Sulfamic acid-catalyzed, environmentally benign synthesis of bis-tetronic acids at ambient temperature

Article abstract of DOI:10.1007/s11164-016-2611-y

Abstract: An enviro-economic protocol has been described for the synthesis of bis-tetronic acids by pseudo-three-component condensation between aldehydes/isatins and tetronic acid using sulfamic acid as a solid acid catalyst. Easy commercial availability of the catalyst at extremely low cost, excellent yields and avoidance of conventional purification procedures are the main merits of this energy efficient protocol. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2611-y

Res Chem Intermed
DOI 10.1007/s11164-016-2611-y
Sulfamic acid-catalyzed, environmentally benign
synthesis of bis-tetronic acids at ambient temperature
Kapil S. Pandit1 Uday V. Desai1 Prakash P. Wadgaonkar2
Kisan M. Kodam3
•
•
•
Received: 17 February 2016 / Accepted: 13 June 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract An enviro-economic protocol has been described for the synthesis of bis-
tetronic acids by pseudo-three-component condensation between aldehydes/isatins and
tetronic acid using sulfamic acid as a solid acid catalyst. Easy commercial availability of
the catalyst at extremely low cost, excellent yields and avoidance of conventional
purification procedures are the main merits of this energy efficient protocol.
Graphical Abstract
O
O
R
O
R
O
H
O
HO
O
OH
O
Sulfamic acid
EtOH, RT
O
2
OH
OH
R1
O
O
O
O
N
H
O
O
R1
O
N
H
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2611-
y) contains supplementary material, which is available to authorized users.
&
Uday V. Desai
uvdchem2011@gmail.com
1
2
3
Organic Chemistry Division, Department of Chemistry, Shivaji University, Kolhapur 416004,
India
Polymer Science and Engineering Division, CSIR, National Chemical Laboratory,
Pune 411008, India
Department of Chemistry, Savitribai Phule Pune University, Pune 411007, India
123

K. S. Pandit et al.
Keywords Sulfamic acid Á Bis-tetronic acids Á Domino reactions Á Green
chemistry Á Organo-catalyst
Introduction
The main issue in the synthesis of complex organic molecules is currently aimed at
improving efficiency, avoidance of toxic agents, reduction in waste and responsible
utilization of natural sources [1–4]. In this context, the use of multicomponent
reactions involving the participation of three or more substrates is of relevance from
both economic and ecological points of view [5–9]. Like multicomponent reactions,
domino reactions also constitute a powerful synthetic strategy to introduce chemical
and structural complexity. Among domino reactions, Knoevenagel–Michael reac-
tions have emerged as a powerful strategy in the synthesis of various oxa- as well as
aza-heterocycles [10–13].
It is well known that Knoevenagel-initiated Domino reactions of aldehydes with
active methylene compounds like dimedone, cyclohexane-1,3-dione, 4-hydroxy-
coumarin, Meldrum’s acid, barbituric acid, pyrazolone, tetronic acid, etc., furnish
biologically active organic compounds. For instance, 1-oxo-hexahydroxanthenes
(Fig. 1A) results from the reaction between salicylaldehydes with two equivalents
of cyclic-1,3-diones [14–20], while tetraketones (Fig. 1B) result from the reaction
between the same diketones with aromatic aldehydes, devoid of the ortho-hydroxyl
group [21–24]. Among these, 1-oxo-hexahydroxanthenes are known for their
important pharmacological properties, such as anti-estrogenic, antimicrobial,
hypoglycaemic, antibacterial and thrombin inhibitory activities and serve as
Fig. 1 Structures of representative biologically active molecules (A–M) of synthetic and natural origin
123

Sulfamic acid-catalyzed, environmentally benign…
neuropeptide YY5 receptor antagonists [25–28], while tetraketones are known to
possess antitumor activity [29–32]. On the other hand, bis-coumarins (Fig. 1C),
which result from the reaction between aldehydes with two equivalents of
4-hydroxycoumarin, are known to act as urease inhibitor, anti-oxidant, polymerase
b-lyase inhibitor, anticoagulant and snake venom NPP1 inhibitor [33–39], while bis-
pyrazoles (Fig. 1D) are known to exhibit antibacterial, antidepressant and antifi-
larial activities [40–42]. The molecules containing quinolone as well as uracil as the
structural motif are known to exhibit important biological activities. For instance,
bis-N-methyl-4-hydroxyquinolones (Fig. 1E) and bis-uracils (Fig. 1F) are known to
exhibit antibacterial as well as anticancer activities [43–47]. Indoles are conven-
tionally not regarded as active methylene compounds. However, they can also
undergo reactions with aldehydes to furnish bis-indolylalkanes, among which
Vibrindole-A, (Fig. 1G) is known to have anticancer activity [48–50]. Among
various active substrates employed for the synthesis of bis-derivatives, our attention
has been focused on relatively less explored tetronic acid (Fig. 1J).
It is well known that tetronic acid (Fig. 1J) constitutes a subclass of b-hydroxy
butenolides, and two important members belonging to this class are pennicillic acid
(Fig. 1K) and ascorbic acid (Fig. 1L). A great number of compounds belonging to
this class are found in many natural products which exhibit a wide array of
biological properties [51–53]. In addition, many heterocycles containing tetronic
acid as a structural motif are known to exhibit important biological activities. [54].
A literature survey within the framework on the use of tetronic acid in the
synthesis of corresponding bis derivatives revealed that, to the best of our
knowledge, there are only two reports on the synthesis of bis-tetronic acids [55–57].
Zhang et al. [55] reported the synthesis of bis-tetronic acids using aldehydes as
starting compounds and diethylamine as well as an electrochemically generated
base (EGB) as the catalysts. The EGB-promoted protocol is operable at 0 °C while
the diethylamine-catalyzed protocol requires more than a stoichiometric amount of
the catalyst, reflux conditions and very long reaction times, and furnishes the desired
bis-tetronic acid in low yield. On the other hand, Daribi et al. [56] have reported the
synthesis of bis-tetronic acids using isatins as starting compounds. This protocol
also suffers from drawbacks such as the use of elevated temperature and the
necessity for ultrasonic activation. Keeping all these facts in mind, we envisaged
that there certainly exists scope for the development of a practically simple protocol
for the synthesis of bis-tetronic acids. Here, we report a sulfamic acid-catalyzed
protocol for the synthesis of bis-tetronic acids (Scheme 1).
Experimental
General experimental procedure for 3/5
To a well-stirred solution of aldehyde 1 or isatin 4 (2 mmol) and tetronic acid 2
(4 mmol) in ethanol (5 mL) was added sulfamic acid (20 mol%) with continuous
stirring. With the progress of the reaction, a yellowish solid separated out. Upon
completion of the reaction (TLC), the resultant solid was filtered, washed with
123

K. S. Pandit et al.
Scheme 1 Sulfamic acid-catalyzed synthesis of bis-tetronic acids
ethanol and dried. The resultant bis-tetronic acid 3/5 was found to be pure and did
not require any further purification.
The spectral data of new compounds is summarized below.
3-((2,5-Dihydro-4-hydroxy-2-oxofuran-3-yl)(4-isopropylphenyl)methyl)-4-hydroxy-
furan-2(5H)-one, 3f Solid; M. P.: 186–189 °C; IR (KBr): 3347, 1710, 1645, 1488,
1
1419, 1223, 1087 cm-1; H-NMR: (300 MHz, DMSO-d6): d 1.15 (s, 3H), 1.17 (s,
3H), 2.76–2.86 (m, 1H), 4.60–4.66 (m, 4H), 4.87 (s, 1H), 7.07 (s, 1H); 13C-NMR:
(75 MHz, DMSO-d6,); d 24.20, 31.38, 33.47, 67.60, 100.66, 126.43, 127.35, 137.44,
146.78, 175.72, 176.99 ppm, LC–MS/MS: mass calculated for [C18H18O6]:
331.1181 [M ? H]?; Obs. mass: 331.1175 [M ? H]?.
3-((4-Chlorophenyl)(2,5-dihydro-4-hydroxy-2-oxofuran-3-yl)methyl)-4-hydroxyfu-
ran-2-(5H)-one, 3g Solid; M. P.: 210–212 °C; IR (KBr): 3429, 1714, 1645, 1482,
1
1414, 1125, 1012 cm-1; H-NMR: (300 MHz, DMSO-d6): d 4.51–4.66 (m, 4H),
4.86–4.98 (m, 1H), 7.15 (s, 4H); 13C-NMR: (75 MHz, DMSO-d6): d 31.47, 67.56,
100.10, 128.32, 129.12, 131.79, 138.73, 175.67, 176.60 ppm; LC–MS/MS: mass
calculated for [C15H11ClO6]: 323.0322 [M ? H]?; Obs. mass: 323.0320 [M ? H]?.
3-((2,5-Dihydro-4-hydroxy-2-oxofuran-3-yl)(3,4-dimethylphenyl)methyl)-4-hydrox-
yfuran-2(5H)-one, 3j Solid; M. P.: 175–178 °C; IR (KBr): 3447, 1743, 1676,
1
1499, 1401, 1155, 1054 cm-1; H-NMR: (300 MHz, DMSO-d6): d 2.15 (s, 6H),
4.59–4.66 (m, 4H), 4.71 (s, 1H), 6.90 (d, 2H, J = 3.2 Hz), 6.99 (d, 1H, J = 7.6 Hz),
7.93 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d 19.37, 20.03, 32.24, 67.41,
99.10,125.18, 128.91, 129.56, 134.25, 135.98, 138.33, 176.14, 176.20 ppm; LC–
MS/MS: mass calculated for [C17H16O6]: 317.1025 [M ? H]? and 339.0845
[M ? Na]?; Obs. mass: 317.1019 [M ? H]? and 339.0837 [M ? Na]?.
3-((2,5-Dihydro-4-hydroxy-2-oxofuran-3-yl)(2,5-dimethylphenyl)methyl)-4-hydrox-
yfuran-2(5H)-one, 3k Solid; M. P.: 206–208 °C; IR (KBr): 3432, 1721, 1632,
1531, 1434, 1369, 1127, 1087, 834 cm-1; 1H-NMR: (300 MHz, DMSO-d6): d 2.21
(s, 3H), 4.51–4.63 (m, 4H), 4.88 (s, 1H), 6.83 (d, 1H, J = 7.4 Hz), 6.91 (d, 1H,
J = 7.6 Hz), 7.04 (s, 1H), 10.15 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d
19.26, 21.38, 29.99, 67.21, 100.13, 127.26, 128.77, 130.32, 132.80, 134.56, 138.00,
174.84, 176.27 ppm, LC–MS/MS: mass calculated for [C17H16O6]: 317.1025
[M ? H]? and 339.0845 [M ? Na]?; Obs. mass: 317.1019 [M ? H]? and
339.0837 [M ? Na]?.
3-((2,5-Dihydro-4-hydroxy-2-oxofuran-3-yl)(5-nitrobenzo[d][1, 3]dioxol-6-yl)methyl)-
4-hydroxyfuran-2(5H)-one, 3l Solid; M. P.: 192–195 °C; IR (KBr): 3427, 1720,
123

Sulfamic acid-catalyzed, environmentally benign…
1643, 1522, 1510, 1412, 1365, 1110, 1042, 842 cm-1 1H-NMR: (300 MHz,
;
DMSO-d6): d 4.51 (s, 4H), 5.26 (s,1H), 6.10 (s, 2H), 6.95 (s, 1H), 7.37 (d, 1H,
J = 7.4 Hz), 11.16 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d 30.67, 66.74,
98.32, 103.15, 105.04, 110.56, 131.95, 142.81, 146.55, 151.17, 174.19, 174.38 ppm;
LC–MS/MS: mass calculated for [C16H11NO10]: 378.0461 [M ? H]?; Obs. mass:
378.0820 [M ? H]?.
3-((2,5-Dihydro-4-hydroxy-2-oxofuran-3-yl)(3-methylthiophen-2-yl)methyl)-4-hy-
droxyfuran-2(5H)-one, 3m Solid; M. P.: 158–161 °C; IR (KBr): 3442, 1723, 1655,
1
1503, 1413, 1126, 1053, 865 cm-1; H-NMR: (300 MHz, DMSO-d6): d 2.06 (s,
3H), 4.56–4.68 (m, 4H), 4.90 (s, 1H), 6.74 (d, 1H, J = 5.1 Hz), 7.12 (d, 1H,
J = 5.0 Hz), 8.69 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d 13.91, 26.85,
67.32, 99.32, 122.08, 130.22, 132.72, 138.69, 175.59, 176.19 ppm; LC–MS/MS:
mass calculated for [C14H12O6S]: 331.0253 [M ? Na]?; Obs. mass: 331.0250
[M ? Na]?.
3,30-(Pyridin-3-ylmethanediyl)bis(4-hydroxyfuran-2(5H)-one), 3o Solid; M. P.:
188–190 °C; IR (KBr): 3465, 1711, 1665, 1577, 1400, 1116, 1087, 965 cm-1
;
1H-NMR: (300 MHz, DMSO-d6): d 4.45 (s, 4H), 4.65 (s, 1H), 7.87–7.91 (m, 1H),
8.28 (d, 1H, J = 7.6 Hz), 8.60 (s, 2H), 8.68 (d, 1H, J = 4.78 Hz), 10.45 (brs, 2H);
13C-NMR: (75 MHz, DMSO-d6): d 30.83, 68.31, 96.53, 127.10, 141.29, 141.57,
143.34, 143.71, 176.30, 181.43 ppm; LC–MS/MS: mass calculated for [C14H11
NO6]: 290.2481 [M ? H]?; Obs. mass: 290.0635 [M ? H].?
3,3-Bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1,3-dihydro-2H-indol-2-one,
Solid; M. P.: 164–167 °C; IR (KBr): 3420, 3152, 3056, 1766, 1565, 1315, 916,
719 cm-1 1H-NMR: (300 MHz, DMSO-d6): d 4.50 (s, 4H), 6.77 (d, 1H,
5a
;
J = 7.8 Hz), 6.85 (t, 1H, J = 7.6 Hz), 7.09 (t, 1H, J = 7.5 Hz), 7.43 (d, 1H,
J = 7.5 Hz), 10.73 (s, 1H), 10.80 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d
48.79, 66.49, 109.72, 121.71, 126.94, 128.15, 130.57, 141.84, 172.36, 174.57,
178.60 ppm; LC–MS/MS: mass calculated for [C16H11NO7]: 330.0614 [M ? H]?
and 352.0434 [M ? Na]?; Obs. mass: 330.0802 [M ? H]? and 352.0601
[M ? Na]?.
3,3-Bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-5-nitro-1,3-dihydro-2H-indol-2-
one, 5b Solid; M. P.: 175–178 °C; IR (KBr): 3440, 3122, 3067, 1772, 1580, 1340,
951, 715 cm-1 1H-NMR: (300 MHz, DMSO-d6): d 4.68 (s, 4H), 6.97(d, 1H,
;
J = 9.3 Hz), 8.13 (s, 2H), 11.13 (s, 1H), 11.93 (brs, 2H); 13C-NMR: (75 MHz,
DMSO-d6): d 47.62, 66.90, 95.79, 109.66, 120.20, 125.73, 133.31, 142.29, 148.97,
172.73, 174.73, 176.34 ppm; LC–MS/MS: mass calculated for [C16H10N2O9]:
375.0464 [M ? H]?; Obs. mass: 375.0597 [M ? H]?.
5-Bromo-3,3-bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1,3-dihydro-2H-indol-2-
one, 5c Solid; M. P.: 182–184 °C; IR (KBr): 3445, 3130, 3054, 1757, 1558, 1340,
1
975, 819 cm-1; H-NMR: (300 MHz, DMSO-d6): d 4.60 (s, 4H), 6.73 (d, 1H,
J = 7.8 Hz), 7.30 (d, 1H, J = 7.1 Hz), 7.41 (s, 1H), 10.58 (s, 1H), 11.97 (brs, 2H);
13C-NMR: (75 MHz, DMSO-d6): d 48.02, 66.72, 111.46, 113.18, 127.67, 130.85,
123

K. S. Pandit et al.
134.61, 141.62, 172.71, 174.26, 175.97 ppm; LC–MS/MS: mass calculated for
[C16H10BrNO7]: 407.9716 [M ? H]?; Obs. mass: 407.9734 [M ? H]?.
3,3-Bis-(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1-methyl-1,3-dihydro-2H-indol-2-
one, 5d Solid; M. P.: 158–161 °C; IR (KBr): 3435, 3101, 2999, 1774, 1563, 965,
1
689 cm-1; H-NMR: (300 MHz, DMSO-d6): d 3.12 (s, 3H), 4.56 (s, 4H), 6.92 (t,
2H, J = 7.4 Hz), 7.21 (t, 1H, J = 7.2 Hz), 7.33 (d, 1H, J = 7.6 Hz), 11.91 (brs,
2H); 13C-NMR: (75 MHz, DMSO-d6): d 26.85, 47.50, 66.60, 96.81, 108.45, 122.31,
124.83, 128.24, 131.32, 143.59, 172.57, 174.06, 175.01 ppm; LC–MS/MS: mass
calculated for [C17H11NO7]: 344.0770 [M ? H]?; Obs. mass: 344.0871 [M ? H]?.
3,3-Bis-(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-5-methyl-1,3-dihydro-2H-indol-2-
one, 5e Solid; M. P.: 162–164 °C; IR (KBr): 3467, 3092, 2918, 1754, 1545, 1313,
868, 777 cm-1; 1H-NMR: (300 MHz, DMSO-d6): d 2.18 (s, 3H), 4.57 (s, 4H), 6.65
(d, 1H, J = 7.8 Hz), 6.92 (d, 1H, J = 7.5 Hz), 7.16 (s, 1H),10.42 (s, 1H), 11.83
(brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d 21.23, 48.21, 66.53, 96.97, 109.27,
126.15, 128.44, 130.22, 132.08, 139.71, 172.65, 173.92, 176.95 ppm; LC–MS/MS:
mass calculated for [C17H13NO7]: 344.0770 [M ? H]?; Obs. mass: 344.0871
[M ? H]?.
5-Chloro-3,3-bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1,3-dihydro-2H-indol-2-
one, 5f Solid; M. P.: 177–179 °C; IR (KBr): 3498, 3153, 2976, 1768, 1554, 1322,
1
977, 788 cm-1; H-NMR: (300 MHz, DMSO-d6): d 4.61 (s, 4H), 6.78 (d, 1H,
J = 7.6 Hz), 7.17 (d, 1H, J = 6.9 Hz), 7.29 (s, 1H), 10.58 (s, 1H), 11.89 (brs, 2H);
13C-NMR: (75 MHz, DMSO-d6): d 48.07, 66.72, 96.32, 110.32, 125.00, 125.48,
128.03, 134.20, 141.18, 172.72, 174.26, 176.12 ppm; LC–MS/MS: mass calculated
for [C16H10ClNO7]: 364.0224 [M ? H]?; Obs. Mass: 364.0281 [M ? H]?.
7-Chloro-3,3-bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1,3-dihydro-2H-indol-2-
one, 5g Solid; M. P.: 184–187 °C; IR (KBr): 3484, 3155, 3012, 1770, 1561, 1358,
866, 777 cm-1 1H-NMR: (300 MHz, DMSO-d6): d 4.58 (s, 4H), 6.86 (t, 1H,
;
J = 7.9 Hz), 7.16 (d, 1H, J = 8.00 Hz), 7.24 (d, 1H, J = 7.4 Hz), 10.81 (s, 1H),
11.88 (brs, 2H); 13C-NMR: (75 MHz, DMSO-d6): d 48.63, 66.68, 96.57, 113.52,
122.86, 123.50, 128.15, 134.18, 139.98, 172.63, 174.10, 176.09 ppm; LC–MS/MS:
mass calculated for [C16H10ClNO7]: 364.0224 [M ? H]?; Obs. Mass: 364.0281
[M ? H]?.
Results and discussion
It is well known that Knoevenagel condensation as well as Michael addition
reactions are typically base catalyzed reactions. Logically, with the choice of an
appropriate base, Knoevenagel–Michael Domino reactions could also be effected.
Based upon this philosophy, recently we have reported the synthesis of 1-oxo-
hexahydroxanthenes and bis-coumarins using diethylamine as the catalyst [18]. As
the synthesis of bis-tetronic acids is also delineated to proceed by the Knoevenagel–
123

Sulfamic acid-catalyzed, environmentally benign…
Table 1 Screening of catalyst for the optimum yield of bis-tetronic acid 3a at ambient temperature
Entry
Catalyst (20 mol%)
Time (h)
Yield (%)a
1
THAM
12
12
12
12
12
12
24
24
24
12
4
NR
40b
50
2
Triethylamine
Piperidine
3
4
Dimethylaminopyridine
DBU
50b
5
60
6
DABCO
52
7
Potassium phosphate
Potassium carbonate
Imidazole
45b
45b
30b
35b
91
8
9
10
11
12
13
14
15
Urea
Sulfamic acid
Sulfamic acidc
Sulfamic acidd
Oxalic acid
8
76
12
6
64
70
p-Toluenesulfonic acid
6
77
Reaction conditions: anisaldehyde (1 mmol), tetronic acid (2 mmol), catalyst (20 mol%), EtOH (5 mL),
RT. The combination with the best yield is shown in bold.
NR No reaction
a
Isolated yield
b
Yield refers to Knoevenagel condensation product
c, d
Sulfamic acid (15 and 10 mol%, respectively)
Michael Domino pathway, we planned to screen the suitability of a basic catalyst in
the synthesis of bis-tetronic acids.
To begin with, a few model reactions were performed at ambient temperature
using anisaldehyde 1a and tetronic acid 2 as the substrates (1:2 equiv.), ethanol as
the reaction medium and triethylamine, piperidine, DBU, DABCO, dimethy-
laminopyridine, Imidazole, Tris-hydroxymethylaminomethane (THAM), urea,
potassium phosphate and potassium carbonate (20 mol%) as the catalysts. The
results are summarized in Table 1. It was noticed that, with the choice of most of
these catalysts, the reaction remained arrested at the Knoevenagel condensation
stage, while, with the choice of piperidine, DBU and DABCO, the reactions
furnished the desired bis-tetronic acid 3a in very low yield. Next, we planned to
screen a few Brønsted acid catalysts for the synthesis of bis-tetronic acids. The
choice of an acid catalyst was based upon the parameters of easy commercial
availability, cost, ease of handling and its environmental compatibility. The model
123

K. S. Pandit et al.
Table 2 Sulfamic acid-catalyzed synthesis of the bis-tetronic acids, 3/5
Product
Aldehyde
Time (h)
Yielda (%)
Melting point (°C)
Obs.
Lit. [Ref.]
3a
3b
3c
3d
3e
3f
4-Methoxybenzaldehyde
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Methylbenzaldehyde
4-Isopropylbenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
Benzaldehyde
4.0
3.5
3.0
4.0
4.5
4.5
4.0
4.0
4.5
4.0
4.5
3.5
4.0
12.0
4.5
12
91
82
88
84
85
91
85
84
89
87
85
88
86
NR
69
NRb
86
85
83
82
85
84
82
174–178
224–226
235–237
230–232
190–192
186–189
210–212
187–190
132–135
175–178
206–208
192–195
158–161
–
174–176 [55]
227–229 [55]
236–238 [55]
232–234 [55]
187–189 [55]
–
3g
3h
3i
–
192–194 [55]
125–127 [55]
3j
3,4-Dimethylbenzaldehyde
2,5-Dimethylbenzaldehyde
6-Nitropiperonal
–
3k
3l
–
–
3m
3n
3o
3p
5a
5b
5c
5d
5e
5f
3-Methyl-2-thiophenecarbaldehyde
n-Butyraldehyde
–
–
Pyridine-3-carbaldehyde
Furfural
188–190
–
–
–
Isatin
6.0
5.5
6.0
6.0
6.0
6.0
6.0
164–167
175–178
182–184
158–161
162–164
177–179
184–187
168–170 [56]
5-Nitroisatin
178–180 [56]
5-Bromoisatin
181–183 [56]
1-Methylisatin
–
5-Methylisatin
163–165 [56]
5-Chloroisatin
–
–
5g
7-Chloroisatin
Reaction conditions: aldehyde/isatin (1 mmol), tetronic acid (2 mmol), SA (20 mol%), Ethanol (5 mL),
RT
NR No reaction
a
Isolated yield
b
Dark brown gummy solid
123

Sulfamic acid-catalyzed, environmentally benign…
Scheme 2 Sulfamic acid catalyzed synthesis of spirocyclic bis-tetronic acids 5
Scheme 3 Plausible mechanism of sulfamic acid-catalyzed synthesis of bis-tetronic acids
reaction between anisaldehyde 1a and tetronic acid 2 was then repeated in the
presence of three acid catalysts, i.e., oxalic acid, sulfamic acid and p-toluenesulfonic
acid, which fulfil the aforementioned requirements. During monitoring of the
reactions, it was noticed that, with the use of all these acids, a pale yellow colored
solid separates out during the reactions. Upon completion of the reaction (TLC), the
resultant solid in each reaction flask was filtered, washed with water and dried. On
the basis of physical as well as spectroscopic data, the resulting product was
identified to be the desired bis-tetronic acid 3a. Most interestingly, with the choice
of sulfamic acid (20 mol%), the desired bis-tetronic acid was obtained as a sole
product and in excellent yield (91 %), while, with the choice of oxalic acid as well
as p-toluenesulfonic acid as catalyst, the desired 3a was obtained in lower yield.
The use of sulfamic acid as an organo-acid catalyst is well documented [58].
Earlier, we have demonstrated the use of sulfamic acid as an organo-catalyst in the
multicomponent synthesis of a-aminophosphonates, a-aminonitriles, 1-oxo-hex-
ahydroxanthenes and a-trimethylsilyloxy phosphonates [59–62]. On the other hand,
there are also reports on sulfamic acid-catalyzed synthesis of bis-indolylalkanes and
bis-pyrazoles [63, 64], and when the current work on the synthesis of bis-tetronic
acid was complete, there appeared a report on the application of sulfamic acid in the
synthesis of bis-Lawsome (Fig. 1M) derivatives [65]. However, to the best of our
knowledge, there are no reports on the use of sulfamic acid in the synthesis of bis-
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K. S. Pandit et al.
tetronic acids. Hence, we planned to explore the use of sulfamic acid in the
synthesis of bis-tetronic acids.
Employing the reaction conditions established for the synthesis of 3a, a variety of
aromatic as well as heteroaromatic aldehydes were allowed to react with tetronic
acid (2 equiv.). It was observed that, irrespective of the presence of electron-
withdrawing or electron-donating groups, all the aromatic aldehydes furnished
corresponding the bis-tetronic acids 3b–m in excellent yield (Table 2). However,
under the same reaction conditions, n-butyraldehyde, a representative aliphatic
aldehyde, failed to furnish the corresponding bis-tetronic acid. Modification of the
reaction conditions as regards change in solvent, increase in the amount of catalyst,
and reaction temperature did not obtain the corresponding bis-tetronic acid in
acceptable yield. To expand the scope of the present protocol, we next planned to
replace the aldehyde component from the reactions with isatins (Scheme 2). We are
indeed happy to disclose that, under the reaction conditions, various isatins also
underwent smooth condensation with tetronic acid to furnish the corresponding bis-
tetronic acids 5a–g in excellent yields (Table 2). A plausible mechanism of sulfamic
acid-catalyzed synthesis of bis-tetronic acids is depicted in Scheme 3. Based upon
the analogy between the structures of bis-coumarins (Fig. 1C) and bis-tetronic acids
(Fig. 1I), we anticipate that, similar to bis-coumarins, bis-tetronic acids may also
exhibit urease inhibitor, anti-oxidant and anticoagulant activities. Currently, these
studies are being pursued in our laboratory.
Conclusion
In summary, we have developed an extremely simple and environmentally benign
protocol for the synthesis of bis-tetronic acids using sulfamic acid as the catalyst.
Commercial availability of the catalyst at extremely low cost, ambient reaction
conditions, excellent yields and avoidance of conventional work-up, as well as
purification procedures, are the notable advantages of this energy-efficient protocol.
Acknowledgments Authors KSP and UVD are grateful to UGC, New Delhi, for financial assistance [F.
No. 43-221/2014 (SR)]. We are also grateful to DST, New Delhi, for financial assistance to the
Department of Chemistry, Shivaji University Kolhapur, under DST–FIST program.
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