One-pot synthesis of novel spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b′]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b′]dipyran-4,10-dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.10.016

An efficient synthesis of novel spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b′]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b′]dipyran-4,10-dione derivatives in high yields under microwave irradiation is described. The reaction was also studied u

Full text of DOI:10.1016/j.tetlet.2008.10.016

Tetrahedron Letters 49 (2008) 7227–7229
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of novel spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b0]-
dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b0]dipyran-
4,10-dione derivatives
*
D. Ashok , D. Shravani
Department of Chemistry, Osmania University, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
An efficient synthesis of novel spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b0]dipyran-4,6-dione and 2,3,8,9-
tetrahydro-benzo[1,2-b:4,3-b0]dipyran-4,10-dione derivatives in high yields under microwave irradiation
is described. The reaction was also studied under conventional heating conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 29 July 2008
Revised 1 October 2008
Accepted 4 October 2008
Available online 8 October 2008
Keywords:
One-pot
Microwave irradiation
Resorcinol
Cyclic ketone
1. Introduction
O
X
X
HO
O
OH
O
O
O
O
+
Pyrrolidine
Flavanone and its derivatives exhibit a broad array of biological
activities1 such as anti-tumour, anti-inflammatory and anti-oxi-
dant. Further flavanones have also been investigated as TNF-
EtOH, 80 oC
X
O
a
1a
2a-2d
3a-3d
inhibitors and as selective oestrogen receptor modulators.2 Due
to these potential applications, various approaches have been re-
ported for the synthesis of flavanone derivatives.3 Although various
synthetic routes are available, novel derivatives of flavanones, in
particular, substituted spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-
b0]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b0]-
dipyran-4,10-dione derivatives,4 are limited. The development of
methodologies for new chemical entities is an important area of
research, which aids in drug-discovery. Earlier, our research
group reported different types of methods for the preparation
of flavanone derivatives.4,5 In continuation of our interest, herein
we describe the synthesis of novel spiro 2,3,7,8-tetrahydro-
benzo[1,2-b:5,4-b0]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo-
[1,2-b:4,3-b0]dipyran-4,10-dione derivatives under microwave
irradiation as well as conventional heating conditions (Scheme
1). In recent years, microwave-assisted organic synthesis (MAOS)
has attracted the attention of synthetic chemists.6 The rate of a
reaction is accelerated under microwave irradiation compared to
conventional heating.
X= CH2, N-Me, N-Bn, N-Boc
Scheme 1. Synthesis of spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b0]dipyran-4,6-
dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b0]dipyran-4,10-dione derivatives.
We chose diacetyl resorcinols and cyclic ketones as convenient
starting materials to afford the spiro 2,3,7,8-tetrahydro-benzo[1,2-
b:5,4-b0]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,
3-b0]dipyran-4,10-dione structures. Accordingly, in the first in-
stance 4,6-diacetyl resorcinol (1a) and cyclohexanone (2a) were
stirred together in the presence of pyrrolidine and subjected to
microwave irradiation for 4 min and then poured into ice-cold
water and filtered to afford the corresponding spiro 2,3,7,8-tetra-
hydro-benzo[1,2-b:5,4-b0]dipyran-4,6-dione derivative 3a, in 95%
yield. The same product was also obtained (90%) under conven-
tional heating (80 °C) in ethanol for 10 h (Table 1, entry 1). To fur-
ther investigate this result, various substituted cyclic ketones such
as N-methyl, N-benzyl and N-tert(butoxycarbonyl) cyclohexa-
nones, 2b–d and cyclopentanone 2e were treated with resorcinol
1a under microwave irradiation in the presence of pyrrolidine to
afford the corresponding spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,
4-b0]dipyran-4,6-dione derivatives 3b–e in good yields (entries
2–5).
* Corresponding author. Tel.: +91 9391024769; fax: +91 040 27664499.
E-mail address: ashokdou@gmail.com (D. Ashok).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.016

7228
D. Ashok, D. Shravani / Tetrahedron Letters 49 (2008) 7227–7229
Table 1
One-pot synthesis of spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b0]dipyran-4,6-dione and 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b0]dipyran-4,10-dione derivatives
Entry
Substituted
resorcinol
Ketone
Time
Productb
Yieldc (%)
(80 °C)d
MW
(80 °C)a
MW
95
O
HO
OH
O
O
O
O
1
4 min
(10 h)
(90)
3a
1a
O
2a
O
O
MeN
BnN
NMe
NBn
O
O
2
3
1a
1a
5 min
5 min
(10 h)
(10 h)
93
89
(90)
(84)
3b
3c
N
Me
2b
O
O
O
O
O
N
2c
Bn
O
O
O
BocN
NBoc
O
O
4
5
6
1a
1a
5 min
4 min
5 min
(10 h)
(10 h)
(12 h)
90
90
92
(93)
(85)
(90)
3d
N
2d
Boc
O
O
O
O
O
O
O
3e
2e
O
O
HO
OH
O
O
O
O
2a
3f
1b
MeN
O
NMe
O
O
7
1b
1b
2b
2c
6 min
6 min
(12 h)
(12 h)
95
90
(90)
(85)
3g
O
O
O
BnN
O
NBn
O
8
9
3h
BocN
O
NBoc
O
O
1b
1b
2d
2e
6 min
5 min
(12 h)
(12 h)
92
95
(90)
(90)
3i
O
O
O
O
10
3j
O
a
Time for conventional heating (80 °C) reaction in ethanol.
b
c
The products were characterized by 1H NMR, mass and IR spectra.
Isolated yields.
d
Yield after conventional heating (80 °C) reaction in ethanol.
Next, the reaction of 2,6-diacetyl resorcinol 1b, and cyclohexa-
All these reactions were also run under conventional heating
(80 °C) in ethanol, in order to compare the efficiency with micro-
wave irradiation (Table 1, entries 1–10). All the obtained products
were fully characterized by spectroscopic methods.7
none 2a in the presence of pyrrolidine under microwave irradia-
tion for 5 min gave the 2,3,8,9-tetrahydro-benzo[1,2-b:4,3-
b0]dipyran-4,10-dione derivative 3f, in 92% yield (entry 6). To fur-
ther explore substrate 1b, cyclic ketones 2b–e were reacted to give
the corresponding products 3g–j in very good yields (entries 7–10).
In conclusion, an efficient synthesis of novel spiro 2,3,7,8-tetra-
hydro-benzo[1,2-b:5,4-b0]dipyran-4,6-dione and 2,3,8,9-tetrahydro-

D. Ashok, D. Shravani / Tetrahedron Letters 49 (2008) 7227–7229
7229
benzo[1,2-b:4,3-b0]dipyran-4,10-dione derivatives under micro-
wave irradiation conditions has been achieved. This new class of
spiro 2,3,7,8-tetrahydro-benzo[1,2-b:5,4-b0]dipyran-4,6-dione and
2,3,8,9-tetrahydro-benzo[1,2-b:4,3-b0]dipyran-4,10-dione derivati-
ves may find utility in medicinal chemistry.
2. Chen, H. Y.; Dykstra, K. D.; Birzin, E. T.; Frisch, K.; Chan, W.; Yang, Y. T.; Mosley,
R. T.; Dininno, F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg. Med.
Chem. Lett. 2004, 14, 1417.
3. (a) Chandrasekhar, S.; Vijeender, K.; Reddy, K. V. Tetrahedron Lett. 2005, 46,
6991; (b) Margaret, M. B.; Michael, L.; Karl, A. S. J. Am. Chem. Soc. 2007, 129,
3830.
4. Reddy, S. P.; Sreenivasulu, B.; Sarma, P. N. Indian J. Chem., Sect. B 1995, 34, 658.
5. Reddy, S. P.; Ashok, D.; Sarma, P. N. Curr. Sci. 1987, 58, 622.
6. (a) Ashok, D.; Pallavi, K. Heterocycl. Commun. 2006, 12, 3; (b) Ashok, D.; Pallavi, K.
Heterocycl. Commun. 2006, 12, 2; (c) Kappe, O. C. Angew. Chem., Int. Ed. 2004, 43,
6250.
2. Representative experimental procedures
2.1. Microwave heating
7. Characterization data for representative products (3a): Brown solid; mp 160–
162 °C; 1H NMR (200 MHz, CDCl3): d 8.4 (1H, s), 6.45 (1H, s), 2.65 (4H, s), 1.9–2.1
(4H, m), 1.3–1.8 (16H, m); 13C NMR (75 MHz, CDCl3); d 190.4, 165.0, 127.5,
Pyrrolidine (0.08 mL) was added to a mixture of 4,6-diacetyl
resorcinol (1a) (0.19 g, 1 mmol) and cyclohexanone (2a) (0.19 mL,
2 mmol), and the mixture was subjected to microwave irradiation
for 4 min in a Multisynth series microwave system (Milestone).
After cooling the reaction mixture to room temperature, it was
poured into ice-cold water and the resulting precipitate was fil-
tered to give the corresponding 2,3,7,8-tetrahydro-benzo[1,2-b:
5,4-b0]dipyran-4,6-dione derivative 3a, in 95% yield.
115.6, 105.4, 81.1, 47.9, 34.9, 24.9, 21.3.IR (KBr):
m
1697, 1469, 1250 cmꢀ1; LC
MS (m/z): 354. Anal. Calcd for C22H26O4: C, 74.58; H, 7.3. Found: C, 74.39; H,
7.35. Compound (3c): White solid; mp 158–160 °C; 1H NMR (300 MHz, CDCl3): d
8.36 (1H, s), 7.24–7.32 (10H, m), 6.47 (1H, s), 3.56 (4H, s), 2.7 (4H, s), 2.62–2.68
(4H, m), 2.35–2.5 (4H, m), 1.99–2.03 (4H, m) 1.73–1.83 (4H, m); 13C NMR
(75 MHz, CDCl3): d 189.3, 188.5, 165.7, 160.0, 154.5, 133.8, 114.8, 111.4, 110.4,
80.0, 48.8, 47.2, 38.9, 33.8. IR (KBr):
m
1693, 1427, 1245 cmꢀ1; LC MS (m/z): 536.
Anal. Calcd for C34H36N2O4: C, 76.12; H, 6.72; N, 5.22. Found: C, 76.11; H, 6.78;
N, 5.11. Compound (3d): Milky white solid; mp 190–192 °C; 1H NMR (300 MHz,
CDCl3): d 8.45 (1H, s), 6.5 (1H, s), 3.75–3.95 (4H, m), 3.1–3.25 (4H, m), 2.73 (4H,
s), 1.9–2.1 (4H, m) 1.55–1.7 (4H, m), 1.45 (18H, s); 13C NMR (75 MHz, CDCl3): d
189.4, 164.5, 154.6, 127.9, 115.9, 105.6, 79.9, 79.2, 47.7, 38.9, 34.1, 27.5. IR (KBr):
2.2. Conventional heating
m
1684, 1472, 1250 cmꢀ1; LC MS (m/z): 556. Anal. Calcd for C30H40N2O8: C,
64.75; H, 7.19; N, 5.04. Found: C, 64.58; H, 7.26; N, 4.94. Compound (3e): Cream
solid; mp 124–126 °C; 1H NMR (300 MHz, CDCl3): d 8.45 (1H, s), 6.35 (1H, s),
2.75 (4H, s), 2.04–2.16 (4H, m), 1.88–1.96 (4H, m) 1.64–1.82 (8H, m); 13C NMR
(75 MHz, CDCl3): d 190.5, 165.47, 127.9, 115.8, 105.7, 90.9, 46.7, 37.5, 23.7. IR
Pyrrolidine (0.08 mL) was added to a solution of 4,6-diacetyl res-
orcinol (1a) (0.19 g, 1 mmol) in ethanol (5 mL), and the mixture was
refluxed for 5 min. Then, cyclohexanone (2a) (0.19 mL, 2 mmol) was
added. The mixture was refluxed for 10 h and after cooling to room
temperature, it was poured into ice-cold water. The resulting precip-
itate was filtered to afford the corresponding 2,3,7,8-tetrahydro-
benzo[1,2-b:5,4-b0]dipyran-4,6-dione derivative 3a, in 90% yield.
(KBr):
73.62; H, 6.75. Found: C, 73.53; H, 6.81. Compound (3f): Cream solid; mp 130–
132 °C; 1H NMR (300 MHz, CDCl3):
7.92 (1H, d, J = 8.3 Hz), 6.53 (1H, d,
1691, 1425,
m
1695, 1484, 1255 cmꢀ1; LC MS (m/z): 326. Anal. Calcd for C20H22O4: C,
d
J = 8.3 Hz), 2.66 (2H, s), 2.62 (2H, s), 1.22–2.18 (20H, m). IR (KBr):
m
1171 cmꢀ1; LC MS (m/z): 354. Anal. Calcd for C22H26O4: C, 74.58; H, 7.3. Found:
C, 74.55; H, 7.37. Compound (3h): Cream solid; mp 110–112 °C; 1H NMR
(300 MHz, CDCl3): d 7.95 (1H, d, J = 10.7 Hz), 7.22–7.4 (10H, m), 6.66 (1H, d,
J = 10.7 Hz), 3.52 (4H, s), 2.7 (4H, s), 2.60–2.69 (4H, m), 2.38–2.52 (4H, m), 2.00–
Acknowledgements
2.12 (4H, m), 1.78–1.9 (4H, m). IR (KBr):
m
1703, 1427, 1180 cmꢀ1; LC MS (m/z):
536. Anal. Calcd for C34H36N2O4: C, 76.11; H, 6.78; N, 5.11. Found: C, 76.10; H,
6.76; N, 5.30. Compound (3i): Cream solid; mp 170–172 °C; 1H NMR (300 MHz,
CDCl3): d 8.02 (1H, d, J = 10.5 Hz), 6.62 (1H, d, J = 10.5 Hz), 3.8–4.05 (4H, m),
3.15–3.30 (4H, m), 2.70 (4H, s), 1.98–2.1 (4H, m), 1.55–1.80 (4H, m), 1.45 (18H,
s); 13C NMR (75 MHz, CDCl3): d 189.2, 188.4, 165.6, 160.0, 154.4, 133.7, 114.7,
111.4, 110.3, 80.0, 79.8, 79.4, 78.7, 48.7, 47.1, 38.8, 33.8, 29.5, 28.3, 28.2. IR
The authors are thankful to Dr. S. Chandrasekhar, Deputy Direc-
tor, IICT, Hyderabad for fruitful discussions and to Professor K.
Veera Reddy, Head, Department of Chemistry, Osmania University,
Hyderabad for providing laboratory facilities. Thanks are also due
to SERO-UGC, INDIA for financial assistance.
(KBr):
m
1703, 1427, 1180 cmꢀ1; LC MS (m/z): 556. Anal. Calcd for C30H40N2O8: C,
64.75; H, 7.19; N, 5.04. Found: C, 64.70; H, 7.22; N, 4.96. Compound (3j): Cream
solid; mp 106–108 °C; 1H NMR (300 MHz, CDCl3): d 7.9 (1H, d, J = 8.8 Hz), 6.5
(1H, d, J = 8.8 Hz), 2.8 (2H, s), 2.75 (2H, s), 1.1–2.2 (16H, m); 13C NMR (75 MHz,
CDCl3): d 190.5, 189.5, 166.7, 161.5, 133.3, 130.7, 128.6, 111.2, 91.5, 90.4, 47.8,
References and notes
45.6, 37.4, 37.3, 23.7, 23.5. IR (KBr):
Anal. Calcd for C20H22O4: C, 73.62; H, 6.75. Found: C, 73.50; H, 6.80.
m
1693, 1463, 1269 cmꢀ1; LC MS (m/z): 326.
1. (a) Harborne, J. B.; Williams, C. A. Nat. Prod. Rep. 1995, 12, 639; (b) Ashok, D.;
Sarma, P. N. Curr. Sci. 1987, 56, 234.