16 ppm; C6D6: 128.0 ppm). Coupling constants are given in Hertz.
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 a THF at 0° C. and received suspension was further stirred at room temperature overnight. Reaction mixture was then quenched with mixture of hydrated MgSO4 and silica and then passed through a short pad of silica which was further washed with Et2O. Evaporation of the combined organic fractions gives desired CAAC-H2 adducts as white sticky solids in typical yield of 90%.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.41-7.31 (m, 4H), 7.28-7.20 (m, 2H), 7.16 (ddd, J=17.0, 7.5, 2.0 Hz, 2H), 4.01 (d, J=8.4 Hz, 1H), 3.91 (p, J=6.9 Hz, 1H), 3.50 (d, J=8.6 Hz, 1H), 3.37 (p, J=6.8 Hz, 1H), 2.54 (d, J=12.7 Hz, 1H), 2.30 (dd, J=12.7, 0.8 Hz, 1H), 1.63 (s, 3H), 1.30 (d, J=6.9 Hz, 3H), 1.26 (s, 3H), 1.16 (t, J=6.8 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H), 1.05 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=152.3, 152.3, 150.7, 138.4, 128.2, 126.5, 126.0, 125.6, 124.1, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.91-7.82 (m, 3H), 7.80 (d, J=1.9 Hz, 1H), 7.56-7.44 (m, 3H), 7.30-7.23 (m, 1H), 7.22 (dd, J=7.7, 2.1 Hz, 1H), 7.17 (dd, J=7.3, 2.1 Hz, 1H), 4.14 (d, J=8.4 Hz, 1H), 3.94 (hept, J=6.9 Hz, 1H), 3.63 (d, J=8.4 Hz, 1H), 3.42 (hept, J=6.8 Hz, 1H), 2.71 (d, J=12.7 Hz, 1H), 2.40 (d, J=12.7 Hz, 1H), 1.73 (s, 3H), 1.35 (d, J=6.9 Hz, 3H), 1.31 (s, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.08 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=152.3, 152.3, 147.9, 138.5, 133.4, 131.8, 127.9, 127.9, 127.5, 126.6, 125.9, 125.5, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=8.27-8.18 (m, 1H), 7.96-7.87 (m, 1H), 7.82-7.72 (m, 1H), 7.53-7.42 (m, 4H), 7.29-7.19 (m, 2H), 7.15 (dd, J=7.0, 2.5 Hz, 1H), 4.34 (d, J=8.6 Hz, 1H), 4.06 (hept, J=6.9 Hz, 1H), 3.85 (d, J=8.6 Hz, 1H), 3.34 (hept, J=6.9 Hz, 1H), 2.84 (d, J=12.6 Hz, 1H), 2.67 (d, J=12.5 Hz, 1H), 1.94 (s, 3H), 1.39-1.32 (m, 6H), 1.23 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.08 (s, 3H), 1.00 (d, J=6.8 Hz, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=0.2, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.28-7.14 (m, 3H), 6.99-6.94 (m, 2H), 6.91 (qd, J=1.6, 0.9 Hz, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.49 (d, J=8.3 Hz, 1H), 3.40 (hept, J=6.8 Hz, 1H), 2.55 (d, J=12.7 Hz, 1H), 2.37 (s, 6H), 2.30 (d, J=12.6 Hz, 1H), 1.64 (s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.28 (s, 3H), 1.19 (dd, J=12.0, 6.8 Hz, 6H), 1.12 (d, J=6.8 Hz, 3H), 1.08 (s, 3H).
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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.25-7.18 (m, 1H), 7.18-7.12 (m, 2H), 3.88 (hept, J=6.9 Hz, 1H), 3.56-3.41 (m, 2H), 3.01 (d, J=8.3 Hz, 1H), 1.91 (d, J=12.7 Hz, 1H), 1.86-1.67 (m, 5H), 1.54-1.46 (m, 1H), 1.36-1.25 (m, 10H), 1.22 (s, 4H), 1.20 (s, 4H), 1.17 (d, J=6.8 Hz, 4H), 1.09 (d, J=6.7 Hz, 7H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=δ 152.4, 152.1, 138.9, 126.3, 123.9, 123.7, 66.6, 62.6, 55.2, 49.9, 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.
Diastereoisomeric ratio of starting iminium salt range between 90/10 to 75/25 and are the same in the product.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.25-7.19 (m, 2H), 7.18-7.12 (m, 2H), 7.09 (m, 3H), 7.00 (dd, J=7.5, 2.0 Hz, 1H), 3.67 (hept, J=6.9 Hz, 1H), 3.21 (dd, J=8.8, 2.8 Hz, 1H), 2.99 (hept, J=6.8 Hz, 1H), 2.79 (q, J=7.3 Hz, 1H), 2.50 (dd, J=8.7, 1.7 Hz, 1H), 2.30-2.15 (m, 1H), 2.05 (dd, J=12.6, 10.9 Hz, 1H), 1.92-1.83 (m, 2H), 1.81-1.71 (m, 2H), 1.75-1.56 (m, 1H), 1.30 (d, J=7.2 Hz, 3H), 1.28-1.21 (m, 6H, overlapping signals), 1.09 (d, J=6.9 Hz, 3H), 0.64 (s, 3H), 0.63 (d, J=6.8 Hz, 3H).
13C{1H} 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.
Diastereoisomeric ratio: 75/25
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.54-7.47 (m, 2H), 7.47-7.35 (m, 3H), 7.33-7.24 (m, 2H), 7.24-7.07 (m, 7H), 6.99-6.87 (m, 2H), 4.23 (p, J=6.9 Hz, OH), 4.14 (d, J=9.2 Hz, 1H), 4.10 (d, J=8.6 Hz, OH), 3.67-3.42 (m, 2H), 3.15 (d, J=12.8 Hz, 1H), 2.82 (td, J=13.2, 6.2 Hz, 2H), 2.47 (dd, J=13.1, 0.8 Hz, OH), 2.16 (p, J=6.8 Hz, OH), 1.80 (s, 1H), 1.73 (s, 1H), 1.56 (s, 2H), 1.44 (d, J=7.0 Hz, 1H), 1.32-1.24 (m, 5H), 1.24-1.18 (m, 1H), 1.14 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 2H), 0.85 (d, J=6.7 Hz, 1H), 0.30 (d, J=6.8 Hz, 2H), 0.16 (d, J=6.7 Hz, 1H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=152.3, 151.9, 151.2, 150.8, 150.1, 146.2, 146.0, 140.1, 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.
Diastereoisomeric ratio: 55/45
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.42-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.20-7.07 (m, 2H), 4.10-3.93 (m, 1H), 3.85 (d, J=8.1 Hz, 1H), 3.83-3.74 (m, 1H), 3.71 (d, J=8.4 Hz, OH), 3.64 (p, J=6.9 Hz, 1H), 3.46 (dd, J=8.3, 0.9 Hz, 1H), 3.44-3.37 (m, 1H), 2.99 (p, J=6.8 Hz, OH), 2.75 (dd, J=12.7, 8.7 Hz, OH), 2.34 (dd, J=11.7, 5.4 Hz, 1H), 2.10 (dd, J=11.7, 9.0 Hz, 1H), 1.95 (ddd, J=12.7, 5.0, 0.9 Hz, OH), 1.67 (s, 1H), 1.58 (s, 2H), 1.32-1.27 (m, 4H), 1.27-1.22 (m, 2H), 1.21-1.14 (m, 5H), 1.12 (t, J=6.6 Hz, 3H), 0.97 (d, J=6.0 Hz, 2H).
13C{1H} NMR (100 MHZ, 25° C., 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.41-7.31 (m, 4H), 7.26-7.21 (m, 1H), 7.17 (d, J=5.3 Hz, 2H), 7.12 (dd, J=5.5, 4.0 Hz, 1H), 3.98 (d, J=8.4 Hz, 1H), 3.49 (d, J=8.3 Hz, 1H), 3.17 (dq, J=15.0, 7.5 Hz, 1H), 2.86-2.65 (m, 2H), 2.60-2.47 (m, 2H), 2.27 (dd, J=12.7, 0.9 Hz, 1H), 1.64 (s, 3H), 1.27-1.20 (m, 6H), 1.19-1.11 (m, 3H), 1.02 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=150.7, 147.6, 147.5, 140.3, 128.2, 127.1, 126.6, 126.0, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.88-7.81 (m, 3H), 7.78 (d, J=2.1 Hz, 1H), 7.54-7.41 (m, 3H), 7.18-7.16 (m, 2H), 7.14-7.10 (m, 1H), 4.09 (d, J=8.6 Hz, 1H), 3.60 (d, J=8.6 Hz, 1H), 3.25-3.12 (m, 1H), 2.89-2.68 (m, 2H), 2.64 (d, J=12.7 Hz, 1H), 2.59-2.45 (m, 1H), 2.36 (d, J=12.7 Hz, 1H), 1.71 (s, 3H), 1.27 (t, J=7.6 Hz, 3H, overlapping) 1.27 (s, 3H, overlapping). 1.14 (t, J=7.5 Hz, 3H), 1.02 (s, 3H).
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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=8.24-8.18 (m, 1H), 7.92-7.87 (m, 1H), 7.75 (dd, J=6.7, 2.8 Hz, 1H), 7.49-7.42 (m, 4H), 7.21-7.15 (m, 2H), 7.11 (dd, J=6.7, 2.8 Hz, 1H), 4.27 (d, J=8.6 Hz, 1H), 3.85 (d, J=8.6 Hz, 1H), 3.33-3.20 (m, 1H), 2.83-2.70 (m, 2H, overlapping), 2.79 (d, J=12.7 Hz, 1H, overlapping), 2.63 (d, J=12.6 Hz, 1H), 2.53 (dq, J=15.0, 7.6 Hz, 1H), 1.35 (s, 3H), 1.29 (t, J=7.6 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H), 1.04 (s, 3H).
13C{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.
1H NMR (400 MHZ, 25° C., CDCl3): 7.16-7.08 (m, 3H), 3.40 (d, J=8.3 Hz, 1H), 3.14-3.05 (m, 1H), 2.98 (d, J=8.3 Hz, 1H), 2.91-2.81 (m, 1H), 2.69-2.58 (m, J=2H), 1.88-1.73 (m, 4H), 1.69 (m, 2H), 1.54-1.46 (m, 1H), 1.30-1.10 (m, 9H, overlapping) 1.21 (s, 3H, overlapping), 1.21 (t, 3H, J=7.6 Hz overlapping), 1.18 (s, 3H, overlapping), 1.17 (t, J=7.5 Hz, 3H, overlapping) 1.04 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=147.9, 147.5, 140.9, 127.1, 126.6, 125.9, 66.3, 63.4, 55.3, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.18-7.10 (m, 7H), 3.51 (d, J=8.5 Hz, 1H), 3.10 (d, J=8.5 Hz, 1H), 3.07-2.95 (m, 2H), 2.96-2.88 (m, 1H), 2.87-2.78 (m, 2H), 2.73-2.56 (m, 2H), 2.08 (d, J=12.8 Hz, 1H), 1.76 (d, J=12.7 Hz, 1H), 1.29-1.23 (m, 12H), 1.17 (t, J=7.6 Hz, 2H, overlapping), 1.16 (s, 3H, overlapping), 1.13 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., CDCl3): δ=147.7, 147.4, 146.5, 140.7, 137.2, 130.4, 126.9, 126.8, 126.0, 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.
1H NMR (400 MHZ, 25° C., CDCl3): δ=7.42-7.30 (m, 4H), 7.28-7.19 (m, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.41 (d, J=8.3 Hz, 1H), 2.48 (d, 1H, J=11.6 Hz, overlapping), 2.47 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 2.25 (d, J=11.6 Hz, 1H), 1.66 (s, 3H), 1.31 (s, 3H), 1.11 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., 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.
Diastereoisomeric ratio of starting iminium salt is 1/1 but product is received in 4/1 mixture.
Analytical data are given for a Major Dia
1H NMR (400 MHZ, 25° C., 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=8.3 Hz, 1H), 3.55 (d, J=8.3 Hz, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.30 (d, J=12.6 Hz, 1H), 1.97 (d, J=12.6 Hz, 1H), 1.45 (s, 3H), 1.00 (s, 3H), 0.60 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., 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.
The sample is dissolved in hexane, injected on the chiral column, and detected with an UV detector at 220 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578 and 546 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Structures of (+)-(R)-Compound 1 (from first fraction) and (−)-(S)-Compound 1 (from second fraction) were determined by single crystal X-ray diffraction.
The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm. The flow-rate is 0.5 mL/min.
Impurity: 12 mg
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm. The flow-rate is 0.5 mL/min.
After collection and evaporation of the first intermediate fraction: 28 times 250 UL, every 5 minutes.
After evaporation of the second intermediate fraction: 20 times 250 μL, every 5 minutes
Impurity: 15 mg
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 0.5 mL/min.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Intermediate: 11 mg
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25° C. with a Peltier controlled cell holder.
CAAC-H2 Adduct Oxidation to Obtain the CAAC·BF4 Iminium Salt (Corresponding to Step c) of the Process According to the Invention for the Preparation of Compounds of Formula (I) According to the Invention)
General procedure: In a Schlenk tube under argon enantiopure CAAC-H2 adducts were dissolved in dry DCM. Received solution was then cooled down in an ice bath to 0° C. and bromine (3 equiv) was added dropwise. Reaction mixture was then brought to RT and stirred overnight. Then water solution of KBF4 (6 equiv) and Na2S2O3 (3 equiv) was then added and resulting biphasic mixture was stirred for an hour. Phases were then separated and water phase was additionally washed with extra DCM. Combined organic phases were dried over anhydrous MgSO4 and filtered. Remaining solution was then reduced to ca. 5 ml and an excess of Et2O was added causing precipitation of white solid. Filtration and copious washing of the precipitate with Et2O and pentane afforded cyclic iminium salt BF 4 in typical yield of 85% as white solids.
Structures of Compounds Isolated and Analysed by NMR for which Study of Single Crystals by Means of X-Ray Diffractometry Allowed for Determination of Absolute Configuration.
(−)-(R)-Compound-16 (received from (+)-(R)-Compound 1) and its enantiomer (+)-(S)-Compound-16 (received from (−)-(S)-Compound 1) have identical spectra
1H 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).
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.
11B NMR (128 MHZ, CDCl3): δ: −0.98.
19F NMR (376 MHZ, CDCl3): δ: −151.0 (small), 151.1
Compounds have opposite [α]D=
(−)-(R)-Compound-17 (received from (+)-(R)-Compound 2) and its enantiomer (+)-(S)-Compound-17 (received from (−)-(S)-Compound 2) have identical spectra.
1H NMR (300 MHZ, CD3CN) δ: ppm) 9.72 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.89-7.97 (m, 3H), 7.58-7.66 (m, 4H), 7.51 (d, J=8.1 Hz, 1HHz), 7.47 (d, J=8.1 Hz, 1H), 3.22 (d, J=14.1 Hz, 1H), 2.88 (d, J=14.1 Hz, 1H), 2.83 (sept, J=6.6 Hz, 1H), 2.60 (sept, J=6.6 Hz, 1H), 2.01 (s, 3H), 1.60 (s, 3H), 1.41 (d, J=6.6 Hz, 3H), 1.40 (s, 3H), 1.21 (d, J=6.6 Hz, 3H), 1.19 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.6 Hz, 3H)
13C NMR (125 MHz, 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.
11B NMR (128 MHZ, CDCl3) δ: −0.91.
19F NMR (376 MHZ, CDCl3): δ: −150.9 (small), −151.0.
Compounds have opposite [α]D=
(+)-(R)-Compound-18 (received from (+)-(R)-Compound 3) and its enantiomer
(−)-(S)-Compound-18 (received from (−)-(S)-Compound 3) have identical spectra:
1H NMR (400 MHZ, CDCl3) δ: 9.89 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.52-7.55 (m, 2H), 7.33-7.38 (m, 4H), 3.30 (d, J=14.0 Hz, 1H), 3.19 (d, J=14.0 Hz, 1H), 2.70 (sept, J=6.5 Hz, 1H), 2.69 (sept, J=6.5 Hz, 1H), 2.15 (s, 3H), 1.54 (s, 3H), 1.37 (d, J=6.5 Hz, 3H), 1.31 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.23 (d, J=6.5 Hz, 3H), 1.20 (d, J=6.5 Hz, 3H).
13C NMR (125 MHZ, 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.
11B NMR (128 MHZ, CDCl3) δ: −0.91.
19F NMR (376 MHZ, CDCl3) δ: ppm) −150.9 (small), −151.0.
Compounds have opposite [α]D=
(−)-(R)-Compound-19 (received from (+)-(R)-Compound 4) and its enantiomer (+)-(S)-Compound-19 (received from (−)-(S)-Compound 4) have identical spectra:
1H NMR (500 MHZ, CDCl3) δ: 9.59 (s, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.06 (s, 2H), 6.97 (s, 1H), 3.16 (d, J=14.0 Hz, 1H), 2.67 (sept, J=6.5 Hz, 1H), 2.66 (d, J=14.0 Hz, 1H), 2.39 (sept, J=6.5 Hz, 1H), 2.31 (s, 6H), 1.87 (s, 3H), 1.52 (s, 3H), 1.35 (d, J=6.5 Hz, 3H), 1.31 (s, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.16 (d, J=6.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H).
13C NMR (125 MHZ, 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.
11B NMR (128 MHz, CDCl3) δ: −0.99.
19F NMR (376 MHZ, CDCl3): δ: (ppm) −151.2 (small), −151.3.
Compounds have opposite [α]D=
(−)-(R)-Compound-20 (received from (+)-(R)-Compound 9) and its enantiomer (+)-(S)-Compound-20 (received from (−)-(S)-Compound 9) have identical spectra:
1H NMR (500 MHZ, CDCl3) δ: 9.55 (s, 1H), 7.47 (t, J=7.5 Hz, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 3.16 (d, J=14.0 Hz, 1H), 2.67 (d, J=14.0 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.33 (dt, J=7.5 Hz, 1H), 2.16 (dt, J=7.5 Hz, 1H), 1.91 (s, 3H), 1.52 (s, 3H), 1.31 (s, 3H), 1.26 (t, J=7.5 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).
13C NMR (125 MHZ, 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.
11B NMR (128 MHZ, CDCl3) δ: −0.98.
19F NMR (376 MHZ, CDCl3): δ: −151.0 (small), −151.1
Compounds have opposite [α]D=
Structures of (+)-(R)-Compound 16, (+)—S-Compund-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.
Structures of compounds isolated and analysed by NMR for which enantiomers were assigned as (+) or (−) based on sign of their optical rotation.
(+)-Compound 21 and (−)-Compound 21 were received from (+) or (−)-Compound 6
1H NMR (400 MHZ, 25° C., acetone-d6): δ=8.82 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.42-7.29 (m, 5H), 7.27-7.22 (m, 1H), 7.18 (dd, J=7.8, 1.5 Hz, 1H), 3.77 (q, J=7.2 Hz, 1H), 3.47 (q, J=7.0 Hz, 1H), 2.93-2.79 (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=6.8 Hz, 3H), 1.24 (d, J=6.7 Hz, 3H), 1.22-1.18 (m, 7H), 0.34 (d, J=6.8 Hz, 3H).
13C{1H} NMR (100 MHZ, 25° C., acetone-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.
11B NMR (128 MHZ, CDCl3) δ: −0.90.
19F NMR (376 MHZ, CDCl3): δ: −152.7 (small), −152.8
(−)-Compound-21 (T=25° C., c=0.101 g/mL, L=10 cm, acetonitrile)=−87.4
(+)-Compound-21 (T=25° C., c=0.103 g/mL, L=10 cm, acetonitrile)=+87.1
(+)-Compound 22 and (−)-Compound 22 were received from (+) or (−)-Compound 13.
1H NMR (400 MHZ, 25° C., CDCl3): δ=9.38 (s, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35-7.29 (m, 3H), 7.27-7.21 (m, 3H), 3.75 (d, J=14.0 Hz, 1H), 2.93 (sept, J=6.9 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 2.72 (d, J=13.7 Hz, 1H), 2.51 (q, J=7.5 Hz, 2H), 2.27 (d, J=13.7 Hz, 1H), 1.89-1.78 (m, 5H), 1.45 (s, 3H), 1.32 (d, J=7.4 Hz, 3H), 1.26 (dd, J=6.9, 1.8 Hz, 6H), 1.11 (t, J=7.5 Hz, 3H), 0.98 (s, 3H).
13C{1H} NMR (100 MHZ, 25° C., 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.
11B NMR (128 MHZ, CDCl3) δ: −0.89.
19F NMR (376 MHZ, CDCl3): δ: −151.1 (small), 151.2.
(−)-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
(+)-Compound 23 and (−)-Compound 23 were received from (+) or (−)-Compound 14.
1H NMR (400 MHZ, 25° C., 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=13.9 Hz, 1H), 2.94 (d, J=14.1 Hz, 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).
13C{1H} 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.
11B NMR (128 MHz, acetone-d6) δ: −0.93.
19F 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
(+)-Compound 24 and (−)-Compound 24 were received from (+) or (−)-Compound 15.
Diastereoisomeric ratio of starting amine is 4/1 and iminium salt is received in same ratio
1H 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 given for major isomer, aromatic region is hard to define as signals for two diastereomers overlap).
13C{1H} NMR (100 MHz, 25° C., 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, 130.6, 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 given for mixture of diasteroisomers)
11B NMR (128 MHZ, acetone-d6) δ: −0.89
19F 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
Procedure for the (−)-(S)—Ru complex: In a glove box, (+)-(S)-compound 19 (2.5 equiv) was dissolved in dry and degassed Toluene (0.5 mL). KHMDS (0.5 M in Toluene, 2.5 equiv) was added. The mixture was allowed to stirred 1 min at 40° C. Then, M10 catalyst (1 equiv) and toluene (0.5 mL) were then added. The mixture was stirred 5 min at 40° C. CuCl (4.5 equiv), Styrenyl ether (1.6 equiv) and Toluene (0.5 mL) were added. The mixture was stirred at 80° C. for 30 min out of the box. Volatiles were removed under vacuum and the product was purified by column chromatography (eluent: toluene). Green fraction was washed with pentane.
The desired complex is obtained as a green solid (61% yield) as a mixture of rotamers (ratio determined by 1H NMR in CDCl3: 76:24).
1H NMR (400 MHz, CDCl3): δ 17.78 (s, 0.23H), 16.45 (s, 0.77H), 8.45 (d, J=9.1 Hz, 1H), 8.23 (s, 1H), 7.75-7.38 (m, 8H), 6.98 (d, J=9.0 Hz, 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).
13C NMR (101 MHZ, 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.
[α]D=(−)-(S)-ruthenium complex (T=25° C., c=0.110 g/mL, L=10 cm, CH2Cl2)=−565.
Analytical data for this compound were consistent with the previously reported data.
The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IE, and detected with an 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 determination: 98%
In a glovebox, a 100 mL Schlenk flask equipped with a magnetic stirring bar and a septum was charged with (+)-(R)-Compound-14 (100.0 mg, 0.23 mmol, 1.0 eq), copper (I) chloride (25.0 mg, 0.25 mmol, 1.1 eq) and sodium acetate (56.5 mg, 0.69 mmol, 3.0 eq). Toluene (11 mL) was added, and the reaction vessel was brought outside of a glovebox. Septum was then change for a glass stopcock with a metal clipper and the reaction mixture was stirred overnight at 110° C. in a close system. After cooling down to RT, the suspension was opened to air, 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%)
1H NMR (400 MHZ, 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=13.4 Hz, 1H), 2.32 (d, J=13.4 Hz, 1H), 1.82 (s, 3H), 1.38-1.30 (m, 12H), 1.26 (d, J=6.7 Hz, 3H), 1.21 (s, 3H).
13C NMR (101 MHZ, CDCl3): δ: 13C NMR (101 MHZ, CDCl3) δ 246.8, 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.
[α]D=(+)-(R)-copper complex (T=25° C., c=0.110 g/mL, L=10 cm, CH2Cl2)=+20
ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IG, and detected with an UV detector at 254 nm and a circular dichroism detector mL/min at 254 nm. The flow-rate is 1 mL/min Heptane/Isopropanol/dichloromethane (80/10/10), 1 mL/min. ee>99.5%
In a glovebox, a Schenck was charged with the (R)-copper complex (23.6 mg, 0.055 mmol, 1.0 eq), [(SMe2)AuCl] (24.2 mg, 0.082 mmol, 1.5 eq), and THF (0.5 mL). The mixture was then heated at 40 degrees for 4 hours. Solvent was removed under reduced pressure and the crude was purified by column chromatography (dichloromethane). The received solid was filtered over packed celite to remove any nanoparticles. (R)-gold complex (19.9 mg, 0.035 mmol) was obtained as a white solid (19.9 mg, 64% yield).
1H NMR (400 MHZ, CD2Cl2): δ: 7.59-7.53 (m, 2H), 7.51 (d, J=7.7 Hz, 1H), 7.48-7.39 (m, 2H), 7.39-7.29 (m, 3H), 2.96 (hept, J=6.8 Hz, 1H), 2.84 (hept, J=6.7 Hz, 1H), 2.65 (d, J=13.4 Hz, 1H), 2.45 (d, J=13.4 Hz, 1H), 1.92 (s, 3H), 1.46 (d, J=2.4 Hz, 3H), 1.45 (d, J=2.4 Hz, 3H), 1.42 (s, 3H), 1.36 (d, J=6.7 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 1.29 (s, 3H).
13C NMR (101 MHZ, 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.
[α]D=(+)-(R)-gold complex (T=25° C., c=0.153 g/mL, L=10 cm, acetonitrile)=+24
As preliminary photophysical and chiroptical characterizations, the unpolarized (black solid line) and circularly polarized luminescence (CPL) of the enantiopure copper complexes ((R) and(S), blue and red solid lines, respectively, with an average gium value of 10−3) were measured using a CPL spectrofluoropolarimeter. The samples were excited using a 90° geometry with a Xenon ozone-free lamp 150 W LS. The following parameters were used: emission slit width≈2 mm, integration time=4 sec, scan speed=50 nm/min, accumulations=5. The concentration of all the samples was ˜10−5 M. Excitation of the samples were performed at 320 nm. The corresponding results are shown in
ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IG, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min Heptane/Isopropanol/dichloromethane (80/10/10), 1 mL/min. ee>98%
[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 the glovebox. Out of the box under Ar atmosphere, dry and degassed THF (3 mL) was added dropwise over 10 min to the solids at −78° C. The suspension was stirred for 10 min at −78° C., after which the cooling bath was removed, and the reaction mixture was allowed to warm up to rt. After stirring for 16 h at room temperature, volatiles were removed under vacuum. The product was purified by column chromatography (pentane/diethyl ether=9:1) to received yellow-orange solid of (+)-(S)—Rh complex (44.9 mg 51% yield)
1H NMR (400 MHZ, CDCl3): 7.99 (d, J=7.3 Hz, 2H), 7.41 (dt, J=17.2, 7.6 Hz, 4H), 7.29 (d, J=7.2 Hz, 1H), 7.11 (dd, J=7.5, 1.8 Hz, 1H), 5.32 (m, 1H), 4.52 (m, 1H), 3.87 (m, 1H), 2.86 (d, J=13.3 Hz, 1H), 2.65 (m, 2H), 2.51-2.40 (m, 1H), 2.38 (s, 3H), 2.07 (d, J=13.2 Hz, 1H), 1.91 (m, 1H), 1.75 (d, J=6.4 Hz, 3H), 1.66 (s, 3H), 1.66-1.49 (m, 3H), 1.48-1.38 (m, 2H), 1.35 (s, 3H), 1.29 (two pairs of d overlapping, 6H), 1.24-1.07 (m, 2H), 0.72 (d, J=6.7 Hz, 3H).
13C NMR (101 MHZ, CDCl3): 269.23 (d, J=46.7 Hz), 147.98, 146.11, 145.89, 136.57, 129.00, 128.50, 128.11, 126.59, 126.53, 124.15, 101.81 (d, J=5.8 Hz), 98.00 (d, J=6.4 Hz), 78.67, 78.65, 72.11 (d, J=14.6 Hz), 66.37 (d, J=14.0 Hz), 49.03, 35.16, 33.29, 31.28, 30.16, 28.84, 28.58, 28.56, 26.27, 25.52, 25.28, 24.58.
[α]D=(+)-(S)-Rhodium complex (T=25° C., c=0.110 g/mL, L=10 cm, CH2Cl2)=+5
ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IB N-5, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min. ee>99%
| Number | Date | Country | Kind |
|---|---|---|---|
| 21306194.8 | Sep 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/074330 | 9/1/2022 | WO |
