Direct Synthesis of 1-Alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils from 1-Alkylimidazolinones and Their Cyclic Analogues

Abstract

Two methods for the direct synthesis of previously inaccessible 1-alkyl-6-(hydroxyalkyl)-3a,6a-diphenylglycolurils have been developed as a result of a study of novel cyclocondensations of 1-alkylureas with tetrahydroimidazooxazolones, tetrahydroimidazooxazinones and 1-(hydroxyalkyl)ureas with 1-substituted imidazolinones. A mechanism to rationalize the highly regioselective formation of the target glycolurils is proposed.

1,6-Disubstituted glycolurils are of practical and theoretical interest.[1] [2] [3] [4] They are used as molecular templates for intramolecular Claisen type condensations[2] and as building blocks for organic and supramolecular chemistry.[3,4] In most cases, they are synthesized by condensation of 1,2-dioxo-1,2-diаrylethanes with 1-substituted ureas.[3b] [3g] [4] This approach allows symmetrically 1,6- and 1,4-disubstituted 3a,6a-diarylglycolurils 1 and 2 to be obtained, with a predominance for 1,6-disubstituted isomers 1 (Scheme [1]).

Recently, during the investigation of the condensation of ureido alcohols with benzyl, we found new precursors of 1,6-di(hydroxyalkyl)-3a,6a-diarylglycolurils 3, namely, tetrahydroimidazooxazolone 4, tetrahydroimidazooxazinone 5, dihydroimidazooxazinone 6, and tetrahydroimidazooxazepinone 7 (Scheme [2]).[5]

Thus, a method for highly regioselective synthesis of 1,6-disubstituted 3а,6а-diphenylglycolurils 1 and 3 based on the reactions of bicyclic compounds 4–7 with 1-methylurea 8а and 1-(hydroxyalkyl)ureas 9a and 9b was proposed.[5] In the course of these investigations, the first representative of 1,6-disubstituted 3а,6а-diphenylglycolurils 3 with different substituents on the nitrogen atoms was developed.[5]

In the work reported herein, the reactions of bicycles 4, 5, and 7 with N-ethyl, N-propyl, and N-butylureas 8b–d and the condensation of imidazolinones 10a–d with N-(hydroxyalkyl)ureas 9a and 9b were studied for the first time, and a direct synthesis of 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils was developed.

We started our investigations with a study of the condensation of bicyclic compounds 4, 5, and 7 with N-alkylureas 8b–d under conditions used previously for the reactions of compounds 4, 5, and 7 with N-methylurea (HCl, MeCN, reflux;[5b] Method 1, Scheme [3]). The reaction time ranged from 20 min to 48 h. It was found that tetrahydroimidazooxazolone 4 reacted with all ureas 8b–d and the 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils 3а–с were formed regioselectively in high yields (78–88%). Tetrahydroimidazooxazinone 5 reacted only with N-(3-hydroxypropyl)urea 9b to form N-(3-hydroxypropyl)-6-ethyl-3a,6a-diphenylglycoluril 3d in 48% yield in a reaction time of 17 h. This result can be explained by the poor solubility of compound 5 in MeCN. Therefore, another solvent (MeOH) was used and glycoluril 3d was synthesized in 90% yield by heating the reaction to reflux for 8 hours.

Unfortunately, ureas 8c and 8d did not react with bicyclic compound 5 and tetrahydrooxazepinone 7 did not react with ureas 8b–d. On evaporating to dryness, aliquots of the reaction mixtures were studied by ¹H NMR spectroscopy. Proton signals corresponding to the target 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils and isomeric 1-alkyl-4-hydroxyalkyl-3а,6а-diphenylglycolurils were not detected. This result is probably due to steric features of the ureas 8 and bicyclic compounds 5 and 7.

The high regioselectivity of the formation of glycolurils 3a–d can be explained not only by the structural features of the intermediate carbocation A but also by the steric hindrance of the NH group as compared to the NH₂ fragment in ureas 8b–d (Scheme [4]).

The limitations of Method 1 prompted us to develop a new approach to the synthesis of compounds 3. Recently, we synthesized 1-alkylimidazolinones 10a–d as novel precursors to glycolurils and their analogues.[6] [7] The condensation of 1-alkylimidazolinones 10a–d with N-(hydroxyalkyl)ureas 9a and 9b was studied for the first time, and a wide range of glycolurils 3a–h was obtained in high yields (74–88%) (Method 2, Scheme [5]). The reaction was carried out under conditions similar to those developed by us for the synthesis of 1-substituted glycolurils.[6] The ¹H NMR spectra of aliquots of the reaction mixtures after evaporation to dryness did not contain the signals due to protons of the isomeric 1-alkyl-4-hydroxyalkyl-3а,6а-diphenylglycolurils, indicating the high regioselectivity of the reaction. In this case, the yields of glycolurils 3e (88%) and 3f (84%) were comparable to, or exceeded, the yields for the same compounds (3e 79% and 3f 88%) obtained earlier by the interaction of bicycles 4 and 5 with N-methylurea 8a.[5b]

The homogeneity of compounds 3a, 3b, and 3d–g was confirmed by powder XRD analysis, in which analysis of the powder diffraction patterns shows that the samples existed as a single phase (see the Supporting Information).

The high regioselectivity of condensations plausibly arises from the fact that ureas 9a and 9b form an intramolecular hydrogen bond (H–O···H–N(1)) in solution. Attack of the urea on carbocation B occurs by the more sterically accessible NH₂ group and adducts C are generated (Scheme [6]). Finally, protonation of the OH group of adducts C and subsequent elimination of H₂O forms cation D, which undergoes intramolecular cyclization to furnish the desired glycolurils 3a–h.

In summary, the reactions of bicycles 4, 5, and 7 with ureas 8b–d and the condensation of imidazolinones 10a–d with N(-hydroxyalkyl)ureas 9a and 9b have been studied for the first time.[8] The scope of Method 1 was determined, showing that tetrahydroimidazooxazolone 4 interacts with all ureas 8b–d but tetrahydroimidazooxazinone 5 reacted only with N-ethylurea 8b. The target 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils 3а–с are formed regioselectively in high yields.[9] Method 2 is a novel approach for the highly regioselective synthesis of 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils 3a–h (including novel glycolurils 3a–d and 3g–h), which are prepared by the reactions of imidazolinones 10a–d with N-(hydroxyalkyl)ureas 9a and 9b. Both approaches allow the selective synthesis of 1-alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils. Mechanisms of both studied reactions are proposed.

• References and Notes

• 1 Kravchenko AN, Baranov VV, Gazieva GA. Russ. Chem. Rev. 2018; 87: 89
  CrossrefSearch in Google Scholar
• 2a Sun S, Edwards L, Harrison P. J. Chem. Soc., Perkin Trans. 1 1998; 437
• 2b Rahimizadeh M, Kam K, Jenkins SI, McDonald RS, Harrison PH. M. Can. J. Chem. 2002; 80: 517
  CrossrefSearch in Google Scholar
• 3a Johnson DW, Palmer LC, Hof F, Iovine PM, Rebek JJr. Chem. Commun. 2002; 2228
  PubMed
• 3b Wu A.-X, Fettiger JC, Isaacs L. Tetrahedron 2002; 58: 9769
  CrossrefSearch in Google Scholar
• 3c Johnson DW, Hof F, Palmer LC, Martin T, Obst U, Rebek JJr. Chem. Commun. 2003; 1638
  PubMed
• 3d Rowan AE, Elemans JA. A. W, Nolte RJ. M. Acc. Chem. Res. 1999; 32: 995
  CrossrefSearch in Google Scholar
• 3e Grotzfeld RM, Branda N, Rebek JJr. Science 1996; 271: 487
  CrossrefPubMedSearch in Google Scholar
• 3f Szabo T, O’Leary BM, Rebek JJr. Angew. Chem. Int. Ed. 1998; 37: 3410
  CrossrefPubMedSearch in Google Scholar
• 3g O’Leary BM, Szabo T, Svenstrup N, Schalley CA, Lützen A, Schäfer M, Rebek JJr. J. Am. Chem. Soc. 2001; 123: 11519
  CrossrefPubMedSearch in Google Scholar
• 3h Rivera JM, Martín T, Rebek JJr. J. Am. Chem. Soc. 2001; 123: 5213
  CrossrefPubMedSearch in Google Scholar
• 3i Nuckolls C, Hof F, Martín T, Rebek JJr. J. Am. Chem. Soc. 1999; 121: 10281
  CrossrefSearch in Google Scholar
• 4a Pryor KE, Rebek JJr. Org. Lett. 1999; 1: 39
  CrossrefSearch in Google Scholar
• 4b Kim HG, Kang JM. Bull. Korean Chem. Soc. 2006; 27: 1791
  Search in Google Scholar
• 4c Kravchenko AN, Baranov VV, Gazieva GA, Chikunov IE, Nelyubina YV. Russ. Chem. Bull. 2014; 63: 416
  CrossrefSearch in Google Scholar
• 4d Kim H, In S, Kang J. Supramol. Chem. 2006; 18: 141
  CrossrefSearch in Google Scholar
• 5a Baranov VV, Antonova MM, Nelyubina YV, Zanin IE, Kravchenko AN, Makhova NN. Mendeleev Commun. 2014; 3: 173
  Search in Google Scholar
• 5b Antonova MM, Baranov VV, Nelyubina YV, Kravchenko AN. Chem. Heterocycl. Compd. 2014; 50: 503
  CrossrefSearch in Google Scholar
• 6 Baranov VV, Antonova MM, Nelyubina YV, Kolotyrkina NG, Kravchenko AN. Synlett 2017; 28: 669
  Thieme ConnectSearch in Google Scholar
• 7 Kravchenko AN, Antonova MM, Baranov VV, Nelyubina Yu V. Synlett 2015; 26: 2521
  Thieme ConnectSearch in Google Scholar
• 8 Synthesis of 1-Alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils 3 Method 1: To a mixture of the corresponding urea 8b–d (1 mmol), bicyclic compounds 4 or 5 (1 mmol) and MeCN (10 mL) for 4 or MeOH (10 mL) for 5, the hydrochloric acid (0.1 mL, 36.5%) was added. The reaction mixture was heated at reflux with stirring for 20 min (for 4) or 8 h (for 5). The reaction mixture was then cooled and the precipitate was filtered off and washed with a mixture of CHCl₃/H₂O (1:1, 4 mL), and dried in air. Method 2: To a solution of the corresponding urea 9a and 9b (1 mmol) and imidazolinone 10a–d (1 mmol) in MeCN (10 mL), the hydrochloric acid (0.1 mL, 36.5%) was added. The reaction mixture was heated at reflux with stirring for 20 min. The reaction mixture was then cooled and the precipitate was filtered off and washed with a mixture of CHCl₃/H₂O (1:1, 4 mL), and dried in air.
• 9 Analytical Data for 1-Ethyl-6-(2-hydroxyethyl)-3a,6a-diphenyltetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (3a): Yield: 88% (Method 1), 76% (Method 2); white solid; mp 275–277 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.21 (t, J = 6.8 Hz, 3 H, Me), 2.91–3.10 (m, 2 Н, CH₂), 3.11–3.30 (m, 2 Н, CH₂), 3.56–3.73 (m, 2 H, CH₂), 4.79 (t, J = 5.5 Hz, 1 H, OH), 6.75–6.89 (m, 2 H, Ph), 6.92–7.01 (m, 2 Н, Ph), 7.02–7.14 (m, 6 Н, Ph), 8.02 (s, 1 H, NH), 8.12 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.84 (Me), 36.95, 44.68, 59.46 (CH₂), 79.28, 89.91 ((Ph)-C-C-(Ph)), 127.11, 127.41, 127.86, 128.04, 128.42 (Ph), 133.73, 137.45 (C(Ph)), 159.87, 160.30 (C=O). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₂₂N₄O₃Na⁺: 389.1584; found: 389.1580.

• References and Notes

• 1 Kravchenko AN, Baranov VV, Gazieva GA. Russ. Chem. Rev. 2018; 87: 89
  CrossrefSearch in Google Scholar
• 2a Sun S, Edwards L, Harrison P. J. Chem. Soc., Perkin Trans. 1 1998; 437
• 2b Rahimizadeh M, Kam K, Jenkins SI, McDonald RS, Harrison PH. M. Can. J. Chem. 2002; 80: 517
  CrossrefSearch in Google Scholar
• 3a Johnson DW, Palmer LC, Hof F, Iovine PM, Rebek JJr. Chem. Commun. 2002; 2228
  PubMed
• 3b Wu A.-X, Fettiger JC, Isaacs L. Tetrahedron 2002; 58: 9769
  CrossrefSearch in Google Scholar
• 3c Johnson DW, Hof F, Palmer LC, Martin T, Obst U, Rebek JJr. Chem. Commun. 2003; 1638
  PubMed
• 3d Rowan AE, Elemans JA. A. W, Nolte RJ. M. Acc. Chem. Res. 1999; 32: 995
  CrossrefSearch in Google Scholar
• 3e Grotzfeld RM, Branda N, Rebek JJr. Science 1996; 271: 487
  CrossrefPubMedSearch in Google Scholar
• 3f Szabo T, O’Leary BM, Rebek JJr. Angew. Chem. Int. Ed. 1998; 37: 3410
  CrossrefPubMedSearch in Google Scholar
• 3g O’Leary BM, Szabo T, Svenstrup N, Schalley CA, Lützen A, Schäfer M, Rebek JJr. J. Am. Chem. Soc. 2001; 123: 11519
  CrossrefPubMedSearch in Google Scholar
• 3h Rivera JM, Martín T, Rebek JJr. J. Am. Chem. Soc. 2001; 123: 5213
  CrossrefPubMedSearch in Google Scholar
• 3i Nuckolls C, Hof F, Martín T, Rebek JJr. J. Am. Chem. Soc. 1999; 121: 10281
  CrossrefSearch in Google Scholar
• 4a Pryor KE, Rebek JJr. Org. Lett. 1999; 1: 39
  CrossrefSearch in Google Scholar
• 4b Kim HG, Kang JM. Bull. Korean Chem. Soc. 2006; 27: 1791
  Search in Google Scholar
• 4c Kravchenko AN, Baranov VV, Gazieva GA, Chikunov IE, Nelyubina YV. Russ. Chem. Bull. 2014; 63: 416
  CrossrefSearch in Google Scholar
• 4d Kim H, In S, Kang J. Supramol. Chem. 2006; 18: 141
  CrossrefSearch in Google Scholar
• 5a Baranov VV, Antonova MM, Nelyubina YV, Zanin IE, Kravchenko AN, Makhova NN. Mendeleev Commun. 2014; 3: 173
  Search in Google Scholar
• 5b Antonova MM, Baranov VV, Nelyubina YV, Kravchenko AN. Chem. Heterocycl. Compd. 2014; 50: 503
  CrossrefSearch in Google Scholar
• 6 Baranov VV, Antonova MM, Nelyubina YV, Kolotyrkina NG, Kravchenko AN. Synlett 2017; 28: 669
  Thieme ConnectSearch in Google Scholar
• 7 Kravchenko AN, Antonova MM, Baranov VV, Nelyubina Yu V. Synlett 2015; 26: 2521
  Thieme ConnectSearch in Google Scholar
• 8 Synthesis of 1-Alkyl-6-hydroxyalkyl-3a,6a-diphenylglycolurils 3 Method 1: To a mixture of the corresponding urea 8b–d (1 mmol), bicyclic compounds 4 or 5 (1 mmol) and MeCN (10 mL) for 4 or MeOH (10 mL) for 5, the hydrochloric acid (0.1 mL, 36.5%) was added. The reaction mixture was heated at reflux with stirring for 20 min (for 4) or 8 h (for 5). The reaction mixture was then cooled and the precipitate was filtered off and washed with a mixture of CHCl₃/H₂O (1:1, 4 mL), and dried in air. Method 2: To a solution of the corresponding urea 9a and 9b (1 mmol) and imidazolinone 10a–d (1 mmol) in MeCN (10 mL), the hydrochloric acid (0.1 mL, 36.5%) was added. The reaction mixture was heated at reflux with stirring for 20 min. The reaction mixture was then cooled and the precipitate was filtered off and washed with a mixture of CHCl₃/H₂O (1:1, 4 mL), and dried in air.
• 9 Analytical Data for 1-Ethyl-6-(2-hydroxyethyl)-3a,6a-diphenyltetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (3a): Yield: 88% (Method 1), 76% (Method 2); white solid; mp 275–277 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.21 (t, J = 6.8 Hz, 3 H, Me), 2.91–3.10 (m, 2 Н, CH₂), 3.11–3.30 (m, 2 Н, CH₂), 3.56–3.73 (m, 2 H, CH₂), 4.79 (t, J = 5.5 Hz, 1 H, OH), 6.75–6.89 (m, 2 H, Ph), 6.92–7.01 (m, 2 Н, Ph), 7.02–7.14 (m, 6 Н, Ph), 8.02 (s, 1 H, NH), 8.12 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.84 (Me), 36.95, 44.68, 59.46 (CH₂), 79.28, 89.91 ((Ph)-C-C-(Ph)), 127.11, 127.41, 127.86, 128.04, 128.42 (Ph), 133.73, 137.45 (C(Ph)), 159.87, 160.30 (C=O). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₂₂N₄O₃Na⁺: 389.1584; found: 389.1580.

• Supplementary Material