Stereogenic boron in 2-amino-1,1-diphenylethanol-based boronate–imine and amine complexes

Racemic boronate–imine and boronate–amine complexes 8 and 10, both featuring a stereogenic boron atom were synthesized from 2-amino-1,1-diphenylethanol (5) and characterized by crystal structure analyses. Proof of enantiomerism at the boron center for the novel boronate–amine complex 10 was established by separation of the enantiomers. Racemization barriers were found to be in the same range for both amine and imine complexes (100–110 kJ/mol).


Introduction
Enantiomerism of main group hetero elements has been investigated thoroughly for compounds with stereogenic sulfur [1], phosphorus [2], nitrogen [3] and silicon atoms [4]. By comparison, stereogenic tetrahedral-coordinated boron has been studied to a much lesser extent. This is partly because it was incorporated in a chiral environment generated by enantiomerically pure ligands [5][6][7][8][9] or counter-ions [10], although some of these complexes have been obtained in a diastereoselective manner [6][7][8][9]. On the other hand, enantiomerism at boron has been observed in acyclic tetra-coordinated complexes 1 [11] and 2 [12], in acyloxyboranes 3 [13][14][15][16] with electron with-drawing substituents X (Scheme 1) that turned out to be crucial to the configurational stability at boron, and recently, in boronate complexes of boradiazaindacene [17]. Pursuing the concept of tridentate ligands derived from 2-amino-2,2-diphenylethanol we have been able to obtain boronate-imine complexes 4 with boron as a stable stereogenic center (Scheme 1). Their racemization barrier was measured and the absolute configuration of the isolated enantiomers was determined by a comparison of the measured and calculated CD spectra [18]. In this article, we describe the synthesis, resolution and characterization of chiral boronate-imine and boronate-amine complexes 8 and 10, respectively. Their backbone is derived from the regioisomeric 2-amino-1,1-diphenylethanol (5) which features the geminal diphenyloxymethyl motif [19].

Results and Discussion
Following a known procedure [20], the amino alcohol 5 was readily accessible from methyl glycinate hydrochloride by the reaction with excess phenylmagnesium bromide. Subsequent condensation with 1-formyl-2-naphthol (6) gave the imine 7 in 87% yield (Scheme 2). In order to generate the boronate-imine complex 8, the imine 7 was treated with 4-chlorophenylboronic acid in boiling toluene in the presence of molecular sieves. The fact that this protocol led to the desired boronate complex 8 in only 17% isolated yield is attributed to steric hindrance, which originates from the diphenylhydroxymethyl group and has a disadvantageous effect on complexation. It is remarkable that considerably higher yields were obtained when regioisomeric complexes 4 were prepared via the same protocol. The formation of boronate complex 8 was indicated by its 11 B NMR shift value of 6.6 ppm [21] and confirmed by X-ray crystal structure analysis as shown in Figure 1. Although the compound crystallized as a conglomerate, the (S)-enantiomer is shown arbitrarily in Figure 1a. The boron-nitrogen distance of 156.3 pm clearly shows the existence of a coordinate bond. The UV spectrum of compound 8 displays a high-wavelength absorption maximum at λ = 395 nm, typical for the imine chromophore, as observed for other boronate-imine complexes. The imine 7 also served for the preparation of the boronate-amine complex 10. For this purpose, it was reduced [22] with cyanoborohydride in methanol in the presence of hydrochloric acid to give the salt of the amine 9. As the latter decomposed to a considerable extent when stored, it was converted immediately into the boronate-amine complex 10. Sodium hydrogen carbonate served as the base to liberate the free amine in situ, and complexation with 4-chlorophenylboronic acid in refluxing toluene gave the complex 10 in 63% isolated yield. The lack of any absorption at wavelengths higher than 350 nm indicated the absence of the imine chromophore.
Here again the formation of the complex can be deduced from the 11 B NMR shift of 5.5 ppm [21]. Suitable crystals of compound 10·CH 3 OH were obtained from methanol/hexane and the result of the X-ray analysis is shown in Figure 1. A comparison of the boron-nitrogen distance in the imine complex 8 (156.3 pm) and the amine complex 10 (159.5 pm) reveals a small elongation of the bond upon saturation of the imine group that results from the change in hybridization at the nitrogen from sp 2 to sp 3 . The structure determination 10·CH 3 OH reveals a hydrogen bridge of the amine hydrogen atom directed to the oxygen atom of the alcohol. The fact that the NH group functions as the hydrogen-bond donor is attributed to an enhanced acidity that is caused by the coordinate bond between nitrogen and boron. Related hydrogen bonding has been observed in diastereomerically pure boronate-amine complexes [9]. showing the hydrogen bonding of the methanol molecule (right). Displacement ellipsoids are drawn at the 30% probability level, radii of hydrogen atoms are chosen arbitrarily and the hydrogen atom labels are omitted for clarity. Selected bond distances and angles are given in Table 1. Upon complexation of the boron, a typical pyramidalization occurs that can be measured in terms of the tetrahedral character (THC). For the complexes 8 and 10, this has been calculated by taking into account the six bond angles θ 1 -θ 6 using the equation of Höpfl (Equation 1) [23]. (1) The corresponding values obtained for the boron and the nitrogen atoms in the complexes 8 and 10 are given in Table 2.
Thus, the tetrahedral character is essentially identical in both complexes for the boron atom. The pyramidalization of nitrogen that occurs upon saturation of the imine bond is evident from the values of the tetrahedral character of the nitrogen atom in the amine complex. The saturation of the carbon-nitrogen bond has a considerable impact on the structure of both of the complexes 8 and 10. This becomes evident from Figure 2, which shows a superposition of the skeletons of complexes 8 (red) and 10 (green). As a consequence of the saturation and the rehybridization at nitrogen, the five-membered rings are connected in a more concave, folded manner in the amine complex 10 than in the rather flat junction of both rings in the imine complex 8. It is possible that steric repulsion is more severe in the amine complex 10 that could slightly weaken the boron-nitrogen bond. In order to prove the enantiomerism based upon stereogenic boron, the racemates of the complexes 8 and 10 were resolved by HPLC on a chiral column. Both complexes displayed peaks of identical intensity resulting from the enantiomers. The differences in the retention times permitted isolation of the pure enantiomers on a semi-preparative scale. Mirror-image CD spectra were obtained for the separated enantiomers of the imine complex 8. Previously, we have been able to assign the absolute configuration to the complex 4a, a regioisomer of 8, by comparison of the measured and calculated CD spectra [18]. The (R)-enantiomer of 4a is characterized by an intense, positive Cotton effect at high wavelength. As a similar effect is observed in the CD spectrum of the enantiomer of 8 that is eluted at lower retention time, the (R)-configuration is attributed to this enantiomer by analogy. As we were interested in whether or not the configurational stability differs in boronate-imine complexes 4 and 8 on the one hand and boronate-amine complex 10 on the other hand, the racemization barrier of the latter was determined. For this purpose, a sample of the enantiomerically pure complex 10 was heated in n-decane at 60 °C, and the decay of the optical purity was followed by chiral HPLC. Thus, the racemization rate at 325.4 K was measured to be 4.1·10 −4 s −1 and the racemization barrier ΔG ‡ amounted to 101.0 kJ·mol −1 [24]. The corresponding values for boronate-imine complexes 4 varied from 105-110 kJ·mol −1 , indicating that the change from the imine to the amine ligand does not alter the configurational stability at boron to any considerable degree. The racemization process involves the breaking of the coordinate boron-nitrogen bond to produce a trigonal boron atom that is then attacked by the nitrogen from the opposite face. As the nitrogen-boron distances were similar in all the boronate complexes 4, 8, and 10, it is plausible that the racemization barrier is also in the same range for all of these compounds.

Conclusion
In summary, it was shown that boron based enantiomerism is not only possible in boronate-imine complexes 4 and 8, but also in amine complexes as well as exemplified by complex 10 that differs from 8 in the saturation of the imine bond to an amine bond. Enantiomers of boronate complexes 8 and 10 are accessible and were shown to be stable at room temperature. The racemization barriers are of similar magnitude in the amine and imine complexes.

1-{[(2-Hydroxy-2,2-diphenylethyl)imino]methyl}naphthalen-2-ol (7)
A mixture of amino alcohol 5 (0.427 g, 2.00 mmol), naphthaldehyde 6 (0.379 g, 2.20 mmol), and sodium sulfate (2.0 g, 14 mmol) was suspended in absolute methanol (25 mL) and dry toluene (25 mL) under a nitrogen atmosphere. The yellow mixture was heated under reflux with stirring for 18 h. After cooling to room temperature, the sodium sulfate was removed by filtration and the filtrate concentrated in a rotary evaporator.  Boronate-amine complex 10 The imine 7, (0.367 g, 1.00 mmol) and sodium cyanoborohydride (0.19 g, 3.0 mmol) were dissolved in absolute methanol (75 mL). After adding 5 mL of hydrochloric acid (10%), the yellow solution gradually became colorless on stirring at room temperature for 1 h. Distilled water (50 mL) was added and the solution extracted three times with chloroform. The combined organic layers were dried with sodium sulfate and the solvent was removed in a rotary evaporator. Immediately, the resulting crude colorless product, 4-chlorophenyl boronic acid (0.122 g, 1.00 mmol) and sodium hydrogen carbonate (0.13 g, 1.5 mmol) were suspended in 100 mL of dry toluene and heated under reflux for 4 h. After the addition of distilled water, the layers were separated and the aqueous phase was extracted with chloroform. The combined organic layers were dried with sodium sulfate and the solvent was removed in a rotary evaporator. The residue was purified by column chromatography (chloroform/ ethyl acetate, 10:1) to yield boronate 10 as a colorless solid (0.210 g, 63%).

Crystal structure determination
Crystals of compounds 8 and 10·CH 3 OH suitable for X-ray analysis were selected by means of a polarization microscope and investigated with a STOE imaging plate diffraction system using graphite monochromatic MoKα radiation (λ = 0.71073 Å). To avoid loss of methanol, and deterioration, crystals of compound 10·CH 3 OH were enclosed in thin walled glass capillaries. Unit cell parameters were determined by least-squares refinements on the positions of 8000 and 3769 reflections in the  3 . In the course of refinement P4 1 was shown to be the correct choice for the crystal under investigation. Data sets were corrected for Lorentz and polarization effects in both cases. Crystal data, as well as details of data collection and structure refinement are listed in Table 3.
The structures were solved by direct methods [25] and subsequent ΔF-syntheses and approximate positions of all the hydrogen atoms were found. Anisotropic displacement parame-ters were applied for all atoms heavier than hydrogen, and, using the subsequently mentioned restraints and constraints, refinements [26] by full-matrix least-squares calculations on F 2 converged (max. shift/esd: 0.000 and 0.001, respectively). For the NH group of 10·CH 3 OH, weak N-H bond length restraints were applied. With bond lengths and angles constrained to idealized values for the CH 3 , CH 2 , CH, and OH groups of the boron complexes and for the methanol molecule of 10·CH 3 OH, the riding model was applied for all the other H atoms. In addition, the H atoms of the CH 3 group of the methanol molecule were allowed to move collectively around the neighbouring C-C axis, and the H atom of the OH group was also allowed to rotate around the neighbouring O-C axis. Isotropic displace-ment parameters of H atoms were constrained to 120% of the equivalent isotropic displacement parameters of the parent N and C atoms for the NH, CH and CH 2 groups and to 150% of the parent C and O atoms for the CH 3 group and the OH group of the methanol molecule in 10·CH 3 OH. CCDC-809030 (compound 8) and CCDC-809031 (compound 10·CH 3 OH) contain the supplementary crystallographic data (excluding structure factors) for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http:// www.ccdc.cam.ac.uk/data_request/cif.