A new synthetic route to dihydrobenzopyran via tandem demethylation cyclisation

Article abstract of DOI:10.3390/50600880

A tandem demethylation-cyclisation reaction resulting in the formation of pyran rings using AlCl₃/EtSH reagent under mild reaction conditions is reported. X-ray diffraction studies on the intermediate support the suggested mechanism.

Full text of DOI:10.3390/50600880

Molecules 2000, 5, 880-885
molecules
ISSN 1420-3049
http://www.mdpi.org
A New Synthetic Route to Dihydrobenzopyran Via Tandem
Demethylation Cyclisation
Geetha Gopalakrishnan1*, Viswanathan Kasinath1, N.D. Pradeep Singh1, R. Thirumurugan2,
S. Shanmuga Sundara Raj3 and G. Shanmugam2
1Centre for Natural Products, SPIC Science Foundation, Guindy, Chennai 600 032, India
Tel.: 044-235-1903, Fax: 044-235-1504, E-mail: geethagopal@hotmail.com
2Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai-600
025, India
3X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
Received: 17 April 2000 / Accepted: 26 May 2000 / Published: 16 June 2000
Abstract: A tandem demethylation-cyclisation reaction resulting in the formation of pyran
rings using AlCl3/EtSH reagent under mild reaction conditions is reported. X-ray diffraction
studies on the intermediate support the suggested mechanism.
Keywords: Osthol, pyranocoumarins, demethylation, cyclisation, hard-soft interactions.
Introduction
In our continuing search for bio-active leads from natural products, a coumarin analog, osthol 1 [1]
and its derivatives were considered, since they are known to exhibit anti-inflammatory and anti-
proliferatory activities[2]. While attempting to prepare a pyrano coumarin analog from osthol, a simple
and convenient method for preparing the same was noted while the reported procedures failed to give
the desired product in good yields.
Dihydrobenzopyrans are synthesised from phenols and isoprene in the presence of AlCl3 [3] or phe-
nols having isoprene units in the 2-position, in the presence of PTSA[4]. Allyl phenols undergo cycli-
sation to yield dihydrobenzopyrans, in the presence of phospate esters [5] or metal carbonyls [6] or
zeolites [7] under high temperatures. Synthesis of dihydrobenzopyrans from aromatic ethers having
isoprenyl group in 2-position involves either harsh acid conditions like refluxing with HBr/AcOH
overnight [8] or multi step synthesis [9].
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
Results and Discussion
The use of AlCl3/EtSH reagent [10] for demethylation of aromatic ethers has been reported. How-
ever, treatment of osthol with AlCl3/EtSH at room temperature resulted in direct cyclisation by trans-
etherification reaction yielding pyrano coumarin, 3. Reaction of osthol with AlCl3-DMS complex
yielded the demethylated product osthenol (4) [11] (Scheme-I).
OCH3
SC2H5
OH
O
an.AlCl
EtSH
3
O
O
O
O
O
O
(1I)
(2 )
an.AlCl
(3 )
an.AlCl / DMS
3
3
NO CYCLISATION
OH
O
O
(
)
4
Scheme 1.
It is noteworthy to mention that no cyclisation was observed while using other Lewis acid-ethane
thiol complexes namely, ZnCl2/EtSH, BF3.OEt2/ EtSH and TiCl4/EtSH under different conditions.
(Tab.1).
Table 1. Reactions of osthol.
S.No
1.
2.
Reagents
BF3.OEt2/ EtSH
AlCl3/EtSH
Time(h)
48a
Productc
Yield(%)
-
2
3
3
3
4
4
-
-
12b
40
20
76
40
62
24
-
3.
4.
5.
6.
7.
8.
AlCl3/EtSH
HBr/AcOH
AlCl3/DMS
ZnCl2/EtSH
TiCl3/EtSH
TiCl4/EtSH
24b
12
24b
48a
48a
48a
-
-
a reflux; b room temperature stirring; c In all these reactions a certain amount of di-
ethyldisulphide was formed and it was maximum in the reaction with TiCl4/EtSH.

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Molecules 2000, 5
In the case of AlCl3/EtSH, the reactive species, Al(SEt)3, has a pronounced hard-hard interaction re-
sulting in demethylation followed by cyclisation, compared to other Lewis acids. Both the nucleo-
philicity of the phenoxy oxygen and the presence of a good leaving group at the appropriate position in
the intermediate complex (V) seems to influence the cyclisation reaction. Both these factors are satis-
fied when AlCl3/EtSH is used. The intermediate 2, which has been isolated and crystallised, underwent
cyclisation only in the presence of AlCl3/EtSH and not with AlCl3 alone. The X-ray diffraction data
obtained on the intermediate II confirmed its structure (Fig-1).
Figure 1.
These observations prove the fact that nucleophilicity of the phenoxy oxygen is increased in the
complex 5 compared to that of the oxygen in the complex 6.
OAlCl2
SC2H5
SC2H5
OAl(SEt)2
O
O
O
O
(6 )
(5 )
Scheme 2.

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Molecules 2000, 5
The need for the good leaving group is demonstrated by the reaction of osthol with AlCl3-DMS
complex. Though the nucleophilicity of the phenoxy oxygen is the same as in the reaction with
AlCl3/EtSH, cyclisation is not observed in the former reaction due to the lack of good leaving group.
Experimental
General
1
Melting points were determined using a Toshniwal (India) apparatus and are uncorrected. Both H-
and 13C-NMR spectra were recorded with a BRUKER DPX-200 MHz instrument using CDCl3 as sol-
vent and TMS as internal standard. Mass spectra were recorded in Shimadzu QP-5000 instrument.
7-Hydroxy-8-(3-methyl-3-thioethylbutyl)-coumarin (2)
To a magnetically stirred supension of anhydrous AlCl3 (0.33 g, 2.5 mmol) in CH2Cl2 (5 mL) at 0°C
was added ethanethiol (2.0 mL) followed by osthol 1 (0.24 g, 1.0 mmol) in CH2Cl2 (3 mL) added
dropwise over a period of 10 min. The temperature of the reaction mixture was allowed to raise to
room temperature (30°C) and stirring continued (12 hrs). The reaction was quenched with cold dilute
HCl (10 mL) and extracted with CH2Cl2 (2 x 15 mL). Removal of the solvent yielded a dark viscous
gum, which on column chromatography (silica gel, 60-120 mesh) with 95:5 hexane: ethyl acetate fur-
nished the cyclised product 3 (0.04g, 20%). Further elution of the column with 90:10 hexane : ethyl
acetate yielded the demethylated compound 2 as a solid which was recrystallised from ethyl acetate.
(0.11 g, 40%). m.p-112-1140C.
1H-NMR (d, ppm) : 1.25 (t, 3H, J=7.4 Hz), 1.30 (s, 6H), 1.67 (bs, 1H), 1.81 (t, 2H, J=7.4 Hz), 2.53
(q, 2H, J=7.4 Hz), 2.95 (t, 2H, J=7.3 Hz), 6.25(d, 1H, J=9.4 Hz), 6.85 (d, 1H, J=8.3 Hz), 7.25 (d, 1H,
J=8.3 Hz), 7.65 (d, 1H, J=9.4 Hz).
13C-NMR: 14.2, 18.8, 22.1, 28.8, 40.7, 46.5, 112.3, 112.5, 113.3, 116.3, 126.4, 144.1, 157.7. MS
(EI, m/z) 292 (M+).
Crystal data
C16H20O3S, M=292.38, monoclinic, a=8.4325(1), b=10.8293(1), c=17.8545(1) Å, b=101.565(1)°,
U=1597 Å, T = 293K, space group P2 /n, Z = 4,
1
Dc =1.216Mg-3, m =0.207 mm-1, F(000) =624, crystal dimensions 0.48 x 0.34 x0.32 mm. Of the
12378 reflections collected by a Siemens SMART CCD area detector diffractometer with graphite
monochromated Mo-K a radiation ( l =0.71073 Å) between 2.21 to 28.29°, -11 < h < 7, -14 < k < 14, -
20 < l < 23, 3901 were independent (Rint =0.054) and 2966 were considered and observed.

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Molecules 2000, 5
Structure solution and refinement
The crystal structure was solved by direct methods (SHELXS-97) [12] and refined anisotropically
by full matrix least-squares on |F|2 (SHELXL-97) [13]. Most of the H-atoms were located in a differ-
ence map and refined freely with isotropic displacement parameters. The final R indices were
R=4.41% for observed reflections and wR(F2)=12.76% for all data. The final difference map extremes
-3
were +0.315 and -0.364 e Å , and the final shift/esd was 0.001.
7,8-(11,11-Dimethyl pyrano)coumarin (3)
The above reaction was quenched after 24 hrs. Usual workup and purification of the crude product
by column chromatography (silica gel, 60-120 mesh, 95:5 hexane : ethyl acetate) yielded the title
compound as a colourless crystalline solid. (0.17 g, 76%). m.p-101-1030C.
1H-NMR: (d, ppm) 1. 38 (s, 6H), 1.85 (t, 2H, J=6.8 Hz), 2.90 (t, 2H, J=6.8 Hz), 6.21 (d, 1H, J=9.3
Hz), 6.75 (d, 1H, J=8.6 Hz), 7.25 (d, 1H, J=8.6 Hz), 7.65 (d, 1H, J=9.3 Hz).
13C-NMR:(d, ppm)16.4, 26.6, 31.5, 75.6, 109.3, 111.5, 111.9, 114.4, 119.5, 126.2, 144.0, 153.2,
157.5, 161.6. Mass (EI, m/z) 230 (M+).
Osthenol (4)
Dimethyl sulphide (2.5 ml) was added dropwise to a suspension of anhydrous AlCl3 (0.33g, 2.5
mmol) in CH2Cl2 (5mL) at 0°C with stirring to yield a completely dissolved AlCl3/DMS solution. To
this solution, osthol 1 (0.24g, 1.0 mmol) in CH2Cl2 (3mL) was added over a period of 10 min.at the
same temperature. Then the reaction mixture was allowed to raise to room temperature (30°C) and stir-
ring continued (24 hrs). The reaction mixture was quenched with cold 1N HCl (10mL) and extracted
with CH2Cl2 (2 x 15mL). Purification of the crude product by column chromatography yielded osthe-
nol (4) [11] (0.14g, 62%).
Acknowledgements: We wish to thank Prof. T.R. Govindachari for a sample of osthol, and one of the
authors (VK) thanks CSIR, New Delhi, Government of India for a Research Fellowship.
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1978, 17, 684-686.

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Molecules 2000, 5
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Samples Availability: Available from MDPI.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.