Microwave-assisted K-10 montmorillonite clay-mediated knoevenagel hetero-Diels-Alder reactions: A novel protocol for the synthesis of polycyclic pyrano[2,3,4-kl]xanthene derivatives

Article abstract of DOI:10.1080/00397910802417825

The intramolecular hetero-Diels-Alder reactions of 2-(cyclohex-2-enyloxy) benzaldehyde by Knoevenagel condensation with symmetrical 1,3-diones under three different conditions afforded the pyrano[2,3,4-kl]xanthene derivatives in a stereoselective manner i

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Microwave-Assisted K-10
Montmorillonite Clay–Mediated
Knoevenagel Hetero-
Diels–Alder Reactions: A Novel
Protocol for the Synthesis
of Polycyclic Pyrano[2,3,4-
kl]xanthene Derivatives
Ekambaram Ramesh a & Raghavachary Raghunathan
a
a Department of Organic Chemistry, University of
Madras, Guindy Campus, Chennai, India
Version of record first published: 28 Jan 2009.
To cite this article: Ekambaram Ramesh & Raghavachary Raghunathan (2009):
Microwave-Assisted K-10 Montmorillonite Clay–Mediated Knoevenagel Hetero-
Diels–Alder Reactions: A Novel Protocol for the Synthesis of Polycyclic Pyrano[2,3,4-
kl]xanthene Derivatives, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:4, 613-625
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Synthetic Communications1, 39: 613–625, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802417825
Microwave-Assisted K-10 Montmorillonite
Clay–Mediated Knoevenagel Hetero-Diels–Alder
Reactions: A Novel Protocol for the Synthesis of
Polycyclic Pyrano[2,3,4-kl]xanthene Derivatives
Ekambaram Ramesh and Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
Abstract: The intramolecular hetero-Diels–Alder reactions of 2-(cyclohex-2-
enyloxy)benzaldehyde by Knoevenagel condensation with symmetrical 1,3-diones
under three different conditions afforded the pyrano[2,3,4-kl]xanthene derivatives
in a stereoselective manner in good yield. The structure of one of the products was
unambiguously established by x-ray analysis.
Keywords: 1,3-Dione, hetero-Diels–Alder reaction, microwave, pyrano xanthene
INTRODUCTION
The intramolecular Diels–Alder reaction[1] is a powerful method for the
synthesis of many polycyclic compounds, including natural products.
However, it is a prerequisite that activating groups have to be built into
dienophiles to achieve the desired reactivity.[2]
Xanthene derivatives are intermediates in organic synthesis
and have many applications in laser technology because of their inter-
esting spectroscopic properties.[3,4] Dibenzoxanthene derivatives find
application as candidates as sensitizers in photodynamic therapy
(PDT).[5] PDT is a method of treating tumors by combined use of a
Received May 15, 2008.
Address correspondence to Raghavachary Raghunathan, Department of
Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025,
India. E-mail: ragharaghunathan@yahoo.com
613

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E. Ramesh and R. Raghunathan
photosensitizer and light.[6] Furthermore, these compounds have
recently received great attention because of their wide range of thera-
peutic and biological properties, such as antibacterial,[7] antiviral,[8]
and anti-inflammatory activities.[9]
In continuation of our work in cycloaddition reactions,[10,11] we dis-
close here our preliminary investigation on the solvent-free, microwave-
assisted Knovenagal intramolecular hetero-Diels–Alder reaction, a
rapid and expedient way for the synthesis of pyrano[2,3,4-kl]xanthene
derivatives with a high degree of stereoselectivity.
This methodology is used for the first time for the synthesis of the
title compound. The precursors for the hetero-Diels–Alder reaction were
readily obtained by the treatment of salicylaldehyde 1–3 with bromocy-
clohexene 4 in dry acetone in the presence of K2CO3 under refluxing
condition to give 5–7 in 51–58% yield. See Table 1.
The structure of the products was ascertained from spectral data.
The IR spectrum of the compound showed a peak at 1683 cmꢀ1. The
1H spectrum of 5 exhibited a multiplet in the range d 1.55–2.02 for
cyclohexane ring protons, –OCH protons appeared at d 4.796 as a
multiplet, alkene proton (H1) appeared as a doublet of doublet in the
region d 5.77 (J ¼ 9.7, 1.8), and alkene (H2) proton appeared as a
multiplet in the region d 5.87–5.92. The aromatic protons resonated in
the region d 6.85–7.43. Finally, an aldehyde proton resonated at d
10.40 ppm.
The O-alkenyl aldehyde thus prepared, 5, when refluxed with
pyrazolone 8 in toluene in the presence of the catalyst ethylenediamine-
diacetate (EDDA) (Scheme 1), afforded a mixture of intramolecular het-
ero-Diels–Alder adducts 9 and 10, which were separated by column
chromatography.
The structure of 9 became evident from the spectral data.
In the 1H NMR spectrum of the compound 9, multiplets appeared in
the region d 1.76–2.32 as a result of cyclohexane ring protons, a single at
d 2.15 as a result of –CH3 protons of the pyrazole ring, and two multi-
plets in the regions d 4.11–4.19 and d 4.72–4.73 for H1 and H3 protons.
Ring junction proton H2 appeared as a doublet at d 4.12 (J ¼ 5.1). The
aromatic protons showed multiplets in the region d 6.82–7.73. Further
the cis-annulation of the ring structure for 9 was discerned by small cou-
pling constant J ¼ 5.1 Hz, which was further confirmed by the single-
crystal X-ray analysis (Figure 1).[12]
The molecular ion peak in the mass spectrum of the compound 9
appeared at m=z 358.3 (Mþ).
1
For the trans-product 10, the H NMR spectrum showed multiplets
in the region d 1.75–2.35 due to cyclohexane ring protons and a singlet at
d 2.32 due to –CH3 protons of the pyrazole ring. Two multiplets appeared

615

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E. Ramesh and R. Raghunathan
Scheme 1. Reaction of bromocyclohexene with salicylaldehyde.
in the regions d 4.13–4.21 and d 4.70–4.72 for H1 and H3 protons. A ring
junction proton appeared as a doublet at d 4.23 (J ¼ 7.8). The aromatic
protons showed multiplets in the region d 6.83–7.71. Further, the trans-
annulation of the compound 10 was discerned by the coupling constant
J ¼ 7.8 Hz. This was further supported by nuclear Overhauser effect
(NOE) studies, which showed weak interaction between H1 and H2.
By applying microwave conditions on solid support, the overall yield
increased to 76% (Table 2). In a short duration of time, microwave
irradiation proved to be highly beneficial for obtaining good yield of
the products with high stereoselectivity.
Figure 1. ORTEP diagram of 9a.

617

618

619

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E. Ramesh and R. Raghunathan
Figure 2.
By applying microwave conditions on solid support, the yield of the
product 9 increased to 74% (Table 2). In a short duration of time, micro-
wave irradiation proved to be highly beneficial for obtaining good yield
of the product with high steroselectivity.
Encouraged by these findings, we contemplated expanding the
substrate scope of the hetero-Diels–Alder reaction by taking other
salicylaldehyde derivatives. Thus, the reaction of 1 with pyrazolone 4
(Scheme 2) was carried out under optimized reaction conditions, and
the results are summarized in Table 2.
Scheme 2.

Polycyclic Pyrano Xanthene Derivatives
621
Scheme 3.
These reactions follow the same pattern as observed for substrates
2,3 but with even better yield and shorter reaction time. Under the
optimum reaction conditions, we have also carried out the intramolecular
Knoevenagel hetero-Diels–Alder reaction by employing various sym-
metrical 1,3-diones, namely indane 1,3 dione (11) and dimedone (13) with
aldehyde 1–3 (Schemes 3 and 4). The results are summarized in Table 2.
The reaction of indane-1,3-dione (11) and 2-(cyclohex-2-enyloxy)
Scheme 4.

622
E. Ramesh and R. Raghunathan
benzaldehydes (1–3) in refluxing toluene proceeded via the domino Kno-
evenagel hetero-Diehls–Alder (DKHDA) reaction to furnish a mixture of
cycloadducts 12 and 13 in an overall yield of 51–53% (Scheme 3).
Interestingly, when subjected to the intramolecular Knoevenagal
hetero-Diels–Alder reaction, all symmetrical 1,3-diones showed similar
results under optimized reaction conditions with the aldehydes 1–3.
In all cases studied, the cis-annulated products were predominately
obtained in all the reactions taken for investigation. As already described
by Tietze et al.,[16] under kinetic control, the endo-transititon state A
forms the cis-adduct, which is energetically more favorable than the
exo-transititon state B (Figure 2).
In conclusion, the preceding studies demonstrate the scope of the
intramolecular Knoevenagal hetero-Diels–Alder reaction for the synth-
esis of pyrano[2,3,4-kl]xanthene derivatives. The observations reported
here show that the reaction medium plays an important role in the out-
come of domino Knoevenagal hetero-Diels–Alder reaction and that this
method can be used for the synthesis of a variety of pyrano[2,3,4-kl]
xanthene derivatives with a high degree of stereoselectivity.
GENERAL PROCEDURE FOR THE INTRAMOLECULAR
DOMINO KNOEVENAGEL HETERO-DIELS–ALDER
REACTION
Method A
To a refluxing solution of active methylene compound (1 mmol) in 10 mL
of dry toluene, the aldehyde 1–3 (1 mmol) was added, and the reaction
mixture was refluxed until the disappearance of the starting material as
evidenced by thin-layer chromatography (TLC). After the completion
of the reaction, the solvent was evaporated in a rotavapor, and the
residue was subjected to flash-column chromatography using hexane–
ethylacetate (8:2).
Method B
A solution of active methylene compound (1 mmol) and the corres-
ponding aldehyde 1–3 (1 mmol) in dry toluene were irradiated in a micro-
wave (600 W power) until TLC showed the disappearance of the starting
material. After the removal of the solvent, the crude reaction mixture was
subjected to flash-column chromatography using silica gel to yield the
product.

Polycyclic Pyrano Xanthene Derivatives
Method C
623
A mixture of active methylene compound (1 mmol), the corresponding
aldehyde (1 mmol), and K-10 montmorillonite clay (1.0 g) was
thoroughly ground in a mortar. The reaction mixture was irradiated in
a microwave until the disappearance of the starting material as evidenced
by TLC. After the completion of the reaction, clay was separated by fil-
tration after extracting the product with dichloromethane (2 ꢁ 15 mL).
Removal of the solvent and purification of the crude reaction mixture
by flash-column chromatography gave the pure product.
Data
Synthesis of 2-(Cyclohex-enyloxy)benzaldehyde 5
A solution of salicylaldehyde (10 mmol) in acetone (20 mL) was treated
with solid K2CO3 (16 mmol) and 3-bromo cyclohexene (12 mmol). The
mixture was refluxed for 3 h, and the resulting mixture was filtered. The
filtrate was evaporated in a vacuum, and the crude viscous liquid was sub-
1
jected to column chromatography to give the pure product. H NMR
(CDCl3): 1.54–2.019 (m, 6H, ring proton), 4.79 (m, 1H, –OCH), 5.77
(dd, H1, J ¼ 9.7, 1.8), 5.87–5.92 (m, H2), 6.85–7.43 (m, 4H, Ar H), 10.39
1
(s, H, –CHO). C NMR (CDCl3): 18.84, 20.22, 28.39, 72.02, 114.48,
125.49, 125.61, 128.13, 129.98, 132.77, 136.45, 158.70, 190.14 ppm.
5,11a,15b-cis-3-Methyl-1-phenylpyrazolo[3,2-c]-5,11a,12,13,14,15b-
octahydro-1H-pyrano[2,3,4-kl]xanthene
1
Yellow solid; mp: 182 ꢂC. H NMR (CDCl3): 1.76–2.32 (m, 6H, ring
proton), 2.15 (s, 3H, –CH3), 4.11–4.19 (m, H1), 4.72–4.73 (m, H3), 4.12
(d, H1, J ¼ 5.1), 6.82–7.73 (m, 9H). 13C NMR (CDCl3): d 13.99, 17.06,
28.78, 30.18, 30.63, 36.47, 67.91, 76.07, 95.88, 115.08, 117.41, 118.72,
119.41, 123.69, 126.81, 127.20, 130.72, 152.16. MS: m=z ¼ 358.3 (Mþ).
Anal. calcd. for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82%. Found: C,
76.93; H, 6.08; N, 8.01%.
5,11a,15b-trans-Indan-1-one[3,2-c]-5,11a,12,13,14,15b-octahydro-1H-
pyrano[2,3,4-kl]xanthene
1
Yellow solid; mp: 210 ꢂC. H NMR (CDCl3): d 1.75–2.35 (m, 6H, ring
proton), 2.32 (s, 3H, –CH3), 4.13–4.21 (m, H1), 4.70–4.72 (m, H3), 4.23

624
E. Ramesh and R. Raghunathan
(d, H2, J ¼ 7.8), 6.83–7.71 (m, 9H). 13C NMR (CDCl3): d 13.93, 17.11,
28.81, 30.23, 30.59, 36.43, 67.89, 76.11, 95.85, 115.18, 117.23, 118.74,
119.41, 123.58, 126.79, 127.22, 130.75, 152.13. MS: m=z ¼ 358.39 (Mþ).
Anal. calcd. for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82%. Found: C,
76.93; H, 6.08; N, 8.03%.
5,11a,15b-cis-Indan-1-one[3,2-c]-5,11a,12,13,14,15b-octahydro-1H-
pyrano[2,3,4-kl]xanthene
1
Yellow crystalline solid; mp: 170 ꢂC. H NMR (CDCl3): d 1.57–2.27 (m,
6H, ring proton), 4.14–4.15 (m, H1), 4.71–4.72 (m, H3), 4.11 (d, H2,
J ¼ 5.0), 4.23 (d, H2, J ¼ 7.8), 6.81–7.73 (m, 8H). 13C NMR (CDCl3): d
15.70, 18.76, 30.47, 31.88, 32.31, 38.14, 69.61, 76.61, 77.77, 97.59,
116.78, 119.12, 120.42, 121.12, 125.40, 128.51, 128.91, 132.43, 138.66,
147.17, 148.25, 153.86. MS: m=z ¼ 229.21 (Mþ). Anal. calcd. for
C22H18O3: C, 79.98; H, 5.49. Found: C, 79.79; H, 5.61%.
5,11a,15b-trans-Indan-1-one[3,2-c]-5,11a,12,13,14,15b-octahydro-1H-
pyrano[2,3,4-kl]xanthene
1
Yellow crystalline solid, mp: 225 ꢂC. H NMR (CDCl3): d 1.57–2.27 (m,
6H, ring proton), 4.14–4.15 (m, H1), 4.71–4.72 (m, H3), 4.11 (d, H2,
J ¼ 5.0), 4.23 (d, H2, J ¼ 7.8), 6.81–7.73 (m, 8H). 13C NMR (CDCl3): d
15.70, 18.76, 30.47, 31.88, 32.31, 38.14, 69.61, 76.61, 77.77, 97.59,
116.78, 119.12, 120.42, 121.12, 125.40, 128.51, 128.91, 132.43, 138.66,
147.17, 148.25, 153.86. MS: m=z ¼ 229.18 (Mþ). Anal. calcd. for
C22H18O3: C, 79.98; H, 5.49. Found: C, 79.76; H, 5.62%.
REFERENCES
1. For reviews on the intramolecular Diels–Alder reaction, see (a) Roush, W. R.
In Comprehensive Organic Synthesis; B. M. Trost, I. Fleming (Eds.);
Pergamon: Oxford, UK, 1991; vol. 5, chapter 4.4, pp. 513–550; (b) Fallis,
A. Harvesting Diels and Alder’s garden: Synthetic investigations of intramo-
lecular [4 þ 2] cycloadditions. Acc. Chem. Res. 1999, 32, 464.
2. (a) House, H. O.; Cronin, T. H. A study of the intramolecular Diels–Alder
reaction. J. Org. Chem. 1965, 30, 1061; (b) Roush, W. R. Total synthesis of
(ꢃ)-dendrobine. J. Am. Chem. Soc. 1978, 100, 3599; (c) Roush, W. R.;
Peseckis, S. M. Intramolecular Diels–Alder reactions: The angularly
methylated trans-perhydroindan ring system. J. Am. Chem. Soc. 1981, 103,
6696; (d) Shea, K. J.; Gilman, J. W. Lewis acid–catalysed intramolecular
Diels-Alder cycloadditions: A mild method for the synthesis of bicyclo
[n.3.1] bridgehead alkenes. Tetrahedron Lett. 1983, 24, 657.

Polycyclic Pyrano Xanthene Derivatives
625
3. Ion, R. M.; Fara, V. L. Photophysical and photochemical properties of dye
molecules in polymers used for fluorescent solar concentrators. Proc. Indian
Acad. Sci. 1995, 107, 825.
4. Sirkecioglu, O.; Tulinli, N.; Akar, A. Synthesis of 14-alkyl-14H-dibenzo[a,j]
xanthenes. J. Chem. Res., Synop. 1995, 502.
5. Ion, R. M. PDT—A photosensitization or a photocatalytic process. Prog.
Catal. 1997, 2, 55.
6. Ion, R. M.; Frackowiak, D.; Plannar, A.; Wiktorowicz, K. The incorporation
of various porphyrins into blood cells measured via flow cytometry,
absorption, and emission spectroscopy. Acta Biochim. Pol. 1998, 45, 833.
7. Hideu, T. [1]Benzopyrano[2,3-b]xanthene derivatives. Jpn. Tokkyo Koho JP
56005480, 27 June 1979; Chem. Abstr. 1981, 95, 80922b.
8. Lamberk, R. W.; Martin, J. A.; Merrett, J. H.; Parkes, K. E. B.; Thomas, G. J.
Preparation of pyrimidine nucleosides as thymidine kinase inhibitors and vir-
ucides. PCT Int. Appl. WO 9706178, 1997; Chem. Abstr. 1997, 126, P212377y.
9. Poupelin, J. P.; Saint-Rut, G.; Fussard-Blanpin, O.; Narcisse, G.; Uchida-
Ernouf, G.; Lakroix, R. Action of hemolysin from Pseudomonas aeruginosa
on the Ehrich ascites tumor cells. Eur. J. Med. Chem. 1978, 13, 67–71.
10. Rathna Durga, R.; Jayashankaran, J.; Raghunathan, R. A rapid access
to
indolo[2,1-a]pyrrolo[40,30:4,5]pyrano[5,6-c]coumarin=[6,5-c]chromone
derivatives by domino Knoevenagal intramolecular hetero-Diels–Alder
reactions. Tetrahedron Lett. 2007, 48, 1385–1389.
11. Jayashankaran, J.; Rathna Durga, R.; Raghunathan, R. An efficient
synthesis of thiopyrano[5,6-c]coumarin=[6,5-c]chromones through intramole-
cular domino Knoevenagel hetero-Diels–Alder reactions. Tetrahedron Lett.
2006, 47, 2265–2270.
12. Sugi Kamala, E. T.; Nirmala, S.; Sudha, L.; Ramesh, E.; Raghunathan, R.
Actacis-3-methyl-1-phenyl-8a,9,10,11,12,12a,12b-hexahydro-1H,3bH-
pyrazolo[3,4:20,30]pyrano[40,50,60-kl]xanthene. Cryst. E Acta Cryst. 2008, E64,
o245–o246.
13. Ramesh, E.; Kathiresan, M.; Raghunathan, R. Solvent-free microwave-
assisted conversion of Baylis–Hillman adducts of ninhydrin into functiona-
lized spiropyrrolidines=pyrrolizidines through 1,3-dipolar cycloaddition.
Tetrahedron Lett. 2007, 48, 1835–1839.
14. Jayashankaran, J.; Rathna Durga R. S., Manian; Raghunathan, R. A facile
synthesis of novel dispiroheterocycles through solvent-free microwave-
assisted [3 þ 2] cycloaddition of azomethine ylides. Tetrahedron Lett. 2004,
45, 7303–7305.
15. Jayashankaran, J.; Rathna Durga R. S., Manian; Raghunathan, R. A
regioselective synthesis of dispiro[oxindole-cyclohexanone]pyrrolidines and
dispiro[oxindole-hexahydroindazole]pyrrolidines by sequential 1,3-dipolar
cycloaddition and annulation through a microwave induced solvent-free
approach. Tetrahedron 2005, 61, 5595–5598.
16. Tietze, L. F.; Stegelmeier, H.; Harms, K.; Brumby, T. Control of the
conformation of transition states in intramolecular Diels-Alder reactions with
inverse electron demand. Angew. Chem. Int. Ed. 1982, 21, 863.