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Review

Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds

by
Boris V. Lyalin
1,
Vera L. Sigacheva
1,
Anastasia S. Kudinova
1,2,
Sergey V. Neverov
1,
Vladimir A. Kokorekin
1,2,3,* and
Vladimir A. Petrosyan
1
1
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp. 47, 119991 Moscow, Russia
2
Institute of Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str. 8, Bldg. 2, 119991 Moscow, Russia
3
All-Russian Research Institute of Phytopathology, Institute Str. 5, 143050 Bol’shiye Vyazemy, Russia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(16), 4749; https://doi.org/10.3390/molecules26164749
Submission received: 30 June 2021 / Revised: 28 July 2021 / Accepted: 29 July 2021 / Published: 5 August 2021
(This article belongs to the Special Issue Recent Advances in the Synthesis, Functionalization and Applications of Pyrazole-Type Compounds I)
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Versions Notes

Abstract

:
The review summarizes for the first time the poorly studied electrooxidative functionalization of pyrazole derivatives leading to the C–Cl, C–Br, C–I, C–S and N–N coupling products with applied properties. The introduction discusses some aspects of aromatic hydrogen substitution. Further, we mainly consider our works on effective synthesis of the corresponding halogeno, thiocyanato and azo compounds using cheap, affordable and environmentally promising electric currents.

Graphical Abstract

1. Introduction

The functionalization of arenes is the key to their diversity, opening the way to practically useful substances. At the beginning of the 21st century, C‒H functionalization of arenes became a popular tool for the implementation of such processes [1], and the center for selective C‒H functionalization (mainly based on metal complex catalysis) was organized in the USA [2,3]. At the same time, a more attractive metal-free C‒H functionalization of arenes has existed for many years. Its development is discussed below, since the review is related to it.
The first to consider is the electrophilic aromatic hydrogen substitution (SEH) [4]. It proceeds via the σH+ adduct formation and proton elimination leading to the target product (Scheme 1a).
The nucleophilic aromatic hydrogen substitution (SNH, Scheme 1b) is problematic due to the difficulty of the hydride ion direct elimination from the σH− adduct. Nevertheless, in the mid-1970s, Chupakhin and Postovsky proposed an indirect way of obtaining the target product, the chemical oxidation of the σH− adduct [5]. To date, such processes have been extensively developed by Chupakhin and Charushin [6,7,8,9].
This review is devoted to electrooxidative functionalization of pyrazoles. Why is it so attractive? The answer is given by Seebach [10], who showed that the interaction of two near-polar co-reactants is provided by the polarity inversion of one of them. This is the essence of electrochemistry, where the electrode transformation of the substrate is accompanied by its polarity inversion. For example, 1,4-dimethoxybenzene (DMB) and pyrazole (Scheme 2) are two non-interacting nucleophiles, but polarity inversion of DMB by electrooxidation leads to the electrophilic radical cation that reacts with pyrazole. In the electrochemical literature, this C‒H functionalization is called anodic substitution, which has been actively studied since the mid-1950s [11,12,13,14,15,16,17,18,19,20].
Note that chemical (electrophilic and nucleophilic) substitution and electrochemical (anodic) substitution in arenes have been being developed in parallel and independently of each other for a long time. In addition, the role of anodic substitution among the corresponding chemical processes was unconsidered.
Only recently we have introduced the concept of anodic substitution as an electrochemical aromatic substitution of hydrogen [21,22]. Such reactions were designated as SNH An (An is anode), since the key stage is anodic oxidation of the substrate. For electron-rich arenes, the processes proceed along two main routes (Scheme 3), depending on the ease of oxidation of nucleophile vs. arene [21]. Route I (arene oxidizes easier than Nu−) proceeds via the interaction between Nu− and the arene radical cation. Route II (Nu− oxidizes easier than arene) proceeds via the formation of Nu•, which either interacts with the arenes homolytically (route IIa) or forms a dimer that interacts with the arene as an electrophile (route IIb).
In general, the multitude of SNH (An) processes, where hydrogen is displaced with a nucleophile, are electrooxidative C‒H functionalizations (C–H An) and can be described by Scheme 4. Such strategy opens up the direct method of C–H functionalization of arenes with the C–C and C–Het coupling realization. The latter is especially shown in the examples of electrooxidative C–H halogenation and thiocyanation of pyrazole derivatives (Section 2 and Section 3). A special place is occupied by the N–N coupling of amino pyrazoles via the N–H functionalization (Section 4), since its patterns are somehow similar to those described above, but not sufficiently studied.
Such processes are attractive for green chemistry [23,24] because they use cheap, affordable and environmentally promising electric current instead of chemical oxidants (often toxic, unrecyclable and used in excess) and complex catalysts (sometimes expensive and toxic). In addition, the varying anode potential eliminates the difficulties of an empirical search for suitable chemical oxidants, while Pt, a frequently used electrode material [25], can be replaced by more attractive ones, e.g., glassy carbon, or ruthenium–titanium oxide (for more information on electrode materials see [25,26,27]).
Since the review is devoted to the poorly studied electrochemical functionalization of pyrazole derivatives, Section 2, Section 3 and Section 4 mainly summarize the investigations of the review’s authors.

2. Electrooxidative C–H Halogenation of Pyrazole and Its Substituted Derivatives

Halogenated pyrazoles are widely used in organic synthesis; in particular, iodo and bromo pyrazoles are the key reagents in transition metal-catalyzed cross-coupling [28]. Moreover, they are important precursors of drugs, such as antihepatitis, anti-Alzheimer, antiparkinsonian and anti-schizophrenic drugs (chloro-pyrazoles) [29,30,31], antiglaucoma drugs (bromo-pyrazoles) [32] and antiatherosclerotic, antimalarial, anti-inflammatory and immunocorrective drugs (iodo-pyrazoles) [33,34,35,36,37,38]. At the same time, chloro- and iodo-pyrazoles are used for preparation of antidiabetic drugs [39,40], bromo- and iodo-pyrazoles—of anticancer [41,42,43,44] and antimicrobial [45,46] agents, and chloro- and bromo-pyrazoles—of agrochemicals [47,48,49,50,51].
The active use of halogeno-pyrazoles has stimulated interest in their efficient and ecologically attractive synthesis, including electrosynthesis (see Introduction). At the same time, the electrochemical halogenation of pyrazoles has practically not been studied before us, but it was preceded by chemical halogenation, the aspects of which are briefly given below.

2.1. Chemical Halogenation of Pyrazoles

The processes (Scheme 5) are usually carried out by the interaction of pyrazoles and halogens (or halogenating reagents), and they occur first at position 4 and only then at other positions [28].

2.1.1. Chlorination

The most common is the interaction of pyrazoles and Cl2. It was used to convert the pyrazole and its alkyl derivatives into the 4-chloro pyrazoles (yields 40–85%, at 0–40 °C, in CH2Cl2 or CCl4). Under severe conditions (at 80–100 °C, in AcOH) dichloropyrazoles and the chloro products of the alkyl groups were also formed [52,53]. At the same time, the corresponding 4-chloro derivatives were obtained by the reaction of 3,5-dimethyl-1H-pyrazole (and its N-substituted derivatives) with N-chlorosuccinimide (yield 95–98%, at 20–25 °C, in CCl4 or H2O) [54,55].

2.1.2. Bromination

The reaction of alkyl-substituted pyrazoles and their carboxylic acids with Br2 (at 20–25 °C) proceeded in yields of 75–96% in non-aqueous media (CH2Cl2, CHCl3 or CCl4) [45,56,57,58], or 50–75% in water [59,60]. The NaOH additives (which binds with HBr formed) allows bromination of low-reactive pyrazole-3-carboxylic acid in the yield of 90% [61]. A number of 4-bromopyrazoles were also obtained by the reaction of 3,5-dimethyl-1H-pyrazole (and its N-substituted derivatives) with N-bromosuccinimide (yields 90–99%, at 20–25 °C, in CCl4 or H2O) [55].

2.1.3. Iodination

Good results in the iodination of pyrazoles with donor substituents were obtained using the I2–NaI–K2CO3 system (yields 75–90% at 20–25 °C in aq. EtOH) [62,63,64]. A solution of N-iodosuccinimide in acidic media (50% aq. H2SO4, CF3SO3H, CF3COOH, AcOH) was also efficient for the iodination [44,62,65]. Finally, the iodination of practically any pyrazoles proceeded efficiently and without toxic waste using the I2–HIO3 system in AcOH–CCl4 [66,67].
In general, the above methods are quite effective, but not ecologically attractive enough due to the frequent use of halogens in their pure form or waste of other halogenating agents (e.g., succinimide). Such problems can be solved using electrochemical methods—C–H An halogenation.

2.2. C-H An Halogenation of Pyrazoles

The halogenation (Scheme 6) usually proceeds [26] via the electrogeneration of a halogen followed by its interaction with pyrazole (cf. Scheme 3, route IIb).
Such processes are mainly carried out under mild conditions in an anodic compartment of a divided cell on a Pt-anode under galvanostatic electrolysis with alkali metal halides in H2O or in H2O–CHCl3. A series of N–H and N–Alk pyrazoles, including those with donor (acceptor) substituents, were objects of study (Table 1, Table 2 and Table 3).

2.2.1. Chlorination

C–H An chlorination of pyrazole 1a (Table 1, entry 1) led to 4-chloropyrazole 1b (yield 46%) and to by-product 1b′ (yield 8%) in H2O–CHCl3 at the theoretical amount of electricity passed (Q/Qt = 1). Apparently, the product 1b undergoes chlorination to 1,4-dichloropyrazole 1b′ (Scheme 7), followed by C–N dehydrogenative cross-coupling to by-product 1b-1b′.
The need for CHCl3 (as an extractant of target product) should be noted, since its absence decreased the yield of product 1b to 34% and increased the yield of by-product 1b-1b′ to 15%. Pyrazoles 2a–7a (entries 2–7), gave the monochlorinated products 2b–7b with different yields (8–71%) depending on the position of Me groups. Di- and trichloroproducts were obtained in entries 5 and 6.
Pyrazoles with acceptor groups (NO2 or COOH) were chlorinated without CHCl3 additives: the yields of the target products 8b–14b were 41–93% (entries 8–14). Only pyrazole 14a, containing both NO2 and COOH groups, was the least reactive. Therefore, the electrochemical method for the synthesis of 4-chloropyrazolcarboxylic acids [68] is noticeably superior to the corresponding chemical one [69].

2.2.2. Bromination

Compared with chlorination, the C‒H An bromination (Table 2) proceeded more effectively for pyrazole and its methyl derivatives (yields of products 1c–6c 55–94%). In some cases, dibromo by-products (entries 2 and 5), low yield (entry 9), or the absence of any reactions (entries 7 and 14) were observed.

2.2.3. Iodination

C‒H An iodination by weakly electrophilic I2 (Table 3) was generally less effective than bromination [73]. Traces of the target products or no reaction were observed in half of the cases (entries 2, 7–9, 11–13). In other cases, the yields were 35–86% (for pyrazole and its methyl derivatives in entries 1, 3–6) and 30–40% (for nitro- and carboxypyrazoles in entries 10 and 14).
A much more effective iodinating agent was HOI, which can be obtained by the reaction of KIO3 with KI (or I2) and H2SO4 [75,76,77,78,79]. The original process [74] includes the electrogeneration of KIO3 (on the NiO(OH) anode [80]), followed by the interaction of HOI generated in situ with the pyrazole (Scheme 8). As a result, the yields of target products increased to 74–93% (entries 1, 2, 4, 8, 10–12, 13).

2.3. The Mechanistic Aspects of C–H (An) Halogenation of Pyrazoles

Since I−, Br−, and Cl− are commonly oxidized at lower anodic potentials than the studied pyrazoles, the process proceeds via the electrooxidation of Hal− to Hal2 followed by interaction of the latter with arenes (see Scheme 3, route IIb and Scheme 6). The possible mechanism [26,71,79] (Scheme 9) includes the initial attack of the halogen on the N2 of Az–H with the formation of σH+ adduct 1. The latter, depending on the R, gives either N–X intermediate (R = H) or σH+ adduct 2 (R = Alk). Therefore, the target Az–X is formed either due to N–C rearrangement of N–X derivative or due to the deprotonation of σH+ adduct 2.
Iodination by HOI proceeds similarly, but for highly basic N-unsubstituted pyrazole and its alkyl derivatives it most likely occurs (Scheme 10) via C–I adduct (the result of protonation of N2 and HOI attack on C4) [74,75,77,78,79].
Additional control experiments showed different properties of N–Cl and N–Br intermediates (Scheme 11). Therefore, the N–C rearrangement of the N–Cl derivative is significantly lower than that for the N–Br (cf. stages N–X→Az–Cl and N–X→Az–Br). At the same time, for the N–Cl bond, homolytic cleavage is observed, while for N–Br it is heterolytic (cf. stages N–X→Ar–CH2-Cl and N–X→Ar–Br).
The above data not only reveal the essence of pyrazoles C‒H An halogenation, but also explain the difference in its efficiency (e.g., the anomalously less efficient chlorination of N-unsubstituted pyrazoles compared to bromination (cf. entries 1, 3 and 4, Table 1 and Table 2), and the formation of by-products (e.g., entries 1 and 6, Table 1).
Therefore, this Section describes the basic patterns of C–H An halogenation, and the efficient (up to 94% yield) gram-scale synthesis of a series of chloro-, bromo- and iodo-pyrazoles in aqueous or aqueous-organic media. The following Section reflects the main points on the related C‒H An thiocyanation of pyrazole derivatives.

3. Electrooxidative C–H Thiocyanation of 5-Aminopyrazoles and Pyrazolo [1,5-a]pyrimidines

Thiocyanation of the C–H bond of arenes is an effective tool for C–S coupling [81,82,83,84]. The resulting aryl thiocyanates are valuable precursors of sulfur and nitrogen-containing compounds (thiols [85], (di)sulfides [86,87], dithiocarbamates [88], thiazoles [89], tetrazoles [90]), and are highly bioactive compounds (antifungal [91], antitumor [92], antiparasitic [93]). Recently synthesized thiocyanates of pyrazole derivatives also have sufficient antifungal [94] and antitumor [95] activity.
One of the key intermediates of C‒H thiocyanation of arenes is the well-known [96,97] pseudohalogene thiocyanogen (SCN)2. It is usually obtained in situ by chemical or electrochemical oxidation of the thiocyanate ion (Scheme 12).
The chemical approach has been actively developed over the past 10–15 years, but it is often associated with the use of an excess of unrecyclable oxidants, which can sometimes be toxic, scalding or poorly available (e.g., Br2 [98], I2 [99], DEAD [100], HIO3 [101], H5IO6 [102], I2O5 [103], H2O2 [102,104,105,106,107], K2S2O8 [108,109], CAN [110], Mn(OAc)3 [111], p-TSA [112], NCS [113], NBS [100], NIS [114], NTS [115], DDQ [116,117]). The electrochemical approach (see [22], Scheme 3, route IIb, and Scheme 13) is devoid of such disadvantages, but it is poorly studied in general [118,119,120]. For pyrazole derivatives, C–H An thiocyanation is studied for the first time in a series of works [22,121,122,123,124,125,126], which are reflected in this Section.

3.1. C–H An Thiocyanation: General Patterns and Approaches

According to the above and developed [22,118,119,120,121,122,123,124,125,126] concepts, C–H An thiocyanation occurs during the anodic oxidation of the thiocyanate ion in the presence of arene, as a rule, via the thiocyanogen (Scheme 13, step I→I′). The latter either interacts with arene (step I′ + II→III), or gives polythiocyanogen [127] (step I′→IV).
These processes were investigated by cyclic voltammetry (CV) [22,123,125,126]. Scheme 13 shows a typical CV curve of SCN−. Peak A corresponds to the oxidation of thiocyanate ion I to thiocyanogen I′, which is detected on the reverse scan by its reduction peak B (B3). If after the addition of arene II, peak B disappears (cf. peaks B1 and B3) or decreases (cf. peaks B2 and B3), then Ar–H II interacts with (SCN)2, respectively, via the route B1 or B2 to form the target Ar–SCN III. If the peak B does not change, then Ar–H II does not react with (SCN)2 (see peak B3 and route B3). In this case the main reaction product is polythiocyanogen IV.
Further, we proposed [122,123] the original system of approaches to the C–H An thiocyanation of arenes (Scheme 14) depending on the reactivity of arenes with respect to (SCN)2: via the generation (SCN)2 at the oxidation potential (Epox) of thiocyanate ion (approach A, cf. Scheme 3, route IIb, and Scheme 13), via electrogeneration (SCN)2 in the presence of ZnCl2 activating additives (approach B) or via the generation of a highly reactive radical cation at Epox of arene (approach C, cf. Scheme 3, route I).
Approach A is used for arenes that react with (SCN)2 (Scheme 13, routes B1 and B2), whereas approaches B and C are used for arenes that do not interact with non-activated (SCN)2.
These patterns and approaches are considered below on the examples of C–H An thiocyanation of the practically useful [128,129,130] derivatives of 5-aminopyrazole and pyrazolo[1,5-a]pyrimidine and the original electrosynthesized 1-(hetero)arylpyrazoles [124,131].

3.2. C–H An Thiocyanation of Pyrazole Derivatives

The studies included a preliminary CV test in addition to electrosynthesis. The initial pyrazoles 1e–15e and their thiocyanation products 1f–15f are presented in Table 4 and Table 5.

3.2.1. CV studies and the Choice of Optimal Approach

Figure 1 shows CV curves of NH4SCN and its mixtures with 3-methyl-1H-pyrazol-5-amine (1e), 2-methyl-5-thiophen-2-yl-7-(trifluoromethyl) pyrazolo[1,5-a]pyrimidine (10e), as well as curves of individual compounds and their thiocyanato products (1e,10e,1f,10f) [125,126]. The CV of NH4SCN (curve 1, Figure 1A,B) has the anodic peak A1 (Epox = 0.70 V) of the thiocyanate ion and a cathodic peak B1 (Epred = 0.34 V) of the thiocyanogen. The peak B1 disappeared after the addition of pyrazole 1e and did not change after the addition of pyrazole 10e (cf. corresponding curves 1 and 4). This clearly shows that pyrazole 1e reacts rapidly with (SCN)2 (see Scheme 13, route B1) and approach A (Scheme 14) is suitable for its thiocyanation. From the other side, the pyrazole 10e does not react with (SCN)2 and approaches B and C may be suitable for its thiocyanation. Note also that on full scans, peaks A3 of thiocyanates 1f,10f were observed, in addition to the peaks A2 of pyrazoles 1e,10e (see curve 5, Figure 1A,B).

3.2.2. Electrosynthesis

Electrolyses were carried out in 0.1M solution of NaClO4 in MeCN (MeCN–H2O) in undivided or divided cells (UC or DC) in controlled-potential or galvanostatic mode (CPE or GE), passing a theoretical or excess amounts of electricity (Q/Qt = 1–3). Pt or glassy carbon (GC) electrodes were used.
The amino compounds 1e–6e gave thiocyanates 1f–6f with yields 64–89% (under CPE at EpoxSCN−) and 57–71% (under GE) at Q/Qt = 1 (Table 4, entries 1–6) when implementing approach A (see Scheme 14).
From the less reactive pyrazolo[1,5-a]pyrimidines 7e–9e, products 7f–9f were obtained with yields 66–85% at Q/Qt = 2 (entries 7–9). The electrode material affected things differently: the yield of thiocyanate 2a (entry 1) was 83% (GC) and 72% (Pt), while the yield of thiocyanate 2g (entry 7) was 64% (GC) and 89% (Pt). Most of the processes (entries 3–9) were successfully carried out in an undivided cell. The possibility of scaling the process was also shown (entries 1, 2 and 7).
It was noted [121,122,123,125] that approach A is not suitable for the thiocyanation of hardly oxidizable (Epox > 1.70 V) pyrazoles 10e–15e with acceptor substituents (Table 5) and leads to trace amounts of target thiocyanates 10f–15f and polythiocyanogen (see Scheme 13, route B3). In this case, the process proceeds quite efficiently with an increase in the reactivity of the thiocyanogen (Scheme 14, approach B) or the initial pyrazole (approach C). As a result, CPE in the presence of ZnCl2 activating additives (approach B) allowed us to obtain products 10f–15f with yields 69–81% [121,123], while metal-free CPE at EpoxAzH with Q/Qt = 3 (approach C) also led to the products 10f–15f with smaller yields of 47–65% [122,123].
Note that the possibility of approach C realization can also be tested by CV: a decrease in the peak B1 is observed on the full scan (cf. curves 5 and 1, Figure 1B), which corresponds to the interaction of the thiocyanate ion and the pyrazole cation radical via the ECE mechanism [122,123,132] (see Scheme 14, approach C, and Scheme 3, route I).
In addition to approaches A–C, an equally effective approach was developed [41] based on the HCl-catalyzed condensation of previously obtained 4-thiocyanatopyrazoles 1e, 2e (see entries 1 and 2, Table 4) with 1,3-dicarbonyl compounds or their derivatives (Scheme 15). As a result, 3-thiocyanatopyrazolo[1,5-a]pyrimidines both without substituents and with donor (acceptor) substituents in the pyrimidine ring were obtained with yields of 77–96% [126].
Developing this direction, the opportunity of transformation of the SCN group into the SH group [94,123] was shown, which opens the way to thiols as promising nucleophiles for C–H functionalization (e.g., see [133,134,135]). Hydrolysis with HCl was the most effective (yields of thiols 7g, 16g, 18g were 61–77%), while the use of chemical reductants or strong acids (LiAlH4, NaBH4, Zn in AcOH, HClO4, H2SO4) was ineffective.
Thus, a series of thiocyanates of substituted pyrazoles and pyrazolo[1,5-a]pyrimidines were obtained on the basis of electrolysis of the “thiocyanate ion/pyrazole” mixture.
In addition, during the development of research on the electrosynthesis of aryl thiocyanates [22] and N-arylpyrazoles [131,136,137,138] we showed [124] the possibility of synthesizing new molecules with pyrazole and thiocyanate fragments (Scheme 16) as promising hybrid polyfunctional [139] structures.
The N–H arylation of pyrazole 1h was carried out by activating its N–H bond (i) followed by the introduction of electrolysis with N-methylpyrrole or N,N-dimethylaniline (ii). In the latter case, the reaction proceeded selectively at the Me group without affecting the aromatic ring. Subsequent C–H An thiocyanation (iii) of the isolated N-arylazoles 1i, 2i led to the target products 1j, 2j.

3.3. Antifungal and Antibacterial Activity of Thiocyanated Pyrazole Derivatives

Tests for antifungal (C. albicans, A. niger) and antibacterial (S. aureus, E. coli) activity [91,94,123,124] showed that thiocyanate-pyrazoles are more active against fungi than bacteria. The greatest activity is observed against A. niger at thiocyanate 7f [94] and thiocyanatoazolylaniline 2j [124], whose minimum inhibitory concentration (MIC) is 0.24–0.48 µg/mL (it is superior to the antifungal drugs amphotericin B and fluconazole and is comparable to itraconazole).
The contribution of thiocyanate and pyrazole fragments to antifungal and antibacterial activity was clearly shown in the individual examples (Figure 2). Thus, the activity of compound 1j increased more than 2000-fold for A. niger and more than 16-fold for C. albicans after the introduction of the SCN group. The presence of 4-nitropyrazole in 4-thiocyanatoaniline 2j’ provided a selective increase in antifungal activity by a factor of 16–64, while N-arylazole 2i was inactive in all cases.
Therefore, this Section is devoted to the efficient C–H An thiocyanation of various pyrazole derivatives (in some cases, their N–H An arylation), leading to pharmacologically active target mono- and polyfunctional products. The next Section is devoted to the N–H functionalization of amino pyrazoles followed by their N–N coupling and obtaining azopyrazoles.

4. (Electro)oxidative N–N Coupling of Aminopyrazoles

Azoarenes are widely used in practice: from dyes and pharmaceuticals [140,141,142] to reagents in syntheses [143,144] and energy-rich materials [145,146]. One of the most popular methods for the synthesis of azoarenes is the oxidation of corresponding amines (Scheme 17), predominantly by chemical oxidants (BaMnO4 [147], Pb(OAc)4 [148], HgO [149], K2FeO4 [150], TCICA [151], t-BuOI [152]) or oxidation systems (CuBr-pyridine-O2 [153], I2-t-BuOOH [154], t-BuOCl-NaI [155]). The synthesis of polyfunctional azopyrazoles by silver catalyzed cascade conversion of diazo compounds [156] is also of interest.
At the same time, a more promising electrochemical approach is poorly studied. In particular, electrosyntheses of azobenzene on the Pt anode [157,158] or N,N’-bis(morpholino)diazene on the NiO(OH) anode [159] are described. Note that NiO(OH) is one of the popular electrogenerated redox mediators [80,159]. The use of such redox-mediators is a trend in modern electroorganic chemistry [18], since it allows the processes to be carried out under milder conditions, increasing their efficiency and selectivity. This Section describes the original approaches to the synthesis of azopyrazoles using electrogenerated redox mediators NiO(OH) [160,161,162] and Br2 [163], or electrogenerated hypohalites as oxidants [164,165].

4.1. (Electro)oxidative N-N Coupling of Aminopyrazoles: Approaches and General Patterns

One-stage Approach A (Scheme 18) is carried out in alkaline medium via the anodic dissolution of the Ni and the formation of adsorbed Ni(OH)2, followed by its anodic oxidation to adsorbed NiO(OH). It oxidizes aminopyrazoles (Az–NH2) to azopyrazoles (Az–N = N–Az) and forms Ni(OH)2, after which the cycle repeats [80,161]. In Approach B, the metal-free oxidant is Br2 [164], which is effectively electro(re)generated on the ruthenium–titanium oxide anode (RTOA).
In addition, special voltammetric tests showed that an increase in the Ni(OH)2 peak (Figure 3, A, peak A1, Epox = 0.46 V) or a decrease in the Br2 peak (Figure 3B, peak B2, Epred = 0.69 V) after the adding of aminopyrazole is proportional to the process efficiency [162,164].
Two-stage approaches (Scheme 19) include preliminary electrogeneration of hypogalites followed by addition of aminopyrazoles [164,165]. Note, that hypohalites exist in equilibrium forms: predominantly HOCl (HOBr) in a neutral medium, and predominantly NaOCl (NaOBr) after adding NaOH (approaches C, D, C’, D’, respectively).
According to the data [80,152,154,155,159,163,164,165], the possible mechanisms (Scheme 20) involve the oxidation of 1-methyl-1H-pyrazol-3-amine 1k (step 1k→[Az–NH2]·+) or its N–H halogenation (step 1k→[NH–X]) followed by N–H amination to hydrazopyrazole [NH–NH] and its oxidation to the target azopyrazole 1k–1k (see also Scheme 3 and Scheme 9).
When Br2 and HOX are used, C–H halogenation of aminopyrazole 1k also occurs (step 1k→1k′(1k″), see Scheme 9), followed by the formation of halogenated azopyrazole (steps 1k′→[NH–X]’→[NH–NH]’→1k′–1k′(1k″–1k″)). These patterns are consistent with the experimental results below.

4.2. Synthesis of Azopyrazoles

Approach A is most versatile and allows us to obtain target azopyrazoles with yields of 52–88% (Table 6, entries 1–6, 8–11). On the contrary, approaches B, C and D are more suitable for 4-substituted pyrazoles (entries 2, 6 and 7) or pyrazole with acceptor (CF3) group (entry 12), where the yields of the corresponding azo products were 62–93%.
Nevertheless, approaches C’ and D’ (entries 1 and 4) allow to obtain rather selectively azopyrazoles 1k–1k and 2k–2k (yields 72–75%), and approaches C and D (entry 8) open the way to azohalogenopyrazoles 6k″–6k″ and 6k″–6k″ (yields 79–80%).
Moreover, the approach A is useful for previously unexplored chemical and electrochemical N–N cross-coupling of aminopyrazoles [162] (Table 7), and yields of the target azo compounds 1k–2k and 4k–5k were 48–50%. Such results create prospects for obtaining useful multifunctional azo compounds [152,156].

5. Conclusions

This review is the first step in summarizing the data on promising, but poorly studied electrooxidative functionalization of C‒H and N‒H bonds in pyrazole derivatives. It paves the way for the efficient synthesis of C‒Cl, C‒Br, C‒I, C‒S and N‒N coupling products using cheap, affordable and environmentally promising electric currents.
Additional advantages are the predominantly galvanostatic electrolysis mode and the reusability of commercially available electrodes, salts and solvents, as well as the gram-scalability of the processes. In half of the cases, a simple isolation of pure target products without chromatography is also possible. Moreover, the key regularities of the corresponding processes are considered, including the dependence of the efficiency of functionalization of pyrazoles on their structure and oxidation potential. An increasingly important role is played by cyclic voltammetry, which makes it possible both to study mechanisms and to predict the efficiency of synthesis.
All this makes the electrooxidative functionalization of pyrazole-type compounds very viable for further application and development.

Author Contributions

Conceptualization, V.A.P.; writing—original draft preparation, V.A.K. and V.A.P.; writing—review and editing, B.V.L., V.L.S., A.S.K. and S.V.N. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Russian Science Foundation. Grant 19-73-20259.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2b, 4b, 9b–13b, 1c–4c, 6c, 8c, 10c–13c, 1d–4d, 8d, 10d–14d, 1f–15f, 1j, 2j, 1k-1k–8k-8k are available from the authors.

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Molecules 26 04749 sch001 550
Scheme 1. Electrophilic (a) and nucleophilic (b) aromatic hydrogen substitution.
Scheme 1. Electrophilic (a) and nucleophilic (b) aromatic hydrogen substitution.
Molecules 26 04749 sch001
Molecules 26 04749 sch002 550
Scheme 2. Electrooxidative N-arylation of pyrazole by 1,4-dimethoxybenzene.
Scheme 2. Electrooxidative N-arylation of pyrazole by 1,4-dimethoxybenzene.
Molecules 26 04749 sch002
Molecules 26 04749 sch003 550
Scheme 3. Main routes of SNH An processes: I (EpoxAr < EpoxNu−) or II (EpoxNu− < EpoxAr).
Scheme 3. Main routes of SNH An processes: I (EpoxAr < EpoxNu−) or II (EpoxNu− < EpoxAr).
Molecules 26 04749 sch003
Molecules 26 04749 sch004 550
Scheme 4. General scheme of the electrooxidative C‒H functionalization (C–H An).
Scheme 4. General scheme of the electrooxidative C‒H functionalization (C–H An).
Molecules 26 04749 sch004
Molecules 26 04749 sch005 550
Scheme 5. Chemical halogenation of pyrazoles (X = Cl, Br, I).
Scheme 5. Chemical halogenation of pyrazoles (X = Cl, Br, I).
Molecules 26 04749 sch005
Molecules 26 04749 sch006 550
Scheme 6. C–H An halogenation of pyrazoles (X = Cl, Br, I).
Scheme 6. C–H An halogenation of pyrazoles (X = Cl, Br, I).
Molecules 26 04749 sch006
Molecules 26 04749 sch007 550
Scheme 7. C‒H An chlorination of pyrazole 1a.
Scheme 7. C‒H An chlorination of pyrazole 1a.
Molecules 26 04749 sch007
Molecules 26 04749 sch008 550
Scheme 8. C–H iodination of pyrazoles via HOI.
Scheme 8. C–H iodination of pyrazoles via HOI.
Molecules 26 04749 sch008
Molecules 26 04749 sch009 550
Scheme 9. C–H An halogenation of pyrazoles (possible mechanisms, X = Cl, Br, I).
Scheme 9. C–H An halogenation of pyrazoles (possible mechanisms, X = Cl, Br, I).
Molecules 26 04749 sch009
Molecules 26 04749 sch010 550
Scheme 10. Iodination of highly basic pyrazoles by HOI.
Scheme 10. Iodination of highly basic pyrazoles by HOI.
Molecules 26 04749 sch010
Molecules 26 04749 sch011 550
Scheme 11. Different behavior of N–Cl and N–Br intermediates (unpublished control experiments).
Scheme 11. Different behavior of N–Cl and N–Br intermediates (unpublished control experiments).
Molecules 26 04749 sch011
Molecules 26 04749 sch012 550
Scheme 12. C–H thiocyanation of arenes via the thiocyanogen.
Scheme 12. C–H thiocyanation of arenes via the thiocyanogen.
Molecules 26 04749 sch012
Molecules 26 04749 sch013 550
Scheme 13. C–H An thiocyanation of arenes (II) via the thiocyanogen (I′) and voltammetric test of the process efficiency.
Scheme 13. C–H An thiocyanation of arenes (II) via the thiocyanogen (I′) and voltammetric test of the process efficiency.
Molecules 26 04749 sch013
Molecules 26 04749 sch014 550
Scheme 14. Approaches and possible mechanisms of C–H An thiocyanation.
Scheme 14. Approaches and possible mechanisms of C–H An thiocyanation.
Molecules 26 04749 sch014
Molecules 26 04749 g001 550
Figure 1. CV curves on Pt working electrode in 0.1M NaClO4 in MeCN, ν = 0.10 V·s−1. (A) NH4SCN (0.002M)—1; 3-methyl-1H-pyrazol-5-amine 1e (0.002M)—2; 3-methyl-4-thiocyanato-1H-pyrazol-5-amine 1f (0.002M)—3; mixture NH4SCN/azole 1e (1:1) with the reverse scan from 0.60 V—4; the same on the reverse scan from 1.45V—5; (B) NH4SCN (0.002M)—1; 2-methyl-5-thiophen-2-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine 10e—2; 2-methyl-3-thiocyanato-5-thiophen-2-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine 10f—3; mixture NH4SCN/ azole 10e (1:1) on the reverse scan from 1.20 V—4; the same on the reverse scan from 2.10 V—5.
Figure 1. CV curves on Pt working electrode in 0.1M NaClO4 in MeCN, ν = 0.10 V·s−1. (A) NH4SCN (0.002M)—1; 3-methyl-1H-pyrazol-5-amine 1e (0.002M)—2; 3-methyl-4-thiocyanato-1H-pyrazol-5-amine 1f (0.002M)—3; mixture NH4SCN/azole 1e (1:1) with the reverse scan from 0.60 V—4; the same on the reverse scan from 1.45V—5; (B) NH4SCN (0.002M)—1; 2-methyl-5-thiophen-2-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine 10e—2; 2-methyl-3-thiocyanato-5-thiophen-2-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine 10f—3; mixture NH4SCN/ azole 10e (1:1) on the reverse scan from 1.20 V—4; the same on the reverse scan from 2.10 V—5.
Molecules 26 04749 g001
Molecules 26 04749 sch015 550
Scheme 15. Synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidine-3-thiols.
Scheme 15. Synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidine-3-thiols.
Molecules 26 04749 sch015
Molecules 26 04749 sch016 550
Scheme 16. N–H An arylation of 4-nitropyrazole followed by C–H An thiocyanation of resulting N-arylazoles.
Scheme 16. N–H An arylation of 4-nitropyrazole followed by C–H An thiocyanation of resulting N-arylazoles.
Molecules 26 04749 sch016
Molecules 26 04749 g002 550
Figure 2. Effect of thiocyanate and pyrazole fragments on antifungal and antibacterial activity.
Figure 2. Effect of thiocyanate and pyrazole fragments on antifungal and antibacterial activity.
Molecules 26 04749 g002
Molecules 26 04749 sch017 550
Scheme 17. Synthesis of azopyrazoles by (electro)oxidative N–N coupling of aminopyrazoles.
Scheme 17. Synthesis of azopyrazoles by (electro)oxidative N–N coupling of aminopyrazoles.
Molecules 26 04749 sch017
Molecules 26 04749 sch018 550
Scheme 18. One-stage redox-mediated N–N coupling of aminopyrazoles using electrogenerated NiO(OH) (Approach A) and Br2 (Approach B).
Scheme 18. One-stage redox-mediated N–N coupling of aminopyrazoles using electrogenerated NiO(OH) (Approach A) and Br2 (Approach B).
Molecules 26 04749 sch018
Molecules 26 04749 g003 550
Figure 3. CV curves, ν = 0.10 V·s−1. (A) On Ni working electrode in 0.2M aq. NaOH: electrogenerated Ni(OH)2—1; after addition of 1-methyl-1H-pyrazol-3-amine 1k (0.002M)—2; (B) on Pt working electrode in 1M aq. NaNO3: NaBr (0.3M)—1; after addition of 1-methyl-1H-pyrazol-3-amine 1k (0.002M)—2.
Figure 3. CV curves, ν = 0.10 V·s−1. (A) On Ni working electrode in 0.2M aq. NaOH: electrogenerated Ni(OH)2—1; after addition of 1-methyl-1H-pyrazol-3-amine 1k (0.002M)—2; (B) on Pt working electrode in 1M aq. NaNO3: NaBr (0.3M)—1; after addition of 1-methyl-1H-pyrazol-3-amine 1k (0.002M)—2.
Molecules 26 04749 g003
Molecules 26 04749 sch019 550
Scheme 19. Two-stage N–N coupling of aminopyrazoles using electrogenerated HOCl (HOBr) or NaOCl (NaOBr) (Approaches C, D, C’, D’, respectively).
Scheme 19. Two-stage N–N coupling of aminopyrazoles using electrogenerated HOCl (HOBr) or NaOCl (NaOBr) (Approaches C, D, C’, D’, respectively).
Molecules 26 04749 sch019
Molecules 26 04749 sch020 550
Scheme 20. N–N coupling of aminopyrazoles (possible mechanisms).
Scheme 20. N–N coupling of aminopyrazoles (possible mechanisms).
Molecules 26 04749 sch020
Table
Table 1. C‒H An chlorination of pyrazoles (Az‒H) 1.
Table 1. C‒H An chlorination of pyrazoles (Az‒H) 1.
EntryAz‒H, Az‒Cl and other Products (Yield, %) [70,71]EntryAz‒H, Az‒Cl (Yield, %) [68,70,71]
1 Molecules 26 04749 i001
1a		 Molecules 26 04749 i002
1b (46 2)		 Molecules 26 04749 i003
1b-1b′ (8 2)		8 Molecules 26 04749 i004
8a		 Molecules 26 04749 i005
8b (41 2)
2 Molecules 26 04749 i006
2a		 Molecules 26 04749 i007
2b (71 3)		9 Molecules 26 04749 i008
9a		 Molecules 26 04749 i009
9b (64 3)
3 Molecules 26 04749 i010
3a		 Molecules 26 04749 i011
3b (34 2)		10 Molecules 26 04749 i012
10a		 Molecules 26 04749 i013
10b (92 3)
4 Molecules 26 04749 i014
4a		 Molecules 26 04749 i015
4b (70 3)		11 Molecules 26 04749 i016
11a		 Molecules 26 04749 i017
11b (69 3)
5 Molecules 26 04749 i018
5a		 Molecules 26 04749 i019
5b (15 2)		 Molecules 26 04749 i020
5b’ (35 2)		12 Molecules 26 04749 i021
12a		 Molecules 26 04749 i022
12b (93 3)
6 Molecules 26 04749 i023
6a		 Molecules 26 04749 i024
6b (47 2)		 Molecules 26 04749 i025
6b’ (13 2)		 Molecules 26 04749 i026
6b’’ (4)2		13 Molecules 26 04749 i027
13a		 Molecules 26 04749 i028
13b (84 3)
7 Molecules 26 04749 i029
7a		 Molecules 26 04749 i030
7b (8 2)		14 Molecules 26 04749 i031
14a		 Molecules 26 04749 i032
14b (4 2)
1 Electrolysis in 100 mL of 4M solution of NaCl in H2O–CHCl3 (entries 1–7), H2O (entries 8–14), 15 °C, pyrazole (12.5–50 mmol), divided cell, Pt anode, Cu cathode, galvanostatic electrolysis (janode = 100 mA·cm−2), Qt = 2412–9650 C, Q/Qt = 1–2; 2 the yield was calculated from the 1H NMR spectroscopic data for the isolated mixture of products with unreacted pyrazoles; 3 the yield was determined for the isolated product.
Table
Table 2. C‒H An bromination of pyrazoles (Az‒H) 1.
Table 2. C‒H An bromination of pyrazoles (Az‒H) 1.
EntryAz‒H, Az‒Br and Other Products (Yield, %) [71,72]EntryAz‒H, Az‒Br (Yield, %) [71,72]
1 Molecules 26 04749 i033
1a		 Molecules 26 04749 i034
1c (70 2)		8 Molecules 26 04749 i035
8a		 Molecules 26 04749 i036
8c (89 2)
2 Molecules 26 04749 i037
2a		 Molecules 26 04749 i038
2c (76 3)		 Molecules 26 04749 i039
2c’ (5 3)		9 Molecules 26 04749 i040
9a		 Molecules 26 04749 i041
9c (15 3)
3 Molecules 26 04749 i042
3a		 Molecules 26 04749 i043
3c (66 3)		10 Molecules 26 04749 i044
10a		 Molecules 26 04749 i045
10c (68 3)
4 Molecules 26 04749 i046
4a		 Molecules 26 04749 i047
4c (94 2)		11 Molecules 26 04749 i048
11a		 Molecules 26 04749 i049
11c (78 2)
5 Molecules 26 04749 i050
5a		 Molecules 26 04749 i051
5c (55 3)		 Molecules 26 04749 i052
5c’ (26 3)		12 Molecules 26 04749 i053
12a		 Molecules 26 04749 i054
12c (84 2)
6 Molecules 26 04749 i055
6a		 Molecules 26 04749 i056
6c (88 2)		13 Molecules 26 04749 i057
13a		 Molecules 26 04749 i058
13c (84 2)
7 Molecules 26 04749 i059
7a		 Molecules 26 04749 i060
7c (0 5)		14 Molecules 26 04749 i061
14a		 Molecules 26 04749 i062
14c (0 3)
1 Electrolysis in 100 mL of 1M solution of NaBr in H2O–CHCl3 (entries 1–7), H2O (entries 8–14), 30 °C, pyrazole (12.5–50 mmol), divided cell, Pt anode, Cu cathode, galvanostatic electrolysis (janode = 30 mA·cm−2), Q = Qt = 2412–9650 C; 2 the yield was determined for the isolated product; 3 the yield was calculated from the 1H NMR spectroscopic data for the isolated mixture of products with (or) unreacted pyrazoles; 5 unpublished data.
Table
Table 3. C‒H (An) iodination of pyrazoles (Az‒H).
Table 3. C‒H (An) iodination of pyrazoles (Az‒H).
EntryAz‒H, Az‒I (Yield, %) [73,74]EntryAz‒H, Az‒I (Yield, %) [73,74]
1 Molecules 26 04749 i063
1a		 Molecules 26 04749 i064
1d (57 1,3, 93 2,3)		8 Molecules 26 04749 i065
8a		 Molecules 26 04749 i066
8d (2 1,4, 82 2,3)
2 Molecules 26 04749 i067
2a		 Molecules 26 04749 i068
2d (5 1,4, 79 2,3)		9 Molecules 26 04749 i069
9a		 Molecules 26 04749 i070
9d (0 1,4)
3 Molecules 26 04749 i071
3a		 Molecules 26 04749 i072
3d (71 1,3)		10 Molecules 26 04749 i073
10a		 Molecules 26 04749 i074
10d (30 1,4, 86 2,3)
4 Molecules 26 04749 i075
4a		 Molecules 26 04749 i076
4d (86 1,3, 93 2,3)		11 Molecules 26 04749 i077
11a		 Molecules 26 04749 i078
11d (0 1,4, 74 2,3)
5 Molecules 26 04749 i079
5a		 Molecules 26 04749 i080
5d (35 1,4)		12 Molecules 26 04749 i081
12a		 Molecules 26 04749 i082
12d (0 1,4, 78 2,3)
6 Molecules 26 04749 i083
6a		 Molecules 26 04749 i084
6d (42 1,5)		13 Molecules 26 04749 i085
14a		 Molecules 26 04749 i086
14d (0 1,5, 79 2,3)
7 Molecules 26 04749 i087
7a		 Molecules 26 04749 i088
7d (0 1,5)		14 Molecules 26 04749 i089
15a		 Molecules 26 04749 i090
15d (40 1,4)
1 Electrolysis in 100 mL of 0.3M solution of NaNO3 in H2O–CHCl3, 30 °C, KI (10 mmol), pyrazole (10 mmol), NaHCO3 (15 mmol), divided cell, Pt anode, Cu cathode, galvanostatic electrolysis (janode = 7.5 mA·cm−2), Q = Qt = 1930 C; 2 two-step process: 1. electrogeneration of KIO3 in 1M aq. KOH, 70 °C, KI (30 mmol), K2Cr2O7 (0.7 mmol), undivided cell, NiO(OH) anode, Ni cathode, galvanostatic electrolysis (janode = 200 mA·cm−2), Qt = 17370 C, Q/Qt = 0.9–1.1; 2. pyrazole (45–150 mmol), KIO3 (9–30 mmol), I2 (18–60 mmol), H2O–CHCl3 (or H2O–CCl4), H2SO4 conc., temperature 50–66 °C, 0.5–14 h; 3 the yield was determined for the isolated product; 4 the yields were calculated from the 1H NMR spectroscopic data for the isolated products with (or) unreacted pyrazoles; 5 unpublished data.
Table
Table 4. C–H An thiocyanation of pyrazole derivatives (Az‒H) via (SCN)2 (approach A) 1.
Table 4. C–H An thiocyanation of pyrazole derivatives (Az‒H) via (SCN)2 (approach A) 1.
EntryAz–H, Az–SCN (Yield, %) [22,122,123,126]EntryAz–H, Az–SCN (Yield, %) [22,122,123,126]
1 Molecules 26 04749 i091
1e		 Molecules 26 04749 i092
1f (83 2,5,6, 72 2,4,6, 74 2,5,7, 69 3,5,7)		6 Molecules 26 04749 i093
6e		 Molecules 26 04749 i094
6f (86 2,4,6)
2 Molecules 26 04749 i095
2e		 Molecules 26 04749 i096
2f (87 2,5,6, 78 2,5,7, 71 3,5,7)		7 Molecules 26 04749 i097
7e		 Molecules 26 04749 i098
7f (83 2,4,6, 80 2,4,7, 75 2,5,7, 77 3,4,7, 71 3,5,7)
3 Molecules 26 04749 i099
3e		 Molecules 26 04749 i100
3f (65 2,4,6, 57 3,4,6)		8 Molecules 26 04749 i101
8e		 Molecules 26 04749 i102
8f (85 2,4,6, 82 2,5,6)
4 Molecules 26 04749 i103
4e		 Molecules 26 04749 i104
4f (75 2,4,6, 68 3,4,6)		9 Molecules 26 04749 i105
9e		 Molecules 26 04749 i106
9f (75 2,4,6, 66 2,5,6)
5 Molecules 26 04749 i107
5e		 Molecules 26 04749 i108
5f (89 2,4,6, 64 2,5,6)
1 Electrolysis in 50–85 mL of 0.1M solution of NaClO4 in MeCN-H2O (entries 1–2), MeCN (entries 3–5, 7–9), MeCN–MeOH (entry 6), 20–25 °C, NH4SCN (3–20 mmol), pyrazole (entries 1–5, 7–9) or its hydrochloride (entry 6) (1–6 mmol), divided cell (entries 1–2), undivided cell (entries 3–9), Qt = 193–985 C, Q/Qt = 1 (entries 1–6), Q/Qt = 2 (entries 7–9). All yields were determined for the isolated and purified products; 2 CPE—controlled potential electrolysis (Eanode = 0.70–1.00 V); 3 GE—galvanostatic electrolysis (janode = 2.50–12.50 mA·cm−2); 4 Pt electrodes; 5 GC electrodes; 6 milligram scale of electrosynthesis; 7 gram scale of electrosynthesis.
Table
Table 5. C–H An thiocyanation of hardly oxidizable pyrazolo[1,5-a]pyrimidines (Az‒H) (approaches B and C) 1.
Table 5. C–H An thiocyanation of hardly oxidizable pyrazolo[1,5-a]pyrimidines (Az‒H) (approaches B and C) 1.
EntryAz–H (Epox, V2), Az–SCN (Yield, %) [122,123]EntryAz–H (Epox, V2), Az–SCN (Yield, %) [122,123]
1 Molecules 26 04749 i109
10e (1.75)		 Molecules 26 04749 i110
10f (81 3,5, 65 4,5, 60 4,6)		4 Molecules 26 04749 i111
13e (1.85)		 Molecules 26 04749 i112
13f (80 3,5, 62 4,5, 55 4,6)
2 Molecules 26 04749 i113
11e (1.77)		 Molecules 26 04749 i114
11f (793,5, 604,5)		5 Molecules 26 04749 i115
14e (1.85)		 Molecules 26 04749 i116
14f (73 3,5, 60 4,5)
3 Molecules 26 04749 i117
12e (1.79)		 Molecules 26 04749 i118
12f (77 3,5, 60 4,5, 52 4,6)		6 Molecules 26 04749 i119
15e (1.88)		 Molecules 26 04749 i120
15f (69 3,5, 63 4,5, 47 4,6)
1 Electrolysis in 60 mL 0.1 M solution of NaClO4 in MeCN, 20–25 °C, undivided cell, Qt = 193 C. All yields was determined for the isolated and purified products; 2 it was determined by CV (working electrode—Pt, reference electrode—SCE, ν = 0.10 V·s−1); 3 Approach B: KSCN (4 mmol), ZnCl2 (2 mmol), pyrazole (1 mmol), CPE (Eanode = 1.00 V), Qt =193 C, Q/Qt = 3; 4 Approach C: NH4SCN (4 mmol), pyrazole (1 mmol), CPE (Eanode = 1.75–1.88 V), Q/Qt = 3; 5 Pt electrodes; 6 GC electrodes.
Table
Table 6. N–N homo-coupling of aminopyrazoles (Az–NH2) using approaches A, B, C (C’), D (D’) 1.
Table 6. N–N homo-coupling of aminopyrazoles (Az–NH2) using approaches A, B, C (C’), D (D’) 1.
EntryAz–NH2, Az–N=N–Az and Other Products (Yield, %) [161,163,165]EntryAz–NH2, Az–N=N–Az and Other Products (Yield, %) [161,163,165]
1 Molecules 26 04749 i121
1k		 Molecules 26 04749 i122
1k-1k (82 2, 34 4, 72 5, 40 6, 75 7)		7 Molecules 26 04749 i123

5k		 Molecules 26 04749 i124
5k-5k (86 3)
Molecules 26 04749 i125
1k′ (593, 224, 15) 		Molecules 26 04749 i126
1k′-1k′ (283, 48 4)		8 Molecules 26 04749 i127
6k		 Molecules 26 04749 i128
6k-6k (792, 2 6)
Molecules 26 04749 i129
1k″ (76, 57) 		Molecules 26 04749 i130
1k″-1k″ (40 6, 14 7)		 Molecules 26 04749 i131
6k′ (3 3)		 Molecules 26 04749 i132
6k′-6k′ (80 3)
2 Molecules 26 04749 i133
1k′		 Molecules 26 04749 i134
1k′-1k′ (77 2, 62 4)		 Molecules 26 04749 i135
6k″ (6)		 Molecules 26 04749 i136
6k″-6k″ (79 6)
3 Molecules 26 04749 i137
1k″		 Molecules 26 04749 i138
1k″-1k″ (87 2)		9 Molecules 26 04749 i139
7k		 Molecules 26 04749 i140
7k-7k (55 2)
4 Molecules 26 04749 i141
2k		 Molecules 26 04749 i142
2k-2k (712, 735)		10 Molecules 26 04749 i143
8k		 Molecules 26 04749 i144
8k-8k (52 2)
Molecules 26 04749 i145
2k′ (25)		 Molecules 26 04749 i146
2k′-2k′ (6 5)		11 Molecules 26 04749 i147
9k		 Molecules 26 04749 i148
9k-9k8 (67 2)
5 Molecules 26 04749 i149
3k		 Molecules 26 04749 i150
3k-3k (86 2)		12 Molecules 26 04749 i151
10k		 Molecules 26 04749 i152
10k-10k (93 4, 86 6)
6 Molecules 26 04749 i153
4k		 Molecules 26 04749 i154
4k-4k (88 2, 62 3, 70 4)
1 Electrolysis in 100 mL of supporting electrolyte, 20–25 °C, undivided cell galvanostatic electrolysis; 2 Approach A: 0.5M aq. NaOH, NiO(OH) anode, pyrazole (3 mmol), janode = 6 mA·cm−2, Qt = 579 C, Q/Qt = 1–4; 3 Approach B: 2M aq. NaBr, RTOA, pyrazole (3 mmol), janode = 100 mA·cm−2, 48% HBr additives during electrolysis until reaching pH~7 (entries 1, 8), Qt = 579 C, Q/Qt = 1–4; 4 Approach C: 1. electrogeneration of NaOBr (HOBr) in 2M aq. NaBr, RTOA, janode = 100 mA·cm−2, Q = 661–1983 C; 2. pyrazole (2 mmol), NaOBr (HOBr) (2–4 mmol), 5 h; 5 Approach C’: see Approach C, but with NaOH (6 mmol) additives; 6 Approach D: 1. electrogeneration of HOCl (NaOCl) in 4M aq. NaCl, RTOA, janode = 161.5 mA·cm−2, Q= 588–1764 C; 2. Pyrazole (2 mmol), HOBr (NaOBr) (2–4 mmol), 5 h; 7 Approach D’: see Approach D, but with NaOH (6 mmol) additives; 8 it was identified after preparation and isolation of the corresponding methyl ester.
Table
Table 7. N–N cross-coupling of aminopyrazoles (Az–NH2) using approach A 1.
Table 7. N–N cross-coupling of aminopyrazoles (Az–NH2) using approach A 1.
EntryAz1–NH2H2N–Az2Az1–N=N–Az2Yield, %
1 Molecules 26 04749 i1551k Molecules 26 04749 i1562k Molecules 26 04749 i1571k-2k50 (1k-2k)
36 (1k-1k)
37(2k-2k)
2 Molecules 26 04749 i1584k Molecules 26 04749 i1595k Molecules 26 04749 i1604k-5k48 (4k-5k)
29 (1k-1k)
23 (2k-2k)
1 Electrolysis in 100 mL of 0.5 M aq. NaOH, 20–25 °C, undivided cell,; 2 Approach A: NiO(OH) anode, Ti cathode, pyrazole (1.5 mmol), galvanostatic electrolysis (janode = 6 mA·cm−2), Q = 2Qt = 579 C.
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Lyalin, B.V.; Sigacheva, V.L.; Kudinova, A.S.; Neverov, S.V.; Kokorekin, V.A.; Petrosyan, V.A. Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds. Molecules 2021, 26, 4749. https://doi.org/10.3390/molecules26164749

AMA Style

Lyalin BV, Sigacheva VL, Kudinova AS, Neverov SV, Kokorekin VA, Petrosyan VA. Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds. Molecules. 2021; 26(16):4749. https://doi.org/10.3390/molecules26164749

Chicago/Turabian Style

Lyalin, Boris V., Vera L. Sigacheva, Anastasia S. Kudinova, Sergey V. Neverov, Vladimir A. Kokorekin, and Vladimir A. Petrosyan. 2021. "Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds" Molecules 26, no. 16: 4749. https://doi.org/10.3390/molecules26164749

APA Style

Lyalin, B. V., Sigacheva, V. L., Kudinova, A. S., Neverov, S. V., Kokorekin, V. A., & Petrosyan, V. A. (2021). Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds. Molecules, 26(16), 4749. https://doi.org/10.3390/molecules26164749

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