Green synthesis of novel bis(hexahydro-1H-xanthene-1,8(2H)-diones) employing p-toluenesulfonic acid (p-TSA) as a solid acid catalyst

Article abstract of DOI:10.1080/00397911.2020.1837170

Green synthesis of novel bis(hexahydro-1H-xanthene-1,8(2H)-diones) which are linked to aliphatic or aromatic spacers via ether or ester linkages were performed in good to excellent yields by the reaction of 5,5-dimethyl-1,3-cyclohexanedione with the appropriate bis-aldehydes using p-TSA as an organic acid solid catalyst. The reaction of the bis-aldehydes with barbituric acid or 1,3-dimethylbarbituric acid instead of 5,5-dimethyl-1,3-cyclohexanedione afforded the corresponding Knoevenagel condensation adducts in good yield.

Full text of DOI:10.1080/00397911.2020.1837170

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Green synthesis of novel bis(hexahydro-1H-
xanthene-1,8(2H)-diones) employing p-
toluenesulfonic acid (p-TSA) as a solid acid catalyst
Ahmed F. Darweesh , Soad K. Salama , Ismail A. Abdelhamid & Ahmed H. M.
Elwahy
To cite this article: Ahmed F. Darweesh , Soad K. Salama , Ismail A. Abdelhamid & Ahmed
H. M. Elwahy (2020): Green synthesis of novel bis(hexahydro-1H-xanthene-1,8(2H)-diones)
employing p-toluenesulfonic acid (p-TSA) as a solid acid catalyst, Synthetic Communications, DOI:
10.1080/00397911.2020.1837170
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https://doi.org/10.1080/00397911.2020.1837170
Green synthesis of novel bis(hexahydro-1H-xanthene-
1,8(2H)-diones) employing p-toluenesulfonic acid (p-TSA) as
a solid acid catalyst
Ahmed F. Darweesh , Soad K. Salama, Ismail A. Abdelhamid , and
Ahmed H. M. Elwahy
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 31 August 2020
Green synthesis of novel bis(hexahydro-1H-xanthene-1,8(2H)-diones)
which are linked to aliphatic or aromatic spacers via ether or ester
linkages were performed in good to excellent yields by the reaction
of 5,5-dimethyl-1,3-cyclohexanedione with the appropriate bis-alde-
hydes using p-TSA as an organic acid solid catalyst. The reaction of
the bis-aldehydes with barbituric acid or 1,3-dimethylbarbituric acid
instead of 5,5-dimethyl-1,3-cyclohexanedione afforded the corre-
sponding Knoevenagel condensation adducts in good yield.
KEYWORDS
Bis(aldehydes); 55-dimethyl-
13-cyclohexanedione; p-TSA
bis(hexahydro-1H-xanthene-
18(2H)-diones); bis(pyrimi-
dine-246(1H3H5H)-trione)
GRAPHICAL ABSTRACT
Introduction
Xanthene derivatives are an important class of heterocyclic compounds containing a
pyran nucleus. Due to their wide variety of medicinal and biological properties such as
anti-inflammatory,[1,2] antibacterial,[3] antiviral,[4] antifungal,[5] antitumor[6] and anti-
proliferative[7] activities, these compounds attracted the attention of organic chemists.
Some derivatives of xanthene have also been found to show promising leishmanicidal
activity while other derivatives have been reported to act as potential a-glucosidase
inhibitors.[8]
Many well-known xanthene-containing medications such as Ro67-4853 (a positive
allosteric modulator of metabotropic glutamate 1 receptors), propantheline bromide (an
CONTACT Ismail A. Abdelhamid
ismail_shafy@yahoo.com; aelwahy@hotmail.com
Chemistry Department, Faculty
of Science, Cairo University, Giza 12613, Egypt.
ß 2020 Taylor & Francis Group, LLC

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A. F. DARWEESH ET AL.
Figure 1. Structures of some pharmacologically active xanthenes as well as some xanthene dyes.
antimuscarinic agent used to treat excessive sweating [hyperhidrosis]), and methanthe-
line (antispasmodic drug) are outlined in Figure 1.[9] Besides, some xanthene derivatives
are used as sensitizers in photodynamic therapy (PDT).[10] They can also be used as
dyes,[11] as pH-sensitive fluorescent materials[12] and can be used in laser technology[13]
as well. Fluorescein and rhodamine are among the most commonly known xanthene
dyes (Figure 1). Recently, xanthene synthesis and applications have been reviewed.[14]
Recently the synthesis of bis(heterocycles) has attracted great attention.[15–17] A com-
bination of several multiple heterocyclic cores as symmetrical or unsymmetrical bis-het-
erocycles in a single molecular system was found to exploit the pharmacological and
altered physical properties of the resulting multivalent ligands. In this regard, several
bis(heterocyclic) derivatives have been reported to exhibit bioactivity that includes anti-
cancer,[18–20] fungicidal[21] and antibacterial[22] properties. They also have diverse appli-
cations as metal ligands,[23] chelating agents,[24] and electrically conducting materials.[25]
Moreover, the employment of homogenous catalysts, heterogeneous catalysts or
nano-catalysts in organic synthesis has recently attracted much attention.[26–31]
Motivated by these findings and as a part of our increasing interest in searching for
environmentally friendly methods for synthesis of heterocyclic as well as bis(heterocy-
clic) compounds,[32–50] we report here on the green synthesis of new, structurally
diverse bis(xanthenes) libraries as to the best of our knowledge, very little is known
about this class of compounds.
Results and discussion
Many strategies have been reported for the synthesis of xanthenes, among them, the
condensation of aldehydes with b-cyclic 1,3-dicarbonyl compounds was found to be the
simplest one for the synthesis of symmetric xanthenes. Various catalysts have been
reported for the preparation of these types of xanthenes including homogeneous[2,51,52]
or reusable heterogeneous nanocatalysts.[53,54] The reactions were carried out in the

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Scheme 1. Reported methods for the synthesis of symmetric xanthenes.
Scheme 2. Synthesis of bis(hexahydro-1H-xanthene-1,8(2H)-dione) 5.
Table 1. Effect of the solvent on the synthesis of compound 5.
Entry
Solvent
Yielda,b (%)
1
2
3
4
5
6
7
Ethanol
Ethanol/ H2O (1:1)
66
88
56
36
42
43
19
H2O
THF
DMF
AcOH
Neat
aThe reaction was performed at refluxing temperature of solvents for 6 h. (monitored by TLC).
bThe reaction was carried out in the presence of 15 mol% of p-TSA.
Table 2. Effect of the amount of p-TSA catalyst and reaction time on the
synthesis of compound 5.
Entry
p-TSA (mol%)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
5
5
5
10
10
15
15
15
2
4
6
4
6
4
6
10
61
69
75
77
83
84
88
Nilb
aThe reaction was performed in Ethanol/H2O (1:1) at reflux.
bThe reaction was performed in Ethanol/H2O (1:1) at room temperature.
presence of solvents or under solvent-free conditions.[13,55,56] They were also performed
under conventional heating as well as under microwave[57,58] or ultrasound irradiation
(Scheme 1).[59,60]
Firstly, we studied the synthesis of bis(hexahydro-1H-xanthene-1,8(2H)-dione) 5 by
investigating the reaction of one equivalent of 4,40-(propane-1,3-diylbis(oxy))dibenzalde-
hyde (4) with four equivalents of 5,5-dimethyl-1,3-cyclohexanedione (1) as a model
reaction at different conditions (Scheme 2). The results are summarized in Tables 1
and 2.
The reaction was carried out in the absence as well as in the presence of p-TSA as a cheap
and readily available organic acid catalyst with excellent catalytic property, especially as a

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A. F. DARWEESH ET AL.
proton donor.[61,62] We studied the effect of various solvents (EtOH, H2O, Ethanol/H2O
(1:1), THF, AcOH, and DMF) on the yield of the reaction. The reaction was also performed
under solvent-free conditions. The best results were obtained when the reaction mixture was
performed in the presence of 15mol% of p-TSA in a mixture of Ethanol/H2O (1:1) as a solv-
ent (Table 1, entry 2). The reaction proceeded also under solvent-free conditions to give the
target molecule but in very low yields (Table 1, entry 7).
To evaluate the effect of the catalyst under the reaction conditions, the reaction was
performed in the presence of different amounts of catalyst loading. As outlined in Table
2, the reaction did not proceed successfully in the absence of the catalyst and the
desired product could not be obtained even after prolonged heating. p-TSA (15 mol%)
was found to be the optimum amount of catalyst (Table 2, entry 6&7). Larger amounts
of the catalyst did not improve the yields while decreasing the amount of catalyst
decreased the yields.
The reaction was attempted at room temperature and also under heating. The reac-
tions afforded good yields of the products at the refluxing temperature of solvents
(Table 2, entry 1–7). On the other hand, no traces of the products were obtained at
room temperature even after a prolonged time (Table 2, entry 8). The influence of the
reaction time on the yield was also investigated. It was found that higher yield occurred
when the reaction time was 6 h. (Table 2, entry 7).
The structure of target compound 5 was established based on spectral data. Thus, its
1
IR spectra revealed the carbonyl group at 1666 cmꢀ1. In the H NMR spectrum, the
hydrogen atom of the pyran ring was observed at 4.45 ppm. Moreover, the 13C NMR
spectrum of 5 was found to be in agreement with the proposed structure, it showed the
pyran C-4 at 30.2 ppm and the carbonyl group at 195.9 ppm. Further structural verifica-
tion was obtained from its mass spectroscopy, which showed the correct molecular ion
peak at m/z 772.
To explore the scope and limitations of this reaction, a range of bis-aldehydes 6–9
were allowed to react with 5,5-dimethyl-1,3-cyclohexanedione (1) under the above-men-
tioned conditions to give the corresponding bis(hexahydro-1H-xanthene-1,8(2H)-diones)
10–13 which are linked to aliphatic spacers via ether linkages in good to excellent yields
(Scheme 3).
Similarly, the reaction of 5,5-dimethyl-1,3-cyclohexanedione (1) with bis-alde-
hydes 14–16 under similar reaction conditions afforded bis(hexahydro-1H-xanthene-
1,8(2H)-diones) 17–19 which are linked to aromatic spacers via ether linkages
(Scheme 4).
Likewise, the bis-aldehydes 20–22 were utilized as versatile precursors to a variety of
novel bis(hexahydro-1H-xanthene-1,8(2H)-dione) derivatives 23–25 containing carboxyl-
ate ester linkages (Scheme 5).
Bis-aldehydes 4, 6–9 and 14–16 were prepared in good yields as previously reported
by the reaction of the potassium salt of the appropriate hydroxybenzaldehyde with the
corresponding bis(bromomethyl) derivatives in boiling DMF.[49,50,63–65]
The bis-aldehydes 20–22 were prepared by the reaction of 4-formylbenzoic acid with
the appropriate dihalo compounds in DMF at reflux.[66,67]
Generally, the employment of bis-aldehyde with formyl substituents either at the
ortho- or para- positions of the ether linkages showed no remarkable effect on product

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Scheme 3. Synthesis of bis(hexahydro-1H-xanthene-1,8-diones) 10–13.
Scheme 4. Synthesis of bis(hexahydro-1H-xanthene-1,8-diones) linked to aromatic spacers 17–19.

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A. F. DARWEESH ET AL.
Scheme 5. Synthesis of bis(hexahydro-1H-xanthene-1,8-diones containing carboxylate ester link-
ages 23–25.
Scheme 6. Plausible mechanism for the formation of 5.
yield and reaction time. Moreover, the length of the spacers was found to have no sig-
nificant improving effect on reaction yields.
The plausible mechanism for the formation of 5 from the reaction of 5,5-dimethyl-
1,3-cyclohexanedione with the corresponding aldehyde 4 is illustrated in Scheme 6. The
mechanism includes one-pot Knoevenagel condensation, Michael addition, and cyclode-
hydration reaction. At first, the electrophilicity of the carbonyl carbon of the bis-alde-
hyde could have been activated by the Hþ from p-TSA followed by attack of two moles

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Scheme 7. Synthesis of tetrakis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) 26 and bis(hexahydro-1H-
xanthene-1,8(2H)-dione) 5.
Scheme 8. Reactivity of bis-aldehyde 4 toward barbituric acid.
of the nucleophilic cyclohexanedione derivatives on the carbonyl carbons to form the
Knoevenagel product II. Subsequent addition of this fragment to another two moles of
5,5-dimethyl-1,3-cyclohexanedione gives the acyclic adduct intermediate 26. Subsequent
intramolecular dehydrative cyclization with the participation of four hydroxyl groups
affords the xanthene derivative 5 (Scheme 6).
In support of this mechanism, we managed to separate the tetrakis(3-hydroxy-5,5-
dimethylcyclohex-2-en-1-one) 26. Thus, performing the same reaction in DCE at reflux-
ing temperature afforded the corresponding tetraketone 26 as a sole product in excellent
yield (Scheme 7). Ring closure of 26 to the corresponding 5 was successfully achieved
by heating of 26 in ethanol/water mixture (1:1) in the presence of p-TSA (15 mol%).
Tetraketones are considered not only as an important class of biologically active com-
pounds but also as significant precursors for the synthesis of various fused
heterocyclic.[68]

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A. F. DARWEESH ET AL.
Scheme 9. Synthesis of bis(pyrimidine-2,4,6-triones) 33–35.
The structure of the compound 26 was confirmed spectroscopically. In the IR spec-
trum, the carbonyl and the hydroxyl stretching frequencies were noticed at 1651 and
3224–3502 cmꢀ1, respectively. The 1H NMR spectrum of 26 displayed a broad at
3.85 ppm characteristic for the OH protons in addition to the pyran C-4 at 4.45 ppm.
Its mass spectroscopy showed the correct molecular ion peak at m/z 808.
In order to broaden the scope of this protocol, we explored the reaction of the bis-
aldehyde 4 with barbituric acid (27) or 1,3-dimethylbarbituric acid (31) instead of
5,5-dimethyl-1,3-cyclohexanedione (1) aiming at synthesizing the corresponding bis(1H-
pyrano[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(3H,5H,7H,9H)-tetraone) 28. The reaction was
carried out in the absence as well as in the presence of p-TSA in acetic acid at reflux.
In both cases, the reaction did not afford compound 28 or the corresponding bis(me-
thanetriyl))tetrakis(6-hydroxypyrimidine-2,4(1H,3H)dione) 29. Instead, the correspond-
ing Knoevenagel adducts 30 were obtained in excellent yield (Scheme 8).
The IR spectrum of compound 30 indicated the presence of the NH and the carbonyl
1
groups at 3328, 1751, and 1666 cmꢀ1. The H NMR spectra of compound 30 exhibited
a singlet signal at 8.24 ppm and two singlet signals at 11.13 and 11.26 ppm belonging to
the olefinic CH and -NH groups, respectively. The molecular formula of 30 was con-
firmed by mass spectrometry which showed the correct molecular ion peak at m/z 504.
Using a similar approach, the corresponding Knoevenagel adducts 33–35 were
obtained in excellent yields upon treatment of the appropriate bis-aldehydes 32, 14 and
16 with barbituric acid (27) or 1,3-dimethylbarbituric (31), respectively (Scheme 9).
Conclusion
We developed a simple one-pot green protocol for the preparation of symmetrical bis-
xanthenes by condensation of various bis-aldehydes, with 5,5-dimethyl-1,3-cyclohexane-
dione using various reaction conditions. Operational simplicity, easy work-up, mild
reaction conditions, clean production of the products in high isolated yields from read-
ily available starting materials are significant advantages of the used protocol. Despite

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9
the remarkable achievements in this area, the synthesis of novel structures of these
interesting molecules using an inexpensive, easily available and metal-free catalyst is still
in demand.
Experimental
General
Melting points were determined in open glass capillaries with a Gallenkamp apparatus.
The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP 3-
300 and Shimaduz FTIR 8101 PC infrared spectrophotometer. NMR spectra were
recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 MHz (1H NMR)
and 75 MHz (13C NMR). Mass spectra (EI) were obtained at 70 eV with a type
Shimadzu GCMQP 1000 EX spectrometer. Analytical thin-layer chromatography was
performed using pre-coated silica gel 60,778 plates (Fluka), and the spots were visual-
ized with UV light at 254 nm. Elemental analyses were performed on a Perkin-Elmer
240 micoanalyser at the Micro analytical Center of Cairo University. All chemicals were
purchased from Sigma-Aldrich and used without further purification.
General procedure for the synthesis of compounds 5, 10–13, 17–19 and 23–25
A mixture of bis-aldehydes 4, 6–9, 14–16 or 20–22 (1 mmol), 5,5-dimethyl-1,3-cyclo-
hexanedione (1) (4 mmol), p-TSA (15 mol%) in ethanol/H2O (15 mL, 1:1) was heated at
reflux for 6 h. The crude solid was isolated and recrystallized from the proper solvent.
9,90-((Propane-1,3-diylbis(oxy))bis(4,1-phenylene))bis(3,3,6,6-tetramethyl-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione) (5)
Yield (88%), colorless powder (ethanol), mp 220–224 ꢁC, IR (KBr): ꢀ ¼ 1666 (CO)
1
cmꢀ1, H NMR (300 MHz, DMSO-d6) d 0.89 (s, 12H, 4CH3), 1.02 (s, 12H, 4CH3),
2.03–2.52 (m, 18H, dimedone H2, H7, H4, H5 & –OCH2–CH2–OCH2–), 4.01 (t, 4H, 2-
OCH2, J ¼ 6.3 Hz), 4.45 (s, 2H, H9), 6.76 (d, 4H, ArH, J ¼ 8.7 Hz), 7.04 (d, 4H, ArH,
J ¼ 8.4 Hz); 13C NMR (DMSO-d6) d 26.4, 28.5, 30.2, 31.7, 50.0, 64.0, 113.6, 114.5, 128.9,
131.7, 136.4, 156.7, 162.5, 195.9. MS (EI, 70 eV): m/z (%) ¼ 772 [Mþ, 6.45%], 500
(4.65%), 365 (3.68%), 274 (100%). Anal. Calcd. for C49H56O8: C, 76.14; H, 7.30. Found:
C, 76.37; H, 7.49%.
ORCID
Ahmed F. Darweesh
Ismail A. Abdelhamid
Ahmed H. M. Elwahy
http://orcid.org/0000-0002-7291-6486
http://orcid.org/0000-0003-1220-8370
http://orcid.org/0000-0002-3992-9488
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