Photoinduced, Copper-Catalyzed Radical Cross-Coupling of

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

pubs.acs.org/OrgLett

Photoinduced, Copper-Catalyzed Radical Cross-Coupling of Cycloketone Oxime Esters, Alkenes, and Terminal Alkynes Jun Chen, Bin-Qing He, Peng-Zi Wang, Xiao-Ye Yu, Quan-Qing Zhao, Jia-Rong Chen,* and Wen-Jing Xiao CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticides & Chemical Biology Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China

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S Supporting Information *

ABSTRACT: A photoinduced, copper-catalyzed three-component radical cross-coupling of cycloketone oxime esters, alkenes, and terminal alkynes is described for the first time. Key to the success of this process was the integration of photoinduced iminyl radicalmediated C−C bond cleavage with the conceptual simplicity of copper-catalyzed radical cross-coupling. This protocol provides access to cyanoalkyl-containing propargylic compounds in good yields. Zard on iminyl radical-mediated β-C−C bond cleavage of cyclobutanone sulfenylimine and carboxymethyl oximes,14 the generation of cyclic iminyl radicals from cycloketone oxime derivatives and manipulation has recently attracted extensive research interest from the synthetic community (Scheme 1B). The vast majority of the known methodologies falls into four different categories according to the reaction modes of cyanoalkyl radicals: (1) direct addition to an unsaturated system,15 (2) cascade addition to unsaturated systems/ oxidation/addition by nucleophiles,16 (3) SET oxidation/ addition by nuleophiles,17 and (4) reductive18 or oxidative19 radical trap. Thus, a wide array of differently functionalized valuable nitriles can be obtained. Surprisingly, application of a cyanoalkyl radical or another carbon-centered radical formed by its addition to alkene in the RCC reaction has been less explored.20 Based on our continuous interest in NCR chemistry,21 we recently disclosed that a visible-light photoredox catalyst or copper catalysis enabled facile conversion of cycloketone oxime esters to iminyl radicals and their C−C bond cleavage.20a Mechanistic studies suggested that a benzylic radical was involved as the key intermediate formed upon addition of a cyanoalkyl radical to styrene. Thus, we wonder if we can develop radical cross-coupling of cycloketone oxime esters, alkenes, and alkynes through a cross-coupling between such a benzylic radical and in-situ-formed copper acetylide complex (Scheme 1C). Given the synthetic and biological significance of both nitrile and alkyne moieties, the products of this protocol should be of great interest to chemists. As illustrated in the proposed pathway, however, several competitive side reactions need to be considered, such as direct reductive HAT of radical A or its direct coupling with alkynes, reductive HAT of radical B, its oxidation to ketone, or

I

n recent years, the combination of transition-metal catalysis and radical chemistry has been established as a robust and powerful method toward construction of diverse C−C and C− heteroatom bonds under mild conditions.1 In particular, such transition-metal-catalyzed radical cross-coupling (RCC) allows construction of ubiquitous alkyl−alkyl bonds from various electrophiles and nucleophiles in a controlled manner that have been the most challenging to realize using traditional crosscoupling.2 For instance, a number of important studies of Fu revealed that nickel catalysis enabled the use of a wide spectrum of primary, secondary, and tertiary alkyl halides as radical precursors, thus rendering their efficient coupling with various carbon- and heteroatom-based nucleophiles.2,3 Building on these inspiring works, many groups devoted a great deal of effort to develop other radical precursor types to achieve a broader range of coupling partners and functional group compatibility. A wide variety of redox-active aliphatic carboxylic acids and their derivatives,4 alkylborons and alkylsilicons,5 sulfones,6 as well as alkyl (hetero)arenes,7 and vinyl (hetero)arenes,8−11 can be converted to the relevant alkyl radicals via SET, HAT, or radical addition (Scheme 1A). Subsequent capture of such radical species by a nucleophilederived metal complex (Nu-M) led to incorporation of diverse nucleophilic partners at the sp3-hybridized carbon centers via high-valent organometallic intermediates. Remarkably, several recent works of Zhang,8 Liu,9 and Liu10 demonstrated that a benzylic radical, formed by addition of CF3, CN, and Ncentered radicals to styrenes, could be trapped by an active Cu(II)-nucleophile species. These three-component crosscouplings provide useful access to 1,2-difunctionalization of alkenes. Despite these impressive advances, the scope of functionalized radical precursors and nucleophiles is still limited. As a versatile class of nitrogen-centered radicals (NCRs),12 iminyl radicals have found extensive application in organic synthesis.13 Particularly, stimulated by the discovery of © XXXX American Chemical Society

Received: May 3, 2019

A

DOI: 10.1021/acs.orglett.9b01529 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Condition Optimizationa

Scheme 1. Radical Cross-Coupling of Alkyl Radicals and Reaction Development with Oxime Derivatives

entry

oxime ester

[Cu] catalyst

1 2 3 4 5 6 7 8 9d 10 11 12e

1a 1a 1a 1a 1a 1a 1a 1a′ 1a′ 1a′ 1a′ 1a′

CuCl CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI

ligand (x) L1 L1 L2 L3 L4 L5 L3 L3 L3 L3 L3

(15) (15) (15) (15) (15) (15) (20) (20) (20) (20) (20)

yield (%)b 52 58 52 61 25 53 63 74 (71)c 56 trace trace trace

a

1a or 1a′ (0.6 mmol), 2a (0.2 mmol), 3a (0.6 mmol), copper salt (10 mol %), ligand (x mol %), and K2CO3 (0.6 mmol, 3.0 equiv) in DMF (2.0 mL) at 30 °C under irradiation of 7 W blue LEDs for 10 h. b Yields were determined by GC analysis using biphenyl as an internal standard. cIsolated yield within the parentheses. dWithout visible-light irradiation, 24 h. eWithout base.

β-elimination to Heck-type product. Notably, in their recent work on copper-catalyzed trifluoromethylalkynylation of styrenes with trimethoxysilyl-substituted alkynes, Liu et al. found that a simple terminal alkyne is not a suitable substrate.9c With these points in mind, we hypothesized that fine-tuning the rate of each intermediate generation by a rational combination of reaction parameters would probably allow us to solve these challenges. Drawing inspiration from the recent wide use of copper salts as photocatalysts in organic synthesis,22 we first examined the feasibility of the model reaction of cyclobutanone oxime ester (1a), 2-vinylnaphthalene (2a), and phenylacetylene (3a) in a ratio of 1:1.5:2 in DMF under visible-light-driven copper catalysis conditions (Table 1).23 Despite the formation of the desired cross-coupled product (4a), a significant amount of side products SP-1 to SP-4 were detected. These side products resulted from the self-coupling of substrates 1a and 3a or the intermolecular two-component coupling among 1a, 2a, and 3a. To our delight, when using 2a as a limiting reagent, a combination of CuCl (10 mol %) as a catalyst and 4,4′dimethoxy-2,2′-bipyridine (L1) (15 mol %) as a ligand led to a cleaner reaction system, furnishing product (4a) in 52% yield (entry 1). A further brief screening of copper salts revealed that CuI is superior to CuCl and increased the yield to 58% (entry 2). The suitable ligand might modulate the reactivity of the photoexcited copper acetylide complex and thus suppress the competitive reactions. Thus, with CuI in hand, we then evaluated a range of ligands (L2−L4) in order to further

improve the efficiency. The results of entries 3−7 indeed demonstrated obvious ligand effects, and use of 4,4′-di-tertbutyl-2,2′-bipyridine (dtbbpy) (L3) (20 mol %) gave 4a in 63% yield (entry 7). We found that structural modification of the acyl moiety on the oxime also had remarkable effects on the reaction. Replacement of p-trifluoromethylbenzoate in 1a with p-methoxylbenzoate (1a′) resulted in a significant increase of yield, with 4a isolated in 71% yield (entry 8). Without visible-light irradiation, the yield of 4a decreased significantly even after prolonged reaction time. In a series of control experiments without copper, ligand, or base, no desired product was detected, confirming the significance of these parameters (entries 10−12). Notably, the use of a superstoichiometric amount of a base should facilitate the in situ formation of the Cu(II) acetylide species prior to the radical trapping step.23 With the optimal conditions established, we first investigated the generality of this cross-coupling by reacting 1a′ and 3a with a representative array of alkenes (2) (Scheme 2A). Notably, most of them are inexpensive and commercially available feedstock materials. For instance, the catalytic system tolerated well a range of neutral styrene (2b) and its derivatives (2c−h) bearing electron-donating (e.g., Ph, OMe, OAc) or electron-withdrawing (e.g., Bpin, Br, CO2Me) substituents at the para-position of the aromatic ring. The expected products (4b−h) were obtained with yields ranging from 36 to 76%. To show the scalability of this process, a gram-scale reaction of 2c B

DOI: 10.1021/acs.orglett.9b01529 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope of the Alkenesa,b

conditions. As highlighted in Scheme 3A, a representative set of aryl alkynes having various electron-rich (tBu, Me, OMe) or Scheme 3. Substrate Scope of the Alkynesa,b

a

Refer to footnote a of Scheme 2. bIsolated yields. c1.0 mmol scale. Determined by chiral HPLC analysis on a chiral stationary phase.

d

electron-deficient (Br) functional groups at the para-, meta-, or ortho-position of the phenyl ring worked smoothly to afford the corresponding products (5a−g) in 52−82% yields. The fused aromatic group substituted alkynes such as 2ethynylnaphthalene (3h) and 1-ethynylpyrene (3i) were also well tolerated to give 5h and 5i in moderate to good yields. In addition to aryl alkynes, thiophene alkynes (3j and 3k) and ethynylferrocene (3l) also proved to be suitable substrates in this process (5j−l). Notably, a range of diversely functionalized aliphatic terminal alkynes such as ((prop-2-yn-1-yloxy)methyl)benzene (3m), 2-methylbut-3-yn-2-ol (3n), and but3-yn-1-ol (3o) also performed well in the reaction with satisfactory yields of 5m−o and excellent chemoselectivity; no C−O coupling products were observed along with 5n and 5o. Pleasingly, in the case of complex substrates, such as bioactive ethynyl estradiol (3p) and diacetone-D-glucose-derived alkyne (3q), the reaction worked smoothly without detrimental effect on the stereochemistry, leading to good yields of 5p and 5q (Scheme 3B). To display the scalability of this protocol, a 1.0 mmol scale reaction of alkyne 3d was also carried out, and product 5d could still be obtained in 75% yield. Finally, the substrate scope with respect to cycloketone oxime esters was explored (Scheme 4). Again, the current catalytic system demonstrated broad substrate and high functional group compatibility. For example, the reaction tolerated well a diverse range of symmetric, monosubstituted cyclobutanone oxime esters (1b−f) with biologically relevant functionality, including esters, cyano, phenyl, and benzyloxy groups at the 3-position, leading to the cross-coupled products 6b−f with 53−71% yields (Scheme 4A). Nonsymmetric cyclobutanone oxime ester (1g) could also participate in the reaction smoothly to produce 6g in 66% yield. Moreover, the sterically very demanding substrates such as 1h and 1i also proved to be suitable for the reaction and resulted in the corresponding products 6h and 6i in 54% and 41% yields,

a

1a′ (0.6 mmol), 2a (0.2 mmol), 3a (0.6 mmol), CuI (10 mol %), L3 (20 mol %), and K2CO3 (0.6 mmol) in DMF (2.0 mL) at 30 °C under irradiation of 7 W blue LEDs for 10 h. bIsolated yields. cGramscale reaction. dDetermined by 1H NMR analysis of the crude mixture. eDetermined by chiral HPLC analysis on a chiral stationary phase.

was performed, and product 4c could be obtained in 57% yield with 1.2 g.23 As shown in the synthesis of 4i−k, the substitution pattern and steric hindrance of the phenyl ring have no obvious effect on the reaction outcome. Moreover, 2vinylnaphthalene (2l) and heteroayl-substituted alkene (2m) were also well accommodated in the reaction, producing 4l and 4m in 61% and 55% yields, respectively. Remarkably, the current reaction system could be further successfully extended to a series of biologically relevant compounds and pharmaceutical-derived alkenes (Scheme 2B). Alkenes (2n− p) that contain a simple amino acid, estrone, and febuxostat scaffolds as well as gibberellic-acid-derived alkene (2q) all participated in the cross-coupling reaction efficiently to give the corresponding products (4n−q) with good yields. Thus, our protocol should be of potential application for late-stage functionalization of drug and drug-like compounds. Finally, we also examined several electron-deficient alkenes, such as acrylates 2r−s, α,β-unsaturated ketone 2t, and diethoxyphosphinylethene 2u under the standard conditions. Unfortunately, in all of these cases, lots of cyclobutanone oxime ester 1a′ remained, and no desired cross-coupling products were detected; instead, two-component coupling side products SP1 were observed with 10−20% NMR yields (Scheme 2C).23 Next, we continued to examine the scope of the alkynes (3) by reacting them with 1a′ and 2d under the standard C

DOI: 10.1021/acs.orglett.9b01529 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

To indentify the active metal species that might be involved in the process, we further utilized EPR spectroscopy to investigate the redox process between CuI catalyst and cyclobutanone oxime ester 1a′ (see Figure S1 in the Supporting Information).23 It was found that, upon addition of 1a′, the solution of CuI/dtbbpy/2a/3a in DMF showed obvious Cu(II) singals, which is in good agreement with Lei’s study.24 Moreover, we measured redox potentials of the ground states of 1a′ (Eredox = −2.18 V vs SCE in DMF), CuI/ dtbbpy (Eredox = −2.31 V vs SCE in DMF), CuI/phenylacetylide (Eredox = −0.89 V vs SCE in DMF), and CuI/dtbbpy/ phenylacetylide (Eredox = −2.82 V vs SCE in DMF). These results showed that SET oxidation by the complexes of CuI/ dtbbpy and CuI/dtbbpy/phenylacetylide is thermodynamically feasible, while the complex of CuI/phenylacetylide alone could not reduce 1a′. Finally, we studied the UV/vis spectra of the complexes of CuI/dtbbpy and CuI/dtbbpy/phenylacetylide. As expected, there is significant absorption above 400 nm for these complexes (see Figure S3 in the Supporting Information). Therefore, visible-light irradiation could result in generation of a photoexcited triplet Cu(I) complex and subsequently facilitate the cross-coupling process.22d,e On the basis of these experimental results and related literature,22,24 we proposed a possible mechanism as shown in Scheme 6. First, iminyl radical species 1a′-A was generated

Scheme 4. Substrate Scope of the Cycloketone Oxime Estersa,b

a

Refer to footnote a of Scheme 2. bIsolated yields. cDetermined to be 1:1 d.r. by 1H NMR analysis of the crude mixture, unless otherwise noted. dDetermined by chiral HPLC analysis on a chiral stationary phase. eAddition of fac-Ir(ppy)3 (2 mol %).

respectively (Scheme 4B). Notably, the current protocol can also be successfully extended to bicyclic ketone derived oxime esters 1j and 1k with the desired products 6j and 6k being formed in good yields (Scheme 4C). Finally, it was found that less strained, five- and six-membered cyclic ketone and camphor-derived oxime esters 1l and 1m were also compatible with the reaction in the presence of photocatalyst fac-Ir(ppy)3 (2 mol %), while resulting in moderate yields of 6l and 6m (Scheme 4D). To gain some insight into the mechanism, we first carried out several control experiments with model substrates 1a′, 2a, and 3a (Scheme 5a). When adding stoichiometric amounts of

Scheme 6. Proposed Reaction Mechanism

Scheme 5. Mechanistic Experiments

through a SET reduction of substrate 1a′ by the photoexcited complex [Cu(I)]* (path a) and its ground state [Cu(I)] complex (path b), with release of an oxidized [Cu(II)] complex. Then, a regioselective C−C bond β-scission of iminyl radical species 1a′-A occurs to form cyanoalkyl radical 1a′-B, which can be quickly captured by alkene 2a to generate a new, relatively more stable alkyl radical 1a′-C. Subsequently, radical species 1a′-C can be intercepted by the [Cu(II)]/phenylacetylide complex that is generated in situ by transmetalation between the initially formed [Cu(II)] and 3a, providing highvalent [Cu(III)] species 1a′-D. Finally, reductive elimination of intermediate 1a′-D gives rise to the final cross-coupling product 4a, regenerating the [Cu(I)] catalyst. Overall, we have developed a visible-light-driven, coppercatalyzed three-component radical cross-coupling of cycloketone oxime esters, alkenes, and terminal alkynes. The protocol is distinguished by mild conditions, broad substrate scope, and high functional group tolerance, providing access to structurally diverse cyanoalkyl-containing propargylic compounds.

radical traps TEMPO and PhSeSePh, the desired reaction was completely inhibited, and the relevant radical trapping products 7 and 8 could be detected. Furthermore, the reaction with radical clock substrate 9 gave rise to ring-opening product 10 in 78% yield, which should result from a radical crosscoupling of radical intermediate 9-B with phenylacetylene (3a) (Scheme 5b). These observations indicated the radical property of the cross-coupling process and the involvement of cyanoalkyl radical 1a’-B and benzylic radical such as 9-A. D

DOI: 10.1021/acs.orglett.9b01529 Org. Lett. XXXX, XXX, XXX−XXX

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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.9b01529.

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Experimental procedures, full analysis data for new compounds, and copies of NMR spectra (PDF)

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 (21622201, 91856119, 21820102003, and 21772053), the Science and Technology Department of Hubei Province (2016CFA050 and 2017AHB047), and the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) for support of this research.

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