Synthesis of Pyridazine Derivatives via Aza-Diels-Alder Reactions of 1,2,3-Triazine Derivatives and 1-Propynylamines

Article abstract of DOI:10.1021/acs.joc.1c00851

A highly regioselective method was developed for the preparation of pyridazine derivatives via the aza-Diels-Alder reaction of 1,2,3-triazines with 1-propynylamines under neutral conditions. This methodology allowed direct access to a wide range of 6-aryl-pyridazin-3-amines in high yields with good functional group compatibility. Key features of this strategy included a broad substrate scope and simple, metal-free, and neutral reaction conditions.

Full text of DOI:10.1021/acs.joc.1c00851

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Synthesis of Pyridazine Derivatives via Aza-Diels−Alder Reactions of
1,2,3-Triazine Derivatives and 1‑Propynylamines
Takayuki Kodama, Ikuo Sasaki, and Hideyuki Sugimura*
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ABSTRACT: A highly regioselective method was developed for the
preparation of pyridazine derivatives via the aza-Diels−Alder reaction of
1,2,3-triazines with 1-propynylamines under neutral conditions. This
methodology allowed direct access to a wide range of 6-aryl-pyridazin-3-
amines in high yields with good functional group compatibility. Key features
of this strategy included a broad substrate scope and simple, metal-free, and
neutral reaction conditions.
annulation of hydrazines with 1,4-bifunctional compounds,10
[4 + 2] annulation of ketene N,S-acetals and N-tosylhydra-
zones,11 formal [3 + 3] cycloaddition of cyclopropene
derivatives and hydrazones,12 [3 + 3] annulation of aldehyde
hydrazones and α,β-unsaturated nitrile,13 catalytic three-
component annulations in one-step procedures,14 and multi-
step synthesis involving a diaza-Wittig reaction.15 Despite these
achievements, a more efficient metal-free synthesis of
pyridazines under neutral conditions is highly desirable to
expand the library of substituted pyridazines.
Inverse electron-demand Diels−Alder reactions of electron-
deficient heterocyclic azadienes provide a powerful strategy for
the preparation of highly substituted heteroaromatic systems
that are not easily accessible by conventional methods.16
Pyridazines can be produced by introducing 1,2,3-triazines into
inverse electron-demand aza-Diels−Alder reactions. Electron-
deficient triazines are used as dienes, while alkynes with
electron-donating substituents are used as dienophiles. Cyclo-
addition initiates a cascade of reactions including the
elimination of a nitrogen molecule (path a) or nitrile (path
b) from the cycloadduct as a result of the retro-Diels−Alder
reaction (Scheme 1). The final product of this transformation
is a pyridine or pyridazine. Pioneering studies on the
cycloaddition reactions of relatively simple 1,2,3-triazines
were reported by Igeta et al.17 Recently, Boger et al. described
the role of substituents in modulating the reactivity and
regioselectivity (C5/N2 vs C4/N1) in cycloaddition reac-
tions.18 For instance, the cycloaddition of 5-substituted 1,2,3-
triazines proceeded via the C4/N1 mode to exclusively provide
INTRODUCTION
■
The synthesis of nitrogen-containing heterocycles is important
in organic chemistry. Among these, pyridazines are of
particular interest because these are frequently found in
natural products and pharmacologically active compounds.1,2
Pyridazine derivatives such as pyridazinomycin (1), an
antifungal antibiotic isolated from Streptomyces violacoeniger,3
and phthalazinone meroterpenoid azamerone (2), isolated
from the marine sediment-derived bacterium Streptomyces sp.
CNQ-766, have been discovered as natural products (Figure
1).4 Additionally, various synthetic pyridazine derivatives have
Figure 1. Naturally occurring pyridazines.
been used in agrochemical, pharmaceutical, and other
applications.2b Examples of important synthetic pyridazine
derivatives include minaprine (3), its structurally related
pyridazines 4−6,5 sulfamethoxypyridazine (7),6 endixaprine
(8),7 and pyridate (9),8 which exhibit antidepressant,
dopaminergic, MAO-A inhibitory, anticonvulsant, antibacterial,
sedative hypnotic, and herbicidal activities, respectively (Figure
2).
A wide array of interesting applications has facilitated the
development of synthetic methods for pyridazines with
different substituents.2a Therefore, extensive efforts have
been directed toward developing new strategies for the
construction of these nitrogen heterocycles including [4 + 2]
annulation of alkoxyallenes with 1,2-diaza-1,3-dienes,9 [4 + 2]
Received: April 13, 2021
Published: June 16, 2021
https://doi.org/10.1021/acs.joc.1c00851
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8926−8932
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Figure 2. Biologically important synthetic pyridazines.
acid-catalyzed reaction of 4-aryl-2,2-dimethoxy-3-butenoates
with 2 equiv of trimethylsilyl azide.19 Further efforts were
directed toward the application of 6-aryl-1,2,3-triazine-4-
carboxylates in the above cycloaddition reaction. Herein, we
describe our results in developing a strategy for the synthesis of
6-aryl-4-methylpyridazin-3-amine derivatives via the aza-
Diels−Alder reaction of 6-aryl-1,2,3-triazin-4-carboxylates
with 1-propynylamine derivatives.
Scheme 1. Aza-Diels−Alder Cycloaddition of 1,2,3-Triazine
with 1-Alkynyl-1-amines
RESULTS AND DISCUSSION
■
We began our research by taking methyl 6-phenyl-1,2,3-triazin-
4-carboxylate (10a) and N,N-dibenzyl-1-propyn-1-amine (11)
in CHCl3 at room temperature (Table 1, entry 1). Under these
conditions, pyridazine 13 was obtained in 50% yield, together
with 37% yield of pyridine 12a, with moderate regioselectivity.
Their structures and regioselectivity were confirmed by using
NOESY NMR data (see the SI). When the reaction was
performed using different solvents such as DCM, benzene, and
Et2O at room temperature (Table 1, entries 2−4), a similar
selectivity was observed. Interestingly, increasing the reaction
temperature to reflux in each solvent slightly improved the
the pyridine products,18a18c18d whereas the reactions of 4-
substituted or 4,6-disubstituted 1,2,3-triazines predominantly
afforded the pyrazine products, which were derived from
cycloaddition across C5/N2.18b
Recently, we developed a novel strategy for the synthesis of
6-aryl-1,2,3-triazin-4-carboxylates via the cyclization of 4-aryl-
2,4-diazido-2-butenoates, which were derived from the Lewis-
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
R
solvent
CHCl3
ClCH2CH2Cl
benzene
Et2O
temp (°C)
time (h)
12
13
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
rt
rt
rt
rt
60
83
80
66
0
−20
rt
60
101
1.5
3.0
3.0
3.0
1.0
1.0
2.0
1.0
4.0
7.0
3.0
1.0
1.0
37
32
38
23
23
31
30
22
45
59
50
53
56
50
55
59
64
68
48
38
86
91
95
CHCl3
ClCH2CH2Cl
benzene
THF
CHCl3
CHCl3
CHCl3
CHCl3
1,4-dioxane
9
10c
11
12
13
10
d
d
a
b
c
Reactions of 10 (0.2 mmol) and 11 (0.6 mmol) were carried out in 5 mL of solvent under an Ar atmosphere. Isolated yield. Reaction was
d
carried out at −20 °C for 7 h, and then stirring was continued at room temperature for 19 h. Not detected.
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Scheme 2. Aza-Diels−Alder Reaction of 1,2,3-Triazine 10 with 1-Propyn-1-amine
Table 2. Substrate Scope
yield of pyridazine 13 (Table 1, entries 5−8). In contrast,
decreasing the temperature of the reaction in the CHCl3
solvent to −20 °C led to an increase in the yield of pyridine
12a (Table 1, entry 10). Next, 1,2,3-triazine 10b was
examined, where the sterically hindered t-Bu group was
present in the ester moiety. When the reaction of 10b and
11 was performed in CHCl3 at room temperature, significant
improvement in the yield of 12b was observed (Table 1, entry
11). Accordingly, increasing the reaction temperature to the
refluxing temperature led to further improvement, exclusively
affording pyridazine 12b in 91% yield. Finally, it was
determined that 1,4-dioxane as the solvent at a refluxing
temperature (101 °C) was the most suitable condition to
generate pyridazine 12b in very high yield (95%, Table 1, entry
13).
Based on these results, the cycloaddition reaction of triazine
10a showed poor regioselectivity. Pyridazine 13a was
preferentially produced at higher reaction temperatures,
whereas the formation of pyridine 12a was preferred at
lower temperatures. In contrast, the cycloaddition reaction of
triazine 10b proceeded in a highly regioselective manner
through the C5/N2 mode (path b) to afford pyridazine 13,
showing complete regioselectivity at high temperatures,
probably due to the significant steric hindrance between R
(= t-Bu) and Bn2N moieties in the cycloaddition intermediate
A generated via path a (Scheme 2).
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With the identification of the optimal conditions, we
embarked to explore the present method with more substrates
(Table 2). Aryl substituents bearing either electron-rich or
electron-deficient groups at the para or meta positions were all
tolerated, affording the desired products in good to high yields
(13b−13d and 13f−13 k). Based on these results, the
electronic characteristics of the substituents on the phenyl
ring did not significantly affect this cycloaddition reaction.
Nevertheless, 2-chloro-substituted 1,2,3-triazines 10e afforded
the desired pyridazine 13e in 65% yield, indicating that the
steric effect slightly influences the reaction. The fused aryl and
heteroaryl groups, including the naphthyl, thienyl, and pyridyl
groups, were also suitable, and the desired pyridazines were
readily obtained (13l−13n, 73−94%). Overall, the present
inverse electron-demand aza-Diels−Alder reaction could
tolerate structurally diverse substrates with different electronic
characteristics, affording a powerful and practical approach to
synthesizing 6-aryl-pyridazin-3-amine scaffolds.
be performed on a scale of hundreds of milligrams, and further
transformations of the cycloadducts were feasible, showing the
applicability of the reaction for the construction of biologically
important pyridazine derivatives.
EXPERIMENTAL SECTION
■
All experiments were performed in well-dried glassware fitted with
rubber septa under an argon atmosphere. Solvents and commercially
available chemicals were purified by standard methods or used as
purchased. Heated reactions were allowed to run using an oil bath on
a hot plate equipped with a temperature probe. Analytical TLC was
performed on silica gel plates 60 F254 (Merck Co.). Flash column
chromatography was performed on silica gel 60A (Kanto Co.).
Melting points (Mp) were determined in open capillaries and are
uncorrected. IR spectra were recorded on a JASCO FTIR-4100A
spectrometer as thin films. NMR spectra were recorded on a JEOL
JNM-ECX-500II spectrometer in CDCl3 with TMS as the internal
standard. High-resolution ESI and APCI mass spectra were recorded
with an Orbitrap analyzer in positive or negative ion mode by using an
Exactive mass spectrometer at the Global Facility Center, Creative
Research Institution (Hokkaido University). 1,2,3-Triazines used in
this study were prepared following our previous work.19 1-Propynyl-
amines were prepared according to the literature20 and distilled
immediately prior to use.
To prove the practicality of this cycloaddition reaction, the
application of the prepared compounds to the synthesis of the
known anticonvulsant pyridazine 6 was demonstrated (Scheme
3). The aza-Diels−Alder reaction of 1,2,3-triazine 10b with
Reaction of 1,2,3-Triazine 10a with 11 (Table 1, Entry 19).
To a solution of 10a19 (40.5 mg, 0.19 mmol) in 5 mL of dry CHCl3
was added freshly distilled 1120 (0.6 mmol) at −20 °C, and the
mixture was stirred for 7 h at the same temperature and then for 19 h
at room temperature. After the solvent was evaporated under vacuum,
the residue was purified by column chromatography (hexane:EtOAc =
2:1) to give pyridine derivative 12a (46.9 mg, 59%) as a red-brown
solid along with 36% yield of 13a.
Scheme 3. Application on the Synthesis of Anticonvulsant
Pyridazine 6
Methyl 6-(Dibenzylamino)-5-methyl-4-phenylpicolinate (12a).
Mp: 106−108 °C; IR (KBr): 2924, 1717, 1586, 1535, 1494, 1438,
1
1390, 1264, 1111, 931, 795, 750, 693 cm−1; H NMR (500 MHz,
CDCl3): δ 7.80 (s, 1H), 7.23−7.34 (m, 15H), 4.71 (s, 4H), 4.00 (s,
3H), 2.41 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.2,
163.7, 145.6, 137.7, 131.0, 128.7, 128.1, 127.7, 127.4, 53.6, 52.9, 19.9;
HRMS (ESI) m/z [M + H]+ calcd for C28H27O2N2, 423.2067; found,
423.2063.
General Procedure for Synthesis of Pyridazines 13. To a
solution of the corresponding 1,2,3-triazine derivative (0.20 mmol, 1
equiv) in 5 mL of dry 1,4-dioxane was added freshly distilled 1120 (0.6
mmol, 3 equiv), and the mixture was stirred for 1 h under reflux. After
the reaction mixture was cooled to room temperature, the solvent was
evaporated under vacuum. The residue was purified by column
chromatography (hexane:EtOAc = 9:1) to give the corresponding
product 13.
N,N-Dibenzyl-4-methyl-6-phenylpyridazin-3-amine (13a). Start-
ing from 10b19 (49.9 mg, 0.19 mmol), silica-gel chromatography
(hexane:EtOAc = 9:1) gave 13a (67.5 mg, 95%) as a white solid. Mp:
124−126 °C; IR (KBr): 3029, 1593, 1535, 1494, 1453, 1409, 1295,
1243, 1112, 903, 743, 697, 661 cm−1; 1H NMR (500 MHz, CDCl3): δ
8.02 (d, J = 6.9 Hz, 2H), 7.56 (s, 1H, Ar), 7.47 (t, J = 7.5 Hz, 2H),
7.42−7.44 (m, 1H), 7.22−7.31 (m, 10H), 4.54 (s, 4H), 2.46 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 162.6, 154.5, 138.3, 136.6,
131.2, 129.2, 128.9, 128.5, 128.4, 127.2, 127.1, 126.6, 54.4, 19.1;
HRMS (ESI) m/z [M + H]+ calcd for C25H24N3, 366.1965; found,
366.1958.
N,N-di-p-methoxybenzyl-1-propyn-1-amine (11′) afforded
pyridazine 14 in 80% yield. Thus, the removal of the PMB
group from 14 was achieved through hydrolysis by CF3CO2H,
affording amine derivative 15. Attempts to introduce a 2-
hydroxyethyl substituent to the 4-amino group on 15 with
several alkylating reagents such as 2-hydroxyethyl bromide,
ethylene oxide, and ethyl bromoacetate were unsuccessful.
Reductive amination using aldehyde, TBSOCH2CHO, and
NaBH(OAc)3 was also attempted, but the desired product
could not be obtained. Finally, acylation using 2-(pivaloyloxy)-
acetic acid and EDCI provided amide 16, which was reduced
using LiAlH4, leading to the desired product 6.
N,N-Dibenzyl-4-methyl-6-(p-tolyl)pyridazin-3-amine (13b).
Starting from t-butyl 6-(p-tolyl)-1,2,3-triazin-4-carboxylate (51.1 mg,
0.19 mmol), silica-gel chromatography (hexane:EtOAc = 9:1) gave
13b (64.5 mg, 90%) as an orange-colored solid. Mp: 107−110 °C; IR
(KBr): 2917, 1745, 1494, 1453, 1415, 1359, 1238, 934, 822, 752, 693
CONCLUSIONS
■
In summary, a highly regioselective aza-Diels−Alder reaction
of 1,2,3-triazines 10 with 1-propynylamines 11 is achieved
under neutral conditions, thereby affording a synthetic route to
a wide range of 6-aryl-4-amino-pyridazines 13 in high yields
with good functional group compatibility. The reaction could
1
cm−1; H NMR (500 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz), 7.54 (s,
1H), 7.23−7.33 (m, 12H), 4.53 (s, 4H), 2.45 (s, 3H), 2.41 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 162.4, 154.5, 139.3, 138.4,
133.7, 131.3, 129.6, 128.5, 128.4, 127.2, 126.9, 126.4, 54.4, 21.4, 19.1;
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HRMS (ESI) m/z [M + H]+ calcd for C26H26N3, 380.2121; found,
380.2117.
129.6, 128.5, 128.3, 127.3, 127.1, 125.0, 123.2, 54.3, 19.3; HRMS
(ESI) m/z [M + H]+ calcd for C25H23BrN3, 444.1070; found,
444.1066.
N,N-Dibenzyl-4-methyl-6-(4-methoxyphenyl)pyridazin-3-amine
(13c). Starting from t-butyl 6-(p-methoxyphenyl)-1,2,3-triazin-4-
carboxylate (65.8 mg, 0.23 mmol), silica-gel chromatography
(hexane:EtOAc = from 9:1 to 2:1) gave 13c (86.2 mg, 95%) as
orange oil. IR (KBr): 2934, 1607, 1512, 1494, 1453, 1411, 1239,
1181, 1027, 840, 744, 699 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.98
(d, J = 9.2 Hz, 2H), 7.50 (s, 1H), 7.27−7.32 (m, 7H), 7.20−7.25 (m,
3H), 6.99 (d, J = 8.6 Hz, 2H), 4.51 (s, 4H), 3.85 (s, 3H), 2.44 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.2, 160.7, 154.3,
138.4, 131.5, 129.1, 128.5, 128.4, 127.9, 127.2, 126.6, 114.3, 55.4,
54.5, 19.0; HRMS (ESI) m/z [M + H]+ calcd for C26H26N3O,
396.2070; found, 396.2067.
N,N-Dibenzyl-4-methyl-6-(4-trifluoromethylphenyl)pyridazin-3-
amine (13i). Starting from t-butyl 6-(4-trifluoromethylphenyl)-1,2,3-
triazin-4-carboxylate (77.4 mg, 0.24 mmol), silica-gel chromatography
(hexane:EtOAc = 9:1) gave 13i (95.0 mg, 92%) as a yellow solid. Mp:
129−132 °C; IR (KBr): 3079, 1746, 1617, 1536, 1494, 1454, 1319,
1130, 1069, 855, 741, 700 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.15
(d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.30−7.31
(m, 8H), 7.24−7.26 (m, 2H), 4.60 (s, 4H), 2.49 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 162.8, 152.9, 140.0, 138.1, 131.0 (q,
2JC‑F = 32.4 Hz), 130.9, 128.6, 128.3, 127.3, 126.7, 125.8, 124.3 (q,
1JC‑F = 272.3 Hz), 54.2, 19.4; HRMS (ESI) m/z [M + H]+ calcd for
N,N-Dibenzyl-4-methyl-6-(4-fluorophenyl)pyridazin-3-amine
(13d). Starting from t-butyl 6-(p-fluorophenyl)-1,2,3-triazin-4-carbox-
ylate (61.6 mg, 0.22 mmol), silica-gel chromatography (hexane:E-
tOAc = 9:1) gave 13d (71.6 mg, 83%) as a yellow solid. Mp: 149−
151 °C; IR (KBr): 3028, 1600, 1510, 1406, 1220, 1161, 1024, 957,
C26H23F3N3, 434.1839; found, 434.1834.
N,N-Dibenzyl-4-methyl-6-(4-nitrophenyl)pyridazin-3-amine
(13j). Starting from t-butyl 6-(4-nitrophenyl)-1,2,3-triazin-4-carbox-
ylate (56.3 mg, 0.19 mmol), silica-gel chromatography (hexane:E-
tOAc = 9:1) gave 13j (73.5 mg, 94%) as a yellow solid. Mp: 125−127
°C; IR (KBr): 3029, 1649, 1597, 1511, 1400, 1346, 1110, 859, 748,
1
849, 744, 696 cm−1; H NMR (500 MHz, CDCl3): δ 8.02 (dd, J =
1
698, 640 cm−1; H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 9.2 Hz,
5.7, 8.6 Hz, 2H), 7.52 (s, 1H), 7.28−7.32 (m, 8H), 7.23−7.25 (m,
2H), 7.16 (t, J = 8.6 Hz, 2H), 4.55 (s, 4H), 2.47 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 163.6 (d,1JC‑F = 274.7 Hz), 153.6, 138.2,
2H), 8.22 (d, J = 9.2 Hz, 2H), 7.62 (s, 1H), 7.16−7.31 (m, 10H),
4.64 (s, 4H), 2.51 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
162.9, 151.8, 148.2, 142.6, 137.9, 130.4, 128.6, 128.2, 127.5, 127.3,
127.1, 124.2, 54.0, 19.6; HRMS (ESI) m/z [M + H]+ calcd for
C25H23N4O2, 411.1816; found, 411.1814.
4
3
132.8 (d, JC‑F = 2.4 Hz), 131.3, 128.4 (d, JC‑F = 19.2 Hz), 127.2,
126.9, 115.9 (d, 2JC‑F = 21.6 Hz), 54.3, 19.2; HRMS (ESI) m/z [M +
H]+ calcd for C25H23FN3, 384.1871; found, 384.1866.
N,N-Dibenzyl-4-methyl-6-(2-chlorophenyl)pyridazin-3-amine
(13e). Starting from t-butyl 6-(2-chlorophenyl)-1,2,3-triazin-4-carbox-
ylate (58.7 mg, 0.20 mmol), silica-gel chromatography (hexane:E-
tOAc = 19:1) followed by preparative TLC (hexane:EtOAc = 2:1)
gave 13e (52.5 mg, 65%) as pale yellow oil. IR (KBr): 2925, 1650,
N,N-Dibenzyl-4-methyl-6-(4-cyanophenyl)pyridazin-3-amine
(13k). Starting from t-butyl 6-(4-cyanophenyl)-1,2,3-triazin-4-carbox-
ylate (56.2 mg, 0.20 mmol), silica-gel chromatography (hexane:E-
tOAc = 4:1) gave 13k (56.8 mg, 73%) as a red-brown solid. Mp:
175−178 °C; IR (KBr): 3028, 2229, 1592, 1493, 1452, 1357, 1215,
1
940, 847, 745, 696 cm−1; H NMR (500 MHz, CDCl3): δ 8.15 (d,
1
1523, 1495, 1358, 1258, 1219, 1075, 1030, 757, 742 cm−1; H NMR
2H), 7.75 (d, J = 8.6 Hz, 2H), 7.56 (s, 1H), 7.22−7.30 (m, 8H),
7.23−7.26 (m, 2H), 4.60 (s, 4H), 2.48 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 162.9, 152.2, 140.8, 138.0, 132.7, 130.6, 128.6,
128.2, 127.3, 126.9, 118.8, 112.6, 54.1, 19.5; HRMS (ESI) m/z [M +
H]+ calcd for C26H23N4, 391.1917; found, 391.1916.
(500 MHz, CDCl3): δ 7.77 (d, J = 6.9 Hz, 1H), 7.58 (s, 1H), 7.46 (d,
J = 9.2 Hz, 1H), 7.23−7.30 (m, 9H), 7.18−7.19 (m, 3H), 4.58 (s,
4H), 2.45 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.3,
154.3, 138.2, 136.3, 132.4, 131.8, 131.2, 130.2, 130.1, 129.5, 128.5,
128.4, 127.2, 54.1, 19.2; HRMS (ESI) m/z [M + H]+ calcd for
C25H23ClN3, 400.1575; found, 400.1571.
N,N-Dibenzyl-4-methyl-6-(2-naphthyl)pyridazin-3-amine (13l).
Starting from t-butyl 6-(2-naphthyl)-1,2,3-triazin-4-carboxylate (65.9
mg, 0.21 mmol), silica-gel chromatography (hexane:EtOAc = 9:1)
gave 13l (84.1 mg, 94%) as an orange-colored solid. Mp: 75−78 °C;
IR (KBr): 3028, 2245, 1649, 1529, 1414, 1027, 957, 906, 865, 829,
741 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.48 (s, 1H), 8.25 (d, J =
8.6 Hz, 1H), 7.92−7.96 (m, 2H), 7.86−7.88 (m, 1H), 7.73 (s, 1H),
7.50−7.52 (m, 2H), 7.29−7.35 (m, 8H), 7.23−7.26 (m, 1H), 4.58 (s,
4H), 2.51 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.6,
154.3, 138.3, 133.9, 133.8, 133.5, 131.2, 128.7, 128.6, 128.5, 128.4,
127.8, 127.3, 127.2, 126.7, 126.5, 125.9, 124.2, 54.4, 19.2; HRMS
(ESI) m/z [M + H]+ calcd for C29H26N3, 416.2121; found, 416.2117.
N,N-Dibenzyl-4-methyl-6-(2-thienyl)pyridazin-3-amine (13m).
Starting from t-butyl 6-(2-thienyl)-1,2,3-triazin-4-carboxylate (61.3
mg, 0.23 mmol), silica-gel chromatography (hexane:EtOAc = 9:1)
gave 13m (63.1 mg, 73%) as a yellow solid. Mp: 115−117 °C; IR
(KBr): 3028, 1589, 1520, 1494, 1454, 1413, 1342, 1238, 843, 752,
693 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.43 (s, 1H), 7.34 (d, J =
4.0 Hz, 1H), 7.31−7.32 (m, 6H), 7.25−7.28 (m, 5H), 7.05 (dd, J =
3.4, 5.2 Hz, 1H), 4.57 (s, 4H), 2.39 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 162.4, 138.2, 128.5, 128.4, 127.9, 127.2, 126.4,
125.8, 124.9, 54.4, 19.1; HRMS (ESI) m/z [M + H]+ calcd for
C23H22N3S, 372.1529; found, 372.1527.
N,N-Dibenzyl-4-methyl-6-(3-pyridyll)pyridazin-3-amine (13n).
Starting from t-butyl 6-(3-pyridyl)-1,2,3-triazin-4-carboxylate (52.3
mg, 0.20 mmol), silica-gel chromatography (hexane:EtOAc = 1:2)
gave 13m (578.8 mg, 78%) as a red-brown solid. Mp: 125−128 °C;
IR (KBr): 3029, 1591, 1493, 1452, 1407, 1357, 1272, 1215, 1114,
1028, 941, 903, 814, 746 cm−1; 1H NMR (500 MHz, CDCl3): δ 9.15
(d, J = 1.7 Hz, 1H), 8.65 (dd, J = 1.7, 4.6 Hz, 1H), 8.42 (ddd, J = 1.7,
2.3, 8.0 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 5.7, 8.0 Hz,
1H), 7.31 (s, 4H), 7.30 (d, J = 1.7 Hz, 4H), 7.24−7.26 (m, 2H), 4.58
(s, 4H), 2.48 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.8,
N,N-Dibenzyl-4-methyl-6-(3-chlorophenyl)pyridazin-3-amine
(13f). Starting from t-butyl 6-(3-chlorophenyl)-1,2,3-triazin-4-carbox-
ylate (46.0 mg, 0.16 mmol), silica-gel chromatography (hexane:E-
tOAc = 9:1) gave 13f (57.9 mg, 90%) as an orange-colored solid. Mp:
90−92 °C; IR (KBr): 3029, 1593, 1526, 1494, 1454, 1356, 1027, 953,
1
795, 736, 694 cm−1; H NMR (500 MHz, CDCl3): δ 8.04 (s, 1H),
7.90−7.92 (m, 1H), 7.53 (s, 1H), 7.39−7.42 (m, 2H), 7.28−7.31 (m,
8H), 7.23−7.26 (m, 2H), 4.57 (s, 4H), 2.47 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 162.7, 153.0, 138.4, 138.2, 135.0, 131.1, 130.2,
129.2, 128.6, 128.3, 127.3, 127.1, 126.7, 124.6, 54.2, 19.3; HRMS
(ESI) m/z [M + H]+ calcd for C25H23ClN3, 400.1575; found,
400.1572.
N,N-Dibenzyl-4-methyl-6-(4-chlorophenyl)pyridazin-3-amine
(13g). Starting from t-butyl 6-(4-chlorophenyl)-1,2,3-triazin-4-carbox-
ylate (40.0 mg, 0.14 mmol), silica-gel chromatography (hexane:E-
tOAc = 9:1) gave 13g (52.3 mg, 93%) as a yellow solid. Mp: 128−130
°C; IR (KBr): 3028, 1594, 1494, 1454, 1244, 1091, 1011, 914, 843,
1
741, 698 cm−1; H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 8.6 Hz,
2H), 7.53 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.28−7.31 (m, 8H),
7.23−7.26 (m, 2H), 4.56 (s, 4H), 2.47 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 162.6, 153.3, 138.2, 135.4, 135.1, 131.2, 129.1,
128.5, 128.3, 127.8, 127.2, 126.9, 54.3, 19.2; HRMS (ESI) m/z [M +
H]+ calcd for C25H23ClN3, 400.1575; found, 400.1569.
N,N-Dibenzyl-4-methyl-6-(3-bromophenyl)pyridazin-3-amine
(13h). Starting from t-butyl 6-(3-bromophenyl)-1,2,3-triazin-4-
carboxylate (63.2 mg, 0.19 mmol), silica-gel chromatography
(hexane:EtOAc = 9:1) gave 13h (68.8 mg, 82%) as a yellow solid.
Mp: 90−92 °C; IR (KBr): 3028, 1564, 1524, 1494, 1448, 1357, 1229,
1029, 951, 794, 733, 695 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.18
(s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.53−7.55 (m, 2H), 7.30−7.36 (m,
9H), 7.24−7.26 (m, 2H), 4.54 (s, 4H), 2.44 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 162.7, 152.9, 138.6, 138.2, 132.1, 131.0, 130.4,
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151.9, 150.2, 147.7, 138.1, 134.0, 132.4, 131.1, 128.5, 128.3, 127.3,
127.0, 123.8, 54.2, 19.3; HRMS (ESI) m/z [M + H]+ calcd for
C24H23N4, 367.1917; found, 367.1914.
MHz, CDCl3): δ 8.02 (s, 2H), 7.74 (s, 1H), 7.46−7.53 (m, 3H), 4.86
(s, 2H), 2.40 (s, 3H), 1.33 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3): δ 177.7, 153.6, 135.7, 130.1, 129.1, 127.8, 127.1, 63.4, 38.9,
27.3, 18.5; HRMS (ESI) m/z [M + Na]+ calcd for C18H21N3O3Na,
350.1475; found, 350.1472.
Preparation of N,N-Di-p-methoxybenzyl-1-propyn-1-amine
(11′). To a solution of N,N-di-p-methoxybenzylamine (12.5 g, 49
mmol) in 50 mL of dry THF was added NaH (60% in oil, 1.45 g, 60
mmol) at 0 °C, and the mixture was stirred for 30 min. Propargyl
bromide (5.5 mL, 73 mmol) was added to the reaction mixture, and
stirring was continued for 19 h at room temperature. The reaction was
quenched with water, and the mixture was evaporated under vacuum.
The residue was diluted with CH2Cl2 (30 mL) and saturated NaCl
solution (30 mL), and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The collected organic layer was dried over Na2SO4,
filtered, and evaporated under vacuum. The residue was purified by
column chromatography (hexane:EtOAc = 9:1) to give N,N-di-p-
methoxybenzyl-2-propyn-1-amine (11.3 g, 79%) as yellow oil. 1H
NMR (500 MHz, CDCl3): δ 7.31 (d, J = 6.9 Hz, 4H), 6.87 (d, J = 6.9
Hz, 4H), 3.79 (s, 6H), 3.61 (s, 4H), 3.24 (s, 2H), 2.28 (dd, J = 2.3,
4.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 158.9, 131.0,
130.3, 113.8, 78.8, 73.4, 56.8, 55.3, 40.9.
2-((4-Methyl-6-phenyl-3-pyridazinyl)amino)ethanol (6). To
a solution of LiAlH4 (12 mg, 0.32 mmol) in 0.6 mL of THF was
added THF (0.6 mL) solution of 16 (21 mg, 0.06 mmol), and the
mixture was stirred for 5 h at room temperature. The reaction was
quenched by addition of EtOAc (1 mL), and the mixture was filtered
through a celite pad, and the filtrate was washed with aqueous
NaHCO3 solution. The organic layer was dried over Na2SO4, filtered,
and evaporated under vacuum. The residue was purified by column
chromatography (EtOAc) to give the title compound 6 (6.5 mg, 42%)
as a white solid. Mp: 149−152 °C; IR (KBr): 3356, 2934, 1621, 1577,
1
1504, 1465, 1378, 1342, 1060, 778, 697 cm−1; H NMR (500 MHz,
CDCl3): δ 7.87 (d, J = 6.9 Hz, 2H), 7.34−7.40 (m, 3H), 7.34 (t, J =
7.5 Hz, 1H), 4.81 (broad, 1H), 3.87 (t, J = 4.6 Hz, 2H), 3.76−3.77
(m, 2H), 2.13 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 157.7,
152.0, 137.0, 128.9, 128.8, 126.1, 125.5, 124.8, 63.1, 45.2, 16.8;
HRMS (ESI) m/z [M + H]+ calcd for C13H16N3O, 230.1288; found,
230.1288.
To a solution of N,N-di-p-methoxybenzyl-2-propyn-1-amine (864
mg, 2.9 mmol) in 1.5 mL of DMSO was added t-BuOK (23 mg, 0.6
mmol), and the mixture was stirred for 2 h at 60 °C. The title
compound 11′ (394 mg, 46%) was obtained as yellow oil after
distillation with a Kugelrohr apparatus (175 °C, oven temperature, 3
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00851.
■
sı
1
kPa) and subjected to the cycloaddition reaction immediately. H
NMR (500 MHz, DMSO-d6): δ 7.18 (d, J = 8.6 Hz, 4H), 6.86 (d, J =
8.6 Hz, 4H), 3.80 (s, 4H), 3.70 (s, 6H), 1.67 (s, 3H).
1H and 13C NMR spectra of compounds 11′, 12a, 13a−
n, 14−16, and 6 and NOESY spectra of compounds 12a
and 13a (PDF)
Representative Synthesis of Pyridazine 14 on a ca. 1 mmol
Scale. To a solution of 10b (243 mg, 0.95 mmol) in 25 mL of dry
1,4-dioxane was added freshly distilled 11′ (589 mg, 2.0 mmol), and
the mixture was stirred for 1 h under reflux. After the reaction mixture
was cooled to room temperature, the solvent was evaporated under
vacuum. The residue was purified by column chromatography
(hexane:EtOAc = 9:1) to give the corresponding product 14 (324
mg, 80%) as yellow oil. IR (KBr): 2933, 1736, 1611, 1512, 1108,
1038, 924, 822, 764, 696, 636 cm−1; 1H NMR (500 MHz, CDCl3): δ
8.04 (d, J = 7.5 Hz, 2H), 7.56 (s, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.42
(t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.6 Hz, 4H),
4.44 (s, 2H), 3.78 (s, 6H), 2.44 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 162.7, 158.8, 154.4, 136.6, 131.4, 130.3, 129.7, 129.2,
128.9, 127.0, 126.6, 113.8, 55.3, 53.5, 19.1; HRMS (ESI) m/z [M +
Na]+ calcd for C27H27N3O2Na, 448.1996; found, 448.1991.
AUTHOR INFORMATION
Corresponding Author
■
Hideyuki Sugimura − Department of Chemistry and
Bioscience, Faculty of Science and Technology, Aoyama
Gakuin University, Sagamihara 252-5258, Japan;
orcid.org/0000-0001-9689-8094; Email: sugimura@
chem.aoyama.ac.jp
Authors
4-Methyl-6-phenylpyridazin-3-amine (15). To 14 (314 mg,
0.74 mmol) was added 2.0 mL of CF3CO2H, and the mixture was
stirred for 1 h at 50 °C. After being cooled to room temperature, the
reaction mixture was neutralized with saturated NaHCO3 solution
and extracted with EtOAc (3 × 5 mL). The combined organic layer
was dried over Na2SO4. After the solvent was evaporated under
vacuum, the residue was purified by column chromatography
(EtOAc) to give the title compound 15 (111 mg, 82%) as a white
solid. Mp: 132−135 °C; IR (KBr): 3491, 3294, 3140, 1631, 1538,
Takayuki Kodama − Department of Chemistry and Bioscience,
Faculty of Science and Technology, Aoyama Gakuin
University, Sagamihara 252-5258, Japan
Ikuo Sasaki − Department of Chemistry and Bioscience,
Faculty of Science and Technology, Aoyama Gakuin
University, Sagamihara 252-5258, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00851
1
1459, 1437, 1375, 1171, 783, 694, 625 cm−1; H NMR (500 MHz,
CDCl3): δ 7.96 (d, J = 6.9 Hz, 2H), 7.39−7.48 (m, 4H), 4.68(s, 2H),
2.24 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 158.6, 153.1,
137.0, 128.8, 126.3, 126.0, 124.2, 16.9; HRMS (ESI) m/z [M + H]+
calcd for C11H12N3, 186.1026; found, 186.1028.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
2-((4-Methyl-6-phenyl-3-pyridazinyl)amino)ethyl Pivalate
(16). To a solution of 15 (16 mg, 0.09 mmol) in 1.6 mL of
CH2Cl2 was added i-Pr2NEt (44 μL, 0.25 mmol), HOBt (28 mg, 0.18
mmol), and EDCI (79 mg, 0.41 mmol), and the mixture was stirred
for 15 min at room temperature. 2-(Pivaloyloxy)acetic acid (58 mg,
0.36 mmol) was added to the mixture, and stirring was continued for
6 h at room temperature. After addition of 10% HCl solution (2 mL),
the mixture was extracted with CH2Cl2 (3 × 5 mL). The combined
organic layer was dried over Na2SO4, filtered, and evaporated under
vacuum. The residue was purified by column chromatography
(hexane:EtOAc = 4:1) to give the title compound 16 (21 mg,
73%) as a white solid. Mp: 173−176 °C; IR (KBr): 2979, 1716, 1523,
■
We thank Ms. Harumi Hayashi (Instrumental Analysis
Division, Global Facility Center, Creative Research Institution,
Hokkaido University) for the HRMS measurements.
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