Kinetic resolution of (±)-2-methyl-1,2,3,4-tetrahydroquinoline and (±)-2-methylindoline

Article abstract of DOI:10.1070/MC2002v012n01ABEH001545

The acylation of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline by (S)-naproxen acyl chloride resulted in their kinetic resolution with the predominant formation of (S,S)-diastereoisomeric amides (de 78-76%), recrystallisation of which followed by acid hydrolysis gave individual (S)-isomers of heterocyclic amines.

Full text of DOI:10.1070/MC2002v012n01ABEH001545

Mendeleev Commun., 2002, 12(1), 27–28
Kinetic resolution of (± ±)-)ꢀetꢁyl)1,-,3,4)tetraꢁydroquinoline and
(
± ±)-)ꢀetꢁylindoline
Victor P. Krasnov,* Galina L. Levit, Irina N. Andreeva, Alexander N. Grisꢁakov, Valery N. Cꢁarusꢁin and
Oleg N. Cꢁupakꢁin
Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation.
Fax: +7 3432 74 1189; e-mail: ca@ios.uran.ru
1
0.1070/MC2002v012n01ABEH001545
The acylation of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline by (S)-naproxen acyl chloride resulted in their
kinetic resolution with the predominant formation of (S,S)-diastereoisomeric amides (de 78–76%), recrystallisation of which fol-
lowed by acid hydrolysis gave individual (S)-isomers of heterocyclic amines.
The kinetic resolution of racemic compounds from various classes
is an effective method for obtaining individual stereoisomers.1
We found previously that the kinetic resolution of 2,3-dihydro-
of amines 1 and - can be isolated from acidic solutions in ee 78
‡‡
and 76%, respectively.
(S,S)-Amides 4a and 5a were hydrolysed on heating under
2
3
-methyl-4H-1,4-benzoxazine derivatives by (S)-2-(6-methoxy-
naphthyl-2)propionyl chloride [(S)-naproxen acyl chloride] gave
S)-2,3-dihydro-3-methyl-4H-1,4-benzoxazines of high optical
reflux in a mixture of concentrated HCl and glacial acetic acid
to give individual (S)-isomers of amines 1 and - (Scheme 2).§§
The yields of (S)-(–)-isomers of amines 1 and - were 30 and
(
2
purity.
In this paper, we report on the use of the above resolving
agent for the preparation of individual (S)-stereoisomers of
-methyl-1,2,3,4-tetrahydroquinoline 1 and 2-methylindoline -,
‡
1
H NMR spectra were recorded on a Bruker DRX 400 spectrometer,
2
the spectra of amides 4a,b and 5a,b were measured in [ H ]DMSO at
6
1
00 °C; the spectra of amines S-1 and S-- were measured in CDCl at
2
3
ambient temperature. All signals are given in ppm (d) with TMS as an
close structural analogues of 2,3-dihydro-3-methyl-4H-1,4-benz-
oxazine.
internal standard.
4
a,b: 7.79–6.96 (m, 10H, arom.), 4.79 (m) and 4.66 (m) (1H, CH–
As the first step, the diastereomeric mixtures of amides 4a,b
and 5a,b were obtained by the interaction of acyl chloride 3
with racemic amines 1 and - in the stoichiometric ratio in the
quinoline), 4.42 (q) and 4.15 (q) (1H, CH–naproxen, J 6.9 Hz), 3.89 (s)
4
and 3.84 (s) (3H, OMe), 2.63 (ddd) and 2.30 (ddd) (1H, C –H –
A
3
quinoline, J 15.0, 5.3 and 5.2 Hz), 2.12 (dddd, 1H, C –H –quinoline,
A
†
presence of TEA (Scheme 1). In both cases, the compositions
4
J 13.0, 7.6, 5.4 and 5.2 Hz), 1.79 (ddd) and ~1.29 (m) (1H, C –H –
B
of diastereoisomeric mixtures 4a,b (5a,b) were 1:1 according to
quinoline, J 15.0, 10.1 and 5.4 Hz), 1.47 (d) and 1.37 (d) (3H, Me–
1
‡
§
3
the H NMR spectra and HPLC data.
naproxen, J 6.9 Hz), ~1.29 (m) and 1.16 (dddd) (1H, C –H –quinoline,
B
When the molar ratio between starting amine 1 (or -) and
acyl chloride 3 was 2:1, without any tertiary amine present in
the reaction mixture, the resulting products 4a,b (5a,b) were
J 13.0, 10.1, 6.7 and 5.3 Hz), 1.04 (d) and 0.93 (d) (3H, Me–quinoline,
J 6.6 Hz).
5
a,b: 7.98–6.94 (m, 10H, arom.), 4.85 (dqd) and 4.66 (dqd) (1H, CH–
indoline, J 8.8, 6.4 and 1.4 Hz), 4.35 (q) and 4.21 (q) (1H, CH–naproxen,
found to be significantly enriched with (S,S)-diastereoisomers
¶
J 6.8 Hz), 3.864 (s) and 3.858 (s) (3H, OMe), 3.38 (dd) and 3.12 (dd)
4
5
a (5a). In the case of amide 4a, de was 78%; in the case of
a, de was 76%. The (S,S)-diastereoisomers 4a and 5a of high
3
(
1H, C –H –indoline, J 15.9 and 8.7 Hz), 2.59 (dd) and 2.58 (dd) (1H,
A
3
C –H –indoline, J 15.9 and 0.6 Hz), 1.53 (d) and 1.52 (d) (3H, Me–
B
diastereoisomeric purity (de > 99%) were obtained after recrys-
tallisation from hexane in yields about 75%. The (R)-isomers
naproxen, J 6.8 Hz), 1.32 (d) and 0.97 (d) (3H, Me–indoline, J 6.5 Hz).
†
†
§
The de values of amides 4 and 5 were measured by HPLC on a Merck-
Hitachi chromatograph with an L-4000A Intelligent Pump, an L-4000A
UV Detector, and a D-2500A Chromato-Integrator [Hibar Pre-packed
i
Column RT250-4, Lichrosorb Si-60]; mobile phase: hexane–Pr OH, 200:1
i
3
–1
(
A), hexane–Pr OH, 80:1 (B), flow rate of 1 cm min ; UV detection at
2
30 nm; t4a 17.0 min, t4b 15.4 min (A); t5a 6.8 min, t5b 5.4 min (B).
To a stirred solution of amine 1 or - (1 mmol) in dry benzene (5 ml) a
¶
solution of acid chloride 3 (0.5 mmol) in dry benzene (3 mmol) was
added. The reaction mixture was stirred for 24 h at room temperature;
then, it was washed sequentially with 1 M HCl, water, 5% NaHCO and
3
water and dried (MgSO ). The solution was evaporated to dryness to give
4
(
S,S)-diastereoisomer 4a (de 78%) in 90% yield or (S,S)-diastereoisomer
5
a (de 76%) in 86% yield.
†
†
4
a: mp 57–59 °C; [a] +66.8° (c 1.3, CHCl ); de 99.0%. HPLC: t
D 3 R
1
1
7.0 min (A). H NMR, d: 7.79–6.96 (m, 10H, arom.), 4.79 (ddq, 1H,
CH–quinoline, J 7.6, 6.7 and 6.6 Hz), 4.42 (q, 1H, CH–naproxen, J 6.9 Hz),
4
3
5
1
.84 (s, 3H, OMe), 2.30 (ddd, 1H, C –H –quinoline, J 15.0, 5.3 and
A
3
.2 Hz), 2.12 (dddd, 1H, C –H –quinoline, J 13.0, 7.6, 5.4 and 5.2 Hz),
.79 (ddd, 1H, C –H –quinoline, J 15.0, 10.1 and 5.4 Hz), 1.47 (d, 3H,
Me–naproxen, J 6.9 Hz), 1.16 (dddd, 1H, C –HB–quinoline, J 13.0, 10.1,
A
4
B
3
6
.7 and 5.3 Hz), 0.93 (d, 3H, Me–quinoline, J 6.6 Hz).
a: mp 106–107 °C; [a] +82.8° (c 1.9, CHCl ); de 99.3%. HPLC: t
R
.8 min (B). H NMR, d: 7.98–6.94 (m, 10H, arom.), 4.85 (dqd, 1H,
5
D
3
1
6
CH–indoline, J 8.7, 6.5 and 1.4 Hz), 4.35 (q, 1H, CH–naproxen, J 6.9 Hz),
3
3
2
.864 (s, 3H, OMe), 3.38 (dd, 1H, C –H –indoline, J 15.9 and 8.7 Hz),
A
.59 (dd, 1H, C –H –indoline, J 15.9 and 0.6 Hz), 1.53 (d, 3H, Me–
3
B
†
To a stirred solution of amine 1 or - (1 mmol) and TEA (1 mmol) in
naproxen, J 6.8 Hz), 0.97 (d, 3H, Me–indoline, J 6.5 Hz).
The aqueous acid layers after preparing amide 4a or 5a were treated
‡
‡
dry benzene (5 ml) a solution of acyl chloride 3 (1 mmol) in dry benzene
(
5 ml) was added dropwise. The reaction mixture was stirred at room
with NaOH up to pH 9–10 under ice cooling, extracted by chloroform,
temperature for 24 h. Then, it was washed successively with 1 M HCl,
water, 5% NaHCO and water and dried (MgSO ). The resulting solution
was evaporated to dryness to give a yellow oily residue, which was treated
washed with brine, and dried (MgSO ). The solution was evaporated to
4
dryness to give amines (R)-1 in 90% yield or (R)-- in 86% yield as colour-
less oils. Optical purity was determined by HPLC with the pre-column
derivatization of amines by acyl chloride 3.
3
4
with hexane to yield amides 4a,b (82%), 5a,b (86%) as yellow oil.
–
27 –

Mendeleev Commun., 2002, 12(1), 27–28
7%, respectively, relative to the starting racemic amines. The
2
optical purity of the obtained stereoisomers was confirmed by
HPLC after the derivatization of amines by acyl chloride 3.
C(23)
C(17)
C(5) C(6)
C(16)
C(14)
C(7) C(24)
C(22)
C(9)
C(15)
O(1)
N(1)
O(2)
C(4)
C(8)
C(2)
C(18)
C(19)
C(3)
C(21)
C(10)
C(12)
C(11)
∆
C(13)
C(20)
Figure 1 Crystal structure of (S,S)-amide 5a.
In conclusion, note that the use of (S)-naproxen acyl chloride
as a resolving agent in the kinetic resolution of racemic hetero-
cyclic amines appears to be a good general procedure for obtaining
individual stereoisomers of high optical purity.
The stereochemical configuration of compound (S)-(–)-1 was
determined by a comparison of the [a]D sign with published
3
data for (R)-(+)-1. The absolute configuration of (S)-- has not
This work was supported by the Russian Foundation for Basic
Research (grant nos. 00-03-32776, 01-03-96424 and 00-15-97390).
been determined before our study. Assignment of the absolute
configuration for the 2-methylindoline fragment of amide 5a
was performed by X-ray diffraction analysis, taking into account
the known absolute configuration of the starting (S)-naproxen
References
1
R. Noyori, M. Tokunaga and M. Kitamuro, Bull. Chem. Soc. Jpn., 1995,
6.
(
Figure 1).
3
2
V. N. Charushin, V. P. Krasnov, G. L. Levit, M. A. Korolyova, M. I. Kodess,
O. N. Chupakhin, M. H. Kim, H. S. Lee, Y. J. Park and K.-Ch. Kim,
Tetrahedron Asymmetry, 1999, 2691.
§
§
Amide 4a or 5a (1 mmol) was heated under reflux in a mixture of
glacial acetic acid (5 ml) and conc. HCl (5 ml) for 15 h. The reaction mix-
ture was evaporated to dryness. Water (10 ml) was added to the residue;
the precipitate was filtered off and washed with water. The combined
filtrates were made alkaline with 10 M NaOH to pH 10 at +5 °C and
extracted with CH Cl . The organic layer was washed with brine and
3
M. P. Paradisi and A. Romeo, J. Chem. Soc., Perkin Trans. 1, 1977, 596.
2
2
dried (MgSO ). The solution was evaporated to dryness to give amines
4
(
S)-1 in 90% yield or (S)-- in 85% yield as colourless oils.
3
(
S)-(–)-1: [a] –85° (c 1.5, benzene). Lit., (R)-1: [a]D +85° (c 2,
D
1
5
7
6
benzene). H NMR, d: 6.96–6.92 (m, 2H, C H, C H), 6.58 (t, 1H, C H,
J 7.4 and 1.2 Hz), 6.44 (dd, 1H, C H, J 8.3 and 1.2 Hz), 3.63 (br. s, 1H,
NH), 3.38 (dqd, 1H, C H, J 9.8, 6.3 and 2.8 Hz), 2.82 (ddd, 1H, C –H ,
J 16.4, 11.4 and 5.6 Hz), 2.71 (ddd, 1H, C –H , J 16.4, 5.4 and 3.7 Hz),
8
2
4
A
4
B
3
1
.91 (dddd, 1H, C –H , J 12.8, 5.7, 3.5 and 2.9 Hz), 1.57 (dddd, 1H,
A
3
C –H , J 12.8, 11.4, 9.9 and 5.4 Hz), 1.19 (d, 3H, Me, J 6.3 Hz).
B
1
4
(
S)-(–)--: [a] –12.2° (c 2.6, benzene). H NMR, d: 7.07 (dd, 1H, C H,
D
5
J 7.2 and 0.3 Hz), 7.00 (ddd, 1H, C H, J 7.5, 7.4 and 0.4 Hz), 6.68 (ddd,
1
3
6
7
H, C H, J 7.5, 7.3 and 0.8 Hz), 6.59 (dd, 1H, C H, J 7.8 and 0.3 Hz),
2
.98 (ddq, 1H, C H, J 8.5, 7.8 and 6.2 Hz), 3.62 (br. s, 1H, NH), 3.13
dd, 1H, C –H , J 15.4 and 8.5 Hz), 2.62 (dd, 1H, C –H , J 15.4 and
3
3
(
A
B
7
.8 Hz), 1.28 (d, 3H, Me, J 6.2 Hz).
Received: 25th December 2001; Com. 01/1871
–
28 –