An approach to biologically important chromenes bearing P-S-heterocycles. Based on the chemistry of Lawesson ’ s reagent

A series of chromenes bearing P-S-heterocycles, were prepared in reasonable yields from the reaction of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide (Lawesson’s reagent, LR, 1 ) with a variety of substituted chromones. The antibacterial and /or antifungal activities for some of the new products obtained were evaluated.


Introduction
][3] At elevated temperatures, LR exists in equilibrium with the monomeric species 1A 4 (Figure 1), which allows it to undergo [2 + 4] cycloaddition with acyclic α-β-unsaturated ketones 1,2,5 to give various heterocyclic compounds.][8] Furthermore, the utility of LR for producing 4-membered P-S-heterocycles was previously reported by us. 9In continuation of this work, the present study has focused on the synthesis of bioactive P-S-heterocyclic systems.The methodology centered on the application of Lawesson's reagent with some chromone derivatives 2, 7, 11, and 15.The structure-activity relationships of some of the isolated products are also briefly discussed.

Results and Discussion
3-Formylchromone (2) was allowed to react with LR in boiling toluene to give a mixture of two products that could be separated by column chromatography.The first (20%) is formulated as 4thioxo-4-chromene-3-carbothialdehyde (3) based upon analytical and spectroscopic arguments.The second product (60%), is formulated as 2-(4-methoxyphenyl)-5H-10aH- [1,3,2]oxathiaphosphinino [4,5-b] The constitutions of the isolated products 3 and 6 were in accord with elemental analyses and spectroscopic properties.The structure of the oxathiaphosphinino chromene 6 was based on the following data: its 31 P-NMR signal (in CDCl 3 , vs. 85% H 3 PO 4 ) was at δ 93.39 which matches a cyclic structure. 10,11The IR spectrum of 6 revealed the absence of an absorption band around 1640 cm -1 corresponding to (C=O), instead, absorption bands at 1220 (C=S), 1580, 1600 (C=C, aromatic) cm -1 were present.Moreover, an absorption band at 650 cm -1 corresponding to (P=S) was present in the spectrum of 6.The 1 H NMR spectrum of 6 (in CDCl 3 , δ ppm) revealed the presence of signals at 3.85 (s, 3H, OCH 3 ), 7.4 (d, 3 J HP = 11.3,1H, P-S-CH).The AB system due to the four aromatic protons of the substituent atomatic ring appeared as two sets of doublet of doublets at 6.95 and 7.56 each with J HH = 9 Hz, 3 J HP = 11 Hz, whereas the aromatic protons of the chromene ring appeared at 7.95, 8.7 (2d, 2H, J HH = 7 Hz), 6.8, 7.1 (2t, 2H, =CH-CH=), 8.8 (d, 3 J HP = 10.5, 1H, P-O-CH=C).The 13  The formation of compound 6 can be interpreted in terms of nucleophilic attack by the Sanion of the monomeric species 1A on the initially formed chromone thione intermediate 4 to give the transient dipolar structure 5, followed by ring closure.
The aromatic protons (13H) appeared as a multiplet at δ H = 6.45-8.32ppm.The 13  According to Scheme 2, the formation of 10a-d is believed to occur via nucleophilic attack of the monomeric species 1A on compound 8 to give intermediate 9, followed by ring closure to afford the thiazaphosphetidin chromene 10.
Formation of the thioamide derivative 12 can be attributed to a partial hydrolysis 9,12 of 11 to yield the respective α-cyano-β-substituted acrylamide intermediate which underwent ketone-tothioketone conversion under the thiating effect 1-3 of LR to afford the thioamide chromene derivative 12.
The proposed mechanism for formation 14 involves initial nucleophilic attack by 1A on 11 to give the transient intermediate 13.This process is followed by ring closure 13  The structure of 17 was confirmed by analytical and spectral data which showed the disappearance of both the cyano and carboxylate groups.The 1 H NMR spectrum of 17 showed a singlet at 3.82 due to methoxy protons, also a singlet at 6.8 due to exocyclic ethylenic protons and a broad band at 10.94 due to the NH proton.
It is noteworthy that, in this reaction, the expected 1,2-thiaphosphetane derivative 18 was not formed.Instead, the thiazaphosphinane chromene 17 (69% yield) was isolated in a pure form.It is believed to be formed via the thioamideacrylate intermediate 16 with concomitant elimination of an alcoholic moiety.8][19]  The prepared products were also tested against one or the other type of bacteria including B. subitilis, B. cereus and E. coli.Compounds 8b,d and 12 exhibited reasonable activities whereas, the phosphorylated derivatives 6, 10b, 14 and 17 showed the highest inhibitory effect against all the tested organisms, possibly attributable to the presence of the phosphorus moiety.
On the basis of our results, compounds 6, 10b, 14 and 17 would be good candidates, lead molecules to be modified in order to improve the anti-microbial activity.

Conclusions
In summary, the present investigations describe an efficient and simple approach to the synthesis of a variety of biologically active 4-and 6-membered P-S-heterocycles in satisfactory yields, with the use of easily available starting materials.

Experimental Section
General Procedures.All melting points are uncorrected.IR spectra were recorded on a Perkin-Elmer spectrophotometer model 297 using KBr disc.The 1 H and 13 C NMR spectra were recorded on a JNM-GX-400 Fa Joel spectrometer, using TMS as an internal reference. 31P-NMR spectra were taken with a Varian CFT-20 (vs.external 85% H 3 PO 4 ).The mass spectra were performed at 70 eV on an MS-50 Kratos (A.E.I.) spectrometer provided with a data system.Elemental analyses were carried out at the Microanalysis Laboratory, Cairo University, Cairo, Egypt.The appropriate precautions in handing moisture-sensitive compounds were observed.
Starting material 2 and LR, 1 were commercially available (From Aldrich Co.).Monoanils 7a,b were prepared as described by Fitton et al. 20 The preparation of the new starting chromone derivatives 7c,d, 11

10b, 12, 14, 17 were
Formation of 19 is frequently observed during thiation processes using LR.screened against various types of fungi including P. brevicompactum, As. niger and As.fumigatus by adopting a food poisoning technique.Compounds 8b,d and 12 are moderately active against P. brevicompactum and As.
fumigatus at 400 mg /mL concentration level, while compounds 6, 10b, 14, and 17 are more active against the same fungi at the same dose level.Compounds 6 and 14 registered 100% spore germination inhibition in As. niger at 500 mg/mL whereas, compound 12 was found to have feeble activity.