Cu-Catalyzed Oxyalkynylation and Aminoalkynylation of Unactivated

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Cu-Catalyzed Oxyalkynylation and Aminoalkynylation of Unactivated Alkenes: Synthesis of Alkynyl-Featured Isoxazolines and Cyclic Nitrones Wen-Jun Han, Yuan-Rui Wang, Jian-Wu Zhang, Fei Chen, Bo Zhou, and Bing Han* State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China S Supporting Information *

ABSTRACT: A convenient and efficient vicinal oxyalkynylation/aminoalkynylation of internal unactivated alkenes is achieved by means of a Cu-catalyzed radical cascade reaction of unsaturated ketoximes with ethynylbenziodoxolone (EBX) reagents. This protocol enables the synthesis of structurally valuable isoxazolines or cyclic nitrones and the introduction of an important alkyne group in a single operation. The reaction is characterized by a broad substrate scope for both unsaturated ketoximes and alkynylation reagents and a low catalyst loading.

T

Scheme 1. Radical Alkynylation of Alkenes

he alkyne group as a ubiquitous structural unit not only exists in many natural compounds and synthetic intermediates but also plays an essential role in the domain of chemical biology and materials sciences.1 Especially, the alkynecontaining heterocycles are often employed as drugs, agrochemicals, and versatile precursors for the synthesis of fine chemicals.2 For instance, compounds I and II are used as pest control agent and herbicide in the agricultural industry, respectively.3,4 Compound III is a key intermediate toward pyrrole alkaloid (±)-trachelanthamidine (Figure 1).5 Thus, the

Figure 1. Pharmacologically active molecules featuring alkynylsubstituted heterocycle.

difunctionalization of alkenes is still limited, and a method for the radical-involving oxyalkynylation process remains challenging. Encouraged by our continued research on iminoxyl and hydrazonyl radical-mediated vicinal functionalization of alkenes and alkynes,13 and motivated by the widespread application of hypervalent iodine reagents,14 herein, we are aimed at achieving a strategy for the vicinal oxyalkynylation and aminoalkynylation of unactivated alkenes by a copper-catalyzed cascade radical cyclization/addition reaction of olefin-tethered ketoximes with EBX reagents. This transformation enables installation of the alkyne group and the construction of an important heterocycle in a single transformation. We set out on our research by stirring ketoxime 1a with EBX reagent 2a in 1,2-dichloroethane (DCE) at 100 °C under an Ar atmosphere. Encouragingly, 1a was completely consumed after 1

development of efficient synthetic approaches to incorporate an alkyne group into organic molecules has attracted great attention from organic chemists.6 Over the past few decades, aside from the palladium(0)-catalyzed Sonogashira reaction,7 significant successes in this field are mainly focused on the transition-metalmediated direct C−H alkynylation of (hetero)arenes and aliphatic hydrocarbons,8−10 as well as alkynylation of olefins.11 Recently, the radical alkynylation of unactivated alkenes has gathered increasing attention because it provides an efficient protocol to simultaneously furnish alkynes and other functional groups into alkenes by a one-pot reaction.12 For example, in 2017, Li and Yu independently reported radical alkynyltrifluoromethylation of alkenes (Scheme 1a and 1b).12a,b Afterward, Wang presented Cu-catalyzed aminoalkynylation of alkenes with hypervalent iodine reagents (Scheme 1c).12c Despite these elegant achievements, the scope of alkynyl-involved radical © XXXX American Chemical Society

Received: March 29, 2018

A

DOI: 10.1021/acs.orglett.8b01004 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Unsaturated Ketoximesa,b

h, affording the oxyalkynylation product 3a in 45% yield (Table 1, entry 1). When a small amount of CuCl2 was added to the Table 1. Optimization of the Oxyalkynylation of Alkenea

entry

catalyst

solvent

t (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10c 11 12c 13d 14e 15 16 17 18 19 20

− CuCl2 CuBr2 CuSO4 Cu(OAc)2 Cu(OTf)2 CuCl CuBr CuI FeBr3 Co(acac)2 Ni(acac)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE CH3CN EtOH 1,4-dioxane toluene DCE DCE

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 80 120

45 71 69 65 69 76 68 70 67 52 62 50 69 58 56 60 70 56 71 63

a

Conditions: compounds 1 (0.3 mmol), EBX reagent (1.5 equiv), Cu(OTf)2 (1 mol %), and DCE (1.5 mL) were stirred under Ar at 100 °C for 1 h. bIsolated yields. cThe reaction was conducted on 5.0 mmol scale, affording 3a in 73% yield (1.055 g). dThe relative configuration of 3o was identified by analyzing the spectra of 1H NMR and NOE.

a

All reactions were performed by stirring 1a (0.3 mmol), 2a (1.5 equiv), copper catalyst (1 mol %), and solvent (1.5 mL) under Ar for 1 h, except as noted. bIsolated yield. cAfter 2 h. dCu(OTf)2 (5 mol %) was used. eCu(OTf)2 (10 mol %) was used.

as manifested by the moderate yields of 3j−n. When substrate 1o, in which the alkene moiety was inserted into a ring, participated in the reaction, the corresponding oxyalkynylation product 3o was produced in 34% yield, accompanied by the side product 3o′ in 15% yield. Significantly, 1,1-disubstituted alkene containing substrate 1p was also suitable for this oxyalkynylation and gave 3p in 54% yield. Next, γ,δ-unsaturated counterparts were also investigated to see whether they could undergo the Nradical cyclization16 to achieve the aminoalkynylation of alkenes. Gratifyingly, a series of γ,δ-unsaturated ketoximes reacted well under the standard conditions, providing the expected aminoalkynylation products 3q−v in modest yields. It is noteworthy that a gram-scale reaction of 1a with EBX reagent was also successful and produced 3a in 73% yield (1.055 g), promising a practical application of this approach. Having successfully achieved oxyalkynylation and aminoalkynylation of unactivated alkenes with various unsaturated ketoximes, we switched our focus toward exploring a range of alkynylation reagents. All kinds of EBX reagents reacted well with 1a, and the consequences are summarized in Scheme 3. Phenylsubstituted alkyne moieties with a wide variety of electronic properties were all feasible for the transformation, as demonstrated by the formation of 3w−ab in good yields. Thiophene-substituted hypervalent iodine reagent 2h was also compliable for the reaction, providing 3ac in 30% yield. Noticeably, when the alkyl-substituted alkynylation reagents were utilized in the reaction, the corresponding products 3ad−ae were obtained in moderate yields as well. The alkyne group is a versatile functional group that has tremendous potential for further functionalization. In this

reaction as the catalyst, the yield of 3a was increased to 71% (Table 1, entry 2). Several copper salts were then tested, which also exhibited beneficial effects on the oxyalkynylation process (Table 1, entries 3−9), among which Cu(OTf)2 provided the optimal yield. Other transition-metal salts,15 acting as the catalysts for the radical reactions, were also examined, but only lower yields were obtained (Table 1, entries 10−12). Furthermore, increasing the amount of the catalyst was harmful to the oxyalkynylation of alkenes (Table 1, entries 13−14). When several other solvents were investigated, only less satisfactory results were acquired (Table 1, entries 15−18). Raising or lowering the temperature was detrimental to the reaction (Table 1, entries 19−20). Having identified a viable system (Table 1, entry 6), many types of unsaturated ketoximes were reacted with alkynylation reagents to explore the applicability of this reaction. As illustrated in Scheme 2, β,γ-unsaturated ketoximes 1a−p were first explored. Substituents on the phenyl ring, such as p-MeO, pCl, p-CF3, and m-Br groups, were compatible with this process; consequently, the oxyalkynylation products 3a−e were obtained in excellent yields. The structure of 3b was corroborated by X-ray crystallography (see Supporting Information). 2-Naphthalenyland 2-thiophene-substituted ketoximes were also appropriate for the reaction, delivering alkynyl-substituted isoxazolines 3f and 3g in good yields. Alkyl groups such as cyclohexyl and phenethyl incorporating ketoximes were also good candidates for this transformation, yielding the products 3h and 3i in 58% and 81% yields, respectively. Notably, the reaction could take place as well when the gem-dimethyl group was removed from the substrates, B

DOI: 10.1021/acs.orglett.8b01004 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of Alkynyl Groupsa,b

Figure 2. Proposed mechanism.

of linked olefins, delivering the radical intermediate C or D. Subsequently, the intermediate C or D attacks the α-position of the alkyne moiety of EBX 2 to generate the intermediate E or F. Finally, the elimination of 2-iodobenzoate from the intermediate E or F under the reduction of Cu(I) yields product 3 and the recycle of Cu(II). In summary, a facile and practical vicinal oxyalkynylation/ aminoalkynylation of internal unactivated alkenes of unsaturated ketoximes has been established by using readily accessible EBX reagents as the alkynylation reagents under the catalysis of Cu(OTf)2. By using this method, a series of structurally valuable alkynyl-furnished isoxazolines and cyclic nitrones are successfully synthesized via an iminoxyl radical-involved tandem reaction. To our knowledge, the current study implements the first case of iminoxyl radical-facilitated vicinal oxyalkynylation and aminoalkynylation of unactitivated alkenes. Further research on the alkynylation of alkenes is currently underway.

a Conditions: compound 1a (0.3 mmol), EBX reagents 2 (1.5 equiv), Cu(OTf)2 (1 mol %), and DCE (1.5 mL) were stirred under Ar at 100 °C for 1 h. bIsolated yields.

context, product 3a serves as a precursor for the preparation of other isoxazoline derivatives. For example, compound 4 was facilely obtained via Pd/C catalyzed reductive hydrogenation. Furthermore, compound 5 was generated upon partial hydrogenation using Lindlar’s catalyst with quinoline (Scheme 4). Scheme 4. Derivatization of 3a

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ASSOCIATED CONTENT

S Supporting Information *

To verify that the reaction experiences an iminoxyl radicalinvolved process, radical trapping and radical probe experiments were carried out (Scheme 5.) When TEMPO (2,2,6,6-tetra-

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01004. Detailed experimental procedures and spectral data for all products (PDF)

Scheme 5. Control Experiments

Accession Codes

CCDC 1821641 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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methylpiperidin-1-oxyl), a well-known C-centered radical scavenger, was added to the reaction, the oxyalkynylation product was scarcely observed but compound 6 was isolated in 92% yield (Scheme 5, eq 1). When ketoxime 7 experienced the standard reaction conditions, the prospective ring-opening alkynylation product 8 was exclusively formed in 31% yield (Scheme 5, eq 2). Obviously, these results illustrate that the reaction includes the iminoxyl radical-promoted cyclization process. According to the aforesaid experimental results and previous literature,12b,c a conceivable mechanism was proposed as shown in Figure 2. Initially, unsaturated ketoxime 1 is oxidized by Cu(II) to yield the iminoxyl radical (resonance structures A and B) and Cu(I) via an SET (single-electron transfer) process. The EBX reagent 2 also can oxidize oxime 1 to produce the iminoxyl radical. The formed iminoxyl radical then undergoes alternative O-/N-atom 5-exo-trig radical cyclization relying on the location

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bing Han: 0000-0003-0507-9742 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21422205, 21272106, and 21632001), the Changjiang Scholars and Innovative Research Team in University (IRT-15R28), the “111” Project, and the Fundamental Research Funds for the Central Universities (lzujbky-2016-ct02 and lzujbky-2016-ct08) for financial support. C

DOI: 10.1021/acs.orglett.8b01004 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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DOI: 10.1021/acs.orglett.8b01004 Org. Lett. XXXX, XXX, XXX−XXX