Silver(I)-Catalyzed Tandem Sigamatropic Rearrangement/1,3-H Shift/6π Aza-electrocyclization of N-Propargylic Hydrazones: A Mild Synthetic Route to 1,6-Dihydropyridazines

Article abstract of DOI:10.1021/acs.joc.6b00428

A highly efficient AgOTf catalyzed [3,3] sigmatropic rearrangement/1,3-H shift/6' aza-electrocyclization cascade reaction of N-propargylic hydrazones has been developed. This method provides a new mild synthetic route to various polysubstituted 1,6-dihydr

Full text of DOI:10.1021/acs.joc.6b00428

Subscriber access provided by UNIV OF CONNECTICUT
Note
Silver (I)-Catalyzed Tandem Sigamatropic Rearrangement/1,3-
H Shift/6pi Aza-electrocyclization of N#Propargylic
Hydrazones: A Mild Synthetic Route to 1,6-Dihydropyridazines
Zong-Cang Ding, Lu-Chuan Ju, Ying Yang, Xiao-Ming An, Yun-Bing
Zhou, Ren-Hao Li, Hai-Tao Tang, Cheng-Ke Ding, and Zhuang-Ping Zhan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00428 • Publication Date (Web): 02 Apr 2016
Downloaded from http://pubs.acs.org on April 6, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Silver (I)ꢀCatalyzed Tandem Sigamatropic Rearrangement/1,3ꢀH
Shift/6π Azaꢀelectrocyclization of N‑Propargylic Hydrazones: A
Mild Synthetic Route to 1,6ꢀDihydropyridazines
ZongꢀCang Ding, LuꢀChuan Ju, Ying Yang, XiaoꢀMing An, YunꢀBing
Zhou, RenꢀHao Li, HaiꢀTao Tang, ChengꢀKe Ding and ZhuangꢀPing
Zhan*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China
R3
R4
N
R2
R1
N
R3
R4
N
R2
R1
AgOTf (10 mol %)
N
EtOAc, rt
via [3,3] sigmatropic rearrangement
1
2
/1,3-H shift/ 6
π
electrocyclization
23 examples, up to 98% yield
ABSTRACT:
A
highly efficient AgOTf catalyzed [3,3] sigmatropic
rearrangement/1,3ꢀH shift/6π azaꢀelectrocyclization cascade reaction of Nꢀpropargylic
hydrazones has been developed. This method provides a new mild synthetic route to
various polysubstituted 1,6ꢀdihydropyridazines including the 3ꢀCF3ꢀsubstituted ones
with high selectivity.
The pyridazineꢀderived structures form the core of many commercial drugs and drug
candidates.1 Among those pyridazine derivatives, pyridazinone and dihydropyridazine
(including 1,4ꢀdihydropyridazine and 1,6ꢀdihydropyridazine) derivatives show
versatile pharmacological activities. The former have been used as antagonists for
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
9
various targets to treat inflammation and diabetes and as antifungal or antibiotic
reagents.2 The latter has been used as antiꢀhypertensive, coronary insufficiency
therapeutic and spasmolytic agents.3 For these reasons, a variety of strategies have
been developed for the synthesis of 1,4ꢀdihydropyridazines.4 Nevertheless, methods
for the preparation of 1,6ꢀdihydropyridazines remain rare and usually rely on the
cycloaddition of aromatic diazonium salts with dienes5 or [4+2] cycloaddition of
αꢀhalogenated hydrazones with alkenes.6 Despite these pioneering methodologies, the
further development of a general and efficient process for the synthesis of
1,6ꢀdihydropyridazines is a highly desirable and yet challenging task.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Transition metal catalyzed skeletal rearrangements involving cleavage and
formation of several covalent bonds have proven to be efficient and attractive
transformations in the construction of nitrogenꢀ and oxygenꢀcontaining heterocyclic
pounds.7 Particularly, the [3,3] rearrangements of propargylic systems have been well
studied.8 We have explored the [3,3] rearrangements of Nꢀpropargylic hydrazones and
expanded the scope of these reactions.9 Interestingly, we have found that the
transformations can be channelled to form different types of products by the proper
choice of substituents of a common substrate. As shown in Scheme 1, we have
reported that the Nꢀpropargylic sulfonylhydrazones undergoes a novel [3,3]
rearrangement to give (1E,3E)ꢀ2ꢀsulfonylꢀ1,3ꢀdienes in the presence of [CuPPh3I]4
(Scheme 1, a).9a However, changing the Nꢀsulfonyl group to a Nꢀaryl or Nꢀalkyl
group leads to the formation of pyrazoles by
a
PtCl4ꢀcatalyzed [3,3]
rearrangement/cyclization sequence (Scheme 1, b).9b As part of our ongoing efforts in
2
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
expanding the synthetic utility of Nꢀpropargylic hydrazones, we have screened a host
of catalysts for promoting the formation of pyridazine derivatives from the same
Nꢀpropargylhydrazones. Fortunately, we have discovered that switching from PtCl4 to
the cheaper AgOTf as the catalyst results in the highly selective formation of
1,6ꢀdihydropyridazine as the sole product (Scheme 1, c). Herein, we report the
synthesis of 1,6ꢀdihydropyridazines from easily available Nꢀpropargyl hydrazones
through AgOTfꢀcatalyzed [3,3] sigmatropic rearrangement/1,3ꢀH shift/6π
azaꢀelectrocyclization cascade with high efficiency under mild conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Transition Metal Catalyzed [3,3]ꢀRearrangement of Nꢀpropargyl
Hydrazones and the Possibilities for Forming Different Products.
We began our investigation by reacting 1a with a catalytic amount of PtCl4 (10
mol %), the catalyst we previously employed to convert Nꢀpropargyl hydrazones to
pyrazoles.9b Pleasingly, the desired 1,6ꢀdihydropyridazine 2a was obtained in 43%
yield, albeit accompanied by the formation of 3a (Table 1, entry 1). The yield of
pyrazole 3a was improved to 62% with the use of Rh2(Oct)4 as the catalyst in reflux
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
Table 1. Optimization of the Reaction Conditionsa
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
1
catalyst
PtCl4
solvent
DCM
yield (2a/3a)b
43%/28%
NRc
2
Rh2(Oct)4
Rh2(Oct)4
Cu(OTf)2
Pd(PPh3)2Cl2
Zn(OTf)2
AuPPh3Cl
AgOAc
AgSbF6
AgOTf
DCM
3d
4
Toluene
DCM
0%/62%
NR
5
DCM
NR
6
DCM
NR
7
DCM
NR
8
DCM
NR
9
DCM
64%/0%
86%/0%
82%/0%
88%/0%
89%/0%
93%/0%
Trace/0%
74%/0%
80%/0%
98%/0%
NR
10
11
12
13
14
15
16
17
18
19
DCM
AgBF4
DCM
AgOTf
CHCl3
DCE
AgOTf
AgOTf
THF
AgOTf
MeCN
Toluene
1,4ꢀdioxane
EtOAc
EtOAc
AgOTf
AgOTf
AgOTf
None
aReaction conditions: The reaction was carried out using 1a (0.3 mmol) and catalyst
(10 mol %) in the solvent (3 mL) for 12 hours at room temperature unless otherwise
noted. bDetermined by NMR. cNR=no reaction. dReacted at 120 oC.
toluene (Table 1, entry 3). Other transitionꢀmetal catalysts, such as Cu(OTf)2,
Pd(PPh3)2Cl2, Zn(OTf)2, AuPPh3Cl and AgOAc failed (Table 1, entries 4ꢀ8). Several
Ag (I) salts were evaluated as the catalyst and we were delighted to find that the use
of AgOTf dramatically improved the yield of 2a to 86% (Table 1, entries 9ꢀ11).
Among the solvents tested, ethyl acetate provided the best results although other
solvents such as chloroform, dichloroethane, tetrahydrofuran, toluene and 1,4ꢀdioxane
also afforded acceptable yields except acetonitrile (Table 1, entries 12ꢀ18). No
reaction could occur in the absence of catalyst (Table 1, entry 19). Hence, the optimal
4
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
reaction conditions were determined to be performing the reaction in ethyl acetate at
room temperature with AgOTf (10 mol%) as the catalyst (Table 1, entry 18).
7
8
9
Next, the substrate scope was probed under the optimized conditions (Scheme 2).
The reaction was compatible with various R1 substituents. Hence, phenyl substituted
with electronꢀdonating groups (ꢀMe, ꢀOMe) or electronꢀwithdrawing groups
(ꢀCOOMe) or halogens (ꢀBr, ꢀF) at different positions were all tolerated (Scheme 2,
products 2aꢀ2h, 91ꢀ98% yields). Moreover, heteroaryl group (2ꢀthienyl) and the bulky
1ꢀnaphthyl or alkyl groups, including cyclohexenyl and nꢀpropyl were found to be
suitable (Scheme 2, products 2iꢀ2l, 31ꢀ90% yields). However, a terminal alkyne led to
no reaction (Scheme 2, product 2m, 0% yield). Branching at the propargyl position
(R4 = methyl or ethyl) did not affect the efficiency and the polysubstituted
1,6ꢀdihydropyridazines 2n and 2o were obtained in 93% and 94% yields respectively
(Scheme 2, products 2nꢀ2o, 93ꢀ94% yields). A survey of various R3 substituents was
also performed. Both electronꢀrich (ꢀOMe) and electronꢀdeficient (ꢀNO2, ꢀBr) phenyl
groups were wellꢀtolerated with latter affording higher yields (Scheme 2, products
2pꢀ2r, 85ꢀ98% yields). The structure of 2r was further confirmed by singleꢀcrystal
Xꢀray diffraction analysis (Figure 1, see supporting information). Replacing the R3
phenyl group with electronꢀwithdrawing tꢀbutyloxy carbonyl group completely shut
down the reaction even in reflux ethyl acetate (Scheme 2, product 2s, 0% yield).
Incorporation of a trifluoromethyl group to a heterocycle has attracted increasing
attention in recent years due to the ubiquity of this motif in pharmaceuticals and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
agrochemicals.10 As expected, the current method had the ability to furnish the
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
Scheme 2. AgOTf Catalyzed Synthesis of 1,6ꢀDihydropyridazines a, b
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: The reaction was carried out using 1 (0.3 mmol) and AgOTf
(10 mol %) in EtOAc (3 mL) at rt for 12 h. bIsolated yields. cReacted at 60 oC for 24h.
dComplex result.
3ꢀCF3ꢀ1,6ꢀdihydropyridazine 2t in 82% yield (Scheme 2, product 2t, 82% yield).
Furthermore, the dihydropyridazine ring bearing a formyl group was also successfully
6
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
synthesized (Scheme 2, product 2u, 91% yield). Unfortunately, when R2 was changed
into electronꢀdonating group like a pentyl gave the complex result (Scheme 2, product
2v). Interestingly, this method was also compatible with the use of aromatic aldehyde
hydrazone as the substrate albeit with moderate efficiency (Scheme 2, product 2w, 45%
yield).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. AgOTf (I) Catalyzed formation of 1,3ꢀDienes.
Note that when 1x (R3=H) was tested as the substrate, the 1,3ꢀdienes 4x and 4x’
were isolated in 62% combined yield (Z:E=4:9), which clearly indicated a AgOTf
catalyzed [3,3] sigmatropic rearrangement and N2 extrusion had occurred (Scheme 3).
Scheme 4. Synthesis of Pyridazinone by Oxidation of 1,6ꢀDihydropyridazine.
Ph
O
N
CF3
Ph
4-BrPh
O
N
CO2Et
4-BrPh
Ph
O
N
CHO
Ph
N
N
N
5a, 100%
5b, 97%
5c, 88%
Pyridazinone derivatives have been demonstrated as building blocks in many
pharmaceuticals and pesticides.2a To demonstrate the synthetic utility of this method,
the oxidation of 1,6ꢀdihydropyridazines 2r, 2t and 2u were performed with SeO2 as
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
the oxidant leading to efficient access to pyridazinones bearing a useful
5
6
7
trifluoromethyl (5b) or an aldehyde group (5c) (Scheme 4).
8
9
Scheme 5. Plausible Reaction Mechanism.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on the experimental results presented above and previous reports,9,11
a
proposed reaction mechanism is depicted in Scheme 5. Coordination of the transition
metal catalyst with the alkyne activates the triple bond of 1, which allows a
6-endo-dig addition of hydrazone onto the metalꢀalkyne complex I leading to the
intermediate II. The allenic intermediate III is formed by the decomposition of II
with concomitant regeneration of the metal catalyst. Rh2(Oct)4ꢀcatalyzed 5-exo-dig
cyclization of intermediate III affords pyrrole derivative 3 (path a). In contrast,
AgOTf promotes the formation of 1,6ꢀdihydropyridazine 2 by 1,3ꢀH shift and
8
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
subsequent 6πꢀazaꢀelectrocyclization of IV (path b, R3 = aryl). In this process, we
propose the ability to catalyze the [3,3] rearrangement of the metals ranks Ag>Pt>Rh
(Table 1), and the intermediate III undergoes Agꢀcatayzed 1,3ꢀH shift at room
temperature and obtain the highly selective 1,6ꢀdihydropyridazine. In contrast, the
[3,3] rearrangement couldn’t be carried out catalyzed by Rh2(Oct)4 at room
temperature ( Table 1, entry 2), and reflux toluene leads to the formation of
intermediate III but shut down the 1,3ꢀH shift thus producing the sole pyrazole
( Table 1, entry 3). In the case of 1x (R3 = H), the intermediate III may be unstable
and undergo N2 extrusion to afford the 1,3ꢀbutadiene 4. If R3 is Boc, we proposed
intermediate II could not be formed due to its carbon atom of the imine to exhibit
weak nucleophilicity caused by the strong electronꢀwithdrawing ability of Boc, which
would lead to the no reaction result here. In addition, the product 2m couldn’t be
obtained may due to the terminal alkyne 1m (R1 = H) failed to be activated by Ag
catalysis under the standard conditions to undergo the [3,3] rearrangement leading to
the recovery of the starting material.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have reported a general and efficient method for the synthesis of
1,6ꢀdihydropyridazines from easily Available Nꢀpropargylhydrazones. The reactions
proceed through a [3,3] rearrangement/1,3ꢀH shift/6π azaꢀelectrocyclization process
and are highꢀyielding with a broad substrate scope under extremely mild conditions.
The Ag (I) catalyst promotes highly selective 1,6ꢀdihydropyridazine formation, in
sharp contrast to our previous synthesis of pyrazoles catalyzed by PtCl4. In addition,
we have also developed a new synthetic route to functionalized pyridazinones. We
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
anticipate that the strategy of this Agꢀcatalyzed cascade process will find its
applications in medicinal chemistry.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents were obtained
commercially and used without further purification. All reaction mixtures were stirred
with a magnetic bar in flameꢀdried tube. 1H and 13C spectra were recorded on a 400 or
500 MHz spectrometer. Chemical shifts were reported in ppm. 1H NMR spectra were
referenced to CDCl3 (7.26 ppm), and 13CꢀNMR spectra were referenced to CDCl3
(77.0 ppm). All 13CꢀNMR spectra were measured with complete proton decoupling.
Peak multiplicities were designated by the following abbreviations: s, singlet; d,
doublet; t, triplet; m, multiplet; brs, broad singlet and J, coupling constant in Hz. IR
spectra were recorded on an FTIR spectrometer as thin film. Absorptions were given
in wavenumbers (cmꢀ1). HRMS spectra were recorded with Micromass QTOF2
Quadrupole/TimeꢀofꢀFlight Tandem mass spectrometer using electron spray
ionization.
General Experimental Procedures for Preparation of Propargyl Hydrazones 1.
To a solution of ethyl 2ꢀoxoacetate or glyoxal (5 mmol) in MeOH (10 ml) was added
the corresponding hydrazine (5 mmol), the reaction mixture was refluxed for about 1
h and then cooled to room temperature. The mixture was filtered through a sintered
discs and the corresponding hydrazone was obtained as white or yellow solid in high
yield. Corresponding hydrazone (4 mmol) and K2CO3 (4.4 mmol) was added to an
oven dried roundꢀbottomed flask, and then DMF (15 mL) was added. Finally,
10
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
corresponding propargyl bromine (4.8 mmol) was added under the protection of N2,
and the reaction mixture was stirred at room temperature. Upon completion
(monitored by TLC), diluted by 20 mL of water and the aqueous phase was extracted
with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4. The
solvent was removed by vacuum and the crude residue was purified by silica gel
column chromatography to afford the corresponding propargyl hydrazones in 62%~
95% yields (eluent: petroleum ether/ EtOAc = 30/1ꢀ5/1). The substrate 1t was
prepared according to our previous work.9b In particular, 1x was prepared from 1s by
heating the mixture of 1s and silica gel in toluene, and then purified by silica gel
column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Experimental Procedures for Ag (I)ꢀCatalyzed Synthesis of
1,6ꢀDihydropyridazine 2. Corresponding propargyl hydrazone 1 (0.3 mmol) and
AgOTf (10 mol%) were added to 10 mL schlenk tube followed by the adding of
EtOAc (3 mL), and the reaction mixture was stirred at room temperature for about 12
h. Upon completion (monitored by TLC), the solvent was removed by vacuum and
the crude residue was purified by silica gel column chromatography to afford the
corresponding 1,6ꢀdihydropyridazine 2 (eluent: petroleum ether/ EtOAc = 30/1).
General Experimental Procedures for Oxidation of 1,6ꢀDihydropyridazine.
Corresponding 1,6ꢀdihydropyridazine (2r, 2t or 2u) (0.5 mmol) and SeO2(1.0 mmol)
were added to 10 mL schlenk tube followed by the adding of Dioxane (5 mL), and the
o
reaction mixture was stirred at 105 C for about 4 h. Upon completion (monitored by
TLC), the solvent was removed by vacuum and the crude residue was purified by
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
silica gel column chromatography (eluent: petroleum ether/ EtOAc = 10/1) to afford
5
6
7
the corresponding pyridazinones 5 as white solid.
8
9
ethyl 1,4ꢀdiphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2a). a yellow oil (88.2
mg, 96% yield); 1H NMR (500 MHz, CDCl3) δ 1.07 (t, 3H, J = 7.2 Hz), 4.11 (q, 2H,
J = 7.2 Hz), 4.51 (d, 2H, J = 4.6 Hz), 5.81 (t, 1H, J = 4.6 Hz),7.10ꢀ7.14 (m, 1H),
7.21ꢀ7.24 (m, 2H), 7.30ꢀ7.37 (m, 3H), 7.39ꢀ7.42 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 13.7, 44.4, 60.6, 115.9, 119.4, 123.2, 126.9, 127.5, 128.0, 129.0, 132.2,
135.5, 138.3, 145.2, 163.6; IR (film): 2980, 1718, 1597, 1492, 1371 cmꢀ1; HRMS
(ESI) m/z Calculated for C19H18N2O2Na+ [M+Na]+ 329.1260, found: 329.1263.
ethyl 1ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2b). a yellow
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
solid (87.5 mg, 91% yield, mp: 123ꢀ125 C); H NMR (400 MHz, CDCl3) δ 1.12 (t,
3H, J = 7.1 Hz), 2.36 (s, 3H), 4.13 (q, 2H, J = 7.1 Hz), 4.49 (d, 2H, J = 4.6 Hz), 5.79
(t, 1H, J = 4.6 Hz),7.09ꢀ7.16 (m, 5H), 7.38ꢀ7.42 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 21.2, 44.5, 60.7, 116.0, 119.1, 123.2, 126.9, 128.8, 129.0, 132.2, 135.3,
135.8, 137.3, 145.4, 163.8; IR (film): 2979, 1717, 1597, 1496, 1372 cmꢀ1; HRMS
(ESI) m/z Calculated for C20H20N2O2Na+ [M+Na]+ 343.1417, found: 343.1421.
ethyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2c). a
1
yellow oil (91.7 mg, 91% yield); H NMR (500 MHz, CDCl3) δ 1.12 (t, 3H, J = 7.1
Hz), 3.81 (s, 3H), 4.14 (q, 2H, J = 7.1 Hz), 4.48 (d, 2H, J = 4.7 Hz), 5.76 (t, 1H, J =
4.7 Hz), 6.86ꢀ6.88 (m, 2H), 7.13ꢀ7.15 (m, 2H), 7.38ꢀ7.41 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 13.9, 44.4, 55.2, 60.7, 113.5, 115.9, 118.6, 123.1, 128.1, 129.0, 130.6,
131.7, 135.8, 145.3, 159.1, 163.8,; IR (film): 2979, 1719, 1598, 1512, 1496, 1369
12
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
cmꢀ1; HRMS (ESI) m/z Calculated for C20H20N2O3Na+ [M+Na]+ 359.1366, found:
359.1367.
7
8
9
ethyl4ꢀ(4ꢀ(methoxycarbonyl)phenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxyl
ate (2d). a yellow solid (107.1 mg, 98% yield, mp: 137ꢀ139 oC); 1H NMR (500 MHz,
CDCl3) δ 1.08 (t, 3H, J = 7.1 Hz), 3.91 (s, 3H), 4.11 (q, 2H, J = 7.1 Hz), 4.53 (d, 2H,
J = 4.4 Hz), 5.83 (t, 1H, J = 4.4 Hz), 7.11ꢀ7.13 (m, 1H), 7.26ꢀ7.28 (m, 2H), 7.38ꢀ7.41
(m, 4H), 8.00 ꢀ8.02 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 13.8, 44.4, 52.0, 60.7,
116.0, 120.3, 123.5, 127.0, 129.0, 129.1, 129.3, 131.6, 134.5, 143.1, 145.0, 163.3,
166.7; IR (film): 2919, 1717, 1558, 1457, 1374cmꢀ1; HRMS (ESI) m/z Calculated for
C21H20N2O4Na+ [M+Na]+ 387.1315, found: 387.1317.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 4ꢀ(2ꢀbromophenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2e). an
o
orange solid (108.5 mg, 94% yield, mp: 98ꢀ100 C ); 1H NMR (500 MHz, CDCl3) δ
1.08 (t, 3H, J = 7.1 Hz), 4.10 (q, 2H, J = 7.1 Hz), 4.48 (s, 1H), 4.71 (s, 1H), 5.76 (t,
1H, J = 4.3 Hz), 7.10ꢀ7.14 (m, 1H), 7.16ꢀ7.20 (m, 1H), 7.23ꢀ7.26 (m, 1H), 7.30ꢀ7.33
13
(m, 1H), 7.37ꢀ7.42 (m, 4H), 7.53ꢀ7.55 (m, 1H); C NMR (125 MHz, CDCl3) δ 13.8,
44.5, 60.6, 115.8, 121.8, 122.8, 123.3, 127.2, 128.9, 129.0, 129.9, 131.8, 132.0, 132.9,
140.2, 145.3, 163.2; IR (film): 2979, 1712, 1593, 1497, 1372 cmꢀ1; HRMS (ESI) m/z
Calculated for C19H17BrN2O2Na+ [M+Na]+ 407.0366 and 409.0345, found: 407.0368
and 409.0347.
ethyl 4ꢀ(3ꢀbromophenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2f). an
orange solid (110.8 mg, 96% yield, mp: 105ꢀ107 oC ); 1H NMR (500 MHz, CDCl3) δ
1.12 (t, 3H, J = 7.1 Hz), 4.14 (q, 2H, J = 7.1 Hz), 4.52 (d, 2H, J = 4.6 Hz), 5.79 (t, 1H,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
8
9
J = 4.6 Hz), 7.11ꢀ7.15 (m, 2H), 7.18ꢀ7.22 (m, 1H), 7.36ꢀ7.42 (m, 5H), 7.43ꢀ7.46 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 44.5, 60.8, 116.1, 120.0, 122.1, 123.5,
125.8, 129.1, 129.5, 130.2, 130.5, 131.2, 134.6, 140.5, 145.1, 163.4; IR (film): 2979,
1712, 1593, 1497, 1372 cmꢀ1; HRMS (ESI) m/z Calculated for C19H17BrN2O2Na+
[M+Na]+ 407.0366 and 409.0345, found: 407.0368 and 409.0347.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 4ꢀ(4ꢀbromophenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2g). a
1
yellow solid (106.4 mg, 92% yield, mp: 120ꢀ121 oC); H NMR (500 MHz, CDCl3) δ
1.14 (t, 3H, J = 7.1 Hz), 4.14 (q, 2H, J = 7.1 Hz), 4.50 (d, 2H, J = 4.6 Hz), 5.77 (t, 1H,
J = 4.6 Hz), 7.07ꢀ7.10 (m, 2H), 7.11ꢀ7.15 (m, 1H), 7.37ꢀ7.40 (m, 4H), 7.44ꢀ7.48 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 13.9, 44.4, 60.8, 116.0, 119.7, 121.5, 123.4,
128.7, 129.0, 131.1, 131.4, 134.5, 137.3, 145.1, 163.4; IR (film): 2979, 1712, 1595,
1495, 1372 cmꢀ1; HRMS (ESI) m/z Calculated for C19H17BrN2O2Na+ [M+Na]+
407.0366 and 409.0345, found: 407.0368 and 409.0347.
ethyl 4ꢀ(4ꢀfluorophenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2h). a
o
1
yellow solid (90.5 mg, 93% yield, mp: 79ꢀ81 C ); H NMR (500 MHz, CDCl3) δ
1.12 (t, 3H, J = 7.0 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.50 (d, 2H, J = 4.7 Hz), 5.77 (t, 1H,
J = 4.7 Hz), 7.01ꢀ7.05 (m, 2H), 7.10ꢀ7.15 (m, 1H), 7.16ꢀ7.20 (m, 2H), 7.37ꢀ7.42 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 13.9, 44.5, 60.8, 115.0 (d, 2JCF = 21.5 Hz), 116.1,
3
4
119.5, 123.4, 128.7 (d, JCF = 8.1 Hz), 129.1, 131.4, 134.4 (d, JCF = 3.5 Hz), 135.0,
1
145.2, 162.4 (d, JCF = 246.1 Hz), 163.6; IR (film): 2981, 1716, 1510, 1497, 1371
cmꢀ1; HRMS (ESI) m/z Calculated for C19H17FN2O2Na+ [M+Na]+ 347.1166, found:
347.1170.
14
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
ethyl 1ꢀphenylꢀ4ꢀ(thiophenꢀ2ꢀyl)ꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2i).
a
5
6
1
yellow oil (83.4 mg, 89% yield); H NMR (500 MHz, CDCl3) δ 1.18 (t, 3H, J = 7.1
Hz), 4.20 (q, 2H, J = 7.1 Hz), 4.46 (d, 2H, J = 4.8 Hz), 5.94 (t, 1H, J = 4.8 Hz),
6.92ꢀ6.93 (m, 1H), 6.98ꢀ7.00 (m, 1H), 7.10ꢀ7.13 (m, 1H), 7.23ꢀ7.25 (m, 1H),
7.35ꢀ7.37 (m, 3H), 7.38ꢀ7.40 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 44.2,
60.9, 116.1, 120.1, 123.4, 124.9, 125.5, 125.7, 127.0, 129.0, 135.4, 139.0, 145.2,
163.5; IR (film): 2979, 1717, 1597, 1496, 1372cmꢀ1; HRMS (ESI) m/z Calculated for
C17H16N2O2SNa+ [M+Na]+ 335.0825, found: 335.0826.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 4ꢀ(naphthalenꢀ1ꢀyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2j). a
yellow solid (96.2 mg, 90% yield, mp: 89ꢀ91 oC); 1H NMR (400 MHz, CDCl3) δ 0.66
(t, 3H, J = 7.1 Hz), 3.80 (q, 2H, J = 7.1 Hz), 4.54 (m, 1H), 4.76 (m, 1H), 5.90 (t, 1H, J
= 4.3 Hz), 7.13ꢀ7.17 (m, 1H), 7.34ꢀ7.36 (m, 1H), 7.41ꢀ7.50 (m, 7H), 7.78ꢀ7.88 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 13.3, 44.7, 60.4, 115.9, 121.6, 123.3, 125.1,
125.3, 125.7, 125.8, 126.2, 127.9, 128.3, 129.1, 130.9, 131.9, 133.2, 134.9, 136.9,
145.4, 163.2 ; IR (film): 3058, 2979, 1716, 1597, 1494, 1372 cmꢀ1; HRMS (ESI) m/z
Calculated for C23H20N2O2Na+ [M+Na]+ 379.1417, found: 379.1421.
ethyl 4ꢀ(cyclohexꢀ1ꢀenꢀ1ꢀyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2k).
a yellow oil (28.8 mg, 31% yield); 1H NMR (500 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.2
Hz), 1.58ꢀ1.64 (m, 2H), 1.65ꢀ1.70 (m, 2H), 2.00ꢀ2.04 (m, 2H), 2.08ꢀ2.13 (m, 2H),
4.28 (q, 2H, J = 7.2 Hz), 4.35 (d, 2H, J = 4.6 Hz), 5.60ꢀ5.66 (m, 1H), 5.65 (t, 1H, J =
13
4.6 Hz), 7.05ꢀ7.09 (m, 1H), 7.29ꢀ7.40 (m, 5H); C NMR (125 MHz, CDCl3) δ 14.2,
21.9, 22.7, 25.3, 28.4, 44.3, 60.8, 115.8, 117.3, 122.9, 124.6, 128.9, 134.2, 135.5,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
9
136.1, 145.5, 164.0; IR (film): 2978, 1712, 1597, 1495, 1457, 1372 cmꢀ1; HRMS
(ESI) m/z Calculated for C19H22N2O2Na+ [M+Na]+ 333.1573, found: 333.1578.
ethyl 1ꢀphenylꢀ4ꢀpropylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2l). a yellow oil
(65.3 mg, 80% yield); 1H NMR (500 MHz, CDCl3) δ 0.93 (t, 3H, J = 7.3 Hz), 1.38 (t,
3H, J = 7.2 Hz), 1.41ꢀ1.49 (m, 2H), 2.43ꢀ2.47 (m, 2H), 4.30 (q, 2H, J = 7.3 Hz),
4.36ꢀ4.38(m, 2H), 5.57ꢀ5.60 (m, 1H), 7.05ꢀ7.09 (m, 1H), 7.28ꢀ7.31 (m, 2H), 7.32ꢀ7.38
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 13.6, 14.2, 21.9, 34.1, 44.4, 60.6, 115.4,
117.9, 122.7, 128.9, 130.6, 133.9, 145.3, 164.0; IR (film): 3044, 2960, 1708, 1598,
1496, 1463, 1375 cmꢀ1; HRMS (ESI) m/z Calculated for C16H20N2O2Na+ [M+Na]+
295.1417, found: 295.1421.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 4ꢀ(4ꢀbromophenyl)ꢀ6ꢀmethylꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate
(2n). a yellow oil (111.4 mg, 93% yield); 1H NMR (500 MHz, CDCl3) δ 1.16 (t, 3H, J
= 7.1 Hz), 1.28 (d, 3H, J = 6.4 Hz), 4.16 (m, 2H), 5.10 (m, 1H), 5.75 (d, 1H, J = 6.9
Hz), 7.07ꢀ7.13 (m, 3H), 7.36ꢀ7.40 (m, 2H), 7.44ꢀ7.50 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 13.9, 16.5, 49.4, 60.8, 116.3, 121.5, 122.8, 123.4, 129.0, 129.2, 130.5, 131.0,
135.0, 137.5, 144.2, 163.4; IR (film): 2980, 1719, 1594, 1498, 1371 cmꢀ1; HRMS
(ESI) m/z Calculated for C20H19BrN2O2Na+ [M+Na]+ 421.0522 and 423.0502, found:
421.0525 and 423.0505.
ethyl 6ꢀethylꢀ1,4ꢀdiphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2o). a yellow oil
(94.3 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 1.00 (t, 3H, J = 7.6 Hz), 1.10 (t,
3H, J = 7.1 Hz), 1.61ꢀ1.72 (m, 1H), 1.80ꢀ1.92 (m, 1H), 4.14 (q, 2H, J = 7.1 Hz),
4.91ꢀ4.97 (m, 1H), 5.80 (d, 1H, J = 6.9 Hz), 7.08ꢀ7.12 (m, 1H), 7.21ꢀ7.24 (m, 2H),
16
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.31ꢀ7.40 (m, 5H), 7.49ꢀ7.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 8.2, 13.8, 23.9,
54.7, 60.6, 116.2, 121.0, 123.0, 127.3, 127.4, 127.9, 129.1, 131.9, 135.8, 138.5, 144.5,
163.6; IR (film): 2981, 1716, 1371 cmꢀ1; HRMS (ESI) m/z Calculated for
C21H22N2O2Na+ [M+Na]+ 357.1573, found: 357.1577.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2p). a
1
yellow oil (85.8 mg, 85% yield); H NMR (500 MHz, CDCl3) δ 1.05 (t, 3H, J = 7.2
Hz), 3.81 (s, 3H), 4.10 (q, 2H, J = 7.2 Hz), 4.46 (d, 2H, J = 4.7 Hz), 5.73 (t, 1H, J =
4.7 Hz), 6.92ꢀ6.95 (m, 2H), 7.20ꢀ7.22 (m, 2H), 7.30ꢀ7.35 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 13.8, 45.0, 55.6, 60.6, 114.3, 117.7, 118.2, 127.0, 127.4, 128.0, 132.4,
134.7, 138.5, 139.3, 156.2, 163.7,; IR (film): 2979, 1718, 1509, 1464, 1371 cmꢀ1;
HRMS (ESI) m/z Calculated for C20H20N2O3Na+ [M+Na]+ 359.1366, found:
359.1369.
ethyl 1ꢀ(4ꢀnitrophenyl)ꢀ4ꢀphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2q). a
1
yellow solid (103.3 mg, 98% yield, mp: 146ꢀ148 oC); H NMR (500 MHz, CDCl3) δ
1.06 (t, 3H, J = 7.1 Hz), 4.12 (q, 2H, J = 7.1 Hz), 4.62 (d, 2H, J = 4.5 Hz), 6.01 (t, 1H,
J = 4.5 Hz), 7.19ꢀ7.22 (m, 2H), 7.33ꢀ7.38 (m, 3H), 7.40ꢀ7.44 (m, 2H), 8.25ꢀ8.28 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 13.7, 44.5, 61.3, 114.6, 122.2, 125.2, 126.8,
128.0, 128.3, 131.7, 137.3, 138.5, 142.4, 149.9, 163.2; IR (film): 2919, 1724, 1594,
1496, 1341 cmꢀ1; HRMS (ESI) m/z Calculated for C19H17N3O4Na+ [M+Na]+ 374.1111,
found: 374.1113.
ethyl 1,4ꢀbis(4ꢀbromophenyl)ꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (2r). a yellow
solid (126.7 mg, 91% yield, mp: 132ꢀ134 oC); 1H NMR (500 MHz, CDCl3) δ 1.12 (t,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
8
9
3H, J = 7.1 Hz), 4.12 (q, 2H, J = 7.1 Hz), 4.45 (d, 2H, J = 4.6 Hz), 5.80 (t, 1H, J = 4.6
Hz), 7.05ꢀ7.08 (m, 2H), 7.21ꢀ7.24 (m, 2H), 7.44ꢀ7.49 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 13.9, 44.4, 61.0, 116.2, 117.4, 120.4, 121.7, 128.7, 131.2, 131.3, 132.0,
135.1, 137.1, 144.2, 163.3; IR (film): 2979, 1720, 1558, 1487, 1370 cmꢀ1; HRMS
(ESI) m/z Calculated for C19H16Br2N2O2Na+ [M+Na]+ 486.9450 and 484.9471, found:
486.9455 and 484.9476.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,4ꢀdiphenylꢀ3ꢀ(trifluoromethyl)ꢀ1,6ꢀdihydropyridazine (2t). a yellow solid (74.3
o
mg, 82% yield, mp: 108ꢀ110 C); 1H NMR (400 MHz, CDCl3) δ 4.58 (d, 2H, J = 4.3
Hz), 5.80 (t, 1H, J = 4.3 Hz), 7.11ꢀ7.15 (m, 1H), 7.28ꢀ7.34 (m, 4H), 7.35ꢀ7.44 (m, 5H);
1
13C NMR (100 MHz, CDCl3) δ 44.5, 115.2, 122.7, 122.9, 124.1 (q, JCF = 272 Hz),
4
2
128.0, 128.1, 128.4 (q, JCF = 1 Hz), 129.1, 130.3, 131.0 (q, JCF = 32 Hz), 136.4,
145.1; IR (film): 3062, 1597, 1378 cmꢀ1; HRMS (ESI) m/z Calculated for
C17H13F3N2Na+ [M+Na]+ 325.0923, found: 325.0925.
1,4ꢀdiphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarbaldehyde (2u). a yellow solid (71.6 mg,
91% yield, mp: 122ꢀ124 oC); 1H NMR (400 MHz, CDCl3) δ 4.65 (d, 2H, J = 4.2 Hz),
5.75 (td, 1H, J1 = 4.2 and J2 = 0.6 Hz), 7.21ꢀ7.25 (m, 3H), 7.34ꢀ7.38 (m, 3H),
7.46ꢀ7.48 (m, 4H), 9.47 (d, 1H, J = 0.6 Hz); 13C NMR (100 MHz, CDCl3) δ 45.7,
116.1, 120.0, 124.3, 127.6, 127.7, 127.8, 129.1, 131.0, 136.8, 139.8, 144.5, 187.7; IR
(film): 3057, 2923, 1683, 1595 cmꢀ1; HRMS (ESI) m/z Calculated for C17H14N2ONa+
[M+Na]+ 285.0998, found: 285.1001.
3,4ꢀbis(4ꢀbromophenyl)ꢀ1ꢀphenylꢀ1,6ꢀdihydropyridazine (2w) a yellow solid (63.2
mg, 45% yield, mp: 242ꢀ244 oC); 1H NMR (500 MHz, CDCl3) δ 4.40 (d, 2H, J = 5.1
18
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz), 6.11 (t, 1H, J = 5.1 Hz), 6.92ꢀ6.95 (m, 2H), 7.03ꢀ7.07 (m, 1H), 7.20ꢀ7.23 (m, 2H),
7.32ꢀ7.40 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 43.3, 115.2, 121.6, 121.7, 121.9,
122.7, 129.0, 129.5, 129.7, 131.0, 131.4, 131.9, 135.4, 137.0, 143.5, 146.2; IR (film):
3063, 1597, 1498 cmꢀ1; HRMS (ESI) m/z Calculated for C22H16Br2N2Na+ [M+Na]+
490.9552 and 488.9572, found: 490.9556 and 488.9576.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 5ꢀmethylꢀ1,4ꢀdiphenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate (3a). a yellow solid (57.0
1
mg, 62% yield); H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H, J = 7.2 Hz), 2.2 (s, 3H),
4.3 (q, 2H, J = 7.2 Hz), 7.36ꢀ7.40 (m, 3H), 7.42ꢀ7.47 (m, 3H), 7.50ꢀ7.55 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 11.3, 14.1, 60.7, 124.3, 125.6, 127.2, 127.9, 128.6, 129.2,
130.3, 132.5, 138.5, 139.3, 141.0, 162.5; HRMS (ESI) m/z Calculated for
+
C19H19N2O2 [M+H]+ 307.1441, found: 307.1445.
ethyl (Z)ꢀ3ꢀphenylpentaꢀ2,4ꢀdienoate (4x). a yellow oil; 1H NMR (400 MHz, CDCl3)
δ 1.06 (t, 3H, J = 7.2 Hz), 3.99 (q, 2H, J = 7.2 Hz), 5.07ꢀ5.12 (m, 1H), 5.43ꢀ5.47 (m,
1H), 5.98 (s,1H),6.64 (ddd, 1H, J1 = 17.2, J2 = 10.4, and J3 = 0.4 Hz), 7.12ꢀ7.15 (m,
2H), 7.32ꢀ7.40 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 13.9, 59.9, 120.4, 123.6,
127.5, 127.7, 128.3, 136.4, 139.5, 154.6, 165.9; IR (film): 2926, 1724, 1623, 1594,
+
1446, 1375 cmꢀ1; HRMS (ESI) m/z Calculated for C13H15O2 [M+H]+ 203.1067,
found: 203.1070.
1
ethyl (E)ꢀ3ꢀphenylpentaꢀ2,4ꢀdienoate (4x’). a yellow oil; H NMR (500 MHz,
CDCl3) δ 1.31 (t, 3H, J = 7.2 Hz), 4.22 (q, 2H, J = 7.2 Hz), 5.29ꢀ5.33 (m, 1H),
5.58ꢀ5.61 (m, 1H), 5.81ꢀ5.82 (m,1H), 7.30ꢀ7.38 (m, 5H), 7.93 (ddd, 1H, J1 = 17.4, J2
= 10.8, and J3 = 0.6 Hz); 13C NMR (125 MHz, CDCl3) δ 14.3, 60.0, 118.4, 124.9,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
128.1, 128.5, 128.9, 133.8, 139.4, 155.5, 166.0; IR (film): 2922, 1724, 1625, 1595,
5
6
7
+
1443, 1378 cmꢀ1; HRMS (ESI) m/z Calculated for C13H15O2 [M+H]+ 203.1067,
8
9
found: 203.1070.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 1,4ꢀbis(4ꢀbromophenyl)ꢀ6ꢀoxoꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarboxylate (5a). a
1
white solid (239.0 mg, 100% yield, mp: 184ꢀ186 oC); H NMR (400 MHz, CDCl3) δ
1.15 (t, 3H, J = 7.2 Hz), 4.21 (q, 2H, J = 7.2 Hz), 6.96 (s, 1H), 7.21ꢀ7.25 (m, 2H),
7.57ꢀ7.64 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 13.7, 62.4, 122.6, 124.2, 126.8,
128.9, 129.6, 132.0, 133.5, 138.7, 139.5, 143.9, 158.9, 162.9; IR (film): 2918, 1727,
+
1670, 1469, 1376 cmꢀ1; HRMS (ESI) m/z Calculated for C19H15Br2N2O3 [M+H]+
478.9423 and 476.9444, found: 478.9428 and 476.9449.
2,5ꢀdiphenylꢀ6ꢀ(trifluoromethyl)pyridazinꢀ3(2H)ꢀone (5b). a white solid (153.4 mg,
o
1
97% yield, mp: 131ꢀ132 C); H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 7.37ꢀ7.40
(m, 2H), 7.43ꢀ7.55 (m, 6H), 7.69ꢀ7.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 123.3
1
4
(q, JCF = 272 Hz), 125.0, 127.9 (q, JCF = 1 Hz), 128.5, 128.93, 128.98, 129.6, 131.8,
133.3, 135.0 (q, 2JCF = 32 Hz), 140.4, 144.3, 158.9; IR (film): 2919, 1683, 1490 cmꢀ1;
HRMS (ESI) m/z Calculated for C17H12F3N2O+ [M+H]+ 317.0896, found: 317.0900.
6ꢀoxoꢀ1,4ꢀdiphenylꢀ1,6ꢀdihydropyridazineꢀ3ꢀcarbaldehyde (5c). a white solid
o
(121.6 mg, 88% yield, mp: 199ꢀ201 C); 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H),
7.35ꢀ7.39 (m, 2H), 7.45ꢀ7.51 (m, 4H), 7.52ꢀ7.58 (m, 2H), 7.70ꢀ7.73 (m, 2H), 9.83 (s,
13
1H); C NMR (100 MHz, CDCl3) δ 125.2, 128.1, 128.4, 129.0, 129.1, 129.6, 130.0,
133.4, 140.6, 140.7, 145.2, 159.3, 187.5; IR (film): 2919, 1705, 1663, 1470 cmꢀ1;
+
HRMS (ESI) m/z Calculated for C17H13N2O2 [M+H]+ 277.0972, found: 277.0975.
20
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Supporting Information.
8
9
1H and13C NMR spectra of all products and crystallographic data (CIF) of 2r. This
material is available free of charge via the Internet at http://pubs.acs.org.
Corresponding Author.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*Eꢀmail: zpzhan@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (No.
21272190) NFFTBS (No. J1310024), and PCSIRT in University is gratefully
acknowledged.
REFERENCES
(1) (a) Wermuth, C. G. MedChemComm, 2011, 2, 935. (b) Wermuth, C. G.; Schlewer, G.;
Bourguignon, J. J.; Maghioros, G.; Bouchet, M. J.; Moire, C.; Kan, J. P.; Worms, P.; Biziere, K. J.
Med. Chem., 1989, 32, 528. (c) Nomoto, Y.; Takai, H.; Ohno, T.; Nagashima, K.; Yao, K.; Yamada,
K.; Kubo, K.; Ichimura, M.; Mihara, A.; Kase, H. J. Med. Chem., 1996, 39, 297.
(2) (a) Coates, W. J. In Comprehensive Heterocyclic Chemistry II, vol. 6; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V. Elsevier Science Ltd, 1996. (b) Gökçe, M.; Utku, S.; Küpeli, E. Eur. J.
Med. Chem., 2009, 44, 3760. (c) Rathish, I. G.; Javed, K.; Bano, S.; Ahmad, S.; Alam, M. S.;
Pillai, K. K. Eur. J. Med. Chem. 2009, 44, 2673. (d) Sönmez, M.; Berber, Đ.; Akbaꢁ, E. Eur. J.
Med. Chem., 2006, 41, 101.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
8
9
(3) (a) Scarsdale, B. L.; Ossining, H. J.; Shroff, J. R.; Conn. R. U.S. Patent 1984, No.
4435395.(b) Riehen, A. V. U.S. Patent 1985, No. 4491581. (c) Frankowiak, G.; Meyer, H.;
Bossert, F.; Heise, A.; Kazda, S.; Stoepel, K.; Towart, R.; Wehinger, E. U.S. Patent 1982, No.
4348395.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Das, A.; Volla, C. M.; Atodiresei, I.; Bettray, W.; Rueping, M. Angew. Chem. Int. Ed.,
2013, 52, 8008. (b) Wu, W.; Yuan, X.; Hu, J.; Wu, X.; Wei, Y.; Liu, Z.; Lu, J.; Ye, J. Org. Lett.,
2013, 15, 4524. (c) Siddiqui, I. R.; Rahila; Rai, P.; Sagir, H.; Waseem, M. A. RSC Adv., 2015, 5,
52355. (d) Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.; Mantellini, F. J. Org. Chem.,
1998, 63, 9880 (e) Pitacco, G.; Attanasi, O. A.; Crescentini, L. D.; Favi, G.; Felluga, F.; Forzato,
C.; Mantellini, F.; Nitti, P.; Valentin, E.; Zangrando, E. Tetrahedron: Asymmetry, 2010, 21, 617. (f)
Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc., 1959, 81, 4342. (g) Zhang, C. J.; Tan, C. Y.; Ge,
J.; Na, Z.; Chen, G. Y. Angew. Chem. Int. Ed., 2013, 52, 14060.
(5) (a) Carlson, B. A.; Sheppard, W. A.; Webster, O. W. J. Am. Chem. Soc., 1975, 97, 5291. (b)
Picherit, C.; Wagner, F.; Uguen, D. Tetrahedron Lett, 2004, 45, 2579.
(6) Lopes, S. M. M.; Henriques, M. S. C.; Paixão, J. A.; Pinho e Melo, T. M. V. D. Eur. J. Org.
Chem., 2015, 6146.
(7) (a) Obradors, C.; Echavarren, A. M. Acc. Chem. Res., 2014, 47, 902. (b) Kazem Shiroodi,
R.; Gevorgyan, V. Chem. Soc. Rev., 2013, 42, 4991.
(8) (a) Martín Castro, A. M. Chem. Rev., 2004, 104, 2939. (b) Zhang, L.; Sun, J.; Kozmin, S. A.
Adv. Synth. Catal., 2006, 348, 2271. (c) Wang, S.; Zhang, G. Zhang, L. Synlett, 2010, 692. (d)
Majumdar, K.; Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B. Synthesis, 2009, 2117. (e)
Majumdar, K. C. Synlett, 2008, 2400.
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
(9) (a) Zhu, Y.; Tang, H.ꢀT.; Zhan, Z.ꢀP. Adv. Synth. Catal., 2013, 355, 1291. (b) Wen, J.ꢀJ.;
Tang, H.ꢀT.; Xiong, K.; Ding, Z.ꢀC.; Zhan, Z.ꢀP. Org. Lett., 2014, 16, 5940.
7
8
9
(10) (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature, 2011, 473, 470. (b) Muller, K.; Faeh, C.;
Diederich, F. Science, 2007, 317, 1881. (c) Purser, S.; Morre, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev., 2008, 37, 320. (d) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier: Amsterdam, 1993. (e)
Hagmann, W. K. J. Med. Chem., 2008, 51, 4359. (f) Yamazaki, T.; Taguchi, T.; Ojima, I. In
Fluorine in Medicinal Chemistry and Chemical Biology, ed. Ojima, I. WileyꢀBlackwell,
Chichester, 2009.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) (a) Menz, H.; Kirsch, S. F. Org. Lett., 2006, 8, 4795. (b) Xin, X. Y.; Wang, D. P.; Wu, F.; Li,
X. C.; Wan, B. S. J. Org. Chem, 2013, 78, 4065. (c) Undeela, S.; Thadkapally, S.; Nanubolu, J. B.;
Singarapu, K. K.; Menon, R. S. Chem. Commun., 2015, 51, 13748.
23
ACS Paragon Plus Environment