Synthesis of some Thiadiazoline Derivatives from 2-Phenyl Chroman-4-one

ABSTRACT 2-Phenyl chroman-4-one 1(a-g) were synthesized by Pechmann condensation of proper phenol with cinnamic acid using poly phosphoric acid. Reactions of their derivatives with thiosemicarbazide were carried out using two methods, method A, using refluxing ethanol, gave low yield (17-20%). This method was modified to increase the yield using solvent free microwave irradiation technique, (method B), which improved the yield up to (30-40%). The treatment of these thiosemicabazones 2(a-g) with excess acetic anhydrid gave substituted thiadiazoline derivatives 3(a-g). The structure of these compounds was confirmed by IR, UV and NMR spectra in addition to their physical properties. On the other hand, the calculated values of the heat of formation and steric energy were established for compounds 2(a-g) and 3(a-g).


INTRODUCTION
Chroman-4-one and their derivatives are used in many organic synthesis.The acid catalyzed condensation of substituted phenol with carboxylic acid such as liglic acid, and crotonic acid gives chroman-4-one derivatives, which underwent ring closure with hydrazine hydrate to form pyrazolines (Ayoub et al., 1985).
In view of these observations, we prefer to synthesize new substituted thiadiazolines containing chromanone moiety of anticipated biological importance.

EXPERIMENTAL
Uncorrected melting points were determined using electro thermal Gallen kamp melting apparatus.IR spectra were obtained via Perkin-Elmer 590B spectrophotometer.UV-spectra obtained via Shimadzu UV-160 spectrophotometer, while 1 H-NMR spectra were obtained from a Bruker a vance 300-MHz, NMR spectrometer.The chemical shifts are reported in δ values for DMSO-d6 solution using TMS as internal standard, with the use of the following abbreviations: s, singlet; d, doublet; m, multiplet; br, broad.

Theoretical calculation:
The geometries of compounds 2(a-g) and 3(a-g) were optimized using PM3 semiempirical methods to obtain Heat of formation (∆H f ).Total steric energy (S.E) was computed using molecular mechanic theory 2 (MM2) in the CS-Chem office-version 10.
Synthesis of substituted 2-phenyl chroman-4-one 1 (a-g) (Ayoub et al.,1985)To a mixture of (25 mmole) of the desired phenol and (3.7 gm, 25 mmole) of cinnamic acid, (20-25)g of polyphosphoric acid was added at room temperature.The mixture was stirred and heated on water bath at (75-80) º C for (1-1.5)h.The mixture was then poured on ice bath.The residue was filtered off, washed with cold water, dried and crystallized from ethanol to afford a white amorphous solid of compounds 1(a-g).Table (1) shows some physical properties and spectral data of these compounds.
Table 1: Some physical properties and spectral data for compounds 1(a-g).
2-phenyl chroman-4-thiosemicarbazone 2(a-g) (Pawar et al., 2009) Method A: To a solution of (2.8 mmole) of substituted 2-phenyl chroman-4-one 1(b-c) in absolute ethanol (10 ml), a solution of (2.8 mmole) of thiosemicarbazid in ethanol and few drops of conc.HCl were added with stirring.The reaction mixture was refluxed for (2-5)h on a water bath.After cooling, the solid product was filtered off and crystallized from ethanol to give white product of compounds 2(b-c).
Table (2) shows some physical properties and spectral data of these compounds.Compounds 2(a-g)( 0.27 mmole) were treated with excess of acetic anhydride (3 ml) and the mixture was refluxed for (6-7)h.The resulting contents were poured over crushed ice.The obtained solid was filtered, dried and crystallized from ethanol to afford the title compounds.Table (3) gives some physical properties and spectral data of these compounds.The prepared 4-chromanone derivatives 1(a-g) were considered as a principle nucleus for the synthesis of many important heterocyclic compounds through their reactions with different compounds (Ayoub et al., 1985) and (Pawar et al., 2009).
The derivatives1(a-g) were prepared via Pechmann condensation of the proper phenols with cinnamic acid using polyphosphoric acid as shown in scheme (1).The proposed mechanism of the conversion 2(a-g) derivatives to 3(a-g) derivatives was summarized in scheme ( 2 Scheme (2) The IR spectra of the 4-chromanones 1 (a-g) showed a strong absorption bands at about (1637-1728 cm -1 ) which belong to the bond stretching of the carbonyl group of the chromanon (Ayoub et al., 1985).The UV spectra of these compounds showed a maximum absorption (λ max ) at (300-316 nm) The 1 H-N.M.R. spectra of compounds 1(b, e, g) were in agreement with the suggested structures.The H-2 in these compounds appeared at δ (4.6-6.9)ppm (Ayoub et al., 1985).Other proton bands are represented in Table (1).
Reactions of 4-chromanone derivatives 1(a-g) with thiosemicarbazide gave thiosemicarbazones 2(a-g).The IR spectra showed absorption band of C=N bond stretching at (1626-1639 cm -1 ) specific for thiosemicarbazons (Pawar et al., 2009), and broad bands at (3236-3338 cm -1 ) corresponding to the N-H bond stretching.The absence of absorption band carbonyl group frequency give a good indication about the formation of these compounds, Table (2).The UV spectra for products 2(a-g) showed λ max at (318-326 nm) due to the presence of the conjugation system that caused a bathochromic shift.The 1 H-NMR spectrum in DMSO showed the prensence of two proton bands, NH and NH 2 at 7.0-6.5 ppm and (8.2-8.6)ppm respectively (Pawar et al., 2009).Other proton chemical shifts are represented in table (2).
Acetylation of thiosemicarbazones 2(a-g) by acetic anhydride gave thiodiazolines derivatives 3(a-g) (scheme 1), (Venkateswarlu et al., 2005) and (Pawar et al., 2009).The main IR absorption bands of these products include stretching vibrations of two C=O and C=N bonds at (1695-1720 cm -1 ),(1572-1655 cm-1) and (1500-1617 cm -1 ) respectively (Pawar et al., 2009), in addition to a broad absorption at (2933-3280 cm -1 ) corresponding to N-H bond stretching.The absence of conjugation was confirmed by decreasing the absorption wave lengths in UV spectra of these compounds to (270-290 nm) i.e hypsochromic shift.The 1 H-NMR spectra of compounds 3(b, e) showed the presence of CH 3 protons of the acetyl groups at 1.3 and 2.15 ppm for H 6 protons and 3.3 and 2.6 ppm for H 7 protons, other proton bands appeared at 12.3 ppm belong to NH proton (Pawar et al., 2009).Compound 3g shows chemical shifts at 2.3 -2 ppm equivalent to nine protons belonging to the protons of the three methyl groups(H 6 ,H 7 and H6).It also shows another chemical shifts at 3.15 ppm equivalent to three protons belonging to the protons of fourth CH 3 group(H 7̀) .The chemical shift of the NH proton appeared at 7.3 ppm (Pandeya et al., 2009).The other proton chemical shifts are represented in Table (3).
In order to estimate the effect of converting the semicarbazone derivatives 2(a-g) to the thiadiazoline derivatives 3(a-g), we employ quantum chemical calculations to calculate the heat of formation of these compounds as shown in Table (4).
From the results, we can see that there is a large decrease in the heat of formation values of compounds 3(a-g), which mean that these compounds are more stable (less active) compared with the intermediate 2(a-g).On the other hand, the values of total steric energy (shown in Table 4) were increased when compound 2(a-g) converted to compounds 3(a-g) due to the formation of more bulky thiadiazoline molecules compared to the thiosemicarbazone molecules.