In(OTf)3-mediated synthesis of substituted pyridazines

Article abstract of DOI:10.1016/j.tet.2015.07.025

In(OTf)₃ (4c)-mediated one-pot (4+2) cyclocondensation of γ-alkynones 3 with N₂H_4(aq) in dioxane affords substituted pyridazines 5 in good yields via a sequential desulfonative or dehydrogenative aromatization. The facile

Full text of DOI:10.1016/j.tet.2015.07.025

Tetrahedron 71 (2015) 6840e6845
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Tetrahedron
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In(OTf)3-mediated synthesis of substituted pyridazines
*
Meng-Yang Chang , Yi-Ju Lu, Yu-Chieh Cheng
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2015
Received in revised form 6 July 2015
Accepted 8 July 2015
Available online 15 July 2015
In(OTf)3 (4c)-mediated one-pot (4þ2) cyclocondensation of
g-alkynones 3 with N2H4(aq) in dioxane
affords substituted pyridazines 5 in good yields via a sequential desulfonative or dehydrogenative aro-
matization. The facile transformation proceeds by a facile synthetic sequence starting with an
argylation of -ketosulfones 1 and a cyclocondensation of -alkynones 3 with N2H4(aq). The method
provides a mild and efficient condition. Moreover, this route can be enlarged to multigram scale.
a-prop-
b
g
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Pyridazines
Cyclocondensation
b-Ketosulfones
Hydrazine
1. Introduction
N2H4(aq) (see Scheme 1). Pyridazine is a versatile building block in
the synthesis of natural products and a useful synthetic in-
termediate.18 A number of articles have highlighted fascinating
developments based on two CeN bond formations.19 2-
Arylpyridazines are also known to exhibit versatile biological ac-
tivities, such as antibacterial activity, antibiotic or anti-depressant
activity.20 After further comparing literature reports on the prep-
aration of substituted pyridazines, herein, we describe one-pot
For transformation from terminal alkynes to methyl ketones,
mercuric salts mediating the hydration of alkynes is a classic
method used in the presence of acids via Markovnikov regiose-
lectivity.1,2 However, new catalysts to the synthetic routes of methyl
ketones from non-activated alkynes still represent continuing
needs in the organic field. Among these protocols, transition-metal
complexes (Au,3 Ag,4 Ag/Au,5 Ru,6 Rh,7 Pt,8 Os,9 Ir,10 Pd,11 Fe,12 Hg,13
Cu,14 or In15) promoting hydration of alkynes is the major pathway.
Notably, few examples have been performed for metal triflates-
promoted reactions. Nishizawa et al. reported the traditional syn-
thesis of 2-methylfurans via the Hg(OTf)2-catalyzed cyclization of
1-alkyn-5-ones.13 Jha et al. reported a microwave-assisted hydra-
tion of arylacetylene with Cu(OTf)2.14a AgOTf-mediated hydration
of alkynes has been developed by Chakraborty and co-workers.4a
There are only two In(III)-mediated examples of synthesis of
substituted furans via the hydration of nonactivated alkynes by
Tan15a and Nakamura.15b To the best of our knowledge, no examples
route on the cyclocondensation of the g-alkynones with N2H4(aq).
Scheme 1. Synthetic route of 5.
2. Results and discussion
for In(OTf)3-mediated one-pot (4þ2) annulation of
with N2H4(aq) have been reported. In continuation of our in-
vestigation on the applications of -ketosulfones (e.g., 2-
g-alkynone
According to previous literature on metal triflate-mediated hy-
dration of alkynes,16d catalytic amounts (2 mol %) of AgOTf (4a),
Hg(OTf)2 (4b), In(OTf)3 (4c) or Cu(OTf)2 (4d) were first examined for
the transformation of model substrate 3a (R¼Tol, Ar¼Ph, Y¼H)
b
1
arylpyrroles, vinylcyclopropanes, 2,6-diaryltetrahydropyrans, 2-
arylfurans and substituted benzenes),16,17 a facile one-pot synthe-
sis of 2-arylpyridazines 5 is developed, including (1)
argylation of 1 with propargylic bromides 2, and (2) In(OTf)3-
promoted cyclocondensation of the resulting -alkynones 3 with
a-prop-
from g-alkynone to a skeleton of 2-arylpyridazine 5a in dioxane at
25 ꢀC for 4 h. As shown in Table 1 and entries 1e4, 4c provided
a better yield (80%) than 4a (72%), 4b (69%) and 4d (25%) for gen-
erating 5a. On the basis of a higher yield and activity, low toxicity
and relatively low price, 4c was chosen as the appropriate catalyst
for synthesizing 5 via one-pot mild (4þ2) cyclocondensation of 3a
g
* Corresponding author. Tel.: þ886 7 3121101x2220; e-mail address: mychang@
kmu.edu.tw (M.-Y. Chang).
http://dx.doi.org/10.1016/j.tet.2015.07.025
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

M.-Y. Chang et al. / Tetrahedron 71 (2015) 6840e6845
6841
Table 1
annulation. Deprotonation of B should give vinyl indium in-
termediate C. Then, protonation by in situ generated HOTf leads to
an alternative iminium cation D, which, following loss of In(OTf)3, is
able to provide E and the recovery of In(OTf)3. Tautomerization of E
affords F. Subsequently, desulfonylative aromatization of the
resulting F generates 5a under air atmosphere.
One-pot conditionsa
With optimized conditions in hand (Table 1, entry 3), we further
explored the substrate scope of the reaction, and the results are
Entry
Catalyst 4 (mol %), solvent (mL), temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
AgOTf 4a (2), dioxane (5), 25
Hg(OTf)2 4b (2), dioxane (5), 25
In(OTf)3 4c (2), dioxane (5), 25
Cu(OTf)2 4d (2), dioxane (5), 25
InCl3 4e (5), dioxane (5), 25
InBr3 4f (2), dioxane (5), 25
In2O3 4g (2), dioxane (5), 25
In(OTf)3 4c (0), dioxane (5), 25
In(OTf)3 4c (5), dioxane (5), 25
In(OTf)3 4c (10), dioxane (5), 25
In(OTf)3 4c (2), dioxane (10), 25
In(OTf)3 4c (2), dioxane (5), 50
In(OTf)3 4c (2), dioxane (5), 100
In(OTf)3 4c (2), MeNO2 (5), 25
In(OTf)3 4c (2), (CH2Cl)2 (5), 25
In(OTf)3 4c (2), benzene (5), 25
In(OTf)3 4c (2), EtOH (5), 25
72
69
shown in Table 2. For adjusting the Ar and Y substituents of
sulfonyl
4-MeOC6H4, 4-MeC6H4, 4-CF3C6H4, 4-PhC6H4, 2-naphthalene, 2-
a-
g
-alkynones 3aej, arylpyridazines 5aej (Ar¼Ph, 4-FC6H4,
80
25c
60
thiophene; Y¼H, Me, Et) were provided in 72e85% yields (entries
68
1e10). To demonstrate the utilization of the route, a-aryl g-ary-
12d (20)e
df
79
lalkynones 3jeab were prepared from
substituted deoxybenzoins with propargyl bromide. By this com-
bination of In(OTf)3/dioxane/N2H4(aq) diarylpyridazines 5jeab
a-propargylation of
9
10
11
12
13
14
15
16
17
77
75
70
63
75
63
51
58
,
(Ar¼Ph, 4-MeOC6H4, 3,4-(MeO)2C6H3, 2,3,4-(MeO)3C6H2; Ar1¼Ph,
4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-CF3C6H4, 3,5-F2C6H3, 4-PhC6H4,
2-naphthalene, 4,7-(MeO)2-1-naphthalene, Y¼H) were isolated in
75e85% yields under the above conditions (entries 11e28).
Changing a sulfonyl group to an aryl group, no obvious yield
changes were observed for the generation of 5. For the Ar and Ar1
groups of 3, the phenyl ring, with both electron-withdrawing and
electron-donating substituents, was well tolerated, providing the
desired product 5 in moderate to good yields. The structures of 5h,
5n, 5p, 5u, 5w, 5z and 5aa were determined by single-crystal X-ray
crystallography.21 However, treatment of 3ac (Ar¼Ar1¼Y¼Ph) with
a
Reactions were run on a 1.0 mmol scale with 3a, N2H4(aq) (80%, 1 mL), 4 h.
Isolated yields.
46% of a hydrazone mixture was isolated.
48% of a hydrazone mixture was isolated.
40 h and 40% of a hydrazone mixture was isolated.
88% of a hydrazone mixture was isolated.
b
c
d
e
f
the
a-phenylacetylene group (an internal alkyne) afforded the
in the presence of N2H4(aq). Then, the use of other In(III) salts was
examined (see entries 5e7). In comparison with these In(III) com-
plexes, such as InCl3 (4e), InBr3 (4f) and In2O3 (4g), 4c was still
a better catalyst for the generation of 5a. 4e-f produced 5a in 60%
and 68% yields, respectively. For 4g, only 12% of 5a was isolated
along with 48% of a hydrazone mixture. To elongate the reaction
time (4 / 40 h), similar results were observed. Furthermore,
controlling 4c as the catalyst, catalyst equivalents, reaction solvents
and temperature were further studied. Without the addition of 4c,
no 5a was yielded (entry 8). When using 5 or 10 mol % of 4c, the
isolated yield was similar to 2 mol % (entries 9e10). By adjusting
reaction concentrations (entries 11) or temperature (entries
12e13), poorer yield occurred. To change the reaction solvents from
dioxane to MeNO2, dichloroethane, benzene and EtOH, dioxane
provided a better yield of 5a due to good solubility with water
(entries 14e17). Based on the above results, we envisioned that
2 mol % of In(OTf)3/dioxane/N2H4(aq) should be an optimal combi-
nation for forming 5a via one-pot reaction of 3a.
Table 2
Synthesis of 5a
Entry
3, Ar¼, Ar1¼, Y¼,
3a, Ph, d, H
3b, 4-FC6H4, d, H
3c, 4-MeOC6H4, d, H
3d, 4-MeC6H4, d, H
3e, 4-CF3C6H4, d, H
3f, 4-PhC6H4, d, H
3g, 2-naphthalene, d, H
3h, 2-thiophene, d, H
3i, Ph, d, Me
3j, Ph, d, Et
3k, Ph, Ph, H
3l, 4-MeOC6H4, Ph, H
3m, 4-MeOC6H4, 4-MeC6H4, H
3n, 4-MeOC6H4, 4-MeOC6H4, H
3o, 4-MeOC6H4, 4-FC6H4, H
3p, 4-MeOC6H4, 4-CF3C6H4, H
3q, 4-MeOC6H4, 3,5-F2C6H3, H
3r, 4-MeOC6H4, 4-PhC6H4, H
3s, 4-MeOC6H4, 2-naphthalene, H
3t, 3,4-(MeO)2C6H3, Ph, H
3u, 3,4-(MeO)2C6H3, 4-MeC6H4, H
3v, 3,4-(MeO)2C6H3, 4-MeOC6H4, H
3w, 3,4-(MeO)2C6H3, 4-FC6H4, H
3x, 3,4-(MeO)2C6H3, 4-PhC6H4, H
3y, 3,4-(MeO)2C6H3, 3,5-F2C6H3, H
3z, 2,3,4-(MeO)3C6H2, Ph, H
3aa, 2,3,4-(MeO)3C6H2, 4-FC6H4, H
3ab, 4,7-(MeO)2-naphthalene, 2,3-CH2O2C6H3, H
3ac, Ph, Ph, Ph
5, yield%b
1
2
3
4
5
6
7
8
5a, 80
5b, 82
5c, 85
5d, 83
5e, 82
5f, 81
5g, 75
5h, 72
5i, 73
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
5j, 72
5k, 85
5l, 83
Based on the results, a possible reaction mechanism is shown in
Scheme 2. How is 5a produced? The mechanism should be initiated
to form A by complexation of an alkynyl motif of a hydrazone
skeleton (in situ generated from condensation of 3a with N2H4)
with 4c, and participation of an amino group of hydrazone could
5m, 83
5n, 80
5o, 78
5p, 75
5q, 82
5r, 83
5s, 84
5t, 85
5u, 80
5v, 82
5w, 81
5x, 82
5y, 75
5z, 80
5aa, 82
5ab, 75
5ac, d c
lead to an ammonium ion
B via intramolecular 6-exo-dig
a
The pyridazine synthesis was run on a 1.0 mmol scale with 3, In(OTf)3 (4c)
(2 mol %), dioxane (5 mL), N2H4(aq) (80%, 1 mL), 4 h at 25 ꢀC.
b
Isolated yield.
Complex mixture was observed.
c
Scheme 2. Possible mechanism.

6842
M.-Y. Chang et al. / Tetrahedron 71 (2015) 6840e6845
complex mixture. No desired 5ac was isolated (entry 29). Moreover,
when 5.0 g of 3a (16.0 mmol) was treated with the combination at
25 ꢀC, 2.04 g of 5a was isolated in a 75% yield. This route can be
enlarged to multigram scale for producing 5a.
The reaction mixture was stirred at rt for 4 h. The reaction mixture
was concentrated and extracted with CH2Cl2 (3ꢁ10 mL). The
combined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc¼10/1w4/1) afforded
5aeab, 5ad and 5af.
Changing the
a-substituent from sulfonyl and aryl groups to
ethyl ester, benzyl amide and benzoyl groups (see Scheme 3), 5ad
and 5a were isolated in 31% and 45% yields, respectively, by the
treatment of 3ad and 3af with the one-pot protocol. For
b
-ketoa-
4.2.1. 3-Methyl-6-phenylpyridazine (5a).19l Yield¼80% (136 mg);
Colorless solid; mp¼105e108 ꢀC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C11H11N2 171.0922, found
mide group of 3ae, trace 5ae was observed. For the generation of 5a,
the major reason should be that N2H4 promoted a retro-aldol
debenzoylation of 3af with a
dehydrogenative aromatization process. Additionally, one-pot
-sulfonyl -alkynone 3ag was
b-diketone motif followed by the
171.0925; 1H NMR (400 MHz, CDCl3):
d 8.07e8.04 (m, 2H), 7.79 (d,
J¼8.8 Hz, 1H), 7.54e7.46 (m, 3H), 7.42 (d, J¼8.4 Hz, 1H), 2.78 (s, 3H);
(4þ2) cyclocondensation of cyclic
a
g
13C NMR (100 MHz, CDCl3):
d
158.44, 157.32, 136.22, 129.86, 128.97
examined. By the above conditions, tetrahydrocinnoline 5af was
isolated in 72% yield. Furthermore, attempts to apply the electro-
cyclization of 5k failed to afford a tetracyclic cinnoline 622 under
Scholl annulation conditions.23
(2ꢁ), 127.59, 126.91 (2ꢁ), 124.27, 21.86.
4.2.2. 3-(4-Fluorophenyl)-6-methylpyridazine (5b).19h Yield¼82%
(154 mg); Colorless solid; mp¼138e140 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C11H10FN2
189.0828, found 189.0832; 1H NMR (400 MHz, CDCl3):
d 8.08e8.03
(m, 2H), 7.52 (d, J¼8.8 Hz, 1H), 7.41 (d, J¼8.8 Hz, 1H), 7.22e7.16
(m, 2H), 2.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
164.02
(d, J¼248.6 Hz), 158.43, 156.31, 134.77 (d, J¼3.8 Hz), 128.78
(d, J¼8.4 Hz, 2ꢁ), 127.56, 123.84, 115.99 (d, J¼22.0 Hz, 2ꢁ), 21.87.
19l
4.2.3. 3-(4-Methoxyphenyl)-6-methylpyridazine (5c).
Yield¼85%
(170 mg); Colorless solid; mp¼136e139 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C12H13N2O
201.1028, found 201.1033; 1H NMR (400 MHz, CDCl3):
d 7.99 (d,
J¼8.8 Hz, 2H), 7.68 (d, J¼8.8 Hz, 1H), 7.32 (d, J¼8.8 Hz, 1H), 7.00 (d,
J¼8.8 Hz, 2H), 3.85 (s, 3H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3):
Scheme 3. Reactions of 3adeag and 5k.
d
160.99, 157.78, 156.69, 128.76, 128.11 (2ꢁ), 127.24, 123.29, 114.27
3. Conclusion
(2ꢁ), 55.30, 21.85.
4.2.4. 3-Methyl-6-(4-methylphenyl)pyridazine (5d).19l Yield¼83%
(153 mg); Colorless solid; mp¼116e118 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C12H13N2
In summary, we have developed a mild, facile and one-pot syn-
thesis of substituted pyridazines 5 in good yields via an In(OTf)3/
dioxane/N2H4(aq)-mediated (4þ2) cyclocondensation of
g-alky-
185.1079, found 185.1088; 1H NMR (400 MHz, CDCl3):
d 7.92 (d,
nones 3 under a desulfonative or dehydrogenative aromatization
process. The plausible mechanism has been discussed and proposed.
The structures of the key products were confirmed by X-ray crys-
tallography. Further investigation regarding synthetic applications
J¼8.0 Hz, 2H), 7.67 (d, J¼8.8 Hz, 1H), 7.30 (d, J¼8.8 Hz, 1H), 7.26 (d,
J¼8.0 Hz, 2H), 2.68 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
158.05, 156.93, 139.70, 133.39, 129.49 (2ꢁ), 127.14, 126.54 (2ꢁ),
of b-ketosulfones will be conducted and published in due course.
123.54, 21.80, 21.15.
4. Experimental section
4.1. General
4.2.5. 3-Methyl-6-(4-trifluoromethylphenyl)pyridazine
(5e).19l Yield¼82% (195 mg); Colorless solid; mp¼184e186 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C12H10F3N2 239.0796, found 239.0801; 1H NMR (400 MHz,
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous magnesium sulfate before concentration in vacuo.
Melting points were determined with a SMP3 melting apparatus. 1H
and 13C NMR spectra were recorded on a Varian INOVA-400 spec-
trometer operating at 400 and at 100 MHz, respectively. Chemical
CDCl3):
d
8.18 (d, J¼8.4 Hz, 2H), 7.80 (d, J¼8.4 Hz, 1H), 7.77 (d,
J¼8.8 Hz, 2H), 7.44 (d, J¼8.8 Hz, 1H), 2.79 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
159.30, 155.95, 139.72, 131.60 (q, J¼31.9 Hz),
127.49, 127.18 (2ꢁ), 125.98 (2ꢁ), 125.94 (q, J¼3.7 Hz), 124.10,
22.06.
4.2.6. 3-(4-Biphenyl)-6-methylpyridazine
(5f). Yield¼81%
(199 mg); Colorless solid; mp¼188e190 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C17H15N2
shifts (d) are reported in parts per million (ppm) and the coupling
247.1235, found 247.1232; 1H NMR (400 MHz, CDCl3):
d 8.14 (d,
constants (J) are given in Hertz. High resolution mass spectra
(HRMS) were measured with a mass spectrometer Finnigan/
Thermo Quest MAT 95XL. X-ray crystal structures were obtained
with an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD).
J¼8.4 Hz, 2H), 7.77 (d, J¼8.8 Hz, 1H), 7.73 (d, J¼8.8 Hz, 2H),
7.66e7.63 (m, 2H), 7.49e7.44 (m, 2H), 7.40e7.36 (m, 2H), 2.75 (s,
3H); 13C NMR (100 MHz, CDCl3):
d 158.43, 156.74, 142.42, 140.20,
135.15, 128.81 (2ꢁ), 127.65, 127.55 (2ꢁ), 127.26, 127.18 (2ꢁ), 127.02
4.2. A representative synthetic procedure of 5aeab, 5ad and
5af is as follows
(2ꢁ), 123.73, 21.97.
4.2.7. 3-Methyl-6-(naphthalen-2-yl)pyridazine (5g).19l Yield¼75%
(165 mg); Colorless solid; mp¼180e183 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C15H13N2
In(OTf)3 (11 mg, 0.02 mmol) was added to a solution of 3a-ag
(1.0 mmol) in dioxane (5 mL) at rt. The reaction mixture was stirred
at rt for 10 min. N2H4(aq) (80%, 1 mL) was added to mixture at 25 ꢀC.
221.1079, found 221.1082; 1H NMR (400 MHz, CDCl3):
d 8.50 (d,

M.-Y. Chang et al. / Tetrahedron 71 (2015) 6840e6845
6843
J¼1.2 Hz, 1H), 8.22 (dd, J¼1.6, 8.4 Hz, 1H), 7.98e7.87 (m, 4H),
7.55e7.50 (m, 2H), 7.42 (d, J¼8.8 Hz, 1H), 2.78 (s, 3H); 13C NMR
129.31, 128.84 (2ꢁ), 127.83, 113.54 (2ꢁ), 55.21, 21.78, 21.22; Anal.
Calcd for C19H18N2O: C, 78.59; H, 6.25. Found: C, 78.68; H, 6.43.
(100 MHz, CDCl3):
d 158.45, 157.13, 133.93, 133.50, 133.29, 128.74,
128.71, 127.70, 127.55, 126.98, 126.55, 126.52, 124.33, 124.10, 21.91.
4. 2.14. 6-Methyl-3, 4-di(4-methoxyphenyl)pyridazine
(5n). Yield¼80% (245 mg); Colorless solid; mp¼112e113 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C19H19N2O2 307.1447, found 307.1450; 1H NMR (400 MHz,
4.2.8. 3-Methyl-6-(thiophen-2-yl)pyridazine
(5h).19n Yield¼72%
(127 mg); Colorless solid; mp¼138e140 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C9H9N2S
CDCl3):
6.83 (d, J¼8.8 Hz, 2H), 6.82 (d, J¼8.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s,
3H), 2.76 (s, 3H); 13C NMR (100 MHz, CDCl3):
159.86, 159.84,
d
7.37 (d, J¼8.8 Hz, 2H), 7.27 (s, 1H), 7.12 (d, J¼8.8 Hz, 2H),
177.0487, found 177.0488; 1H NMR (400 MHz, CDCl3):
d 7.69 (d,
J¼8.8 Hz, 1H), 7.63 (dd, J¼1.2, 3.6 Hz, 1H), 7.46 (dd, J¼1.2, 5.2 Hz,
d
1H), 7.33 (d, J¼8.8 Hz, 1H), 7.14 (dd, J¼3.6, 5.2 Hz, 1H), 2.72 (s, 3H);
158.02, 157.38, 138.51, 131.22 (2ꢁ), 130.30 (2ꢁ), 129.43, 129.21,
13C NMR (100 MHz, CDCl3):
d 158.30, 153.08, 140.68, 128.78,
127.55, 114.10 (2ꢁ), 113.56 (2ꢁ), 55.24, 55.19, 21.78; Anal. Calcd for
127.94, 127.39, 125.83, 122.61, 21.93; Anal. Calcd for C9H8N2S: C,
61.33; H, 4.58. Found: C, 61.54; H, 4.75. Single-crystal X-ray dia-
gram: crystal of compound 5h was grown by slow diffusion of
EtOAc into a solution of compound 5h in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the monoclinic crystal
C19H18N2O2: C, 74.49; H, 5.92. Found: C, 74.53; H, 6.08. Single-
crystal X-ray diagram: crystal of compound 5n was grown by
slow diffusion of EtOAc into a solution of compound 5n in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the triclinic
ꢀ
ꢀ
crystal system, space group P ꢂ1, a¼9.7886(6) A, b¼11.7178(7) A,
system, space group P 21/c, a¼6.1629(2) A, b¼7.9773(3) A,
c¼14.1885(8) A, V¼1590.23(16) A , Z¼2, dcalcd¼1.280 mg/cm3,
3
ꢀ
ꢀ
ꢀ
ꢀ
c¼16.7489(7) A, V¼821.82(5) A , Z¼4, dcalcd¼1.424 mg/cm3,
F(000)¼648,
2q R indices (all data)
range 1.456w26.432ꢀ,
3
ꢀ
ꢀ
F(000)¼368,
2
q
range 2.437w26.397ꢀ,
R
indices (all data)
R1¼0.1110, wR2¼0.1918.
R1¼0.0307, wR2¼0.0778.
4 . 2 .15 . 4 - ( 4 - F l u o r o p h e nyl ) - 3 - ( 4 - m e t h o x y p h e nyl ) - 6 -
methylpyridazine (5o). Yield¼78% (229 mg); Colorless solid;
mp¼130e133 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C18H16FN2O 295.1247, found 295.1248; 1H
4.2.9. 3-Ethyl-6-phenylpyridazine (5i). Yield¼73% (134 mg); Col-
orless solid; mp¼45e48 ꢀC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C12H13N2 185.1079, found
185.1075; 1H NMR (400 MHz, CDCl3):
d
8.07e8.06 (m, 2H), 7.81 (d,
NMR (400 MHz, CDCl3):
d
7.34 (d, J¼8.8 Hz, 2H), 7.28 (s, 1H),
J¼8.8 Hz, 1H), 7.54e7.46 (m, 3H), 7.43 (d, J¼8.8 Hz, 1H), 3.08 (q,
7.20e7.14 (m, 2H), 7.05e6.99 (m, 2H), 6.82 (d, J¼8.8 Hz, 2H), 3.80 (s,
J¼7.6 Hz, 2H), 1.42 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
3H), 2.78 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.84 (d,
d
163.14, 157.42, 136.23, 129.84, 128.96 (2ꢁ), 126.89 (2ꢁ), 126.55,
J¼247.8 Hz), 160.02, 158.15, 157.32, 137.87, 133.15 (d, J¼3.0 Hz),
131.27 (2ꢁ), 130.81 (d, J¼8.3 Hz, 2ꢁ), 128.90, 127.72, 115.84 (d,
J¼22.0 Hz, 2ꢁ), 113.67 (2ꢁ), 55.22, 21.79.
124.40, 28.96, 13.56.
4.2.10. 3-Phenyl-6-n-propylpyridazine (5j). Yield¼72% (143 mg);
Colorless solid; mp¼48e50 ꢀC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C13H15N2 199.1235, found
4.2.16. 3-(4-Methoxyphenyl)-6-methyl-4-(4-trifluoromethylphenyl)
pyridazine (5p). Yield¼75% (258 mg); Colorless solid;
mp¼138e140 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C19H16F3N2O 345.1215, found 345.1212; 1H
199.1238; 1H NMR (400 MHz, CDCl3):
d 8.09e8.07 (m, 2H), 7.82 (d,
J¼8.8 Hz, 1H), 7.54e7.46 (m, 3H), 7.42 (d, J¼8.8 Hz, 1H), 3.03 (t,
J¼7.6 Hz, 2H), 1.91e1.82 (m, 2H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR
NMR (400 MHz, CDCl3):
d
7.60 (d, J¼8.4 Hz, 2H), 7.34e7.32 (m, 4H),
(100 MHz, CDCl3):
127.10, 126.89 (2ꢁ), 124.34, 37.62, 22.80, 13.77.
d
162.05, 157.39, 136.18, 129.87, 128.97 (2ꢁ),
7.32 (s,1H), 6.83 (d, J¼8.8 Hz, 2H), 3.81 (s, 3H), 2.82 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 160.21, 158.21, 157.12, 140.91, 137.55, 131.34
(2ꢁ), 129.37 (2ꢁ), 128.36,127.89,125.71 (d, J¼3.0 Hz, 2ꢁ), 125.64 (d,
19l
4.2.11. 6-Methyl-3,4-diphenylpyridazine
(5k).
Yield¼85%
J¼3.8 Hz, 2ꢁ), 113.80 (2ꢁ), 55.24, 21.76; Anal. Calcd for
(209 mg); Colorless solid; mp¼117e120 ꢀC (recrystallized from
C19H15F3N2O: C, 66.27; H, 4.39. Found: C, 66.38; H, 4.58. Single-
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C17H15N2
crystal X-ray diagram: crystal of compound 5p was grown by
slow diffusion of EtOAc into a solution of compound 5p in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the monoclinic
247.1235, found 247.1233; 1H NMR (400 MHz, CDCl3):
d 7.42e7.40
(m, 2H), 7.39 (s, 1H), 7.36e7.26 (m, 6H), 7.21e7.18 (m, 2H), 2.84 (s,
3H); 13C NMR (100 MHz, CDCl3):
d
158.40, 157.96, 139.78, 136.66,
crystal system, space group P 21/n, a¼6.1166(11) A, b¼10.929(2) A,
3
ꢀ ꢀ
ꢀ
ꢀ
136.49, 129.95 (2ꢁ), 129.02 (2ꢁ), 128.76, 128.70, 128.67 (2ꢁ),
128.27, 128.12 (2ꢁ), 21.65.
c¼24.165(5) A, V¼1610.2(5) A , Z¼4, dcalcd¼1.420 mg/cm3, F(000)¼
712, 2
q
range 1.691w26.452ꢀ, R indices (all data) R1¼0.0527,
wR2¼0.1147.
4.2.12. 3-(4-Methoxyphenyl)-6-methyl-4-phenylpyridazine
(5l). Yield¼83% (229 mg); Colorless gum; HRMS (ESI, Mþþ1) calcd
for C18H17N2O 277.1341, found 277.1345; 1H NMR (400 MHz, CDCl3):
4.2.17. 4-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)-6-
methylpyridazine (5q). Yield¼82% (256 mg); Colorless solid;
mp¼117e119 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C18H15F2N2O 313.1153, found 313.1155; 1H
d
7.37e7.29 (m, 5H), 7.28 (s,1H), 7.21e7.17 (m, 2H), 6.80 (d, J¼8.8 Hz,
2H), 3.78 (s, 3H), 2.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
159.86,
158.07, 157.25, 138.67, 137.21, 131.25 (2ꢁ), 129.18, 128.90 (2ꢁ),
128.59 (2ꢁ), 128.43, 127.72,113.50 (2ꢁ), 55.15, 21.82; Anal. Calcd for
NMR (400 MHz, CDCl3):
d
7.35 (d, J¼8.8 Hz, 2H), 7.27 (s, 1H), 6.85 (d,
J¼8.8 Hz, 2H), 6.80 (t, J¼2.4 Hz, 1H), 6.76e6.71 (m, 2H), 3.82 (s, 3H),
C
18H16N2O: C, 78.24; H, 5.84. Found: C, 78.41; H, 5.89.
2.80 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.99 (d, J¼248.7 Hz),
162.86 (d, J¼248.7 Hz), 160.27, 158.24, 156.88, 140.51, 136.57, 131.18
(2ꢁ), 128.21, 127.51, 113.84 (2ꢁ), 112.12 (d, J¼26.6 Hz), 112.12 (d,
J¼11.4 Hz), 104.10 (t, J¼25.0 Hz), 55.25, 21.80; Anal. Calcd for
4 . 2 .13 . 3 - ( 4 - M e t h o x y p h e nyl ) - 4 - ( 4 - m e t hyl p he nyl ) - 6 -
methylpyridazine (5m). Yield¼83% (241 mg); Colorless solid;
mp¼110e113 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C19H19N2O 291.1497, found 291.1502; 1H NMR
C18H14F2N2O: C, 69.22; H, 4.52. Found: C, 69.35; H, 4.63.
(400 MHz, CDCl3):
d
7.37 (d, J¼8.4 Hz, 2H), 7.28 (s, 1H), 7.13 (d,
4.2.18. 4-(4-Biphenyl)-3-(4-methoxyphenyl)-6-methylpyridazine
(5r). Yield¼83% (292 mg); Yellowish gum; HRMS (ESI, Mþþ1) calcd
for C24H21N2O 353.1654, found 353.1655; 1H NMR (400 MHz,
J¼8.4 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H), 6.82 (d, J¼8.8 Hz, 2H), 3.80 (s,
3H), 2.77 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
159.89,
158.02, 157.41, 138.95, 138.57, 134.16, 131.27 (2ꢁ), 129.37 (2ꢁ),
d
CDCl3):
d
7.62e7.57 (m, 4H), 7.48e4.35 (m, 6H), 7.29 (d, J¼8.8 Hz,

6844
M.-Y. Chang et al. / Tetrahedron 71 (2015) 6840e6845
2H), 6.84 (d, J¼8.8 Hz, 2H), 3.81 (s, 3H), 2.84 (s, 3H); 13C NMR
colorless prisms. The compound crystallizes in the monoclinic
ꢀ
ꢀ
(100 MHz, CDCl3):
d
160.15, 157.92, 157.50, 141.50, 139.89, 135.73,
crystal system, space group P 21/c, a¼15.8783(8) A, b¼9.1753(5) A,
3
ꢀ ꢀ
131.38 (2ꢁ), 129.43 (2ꢁ), 128.90 (2ꢁ), 128.71, 128.36 (2ꢁ), 127.83,
c¼11.1547(6) A, V¼1614.43(15) A , Z¼4, dcalcd¼1.334 mg/cm3,
127.33 (2ꢁ), 127.00 (2ꢁ), 113.70 (2ꢁ), 55.24, 21.53; Anal. Calcd for
F(000)¼680,
2q R indices (all data)
range 1.291w26.416ꢀ,
R1¼0.0589, wR2¼0.1236.
C
24H20N2O: C, 81.79; H, 5.72. Found: C, 81.92; H, 5.69.
4.2.19. 3-(4-Methoxyphenyl)-6-methyl-4-(naphthalen-2-yl)pyr-
idazine (5s). Yield¼84% (274 mg); Yellowish gum; HRMS (ESI,
Mþþ1) calcd for C22H19N2O 327.1497, found 327.1499; 1H NMR
4.2.24. 4-(4-Biphenyl)-3-(3,4-dimethoxyphenyl)-6-methylpyridazine
(5x). Yield¼82% (313 mg); Yellowish gum; HRMS (ESI, Mþþ1) calcd
for C25H23N2O2 383.1760, found 383.1766; 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
7.89 (d, J¼8.0 Hz, 1H), 7.89 (d, J¼8.4 Hz, 1H),
CDCl3): d 7.61e7.58 (m, 4H), 7.48e7.44 (m, 2H), 7.40 (s, 1H),
7.51e7.37 (m, 5H), 7.31 (d, J¼8.8 Hz, 2H), 7.25 (dd, J¼0.8, 8.4 Hz, 1H),
7.40e7.36 (m,1H), 7.30 (d, J¼8.4 Hz, 2H), 7.05 (dd, J¼2.0, 8.0 Hz,1H),
6.62 (d, J¼9.2 Hz, 2H), 3.69 (s, 3H), 2.89 (s, 3H); 13C NMR (100 MHz,
7.04 (br s, 1H), 6.79 (d, J¼8.4 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 3H), 2.84
CDCl3):
d
160.18, 158.45, 157.32, 139.04, 134.42, 133.54, 130.73 (2ꢁ),
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 158.01, 157.37, 155.78, 149.65,
130.64, 130.52, 129.31, 128.59, 128.29, 127.49, 126.99, 126.40, 125.27,
148.51, 141.57, 139.90, 139.21, 135.93, 129.42 (2ꢁ), 128.95 (2ꢁ),
128.32, 127.88, 127.36 (2ꢁ), 126.99 (2ꢁ), 123.08, 113.12, 110.70,
55.83, 55.64, 21.57.
124.77, 113.52 (2ꢁ), 55.12, 21.25.
4.2.20. 3-(3,4-Dimethoxyphenyl)-6-methyl-4-phenylpyridazine
(5t). Yield¼85% (260 mg); Colorless solid; mp¼117e119 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C19H19N2O2 307.1447, found 307.1450; 1H NMR (400 MHz,
4.2.25. 4-(3,5-Difluorohenyl)-3-(3,4-dimethoxyphenyl)-6-
methylpyridazine (5y). Yield¼75% (257 mg); Colorless gum; HRMS
(ESI, Mþþ1) calcd for C29H17F2N2O2 343.1258, found 357.1608; 1H
CDCl3):
J¼8.4 Hz, 1H), 6.96 (d, J¼2.0 Hz, 1H), 6.77 (d, J¼8.0 Hz, 1H), 3.86 (s,
3H), 3.63 (s, 3H), 2.78 (s, 3H); 13C NMR (100 MHz, CDCl3):
158.13,
d
7.36e7.32 (m, 3H), 7.30 (s, 1H), 7.22e7.19 (m, 2H), 7.01 (d,
NMR (400 MHz, CDCl3):
d
7.28 (s, 1H), 7.06 (d, J¼2.0 Hz, 1H), 6.90
(dd, J¼2.0, 8.4 Hz, 1H), 6.84e6.72 (m, 4H), 3.88 (s, 3H), 3.76 (s, 3H),
d
2.80 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
163.02 (d, J¼248.7 Hz),
157.17, 149.38, 148.34, 138.90, 137.36, 129.10, 128.89 (2ꢁ), 128.67
162.89 (d, J¼248.6 Hz), 158.35, 156.79, 149.82, 148.79, 140.66 (t,
J¼9.9 Hz), 136.62, 128.32, 127.50, 122.92, 112.82, 112.08 (d,
J¼26.5 Hz),112.08 (d, J¼11.3 Hz),110.75,104.04 (t, J¼25.1 Hz), 55.84,
55.78, 21.82.
(2ꢁ), 128.46, 127.86, 122.90, 113.11, 110.60, 55.78, 55.56, 21.80.
4.2.21. 3-(3,4-Dimethoxyphenyl)-6-methyl-4-(4-methylphenyl)pyr-
idazine (5u). Yield¼80% (256 mg); Colorless solid; mp¼125e127 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C20H21N2O2 321.1603, found 321.1610; 1H NMR (400 MHz,
4.2.26. 3-(2,3,4-Trimethoxyphenyl)-6-methyl-4-phenylpyridazine
(5z). Yield¼80% (269 mg); Colorless solid; mp¼156e158 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C20H21N2O3 337.1552, found 337.1553; 1H NMR (400 MHz,
CDCl3):
d
7.29 (s, 1H), 7.14 (d, J¼8.4 Hz, 2H), 7.09 (d, J¼8.0 Hz, 2H),
7.00 (dd, J¼2.0, 8.4 Hz, 1H), 6.98 (d, J¼2.0 Hz, 1H), 6.77 (d, J¼8.4 Hz,
1H), 3.87 (s, 3H), 3.66 (s, 3H), 2.78 (s, 3H), 2.35 (s, 3H); 13C NMR
CDCl3): d 7.35 (s, 1H), 7.28e7.25 (m, 3H), 7.20e7.16 (m, 3H), 6.74 (d,
(100 MHz, CDCl3):
d
158.10, 157.30, 149.36, 148.36, 139.04, 138.53,
J¼8.8 Hz, 1H), 3.88 (s, 3H), 3.63 (s, 3H), 3.35 (s, 3H), 2.81 (s, 3H); 13
C
134.32, 129.36 (2ꢁ), 129.33, 128.81 (2ꢁ), 127.83, 122.86, 113.12,
110.61, 55.80, 55.57, 21.78, 21.18. Single-crystal X-ray diagram:
crystal of compound 5u was grown by slow diffusion of EtOAc into
a solution of compound 5u in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the monoclinic crystal system, space
NMR (100 MHz, CDCl3): d 158.75, 156.23, 154.62, 151.11, 141.70,
140.38, 137.18, 128.41, 128.37 (2ꢁ), 128.27 (2ꢁ), 126.63, 125.73,
124.29, 107.13, 60.64, 60.51, 55.99, 21.97. Single-crystal X-ray dia-
gram: crystal of compound 5z was grown by slow diffusion of EtOAc
into a solution of compound 5z in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the monoclinic crystal system, space
ꢀ
ꢀ
ꢀ
group P 21/n, a¼7.8618(3) A, b¼10.9341(4) A, c¼19.6250(7) A,
V¼1678.08(11) A , Z¼4, dcalcd¼1.268 mg/cm3, F(000)¼680, 2
q
range
group P 21/c, a¼13.0301(7) A, b¼17.7043(10) A, c¼7.4858(4) A,
3
ꢀ
3
ꢀ
ꢀ
ꢀ
ꢀ
2.135w26.359ꢀ, R indices (all data) R1¼0.0583, wR2¼0.1234.
V¼1722.63(16) A , Z¼4, dcalcd¼1.297 mg/cm3, F(000)¼712, 2
q
range
1.567w26.407ꢀ, R indices (all data) R1¼0.0547, wR2¼0.1192.
4.2.22. 3-(3,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)-6-
methylpyridazine (5v). Yield¼82% (276 mg); Yellowish gum; HRMS
(ESI, Mþþ1) calcd for C20H21N2O3 337.1552, found 337.1552; 1H
4.2.27. 4-(4-Fluorophenyl)-3-(2,3,4-Trimethoxyphenyl)-6-
methylpyridazine (5aa). Yield¼82% (290 mg); Colorless solid;
mp¼173e174 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C20H20FN2O3 355.1458, found 355.1455; 1H
NMR (400 MHz, CDCl3):
d
7.28 (s, 1H), 7.13 (d, J¼8.8 Hz, 2H), 7.03 (d,
J¼2.0 Hz, 1H), 6.97 (dd, J¼2.0, 8.0 Hz, 1H), 6.85 (d, J¼8.8 Hz, 2H),
6.77 (d, J¼8.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.70 (s, 3H), 2.77 (s,
NMR (400 MHz, CDCl3): d 7.31 (s, 1H), 7.18e7.13 (m, 3H), 6.99e6.93
3H); 13C NMR (100 MHz, CDCl3):
d
159.90, 158.07, 157.32, 149.34,
(m, 2H), 6.74 (d, J¼8.8 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.40 (s, 3H),
148.45, 138.71, 130.27 (2ꢁ), 129.42, 129.30, 127.66, 122.84, 114.13
2.80 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.77 (d, J¼247.1 Hz),
(2ꢁ), 113.05, 110.63, 55.80, 55.65, 55.30, 21.76; Anal. Calcd for
158.79, 156.13, 154.68, 151.04, 141.78, 139.43, 133.22, 133.17 (d,
J¼8.4 Hz, 2ꢁ), 126.47, 125.61, 124.11, 115.36 (d, J¼22.0 Hz, 2ꢁ),
107.28, 60.71, 60.68, 55.99, 21.97; Anal. Calcd for C20H19FN2O3: C,
67.79; H, 5.40. Found: C, 67.92; H, 5.62. Single-crystal X-ray dia-
gram: crystal of compound 5aa was grown by slow diffusion of
EtOAc into a solution of compound 5aa in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the monoclinic crystal system,
C
20H20N2O3: C, 71.41; H, 5.99. Found: C, 71.62; H, 6.12.
4.2.23. 4-(4-Fluorohenyl)-3-(3,4-dimethoxyphenyl)-6-
methylpyridazine (5w). Yield¼81% (262 mg); Colorless solid;
mp¼144e146 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C19H18FN2O2 325.1352, found 325.1351; 1H
ꢀ
ꢀ
ꢀ
NMR (400 MHz, CDCl3):
d
7.27 (s, 1H), 7.20e7.15 (m, 2H), 7.05e6.99
space group P 21/c, a¼8.5581(9) A, b¼17.768(2) A, c¼12.2073(13) A,
3
ꢀ
(m, 3H), 6.91 (dd, J¼2.0, 8.4 Hz, 1H), 6.76 (d, J¼8.4 Hz, 1H), 3.86 (s,
V¼1788.4(3) A , Z¼4, dcalcd¼1.316 mg/cm3, F(000)¼744, 2
q
range
3H), 3.70 (s, 3H), 2.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.76
2.077w26.373ꢀ, R indices (all data) R1¼0.0732, wR2¼0.1042.
(d, J¼247.9 Hz), 158.21, 157.14, 149.45, 148.53, 137.76, 133.29 (d,
J¼3.0 Hz), 130.74 (d, J¼8.3 Hz, 2ꢁ), 128.99, 127.61, 122.88, 115.78 (d,
J¼22.0 Hz, 2ꢁ), 112.99, 110.62, 55.78, 55.64, 21.80. Single-crystal X-
ray diagram: crystal of compound 5w was grown by slow diffusion
of EtOAc into a solution of compound 5w in CH2Cl2 to yield
4.2.28. 4-(3,4-Methylenedioxyphenyl)-3-(4,7-dimethoxynaphthalen-
1-yl)-6-methylpyridazine (5ab). Yield¼75% (300 mg); Colorless
solid; mp¼175e177 ꢀC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C24H21N2O4 401.1501, found 401.1503;

M.-Y. Chang et al. / Tetrahedron 71 (2015) 6840e6845
6845
1H NMR (400 MHz, CDCl3):
d
8.16 (d, J¼9.2 Hz, 1H), 7.41 (s, 1H), 7.28
9. For Os, see: Harman, W. D.; Dobson, J. C.; Taube, H. J. Am. Chem. Soc. 1989, 111,
3062.
10. For Ir, see: (a) Kanemitsu, H.; Uehara, K.; Fukuzumi, S.; Ogo, S. J. Am. Chem. Soc.
2008, 130, 17141; (b) Ogo, S.; Uehara, K.; Abura, T.; Watanabe, Y.; Fukuzumi, S. J.
Am. Chem. Soc. 2004, 126, 16520; (c) Hirabayashi, T.; Okimoto, Y.; Saito, A.;
Morita, M.; Sakaguchi, S.; Ishii, Y. Tetrahedron 2006, 62, 2231.
11. For Pd, see: (a) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127; (b)
Kamijo, S.; Yamamoto, Y. J. Org. Chem. 2003, 68, 4764; (c) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Parisi, L. M. Tetrahedron 2003, 59, 4661; (d) Picquet, M.;
Bruneau, C.; Dixneuf, P. H. Tetrahedron 1999, 55, 3937; (e) Cacchi, S.; Fabrizi, G.;
Moro, L. J. Org. Chem. 1997, 62, 5327; (f) Li, Y.; Yu, Z. J. Org. Chem. 2009, 74, 8904;
(g) Arcadi, A.; Rossi, E. Tetrahedron Lett. 1996, 37, 6811; (h) Saito, A.; Enomoto, Y.;
Hanzawa, Y. Tetrahedron Lett. 2011, 52, 4299.
12. For Fe, see: (a) Damiano, J. P.; Pastel, M. J. Organomet. Chem. 1996, 522, 303; (b)
Wu, X.-F.; Bezier, D.; Darcel, C. Adv. Synth. Catal. 2009, 351, 367; (c) Cabrero-
Antonio, J. R.; Leyva-Perez, A.; Corma, A. Chem.dEur. J. 2012, 18, 11107; (d) Park,
J.; Yeon, J.; Lee, P. H.; Lee, K. Tetrahedron Lett. 2013, 54, 4414.
13. For Hg, see: Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679.
14. For Cu, see: (a) Jha, M.; Shelke, G. M.; Pericherla, K.; Kumar, A. Tetrahedron Lett.
2014, 55, 4815; (b) Hassam, M.; Li, W.-S. Tetrahedron 2015, 71, 2719.
15. In-mediated synthesis of furans. For InCl3, see: (a) Feng, X.; Tan, Z.; Chen, D.;
Shen, Y.; Guo, C.-C.; Xiang, J.; Zhu, C. Tetrahedron Lett. 2008, 49, 4110 For In(OTf)3,
see: (b) Tsuji, H.; Yamagata, K.-i.; Ueda, Y.; Nakamura, E. Synlett 2010, 1015.
16. (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2014, 70, 8908; (b) Chang,
M.-Y.; Cheng, Y.-J.; Lu, Y.-J. Org. Lett. 2014, 16, 6252; (c) Chang, M.-Y.; Lu, Y.-J.;
Cheng, Y.-C. Tetrahedron 2015, 71,1192; (d) Chang, M.-Y.; Cheng, Y.-J.; Lu, Y.-J. Org.
Lett. 2015, 17, 1264; (e) Chang, M.-Y.; Cheng, Y.-J.; Lu, Y.-J. Org. Lett. 2015, 17, 3142.
(d, J¼8.0 Hz, 1H), 7.05 (dd, J¼2.4, 9.2 Hz, 1H), 6.76 (d, J¼2.4 Hz, 1H),
6.68 (d, J¼8.0 Hz, 1H), 6.63 (dd, J¼1.6, 8.0 Hz, 1H), 6.58 (s, 1H), 6.56
(d, J¼1.6 Hz, 1H), 5.85 (s, 2H), 3.99 (s, 3H), 3.69 (s, 3H), 2.86 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 158.68, 158.33, 158.10, 156.25, 147.99,
147.66, 140.24, 133.76, 130.47, 129.96, 127.08, 125.96, 123.89, 122.75,
120.72, 117.37, 108.67, 108.38, 103.79, 101.73, 101.24, 55.48, 55.09,
21.98.
4.2.29. 4-Ethoxycarbonyl-6-methyl-3-phenylpyridazine
(5ad). Yield¼31% (75 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd
for C14H15N2O2 243.1134, found 243.1138; 1H NMR (400 MHz,
CDCl3): d 7.61e7.58 (m, 2H), 7.60 (s, 1H), 7.48e7.45 (m, 3H), 4.19 (q,
J¼7.2 Hz, 2H), 2.83 (s, 3H), 1.08 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3):
d
166.56, 158.91, 156.61, 136.71, 129.98, 129.21, 128.77 (2ꢁ),
128.28 (2ꢁ), 126.09, 62.22, 21.90, 13.57.
4.2.30. 3-Methyl-5,6,7,8-tetrahydrocinnoline
(5af). Yield¼72%
(107 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for C9H13N2
149.1079, found 149.1082; 1H NMR (400 MHz, CDCl3):
d 6.99 (s, 1H),
3.07 (t, J¼6.4 Hz, 2H), 2.73 (t, J¼6.4 Hz, 2H), 2.59 (s, 3H), 1.93e1.87
17. For recent synthesis of b-ketosulfones, see: (a) Pospisil, J.; Sato, H. J. Org. Chem.
(m, 2H), 1.82e1.76 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 158.26,
2011, 76, 2269; (b) Sreedhar, B.; Rawat, V. S. Synlett 2012, 413; (c) Kumar, A.;
Muthyala, M. K. Tetrahedron Lett. 2011, 52, 5368; (d) Lu, Q.; Zhang, J.; Zhao, G.;
Qi, Y.; Wang, H.; Lei, W. J. Am. Chem. Soc. 2013, 135, 11481; (e) Tsui, G. C.; Gle-
nadel, Q.; Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208; (f) Zhou, G.; Ting, P. T.;
Aslanian, R. G. Tetrahedron Lett. 2010, 51, 939; (g) Tang, X.; Huang, L.; Xu, Y.;
Yang, J.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2014, 53, 4205; (h) Chawla, R.;
Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2014, 10, 2032; (i) Singh, A. K.;
Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 4742; (j) Shi, X.; Ren, X.;
Ren, Z.; Li, J.; Wang, Y.; Yang, S.; Gu, J.; Gao, Q.; Huang, G. Eur. J. Org. Chem. 2014,
10, 5083; (k) Xuan, J.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Chem.dEur. J.
2014, 20, 3045.
157.20, 137.38, 126.78, 29.51, 27.87, 22.44, 21.79, 21.57.
Acknowledgements
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for its financial support (MOST
104-2113-M-037-012).
18. For reviews on synthesis of pyridazines, see: (a) Boger, D. L. Chem. Rev.
1986, 86, 781; (b) Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30;
(c) Bourguignon, J. J.; Oumouch, S.; Schmitt, M. Curr. Org. Chem. 2006, 10,
277; (d) Elnagdi, M. H.; Al-Awadi, N. A.; Abdelhamid, I. A. Adv. Heterocycl.
Chem. 2009, 97, 1; (e) Haider, N.; Holzer, W. Sci. Syn. 2004, 16, 125; (f) Kolar,
P.; Tisler, M. Adv. Heterocycl. Chem. 1999, 75, 167.
Supplementary data
Supplementary data (Experimental procedure and scanned
photocopies of NMR (CDCl3) spectral data were supported) asso-
ciated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2015.07.025.
19. For representative examples on the synthesis of pyridazines, see: (a) Draper, T.
L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748; (b) South, M. S.; Jakuboski, T. L.;
Westmeyer, M. D.; Daniel, D. R. J. Org. Chem. 1996, 61, 8921; (c) Helm, M. D.;
Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2005, 44, 3889; (d)
Yang, X.; Knochel, P. Org. Lett. 2006, 9, 1941; (e) Hamasaki, A.; Ducray, R.; Boger,
D. L. J. Org. Chem. 2006, 71, 185; (f) Aliyama, T.; Moita, H.; Fuchibe, K. J. Am.
Chem. Soc. 2006, 128, 13070; (g) Xie, H.; Zu, L.; Oueis, H. R.; Li, H.; Wang, J.;
Wang, W. Org. Lett. 2008, 10, 1923; (h) Sengmany, S.; Leonel, E.; Polissaint, F.;
Nedelec, J.-Y.; Pipelier, M.; Thobie-Gautier, C.; Dubreuil, D. J. Org. Chem. 2007, 72,
5631; (i) Gao, Q.; Zhu, Y.; Lian, M.; Liu, M.; Yuan, J.; Wu, A.; Yin, G. J. Org. Chem.
2012, 77, 9865; (j) Attanasi, O. A.; Favi, G.; Fillippone, P.; Perrulli, F. R.; San-
teusanio, S. Org. Lett. 2009, 11, 309; (k) Petiot, P.; Gagnon, A. Eur. J. Org. Chem.
2013, 24, 5282; (l) Mboyi, C. D.; Duhayon, C.; Canac, Y.; Chauvin, R. Tetrahedron
2014, 70, 4957; (m) Lin, S.; Liu, Z.; Hu, Y. J. Comb. Chem. 2007, 9, 742; (n) Aldous,
D. J.; Bower, S.; Moorcroft, N.; Todd, M. Synlett 2001, 150.
20. For the potential biological activities of pyridazines, see: (a) Benson, S. C.;
Palabrica, C. A.; Snyder, J. K. J. Org. Chem. 1987, 52, 4610; (b) Rohet, F.; Rubat, C.;
Coudert, P.; Couquelet, J. Bioorg. Med. Chem. 1997, 5, 655; (c) Tucker, J. A.; All-
wine, D. A.; Grega, K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.; Brickner, S.
J.; Hutchinson, D. K.; Ford, C. W.; Zurenko, G. E.; Conradi, R. A.; Burton, P. S.;
Jensen, R. M. J. Med. Chem. 1998, 41, 3723; (d) Gyoten, M.; Nagaya, H.; Fukuda,
S.; Ashida, Y.; Kawano, Y. Chem. Pharm. Bull. 2003, 51, 122; (e) Tamayo, N.; Liao,
L.; Goldberg, M.; Powers, D.; Tudor, Y. Y.; Yu, V.; Wong, L. M.; Henkle, B.;
Middleton, S.; Syed, R.; Harvey, T.; Jang, G.; Hungate, R.; Dominguez, C. Bioorg.
Med. Chem. Lett. 2005, 15, 2409; (f) Emmerich, J.; Hu, Q.; Hanke, N.; Hartmann,
R. W. J. Med. Chem. 2013, 56, 6022.
References and notes
1. (a) Larock, R. C.; Leong, W. W. In Comprehensive Organic Synthesis; Pergamon;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Oxford: UK, 1991; Vol. 4, p 269;
(b) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; p 76.
2. For review articles of hydration of alkynes, see: (a) Hintermann, L.; Labonne, A.
Synthesis 2007, 1121; (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004,
104, 3079; (c) Corma, A.; Leyva-Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111,
1657.
3. For Au, see: (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729; (b) Teles, J.
H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415; (c) Mizushima,
E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 4563; (d)
Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003,
125, 11925; (e) Roembke, P.; Schmidbaur, H.; Cronje, S.; Raubenheimer, H. J. Mol.
Catal. A: Chem. 2004, 212, 35; (f) Vasudevan, A.; Verzal, M. K. Synlett 2004, 631;
(g) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448; (h)
Hashmi, A. S. K.; Hengst, T.; Lothschutz, C.; Rominger, F. Adv. Synth. Catal. 2010,
352, 1315.
4. For Ag, see: (a) Das, R.; Chakraboty, D. Appl. Organomet. Chem. 2012, 26, 722; (b)
Kataoka, Y.; Matsumoto, O.; Tani, K. Chem. Lett. 1996, 727.
5. For Ag/Au, see: (a) Arcadi, A.; Alfonsi, M.; Chiarini, M.; Marinelli, F. J. Organomet.
Chem. 2009, 694, 576; (b) Belting, V.; Krause, N. Org. Biomol. Chem. 2009, 7,
1221; (c) Wang, T.; Zhang, J. Dalton Trans. 2010, 39, 4270.
21.. CCDC 1057388 (5h), 1053820 (5n), 1053819 (5p), 106140 (5u), 106141 (5w),
1062652 (5z) and 1053821 (5aa) contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html(or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
6. For Ru, see: (a) Taqui Khan, M. M.; Halligudi, S. B.; Shukla, S. J. Mol. Catal. 1990,
58, 299; (b) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867;
(c) Grotjahn, D. B.; Incarnito, C. D.; Rheingold, A. L. Angew. Chem., Int. Ed. 2001,
40, 3884; (d) Chevallier, F.; Breit, B. Angew. Chem., Int. Ed. 2006, 45, 1599; (e)
Labonne, A.; Kribber, T.; Hintermann, L. Org. Lett. 2006, 8, 5853; (f) Tokunaga,
M.; Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.; Wakatsuki, Y. J. Am. Chem.
Soc. 2001, 123, 11917.
7. For Rh, see: Blum, J.; Huminer, H.; Alper, H. J. Mol. Catal. 1992, 75, 153.
8. For Pt, see: (a) Hartman, J.; Hiscox, W. C.; Jennings, P. W. J. Org. Chem. 1993, 58,
7613; (b) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997, 62, 669; (c) Lucey,
D. W.; Atwoood, J. D. Organometallics 2002, 21, 2481; (d) Hiscox, W.; Jennings,
P. W. Organometallics 1990, 9, 1997; (e) Kataoka, Y.; Matsumoto, O.; Ohashi, M.;
Yamagata, T.; Tani, K. Chem. Lett. 1994, 1283.
22. Young, B. S.; Kohler, F.; Herges, R.; Haley, M. M. J. Org. Chem. 2011, 76, 8483.
23. (a) Boden, N.; Bushby, R. J.; Headdock, G.; Lozman, O. R.; Wood, A. Liq. Cryst.
2001, 28, 139; (b) King, B. T.; Kroulik, J.; Robertson, C. R.; Rempala, P.; Hilton, C.
L.; Korinek, J. D.; Gortari, L. M. J. Org. Chem. 2007, 72, 2279; (c) Simpson, C. D.;
Mattersteig, G.; Martin, K.; Gherghel, L.; Bauer, R. E.; Rader, H. J.; Mullen, K. J.
Am. Chem. Soc. 2004, 126, 3139; (d) Churruca, F.; SanMartin, R.; Carril, M.; Ur-
tiaga, M. K.; Solans, X.; Tellitu, I.; Dominguez, E. J. Org. Chem. 2005, 70, 3178; (e)
Navale, T. S.; Thakur, K.; Rathore, R. Org. Lett. 2011, 13, 1634; (f) Zhang, X.; Jiang,
X.; Zhang, K.; Mao, L.; Luo, J.; Chi, C.; Chan, H. S. O.; Wu, J. J. Org. Chem. 2010, 75,
8069.