Tetrabutylammonium Bromide: An Efficient Catalyst for the Synthesis of Xanthenediones under Solvent-free Conditions

Introduction

Xanthene derivatives especially xanthenediones have been attracting great interest because of their importance in synthetic organic chemistry. Many products that contain the subunit of xanthene exhibit use fuland diverse biological activities such as analgesic,¹antiviral,²antibacterial,³ and anti-inflammatory activities.⁴Some of them have been used as antagonist for paralyzing the action of zoxazolamine,⁵ and in photodynamictherapy.⁶ Moreover, they can be use as dyes⁷ and are used extensivelyin laser technology⁸and pH sensitive fluorescent materials for visualization of biomolecules.⁹Many synthetic procedures for preparing xanthenediones have been reported by the  condensation of aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione in the presence of alumina-sulfuric acid,¹⁰Fe₃O₄ nanoparticles,¹¹ Fe³⁺-montmorillonite,¹²ZrOCl₂.8H₂O,¹³succinimide-N-sulfonic acid,¹⁴[Et3NH][HSO4],¹⁵ PMA-SiO₂ ,¹⁶silica sulfuric acid,¹⁷nano Fe₃O₄@SiO₂-SO₃H,¹⁸DSIMHS,¹⁹ and  zinc oxide nanoparticles.²⁰

Although most of these methods offer distinctadvantages, they suffer from certain drawbacks such as high cost, unsatisfactory yields, the use of volatile organic solvents, stoichiometric amount of catalyst, and also environmentally toxic catalyst. Therefore, the search for green and readily available catalyst is still being actively pursed.

In recent years,  tetrabutylammonium  bromide (TBAB) has immerged as an extremely useful homogeneous catalyst invariousorganic transformations,²¹ including conjugate addition of thiols to electron deficient alkenes,²²transthioacetalisation of acetals,²³trimethylsilylation of alcohols,²⁴synthesis of aryl-14H-dibenzo[a, j]xanthenes,²⁵synthesis of biscoumarin and 3,4-dihydropyrano[c]chromene  derivatives,²⁶synthesis of quinazolin-4(3H)-ones,²⁷synthesis of tetrahydrobenzo[b]pyran derivatives,²⁸and synthesis of optically active polyamides.²⁹TBAB is an inexpensive readily available ionic liquid with inherent properties like environmental compatibility, greater selectivity, operational simplicity, non-corrosive nature and ease of reusability. Herein,we wish to report a simple and efficient method for the synthesis of xanthenediones from aromatic aldehydes, 5,5-dimethyl-1, 3-cyclohexane-dione and TBAB as acatalyst under solvent-free conditions(Scheme 1).

Scheme1: TBAB   catalyzed  synthesis  of  xathenediones  Click here to View scheme

 

Experimental

Material and Methods

All  chemical compounds have purchased from Fluka, Romill and Merck companies and used without further purifications. The progress of the reaction was monitored by thin layer chromatography (TLC). Melting points were determined using Buchi B-540 melting point apparatus. FT-IR were recorded by JACSO FT-IR 410 spectrophotometer with KBr plates and ¹H NMR spectra were recorded by Bruker DRX-500 MHz in CDCl₃. Chemical shifts were expressed in δppm.

General procedure for the synthesis of xanthenediones under solvent-free conditions

A mixture of aromatic aldehydes (1 mmol), 5,5-dimethyl-1, 3-cyclohexanedione (2.2 mmol) and TBAT(40 mol%) under solvent-free conditions was heated at 120 °C and stirred for the required time (Table 2). After completion of the reaction, monitored by TLC, the reaction mixture was allowed to cool to room temperature. The crude product was recrystallized from hot ethanol to afford pure product.

Spectral data

3,3,6,6-Tetramethyl-9-(phenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3a): ¹H NMR (CDCl₃, 500 MHz) δ: 1.00 (s, 6H), 1.14 (s, 6H), 2.16-2.26 (q, 4H), 2.47 (s, 4H), 4.76 (s, 1H), 7.09-7.30 (m, 4H). IR (KBr) cm^-1: 2954, 1661, 1364, 1198.

3,3,6,6-Tetramethyl-9-(4-chlorophenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3b): ¹H NMR (CDCl₃, 500 MHz) δ: 0.98 (s, 6H), 1.09 (s, 6H) 2.14-2.24 (q, 4H), 2.45 (s, 4H), 4.7 (s, 1H), 7.16-7.25 (m, 4H). IR (KBr) cm^-1: 2956, 2877, 1662, 1364, 1197, 845.

3,3,6,6-Tetramethyl-9-(3-chlorophenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3c): ¹H NMR (CDCl₃, 500 MHz) δ: 0.99 (s, 6H), 1.09 (s, 6H) 2.15-2.24 (q, 4H), 2.46 (s, 4H), 4.71 (s, 1H), 7.06-7.25 (m, 4H). IR (KBr) cm^-1: 2958, 2877, 1670, 1361, 1192, 1139.

3,3,6,6-Tetramethyl-9-(2-chlorophenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3d): ¹H NMR (CDCl₃, 500 MHz) δ: 1.00 (s, 6H), 1.09 (s, 6H) 2.13-2.23 (q, 4H), 2.43 (s, 4H), 4.98 (s, 1H), 7.04-7.41 (m, 4H). IR (KBr) cm^-1: 2961, 1665, 1526, 1353, 1202.

3,3,6,6-Tetramethyl-9-(4-bromophenyl) -1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3e): ¹H NMR (CDCl₃, 500 MHz) δ: 0.97 (s, 6H), 1.09 (s, 6H) 2.01-2.21 (q, 4H), 2.45 (s, 4H), 4.68 (s, 1H), 7.15-7.32 (m, 4H). IR (KBr) cm^-1: 2955, 1662, 1363, 1196.

3,3,6,6-Tetramethyl-9-(3-bromophenyl) -1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3f): ¹H NMR (CDCl₃, 500 MHz) δ: 1.00 (s, 6H), 1.1 (s, 6H) 2.16-2.26 (q, 4H), 2.46 (s, 4H), 4.7 (s, 1H), 7.08-7.35 (m, 4H), 8.07-8.09 (d, 2H) IR (KBr) cm^-1: 2953, 1668, 1362, 1201.

3,3,6,6-Tetramethyl-9-(2-bromophenyl) -1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3g): ¹H NMR (CDCl₃, 500 MHz) δ: 1.01 (s, 6H), 1.09 (s, 6H) 2.13-2.22 (q, 4H), 2.44 (s, 4H), 5.01 (s, 1H), 6.94-7.44 (m, 4H). IR (KBr) cm^-1: 2954, 1668, 1359, 1202, 1014, 742.

3, 3, 6, 6-Tetramethyl-9-(4-nitro-Phenyl)-1, 8- dioxo-1,2,3,4,5,6,7,8-octahydroxanthene (3h): ¹H NMR (CDCl₃, 500 MHz) δ: 0.98 (s, 6H), 1.11 (s, 6H) 2.14-2.26 (q, 4H), 2.44 (s, 4H), 4.81 (s, 1H), 7.46-7.48 (d, 2H), 8.07-8.09 (d, 2H). IR (KBr) cm^-1: 2957, 1660, 1518, 1353, 1201.

3, 3, 6, 6-Tetramethyl-9-(3-nitro-Phenyl)-1, 8- dioxo-1,2,3,4,5,6,7,8-octahydroxanthene (3i):¹H NMR (CDCl₃, 500 MHz) δ: 0.99 (s, 6H), 1.11 (s, 6H) 2.01-2.26 (q, 4H), 2.50 (s, 4H), 4.83 (s, 1H), 7.25-8.00 (m, 4H). IR (KBr) cm^-1: 2960, 1664, 1526, 1353, 1200.

3, 3, 6, 6-Tetramethyl-9-(2-nitro-Phenyl)-1, 8- dioxo-1,2,3,4,5,6,7,8-octahydroxanthene (3j):¹H NMR (CDCl₃, 500 MHz) δ: 0.99 (s, 6H), 1.08 (s, 6H) 2.13-2.23 (q, 4H), 2.45 (s, 4H), 5.5 (s, 1H), 7.21-7.75 (m, 4H). IR (KBr) cm^-1: 2957, 1660, 1518, 1353, 1201.

3,3,6,6-Tetramethyl-9-(3-methoxy phenyl )-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3k): ¹H NMR (CDCl₃, 500 MHz) δ: 0.99 (s, 6H), 1.07 (s, 6H) 2.11-2.26 (q, 4H), 2.44-2.46 (q, 4H), 3.71 ( s, 3H), 4.81 (s, 1H), 6.69-7.35 (m, 4H). IR (KBr) cm^-1: 2956, 1664, 1366, 1199.

3,3,6,6-Tetramethyl-9-(2-methoxy phenyl )-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3l): ¹H NMR (CDCl₃, 500 MHz) δ: 0.93 (s, 6H), 1.07 (s, 6H) 2.09-2.21 (q, 4H), 2.44-2.46 (q, 4H), 3.76 ( s, 3H), 4.84 (s, 1H), 6.73-7.41 (m, 4H). IR (KBr) cm^-1: 2951, 1666, 1361, 1197, 754.

3,3,6,6-Tetramethyl-9-(4-fluoro phenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3m): ¹H NMR (CDCl₃, 500 MHz) δ: 0.98 (s, 6H), 1.09 (s, 6H) 2.14-2.24 (q, 4H), 2.45 (s, 4H), 4.71 (s, 1H), 6.86-7.25 (m, 4H). IR (KBr) cm^-1: 2958, 1660, 1527, 1365, 1197, 845.

3,3,6,6-Tetramethyl-9-(4-hydroxy phenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3n): ¹H NMR (CDCl₃, 500 MHz) δ: 0.98 (s, 6H), 1.08 (s, 6H) 2.14-2.24 (q, 4H), 2.44 (s, 4H), 4.66 (s, 1H), 6.58-7.25 (m, 4H). IR (KBr) cm^-1: 3358, 2960, 2868, 1660, 1363, 1200.

3,3,6,6-Tetramethyl-9-(2-thienyl)-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydroxanthene (3o): ¹H NMR (CDCl₃, 500 MHz) δ: 1.99 (s, 6H), 1.02 (s, 6H) 2.25 (s, 4H), 2.44 (s, 4H), 5.14 (s, 1H), 6.81-7.25 (m, 3H). IR (KBr) cm^-1: 2956, 2875, 1665, 1363, 1199.

Results and Discussion

During initial exploratory reaction, condensation of benzaldehyde and 5,5-dimethyl-1, 3-cyclohexanedione were taken as a model reaction to establish the feasibility of our strategy and to optimize reaction conditions, the results of which are summarized in Table 1. As expected, the catalytic system is influenced by various reaction parameters such as amounts of the catalyst employed  (entries  1-4), effect of temperature(entries  4,5), amount of 5,5-dimethyl-1, 3-cyclohexanediones (entries  6) and solvent system(entries  7-11). Through thorough investigation, the best result in 92% yield was obtained by carrying out the reaction with  1:2.2 mol ratios of benzaldehyde and 5,5-dimethyl-1, 3-cyclohexanedione at 120°C and the dosage of 40 mol% catalyst for 8h under solvent-free conditions.

Encouraged by the remarkable results obtained with the above reaction conditions and in order to show the generality and scope of this new protocol,we performed the reaction with a variety of aromatic aldehydes with different  substituents.  The results are shown in Table 2.   From  the results, we found that all aromatic aldehydes carrying either electron-donating or electron-withdrawing group substituents reacted efficiently to give excellent yields.  The  high  yield  was also obtained in the case of the heterocyclic aldehyde (Table 2,  entry 16). The desired products were characterized by ¹H NMR, infrared(IR), melting points and also, by comparison with authentic samples.

Table1: The reaction of benzaldehyde and 5.5-dimethyl-1,3-cyclohexanedione under different reaction conditions^a

Entry	Solvent	Amount of catalyst (mol%)	Temperature (°c)	Yield b
1	None	10	120	–
2	None	20	120	–
3	None	30	120	82
4	None	40	120	85
5	None	40	100	–
6	None	40	120	92c
7	H2O	40	Reflux	–
8	CHCl3	40	Reflux	–
9	CH2Cl2	40	Reflux	–
10	EtOH	40	Reflux	20
11	EtOAC	40	Reflux	50

 

^aReaction conditions: benzaldehyde (1 mmol), 5,5-dimthyl-1,3-cyclohexanedione (2 mmol)

^bIsolated yield

^cReaction conditions: benzaldehyde (1 mmol), 5.5-dimethyl-1,3-cyclohexandione ( 2.2 mmol), 8h

Table2: The synthesized of xanthenediones catalyzed by TBAB

Entry	Ar	Product	Time (h)	Yield (%)	M.P. (°C)
					Found             Reportedref
1	C6H5	3a	8	92	202-204	205-20630
2	4-ClC6H4	3b	5	96	228-230	231-23319
3	3-ClC6H4	3c	6	97	180-182	179-18113
4	2-ClC6H4	3d	8	92	226-228	227-22819
5	4-BrC6H4	3e	4.5	94	238-239	240-24219
6	3-BrC6H4	3f	8	97	188-190	189-19119
7	2-BrC6H4	3g	8	90	226-228	226-22931
8	4-NO2C6H4	3h	5	97	225-227	222-22419
9	3-NO2C6H4	3i	9	97	167-169	171-17218
10	2-NO2C6H4	3j	8	70	256-258	250-25618
11	3-MeOC6H4	3k	10	96	164-166	161-16332
12	2-MeOC6H4	3l	12	85	253-255	257-25833
13	4-FC6H4	3m	10	95	223-225	221-22319
14	4-OHC6H4	3n	18	90	243-245	245-24719
15	C4H3S	3p	15	90	158-161	163-16510

^aIsolated  yield

Conclusion

In conclusion, we have explained an efficient method for the synthesis of xanthenediones catalyzed by TBAB as an inexpensive and readily available ionic liquid.The methodology has the advantages of high yield, lack of organic solvent, and easy work up for separation of products.

Acknowledgment

The authors are thankful to the Islamic Azad University of Central Tehran Branch for the support of this project.

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