Synthesis and evaluation of novel chloropyridazine derivatives as potent human rhinovirus (HRV) capsid-binding inhibitors

Article abstract of DOI:10.1016/j.bmc.2008.11.061

Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel chloropyridazine derivatives (compounds 5a-g) as p

Full text of DOI:10.1016/j.bmc.2008.11.061

Bioorganic & Medicinal Chemistry 17 (2009) 621–624
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of novel chloropyridazine derivatives as potent
human rhinovirus (HRV) capsid-binding inhibitors
*
Shi-Yong Fan, Zhi-Bing Zheng , Chun-Lai Mi, Xin-Bo Zhou, Hui Yan, Ze-Hui Gong, Song Li
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-
HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel
chloropyridazine derivatives (compounds 5a–g) as potent human rhinovirus (HRV) capsid-binding inhib-
itors. Results showed that compound 5e and 5f exhibited effective anti-HRV activity against HRV-2 and
HRV-14. In addition, compound 5e and 5f showed lower cytotoxicity than Pirodavir.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 September 2008
Revised 24 November 2008
Accepted 25 November 2008
Available online 3 December 2008
Keywords:
Chloropyridazine derivatives
Common colds
Capsid-binding inhibitors
Anti-HRV activity
1. Introduction
more effective HRV capsid-binding inhibitors with lower toxicity.
In our previous work, we synthesized 70 compounds and these
Human rhinovirus (HRV) is the most important etiologic agent
causing common colds and belongs to the family of picornaviruses.
Although HRV infections are generally self-limiting, they are also
associated with several serious upper and lower respiratory tract
complications such as otitis media, chronic bronchitis, and asth-
ma.1–3 No effective anti-HRV agent is currently available for the
control of HRV and the large number of different serotypes
(À105) makes the development of vaccines unlikely.4,5
compounds were evaluated initially. Based on the initial evalua-
tion results, we chose some of them for further study. In this pa-
per we mainly describe several compounds that showed potent
anti-HRV activity against HRV-2 and HRV-14 and their
cytotoxicity.
2. Chemistry
During the past several decades, HRV capsid-binding inhibi-
tors have been studied as promising anti-HRV agents.4,5 HRV
capsid-binding inhibitors block viral infection by inhibiting viral
uncoating and/or viral attachment to cellular receptors on host
cells. The binding site of capsid-binding inhibitors appears to
be a hydrophobic pocket inside VP1 located under the canyon
floor.6–8 The most studied and advanced HRV capsid-binding
inhibitors are Pleconaril and Pirodavir (Fig. 1). Pleconaril has
been shown to shorten the duration of upper respiratory illness
in two large Phase III clinical studies in adults, but unfortunately,
the development of Pleconaril for the treatment of HRV was
ceased due to safety and efficacy concerns.9–11 Pirodavir could
inhibit 80% of all HRV strains at a concentration of 64 ng/ml
and it could decrease rhinovirus infection and reduce the virus
shedding in clinical experiment.12,13 According to the known re-
search results, we chose Pirodavir as the lead compound and
synthesized a series of its derivatives with the aim of gaining
The protocol for the synthesis of compound 5a–f is shown in
Scheme 1. The 4-chloro group of 1a–b was substituted by 2a–b
in the presence of Na2CO3, yielding 3a–c, then the intermediates
3a–c were coupled with 4a–f, which were chosen from different
5-substituted pyridin-2-ol or 4-substituted phenol, yielding the
compound 5a–f by Mitsunobu reaction. Compound 5g was synthe-
sized via the route outlined in Scheme 2. The hydroxyl group of 3a
was converted to chloro group in the presence of SOCl2 afforded
the intermediate 6. The intermediate 6 was reacted with 4g in
the presence of K2CO3 gave compound 5g.
* Corresponding author. Tel./fax: +86 10 6693 1642.
E-mail address: zzbcaptain@yahoo.com.cn (Z.-B. Zheng).
Figure 1. Structure of Pleconaril and Pirodavir.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.11.061

622
S.-Y. Fan et al. / Bioorg. Med. Chem. 17 (2009) 621–624
cytotoxicity. The 5e and 5f showed similar inhibition potency and
Cl
Cl
X
i
HN
HO
Y
cytotoxicity, suggesting that the change from phenyl ring to pyri-
dine ring had little effect on the anti-HRV activity and cytotoxicity.
The fact that compounds 5a, 5c, and 5d exhibited obviously differ-
ent activity indicated that the substituted group on the aryl ring
played a most important role on the anti-HRV activity of the
compounds.
In conclusion, a novel series of chloropyridazine derivatives
were synthesized as potent human rhinovirus capsid-binding
inhibitors. The anti-HRV activity of them was evaluated in vitro
by using cell culture cytopathic effect assays. Among newly syn-
thesized compounds, 5e and 5f exhibited excellent anti-HRV activ-
ity and low cytotoxicity that suggest they are very promising
candidates for further development as anti-HRV agents.
N
N
N
Y
Cl
X
OH
OH
N N
2a Y=N
2b Y=C
1a X=Cl
1b X=H
3a X=Cl, Y=N
3b X=Cl, Y=C
3c X=H, Y=C
R
Cl
X
ii
3a-c
R
N
N
N
Y
Z
Z
O
4a Z=C, R=(CH2)3CH3,
4b Z=C, R=COOCH3
4c Z=C, R=OCH2CH3
4d Z=C, R=CHO
5a X=Cl,Y=N, Z=C, R=(CH2)3CH3
5b X=Cl,Y=C, Z=C, R=COOCH3
5c X=Cl,Y=N, Z=C, R=OCH2CH3
5d X=Cl,Y=N, Z=C, R=CHO
5e X=H,Y=C, Z=N, R=COOCH2CH3
5f X=H,Y=C, Z=C, R=COOCH2CH3
4e Z=N, R=COOCH2CH3
4f Z=C,R=COOCH2CH3
Scheme 1. Synthesis of compound 5a–f. Reagents and conditions: (i) Na2CO3, DMA,
rt; (ii) Ph3P, DEAD, THF, rt.
5. Experimental
1H NMR spectra are recorded on JNM-ECA-400 400 MHz instru-
ment in the solvent indicated below. Chemical shift values are re-
ported in parts per million (ppm) relative to those for
tetramethylsilane used as an internal reference standard. Spectral
splitting patterns are designated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or br s (broad singlet). Melting
points were determined using a RY-1 apparatus and are uncor-
rected. Mass spectra were obtained from Micromass ZabSpec
high-resolution magnetic mass spectrometer. HRESIMS spectra
were recorded on Apex-Qe-FTMS instrument. Thin-layer chroma-
tography (TLC) was carried out on silica gel GF/UV 254 and the
chromatograms were performed on silica gel (200–300 mesh) visu-
alized under UV light at 254 and 365 nm. All purchased starting
materials and reagents were used without further purification or
purified by standard methods prior to use. All moisture- and air-
sensitive reactions and reagent transfers were carried out under
dry nitrogen. The reported yields were for purified materials but
were not optimized.
N
N
N
OH
N
Cl
Cl
Cl
Cl
iii
iv
3a
N
N
N
N
N
N
N
N
Cl
O
N N
4g
5g
6
Scheme 2. Synthesis of compound 5g. Reagents and conditions: (iii) SOCl2, CH2Cl2,
reflux; (iv) K2CO3, DMF, 80 °C.
3. Biology
The anti-HRV activity and the cytotoxicity of the compounds
5a–g on the two test strains HRV-2 and HRV-14 were evaluated
by using cell culture cytopathic effect (CPE) assays. The procedure
of the biological evaluation was previously reported,12,14 and the
results are listed in Tables 1 and 2.
5.1. 2-(4-(3,6-Dichloropyridazin-4-yl) piperazin-1-yl) ethanol
(3a)
4. Results and discussion
To a stirred solution of 1a (9.18 g, 0.05 mol) in N,N-dimethyl
acetylamide (DMA, 20 ml) at room temperature was added Na2CO3
(5.30 g, 0.05 mol) followed by the solution of 2a (6.54 g, 0.05 mol)
in DMA (10 ml) dropwise. Ice water (100 ml) was added after stir-
ring for 12 h and the reaction mixture was stirred for another
30 min. Compound 3a (10.20 g, 73.6%) was obtained by filtration
as a white solid. Mp 139–140 °C; 1H NMR (400 MHz, CDCl3) d
ppm: 6.88 (s, 1H), 3.71–3.68 (t, 2H, J = 5.0 Hz), 3.38–3.36 (t, 4H,
J = 4.5 Hz), 2.76–2.73 (t, 4H, J = 4.8 Hz), 2.68–2.66 (t, 2H,
J = 5.1 Hz); FAB-MS (m/z): 277.1 [M+1]; HRESIMS (C10H14Cl2
N4O + H): calcd 277.06174, found 277.06141.
The anti-HRV-2 activity and the cytotoxicity of 5a–g are shown
in Table 1, the compounds 5a–d have weak activity for inhibition
of HRV-2 in both visual assay and neutral assay (EC50: 0.31–56
and 0.1–46
HRV-2 (EC50: >100
tency for anti-HRV-12 (EC50: <0.032
(CC50: >100 g/ml). Although 5e and 5f have 10-fold lower potency
l
g/ml, respectively), and 5g has no inhibition for
g/ml). The compounds 5e and 5f have high po-
g/ml) and lower cytotoxicity
l
l
l
than Pirodavir, their cytotoxicity also 10-fold lower than Pirodavir,
meaning that they have the same toxicity/antiviral activity selec-
tivity number (CC50/EC50: 3125).
The anti-HRV-14 activity and the cytotoxicity of 5a–g were
shown in Table 2. The compounds 5a, 5b, 5d, and 5g have moder-
5.2. 2-(1-(3,6-Dichloropyridazin-4-yl) piperidin-4-yl) ethanol
(3b)
ate activity for anti-HRV-14 (EC50: 0.15–43
5f have higher potency of inhibition of HRV-14 than Pirodavir
(EC50: 0.036, 0.032, and 0.032–0.081 g/ml, respectively) and low-
er cytotoxicity (CC50: >100 g/ml). Their toxicity/antiviral activity
lg/ml). The 5c, 5e, and
l
To a stirred solution of 1a (9.18 g, 0.05 mol) in DMA (20 ml) at
room temperature was added Na2CO3 (5.30 g, 0.05 mol) followed
by the solution of 2b (6.54 g, 0.05 mol) in DMA (10 ml) dropwise.
Ice water (100 ml) was added after stirring for 12 h and the reac-
tion mixture was extracted with CH2Cl2 (3Â 50 ml). The combined
organic phases were washed with brine (3Â 50 ml), dried (Na2SO4),
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel afforded 3b (6.2 g,
44.9%) as a white solid. Mp 90–91 °C; 1H NMR (400 MHz, CDCl3)
d ppm: 7.35 (s, 1H), 4.42–4.40 (t, 1H, J = 5.3 Hz), 3.73–3.70 (d,
2H, J = 12.6 Hz), 3.49–3.44 (q, 2H, J = 6.4 Hz), 2.87–2.81 (q, 2H,
l
selectivity numbers are much higher than Pirodavir (CC50/EC50
:
3125–123, respectively).
Pirodavir is a capsid-binding, anti-picornaviral agent against
most HRV serotypes. The goal of the current study was to extend
the structure–activity relationships by using Pirodavir as a lead
compound. According to the biological evaluation results, if a
3,6-dichloropyridazine replaced the 6-methylpyridazine in Piroda-
vir, the derivative compounds 5a–d and 5g have lower or have no
activity for inhibition of HRV-12 and HRV-14. The 3-chloropyrid-
azine derivatives 5e and 5f have more anti-HRV activity and lower

S.-Y. Fan et al. / Bioorg. Med. Chem. 17 (2009) 621–624
623
Table 1
The anti-HRV activity and the cytotoxicity of 5a–g on HRV-2
Compound
Visual assay
Neutral red assay
EC50
(lg/ml)
CC50
(l
g/ml)
SI
EC50
(lg/ml)
CC50
(l
g/ml)
SI
5a
5b
5c
5d
5.7
10
30
35
56
1.8
97
0
0
>1.9*
0.1
>1.9
5.8
12
0
58
0
0.31
>35*
>56*
>12*
46
50
1.1
5e
5f
5g
Pirodavir
<0.032
<0.032
>100
>100
>100
>100
>10
>3125
>3125
0
<0.032
<0.032
>42*
>100
>100
42
>3125
>3125
0
<0.0032
>3125
<0.0032
>10
>3125
SI (selectivity index) = CC50 (toxicity)/EC50 (antiviral activity).
*
Cytopathic effect was indistinguishable from drug cytotoxicity.
Table 2
The anti-HRV activity and the cytotoxicity of 5a–g on HRV-14
Compound
Visual assay
Neutral red assay
EC50
(lg/ml)
CC50
(l
g/ml)
SI
EC50
(lg/ml)
CC50
(l
g/ml)
SI
5a
5b
0.15
7.1
18
56
120
8
0.55
1.9
4.7
3.5
0
>4.7*
5c
5d
5e
5f
0.036
43
<0.032
<0.032
12
35
972
>2
>3125
>3125
3
<0.032
12
43
>100
>100
39
>370
0
>3125
>3125
2.5
>100
>100
>100
35
>43*
<0.032
<0.032
15
5g
Pirodavir
0.081
>10
>123
0.01
>10
>1000
SI (selectivity index) = CC50 (toxicity)/EC50 (antiviral activity).
*
Cytopathic effect was indistinguishable from drug cytotoxicity.
J = 10.4 Hz), 1.78–1.75 (d, 3H, J = 12.4 Hz), 1.43–1.38 (q, 2H,
J = 6.7 Hz), 1.27–1.24 (m, 2H); FAB-MS (m/z): 276.0 [M+1]; HRE-
SIMS (C11H15Cl2N3O + H): calcd 276.06649, found 276.06684.
5.5. Methyl 4-(2-(1-(3,6-dichloropyridazin-4-yl) piperidin-4-yl)
ethoxy) benzoate (5b)
The compound was prepared with a 42.3% yield according to the
methodfor5a using3band4b. Whitesolid;mp116–117 °C;1H NMR
(400 MHz, DMSO-d6) d ppm: 7.92–7.90 (d, 2H, J = 8.9 Hz), 7.36 (s,
1H), 7.07–7.05 (d, 2H, J = 8.7 Hz), 4.15–4.12 (t, 2H, J = 6.2 Hz), 3.81
(s, 3H), 3.75–3.72 (d, 2H, J = 12.3 Hz), 2.91–2.85 (m, 2H), 1.86–1.83
(d, 2H, J = 12.3 Hz), 1.75 (br s, 3H), 1.40–1.32 (m, 2H); EI-MS (m/z):
409.0 [M+]; HRESIMS (C19H22Cl2N3O3 + H): calcd 410.10327, found
410.10373.
5.3. 2-(1-(3-Chloropyridazin-4-yl) piperidin-4-yl) ethanol (3c)
The compound was prepared with a 45.6% yield according to the
method for 3b using 1b and 2b. Mp 79–80 °C;1H NMR (400 MHz,
DMSO-d6) d ppm: 7.48–7.46 (d, 1H, J = 9.8 Hz), 7.38–7.36 (d, 1H,
J = 9.5 Hz), 4.39 (br s, 1H), 4.32–4.29 (d, 2H, J = 13.4 Hz), 3.48–3.45
(m, 2H), 2.91–2.89 (m, 2H), 1.74–1.69 (m, 3H), 1.39–1.35 (q, 2H,
J = 6.4 Hz), 1.13–1.10 (m, 2H); FAB-MS (m/z): 242.0 [M+1]; HRESIMS
(C11H16ClN3O + H): calcd 242.10547, found 242.10558.
5.6. 4-(4-(2-(4-Ethoxyphenoxy) ethyl) piperazin-1-yl)-3,6-
dichloro pyridazine (5c)
5.4. 4-(4-(2-(4-Butylphenoxy) ethyl) piperazin-1-yl)-3,6-
dichloro pyridazine (5a)
The compound was prepared with a 54.5% yield according to
the method for 5a using 3a and 4c. White solid; mp 93–94 °C; 1H
NMR (400 MHz, CDCl3) d ppm: 6.87–6.84 (m, 5H), 4.12–409 (t,
2H, J = 5.0 Hz), 4.01–3.96 (q, 2H, J = 7.0 Hz), 3.38 (br s, 4H), 2.90
(br s, 2H), 2.81 (br s, 4H), 1.41–1.38 (m, 3H); EI-MS (m/z): 396.1
[M+]; HRESIMS (C18H23Cl2N4O2 + H): calcd 397.11926, found
397.12011.
To a stirred solution of 3a (0.56 g, 2.0 mmol), triphenylposphine
(0.63 g, 2.4 mmol) and 4a (0.36 g, 2.4 mmol) in anhydrous THF
(15 ml) at 0 °C under nitrogen was added a solution of diethyl dia-
zenedicarboxylate (DEAD, 0.45 ml, 2.4 mmol) in anhydrous THF
(5 ml). The reaction mixture was warmed to room temperature
and then stirred for 12 h. The reaction solvent was removed under
reduced pressure and the resultant residue was dissolved in CH2Cl2
(200 ml). The organic layer was washed with water (100 ml), brine
(100 ml), and dried (Na2SO4). Removal of the solvent under reduced
pressure afforded crude product of 5a. Column chromatography of
the crude product on silica gel afforded 5a (0.38 g, 46.6%) as a white
solid. Mp 83–84 °C; 1H NMR (400 MHz, CDCl3) d ppm: 7.11–7.09 (d,
2H, J = 8.4 Hz), 6.85 (s, 1H), 6.84–6.82 (d, 2H, J = 8.4 Hz), 4.14–4.11 (t,
2H, J = 5.3 Hz), 3.37–3.35 (t, 4H, J = 4.5 Hz), 2.91–2.88 (t, 2H,
J = 5.3 Hz), 2.80–2.78 (t, 4H, J = 4.5 Hz), 2.57–2.53 (t, 2H, J = 7.8 Hz),
1.58–1.53 (m, 2H), 1.37–1.33 (m, 2H), 0.94–0.90 (t, 3H, J = 7.3 Hz);
EI-MS (m/z): 408.0 [M+]; HRESIMS (C20H27Cl2N4O + H): calcd
409.15564, found 409.15593.
5.7. 4-(2-(4-(3,6-Dichloropyridazin-4-yl) piperazin-1-yl) ethoxy)
benzaldehyde (5d)
The compound was prepared with a 52.5% yield according to
the method for 5a using 3a and 4d. White solid; mp 111–112 °C;
1H NMR (400 MHz, CDCl3) d ppm: 9.9 (s, 1H), 7.87–7.85 (d, 2H,
J = 8.7 Hz), 7.04–7.02 (d, 2H, J = 8.7 Hz), 6.87 (s, 1H), 4.24 (br s,
2H), 3.38 (br s, 4H), 2.95 (br s, 2H), 2.81 (br s, 4H); EI-MS (m/z):
380.0 [M+]; HRESIMS (C17H19Cl2N4O2 + H): calcd 381.08796, found
381.08779.

624
S.-Y. Fan et al. / Bioorg. Med. Chem. 17 (2009) 621–624
5.8. Ethyl 6-(2-(1-(3-chloropyridazin-4-yl) piperidin-4-yl)
ethoxy) pyridine-3-carboxylate (5e)
8 h. After cooling to room temperature, the reaction was quenched
by addition of water (50 ml). The aqueous layer was extracted with
CH2Cl2 (3Â 50 ml). The combined organic phases were washed
with brine (3Â 30 ml), dried (Na2SO4). Removal of the solvent un-
der reduced pressure afforded crude product of 5g. Column chro-
matography of the crude product on silica gel afforded 5g (0.38 g,
45.6%) as a white solid. Mp 160–161 °C; 1H NMR (400 MHz,
DMSO-d6) d ppm: 9.19 (s, 1H), 8.20 (s, 1H), 7.77–7.75 (m, 2H),
7.41 (s, 1H), 7.15–7.13 (m, 2H), 4.19–4.17 (t, 2H, J = 5.6 Hz), 3.35
(br s, 4H), 2.80–2.78 (t, 2H, J = 5.6 Hz), 2.51 (br s, 4H); EI-MS (m/
z): 419.2 [M+]; HRESIMS (C18H19Cl2N7O + H): calcd 420.11009,
found 420.11149.
The compound was prepared with a 40.4% yield according to the
method for 5a using 3c and 4e. White solid; mp 112–113 °C; 1H
NMR (400 MHz, CDCl3) d ppm: 8.82–8.81 (d, 1H, J = 2.3 Hz), 8.17–
8.15 (dd, 1H, J1 = 8.7 Hz, J2 = 2.4Hz), 7.19–7.17 (d, 1H, J = 9.6 Hz),
6.93–6.91 (d, 1H, J = 9.6 Hz), 6.76–6.74 (d, 1H, J = 8.0 Hz), 4.4–4.43
(t, 4H, J = 6.4 Hz), 4.38–4.35 (q, 2H, J = 7.0 Hz), 3.00–2.94 (t, 2H,
J = 12.6 Hz), 1.91–1.87 (d, 2H, J = 13.7 Hz), 1.79–1.76 (m, 4H),
1.41–1.37 (m, 4H); FAB-MS (m/z): 391.0 [M+1]; HRESIMS
(C19H24ClN4O3 + H): calcd 391.15314, found 391.15401.
5.9. Ethyl 4-(2-(1-(3-chloropyridazin-4-yl) piperidin-4-yl)
ethoxy) benzoate (5f)
Acknowledgments
We thank Dr. Dale L. Barnard of the Institute for Antiviral Re-
search, Utah State University for carrying out most of the biological
evaluation works. We also acknowledge the financial supports of
the National Natural Science Foundation of China (Grant No.
30600782).
The compound was prepared with a 42.3% yield according to
the method for 5a using 3c and 4f. White solid; mp 115–116 °C;
1H NMR (400 MHz, CDCl3) d ppm: 8.00–7.98 (m, 2H), 7.19–7.17
(d, 1H, J = 9.6 Hz), 6.93–6.91 (m, 3H), 4.38–4.33 (m, 4H), 4.09–
4.07 (q, 2H, J = 6.4 Hz), 3.00–2.95 (t, 2H, J = 12.4 Hz), 1.87–1.78
(m, 5H), 1.40–1.37 (m, 5H); FAB-MS (m/z): 390.0 [M+1]; HRESIMS
(C20H24ClN3O3 + H): calcd 390.15790, found 390.15801.
Supplementary data
5.10. 3,6-Dichloro-4-(4-(2-chloroethyl) piperazin-1-yl)
pyridazine (6)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2008.11.061.
To a stirred solution of SOCl2 (1.49 g, 12.5 mmol) in anhydrous
CH2Cl2 (10 ml) at room temperature was added 3a (0.69 g,
2.5 mmol) in anhydrous CH2Cl2 (30 ml) dropwise. The reaction
mixture was refluxed for 8 h. After cooling to room temperature,
the reaction was quenched by addition of a NaHCO3 aqueous solu-
tion (200 ml). The aqueous layer was extracted with CH2Cl2 (3Â
100 ml). The combined organic phases were washed with brine
(3Â 70 ml), dried (Na2SO4), and concentrated under reduced pres-
sure afforded 6 (0.55 g, 74.3%) as a pale yellow solid. Mp 84–85 °C;
1H NMR (400 MHz, CDCl3) d ppm: 7.41 (s, 1H), 3.74–3.71 (t, 2H,
J = 6.4 Hz), 3.33–3.31 (t, 4H, J = 4.8 Hz), 2.73–2.70 (t, 2H,
J = 6.8 Hz), 2.62–2.61 (t, 4H, J = 4.8 Hz); FAB-MS (m/z): 276.0
[M+1]; HRESIMS (C10H13Cl3N4 + H): calcd 295.02786, found
295.02806.
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A solution of 6 (0.59 g, 2.0 mmol), 4g (041 g, 2.5 mmol), and
K2CO3 (0.70 g, 5.0 mmol) in DMF (20 ml) was heated to 80 °C for