Process for preparing symmetric pincer ligands from the group of the M-terphenyl compounds

Abstract

The present invention relates to a process for preparing compounds of the formula ABA ##STR00001## by reacting a compound of the formula (A) ##STR00002## with a compound of the formula (B) ##STR00003## with X=OR or NHR and R=H or a protecting group function and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group comprising hydrogen, (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, (C.sub.6-C.sub.20)-aryl, O(C.sub.6-C.sub.20)-aryl, where two of the R.sup.1 to R.sup.4 radicals may also be joined via a covalent bond, and halogen, which is characterized in that the reaction is conducted electrochemically.

Claims

1. A process for preparing compounds of the formula (ABA) ##STR00022## by reacting a compound of the formula (A) ##STR00023## with a compound of the formula (B) ##STR00024## with X=OH or NRR; and R=H or a protecting group function; and R=H or a protecting group function; or R and R may together form covalently bonded protecting group radicals and R.sup.1, R.sup.2 , R.sup.3 , R.sup.4 , R.sup.6 , and R.sup.8 are each independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, N[(C.sub.1-C.sub.12)-alky, ].sub.2, NH(C.sub.1-C.sub.12)-alky, (C.sub.6-C.sub.20)-aryl, O(C.sub.6-C.sub.20)-aryl, and halogen; and R.sup.5 and R.sup.7 are each independently selected from the group consisting of (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, N[(C.sub.1-C.sub.12)-alkyl].sub.2, NH(C.sub.1-C.sub.12)alkyl, (C.sub.6-C.sub.20)-aryl, O(C.sub.6-C.sub.20)-aryl, and halogen; where adjacent radicals from the group of the R.sup.1 to R.sup.8 radicals may be joined via a covalent bond, characterized in that the reaction is conducted electrochemically.

2. The process according to claim 1, characterized in that the electrochemical process step comprises: aa) a mixture of at least one solvent and at least one conductive salt is produced, bb) the compounds to be converted are added to this mixture, with addition of the compound of the formula (A) in a molar excess based on the compound (B), cc) at least two electrodes are introduced into the reaction solution obtained in bb) and a voltage is applied to the electrodes, dd) the compounds (A) and (B) are converted to the compound (ABA), ee) the voltage is switched off and optionally ff) the compound (ABA) is isolated and/or purified.

3. The process according to claim 1, characterized in that the molar ratio of the compound (A) to the compound (B) is in the range from 1.5:1 to 4:1.

4. The process of claim 3, wherein the molar ratio of the compound (A) to the compound (B) is in the range from 1.8:1 to 2.5:1.

5. The process of claim 4, wherein the molar ratio of the compound (A) to the compound (B) is 2:1.

6. The process according to claim 1, characterized in that compounds of the formula (A)are compounds in which X=NHR.

7. The process according to claim 1, characterized in that compounds of the formula (A) are compounds in which X=NH.sub.2.

8. The process according to claim 1, characterized in that R.sup.6 and R.sup.8 are identical.

9. The process of claim 8, wherein R.sup.6 and R.sup.8 are hydrogen.

10. The process according to claim 1, characterized in that the reaction is conducted in the presence of a solvent and the solvent is selected from the group consisting of acetonitrile, propylene carbonate, methyl carbonate, nitromethane, ethylene glycol dimethyl ether, methanesulphonic acid, benzene, toluene, water, methanol, ethanol, propanol, isopropanol, halogenated solvents, halogenated or non-halogenated acids, and mixtures thereof.

11. The process according to claim 10, characterized in that the solvent is methanol, formic acid, trifluoroacetic acid, hexafluoroisopropanol or mixtures thereof.

12. The process of claim 11, where the solvent is methanol, hexafluoroisopropanol, or mixtures thereof.

13. The process of claim 12, wherein the solvent is hexafluoroisopropanol.

14. The process according to claim 1, characterized in that the reaction is conducted without the use of organic oxidizing agents.

15. The process according to claim 1, characterized in that the electrochemical process step is conducted in the presence of at least one conductive salt.

16. The process according to claim 15, characterized in that the counterions of the conductive salts are selected from the group consisting of arsenate, sulphate, hydrogensulphate, alkylsulphate, alkylphosphate, perchlorate, fluoride, aryisulphate, hexafluorophosphate, and tetrafluoroborate.

17. The process according to claim 15, characterized in that the conductive salt is selected from the group consisting of quaternary ammonium borates, ammonium fluoroalkylphosphates, ammonium fluoroalkylarsenates, ammonium trifluoromethylsulphonates, ammonium bis(fluoromethanesulphon)imides, ammonium tris(fluoromethanesulphonyl)methides, methyltributylammonium methylsulphate, methyltriethylammonium methylsulphate, tetrabutylammonium hexafluorophosphate, tetraethylanunonium tetrafluoroborate, lithium hexafluorophosphate, and tetraethylanunonium tetrafluoroborate.

18. The process of claim 17, wherein the conductive salt is methyltriethylammonium methylsulphate or Bu.sub.3NMe.sup.+MeOSO.sub.3.sup.(methyltributylammonium methylsulphate).

19. The process of claim 18, wherein the conductive salt is methyltributylammonium methylsulphate.

20. The process of claim 15, wherein the at least one conductive salt is a tetra(C.sub.1-C.sub.6-alkyl)ammonium or 1,3-di(C.sub.1-C.sub.6-alkyl)imidazolium salt, with the proviso that the alkyl groups may be halogen-substituted.

21. The process of claim 1, wherein protecting group function of R and R is selected from the group consisting of tert-butyloxycarbonyl, methyloxycarbonyl, benzyloxycarbonyl, phenyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, sulphonyl, and sulphenyl.

22. The process of claim 1, wherein R and R may together form radicals of the formula PGa or PGb ##STR00025##

23. The process of claim 1, wherein R.sup.1, R.sup.2, R.sup.3,R.sup.4,R.sup.6 and R.sup.8 are each independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, N[(C.sub.1-C.sub.12)-alkyl].sub.2, and halogen.

24. The process of claim 23, wherein R.sup.1,R.sup.2,R.sup.3,R.sup.4,R.sup.6 and R.sup.8 are each independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.12)-alkyl, and O(C.sub.1-C.sub.12)-alkyl.

25. The process of claim 1, wherein R.sup.5 and R.sup.7 are each independently selected from the group consisting of (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, N[(C.sub.1-C.sub.12)-alkyl].sub.2, and halogen.

26. The process of claim 25, wherein R.sup.5 and R.sup.7 are each independently selected from the group consisting of (C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, and N[(C.sub.1-C.sub.12)-alkyl].sub.2.

Description

(1) The examples adduced below illustrate the present invention by way of example, without any intention that the invention, the scope of application of which is apparent from the entirety of the description and the claims, be restricted to the embodiments specified in the examples.

EXPERIMENTAL

(2) General Methods

(3) Chromatography (GC/GCMS)

(4) Preparative liquid chromatography for separation of substance mixtures was conducted using 60 M silica gel (0.040-0.063 mm) from MACHERY-NAGEL GMBH & CO. KG, Dren at a maximum pressure of 2 bar. All the eluents used (ethyl acetate, technical grade quality; cyclohexane, technical grade quality) were purified beforehand by distillation on a rotary evaporator.

(5) Thin-layer chromatography (TLC) was conducted on ready-made PSC silica gel 60 F.sub.254 plates from MERCK KGaA, Darmstadt. The various substances were detected first under UV light and then by staining by means of cerium-molybdophosphoric acid reagent (5.6 g of molybdophosphoric acid, 2.2 g of cerium(IV) sulphate tetrahydrate and 13.3 g of conc. sulphuric acid in 200 ml of water), followed by heating with a hot air gun.

(6) Gas Chromatography (GC/GCMS)

(7) The gas chromatography studies (GC) on product mixtures and pure substances were effected with the aid of the GC-2010 gas chromatograph from Shimadzu, Japan. Analysis is effected on an HP-5 quartz capillary column from Agilent Technologies, USA (length: 30 m; internal diameter: 0.25 mm; film thickness of the covalently bound stationary phase: 0.25 m; carrier gas: hydrogen; injector temperature: 250 C.; detector temperature: 310 C.; programme: hard method: start temperature 50 C. for 1 min, heating rate: 15 C./min, end temperature 290 C. for 8 min). Gas chromatography-mass spectrometry analyses (GC-MS) of product mixtures and pure substances were recorded with the aid of the GC-2010 gas chromatograph combined with the GCMS-QP2010 mass detector from Shimadzu, Japan. Analysis is effected on an HP-1 quartz capillary column from Agilent Technologies, USA (length: 30 m; internal diameter: 0.25 mm; film thickness of the covalently bound stationary phase: 0.25 m; carrier gas: hydrogen; injector temperature: 250 C.; detector temperature: 310 C.; programme: hard method: start temperature 50 C. for 1 min, heating rate: 15 C./min, end temperature 290 C. for 8 min; GC-MS: ion source temperature: 200 C.).

(8) Mass Spectrometry

(9) All electrospray ionization analyses (ESI+) were conducted on a QTof Ultima 3 from Waters Micromasses, Milford, Mass. EI mass spectra and the high-resolution EI spectra were analysed on an instrument of the MAT 95 XL sector field instrument type from Thermo Finnigan, Bremen.

(10) NMR Spectroscopy

(11) The NMR spectroscopy studies were conducted on multi-nucleus resonance spectrometers of the AC 300 or AV II 400 type from Bruker, Analytische Messtechnik, Karlsruhe. The solvent used was CDCl3. The .sup.1H and .sup.13C spectra were calibrated according to the residual content of undeuterated solvent using the NMR Solvent Data Chart from Cambridge Isotopes Laboratories, USA. Some of the .sup.1H and .sup.13C signals were assigned with the aid of H,H-COSY, H,H-NOESY, H,C-HSQC and H,C-HMBC spectra. The chemical shifts are reported as values in ppm. For the multiplicities of the NMR signals, the following abbreviations were used: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), tq (triplet of quartets). All coupling constants J were reported in hertz (Hz) together with the number of bonds covered. The numbering given in the assignment of signals corresponds to the numbering shown in the formula schemes, which need not necessarily correspond to IUPAC nomenclature.

(12) Single Crystal Structure Analyses

(13) The single crystal structure analyses were conducted in the Institute of Organic Chemistry at the Johannes Gutenberg University of Mainz on an IPDS 2T instrument from STOE & Cie GmbH, Darmstadt.

(14) Melting Points

(15) The relevant melting points were measured with the aid of the SG 2000 melting point determination instrument from HW5, Mainz, and were adopted in uncorrected form.

(16) General Procedures

(17) GP1: Electrochemical Cross-Coupling in L Cells

(18) 5 mmol of the species A to be oxidized (deficiency component) were reacted with a 2-3-fold excess (10-15 mmol) of the coupling partner B in 33 ml of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) or 33 ml of (HFIP with 18% by volume of methanol (MeOH) based on the sum total of HFIP and MeOH) in an undivided flange cell with a BDD anode and nickel mesh cathode. The conductive salt used was Bu.sub.3NMe.sup.+MeOSO.sub.3.sup. (MTBS) with a concentration of 0.09 M. The electrolysis was galvanostatic. The outer shell of the electrolysis cell was kept at a controlled temperature of about 10 C. by means of a thermostat, while the reaction mixture was stirred and heated to 50 C. with the aid of an oil bath. After the electrolysis had ended, the cell contents were transferred to a 50 ml round-bottom flask and the solvent was removed under reduced pressure on a rotary evaporator at 50 C., 200-70 mbar. Mineralization products and the conductive salt present were separated by elution by means of ethyl acetate (300 ml) using 50 g of silica gel 60. Unconverted reactant was recovered by means of short-path distillation in a Kugelrohr still (100 C., 10.sup.3 mbar). The reaction products formed were separated by column chromatography as specified in each case.

(19) Electrode Material:

(20) TABLE-US-00001 Anode: BDD (15 m diamond layer) on silicon support Cathode: nickel mesh

(21) Electrolysis Conditions:

(22) TABLE-US-00002 Temperature: 50 C. Current density: 2.8 mA/cm.sup.2 Charge: 2-4 F based on the deficiency component Terminal voltage: 3-6 V

(23) One-stage Pincer Ligand Synthesis

Example 1

2,2-Dihydroxy-5,5-dimethyl-2-N,N-dimethylamino-3,3,4-trimethoxy[1,1;51]terphenyl (1)

(24) The performance of the electrolysis was effected according to GP1 with 1.38 g (10 mmol, 2.0 equiv.) of 4-methylguaiacol and 0.76 g (5 mmol, 1.0 equiv.) of 3-(N,N-dimethylamino)anisole. The current was 15 mA; the amount of charge, with 4F per 3-(N,N-dimethylamino)anisole, was 1929.7 C. The crude product was prepurified by column chromatography on silica gel 60 with eluent mixture gradient of 95:5 then 9:1 and finally 4:1 (cyclohexane (CH):ethyl acetate (EA)). The fractions obtained were examined for the presence of the product and purified again on silica gel 60 with a 1:1:0.01 then 1:1:0.02 eluent (dichloromethane (DCM):cyclohexane (CH):methanol (MeOH)). A further purification of mixed fractions was conducted by Kugelrohr distillation (150 C., 180 C., 190 C. and 205 C., 10.sup.3 mbar). The product was obtained as a yellow oil.

(25) ##STR00020##

(26) Yield: 54 mg (0.13 mmol, 3%)

(27) GC (hard method, HP-5): t.sub.R=18.40 min

(28) R.sub.f (DCM:MeOH=99:1)=0.36

(29) .sup.1H NMR (300 MHz, CDCl.sub.3) [ppm]=2.28 (s, 3H, H-8 o. H-11), 2.29 (s, 3H, H-8 o. H-11), 2.85 (bs, 6H, H-9), 3.77 (s, 3H, H-10), 3.81 (s, 3H, H-7 o. H-12), 3.82 (s, 3H, H-7 o. H-12), 6.40 (bs, 1H, H-13 o. H-14), 6.57 (s, 2H, H-4, H-4), 6.59-6.61 (m, 1H, H-6), 6.67 (m, 1H, H-3), 6.68-6.72 (m, 2H, H-6, H-6).

(30) .sup.13C NMR (101 MHz, CDCl.sub.3) [ppm]=21.10 (C-8 o. C-11), 21.22 (C-8 o. C-11), 43.44 (C-9), 55.71 (C-10), 55.81 (C-7 o. C-12), 56.91 (C-7 o. C-12), 104.68 (C-3), 111.99, 112.07, 113.08, 113.26, 113.86, 116.59, 118.44, 120.83, 121.01, 121.50, 130.30, 132.23, 144.14, 146.66, 149.30 (C-3 o. C-3), 150.03 (C-3 o. C-3), 157.70 (C-4).

(31) HRMS (ESI, pos. mode): m/z for C.sub.25H.sub.30NO.sub.5 [M+H.sup.+]:

(32) calculated: 424.2124; found: 424.2131

(33) Elemental analysis: calculated: C: 70.90% H: 6.90% N: 3.31%

(34) found: C: 69.33% H: 6.95% N: 3.17%

Example 2

2,2-Dihydroxy-3,3,4-trimethoxy-5,5,2-trimethyl[1,1;51]terphenyl (2)

(35) The electrolysis was conducted according to GP1 with 1.45 g (10.5 mmol, 2.0 equiv.) of 4-methylguaiacol and 639 mg (5.23 mmol, 1.0 equiv.) of 3-methylanisole. The current density was 2.8 mA/cm.sup.2, the charge 2 F per 4-methylguaiacol (Q=2018 C). After removal of the solvent, the product mixture was purified by column chromatography on silica gel 60 with an eluent of 9:1 (CH:EA). The product was obtained as a yellowish oily substance.

(36) ##STR00021##

(37) Yield: 68 mg (0.17 mmol, 3%)

(38) GC (hard method, HP-5): t.sub.R=21.35 min

(39) R.sub.f (Cy:EA=4:1)=0.39

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) [ppm]=2.28 (s, 3H, 14-H), 2.29 (s, 3H, 9-H), 2.30 (s, 3H, 10-H), 3.89 (s, 3H, 8-H), 3.90 (s, 3H, 13-H), 3.91 (s, 3H, 11-H), 6.00 (bs, 2H, 7-H, 12-H), 6.69-6.72 (m, 4H, 4-H, 4-H, 6-H, 6-H), 6.93 (s, 1H, 3-H), 7.19 (s, 1H, 6-H).

(41) .sup.13C NMR (101 MHz, CDCl.sub.3) [ppm]=20.33 (C-10), 21.23, 21.26 (C-9, C-14), 56.13, 56.14 (C-11, C-13), 56.17 (C-8), 110.72 (C-4), 111.56 (C-4), 113.02 (C-3), 123.69, 123.76 (C-6, C-6), 124.44 (C-5), 125.25, 125.53 (C-1, C-1), 128.88 (C-6), 129.39 (C-1), 130.62, 133.66 (C-5, C-5), 138.05 (C-2), 140.63, 141.07, 146.40 (C-3, C-3, C-4), 147.66 (C-2), 155.37 (C-2).

(42) HRMS (ESI, pos. mode): m/z for C.sub.24H.sub.26O.sub.5 (M+Na.sup.+):

(43) calculated: 417.1678; found: 417.1670

(44) Melting point: 67.7 C. (crystallized from DCM)