Mélissa Gao

Martin Vuagnat

Mu-Yi Chen

Xavier Pannecoucke

Philippe Jubault

Tatiana Besset
email: tatiana.besset@insa-rouen.fr

Design and Use of Electrophilic Thiocyanating and Selenocyanating Reagents: a New Trend for the Construction of SCN-and SeCN-containing Compounds

Keywords: thiocyanation reaction, electrophilic reagents, methodologies, synthetic transformations, selenocyanation reaction

Organothiocyanate and organoselenocyanate compounds are of paramount importance in organic chemistry as they are key intermediates to access sulfur-and selenium-containing compounds. Therefore, among the different synthetic pathways to get SCN-and SeCN-containing molecules, original methodologies using electrophilic reagents has recently been explored. This Minireview will showcase the recent advances, which have been made. In particular, the design of several electrophilic sources and their applications for the thiocyanation and the selenocyanation of various classes of compounds will be highlighted and discussed.

Introduction

Organothiocyanate compounds and their selenated analogs are of high importance in organic chemistry and are found in agrochemicals, pharmaceuticals and materials. [1], [2] These key molecules are a linchpin in organic synthesis to access a large variety of molecules of interest (Figure 1). [1a],[1c],[2c], [3] Traditionally, they were synthesized by cyanation of sulfur-and selenium-containing molecules. [3], [4] A complementary and widespread approach relied on the direct introduction of the SCN [5] or the SeCN [6] moiety with a nucleophilic or a radical reagent. [3] In addition, the in situ generation [3h], [7] of an electrophilic reagent from a nucleophilic one was widely used. In sharp contrast, only a handful of electrophilic reagents was available until recently. Indeed, from the pioneer works, a regain of interest was showed to imagine and synthesize several original electrophilic SCN and SeCN sources as highlighted by the original reagents, which were successfully synthesized and applied in various transformations over the last years (Figure 2).

In this review, we intend to discuss and showcase the recent advances made for the direct introduction of a thiocyanate or a selenocyanate moiety using electrophilic sources. Note that the in situ generation of electrophilic sources will be out of the scope of the Minireview. [3h] Figure 2. Electrophilic SCN and SeCN reagents.

Historical Context

Since the emergence of the thiocyanogen chloride as an electrophilic thiocyanating reagent in 1958, several major contributions were reported in the last half of the century. In this section, the synthesis of this SCN source and a selection of its applications will be described. [8] In 1958, Bacon and Angus reported the use of the thiocyanogen chloride I as an electrophilic thiocyanogen reagent (Scheme 1). [9] It was prepared from thiocyanogen 1 and gaseous chlorine and kept in solution as stable in a few solvents such as toluene, CHCl3 and CCl4. Note that since it decomposed rapidly overtime, it was generally used in a short time after being made. When it was reacted on ethylene, the product 3a resulting from the concomitant formation of a C-Cl and C-SCN bond was obtained in a 80% yield. The reaction was also carried out, at low temperature, on several olefins such as aliphatic ones, styrene and cyclohexene and in the last case, the compound 3b was obtained in a high yield. The thiocyanation of N,N-dimethylaniline 4a and phenol 4b gave the thiocyanated products 5a and 5b in 75% and 84% yields, respectively. Scheme 1. Synthesis of thiocyanogen chloride I and its application on the functionalization of alkene derivatives 2 as well as on N,N-dimethylaniline 4a and phenol 4b.

In 1973 and then in 1976, Guy and Pearson reported the thiocyanation of various alkenes 6 using the thiocyanogen chloride I in acetic acid (Scheme 2). [10] Depending on the alkenes, a mixture of chlorinated and acetoxylated products was obtained in different ratios. For instance, when the cyclohexene was engaged in these reaction conditions, the trans-1chloro-2-thiocyanatocyclohexane was obtained as the major compound (7aa) in 77% yield along with the trans-1-acetoxy-2-thiocyanatocyclohexane (7ab, 15% yield). In case of the styrene, both the acetoxylated and the chlorinated products (7ba and 7bb) were obtained. Scheme 2. Thiocyanation of various alkenes using the thiocyanogen chloride I in acetic acid.

In 1991, Baldakhonova and co-workers used the thiocyanogen chloride, in situ generated from lead rhodanide and chlorine, for the direct thiocyanation of vinyl (thio)ethers 8. [11] Note that when aryl chlorovinyl ethers (10a and 10b) were engaged, a two-step process was necessary to afford the expected thiocyanated vinyl ethers (11a and 11b) in up to 69% yield over the two steps (Scheme 3). Note that another application of the thiocyanogen chloride was depicted by the group of Hey-Hawkins for the thiocyanation of a nido-dicarbaborate anion (7,8-nido-C2B9H12 -). [12] Scheme 3. Thiocyanation of vinyl (thio)ethers using the thiocyanogen chloride I.

Using the thiocyanogen chloride as the SCN source, chemists developed interesting transformations, although restricted to the functionalization of alkenes, alkynes or few aromatic derivatives. Indeed, the use of the thiocyanogen chloride as a SCN source often required synthetic constraints due to it short-timed stability and the need to freshly prepare it. Therefore, to address these persisting challenges, new tools were needed to push the field further and among them, the design of electrophilic thiocyanation sources emerged as a powerful strategy.

Design of New Electrophilic Reagents: Synthesis and Applications

Even if this field has remained almost steady for more than 40 years, the design of original electrophilic SCN sources led recently to major milestones in the way to prepare organocyanate compounds. In this section, we will discuss how the chemists have managed to develop new electrophilic thiocyanating reagents and have applied them in various transformations.

Electrophilic RSO2SCN Reagents

In 1964, Rosenthal and Goerdeler developed the synthesis of several arylsulfonyl thiocyanate reagents II starting from the corresponding sodium arylsulfonyl derivatives with thiocyanogen (SCN)2 (Scheme 4). [13] Using the 4-chlorophenylsulfonylthiocyanate reagent IIc, the difunctionalization of alkenes was possible (4 examples) and the concomitant formation of C-SCN and C-SO2C6H4Cl bonds occurred with a total control of the regioselectivity leading, for instance, to the corresponding thiocyanated alkanes (13a-13c) in good yields. This methodology was then applied to the functionalization of alkynes and the expected alkenes 15a and 15b were synthesized in 75% and 77% yields, respectively. More recently, another application of these reagents was reported. Indeed, in 2015, Somov and co-workers depicted the electrophilic thiocyanation of the 1-bromotricycloheptane using the methanesulfonyl thiocyanate and the benzenesulfonyl thiocyanate reagent. [14] Scheme 4. Synthesis of the arylsulfonyl thiocyanate reagents II and the thiocyanation of alkene and alkyne derivatives using the 4chlorophenylsulfonyl-thiocyanate IIc.

Synthesis of an Electrophilic Thioperoxocyanate Reagent

In 2014, the group of Buchwald reported the synthesis of the electrophilic source III derived from an hypervalent iodide derivative. [15] Indeed, the chlorobenziodoxole was reacted with AgNCS at room temperature offering an efficient access to the electrophilic thiocyanate source III as ascertained by X-ray analysis (Scheme 5).

Scheme 5. Synthesis of the electrophilic source III.

Electrophilic N-Thiocyanating Reagents

Among all the available reagents for the thiocyanation reaction, a lot of efforts was devoted to the synthesis of electrophilic N-thiocyanating reagents.

3.3.a The N-Thiocyanatosuccinimide and N-Thiocyanato-phthalimide Reagents

In 1995, the group of Still reported the thiocyanation of (hetero)arenes using the N-thiocyanatosuccinimide reagent IV from the commercially available NBS and NaSCN (Scheme 6). [16] The N,N-dimethylaniline was selectively functionalized at the para position and the product 17a was obtained in a 99% yield. In addition, the thiocyanation of the electron-rich arene 16b along with the thiophene derivatives 16c and 16d was also depicted. In 2008, the N-thiocyanatosuccinimide IV was applied for the -thiocyanation of (chiral) N-acyl imides, which were further used for the synthesis of 5-substituted and 5,5-disubstituted 2,4-thiazolidinediones (Scheme 7). [17] Indeed, using nBu2BOTf as a Lewis acid and in the presence of the reagent IV, the -thiocyanation of N-acyl carboximides was depicted, leading to the corresponding products 19a-19d. The reaction was tolerant to various functional groups such as a terminal alkyne (18b), an olefin (18c) and a heterocycle (18d), and the expected products (19b-19d) were obtained in good yields. This methodology was extended to the asymmetric -thiocyanation of 4-(R)-phenylmethyl-2-oxazolidinone derivatives leading to the compounds 19e and 19f in good yields and with an excellent diastereoselectivity (up to 99:1 d.r.).

In 2018, during their study about the synthesis of alkynylthiocyanates, Zhao and co-workers reported the synthesis of thiocyanoketones 21 (Scheme 8). [18] Indeed, under silver and gold catalysis, the hydrothiocyanation of terminal alkynes 20 with N-thiocyanosuccinimide IV was developed in a one pot two steps process (silver-catalyzed hydration of the alkyne followed by the subsequent gold-catalyzed thiocyanation of the resulted ketone derivative). Electron-rich aromatic alkynes were mainly functionalized in this process and substituents at the para, meta and ortho positions were well tolerated (20b-20g). Terminal alkynes bearing a disubstituted arene were converted into the -thiocyanoketones (21h-21j) in moderate to good yields. The transformation was also suitable for heteroaromatic alkyne 20k and alkenyl-substituted compound 20l and the expected products (21k and 21l) were obtained in 72% and 70% yields, respectively. Scheme 8. Hydrothiocyanation of terminal alkynes 20 with the reagent IV under silver-and gold-catalysis.

In the same vein, the N-thiocyanatophthalimide V was also studied as an electrophilic source of the SCN residue (Scheme 9). Its synthesis was described by Chen and co-workers. [19] Starting from the N-chlorophthalimide and copper thiocyanate, the expected product was isolated in a 87% yield. Note that the reagent V was also prepared using the N-bromophthalimide and silver thiocyanate. [18] Scheme 9. Synthesis of the N-thiocyanatophthalimide V by means of two synthetic routes.

Interested by the functionalization of terminal alkynes with SCN sources, Zhao and co-workers developed a silvercatalyzed thiocyanation of terminal alkynes 22 with the N-thiocyanophthalimide V to access the corresponding alkynylthiocyanates 23 (Scheme 10). [18] This transformation was applied to a wide range of terminal alkynes (27 examples). Aromatic alkynes substituted with electron-donating groups, electron-withdrawing ones and halogens were thiocyanated in moderate to good yields (23b-23m). Moreover, the reaction was tolerant to various functional groups such as ester (22f) and aldehyde (22j). Disubstituted aromatic alkynes (22n-22o), 9-ethynylphenanthrene 22p and a thiophene derivative 22q were smoothly functionalized. In addition, alkenyl-and alkyl-substituted alkynes (22r-22u) were also suitable in this transformation.

Scheme 10. Thiocyanation of terminal alkynes with the reagent V. [a] Reaction on 1 mmole scale.

The N-thiocyanatophthalimide reagent V was further applied in the enantioselective -thiocyanation of cyclic -ketoesters 24 by a bifunctional cinchona alkaloid catalysis (Scheme 11). [19] From this approach, a panel of SCN-containing molecules were obtained in good to excellent yields (up to 99%) with high enantioselectivity (up to 94% ee). -Ketoesters (24a-i) derived from indanone with substituents (mainly halogens) at various positions on the aromatic ring were thiocyanated. Other esters were also smoothly functionalized (24g-i). When a -ketoester derived from tetralone or possessing a sevenmembered ring was used as a substrate, the expected products (25j and 25k) were obtained in good to excellent yields with 65% and 36% ee, respectively. Scheme 11. Enantioselective -thiocyanation of cyclic -ketoesters with the reagent V; ee values were determined by chiral HPLC analysis. [a] CH2Cl2 instead of CH3CHCl2. [b] After a single recrystallization.

One year later, the same group reported an extension of their methodology to the -thiocyanation of 3-substituted oxindoles 26 (Scheme 12). [20] Indeed, using a similar catalytic system and the 2-naphtol as a co-catalyst, the expected thiocyanated products 27 were afforded in excellent yields (er up to 94:6). Note that the stereoselectivity outcome of the reaction was substrate-dependent. Schema 12. Asymmetric -thiocyanation of 3-substituted oxindoles using the N-thiocyanatophthalimide V.

In 2019, the group of Knochel developed a methodology for the electrophilic thiolation of organozinc chlorides by coppercatalysis. During this study, they successfully extended their approach to the thiocyanation of three arylzinc chlorides (28a-28c) with the reagent V, offering an access to the corresponding products 29a-29c in high yields (Scheme 13). [21] Scheme 13. Copper-catalyzed thiocyanation of arylzinc chlorides with the reagent V.

This year, a palladium-catalyzed directed mono-thiocyanation of (hetero)arenes by C-H bond activation was reported by the group of Besset (Scheme 14). [22] With this ligand-and additive-free approach, a panel of SCN-containing products was selectively synthesized using the reagent V in up to 78% yield. The 2-phenylpyridine 30a and the naphthalene analogue 30b were smoothly functionalized. The thiocyanation reaction was suitable with 2-aryl-pyridines with various substituents at the para position such as a halogen 30c or a fluorinated group 30d, at the meta position 30e and even with the disubstituted derivative 30f. When the 2-(2-thienyl)pyridine 30g was reacted under these reaction conditions, the SCNcontaining product 31g was obtained in a 41% yield. Moreover, by changing the nature of the directing group (pyrimidine vs pyridine), the corresponding product 31h was obtained in a 44% yield. Scheme 14. Palladium-catalyzed ortho thiocyanation of (hetero)arenes by C-H bond activation using the reagent V as the SCN source.

3.3.b The N-Thiocyanatosaccharin Source

Recently, a new electrophilic thiocyanating reagent has emerged, namely the N-thiocyanatosaccharin VI. The first synthesis and application of this original source was reported by Yin, Chen and co-workers in 2018. [23] The Nthiocyanatosaccharin VI was prepared in a 71% yield over two steps: chlorination of the saccharin with tert-butyl hypochlorite followed by a treatment with AgSCN. Note that the reagent VI is sensitive to light and air and therefore, should be stored at low temperature under an inert atmosphere (Scheme 15). The potential of this reagent as an electrophilic SCN source was investigated with the direct thiocyanation of a panel of nucleophiles (Scheme 16). [23] Firstly, on the 5-bromoindole 32a, the thiocyanation gave selectively the expected 3thiocyanated product 33a in a 95% yield. When the 3-methyl indole was used as a substrate, the 2-thiocyanation occurred with a remarkably high yield (33b). The transformation was also performed on the benzothiophene 32c and the oxindole 34a leading to the corresponding thiocyanated compounds with high yields (33c and 35a, respectively). Aniline, phenol and anisole derivatives were also investigated. On aniline, the thiocyanated product was obtained with a particularly good yield (37a). When the para position was functionalized by a bromine atom, only the N-functionalization was observed with a good yield (37b). In contrast, 3,5-dimethoxyaniline led to a mixture of para and ortho thiocyanated products (37c, 37c'). A mixture of N-functionalization and ortho-functionalization was observed with the 4-chloroaniline (36d, 36d'). On phenol and anisole derivatives (36e and 36f), only the para-functionalization was observed with high yields (37e and 37f). On acyclic aromatic ketones (38a and 38b), the transformation gave the corresponding thiocyanated products with moderate to good yields (39a and 39b). However, the reaction was more efficient in case of the indanones 38c and 38d. Finally, the thiocyanation reaction was also conducted on -ketoesters derived from indanone and tetralone leading to the corresponding products 41a-41d in good yields. Note that in case of the acyclic β-ketoester 40e, the reaction was possible under slightly modified reaction conditions. One year later, Zhao and co-workers developed a selenide-catalyzed thiocyanoaminocyclization of the alkene derivatives 42 using the electrophilic N-thiocyanatosaccharin VI as the SCN source (Scheme 17). [24] In the presence of a catalytic amount of diphenyl selenide and a Lewis acid (BF3•Et2O), an access to SCN-containing azaheterocycles was achieved with a good regioselectivity and an excellent diastereoselectivity (> 19:1). When the reaction was carried out with alkenes bearing an aromatic moiety as the R 1 substituent (42a-42d), the corresponding products selectively resulted from a 6endo-cylization (43a-43d). Otherwise, when the R 1 substituent was a hydrogen or an alkyl group, the olefins underwent a 5-exo-cyclization and the transformation led to the final product in good to excellent yields (44a-44i). The length of the alkyl chain did not impact the outcome of the reaction (44b-44e). However, when an alkene with a bulkier R 1 substituent was used (tert-butyl group, 43f), the yield dropped to 51%. Note that the reaction also worked well with a derivative having a cyclohexyl group (42g). Finally, when the protecting group was changed from nosyl to mesyl (42h) or tosyl (42i), the transformation proceeded smoothly, albeit in slightly lower yields. The authors proposed the following mechanism (Scheme 17): activation of the N-thiocyanatosaccharin VI with BF3•Et2O, followed by a reaction with the diphenyl selenide would afford the intermediate A. Then, the species B would be obtained and after reaction with 42, would lead to the corresponding iranium ion species C. Depending on the nature of the R 1 substituent, the cyclization would then proceed either via a 6-exo-or a 5-endo-cyclization providing hence the expected products 43 or 44 and would regenerate the catalyst. In 2020, Tripathi and co-workers reported the thiocyanation of unsaturated thioamides with the N-thiocyanatosaccharin VI via a Lewis base and a Brønsted acid co-catalyzed reaction (Scheme 18). [25] Using triphenylphosphine selenide and diphenyl phosphate as co-catalysts, an efficient access to thiocyanated thiazoline derivatives 46 was developed (up to 97% yield). The thiocyanation of the ,-unsaturated thioamides 45 was effective with both electron-rich and electron-poor arenes (46a-46f). The transformation was also tolerant to cyano (45d) and ketone (45e) groups along with thiophene (45g), albeit in the last two cases the corresponding products were obtained in only 54% yield and 63% yield, respectively. The transformation also proceeded smoothly when the phenyl group on the olefin was replaced by a chlorinated arene (45h and 45i) or a methyl group (45j). This methodology was also applied to the functionalization of 1,2-disubstituted olefins 47 providing the expected compounds 48 in good yields regardless of the substituents on the aromatic ring via a 5-exo-trig cyclization process. It is worth mentioning that by switching the reagent VI to the N-thiocyanatophthalimide V, the thiocyanation of ,-unsaturated amides was also efficiently achieved.

3.3.c The N-(Cyanosulfanyl)aniline Reagents

In 2016, Besset and co-workers developed the thiocyanation of aniline derivatives with silver thiocyanate. Several functionalized N-(cyanosulfanyl)anilines (VIIa-VIId) were prepared in up to 85% yield (Scheme 19). [26] Note that when using NaSCN instead of AgSCN, the thiocyanation of the 4-fluoroaniline led to the corresponding thiocyanated aniline VIIc in a similar yield. [26], [27] The reagent VIIc was then used in a Friedel-Crafts type reaction with the indole 49 and the 1,3,5trimethoxybenzene 51, leading to the corresponding products 50 and 52, respectively, in high yields (Scheme 19).

3.3.d The N-Thiocyanatosulfoximine Source

In 2018, the group of Bolm studied the synthesis of the N-thiocyanato sulfoximine derivatives as new electrophilic thiocyanating reagents (Scheme 20). [28] Indeed, prepared from N-bromo sulfoximines and ammonium thiocyanate, the Nthiocyanato sulfoximine derivatives VIII were obtained in good to high yields (up to 90% yield). In the presence of these electrophilic reagents and using the fac-[Ir(ppy)3] complex as a photocatalyst, the concomitant difunctionalization of styrene derivatives was achieved under blue light irradiation. With the N-thiocyanato sulfoximine, a panel of styrene derivatives was efficiently functionalized leading to the corresponding para-and meta-substituted products (54b-54d) in good yields, although ortho-substituted ones (54e and 54f) were obtained in lower yields. Pleasingly, various N-thiocyanato sulfoximine derivatives with different substitution patterns and electronic properties on the aromatic ring were reacted with styrene leading to the corresponding compounds (54g-54k). Note that even the S,S-diphenyl sulfoximine 54l and the S-ethyl Sphenyl sulfoximine 54m were suitable on this reaction. The authors suggested the following mechanism to explain the transformation: after excitation of the photocatalyst fac-[Ir III (ppy)3] under fluorescent light irradiation into the complex fac-[*Ir III (ppy)3], a single electron transfer to the N-thiocyanato sulfoximine VIII would lead to the generation of a fac-[Ir IV (ppy)3] species along with a SCN anion and a sulfoximidoyl radical A. This latter would react with the styrene 53 to afford the intermediate B, which would undergo a SET to give the intermediate C and after a final reaction with the thiocyanate anion, the desired product 54 would be obtained. Scheme 20. Photocatalyzed difunctionalization of styrene derivatives with the N-thiocyanato sulfoximine reagents VIII.

3.3.e The N-Thiocyanato-dibenzenesulfonimide Reagent

In 2019, Chen and co-workers described the first synthesis of the N-thiocyanato-dibenzenesulfonimide reagent IX and studied its application in various thiocyanation reactions (Scheme 21). [29] The N-thiocyanato-dibenzenesulfonimide IX was prepared in two steps. Starting from the dibenzenesulfonimide in the presence of tert-BuOCl, the corresponding chlorinated product was isolated in a 81% yield. Then, this latter was engaged with AgSCN to furnish the reagent IX in a 75% yield. Note that this reagent was slightly sensitive to light. The electrophilic reagent IX was used for the difunctionalization of olefins (Scheme 22). [29] Indeed, the group of Chen reported the synthesis of SCN-containing lactones 56 starting from alkenes bearing a carboxylic acid group 55 in presence of a catalytic amount of TMSCl. Other olefinic derivatives were also studied such as olefinic 1,3-diketones 57, silyl enol ethers 59 or alkene alcohols 61 leading to the corresponding thiocyanated dihydrofurans 58, ketones 60 and tetrahydrofurans 62, respectively. Finally, 1,1-disubstituted alkenes 63 were functionalized, the solvent (R 3 OH) playing the role of the nucleophile. The same year, the group of Chen independently investigated the thiocyanation of several classes of compounds using the reagent IX (Scheme 23). [30] First, the thiocyanation of indole derivatives was selectively achieved at the C3 position leading to the corresponding thiocyanated products (66a-66h) in good to excellent yields (up to 98% yield). The transformation was tolerant to halogens (65c, 65f and 65g) and to the cyano group (65d). A N-protected indole, a benzothiophene, a benzofuran and an 7-azaindole were also suitable substrates (65e-65h). Then, the methodology was extended to the selective para-thiocyanation of aniline derivatives (66i-65l) in good yields. In contrast, when parahalogenated anilines (65m-65o) were used, only the N-thiocyanation occurred. Interestingly, the thiocyanation was also possible on heteroaromatic derivatives such as the 8-aminoquinoline (65p). A series of phenol derivatives (65q-65t) was also functionalized along with the 2-methyl-anisole (65u) and the naphtol (65v). In the presence of TfOH, the thiocyanation of arenes was possible as shown with compounds 66w-66z. In presence of Zn(OTf)2 as a Lewis acid, the thiocyanation of 1-indanone derivatives (67a-67d), the tetralone 67e and the propiophenone 67f was achieved. Finally, the difunctionalization of styrene derivatives was also studied and the corresponding amino thiocyanato products (70a-70b) were obtained in good yields. The methodology was also applied to cyclic alkenes such as the cyclopentene 69c and the cyclohexene 69d. However, in the case of the 1,1-diphenylethylene 69e, only the thiocyanated product was obtained.

The N-thiocyanato-dibenzenesulfonimide IX was also used for the synthesis of -thiocyano carbonyl derivatives by means of a Lewis acid mediated thiocyano semipinacol rearrangement of allylic alcohols (Scheme 24). [31] A panel of 1,1disubstituted alkene alcohols 71 was functionalized and the corresponding rearranged 2thiocyanatomethylcyclopentanone derivatives 72 were obtained in good to excellent yields. Note that various aromatic derivatives (71a-71h) with different substitution patterns and electronic properties as well as the aliphatic compound 71i was suitable in this transformation. The approach was extended to other tertiary alcohols such as the molecule derived from the cyclopentanol 73a and the acyclic tertiary alcohol 73b. Even secondary alcohols were tolerated leading to the corresponding -quaternary center -thiocyanato aldehydes 74c and 74d. In addition, the methodology was also successfully applied to the functionalization of trisubstituted alkenes (75a-75e) and the SCN-containing compounds (6 examples), bearing indanone, 1,2-dihydronaphthalene and chromene scaffolds for instance, were obtained in up to 86% yield with a good diastereoselectivity. Scheme 23. First application of IX for the thiocyanation of (hetero)arenes, -ketones and alkene derivatives. [a] TfOH (1.0 equiv.), 60 °C, 12 h. [b] CH2Cl2, rt, 10 min. Scheme 24. Synthesis of -thiocyano carbonyl derivatives by means of a Lewis acid mediated thiocyano semipinacol rearrangement of allylic alcohols using the reagent IX. [a] Reaction was performed at 0 °C. [b] AcCl was used. [c] TMSCl was used.

Electrophilic Hypervalent Iodine Reagent for the Thiocyanation Reaction

In 2019, in the course of their investigation regarding the design of an electrophilic selenocyanating reagent, the group of Xiao, Su, Yang synthesized the first thiocyanobenziodoxolone X in two steps from the commercially available 2iodobenzoic acid with a 60% overall yield (Scheme 25). [32] Under grinding conditions, the -thiocyanation of the N-acetyl--arylenamine 77 was achieved leading to the corresponding tetralone 78 in 64% yield.

Design of New Electrophilic Selenocyanating Reagents: Synthesis and Applications

As numerous organoselenium compounds demonstrated biological activities such as the SeCN-aspirin analogue (Se-NSAID, Figure 1), a lot of attention was paid to the development of straightforward methodologies to synthesize them. Very recently, the use of electrophilic reagents has emerged although restricted so far to a handful of examples. In this section, the synthesis of the SeCN-containing sources and their applications will be depicted.

The Selenocyanobenziodoxolone Reagent

So far very few electrophilic sources have been designed and among them, the selenocyanobenziodoxolone reagent XI was studied. [33] In 2019, the group of Xiao, Su and Yang reported the synthesis of the selenocyanobenziodoxolone XI and its application as an electrophilic source (Scheme 26). [32] The reagent XI was prepared in two steps. Starting from the 2iodobenzoic acid and in the presence of the tert-butyl hypochlorite, the 1-chloro-1,2-benziodoxol-3(1H)-one was synthesized. Then, this latter reacted with AgSeCN to afford the selenocyanobenziodoxolone XI in a 86% yield. This reagent was then applied to the functionalization of various nucleophiles under solvent-free conditions (grinding conditions). Various -keto esters including indanone derivatives (79a and 79b) and the acyclic β-ketoester 79c were functionalized in good yields. The reaction was also efficient with the cyclohexanone derived -ketoester 79d, offering an access to the corresponding product 80d in a 81% yield. The selenocyanation was also performed on aromatic enamines (81a-81c) with different substituents, providing the corresponding selenocyanated aromatic ketones (82a-82c) in good yields. When cyclic enamines (81d-81e) were reacted under these reaction conditions, the corresponding ketones were obtained in high yields. The methodology was then further applied to the functionalization of steroid derivatives, leading to the SeCN-containing product 82f in a 87% yield. Scheme 26. The selenocyanobenzodioxolone reagent XI: synthesis and applications. [a] A final hydrolysis step was necessary to release the products 82.

The N-Selenocyanatosaccharin Reagent

Very recently, Chen's group developed a methodology for the asymmetric selenocyanation of -ketoesters by means of a Lewis acid catalysis (Scheme 27). [34] To reach that goal, a new electrophilic reagent XII derived from saccharin was synthesized in two steps in an overall 68% yield. In the presence of the selenocyanatosaccharin XII, a nickel-catalyzed selenocyanation of various -ketoesters was achieved in high yields (up to 99% yield) and a good control of the enantioselectivity (up to 92% ee). The reaction showed a good functional group tolerance regardless to the nature of the substituent on the aromatic part of the tetralone derivatives (83a-83e). Note that the nature of the ester did have an impact as the derivative 84e was obtained in a 80% yield although with only 45% ee. However, when the indanone derivative 83f was used as a substrate, the selenocyanated product 84f was obtained in a high yield (87%) as a racemic mixture.

Scheme 27. Synthesis of the selenocyanatosaccharin XII and its use to functionalize various -ketoesters. [a] Reaction on 1 mmole scale. [b] The product was obtained as a racemic mixture.

The N-Selenocyanatophthalimide Source

Very recently, Xiao, Ren, Huang and co-workers reported the synthesis of the electrophilic selenocyanate source XIII [35] from N-chlorophthalimide and silver selenocyanate in a 87% yield (Scheme 28). [36] The selenocyanatophthalimide reagent XIII was then applied to the selenocyanation of enaminone derivatives 85 or 87, which after cyclization led to the corresponding 3-selenocyanato-substituted chromones 86 and quinolinones 88. Scheme 28. Synthesis of the N-selenocyanatophthalimide XIII and its applications to the functionalization of enaminone derivatives.

Conclusion

In summary, the selective introduction of SCN and SeCN groups onto molecules is of matter of importance in the organic chemistry field. Therefore, a growing attention was paid by the scientific community to the quest of efficient synthetic solutions. In this Minireview were discussed the major advances made over the last years to build up thiocyanated or selenocyanated molecules thanks to the design and use of a panel of electrophilic reagents with various backbones. These emergent reagents were able to react with various classes of nucleophiles, expanding further the chemical space of molecular complexity. By unlocking the door towards unprecedented thiocyanation or selenocyanation reactions, the newly-designed tools will definitely have a strong impact on the way to synthesize SCN-and SeCN-containing molecules and will offer new perspectives in the field of organic synthesis. Nevertheless, the use of these reagents in more challenging transformations is still a goal to be reached and major advances are expected in the coming-years.

Figure 1 .

 1 Figure 1. Selected examples of thiocyanated and selenocyanated compounds of interest.

Scheme 6 .

 6 Scheme 6. Synthesis of the N-thiocyanatosuccinimide reagent IV and its applications. [a] MeOH, 0 °C, 2 h. [b] 2 h.

Scheme 15 .

 15 Scheme 15. Synthesis of N-thiocyanatosaccharin VI.

Scheme 16 .

 16 Scheme 16. Application of the electrophilic N-thiocyanatosaccharin reagent VI for the direct thiocyanation of various nucleophiles. [a] TfOH (1.0 equiv.) in MeCN. [b] 12 h. [c] VI (1.0 equiv.). [d] Zn(BF4)2•H2O (0.2 equiv.) instead of Me3SiCl (1.0 equiv.). [e] DMAP (4.0 equiv.), toluene, 30 °C, 20 h.

Scheme 17 .

 17 Scheme 17. Scope and mechanism of the regio-and diasteroselective thiocyanoaminocyclization of alkenes with the reagent VI. [a] Toluene was used as the solvent instead of DCE. All diastereoselectivities are > 19:1. DCE = 1,2-dichloroethane, Ns = Nosyl, Ms = Mesyl, Ts = Tosyl.

Scheme 18 .

 18 Scheme 18. Lewis base/brønsted acid catalyzed thiocyanation of thioamide derivatives with the reagent VI. [a] 4 h of reaction instead of 2 h.

Scheme 19 .

 19 Scheme 19. Synthesis of the N-(cyanosulfanyl)aniline VII derivatives and the electrophilic thiocyanation of the indole 49 and the 1,3,5trimethoxybenzene 51 using the reagent VIIc. [a] 18 h. [b] NaSCN instead of AgSCN.

Scheme 21 .

 21 Scheme 21. Synthesis of the N-thiocyanato-dibenzenesulfonimide IX.

Scheme 22 .

 22 Scheme 22. Applications of N-thiocyanato-dibenzenesulfonimide IX. No TMSCl was used in case of silyl enol ethers 59.

Scheme 25 .

 25 Scheme 25. Thiocyanation of the N-acetyl--arylenamine 77 with the reagent X.

Acknowledgements

This work was partially supported by Normandie Université (NU), the Région Normandie, the Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (URN), INSA Rouen Normandie, Labex SynOrg (ANR-11-LABX-0029) and Innovation Chimie Carnot (I2C). M.G., M.V. and T.B. thank the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 758710). M.-Y.C. thanks the French National Research Agency for a doctoral fellowship (ANR-17-CE07-0037-01). M.V. thanks the ERC for a doctoral fellowship (grant agreement no. 758710). M.G. thanks the Region Normandy for a doctoral fellowship.