Environmentally-Safe Conditions for a Palladium-Catalyzed Direct C3-Arylation with High Turn Over Frequency of Imidazo[1,2-b]pyridazines Using Aryl Bromides and Chlorides

Article abstract of DOI:10.1002/asia.201600827

Pd(OAc)₂ was found to catalyze very efficiently the direct arylation of imidazo[1,2-b]pyridazine at C3-position under a very low catalyst loading and phosphine-free conditions. The reaction can be performed in very high TOFs and TONs employing as little as 0.1–0.05 mol % catalyst using a wide range of aryl bromides. In addition, some electron-deficient aryl chlorides were also found to be suitable substrates. Moreover, 31 examples of the cross couplings were reported using green, safe, and renewable solvents, such as pentan-1-ol, diethylcarbonate or cyclopentyl methyl ether, without loss of efficiency.

Full text of DOI:10.1002/asia.201600827

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Accepted Article
Title: Environmentally-Safe Conditions for the Palladium-Catalyzed Direct C3-
Arylation with High Turn Over Frequency of Imidazo[1,2-b]pyridazines Using
Aryl Bromides and Chlorides
Authors: Sabah Chikhi; Safia Djebbar; Jean-Francois Soule; Henri Doucet
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Chemistry - An Asian Journal
10.1002/asia.201600827
FULL PAPER
Environmentally-Safe Conditions for the Palladium-Catalyzed
Direct C3-Arylation with High Turn Over Frequency of
Imidazo[1,2-b]pyridazines Using Aryl Bromides and Chlorides
Sabah Chikhi,[a,b] Safia Djebbar,[b] Jean-François Soulé,*[a] and Henri Doucet*[a]
Abstract: Phosphine-free Pd(OAc)2 was found to catalyze very
efficiently the direct arylation of imidazo[1,2-b]pyridazine at C3
position under a very low catalyst loading. The reaction can be
performed employing as little as 0.1–0.05 mol% catalyst with wide
range of aryl bromides in very high TOFs and TONs. In addition,
some electron-deficient aryl chlorides were also found to be suitable
substrates. Moreover, 31 examples of those couplings were
reported using green, safe and renewable solvents such as pentan-
1-ol, diethylcarbonate or cyclopentyl methyl ether, without loss of
efficiency.
solvents.[4] Some reports demonstrated that C–H bond arylation
could be conducted in carbonates,[5] such as diethylcarbonate
(DEC), which is a polar, aprotic, nontoxic, and biodegradable
solvent.[6] Cyclopentyl methyl ether (CPME) is also a suitable
alternative solvent for C–H bond activation/functionalization.[7]
Highly polar and protic solvents, such as alcohols[8] or water,[9]
have also been used in transition metal-catalyzed C–H bond
activation. However, the merging of low loading phosphine-free
palladium catalyst conditions with eco-friendly or bio-sourced
solvent remains a challenge, especially with aryl chlorides.
As a continuation of our researches on the development of
environmentally-safe conditions for the Pd-catalyzed direct
arylation, and based on our previous work on direct arylation of
imidazo[1,2-a]pyridine,[3d] which displayed a very high reactivity,
we turned our attention to the reactivity of imidazo[1,2-
Introduction
In recent years, the Pd-catalyzed direct arylation of several
heteroaromatics using aryl halides, via a C−H bond activation,
has become one of the most environmentally friendly methods
for the C-C bond formation.[1] Indeed, compared to other
classical Pd-catalyzed reactions such as Stille, Suzuki or
Negishi couplings, they do not require the preliminary synthesis
of organometallic derivatives, and only HX associated to a base
is generated as by-product. However, many challenge remains
in order to get sustainable reaction conditions. For example, the
major drawback of most of the described procedures is that they
generally require 5-10 mol% palladium catalyst associated to
10–20 mol% of phosphine ligands. Since the discovery by de
Vries and co-workers that only trace amount of phosphine-free
catalyst Pd(OAc)2 (i.e., 0.1−0.01 mol%) are able to catalyze
Heck and Suzuki reactions[2] –due to the soluble palladium(0)
clusters formation at elevated temperature– this technology has
been largely employed to promote the arylation of
heteroarenes.[3] An additional drawback of Pd-catalyzed direct
arylation in terms of green chemistry is that they often employ
DMF or DMA as toxic or non-renewable solvents. According to
the solvent selection guides published by chemical companies,
DMF or DMA should be replaced by more sustainable
b]pyridazine in direct arylation.
Such heterocycles have
potential applications in medicinal chemistry. As examples, the
3-arylimidazo[1,2-b]pyridazine scaffold displays selective
inhibition of Mps1 (TTK) Kinase.[10] In 2010, Berteina-Raboin,
Guillaumet and co-workers described the first and unique
example of direct arylations of 6-chloroimidazo[1,2-b]pyridazine
with aryl bromides.[11] They reported that the use of 10 mol%
Pd(OAc)2 associated to 20 mol% PPh3 in toluene promotes
efficiently such couplings in good yields. Due to the important
biological properties of 3-arylimidazo[1,2-b]pyridazines, the
discovery of more environmentally-safe conditions for the direct
coupling of imidazo[1,2-b]pyridazine derivatives with aryl
bromides, especially using low loadings of a phosphine-free
catalyst in renewable solvents, would be
advantage for industrial applications.
a considerable
Results and Discussion
Imidazo[1,2-b]pyridazine and 4-bromobenzonitrile were used as
model substrates, and we choose our previously described
optimized reaction conditions for the direct arylation of
imidazo[1,2-a]pyridine (i.e., Pd(OAc)2 as catalyst, 2 equivalents
of KOAc, in DMA at 150 ºC) (Table 1).[3d] We found that the C3
arylated product 1 was obtained in very high yield using only 1
mol% of Pd(OAc)2 without phosphine ligand (Table 1, entry 1).
The TONs of the reaction were increased to 1940 and 8900
using 0.05 or 0.01 mol% catalyst loadings, respectively (Table 1,
entries 2-4). In order to discover safer reaction conditions, we
decided to evaluate greener solvents for this coupling using 0.05
mol% of Pd(OAc)2. Pentan-1-ol, DEC, and CPME allowed the
formation of desired product 1 in high yields (Table 1, entries 6,
8, and 10). As the association of palladium salts to pyridine
derivatives as ligands provides in some cases very efficient
[a]
Ms. S. Chikhi, Dr. J.-F. Soulé,* Dr. H. Doucet*
Institution Institut des Sciences Chimiques de Rennes, UMR 6226
CNRS – Université de Rennes 1 Campus de Beaulieu, 35042
Campus de Beaulieu, 263 avenue du Général Leclerc 35042
Rennes Cedex (France)
E-mail: jean-francois.soule@univ-rennes1.fr, henri.doucet@univ-
rennes1.fr
[b]
Ms. S. Chikhi, Dr. S. Djebbar
Laboratoire d’hydrométallurgie et chimie inorganique moléculaire
Faculté de Chimie U.S.T.H.B.
Bab-Ezzouar, Alger, Algeria.
Supporting information for this article is given via a link at the end of
the document
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Chemistry - An Asian Journal
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FULL PAPER
catalysts for direct arylation reactions,[12] we also performed a
comparison study using 1,10-phenanthroline as ligand (Table 1,
entries 5, 7, 9 and 11). In all cases, the addition of 0.05 mol% of
1,10-phenanthroline to the reaction mixture did not allowed any
yield improvement or change in the regioselectivity. We also
performed the reaction at a lower temperature of 100 ºC (Table
evident. The reaction performed in CPME was the slowest for
the formation of arylated product 1 (TOF10min = 3000 h-1), albeit
the reaction was complete after 2 h. Pentan-1-ol displayed a
higher efficiency, as a TOF10min of 5040 h-1 was obtained after 10
minutes. The reaction performed in DEC indicated a TOF10min of
7560 h-1 after 10 minutes. The highest TOF after 10 minutes
was obtained when the reaction was performed in DMA, with
complete conversion after only 30 minutes and a TOF10min of
10320 h-1 after 10 minutes. Similar experiments were conducted
with electron-rich 4-bromoanisole (Figure 1b). With all solvents
conditions, the desired C3-arylated imidazo[1,2-b]pyridazine 2
was obtained, but again marked differences were observed.
Again, the reaction in DMA was the most efficient to deliver the
coupling product 2, although a lower TOF10min of 2760 h-1 than
with 4-bromobenzonitrile was obtained. The reaction performed
in pentan-1-ol also displayed a high TOF (TOF10min = 1920 h-1);
whereas, in DEC or CPME the reactions were not complete after
5 h, with conversions of 80% and 42%, respectively and lower
1, entries 12-14).
However, lower TONs were obtained
whatever the employed solvent. As expected, in the absence of
Pd(OAc)2 catalyst, no reaction occurred (Table 1, entry 15). It is
important to note that all the reactions which employed 0.05 or
0.01 mol% catalyst were performed using new Schlenk tubes
and new stirring bars to avoid contamination by palladium
residues.
Table 1. Influence of the Reaction Conditions
TOFs10min of 960 h-1 and 480 h-1
.
Entry
(x mol %)
Solvent
Conv.
(%)[a]
Yield in
TON
1 (%)[b]
2000
1800
1600
1400
1200
1
1
DMA
100
100
100
92
98
98
97
89
65
97
0
98
2
0.5
DMA
196
1940
8900
1300
1940
0
3
0.05
0.01
0.05
0.05
0.05
DMA
1000
4
DMA
CN
CN
Br
800
600
400
200
0
N
N
Pd(OAc)2 (0.05 mol%)
5[c]
6
DMA
69
KOAc (2 equiv.)
Solvent,
150 ºC, t (h)
N
N
N
1
(1.1 equiv.)
N
pentan-1-ol
pentan-1-ol
100
0
7[c]
0
0.5
1
1.5
2
2.5
3
a.
8
0.05
0.05
0.05
0.05
0.5
DEC
100
78
100
38
67
37
71
–
90
78
96
36
66
37
68
–
1900
1560
1920
720
132
74
2000
1800
1600
1400
1200
1000
800
9[c]
DEC
10
CPME
CPME
DMA
11[c]
12[d]
13[d]
14[d]
15
0.5
pentan-1-ol
DEC
OMe
600
OMe
N
N
Pd(OAc)2 (0.05 mol%)
0.5
136
–
400
+
KOAc (2 equiv.)
Solvent,
150 ºC, t (h)
N
N
N
2
200
Br
(1.1 equiv.)
0
DMA
N
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
b.
[a] Based on 4-bromobenzonitrile consumption using GC-MS analysis
with dodecane as internal standard. [b] Isolated yield. [c] In the
presence of 0.05 mol% of 1,10-phenanthroline. [d] Reaction
performed at 100 ºC.
Figure 1. TON vs Time of Pd-Catalyzed Coupling Reactions between
Imidazo[1,2-b]pyridazine in Different Solvents: a) with 4-bromobenzonitrile or
b) with 4-bromoanisole.
As full consumption of 4-bromobenzonitrile was observed in all
cases in the presence of 0.05 mol% catalyst using DMA, DEC,
CPME, or pentan-1-ol, we decided to plot a TON versus time of
this model reaction with the different solvents (Figure 1a).
Remarkably, all the solvents were compatible under our
standard catalytic conditions (0.05 mol% Pd(OAc)2, KOAc (2
equiv.) at 150 ºC), but clear differences among them were
With these catalytic systems in hands, we decided to investigate
the scope of aryl bromides in the Pd-catalyzed direct C3-
arylation of imidazo[1,2-b]pyridazine using a low loading of
phosphine-free palladium catalyst (i.e., Pd(OAc)2 0.05 mol%)
(Scheme 1). As seen above, 4-bromoanisole reacted nicely with
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FULL PAPER
N
N
N
N
imidazo[1,2-b]pyridazine to give the arylated heterocycle 2 in
79% isolated yield. Bromobenzenes para-substituted by nitro,
formyl or acetyl groups gave the C3-arylated products 3-5 in
Pd(OAc)2 (0.05 mol%)
R
H
+
R
KOAc (2 equiv.),
DMA, 150 ºC,
16 h
Br
N
N
(1.1 equiv.)
high yields in both DMA and pentan-1-ol.
Ethyl 4-
N
N
N
N
N
N
OMe
NO2
CHO
COMe
N
N
bromobenzoate was also tolerated by the optimized reaction
conditions to afford 6 in 91% yield. Using solvent free-conditions,
a slightly lower yield of 51% was obtained. Chloro or fluoro
substituents at para-position of bromobenzene have almost no
effect on the reaction, as the coupling products 7 and 8 were
isolated in 89% and 93% yields, respectively. The reaction with
4-bromotoluene as coupling partner smoothly proceeded in DMA
or in pentan-1-ol to afford the coupling product 9 in 82% or 78%
yield. Interestingly, 4-iodoaniline, which is a very electron-rich
substrate, was also tolerated to afford the heterocycle 10 in
91%; whereas, 4-bromoaniline was unreactive. It is important to
note that the direct arylation proceeded faster than amination
reaction.[13] The reaction performed in pentan-1-ol instead of
DMA led to a lower yield of 58% in 10. Meta-substituted aryl
bromides reacted with imidazo[1,2-b]pyridazine in the same line
N
N
N
N
79% (67%)[a]
3
95% (93%)[a]
4
97% (95%)[b]
5
92% (84%)[a] (83%)[b]
2
(65%)[b] (45%)[c] (54%)[d]
(92%)[b] (96%)*
(98%)[c] (97%)*
N
N
N
N
N
N
CO2Et
N
Cl
F
Me
N
N
N
N
N
7
89%
9
82% (78%)b
Br
6
91% (51%)[d]
8
93% (94%)[b]
CO2Me
COMe
N
N
N
N
N
N
N
NH2
N
N
N
N
N
10 91%[e] (58%)[b,e]
11 92% (86%)[b]
12 89% (84%)[b]
13 85%
CF3
NH2
NC
N
CHO
N
N
N
N
N
N
N
N
N
CF3
15 90% (91%)*
N
N
14 82%[e]
16 93% (92%)[b]
17 91%
CF3
N
N
N
N
N
N
N
than the para-substituted ones.
As examples, methyl 3-
N
N
N
N
N
bromobenzoate and 3-bromoacetophenone gave the desired
coupling products 11 and 12 in excellent yields in DMA or
N
18 96% (91%)* (89%)[b]
20 79% (67%)[a]
21 87% (82%)[b]
19 74%
N
N
N
N
N
pentan-1-ol.
selective
1,3-Dibromobenzene could be used for the
mono-heteroarylation, affording 3-(3-
N
N
N
N
23 73% (75%)[a] (71%)[b]
22 94% (62%)[c]
bromophenyl)imidazo[1,2-b]pyridazine 13, in which one C–Br
bond remained untouched and could be used in further Pd-
catalyzed reactions. 3-Iodoaniline was nicely coupled with
imidazo[1,2-b]pyridazine in DMA to afford 14 in 82% yield
without amination as side-reaction. A very electron-deficient aryl
bromide, such as 3,5-bis(trifluoromethyl)bromobenzene, was
also tolerated by the optimized conditions to afford the arylated
heterocycle 15 in 90% yield. The reaction seems to be
insensitive to the steric hindrance. Indeed, aryl bromides
bearing 2-cyano, 2-formyl or 2-trifluoromethyl substituents nicely
reacted to afford 16-18 in good yields. Notably, such ortho-
substituted aryl bromides could be coupled in pentan-1-ol
without loss of efficiency. From 1- bromonaphthalene or 1-
bromopyrene, the C3 polycyclic hydrocarbons substituted
imidazo[1,2-b]pyridazine 19 and 20 were isolated in 74% and
79% yields, respectively. Heteroaryl bromides, such as 3-
bromoquinoline, 3-bromopyridine and 5-bromopyrimidine were
also successfully coupled to give the heterocycle dyads 21-23 in
73-94% yields. Again, these reactions could be performed in
pentan-1-ol or CPME instead of DMA. We also demonstrated
that the coupling products could be isolated by recrystallization
in cyclohexane after simple removal of DMA (e.g., 3, 5, 15, and
18 in scheme 1), instead of silica gel column chromatography,
affording a very environmentally-attractive procedure for the
synthesis of such compounds.
Scheme 1. Scope of Aryl Bromides in Pd-Catalyzed Direct Arylation of
Imidazo[1,2-b]pyridazine. [a] Reaction performed in DEC instead of DMA. [b]
Reaction performed in pentan-1-ol instead of DMA. [c] Reaction performed in
CPME instead of DMA. [d] Reaction performed under neat conditions. [e]
Reaction performed from ArI instead of ArBr. * Reaction performed on 10
mmol scale; after removal of DMA under vacuo, the product was isolated by
simple recrystallization in cyclohexane.
Having successfully coupled a wide range of aryl bromides with
imidazo[1,2-b]pyridazine, we next investigated the efficiently of
this simple catalytic system –namely, phosphine-free Pd(OAc)2
in the presence of KOAc– to promote direct arylation using aryl
chlorides. Rare use has been made of (hetero)aryl chlorides in
Pd-catalyzed direct arylations, despite the fact that among aryl
halides, aryl chlorides exhibit the wider diversity of available
compounds at an affordable cost. In most cases, expensive
ligands or catalytic systems should be used to overcome their
poor reactivity in Pd-catalyzed direct arylation.[14] Only a few
reports focused on the use of phosphine-free palladium
catalyts.[3e, 15] First, we decided to evaluate several solvents for
this coupling using 4-chlorobenzonitrile as aryl source in the
presence of 0.1 mol% of Pd(OAc)2 and 2 equivalents of KOAc
as base without any additive (Figure 2). Interestingly, a full
conversion was observed in DMA after 2 h with a TOF30min of
840 h-1 after 30 minutes. The reaction was more sluggish in
other solvents such as pentan-1-ol or DEC, but full conversions
could be reached after 6 h. It is important to note that DEC has
been previously used as eco-friendly solvent in Pd-catalyzed
direct arylation of several heteroarenes in the presence of aryl
chlorides as aryl source, but diphosphine ligands were added to
the reaction mixture.[16] To the best of our knowledge, this is one
of the rare examples of merging phosphine-free palladium
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Chemistry - An Asian Journal
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Scheme 2. Scope of Aryl Chlorides in Pd-Catalyzed Direct Arylation of
Imidazo[1,2-b]pyridazine. [a] Reaction performed in DEC instead of DMA. [b]
Reaction performed in pentan-1-ol instead of DMA. [c] Reaction performed
under neat conditions.
catalyst with eco-friendly or bio-sourced solvents for the direct
arylation of heteroarenes using aryl chlorides as aryl source. On
the contrary, CPME as solvent was almost ineffective for this
transformation.
In addition, we investigated the Pd-catalyzed direct arylation of
1000
900
800
700
600
6-chloroimidazo[1,2-b]pyridazine
conditions, namely 0.1 mol% Pd(OAc)2 associated to KOAc as
base in pentan-1-ol. Electron-poor para-substituted aryl
bromides, such as 4-bromonitrobenzene and 4-
in
environmentally-safe
bromobenzaldehyde, gave the coupling products 30 and 31 in
78% and 82% yields, respectively. Notably, the reaction could
also be performed from 4-chloronitrobenzene to afford 30 in a
similar yield, albeit DMA should be used as solvent. The
reaction with 1,4-dibromobenzene selectively gave the
monoarylated product 32 in 75% yield, which contains a C–Br
bond allowing further transformations. A second direct arylation
from 32 via the activation of its C–Br bond was not observed.
This poor reactivity is due to a slow oxidative addition of 32 to
palladium owing the electron-donor character of the first
introduced heteroarene. Bulky aryl bromides, such as methyl 2-
bromobenzoate and 1-bromonaphthalene, were also tolerated
by the optimized environmentally-safe conditions to afford the
products 33 and 34 in 59% and 76% yields, respectively.
Heteroaryl bromides have also been successfully coupled with
6-chloroimidazo[1,2-b]pyridazine to offer 35 and 36 in good
yields. In all cases, no cleavage of the imidazopyridazine C–Cl
bond was observed. This chemoselectivity might be explained
by the poor reactivity of electron-rich aryl chlorides under
phosphine-free palladium conditions.
500
CN
CN
400
N
Pd(OAc)2 (0.1 mol%)
N
300
200
100
0
KOAc (2 equiv.)
Solvent,
150 ºC, t (h)
N
N
N
1
Cl
(1.1 equiv.)
N
0
1
2
3
4
5
6
Figure 2. TON vs Time of Pd-Catalyzed Coupling Reaction Between
Imidazo[1,2-b]pyridazine with 4-Chloronitrobenzene in Different Solvents.
Having found effective conditions for the use of activated aryl
chlorides, namely, 0.1 mol% of Pd(OAc)2 in the presence of 2
equivalents of KOAc in DMA, we turned our attention to the aryl
chloride scope for these Pd-catalyzed C–H bond arylations.
Chlorobenzenes substituted by electron-withdrawing groups at
para-position such as CN, NO2, CF3, CO2Me allowed the
synthesis of the 3-arylated imidazo[1,2-b]pyridazines 1, 3, 24
and 25 in 69-92% yields. From 3-chlorobenzonitrile and 3-
chloronitrobenzene, the coupling products 26 and 27 were
isolated in excellent yields. Under the same conditions, the
reaction proceeded smoothly in the presence of ortho-
substituted aryl chlorides.
chloronitrobenzene or 2-chloro-5-nitrobenzonitrile, the C3
arylated products 28 and 29 were obtained in 65% and 72%
yields, respectively.
successfully performed in DEC and pentan-1-ol as alternative
sustainable solvents. However, aryl chlorides bearing an
Cl
Cl
N
N
N
Pd(OAc)2 (0.1 mol%)
H
N
+
R
R
KOAc (2 equiv.)
pentan-1-ol,
150 ºC, 16 h
Br
Cl
N
N
For examples, from 2-
(1.1 equiv.)
NO2
Cl
Cl
Cl
CO2Me
N
N
N
N
N
N
CHO
N
Br
N
Some of these couplings were also
N
N
N
N
30 78% (72)%[a]
Cl
31 82%
32 75%
33 59%
Cl
Cl
electron-donating substituent (e.g., OMe or Me) were unreactive
under these phosphine-free conditions.
N
N
N
N
N
N
N
N
N
N
N
34 76%
35 62%
36 58%
N
N
N
Pd(OAc)2 (0.1 mol%)
H
N
+
R
R
KOAc (2 equiv.)
DMA,
150 ºC, 16 h
Cl
Scheme 3. Scope of Aryl Bromides and Chlorides in Pd-Catalyzed Direct
Arylation of 6-Chloroimidazo[1,2-b]pyridazine. [a] The reaction was performed
from 4-chloronitrobenzene instead of 4-bromonitrobenzene, and DMA was
used as solvent instead of pentan-1-ol.
N
N
(1.1 equiv.)
N
N
N
N
N
N
N
CN
NO2
CF3
CO2Me
N
N
1
N
N
N
73% (68%)[a]
3
92% (81%)[b]
NO2
N
N
25 72% (62%)[a]
24 69% (76%)[a]
(64%)[b] (11%)[d]
Finally, we investigated the synthesis of 2,3-diarylimidazo[1,2-
CN
N
N
N
b]pyridazine derivatives (Scheme 4).
From 3-(4-
NO2
N
N
N
fluorophenyl)imidazo[1,2-b]pyridazine 8, we attempted to
functionalize directly the C2 position through Pd-catalyzed direct
arylation. However, this synthetic scheme failed. Hence, we
considered a two steps synthesis involving the preparation of 2-
N
N
O2N
NC
N
N
27 72% (65%){b]
28 65%
29 72%
26 72% (58%)[a]
bromo-3-(4-fluorophenyl)imidazo[1,2-b]pyridazine
37
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Chemistry - An Asian Journal
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FULL PAPER
spectra were recorded at 100 MHz on the same spectrometer and
reported in ppm. All reagents were weighed and handled in air.
intermediate. From aryl bromide derivative 37, classical Suzuki
reaction conditions using phenylboronic acid or 3-thienylboronic
acid as coupling partners allowed the formation of 2,3-
diarylimidazo[1,2-b]pyridazines 38 and 39 in 86% and 89%
yields, respectively.
Preparation of the PdCl(dppb)(C3H5) catalyst:[17] An oven-dried 40-mL
Schlenk tube equipped with
a magnetic stirring bar under argon
atmosphere, was charged with [Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and
dppb (426 mg, 1 mmol). 10 mL of anhydrous dichloromethane were
added, then the solution was stirred at room temperature for twenty
minutes. The solvent was removed in vacuum. The yellow powder was
used without purification. 31P NMR (81 MHz, CDCl3) δ (ppm) = 19.3 (s).
N
N
F
NBS (1.1 equiv.)
F
N
N
N
CHCl3, 60 ºC, 16 h
N
Br
37 95%
8
S
General Procedure. As a typical experiment, the reaction of the aryl
halides (1 mmol), imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol) or 6-
chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), and KOAc (0.196 g,
2 mmol) at 150 °C over 16 h in 4 mL of a freshly prepared solution of
solvent (see tables or schemes) which contains the appropriate amount
of Pd(OAc)2 (see preparation of this solution below), under argon affords
the coupling product after evaporation of the solvent and purification on
silica gel or recrystallization in cyclohexane.
B(OH)2
PdCl(C3H5)(dppb) (2 mol%)
K3PO4 (2 equiv.)
1,4-dioxane, 80 ºC, 15 h
B(OH)2
(1.2 equiv.)
N
(1.2 equiv.)
Br
(1.2 equiv.)
N
F
F
N
N
N
N
PdCl(C3H5)(dppb) (2 mol%)
KOAc (2 equiv.)
DMA,
S
150 ºC, 15 h
39 89%
38 86%
A solution of Pd(OAc)2 was freshly prepared using 2.8 mg of Pd(OAc)2
(0.0125 mmol) and 100 mL of the appropriate solvent (DMA, pentan-1-ol,
DEC, or CPME) under argon.”
Scheme 4. Examples of Synthesis of 2,3-Diarylimidazo[1,2-b]pyridazine
Derivatives..
4-(Imidazo[1,2-b]pyridazin-3-yl)benzonitrile (1): Following the general
procedure using 4-bromobenzonitrile (0.182 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 70:30) to afford the desired
compound 1 (0.216 g, 98%) as a yellow solid (mp = 156-158 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.71 (dd, J = 1.6 and 4.5 Hz, 1H, H6),
8.49 (s, 1H, H2), 8.42 (d, J = 8.5 Hz, 2H), 8.27 (dd, J = 1.6 and 9.2 Hz,
1H, H8), 7.97 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 4.5 and 9.2 Hz, 1H, H7).
13C NMR (100 MHz, d6-DMSO) δ (ppm) 144.3, 140.9, 134.7, 132.9,
132.6, 126.3, 126.1, 125.5, 118.9, 118.1, 109.5. Elemental analysis:
calcd (%) for C13H8N4 (220.23): C 70.90, H 3.66; found: C 71.19, H 3.86.
Conclusions
In summary, we have developed environmentally-safe
conditions for the direct C3 arylation of imidazo[1,2-
b]pyridazines. We found that the reaction proceed with very
high TOFs and TONs using as little as 0.1–0.05 mol% of
phosphine-free Pd(OAc)2 as catalyst precursor. With this
procedure, there is no need to eliminate phosphine residues at
the end of the reaction. In addition, for several examples (i.e.,
31 compounds over 36), we demonstrated that DMA, which is a
toxic solvent, can be successfully substituted by eco-friendly or
3-(4-Methoxyphenyl)imidazo[1,2-b]pyridazine (2): Following the
general procedure using 4-bromoanisole (0.187 g,
1 mmol) and
bio-resourced
solvents,
such
as
pentan-1-ol
and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to afford the
desired compound 2 (0.178 g, 79%) as a yellow solid (mp = 75-79 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.59 (dd, J = 1.6 and 4.4 Hz, 1H,
H6), 8.20-8.15 (m, 2H, H2 and H8), 8.05 (d, J = 8.9 Hz, 2H), 7.23 (dd, J =
4.4 and 9.2 Hz, 1H, H7), 7.06 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H). 13C NMR
(100 MHz, d6-DMSO) δ (ppm) 158.8, 143.7, 139.3, 131.8, 127.8, 127.3,
125.9, 120.9, 116.5, 114.1, 55.1. Elemental analysis: calcd (%) for
C13H11N3O (225.25) C 69.32, H 4.92; found: C 69.58, H 5.17.
diethylcarbonate, providing a greener approach to the synthesis
of 3-aryl imidazo[1,2-b]pyridazines. The reaction conditions
allowed the use of a wide variety of substituents on the aryl
bromide such as ester, acetyl, formyl, propionyl, benzoyl, nitro,
nitrile, bromo, chloro, fluoro, methoxy and amino. In addition,
heteroaryl bromides could also employed. Moreover, some
electron-deficient aryl chlorides, which are very attractive
substrates in terms of atom-economy and cost, have been used
instead of aryl bromides with comparable yields.
3-(4-Nitrophenyl)imidazo[1,2-b]pyridazine (3): Following the general
procedure using 4-bromonitrobenzene (0.200 g,
1
mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 55:45) to afford the
desired compound 3 (0.228 g, 95%) as a yellow solid (mp = 207-210 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.76 (dd, J = 1.7 and 4.4 Hz, 1H,
H6), 8.57 (s, 1H, H2), 8.52 (d, J = 8.9 Hz, 2H), 8.37 (d, J = 8.9 Hz, 2H),
8.31 (dd, J = 1.7 and 9.1 Hz, 1H, H8), 7.42 (dd, J = 4.4 and 9.1 Hz, 1H,
H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 145.8, 144.4, 141.2, 135.3,
134.9, 126.5, 126.4, 126.3, 124.1, 118.5. Elemental analysis: calcd (%)
for C12H8N4O2 (240.22): C 60.00, H 3.36; found: C 59.79, H 3.48.
Experimental Section
All reactions were carried out under argon atmosphere with standard
Schlenk techniques. 1,4-Dioxane, DMA, diethylcarnonate and pentan-1-
ol were purchased from Acros Organics and were not purified before use.
1H NMR spectra were recorded on Bruker GPX (400 MHz) spectrometer.
Chemical shifts (δ) were reported in parts per million relative to residual
DMSO (2.50 ppm (quintet, JHD=1.9 Hz) ppm for 1H; 39.52 ppm for 13C),
constants were reported in Hertz. 1H NMR assignment abbreviations
were the following: singlet (s), doublet (d), triplet (t), quartet (q), doublet
of doublets (dd), doublet of triplets (dt), and multiplet (m). 13C NMR
4-(Imidazo[1,2-b]pyridazin-3-yl)benzaldehyde (4): Following the
general procedure using 4-bromobenzaldehyde (0.183 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
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Chemistry - An Asian Journal
10.1002/asia.201600827
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flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 4 (0.217 g, 97%) as a yellow solid (mp = 138-141 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 9.98 (s, 1H), 8.66 (d, J = 4.4 Hz,
1H, H6), 8.43 (s, 1H, H2), 8.37 (d, J = 8.2 Hz, 2H), 8.22 (d, J = 9.2 Hz,
1H, H8), 7.96 (d, J = 8.2 Hz, 2H), 7.33 (dd, J = 4.4 and 9.2 Hz, 1H, H7).
13C NMR (100 MHz, d6-DMSO) δ (ppm) 192.6, 144.5, 141.2, 125.1,
135.0, 134.4, 130.2, 126.6, 126.4, 126.3, 118.3. Elemental analysis:
calcd (%) for C13H9N3O (223.24): C 69.95, H 4.06; found: C 70.12, H 4.21.
compound 9 (0.172 g, 82%) as a yellow solid (mp = 105-108 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.63 (dd, J = 1.6 and 4.5 Hz, 1H, H6),
8.22 (s, 1H, H2), 8.20 (d, J = 9.2 Hz, 1H, H8), 8.04 (d, J = 8.2 Hz, 2H),
7.33 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 4.7 and 9.2 Hz, 1H, H7), 2.36 (s,
3H). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 143.8, 139.6, 137.2, 132.4,
129.2, 127.3, 126.2, 126.0, 125.6, 116.8, 20.9. Elemental analysis: calcd
(%) for C13H11N3 (209.25) C 74.62, H 5.30; found: C 74.97, H 5.46.
4-(Imidazo[1,2-b]pyridazin-3-yl)aniline (10): Following the general
procedure using 4-iodoaniline (0.219 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (CH2Cl2-MeOH, 98:2) to afford the desired
compound 10 (0.191 g, 91%) as a yellow solid (mp = 150-152 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.57 (dd, J = 1.6 and 4.5 Hz, 1H, H6),
8.13 (dd, J = 1.9 and 9.2 Hz, 1H, H8), 8.11 (s, 1H, H2), 7.80 (d, J = 8.5
Hz, 2H), 7.18 (dd, J = 4.7 and 9.2 Hz, 1H, H7), 6.69 (d, J = 8.5 Hz, 2H),
5.37 (brs, 2H). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 148.7, 143.4,
138.8, 130.8, 128.4, 127.5, 115.8, 115.7, 113.6. Elemental analysis:
calcd (%) for C12H10N4 (210.24) C 68.56, H 4.79; found: C 68.84, H 4.56.
1-(4-(Imidazo[1,2-b]pyridazin-3-yl)phenyl)ethan-1-one (5): Following
the general procedure using 4-bromoacetophenone (0.199 g, 1 mmol)
and imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 65:35) to
afford the desired compound 5 (0.218 g, 92%) as a yellow solid (mp =
136-138 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.71 (dd, J = 1.6
and 4.4 Hz, 1H, H6), 8.45 (s, 1H, H2), 8.36 (d, J = 8.4 Hz, 2H), 8.26 (dd,
J = 1.6 and 9.2 Hz, 1H, H8), 8.08 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 4.4
and 9.2 Hz, 1H, H7), 2.62 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ
(ppm) 197.2, 144.2, 140.6, 135.4, 134.3, 132.8, 128.7, 126.3, 126.2,
125.7, 117.8, 26.7. Elemental analysis: calcd (%) for C14H11N3O
(237.26): C 70.87, H 4.67; found: C 71.13, H 4.51.
Methyl 3-(imidazo[1,2-b]pyridazin-3-yl)benzoate (11): Following the
general procedure using methyl 3-bromobenzoate (0.215 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to afford the
desired compound 11 (0.233 g, 92%) as a pale yellow solid (mp = 119-
121 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.78 (s, 1H), 8.69 (dd, J
= 1.7 and 4.6 Hz, 1H, H6), 8.38 (d, J = 7.8 Hz, 1H), 8.36 (s, 1H, H2), 8.24
(dd, J = 1.7 and 9.2 Hz, 1H, H8), 7.96 (ddd, J = 6.1, 6.4 and 7.8 Hz, 1H),
7.67 (dd, J = 7.5 and 7.8Hz, 1H), 7.33 (dd, J = 4.4 and 9.2 Hz, 1H, H7),
3.90 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 166.1, 144.1, 140.1,
133.4, 130.9, 130.1, 129.2, 129.0, 128.3, 126.5, 126.2, 117.5, 52.3.
Elemental analysis: calcd (%) for C14H11N3O2 (253.26) C 66.40, H 4.38;
found: C 66.57, H 4.71.
Ethyl 4-(imidazo[1,2-b]pyridazin-3-yl)benzoate (6): Following the
general procedure using ethyl 4-bromobenzoate (0.229 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 6 (0.243 g, 91%) as a pale yellow solid (mp = 108-110
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.75 (dd, J = 1.6 and 4.5 Hz,
1H, H6), 8.49 (s, 1H, H2), 8.35 (d, J = 8.5 Hz, 2H), 8.3 (dd, J = 1.9 and
9.2 Hz, 1H, H8), 8.09 (d, J = 8.5 Hz, 2H), 7.42 (dd, J = 4.5 and 9.2 Hz,
1H, H7), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, d6-DMSO) δ (ppm) 165.4, 144.5, 140.2, 133.2, 132.6, 129.5, 128.6,
126.3, 126.0, 125.9, 118.5, 60.8, 14.2. Elemental analysis: calcd (%) for
C15H13N3O2 (267.29): C 67.40, H 4.90; found: C 67.58, H 5.12.
1-(3-(Imidazo[1,2-b]pyridazin-3-yl)phenyl)ethan-1-one (12): Following
the general procedure using 3-bromoacetophenone (0.197 g, 1 mmol)
and imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (CH2Cl2-MeOH, 98:2) to
afford the desired compound 12 (0.211 g, 89%) as a pale yellow solid
(mp = 143-146 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.72 (s, 1H),
8.69 (dd, J = 1.6 and 4.5 Hz, 1H, H6), 8.39 (d, J = 7.7 Hz, 1H), 8.39 (s,
1H, H2), 8.25 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 7.98 (ddd, J = 6.5, 6.7
and 7.7 Hz, 1H), 7.68 (dd, J = 7.1 and 7.4 Hz, 1H), 7.34 (dd, J = 4.4 and
9.2 Hz, 1H, H7), 2.67 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ (ppm)
197.8, 144.1, 140.0, 137.2, 133.4, 130.6, 129.1, 128.9, 127.4, 126.4,
126.2, 125.7, 117.5, 26.9. Elemental analysis: calcd (%) for C14H11N3O
(237.26) C 70.87, H 4.67; found: C 71.05, H 4.98.
3-(4-Chlorophenyl)imidazo[1,2-b]pyridazine (7): Following the general
procedure using 1-bromo-4-chlorobenzene (0.191 g,
1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 7 (0.204 g, 89%) as a pale yellow solid (mp = 144-148
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.66 (dd, J = 1.6 and 4.5 Hz,
1H, H6), 8.32 (s, 1H, H2), 8.25-8.19 (m, 3H), 7.59 (d, J = 8.5 Hz, 2H),
7.32 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ
(ppm) 144.0, 140.0, 133.2, 132.1, 128.7, 127.8, 127.3, 126.1, 126.1,
117.4. Elemental analysis: calcd (%) for C12H8ClN3 (229.67): C 62.76, H
3.51; found: C 62.80, H 3.72.
3-(4-Fluorophenyl)imidazo[1,2-b]pyridazine (8): Following the general
procedure using 1-bromo-4-fluorobenzene (0.175 g,
1
mmol) and
3-(3-Bromophenyl)imidazo[1,2-b]pyridazine (13): Following the
general procedure using 1,3-dibromobenzene (0.236 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to afford the
desired compound 13 (0.233 g, 85%) as a grey solid (mp = 92-95 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.69 (dd, J = 1.7 and 4.5 Hz, 1H,
H6), 8.44 (t, J = 1.9 Hz, 1H), 8,38 (s, 1H, H2), 8.24 (dd, J = 1.7 and 9.1
Hz, 1H, H8), 8.17 (ddd, J = 6.1, 6.7 and 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz,
1H), 7.48 (dd, J = 7.1 and 7.4 Hz, 1H), 7.33 (dd, J = 4.5 and 9.1 Hz, 1H,
H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 144.1, 140.2, 133.6, 130.8,
130.7, 130.3, 128.2, 126.2, 125.6, 125.0, 122.0, 117.6. Elemental
analysis: calcd (%) for C12H8BrN3 (274.12) C 52.58, H 2.94; found: C
52.67, H 3.14.
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to afford the
desired compound 8 (0.200 g, 94%) as a pale yellow solid (mp = 108-111
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.64 (dd, J = 1.6 and 4.4 Hz,
1H, H6), 8.25 (s, 1H, H2), 8.23-8.15 (m, 3H), 7.36 (t, J = 8.9 Hz, 2H),
7.29 (dd, J = 4.4 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ
(ppm) 161.5 (d, J = 244.5 Hz), 143.9, 139.7, 132.7, 128.4 (d, J = 8.2 Hz),
126.4, 126.1, 125.0 (d, J = 3.0 Hz), 117.1, 115.6 (d, J = 19.4 Hz).
Elemental analysis: calcd (%) for C12H8FN3 (213.22): C 67.60, H 3.78;
found: C 67.69, H 3.66.
3-(P-tolyl)imidazo[1,2-b]pyridazine (9): Following the general
procedure using 4-bromotoluene (0.171 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 70:30) to afford the desired
3-(Imidazo[1,2-b]pyridazin-3-yl)aniline (14): Following the general
procedure using 3-iodoaniline (0.219 g, 1 mmol) and imidazo[1,2-
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Chemistry - An Asian Journal
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b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (CH2Cl2-MeOH, 98:2) to afford the desired
compound 14 (0.172 g, 82%) as a brown solid (mp = 112-115 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.61 (dd, J = 1.6 and 4.5 Hz, 1H, H6),
8.18 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 8.08 (s, 1H, H2), 7.35 (dd, J = 2.0
and 2.1 Hz, 1H), 7.29-7.20 (m, 2H), 7.14 (dd, J = 7.5 and 7.6 Hz, 1H), 6.6
(md, J = 7.9 Hz, 1H), 5.20 (brs, 2H). 13C NMR (100 MHz, d6-DMSO) δ
(ppm) 148.8, 143.7, 139.5, 132.4, 129.1, 128.8, 128.1, 125.9, 116.7,
114.3, 113.6, 111.7. Elemental analysis: calcd (%) for C12H10N4 (210.24)
C 68.56, H 4.79; found: C 68.79, H 4.89.
3-(Naphthalen-1-yl)imidazo[1,2-b]pyridazine (19): Following the
general procedure using 1-bromonaphthalene (0.207g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 19 (0.182 g, 74%) as a yellow solid (mp = 173-176
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.46 (dd, J = 1.7 and 4.4 Hz,
1H, H6), 8.27 (dd, J = 1.7 and 9.2 Hz, 1H, H8), 8.11-8.02 (m, 3H), 7.74
(dd, J = 1.6 and 7.1 Hz, 1H), 7.66 (dd, J = 7.1 and 7.4 Hz, 1H), 6.60-7.51
(m, 2H), 7.50-7.44 (m, 1H), 7.30 (dd, J = 4.4 and 9.2 Hz, 1H, H7). 13C
NMR (100 MHz, d6-DMSO) δ (ppm) 143.7, 139.0, 134.0, 133.3, 131.4,
129.2, 128.9, 128.4, 126.7, 126.6, 126.2, 125.9, 125.7, 125.4, 125.3,
117.5. Elemental analysis: calcd (%) for C16H11N3 (245.28): C 78.35, H
4.52; found: C 78.57, H 4.59.
3-(3,5-Bis(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine
Following the general procedure using
(15):
3,5-
bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 70:30) to afford the desired
compound 15 (0.298 g, 90%) as a grey solid (mp = 156-159 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.88 (s, 2H), 8.77 (dd, J = 1.6 and
4.5 Hz, 1H, H6), 8.66 (s, 1H), 8.29 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 8.06
(s, 1H, H2), 7.4 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-
DMSO) δ (ppm) 141.2, 140.6, 134.8, 130.9, 128.4 (q, J = 44.9 Hz), 125.6,
124.6, 124.0, 123.1 (q, J = 272.1 Hz), 120.2, 118.1. Elemental analysis:
calcd (%) for C14H7F6N3 (331.22) C 50.77, H 2.13; found: C 50.98, H 2.08.
3-(Pyren-1-yl)imidazo[1,2-b]pyridazine (20): Following the general
procedure using 1-bromopyrene (0.281g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 80:20) to afford the desired
compound 20 (0.252 g, 79%) as a yellow solid (mp = 190-194 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.50 (dd, J = 1.6 and 4.6 Hz, 1H, H6),
8.42 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.34-8.30 (m, 2H),
8.29-8.25 (m, 3H), 8.20 (s, 1H, H2), 8.16 (d, J = 9.2 Hz, 1H), 8.12 (dd, J
= 7.4 and 7.6 Hz, 1H), 7.89 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 7.34 (dd, J
= 4.4 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 123.7,
124.0, 124.7, 124.8, 125.4, 125.7, 126.0, 126.5, 126.8, 127.3, 128.1,
128.7, 129.2, 130.3, 130.8, 131.1, 134.6, 139.2, 143.9, 117.7, 122.9.
Elemental analysis: calcd (%) for C22H13N3 (319.36): C 82.74, H 4.10;
found: C 82.89, H 3.87.
2-(Imidazo[1,2-b]pyridazin-3-yl)benzonitrile (16): Following the
general procedure using 2-bromobenzonitrile (0.182 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to afford the
desired compound 16 (0.205 g, 93%) as a grey solid (mp = 214-218 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.62 (dd, J = 1.6 and 4.5 Hz, 1H,
H6), 8.28 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 8.18 (s, 1H, H2), 8.04 (d, J =
7.6 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.88 (dd, J = 7.6 and 7.8 Hz, 1H),
7.66 (d, J = 7.6 and 7.8 Hz, 1H), 7.38 (dd, J = 4.4 and 9.2 Hz, 1H, H7).
13C NMR (100 MHz, d6-DMSO) δ (ppm) 144.0, 139.7, 134.3, 133.7,
133.3, 131.1, 130.5, 129.1, 126.2, 124.4, 118.5, 118.1, 111.3. Elemental
analysis: calcd (%) for C13H8N4 (220.23): C 70.90, H 3.66; found: C 71.03,
H 3.52.
3-(Imidazo[1,2-b]pyridazin-3-yl)quinoline (21): Following the general
procedure using 3-bromoquinoline (0.208 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 55:45) to afford the desired
compound 21 (0.214 g, 87%) as a yellow solid (mp = 230-233 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 9.58 (d, J = 2.3 Hz, 1H), 9.20 (d, J =
2.4 Hz, 1H), 8.76 (dd, J = 1.7 and 4.4 Hz, 1H, H6), 8.58 (s, 1H, H2), 8.29
(dd, J = 1.7 and 9.2 Hz, 1H, H8), 8.07 (dd, J = 3.1 and 8.2 Hz, 2H), 7.78
(ddd, J = 1.4, 6.8, and 8.5 Hz, 1H), 7.66 (dd, J = 7.0 and 8.2 Hz, 1H),
7.38 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ
(ppm) 148.8, 146.4, 144.3, 140.4, 133.7, 131.2, 129.6, 128.8, 128.4,
127.3, 127.3, 126.2, 124.7, 122.0, 117.9. Elemental analysis: calcd (%)
for C15H10N4 (246.27): C 73.16, H 4.09; found: C 73.27, H 4.19.
2-(Imidazo[1,2-b]pyridazin-3-yl)benzaldehyde (17): Following the
general procedure using 2-bromobenzaldehyde (0.183 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 17 (0.203 g, 91%) as a grey solid (mp = 157-160 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 9.76 (s, 1H), 8.51 (dd, J = 1.6 and
4.4 Hz, 1H, H6), 8.24 (dd, J = 1.7 and 9.3 Hz, 1H, H8), 8.08 (s, 1H, H2),
8.02 (dd, J = 1.5 and 7.7 Hz, 1H), 7.83 (dt, J = 1.5 and 7.6 Hz, 1H), 7.75-
7.66 (m, 2H), 7.32 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz,
d6-DMSO) δ (ppm) 191.4, 144.0, 139.5, 134.5, 134.1, 133.9, 131.7,
130.0, 129.2, 128.3, 126.1, 125.2, 118.1. Elemental analysis: calcd (%)
for C13H9N3O (223.24): C 69.95, H 4.06; found: C 69.79, H 4.41.
3-(Pyridin-3-yl)imidazo[1,2-b]pyridazine (22): Following the general
procedure using 3-bromopyridine (0.157 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 55:45) to afford the desired
compound 22 (0.184 g, 94%) as a grey solid (mp = 118-120 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 9.31 (d, J = 2.3 Hz, 1H), 8.67 (d, J =
4.5 Hz, 1H, H6), 8.57 (d, J = 5.3 Hz, 1H), 8.54 (ddd, J = 2.1, 7.5 and 7.7
Hz, 1H), 8.38 (s, 1H, H2), 8.25 (d, J = 9.2 Hz, 1H, H8), 7.54 (dd, J = 5.1
and 7.7 Hz, 1H), 7.33 (dd, J = 4.4 and 9.2 Hz, 1H, H7). 13C NMR (100
MHz, d6-DMSO) δ (ppm) 148.4, 147.1, 144.1, 140.2, 133.2, 133.2, 126.2,
124.7, 124.5, 123.6, 117.7. Elemental analysis: calcd (%) for C11H8N4
(196.21): C 67.34, H 4.11; found: C 67.58, H 4.27.
3-(2-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (18): Following
the general procedure using 2-(trifluoromethyl)bromobenzene (0.225 g, 1
mmol) and imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 65:35) to
afford the desired compound 18 (0.253 g, 96%) as a yellow solid (mp =
176-179 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.49 (dd, J = 1.5
and 4.5 Hz, 1H, H6), 8.22 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 7.94 (d, J =
7.7 Hz, 1H), 7.86 (s, 1H), 7.82 (dd, J = 6.9 and 8.7 Hz, 1H), 7.74 (dd, J =
6.9 and 7.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.3 (dd, J = 4.5 and 9.2 Hz,
1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 143.8, 138.7, 133.7,
133.5, 132.4, 129.8, 120.0 (q, J = 29.1 Hz), 126.6, 126.4 (q, J = 2.1 Hz),
125.8, 124.5, 123.8 (q, J = 274.2 Hz), 117.8. Elemental analysis: calcd
(%) for C13H8F3N3 (263.22): C 59.32, H 3.06; found: C 59.51, H 2.85.
3-(Pyrimidin-5-yl)imidazo[1,2-b]pyridazine (23): Following the general
procedure using 5-bromopyrimidine (0.159 g, 1 mmol) and imidazo[1,2-
b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 55:45) to afford the desired
compound 23 (0.144 g, 73%) as a grey solid (mp = 230-234 ºC). 1H
NMR (400 MHz, d6-DMSO) δ (ppm) 8.56 (s, 2H), 9.18 (s, 1H), 8.72 (dd, J
= 1.6 and 4.5 Hz, 1H, H6), 8.50 (s, 1H, H2), 8.29 (dd, J = 1.6 and 9.2 Hz,
1H, H8), 7.39 (dd, J = 4.4 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-
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Chemistry - An Asian Journal
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DMSO) δ (ppm) 171.4, 156.9, 153.6, 144.4, 140.6, 133.8, 126.3, 123.4,
118.3. Elemental analysis: calcd (%) for C10H7N5 (197.20): C 60.91, H
3.58; found: C 61.17, H 3.79.
1H, H6), 8.24 (dd, J = 1.6 and 9.3 Hz, 1H, H8), 8.21 (d, J = 8.0 Hz, 1H),
8.12 (s, 1H. H2), 7.91 (ddd, J = 1.5, 7.3 and 8.2 Hz, 1H), 7.82 (d, J = 7.3
Hz, 1H), 7.76 (ddd, J = 1.7, 7.3 and 8.2 Hz, 1H), 7.30 (dd, J = 4.4 and 9.3
Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 147.6, 143.7, 139.6,
134.0, 133.2, 133.1, 130.1, 126.1, 125.0, 122.2, 118.1. Elemental
analysis: calcd (%) for C12H8N4O2 (240.22): C 60.00, H 3.36; found: C
60.31, H 3.19
3-(4-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (24): Following
the general procedure using 4-(trifluoromethyl)chlorobenzene (0.180 g, 1
mmol) and imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 65:35) to
afford the desired compound 24 (0.182 g, 69%) as a yellow solid (mp =
94-98 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.70 (dd, J = 1.6 and
4.4 Hz, 1H, H6), 8.44 (s, 1H, H2), 8.42 (d, J = 8.8 Hz, 2H), 8.27 (dd, J =
1.6 and 9.2 Hz, 1H, H8), 7.87 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 4.4 and
9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 144.3, 140.5
134.1, 132.4, 127.5 (q, J = 30.5 Hz), 126.3, 126.2, 125.7, 125.5 (m),
124.2 (q, J = 278.5 Hz), 117.8. Elemental analysis: calcd (%) for
C13H8F3N3 (263.22): C 59.32, H 3.06; found: C 59.27, H 3.18.
2-(Imidazo[1,2-b]pyridazin-3-yl)-5-nitrobenzonitrile (29): Following the
general procedure using 2-chloro-5-nitrobenzonitrile (0.183 g, 1 mmol)
and imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 55:45) to
afford the desired compound 29 (0.191 g, 72%) as a yellow solid (mp =
232-234 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.91 (d, J = 2.6 Hz,
1H), 8.71 (d, J = 4.5 Hz, 1H, H8), 8.66 (dd, J = 2.5 and 8.7 Hz, 1H), 8.42
(s, 1H, H2), 8.39 (d, J = 9.2 Hz, 1H, H6), 8.35 (dd, J = 1.8 and 9.2 Hz, 1H,
H6), 7.47 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C NMR (100 MHz, d6-
DMSO) δ (ppm) 146.4, 144.5, 140.8, 138.3, 136.6, 136.0, 130.9, 129.2,
127.9, 126.5, 122.8, 119.7, 111.4. Elemental analysis: calcd (%) for
C13H7N5O2 (265.23): C 58.87, H 2.66; found: C 59.11, H 2.89
Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)benzoate (25): Following the
general procedure using methyl 4-chlorobenzoate (0.170 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 25 (0.182 g, 72%) as a white solid (mp = 165-167 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.70 (dd, J = 1.6 and 4.4 Hz, 1H,
H6), 8.43 (s, 1H, H2), 8.35 (d, J = 8.4 Hz, 2H), 8.25 (dd, J = 1.6 and 9.2
Hz, 1H, H8), 8.07 (d, J = 8.4 Hz, 2H), 7.35 (dd, J = 4.4 and 9.2 Hz, 1H,
H7), 3.88 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 165.9, 144.1,
140.6, 134.3, 132.9, 129.5, 128.1, 126.2, 126.1, 125.7, 117.8, 52.1.
Elemental analysis: calcd (%) for C14H11N3O2 (253.26): C 66.40, H 4.38;
found: C 66.49, H 4.59.
6-Chloro-3-(4-nitrophenyl)imidazo[1,2-b]pyridazine (30): Following
the general procedure using 4-bromonitrobenzene (0.200 g, 1 mmol) and
6-chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 60:40) to
afford the desired compound 30 (0.214 g, 78%) as a yellow solid (mp =
215-218 ºC). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.53 (s, 1H), 8.40-8.36
(m, 4H), 8.33 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 9.4 Hz, 1H). This is a
known compound and the spectral data are identical to those reported in
literature.[11]
3-(Imidazo[1,2-b]pyridazin-3-yl)benzonitrile (26): Following the
general procedure using 3-chlorobenzonitrile (0.137 g, 1 mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 65:35) to afford the
desired compound 26 (0.159 g, 72%) as a white solid (mp = 194-198 ºC).
1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.72 (dd, J = 1.7 and 4.4 Hz, 1H,
H6), 8.65 (s, 1H), 8.52 (ddd, J = 7.7, 7.9 and 8.0 Hz, 1H), 8.45 (s, 1H,
H2), 8.26 (dd, J = 1.7 and 9.2 Hz, 1H, H8), 7.84 (ddd, J = 7.7, 7.9 and 8.0
Hz, 1H), 7.73 (d, J = 7.7 and 7.9 Hz, 1H), 7.37 (dd, J = 4.4 and 9.2 Hz,
1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 144.2, 140.4, 133.9,
131.0, 130.4, 130.0, 129.7, 129.1, 126.2, 125.1, 118.7, 117.9, 111.9.
Elemental analysis: calcd (%) for C13H8N4 (220.24): C 70.90, H 3.66;
found: C 71.18, H 3.65.
4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)benzaldehyde (31): Following
the general procedure using 4-bromobenzaldehyde (0.183 g, 1 mmol)
and 6-chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue
was purified by flash chromatography on silica gel (pentane-Et2O, 60:40)
to afford the desired compound 31 (0.211 g, 82%) as a yellow solid (mp =
145-148 ºC). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.05 (s, 1H), 8.28-
8.23 (m, 2H), 8.18 (s, 1H), 8.05-7.94 (m, 3H), 7.15 (d, J = 9.4 Hz, 1H).
This is a known compound and the spectral data are identical to those
reported in literature.[11]
3-(4-Bromophenyl)-6-chloroimidazo[1,2-b]pyridazine (32): Following
the general procedure using 1,4-dibromobenzene (0.236 g, 1 mmol) and
6-chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 60:40) to
afford the desired compound 32 (0.231 g, 75%) as a yellow solid (mp =
152-154 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.37 (s, 1H, H2),
8.32 (d, J = 9.5 Hz, 1H, H8), 8.07 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.7 Hz,
2H), 7.45 (d, J = 9.5 Hz, 1H, H7). 3C NMR (100 MHz, d6-DMSO) δ (ppm)
146.5, 138.9, 134.0, 131.8, 128.2, 128.1, 127.0, 126.8, 121.2, 118.9.
Elemental analysis: calcd (%) for C12H7BrClN3 (308.56): C 46.71, H 2.29;
found: C 46.78, H 2.35.
3-(3-Nitrophenyl)imidazo[1,2-b]pyridazine (27): Following the general
procedure using 3-chloronitrobenzene (0.157 g,
1
mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 55:45) to afford the
desired compound 27 (0.173 g, 72%) as a yellow solid (mp = 170-174
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 9.13 (s, 1H), 8.75 (dd, J =
1.6 and 4.4 Hz, 1H, H6), 8.57 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H, H2), 8.28
(dd, J = 1.6 and 9.2 Hz, 1H, H8), 8.21 (dd, J = 2.5 and 8.3 Hz, 1H), 7.81
(dd, J = 8.0 and 8.3 Hz, 1H), 7.38 (dd, J = 4.5 and 9.2 Hz, 1H, H7). 13C
NMR (100 MHz, d6-DMSO) δ (ppm) 148.1, 144.3, 140.5, 134.1, 132.2,
130.2, 130.0, 126.3, 125.0, 122.1, 119.8, 118.0. Elemental analysis:
calcd (%) for C12H8N4O2 (240.22): C 60.00, H 3.36; found: C 60.23, H
3.57
Methyl
2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzoate
(33):
Following the general procedure using methyl 2-bromobenzoate (0.215 g,
1 mmol) and 6-chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the
residue was purified by flash chromatography on silica gel (pentane-Et2O,
55:45) to afford the desired compound 33 (0.170 g, 59%) as a yellow
solid (mp = 144-147 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.29 (d,
J = 9.5 Hz, 1H, H8), 8.07 (s, 1H, H2), 7.96 (dd, J = 1.5 and 7.7 Hz, 1H),
7.75 (ddd, J = 1.5, 7.4 and 7.5 Hz, 1H), 7.68-7.60 (m, 2H), 7.40 (d, J =
9.5 Hz, 1H, H7), 3.57 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ (ppm)
167.1, 145.8, 137.9, 133.7, 132.3, 131.8, 130.4, 129.9, 129.2, 128.4,
3-(2-Nitrophenyl)imidazo[1,2-b]pyridazine (28): Following the general
procedure using 2-chloronitrobenzene (0.157 g,
1
mmol) and
imidazo[1,2-b]pyridazine (0.131 g, 1.1 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 55:45) to afford the
desired compound 28 (0.156 g, 65%) as a yellow solid (mp = 180-185
ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.47 (dd, J = 1.6 and 4.5 Hz,
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Chemistry - An Asian Journal
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128.0, 126.8, 118.7, 52.1.
C14H10ClN3O2 (287.70): C 58.45, H 3.50; found: C 58.76, H 3.41.
Elemental analysis: calcd (%) for
= 1.6 and 9.2 Hz, 1H, H8), 7.64-7.58 (m, 4H), 7.39-7.26 (m, 6H). 13C
NMR (100 MHz, d6-DMSO) δ (ppm) 162.2 (d, J = 245.3 Hz), 143.7, 141.8,
138.3, 133.8, 132.9 (d, J = 8.4 Hz), 128.5, 127.9, 127.7, 125.3, 125.1 (m),
123.4, 118.1, 115.9 (d, J = 22.3 Hz).
6-Chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine (34): Following
the general procedure using 1-bromonaphthalene (0.207g, 1 mmol) and
6-chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 45:55) to
afford the desired compound 34 (0.213 g, 76%) as a white solid (mp =
180-183 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.36 (d, J = 9.5 Hz,
1H, H7), 8.12 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H, H2), 8.07 (d, J = 8.4 Hz,
1H), 7.74 (dd, J = 1.5 and 7.0 Hz, 1H), 7.68 (dd, J = 7.3 and 8.2 Hz, 1H),
7.62-7.55 (m, 2H), 7.5 (ddd, J = 1.6, 6.6 and 8.6 Hz, 1H), 7.43 (d, J = 9.5
Hz, 1H, H8). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 146.4, 138.0, 135.0,
133.3, 129.6, 129.1, 128.5, 128.1, 126.9, 126.3, 125.5, 126.3, 125.5,
125.2, 124.9, 119.0. Elemental analysis: calcd (%) for C16H10ClN3
(279.73): C 68.70, H 3.60; found: C 69.12, H 3.98.
Elemental analysis: calcd (%) for C18H12FN3 (289.31): C 74.73, H 4.18;
found: C 74.89, H 4.07.
3-(4-fluorophenyl)-2-(thiophen-3-yl)imidazo[1,2-b]pyridazine
(39):
The reaction of 2-bromo-3-(4-fluorophenyl)imidazo[1,2-b]pyridazine (37)
(0.146 g, 0.5 mmol), thiophen-3-ylboronic acid (0.077 g, 0.6 mmol) and
K3PO4 (0.212 g, 1 mmol) at 80 °C over 15 h in 1,4-dioxane (1 mL) in the
presence of PdCl(C3H5)(dppb) (6 mg, 0.01 mmol) under argon affords,
after evaporation of the solvent and purification on silica gel, product 39
(0.131 g, 89%) as a white solid (mp = 186-189 ºC). 1H NMR (400 MHz,
d6-DMSO) δ (ppm) 8.46 (dd, J = 1.6 and 4.4 Hz, 1H, H6), 8.17 (dd, J =
1.6 and 9.2 Hz, 1H, H8), 7.65-7.60 (m, 2H), 7.55 (dd, J = 3.1 and 5.1 Hz,
1H), 7.4 (t, J = 8.8 Hz, 2H), 7.28 (dd, J = 4.4 and 9.2 Hz, 2H), 7.21 (dd, J
= 1.0 and 5.1 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 162.3 (d,
J = 248.3 Hz), 143.6, 138.3, 138.1, 135.1, 133.0 (d, J = 9.5 Hz), 126.5,
126.4, 125.0, 124.9 (m), 123.2, 122.9, 118.0, 115.9 (d, J = 21.7 Hz).
Elemental analysis: calcd (%) for C16H10FN3S (295.34): C 65.07, H 3.41;
found: C 65.28, H 3.56.
3-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)quinoline (35): Following the
general procedure using 3-bromoquinoline (0.208 g, 1 mmol) and 6-
chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 20:80) to
afford the desired compound 35 (0.174 g, 62%) as a yellow solid (mp =
218-221 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 9.55 (d, J = 2.3 Hz,
1H), 9.08 (d, J = 2.3 Hz, 1H), 8.59 (s, 1H), 8.38 (d, J = 9.5 Hz, 1H, H7),
8.11-8.06 (m, 2H), 7.82 (ddd, J = 1.5, 6.9 and 8.5 Hz, 1H), 7.69 (dd, J =
6.9 and 8.2 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H, H8). 13C NMR (100 MHz,
d6-DMSO) δ (ppm) 148.7, 146.7, 146.6, 129.2, 134.5, 131.8, 130.0,
128.8, 128.5, 128.3, 127.4, 127.2, 125.3, 121.4, 119.4. Elemental
analysis: calcd (%) for C15H9ClN4 (280.72): C 64.18, H 3.23; found: C
64.28, H 3.45.
Acknowledgements
Acknowledgements Text.
Keywords: Palladium • Heterocycles • Aryl Halides • Green
Solvents • Phosphine-free
6-Chloro-3-(pyridin-3-yl)imidazo[1,2-b]pyridazine (36): Following the
general procedure using 3-bromopyridine (0.157 g, 1 mmol) and 6-
chloroimidazo[1,2-b]pyridazine (0.169 g, 1.1 mmol), the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 60:40) to
afford the desired compound 36 (0.134 g, 58%) as a yellow solid (mp =
144-147 ºC). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.23 (d, J = 2.0 Hz, 1H),
8.63 (dd, J = 1.5 and 4.8 Hz, 1H), 8.42 (td, J = 1.9 and 8.0 Hz, 1H), 8.01
(s, 1H), 7.99 (d, J = 9.4 Hz, 1H), 7.46-7.43 (m, 1H), 7.14 (d, J = 9.4 Hz,
1H). This is a known compound and the spectral data are identical to
those reported in literature.[11]
[1]
a) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013-3039; b) L. Ackermann,
R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792-9826; c)
F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269-10310; d) X. Chen, K.
M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094-
5115; e) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147-
1169; f) E. M. Beck, M. J. Gaunt, Top. Curr. Chem. 2010, 292, 85-121;
g) J. Roger, A. L. Gottumukkala, H. Doucet, ChemCatChem 2010, 2,
20-40; h) T. Satoh, M. Miura, Synthesis 2010, 3395-3409; i) C.-L. Sun,
B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677-685; j) S. H. Cho, J.
Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 2011, 40, 5068-5083; k) N.
Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. Int.
Ed. 2012, 51, 10236-10254; l) B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 2012,
41, 5588-5598; m) M. C. White, Synlett 2012, 23, 2746-2748; n) J.
Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51,
8960-9009; o) S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4,
886-896; p) M. He, J.-F. Soulé, H. Doucet, ChemCatChem 2014, 6,
1824-1859; q) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv. Synth.
Catal. 2014, 356, 17-117; r) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li,
W. Su, Org. Chem. Front. 2014, 1, 843-895; s) M. R. Yadav, R. K. Rit,
M. Shankar, A. K. Sahoo, Asian J. Org. Chem. 2015, 4, 846-864; t) K.
Hirano, M. Miura, Chem. Lett. 2015, 44, 878-873; u) K. Yuan, J.-F.
Soulé, H. Doucet, ACS Catal. 2015, 5, 978-991; v) C. B. Bheeter, L.
Chen, J.-F. Soulé, H. Doucet, Catal. Sci. Technol. 2016, 6, 2005-2049.
a) A. H. M. De Vries, J. M. C. A. Mulders, J. H. M. Mommers, H. J. W.
Henderickx, J. G. De Vries, Org. Lett. 2003, 5, 3285-3288; b) M. T.
Reetz, J. G. De Vries, Chem. Commun. 2004, 1559-1563; c) J. G. de
Vries, Dalton Trans. 2006, 421-429.
2-Bromo-3-(4-fluorophenyl)imidazo[1,2-b]pyridazine
Fluorophenyl)imidazo[1,2-b]pyridazine (8) (0.213,
(37):
mmol), N-
3-(4-
1
bromosuccinimide (0.196 g, 1.1 mmol) were heated in 5 mL chloroform at
reflux for 12 hour. The solvent was evaporated and the residue was
purified by flash chromatography on silica gel (pentane-Et2O, 45:55) to
afford the desired compound 37 (0.278 g, 95%) as a white solid (mp =
172-173 ºC). 1H NMR (400 MHz, d6-DMSO) δ (ppm) 8.57 (dd, J = 1.6
and 4.6 Hz, 1H, H6), 8.17 (dd, J = 1.6 and 9.2 Hz, 1H, H8), 7.82 (dd, J =
5.4 and 8.4 Hz, 2H), 7.41 (t, J = 8.9 Hz, 2H), 7.35 (dd, J = 4.6 and 9.2 Hz,
1H, H7). 13C NMR (100 MHz, d6-DMSO) δ (ppm) 162.0 (d, J = 247.1 Hz),
144.2, 138.2, 131.8 (d, J = 8.1 Hz), 125.0, 124.1, 123.0, 121.8, 118.7,
115.5 (d, J = 21.4 Hz). Elemental analysis: calcd (%) for C12H7BrFN3
(292.11): C 49.34, H 2.42; found: C 49.57, H 2.56.
[2]
[3]
a) X. Wang, D. V. Gribkov, D. Sames, J. Org. Chem. 2007, 72, 1476-
1479; b) J. J. Dong, J. Roger, F. Pozgan, H. Doucet, Green Chem.
2009, 11, 1832-1846; c) D. Zhao, W. Wang, S. Lian, F. Yang, J. Lan, J.
You, Chem. Eur. J. 2009, 15, 1337-1340; d) H. Y. Fu, L. Chen, H.
Doucet, J. Org. Chem. 2012, 77, 4473-4478; e) P. Ehlers, A. Petrosyan,
J. Baumgard, S. Jopp, N. Steinfeld, T. V. Ghochikyan, A. S. Saghyan, C.
Fischer, P. Langer, ChemCatChem 2013, 5, 2504-2511; f) S. Islam, I.
Larrosa, Chem. Eur. J. 2013, 19, 15093-15096; g) S. Hayashi, T.
Koizumi, Polym. Chem. 2015, 6, 5036-5039; h) W. Hagui, N. Besbes, E.
Srasra, J.-F. Soulé, H. Doucet, RSC Adv. 2016, 6, 17110-17117.
3-(4-Fluorophenyl)-2-phenylimidazo[1,2-b]pyridazine
(38):
The
reaction of 2-bromo-3-(4-fluorophenyl)imidazo[1,2-b]pyridazine (37)
(0.146 g, 0.5 mmol), phenylboronic acid (0.073 g, 0.6 mmol) and K3PO4
(0.212 g, 1 mmol) at 80 °C over 15 h in 1,4-dioxane (1 mL) in the
presence of PdCl(C3H5)(dppb) (6 mg, 0.01 mmol) under argon affords,
after evaporation of the solvent and purification on silica gel, product 38
(0.124 g, 86%) as a pale yellow solid (mp = 126-129 ºC). 1H NMR (400
MHz, d6-DMSO) δ (ppm) 8.49 (dd, J = 1.7 and 4.4 Hz, 1H, H6), 8.2 (dd, J
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[4]
a) K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A.
Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry, M. Stefaniak,
Green Chem. 2008, 10, 31-36; b) C. Capello, U. Fischer, K.
Hungerbuhler, Green Chem. 2007, 9, 927-934; c) R. K. Henderson, C.
Jimenez-Gonzalez, D. J. C. Constable, S. R. Alston, G. G. A. Inglis, G.
Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green Chem. 2011,
13, 854-862.
S. Sakamoto, S. Ando, M. Maeda, M. Higaki, Y. Baba, Y. Nakamura, J.
Med. Chem. 2015, 58, 1760-1775.
[11] A. El Akkaoui, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Eur. J.
Org. Chem. 2010, 2010, 862-871.
[12] a) F. Shibahara, E. Yamaguchi, T. Murai, J. Org. Chem. 2011, 76,
2680-2693; b) S. Suzuki, Y. Segawa, K. Itami, J. Yamaguchi, Nat.
Chem. 2015, 7, 227-233.
[5]
[6]
a) P. Arockiam, V. Poirier, C. Fischmeister, C. Bruneau, P. H. Dixneuf,
Green Chem. 2009, 11, 1871-1875; b) J. J. Dong, J. Roger, C. Verrier,
T. Martin, R. Le Goff, C. Hoarau, H. Doucet, Green Chem. 2010, 12,
2053-2063; c) C. Fischmeister, H. Doucet, Green Chem. 2011, 13, 741-
753; d) A. Hfaiedh, K. Yuan, H. Ben Ammar, B. Ben Hassine, J.-F.
Soulé, H. Doucet, ChemSusChem 2015, 8, 1794-1804.
a) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 706-716; b) M. Selva,
Pure Appl. Chem. 2007, 79, 1855-1867; c) T. Sakakura, K. Kohno,
Chem. Commun. 2009, 1312-1330; d) B. Schäffner, F. Schäffner, S. P.
Verevkin, A. Börner, Chem. Rev. 2010, 110, 4554-4581; e) A. E. Diaz-
Alvarez, J. Francos, B. Lastra-Barreira, P. Crochet, V. Cadierno, Chem.
Commun. 2011, 47, 6208-6227; f) C. Samori, M. Basaglia, S. Casella, L.
Favaro, P. Galletti, L. Giorgini, D. Marchi, L. Mazzocchetti, C. Torri, E.
Tagliavini, Green Chem. 2015, 17, 1047-1056.
a) K. Beydoun, H. Doucet, ChemSusChem 2011, 4, 526-534; b) S.
Bensaid, H. Doucet, C. R. Chim. 2014, 17, 1184-1189.
a) L. Ackermann, R. Vicente, Org. Lett. 2009, 11, 4922-4925; b) S.
Bensaid, N. Laidaoui, D. El Abed, S. Kacimi, H. Doucet, Tetrahedron
Lett. 2011, 52, 1383-1387.
a) G. L. Turner, J. A. Morris, M. F. Greaney, Angew. Chem., Int. Ed.
Engl. 2007, 46, 7996-8000; b) S. A. Ohnmacht, P. Mamone, A. J.
Culshaw, M. F. Greaney, Chem. Commun. 2008, 1241-1243; c) P. B.
Arockiam, C. Fischmeister, C. Bruneau, P. H. Dixneuf, Angew. Chem.,
Int. Ed. Engl. 2010, 49, 6629-6632; d) Y.-X. Su, Y.-H. Deng, T.-T. Ma,
Y.-Y. Li, L.-P. Sun, Green Chem. 2012, 14, 1979-1981.
[13] A. Takfaoui, R. Touzani, J.-F. Soulé, P. H. Dixneuf, H. Doucet, Asian J.
Org. Chem. 2015, 4, 1085-1095.
[14] a) A. L. Gottumukkala, H. Doucet, Eur. J. Inorg. Chem. 2007, 3629-
3632; b) L. Ackermann, R. Vicente, R. Born, Adv. Synth. Catal. 2008,
350, 741-748; c) D. Roy, S. Mom, M. Beaupérin, H. Doucet, J. C.
Hierso, Angew. Chem., Int. Ed. Engl. 2010, 49, 6650-6654; d) P. V.
Kumar, W.-S. Lin, J.-S. Shen, D. Nandi, H. M. Lee, Organometallics
2011, 30, 5160-5169; e) S. Mom, M. Beauperin, D. Roy, S. Royer, R.
Amardeil, H. Cattey, H. Doucet, J. C. Hierso, Inorg. Chem. 2011, 50,
11592-11603; f) L. Theveau, C. Verrier, P. Lassalas, T. Martin, G.
Dupas, O. Querolle, L. Van Hijfte, F. Marsais, C. Hoarau, Chem. Eur. J.
2011, 17, 14450-14463; g) H. Cao, Y. Lin, H. Zhan, Z. Du, X. Lin, Q.-M.
Liang, H. Zhang, RSC Adv. 2012, 2, 5972-5975; h) D. Ghosh, H. M.
Lee, Org. Lett. 2012, 14, 5534-5537; i) B. Liu, Z. Wang, N. Wu, M. Li, J.
You, J. Lan, Chem. Eur. J. 2012, 18, 1599-1603; j) D. Roy, S. Mom, S.
Royer, D. Lucas, J.-C. Hierso, H. Doucet, ACS Catal. 2012, 2, 1033-
1041; k) X.-B. Shen, Y. Zhang, W.-X. Chen, Z.-K. Xiao, T.-T. Hu, L.-X.
Shao, Org. Lett. 2014, 16, 1984-1987.
[7]
[8]
[15] S. Sahnoun, S. Messaoudi, J.-D. Brion, M. Alami, Org. Biomol. Chem.
2009, 7, 4271-4278.
[16] A. L. Gottumukkala, H. Doucet, Eur. J. Inorg. Chem. 2007, 2007, 3629-
3632.
[17] T. Cantat, E. Génin, C. Giroud, G. Meyer, A. Jutand, J. Organomet.
Chem. 2003, 687, 365-376.
[9]
[10] K.-i. Kusakabe, N. Ide, Y. Daigo, T. Itoh, T. Yamamoto, H. Hashizume,
K. Nozu, H. Yoshida, G. Tadano, S. Tagashira, K. Higashino, Y. Okano,
Y. Sato, M. Inoue, M. Iguchi, T. Kanazawa, Y. Ishioka, K. Dohi, Y. Kido,
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Phosphine-free Pd(OAc)2–catalyzed
direct arylation of imidazo[1,2-
S. Chikhi, S. Djebbar,] J.-F. Soulé,*[a]
and H. Doucet*
b]pyridazines at C3 position under
very low catalyst concentration in eco-
friendly solvents. Both aryl bromides
and aryl chlorides have been used as
coupling partners. TOFs up to 10000
h-1 have been obtained.
Page No. – Page No.
Environmentally-Safe Conditions for
the Palladium-Catalyzed Direct C3-
Arylation with High Turn Over
Frequency of Imidazo[1,2-
b]pyridazines Using Aryl Bromides
and Chlorides
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