Synthesis of 5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines as potential D1 receptor ligands

Article abstract of DOI:10.1002/jhet.5570410602

A new access to 5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines 25a-28a (n=1) and 5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines 25b-28b (n=2) has been developed by first preparing the functional pyridine moiety followed by intramolecular cyclization forming the partially reduced ring.

Full text of DOI:10.1002/jhet.5570410602

Nov-Dec 2004
857
Synthesis of 5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and
5-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines as
Potential D1 Receptor Ligands
Thomas Hussenether and Reinhard Troschütz*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander-University,
Schuhstraße 19, D-91052 Erlangen, Germany
Received February 24, 2004
A new access to 5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines 25a-28a (n=1) and 5-phenyl-6,7,8,9-
tetrahydro-5H-pyrido[3,2-c]azepines 25b-28b (n=2) has been developed by first preparing the functional
pyridine moiety followed by intramolecular cyclization forming the partially reduced ring.
J. Heterocyclic Chem., 41, 857 (2004).
development of further compounds with potential selectiv-
ity for the D1 receptor subtype based on a combination of
lead structures 3 and 4. The function of the electronega-
tive chloro substituent in 4 should be replaced in terms of
bioisosterical considerations inserting formally a nitrogen
atom into aromatic ring A. As a consequence, in this paper
we present a new access to 5-phenyltetrahydro-1,6-naph-
thyridines 25a-28a (n=1) and the ring-extended phenyl-
tetrahydropyrido[3,2-c]azepines 25b-28b (n=2).
Introduction.
Dopamine (1) is a naturally occurring catecholamine
which functions biochemically as neurotransmitter [1].
The dopamine receptors currently known are classified
into five subtypes (D1-D5) [2,3].
Brain dopaminergic systems are implicated in a number
of disorders, including psychomotor stimulant abuse,
schizophrenia [4] and Parkinson's disease [5,6]. In the car-
diovascular system, the administration of low doses of
dopamine produces arteriolar dilation in certain organ
beds, including the kidney [7].
In order to study physiological functions of dopamine
receptors and to achieve new drugs for specific therapeutic
use, highly selective and potent compounds have been
developed. For example, the D1 receptor antagonist
SCH23390 (2) plays an important role as radio ligand in
receptor binding studies [8,9]. The phenyltetrahydroiso-
quinoline derivative 3, its ring-contracted homolog, still
possesses an antagonistic effect on D1 [10]. In contrast,
Fenoldopam (4), a selective D1 agonist, is utilized in the
United States to manage severe hypertensions [11]
(Scheme 1). Our works have been concentrated on the
Results and Discussion.
A short retrosynthetic consideration, outlined in scheme
2, clarifies our approach, i.e. first synthesis of a functional
pyridine derivative and following intramolecular imine
formation and further transformations. A dehydrogenation
of title compounds 25a,b-28a,b gives rise to those imines.

858
T. Hussenether and R. Troschütz
Vol. 41
Successive cleavage of both the imine bond and the pyri-
dine ring, emphasized by broken lines, leads via 2-
amino acids 5a,b using carbonyldiimidazole (CDI), and
following addition of magnesium benzoylacetate (6) [12].
In H nmr spectra 7a,b were found to exist mainly as
1
(aminoalkyl)-3-benzoylpyridines to C building blocks
3
and appropriate enaminones. The latter can be generated
from diketones by ammonolysis.
As starting material, 1,3-diketones 7a,b could be easily
prepared by in situ activation of the N-phthaloyl protected
hydroxymethyleneketones, beside a small amount of dike-
tones 7'a,b. Compounds 7a,b were converted into their
appropriate enamines 8a,b by an excess of ammonium
acetate heating in toluene under azeotropic removal of

Nov-Dec 2004
Synthesis of 5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-Phenyl-6,7,8,9-
859
tetrahydro-5H-pyrido[3,2-c]azepines
water [13]. For ring closure to a pyridine derivative, these
enamines were treated with different kinds of 1,3-biselec-
trophilic agents. By the use of 1,1,3,3-tetramethoxy-
propane (9), a diacetal of malonaldehyde, we isolated
pyridines 10a,b [14]. In order to achieve more functional-
ized pyridines, enamines 7a,b were treated with substi-
[28] and D4.4 [29] affinities cloned human dopamine
receptor subtypes stably expressed in Chinese hamster
ovary cells (CHO) and the radioligand [ H]spiperone were
used for competition experiments.
The title compounds 25a,b-28a,b showed no apprecia-
ble affinity to any of the dopamine receptors tested.
3
tuted biselectrophilic C compounds. Unfortunately, no
3
suitable agents for a direct pyridine formation could be
found, so we were forced to accept dihydropyridines as
intermediates. According to this, dihydropyridones 13a,b
were prepared by refluxing acryloyl chloride (11) and 8a,b
in tetrahydrofuran [15,16]. For obtaining the 3-acetami-
dopyridones 14a,b, commercially available 3-acetamido-
acrylic acid (12) first was activated in situ to a mixed anhy-
dride with ethyl chloroformate and reacted with enamines
8a,b [17]. Resulting dihydropyridones 13a,b and 14a,b
were oxidized with manganese (IV) oxide [17] and gave
the desired 2-hydroxypyridines 15a,b and 16a,b, which
were found to exist in their tautomeric 2(1H)-pyridone
EXPERIMENTAL
Starting materials were obtained from commercial sources and
were used without further purification. Solvents were dried by
standard procedures. All anhydrous reactions were performed in
oven-dried glassware. Reaction progress was observed by thin
layer chromatography making use of commercial silica gel plates
(Merck, silica gel F
on aluminum sheets). All preparative
254
chromatography was done on silica gel 60 (Merck). The medium
pressure liquid chromatography (mplc) apparatus was composed
of a Büchi B688 chromatography pump, a LKB Multirac 2111
fraction collector, and Buechi glass columns of different sizes.
Melting points were determined in open capillary tubes on a
Buechi 510 melting point apparatus and are uncorrected.
Elemental analyses were performed by the Institut für
Organische Chemie (university of Erlangen/Nuremberg) using
1
form according to H nmr spectra. In the next step the
N-phthalimido protecting group in 10a,b,15a,b,16a,b was
cleaved by refluxing in 6 M aqueous hydrochloric acid to
reclaim a primary amino moiety for intramolecular ring
closure with the benzoyl group [18]. Probably during neu-
tralization of the reaction mixture the imines 17a,b-19a,b
were formed spontaneously.
1
Carlo Erba Elemental Analyzer 1108. H nuclear magnetic reso-
1
nance ( H-nmr) spectra were determined with a Bruker AM 360
(360 MHz) spectrometer in appropriate deuterated solvents and
are expressed in parts per million (δ, ppm) downfield from
tetramethylsilane (internal standard). Nmr data are given as mul-
tiplicity (s, singlet; d, doublet; t, triplet; m, multiplet), coupling
constants (J), and number of protons. Mass spectra (MS) were
taken with a Finnigan MAT TSQ 70 mass spectrometer in the
electron impact mode (70eV). Infrared (ir) spectra were obtained
on a Jasco FT/IR 410 or Perkin-Elmer 1740 spectrometer.
In order to develop a method offering better results, we
performed an alternative synthetic pathway by first consid-
ering aminopyridoazepine 19b (R=NH n=2) as target
2,
compound. Therefore, diketone 7b (n=2) was stirred in
N,N-dimethylformamide dimethyl acetal (DMF-DMA)
(20) to get the dimethylaminomethylendiketone 21, which
was treated with the magnesium salt of cyanoacetamide
(22) for ring closure in the next step [19]. The 3-cyanopy-
ridone 23, was refluxed in 6 M hydrochloric acid in order
to cleave the phthalimido protecting group as well and to
hydrolyze the cyano moiety. The resulting acid 24 was
rearranged by a modified Curtius reaction employing
diphenylphoshoryl azide (DPPA) and triethylamine in ter-
tiary butanol leading to compound 19b [20,21]. Due to no
improvements in overall yield and an increased experi-
mental effort, this way was not used for preparing other
naphthyridines and pyridoazepines.
2-[(3Z)-3-Hydroxy-5-oxo-5-phenylpent-3-en-1-yl)]-1H-isoin-
dole-1,3(2H)-dione (7a).
3-Oxo-3-phenylpropionic acid (6) (19.70 g, 0.12 mole) was
dissolved in 150 ml of dry tetrahydrofuran, and 6.87 g (60
mmoles) of magnesium ethoxide was added to the solution. After
stirring for 4 hours, the mixture was concentrated in vacuo.
Ethanol formed was aceotropically removed by using benzene as
a co-solvent to give powdered magnesium 3-oxo-3-phenylpropi-
onate. This was collected by filtration, washed profoundly with
ether and dried in vacuo. N,N'-Carbonyldiimidazole (CDI) (17.84
g, 0.11 mole) of was added portion-wise to a solution of 21.92 g
(0.1 mole) of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propi-
onic acid (5a) in 200 ml of dry N,N-dimethylformamide under a
nitrogen atmosphere. After stirring at room temperature for 1
hour, magnesium 3-oxo-3-phenylpropionate was added com-
pletely to the mixture. The whole was stirred for another 4 hours
at room temperature, acidified with 2 M hydrochloric acid and
extracted three times with ethyl acetate. The combined organic
layer was washed with water, 5% aqueous sodium hydrogen car-
bonate, and brine, and then dried over sodium sulfate. Removal
of the solvent gave crude 7a which was purified by mplc using
cyclohexane:ethyl acetate (7:3) as eluent to yield 24.4 g (76%) as
colorless powder, mp 114-115 °C (MeOH); ir (potassium bro-
Finally, the dihydronaphthyridines 17a-19a (n=1) and
dihydropyridoazepines 17b-19b (n=2) were reduced with
NaBH in methanol to give rise to the title compounds
4
25a,b,27a,b,28a,b [22,23]. For further structural variation
and for structure-activity-relationship studies, 25a,b were
N-methylated with formaldehyde/formic acid using the
Eschweiler-Clark methodology to obtain 26a,b [24,25].
(Scheme 3).
Dopamine D1 receptor binding was determined by mea-
-1 1
mide): 1780 (phthaloyl), 1701 (CO), 1610 cm ; H nmr (DMSO-
d ): δ 2.82 (t, J = 7 Hz, 2H, COCH CH N), 3.92 (t, J = 7 Hz, 2H,
3
suring the ability to displace [ H]SCH 23390 from porcine
6
2
2
COCH CH N), 6.11 (s, 1H, =CH-), 7.50 - 7.72 (m, 3H, ben-
D1 receptors [26]. To assess D2long, D2short, [27] D3
2
2

860
T. Hussenether and R. Troschütz
Vol. 41
zoyl), 7.80 – 7.91 (m, 6H, benzoyl, phthaloyl), 15.78 (broad, s,
1H, OH, deuterium oxide-exchangeable); ms: m/z 321 (M ), 174,
160.
To a solution of 3.20 g (10 mmoles) 2-[(3Z)-3-amino-5-oxo-5-
phenylpent-3-en-1-yl)]-1H-isoindole-1,3(2H)-dione (8a) in 50
ml of toluene:glacial acetic acid (7:3) was added 1.61 g (10
mmoles) 1,1,3,3-tetramethoxypropane and five drops of water.
The reaction mixture was heated at reflux for 8 hours. Solvent
was removed in vacuo and the residue was taken up in 20 ml of
water. After neutralization with saturated aqueous sodium hydro-
gen carbonate, the mixture was extracted three times with ether.
The combined organic layer was washed twice with saturated
aqueous sodium hydrogen carbonate solution, once with water,
and dried over sodium sulfate. Solvent was removed in vacuo and
the oily residue was purified by mplc using cyclohexane:ethyl
acetate (1:1) as eluent to yield 1.25 g (35%) as light yellow pow-
der, mp 78-80 °C; ir (sodium chloride): 1772 (phthaloyl), 1713
+
Anal. Calcd. for C
H NO (321.34): C, 71.02; H, 4.71; N,
19 15 4
4.36. Found: C, 71.21; H, 4.58; N, 4.40.
2-[(4Z)-4-Hydroxy-6-oxo-6-phenylhex-4-en-1-yl)-1H-isoindole-
1,3(2H)-dione (7b).
Preparation and purification according to 7a using 23.32 g (0.1
mole) of 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyric acid
(5b) to yield 26.2 g (78%) as colorless powder , mp 98-99 °C
(MeOH); ir (potassium bromide): 1778 (phthaloyl), 1702 (CO),
-1 1
1612 cm ; H nmr (CDCl ): δ 2.13 (tt, J = 7 Hz, J = 7 Hz, 2H,
3
1
2
COCH CH CH N), 2.49 (t, J = 7 Hz, 2H, COCH CH CH N),
2
2
2
2
2
2
-1
1
3.77 (t, J = 7 Hz, 2H, CO CH CH CH N), 6.21 (s, 1H, =CH-),
(CO), 1665 cm ; H nmr (DMSO-d ): δ 3.34 (t, J = 7 Hz, 2H,
2
2
2
6
7.46 - 7.54 (m, 3H, benzoyl), 7.70 – 7.87 (m, 6H, phthaloyl),
15.99 (broad, s, 1H, OH, deuterium oxide-exchangeable); ms:
ArCH CH N), 3.93 (t, J = 7 Hz, 2H, ArCH CH N), 7.47 (dd,
2
2
2
2
J = 8 Hz, J = 5 Hz, 1H, pyridine H-5), 7.45 - 7.48 (m, 2H, ben-
1
2
+
m/z 335 (M ), 175, 162, 105.
zoyl), 7.63 – 7.70 (m, 3H, benzoyl), 7.76 (dd, J = 8 Hz, J = 2
1
2
Anal. Calcd. for C
H NO (335.36): C, 71.63; H, 5.11; N,
Hz, 1H, pyridine H-4), 7.80 – 7.87 (m, 4H, phthaloyl), 8.65 (dd,
20 17 4
+
4.18. Found: C, 72.00; H, 5.55; N, 3.99.
J = 5 Hz, J = 2 Hz, 1H, pyridine H-6); ms: m/z 356 (M ), 327,
1
2
196, 180.
Anal. Calcd. for C
7.86. Found: C, 73.94; H, 4.42; N, 7.85.
2-[(3Z)-3-Amino-5-oxo-5-phenylpent-3-en-1-yl)]-1H-isoindole-
1,3(2H)-dione (8a).
H N O (356.38): C, 74.15; H, 4.53; N,
22 16 2 3
2-[(3Z)-3-Hydroxy-5-oxo-5-phenylpent-3-en-1-yl)]-1H-isoin-
dole-1,3(2H)-dione (7a) (14.45 g, 45 mmoles) and 17.34 g (0.3
mole) ammonium acetate were refluxed in 200 ml toluene adding
3 ml glacial acetic acid. Water was removed azeotropically using
a Dean Stark apparatus. When separation of water was finished,
the reactions mixture was cooled to room temperature, washed
twice with saturated aqueous sodium hydrogen carbonate, once
with water, and dried over sodium sulfate. After removal of the
solvent, the residue was crystallized from ethanol to yield 10.62 g
(74%) as pale yellow crystals, mp 119-121 °C (EtOH); ir (sodium
2-[3-(3-Benzoylpyridin-2-yl)propyl]-1H-isoindole-1,3(2H)-
dione (10b).
Preparation and purification according to 10a using 3.34 g (10
mmoles) of 2-[(4Z)-4-amino-6-oxo-6-phenylhex-4-en-1-yl)]-1H-
isoindole-1,3(2H)-dione (7b) to yield 1.20 g (32%) as light yel-
low powder, mp 91-93 °C; ir (sodium chloride): 1768
-1
1
(phthaloyl), 1708 (CO), 1660 cm ; H nmr (CDCl ): δ 2.15 (tt,
3
J = 6 Hz, J = 7 Hz, 2H, ArCH CH CH N), 2.87 (t, J = 7 Hz,
1
2
2
2
2
2H, ArCH CH CH N), 3.71 (t, J = 6 Hz, 2H, ArCH CH CH N),
2
2
2
2
2
2
chloride): 3583, 3403, 2926 (NH ), 1772 (phthaloyl), 1712 (CO),
2
7.22 (dd, J = 7 Hz, J = 4 Hz, 1H, pyridine H-5), 7.38 - 7.44
1
2
-1
1
1610 cm
; H nmr (DMSO-d ): δ 2.58 (t, = 7 Hz, 2H,
6
(m, 2H, benzoyl), 7.50 – 7.65 (m, 3H, benzoyl), 7.70 – 7.77 (m,
4H, phthaloyl), 7.81 (dd, J = 7 Hz, J = 2 Hz, 1H, pyridine H-4),
COCH CH N), 3.90 (t, J = 7 Hz, 2H, COCH CH N), 5.58 (s,
2
2
2
2
1
2
1H, =CH-), 7.32 - 7.45 (m, 3H, benzoyl), 7.66-7.72 (m, 2H, ben-
8.65 (dd, J = 4 Hz, J = 2 Hz, 1H, pyridine H-6); ms: m/z 370
1
2
zoyl), 7.82 – 7.90 (m, 4H, phthaloyl), 7.96 (broad, s, 1H, NH ,
+
2
(M ), 341, 182.
deuterium oxide-exchangeable), 9.89 (broad, s, 1H, NH , deu-
2
Anal. Calcd. for C
H N O (370.41): C, 74.58; H, 4.90; N,
23 18 2 3
+
terium oxide-exchangeable); ms: m/z 320 (M ), 172, 160.
7.56. Found: C, 74.78; H, 4.58; N, 7.21.
Anal. Calcd. for C
H N O (320.35): C, 71.24; H, 5.03; N,
19 16 2 3
2-[2-(3-Benzoyl-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)ethyl)-
8.74. Found: C, 71.29; H, 4.77; N, 8.77.
1H-isoindole-1,3(2H)-dione (13a).
2-[(4Z)-4-Amino-6-oxo-6-phenylhex-4-en-1-yl)]-1H-isoindole-
1,3(2H)-dione (8b).
To a solution of 3.20 g (10 mmoles) of 2-[(3Z)-3-amino-5-oxo-
5-phenylpent-3-en-1-yl)]-1H-isoindole-1,3(2H)-dione (8a) in 50
ml of dry tetrahydrofuran was added cautiously 1.18 g (13
mmoles) acryloyl chloride (11). The mixture was stirred for 15
minutes at room temperature and afterwards heated at reflux for
16 hours. After cooling, the reaction mixture was quenched with
100 ml of saturated aqueous sodium hydrogen carbonate solu-
tion. The organic layer was separated and the aqueous layer was
extracted four times with chloroform. The combined organic
layer was washed with water, and dried over sodium sulfate. The
solvent was removed in vacuo and the residue was purified by
flash chromatography using cyclohexane:ethyl acetate (1:1) as
eluent to yield 2.54 g (68%) as colorless powder, mp 169-170 °C;
ir (potassium bromide): 3286, 3222, 1772 (phthaloyl), 1718
Preparation and purification according to 8a using 15.08 g (45
mmoles) of 2-[(4Z)-4-hydroxy-6-oxo-6-phenylhex-4-en-1-yl)-
1H-isoindole-1,3(2H)-dione (7b) to yield 10.38 g (69%) as pale
yellow crystals, mp 126-128 °C (EtOH); ir (sodium chloride):
3395, 3059, 2934 (NH ), 1769 (phthaloyl), 1713 (CO), 1607
2
-1
1
cm ; H nmr (CDCl ): δ 2.04 (tt, J = 7 Hz, J = 6 Hz, 2H,
3
1
2
COCH CH CH N), 2.33 (t, = 6 Hz, 2H, COCH CH CH N),
2
2
2
2
2
2
3.67 (t, J = 7 Hz, 2H, COCH CH CH N), 5.72 (s, 1H, =CH-),
2
2
2
5.80 (broad, s, 1H, NH , deuterium oxide-exchangeable), 7.40 -
2
7.47 (m, 3H, benzoyl), 7.70-7.75 (m, 2H, benzoyl), 7.81 – 7.90
(m, 4H, phthaloyl), 10.28 (broad, s, 1H, NH , deuterium oxide-
2
+
exchangeable); ms: m/z 334 (M ), 174, 161.
Anal. Calcd. for C
H N O (334.38): C, 71.84; H, 5.43; N,
20 18 2 3
-1
1
(CO), 1659 (lactam) cm ; H nmr (DMSO-d ): δ 2.29 (t, J = 5
6
8.38. Found: C, 71.75; H, 5.81; N, 7.99.
Hz, 2H, pyridine H-4), 2.35 (t, J = 5 Hz, 2H, pyridine H-3), 2.57
2-[2-(3-Benzoylpyridin-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione
(10a).
(t, J = 5 Hz, 2H, ArCH CH N), 3.80 (t, J = 5 Hz, 2H,
2 2
ArCH CH N), 7.29 - 7.51 (m, 5H, benzoyl), 7.80 – 7.85 (m, 4H,
2
2

Nov-Dec 2004
Synthesis of 5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-Phenyl-6,7,8,9-
861
tetrahydro-5H-pyrido[3,2-c]azepines
phthaloyl), 9.91 (s, broad, 1H, NH, deuterium oxide-exchange-
able); ms: m/z 374 (M ), 226, 214.
(DMSO-d ): δ 1.81 (tt, J = 7 Hz, J = 6 Hz, 2H,
6 1 2
+
ArCH CH CH N), 1.81 (s, 3H, acetyl), 2.12 (t, J = 7 Hz, 2H,
2
2
2
Anal. Calcd. for C
H
N O (374.40): C, 70.58; H, 4.95; N,
ArCH CH CH N), 2.43 (m, 1H, pyridine H-4), 2.60 (m, 1H,
22 18
2
4
2 2 2
7.48. Found: C, 70.49; H, 5.14; N, 7.46.
pyridine H-4), 3.50 (t, J = 6 Hz, 2H, ArCH CH CH N), 4.43 (m,
2 2 2
1H, pyridine H-3), 7.33 – 7.42 (m, 5H, benzoyl), 7.84 – 7.86 (m,
4H, phthaloyl), 8.11 (s, broad, 1H, AcNH, deuterium oxide-
exchangeable), 10.04 (s, broad, 1H, NH, deuterium oxide-
2-[3-(3-Benzoyl-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)propyl)-
1H-isoindole-1,3(2H)-dione (13b).
+
+
Preparation and purification according to 13a using 3.34 g
(10 mmoles) of 2-[(4Z)-4-amino-6-oxo-6-phenylhex-4-en-1-
yl)]-1H-isoindole-1,3(2H)-dione (8b) to yield 2.46 g (66%) as
colorless powder, mp 166-167 °C; ir (potassium bromide):
exchangeable); ms: m/z 386 (M -CH COHNH ), 357, 226.
2
2
Anal. Calcd. for C
H N O (445.48): C, 67.41; H, 5.20; N,
25 23 3 5
9.43. Found: C, 67.33; H, 4.89; N, 9.55.
2-[2-(3-Benzoyl-6-oxo-1,6-dihydropyridin-2-yl)ethyl)-1H-isoin-
dole-1,3(2H)-dione (15a).
-1
3116, 2934, 1774 (phthaloyl), 1718 (CO), 1666 (lactam) cm ;
1
H nmr (DMSO-d ): δ 1.78 (tt, J = 7 Hz, J = 5 Hz, 2H,
6
1
2
ArCH CH CH N), 2.16 (t, J = 7 Hz, 2H, ArCH CH CH N),
2-[2-(3-Benzoyl-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)ethyl)-
1H-isoindole-1,3(2H)-dione (13a) (2.24 g, 6 mmoles) and 2.61 g
(30 mmoles) of activated manganese (IV) oxide were suspended in
30 ml of dry o-xylene. The mixture was heated at reflux under an
air atmosphere for 8 hours. Reaction water was separated using a
Dean Stark apparatus. After cooling the solid phase was filtered off
through a Celite® bed and washed profoundly with ethyl acetate.
The filtrate was concentrated to dryness in vacuo. The residue was
purified by flash chromatography using cyclohexane:ethyl
acetate:methanol (5:4:1) as eluent to yield 1.52 g (68%) as color-
less powder, mp 201-202 °C; ir (potassium bromide): 3463, 2951,
2
2
2
2
2
2
2.34 (t, J = 5 Hz, 2H, pyridine H-4), 2.46 (t, J = 5 Hz, 2H, pyri-
dine H-3), 3.47 (t, J = 5 Hz, 2H, ArCH CH CH N), 7.32 – 7.41
2
2
2
(m, 3H, benzoyl), 7.51 – 7.59 (m, 2H, benzoyl), 7.81 – 7.85 (m,
4H, phthaloyl), 9.77 (s, broad, 1H, NH, deuterium oxide-
+
exchangeable); ms: m/z 388 (M ), 228, 214.
Anal. Calcd. for C
H N O (388.43): C, 71.12; H, 5.19; N,
23 20 2 4
7.21. Found: C, 71.04; H, 5.15; N, 7.54.
N-{5-Benzoyl-6-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)ethyl]-2-oxo-1,2,3,4-tetrahydropyridin-3-yl}acetamide (14a).
-1
1
Sodium (506 g, 22 mmoles) was completely dissolved in 20 ml of
dry ethanol; 2.84 g (22 mmoles) 2-acetamidoacrylic acid was added
and the reaction mixture was stirred at room temperature for 30 min-
utes. Excess of solvent was removed and dried in vacuo to get crude
sodium 2-acetamidoacrylate (12), which was suspended in 60 ml of
dry tetrahydrofuran and cooled to –75 °C. Ethyl chloroformate (2.38
g, 22 mmoles) of was dropped cautiously into the suspension. After
the addition was completed, the reaction mixture was, without cool-
ing, allowed to warm to room temperature at which time 6.40 g (20
mmoles) of 2-[(3Z)-3-amino-5-oxo-5-phenylpent-3-en-1-yl)]-1H-
isoindole-1,3(2H)-dione (8a) was added and the mixture was heated
at reflux for 12 hours. After cooling, the reaction mixture was
quenched with 50 ml of saturated aqueous sodium hydrogen carbon-
ate. The organic layer was separated and the aqueous layer was
extracted three times with chloroform. The combined organic layer
was washed with water, and dried over sodium sulfate. The solvent
was removed in vacuo and the residue was purified by flash chro-
matography using cyclohexane:ethyl acetate:methanol (5:4:1) as
eluent to yield 6.07 g (64%) as colorless powder, mp 216-218 °C; ir
(potassium bromide): 3336, 2945, 1772 (phthaloyl), 1707 (CO),
1774 (phthaloyl), 1713 (CO), 1669, 1646 cm ; H nmr (DMSO-
d ): δ 3.04 (t, J = 5 Hz, 2H, ArCH CH N), 3.91 (t, J = 5 Hz, 2H,
6
2
2
ArCH CH N), 6.19 (d, J = 10 Hz, 1H, pyridine H-3), 7.31 (d, J =
2
2
10 Hz, 1H, pyridine H-4), 7.34 – 7.58 (m, 5H, benzoyl), 7.77 –
7.81 (m, 4H, phthaloyl), 12.28 (s, broad, 1H, NH, deuterium
+
oxide-exchangeable); ms: m/z 372 (M ), 343, 212.
Anal. Calcd. for C
H N O (372.38): C, 70.96; H, 4.33; N,
22 16 2 4
7.52. Found: C, 70.71; H, 4.56; N, 7.64.
2-[3-(3-Benzoyl-6-oxo-1,6-dihydropyridin-2-yl)propyl)-1H-
isoindole-1,3(2H)-dione (15b).
Preparation and purification according to 15a using 2.33 g (6
mmoles) of 2-[3-(3-benzoyl-6-oxo-1,4,5,6-tetrahydropyridin-2-
yl)propyl)-1H-isoindole-1,3(2H)-dione (13b) to yield 1.55 g
(67%) as colorless powder, mp 212-214 °C; ir (potassium bro-
mide): 3442, 2924, 1769 (phthaloyl), 1719 (CO), 1668, 1650
-1
1
cm ; H nmr (DMSO-d ): δ 1.91 (tt, J = 6 Hz, J = 8 Hz, 2H,
6
1
2
ArCH CH CH N), 2.66 (t, J = 8 Hz, 2H, ArCH CH CH N),
2
2
2
2
2
2
3.60 (t, J = 6 Hz, 2H, ArCH CH CH N), 6.19 (d, J = 10 Hz, 1H,
2
2
2
pyridine H-3), 7.39 (d, J = 10 Hz, 1H, pyridine H-4), 7.45 – 7.60
(m, 5H, benzoyl), 7.81 – 7.91 (m, 4H, phthaloyl), 12.12 (s,
broad, 1H, NH, deuterium oxide-exchangeable); ms: m/z 386
-1 1
1655 (lactam ) cm ; H nmr (DMSO-d ): δ 1.84 (s, 3H, acetyl), 2.31
6
(m, 1H, pyridine H-4), 2.50 (t, J = 5 Hz, 2H, ArCH CH N), 2.73 (m,
2
2
+
1H, pyridine H-4), 3.83 (t, J = 5 Hz, 2H, ArCH CH N), 4.36 (m, 1H,
(M ), 238, 226.
2
2
pyridine H-3), 7.31 - 7.53 (m, 5H, benzoyl), 7.79 – 7.86 (m, 4H,
phthaloyl), 8.08 (s, broad, 1H, AcNH, deuterium oxide-exchange-
able), 10.20 (s, broad, 1H, NH, deuterium oxide-exchangeable); ms:
Anal. Calcd. for C
7.25. Found: C, 71.81; H, 4.66; N, 7.60.
H N O (386.42): C, 71.49; H, 4.70; N,
23 18 2 4
N-{5-Benzoyl-6-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}acetamide (16a).
+-
+
m/z 372 (M CH COHNH ), 343, 212.
2
2
Anal. Calcd. for C
H N O (431.45): C, 66.81; H, 4.91; N,
24 21 3 5
Preparation and purification according to 15a using 4.31 g (10
mmoles) of N-{5-benzoyl-6-[2-(1,3-dioxo-1,3-dihydro-2H-isoin-
dol-2-yl)ethyl]-2-oxo-1,2,3,4-tetrahydropyridin-3-yl}acetamide
(14a) and 4.35 g (50 mmoles) of activated manganese (IV) oxide
in 50 ml of toluene to yield 3.26 g (76%) as colorless powder, mp
245-247 °C; ir (potassium bromide): 3278, 1770 (phthaloyl),
9.74. Found: C, 66.99; H, 4.51; N, 9.78.
N-{5-Benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)
propyl]-2-oxo-1,2,3,4-tetrahydropyridin-3-yl}acetamide (14b).
Preparation and purification according to 14a using 6.68 g (20
mmoles) of 2-[(4Z)-4-amino-6-oxo-6-phenylhex-4-en-1-yl)]-1H-
isoindole-1,3(2H)-dione (8b) to yield 6.59 g (74%) as colorless
powder, mp 183-185 °C; ir (potassium bromide): 3384, 3232,
-1
1
1718 (CO), 1704 (AcNH), 1633 cm ; H nmr (DMSO-d ): δ
6
2.02 (s, 3H, acetyl), 2.99 (t, J = 5 Hz, 2H, ArCH CH N), 3.93 (t,
2
2
-1
1
1768 (phthaloyl), 1709 (CO), 1668 (lactam) cm ; H nmr
J = 5 Hz, 2H, ArCH CH N), 7.42 - 7.49 (m, 2H, benzoyl), 7.55 –
2 2

862
T. Hussenether and R. Troschütz
Vol. 41
7.62 (m, 3H, benzoyl), 7.81 – 7.90 (m, 4H, phthaloyl), 8.22 (s,
1H, pyridine H-4), 9.32 (s, broad, 1H, AcNH, deuterium oxide-
exchangeable), 12.39 (s, broad, 1H, NH, deuterium oxide-
yl)ethyl)-1H-isoindole-1,3(2H)-dione (15a) and chloro-
form:methanol (95:5) as eluent to yield 215 mg (32%) as color-
less powder, mp >300 °C (decomposition); ir (potassium bro-
+
-1 1
exchangeable); ms: m/z 429 (M ), 269, 227.
mide): 2435, 2954, 2790, 1678 (CO), 1621 cm ; H nmr
Anal. Calcd. for C
H
N O (429.44): C, 67.13; H, 4.46; N,
(DMSO-d ): δ 2.65 (t, J = 8 Hz, 2H, H-8), 3.72 (t, J = 8 Hz, 2H,
24 19
3
5
6
9.78. Found: C, 66.87; H, 4.10; N, 9.78.
H-7), 6.19 (d, J = 10 Hz, 1H, H-3), 7.20 (d, J = 10 Hz, 1H, H-4),
7.41 - 7.51 (m, 5H, phenyl), 12.18 (s, broad, 1H, NH, deuterium
oxide-exchangeable); ms: m/z 224 (M ), 223, 196, 195.
N-{5-Benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-
propyl]-2-oxo-1,2-dihydropyridin-3-yl}acetamide (16b).
+
Anal. Calcd. for C
H N O (224.26): C, 74.98; H, 5.39; N,
14 12 2
Preparation and purification according to 16a using 4.45 g (10
mmoles) of N-{5-benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-2H-isoin-
dol-2-yl)propyl]-2-oxo-1,2,3,4-tetrahydropyridin-3-yl}
acetamide (14b) to yield 3.15 g (71%) as colorless powder, mp
267-269 °C; ir (potassium bromide): 3336, 1772 (phthaloyl),
12.49. Found: C, 74.78; H, 5.58; N, 12.21
5-Phenyl-1,7,8,9-tetrahydro-2H-pyrido[3,2-c]azepin-2-one
(18b).
Preparation and purification according to 17a using 772 mg (2
mmoles) of 2-[3-(3-benzoyl-6-oxo-1,6-dihydropyridin-2-
yl)propyl)-1H-isoindole-1,3(2H)-dione (15b) and chloro-
form:methanol (95:5) as eluent to yield 114 mg (24%) as color-
less powder, mp >300 °C (decomposition); ir (potassium bro-
-1
1
1717 (CO), 1704 (AcNH), 1641 cm ; H nmr (DMSO-d ): δ
6
1.90 (tt, J = 8 Hz, J = 6 Hz, 2H, ArCH CH CH N), 2.05 (s, 3H,
1
2
2
2
2
acetyl), 2.61 (t, J = 8 Hz, 2H, ArCH CH CH N), 3.59 (t, J = 6
2
2
2
Hz, 2H, ArCH CH CH N), 7.43 – 7.50 (m, 2H, benzoyl), 7.55 –
2
2
2
-1
1
mide): 3440, 2951, 2860, 1668 (CO), 1608 cm ; H nmr
7.66 (m, 3H, benzoyl), 7.83 – 7.88 (m, 4H, phthaloyl), 8.18 (s,
1H, pyridine H-4), 9.34 (s, broad, 1H, AcNH, deuterium oxide-
exchangeable), 12.41 (s, broad, 1H, NH, deuterium oxide-
(DMSO-d ): δ 2.31 (tt, J = 7 Hz, J = 7 Hz, 2H, H-8), 2.50 (t, J =
6
1
2
7 Hz, 2H, H-9), 3.43 (t, J = 7 Hz, 2H, H-7), 6.24 (d, J = 10 Hz,
1H, H-3), 7.11 (d, J = 10 Hz, 1H, H-4), 7.39 - 7.47 (m, 3H,
phenyl), 7.51 - 7.61 (m, 2H, phenyl), 12.05 (s, broad, 1H, NH,
+
exchangeable); ms: m/z 443 (M ), 283, 241.
Anal. Calcd. for C
H N O (443.46): C, 67.71; H, 4.77; N,
25 21 3 5
+
deuterium oxide-exchangeable) ms: m/z 238 (M ), 237, 210.
9.48. Found: C, 67.89; H, 4.99; N, 9.11.
Anal. Calcd. for C
12.49. Found: C, 74.78; H, 5.58; N, 12.21.
H N O (224.26): C, 74.98; H, 5.39; N,
14 12 2
5-Phenyl-7,8-dihydro-1,6-naphthyridine (17a).
2-[2-(3-Benzoylpyridin-2-yl)ethyl]-1H-isoindole-1,3(2H)-
dione (10a) (1.07 g, 3 mmoles) was suspended in 30 ml of 6 M
aqueous hydrochloride acid and heated at reflux for 14 hours.
The reaction mixture was neutralized cautiously under ice-cool-
ing by adding 6 M aqueous sodium hydroxide and extracted three
times with diethyl ether. The combined organic layer was washed
with saturated aqueous sodium hydrogen carbonate, dried over
sodium sulfate, and concentrated in vacuo. The residue was puri-
fied by mplc using cyclohexane:ethyl acetate:methanol (5:4:1) as
eluent to yield 225 mg (36%) as colorless powder, 178-180 °C; ir
3-Amino-5-phenyl-7,8-dihydro-1,6-naphthyridin-2(1H)-one (19a).
Preparation and purification according to 17a using 2.14 g (5
mmoles) of N-{5-benzoyl-6-[2-(1,3-dioxo-1,3-dihydro-2H-isoin-
dol-2-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}acetamide (16a)
and chloroform:methanol (9:1) as eluent to yield 347 mg (29%)
as colorless powder; mp >300 °C (decomposition); ir (potassium
-1
1
bromide): 3463, 3364, 2891, 1641 (CO), 1595 cm ; H nmr
(DMSO-d ): δ 2.53 (t, J = 8 Hz, 2H, H-8), 3.67 (t, J = 8 Hz, 2H,
6
H-7), 4.93 (s, broad, 2H, NH , deuterium oxide-exchangeable),
2
-1
(potassium bromide): 3058, 2952, 2845, 1609, 1578, 1562 cm ;
6.33 (s, 1H, H-4), 7.42 - 7.48 (m, 5H, phenyl), 11.91 (s, broad,
1
+
H nmr (CDCl ): δ 3.03 (t, J = 7 Hz, 2H, H-8), 4.02 (t, J = 7 Hz,
1H, NH, deuterium oxide-exchangeable) ms: m/z 239 (M ), 238.
3
2H, H-7), 7.22 (dd, J = 8 Hz, J = 4 Hz, 1H, H-3), 7.46 - 7.51
Anal. Calcd. for C
H N O (239.28): C, 70.28; H, 5.48; N,
1
2
14 13 3
(m, 3H, phenyl), 7.55 – 7.61 (m, 3H, phenyl, H-4), 8.58 (dd, J =
17.56. Found: C, 70.11; H, 5.36; N, 17.51.
1
+
4 Hz, J = 2 Hz, 1H, H-2); ms: m/z 208 (M ), 180.
2
3-Amino-5-phenyl-1,7,8,9-tetrahydro-2H-pyrido[3,2-c]azepin-2-
one (19b).
Anal. Calcd. for C
H N (208.27): C, 80.74; H, 5.81; N,
14 12 2
13.45. Found: C, 80.66; H, 5.58; N, 13.23.
Method A: Preparation and purification according to 17a using
2.22 g (5 mmoles) of N-{5-benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-
2H-isoindol-2-yl)propyl]-2-oxo-1,2-dihydropyridin-3-
yl}acetamide (16b) and chloroform: methanol (9:1) as eluent to
yield 304 mg (24%) as colorless powder. Method B: 2-Hydroxy-5-
phenyl-8,9-dihydro-7H-pyrido[3,2-c]azepin-3-carboxylic acid
(24) (85 mg, 0.3 mmole), 82 mg (0.3 mmole) diphenylphosphory-
lazid (DPPA) and 30 mg (0.3 mmole) triethylamine were dissolved
in 10 ml of dry tert-butyl alcohol and heated at reflux for 3 hours.
Water (10 ml) was added and heated at reflux for another 1.5 hour.
After cooling 10 ml of 6 M aqueous hydrochloric acid was added
and stirred for 1 hour. The reaction mixture was neutralized by por-
tion-wise addition of sodium carbonate. Chloroform (10 ml) was
added and the mixture was shaken well. The organic layer was sep-
arated, and the aqueous layer was extracted twice with chloroform.
The combined organic layer was dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by column chro-
matography using chloroform:methanol (9:1) as eluent to yield 31
5-Phenyl-8,9-dihydro-7H-pyrido[3,2-c]azepine (17b).
Preparation and purification according to 17a using 1.11 g (3
mmoles) of 2-[3-(3-benzoylpyridin-2-yl)propyl]-1H-isoindole-
1,3(2H)-dione (10b) and cyclohexane:ethyl acetate: methanol
(50:35:15) as eluent to yield 206 mg (31%) as colorless powder,
mp 183-185 °C; ir (potassium bromide): 3086, 2977, 1601, 1553
-1 1
cm ; H nmr (CDCl ): δ 2.48 (tt, J = 7 Hz, J = 7 Hz, 2H, H-8),
3
1
2
2.87 (t, J = 7 Hz, 2H, H-9), 3.49 (t, J = 7 Hz, 2H, H-7), 7.26 (dd,
J = 7 Hz, J = 4 Hz, 1H, H-3), 7.35 - 7.50 (m, 4H, phenyl, H-4),
1
2
7.60 – 7.65 (m, 2H, phenyl), 8.62 (dd, J = 4 Hz, J = 2 Hz, 1H,
1
2
+
+
H-2); ms: m/z 222 (M -CH COHNH ), 194.
2
2
Anal. Calcd. for C
H N (222.29): C, 81.05; H, 6.35; N,
15 14 2
12.60. Found: C, 81.00; H, 6.45; N, 12.25.
5-Phenyl-7,8-dihydro-1,6-naphthyridin-2(1H)-one (18a).
Preparation and purification according to 17a using 1.12 g (3
mmoles) of 2-[2-(3-benzoyl-6-oxo-1,6-dihydropyridin-2-

Nov-Dec 2004
Synthesis of 5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-Phenyl-6,7,8,9-
863
tetrahydro-5H-pyrido[3,2-c]azepines
mg (41%) as colorless powder; mp >300 °C (decomposition); ir
(potassium bromide): 3377, 3186, 2937, 1658 (CO), 1616, 1570
tralized with 6 M aqueous sodium hydroxide under ice-cooling,
pH was adjusted to 3-4 using acetic acid and sodium acetate as
buffer, and extracted five times with chloroform. The combined
organic layer dried over sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography
using chloroform:methanol:acetic acid (85:15:0.5) as eluent to
yield 97 mg (23%) as colorless powder, 250-251 °C (decomposi-
tion); ir (potassium bromide): 3435, 1731 (COOH), 1632, 1589
-1
1
cm ; H nmr (DMSO-d ): δ 2.24 (tt, J = 8 Hz, J = 7 Hz, 2H,
6
1
2
H-8), 2.40 (t, J = 8 Hz, 2H, H-9), 3.40 (t, J = 7 Hz, 2H, H-7), 4.93
(s, broad, 2H, NH , deuterium oxide-exchangeable), 6.19 (s, 1H,
2
H-4), 7.37 - 7.47 (m, 3H, phenyl), 7.54 – 7.59 (m, 2H, phenyl),
11.80 (s, broad, 1H, NH, deuterium oxide-exchangeable) ms: m/z
+
253 (M ), 252, 225.
-1
1
Anal. Calcd. for C
H
N O (253.31): C, 71.13; H, 5.97; N,
cm ; H nmr (DMSO-d ): δ 1.70 (tt, J = 7 Hz, J = 8 Hz, 2H,
15 15
3
6 1 2
16.59. Found: C, 70.92; H, 5.99; N, 16.91.
ArCH CH CH N), 2.02 (t, J = 8 Hz, 2H, ArCH CH CH N),
2 2 2 2 2 2
3.76 (t, J = 6 Hz, 2H, ArCH CH CH N), 7.44 – 7.59 (m, 6H,
2
2
2
2-[5-Benzoyl-6-(dimethylamino)-4-oxohex-5-en-1-yl]-1H-isoin-
dol-1,3(2H)-dione (21).
phenyl, 2-OH, 1H deuterium oxide-exchangeable), 8.64 (s, 1H,
H-4), 13.22 (s, broad, 1H, COOH, deuterium oxide-exchangeable
+
2-[(4Z)-4-Hydroxy-6-oxo-6-phenylhex-4-en-1-yl)-1H-isoin-
dole-1,3(2H)-dione (7b) (3.66 g, 10.9 mmoles) was dissolved in
10 ml of dry tetrahydrofuran, 1.43 g (12 mmoles) of N,N-
dimethylformamide dimethyl acetal (DMF-DMA) was added
slowly, and stirred for 15 hours at room temperature. The mixture
was concentrated in vacuo. The oily, red residue was taken up in
n-butyl alcohol. The product was crystallized by drop-wise addi-
tion of n-hexane. The solid was collected by suction and recrys-
tallized from ethanol/n-hexane to yield 2.61 g (60%) as yellow
crystals, mp 107-109 °C; ir (potassium bromide): 3412, 2988,
); ms: m/z 282 (M ), 281, 263.
Anal. Calcd. for C
H N O (282.30): C, 68.00; H, 5.00; N,
16 14 2 3
9.92. Found: C, 68.23; H, 5.00; N, 10.11.
5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (25a).
5-Phenyl-7,8-dihydro-1,6-naphthyridine (17a) (208 mg, 1
mmole) was dissolved in 10 ml of dry methanol and cooled to
0°C by an ice-bath. Sodium borohydride (38 mg, 1 mmole) was
added and stirred for 30 minutes. The mixture was acidified by
addition of 2 N aqueous sulfuric acid, pH was adjusted to about 8
with sodium carbonate, and extracted three times with diethyl
ether. The combined organic layer was washed with saturated
aqueous sodium hydrogen carbonate, dried over sodium sulfate,
and concentrated in vacuo to yield 155 mg (74%) as pure, color-
less powder, mp 168-170 °C (decomposition); ir (sodium chlo-
-1 1
2897, 1779 (phthaloyl), 1712 (CO), 1601 cm ; H nmr (CDCl ):
3
δ 1.66 (tt, J = 7 Hz, J = 7 Hz, 2H, COCH CH CH N), 2.33 (t, J
1
2
2
2
2
= 7 Hz, 2H, COCH CH CH N), 2.91 (s, 6H, NMe ), 3.54 (t, J =
2
2
2
2
7 Hz, 2H, COCH CH CH N), 7.33 - 7.48 (m, 5H, benzoyl), 7.64
2
2
2
+
– 7.89 (m, 5H, H-6, phthaloyl); ms: m/z 390 (M ), 202, 105.
Anal. Calcd. for C N O (390.44): C, 70.75; H, 5.68; N,
-1
1
H
ride): 3244, 2877, 2841, 1551 cm ; H nmr (CDCl ): δ 2.05 (s,
23 22
2 4
3
7.17. Found: C, 71.14; H, 6.06; N, 6.84.
broad, 1H, NH, deuterium oxide-exchangeable), 2.95 – 3.40 (m,
4H, H-7, H-8), 5.08 (s, 1H, H-5), 6.99 (dd, J = 8 Hz, J = 4 Hz,
1
2
5-Benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)propyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile (23).
1H, H-3), 7.05 (dd, J = 8 Hz, J = 1 Hz, 1H, H-4), 7.23 – 7.38
1
2
(m, 5H, phenyl), 8.40 (dd, J = 4 Hz, J = 1 Hz, 1H, H-2); ms:
1
2
+
Cyanoacetamide (420 mg, 5 mmoles) was added to a suspen-
sion of 570 mg (5 mmoles) of magnesium ethoxide in 30 ml of
dry tetrahydrofuran and heated to 70 °C for 1 hour. 2-[5-Benzoyl-
6-(dimethylamino)-4-oxohex-5-en-1-yl]-1H-isoindol-1,3(2H)-
dione (21) (1.95 g, 5 mmoles) was added and heated at 70 °C for
another 14 hours. After cooling the reaction mixture was acidi-
fied cautiously with 2 N aqueous sulfuric acid, and extracted
three times with dichloromethane. The combined organic layer
was washed with saturated aqueous sodium hydrogen carbonate,
dried over sodium sulfate, and concentrated in vacuo. The
residue was purified by mplc using cyclohexane:ethyl
acetate:methanol (50:45:5) as eluent to yield 781 mg (38%) as
pale yellow powder, mp 213-214 °C (decomposition); ir (potas-
sium bromide): 3463, 2228 (CN), 1770 (phthaloyl), 1713 (CO),
m/z 210 (M ), 180, 133.
Anal. Calcd. for C
H
N
(210.28): C, 79.97; H, 6.71; N,
2
14 14
13.32. Found: C, 80.12; H, 6.88; N, 12.92.
5-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine (25b).
Preparation according to 25a using 222 mg (1 mmole) of 5-
phenyl-8,9-dihydro-7H-pyrido[3,2-c]azepine (17b) to yield 155
mg (69%) as pure, colorless powder, mp 182-184 °C; ir (sodium
-1 1
chloride): 3273, 2927, 2848, 1573 cm ; H nmr (CDCl ): δ 1.75
3
– 1.98 (m, 2H, H-8), 1.84 (s, broad, 1H, NH, deuterium oxide-
exchangeable), 3.18 – 3.48 (m, 4H, H-7, H-9), 5.15 (s, 1H, H-5),
6.87 (dd, J = 8 Hz, J = 5 Hz, 1H, H-3), 6.95 (dd, J = 8 Hz, J =
1
2
1
2
2 Hz, 1H, H-4), 7.38 – 7.45 (m, 5H, phenyl), 8.34 (dd, J = 5 Hz,
1
+
J = 2 Hz, 1H, H-2); ms: m/z 224 (M ), 195.
2
-1 1
1658 (lactam) cm ; H nmr (DMSO-d ): δ 1.92 (tt, J = 6 Hz, J
Anal. Calcd. for C
H N (224.31): C, 80.32; H, 7.19; N,
6
1
2
15 16 2
= 6 Hz, 2H, ArCH CH CH N), 2.67 (t, J = 6 Hz, 2H,
12.49. Found: C, 80.11; H, 7.30; N, 12.13.
2
2
2
ArCH CH CH N), 3.60 (t, J = 6 Hz, 2H, ArCH CH CH N),
2
2
2
2
2
2
6-Methyl-5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (26a).
7.46 - 7.53 (m, 2H, benzoyl), 7.59 – 7.69 (m, 3H, benzoyl), 7.83
+
– 7.90 (m, 4H, phthaloyl); ms: m/z 412 (M +1), 411, 379.
5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (25a) (105 mg,
0.5 mmole) was heated at reflux in 4 ml of a mixture of aqueous
formaldehyde (37%):formic acid (98%) (4:3) for 4 hours under a
nitrogen atmosphere. After cooling the reaction mixture was con-
centrated in vacuo. The residue was taken up in 10 ml of saturated
aqueous sodium carbonate, and extracted three times with
dichloromethane. The combined organic layer was washed with
saturated aqueous sodium carbonate, dried over sodium sulfate and
concentrated in vacuo. The residue was purified by column chro-
matography using cyclohexane:ethyl acetate:methanol (50:45:5) as
Anal. Calcd. for C
H N O (411.42): C, 70.07; H, 4.16; N,
24 17 3 4
10.21. Found: C, 69.94; H, 4.55; N, 10.04.
2-Hydroxy-5-phenyl-8,9-dihydro-7H-pyrido[3,2-c]azepin-3-car-
boxylic Acid (24).
5-Benzoyl-6-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)propyl]-2-oxo-1,2-dihydropyridin-3-carbonitrile (23) (617 g,
1.5 mmoles) was suspended in 15 ml of 6 M aqueous hydrochlo-
ride acid and heated at reflux for 12 hours. The mixture was neu-

864
T. Hussenether and R. Troschütz
Vol. 41
-1
eluent to yield 65 mg (58%) as colorless powder, mp 74-76 °C; ir
(potassium bromide): 2983, 2949, 2795, 1574, 1446 cm ; H nmr
(potassium bromide): 3319, 3257, 2875, 1651 (CO), 1591 cm ;
-1 1
1
H nmr (DMSO-d ): δ 1.94 (s, broad, 1H, NH, deuterium oxide-
6
(DMSO-d ): δ 2.13 (s, 3H, Me), 2.50-2.60 (m, 2H, H-8), 3.09 –
exchangeable), 3.30 – 3.03 (m, 4H, H-7, H-8), 4.63 (s, 1H, H-5),
6
3.19 (m, 2H, H-7), 4.30 (s, 1H, H-5), 6.90 (d, J = 8 Hz, 1H, H-4),
7.04 (dd, J = 8 Hz, J = 5 Hz, 1H, H-3), 7.23 – 7.38 (m, 5H,
phenyl), 8.30 (d, J = 5 Hz, 1H, H-2); ms: m/z 224 (M ), 180, 147.
4.69 (s, broad, 2H, NH , deuterium oxide-exchangeable), 5.81 (s,
2
1H, H-4), 7.17 – 7.43 (m, 5H, phenyl), 11.20 (s, broad, 1H, NH,
1
2
+
+
1H, deuterium oxide-exchangeable); ms: m/z 241 (M ), 212,
Anal. Calcd. for C (224.31): C, 80.32; H, 7.19; N,
H
N
271, 164.
15 16
2
Anal. Calcd. for C
H N O (241.30): C, 69.69; H, 6.27; N,
14 15 3
12.49. Found: C, 79.99; H, 7.09; N, 12.18.
17.41. Found: C, 70.00; H, 6.01; N, 17.35.
6-Methyl-5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine
(26b).
3-Amino-5-phenyl-1,5,6,7,8,9-hexahydro-2H-pyrido[3,2-c]-
azepin-2-one (28b).
Preparation according to 26a using 112 mg (0.5 mmole) of 5-
phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine (25b) to
yield 61 mg (51%) as colorless powder, mp 103-104 °C; ir
Preparation and according to 25a using 253 mg (0.5 mmole) of
3-amino-5-phenyl-1,7,8,9-tetrahydro-2H-pyrido[3,2-c]azepin-2-
one (19b). The product was purified by column chromatography
using chloroform:methanol (82:18) as eluent to yield 227 mg
(89%) as colorless powder, mp 218-220 °C; ir (potassium bro-
-1
1
(sodium chloride): 2926, 2851, 1598, 1448 cm ; H nmr
(CDCl ): δ 2.41 (s, 3H, Me), 2.90 – 3.24 (m, 4H, H-8, H-9), 4.72
3
– 5.01 (m, 2H, H-7), 5.04 (s, 1H, H-5), 7.09 (dd, J = 8 Hz, J =
1
2
-1
1
mide): 3340, 3354, 2925, 1645 (CO), 1587 cm ; H nmr
5 Hz, 1H, H-3), 7.22 – 7.36 (m, 6H, phenyl, H-4), 8.42 (dd, J =
1
+
(CDCl ): δ 1.50 – 1.69 (m, 2H, H-8), 2.22 (s, broad, 1H, NH,
5 Hz, J = 2 Hz, 1H, H-2); ms: m/z 238 (M ), 194, 161.
3
2
deuterium oxide-exchangeable), 2.67 – 3.96 (m, 4H, H-7, H-9),
Anal. Calcd. for C
11.75. Found: C, 81.00; H, 7.71; N, 11.86.
H N (238.34): C, 80.63; H, 7.61; N,
16 18 2
4.67 (s, broad, 2H, NH , deuterium oxide-exchangeable), 4.83 (s,
2
1H, H-5), 5.93 (s, 1H, H-4), 7.18 – 7.38 (m, 5H, phenyl), 11.24
(s, broad, 1H, NH, 1H, deuterium oxide-exchangeable); ms: m/z
255 (M ), 238, 226.
5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (27a).
+
Preparation according to 25a using 112 mg (0.5 mmole) of
5-phenyl-7,8-dihydro-1,6-naphthyridin-2(1H)-one (18a). The
product was purified by column chromatography using chloro-
form:methanol (9:1) as eluent to yield 94 mg (83%) as colorless
powder, mp >300 °C (decomposition); ir (sodium chloride):
Anal. Calcd. for C
H N O (255.32): C, 70.56; H, 6.71; N,
15 17 3
16.46. Found: C, 70.87; H, 6.82; N, 16.10.
Acknowledgement.
-1 1
3446, 2921, 2850, 1654 (CO), 1618 cm ; H nmr (DMSO-d ): δ
Thanks are due to Prof. Dr. P. Gmeiner and Dr. H. Hübner for
providing biochemical test systems as well as to Mr. Dr. R.
Waibel for NMR data and interpretation. We thank Mrs. B. Maar,
Mrs. M. Unzeitig, Mrs. A. Seitz, Mrs. N. Bäuerlein, Mrs. H.
Szczepanek, Mrs. P. Schmitt, Mrs. S. Würdemann and Mrs. P.
Hübner for helpful technical assistance.
6
1.24 (s, broad, 1H, NH, deuterium oxide-exchangeable), 2.42 –
3.09 (m, 4H, H-7, H-8), 4.75 (s, 1H, H-5), 6.03 (d, J = 10 Hz, 1H,
H-4), 6.71 (d, J = 10 Hz, 1H, H-3), 7.20 – 7.39 (m, 5H, phenyl),
11.46 (s, broad, 1H, NH, 1H, deuterium oxide-exchangeable);
+
ms: m/z 226 (M ), 221, 92.
Anal. Calcd. for C
H N O (226.28): C, 74.31; H, 6.24; N,
14 14 2
12.38. Found: C, 74.23; H, 6.44; N, 12.03.
REFERENCES AND NOTES
5-Phenyl-1,5,6,7,8,9-hexahydro-2H-pyrido[3,2-c]azepin-2-one
(27b).
[1] H. Blaschko, Brit. Med. Bull., 29, 105 (1973).
[2] P. Seeman and H. H. M. Van Tol, Curr. Opin. Neurol.
Neurosug., 6, 602 (1993).
[3] A. K. Neve and R. L. Neve, in The Dopamine Receptors, K.
A. Neve, R. L. Neve, eds., Humana Press, Totowa, New Jersey, 1997, pp
27-76.
[4] M. Rowley, L. J. Bristow and P. H. Hutson, J. Med. Chem., 44,
477 (2001).
[5] M. R. Weed, W. L. Woolverton and I. A. Paul, Eur. J.
Pharmacol., 361, 129 (1998).
[6] G. Thews, E. Mutschler and P. Vaupel, Anatomie,
Physiologie, Pathophysiologie des Menschen, Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart, 1999, p 681.
[7] J. L. Mc Nay, R. H. Mc Donald and L. I. Goldberg,
Circulation Res., 16, 510 (1965).
Preparation according to 25a using 119 mg (0.5 mmole) of 5-
phenyl-1,7,8,9-tetrahydro-2H-pyrido[3,2-c]azepin-2-one (18b).
The product was purified by column chromatography using chlo-
roform:methanol (9:1) as eluent to yield 100 mg (83%) as color-
less powder, mp >300 °C (decomposition); ir (potassium bro-
-1
1
mide): 2962, 1639 (CO), 1614 cm ; H nmr (CDCl ): δ 1.72 –
3
1.99 (m, 2H, H-8), 2.08 (s, broad, 1H, NH, deuterium oxide-
exchangeable), 2.91 – 3.34 (m, 4H, H-7, H-9), 4.98 (s, 1H, H-5),
6.26 (d, J = 9 Hz, 1H, H-3), 6.85 (d, J = 9 Hz, 1H, H-4), 7.27 –
7.33 (m, 3H, phenyl), 7.35 – 7.41 (m, 2H, phenyl), 13.17 (s,
broad, 1H, NH, deuterium oxide-exchangeable); ms: m/z 240
+
(M ), 211, 163.
[8] C. I. Iorio, A. Barnett, F. H. Leitz, V. P. Houser and C. A.
Korduba, J. Pharmacol. Exp. Ther., 226, 462 (1983).
[9] F. Eiden, H. Lentzen, Pharmazie in unserer Zeit, 25, 28
(1996).
[10] D. L. Minor, S. D. Wyrick, P. S. Charifson, V. J. Watts, D. E.
Nichols, R. B. Mailman, J. Med. Chem., 37, 4317 (1994).
[11] J. B. Post IV and W. H. Frishman, J. Clin. Pharmacol., 38, 2
(1998).
Anal. Calcd. for C
11.66. Found: C, 74.78; H, 6.58; N, 11.61.
H N O (240.31): C, 74.97; H, 6.71; N,
15 16 2
3-Amino-5-phenyl-5,6,7,8-tetrahydro,1,6-naphthyridin-2(1H)-
one (28a).
Preparation and according to 25a using 239 mg (1 mmole) of
3-amino-5-phenyl-7,8-dihydro-1,6-naphthyridin-2(1H)-one
(19a). The product was purified by column chromatography
using chloroform:methanol (82:18) as eluent to yield 202 mg
(84%) as colorless powder, mp >300 °C (decomposition); ir
[12] S. Ohta, A. Tsujimura and M. Okamoto, Chem. Pharm. Bull.,
29, 2762 (1981).
[13] B. Singh and D. Y. Lesher, J. Heterocyclic Chem., 27, 2085

Nov-Dec 2004
Synthesis of 5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-Phenyl-6,7,8,9-
tetrahydro-5H-pyrido[3,2-c]azepines
865
(1990).
Leipzig, 1996, pp 535-539.
[14] Y. Huang and R. W. Hartmann, Synth. Commun., 28, 1197
(1998).
[15] K. Paulvannan and J. R. Stille, J. Org. Chem., 59, 1613
(1994).
[16] K. Paulvannan and T. Chen, J. Org. Chem., 65, 6160 (2000).
[17] L. J. Beholz, P. Benovsky, D. L. Ward, N. S. Barta and J. R.
Stille, J. Org. Chem., 62, 1033 (1997).
[23] A. Shiozawa, Y. Ichikawa, M. Ishihawa and H. Mirazaki, Ger.
Offen. DE 3143016 A1 19820527 (1982); Chem. Abstr., 97, 144876
(1982).
[24] H. T. Clarke, H. B.Gillespie and S. Z. Weisshaus, J. Am.
Chem. Soc., 55, 4571 (1933).
[25] P. S. Charifson, S. D. Wyrick, A. Hoffman and R. M.
Simmons, J. Med. Chem., 31, 1941 (1988).
[18] E. Coulon, M C. Caño de Andrade, V. Ratovelomanana-Vidal
and J.-P. Genêt, Tetrahedron Lett., 39, 6467 (1998).
[19] W. D. Jones, R. A. Schnettler and E. W. Huber, J. Heterocyclic
Chem., 27, 511 (1990).
[26] H. Hübner, C. Haubmann, W. Utz and P. Gmeiner, J. Med.
Chem. 43, 756 (2000).
[27] G. Hayes, T. J. Biden, L. A. Selbie and J. Shine, Mol.
Endocrinol. 6, 920 (1992).
[20] T. Shiori, K. Ninomiya and S. Yamada, J. Am. Chem. Soc., 67,
1017 (1945).
[21] K. Ninomiya, T. Shiori, and S. Yamada, Tetrahedron, 20, 2151
(2151).
[28] P. Sokoloff, M. Andrieux, R. Besançon, C. Pilon, M.-
P.Martres, B. Giros and J.-C Schwartz, Eur. J. Pharmacol. 225, 331
(1992).
[29] V. Asghari, S. Sanyal, S. Buchwaldt, A. Paterson, V.
Jovanovic and H. H. M. Van Tol, J. Neurochem. 65, 1157 (1995).
[22] Organikum, Johann Ambrosius Barth Verlag, Heidelberg,