Regio- and Stereoselective Switchable Synthesis of (E)- and (Z)-N-Carbonylvinylated Pyrazoles

Regio- and stereoselective switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Ag2CO3 plays a key role in the switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles. Ag2CO3-free reactions lead to thermodynamically stable (E)-N-carbonylvinylated pyrazoles in excellent yields whereas reactions with Ag2CO3 give (Z)-N-carbonylvinylated pyrazoles in good yields. It is noteworthy that (E)- or (Z)-N1-carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag+ acts as coordination guidance.


CN) 2 Cl][BPh 4 ]
and [Ru(dppp) 2 (CH 3 CN)Cl][BPh 4 ])-catalyzed stereoselective N-vinylation of pyrazoles and alkynes, and efficiently synthesized (E)-and (Z)-N-vinylated pyrazoles, respectively (Scheme 1B) [29]. In another recent report, Verma and co-workers realized KOH-mediated stereoselective synthesis of (Z)-and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, in which the stereochemical outcome of the reaction was governed by time and the quantity of the base (Scheme 1C) [30]. Although two examples revealed good stereoselective synthesis of (Z)-and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, no work has been directed to study the stereoselective addition of pyrazoles with conjugated carbonyl alkynes to prepare N-carbonylvinylated pyrazoles, presumably due to the incompatibility of carbonyl group with its optimal reaction conditions. In addition, in their work, no in-depth and detailed investigations into the regio-and stereoselective N 1 or N 2 vinylation of the asymmetrically substituted pyrazoles and alkynes were performed. So, the regio-and stereoselective switchable synthesis of (E)-and (Z)-N-carbonylvinylated pyrazoles is challenging.  [29]. In another recent report, Verma and co-workers realized KOH-mediated stereoselective synthesis of (Z)-and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, in which the stereochemical outcome of the reaction was governed by time and the quantity of the base (Scheme 1C) [30]. Although two examples revealed good stereoselective synthesis of (Z)and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, no work has been directed to study the stereoselective addition of pyrazoles with conjugated carbonyl alkynes to prepare N-carbonylvinylated pyrazoles, presumably due to the incompatibility of carbonyl group with its optimal reaction conditions. In addition, in their work, no in-depth and detailed investigations into the regio-and stereoselective N 1 or N 2 vinylation of the asymmetrically substituted pyrazoles and alkynes were performed. So, the regio-and stereoselective switchable synthesis of (E)-and (Z)-N-carbonylvinylated pyrazoles is challenging.  Considering the importance of pyrazoles, our recent research interests have focused on the synthesis of pyrazoles. A variety of N-unsubstituted pyrazoles bearing indole units have been synthesized from the cyclocondensation reaction of β-ethyltho-β-indolyl-α, β-unsaturated ketones and hydrazine hydrate or semicarbazide  )-catalyzed stereoselective N-vinylation of pyrazoles and alkynes, and efficiently synthesized (E)-and (Z)-N-vinylated pyrazoles, respectively (Scheme 1B) [29]. In another recent report, Verma and co-workers realized KOH-mediated stereoselective synthesis of (Z)-and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, in which the stereochemical outcome of the reaction was governed by time and the quantity of the base (Scheme 1C) [30]. Although two examples revealed good stereoselective synthesis of (Z)and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, no work has been directed to study the stereoselective addition of pyrazoles with conjugated carbonyl alkynes to prepare N-carbonylvinylated pyrazoles, presumably due to the incompatibility of carbonyl group with its optimal reaction conditions. In addition, in their work, no in-depth and detailed investigations into the regio-and stereoselective N 1 or N 2 vinylation of the asymmetrically substituted pyrazoles and alkynes were performed. So, the regio-and stereoselective switchable synthesis of (E)-and (Z)-N-carbonylvinylated pyrazoles is challenging.   Considering the importance of pyrazoles, our recent research interests have focused on the synthesis of pyrazoles. A variety of N-unsubstituted pyrazoles bearing indole units have been synthesized from the cyclocondensation reaction of β-ethyltho-β-indolyl-α, β-unsaturated ketones and hydrazine hydrate or semicarbazide hydrochlorides as a hydrazine equivalent in organic solvent or water [31][32][33]. Furthermore, by controlling the reaction conditions, the regioselective synthesis of isomeric 3-(1-substituted pyrazol-3(5)yl) indoles was also successfully realized when βethyltho-β-indolyl-α, β-unsaturated ketones reacted with monosubstituted hydrazines [34]. Subsequently, we developed the Ag 2 CO 3 -catalyzed aza-Michael addition of pyrazoles to α, βunsaturated carbonyl compounds, to afford a series of N-alkylated pyrazoles in excellent yields and with high regioselectivity [35]. As a continuation of our interest in the synthesis of pyrazole derivatives, most recently, we studied the regio-and stereoselective aza-Michael addition of pyrazoles and conjugated carbonyl alkynes for the switchable synthesis of (E)-and (Z)-Ncarbonylvinylated pyrazoles (Scheme 1D). It was found that pyrazoles efficiently reacted with the conjugated carbonyl alkynes in the absence of Ag 2 CO 3 to preferentially generate (E)-N-carbonylvinylated pyrazoles in excellent yields, while in the presence of 50 mol% of Ag 2 CO 3 , the reactions favored to afford (Z)-N-carbonylvinylated pyrazoles in good yields, in which Ag 2 CO 3 played the key role. Herein, we report our finding.

Results and Discussion
The reaction of 3, 5-dimethyl-1H-pyrazole 1aa and ethyl propiolate 2a was chosen to screen the reaction conditions. The summary of these results is listed in Table 1. We proceeded the first reaction without any additives in 1, 2-dichloroethane (DCE) at room temperature for 24 h, and found this reaction produced two stable products in 60% and 30% yields, respectively ( Table 1, entry 1). The products were characterized as (E)-ethyl 3-(3, 5-dimethyl-1H-pyrazol-1-yl) acrylate 3a (60%) and its (Z)-isomer 4a (30%) from the spectral and analytical data, which indicated that the reaction gave (E)-3a in preference to (Z)-4a. The reaction showed dependence on the reaction temperature; with increasing reaction temperature, the reaction became more efficient, in which the reaction time was significantly shorter and the yield of (E)-3a was markedly higher (Table 1, entries 2-5), and (E)-3a was obtained at 90% yield when the reaction ran at 60 • C for 8 h (Table 1, entry 4). Using other solvents such as toluene and 1, 4-dioxane, the reaction efficiency was not significantly improved (Table 1, entries 6 and 7). Because Ag + easily coordinates with both the nitrogen atom of imine and oxygen atom of the carbonyl group [35][36][37][38], we envisioned that the coordination guidance of Ag + probably favors the formation of (Z)-isomer 4a. Thus, with 10 mol% of readily available Ag 2 CO 3 as the catalyst, we proceeded the reaction in DCE at 60 • C and 20 • C, respectively. As expected, 4a as the major product was generated at 51% and 29% yields, respectively ( Table 1, entries 8 and 9). Encouraged by this result, we further increased the amount of Ag 2 CO 3 ( Table 1, entries [10][11][12][13][14][15]. Raising the amount of Ag 2 CO 3 to 50 mol% effectively improved the yield of 4a to 81% (Table 1, entry 13), while when further raising the amount of Ag 2 CO 3 , the yield of 4a failed to be obviously improved ( After optimizing the reaction conditions, we explored the universality of the procedure (Scheme 2). Firstly, the generality of the reactions of various symmetrically substituted pyrazoles and conjugated carbonyl alkynes was examined, and the results are summarized in Scheme 2. Using ethyl propionate 2a as the partner, we initially studied the scope of symmetrically substituted pyrazoles 1a. A variety of 1a, such as 3, 5-identically disubstituted pyrazoles 1aa-1ad, 4-substituted pyrazoles 1ae-1ao, and 3, 5-identical disubstituted-4substituted pyrazoles 1ap-1ar, smoothly reacted with 2a under the optimized conditions A and B to efficiently afford corresponding N-carbonylvinylated pyrazoles 3a-3r and 4a-4r in good yield and with good stereoselectivity, respectively. Clearly, the steric effects and electronic characters of substituents in 1a revealed a significant effect on the reaction rate. With the increase in steric bulk of the C3 or C5 substituent of 1aa-1ad, the reaction rate decreases. Pyrazoles with electron-donating groups, such as Me (1af), OCH 3 (1ag) and Ph (1ah), displayed faster reaction rates than pyrazoles with electron-withdrawing groups, such as X (1ai-1ak), NO 2 (1al), CN (1am), CO 2 Et (1an), and COCH 3 (1ao). Moreover, many active substituents, such as X, NO 2 , CN, CO 2 Et, and COCH 3 , of 1a could be well tolerated in the chemical transformations. Then, under the optimized reaction conditions A and B, the scope of conjugated carbonyl alkynes 2 was examined. Like 2a, methyl propionate 2b, isopropyl propionate 2c and tert-butyl propiolate 2d efficiently reacted with 1aa to produce N-carbonylvinylated pyrazoles 3s-3u and 4s-4u at good yields and with high stereoselectivity, respectively. In the case of 1-phenylprop-2-yn-1-one 2e, the desired products 3v and 4v were also obtained at 92% yield and 87% yield, respectively. visioned that the coordination guidance of Ag + probably favors the formation of (Z)-isomer 4a. Thus, with 10 mol% of readily available Ag2CO3 as the catalyst, we proceeded the reaction in DCE at 60 °C and 20 °C, respectively. As expected, 4a as the major product was generated at 51% and 29% yields, respectively ( Table 1, entries 8 and 9). Encouraged by this result, we further increased the amount of Ag2CO3 (Table 1, entries [10][11][12][13][14][15]. Raising the amount of Ag2CO3 to 50 mol% effectively improved the yield of 4a to 81% (Table 1, entry 13), while when further raising the amount of Ag2CO3, the yield of 4a failed to be obviously improved ( Next, under the optimal reaction conditions A and B, we investigated in detail the reactions of the asymmetrically substituted pyrazoles 1b with conjugated carbonyl alkynes 2 to examine the regioselectivity of the method. When 3-substituted pyrazoles 1ba-1bh reacted with 2a, N 1 -carbonylvinylated pyrazoles 5a-5h and 6a-6h were always obtained as major products with good regioselectivity, respectively, and, especially, 1bg exclusively afforded 5g (82% yield) and 6g (84% yield). Although the electronic character imparted an obvious impact on the reaction rates, they had no significant influence on the regioselectivity of the reactions. Notably, since R f values of 5h and 5h are the same, their mixtures were obtained when the reaction of 1bh and 2a was carried out under condition A, in which their molar ratio was determined as 2:1 from 1 H NMR analysis. The compound 3-Methyl-5phenyl-1H-pyrazole 1i also favored the formation of 5i with a 5i/5i ratio of 2:1 and 6i with a 6i/6i ratio of 2:1, suggesting that the steric effect of the C5 substituent of 1i seemingly exerted a negligible influence on the regioselectivity. In the same fashion, a variety of conjugated carbonyl alkynes 2b-2e also efficiently reacted with 1ba to afford 5j-5m and 6j-6m with good regioselectivity. Except for 5h and 5h , the other isomeric products of 5 and 5 , or 6 and 6 could easily be isolated by column chromatography due to their different R f values. It is noteworthy that the molecular structures of 3l, 4o, 5c, 5k and 6c were further confirmed by X-ray crystallographic analysis (Figure 2) [39]. In 3l, 5c and 5k , the pyrazolyl and carbonyl groups are positioned anti to each other (E configuration), and these two groups are positioned cis to each other in 4o and 6c (Z configuration).
Furthermore, we carried out gram-scale reactions to demonstrate the practicality of the chemical procedure (Schemes 3 and 4). Gratifyingly, 1aa (0.96 g, 10.0 mmol) effectively reacted with 2a (1.18 mL, 12.0 mmol) to successfully afford 1.57 g (81% yield) of 3a and 1.455 g (75% yield) of 4a under the optimized conditions A and B.
Molecules 2023, 28  Next, under the optimal reaction conditions A and B, we investigated in detail the reactions of the asymmetrically substituted pyrazoles 1b with conjugated carbonyl alkynes 2 to examine the regioselectivity of the method. When 3-substituted pyrazoles 1ba-1bh reacted with 2a, N 1 -carbonylvinylated pyrazoles 5a-5h and 6a-6h were always obtained as major products with good regioselectivity, respectively, and, especially, 1bg exclusively afforded 5g (82% yield) and 6g (84% yield). Although the electronic character imparted an obvious impact on the reaction rates, they had no significant influence on the regioselectivity of the reactions. Notably, since Rf values of 5h and 5h′ are the same, their mixtures were obtained when the reaction of 1bh and 2a was carried out under condition A, in which their molar ratio was determined as 2:1 from 1 H NMR analysis. The compound 3-Methyl-5-phenyl-1H-pyrazole 1i also favored the formation of 5i with a 5i/5i′ ratio of 2:1 and 6i with a 6i/6i'ratio of 2:1, suggesting that the steric effect of the C5 substituent of 1i seemingly exerted a negligible influence on the regioselectivity. In the same fashion, a variety of conjugated carbonyl alkynes 2b-2e also efficiently reacted with 1ba to afford 5j-5m and 6j-6m with good regioselectivity. Except for 5h and 5h′, the other isomeric products of 5 and 5′, or 6 and 6′ could easily be isolated by column chromatography due to their different Rf values. It is noteworthy that the molecular structures of 3l, 4o, 5c, 5k′ and 6c were further confirmed by X-ray crystallographic analysis ( Figure 2) [39]. In 3l, 5c and 5k′, the pyrazolyl and carbonyl groups are positioned anti to each other (E configuration), and these two groups are positioned cis to each other in 4o and 6c (Z configuration). Based on the above results, a plausible mechanistic pathway for the formation of 3 and 4 was proposed (Scheme 5). In the absence of Ag2CO3, 1aa and 2a underwent a Michael addition reaction to directly give (E)-3a due to thermodynamical stability of the E configuration (Path a). In the presence of Ag2CO3, the reaction proceeded based on Path b. Since Ag + easily coordinates with both the nitrogen atom of imine and oxygen atom of the carbonyl group [35][36][37][38], it is clear that the reaction commenced from the coordination of Ag + to  Furthermore, we carried out gram-scale reactions to demonstrate the practicality of the chemical procedure (Schemes 3 and 4). Gratifyingly, 1aa (0.96 g, 10.0 mmol) effectively reacted with 2a (1.18 mL, 12.0 mmol) to successfully afford 1.57 g (81% yield) of 3a and 1.455g (75% yield) of 4a under the optimized conditions A and B.  structures of 3l, 4o, 5c, 5k and 6c [39].
Based on the above results, a plausible mechanistic pathway for the formation of 3 and 4 was proposed (Scheme 5). In the absence of Ag 2 CO 3 , 1aa and 2a underwent a Michael addition reaction to directly give (E)-3a due to thermodynamical stability of the E configuration (Path a). In the presence of Ag 2 CO 3, the reaction proceeded based on Path b. Since Ag + easily coordinates with both the nitrogen atom of imine and oxygen atom of the carbonyl group [35][36][37][38], it is clear that the reaction commenced from the coordination of

General Information
1 H and 13 C{1H} NMR spectra were recorded on a Bruker DRX-600 spectrometer and all chemical shift values referred to δ TMS = 0.00 ppm (δ ( 1 H)) and CDCl3(δ ( 13 C), 77.16 ppm). The HRMS analysis was achieved on a Bruck microTof by using the ESI method. All the melting points were uncorrected. Analytical TLC plates with Sigma-Aldrich silica gel 60F200 were viewed by UV light (254 nm). Chromatographic purifications were performed on SDZF silica gel 160 (Supplementary Materials).

General Information
1 H and 13 C{1H} NMR spectra were recorded on a Bruker DRX-600 spectrometer and all chemical shift values referred to δ TMS = 0.00 ppm (δ ( 1 H)) and CDCl 3 (δ ( 13 C), 77.16 ppm). The HRMS analysis was achieved on a Bruck microTof by using the ESI method. All the melting points were uncorrected. Analytical TLC plates with Sigma-Aldrich silica gel 60F200 were viewed by UV light (254 nm). Chromatographic purifications were performed on SDZF silica gel 160 (Supplementary Materials).

Conclusions
In summary, for the first time, the regio-and stereoselective synthesis of (E)-and (Z)-N-carbonylvinylated pyrazoles was successfully realized by the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Symmetrically substituted pyrazoles stereoselectively gave (E)-and (Z)-N-carbonylvinylated pyrazoles in good yields, respectively. In the case of asymmetrically substituted pyrazoles, the reaction revealed not only excellent stereo-selectivity but also good regioselectivity. These features, such as the high regio-and stereoselectivity, commercially available catalyst, good substrate scope, mild conditions and scalability, made the methodology very practical and attractive. Further investigations on the applications of N-carbonyl vinylated pyrazoles are currently underway in our laboratory.