Multi-Metal-Catalyzed Oxidative Radical Alkynylation with Terminal

Article Cite This: J. Am. Chem. Soc. 2018, 140, 6006−6013

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Multi-Metal-Catalyzed Oxidative Radical Alkynylation with Terminal Alkynes: A New Strategy for C(sp3)−C(sp) Bond Formation Shan Tang,†,§ Yichang Liu,†,§ Xinlong Gao,† Pan Wang,† Pengfei Huang,† and Aiwen Lei*,†,‡ †

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College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China S Supporting Information *

ABSTRACT: A new way for C(sp3)−C(sp) cross-coupling with terminal alkynes has been developed by using a multi-metal-catalyzed reaction strategy. Alkyl radicals generated from different approaches are able to couple with terminal alkynes by judicious selection of the catalyst combination. This reaction protocol offers an efficient alternative approach for the synthesis of substituted alkynes from terminal alkynes besides traditional Sonogashira coupling. Mechanistic studies have also been carried out to clarify the role of each metal catalyst in the radical alkynylation processes. The reactions were found to go through radical reaction pathways. Synergistic cooperation of the metal catalysts is the key for controlling the reaction selectivity of alkyl radicals toward C(sp3)−C(sp) bond formation.

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INTRODUCTION Substituted alkynes are fundamental structure motifs, which widely exist in natural products, bioactive molecules, and functional materials.1 They also serve as versatile synthetic intermediates in organic transformations. Over the past several decades, transition-metal-catalyzed Sonogashira coupling has been proven to be one of the most efficient and reliable approaches for the synthesis of substituted alkynes.2 The Sonogashira coupling of aryl electrophiles has been well established for the construction of C(sp2)−C(sp) bonds. In contrast, Sonogashira coupling of alkyl electrophiles for C(sp3)−C(sp) bond formation still remains challenging. Fu and co-workers were pioneers in the Pd/Cu-cocatalyzed Sonogashira coupling with unactivated primary halides,3 and their protocol was extended to unactivated secondary halides by the group of Glorius.4 Similarly, Hu and co-workers developed a Ni/Cu-cocatalyzed Sonogashira-type coupling with unactivated primary halides,5 and Liu et al. modified the reaction system to be able to deal with secondary halides.6 More recently, an ultraviolet-light-promoted metal-free reaction protocol was developed by Li and co-workers to achieve the Sonogashira-type coupling with alkyl halides.7 Obviously, the developed Sonogashira-type alkynylation for C(sp3)−C(sp) bond formation largely relies on the cross-coupling with alkyl halides (Scheme 1a).8 It is highly appealing to develop new reaction approaches to allow C(sp3)−C(sp) cross-coupling with more alternatives. In 2016, our group developed a multi-metal-catalyzed oxidative radical alkynylation of unactivated alkanes with terminal alkynes (Scheme 1b).9 By using a catalyst combination of Cu(OTf)2, Ni(acac)2, and AgOAc, in situ generated cyclohexyl radical could couple with p-tolylacetylene to afford © 2018 American Chemical Society

7a in 73% yield. Good to high yields were observed for both aryl and aliphatic terminal alkynes (7b−7s). Cyclic alkanes could give single products (7t−7v), while linear alkanes afforded a mixture of regioisomers (7w). Since a lot of alkyl radicals can be easily generated under oxidative conditions, we envisioned a general method for C(sp3)−C(sp) cross-coupling based on this multi-metal-catalyzed oxidative radical alkynylation strategy (Scheme 1c). By judicious selection of the catalyst combination, tetrahydrofuran methyl radicals, α-cyano alkyl radicals, methyl radical, and unactivated alkyl radicals generated under oxidative conditions were all found to be able to couple with terminal alkynes. Synergistic cooperation of different metal catalysts was the key for controlling the reaction selectivity of these alkyl radicals toward C(sp3)−C(sp) bond formation. In this paper, we report the reaction development for C(sp3)− C(sp) cross-coupling of terminal alkynes with different alkyl radical sources. Moreover, a comprehensive mechanistic study has been conducted to understand this novel multi-metalcatalyzed radical oxidative alkynylation reaction protocol.

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RESULTS AND DISCUSSION Oxidative Alkynylation of Tetrahydrofuran Methyl Radicals. Propargyltetrahydrofurans can serve as useful intermediates in the synthesis of some bioactive products and materials.10 Chemler and co-workers reported that tetrahydrofuran methyl radicals could be generated from 4-penten-1-ol derivatives under copper-catalyzed oxidative conditions.11 We envisioned the synthesis of propargylic tetrahydrofurans through a cascade oxidative cyclization/C(sp3)−C(sp) crossReceived: March 11, 2018 Published: April 20, 2018 6006

DOI: 10.1021/jacs.8b02745 J. Am. Chem. Soc. 2018, 140, 6006−6013

Article

Journal of the American Chemical Society Scheme 1. C(sp3)−C(sp) Cross-Coupling with Terminal Alkynes

Scheme 2. Radical C(sp3)−C(sp) Cross-Coupling between 4-Penten-1-ol and Different Terminal Alkynesa

a

Standard conditions A: 1a (5.0 equiv), 2 (0.50 mmol), Cu(OTf)2 (15 mol %), CuOAc (15 mol %), Ni(acac)2 (15 mol %), Ag2O (7.5 mol %), DTBP (2.0 equiv), PhCF3 (6.0 mL), 130 °C, 4 h. Isolated yields are shown. bPhCl (6.0 mL) was used instead of PhCF3 (6.0 mL), and DTBP (4.0 equiv) was used. cThe yield was determined by NMR with CH2Br2 as the internal standard.

Scheme 3. Radical C(sp3)−C(sp) Cross-Coupling between Different Alkenols and p-Tolylacetylenea

coupling between 4-penten-1-ol derivatives and terminal alkynes (eq 1).

On the basis of the multi-metal-catalyzed oxidative radical alkynylation strategy, we found that 4-penten-1-ol with ptolylacetylene could furnish propargylic tetrahydrofuran 3a in 70% isolated yield by using Cu(OTf)2, CuOAc, Ni(acac)2, and Ag2O as combined catalysts (the effect of the reaction parameters is shown in Table S1, Supporting Information). The scope of terminal alkynes was then studied (Scheme 2). Phenylacetylenes bearing electron-donating, electron-withdrawing, and halide substituents were all suitable (3b−3f). Due to the fast homocoupling of the alkyne substrate, electron-rich 4methoxyphenylacetylene only gave a 54% isolated yield (3c). Other aromatic alkynes such as 2-ethynylnaphthalene and 2ethynylthiophene were also able to furnish the desired products with decreased reaction yields (3g and 3h). Aliphatic alkynes also showed good reactivity in the synthesis of propargylic tetrahydrofurans (3i−3l). It was worth noting that (triisopropylsilyl)acetylene could furnish the desired product with a satisfactory yield (3m). In the next step, different alkenols were applied as substrates under the standard conditions (Scheme 3). Various primary

a

Standard conditions A: 1 (5.0 equiv), 2a (0.50 mmol), Cu(OTf)2 (15 mol %), CuOAc (15 mol %), Ni(acac)2 (15 mol %), Ag2O (7.5 mol %), DTBP (2.0 equiv), PhCF3 (6.0 mL), 130 °C, 4 h. Isolated yields are shown. bAgOAc (15 mol %) was used instead of Ag2O, and DTBP (3.0 equiv) and PhCF3 (2.5 mL) were used. cDTBP (6.0 equiv) and PhCF3 (2.5 mL) were used.

alcohols were suitable in this transformation, which furnished the desired products in good to high yields (3n−3u). It was worth noting that this transformation was applicable to the 6007


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Journal of the American Chemical Society

alkynes (4e). 2-Ethylnylnaphthalene afforded the corresponding propargylic nitriles in 62% yield (4f) while 2-ethynylthiophene also furnished the desired product in 55% yield (4g). Analogues of AIBN were also tested. 2,2-Azobis(2-methylbutyronitrile) showed reactivity similar to that of AIBN (4h), while 1,1′-azobis(cyanocyclohexane) demonstrated decreased reaction efficiency (4i). Oxidative Alkynylation of Methyl Radical. Methylation is a fundamental transformation in organic chemistry. Recently, peroxides have been recognized as efficient methylation reagents since they can generate methyl radical during the decomposition process.13 Thus, peroxides might be used to achieve the direct methylation of terminal alkynes through our multi-metal-catalyzed radical alkynylation protocol (eq 3).

synthesis of spiro-bicyclic heterocycles with high reaction efficiency. With the increase of the substituted ring size, the reaction yields grew from 80% to 94% (3q−3t). In addition, the oxidative cyclization proceeded in a 6-exo-trig fashion to afford propargyltetrahydropyran 3u when 5-hexen-1-ol was utilized as the substrate. Under slightly modified reaction conditions, secondary and tertiary alkenols were also able to furnish the desired products, accessing bridged-bicyclic and spiro-bicyclic heterocycles (3v−3y). Internal alkenols were not suitable substrates at this moment. Oxidative Alkynylation of α-Cyano alkyl Radicals. 2,2Azobis(isobutyronitrile) (AIBN) is one of the most widely used and commercially available radical initiators in organic synthetic chemistry and polymer chemistry. AIBN and its analogues are known to generate α-cyano alkyl radicals under mild conditions.12 We herein illustrate a novel way for the synthesis of propargylic nitriles from the direct coupling between AIBN and terminal alkynes (eq 2).

By utilizing tert-butyl peroxybenzoate (TBPB) as the methyl radical source, we found that the combination of Cu(OTf)2, Ni(acac)2, and AgOAc as catalysts could give good results for the methylation of terminal alkynes (Scheme 5). A 78% yield

After a certain degree of optimization, we found that a catalyst combination of Cu(OTf)2, CuI, Fe(acac)2, and AgF could efficiently facilitate the C(sp3)−C(sp) cross-coupling between isobutyronitrile radical and terminal alkynes (Scheme 4). The effect of the reaction parameters was studied to understand the role of the four different transition-metal catalysts (see Table S2, Supporting Information, for details). Phenylacetylenes bearing electron-neutral substituents such as methyl, chloride, and phenyl groups gave the desired products in similar yields (4a−4d). Electron-rich 4-methoxyphenylacetylene also showed reactivity similar to that of electron-neutral

Scheme 5. Radical C(sp3)−C(sp) Cross-Coupling between Alkyl Peroxybenzoates and Different Terminal Alkynesa

Scheme 4. Radical C(sp3)−C(sp) Cross-Coupling between AIBN and Different Terminal Alkynesa

a

Standard conditions C: TBPB (2.0 equiv), 2 (0.50 mmol), Cu(OTf)2 (5.0 mol %), Ni(acac)2 (5.0 mol %), AgOAc (10 mol %), DBU (10 mol %), PhCl (7.0 mL), 100 °C, 3 h. Isolated yields are shown. bYields were determined by 1H NMR with CH2Br2 as the internal standard.

could be obtained in the case of p-tolylacetylene (5a). The effect of each catalyst on the reaction yield is demonstrated in Table S3, Supporting Information. Substituted phenylacetylenes bearing halide, electron-donating, and electron-withdrawing groups were all able to furnish the desired methylation products in good yields (5b−5f). 2-Ethylnylnaphthalene was also suitable in this transformation with moderate reaction

a

Standard conditions B: AIBN (1.2 equiv), 2 (0.50 mmol), Cu(OTf)2 (7.5 mol %), CuI (7.5 mol %), Fe(acac)2 (7.5 mol %), AgF (10 mol %), DTBP (5.0 equiv), DCE (1.0 mL), PhCF3 (1.0 mL), 80 °C, 12 h. Isolated yields are shown. bDCE (2.5 mL) and PhCl (2.5 mL) were used. 6008


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ethynylthiophene, did afford the desired products but in decreased reaction yields (7d and 7e). Notably, but-3-yn-1-yl, an aliphatic alkyne, could produce the decarbonylative crosscoupling product with increased reaction efficiency (7f). Acyclic aliphatic aldehydes were also tested. Notably, site-specific substituted alkynes could be obtained although with low reaction yields (7g−7i). Mechanistic Insights. In all the above-mentioned transformations, using a suitable catalyst combination was the key for achieving the C(sp3)−C(sp) cross-coupling. Thus, a series of experiments were carried out to understand the role of each catalyst. The oxidative C(sp3)−H alkynylation of cyclohexane (8a) with p-tolylacetylene (2a) was selected as a model reaction for investigation.9 The effect of each catalyst on the reaction yield is demonstrated in Table 1. By using Cu(OTf)2/

yields (5g). Notably, aliphatic alkynes such as but-3-yn-1-yl benzoate and but-3-yn-1-ylbenzene could undergo methylation with good reaction efficiency (5h and 5i). Besides methylation, our method was also applicable to the ethylation and propylation of terminal alkynes with corresponding alkyl peroxybenzoates but with decreased reaction yields (5j and 5k). Oxidative Alkynylation of Alkyl Radicals Generated from Aliphatic Aldehydes. Aldehydes are readily available and inexpensive bulk chemicals, which have been utilized as a source of acyl radicals. It is known that aliphatic acyl radicals can undergo fast decarbonylation to deliver alkyl radicals. As shown in Scheme 1b, we achieved the direct oxidative C(sp3)− H alkynylation of unactivated alkanes with terminal alkynes.9 However, the alkyl radicals generated from hydrogen abstraction of acyclic alkanes usually have poor regioselectivity. Thus, mixtures of regioisomers were obtained for acyclic alkanes. In comparison, aliphatic aldehydes could furnish sitespecific alkyl radicals under oxidative conditions.14 Herein, we describe a decarbonylative C(sp3)−C(sp) cross-coupling between aliphatic aldehydes and terminal alkynes (eq 4).

Table 1. Effect of Catalysts on the Yields of C(sp3)−C(sp) Cross-Couplinga

A satisfactory reaction efficiency could be achieved by using Cu(OTf)2, Fe(acac)2, and AgOAc as combined catalysts and DTBP as the oxidant (the effect of the reaction parameters is shown in Table S4, Supporting Information). As shown in Scheme 6, a 50% isolated yield of 7a could be obtained from

entry

variation from the standard conditions

yield (%)

1 2 3 4 5

none without Cu(OTf)2 without Ni(acac)2 CuOTf instead of Cu(OTf)2 without AgOAc

75 nd 6 nd 63

a

Standard conditions E: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5 mol %), Ni(acac)2 (7.5 mol %), dppb (7.5 mol %), AgOAc (10 mol %), DTBP (1.5 mmol), PhCl (3.0 mL), 130 °C, 3 h. Yields were determined by GC analysis with biphenyl as the internal standard. nd = not detected.

3

Scheme 6. Radical C(sp )−C(sp) Cross-Coupling between Aliphatic Aldehydes and Terminal Alkynesa

Ni(acac)2/AgOAc as the catalysts and dppb as the ligand, the C(sp3)−C(sp) bond formation product 7a could be obtained in 75% yield (Table 1, entry 1). No desired product could be observed in the absence of Cu(OTf)2, while 6% 7a was formed in the absence of Ni(acac)2 (Table 1, entries 2 and 3). Moreover, CuOTf failed to give the desired product, which demonstrated the crucial role of Cu(OTf)2 in this transformation (Table 1, entry 4). Silver catalyst had a minor effect on the reaction yield. An acceptable yield could still be obtained in the absence of AgOAc (Table 1, entry 5). Though silver catalyst was not indispensable in the alkynylation reaction, the addition of silver catalyst was important for ensuring a good reaction efficiency with both electron-deficient and electron-rich alkynes. The effect of silver on the reaction yields of terminal alkynes with different electron densities is shown in Table 2. Silver catalyst was essential for achieving a good reaction efficiency, especially for the reaction with electron-deficient phenylacetylenes (Table 2, entries 1−3). To gain some insight into the active metal species during the reaction, EPR detection of the reaction system was performed (Figure 1). Obvious Cu(II) signals were observed under the standard reaction conditions. Moreover, the Cu(II) signal during the reaction was different from the signal of Cu(OTf)2 without ligand and Cu(OTf)2 with dppb, which indicated the generation of new Cu(II) species in the reaction process. It has been reported that Ag(I) itself can activate C(sp)−H bonds to form alkynylsilver(I) species.15 However, no desired C(sp3)− C(sp) bond formation product could be observed by adding

a Standard conditions D: 6 (6.0 equiv), 2 (0.50 mmol), Cu(OTf)2 (5.0 mol %), Fe(acac)2 (5.0 mol %), AgOAc (10 mol %), dppb (5.0 mol %), DTBP (0.0 equiv), PhCl (6.0 mL), 130 °C, 3 h. Isolated yields are shown. bPhCF3 (6.0 mL) was used instead of PhCl (6.0 mL).

the reaction between cyclohexanecarboxaldehyde and ptolylacetylene. Electron-rich 4-methoxyphenylacetylene furnished the desired product in an increased yield (7b). Phenylacetylene bearing an o-chloride gave the C(sp3)−C(sp) cross-coupling product in 44% yield (7c). Other aromatic alkynes, including 2-ethynyl-6-methoxynaphthalene and 26009


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Besides the combination of Cu(II)/Ag(I), Cu(II)/Cu(I)/ Ag(I) was also used as the catalyst combination for the oxidative alkynylation with some radical sources (Schemes 3−5). In our previous study, we demonstrated that C(sp)−H bond cleavage was the rate-determining step in copperpromoted homocoupling of a terminal alkyne.16 Thus, the homocoupling of a terminal alkyne was chosen as the model reaction to compare the different reaction rates of C(sp)−H bond cleavage by utilizing different transition-metal catalysts and their combinations. In the presence of 7.5 mol % Cu(OTf)2, a 12% yield of homocoupling product 10a was obtained (Table 4, entry 1). A 7.5 mol % concentration of

Table 2. Effect of AgOAc on the Reaction Yields with Different Terminal Alkynesa

entry

R

yield (%) without AgOAc

yield (%) with AgOAc

1 2 3

Ac Me OMe

14 63 76

50 73 91

a

Standard conditions E: 8a (4.0 mL), 2 (0.50 mmol), Cu(OTf)2 (7.5 mol %), Ni(acac)2 (7.5 mol %), dppb (7.5 mol %), and DTBP (1.5 mmol) in PhCl (3.0 mL) at 130 °C for 3 h. Isolated yields are shown.

Table 4. Homocoupling of a Terminal Alkyne by Utilizing Different Catalystsa

entry

[Cu(OTf)2] (mol %)

[CuOAc] (mol %)

[Ni(acac)2] (mol %)

[AgOAc] (mol %)

yield (%)

1 2 3 4 5 6 7

7.5 0 0 0 7.5 7.5 7.5

0 7.5 0 0 7.5 0 0

0 0 7.5 0 0 7.5 0

0 0 0 10 0 0 10

12 9 nd 2 40 13 27

a

Reaction conditions: 2a (0.50 mmol), catalysts, and DTBP (1.5 mmol) in PhCl (3.0 mL) at 130 °C for 3 h. The yield was determined by GC analysis with biphenyl as the internal standard.

Figure 1. Electron paramagnetic resonance (EPR) spectra (X band, 9.4 Hz, 190 K). (Black line) Standard conditions: cyclohexane (4.0 mL), p-tolylacetylene (0.50 mmol), Cu(OTf)2 (0.038 mmol), Ni(acac)2 (0.038 mmol), dppb (0.038 mmol), AgOAc (0.050 mmol), and DTBP (1.5 mmol) in PhCl (3.0 mL) at 130 °C for 1 h. (Red line) Cu(OTf)2 in PhCl. (Blue line) Cu(OTf)2 and dppb in PhCl.

CuOAc led to the formation of 9% 10a (Table 4, entry 2). Ni(acac)2 was unable to furnish 10a under similar conditions (Table 4, entry 3). Moreover, the homocoupling product was observed in 2% yield when 10 mol % AgOAc was added (Table 1, entry 4). Then the reactions utilizing two catalysts were conducted. The combination of Cu(OTf)2 and CuOAc gave the highest yield of 10a (Table 4, entry 5). The combination of Cu(OTf)2 and Ni(acacc)2 gave a result similar to that of Cu(OTf)2 solely (Table 4, entry 6), while the combination of Cu(OTf)2 and AgOAc gave a higher yield of 10a than that of only Cu(OTf)2 (Table 4, entry 7). Ag(I)15 and Cu(I)16 have both been reported to promote the C(sp)−H bond cleavage of a terminal alkyne by forming π-complexes with the triple bond of the alkyne. This explained why both Ag(I) and Cu(I) can promote the homocoupling of a terminal alkyne in the presence of Cu(OTf)2. To compare the differences between Ag(I) and Cu(I), the homocoupling reaction rates of 2a with a stoichiometric amount of Cu(II)/Cu(I), Cu(II)/Ag(I), and Cu(II)/Cu(I)/ Ag(I) were determined. The homocoupling reaction rate by using Cu(II)/Cu(I) together was much faster even at lower temperature than that by using Cu(II)/Ag(I) together (Figure 2, comparing the black line with the blue line). However, adding Ag(I) salt into the Cu(II)/Cu(I) system could suppress the homocoupling reaction under 80 °C (Figure 2, comparing the red line with the black line). This might be due to the competition between Cu(I) and Ag(I) in coordinating with the terminal alkyne. According to these results, the generation rate of the alkynylmetal species could be tuned by utilizing different catalyst combinations. The choice of copper and silver catalyst combinations was important for achieving a good reaction

different Ag(I) salts in the absence of Cu(OTf)2. Instead, direct reductive addition product 9a was obtained in 12−16% yield (Table 3, entries 1−3). According to these experimental results, alkynylcopper(II) species were more likely to be formed instead of alkynylsilver(I) species during the C(sp3)−C(sp) cross-coupling process. Table 3. Reaction Results by Adding Different Silver Salts in the Absence of Coppera

entry

[Ag]

yield (%) of 7a

yield (%) of 9a

1 2 3

10 mol % AgOAc 5 mol % Ag2O 5 mol % Ag2CO3

nd nd nd

14 12 16

a

Reaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5 mol %), Ni(acac)2 (7.5 mol %), silver, dppb (7.5 mol %), and DTBP (1.5 mmol) in PhCl (3.0 mL) at 130 °C for 3 h. Isolated yields are shown. 6010


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transition-metal acetylacetonate salts were then tested. Fe(acac)2 and Fe(acac)3 demonstrated reactivities similar to that of Ni(acac)2 in this C(sp3)−C(sp) cross-coupling reaction (Table 5, entries 7 and 8). Co(acac)2 and Co(acac)3 also enhanced this reaction but with lower reaction efficiency (Table 5, entries 9 and 10). Interestingly, even Cu(acac)2 could enhance this alkynylation reaction (Table 5, entry 11). A control experiment regarding the role of acetylacetonate ion was also conducted (Table 5, entry 12). Adding K(acac) into the reaction suppressed the C(sp3)−C(sp) cross-coupling process. In our previous study, we illustrated that cyclohexyl radical could be stabilized by forming a Ni(III) complex.17 Later on, Lan and co-workers also demonstrated that Cu(acac)2 could easily react with cyclohexyl radical to generate a Cu(III) complex.18 On the basis of these results, we thought that cocatalysts such as Ni(acac)2 and Fe(acac)2 were more favorable than Cu(OTf)2 to mediate the reactions with alkyl radicals by forming Ni(III) or Fe(III) species. Thus, metal acetylacetonate salts were likely to be the key catalysts for promoting the radical cross-coupling between alkyl radicals and alkynylmetal species. To provide an overview, the effect of ligands was also explored (Table 6). Similar to silver catalyst, a ligand was also

Figure 2. Kinetic profile of the homocoupling reaction of 2a by using a stoichiometric amount of metal salts: black line, Cu(OTf)2 (1.0 mmol), CuOAc (1.0 mmol), and 2a (0.50 mmol) in PhCl (3.0 mL), 80 °C; red line, Cu(OTf)2 (1.0 mmol), CuOAc (1.0 mmol), AgOAc (1.0 mmol), and 2a (0.50 mmol) in PhCl (3.0 mL), 80 °C; blue line, Cu(OTf)2 (1.0 mmol), AgOAc (1.0 mmol), and 2a (0.50 mmol) in PhCl (3.0 mL), 130 °C.

efficiency since the generation rate of the alkynylmetal species needs to match the different generation rates of the alkyl radicals. Further efforts were taken to gain some insight into the role of nickel catalyst in this transformation. To simplify the reaction system, the reactions between 8a and 2a were carried out in the absence of ligands. In the absence of nickel catalysts, the combination of Cu(OTf)2/AgOAc only afforded a 6% yield of the C(sp3)−C(sp) bond formation product 7a along with a 2% yield of the terminal alkyne homocoupling product 10a (Table 5, entry 1). Afterward, different nickel catalysts were added into the reaction system. Only Ni(acac)2 showed a high reactivity in promoting the C(sp3)−H alkynylation reaction, while other nickel catalysts did not exert positive effects on the C(sp3)−C(sp) bond formation (Table 5, entries 2−6). Other

Table 6. Effect of Ligandsa

entry

ligand

yield (%)

1 2 3 4 5 6 7

none 5 mol % dppb 7.5 mol % dppb 10 mol % dppb 15 mol % dppb 15 mol % PPh3 15 mol % Bipy

53 70 79 70 5 64 51

a Reaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5 mol %), Ni(acac)2 (7.5 mol %), ligand, AgOAc (10 mol %), DTBP (1.5 mmol), PhCl (3.0 mL), 130 °C, 3 h. Yields were determined by GC analysis with biphenyl as the internal standard.

Table 5. Reaction Results with Cocatalystsa

entry

M

yield (%) of 3aa

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

none Ni(OAc)2·4H2O Ni(OTf)2 NiCl2 Ni(COD)2 Ni(acac)2 Fe(acac)2 Fe(acac)3 Co(acac)2 Co(acac)3 Cu(acac)2 K(acac)b

6 4 6 4 nd 53 48 59 36 20 38 nd

not indispensable for the C(sp3)−C(sp) bond formation. A moderate yield could be obtained in the absence of a ligand (Table 6, entry 1). The best result was obtained by using an equal amount of dppb compared with the copper and nickel catalyst (Table 6, entries 2−4). An excess amount of ligand would suppress the alkynylation reaction (Table 6, entry 5). PPh3 was less effective than dppb in this transformation (Table 6, entry 6). Addition of bipyridine did not increase the reaction yield (Table 6, entry 7). It has been reported that phosphine ligands can coordinate with Ni(acac)2 to form six-coordinated nickel complexes.19 Phosphine ligand was likely to play a role in stabilizing the nickel complexes during the reaction. After understanding the role of each catalyst in the radical alkynylation reaction, efforts were made to explore the radical generation processes in all the transformations. Radical trapping experiments were carried out by adding 1 equiv of 1,1diphenylethylene under the standard conditions. The alkenylation products with 1,1-diphenylethylene could all be observed though in different yields (Scheme 7, 9b−9e). The GC−MS

a

Reaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5 mol %), [M] (7.5 mol %), AgOAc (10 mol %), and DTBP (1.5 mmol) in PhCl (3.0 mL) at 130 °C for 3 h. bA 15 mol % concentration was added. 6011


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to couple with terminal alkynes by judicious selection of the catalyst combination. The reaction protocol is complementary to the traditional Sonogashira coupling for the synthesis of substituted alkynes. The reactions are found to go through radical reaction pathways, and synergistic cooperation of the metal catalysts is the key for controlling the reaction selectivity of alkyl radicals toward C(sp3)−C(sp) bond formation. Cu(OTf)2 is the crucial catalyst in the C(sp)−H bond activation. Ag(I) and Cu(I) catalysts can tune the reaction rate of C(sp)−H bond cleavage through coordination with the carbon−carbon triple bond. Metal acetylacetonate salts such as Ni(acac)2 and Fe(acac)2 are important for promoting the radical cross-coupling reaction of alkynylmetal species with alkyl radicals. Overall, the appropriate combination of these transition-metal salts is crucial for achieving a good reaction efficiency.

Scheme 7. Radical Trapping Experiments

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ASSOCIATED CONTENT

S Supporting Information *

analysis of the trapped radicals is shown in the Supporting Information, Figures S1−S4. These results testified the assumption that the transformations reported in this paper all proceeded through radical alkynylation processes. A proposed mechanism for the oxidative radical alkynylation of cyclohexane (8a) with p-tolylacetylene (2a) is presented in Scheme 8. Initially, an alkynylcopper(II) complex (B) is

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b02745. Experiment details and spectral data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

Scheme 8. Proposed Catalytic Cycles for the Oxidative Radical Alkynylation between Cyclohexane and pTolylacetylene

*[email protected] ORCID

Aiwen Lei: 0000-0001-8417-3061 Author Contributions §

S.T. and Y.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grants 21390402 and 21520102003) and the Hubei Province Natural Science Foundation of China (Grant 2017CFA010). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated. Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.

generated from the Cu(OTf)2/AgOAc-cocatalyzed C(sp)−H activation of 2a. Afterward, transmetalation takes place between Ni(acac)2 and B to afford a Ni(II) complex (A). At the same time, cyclohexyl radical is generated through hydrogen abstraction by the in situ generated tert-butoxyl radical. Then the generated cyclohexyl radical reacts with A to give the alkynylation product 7a and Ni(acac).20 Finally, Ni(acac) is oxidized by DTBP to regenerate Ni(acac)2. By using the optimized catalytic system, C(sp3)−H bond cleavage of 8a and C(sp)−H bond cleavage of 2a are at considerable reaction rates. The dppb ligand is supposed to play a role in stabilizing the nickel complexes during the reaction process. Similar reaction mechanisms are expected for the alkyl radicals generated from other radical sources. Besides the differences in the radical generation processes, the speeds of C(sp)−H bond cleavage are also different by using different copper and silver catalyst combinations.

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REFERENCES

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CONCLUSION In summary, we have developed a versatile method for the direct C(sp3)−C(sp) cross-coupling with terminal alkynes. Alkyl radicals generated from different approaches are all able 6012


Article

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Multi-Metal-Catalyzed Oxidative Radical Alkynylation with Terminal

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