Synthesis of Pyridazine and Pyrrole Analogues of 2-Aminotetralin as Potential Dopaminergics

Article abstract of DOI:10.1002/jhet.3180

Syntheses of pyridazine and pyrrole analogues of 2-aminotetralin starting from 3-cyclohexene-1-carboxylic acid are reported. All syntheses involve the following key steps: Curtius rearrangement for amine functionality, inverse electron demand Diels–Alder

Full text of DOI:10.1002/jhet.3180

Month 2018
Synthesis of Pyridazine and Pyrrole Analogues of 2-Aminotetralin as
Potential Dopaminergics
Ramazan Kocak,
Arif Dastan,*
and Nurullah Saracoglu*
Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum 25240, Turkey
*
E-mail: adastan@atauni.edu.tr; nsarac@atauni.edu.tr
Received October 31, 2017
DOI 10.1002/jhet.3180
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Syntheses of pyridazine and pyrrole analogues of 2-aminotetralin starting from 3-cyclohexene-1-
carboxylic acid are reported. All syntheses involve the following key steps: Curtius rearrangement for amine
functionality, inverse electron demand Diels–Alder addition with 1,2,4,5-tetrazine for pyridazine ring syn-
thesis, and pyridazine-to-pyrrole ring contraction for pyrrole ring formation.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
benzene afforded the benzyl carbamate 7 in 76% yield
through the Curtius rearrangement [14–17]. Inverse
electron demand Diels–Alder additions (iEDDA) between
1,2,4,5-tetrazines and olefins are very well known for the
preparation of pyridazines [18–27]. These reactions result
in the formation of bicyclic intermediates via nitrogen
elimination readily and subsequent rearranging, yielding
dihydropyridazines, which may be further oxidized to
pyridazines. A reaction of cyclohexene derivative 7 with
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (8a) in dry
methylene chloride led to the formation of the
corresponding 1,4-dihydropyridazine, which was then
converted to the desired pyridazine 9a in 68% overall
yield by oxidizing with phenyliodo-bis(trifluoroacetate)
Mono- and dihydroxy-2-aminotetralin (1) structures are
rigid analogues of dopamine (2) and exhibit a wide range
pharmacological activity such as dopaminergic,
serotonergic, and adrenergic effects (Fig. 1) [1–3]. The
position of the hydroxyl groups is critical in determining
the receptor preference [4]. Compounds 3–5 are examples
of heterocyclic isosteres of hydroxy-2-aminotetralins,
which were shown to possess DA agonist activity (Fig. 1)
[
5–13]. This encouraged us to replace the phenolic
portion of 2-aminotetralin with ester and pyridine-
substituted pyridazines and pyrroles may be the
compounds with potential dopaminergic activities.
(PIFA). Cycloaddition of 7 with 3,6-di(2-pyridyl)-1,2,4,5-
tetrazine (8b) progressed more slowly than its analogue
8a and a higher reaction temperature was required to carry
out the aimed transformation. When the reaction was
performed under reflux conditions in acetonitrile (MeCN),
the formation of 3,6-di(pyridin-2-yl)-1,4-dihydro-1,2,4,5-
tetrazine (10b) along with 10a was observed. Since
dipyridyl-tetrazine 8b behaves as an oxidizing agent at the
same time, using two equivalents of 8b with 7 for 3 days
led to the formation of 9b (92%) and 10b (92%) [28,29].
In the next step, a carbobenzyloxy protecting group of N-
Cbz-protected amines 9a and 9b was easily removed with
palladium-catalyzed hydrogenations to give the
corresponding free amines 11a and 11b in 62% and 70%
yield, respectively. Both of the pyridazines 11a and 11b
were also converted into the corresponding pyrroles 12a
RESULTS AND DISCUSSIONS
We report here the fast, efficient preparation of
pyridazine and pyrrole motifs of 2-aminotetralin directly
starting from readily available compounds (Scheme 1).
Carboxylic acid acts as the convenient precursor of an
amine group. Our initial effort was to synthesize benzyl
cyclohex-3-en-1-ylcarbamate (7). First, cyclohex-3-ene-1-
carboxylic acid (6) was reacted with diphenylphosphoryl
azide (DPPA) in the presence of triethylamine (NEt ) at
3
room temperature for 1 day in benzene. The initially
formed acyl azide was rearranged with the loss of
nitrogen to afford the isocyanate, which was trapped in
situ with benzyl alcohol. Refluxing the mixture in
©
2018 Wiley Periodicals, Inc.

R. Kocak, A. Dastan, and N. Saracoglu
Vol 000
EXPERIMENTAL SECTION
All reactions were carried out under nitrogen and
1
monitored by TLC and/or H-NMR spectroscopy.
All solvents were dried and distilled before use.
Column chromatography was performed on silica gel
(
(
60 mesh, Merck) or activated neutral aluminum oxide
Sigma Aldrich). TLC was carried out on silica gel 60
HF254 aluminum plates (Fluka). Melting points are
1
13
uncorrected. The H-NMR and C-NMR spectra were
recorded on 400 M Hz NMR spectrometers. Apparent
splitting is given in all cases in ppm and coupling
constants J in Hz. All new compounds gave satisfactory
HRMS. All substances reported in this paper are in their
racemic forms.
Figure 1. Structures of dihydroxy-2-aminotetralin (1), dopamine (2), and
some heterocyclic isosteres 3–5.
and 12b via a ring contraction process with 20 equivalents
of zinc dust in refluxing acetic acid according to the
Boger procedure, which is a highly reliable synthetic
approach [30–32]. Furthermore, an alternative pathway
including pyridazine-to-pyrrole ring contraction and
deprotection steps starting from pyridazine 9a/9b afforded
the desired products 12a/12b.
Benzyl cyclohex-3-en-1-ylcarbamate (7). 3-Cyclohexene-
1-carboxylic acid (6) (1.0 g, 7.9 mmol) was added to a
solution of benzene (90 mL), triethylamine (NEt )
3
(963 mg, 9.5 mmol), and diphenylphosphoryl azide
(DPPA) (2.62 g, 9.5 mmol). The mixture was vigorously
stirred at room temperature for 1 day. Benzyl alcohol
(13.34 g, 123.5 mmol) was added to the reaction medium.
CONCLUSION
After refluxing for 2 days, the reaction mixture was cooled
room temperature, and the solvent was evaporated under
reduced pressure. The crude reaction mixture was purified
by column chromatography on silica gel (EtOAc/n-hexane
(1:1), then EtOAc). The obtained solid was recrystallized
We present the fast, efficient preparation of pyridazine
and pyrrole analogues of 2-aminotetralin. New
heterocyclic analogues may be candidates for the
development of dopaminergic agents. Further work is
focusing on the enantioselective synthesis of these
pyridazine and pyrrole analogues and evaluation of their
biological activity.
from CH
Cl /n-hexane (9:1) to give 7. Yield: 76%; white
2
2
1
crystals; m.p. = 64–65°C. H-NMR (400 MHz, CDCl
):
3
δ = 7.38–7.28 (m, 5H), 5.68 (bd, A part of AB system,
J = 10.0 Hz, 1H), 5.59 (bd, B part of AB system,
Scheme 1. Synthesis of pyridazine 11 and pyrrole 12 as analogues of 2-aminotetralin.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Pyridazine and Pyrrole Analogues of 2-Aminotetrali
J = 10.0 Hz, 1H), 5.10 (s, 2H), 4.81 (bs, 1H, NH), 3.92–3.80
157.8, 156.3, 156.1, 155.7, 148.4, 137.0, 136.9, 136.4,
136.2, 135.1, 128.5 (2C), 128.1 (2C), 125.1, 125.0,
123.6, 123.6, 66.7, 45.7, 33.4, 27.6, 25.0. HRMS (Q-
(
1
m, 1H), 2.40 (d, J = 17.2 Hz, 1H), 2.22–2.04 (m, 2H),
1
3
.94–1.80 (m, 2H), 1.63–1.51 (m, 1H).
C-NMR
+
(
100 MHz, CDCl ): δ = 155.9, 136.8, 128.6, 128.3, 128.2,
TOF): m/z [M + H] calcd for C H N O : 438.1930,
3
26 23 5 2
1
27.1, 124.4, 66.7, 46.3, 32.1, 28.4, 23.5. HRMS
found: 438.1923.
3,6-Di(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (10b).
+
(Q-TOF): m/z [M + H] calcd for C H NO : 232.1338,
1
4
17
2
2
9
found: 232.1324.
Yield: 92%; orange solid; m.p. = 196–197 (lit mp 191–
1
Dimethyl
6-(((benzyloxy)carbonyl)amino)-5,6,7,8-
(9a).
193°C). H-NMR (400 MHz, CDCl ): δ = 8.59 (bs, 2H,
3
tetrahydrophthalazine-1,4-dicarboxylate
cyclohex-3-en-1-ylcarbamate (7) (500 mg, 2.16 mmol)
and dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate (8a)
Benzyl
NH) 8.57 (d, J = 4.9 Hz, 2H), 8.05 (d, J = 7.7 Hz, 2H),
7.75 (dt, J = 7.7 Hz, J = 1.8 Hz, 2H), 7.34 (ddd,
J = 7.7 Hz, J = 4.9 Hz, J = 1.2 Hz, 2H). C-NMR
(100 MHz, CDCl ): δ = 148.4, 147.5, 146.6, 136.7,
124.9, 121.3.
1
3
(471 mg, 2.38 mmol) were dissolved in 25 mL of
3
CH Cl The mixture was stirred at room temperature for
2
2.
2
days. Then [bis(trifluoroacetoxy)iodo]benzene (PIFA)
General procedure for hydrogenation of carbamat 9a and
(1.12 g, 2.59 mmol) was added and the mixture stirred
9b.
Carbamat 9 (1.0 mmol) was dissolved in MeOH
for an additional 6 h at the same temperature. At the end
of the reaction, the solvent was evaporated under reduced
pressure. The crude reaction mixture was purified by
column chromatography on silica gel (n-hexane, then
EtOAc). The obtained solid was recrystallized from
CH Cl /n-hexane (9:1) to give 9a. Yield: 68%; white
(20 mL) and 10% Pd/C was added. The mixture was
stirred under H2 atmosphere for 20 h. The Pd/C was
removed by filtration, and the solvent was evaporated.
Chromatography (SiO , EtOAc/MeOH (20:1)) afforded
2
11 as solid. The obtained solid was crystallized from
MeOH/diethyl ether (9:1).
2
2
1
crystals; m.p. = 121–122°C. H-NMR (400 MHz,
Dimethyl
6-amino-5,6,7,8-tetrahydrophthalazine-1,4-
CDCl ): δ = 7.39–7.29 (m, 5H), 5.10 (s, 2H), 4.97 (bd,
dicarboxylate (11a).
Yield: 62%; green crystals; m.
3
1
J = 6.1 Hz 1H), 4.04–4.01 (m, 7H), 3.38 (dd, A part of
AB system, J = 18.5 Hz, J = 5.0 Hz, 1H), 3.20 (dt,
J = 19.3 Hz, J = 5.3 Hz, 1H), 3.14–3.03 (m, 1H), 2.90
p. = 144–145°C. H-NMR (400 MHz, MeOD-d4):
δ = 5.00 (bs, 2H), 4.06 (s, 3H), 4.05 (s, 3H), 3.89–
3.57 (m, 3H), 3.24–3.11 (m, 2H), 2.41–2.32 (m, 1H),
1
3
(
2
dd, B part of AB system, J = 18.5 Hz, J = 8.6 Hz, 1H),
2.01–1.86 (m, 1H). C-NMR (100 MHz, MeOD-d4):
δ = 165.9, 165.8, 153.8, 153.4, 139.6, 137.8, 53.9,
53.8, 46.7, 31.0, 26.0, 25.3. HRMS (Q-TOF): m/z
1
3
.22–2.11 (m, 1H), 1.85–1.71 (m, 1H).
C-NMR
(
100 MHz, CDCl ): δ = 165.1, 165.0, 155.7, 152.9,
3
+
1
5
52.5, 137.5, 136.8, 136.3, 128.7, 128.3, 128.2, 67.0,
[M + H] calcd for C H N O : 266.1141, found:
12 15 3 4
3.4, 53.35, 45.1, 32.4, 26.9, 24.3. HRMS (Q-TOF): m/z
266.1127.
+
[M + H] calcd for C H N O : 400.1509, found:
1,4-Di(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-6-amine
2
0 21 3 6
4
00.1506.
(11b). Yield: 70%; green crystals; m.p. = 219–220°C.
1
H-NMR (400 MHz, MeOD-d ): δ =8.74 (d, J = 4.9 Hz,
Reaction of benzyl cyclohex-3-en-1-ylcarbamate (7) with
,6-di(2-pyridyl)-1,2,4,5-tetrazine (8b). Benzyl cyclohex-3-
4
3
2H), 8.05 (t, J = 7.7 Hz, 2H), 7.88 (ddd, J = 7.8 Hz,
J = 4.2 Hz, J = 0.7 Hz, 2H), 7.56 (dd, J = 7.5 Hz,
J = 4.9 Hz, 2H), 4.87 (bs, 2H), 3.20–2.95 (m, 4H), 2.78
(dd, J = 17.9 Hz, J = 9.2 Hz, 1H), 2.10–2.00 (m, 1H),
en-1-ylcarbamate (7) (500 mg, 2.16 mmol) and 3,6-di(2-
pyridyl)-1,2,4,5-tetrazine (8b) (1.02 mg, 4.32 mmol) were
dissolved in 25 mL CH CN The reaction was warmed at
reflux for 3 days and the solvent was evaporated under
reduced pressure. The crude reaction mixture was
purified by column chromatography on silica gel
3
.
13
1.67–1.54 (m, 1H). C-NMR (100 MHz, MeOD-d ):
4
δ = 160.4, 160.0, 156.7, 156.67, 149.9, 149.87, 138.9,
138.8, 138.78, 138.3, 126.1 (2C), 125.4 (2C), 46.7, 36.4,
+
(EtOAc). 10b was obtained in the first fraction and 9b
31.2, 26.6. HRMS (Q-TOF): m/z [M + H] calcd for
was obtained in the second fraction. Also, 9a was
recrystallized from CH Cl /n-hexane (9:1).
C H N : 304.1562, found: 304.1556.
18 17 5
2
2
General procedure of ring contraction of pyridazines to
pyrroles.
Benzyl (1,4-di(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-6-
yl)carbamate (9b).
Zinc dust (25.04 mmol) was added to a
Yield: 92%; brown crystals; m.
p. = 75–76°C. H-NMR (400 MHz, CDCl ): δ = 8.67
solution of pyridazine 11 (1.25 mmol) in 10 mL of
glacial acetic acid and the reaction was stirred at room
temperature for overnight. The reaction mixture was
filtered through Celite, the filtrate was neutralized with
1
3
(
2
(
dd, J = 9.1 Hz, J = 4.8 Hz, 2H), 7.99 (t, J = 8.4 Hz,
H), 7.85 (t, J = 7.7 Hz, 2H), 7.38–7.27 (m, 7H), 5.08
bd, J = 6.8 Hz 1H)), 5.05 (s, 2H), 4.09–3.93 (m, 1H),
the addition of saturated aqueous NaHCO , and extracted
3
3
1
.32 (dd, A part of AB system, J = 18.3 Hz, J = 4.8 Hz,
H), 3.25–3.15 (m, 2H), 3.08 (dd, B part of AB system,
with EtOAc (2 × 25). The combined organic layer was
dried over Na SO4 and evaporated under vacuo. The
2
J = 18.3 Hz, J = 8.3 Hz, 1H), 2.14–2.03 (m, 1H), 1.81–
obtained solid was crystallized from MeOH/diethyl ether
(9:1) to give 12.
13
1
.65 (m, 1H). C NMR (100 MHz, CDCl ): δ = 158.2,
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Kocak, A. Dastan, and N. Saracoglu
Vol 000
Dimethyl
dicarboxylate (12a).
p. = 264–265°C. H-NMR (400 MHz, MeOD-d4):
δ = 4.92 (bs, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.59–3.50
5-amino-4,5,6,7-tetrahydro-2H-isoindole-1,3-
1.25 mmol) in 10 mL of glacial acetic acid, and the
reaction was stirred at room temperature for overnight.
The reaction mixture was filtered through Celite, the
filtrate was neutralized with the addition of saturated
Yield: 60%; white crystals; m.
1
(m, 1H), 3.40 (dd, J = 16.6 Hz, J = 5.0 Hz, 1H), 3.11
aqueous NaHCO , and extracted with EtOAc (2 × 25).
3
(
2
dt, J = 17.2 Hz, J = 4.8 Hz, 1H), 2.89–2.72 (m, 2H),
The combined organic layer was dried over Na SO and
2
4
1
3
.25–2.16 (m, 1H), 1.92–1.80 (m, 1H).
C-NMR
evaporated under vacuo. Chromatography (AlO , EtOAc)
3
(
100 MHz, MeOD-d ): δ = 162.5, 162.4, 127.1, 124.9,
4
afforded as a green solid. The obtained solid was
1
22.5, 122.4, 52.1, 52.06, 48.9, 28.8, 28.2, 21.7. HRMS
crystallized from MeOH/diethyl ether (9:1) to give (13b).
Yield: 67%; green crystals; m.p. = 186–188°C. H-NMR
+
1
(Q-TOF): m/z [M + H] calcd for C H N O : 253.1188,
1
2 16 2 4
found: 253.1179.
(
400 MHz, CDCl ): δ = 10.54 (bs, 1H, NH), 8.56 (d,
3
1
,3-Di(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-5-amine
J = 4.5 Hz, 2H), 7.68–7.61 (m, 2H), 7.48–7.28 (m, 7H),
.05 (dd, J = 7.2 Hz, J = 5.0 Hz, 2H), 5.11 (s, 2H), 4.99
bd, J = 8.4 Hz, 1H), 4.27–4.16 (bs, 1H), 3.28 (dd, A
(
3
12b).
Yield: 65%; light green crystals; m.p. = 301–
7
(
1
02°C. H-NMR (400 MHz, MeOD-d ): δ = 8.58 (d,
4
J = 4.8 Hz, 2H), 7.83 (t, J = 7.8 Hz, 2H), 7.63 (dd,
J = 8.0 Hz, J = 4.6 Hz, 2H), 7.21 (t, J = 5.7 Hz, 2H),
part of AB system, J = 15.6 Hz, J = 5.2 Hz, 1H), 2.99 (t,
J = 6.3 Hz, 2H), 2.81 (dd, B part of AB system,
J = 15.6 Hz, J = 6.3 Hz, 1H), 2.15–1.90 (m, 2H). C-
NMR (100 MHz, CDCl ): δ = 156.0, 150.5, 150.4,
1
4.89 (bs, 3H), 3.67–3.58 (m, 1H), 3.47 (dd, J = 15.6 Hz,
13
J = 5.0 Hz, 1H), 3.18 (dt, J = 16.5 Hz, J = 5.0 Hz, 1H),
3
3.10–2.99 (m, 1H), 2.95 (dd, J = 15.6 Hz, J = 9.3 Hz,
49.5, 136.7, 136.4, 128.6 (2C), 128.23, 128.20 (2C),
27.7, 127.2, 120.42, 120.35, 119.8, 119.3, 119.27,
1
3
1H), 2.34–2.25 (m, 1H), 2.04–1.94 (m, 1H). C-NMR
1
1
(100 MHz, MeOD-d ): δ = 151.7 (2C), 150.4, 150.3,
4
18.7, 66.7, 46.9, 31.3, 28.7, 21.5. HRMS (Q-TOF): m/z
1
1
38.1(2C), 128.6, 128.4, 121.9, 121.86, 121.0, 120.8,
+
[M + H] calcd for C H N O : 425.1978, found:
26 24 4 2
20.6, 118.7, 49.4, 30.3, 28.9, 22.8. HRMS (Q-TOF):
4
25.1969.
+
m/z [M + H] calcd for C H N : 291.1610, found:
1
8 18 4
Hydrogenation of carbamates 13a and 13b. Carbamat
3 (1.0 mmol) was dissolved in MeOH (20 mL) and 10%
2
91.1602.
1
Dimethyl 5-(((benzyloxy)carbonyl)amino)-4,5,6,7-tetrahydro-
Pd/C was added. The mixture was stirred under H2
2H-isoindole-1,3-dicarboxylate (13a).
Zinc dust (1.64 g,
atmosphere for 20 h. The Pd/C was removed by filtration,
and the solvent was evaporated. Chromatography (SiO2,
25.04 mmol) was added to a solution of pyridazine 9a
(500 mg, 1.25 mmol) in 10 mL of glacial acetic acid,
EtOAc/MeOH (20:1)) afforded 12 as solid. The obtained
and the reaction was stirred at room temperature for
overnight. The reaction mixture was filtered through
Celite, the filtrate was neutralized with the addition of
solid was crystallized from MeOH/diethyl ether (9:1).
Dimethyl 5-amino-4,5,6,7-tetrahydro-2H-isoindole-1,3-
dicarboxylate (12a) was obtained in 63% yield. 1,3-
Di(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-5-amine
saturated aqueous NaHCO , and extracted with EtOAc
3
(2 × 25). The combined organic layer was dried over
(
12b) was obtained in 68% yield.
Na SO4 and evaporated under vacuo. Chromatography
2
(
SiO , EtOAc) afforded as a white solid. The obtained
2
solid was recrystallized from MeOH/diethyl ether (1:1)
to give 13a. Yield: 64%; white crystals; m.p. = 200–
Acknowledgments. This work was supported by Research Fund
of Atatürk University, project number: 2016/145. The authors are
grateful to the Research Fund of Atatürk University for financial
support.
1
2
01°C. H-NMR (400 MHz, CDCl ): δ = 9.56 (bs, 1H,
3
NH), 7.38–7.28 (m, 5H), 5.10 (s, 2H), 4.90 (bd,
J = 8.0 Hz 1H), 4.10–4.00 (m, 1H), 3.87 (s, 3H), 3.86
(s, 3H), 3.18 (dd, A part of AB system, J = 16.9 Hz,
J = 5.1 Hz, 1H), 2.93 (dt, A part of AB system,
J = 17.7 Hz, J = 5.8 Hz, 1H), 2.83 (dt, B part of AB
system, J = 17.7 Hz, J = 6.7 Hz, 1H), 2.66 (dd, B
part of AB system, J = 16.9 Hz, J = 7.6 Hz, 1H),
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SUPPORTING INFORMATION
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Additional Supporting Information may be found online
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet