HETEROCYCLES

Paper | Regular issue | Vol. 85, No. 1, 2012, pp. 43-56
Received, 9th August, 2011, Accepted, 8th November, 2011, Published online, 14th November, 2011.
DOI: 10.3987/COM-11-12333

■ Unexpected Tandem Reaction of New Type Morita-Baylis-Hillman Adducts Promoted by [Hmim]HSO4/NaNO3 System

Weihui Zhong,* Guan Wang, and Kai Chen

Key Laboratory of Pharmaceutical Engineering of Ministry of Educations, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310014, China

Abstract

A tandem reaction of new type Baylis-Hillman adducts 1 was prompted by ionic liquid [Hmim]HSO4/NaNO3 system and the unexpected products 6-aryl-2H-pyran-3-carboxylates 2 and imidazolium salts 3 were efficiently formed via the rearrangement and substitution reaction. While mediated by [Emim]HSO4/NaNO3 system, the key intermediates 4 were isolated. A plausible mechanism for the transformation was given.

INTRODUCTION
Tandem reactions are of great importance in organic synthesis due to generation of some important products in a single operation with high atom economy and bond-forming efficiency. Recently, more and more novel types of tandem reactions, including tandem Michael addition,1 substitution,2 cyclization3-5 and rearrangement reaction,6 were extensively applied to organic synthesis, especially the synthesis of natural optically active products7 and heterocyclic compounds. The Baylis-Hillman reaction is a synthetically useful method for carbon-carbon bond-forming reactions to yield functionalized allylic alcohols,8 thereby providing handles for further manipulation in a multitude of synthetic organic transformations.9 In continuation of our research on new type Baylis-Hillman adducts 1 prepared from aryl methyl ketones via a combination of the Vilsmeier and the Baylis-Hillman reactions,10-13 we investigated the tandem reaction of new type Baylis-Hillman adduct 1 under the [Hmim]HSO4/NaNO3 system14 (Scheme 1). To our surprise, the unexpected products 6-aryl-2H-pyran-3-carboxylates 2 and/or imidazolium salt 3 were isolated.

RESULTS AND DISCUSSION
Initially, we mixed 1.0 mmol of (Z)-methyl 5-chloro-3-hydroxy-5-(4-methoxyphenyl)-2-methylenepent-4-enoate 1a with 1.1 mmol of NaNO3 in ionic liquid [Hmim]HSO4 at 80 oC for 12 h, the unexpected product methyl 6-(4-methoxyphenyl)-2H-pyran-3-carboxylate 2a was isolated in 80% yield (Scheme 2).

Encouraged by this result, several other nitrate salts have been used to investigate the above reaction and the results were summarized in Table 1. No desired product 2a was detected using NH4NO3-[Hmim]HSO4 system at 80 °C for 12 h (Table 1, entry 2). Zn(NO3)2-[Hmim]HSO4 system could produce 2a with only 10% yield (Table 1, entry 3). Compared to the NaNO3-[Hmim]HSO4 system, a slightly lower yield was found using KNO3-[Hmim]HSO4 system (Table 1, entry 4). The highest yield (80%) of 2a was obtained in NaNO3-[Hmim]HSO4 system at 80 °C for 12 h (Table 1, entry 1). Moreover, proper temperature was found to be essential to this reaction and the system showed homogeneous at 80 °C. At lower temperatures, 2a was obtained in lower yield even with longer reaction time (Table 1, entries 5 and 6), while higher temperatures led to unknown side reactions and very complicated results (Table 1, entries 7 and 8).

Another type BH adduct 1b with a para-nitro group on the aromatic ring was also investigated under the similar conditions. To our surprise, when substrate 1b was mixed with the NaNO3-[Hmim]HSO4 system at 80 °C for 12h, only imidazolium salt 3b was isolated in 82%, which was confirmed by 1H-NMR, 13C-NMR and MS spectra (Scheme 3). This interesting result indicated that the different type of the substituted groups on the aromatic ring had evident influence on the products.

In order to confirm our presumption, various new type Baylis-Hillman adducts 1 were used for the tandem rearrangement-substitution reaction under similar conditions and the full results are summarized in Table 2. It was found that the substrates 1 with electron-donoring groups on the aromatic ring gave the corresponding 2H-pyrans 2 in good yields (80-75%) (Table 2, entries 1, 3 and 4), while those with electron-withdrawing groups produced the corresponding imidazolium salts 3 in good yields (98-78%) (Table 2, entries 2, 6-9). Interestingly, the substrates 1e could give both of the products with the ratio of 2e : 3e = 1 : 2. In addition, when 2.2 equivalents of NaNO3 was added to this reaction, the ratio of these two products was not obviously changed (Table 2, entry 5).

In order to clarify the formation mechanism of these products, ionic liquid [Emim]HSO4 was prepared,15 which could avoid theoretical formation of imidazolium salts 3. As we anticipated, the reactions of the Baylis-Hillman adducts 1 under the ionic liquid [Emim]HSO4/NaNO3 system gave SN2’ products (2E,4Z)-5-chloro-2-(nitrooxymethyl)-5-arylpenta-2,4-dienoates 4 with satisfactory yields (Table 3).

However, these intermediates 4a-c were unstable at high temperature. Treatment of this intermediate 4a with 3-methylbenzenethiol afforded the desired product (2Z,4Z)-methyl 5-chloro-5-(4-methoxyphenyl)-2-(m-tolylthiomethyl)penta-2,4-dienoate 5a in 63% yield (Scheme 4).

To confirm the regularity, we used various of nucleophilic reagents to react with the Baylis-Hillman adducts 1 under the ionic liquid [Emim]HSO4/NaNO3 system in one pot, and afforded the compounds 5a-i in good yields (Scheme 5, Table 4). During our experiments, we found without addition of NaNO3, not desired compounds 5, but the rearrangemented compound 6 (R1= p-Cl) was isolated and conformed by NMR and MS, which demonstrated the NaNO3 play an important role in the reactions, and the intermediates 4 were existed in the reaction paths (Scheme 5). It was also found from Table 4 that the substrates 1 with electron-donoring groups on the aromatic ring gave the higher yields than those with electron-withdrawing groups. In other words, the more stable the intermediates 4 with electron-donoring groups are, the more possible to form the 2H-pyrans 2 in [Hmim]HSO4/NaNO3 system.

According to the above results, a plausible mechanism16 for the formation of products 2, 3 and 4 was shown in Scheme 6. Firstly, the BH adduct 1 was attacked by nitrate anion in ionic liquid to give SN2’ products 4, where [Hmim]HSO4 played a dual role of Brønsted acid catalyst and solvent for both rearrangement and substitution.12 Intermediates 4 are unstable at high temperature and could be readily converted into 2 and 3 via path A or path B dependent on the activities of substrates.

In summary, the present study investigated the tandem reaction of new type Morita-Baylis-Hillman adducts in ionic liquids/NaNO3 system, which provided a new and efficient way for the synthesis of 2H-pyrans and imidazolium salts. The new applications of ionic liquids/NaNO3 system are now being investigated in our lab.

EXPERIMENTAL
Unless otherwise indicated, chemicals and solvents were purchased from commercial suppliers and without further purification. Flash column chromatography was performed using silica gel (200-400 mesh). IR spectra were recorded on a Nicolet Avatar-370 instrument. Mass spectra were measured with Termo Finnigan LCQ-Advantage. 1H NMR and 13C NMR spectra were recorded at VARAIN-400 or BRUKER AVANCE III-500 using CDCl3 or DMSO as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts were given in δ relative to TMS, the coupling constants J were given in Hertz. The low-resolution mass spectra were obtained with the Thermo Trace GC Ultra-DSQ II and Agilent 6120 (Quadrapole LC-MS) mass spectrometer. High resolution mass spectra (HRMS) analyze were measured on an Agilent 6210 TOF LC/MS using ESI or EI (electrospray ionization) techniques.

General procedure for the synthesis of 2H-pyrans 2 and/or imidazolium salts 3
A mixture of Baylis-Hillman adducts 1 (1 mmol) and NaNO3 (1.1 mmol) was stirred in 2 mL of [Hmim]HSO4 at 80 °C for 12 h. The reaction mixture was cooled to rt. After completion of the reaction (monitored by TLC), the product was extracted with EtOAc (3 × 10 mL). The combined extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (CH2Cl2-MeOH, 16 : 1 ) to afford the products 2 and 3.

General procedure for the synthesis of (2E,4Z)-5-chloro-2-(nitrooxymethyl)-5-arylpenta-2,4- dienoates 4
A mixture of Baylis-Hillman adducts 1 (1 mmol) and NaNO3 (1.1 mmol) was stirred in 2 mL of [Emim]HSO4 at rt for 3 h. After completion of the reaction (monitored by TLC), the product was extracted with EtOAc (3 × 10 mL). The combined extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane-EtOAc, 8 : 1) to afford the desired products 4.

General procedure for the synthesis of compounds 5
A mixture of Baylis-Hillman adducts 1 (1 mmol) and NaNO3 (1.1 mmol) was stirred in 2 mL of [Emim]HSO4 at rt for 3 h. The reaction mixture was heat to 60 °C and o-MeC6H4SH (1.1 mmol) was added. The mixture was further stirred at rt for 2-3 h. After completion of the reaction (monitored by TLC), the product was extracted with EtOAc (3 × 10 mL). The combined extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane-EtOAc, 8 : 1) to afford the desired product 5.

Methyl 6-(4-methoxyphenyl)-2H-pyran-3-carboxylate (2a)
White solid. Mp 166-169 °C. IR (KBr) (νmax, cm-1): 3188, 2936, 1670. 1H NMR (400 MHz, DMSO-d6) δH: 3.75 (3H, s, COOCH3), 3.82 (3H, s, Ar-OCH3), 4.66 (2H, s, O-CH2-C=C), 7.04-7.79 (4H, m, ArH), 7.61 (1H, d, J = 11.2 Hz, O-C=CH-C), 7.73 (1H, d, J = 11.2 Hz, CH=C-COOMe). 13C NMR (100 MHz, DMSO-d6) δC: 52.1, 55.5, 59.8, 92.2, 104.5, 114.3(2C), 119.1, 128.4, 128.7, 137.5, 139.8, 161.0, 166.6; MS (CI) 246.0 [M]+. HRMS (CI) calcd for [C14H14O4]: 246.0892; found: 246.0895.

Methyl 6-p-tolyl-2H-pyran-3-carboxylate (2c)
White solid. Mp 166-169 °C. IR (KBr) (νmax, cm-1): 3183, 2943, 1674. 1H-NMR (400 MHz, DMSO-d6) δH: 2.36 (3H, s, Ar-CH3), 3.76 (3H, s, COOCH3), 4.67 (2H, s, OCH2C), 7.30 (1H, d, J = 8.0, O-C=CH), 7.64-7.71 (4H, m, ArH), 7.74 (1H, d, J = 2.8, MeOOC-C=CH); 13C NMR (100 MHz, DMSO-d6) δC: 20.8, 52.1, 59.8, 120.2, 126.6(2C), 129.4(2C), 129.5, 133.2, 137.1, 139.9, 140.4, 166.6; MS (CI) 231.3 [M+1]+. HRMS (CI) calcd for [C14H14O3]: 230.0943; found: 230.0939.

Ethyl 6-(4-methoxyphenyl)-2H-pyran-3-carboxylate (2d)
White solid. Mp 166-169 °C. IR (KBr) (νmax, cm-1): 3176, 2945, 1665. 1H NMR (400 MHz, DMSO-d6) δH: 1.27 (3H, t, J = 7.2, CH2CH3), 3.82 (3H, s, Ar-OCH3), 4.42 (2H, q, J = 7.2, CH2CH3), 4.66 (2H, s, OCH2), 7.04 (2H, m, ArH), 7.62 (1H, d, J = 11.2, C=CH-CH=C-O), 7.73 (1H, d, J = 11.2, C=CH- CH=C-O), 7.78-7.80 (2H, m, ArH); 13C NMR (100 MHz, DMSO-d6) δC: 14.1, 55.4, 59.8, 60.6, 144.2(2C), 119.1, 128.3(2C), 128.9, 137.2, 139.5, 160.9, 166.1(2C); MS (CI) 261.3 [M+1]+. HRMS (CI) calcd for [C15H16O4]: 260.1049; found: 260.1045.

Methyl 6-phenyl-2H-pyran-3-carboxylate (2e)
White solid. Mp 163-165 °C. IR (KBr) (νmax, cm-1): 3163, 2959, 1660. 1H NMR (400 MHz, DMSO-d6) δH: 3.87 (3H, s, COOCH3), 4.42 (2H, s, OCH2C), 7.30 (1H, d, J = 11.2, O-C=CH), 7.24 (H, s, ArH), 7.42 (2H, d, J = 3.6, ArH), 7.73 (2H, d, J = 3.6, ArH), 7.42 (2H, d, J = 11.2, MeOOC-C=CH); 13C NMR (100 MHz, DMSO-d6) δC: 52.1, 59.8, 121.0, 126.6(2C), 128.8(2C), 129.9, 130.3, 135.9, 136.9, 139.7, 166.5; MS (ESI) 217.1 [M+1]+. HRMS (ESI) calcd for [C13H12O3]: 216.0786; found: 216.0780.

1-((2E,4Z)-5-Chloro-2-(methoxycarbonyl)-5-(4-nitrophenyl)penta-2,4-dienyl)-3-methyl-1H-imidazol-3-iumhydrogensulfate (3b)
Yellow solid. Mp 260-262 °C. IR (KBr) (νmax, cm-1): 3442, 2945, 1694. 1H NMR (400 MHz, DMSO-d6) δH: δ (ppm) 3.77 (3H, s, N-CH3), 3.86 (3H, s, COOCH3), 5.43 (2H, s, N-CH2), 7.36-7.40 (2H, m, ArH), 7.77 (1H, d, J = 5.6 Hz, Cl-C=CH), 7.86 (1H, d, J = 11.2 Hz, Me-N-CH=C), 7.95 (1H, d, J = 11.2 Hz, N-CH=C), 8.06 (1H, d, J = 5.6 Hz, ClC=C-CH=C), 8.07-8.09 (2H, m, ArH), 9.21 (1H, s, N=CH-C). 13C NMR (100 MHz, DMSO-d6) δC: 36.8, 52.1, 59.8, 121.0, 126.7(2C), 128.8(2C), 129.9, 130.3, 135.9, 136.9, 139.6, 141.8, 147.4, 148.0, 166.5; MS (ESI) 362.1 [M]+. HRMS (ESI) calcd for [C17H17ClN3O4+]: 362.0908; found: 362.0900.

3-((2E,4Z)-5-Chloro-2-(methoxycarbonyl)-5-phenylpenta-2,4-dienyl)-1-methyl-1H-imidazol-3-ium- hydrogensulfate (3e)
White solid. Mp 260-262 °C. IR (KBr) (νmax, cm-1): 3443, 2942, 1699. 1H NMR (400 MHz, DMSO-d6) δH: 3.76 (3H, s, N-CH3), 3.86 (3H, s, COOCH3), 4.67 (2H, s, N-CH2), 7.29 (2H, d, J = 8.8 Hz, ArH), 7.65 (2H, d, J = 3.2 Hz, Cl-C=CH, ClC=C-CH=C), 7.66 (2H, d, J = 6.4 Hz, Me-N-CH=C, N-CH=C), 7.70 (2H, d, J = 8.8 Hz, ArH), 7.74 (H, d, J = 3.2 Hz, ArH), 9.03 (1H, s, N=CH-C). 13C NMR (100 MHz, DMSO-d6) δC: 35.8, 44.8, 61.2, 118.7, 122.7, 123.5, 125.7, 127.3(2C), 129.3(2C), 133.0, 136.7, 139.1, 141.0, 143.1, 165.4; MS (ESI) 317.1 [M]+. HRMS (ESI) calcd for [C17H18ClN2O2+]: 317.1057; found: 317.1062.

3-((2E,4Z)-5-Chloro-5-(3-chlorophenyl)-2-(methoxycarbonyl)penta-2,4-dienyl)-1-methyl-1H-imid-azol-3-ium hydrogensulfate (3f)
White solid. Mp 265-268 °C. IR (KBr) (νmax, cm-1): 3456, 2938, 1676. 1H NMR (400 MHz, DMSO-d6) δH: 3.77 (3H, s, N-CH3), 3.87 (3H, s, COOCH3), 5.44 (2H, s, N-CH2), 7.54-7.58 (2H, m, ArH), 7.59-7.61 (2H, m, ArH), 7.73 (1H, d, J = 13.6 Hz, Me-N-CH=C), 7.75 (1H, d, J = 8.8 Hz, Cl-C=CH), 7.94 (1H, d, J = 13.6 Hz, N-CH=C), 7.95 (1H, d, J = 8.8 Hz, ClC=C-CH=C), 9.20 (1H, s, N=CH-C). 13C NMR (100 MHz, DMSO-d6) δC: 35.9, 44.7, 52.6, 121.1, 122.7, 123.5, 126.2, 126.7, 126.9, 130.5, 130.7, 133.7, 136.8, 137.7, 138.6, 140.8, 165.8; MS (ESI) 351.0 [M]+. HRMS (ESI) calcd for [C17H17Cl2N2O2+]: 351.0667; found: 351.0653.

3-((2E,4Z)-5-Chloro-2-(ethoxycarbonyl)-5-(4-nitrophenyl)penta-2,4-dienyl)-1-methyl-1H-imidazol- 3-ium hydrogensulfate (3g)
Yellow solid. Mp 272-273 °C. IR (KBr) (νmax, cm-1): 3469, 2934, 1689. 1H NMR (400 MHz, DMSO-d6) δH: 1.24 (3H, t, J = 7.2, COOCH2CH3), 3.86 (3H, s, N-CH3), 4.22 (2H, q, J = 7.2, COOCH2CH3), 5.48 (2H, s, N-CH2), 7.73-7.78 (2H, m, N-HC=CH-N), 7.95 (1H, d, J = 11,6, ClC=C-CH=C), 8.12 (1H, d, J = 11.2, ClC=HC-C=C), 8.29-8.34 (4H, m, ArH), 9.24 (1H, s, N=CH-N); 13C NMR (100 MHz, DMSO-d6) δC: 13.9, 35.8, 44.8, 61.5, 122.8, 123.5, 123.8(2C), 128.3, 128.7(2C), 136.9, 138.1, 139.9, 141.5, 148.2(2C), 165.1; MS (ESI) 376.1 [M]+. HRMS (ESI) calcd for [C18H19ClN3O4+]: 376.1064; found: 376.1067.

1-((2E,4Z)-5-Chloro-5-(4-fluorophenyl)-2-(methoxycarbonyl)penta-2,4-dienyl)-3-methyl-1H-imid- azol-3-ium hydrogensulfate (3h)
White solid. Mp 257-258 °C. IR (KBr) (νmax, cm-1): 3455, 2940, 1705. 1H NMR (400 MHz, DMSO-d6) δH: 3.77 (3H, s, N-CH3), 3.86 (3H, s, COOCH3), 5.43 (2H, s, N-CH2), 7.38 (2H, t, J = 8.8 Hz, ArH), 7.23 (1H, d, J = 3.6 Hz, Cl-C=CH), 7.64 (1H, d, J = 3.6 Hz, ClC=C-CH=C), 7.86 (1H, d, J = 11.2 Hz, Me-N-CH=C), 7.95 (1H, d, J = 11.2 Hz, N-CH=C), 8.06-8.09 (2H, m, ArH), 9.21 (1H, s, N=CH-C). 13C NMR (100 MHz, DMSO-d6) δC: 35.8, 44.8, 52.6, 115.8 (J = 22 Hz, 2C), 119.7, 122.6, 123.5, 126.1, 130.0 (J = 9 Hz, 2C), 132.3, 136.8, 139.0, 141.7, 162.2, 165.9; MS (ESI) 335.0 [M]+. HRMS (ESI) calcd for [C17H17ClFN2O2+]: 335.0963; found: 335.0962.

3-((2E,4Z)-5-Chloro-2-(ethoxycarbonyl)-5-(4-fluorophenyl)penta-2,4-dienyl)-1-methyl-1H-imidazol-3-ium hydrogensulfate (3i)
White solid. Mp 263-266 °C. IR (KBr) (νmax, cm-1): 3449, 2966, 1673. 1H NMR (400 MHz, DMSO-d6) δH: 1.24 (3H, t, J = 7.2, COOCH2CH3), 3.72 (3H, s, N-CH3), 4.20 (2H, q, J = 7.2Hz, COOCH2CH3), 5.37 (2H, s, N-CH2), 7.39 (2H, t, J = 8.8 Hz, ArH), 7.68 (1H, t, J = 1.6Hz N-HC=CH-N), 7.72 (1H, t, J = 1.6 Hz, N-HC=CH-N), 7.77 (1H, d, J = 11.6, ClC=HC-C=C), 7.95 (1H, d, J = 11.6 Hz, ClC=C-CH=C), 8.02 (2H, m, J1 = 5.6 Hz, J2=9.2Hz, ArH), 9.10 (1H, s, N=CH-N); 13C NMR (100 MHz, DMSO-d6) δC: 14.1, 36.0, 44.9, 61.5, 115.9 (J = 22 Hz, 2C), 119.7, 122.8, 123.6, 126.3, 130.0 (J = 9 Hz, 2C), 132.5, 136.8, 138.9, 141.8, 163.7 (J = 226 Hz), 165.5; MS (ESI) 349.1 [M]+. HRMS (ESI) calcd for [C18H19ClFN2O2+]: 349.1119; found: 349.1102.

(2E,4Z)-Methyl-5-chloro-5-(4-methoxyphenyl)-2-(nitrooxymethyl)penta-2,4-dienoate(4a)
Yellow solid. Mp 78-80 °C. IR (KBr) (νmax, cm-1): 3157, 2925, 1656. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.84 (3H, s, CH3), 3.85 (3H, s, CH3), 4.42 (2H, s, CH2), 6.91-6.93 (2H, m, ArH), 6.99 (1H, d, J = 11.6 Hz, CH=CH), 7.67-7.70 (2H, m, ArH), 7.87 (1H, d, J = 11.6 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 25.3, 52.8, 55.8, 114.3(2C), 118.0, 128.6, 128.8(2C), 129.6, 137.9, 143.2, 161.5, 166.3. MS (EI): m/z (%) = 265(69, M-62), 223(71), 205(92), 179(100). HRMS (EI) calcd for [C14H14ClNO6]: 327.0510; found: 327.0515.

(2E,4Z)-Ethyl-5-chloro-5-(3-chlorophenyl)-2-(nitrooxymethyl)penta-2,4-dienoate(4b)
White solid. Mp 80-83 °C. IR (KBr) (νmax, cm-1): 3139, 2921, 1671. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 1.37 (3H, t, J = 7.2 Hz, CH2CH3), 4.32 (2H, q, J1 = 7.2 Hz, J2 = 14.4 Hz, CH2CH3), 4.41 (2H, s, CH2), 7.06 (1H, d, J = 11.2 Hz, CH=CH), 7.33-7.38 (2H, m, ArH), 7.58-7.69 (2H, m, ArH), 7.82 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 29.7, 37.4, 52.5, 119.8, 123.7, 128.3, 128.9, 129.7, 130.7, 135.3, 136.5, 137.4, 141.9, 166.2. MS (EI): m/z (%) = 329 (5, [M-16]+), 283(32), 237(100). HRMS (EI) calcd for [C14H13Cl2NO5]: 345.0171; found: 345.0175.

(2E,4Z)-Methyl-5-chloro-5-(4-fluorophenyl)-2-(nitrooxymethyl)penta-2,4-dienoate(4c)
White solid. Mp 85-87 °C. IR (KBr) (νmax, cm-1): 3148, 2959, 1668. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.86 (3H, s, CH3), 4.40 (2H, s, CH2), 7.01 (1H, d, J = 11.2 Hz, CH=CH), 7.13-7.08 (2H, m, ArH), 7.82-7.70 (2H, m, ArH), 7.84 (1H, d, J = 11.6 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 24.5, 52.5, 115.7 (J = 22 Hz, 2C), 119.4, 128.9 (J = 8 Hz, 2C), 129.6, 133.1, 136.9, 141.6, 163.6 (J = 250 Hz), 165.8. MS (EI): m/z (%) = 299 (12, [M-16]+), 253(37), 221(100), 193(77), 157(32). HRMS (EI) calcd for [C13H11ClFNO5]: 315.0310; found: 315.0308.

(2Z,4Z)-Methyl-5-chloro-5-(4-methoxyphenyl)-2-(m-tolylthiomethyl)penta-2,4-dienoate (5a)
Yellow liquid. IR (KBr) (νmax, cm-1): 3134, 2955, 1661. 1H-NMR (CDCl3, 400MHz): δ (ppm) 2.24 (3H, s, CH3), 3.82 (3H, s, CO2CH3), 3.83 (3H, s, OCH3), 3.91 (2H, s, SCH2), 6.44 (1H, d, J = 12 Hz, CH=CH), 6.84 (2H, dd, J1 = 2 Hz, J2 = 4.4 Hz, ArH), 6.95 (1H, d, J = 4.0 Hz, ArH), 7.13-7.09 (1H, m, ArH), 7.27-7.24 (2H, m, ArH), 7.41-7.39 (2H, dd, J1 = 2 Hz, J2 = 3.2 Hz, ArH), 7.73 (1H, d, J = 11.6 Hz, CH=CH). 13C-NMR (CDCl3, 100MHz): δ (ppm) 21.3, 32.8, 52.3, 55.5, 113.6(2C), 118.3, 128.2(2C), 128.4, 128.6, 129.5, 129.9, 130.8, 133.3, 134.9, 135.5, 138.6, 140.4, 160.7, 167.1; MS (EI): m/z (%) = 388 (5, M+), 265(100), 233(80), 205(55), 179(52). HRMS (EI) calcd for [C21H21ClO3S]: 388.0900; found: 388.0904.

(2Z,4Z)-Methyl 5-chloro-5-(4-methoxyphenyl)-2-(p-tolylthiomethyl)penta-2,4-dienoate (5b)
Yellow liquid. IR (KBr) (νmax, cm-1): 3135, 2942, 1689. 1H-NMR (CDCl3, 400 MHz)：δ (ppm) 2.24 (3H, s, CH3), 3.67 (3H, s, CH3), 3.82 (3H, s, CH3), 3.91 (2H, s, CH2), 6.40 (1H, d, J = 11.2 Hz, CH=CH), 6.58 (2H, d, J = 8.8 Hz, ArH), 6.73-6.86 (4H, m, ArH), 7.38 (2H, d, J = 8.8 Hz, ArH), 7.73 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 21.2, 39.1, 52.2, 56.0, 114.8(2C), 126.6, 126.9, 128.8(2C), 129.3(2C), 130.1(2C), 131.8, 132.9, 136.7, 136.8, 136.9, 161.5, 163.4. MS (ESI) 389.9 [M+1]+. HRMS (ESI) calcd for [C21H21ClO3S]: 388.9076; found: 388.9082.

(2Z,4Z)-Methyl-5-chloro-2-((4-chlorophenylthio)methyl)-5-(4-methoxyphenyl)penta-2,4-dienoate (5c)
Yellow liquid. IR (KBr) (νmax, cm-1): 3157, 2925, 1656. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.87 (3H, s, CH3), 3.90 (3H, s, CH3), 3.95(2H, s, CH2), 6.94 (1H, d, J = 11.2 Hz, CH=CH), 7.26-7.54 (8H, m, ArH), 7.7 7(1H, d, J =11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 39.1, 52.1, 56.0, 114.8(2C), 126.5, 126.9, 128.9(2C), 129.3(2C), 131.6(2C), 131.8, 133.1, 134.3, 136.7, 136.9, 161.5, 163.4. MS (ESI) 410.2 [M+1]+. HRMS (ESI) calcd for [C20H18Cl2O3S]: 409.3261; found: 409.3269.

(2E,4Z)-Methyl-5-chloro-5-(4-methoxyphenyl)-2-((p-tolylamino)methyl)penta-2,4-dienoate (5d)
Yellow liquid. IR (KBr) (νmax, cm-1): 3457, 3130, 2931, 1650. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 2.21 (3H, s, CH3), 3.60 (3H, s, CH3), 3.84 (3H, s, CH3), 4.14 (2H, s, CH2), 6.48 (1H, d, J = 11.2 Hz, CH=CH), 6.65 (2H, d, J = 8.8 Hz, ArH), 6.73-6.80 (4H, m, ArH), 7.28 (2H, d, J = 8.8 Hz, ArH), 7.74 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 21.1, 41.8, 52.0, 56.0, 114.3(2C), 114.8(2C), 126.5, 126.7, 128.9(2C), 130.0(2C), 131.8, 135.1, 136.7, 140.7, 144.9, 161.5, 166.7. MS (ESI) 372.9 [M+1]+. HRMS (ESI) calcd for [C21H22ClNO3]: 371.8573; found: 371.8564.

(2E,4Z)-Methyl-2-(azidomethyl)-5-chloro-5-(4-methoxyphenyl)penta-2,4-dienoate (5e)
Yellow liquid. IR (KBr) (νmax, cm-1): 3154, 2922, 1956, 1658. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.81 (3H, s, CH3), 3.83 (3H, s, CH3), 4.23 (2H, s, CH2), 6.91-6.93 (2H, m, ArH), 7.01 (1H, d, J = 11.2 Hz, CH=CH), 7.77-7.80 (2H, m, ArH), 7.88 (1H, d, J =11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 49.4, 52.0, 56.0, 114.8(2C), 126.5, 128.9(2C), 131.8, 135.8, 136.7, 138.1, 161.5, 167.2. MS (ESI) 308.7 [M+1]+. HRMS (ESI) calcd for [C14H14ClN3O3]: 307.7323; found: 307.7326.

(2Z,4Z)-Methyl-5-chloro-5-(4-fluorophenyl)-2-(p-tolylthiomethyl)penta-2,4-dienoate (5f)
Yellow liquid. IR (KBr) (νmax, cm-1): 3149, 2933, 1641. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 2.47 (3H, s, CH3), 3.82 (3H, s, CH3), 3.91 (2H, s, CH2), 7.01 (1H, d, J = 11.2 Hz, CH=CH), 7.35-7.37 (4H, m, ArH), 7.49-7.83 (4H, m, ArH), 7.84 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 21.3, 32.1, 52.3, 115.4(2C), 119.8, 128.0(2C), 129.2(2C), 131.6, 131.7(2C), 133.1 (J = 61 Hz), 137.5, 140.3, 146.4, 147.9 (J = 37 Hz), 162.1, 167.2. MS (ESI) 377.9 [M+1]+. HRMS (ESI) calcd for [C20H18ClFO2S]: 376.8721; found: 376.8719.

(2Z,4Z)-Methyl-5-chloro-2-((4-chlorophenylthio)methyl)-5-(4-fluorophenyl)penta-2,4-dienoate (5g)
Yellow liquid. IR (KBr) (νmax, cm-1): 3174, 2934, 1689. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.88 (3H, s, CH3), 3.94 (2H, s, CH2), 7.00 (1H, d, J = 11.2 Hz, CH=CH), 7.21-7.31 (4H, m, ArH), 7.47-7.63 (4H, m, ArH), 7.84 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 32.1, 52.3, 115.4(2C), 119.8, 128.0(2C), 129.0(2C), 130.7, 131.2(2C), 132.2 (J = 123 Hz), 134.5, 140.3, 146.3, 147.9 (J = 32 Hz), 162.1, 167.2. MS (ESI) 398.3 [M+1]+. HRMS (ESI) calcd for [C19H15Cl2FO2S]: 397.2906; found: 397.2914.

(2E,4Z)-Methyl-5-chloro-5-(4-fluorophenyl)-2-[(p-tolylamino)methyl]penta-2,4-dienoate (5h)
Yellow liquid. IR (KBr) (νmax, cm-1): 3467, 3199, 2913, 1687. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 2.43 (3H, s, CH3), 3.85 (3H, s, CH3), 4.12 (2H, s, CH2), 7.01 (1H, d, J = 11.2 Hz, CH=CH), 7.31-7.37 (4H, m, ArH), 7.64-7.74 (4H, m, ArH), 7.84 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 21.3, 48.5, 52.3, 113.4 (2C), 115.4 (2C), 119.8, 128.0 (2C), 129.6, 130.7 (J = 180 Hz, 2C), 134.4, 139.3, 144.6, 146.2, 147.9 (J = 30 Hz), 162.1, 167.1. MS (ESI) 360.8 [M+1]+. HRMS (ESI) calcd for [C20H19ClFNO2]: 359.8218; found: 359.8215.

(2E,4Z)-Methyl-2-(azidomethyl)-5-chloro-5-(4-fluorophenyl)penta-2,4-dienoate (5i)
Yellow liquid. IR (KBr) (νmax, cm-1): 3145, 2911, 1949, 1662. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.84 (3H, s, CH3), 4.22 (2H, s, CH2), 7.01 (1H, d, J = 11.2 Hz, CH=CH), 7.13-7.18 (2H, m, ArH), 7.67-7.69 (2H, m, ArH), 7.87 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 49.4, 52.0, 115.0 (2C), 126.5, 130.9 (J = 132 Hz, 2C), 134.0, 136.3 (J = 89 Hz), 138.1, 141.6, 162.9 (J = 101 Hz), 167.2. MS (ESI) 296.7 [M+1]+. HRMS (EI) calcd for [C13H11ClFN3O2]: 295.6967; found: 295.6959.

(2E,4Z)-Methyl-5-chloro-5-(4-chlorophenyl)-2-(hydroxymethyl)penta-2,4-dienoate (6)
Yellow liquid. IR (KBr) (νmax, cm-1): 3644, 2953, 1648. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 3.87 (3H, s, CH3), 4.51 (2H, s, CH2), 7.09 (1H, d, J = 11.2 Hz, CH=CH), 7.09-7.41 (2H, m, ArH), 7.65-7.68 (2H, m, ArH), 7.89 (1H, d, J = 11.2 Hz, CH=CH). 13C-NMR (100 MHz, CDCl3) δ (ppm) 37.4, 52.5, 119.8, 123.7, 128.3 (2C), 128.9 (2C), 129.7, 130.7, 135.4, 136.5, 166.2. MS (ESI) 288.4 [M+1]+. HRMS (ESI) calcd for [C13H12Cl2O3]: 287.1386; found: 287.1380.

ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China [21076194] for financial support.

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