Palladium-Catalyzed Electrochemical C–H Alkylation of Arenes

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Palladium-Catalyzed Electrochemical C−H Alkylation of Arenes Qi-Liang Yang,†,‡ Chuan-Zeng Li,‡,§ Liang-Wei Zhang,‡ Yu-Yan Li,*,§ Xiaofeng Tong,† Xin-Yan Wu,*,† and Tian-Sheng Mei*,‡ †

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Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China § Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China S Supporting Information *

ABSTRACT: Palladium-catalyzed electrochemical C−H functionalization reactions have emerged as attractive tools for organic synthesis. This process offers an alternative to conventional methods that require harsh chemical oxidants. However, this electrolysis requires divided cells to avoid catalyst deactivation by cathodic reduction. Herein, we report the first example of palladium-catalyzed electrochemical C−H alkylation of arenes using undivided electrochemical cells in water, thereby providing a practical solution for the introduction of alkyl groups into arenes.

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the need for a stoichiometric amount of a transition-metal chemical oxidant constitutes a practical disadvantage in these systems.6 Thus, the development of novel oxidation systems is in high demand.7 Transition-metal-catalyzed electrochemical C−H bond functionalization has emerged as an attractive tool for organic synthesis, since it avoids the use of dangerous and toxic chemical oxidants, thereby eliminating side reactions and byproducts.8−10 Inspired by seminal work from Amatore, Jutand, and Kakiuchi,11 our group has developed Pd-catalyzed electrochemical C(sp3)−H and C(sp2)−H oxygenation.12 In addition, we recently demonstrated Pd-catalyzed electrochemical aryl C−H methylation with MeBF3K (Scheme 1b).13 Unfortunately, this alkylation is mainly limited to methylation.14 The use of divided electrochemical cells is also problematic, since it complicates the setup.15 Herein, we report Pd-catalyzed electrochemical C−H alkylation of arenes and alkyl boron reagents using an undivided cell in water (Scheme 1c). Initially, we chose 2-(o-tolyl)pyridine (1a) and potassium trifluoromethylborate (MeBF3K) as reaction partners and probed various reaction conditions for the electrochemical C− H alkylation in an undivided cell. After extensive optimization, we found that a 70% isolated yield of desired product (2a) could be obtained under constant-current electrolysis at 1.0 mA in the presence of 10 mol % Pd(OAc)2 and 2 equivalents

uring the past decades, transition-metal-catalyzed siteselective C−H functionalization reactions have developed into promising transformations for the construction of carbon−carbon (C−C) bonds.1 Palladium-catalyzed C−H cross-coupling reactions, in particular, have received significant attention.2 In 2006, Yu and co-workers elegantly demonstrated the first example of Pd-catalyzed aryl C−H cross-couplings with alkyl tin and alkyl boron reagents (Scheme 1a).3 With this seminal report as inspiration, many examples of Pd-catalyzed aryl C−H couplings with organoboron reagents have been developed.4,5 While these transformations hold great promise in expedient construction of C−C bonds in organic synthesis, Scheme 1. Pd-Catalyzed C−H Alkylation

Special Issue: Organometallic Electrochemistry: Redox Catalysis Going the Smart Way Received: August 1, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.organomet.8b00550 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 2. Evaluation of Arylpyridinesa

of MeBF3K in a TFE/AcOH/H2O solution (2 mL/2 mL/0.5 mL) (Table 1, entry 1). Decreasing or increasing the electric Table 1. Reaction Optimization with Substrate 1aa

entry

variation from standard conditions

yield (%)b

1 2 3 4 5 6

none 0.5 mA instead of 1 mA 1.5 mA instead of 1 mA 40 °C instead of 60 °C 80 °C instead of 60 °C TFE/AcOH = 2.25 mL/2.25 mL instead of TFE/AcOH/H2O = 2 mL/2 mL/0.5 mL TFE/H2O = 2.25 mL/2.25 mL instead of TFE/AcOH/ H2O = 2 mL/2 mL/0.5 mL AcOH/H2O = 2.25 mL/2.25 mL instead of TFE/AcOH/H2O = 2 mL/2 mL/0.5 mL no Pd(OAc)2 no electric current

75 (70)c 67 63 34 32 65

7 8 9 10

52 64 nr nr

a Standard conditions: 1a (0.3 mmol), MeBF3K (2.0 equiv), Pd(OAc)2 (10 mol %), and TFE/AcOH/H2O (2 mL/2 mL/0.5 mL), in an undivided cell with two platinum electrodes (each 1.5 × 1.0 cm2), 60 °C, 1.0 mA, 18 h, 2.2 F mol−1. TFE = trifluoroethanol. b The yield was determined by GC analysis with tridecane as the internal standard. cIsolated yield in parentheses.

a

Standard conditions: 1 (0.3 mmol), MeBF3K (2.0 equiv), Pd(OAc)2 (10 mol %), and TFE/AcOH/H2O (2 mL/2 mL/0.5 mL), in an undivided cell with two platinum electrodes (each 1.5 × 1.0 cm2), 60 °C, 1.0 mA, 18−36 h.

current results in lower yields (entries 2 and 3). Various temperatures were examined, and 60 °C afforded the best yield (entries 4 and 5). Evaluating different solvents revealed that the combination TFE/AcOH/H2O (2 mL/2 mL/0.5 mL) was optimal (entries 6−8). Finally, control experiments indicated that Pd(OAc)2 and electricity are essential for this reaction (entries 9 and 10). With the optimized reaction conditions in hand, the scope of arylpyridines was investigated to test the generality and limitations of the reaction. As shown in Scheme 2, arenes substituted with various functional groups such as alkyl, ether, fluoro, and trifluoromethyl groups were well tolerated under the standard reaction conditions (2a−o). In general, substrates with electron-rich (Me, Et, i-Pr, t-Bu, OMe) substituents reacted particularly well (2i−m). A strongly electron withdrawing group, such as CF3, afforded a lower yield as a result of lower conversion (2o). This alkylation proved sensitive toward steric encumbrance near the targeted C−H bond: the less hindered ortho position was preferentially alkylated in the case of substrates bearing a meta substitutent (2g,p). A dialkylated product was normally formed in the case of substrates bearing a para substituent. To our delight, the presence of a methyl group in the 3-position of a pyridine ring ensures the monoselectivity (2h−o), presumably due to increased steric encumbrance for the monoalkylated products. Encouraged by the feasibility of Pd-catalyzed electrochemical methylation using MeBF3K as a coupling partner, we examined the reactivity of a series of alkyl boron reagents (Scheme 3). To our satisfaction, potassium trifluoroethylborate (EtBF3K) and potassium trifluorobutylborate (n-BuBF3K) are viable alkylation reagents, providing the corresponding alkylation in moderate yields (3a−d,f−h). However, potassium trifluorophenethylborate (PhEtBF3K) results in a lower yield as a result of lower conversion (3e).

Scheme 3. Evaluation of Alkyltrifluoroboratesa

a

Standard conditions: 1 (0.3 mmol), MeBF3K (2.0 equiv), Pd(OAc)2 (10 mol %), and TFE/AcOH/H2O (2 mL/2 mL/0.5 mL), in an undivided cell with two platinum electrodes (each 1.5 × 1.0 cm2), 60 °C, 1.0 mA, 18−36 h.

In order to gain further insight into this electrochemical C− H alkylation reaction, palladacycle 4 was prepared according to a literature report.16 Catalytic reactions suggested that this palladacyle is a viable intermediate for C−H coupling reactions (Scheme 4). Furthermore, a cyclic voltammogram (CV) of palladacyle 4 in CH3CN reveals one oxidation peak at 0.94 V versus Ag/AgCl and one irreversible reduction peak at 0.77 V (curve d, Figure 1), both of which are significantly lower than the onset potential for the oxidation of substrate 1a (curve c, 1.70 V) and MeBF3K (curve b, 1.38 V). A catalytic current and the disappearance of the reductive wave were observed when B

DOI: 10.1021/acs.organomet.8b00550 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 4. Catalytic Reaction with Palladacycle 4

Scheme 5. Kinetic Isotope Effect Studies

Scheme 6. Proposed Catalytic Cycle

Figure 1. Cyclic voltammograms recorded on a platinum electrode (area 0.03 cm2) at 100 mV s−1: (a) in MeCN containing 0.1 M nBu4NPF6; (b) in solution (a) after addition of 5 mM MeBF3K; (c) in solution (a) after addition of 5 mM 1a; (d) in solution (a) after addition of 5 mM palladacycle 4; (e) in solution (d) after addition of 20 mM MeBF3K.

undivided cell in water. This method offers an alternative to conventional organic synthesis which requires strong chemical oxidants. In addition, this protocol represents an environmentally friendly tool for the use of an electrochemical strategy. Investigations aimed at understanding the reaction mechanism and alkylation of C(sp3)−H bonds are currently underway in our laboratory.

MeBF3K was added into a solution of palladacyle 4 (curve e), suggesting that methylation takes place smoothly in the Pd(III) or Pd(IV) catalyst center.17 In addition, a kinetic isotope effect (KIE) value of 2.0 was observed in the intermolecular kH/kD value (Scheme 5a). Futhermore, a similar kinetic isotope effect was detected in parallel experiments (kH/kD = 2) (Scheme 5b). This indicates that the C−H cleavage occurs during the rate-determining step.18 On the basis of the above experimental results, a plausible mechanism is proposed for the Pd-catalyzed electerochemical C−H alkylation (Scheme 6). Initially, the nitrogen atom in substrate 1a coordinates with the palladium catalyst to generate complex 5. Next, C−H activation takes place to give palladacyle 4, which is the rate-determining step. Then complex 4 could be oxidized by anodic oxidation in the presence of potassium trifluoromethylborate to generate Pd(III) or Pd(IV) species 6,7 which could afford methylated product 2a and regenerate Pd(II) species upon reductive elimination. However, at this stage, we could not rule out the possibility that this alkylation undergoes Pd(II)/Pd(0) catalysis.2,7 In summary, we have developed a protocol for palladiumcatalyzed C(sp2)−H alkylation via anodic oxidation using a

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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.organomet.8b00550. Experimental details, characterization data, and 1H and 13 C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for Y.-Y.L.: [email protected]. *E-mail for X.-Y.W: [email protected]. *E-mail for T.-S.M.: [email protected]. ORCID

Tian-Sheng Mei: 0000-0002-4985-1071 Notes

The authors declare no competing financial interest. C

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ACKNOWLEDGMENTS This work was financially supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB20000000), “1000-Youth Talents Plan”, NSF of China (Grants 21572245, 21772222, 21772220), and S&TCSM of Shanghai (Grants 17JC1401200, 18JC1415600).

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