An efficient synthetic route to chiral 4-alkyl-1,2,3,4-tetrahydroquinolines: Enantioselective synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline

Article abstract of DOI:10.1016/S0957-4166(00)00468-7

An efficient synthetic route to non-racemic chiral 4-alkyl-1,2,3,4-tetrahydroquinoline is described. (4R)-4-Ethyl-1,2,3,4-tetrahydroquinoline was obtained by the organoaluminum promoted modified Beckmann rearrangement involving the oxime sulfonate of (3R)

Full text of DOI:10.1016/S0957-4166(00)00468-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4687–4691
An efficient synthetic route to chiral
4
-alkyl-1,2,3,4-tetrahydroquinolines: enantioselective
synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline
Neelakandha S. Mani* and Min Wu
Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., 10275 Science Center Dr., San Diego, CA,
2121, USA
9
Received 9 October 2000; accepted 6 November 2000
Abstract
An efficient synthetic route to non-racemic chiral 4-alkyl-1,2,3,4-tetrahydroquinoline is described.
(
4R)-4-Ethyl-1,2,3,4-tetrahydroquinoline was obtained by the organoaluminum promoted modified Beck-
mann rearrangement involving the oxime sulfonate of (3R)-3-ethylindan-1-one. The required optically
active indanone was obtained via an asymmetric conjugate reduction of (E)-ethyl 3-phenylpent-2-enoate.
©
2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Although substituted 1,2,3,4-tetrahydroquinolines with one or more stereogenic centers due to
1
substituents on the hydroaromatic ring are well known in the literature, very little work has
2
been reported on their preparation in optically active form. In connection with our work on the
3,4
nonsteroidal androgen receptor modulator LG 121071 and related analogs, we needed an
asymmetric route suitable to prepare these compounds in both enantiomeric forms. An efficient
Scheme 1.
*
Corresponding author. Present address: The R.W. Johnson Pharmaceutical Research Institute, 3210 Merryfield
Row, San Diego, CA 92121, USA. Tel: (858) 784-3289; fax: (858) 450-2089; e-mail: nmani@prius.jnj.com
0
957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00468-7

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N. S. Mani, M. Wu / Tetrahedron: Asymmetry 11 (2000) 4687–4691
synthesis of enantiopure 4-ethyl-1,2,3,4-tetrahydroquinoline with predetermined absolute
configuration was thus required (Scheme 1). We were surprised to find that there are no methods
on record for the synthesis of chiral 4-alkyl-tetrahydroquinolines with known absolute configu-
ration. We wish to report herein the results of our studies in this direction. A preparatively
useful synthetic route to obtain enantiopure 4-alkyl-1,2,3,4-tetrahydroquinolines is described,
illustrated by the synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline.
2
. Results and discussion
Since we were unable to find any non-racemic chiral 4-alkyl-1,2,3,4-tetrahydroquinolines with
known absolute configuration in the literature, we focused our attention on a synthetic strategy,
which would allow for direct correlation of stereochemistry with that of an intermediate of
known absolute configuration. The synthetic pathway we designed consists of a modified
5–7
Beckmann rearrangement involving a 3-substituted indanone oxime (Scheme 2).
Scheme 2.
Optically active 3-substituted indanones of known stereochemistry have been reported in the
8
9,10
literature. Moreover, their absolute configuration could be easily determined by ORD.
Beckmann rearrangement of the unsubstituted indanone oxime has been shown to be highly
5
regioselective. More importantly, Yamamoto’s organoaluminum promoted modified Beckmann
6
,7
rearrangement of the unsubstituted 1-indanone oxime mesylate has been shown to yield
,2,3,4-tetrahydroquinoline as the predominant product. Preparation of chiral 3-alkylindanones
1
was envisaged through the classical cyclodehydration from the corresponding 3-alkylhydrocin-
namic acid. Enantioselective synthesis of carboxylic acid derivatives with a stereocenter b to the
carbonyl has been an area of intense investigation and several methods are now available for
11–13
their preparation in high enantiomeric purity.
Asymmetric conjugate reduction of an
a,b-unsaturated ester appeared most suitable, since Buchwald et al. have recently shown that
conjugate reduction of a,b-unsaturated esters using copper hydride with p-tol-BINAP as a chiral
ligand and polymethylhydrosiloxane as the hydride source gave products with a stereocenter b
14
to the carbonyl in very good enantiomeric purity. A Reformatsky reaction or a Horner–
Emmons reaction with an aromatic ketone could easily furnish the required 3-alkyl cinnamic
1
4,15
acid derivatives.
Synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline using this methodology
is outlined in Scheme 3.
Following Buchwald’s procedure, asymmetric conjugate reduction of (E)-ethyl 3-phenylpent-
2
-enoate 1 using a catalyst formed from (R)-p-tol-BINAP, CuCl, and NaOt-Bu and an excess
of polymethylhydrosiloxane (4 equiv.) furnished (R)-3-phenylpentanoate 2 (86% ee). Basic
hydrolysis to the carboxylic acid followed by cyclization using polyphosphoric acid furnished
(
R)-3-ethyl-1-indanone in 80% yield. Treatment of this indanone with hydroxylamine hydrochlo-
ride in methanolic KOH furnished the oxime 5. Treatment of 5 with methanesulfonyl chloride

N. S. Mani, M. Wu / Tetrahedron: Asymmetry 11 (2000) 4687–4691
4689
Scheme 3.
and triethylamine furnished an unstable mesylate which was immediately treated with an excess
of DIBAH to furnish (R)-(+)-4-ethyl-1,2,3,4-tetrahydroquinoline in very good overall yield.
In conclusion, an efficient enantioselective synthesis of 4-ethyl-1,2,3,4-tetrahydroquinoline
correlating optical rotation and absolute configuration has been achieved. The methodology
appears to be suitable for preparing various 4-alkyl-1,2,3,4-tetrahydroquinolines.
3
. Experimental section
3
.1. General methods
1
H NMR spectra were recorded at 400 or 500 MHz using CDCl as solvent and TMS (0.00
3
1
1
ppm H) or CHCl (7.26 ppm H) as internal standards. Chemical shifts (l) are given in parts
3
per million (ppm) and coupling constants (J) are given in hertz (Hz). Infrared spectra were taken
on a Nicolet Impact 410 spectrometer. Optical rotations were measured on a Perkin–Elmer 241
polarimeter.
3
.2. (R)-3-Phenylpentanoic acid 3
1
4
(
R)-Ethyl 3-phenylpentanoate (2) 800 mg, 3.87 mmol) was dissolved in ethanol (4 mL)
Aqueous NaOH (10%, 2 mL) was added and the reaction mixture was refluxed for 4 h. The
mixture was cooled to rt, acidified to pH 2 with 0.5N HCl and extracted with ethyl acetate (2×20
mL). The combined organic layer was washed with brine and dried over MgSO . After filtration,
4
the solvents were evaporated and the crude product was purified by column chromatography
25
(
silica gel, ethyl acetate:hexanes 1:4) to yield the free acid as a colorless oil (680 mg, 91%); [h]D

4690
N. S. Mani, M. Wu / Tetrahedron: Asymmetry 11 (2000) 4687–4691
8
21
D
1
−
17.3 (c=0.55, ethanol) {lit. [h] −18.4 (c=1.6, ethanol)}; H NMR (400 MHz, CDCl ) l 0.80
3
(
3H, t, J=7.5), 1.61–1.78 (2H, m), 2.65 (2H, oct., J=7.5), 2.99 (1H, m), 7.17–7.23 (3H, m),
7
.26–7.31 (2H, m).
3
.3. (R)-3-Ethyl-1-indanone 4
(R)-3-Phenylpentanoic acid (600 mg, 3.36 mmol) was treated with PPA (15 g) and the
resulting mixture heated to 70°C. After 3 h, the reaction mixture was poured on to ice and
extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water,
saturated sodium bicarbonate, and brine and dried over MgSO . After filtration, the solvents
4
were evaporated under reduced pressure and the crude product was purified by column
chromatography (silica gel, ethyl acetate:hexanes 1:9) to yield the indanone 4 as a colorless oil
2
5
8
19
1
(
450 mg, 83%); [h] −15.5 (c=0.67, ethanol) {lit. [a] −20.5 (c=1.3, ethanol)}; H NMR (400
D
D
MHz, CDCl ) l 0.98 (3H, t, J=7.5), 1.51 (m, 1H), 1.98 (1H, m), 2.35 (1H, dd, J=3.5, 19.0),
3
2
.83 (1H, dd, J=3.5, 19.0), 3.32 (1H, m), 7.36 (1H, t, J=8.0), 7.50 (1H, d, J=8.0), 7.59 (1H,
t, J=8.0), 7.73 (1H, J=7.5).
3
.4. (R)-3-Ethyl-1-indanone oxime 5
To a solution of (R)-3-ethyl-1-indanone (250 mg, 1.56 mmol) in 5 mL of methanol was added
hydroxylamine hydrochloride (162 mg, 2.33 mmol) and aq. KOH (50%, 0.53 mL, 4.72 mmol).
The mixture was refluxed for 3 h when TLC indicated complete conversion. After cooling to
room temperature, the reaction mixture was neutralized with dilute HCl and extracted with ethyl
acetate (3×20 mL). The combined organic layer was washed with water, brine and dried over
MgSO . After filtration, the solvents were evaporated under reduced pressure to obtain the
4
crude oxime, which was purified by recrystallization from ethyl acetate–hexanes to yield a pale
1
6
25
yellow solid (243 mg, 89%). Mp 81–83°C (lit. for racemate 82–83°C); [h]D +18.6 (c=0.6,
1
ethanol)); H NMR (400 MHz, CDCl ) l 0.98 (3H, t, J=7.5), 1.51 (m, 1H), 1.88 (1H, m), 2.64
3
(
1H, dd, J=3.5, 19.0), 3.13 (1H, dd, J=8.1, 19.0), 3.23 (1H, m), 7.26 (1H, t, J=8.0), 7.38 (2H,
m), 7.69 (1H, d, J=7.5).
3
.5. (R)-4-Ethyl-1,2,3,4-tetrahydroquinoline 7
A solution of 4-ethyl-1-indanone oxime (300 mg, 1.83 mmol), triethylamine (0.51 mL, 3.66
mmol) in 10 mL of dry dichloromethane was cooled to −25°C. Methanesulfonyl chloride (0.17
mL, 2.19 mmol) was added over a period of 10 min. After stirring for 1 h, the reaction was
diluted with dichloromethane (50 mL) and washed with ice-cold 1N hydrochloric acid followed
by saturated sodium bicarbonate solution and brine. The dichloromethane solution was dried
over MgSO for 10 h. After filtration with aid of dry dichloromethane, the solution was
4
concentrated under reduced pressure (maintaining the bath temperature at 20°C) to about 10–15
ml. The concentrated solution thus obtained was cooled to −78°C and DIBAH (1 M in hexanes,
6
.4 mL) was added. After 10 min, the solution was warmed to 0°C and stirred for 8 h. The
reaction mixture was diluted with dichloromethane (150 mL) and quenched with water. The
organic layer was washed with brine and dried over MgSO . After filtration, the solvents were
4
evaporated under reduced pressure and the crude product was purified by flash column
chromatography (silica gel, ethyl acetate:hexanes 1:10) to furnish (R)-4-ethyl-1,2,3,4-tetra-

N. S. Mani, M. Wu / Tetrahedron: Asymmetry 11 (2000) 4687–4691
4691
2
5
hydroquinoline 7 as pale yellow oil (216 mg, overall 73% in two steps); [h] +29.1 (c=1.4,
D
1
ethanol); H NMR (500 MHz, CDCl ) l 1.01 (3H, t, J=7.5), 1.51–1.94 (4H, m), 2.66 (1H, m),
3
3
.24–3.36 (2H, m), 3.84 (1H, br), 6.50 (1H, d, J=8.0), 6.63 (1H, dt, J=1.0, 8.0), 6.98 (1H, dt,
+
+
’
J=1.0, 8.0), 7.03 (1H, d, J=8.0); MS (70 eV) m/z 161 M , 132 (M−CH CH ) . Spectroscopic
data was consistent with previously reported data for this compound.
3
2
3
Acknowledgements
We wish to thank Dr. Don Karanewsky for his very helpful suggestions and support.
References
1
2
3
. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031–15070.
. Reichardt, C.; Aman, W.; Harms, K.; Schaefer, G.; Stein, J. J. Prakt. Chem./Zhem-Ztg. 1998, 340, 513–529.
. Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X.-N.; Marschke, K. B.; Jones, T. K. J. Med. Chem. 1999,
4
2, 210–212.
4
. Edwards, J. P.; Higuchi, R. I.; Winn, D. T.; Pooley, C. L. F.; Caferro, T. R.; Hamann, L. G.; Zhi, L.; Marschke,
K. B.; Goldman, M. E.; Jones, T. K. Bioorg. Med. Chem. Lett. 1999, 9, 1003–1008.
. Gawley, R. E. Org. React. 1988, 35, 1–420.
. Hattori, K.; Matsumura, Y.; Miyazaki, T.; Yamamoto, H. J. Am. Chem. Soc. 1981, 103, 7368–7370.
. Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem.
Soc. 1983, 105, 2831–2843.
5
6
7
8
9
. Brienne, M.-J.; Ouannes, C.; Jacques, J. Bull. Soc. Chim. Fr. 1967, 2, 613–623.
. Smith, H. E.; Padilla, B. G.; Neergaard, J. R.; Chen, F.-M. J. Am. Chem. Soc. 1978, 100, 6035–6038.
1
1
1
1
1
0. Fontana, L. P.; Chandramouly, T.; Smith, H. E.; Polavarapu, P. L. J. Org. Chem. 1988, 53, 3379–3381.
1. Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem. 1998, 63, 8067–8070.
2. Romero, D. L.; Manninen, P. R.; Han, F.; Romero, A. G. J. Org. Chem. 1999, 64, 4980–4984.
3. Pippel, D. J.; Curtis, M. D.; Du., H.; Beak, P. J. Org. Chem. 1998, 63, 2–3.
4. Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9
473–9474.
1
1
5. Shriner, R. L. Org. React. 1942, 1, 1–37.
6. Bott, K. Chem. Ber. 1967, 100, 2791–2797.
.