{Influence of electrochemical conditions on the regio- and stereoselectivity of selenocyclization of alkenyl hydantoins} J. Serb. Chem. Soc. 86 (6) 585–590 (2021) Short communication JSCS–5445 585 SHORT COMMUNICATION Influence of electrochemical conditions on the regio- and stereoselectivity of selenocyclization of alkenyl hydantoins BILJANA M. ŠMIT1*, PETAR B. STANIĆ1, LJUBINKA G. JOKSOVIĆ2, DARKO P. AŠANIN1 and ZORAN SIMIĆ2 1Institute for Information Technologies, University of Kragujevac, Jovana Cvijića bb, Kragujevac, Serbia and 2Faculty of Science, University of Kragujevac, Radoja Domanovića 12, Kragujevac, Serbia (Received 22 October 2020, revised 21 February, accepted 23 March 2021) Abstract: 5-Alkenyl hydantoins and alkenyl spirohydantoins are converted into bicyclic and tricyclic hydantoins, under indirect electrochemical conditions, generating the phenylselenyl cation in situ. The reactions proceeded in good to exelent yields. The influence of electrochemical conditions on regio- and diastereoselectivity of the selenocyclization reactions is investigated. Keywords: electrosynthesis; constant-current electrolysis; selenylation; ring closure. INTRODUCTION The use of electrochemical methods in organic synthesis has become inc- reasingly more popular due to simple procedures and laboratory techniques and the use of cleaner and greener solvents. It is worth noting that the outcomes of the reactions can be vastly different, while some reactions can only be carried out under electrochemical conditions.1 The hydantoin core represents an important pharmacophore occurring in many biologically active compounds mostly known due to their antimicrobial, anticancer and anticonvulsant activity.2,3 Spirohydan- toins4 and fused5 polycyclic hydantoins are the leading compounds in drug disco- very, due to their various biological activities. Selenocyclization is a convenient and useful tool for the construction of heterocycles.6,7 We described a method- ology for the synthesis of bicyclic and tricyclic fused hydantoin scaffold, using selenocyclization for the construction of sterically constrained structures that have potential in peptidomimetic drug design.8,9 In this work we decided to use the electrochemically generated phenylselenyl cation in the cyclization of 5-alk- enyl hydantoins and alkenyl spirohydantoins and explore whether these condit- * Corresponding author. E-mail: biljana.smit@uni.kg.ac.rs https://doi.org/10.2298/JSC201022023S ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 586 ŠMIT et al. ions have an effect on the course of the reaction, especially on regio- and stereo- selectivity. EXPERIMENTAL General. All alkenyl hydantoins used as substrates were synthesized according to the procedures described previously.8 Reagent Ph2Se2 was used as supplied by Aldrich. Gas– liquid chromatography (GLC) was performed by Varian instument model 3400. 1H-NMR spectra were run in CDCl3 on a Varian Gemini 2000 spectrometer at 200 MHz. General procedure for the electrochemical selenocyclization of hydantoins (1a–j). A sol- ution of 1a–j (1 mmol), Ph2Se2 (156 mg, 0.5 mmol), silica gel (150 mg, 5 mmol) and NaClO4 (123.5 mg, 1 mmol) in MeCN (10 ml) was placed in an undivided electrolysis cell and elec- trolyzed under a constant current (10 mA) at room temperature. After completion, the reaction mixture was stirred overnight. The solvent was distilled off, residue dissolved in CH2Cl2, washed with sat. NaHCO3 solution and brine, and dried over anh. Na2SO4. The solvent was evaporated and the reaction mixture was analyzed by GLC and 1H-NMR spectroscopy. RESULTS AND DISCUSSION The alkenyl hydantoins contain a double bond and an internal nitrogen nuc- leophile, and they are suitable substrates for the intramolecular electrophilic cyc- lization. Over several decades, electrophilic selenium reagents have been proven to be quite useful for this purpose. In some cases, electrochemical selenylations have advantages over other related methods.10,11 The cyclization of the previously synthesized 5-alkenyl hydantoins 1a–g and alkenyl spirohydantoins 1h–j was performed by the means of electrochemically generated phenylselenyl cation, which originates from diphenyldiselenide in a MeCN solution of NaClO4 (Scheme 1). Perchlorate in this process serves as a mediator. Before that, we tried to perform the reaction of the commercially avail- able product 1d, with other supporting electrolytes (LiCl, KCl, NaBr, KI), sol- vents and electrodes, but NaClO4 in MeCN and C–Pt electrodes gave the best results (Table I, Entry 6). Scheme 1. Selenocyclization of alkenyl hydantoins 1a–g and alkenyl spirohydantoins 1h–j. ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ ELECTROCYCLIZATION OF ALKENYL HYDANTOINS 587 TABLE I. Optimization of electrochemical conditions for the cyclization reaction of 1d Entry Anode–cathode Supporting electrolyte Solvent Overall yielda (6/5), % Diasteromeric ratioa cis/trans, % 1 Pt–Pt KCl CH3CN 10 78:21 2 Pt–Pt NaBr CH3CN 6 – 3 Pt–Pt KI CH3CN 5 75:25 4 Pt–Pt NaClO4 CH3CN 31 62:38 5 Pt–Pt NaClO4 CH3CN 4 – 6 C–Pt NaClO4 CH3CN 63 (46:54) 6(59:41); 5(69:31) 7 C–Cu Et4NBr CH3CN 1 – 8 C–Cu NaClO4 CH3CN 47 (68:32) 6(51:49); 5(7:93) 9 C–Cu LiCl CH3CN traces – 10 C–Cu KI CH3CN 34 (42:58) 6(52:48); 5(72:28) 11 C–Pt NaClO4 CH2Cl2:CH3CN=2:1 Traces – 12 C–Pt NaClO4 Py:CH3CN=1:1 Traces – 13 C–Pt NaClO4 Toluene:CH3CN=2:1 57 (83:17) 6(48:52); 5(84:16) 14 C–Pt NaClO4 THF Undetectable – 15 C–Pt NaClO4 Ethanol Undetectable – 16 C–Pt NaClO4 DMF Traces – aRatio of regio and diastereoisomers are obtained from GLC and 1H-NMR spectra The easy oxidation of perchlorate at the anode provides in situ generation of PhSe+ able to react with the π-electron system of the substrate. The reaction yields products resulting from the nucleophilic attack of the nitrogen atom to the cyclic seleniranium ion intermediate during the cyclization step. Under the chosen reaction conditions, a series of alkenyl hydantoins 1a–j was subjected to electrochemical selenocyclization (Table II). In the previously reported results,8,9 the reaction was regiospecific and 5-membered regioisomers were formed via favorable 5-exo-trig ring closure process which is both kinetic- ally and thermodynamically favoured.12 Products where the bridgehead substi- tuent and CH2SePh group are in cis positions one to another were formed pre- dominantly. In contrast, when the phenylselenyl cation is electrochemically gen- erated in situ, it was noticed that the regio- and diastereoselectivity both depend on the steric hindrance at C-5 of the hydantoin ring and the C-C double bond. 5-Exo-trig cyclization products are also obtained regiospecifically in most cases, but with poorer stereoselectivity. The amount of trans-diastereoisomers is inc- reased in comparison to the previous results, implying higher thermodynamic control of the cyclization process. Exceptions are the cyclizations of 1c and 1j where the steric hindrance is most pronounced and the kinetic control is favoured, increasing the cis-selectivity. Only in the absence of steric hindrance in the starting alkenyl hydantoin, 6-membered regioisomers are formed via 6-endo- -trig ring closure process. In the case of 1a, where a methyl group is attached on C-5 and the double bond is unsubstituted, the six-membered regioisomer is obtained almost exclusively and as a trans-isomer stereospecifically. Six-mem- ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 588 ŠMIT et al. bered product is also obtained in the cyclization of 1d, where a methyl group is attached on C5 and the double bond is terminally disubstituted, but without regio- and stereoselectivity. When the double bond is non-terminally substituted, like in 1e, despite having a methyl group attached on C-5, the six-membered regioisomer is not formed at all. It is assumed that the methyl group on the double bond directly hinders the approach of seleniranium cation to the nitrogen atom during cyclization. Regardless of the substitution of the double bond, the cyclization of alkenyl spirohydantoins 1h–j depends on the size of the cycloalkyl group. The product of 6-endo-trig ring closure occurs predominantly only in the case of 1h without any stereocontrol, while the minor product of 5-exo-trig ring closure occurs with the reversed stereoselectivity compared to results reported previously.9 The bulkier six-membered ring in 1i and 1j presumably prevents the formation of another six-membered ring. TABLE II. Selenocyclization of alkenyl hydantoins 1a–g and alkenyl spirohydantoins 1h–j Substrate Yield, % Regioisomer ratioa 2:3 dr (cis/trans)a 2 dr (cis/trans)a 3 72 1:99 – 0:100 88 100:0 70:30 – 96 100:0 71:29 – 63 54:46 69:31 59:41 73 100:0 56:44 – 63 100:0 44:56 – 75 100:0 48:52 – 86 35:65 24:76 50:50 ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ ELECTROCYCLIZATION OF ALKENYL HYDANTOINS 589 TABLE II. Continued Substrate Yield, % Regioisomer ratioa 2:3 dr (cis/trans)a 2 dr (cis/trans)a 3 97 100:0 68:32 – NH HN O O 82 100:0 100:0 – aRatio of regio- and diastereoisomers are obtained from GLC and 1H NMR spectra CONCLUSION The influence of electrochemical conditions on selenocyclization reactions of alkenyl hydantoins and spirohydantoins has been explored. Various different solvent/mediator systems have been taken into consideration and MeCN/NaClO4 showed the best results. Steric hindrances in the starting alkenyl hydantoins inf- luence the regio- and the stereochemical outcome of the reactions and in these conditions thermodynamic control is more present. Acknowledgement. This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Cont. No: 451-03-9/2021-14). И З В О Д УТИЦАЈ ЕЛЕКТРОХЕМИЈСКИХ УСЛОВА НА РЕГИО- И СТЕРЕОСЕЛЕКТИВНОСТ СЕЛЕНОЦИКЛИЗАЦИЈЕ АЛКЕНИЛХИДАНТОИНА БИЉАНА М. ШМИТ1, ПЕТАР Б. СТАНИЋ1, ЉУБИНКА Г. ЈОКСОВИЋ2, ДАРКО П. АШАНИН1 и ЗОРАН СИМИЋ2 Институт за информационе технологије, Универзитет у Крагујевцу, Јована Цвијића бб, Крагујевац и 1Природно–математички факултет, Универзитет у Крагујевцу, Радоја Домановића 12, Крагујевац 5-Алкенилхидантоини и алкенилспирохидантоини су преведени у бицикличне и трицикличне хидантоине под индиректним електрохемијским условима при којима се фенилселенил-катјони стварају in situ. Реакције су се одигравале у добрим до одличним приносима. Испитиван је утицај електрохемијских услова на регио- и дијастереоселек- тивност реакција селеноциклизације. (Примљено 22. октобра 2020, ревидирано 21 фебруара, прихваћено 23. марта 2021) REFERENCES 1. Y. Jiang, K. Xu, C. Zeng, Chem. Rev. 118 (2018) 4485 (https://doi.org/10.1021/acs.chemrev.7b00271) 2. J. C. Thenmozhiyal, P.T. Wong, W. Chui, J. Med. Chem. 47 (2004) 1527 (https://dx.doi.org/10.1021/jm030450c) 3. A. Volonterio, C. R. de Arellano, M. Zanda, J. Org. Chem. 70 (2005) 2161 (https://dx.doi.org/10.1021/jo0480848) 4. Y. Fujiwara, G. C. Fu, J. Am. Chem. Soc. 133 (2011) 12293 (https://dx.doi.org/10.1021/ja2049012) ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 590 ŠMIT et al. 5. F. Brockmeyer, D. Kröger, T. Stalling, P. Ullrich, J. Martens, Helv. Chim. Acta 95 (2012) 1857 (https://dx.doi.org/10.1002/hlca.201200441) 6. D. W. Knight, Prog. Heterocyc. Chem. 14 (2002) 19 (https://dx.doi.org/10.1016/S0959- 6380(02)80004-6) 7. N. Petragnani, H. A. Stefani, C. J. Valduga, Tetrahedron 57 (2001)1411 (https://dx.doi.org/10.1016/S0040-4020(00)01033-4) 8. B. M. Šmit, R. Z. Pavlović, Tetrahedron 71 (2015) 1101 (https://dx.doi.org/10.1016/j.tet.2014.12.088) 9. B. M. Šmit, M. Rodić, R. Z. Pavlović, Synthesis-Stuttgart 48 (2016) 387 (https://dx.doi.org/10.1055/s-0035-1561285) 10. P. Röse, S. Emge, J. Yoshida, G. Hilt, Beilstein J. Org. Chem. 11 (2015) 174 (https://dx.doi.org/10.3762/bjoc.11.18) 11. D. Stevanović, A. Pejović, M. D. Vukićević, G. Dobrikov, V. Dimitrov, M. S. Denić, N. S. Radulović, R. D. Vukićević, Helv. Chim. Acta 96 (2013) 1103 (https://dx.doi.org/10.1002/hlca.201200610) 12. B. M. Šmit, R. Z. Pavlović, D. A. Milenković, Z. S. Marković, Beilstein J. Org. Chem. 11 (2015) 1865 (https://dx.doi.org/10.3762/bjoc.11.200). ________________________________________________________________________________________________________________________ (CC) 2021 SCS. 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