HYDROGENATION OF ESTERS TO ALCOHOLS IN THE PRESENCE OF AN MN-PNN COMPLEX

Abstract

A method for hydrogenating an ester of the general formula (III)

##STR00001## with molecular hydrogen to give the alcohols

##STR00002## at a temperature of 50 to 200? C. and a pressure of 0.1 to 20 MPa abs in the presence of a manganese(I) complex, in which the manganese complex comprises a tridentate ligand L with the general formula (II)

##STR00003## and comprises at least two carbonyl ligands.

Claims

1.-6. (canceled)

7. A method for hydrogenating an ester of the general formula (III) ##STR00029## in which the radicals R.sup.a and R.sup.b are each independently a carbon-containing organic, linear or branched, non-cyclic or cyclic, saturated or unsaturated, aliphatic, aromatic or araliphatic radical which is unsubstituted or interrupted or substituted by heteroatoms or functional groups and has a molar mass of 15 to 10 000 g/mol, wherein the two radicals R.sup.a and R.sup.b may also be bonded to each other, with molecular hydrogen to give the alcohols ##STR00030## at a temperature of 50 to 200? C. and a pressure of 0.1 to 20 MPa abs in the presence of a manganese(I) complex, in which the manganese complex comprises a tridentate ligand L of the general formula (II) ##STR00031## and comprises at least two carbonyl ligands, wherein R.sup.1, R.sup.2 are each independently an aliphatic hydrocarbon radical having 1 to 8 carbon atoms, an aromatic hydrocarbon radical having 6 or 10 carbon atoms or an araliphatic hydrocarbon radical having 7 to 12 carbon atoms, where the hydrocarbon radicals specified are unsubstituted or substituted by 1 to 3 methoxy, thiomethoxy or dimethylamino groups, and the two radicals R.sup.1 and R.sup.2 may be bonded to each other to form a 5- to 10-membered ring including the phosphorus atom, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.10, R.sup.11 are each independently hydrogen, linear C.sub.1 to C.sub.4-alkyl, branched C.sub.3 to C.sub.4-alkyl, methoxy, hydroxyl, trifluoromethyl, nitrile or dialkylamino each independently having 1 to 4 carbon atoms per alkyl group, R.sup.7, R.sup.8, R.sup.9 are each independently hydrogen, linear C.sub.1 to C.sub.4-alkyl or branched C.sub.3 to C.sub.4-alkyl, n, m are each independently 0 or 1, and the solid-dashed double lines are a single or double bond, with the proviso that in the case of n=1, both solid-dashed double lines are a single bond and m is 1, and in the case of n=0, one solid-dashed double line is a single bond and the other solid-dashed double line is a double bond, wherein, in the case of a double bond on the side facing the phenyl ring m=1, in the case of a double bond on the side facing the pyridyl ring m=0, or both solid-dashed double lines are a single bond and m equals 1.

8. The method according to claim 7, wherein the manganese complex has a general formula (I)
[Mn(L)(CO).sub.2+nX.sub.1?n]Z.sub.(n)(I) wherein X is an anionic monodentate ligand having a charge of ?1 Z is an anionic counterion having a charge of ?1 N is 0 or 1.

9. The method according to claim 7, wherein a molar ratio between the ester and the manganese(I) complex I is from 100 to 100 000.

10. The method according to claim 7, wherein the reaction is carried out in the presence of a base as co-catalyst.

11. The method according to claim 7, wherein the ester III is sclareolide, which is hydrogenated to the corresponding diol.

12. A method for producing (?) Ambrox, comprising hydrogenating sclareolide to Ambrox-1,4-diol in a first step (i) according to claim 11, and the resulting Ambrox-1,4-diol is cyclized to (?) Ambrox in a second step (ii).

Description

EXAMPLES

General Information

[0156] Unless otherwise stated, all reactions were prepared at room temperature under an argon atmosphere using so-called Schlenk and high vacuum techniques or in an MBraun Inert Atmosphere glove box. Organic solvents were sourced from Aldrich or Acros. Commercially available starting compounds were sourced from Aldrich, ABCR or TCI and used as received. NMR spectra were measured on Bruker AVANCE III 300, Bruker AVANCE III 400 and Bruker AVANCE III 500 spectrometers and the protons (.sup.1H) or carbon (.sup.13C) resonance signals of the solvent served as reference. Chemical shifts (?) are expressed in ppm. .sup.31P-NMR spectra refer to an external standard (ampoule D.sub.3PO.sub.4) of the Organic Chemistry Institute of the University of Heidelberg. GC analyzes were carried out on an Agilent Technologies 6890N gas chromatograph equipped with an FID detector; column used: DB-FFAP (30 m?0.32 mm?0.25 ?m). Initial temperature: 55? C.; hold time 1 min; ramp: 25? C./min to 250? C.; hold time: 8 min.

[0157] In Example 1, the preparation of a representative ligand II is described. The other ligands were prepared analogously to this specification.

Example 1: Preparation of Ligand L1

[0158] ##STR00018##

[0159] (2-(Diphenylphosphaneyl)phenyl)methanamine (1.00 g, 3.43 mmol) was added at room temperature to a solution of picolinaldehyde (368 mg, 3.43 mmol) in ethanol (10 mL) and the resulting mixture stirred at room temperature for 2 hours. NaBH.sub.4 (208 mg, 5.49 mmol) was added and the mixture was stirred at room temperature for a further 2 hours. Aqueous saturated NaHCO.sub.3 solution (15 ml) and CH.sub.2Cl.sub.2 (25 mL) were then added. After phase separation, the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2?25 ml). The combined organic phase was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane/EtOAc/NEt.sub.3, 9:1 to 1:1; a mixture of 10% NEt.sub.3 in EtOAc was used) and N-(2-(diphenylphosphaneyl)benzyl)-1-(pyridin-2-yl) methanamine (1) was obtained as a colorless oil (600 mg, 46% yield).

[0160] .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2) ? 8.48-8.46 (m, 1H), 7.57 (td, J=7.7, 1.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.36-7.30 (m, 7H), 7.28-7.24 (m, 4H), 7.19-7.10 (m, 4H), 6.91 (ddd, J=7.7, 4.5, 1.4 Hz, 1H), 4.02 (d, J=1.7 Hz, 2H), 3.79 (s, 2H). .sup.31P NMR (203 MHz, CD.sub.2Cl.sub.2) ?-15.94.

[0161] HRMS (ESI) C.sub.25H.sub.23N.sub.2P ([M].sup.+): calculated: 382.1599; found: 382.1611.

[0162] In Example 2, the preparation of a representative manganese(I) catalyst complex (I) with a ligand II is described.

Example 2: Preparation of Catalyst K1

[0163] ##STR00019##

[0164] A solution of [Mn(CO).sub.5Br] (720 mg, 2.62 mmol) in 15 ml of toluene are added to a solution of the ligand L1 (1 g, 2.62 mmol) in 15 ml of toluene under an argon atmosphere. The reaction mixture is stirred at 60-80? C. for 30 minutes until no visible CO evolution can be observed. The mixture is then stirred for a further 16 hours at 110? C., producing a yellow precipitate. After cooling to room temperature, the toluene is removed from the reaction mixture under reduced pressure. The yellow residue is washed with 10 ml of absolute hexane and then with 10 ml of absolute diethyl ether under an argon atmosphere and filtered off. The filter cake is dried in a high vacuum and the catalyst K1 is obtained as a yellow powder at a yield of 80% (1.2 g). The catalyst complex is stored under exclusion of light at 0? C.

[0165] .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2) ? 9.09 (d, J=5.5 Hz, 1H), 8.07 (s, 2H), 7.67 (t, J=7.1 Hz, 1H), 7.57-7.22 (m, 11H), 7.05 (t, J=8.5 Hz, 2H), 6.81 (t, J=8.2 Hz, 1H), 4.59-3.59 (m, 5H). .sup.13C NMR (126 MHz, CD.sub.2Cl.sub.2) ? 154.62, 151.77, 135.76 (d, J=16.5 Hz), 133.55-133.09 (m), 129.76, 129.56, 129.00, 128.79 (d, J=3.2 Hz), 128.70, 127.93 (d, J=8.4 Hz), 127.18 (dd, J=7.9, 2.2 Hz), 126.13 (d, J=5.2 Hz), 125.92 (d, J=2.0 Hz), 124.93 (d, J=9.0 Hz), 124.63 (d, J=9.5 Hz), 120.93, 117.01, 56.86 (d, J=2.6 Hz), 55.71 (d, J=8.1 Hz). .sup.31P-NMR (203 MHz, CD.sub.2Cl.sub.2) ? 68.39.

Example 3: Preparation of Catalyst K2

[0166] ##STR00020##

[0167] A solution of [Mn(CO).sub.5Br] (85 mg, 0.31 mmol) in 10 ml of toluene are added to a solution of the ligand L2 (0,155 g, 0.31 mmol) in 10 ml of toluene under an argon atmosphere. The reaction mixture is stirred at 60-80? C. for 30 minutes until no visible CO evolution can be observed. The mixture is then stirred fora further 16 hours at 110? C., producing a yellow precipitate. After cooling to room temperature, the toluene is removed from the reaction mixture under reduced pressure. The yellow residue is washed with 10 ml of absolute hexane and then with 10 ml of absolute diethyl ether under an argon atmosphere and filtered off. The filter cake is dried in a high vacuum and the catalyst K2 is obtained as a yellow powder at a yield of 75% (0.16 g). The catalyst complex is stored under exclusion of light at 0? C.

Example 4: Preparation of Catalyst K3

[0168] ##STR00021##

[0169] A solution of [Mn(CO).sub.5Br] (97 mg, 0.35 mmol) in 10 ml of toluene are added to a solution of the ligand L3 (0.14 g, 0.35 mmol) in 10 ml of toluene under an argon atmosphere. The reaction mixture is stirred at 60-80? C. for 30 minutes until no visible CO evolution can be observed. The mixture is then stirred for a further 16 hours at 110? C., producing a yellow precipitate. After cooling to room temperature, the toluene is removed from the reaction mixture under reduced pressure. The yellow residue is washed with 10 ml of absolute hexane and then with 10 ml of absolute diethyl ether under an argon atmosphere and filtered off. The filter cake is dried in a high vacuum and the catalyst K3 is obtained as a yellow powder at a yield of 56% (0,115 g). The catalyst complex is stored under exclusion of light at 0? C.

Example 5: Preparation of Catalyst K4

[0170] ##STR00022##

[0171] A solution of [Mn(CO).sub.5Br] (0.36 g, 1.31 mmol) in 10 ml of toluene are added to a solution of the ligand L4 (0.54 g, 1.31 mmol) in 10 ml of toluene under an argon atmosphere. The reaction mixture is stirred at 60-80? C. for 30 minutes until no visible CO evolution can be observed. The mixture is then stirred for a further 16 hours at 110? C., producing a yellow precipitate. After cooling to room temperature, the toluene is removed from the reaction mixture under reduced pressure. The yellow residue is washed with 10 ml of absolute hexane and then with 10 ml of absolute diethyl ether under an argon atmosphere and filtered off. The filter cake is dried in a high vacuum and the catalyst K4 is obtained as a yellow powder at a yield of 82% (0.65 g). The catalyst complex is stored under exclusion of light at 0? C.

Example 5: Preparation of Catalyst K5

[0172] ##STR00023##

[0173] A solution of [Mn(CO).sub.5Br] (0,236 g, 0.86 mmol) in 10 ml of toluene are added to a solution of the ligand L5 (0.34 g, 0.86 mmol) in 10 ml of toluene under an argon atmosphere. The reaction mixture is stirred at 60-80? C. for 30 minutes until no visible CO evolution can be observed. The mixture is then stirred for a further 16 hours at 110? C., producing a yellow precipitate. After cooling to room temperature, the toluene is removed from the reaction mixture under reduced pressure. The yellow residue is washed with 10 ml of absolute hexane and then with 10 ml of absolute diethyl ether under an argon atmosphere and filtered off. The filter cake is dried in a high vacuum and the catalyst K5 is obtained as a yellow powder at a yield of 75% (0.38 g). The catalyst complex is stored under exclusion of light at 0? C.

Examples 6, 7, 8 and 9: Hydrogenation of Sclareolide

[0174] In an argon-filled glove box, sclareolide (375 mg, 1.5 mmol), manganese catalyst (0.1 mol %), KOtBu (3.36 mg, 2 mol %) and dry ethanol (2 ml) are filled into 10 mL vials with crimp caps and PTFE-coated magnetic stirrer bars. The vials are sealed with the crimp cap comprising a rubber septum, the septum is pierced with a cannula and the vials are placed in a HEL CAT-7 autoclave. The autoclave is sealed, removed from the glove box and pressurized to 50 bar H.sub.2 under inert conditions, and the autoclave is inserted into a preheated aluminum block. The reaction mixture is stirred at 100? C. for 20 h, cooled in an ice bath and the remaining H.sub.2 pressure is carefully released. Mesitylene is then added to the respective batches as internal standard and the reaction mixtures are analyzed by gas chromatography.

##STR00024##

TABLE-US-00001 Example Catalyst Conversion GC yield of diol 6 K1 full 93% 7 K2 full 91.5%.sup. 8 K4 34% 34% 9 K5 full 94%

Example 10: Hydrogenation of Sclareolide

[0175] ##STR00025##

[0176] In an argon-filled glove box under inert conditions, sclareolide (750 mg, 3 mmol), K1 (1.7 mg, 0.003 mmol), potassium tert-butoxide (3.36 mg, 0.003 mmol) and 4 ml of dry ethanol are weighed into a 100 ml Premex autoclave with Teflon insert and magnetic stirrer bar. The autoclave is sealed and evacuated. It is then flushed three times with nitrogen and then three times with hydrogen and pressurized with hydrogen to 40 bar cold pressure. The reaction mixture is then heated in the autoclave at 90? C. with stirring for 20 h. After cooling to room temperature, the remaining hydrogen is released and the reaction mixture is analyzed by GC. Sclareolide conversion: 98%, yield of diol: 92%.

(2R, 8aS)-1-(2-hydroxyethyl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol

[0177] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 3.78 (dt, J=10.2, 4.4 Hz, 1H), 3.46 (ddd, J=10.2, 8.2, 5.7 Hz, 1H), 3.08 (s, 2H), 1.90 (dt, J=12.3, 3.3 Hz, 1H), 1.72-1.21 (m, 10H), 1.19 (s, 3H), 1.13 (dd, J=13.4, 4.4 Hz, 1H), 0.99-0.91 (m, 2H), 0.88 (s, 3H), 0.79 (s, 6H).

[0178] .sup.13C-NMR (101 MHz, CDCl.sub.3) ? 73.03, 64.09, 59.18, 56.04, 44.29, 41.91, 39.36, 38.98, 33.41, 33.28, 27.89, 24.64, 21.48, 20.47, 18.42, 15.31.

Example 11: Hydrogenation of Sclareolide

[0179] ##STR00026##

[0180] In an argon-filled glove box, sclareolide (375 mg, 1.5 mmol), manganese catalyst K1 (0.1 mol %), KOtBu (3.36 mg, 2 mol %) and dry ethanol (2 ml) are filled into a 10 ml vial with crimp cap and PTFE-coated magnetic stirrer bar. The vials are sealed with the crimp cap comprising a rubber septum, the septum is pierced with a cannula and the vials are placed in a HEL CAT-7 autoclave. The autoclave is sealed, removed from the glove box and pressurized to 50 bar H.sub.2, and the autoclave is inserted into a preheated aluminum block. The reaction mixture is stirred at 90? C. for 16 h, cooled in an ice bath and the remaining H.sub.2 pressure is carefully released. The reaction mixture is filtered over silica and the silica is washed several times with ethanol. The ethanol is removed from the combined filtrates in vacuo to dryness and the product is analyzed by NMR. The isolated yield of sclareolide diol is quantitative (yield>99%) and the substance is pure according to the 1H-NMR spectrum.

Example 12: Hydrogenation of Sclareolide

[0181] ##STR00027##

[0182] In an argon-filled glove box under inert conditions, sclareolide (375 mg, 1.5 mmol), K1 (0.88 mg, 0.1 mol %), potassium ethoxide (2.52 mg, 2 mol %) and 2 ml of dry ethanol are weighed into a 30 ml Premex autoclave with Teflon insert and magnetic stirrer bar. The autoclave is sealed and evacuated. It is then flushed three times with nitrogen and then three times with hydrogen and pressurized with hydrogen to 40 bar cold pressure. The reaction mixture is then heated in the autoclave at 90? C. with stirring for 16 h. After cooling to room temperature, the remaining hydrogen is released and the reaction mixture is analyzed by GC. Sclareolide conversion: >99%, yield of diol: 98%.

[0183] Examples 11, 12, 13, 14, and 15: Hydrogenation of other esters with the catalyst K1 In an argon-filled glove box, the respective ester (3 mmol), manganese catalyst K1 (1.72 mg, 0.1 mol %), KOtBu (6.72 mg, 2 mol %) and dry ethanol (4 ml) are filled into 10 mL vials with crimp caps and PTFE-coated magnetic stirrer bars. The vials are sealed with the crimp cap comprising a rubber septum, the septum is pierced with a cannula and the vials are placed in a HEL CAT-7 autoclave. The autoclave is sealed, removed from the glove box and pressurized to 50 bar H.sub.2, and the autoclave is inserted into a preheated aluminum block. The reaction mixture is stirred at 100? C. for 20 h, cooled in an ice bath and the remaining H.sub.2 pressure is carefully released. The reaction mixtures are filtered over silica and the silica is washed several times with ethanol. The ethanol is removed from the combined filtrates in vacuo to dryness and the product is analyzed by NMR.

##STR00028##

Phenylmethanol, 2a

[0184] .sup.1H NMR (301 MHz, CDCl.sub.3) ? 7.39-7.26 (m, 5H), 4.66 (s, 2H), 1.98 (s, 1H). .sup.13C NMR (76 MHz, CDCl.sub.3) ? 140.89, 128.58, 127.66, 127.02, 65.34.

Dodecan-1-ol, 2b

[0185] .sup.1H NMR (301 MHz, CDCl.sub.3) ? 3.64 (t, J=6.6 Hz, 2H), 1.55 (q, J=7.1 Hz, 2H), 1.37-1.26 (m, 18H), 0.93-0.83 (m, 3H).

[0186] .sup.13C NMR (76 MHz, CDCl.sub.3) ? 63.09, 32.82, 31.92, 29.67, 29.64, 29.62, 29.61, 29.45, 29.35, 25.75, 22.69, 14.11.

1,4-phenylenedimethanol, 2c

[0187] .sup.1H NMR (301 MHz, CDCl.sub.3) ? 7.37 (s, 4H), 4.70 (s, 4H), 1.64 (s, 2H). .sup.13C NMR (76 MHz, CDCl.sub.3) ? 127.25, 88.96.

Furan-2-ylmethanol, 2d

[0188] .sup.1H NMR (301 MHz, CDCl.sub.3) ? 7.39 (s, 1H), 6.31 (d, J=15.0 Hz, 2H), 4.58 (s, 2H), 2.27 (s, 1H).

[0189] .sup.13C NMR (76 MHz, CDCl.sub.3) ? 154.03, 142.57, 110.36, 107.76, 57.42.

Pentane-1,4-diol, 2e

[0190] .sup.1H NMR (301 MHz, CDCl.sub.3) ? 3.94-3.78 (m, 1H), 3.77-3.58 (m, 2H), 2.72 (s, 2H), 1.76-1.39 (m, 4H), 1.21 (d, J=6.2 Hz, 3H).

[0191] .sup.13C NMR (76 MHz, CDCl.sub.3) ? 67.95, 62.89, 36.26, 29.14, 23.60.