Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
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 1,6dihydropyridazines 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.
D
Scheme 1. Different Cyclization Reactions of OlefinSubstituted Hydrazones
ihydropyridazine derivatives have been found in many bioactive compounds and pharmaceuticals.1,2 In the past 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 1,6dihydropyridazines 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 olefinsubstituted 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 hydrazones with amines has been developed by the group of Wang and Li.9 In addition, γ,δ-unsaturated hydrazones undergo 5-exotrig 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 5exo-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 © XXXX American Chemical Society
reported a copper-promoted 6-endo-trig cyclization of β,γunsaturated hydrazones for the synthesis of 1,6-dihydropyridazines (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
A
DOI: 10.1021/acs.orglett.8b01240 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Copper-Promoted Cyclization of β,γ-Unsaturated Hydrazonesa
entry
Cu salts (x equiv)
solvent
temp (°C)
yield (%)
1 2 3 4 5 6 7 8b 9 10 11 12
Cu(OAc)2 (0.2) CuBr2 (0.2) CuCl2 (0.2) CuI (0.2) 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)
CH3CN CH3CN CH3CN CH3CN toluene DMSO DMF CH3CN CH3CN CH3CN CH3CN CH3CN
70 70 70 70 70 70 70 70 70 70 100 60
15 0 0 0 8 6 10 45 83 81 75 65
a
Reaction conditions: 1a (0.2 mmol), Cu salts (x equiv), solvent (2 mL), air; isolated yield. bHOAc (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-dihydropyridazines. 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 electronwithdrawing groups such as trifluoromethyl and ester groups were also tolerated and afforded the corresponding 1,6dihydropyridazines 2i,j,l,m,o−r in good yields. 2-Methyl-, 2methoxy-, 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 1,6dihydropyridazine 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-1ylidene)acetohydrazide 1v or (E)-N′-(6,10-dimethylundeca1,9-dien-4-ylidene)acetohydrazide 1w was used as the substrate. Next, β,γ-unsaturated hydrazones bearing different substituents 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 1,6dihydropyridazines 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
Letter
Organic Letters Table 2. Copper-Promoted Cyclization of Various Hydrazones 1a
Scheme 3. Further Transformation of 1,6Dihydropyridazines 2
To gain insight into the reaction mechanism, radical-trapping experiments have been carried out under the standard conditions (Scheme 4). When the radical scavenger 2,2,6,6Scheme 4. Control Experiments
tetramethylpiperdin-1-oxyl (TEMPO), butylated hydroxytoluene (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 Nradical cascade reaction or dehydrogenative amination of β-1styrene- 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 (2 mL), 70 °C, air, 30 min; isolated yield. b100 °C.
Scheme 5. Possible Reaction Mechanism
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-phenylbut-3-en-1-ylidene)acetohydrazide 1ac was employed as the substrate (Table 2, entry 6). To demonstrate the synthetic utility of this reaction, 1,6dihydropyridazines 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, 1,6dihydropyridazines 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 1,6dihydropyridazine 2 and Cu(0). Alternatively, oxidation of the intermediate B by Cu(OAc)2 produces the 1,6-dihydropyridazine 2 and CuOAc. C
DOI: 10.1021/acs.orglett.8b01240 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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. Res. 2018, 51, 484. (b) Xia, Y.; Wang, J. Chem. Soc. Rev. 2017, 46, 2306. (c) Kölmel, D. K.; Kool, E. T. Chem. Rev. 2017, 117, 10358. (d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (7) (a) Zhu, M.-K.; Chen, Y.-C.; Loh, T.-P. Chem. - Eur. J. 2013, 19, 5250. (b) Duan, X.-Y.; Yang, X.-L.; Jia, P.-P.; Zhang, M.; Han, B. Org. Lett. 2015, 17, 6022. (c) Wei, Q.; Chen, J.-R.; Hu, X.-Q.; Yang, X.-C.; Lu, B.; Xiao, W.-J. Org. Lett. 2015, 17, 4464. (d) Hu, X.-Q.; Chen, J.; Chen, J.-R.; Yan, D.-M.; Xiao, W.-J. Chem. - Eur. J. 2016, 22, 14141. (e) Pünner, F.; Sohtome, Y.; Sodeoka, M. Chem. Commun. 2016, 52, 14093. (f) Yang, M.-N.; Yan, D.-M.; Zhao, Q.-Q.; Chen, J.-R.; Xiao, W.-J. Org. Lett. 2017, 19, 5208. (g) Zhao, Q.-Q.; Chen, J.; Yan, D.-M.; Chen, J.-R.; Xiao, W.-J. Org. Lett. 2017, 19, 3620. (h) Yang, X.-L.; Peng, X.-X.; Chen, F.; Han, B. Org. Lett. 2016, 18, 2070. (i) Duan, X.Y.; Yang, X.-L.; Fang, R.; Peng, X.-X.; Yu, W.; Han, B. J. Org. Chem. 2013, 78, 10692. (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.N.; Li, W. Org. Lett. 2018, 20, 510. (10) Duan, X.-Y.; Zhou, N.-N.; Fang, R.; Yang, X.-L.; Yu, W.; Han, B. Angew. Chem., Int. Ed. 2014, 53, 3158. (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-styreneor 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.
In summary, we have developed a copper-promoted 6-endotrig 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-dihydropyridazines 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 S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01240. Detailed experimental procedures, characterization data, and NMR spectra for all products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zheng-Hui Guan: 0000-0003-4901-5951 Notes
The authors declare no competing financial interest.
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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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REFERENCES
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DOI: 10.1021/acs.orglett.8b01240 Org. Lett. XXXX, XXX, XXX−XXX
