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Letter Cite This: Org. Lett. 2018, 20, 4411−4415

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Copper-Mediated Aminoazidation, Aminohalogenation, and Aminothiocyanation of β,γ-Unsaturated Hydrazones: Synthesis of Versatile Functionalized Pyrazolines Li-Jing Wang,*,†,‡ Pei-Xing Ren,† Lin Qi,† Manman Chen,† Yan-Lei Lu,† Jing-Ye Zhao,† Rui Liu,† Jia-Min Chen,† and Wei Li*,†,‡ †

College of Chemistry & Environmental Science, Hebei University, 180 Wusi Donglu, Baoding 071002, People’s Republic of China Key Laboratory of Medicinal Chemistry, and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, Hebei University, 180 Wusi Donglu, Baoding 071002, People’s Republic of China

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‡

S Supporting Information *

ABSTRACT: A versatile method for the rapid synthesis of diverse functionalized pyrazolines has been developed based on copper-mediated aminofunctionalization of β,γ-unsaturated hydrazones. The scope of this strategy encompasses a range of difunctionalization reactions: aminoazidation, aminohalogenation, and aminothiocyanation. These reactions provide straightforward access to a series of useful pyrazoline building blocks containing various functional groups that are hard to access traditionally. Scheme 1. Synthesis of Functionalized Pyrazolines via β,γUnsaturated Hydrazones

T

he synthesis of pyrazoline derivatives has gained considerable attention from the synthetic community, because of their remarkable biological activity and widespread natural occurrence, as well as versatile utility as synthetic intermediates in organic synthesis.1 Among the great deal of effort toward efficient syntheses of functionalized pyrazolines from diverse precursors,2,3 the direct cyclization/difunctionalization of β,γ-unsaturated hydrazones with a functional group reagent source is an attractive method, because of the easy availability of the substrates and the simultaneous setup of a second valuable functional group.4−7 For instance, Han, Loh, and Sodeoka et al. found that in the presence of oxidants, β,γunsaturated hydrazones could give a hydrazonyl radical intermediate I. Intermediate I then undergoes fast 5-exo-trig cyclization to yield the corresponding C-centered radical II, which could be trapped by radical acceptors to produce functionalized pyrazolines (reaction 1a in Scheme 1).4 Subsequently, Xiao and co-workers reported an alternative strategy for generating intermediates I and II by using photocatalysts and bases under visible light (see reaction 1b in Scheme 1).5 In addition, the same group also found that under the photoredox-catalyzed condition, CF3 radical could undergo a radical addition with the unsaturated hydrazones to give a new radical intermediate III, which was then oxidized to carbocation intermediate IV. A final nucleophilic cyclization leads to the corresponding products (reaction 2 in Scheme 1).6 Furthermore, a palladium catalyst was also applied by Xiao and Chen to the aminoarylation of unsaturated hydrazones, in which the alkylpalladium complex V is a key intermediate (reaction 3 in Scheme 1).7 Although impressive progress has been made in recent years, given the fact that, in most cases, © 2018 American Chemical Society

the biological profile of pyrazolines is dependent on their substitution patterns and structural diversity, the research is far from exhaustive and much remains to be explored. In Received: May 22, 2018 Published: July 16, 2018 4411

DOI: 10.1021/acs.orglett.8b01620 Org. Lett. 2018, 20, 4411−4415

Letter

Organic Letters particular, the introduction of many useful functional groups, such as azide group, halogen group, and thionitrile group to the pyrazoline core is still a challenge. We envisioned a new synthesis of pyrazoline derivatives incorporating the features mentioned above based on a strategy that we recently established during the research of the copper-catalyzed diamination of alkenes of unsaturated ketohydrazones with amines.8 We speculate that β,γ-unsaturated hydrazones with CuII could form an alkyl-copper intermediate VI, which undergoes homocleavage to form a radical intermediate VII. Then, intermediate VII couples with a CuII complex (CuII−NR12) to generate intermediate VIII and this is followed by a reductive elimination process to generate the desired products. Herein, we test whether we can realize aminoazidation, aminohalogenation, and aminothiocyanation of β,γ-unsaturated hydrazones by introducing nucleophilic reagents such as NaN3, halide salts, and KSCN, which could replace the role of amines and convert to the corresponding CuII complexes (reaction 4 in Scheme 1). We first applied this general strategy to the aminoazidation of β,γ-unsaturated hydrazones with NaN3. When a mixture of N-phenyl-β,γ-unsaturated hydrazone 1a (0.2 mmol), 2.0 equiv NaN3, and 1.0 equiv Cu(OAc)2 in CH3CN was stirred at room temperature, the expected azidation/cyclization cascade indeed occurred to give the desired product 3a in 64% yield, with a small amount of 4a after 16 h (Table 1, entry 1). Encouraged by this result, we continued to test the effect of temperature, (entries 2 and 3), and the yield could be improved to 66% at 30 °C (entry 2). A simple survey of the reaction media did not give better yields (entries 4 and 5). We then evaluated several oxidants, such as K2S2O8, Na2S2O8, DTBP, DCP, and TBHP, but these led only to low yields (entries 6−10). Subsequently, we investigated the influence of bases such as K2CO3, Na2CO3, and TMEDA, but there were no good results yet (entries 11− 13). When the copper salt was changed to Cu(OTf)2, CuBr2, or Cu(acac)2, it did not help improve the yield (entries 14− 16). Furthermore, we studied the loading of Cu(OAc)2 on the reaction and found that 1.0 equiv of Cu(OAc)2 was still the best choice (entries 17 and 18). Then, the loading of NaN3 was also evaluated and the yield could be improved to 80% by using 4.0 equiv of NaN3 (entries 19 and 20). Finally, control experiments with air or oxygen confirmed that the argon atmosphere was essential to the present reaction (entries 21 and 22). With the optimal reaction conditions in hand (Table 1, entry 20), the scopes of β,γ-unsaturated hydrazones were then examined. The results are summarized in Scheme 2. It was found that the substitution patterns and electronic properties of the aryl ring of the substrates 1 did not lead to an obvious difference in reaction efficiency and reactivity. Numerous β,γunsaturated hydrazones bearing electron-donating (e.g., Me, OMe, isopropyl) and electron-withdrawing groups (e.g., F, Cl, Br) at either the 3- or 4-position of the phenyl ring reacted well to provide the expected azido-substituted pyrazolines 3a−3j with good to high yields (63%−80%). Note that the structure of 3c was unambiguously confirmed by X-ray analysis. Moreover, we investigated the hydrazone substrates bearing aryls. The hydrazone bearing a naphthyl group could give the desired product 3k in a yield of 67%. The heteroarenes, such as 2-indolyl and 2-thienyl-substituted hydrazones 1l and 1m also proved to be applicable substrates, leading to 3l and 3m in 88% and 77% yields, respectively. We continued to survey the aliphatic β,γ-unsaturated hydrazine 1n, which could give the

Table 1. Optimization of Reaction Conditions for Aminoazidation of 1a with NaN3a

entry c

1 2 3d 4 5 6 7 8 9 10 11 12 13 14 15 16 17e 18f 19g 20h 21i 22j

solvent

[Cu]

CH3CN CH3CN CH3CN MeOH DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OTf)2 CuBr2 Cu(acac)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

additives (equiv)

K2S2O8 (2.0) Na2S2O8 (2.0) DTBP (2.0) DCP (2.0) TBHP (2.0) K2CO3 (1.2) Na2CO3 (1.2) TMEDA (1.2)

-

yield of 3ab (%) 64 66 37 24 22 65 62 64 62 48 47 40 48 38

59 53 74 80 42 trace

a All reactions were performed by using 1a (0.2 mmol), 2a (2.0 equiv), copper salts (1.0 equiv), and CH3CN (2 mL) under argon and stirred at 30 °C, unless noted otherwise. bIsolated yield. cReaction was performed at room temperature. dReaction was performed at 40 °C. e1.5 equiv of Cu(OAc)2 was used. f2.0 equiv of Cu(OAc)2 was used. g3.0 equiv of NaN3 was used. h4.0 equiv of NaN3 was used. i Reaction was performed under an air atmosphere. jReaction was performed under an oxygen atmosphere.

desired product in 51% yield. Then, we examined the possible structural scope of the N-phenyl moiety. Fortunately, many substituted hydrazones with a series of electronic properties operated well under the standard conditions to produce the corresponding products (3o−3u) in good to excellent yields (73%−82%). The N-methyl substituted substrates 1v could also afford the desired product in 60% yield. However, N-2pyridyl-, N-tosyl-, and N-acetyl-substituted ketohydrazones were inert in this reaction (3w−3y). Furthermore, to expand the scope of this reaction, we also investigated substrates 1z and 1za, but they were not suitable for this transformation. Organic azides are versatile intermediates in organic synthesis and can be easily converted to a range of useful nitrogen-containing organic compounds.9 For instance, in the presence of CuI, 3a could undergo a typical click reaction with phenylacetylene to give the triazole product 5 with excellent yield (see Scheme 3a). Compound 3a could also easily generate to 6 in a yield of 76% through a Staudinger reduction and in situ protection sequence (Scheme 3b). To further expand this method, we next examined the aminohalogenation of β,γ-unsaturated hydrazones with halide salts to furnish halogenated pyrazolines. Organic halides are present in a wide range of pharmaceuticals, agrochemicals, and natural products and also serve as extremely useful materials in 4412

DOI: 10.1021/acs.orglett.8b01620 Org. Lett. 2018, 20, 4411−4415

Letter

Organic Letters Scheme 2. Cu-Mediated Alkene Aminoazidationa

Table 2. Optimization of Reaction Conditions for Aminoiodination of 1a with KIa

entry

solvent

[Cu]

t (°C)

1 2c 3 4 5 6 7 8 9d 10e 11 12 13 14 15f 16g 17f,h

CH3CN CH3CN CH3CN CH3CN DMF MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuCl2 CuBr2 [Cu] Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

30 30 40 60 30 30 30 30 30 30 30 30 30 30 30 30 30

additives

yieldb (%)

NEt3 DMAP TMEDA Na2CO3 TMEDA TMEDA TMEDA

34 30 32 26 22 42 32 34 40 33 53 51 62 40 66 64 60

a

All reactions were performed by using 1a (0.2 mmol), 2b (2.0 equiv), copper salts (1.0 equiv), additives (1.2 equiv), and MeOH (2 mL) under argon and stirred at 30 °C, unless noted otherwise. b Isolated yield. c1.5 equiv of Cu(OAc)2 was used. d[Cu] = Cu(2ethylhexanoate)2. e2.0 equiv of NaI was used. f1.5 equiv of TMEDA was used. g2.0 equiv of TMEDA was used. h4.0 equiv of KI was used.

a

All reactions were performed by using 1 (0.2 mmol), 2a (4.0 equiv), Cu(OAc)2 (1.0 equiv), and CH3CN (2 mL) under argon and stirred at 30 °C, unless noted otherwise. Isolated yields.

Scheme 3. Derivatization of the Aminoazidation Product 3a

Scheme 4. Cu-Mediated Alkene Aminoiodinationa

organic synthesis.10 Thus, we explored this transformation by using 1a and KI (2b) as the model substrate (Table 2). When 2.0 equiv KI was used instead of NaN3 under the standard reaction conditions described for entry 20 in Table 1, the desired product 7aa was obtained in a yield of 34% (Table 2, entry 1). We then investigated various reaction conditions, and the yield could be increased to 66% eventually when using 0.2 mmol of 1a, 2.0 equiv of KI, 1.0 equiv of Cu(OAc)2, and 1.5 equiv of TMEDA in the presence of 2 mL of MeOH at 30 °C (Table 2, entry 15). We briefly examined the scope of this copper-mediated aminoiodination. The diversity of this transformation turned out to be good (Scheme 4). Generally, the electronic properties of the phenyl moieties in substrates 1 did not have a distinct influence on the efficiency of the aminoiodination, and good yields of the iodo-substituted pyrazolines (7aa-ee, 7jo, and 7kq) were obtained. Moreover, 2-naphthyl, 2-indolyl, and 2-thienyl-substituted hydrazones (1f−1h) could also give the desired product in yields of 61%, 58%, and 45%,

a

All reactions were performed by using 1 (0.2 mmol), 2b (2.0 equiv), Cu(OAc)2 (1.0 equiv), TMEDA (1.5 equiv), and MeOH (2 mL) under argon and stirred at 30 °C, unless noted otherwise. Isolated yields.

respectively. It is worth mentioning that the aliphatic substrate 1n also produced the desired product in 27% yield. After our investigation of aminoiodination, we moved on to determine whether the above reaction system was applicable to aminobromination and aminochlorination. When using NaBr and NaCl as halide salts, the reaction proceeded smoothly to 4413

DOI: 10.1021/acs.orglett.8b01620 Org. Lett. 2018, 20, 4411−4415

Letter

Organic Letters obtain the desired bromo-substituted pyrazoline 8 and chlorosubstituted pyrazoline 9 in yields of 66% and 54%, respectively. Furthermore, it is interesting that the thiocyanate product 10 could also be constructed in a yield of 30% by adding KSCN under the standard reaction conditions (Scheme 5).

Scheme 7. Proposed Mechanism

Scheme 5. Cu-Mediated Alkene Aminobromination, Aminochlorination, and Aminothiocyanationa

compatibility. Further investigation on the reaction mechanism and the application of this method to the synthesis of other functionalized nitrogen-containing heterocycles are underway in our laboratory.

a

All reactions were performed by using 1 (0.2 mmol), 2 (2.0 equiv), Cu(OAc)2 (1.0 equiv), TMEDA (1.5 equiv), and MeOH (2 mL) under argon and stirred at 30 °C, unless noted otherwise. Isolated yields.

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ASSOCIATED CONTENT

S Supporting Information *

To gain some insights into the reaction mechanism, two control experiments were performed as shown in Scheme 6.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01620. Detailed experimental procedures and spectral data for all products (PDF)

Scheme 6. Control Experiment

Accession Codes

CCDC 1844044 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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First, the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 equiv) was added under the reaction conditions of Table 1, entry 20, which led to a TEMPO trapped product 11 in a yield of 97% with no observation of 3a (reaction 1 in Scheme 6). Furthermore, when TEMPO (1 equiv) was added under the reaction conditions of Table 2, entry 15, substrate 1a was recovered in 82% yield and the TEMPO trapped product 11 was in a yield of 5% (reaction 2 in Scheme 6). These observations clearly suggest that a radical pathway with a Ccentered radical intermediate was involved in the above processes. Based on the above-mentioned results and literature reports,8,11,12 a plausible mechanism’s pathway may be involved, as shown in reaction 4 in Scheme 1. In addition, we observed a copper mirror in the flask, so there could be progress in the disproportionation of CuI to produce CuII and Cu0 (see Scheme 7). In summary, we have developed a general and versatile method for the copper-mediated aminofunctionalization of β,γunsaturated hydrazones. A wide series of nucleophilic anion sources were found to participate in this type of reaction, including NaN3, KI, NaBr, NaCl, and KSCN. This strategy offers rapid access to a broad spectrum of interesting functionalized pyrazolines through tandem N−C/C−N, N− C/C−I, N−C/C−Br, N−C/C−Cl, or N−C/C−SCN bond formation, in good yields with nice functional group

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (L.-J. Wang). *E-mail: [email protected] (W. Li). ORCID

Li-Jing Wang: 0000-0002-2411-2758 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21702043), the Hebei Province Science Foundation for Key Program (No. B2016201031), and the Hebei Province Science Foundation for Youths (No. B2017201041) for financial support. We also thank Dr. Xian-Rong Song (Jiangxi Science & Technology Normal University) for X-ray structural analysis.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01620 Org. Lett. 2018, 20, 4411−4415