AROMATIC COMPOUNDS FROM FURANICS

Abstract

Described are methods for preparing phenols, benzene carboxylic acids, esters and anhydrides thereof from furanic compounds by reaction with a dienophile, wherein the furanic compounds are reacted with a hydrazine and/or oxime and then reacted with a dienophile.

Claims

1. A method of preparing a compound having a backbone comprising formula (I): ##STR00058## wherein: G is OH, CHO, CO.sub.2H, an ether, an ester, or an anhydride of a biomass-derived compound, the method comprising: (i) reacting a biomass-derived compound having a backbone comprising formula (II) with a compound of formula (III): ##STR00059## wherein: X is O and z is 0, or X is N and z is 1, R.sub.1 is hydrocarbyl group, a heteroatom containing hydrocarbyl group, or a link to a heterogeneous support, and R.sub.2 is hydrogen, a hydrocarbyl group, a heteroatom containing hydrocarbyl group, or a link to a heterogeneous support, to give a compound with having a backbone structurc according to comprising formula (IV): ##STR00060## (ii) reacting the compound having a backbone comprising formula (IV) with a dienophile to give a compound having a backbone comprising formula (V): ##STR00061## (iii-a) hydrolyzing said compound having the backbone comprising formula (V) to yield the compound having the backbone comprising formula (I), wherein G is CHO, or (iii-b) optionally decarbonylating the product of step (iii-a) to provide the compound having the backbone comprising formula (I), wherein G is OH, or (iii-c) optionally oxidizing the product of step (ii), (iii-a), or a combination thereof to yield the compound having the backbone of formula (I), wherein G is CO.sub.2H, or (iii-d) converting the compound having the backbone comprising formula (I), wherein G is OH, CHO, or CO.sub.2H to the ether, ester, or anhydride thereof.

2. The method according to claim 1, wherein said compound having a backbone comprising formula (II) is furfural, furan-2,5-dicarbaldehyde, methoxymethylfurfural, chloromethylfurfural, 5-hydroxymethylfurfural, or a mixture thereof.

3. The method according to claim 1, wherein the compound having a backbone comprising formula (I) is a phenol, a hydroxyl tricarboxylic acid, a hydroxyl dicarboxylic acid, a hydroxyl carboxylic acid, a benzene dicarboxylic acid, a benzene tricarboxylic acid, or a benzene tetracarboxylic acid, or an ester, ether or anhydride thereof.

4. The method according to claim 1, wherein the reaction of step (ii) is catalyzed by a Lewis acid, Brnsted acid, or a combination thereof.

5. The method according to claim 1, wherein the dienophile is ethylene.

6. The method according to claim 5, wherein the compound having a backbone comprising formula (II) is 5-hydroxymethylfurfural, 5-methoxymethylfurfural, 5-chloromethylfurfural or 2,5-furandicarboxaldehyde, and the compound having a backbone comprising formula (I) is terephthalic acid.

7. The method according to claim 6, wherein step (ii) further comprises a catalyst that is a Brnsted acid and/or a Lewis acid supported on a solid material.

8. The method according to claim 6, wherein the compound having a backbone comprising formula (II) is furfural and the compound having a backbone comprising formula (I) is phenol or an ester thereof.

9. The method according to claim 1, wherein the dienophile is an alkyne.

10. The method according to claim 9, wherein the compound having a backbone comprising formula (III) is a hydroxylamine, wherein X is O.

11. The method according to claim 10, wherein the dienophile is a propiolate and the compound having a backbone of formula (II) is 2,5-furandicarboxaldehyde, furfural, 5-hydroxymethylfurfural, 5-methoxymethylfurfural, 5 chloromethylfurfural, or a combination thereof.

12. The method according to claim 1, wherein the dienophile is acrylic acid or an acrylate ester.

13. The method according to claim 1, further comprising hydrolyzing and oxidizing the compound having a backbone comprising formula (V) to for thc preparation of an ester having a backbone structure according comprising formula (Ia): ##STR00062## wherein, R.sub.7 is optionally substituted and is a heteroatom-containing hydrocarbyl group.

14. The method according to claim 1, wherein the compound having a backbone comprising formula (III) is provided on a heterogeneous solid support, and the method further comprises recovering the compound having a backbone comprising formula (III) by separating solid material comprising the compound having a backbone comprising formula (III) from a liquid phase comprising an aromatic compound having the backbone comprising formula (I).

15. The method according to claim 1, wherein the compound having a backbone comprising formula (II) is an effluent from a reactor for the (catalytic) dehydration of carbohydrates, wherein the effluent comprises water or an organic solvent.

16. The method according to claim 1, wherein the dienophile is maleic anhydride and the compound having the backbone comprising formula (V) is converted into the compound having a backbone comprising formula (I) in a single step comprising hydrolysis and oxidation.

17. A method of preparing an aromatic compound, comprising: activating a furanic compound in an effluent from a catalytic dehydration of carbohydrates using a solid-supported hydrazine compound, solid-supported hydroxylamine compound, or a combination thereof, wherein the activating is performed in the absence of reducing the furanic compound, and reacting the activated furanic compound with a dienophile.

18. The method according to claim 1, wherein the dienophile is ethylene and the compound having a backbone comprising formula (I) is benzaldehyde, phenol, benzoic acid, a benzoic acid ester, or a benzoic acid ether.

19. The method according to claim 7, wherein the solid support is a heterogeneous support.

20. The method according to claim 1, wherein R.sub.1, R.sub.2, or both R.sub.1 and R.sub.2 are substituted.

Description

EXAMPLES

[0093] The invention will now be further illustrated by the following non-limiting examples of various steps of the methods of the invention.

Example 1

[0094] ##STR00025##

[0095] To a reactor was added magnesium sulfate (14.44 g, 1 eq.) and ethyl acetate (58.6 mL), and the mixture was stirred. To this was added furfural (11.53 g, 9.94 mL, 1 equivalents (eq.), and after 2 minutes 1,1-dimethylhydrazine (7.284 g, 9.22 mL, 1.01 eq.) was then added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the solids, then the cake was washed with ethyl acetate (220 mL). To the resulting yellow solution of furfural-dimethylhydrazone was added maleic anhydride (15.00 g) and ethyl acetate (30 mL), and the mixture was stirred vigorously. After 3 minutes, trifluoroacetic acid (684 mg, 459 L) was added, and the reaction was heated to 60 C. and held for 3 hours. The reaction mixture was cooled to 0 C. and stirred for 20 minutes, then the formed solid was isolated by vacuum filtration. The filtrate appeared to contain product. The cake was washed with ice-cold EtOAc (230 mL), then dried in a vacuum oven to yield a bright yellow solid (18.5 g, yield 71% over 2-steps).

[0096] In a variation, the reaction could be stirred for about 3 hours. Magnesium sulfate is suitable not required for a good yield of hydrazone and is optionally omitted. A wide variety of solvents were found to be suitable for the formation of the hydrazone. The Diels-Alder reaction can also be performed in a range of solvents. The reaction can be catalyzed by a range of acid catalysts. The Diels-Alder reaction proceeds without TFA, but slower. The Diels-Alder was also observed to proceed at ambient temperature. Further results indicate that the reaction can be telescoped even when the solvent is wet from the first reaction. For example, a one-pot synthesis with reagents added to a reactor sequentially and without work-up can be used. The reaction mixture was darker in color than with dry solvent for the DA reaction, but the reaction is quite clean by HPLC.

Example 2

[0097] ##STR00026##

[0098] To a reactor was added magnesium sulfate (7.37 g, 1 eq.) and ethyl acetate (29.9 mL), and the mixture was stirred. To this was added HMF (7.718 g, 1 eq.), and after 2 minutes 1,1-dimethylhydrazine (3.715 g, 4.702 mL, 1.01 eq.) was then added dropwise, and the reaction was stirred at room temperature for 16 hours (3 hours is expected to be sufficient). The reaction mixture was filtered to remove the solids, then the cake was washed with ethyl acetate (220 mL). To the resulting orange solution of HMF-dimethylhydrazone was added maleic anhydride (7.652 g, 1.275 eq.) and ethyl acetate (30 mL), and the mixture was stirred vigorously. After 3 minutes, trifluoroacetic acid (349 mg, 234 L, 0.05 eq.) was added, and the reaction was heated to 60 C. and held for 1 hour. The reaction mixture was cooled to ambient temperature then washed with saturated sodium bicarbonate solution (30 mL), then water. The resulting organic solution was dried over sodium sulfate, filtered and reduced to yield and oil. This was purified over silica, eluting with ethyl acetate/heptane. The appropriate fractions were collected and reduced to yield the desired product as an orange oil (1.975 g, 13% over 2-steps).

Example 3

[0099] ##STR00027##

[0100] To a reactor was added O-benzylhydroxylamine hydrochloride (766 mg, 1.2 eq.) and absolute ethanol (3 mL), and the mixture was stirred vigorously, then pyridine (1.264 g, 1.293 mL, 4 eq.) was added dropwise. To this was added furfural (384 mg, 331 L, 1 eq.) dropwise. This was stirred at room temperature for 4 hours (the reaction is expected to be complete in minutes, e.g. less than 15 minutes), then the ethanol was removed by rotary evaporation to yield a white solid and light yellow liquid. To this dissolved/suspended in dichloromethane (15 mL), and the mixture extracted twice with a 5% citric acid solution (30 mL). The combined aqueous was back extracted with dichloromethane (15 mL) and the combined organics dried over sodium sulfate, filtered, and reduced to yield a light-yellow oil. This was then purified on over silica eluting with an n-Hexane:EtOAc solvent system. Appropriate fractions were collected and reduced to yield the desired product as a clear oil (719 mg, 103%).

Example 4

[0101] ##STR00028##

[0102] To a reactor was charged methyl propiolate (26.6 mg, 28.2 L, 1.275 eq.) and ethyl acetate (100 L), and stirring was started. To this was added a solution of the furfural-benzyloxime (50 mg, 1 eq.) in ethyl acetate (100 L) dropwise over 5 mins. The reaction mixture was cooled to 0 C. and then aluminium chloride (40 mg) was added. The cooling was removed and the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0 C. then quenched by the dropwise addition of water (2 mL). Ethyl acetate (2 mL) was added and the organics were separated. The aqueous was extracted with a second portion of ethyl acetate (5 mL). The combined organics were washed with water, dried over sodium sulfate, filtered and reduced to an oil by rotary evaporation. Purified over silica eluting with an n-Hexane:EtOAc solvent system. Appropriate fractions were collected and reduced to yield the desired product as brown oil (5 mg, 7%).

Example 5

[0103] ##STR00029##

[0104] To a reactor was added O-benzylhydroxylamine hydrochloride (766 mg, 1.2 eq.) and absolute ethanol (3 mL), and the mixture was stirred vigorously, then pyridine (1.264 g, 1.293 mL, 4 eq.) was added dropwise. To this was added 2,5-furandicarboxaldehyde (248 mg, 1 eq.) dropwise. This was stirred at room temperature for 4 h (the reaction is expected to be complete in minutes, e.g. less than 15 minutes). Then the ethanol was removed by rotary evaporation to yield a white solid and light yellow liquid. To this dissolved/suspended in dichloromethane (15 mL), and the mixture extracted twice with a 5% citric acid solution (30 mL). The combined aqueous was back extracted with dichloromethane (15 mL) and the combined organics dried over sodium sulfate, filtered, and reduced to yield a light yellow oil. This was then purified over silica eluting with an n-Hexane:EtOAc solvent system. Appropriate fractions were collected and reduced to yield the desired product as a light yellow oil (646 mg, 97%).

Example 6

[0105] ##STR00030##

[0106] To a reactor was charged methyl propiolate (32.0 mg, 33.9 L, 1.275 eq.) and ethyl acetate (250 L), and stirring was started. To this was added a solution of the 2,5-furandicarboxaldehyde-bis-benzyloxime (100 mg, 1 eq.) in ethyl acetate (250 L) dropwise over 5 mins. The reaction mixture was cooled to 0 C., then aluminium chloride (100 mg, 2 eq.) was added. The cooling was removed and the reaction allowed to warm to room temperature and stir for 1 hour. The reaction mixture was cooled to 0 C. then quenched by the dropwise addition of water (2 mL). Ethyl acetate (2 mL) was added and the organics were separated. The aqueous was extracted with a second portion of ethyl acetate (5 mL). The combined organics were washed with water, dried over sodium sulfate, filtered and reduced to an oil by rotary evaporation. Purified over silica eluting with an n-Hexane:EtOAc solvent system. Appropriate fractions were collected and reduced to yield 3 separate region-isomers of the desired product: [0107] Product 1 isolated as a yellow oil (25 mg, 20%). [0108] Product 2 isolated as a yellow oil (20 mg, 16%). [0109] Product 3 isolated as a brown oil (15 mg, 12%). [0110] Overall yield=60 mg, 48%.

Example 7

[0111] To a reactor was charged 3-formylphthalic anhydride-dimethylhydrazone (2.5 g, 1 eq.) and 10% aqueous nitric acid (25 mL), and this was heated to 100 C. with vigorous stirring. After 30 minutes, when all of the solid had dissolved and no more gas was given off, the reactor was configured to distill water. The reaction mixture was reduced to 10mL in volume, then cooled to around 75 C. The surface of the reactor was scratched with a pipette to induce crystallization. The solid which formed was isolated by filtration. The cake was washed with ice-cold water (210 mL), then dried in a vacuum oven to yield a cream colored solid (1.97 g; 89%). The product is possibly hemi-mellitic anhydride.

Example 8

[0112] ##STR00031##

[0113] To a reactor was charged N-aminopiperidine (5.26 g, 5.67 mL), and toluene (25 mL), and the mixture was stirred vigorously. To this was added furfural (5.00 g, 4.31 mL) dropwise. This was stirred at room temperature for 2 minutes then heated to reflux under Dean-Stark conditions. This was maintained until no more water was observed to collect in the Dean-Stark trap (40 minutes). The reaction mixture was the reduced by rotary evaporation to yield a red/brown oil. NMR analysis confirmed this as the desired product (9.23 g, 99%).

Example 9

[0114] ##STR00032##

[0115] To a reactor was charged 1,1-dimethylhydrazine (3.715 g, 4.702 mL), magnesium sulfate (7.37 g) and ethyl acetate (29.9 mL), and the mixture was stirred vigorously. To this was added 5-methoxymethylfurfural (8.577 g) dropwise. This was stirred at room temperature for 16 h then the reaction mixture was filtered and the cake washed with ethyl acetate (250 mL). The filtrate was reduced by rotary evaporation to yield an orange oil. NMR analysis confirmed this as the desired product (11.0 g, 99%).

Example 10

[0116] ##STR00033##

[0117] To a reactor was charged 1,1-dimethylhydrazine (553 mg, 700 L), magnesium sulfate (2.407 g) and dichloromethane (3 mL), and the mixture was stirred vigorously. To this was added 2,5-furandicarboxaldehyde (248 mg) dropwise. This was stirred at room temperature for 5 h then the reaction mixture was filtered and the cake washed with DCM (210 mL). The filtrate was reduced by rotary evaporation to yield a yellow oil. NMR analysis confirmed this as the desired product (402 mg, 97%).

Example 11

[0118] ##STR00034##

[0119] To a reactor was charged O-benzylhydroxylamine hydrochloride (766 mg) and absolute ethanol (3 mL), and the mixture was stirred vigorously. To this was added pyridine (1.264 g, 1.293 mL) dropwise, quickly. To this was added 5-hydroxymethylfurfural (504 mg) dropwise. This was stirred at room temperature for 4 h then the ethanol was removed by rotary evaporation. This dissolved in dichloromethane (15 mL), and the mixture extracted twice with a 5% citric acid solution (30 mL). The combined aqueous was back extracted with dichloromethane (15 mL) and the combined organics dried (Na.sub.2SO.sub.4), filtered, and reduced to yield a clear oil. NMR analysis confirmed this as the desired product (803 mg, 87%) as a mixture of regio-isomers.

Example 12

[0120] ##STR00035##

[0121] To a reactor was charged the above furfural hydrazone (1.382 g), hydroquinone (2 mg) and methyl acrylate (861 mg, 906 L). The tube was sealed and the mixture heated to 200 C. in a microwave, with stirring, and held for 3 hours. The reaction mixture was cooled to 20 C., then purified by flash chromatography. Appropriate fractions were collected and reduced to yield a yellow oil. NMR analysis confirmed this as the meta-isomer of the desired product (1.05 g, 51%). Trace amounts of the ortho-isomer (100 mg impure) were also isolated.

Example 13

[0122] ##STR00036##

[0123] To a reactor was charged the above furfural hydrazone (415 mg), copper triflate (5 mg) and 1,4-dioxane (5.75 mL), and the solution was stirred and bubbled through with nitrogen gas. The reactor was then sealed and brought to 35 bar of pressure with ethylene gas. The mixture was then heated to 250 C., with vigorous stirring, and held for 7 hours. The reactor was cooled to room temperature, the pressure was released, and the system flushed with nitrogen gas. The resulting mixture was reduced to an oil by rotary evaporation, and purified by flash chromatography. Appropriate fractions collected and reduced to yield a yellow oil. NMR analysis confirmed this as the desired product (98 mg, 22%).

Example 14

[0124] ##STR00037##

[0125] To a reactor was charged maleic anhydride (0.50 g) and ethyl acetate (2.54 mL) and this mixture was heated to 60 C. with vigorous stirring until the maleic anhydride dissolved. To this was added the hydrazone (0.729 g) in ethyl acetate (2.54 mL). The reaction was stirred at 60 C. for 150 minutes then at 20 C. for 40 hours. Reduced to an oil by rotary evaporation, and purified by flash chromatography. Appropriate fractions collected and reduced to yield a yellow solid. NMR analysis confirmed this as the desired product (430 mg, 41%).

Example 15

[0126] ##STR00038##

[0127] To a reactor was charged the hydrazone (547 mg), copper triflate (5 mg) and 1,4-dioxane (5.75 mL), and the solution was stirred and bubbled through with nitrogen gas. The reactor was then sealed and brought to 35 bar of pressure with ethylene gas. The mixture was then heated to 250 C., with vigorous stirring, and held for 7 hours. The reactor was cooled to room temperature, the pressure was released, and the system flushed with nitrogen gas. The resulting mixture was reduced to an oil by rotary evaporation, and purified by flash chromatography. Appropriate fractions collected and reduced to yield a yellow oil. NMR analysis confirmed this as the desired product (98 mg, 17%).

Example 16

[0128] ##STR00039##

[0129] To a reactor was charged maleic anhydride (37.4 mg) and ethyl acetate (225 mg, 250 L), and the mixture was stirred vigorously. To this was added a solution of the hydrazone (62.5 mg) in ethyl acetate (225 mg, 250 L) dropwise over 2 mins. The reaction immediately became bright orange in colour. Trifluoroacetic acid (1.7 mg, 1.1 L) was then added, the tube was stoppered tightly and the reaction was stirred at room temperature for 40 hours. Reduced by rotary evaporation then purified by flash chromatography. Appropriate fractions collected and reduced to yield a brown solid. NMR analysis confirmed this as the desired product (95 mg, 98%) as a mixture of regio-isomers.

Example 17

[0130] ##STR00040##

[0131] To a reactor was added methyl propiolate (26.6 mg, 28.2 L) and ethyl acetate (90.2 mg, 100 L), and the mixture was stirred vigorously. To this was added a solution of furfural-oxime (50 mg) in ethyl acetate (90.2 mg, 100 L) dropwise over 5 mins. This was stirred for 5 minutes then the reaction was cooled to 0 C., then aluminium chloride (40 mg) was added. The cooling was removed and the reaction allowed to warm to room temperature. The mixture was cooled to 0 C. then quenched by the dropwise addition of ice-water (2 mL). Ethyl acetate (2 mL) was added and the organics were separated and the aqueous extracted with a second portion of ethyl acetate (5 mL). The combined organics were washed with water, dried (Na.sub.2SO.sub.4), filtered and reduced to an oil by rotary evaporation. Purified by flash chromatography. Appropriate fractions collected and reduced to yield a yellow oil. NMR analysis confirmed this as the desired product (55 mg, 78%) as a mixture of regio-isomers.

Example 18

[0132] ##STR00041##

[0133] To a reactor was charged maleic anhydride (37.4 mg) and ethyl acetate (225 mg, 250 L), and the mixture was stirred vigorously. To this was added a solution of DFF-Oxime (100 mg) in ethyl acetate (225 mg, 250 L) dropwise over 2 mins. This was stirred for 5 minutes then the reaction was cooled to 0 C., then aluminium chloride (40 mg) was added. The cooling was removed and the reaction allowed to warm to room temperature. The mixture was cooled to 0 C. then quenched by the dropwise addition of ice-water (2 mL). Ethyl acetate (2 mL) was added and the organics were separated and the aqueous extracted with a second portion of ethyl acetate (5 mL). The combined organics were washed with water, dried (Na.sub.2SO.sub.4), filtered and reduced to an oil by rotary evaporation. Purified by flash chromatography. Appropriate fractions collected and reduced to yield a yellow oil. NMR analysis confirmed this as the desired product (25 mg, 20%) as a mixture of regio-isomers.

Example 19

[0134] ##STR00042##

[0135] To a reactor was charged a 10% solution of nitric acid in water (1200 mL), and this was heated to 95 C. with stirring. Furfural unsymmetrical dimethylhydrazine (UDH) hydrazone-maleic anhydride Diels-Alder (DA) product (150 g) was then added slowly and portionwise, limited by NO.sub.2 evolution, over 60 minutes. The reaction mixture was cooled 0 C., and the solid which precipitate was isolated by filtration and washed with ice-cold water (20 mL). The resulting solid was dried in a vacuum oven at 30 C. overnight to yield a white solid. NMR analysis confirmed this as the desired product (75 g, 52%). The filtrates were reduced to around of their original volume by rotary evaporation, then were cooled 0 C., and the solid which precipitate was isolated by filtration and washed with ice-cold water (5 mL). The resulting solid was dried in a vacuum oven at 30 C. overnight to yield a white solid. NMR analysis confirmed this as the desired product (17 g, 52%).

Example 20

[0136] ##STR00043##

[0137] To a reactor was charged a 10% solution of nitric acid in water (500 L), and the above benzaldehyde hydrazone (100 mg), and this was heated to 95 C. with stirring for 30 minutes. The reaction mixture was cooled to 20 C., and the organics were extracted with dichloromethane (22 mL). The combined organics were dried (Na.sub.2SO.sub.4), filtered and educed by evaporation to yield a white solid. NMR analysis confirmed this as benzoic acid (68 mg, 82%).

Example 21

[0138] ##STR00044##

[0139] To a reactor was charged a 10% solution of sulfuric acid in water (5000 L), toluene (500 L) and the above benzaldehyde hydrazone (100 mg), and this was heated to 110 C. with stirring in a microwave for 20 minutes. The reaction mixture was cooled to 20 C., and the organic phase was separated. The aqueous phase was extracted with toluene (500 L), and the combined organics were dried (Na.sub.2SO.sub.4), filtered and carefully reduced by evaporation to yield a clear liquid. NMR analysis confirmed this as benzaldehyde (62 mg, 86%).

Example 22

[0140] ##STR00045##

[0141] To a reactor was charged a 10% solution of hydrochloric acid in water (500 L), toluene (500 L) and the above benzaldehyde hydrazone (100 mg), and this was heated to 110 C. with stirring in a microwave for 20 minutes. The reaction mixture was cooled to 20 C., and the organic phase was separated. The aqueous phase was extracted with toluene (500 L), and the combined organics were dried (Na.sub.2SO.sub.4), filtered and carefully reduced by evaporation to yield a clear liquid. NMR analysis confirmed this as benzaldehyde (56 mg, 78%).

Example 23

[0142] ##STR00046##

[0143] To a reactor was charged a 10% solution of phosphoric acid in water (500 L), toluene (500 L) and the above benzaldehyde hydrazone (100 mg), and this was heated to 110 C. with stirring in a microwave for 20 minutes. The reaction mixture was cooled to 20 C., and the organic phase was separated. The aqueous phase was extracted with toluene (500 L), and the combined organics were dried (Na.sub.2SO.sub.4), filtered and carefully reduced by evaporation to yield a clear liquid. NMR analysis confirmed this as benzaldehyde (50 mg, 71%).

Example 24

[0144] ##STR00047##

[0145] To a reactor was charged boric acid (3.1 g), 30% hydrogen peroxide (2.5 g), and tetrahydrofuran (30 mL). This was stirred vigorously, then concentrated sulfuric acid (1 mL) was added dropwise. This was stirred at room temperature for 30 minutes, then a solution of benzaldehyde (1.06 g) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred at room temperature. The reaction mixture was filtered and the solid washed with tetrahydrofuran (5 mL). the combined filtrates were neutralized with aqueous saturated sodium hydrogen carbonate solution and was extracted with dichloromethane (240 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and reduced to yield a white solid. NMR analysis confirmed this as the desired product (780 mg, 83%).

Example 25

[0146] ##STR00048##

[0147] Several reaction conditions were screened for the effect on the above Diels-Alder reaction of furfural unsymmetrical dimethyl hydrazone (1 eq.) and maleic anhydride (1 eq. unless indicated otherwise).

[0148] The reaction was investigated with various solvents (concentration of 1.8 mol/L hydrazone) at 60 C., in the absence of a catalyst. The various solvents are 2-methyltetrahydrofuran (2-MTHF), acetone, acetic acid, anisole (PhOMe), cyclohexane, dichloromethane (DCM), dimethyl carbonate (DMC) 1,4-dioxane (dioxane), dimethylformamide, dimethylsulfoxide, ethyl acetate (EtOAc), ethanol, acetonitrile, nitromethane, methyl acetate (MeOAc), methylisobutylketone (MIBK), methyl t-butylether (MTBE), chlorobenzene, benzonitrile (PhCN), triethylamine, 2,2,2-trifluoroethanol, trifluoroacetic acid and toluene. The results for the 8 best solvents are shown in FIG. 1.

[0149] A selection of the best solvents were then subjected to reaction with varying amounts of maleic anhydride (1 equivalent, 1.15 equivalents, and 1.3 equivalents, with a concentration of 1.8 mol/L hydrazone) at 60 C., in the absence of a catalyst. The results, peak-to-peak conversion in time, are shown in FIG. 2.

[0150] A selection of the best solvents were then subjected to reaction with varying catalysts (0.05 equivalent, with a concentration of 1.8 mol/L hydrazone) at 60 C., with 1 equivalent on maleic anhydride. The various catalysts are trifluoroacetic acid (TFA), methanesulfonic acid (MSA), tetrafluoroboric acid diethyl ether complex (BF4/ether), trifluoromethanesulfonic acid (TfOH), para-toluenesulfonic acid (pTSA), Amberlyst resin, sulfuric acid (H.sub.2SO.sub.4), formic acid and acetic acid. The results for the best 3 scenarios are shown in FIG. 3.

Example 26

Furfural-Dibenzyl-Hydrazone Synthesis

[0151] ##STR00049##

[0152] To a reactor was charged 1,1-dibenzylhydrazine (10.7 g), magnesium sulfate (6.13 g) and ethyl acetate (24.8 ml), and the mixture was stirred vigorously. To this was added furfural (4.84 g, 4.18 ml) dropwise. This was heated to 60 C. with stirring for 2 h then the reaction mixture was filtered while hot. The filtrate was slowly cooled to 0 C. with stirring, allowing for a solid to form. This was isolated by filtration, and washed with ice-cold ethyl acetate (10 ml). The resulting solid was dried in a vacuum oven at 35 C. to yield a light yellow solid. NMR analysis confirmed this as the desired product (12.5 g, 85%).

Example 27

Furfural-Piperidyl-Hydrazone Synthesis

[0153] ##STR00050##

[0154] To a reactor was charged N-amino-piperidene (241 mg, 260 L), magnesium sulfate (290 mg) and ethyl acetate (1.2 ml), and the mixture was stirred vigorously.

[0155] To this was added furfural (232 mg, 200 l) dropwise. This was heated to 60 C. with stirring for 1.5 h then the reaction mixture was filtered. The resulting solution was used crude in the following reaction.

Example 28

Furfural-Phenyl-Methyl-Hydrazone Synthesis

[0156] ##STR00051##

[0157] To a reactor was charged 1-methyl-1-phenylhydrazine (294 mg, 284 L), magnesium sulfate (289 mg) and ethyl acetate (1.2 ml), and the mixture was stirred vigorously. To this was added furfural (232 mg, 200 l) dropwise. This was heated to 60 C. with stirring for 1.5 h then the reaction mixture was filtered. The resulting solution was used crude in the following reaction.

Example 29

Furfural-Dibenzyl-Hydrazone/Maleic Anhydride Diels Alder:

[0158] ##STR00052##

[0159] To a reactor was charged furfural-dibenzyl-hydrazone (700 mg) and ethyl acetate (1.2 ml), and this was heated to 60 C. with stirring to obtain solution. A solution of maleic anhydride (295 mg, 1.25 molar equivalents) in ethyl acetate (1.9 ml) was then charged, followed by trifluoroacetic acid (14 mg, 9 L), and the mixture was heated to 60 C. and held for 1 hour. Analysis by LCMS showed 100% conversion to the desired aromatic hydrazone. Aternatively, no trifluoracetic acid was added, and the reaction heated at 60 C. for 6 hours, then analysis should 100% conversion to desired aromatic.

Example 30

Furfural-Dibenzyl-Hydrazone/Maleic Anhydride Diels Alder:

[0160] ##STR00053##

[0161] To a stirred solution of the hydrazone in ethyl acetate (prepared previously), was added a solution of maleic anhydride (295 mg, 1.25 molar equivalents) in ethyl acetate (1.9 ml), followed by trifluoroacetic acid (14 mg, 9 L), and the mixture was heated to 60 C. and held for 3 hours. Analysis by LCMS showed 100% conversion to the desired aromatic hydrazone.

Example 31

Furfural-Dibenzyl-Hydrazone/Maleic Anhydride Diels Alder:

[0162] ##STR00054##

[0163] To a stirred solution of the hydrazone in ethyl acetate (prepared previously), was added a solution of maleic anhydride (295 mg, 1.25 molar equivalents) in ethyl acetate (1.9 ml), followed by trifluoroacetic acid (14 mg, 9 L), and the mixture was heated to 60 C. and held for 6 hours. Analysis by LCMS showed 46% conversion to the desired aromatic hydrazone.

Example 31

[0164] Hydrolysis/oxidation of Furfural-UDH-Hydrazone-Maleic Anhydride DA Product (with 65% HNO3):

##STR00055##

[0165] To a reactor was charged a 65% solution of nitric acid (150 mL). The stirring was started vigorously and the reactor was heated to 95 C. A flow of nitrogen was applied across the flask , and vented a scrubber containing sodium hydroxide solution. Furfural unsymmetrical dimethylhydrazine (UDH) hydrazone-maleic anhydride Diels-Alder (DA) product (150 g) was then added in portions over 60 minutes. 5 minutes after complete addition, 65% nitric acid was added dropwise until no further gas evolution was observed. Water (150 ml) was then added and the reaction mixture was allowed to cool slowly to 20 C., then was cooled to 0 C., and the solid which precipitate was isolated by filtration and washed with ice-cold water (20 mL). The resulting solid was dried in a vacuum oven at 30 C. overnight to yield a white solid. NMR analysis confirmed this as the desired product (110 g, 76%). The filtrates were reduced to around of their original volume by rotary evaporation, then were cooled 0 C., and the solid which precipitate was isolated by filtration and washed with ice-cold water (5 mL). The resulting solid was dried in a vacuum oven at 30 C. overnight to yield a white solid. NMR analysis confirmed this as the desired product (17 g, 12%).

Example 32

MMF-Hydrazone/Maleic Anhydride Diels Alder:

[0166] ##STR00056##

[0167] Several reaction conditions were screened for the effect on the above Diels-Alder reaction of MMF-unsymmetrical dimethyl hydrazone (1 eq.) and maleic anhydride (1 eq.).

[0168] The reaction was investigated with various solvents (concentration of 0.7 mol/L hydrazone) at 20 C. with catalysis by TFA, and at 60 C. both in the presence and absence of TFA as catalyst, for a period of 4 hours. The various solvents are dichloromethane (DCM), ethyl acetate (EtOAc), acetonitrile, and toluene. The results are shown in FIG. 4.

Example 33

Furfural-UDH-Hydrazone/1,1,1,3,3,3-Hexfluoroisopropyl Acrylate Diels Alder:

[0169] To a reactor was charged furfural-UDH-Hydrazone (387 L), hydroquinone (4 mg), 1,1,1,3,3,3-hexfluoroisopropyl acrylate (488 L), and toluene (2 ml). The tube was sealed and the mixture heated to 190 C. in a microwave, with stirring, and held for 3 hours. The reaction mixture was analysed by HPLC, showing the meta-isomer of the product to be present as the major product in around 60% yield, with furfural-UDH-Hydrazone the predominant other component. A minor peak for the ortho-isomer is also present.

Example 34

Furfural-UDH-Hydrazone/1,1,1,3,3,3-Hexfluoroisopropyl Acrylate Diels Alder:

[0170] ##STR00057##

[0171] To a reactor was charged 2-methyl-CBS-oxazaborolidine (24 mg) and DCM (1 ml) and the stirring was started. Trifluoromethanesulfonic acid (6 L) was then added and the mixture was stirred for 30 minutes at room temperature. To this was added 1,1,1,3,3,3-hexfluoroisopropyl acrylate (165 L), followed by furfural-UDH-Hydrazone (330 L). The reaction was stirred at room temperature for 4 hours. The reaction mixture was analysed by NMR, showing the reaction to have proceeded to yield the desired products. The yield was not determined.