Letter pubs.acs.org/OrgLett
Synthesis of Dihydropyrazoles via Ligand-Free Pd-Catalyzed Alkene Aminoarylation of Unsaturated Hydrazones with Diaryliodonium Salts Meng-Nan Yang,† Dong-Mei Yan,† Quan-Qing Zhao,† Jia-Rong Chen,*,† and Wen-Jing Xiao*,†,‡ †
CCNU−uOttawa Joint Research Centre, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, 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 Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China S Supporting Information *
ABSTRACT: A ligand-free, palladium-catalyzed aminoarylation reaction of the unactivated alkenes in β,γ-unsaturated hydrazones is described. This protocol enables efficient and simultaneous formation of C(sp3)−N and C(sp3)−C(sp2) bonds under mild conditions, providing a practical and general approach to various diversely substituted dihydropyrazoles in generally good yields, without the use of any stoichiometric external oxidant. Scheme 1. Exploration of β,γ-Unsaturated Hydrazones for Nitrogen Heterocycle Synthesis
T
he synthesis of privileged N−N bond-containing dihydropyrazoles has gained a great deal of research effort from the synthetic community due to their prevalence in many natural products and pharmacologically active molecules as well as versatile utility as building blocks in organic synthesis (Figure 1).1 Many recent methods for their preparation have mainly
Figure 1. Selected examples of bioactive molecules with dihydropyrazole core.
alkene terminus. On the other hand, in recent years, palladiumcatalyzed alkene difunctionalization through C−N bond formation has been established as a powerful and widely applied synthetic tool for construction of diverse nitrogen heterocycles.5,6 Among most of these processes, the initial aminopalladation typically involves amides, carbamates as well as sulfonamides as nucleophilic nitrogen sources, thus enabling selective and efficient C−N bond formation. Inspired by such a type of catalytic activation mode, we envisioned that by combining palladium-catalyzed aminopalladation of alkene with appropriate aryl sources, we might realize an intermolecular aminoarylation of β,γ-unsaturated hydrazones (Scheme 1b). Unfortunately, our initial attempts to use aryl halides as aryl sources proved to be unsuccessful probably due to the poor compatibility of the hydrazone moiety with the relatively harsh reaction conditions.7
focused on catalytic cyclization or cycloaddition reactions using organocatalysts or metal catalysts.2 Given the important effects of the substitution patterns and structural diversity on their biological profile, development of general, efficient and operationally simple methods for the construction of such a class of nitrogen heterocycles is still highly desirable. In this regard, we in 2014 reported a new method for the synthesis of 4,5-dihydropyrazoles by photoredox-catalyzed hydrazonyl radical-mediated intramolecular hydroamination of β,γ-unsaturated hydrazones under visible light irradiation (Scheme 1a).3 This strategy also allowed further incorporation of various functional groups into the terminal alkene by trapping the related key intermediates with suitable radical acceptors.4 However, despite the synthetic utility and broad substrate scope of these transformations, it has not been possible to apply the above photocatalytic systems to those β,γunsaturated hydrazones equipped with an aryl group at the © 2017 American Chemical Society
Received: August 10, 2017 Published: September 12, 2017 5208
DOI: 10.1021/acs.orglett.7b02480 Org. Lett. 2017, 19, 5208−5211
Letter
Organic Letters
PhCF3 and o-xylene, toluene still proved to be the best reaction medium (entries 2 vs 6−10). Further evaluation of several other organic and inorganic bases did not result in any improvement of the yield (entries 11−14). Notably, reducing the amounts of 2a and base loading to 1.2 equiv respectively at slightly diluted conditions could still afford 3aa in 78% yield (entry 15). Notably, replacement of 2a with its byproduct PhI under standard conditions led to no 3aa.7 With the optimized conditions in hand, we then explored the generality and limitation of this ligand-free palladium-catalyzed aminoarylation reaction using a range of β,γ-unsaturated hydrazones (Scheme 2a). It was found that the electronic and
Owing to the highly electron-deficient property of the iodine center and excellent leaving-group ability of the ArI moiety in hypervalent iodine(III) reagents, this compound class has also recently found widespread applications as mild, nontoxic and selective arylating reagents and oxidants in metal-catalyzed cross-coupling reactions and heterocycle synthesis. 8 In particular, the utilization of diaryliodonium salts in copper-9 and palladium-catalyzed10 difunctionalization of unsaturated systems has opened new synthetic possibilities for construction of diverse novel carbocyclic and heterocyclic scaffolds. Mechanistically, it was postulated that the use of iodine(III) reagent enabled generation of highly reactive high-valent metal sepecies that allowed arylation at mild reaction conditions. Thus, we considered the diaryliodonium salts as the aryl sources (Scheme 1b, step 2). Herein, we report the first example of palladium-catalyzed alkene aminoarylation of β,γunsaturated hydrazones. To test our design plan outlined in Scheme 1b, we initially selected β,γ-unsaturated hydrazone 1a and diphenyliodonium tetrafluoroborate 2a as the model substrates to optimize the reaction conditions (Table 1).7 When a mixture of 1a and 2a in
Scheme 2. Substrate Scope of β,γ-Unsaturated Hydrazones and Diaryliodonium Saltsa,b
Table 1. Condition Optimizationa
entry 1 2 3 4 5 6 7 8 9 10 11 12d 13d 14d 15d,e
[Pd] Pd(OAc)2 Pd(TFA)2 Pd(acac)2 Pd(BF4)2(MeCN)4 PdCl2(PhCN)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
base
yield (%)b
Pr2NEt Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt NaHCO3 K2CO3 NEt3 Cs2CO3 i Pr2NEt
70 85(79)c 50 83 82 49 63 58 73 25 43 57 61 59 84(78)c
solvent toluene toluene toluene toluene toluene CH2Cl2 CHCl3 PhCl PhCF3 o-xylene toluene toluene toluene toluene toluene
i i
a
1 (0.20 mmol), 2 (0.24 mmol), Pd(TFA)2 (5 mol %), iPr2NEt (1.2 equiv) in toluene (4.0 mL) at rt for 24−36 h. bIsolated yield. c1.0 mmol scale.
a
1a (0.20 mmol), 2a (0.30 mmol), palladium catalyst (5 mol %), and base (0.40 mmol) in 3.0 mL of solvent at rt for 24 h. bDetermined by 1 H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. cIsolated yield in parentheses. d1.2 equiv of 2a was used. e 1.2 equiv of iPr2NEt and 4.0 mL of toluene were used.
positional effects of the substituents on the aryl ring did not lead to obvious difference in reaction efficiency and reactivity. In addition to 1a, a range of β,γ-unsaturated hydrazones 1b−g bearing an electron-donating (e.g., Me, OMe) or electronwithdrawing (e.g., Cl, Br) subsituent on the para- or metaposition of the phenyl ring reacted well to give the expected products 3ba-ga with generally good yields (60−78%). Moreover, the reaction with a series of linear and cyclic aliphatic hydrazone substrates 1h−k also proceeded smoothly, with products 3ha-ka being formed in 52−87% yield. The heteroarenes, such as 2-thienyl- and 2-furyl-substituted hydrazones 1l and 1m also proved to be suitable for the reaction, leading to 3la and 3ma in 39% and 56% yields, respectively. Notably, this alkene aminoarylation reaction could be extended by variation of the sulfoamide moiety. For
toluene was treated with 5 mol % of Pd(OAc)2 without any ligand in the presence of 2.0 equiv of iPr2NEt as a base at room temperature, the desired reaction proceeded smoothly to give the aminoarylation product 3aa with 70% NMR yield (entry 1). The dihydropyrazole 3aa was also unambiguously confirmed by NMR, HRMS and single crystal X-ray crystallographic analysis.11 Then, we performed a brief screening of commonly used palladium(II) salts, and identified Pd(TFA)2 to be the best one with 3aa being isolated in 79% yield (entry 2). With the catalyst Pd(TFA)2, we next examined the effect of the solvents on the reaction, and found that the reaction was highly sloventdependent. Compared to the solvents DCM, CHCl3, PhCl, 5209
DOI: 10.1021/acs.orglett.7b02480 Org. Lett. 2017, 19, 5208−5211
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Organic Letters example, the reactions of substrates 1n and 1o with para-chloro or 2,4,6-trimethyl groups on the aromatic ring worked well to afford the corresponding products 3na and 3oa in 56−68% yield. Then, we continued to examine the substrate scope briefly by reacting 1a with a representative set of diaryliodonium salts (Scheme 2b). Once again, the present catalytic system proved to be suitable for the diaryliodonium salts 2b−d with electron-withdrawing (e.g., CN, Br) or weakly electrondonating groups on the aryl ring and 1-naphthyl-substituted one 2e, furnishing the desired products 3ab−ae in 37−94% yield. As shown in the synthesis of 3aa, the reaction could also be performed on 1.0 mmol scale to provide the product in 61% yield. Product 3aa could also undergo a sequential Ts deprotection/aromatization to give pyrazole 3aa′ with quantative yield under basic conditions.7 Next, we applied the catalytic system to these β,γ-unsaturated hydrazones equipped with an aryl group at the 2-position of the alkene (Scheme 3). If successful, the reaction would provide a
analogous to 1 but with a phenyl group at the alkene terminus were unsuccessful (results not shown). The present alkene aminoarylation could be extended to γ,δunsaturated hydrazones. For instance, the reactions between substrates 6a, 6b and 2a proceeded smoothly in a 6-endo cyclization manner, giving the synthetically and biologically valuable tetrahydropyridazines 7a and 7b in 60% and 47% yields, respectively (eq 1).11 Then, we performed the model
Scheme 3. Synthesis of Dihydropyrazoles with a Tetrasubstituted Carbon Centera,b
reaction with deuterated substrate 1a-D to explore syn- vs antiaddition processes (eq 2). The reaction of 1a-D with 2a gave 3aa-D with 46% yield and 3:2 dr, indicating that both pathways are operative in the catalytic cycle.7 On the basis of the literature reports,6,8,10,13 we currently prefer the Pd(II)/(IV) catalytic cycle for this aminoarylation reaction as depicted in Scheme 4, though an alternative Pd(0)/ Scheme 4. Proposed Mechanism
a
(II) catalytic cycle cannot be excluded. Taking the syn-addition pathway as an example with 1a-D and 2a,7 an initial coordination of the pendant alkene to the catalyst Pd(TFA)2 followed by deprotonation and intramolecular syn-aminopalladation leads to a alkylpalladium complex B via Pd-amido complex A.6 The diaryliodonium salt 2a serves not only as aryl source but also as terminal oxidant. Thus, oxidation of alkylpalladium complex B by 2a forms a transient Pd(IV) intermediate C. Reductive elimination of C affords the product 3aa and regenerates Pd(II) catalyst. In conclusion, we have developed an efficient ligand-free Pd(II)-catalyzed aminoarylation reaction of the unactivated alkenes in β,γ- and γ,δ-unsaturated hydrazones with diaryliodonium salts as both aryl source and terminal oxidant. This protocol features great functional group compatibility, uses convenient materials as well as mild reaction conditions, and provides a practical access to diversely substituted dihydropyrazoles and tetrahydropyridazines.
1 (0.20 mmol), 2 (0.30 mmol), Pd(OAc)2 (5 mol %), NaHCO3 (2.0 equiv) in toluene (3.0 mL) at rt for 24 h. bIsolated yield.
practical access to 5-aryl-substituted 4,5-dihydropyrazoles, which have recently been established as a promising scaffold for drug discovery.12 Again, a wide range of β,γ-unsaturated hydrazones 4a−f with diverse electron-donating or electron− withdrawing groups on the aromatic ring and aliphatic hydrazone 4g were well tolerated, when using Pd(OAc)2 as catalyst and NaHCO3 as the base instead; and the desired products 5aa−ga with a tetrasubstituted carbon center were formed in 37−93% yield (Scheme 3a). Moreover, as demonstrated in the synthesis of dihydropyrazoles 5ha−la, variation in the electronic and steric properties of R3 substituent also proved to be possible (Scheme 3b). Notably, an array of diaryliodonium salts 2b, 2e and 2f reacted well with hydrazone 4a to furnish the corresponding products in 62−80% yield (Scheme 3c). However, our attempts to employ hydrazones 5210
DOI: 10.1021/acs.orglett.7b02480 Org. Lett. 2017, 19, 5208−5211
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Organic Letters
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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.7b02480. Detailed experimental procedures and full spectroscopic data for all compounds (PDF) X-ray crystallographic data for 1a (CIF) X-ray crystallographic data for 3aa (CIF) X-ray crystallographic data for 7a (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *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, and 21622201), the Distinguished Youth Foundation of Hubei Pro vince (No. 20 16 CFA0 50), and C CNU (No. CCNU17TS0011 and CCNU16JCZX02) for financial support. The Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also appreciated.
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DOI: 10.1021/acs.orglett.7b02480 Org. Lett. 2017, 19, 5208−5211
