N,N-disulfo-1,1,3,3-tetramethylguanidinium carboxylate ionic liquids as reusable homogeneous catalysts for multicomponent synthesis of tetrahydrobenzo[a]xanthene and tetrahydrobenzo[a]acridine derivatives

Article abstract of DOI:10.1016/j.molliq.2016.11.112

Three new –SO₃H functionalized N,N-disulfo-tetramethylguanidinium carboxylate ionic liquids [DSTMG][CX₃COO], ( where X?=?H, Cl, F) were prepared as viscous liquids from the reaction of [DSTMG][Cl] with equimolar amount of three carbo

Full text of DOI:10.1016/j.molliq.2016.11.112

N,N-disulfo-1,1,3,3-tetramethylguanidinium carboxylate ionic liquids as
reusable homogeneous catalysts for multicomponent synthesis of tetrahy-
drobenzo[a]xanthene and tetrahydrobenzo[a]acridine derivatives
Arup Kumar Dutta, Pinky Gogoi, Susmita Saikia, Ruli Borah
PII:
DOI:
Reference:
S0167-7322(16)32482-5
doi:10.1016/j.molliq.2016.11.112
MOLLIQ 6659
To appear in:
Journal of Molecular Liquids
Received date:
Accepted date:
29 August 2016
25 November 2016
Please cite this article as: Arup Kumar Dutta, Pinky Gogoi, Susmita Saikia, Ruli Bo-
rah, N,N-disulfo-1,1,3,3-tetramethylguanidinium carboxylate ionic liquids as reusable
homogeneous catalysts for multicomponent synthesis of tetrahydrobenzo[a]xanthene
and tetrahydrobenzo[a]acridine derivatives, Journal of Molecular Liquids (2016),
doi:10.1016/j.molliq.2016.11.112
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ACCEPTED MANUSCRIPT
Dr. Ruli Borah
Associate Professor
Department of Chemical
Sciences
Tezpur Central University
Napaam, Tezpur, Assam
INDIA-784 028
e-mail : ruli@tezu.ernet.in
Fax :+91 3712 267005/6
th
The Editor in Chief
14 Aug- 2016
Journal of Molecular Liquids
Elsevier Publication
Sub: Submission of revised manuscript to “Journal of Molecular Liquids’’
Dear Sir,
I am pleased to submit the revised manuscript entitled “N,N-disulfo-1,1,3,3-tetramethylguanidinium
carboxylate ionic liquids as reusable homogeneous catalysts for multicomponent synthesis of
tetrahydrobenzo[a]xanthene and tetrahydrobenzo[a]acridine derivatives” for rapid publication in
your esteemed journal “Journal of Molecular Liquids“ after modification of Highlight and other
correction on different points as raised by the two reviewers. All the changes are listed pointwise in the
response letter and also highlighted by yellow colour in the revised manuscript.
Kindly acknowledge the same.
With best regards,
Yours sincerely
Dr. Ruli Borah
1

ACCEPTED MANUSCRIPT
Graphical abstract
2

ACCEPTED MANUSCRIPT
N,N-disulfo-1,1,3,3-tetramethylguanidinium carboxylate ionic liquids as
reusable homogeneous catalysts for multicomponent synthesis of
tetrahydrobenzo[a]xanthene and tetrahydrobenzo[a]acridine derivatives
Arup Kumar Dutta, Pinky Gogoi, Susmita Saikia and Ruli Borah*
Department of chemical sciences, Tezpur University, Napaam, Tezpur, Assam, India-784028
E. mail: rulitezu@gmail.com; Tel: =913712267008(ext.5057); Fax: + 913712-267005/6
Abstract
Three new –SO H functionalized N,N-disulfo-tetramethylguanidinium carboxylate ionic liquids
3
[
[
DSTMG][CX COO], ( where X= H, Cl, F) were prepared as viscous liquids from the reaction of
3
DSTMG][Cl] with equimolar amount of three carboxylic acids (AcOH, CCl COOH and
3
CF COOH) for the first time at 60° C in 1 hr. Their structures were confirmed from IR, NMR
3
and elemental analyses data. The Hammett acidity and TGA analysis were also investigated. The
two ionic liquids [DSTMG][CF COO] and [DSTMG][CCl COO] were employed as reusable
3
3
homogeneous catalysts for the one-pot synthesis of tetrahydrobenzo[a]xanthenones and
tetrahydrobenzo[a]acridinones under solvent-free thermal method. The preparation of
tetrahydrobenzo[a]acridinones was observed first time using 2-naphthol as reactant via four-
component route in the presence of IL catalyst.
Key words: TMG, disulfonic carboxylate ionic liquid, tetrahydrobenzo[a]xanthenone,
tetrahydrobenzo[a]acridinone , reusable catalyst
3

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1
. Introduction
A large number of Brønsted acidic ionic liquids (ILs) bearing –SO H have
3
been observed in recent times using either imidazolium or N-heterocycle as
carbocation in combination with organic or inorganic anions. However no
examples were found in literature for the synthesis of TMG-based sulfonic acid
functionalized ionic liquids. Reddy et al [1] and Kalla et al reported the
preparation of tetramethylguanidinium chlorosulfonate as colorless solid from the
reaction of equal equivalent of TMG with chlorosulfonic acid in dichloromethane
at 0° C [2].
TMG is a strong organic base with pKa value of 15.2 in aqueous solution
which generates stable-acyclic guanidine cation by protonation of basic imino
nitrogen (=NH)[3-5]. The unusual thermodynamic stability of guanidine cation is
attributed to the resonance stabilization via delocalization of positive charge over
two amino nitrogen, Y-aromaticity and solvation of the protonated form [5]. As
results, there is a scope to synthesize disulfonic group bearing
tetramethylguanidinium carboxylate ILs [DSTMG][CX COO], (where X= H, Cl,
3
F) as reusable acid catalysts for the multicomponent synthesis of
tetrahydrobenzo[a]xanthenones
and
tetrahydrobenzo[a]acridinones
under
environmentally benign conditions. The acidity of such IL depends on the strength
4

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of ionic interaction between N,N-disulfo-tetramethylguanidinium cation and
carboxylate anion which can easily be monitored by Hammett acidity study [6].
Benzoacridines and benzoxanthenes are two important classes of bioactive
compounds
bearing
wide
pharmacological
profiles
[7,8].
Tetrahydrobenzo[a]acridinones are examples of such type of multifunctional 1, 4-
dihydropyridine derivatives [9, 10]. The diversity-oriented strategies of DHPM
unit have extended their studies to explore the complex structure-activity
relationship at the molecular receptor level in presence of various substituents
[11,12].
The acridinedione derivatives were also investigated for their potential as
laser dyes, photochemical/physical properties, electrochemical properties, and
interactions with DNA [13-16]. On the other hand, benzoxanthene derivatives are
also explored as leuco-dye in laser technologies and in pH sensitive fluorescence
materials for visualization of biomolecules [17, 18]. Most of the reported three
component preparation of tetrahydrobenzo[a]acridinones involves from the
reaction of 2-naphthylamine, dimedone and aromatic aldehyde in solution or
solvent-free medium at different temperature in presence of non-recyclable acid
catalyst[19,20]. No reports are observed for this synthesis using ionic liquid as
5

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medium or catalyst and also 2-naphthol as one of the alternative starting material
of expensive 2-naphthylamine via multicomponent (MC) approach.
Herein, we have synthesized the above heterocycle from the four-component
reaction of 2-naphthol, dimedone, aromatic aldehydes and ammonium chloride
using 5 mol% of reusable [DSTMG][CCl COO] (IL-3) or [DSTMG][CF COO]
3
3
(
IL-4) ionic liquids in neat condition at 85° C. It was observed in literature that
several groups efficiently utilized neutral or acidic ionic liquids as catalyst or
medium for the MC synthesis of tetrahydrobenzo[a]xanthenones in solvent-free
thermal method with longer reaction time [21-24]. But the same reaction took less
time under microwave irradiation in solvent-free medium [25]. Under thermal
condition, some of those ILs mediated methods needed high temperature (100-
1
2
2
20°C) to produce better results [26,27].
. Experimental
.1. Reagents and equipment
All chemicals were purchased from chemical suppliers in pure form. Perkin
Elmer spectrometer was used to record the FT-IR spectra of different products.
1
13
JEOL 400 spectrometer was utilized to take the HNMR and CNMR of ILs and
organic products in DMSO-d and CDCl solvents. The Hammett acidity of TMG-
6
3
based ILs was measured on UV 2550 spectrophotometer. Thermogravimetric
analysis was performed on Shimadzu TGA 50. All CHN elemental analyses were
6

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collected using Perkin Elmer 20 analyzer. Buchi-560 melting point apparatus was
used to measure melting point. The spectral data and melting points of known
tetrahydrobenzo[a]xanthenones (1) and acridinone derivatives (5) were compared
with the literature data [20,21].
2
2
.2. Experimental procedures
.2.1. Preparation of N,N-disulfotetramethyl guanidinium carboxylate ionic liquids
[
DSTMG][CX COO] where X= H, Cl, F:
3
The parent ionic liquid [DSTMG][Cl] was prepared by dropwise addition of
ClSO H (10 mmol) to a solution of TMG (5 mmol) in dry hexane (5 mL) at 0 °C in
3
a two necked 50 mL round bottomed flask fitted with a vacuum system through
water and alkali trap for removal of HCl gas. The mixture was stirred continuously
for one hour at room temperature to get [DSTMG][Cl] as pale yellow liquid
immiscible with hexane. To the crude IL solution, 5 mmol of carboxylic acid
(
CH COOH, CCl COOH and CF COOH) was added slowly with vigorous stirring
3
3
3
and heated up to 60 °C for 1h to complete the elimination of HCl gas. The reaction
mixture was cooled to room temperature and diluted with 10 mL of hexane.
Decantation of IL immiscible hexane solution yielded the IL as crude viscous
material within the reaction vessel. Further purification of the product was
performed by repeating the above dilution and decantation process three times with
dry hexane (3 x 5 mL). Finally the ionic liquid residue was dried under vacuum to
7

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get 96-98% yields of [DSTMG][CX COO] as yellow/reddish colored viscous
3
liquids.
2
.2.2. General procedure for the synthesis of tetrahydrobenzo[a]xanthenone
derivatives (1): In a 50 mL round bottomed flask, a three component mixture of 2-
naphthol (1 mmol), aromatic aldehyde (1mmol) and dimedone (1 mmol) was
treated with 5 mol % of IL-3 or IL-4 at 75 °C under solvent-free condition for the
specified time. After completion of the reaction as observed from TLC technique
the product mixture was extracted from the IL catalyst using dry dichloromethane
(3 x 3 mL) as IL immiscible solvent. The isolation of crude product involved the
decantation and evaporation of the CH Cl layer under reduced pressure. The IL
2
2
catalyst was further purified by addition of more dichloromethane (2 x 3 mL) to
the reaction vessel with continuous stirring and removal of the CH Cl layer
2
2
through decantation. Then the purified IL was utilized as recyclable homogeneous
catalyst for the next run. The crude product, thus isolated was subjected to further
purification by recrystallization in 15% aqueous ethanol to get analytically pure
product.
2
.2.3. General procedure for the synthesis of tetrahydrobenzo[a]acridinone
derivatives (5): A four component mixture of dimedone (1 mmol), 2-naphthol
1mmol), aromatic aldehydes (1 mmol) and NH Cl (1 mmol) was treated with 5
(
4
mol% of IL-3 or IL-4 in a 50 mL round bottomed flask at 85 °C in neat condition.
8

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After completion of the reaction as monitored by TLC technique, the crude mixture
was extracted from the ionic liquid phases using dry dichloromethane (3 x 3 mL)
as immiscible solvent. Decantation of organic layer separated the product mixture
from the viscous IL catalyst remain in the reaction vessel. Distillation of CH Cl
2
2
solution yielded the crude tetrahydrobenzoacridinone derivative as solid residue.
Recrystallization of the crude product from 15% aqueous ethanol gave analytically
pure product. The IL catalyst within the reaction vessel was reactivated for next
cycle after diluting with CH Cl (2 x 3 mL) and then decantation of the
2
2
dichloromethane solution.
3
. Results and discussion
3
.1. Preparation and characterization of ILs
We have synthesized the three acidic N,N-disulfo-tetramethylguanidinium
carboxylate ILs such as [DSTMG][CH COO] (IL-2), [DSTMG][CCl COO] (IL-3)
3
3
and
[DSTMG][CF COO]
(IL-4)
from
the
reaction
of
N,N-
3
disulfotetramethylguanidinium chloride [DSTMG][Cl] (IL-1) with equivalent
amount of carboxylic acid (AcOH, CCl COOH and CF COOH) at 60 °C in hexane
3
3
for 45-60 min stirring (Scheme 1). All these ILs were characterized using different
spectroscopic and analytical tools which are discussed below.
9

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HO S
SO H
3
3
NH
N
dry hexane/ClSO H
Cl
3
N
N
rt, 45-60 min
N
N
[DSTMG][Cl] IL-1
CX COOH 60 °C/ 1h
3
HO S
SO3H
3
X= H, [DSTMG][CH COO], IL-2
3
N
[
CX COO]
Cl, [DSTMG][CCl COO], IL-3
3
3
F, [DSTMG][CF COO], IL-4
N
N
3
Scheme 1 Synthetic route of TMG-based –SO H functionalized ILs
3
1
13
3
.1.1. FT-IR, H NMR and C NMR spectral analysis
Fig. 1 displays the various characteristic absorption peaks for –SO H
3
-
1
groups, and stable-guanidinium cation in the IR region within 600-2000 cm for
the four synthesized ILs. The symmetric and antisymmetric S-O stretching
-
1
-1
frequencies were observed at 1141-1161 cm and 1027-1038 cm of –SO H
3
-
1
groups. The peak at 860-871 cm represented the stretching vibration of N-S bond.
-
1
The strong absorption peak around 1608-1613 cm confirmed the attachment of
carboxylate anion with N,N-disulfo-tetramethylguanidinium cation. Furthermore,
-
1
the band at 1560-1568 cm can be assigned for the -C= N- stretching vibration of
-
1
guanidinium cation. The smaller peak at 1409-1413 cm may be attributed for C-H
bending and rocking vibration. The absence of two -NH- stretching vibrations at
1
0

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-
1
-1
3
474 cm and 3398 cm eliminated the formation of tetramethylguanidinium
chlorosulfonate IL as reported by Reddy et al and Kalla et al [1,2].
Fig. 1 FT-IR spectra of three ionic liquids
1
13
The typical H NMR and C NMR spectra of IL-4 was displayed the Fig. 2. The
1
single peak around 12-12.4 ppm for two proton in H NMR spectra of the three ILs
in DMSO-d confirmed the attachment of two -SO H groups in the imino (=NH)
6
3
nitrogen of tetramethylguanidinium cation (Fig. 2(B)). The twelve protons of two –
NMe groups appeared as singlet in the region 3-3.2 ppm. The presence of
2
1
3
characteristic C= O signal at 155-170 ppm in C NMR spectra fully supported the
existence of carboxylate anions in each ionic liquid (Fig. 2(c)). The four N-methyl
carbons appeared at 38.8 ppm which is also agreement with the literature data [1].
Interestingly, the same spectra displayed two peaks in the aromatic region around
1
1

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1
34.7 ppm and 119.9 ppm in contrast to the reported value of C= N carbon at 161.0
ppm by Kalla et al [2]. These two peaks can be easily attributed for two types of
chemical environment of C=N carbon present in the resonating structures of N,N-
disulfo tetramethylguanidinium cations as shown in Fig. 2(A). Further evidences
were observed from the elemental analysis data of the three ILs.
HO S
SO H
HO S
SO H
HO3S
SO3H
3
3
3
3
N
C
N
C
N
C
H C
3
CH3
H C
3
H3C
CH3
CH3
N
N
N
N
N
N
CH3
CH3
CH3
CH3
CH3
CH3
1
2

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Fig. 2 (A) Resonating structure of N,N-disulfotetramethylguanidinium cation; (B)
1
13
H NMR spectrum of IL-4; (C) C NMR spectrum of IL-4
.1.2. Spectral data of TMG- based ionic liquids
N,N-Disulfo-tetramethylguanidiniumchloride (IL-1): Pale yellow viscous liquid;
3
-
1 1
FT-IR: 3301, 1630, 1560, 1149, 1027, 860 cm ; H NMR (400MHz, DMSO-d ): δ
6
13
3
.01 (s, 12H), 14.2 (s, 2H); C NMR (100MHz, DMSO-d ): δ 39.1, 119.8, 134.7;
6
CHN analysis: Calculated for C H N O S (%): Cal. C 25.07, H 5.11, N 12.53;
7
17
3
8 2
Found C 25.02, H 5.16, N 12.5.
N,N-Disulfo-tetramethylguanidiniumacetate (IL-2): Reddish viscous liquid, FT-
-
1 1
IR: 3313, 1611, 1564, 1411, 1158, 1036, 871 cm ; H NMR (400MHz, DMSO-d ):
6
1
3
δ 1.91(s, 3H), 2.96 (s, 12H), 14.18 (s, 2H); C NMR (100MHz, DMSO-d ): δ
6
1
3

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1
5.5, 39.1, 119.7, 134.7, 151.71; CHN analysis: Calculated for C H N O S (%):
7
17
3
8 2
Cal. C 25.07, H 5.11, N 12.53; Found C 25.02, H 5.16, N 12.5.
N,N-Disulfo-tetramethylguanidinium-trichloroacetate (IL-3): Pale yellow liquid,
-
1
1
FT-IR: 3299, 1608, 1568, 1409, 1141, 1030, 868 cm ; H NMR (400MHz,
1
3
DMSO-d ): δ 3.02 (s, 12H), 14.14 (s, 2H); C NMR (100MHz, DMSO-d ): δ 39.4,
6
6
6
2.4, 119.7, 134.6, 158.5; CHN analysis: Calculated for C H N O S Cl (%): Cal.
7
14
3
8
2
3
C 19.16, H 3.22, N 9.58; Found C 19.15, H 3.25, N 9.55.
N,N-Disulfo-tetramethylguanidinium-trifluoroacetate (IL-4): Light reddish liquid,
-
1
1
FT-IR: 3321, 1610, 1562, 1413, 1161, 1038, 868 cm ; H NMR (400MHz,
1
3
DMSO-d ): δ 3.09 (s, 12H), 14.01 (s, 2H); C NMR (100MHz, DMSO-d ): δ 38.8,
6
6
5
5.3, 119.8, 134.6, 163.3; CHN analysis: Calculated for C H N O S F (%): Cal.
7
14
3
8 2 3
C 21.59, H 3.62, N 10.79; Found C 21.55, H 3.68, N 10.77.
1
4

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3
.1.3. Thermogravimetric analysis (TGA)
Fig. 3 TGA curves of ILs
The TGA patterns of four ILs displayed in Fig. 3. Initial 5-15 % weight loss
around 95-100° C of the three carboxylate ILs can be attributed for absorbed
moisture. The TGA curve of parent IL [DSTMG][Cl] expresses higher amount of
moisture content (approx. 25 %). Then the major weight loss started from 270-300
°
C that indicates greater stability of TMG-based –SO H functionalized ILs which
3
is generally higher than the common reaction temperature of organic synthesis.
The curve for [DSTMG][CF COO] (IL-4) shows thermal stability up to 300° C.
3
The stability of these ILs can be expressed in the decreasing order:
1
5

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[
DSTMG][CF COO] (IL-4)> [DSTMG][CCl COO] (IL-3)> [DSTMG][CH COO]
3
3
3
(
IL-2)> [DSTMG][Cl] (IL-1).
3
.1.4. UV visible Hammett acidity study
The Brønsted acidity of the four ILs was determined from Hammett plot [6]
on UV-visible spectrophotometer (Fig. 4) by calculating of Hammett acidity
o
function H according to equation-1.
+
H° = pK(I) aq + log[I] /[HI]
(Eq-1)
Where pK(I)aq is the pKa value of the 4-nitroaniline in aqueous solution. The
method involves the preparation of equimolar solution of 4-nitroaniline as
indicator (pKa = 0.99) with acidic IL in ethanol. The 4-nitroaniline showed
maximum absorption in the region of 378-379 nm whose absorbance gradually
+
reduced with increasing acidity of the catalysts. The protonated form [HI] of 4-
nitroaniline did not show any absorbance because of its lower molar absorptivity.
o
The calculated values of Hammett function (H ) were tabulated in Table 1 which
o
reflected the decreasing order of acidities against increasing values of H as IL-4 >
IL-3 > IL-2 > IL-1. The acidity order clearly demonstrated the presence of strong
ionic interaction between more electronegative carboxylate anion and
thermodynamically stable-guanidinium cation for the highest acidic ionic liquid
1
6

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[
DSTMG][CF COO] (IL-4) which was again supported by the thermal stability in
3
TGA analysis (Fig. 3).
Fig. 4 Hammett acidity measurement of Ionic liquid
Table 1 Hammett function (H°) values for ionic liquids
o
Entry
IL
Amax
[I]%
100.0
58.91
31.88
17.32
12.59
[IH]%
0
H
1
2
3
4
5
Blank
2.638
1.554
0.841
0.457
0.332
-
[DSTMG]Cl
41.09 1.14
68.12 0.66
82.68 0.31
87.41 0.15
[DSTMG][CH COO]
3
[DSTMG][CCl COO]
3
[DSTMG][CF COO]
3
1
7

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3
.2. Catalytic activity study
The catalytic activity of the three carboxylate ILs was investigated for the
multicomponent synthesis of tetrahydrobenzo[a]xanthenones and
tetrahydrobenzo[a]acridinones in solution and neat condition at different
temperature.
3
.2.1. Optimization of reaction conditions
Initially, the amount of four ILs were optimized as acidic catalysts for the
multicomponent synthesis of tetrahydrobenzo[a]xanthenone (1a) and
tetrahydrobenzo[a]acridinone (5a) according to the reaction schemes as shown in
Table 2 and Table 3 with 20 mol% of IL at different temperatures without any
solvent (Table 2 and Table 3, entries 1-4). Using these conditions, the catalytic
activity of IL-3 and IL-4 were observed to be higher than the IL-1 and IL-2 in
terms of yields of product (1a) and reaction time (Table 2, entries 1-4) at 75° C.
The acidity order as observed from the Hammett plot (Fig.4) also supports the
above catalytic activities of the four ILs.
The same multicomponent reaction generated side products from parallel
reactions at 75 °C with IL-1 and IL-2 (Table 2, entries 1-2) which were identified
as mixture of aryldi-(2-hydroxy-1-naphthyl)methane (2a) and 1,8-
dioxodecahydroxanthenone (4a). Similar results were also observed for the IL-3
1
8

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and IL-4 at room temperature reactions within one hour (Table 2, entries 3, 4). The
amount of catalyst was optimized as 5 mol% for the two efficient catalysts IL-3
and IL-4 by comparing their results with 10 mol % at 75 °C (Table 2, entries 5-6)
which required only 10-12 min to form 90-94 % of expected product. By
increasing the reaction temperature to 85°C, we didn’t find any appreciable change
in the yields of product using 5 mol % of the two ILs (Table 2, entries 7-8).
1
9

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Table 2 Optimization of reaction condition for the synthesis of
tetrahydrobenzo[a]xanthenone (1a)
O
OH
+
O
OH OH
(
1mmol)
+
ILs (cat.)
(
1a)
(2a)
Solvent free
Dimedone
(
1mmol)
+
O
O
O
O
Benzaldehyde
1mmol)
(
+
O
OH OH
3a)
(
(4a)
a, b
Entry Ionic
liquids
mol % Temp Time
% of yield
b
(°C)
75
(min)
40
(1a)
60
(2a)
(3a)
(4a)
1
2
3
4
5
6
7
8
IL-1
IL-2
IL-3
IL-4
IL-3
IL-4
IL-3
IL-4
20
20
7
-
10
15
-
75
25
70
-
-
20
rt/75
rt/75
75
1h/12
1h/10
12/12
10/10
12
-/90
-/94
91/90
94/93
92
35/-
43/-
20
40/-
45/-
-
10/5
10/5
5
-
-
-
-
-
-
-
-
-
75
-
85
-
5
85
10
94
-
a
b
Isolated yield; The known side products were purified with thin layer chromatographic
technique and compared their melting points and NMR spectra with reported data[28-30].
2
0

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Table 3 Optimization of reaction condition for the synthesis of
tetrahydrobenzo[a]acridinones (5a)
OH
O
(
1mmol)
+
NH Cl (1 mmol)
ILs (cat)/solvent-free
+ (2a) + (3a) + (4a)
4
Dimedone
(
1 mmol)
+
N
H
Benzaldehyde
(5a)
(
1 mmol)
a
Entry
Ionic
liquids
IL-1
IL-2
IL-3
IL-4
IL-3
IL-4
IL-3
Mol% Temp Time
% of yield
b
(°C)
85
(min) (5a)
(2a) (3a) (4a)
1
2
3
4
5
6
7
8
20
20
50
30
55
65
12
15
-
-
13
10
-
85
20
rt /85 1h/15
rt /85 1h/12
-/89
-/92
89/88
92/90
91
30/- 46/-
37/- 43/-
20
-
10/5
10/5
5
85
85
95
95
15
12
15
12
-
-
-
-
-
-
-
-
-
-
-
IL-4
5
93
-
a
b
Isolated yield; All these acridinone derivatives were characterized by comparing their
melting points and NMR spectra with reported data [13-15]
Similarly, the four component reactions of tetrahydrobenzo[a]acridinone
(
5a) produced 89-92 % of expected product at 85 °C with 20 mol% of IL-3 and
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IL-4 within short time (Table 3, entries 3-4). For the weaker acidic ILs, the model
reaction produced small amounts of aryldi-(2-hydroxy-1-naphthyl)methane (2a)
and 1,8-dioxodecahydro- xanthenone (4a) as side products along with acridinone
derivative (5a) (Table 3, entries 1-2). On the other hand we isolated a mixture of
aryldi-(2-hydroxy-1-naphthyl) methane (2a) and aryl-di-(3-hydroxy-5,5-dimethyl-
2
-cycloxenone) (3a) from the room temperature reaction in presence of 20 mol%
of either IL-3 or IL-4 for 1 hour (Table 3, entries 3-4).
It was observed that the use of 5 mol% of IL-3 and IL-4 was sufficient for
the selective formation of 88-90 % of product (5a) at 85 °C (Table 3, entries 5-6).
Similarly the reaction rate didn’t change much when the temperature was raised to
9
5° C under optimized condition (Table 3, entries 7-8). These optimization studies
revealed the existence of parallel reactions for the multicomponent synthesis of
tetrahydrobenzo[a]xanthenone (1a) and tetrahydrobenzo[a]acridinone (5a)
derivatives at different temperature junction.
Solvent study for the preparation of model compounds (1a) and (5a) was
investigated in polar and non-polar solvents such as EtOH, CH Cl , CH CN and
2
2
3
CHCl at room temperature stirring for one hour in presence of 5 mol% of IL-3
3
and IL-4. These observations didn’t show any selective formation of the desired
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products in solutions. They formed only a mixture of side products that have
already been observed in the Table 2 and Table 3 (entries 1-2 and 3-4).
Table 4 Substrate scope study for the synthesis of tetrahydrobenzo[a]xanthenone
(
1) derivatives
O
R
O
O
OH
5 mol% of
IL-3/ IL-4
+
RCHO
mmol
+
O
o
Neat/ 75 C
1
1
mmol
1mmol
(1)
R= Aryl group with electron withdrawing or donating substituent
a, b
Entry
Aldehyde
Time (min)
% of Yield
1)
(
IL-3
IL-4
IL-3
IL-4
1
2
Benzaldehyde
12
15
10
12
90 (1a)
94 (1a)
4-Nitrobenzaldehyde
88 (1b) 90 (1b)
90 (1c) 92 (1c)
93 (1d) 95 (1d)
3
4
5
6
4-Chlorobenzaldehyde
4-Anisaldehyde
14
13
12
14
12
10
10
11
4-Tolualdehyde
92 (1e)
89 (1f)
95 (1e)
92 (1f)
2-Naphthaldehyde
a
b
Isolated yield; Reactions were performed at 75 °C using 5 mol % of IL-3 or IL-4
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Table 5 Substrate scope study for the synthesis of tetrahydrobenzo[a]acridinone
(
5) derivatives
O
R
O
NH Cl (1 mmol)
Neat/ 85 C
OH
4
o
+
RCHO
mmol
+
O
5
mol% of
IL-3/ IL-4
N
H
1
1
mmol
1mmol
(5)
R= Aryl group with electron withdrawing or donating substituent
a, b
Entry
Aldehyde
Time (min)
% of Yield
5)
(
IL-3
IL-4
IL-3
IL-4
1
2
Benzaldehyde
15
18
12
14
88 (5a)
85 (5b)
90 (5a)
88 (5b)
4-Nitrobenzaldehyde
3
4
5
6
4-Chlorobenzaldehyde
4-Anisaldehyde
16
13
14
16
12
10
12
14
87 (5c)
91 (5d)
90 (5e)
87 (5f)
90 (5c)
94 (5d)
94 (5e)
90 (5f)
4-Tolualdehyde
2-Naphthaldehyde
a
b
Isolated yield; Reactions were carried out using 5 mol % of IL-3 or IL-4 at 85 °C
3
.2.2. Substrate scope study and tentative mechanism
The optimized conditions were successfully utilized for the generation of
different derivatives of xanthenones and acridinones with variety of substituted
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aromatic aldehyde using IL-3 and IL-4 as catalysts. All those results were included
in Table 4 and Table 5. Aliphatic aldehydes gave complex mixtures of products
under optimized condition. The product formation was not affected by the nature
of electron withdrawing or donating group bearing aromatic aldehydes (Table 4
and Table 5, entries 1-6).
The tentative mechanisms of these MC reactions can be proposed through
activation of aldehyde by acidic IL followed by nucleophilic attack of dimedone
molecule and then subsequent steps according to the reaction Scheme 2.
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Scheme 2
Tentative mechanism of tetrahydrobenzo[a]xanthenone and
tetrahydrobenzo[a]acridinone derivatives
.2.3. Reusability test of ionic liquids
3
The reusability study of IL-3 and IL-4 was investigated for the preparation of
model compounds tetrahydrobenzo[a]xanthenones (1a) and acridinone derivatives
(5a) starting from the respective three-component mixtures containing 5 mmol of
each component under the optimized conditions using 5 mol% of catalyst. After
completion of one cycle, the IL catalyst was recovered as viscous liquid within the
reaction vessel for the next cycle by following the optimized procedure as
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mentioned in the experimental procedure (Section 2.2.2 and 2.2.3). The recovered
IL from every consecutive cycle was used for next run in the same reaction vessel
using 5 mmol of each component for the two types of MC reactions. Fig. 5 shows
higher yields of product up to six consecutive cycles with a slight increase in
reaction time which clearly represents them as efficient homogeneous catalytic ILs
under the reaction conditions. The identical FT-IR spectra of reused catalyst after
th
6
run (Fig. 6) and the fresh catalyst (Fig. 1) provides enough evidence of
retention of catalytic activity of IL-3 and IL-4.
Fig. 5 Recycling of IL-3 and IL-4
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th
Fig. 6 FT-IR spectra of reused catalysts after 6 cycle
4
. Conclusion
In this study, we developed a new series of Brønsted acidic N,N di-sulfo-
tetramethyl guanidinium carboxylate ionic liquids and characterized them with
various spectroscopic and analytical tool. The higher acidic/stable ILs
[
DSTMG][CF COO] and [DSTMG][CCl COO] were employed as efficient
3
3
reusable homogeneous catalysts for the multicomponent synthesis of
tetrahydrobenzo[a]xanthenone and tetrahydrobenzo[a]acridinone derivatives under
solvent-free medium at 75-85 °C that produce excellent yields within short time.
Furthermore, we have introduced the first ever IL catalyzed and also four
component methods for the synthesis of tetrahydrobenzo[a]acridinone derivatives.
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Acknowledgement
The authors are thankful to Sophisticated Analytical Instrumentation Centre,
Tezpur University, for analysis of different samples for this work and also to CSIR,
New Delhi, India for granting a research project no. 02(0067)/12/EMR-II to R. B.
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