Bidentate Schiff bases derived from ( S )-α-methylbenzylamine as chiral ligands in the electronically controlled asymmetric addition of diethylzinc to aldehydes

A group of bidentate Schiff bases derived from enantiomerically pure ( S )-  -methylbenzylamine was synthesized. Crystal structure was determined for three compounds. Schiff bases were used as chiral ligands in the asymmetric addition of Et 2 Zn to aldehydes. The obtained enantioselectivity was e.e.=8-94% depending on the substrate and the best was observed for ( S,E )-2-(1-(1-phenylethylimino)-ethyl)phenol. The enantioselectivity increase was connected with the substituent-induced electronic effects in the substrate molecules. Molecular modeling resulted in the models of the 3D structures of Zn-Zn complex catalysts containing investigated Schiff bases, which were consistent with the reported chirality of the addition product and explained observed e.e. The presented transition state models allow explaining the change of the absolute configuration of diethylzinc addition product in the case of using ortho -substituted aldehydes.


Introduction
Bidentate chiral salicylidene Schiff bases (SB) derived from (S)--methylbenzylamine have been of particular interest due to: significant ability of chelation and great stability of metal complexes 1 , interesting antifungal activity 2 and potential use as important intermediates in the synthesis of benzoxazines having antimicrobial 3 , antitumour 4 or anthelmintic 5 activities.Moreover, enantiopure Schiff bases, after chelation with appropriate metals, have been used as catalysts in such reactions as: cyclopropanation of styrene 6 , trimethylsilylcyanation of aldehydes 7 , Heck or Suzuki coupling reactions 8 .These reactions belong to the group of processes of catalytic asymmetric carbon-carbon bond formation, which is one of the most extensively applied methods in organic chemistry.The use of chiral Schiff bases in the asymmetric synthesis was broadly described in literature 9 .However, only few examples of very effective imines have been presented 10 .Bidentate salicylidene SB, obtained from (S)--methylbenzylamine and its derivatives, can be prepared by solvent-free methods 11 and can also be used to obtain efficient aminophenol ligands for the enantioselective addition reactions 12 .
Enantioselectivity of catalytic asymmetric reactions has usually been coupled to the steric hindrance effects.By contrast, a concept of electronic control or electronic tuning in the asymmetric catalysis reactions has been less explored and is still poorly understood.This effect was previously described e.g. by Landis et al. 13 in the asymmetric hydrogenation or by Park 14 in the cyclopropanation of alkenes.Zhang et al. 15 for the first time observed that the enantioselectivity of diethylzinc addition to aldehydes could depend on the electronic effects related to the nature of the aryl aldehydes and increases with more reactive substrates.In this article we report the synthesis of nine Schiff bases derived from (S)--methylbenzylamine and their efficiency as chiral ligands.Also, the remarkable findings about electronic effects in the asymmetric addition of diethylzinc to aldehydes are reported.
All products have been purified by crystallization from appropriate solvents (2-4, 8, 9) or by distillation under reduced pressure (1, 5-7).The compounds similar to ours 1, 2, 4, 8 and 9 have been previously described in Ref. 6,7,16 and 17.The detailed analysis revealed that our compounds have already been synthesized as the same enantiomers (2, 4, 8) 6,7 , or as Renantiomers (1, 9) 16,17 while all our compounds have S-configuration.Comparison of our results with the above references showed that there are some differences between the results of the optical rotation measurements in the case of 1, 2, 4, 8, 9.The discrepancy could be caused by: the use of the different solvent for the measurement 6,16,17 for 2, 4, 8, different enantiomeric purity of -methylbenzylamine 17 for 9, or a lack of the Schiff base 1 purification 16 .All SB described here were of high purity that was confirmed by the MS analyses.
The UV-Vis absorption spectra were also recorded for all obtained Schiff bases (methanol solutions).Results are presented on Figure 1.The solution spectra indicated that the electronic properties of SB 1-9 were strongly dominated by the donor-acceptor chromophore (Fig. 1).Electronic absorption spectra of Schiff bases showed the π→π* transitions related to aromatic rings at about 205-250 nm and π→π* transitions related to imine group at about 275-350 nm.Moreover, the longer wavelength band at 325-450 nm, characteristic for 1 and 8, was assigned in accordance with Ref. 18 and 19 to an intramolecular charge transfer involving the whole molecule.This effect could be caused by the probable keto-amine tautomer formation in a methanol solution.The tautomerization of chiral hydroxy SB was described before 20 and usually is connected with an intra-and intermolecular hydrogen bond between phenolic hydroxyl and iminium nitrogen.
The crystal structures for imines 2, 8 and 9 have been determined by the X-ray analysis.Details of the diffraction experiments and structure refinement are presented in Table 1.The molecular structure of 2, 8 and 9 with the atom numbering scheme is presented on Fig. 2.
The molecular conformation of all investigated compounds 2, 8 and 9 was determined by almost identical intramolecular hydrogen bonds between O1 hydroxyl group and the imine N1 atom.The presence of the intramolecular O-H...N hydrogen bond was detected in all structures of analogous imines as found with the CSD 21 .In all reported structures 2, 8 and 9 the molecule had the E-conformation.The presence of bromine atom in 9 allowed determining the absolute configuration as S which was consistent with the chirality of the substrate used in the synthesis.For 2 and 8, the absolute structure could not be determined reliably with the Flack method 22 .Therefore, the correct chirality was chosen as S by the comparison to that determined for 9.
The inspection of CSD revealed the report on the crystal structure of R-enantiomer of 9 23 .Comparison of the structure 9 with that reported for R-enantiomer showed that the cell parameters of our structure were of higher precision and the structure determination resulted in the R value lower by 1%.However, some differences in the molecular conformation were found which reflected the opposite configuration on C1.The structure of S-enantiomer reported here was similar to that of S-enantiomer of the chloro-analog 24 , for which the two torsion angles described above are 120.7 and 48.2°.
We determined the structure of 2, to obtain the reference structure of the compound with no additional substituent in the phenolic ring.The CSD search revealed the report on the racemate of 2 crystallizing in the P2(1)/n space group and the optically pure form crystallizing in the C2 space group 25 .
SB (1-9) were tested as chiral ligands in the enantioselective addition of diethylzinc to aldehydes (Scheme 2).In the first stage, ligands (1-9) were used in an amount of 20 mol %.Diethylzinc in amount of 2 equiv. in relation to 1 equiv. of benzaldehyde was used according to procedures described before in Ref. 26.Previous reports 27 and 28 showed that the enantioselectivity depends on temperature during the catalyst formation.Therefore, different temperature values were examined for the first step of reaction.All results of studied reactions are summarized in Table 2. a Reaction was carried at the temperature range from 0°C to +20°C.b Reaction was carried at the temperature range from -20°C to +20°C.c Reaction was carried at the temperature range from -70°C to +20°C.d Determined by GC using Zebron ZB-5 capillary column (for crude samples).e Isolated products.f Determined by HPLC using OD-H column.g The configuration was determined by the measurement of the optical rotation and by comparison with literature values 29 .
The best results for investigated SB chiral ligands were observed when both the catalyst formation and addition to benzaldehyde were performed at 0° C (then the reaction was carried at 20° C).The absolute configuration of the product depended on the absolute configuration of the used SB ligand.The obtained results indicated that bidentate ligands (1-9) having the Sconfiguration gave (S)-1-phenylpropanol as a major product, but only with a weak asymmetric induction in the investigated process.However, relatively good yields of product (41-99%) and poor yields of by-product (<22%) have been achieved.
The modest enantiomeric excesses in the addition Et2Zn to benzaldehyde, e.e.=8-27% were obtained.The highest enantiomeric excess was observed for ligand 1 (Table 2: entry 1).The results showed that the presence of the methyl moiety (R 1 substituent, Scheme 1), bonded to imine group was a discriminating factor for the substrate orientation.Similar effects of the methyl substituent on the imine carbon atom for Schiff base ligands derived from 4hydroxy[2.2]paracyclophane were reported by Danilova et al. 30 .
Based on the crystal structure of 2, models of the active complex with ligand 1 having opposite R-configuration as well as S-configuration were proposed.Both models were optimized by Molecular Mechanics method in Arguslab program using UFF force field 31 and were consistent with the literature examples for chiral bidentate ligands 26,32,33 .The first model with (R)-1 showed that the addition to Re face of the aldehyde was preferred.The bulk of the phenyl ring in the R-enantiomer of the ligand enforces binding of benzaldehyde with its Re face exposed to ethyl group addition.Therefore, the obtained models suggested the importance of the absolute configuration of ligand for chirality of the addition product.
The model with (S)-1 showed that substituent R 1 =CH3 might have only limited effect on the orientation of the substrate although preference for the Si face, which was consistent with observed e.e.=27% (Table 2: entry 1) and S-configuration of addition product.It was also noticed that replacement of this methyl group by the bigger group could increase the enantiomeric excess due to the increased bulk near the expected position of benzaldehyde (Fig 3).The presence of the substituent in the ligand phenolic ring also decreased the enantiomeric excess, which was probably connected with either bulk or electronic effects of the substituent.However, Fig. 3 showed that the presence of substituents in phenolic ring, even on C6 (see: Fig. 2), had only secondary importance for the stereochemistry of the end product of Et2Zn addition to benzaldehyde since they would be positioned too far away from the reaction center in the transition state.Similar effect was described by Parrott II 34 and Tanaka 35 .The presented model obtained for ligand 1 showed, that there is only a little difference between the addition to Re and Si faces (Fig. 3).Calculation indicated that in both Re and Si orientation of the substrate, the - stacking interactions could stabilize the transition state.Also, R 1 substituent might be a factor responsible for slight asymmetric induction.This conclusion was consistent with our experimental data indicating that the absence of -CH3 group in other investigated ligands resulted in the decrease of enantioselectivity (Table 2: entries 4-11).
In spite of only modest e.e.=27% obtained for ligand 1, the ligand was examined in a series of reactions with a variety of aromatic and aliphatic aldehydes under optimized conditions (Table 3).a Isolated products.b Determined by HPLC using OD-H column or by GC using -Dex capillary column.c The configuration was determined by the measurement of the optical rotation and by comparison to literature values 29 .
When o-, m-, p-methoxy-, p-dimethylamino, o-chloro-, o-bromobenzaldehyde and also cyclohexanecarbaldehyde (Table 3: entries 1-5, 9-10) were used, the enantiomeric excesses were lower or at the same level as for benzaldehyde (Table 2: entry 1).However, in the case of mchloro and p-chlorobenzaldehyde as well as p-bromobenzaldehyde the e.e.'s of addition products were significantly higher (e.e.=94%, 53% and 96%) (Table 3: entries 6-8).The presence of electron-withdrawing substituents in substrates, that caused an increase of Lewis acidity on the carbon atom of carbonyl group, was responsible for increasing reactivity of the substrate.Zhang 15 reported the linear relation between enantioselectivity and the Hammett constant for para-substituted substrates using pyridylphenols as ligands.In contrast, in our group of ligands such linear dependence was not so clear.In some reports e.g.Ref. 36 about the electronic effects in the organic reactions, the reasons of this phenomenon were inadequately described.In accordance with mechanism proposed by Zhang 15 for diethylzinc addition and Landis 13 for asymmetric hydrogenation, the aldehyde binding to zinc complex with Schiff base ligand, involved in the salicylidene moiety the imine bond conjugated with the aromatic ring, led to the formation of transition state that was stabilized by the electron-withdrawing substituents on para-position.The UV-Vis spectra (Fig. 1) described above revealed the tautomeric equilibrium for the analyzed Schiff base 1.The tautomerization effect probably also affected the interaction between the substrate and the ligand as well as the geometry of the catalyst complex and the transition state (Fig. 3).The appropriate molecular calculation studies are currently in progress also for other SB ligands 37 .The tautomerization of Schiff bases was described in literature and is important phenomenon for understanding many physicochemical properties, such as photo-and thermochromism as well as the biological activity 38 .
For aldehydes with ortho-substituents and for m-methoxybenzaldehyde, the change from S to R configuration of the addition product was observed.The Re face of the ethyl group addition seems to be stabilized by the π-π interaction between the substrate and the ligand rings as well as the electrostatic interactions between the aldehyde H atom and the imine moiety (Fig. 3).However, these effects give no significant e.e. for the major R-product (Table 3).The bulk of investigated ortho substituents probably had some influence on the absolute configuration of the product.
The use of diethylzinc addition reaction for the stereoselective synthesis of biologically active compounds is very extensive.Schiff base chiral ligands described in this paper are also during investigation for the application in the synthesis of formoterol 39 derivatives that are possible 2-adrenergic receptor agonists.

Conclusions
Nine bidentate Schiff bases were synthesized from enantiomerically pure (S)-methylbenzylamine and were used as chiral ligands in the addition of Et2Zn to various aldehydes.Due to the characteristic steric position of methyl group in (S,E)-2-(1-(1phenylethylimino)ethyl)phenol 1 this ligand promoted the formation of (S)-1-aryl-1-propanol as a predominant product.The average enantiomeric excess was e.e.=27% for benzaldehyde as a substrate.The increase up to e.e.=94% and 96% found for m-chlorobenzaldehyde and pbromobenzaldehyde, respectively, was a consequence of the increased Lewis acidity of the carbon atom of the carbonyl group.The probable formation of keto-amine tautomer of 1 observed on the UV-Vis spectra also affected the enantioselectivity.Moreover, the observed change of the absolute configuration of Et2Zn addition products could be related to the - stacking efects between aromatic rings of the substrate with ortho-or meta-substituents and the ligand as well as to some electrostatic interactions near the imine moiety.from POCh Gliwice, Poland.Toluene was distilled from sodium prior to use.Diethylzinc, (S)-methylbenzylamine (e.e.=99%), aldehydes were purchased from Sigma-Aldrich or Fluka.3,5-Di-tert-butyl-2-hydroxybenzaldehyde, 3-tert-butyl-5-methyl-2-hydroxybenzaldehyde, 2hydroxy-3-methylbenzaldehyde and 2-hydroxy-3-isopropylbenzaldehyde were obtained according to literature procedures 42,43 .

Figure 3 .
Figure 3. Model of the active complex Zn-Zn formed with ligand 1 with the orientation of the substrate as obtained with MM calculations 31 .The addition to Si (green) and Re (cyan) faces are equally possible.

Table 1 .
Crystal data and structure refinement for 2

Table 2 .
Addition of diethylzinc to benzaldehyde in a presence of catalysts containing the Schiff bases 1-9

Table 3 .
Addition of diethylzinc to aldehydes catalyzed by the Schiff base 1