3-(3,4-dimethoxyphenyl)prop-2-enal

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3,4-dimethoxyphenylpropane (1 g) in 40 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of para-toluenesulphonic acid (0.04 to 0.1 g and 4.5 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 7 to 16 hrs. The mixture was cooled and the precipitated DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (50 ml) and the ether layer was washed with aqueous NaOH (15%, 2×10 ml). The combined aqueous layers are further extracted with ether (3×10 ml). The ether layers were combined and washed with saturated sodium chloride (3×10 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (40-50 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 3,4-dimethoxycinnamaldehyde in 79% yield as a yellow solid; mp 74-77° C. ; 1H NMR δ 9.67 (1H, d, H-3′), 7.43 (1H, d, H-1′), 7.15 (1H, d, H-5), 7.08 (1H, s, H-3), 6.91 (1H, d, H-3), 6.61 (1H, dd, H-2′), 3.94 (s, 3H, 3-OCH3), 3.93 (s, 3H, 4-OCH3). The remaining physical and spectral data was found similar as reported. The mixture was cooled the precipitated DDQH2 was filtered further washed with chloroform evaporated under reduced pressure the ether layer was washed with aqueous NaOH (15%, 2×10 ml) The combined aqueous layers are further extracted with ether (3×10 ml) washed with saturated sodium chloride (3×10 ml) dried over anhydrous sodium sulphate filtered The solvent was removed to afford a crude yellow liquid which the column was eluted with hexane (40-50 ml) solvent was removed under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3 by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.1 g, 0.52 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.1 g, 0.52 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%) The product gave the following analytical data

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3, by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%) The product gave the following analytical data

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In order to study the contribution of the length of the conjugation bridge to the AR activity, compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13. Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solution of 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated. The residue was dissolved in EtOAc and washed with water, 2% NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography and eluted with hexanes-ethyl acetate mixture to give a light yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P. Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of 2,4-petanedione (3 eq.) and B2O3 (1 eq.) in EtOAc was stirred at 40° C. for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1 eq.) were added. The resulting reaction mixture was stirred at 40° C. for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at the temperature and stirred at 40° C. for 16 h. To the red reaction mixture, 1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. After cooling to rt, the aqueous was separated and the organic was washed with water to pH˜7 and dried over Na2SO4. The crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid. A solution of the intermediate (1 eq.) and B2O3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C. for 1 h. After cooling to 60° C., 1% HCl aq was added and the mixture was stirred at 60° C. for 0.5 h. The reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Q110 as a red solid. Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring H and trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48 (1H, trans double bond H), 6.18-6.12 (1H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3). were synthesized Compound Q110 was synthesized The mixture was sonicated for 2 h with TLC monitoring After completion of the reaction the solid was filtered out the filtration was concentrated The residue was dissolved in EtOAc washed with water, 2% NaHCO3, and brine The organic extract was dried over Na2SO4 concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography eluted with hexanes-ethyl acetate mixture

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In order to study the contribution of the length of the conjugation bridge to the AR activity, compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13. Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solution of 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated. The residue was dissolved in EtOAc and washed with water, 2% NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography and eluted with hexanes-ethyl acetate mixture to give a light yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P. Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of 2,4-petanedione (3 eq.) and B2O3 (1 eq.) in EtOAc was stirred at 40° C. for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1 eq.) were added. The resulting reaction mixture was stirred at 40° C. for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at the temperature and stirred at 40° C. for 16 h. To the red reaction mixture, 1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. After cooling to rt, the aqueous was separated and the organic was washed with water to pH˜7 and dried over Na2SO4. The crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid. A solution of the intermediate (1 eq.) and B2O3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C. for 1 h. After cooling to 60° C., 1% HCl aq was added and the mixture was stirred at 60° C. for 0.5 h. The reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Q110 as a red solid. Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring H and trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48 (1H, trans double bond H), 6.18-6.12 (1H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3). were synthesized Compound Q110 was synthesized The mixture was sonicated for 2 h with TLC monitoring After completion of the reaction the solid was filtered out the filtration was concentrated The residue was dissolved in EtOAc washed with water, 2% NaHCO3, and brine The organic extract was dried over Na2SO4 concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography eluted with hexanes-ethyl acetate mixture

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The starting material is prepared as follows: To the mixture of 19.2 g of 3,4-dimethoxycinnamaldehyde, 24 g of magnesium sulfate and 100 ml of benzene, 6.2 g of methylamine in 120 ml of benzene are added and the suspension is stirred at room temperature for 8 hours. It is filtered and the filtrate added dropwise to the solution of 3.8 g of sodium borohydride in 200 ml to anhydrous ethanol while stirring and cooling with ice. Stirring is continued over night at room temperature, the mixture cooled again, 25 ml of concentrated hydrochloric acid are added and the solution evaporated under reduced pressure. The residue is taken up in 150 ml of water the solution washed with diethyl ether, made basic with sodium hydroxide and the mixture extracted with diethyl ether. The extract is dried and evaporated, to yield the N-methyl-3,4-dimethoxycinnamylamine as an oil; the cyclamate thereof melts at 145°-147°. The starting material is prepared are added It is filtered the filtrate added dropwise to the solution of 3.8 g of sodium borohydride in 200 ml to anhydrous ethanol while stirring cooling with ice Stirring is continued over night at room temperature the mixture cooled again 25 ml of concentrated hydrochloric acid are added the solution evaporated under reduced pressure washed with diethyl ether the mixture extracted with diethyl ether The extract is dried evaporated

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3,4-dimethoxyphenylpropane (1 g) in 40 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of para-toluenesulphonic acid (0.04 to 0.1 g and 4.5 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 7 to 16 hrs. The mixture was cooled and the precipitated DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (50 ml) and the ether layer was washed with aqueous NaOH (15%, 2×10 ml). The combined aqueous layers are further extracted with ether (3×10 ml). The ether layers were combined and washed with saturated sodium chloride (3×10 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (40-50 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 3,4-dimethoxycinnamaldehyde in 79% yield as a yellow solid; mp 74-77° C. ; 1H NMR δ 9.67 (1H, d, H-3′), 7.43 (1H, d, H-1′), 7.15 (1H, d, H-5), 7.08 (1H, s, H-3), 6.91 (1H, d, H-3), 6.61 (1H, dd, H-2′), 3.94 (s, 3H, 3-OCH3), 3.93 (s, 3H, 4-OCH3). The remaining physical and spectral data was found similar as reported. The mixture was cooled the precipitated DDQH2 was filtered further washed with chloroform evaporated under reduced pressure the ether layer was washed with aqueous NaOH (15%, 2×10 ml) The combined aqueous layers are further extracted with ether (3×10 ml) washed with saturated sodium chloride (3×10 ml) dried over anhydrous sodium sulphate filtered The solvent was removed to afford a crude yellow liquid which the column was eluted with hexane (40-50 ml) solvent was removed under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3 by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.1 g, 0.52 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.1 g, 0.52 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%) The product gave the following analytical data

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3 by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.1 g, 0.52 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.1 g, 0.52 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%) The product gave the following analytical data

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3, by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%) The product gave the following analytical data

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared as described in Example 3, by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%). The product gave the following analytical data: The compound was prepared After refluxing for 1 h recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%) The product gave the following analytical data