Coordination Compounds Based on 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid †

Syntheses of 2,6-bis[((3S)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]pyridine and its coordination compounds with Cu2+, Co2+, Co3+, or Fe3+ are described. By means of 1H- and 13C-NMR spectra it was proved that 2,6-bis[((3S)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]pyridine as well as its coordination compound with Co3+ exist in the form of a mixture of three conformers, differing in the conformations at the two amide groups present. The prepared coordination compounds were tested in the enantioselective catalysis of the nitroaldol addition of nitromethane with 2-nitrobenzaldehyde or 4-nitrobenzaldehyde, and in the Michael addition of ethyl 2-oxocyclohexanecarboxylate to but-3-en-2-one.


Introduction
The study of catalysis of enantioselective reactions continues to attract attention.Although the focus has shifted towards design of the optimum catalyst for carrying out a certain particular reaction, a number of papers are still being published, generally dealing with tests of chiral ligands with "potential ability" to catalyze enantioselective reactions.In particular, such ligands are taken from the "chiral pool" of natural homochiral amino acids, their derivatives and other compounds derived from them (chiral aminoalcohols, aminoamides etc.) [1][2][3][4].The derivatives of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic Acid) [5,6] (a chiral α-amino acid not found in nature) which structurally resemble anellated oxazolines [7,8] have not been studied yet in enantioselective catalytic reactions.
Formation of two amide bonds results in the creation of forms AA, BB, AB and BA with comparable probability.Forms AB and BA are identical and will be referred to henceforth as form AB+BA.The forms discussed are depicted in Figure 1.The unsymmetrical form AB+BA is formed in a double amount as compared with forms AA or BB.From the standpoint of symmetry, form AB+BA belongs to the point group C 1 and would exhibit two sets of signals in both 1 H-and 13 C-NMR spectra.The intensity of both sets of multiplets in the 1 H NMR spectrum should be comparable with the intensity of multiplets of forms AA and BB, because forms AA and BB belong to point group C 2 and will exhibit only one set of signals for each of the forms in 1 H-NMR spectrum.According to the quantum-chemical simulations, the 1 H-NMR spectrum should contain 4 sets of multiplets with similar intensities.This prediction fully corresponds with the experimental NMR spectrum of compound 2 (Figure 2), in which there really are four sets of signals of comparable intensities for the individual protons.This situation can be easily observed on the multiplets of protons H(3) and H(1) of the tetrahydroisoquinoline skeleton (δ 4.6-5.6)and the signals of the OCH 3 groups (δ 3.4-3.7).No mutual transformation of individual forms on the NMR time scale was observed up to 50 °C.

Scheme 2
The optical purity of the non-racemic product determined by HPLC on chiral column by comparison with the racemic substance was 94.6 % (Figure 3).The proportion of conformers in the (S)-enantiomer is ca 5:2 according to the 1 H-NMR spectrum (Figure 4).The same conclusions were obtained based on the geometry optimization of acetyl derivative carried out at the B3LYP/TZVP level [11][12][13] (Figure 5).In order to achieve better correlation of the results with the 1 H-NMR spectrum the calculation included the solvent (chloroform) effect by means of the polarised continuum method (PCM) [14].Out of the pair of optimized structures (Figure 5) structure A was assigned to predominating rotameric form in NMR spectrum on the basis of calculated energies.
In the case of compounds having an RNHCO-group attached to nitrogen atom of tetrahydroisoquinoline skeleton [6] the 1 H-NMR spectrum only exhibits the presence of only one of the two possible rotamers, due to the existence of strong intramolecular hydrogen bond (Figure 6).The quantum-chemical calculation results clearly indicate that the electron density at the tetrahydroisoquinoline residue nitrogen atom is noticeably higher in the molecule of compound 2 than in that of the acetyl derivative 3a.Due to the steric demands of the Tic residues in the molecule of 2 these residues are deviated, which disturbs the planarity and leads to partial loss of conjugation in the N-CO-Py grouping.Hence, according to these calculations compound 2 could operate as a tridentate ligand and coordinate with transition metals.This presumption was later confirmed experimentally.
Of all the coordination compounds prepared only proved suitable for NMR measurements, namely the 2,6-bis-[((3S)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]pyridine Co 3+ complex.Both its 1 H-and 13 C-NMR spectra were of adequate quality with slightly broadened signals (Figure 7).The 1 H-NMR spectrum of this coordination compound resembles that of the free ligand.From the 13 C-NMR spectrum it is obvious that it also corresponds to a mixture of three compounds of the types AA, BB, AB+BA, which are present at roughly equimolecular ratios (the tetrad of signals for corresponding carbons in the spectrum).The ability of the prepared coordination compounds to catalyze enantioselective reactions was tested on the Henry nitroaldol addition of nitromethane with 2-nitro-or 4-nitrobenzaldehyde (Scheme 5), under the conditions described in [19], and on the Michael addition reaction of ethyl 2-oxocyclohexanecarboxylate with but-3-en-2-one (Scheme 6), under the condition described in [20][21][22][23].

Scheme 6
In the Michael addition reaction of ethyl 2-oxocyclohexanecarboxylate with but-3-en-2-one catalysed by coordination compound 5e the required product was obtained in high chemical yield but with an enantiomeric excess of only 7.2 % (Table 3).This lower efficiency is obviously due to the far higher steric demands in the surroundings of coordination centres than are those of, e.g., the catalysts based on 2,6-bis(oxazolyl)pyridines [15].Another problem lies in the fact that the coordination compounds derived from substance 2 are present (obviously all of them) in three rotameric forms (Figure 1), and it is not quite clear whether these forms can be transformed into one another during the interaction with the molecules undergoing the catalysed reaction, neither is it known which of the forms is active in the catalysed reaction.

General
The NMR spectra were measured at 298 K with a Bruker AVANCE 500 spectrometer equipped with 5 mm broadband probe at the frequencies of 500.13MHz ( 1 H) and 125.77MHz ( 13 C) and with a Bruker AMX 360 spectrometer at the frequencies 360.14 MHz ( 1 H) and 90.57MHz ( 13 C) in CDCl 3 and DMSO-D 6 respectively.Spectra were calibrated on TMS (in CDCl 3 ) or on the central signal of the solvent multiplet in DMSO-D 6 (δ 2.55, and 39.6 respectively).J values are given in Hertz.The 13 C NMR spectra were measured in standard way and by means of the APT pulse sequence.The proton signals were assigned with the help of H-H COSY pulse sequence.Optical purity was determined by chiral HPLC.HPLC system consisted of a Spectra Series P200 gradient pump (Fremont, CA, USA), a HP 1100 Series autosampler, a HP 1100 Series thermostated column compartment from Hewlett Packard (Waldbronn, Germany), and a SPD-10A VP UV-Vis detector from Shimadzu (Prague, Czech Republic).The enantiomers of the compound 3 were measured at 209 nm (Figure 6).Data from chromatographic runs were processed using a chromatography station for Windows CSW (version 1.7) software from DataApex (Prague, Czech Republic).Separation of the respective enantiomers was performed using a 250 × 4.6 mm OD-R Chiralcel column from Daicel Chemical Industries (Tokyo, Japan).The mobile phase was prepared by mixing buffer (0.3 M sodium perchlorate, pH 3.0 set by HClO 4 ) with acetonitrile 50/50 (v/v).HPLC separation was performed at 25°C with a flow rate of 0.8 mL/min.Melting points were determined with a Kofler hot stage microscope and were not corrected.The microanalyses were performed on a FISONS EA 1108 CHNS automatic analyser.Optical rotations were measured on PERKIN ELMER 341 Polarimeter at λ 589.3 nm and 298 K, concentration c is given in g/100 mL.The starting material (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (CMS Chemicals LTD), mp 331 °C (decomp) was 99.1% pure, according to titration with HClO 4 , and had [ ] 20 D α = -175.8°(c 1.1N NaOH, aq) [ref.[24] gives [ ] 20 D α = -177.4° (c 1.1N NaOH, aq)].

Coordination compounds of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid with transition metals
Coordination compounds 4a,b were prepared according to a procedure described in ref. [15].A suspension was prepared in methanol from equimolecular amounts of (S)-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid and the transition metal salt.After 12 h vigorous stirring, the precipitate formed was collected by suction, and then washed with methanol and ether.pyridine and transition metal salt were dissolved in dry methanol.The corresponding coordination compound was obtained after evaporation of the solvent and washing with ether and hexane.Cobalt(III) acetate was prepared by oxidation of cobalt(II) acetate with aqueous solution of peroxyacetic acid [28].The structure of coordination compound 5d containing Co(III) can be studied by means of NMR.These spectra clearly show that the product is a mixture of three isomeric forms -two symmetrical ones, and one unsymmetrical, the latter being present in a double amount.Hence, the NMR spectrum exhibits 4 sets of signals of comparable intensities (for the proton at the 4-position of pyridine ring only 3 multiplets for 4 protons). 1H-NMR (DMSO-D 6 ) (see Figure 7

2-Nitro-1-(4-nitrophenyl)ethanol (6)
The reaction of nitromethane with 4-nitrobenzaldehyde catalyzed by the coordination compound (Scheme 5) was carried out by the known procedure [19]: a solution of nitromethane (1.4 mL, 25 mmol) and 4-nitrobenzaldehyde (0.38 g, 2.5 mmol) in dry ethanol (2 mL) was treated with coordination compound (5 mol %, 0.125 mmol).The reaction course was monitored by means of TLC (silica gel -ethyl acetate-hexane 1:4 by vol.).After keeping at the chosen temperature for a chosen time interval, the reaction was stopped by evaporating the solvent in vacuum without heating.The evaporation residue was treated with CoCl 2 (0.05 g, 0.385 mmol) in ethanol (10 mL) in order to transform any possible uncoordinated ligand present into the coordination compound.Methanol was evaporated under vacuum, and the residue was dissolved in ether.The coordination compounds and the unreacted CoCl 2 were removed from the ether solution by flash chromatography (silica gel 60 µm -ether).The ethereal filtrate was then extracted with 10% aqueous solution of sodium sulphite (2 × 20 mL) and with H 2 O (1 × 10 mL).This procedure removed all unreacted aldehyde.Drying and removal of ether by evaporation without heating gave pure 2-nitro-1-(4-nitrophenyl)ethanol; m.p. 82-84 °C.The enantiomeric excess was then calculated from chemical purity and optical rotation.The reaction of nitromethane with 2-nitrobenzaldehyde was carried out in the same way as that with 4nitrobenzaldehyde above to afford 2-nitro-1-(2-nitrophenyl)ethanol (7); m.p. 80-82 °C, o.r.+31.4 (c = 1, CH 2 Cl 2 ).
Ethyl 2-oxo-1-(3-oxobutyl)cyclohexanecarboxylate (8) The reaction of ethyl 2-oxocyclohexanecarboxylate with but-3-en-2-one catalyzed with the coordination compounds (Scheme 6) was carried out by known procedures [20][21][22][23].A solution (or suspension) of ethyl 2-oxocyclohexanecarboxylate (0.16 mL, 1 mmol) and coordination compound (5 mol %, 0.05 mmol) in CH 2 Cl 2 (1 mL) was vigorously stirred and treated with but-3-en-2-one (0.20 mL, 2 mmol).The reaction course was monitored by means of TLC (silica gel -ether-hexane 1:2 by vol.).After keeping at the chosen temperature for a chosen time interval, the reaction was stopped by evaporation of solvent without heating, whereupon the evaporation residue was dissolved in ether.The coordination compound was removed from the resulting ethereal solution by means of flash chromatography (silica gel 60 µm -ether).The ether solvent was evaporated without heating to give pure ethyl 2-oxo-1-(3-oxobutyl)cyclohexanecarboxylate as an oily substance.Its chemical purity was checked by means of liquid chromatography and its enantiomeric purity by measuring optical rotation of the product.The enantiomeric excess was then calculated from chemical purity and optical rotation.

Figure 3 .
Figure 3. Chiral HPLC separation of the enantiomers of acetyl derivative 3. Upper chromatogram represents separation of racemic mixture and lower the enantiomeric purity of the (S)-enantiomer 3a (e.e. 94.6%).For separation conditions see Experimental.

Table 4 .
Microanalysis data for compounds