Efficient, high-yield protocol for the one-pot synthesis of benzopyran derivatives catalyzed by p-TSA in aqueous media

Article abstract of DOI:10.1080/00397911.2010.533804

A short and simple synthesis of benzopyran derivatives was accomplished in good to excellent yields by the reaction of salicylaldehyde with 1,3-cyclohexanediones in aqueous media catalyzed by para-toluenesulfonic acid. The structures were established by s

Full text of DOI:10.1080/00397911.2010.533804

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Efficient, High-Yield Protocol for the
One-Pot Synthesis of Benzopyran
Derivatives Catalyzed by p-TSA in
Aqueous Media
Lingaiah Nagarapu a , Shuklachary Karnakanti a , Rajashaker Bantu a
& B. Sridhar b
a Organic Chemistry Division II, Indian Institute of Chemical
Technology, Hyderabad, India
b Laboratory of X-ray Crystallography, Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 06 Sep 2011.Published
online: 16 Dec 2011.
To cite this article: Lingaiah Nagarapu , Shuklachary Karnakanti , Rajashaker Bantu & B. Sridhar
(2012): Efficient, High-Yield Protocol for the One-Pot Synthesis of Benzopyran Derivatives Catalyzed
by p-TSA in Aqueous Media, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:7, 967-974
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Synthetic Communications1, 42: 967–974, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.533804
EFFICIENT, HIGH-YIELD PROTOCOL FOR THE ONE-POT
SYNTHESIS OF BENZOPYRAN DERIVATIVES
CATALYZED BY p-TSA IN AQUEOUS MEDIA
Lingaiah Nagarapu,1 Shuklachary Karnakanti,1
Rajashaker Bantu,1 and B. Sridhar2
1Organic Chemistry Division II, Indian Institute of Chemical Technology,
Hyderabad, India
2Laboratory of X-ray Crystallography, Indian Institute of Chemical
Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A short and simple synthesis of benzopyran derivatives was accomplished in good
to excellent yields by the reaction of salicylaldehyde with 1,3-cyclohexanediones in aqueous
media catalyzed by para-toluenesulfonic acid. The structures were established by spectro-
scopic data and further confirmed by x-ray analysis. In addition, water was chosen as a
green solvent.
Keywords 1,3-Cyclohexanediones; one-pot synthesis; p-TSA; salicylaldehyde; water
INTRODUCTION
Recently, benzopyran derivatives have attained considerable significance in
potential biological and pharmacological target compounds.[1] The prime driving
force in this area is the need for their anti-estrogenic activity,[2] insulin-sensitizing
activities,[3] selective thrombin inhibitory activity,[4] antimicrobial activity,[5] antibac-
terial activity,[6] and hypoglycemic activity. The construction of new analogs of het-
erocyclic compounds is a major challenge in synthetic organic and medicinal
chemistry. Because of their broad spectrum of biological interest, chemists have
developed a few methods for the synthesis of benzopyran derivatives.[7] To the best
of our knowledge, there are no reports on the use of para-toluenesulfonic acid
Received September 24, 2010.
Address correspondence to Lingaiah Nagarapu, Organic Chemistry Division II, Indian Institute of
Chemical Technology, Uppal Road, Hyderabad 500 607, India. E-mail: lnagarapuiict@yahoo.com,
Nagarapu@iict.res.in
967

968
L. NAGARAPU ET AL.
(p-TSA) catalyst for this conversion. This fact has prompted us to investigate p-TSA
for the synthesis of benzopyran derivatives in a facile and practical manner. Because
of the toxic and volatile nature of many organic solvents, water as reaction medium
was considered a very promising and attractive substitute for volatile organic sol-
vents and is widely used in the green chemistry. There has been growing recognition
that water is an attractive medium for many organic reactions, resulting in less
expensive, less dangerous, and environmentally friendly reactions such as Diels–
Alder reactions[8] and Claisen rearrangement reactions.[9] As part of our current stu-
dies on the development of new routes to heterocyclic systems,[10] we now report an
efficient and clean synthetic route to benzopyran derivatives in aqueous medium cat-
alyzed by p-TSA by the reaction of substituted salicylaldehyde with 5,5-dimethyl-
1,3-cyclohexanedione and 1,3-cyclohexanediones.
RESULTS AND DISCUSSION
When the reaction of salicylaldehyde with 5,5-dimethyl-1,3-cyclohexanedione
was performed in water in the presence of p-TSA at 90 ꢀC, good yields of benzopyran
derivatives (3a) were obtained (Scheme 1). To apply this reaction to a library syn-
thesis, various kinds of salicylaldehydes and 1,3-cyclohexanediones were subjected
to give the corresponding benzopyran derivatives, and representive examples are
shown in Scheme 1. All the benzopyran derivatives were obtained in excellent yields
with good purity. The isolated products were completely characterized by infrared
(IR), 1H NMR, 13C NMR, and mass spectroscopic analyses. The formation of com-
pound 3a was evident from the appearance ofꢁa1n [M þ H]þ peak at m=z 367 in mass
=
spectrum (ESI), -C O stretching at 1622 cm in IR, and the appearance of the
characteristic methine proton as a singlet at d 4.59 in 1H NMR. To further conform
the structure of the product, x-ray analysis was conducted. (Crystal data for 3a:
white crystals, C23H26O4, M ¼ 366.44, monoclinic, space group P21=c, a ¼ 7.0598(7)
3
ꢀ
˚
˚
˚
˚
A, b ¼ 20.267(2) A, c ¼ 13.6666(13) A, b ¼ 93.384(2) , V ¼ 1952.0(3) A , dcalc
¼
1.247 Mg mꢁ3). Data were collected at room temperature using a Bruker Smart Apex
charge couple detector (CCD) diffractometer with graphite monochromated MoKa
˚
radiation (k ¼ 0.71073 A) with the x-scan method. Preliminary lattice parameters
and orientation matrices were obtained from four sets of frames. Unit cell dimen-
sions were determined from the setting angles of 5450 reflections for compound
Scheme 1. (3a) R2 & R3 ¼ H, R1 ¼ Me; (3b) R2 ¼ H, R3 ¼ Br, R1 ¼ Me; (3c) R2 ¼ H, R3 ¼ Cl, R1 ¼ Me; (3d)
R2 ¼ Br, R3 ¼ Cl , R1 ¼ Me; (3e) R2 ¼ H, R3 ¼ H, R1 ¼ H; (3f) R2 ¼ H, R3 ¼ Br, R1 ¼ H; (3g) R2 ¼ H,
R3 ¼ Cl, R1 ¼ H; and (3h) R2 ¼ Br, R3 ¼ Cl, R1 ¼ H.

BENZOPYRAN DERIVATIVES
969
3a, as AH84. Integration and scaling of intensity data were accomplished using the
SAINT program.[11] The structure was solved by direct methods using SHELXS97,
and refinement was carried out by full-matrix least-squares technique using
SHELXL97.[12] The hydroxyl H atom was located in difference Fourier maps and
their positions and isotropic thermal parameters were located and refined. All other
hydrogen atoms were positioned geometrically and were treated as riding on their
˚
parent carbon atoms, with C-H distance of 0.93ꢁ0.98 A, with Uiso(H) ¼ 1.2Ueq
(C) or 1.5Ueq (C). The structure was refined with R1 ¼ 0.0383, wR2 ¼ 0.0971 for
3204 reflections with I > 2r(I). The structure is shown in Fig. 1.
p-TSA showed remarkable reactivity as a hard–soft reagent and considerably
accelerated the reactions. On the basis of all our experimental results, together with
literature reports, we have proposed a plausible mechanism for the formation of ben-
zopyran derivatives 3a–h in the presence of p-TSA (Scheme 2). The hypothesis sup-
ported the fact that the reaction proceeds via a one-pot Knoevenagel condensation,
Michael addition, cyclodehydration, and enolization (Scheme 2). The simplicity,
together with the use of inexpensive, nontoxic, and environmentally benign p-TSA
catalyst under water media, is an other remarkable feature of the procedure. The
reaction mixture cooled to room temperature, and the precipitate formed was filtered
and dried to give the crude residue, which was crystallized in ethanol to give pure
3a–h in excellent yields.
Finally, the reuse of water and p-TSA was studied. At completion, monitored
by thin-layer chromatography (TLC), the reaction mixture was allowed to cool to
room temperature, the solid of the products was isolated by filtration, and the filtrate
together with p-TSA could be reused directly. Investigations using 1 and 2 as model
substrates showed that successive reuse of the recovered water (filtrate) and p-TSA
was feasible. A summary of the reuse of water and p-TSA is shown in Table 1. Even
in the third round the yield of the product 3 is fairly high.
In conclusion, we have reported herein a p-TSA-catalyzed, highly efficient,
one-pot Knoevenagel condensation, Michael addition, and cyclodehydration
Figure 1. X-ray crystal structure AH84. Displacement ellipsoids are drawn at 30% probability level, and H
atoms are shown as small spheres of arbitrary radii. (Figure is provided in color online.)

970
L. NAGARAPU ET AL.
Scheme 2. Plausible mechanisam for the synthesis of benzopyran derivatives.
Table 1. Reuse of water and p-TSA for the synthesis of 9-(2-hydroxy-4,4-dimethyl-6-oxo-
cyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (3a)
Entry
Condition
Time (min)
Yielda (%)
0
1
2
3
90ꢀC
90ꢀC
90ꢀC
90ꢀC
30
30
30
30
83.3
82.5
81.0
81.0
aIsolated yields.
synthesis of benzopyran derivatives 3a–h by the condensation of substituted salicy-
laldehydes and 5,5-dimethyl-1,3-cyclohexanedione or 1,3-cyclohexanedione under
water in excellent yields. The method has the ability to tolerate structurally and elec-
tronically divergent substituents in aldehydes; variable reaction conditions, shorter
reaction times, and simple workup procedure are other advantages. Further, the
present procedure is readily amenable to large-scale synthesis and the generation
of combinatorial benzopyran libraries.
EXPERIMENTAL
All the commercial reagents and solvents were used without further purifi-
cation unless otherwise stated. Melting points were recorded on a Buchi 535
melting-point apparatus and are uncorrected. All the reactions were monitored by
TLC performed on precoated silica-gel 60 F254 plates (Merck). Compounds were

BENZOPYRAN DERIVATIVES
971
visualized with ultraviolet light at 254 nm and 365 nm using I2 and heating plates
after dipping in 2% phosphomolybdic acid in 15% aqueous H2SO4 solution. IR spec-
tra were recorded on a Perkin-Elmer 683 or a 1310 Fourier transform (FT)–IR spec-
trometers with KBr pellets. NMR spectra were recorded on Varian Unity 400-MHz
and Bruker AMX 300 spectrometers using tetramethylsilane (TMS) as an internal
standard. 13C NMR was recorded on a Varian Unity 100-MHz instrument using
CDCl3 as internal standard. Mass spectra were recorded on VG Micromass
7070H and a Finnigan Mat 1020B mass spectrometers operating at 70 eV.
Typical Experimental Procedure for the Preparation of Compounds
3a–h
Substituted salicylaldehyde (1.1 mmol), 5,5-dimethyl 1,3-cyclohexanediones, or
1,3-yclohexanediones (2.2 mmol) in water (3 mL) were mixed in a flask, and p-TSA
(10 mol%) was added at room temperature. The resulting mixture was stirred
at 90 ꢀC for 30 min, and completion of the reaction was monitored by TLC
(ethylacetate–hexane 4:6). The reaction mixture was allowed to come to room tem-
perature, and the precipitate was isolated by filtration through a Buckner funnel,
washed with water followed by petroleum ether, and then dried to give the desired
product. The crude product was recrystallized from ethanol.
9-(2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-3,3-
dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (3a)[7b]
Yield: 83.3% (2.49 g), mp 218–220 ꢀC. IR: nmax 3153, 2958, 1622, 1488, 1376,
1
1312, 1233, 1185, 1151, 1077, 1019, 762, 655, 582, 475 cmꢁ1. H NMR (300 MHz,
CDCl3): d 10.31 (s, 1H, -OH), 7.08–7.16 (m, 1H, Ar-H), 6.93–7.01 (m, 3H, Ar-H),
4.59 (s, 1H, -CH), 2.54 (q, J ¼ 17.7, 20.0 Hz, 2H, -CH2), 2.35 (s, 2H, -CH2), 2.30
(s, 2H, -CH2), 1.93 (q, J ¼ 6.0, 16.4 Hz, 2H, -CH2), 1.14 (s, 3H, -CH3), 1.03 (s,
3H, -CH3), 1.00 (s, 6H, 2 ꢂ CH3). 13C NMR (300 MHz, CDCl3): d 200.40, 196.13,
170.53, 168.78, 151.04, 127.98, 127.52, 124.53, 118.31, 115.78, 111.07, 96.20, 50.58,
49.93, 43.24, 41.60, 32.33, 31.02, 29.43, 27.79, 27.21. MS (ESI): 367 (M þ 1), 389
(M þ Na). Anal. calcd. for C23H26O4: C, 75.38; H, 7.15; O, 17.46. Found: C,
75.33; H, 7.15. HRMS (ESI) m=z calcd. for C23H26O4: 366.0000, found 367.1918
(M þ H), 389.1737 (M þ Na).
7-Bromo-9-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-
3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (3b)[7b]
Yield: 90.9% (2.01 g), mp 252–254 ꢀC. IR: nmax 3103, 2963, 1618, 1475, 1374,
1
1302, 1231, 1178, 1075, 1037, 884, 817, 657, 590, 478 cmꢁ1. H NMR (500 MHz,
CDCl3): d 10.23 (s, 1H, -OH), 7.21–7.24 (dd, J ¼ 1.9, 6.8 Hz, 1H, Ar-H), 7.08 (s,
1H, Ar-H), 6.87 (d, J ¼ 8.7 Hz, 1H, Ar-H), 4.53 (s, 1H, -CH-), 2.28–2.59 (m, 6H,
3 ꢂ CH2), 1.95 (s, 2H, -CH2), 1.33 (s, 3H, -CH3), 0.99–1.05 (m, 9H, 3 ꢂ CH3). MS
(ESI): 445 (Mþ), 447 (M þ 2). Anal. calcd. for C23H25BrO4: C, 62.03; H, 5.66; Br,
17.94; O, 14.37. Found: C, 62.03; H, 5.65. HRMS (ESI) m=z calcd. for C23H25BrO4:
445.0000, found 445.1003 (M)þ.

972
L. NAGARAPU ET AL.
7-Chloro-9-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-
enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (3c)[7b]
Yield: 91.4% (2.33 g), mp 238–240. IR: nmax 3102, 2965, 2710, 1624, 1571, 1476,
1374, 1301, 1233, 1179, 1077, 1038, 1015, 879, 819, 657, 618, 591, 549, 469 cmꢁ1. 1H
NMR (300 MHz, CDCl3 þ DMSO-d6): d 10.26 (s, 1H, -OH), 7.09 (dd, J ¼ 2.2,
2.6 Hz, 1H, Ar-H), 6.91–6.97 (m, 2H, Ar-H), 4.55 (s, 1H, -CH), 2.52 (q, J ¼ 17.3,
18.5 Hz, 2H, -CH2), 2.37 (d, J ¼ 4.9 Hz, 2H, -CH2), 2.30 (s, 2H, -CH2), 1.96 (s,
2H, -CH2), 1,14 (s, 3H, -CH3), 1.00–1.05 (m, 9H, 3 ꢂ CH3). MS (ESI): 401 (Mþ),
403 (M þ 2). Anal. calcd. for C23H25ClO4: C, 68.91; H, 6.29; Cl, 8.84; O, 15.96.
Found: C, 68.89; H, 6.24. HRMS (ESI) m=z calcd. for C23H25ClO4: 400.0000, found
401.1529 (M þ H), 423.1328 (M þ Na).
5-Bromo-7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-
1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (3d)
Yield: 73.4% (1.49 g), mp 244–246. IR: nmax 3184, 2940, 1647, 1599, 1452, 1375,
1313, 1257, 1207, 1183, 1150, 1017, 887, 855, 803, 722, 662, 587, 475 cmꢁ1. 1H NMR
(300 MHz, CDCl3 þ DMSO-d6): d 10.18 (s, 1H, -OH), 7.36 (d, J ¼ 2.2 Hz, 1H,
Ar-H), 6.90 (d, J ¼ 2.0 Hz, 1H, Ar-H), 4.53 (s, 1H, -CH), 2.62 (q, J ¼ 17.7,
18.5 Hz, 2H, -CH2), 2.38 (d, J ¼ 4.5 Hz, 2H, -CH2), 2.31 (s, 2H, -CH2), 1.97 (s,
2H, -CH2), 1.16 (s, 3H, -CH3), 1.00–1.05 (m, 9H, 3 ꢂ CH3). 13C NMR (300 MHz,
CDCl3): d 196.47, 195.10, 163.43, 144.77, 128.68, 127.79, 127.41, 126.35, 112.78,
109.93, 108.78, 94.79, 49.58, 49.03, 39.81, 30.77, 28.24, 26.92, 26.03, 25.64, 25.17.
MS (ESI): 479 (Mþ), 481 (M þ 2). Anal. calcd. for C23H24BrClO4: C, 57.58; H,
5.04; Br, 16.65; Cl, 7.39; O, 13.34. Found: C, 57.57; H, 5.04. HRMS (ESI) m=z calcd.
for C23H23ClBrO4: 478.0000, found 479.0618 (M þ H), 481.0602 (M þ 2), 501.0421
(M þ Na), 503.0415 (M þ Na þ 2).
9-(2-Hydroxy-6-oxo-cyclohex-1-enyl)-2,3,4,9-tetrahydro-xanthen-
1-one (3e)[7b]
Yield: 82.5% (2.09 g), mp 236–238. IR: nmax 2951, 2538, 1830, 1641, 1553, 1485,
1
1421, 1372, 1294, 1235, 1192, 1142, 1071, 993, 924, 850, 773, 564, 493 cmꢁ1. H
NMR (300 MHz, DMSO-d6): d 10.49 (s, 1H, -OH), 6.80–7.14 (m, 4H, Ar-H), 5.07
(s, 1H, -CH), 1.60–2.40 (m, 12H, 6 ꢂ CH2). MS (ESI): 311 (M þ 1). Anal. calcd.
for C19H18O4: C, 73.53; H, 5.85; O, 20.62. Found: C, 73.52; H, 5.84. HRMS (ESI)
m=z calcd. for C19H18O4: 310.0000, found 311.1295 (M þ H), 333.1081 (M þ Na).
7-Bromo-9-(2-hydroxy-6-oxo-cyclohex-1-enyl)-2,3,4,9-
tetrahydro-xanthen-1-one (3f)[7b]
Yield: 88.4% (1.70 g), mp 236–238. IR: nmax 3105, 2955, 1640, 1596, 1477, 1374,
1279, 1233, 1186, 1144, 1070, 981, 819, 763, 620, 530, 470 cmꢁ1. 1H NMR (300 MHz,
DMSO-d6): d 10.60 (s, 1H, -OH), 7.25 (d, J ¼ 3.0 Hz, 1H, Ar-H), 7.09 (d, J ¼ 2.2 Hz,
1H, Ar-H), 6.89 (dd, J ¼ 5.2, 6.0 Hz, 1H, Ar-H), 4.51 (s, 1H, -CH), 1.76–2.85 (m,
12H, 6 ꢂ CH2). 13C NMR (300 MHz, CDCl3 þ DMSO-d6) : 202.18, 193.99, 167.43,
166.15, 148.45, 129.74, 129.28, 128.61, 126.86, 116.51, 116.10, 115.09, 47.57, 35.57,

BENZOPYRAN DERIVATIVES
973
35.02, 33.26, 26.02, 22.80, 18.95. MS (ESI): 389 (Mþ), 391 (M þ 2). Anal. calcd. for
C19H17BrO4: C, 58.63; H, 4.40; Br, 20.53; O, 16.44. Found:C, 58.63; H, 4.39. HRMS
(ESI) m=z calcd. for C19H17BrO4: 389.0000, found 391.0551 (M þ 2).
7-Chloro-9-(2-hydroxy-6-oxo-cyclohex-1-enyl)-2,3,4,9-
tetrahydro-xanthen-1-one (3g)[7b]
Yield: 84.5% (1.85 g), mp 244–246. IR: nmax 3110, 2954, 1645, 1596, 1477, 1416,
1375, 1280, 1239, 1188, 1141, 1068, 984, 917, 824, 576, 460 cmꢁ1 1H NMR
.
(500 MHz, CDCl3): d 10.60 (s, 1H, -OH), 7.09 (d, J ¼ 6.3 Hz, 1H, Ar-H),
6.91–6.96 (m, 2H, Ar-H), 4,51 (s, 1H, -CH), 1.77–2.81 (m, 12H, 6 ꢂ CH2). 13C
NMR (300 MHz, CDCl3 þ DMSO-d6): 201.86, 193.94, 167.23, 165.96, 147.56,
127.13, 126.76, 125.61, 124.53, 115.52, 110.65, 99.74, 47.08, 35.47, 34.82, 33.05,
26.35, 22.69, 19.03. MS (ESI): 345 (Mþ), 347 (M þ 2). Anal. calcd. for C19H17ClO4:
C, 66.19; H, 4.97; Cl, 10.28; O, 18.56. Found: C, 66.18; H, 4.97.
5-Bromo-7-chloro-9-(2-hydroxy-6-oxo-cyclohex-1-enyl)-2,3,4,9-
tetrahydro-xanthen-1-one (3h)
Yield: 73.3% (1.31 g), mp 238–240. IR: nmax 2949, 2887, 2526, 1651, 1560, 1452,
1363, 1279, 1245, 1185, 1133, 1063, 1007, 857, 765, 707, 538, 500, 438 cmꢁ1. 1H NMR
(500 MHz, CDCl3): d 10.44 (s, 1H, -OH), 7.30 (d, J ¼ 2.6 Hz, 1H, Ar-H), 6.95 (d,
J ¼ 1.7 Hz, 1H, Ar-H), 5.04 (s, 1H, -CH), 1.93–2.12 (m, 4H, 2 ꢂ CH2), 2.25–2.51
(m, 8H, 4 ꢂ CH2). MS (ESI): 423 (Mþ), 425 (M þ 2). Anal. calcd. for C19H16BrClO4:
C, 53.86; H, 3.81; Br, 18.86; Cl, 8.37; O, 15.11. Found: C, 53.85; H, 3.81.
Crystallographic Data
Crystallographic data have been deposited for compound AH84 with the
Cambridge Crystallographic Data Centre [CCDC No. 781568]. Copies of the data
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44(0) 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk.
ACKNOWLEDGMENTS
The authors are thankful to the director of the Indian Institute of Chemical
Technology (IICT) and head of the Organic Chemistry Division II, IICT, for their
constant encouragement and support. S. C. K. thanks the Council of Scientific
and Industrial Research, New Delhi, for the award of a fellowship.
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