Synthesis of 7-(4-piperidyl)- [1,6]naphthyridin-5-one and 3-(4-piperidyl)isoqunolin-1-one

Article abstract of DOI:10.1007/s10593-010-0457-6

7-(4-Piperidyl)[1,6]napththiridin-5-one was synthesized on the basis of 2-methylnicotinic acid. 3-(4-Piperidyl)isoquinolin-1-one was synthesized from the diethylamide of o-toluic acid and Weinreb′s amide of N-Boc-isonipecotic acid.

Full text of DOI:10.1007/s10593-010-0457-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
SYNTHESIS OF 7-(4-PIPERIDYL)-
[1,6]NAPHTHYRIDIN-5-ONE AND
3-(4-PIPERIDYL)ISOQUNOLIN-1-ONE
D. A. Kovalskiy1* and V. P. Perevalov2
7-(4-Piperidyl)[1,6]napththiridin-5-one was synthesized on the basis of 2-methylnicotinic acid.
3-(4-Piperidyl)isoquinolin-1-one was synthesized from the diethylamide of o-toluic acid and Weinreb's
amide of N-Boc-isonipecotic acid.
Keywords: Weinreb's amide, isocoumarin, isoquinoline, 1,6-naphthyridine, 3-(4-piperidyl)isoquinolin-
1-one, 7-(4-piperidyl)[1,6]naphthyridin-5-one, metallation.
Previously we synthesized 2-piperidylisoquinolines and 7-piperidyl[1,6]naphthyridines [1,2] from which
we synthesized tertiary amines, amides, and sulfamides. In the search for biologically active compounds it is
important to vary the substituents on the molecule studied. This is achieved, firstly by using starting materials
with different substituents and, secondly, by introducing additional functional groups at later stages.
In the publications quoted the results of work on the introduction of hydroxyl groups in positions 1 and
5 in 2-piperidylisoquinoline and 7-piperidyl[1,6]naphthyridine respectively. Derivatives of the –OSO2R type
(e.g., OTf) are excellent leaving groups in reactions with O-, N-, and C-nucleophiles, which opens the way to
further modification of the heterocyclic nucleus. Direct introduction of hydroxyl groups into isoquinoline and
naphthyridine is practically impossible, therefore we sought alternative routes based on the formation of the
required group during the course of the synthesis.
There are data in the literature on the interaction of dilithium derivatives of 2-methylnicotinic acid and
aromatic nitriles with the formation of 7-aryl[1,6]naphthyridin-5-ones [3]. To carry out this scheme we first
synthesized N-Boc-4-cyanopiperidine by introducing Boc groups into 4-piperidinecarboxamide with subsequent
dehydration with phosphorus oxychloride in the presence of a base.
O
N
1. Boc2O
NH2
N
2. POCl3, Et3N
HN
Boc
1
2
_______
* To whom correspondence should be addressed, e-mail: DKovalskiy@asinex.com.
1ASINEX, Moscow 125480, Russia.
2D. I. Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia; e-mail:
pvp@muctr.edu.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1864-1869, December, 2009.
Original article submitted April 17, 2009.
0009-3122/09/4512-1503©2009 Springer Science+Business Media, Inc.
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The nitrile 2 obtained was used, as described in paper [3], as an electrophile in the reaction with the
dianion obtained in situ by treatment of 2-methylnicotinic acid with 2 equivalents of lithium diisopropylamide.
Acid hydrolysis then removed the Boc groups.
O
O
O
1. (i-Pr)2NLi
2. 2
HCl
NH
NH
OH
· 2HCl
N
N
N
Me
4
NH
3
N
Boc
The yield of N-Boc-7-(4-piperidyl)[1,6]naphthyridin-5-one (3) appeared to be considerably lower than
for the case with aromatic nitriles. It is probable that this is caused by a side reaction associated with the
possibility of deprotonation of nitrile 3 at the methylene-active unit.
An attempt to synthesize the corresponding isoquinolone by the same scheme starting from o-toluic acid
was unsuccessful and the required product was not detected by chromato-mass spectrometric analysis. However,
on metallation of the acid an intense coloration of the reaction mixture was observed, characteristic of the
formation of the tolyl anion.
There are several methods reported in the literature for the synthesis of 3-substituted isoquinolinones,
two of which are based on the metallation of monomethyl- and dimethylamides of o-toluic acid [4,5]. When
both schemes were carried out with nitrile 2 it was shown that, in the first case a mixture of compounds was
produced which did not include the desired product, while in the second case N-Boc-3-(4-piperidyl)isoquinolin-
1-one (5) in a yield of 16%.
R
Me
O
O
N
1. R1Li
NH
2. 2
Me
5
N
Boc
R = H, R1= Bu; R = Me, R1 = (i-Pr)2N
Table 1. Characteristics of Compounds 3-5, 9b, 10a,b
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
[M+H]+,
Yield,
%
mp, °C
m/z
С
H
Cl
N
12.68
12.76
3
С18H23N3O3
С13H17Cl2N3O
С19H24N2O3
С20H26N2O4
С14H17ClN2O
С15H19ClN2O2
65.82
65.63
51.55
51.67
69.40
69.49
67.08
67.02
63.58
63.51
61.15
61.12
7.10
7.04
5.80
5.67
7.44
7.37
7.33
7.31
6.49
6.47
6.53
6.50
330
230, 224
329
189-193
>250
51
89
96*
75
99
97
4
23.54
23.46
13.97
13.90
8.59
8.53
10.55
10.58
10.51
10.58
5
210-212
237-241
>250
9b
10a
10b
359
13.31
13.39
12.08
12.03
229, 223
259, 253
9.47
9.50
>250
_______
* Yield starting from isocoumarin 8a.
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The continuing low yield forced us to tackle the problem from the other side. It is known that
isocoumarin reacts with N-nucleophiles to form pyridones. A scheme for the preparation of 3-substituted
isocoumarins, described in [6], was a ready base for the synthesis 3-piperidylisoquinolones. Thus, the ketones
7a,b were obtained by treating the diethylamides of o-toluic acid 6a,b with tert-butyl lithium followed by
acylation with Weinreb’s amide [1]. The ketones cyclized to 3-piperidylisocoumarins 8a,b on treatment with
acetic acid, and these were converted into N-Boc-3-(4-piperidyl)isoquinolin-1-ones 5,9b by treatment with
ammonia on heating under pressure.
Et
Et
O
N
O
Et
Et
O
N
O
1. t-BuLi
AcOH
Boc
R
R
O
2.
Me
R
Me
O
N
N
6a,b
Boc
8a,b
N
N
OMe
Boc
7a,b
O
O
NH3
HCl
NH
· HCl
NH
R
R
NH
N
10a,b
5 ,9b
Boc
6 8, 10 a R = H, 6 10 b R = OMe
Comparison of the results of experiments carried out under the two schemes described above showed
that the yields of isoquinolinones 5 and 9b obtained by the second variant, i.e., starting from diethylamides 6a
and 6b, were considerably higher, 30 and 40% respectively.
Thus the preparation of 7-(4-piperidyl)-1,6-naphthyridin-5-one and 3-(4-piperidyl)isoquinolin-1-one
differs from the route which we described previously [1,2] for derivatives of isoquinoline and 1,6-naphthyri-
dine. The presence of two reaction centers – the OH and NH groups – opens the route to the synthesis of new
compounds possessing potential biological activity.
EXPERIMENTAL
1H NMR spectra were recorded on a Mercury 400 (400 MHz) machine in DMSO-d6 or CDCl3 solution
with TMS as internal standard. Melting points were measured on a Gallenkamp machine. Progress of reactions
was monitored by TLC of Silica gel/TLC cards (Fluka) with various eluants. Chromato-mass spectra were
recorded with a Surveyor MSQ apparatus (Thermo Finnigan) with chemical ionization in solution (15 eV) with
a YMC (Hydrosphere C18, 12 nm, S -3µm, 33.3 mm i.d.) in an eluant gradient (acetonitrile – 0.1% aqueous
solution of formic acid with a rate of flow of the eluant of 1.3 ml/min). A mixture of hexane and ethyl acetate
was used as the eluant for chromatography, with "DuraSil H" (60-100 µm) as the carrier.
N-Boc-4-Cyanopiperidine (2). Di-tert-butyl pyrocarbonate (187 g, 0.86 mol) in acetonitrile (200 ml)
was added dropwise to a suspension of isonipecotamide 1 (100 g, 0.78 mol) in acetonitrile (400 ml) and stirred
for 4 h. At the end of the reaction the precipitate was filtered off and washed with cold acetonitrile. The mother
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Table 2. 1H NMR Spectra of Compounds 2-5, 6b, 8a,b, 9b, 10a,b
Com-
pound
Chemical shifts, δ, ppm, J (Hz)*
1.49 (9Н, s, t-Bu); 1.71 (4H, m, CH2CHCH2); 2.80–2.85 (3H, m, CH2N+CH),
4.19 (2H, m, CH2N)
1.41 (9Н, s, t-Bu); 1.52–1.64 (2Н, m, CH2CH); 1.87 (2Н, m, CH2CH);
2.64 (1Н, m, CH2CHCH2); 2.76 (2Н, m, CH2N); 4.08 (2Н, m, CH2N);
6.41 (1Н, s, Н-8); 7.38 (1Н, dd, J = 7.3 and J = 4.6, Н-3); 8.41 (1Н, d, J = 8.2, Н-4);
8.81 (1Н, d, J = 3.2, Н-2); 11.39 (1Н, br. s, ОН)
2
3
1.90 and 2.11 (4H, both m, CH2CHСH2);
4
5
2.81-3.00 (3Н, m, CH2N + CH2CHCH2); 3.39 (2H, m, CH2N); 6.59 (1Н, s, Н-8);
7.62 (1Н, dd, J = 7.3 and J = 5.5, H-3); 8.79 (1Н, d, J = 7.8, Н-4);
8.98 (1Н, d, J = 8.9, Н-2); 9.09 (1Н, br. s, NH); 9.30 (1Н, br. s, HCl);
11.81 (1Н, br. s, ОН)
1.40 (9H, s, t-Bu); 1.55 (2H, m, CH2CH), 1.89 (2H, m, CH2CH);
2.60 (1Н, m, CH2CHCH2); 2.75 (2Н, m, CH2N); 4.06 (2Н, m, CH2N);
6.31 (1Н, s, Н-4); 7.39 (1Н, t, J = 7.3, Н-6); 7.55 (1Н, d, J = 7.8, Н-5);
7.62 (1Н, t, J = 7.3, Н-7); 8.10 (1Н, d, J = 7.8, Н-8); 11.09 (1Н, br. s, OH)
0.92 (3Н, t, J = 7.1, СН3СН2); 1.14 (3Н, t, J = 7.1, СН3СН2); 2.11 (3Н, s, CH3);
3.02 (2H, q, J = 7.0, СН3СН2); 3.46 (2Н, q, J = 7.0, СН3СН2);
3.79 (3Н, s, ОСН3); 6.73−6.81 (2Н, m, Н-3,5); 7.02 (1Н, d, J = 8.2, Н-6)
1.39 (9H, s, t-Bu); 1.47 (2H, m, CH2CH), 1.91 (2H, m, CH2CH);
2.66 (1Н, m, CH2CHCH2); 2.83 (2Н, m, CH2N); 4.04 (2Н, m, CH2N);
6.59 (1Н, s, H-4); 7.55 (2Н, m, Н-5 + Н-7); 7.80 (1Н, t, J = 7.3, Н-6);
8.10 (1Н, d, J = 7.8, Н-8)
6b
8а
1.40 (9Н, s, t-Bu); 1.48 (2Н, m, CH2CH); 1.87 (2Н, m, CH2CH);
2.72 (1Н, m, СН2СН2СН2); 2.83 (2Н, m, CH2N); 3.87 (3Н, s, ОСН3);
4.03 (2Н, m, CH2N); 6.50 (1Н, s, H-4); 7.08 (2Н, m, Н-5, 7);
8.00 (1Н, d, J = 8.7, Н-8)
8b
1.40 (9Н, s, t-Bu); 1.48 (2Н, m, CH2CH); 1.87 (2Н, m, CH2CH);
2.72 (1Н, m, СН2СН2СН2); 2.83 (2Н, m, CH2N); 3.83 (3Н, s, ОСН3);
3.89 (1Н, m, CH2N); 4.02 (1Н, m, CH2N); 6.31 (1Н, s, Н-4); 6.95 (2Н, m, Н-5,7);
8.01 (1Н, d, J = 8.7, Н-8); 10.95 (1Н, br. s, ОН)
9b
1.78-1.91 (2Н, m, CH2CHCH2); 2.11 (2Н, m, CH2CHCH2);
2.71 (1Н, m, CH2CHCH2); 2.92 (2Н, m, CH2N); 3.33 (2Н, m, CH2N);
6.30 (1Н, s, Н-4); 7.41 (1Н, t, J = 7.8, Н-6); 7.62 (2Н, m, Н-5, 7);
8.11 (1Н, d, J = 7.8, Н-8); 9.00 (2Н, br. s, NH + HCl); 11.13 (1Н, br. s, ОН)
1.85 (2Н, m, CH2CHCH2); 2.09 (2Н, m, CH2CHCH2);
10a
10b
2.71 (1Н, m, СН2СНСН2); 2.92 (2Н, m, CH2N); 3.05 (2Н, m, CH2N);
3.82 (3Н, s, ОСН3); 6.25 (1Н, s, Н-4); 6.97 (1Н, d, J = 8.7, Н-7);
7.08 (1Н, s, Н-5); 8.02 (1Н, d, J = 8.7, Н-8); 9.05 (1Н, br. s, NH);
9.14 (1Н, br. s, HCl); 10.96 (1Н, br. s, OH)
_______
* Compound 2 was recorded in CDCl3, compounds 3-6, 8-10a,b were
recorded in DMSO-d6.
liquor was evaporated to 2/3 of the original volume and the precipitate was filtered off. The combined solids
were dried to give N-Boc-piperidine-4-carboxamide (167 g, 94%). Phosphorus oxychloride (93 g, 0.6 mol) was
added dropwise to a solution of N-Boc-piperidine-4-carboxamide (115 g, 0.5 mol) in dichloromethane (400 ml)
and triethylamine (100 g, 1 mol), at 0°C and stirred for 2 h. At the end of the reaction a saturated solution of
potash was added dropwise. The organic layer was separated, dried over Na2SO4, and evaporated. Compound 2
(72.9 g, 69%) was obtained after purification by column chromatography.
N-Boc-7-(4-Piperidyl)[1,6]naphthyridin-5-one (3). BuLi (31 ml, 0.05 mol, 1.6 mol/l in hexane) was
added to a solution of diisopropylamine (5.56g, 0.05 mol) in THF (100 ml) at -65°C in an atmosphere of argon.
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The mixture was kept for 20 min, then 2-methylnicotinic acid (2.74 g, 0.02 mol) was added and stirred for 2 h.
A solution of compound 2 (6.3 g, 0.03 mol) in THF (50 ml) was added dropwise to the intensely colored
reaction mass, stirred for 4 h, and treated with saturated NH4Cl solution (50 ml). The solvent was evaporated to
¾ of the original volume, the precipitate was filtered off and recrystallized from ethyl acetate to give
naphthyridine 3 (3.34 g, 51%).
7-(4-Piperidyl)[1,6]naphthyridin-5-one Hydrochloride (4). Dioxane (20 ml), saturated with hydrogen
chloride, was added to a boiling solution of compound 3 (3.34 g, 10 mmol) in 2-propanol (50 ml). The
precipitate was filtered off, washed with 2-propanol, and dried to give compound 4 (2.7 g, 99%).
Diethylamide of o-toluic acid (6a). Diethylamine (58.4 g, 0.8 mol) in dichloromethane (200 ml) was
added dropwise to a solution of o-toluoyl chloride (50 g, 0.32 mol) in dichloromethane (350 ml) and stirred for
1 h. At the end of the reaction diethylamine hydrochloride was filtered off and washed with a saturated solution
of potash. The organic layer was separated, dried over Na2SO4, and evaporated. The diethylamide 6a (56.2 g,
91%) was obtained after distillation (b.p. 108-112°C, m.p. 60-61°C).
Diethylamide 6b was obtained analogously from 2-methyl-5-methoxybenzoyl chloride (29.3 g,
0.16 mol) in a yield of 31.2 g (88%) as a viscous liquid.
N-Boc-3-(4-Piperidyl)isocoumarin (8b). t-Bu Li (80 ml, 0.14 mol, 1.7 mol/l in pentane) was added
dropwise to a solution of amide 6b (25 g, 0.11 mol) in THF (250 ml) at -75°C in an atmosphere of argon and
stirred for 3 h. The methoxymethylamide of N-Boc-isonipecotic acid (30.7 g, 0.11 mol) was added dropwise,
kept for 3 h, and treated with saturated NH4Cl solution (100 ml). The solution was evaporated, extracted with
ethyl acetate, the organic layer was separated, dried over Na2SO4, and purified by flash chromatography. The
viscous oil, containing predominantly ketone 7b, was boiled in a mixture of toluene (100 ml) and acetic acid
(50 ml). At the end of the reaction the solution was evaporated, treated with a saturated solution of potash, and
extracted with ethyl acetate. Compound 8b (21.5 g, 53%) was obtained after purification by column
chromatography.
N-Boc-6-methoxy-3-(4-piperidyl)isoquinolin-1-one (9b). A solution of compound 8b (21.5 g,
0.06 mol) in methanol (200 ml) was saturated with ammonia, and heated to 100°C for 5 h in a high pressure
reactor. At the end of the reaction the solvent was evaporated, the precipitate was filtered off, washed with
hexane, and dried to give compound 9b (16.2 g, 75%).
6-Methoxy-3-(4-piperidyl)isoquinolin-1-one Hydrochloride (10b). Dioxane (50 ml), saturated with
hydrogen chloride, was added by portions to a boiling solution of substance 9b (10 g, 28 mmol) in 2-propanol
(150 ml). At the end of the reaction the precipitate was filtered off, washed with 2-propanol, and dried to give
10b (8 g, 97%).
Compounds 8a, 5, and 10a (Tables 1 and 2) were made analogously.
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