Combined inorganic base promoted N-addition/[2,3]-sigmatropic rearrangement to construct homoallyl sulfur-containing pyrazolones

The first sequentially combined inorganic base promoted N-addition/[2,3]-sigmatropic rearrangement reaction of α-alkylidene pyrazolinones and propargyl sulfonium salts has been reported to construct homoallyl sulfur-containing pyrazolones with moderate to excellent yields. α-Alkylidene pyrazolinones function as N-nucleophilic agents distinguished from the reported C-addition reactions. Propargyl sulfonium salts were first involved in the [2,3]-sigmatropic rearrangement protocol differentiated from the well-established annulation reactions. The excellent regioselectivity, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this cascade process.


Introduction
Organosulfur compounds that exist broadly in biologically active natural products as well as pharmaceuticals and are engaged in numerous chemical transformations, have been attracting vivid interest from academia and industry. 1 Sulfur ylides are among the most versatile class of structural motifs, having widespread applications ranging from classical cyclopropanation, epoxidation and aziridination to more complicated [n + 1]-cycloadditions, domino reactions and rearrangement reactions based on transition metal catalysis, organocatalysis and photocatalysis. 2 As an efficient C-C bondforming strategy, [2,3]-sigmatropic rearrangements of sulfur ylides have been widely explored and applied since their discovery in the late 1960s. 3,4 The transition metal carbenoidmediated rearrangement reactions between allyl suldes and diazo species named Doyle-Kirmse reactions are representative examples and have made impressive progress especially in to the content of catalytic and asymmetric variants in the past decade (Scheme 1a). 5 Metal-free generation of sulfur ylides in situ between allyl thioethers and arynes followed by [2,3]sigmatropic rearrangements are also alternative methods (Scheme 1b). 6 Despite the aforementioned excellent work, the Scheme 1 [2,3]-Sigmatropic rearrangements of sulfur ylides (a and b) and N-2 initiating nucleophilic reaction of a,b-unsaturated pyrazolone (c). attempt to utilize propargyl sulfonium salts to form key species of sulfur ylides accompanied by subsequent [2,3]-sigmatropic rearrangements process has not been achieved.
Propargyl sulfonium salts, because of their easy acquirements and multiple reaction sites, are versatile and promising building blocks. Generally, propargyl sulfonium salts can isomerize to allenic sulfonium salts in the presence of the base, which are active forms and possess three reactive sites of acarbon, b-carbon and a 0 -carbon (Scheme 1c). Kanematsu's, 7 Huang's 8 and our group 9 have reported the [n + 2] or [n + 1] cascade annulation reactions based on a-carbon and b-carbon sites. Meanwhile, pyrazolones represent a class of privileged heterocycles that exhibit extensive physiological and pharmacological activities and are valuable drug candidates. 10 Accordingly, fruitful protocols have been explored to access versatile pyrazolones architectures based on the multiple reactive sites of pyrazolin-5-ones and a,b-unsaturated pyrazolones. 11,12 As to a,bunsaturated pyrazolones having g-H, the preferential g-C nucleophilic property facilities their functioning as C3 synthons to construct spiro-pyrazolones by [3 + n] annulation. 13 In contrast, the N-2 initiating nucleophilic reaction of a,b-unsaturated pyrazolones was less investigated. Recently our group reported the rst regioselective NaOAc$3H 2 O-promoted Naddition/substitution reaction between a-alkylidene pyrazolinones and propargyl sulfonium salts (Scheme 1c). 14 Accidentally, we found that strong inorganic bases can efficiently promoted the rearrangement of sulfur salts. Based on our processive interests on constructing functionalized pyrazolones and exploring the diverse reactive pathway of propargyl sulfonium salts, 9,15 we herein report the realization of regioselective NaOAc$3H 2 O/KOH-promoted N-addition/ [2,3]-sigmatropic rearrangement reaction of a-alkylidene pyrazolinones and propargyl sulfonium salts, delivering bioactive homoallyl sulfur-containing pyrazolones in moderate to excellent yields (Scheme 1d).

Results and discussion
We began our investigation by selecting a-alkylidene pyrazolinone 1a and propargyl sulfonium salt 2a as model substrates (Table 1). When 1a (0.2 mmol, 1.0 equiv.), 2a (0.24 mmol, 1.2 equiv.) and NaOAc$3H 2 O (0. 1 mmol, 0.5 equiv.) in CH 3 CN (2 mL) were mixed and stirred for 10 minutes at 20 C, the a-alkylidene pyrazolinone 1a was consumed completely. Aer the reaction temperature was decreased to 0 C, KOH (0.4 mmol, 2.0 equiv.) was added and the reaction was stirred for 6 h at 0 C to afford N-addition/ [2,3]-sigmatropic rearrangement product 3a with 82% yield (Table 1, entry 4). When the mixture of NaOAc$3H 2 O and KOH was added in one portion, a-alkylidene pyrazolinone could not be consumed completely even aer 12 h and the operation caused decreased yield. Extensive exploration of a range of bases indicated that NaOAc$3H 2 O or anhydrous NaOAc was most efficient to promote the process (entries 4-5 vs. 1-3 and 6-10 in Table 1). The combined usage of bases NaOAc$3H 2 O and KOH was  (Table 1, entry 4), we commenced to explore the substrate scope of the reaction (Scheme 2). Generally, the existence of methyl group (R 1 ¼ H) at a-position of alkylidene pyrazolinones was pivotal for the success of the reaction and various aryl and alkyl-substituted alkylidene pyrazolinones 1 was adaptable to the transformation. Acetophenones derived alkylidene pyrazolinones 1 with methyl, methoxy, chloro-, bromo-, iodo-, nitro-and cyano-groups on ortho-, meta-or para-positions, could react effectively with propargyl sulfonium salt 2a to furnish the related homoallyl sulfur-containing pyrazolones in 59-91% yields (3a-3n in Scheme 2). As to the same substituent on phenyl group, such as methyl, methoxy and chloro-, orthoand meta-positions exhibited higher yields than para-position (3b vs. 3i, 3l; 3c vs. 3j, 3m; 3d vs. 3k, 3n). Naphthyl-substituted aalkylidene pyrazolinones were well-tolerated to provide 3o, 3p and 3q in 66, 76 and 83% yields, respectively. Hetero-aromatic unsaturated pyrazolinones containing thiophene and Nmethyl protected pyrrole could participate in the reaction to afford corresponding product 3r and 3s in 57 and 70% yields, respectively. Double alkyl-substituted alkylidene pyrazolinone could also be engaged in the reaction to produce the predicted 3t with 72% yield. In contrast, when the methyl group was replaced by ethyl (R 1 ¼ CH 3 ) or benzyl groups (R 1 ¼ Ph), the desired reaction was sluggish, abundant alkylidene pyrazolinones were recovered and no target products 3u or 3v could be separated. In addition, the structure of homoallyl sulfurcontaining pyrazolone derivative 3a was assigned unambiguously by using single crystal X-ray analysis. 16 Scheme 2 Scope of Disubstituted a-Alkylidene Pyrazolinones. a Unless otherwise noted, the reactions were performed under air and aalkylidene pyrazolinones 1 (0.2 mmol, 1.0 equiv.), sulfonium salt 2a (0.24 mmol, 1.2 equiv.) and NaOAc$3H 2 O (0.1 mmol, 0.5 equiv.) in CH 3 CN (2.0 mL) were mixed, stirred for 10-40 minutes at 20 C until starting material 1a disappeared (monitored by TLC), then the reaction temperature was decreased to 0 C and KOH (2.0 equiv.) was added to keep stirring at 0 C for 6-10 h. b Isolated yield.
Subsequently, we went on to evaluate the effect of different substituents on pyrazolinone ring (Scheme 3). a-Alkylidene pyrazolinones 1 with the para-substituted phenyl-ring of R 1 worked well to deliver the corresponding products 3aa, 3ab, 3ac and 3ad with moderate yields of 63, 60, 73 and 66%, respectively. Electron-withdrawing groups on the phenyl group gave better yields than electron-donating groups (3ac, 3ad vs. 3aa, 3ab). ortho-Ethyl, uoro-substituted phenyl ring of R 1 gave relatively lower yields of 50 and 55% partially because of the instability of 1. It is noteworthy that the substrate having electron-withdrawing group C 6 F 5 -supplied the desired product 3ag with a moderate yield of 70%. a-Alkylidene pyrazolinones 1 with 4-uoro-, 4-methoxy and 4-bromo-substituted phenyl ring of R 2 could also be applied to the reaction and provide the related homoallyl sulfur-containing pyrazolones 3ah, 3ai and 3aj with 51, 71 and 50% yields. a-Alkylidene pyrazolinones 1 including alkyl group of R 2 showed excellent compatibility and afforded 3ak with 83% yield. Moreover, trimethyl involved alkylidene pyrazolinone displayed proof of tolerance and 81% yield was obtained (3al).
To further broaden the scope of the reaction, other representative propargyl sulfonium salts were also investigated (Scheme 4). Diethyl thioether derived propargyl sulfonium salt 2b was adaptable to give the predicted homoallyl sulfurcontaining pyrazolone 4 in 23% yield, together with additional isomerization product 5 in 47% yield. Trimethylsilylcontaining propargyl sulfonium salt 2c can also be applied to the reaction but the desilylation product 3a was obtained with a yield of 79%. Methyl substituted propargyl sulfonium salt 2d did not engage in the reaction under standard condition, mainly because NaOAc$3H 2 O was not suitable to transform propargyl sulfonium salt 2d into active allenic form and alkylidene pyrazolinone 1a was nearly fully recovered aer stirred at 20 C for 20 h. When NaOAc$3H 2 O was replaced by Cs 2 CO 3 , the reaction could proceed to afford the desired product 6 with 62% yield. Substrate 1d could also react with 2d smoothly to provide 7 with 68% yield under the same conditions.
To demonstrate the further synthetic utility of this protocol, we performed the large-scale operation using a-alkylidene pyrazolinone 1a (1.01 g, 3 mmol) and propargyl sulfonium salt 2a (1.2 equiv.) as the representative substrates under the optimized conditions, providing the related product 3a (1.00 g) with 79% yield (Scheme 5). The typical transformation was also conducted by oxidation of 3a with m-chloro peroxybenzoic acid (2.0 equiv.), sulnyl product 8 and sulfonyl product 9 were obtained in Scheme 5 with 33% and 39% yields, respectively.
According to the experimental observations and previous reports, 8,9,14 a possible mechanism is proposed to account for the formation of homoallyl sulfur-containing pyrazolone derivatives 3 (Scheme 6). Under the activation of inorganic base NaOAc$3H 2 O, a-alkylidene pyrazolone 1 can form intermediate I and propargyl sulfonium salt 2a can isomerize to allenic sulfonium salts II. The N-nucleophilic attack of I to allenic sulfonium salts II initiates the reaction and gives intermediate III aer protonation. Subsequently, the deprotonation of methyl-carbon by KOH provides the key sulfur ylide IV. Finally, Scheme 4 Scope of propargyl sulfonium salts. a Unless otherwise noted, the reactions were performed under air and a-alkylidene pyrazolinone 1a or 1d (0.2 mmol, 1.0 equiv.), sulfonium salts 2b, 2c or 2d (0.24 mmol, 1.2 equiv.) and NaOAc$3H 2 O (0.1 mmol, 0.5 equiv.) in CH 3 CN (2.0 mL) were mixed and stirred at 20 C until starting material 1a or 1d disappeared (monitored by TLC), then the reaction temperature was decreased to 0 C and KOH (2.0 equiv.) was added to keep stirring at 0 C for related time. b Isolated yield. c Cs 2 CO 3 (0.1 mmol, 0.5 equiv.) was utilized instead of NaOAc$3H 2 O under the standard condition and the reaction was kept stirring at 0 C for 15 h. the [2,3]-sigmatropic rearrangement of key species IV affords the desired product 3.

Conclusions
In summary, we have developed a sequentially combined inorganic bases promoted N-addition/ [2,3]-sigmatropic rearrangement reaction between a-alkylidene pyrazolinones and propargyl sulfonium salts for the rst time, delivering bioactive homoallyl sulfur-containing pyrazolones in moderate to excellent yields. In this reaction, a-alkylidene pyrazolinones function as N-nucleophilic agents distinguished from reported Caddition reactions. Meanwhile, propargyl sulfonium salts were rst involved in [2,3]-sigmatropic rearrangement protocols differentiated from the well-established annulation reactions. Gram-scale synthesis and convenient transformations are furnished. The proposed mechanism is also discussed. Excellent regioselectivity, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this reaction process.

General information
All reactions were performed in oven-dried or ame-dried round-bottom asks and vials. Stainless steel syringes and cannula were used to transfer air-and moisture-sensitive liquids. Flash chromatography was performed using silica gel 60 (230-400 mesh) from Aladdin. Commercial reagents were purchased from Aladdin, J&K, Macklin and Meryer and used as received. All solvents were used aer being freshly distilled unless otherwise noted. Proton nuclear magnetic resonance ( 1 H NMR) spectra and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on Bruker UltraShield-600 (600 MHz). The mass spectroscopic data were obtained using a Micromass Platform II single quadrupole instrument. Infrared (IR) spectra were obtained using a PerkinElmer Spectrum 100 FT-IR spectrometer.
General procedure for the synthesis of a-alkylidene pyrazolinones (1) a-Alkylidene pyrazolinones 1 were prepared through a known procedure: 12b,13b,14,17 aryl formyl acetate (5.5 mmol, 1.1 equiv.) was slowly added to the mixture of the corresponding hydrazine (5 mmol, 1.0 equiv.) in glacial acetic acid (2 mL). The mixture was stirred at room temperature for 24 h. NEt 3 (5 mmol, 1.0 equiv.) was added to neutralize the hydrochloride while phenylhydrazine hydrochloride was used. Aer the reaction was completed, ethyl (50 mL) was added. The precipitate was ltered and washed with 5 mL of ether (three times). The corresponding pyrozolone products were obtained as solid and used in the following step.
Under nitrogen atmosphere, a mixture of pyrazolone (5 mmol, 1.0 equiv.), acetophenone (6 mmol, 1.2 equiv.) and pyridine (0.8 mL, 10 mmol) in THF (10 mL) was stirred for 10 min followed by slow addition (30 min) of Titanium isopropoxide (4.3 mL, 15 mmol). The mixture was stirred at room temperature for 24 h. The resulting reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N aqueous HCl, saturated aqueous solution of NaHCO 3 and brine. The organic layer was dried over Na 2 SO 4 , concentrated, and puried by column chromatography to provide a-alkylidene pyrazolinone derivatives 1. If the products are mixed with excess liquid acetophenes, they can be further puried by washing with petroleum ether.
Propargyl Sulfonium Salts (2a, 2b, 2c, 2d and 2e) were prepared through a known procedure. 18 General procedure for the reaction of unsaturated pyrazolones with propargyl sulde ylide To a ame-dried sealable 3-dram vial equipped with a stir bar was added unsaturated pyrazolinones 1 (0.2 mmol, 1.0 equiv.), NaOAc$3H 2 O (0.1 mmol, 0.5 equiv.) and 2a (44 mg, 0.24 mmol, 1.2 equiv.) under air. Subsequently treated CH 3 CN (2 mL, c ¼ 0.1 M) was added to vial via syringe. The reaction mixture was stirred for 10-40 min at 20 C until unsaturated pyrazolones 1 was fully consumed (monitored by TLC). Then the reaction was stirred at 0 C for 6-10 h. The organic solvent was removed under reduced pressure and puried through column chromatography (eluent: petroleum ether and EtOAc) to afford the desired product 3.

Reaction of unsaturated pyrazolones 1d with methyl propargyl sulde ylide 2d
To a ame-dried sealable 3-dram vial equipped with a stir bar was added unsaturated pyrazolinones 1d (72 mg, 0.2 mmol, 1.0 equiv.), Cs 2 CO 3 (33 mg, 0.1 mmol, 0.5 equiv.) under air. Subsequently treated CH 3 CN (2 mL, c ¼ 0.1 M) was added to vial via syringe. The reaction mixture was stirred for 2 h at 20 C until unsaturated pyrazolones 1d was fully consumed (monitored by TLC). Then the reaction was stirred at 0 C for 15 h. The organic solvent was removed under reduced pressure and puried through column chromatography (eluent: petroleum ether and EtOAc) to afford the desired product 7 (65 mg, 68% yield, conversion: 81%).

Gram-scale synthesis of 3a
To a ame-dried sealable 3-dram vial equipped with a stir bar was added unsaturated pyrazolinones 1a (1.01 g, 3.0 mmol, 1.0 equiv.), NaOAc$3H 2 O (204 mg, 1.5 mmol, 0.5 equiv.) and 2a (0.65 g, 3.6 mmol, 1.2 equiv.) under air. Subsequently treated CH 3 CN (25 mL, c ¼ 0.12 M) was added to vial via syringe. The reaction mixture was stirred for 20 min at 20 C until unsaturated pyrazolones 1a was fully consumed (monitored by TLC). Then the reaction was stirred at 0 C for 10 h. The organic solvent was removed under reduced pressure and puried through column chromatography (eluent: petroleum ether and EtOAc) to afford the desired product 3a with a yield of 79% (1.01 g).