Synthesis of 7-(3-piperidyl)-[1,6]naphthyridine and 7-(4-pipe-ridyl)[1,6] naphthyridine

Article abstract of DOI:10.1007/s10593-009-0387-3

7-(3-Piperidyl)- and 7-(4-piperidyl)[1,6]naphthyridines have been synthesized from 2-methylpyridine-3-carbaldehyde cyclohexylimine and the methylmethoxycarboxamides (Weinreb amides) of N-Boc- substituted nipecotic and isonipecotic acids.

Full text of DOI:10.1007/s10593-009-0387-3

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
SYNTHESIS OF 7-(3-PIPERIDYL)-
[1,6]NAPHTHYRIDINE AND 7-(4-PIPE-
RIDYL)[1,6]NAPHTHYRIDINE
D. A. Kovalskiy1* and V. P. Perevalov2
7-(3-Piperidyl)- and 7-(4-piperidyl)[1,6]naphthyridines have been synthesized from 2-methylpyridine-
3-carbaldehyde cyclohexylimine and the methylmethoxycarboxamides (Weinreb amides) of N-Boc-
substituted nipecotic and isonipecotic acids.
Keywords: Weinreb amide, isoquinoline, naphthyridine, piperidine.
We have previously synthesized 3-(3-piperidyl)isoquinoline and 3-(4-piperidyl)isoquinoline via
acylation of the methyl group of o-tolylaldehyde cyclohexylimine by the methylmethoxycarboxamides of N-Boc
nipecotic and isonipecotic acids (Weinreb amides) and subsequent cyclization [1]. Aza analogs of 3-substituted
isoquinolines are the 7-substituted [1,6]-, [2,6]-, [3,6]- and [4,6]naphthyridines. There are virtually no literature
reports of the preparation of such structures with the exception of a group of publications [2, 3] describing the
cyclization of 2-imino- and 2-oximino-3-ethynylpyridines. The main attraction of this scheme is that both
7-substituted and 7,8-disubstituted [1,6]naphthyridines can be synthesized depending on the nature of the
electrophile. However, the shortcomings of the method are the limited range of readily available acetylenes and
the high cost of the palladium catalysts.
The method we have used previously in the synthesis of 3-substituted isoquinolines provides the basis
for the preparation of the [1,6]naphthyridines containing a piperidine unit in the 7 position. When compared
with the isoquinoline the naphthyridine fragment has an extra nitrogen atom which can behave as a proton
acceptor and so increase the bonding with biological substrates.
Me
OMe
O
NH2
OH
N
O
1. CDI
LiAlH4
THF
O
N
2. MeNHOMe
N
Me
N
Me
N
Me
N
Me
3
1
2
CDI − 1,1'-carbonyldiimidazole
_______
* To whom correspondence should be addressed, e-mail: DKovalskiy@asinex.com.
1Asinex Ltd, Moscow 125480, Russia.
2D. Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia; e-mail: pvp@muctr.edu.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1319-1323, September, 2009.
Original article submitted March 24, 2009.
0009-3122/09/4509-1053©2009 Springer Science+Business Media, Inc.
1053

The 2-methylpyridine-3-carbaldehyde cyclohexylimine (3) was chosen as precursor of the
[1,6]naphthyridine fragment and synthesized by a standard method.
The N-Boc-substituted methylmethoxycarboxamides of the 4- and 3-piperidinecarboxylic acids [1]
(4 and 5 respectively) served as the source of the piperidyl fragment. Metallation of imine 3 was carried out
using diisopropylamide and lithium 2,2,6,6-tetramethylpiperidide. It was found that metallation with (i-Pr)2NLi
is more efficient and leads to a higher yield of the target compound while needing the use of two equivalents of
the base.
N
HCl
NH4Cl
N
· 2HCl
N
N
N
N
O
NH
N
Boc
N
Boc
7
8
6
C(O)NMeOMe
1) (i-Pr)2NLi (2 equiv.);
2)
2)
N
Boc
4
3
C(O)NMeOMe
1) (i-Pr)2NLi (2 equiv.);
N
Boc
5
N
NH4Cl
HCl
N
N
N
· 2HCl
N
N
O
N
N
H
N
11
Boc
10
9
Boc
TABLE 1. Characteristics of Compounds 7, 9-12
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
[M + H]+, m/z
mp, °C
Yield, %
C
H
N
7
С18H23N3O2
С13H17Cl2N3
С18H23N3O2
69.07 7.35
68.98 7.40
54.61 6.05
54.56 5.99
69.04 7.43
68.98 7.40
13.42
13.41
14.59
14.68
13.38
13.41
14.72
14.68
314
105-108
240-245
112-115
220-222
121-122
67
96
54
94
56
8*
10
11*2
12
214, 208
314
С13H17 Cl2N3 54.67 6.03
214, 208
54.56 5.99
С18H22BrN3O2 55.67 5.91
10.44
10.71
286, 288,
292, 294
55.11 5.65
_______
* Found, %: Cl 24.82; calculated, %: Cl 24.77.
*2 Found, %: Cl 24.87; calculated, %: Cl 24.77.
1054

TABLE 2. 1H NMR Spectra of Compounds 1-3, 7, 8, 10-13
Com-
pound
Chemical shifts, δ, ppm (J, Hz, DMSO-d6)
1
2.47 (3Н, s, СН3); 3.22 (3Н, s, ОСН3); 3.45 (3Н, s, NCH3);
7.25 (1Н, dd, J = 6.9 and J = 5.0, Н-5); 7.67 (1Н, d, J = 7.3, Н-4);
8.48 (1Н, d, J = 3.7, Н-6)
2
3
2.74 (3Н, s, СН3); 7.41 (1Н, dd, J = 7.4 and J = 5.0, Н-5); 8.13 (1Н, d, J = 7.8, Н-4);
8.63 (1Н, d, J = 3.2, Н-6); 10.22 (1Н, s, СНО)
1.20-1.82 (10Н, m, (СН2)5); 2.64 (3Н, s, СН3); 3.29 (1Н, m, СН2СНСН2);
7.26 (1Н, dd, J = 7.3 and J = 5.0, Н-5); 8.06 (1Н, d, J = 7.8, Н-4);
8.46 (1Н, d, J = 3.2, Н-6); 8.61 (1Н, s, СН=N)
7
1.42 (9Н, m, С(СН3)3); 1.79-1.92 (2Н, m, CH2CH); 2.01-2.11 (2Н, m, CH2CH);
2.92 (2Н, m, CH2N); 3.05 (1Н, m, CH2CHCH2); 4.28 (2Н, m, CH2N);
7.45 (1Н, dd, J = 7.8 and J = 4.1, Н-3); 7.73 (1Н, s, Н-8); 8.23 (1Н, d, J = 7.8, Н-4);
9.04 (1Н, d, J = 2.7, Н-2); 9.23 (1Н, s, Н-5)
8
2.03-2.20 (4Н, m, CH2CHCH2); 3.00-3.11 (2Н, m, CH2N); 3.30 (1Н, m, CH2CHCH2);
3.39 (2Н, m, CH2N); 7.78 (1Н, dd, J = 8.2 and J = 4.6, Н-3); 7.90 (1Н, s, Н-8);
8.72 (1H, d, J = 8.2, Н-4); 9.09 (1Н, br. s, NH); 9.20 (1H, d, J = 3.2, Н-2);
9.31 (1Н, br. s, HCl); 9.53 (1Н, s, Н-5)
10
11
1.39 (9Н, m, С(СН3)3); 1.45-2.10 (4Н, m, СНСН2СН2); 2.82 (1Н, m, CH2N);
2.96 (1Н, m, CH2N); 3.10 (1Н, m, CH2CHCH2); 3.92 (1Н, m, CH2N);
4.15 (1Н, m, CH2N); 7.61 (1Н, dd, J = 7.7 and J = 4.1, Н-3); 7.78 (1Н, s, Н-8);
8.50 (1Н, d, J = 7.8, Н-4); 9.06 (1Н, d, J = 2.7, Н-2); 9.23 (1Н, s, Н-5)
1.81-2.12 (4Н, m, СНСН2СН2); 2.96 (1Н, m, CH2CHCH2); 3.35 (2Н, m, CH2N);
3.56 (2Н, m, CH2N); 7.81 (1Н, dd, J = 8.2 and J = 4.6, Н-3); 8.06 (1Н, s, Н-8);
8.81 (1H, d, J = 8.2, Н-4); 9.26 (1H, d, J = 3.2, Н-2); 9.50 (1Н, br. s, NH);
9.55 (2Н, m, Н-5 + HCl)
12
13
1.42 (9Н, m, С(СН3)3); 1.75-1.89 (4Н, br. s, CH2CHCH2); 2.91 (2Н, br. s, CH2N);
3.69 (1Н, m, CH2CHCH2); 4.12 (2Н, m, CH2N); 7.72 (1Н, dd, J = 8.2 and J = 4.1, Н-3);
8.58 (1Н, d, J = 7.8, Н-4); 9.19 (1Н, d, J = 3.7, Н-2); 9.31 (1Н, s, Н-5)
1.42 (9Н, m, С(СН3)3); 1.79 (4Н, br. s, CH2CHCH2); 2.90 (2Н, br. s, CH2N);
3.65 (1Н, m, CH2CHCH2); 4.12 (2Н, m, CH2N); 8.93 (1Н, s, Н-4); 9.24 (1Н, s, Н-2);
9.29 (1Н, s, Н-5)
1
The H NMR spectra (Table 2) of the N-Boc-substituted 7-piperidyl[1,6]naphthyridines 7 and 10 show
signals for the piperidyl fragment at 1.5-4.0 and a set of signals in the range 7.45-9.55 ppm for the aromatic
fragment protons. The spectra of compounds 8 and 11 show general agreement with a low field shift for the
aromatic proton signals of 0.16-0.49 ppm relative to those of compounds 7 and 10. This points to the formation
of a hydrochloride in the naphthyridine fragment in which the protons signals of the salt part are strongly
broadened as a result of exchange with water present in the DMSO. The salt part of the piperidine fragment
appears as broadened signals at 9.31 and 9.55 ppm for compounds 8 and 11 respectively. The nine protons of the
tert-butoxycarbonyl group resonate as a sharp singlet at 1.4-1.5 ppm.
The presence of halogens (bromine or iodine) in the heterocyclic ring permit the introduction of O-, N-,
and C-nucleophiles. The study [2] described the synthesis of 8-iodo[1,6]naphthyridines via the cyclization of
2-ethynyl-3-iminopyridines in the presence of iodine monochloride. The introduction of halogens into an
already prepared [1,6]naphthyridine can theoretically occur at positions 3 and 8.
We have found that bromination of compound 7 using N-bromosuccinimide in acetic acid gives the
8-bromo-7-piperidyl[1,6]naphthyridine 12 despite the presence of a bulky substituent in an ortho position.
Br
N
N
N
NBS
+
N
N
N
N
Br
N
Br
13
N
Boc
Boc
Boc
7
12
1055

Bromination does not proceed to completion but heating to 60ºC in the presence of excess N-bromo-
succinimide accumulates the dibromo derivative 13. The use of N-iodosuccinimide demands refluxing and leads
to a complex mixture of compounds.
Hence we have prepared the novel naphthyridine derivatives 7-(3-piperidyl)- and 7-(4-piperidyl)-
[1,6]naphthyridine. The route presented above has been used for the first time in the preparation of
naphthyridines and permits the introduction of different substituents into position 7 of the heterocyclic system.
EXPERIMENTAL
1H NMR spectra were recorded on a Mercury 400 (400 MHz) instrument using DMSO-d6 with TMS
internal standard. Melting points were measured on a Gallenkamp instrument. The course of a reaction was
monitored using TLC on Silica gel/TLC-card (Fluka) plates in different eluents. Column chromatography was
performed on Durasil H silica gel (60-100 µm) with a hexane–ethyl acetate gradient.
Chromato mass spectrometry was carried out on a Surveyor MSQ instrument (Thermo Finnigan) with
chemical ionization in solution (15 eV) using a YMC column (Hydrosphere C18, 12 nm, S-3 µm, 33×3 mm i.d.)
and with gradient elution (acetonitrile – 0.1% aqueous formic acid solution, eluent flow rate 1.3 ml/min).
2-Methylnicotinic Acid Methoxymethylamide (1). N,N-Carbonyldiimidazole (56 g, 0.35 mol) was
added portionwise with stirring to a suspension of 2-methylnicotinic acid (47 g, 0.34 mol) in acetonitrile
(300 ml). After 30 min N,O-dimethylhydroxylamine hydrochloride (39.8 g, 0.41 mol) was added followed by a
solution of triethylamine (42 g, 0.41 mol) in acetonitrile (50 ml). The product was held for 5-7 h and
triethylamine hydrochloride was filtered off and washed with cold ethyl acetate. The mother liquor was
evaporated to two thirds of the original volume, diluted with ethyl acetate (150 ml), and washed with a 5%
solution of sodium bicarbonate. The organic layer was separated, dried with Na2SO4, and evaporated.
Distillation (bp 120-125ºC, 1 mm Hg) gave amide 1 (53.1 g, 86%).
2-Methylpyridine-3-carbaldehyde (2). A solution of amide 1 (11 g, 0.06 mol) in THF (100 ml) was
added dropwise to a suspension of lithium aluminium hydride (2.2 g, 0.06 mol) in THF (100 ml) at -50ºC and
held for 30 min. The product was treated dropwise with 50% aqueous THF solution (15-20 ml) and the
inorganic residue was washed with ethyl acetate. The organic layer was dried with Na2SO4 and evaporated.
Flash chromatographic purification gave the aldehyde 2 (6.7 g, 92%).
2-Methylpyridine-3-carbaldehyde Cyclohexylimine (3). A solution of carbaldehyde 2 (6.5 g,
0.05 mol), cyclohexylamine (5.2 g, 0.05 mol), and p-toluenesulfonic acid (0.01 g) in benzene (150 ml) was
refluxed in a Dean-Stark apparatus. The solvent was evaporated and the oil obtained was mixed with ether (40
ml) and cooled. The precipitate was filtered off to give the imine 3 (6.5 g, 61%).
7-(N-Boc-4-piperidyl)[1,6]naphthyridine (7). BuLi (2.5 molar in hexane, 60 ml, 0.16 mol) was added to
a solution of diisopropylamine (15.9 g, 0.16 mol) in THF (370 ml) at -60ºC. After 10 min at -60ºC a solution of
imine 3 (15.15 g, 0.075 mol) in THF (50 ml) was added dropwise. The violet colored solution obtained was stirred
under an argon stream at -60ºC for 20 min and then a solution of amide 4 (26.5 g, 0.1 mol) in THF was added in
one portion. The product was stirred for 30 min and treated with a saturated solution of NH4Cl (100 ml). Solvent
was evaporated, the residue was extracted with ethyl acetate, and the extract was evaporated. The oily product
obtained was treated with aqueous ammonia (150 ml), treated with several drops of acetic acid, and stirred at 80ºC
for 2 h. It was then extracted with ethyl acetate and the organic layer was washed with water, dried over Na2SO4,
and evaporated. Flash column chromatographic purification gave compound 7 (15.7 g, 67%).
Naphthyridine 10 (Tables 1 and 2) was prepared similarly.
7-(4-Piperidyl)[1,6]naphthyridine Dihydrochloride (8). Dioxane saturated with hydrogen chloride
(15-20 ml) was added dropwise to a refluxing solution of compound 7 (15.7 g, 0.05 mol) in 2-propanol (50 ml).
At the completion of the reaction the precipitate was filtered off, washed with 2-propanol, and dried to give
compound 8 (15.5 g, 96%).
1056

Dihydrochloride 11 was prepared similarly.
7-(N-Boc-4-piperidyl)-8-bromo[1,6]naphthyridine (12). A mixture of the naphthyridine 7 (0.4 g,
1.3 mmol) and N-bromosuccinimide (0.22 g, 1.3 mmol) in glacial acetic acid (8 ml) was stirred for 12 h. Solvent
was evaporated and the residue was treated with a saturated solution of potassium carbonate (15 ml) and
extracted with ethyl acetate. Column chromatographic purification gave the bromide 12 (0.28 g, 56%) and the
dibromide 13 (0.026 g, 4%).
REFERENCES
1.
D. A. Kovalskiy and V. P. Perevalov, Khim. Geterotsikl. Soedin., 1204 (2009). [Chem. Heterocycl.
Comp., 45, 957 (2009)].
2.
3.
Q. Huang and R. Larock, J. Org. Chem., 67, 3437 (2002).
A. Numata and Y. Kondo, Synthesis, 306 (1999).
1057