New synthetic approaches to CNS drugs. A straightforward, efficient synthesis of tetrahydroindol-4-ones and tetrahydroquinolin-5-ones via palladium-catalyzed oxidation of hydroxyenaminones

Article abstract of DOI:10.1016/S0040-4039(02)01901-9

We have developed a facile and efficient synthesis of new conformationally restricted butyrophenones in the indole and quinoline series via palladium-catalyzed oxidation of hydroxyenaminones, and subsequent cyclization followed by spontaneous aromatizatio

Full text of DOI:10.1016/S0040-4039(02)01901-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7929–7932
New synthetic approaches to CNS drugs. A straightforward,
efficient synthesis of tetrahydroindol-4-ones and
tetrahydroquinolin-5-ones via palladium-catalyzed oxidation of
hydroxyenaminones†,‡
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, E-15782 Santiago de Compostela, Spain
Received 18 June 2002; accepted 5 September 2002
Abstract—We have developed a facile and efficient synthesis of new conformationally restricted butyrophenones in the indole and
quinoline series via palladium-catalyzed oxidation of hydroxyenaminones, and subsequent cyclization followed by spontaneous
aromatization. © 2002 Elsevier Science Ltd. All rights reserved.
Haloperidol (Haldol®, Jannsen 1959) is the prototype
of a group of butyrophenone derivatives with a potent
and antipsychotic activity. For some time, we have
been interested in the utilization of cyclohexanedione I
as a versatile synthon in the preparation of condensed
heterocyclic systems as intermediates in the synthesis of
butyrophenone-type CNS agents. In previous papers1–3
we have reported the preparation (and in most of them,
the antipsychotic activity as well) of heterocyclic con-
strained butyrophenones by nucleophilic substitution of
the tosylate group in the corresponding heterocyclic
condensed systems II with CNS amine building blocks.
Now, we want to study its use in the synthesis of
tosylates of 7-hydroxymethyltetrahydroquinolin-5-ones
and 6-hydroxymethyltetrahydroindol-4-ones as inter-
mediates in the synthesis of conformationally con-
strained aminobutyrophenones in the tetrahydro-
quinoline and tetrahydroindole series (III, IV).
In previous papers4,5 we have reported the preparation
of 4,5,6,7-tetrahydroindol-4-one derivates by applying
the Knorr pyrrole synthesis methodology to several
5-substituted-1,3-cyclohexanediones. For the synthesis
of 2,3-unsubstituted tetrahydroindoles, a modification
Keywords: cyclic ketones; enamines; tetrahydroquinolines; tetrahydroindoles.
* Corresponding author. Tel.: +34 981 594 628; fax: +34 981 594 912; e-mail: qofara@usc.es
† This is the 27th paper in the series ‘‘Synthesis and CNS Activity of Conformationally Restricted Butyrophenones’’; for preceding paper, see Ref.
3.
‡ Dedicated to Professor B. S. Thyagarajan of the University of San Antonio (Texas) on the occasion of his retirement.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01901-9

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B. Pita et al. / Tetrahedron Letters 43 (2002) 7929–7932
of the Knorr method reported by Bobbit et al.6 was
used, giving the desired compounds in low yields.4 The
successful synthesis of pyrroles and indoles via palla-
dium-catalyzed oxidation of hydroxyenaminones
reported by Ohta7 prompted us to extend this proce-
dure to the preparation of our above mentioned
compounds.
absence of either base, aryl bromide or palladium cata-
lyst, the reaction did not proceed. Thus, the palladium-
catalyzed oxidation of the g-hydroxyenaminones gave
the corresponding quinolin-5-ones in moderate yields
(Table 2). The preparation of the sulfonate ester 5c9
was carried out from tetrahydroquinolin-5-one 4c by
BBr3 demethylation and subsequent tosylation of the
resulting crystalline alcohol, affording the white crys-
talline sulfonate ester 5c (mp 119.5–120.5°C, toluene).
On the other hand, we have previously reported the
preparation of several 7-aminomethyltetrahydro-
quinolin-5-ones with high affinity on CNS receptors, by
using some strategies leading to the quinolinone ring.2
Now, we have studied the application of the palladium-
catalyzed oxidation of g-hydroxyenaminones as a new
approach to the synthesis of the above mentioned
heterocycles.
b-Hydroxyenaminones 3e–g were prepared by conden-
sation of 5-methoxymethyl-1,3-cyclohexanedione 1c
with b-aminoalcohols 2b–d (3-amine-2-butanol 2c was
prepared by reduction of 3-nitro-2-butanol with ammo-
nium formate and 2-amine-3-pentanol by synthesis of
the a-oximinoketone of 3-pentanone and subsequent
lithium aluminium hydride reduction). As in above, the
key step was the cyclization of hydroxyenaminones,
which was examined under several reaction conditions.
The best yields were achieved when a mixture of b-
hydroxyenaminones 3e–g, in DMF and tetra-
kis(triphenylphosphine)-palladium(0), mesityl bromide,
potassium carbonate was heated at 150°C.10 Tetra-
In this communication we describe the alternative
efficient synthesis of tetrahydroquinolin-5-ones and tet-
rahydroindol-4-ones from cyclohexanediones via palla-
dium-catalyzed oxidation of b- and g-hydroxy-
enaminones, respectively. The key step of the synthesis
of tetrahydroquinolin-5-ones 4a–d was the palladium-
catalyzed oxidation of the hydroxyenaminones 3a–d
(Table 1) which were prepared by condensation of the
b-dicarbonyl compounds 1a–d with the corresponding
b- or g-aminoalcohols 2a–d (Table 1), and subsequent
cyclization followed by spontaneous aromatization.
Table 2. Synthesis of tetrahydroquinolin-5-ones 4a–d
The oxidation of the hydroxyenaminones 3a–d in the
presence of a palladium catalyst was examined under
several reaction conditions. The best results were
achieved when a mixture of hydroxyenaminone, mesityl
bromide as oxidant, potassium carbonate, palladium
acetate, and triphenylphosphine as cocatalyst, in DMF
were heated at 150°C.8 The amount of triphenylphos-
phine is a crucial factor for the success of the reaction;
an excess greater than 3 equiv. considerably decreases
the reaction rates. Other catalysts as tetrakis(triphenyl-
phosphine)palladium(0) or dichlorobis(triphenylphos-
phine)palladium(II) proved to be less efficient. In the
Entry
Substrate
R1
Tetrahydroquinolin-5-one
(Yield%)
R2
H
1
2
3
4
3a
3b
3c
3d
H
4a (30)
4b (35)
4c (35)
4d (35)
CH3 CH3
H
H
CH2OCH3
CH2OBn
Table 1. Synthesis of hydroxyenaminones 3a–g
Entry
Ketone
Aminoalcohol
Product
R1
R2
R3
R4
n
(Yield%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1c
1c
1c
H
CH3
H
H
H
H
CH3
2a
2a
2a
2a
2b
2c
2d
H
H
H
H
H
CH3
CH3
H
H
H
H
H
CH3
C2H5
1
1
1
1
0
0
0
3a (60)
3b (60)
3c (60)
3d (60)
3e (86)
3f (86)
3g (92)
CH2OCH3
CH2OBn
CH2OCH3
CH2OCH3
CH2OCH3
H
H

B. Pita et al. / Tetrahedron Letters 43 (2002) 7929–7932
7931
Acknowledgements
Table 3. Synthesis of tetrahydroindol-4-ones 6e–g
This work was supported by the Xunta de Galicia
(Spain) under grant PGIDT01PXI20309PR. Beatriz
Pita is grateful to the University of Santiago de Com-
postela for a predoctoral fellowship.
References
Entry
Substrate
R3
Tetrahydroindol-4-one
R4
(Yield%)
Mp (°C)
1. (a) Brea, J.; Rodrigo, J.; Carrieri, A.; Sanz, F.; Cadavid,
M. I.; Enguix, M. J.; Villazo´n, M.; Mengod, G.; Caro,
Y.; Masaguer, C. F.; Ravin˜a, E.; Centeno, N. B.; Carotti,
A.; Loza, M. I. J. Med. Chem. 2002, 45, 54–71; (b)
Ravin˜a, E.; Masaguer, C. F. Current Med. Chem. CNS
Agents 2001, 1, 43–62.
1
2
3
3e
3f
H
CH3
CH3
H
CH3
C2H5
6e (40)
6f (60)
6g (70)
87–89
141–142
157–158
3g
2. Pita, B.; Masaguer, C. F.; Ravin˜a, E. Tetrahedron Lett.
2000, 41, 9829–9833.
3. Bilbao, E. R.; Alvarado, M.; Masaguer, C. F.; Ravin˜a, E.
Tetrahedron Lett. 2002, 43, 3551–3554.
4. Masaguer, C. F.; Ravin˜a, E. Tetrahedron Lett. 1996, 37,
5171–5174.
hydroindol-4-ones 6e–g were thus obtained as white
crystalline solids in moderate to good yields (Table 3).
5. Masaguer, C. F.; Ravin˜a, E.; Loza, I.; Fontenla, J. A.
Bioorg. Med. Chem. Lett. 1997, 7, 913–918.
6. Bobbitt, J. M.; Kulkarni, C. L.; Dutta, C. P.; Kofod, H.;
Chiong, K. N. J. Org. Chem. 1978, 43, 3541–3544.
7. Aoyagi, Y.; Mizusaki, T.; Ohta, A. Tetrahedron Lett.
1996, 37, 9203–9206.
In order to obtain the sulfonate esters, demethylation
of 6e–g was carried out by using 1 equiv. of BBr3 at
−70°C to +20°C affording the alcohols 7e–g in good
yields (Table 4). Tosylation of 7e–g by using p-toluene-
sulphonyl chloride in pyridine gave the corresponding
sulfonate esters 8e–g11 as white crystalline solids (Table
4).12
8. General Procedure:
A mixture of the g-hydroxy-
enaminone 3a–d (1 mmol), mesityl bromide (1.1 mmol),
palladium acetate (0.03 mmol), triphenylphosphine (0.06
mmol), potassium carbonate (1.2 mmol) and DMF (5 ml)
was heated at 150°C for 4 h. The resulting mixture was
filtered through a Celite pad and then evaporated under
reduced pressure to give an oily residue, which was
purified by column chromatography to give the corre-
sponding quinolines.
In conclusion, we have developed a facile and efficient
synthesis of new conformationally restricted butyrophe-
nones in the indole and quinoline series via palladium-
catalyzed oxidation of hydroxyenaminones and
subsequent cyclization followed by spontaneous aroma-
tization. Because of the simplicity of the methodology
and the shorter reaction times than those expected, this
synthetic procedure proved to be attractive and of great
practical value. This methodology provides a new
approach to the synthesis of potential CNS-active
agents. Work in progress in our Laboratory will be
reported in due course.
1
9. Compound 5c: H NMR (CDCl3, 300 MHz) l 8.68 (dd,
1H, J=4.8, 1.8 Hz, H-2), 8.24 (dd, 1H, J=7.8, 1.8 Hz,
H-4), 7.78 (d, 2H, J=8.3 Hz, Ar), 7.35 (d, 2H, J=8.1 Hz,
Ar), 7.30 (dd, 1H, J=7.8, 4.8 Hz, H-3), 4.10 (d, 2H,
J=5.5 Hz, CH2OTs), 2.93–2.83 (m, 1H, aliphatics), 2.65–
2.55 (m, 4H, aliphatics), 2.46 (s, 3H, CH3-Ph).
Table 4. Synthesis of 6-(p-toluenesulfonyloxymethyl)-4,5,6,7-tetrahydroindol-4-ones 8e–g
Entry
Substrate
Alcohol
Tosylate
R3
R4
Mp (°C)
Mp (°C)
1
2
3
6e
6f
6g
H
CH3
CH3
H
CH3
CH2CH3
7e
7f
7g
169–171
213–214
178–180
8e
8f
8g
162–164
207–209
188–189

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B. Pita et al. / Tetrahedron Letters 43 (2002) 7929–7932
10. General Procedure: To a solution of the b-hydroxy-
enaminone 3e–g (1 mmol) in 5 ml of DMF, mesityl
bromide (1 mmol), tetrakis(triphenylphosphine)palla-
dium(0) (0.025 mmol), and potassium carbonate (2
mmol) was added, and the mixture heated at 150°C for 2
h. After cooling, the mixture was filtered through a Celite
pad and evaporated in vacuo to give an oily residue,
which was purified by column chromatography to yield
the corresponding indoles.
1H, NH), 7.78 (d, 2H, J=8.3 Hz, Ar), 7.35 (d, 2H,
J=8.2 Hz, Ar), 4.01–3.99 (m, 2H, CH2OTs), 2.93–2.83
(m, 1H, aliphatics), 2.64–2.56 (m, 2H, aliphatics), 2.46 (s,
3H, CH3-Ph), 2.35–2.25 (m, 2H, aliphatics), 2.16 (s, 3H,
CH3), 2.11 (s, 3H, CH3).
12. Complete details of the synthesis and spectral data 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 corre-
spond to isolated pure compounds.
11. Compound 8f: 1H NMR (CDCl3, 300 MHz) l 7.88 (s,