A simple, efficient method for regioselective synthesis of 7-aminomethyl-7,8-dihydro-6H-quinolin-5-ones, new potential CNS agents

Article abstract of DOI:10.1016/S0040-4039(00)01780-9

We have developed an efficient and convenient strategy for the regioselective synthesis of new conformationally restricted butyrophenones of the quinoline series. The 7-aminomethyl-7,8-dihydro-6H-quinolin-5-ones 9 were obtained from protected alcohol 5 via the tosylate, and also in a one-pot reaction via bromo derivative 6, with moderate-to-good overall yields in both cases. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01780-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9829–9833
A simple, efficient method for regioselective synthesis of
7-aminomethyl-7,8-dihydro-6H-quinolin-5-ones, new
potential CNS agents
Beatriz Pita, Christian F. Masaguer and Enrique Ravin˜a*
Departamento de Qu´ımica Orga´nica, Laboratorio de Qu´ımica Farmace´utica, Facultad de Farmacia,
Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain
Received 20 August 2000; accepted 10 October 2000
Abstract
We have developed an efficient and convenient strategy for the regioselective synthesis of new
conformationally restricted butyrophenones of the quinoline series. The 7-aminomethyl-7,8-dihydro-6H-
quinolin-5-ones 9 were obtained from protected alcohol 5 via the tosylate, and also in a one-pot reaction
via bromo derivative 6, with moderate-to-good overall yields in both cases. © 2000 Elsevier Science Ltd.
All rights reserved.
Schizophrenia is a serious mental illness that afflicts nearly 1% of the world’s population.
Front-line therapy consists of administration of conventional neuroleptics (or conventional
antipsychotics) such as haloperidol, the prototype of a group of very potent antipsychotic
butyrophenone derivatives. Because these drugs appear to act mainly via blockade of central D2
dopamine receptors, the hypothesis that activation of these receptors is a primary factor in the
pathogenesis of schizophrenia has gained wide acceptance.1 Unfortunately, dopamine receptor
blockade is also intimately associated with the extrapyramidal side effects (EPS, a short-term
parkinsonism like condition) of these drugs. Furthermore, classical antipsychotics are not
effective against the negative symptoms of schizophrenia.2 Therapeutic advantages may be
offered by compounds with affinities for multiple receptors. Clozapine, which binds to both
dopamine and serotonin receptors, is the most noteworthy of these drugs due to its efficacy and
its lack of EPS. However, clozapine causes a low but significant incidence of agranulocytosis,
and requires periodic blood monitoring during continued therapy.3 Since the currently available
agents thus have serious limitations, there is a major medical need for better therapies.
* Corresponding author. Fax: +34 981 594912; e-mail: qofara@usc.es
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01780-9

9830
OH
CH3
N
N
O
N
N
Cl
Cl
N
H
F
Haloperidol
Clozapine
In previous papers we have reported the synthesis and neuroleptic activity of aminoalkylben-
zocycloalkanones,4 which are conformationally restricted butyrophenone analogues of haloperi-
dol with the aminobutyl side chain partially incorporated in a semirigid framework. We have
also prepared and studied the CNS activity of several cyclic butyrophenone derivatives of
pyrrole,5 furan,6 thiophene,7 and indole.8 We report here an efficient, convenient method for the
preparation of a series of butyrophenone quinoline derivatives, the 7-aminomethyl-7,8-dihydro-
6H-quinolin-5-ones. The proposed method includes the preparation of 3-amino-5-
methoxymethyl-2-cyclohexen-1-one (4, Scheme 1), a potentially useful synthon for the synthesis
of other b-substituted cycloalkanones with fused heterocycles containing N (as practical
ambident nucleophiles, enaminones are frequently employed as building blocks for the prepara-
tion of a variety of bicyclic compounds of biological interest).9 Because of this great synthetic
potential of enaminone 4, we optimized its preparation before using it as the basis of a
convenient synthesis of the target 7-aminomethyl-dihydroquinolinones 9.
O
OCH3
OCH3
H3CO
H3CO
ii
iii
ref 10
OR
OCH3
OH
H3CO
H3CO
O
1 R= H
3
i
2 R= CH3
O
O
O
iv
v
Br
OCH3
OCH3
N
H2N
N
4
6
5
vi
vii
O
O
O
R
N
viii
ix
OH
OTs
N
N
N
R
7
8
9a-c
Scheme 1. (i) CH3I, NaH 60%, THF, rt. (ii) Dowex 50W-X4, MeOH, rt. (iii) NH3(g)/MeOH, −20°C to rt. (iv) Method
A: (a) CH2ꢀCHꢁCHO, MeOH/AcOH (b) Pd(PPh3)4, 10% Pd/C, K2CO3, DMF, reflux. Method B: Pd/C,
,
CH2ꢀCHꢁCHO, 4 A molecular sieves, toluene, reflux. Method C: (a) CH2ꢀCHꢁCHO, MeOH/AcOH (b) DBU/MIK,
110°C (c) DDQ, rt. (v) BBr3 (2 equiv.)/DCM, −78°C to rt. (vi) NRR, K2CO3, KI, MIK, reflux. (vii) BBr3 (1
equiv.)/DCM, −78°C to rt. (viii) TsCl/py; (ix) NRR, Hu¨nig’s base, THF, reflux.

9831
1,4-Dihydro-3,5-dimethoxybenzyl alcohol (1) was readily prepared from inexpensive 3,4,5-
trimethoxybenzoic acid in 85% yield, as previously described.10 Methylation of its hydroxyl
group (ICH3, 95%), followed by mild acidic hydrolysis of the resulting enolether 2 (Dowex
50W-X4 resin) provided the b-methoxyenone 3 in 63% yield. Ammonolysis of 3 in methanol
afforded the desired enamine 4 in good yield.11
The key step in the synthesis of compounds 9 was the cyclization of the enaminone 4 to obtain
the quinolinone system. 7,8-Dihydro-6H-quinolin-5-ones, which are versatile intermediates in
organic synthesis and medicinal chemistry,12 are usually prepared in low yield from propynal
and the corresponding enaminone.13 These low yields and the difficulty in preparing propynal
prompted us to seek alternative methods. We found that palladium-catalyzed reaction of
enaminone 4 with acrolein in methanol overnight, followed by removal of the solvent, addition
of DMF and refluxing in the presence of Pd(PPh3)4, 10% Pd/C and potassium carbonate, gave
the corresponding dihydroquinolinone 5 in good yield (70%, Method A).14 Alternatively,
reaction of the enaminone with acrolein in toluene in the presence of molecular sieves and a
catalytic amount of Pd as dehydrogenating agent also afforded 5 in 70% yield (Method B).
Finally, a 65% overall yield of 5 (Method C) was obtained more onerously by reaction of 4 with
acrolein in methanol and acetic acid, followed by treatment with DBU at 110°C in methyl
isobutyl ketone and oxidation with DDQ.15
All three methods proved to be regioselective when a substituted acrolein was used. Thus,
reaction between 3-amino-2-cyclohexen-1-one and crotonaldehyde under the conditions of the
above methods afforded 7,8-dihydro-4-methyl-6H-quinolin-5-one without any NMR evidence of
the 2-methyl regioisomer.
Demethylation of 5 using 1 equiv. of BBr3 at −70°C to +20°C gave the alcohol 7 (70%; mp
92–94°C) as a white crystalline solid. Tosylation of 7 using p-toluenesulfonyl chloride in pyridine
afforded the corresponding sulfonate ester 8 (85%; mp 119.5–120.5°C). The aminomethyldihy-
droquinolinones 9 were then obtained cleanly and in good yield from 8 by nucleophilic reaction
with 1-(2-methoxyphenyl)piperazine (10), 4-(4-fluorobenzoyl)piperidine (11) or 4-(6-fluoro-1,2-
benzisoxazol-3-yl)piperidine (12) (Table 1).16,17 The amino substituents 10–12 were chosen
because of the known CNS activity of related compounds containing them.7
Table 1
7-Aminomethyl-7,8-dihydro-6H-quinolin-5-ones 9a–c
Compound
NRR
Mp (°C)
Yield from 7 (%)
9a
9b
9c
10
11
12
129–130
149–150
150–151
45
55
35
Alternatively, demethylation and bromination of 5 were achieved in a one-pot reaction by
treating the substrate with 2 equiv. of BBr3 in CH2Cl2 at −70°C and bringing the mixture slowly
up to room temperature, which yielded the bromoderivative 6 in 50% yield. Subsequent
nucleophilic displacement of the bromine atom from 6 by refluxing with the corresponding
amine in methyl isobutyl ketone in the presence of K2CO3 and a catalytic amount of KI
afforded 7-aminomethyl-7,8-dihydro-6H-quinolin-5-ones (9a–c) in moderate yield.18
In conclusion, we have developed an efficient, convenient strategy for the regioselective
synthesis of new conformationally restricted butyrophenones in the quinoline series. The

9832
hexahydroquinolinones 9 were obtained from protected alcohol 5 either via the corresponding
tosylate or in a one-pot reaction via the bromo derivative. This methodology provides a new
approach to potential CNS-active agents. Work in progress in our laboratory will be reported
in due course.
Acknowledgements
This work was supported by the Xunta de Galicia under grant XUGA20319B97. B.P. was
aided by grants from the Xunta de Galicia and the University of Santiago de Compostela, and
wishes to thank the programme Ciencia y Tecnolog´ıa para el Desarrollo (CYTED).
References
1. Davis, K. L.; Kahn, R. S.; Ko, G.; Davidson, M. Am. J. Psychiatry 1991, 148, 474–486.
2. Simpson, G. M.; Pi, E. H.; Sramek, J. J. Drugs 1981, 21, 138–151.
3. West, S. A.; Nemeroff, C. B. Drugs Today 1993, 29, 183–188.
4. (a) Cortizo, L.; Santana, L.; Ravin˜a, E.; Orallo, F.; Fontenla, J. A.; Castro, E.; Calleja, J. M.; Ceballos, M. L.
J. Med. Chem. 1991, 34, 2242–2247. (b) Fontenla, J. A.; Osuna, J. A.; Rosa, E.; Castro, E.; Loza, M. I.;
G.-Ferreiro, T.; Calleja, J. M.; Sanz, F.; Rodriguez, J.; Fueyo, J.; Ravin˜a, E.; Masaguer, C. F.; Vidal, A.; de
Ceballos, M. J. Med. Chem. 1994, 37, 2564–2573.
5. (a) Masaguer, C. F.; Ravin˜a, E. Tetrahedron Lett. 1996, 37, 5171–5174. (b) Masaguer, C. F.; Casariego, I.;
Ravin˜a, E. Chem. Pharm. Bull. 1999, 47, 621–632.
6. Casariego, I.; Masaguer, C. F.; Ravin˜a, E. Tetrahedron Lett. 1997, 38, 5555–5558.
7. Ravin˜a, E.; Negreira, J.; Cid, J.; Masaguer, C. F.; Rosa, E.; Rivas, M. E.; Fontenla, J. A.; Loza, M. I.; Tristan,
H.; Cadavid, M. I.; Sanz, F.; Lozota, E.; Carotti, A.; Carrieri, A. J. Med. Chem. 1999, 42, 2774–2779.
8. Masaguer, C. F.; Ravin˜a, E.; Fontenla, J. A.; Brea, J.; Tristan, H.; Loza, M. I. Eur. J. Med. Chem. 2000, 35,
83–95 and references cited therein.
9. (a) Singh, H.; Chimni, S.; Kumar, S. Tetrahedron 1995, 51, 12775–12780. (b) Pitts, W.; Jetter, J.; Pinto, D.;
Orwat, M.; Batt, D. Bioorg. Med. Chem. Lett. 1998, 8, 307–312. (c) Foster, J.; Nicholson, J.; Butcher, R.; Stables,
J.; Edafiogho, I.; Goodwin, A.; Henson, M.; Smith, C.; Scott, K. Bioorg. Med. Chem. 1999, 7, 2415–2425.
10. Chapman, O. L.; Fitton, P. J. Am. Chem. Soc. 1963, 85, 41–47.
11. Compound 4: 85%; cream-coloured crystals, mp=110–111°C (EtOAc); IR (KBr) 3101, 1689, 1256, 1122 cm−1
;
1
MS (EI) 155 (M+), 140, 110, 83; H NMR (CDCl3, 300 MHz) l 5.22 (s, 1H, CH), 5.02 (brs, 1H, NH), 3.33 (s,
2H, CH2), 3.32 (s, 3H, OCH3), 2.33 (m, 4H, CH2), 2.11 (m, 1H, CH).
12. (a) Caprathe, B. W.; Jaen, J. C.; Wise, L. D. J. Med. Chem. 1991, 34, 2736–2746. (b) Hartmann, R. W.;
Frotscher, M. Arch. Pharm. 1999, 332, 358–362.
13. (a) Zymalkowski, F.; Rimek, H. Arch. Pharm. 1961, 294, 759–765. (b) Albright, J. D.; Du, X. J. Heterocycl.
Chem. 2000, 37, 41–46. (c) Bell, I. M.; Erb, J.; Freidinger, R.; Gallicchio, S.; Guare, J. P.; Guidotti, M. T.;
Halpin, R. A.; Hobbs, D. W.; Homnick, C. F.; Kuo, M. S. and colleagues. J. Med. Chem. 1998, 41, 2146–2163.
1
14. Compound 5: IR (KBr) 2894, 1688, 1583; MS (EI) 191 (M+), 159, 146; H NMR (CDCl3, 300 MHz) l 8.66 (dd,
1H, J=4.7, 1.8 Hz, H-2), 8.23 (dd, 1H, J=7.8, 1.8 Hz, H-4), 7.27 (dd, 1H, J=4.7, 7.8 Hz, H-3), 3.43 (d, 2H,
J=5.1 Hz, CH2O), 3.35 (s, 3H, CH3O) 3.3–2.4 (m, 5H, aliphatics).
15. A similar procedure starting from commercially available 3-amino-5,5-dimethylcyclohexen-2-one has been
described for the synthesis of 7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one; Curran, A. C. W. J. Chem. Soc.,
Perkin Trans. 1 1976, 975–977. See also Jaen, J. C.; Kropko, M. L.; Theiss, J. C. Eur. J. Med. Chem. 1993, 28,
547–553.
16. Compound 9b: mp=149–150°C (iso-PrOH); IR (KBr) 3101, 1689, 1256, 1122 cm−1; MS (EI) 366.0 (M+), 331,
1
220, 146; H NMR (CDCl3, 300 MHz) l 8.68 (dd, 1H, J=4.8, 1.8 Hz, H-2), 8.26 (dd, 1H, J=7.8, 1.8 Hz, H-4),
7.95 (m, 2H, Ar), 7.30 (dd, 1H, J=7.8, 4.8 Hz, H-3), 7.14 (m, 2H, Ar), 4.05 (d, 2H, J=5.2 Hz, CH2ꢁN), 3.4–1.2
(m, 14H, aliphatics).
.

9833
17. Complete details of the synthesis, spectral characteristics and biological evaluation of compounds 9 will be
published elsewhere in a full paper. All compounds gave satisfactory microanalyses (C, H, N 0.4%) and spectral
data (1H and 13C NMR, FTIR, MS). Yields given correspond to isolated pure compounds.
18. The cyclopropylquinolinone 1,1a,2,7a-tetrahydro-3-azacyclopropa[b]naphthalen-7-one was isolated as an elimina-
tion by-product (30% yield). A similar elimination has been observed in the tetralone series: see Ref 4(a).
.