Copper-Promoted 6- endo-trig Cyclization of β,γ-Unsaturated Hydrazones for the Synthesis of 1,6-Dihydropyridazines

Article abstract of DOI:10.1021/acs.orglett.8b01240

A novel and efficient strategy for the synthesis of 1,6-dihydropyridazines via copper-promoted 6-endo-trig cyclization of readily available β,γ-unsaturated hydrazones have been developed. A series of 1,6-dihydropyridazines have been synthesized by this method with good yields, high functional group tolerance, and remarkable regioselectivity under mild conditions. Importantly, the 1,6-dihydropyridazines can be efficiently converted to biologically important pyridazines in the presence of NaOH.

Full text of DOI:10.1021/acs.orglett.8b01240

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Promoted 6-endo-trig Cyclization of β,γ-Unsaturated
Hydrazones for the Synthesis of 1,6-Dihydropyridazines
Yong-Qiang Guo,† Mi-Na Zhao,† Zhi-Hui Ren,† and Zheng-Hui Guan*,†
†Key Laboratory of Synthetic and Nature Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials
Science, Northwest University, Xi’an 710127, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient strategy for the synthesis of 1,6-
dihydropyridazines via copper-promoted 6-endo-trig cyclization of
readily available β,γ-unsaturated hydrazones have been developed. A
series of 1,6-dihydropyridazines have been synthesized by this method
with good yields, high functional group tolerance, and remarkable
regioselectivity under mild conditions. Importantly, the 1,6-dihydro-
pyridazines can be efficiently converted to biologically important pyridazines in the presence of NaOH.
ihydropyridazine derivatives have been found in many
bioactive compounds and pharmaceuticals.1,2 In the past
Scheme 1. Different Cyclization Reactions of Olefin-
Substituted Hydrazones
D
few decades, a number of methods have been developed for the
synthesis of various dihydropyridazines.3 However, most of
these methods are focused on versatile 1,4-dihydropyridazines,
and protocols for the synthesis of 1,6-dihydropyridazines have
been less developed. The existing synthetic strategies for the
1,6-dihydropyridazines mainly rely on the cycloaddition of
aromatic diazonium salts with dienes4 or [4 + 2]-cycloaddition
of α-halogenated hydrazones with alkenes.5 Despite these
fascinating achievements, the development of novel and
efficient methods for the straightforward synthesis of 1,6-
dihydropyridazines that are compatible with various functional
groups and use readily available starting materials remain highly
desirable.
Hydrazones and their derivatives are versatile building blocks
in organic synthesis because of their ready accessibility and high
reactivity.6 In recent years, intramolecular cyclization of olefin-
substituted hydrazones for the synthesis of azaheterocycles have
been intensively investigated (Scheme 1, eq 1).7 For instance,
visible-light photocatalytic hydroamination of β,γ-unsaturated
hydrazones for the synthesis of 4,5-dihydropyrazoles has been
developed by Chen and Xiao’s group.8 Copper-catalyzed intra-/
intermolecular alkene diamination of β,γ-unsaturated hydra-
zones with amines has been developed by the group of Wang
and Li.9 In addition, γ,δ-unsaturated hydrazones undergo 5-exo-
trig radical cyclization at the N2 atom to synthesize azomethine
imines has been developed by Han and co-workers.10 Recently,
palladium-catalyzed aminomethylamination/aromatization of
β,γ-unsaturated hydrazones with aminals for the construction
of β-aminoethylpyrazoles has been developed by the group of
Huang.11 However, these reactions have been restricted to 5-
exo-trig cyclization, whereas 6-endo-trig cyclization reaction has
scarcely been developed,12 probably because the Gibbs free
energy of the transition states for 5-exo-trig cyclization is lower
than its 6-endo-trig variant.12a Therefore, the development of a
novel and efficient 6-endo-trig cyclization of olefin substituted
hydrazones is still a challenging task. In this paper, we have
reported a copper-promoted 6-endo-trig cyclization of β,γ-
unsaturated hydrazones for the synthesis of 1,6-dihydropyr-
idazines (Scheme 1, eq 2).
We began our study by investigating the copper-catalyzed
cyclization reaction of (E)-N′-(1-phenylbut-3-en-1-ylidene)-
acetohydrazide 1a in CH3CN at 70 °C. Unexpectedly, the 1-
(3-phenylpyridazin-1(6H)-yl)ethanone 2a was obtained in 15%
yield in the presence of Cu(OAc)2 catalyst (Table 1, entry 1).
Formation of 2a could be explained through the intramolecular
6-endo-trig cyclization of β,γ-unsaturated hydrazone 1a. This
interesting result encouraged us to optimize the reaction
conditions to provide a general protocol for the synthesis of
1,6-dihydropyridazines.
Received: April 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Copper-Promoted Cyclization of β,γ-Unsaturated
Hydrazones
a
entry
Cu salts (x equiv)
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
Cu(OAc)2 (0.2)
CuBr2 (0.2)
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMSO
DMF
70
70
70
70
70
70
70
70
70
70
100
60
15
0
CuCl2 (0.2)
0
CuI (0.2)
0
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (1.2)
Cu(OAc)2 (1.5)
Cu(OAc)2 (1.2)
Cu(OAc)2 (1.2)
8
6
10
45
83
81
75
65
b
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
a
Reaction conditions: 1a (0.2 mmol), Cu salts (x equiv), solvent (2
b
mL), air; isolated yield. HOAc (2.0 equiv) was added.
A series of copper catalysts were then screened to examine if
they could improve the reaction efficiency. However, no desired
reaction occurred when other Cu salts, such as CuBr2, CuCl2,
or CuI, were used as catalyst (Table 1, entries 2−4). No
improvement was observed when toluene, DMSO, or DMF was
used as the solvent (Table 1, entries 5−7). Next, various
oxidants, ligands, and additives, such as O2, K2S2O8, 2,2′-
dipyridyl, 1,10-phenanthroline, and HOAc, were screened for
further improving the reaction outcome. It was found that 45%
yield of 2a was obtained in the presence of HOAc (2.0 equiv)
(Table 1, entry 8). However, no further improvement could be
obtained. Therefore, the loading of the Cu(OAc)2 was
increased (Table 1, entries 9 and 10). It was found that the
significantly improved reaction yield (83%) was obtained in the
presence of 1.2 equiv of Cu(OAc)2 (Table 1, entry 9). Finally,
the reaction temperature was also varied, and 70 °C gave the
best result (Table 1, entries 11 and 12).
With the optimized reaction conditions established, a series
of β,γ-unsaturated hydrazones were investigated for extending
the substrate scope (Scheme 2). This reaction displayed high
functional group tolerance and proved to be a quite general
methodology for preparation of substituted 1,6-dihydropyr-
idazines. Hydrazones with electron-donating groups on aryl
rings, such as methyl, tert-butyl, methoxyl, and [1,3]dioxole, all
gave the corresponding 1,6-dihydropyridazines 2b,c,e,f,h in
67−85% yields. Hydrazones with an electron-withdrawing
group such as fluoro, chloro, bromo, and strong electron-
withdrawing groups such as trifluoromethyl and ester groups
were also tolerated and afforded the corresponding 1,6-
dihydropyridazines 2i,j,l,m,o−r in good yields. 2-Methyl-, 2-
methoxy-, 2-fluoro-, or 2-chloro-substituted hydrazones 1d, 1g,
1k, or 1n reacted smoothly and resulted in the desired products
2d, 2g, 2k, and 2n in moderate yields. These results indicate
that this transformation was sensitive to steric hindrance on the
aromatic rings of the substrates. 2-Naphthyl hydrazone 1s
participated in the reaction smoothly to give the desired 1,6-
dihydropyridazine 2s in 71% yield. In addition, heterocyclic
substituted substrates, such as furyl hydrazone 1t and thienyl
hydrazone 1u, also proceeded smoothly to give the
a
Reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (1.2 equiv), CH3CN
(2 mL), 70 °C, air, 30 min; isolated yield.
corresponding 1,6-dihydropyridazines 2t,u in 65% and 61%
yields, respectively. However, no reaction occurred when an
aliphatic hydrazone such as (E)-N′-(1-cyclohexylbut-3-en-1-
ylidene)acetohydrazide 1v or (E)-N′-(6,10-dimethylundeca-
1,9-dien-4-ylidene)acetohydrazide 1w was used as the substrate.
Next, β,γ-unsaturated hydrazones bearing different substitu-
ents on the nitrogen atom or olefin moiety were investigated to
extend the substrate scope (Table 2). Hydrazones with
different groups on the nitrogen atom, such as tert-butyrate,
and benzoate reacted efficiently to give corresponding 1,6-
dihydropyridazines 2x,y in 75% and 63% yields (Table 2,
entries 1 and 2). Notably, β,γ-unsaturated hydrazone with a
phenyl group on the γ-position exhibited good reactivity and
gave the corresponding 1,6-dihydropyridazine 2z in 62% yield
(Table 2, entry 3). Substrates with a phenyl or methyl group on
B
DOI: 10.1021/acs.orglett.8b01240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Copper-Promoted Cyclization of Various
Hydrazones 1
Scheme 3. Further Transformation of 1,6-
Dihydropyridazines 2
a
To gain insight into the reaction mechanism, radical-trapping
experiments have been carried out under the standard
conditions (Scheme 4). When the radical scavenger 2,2,6,6-
Scheme 4. Control Experiments
tetramethylpiperdin-1-oxyl (TEMPO), butylated hydroxyto-
luene (BHT), or 1,1-diphenylethene was added to the reaction,
the desired product 2a was obtained in 42%, 56%, and 67%
yields, respectively. These results indicate that the radical
mechanism was less likely. Although the precise reaction
mechanism is not clear at this moment, the reaction mechanism
should be different from the visible-light photocatalytic N-
radical cascade reaction or dehydrogenative amination of β-1-
styrene- or β-2-prop-1-ene-substituted hydrazones, which was
apparently a radical pathway.12
On the basis of the aforementioned results and previous
studies,13 a tentative mechanism for the reaction is proposed in
Scheme 5. Initially, oxidation of the hydrazone 1 by Cu(OAc)2
a
Reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (1.2 equiv), CH3CN
Scheme 5. Possible Reaction Mechanism
b
(2 mL), 70 °C, air, 30 min; isolated yield. 100 °C.
the β-position of the olefin moiety were also tolerated in the
reaction to give the desired products 2aa,ab in 92% and 67%
yields, respectively (Table 2, entries 4 and 5). Additionally, 1-
(4,4-dimethyl-3-phenylpyridazin-1(4H)-yl)ethanone 2ac was
obtained in 67% yield when (E)-N′-(2,2-dimethyl-1-phenyl-
but-3-en-1-ylidene)acetohydrazide 1ac was employed as the
substrate (Table 2, entry 6).
To demonstrate the synthetic utility of this reaction, 1,6-
dihydropyridazines were subjected to further transformation
(Scheme 3). The biologically important pyridazines 3 could be
easily synthesized from the 1,6-dihydropyridazines 2 in the
presence of NaOH in CH3CN at 90 °C. For example, 1,6-
dihydropyridazines 2a and 2o were easily transformed into the
corresponding pyridazines 3a and 3o in 95% and 96% yields.
The thienyl-substituted dihydropyridazine 2u shows similar
reactivity with 2a to give the corresponding pyridazine 3u in
93% yield. In addition, 3,5-diphenylpyridazine 3aa was also
obtained in 97% yield when 1-(3,5-diphenylpyridazin-1(6H)-
yl)ethanone 2aa was used as the substrate.
forms the copper complex A. Intramolecular cyclization of the
copper complex A affords the intermediate B. Then β-H
elimination of the intermediate B generates the 1,6-
dihydropyridazine 2 and Cu(0). Alternatively, oxidation of
the intermediate B by Cu(OAc)2 produces the 1,6-dihydropyr-
idazine 2 and CuOAc.
C
DOI: 10.1021/acs.orglett.8b01240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
S.; Chen, J.-R.; Hu, X.-Q.; Cheng, H.-G.; Lu, L.-Q.; Xiao, W.-J. Adv.
Synth. Catal. 2013, 355, 3539.
(6) For reviews, see: (a) Xu, P.; Li, W.; Xie, J.; Zhu, C. Acc. Chem.
In summary, we have developed a copper-promoted 6-endo-
trig cyclization of β,γ-unsaturated hydrazones for the synthesis
of 1,6-dihydropyridazines. The reaction employs readily
available starting materials, tolerates a wide range of functional
groups, and provides a practical protocol for the synthesis of
1,6-dihydropyridazines in good yields. The 1,6-dihydropyrida-
zines can be easily transformed into biologically important
pyridazine derivatives. Further scope and mechanism studies of
the reaction are currently in progress in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
(e) Punner, F.; Sohtome, Y.; Sodeoka, M. Chem. Commun. 2016, 52,
̈
S
14093. (f) Yang, M.-N.; Yan, D.-M.; Zhao, Q.-Q.; Chen, J.-R.; Xiao,
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Y.; Yang, X.-L.; Fang, R.; Peng, X.-X.; Yu, W.; Han, B. J. Org. Chem.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01240.
Detailed experimental procedures, characterization data,
and NMR spectra for all products (PDF)
(8) Hu, X.-Q.; Chen, J.-R.; Wei, Q.; Liu, F.-L.; Deng, Q.-H.;
Beauchemin, A. M.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 12163.
(9) Chen, M.; Wang, L.-J.; Ren, P.-X.; Hou, X.-Y.; Fang, Z.; Han, M.-
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(10) Duan, X.-Y.; Zhou, N.-N.; Fang, R.; Yang, X.-L.; Yu, W.; Han, B.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guanzhh@nwu.edu.cn.
ORCID
(11) Li, L.; Liu, P.; Su, Y.; Huang, H. Org. Lett. 2016, 18, 5736.
(12) DFT calculations show that the Gibbs free energy of the
transition states for 6-endo-trig cyclization would be slightly lower than
its 5-exo-trig variant only when β-styrenyl-substituted hydrazones were
employed as the substrates; thus, the reported 6-endo-trig cyclization
reaction of β,γ-unsaturated hydrazones was restricted to β-1-styrene-
or β-2-prop-1-ene-substituted hydrazones; see: (a) Hu, X.-Q.; Qi, X.;
Chen, J.-R.; Zhao, Q.-Q.; Wei, Q.; Lan, Y.; Xiao, W.-J. Nat. Commun.
2016, 7, 11188. (b) Jiang, D.-F.; Hu, J.-Y.; Hao, W.-J.; Wang, S.-L.; Tu,
S.-J.; Jiang, B. Org. Chem. Front. 2018, 5, 189.
(13) (a) Shen, K.; Wang, Q. J. Am. Chem. Soc. 2017, 139, 13110.
(b) Khoder, Z. M.; Wong, C. E.; Chemler, S. R. ACS Catal. 2017, 7,
4775. (c) Du, W.; Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H.
Chem. Commun. 2014, 50, 7437. (d) Bovino, M. T.; Chemler, S. R.
Angew. Chem., Int. Ed. 2012, 51, 3923. (e) Yu, X.; Zhou, F.; Chen, J.;
Xiao, W. Acta Chim. Sinica 2017, 75, 86.
Zheng-Hui Guan: 0000-0003-4901-5951
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (216222203 and
21472147), China Postdoctoral Science Foundation Funded
Project (2017M620466), and the PhD Scientific Research
Project of Baoji University of Arts and Sciences (ZK2018057).
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DOI: 10.1021/acs.orglett.8b01240
Org. Lett. XXXX, XXX, XXX−XXX