Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl2 and NH4SCN/KSeCN

A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NH4SCN/KSeCN as thio/selenocyanogen sources and PhICl2 as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl–SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.

As the S/SeCN-containing organic compounds play an important role in organic and medicinal chemistry, organic chemists have devoted a great deal of efforts to developing efficient thio/ selenocyanation approaches [33][34][35][36][37][38][39][40][41].Specifically, a plethora of synthetic strategies have been reported for the thiocyanation of heteroaromatic compounds including arenes, indoles, carbazoles, pyrroles, and imidazopyridines [42][43][44][45].However, the electrophilic thiocyanation of biologically important pyrazoles has been less explored [46][47][48].Among them, the majority of the reported methods proceed through a radical pathway, with the SCN radical generated by the reaction of the thiocyanate source with a corresponding oxidant (Scheme 1a-c) [49].For example, Xu reported that a series of 4-thiocyanated 5-hydroxy-1H-pyrazoles was synthesized by a K 2 S 2 O 8promoted direct thiocyanation of pyrazolin-5-ones at room tem-perature, using NH 4 SCN as thiocyanogen source (Scheme 1a) [20].Similarly, utilizing NH 4 SCN and K 2 S 2 O 8 , Yotphan and colleagues realized a direct thiocyanation of N-substituted pyrazolones under metal-free conditions [49].Besides, Choudhury and co-workers developed an additive and metal-free methodology for the C-H thiocyanation of aminopyrazoles, using H 2 O 2 as a benign oxidizing agent (Scheme 1b) [41].Pan presented a method for the C-H thiocyanation of pyrazoles by using a sustainable catalyst of graphite-phase carbon nitride (g-C 3 N 4 ) under visible light irradiation (Scheme 1c) [2].Furthermore, Yao harnessed an electrochemical approach to form the electrophilic SCN + intermediate, which reacted with pyrazoles to give the corresponding thiocyanated pyrazoles (Scheme 1d) [50].However, to our knowledge, there are only few reports on the electrophilic selenocyanation of heterocycles [51][52][53] including the biologically important pyrazoles.In this regard, it should be highly desirable to develop an efficient method for a smooth selenocyanation of pyrazole compounds.

Results and Discussion
In our previous work we reported that a regioselective C-5 thiocyanation of the 2-pyridone skeleton could be realized via a PhICl 2 -mediated electrophilic thiocyanation approach [54].Inspired by this previous work, we were interested at investigating whether a direct C-4 selenocyanation as well as a thiocyanation of the pyrazole skeleton could be realized using the same protocol.At the outset of the study, 3,5-dimethyl-1-phenyl-1Hpyrazole (1a, 1 equiv) was chosen as the model substrate to react with NH 4 SCN (1 equiv) and PhICl 2 (1 equiv) in THF at 0 °C under N 2 atmosphere.To our delight, the desired thiocyanated product 2a was obtained in 68% yield (Table 1, entry 1).Encouraged by this result, we proceeded to investigate the other parameters that would possibly affect the efficiency of the reaction.First, upon a comparison of different reaction temperatures, we found that the reaction operated at 0 °C gave the best result (Table 1, entries 1-3).Then, other SCN-containing inorganic salts including KSCN, AgSCN, and CuSCN were screened, and the results showed that none of them gave better results than NH 4 SCN (Table 1, entries 4-6).Next, other oxidants including phenyliodine(III) diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA), iodosobenzene (PhIO), and NCS were applied, and the results indicated that PhICl 2 was the most effective oxidant (Table 1, entries 7-10).Later on, when the dosage of PhICl 2 and NH 4 SCN was increased to 2.0 equivalents, the yield of product 2a significantly increased to 82% (Table 1, entry 11).However, when the loading of PhICl 2 and NH 4 SCN were further increased to 3.0 equivalents, the reaction did not afford a better outcome (Table 1, entry 12).Furthermore, solvent screening showed that toluene was the most appropriate solvent, while the reaction led to a much lower yield when DMF, MeOH, MeCN, or DCM were used as solvents (Table 1, entries [13][14][15][16][17]. On the basis of the above experimental results, the optimized conditions for the thiocyanation of the model substrate were concluded to be: 2.0 equivalents of PhICl 2 and NH 4 SCN in toluene at 0 °C, under N 2 atmosphere (Table 1, entry 17).
With the optimized reaction conditions in hand, the substrate scope of this thiocyanation approach was next investigated (Scheme 2).The results showed that the newly established PhICl 2 /NH 4 SCN protocol was suitable for a wide range of substrates.Specifically, when N-aryl substrates containing electrondonating groups (-Me, -OMe) were subjected to the standard reaction conditions, the corresponding products 2b-e were obtained in good yields (80-91%).It was found that there was no significant influence on the outcome of the reactions of various N-aryl-substituted pyrazoles with a methyl group at the ortho-, meta-or para-positions of the phenyl group.Next, N-arylated substrates bearing electron-withdrawing groups (-F, -Cl, -Br, -I, -CF 3 , -NO 2 ) were tested, and the desired products 2f-k were conveniently obtained in moderate to good yields.Notably, the reaction of the substrate bearing a -CF 3 group afforded the corresponding product 2j in 93% yield.However, the substrate possessing a -NO 2 substituent gave an inferior yield of the product 2k.Then, we proceeded to investigate the effects of different substituents R 2 and R 3 .When the methyl substituent (R 2 ) was replaced with an aryl group, the corresponding thiocyanated products 2l-o could be obtained in acceptable to mod- a Reaction conditions: under N 2 atmosphere, a mixture of oxidant and [SCN] in solvent (2 mL) was stirred at 0 °C for 0.5 h, then 1a (0.20 mmol) was added, and stirring continued at 0 °C for 8 h.b Yield of the isolated product.c NR = no reaction.d ND = no desired product.
erate yields.On the other hand, the method was equally applicable to the substrate bearing two aryl substituents (R 2 and R 3 ), albeit the reaction afforded product 2n in a much lower yield, possibly caused by steric congestion.In addition, when the aryl substituent of R 1 was replaced with a tert-butyl group, this method also worked well to give product 2o in moderate yield.Notably, when the C3 and C5-unsubstituted substrate 1p was subjected to the standard conditions, the 4-thiocyanated product 2p was obtained regioselectively in 87% yield.Strikingly, the thiocyanation of the pharmaceutically active compound edaravone could also be realized under the optimized conditions, affording the corresponding product 2q in good yield.
Furthermore, we turned our attention to the applicability of this protocol for the selenocyanation of the pyrazole skeleton (Scheme 3).Gratifyingly, the method was equally applicable to selenocyanation of pyrazoles bearing various substituents, with the corresponding selenocyanated products 3a-o achieved in acceptable to good yields.Similarly, the selenocyanation of C3and C5-unsubstituted substrate 1p regioselectively furnished the 4-selenocyanated pyrazole 3p in good yield.
The utility of this approach was further demonstrated by a scale-up experiment.When 10.0 mmol of compound 1a were treated with 20.0 mmol of NH 4 SCN/KSeCN and PhICl 2 under the standard reaction conditions, the desired products 2a and 3a were obtained in 88% and 80% yield, respectively (Scheme 4).
The obtained 4-thio/selenocyanated pyrazoles could be further derivatized by known approaches.Specifically, products 2a and 3a could react with TMSCF 3 in the presence of Cs 2 CO 3 [55] to give the corresponding SCF 3 -and SeCF 3 -containing compounds 2r and 3q in moderate yields.Moreover, products 2a and 3a could be conveniently transformed into thiomethyl and selenomethyl-substituted pyrazole derivatives 2s and 3r by treatment with CH 3 MgBr in THF [56] (Scheme 4).

Conclusion
In conclusion, we have accomplished the synthesis of a series of C-4 thio/selenocyanated pyrazoles via a hypervalent iodinemediated electrophilic thio/selenocyanation approach under mild reaction conditions.Furthermore, the obtained S/SeCNcontaining pyrazoles can be converted to S/SeCF 3 -and S/SeMe-containing pyrazole derivatives.Further investigations Scheme 3: PhICl 2 /KSeCN-mediated selenocyanation of pyrazoles.Reaction conditions: under N 2 atmosphere, a mixture of PhICl 2 (2.00 mmol) and KSeCN (2.00 mmol) in toluene (5 mL) was stirred at 0 °C for 0.5 h, then 1a (1.00 mmol) was added and stirring continued at 0 °C for 8 h.Isolated yields are given.
Scheme 4: Gram-scale synthesis of compounds 2a and 3a and their derivatization.

Figure 1 :
Figure 1: Representative pyrazoles with pharmacological activities and S/Se-containing pharmaceutical molecules.

Table 1 :
Optimization of oxidative thiocyanation of pyrazole.a

Scheme 2 :
PhICl 2 /NH 4 SCN-mediated thiocyanation of pyrazoles.Reaction conditions: under N 2 atmosphere, a mixture of PhICl 2 (2.00 mmol) and NH 4 SCN (2.00 mmol) in toluene (5 mL) was stirred at 0 °C for 0.5 h, then 1a (1.00 mmol) was added and stirring continued at 0 °C for 8 h.Isolated yields are given.which was further transformed into intermediate B by release of one molecule of iodobenzene.Next, the nucleophilic attack of chloride anion to the bivalent selenium center of intermediate B resulted in the formation of two molecules of Cl-SeCN.Subsequently, Cl-SeCN under-goes an electrophilic addition reaction with pyrazole 1 to give intermediate C, which, after deprotonative rearomatization affords the 4-selenocyanated pyrazole 3.