Synthesis of xanthene and coumarin derivatives in water by using β-Cyclodextrin

Article abstract of DOI:10.1007/s11164-020-04308-3

Simple and green procedure was developed for the synthesis of various xanthene and coumarin derivatives using beta-cyclodextrin (β-CD) as reusable catalyst at 70?°C in water. Condensation of salicylaldehyde (1?mmol) and dimedone (2?mmol) or 1,3 cyclohexadione (2?mmol) gave corresponding xanthene derivatives, while condensation of salicylaldehyde (1?mmol) with Meldrum’s acid (1?mmol) or 4-Hydroxy-6-methyl-2H-pyran-2-one (1?mmol) gave respective coumarin derivatives in impressive yields. Involvement of β-CD as catalyst was ascertained by inclusion complex evaluation of β-CD-salicylaldehyde with ¹H NMR analysis at 70?°C. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-020-04308-3

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04308-3
Synthesis of xanthene and coumarin derivatives in water
by using β‑Cyclodextrin
Siddharth R. Kamat1 · Ananda H. Mane2 · Audumbar D. Patil3 ·
Trushant R. Lohar3 · Rajashri S. Salunkhe3
Received: 8 May 2020 / Accepted: 21 October 2020
© Springer Nature B.V. 2020
Abstract
Simple and green procedure was developed for the synthesis of various xanthene and
coumarin derivatives using beta-cyclodextrin (β-CD) as reusable catalyst at 70 °C in
water. Condensation of salicylaldehyde (1 mmol) and dimedone (2 mmol) or 1,3
cyclohexadione (2 mmol) gave corresponding xanthene derivatives, while condensa-
tion of salicylaldehyde (1 mmol) with Meldrum’s acid (1 mmol) or 4-Hydroxy-6-
methyl-2H-pyran-2-one (1 mmol) gave respective coumarin derivatives in impres-
sive yields. Involvement of β-CD as catalyst was ascertained by inclusion complex
evaluation of β-CD-salicylaldehyde with 1H NMR analysis at 70 °C.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04308-3) contains supplementary material, which is available to authorized users.
*
Siddharth R. Kamat
siddharth.kamat888@gmail.com; srkamat@dkte.ac.in
1
2
3
Department of Chemistry, D.K.T.E.S’s. Textile and Engineering Institute, Ichalkaranji,
M.S 416115, India
Department of Chemistry, K.I.T’s, College of Engineering, Gokul Shirgaon, Kolhapur,
M.S 416234, India
Department of Chemistry, Shivaji University, Kolhapur, M.S 416004, India
Vol.:(0123456789)
1 3

S. R. Kamat et al.
Graphic abstract
Keywords β-CD · Inclusion complex · 1H NMR analysis · Xanthenes · Coumarins
Introduction
Xanthene derivatives have engrossed enormous interest in the feld of medical and
material chemistry in last few decades [1]. Novel methodologies and number of
catalysts have been reported for the synthesis of xanthene derivatives [2]. The cata-
lyst like CsF [3], L-proline [4], PTSA [5], nanoparticles [6–8], ionic liquid [9–11],
tetra-n-butylammonium fuoride [12], cellulose sulfuric acid [13], CeCl3-7H2O
Table 1 Literature review on cyclodextrin used in organic synthesis as catalyst
Sr. no Organic synthesis
Catalyst
Refs
1
2
3
Synthesis of xanthenes
Enantioselective reduction of ketones
Synthesis of spirooxindoles
Cyclodextrin nanosponges S. Sadjadi, et al. [39]
Fe3O4@SiO2/Pr-β-CD
M. J. Nasab et al. [40]
β-cyclodextrin (Fe3O4/
COS@β-CD-SO3H
NPs)
B. Akhlaghinia et al. [41]
4
5
Synthesis of chromeno[4,3-b]quinolin-
isonicotinamides
β-cyclodextrin
M. R. Bhosle et al. [42]
Synthesis of kojic acid-based heterocy- β-cyclodextrin nanosponge R. Kardooni et al. [43]
clic compounds
1 3

Synthesis of xanthene and coumarin derivatives in water by…
[14], 2,4,6-Trichloro-1,3,5-Triazine [15], TEBA [16] have been used. The catalyst-
free synthesis of these derivatives has been described in water [17] and DMF [18].
Coumarin-based organic molecules [19] are known to have biological activity such
as antianaphylactic, anticoagulant, diuretic [20], anticonvulsant [21], antimicrobial
[22] and insecticidal properties [23]. Coumarin derivatives are extensively used as
laser dye and optical brighteners [24]. Reported syntheses of coumarins include the
use of biosurfactant [25], L-prolin [26], ionic liquid [27, 28], K3PO4 [29], FeCl3
[30], ZnS nanoparticles immobilized on graphitic carbon nitride [31], poly(4-sty-
renesulfonic acid) mesoporous graphene oxide [32] and Fe3O4@SiO2@(CH2)3‐
urea‐benzimidazole with sulfonic acid [33]. Cyclodextrins are cyclic oligosaccha-
rides, history of the cyclodextrins (CD’s) as supramolecule is very fascinating [34].
Hydrophobic cavities of β-CD hold the organic compounds selectively and assess
the organic reactions with good selectivity [35–38]. Among the α, β and γ cyclodex-
trins (CD’s), β-CD has been extensively used in organic synthesis as catalyst. Some
reported methodologies are summarized below (Table 1).
Experimental
β-CD was purchased from Himedia, and all remaining chemicals from Sigma
Aldrich, Spectrochem, s. d. Fine chemical Limited (India). These chemicals were
used as such exclusive of extra purifcation. Melting points were determined in an
open capillary and are uncorrected. Infrared spectra were recorded on PerkinElmer
FT-IR spectrometer (KBr discs~5% w/w). NMR spectra were recorded on Bruker
Avon 300 MHz spectrometer using CDCl3 as solvent and tetramethylsilane as inter-
1
nal reference. HNMR spectra of β-CD and β-CD-salicylaldehyde inclusion com-
plex were recorded on Bruker Avon 400 MHz spectrometer using D2O as solvent
and tetramethylsilane as internal reference.
General procedure for synthesis of xanthene derivatives
β-CD (1.135 gm, 1 mmol) was dissolved in water (15 mL) at 70 °C, and to this
solution, salicylaldehyde (0.122 g, 1 mmol) and dimedone (0.280 g, 2 mmol) were
added in 50-mL-round bottom fask. The reaction mixture was stirred at 70 °C till
the reaction was completed (monitored by TLC, ethyl acetate: petroleum ether: 2:8).
The reaction mixture was extracted with chloroform (3×15 mL), and the organic
layer was dried over anhydrous Na2SO4. After removal of solvent, crude product
was obtained and recrystallized with 95% EtOH.
The reusability of β-CD as reaction medium was found to be suitable for fve
times with no noteworthy loss in yield of product.
General procedure for synthesis of coumarin derivatives
β-CD (1.135 g, 1 mmol) was dissolved in water (15 mL) at 70 °C and to this solu-
tion salicylaldehyde (0.122 g, 1 mmol), and Meldrum’s acid (0.144 g, 1 mmol) or
1 3

S. R. Kamat et al.
Scheme 1 Synthesis of xanthenes derivatives
Scheme 2 Synthesis coumarin derivatives
4-Hydroxy-6-methyl-2H-pyran-2-one (0.126 g, 1 mmol) were added in 50-mL-
round bottom fask. The reaction mixture was stirred till the reaction was completed
(monitored by TLC, ethyl acetate: petroleum ether: 2:8). Further steps are similar as
mentioned above for synthesis of xanthene derivatives.
1 3

Synthesis of xanthene and coumarin derivatives in water by…
Table 2 Optimization of
Entry
β-CD (mmol)
Time (Min)
Temp. (°C)
Yieldb (%)
the reaction temperature
for the synthesis of 1-oxo-
1
2
3
4
5
6
7
8
–
1
1
1
1
1
1
1
120
90
75
70
65
50
50
50
rt
rt
Nil
40
52
69
88
95
94
93
hexahydroxanthene derivativesa
40
50
60
70
80
90
rt: room temperature=25–28 °C
aReaction condition: Salicylaldehyde (1 mmol), dimedone (2 mmol),
β-CD (1 mmol), 15 mL water
bIsolated yield of product
Table 3 Synthesis of xanthene derivatives by using β-CD at 70 °C temperature in watera
Entry R1
R2
R3
Product Time (min.) Yield b(%) Mp (°C)
Refs
Found
Lit
1
2
3
4
5
6
7
8
H
H
OMe
OMe
OEt
H
H
Cl
H
H
OMe
OMe
OEt
H
H
Cl
2OH-naphtha-
lene-1-car-
baldehyde
H
CH3 3a
50
15
30
60
30
15
15
60
50
25
30
90
30
20
20
90
82
95
95
94
84
92
93
94
85
92
93
92
82
92
90
92
82
208–210 210–212 [15]
204–206 203–205 [15]
230–232 229–231 [15]
NO2 CH3 3b
CH3 3c
NO2 CH3 3d
H
212–214
188–190
–
–
–
–
H
CH3 3e
CH3 3f
CH3 3 g
CH3 3 h
Br
Cl
Cl
H
NO2
H
NO2
H
Br
Cl
Cl
250–252 251–253 [15]
234–236 236–268 [15]
250–252 236–237 [15]
246–248 245–246 [16]
244–246 244–246 [15]
9
H
H
H
H
H
H
H
H
3i
3j
10
11
12
13
14
15
16
17
3 k
3 l
3 m
3n
3o
3p
60
195–197
210–212
220–222
–
–
–
–
–
–
240–242 238–239 [15]
215–217 217–219 [15]
252–254 255–256 [15]
CH3 3q
242–246
240–242
[15]
aReaction conditions: salicylaldehyde (1 mmol), dimedone (2 mmol) or 1,3-cyclohexadione, β-CD
(1 mmol), solvent water (15 mL) at 70 °C temperature
bIsolated yield of product
1 3

S. R. Kamat et al.
Results and discussion
Condensation of various salicylaldehyde (1 mmol) with dimedone (2 mmol) or
1,3-cyclohexadione (2 mmol) gave xanthene derivatives (scheme 1), whereas
condensation of salicylaldehydes (1 mmol) with Meldrum’s acid (1 mmol) or
4-Hydroxy-6-methyl-2H-pyran-2-one (1 mmol) gave respective coumarin deriva-
tives (scheme 2).
To assure the catalytic activity of β-CD, some series of experiments were per-
formed (Table 2). Initially, the reaction in between salicylaldehyde (1 mmol) and
dimedone (2 mmol) was carried out as model reaction without using any catalyst
in water at room temperature; no product formation was observed. Subsequently
with β-CD (1 mmol) as catalyst the model reaction formed the corresponding
product very less amount (40%). The yield of the product was observed to be
improved with the increase in reaction temperature and was maximum at 70 °C.
This might be due to complete solubilization of β-CD at 70 °C forming homoge-
neous solution of β-CD in water which lead to form the inclusion complex with
substrate molecules via host–guest infarctions. There was negligible change in
yield of the product above the 70 °C. The instability of inclusion complex of β-
CD with substrate (dimedone) in model reaction at higher temperature leads to
decrease in the yield of product above the 70 °C.
The scope and applicability of present protocol was examined for various salic-
ylaldehydes such as salicylaldehyde, 5-Nitro-salicylaldehyde, 3-Methoxy salicy-
laldehyde, 3-Ethoxy-salicylaldehyde, 5-Bromo-salicylaldehyde, 5-Chloro-salic-
ylaldehyde, 3,5-Dichloro-salicylaldehyde, 3-Methoxy-5-Nitro salicylaldehyde
Table 4 Synthesis of coumarin derivatives by using β-CD at 70 °C temperature in watera
Entry
1
4
Product Time (min.) Yieldb (%) Mp (°C)
Ref
R1
R2
Found
Lit
1
2
3
4
5
6
7
8
H
H
H
H
Br
Cl
H
4a 5a
4a 5b
4a 5c
4a 5d
4a 5e
4b 6a
20
15
15
30
20
30
40
15
15
50
94
98
97
95
96
98
97
96
97
190–192 180–190 [24]
218–220 216–217 [24]
OMe
OEt
H
H
H
176–178
–
–
194–196 196–194 [24]
118–120 120–122 [24]
144–146 144–145 [28]
H
NO2 4b 6b
H
H
Cl
210–212
172–174 170–172 [28]
202–204
200–202 198–200 [28]
–
–
OMe
OEt
Cl
4b 6c
4b 6d
4b 6e
6f 30
9
10
11
98
85
222–224
–
–
2OH- naphtha-
4b
–
–
–
lene-1-car-
baldehyde
aReaction conditions: salicylaldehyde (1 mmol), Meldrum’s acid or 4-Hydroxy-6-methyl-2H-pyran-2-
one (1 mmol), β-CD (1 mmol), solvent water (15 mL) at 70 °C temperature
bIsolated yield of product
1 3

Synthesis of xanthene and coumarin derivatives in water by…
and 2-Hydroxy-1-naphthyladehyde. The observations and results are presented in
Table 3. The monosubstituted salicylaldehydes such as 5-Nitro-salicylaldehyde,
3-Methoxy salicylaldehyde, 3-Ethoxy-salicylaldehyde, 5-Bromo-salicylaldehyde,
5-Chloro-salicylaldehyde reacts very efciently and yield the corresponding
crude products more than 90% (Table 3).
However, 3-Methoxy-5-Nitro salicylaldehyde, 3,5-Dichloro salicylaldehyde, and
2-Hydroxy-1-naphthyladehyde reacts slowly to yield the corresponding xanthene
derivatives in poor yield (Table 3, entry 4, 12, 16, 17).
The unfortunate results showed that the disubstituted salicylaldehyde and polynu-
clear aldehydes are not that much suitable for above optimized reaction conditions.
This is due to larger size of substrate (disubstituted salicylaldehyde and polynuclear
aldehydes) which could not ft themselves in the hydrophobic cavity of β-CD and
hence forms unstable inclusion complex via host–guest interaction. The unstable
inclusion complex of β-CD with substrate leads to increase the duration of reaction,
poor yield of product. Those substrates remain outside the hydrophobic cavity of
β-CD due to unstable inclusion complex formation not converted in to the product
hence leads to poor yield of product.
Inspired by previous results obtained for the synthesis of 1-oxo-hexahydroxan-
thene derivatives (scheme 1), we extended the use of β-CD as green and sustainable
catalyst for the synthesis 3-carboxycoumarins and 3-acetoacetylcoumarin deriva-
tives. Substituted salicylaldehydes such as 5-Nitro-salicylaldehyde, 3-Methoxy
salicylaldehyde, 3-Ethoxy-salicylaldehyde, 5-Bromo-salicylaldehyde, 5-Chloro-
salicylaldehyde, 3,5-Dichloro-salicylaldehyde and 2-Hydroxy-1-naphthyladehyde
generates corresponding coumarin derivatives.
3,5-Dichloro salicylaldehyde and 2-Hydroxy-1-naphthyladehyde react slowly to
yield the corresponding coumarin derivatives in poor yield (Table 4, entry 10–11).
The reactivity of salicylaldehyde is not afected by the nature of functional group
attached. The all active methylene substrates dimedone,1,3-cyclohexadione, Mel-
drum’s acid or 4-Hydroxy-6-methyl-2H-pyran-2-one are found to be very comfort-
able with electron donating as well as electron withdrawing functional groups. As
discussed earlier in some reactions, yield is poor due to larger size of salicylalde-
hyde. These observations support the importance of stable inclusion complex of
β-CD during completion of reaction.
The isolated crude product of xanthene as well as coumarin derivatives were
1
recrystallized with 95% EtOH and further analyzed with IR, H NMR, 13C NMR
spectra to confrm the proposed structures of the synthesized compounds. Spectral
analyses of some representative compounds are summarized below.
Spectral analysis
5-Methoxy-7-nitro-9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (3d); IR (KBr, cm−1): υmax 3420, 2962, 1668,
1637, 1615, 1518, 1489, 1450, 1370,1334, 1301, 1269, 1198, 1163, 1100, 1065,
1019, 889, 743, 576; 1H NMR (300 MHz, CDCl3): δ 8.88 (1H, brs), 759–7.67 (2H,
m), 4.91 (1H, s), 3.94 (3H, s), 2.55 (3H, s), 2.42 (2H, s), 2.28–2.30 (3H, m), 1.05
1 3

S. R. Kamat et al.
(6H, s), 1.14 (6H, s); 13C NMR (75 MHz, CDCl3): δ 197.5, 189.6, 164.4, 150.1,
148.6, 140.9, 130.6, 118.4, 117.2, 115.2, 114.0, 105.3, 104.3, 56.3, 50.4, 40.9, 32.1,
31.3, 29.6, 29.2, 27.2, 26.1.
5-Ethoxy-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (3e); IR (KBr, cm−1): υmax 3270, 2965, 1635,
1580, 1377, 1271, 1229, 1089, 1072; 1H NMR (300 MHz, CDCl3): δ 10.47 (1H, bs),
6.93 (1H, t, J=7.8 Hz, J=7.8 Hz), 6.77 (1H, d, J=8.1 Hz), 6.59 (1H, d, J=7.5 Hz),
4.64 (1H, s), 4.10–4.17 (2H, m), 2.54–2.72 (2H, m),. 2.34–2.39 (4H, m), 1.99 (2H,
s), 1.65 (1H, s), 1.47 (3H, t, J=6.0 Hz, J=6.0 Hz), 1.14 (3H, s), 1.01–1.14 (8H,
m); 13C NMR (75 MHz, CDCl3): δ 200.9, 196.5, 170.5, 169.0, 146.5, 141.1, 125.2,
124.1, 119.8, 118.2, 112.2, 110.8, 64.9, 50.6, 49.6, 43.2, 41.5, 32.2, 30.9, 29.8, 29.1,
27.8, 27.1, 26.4, 14.8.
9,10-dihydro-12-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-9,9-dimethyl-
8H-benzo[a]xanthen-11(12H)-one (3q); IR (KBr, cm−1): υmax 3174, 2932, 1642,
1
1591, 1372, 1314, 1260, 1234, 1011, 1025, 812, 746, 609; H NMR (300 MHz,
CDCl3): δ 10.65 (1H, s), 7.71–7.79 (3H, m), 7.45–7.50 (1H, m), 7.36–7.41 (1H, m),
7.26–7.28 (1H, m), 5.28 (1H, s), 2.40–2.72 (2H, m), 2.34 (2H, s), 1.80–2.06 (2H,
m), 1.57 (2H, s), 1.28 (3H, s), 1.08–1.17 ( 3H, s), 0.87–0.95 (3H, m), 0.733 (3H,
s); 13C NMR (75 MHz, CDCl3): δ 201.29, 196.97, 170.44, 149.00, 131.41, 131.12,
128.49, 126.70, 124.59, 122.85, 117.72, 116.54, 116.17, 111.23, 50.91, 50.17,
43.22, 41.50, 32.32, 30.59, 29.85, 29.27, 27.03, 26.46, 25.48.
5-Methoxy-9-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-2,3,4,9-tetrahydro-1H-xan-
then-1-one (3 k); IR (KBr, cm−1): υmax 3120, 2952, 2833, 1644, 1614, 1597, 1582,
1479, 1458, 1437, 1422, 1372, 1330, 1275, 1190, 1133, 1096, 980, 934, 854, 830,
1
758, 747, 643, 587, 529; H NMR (300 MHz, CDCl3): δ 10.86 (1H, bs), 6.96 (1H,
t, J=9 Hz, J=9 Hz), 6.78 (1H, d, J=7.8 Hz), 6.18 (1H, d, J=7.8 Hz), 4.65 (1H, s),
3.91 (3H, s), 2.39–2.89 (6H, m), 2.02–2.10 (6H, m); 13C NMR (75 MHz, CDCl3):
δ 203.03, 201.46, 197.09, 170.83, 146.93, 125.57, 124.29, 119.82, 119.66, 112.15,
110.36, 100.34, 56.10, 36.03, 28.02, 19.99, 19.69.
5-Methoxy-7-nitro-9-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-2,3,4,9-tetrahydro-
1H-xanthen-1-one (3 l); IR (KBr, cm−1): υmax 3463, 2950, 1671, 1655, 1588, 1523,
1490, 1359, 1335, 1269, 1176, 1095, 953, 865, 744; 1H NMR (300 MHz, CDCl3): δ
9.30 (1H, brs), 7.57 (2H, d, J=11.4 Hz), 4.92 (1H, s,), 3.94 (3H, s), 2.66–2.79 (4H,
m), 2.44 (4H, bs), 2.0 (4H, bs); 13C NMR (75 MHz, CDCl3): δ 197.8, 166.1, 150.3,
148.8, 140.9, 130.7, 116.9. 115.3, 105.4, 56.8, 36.5, 27.2, 25.9, 20.0.
5-Ethoxy-9-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (3 m); IR (KBr, cm−1): υmax 2953, 1640, 1580, 1371, 1288, 1220,
1
1187, 1080, 752; H NMR (300 MHz, CDCl3): δ 10.81 (1H, bs), 6.93 (1H, t,
J=7.8, J=7.8 Hz), 6.771 (1H, d, J=8.1 Hz), 6.60 (1H, d, J=7.5 Hz), 4.64, (1H,
s), 4.10–4.17 (2H, m), 2.43–2.83 (7H, m), 2.0–4-2.14 (4H, m), 1.45–1.85 (5H, m);
13
CNMR (75 MHz, CDCl3): δ 201.40, 196.90, 172.60, 171.00, 146.30, 140.90,
125.60, 124.20, 119.90, 119.70, 112.20, 112.10, 64., 37.00, 36.00, 29.70, 28.00,
19.60, 14.80.
8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (5b); IR (KBr, cm−1): υmax
3464, 2916, 1748, 1673, 1603, 1507, 1470, 1418, 1368, 1282, 1099, 1028, 960, 815;
1H NMR (300 MHz, CDCl3): δ 12.31 (1H, bs), 8.94 (1H, s, CH), 7.39–7.45 (1H,
1 3

Synthesis of xanthene and coumarin derivatives in water by…
m), 7.30–7.34 (2H, m), 4.03 (3H, s); 13C NMR (75 MHz, CDCl3): δ 163.72, 162.46,
151.73, 147.41, 144.16, 126.18, 121.34, 119.11, 117.08, 115.04, 56.49.
8-Ethoxy-2-oxo-2H-chromene-3-carboxylic acid (5c); IR (KBr, cm−1): υmax 3445,
1
2923, 1747, 1600, 1419, 1373, 1287, 1208, 1108, 1004, 817; H NMR (300 MHz,
CDCl3): δ 12.36 (1H, s), 8.94 (1H, s), 7.28–7.42 (3H, m), 4.21–4.28 (2H, m), 1.55
(3H, t, J=6.9 Hz, J=6.9 Hz); 13C NMR (75 MHz, CDCl3): δ 163.90, 162.52,
151.78, 146.82, 144.34, 129.84, 127.55, 126.14, 121.23, 119.20, 118.17, 114.93,
65.32, 14.64.
8-Nitro-3-acetoacetylcoumarin (6b); IR (KBr, cm−1): υmax 1741, 1610, 1576,
1
1529, 1479, 1425, 1344, 1280, 1187, 1107, 999, 925, 822; H NMR (300 MHz,
CDCl3): δ 15.75 (1H, s), 8.73 (1H, s), 8.48–8.61 (2H, m), 7.52 (1H, d, J=9.3), 7.02
(1H, s), 2.32 (3H, s); 13C NMR (75 MHz, CDCl3): δ 200.67, 169.81, 157.43, 156.48,
144.37, 143.69, 129.86, 128.14, 127.58, 125.16, 122.83, 118.50, 117.85, 102.22,
27.89.
8-Methoxy-3-acetoacetylcoumarin (6c); IR (KBr, cm−1): υmax 1748, 1608, 1558,
1
1507, 1363, 1183, 1116, 1034, 816; H NMR (300 MHz, CDCl3): δ 15.92 (1H, s),
8.65 (1H, s), 7.29–7.32 (1H, m), 7.17–7.22 (2H, m), 7.07 (1H, s), 4.01 (3H, s), 2.29
(3H, s); 13C NMR (75 MHz, CDCl3): δ 199.95, 171.82, 157.53, 146.95, 145.69,
144.03, 124.81, 120.75, 119.13, 115.37, 101.78, 56.35, 27.65.
8-Ethoxy-3-acetoacetylcoumarin (6d); IR (KBr, cm−1): υmax 1748, 1601, 1507,
1
1472, 1419, 1364, 1183, 1110, 1034, 1003, 815; H NMR (300 MHz, CDCl3): δ
15.89 (1H, s), 8.64 (1H, s), 7.18–7.28 (3H, m), 7.06 (1H, s), 4.19–4.26 (2H, m),
2.29 (3H, s), 1.53 (3H, t, J=7.2, J=6.9); 13C NMR (75 MHz, CDCl3): δ 199.86,
171.99, 157.70, 146.30, 145.76, 144.23, 124.79, 120.68, 119.22, 116.61, 101.72,
65.08, 27.62, 14.73.
Fig. 1 Plausible reaction mechanism of synthesis of xanthene derivatives
1 3

S. R. Kamat et al.
(b)
(a)
Fig. 2 a Schematic side view of cyclodextrin, b α-D-glucopyranose unit in cyclodextrin
6,8-Dichloro-3-acetoacetylcoumarin (6e); IR (KBr, cm−1): υmax 1748, 1608,
1
1574, 1416, 1365, 1273, 1183, 1096, 1011, 829; H NMR (300 MHz, CDCl3):
δ 15.76 (1H, s), 8.56 (1H, s), 7.68 (1H, d J = 3.0 Hz), 7.55 (1H, d J = 3.0 Hz),
7.02 (1H, s), 2.31 (3H, s); 13C NMR (75 MHz, CDCl3): δ 200.49, 170.24, 156.31,
148.59, 143.49, 133.50, 130.07, 127.00, 122.57, 122.50, 120.27, 102.17, 27.80.
2-(1-hydroxy-3-oxobut-1-en-1-yl)-3H-benzo[f]chromen-3-one (6f); IR (KBr,
1
cm−1): υmax 1736, 1601, 1567, 1471, 1434, 1350, 1271, 1177, 1092, 966, 820; H
NMR (300 MHz, CDCl3): δ 16.08 (1H, bs), 9.45 (1H, s), 8.40 (1H, d, J=9.0), 8.10
(1H, d, J=9.0), 7.95 (1H, d, J=6), 7.77 (1H, t, J=7.8 Hz, J=7.8 Hz), 7.63 (1H,
t,, J=7.5 Hz, J=7.5 Hz), 7.49 (1H, d, J=9 Hz), 2.31 (3H, s), 7.12 (1H, s); 13C
NMR (75 MHz, CDCl3): δ 199.40, 172.64, 158.16, 154.91, 140.96, 135.79, 130.26,
129.42, 129.19, 129.08, 126.60, 121.74, 118.97, 116.48, 113.04, 101.49, 27.47.
Reaction mechanism
β-CD speed up the enolization of active methylene compounds (dimedone/ 1,3
cyclohexadione) (2) and facilitate domino Knoevenagel condensation (step–I)
reaction forming the intermediate, which further cyclize after dehydration (step-
II). In step-III, Michael addition reaction of the second molecule of active meth-
ylene compound (2) and cyclized product gives corresponding 1-oxo-hexahydrox-
anthene derivative (3) (Fig. 1).
β-CD-salicylaldehyde inclusion complex forms via host–guest interaction
which leads to solubilize the salicylaldehyde in water and accelerate product for-
mation. The host–guest interactions in between β-CD and salicylaldehyde were
confrmed by 1H NMR analysis.
The H3 and H5 protons of α-D-glucopyranose unit in cyclodextrin show more
upfeld shift compared to H2 and H4 protons (Fig. 2a,b). The H2 and H4 protons
1 3

Synthesis of xanthene and coumarin derivatives in water by…
Fig. 3 a 1H NMR spectrum of β-CD-salicylaldehyde inclusion complex at 25 °C temperature. b 1H NMR
spectrum of β-CD-salicylaldehyde inclusion complex at 70 °C temperature
are located outside the cavity of cyclodextrin; hence, they show negligible or zero
upfeld shifting in 1HNMR spectrum.
The 1HNMR spectrum of β-CD-salicylaldehyde inclusion complex 25 °C
(Fig. 3a) showed three indistinguishable multiplates of protons of α-D-
glucopyranose unit in at δ 3.49, δ 3.70 and δ 4.80 ppm. The hydroxyl protons (OH)
of β-CD not appeared in 1H NMR spectrum due to D2O exchange however hydroxyl
proton (OH) of salicylaldehyde appeared at δ 6.35 ppm. The four protons of salicy-
laldehyde ring were resonated as two sets multiplates in the range of δ 6.84–7.83
1 3

S. R. Kamat et al.
1
1
Fig. 4 a H NMR spectrum of β-CD in D2O at 70 °C temperature. b Magnifed view of H NMR spec-
trum of β-CD-salicylaldehyde inclusion complex at 70 °C
Table 5 1H NMR chemical shifts (δ ppm) of C-H protons of β-CD and β-CD salicylaldehyde inclusion
complexa
β-CD (δ ppm)
H1
H2
H3
H4
H5
H6
5.574
4.158
4.443
4.075
4.378
4.332
β-CD+Salicylaldehyde
5.551
4.147
4.389
4.075
4.209
4.344
inclusion complex (δ ppm)
upfeld shifting (Δδ ppm)
+0.023
+0.011
+0.054
0.00
+0.169
−0.012
a 1H NMR spectra were recorded with 400 MHz frequency using D2O as solvent at 70 °C temperature
1 3

Synthesis of xanthene and coumarin derivatives in water by…
ppm while sharp singlet at δ 9.80 ppm corresponds to proton of aldehyde group.
1HNMR spectrum of β–CD-salicylaldehyde inclusion complex at 70 °C (Fig. 3b)
temperature showed sharp singlet at δ 10.46 ppm corresponding to proton of alde-
hyde group. The aromatic proton ortho to aldehyde group was observed as doublet
at δ 7.54 ppm, J=6.3 Hz. The proton at meta position to aldehyde showed triplet at
δ 7.64 ppm, J=5.4 Hz while the proton at meta position to hydroxyl group showed
triplet at δ 8.15 ppm, J=5.4 Hz. The proton ortho to hydroxy group was observed
1
as doublet at δ 8.26 ppm, J=5.7 Hz. In this HNMR spectrum, the hydroxyl pro-
tons (OH) of β-CD and salicylaldehyde not appeared, which vanishes due to D2O
exchange. This observation supports the formation β-CD-salicylaldehyde inclusion
complex.
Comparison of NMR spectra of β‑CD and β‑CD‑salicylaldehyde inclusion complex
at 70 °C
The 1HNMR spectrum of β-CD at 70 °C (Fig. 4a) showed the four distinctive chemi-
cal shifts of protons attached to carbon atom of glucose unit in β-CD. The doublet at δ
5.57 ppm, J=2.7 Hz, was due to the proton attached to carbon number one; however,
the protons attached with C-2, C-3, C-4, C-5 and C-6 were resonated as three indistin-
1
guishable multiplates. The hydroxyl protons (OH) of β-CD not appeared in HNMR
spectrum due to D2O exchange.
1
The magnifed view of HNMR spectrum of β-CD-salicylaldehyde inclusion com-
plex (Fig. 4b) at 70 °C showed upfeld shift of H3 and H5 protons by δ 0.054 ppm and
δ 0.169 ppm respectively (Table 5), which confrms the β-CD-salicylaldehyde inclu-
sion complex formation by host–guest interaction.
Conclusion
The present protocol of synthesis of xanthene and coumarin derivatives is eco-
friendly as reactions proceed in water which fulfll prime requirement of chemical
industries now a day. The NMR study of β-CD-salicylaldehyde inclusion complex at
elevated temperature is faster method of analysis than lyophilization or cryodesicca-
tion method.
Acknowledgement We gratefully acknowledge the fnancial support from the University Grants Com-
mission (UGC), New Delhi, India for BSR-SAP fellowship No.F.7-183/2007(BSR), Dated 27th Jan.
2014.
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