Sulfone groups are very important functional groups, exist in various natural products,
bioactive molecules, pharmaceuticals, and functional materials, and can enhance the
activity of compounds.[1] According to statistics, in 2021 of the world's top 200 best-selling small-molecule
drugs containing sulfone-based drugs accounted for 20, with sales of up to $27.5 billion.[2] The introduction of the sulfone group is one of the frontier research hotspots in
the field of organic synthesis and pharmaceuticals.[3] In particular, the development of convenient and efficient strategies for the incorporation
of sulfone groups into heterocyclic compounds has attracted widespread interest among
organic synthesis practitioners.[4]
Pyrazoles, as one of the high-value N-heterocyclic scaffolds, are epitomized in various
pharmaceuticals and bioactive molecules, with a variety of biological activities.[5] In particular, site-selective incorporation of sulfone groups can dramatically enhance
the pharmacological profile of pyrazoles.[6] For example, pyrazole derivative I
[7] incorporated with the sulfone group has important anti-inflammatory activity; compound
II
[8] is a potential pesticide with excellent larvicidal and herbicidal activity; and
compound III
[9] is a modulator of cystic fibrosis transmembrane conductance regulator (CFTR), and
it is a key component of Trikafta (Scheme [1a]).[10] Given this, the development of efficient, convenient, and practical strategies to
access sulfonated pyrazole derivatives is of great significance and has been widely
concerned. Wei[11] and Wang’s[12] groups have successively developed I2/TBHP and TBAI/TBPB systems to deliver sulfonated pyrazole from pyrazolones and sodium
sulfites. Although these elegant methods have been developed successively, the presence
of stoichiometric oxidants is necessary, and the absence of chemical oxidants remains
elusive.
Scheme 1 The background of sulfonated pyrazole
Organic electrochemistry is the study of chemical reactions which take place at the
interface of an electrode and electrolyte, involving the activation of the substrate
by electron transfer. Although a series of important achievements have been made in
organic electrochemistry in the last decade, few studies have been carried out in
the absence of external electrolytes.[13] Considering the importance of the sulfonated pyrazole frameworks, and together with
our growing interest in organic electrochemistry[13i]
[14] and sulfone-containing compound synthesis,[15] herein we wish to report an external oxidant-free electrochemical method for the
sulfonylation of pyrazolones with sodium sulfinates via a radical pathway. The established
electrochemical reaction works smoothly under external oxidant-free conditions and
has the advantages of excellent functional group tolerance, easy-to-gram-scale synthesis,
and avoiding the use of stoichiometric chemical oxidants.
As shown in Table [1], 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1a) and sodium 4-methylbenzenesulfinate (2b) were selected as the temple coupling substrate to optimize the reaction conditions,
including electrode material, current, solvent, and halogen anion source under room
temperature in an inert atmosphere. By optimizing various reaction parameters, it
was found that the desired product 1c could be delivered in 90% yield by performing the reaction with a constant current
of 10 mA electrolysis 2 h in an undivided cell employing NH4I (30 mol%) was the electrolyte and catalyst (Table [1], entry 1). The control experiment shows that both current and NH4I are the key factors of the transformation (Table [1], entries 2 and 3). The yield of desired product 1c decreased slightly when the amount of NH4I was reduced to 20 mol% (Table [1], entry 4). Moreover, other iodized salts, such as n-Bu4NI, KI, and NaI, were individually examined for their ability to deliver the desired
product 1c in yields of 58%, 82%, and 73%, respectively (Table [1], entry 5). However, the yield of the desired product was reduced to 75%, 7% by employing
CH3CN or H2O as the reaction solvent (Table [1], entry 6). To our delight, 1c was delivered with a yield of 83% when the reaction was performed using dichloromethane
as the solvent (Table [1], entry 7). Furthermore, the influence of the electrode materials for the electrochemical/I– dual-catalyzed sulfonylation of pyrazolones with sodium sulfinates access to sulfonated
pyrazoles under external oxidant-free conditions was also investigated. The results
show that C (+) | Pt (–) was the best choice (Table [1], entries 8 and 9). Finally, either increasing or decreasing the current of the reaction
is detrimental to the yield of the desired product (Table [1], entry 10).
Table 1 Optimization of the Reaction Conditionsa
|
|
Entry
|
Deviation from standard conditions
|
Yield (%)b
|
|
1
|
none
|
90
|
|
2
|
without current
|
0
|
|
3
|
without NH4I
|
trace
|
|
4
|
NH4I (20 mol%)
|
72
|
|
5
|
n-Bu4NI, KI, or NaI instead of NH4I
|
58, 82, 73
|
|
6
|
CH3CN or H2O as solvent
|
75, 7
|
|
7
|
CH2Cl2 instead of CH3CN
|
83
|
|
8
|
Pt (+) instead of C (+)
|
57
|
|
9
|
C (–) instead of Pt (–)
|
49
|
|
10
|
5 mA and 15 mA instead of 10 mA
|
78, 72
|
a Reaction conditions: carbon rods (φ = 6 mm) as the anode, Pt plate (1 × 1 cm2) as the cathode, constant current = 10 mA, 1a (0.25 mmol), 2b (0.5 mmol), NH4I (30 mol%), CH3CN/H2O (6.3 mL, v = 3: 0.1), r.t., N2, 2 h.
b Isolated yields.
With the standard conditions in the hand, we began to investigate the substrate scope
of this external oxidant-free protocol (Table [2]). Firstly, the scope of the pyrazole was investigated based on sodium 4-methylbenzenesulfinate
(2b). The results showed that both electron-donor and electron-deficient groups on the
para site of the pyrazolone benzene ring can give the corresponding products in moderate
to good yields under standard conditions (1c–8c).
Table 2 Scope of Substratea,b
|
|
a Reaction conditions: carbon rods (φ = 6 mm) as the anode, Pt plate (1 × 1 cm2) as the cathode, constant current = 10 mA, a (0.25 mmol), b (0.5 mmol), NH4I (30 mol%), CH3CN/H2O (6.3 mL, v = 3: 0.1), r.t., N2, 2 h; n. d. = not detected.
b Isolated yields.
To prove the scalability of this protocol, a large-scale synthesis of the sulfonated
pyrazole 1c was performed. Even the model reaction that was scaled up to 40-fold can get 74%
yields, simply by performing the reaction at room temperature in a three-neck flask.
Subsequently, the steric hindrance effect has been investigated, and the corresponding
products can be obtained in moderate to excellent yields from the meta or ortho site of benzene ring, polysubstituted, or naphthyl pyrazolones under the established
conditions (9c–15c). To our delight, the desired products 16c–18c can be delivered smoothly when R1 and R2 are converted into methyl, phenyl, or ester groups. In the following stage, sodium
sulfinates were systematically examined by employing 1a as the benchmark. Notably, the desired products can be obtained with excellent yields
when the different positions of sodium aryl sulfonate have electron-donating or electron-withdrawing
groups were carried out under the given conditions (19c–30c). Besides, both aromatic heterocyclic and alkyl sodium sulfite can deliver the desired
products in excellent yields under established conditions (31c–34c). Unfortunately, 35c was not observed when 5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid was performed in the present protocol, which may be affected
by the carboxyl group.
Intrigued by the outstanding efficacy of the electrochemical/I– dual-catalyzed sulfonylation of pyrazolones under external oxidant-free conditions,
we became interested in clarifying the mechanism of this transformation. To this end,
various control and cyclic voltammetry (CV) experiments were performed based on model
reaction. Firstly, only trace amounts of desired product 1c were observed in the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), 2,6-di-tert-butyl-4-hydroxytoluene (BHT) or CBr4 suggesting that the electrochemical/I– dual-catalyzed sulfonylation of pyrazolones may proceed via a radical pathway (Scheme
[2a]). Satisfactorily, this conclusion was further confirmed by the trapped products
1d (Figure S1). Secondly, intermediate validation experiments demonstrated that A
[16] and E
[15c] should be the intermediate of the transformation (Scheme [2b]).
Scheme 2 Control experiments
To understand the role of NH4I in the present transformation, various stoichiometric experiments were performed
as shown in Scheme [2c], suggesting that anodic oxidation I– to I+ delivers the product faster than the route of iodine radicals. Finally, the CV experiments
were carried out and the results are summarized in Figure [1]. The electrochemical behavior of the mixed NH4I and 2b demonstrate that the in situ generated iodine radical or I+ with 2b has undergone undisguised electron transfer (Figure [1], blue line).
Figure 1 CV experiments with glass carbon as the working electrode, Pt (1.5 × 1.5 cm2) as the counter electrode, Ag/AgCl as the reference electrode in 0.05 M n-Bu4NBF4, CH3CN (10.0 mL), scan rate 50 mV/s, 1b (0.25 mM), NH4I (0.25 mM).
Based on these preliminary results mentioned above and the previous reports,[11]
[12] a plausible mechanistic pathway for electrochemical/I– dual-catalyzed sulfonylation of pyrazolones was proposed and is shown in Scheme [3]. Initially, iodide anion was anodized to I• (0.66 V vs. Ag/AgCl) and I+ (1.11 V vs. Ag/AgCl) catalyst species.[16] Subsequently, the intermediate A can be produced by the reaction of I+ with 1a (path A) or via the radical cross-coupling of D and I• (path B). The desired product 1c was generated through the rapid tautomerization of sulfonated pyrazolone B, which was produced from the reaction of sodium sulfonate 2b and intermediate A. Moreover, according to the experimental results, the delivery of product 1c through the radical addition and iodine radical induce dehydrogenation of G cannot be ruled out (path C). The released iodine ions will be oxidized again on
the surface of the anode for catalytic cycling, while H+ will be reduced on the surface of the cathode to release hydrogen gas as a greener
byproduct.
Scheme 3 Postulated reaction pathway
In conclusion, an electrochemical/I– dual-catalyzed sulfonylation of pyrazolones with sodium sulfonate access to sulfonated
pyrazoles under external oxidant-free conditions have been disclosed.[17] A variety of sulfonated pyrazoles can be effectively synthesized by employing the
present protocol. A series of control experiments have confirmed that the established
electrochemical conversion undergoes a radical process. Besides, this electrochemical-induced
sulfonylation of pyrazolones strategy can be easily scaled up for synthesis with biologically
active sulfonated pyrazoles.
