L. Ait Said, M.M. El Hammoumi, C. El Haimer et al.
Journal of Molecular Structure 1241 (2021) 130691
ing different diseases. They contain natural, pharmaceutical and bi-
4.4. Synthesis of (1R, 2R, 4S) −1-methyl-2- (R) -N-benzyl
(α-methyl-benzyl) amino −4-isopropenyl-cyclohexanol 2b and (1R,
2R, 4S) −1-methyl −2- (R) -N-methy (α-methyl-benzyl) amino
−4-isopropenyl-cyclohexanol 3b
The aim of this work is to show a simple way to the synthesis
of pure β-amino alcohols and trans-limonene-1, 2-diol. We started
by a synthesis of two secondary amine and carbamate. This was
also carried out from the same primary amine which is (R)-(+)-α-
Methylbenzylamine. We have also isolated both the cis and trans
diastereomers of (R)-(+)-limonene oxide.
The 1:
1 cis and trans limonene oxide (2.4 mmol), water
(0.55 ml) and secondary amine 2a or 3a (5 mmol) were placed in
a flask under magnetic stirring at 100 °C. After 24 h, the product
reaction was obtained by column chromatography using as eluent
The results of this work is initial. Yet, they provide a starting
point to design other modifications from the limonene oxide ar-
chitecture in order to guide further structure activity relationship
studies.
hexane ̸ ether 8: 2 β-aminoalcohol 2b was obtained in a yield of
50%, and β-aminoalcohol 3b with a yield of 60%.
4.5. Synthesis of (1R, 2R, 4R) -Limonene-1, 2-diol
The 1:
1 cis and trans limonene oxide (2.4 mmol), water
4. Results and discussion
(0.55 ml) and the carbamate 3 (5 mmol) were placed in a flask
under magnetic stirring at 100 °C. After 24 h, the reaction product
has been obtained by column chromatography, using hexane ̸ ether
4.1. Synthesis of (R) -N-benzyl- (α-methyl-benzyl) amine, 2a
7: 3 as eluent. (1R, 2R, 4R) -Limonene-1, 2-diol was obtained with
The reaction was carried out by dissolving 5 g (45 mmol) of
(R) -α-methylbenzylamine in 75 mL of ethanol, and adding 5 mL
(19 mmol) of benzaldehyde (recently distilled) to it. The solution
heated up to boiling (a bath temperature: 110 °C). After 6 h, the re-
action mixture was cooled with an ice bath and 0.92 g (22.5 mmol)
of NaBH4 was added. It allowed itself to react for 12 h. The ethanol
evaporated and 25 ml of H2O, solid KOH until pH> 10, and solid
NaCl were added. The reaction mixture is extracted with ether, and
the ethereal phase is washed with dissolution of saturated NaCl
and H2O. It was allowed to dry over anhydrous Na2SO4, the ether
was filtered and evaporated, obtaining 8.71 g (99.5%) of 2a.
60 mL of hot 2 M HCl was added to 8.71 g of 2a. The crystalline
hydrochloride was infiltrated and washed with H2O. 7.76 g (76%) of
2a hydrochloride was obtained.
a yield of 80%.
Declaration of Competing Interest
No.
Acknowledgements
I confirm that Hassan II University has funded our research.
(R)-N-benzyl-(α-methyl-benzyl) amine, 2a
IR (νmax, cm−1): 3400, 3200, 3050, 1600,710, 1H NMR δ (ppm)
(300 MHz, CDCl3): 1.52 (3H, d, CH3), 3.75 (1H, q, CH), 3.95 (2H, q,
CH2), 7.3–7.5 (10H, m, ArH), 13C NMR δ (ppm) (50 MHz, CDCl3):
24.5 (CH3), 51.7 (CH2), 57.8 (CH), 126.9–128.9 (10xCH, Ar), 141 (C,
Cipso), 145.9(C, Cipso).
To generate 2a as free amine, 7 g (28 mmol) hydrochloride of 2a
was added to 80 mL of KOH (2 M) slowly, and it was carried out
while stirring for 3 h. Then solid NaCl was added and extracted
with ether. The organic phase was allowed to dry over anhydrous
Na2SO4, which was infiltrated and the ether was evaporated, ob-
taining 5.20 g (89%) of 2a.
(R) -N-(α-methyl-benzyl) carbamate de ethyle, 3
IR (νmax, cm−1): 3324, 2980, 1699, 1537, 1248, 762, 700, 1H
NMR δ (ppm) (300 MHz, CDCl3): 1.23 (3H, t, J = 6.8 Hz, OCH2CH3),
1.49 (3H, d, J = 6.4 Hz, CH3), 4.11(1H, q, J = 6.4 Hz, CH), 4.10
(2H, q, J = 6.8 Hz, OCH2CH3), 7.28 (4H, m, Ar-H), 13C δꢀ(ppm) NMR
(50 MHz, CDCl3): 14.6 (CH3, OCH2CH3), 22.5 (CH3, C-2 ), 50.6 (CH,
C-1), 60.7(CH2, OCH2CH3), 125.9 (2C, Ar-Corto), 127.0 (C, Ar-Cpara),
128.0 (2C, Ar-Cmeta), 144.6 (Cipso),156.8 (C, NHCO2CH2CH3).
(R)-N-methyl-(α-methyl-benzyl) amine, 3a
4.2. Synthesis of (R) -N- (α-methyl-benzyl) ethyl carbamate, 3
The reaction was carried out first by dissolving 5 g (45 mmol)
of R -α-methylbenzylamine in 6.3 mL of triethylamine and 37.6 ml
of diethyleter. After that, 4.8 mL of ethyl chloroformate is added
dropwise at 0 °C for 30 min. Next, the reaction was stirred at a
temperature room for 2 h. Then, 200 ml of ether was added. It was
washed with HCl (2 M) and with dissolution of saturated NaHCO3
and NaCl. Finally, it was dried over anhydrous Na2SO4, which was
infiltrated and the ether was evaporated, obtaining 7.45 g of (95%)
of 3.
IR (νmax, cm−1): 3320, 2980, 1671, 1439, 1451, 760, 700, NMR1H
δ (ppm) (300 MHz, CDCl3): 1.37 (3H, d, J = 6.45 Hz, CH3), 2.31(3H,
s, CH3), 3.57(1H, q, J = 6.4 Hz, CH),7.31 (m, Ar-H), 13C NMR δ(ppm)
(50 MHz, CDCl3): 23.8(CH3), 34.5(CH3, CH3), 60.2(CH), 126.5 (2C,
Ar-Corto), 126.8 (2C, Ar-Cpara), 128.3 (2C, Ar-Cmeta), 145.4(Cipso).
(1R,2R,4S)−1-methyl-2-(R)-N-benzyl(α-methyl-benzyl) amino
−4-isopropenyl-cyclohexanol 2b
HPLC-MS: 362.14786, IR (νmax
,
cm−1): 3500, 3200, 3050,
1600,710, 1H δ (ppm) NMR (300 MHz, CDCl3): 1.38 (3H, d, CH3),
1.54 (2H, m, CH2), 1.70 (3H, s, CH3), 1.72 (3H, s, CH3), 2.11 (3H, m,
CH et CH2), 2.27 (2H, m, CH2), 3.65 (1H, q, CH), 3.89 (2H, c,CH2),
4.68 (2H, s, CH2), 4.71 (1H, s, CH), 7.25–7.36 (10H, m,ArH), 13C
NMR δ (ppm) (50 MHz, CDCl3): 21.20 (CH3), 24.14 (CH3), 26.27
(CH2), 33.74 (CH2), 34.57 (CH2), 37.54 (CH), 51.39 (CH2), 57.46 (CH),
71.33(C), 74 (CH), 109.10 (CH2) 126.43–128.66 (10xCH, Ar), 140.90
(C, Cipso), 150(C, Cq).
4.3. Synthesis of (R) -N-methyl- (α-methyl-benzyl) amine, 3a
The reaction was carried out by dissolving 5.45 g (27.9 mmol)
of 3 in 4 mL of THF and was added dropwise at 0 °C to a suspen-
sion of LiAlH4 3.15 g (82.3 mmol) in 40 mL of THF .It was stirred
for 30 min. After that, the dissolution heated up to boiling at a
bath temperature of 75 °C. After 3 h, the reaction mixture cooled
down to 0 °C, and 10 ml of THF was added with 1 ml of H2O little
by little until the color changed from gray to white. It was filtered
through silica and left to dry over anhydrous Na2SO4. The solvent
was evaporated off. Finally, 2.37 g (17.6 mmol; 63%) of 3a was ob-
tained.
(1R,2R,4S)−1-methyl-2-(R)-N-methy(α-methyl-benzyl) amino
−4-isopropenyl-cyclohexanol 3b
HPLC-MS:288.23239, IR (νmax
,
cm−1): 3500, 3200, 3050,
1600,710, 1HNMR δ (ppm) (300 MHz, CDCl3): 1.28 (3H, d, CH3),
1.54 (2H, m, CH2), 1.70 (3H, s, CH3), 1.72 (3H, s, CH3), 2.11 (3H, m,
CH et CH2), 2.27 (2H, m, CH2), 4.05 (1H, q,CH), 4.62 (2H, s, CH2),
4.69 (1H, s, CH), 7.20–7.28 (5H,m,ArH), 13C δ (ppm) NMR (50 MHz,
3