A New Synthetic Route to Dihydrobenzopyran Via Tandem

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.


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 antiproliferatory 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 AlCl 3 [3] or phenols having isoprene units in the 2-position, in the presence of PTSA [4].Allyl phenols undergo cyclisation 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].

Results and Discussion
The use of AlCl 3 /EtSH reagent [10] for demethylation of aromatic ethers has been reported.However, treatment of osthol with AlCl 3 /EtSH at room temperature resulted in direct cyclisation by transetherification reaction yielding pyrano coumarin, 3. Reaction of osthol with AlCl 3 -DMS complex yielded the demethylated product osthenol (4) [11] (Scheme-I).It is noteworthy to mention that no cyclisation was observed while using other Lewis acid-ethane thiol complexes namely, ZnCl 2 /EtSH, BF 3 .OEt 2 / EtSH and TiCl 4 /EtSH under different conditions.(Tab.1).TiCl 4 /EtSH 48 a -a reflux; b room temperature stirring; c In all these reactions a certain amount of diethyldisulphide was formed and it was maximum in the reaction with TiCl 4 /EtSH.
In the case of AlCl 3 /EtSH, the reactive species, Al(SEt) 3 , has a pronounced hard-hard interaction resulting in demethylation followed by cyclisation, compared to other Lewis acids.Both the nucleophilicity 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 satisfied when AlCl 3 /EtSH is used.The intermediate 2, which has been isolated and crystallised, underwent cyclisation only in the presence of AlCl 3 /EtSH and not with AlCl 3 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.

Scheme 2.
The need for the good leaving group is demonstrated by the reaction of osthol with AlCl 3 -DMS complex.Though the nucleophilicity of the phenoxy oxygen is the same as in the reaction with AlCl 3 /EtSH, cyclisation is not observed in the former reaction due to the lack of good leaving group.

General
Melting points were determined using a Toshniwal (India) apparatus and are uncorrected.Both 1 Hand 13 C-NMR spectra were recorded with a BRUKER DPX-200 MHz instrument using CDCl 3 as solvent and TMS as internal standard.Mass spectra were recorded in Shimadzu QP-5000 instrument.

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 difference map and refined freely with isotropic displacement parameters.The final R indices were R=4.41% for observed reflections and wR(F 2 )=12.76% for all data.The final difference map extremes were +0.315 and -0.364 e Å -3 , and the final shift/esd was 0.001.