Brønsted Acidic Ionic Liquid as an Efficient and Reusable Catalyst for Synthesis of 14-Aryl- or 14-Alkyl-14H-dibenzo[a,j]xanthenes under Solvent-Free Conditions

LETTER 741

Brønsted Acidic Ionic Liquid as an Efficient and Reusable Catalyst for Synthesis of 14-Aryl- or 14-Alkyl-14H-dibenzo[a,j]xanthenes under Solvent-Free Conditions

Synthesis of 14H-Dibenzo[a,j]xanthenes under Solvent-Free Conditions

Abdol R. Hajipour,*

^a,b

Yosof Ghayeb,

^b

Nafisehsadat Sheikhan,

^b

Arnold E. Ruoho

^a

a Department of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue, Madison 53706-1532, WI, USA

b Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran Fax +98(311)3912350; E-mail: haji@cc.iut.ac.ir

Received 8 June 2009

SYNLETT 2010, No. 5, pp 0741–074416.3.2010 Advanced online publication: 17.02.2010 DOI: 10.1055/s-0029-1219399; Art ID: S06309ST

© Georg Thieme Verlag Stuttgart · New York

Abstract: A mild and efficient method has been developed for the preparation of 14-aryl- or 14-alkyl-14H-dibenzo[a,j]xanthenes from one-pot condensation of aldehydes with 2-naphthol using cat- alytic amount of Brønsted acidic ionic liquid ([TEBSA][HSO₄]) un- der thermal solvent-free conditions. Excellent yields, short reaction times, easy workup and reusability of the catalyst as well as solvent- free conditions are advantages of this procedure.

Keywords: [TEBSA][HSO₄], Brønsted acidic ionic liquid, xan- thenes, solvent-free, one-pot

Xanthene derivatives due to large number of biological and pharmacological properties like antibacterial,

¹

antiviral

²

and anti-inflammatory

³

have received a great deal of attention. These compounds have also been used as dyes,

^4,5

in laser technology,

⁶

in fluorescent materials for visualization of biomolecules

⁷

and in photodynamic therapy.

⁸

Thus, the synthesis of xanthene derivatives (es- pecially benzoxanthenes) is very important. Different pro- cedures have been reported for the preparation of xanthene derivatives such as the reaction of aryloxymag- nesium halides with triethylorthoformate,

⁹

trapping of benzynes by phenols

¹⁰

and the reaction of 2-naphthol with 2-naphthol-1-methanol,

¹¹

formamide,

¹²

carbon monox- ide.

¹³

In addition, 14H-dibenzo[a,j]xanthenes have been synthesized by the one-pot condensation of 2-naphthol with aldehydes in the presence of various catalysts such as Yb(OTf)

₃

,

¹⁴

NH

₄

H

₂

PO

₄

–SiO

₂

,

¹⁵

sulfamic acid,

¹⁶

Am- berlyst-15,

¹⁷

HClO

₄

–SiO

₂

,

¹⁸

I

₂

,

¹⁹

cyanuric chloride,

²⁰

BF

₃

·SiO

₂²¹

and alum.

²²

However, some of these proce- dures have disadvantages including long reaction times, the use of toxic and volatile catalysts and solvents, excess reagents, special apparatus and harsh reaction conditions.

Accordingly, the development of new and green methods for convenient preparation of dibenzoxanthenes is very at- tractive.

In recent years, ionic liquids have been widely used in many reactions as catalyst or dual catalyst–solvent

^23,24

be- cause of their specific properties like undetectable vapor pressure, wide liquid range, reusability and high thermal stability.

^25,26

Brønsted acidic ionic liquids consist of help-

ful characteristics of solid acids and mineral liquid acids, and are designed to replace customary mineral liquid ac- ids like sulfuric acid and hydrochloric acid in chemical procedures.

^27,28

N-(4-Sulfonic acid) butyl triethyl ammo- nium hydrogen sulfate ([TEBSA][HSO

₄

]) has been syn- thesized and applied as an effective and reusable catalyst for estrification of various alcohols by different acids

²⁹

and nitration of aromatic compounds.

³⁰

In continuation of our investigations on the development of new synthetic methodologies,

^31,32

we herein report a new, convenient, mild and efficient procedure for the syn- thesis of 14-aryl- or 14-alkyl-14H-dibenzo[a,j]xanthenes from one-pot condensation of various aldehydes with 2- naphthol in the presence of [TEBSA][HSO

₄

] as an effec- tive and recoverable catalyst under solvent-free condi- tions (Scheme 1).

Scheme 1

Initially to optimize the amount of ionic liquid, the reac- tion of 2-naphthol (1 mmol) and 3-nitrobenzaldehyde (1 mmol) was performed under solvent-free conditions at 120 °C in the presence of different quantities of [TEBSA]

[HSO

₄

] (Table 1). As shown in Table 1, the yield of prod-

RCHO

OH

+ 15 mol% IL

120 °C, solvent-free

1 2 3

R = Ph, aryl and alkyl

O R

IL = Et3N⁺CH2(CH2)2CH2SO3HHSO4–

Table 1 Effect of Temperature and Different Amounts of [TEBSA]

[HSO₄] on the Reaction of 2-Naphthol with 3-Nitrobenzaldehyde Entry [TEBSA][HSO₄]

(mmol)

Temp (°C)

Time (min)

Yield of 3f (%)^a

1 0.2 120 5 85

2 0.15 120 5 91

3 0.1 120 5 84

4 0.05 120 5 75

5 0.025 120 5 60

6 0.15 100 10 83

a Isolated yields.

742 A. R. Hajipour et al. LETTER

Synlett 2010, No. 5, 741–744 © Thieme Stuttgart · New York

uct 3f in the presence of 0.15 mmol of [TEBSA][HSO

₄

] gave the best yields. (Table 1, entries 1–5). Therefore 15 mol% of ionic liquid was chosen as the best quantities of [TEBSA][HSO

₄

]. This reaction was also carried out at 100 °C, but the reaction time was longer and the yield of product 3f was lower (Table 1, entry 6).

Thus, we employed 15 mol% of ionic liquid for one-pot synthesis of 14-aryl- or 14-alkyl-14H-dibenzo[a,j]xan- thenes from various aldehydes and 2-naphthol under sol- vent-free conditions at 120 °C (Table 2). Aldehydes reacted with 2-naphthol to produce the corresponding 14- aryl- or 14-alkyl-14H-dibenzo[a,j]xanthenes in high to excellent yields and very short reaction times. It was ob- served that aromatic aldehydes with electron-withdrawing substituents were converted to the corresponding xan- thenes in higher yields and shorter reaction times than those with electron-donating substituents. It should be mentioned that sterically hindered benzaldehyde like 2,6- dichlorobenzaldehyde was converted to 14-(2,6-dichlo- rophenyl)-14H-dibenzo[a,j]xanthene in a reasonably high

yield (Table 2, entry 4). Also, aliphatic aldehydes were employed and the corresponding xanthenes were obtained in good yields with longer reaction times (Table 2, entries 13–16). When pyridine-2-carbaldehyde and pyridine-3- carbaldehyde were used, the yields of the products were moderate (Table 2, entries 17 and 18).

The reusability of the [TEBSA][HSO

₄

] was also investi- gated. After each run, water was added to the reaction mixture and the product was filtered and the ionic liquid in the aqueous phase was extracted with CH

₂

Cl

₂

three times. Then the water was evaporated and the catalyst was dried at 65 °C under reduced pressure for two hours and reused in the reaction of 3-nitrobenzaldehyde and 2-naph- thol under solvent-free conditions at 120 °C (Table 3, en- tries 1–5). The results demonstrate that the catalyst can be employed five times, although the activity of the catalyst gradually decreased. This shows that Brønsted acidic ion- ic liquid ([TEBSA][HSO

₄

]) is an effective and recyclable catalyst for the synthesis of 14-aryl- or 14-alkyl-14H- dibenzo[a,j]xanthenes.

Table 2 One-Pot Synthesis of 14-Aryl- or 14-Alkyl-14H-dibenzo[a,j]xanthenes in the Presence of Brønsted Acidic Ionic Liquid at 120 °C under Solvent-Free Conditions^a

Entry Aldehyde R Product Time (min) Yield (%)^b Mp (°C)

Found Reported^ref.

1 Ph 3a 8 86 184–186 184–185²¹

2 2-ClC₆H₄ 3b 5 92 216–217 214–216²¹

3 4-ClC₆H₄ 3c 5 91 282–284 289–290²¹

4 2,6-Cl₂C₆H₃ 3d 5 78 258–260 –

5 4-BrC₆H₄ 3e 5 89 284–286 297–298²¹

6 3-O₂NC₆H₄ 3f 5 91 210–212 210–211²¹

7 4-O₂NC₆H₄ 3g 5 93 303–306 311–312²¹

8 4-NCC₆H₄ 3h 5 90 309–311 291–292¹⁴

9 4-MeOCOC₆H₄ 3i 5 89 244–246 –

10 3-MeOC6H4 3j 17 83 174–176 –

11 4-MeOC₆H₄ 3k 15 79 201–203 203–205²¹

12 4-MeC₆H₄ 3l 10 84 228–230 227–229²¹

13 i-Pr 3m 50 75 142–144 155–157²¹

14 Et 3n 20 83 150–152 150–152²¹

15 n-Pr 3o 45 78 153–155 152–154²¹

16 Bn 3p 40 80 172–174 178–180¹⁵

17 2-pyridyl 3q 15 70 235–237 240–242¹⁴

18 3-pyridyl 3r 50 68 198–200 200–202³³

a Ratio aldehyde/2-naphthol/IL = 1:2:0.15

b Yields refer to isolated products and all synthesized xanthene derivatives were characterized by spectral data (IR, ¹H NMR and ¹³C NMR) and melting points and comparison with authentic samples.

LETTER Synthesis of 14H-dibenzo[a,j]xanthenes under Solvent-Free Conditions 743

Synlett 2010, No. 5, 741–744 © Thieme Stuttgart · New York

In conclusion, we have reported a facile, convenient and solvent-free method for the preparation of 14-aryl- or 14- alkyl-14H-dibenzo[a,j]xanthenes from coupling of vari- ous aromatic and aliphatic aldehydes with 2-naphthol in the presence of N-(4-sulfonic acid) butyl triethyl ammoni- um hydrogen sulfate ([TEBSA][HSO

₄

]) as an efficient catalyst. Employing a relatively nontoxic (halogen-free) and reusable Brønsted acidic ionic liquid as an effective catalyst, high catalytic efficiency, short reaction time, high yields, straightforward workup and environmentally benign method are benefits of this method.

Acknowledgment

We gratefully acknowledge the financial support received for this project from the Isfahan University of Technology (IUT), IR Iran (A.R.H.), and Grants GM 033138, MH 065503, NS 033650 (A.E.R.) from the National Institutes of Health. Further financial support from the Center of Excellency in Sensor and Green Chemi- stry Research (IUT) is gratefully acknowledged.

References and Notes

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(34) All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. [TEBSA][HSO₄] was

synthesized according to reported procedure.²⁹ Products were characterized by spectroscopy data (IR, ¹H NMR,

13C NMR spectra) and melting point. ¹H NMR (300, 400 and 500 MHz) and ¹³C NMR (75, 100 and 125 MHz) spectra were run in DMSO-d₆ and CDCl₃ solvents relative to TMS (d = 0.00 ppm). IR spectra were recorded on a Shimadzu 435 IR spectrophotometer and performed using KBr pellets. All melting points were taken on a Gallenkamp melting apparatus and are uncorrected.

Preparations of Brønsted Acidic Ionic Liquid {N-(4- Sulfonic Acid) Butyl Triethyl Ammonium Hydrogen Sulfate ([TEBSA][HSO₄])}: 1,4-Butane sultone (10 mmol, 1.0 mL), triethylamine (10 mmol, 1.4 mL) and MeCN (5 mL) were charged into a 100-mL round-bottom flask. Then, the mixture was refluxed for 10 h. The white solid zwitterion was filtered and washed with EtOAc to remove nonionic residues and dried in vacuum (2 g, 85% yield). Then, a stoichiometric amount of concentrated sulfuric acid (96%, 0.5 mL) was added dropwise to zwitterions and the mixture was stirred for 6 h at 80 °C to produce the Brønsted acidic ionic liquid. ¹H NMR (400 MHz, DMSO-d₆): d = 1.16 (br s, 9 H), 1.59–1.73 (m, 4 H), 2.53 (t, J = 7.6 Hz, 2 H), 3.09–3.25 (m, 8 H), 6.46 (s, 2 H). ¹³C NMR (100 MHz, DMSO-d₆):

d = 7.60, 20.27, 22.23, 50.67, 52.48, 56.15.

Table 3 Reusability of [TEBSA][HSO4] in the Preparation of 14-(3-Nitrophenyl)-14H-dibenzo[a,j]xanthene

Entry Time (min) Yield (%)^a

1 5 91

2 5 91

3 8 88

4 8 85

5 8 81

a Isolated yields.

744 A. R. Hajipour et al. LETTER

Synlett 2010, No. 5, 741–744 © Thieme Stuttgart · New York General Procedure for the Preparation of 14-Aryl- or 14- Alkyl-14H-dibenzo[a,j]xanthenes: A mixture of aldehyde (1 mmol), 2-naphthol (2 mmol) and [TEBSA][HSO₄] (0.15 mmol) was stirred at 120 °C in an oil bath. The completion of the reaction was monitored with TLC (EtOAc–cyclo- hexane, 1:3). After the appropriate time (as shown in Table 2), the mixture was cooled to r.t. and H₂O (10 mL) was added and the product was filtered and then recrystallized from EtOAc. The products were characterized by spectral data (IR, ¹H NMR and ¹³C NMR) and comparison of their physical data with the literature data. The spectral data of some synthesized compounds are given below.

Compound 3d: ¹H NMR (400 MHz, DMSO-d₆): d = 7.03 (s, 1 H), 7.11–7.21 (m, 2 H), 7.39–7.47 (m, 4 H), 7.55 (t, J = 8.0 Hz, 2 H), 7.65–7.69 (m, 1 H), 7.95 (t, J = 10.0 Hz, 4 H), 8.48 (d, J = 8.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): d = 36.79, 112.77, 118.16, 124.26, 126.33, 126.95, 128.81, 129.19, 130.23, 131.34, 132.79, 138.40, 150.31. IR (KBr): 3057, 1622, 1598, 1515, 1463, 1429, 1404, 1353, 1252 cm^–1. HRMS: m/z [M + H⁺] calcd for C₂₇H₁₆Cl₂O: 427.0578;

found: 426.8718.

Compound 3i: ¹H NMR (500 MHz, CDCl₃): d = 3.82 (s, 3 H), 6.56 (s, 1 H), 7.47 (dt, J = 0.9, 7.9 Hz, 2 H), 7.55 (d, J = 8.9 Hz, 2 H), 7.61–7.67 (m, 4 H), 7.83–7.89 (m, 6 H), 8.38 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): d = 38.54, 52.36, 116.88, 118.45, 122.86, 124.82, 127.37, 128.74, 129.33, 129.65, 130.32, 131.48, 131.73, 149.12, 150.42,

167.05. IR (KBr): 3060, 2998, 2950, 1709, 1621, 1607, 1591, 1515, 1459, 1433, 1402, 1287, 1251, 1241, 1190, 1116 cm^–1. HRMS: m/z [M + H⁺] calcd for C₂₉H₂₀O₃: 417.1412;

found: 417.1561.

Compound 3j: ¹H NMR (300 MHz, CDCl₃): d = 3.59 (s, 3 H), 6.42 (s, 1 H), 6.48 (d, J = 8.2 Hz, 1 H), 7.04 (t, J = 8.4 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 1 H), 7.37 (t, J = 7.2 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.71–7.82 (m, 4 H), 8.36 (d, J = 8.7 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): d = 38.17, 55.23, 111.19, 115.16, 117.40, 118.23, 121.00, 122.94, 124.45, 127.00, 128.99, 129.07, 129.50, 131.27, 131.68, 145.01, 148.96, 159.97. IR (KBr): 3070, 3015, 2961, 2934, 2899, 1603, 1593, 1581, 1514, 1486, 1457, 1431, 1401, 1271, 1252, 1241 cm^–1.

Compound 3l: ¹H NMR (500 MHz, CDCl₃): d = 2.18 (s, 3 H), 6.51 (s, 1 H), 7.00 (d, J = 8.0 Hz, 2 H), 7.44–7.48 (m, 4 H), 7.53 (d, J = 8.9 Hz, 2 H), 7.63 (t, J = 8.3 Hz, 2 H), 7.83 (d, J = 8.9 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2 H), 8.45 (d, J = 8.5 Hz, 2 H). IR (KBr): 3070, 3020, 2902, 1620, 1591, 1509, 1458, 1431, 1401, 1247 cm^–1.

Compound 3m: ¹H NMR (500 MHz, CDCl₃): d = 0.88 (d, J = 6.9 Hz, 6 H), 2.31–2.35 (m, 1 H), 5.50 (d, J = 3.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 7.1 Hz, 2 H), 7.65 (t, J = 7.0 Hz, 2 H), 7.83 (d, J = 8.8 Hz, 2 H), 7.92 (d, J = 8.1 Hz, 2 H), 8.35 (d, J = 8.5 Hz, 2 H). IR (KBr): 3068, 2959, 2925, 2876, 1631, 1620, 1590, 1516, 1457, 1434, 1398, 1251, 1237 cm^–1.