Mechanistic Aspects of Pincer Nickel(II)-Catalyzed C–H Bond

Feb 15, 2018 - The tube containing the reaction mixture was heated at 100 °C in a preheated oil bath and progress of the alkylation reaction was moni...
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Mechanistic Aspects of Pincer Nickel(II)-Catalyzed C−H Bond Alkylation of Azoles with Alkyl Halides Ulhas N. Patel,†,∥ Shailja Jain,‡ Dilip K. Pandey,†,∥ Rajesh G. Gonnade,§ Kumar Vanka,‡ and Benudhar Punji*,†,∥ †

Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, ‡Physical and Materials Chemistry Division, and Centre for Material Characterization, CSIR−National Chemical Laboratory (CSIR−NCL), Dr. Homi Bhabha Road, Pune 411 008, India ∥ Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 020, India §

S Supporting Information *

ABSTRACT: The quinolinyl-based pincer nickel complex, κN,κN,κN-{C9H6N-(μ-N)-C6H4−NMe2}NiCl [(QNNNMe2)NiCl; (1)] has recently been demonstrated to be an efficient and robust catalyst for the alkylation of azoles with alkyl halides under copper-free conditions. Herein, we report the detailed mechanistic investigation for the alkylation of azoles catalyzed by (QNNNMe2)NiCl (1), which highlights an iodineatom transfer (IAT) mechanism for the reaction involving a NiII/NiIII process. Deuterium labeling experiments indicate reversible cleavage of the benzothiazole C−H bond, and kinetic studies underline a fractional negative rate order with the substrate benzothiazole. The involvement of an alkyl radical during the alkylation is validated by radical clock and external additive experiments. An active intermediate species (QNNNMe2)Ni(benzothiazolyl) (5a) has been isolated and structurally characterized. The complex (QNNNMe2)Ni(benzothiazolyl) (5a) is found to be the resting state of catalyst 1. Kinetic analysis of electronically different intermediates suggests that the step involving the reaction of 5a with alkyl iodide is crucial and a rate-influencing step. DFT calculations strongly support the experimental findings and corroborate an IAT process for the alkylation reaction.

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INTRODUCTION Transition-metal-catalyzed C−H bond alkylation of heteroarenes with unactivated alkyl halides bearing β-hydrogens is one of the most promising and challenging reactions because of the trivial β-hydride elimination and/or hydrodehalogenation of the alkyl electrophiles upon addition to transition-metals.1 Regardless, various metal catalysts are known to efficiently catalyze the alkylation of heteroarenes under diverse reaction conditions.2,3 Particularly, the alkylation of azoles by nickel is significant as azoles are ubiquitously found in many biological and pharmaceutical compounds,4 and nickel is among the inexpensive and earth-abundant metals.5 The C-2 alkylation of azoles employing nickel catalysis has been independently demonstrated by Hu6 and Ackermann,7 wherein reactions were performed at high temperature, and an additional copper cocatalyst was employed. Miura has reported a copper-free method for the alkylation of azoles.5b However, this was demonstrated with very limited scope, and the reactions were reported with extremely low yields of the coupled products. Our group has reported an improved and robust nickel catalyst system for the alkylation of azoles under copper-free conditions, and the reactions were demonstrated at relatively mild reaction temperatures.8 © XXXX American Chemical Society

Despite the significant progress in C−H bond alkylation of azoles by nickel,9 a comprehensive mechanistic study for this process is not available.2d,10 This could be partially attributed to the usage of in situ generated catalysts or a precatalyst, which were not the actual catalyst during the reaction. The absence of conclusive mechanistic insight for nickel-catalyzed alkylation has compelled the assumption of various catalytic pathways. For example, Ackermann has hypothesized a NiI/NiIII catalytic cycle for the alkylation with NiI-species as active catalyst for the reaction,7 whereas Miura has proposed a Ni0/NiII pathway.5b Unfortunately, both the proposals have been made without much experimental evidence. Hu has deliberated the heterogeneous nickel particles as active catalyst during the alkylation of azoles that were generated upon degradation of the pincer catalyst (MeNN2)NiCl.6 Recently, we have developed a well-defined and robust nickel catalyst system, κN,κN,κN{C9H6N-(μ-N)-C6H4−NMe2}NiCl [(QNNNMe2)NiCl; (1)] for the alkylation of benzothiazoles with alkyl halides, and we found that the catalysis follows a molecular pathway.8 In addition, we have proposed a speculative pathway on the Received: January 15, 2018

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DOI: 10.1021/acs.organomet.8b00025 Organometallics XXXX, XXX, XXX−XXX

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Organometallics working mode of the catalyst system. Herein, we have studied the in-depth mechanism of the pincer nickel-catalyzed alkylation of azoles with alkyl halides, wherein a NiII/NiIII catalytic cycle has been disclosed that proceeds via an iodine atom transfer (IAT) pathway. Detailed kinetics, controlled reactivity study, and deuterium labeling experiments have been performed to obtain information about various steps during the alkylation. The isolation and reactivity of a crucial intermediate species (QNNNMe2)Ni(2-benzothiazolyl) has been demonstrated. DFT calculations were carried out for the important elementary steps to gather information on energetically viable intermediates during the reaction. All the experimental and theoretical findings have led us to present an updated mechanistic cycle for the pincer nickel-catalyzed C−H bond alkylation of azoles with alkyl halides.

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RESULTS AND DISCUSSION Recently, we have developed a series of quinolinyl-based pincer nickel complexes, κN,κN,κN-{C9H6N-(μ-N)-C6H4−NR2}NiX [(QNNNR2)NiX; R = Me, Et and X = Cl, Br, OAc] and employed them for the C-2 alkylation of azoles with alkyl halides.8 Among them, the catalyst (QNNNMe2)NiCl (1) was demonstrated to be very robust, and the alkylations were exhibited in the absence of a copper cocatalyst (Scheme 1).

Figure 1. Reaction profile for the 1-catalyzed alkylation of benzothiazole (2a) with 1-iodooctane (3a). Plot was fitted linear with Origin Pro 8.

induction period for the production of 4aa, which suggests that 1 acts as an active catalyst. The rate order of the alkylation reaction in each component was independently determined at 100 °C in 1,4-dioxane using the initial rate approximation. The rate of the alkylation reaction is almost similar to different initial concentrations of 1iodooctane, suggesting that the reaction is zeroth-order in the concentration of 1-iodooctane (see the Supporting Information for details). Similarly, the rate of the alkylation reaction is independent of the concentration of LiOtBu, and provides a zeroth-order behavior for this component. Further, the reaction rate on various loadings of catalyst 1 was measured by the initial rate of the product formation (see Figure S3 in the Supporting Information). The plot of log(rate) vs log(conc. 1) furnished a slope of 1.3, suggesting a fractional and complex rate order in the loading of catalyst 1 (Figure 2). Considering the

Scheme 1. Nickel-Catalyzed Alkylation of Benzothiazole

Preliminary findings suggested that the catalysis proceeds via a homogeneous process, and complex 1 acts as an active catalyst in the reaction.8 Considering the excellent catalytic activity and well-defined nature of catalyst 1, we were prompted to perform a detailed mechanistic study of (QNNNMe2)NiCl (1)-catalyzed alkylation of azoles with alkyl halides. The coupling of benzothiazole (2a) with 1-iodooctane (3a), to obtain the alkylated product 4aa, was chosen as a model reaction for the mechanistic study (Scheme 1). Kinetic Analysis of ( QNNN Me2)NiCl (1)-Catalyzed Alkylation of Azoles. All the kinetic experiments were performed in flame-dried screw cap tubes under an argon atmosphere. A tube was charged with catalyst 1 (0.02 mmol, 0.01 M), LiOtBu (0.048 g, 0.60 mmol), 1-iodooctane (0.11 mL, 0.60 mmol, 0.30 M), benzothiazole (0.044 mL, 0.40 mmol, 0.20 M), and n-dodecane (0.04 mL, 0.17 mmol, 0.085 M, internal standard), and 1,4-dioxane (1.81 mL) was added to make the total volume to 2.0 mL. The tube containing the reaction mixture was heated at 100 °C in a preheated oil bath and progress of the alkylation reaction was monitored by gas chromatography (GC) at regular intervals. The reaction profile for the nickel-catalyzed alkylation of benzothiazole up to 75 min is shown in Figure 1. The formation of the alkylation product followed a linear line, and the reaction did not need an

Figure 2. Plot of log(rate) vs log(conc. 1).

involvement of the catalyst in multiple steps in the catalysis, the observed rate order seems to be reasonable. Notably, the rate of the reaction decreases upon increasing the concentration of benzothiazole, and a slope of −0.4 was obtained from the plot of log(rate) vs log(conc. benzothiazole) (Figure 3). This fractional negative rate order on benzothiazole suggests the probable formation of a dormant Ni-species upon increased B

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alkylation reaction (Scheme 3). Thus, the reaction of benzothiazole with 5-bromo-1-pentene (3b) under standard Scheme 3. Alkylation Reactions for Radical Clock Experiments

Figure 3. Plot of log (rate) vs log (conc. benzothiazole).

concentration of benzothiazole. Possible formation of a catalytic inactive Ni-species via the reaction of benzothiazolyl lithium to any high-valent nickel species, such as (QNNNMe2)Ni(benzothiazolyl)(iodide), can be presumed in the presence of an excess of benzothiazole. This probability has been considered and examined by DFT energy calculations (see the Supporting Information for details) Isotope Labeling Studies. To probe the essence of the C−H bond cleavage process, we have performed deuterium labeling experiments. Thus, a reaction between 6-ethoxy benzothiazole (2b) and 2-D-benzothiazole ([2-D]-2a) in the presence of LiOtBu (and in the presence/absence of catalyst 1), at an early reaction time, showed a significant H/D scrambling between them (Scheme 2). This H/D scrambling suggests that

catalytic conditions afforded exclusively the expected alkylated product 2-(pent-4-en-1-yl)benzo[d]thiazole (4ab) in 40% yield. However, the reactions of benzothiazole (2a) with cyclopropylmethyl bromide (3c) and 6-bromo-1-hexene (3d) produced the ring opened 2-(but-3-en-1-yl)benzo[d]thiazole (4ac) and 5-exocyclized 2-(cyclopentylmethyl)benzo[d]thiazole (4ad) as exclusive products, respectively. These findings strongly support the involvement of an alkyl radical intermediate during the reaction. Thus, the two-electron oxidative addition of alkyl halide to nickel catalyst is ruled out, and the addition of alkyl as a radical to the nickel center can be presumed. Controlled Reactivity and Resting State of Catalyst 1. The status of catalyst (QNNNMe2)NiCl (1) under the catalytic conditions was followed by 1H NMR spectroscopy to know the resting state of the catalyst, and to identify any possible catalytic active intermediates during the alkylation. Thus, the catalyst (QNNNMe2)NiCl was treated with 1-iodooctane in the presence of LiOtBu in toluene-d8, and the reaction mixture was heated at 100 °C (Scheme 4). The 1H NMR analysis of the reaction

Scheme 2. H/D Scrambling Experiment

Scheme 4. Controlled Reaction of Complex 1

the C−H bond clevage process is reversible and almost remains in equilibrium. Further, the rates of the alkylation reactions employing 2-H-benzothiazole (2a) and 2-D-benzothiazole ([2D]-2a) with 1-iodooctane were measured (see Figure S5 in the Supporting Information). The equilibrium isotope effect (EIE) value was found to be 0.97 (kH/kD). Both these labeling experiments highlighted that the C−H bond cleavage is facile, and is not a rate-influencing step in the alkylation reaction. Probing the Radical Pathway. Nickel catalysts are known to execute single-electron transfer (SET) processes during the catalytic reactions, in addition to the 2e redox pathway.9c,10b,11 Previously, we had performed the radical inhibitor experiments, wherein addition of TEMPO or galvinoxyl completely suppressed the (QNNNMe2)NiCl (1)-catalyzed alkylation reaction.8 This finding gave a preliminary impression that the reaction might involve a radical intermediate. To gain more insights into the 1e versus 2e pathway, we have performed radical clock experiments for the (QNNNMe2)NiCl-catalyzed

mixture shows exclusive presence of the complex (QNNNMe2)NiCl (1). Neither the formation of any new species nor the decomposition of complex 1 was observed, which suggests that the reaction of 1 with 1-iodooctane is not the first step of the reaction. In another experiment, catalyst 1 was treated with benzothiazole in the presence of LiOtBu in toluene-d8, and C

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Organometallics the reaction mixture was heated at 100 °C (Scheme 4). The 1H NMR analysis of the reaction mixture showed the formation of the new complex, (QNNNMe2)Ni(2-benzothiazolyl) (5a) in 93% yield. The synthesis and characterization details of complex 5a is discussed (vide infra). Surprisingly, the complex 5a could be obtained even at room temperature from the reaction of 1 with benzothiazole in the presence of LiOtBu, albeit in lower yield (35% and 48% after 6 and 18 h, respectively; see Figure S6 in the Supporting Information). This highlights that the formation of complex 5a is facile, and the observed complex 5a might be a vital intermediate during the alkylation. All these observations further suggest that the reaction of catalyst 1 with benzothiazole is the early step of the alkylation, rather than the reaction of catalyst 1 with 1iodooctane. Furthermore, in order to know whether 5a could be the resting state of catalyst 1, a standard catalytic reaction was performed in a J-Young NMR tube employing 20 mol % of 1 in toluene-d8. Upon heating the reaction mixture at 100 °C for 30 min, the major nickel species observed was (QNNNMe2)Ni(2-benzothiazolyl) (5a). This clearly suggests that the intermediate 5a is the resting state of the catalyst during the alkylation reaction. Synthesis and Characterization of (QNNNMe2)Ni(2Benzothiazolyl) (5a) and Derivatives. The treatment of complex ( QNNN Me2)NiCl (1) with one equivalent of benzothiazole in the presence of LiOtBu in toluene at 100 °C produced the complex (QNNNMe2)Ni(2-benzothiazolyl) (5a) in 91% isolated yield (Scheme 5). Similarly, the reactions of 1

Figure 4. Thermal ellipsoid plot of (QNNNMe2)Ni(2-benzothiazolyl) (5a). All hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Ni(1)−C(18), 1.936(8); Ni(1)−N(1), 1.866(7); Ni(1)−N(2), 1.890(7); Ni(1)−N(3), 1.964(7). Selected bond angles (deg): N(1)− Ni(1)−C(18), 173.2(3); N(1)−Ni(1)−N(2), 84.2(3); N(1)−Ni(1)− N(3), 85.9(3); N(2)−Ni(1)−N(3), 169.7(3).

NNN-pincer ring, with the torsion angle of N2−Ni−C18−S1 being around 72°. Reactivity of (QNNNMe2)Ni(2-Benzothiazolyl) (5a). The probability of complex (QNNNMe2)Ni(2-benzothiazolyl) (5a) being an intermediate during the alkylation reaction was investigated by performing the reaction of 5a with different electrophiles under various reaction conditions. Thus, the reaction of 5a (0.012 g, 0.0264 mmol) with 1.0 equiv of 1iodooctane in the presence of LiOtBu (1.0 equiv) in toluene-d8 at 100 °C afforded the product 4aa in 86% yield (Scheme 6a).12

Scheme 5. Synthesis of (QNNNMe2)Ni(2-Benzothiazolyl) (5a) and Derivatives

Scheme 6. Reactivity of (QNNNMe2)Ni(2-Benzothiazolyl) (5a) with Electrophiles

with 6-ethoxy-benzothiazole and 6-fluoro-benzothiazole afforded the complexes (QNNNMe2)Ni(2-(6-ethoxy benzothiazolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro benzothiazolyl)) (5c), respectively. All the complexes 5a−5c were fully characterized by 1H and 13C NMR spectroscopy, as well as by HRMS. The molecular structure of 5a was further confirmed by a single crystal X-ray diffraction study (Figure 4). The coordination geometry around nickel in complex 5a is distorted square planar. Selected bond lengths and bond angles are given in the figure caption. The Ni−N1(amido) bond length is 1.866(7) Å, which is slightly longer than the corresponding Ni−N1(amido) bond length in (QNNNMe2)NiCl (1.8441(18) Å).8 This could be due to the strong trans influence exerted by benzothiazolylmoiety toward nickel in 5a than the trans influence by the Clligand in the complex 1. The Ni−N2(quinolinyl) and Ni−N3(amino) bond lengths 1.890(7) and 1.964(7) Å, respectively, are comparable with the corresponding bond lengths in complex 1 (Ni−N2 = 1.899 and Ni−N3 = 1.955 Å). The N(2)−Ni(1)− N(3) bite is 169.7(3)°, which is similar to that observed in other quinolinyl-based nickel complexes (QNNNR2)NiX.8 The ring of the benzothiazolyl-moiety is almost perpendicular to the

The same reaction in the absence of LiOtBu also produced 4aa in 75% yield (Scheme 6b). These observations suggest that the complex 5a is a crucial intermediate during the alkylation reaction and that the base is not necessary for the addition of alkyl halide to intermediate 5a. As expected, the reaction of complex 5a with 6-bromo-1-hexene (3d) produced exclusively the 5-exocyclized product, 2-(cyclopentylmethyl)benzo[d]thiazole (4ad) (Scheme 6c). This highlights the fact that the oxidative addition of alkyl halide to intermediate 5a proceeds D

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findings on the probable reaction pathway of (QNNNMe2)Ni(2benzothiazolyl) (5a) with 1-iodooctane. Quantum Chemical Calculations. Full quantum chemical calculations were done with density functional theory (DFT) at the PBE/TZVP level of theory in order to understand the mechanism for the formation of the alkylated product 4aa by the Ni(II) catalyst 1. Since the complex (QNNNMe2)Ni(2benzothiazolyl) (5a) was found as an active catalytic intermediate, and the experimental findings strongly support the involvement of an alkyl radical during the nickel catalyzed alkylation of benzothiazole, we have investigated the probable pathway for the reaction of 5a with 1-iodooctane through DFT. Two pathways have been considered: either (i) the iodide radical or (ii) the octyl radical can react with 5a to give the Ni(III) intermediate. The formation of (QNNNMe2)Ni(2benzothiazolyl)(octyl) (A) by the reaction of 5a with the octyl radical is endergonic by 58.6 kcal/mol (Scheme 7) and

through a radical pathway and that the nickel species alone is responsible for the formation of the radical species. Surprisingly, in all these reactions, neither the nickel species nor the free ligand was detected by 1H NMR, suggesting that the formation of a paramagnetic nickel species during the reaction. Reaction Rates of Intermediates (Electronic Influence on Alkylation). In order to understand the electronic effect of the substrates on the alkylation reaction, and particularly, on the step involving the reaction of alkyl iodide with the NiII species, we have measured the rates of the reactions of differently substituted intermediates (QNNNMe2)Ni(2-(6ethoxy benzothiazolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro benzothiazolyl)) (5c) with 1-iodooctane. Each of the complexes 5b and 5c was treated with 1-iodooctane (1.0 equiv) in a J-Young NMR tube in toluene-d8 and the formation of coupled product was monitored by 1H NMR. The rates of the reactions of 5b and 5c with 1-iodooctane were found to be 2.65 × 10−4 and 1.43 × 10−4 M min−1, respectively (Figure 5).

Scheme 7. Formation of Complex (QNNNMe2)Ni(2benzothiazolyl)(octyl) (A) by the Combination 5a with the Octyl Radicala

a

The free energy value (in kcal/mol) shows that reaction is highly unfavorable.

the formation of (QNNNMe2)Ni(2-benzothiazolyl)(iodide) (B) by reaction with the iodide radical is endergonic by 32.5 kcal/ mol (Figure 6). Considering the given experimental conditions of elevated temperature (100 °C), formation of B is expected to

Figure 5. Rates of the reactions of (QNNNMe2)Ni(2-(6-ethoxy benzothiazolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro benzothiazolyl)) (5c) with 1-iodooctane.

The alkylation reaction is faster with an electronically rich intermediate (substrate) compared to the electronically deficient counterpart, which suggests that the nickel species might be developing an electropositive transition state (high oxidation state) during the catalysis, and hence, is stabilized by the electron-donating substituents on the benzothiazole. Because the impact of electronic factor is significant in this step, we assume that the reaction involving (QNNNMe2)Ni(benzothiazolyl) and 1-iodooctane is very crucial and is the rate influencing step during the alkylation. Additionally, we have performed DFT calculations to complement the experimental

Figure 6. Free energy profile for the formation of alkylated product 4aa by Ni(II) catalyst. All values are given in kcal/mol. E

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Organometallics be favorable. The octyl radical then coordinates to the NiIII center in B to form the Ni(IV) complex C. Complex C can then undergo reductive elimination to yield the experimentally observed product 4aa via TS-1. The energy barrier for this process is 33.9 kcal/mol. Probable Catalytic Cycle. On the basis of the experimental results and DFT calculations described here, and the earlier observations of our group8 and others,10b,c,e,13 we have drawn a more authenticated catalytic cycle for the (QNNNMe2)NiCl (1) catalyzed alkylation of benzothiazole with alkyl halides (Figure 7). First, base-assisted reversible C(2)−H

catalyzed by a well-defined (QNNNMe2)NiCl (1) catalyst. Kinetics analysis, reactivity studies and DFT energy calculations on the (QNNNMe2)NiCl (1)-catalyzed alkylation of azoles emphasize a Ni(II)/Ni(III) pathway for the reaction, with the oxidative addition of alkyl iodide to the (QNNNMe2)Ni(II)species via an IAT process. The kinetic rate order of alkylation reaction with catalyst 1 is quite complex and the reaction has a fractional negative order for the benzothiazole substrate. Deuterium labeling experiments highlight that the C−H bond cleavage of azoles is a reversible process. Further, the reaction of catalyst 1 with benzothiazole leading to the formation of inermediate (QNNNMe2)Ni(2-benzothiazolyl) (5a) is very facile, and the intermediate 5a is demonstrated as the resting state of catalyst 1. Kinetic analysis of electronically different nickel intermediates 5b and 5c indicate that the reaction of (QNNNMe2)Ni(2-benzothiazolyl) with alkyl iodide is very crucial and might be involved in the rate-limiting step. DFT calculations strongly support the iodine atom transfer process for the oxidative addition of alkyl iodide to the intermediate (QNNNMe2)Ni(2-benzothiazolyl) (5a). All these investigations provide a significant mechanistic input into the alkylation of azoles by nickel, which can shed light into other nickel catalyzed C−H bond alkylation reactions.

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EXPERIMENTAL SECTION

General Experimental Considerations. All manipulations were conducted under an argon atmosphere either in a glovebox or using standard Schlenk techniques in predried glass wares. The catalytic reactions and kinetic experiments were performed in flame-dried reaction vessels with Teflon screw cap. Solvents were dried over Na/ benzophenone or CaH2 and distilled prior to use. Liquid reagents were flushed with argon prior to use. The (QNNNMe2)NiCl (1) was synthesized according to previously described procedure.8 All other chemicals were obtained from commercial sources and were used without further purification. Yields refer to the isolated compounds, estimated to be >95% pure as determined by 1H NMR. NMR (1H and 13 C) spectra were recorded at 200, 400, or 500 (1H), 100 or 125 {13C, DEPT (distortionless enhancement by polarization transfer)}, respectively, on Bruker AV 400 and AV 500 spectrometers in CDCl3 or toluene-d8 solutions; chemical shifts (δ) are given in ppm. GC Method. Gas chromatography analyses were performed using a Shimadzu GC-2010 gas chromatograph equipped with a Shimadzu AOC-20s autosampler and a Restek RTX-5 capillary column (30 m x 250 μm). The instrument was set to an injection volume of 1 μL, an inlet split ratio of 10:1, and inlet and detector temperatures of 250 and 320 °C, respectively. UHP-grade argon was used as carrier gas with a flow rate of 30 mL/min. The temperature program used for all the analyses is as follows: 80 °C, 1 min; 30 °C/min to 200 °C, 2 min; 30 °C/min to 260 °C, 3 min; 30 °C/min to 300 °C, 3 min. Response factors for all the necessary compounds with respect to standard n-dodecane were calculated from the average of three independent GC runs. Synthesis of (QNNNMe2)Ni(2-Benzothiazolyl) (5a). A Schlenk flask was introduced with (QNNNMe2)NiCl (1) (0.10 g, 0.280 mmol), benzothiazole (0.038 g, 0.280 mmol), and LiOtBu (0.033 g, 0.420 mmol), and toluene (10 mL) was added into it. The resultant reaction mixture stirred at 100 °C for 5 h. At ambient temperature, the reaction mixture was filtered via cannula, concentrated to minimum, and npentane was added to precipitate out the complex 5a. Compound 5a was recrystallized in n-pentane under slow evaporation to obtain single crystals suitable for X-ray analysis. Yield: 0.116 g, 91%. mp = 155−157 °C. 1H NMR (500 MHz, CDCl3): δ = 8.08 (d, 3JH−H = 8.1 Hz, 1H, Ar−H), 8.02 (d, 3JH−H = 8.1 Hz, 1H, Ar−H), 7.91 (d, 3JH−H = 7.8 Hz, 1H, Ar−H), 7.61 (d, 3JH−H = 8.3 Hz, 1H, Ar−H), 7.48−7.38 (m, 3H, Ar−H), 7.25−7.16 (m, 2H, Ar−H), 7.10−7.08 (m, 2H, Ar−H), 6.94 (dd, 3JH−H = 7.8 Hz, 3JH−H = 5.4 Hz, 1H, Ar−H), 6.86 (d, 3JH−H = 7.8 Hz, 1H, Ar−H), 6.33 (vt, 3JH−H = 7.5 Hz, 1H, Ar−H), 3.06 (s, 6H,

Figure 7. Plausible alkylation pathway catalyzed by (QNNNMe2)NiCl.

cleavage of benzothiazole occurs, which is followed by the reaction with (QNNNMe2)NiCl, leading to the formation of (QNNNMe2)Ni(2-benzothiazolyl) (5a). Complex 5a is found to be the resting state of the catalyst. Intermediate 5a reacts with alkyl iodide in the rate-influencing step via the iodine atom transfer (IAT)11,14 process to produce the Ni(III) species B and the alkyl radical. The alkyl radical can rebound with B to produce the Ni(IV) species C. Reductive elimination of the coupled product from species C will regenerate the Ni(II) complex and complete the catalytic cycle. Experimental results strongly support the intermediacy of complex 5a and the involvement of the alkyl radical, and DFT calculations highlight the oxidative addition of alkyl iodide to 5a through an IAT mechanism. Though the nickel-catalyzed alkylation of azoles is relatively well precedented, the mechanistic proposals are made quoting the conventional alkylation pathways (Ni(I)/Ni(III)) and with extremely less experimental inputs. Herein, we have extensively demonstrated a new mechanistic route for the alkylation of azoles employing the well-defined nickel catalyst. The alkylation occurs via the Ni(II)/Ni(III) pathway with the oxidative addition of alkyl iodide to (QNNNMe2)Ni(II)(benzothiazolyl) species via the IAT process. This pathway is strongly supported by experimental findings and DFT calculations.

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CONCLUSION In summary, we have demonstrated an in-depth mechanistic study for the C−H bond alkylation of azoles with alkyl halides, F

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Organometallics CH3). 13C NMR (100 MHz, CDCl3): δ = 194.5 (Cq), 155.0 (Cq), 150.9 (CH), 148.5 (Cq), 148.4 (Cq), 147.6 (Cq), 146.9 (Cq), 139.0 (Cq), 138.3 (CH), 130.0 (Cq), 129.8 (CH), 128.7 (CH), 124.5 (CH), 122.3 (CH), 121.3 (CH), 120.8 (CH), 120.6 (CH), 120.1 (CH), 116.5 (CH), 114.9 (CH), 112.2 (CH), 110.4 (CH), 51.9 (CH3). HRMS (ESI): m/z calcd for C24H20N4NiS+H+ [M + H]+, 455.0835; found, 455.0840. Anal. Calcd for C24H20N4NiS: C, 63.33; H, 4.43; N, 12.31; S, 7.04. Found: C, 63.56; H, 4.72; N, 12.55; S, 6.90. Synthesis of (QNNNMe2)Ni(2-(6-Ethoxy Benzothiazolyl) (5b). This compound was synthesized following the procedure similar to synthesis 5a, using (QNNNMe2)NiCl (1; 0.10 g, 0.280 mmol), 6-ethoxy benzothiazole (0.053 g, 0.295 mmol) and LiOtBu (0.034 g, 0.420 mmol). Yield: 0.104 g, 74%. mp = 150−153 °C. 1H NMR (200 MHz, CDCl3): δ = 8.04−7.90 (m, 2H, Ar−H), 7.61−6.88 (m, 10H, Ar−H), 6.62 (bs, 1H, Ar−H), 4.11−4.09 (m, 2H, CH2), 3.11 (bs, 6H, CH3), 1.46 (bs, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ = 190.1 (Cq), 155.2 (Cq), 151.0 (CH), 150.1 (Cq), 148.6 (Cq), 148.4 (Cq), 147.6 (Cq), 146.9 (Cq), 140.0 (Cq), 138.2 (CH), 130.0 (Cq), 129.8 (CH), 128.7 (CH), 121.3 (CH), 120.9 (CH), 120.1 (CH), 116.4 (CH), 114.9 (CH), 113.7 (CH), 112.1 (CH), 110.4 (CH), 104.9 (CH), 64.3 (CH2), 51.9 (CH3) 15.1 (CH3). HRMS (ESI): m/z calcd for C26H24N4NiOS+H+ [M + H]+, 499.1097; found, 499.1093. Synthesis of (QNNNMe2)Ni(2-(6-Fluoro Benzothiazolyl) (5c). This compound was synthesized following the procedure similar to synthesis of 5a, using (QNNNMe2)NiCl (1; 0.15 g, 0.420 mmol), 6fluoro benzothiazole (0.068 g, 0.444 mmol) and LiOtBu (0.053 g, 0.63 mmol). Yield: 0.148 g, 74%. mp = 156−158 °C. 1H NMR (200 MHz, CDCl3): δ = 8.05 (dd, 3JH−H = 8.2 Hz, 4JH−H = 1.4 Hz, 1H, Ar−H), 7.96 (dd, 3JH−H = 8.8, 4.8 Hz, 1H, Ar−H), 7.62−7.34 (m, 4H, Ar−H), 7.22−7.07 (m, 4H, Ar−H), 7.00−6.85 (m, 2H, Ar−H), 6.63 (t, 3JH−H = 8.1 Hz, 1H, Ar−H), 3.07 (s, 6H, CH3). 13C NMR (125 MHz, CDCl3): δ = 193.6 (Cq), 159.2 (d, 1JC−F = 238.2 Hz, Cq), 151.9 (Cq), 150.8 (CH), 148.4 (2 × Cq), 147.6 (Cq), 146.9 (Cq), 139.9 (Cq), 138.4 (CH), 130.0 (Cq), 129.9 (CH), 128.7 (CH), 121.3 (CH), 120.9 (CH), 120.1 (CH), 116.5 (CH), 114.9 (CH), 112.6 (d, 2JC−F = 20.0 Hz, CH), 112.2 (CH), 110.4 (CH), 107.0 (d, 2JC−F = 22.9 Hz, CH), 51.9 (CH3). 19F-NMR (377 MHz, CDCl3): δ = −121.3. HRMS (ESI): m/z calcd for C24H19FN4NiS+H+ [M + H]+, 473.0741; found, 473.0737. Representative Procedure for Reaction Rate Determination. For the rate of alkylation reaction, see Figure 1. A screw cap tube equipped with magnetic stir bar was introduced with catalyst 1 (0.007 g, 0.02 mmol, 0.01 M), LiOtBu (0.048 g, 0.60 mmol), 1-iodooctane (0.11 mL, 0.144 g, 0.60 mmol, 0.30 M), benzothiazole (0.044 mL, 0.054 g, 0.4 mmol, 0.20 M), n-dodecane (0.04 mL, 0.17 mmol, internal standard), and 1,4-dioxane (1.81 mL) was added to make the total volume 2.0 mL. The reaction mixture was then stirred at 100 °C in a preheated oil bath. At regular time intervals (10, 15, 20, 30, 45, 60, 75 min, etc.), the reaction vessel was cooled to ambient temperature and an aliquot of sample was withdrawn to the GC vial under an argon atmosphere. The sample was diluted with acetone and subjected to GC analysis. The concentration of the product 4aa obtained in each sample was determined with respect to the internal standard ndodecane. The final data was obtained by averaging the results of three independent experiments. Plot was drawn for the concentration of product vs time (min) as shown in Figure 1, and fitted linear with Origin Pro 8. Slope of the linear fitting represents the reaction rate. The rate was determined by initial rate method. Representative Procedure for Rate-Order Determination. Rate-order determination on benzothiazole is shown in Figure 3 and Figure S1 in the Supporting Information. To determine the order of the alkylation reaction on benzothiazole, initial rates at different initial concentrations of benzothiazole were recorded. The final data was obtained by averaging the results of three independent experiments for the same initial concentration. In the standard experiment, a Teflonscrew cap tube equipped with magnetic stir bar was introduced catalyst 1 (0.02 mmol, 0.01 M), LiOtBu (0.048 g, 0.6 mmol) 1-iodooctane (0.60 mmol, 0.30 M), specific amount of benzothiazole (as shown in Table S1 in the Supporting Information), n-dodecane (0.17 mmol, internal standard), and 1,4-dioxane (appropriate amount) was added

to make the total volume 2.0 mL. The reaction mixture was then heated at 100 °C in a preheated oil bath. At regular intervals (10, 15, 20, 30, 45, 60 min, etc.), the reaction vessel was cooled to ambient temperature and an aliquot of sample was withdrawn to the GC vial. The sample was diluted with acetone and subjected to GC analysis. The concentration of the product 4aa obtained in each sample was determined with respect to the internal standard n-dodecane. The data of the concentration of the product vs time (min) plot was fitted linear with Origin Pro 8. The slope of the linear fitting represents the reaction rate for that particular concentration of benzothiazole. The order of the reaction was then determined by plotting log(rate) vs log(conc benzothiazole) for benzothiazole substrate. Computational Details. All DFT calculations were carried out using the Turbomole 7.1 suite of programs15 and the PBE functional.16 The TZVP basis set has been employed.17 The resolution of identity (RI),18 along with the multipole accelerated resolution of identity (marij)19 approximations have been employed for an accurate and efficient treatment of the electronic Coulomb term in the DFT calculations. Solvent correction has been incorporated with optimization calculations using the COSMO model,20 with 1,4dioxane (ε = 2.25) as the solvent. The energies reported in the figure are ΔG values, with zero-point energy corrections, internal energy, and entropic contributions included through frequency calculations on the optimized minima, with the temperature taken to be 298.15 K. Harmonic frequency calculations were performed for all stationary points to confirm them as local minima or transition state structures.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00025. Detailed experimental procedures, analytical data for compounds, 1H and 13C NMR spectra of nickel complexes, and alkylated compounds (PDF) Cartesian coordinates of compounds (PDF) Accession Codes

CCDC 1568732 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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AUTHOR INFORMATION

Corresponding Author

*B.P.: tel, + 91 20 2590 2733; fax, + 91 20 2590 2621; e-mail, b. [email protected]. ORCID

Rajesh G. Gonnade: 0000-0002-2841-0197 Kumar Vanka: 0000-0001-7301-7573 Benudhar Punji: 0000-0002-9257-5236 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful to the SERB, New Delhi, India (EMR/2016/ 000989) for financial support. U.N.P. and D.K.P. thank UGC New Delhi for the research fellowships.

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REFERENCES

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DOI: 10.1021/acs.organomet.8b00025 Organometallics XXXX, XXX, XXX−XXX