Lei Yingjie, Liu Fude, Shi Xiaofeng
(Department of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin 300384)

Abstract: A convenient method to synthesize four 2-(methylthio)isoflavones (5a-d) in one-pot procedure by means of a mixture of carbon disulfide, iodomethane, and the deoxybenzoin compounds, prepared by a Friedel-Crafts acylation of resorcinol with arylacetic acids followed by Mitsunobu reaction, at the NaHCO₃/KCl alkaline solutions in presence of the phase transfer catalyst tri (3,6-dioxaheptyl)amine (TDA-1) was discussed. The formation of the corresponding isoflavones was confirmed by IR, ¹HNMR and elemental analysis studies, yielding in within 85-92% respectively.
Keywords: Deoxybenzoin; 2-(Methylthio)isoflavone; Synthesis; Tri (3,6-dioxaheptyl) amine.

1 INTRODUCTION
The isoflavones, mainly occurring in species of the leguminosae family, have demonstrated numerous biological activities such as antiviral, antiinflammatory, antiallergic, antimutagenic and anticarcinogenic activities ^[1-2]. Among all the possible and potential sites of the isoflavone molecules, the 2-postion is expected to be an ideal site for the introduction of major diversity in the library in that a substituent could be easily introduced as a nucleophile by means of Michael addition, even though most natural isoflavones possess no substituent but proton or rarely a hydroxyl group at this position. Therefore, substituents with alkylthio groups on the 2-postion, or 2-(alkylthio)isoflavones, as potential drug candidates for hormone-dependent breast cancer have obtained much attention^[3].
    However, only a few methods have been reported for the synthesis of 2-(alkylthio) isoflavones^[4]. Further more, these methods suffer several disadvantages such as low yields, multiple steps, and harsh conditions. Lee GH and Pak CS reported a one-pot synthesis of 2-methylthio isoflavones from 2'-hydroxy acetophenone analogues by using ketene dithioacetal as a base ^[5]. Nevertheless, this method also requires skillful handling of the base, low temperature and anhydrous reaction conditions. Kim YW et al. described a convenient conversion of deoxybenzoins into 2-(alkylthio)isoflavones with aqueous NaOH solution at room temperature in the presence of tetrabutylammonium hydrogensulfate ^[6]. Anyway, it is still desirable to have new, efficient methods for the syntheses of these  compounds.
     Tri(3,6-dioxaheptyl)amine(TDA-1),being recognized as environmentally benign media, have been widely applied in many reactions as catalysts, such as alkylation, esterification, oligomerization and carbene complexing^[7-8]. Therefore, in the present study, we introduce TDA-1 as a phase transfer catalyst and sodium bicarbonate as a base, to carry out the convenient synthesis of 2-(methylthio)-isoflavones from a mixture of carbon disulfide, iodomethane and a selected deoxybenzoin compound, in order to supply an alternative approach to introduce of alkylthio groups on the 2-postion within isoflavone molecules (Scheme 1).

2 EXPERIMENTAL
2.1 Materials and Instruments
All chemicals were obtained commercially and used without further purification. Melting points were determined with an X-4 apparatus and were uncorrected. Infrared spectra were recorded with KBr pellets on a Nicolet Inpact 170S FT-IR spectrometer in the 4000- 400 cm^-1 region. Elemental analyses for C and H were performed on a Perkin Elmer 240 analytical apparatus. ¹H-NMR spectra were measured on a Bruker DPX 300MHz in DMSO solutions with TMS as internal standard.

Scheme 1 The synthetic route for the compounds of 5a-d

2.2 Synthesis of 2',4'-dihydroxydeoxybenzoins(3a-c) 
To freshly molten anhydrous ZnCl₂ (18mmol), an appropriate phenylacetic acid (15mmol) was added with vigorous stirring and heating at about 120ºC followed by the slow addition of resorcinol (15mmol) for 3-4 hours.The reaction mixture was cooled and poured into ice water. The separated oil was extracted with ethyl acetate twice(2×30 mL). The combined organic layer was washed with water and then brine, dried over magnesium sulfate (MgSO₄), and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to give the corresponding product (3a-c).
2.3 Synthesis of 4'-alkoxy-2'-hydroxydeoxybenzoins (4a-d) 
To a solution of 2-aryl-1-(2,4-dihydroxy phenyl) ethanone (3a-c) (10mmol) and an alcohol (10.5mmol) in THF (50mL), was added triphenyl phosphine (2.62g,10mmol) and followed by diisopropyl azodicarboxylate (2mL,10mmol). The resulting yellow solution was kept at 0ºC and stirred for 20 min. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether 1:2,v/v) to give the desired deoxybenzoin (4a-d).
2.4 Synthesis of 2-(methylthio) isoflavone (5a-d)                          
To a solution of deoxybenzoin (4a-d) (5mmol) in a mixture of 1mol·L^-1 NaHCO₃ with the same equivalents of KCl (20 mL), was added TDA-1 (0.32 mL, 1mmol) and carbon disulfide (3 mL, 50mmol) and followed by iodomethane (10mmol). The resulting mixture was stirred and slightly heated at 40ºC for 6 hours. The reaction mixture was poured into water (100mL) and extracted with ethyl acetate twice (2×30 mL). The separated organics were washed with aqueous sulfuric acid ,water and then with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether 1:1, v/v) to give the product (5a-d).

3 RESULTS AND DISCUSSION
3.1 Physical characterization of the products
The specific details of the products are listed below.
    Compound 3a: using the previous procedure and starting from phenylacetic acid, a white solid, y=85%. mp. 112-114ºC[lit^[9]115ºC]. Compound 3b: using the previous procedure and starting from p-methylphenylacetic acid, a white solid, y=88%. mp. 111-113ºC[lit^[9]115-116ºC]. Compound 3c: using the previous procedure and starting from p-methoxyphenylacetic acid, a white solid, y=87%. mp.158-160ºC[lit^[9] 163ºC].
    Compound 4a: using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethan-one and methanol, a white solid, y=88%. mp. 87-89ºC [lit^[9] 92ºC]. Compound 4b: using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methyl phenyl)ethanone and methanol, a white solid, y=92%. mp. 68-70ºC[lit^[9] 71-72ºC]. Compound 4c: using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2- (4-methoxy phenyl)ethanone and methanol, a white solid, y=82%. mp.101-103℃[lit^[9]104ºC]. Compound 4d: using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethan- one and benzyl alcohol, a white solid, y=90%. mp.102-104ºC [lit^[6]104-105ºC].
    Compound 5a: using the previous procedure and starting from 1-(2-hydroxy-4- methoxyphenyl)-2- phenyl ethanone, a white solid, y=90%. mp.133-135ºC[lit^[6]136-139ºC]. IR(KBr) n/cm^-1: 1629, 1584, 1499, 1373, 1252, 1201, 1017, 835；¹H-NMR(DMSO-d₆) d: 8.15(1H,d,J=8.8Hz,5-H), 7.44-7.32(5H,m,ArH), 6.92 (1H,dd,J=8.8,2.4Hz, 6-H), 6.83(1H,d,J=2.4Hz,8-H), 3.91(3H,s,OCH₃), 2.53(3H,s, CH₃). Anal. Calcd. For C₁₇H₁₄O₃S: C, 68.44; H, 4.73. Found: C, 68.40; H, 4.71. Compound 5b: using the previous procedure and starting from 1-(2-hydroxy -4-methoxyphenyl)- 2-(4- methylphenyl) ethanone, a white solid, y=92%. mp. 184-186ºC[lit^[6] 188-189ºC]. IR(KBr) n/cm^-1: 1632, 1612, 1544, 1433, 1368, 1287, 1196, 1067, 841；¹H-NMR(DMSO-d₆) d: 8.14(1H,d,J=8.8Hz,5-H), 7.38 (2H,d,J=8.0Hz,2',6'-H), 7.20(2H, d,J=8.0Hz, 3',5'-H), 6.95(1H,dd, J=8.9,2.4Hz, 6-H),6.83(1H, d,J=2.4Hz, 8-H), 3.90(3H,s,OCH₃), 2.53(3H,s,CH₃), 2.37(3H,s, CH₃). Anal. Calcd. For C₁₈H₁₆O₃S: C, 69.21; H,5.16. Found: C,69.18; H,5.13. Compound 5c: using the previous procedure and starting from 1-(2-hydroxy- 4-methoxyphenyl)-2-(4- methoxyphenyl)ethanone, a white solid, y=92%. mp. 165-167ºC[lit^[6] 169-170ºC]. IR(KBr) n/cm^-1: 1616, 1585, 1540, 1437, 1374, 1286, 1198, 1022, 844；¹H-NMR(DMSO-d₆) d: 8.12(1H,d, J=8.8Hz,5-H), 7.27 (2H,d,J=8.0 Hz,2', 6'-H), 7.02(2H,d, J=8.0Hz, 3',5'-H), 6.93(1H,dd,J=8.9,2.4Hz,6-H), 6.83 (1H,d,J= 2.3Hz, 8-H), 3.90(3H,s,OCH₃), 3.82 (3H,s, OCH₃), 2.52 (3H, s,CH₃). Anal. Calcd. For C₁₈H₁₆O₄S: C, 65.84; H, 4.91. Found: C, 65.82; H,4.89.   Compound 5d: using the previous procedure and starting from 1-[2-hydroxy -4-(phenylmethoxy)phenyl]- 2-phenylethanone, a white solid, y=91%.mp.127- 129ºC[lit^[6] 130-132ºC]. IR(KBr) n/cm^-1: 1613, 1541, 1502, 1458, 1364, 1267, 1196, 1030, 943；¹H-NMR(DMSO-d₆) d: 8.14(1H,d,J=8.8Hz,5-H),7.45-7.32(10H,m,ArH),7.04 (1H,dd,J=8.8, 2.3Hz, 6-H), 6.93(1H,d,J=2.3Hz,8-H), 5.15(2H,s,ArCH₂), 2.52(3H,s, CH₃). Anal. Calcd. For C₂₃H₁₈O₃S: C,73.77; H,4.85. Found: C,73.74; H,4.84.
3.2 Synthesis approach to the title compounds
The synthesis of the target compounds was carried out, as outlined in Scheme 1. Compound 3(a-c) was prepared from resorcinol and phenylacetic acid in the presence of zinc chloride in good yield, which is no less than that of the boron trifluoride diethyl etherate as the lewis acid in literature ^[6]. In addition, deoxybenzoins exhibit a considerable difference in reactivity on their hydroxyl groups. Therefore, the 4-hydroxyl group of compound 3(a-c) was selectively protected with a benzyl group under Mitsunobu reaction conditions to give a monoalkyl ether 4(a-d) and the yields were excellent.
    Cyclized reaction of the deoxybenzoins to 2-(methylthio)isoflavones was reported to be carried out in a THF aqueous NaOH solution in the presence of tetrabutylammonium hydrogensulfate ^[6]. During the course of our research, we investigated this procedure by using sodium bicarbonate as a base and TDA-1 as a phase transfer catalyst since we envisioned that in this condition the active methylene group within deoxybenzoins may promote the intermediate O-aryl-S-alkyl dithiocarbonates^[10] to undergo further cyclization reaction. As expected, the reaction apparently occurred in a stepwise manner as monitored by TLC. Interestingly, the formation of dithioacetal intermediate is very fast but the subsequent cyclization is the rate-determining step, and thereby requires a longer reaction time to be completed.
    Anyway, total yields of the desired products 5(a-d) are within 85-92% respectively, which is in accordance with or somewhat better than that of the literature^[6]. Therefore, this method proved to be efficient to prepare the 2-(methylthio)isoflavones, which can be used as useful intermediates to introduce various nucleophiles at the 2-position.

4 CONCLUSION      
In summary, we have described a convenient phase transfer catalysis procedure allowing the efficient conversion of deoxybenzoins into 2-(methylthio) isoflavones in a single step at the sodium bicarbonate solution in presence of TDA-1. This method can be very useful to generate a number of isoflavones from easily available deoxybenzoins in a short period of time. Further studies on reaction scopes and applications of this method are currently underway.

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相转移催化合成2-甲硫基异黄酮
雷英杰，刘福德，史小凤
（天津理工大学化学化工学院，天津，300384）
摘要 以间苯二酚和取代苯乙酸生成的脱氧安息香为原料，三(3,6-二氧杂庚基)胺 (TDA-1)为相转移催化剂, NaHCO₃/KCl体系为碱性介质，研究了Mitsunobu反应制备的4′-烷氧基-2-羟基脱氧安息香与二硫化碳和碘甲烷一步法制备四种2-甲硫基异黄酮类化合物的合成工艺，其结构经IR和¹HNMR以及元素分析测试技术加以确证，合成收率为85-92%。
关键词 脱氧安息香；2-甲硫基异黄酮；合成；三(3,6-二氧杂庚基)胺