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T.d.S. Fonseca et al. / Applied Catalysis A: General 492 (2015) 76–82
A denote the majority enantiomer and B denote the minority
enantiomer represented by the chromatographic peak areas.
14. After, the aqueous solution was extracted with Et2O (3 × 50 mL)
and the organic phases were combined and washed with brine
(30 mL), dried with Na2SO4, filtered and the solvent evaporated
under reduced pressure affording (R)-indanamine (R-5) as a brown
oil in 70% yield.
e.e.s
c =
(3)
e.e.s + e.e.p
Enantioselectivity was expressed as enantiomeric ratio (E) and
calculated by Eq. (4):
2.9. Synthesis of (R)-N-propargyl-1-aminoindan (R-6)
A suspension of (R)-indanamine (R-5) (70 mg, 0.53 mmol),
K2CO3 (76 mg, 0.53 mmol) and propargyl chloride (39.4 L,
0.53 mmol) in acetonitrile (5.3 mL) was stirred at 60 ◦C for 16 h.
After this time, the solvent was evaporated under reduced pres-
sure and the crude product was diluted with 10 mL of a 10% NaOH
solution. The resulting aqueous solution was extracted with CH2Cl2
(3 × 50 mL) and the organic phases were combined and dried
with Na2SO4, filtered and the solvent evaporated under reduced
pressure. The reaction crude was finally purified by flash chro-
matography on silica gel (40–60% EtOAc/hexane) affording the
corresponding (R)-N-propargyl-1-aminoindan (R-6) as an orange
liquid in 79% yield.
ln[l − c(l + e.e.p)]
E =
(4)
ln[l − c(l − e.e.p)]
The results of the e.e.s and e.e.p are expressed in a percentage
using Eqs. (5) and (6):
A − B
e.e.s =
× 100
× 100
(5)
(6)
A + B
A − B
e.e.p
=
A + B
Additionally, the conversion (c) is also calculated in a percent-
age, using (5) and (6).
2.5. Synthesis of rac-indanol (rac-2)
2.10. Synthesis of (R)-rasagiline mesylate (R-7)
To a solution of indanone (1) (1000 mg, 7.50 mmol) in methanol
(75.5 mL), sodium borohydride (1142.3 mg, 30.20 mmol) was
slowly added at 0 ◦C. The reaction mixture was stirred at 0 ◦C for
30 min and then for 2.5 h at room temperature, after which the
solvent was evaporated under reduced pressure. The resulting sus-
pension was acidified with 10 mL of 1N HCl and extracted with
EtOAc (3 × 50 mL). Organic phases were combined and dried over
Na2SO4, filtered and the solvent was evaporated under reduced
pressure, and the resulting crude purified after flash chromatogra-
phy (10–90% EtOAc/hexane) to afford rac-indanol (rac-2) as a white
solid in 86% yield.
A suspension of (R)-N-propargyl-1-aminoindan (R-6) (50 mg,
0.29 mmol) in 5 mL of isopropanol and 3 L of methanesulfonic acid
was heated to reflux for 1 h. After, the mixture was allowed to cool
to 5 ◦C. The obtained suspension was filtered, and the collected solid
was washed with 1.5 mL of isopropanol, affording the correspond-
ing optically active (R)-rasagiline mesylate (R-7) as a white solid in
98% yield.
2.11. General procedure for the lipase-catalyzed hydrolysis of
rac-indanyl acetate (rac-3) (screening)
A suspension of rac-indanyl acetate (rac-3) (30 mg, 0.17 mmol)
and lipase (ratio 2:1 in weight respect to the rac-3) in a mixture
of phosphate buffer 100 mM pH 7.0/THF (80/20, v/v) was shaken
at 30 ◦C and 250 rpm for 24 h. After this time, the products were
extracted with EtOAc (3 × 10 mL) and the organic phases were
combined and dried with Na2SO4, filtered and the solvent evap-
orated under reduced pressure. The reaction crude was purified by
flash chromatography on silica gel (5–95% EtOAc/hexane), yielding
(S)-indanyl acetate (S-3) and (R)-indanol (R-2) being their enan-
tiomeric excess determined by GC.
2.6. Synthesis of rac-indanyl acetate (rac-3)
DMAP (143.8 mg, 1.25 mol) and acetic anhydride (1185.6 L,
12.48 mmol) were added to
a rac-indanol (rac-2), 500 mg,
4.16 mmol) solution in dichloromethane (40 mL). The reaction was
stirred at room temperature during 4 h and after that time, the
solvent was evaporated under reduced pressure. The resulting
crude was purified by flash chromatography on silica gel (5–95%
EtOAc/hexane) to afford the desired rac-indanyl acetate (rac-3) as
a yellow liquid in 80% yield.
2.12. General procedure for the lipase-catalyzed acetylation of
2.7. Synthesis of (R)-azidoindane (R-4)
rac-indanol (rac-2)
Over a solution under a nitrogen atmosphere of (S)-indanol
(S-2) (500 mg, 3.70 mmol) in dry toluene (37 mL), DPPA (956 L,
4.44 mmol) was added for 10 min at 0 ◦C, after DBU (663.0 L,
4.44 mmol) was added dropwise at 0 ◦C for 2 h and the resulting
mixture was stirred at room temperature for 20 h. After this time,
the solvent was evaporated under reduced pressure and the crude
product was purified by flash chromatography on silica gel (hexane)
to afford (R)-azidoindane (R-4) as a yellow liquid in 70% yield.
To a suspension of the rac-2 (30 mg, 0.22 mmol) and lipase
(15 mg) in dry organic solvent (2.2 mL) under nitrogen atmosphere,
vinyl acetate (103 L, 1.10 mmol) was added, and the reaction was
shaken at temperatures ranging from 30 to 50 ◦C and 250 rpm.
Aliquots were regularly analysed by GC analysis and after the ade-
quate time, the reaction was stopped and the enzyme filtered off
and washed with the respective solvent (50 mL). The solvent was
evaporated under reduced pressure and the reaction crude puri-
fied by flash chromatography on silica gel (5–95% EtOAc/hexane),
yielding (S)-indanol (S-2) and (R)-indanyl acetate (R-3), being their
enantiomeric excess determined by GC.
2.8. Synthesis of (R)-indanamine (R-5)
A suspension of (R)-azidoindane (R-4) (200 mg, 1.26 mmol),
PPh3 (366.8 mg, 1.40 mmol) and KOH (70.56 mg, 1.26 mmol) in THF
(9.45 mL) and water (3.15 mL) was stirred at room temperature for
24 h. After this time, the solvent was evaporated under reduced
pressure and the crude product was diluted with 5 mL of a 25% HCl
solution to pH 2. The resulting aqueous solution was washed with
Et2O (3 × 50 mL) and treated with 8 mL of 25% NaOH solution to pH
rac-Indanol (rac-2): Solid. Rf (10% EtOAc/hexane): 0.25. m.p.:
52–55 ◦C. IR ꢀmax (cm−1): 3209, 1475, 1455, 1326, 1053, 760 and
738 cm−1 1H NMR (500 MHz, CD3OD) ı (ppm): 1.9 (m, 1H), 2.4 (m,
.
1H), 2.8 (m, 1H), 3.0 (m, 1H), 5.1 (t, 1H, J = 6.2 Hz), 7.2 (m, 3H) and
7.4 (dd, 1H, J = 6.0 Hz and 2.6 Hz). 13C NMR (125 MHz, CD3OD) ı
(ppm): 29.9 (CH2), 35.9 (CH2), 76.4 (CH), 124.3 (CH), 125.0 (CH),
126.8 (CH), 128.4 (CH), 143.4 (C) and 145.1 (C).