Isolation and Characterization of Regioisomers of Pyrazole-Based

Article pubs.acs.org/Organometallics

Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α‑Alkylation of Ketones Using Alcohols Ramesh Mamidala, Shaikh Samser, Nishant Sharma, Upakarasamy Lourderaj,* and Krishnan Venkatasubbaiah* School of Chemical Sciences, National Institute of Science Education and Research (NISER), HBNI, Bhubaneswar, 752050 Orissa, India S Supporting Information *

ABSTRACT: Regioisomers of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)1H-pyrazole-based palladacycles (1 and 2) were synthesized by the aromatic C−H bond activation of N/3-aryl ring. The application of these regioisomers as catalysts to enable the formation of α-alkylated ketones or quinolines with alcohols using a hydrogen borrowing process is evaluated. Experimental results reveal that palladacycle 2 is superior over palladacycle 1 to catalyze the reaction under similar reaction conditions. The reaction mechanisms for the palladacycles 1 and 2 catalyzed α-alkylation of acetophenone were studied using density functional theoretical (DFT) methods. The DFT studies indicate that palladacycle 2 has an energy barrier lower than that of palladacycle 1 for the alkylation reaction, consistent with the better catalytic activity of palladacycle 2 seen in the experiments. The palladacycle−phosphine system was found to tolerate a wide range of functional groups and serves as an efficient protocol for the synthesis of α-alkylated products under solvent-free conditions. In addition, the synthetic protocol was successfully applied to prepare donepezil, a drug for Alzheimer’s disease, from simple starting materials.

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approach for the α-alkylation of ketones is to use alcohols as an alkylating agent.4 Over the past decade, several groups have reported various metal-catalyzed methods for the α-alkylation of ketones using alcohols as an alkylating agent.5−12 For instance, Chao and co-workers reported the α-alkylation of ketones by trialkylamines under heterogeneous Pd/C catalysis.13 A homogeneous pincer-type Pd-NHC catalyst was reported for the α-alkylation of acetophenone using benzyl alcohol at 125 °C, giving a mixture of alcohol and ketone as products.14 More recently, Beller and co-workers elegantly reported the manganese-based catalytic system for the α-alkylation of ketones.12 However, many of these catalytic systems suffer from low product selectivity, low yield, and high reaction temperature. We have also been pursuing the synthesis of 1,3,5-triphenyl-based palladacycles and their application toward catalysis.15 We recently described the synthesis of the 3,5-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolebased palladacycle and its application toward N-alkylation of amines.15b In the study reported here, we describe the isolation of regioisomers of palladacycles, their characterization, and activity toward α-alkylation of ketones. As alluded vide supra, the reactivity difference in regioisomers, especially the palladacycles, has not been examined. We also discuss the activity of regioisomers of the palladacycles as catalysts, which have been studied by experiments and density functional theory (DFT) calculations.

INTRODUCTION Palladacycles are an important family of organometallic compounds. The interest in the use of palladacycles has been due to their potential applications in various fields such as catalysis, medicinal science, and organic synthesis.1 Since the discovery of the application of palladacycles in catalysis by Hermann and co-workers in 1995, intense research has been focused on their synthesis, structural analysis, and application toward catalysis.1a Among the several available methods for the preparation of palladacycles, ortho-metalation of C−H bonds is an attractive methodology.2 While C−H bond activation has been thoroughly studied, the recognition of chemically similar C−H bonds have turned out to be an arduous task. Different approaches have been identified to achieve C−H bond activation of chemically similar environments.3 In many instances, the regioisomers have been isolated and structurally characterized. For example, Solan and co-workers demonstrated the preferential palladation of the naphthalene ring using N-donors as directing ligands.3h Recently, Wendt and co-workers3i reported metal-controlled regioselectivity in the directed aromatic substitution of 2-(1-naphthyl)pyridine. Although the regioisomers of palladacycles have been reported, in many instances, their application for catalysis has not been examined. α-Alkylation of carbonyl compounds is one of the most fundamental reactions used to form a C−C bond. Traditionally, the α-alkylation of ketones was achieved by the reaction of ketones with electrophiles such as alkyl halides. However, this method involves the use of toxic organohalides and formation of a large amount of inorganic salts as waste. An alternative, greener © XXXX American Chemical Society

Received: June 23, 2017

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DOI: 10.1021/acs.organomet.7b00478 Organometallics XXXX, XXX, XXX−XXX

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RESULTS AND DISCUSSION The pyrazole ligand was readily synthesized by the condensation of 1,3-diphenylpropane-1,3-dione and 4-(trifluoromethyl)phenyl)hydrazine using a reported procedure.15 The ligand was fully characterized by 1H, 13C, 19F NMR, and HRMS. Next, typical cyclopalladation reaction in acetic acid was carried out to obtain the acetate-bridged dimeric complex (Scheme 1). The resultant solid was crystallized from dichloromethane and n-hexane. When we analyzed the crystals in a microscope, we noticed two different types of crystals. The two forms were then separated by fractional crystallization. The first crop was isolated as a light yellow crystal with 39% yield (palladacycle 1), whereas the third crop was isolated as yellowish green crystals with 43% yield (palladacycle 2). The 1H NMR in CDCl3 showed distinct peaks for both the isomers, notably the pyrazole hydrogen resonates at 6.06 and 6.26 ppm for the palladacycles 1 and 2, respectively (Figure 1). The 19F NMR spectra of palladacycles 1 and 2 show singlets at −62.4 and −63.6 ppm, respectively. The structures of palladacycles 1 and 2 were further unambiguously established by X-ray diffraction analysis.

Palladacycle 1 (Figure 2) crystallizes in the triclinic space group P1̅, whereas palladacycle 2 (Figure 3) crystallizes in the orthorhombic space group Pccn. X-ray analysis reveals that both the palladacycles 1 and 2 are dimeric in nature, bridged together by acetates with the pyrazole ligands aligned in a staggered fashion. The geometry around the palladium atom in both structures exhibits a distorted square planar geometry. The Pd−C (1.978(3) Å for 2; 1.940 (3) Å for 1) and Pd−N (2.024(3) Å for 2; 2.015(3) Å for 1) distances are comparable with those of the reported cyclometalated palladium compounds.15 The Pd−C distance in palladacycle 1 is shorter than the corresponding distance in palladacycle 2. However, the Pd···Pd distance in palladacycle 2 is slightly shorter than the Pd···Pd distance observed in palladacycle 1. To explore the optimum reaction conditions for the alkylation of acetophenone with benzyl alcohol, we have screened various bases and temperatures using palladacycle 2 and the ancillary ligand P(2-Fur)3P(C4H3O)3 under solvent-free conditions. Of the different conditions screened, LiOH at 80 °C resulted in a quantitative yield of the desired product using palladacycle 2

Scheme 1. Synthesis of Palladacycles 1 and 2

Figure 1. 1H NMR spectra of palladacycles 1 and 2 (only the aromatic region is shown for clarity). B


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Organometallics

Figure 2. Molecular structure of palladacycle 1 (30% probability thermal ellipsoids). Hydrogen atoms are omitted for clarity. Selected bond lengths (Å) and bond angles (degree): Pd1−C15 1.940(3), Pd1−N1 2.015(3), Pd1−O1 2.132(2), Pd1−O3 2.035(2), Pd1−Pd2 2.8885(3), C15−Pd1−N1 80.68(12), C15−Pd1−O1 176.02(11), N1−Pd1−O1 99.54(10), C15−Pd1−O3 92.91(11), N1−Pd1−O3 171.27(10), O3−Pd1−O1 87.27(9), C15−Pd1−Pd2 97.60(9), N1−Pd1−Pd2 103.77(7), O1−Pd1−Pd2 78.47(6), O3−Pd1−Pd2 82.85(7).

Figure 3. Molecular structure of palladacycle 2 (30% probability thermal ellipsoids). Hydrogen atoms are omitted for clarity. Selected bond lengths (Å) and bond angles (degree): Pd1−C9 1.978(3), Pd1−N2 2.024(3), Pd1−O1 2.151(2), Pd1−O2 2.052(2), Pd1−Pd1* 2.848(5), C9−Pd1−N2 80.48(12), C9−Pd1−O1 177.01(11), N2−Pd1−O1 99.69(10), C9−Pd1−O2 93.74(12), N2−Pd1−O2 173.03(10), O2−Pd1−O1 86.29(10), C9−Pd1−Pd1* 98.22(9), N2−Pd1−Pd1* 101.90(8), O1−Pd1−Pd1* 78.81(6), O2−Pd1−Pd1* 82.69(7).

(Table S1, entry 4, Supporting Information). However, use of the palladacycle 1 gave relatively low yield (Table S1, entries 1 and 16, Supporting Information). When the reaction was performed using commercially available palladium sources such as Pd(OAc)2, PdCl2, and Pd2(dba)3, no product formation was observed under similar reaction conditions (Table S1, entries 13, 14, and 15 respectively, Supporting Information). The catalytic performances of the palladacycles 1 and 2 were evaluated using the model substrates acetophenone and benzyl alcohol. The reactions were performed under solvent-free conditions at 60 °C using 1 mol % of catalyst. The catalytic performances of the palladacycles 1 and 2 are compared in Figure 4. At 60 °C using 1 mol % of catalyst loading, palladacycle 2 displayed superior activity over palladacycle 1. Although both the palladacycles were active for the α-alkylation of acetophenone with benzyl alcohol, we chose palladacyle 2 for further studies because of its superior activity over palladacycle 1. In order to know the catalytic efficiency of palladacycle 2, we examined a 2.0 g (16.7 mmol) scale reaction by loading 0.001 mol % of catalyst at 130 °C for 48 h. Palladacycle 2 exhibited high turnover number (TON) up to 32000 (66%). Encouraged by these results, we have evaluated the substrate scope and limitations using palladacycle 2 for the alkylation of

Figure 4. Reactivity study of palladacycles using acetophenone and benzyl alcohol at 60 °C. Reaction conditions: 0.5 mmol acetophenone, 0.6 mmol benzyl alcohol, 25 mol % of LiOH, 1 mol % of palladacycle 1 (or) 2, and 2 mol % of P(2-Fur)3. Conversions were analyzed using 1 H NMR by taking p-xylene as the internal standard.

various ketones using different aryl and aliphatic primary alcohols. In most cases, electron-rich as well as electron-deficient substituted acetophenones or benzyl alcohols were successfully alkylated to the desired products in good to excellent isolated C


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Organometallics Table 1. Scope of the α-Alkylation of Aryl Ketones Using Aryl and Aliphatic Alcoholsa

Reaction conditions: 1 mmol ketone, 1.2 mmol alcohol, 0.25 mmol LiOH, 1 × 10−2 mmol palladacycle 2, 2 × 10−2 mmol P(2-Fur)3. bReactions were performed at 100 °C for 24 h, and 2 mmol alcohol was used. cReactions were performed using palladacycle 1 for 12 h. dReactions were performed using palladacycle 2 for 12 h. e3 mmol alcohol was used. ND = not detected. a

ketone moiety.16 Under the optimized conditions, the reaction of β-pregnenolone with 4-methyl benzyl alcohol proceeded smoothly to give the corresponding α-alkylated product (Table 1, entry 17) in 78% yield, without affecting the other functional groups such as CC and −OH. In addition, we also explored this methodology to substrates such as aliphatic alcohols or methylene ketones at slightly higher temperature. Aliphatic alcohols such as 1-butanol, ethanol, 2-phenyl ethanol, and 1-octanol could be used as the electrophilic partner for obtaining the corresponding ketones (Table 2, entries 19−22). The alkylation of cyclic or methylene ketones such as 1-tetralone, 5,6-dimethoxy-1-indanone, or propiophenone resulted in the corresponding alkylated products in good to excellent isolated yields (Table 2, entries 23−26). Good to excellent yields

yields under mild reaction conditions (Table 1, entries 1−9). The ortho-substituted benzylic alcohols or aryl ketones (Table 1, entries 10, 14, 15, 16, and 18) as well as aliphatic ketones (Table 1, entry 11) were selectively alkylated to the corresponding α-alkylated ketones. Substrates having two α-carbons that are prone to potential alkylation generally showed selectivity issues. Interestingly, we found that the present catalytic system offers a regioselective alkylation in the case of 2-pentanone and 1-(4-methoxyphenyl)propan-2-one with benzyl alcohol (Table 1, entries 12 and 13). The present catalytic system was also successfully applied to the α-alkylation of biologically important steroid β-pregnenolone. In general, β-pregnenolone under metal reaction conditions is susceptible to isomerization of the CC bond to produce progesterone, which has an α,β-unsaturated D


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Organometallics Table 2. Scope of the α-Alkylation of Aryl or Heteroaryl Ketones Using Aryl or Heteroaryl Alcoholsa

a Reaction conditions: 1 mmol ketone, 2 mmol alcohol, 0.25 mmol LiOH, 1 × 10−2 mmol palladacycle 2, 2 × 10−2 mmol P(2-Fur)3. bReactions were performed at 100 °C for 24 h. cReactions were performed at 120 °C for 24 h. dReactions were performed at 120 °C for 48 h, and 2 mol % of palladacycle 2 and 25 mol % of LiOtBu were used. eReactions were performed using palladacycle 1 for 12 h. fReactions were performed using palladacycle 2 for 12 h. g3 mmol alcohol was used.

palladacycle 2, we were able to synthesize donepezil starting from N-benzyl-4-piperidinemethanol and 5,6-dimethoxyindanone in moderate yield (46%, Scheme 2), which is marginally higher than the yields reported by Glorius and co-workers6d using a Ru-based catalytic system. We further tested the synthetic utility of the catalyst for the alkylation of 4-piperidinemethanol with benzyl alcohol to obtain N-benzyl-4-piperidinemethanol. The yields were comparable or better than the yields reported by Yamada and co-workers using an Ir-based catalytic system.18 Quinolines are an important class of heterocyclic compounds used in the design of pharmacologically active compounds that are used as anti-inflamatory, antimalarial, and antiasthmatic drugs.19 They can be prepared by using conventional Friedländer annulation reaction from 2-aminobenzaldehyde and ketones.20 However, the low stability of 2-aminobenzaldehyde and selfcondensation byproduct limits the use of this method. Modified Friedländer quinoline synthesis using more stable 2-aminobenzyl alcohol under hydrogen-borrowing conditions has been reported as a versatile method.21 Using palladacycle 2, with the optimized conditions for the α-alkylation of ketones mentioned above,

were also achieved in the case of heteroaryl ketones or heteroaryl alcohols as coupling partners at relatively mild conditions (Table 2, entries 27, 28, and 29). Whereas it has been a challenge to alkylate nonactivated methylene ketones with less reactive aliphatic alcohols, in our case, the alkylation of methylene ketones with aliphatic alcohols was carried at moderate temperatures (Table 2, entry 31). To increase the adaptability of our catalytic system, we applied our strategy to estrone and trans-dehydroandrosterone. The reaction of estrone with benzyl alcohol and trans-dehydroandrosterone with p-methylbenzyl alcohol proceeded smoothly to the corresponding alkylated products in 78 and 76% yields, respectively (Table 2, entries 30 and 32). It should be noted that selective monobenzylation of trans-dehydroandrosterone was achieved without isomerization under the optimized reaction conditions. It is worth mentioning that our protocol offers the α-alkylation of β-pregnenolone, estrone, and trans-dehydroandrosterone without the use of any protection and deprotection of other functional groups.12 Another important biologically active molecule is donepezil, which is used in the treatment of Alzheimer’s disease.17 Using E


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Organometallics Scheme 2. Synthesis of Donepezil and N-Benzyl-4-piperidinemethanol

Reaction of lithium alkoxide with in situ formed phosphinecoordinated palladium species (PPX) generated the palladium alkoxide species (PPX-BA) which underwent β-hydride elimination to generate the Pd−H (PPX-H) intermediate and the aldehyde. The in situ generated base-catalyzed α,β-unsaturated carbonyl compound accessed the Pd−H, which upon reaction with alcohol releases the product. Control experiments were performed to validate the proposed mechanism (Scheme S1 and Figure S1). Reaction of acetophenone with benzaldehyde under the optimized reaction conditions resulted in only α,β-unsaturated compound in 95% yield. Reaction of α,β-unsaturated compound with benzyl alcohol in the presence of palladacycle 2 (1 mol %), P(2-Fur)3 (2 mol %), and LiOH (25 mol %) at 80 °C for 12 h resulted in 80% of the desired product. These results support our proposed mechanism. To probe the high activity of palladacycle 2 over 1 for the α-alkylation of ketones using alcohols, the mechanism of the catalytic reactions was investigated using DFT methods (Supporting Information). The free energy profiles for the reaction between acetophenone and benzyl alcohol using both the palladacycles (1 and 2)−phosphine PP1 and PP2 were mapped. Optimized geometries of both of these catalysts (Figure 5) suggest that they have a planar geometry around Pd. In PP1, the distances Pd−P, Pd−O, and Pd−N are 2.3, 2.11, and 2.15 Å, respectively. On the other hand, in PP2, Pd−P, Pd−O, and Pd−N distances are 2.54, 2.06, and 2.18 Å respectively. Palladacycles PP1 and PP2 have a free energy difference of 12.03 kcal/mol, with PP1 being more stable than PP2. The initial step in the catalytic reactivity is the reaction of LiOH with benzyl alcohol (BA), giving lithium benzyloxide (Li-BA). The free energy change during the reactions was computed with respect to the reactants PP1 + Li-BA and PP2 + Li-BA. The free energy profile for the catalytic cycle of PP1 is given in Figure 6, and the structures of the stationary points obtained on the free energy path along with free energy values (Figure S2 and Table S2) are given in the Supporting Information. In the presence of base (LiOH), BA is converted to lithiated benzyl alcohol (Li-BA) with H2O as the side product. Li-BA then reacts with the catalyst PP1 to form an intermediate PP1-Int1, which has a free energy of −19.8 kcal/mol with respect to the reactants. In complex PP1-Int1, the Pd−O(Li-BA) and Li(Li-BA)−O(OAc) distances are 4.14 and 1.84 Å, respectively. PP1-Int1 is converted to another complex PP1-Int2 that involves the transfer of Li atom from Li-BA to the OAc group along with the formation of a new bond between the Pd and O atom of Li-BA through a transition state PP1-TS1. Pd−O(Li-BA) and Li−O(OAc) distances in PP1-TS1 are 2.54 and 1.78 Å, respectively. In PP1-Int2, the distances Pd−O(Li-BA) and Li−O(OAc) are 2.11 and 1.92 Å, respectively. Then lithium

Table 3. Synthesis of Quinolines Using 2-Aminobenzyl Alcohol and Ketonesa

a

Reaction conditions: 1 mmol 2-aminobenzyl alcohol, 1.2 mmol ketone, 0.25 mmol LiOH, 1 × 10−2 mmol palladacycle 2, and 2 × 10−2 mmol P(2-Fur)3.

2-aminobenzyl alcohol was reacted with acetophenone to provide the corresponding qunoline in 89% yield (Table 3, entry 35). Good isolated yields were obtained when we used 4-methyl acetophenone and 4-fluoroacetophenone (Table 3, entries 36 and 37). Propiophenone, butyrophenone, and 1-tetralone were also reacted with 2-aminobenzyl alcohol to yield the corresponding quinoline derivatives in 82, 78, and 91% yield, respectively (Table 3, entries 38, 39, and 40). Palladacycle 2 showed regioselectivity toward the formation of 2-propylquinoline when 2-pentanone was used as a substrate (Table 3, entry 41). Further, we investigated the catalytic activity of the palladacycles 1 and 2 by choosing 12 h reaction time at respective temperatures that are listed in Tables 1 (entries 1, 10, 14, and 18) and 2 (entry 22). Palladacycle 2 exhibited better yields over palladacyle 1. Notably, a remarkable difference was observed when ortho-substituted acetophenone or ortho-benzyl alcohols were used as substrates, and in such cases, palladacycle 1 was almost unreactive or not efficient to produce the desired products (Table 1, entries 10, 14, and 18). It is of interest to understand the mechanism for the catalytic reaction. As shown in Scheme 3, we have proposed a plausible mechanism for the reaction based on our experimental results and literature reports22 for α-alkylation of ketones with alcohols. F


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Organometallics Scheme 3. Proposed Catalytic Pathway for α-Alkylation of Ketones Using Alcohols

from benzyl CH2 to Pd atom through a transition state PP1-TS2. PP1-TS2 has a free energy of 51.1 kcal/mol. Pd−H(−CH2 benzyl) distances in PP1-BA, PP1-TS2, and PP1-H are 3.1, 2.93, and 1.59 Å, respectively. The intermediate benzaldehyde then reacts with the reactant acetophenone to give the preproduct (Pre-P) with the removal of H2O. Pre-P then reacts with PP1-H to form an alkoxide complex PP1-Alko, which has a free energy of −5.8 kcal/mol. PP1-Alko complex is formed by H atom transfer from the Pd atom to the double bond of Pre-P accompanied by the bond formation between the O atom of Pre-P and Pd atom. This is apparent from the Pd−H bond distances that are 1.59 Å in PP1-H and 5.1 Å in PP1-Alko. Also, Pd−O(Pre-P) distance in PP1-Alko is 2.1 Å. In the final step, PP1-Alko reacts with Li-BA to form lithiated alkoxide, and Li-Alko regenerates the active species PP1-BA for the next cycle. The free energy change for the formation of Li-Alko and PP1-BA is −23.8 kcal/mol. Li-Alko then reacts with H2O to give the final product of this reaction. The free energy profile (Figure 7) was mapped for the same reaction using palladacycle PP2 as catalyst, and the stationary

Figure 5. Optimized geometries of palladacycle-phosphine catalysts 1 (PP1: left) and 2 (PP2: right). Phenyl and furyl H atoms are not shown for clarity.

Figure 6. Free energy profile for reaction between Li-BA with PP1.

acetate (LiOAc) dissociates from catalyst PP1, resulting in the benzylated complex with PP1, PP1-BA. Pd−O(BA) distance in PP1-BA is 2.06 Å. PP1-BA has a free energy of −9.2 kcal/mol. PP1-BA is then converted to complex PP1-H (with benzaldehyde as the intermediate) that involves the transfer of H atom

Figure 7. Free energy profile for reaction between Li-BA with PP2. G


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more stabilized for the reaction involving 2. In addition, the overall free energy barrier for the reaction using palladacycle 2 is stabilized by ∼9 kcal/mol compared to that of palladacycle 1. Hence, palladacycle 2 is expected to be more favorable than palladacycle 1, which is consistent with experimental results. Our catalytic system broadens the scope of the hydrogenborrowing catalysis in alkylation reactions. Furthermore, we were able to exploit this catalytic system for the synthesis of the biologically active and important molecule donepezil.

point structures are given in the Supporting Information (Figure S2). The first step is the formation of a complex PP2-Int1, where Li-BA comes close to Pd metal, with Pd−O(Li-BA) and Li−O(OAc) distances being 3.5 and 1.9 Å, respectively. It has a free energy of −21.8 kcal/mol and is more stable than the similar intermediate PP1-Int1 by 2 kcal/mol. PP2-Int1 is converted to another complex PP2-Int2 through a transition state PP2-TS1, which has a barrier of 4.9 kcal/mol. The similar step was encountered in the case of the reaction catalyzed by PP1 (PP1-TS1) with a barrier of 9 kcal/mol, indicating that the reaction catalyzed by catalyst PP2 would be more favorable than by catalyst PP1. Like PP1-TS1, this transition state also corresponds to the transfer of Li atom from Li-BA to the leaving group LiOAc, and the formation of a new bond between Pd metal and O atom of Li-BA. PP2-TS1 connects to PP2-Int2 on the other side with a free energy change of −41.5 kcal/mol. PP2-Int2 is more stable than PP1-Int2 by 10.8 kcal/mol. The leaving group LiOAc then dissociates to give PP2-BA having a free energy change of −19.8 kcal/mol. PP2-BA is more stabilized than PP1-BA by 10.6 kcal/mol, making the reaction more favorable when catalyst PP2 is used. In the next step, PP2-BA is converted to PP2-H via transition state PP2-TS2, which is 42.4 kcal/mol higher than reactants. The products (PP2-H) for this step using PP2 are stabilized by 18.6 kcal/mol more than the products using PP1 (PP1-H). In the next step, PP2-H reacts with Pre-P to form PP2-Alko as the product with free energy change of −16.2 kcal/mol. It is more stable than that of PP1-Alko by 10.4 kcal/mol. In the final step, PP2-Alko reacts with Li-BA to regenerate PP2-BA (active species) and Li-Alko with a free energy change of −34.3 kcal/mol. Product obtained in this step is also more stable than that obtained using catalyst PP1 by 10.5 kcal/mol. Li-Alko can then react with water to give the final product. In addition, another reaction path involving an isomer of palladacycle 2 with the phosphine ligand trans to pyrazole nitrogen (PP3) was also studied. The free energy profile for this path was found to be similar to that for PP1 (Figure S4, Supporting Information). Hence, this path was ruled out to account for the observed experimental results. The free energies of the important intermediates and transition states for the reaction paths using palladacycles 1 and 2 are compared in Table S2 (Supporting Information). Of interest is the difference in free energies (ΔΔG) of the concerned stationary points (k) along the path for the two reactions, that is, ΔΔG = ΔGk(PP2) − ΔGk(PP1). We can see that overall energies for reaction using PP2 are lower than that when using PP1, with the largest stabilization of 18.6 kcal/mol for PP2-H compared to that of PP1-H. In addition, the overall barrier for the reaction using PP2 (2TS2 vs 1TS2) is lowered by ∼9 kcal/mol compared to that when using PP1. These findings indicate that reaction using PP2 is expected to be favorable compared to that with PP1, consistent with the experiments.

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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. 7b00478. Experimental procedures and compound characterization (PDF) Accession Codes

CCDC 1555731−1555733 contain 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 [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

*Tel: 091-6742494165. E-mail: [email protected]. ORCID

Ramesh Mamidala: 0000-0003-0399-4437 Shaikh Samser: 0000-0002-2669-2020 Upakarasamy Lourderaj: 0000-0002-5550-9694 Krishnan Venkatasubbaiah: 0000-0002-4858-8590 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Science & Engineering Research Board (SERB) (SR/S1/IC-58/2012, SR/S2/RJN-49/2011 and SR/ S1/PC/0060/2010), New Delhi, and Department of Atomic Energy (DAE) for financial support. R.M. and S.S. thank CSIR and DST for research fellowships.

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REFERENCES

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CONCLUSIONS In summary, cyclometalation of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole with palladium acetate afforded regioselective palladacycles 1 and 2. We successfully studied their applications as catalysts for the alkylation of ketones using alcohols under solvent-free conditions. Experimental studies reveal that palladacycle 2 is more active than palladacycle 1. Comparison of the energy profiles for reactions involving palladacycles 1 and 2 using DFT methods reveals that the reactions proceed through similar pathways. However, the intermediates and transition states are H


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Isolation and Characterization of Regioisomers of Pyrazole-Based

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