A New Family of Vinyl Selenocyanates with the Amide Function Based on the Reaction of Potassium Selenocyanate with 3-Trimethylsilyl-2-Propynamides

: An efﬁcient approach to a novel family of (Z)-3-amino-3-oxo-1-propenyl selenocyanates was developed based on the reaction of KSeCN with 3-trimethylsilyl-2-propynamides in the presence of ammonium chloride in methanol. The reaction was accompanied by a desilylation process. The products were not formed under the same reaction conditions in the absence of ammonium chloride, which was used for the ﬁrst time in the reactions of selenocyanates with acetylenes. The use of this new methodology allowed the reaction to carry out in a regio-and stereoselective fashion as anti-addition affording vinyl selenocyanates with a (Z)-conﬁguration in high yields.

The intensively studied selenium drug ebselen has a number of valuable biological properties such as anti-inflammatory, neuroprotective and glutathione peroxidase-like activities [20][21][22]. Ebselen is being clinically evaluated as a therapeutic agent in several other areas, including the treatment of COVID-19, hearing loss, and bipolar disorder [20][21][22]. Ebselen and a number of organoselenium compounds with biological activity contain the amide group [20][21][22]. The presence of the amide function can be considered favorable for the manifestation of possible biological activity.
A very convenient and promising approach to the introduction of the selenium atom is based on alkali metal selenocyanates [23][24][25][26]. This approach to organoselenium compounds has been widely developed due to the ease of the reaction of metallic selenium with alkali metal cyanides and the high synthetic potential of organic selenocyanates [23][24][25][26].
Treatment of organic selenocyanates with bases and reducing agents such as LiEt 3 BH, DIBAL [27], NaBH 4 [28,29], KOH, K 3 PO 4 [30,31], and K 2 CO 3 [32] leads to the formation of dialkyl(diaryl)diselenides, which are in turn very important reagents for organoselenium chemistry [33]. The reduction of organic selenocyanates to selenolates with sodium borohydride followed by the reaction of the generated selenolates with vinyl halides [31] or with terminal acetylenes in the presence of t-BuOK [34] makes it possible to obtain a wide range of functionalized organyl vinyl selenides. Disubstituted selenides with different substituents at selenium were also obtained from arylselenocyanates by the direct substitution of the cyano group for a hydrocarbon fragment in the reaction with alcohols in the presence of tributylphosphine [35,36], as well as by the reaction of benzylselenocyanates with lithium selenides with different substituents at selenium were also obtained from arylselenocyanates by the direct substitution of the cyano group for a hydrocarbon fragment in the reaction with alcohols in the presence of tributylphosphine [35,36], as well as by the reaction of benzylselenocyanates with lithium acetylenides [37]. Aryl selenocyanates, upon boiling in water in the presence of monovalent copper iodide and 1,2-cyclohexyldiamine, yield symmetric diaryl selenides [38].
Direct selenocyanation into the aromatic ring of arenes and heteroarenes is known to be initiated by CAN (cerium (IV) ammonium nitrate, (NH 4 ) 2 Ce(NO 3 ) 6 ) [59], CuCl-K 2 S 2 O 8 -TBAI [60], tert-butyl hydroperoxide (TBHP)-NIS [61], affording the corresponding aromatic and heteroaromatic selenocyanates (Scheme 1a) [26]. However, methods for the preparation of organylselenocyanates based on the addition of inorganic selenocyanates to multiple bonds of olefins and acetylenes can rarely be found in the literature. The development of such a direction would expand the synthetic potential of the selenocyanate reagents and open up new ways to obtain novel organoselenium compounds, including poorly studied vinyl selenocyanates [43,[62][63][64][65].
One of the few known examples is the addition of potassium selenocyanate at the double bond of substituted styrenes (Scheme 1c) initiated by transition metal salts (CAN or CuCl 2 , CuBr 2 ) giving saturated bis(selenocyanates) or oxo selenocyanates in the presence of oxygen [59], as well as the addition of selenocyanate to olefins (Scheme 1d) to obtain saturated alkoxy selenocyanates in alcohols or halogen selenocyanates in acetonitrile [63].
The method of the catalytic addition of potassium selenocyanate to organyl propiolates giving the mixture of corresponding (Z)-and (E)-vinyl selenocyanates was recently developed (Scheme 1e) [64]. The reaction was catalyzed by a deep eutectic solvent (DES) choline chloride/glycolic acid under the action of ultrasound at 25-35 • C. (Scheme 1d).
We developed an efficient approach to a novel family of (Z)-3-amino-3-oxo-1-propenyl selenocyanates based on the reaction of potassium selenocyanate with 3-trimethylsilyl-2-propynamides in the presence of ammonium chloride in methanol (Scheme 1f). This approach is superior to the known methods regarding efficiency and selectivity, high yields, mild reaction conditions (room temperature), the use of cheap and available reagent such as ammonium chloride, and green solvent such as methanol.
An alternative approach is to use terminal propynamides; however, as terminal propynamides are known to be difficult to obtain, methods for their preparation are limited. 3-Trimethylsilylpropynamides can be easily obtained from 3-trimethylsilylpropiolic acid by the methods developed in this institute [66].

Results and Discussion
The aim of our research is to develop an efficient and selective approach to novel vinyl selenocyanates, containing the amide function at the double bond, based on 3-trimethylsilyl-2-propynamides and potassium selenocyanate. It should be emphasized that to date, not a single representative of 3-amino-3-oxo-1-propenylselenocyanates has been described in the literature.
The reaction of N-phenyl-3-trimethylsilyl-2-propynamide 1a with potassium selenocyanate was studied in order to find favorable conditions for the synthesis of vinyl selenocyanates.
The reaction of propynamide 1a with excess potassium selenocyanate (3.5 eq) at room temperature in methanol for 23 h was accompanied by gumming. The isolated mixture contained the product 3 (87 mol%) of the methanol addition to the triple bond of propynamide [67] and diadduct 4 (13 mol%) [68], resulted from the addition of methanol to the double bond of the product 3 (Table 1, entry 1). The expected selenocyanate 2a was not detected ( 1 H-NMR data). Refluxing propynamide 1a with 1.0 equivalent of potassium selenocyanate in methanol for 3 h also resulted in strong gumming and only methanol addition with the formation of a mixture of mono-adduct 3 (35 mol%) and diadduct 4 (65 mol%) was observed (Table 1, entry 2).  Previously, we obtained amide-containing divinyl diselenide 6 and their analogues by the reaction of N-substituted 3-trimethylsilyl-2-propynamides with sodium diselenide in aqueous THF [69]. In this case, the formation of diselenide 6 in the reaction mixture is obviously due to the cleavage of the Se-CN bond of organyl selenocyanate 2a under the action of an excess potassium selenocyanate. It should be emphasized that the addition of methanol to the triple bond in the presence of ammonium chloride was not  We found that the reaction of propynamide with potassium selenocyanate proceeded efficiently in the presence of ammonium chloride. Thus, the reaction of propynamide 1a with excess potassium selenocyanate (3.5 eq) in the presence of ammonium chloride (1 eq) at room temperature for 23 h gave Z-3-anilino-3-oxo-1-propenyl selenocyanate 2a in 65% yield. Along with selenocyanate 2a and unreacted terminal amide 5 (31 mol%), the mixture contained diselenide 6 (6 mol%, Table 1, entry 3). Under these conditions, the reaction was completed for 68 h, giving the target product 2a in 36% yield along with diselenide 6 (62 mol%) ( Table 1, entry 4).
Previously, we obtained amide-containing divinyl diselenide 6 and their analogues by the reaction of N-substituted 3-trimethylsilyl-2-propynamides with sodium diselenide in aqueous THF [69]. In this case, the formation of diselenide 6 in the reaction mixture is obviously due to the cleavage of the Se-CN bond of organyl selenocyanate 2a under the action of an excess potassium selenocyanate. It should be emphasized that the addition of methanol to the triple bond in the presence of ammonium chloride was not observed.
When amide 1a was refluxed with potassium selenocyanate (1:1) and ammonium chloride in methanol for 5 h, the precipitation of elemental selenium was observed and the yield of organyl selenocyanate 2a was only 51% ( Table 2, entry 1). With a 1.5-fold excess of potassium selenocyanate in the presence of ammonium chloride, selenocyanate 2a in 60% yield was formed in 5 h along with propynamide 5 (23 mol%) and diselenide 6 (10 mol%) ( Table 2, entry 2). With an increase in the heating duration to 10 h, the content of selenocyanate 2a increased from 67% (5 h) to only 72% (10 h) and the yield of compound 2a increased to 62% (Table 2, entries 2,3). Only an increase in the content of potassium selenocyanate to 4.5 equivalents made it possible to complete the reaction for 3 h and to obtain selenocyanate 2a in 73% yields ( Table 2, entry 4).  At room temperature, in the presence of excess ammonium chloride, the reaction of N-phenyl-3-trimethylsilyl-2-propynamide 1a with selenocyanate proceeded more slowly (19-29 h) (Table 3) compared to heating (3-5 h) ( Table 2). However, when multiple excesses of ammonium chloride were used without heating, side diselenide 6 was not formed ( 1 H-NMR) and resinification of the reaction mixture and precipitation of selenium were not observed. According to 1 H-NMR and elemental analysis, the resulting target organylselenocyanate 2a was of high purity and did not require additional purification (Table 3).
In search of the optimal conditions of the method, we studied the effect of the amount of ammonium chloride taken into the reaction, as well as the volume of the sol- At room temperature, in the presence of excess ammonium chloride, the reaction of N-phenyl-3-trimethylsilyl-2-propynamide 1a with selenocyanate proceeded more slowly (19-29 h) (Table 3) compared to heating (3-5 h) ( Table 2). However, when multiple excesses of ammonium chloride were used without heating, side diselenide 6 was not formed ( 1 H-NMR) and resinification of the reaction mixture and precipitation of selenium were not observed. According to 1 H-NMR and elemental analysis, the resulting target organylselenocyanate 2a was of high purity and did not require additional purification (Table 3).  A decrease in the volume of the solvent also leads to an increase in the efficie the reaction. The best result was achieved using 0.4 mL of methanol (amide conc tion 1.18 mmol/L); the reaction was completed within 19 h in the presence of 5-10 alents of ammonium chloride-affording Z-3-anilino-2-oxo-1-propenyl selenocyan in 90% yield (Table 3, example 6,7). When the amount of ammonium chloride w duced to 3 equivalents, the conversion dropped to 89% at a 19 h reaction time (T entry 8). Thus, the optimal reaction conditions found include the follo 3-trimethylsilyl-2-propynamide 1a (0.47 mmol), selenocyanate (3.5 equiv), amm chloride (5 equiv), methanol (0.4 mL), and stirring for 19 h at room temperature. T of 0.4 mL of methanol (Table 3, entry 6,7) instead of 0.6 mL ( Table 3, entry 1-5) dec the reaction time and reduces the required amount of ammonium chloride to 5 equ Using these optimal conditions for the preparation of 2a, we synthesized a n of novel N-substituted (Z)-3-amino-3-oxo-1-propenyl selenocyanates 2b-l in 6 yields based on 3-trimethylsilyl-2-propynamides 1a-l including primary amide 1 matic secondary amides 1c-m, and tertiary amides 1n,l (Scheme 2).

Entry
Time ( In search of the optimal conditions of the method, we studied the effect of the amount of ammonium chloride taken into the reaction, as well as the volume of the solvent, on the efficiency of the reaction. With an increase in the amount of ammonium chloride in the series, 5, 10, and 20 equivalents in a solvent volume of 0.6 mL, which corresponds to an initial amide concentration of 0.78 mmol/L for 23 h, the conversion of the target product 2a increases in the sequence 77, 83, 90%, respectively, and the yield of 2a by 1 H NMR also increases by 69, 78, 82% (Table 3, entries 1,2,3) Further increase in the amount of NH 4 Cl up to 30 equiv leads to a slight increase in the conversion of selenocyanate 1a from 90% (at 20 equiv.) to 92% (30 equiv.), while the NMR yield of 2a did not change-having a value of 82% (Table 3, entries 3,4). The increase in the duration of the process up to 29 h at a concentration of the original 1a 0.78 mol/L in the presence of NH 4 Cl (20 equiv) resulted in complete conversion and high isolated yield (90%) of organyl selenocyanate 2a (Table 3,

entry 5).
A decrease in the volume of the solvent also leads to an increase in the efficiency of the reaction. The best result was achieved using 0.4 mL of methanol (amide concentration 1.18 mmol/L); the reaction was completed within 19 h in the presence of 5-10 equivalents of ammonium chloride-affording Z-3-anilino-2-oxo-1-propenyl selenocyanate 2a in 90% yield (Table 3, example 6,7). When the amount of ammonium chloride was reduced to 3 equivalents, the conversion dropped to 89% at a 19 h reaction time ( Table 3, entry 8). Thus, the optimal reaction conditions found include the following: 3-trimethylsilyl-2propynamide 1a (0.47 mmol), selenocyanate (3.5 equiv), ammonium chloride (5 equiv), methanol (0.4 mL), and stirring for 19 h at room temperature. The use of 0.4 mL of methanol (Table 3, entry 6,7) instead of 0.6 mL ( Table 3, entry 1-5) decreases the reaction time and reduces the required amount of ammonium chloride to 5 equiv.
Using these optimal conditions for the preparation of 2a, we synthesized a number of novel N-substituted (Z)-3-amino-3-oxo-1-propenyl selenocyanates 2b-l in 64-95% yields based on 3-trimethylsilyl-2-propynamides 1a-l including primary amide 1b, aromatic secondary amides 1c-m, and tertiary amides 1n,l (Scheme 2). In the course of the study, the influence of the nature of the N-substituent of the amide group of the starting acetylenic amides 1a-l on their reactivity in the nucleophilic addition of selenocyanate at the triple bond was found. Obviously, the different reactivity in the series of acetylenic amides 1a-l depends on the magnitude of the electron-withdrawing effect of the amide group, which polarizes the triple bond to a different degree, depending on the donor-acceptor properties of the N-substituent [70].
Thus, if the addition of selenocyanate to N-phenylacetylenic amide 1a took 19 h, then in the case of amides with more electron-withdrawing amide groups 3-and 4-monohalophenylamides 1d-g, the reaction was completed in 16-17 h, and 2-chloroanilide 1c and 3,4-dichlorophenylamide 1h reacted for 13 h. The addition of selenocyanate to propynamides containing strongly electron-withdrawing N-substituents 2,4,6-trihalophenylamides 1i,j and diphenylamide 1l was completed in 10 h. Electron-donating substituents (two methyl groups) in the benzene ring of the amide 1k decrease the reactivity of the triple bond.
Thus, the reactivity of the starting propynamides 1a-l with substituents NR1R2 increases approximately in the following order: 3,4-(Me)2C6H3NH (1k) < NH2 (1b) < PhNH In the course of the study, the influence of the nature of the N-substituent of the amide group of the starting acetylenic amides 1a-l on their reactivity in the nucleophilic addition of selenocyanate at the triple bond was found. Obviously, the different reactivity in the series of acetylenic amides 1a-l depends on the magnitude of the electron-withdrawing effect of the amide group, which polarizes the triple bond to a different degree, depending on the donor-acceptor properties of the N-substituent [70].
Thus, if the addition of selenocyanate to N-phenylacetylenic amide 1a took 19 h, then in the case of amides with more electron-withdrawing amide groups 3-and 4-monohalophenylamides 1d-g, the reaction was completed in 16-17 h, and 2-chloroanilide 1c and 3,4-dichlorophenylamide 1h reacted for 13 h. The addition of selenocyanate to propynamides containing strongly electron-withdrawing N-substituents 2,4,6-trihalophenylamides 1i,j and diphenylamide 1l was completed in 10 h. Electron-donating substituents (two methyl groups) in the benzene ring of the amide 1k decrease the reactivity of the triple bond.
The method of the catalytic addition of KSeCN to the triple bond of activated terminal acetylenes, propiolates, propynthioates, methylpropynones, and 1-(ethynylsulfonyl)-4methylbenzene proceeding with the formation of the mixture of corresponding Z-and E-vinyl selenocyanates was reported [64]. The reaction was catalyzed by a deep eutectic solvent: choline chloride/glycolic acid under the action of ultrasound. The supposed mechanism includes the activation of the triple bond by intermolecular H-bonding of the carbonyl group [64]. Taking into account that ammonium chloride can be the source of protons, a similar mechanism of activation of the triple bond by the bonding of the carbonyl group can be assumed in this case (Scheme 3).
Most of the obtained compounds do not contain impurities of by-products (elemental analysis and NMR data) and do not require additional purification after removing the solvent.
Starting 3-trimethylsilyl-2-propynamides 1a−l were prepared from 3-trimethylsilylpropiolic acid and amines by the methods which were previously developed in this institute [66,70]. Trimethylsilyl-2-propynamides 1c and 1i−k are new compounds and were prepared for the first time (Scheme 4). It is worth noting that the reaction proceeded in a regio-and stereoselective fashion as anti-addition-affording vinyl selenocyanates only with a (Z)-configuration in high yields.
Most of the obtained compounds do not contain impurities of by-products (elemental analysis and NMR data) and do not require additional purification after removing the solvent.
Starting 3-trimethylsilyl-2-propynamides 1a−l were prepared from 3-trimethylsilylpropiolic acid and amines by the methods which were previously developed in this institute [66,70]. Trimethylsilyl-2-propynamides 1c and 1i−k are new compounds and were prepared for the first time (Scheme 4).
The structural assignment of the obtained compounds was carried out based on the multinuclear NMR investigations and confirmed by FTIR data and elemental analysis. The structural assignment of the obtained compounds was carried out based on the multinuclear NMR investigations and confirmed by FTIR data and elemental analysis.

Conclusions
We have developed an efficient approach to novel N-substituted (Z)-3-amino-3-oxo-1propenyl selenocyanates based on the reaction of 3-trimethylsilyl-2-propynamides with the potassium selenocyanate catalyzed by ammonium chloride in methanol. The reaction did not realize under the same conditions in the absence of ammonium chloride, which was used for the first time in the reactions of selenocyanates with acetylenes. The reaction proceeded in a regio-and stereoselective fashion as anti-addition-affording vinyl selenocyanates with a (Z)-configuration in high yields.
The known methods for the preparation of vinyl selenocyanates are technically difficult and expensive. Some reactions were carried out under the action of ultrasound in a deep eutectic solvent (DES) containing glycolic acid as one of the components [64] or in lactic acid [65] and gave a mixture of (Z)-and (E)-isomers. In our case, mild reaction conditions (room temperature), cheap and available reagent such as ammonium chloride, and green solvent such as methanol were used. We developed a stereoselective method (unlike the known methods), which gives vinyl selenocyanates with only (Z)-configuration.
It should be emphasized that, to date, not a single representative of 3-amino-3-oxo-1-propenylselenocyanates has been described in the literature. It is worth noting that the amide function is usually favorable for the manifestation of biological activity.
The products obtained are a new family of vinyl selenocyanates, which can be used as intermediates for organic synthesis and compounds with possible biological activity.
Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/catal13091257/s1: 1 H and 13 C NMR spectra of the obtained compounds.