Diels-Alder reaction with furanics to obtain aromatics

Abstract

The present invention is directed to the preparation of phthalic anhydride compounds and the intermediate phthalide compounds. In particular, the invention is directed to an improved bio-based route from furanic compounds to phthalic anhydride compounds by reacting furfuryl alcohol (i.e. 2-hydroxymethylfuran) or an analogue thereof having a nucleophilic atom on the 2-methyl, with a dienophile comprising an α,β-unsaturated carbonyl comprising an α′-leaving group. The inventions further involved preparation of phthalic anhydride compounds, phthalic acid compounds and reduction products of the intermediate phthalide compounds.

Claims

1. A method for preparing a phthalide compound precursor according to formula IV, comprising reacting a furanic compound according to formula I with a dienophile according to formula II: ##STR00029## wherein: X is selected from the group consisting of O, NH and S; R.sup.4 is selected from the group consisting of H, Me, CH.sub.2OR.sup.5, CH.sub.2NR.sup.5R.sup.6, CHO, CO.sub.2R.sub.5, CONR.sup.5R.sup.6, and CR.sup.5═N—NR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.12 aryl, and C(O)R.sup.7, wherein R.sup.7 is selected from the group consisting of alkoxy, OH, NH.sub.2 and a solid support; R.sup.1 is a leaving group selected from the group consisting of halide, O-EWG, NH-EWG and S-EWG, wherein EWG is an electron withdrawing group; and R.sup.2 is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl and C(Y)R.sup.3, wherein Y is one or two selected from the group consisting of H, halide, O and combinations thereof, R.sup.3 is alkoxy, OH, NH.sub.2, or SH.

2. The method according to claim 1, wherein X is O, R.sup.4 is H, and/or R.sup.2 is H.

3. The method according to claim 1, wherein the EWG is selected from the group consisting of carbonyls, halide-substituted hydrocarbyls, nitrile-substituted hydrocarbyls, sulfonyl-substituted hydrocarbyls and nitro-substituted hydrocarbyls, optionally linked to a solid support.

4. The method according to claim 1, comprising reacting the furanic and the dienophile in the presence of a base.

5. The method according to claim 1, comprising contacting the furanic compound and the dienophile in a ratio of between 5:1 to 1:5.

6. The method according to claim 1, comprising reacting the furanic compound and the dienophile at a temperature below 200° C.

7. The method according to claim 1, comprising reacting the furanic compound according to formula I with the dienophile according to formula II through intermediate compound IIIa and/or intermediate compound IIIb ##STR00030##

8. The method according to claim 7, that is carried out in one single step and without isolating one or more intermediate compounds.

9. The method according to claim 7, comprising isolating intermediate compound IIIa and/or intermediate compound IIIb, followed by reacting said intermediate compound or intermediate compounds to the precursor according to formula IV.

10. A method for preparing a compound according to formulae V, VI, VII, IIX, IX, X, XI, XII or XIII, or an ester, amide or imide thereof: ##STR00031## ##STR00032## comprising reacting a precursor of formula IV in one or more further reactions, wherein the precursor of formula IV is prepared using the method according to claim 1.

11. The method according to claim 10, further comprising ring-opening and aromatizing the precursor of formula IV by contacting the precursor of formula IV with an acid, optionally in combination with an activating agent to provide the phthalide compound of formula V ##STR00033##

12. The method according to claim 11, further comprising oxidizing said phthalide compound according to formula V to provide the phthalic anhydride compound according to formula VI ##STR00034##

13. The method according to claim 12, further comprising hydrolyzing said phthalic anhydride compound according to formula VI or formula V followed by oxidizing ##STR00035##

14. The method of claim 1, further comprising reducing the phthalide analogue precursor according to formula IV to provide a compound according to formula IIX and/or IX ##STR00036##

15. The method according to claim 14, further comprising: oxidizing the compound according to formula IIX to provide a compound according to formula X; oxidizing the compound according to formula IX to provide a compound according to formula XI; oxidizing and then reducing the compound according to formula IIX to provide a compound according to formula XI; oxidizing the compound according to formula IIX followed by hydrolyzing to provide a compound according to formula XII; or oxidizing the compound according to formula IX followed by hydrolyzing to provide a compound according to formula XIII ##STR00037##

16. A compound of formulae IIIa, IIIb, IIX, IX, X, XI, XII or XIII or an ester, amide or imide thereof ##STR00038## wherein: X is selected from the group consisting of O, NH and S; R.sup.4 is selected from the group consisting of H, Me, CH.sub.2OR.sup.5, CH.sub.2NR.sup.5R.sup.6, CHO, CO.sub.2R.sub.5, CONR.sup.5R.sup.6, and CR.sup.5═N—NR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are, independently, selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.12 aryl, and C(O)R.sup.7, wherein R.sup.7 is selected from the group consisting of alkoxy, OH, NH.sub.2 and a solid support; R.sup.1 is a leaving group selected from the group consisting of halide, O-EWG, NH-EWG and S-EWG, wherein EWG is an electron withdrawing group; and R.sup.2 is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl and C(Y)R.sup.3, wherein Y is one or two selected from the group consisting of H, halide, O and combinations thereof, R.sup.3 is alkoxy, OH, NH.sub.2, or SH; wherein only one of R.sup.2 and R.sup.4 is H when the compound is of formula XI and X is O.

17. The method according to claim 1, wherein (i) R.sup.1 is O-EWG; or (ii) Y is H.

18. The method according to claim 3, wherein the EWG is (i) a fluoride-substituted hydrocarbyl or (ii) 1, 1, 1,3,3,3-hexafluoroisopropyl or trifluoroethanol.

19. The method according to claim 11, wherein the acid is selected from the group consisting of methanesulfonic acid, sulfuric acid, an acidic ion exchange resin, and a zeolite.

20. The method according to claim 11, wherein the activating agent is acetic acid.

Description

EXAMPLE 1—1,1,1,3,3,3-HEXAFLUOROISOPROPYLACRYLATE

(1) A suspension of 1,1,1,3,3,3-hexafluoroisopropanol (49.91 g, 297 mmol, 1.2 eq.) and scandium(III) triflate (0.10 g, 0.20 mmol, 0.08 mol %) were stirred at 20° C. and acryloyl chloride (22.40 g, 248 mmol, 1 eq.) was added dropwise over the course of 5 minutes. After stirring the mixture for 20 hours at 20° C., sodium bicarbonate was added to the stirred suspension until pH>7 was achieved. The solids were removed by filtration, and filtrates were distilled under nitrogen to yield the desired product.

EXAMPLE 2—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(2) ##STR00011##

(3) A suspension of furfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1.1 eq.) and sodium bicarbonate (1 mol %) was stirred at 80° C. for 22 hours then the mixture was cooled to 20° C. and the product was isolated as a solid (64% yield) following flash chromatography.

EXAMPLE 3—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(4) ##STR00012##

(5) A suspension of furfuryl alcohol (1 eq.), 1,1,1-trifluoroethylacrylate (1 eq.) and sodium bicarbonate (20 mol %) were stirred at 80° C. for 22 hours. This yielded 7,7a-Dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (33% yield, 39% selectivity).

EXAMPLE 4—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(6) ##STR00013##

(7) A suspension of furfuryl alcohol (1 eq.), methyl acrylate (1 eq.) and sodium bicarbonate (20 mol %) were stirred at 80° C. for 22 hours. This yielded 7,7a-Dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (2% yield, 8% selectivity).

EXAMPLE 5—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(8) ##STR00014##

(9) A suspension of furfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1.5 eq.) and sodium bicarbonate (20 mol %) was stirred at 80° C. for 22 hours. This yielded 7,7a-Dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (68% yield, 88% selectivity).

EXAMPLE 6—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(10) ##STR00015##

(11) A suspension of furfuryl alcohol (1 eq.), 4-nitrophenol acrylate (1.1 eq.) and sodium bicarbonate (2 mol %) was stirred at 80° C. for 36 hours. This yielded 7,7a-Dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (86% yield, 91% selectivity).

EXAMPLE 7—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(12) A suspension of furfuryl alcohol (1 eq.) and acrylic anhydride (1 eq.) were stirred at 45° C. for 16 hours. This yielded 7,7a-Dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (43% yield, 44% selectivity).

EXAMPLE 8—SCREENING OF CONDITIONS FOR DIELS-ALDER LACTONISATION to 7,7a-Dihydro-3H-3a,6-epoxyisobenzofuran-1(6H)-one

(13) ##STR00016##

(14) A mixture of furfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1 eq.), catalyst (see Table X) and solvent (see Table 1; concentration=1.1 M) was stirred at the stated temperature (see Table 1). The results of these reactions are shown in Table 1.

(15) TABLE-US-00001 TABLE 1 mol % Yield Selectivity Solvent Cat. Cat. T (° C.) (%) (%) Neat NaHCO.sub.3 2 60 34 43 20 60 17 20 0.5 80 38 70 1 80 64 82 2 80 54 66 20 80 26 28 NaCH.sub.3CO.sub.2 2 80 44 55 20 80 23 27 NaCHCl.sub.2CO.sub.2 2 80 31 50 20 80 45 58 NEt.sub.3 2 80 30 34 EtOAc NaHCO.sub.3 2 80 43 83

EXAMPLE 9—SCREENING OF ACID CONDITIONS FOR AROMATIZATION TO PHTHALIDE

(16) ##STR00017##

(17) The lactone (1 eq.) is added to a stirred solution of the desired acid (See Table Y), in solvent (where applicable—See Table 2—all reactions with solvent performed at 0.33 M) at 20° C., then the mixture is heated to the stated temperature (see Table 2) for 1 hour. The results of these reactions are shown in Table Y.

(18) TABLE-US-00002 TABLE 2 Solvent Cat. T (° C.) Yield (%) Neat MSA* (13 eq.) 20 66 Toluene MSA (0.1 eq.) 80 66 Hf(OTf).sub.4 (0.1 eq.) 80 60 TfOH (0.1 eq.) 80 63 TfOH (0.01 eq.) 80 63 Silica-TfOH (0.01 eq.) 80 58 CHCl.sub.3 TfOH (0.1 eq.) 80 79 AcOH TfOH (0.1 eq.) 80 56 *MSA: methanesulfonic acid

EXAMPLE 10—SCREENING OF DRY, ASSISTED ACID CONDITIONS FOR AROMATIZATION TO PHTHALIDE

(19) ##STR00018##

(20) The lactone (1 eq.) is added to a stirred solution of the desired acid (See Table Z) and acetic anhydride (See Table Z), in solvent (where applicable—See Table Z—all reactions with solvent performed at 1 M), at 20° C., then the mixture is heated to the stated temperature (see Table 3). The results of these reactions are shown in Table 3.

(21) TABLE-US-00003 TABLE 3 Solvent Cat. Ac.sub.2O T (° C.) Yield (%) Neat MSA (13 eq) 20 vol % 20 75 MSA (0.5 eq.) 4 eq. 20 97 MSA (0.5 eq.) 4 eq. 80 98 MSA (0.1 eq.) 4 eq. 80 95 MSA (0.02 eq.) 4 eq. 80 94 MSA (0.01 eq.) 4 eq. 80 39 TfOH (0.01 eq.) 4 eq. 80 95 H.sub.2SO.sub.4 (0.01 eq.) 4 eq. 80 80 Amberlyst-15 (0.1 eq) 4 eq. 80 82 EtOAc Amberlyst-15 (0.1 eq) 4 eq. 80 78 Amberlyst-15 (0.1 eq) 2 eq. 80 89

EXAMPLE 11—7-METHYL-3,10-DIOXATRICYCLO[5.2.1.0]DEC-8-EN-4-ONE

(22) ##STR00019##

(23) A suspension of 5-methylfurfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1 eq.) and sodium bicarbonate (1 mol %) were stirred at 80° C. for 22 hours. This yielded 7-methyl-3,10-dioxatricyclo[5.2.1.0]dec-8-en-4-one (74% yield) as a solid following flash chromatography. The structure was confirmed by nuclear magnetic resonance (NMR) and by X-ray crystallography.

EXAMPLE 12—7-METHYL-3,10-DIOXATRICYCLO[5.2.1.0]DEC-8-EN-4-ONE

(24) ##STR00020##

(25) A solution of 5-methylfurfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1 eq.) and triethylamine (1 mol %) were stirred at 80° C. for 24 hours. This yielded a mixture of 7-methyl-3,10-dioxatricyclo[5.2.1.0]dec-8-en-4-one and 5-methylfurfuryl alcohol in a 3:5 ratio. The structure was confirmed by NMR.

EXAMPLE 13—7,7A-DIHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(6H)-ONE

(26) ##STR00021##

(27) A solution of furfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroiso-propylacrylate (1 eq.) and triethylamine (1 mol %) were stirred at 80° C. for 24 hours. This yielded a mixture of 7,7a-dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one and furfuryl alcohol in a 3:2 ratio. The structure was confirmed by NMR.

EXAMPLE 14—TETRAHYDRO-3H-3A,6-EPOXYISOBENZOFURAN-1(4H)-ONE

(28) ##STR00022##

(29) A suspension of 7,7a-dihydro-311-3a,6-epoxyisobenzofuran-1(6H)-one (1 eq.) and 10% palladium on carbon (20 mg/g substrate) in 2-methyltetrahydrofuran (5 ml/g substrate) was pressuried to 15 bar with hydrogen and then stirred for 16 hours at 20° C. The catalyst was removed by filtration, and the solvent removed by reduced pressure evaporation. This yielded tetrahydro-311-3a,6-epoxyisobenzofuran-1(4H)-one (quantitative yield) as an oil. The structure was confirmed by NMR.

EXAMPLE 15—7-METHYL-3,10-DIOXATRICYCLO[5.2.1.0]DECAN-4-ONE

(30) ##STR00023##

(31) A suspension of 7-methyl-3,10-dioxatricyclo[5.2.1.0]dec-8-en-4-one (1 eq.) and 10% palladium on carbon (20 mg/g substrate) in 2-methyltetrahydrofuran or methanol (5 ml/g substrate) was pressuried to 15 bar with hydrogen and then stirred for 16 hours at 20° C. The catalyst was removed by filtration, and the solvent removed by reduced pressure evaporation. This yielded 7-methyl-3, 10-dioxatricyclo[5.2.1.0]decan-4-one (quantitative yield) as an oil. The structure was confirmed by NMR.

EXAMPLE 16—1,6,7,7A-TETRAHYDRO-1-OXO-3H-3A,6-EPOXYISOBENZOFURAN-7-CARBOXYLIC ACID

(32) ##STR00024##

(33) A solution of furfuryl alcohol (1 eq.) and maleic anhydride (1 eq.) in dichloromethane or chloroform (3.1 ml/g furfuryl alcohol) was stirred at 20° C. for 24 hours, to yield a slurry. The solid was isolated by filtration, then slurried in tetrahydrofuran (1 ml/g of solid). After stirring for 30 minutes the solid was isolated by filtration, washed, and dried. This yielded 1,6,7,7a-tetrahydro-1-oxo-3H-3a,6-epoxyisobenzofuran-7-carboxylic acid (52% and 55% respectively) as a solid. The structure was confirmed by NMR.

EXAMPLE 17—HEXAHYDRO-1-OXO-3H-3A,6-EPOXYISOBENZOFURAN-7-CARBOXYLIC ACID

(34) ##STR00025##

(35) A suspension of 1,6,7,7a-tetrahydro-1-oxo-3H-3a,6-epoxyisobenzofuran-7-carboxylic acid (1 eq.) and 10% palladium on carbon (20 mg/g substrate) in tetrahydrofuran or methanol (5 ml/g substrate) was pressurised to 15 bar with hydrogen and then stirred for 16 hours at 20° C. When THF was used, methanol was added after reaction to solubilize the product. The catalyst was removed by filtration, and the solvent removed by reduced pressure evaporation. This yielded hexahydro-1-oxo-3H-3a,6-epoxyisobenzofuran-7-carboxylic acid (81.9% and 84.1% yield respectively) as a solid. The structure was confirmed by NMR.

EXAMPLE 18—1,3-DIHYDRO-3-OXO-4-ISOBENZOFURANCARBOXYLIC ACID & PHTHALIDE

(36) ##STR00026##

(37) 1,6,7,7a-tetrahydro-1-oxo-311-3a,6-epoxyisobenzofuran-7-carboxylic acid (1 eq.) is added to a stirred solution of sulfuric acid (0.5 eq.) and acetic anhydride (4 eq.) at 0° C. After complete addition, the mixture was heated to 45° C. and held for 14 hours, then cooled to 0° C. The resulting solids were isolated by filtration (50 wt %). This was shown to be a mixture of 1,3-dihydro-3-oxo-4-Isobenzofurancarboxylic acid and phthalide in a 1:1 ratio. The filtrates were quenched with water and then extracted with DCM. The organics were dried and then concentrated by reduced pressure evaporation. This yielded 1,3-dihydro-3-oxo-4-isobenzofurancarboxylic acid (23.2% yield) as a solid. The structure was confirmed by NMR.

EXAMPLE 19-6-METHYLPHTHALIDE

(38) ##STR00027##

(39) 7-methyl-3,10-dioxatricyclo[5.2.1.0]dec-8-en-4-one (1 eq.) was added over 15 minutes to a stirred solution of acetic anhydride (4 eq.) and sulfuric acid (0.5 eq.) at 0° C. After complete dissolution, the mixture was heated to 60° C. and held for 2 hours. Analysis by NMR confirmed a clean, quantitative conversion to 6-methylphthalide.

EXAMPLE 20—6-METHYL-3,10-DIOXATRICYCLO[5.2.1.0]DEC-8-EN-4-ONE

(40) ##STR00028##

(41) A solution of furfuryl alcohol (1 eq.), 1,1,1,3,3,3-hexafluoroisopropyl crotonate (1 eq.) and sodium bicarbonate (1 mol %) were stirred at 80° C. for 22 hours. This yielded 6-methyl-3,10-dioxatricyclo[5.2.1.0]dec-8-en-4-one as a liquid following flash chromatography. The structure was confirmed by NMR.