Der Pharmacia Lettre

[DBN][HSO4]-Promoted Facile and Green Synthesis of Xanthene Derivatives via Knoevenagel Condensation

Vitthal Vinayaka^* and Santosh M. Surwase Department of Chemistry, University of Shri Chhatrapati Shivaji, Maharashtra, India
^*Corresponding Author:
Vitthal Vinayaka, Department of Chemistry, University of Shri Chhatrapati Shivaji, Maharashtra, India, Tel: (91)7899250177, Email: dhole99@gmail.com

, Citations: Vinayaka, Vitthal, Surwase Santosh M, [DBN][HSO₄]-Promoted Facile and Green Synthesis of Xanthene Derivatives via Knoevenagel Condensation. Der Pharm Lett 13 (2021): 49-583 ,
Copyright: © 2021 Vitthal. V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Introduction

Xanthenes derivatives have been investigated for a wide range of pharmacologic indications such as potent antiviral, antimalarial, analgesic, antimicrobial, anticancer, anti-inflammatory, antioxidant, antiproliferative activity, urease activity, BMP-2 targeted osteogenic agents, trypanothione reductase (TryR) inhibition, selective estrogen receptor modulators selective positive allosteric modulators of the δ-opioid receptor. Additionally, some of the xanthene derivatives are used as antagonists for paralyzing the action of oxalamine, in laser technology, dyes, as bactericides in agriculture, and number of natural products accommodates the xanthenes nucleus. The structures of representative compounds (Figure 1) [1].

Ionic liquids (ILs) have attracted interest as environmentally benign media for catalysis, synthesis, separation, adjustable physical and chemical properties. ILs includes numerous exclusive properties, such as extensive liquid range, nonvolatility, low toxicity, high thermal stability, noncombustible, excellent solubility, and recyclability. ILs act as “neoteric solvents” for a wide range of industrial and chemical processes. In recent times, ILs has been originating to be valuable as environmental friendly media for countless organic revolutions. Thus, the introduction of a dynamic, inexpensive, mild, and environmental friendly catalyst for significant cyclization reaction superior to analogues of pharmaceutical and biological prominence is in demand.

Thus, the extension of synthetic strategies for the construction of this molecule using an economical, reusable, mild, and nontoxic catalyst is of massive importance from the industrial and academic points of view. Even though various modes have been reported in the literature, these reactions can be accomplished under a variability of tentative conditions, and several improvements have been reported in recent years, such as sulfuric acid or hydrochloric acid, silica sulfuric acid, sulfamic acid, p-dodecylbenzenesulfonic acid, boric acid, pTSA, NaHSO₄-SiO₂, TiO₂-SO4₂ molecular iodine, amberlyst cyanuric chloride, core/shell Fe₃O₄@GA@isinglass, Feþ3 montmorillonite, FeCl₃/[bmim] [BF4], [Hmim]Tfa, SmCl₃, trimethylsilyl chloride (TMSCl), acyclic acidic ionic liquids and InCl₃/ionic liquid [2].

However, numerous of these testified methods become infected with several disadvantages such as strong acidic conditions, use of hazardous or costly reagents, long reaction times, low yields of products, and sophisticated treatment. Moreover, many of these schemes utilize organic solvents as the reaction medium. Hence, the further innovation toward contemporary reaction with easy isolation of product, reusability of catalyst, perhaps with minimal or no waste is highly attractive. Recently, DBN was widely used as catalysts in different research area. The combination of DBN with cation to give the formation of novel ionic liquids. The large number of functionalized ILs has been considered for diverse purposes. ILs have been deemed as environment friendly substitutes and recyclable for volatile organic solvents attributing to their good-looking thermal and chemical stability, negligible vapour pressure, high ionic conductance and non-flammability. Due to this wide range of applications, they are used as a suitable solvent for wide array of synthetic protocols. The synthesis of this ionic liquid via assembling the zwitterionic precursors to these functionalized acidic -SO3H ionic liquid.

As per our investigation, the existential of this work is to begin a rapid and efficient synthetic protocol for obtaining xanthene derivatives under ecofriendly conditions. As an extension of emerging economic and efficient strategy to develop pharmaceutically and biologically significant molecules, herein, we reported synthesis of library of xanthene derivatives promoted by synergistic effect of ionic liquid without any added catalyst in good to excellent yields [3].

Experimental Section

Materials and methods

All of the reagents used were of laboratory grade. Melting points of all of the synthesized analogues were resolute in an open capillary tube and are uncorrected. The progress of the reaction was monitored by thin-layer chromatography on Merck’s silica plates, and imagining was accomplished by iodine/ultraviolet light. 1H NMR spectra were recorded with a Bruker AvIII HD-400 MHz spectrometer operating at 400 MHz using DMSO solvent and tetramethylsilane (TMS) as the internal standard and chemical shift in δ ppm. Mass spectra were recorded on a Waters UPLCTQD (ESI-MS and APCI-MS) instrument, and elemental analysis was recorded on the CHNS auto-analyzer (Thermo Fischer EA1112 SERIES). Chemical shifts (δ) are reported in parts per million using TMS as an internal standard. The splitting pattern abbreviations are designed as singlet (s); doublet (d); double doublet (dd); bs (broad singlet), triplet (t); quartet (q); and multiplets (m) [4].

Preparation of [DBN] [HSO₄]

General Procedure for the Synthesis of [DBN] [HSO₄] is given in supporting information.

General procedure for synthesis of xanthene derivatives

A mixture of aldehyde (1a) (1 mmol) and dimedone (1 mmol) in [DBN] [HSO₄] 20 mol% was stirred at 80^οC; the evolution of reaction was supervised by thin-layer chromatography [ethyl acetate/n-hexane (3:7)] as a solvent after a stirring reaction mixture was cooled for 15 min and a poured on crushed ice. Thus, acquired solid was filtered, dried, and purified by crystallization using ethanol as a solvent. The synthesis compound is confirmed by MP, ¹H NMR and ¹³C NMR spectra [5].

3,3,6,6-tetramethyl-9-phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3a)

The compound 3a was synthesized from condensation reaction 1a and 2 as white solid;

Mp: 204-205οC; Yield: 93%; ¹H NMR (500 MHz, cdcl3) δ 11.94 (s, 1H), 7.28 (t, J=7.6 Hz, 2H), 7.22-7.10 (m, 3H), 5.63 (d, J=60.1 Hz, 1H), 2.66-2.12 (m, 9H), 1.16 (dd, J=64.4, 29.0 Hz, 12H); ¹³C NMR (101 MHz, cdcl3) δ 196.66, 165.08, 144.17, 136.06, 130.50, 128.52, 120.85, 51.42, 43.24, 33.44, 32.35, 30.57 and 30.34 [6].

3,3,6,6-tetramethyl-9-(p-tolyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3c)

The compound 3c was synthesized from condensation reaction 1c and 2 as yellow solid;

Mp: 232-233^οC; Yield: 92%; ¹H NMR (400 MHz, cdcl₃) δ 7.15 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.6 Hz, 2H), 4.69 (s, 1H), 2.44 (s, 4H), 2.21 (s, 3H), 2.18-2.08 (m, 4H), 1.07 (s, 6H), 0.96 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 197.37, 163.18, 142.22, 136.62, 129.72, 129.21, 116.68, 78.34, 77.86, 51.76, 41.82, 33.14, 32.41, 30.24, 28.32 and 22.03 [8].

9-(3-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3d)

The compound 3d was synthesized from condensation reaction 1d and 2 as yellow solid;

Mp: 162-163^οC; Yield: 88%; ¹H NMR (400 MHz, cdcl₃) δ 7.04 (t, J=8.3 Hz, 1H), 6.80 (d, J=6.8 Hz, 2H), 6.57 (d, J=7.2 Hz, 1H), 4.68 (s, 1H), 3.67 (s, 3H), 2.41 (s, 4H), 2.12 (q, J=16.4 Hz, 4H), 1.02 (s, 6H), 0.92 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 197.27, 163.34, 160.27, 146.69, 129.78, 121.73, 116.43, 115.27, 112.79, 56.02, 51.71, 41.76, 33.10, 32.74, 30.20, 28.30 [9].

9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3e)

The compound 3e was synthesized from condensation reaction 1e and 2 as yellow solid;

Mp: 250-251^οC; Yield: 93%; ¹H NMR (400 MHz, cdcl₃) δ 7.24-7.10 (m, 2H), 6.71 (dd, J=5.9, 2.7 Hz, 2H), 4.66 (s, 1H), 3.69 (d, J=4.8 Hz, 3H), 2.43 (s, 4H), 2.24 – 2.09 (m, 4H), 1.06 (s, 6H), 0.95 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 197.41, 163.06, 158.91, 137.48, 130.26, 116.73, 114.42, 56.06, 51.75, 41.82, 33.15, 31.93, 30.24 and 28.30.

9-(3,4-dimethoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3f)

The compound 3f was synthesized from condensation reaction 1f and 2 as yellow solid;

Mp: 201-202^οC; Yield: 90%; ¹H NMR (400 MHz, cdcl₃) δ 6.89 (s, 1H), 6.72 (td, J=8.3, 4.4 Hz, 2H), 4.69 (s, 1H), 3.84 (d, J=1.7 Hz, 3H), 3.78 (d, J=1.8 Hz, 3H), 2.45 (s, 4H), 2.28 – 2.10 (m, 4H), 1.09 (s, 6H), 0.99 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ191.86, 169.54, 155.65, 153.88, 142.69, 133.63, 128.25, 127.62, 121.81, 56.49, 55.62, 51.17, 43.14, 33.88, 31.97, 30.30 and 28.14 [10].

3,3,6,6-tetramethyl-9-(3-nitrophenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3g)

The compound 3g was synthesized from condensation reaction 1g and 2 as red solid;

Mp: 170-171^οC; Yield: 84%; ¹H NMR (400 MHz, cdcl₃) δ 8.07 –7.91 (m, 2H), 7.79 (d, J=6.7 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 4.82 (s, 1H), 2.50 (s, 4H), 2.20 (q, J=16.4 Hz, 4H), 1.10 (s, 6H), 0.98 (s, 6H), ¹³C NMR (101 MHz, cdcl₃) δ 198.43, 168.97, 148.57, 142.41, 132.54, 129.55, 128.29, 126.83, 121.69, 52.95, 42.61, 33.98, 32.26, 30.52 and 28.15.

9-(3-iodophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3h)

The compound 3h was synthesized from condensation reaction 1h and 2 as pale yellow solid;

Mp: 275-276^οC; Yield: 85%; ¹H NMR (400 MHz, cdcl₃) δ 7.54 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 6.95 (t, J=7.8 Hz, 1H), 4.66 (s, 1H), 2.46 (s, 4H), 2.30 – 2.10 (m, 4H), 1.09 (s, 6H), 1.00 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 192.02, 166.84, 141.47, 133.58, 130.03, 128.62, 128.37, 124.88, 113.50, 51.46, 42.60, 34.02, 31.97, 30.21 and 28.43 [11].

9-(4-bromophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3i)

The compound 3i was synthesized from condensation reaction 1i and 2 as red solid;

Mp: 259-260^οC; Yield: 87%; ¹H NMR (400 MHz, cdcl₃) δ 7.34 (d, J=6.8 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 4.70 (s, 1H), 2.47 (s, 4H), 2.21 (q, J=16.5 Hz, 4H), 1.11 (s, 6H), 0.99 (s, 6H). ¹³C NMR (101 MHz, cdcl₃) δ 197.27, 163.42, 144.19, 132.10, 131.12, 121.19, 116.15, 78.33, 78.01, 77.69, 51.66, 41.82, 33.16, 32.53, 30.22 and 28.27.

9-(4-chlorophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3j)

The compound 3j was synthesized from condensation reaction 1 and 2j as yellow solid;

Mp: 234-235^οC; Yield: 91%; ¹H NMR (400 MHz, cdcl₃) δ 7.25 (d, J=8.5 Hz, 2H), 7.22 – 7.15 (m, 2H), 4.72 (s, 1H), 2.48 (s, 4H), 2.20 (q, J=16.4 Hz, 4H), 1.11 (s, 6H), 0.99 (s, 6H). ¹³C NMR (101 MHz, cdcl₃) δ 197.29, 163.45, 143.71, 132.94, 130.75, 129.14, 116.19, 78.38, 78.06, 77.74, 51.67, 41.80, 33.15, 32.44, 30.22 and 28.25.

9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3k)

The compound 3k was synthesized from condensation reaction 1k and 2 as red solid;

Mp: 244-245^οC; Yield: 85%; ¹H NMR (400 MHz, cdcl₃) δ 7.32 (s, 1H), 7.07 (d, J=7.9 Hz, 2H), 6.55 (d, J=7.9 Hz, 2H), 4.67 (s, 1H), 2.47 (s, 4H), 2.22 (q, J=16.4 Hz, 4H), 1.09 (s, 6H), 1.00 (s, 6H). ¹³C NMR (101 MHz, cdcl₃) δ 198.31, 163.46, 155.71, 136.48, 130.30, 116.86, 116.24, 51.73, 41.82, 33.24, 31.94, 30.12 and 28.36 [12].

9-cyclohexyl-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3l)

The compound 3l was synthesized from condensation reaction 1l and 2 as white solid;

Mp: 178-179^οC; Yield: 85%; ¹H NMR (400 MHz, cdcl₃) δ 7.68 (s, 2H), 5.47 (s, 1H), 3.32 (s, 2H), 2.51 (s, 4H), 2.24 (s, 4H), 1.23 (s, 1H), 1.04 (d, J=18.0 Hz, 12H); ¹³C NMR (101 MHz, cdcl₃) δ 194.31, 166.55, 112.78, 51.44, 41.72, 35.52, 34.02, 32.26, 30.21, 28.43, 26.94, 25.53, 24.22, 24.16 and 24.08

Conclusion

In conclusion, an environmentally and highly efficient green methodology has been established for the synthesis of functionalized xanthene derivatives using an inexpensive and recoverable [DBN] [HSO₄] catalytic solvent-free in 45 min. This, to the best of our knowledge, has no examples. This reaction scheme exposes a number of advantages, such as uniqueness, high atom efficiency, mild reaction conditions, clean reaction profiles, easy workup procedure and Eco friendliness. Furthermore, the prevention of hazardous organic solvents during the entire procedure (synthesis, ionic liquid preparation, and workup procedure) makes it a convenient and attractive method for the synthesis of these important compounds.

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Citation: Vinayaka, Vitthal, Surwase Santosh M, [DBN][HSO₄]-Promoted Facile and Green Synthesis of Xanthene Derivatives via Knoevenagel Condensation. Der Pharm Lett 13 (2021): 49-583

Copyright: © 2021 Vitthal. V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.