Strategy for the synthesis of pyridazine heterocycles and their derivatives

Article abstract of DOI:10.1021/jo400989q

The first synthesis of novel fused pyridazines has been realized starting from 1,3-diketones involving a Diaza-Wittig reaction as a key step. A convenient strategy was elaborated to access versatile pyridazine derivatives allowing the variation of substituents at position 6 of the heterocyclic ring. In a first part, pyridazines bearing an ester group were synthesized as a model to evaluate the methodology. In a second part, an improved procedure has been used for the synthesis of pyridazines bearing a ketone group and different methods of cyclization were carried out, leading to several hitherto unknown biheterocyclic compounds. This reaction scheme represents an attractive methodology for the synthesis of novel fused pyridazine derivatives.

Full text of DOI:10.1021/jo400989q

Article
pubs.acs.org/joc
Strategy for the Synthesis of Pyridazine Heterocycles
and Their Derivatives
Hassen Bel Abed,† Oscar Mammoliti,‡ Omprakash Bande,† Guy Van Lommen,‡ and Piet Herdewijn*,†
†Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10,
B-3000 Leuven, Belgium
‡Galapagos, Laboratory of Medicinal Chemistry, Generaal De Wittelaan L11 A3, B-2800 Mechelen, Belgium
S
* Supporting Information
ABSTRACT: The first synthesis of novel fused pyridazines has been realized starting from 1,3-diketones involving a Diaza−
Wittig reaction as a key step. A convenient strategy was elaborated to access versatile pyridazine derivatives allowing the variation
of substituents at position 6 of the heterocyclic ring. In a first part, pyridazines bearing an ester group were synthesized as a
model to evaluate the methodology. In a second part, an improved procedure has been used for the synthesis of pyridazines
bearing a ketone group and different methods of cyclization were carried out, leading to several hitherto unknown biheterocyclic
compounds. This reaction scheme represents an attractive methodology for the synthesis of novel fused pyridazine derivatives.
Some of them can be obtained from substituted 3-amino-pyridazine,
which is easily available from substituted 3-chloro-pyridazine,
and further cyclized to a biheterocyclic structure. Generally
rings fused to pyridazines are 5-membered rings. Triazolo[4,3-b]-
pyridazine such as PIM-1 inhibitor 511 can be considered as an
example of this class of fused pyridazines. These derivatives were
obtained after hydrazinolysis and cyclization of substituted
3-chloro-pyridazines. Another example of this class of compounds is
a VEGFR2 kinase inhibitor based on a imidazo[1,2-b]pyridazine
6 scaffold,12 which can be obtained by condensing substituted
3-amino-pyridazines with 2-chloro-acetaldehyde.
The second class represents pyridazines fused to a 6- or
5-membered ring, without a bridgehead nitrogen atom. Examples
of this class of compounds are the phosphodiesterase 10A
inhibitors 713 and the melanin-concentrating hormone 1
antagonist14 8 (Figure 2).
INTRODUCTION
■
Recently, pyridazines have been considered by GlaxoSmithKline
as one of the “most developable” heteroaromatic rings for drug
design.1 Pyridazine analogues proved to be useful ligands for
different targets and have been proposed as “privileged structure”
for drug discovery.2 Several compounds with pyridazine rings
demonstrate biological activity (1−4), and many examples of
pyridazine structures are naturally occurring.3 Pyridazines were
recognized as selective GABA-A receptor antagonists, such as
minaprine 1.4 Volonterio et al. developed the synthesis of
pyridazine-based scaffolds such as 2 to target protein/protein
interaction as α-helix mimetics.5 3-Amino-6-aryl-pyridazines
have been considered as an interesting pharmacophore in drug
discovery. Some compounds show biological activity ranging
from obesity6 or neurodegenerative diseases7 to inflammatory
pain such as the selective CB2 agonist 3.8 Among kinase
inhibitors, different compounds containing the diazine pyridazine
have been identified. For example, compound 4 is based on a
pyridazinone ring and has been identified as a potent p38 MAP
inhibitor9 (Figure 1).
As part of an ongoing project on the synthesis of small hetero-
cycles of pharmaceutical interest,15 a strategy for the synthesis of
functionalized pyridazines by a diaza-Wittig16 reaction has been
developed. In search for operationally simple synthetic processes,
we have now developed a convenient and safe method for the
The nitrogen containing heterocycle pyridazine is a key
intermediate in the synthesis of several fused heterocycles used in
drug discovery.10 Fused pyridazines can be distinguished into
two classes. The first one has a bridgehead nitrogen atom.
Received: May 6, 2013
© XXXX American Chemical Society
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modifications in a site-selective way could be appealing. The
starting material chosen is the readily available methyl aceto-
acetate 9 which has been subjected to a diazo transfer reaction19
with p-acetamidobenzenesulfonyl azide (p-ABSA) in acetonitrile
for 2 h at room temperature to obtain the α-diazo-β-ketoester 10
in good yields. Following the titanium aldol method developed
by the Calter group,20 the diazo derivative 10 was converted to
the aldol 11 in moderate to good yields. Mild oxidation of 11
with IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide)21 led
to the α-diazo-β-ketoester, which was used without further
purification. The final step to obtain the pyridazine derivatives is
the diaza-Wittig reaction. Formation of the phosphazine inter-
mediate and the subsequent diaza-Wittig reaction occur as a
tandem process with HMPT (hexamethyl phosphorus triamide)
in dichloromethane at room temperature for 16 h to afford the
pyridazine 12 in good yields (Scheme 1).
Due to the toxicity22 of HMPT used for the diaza-Wittig
reaction, an improvement of the method to synthesize pyrida-
zines has been investigated. Different phosphines have been
screened to convert the derivative 11c into the pyridazine 12c
after oxidation with IBX. A first attempt to replace HMPT by
triphenylphosphine was not successful. In fact, after two days of
reaction in diethyl ether at room temperature, no α-diazo-
β-ketoester was converted into the corresponding pyridazine
(Table 1, entry 2). An increase of the temperature to 60 °C
by using tetrahydrofuran as a solvent led to the same result
(Table 1, entry 3). By using triethyl phosphite, the pyridazine was
obtained in a lower yield than with HMPT (Table 1, entry 4).
Triethylphosphine allowed the formation of the pyridazine in 5 h
in dichloromethane (Table 1, entry 5). Due to the toxicity and
facile oxidation of triethylphosphine,23 the tributylphosphine was
explored and the pyridazine was obtained in less than 1 h at room
temperature (Table 1, entry 6) in good yields. Diisopropyl ether
(i-Pr2O) proved to be the best solvent for this reaction, allowing
the pyridazine 12c to be obtained as a precipitate in less than
30 min in high yields (Table 1, entry 8). This modification repre-
sents an improved and safe method for the synthesis of the
pyridazine derivatives 12.
Figure 1. Biologically active pyridazine derivatives.
synthesis of 6-substituted 4-hydroxy-3-methoxycarbonyl pyrida-
zines starting from methyl acetoacetate. We described herein the
synthesis of a whole series of existing and new biheterocyclic
scaffolds such as pyrazolo[4,3-c]pyridazines, thieno[3,2-c]-
pyridazines, isoxazolo[4,5-c]pyridazines, and 5H,6H,7H-pyrida-
zino[4,3-e][1,4]diazepine starting from α-diazo-1,3-diketone
precursors.
RESULTS AND DISCUSSION
■
In order to explore novel heterocycles for drug design projects,
we became interested in developing convenient methods for the
synthesis of the pyridazine ring.17 The synthesis of 6-substituted
4-hydroxy-3-methoxycarbonyl pyridazine derivatives was first
envisioned as starting material. This compound can be obtained
by the method described by Zalesov et al. using furan-4,5-dione
as an intermediate.18 However, this method has several limita-
tions, and only aryl substituted pyridazines are accessible.
A method allowing the introduction of various substituents at
position 6 such as alkyls, cycloalkyls, aryls, and heteroaryls
could be more valuable. Moreover, a strategy which allows
The selection of appropriate aldehydes (R1CHO, Scheme 1)
allows the synthesis of pyridazine with different substituents at
position 6 such as alkyl (Table 2, entry 1), cycloalkyl (Table 2,
entry 2), aryl (Table 2, entry 3), and heteroaryl (Table 2, entry 4).
Figure 2. Biologically active fused pyridazine derivatives.
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Scheme 1. Synthesis of 6-Substituted 4-Hydroxy-3-methoxycarbonyl Pyridazines
The yield of the diaza-Wittig reaction was higher with alkyl and
cycloalkyl groups than aryl and heteroaryl groups. Invariably, the
use of P(n-Bu)3 gives higher yields of pyridazines than the use of
HMPT. Some of the derivatives were obtained as precipitates
(Table 2, entry 1−3) in less than 30 min of reaction.
Table 1. Influence of Phosphines and Solvents on the
Diaza-Wittig Reaction
a
For the building of pyridazines bearing a 3-keto group, starting
material of type 13 is needed. This approach will, likewise, allow
us to obtain pyridazine derivatives, useful for the formation of
new bicyclic heterocycles.
The reaction scheme starts with the synthesis of β-hydroxy
ketone. In order to avoid any side reaction during the synthetic
route, R1 has been chosen to be an aryl or heteroaryl group
(Figure 3). Different methods for the synthesis of 1,3-diketone
b
entry
phosphine
solvent
conditions
yield of 12c (%)
c
1
2
3
4
5
6
7
8
HMPT
P(Ph)3
CH2Cl2
Et2O
16 h, RT
48 h, RT
16 h, 60 °C
16 h, RT
5 h, RT
60
d
d
P(Ph)3
THF
c
P(OEt)3
P(Et)3
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
37
c
52
c
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
1 h, RT
58
c
30 min, RT
30 min, RT
53
e
i-Pr2O
70
a
All reactions were performed using 1 mmol of 11c and 364 mg of
IBX in refluxing acetonitrile for 2 h, followed by a filtration to obtain
the α-diazo-β-ketoester. The crude compound was stirred with 183 μL
b
of phosphine following the conditions described above. Isolated yield.
c
d
Purification by flash column chromatography on silica gel. α-Diazo-
e
β-ketoester recovered. Precipitation of 12c.
Figure 3. Diazo derivatives.
a
Table 2. Synthesis of 6-Substituted 4-Hydroxy-3-methoxycarbonyl Pyridazines
a
All reactions were performed using 1 mmol of 11 and 364 mg of IBX in refluxing acetonitrile for 2 h, followed by a filtration to obtain the
corresponding α-diazo-β-ketoester. The crude compound was stirred with 183 μL of HMPT in dichloromethane for 16 h (HMPT method) or with
b
c
250 μL of P(n-Bu)3 in i-Pr2O for 30 min (P(n-Bu)3 method). Isolated yield. Purification by flash column chromatography on silica gel.
d
Precipitation of 12.
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Scheme 2. Synthesis of α-Diazo-1,3-diketone
Scheme 3. Synthesis of Pyridazine Derivatives Bearing a Ketone Group
have been described in the past.24 We have followed two different
approaches. The first one is based on L-proline organocatalysis
discovered by List et al.25 This strategy was applied on aldehydes
bearing an electron withdrawing group (nitro group and cyano
group) 14 to afford β-hydroxy ketone 15 (Scheme 2). The final
α-diazo-1,3-diketone 16 was obtained by mild oxidation with IBX,
followed by a diazo transfer reaction with p-ABSA. However,
when using other aldehydes, the reaction becomes slow and at
least one day of reaction is required to afford the corresponding
β-hydroxy ketone.26
Therefore, for the other α-diazo-1,3-diketone derivatives, a
strategy based on the Mukaiyama aldol reaction27 has been used.
The acetophenone derivative 17 was converted to the
corresponding silyl enol ether at −78 °C with LiHMDS and
trimethylsilyl chloride. The silyl enol ether from 17 reacted with
acetaldehyde or propionaldehyde in the presence of titanium
tetrachloride to afford 18. The desired diazo compound 19 was
obtained after oxidation with IBX and diazo transfer reaction
with p-ABSA.
afford the β-hydroxy-α-diazo diketone 22 (Scheme 3). It should be
noted that these aldol products 22 are easily degraded (water
elimination)28 to give the corresponding enone 23 (complete
degradation was observed during purification by flash column
chromatography on silica gel).
Derivative 22 was oxidized with IBX in refluxing acetonitrile.
The crude product was used without further purification in the
diaza-Wittig reaction. Treatment with tributylphosphine in
diisopropyl ether for 30 min led to the desired pyridazine 24
bearing a ketone group at position 3.
This strategy led to the synthesis of nine novel pyridazine
derivatives covering different substitutions, such as several aryl
ketones (Table 3, entries 1−3, 5−9) and a heteroaryl ketone
(Table 3, entry 4). On the pyridazine ring, it was possible to
introduce various R3 groups such as alkyl (Table 3, entry 1, 2, 4, 5, 9),
cycloalkyl (Table 3, entry 8), aryl (Table 3, entry 3, 7), and
heteroaryl (Table 3, entry 6). The use of 19b allowed the
synthesis of a tetrasubstituted pyridazine (Table 3, entry 5) with
R2 being a methyl group. The pyridazine analogues 24b−j have
been subjected to different cyclization methods to obtain various
fused pyridazines (Scheme 4, Table 4).
A commercially available reagent 20 was used to synthesize the
α-diazo-1,3-diketone 21 by a Regitz reaction with p-ABSA.
Five different α-diazo-1,3-diketones, 16a, 16b, 19a, 19b, and 21,
became available in this way.
The α-diazo-1,3-diketone derivatives were used for the synthesis
of pyridazines. The first step was the titanium aldol reaction to
The first scaffold investigated was the pyrazolo[4,3-c]pyrida-
zine 25. After chlorination of 24 with phosphorus oxychloride,
the crude product was refluxed with hydrazine hydrate in
ethanol for 4 h to lead to the desired product 25 (method A).
D
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a
Table 3. Synthesis of 6-Substituted 4-Hydroxypyridazines Bearing a Ketone Group on Position 3
a
All reactions were performed using 1 mmol of 22 and 364 mg of IBX in refluxing acetonitrile for 2 h, followed by a filtration to obtain the
b
corresponding α-diazo-β-ketoester. The crude compound was stirred with 250 μL of P(n-Bu)3 in i-Pr2O for 30 min at room temperature. Isolated
yield. Precipitation of 24. Purification by flash column chromatography on silica gel.
c
d
A condensation of the methyl thioglycolate on the chlorinated
pyridazine in refluxing ethanol for 16 h led to the thieno[3,2-
c]pyridazine 26 (method B); only 26d contained a methyl ester
group, whereas the other derivatives synthesized (26a, 26b, and
26c) bore an ethyl ester group due to possible transesterification
with ethanol during the reaction.
In our search for novel scaffolds, we described the first
synthesis of 5H,6H,7H-pyridazino[4,3-e][1,4]diazepine 27.
Treatment of 24 with POCl3, followed by a cyclization with
ethylene diamine in refluxing ethanol for 16 h, led to the fused
pyridazine 27 (method C). Another novel scaffold that was
synthesized with this strategy is isoxazolo[4,5-c]pyridazine 28.
The ketone of the chlorinated pyridazine was converted into an
oxime with hydroxylamine hydrochloride and finally cyclized by
heating at 40 °C for 2 h with sodium hydride in tetrahydrofuran
to afford 28 (method D).
CONCLUSION
■
In conclusion, we have developed a synthetic scheme for the
synthesis of pyridazine derivatives bearing an ester group 12
starting from methyl acetoacetate 9. The method has been
improved by replacing HMPT by P(n-Bu)3 to perform the diaza-
Wittig reaction in a shorter reaction time and with better yields.
Based on this methodology and starting from 1,3-diketones 13, it
was possible to synthesize novel pyridazines bearing a ketone
group 24 with different substituents at position 6. These pyridazine
analogues were used for the development of a 20-member library
of novel biheterocyclic compounds such as pyrazolo[4,3-c]pyridazine
E
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diluted with 100 mL of Et2O/n-hexane (1:1), and then filtered. The
filtrate was concentrated and the residue purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:2) to afford the
desired compound 10 (5 g, 35.18 mmol, 82% yield) as yellow oil. Data
Scheme 4. Synthesis of Fused Pyridazines by Four Different
Methods (A, B, C, D)
for 10: 1H NMR (500 MHz, DMSO-d6) δ 3.65 (s, 3H), 2.18 (s, 3H); 13
NMR (125 MHz, DMSO-d6) δ 189.3, 161.5, 52.3, 27.9.
C
General Procedure for the Preparation of 11a−d by Titanium
Aldol Reaction. To a solution of 10 (1 g, 7.04 mmol) in 50 mL of
CH2Cl2 under argon at −78 °C was added dropwise TiCl4 (849 μL, 7.74
mmol) followed by Et3N (1.08 mL, 7.74 mmol). The resulting red
solution was stirred at −78 °C for 1 h, after which a solution of aldehyde
(6.34 mmol) in CH2Cl2 was slowly added. The reaction mixture was
stirred at −78 °C for 4 h, and then the reaction was quenched with
50 mL of saturated aqueous NH4Cl and warmed to room temperature. The
organic layer was separated and then washed with 40 mL of saturated
aqueous NaHCO3. The aqueous layers were extracted with 50 mL of
CH2Cl2. The combined organic layers were dried over Na2SO4 and con-
centrated in vacuo. The product was purified by flash column chromato-
graphy on silica gel (EtOAc/n-hexane = 1:3) to afford the aldol product 11.
Methyl 2-diazo-5-hydroxy-3-oxoheptanoate (11a): yellow oil,
1.2 g (85% yield); synthesized from propionaldehyde. Spectral and
analytical data were in agreement with previous reports.15b
Methyl 5-cyclohexyl-2-diazo-5-hydroxy-3-oxopentanoate (11b):
yellow oil, 1.3 g (73% yield); synthesized from cyclohexane carbo-
xaldehyde. Spectral and analytical data were in agreement with previous
reports.15b
Methyl 2-diazo-5-hydroxy-3-oxo-5-phenylpentanoate (11c): yel-
low oil, 1.3 g (75% yield); synthesized from benzaldehyde. Spectral and
analytical data were in agreement with previous reports.15b
Methyl 2-diazo-5-(furan-2-yl)-5-hydroxy-3-oxopentanoate (11d):
yellow oil, 840 mg (50% yield); synthesized from 2-furfural. Spectral and
analytical data were in agreement with previous reports.15b
HMPT Method: Preparation of Pyridazine Derivatives 12a−d.
To a solution of 11 (1 mmol) in 10 mL of acetonitrile under argon was
added IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide) (364 mg,
1.3 mmol). The mixture was refluxed for 2 h and was allowed to warm to
room temperature and then filtered. The filtrate was concentrated to
afford the α-diazo-β-ketoester used directly without further purification
for the next step.
To a solution of α-diazo-β-ketoester in 10 mL of CH2Cl2 was added
HMPT (hexamethylphosphorous triamide) (183 μL, 1 mmol). The
reaction mixture was stirred under argon at room temperature for 16 h.
After completion of the reaction (monitored by TLC), the reaction
mixture was quenched with the addition of water. The organic layer was
washed with water (2 × 10 mL), dried over Na2SO4, and concentrated in
vacuo. A purification by flash column chromatography on silica gel
(EtOAc/n-hexane = 9:1) afforded the desired pyridazine 12.
P(n-Bu)3 Method: Preparation of Pyridazine Derivatives
12a−d. To a solution of 11 (1 mmol) in 10 mL of acetonitrile under
argon was added IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide)
(364 mg, 1.3 mmol). The mixture was refluxed for 2 h and was allowed to
warm to room temperature and then filtered. The filtrate was
concentrated to afford the α-diazo-β-ketoester used directly without
further purification for the next step.
To a solution of α-diazo-β-ketoester in 20 mL of i-Pr2O was added
P(n-Bu)3 (250 μL, 1 mmol). The reaction mixture was stirred under argon
at room temperature for 30 min, after which time a precipitate was formed.
The suspension was filtered, washed with i-Pr2O, and dried to afford 12.
Methyl 6-ethyl-4-hydroxypyridazine-3-carboxylate (12a): white
solid, 124 mg (68% yield with HMPT method) and 155 mg (85% yield
with P(n-Bu)3 method); mp 179−182 °C. Spectral and analytical data
were in agreement with previous reports.15b
Methyl 6-cyclohexyl-4-hydroxypyridazine-3-carboxylate (12b):
beige solid, 146 mg (62% yield with HMPT method) and 170 mg
(72% yield with P(n-Bu)3 method); mp 215−217 °C. Spectral and
analytical data were in agreement with previous reports.15b
25 and thieno[3,2-c]pyridazine 26. It is also the first report deal-
ing with the synthesis of 5H,6H,7H-pyridazino[4,3-e][1,4]-
diazepine 27 and isoxazolo[4,5-c]pyridazine 28.
EXPERIMENTAL SECTION
■
For all reactions, analytical grade solvents were used. All moisture-
sensitive reactions were carried out in oven-dried glassware (135 °C)
under a nitrogen or argon atmosphere. Reaction temperatures are
reported as bath temperature. Precoated aluminum sheets were used for
TLC. Compounds were visualized with UV light (λ = 254 nm). Products
were purified by flash chromatography on silica gel 63−200, 60 Å.
Melting points were obtained on a melting point apparatus with open
capillary tubes. 1H and 13C NMR spectra were recorded on 300 MHz,
500 MHz, and 600 MHz spectrometers using CDCl3 and DMSO-d6 as
the solvent. The 1H and 13C chemical shifts were referenced to residual
solvent signals at δ 1H/13C 7.26/77.00 (CDCl3) and 2.50/39.50
(DMSO-d6) relative to TMS as internal standard. Coupling constants
J [Hz] were directly taken from the spectra. Splitting patterns are
designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). High resolution mass spectra were acquired
on a quadrupole orthogonal acceleration time-of-flight mass spec-
trometer. Samples were infused at 3 μL/min, and spectra were obtained
in positive (or negative) ionization mode with a resolution of 15000
(fwhm) using leucine enkephalin as lock mass. Electrospray MS spectra
were obtained on a LC/MS spectrometer. All the LC/MS analysis
methods use MeCN/H2O gradients. Water contains either 0.1% TFA or
0.1% NH3.
Methyl 2-Diazo-3-oxobutanoate (10). To a solution of com-
pound 9 (5 g, 43.06 mmol) in 30 mL of acetonitrile under argon at 0 °C
were added successively triethylamine (7.8 mL, 55.98 mmol) and
p-acetamidobenzenesulfonyl azide (p-ABSA) (10.4 g, 43.06 mmol).
The mixture was stirred for 2 h, allowed to warm to room temperature,
Methyl 4-hydroxy-6-phenylpyridazine-3-carboxylate (12c): pale
yellow solid, 138 mg (60% yield with HMPT method) and 161 mg
(70% yield with P(n-Bu)3 method); mp 211−212 °C. Spectral and
analytical data were in agreement with previous reports.15b
F
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Methyl 6-(furan-2-yl)-4-hydroxypyridazine-3-carboxylate (12d):
brown solid, 59 mg (27% yield with HMPT method) and 77 mg (35%
yield with P(n-Bu)3 method; a purification by flash column
chromatography on silica gel (EtOAc/n-hexane = 9:1) afforded the
Table 4. Synthesis of Fused Pyridazine Analogues
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Table 4. continued
a
b
c
Isolated yield. Synthesis of thieno[3,2-c]pyridazine 26 with method B, see the Experimental Section for details. Synthesis of 5H,6H,7H-
d
pyridazino[4,3-e][1,4]diazepine 27 with method C, see the Experimental Section for details. Synthesis of pyrazolo[4,3-c]pyridazine 25 with method
A, see the Experimental Section for details. Synthesis of isoxazolo[4,5-c]pyridazine 28 with method D, see the Experimental Section for details.
e
desired pyridazine 12d); mp 192−195 °C. Spectral and analytical data
were in agreement with previous reports.15b
General Procedure for the Preparation of β-Hydroxy Ketone
Derivatives 15a,b by Organocatalysis. To a solution of aldehyde 14
(1 mmol) in a mixture of DMSO (4 mL) and acetone (1 mL) was added
L-proline (29 mg, 0.25 mmol). The resulting mixture was stirred under
argon at room temperature for 5 h. The reaction mixture was treated
with 10 mL of saturated aqueous NH4Cl, the layers were separated, and
the aqueous layer was extracted several times with EtOAc, dried over
Na2SO4, and concentrated in vacuo. A purification by flash column
H
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chromatography on silica gel (EtOAc/n-hexane = 1:2) afforded the
desired aldol product 15.
2-Diazo-1-(4-nitrophenyl)butane-1,3-dione (16a): yellow solid,
198 mg (85% yield); mp 84−87 °C. Data for 16a: 1H NMR (500 MHz,
DMSO-d6) δ 8.34 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 8.7 Hz, 2H), 2.46
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 188.8, 184.0, 149.3, 142.9,
129.1, 123.9, 84.8, 28.7.
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (15a): pink solid, 119 mg
(57% yield); mp 65−68 °C. Data for 15a: 1H NMR (500 MHz, DMSO-
d6) δ 8.19 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 5.70 (d, J =
4.8 Hz, 1H), 5.13−5.16 (m, 1H), 2.75 (d, J = 6.6 Hz, 2H), 2.14 (s, 1H);
13C NMR (125 MHz, DMSO-d6) δ 206.3, 153.3, 146.5, 127.0, 123.4,
68.1, 52.4, 30.4; HRMS calcd for C10H11NO4 [M + Na]+ 232.0581,
found 232.0584.
4-(2-Diazo-3-oxobutanoyl)benzonitrile (16b): beige solid, 164 mg
1
(77% yield); mp 106−110 °C. Data for 16b: H NMR (500 MHz,
DMSO-d6) δ 8.01 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 2.45 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 189.0, 184.2, 141.4, 132.8,
128.4, 118.2, 114.4, 84.6, 28.7.
4-(1-Hydroxy-3-oxobutyl)benzonitrile (15b): beige solid, 104 mg
(55% yield); mp 83−88 °C. Data for 15b: 1H NMR (500 MHz, DMSO-
d6) δ 7.82 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 5.65 (d, J =
4.7 Hz, 1H), 5.10−5.13 (m, 1H), 2.76 (d, J = 5.8 Hz, 2H), 2.16 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 151.1, 132.2, 126.8, 119.0, 109.7,
2-Diazo-1-(thiophene-2-yl)butane-1,3-dione (19a): yellow oil, 169
1
mg (87% yield). Data for 19a: H NMR (600 MHz, CDCl3) δ 7.69−
7.70 (m, 1H), 7.60−7.61 (m, 1H), 7.15−7.16 (m, 1H), 2.60 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 190.8, 175.1, 141.9, 133.5, 130.4, 127.9,
81.7, 29.3.
68.3, 52.4, 30.4; HRMS calcd for C11H11NO2 [M + Na]+ 212.0682,
found 212.0677.
1-(4-Chlorophenyl)-2-diazopentane-1,3-dione (19b): pale yellow
solid, 192 mg (81% yield); mp 88−92 °C. Data for 19b: 1H NMR (500
MHz, DMSO-d6) δ 7.75 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H),
2.86 (q, J = 7.3 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 192.6, 184.1, 137.2, 136.4, 129.6, 128.8, 83.2, 33.8, 8.2.
2-Diazo-1-phenylbutane-1,3-dione (21). To a solution of
compound 20 (3 g, 18.50 mmol) in 50 mL of acetonitrile under
argon at 0 °C were added successively triethylamine (3.3 mL, 24.05
mmol) and p-acetamidobenzenesulfonyl azide (p-ABSA) (4.4 g, 18.50
mmol). The mixture was stirred for 2 h and was allowed to warm to
room temperature, diluted with 100 mL of Et2O/n-hexane (1:1), and
then filtered. The filtrate was concentrated and the residue purified by
flash column chromatography on silica gel (EtOAc/n-hexane = 1:3) to
afford the desired compound 21 (3.1 g, 16.45 mmol, 89% yield) as
yellow solid; mp 78−81 °C. Data for 21: 1H NMR (500 MHz, DMSO-
d6) δ 7.73 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.52−7.55
(m, 2H), 2.46 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 189.8, 185.0,
137.5, 132.5, 128.8, 127.6, 83.6, 28.8.
General Procedure for the Preparation of 22b−j by Titanium
Aldol Reaction. To a solution of α-diazo-1,3-diketone (16a, 16b, 19a,
19b, and 21) (1 mmol) in 10 mL of CH2Cl2 under argon at −78 °C was
added dropwise TiCl4 (121 μL, 1.1 mmol) followed by Et3N (153 μL,
1.1 mmol). The resulting red solution was stirred at −78 °C for 1 h, after
which a solution of aldehyde (0.9 mmol) in CH2Cl2 was slowly added.
The reaction mixture was stirred at −78 °C for 4 h, and then the reaction
was quenched with 10 mL of saturated aqueous NH4Cl and warmed to
room temperature. The organic layer was separated and then washed
with 15 mL of saturated aqueous NaHCO3. The aqueous layers were
extracted with 20 mL of CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The product was purified
by flash column chromatography on silica gel (EtOAc/n-hexane = 1:3)
to afford the aldol product 22.
General Procedure for the Preparation of β-Hydroxy Ketone
Derivatives 18a,b by Mukaiyama Aldol Reaction. To a solution of
ketone 17 (1 mmol) in 10 mL of THF under argon at −78 °C was slowly
added a solution of 1 M LiHMDS (1.2 mL, 1.2 mmol), and the reaction
mixture was stirred for 1 h at −78 °C, prior to the addition of
chlorotrimethylsilane (153 μL, 1.2 mmol) in THF. The mixture was
further stirred for 1 h and then allowed to warm up to room temperature.
The reaction was first quenched with 10 mL of saturated aqueous
NH4Cl. After addition of EtOAc (20 mL), the layers were separated, and
the aqueous layer was extracted several times with EtOAc, dried over
Na2SO4, and concentrated in vacuo to afford the corresponding silyl
enol ether used directly without further purification for the next step.
To a solution of silyl enol ether in 10 mL of CH2Cl2 under argon at
−78 °C was added acetaldehyde (85 μL, 1.5 mmol) for 18a or propional-
dehyde for 18b (110 μL, 1.5 mmol) followed by a slow addition of TiCl4
(121 μL, 1.1 mmol). The resulting red solution was stirred at −78 °C for
5 h, and then the reaction was quenched with 10 mL of saturated
aqueous NH4Cl and warmed to room temperature. The organic layer
was separated and then washed with 15 mL of saturated aqueous
NaHCO3. The aqueous layers were extracted with 20 mL of CH2Cl2.
The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The product was purified by flash column chromatography on
silica gel (EtOAc/n-hexane = 1:3) to obtain the desired β-hydroxy
ketone 18.
3-Hydroxy-1-(thiophene-2-yl)butan-1-one (18a): colorless oil,
107 mg (63% yield). Data for 18a: 1H NMR (500 MHz, DMSO-d6) δ
7.98 (d, J = 4.9 Hz, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.24 (t, J = 4.8 Hz, 1H),
4.70 (d, J = 4.9 Hz, 1H), 4.15−4.17 (m, 1H), 2.85−3.09 (m, 2H), 1.14
(d, J = 6.2 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 192.1, 144.7,
134.9, 133.6, 128.8, 63.8, 48.4, 23.8; HRMS calcd for C8H10O2S
[M + Na]+ 193.0294, found 193.0297.
1-(4-Chlorophenyl)-3-hydroxypentan-1-one (18b): yellow oil, 145
mg (68% yield). Data for 18b: 1H NMR (500 MHz, DMSO-d6) δ 7.97
(d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 4.62 (d, J = 5.5 Hz, 1H),
3.89−3.95 (m, 1H), 3.90−3.94 (m, 1H), 2.94−3.10 (m, 2H), 1.40−1.48
(m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ
198.5, 138.0, 136.0, 130.1, 128.8, 68.6, 45.9, 30.2, 10.0; HRMS calcd for
C11H13ClO2 [M + Na]+ 235.0497, found 235.0502.
2-Diazo-5-hydroxy-1-(4-nitrophenyl)heptane-1,3-dione (22b):
1
yellow oil, 201 mg (69% yield). Data for 22b: H NMR (300 MHz,
DMSO-d6) δ 8.33 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 4.75−
4.77 (m, 1H), 3.82−3.87 (m, 1H), 2.86−2.91 (m, 2H), 1.37−1.47 (m,
2H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 190.0,
184.3, 149.3, 143.1, 129.1, 123.8, 85.2, 68.4, 47.9, 30.0, 10.0; HRMS
calcd for C13H13N3O5 [M + Na]+ 314.0748, found 314.0752.
4-(2-Diazo-5-hydroxy-3-oxoheptanoyl)benzonitrile (22c): yellow
oil, 220 mg (81% yield). Data for 22c: 1H NMR (600 MHz, DMSO-d6)
δ 7.99 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 4.73−4.75 (m, 1H),
3.85−3.87 (m, 1H), 2.83−2.93 (m, 2H), 1.30−1.46 (m, 2H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 190.1, 184.5, 141.5,
132.7, 128.4, 118.2, 114.4, 84.8, 68.4, 47.9, 30.0, 10.0; HRMS calcd for
C14H13N3O3 [M + Na]+ 294.0849, found 294.0849.
General Procedure for the Preparation of α-Diazo-1,3-
diketones 16a, 16b, 19a, and 19b. To a solution of β-hydroxy
ketone (15a, 15b, 18a, 18b) (1 mmol) in 10 mL of acetonitrile under
argon at 0 °C was added IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-
oxide) (364 mg, 1.3 mmol). The mixture was refluxed for 2 h and was
allowed to warm to room temperature and then filtered. The filtrate was
concentrated to afford the 1,3-diketone used directly without further
purification for the next step.
To a solution of 1,3-diketone in 15 mL of acetonitrile under argon at
0 °C were added successively triethylamine (181 μL, 1.3 mmol) and
p-acetamidobenzenesulfonyl azide (p-ABSA) (240 mg, 1 mmol). The
mixture was stirred for 2 h, allowed to warm to room temperature,
diluted with a mixture of diethyl ether/hexane (1/1, 30 mL), and then
filtered. The filtrate was concentrated and the residue purified by flash
column chromatography on silica gel (EtOAc/n-hexane = 1:4) to afford
the α-diazo-1,3-diketones 16a, 16b, 19a, and 19b.
4-[2-Diazo-5-(2-fluorophenyl)-5-hydroxy-3-oxopentanoyl]-
1
benzonitrile (22d): yellow oil, 169 mg (50% yield). Data for 22d: H
NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6
Hz, 2H), 7.52−7.56 (m, 1H), 7.29−7.34 (m, 1H), 7.20−7.23 (m, 1H),
7.12−7.16 (m, 1H), 5.63 (d, J = 4.9 Hz, 1H), 5.34−5.38 (m, 1H), 3.36
(m, 1H), 3.01 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 189.0, 184.4,
160.0, 158.0, 141.3, 132.8, 131.7, 129.0, 128.4, 127.9, 124.5, 118.2, 115.1,
114.4, 84.8, 62.8, 48.5; HRMS calcd for C18H12FN3O3 [M + Na]+
360.0755, found 360.0761.
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2-Diazo-5-hydroxy-1-(thiophene-2-yl)heptane-1,3-dione (22e):
yellow oil, 194 mg (77% yield). Data for 22e: H NMR (500 MHz,
7.96 (d, J = 8.3 Hz, 2H), 6.46 (s, 1H), 2.62 (q, J = 7.6 Hz, 2H), 1.24 (t, J =
7.6 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 191.9, 169.1, 156.8,
152.8, 138.7, 133.0, 129.8, 118.1, 116.3, 115.9, 24.1, 12.5; HRMS calcd
for C14H11N3O2 [M + H]+ 254.0924, found 254.0928.
4-[6-(4-Fluorophenyl)-4-hydroxypyridazine-3-carbonyl]-
benzonitrile (24d): beige solid, 144 mg (45% yield); mp 237−240 °C.
Data for 24d: 1H NMR (600 MHz, DMSO-d6) δ 13.94 (br s, 1H), 8.05
(m, 4H), 7.73−7.76 (m, 1H), 7.66−7.69 (m, 1H), 7.46−7.49 (m, 1H),
7.43−7.45 (m, 1H), 6.78 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ
191.7, 159.9, 158.3, 152.9, 138.7, 133.4, 133.3, 133.0, 130.9, 130.0, 125.9,
118.9, 118.2, 116.6, 116.5, 116.0; HRMS calcd for C18H10FN3O2
[M + H]+ 320.0830, found 320.0831.
1
DMSO-d6) δ 8.04−8.05 (m, 1H), 7.92−7.93 (m, 1H), 7.23−7.25 (m,
1H), 4.66 (d, J = 5.7 Hz, 1H), 3.84−3.88 (m, 1H), 2.91−2.98 (m, 2H),
1.33−1.48 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 175.4, 141.8, 134.6, 132.0, 128.4, 82.4, 68.3, 48.0, 30.0,
10.0; HRMS calcd for C11H12N2O3S [M + Na]+ 275.0461, found
275.0468.
1-(4-Chlorophenyl)-2-diazo-5-hydroxy-4-methylheptane-1,3-
dione (22f): yellow oil, 186 mg (63% yield); Inseparable diastereomeric
mixture. Data for 22f (major isomer): 1H NMR (300 MHz, CDCl3) δ
8.01 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 4.60−4.67 (m, 1H),
4.18 (d, J = 4.8 Hz, 1H), 3.10−3.16 (m, 1H), 1.63−1.72 (m, 2H), 0.98−
1.20 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 191.3, 171.6, 140.3, 133.5,
130.5, 128.8, 84.3, 57.4, 36.3, 23.0, 13.2, 10.0; HRMS calcd for
C14H15ClN2O3 [M + Na]+ 317.0664, found 317.0657.
6-Ethyl-3-(thiophene-2-carbonyl)pyridazin-4-ol (24e): orange
1
solid, 129 mg (55% yield); mp 236−239 °C. Data for 24e: H NMR
(600 MHz, DMSO-d6) δ 13.41 (br s, 1H), 8.13−8.14 (m, 1H), 7.69−
7.70 (m, 1H), 7.24−7.26 (m, 1H), 6.42 (s, 1H), 2.61 (q, J = 7.6 Hz, 2H),
1.23 (t, J = 7.7 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 184.0,
169.1, 156.5, 153.0, 142.2, 136.8, 136.5, 129.1, 116.0, 24.1, 12.5; HRMS
calcd for C11H10N2O2S [M + H]+ 235.0536, found 235.0540.
3-(4-Chlorobenzoyl)-6-ethyl-5-methylpyridazin-4-ol (24f): color-
less oil, 158 mg (57% yield). Data for 24f: 1H NMR (600 MHz, DMSO-d6)
δ 13.37 (br s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 2.69
(q, J = 7.3 Hz, 2H), 1.95 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6) δ 191.9, 168.6, 153.1, 150.6, 139.0, 134.4, 131.2,
129.1, 125.5, 22.6, 12.7, 9.1; HRMS calcd for C14H13ClN2O2 [M + H]+
277.0738, found 277.0739.
2-Diazo-5-hydroxy-1-phenyl-5-(thiophene-2-yl)pentane-1,3-
1
dione (22g): yellow oil, 171 mg (57% yield). Data for 22g: H NMR
(300 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.60 (m, 1H), 7.51 (t, J = 7.7 Hz,
2H), 7.41 (dd, J = 4.9, 1.3 Hz, 1H), 6.97−7.02 (m, 2H), 5.88−5.90 (m,
1H), 5.38−5.40 (m, 1H), 3.24−3.46 (m, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 189.7, 185.1, 149.7, 137.5, 132.6, 128.8, 127.7, 126.8,
124.5, 123.2, 83.9, 65.2, 50.4; HRMS calcd for C15H12N2O3S [M + Na]+
323.0461, found 323.0460.
2-Diazo-5-hydroxy-1,5-diphenylpentane-1,3-dione (22h): yellow
oil, 153 mg (52% yield). Data for 22h: 1H NMR (300 MHz, DMSO-d6)
δ 7.46−7.60 (m, 3H), 7.4−7.44 (m, 4H), 7.28−7.42 (m, 3H), 5.28 (m,
1H), 3.56 (m, 1H), 3.33−3.44 (m, 2H); 13C NMR (125 MHz, DMSO-
d6) δ 192.4, 184.7, 142.6, 136.7, 132.6, 128.7, 128.2, 127.4, 127.1, 125.5,
83.6, 70.3, 49.4; HRMS calcd for C17H14N2O3 [M + Na]+ 317.0897,
found 317.0901.
5-Cyclohexyl-2-diazo-5-hydroxy-1-phenylpentane-1,3-dione
(22i): yellow oil, 237 mg (79% yield). Data for 22i: 1H NMR (500 MHz,
DMSO-d6) δ 7.71 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.52 (t, J =
7.6 Hz, 2H), 4.61 (d, J = 5.8 Hz, 1H), 3.74−3.78 (m, 1H), 2.90 (d, J = 5.7
Hz, 2H), 1.59−1.76 (m, 5H), 0.95−1.28 (m, 6H); 13C NMR (125 MHz,
DMSO-d6) δ 191.4, 185.2, 137.6, 132.5, 128.7, 127.7, 83.6, 71.0, 45.5,
43.7, 28.8, 27.6, 26.2, 25.9, 25.8; HRMS calcd for C17H20N2O3 [M +
Na]+ 323.1366, found 323.1363.
3-Benzoyl-6-(thiophene-2-yl)pyridazin-4-ol (24g): orange solid,
1
150 mg (53% yield); mp 206−209 °C. Data for 24g: H NMR (600
MHz, DMSO-d6) δ 7.88−7.92 (m, 4H), 7.72 (t, J = 7.4 Hz, 1H), 7.57
(t, J = 7.7 Hz, 2H), 7.29−7.31 (m, 1H), 6.94 (br s, 1H); 13C NMR (150
MHz, DMSO-d6) δ 192.4, 135.5, 134.3, 131.0, 129.6, 129.0, 128.9;
HRMS calcd for C15H10N2O2S [M + H]+ 283.0536, found 283.0534.
3-Benzoyl-6-phenylpyridazin-4-ol (24h): brown solid, 133 mg (48%
yield); mp 201−204 °C. Data for 24h: 1H NMR (600 MHz, DMSO-d6)
δ 7.89 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.72 (t, J = 7.4 Hz,
1H), 7.56−7.62 (m, 5H), 6.85 (s, 1H); 13C NMR (150 MHz, DMSO-
d6) δ 192.6, 135.4, 134.3, 131.2, 129.5, 129.3, 129.0, 127.4, 115.3; HRMS
calcd for C17H12N2O2 [M + H]+ 277.0971, found 277.0978.
3-Benzoyl-6-cyclohexylpyridazin-4-ol (24i): beige solid, 147 mg
2-Diazo-5-hydroxy-6-methyl-1-phenylheptane-1,3-dione (22j):
1
1
(52% yield); mp 233−235 °C. Data for 24i: H NMR (600 MHz,
yellow oil, 221 mg (85% yield). Data for 22j: H NMR (500 MHz,
DMSO-d6) δ 13.36 (br s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.69 (t, J = 7.4
Hz, 1H), 7.55 (t, J = 8.1 Hz, 2H), 6.40 (s, 1H), 2.54−2.59 (m, 1H),
1.69−1.90 (m, 5H), 1.33−1.52 (m, 5H); 13C NMR (150 MHz, DMSO-
d6) δ 192.7, 159.5, 154.1, 135.4, 134.3, 129.4, 129.0, 114.2, 40.1, 31.0,
25.7, 25.1; HRMS calcd for C17H18N2O2 [M + H]+ 283.1441, found
283.1440.
DMSO-d6) δ 7.71 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.52 (t, J =
7.6 Hz, 2H), 4.65 (br s, 1H), 3.76−3.78 (m, 1H), 2.85−2.95 (m, 2H),
1.60−1.64 (m, 1H), 0.85 (m, 6H); 13C NMR (125 MHz, DMSO-d6) δ
191.3, 185.2, 137.6, 132.5, 128.7, 127.7, 83.7, 71.5, 45.4, 33.6, 18.7, 17.5;
HRMS calcd for C14H16N2O3 [M + Na]+ 283.1053, found 283.1052.
General Procedure for the Preparation of Pyridazine
Derivatives 24b−j. To a solution of 22 (1 mmol) in 10 mL of
acetonitrile under argon was added IBX (1-hydroxy-1,2-benziodoxol-
3(1H)-one 1-oxide) (364 mg, 1.3 mmol). The mixture was refluxed for 2
h and was allowed to warm to room temperature and then filtered. The
filtrate was concentrated and used directly without further purification
for the next step.
To the previously prepared crude in 15 mL of i-Pr2O was added P(n-
Bu)3 (250 μL, 1.0 mmol). The reaction mixture was stirred under argon
at room temperature for 30 min, after which time a precipitate was
formed. The suspension was filtered, washed with i-Pr2O, and dried to
afford 24b, 24c, 24e, 24f, and 24j. 24d, 24g, 24h, and 24i were purified
by flash column chromatography on silica gel (EtOAc/n-hexane = 8:2)
due to no formation of precipitate.
3-Benzoyl-6-(propan-2-yl)pyridazin-4-ol (24j): beige solid, 133 mg
1
(55% yield); mp 228−231 °C. Data for 24j: H NMR (600 MHz,
DMSO-d6) δ 13.41 (br s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.70 (t, J = 7.4
Hz, 1H), 7.55 (t, J = 7.9 Hz, 2H), 6.43 (s, 1H), 2.88−2.93 (m, 1H), 1.27
(d, J = 7.1 Hz, 6H); 13C NMR (150 MHz, DMSO-d6) δ 192.7, 169.3,
160.5, 154.2, 135.4, 134.3, 129.4, 129.0, 113.8, 30.3, 21.1; HRMS calcd
for C14H14N2O2 [M + H]+ 243.1128, found 243.1130.
Method A: Preparation of Pyrazolo[4,3-c]pyridazine Ana-
logues 25a−f. A solution of 24 (1 mmol) in 5 mL of POCl3 was heated
at 95 °C for 4 h, after which the reaction mixture was cooled down to
room temperature. POCl3 was evaporated, and the residue was dissolved
in EtOAc and washed 2 times with 20 mL of saturated aqueous
NaHCO3. The organic layer was dried over Na2SO4 and concentrated in
vacuo to afford the chlorinated pyridazine used directly without further
purification for the next step.
To a solution of chlorinated pyridazine in 5 mL of EtOH was added
hydrazine hydrate 64% (63 μL, 1.3 mmol) followed by Et3N (181 μL,
1.3 mmol), and the mixture was refluxed for 4 h. After completion of the
reaction (monitored by TLC), the reaction mixture was allowed to cool
to room temperature. CH2Cl2 was added, and the organic layer was then
washed 2 times with 10 mL of saturated aqueous NaHCO3 and 1 time
with 10 mL of saturated aqueous NaCl. The organic layer was dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by flash
6-Ethyl-3-(4-nitrobenzoyl)pyridazin-4-ol (24b): brown solid, 164
mg (60% yield); mp 241−244 °C. Data for 24b: 1H NMR (500 MHz,
DMSO-d6) δ 13.54 (br s, 1H), 8.34 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.4
Hz, 2H), 6.47 (s, 1H), 2.63 (q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H);
13C NMR (125 MHz, DMSO-d6) δ 157.0, 152.7, 150.4, 140.2, 130.6,
124.1, 116.5, 24.3, 12.5; HRMS calcd for C13H11N3O4 [M + H]+
274.0822, found 274.0829.
4-(6-Ethyl-4-hydroxypyridazine-3-carbonyl)benzonitrile (24c):
1
yellow solid, 144 mg (57% yield); mp 233−235 °C. Data for 24c: H
NMR (600 MHz, DMSO-d6) δ 13.55 (br s, 1H), 8.02 (d, J = 8.3 Hz, 2H),
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column chromatography on silica gel (EtOAc) to obtain the desired
pyrazolo[4,3-c]pyridazine 25.
134.4, 132.3, 122.7, 119.6, 62.3, 28.8, 14.2, 13.8; HRMS calcd for
C17H15N3O4S [M + H]+ 358.0856, found 358.0860.
4-{6-Ethyl-1H-pyrazolo[4,3-c]pyridazin-3-yl}benzonitrile (25a):
Ethyl 3-ethyl-7-(thiophene-2-yl)thieno[3,2-c]pyridazine-6-carbox-
ylate (26b): beige solid, 121 mg (38% yield); mp 139−142 °C. Data for
26b: 1H NMR (600 MHz, CDCl3) δ 7.81−7.83 (m, 2H), 7.58−7.59 (m,
1H), 7.19−7.21 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.20 (q, J = 7.7 Hz,
2H), 1.47 (t, J = 7.7 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (150
MHz, DMSO-d6) δ 161.8, 159.6, 156.3, 137.9, 134.5, 131.7, 131.5,
131.0, 128.7, 126.5, 118.1, 62.3, 29.4, 14.0; HRMS calcd for
C15H14N2O2S2 [M + H]+ 319.0569, found 319.0579.
Ethyl 7-phenyl-3-(thiophene-2-yl)thieno[3,2-c]pyridazine-6-car-
boxylate (26c): yellow solid, 120 mg (33% yield); mp 157−161 °C.
Data for 26c: 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.97 (d,
J = 3.4 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.59−7.61 (m, 2H), 7.51−7.53
(m, 3H), 7.29 (d, J = 4.6 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.15 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.4, 156.9, 149.5, 141.5,
140.4, 138.4, 133.5, 132.0, 130.8, 130.4, 128.9, 128.7, 127.7, 127.3, 115.8,
62.1, 13.8; HRMS calcd for C19H14N2O2S2 [M + H]+ 367.0569, found
367.0570.
Methyl 3,7-diphenylthieno[3,2-c]pyridazine-6-carboxylate (26d):
brown solid, 148 mg (41% yield); mp 140−144 °C. Data for 26d: 1H
NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.25 (d, J = 7.3 Hz, 2H),
7.60−7.64 (m, 4H), 7.53−7.57 (m, 4H), 3.81 (s, 3H); 13C NMR (125
MHz, DMSO-d6) δ 161.7, 157.0, 153.2, 141.6, 138.5, 136.1, 133.1,
132.0, 130.8, 130.2, 129.3, 128.7, 127.7, 127.3, 117.9, 53.1; HRMS calcd
for C20H14N2O2S [M + H]+ 347.0849, found 347.0846.
Method C: Preparation of 5H,6H,7H-Pyridazino[4,3-e][1,4]-
diazepine Analogues 27a−h. A solution of 24 (1 mmol) in 5 mL of
POCl3 was heated at 95 °C for 4 h, after which the reaction mixture was
cooled down to room temperature. POCl3 was evaporated, and the
residue was dissolved in EtOAc and washed 2 times with 20 mL of
saturated aqueous NaHCO3. The organic layer was dried over Na2SO4
and concentrated in vacuo to afford the chlorinated pyridazine, used
directly without further purification for the next step.
To a solution of chlorinated pyridazine in 5 mL of EtOH was added
ethylene diamine (87 μL, 1.3 mmol) followed by Et3N (181 μL, 1.3
mmol), and the mixture was refluxed for 16 h. After completion of the
reaction (monitored by TLC), the reaction mixture was allowed to cool
to room temperature. CH2Cl2 was added, and the organic layer was then
washed 2 times with 10 mL of saturated aqueous NaHCO3 and 1 time
with 10 mL of saturated aqueous NaCl. The organic layer was dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by flash
column chromatography on silica gel (MeOH/EtOAc = 1:9) to obtain
the desired 5H,6H,7H-pyridazino[4,3-e][1,4]diazepine 27.
3-Ethyl-9-(4-nitrophenyl)-5H,6H,7H-pyridazino[4,3-e][1,4]-
diazepine (27a): pale yellow solid, 229 mg (77% yield); mp 213-215 °C.
Data for 27a: 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J = 8.8 Hz, 2H,
H3′, H5′), 7.65 (m, 3H, NH, H2′, H6′), 6.72 (s, 1H, H4), 4.10−4.11
(m, 2H, H7), 3.51−3.52 (m, 2H, H6), 2.75 (q, J = 7.6 Hz, 2H, CH2),
1.23 (t, J = 7.6 Hz, 3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ 168.0
(C9), 161.7 (C3), 148.6 (C4′), 147.3 (C), 146.6 (C), 139.8 (C1′), 130.3
(C2′, C6′), 122.7 (C3′, C5′), 109.9 (C4), 53.3 (C6), 47.5 (C7), 28.0
(CH2), 13.4 (CH3); HRMS calcd for C15H15N5O2 [M + H]+ 298.1298,
found 298.1306.
1
beige solid, 207 mg (83% yield); mp 336−338 °C. Data for 25a: H
NMR (600 MHz, DMSO-d6) δ 8.76 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.5
Hz, 2H), 7.80 (s, 1H), 3.16 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.4 Hz, 3H);
13C NMR (150 MHz, DMSO-d6) δ 159.0, 144.1, 141.0, 135.9, 133.8,
133.0, 127.3, 118.9, 111.1, 105.2, 28.9, 14.6; HRMS calcd for C14H11N5
[M + H]+ 250.1087, found 250.1089.
4-[6-(2-Fluorophenyl)-1H-pyrazolo[4,3-c]pyridazin-3-yl]-
benzonitrile (25b): white solid, 249 mg (79% yield); mp 390−393 °C.
Data for 25b: 1H NMR (300 MHz, DMSO-d6) δ 14.25 (br s, 1H), 8.78
(d, J = 8.3 Hz, 2H), 8.25 (s, 1H), 8.05−8.14 (m, 3H), 7.59−7.61 (m,
1H), 7.45 (t, J = 8.4 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.7,
158.4, 149.6, 144.2, 141.3, 135.7, 133.3, 133.1, 131.7, 127.4, 125.1, 118.9,
116.7, 116.4, 111.4, 107.8; HRMS calcd for C18H10FN5 [M + H]+
316.0993, found 316.0989.
3-(4-Chlorophenyl)-6-ethyl-7-methyl-1H-pyrazolo[4,3-c]-
pyridazine (25c): beige solid, 237 mg (87% yield); mp 323−327 °C.
1
Data for 25c: H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz,
2H), 7.68 (d, J = 8.6 Hz, 2H), 3.17 (q, J = 7.5 Hz, 2H), 2.61 (s, 3H), 1.37
(t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 157.2, 143.6,
141.6, 134.7, 133.5, 130.6, 129.1, 128.4, 115.9, 25.6, 13.9, 12.0; HRMS
calcd for C14H13ClN4 [M + H]+ 273.0901, found 273.0905.
3-Phenyl-6-(thiophene-2-yl)-1H-pyrazolo[4,3-c]pyridazine (25d):
pale yellow solid, 225 mg (81% yield); mp 345−348 °C. Data for
25d: 1H NMR (600 MHz, DMSO-d6) δ 13.94 (br s, 1H), 8.59 (d, J = 8.4
Hz, 2H), 8.35 (s, 1H), 8.06 (d, J = 3.7 Hz, 1H), 7.76 (d, J = 5.0 Hz, 1H),
7.60 (t, J = 7.9 Hz, 2H), 7.50 (m, 1H), 7.26 (m, 1H); 13C NMR (150
MHz, DMSO-d6) δ 148.9, 144.5, 143.2, 141.2, 133.5, 131.3, 129.4,
129.2, 129.0, 128.5, 127.0, 126.5, 101.3; HRMS calcd for C15H10N4S [M
+ H]+ 279.0699, found 279.0701.
3,6-Diphenyl-1H-pyrazolo[4,3-c]pyridazine (25e): beige solid, 215
mg (79% yield); mp 332−335 °C. Data for 25e: 1H NMR (600 MHz,
DMSO-d6) δ 13.96 (br s, 1H), 8.63 (d, J = 7.3 Hz, 2H), 8.34 (s, 1H),
8.30 (d, J = 7.4 Hz, 2H), 7.59−7.62 (m, 4H), 7.49−7.56 (m, 2H); 13C
NMR (150 MHz, DMSO-d6) δ 152.7, 144.6, 143.0, 137.0, 133.8, 131.4,
129.6, 129.2, 129.1, 129.0, 127.5, 127.0, 103.7; HRMS calcd for
C17H12N4 [M + H]+ 273.1135, found 273.1133.
3-Phenyl-6-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridazine (25f):
1
beige solid, 179 mg (75% yield); mp 272−275 °C. Data for 25f: H
NMR (600 MHz, DMSO-d6) δ 13.70 (br s, 1H), 8.58 (d, J = 8.3 Hz,
2H), 7.71 (s, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 3.46−
3.51 (m, 1H), 1.41 (d, J = 6.9 Hz, 6H); 13C NMR (150 MHz, DMSO-d6)
δ 162.2, 144.3, 142.7, 133.6, 131.6, 129.0, 128.9, 126.9, 103.5, 34.4, 22.9;
HRMS calcd for C14H14N4 [M + H]+ 239.1291, found 239.1293.
Method B: Preparation of Thieno[3,2-c]pyridazine Analogues
26a−d. A solution of 24 (1 mmol) in 5 mL of POCl3 was heated at
95 °C for 4 h, after which the reaction mixture was cooled down to room
temperature. POCl3 was evaporated, and the residue was dissolved in
EtOAc and washed 2 times with 20 mL of saturated aqueous NaHCO3.
The organic layer was dried over Na2SO4 and concentrated in vacuo to
afford the chlorinated pyridazine, used directly without further
purification for the next step.
To a solution of chlorinated pyridazine in 5 mL of EtOH was added
methyl thioglycolate (134 μL, 1.5 mmol) followed by Et3N (417 μL,
3 mmol), and the mixture was refluxed for 16 h. After completion of the
reaction (monitored by TLC), the reaction mixture was allowed to cool
to room temperature. CH2Cl2 was added, and the organic layer was then
washed 2 times with 10 mL of saturated aqueous NaHCO3 and 1 time
with 10 mL of saturated aqueous NaCl. The organic layer was dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by flash
column chromatography on silica gel (EtOAc/n-hexane = 1:9) to obtain
the desired thieno[3,2-c]pyridazine 26.
Ethyl 3-ethyl-7-(4-nitrophenyl)thieno[3,2-c]pyridazine-6-carboxy-
late (26a): brown solid, 185 mg (52% yield); mp 143−145 °C. Data for
26a: 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.36 (d, J = 8.8 Hz,
2H), 7.89 (d, J = 8.9 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 3.12 (q, J = 7.6
Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 161.1, 159.6, 156.4, 147.5, 139.4, 139.0, 138.0,
4-[3-(2-Fluorophenyl)-5H,6H,7H-pyridazino[4,3-e][1,4]diazepin-
9-yl]benzonitrile (27b): white solid, 271 mg (79% yield); mp 251−
1
255 °C. Data for 27b: H NMR (500 MHz, DMSO-d6) δ 8.02−8.05
(m, 1H, H6″), 7.96−7.97 (m, 1H, NH), 7.84 (d, J = 8.2 Hz, 2H, H2′, H6′),
7.64 (d, J = 7.8 Hz, 2H, H3′, H5′), 7.53−7.57 (m, 1H, H4″), 7.36−7.41
(m, 2H, H3″, H5″), 7.32 (s, 1H, H4), 4.16−4.17 (m, 2H, H7), 3.56−
3.57 (m, 2H, H6); 13C NMR (125 MHz, DMSO-d6) δ 168.0 (C9), 161.1
(C3), 159.1 (C2″), 151.8 (C), 146.5 (C), 139.8 (C1′), 131.7 (C4″),
K
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131.5 (C3′, C5′), 130.7 (C6″), 130.0 (C2′, C6′), 125.0 (C5″), 124.3
(C1″), 118.9 (C3″), 116.5 (CN), 112.3 (C4′), 111.0 (C4), 53.4
(C6), 47.6 (C7); HRMS calcd for C20H14FN5 [M + H]+ 344.1306,
found 344.1301.
3,9-Diphenyl-5H,6H,7H-pyridazino[4,3-e][1,4]diazepine (27f): yel-
low solid, 231 mg (77% yield); mp 186−189 °C. Data for 27f: 1H NMR
(600 MHz, DMSO-d6) δ 8.01 (m, 2H, H2′, H6′), 7.60−7.61 (m, 1H,
NH), 7.35−7.56 (m, 8H, H3′, H4′, H5′, H2″, H3″, H4″, H5″, H6″),
7.31 (s, 1H, H4), 4.09−4.10 (m, 2H, H7), 3.58−3.60 (m, 2H, H6); 13C
NMR (150 MHz, DMSO-d6) δ 169.3 (C9), 155.3 (C3), 146.8 (C),
141.9 (C), 140.9 (C1′), 136.3 (C1″), 129.8 (C4′), 129.1 (C2′, C6′),
129.0 (C3″, C5″), 128.7 (C4″), 127.5 (C3′, C5′), 126.7 (C2″, C6″),
108.5 (C4), 52.4 (C6), 48.3 (C7); HRMS calcd for C19H16N4 [M + H]+
301.1448, found 301.1446.
3-Ethyl-9-(thiophene-2-yl)-5H,6H,7H-pyridazino[4,3-e][1,4]-
diazepine (27c): yellow solid, 209 mg (81% yield); mp 185−188 °C.
Data for 27c: 1H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J = 4.9 Hz, 1H,
H5′), 7.36 (d, J = 3.0 Hz, 1H, H3′), 7.31 (br s, 1H, NH), 7.05 (t, J = 4.0
Hz, 1H, H4′), 6.69 (s, 1H, H4), 3.98−3.99 (m, 2H, H7), 3.52−3.53 (m,
2H, H6), 2.78 (q, J = 7.6 Hz, 2H, CH2), 1.26 (t, J = 7.6 Hz, 3H, CH3);
13C NMR (125 MHz, DMSO-d6) δ 162.6 (C9), 162.1 (C3), 146.0 (C),
145.1 (C), 139.9 (C2′), 130.5 (C3′), 129.2 (C4′), 127.2 (C5′), 110.2
(C4), 51.4 (C6), 48.3 (C7), 28.0 (CH2), 13.4 (CH3); HRMS calcd for
C13H14N4S [M + H]+ 259.1012, found 259.1007.
3-Cyclohexyl-9-phenyl-5H,6H,7H-pyridazino[4,3-e][1,4]diazepine
(27g): white solid, 242 mg (79% yield); mp 244−247 °C. Data for 27g:
1H NMR (500 MHz, DMSO-d6) δ 7.34−7.39 (m, 6H, NH, H2′, H3′,
H4′, H5′, H6′), 6.67 (s, 1H, H4), 4.01−4.03 (m, 2H, H7), 3.51−3.52
(m, 2H, H6), 2.68−2.72 (m, 1H, CH), 1.70−1.90 (m, 5H, CH2, CH2,
CH), 1.24−1.50 (m, 5H, CH2, CH2, CH); 13C NMR (125 MHz,
DMSO-d6) δ 169.4 (C9), 164.3 (C3), 146.7 (C), 142.0 (C), 140.6
(C1′), 129.1 (C2′, C6′), 128.6 (C4′), 127.4 (C3′, C5′), 108.9 (C4),
52.3 (C6), 48.3 (C7), 43.3 (CH), 32.2 (2xCH2), 26.1 (2xCH2), 25.8
(CH); HRMS calcd for C19H22N4 [M + H]+ 307.1917, found 307.1909.
9-(4-Chlorophenyl)-3-ethyl-4-methyl-5H,6H,7H-pyridazino[4,3-
e][1,4]diazepine (27d): beige solid, 247 mg (82% yield); mp 242−
247 °C. Data for 27d: 1H NMR (300 MHz, DMSO-d6) δ 7.38−7.39 (m,
4H, H2′, H3′, H5′, H6′), 6.64 (br s, 1H, NH), 4.01−4.04 (m, 2H, H7),
3.58−3.60 (m, 2H, H6), 2.86 (q, J = 7.6 Hz, 2H, CH2), 2.09 (s, 3H,
CH3), 1.22 (t, J = 7.5 Hz, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) δ
168.6 (C9), 159.7 (C3), 144.6 (C), 141.2 (C), 139.7 (C1′), 133.3 (C4′),
130.8 (C2′, C6′), 127.5 (C3′, C5′), 117.6 (C4), 52.5 (C6), 48.7 (C7),
26.7 (CH2), 13.3 (CH3), 11.7 (CH3); HRMS calcd for C16H17ClN4
[M + H]+ 301.1214, found 301.1217.
9-Phenyl-3-(propan-2-yl)-5H,6H,7H-pyridazino[4,3-e][1,4]-
diazepine (27h): white solid, 208 mg (78% yield); mp 208−212 °C.
1
Data for 27h: H NMR (500 MHz, DMSO-d6) δ 7.34−7.39 (m, 6H,
NH, H2′, H3′, H4′, H5′, H6′), 6.70 (s, 1H, H4), 4.01−4.02 (m, 2H,
H7), 3.52−3.53 (m, 2H, H6), 3.02−3.07 (m, 1H, CH), 1.25 (d, J = 6.9
Hz, 6H, 2xCH3); 13C NMR (125 MHz, DMSO-d6) δ 169.4 (C9), 165.2
(C3), 146.7 (C), 142.0 (C), 140.6 (C1′), 129.1 (C2′, C6′), 128.6 (C4′),
127.4 (C3′, C5′), 108.5 (C4), 52.3 (C6), 48.3 (C7), 33.5 (CH), 22.2
(2xCH3); HRMS calcd for C16H18N4 [M + H]+ 267.1604, found
267.1602.
9-Phenyl-3-(thiophene-2-yl)-5H,6H,7H-pyridazino[4,3-e][1,4]-
diazepine (27e): white solid, 242 mg (79% yield); mp 193−196 °C.
1
Data for 27e: H NMR (600 MHz, DMSO-d6) δ 7.73−7.74 (m, 1H,
H5″), 7.69−7.70 (m, 1H, H3″), 7.61−7.62 (m, 1H, NH), 7.34−7.44 (m,
5H, H2′, H3′, H4′, H5′, H6′), 7.25 (s, 1H, H4), 7.21−7.23 (m, 1H,
H4″), 4.07−4.08 (m, 2H, H7), 3.56−3.58 (m, 2H, H6); 13C NMR (150
MHz, DMSO-d6) δ 169.1 (C9), 151.2 (C3), 146.7 (C), 141.8 (C), 141.0
(C2″), 140.5 (C1′), 129.5 (C4′), 129.1 (C2′, C6′), 128.7 (C3″), 128.4
(C4″), 127.5 (C3′, C5′), 126.1 (C5″), 106.2 (C4), 52.3 (C6), 48.3
(C7); HRMS calcd for C17H14N4S [M + H]+ 307.1012, found 307.1016.
Method D: Preparation of Isoxazolo[4,5-c]pyridazine Ana-
logues 28a,b. A solution of 24 (1 mmol) in 5 mL of POCl3 was heated
at 95 °C for 4 h, after which the reaction mixture was cooled down to
room temperature. POCl3 was evaporated, and the residue was dissolved
in EtOAc and washed 2 times with 20 mL of saturated aqueous
NaHCO3. The organic layer was dried over Na2SO4 and concentrated in
vacuo to afford the chlorinated pyridazine, used directly without further
purification for the next step.
To a solution of chlorinated pyridazine in 5 mL of EtOH and 1 mL of
pyridine was added hydroxylamine hydrochloride (208 mg, 3 mmol),
and the mixture was refluxed for 16 h. After conversion of the ketone
into the corresponding oxime (monitored by TLC), the reaction
L
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mixture was allowed to cool to room temperature. CH2Cl2 was added,
and the organic layer was then washed 2 times with 10 mL of saturated
aqueous NaHCO3 and 1 time with 10 mL of saturated aqueous NaCl.
The organic layer was dried over Na2SO4 and concentrated in vacuo; to
the residue obtained dissolved in THF was slowly added NaH 60%
(52 mg, 1.3 mmol) under argon at room temperature. The reaction
mixture was heated at 40 °C for 2 h; after completion of the reaction
(monitored by TLC), the reaction mixture was allowed to cool to room
temperature. CH2Cl2 was added, and the organic layer was then washed
2 times with 10 mL of saturated aqueous NaHCO3 and 1 time with
10 mL of saturated aqueous NaCl. The organic layer was dried over
Na2SO4 and concentrated in vacuo, and the residue was purified by flash
column chromatography on silica gel (EtOAc/n-hexane = 1:4) to obtain
the desired isoxazolo[4,5-c]pyridazine 28.
3-(4-Chlorophenyl)-6-ethyl-7-methyl-isoxazolo[4,5-c]pyridazine
(28a): beige solid, 167 mg (61% yield); mp 189−192 °C. Data for 28a:
1H NMR (600 MHz, DMSO-d6) δ 8.55 (d, J = 8.7 Hz, 2H, H2′, H6′),
7.78 (d, J = 8.7 Hz, 2H, H3′, H5′), 3.20 (q, J = 7.5 Hz, 2H, CH2), 2.60 (s,
3H, CH3), 1.37 (t, J = 7.5 Hz, 3H, CH3); 13C NMR (150 MHz, DMSO-d6)
δ 162.3 (C), 156.2 (C3), 154.4 (C6), 144.6 (C1′), 136.9 (C4′), 130.0
(C2′, C6′), 129.8 (C3′, C5′), 125.2 (C7), 117.3 (C), 25.8 (CH2), 13.3
(CH3), 10.4 (CH3); HRMS calcd for C14H12ClN3O [M + H]+ 274.0742,
found 274.0743.
Baudemprez for NMR experiments, and Mrs. Chantal Biernaux
for excellent editorial help. We are indebted to Dr. Samia and Dr.
Dumbre for helpful discussions.
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3-Phenyl-6-(thiophene-2-yl)-isoxazolo[4,5-c]pyridazine (28b): or-
ange solid, 128 mg (46% yield); mp 208−211 °C. Data for 28b: H
1
NMR (600 MHz, DMSO-d6) δ 8.80 (s, 1H, H7), 8.52−8.54 (m, 2H,
H2′, H6′), 8.15 (d, J = 3.7 Hz, 1H, H5″), 7.88 (d, J = 5.0 Hz, 1H, H3″),
7.71−7.72 (m, 3H, H3′, H4′, H5′), 7.32 (t, J = 5.0 Hz, 1H, H4″); 13C
NMR (150 MHz, DMSO-d6) δ 156.7 (C), 155.1 (C3), 153.0 (C6),
145.9 (C2″), 139.6 (C1′), 132.1 (C4′), 131.4 (C3″), 129.5 (C2′, C6′),
128.9 (C4″), 128.7 (C5″), 128.3 (C3′, C5′), 125.9 (C7), 101.8 (C);
HRMS calcd for C15H9N3OS [M + H]+ 280.0539, found 280.0543.
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Imamura, S. Bioorg. Med. Chem. 2012, 20, 7051−7058.
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M. W.; Zhang, M.; Vickers, T.; Sorensen, K.; Norton, C.; Wen, J.; Heise,
C. E.; Saunders, J.; Conlon, P.; Madan, A.; Schwarz, D.; Goodfellow, V.
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6491.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of compounds 10, 15, 16, 18, 19,
21, and 22−28, as well as LC/MS analysis of compounds 24b−j,
25a−f, 26a−d, 27a−h, and 28a,b. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) (a) Galiullina, S. V.; Zakharova, V. M.; Kantin, G. P.; Nikolaev, V.
A. Zh. Org. Khim 2007, 43, 607−614. (b) Supurgibekov, M. B.; Hennig,
L.; Schulze, B.; Nikolaev, V. A. Zh. Org. Khim 2008, 44, 1840−1843.
(c) Supurgibekov, M. B.; Yanyuk, N. S.; Nikolaev, V. A. Zh. Org. Khim
2011, 47, 1252−1255.
AUTHOR INFORMATION
Corresponding Author
*E-mail: piet.herdewijn@rega.kuleuven.be. Tel: +32 (0)16/
33.73.87. Fax: +32 (0)16/33.73.40.
■
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Int. Ed. 2005, 44, 3889−3892. (c) Yang, X.; Knochel, P. Org. Lett. 2006,
9, 1941−1943. (d) Hamasaki, A.; Ducray, R.; Boger, D. L. J. Org. Chem.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The IWT (Agentschap voor Innovatie door Wetenschap en
Technologie) and the Galapagos company are acknowledged for
providing a PhD scholarship (Baekeland-project 90704). We are
grateful to Prof. Jef Rozenski for recording HRMS spectra, Luc
M
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= 3.8 Hz, 1H), 7.56−7.74 (m, 4H), 7.26 (t, J = 3.9 Hz, 1H), 7.02 (d, J =
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N
dx.doi.org/10.1021/jo400989q | J. Org. Chem. XXXX, XXX, XXX−XXX