Synthesis and Structural Analysis of Chiral Bis-dihydro[1,3]-naphthoxazines and Imidazolidine Derivatives Prepared by Three-Component Mannich-Type Condensation

: Enantiomerically pure ( S )-1-phenylethan-1-amine has been applied in Mannich-type condensation between formaldehyde and naphthalenediols leading to the synthesis of chiral bis-dihydro[1,3] naphthoxazines in excellent yields. Salen-type structures have been synthesized, applying R , R - or S , S -cyclohexane-1,2-diamines in condensation with formaldehyde and naphthalene-2-ol. The obtained chiral imidazolidine derivatives of the type 1,1 (cid:48) -(((3a,7a)-hexahydro-1 H -benzo[ d ]imidazole-1,3(2 H )diyl)bis(methylene))bis(naphthalen-2-ol) were evaluated as pre-catalysts for the addition of diethyl zinc to aldehydes. The structures of the newly synthesized compounds were elucidated using 1 D and 2 D NMR experiments (COSY, HMBC, HSQS), elemental analysis, mass spectrometry (HRMS spectra) and single-crystal X-ray diffraction (SCXRD). The products were further characterized with powder X-ray diffraction (PXRD) and thermal analysis (DSC).


Introduction
Multicomponent reactions are an attractive tool for creating complex polyfunctional organic compounds [1,2].The synthesis of dihydrooxazines by three-component Mannichtype condensation of naphthol, amine and formaldehyde has a high potential for obtaining an important class of heterocyclic compounds.Structurally diverse dihydro [1,3]oxazines have demonstrated a broad range of biological activities (bactericides, fungicides, antiinflammatory, antitumor, anti-HIV) and have found applications in materials science [3,4].
The synthesis of dihydro [1,3]oxazines occurs most commonly through one-pot condensation between aromatic alcohol, formaldehyde and amine applying different solvents or in some examples under solvent-free conditions [3].The use of readily available chiral amines offers the opportunity for synthesis of chiral dihydrooxazines.To date, there are only a limited number of examples describing the synthesis of enantiopure dihydro [1,3]naphthoxazine using chiral amines.These compounds are employed as intermediates in the synthesis of N-substituted aminobenzylnaphthols and demonstrate a significant activity in asymmetric catalysis [5].In our previous studies, we demonstrated a practicable approach for the synthesis of 1,3-naphthoxazines through a three-component condensation involving naphthalene-2-ol, formaldehyde and a series of chiral amines.The subsequent reduction obtained the corresponding N-methyl derivatives in a convenient way [6].In a similar synthetic approach, we applied 2,6-, 2,3-and 1,5-dihydroxy naphthalenes in the condensation reaction (Betti reaction) with aromatic aldehydes and (S)-(−)-1-phenylethane-1-amine, synthesizing chiral aminobenzylnaphthols in good yields [7].
In this study, we present the synthesis of bis-dihydro [1,3]naphthoxazines applying 2,3-and 2,6-dihydroxy naphthalenes, (S)-(−)-1-phenylethane-1-amine and formaldehyde.Of further interest was the condensation of cyclohexane-1,2-diamine, naphthalene-2-ol and formaldehyde due to the opportunity to obtain salen-type structures [8,9].The structural elucidation of isolated chiral compounds applying advanced NMR and X-ray crystallographic experiments was of particular importance for understanding the possible catalyst applications of the compounds.Some of the synthesized structures were preliminarily evaluated in a model catalytic reaction.

General Procedure for Enantioselective Addition of Diethylzinc to Aldehydes
To a solution of the corresponding ligand ((R,R)-9 or (S,S)-9) (3 mol %) in toluene (4 mL), Et 2 Zn (1.7 mmol, 1M solution in hexane) was added dropwise at 0 • C in an Ar atmosphere.The mixture was stirred for 30 min at 0 • C and then the corresponding aldehyde (1.0 mmol) was added at −20 • C. The reaction mixture was stirred at 20 • C and monitored by TLC (petroleum ether/MTBE = 5:1) until the aldehyde was consumed.The mixture was quenched (aq.NH 4 Cl), extracted with Et 2 O and dried over anhydrous Na 2 SO 4 .After evaporation of the solvent, the crude product was purified by column chromatography (petroleum ether/MTBE = 5:1).

Powder X-ray Diffraction (PXRD)
Powder XRD patterns were determined for the powdered compounds 3, (R,R)-9 and (S,S)-9 to establish crystalline properties, purity and eventual presence of polymorphs.Powder samples of the synthesized compounds were analyzed on an Empyrean Powder X-ray diffractometer (Malvern Panalytical, Almelo, The Netherlands) in the 2-50 • 2θ range using Cu radiation (λ = 1.5406Å) and a PIXcel3D detector.The diffraction patterns of the crystals were compared with those of starting compounds and the computed from SCXRD pattern to confirm the presence or absence of additional phases.

Single-Crystal X-ray Diffraction (SCXRD)
Single crystals of compounds 3 and (R,R)-9 with suitable size (~0.3 × 0.3 × 0.3 mm 3 ) and diffracting quality were mounted on nylon loops.Diffraction data for 3 were collected on a SupernovaDual diffractometer equipped with an Atlas CCD detector while diffraction data for (R,R)-9 were collected on a Bruker D8 Venture diffractometer equipped with a PHOTON II CPAD detector.Both diffractometers operate with a micro-focus sealed X-ray source, generating MoKα radiation with λ = 0.71073 Å.The collected data were processed with CrysAlisPro [10] (for 3) or APEX4 [11] (for (R,R)-9) programs.The structures were solved with intrinsic phasing methods and refined by the full-matrix least-squares method of F 2 using ShelxT [12]and ShelxL [13] as implemented in the OLEX2-ver.1.5graphical interface [14].All non-hydrogen atoms were located successfully from Fourier map and were refined anisotropically.Hydrogen atoms were placed on calculated positions riding on the parent carbon atoms (U eq = 1.2 for C-H aromatic = 0.93 Å and C-H methylenic = 0.97 Å) while those riding on a heteroatoms were refined from electron density maps.Ortep-3v2 software [15] was used to prepare the figures visualizing the compounds in the asymmetric unit.Complete crystallographic data for the structure of compounds 3 and (R,R)-9 reported in this paper have been deposited in the CIF format with the Cambridge Crystallographic Data Center as 2294902 and 2294903, respectively.These data, last accessed on 14 September 2023, can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.

Thermal Analysis (DSC)
Differential scanning calorimetry was conducted to estimate thermotropic properties and thermal behaviors of the new compounds.DSC analyses were performed on a Discovery DSC250 (TA instruments, New Castle, DE, USA).Samples weighing between 1 and 5 mg were heated in aluminum pans from 30 to 250 • C (10 • C•min −1 ) in nitrogen (flow rate 25 mL•min −1 ).Endothermic/exothermic effects of solvent evaporation, melting point and decomposition of the synthesized compounds were determined from the DSC experiments.

Synthesis
The condensation reactions of naphthalene-2,3-diol (1) or naphthalene-2,6-diol ( 4), (S)-(−)-1-phenylethane-1-amine (2) and formaldehyde (applied as formalin, 37% aq.solution or paraformaldehyde) were performed in ethanol at 50 °C as shown in Scheme 1a.The products 3 and 5 were isolated in high yields (98% and 94%, respectively) after short reaction times (1-3 h) and purification by column chromatography.As the next step, preparation the corresponding N-methyl derivatives through reduction with LiAlH4 was attempted [6].Surprisingly, all reduction experiments applying different conditions and reducing agents (LiAlH4 or NaBH4) were unsuccessful and even traces of the desired Nmethylated compounds could not be detected.The condensation of cyclohexane-1,2-diamine ( 6), naphthalene-2-ol ( 7) and formaldehyde (Scheme 1b) was of particular interest, since the formation of a salen-type structure was expected.Salen ligands are described as efficient catalysts in certain enantioselective processes [8].The initial condensation experiments were performed with racemic cyclohexane-1,2-diamine (6) in ethanol as a solvent at room temperature (Scheme 1b).An aqueous solution of formaldehyde (37%) was used in large excess and the reaction outcome was monitored by TLC.The formation of the expected bis-dihydro [1,3]naphthoxazine 8 was recognized in the crude reaction mixture by NMR spectroscopy (Figure 1, Table 1).The amine 6 was consumed over the course of a 3 h reaction time (Table 2, entry 1).Besides this, an additional compound with similar structure was identified and determined as imidazolidine 9 (Scheme 1b).The experiments for separation and isolation (column chromatography, crystallization) of products 8 and 9 in pure form were unsuccessful.However, it was possible to distinguish the two compounds in a mixture and to determine undoubtedly the structures by using NMR and HRMS experiments.In Figure 1, representative 1 H NMR spectra of 8 and 9 are shown and in Table 1 the characteristic chemical shifts of the individual compounds are introduced.The condensation of cyclohexane-1,2-diamine (6), naphthalene-2-ol ( 7) and formaldehyde (Scheme 1b) was of particular interest, since the formation of a salen-type structure was expected.Salen ligands are described as efficient catalysts in certain enantioselective processes [8].The initial condensation experiments were performed with racemic cyclohexane-1,2-diamine (6) in ethanol as a solvent at room temperature (Scheme 1b).An aqueous solution of formaldehyde (37%) was used in large excess and the reaction outcome was monitored by TLC.The formation of the expected bis-dihydro [1,3]naphthoxazine 8 was recognized in the crude reaction mixture by NMR spectroscopy (Figure 1, Table 1).The amine 6 was consumed over the course of a 3 h reaction time (Table 2, entry 1).Besides this, an additional compound with similar structure was identified and determined as imidazolidine 9 (Scheme 1b).The experiments for separation and isolation (column chromatography, crystallization) of products 8 and 9 in pure form were unsuccessful.However, it was possible to distinguish the two compounds in a mixture and to determine undoubtedly the structures by using NMR and HRMS experiments.In Figure 1, representative 1 H NMR spectra of 8 and 9 are shown and in Table 1 the characteristic chemical shifts of the individual compounds are introduced.In order to optimize the formation of compound 8 preferentially, a series of experiments have been performed (Table 2).In general, prolonged reaction time and heating up to 50 °C promotes the formation of compound 9 (compare entries 1 to 6).If the mixture is refluxed for 2.5 h, compound 9 is formed preferentially (entry 7).The result introduced in entry 5 needs some comment.In fact, the ratio 8:9 after 18 h at 50 °C was 10:7.After washing the crude mixture with acetonitrile, the ratio was shifted in favor of 9 (8:9 = 20:19) However, pure 8 could not be isolated from the filtrate (due to stability problems, vide infra).
When toluene was used as solvent and the mixture heated at 50 °C for 24 h, the ratio of the two products 8 and 9 formed was 5:1 (entry 8, Table 1).Even at this ratio, the isolation of bis-dihydro [1,3]naphthoxazine 8 in pure form was impossible.All attempts to purify 8 by crystallization using various solvents and mixtures of solvents did not lead to a positive result.Furthermore, 8 is unstable under column chromatography conditions even when the silica gel is deactivated with Et3N.On standing, bis-dihydro[1,3]naphthoxazine 8 is transformed slowly into 9, detected by its increased fraction in the ratio.Pure 9 is stable at room temperature; however, if mixed with formaldehyde, the formation of 8 was  In order to optimize the formation of compound 8 preferentially, a series of experiments have been performed (Table 2).In general, prolonged reaction time and heating up to 50 • C promotes the formation of compound 9 (compare entries 1 to 6).If the mixture is refluxed for 2.5 h, compound 9 is formed preferentially (entry 7).The result introduced in entry 5 needs some comment.In fact, the ratio 8:9 after 18 h at 50 • C was 10:7.After washing the crude mixture with acetonitrile, the ratio was shifted in favor of 9 (8:9 = 20:19).However, pure 8 could not be isolated from the filtrate (due to stability problems, vide infra).
When toluene was used as solvent and the mixture heated at 50 • C for 24 h, the ratio of the two products 8 and 9 formed was 5:1 (entry 8, Table 1).Even at this ratio, the isolation of bis-dihydro [1,3]naphthoxazine 8 in pure form was impossible.All attempts to purify 8 by crystallization using various solvents and mixtures of solvents did not lead to a positive result.Furthermore, 8 is unstable under column chromatography conditions even when the silica gel is deactivated with Et 3 N.On standing, bis-dihydro [1,3]naphthoxazine 8 is transformed slowly into 9, detected by its increased fraction in the ratio.Pure 9 is stable at room temperature; however, if mixed with formaldehyde, the formation of 8 was observed in a short time, forming nearly a 1:1 ratio of 8:9.It is important to emphasize that reduction experiments for treatment of mixtures of 8 and 9 with LiAlH 4 or NaBH 4 led to destruction of 8, whereas 9 remained almost unchanged.
It is interesting to note that the synthesis of compound 8 was recently described (racemic diamine 6 was used) [9].The structural proof was reported based on elemental analysis and IR spectroscopy and no NMR data were presented.However, the compound described as 8 was further used as a ligand to prepare salen-type complexes with the transition metal Mn, which were characterized by single-crystal X-ray crystallography.Consequently, based on the published results of [9] and our results, it is possible to assume that salen-type metal complexes could be formed from mixtures of 8 and 9 under suitable conditions.
In further experiments, the formation of 9 could be optimized (entries 9-12).In refluxing mixtures of diamine 6, naphthalene-2-ol and formaldehyde (37 aq.solution or paraformaldehyde, 2 equivalent), the reaction outcome was exclusively shifted to the formation of compound 9. Conveniently, the imidazolidine 9 crystalize in the reaction mixture and could be isolated by filtration.The highest yield of pure 9 (63% after column chromatography) was realized by heating the reaction mixture at 50 • C for 24 h (entry 12).
The optimized conditions (entry 12) were applied for the synthesis of the corresponding chiral derivatives (Figure 2) applying (R,R)-6 (in free base form) and (S,S)-6 (as tartrate salt).The yields of pure compounds we could realize were 47% for (R,R)-9 (isolated by crystallization) and 31% for (S,S)-9 (isolated by column chromatography).
fluxing mixtures of diamine 6, naphthalene-2-ol and formaldehyde (37 aq.solution or p aformaldehyde, 2 equivalent), the reaction outcome was exclusively shifted to the f mation of compound 9. Conveniently, the imidazolidine 9 crystalize in the reaction m ture and could be isolated by filtration.The highest yield of pure 9 (63% after colum chromatography) was realized by heating the reaction mixture at 50 °C for 24 h (entry 1 The optimized conditions (entry 12) were applied for the synthesis of the correspon ing chiral derivatives (Figure 2) applying (R,R)-6 (in free base form) and (S,S)-6 (as tartr salt).The yields of pure compounds we could realize were 47% for (R,R)-9 (isolated crystallization) and 31% for (S,S)-9 (isolated by column chromatography).

Enantioselective Addition of Et 2 Zn to Aldehydes Catalyzed by Ligands (R,R)-9 and (S,S)-9
The imidazolidine derivatives (R,R)-9 and (S,S)-9 possess suitable structure and properties to be used as ligands in the model reaction for the enantioselective addition of diethylzinc to aldehydes by using a standard procedure (Scheme 2).The imidazolidine derivatives of 9 were applied in 3 mol % quantity by using of standard conditions described in the literature (see Section 2) [7,[16][17][18].A series of aromatic aldehydes were tested in the addition reaction, leading to the chiral secondary alcohols of type 11.The yields obtained (Table 3) ranged from moderate to very good; however, in several cases (entries 4-6 and 10), this was after prolonged reaction times.The enantioselectivities achieved were moderate.The prolonged reaction times indicates the relatively low efficiency of the chiral catalyst formed in situ in respect to the enantioselectivity, although the chemical yields were acceptable and, in some cases, even very high.
yields obtained (Table 3) ranged from moderate to very good; however, in several cas (entries 4-6 and 10), this was after prolonged reaction times.The enantioselectivit achieved were moderate.The prolonged reaction times indicates the relatively low e ciency of the chiral catalyst formed in situ in respect to the enantioselectivity, althou the chemical yields were acceptable and, in some cases, even very high.The best asymmetric induction was achieved by the addition reaction of diethylzi to 2-methoxybenzaldehyde catalyzed by ligands (R,R)-9 and (S,S)-9 (53% and 58% ee, spectively, Table 3).

Crystal Structure Description
Single crystals of compounds 3 and (R,R)-9 were obtained by slow evaporation from a hot methanol solution.Compounds 3 and (R,R)-9 crystallize in non-centrosymmetric monoclinic P2 1 and orthorhombic P2 1 2 1 2 1 space groups with one molecule in the asymmetric unit (ASU) and two and four molecules in the unit cell, respectively (Table S1).The ORTEP view of the molecules in the ASU of compounds 3 and (R,R)-9 with appropriate labeling scheme is shown in Figure 3. Selected bond lengths and angles from the single-crystal X-ray diffraction experiment are provided in Table 4 and they are comparable with other similar structures in the Cambridge structural database (ref.codes PAFCEH [19], OWEHEE [20], VESHAD [21], SOVYOR [22], HAJWUO [23], CAXJEU [24] and AFIHII [25]).
The molecule of compound 3 (Figure 3a) can be divided into two main fragments-a central 2,3,4,9,10,11-hexahydronaphtho[1,2-e:4,3-e ]bis( [1,3]oxazine) core covalently bonded with two ethyl benzene side chains.Furthermore, the 2,3,4,9,10,11-hexahydronaphtho[1,2e:4,3-e ]bis( [1,3]oxazine) core can be divided into a fused naphthalene and two 1,3-oxazinane rings sharing the common C1-C2 and C3-C4 carbon atoms.The naphthalene ring is planar with an rmsd of 0.012 Å while the two 1,3-oxazinane rings are non-planar (rmsd ~0.200 Å) and have a "half-chair" conformation.The two N atoms from the 1,3-oxazinane rings (namely N12 and N22) are covalently bonded to the α-carbon atoms-labeled C13 or C24-of the ethylbenzene moieties.The angle between the normal of the mean planes of the benzene rings C15-C16-C17-C18-C19-C20 and C26-C27-C28-C29-C30-C31 from the ethylbenzene fragments and the naphthalene fragment are 135.77(13) • and 140.33 (14) • , respectively.The twist/fold angles between the C15-C16-C17-C18-C19-C20/naphthalene and C26-C27-C28-C29-C30-C31/naphthalene fragments are 126.02(16)   The molecule of 3 lacks proton-donating groups (like C-OH, NH, NH2); th typical hydrogen bonding interactions are not expected.The packing of the mole the crystal structure is governed by weak C-H…O and C-H…π interactions.On t hand, the molecule of (R,R)-9 has two proton-donating hydroxyl groups (-OH) N atoms from the imidazole moiety acting as proton acceptors.Thus, formation molecular hydrogen bonding interactions of the O-H…N type is expected and (Figure 4, Table 5).The crystal structure of (R,R)-9 is further stabilized by weak interactions (π...π interactions are not detected).The molecule of compound (R,R)-9 (Figure 3b) consists of a central octahydro-1Hbenzo[d]imidazole fragment that is connected with two 1-methylnaphthalen-2-ol side chains via N-C covalent bonds (N3-C7 and N2-C5).Furthermore, the octahydro-1Hbenzo[d]imidazole moiety (rmsd = 0.207 Å) is built up by fused six-membered cyclohexane and five-membered imidazolidine aliphatic rings sharing the C15 and C16 carbon atoms.The cyclohexane and the imidazolidine rings are non-planar (rmsd = 0.239 Å and 0.200 Å) and have "chair" and "half-chair" conformation, respectively.The 1-methylnaphthalen-2-ol side chains are planar with an rmsd of 0.040 Å (for the N3-bonded one) and 0.015 Å (for N2-bonded one).The angles between the normal of the mean planes of the N3bonded and N2-bonded 1-methylnaphthalen-2-ol fragments and the central octahydro-1H-benzo [d] The molecule of 3 lacks proton-donating groups (like C-OH, NH, NH 2 ); therefore, typical hydrogen bonding interactions are not expected.The packing of the molecules in the crystal structure is governed by weak C-H. ..O and C-H. ..π interactions.On the other hand, the molecule of (R,R)-9 has two proton-donating hydroxyl groups (-OH) and two N atoms from the imidazole moiety acting as proton acceptors.Thus, formation of intramolecular hydrogen bonding interactions of the O-H. ..N type is expected and detected (Figure 4, Table 5).The crystal structure of (R,R)-9 is further stabilized by weak C-H. ..O interactions (π...π interactions are not detected).The thermal stability of compounds 3, 5, (R,R)-9 and (S,S)-9 was evaluated using differential scanning calorimetry in the temperature region of 30-250 °C.The DSC thermograms of compound 3, (R,R)-9 and (S,S)-9 (Figure 5a,c,d) disclose a similar thermal comportment, e.g., a sharp endothermic effect followed by sharp exothermic effect.For all 3, (R,R)-9 and (S,S)-9 compounds, the endothermic effect is related to the melting of the compounds while the immediately following exothermic effect is associated with the decomposition of the compounds.According to the DSC data, the melting behavior for (R,R)-9 and (S,S)-9 is similar, with maximums at 191 and 188 °C, respectively (Figure 5c,d).The thermal comportment of 5 features also an endothermic and an exothermic effect (Figure 5b).For compound 5, the melting is observed at ~185 °C while the decomposition is delayed with ~40 °C after the melting has finished.The thermal stability of compounds 3, 5, (R,R)-9 and (S,S)-9 was evaluated using differential scanning calorimetry in the temperature region of 30-250 • C. The DSC thermograms of compound 3, (R,R)-9 and (S,S)-9 (Figure 5a,c,d) disclose a similar thermal comportment, e.g., a sharp endothermic effect followed by sharp exothermic effect.For all 3, (R,R)-9 and (S,S)-9 compounds, the endothermic effect is related to the melting of the compounds while the immediately following exothermic effect is associated with the decomposition of the compounds.According to the DSC data, the melting behavior for (R,R)-9 and (S,S)-9 is similar, with maximums at 191 and 188 • C, respectively (Figure 5c,d).The thermal comportment of 5 features also an endothermic and an exothermic effect (Figure 5b).For compound 5, the melting is observed at ~185 • C while the decomposition is delayed with ~40 • C after the melting has finished.Overall, the DSC characterization of compounds 3, 5, (R,R)-9 and (S,S)-9 reveals their high purity and stability up to and above 180 °C (no decomposition or phase transitions are observed).The purity and the lack of polymorphs or isomerization in compounds 3 and (R,R)-9 are also confirmed by comparing the powder diffraction patterns of the bulk samples (in blue, Figure 6) and those generated from the single-crystal structural analysis (in red, Figure 6).Overall, the DSC characterization of compounds 3, 5, (R,R)-9 and (S,S)-9 reveals their purity and stability up to and above 180 • C (no decomposition or phase transitions are observed).The purity and the lack of polymorphs or isomerization in compounds 3 and (R,R)-9 are also confirmed by comparing the powder diffraction patterns of the bulk samples (in blue, Figure 6) and those generated from the single-crystal structural analysis (in red, Figure 6).

Figure 3 .
Figure 3. ORTEP[15] view of the molecules present in the ASU of (a) 3, (b) (R,R)-9, with ap labeling scheme.The thermal ellipsoids are given with 50% probability level.

Figure 3 .
Figure 3. ORTEP [15] view of the molecules present in the ASU of (a) 3, (b) (R,R)-9, with appropriate labeling scheme.The thermal ellipsoids are given with 50% probability level.

Figure 4 .
Figure 4. Visualization of the detected hydrogen-bonding interactions of the O-H…N type (red dots), weak C-H…O interactions (the strongest one is labeled, e.g., C5-H5A…O1, 2.495 Å) and short contacts stabilizing the crystal structure of compound (R,R)-9.

Table 1 .
Characteristic chemical shifts (in ppm) of selected protons allowing one to distinguish between compounds 8 and 9 in mixtures.

Table 1 .
Characteristic chemical shifts (in ppm) of selected protons allowing one to distinguish between compounds 8 and 9 in mixtures.

Table 4 .
Selected bond lengths and angles for compounds 3 and (R,R)-9.