Facile solvent-free one-pot synthesis of pyranobenzopyrans and their derivatives

Article abstract of DOI:10.1007/s12039-011-0135-y

The condensation of hydroxyl coumarins in a facile one-pot procedure with active methylene esters to afford novel benzopyrans under solventless conditions is described. The products underwent further condensation and cyclization reactions to form novel heterocycles. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0135-y

c
J. Chem. Sci. Vol. 123, No. 5, September 2011, pp. 667–672. ꢀ Indian Academy of Sciences.
Facile solvent-free one-pot synthesis of pyranobenzopyrans
and their derivatives
P SIRISHA, SUHAS PEDNEKAR∗, ANANT R KAPDI and MINAL NAIK
Organic Chemistry Research Laboratory, Ramnarain Ruia College, Matunga, Mumbai 400 019, India
e-mail: pednekarsuhas@gmail.com
MS received 9 December 2010; revised 8 May 2011; accepted 30 May 2011
Abstract. The condensation of hydroxyl coumarins in a facile one-pot procedure with active methylene
esters to afford novel benzopyrans under solventless conditions is described. The products underwent further
condensation and cyclization reactions to form novel heterocycles.
Keywords. Dimethylacetone-1,3-dicarboxylate; pyranobenzopyrans; 4-hydroxycoumarins; solvent-free.
1. Introduction
2. Experimental
Coumarin derivatives have revealed promising biolog- 2.1 Materials
ical activity with interesting potential in therapeutic
application1 besides their traditional use as antico-
agulants,2 antifungal,3 anti-inflammatory agents,4 etc.
They have also shown important property as antibiotics
(novobiocin and analogs),5 anti-AIDS agents (calano-
lides)6 and antitumor drugs.7,8 Benzopyrans form an
important class of coumarin derivatives known for their
diverse biological activities.9–12 The biological impor-
tance and the therapeutic action of benzopyrans have
generated a lot of interest over the years. A thorough
literature survey revealed that condensation of various
active methylene groups on 4-hydroxycoumarin13–15
gave different benzopyran systems.
All solvents and reagents were obtained from commer-
cial sources and were used without purification unless
stated.
2.2 Apparatus
Elemental analysis was performed using a Heraeus
CHN-O rapid analyzer. IR and UV spectra were
recorded with a Shimadzu IR-470 spectrometer and
UV/Vis Shimadzu 2100 respectively. Melting points
were taken on Scientific Melting point apparatus.
Pyranobenzopyrans and its derivatives are reported
to possess various biological activities such as antibac-
terial, antifungal, CNS depressant, antiviral, ulcer
inhibitor, etc.16–22 Suksdorfin and DCK which contain
pyranobenzopyran moiety are known to be potent
anti-HIV agents.18 We therefore would like to report
on a simple and efficient protocol for the synthe-
sis of substituted pyranobenzopyran derivatives. In
this report we have condensed 4-hydroxycoumarin;
1a, 4,7-dihydroxycoumarin; 1b and 6-methyl-4-
hydroxycoumarin 1c with dimethylacetone1,3-
dicarboxylate 2 with a view to obtain novel
pyranobenzopyrans for further synthetic endeavours.
2.3 Representative general procedure for one-pot
synthesis of 3a–c
A mixture of 1a (10 mmol) and 2 (2.1 mL, 12 mmol)
were refluxed together in the presence of 4 to 5 drops
of pyridine for 1 h. After completion of the reaction, as
indicated by TLC, the reaction mixture was poured onto
crushed ice and stirred for 2–3 h. The solid separated
was filtered under suction, washed with ice-cold water
25 mL and then recrystallized from toluene to afford
pure product 3a: White coloured solid (1.42 g, 88%).
M.p. 201–202◦C; IR (neat) υmax 1264, 1762, 1722,
1
1631, 1600, 2908, 2950, 3065, 3111 cm−1; H-NMR
(CDCl3, 300 MHz) δ 3.76 (s, 3H), 3.97 (s, 2H), 6.26
(s, 1H), 7.26–8.13 (m, 4H) ppm; ESI-MS (m/z) 287
(M++H+), 255, 227, 122; Anal. Calcd. for C15H10O6:
C-62.94; H-3.52. Found: C-62.91; H-3.36.
∗For correspondence
667

668
P Sirisha et al.
O
OH
O
O
O
COOMe
Pyridine (10 mol%)
R1
CO(CH2COOMe)2
R1
+
reflux, 1.0 hr
80-90%
O
O
R1 = 7-H, 7-OH, 6-Me
1a-c
2
3a-c
Scheme 1. One-pot synthesis of pyranobenzopyrans.
Table 1. Synthesis of compounds 3a–c from 1a–ca.
Time
(h)
Sl. No.
Reactant 1a−c
Product 3a−c
%Yield
88
1
1
1a
3a
2
3
1
78
90
1b
3b
1
1c
3c
a1(a–c) (10 mmol) and 2 (2.1 mL, 12 mmol) with Pyridine (10 mol%) refluxed for 1 h.
O
2
a) CO(CH2COOMe)2 (1.2 Eq)
OH
O
O
O
Pyridine (10 mol%)
R4
reflux, 1.0 hr
R1
R1
3 4a-e
b) HNR2R
(1.2 Eq)
O
O
CH3CN, reflux 5-6 hr
1
4
2 3
1a
1c
5a−h
R = CONR R
R = H ( ), Me (
)
60-80%
Scheme 2. One-pot synthesis of amide substituted pyranobenzopyrans.

Facile solvent-free one-pot synthesis of pyranobenzopyrans and their derivatives
669
Table 2. Synthesis of compounds 5a–h from 4a–eb.
Time
(h)
S1. No
Reactant 4a−e
Product 5a−h
% Yield
80
1
3
4a
5a
2
4
60
4b
5b
3
4
5
6
7
8
6
4
4
6
6
6
78
75
72
85
80
75
4c
5c
4d
5d
4e
5e
4a
5f
4d
5g
4e
5h
b1(a–c) (10 mmol) and 2 (2.1 mL, 12 mmol) with Pyridine (10 mol%) reflux for 1 h. (4a–e)
(1 mmol) in MeCN 10 mL, refluxed for 4–6 h

670
P Sirisha et al.
O
OH
O
2
a) CO(CH2COOMe)2 (1.2 Eq)
N
O
O
N
Pyridine (10 mol%)
reflux, 1.0 hr
NH2
R1
S
R1
6a
b) CSNH2(NHNH2)
(4.0 Eq)
O
PPA, 110 oC, 4-6 hr
O
1
1a
1b
7a-c
R = 7-H ( ), 7-OH ( ),
55-65%
1c
6-Me (
)
Scheme 3. Efficient synthetic protocol for thia-diazole.
2.4 Representative procedure for one-pot
synthesis of 5a–h
(neat) υmax 3210, 2952, 2851, 2802, 1757, 1726 cm−1;
Anal. Calcd for C19H18N2O5: C-64.40, N-7.56, H-5.99
Found:. C-64.81, N-7.50, H-5.90.
A mixture of 1a (10 mmol) and 2 (2.1 mL, 12 mmol)
were refluxed together in the presence of 4 to 5 drops
of pyridine for 1 h until the starting material was com-
pletely consumed (monitored by TLC). Then a solution
of the secondary amine 4a (12 mmol) in CH3CN 10 mL
2.5 Representative procedure for one-pot
synthesis of 7a–c
was added and refluxed for 4–6 h until the conversion A mixture of 1a (10 mmol) and 2 (2.1 mL, 12 mmol)
was complete (monitored by TLC). A white coloured were refluxed together in the presence of 4 to 5 drops of
compound which was formed during the reaction was pyridine for 1 hour until the starting material was com-
filtered and washed with water 25 mL. The solid residue pletely consumed (monitored by TLC). A mixture of
was dried and recrystallised from ethanol to afford 5a: 6a (1.82 g, 20 mmol) and 10 mL of polyphosphoric acid
White coloured solid (2.23 g 78%). M.p. 218–220◦C; IR was added and heated for about 3–4 h at 100–110◦C.
Table 3. Synthesis of compounds 7a–c from 1a–cc.
Time
(h)
S1. No.
Reactant 1a−b
Product 7a−c
Yield%
57
1
4
1a
1b
7a
7b
7c
2
3
6
6
62
65
1c
c1(a–c) (10 mmol), 2 (2.1 mL, 12 mmol) with Pyridine (10 mol%) reflux for 1 h. 6a (1.82 g,
20 mmol) and 10 mL of polyphosphoric acid was added and reaction stirred for about 4–6 h
at 110◦C.

Facile solvent-free one-pot synthesis of pyranobenzopyrans and their derivatives
671
The progress of the reaction was monitored on TLC. for the synthesis of amides from esters.27 Here we have
The reaction mixture was then poured into crushed ice presented a simple protocol for the conversion of esters
and stirred for about 2 h. The solid was filtered under into amides at ambient temperature using a mild base
suction. The residue was dried and recrystallised from a such as pyridine. It was observed that the ester group
mixture of 80% ethanol and DMF to afford 7a: Cream was extremely reactive and various secondary amines
coloured solid (1.51 g 53%). M.p. 267–268◦C; IR (neat) (4a–e) could be condensed on to pyranobenzopyrans
υmax 3227, 3060, 3040, 2896, 2960, 2825, 1787, 1721, in good yields. Also different pyranobenzopyrans 3a–c
1
1640 cm−1; H-NMR (DMSOd6, 300 MHz) δ 3.01 could be condensed with 6a to give the cyclized prod-
(s, 2H), 6.42 (s,1H), 7.31–8.52 (m, 4H), 7.90–8.11 ucts 7a–c. One pot reactions are more efficient than
(s, 2H) ppm; EI-MS (m/z) 327 (M+), 227, 198, 170. the conventional methods as they reduce the time and
Anal. Calcd for C16H11N3O4S: C-55.04, N-12.84, S- energy required for the work-up and isolation of the
9.80, H-2.77. Found: C-55.37, N-12.65, S-9.76, H-2.52. product, thus adhering to green chemistry principles.28
See Supplementary information for complete charac- Since we were able to isolate and characterize 3a and 3c
terization and experimental details of the remaining as well as their various derivatives, we tried to improve
analogs.
the efficiency of the process by carrying out one-pot
reaction (schemes 2 and 3, tables 2 and 3).
3. Results and discussion
4. Conclusion
The condensation of β-ketoesters with phenolic com-
pounds in the presence of concentrated sulfuric acid
is called Pechmann reaction.23 Various lewis acid cat-
alysts have also been employed in the past for this
purpose. Base catalysed condensation has also been
reported.24 In the present investigation an attempt has
been made to synthesize pyranobenzopyrans 3a–c by
condensing substituted 4-hydroxycoumarins 1a–c with
dimethylcetone1,3-dicarboxylate. For this purpose, we
In summary, we have developed a sequential one-pot
reaction for the synthesis of a variety of substituted ben-
zopyrans using simple chemistry that would save time
and resources thereby making the process efficient and
environmentally benign. The simplicity, ease of work-
up, together with the use of inexpensive and efficient
base catalyst, is the notable feature of this procedure.
first employed various catalysts like concentrated sulfu- Supplementary information
ric acid, aluminium trichloride but no conversion to the
The electronic supplementary information can be seen
desired product was observed with only starting mate-
rial being recovered. The reaction was then performed
using a base catalyst such as pyridine, in the presence
of various solvents like ethanol and ethyl acetate but
the reaction time was very long with poor yields. On
the other hand, simply mixing and refluxing the two
reactants together neatly, in the presence of catalytic
amount of pyridine (10 mol%) resulted in the formation
of compound 3a–c in good yields (scheme 1, table 1).
With the desired pyranobenzopyrans 3a–c in hand,
we initially set out to test the reactivity of the active
methylene group by performing Mannich and Knoeve-
nagel reactions on it. But the conversions to desired
product were not effected indicating the inactivity of the
moiety. The reactivity of the ester group was then tested
by condensing pyranobenzopyrans 3a and 3c with vari-
ous secondary amines to synthesize substituted amides
5a–h in good to excellent yields (scheme 2, table 2).
The synthesis of amides from esters in general could
be effected using trialkylaluminium or under vigor-
ous conditions with a strong base and higher temper-
ature.25,26 Microwave heating has also been employed
in www.ias.ac.in/chemsci.
Acknowledgements
Authors are thankful to Ramnarain Ruia College for
providing research facilities and University Grants Com-
mission (UGC) for funding.
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