Isoselenocyanates: A Powerful Tool for the Synthesis of

Selenium-containing heterocyclic compounds have been well recognized, not only because of their remarkable reactivities and chemical properties, but also because of their diverse pharmaceutical applications. In this context, isoselenocyanates have been emerged as a powerful tool for the synthesis of selenium-containing heterocycles, since they are easy to prepare and store and are safe to handle. In this review the recent advances in the development of synthesis methods for selenium-containing heterocycles from isoselenocyanates are presented and discussed.


Introduction
Selenium was discovered in 1817 by J.J. Berzelius [1] and the first organoselenium compound, i.e., ethylselenol, was reported by F. Wöhler and C. Siemens in 1847 [2].Most progress in the area of the synthetic organic chemistry of Se was accomplished more than 100 years later, in contrast to the chemistry of O-and S-containing organic molecules, which is much better developed.Although the chemistry of Se-containing compounds is often similar to that of the corresponding S analogues, some significant differences are also known, and because of the toxicity and instability of many Se compounds, the synthesis of Se heterocycles is much less developed.Despite the high toxicity of many selenium compounds, organic derivatives of selenium have been synthesized as anticancer [3][4][5], and for other medicinal applications [6], as well as biologically active substances exhibiting antiviral [7], antibacterial [8], antihypertensive [9], and fungicidal properties [10].As a result, seleniumcontaining heterocycles are of increasing interest because of their chemical properties and biological activities.Also, new approaches for the synthesis of selenium heterocycles by using more stable, less toxic, and easily accessible Se reagents are of great interest.In this context, isoselenocyanates have emerged as a powerful tool for the synthesis of selenium-containing heterocycles, since they are easy to prepare and store, less-toxic and safe to handle.In this review article, the recent progress in the development of synthesis methods of selenium-containing heterocycles from isoselenocyanates is presented and discussed in the form of their reactions with various nucleophiles.

Synthesis of isoselenocyanates and acylisoselenocyanates
The literature to date contains few descriptions of the preparation of isoselenocyanates 1 (Scheme 1) [11][12][13][14][15][16][17][18][19].The classical method of synthesis of organic isoselenocyanates involves the addition of elemental selenium to isonitriles 3 [11] or synthesis from the corresponding formamides 4 [12][13][14] Several other methods have also been investigated.An apparently more convenient procedure consists of treatment of a primary amine 5 with equimolar amounts of CSe 2 and HgCl 2 in the presence of triethylamine to give the corresponding isoselenocyanate 1 in reasonable yields [15].The disadvantages of this method are that the presence of isoselenocyanate and the amine-mercuric chloride adduct leads to the formation of the corresponding selenourea and carbodiimide (R-N=C=N-R) as major side products, which make the purification of the desired material difficult [15].Other methods of only limited applicability include, the alkylation of selenocyanate ion [16], the reaction of N-aryl-carbimidic dichlorides with sodium selenide [17], the treatment of isocyanates with phosphorous(V) selenide [17b], photochemical rearrangement of selenocyanates 6 [18] and via cycloaddition by the reaction of nitrile oxides 7 with primary selenoamides [19].Acylisoselenocyanates 2 were prepared by a reaction of acyl chloride with potassium selenocyanate (Scheme 2), a method first investigated by Douglas [20].The acylisoselenocyanates were never isolated.It was assumed that a polymeric form was present in equilibrium with the monomer that underwent the observed reaction.The generation of the acylisoselenocyanates was confirmed by a subsequent reaction with nucleophiles (Scheme 3) [21].Douglas reported a reaction of the acylisoselenocyanates with amine in 1937 [20].
Se HN Ph A one-pot synthesis of 2-imino-5-methylene-1,3-selenazolidines in high yields has been achieved by the reaction of alkylisoselenocyanates with propargylamines [25,26].In these reactions primary amines gave higher yields, as compared to secondary amines (Scheme 6).

Scheme 6
In the 1 H-NMR spectra of 14 in CDCl 3 , selenium coupling with the H 5b proton 3 J( 77 Se-1 H) = 23.9Hz was observed, but the same coupling has not observed with the H 5a proton.The H 5b proton is more downfield as compared to the H 5a proton (Figure 1).

Figure 1
The NOE experiment of compound 14 showed a NOE of H 5a proton with H 5b (26%) and NOE of the H 5b proton with H 4 protons (4.5%) (Figure 2).From the above result it was confirmed that selenium shows coupling with the trans proton [26].This observation is an important aid for determining structures and conformations of organoselenium compounds for which such NMR information is not available.The selenazoles 15 were synthesized by the reaction of allenyl isoselenocyanate with a nitrogencontaining nucleophile (Scheme 7) [27].Due to their pronounced tendency to polymerize, the isoselenocyanates can only be handled in solution.The synthesis of selenazoles 15 shows that allenyl isoselenocyanate reacts distinctly more slowly with nucleophiles than the unusually reactive allenyl isothiocyanate [28].The reaction of chirally pure isoselenocyanate with 28% ammonia aqueous solution in dioxane gave (4R,5R)-5-ethyl-2-imino-4-methylselenazolidine (16, Scheme 8) [29].The order of inhibitory activity against iNOS of the series of 16 was (4R,5R) > (4S,5S) > (4R,5S) > (4S,5R).Inversion of the R-configuration at the 4-position of 16 to the S-configuration reduced the inhibitory activity against iNOS and nNOS and the selectivity for iNOS.Among the oxazolidines [30], thiazolidines [31] and selenazolidines synthesized so far, compound 16 showed the best selectivity for iNOS (IC 50 nNOS/IC 50 iNOS = 85).

Scheme 8
The reaction of N-arylbenzimidoyl isoselenocyanates with primary and secondary amines in acetone at room temperature, followed by treatment with a base, led to 6H-(5,1,3)benzoselenadiazocine derivatives of type 17 (Scheme 9) [32].

Scheme 12
The reaction of aryl isoselenocyanates with methyl 3-amino-4-chloro-1-ethylpyrrolo[3,2c]quinoline-2-carboxylate in boiling pyridine leads to tetracyclic selenoheterocycles of type 24 in high yields via an intermediate selenoureido derivative and cyclization via nucleophilic substitution of Cl by Se (Scheme 13) [36].(26) were synthesized by the reaction in pyridine of 5(4)-aminoimidazole-4(5)carbonitrile with various isoselenocyanates (Scheme 14).The outcome of cyclization reactions involving 5(4)-iminoimidazole-4(5)-carbonitrile and isoselenocyanates depends to a remarkable extent on the R portion of the isoselenocyanates.The predominant formation of purine-type products presumably comes from preferential nucleophilic attack on the imino group by the nitrogen atom of the selenoureido intermediate [37].Scheme 16 Addition of the NH 2 group of anthranilonitriles to phenyl isoselenocyanate leads to the selenourea derivative A, which undergoes a ring closure to give B (or its tautomer).An isomerization via ring opening to C and a new ring closure leads to D, which tautomerizes to give 27 [36], a reaction similar to the Dimroth rearrangement [39].An analogous isomerization has been reported by Taylor and Ravindranathan [40], who obtained the imino derivative of type B as a stable compound.
The mechanism of the reaction is as shown in Scheme 18.The formation of 29 is initiated on the nucleophilic addition of the phenylate amine of phenylhydrazine to the isoselenocyanate carbon, affording the 2-phenyl-1,2-dihydro-3H-1,2,4-triazole-3-selones 29, whereas the formation of 30a is initiated by the nucleophilic addition of terminal amine of the phenylhydrazine to the isoselenocyanate carbon, affording 1-phenylselenosemicarbazides 30a.The cyclization of 30a in the presence of triethylamine took place and the product was then trapped by alkyl halides at reflux to afford 3alkylseleno-1-phenyl-5-p-tolyl-1H-1,2,4-triazoles 30.
The mechanism of the reaction is shown in Scheme 20.The addition of hydrazine to the isoselenocyanate leads to the adduct 31a, which immediately reacts with the third component to give 31b.Finally, an intramolecular condensation with elimination of H 2 O, i.e., the formation of a hydrazone, leads to the selenium-containing heterocycles 31.
A plausible reaction mechanism for this transformation is shown in Scheme 23.First, alk-2-yn-1-ol 33 undergoes selenoimidoylation by the reaction with selenium and isocyanide to yield oxyimidoylselenoate 36, which underwent intramolecular cycloaddition affording new selenium-containing heterocycles 34.The stereoselectivity of the C=C double bonds of the products can be explained by a trans addition mechanism (36 => 37 => 34), where proton coordination to the carboncarbon triple bond facilitates nucleophilic addition of selenium to this triple bond from the opposite side.2-Selenoxo-1,3-oxolidine 35 is formed by the nucleophilic addition of nitrogen to the carboncarbon triple bond of 36.The product selectivity observed is due to the higher nucleophilicity of the selenium atom.In fact, the product ratio was almost the same when the reaction time was shortened to 1 h.Isolated 34 and 35 were not interconverted under similar reaction conditions.
Phenyl isoselenocyanates undergo nucleophilic addition of sodium hydrogen selenide in the presence of a salt of a primary amine and formaldehyde to form 3,5-disubstituted tetrahydro-1,3,5selenodiazine-2-selenones 61 (Scheme 35) [57].The best yields were obtained in the case when phenyl isoselenocyanates containing an electron-accepting substituent were used for the additioncyclization reaction.

Reactions with carbanions
The carbanion obtained from malononitrile (62a) and triethylamine was reacted in DMF with isoselenocyanates to give an intermediate of type 63.The latter reacted with 1,2-dibromoethane (64) to give another intermediate 65, which cyclized to yield 1,3-selenazolidine derivatives of type 66.Similar reactions were performed starting with ethyl cyanoacetate (62b).Only one isomer was obtained in the case of the cyanoacetates (Scheme 36) [58].Treatment of the intermediates 63 with bromoacetyl bromide (70) led to the formation of a single product, 4-oxo-1,3-selenazolidine (73).As the reaction between thioureas and acyl halides is known to give S-acylated isothioureas [59], the formation of the 4-oxo-1,3-selenazolidine derivatives 73 in the reactions with 2-bromoacetyl bromide 70 can be explained by the reaction mechanism shown in Scheme 37. Similar S/N migrations of the acetyl group are known and have been studied in depth kinetically [60] and were described recently by Pihlaja and coworkers [61].Finally, the Se-atom attacks the α-carbon atom of the amide group and forms the 1,3-selenazolidinone ring by displacing the bromide ion to give 73.
An analogous cyclization was observed when 75 were reacted with the Na salt of diethyl malonate in EtOH at room temperature to yield the eight-membered selenaheterocycles 76 (Scheme 38).The crystal structure of the 76 revealed the presence of a co-crystal comprising two compounds [32].

Scheme 38
The reaction of N-phenylbenzamides 77 with excess SOCl 2 under reflux gave N-phenylbenimidoyl chlorides 78, which on treatment with KeSeCN in acetone yielded imidoyl isoselenocyanates of type 79.These were transformed into selenourea derivatives 80 by the reaction with NH 3 , primary or secondary amines.In acetone at room temperature, 80 reacted with activated bromomethylene compounds such as 2-bromoacetates, acetamides, and acetonitriles, as well as phenacyl bromides and 4-cyanobenzyl bromides, to give 1,3-selenazol-2-amines of type 82 (Scheme 39) [62].A reaction mechanism via alkylation of Se-atom of 80, followed by ring closure and elimination of anilines, is most likely [63].The condensation of benzoyliminoisoselenocyanate in basic media with malononitrile and halides allowed the preparation of aminoselenophenes 83 (Scheme 40) [64].

Scheme 44
The reaction mechanism for the formation of 90 is shown in Scheme 45.The addition of Ph 3 P to the azodicarboxylate 89 generates the zwitterion 91, which, as a nucleophile, attacks the isoselenocyanate to give 92.Ring closure by nucleophilic addition of the N-atom at the ester group leads to 93, and elimination of Ph 3 PO via the intermediate 94 yields the product 90.The use of the diethyl azodicarboxylate (oxidant)/Ph 3 P (reducing agent) system is well established [68] and is known as the Mitsunobu reaction [69] when the reactant is an alcohol.The betaine 91 is the initially formed intermediate in all cases and it reacts with the alcohol.In the present case, this intermediate reacts as a nucleophile with the strongly electrophilic isoselenocyanate.A second example of a reaction between an isoselenocyanate and a diazo compound is shown in Scheme 47 [71].In this case, the primarily formed cycloadduct 96 has been isolated.It should be noted that the 1,3-dipolar cycloaddition occurs regioselectively to give the 1,2,3-selenadiazole derivative 96.

Conclusions
In summary, isoselenocyanates have been emerged as a powerful tool for the synthesis of selenium-containing heterocycles.This review provides a comprehensive survey of the progress in the various reactions of isoselenocyanates, their application in the preparation of various types of selenium-containing heterocycles.