CC BY
30DOI: 10.17516/1998-2836-0164 yflK 547.785.59
N-Alkylation Reaction in the Synthesis of Tetra-Substituted Glycoluryls
Anastasia А. Sinitsyna* and Sergey G. Il'yasov
Institute for Problems of Chemical and Energetic Technologies SB RAS Biysk, Russian Federation
Received 20.12.2019, received in revised form 16.01.2020, accepted 03.02.2020
Abstract. A new method is suggested herein for the synthesis of tetrasubstituted glycolurils by treatment of disubstituted glycolurils (di-tert-butylglycolurils, di-isopropylglycoluril) with alkylating agents such as methyl iodide, ethyl bromide and benzyl chloride in acetonitrile in the presence of KOH. Optimum conditions for the preparation of the target product in high yield were studied by the example of the synthesis of dibenzyl-di-tert-butylglycoluril: time 3 h and reaction temperature 75°C at a 1:4 M/M molar ratio of disubstituted glycoluril to benzyl chloride. Thus, the target product yield was 83%. It was also found that benzyl chloride should be used as the alkylating agent because the product yield under the same equal conditions was higher with benzyl chloride than with benzyl bromide which in turn is more toxic and less available.
Keywords: ureas, glycoluryls, disubstituted glycoluryls, N-alkylation, heterocycles.
Citation: Sinitsyna A.A., Il'yasov S.G. N-alkylation reaction in the synthesis of tetra-substituted glycoluryls, J. Sib. Fed. Univ. Chem., 2020, 13(1), 40-45. DOI: 10.17516/1998-2836-0164
© Siberian Federal University. All rights reserved
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). Corresponding author E-mail address: nastya.sinitsyna.1994@mail.ru
Реакция N-алкилирования в синтезе тетразамещенных гликольурилов
А.А. Синицына, С.Г. Ильясов
Институт проблем химико-энергетических технологий СО РАН
Российская Федерация, Бийск
Аннотация. Предложен новый способ получения тетразамещенных гликольурилов, заключающийся в обработке дизамещенных гликольурилов (дитрет-бутилгликольурила, диизопропилгликольурила) алкилирующими агентами: йодистый метил, бромистый этил и хлористый бензил в среде ацетонитрила в присутствии основания КОН. На примере получения дибензил-дитрет-бутилгликольурила изучены оптимальные условия для получения продукта с высоким выходом: продолжительность 3 ч и температура реакции 75 °С при мольном соотношении дизамещенного гликольурила к бензил хлориду 1:4 моль/моль. Таким образом, выход целевого продукта составил 83 %. Также установлено, что в качестве алкилирующего агента следует использовать хлористый бензил в связи с тем, что выход продукта в одних и тех же условиях выше, чем при использовании бромистого бензила, который, в свою очередь, является наиболее токсичным и менее доступным.
Ключевые слова: мочевины, гликольурилы, дизамещенные гликольурилы, ^алкилирование, гетероциклы.
Цитирование: Синицына, А.А. Реакция N-алкилирования в синтезе тетразамещенных гликольурилов / А.А. Синицына, С.Г. Ильясов // Журн. Сиб. федер. ун-та. Химия, 2020. 13(1). С. 40-45. DOI: 10.17516/1998-2836-0164
N-alkyl-substituted 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones (glycolurils) are known to exhibit a broad spectrum of biological activity. In particular, 2,4,6,8-tetramethylglycoluril (Mebicar) and 2,6-diethyl-4,8-dimethylglycoluril (Albicar) are compounds having anxiolytic properties [1-3].
Thus, synthesis of new N-alkyl-substituted glycolurils or improvement in the well-known synthetic methods is permanently receiving interest among researchers.
The chemical structure of glycoluril represents an extremely attractive object for further targeted modification because glycoluril comprises four active nucleophilic sites through which substitution reactions may take place [4, 5].
The literature [6, 7] describes a method for preparing 2,6-dimethyl-4,8-di-tert-butylglycoluril via cyclocondensation of 1-methyl-3-tert-butylurea with glyoxal, in which case a racemic mixture is formed that consists of the three compounds: cis- and trans-isomers of dimethyl-di-tert-butylglycoluril and hydantoin. With that, the yield of trans-isomers was found to be threefold that of cis-isomers [8].
Glycoluril tetraderivatives can be not only bioactive but also highly energetic. Tetranitroglycoluril (SORGUIL) is produced by nitration of glycoluril through the formation of dinitroglycoluril (DINGU) [9, 10].
The present paper reports the results on the synthesis of tetrasubstituted glycolurils by the N-alkylation reaction in order to expand the series of tetrasubstituted glycolurils and examine their presumed biological activity in the PASS program.
Experimental
The work was performed with instruments of the Biysk Regional Center for Shared Use of Scientific Equipment of the SB RAS (IPCET SB RAS, Biysk).
Infrared spectra were recorded in KBr pellets on a FT-801 FTIR spectrometer under conditions of disturbed total internal reflection.
NMR spectra were taken on a Bruker Avance III 500 spectrometer operated at 400.13 MHz for 1H and at 100.61 MHz for 13С. The spectra were acquired from the solution in CD3CN.
General synthesis of di-tert-benzylglycoluril: To acetonitrile (20 mL) was added disubstituted glycoluril (0.0025 M), alkylating agent (0.01 M) (methyl iodide, ethyl bromide or benzyl chloride) and KOH (0.01 M). The reaction mass was heated to 75 °С and held for 3 h. Afterwards, the precipitated KHal salt was discarded and the solvent was withdrawn from the mother solution. The resulting solid residue was washed with diethyl ether and then with water to dissolve the residual salt, and then with diethyl ether again. The resultant powder was collected by filtration and dried under atmospheric pressure.
3a. 2,6-Dimethyl-4,8-di-tert-butyl-2,4,6,8-tetraaza[3.3.0]octane-2,7-dione: Yield 40%. Mp = 144-146 °С. IR, cm-1: 2984, 2971, 2910, 2887, 1711, 1690. NMR (400 MHz, CD3CN) 5,17 (s, 2H, N-CH-N), 2,80 (s, 6H, CH3), 1,44 (s, 18H, C(CH3)3. 13C NMR (100 MHz, CD3CN) 5 158.87 (C=O), 69.94 (N-CH-N), 53.51 (C(CH3)), 28.34 (CH3).
3b. 2,6-Diethyl-4,8-di-tert-butyl-2,4,6,8-tetraaza[3.3.0]octane-2,7-dione: Yield: 59%. Mp = 122-124 °С. IR, cm-1: 3445, 3340, 3222, 2973, 2933,2875, 1686, 1655. NMR (400 MHz, CD3CN) 5.28 (s, 2H, N-CH-N), 3.17-3.23 (q, 4H, CH2), 1.27 (s, 18H, CH3), 1.02-1.05 (t, 6H, CH, CH3). 13C NMR (100 MHz, CD3CN) 5 158.95 (C=O), 67.92 (N-CH-N), 53.83 (C(CH3)), 35.21 (CH2-CH3), 28.34 (CH3), 11.75 (CH2-CH3).
3c. 2,6-Dibenzyl-4,8-di-tert-butyl-2,4,6,8-tetraaza[3.3.0]octane-2,7-dione: Yield 83%. Mp = 223-225 °С. IR, cm-1: 3062, 3028, 2968, 2934, 2892, 1704 (C=O), 1687 (C=O). NMR (400 MHz, CD3CN) 7.39-7.19 (m, 10Н, Ph); 5.43 (s, 2H, N-CH-N), 4.79 (J= 17.3 Hz, d, 2H, CH2-Ph), 4.75 (J= 17.3 Hz, d, 2H, CH2-Ph), 1.30 (s, 18H, CH3). 13C NMR (100 MHz, CD3CN) 5 159.14 (C=O), 138.11 (/-Ph), 128.60 (m-Ph), 126.16 (o,p-Ph), 68.41 (N-CH-N), 54.08 (C(CH3)), 43.73 (CH2-Ph), 28.27 (CH3).
4a. 2,6-Dimethyl-4,8-diisopropyl-2,4,6,8-tetraza[3.3.0]octane-2,7-dione: Yield 34%. IR, cm-1 2976, 2942, 2884,1698 (C=O). 1Н NMR (400 MHz, CD3CN) 5.11 (s, 2H, N-CH-N), 3.77-3.73 (m, 2H, CH), 1.88 (s, 6H, CH3), 1.30-1.22 (m, 12H, CH3). 13C NMR (100 MHz, CD2Cl2) 5 159.17 (C=O), 70.78 (N-CH-N), 46.67 (CH), 20.58 (CH3), 19.35 (CH3).
4b. 2,6-Diethyl-4,8-diisopropyl-2,4,6,8-tetraaza[3.3.0]octane-2,7-dione: Yield 51%. IR, cm-1:2974, 2937, 2881, 1693 (C=O). 1Н NMR (400 MHz, CD3CN) 5.16 (s, 2H, N-CH-N), 3.69-3.66 (m, 2H, CH(CH3)2), 3.51-3.09 (m, 4H, CH2), 1.07-1.35 (18H, CH3). 13C NMR (100 MHz, CD3CN) 5 158.66 (C=O), 68.16 (N-CH-N), 47.26 (CH), 36.60 (CH2), 19.63, 19.91 (CH3), 11.97 (CH3).
4c. 2,6-Dibenzyl-4,8-diisopropyl-2,4,6,8-tetraaza[3.3.0]octane-2,7-dione: Yield 58%. IR, cm-1: 3320, 3172, 2976, 2934, 2892, 1714 (C=O), 1688 (C=O). 1Н NMR (400 MHz, CD3CN) 7.40-7.24
(m, 10H, Ph); 5.06 (s, 2H, N-CH-N), 4.72 (J= 16.4 Hz, d, 2H, CH2-Ph), 4.35 (J= 16.4 Hz, d, 2H, CH2-Ph), 3.43-3.45 (m, 2H, CH), 1.22 (s, 12H, CH3). 13C NMR (100 MHz, CD3CN) 5 158.94 (C=O), 137.69 (/-Ph), 128.60 (m-Ph), 127.19 (o,p-Ph), 69.29 (N-CH-N), 48.05 (CH), 45.55 (CH2-Ph), 19.46 (CH3).
JSt^su^^si^i^d dtecussron
discusliidtcugldcohirils were preparedby c^^c^l^i^^^dic^n ef monosubstiCuted urea with glyoxal by the reported procedure [11]. The general protocol for the study is illustrated in Fig. 1.
Figures 2-4 show the product yield plotted against the reaction temperature and time and molar ratio of starting components by the example of the synthesis of dibenzyl-d/'-tert-butylglycoluril.
As is seen in Fig. 2, nhe target product yield at 25 °C and 3n °C was as low as 9 and 21%, respectively, whereas the temperature rise to 45 °C resulted in a threefold incre ase in the yield. The maximumy ield ofdibenzyl-d/'-fer/-butylglycolyrilof83% c alculated as d/'-feri-butylglyco luril was achieved when the reaction temperature was 75 °C, which is close to the solvent boiling point.
w tf
"N NH
H +
Yn
HN ^N
FJ2Ha! + KOH
eK A ^R2
H
RiV^R
O
3a - sic
R
№ r1 r2
de c(ch3)3 aHt
3b c(C h3)3 C2H5
de c(ch3)3 B n
4a ch(ch3)2 ch3
4b nsi^ct)3C2 C^
as CH(CH3)t Bll
Fiom. Gcnetdlschsme fss the studyofSheN-aCkoiaSionre3ctionafdisabeC3Catedglycoluriis
100
.ill
25 3 5 45 55 75 Temperature, °C
Fig. 2. Yield of 3c plottedi^ainct retctionterr^scature
100 1
IIII
13 5 7 Time, h
Fig. 3. Yield of 3c plotted against reaction time
100 a
-■I»
1:2 1:3 1:4 1:5 1:6 Molar ratio, M/M
Fig. 4. Yieldof 3c plotted againstmolarratioofdi-tert-butylglycoluriltobenzylchloride
The reaction time increment from 1 to 3 h sharply enhanced the product yield (Fig. 3), and the further rise in reaction time almost did not favor an increase in the target product yield. Thus, the holding time of 3 h was more appropriate.
The experimental results demonstrated that the 1:4 M/M molar ratio of di-tert-butylglycoluril to benzyl chloride was optimum. It is seeninFig. 4 that the product yield declined as the alkylating agent concentration in the initial mixture was raised Го 1:6 M/M. It was also found that benzyl chloride should be used 6S theainylatinn agent bccaare it gave a higher aield afshe iacgrtproduui rhan benzyl bromada, atd itos applioniien zsmorepreferaZie swingtoite lowrr ioxirity and greaifr aorilabztity comparedio Oepeat trbmide.
It: cbnternferedfrom die aforesaid that the following conditions are required for the maximum yield of dibenzyl-di-tert-butylglycoluril: 1:4 molar ratio of the reactants, temperature 75 °С and time 3 h. In this case, the target product yield was 83%.
Conclusions
Never-before-seen glycoluril tetraderivatives were synthesized herein and dimethyl-di-tert-butylglycoluril was derived by the new method. High-yielding conditions were determined by the example of dibenzyl-di-tert-butylglycoluril: 1:4 M/M molar ratio of di-tert-butylglycoluril to benzyl сЫопее,Гетапга7иге 750С aMti me3 h.
Acknowledgements / Благодарности
The reported study was funded by RFBR, project number 19-33-90060.
- 44 -
Исследование выполнено при финансовой поддержке РФФИ в рамках научного проекта № 19-33-90060.
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