I2-Promoted [4 + 2] cycloaddition of: In situ generated azoalkenes with enaminones: Facile and efficient synthesis of 1,4-dihydropyridazines and pyridazines

Article abstract of DOI:10.1039/d0ob01958e

A facile and efficient strategy for the synthesis of 1,4-dihydropyridazines and pyridazines through I2-promoted [4 + 2] cycloaddition of in situ generated azoalkenes with enaminones has been developed. The switch in selectivity is attributed to the judici

Full text of DOI:10.1039/d0ob01958e

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DOI: 10.1039/D0OB01958E
ARTICLE
I2-promoted [4 + 2] Cycloaddition of in Situ Generated Azoalkenes
with Enaminones: Facile and Efficient Synthesis of 1,4-
Dihydropyridazines and Pyridazines
Received 00th January 20xx,
Accepted 00th January 20xx
Jiajun Feng,a Tiantong He,a Yuxing Xie,b Yang Yu,c Jonathan B. Baell,a,d and Fei Huang*a,b
DOI: 10.1039/x0xx00000x
A facile and efficient strategy for the synthesis of 1,4-dihydropyridazines and pyridazines through I2-promoted [4+2]
cycloaddition of in situ generated azoalkenes with enaminones has been developed. The switch in selectivity is attributed
to the judicious choice of different reaction temperature. The key features of this work include the controllable and
selective synthesis, good functional group tolerance, good to excellent reaction yields, metal/base-free conditions, and
also
applicability
to
one-pot
methodology.
hydrazones.13 Some efficient methods such as the acid-
catalyzed recyclization14 and Lewis acid-mediated Mannich-
type addition have recently been reported for the synthesis of
1,4-dihydropyridazines.15 Despite the importance of these
reported methods, they still suffer from the requirements of
metal catalysts, stoichiometric amounts of oxidants, additives,
limited substrate scope or inaccessible starting materials.16
Introduction
Pyridazines and 1,4-dihydropyridazine derivatives, the six-
membered heterocycles which contain unique and valuable N-
N bonds derivatives, are widely found in many natural
products and pharmaceutically active compounds,1 such as
minaprine for treatment of various depressive states,1c
hydralazine as a vasodilator for hypertension treatment,1d
pyridazomycin as an antifungal and antibiotic,1e,1f and CK-103A
for treatment of ocular inflammation1g (Figure 1). For these
reasons, varieties of strategies have been developed for the
synthesis of pyridazines and 1,4-dihydropyridazines. The
classical routes to the pyridazines mainly include the 1,4-
dicarbonyl compounds reaction with hydrazines2 and [4 + 2]
cycloadditions of 1,2,4,5-tetrazine with alkynes.3 In recent
years, some efficient methods such as the intramolecular
diaza-Wittig reaction,4 addition of diazo compounds to
Morita−Baylis−Hillman carbonates,5 [4 + 2] cycloaddition of
Therefore, the development of
a facile and efficient
controllable strategy without metal and additives from easily
available starting materials for the construction of both 1,4-
dihydropyridazines and pyridazines is highly desirable.
COOH
NH2
N
N
N
Cl
N
N
N
N
N
Ph
N
O
N
H2N
Ph
N
EtO2C
EtO2C
N
H
N
O
H
H2N
O
Minaprine
antidepressant
Hydralazine
antihypertensive
Pyridazomycin
antifungal and antibiotic
1,2,3-triazines
with
ynamines,6
cascade
CK-103A
anti-inflammatory
imination/electrocyclization,7 6-endo-trig cyclization of β,γ-
unsaturated hydrazones8 and ring-contractive extrusion
reactions of 2,5-dihydro-1,4,5-thiadiazepine S-oxides have
been reported for the synthesis of pyridazines.9 For the 1,4-
dihydropyridazines, the known synthetic strategies for the 1,4-
dihydropyridazines include the reaction of 1,4-dicarbonyl
compounds with hydrazines,10 the reaction between 1,2-diaza-
1,3-butadienes and activated methine compounds,11 the
cycloaddition of 1,2,4,5-tetrazines with different dienophiles12
and the reaction of activated alkenes with aldehyde-derived
Fig.1 Example of pharmaceutically active compounds
containing pyridazine and 1,4-dihydropyridazine cores.
As easily available and high reactivity, hydrazones and their
derivatives have displayed numerous applications in synthetic
chemistry by participating in the construction of various
organic products.17 One of the most important conversion
approaches is the formation of 1,2-diaza-1,3-dienes
(azoalkenes)
from
dehydrohalogenation
of
α-halo
a. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, P. R.
China. E-mail: huangfei0208@yeah.net
ketohydrazones under base conditions, which has emerged as
a powerful tool for the synthesis of N-heterocyclic compounds
through cycloaddition reactions (Scheme 1a).18 However, [4 +
2] cycloaddition of non-prefunctionalized ketohydrazones to
give six-membered N-heterocycles has rarely been
documented.19 For example, Han et. al. reported the first
example hydrazonyl radical-involved tandem oxidative
b. School of Food Science and Pharmaceutical Engineering, Nanjing Normal
University, Nanjing 210023, P. R. China.
c. School of Environmental Science and Engineering, Nanjing Tech University,
Nanjing 211816, P. R. China.
d. Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria 3052, Australia.
†
Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
R2
a) Cycloaddition reactions of -halo ketohydrazones
[4+1]
dehydrogenation/aza-Diels-Alder reaction for the synthesis of
tetrahydropyridazines in the presence of TEMPO (3.0 equiv) as
the mediator and oxidant (Scheme 1b).19a Luo et. al. developed
a distinctive oxidative radical [4 + 2] cycloaddition for the
synthesis of tetrahydropyridazines using copper as a catalyst
(Scheme 1c).19b Therefore, the development of non-
prefunctionalized ketohydrazones, mild, efficient, metal-free
and additive-free [4 + 2] cycloaddition reactions to give six-
membered N-heterocycles are still in high demand.
Enaminones are versatile building blocks in organic synthesis
due to the ambident nucleophilicity of enamine and the
ambident electrophilicity of enone.20 Reactions of the
hydrazones with enaminones have been developed for the
synthesis of valuable organic products.21 For example, we
previous reported copper-catalyzed formal carbene migratory
insertion into the olefinic C=C bonds of α-oxo ketene N,S-
acetals with hydrazones for synthesis of iminofurans (Scheme
1d).21b Very recently, Gong and co-workers disclosed an
efficient two-step synthetic strategy to construct pyridazines
via [4 + 2] cycloaddition–elimination, which use α-halogeno
hydrazones as starting materials (Scheme 1e).21e In this
context, it’s necessary to establish more facile and efficient
strategy by using non-prefunctionalized ketohydrazones as the
N2-annulation synthons to allow divergent synthesis of 1,4-
dihydropyridazines and pyridazines under metal/base-free
conditions. In recent years, the molecular iodine-promoted
intermolecular cyclization has been intensively developed to
construct of heterocyclic compounds owing to its low toxicity,
inexpensive, and ready availability.22 Herein, we present I2-
promoted [4 + 2] cycloaddition of N-sulfonylhydrazones with
enaminones for synthesis of 1,4-dihydropyridazines and
pyridazines via in situ generation of azoalkene (Scheme 1f).
The switch in selectivity is attributed to the judicious choice of
different reaction temperature.
View Article Online
DOI: 10.1039/D0OB01958E
O
N
N
ref 18b
R3
R1
R2
R2
R2
N
N
NH
Base
HX
[4+2]
ref 18c
N
N
N
X
R1
N
R1
X= Cl, Br
R1
R2
N
O
[4+3]
ref 18d
R1
b) Han's work: synthesis of tetrahydropyridazines
Ar
R3
R2
Ar
N
R2
NH
Tempo (3.0 equiv)
Ar, toluene, 80 o
42-72 h
c) Luo's work: synthesis of tetrahydropyridazines
+
N
N
R3
C
R3
R1
R1
Ts
Cu(CH3CN)4BF4 (5 mol%)
(PhO)2P(O)OH (5 mol%)
R2
R3
R2
N
NNHTs
N
R3
R1
+
I2 (5 mol%), TBHP (4 equiv)
24 h
Ar
Ar
R1
d) Our previous work: synthesis of iminofurans
CuBr2 cat.
NR4
R2
R1
NNHTs
O
NHR4
SMe
tBuOLi
toluene, 110 o
+
O
R1 R2
R3
C
R3
e) Gong's work: synthesis of pyridazine and tetrahydrocinnoline derivatives
Ts
N
O
N
N
HBr (aq)
R2
R3
dioxane, 100 o
C
R3
N
R1
N
NH
N
N
O
N
R3
Boc
N
R1
X
R1
K2CO3, DCM, r.t.
MSA
O
DCM, r.t.
R2= Boc, Ts, X=Cl, Br
R3
R1
O
f) This work: synthesis of 1.4-dihydropyridazines and pyridazines
R3
N
R3
N
O
N
I2
I2
NH
N
R4
N
R4
N
R1
+
R4
R2
R1
DMSO
120 o
DMSO
R2
O
R1
C
80 o
C
R2
3
O
4
1
2
Scheme 1 Previous works and present Study.
Results and discussion
To establish the optimal reaction conditions, we set out to
investigate the [4 2] cycloaddition reaction of N-
+
tosylhydrazone 1a and enaminone 2a as model substrates
(Table 1). To our delight, the desired product 1,4-
dihydropyridazine 3a was furnished in 61% isolated yield when
the reaction proceeded in the presence of 1.0 equiv iodine at
80 °C for 5 h in toluene (Table 1, entry 1). First, various
solvents were screened with I2 (1.0 equiv) as the promoter at
o
80 C. It was found that DMSO was the most effective solvent
with significantly improving the reaction yield up to 91% (Table
1, entry 5), while no improvement was observed in other
solvents such as DMF, CH3CN and H2O (Table 1, entries 2-4). To
increase the yield of the desired product 3a, variation of
additives (TBHP, DTBP, K2S2O8, DDQ, AcOH, and K2CO3) were
also investigated (Table 1, entries 6-11). With respect to these
oxidants, DTBP showed no significant change in the reaction
yield, while the use of other oxidants (TBHP, K2S2O8 and DDQ)
resulted in a sharp drop in the yield of 3a. It is noteworthy that
K2S2O8 and DDQ might assist the release of Ts group, affording
the pyridazine product 4a in 14% and 12% yield, respectively
(Table 1, entries 8-9). Moreover, additives such as bases and
acids did not further improve the yield of 3a (Table 1, entries
10-11). Further
Table 1 Screening of reaction conditionsa
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Ts
N
N
With the optimal reaction conditions in hand, the substrates
scope of this conversion was then investigated with a diverse
View Article Online
DOI: 10.1039/D0OB01958E
O
N
NNHTs
iodine reagent, additive
solvent, temp.
N
+
+
Ph
Ph
N
Ph
Ph
Ph
Ph
O
set of hydrazones
1 and enaminones 2. (Scheme 2).
O
1a
2a
3a
4a
Acetophenone-derived N-tosylhydrazones bearing electron-
withdrawing groups (e.g., NO2, F, Cl, Br) and electron-donating
(e.g., CH3, OCH3) at the para-position of the phenyl were well
tolerated to afford the corresponding products 3b-i in good to
excellent yields (64-91%). To verify the structure of the 1,4-
dihydropyridazines, 3e was selected as the representative
compound and was firmly confirmed by single crystal X-ray
analysis. The formation of 3f (64%), 3g (67%) and 3h (66%)
exhibited that no obvious steric effect was obtained in this
transformation. To our delight, the N-tosylhydrazones derived
from alkyl ketones 1j could also participate in this reaction,
affording the expected product 3j in 54% yield. Notably,
sterically bulky 2-naphthyl-derived N-tosylhydrazones 1k was
also compatible, giving the desired product 3k in 77% yield. In
addition, heterocyclic substituted substrates, such as 2-furyl-
derived and 2-thienyl-derived N-tosylhydrazones led to the
corresponding products 3l, 3m in 86% and 88% yields,
respectively. Moreover, the α-substituted N-tosylhydrazones
were also investigated, when α-methyl-substituted N-
tosylhydrazones 1n was used as the substrate, the desired
product 3n was obtained in 27% yield. However, sterically
hindered α-phenyl-substituted N-tosylhydrazones 1o gave a
trace amount of the desired product 3o. Furthermore,
different N-sulfonylhydrazones 3p-r were well tolerated in the
reaction to give the desired product 3p-r in excellent yields
(88-90%). Finally, hydrazones with different groups on the
nitrogen atom were tested. N-phenylhydrazones 1s was also
compatible, albeit forming the desired product 3s in low yield
(30%). Unfortunately, the N-benzoylhydrazones 1t wasn’t
suitable for the reaction, without obtaining the desired
product 3t.
Next, we turn our attention to investigating the scope of
enaminones under the optimized reaction conditions. The
reaction is not significantly affected by the electronic nature of
the substituents on the phenyl ring, both electron-withdrawing
(e.g., CF3, F, Cl, Br,) and electron-donating (e.g., CH3, OCH3)
groups performing well and delivering in good to high yields
(73-90%). 4-F, 3-F, 2-F groups on the phenyl of substrates 2
prove no steric effect on the yield of 3v (74%), 3y (79%) and 3z
(76%), respectively. More importantly, naphthalenyl and alkyl-
substituted substrates were also compatible, leading to 3zc
and 3zd in 74 and 75% yields, respectively. In addition, the
heteroaryl-based enaminones were also successfully employed
to provide the corresponding products 3ze-zf in good yields
(62-65%). It is worth noting that enaminones bearing different
N-substitution also gave satisfactory results. When N,N-
dibenzyl enaminones 2n was used as substrate, the desired
product 3a was isolated in 65% yield.
yieldb (%)
entry iodine reagent additive
solvent
temp. (oC)
3a
4a
1
2
I2
I2
-
-
toluene
DMF
CH3CN
H2O
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
40
100
110
120
120
61
38
30
32
91
90
48
16
trace
trace
trace
trace
trace
trace
trace
14
3
I2
-
4
I2
-
5
I2
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
I2
DTBP
7
I2
TBHP
8
I2
K2S2O8
9
I2
DDQ
trace
90
trace
nd
12
10
11
12
13
14
15
16
17
18
19c
20d
21e
22e
23e
24e
25e
26f
I2
I2
-
KI
PIDA
KIO3
TBAI
NH4I
NIS
I2
I2
I2
I2
I2
I2
I2
I2
AcOH
K2CO3
trace
trace
nd
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
nd
nd
trace
trace
nd
nd
nd
nd
nd
nd
54
84
91
85
71
81
72
trace
trace
trace
trace
trace
trace
18
nd
nd
85
86
aConditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst (0.3 mmol),
additive (2.0 equiv) solvent (3 mL), air, 5 h, ND = not detected.
bisolated yield, cI2 (0.8 equiv), dI2 (1.2 equiv), e24 h. fReaction stirred
under N2
control experiment was conducted without detecting the
desired product in the absence of I2, indicating the necessity of
I2 in this reaction (Table 1, entry 12). Next, a series of Iodine
reagents, including KI, PIDA, KIO3, TBAI, NH4I and NIS, were
examined for the model reaction (Table 1, entries 13-18).
Among them, the NIS performed as the best choice by
affording 54% of 3a (Table 1, entry 18), while the other iodide
sources failed to work (Table 1, entries 13-17). Furthermore,
the lower loading of I2 (0.8 equiv) showed a decreased reaction
yield for 3a (84%) and no significant change on higher loading
of I2 (1.2 equiv) (Table 1, entries 19 and 20). Finally, lowering
or elevating temperature did not improve the reaction
efficiency to form 1,4-dihydropyridazine 3a (Table 1, entries
21-25). To our surprise, further elevating temperatures to 120
°C obviously improved the yield of the pyridazine product 4a
(85% isolated yield) without using any additives,
demonstrating that increasing the temperature would assist
release of the Ts group (Table 1, entry 25). When we
performed the reaction in
a nitrogen atmosphere, no
significant change in the yield of 4a was observed (Table 1,
entry 26). Thus, we found that the switch in selectivity is
attributed to the judicious choice of different reaction
temperature.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
R3
N
R3
Scheme 3 Scope of I2-prometed [4 + 2] Cycloaddition Synthesis of
DOI: 10.1039/D0OB01958E
Pyridazines with Various Hydrazones and Enaminones. Reaction
conditions: 1 (0.3 mmol), 2a (0.45 mmol), I2 (0.3 mmol), DMSO (3
mL), 0.1 MPa air, 120 oC. Yields refer to the isolated products.
O
View Article Online
I2 (1.0 equiv)
DMSO, 80 o
NH
N
+
N
R4
N
R4
C
R2
R1
R1
R2
3
O
1
2
Ts
Ts
N
N
N
a
3a
, R = H, 91% (65%)
N
3b, R = NO2, 82%
Ph
3c
Ph
Ph
, R = F, 78%
, R = Cl, 80%
Considering that N-tosylhydrazones are very readily formed
by the condensation of ketones and hydrazines under acidic
conditions, we explored the possibility of performing a one-pot
transformation of the ketones, tosylhydrazine, and
enaminones. First, the condensation of ketones and
tosylhydrazine in the presence of 20% HOAc in EtOH almost
quantitatively yielded N-tosylhydrazones 1. After removing
ethanol, addition of iodine, enaminones 2 and DMSO to the
mixture stirred at 80 °C for 3-5 h. As shown in Scheme 4a,
some of the representative substrates were found to be
transformed into the desired products in comparable yields.
One-pot three-component
O
3d
Br
O
O
3e
, 80%
Ts
R
Ts
N
Ts
N
N
N
N
3f
, 4-Me, 64%
N
Ph
3g
3h
, 3-Me, 67%
, 2-Me, 66%
Ph
Me
Me
O
O
MeO
3i
3j
, 82%
, 54%
Ts
Ts
Ts
Ts
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
X
Me
O
O
Ph
O
O
Cl
3l
, X = O, 86%
3k
3n
3o
, trace
, 77%
, 27%
3m
, X = S, 88%
R
3u
3v
, R = 4-CF3, 79%
, R = 4-F, 74%
R
N
Ts
N
3w
, R = 4-Cl, 73%
, R = 4-Br, 76%
, R = 3-F, 79%
, R = 2-F, 76%
3p
3q
, R = Cl, 88%
, R = Br, 90%
, R = OMe, 90%
N
3x
3y
N
R
O
N
S
N
O
Ph
3r
Ph
3z
a) One-Pot Two-Steps Synthesis of 1,4-dihydropyridazine
O
O
, R = Ph, 30%
O
O
3za
, R = 4-Me, 90%
Ph
3s
3t
Ts
3zb
, R = 4-OMe, 73%
Ts
NH
R2
N
, R = COPh, trace
O
N
O
2
N
AcOH (0.2 equiv)
EtOH, 80 oC, 3 h
N
R2
+
TsNHNH2
Ts
Ts
N
Ts
N
Ts
R1
R1
I2 (1.0 equiv)
R1
Ph
N
N
N
DMSO, 80 o
Ts
C
N
N
N
S
1
O
3
Me
Ph
Ph
Ph
Ph
Ts
Ts
N
Ts
O
O
O
O
N
N
N
N
N
3zc
3zd
3ze
3zf
, 65%
, 74%
, 75%
, 62%
N
N
Ph
Ph
O
Ph
O
Ph
O
O
O
3l
, 83%
Cl
MeO
Scheme 2 Scope of I2-prometed [4 + 2] Cycloaddition Synthesis of
1,4-Dihydropyridazines with Various Hydrazones and Enaminones.
Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), I2 (0.3 mmol),
DMSO (3 mL), 0.1 MPa air, 80 oC. Yields refer to the isolated
products. a(E)-3-(dibenzylamino)-1-phenylprop-2-en-1-one 2n as
substrate.
3a
3d
3i
, 84%
Ts
, 76%
, 79%
Ts
Ts
N
N
Br
N
Me
N
N
N
Ph
Ph
Ph
O
O
O
3x
3za
3zd
, 71%
, 87%
, 73%
b) One-Pot Three-Component Synthesis of 1,4-dihydropyridazine
Ts
N
O
O
I2, (1.0 equiv)
DMSO, 80 o
N
TsNHNH2
+
+
Ph
Ph
N
Ph
To our delight, when the reaction temperature was elevated
to 120 °C, the Ts group would release and pyridazines were
obtained. This reaction displayed high functional group
tolerance and proved to be a quiet general methodology for
preparation of pyridazines. The substrate scope of the
pyridazine is shown in Scheme 3. Generally, the reactions
tolerated a broad range of N-tosylhydrazones and substituted
enaminones, giving the corresponding products 4a-l in good to
high yield (68-89%).
C
Ph
O
sm1a
sm1b
2a
3a
, 42%
Scheme
4 One-Pot Reaction of Ketones, Tosylhydrazine and
Enaminones. Reaction conditions: Ketones (0.3 mmol),
tosylhydrazines (0.305 mmol) enaminones 2 (0.45 mmol), I2 (0.3
mmol), DMSO (3 mL), 0.1 MPa air, 80 oC. Yields refer to the isolated
products.
Ts
NH
N
transformation of acetophenone, tosylhydrazine and
enaminone was also explored, furnishing the desired
compound 3a in 42% yield (Scheme 4b).
O
N
I2 (1.0 equiv)
N
R4
+
R4
N
R1
DMSO, 120 o
C
R1
O
1
2
4
To demonstrate the potential applications for organic
synthesis, the gram-scale preparation of 3a and 4l with slightly
decreased efficiency demonstrate the practicability of this
method (Scheme 5a-b). Considering that heteroaromatic N-
oxides existed in a number of biologically active compounds,23
treatment of 4a with m-CPBA as the oxidant resulted in the
facile formation of the pyridazine N-oxide derivative 5 in a 72%
yield (Scheme 5c).
N
N
4a
4b
4c
4d
4e
, R = H, 85%
, R = Cl, 85%
, R = Br, 89%
, R = Me, 68%
, R = OMe, 69%
N
N
R
N
4g
4h
4i
, R = Cl, 80%
, R = Me, 81%
, R = OMe, 72%
Ph
Ph
O
O
O
R
N
N
N
N
N
O
N
N
Ph
S
Ph
Ph
O
Br
O
F3C
O
4f
4j
4k
4l
, 86%
, 78%
, 69%
, 66%
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
Ts
N
O
NNHTs
O
View Article Online
I2 (1.0 equiv)
DMSO, 80 o
Ts
Ts
N
Ts
DOI: 10.1039/D0OB01958E
Ph
N
a)
+
N
N
NH
NH
N
C
2a
N
N
I2
N
O
I
aza-D-A
reaction
1a
2a
Ph
, 4 mmol
1.15 g
, 6 mmol
1.05 g
Ph
Ph
3a,
81%, 1.35 g
HI
HI
1a
A
B
N
N
NNHTs
+
O
I2 (1.0 equiv)
DMSO, 120 o
Ts
N
Ts
b)
C
N
N
O
N
O
Br
N
F3C
Br
N
F3C
N
-HNMe2
-TsH
Ph
Ph
1u
2m
Ph
, 3 mmol
1.07 g
, 4.5 mmol
1.14 g
Ph
4l
, 80%, 0.97 g
Ph
Ph
O
O
C
3a
4a
O
N
N
N
m-CPBA (2.0 equiv)
CHCl3, 0 oC to r.t., 4 h
N
c)
Scheme 6 Proposed Mechanism.
O
O
4a
5
, 72%
Scheme 5 Gram-scale Experiments and Application of the Synthetic
Methodology.
Conclusions
In summary, we have developed the I2-promote [4 + 2]
cycloaddition of in situ generated azoalkenes with enaminones
for the synthesis of 1,4-dihydropyridazines and pyridazines.
The switch in selectivity is attributed to the judicious choice of
different reaction temperature. The gram-scale preparation
experiment and synthesis of pyridazine N-oxide derivative
demonstrate the potential applicability of our synthetic
method. Notable features of this metal/base-free strategy
include controllable and selective synthesis, broad functional
group compatibility, and also applicability to one-pot
methodology.
To gain insight into the reaction mechanism, we performed
some control experiments. When the oxidative radical
scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added to the reaction system, this conversion was partially
inhibited leading to 3a in 42 yields. The addition of a non-
oxidizing radical scavenger 2,6-di-tert-butyl-4-methyl phenol
(BHT) obtained the product 3a without any inhibition or
sluggishness, indicating that a radical pathway might not be
involved in this transformation (eqn (1)). The reaction of N-
sulfonylhydrazone 1a with iodine (1.0 equiv) in CH3CN at room
temperature for 1 h could afford α-iodo N-sulfonylhydrazones
A.19b,22d After removing the CH3CN, enaminone 2a and DMSO
were added to the mixture stirred at 80 °C for 2 h, giving the
desired product 3a in 75% yield (eqn (2)), showing that α-iodo
N-sulfonylhydrazones A was an intermediate for the formation
of 3a.
Experimental
General information
The solvents were dried and distilled prior to use by the
literature methods. Analytical TLC plates, Sigma-Aldrich silica
gel 60F200 were viewed by UV light (254 nm). Column
chromatographic purifications were performed on SDZF silica
1
gel 160. H and 13C NMR spectra were obtained on a Bruker
Ts
O
N
I2 (1.0 equiv)
NNHTs
N
NMR spectrometer at 400 MHz and 100 MHz, respectively, and
referenced internally based on the residual solvent signal. The
+
Ph
N
DMSO, 80 o
C
Ph
(1)
Ph
Ph
1a
2a
radical inhibitor
3a O
1
data reporting for H NMR spectra is as follows: chemical shift
TEMPO (2.0 equiv)
BHT (2.0 equiv)
42%
85%
(δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant in hertz, and number
of protons. The data reporting for 13C spectra is given as
chemical shift (δ, ppm). High-resolution mass spectra (HRMS)
were obtained on an Agilent mass spectrometer using
electrospray ionization-time of flight (ESI-TOF). Melting points
were measured with a melting point instrument without
correction. All the chemical reagents were purchased from
commercial sources and used as received unless otherwise
indicated.
O
Ts
N
Ph
N
NNHTs
N
CH3CN
r.t., 1 h
NNHTs
2a
+
I2
Ph (2)
I
Ph
Ph
DMSO, 80 oC, 2 h
Ph
O
1a
A
3a
, 75%
On the basis of the above results as well as the literature
reports,18,24 a plausible reaction mechanism has been proposed
(Scheme 6). The α-iodination of N-sulfonylhydrazones 1a took place
to form intermediate A, and subsequently, the intermediate A was
transformed to the azoalkene B by the elimination of HI. Then, the
[4 + 2] cycloaddition of azoalkene B with enaminone 2a to generate
intermediate C. Finally, the intermediate C can be converted to the
desired product 3a via the release of dimethylamine, which can be
generated pyridazine 4a by elimination of TsH.
General
procedure
for
the
synthesis
of
1.4-
dihydropyridazines (3) - Synthesis of 3a: a mixture of (E)-4-
methyl-N'-(1-phenylethylidene) benzene sulfonohydrazide 1a
(86 mg, 0.3 mmol), (E)-3-(dimethylamino)-1-phenylprop-2-en-
1- one 2a (79 mg, 0.45 mmol), I2 (76 mg, 0.3 mmol) in 3 mL
DMSO was stirred at 80 oC for 5 h. After completion, the
reaction mixture was cooled to room temperature and diluted
with 15 mL of water. The water layer was extracted with (3 x
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Organic & Biomolecular Chemistry
Page 6 of 12
ARTICLE
Journal Name
15 mL) of EtOAc and then (2 x 15 mL) of brine wash. The Phenyl(6-(p-tolyl)-2-tosyl-2,5-dihydropyridazin-4-yl)methano-
View Article Online
o
1
organic layer was dried over sodium sulfate and concentrated ne (3f): 83 mg, yield 64%, white solid,DmOI.:p1.0:.1108399/-D109O1B0C19.58HE
under reduced pressure to get the crude compound. The crude NMR (400 MHz,CDCl3) δ 7.89 – 7.84 (m, 3H), 7.72 (d, J = 8.2 Hz,
compound was purified by silica gel column chromatography 2H), 7.64 – 7.56 (m, 3H), 7.50 (t, J = 7.4 Hz, 2H), 7.36 (d, J = 8.2
(eluent: petroleum ether (60-90 oC)/EtOAc/DCM = 10:1:1, Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 3.50 (s, 2H), 2.43 (s, 3H), 2.39
v/v/v), affording 3a as a white solid (113 mg, 91%).
Phenyl(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)methanon- 145.51, 141.42, 137.89, 135.07, 133.43, 132.03, 131.94,
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.93, 151.09,
o
1
e (3a): 113 mg, yield 91 %, white solid, m.p.: 155-157 C. H 129.98, 129.32, 128.79, 128.73, 128.45, 126.48, 111.56, 22.08,
NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.4 Hz, 2H), 7.86 (s, 1H), 21.81, 21.57. HRMS (ESI) m/z calcd for C25H23N2O3S [M+H]+:
7.82 (dd, J = 7.9, 1.6 Hz, 2H), 7.64 – 7.57 (m, 3H), 7.51 (t, J = 7.4 431.1424, Found: 431.1427.
Hz, 2H), 7.47 – 7.40 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H), 3.53 (s, Phenyl(6-(m-tolyl)-2-tosyl-2,5-dihydropyridazin-4-yl)methan-
2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.90, one (3g): 86 mg, yield 67%, white solid, m.p.: 142-144 C. H
151.12, 145.64, 137.87, 135.03, 134.80, 133.45, 132.01, NMR (400 MHz,CDCl3) δ 7.90 – 7.84 (m, 3H), 7.64 – 7.56 (m,
131.03, 130.12, 128.82, 128.76, 128.63, 128.48, 111.61, 22.18, 5H), 7.50 (t, J = 7.4 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.31 (t, J =
21.84. HRMS (ESI) m/z calcd for C24H21N2O3S [M+H]+: 417.1267, 7.5 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H), 3.51 (s, 2H), 2.43 (s, 3H),
o
1
Found: 417.1262.
2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.93, 151.27,
(6-(4-Nitrophenyl)-2-tosyl-2,5-dihydropyridazin-4-yl)(phenyl)- 145.57, 138.26, 137.88, 135.08, 134.76, 133.46, 131.98,
methanone (3b): 113 mg, yield 82%, yellow solid, m.p.: 188- 131.79, 129.99, 128.81, 128.74, 128.51, 128.48, 127.24,
190 oC. 1H NMR (400 MHz,CDCl3) δ 8.28 (d, J = 8.9 Hz, 2H), 7.96 123.72, 111.62, 22.22, 21.82, 21.61. HRMS (ESI) m/z calcd for
(d, J = 8.9 Hz, 2H), 7.88 – 7.83 (m, 3H), 7.64 – 7.58 (m, 3H), 7.52 C25H23N2O3S [M+H]+: 431.1424; Found: 431.1417.
(t, J = 7.4 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 3.56 (s, 2H), 2.45 (s, Phenyl(6-(o-tolyl)-2-tosyl-2,5-dihydropyridazin-4-yl)methano-
o
1
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.64, 149.07, 148.92, ne (3h): 85 mg, yield 66%, white solid, m.p.: 103-105 C. H
146.05, 140.53, 137.50, 134.44, 133.13, 132.29, 130.22, NMR (400 MHz,CDCl3) δ 7.88 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H),
128.88, 128.82, 128.46, 127.35, 123.87, 111.59, 22.26, 21.89. 7.64 (d, J = 7.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4
HRMS (ESI) m/z calcd for C24H20N3O5S [M+H]+: 462.1118, Hz, 2H), 7.37 – 7.32 (m, 3H), 7.31 – 7.26 (m, 1H), 7.22 (t, J = 8.6
Found: 462.1109.
Hz, 2H), 3.46 (s, 2H), 2.44 (s, 3H), 2.24 (s, 3H);13C{1H} NMR (100
(6-(4-Fluorophenyl)-2-tosyl-2,5-dihydropyridazin-4-yl)(pheny- MHz, CDCl3) δ 193.62, 153.85, 145.55, 137.80, 136.71, 135.38,
l)methanone (3c): 102 mg, yield 78%, white solid, m.p.: 171- 135.23, 133.47, 132.05, 131.45, 129.96, 129.72, 128.81,
173 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.83 (m, 3H), 7.83 – 128.74, 128.50, 128.07 , 125.96, 111.37, 25.50 , 21.80, 21.35.
7.77 (m, 2H), 7.63 – 7.56 (m, 3H), 7.50 (t, J = 7.4 Hz, 2H), 7.37 HRMS (ESI) m/z calcd for C25H22N2O3SNa [M+Na]+: 453.1243;
(d, J = 8.2 Hz, 2H), 7.11 (t, J = 8.6 Hz, 2H), 3.49 (s, 2H), 2.44 (s, Found: 453.1242.
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.86, 164.47 (d, J = (6-(4-Methoxyphenyl)-2-tosyl-2,5-dihydropyridazin-4-yl)(phe-
252.0 Hz), 150.08, 145.69, 137.77, 134.88, 133.36, 132.06, nyl)methanone (3i): 110 mg, yield 82%, white solid. m.p.: 172-
131.02 (d, J = 3.2 Hz), 130.07, 128.80, 128.78, 128.64 (d, J = 8.7 173 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.86 (d, J = 6.6
Hz), 128.44, 115.75 (d, J = 21.9 Hz), 111.41, 22.19, 21.85; 19F Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.63 – 7.56 (m, 3H), 7.50 (t, J =
NMR (376 MHz, CDCl3) δ -108.78 (s, 1F). HRMS (ESI) m/z calcd 7.3 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.85
for C24H20FN2O3S [M+H]+: 435.1173, Found: 435.1163.
(s, 3H), 3.49 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
(6-(4-Chlorophenyl)-2-tosyl-2,5-dihydropyridazin-4-yl)(pheny- δ 194.03, 161.90, 150.71, 145.52, 137.95, 135.13, 133.50,
l)methanone (3d): 103 mg, yield 80%, white solid, m.p.: 178- 131.95, 130.01, 128.82, 128.76, 128.47, 128.23, 127.40,
180 oC. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.84 (d, J = 7.1 113.96, 111.42, 55.53, 22.05, 21.85. HRMS (ESI) m/z calcd for
Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.64 – 7.57 (m, 3H), 7.51 (t, J = C25H23N2O4S [M+H]+: 447.1373, Found: 447.1363.
7.4 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.49 (6-Methyl-2-tosyl-2,5-dihydropyridazin-4-yl)(phenyl)methan-
o
1
(s, 2H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.87, one (3j): 57 mg, yield 54%, brown solid. m.p.: 156-158 C. H
150.06, 145.76, 137.74, 137.17, 134.85, 133.32, 132.26, NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H),
132.11, 130.11, 128.93, 128.82, 128.46, 127.82, 111.50, 22.10, 7.60 – 7.53 (m, 3H), 7.50 – 7.44 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H),
21.87. HRMS (ESI) m/z calcd for C24H20ClN2O3S [M+H]+: 3.04 (s, 2H), 2.44 (s, 3H), 2.01 (s, 3H); 13C{1H} NMR (100 MHz,
451.0878, Found: 451.0874.
CDCl3) 13C NMR (101 MHz, CDCl3) δ 193.86, 155.27, 145.37,
(6-(4-Bromophenyl)-2-tosyl-2,5-dihydropyridazin-4-yl)(pheny- 137.77, 135.43, 133.43, 131.95, 129.93, 128.73, 128.70,
l)methanone (3e): 119 mg, yield 80%, white solid, m.p.:177- 128.34, 110.88, 25.68, 23.78, 21.81. HRMS (ESI) m/z calcd for
o
1
180 C. H NMR (400 MHz, CDCl3) δ 7.87 – 7.82 (m, 3H), 7.67 C19H19N2O3S [M+H]+: 355.1111, Found: 355.1105.
(d, J = 8.6 Hz, 2H), 7.63 – 7.58 (m, 3H), 7.56 (d, J = 8.6 Hz, 2H), (6-(Naphthalen-2-yl)-2-tosyl-2,5-dihydropyridazin-4-yl)(phen-
7.51 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 3.49 (s, 2H), 2.44 yl)methanone (3k): 107 mg, yield 77%, white solid. m.p.: 217-
o
1
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.85, 151.14, 219 C. H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.07 (dd, J =
145.76, 137.73, 134.82, 133.71, 133.32., 132.12, 131.90, 8.7, 1.7 Hz, 1H), 7.93 – 7.89 (m, 4H), 7.86 (d, J = 8.8 Hz, 2H),
130.10, 128.82, 128.46, 128.01, 125.64, 111.51, 22.04, 21.88. 7.66 – 7.62 (m, 2H), 7.62 – 7.58 (m, 1H), 7.57 – 7.50 (m, 4H),
HRMS (ESI) m/z calcd for C24H20BrN2O3S [M+H]+: 495.0370, 7.38 (d, J = 8.1 Hz, 2H), 3.66 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR
Found:495.0377.
(100 MHz, CDCl3) δ 194.08, 150.88, 145.67, 137.93, 135.00,
6 | J. Name., 2012, 00, 1-3
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ARTICLE
134.58, 133.51, 132.92, 132.28, 132.05, 130.09, 129.03, 7.60 (m, 2H), 7.57 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H),
View Article Online
128.87, 128.82, 128.55, 128.39, 127.83, 127.73, 127.46, 7.47 – 7.40 (m, 3H), 7.02 (d, J = 9.0 Hz, D2OHI):,130..180639(/sD,03OHB)0,1395.583E
126.84, 123.12, 111.79, 22.01, 21.86. HRMS (ESI) m/z calcd for (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.88, 164.29,
C28H23N2O3S [M+H]+: 467.1424, Found: 467.1430.
(6-(Furan-2-yl)-2-tosyl-2,5-dihydropyridazin-4-yl)(phenyl)me-
151.00, 137.87, 135.05, 134.80, 131.96, 130.98, 130.73,
128.78, 128.73, 128.61, 127.66, 126.52, 114.59, 111.40, 77.48,
thanone (3l): 105 mg, yield 86%, yellow solid. m.p.: 136-138 77.16, 76.84, 55.86, 22.17 (s). HRMS (ESI) m/z calcd for
1
oC. H NMR (400 MHz,CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.82 (s, C24H20N2O4SNa [M+Na]+: 455.1036, Found: 455.1034.
1H), 7.61 – 7.55 (m, 4H), 7.49 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 8.2 (2,6-Diphenyl-2,5-dihydropyridazin-4-yl)(phenyl)methanone
o
1
Hz, 2H), 6.89 (d, J = 3.4 Hz, 1H), 6.50 (dd, J = 3.4, 1.7 Hz, 1H), (3s): 30 mg, yield 30%, white solid, m.p.: 182-184 C. H NMR
3.41 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (400 MHz, CDCl3) δ 8.04 – 7.99 (m, 2H), 7.64 (d, J = 6.8 Hz, 2H),
193.71, 149.49, 145.57, 145.30, 143.10, 137.7, 135.22, 133.30, 7.63 (s, 1H), 7.54 – 7.50 (m, 1H), 7.50 – 7.43 (m, 7H), 7.41 –
132.04, 129.99, 128.81, 128.75, 128.51, 113.43, 112.00, 7.36 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 3.72 (d, J = 6.7 Hz, 2H);
111.31, 21.83, 21.32. HRMS (ESI) m/z calcd for C22H19N2O4S 13C{1H} NMR (100 MHz, CDCl3) δ 194.04, 148.55, 143.90,
[M+H]+: 407.1060, Found: 407.1056.
139.27, 138.32, 136.04, 131.01, 130.36, 129.48, 128.64,
Phenyl(6-(thiophen-2-yl)-2-tosyl-2,5-dihydropyridazin-4-yl)m- 128.62, 128.58, 126.41, 124.82, 117.63, 108.22, 22.18. HRMS
ethanone (3m): 114 mg, yield 88%, white solid, m.p.: 157-159 (ESI) m/z calcd for C23H19N2O [M+H]+: 339.1492, Found:
1
oC. H NMR (400 MHz,CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.84 (s, 339.1483.
1H), 7.62 – 7.56 (m, 3H), 7.50 (t, J = 7.4 Hz, 2H), 7.43 (dd, J = (6-Phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)(4-(trifluorometh-
7.5, 4.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.06 (dd, J = 5.0, 3.8 yl)phenyl)methanone (3u): 115 mg, yield 79%, white solid,
Hz, 1H), 3.50 (s, 2H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, m.p.: 190-192 C. H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0
CDCl3) δ 193.76, 147.12, 145.62, 140.09, 137.75, 135.00, Hz, 2H), 7.84 (s, 1H), 7.83 – 7.76 (m, 4H), 7.72 (d, J = 7.9 Hz,
133.12, 131.99, 129.93, 129.90, 128.97, 128.77, 128.74, 2H), 7.49 – 7.40 (m, 3H), 7.37 (d, J = 7.9 Hz, 2H), 3.53 (s, 2H),
128.64, 127.65, 111.42, 22.52, 21.83. HRMS (ESI) m/z calcd for 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.55, 151.18,
o
1
C22H19N2O3S2 [M+H]+: 423.0832, Found: 423.0825.
145.78, 141.09, 135.32, 134.63, 133.40 (q, J = 32.9 Hz), 133.30,
(6-(4-Chlorophenyl)-5-methyl-2-tosyl-2,5-dihydropyridazin-4- 131.15, 130.07, 129.02, 128.66, 128.52, 126.53, 125.81 (q, J =
yl)(phenyl)methanone (3n): 38 mg, yield 27%, white solid, 3.6 Hz), 123.76 (q, J = 272.6 Hz), 111.26, 21.98, 21.78; 19F NMR
o
1
m.p.: 136-138 C. H NMR (400 MHz,CDCl3) δ 7.86 – 7.80 (m, (376 MHz, CDCl3) δ -62.93 (s, 3F). HRMS (ESI) m/z calcd for
5H), 7.62 – 7.57 (m, 3H), 7.52 – 7.47 (m, 2H), 7.39 (d, J = 8.7 Hz, C25H19F3N2O3SNa [M+Na]+: 507.0961, Found: 507.0952.
2H), 7.35 (d, J = 8.0 Hz, 2H), 4.28 (q, J = 6.9 Hz, 1H), 2.42 (s, (4-Fluorophenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)-
3H), 1.21 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ methanone (3v): 96 mg, yield 74%, white solid, m.p.: 173-175
193.47, 153.65, 145.76, 138.06, 136.96, 135.51, 133.30, oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.83 (s,
132.13, 130.03, 129.06, 128.84, 128.72, 128.46, 128.20, 1H), 7.80 (dd, J = 7.9, 1.4 Hz, 2H), 7.68 – 7.63 (m, 2H), 7.48 –
117.34, 26.39, 21.83, 18.72. HRMS (ESI) m/z calcd for 7.40 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H), 7.19 (t, J = 8.6 Hz, 2H),
C25H22ClN2O3S [M+H]+: 465.1034, Found: 465.1023.
(2-((4-Chlorophenyl)sulfonyl)-6-phenyl-2,5-dihydropyridazin-
3.51 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
192.39, 165.08 (d, J = 253.0 Hz), 151.07, 145.66, 134.74,
4-yl)(phenyl)methanone (3p): 115 mg, yield 88%, white solid, 134.71, 134.05 (d, J = 3.2 Hz), 133.42, 131.24 (d, J = 8.9 Hz),
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m.p.: 145-147 C. H NMR (400 MHz, CDCl3) δ 7.95 – 7.90 (m, 131.07, 130.05 , 128.65, 128.49, 126.55, 115.95 (d, J = 21.8
2H), 7.83 (s, 1H), 7.80 (dd, J = 8.0, 1.4 Hz, 2H), 7.64 – 7.57 (m, Hz), 111.46, 22.24, 21.82; 19F NMR (376 MHz, CDCl3) δ -106.81
3H), 7.55 (d, J = 8.7 Hz, 2H), 7.53 – 7.40 (m, 5H), 3.55 (s, 2H); (s, 1F). HRMS (ESI) m/z calcd for C24H19FN2O3SNa [M+Na]+:
13C{1H} NMR (100 MHz, CDCl3) δ 193.78, 151.66, 141.19, 457.0993, Found: 457.0998.
137.70, 134.79, 134.55, 134.43, 132.13, 131.23, 129.87, (4-Chlorophenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)-
129.76, 128.91, 128.80, 128.72, 126.52, 112.04, 22.26. HRMS methanone (3w): 99 mg, yield 73%, white solid, m.p.: 179-182
(ESI) m/z calcd for C23H17ClN2O3SNa [M+Na]+: 459.0541, Found: oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.83 (s,
459.0536.
1H), 7.81 (dd, J = 8.0, 1.4 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.48
(d, J = 8.4 Hz, 2H), 7.47 – 7.40 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H),
(2-((4-Bromophenyl)sulfonyl)-6-phenyl-2,5-dihydropyridazin-
4-yl)(phenyl)methanone (3q): 128 mg, yield 89%, white solid, 3.51 (s, 2H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
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m.p.:185-186 C. H NMR (400 MHz, CDCl3) δ 7.88 – 7.77 (m, 192.56, 151.11, 145.70, 138.35, 136.18, 134.91, 134.72,
5H), 7.87 – 7.78 (m, 5H), 7.74 – 7.68 (m, 2H), 7.64 – 7.57 (m, 133.40, 131.10, 130.21, 130.07, 129.11, 128.67, 128.51,
3H), 7.54 – 7.41 (m, 5H), 3.54 (s, 2H); 13C{1H} NMR (100 MHz, 126.56, 111.38, 22.16, 21.84. HRMS (ESI) m/z calcd for
CDCl3) δ 193.75, 151.68, 137.68, 135.32, 134.53, 134.39, C24H20ClN2O3S [M+H]+: 451.0878, Found: 451.0874.
132.73, 132.12, 131.22, 129.86, 128.82, 128.80, 128.79, (4-Bromophenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)-
128.70, 126.52, 112.06, 22.24. HRMS (ESI) m/z calcd for methanone (3x): 113 mg, yield 76%, white solid, m.p.: 192-193
C23H17BrN2O3S [M+H]+: 481.0216 , Found: 481.0216.
(2-((4-Methoxyphenyl)sulfonyl)-6-phenyl-2,5-dihydropyrida-
oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 2H), 7.83 (s,
1H), 7.80 (d, J = 6.9 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.49 (d, J =
zin-4-yl)(phenyl)methanone (3r): 117 mg, yield 90%, white 8.3 Hz, 2H), 7.47 – 7.39 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H), 3.51 (s,
solid, m.p.: 150-152 oC. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.68,
8.9 Hz, 2H), 7.87 (s, 1H), 7.81 (dd, J = 7.9, 1.6 Hz, 2H), 7.63 – 151.10, 145.70, 136.55, 134.92, 134.64, 133.27, 132.04,
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
131.10, 130.33, 130.06, 128.64, 128.47, 126.81, 126.52, Naphthalen-2-yl(6-phenyl-2-tosyl-2,5-dihydropyrVidieawzAirntic-4le-Oynl)li-ne
DOI: 10.1039/D0OB01958E
111.31, 22.10, 21.84. HRMS (ESI) m/z calcd for C24H20BrN2O3S methanone (3zd): 105 mg, yield 75%, white solid, m.p.: 166-
[M+H]+: 495.0373, Found: 495.0363.
168 oC. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.99 – 7.92 (m,
(3-Fluorophenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)- 4H), 7.89 (d, J = 8.3 Hz, 2H), 7.85 (dd, J = 7.9, 1.7 Hz, 2H), 7.74
methanone (3y): 103 mg, yield 79%, white solid, m.p.: 150-152 (dd, J = 8.4, 1.7 Hz, 1H), 7.65 – 7.58 (m, 2H), 7.48 – 7.41 (m,
oC. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.85 (s, 3H), 7.38 (d, J = 8.1 Hz, 2H), 3.58 (s, 2H), 2.44 (s, 3H); 13C{1H}
1H), 7.79 (dd, J = 8.0, 1.6 Hz, 2H), 7.50 – 7.38 (m, 5H), 7.36 (d, J NMR (100 MHz, CDCl3) δ 193.72, 151.15, 145.58, 135.13,
= 8.6 Hz, 2H), 7.30 – 7.24 (m, 2H), 3.49 (s, 2H), 2.42 (s, 3H); 135.05, 135.03 134.78, 133.45, 132.48, 131.00, 130.03, 129.76,
13C{1H} NMR (100 MHz, CDCl3) δ 192.30, 162.68 (d, J = 248.6 129.13, 128.81, 128.62, 128.43, 128.16, 127.98, 127.09,
Hz), 151.14 , 145.73, 139.85 (d, J = 6.4 Hz), 135.31, 134.66, 126.56, 125.23, 111.86, 22.29, 21.80. HRMS (ESI) m/z calcd for
133.31, 131.09, 130.51 (d, J = 7.8 Hz), 130.09, 128.63, 128.46, C28H23N2O3S [M+H]+: 467.1424, Found: 467.1424.
126.53, 124.46 (d, J = 3.1 Hz), 118.98 (d, J = 21.2 Hz), 118.81 (d, Furan-2-yl(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)metha-
o
J = 22.7 Hz), 111.27, 22.03, 21.80; 19F NMR (376 MHz, CDCl3) δ - none (3ze): 76 mg, yield 62%, yellow solid, m.p.: 167-169 C.
111.40 (s, 1F). HRMS (ESI) m/z calcd for C24H20FN2O3S [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.93 (d, J = 8.3 Hz,
435.1173, Found: 435.1171.
2H), 7.78 (dd, J = 8.0, 1.6 Hz, 2H), 7.67 (dd, J = 1.7, 0.8 Hz, 1H),
(2-Fluorophenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)- 7.44 – 7.38 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 3.6,
methanone (3z): 99 mg, yield 76%, white solid, m.p.: 166-168 0.5 Hz, 1H), 6.58 (dd, J = 3.5, 1.7 Hz, 1H), 3.46 (s, 2H), 2.41 (s,
1
oC. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.83 – 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.37, 152.57, 150.96,
7.76 (m, 3H), 7.55 – 7.48 (m, 1H), 7.46 – 7.39 (m, 4H), 7.37 (t, J 146.07, 145.50, 134.75, 133.60, 133.47, 130.92, 130.00,
= 6.1 Hz, 2H), 7.30 – 7.25 (m, 1H), 7.20 (t, J = 9.1 Hz, 1H), 3.51 128.54, 128.47, 126.44, 118.11, 112.19, 110.62, 21.77, 21.75.
(s, 2H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.07, HRMS (ESI) m/z calcd for C22H19N2O4S [M+H]+: 407.1060,
159.31 (d, J = 250.0 Hz), 151.22, 145.63, 135.68 (d, J = 2.6 Hz), Found: 407.1053.
134.63, 133.23, 132.77 (d, J = 8.2 Hz), 131.04, 129.99, 128.56, (6-Phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)(thiophen-2-yl)m-
128.42, 126.45, 126.22 (d, J = 15.8 Hz), 124.66 (d, J = 3.5 Hz), ethanone (3zf): 82 mg, yield 65%, white solid, m.p.: 146-148
116.46 (d, J = 21.9 Hz), 112.33 (d, J = 1.1 Hz), 21.75, 21.61; 19
F
oC. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.92 (d, J = 8.3 Hz,
NMR (376 MHz, CDCl3) δ -113.55 (s). HRMS (ESI) m/z calcd for 2H), 7.79 (dd, J = 7.9, 1.5 Hz, 2H), 7.67 (dd, J = 5.0, 1.1 Hz, 1H),
C24H20FN2O3S [M+H]+: 435.1173, Found: 435.1163.
7.63 (dd, J = 3.8, 1.1 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.38 (d, J =
(6-Phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)(p-tolyl)methano- 8.0 Hz, 2H), 7.19 (dd, J = 4.9, 3.7 Hz, 1H), 3.51 (s, 2H), 2.43 (s,
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ne (3za): 116 mg, yield 90%, white solid, m.p.: 154-156 C. H 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.41, 150.84, 145.59,
NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.86 (s, 2H), 7.81 (dd, J = 142.09, 134.73, 133.45, 133.05, 132.79, 132.12, 131.00,
7.8, 1.5 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.47 – 7.39 (m, 3H), 130.06, 128.61, 128.47, 128.06, 126.51, 111.77, 22.48, 21.81.
7.37 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 3.51 (s, 2H), HRMS (ESI) m/z calcd for C22H19N2O3S2 [M+H]+: 423.0832,
2.45 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ Found: 423.0823.
193.64, 151.04, 145.53, 142.67, 135.01, 134.76, 134.64, General procedure for the synthesis of pyridazines (4) -
133.39, 130.95, 130.00, 129.39, 128.96, 128.58, 128.40, Synthesis of 4a:
a
mixture of (E)-4-methyl-N'-(1-
126.50, 111.68, 22.21, 21.80, 21.68. HRMS (ESI) m/z calcd for phenylethylidene) benzene sulfonohydrazide 1a (86 mg, 0.3
C25H23N2O3S [M+H]+: 431.1424, Found: 431.1426.
mmol), (E)-3-(dimethylamino)-1-phenylprop-2-en-1- one 2a
(4-Methoxyphenyl)(6-phenyl-2-tosyl-2,5-dihydropyridazin-4-
(79 mg, 0.45 mmol), I2 (76 mg, 0.3 mmol) in 3 mL DMSO was
yl)methanone (3zb): 98 mg, yield 73%, white solid, m.p.: 160- stirred at 120 oC for 24 h. After completion, the reaction
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162 C. H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), mixture was cooled to room temperature and diluted with 15
7.84 (s, 1H), 7.80 (dd, J = 7.8, 1.4 Hz, 2H), 7.65 (d, J = 8.7 Hz, mL of water. The water layer was extracted with (3 x 15 mL) of
2H), 7.43 (q, J = 6.4 Hz, 3H), 7.36 (m, 2H), 6.99 (d, J = 8.7 Hz, EtOAc and then (2 x 15 mL) of brine wash. The organic layer
2H), 3.90 (s, 3H), 3.51 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 was dried over sodium sulfate and concentrated under
MHz, CDCl3) δ 192.68, 162.89, 150.97, 145.52, 134.82, 134.03, reduced pressure to get the crude compound. The crude
133.46, 131.11, 130.95, 130.26, 130.01, 128.60, 128.43, compound was purified by silica gel column chromatography
126.53, 114.03, 111.73, 55.63, 22.44, 21.83. HRMS (ESI) m/z (eluent: petroleum ether (60-90 oC)/EtOAc/DCM = 10:1:1,
calcd for C25H23N2O4S [M+H]+: 447.1373, Found: 447.13967.
v/v/v), affording 4a as a white solid (66 mg, 85%).
1-(6-Phenyl-2-tosyl-2,5-dihydropyridazin-4-yl)ethan-1-one
Phenyl(6-phenylpyridazin-4-yl)methanone (4a): 66 mg, yield
(3zc): 79 mg, yield 74%, white solid, m.p.: 208-210 oC. 1H NMR 85%, white solid, m.p.: 107-108 oC. 1H NMR (400 MHz, CDCl3) δ
(400 MHz, CDCl3) δ 8.06 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.75 9.39 (d, J = 1.9 Hz, 1H), 8.16 – 8.11 (m, 2H), 8.10 (d, J = 1.9 Hz,
(dd, J = 7.8, 1.0 Hz, 2H), 7.43 – 7.34 (m, 5H), 3.31 (s, 2H), 2.42 1H), 7.86 (dd, J = 8.3, 1.2 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.61 –
(s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.09, 7.56 (m, 2H), 7.56 – 7.52 (m, 3H); 13C{1H} NMR (100 MHz,
151.03, 145.54, 134.77, 133.45, 131.78, 130.93, 130.02, CDCl3) δ 193.50, 160.02, 148.07, 135.68, 135.37, 135.17,
128.56, 128.47, 126.43, 112.71, 24.72, 21.80, 21.39. HRMS 134.41, 130.77, 130.22, 129.32, 129.17, 127.40, 122.89. HRMS
(ESI) m/z calcd for C19H19N2O3S [M+H]+: 355.1111, Found: (ESI) m/z calcd for C17H13N2O [M+H]+: 261.1022, Found:
355.1098.
261.1018.
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
(6-(4-Chlorophenyl)pyridazin-4-yl)(phenyl)methanone (4b): 130.36, 129.82, 129.25, 127.34, 122.83, 21.92. HRMS (ESI) m/z
View Article Online
+
85 mg, yield 85%, white solid, m.p.: 117 - 119 oC. 1H NMR (400 calcd for C18H15N2O [M+H] : 275.1179, Found: 275.1177.
MHz, CDCl3) δ 9.36 (d, J = 1.9 Hz, 1H), 8.12 – 8.04 (m, 3H), 7.84 (4-Methoxyphenyl)(6-phenylpyridazin-4-yl)methanone (4i):
(d, J = 7.4 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.7 Hz, 63 mg, yield 72%, white solid. 1H NMR (400 MHz, CDCl3) δ 9.34
2H), 7.50 (d, J = 8.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (d, J = 1.6 Hz, 1H), 8.15 – 8.09 (m, 2H), 8.05 (d, J = 1.6 Hz, 1H),
193.26, 158.93, 148.17, 137.17, 135.25, 135.24, 134.46, 7.84 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 5.5 Hz, 3H), 7.00 (d, J = 8.7
134.05, 130.17, 129.55, 129.18, 128.60, 122.59. HRMS (ESI) Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.76,
m/z calcd for C17H11ClN2ONa [M+Na]+, 317.0458; Found: 164.68, 159.86, 148.04, 136.01, 135.74, 132.74, 130.66,
DOI: 10.1039/D0OB01958E
317.0450.
129.26, 128.16, 127.34, 122.75, 114.43, 55.79.
(6-(4-Bromophenyl)pyridazin-4-yl)(phenyl)methanone (4c): Naphthalen-2-yl(6-phenylpyridazin-4-yl)methanone (4j): 64
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90 mg, yield 89%, white solid, m.p.: 172-173 C. H NMR (400 mg, yield 69%, white solid, m.p.: 159-161 oC. 1H NMR (400
MHz, CDCl3) δ 9.37 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), MHz, CDCl3) δ 9.44 (d, J = 1.9 Hz, 1H), 8.28 (s, 1H), 8.17 – 8.12
8.01 (d, J = 8.6 Hz, 2H), 7.84 (dd, J = 8.4, 1.3 Hz, 2H), 7.73 – (m, 3H), 8.02 – 7.96 (m, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.70 – 7.64
7.68 (m, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H); (m, 1H), 7.61 – 7.57 (m, 1H), 7.56 – 7.51 (m, 3H); 13C{1H} NMR
13C{1H} NMR (100 MHz, CDCl3) δ 193.25, 159.02, 148.23, (100 MHz, CDCl3) δ 193.36, 160.01, 148.10, 136.03, 135.66,
135.25, 134.51, 134.47, 132.53, 130.18, 129.19, 128.83, 135.56, 132.93, 132.66, 132.27, 130.74, 129.82, 129.56,
125.60, 122.56. HRMS (ESI) m/z calcd for C17H12BrN2O [M+H]+, 129.34, 129.29, 128.04, 127.52, 127.37, 124.77, 122.93. HRMS
339.0128; Found: 339.0119.
(ESI) m/z calcd for C21H15N2O [M+H]+: 311.1179, Found:
Phenyl(6-(p-tolyl)pyridazin-4-yl)methanone (4d): 56 mg, yield 311.1172.
68%, light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = Furan-2-yl(6-phenylpyridazin-4-yl)methanone (4k): 50 mg,
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1.8 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.85 yield 66%, light yellow solid, m.p.: 113-114 C. H NMR (400
(d, J = 7.4 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, MHz, CDCl3) δ 9.60 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H),
2H), 7.34 (d, J = 8.1 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 8.15 – 8.11 (m, 2H), 7.79 (dd, J = 1.6, 0.6 Hz, 1H), 7.56 – 7.51
MHz, CDCl3) δ 193.55, 159.90, 147.79, 141.10, 135.39, 135.08, (m, 3H), 7.45 (dd, J = 3.7, 0.5 Hz, 1H), 6.69 (dd, J = 3.7, 1.7 Hz,
134.33, 132.81, 130.18, 130.02, 129.12, 127.22, 122.55, 21.49. 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.91, 160.18, 151.78,
(6-(4-Methoxyphenyl)pyridazin-4-yl)(phenyl)methanone (4e): 148.55, 147.61, 135.71, 134.26, 130.70, 129.28, 127.36,
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60 mg, yield 69%, white solid, m.p.: 149-151 C. H NMR (400 122.67, 121.94, 113.36. HRMS (ESI) m/z calcd for C15H11N2O2
MHz, CDCl3) δ 9.30 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), [M+H]+: 251.0815, Found: 251.0806.
8.03 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.3, 1.1 Hz, 2H), 7.69 (t, J = (2-Bromophenyl)(6-(4-(trifluoromethyl)phenyl)pyridazin-4-
7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.87 yl)methanone (4l): 105 mg, yield 86%, yellow solid, m.p.: 143-
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(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.62, 161.87, 144 C. H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 1.9 Hz, 1H),
159.49, 147.45, 135.41, 135.06, 134.32, 130.18, 129.11, 8.23 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 8.3
128.77, 128.00, 122.12, 114.70, 55.53. HRMS (ESI) m/z calcd Hz, 2H), 7.71 (dd, J = 7.9, 1.2 Hz, 1H), 7.54 – 7.45 (m, 3H);
for C18H15N2O2 [M+H]+: 291.1128, Found: 291.1125.
13C{1H} NMR (100 MHz, CDCl3) δ 193.72, 159.27, 148.45,
Phenyl(6-(thiophen-2-yl)pyridazin-4-yl)methanone (4f): 62 138.92, 137.90, 133.94, 133.25, 133.22, 132.52 (q, J = 32.7 Hz),
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mg, yield 78%, yellow solid, m.p.: 147-149 C. H NMR (400 130.11, 128.14, 127.76, 126.26 (q, J = 3.7 Hz), 123.94 (q, J =
MHz, CDCl3) δ 9.23 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 272.0 Hz), 122.59, 119.88; 19F NMR (376 MHz, CDCl3) δ -62.83
7.84 (d, J = 7.3 Hz, 2H), 7.72 (d, J = 3.4 Hz, 1H), 7.68 (d, J = 7.4 (s, 3F). HRMS (ESI) m/z calcd for C18H10BrF3N2ONa [M+Na]+:
Hz, 1H), 7.58 – 7.52 (m, 3H), 7.16 (dd, J = 4.8, 3.9 Hz, 1H).; 428.9821; Found: 428.9808.
13C{1H} NMR (100 MHz, CDCl3) δ 193.19, 155.67, 147.75, General procedure for the gram-scale synthesis of 3a. A
139.90, 135.23, 135.03, 134.42, 130.30, 130.15, 129.14, mixture of (E)-4-methyl-N'-(1-phenylethylidene) benzene
128.41, 127.34, 121.19. HRMS (ESI) m/z calcd for C15H11N2OS sulfonohydrazide 1a (1.15 g, 4 mmol), (E)-3-(dimethylamino)-
[M+H]+: 267.0587, Found: 267.0583.
(4-Chlorophenyl)(6-phenylpyridazin-4-yl)methanone (4g): 71 mmol) in 5 mL DMSO was stirred at 80 oC for 6 h. After
1-phenylprop-2-en-1- one 2a (1.05 g, 6 mmol), I2 (1.02 g, 4
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1
mg, yield 80%, white solid, m.p.: 176 - 177 C. H NMR (400 completion (monitored by TLC), the reaction mixture was
MHz, CDCl3) δ 9.35 (d, J = 1.8 Hz, 1H), 8.15 – 8.08 (m, 2H), 8.07 cooled to room temperature and diluted with 30 mL of water.
(d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.58 – 7.50 (m, 5H); The water layer was extracted with (3 x 30 mL) of EtOAc and
13C{1H} NMR (100 MHz, CDCl3) δ 192.28, 160.05, 147.76, then (2 x 30 mL) of brine wash. The organic layer was dried
141.13, 135.52, 134.80, 133.66, 131.51, 130.83, 129.56, over sodium sulfate and concentrated under reduced pressure
129.33, 127.36, 122.70. HRMS (ESI) m/z calcd for to get the crude compound. The crude compound was purified
C17H11ClN2ONa [M+Na]+, 317.0458; Found: 317.0446.
by silica gel column chromatography (eluent: petroleum ether
(6-Phenylpyridazin-4-yl)(p-tolyl)methanone (4h): 67 mg, yield (60-90 oC)/EtOAc/DCM = 10:1:1, v/v/v), affording 3a as a white
81%, white solid, m.p.: 173-175 oC. 1H NMR (400 MHz, CDCl3) δ solid (1.35 g, 81%).
9.35 (d, J = 1.9 Hz, 1H), 8.15 – 8.09 (m, 2H), 8.07 (d, J = 1.9 Hz, General procedure for the gram-scale synthesis of 4h. A
1H), 7.75 (d, J = 8.2 Hz, 2H), 7.56 – 7.50 (m, 3H), 7.34 (d, J = 8.0 mixture
Hz, 2H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.00, ethylidene) benzene sulfonohydrazide 1u (1.07 g, 3 mmol), (E)-
159.89, 148.06, 145.64, 135.69, 135.52, 132.78, 130.67, 1-(2-bromophenyl)-3-(dimethylamino)prop-2-en-1-one 2o
of
(E)-4-methyl-N'-(1-(4-(trifluoromethyl)phenyl)
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J. Name., 2013, 00, 1-3 | 9
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ARTICLE
Journal Name
(1.14 g, 4.5 mmol), I2 (0.76 g, 3 mmol) in 5 mL DMSO was 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J = 7.7 Hz, 2H),
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13
1
stirred at 120 oC for 48 h. After completion (monitored by TLC), 7.54 – 7.48 (m, 3H); C{ H} NMR (100 MHz, CDCl3) δ 190.69,
the reaction mixture was cooled to room temperature and 160.05, 143.76, 134.84, 134.71, 133.37, 131.62, 130.13,
diluted with 30 mL of water. The water layer was extracted 129.34, 129.30, 127.44, 112.72. HRMS (ESI) m/z calcd for
with (3 x 30 mL) of EtOAc and then (2 x 30 mL) of brine wash. C17H13N2O2 [M+H]+: 277.0972, Found: 277.0966.
The organic layer was dried over sodium sulfate and
DOI: 10.1039/D0OB01958E
concentrated under reduced pressure to get the crude
compound. The crude compound was purified by silica gel
Conflicts of interest
column chromatography (eluent: petroleum ether (60-90
oC)/EtOAc/DCM = 10:2:1, v/v/v), affording 4h as a yellow solid
(0.97 g, 85%).
There are no conflicts to declare.
General procedure for one-pot two-steps synthesis of 1,4-
dihydropyridazine (3) - Synthesis of 3a: the acetic acid (4 mg,
0.06 mmol) was added to a mixture of tosylhydrazine (57 mg,
0.305 mmol) and ketones (36 mg, 0.3 mmol) in anhydrous
ethanol (3 mL), and then heated at reflux for 3 hours. After
completion, the reaction mixture was cooled to room
temperature and concentrated under reduced pressure to get
the crude compound 1. Then addition of iodine (76 mg, 0.3
mmol), enaminones 2 (79 mg, 0.45 mmol) and DMSO (3 mL) to
the crude compound 1 stirred at 80 °C for 5 h. After
completion (monitored by TLC), the reaction mixture was
cooled to room temperature and diluted with 15 mL of water.
The water layer was extracted with (3 x 15 mL) of EtOAc and
then (2 x 15 mL) of brine wash. The organic layer was dried
over sodium sulfate and concentrated under reduced pressure
to get the crude compound. The crude compound was purified
by silica gel column chromatography (eluent: petroleum ether
(60-90 oC)/EtOAc/DCM = 10:1:1, v/v/v), affording 3a as a white
solid (105 mg, 84%).
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21901124), Jiangsu University Natural Science Research
Program (19KJB150032, 19KJB610013), and China Postdoctoral
Science Foundation (2019M651809).
Notes and references
1
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3a. A mixture of acetophenone sm1a (36 mg, 0.3 mmol),
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o
at 80 C for 24 h. After completion (monitored by TLC), the
reaction mixture was cooled to room temperature and diluted
with 15 mL of water. The water layer was extracted with (3 x
15 mL) of EtOAc and then (2 x 15 mL) of brine wash. The
organic layer was dried over sodium sulfate and concentrated
under reduced pressure to get the crude compound. The crude
compound was purified by silica gel column chromatography
(eluent: petroleum ether (60-90 oC)/EtOAc/DCM = 10:1:1,
v/v/v), affording 3a as a white solid (52 mg, 42%).
3
4
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8
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1
yellow solid, m.p.: 140-141 oC. H NMR (400 MHz, CDCl3) δ
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DOI: 10.1039/D0OB01958E
Table of contents:
R3
R3
N
N
NH
80 o
C
N
Controllable and selective synthesis
Metal/base-free





R4
R2
R1
R1
I2
R2
N
O
O
+
Good fucational group tolerance
Good to excellent yields
One-pot methodology
DMSO
O
N
R4
N
R4
R1
120 o
C
R2
A facile and efficient strategy for the synthesis of 1,4-dihydropyridazines and pyridazines
through I2-promoted [4+2] cycloaddition of in situ generated azoalkenes with enaminones
has been developed. The switch in selectivity is attributed to the judicious choice of
different reaction temperature.