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Synthesis of polysubstituted 5-hydroxyhydantoins via ring-opening of isatins
Tetrahedron Letters 58 (2017) 2468–2474
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of polysubstituted 5-hydroxyhydantoins via ring-opening of isatins Lei Li, Hui Xu, Lirong Yan, Zhongyun Xu, Zhi Ling, Liangce Rong ⇑, Shu-Jiang Tu Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China
a r t i c l e
i n f o
Article history: Received 10 January 2017 Revised 6 May 2017 Accepted 12 May 2017 Available online 15 May 2017 Keywords: 5-Hydroxyhydantoins Isatin Anhydride 1,3-Dimethylurea Tandem reaction
a b s t r a c t A simple and efficient tandem reaction approach was developed for the synthesis of 5-hydroxyhydantoins from one-pot reaction of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (1,3-diethylurea). The products were gained through the ring-opening of isatins process. The advantages of this report are simple operation, mild reaction conditions, good yields and easily available raw materials. It was very important for us to obtain the intermediate product and that provided a solid basis for the correct interpretation of the reaction mechanism. Ó 2017 Elsevier Ltd. All rights reserved.
The hydantoin skeleton is an important structural component that appears in many natural products1–5 and drug structures,6–12 with various activities, such as anticonvulsive,13 antidepressant,14 antiviral,15 or anticoagulant16 and so on. For example, Phenytoin17 was used in treatment of epilepsy disease; Nilutamide18 was a very efficient nonsteroidal, orally active antiandrogen in the therapy of metastatic prostate cancer, which was approved by the FDA in 1996; (+)-hydantocidin19 has herbicidal and plant growth regulatory activities; (R)-5-(4-bromobenzyl)-3-(3,5-dimethylphenyl)1,5-dimethylimidazolidine-2,4-dione6 is a potent antagonists of LFA-1-mediated cell adhesion, which was regarded as potential therapeutic agents in autoimmune diseases; Compound (Z)5-(3-hydroxy-4-methoxybenzylidene)imidazolidine-2,4-dione20 has the efficient inhibitory effect on tyrosinase and melanin; Moreover, the natural product, Exiguamine A21, isolated from the marine sponge Neopetrosia exigua, was found to be the most potent inhibitor of IDO to date. 5-Hydroxyhydantoins were also the crucial derivatives of hydantoin, which was found involving in some inflammatory processes.22 5-Hydroxyhydantoin and 5-methyl-5-hydroxyhydantoin were obtained from oxidative degradation of cytosine and thymine, and have been detected in cancer cells, and that could damage DNA resulting in some mutagenesis and carcinogenesis processes.23 (Fig. 1). Considering the importance of hydantoin derivatives, many synthetic strategies have been reported for the synthesis of these ⇑ Corresponding author. E-mail address: [email protected] (L. Rong). http://dx.doi.org/10.1016/j.tetlet.2017.05.043 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
compounds,24 especially the 5-substituted hydantoin (Figure 1). For example, Murray reported to synthesize 5-substituted and 5,5-disubstituted hydantoins from the corresponding aldehydes or ketones using gallium(III) triflate as catalyst.25 5-Methylenehydantoins could be gained from different synthetic routes via a variety of reactions, such as Dielse-Alder, epoxidation, methanol addition and conjugate addition reactions.26 Meza-León reported to give 5-hydroxy hydantoins from the reaction of a-ketoacids and carbodiimides under visible light conditions.27 Investigating these reported methods, the disadvantages are obvious, such as multi-steps procedures, strong acidic or basic conditions, relatively low yields. Therefore, to develop the new synthetic approaches for the preparation of 5-substituted hydantoins is still an important research subject. Herein, we report a facile route for the syntheses of 5-hydroxyhydantoins form the tandem reactions of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (or 1,3-diethylurea) under mild conditions. As the versatile synthetic material, isatins could be used to synthesize many important compounds.28 In our recent reported reactions, isatins reacted with substitutional acetophenone to give 3-(2-aryl-2-oxoethylidene)indolin-2-one, then it reacted with 1,3dimethylurea and the corresponding polysubstituted imidazole derivatives could be gained with good yields.29 In order to continue the application of isatins in organic synthesis, we use isatin, phthalic anhydride and 1,3-dimethylurea, catalyzed by p-toluenesulfonic acid monohydrate (PTSAH2O) in acetonitrile medium, to our delight, the adventitious product was obtained with high yield.
L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474
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Fig. 1. Some important 5-substituted hydantoins.
Scheme 1. The model reaction of isatin, phthalic anhydride and 1,3-dimethylurea.
Table 1 Screening the reaction conditions.a Entry
Catalyst mol%
Solvent
Time/h
Yielda/%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Et3N (20) C5H11N (20) DBU (20) DMAP (20) K2CO3 NaOH ZnCl2 (20) SnCl22H2O (20) I2 (20) HOAc (20) NH2SO3H (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (30) p-TSAH2O (40) p-TSAH2O (50)
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF Toluene CH3CH2OH DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 5 6 5 5 5
0 0 0 0 0 0 0 0 0 trace 12 51 32 17 41 29 62 83 82 83 84 83
Conditions: isatin 1a (1 mmol), phthalic anhydride 2 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), Temperature (80 °C), Solvent (3 mL). a Isolated yields.
Based on the spectral data (IR, 1H NMR, 13C NMR, and HRMS), we can determine it is polysubstituted 5-hydroxyhydantoins. Under investigation, this is novel process for preparation of 5-hydroxyhydantoins from isatin. Encouraged by this result, we want to synthesize more 5-hydroxyhydantoins compounds. Firstly, we screened the reaction conditions. Isatin 1a, phthalic anhydride 2 and 1,3-dimethylurea 3 were reacted in different solvents used various catalysts to obtain the optimal conditions (Scheme 1). The results were summarized in Table 1. As shown in Table 1, the alkaline catalysts have no catalytic effect on the model reaction (Table 1, entries 1–6), so do the Lewis catalysts (Table 1, entries 7–9). However, Brönsted acids showed the very good catalytic effect on the model reaction, and p-toluenesulfonic acid monohydrate (PTSAH2O) performed particularly outstanding (Table 1, entries 10–12). Subsequently, we mainly study the model reaction under different loading of PTSAH2O, solvents and reaction time conditions (Table 1, entries 13–16). The results showed that the best results could be obtained when the catalyst loading was 20%, acetonitrile as solvent and 5 h reaction time (Table 1, entry 18). From the preferred condition in hand, also for testing the effectiveness of the present method, different isatins were chosen to react with phthalic anhydride and 1,3-dimethylurea under screened condition (Scheme 2), and expected products were
Scheme 2. The reaction of isatin, anhydride, and 1,3-dimethylurea.
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L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474 Table 2 The synthetic results of compounds 4.a
Conditions: isatins 1 (1 mmol), anhydride 2 (1 mmol), 1,3-dimethylurea (or 1,3-diethylurea) 3 (1.5 mmol), Temperature (80 °C), p-TSAH2O (0.2 mmol), CH3CN (3 mL). about 5 h (monitored by TLC). a Isolated yields.
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used to synthesize 5-hydroxyhydantoin derivatives, however, with less active, only four products were obtained. The results were listed in Table 2. The structures of all the products were determined on the basis of spectroscopic data, particularly 1H NMR, 13C NMR analysis and HRMS spectra. Compounds 4a and 4n were chosen as examples to analyze their structures. In 4a 1H NMR, its spectrum revealed a singlet signal at d = 2.29 (3H), 2.50 (3H) ppm due to two methyl groups. The proton signals of 8.02 (d, J = 7.6 Hz, 1H), 7.96–7.94 (m, 1H), 7.92–7.89 (m, 3H), 7.65 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49–7.47 (m, 2H) are eight phenyl protons and one proton of a hydroxyl group. In its 13C NMR, the methyl carbon chemical shifts (2xCH3) appear at 24.5, and 24.2 ppm. The other chemical shifts of 17 carbon atoms show at 171.3, 167.4, 166.6, 154.9, 135.5, 135.3, 135.2, 132.1, 132.0, 131.8, 130.8, 130.2, 130.1, 129.8, 124.0, 123.8, and 84.8, respectively. In 4n 1H NMR, the two methyls chemical shifts appear at 2.48 and 2.88 ppm. Two methylene chemical shifts were found at 2.79–2.69 (m, 2H) and 2.64–2.54 (m, 2H) ppm. The four aromatic hydrogen show at 7.96 (dd, J = 2.4 Hz, 7.2 Hz, 1H), 7.61–7.52 (m, 2H), 7.20 (dd, J = 7.2, 0.2 Hz, 1H) ppm. The hydroxyl group chemical shift appears at 7.47 (s, 1H) ppm. The carbon chemical shifts of methyl and methylene were found at 28.8, 28.7, 24.6, and 24.4, respectively. Other chemical shifts of carbon revealed at 176.8, 176.0, 171.0, 155.3, 133.5, 131.0, 130.8, 130.5, 129.6, 129.6, and 84.6 ppm. Moreover, the structures of 4i and 4n were also confirmed by X-ray diffraction analysis and the crystal structures further prove the structures of the products. The crystal structure 4i and 4n were shown in Figs. 2 and 3. We also studied the possible reaction process. When 5-fluoroisatin 1 and 1,3-dimethylurea 3 were reacted each other catalyzed by PTSA H2O about 3 h, a solid compound 5 was obtained with excellent yield. After the analysis of 1H NMR, we found it was a new product. Subsequently, 5-methylisatin and 5-methoxyisatin were also reacted with 1,3-dimethylurea and corresponding compounds were gained with high yields. Luckily, the crystal of product from 5-methoxyisatin was obtained. With the help of Xray diffraction analysis, we found it was the eutectic crystal of intermediate and PTSA. Interestingly, these intermediates 5 were also the derivatives of 5-hydroxyhydantoin (The data of 5 can be seen in Supplementary information). The results were listed in Table 3. The crystal structure 5c was shown in Fig. 4. In order to further confirm the synthetic route of product 4, we studied the reaction of 5a with succinic anhydride (reaction 1) or phthalic anhydride (reaction 2) in acetonitrile condition. Delightedly, the expected products 4b and 4o were smoothly given with
Fig. 2. The crystal structure of 4i.
Fig. 3. The crystal structure of 4n.
gained with excellent yields. We found the location and nature of substituted groups on isatins had little effect on yields. Then the succinic anhydride was also applied in this synthesis, to our delight, the reactions were carried out smoothly, and corresponding 5-hydroxyhydantoins were gained with good yields. Similarly, the nature and position of the substituents have no effect on the reactions. Further study found that 1,3-diethylurea could be also
Table 3 The reaction of isatins of 1,3-dimethylurea.a
R O
R
O
N H
H 3C
O +
N H
1
N H
SO3H
O HO S +- NH3 O O
CH3 CN
3 F
H 3C O
O
HO N + - NH3
S O O 5a (90%)
O
N O
N
5 CH 3
N
O
H3 C
O
H 3C O
OCH 3
HO N + - NH3
S O O 5b (93%)
O
N
H 3C
O
O
N
HO N + - NH3
S O O 5c (96%)
O
Conditions: isatins 1 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), Temperature (80 °C), p-TSAH2O (1 mmol), CH3CN (3 mL). about 3 h (monitored by TLC). a Isolated yields.
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L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474
Fig. 4. The crystal structure of 5c.
Scheme 3. Testing reactions.
Fig. 5. The plausible reaction mechanism.
82% and 78% yields, respectively (Scheme 3). The facts showed that 5 was the intermediate product of this synthesis. Under the experimental facts, the possible reaction mechanism was provided as follows (Fig. 5): Firstly, in the presence of proton acid PTSA, A reacted with 3 to give intermediate B, then, interme-
diate B loses a proton to obtain intermediate C. Intermediate C takes place a intramolecular cyclization reaction, through domino process of D, E and F, under acidic condition, the eutectic crystal intermediate 5 were gained from first ring-opening of isatin. Then, 5 transferred a proton to succinic anhydride 3 to give intermediate
L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474
G. Subsequently, intermediate H was created from intermediate G, and the second ring-opening of anhydride to give I. The second intramolecular cyclization of I resulted to J. At last, the 5-hydroxyhydantoin was generated after a H2O was lost. In fact, this is a tandem reaction through two times ring-opening and two ring-closing process, and protonic acid PTSA plays an important role in the reaction. In conclusion, a simple and efficient tandem reaction approach was developed for the synthesis of novel 5-hydroxyhydantoins from one-pot reaction of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (1,3-diethylurea). The products were gained through two times ring-opening and two ring-closing process. The advantages of this report were simple operation, mild reaction conditions, good yields and easily available raw materials. It was very important for us to obtain the intermediate product and that provided a solid basis for the correct interpretation of the reaction mechanism. Experimental Melting points were determined on XT-5 microscopic meltingpoint apparatus and were uncorrected. IR spectra were recorded on a FT Bruker Tensor 27 spectrometer. 1H NMR and 13C NMR spectra were obtained from solution in DMSO-d6 with Me4Si as an internal standard using a Bruker-400 spectrometer. HRMS spectra were obtained with a Bruker microTOF-Q 134 instrument. X-ray diffractions were recorded on a Siemens P4 or Simart-1000 diffractometer.
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5-Hydroxy-5-(2-(pyrrolidin-1-yl-2,5-dione)phenyl)-1,3-dimethylhydantoin (4n) Yield: 257 mg (81%); faint yellow solid; m.p.: 231–232 °C. IR (KBr): 3407, 2945, 1717, 1680, 1454, 1376, 1272, 1178, 1065, 994, 883, 824, 789, 760, 721, 669 cm 1. 1H NMR (400 MHz, DMSO-d6): d = 7.98–7.93 (dd, J = 0.8, 0.4 Hz, 1H), 7.61–7.52 (m, 2H), 7.47 (s, 1H), 7.20 (dd, J = 7.2 Hz, 1H), 2.88 (s, 3H), 2.79–2.69 (m, 2H), 2.64–2.54 (m, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d = 176.8, 176.0, 171.0, 155.3, 133.5, 131.0, 130.8, 130.5, 129.6, 129.6, 84.6, 28.8, 28.7, 24.6, 24.4. HRMS (ESI): m/z calcd for C15H15N3O5Na [M+Na]+: 340.0909; found: 340.0912. Acknowledgment We are grateful to National Natural Science Foundation of China (NSFC) (21571087), Natural Science Foundation of Jiangsu Normal University (13XLR005), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Brand Major of Universities in Jiangsu Province (PPZY2015B110) (Sponsored by TAPP) for financial support. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.05. 043. References
General procedures for the synthesis of polysubstituted 5-hydroxyhydantoins General procedures: The mixture of substituted isatins 1 (1 mmol), phthalic anhydride or succinic anhydride 2 (1 mmol), 1,3-dimethylurea (1,3-diethylurea) 3 (1.5 mmol), p-TSAH2O (0.2 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 5 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 4 was purified by recrystallization from EtOH. General procedures for the synthesis of 2-(4-hydroxy-1,3-dimethyl2,5-dioxoimidazolidin-4-yl)benzenaminium 4-methylbenzenesulfonate
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
General procedures: The mixture of substituted isatins 1 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), p-TSAH2O (1 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 3 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 5 was purified by recrystallization from EtOH.
17. 18. 19. 20. 21. 22.
5-Hydroxy-5-(2-(isoindolin-2-yl-1,3-dione)phenyl)-1,3-dimethylhydantoin (4a) Yield: 303.2 mg (83%); faint yellow solid; m.p.:155–157 °C. IR (KBr): 3411, 2946, 1781, 1725, 1451, 1376, 1273, 1162, 1066, 995, 892, 759, 721, 663 cm 1. 1H NMR (400 MHz, DMSO-d6): d = 8.02 (d, J = 7.6 Hz, 1H), 7.96–7.94 (m, 1H), 7.92–7.89 (m, 3H), 7.65 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49–7.47 (m, 2H), 2.50 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d = 171.3, 167.4, 166.6, 154.9, 135.5, 135.3, 135.2, 132.1, 132.0, 131.8, 130.8, 130.2, 130.1, 129.8, 124.0, 123.8, 84.8, 24.5, 24.2. HRMS (ESI): m/z calcd for C19H15N3O5Na [M+Na]+: 388.0909; found: 388.0919.
23. 24.
25. 26. 27. 28.
Meusel M, Gutschow M. Org Prep Proced Int. 2004;36:391. Chevolot L, Padua S, Ravi BN, Blyth PC, Scheuer PJ. Heterocycles. 1977;7:891. Fathiafshar R, Allen TM. Can J Chem. 1988;66:45. Jimenez C, Crews P. Tetrahedron Lett. 1994;35:1375. Chen IS, Chang CT, Sheen WS, et al. Phytochemistry. 1996;41:525. Last-Barney K, Davidson W, Cardozo M, et al. J Am Chem Soc. 2001;123:5643. Jansen M, Potschka H, Brandt C, Loscher W, Dannhardt G. J Med Chem. 2003;46:64. Zha CX, Brown GB, Brouillette WJ. J Med Chem. 2004;47:6519. Thenmozhiyal JC, Wong PTH, Chui WK. J Med Chem. 2004;47:1527. Balog A, Salvati ME, Shan WF, et al. Bioorg Med Chem Lett. 2004;14:6107. Zhang XQ, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui ZH. Bioorg Med Chem Lett. 2006;16:5763. Muccioli GG, Martin D, Scriba GKE, et al. J Med Chem. 2005;48:2509. Metha N, Risinger Dinguid CA, Soroko FE. J Med Chem. 1981;24:465. Wessels FL, Schwan TJ, Pong SF. J Pharm Sci. 1980;69:1102. Bharucha KR, Pavilinis V, Ajdukovic D, Shrenk HM. Ger. Offen. 2,329,745, 1975; Chem. Abstr. 1974, 80, 95948d. Caldwell AG, Harris CJ, Stepney R, Wittaker N. J Chem Soc, Perkin Trans 1. 1980;495. (a) Bosch J, Roca T, Dom&nech J, Suriol M. Bioorg Med Chem Lett. 1859;1999:9; (b) Anger T, Madge DJ, Mulla M, Riddall D. J Med Chem. 2001;44:115. (a) Lamothe M, Lannuzel M, Perez M. J Comb Chem. 2002;4:73; (b) Anderson J. BJU Int. 2003;91:455. Haruyama H, Takayama T, Kinoshita T, Kondo M, Nakajima M, Haneishi T. J Chem Soc, Perkin Trans 1. 1991;1637. Ha YM, Kim J-A, Park YJ, et al. Biochim Biophys Acta. 2011;1810:612. (a) Brastianos HC, Vottero E, Partick BO, et al. J Am Chem Soc. 2006;128:16046; (b) Carr G, Chung MKW, Mauk AG, Andersen RJ. J Med Chem. 2008;51:2634. Lenaga K, Nakamura K, lshii A, Taga T, Miwa Y, Yoneda F. J Chem Soc, Perkin Trans 1. 1989;1153. Le Bihan Y-V, Izquierdo MA, Coste F, et al. Nucleic Acids Res. 2011;39:6277. (a) Ohashi T, Takahashi S, Nagamachi T, Yoneda K, Yamada H. Agric Biol Chem. 1981;45:831; (b) Cativiela C, Fraile JM, García JI, Lázaro B, Mayoral JA, Pallarés A. Appl Catal A. 2002;224:153; (c) Cativiela C, Fraile JM, García JI, L_azaro B, Mayoral JA, Pallarés A. Green Chem. 2003;5:275; (d) Cativiela C, Fraile JM, García JI, Lázaro B, Mayoral JA, Pallarés A. Appl Catal A. 2004;274:9. Murray RS, Whitehead DM, Stratb FL, Stuart J, Conway SJ. Org Biomol Chem. 2008;6:988. Fraile JM, Lafuente G, Mayoral JA, Pallarés A. Tetrahedron. 2011;67:8639. Meza-León RL, Bernès S, Cortés-López GN, Mastranzo VM, Sosa-Rivadeneyra M, Sartillo-Piscil F. Tetrahedron Lett. 2016;57:4232. (a) Tang Z, Liu Z, An Y, et al. J Org Chem. 2016;81:9158; (b) Xu J, Yuan S, Miao M, Chen Z. J Org Chem. 2016;81:11454;
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(c) Qi WJ, Han Y, Yan CG. Tetrahedron. 2016;72:5057; (d) Kumari S, Singh H, Khurana JM. Tetrahedron Lett. 2016;57:3081; (e) Qi WJ, Han Y, Yan C-G. Tetrahedron. 2016;72:5057; (f) Wang ZS, Gao LL, Xu ZY, et al. Tetrahedron. 2017;73:385;
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Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of polysubstituted 5-hydroxyhydantoins via ring-opening of isatins Lei Li, Hui Xu, Lirong Yan, Zhongyun Xu, Zhi Ling, Liangce Rong ⇑, Shu-Jiang Tu Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China
a r t i c l e
i n f o
Article history: Received 10 January 2017 Revised 6 May 2017 Accepted 12 May 2017 Available online 15 May 2017 Keywords: 5-Hydroxyhydantoins Isatin Anhydride 1,3-Dimethylurea Tandem reaction
a b s t r a c t A simple and efficient tandem reaction approach was developed for the synthesis of 5-hydroxyhydantoins from one-pot reaction of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (1,3-diethylurea). The products were gained through the ring-opening of isatins process. The advantages of this report are simple operation, mild reaction conditions, good yields and easily available raw materials. It was very important for us to obtain the intermediate product and that provided a solid basis for the correct interpretation of the reaction mechanism. Ó 2017 Elsevier Ltd. All rights reserved.
The hydantoin skeleton is an important structural component that appears in many natural products1–5 and drug structures,6–12 with various activities, such as anticonvulsive,13 antidepressant,14 antiviral,15 or anticoagulant16 and so on. For example, Phenytoin17 was used in treatment of epilepsy disease; Nilutamide18 was a very efficient nonsteroidal, orally active antiandrogen in the therapy of metastatic prostate cancer, which was approved by the FDA in 1996; (+)-hydantocidin19 has herbicidal and plant growth regulatory activities; (R)-5-(4-bromobenzyl)-3-(3,5-dimethylphenyl)1,5-dimethylimidazolidine-2,4-dione6 is a potent antagonists of LFA-1-mediated cell adhesion, which was regarded as potential therapeutic agents in autoimmune diseases; Compound (Z)5-(3-hydroxy-4-methoxybenzylidene)imidazolidine-2,4-dione20 has the efficient inhibitory effect on tyrosinase and melanin; Moreover, the natural product, Exiguamine A21, isolated from the marine sponge Neopetrosia exigua, was found to be the most potent inhibitor of IDO to date. 5-Hydroxyhydantoins were also the crucial derivatives of hydantoin, which was found involving in some inflammatory processes.22 5-Hydroxyhydantoin and 5-methyl-5-hydroxyhydantoin were obtained from oxidative degradation of cytosine and thymine, and have been detected in cancer cells, and that could damage DNA resulting in some mutagenesis and carcinogenesis processes.23 (Fig. 1). Considering the importance of hydantoin derivatives, many synthetic strategies have been reported for the synthesis of these ⇑ Corresponding author. E-mail address: [email protected] (L. Rong). http://dx.doi.org/10.1016/j.tetlet.2017.05.043 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
compounds,24 especially the 5-substituted hydantoin (Figure 1). For example, Murray reported to synthesize 5-substituted and 5,5-disubstituted hydantoins from the corresponding aldehydes or ketones using gallium(III) triflate as catalyst.25 5-Methylenehydantoins could be gained from different synthetic routes via a variety of reactions, such as Dielse-Alder, epoxidation, methanol addition and conjugate addition reactions.26 Meza-León reported to give 5-hydroxy hydantoins from the reaction of a-ketoacids and carbodiimides under visible light conditions.27 Investigating these reported methods, the disadvantages are obvious, such as multi-steps procedures, strong acidic or basic conditions, relatively low yields. Therefore, to develop the new synthetic approaches for the preparation of 5-substituted hydantoins is still an important research subject. Herein, we report a facile route for the syntheses of 5-hydroxyhydantoins form the tandem reactions of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (or 1,3-diethylurea) under mild conditions. As the versatile synthetic material, isatins could be used to synthesize many important compounds.28 In our recent reported reactions, isatins reacted with substitutional acetophenone to give 3-(2-aryl-2-oxoethylidene)indolin-2-one, then it reacted with 1,3dimethylurea and the corresponding polysubstituted imidazole derivatives could be gained with good yields.29 In order to continue the application of isatins in organic synthesis, we use isatin, phthalic anhydride and 1,3-dimethylurea, catalyzed by p-toluenesulfonic acid monohydrate (PTSAH2O) in acetonitrile medium, to our delight, the adventitious product was obtained with high yield.
L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474
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Fig. 1. Some important 5-substituted hydantoins.
Scheme 1. The model reaction of isatin, phthalic anhydride and 1,3-dimethylurea.
Table 1 Screening the reaction conditions.a Entry
Catalyst mol%
Solvent
Time/h
Yielda/%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Et3N (20) C5H11N (20) DBU (20) DMAP (20) K2CO3 NaOH ZnCl2 (20) SnCl22H2O (20) I2 (20) HOAc (20) NH2SO3H (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (20) p-TSAH2O (30) p-TSAH2O (40) p-TSAH2O (50)
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF Toluene CH3CH2OH DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 5 6 5 5 5
0 0 0 0 0 0 0 0 0 trace 12 51 32 17 41 29 62 83 82 83 84 83
Conditions: isatin 1a (1 mmol), phthalic anhydride 2 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), Temperature (80 °C), Solvent (3 mL). a Isolated yields.
Based on the spectral data (IR, 1H NMR, 13C NMR, and HRMS), we can determine it is polysubstituted 5-hydroxyhydantoins. Under investigation, this is novel process for preparation of 5-hydroxyhydantoins from isatin. Encouraged by this result, we want to synthesize more 5-hydroxyhydantoins compounds. Firstly, we screened the reaction conditions. Isatin 1a, phthalic anhydride 2 and 1,3-dimethylurea 3 were reacted in different solvents used various catalysts to obtain the optimal conditions (Scheme 1). The results were summarized in Table 1. As shown in Table 1, the alkaline catalysts have no catalytic effect on the model reaction (Table 1, entries 1–6), so do the Lewis catalysts (Table 1, entries 7–9). However, Brönsted acids showed the very good catalytic effect on the model reaction, and p-toluenesulfonic acid monohydrate (PTSAH2O) performed particularly outstanding (Table 1, entries 10–12). Subsequently, we mainly study the model reaction under different loading of PTSAH2O, solvents and reaction time conditions (Table 1, entries 13–16). The results showed that the best results could be obtained when the catalyst loading was 20%, acetonitrile as solvent and 5 h reaction time (Table 1, entry 18). From the preferred condition in hand, also for testing the effectiveness of the present method, different isatins were chosen to react with phthalic anhydride and 1,3-dimethylurea under screened condition (Scheme 2), and expected products were
Scheme 2. The reaction of isatin, anhydride, and 1,3-dimethylurea.
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L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474 Table 2 The synthetic results of compounds 4.a
Conditions: isatins 1 (1 mmol), anhydride 2 (1 mmol), 1,3-dimethylurea (or 1,3-diethylurea) 3 (1.5 mmol), Temperature (80 °C), p-TSAH2O (0.2 mmol), CH3CN (3 mL). about 5 h (monitored by TLC). a Isolated yields.
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used to synthesize 5-hydroxyhydantoin derivatives, however, with less active, only four products were obtained. The results were listed in Table 2. The structures of all the products were determined on the basis of spectroscopic data, particularly 1H NMR, 13C NMR analysis and HRMS spectra. Compounds 4a and 4n were chosen as examples to analyze their structures. In 4a 1H NMR, its spectrum revealed a singlet signal at d = 2.29 (3H), 2.50 (3H) ppm due to two methyl groups. The proton signals of 8.02 (d, J = 7.6 Hz, 1H), 7.96–7.94 (m, 1H), 7.92–7.89 (m, 3H), 7.65 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49–7.47 (m, 2H) are eight phenyl protons and one proton of a hydroxyl group. In its 13C NMR, the methyl carbon chemical shifts (2xCH3) appear at 24.5, and 24.2 ppm. The other chemical shifts of 17 carbon atoms show at 171.3, 167.4, 166.6, 154.9, 135.5, 135.3, 135.2, 132.1, 132.0, 131.8, 130.8, 130.2, 130.1, 129.8, 124.0, 123.8, and 84.8, respectively. In 4n 1H NMR, the two methyls chemical shifts appear at 2.48 and 2.88 ppm. Two methylene chemical shifts were found at 2.79–2.69 (m, 2H) and 2.64–2.54 (m, 2H) ppm. The four aromatic hydrogen show at 7.96 (dd, J = 2.4 Hz, 7.2 Hz, 1H), 7.61–7.52 (m, 2H), 7.20 (dd, J = 7.2, 0.2 Hz, 1H) ppm. The hydroxyl group chemical shift appears at 7.47 (s, 1H) ppm. The carbon chemical shifts of methyl and methylene were found at 28.8, 28.7, 24.6, and 24.4, respectively. Other chemical shifts of carbon revealed at 176.8, 176.0, 171.0, 155.3, 133.5, 131.0, 130.8, 130.5, 129.6, 129.6, and 84.6 ppm. Moreover, the structures of 4i and 4n were also confirmed by X-ray diffraction analysis and the crystal structures further prove the structures of the products. The crystal structure 4i and 4n were shown in Figs. 2 and 3. We also studied the possible reaction process. When 5-fluoroisatin 1 and 1,3-dimethylurea 3 were reacted each other catalyzed by PTSA H2O about 3 h, a solid compound 5 was obtained with excellent yield. After the analysis of 1H NMR, we found it was a new product. Subsequently, 5-methylisatin and 5-methoxyisatin were also reacted with 1,3-dimethylurea and corresponding compounds were gained with high yields. Luckily, the crystal of product from 5-methoxyisatin was obtained. With the help of Xray diffraction analysis, we found it was the eutectic crystal of intermediate and PTSA. Interestingly, these intermediates 5 were also the derivatives of 5-hydroxyhydantoin (The data of 5 can be seen in Supplementary information). The results were listed in Table 3. The crystal structure 5c was shown in Fig. 4. In order to further confirm the synthetic route of product 4, we studied the reaction of 5a with succinic anhydride (reaction 1) or phthalic anhydride (reaction 2) in acetonitrile condition. Delightedly, the expected products 4b and 4o were smoothly given with
Fig. 2. The crystal structure of 4i.
Fig. 3. The crystal structure of 4n.
gained with excellent yields. We found the location and nature of substituted groups on isatins had little effect on yields. Then the succinic anhydride was also applied in this synthesis, to our delight, the reactions were carried out smoothly, and corresponding 5-hydroxyhydantoins were gained with good yields. Similarly, the nature and position of the substituents have no effect on the reactions. Further study found that 1,3-diethylurea could be also
Table 3 The reaction of isatins of 1,3-dimethylurea.a
R O
R
O
N H
H 3C
O +
N H
1
N H
SO3H
O HO S +- NH3 O O
CH3 CN
3 F
H 3C O
O
HO N + - NH3
S O O 5a (90%)
O
N O
N
5 CH 3
N
O
H3 C
O
H 3C O
OCH 3
HO N + - NH3
S O O 5b (93%)
O
N
H 3C
O
O
N
HO N + - NH3
S O O 5c (96%)
O
Conditions: isatins 1 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), Temperature (80 °C), p-TSAH2O (1 mmol), CH3CN (3 mL). about 3 h (monitored by TLC). a Isolated yields.
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Fig. 4. The crystal structure of 5c.
Scheme 3. Testing reactions.
Fig. 5. The plausible reaction mechanism.
82% and 78% yields, respectively (Scheme 3). The facts showed that 5 was the intermediate product of this synthesis. Under the experimental facts, the possible reaction mechanism was provided as follows (Fig. 5): Firstly, in the presence of proton acid PTSA, A reacted with 3 to give intermediate B, then, interme-
diate B loses a proton to obtain intermediate C. Intermediate C takes place a intramolecular cyclization reaction, through domino process of D, E and F, under acidic condition, the eutectic crystal intermediate 5 were gained from first ring-opening of isatin. Then, 5 transferred a proton to succinic anhydride 3 to give intermediate
L. Li et al. / Tetrahedron Letters 58 (2017) 2468–2474
G. Subsequently, intermediate H was created from intermediate G, and the second ring-opening of anhydride to give I. The second intramolecular cyclization of I resulted to J. At last, the 5-hydroxyhydantoin was generated after a H2O was lost. In fact, this is a tandem reaction through two times ring-opening and two ring-closing process, and protonic acid PTSA plays an important role in the reaction. In conclusion, a simple and efficient tandem reaction approach was developed for the synthesis of novel 5-hydroxyhydantoins from one-pot reaction of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (1,3-diethylurea). The products were gained through two times ring-opening and two ring-closing process. The advantages of this report were simple operation, mild reaction conditions, good yields and easily available raw materials. It was very important for us to obtain the intermediate product and that provided a solid basis for the correct interpretation of the reaction mechanism. Experimental Melting points were determined on XT-5 microscopic meltingpoint apparatus and were uncorrected. IR spectra were recorded on a FT Bruker Tensor 27 spectrometer. 1H NMR and 13C NMR spectra were obtained from solution in DMSO-d6 with Me4Si as an internal standard using a Bruker-400 spectrometer. HRMS spectra were obtained with a Bruker microTOF-Q 134 instrument. X-ray diffractions were recorded on a Siemens P4 or Simart-1000 diffractometer.
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5-Hydroxy-5-(2-(pyrrolidin-1-yl-2,5-dione)phenyl)-1,3-dimethylhydantoin (4n) Yield: 257 mg (81%); faint yellow solid; m.p.: 231–232 °C. IR (KBr): 3407, 2945, 1717, 1680, 1454, 1376, 1272, 1178, 1065, 994, 883, 824, 789, 760, 721, 669 cm 1. 1H NMR (400 MHz, DMSO-d6): d = 7.98–7.93 (dd, J = 0.8, 0.4 Hz, 1H), 7.61–7.52 (m, 2H), 7.47 (s, 1H), 7.20 (dd, J = 7.2 Hz, 1H), 2.88 (s, 3H), 2.79–2.69 (m, 2H), 2.64–2.54 (m, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d = 176.8, 176.0, 171.0, 155.3, 133.5, 131.0, 130.8, 130.5, 129.6, 129.6, 84.6, 28.8, 28.7, 24.6, 24.4. HRMS (ESI): m/z calcd for C15H15N3O5Na [M+Na]+: 340.0909; found: 340.0912. Acknowledgment We are grateful to National Natural Science Foundation of China (NSFC) (21571087), Natural Science Foundation of Jiangsu Normal University (13XLR005), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Brand Major of Universities in Jiangsu Province (PPZY2015B110) (Sponsored by TAPP) for financial support. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.05. 043. References
General procedures for the synthesis of polysubstituted 5-hydroxyhydantoins General procedures: The mixture of substituted isatins 1 (1 mmol), phthalic anhydride or succinic anhydride 2 (1 mmol), 1,3-dimethylurea (1,3-diethylurea) 3 (1.5 mmol), p-TSAH2O (0.2 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 5 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 4 was purified by recrystallization from EtOH. General procedures for the synthesis of 2-(4-hydroxy-1,3-dimethyl2,5-dioxoimidazolidin-4-yl)benzenaminium 4-methylbenzenesulfonate
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
General procedures: The mixture of substituted isatins 1 (1 mmol), 1,3-dimethylurea 3 (1.5 mmol), p-TSAH2O (1 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 3 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 5 was purified by recrystallization from EtOH.
17. 18. 19. 20. 21. 22.
5-Hydroxy-5-(2-(isoindolin-2-yl-1,3-dione)phenyl)-1,3-dimethylhydantoin (4a) Yield: 303.2 mg (83%); faint yellow solid; m.p.:155–157 °C. IR (KBr): 3411, 2946, 1781, 1725, 1451, 1376, 1273, 1162, 1066, 995, 892, 759, 721, 663 cm 1. 1H NMR (400 MHz, DMSO-d6): d = 8.02 (d, J = 7.6 Hz, 1H), 7.96–7.94 (m, 1H), 7.92–7.89 (m, 3H), 7.65 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49–7.47 (m, 2H), 2.50 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d = 171.3, 167.4, 166.6, 154.9, 135.5, 135.3, 135.2, 132.1, 132.0, 131.8, 130.8, 130.2, 130.1, 129.8, 124.0, 123.8, 84.8, 24.5, 24.2. HRMS (ESI): m/z calcd for C19H15N3O5Na [M+Na]+: 388.0909; found: 388.0919.
23. 24.
25. 26. 27. 28.
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