Synthesis of cis- and trans-3-Aminocyclohexanols by Reduction of β-Enaminoketones

We describe a protocol developed for the preparation of β-enaminoketones derived from 1,3-cyclohexanediones, and their subsequent reduction by sodium in THF-isopropyl alcohol to afford cis- and trans-3-aminocyclohexanols.


Scheme 2.
Reduction of β-enaminoketones 1 and 2. A percolation of the reaction mixture followed by GC-MS analysis using a cyclosil-B chiral column revealed the presence of four major stereoisomers in identical ratio for compound 3 and two stereoisomers for compound 4 (cis and trans in 89:11 ratio). The diastereoisomeric separation of 3 was not attempted; however, column chromatography separation of 4 afforded the cis-4 and trans-4 in 69 and 6% yield, respectively.
Considering the X-ray structure of β-enaminoketone 2, a reasonable explanation of the high cis:trans diastereoselectivity in its reduction step can be explained assuming that the allyl anion A obtained by successive electron-transfers from the sodium to the conjugate system of enaminone, is the more stable conformation, because it avoids the interaction of C-10 or Ph with C2-H observed in conformation B. Thus, protonation with isopropyl alcohol of the corresponding allyl anion in the conformation A takes place selectively from the bottom-face, since the top-face is hindered by the methyl group ( Figure 2).  Table 1. In the 1 H-NMR spectra of compound cis-4, protons H 1 and H 3 exhibit a triplet of triplets multiplicity, with coupling constants of 11.2, 4.8 Hz and 11.6, 4.0 Hz, respectively. Analysis of these coupling constants confirms the axial disposition of both protons establishing then an equatorial distribution of the OH and NHR groups. Additionally, proton H 2b presents a quadruple signal (J = 11.6 Hz) which determines its axial position whereas H 2a is occupies an equatorial position. The multiplicity of H 4a (ddt) shows three couplings constants 2 J = 12.8 Hz, 3 J ec/ax = 3.6 Hz and 4 J H4a/H6a = 2 Hz, this scalar coupling establishes that H 1 and H 3 occupy axial positions ( Figure 3).  The 1 H-NMR spectra of the compound trans-4 displays similar data to those observed for the cis-4 stereoisomer, the main difference being the chemical shift for protons H 2a , H 2b , and H 4a . On the other hand, its 13 C-NMR data shows that C 4 is shifted downfield by 2.0 ppm. This can be attributed to a lesser ring strain around this atom. In addition, the coupling pattern for proton H 2a is different due to dihedral angles variations ( Figure 5).

cis-4 trans-4
Compound trans-4 shows a triplet of triplets for the H 1 and H 3 protons (J = 11.8, 4.4 Hz and J = 11.6, 4.0 Hz respectively), which are similar to those observed for cis-4. However, in the NOESY experiment ( Figure 6) these two protons do not interact spatially, suggesting an anti-arrangement of the hydroxyl and amino groups. In order to establish the relative configuration at C-1 and C-3 of compound 4, we also carried out a NOESY experiment (Figure 7). If a chair conformation is considered for compound trans-4 (A), the fact that H 3 has a dihedral angle below 60° with respect to H 2a , H 2b , H 4a and H 4b , would generate coupling constants with magnitude around ~3-5 Hz according to the Karplus rule, however, this is not observed in the spectrum of this compound. These experimental data thus confirm that the compound trans-4 does not adopt a chair conformation as its isomer cis-4 does. Therefore, we carried out an additional NOESY experiment in order to establish the relative configurations at C-1 and C-3, analyzing the coupling constants and spatial interactions of the two possible conformations C and D (Table 2).  1 3, 2 eq , 4 eq , Me upfield 2 eq , 6 eq 3 1, 2 eq , 4 eq , 7ax Me upfield , 4 eq 6 eq --6 ax , Me downfield 4 eq --Me-7, Me-8 In conformation D, proton H 3 shows a dihedral angle larger than 120° with H 2a and H 4a , this spatial arrangement exhibits coupling constants of ~12.0 Hz, and the coupling with H 2b and H 4b of 4.0 Hz. On the other hand the NOESY experiment shows the spatial proximity of H 4b to both methyl groups at C 5 , and of proton H 1 to both H 2a and H 6a . In addition the fact that proton H 3 shows a proximity to H 4b , suggests a boat conformation for compound trans-4. The shielding of H 4a is caused by the proximity of the NHR substituent, the torsional effect and the steric hindrance of the boat conformation explains the variation of the chemical shift of C 4 in comparison to that of compound cis-4.

Experimental
Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer-Johns apparatus and are uncorrected. NMR studies were carried out with a Varian Gemini 200 and Varian Inova 400 instruments using TMS as a standard ( 1 H, 13 (2). A solution of 4,4-dimethyl-1,3cyclohexanedione (1.0 g, 7.13 mmole) and (S)-α-methylbenzylamine (1.0 mL, 7.84 mmole) was refluxed in toluene (30 mL) during 3.5 h, while the water formed was removed azeotropically using a Dean-Stark trap. After this time, the solvent was removed and the yellow solid obtained was purified by crystallization (CH 2 Cl 2 /hexane) to give compound 2 (1.51 g, 87%), mp = 135-137 °C.

General Procedure for the Reduction of β-Enaminoketones 1 and 2
The β-enaminoketones (2.0 mmol) were dissolved in a mixture of isopropyl alcohol (2 mL) and THF (5 mL). The resulting solution was treated with an excess of small pieces of metallic sodium (0.27 g, 12.0 g-atoms) and stirred from 0 °C to room temperature until the reaction was complete (TLC). After removal of the unreacted sodium, the reaction mixture was poured into a saturated aqueous solution of NH 4 Cl and extracted with AcOEt. The organic layers were combined, dried over Na 2 SO 4 filtered and evaporated under reduced pressure. The resulting materials were submitted to an initial percolation and then were submitted to HPLC-MS analysis. The materials were separated by column chromatography (silica gel, 230-400) eluting with 65:25:10 proportions of hexane/ethyl acetate/isopropyl alcohol or 95:5, CH 2 Cl 2 /CH 3 OH.

Conclusions
In conclusion, 1,3-amino alcohols 3 and 4 were obtained as diastereoisomeric mixtures in good yield by reduction of the corresponding β-enaminoketones 1 and 2, which were analyzed by gas chromatography/mass spectrometry using a chiral column. Two diastereomeric pairs were identified for compound 3 and two diasteromeric pairs, cis-4 and trans 4, for compound 4. Chromatographic techniques allowed the separation of cis-4 and trans-4. On the other hand, NMR NOESY experiments enabled us to establish a chair conformation and a syn-orientation of the hydroxyl and amino groups for cis-4 and a boat conformation with anti-orientation of the hydroxyl and amino groups for trans-4.