An efficient synthesis of optically pure (S)-2-functionalized 1,2,3,4-tetrahydroquinoline

Article abstract of DOI:10.1016/j.tetlet.2003.11.086

Using a copper-catalyzed coupling reaction of amino acid and aryl halide, followed by intramolecular cyclization of N-aryl-1-hydroxyl-3-propylamines under the Swern's condition as the key steps, (S)-2-hydroxymethyl-1,2,3,4- tetrahydroquinoline was synthesized as an example of optically pure 2-functionalized 1,2,3,4-tetrahydroquinolines.

Full text of DOI:10.1016/j.tetlet.2003.11.086

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1027–1029
An efficient synthesis of optically pure (S)-2-functionalized
1,2,3,4-tetrahydroquinoline
Ke Ding,a Judy Flippen-Anderson,b, Jeffrey R. Deschampsb and Shaomeng Wanga,*
aDepartments of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive,
Ann Arbor, MI 48109-0934, USA
bLaboratory for the Structure of Matter, Naval Research Lab, Washington, DC 20375, USA
Received 25 October 2003; revised 13 November 2003; accepted 19 November 2003
Abstract—Using a copper-catalyzed coupling reaction of amino acid and aryl halide, followed by intramolecular cyclization of
N-aryl-1-hydroxyl-3-propylamines under the SwernÕs condition as the key steps, (S)-2-hydroxymethyl-1,2,3,4-tetrahydroquinoline
was synthesized as an example of optically pure 2-functionalized 1,2,3,4-tetrahydroquinolines.
Ó 2003 Elsevier Ltd. All rights reserved.
Substituted tetrahydroquinolines are the core structures
in many important pharmacological agents and drug
molecules, such as anti-arrhythmic and cardiovascular
agents, anti-cancer drugs, immunosuppressants, ligands
for 5-HT1A and NMDA receptors.1–8 In fact 2-substi-
tuted tetrahydroquinoline oxamniquine (1) has been
used in clinic to treat MansonÕs schistosomiasis since
1979. For these reasons, many efforts have been made to
synthesize tetrahydroquinoline derivatives.9–12 Recently,
we found that N-substituted 2,3,4,4a,5,6-hexahydro-1H-
pyrazine[1,2-a]quinolines (2) are quite potent ligands for
the dopamine 3 (D3) receptor.13 Although the racemic
form of 2 can be synthesized efficiently using previously
published methods,14;15 the synthesis of the optically
pure form of 2 has not been reported. The key inter-
mediate to obtain the optically pure form of 2 is the
chiral 2-hydroxymethyl tetrahydroquinoline 3. Herein,
we report an efficient method to synthesize the optically
pure substituted 2-hydroxymethyl tetrahydroquinoline 3
(Fig. 1).
HO
O2N
R1
N
H
R
N
HN
OH
N
H
N
R
1
3
2
Oxamniquine
Figure 1. Examples of important tetrahydroquinoline derivatives.
and co-workers,17 followed by intramolecular acylation
as the key reactions to synthesize (S)-2-hydroxymethyl-
7-methoxy-1,2,3,4-tetrahydroquinoline (Scheme 1).
3-Bromoanisole was treated with L-aspartic acid under
HayesÕ condition, followed by esterification to obtain
N-aryl-aspartic diester 4 in a yield of 65% (two steps).
Compound 4 was then reduced by NaBH4, and the
resulting diol 5 was reacted with triphosgene to produce
oxazolidinone 6 and 7 (approximately 3:1 ratio). The
major product 6 was oxidized by JoneÕs reagent, fol-
lowed by intramolecular acylation to yield the desired
cyclization product 9. Unfortunately, the yield of JoneÕs
oxidation was quite poor (<15%), which might be due to
the instability of the oxazolidinone under the very
strong acidic condition, so a large quantity of 9 could
not be obtained. Although the following intramolecular
acylation, reduction and deprotection worked very well,
an alternative method had to be developed to obtain 11
in satisfactory yield.
Our initial idea was to use copper-catalyzed coupling
reaction of amino acid and aryl halide, which was ini-
tially developed by Ma et al.16 and modified by Hayes
Keywords: Tetrahydroquinoline; Synthesis; Copper; Swern oxidation;
Optically pure.
* Corresponding author. Tel.: +1-734-615-0362; fax: +1-734-647-9647;
e-mail: shaomeng@umich.edu
Current address: Rutgers, the State University of New Jersey,
Department of Chemistry and Chemical Biology, 610 Taylor Road,
Piscataway, NJ 08854-8087, USA.
Since the major problem in Scheme 1 was the low yield
of JoneÕs oxidation, we planned to produce the
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.086

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K. Ding et al. / Tetrahedron Letters 45 (2004) 1027–1029
OH
OH
1. (Bu)4NOH, CuI,
L-Aspartic acid
OH
MeO
N
NaBH4, MeOH
0 C ~ R.T.
+
MeO
N
°
CH3CN, 80
C
CO2Me
CO2Me
°
Triphosgene
O
O
O
O
85%
2. MeOH, AcCl, refux
65%
MeO
N
H
MeO
Br
MeO
N
H
18%
50%
OH
3
4
5
6
7
OH
O
N
1. (COCl)2 then AlCl3
2. MeI, K2CO3, DMF
CO2H
Jone's Oxidization
<15%
KOH, EtOH
MeO
H2, Pd-C
95%
>85%
MeO
N
MeO
N
MeO
MeO
N
N
H
85%
O
O
O
O
HO
O
O
O
O
6
8
11
9
10
Scheme 1.
OH
O
OH
(COCl)2, DMSO,
Et3
O
N
MeO
N
MeO
N
MeO
N
O
O
O
O
O
O
6
12
9
Scheme 2.
carboxylic acid 9 by another strategy. 4-(2-Hydroxy-ethyl)-
3-(3-methoxy-phenyl)-oxazolidin-2-one 6 should be able
to be oxidized under SwernÕs condition18 to yield the
aldehyde 12 easily, and the aldehyde 12 could be oxi-
dized to get the carboxylic acid 9 in a satisfactory yield
(Scheme 2). Unexpectedly, under SwernÕs condition,18
the desired aldehyde 12 was not obtained. Instead,
cyclization products 13, 14, 15 and 16 were produced,
and the total yield was about 75% (Scheme 3, according
to 1H NMR, 13:14 ¼ 10:1 and 15:16 ¼ 10:1). This
unexpected result might be attributed to the high reac-
tivity of the disubstituted phenyl ring in 6. Compound
13 was purified by recrystallization (to remove the minor
C5
C3
C6
C4
C2
C7
C12
C1
N11
C1A
C8
C13
01
C10
09
1
product 14) and the structure was determined by H
NMR, 13C NMR and X-ray crystallographic analyses
(Fig. 2).
010
Figure 2. X-ray structure of compound 13. Thermal ellipsoids are at
the 50% probability level, H atoms are shown as circles of an arbitrary
radius.
Both the reduction of double bond in compound 13 by
hydrogenation and the removal of the methylthio group
in 15 by Et3SiH in trifluoroacetic acid produced com-
pound 9 in excellent yields (Scheme 4). Finally, depro-
tection using the same reaction condition as shown in
Scheme 1 led to (S)-2-hydroxymethyl-tetrahydroquino-
line, which can be used to synthesize optically pure
OMe
+
MeO
N
35% (13 + 14)
N
OH
O
O
O
O
(COCl)2, DMSO,
Et3N
14
13
MeO
N
SMe
OMe SMe
O
O
6
+
40% (15 + 16)
MeO
N
N
O
O
O
O
15
16
Scheme 3.

K. Ding et al. / Tetrahedron Letters 45 (2004) 1027–1029
1029
H
2, Pd-C or
TFA, (Et)3SiH
KOH, EtOH
MeO
N
MeO
N
OH
MeO
N
H
>90%
O
O
O
O
13
9
10
SMe
TFA, (Et)3SiH
(~75%)
KOH, EtOH
OH
MeO
N
MeO
N
MeO
N
H
O
O
O
9
O
10
15
Scheme 4.
4. Nagata, R.; Tanno, N.; Kodo, T. PCT Int. Appl., WO
9308188, 1993.
N-substituted 2,3,4,4a,5,6-hexahydro-1H-pyrazine[1,2-
a]quinolines as a class of novel D3 ligands.
5. Ejima, A.; Ohsuki, S.; Ohki, H.; Naito, H. U.S. 6,169,086.
6. Stanton, J. L.; Ackerman, M. H. J. Med. Chem. 1983, 26,
986–989.
7. Kojima, K.; Aizawa, Y.; Samata, N.; Sakai, J.; Koyama,
K.; Tonohiro, T.; Sugimoto, M.; Hara, T.; Hisamoto, M.;
Homma, H. PCT Int. Appl., WO 9623789, 1996.
8. Katritsky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031–15070, and references cited therein.
9. Gallou-Dagommer, I.; Gastaud, P.; Rajanbabu, T. V. Org.
Lett. 2001, 3, 2053–2056, and references cited therein.
In summary, using a copper-catalyzed coupling reaction
of amino acid and aryl halide, followed by intramole-
cular cyclization of N-aryl-1-hydroxyl-3-propylamine
derivatives under the SwernÕs condition as the key steps,
a new and efficient method was developed to synthesize
optically pure 2-hydroxymethyl tetrahydroquinoline.
Further applications of this method for the synthesis of
novel optically pure D3 ligands and other compounds
with interesting biological properties are underway in
our laboratory and will be reported in due course.
10. Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org.
Chem. 2003, 68, 10442–10451.
11. Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3,
2189.
12. Fabio, R. D.; Alvaro, G.; Bertani, B.; Donati, D.;
Giacobe, S.; Marchioro, C.; Palma, C.; Lynn, S. M. J.
Org. Chem. 2002, 67, 7319–7328.
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