Asymmetric reduction of methoxy substituted β-tetralones using transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2004.10.017

Asymmetric reductions of methoxy substituted 2-tetralones were studied. The asymmetric transfer hydrogenation reaction developed by Noyori using chiral η⁶-arene-ruthenium complexes (arene = p-cymene or benzene) was found to efficiently reduce various methoxy substituted 2-tetralones with >80% ee. Their enantiomeric excesses were found to depend on the position of the methoxy group and the types of the arene complexes. The conditions were identified for the asymmetric reduction of 8-methoxy-2-tetralone to the corresponding 2-tetralol in 98% ee, which was notably higher in enantioselectivity than the other methoxy substituted 2-tetralones.

Full text of DOI:10.1016/j.tetasy.2004.10.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3715–3717
Asymmetric reduction of methoxy substituted b-tetralones
using transfer hydrogenation
Muneto Mogi, Kaoru Fuji and Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Misasagi,
Yamashina, Kyoto 607-8414, Japan
Received 16 September 2004; accepted 13 October 2004
Abstract—Asymmetric reductions of methoxy substituted 2-tetralones were studied. The asymmetric transfer hydrogenation reac-
tion developed by Noyori using chiral g6-arene–ruthenium complexes (arene = p-cymene or benzene) was found to efficiently reduce
various methoxy substituted 2-tetralones with >80% ee. Their enantiomeric excesses were found to depend on the position of the
methoxy group and the types of the arene complexes. The conditions were identified for the asymmetric reduction of 8-methoxy-
2-tetralone to the corresponding 2-tetralol in 98% ee, which was notably higher in enantioselectivity than the other methoxy sub-
stituted 2-tetralones.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(+)-cis-1-amino-2-indanol 13d or (R,R)-N-(2-amino-1,2-
diphenylethyl)-p-toluenesulfonamide 23c,7 ligand, which
resulted in 98% ee and 99% ee, respectively. However
in the case of 2-tetralone, the asymmetric reduction re-
sulted in reduced enantiomeric excess with only 81% ee
and 82% ee, respectively.
Enantiomerically pure 2-tetralols substituted by meth-
oxy or hydroxy groups serve as important synthetic
intermediates for a number of pharmaceutically active
2-aminotetralin derivatives, such as dopaminergic1 and
serotonergic2 agonists. Although several asymmetric
syntheses of an unsubstituted 2-tetralol via reduction
of the corresponding prochiral 2-tetralone have been re-
ported,3 examples with methoxy substituted 2-tetralols
are limited to enzymatic reduction that resulted in high
enantioselectivity specifically for the reduction of 5-
methoxytetralone.4 Furthermore, a chemoenzymatic
synthesis of a chiral 8-methoxy-2-tetralol has been
reported, however, the preparation involves multiple
steps.5
O
OH
*
[RuCl2(p-cymene)] 2
1 or 2, KOH, 2-propanol
98-99% ee
O
HO
*
[RuCl2(p-cymene)] 2
1 or 2, KOH, 2-propanol
Asymmetric transfer hydrogenation6 developed by Noy-
ori using chiral g6-arene–ruthenium complexes is a safe,
due to its use of 2-propanol as the hydrogen source and
thus the reaction does not require hydrogenation appa-
ratus, and highly practical system for the preparation of
various types of chiral alcohols. Noyori et al. and Wills
et al. have reported the asymmetric transfer hydrogena-
tion of 1-tetralone with excellent enantiomeric excess by
using [RuCl2(p-cymene)]2 catalyst with their (1S,2R)-
81-82% ee
Ts
NH
OH
NH2
NH2
1
2
Thus, we became interested in further optimization of
the asymmetric transfer hydrogenation specifically for
the reduction of methoxy substituted 2-tetralones
*
Corresponding author. Tel.: +81 75 5954700; fax: +81 75 5954775;
e-mail: node@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.017

3716
M. Mogi et al. / Tetrahedron: Asymmetry 15 (2004) 3715–3717
because despite their pharmaceutical usefulness, their
asymmetric reduction using chemical catalysts is not
known to date. Furthermore, since methoxy substituted
2-tetralones are readily available from commercial
sources, this would be a convenient method to prepare
various methoxy substituted chiral tetralols. We herein
report an extended study of the asymmetric transfer
hydrogenation for the preparation of various methoxy
substituted chiral 2-tetralols from the prochiral 2-tetra-
lones 3–8 (Fig. 1).
In order to evaluate the effect of the substituent at the 8-
position using other electron donating and withdrawing
groups, the asymmetric transfer hydrogenation of 8-
hydroxytetralone 9 and 8-acetoxytetralone 10 was per-
formed (Scheme 1). However, the attempts resulted in
no reaction for both cases. One could speculate that
the OÀ anion generated in the reaction system possibly
poisoned the catalyst. This indicated the limitation of
the reduction of hydroxy substituted 2-tetralone using
KOH and 2-propanol.
[RuCl2(p-cymene)] 2
8
R
R
O
O
OMe
OMe
7
1 or 2
O
HO
R
6
KOH, 2-propanol
50 oC, 45 min.
5
9: R = OH
10: R = OAc
3: R = H
8
4: R = 5-OMe
5: R = 6-OMe
6: R = 7-OMe
7: R = 8-OMe
Scheme 1. Attempts of the asymmetric transfer hydrogenation on 8-
hydroxytetralone 9 and 8-acetoxytetralone 10.
Figure 1. Methoxy substituted 2-tetralone substrates 3–8.
Next, a Ru–benzene complex was evaluated for the
reduction of 2-tetralones (Table 2, entries 1–12).
Although this Ru–benzene complex was previously re-
ported to provide lower enantiomeric excesses compared
to the Ru–p-cymene complex in the case of a-ketones
such as acetophenone derivatives,3d the Ru–benzene
complex surprisingly provided equal or better enantio-
meric excesses for the reduction of the 2-tetralone deriv-
atives. Furthermore, ligand 2 (Noyori ligand) was found
to provide the chiral 2-tetralol derivatives with over 88%
ee in all cases (Table 2, entries 7–12).
2. Results and discussion
Initially, the catalyst–ligand combination reported by
Wills et al. and Noyori et al., that is, Ru–p-cymene com-
plex with either (1S,2R)-(À)-cis-1-amino-2-indanol 1 or
(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfona-
mide 2, in 2-propanol was applied to screen the reduc-
tion of various methoxy substituted 2-tetralones 3–8
(Table 1, entries 1–12).8 Although the reduction of the
unsubsitituted 2-tetralone 3 provided the product with
78% ee, remarkably higher enantiomeric excesses were
obtained for 8-methoxy substituted ketone 7 with 92%
ee and 96% ee using the ligands 1 and 2, respectively.
Table 2. Results of the asymmetric transfer hydrogenation of sub-
strates 3–8 using [RuCl2(benzene)]2
[RuCl2(benzene)]2
1 or 2
O
HO
R
R
KOH, 2-propanol
50 oC, 45 min.
Table 1. Results of the asymmetric transfer hydrogenation of sub-
strates 3–8 using [RuCl2(p-cymene)]2
3 - 8
[RuCl2(p-cymene)] 2
Entry
Ketone
Chiral ligand
Yielda (%)
Eeb (%)
1 or 2
O
HO
1
3
4
5
6
7
8
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
80
95
83
82
77
79
72
99
97
82
81
79
84
87
83
84c
92
86
88
88
92
88c
98
89
R
R
KOH, 2-propanol
50 oC, 45 min.
2
3
3 - 8
4
Entry
Ketone
Chiral ligand
Yielda (%)
Eeb (%)
5
6
1
3
4
5
6
7
8
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
81
80
85
81
74
71
87
82
83
81
80
77
78
82
83
78c
92
81
78
77
80
74c
96
73
7
2
8
3
9
4
10
11
12
5
6
7
a Isolated yield.
8
b Enantiomeric excess was determined by using chiral HPLC with a
Chiralcel AD column unless otherwise noted.
c PLC using a Chiralcel OJ column.
9
10
11
12
a Isolated yield.
b Enantiomeric excess was determined by using chiral HPLC with a
Chiralcel AD column unless otherwise noted.
c HPLC using a Chiralcel OJ column.
The effect of the position of the methoxy group was
again noted in this catalyst system that while only a
marginal difference in the enantioselectivity was ob-

M. Mogi et al. / Tetrahedron: Asymmetry 15 (2004) 3715–3717
3717
Tepper, P. G.; Dijkstra, D.; Damsma, G.; Wikstrom, H.;
Pugsley, T. A.; Akunne, H. C.; Heffner, T. G.; Glase, S. A.;
Wise, L. D. J. Med. Chem. 1996, 39, 4233–4237.
served among the substrates 3, 4, 6, and 8, a notable in-
crease in selectivity was seen for 6-methoxy-2-tetralone 5
with 92% ee (Table 2, entry 9) and 8-methoxy-2-tetra-
lone 7 affording (2R)-8-methoxy-2-tetralol with 98% ee
(Table 2, entry 11). This new finding of the enantioselec-
tivity toward 8-methoxy-2-tetralone 7 is especially valu-
able for the study of serotonin (5-HT) and dopamine
(DA) receptor agonists since substrate 7 is readily avail-
able either commercially or by the reported procedure of
Nichols and co-workers9 while the obtained enantiomer-
ically pure 8-methoxy-2-tetralol can be easily converted
to the chiral 8-methoxy-2-aminotetralin derivatives by
the known method in good yields.5
2. Liu, Y.; Yu, H.; Mohell, N.; Nordvall, G.; Lewander, T.;
Hacksell, U. J. Med. Chem. 1995, 38, 150–160.
3. (a) Terashima, S.; Tanno, N.; Koga, K. Chem. Lett. 1980,
981–984; (b) Kawasaki, M.; Suzuki, Y.; Terashima, S.
Chem. Lett. 1984, 239–242; (c) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521–2522; (d) Palmer, M.; Walsgrove, T.; Wills,
M. J. Org. Chem. 1997, 62, 5226–5228.
4. Manitto, P.; Speranza, G.; Monti, D.; Fontana, G.;
Panosetti, E. Tetrahedron 1995, 51, 11531–11546.
5. Orsini, F.; Sello, G.; Travaini, E.; Gennaro, P. D. Tetra-
hedron: Asymmetry 2002, 13, 253–259.
6. For its excellent review, see: (a) Noyori, R.; Yamakawa,
M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931–7944; (b)
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045–2061.
3. Conclusion
7. Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562–7563.
In conclusion, an application of the asymmetric transfer
hydrogenation for the preparation of various methoxy
substituted chiral 2-tetralols, was evaluated. The result-
ing materials are interesting intermediates for the chiral
synthesis of many serotonin and dopamine agonists.
The reaction conditions using the [RuCl2(benzene)]2
complex with (R,R)-N-(2-amino-1,2-diphenylethyl)-p-
toluenesulfonamide (Noyori ligand) were found to give
the best results, with moderate to excellent enantiomeric
excesses, most notably for (2R)-8-methoxy-2-tetralol,
which was obtained in 98% ee.
8. A general procedure for the asymmetric transfer hydrogen-
ation of 2-tetralones: A mixture of benzene or p-cymene
ruthenium(II) chloride dimer (0.0057mmol) and (R,R)-N-
(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide or (1S,
2R)-(À)-cis-1-amino-2-indanol (0.011mmol) in 2-propanol
(2.0mL) was stirred at 80°C for 30min under Ar. In a
separate flask,
a
solution of potassium hydroxide
(0.057mmol) in 2-propanol (1.5mL) was stirred at 50°C
for 30min. To a solution of the prochiral tetralone
(0.284mmol) in 2-propanol (5.0mL) was added the catalyst
mixture followed by KOH solution and stirred at 50°C for
45min. After the reaction, the mixture was immediately
passed through a pad of Celite and silica gel and then
concentrated under reduced pressure. The obtained product
was purified by silica gel preparatory TLC to afford the
chiral tetralol.
References
1. (a) Arvidsson, L. E.; Hacksell, U.; Nilsson, J. L. G.; Hjorth,
S.; Carlsson, A.; Lindberg, P.; Sanchez, D.; Wilkstroem, H.
J. Med. Chem. 1981, 24, 921–923; (b) van Vliet, L. A.;
9. Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Commun. 1995,
25, 2775–2780.