Single-step synthesis of a new series of meso di-Mannich bases from the cyclic aminal (2S,7R,11S,16R)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane and p-substituted phenols

Background The results presented herein show that the cyclic aminal (2S,7R,11S,16R)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane (6), derived from cis-(meso)-1,2-diaminocyclohexane and formaldehyde, is a suitable substrate for the preption of a series of cis-meso Mannich bases such as 8a-l by reaction with p-substituted phenols 7a-l in basic media. These compounds are valuable synthetic products and may find application in asymmetric catalysis. Results The products were characterized principally by NMR and IR spectroscopy. Both the benzylic and aminalic protons of the perhydrobenzimidazolidine moiety were diastereotopic due to the presence of stereogenic nitrogen centers. The occurrence of intramolecular hydrogen bonding interactions was confirmed by the broad OH stretching vibration band in the IR spectra. Vibrational spectra were calculated using B3LYP at 6-31G(d,p) level, and the calculated frequencies for the νOH vibrations were compared to those of the experimental spectra. Hydrogen bonding interactions in the solid state were observed through the X-ray crystallography of 8j. Additionally, Mulliken charges and Fukui indices for 6 were calculated as theoretical descriptors of electrophilicity. Conclusion A new series of meso Mannich bases called 4,4′-disubstituted-2,2′-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)} diphenols (8a-l) which are derived from cis-(meso)-1,2-diaminocyclohexane, were obtained from cyclic aminal 6. These results confirmed the behavior of 6 as an electrophilic preformed reagent in Mannich reactions in basic media.

Mannich bases are an interesting family of compounds in organic chemistry, and these compounds have been widely used in diverse chemistry fields due to their biological and pharmacological activities [1][2][3][4]. Moreover, the Mannich bases have been used as molecular models for studies of intramolecular proton transference processes [5,6] due to their interesting thermodynamic stability. Our interest in Mannich bases is focused on their application as model systems for studying inter and intramolecular hydrogen bond interactions between the phenolic OH atoms and the amine N atoms in phenolic derivatives [7][8][9]. Mannich bases can be obtained by multi-component Mannich condensation reactions between an amine, formaldehyde and active hydrogen compounds in acidic media in low to moderate yields [10]. The main subject of research is the reactivity of cyclic aminals toward nucleophiles and electrophiles. Our results using phenols as nucleophiles have led to the synthesis of di-Mannich bases, demonstrating that cyclic aminals behave as preformed electrophilic reagents.
We believe that the electrophilic behavior of cyclic aminals is determined by their structural features, especially the presence of 1,1-and 1,2-diamine functionalities. The interactions of the nonbonding electron pairs of nitrogen atoms and the presence or absence of stereoelectronic effects play an important role in the relative stability and chemical reactivity of this type of cyclic aminal [16]. Our hypothesis was supported by experiments using a cyclic aminal 6H,13H-5:12,7:14dimethanedibenzo[d,i] [1,3,6,8]tetraazecine DMDBTA (3) (Figure 1), a cyclic aminal analog similar to TATD 1. All the efforts to synthesize type (2) di-Mannich bases were unsuccessful, and N-substituted benzimidazoles were obtained using electron-rich phenols [17], due to spontaneous reaction under air oxidative conditions and thermodynamically driving by aromatisation. To obtain cyclic aminals with molecular structures that do not involve electron delocalization of the nonbonding pairs, we employed aliphatic 1,2-diamines such as 1,2diaminocyclohexane (4).

Results and discussion
Cyclic aminal 6 was prepared in high yield (90%) by the condensation of cis-(meso)-1,2-diaminocyclohexane with paraformaldehyde in N,N-DMF, according to the previously reported procedure [27].
The experimental FT-IR spectra of the Mannich bases (8a-l) ( Table 2) showed a broad absorption band between 3300-2350 cm -1 , which was assigned to the O-H stretching vibration of the phenolic moiety and is a result of OH•••N hydrogen bonding interactions, suggesting that the proton remains covalently bonded to the hydroxyl group and that proton transfer to the amino group did not occur. To understand the effect of hydrogen bonding interactions on the molecular structure of these compounds, we performed theoretical calculations. Thus, geometry optimizations and vibrational frequencies of the products were performed in Gaussian 1998 using DFT B3LYP methods at the 6-31G (d,p) level [28].
The computational calculations showed that the calculated frequencies of the νOH vibrations of compounds 8a-l (3335 and 3345 cm -1 ) were higher than that of the experimental spectra, where these vibrations appeared as very broad and weak absorptions. As described by several authors who studied similar compounds [29,30], these differences can be attributed to the strong anharmonicity of this type of vibration, which was not included in the calculation process. The calculated frequencies of the aromatic and fused rings of the perhydrobenzimidazolidine moiety were located in the expected ranges. For the calculated C-O stretching frequencies of the phenol precursors (7a-l) we noted that the calculated values are systematically lower than the experimental results of respective product (8a-l), suggesting that the C-O bond length was shortened due to intramolecular hydrogen bonding (Table 2).
However, the use of this band to understand the effects of hydrogen bonding in the structures of 8a-l is limited due to its low intensity and the presence of aromatic ring deformation vibrations in this region, which prevented assignment. The 13 C NMR spectra of all of the synthesized compounds 8a-l (Table 3) showed two signals between 21.0 and 25.0 ppm, which were assigned to the methylene carbon atoms of the cyclohexane ring. The signal at 61.0 ppm was assigned to the methine chiral carbon atoms. Using HMQC and HMBC bidimensional experiments, the signal at 73.5 ppm was assigned to the aminalic carbon atom (N-CH 2 -N). Moreover, the benzylic carbon atoms showed a signal at 55.0 ppm. The carbon atoms of the aromatic rings appeared as six signals between 115 and 158 ppm. The 1 H NMR spectra of compounds 8a-l (Table 4) showed that the hydrogen atoms in the ArCH 2 group were diastereotopic, presenting two doublets around 3.64 and 4.04 ppm and a geminal coupling 2 J H,H constant of 14.0 Hz. The 1 H NMR signals above 6.0 ppm allowed us to determine the substitution pattern of the aromatic rings and confirmed the ortho-regioselective aminomethylation of the Mannich bases.
In the 1 H NMR spectra of the products obtained from p-substituted phenols, signals as singlets and doublets with meta coupling (around 2.0 Hz) in an ABX system were observed and were assigned to hydrogen atoms in the ortho position with respect to the methylene group and the meta position with respect to the hydroxyl group. In addition, signals as doublets and doublets of   Table 2 shows the measured vibrational modes of compounds 8a-l, obtained using FT-IR spectroscopy.
doublets with typical ortho and meta coupling constants (8.4 Hz and 2.4 Hz, respectively), were also detected. The 1 H NMR spectrum of compound (8i) showed an ABCD coupling system with a triplet of doublets around 6.77 ppm with a meta coupling constant of 4 J = 1.1 Hz and an ortho coupling constant of 3 J = 7.4 Hz with the signal at 6.96 ppm, which appeared as a doublet and was assigned to the R = H atoms and the hydrogen atom in the ortho position with respect to the methylene group attached to the aromatic ring. However, the signal at 6.82 ppm appeared as a doublet of doublets with a meta coupling constant 4 J = 1.0 Hz and an ortho coupling constant of 3 J = 8.1 Hz with the signal at 7.17 ppm, which appeared as a multiplet and was assigned to the hydrogen in the ortho position and the hydrogen atoms in the meta position with respect to the hydroxyl group, respectively. The hydrogen atoms of the hydroxyl groups were shifted to a low field (above 10.6 ppm), confirming the existence of intramolecular hydrogen bonding interactions.
The cyclohexane ring can be identified in the 1 H NMR spectra as four multiplet signals between 1.39 and 3.11 ppm. These hydrogen atoms are diastereotopic due to the presence of chiral carbon atoms and stereogenic nitrogen centers. For the signal at 3.11 ppm, which presented a vicinal 1 H/ 1 H coupling constant of 4.0 Hz, we calculated the torsional angles between the methine hydrogens and methylene hydrogens using MestReJ software, which employs the modified Karpluss relation and the dependence of the coupling constant on the torsion angle [31]. The averages over all of the structures (8a-l) were 120°(α-eq,β-eq) and 52°(α-eq,α-ax), respectively. The signals that appeared as doublets at 3.39 and 3.85 ppm with a coupling constant of 6.5 Hz were assigned as the aminalic hydrogen atoms. This experimental evidence is in good agreement with the proposed molecular structures of compounds 8a-l, which belong to the C 1 symmetric chiral point group and presents the lowest degree of symmetry. Because the aminalic protons have a distinct chemical environment due to their spatial orientation (axial and equatorial dispositions in the imidazolidine ring, respectively), the deprotection of the equatorial proton, which was shifted to higher frequencies is evidenced in the doublet signals separated by 0.42 ppm. These results can be explained considering a hyperconjugation effect, which can be attributed to the interaction between nitrogen lone pairs and antibonding orbital σ* C,Hax (n N → σ* C,Hax ), the latter of which was synperiplanar to the nitrogen lone pairs (Figure 2) [32]. A consequence of this effect is the  Table 3 represents all the measured signals for carbon atoms in compounds 8a-l in the 13 C NMR spectra and their assignation in the molecular structure. elongation of the C-H ax bond with respect to the C-H eq bond, which was equal to 0.02 Å, as observed in the optimized molecular structure.
To understand the incidence of cis isomerism in the molecular structure of compounds 8a-l, efforts were made to obtain monocrystals suitable for X-ray diffraction analysis. A monocrystal of compound 8j was obtained via recrystallization from a mixture of chloroform and methanol. Compound 8j exists mainly with the OH groups engaged in an intramolecular hydrogen bond with the N atoms of imidazolidine ring. The molecular structure of compound 8j (Figure 3) is stabilized by two O-H · · · N intramolecular hydrogen bonds.
The imidazolidine ring adopts an envelope conformation, and the fused six-membered ring adopts a chair conformation. The dihedral angle between the mean planes of these rings, defined by C9-N1-C2 and C5-C4 -C8, is 47.84(12)°. The substituents on the N atoms of the five-membered ring are arranged syn with respect to the central ring. The phenyl rings are oriented at angles of 82.15 (14)°(C11-C16) and 83.97 (16)°(C20-C25) with respect to the mean plane of the heterocyclic ring, defined by N1-C2-C9. The two phenyl rings form a dihedral angle of 41.25 (9)°.
To understand the relationship between the molecular structure and observed reactivity of 6, we used two approaches, including: (a) the correlation between the electrophilicity of cyclic aminal 6 with the Fukui function of the methylene bridges and (b) the HOMO-LUMO gap, which was calculated as the difference between the HOMO of the nucleophile (we used phenol 7i, which possessed a calculated HOMO energy of −0.34552 Hartree) and the LUMO of cyclic aminal 6 ( Figure 4). In the first approach, the DFT B3LYP method at the 6-31G (d,p) level allowed us to obtain the Mulliken charges of the methylene bridges on the cyclic aminal. Because the differences between values were small, the electronic density and polarizability of the C-N bonds of the aminal moiety were similar in all of the methylene bridges for cyclic aminal 6 in the gas phase. However, Mulliken charges are not a good theoretical descriptor of electrophilicity. Thus, we used condensed Fukui functions, which are better theoretical descriptors. We applied the methodology proposed by Yang and Mortimer [33], which is based on a Mulliken population analysis and the following finite difference approximation: For a system of N electrons, independent calculations were made for the corresponding N and (N-1) systems with the same molecular geometry. According to this approach (Table 5), marked differences were observed in the electrophilicity of methylene bridges in aminal 6.
The condensed Fukui function for 6 suggests that the carbon atoms labeled as C19 and C20 are the most reactive sites for the nucleophilic attack of p-substituted phenol 7a-l ( Figure 5). The calculated HOMO-LUMO gap between 6 and phenol 7i was 218.2 kCal/mol, which is consistent with the calculated Fukui indices, corroborating the electrophilic character of aminal 6. Furthermore, both the HOMO and LUMO in cyclic aminal 6 was influenced by aminal cis isomerism, such that the calculated HOMO representation for aminal 6 is indicative of a σ type interaction between the nonbonding molecular orbitals of the nitrogen atoms, which is favored by the eclipsed conformation as a result of cis isomerism (Figure 4).  Finally, we propose that the reaction between 6 and psubstituted phenols 7a-l is mediated by the hydrogen bond between any of the four nitrogen atoms in the cyclic aminal and the hydroxyl group of one molecule of phenol, in accordance with the mechanism for the reaction of cyclic aminal 1 previously reported in the literature [11].