Letter pubs.acs.org/OrgLett
Photocatalytic Hydrazonyl Radical-Mediated Radical Cyclization/ Allylation Cascade: Synthesis of Dihydropyrazoles and Tetrahydropyridazines Quan-Qing Zhao,† Jun Chen,† Dong-Mei Yan,† Jia-Rong Chen,*,† and Wen-Jing Xiao†,‡ †
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticides and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China S Supporting Information *
ABSTRACT: A novel photocatalytic hydrazonyl radical-mediated radical cyclization/allylation cascade reaction of β,γ-unsaturated hydrazones is developed using allyl sulfones and Morita−Baylis− Hillman adduct as allyl sources, which provides an efficient and practical access to various diversely functionalized dihydropyrazoles and tetrahydropyridazines. The reaction is enabled by controllable generation of hydrazonyl radicals via an oxidative deprotonation electron transfer strategy and selective trapping of the resultant Ccentered radicals under visible light irradiation.
D
hydrazonyl radical-mediated cyclization has emerged as new powerful platform for their assembly.4,5 In these reactions, stoichiometeric oxidants were typically employed to generate the key hydrazonyl radicals. Recently, our group reported the first efficient and mild method for controllable generation of hydrazonyl radicals from β,γ-unsaturated hydrazones via an oxidative deprotonation electron transfer strategy under visible light irradiation.6,7 Employing these reactive intermediates, we successfully invented a range of transformations of hydrazonyl radicals, such as a hydroamination, oxyamination, and radical cascade, providing a practical access to dihydropyrazole and tetrahydropyridazine derivatives (Scheme 1a). The advantages of these processes include the photocatalytic direct generation of hydrazonyl radicals from N−H bonds, the easily accessible substrates prepared from the ketones and hydrazines, and readily tunable chemoselectivity enabled by modification of photocatalytic systems. Mechanistic studies also suggested that carbon radicals are also involved in these processes, which could be formed by addition of a hydrazonyl radical to the terminal alkene moiety. Inspired by these achievements and to fully explore the synthetic potential of the hydrazonyl and carbon radical intermediates, we accordingly envisage the development of a novel photocatalytic hydrazonyl radicalmediated radical cyclization/allylation cascade reaction of β,γunsaturated hydrazones using suitable allyl sources (Scheme 1b).8 Notably, the reaction would provide a complementary approach to various diversely functionalized dihydropyrazoles
ihydropyrazoles and tetrahydropyridazines are privileged and valuable N−N bond-containing heterocyclic scaffolds, which are frequently found in natural products and pharmacologically active compounds and also serve as versatile intermediates in organic synthesis (Figure 1).1 In most cases, they demonstrate diverse acitivities depending on their substitution patterns and functional groups. Consequently, a great deal of research effort has been devoted to development of elegant and creative strategies for the construction of these nitrogen heterocycles, of which most methods are based on thermal cycloaddition reactions.2,3 Recently, the strategy of
Figure 1. Natural products and biologically active compounds containing dihydropyrazole and tetrahydropyridazine cores. © 2017 American Chemical Society
Received: May 28, 2017 Published: June 22, 2017 3620
DOI: 10.1021/acs.orglett.7b01609 Org. Lett. 2017, 19, 3620−3623
Letter
Organic Letters
proved to be optimal, resulting in a slightly increased yield of 3a (entry 4, 34%). With photocatalyst Ir(ppy)2(bpy)PF6, we then continued to investigate the effect of the solvent on the reaction and found that CH3CN was still the best choice (entries 5−9). Interestingly, when the reaction was performed in the presence of 3.0 equiv of 2a and 2.0 equiv of K2CO3 under diluted conditions, the yield could be significantly improved, with 3a being isolated in 58% yield (entry 12).11 In accordance with our previous studies, a series of control experiments established that no desired product was detected without a photocatalyst, visible light irradiation, or base (entries 13−15). With the optimal reaction conditions in hand, we therefore explored the generality of a photocatalytic hydrazonyl radicalmediated radical cyclization/allylation cascade using a range of β,γ-unsaturated hydrazones. As shown in Scheme 2, this
Scheme 1. Visible Light Photocatalytic Generation of Hydrazonyl Radicals and Reaction Design
Scheme 2. Substrate Scope of β,γ-Unsaturated Hydrazones and Allyl Sulfonesa,b and tetrahydropyridazines. Herein, we describe the development of this protocol. Inspired by the recent wide application of allyl sulfones in photocatalysis allylation reaction,9 we initially chose these reagents as competitive allyl radical precursors. When a mixture of β,γ-unsaturated hydrazone 1a and allyl sulfone 2a in CH3CN was irradiated by 3 W blue LEDs at room temperature in the presence of photocatalyst Ru(bpy)3(PF6)2 (2 mol %) and K2CO3, the desired cascade reaction indeed worked well. And a 28% yield of the expected product 3aa was observed, which was unambiguously determined by single crystal X-ray crystallographic analysis (Table 1, entry 1).10 A further brief screen of commonly used photocatalysts showed that Ir(ppy)2(bpy)PF6 Table 1. Condition Optimizationa
entry
photocatalyst
solvent
base
yieldb (%)
1 2 3 4 5 6 7 8 9 10c 11c,d 12c,d,e 13c,d 14c,d 15c,d,g
Ru(bpy)3(PF6)2 Ru(bpy)3Cl2·6H2O Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6 − Ir(ppy)2(bpy)PF6 Ir(ppy)2(bpy)PF6
MeCN MeCN MeCN MeCN PhMe THF DMF CHCl3 DMSO MeCN MeCN MeCN MeCN MeCN MeCN
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 − K2CO3
28 33 33 34 32 32 23 15 17 37 53 71(58)f N.R. N.R. N.R.
a
1 (0.20 mmol), 2 (0.60 mmol), Ir(ppy)2(bpy)PF6 (2 mol %), K2CO3 (2.0 equiv) in CH3CN (4.0 mL) at rt under irradiation by 3 W blue LEDs for 10 h. bIsolated yield. c2.0 equiv of NaOH were used.
protocol shows broad substrate scope and functional group tolerance with aromatic substituents. For example, in addition to 1a, a series of hydrazone substrates 1b−d with weak electron-withdrawing (e.g., Cl, Br) or electron-donating (e.g., Me) groups on the para-position of the aromatic ring reacted well with allyl sulfone 2a. The corresponding products 3ba−da were obtained in 53−57% yield. Moreover, as shown in the synthesis of dihydropyrazoles 3ea and 3fa, the substitution patterns of the aromatic ring have no obvious effect on the cascade reaction. The reaction with 2-naphthyl-substiuted hydrazone 1g also proved to be suitable for the reaction, furnishing a 53% yield of product 3ga. In consonance with our previous works,6 the catalytic system could be successfully extended to a representative set of linear and cyclic aliphatic β,γ-unsaturated hydrazones 1h−j; the expected products 3h−j were obtained in good yields (60−64%). Then, we continued
a
1a (0.20 mmol), 2a (0.24 mmol), photocatalyst (2 mol %), and base (1.5 equiv) in 3.0 mL of solvent at rt under irradiation of 3 W blue LEDs for 10 h. bDetermined by 1H NMR analysis using 1,3,5trimethoxybenzene as an internal standard. c2.0 equiv of K2CO3 were used. d3.0 equiv of 2a were used. e4.0 mL of CH3CN were used. f Isolated yield in parentheses. gWithout visible light irradiation. N.R. = no reaction. 3621
DOI: 10.1021/acs.orglett.7b01609 Org. Lett. 2017, 19, 3620−3623
Letter
Organic Letters
yields. In the case of 3oc synthesis, both the use of sunlight as the light soucrce and gram-scale reaction provided comparable results, demonstrating the preparative utility of this methodology.11 Notably, the X-ray crystal structure of 3oc also confirmed the E-stereochemistry of the acrylate moiety.10 Based on our previous mechanistic study6,11 and related literature,9 we proposed a plausible mechanism for the present hydrazonyl radical-mediated radical cyclization/allylation cascade reaction using 1a as an example (Figure 2). According to
to investigate the possible structural variation of the sulfone moiety. Incorporation of a neutral or an electron-defficient aryl or a quinolin-8-yl group could also be well accommodated to give products 3ka−na in moderate yields together with formation of dihydropyrazole-fused benzofultam derivatives in the case of substrates 1l−m. The reaction with simple Mssubstituted hydrazone 1o also proceeded smoothly to deliver a 75% yield of 3oa when using NaOH as a base. As for the allyl sulfone 2b with ethyl ester, its reaction with hydrazones 1a and 1i also worked well to give 3ab and 3ib in 60% yield. It should be noted that the generally moderate yields are due to the formation of some unknown side products though with full conversion. As for the substrates 1l−m, compounds 3la′ and 3ma′ were also isolated in 36% and 26% yields. Encouraged by these results, we prepared hydrazones 1p and 1q bearing a phenyl group at the 2-position of the alkene moiety. It was found that these hydrazones also reacted well with allyl sulfone 2a in a 6-endo radical cyclization/allylation fashion under the standard conditions, probably due to the relatively greater stability of the resultant C-centered readical intermediate involved in the process (eq 1). The corresponding synthetically and biologically valuable tetrahydropyridazines 3pa−qa were obtained in 52−72% yield.
Figure 2. Proposed mechanism.
our oxidative deprotonation electron transfer model, the in situ generated anionic intermediate A is initially oxidized to the key hydrazonyl radical B by the photoexcited state photocatalyst *[Ir(ppy)2(bpy)]3+ via an SET process. Then, the hydrazonyl radical B undergoes an intramolecualr radical addition to the terminal alkene moiety to afford the C-centered radical intermediate C, which can further add to the allyl sulfone 2a, resulting in the β-sulfonyl radical D. Finally, homolytic fragmentation of intermediate D occures to give the final product 3aa with release of the sulfonyl radical E. At the same time, the sulfonyl radical E undergoes another SET reduction by the reducing [Ir(ppy)2bpy]2+ species to furnish the sulfinate anion and regenerate the ground state photocatalyst, closing the photocatalytic cycle. The trapping of intermediate C by 2c should also proceed through a similar pathway. The exclusive formation of the (E)-configuration of 3 was due to the thermodynamically favored stepwise pathway.9h In conclusion, we have developed a novel and efficient photocatalytic hydrazonyl radical-mediated radical cyclization/ allylation cascade reaction of β,γ-unsaturated hydrazones using allylsulfones and a Morita−Baylis−Hillman adduct as allyl sources without a stoichiometric external oxidant. Great functional group compatibility, scalability, convenient materials, and mild reaction conditions characterize this protocol. This method enables the synthesis of a wide range of dihydropyrazoles and tetrahydropyridazines with generally good yields.
Inspired by the unique reactivity of Morita−Baylis−Hillman adducts in organic synthesis,12 we then simply examined the designed photocatalytic hydrazonyl radical-mediated radical cyclization/allylation cascade with Morita−Baylis−Hillman acetate 2c as an allyl source (Scheme 3). By employing the combination of photocatalyst Ir(ppy)2(bpy)PF6 and NaOH under the otherwise same conidtions,11 hydrazones 1o, 1r, and 1s with a neutral, halogenated, or methyl-substituted phenyl ring all reacted well with 2c to give the desired products in high Scheme 3. Exploration of Morita−Baylis−Hillman Acetate as a Allyl Sourcea,b
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01609. Detailed experimental procedures and full spectroscopic data for all compounds (PDF) X-ray crystallographic data for 3aa (CIF) X-ray crystallographic data for 3oc (CIF)
a
1 (0.20 mmol), 2c (0.6 mmol), NaOH (2.0 equiv), and Ir(ppy)2(bpy)PF6 (2 mol %) in CH3CN (4.0 mL) at rt under irradiation by 3 W blue LEDs for 10 h. bIsolated yield. cUnder sunlight irradiation for 8 h. 3622
DOI: 10.1021/acs.orglett.7b01609 Org. Lett. 2017, 19, 3620−3623
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jia-Rong Chen: 0000-0001-6054-2547 Wen-Jing Xiao: 0000-0002-9318-6021 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the NNSFC (Nos. 21472058, 21472057, 21622201, and 21232003), the Distinguished Youth Foundation of Hubei Province (No. 2016CFA050), and CCNU (Nos. CCNU17TS0011 and CCNU16JCZX02) for financial support. The Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also appreciated. We thank Dr. Xiaotian Qi (Chongqing University) for DFT calculations.
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DOI: 10.1021/acs.orglett.7b01609 Org. Lett. 2017, 19, 3620−3623
