Palladium N-heterocyclic carbene catalyzed expected and unexpected C–C and C–N functionalization reactions of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones

Abstract

A palladium N-heterocyclic carbene [Pd(NHC)Cl₂] complex of vitamin B₁ developed earlier in our laboratory was successfully employed as an efficient catalyst for the regioselective C–C and C–N functionalization reactions of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones 1a–b. The catalyst was attempted for the C–H arylation, acylation and alkoxylation of 1a–b using the respective coupling substrates such as aryl iodides 2a–c, benzylic alcohols 3a–d and methanol/ethanol 4. It was surprisingly noted that the acylation and alkoxylation reactions underwent a diverse pathway to yield some unexpected products rather than the targeted ones. In the case of the arylation reactions only the targeted products have been observed. This has made the protocol very interesting compared to the conventional coupling reactions.

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1. Introduction

Over the past decade, transition-metal-catalyzed functionalization of C–H bonds has emerged as one of the most sustainable and intriguing protocols to construct C–C and C-heteroatom (O, S, N, Cl, Br, I) bonds with high chemo-, stereo- and regioselectivity.¹ Complexes and salts of iron, cobalt, nickel, copper, ruthenium, rhodium and palladium have been identified as efficient catalysts for regioselective C–H functionalization reactions.^1,2 Amongst them, Pd-catalyzed regioselective C–C and C–N functionalization reactions are of greater interest due to their better efficacy and high turnover numbers.^1c,2c,3

The pyrazolone derivatives represent a class of important privileged five-membered-ring lactams embedded in various natural and pharmaceutical products possessing a broad spectrum of biological activities. Many of them exhibited significant anti-inflammatory, antiviral, antitumor and antibacterial properties.⁴ Among the pyrazolone derivatives, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a itself is a neuroprotective drug known as edaravone⁵ which acts as a radical scavenger to interrupt the preoxidative chain reactions and membrane disintegrations associated with brain ischemia.⁶ A few examples of transition-metal-catalyzed C–H functionalization of 1a have appeared in the literature.⁷ In this regard, our present study to develop a multiple and divergent C–H functionalizations approach to readily access analogues of 1a would be valuable for diversity-oriented synthesis (DOS) of drug candidates and their biological screening.

Most of the reported complexes of Pd(II) with NHC ligands were derived from imidazolium ionic liquids.⁸ They are complicated to synthesize,⁹ toxic and poorly biodegradable.¹⁰ Our attempt is to look for new biodegradable and nontoxic NHC ligand from a natural source, vitamin B₁, to incorporate one of the main principles of green chemistry.¹¹

Recently, we have developed a well-defined palladium N-heterocyclic carbene [Pd(NHC)Cl₂] complex of vitamin B₁ and have shown its performance as a good catalyst for the regioselective halogenation¹² and thiolation¹³ of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones via C–H bond activation. These results inspired us further to investigate its application toward the C–H arylation, acylation and alkoxylation of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones using various coupling substrates such as aryl iodides, benzylic alcohols and methanol/ethanol respectively.

In continuation of our previous research,¹⁴ herein we have attempted the catalytic application of Pd(NHC)Cl₂ complex toward the regioselective C–H arylation, acylation and alkoxylation of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones. It was surprisingly noted that the acylation and alkoxylation reactions underwent a diverse pathway to yield some unexpected products rather than the targeted products. In case of the arylation reactions only targeted products have been observed with excellent regioselectivity. This is the first ever report for the regioselective cum unexpected C–C and C–N functionalization reactions of 1a and its analogues using Pd(NHC)Cl₂ as a catalyst.

2. Results and discussion

Initially, the screening reactions for C–H arylation were performed with respect to the Pd-sources, oxidants and the solvents by using 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a (1 mmol) as the model substrate and 4-iodotoluene 2a (1 mmol) as the arylating reagent in accordance with the Wang's arylation procedure.¹⁵ The reactions proceeded smoothly to give the arylation product 5aa in moderate to good yields with exclusive regioselectivity. Among the Pd-sources used, Pd(NHC)Cl₂ was found to be the most efficient (Table 1, entries 4–7) over the other palladium species such as Pd(OAc)₂, PdCl₂ and Pd(PPh₃)₄ (Table 1, entries 9–11). Meanwhile, the effect of various oxidants, and solvents on the model reaction was also investigated. Best results were obtained by using Ag₂O as the oxidant in AcOH (Table 1, entries 5–11). Thus, the optimal arylation conditions were set as 5 mol% of Pd(NHC)Cl₂ as the catalyst with Ag₂O (0.5 mmol) as an oxidant in AcOH at 100 °C using 1 mmol of 1a and 1 mmol 2a forming the product 5aa with 80% yield in 5 h (Table 1, entry 5).

Table 1 Optimization of the reaction conditions for the synthesis^a of 5aa

Entry	Catalyst	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a (1 mmol), 4-iodotoluene 2a (1 mmol), Pd-source (5 mol%), oxidant (0.5 mmol) and solvent (2 mL) at 100 °C for 5 h.b Isolated yield.
1	Pd(NHC)Cl2	Oxone	AcOH	32
2	Pd(NHC)Cl2	PhI(OAc)2	AcOH	61
3	Pd(NHC)Cl2	K2S2O8	AcOH	28
4	Pd(NHC)Cl2	Ag2SO4	AcOH	72
5	Pd(NHC)Cl2	Ag2O	AcOH	80
6	Pd(NHC)Cl2	Ag2O	DMSO	73
7	Pd(NHC)Cl2	Ag2O	DMF	71
8	Pd(NHC)Cl2	Ag2O	Toluene	37
9	Pd(OAc)2	Ag2O	AcOH	68
10	PdCl2	Ag2O	AcOH	59
11	Pd(PPh3)4	Ag2O	AcOH	62

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With the established optimized reaction conditions in hand, scope and limitations for C–H arylation of various pyrazol-5(4H)-ones with substituted aryl iodides was investigated. As summarized in Scheme 1, the reaction of aryl iodides 2a–c bearing both electron-donating as well as withdrawing substituents in the para-position of the iodo group proceeded smoothly to afford the corresponding arylation products 5aa–ac/5ba–bc in good to excellent yields.

Scheme 1 Pd(NHC)Cl₂ catalyzed regioselective C–H arylation of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones^a 1a–b. ^aReaction conditions: 1-aryl-3-methyl-1H-pyrazol-5(4H)-one 1 (1 mmol), aryl iodide 2 (1 mmol), Pd(NHC)Cl₂ (5 mol%), Ag₂O (0.5 mmol) and AcOH (2 mL) at 100 °C for 5 h. ^bIsolated yield.

Based on previous investigations and our results, the mechanistic pathway of Pd(NHC)Cl₂ catalyzed regioselective C–H arylation of 1 has been assumed to involve a Pd(II)–Pd(IV) catalytic cycle^2c,15,16 (Scheme 2). First, Ag₂O may oxidize the ortho-C–H bond of 1 to form the intermediate A. A may then undergo transmetallation with Pd(NHC)Cl₂ to generate Pd(II) intermediate B, which upon oxidative addition with aryl iodide 2 forms a Pd(IV) intermediate C. Finally, arylation product 5 is obtained via reductive elimination from C leading to the regeneration of the Pd(II) catalyst.

Scheme 2 Plausible catalytic cycle for Pd(NHC)Cl₂ catalyzed C–H arylation of 1.

To further explore the utility of Pd(NHC)Cl₂ complex in C–H activation, more catalytic reactions were performed. As shown in Scheme 3, we first chose benzyl alcohol 3a (1.0 mmol) as an acylating reagent to react with 1a (1.0 mmol) in presence of 1.5 mmol tert-butyl hydroperoxide (TBHP) and 5 mol% Pd(NHC)Cl₂ in AcOH at 90 °C for 6 h by following some widely used conditions¹⁷ for C–H acylation in Pd/TBHP catalytic systems. However, when the reaction was performed as the standard reaction conditions above, it was surprisingly noted that the unexpected products 6aa and 7aa were obtained instead of expected C–H acylation product 10a. This might be due to the oxidation of 3a to benzaldehyde in Pd/TBHP which undergo Knoevenagel condensation with 1a to give 6aa and 6aa further undergo Michael addition by 1a to form 7aa. The possible mechanism is shown in Scheme 4. The structures of unexpected products 6aa and 7aa were confirmed well by NMR spectroscopy.

Scheme 3 Scope of benzyl alcohols for the synthesis^a of 6/7. ^aReaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a (1 mmol), benzylic alcohol 3 (1.0 mmol), Pd(NHC)Cl₂ (5 mol%), TBHP (1.5 mmol) and AcOH (2 mL) at 90 °C for 6 h. ^bIsolated yield.

Scheme 4 Plausible reaction mechanism for the synthesis of 6 and 7.

The effectiveness of the model reaction was tested against various oxidants in AcOH. Among them, TBHP was found to be the most effective (Table 2, entry 3) over other oxidants such as PhI(OAc)₂, K₂S₂O₈ and oxone (Table 2, entries 5–7). The efficiency of the model reaction was also considerably affected by the choice of solvents (Table 2, entries 1–4). In AcOH 6aa was formed to be the major product (Table 2, entry 3) while in EtOH 7aa was the major one (Table 2, entry 4).

Table 2 Optimization of the reaction conditions for the synthesis^a of 6aa and 7aa

Entry	Catalyst	Oxidant	Solvent	Yield^b (%)
				6aa	7aa
a Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a (1 mmol), benzyl alcohol 3a (1.0 mmol), Pd(NHC)Cl2 (5 mol%), oxidant (1.5 mmol) and solvent (2 mL) at 90 °C for 6 h.b Isolated yield, n.d., not detected.
1	Pd(NHC)Cl2	TBHP	DMF	37	40
2	Pd(NHC)Cl2	TBHP	Dioxane	n.d.	n.d.
3	Pd(NHC)Cl2	TBHP	AcOH	75	13
4	Pd(NHC)Cl2	TBHP	EtOH	10	72
5	Pd(NHC)Cl2	PhI(OAc)2	AcOH	Trace	Trace
6	Pd(NHC)Cl2	K2S2O8	AcOH	Trace	Trace
7	Pd(NHC)Cl2	Oxone	AcOH	n.d.	n.d.

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Under these optimized conditions, a scope of substituted benzyl alcohols was investigated (Scheme 3). The reaction of substituted benzyl alcohols 3b–d bearing both electron-donating as well as withdrawing functions in the para-position proceeded smoothly to afford the corresponding products 6ab–ad/7ab–ad in moderate to good yields. From the NMR spectra of 7aa–ad it was observed that both the enol and imine tautomers of 4-substituted pyrazol-5-one co-existed in the same molecule.

Next, in our effort on Pd(NHC)Cl₂ catalyzed C–H alkoxylation of 1a with methanol (Scheme 5) under the Wang's alkoxylation conditions,¹⁸ an oily product was obtained in 78% yield (Table 3, entry 4) with spectral data and elemental analysis inconsistent with the expected structure 9a, (R = H, R₁ = Me). Indeed, the data were in good agreement with the structure of an unprecedented product 8a (R = H). This might be due to the coupling reaction of solvent DCE with 1a instead of MeOH in presence of Pd-catalyst and K₂S₂O₈. It was also noted that the same product 8a was observed by employing EtOH as the alkoxylating agent (Table 3, entry 5). When 1,2-dichloroethane (DCE) was replaced with dichloromethane (DCM)/dioxane under the same reaction condition, none of the products 8a or 9a were detected (Table 3, entries 6–7). Other oxidants such as oxone, PhI(OAc)₂ and TBHP gave only a trace amount of product 8a (Table 3, entries 1–3). With these optimized conditions, the feasibility of the reaction was also checked by using substituted pyrazol-5(4H)-one 1b and the results are shown in Scheme 5.

Scheme 5 Reaction Scope for the synthesis^a,b of 8a–b. ^aReaction conditions: 1-aryl-3-methyl-1H-pyrazol-5(4H)-one 1 (1 mmol), MeOH (2 mL), Pd(NHC)Cl₂ (5 mol%), K₂S₂O₈ (0.5 mmol) and DCE (2 mL) at 55 °C for 5 h. ^bIsolated yield.

Table 3 Optimization of the reaction conditions for the synthesis^a of 8a

Entry	Catalyst	Oxidant	R1OH	Solvent	Yield^b(%)
a Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a (1 mmol), MeOH or EtOH (2 mL), Pd(NHC)Cl2 (5 mol%), oxidant (0.5 mmol) and solvent (2 mL) at 55 °C for 5 h.b Isolated yield, n.d., not detected.
1	Pd(NHC)Cl2	Oxone	MeOH	DCE	28
2	Pd(NHC)Cl2	PhI(OAc)2	MeOH	DCE	36
3	Pd(NHC)Cl2	TBHP	MeOH	DCE	20
4	Pd(NHC)Cl2	K2S2O8	MeOH	DCE	78
5	Pd(NHC)Cl2	K2S2O8	EtOH	DCE	73
6	Pd(NHC)Cl2	K2S2O8	MeOH	DCM	n.d.
7	Pd(NHC)Cl2	K2S2O8	MeOH	Dioxane	n.d.

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Based on these experimental outcomes and by referring to the leading references,^{2c,16d,16e,19} a tentative mechanism have been proposed for the Pd(NHC)Cl₂ catalyzed synthesis of 8a (Scheme 6). First, substrate 1a tautomerized to 1a′ which may undergo the C–H activation to generate a palladacycle intermediate A. Oxidative addition of DCE to the palladacycle A may form Pd(IV) species B. B may then undergo insertion reaction to yield intermediate C. Finally, product 8a is obtained via reductive elimination from C leading to the regeneration of the Pd(II) catalyst.

Scheme 6 Plausible catalytic cycle for Pd(NHC)Cl₂ catalyzed synthesis of 8a.

To our surprise, a homo-coupling product 11a (Scheme 7) was also observed when a mixture of 1a (1 mmol), Pd(NHC)Cl₂ (5 mol%) and Ag₂O (0.5 mmol) was stirred in AcOH (2 mL) at 100 °C for 9 h (Scheme 7). This might be due to the tautomerization of 1a to its enol form in polar solvent.¹³ The C₄–H of the enol form of pyrazole ring might be activated in presence of Pd-catalyst resulting the homo-coupling product 11a. The formation of 11a was confirmed well by ¹H NMR and mass spectrometry.

Scheme 7 Pd(NHC)Cl₂ catalyzed homo-coupling of 1a.

3. Conclusion

A novel strategy for the catalytic application of Pd(NHC)Cl₂ complex for the regioselective C–C and C–N functionalization reactions of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones has been successfully developed. The protocol was found to be simple, efficient and unique to demonstrate some unexpected C–H functionalization reactions of 1-aryl-3-methyl-1H-pyrazol-5(4H)-ones. Moreover, the present study has not only led some unexpected products with regioselectivity, but also provided the analogues of valuable drug candidates for the pharmacological screening.

Acknowledgements

The authors thank Head, Department of Chemistry, Sardar Patel University for providing necessary research and analysis facilities. VBP and SCK acknowledge University Grants Commission-New Delhi, India for Basic Scientific Research (UGC-BSR) Fellowship awarded to them during 2015–2018. The authors also acknowledge DST, New Delhi for the assistance in the form of mass analysis at PURSE central facility at Sardar Patel University sponsored under PURSE program grant vide sanction letter DO. No. SR/59/Z-23/2010/43 dated 16th March 2011.

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Footnote

† Electronic supplementary information (ESI) available: The spectral data of synthesized compound are shown in ESI. See DOI: 10.1039/c6ra22779a

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