CHIRAL METAL COMPLEX COMPOUNDS

Abstract

The invention comprises novel chiral metal complex compounds of the formula

##STR00001##

wherein M, PR.sup.2, R.sup.3 and R.sup.4 are outlined in the description, its stereoisomers, in the form as a neutral complex or a complex cation with a suitable counter ion. The chiral metal complex compounds can be used in asymmetric reactions, particularly in asymmetric reductions of ketones, imines or oximes.

Claims

1. A chiral metal complex compound of formula I ##STR00110## and its stereoisomers, wherein each is independently a broken wedge bond (a) or a solid wedge bond (b) a) b); M is a metal selected from the manganese group or the iron group of the periodic system; each PR.sup.2 is ##STR00111## wherein R.sup.5 and R.sup.6 each independently C.sub.1-4-alkyl or aryl; or ##STR00112## wherein R.sup.7 and R.sup.8 each independently C.sub.1-4-alkyl; R.sup.3 is CO, halogen or hydrogen; and R.sup.4 is CO, halogen or HBH.sub.3, wherein the chiral metal complex is in the form of (i) a neutral complex, or (ii) a complex cation with a suitable counter ion.

2. The chiral metal complex compound of claim 1 wherein R.sup.3 is CO or hydrogen; and R.sup.4 is CO or HBH.sub.3.

3. The chiral metal complex compound of claim 1, wherein M is selected from the manganese group of the periodic system.

4. The chiral metal complex compound of claim 1, wherein M is selected from manganese and iron.

5. The chiral metal complex compound of claim 1, wherein PR.sup.2 is ##STR00113##

6. The chiral metal complex compound of claim 1, wherein PR.sup.2 is ##STR00114##

7. The chiral metal complex compound of claim 1, having the structure of formula Ia ##STR00115##

8. The chiral metal complex compound of claim 1, having the structure of formula Ib ##STR00116##

9. The chiral metal complex compound of claim 1, having the structure of formula Ic ##STR00117##

10. The chiral metal complex compound of claim 1, having the structure of formula Id; ##STR00118## wherein X is a halogen or a pseudohalogen.

11. The chiral metal complex compound of claim 1, having the structure of formula Ie; ##STR00119##

12. The chiral metal complex compound of claim 1, having the structure of formula If; ##STR00120## wherein PR.sup.2 is ##STR00121##

13. The chiral metal complex compound of claim 1, having the structure of formula Ig ##STR00122## wherein PR.sup.2 is ##STR00123##

14. A process for the preparation of a chiral metal complex compounds of formula I, comprising reacting with a metal salt a Bis(phospholanoethyl)amine derivative of formula III ##STR00124## wherein each PR.sup.2 is ##STR00125## wherein R.sup.5 and R.sup.6 are each independently C.sub.1-4-alkyl or aryl; or ##STR00126## wherein R.sup.7 and R.sup.8 are each independently C.sub.1-4-alkyl.

15. The process of claim 14, wherein the Bis(phospholanoethyl)amine derivative is reacted with Mn(CO).sub.5X.sup., wherein X.sup. is a halogen or a pseudohalogen, to form the chiral metal complex compound of formula Id ##STR00127##

16. The process of claim 14, wherein the bis(phospholanoethyl)amine derivative is reacted with FeX.sub.2, wherein X is a halogen, and with carbon monoxide to form an iron complex intermediate of the formula IV ##STR00128## and the iron complex intermediate of formula IV is reacted with a hydride forming agent to form the chiral metal complex compound of formula Ie ##STR00129##

17. A chiral iron complex intermediate of formula IV ##STR00130## wherein each PR.sup.2 is ##STR00131## wherein R.sup.5 and R.sup.6 are each independently C.sub.1-4-alkyl or aryl; or ##STR00132## wherein R.sup.7 and R.sup.8 are each independently C.sub.1-4-alkyl; and X is a halogen.

18. A method of catalyzing an asymmetric reaction, said method comprising catalyzing said reaction with a chiral metal complex compounds of claim 1.

19. The method of claim 18, wherein the asymmetric reaction is an asymmetric reduction.

20. The method of claim 19, wherein the reduction is an asymmetric reduction of a CX double bond.

21. The method of claim 20, wherein the CX double bond is a bond of a ketone, ketoester, imine or oxime.

22. The chiral metal complex compound of claim 1, wherein the metal is selected from the group consisting of manganese, rhenium, iron, ruthenium and osmium.

23. The chiral metal complex compound of claim 1, wherein R.sup.5 and R.sup.6 are each methyl, or R.sup.7 and R.sup.8 are each methyl.

24. The chiral metal complex compound of claim 5, wherein R.sup.5 and R.sup.6 are each independently C.sub.1-4-alkyl.

25. The chiral metal complex compound of claim 10, wherein X is bromine.

26. The chiral iron complex intermediate of claim 17, wherein X is bromine.

Description

EXAMPLES

Abbreviations

[0096] MeOH methanol
DMSO dimethyl sulfoxide
EA element analysis
RT room temperature
TBAF Tetra-n-butylammonium fluoride
THF tetrahydrofuran

X-Ray Crystal Structure Analysis of X:

[0097] Data were collected on a Bruker Kappa APEX II Duo diffractometer. The structures were solved by direct methods (SHELXS-97: Sheldrick, G. M. 5 Acta Cryst. 2008, A64, 112.) and refined by full-matrix least-squares procedures on F2 (SHELXL-2014: G. M. Sheldrick, Acta Cryst. 2015, C71, 3.). XP (Bruker AXS) was used for graphical representations.

1. Ligand Synthesis

1.1 Synthesis of (2R,5R)-2,5-dimethylphospholane

[0098] ##STR00029##

[0099] The title compound was synthesized according to the reported procedure (T. Hammerer, A. Dambkes, W. Braun, A. Salzer, G. Franci, W. Leitner, Synthesis 2012, 44, 2793-2797).

[0100] To a cooled solution of (R,R)-2,5-dimethyl-1-(trimethylsilyl) phospholane (9.42 g, 50.0 mol) with an isopropanol cooling bath (79 C.) MeOH (1.63 g, 51.0 mol) was added dropwise. The resulting solution was allowed to warm up to room temperature and stirred overnight. The side products were condensed into another Schlenk flask by heating the solution up to 60 C. The product was isolated as a colorless liquid with a yield of 95% (5.52 g, 47.5 mmol).

1.2 Syntheses of Bis(2-chloroethyl)trimethylsilylamine

[0101] ##STR00030##

[0102] The title compound was synthesized following the reported procedure (A. A. Danopoulos, A. R. Willis, P. G. Edwards, Polyhedron 1990, 9, 2413-2418).

[0103] To a stirred and cooled (0 C.) suspension of Bis(2-chloroethyl)amine hydrochloride (10 g, 56.0 mmol) in 100 mL Et.sub.2O, 0.25 mL DMSO and Triethylamine (17.0 g, 168.0 mmol) Trimethylchlorosilane (21.3 g, 196 mmol) was added dropwise over half an hour at 0. The solution was stirred for one hour at 0 C., warmed up to room temperature and stirred for further 3-5 days. The solution was filtered and the volatiles of the liquid portion were removed in vacuo and the product was achieved as yellow viscose liquid (9.96 g, 46.5 mmol, 83% yield).

1.3 Synthesis of Bis(2-((2R,5R)-2,5-dimethylphospholanoethyl))amine

[0104] ##STR00031##

[0105] The title compound was synthesized referring to the reported procedure (M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron. Asymmetry 1991, 2, 569-592).

[0106] (2R,5R)-2,5-dimethylphospholane (6.9 g, 0.059 mmol) was dissolved in 80 mL n-hexane and cooled to 79 C. n-Butyllithium (2.5 M in n-hexane, 25 mL, 62.5 mmol) was added dropwise to the solution. The solution was stirred for half an hour at this temperature, warmed up to room temperature and the resulting slightly yellow solution was stirred for further five hours. 10 mL of THF was added and the solution was again cooled down to 79 C. 6.32 g (29.5 mmol) Bis(2-chloroethyl)trimethylsilylamine diluted in 10 mL of THF was dropwise added while a white solid precipitated. The slightly yellow suspension was stirred for 16 h at room temperature. Afterwards 30 mL of water and 60 mL of TBAF (1M solution in THF, 60 mmol) was added and the resulting two-phase system was stirred for further 3-5 days. Most of the organic solvents were removed in vacuo and the product was extracted three times with Et.sub.2O from the aqueous phase. The organic layer was dried over MgSO.sub.4, filtered, the volatiles of the liquid portion were removed and the yellow product was dried in vacuo (6.76 g, 22.4 mmol, 71% yield). The pincer ligand was used without further purification.

[0107] .sup.1H NMR (400.13 MHz; CD.sub.3Cl): =1.08-1.12 (dd, 6H, CH.sub.3, J=7.2 Hz); 1.16-1.23 (dd, 6H, CH.sub.3, J=7.2 Hz; m, 2H, CH.sub.2); 1.34-1.47 (m, 4H, CH.sub.2); 1.61-1.68 (m, 2H, CH.sub.2); 1.84-1.92 (m, 2H, CHI); 1.93-2.02 (m, 2H, CH.sub.2); 2.03-2.15 (m, 4H, CH.sub.2, CHI); 2.62-2.78 (m, 4H, CH.sub.2), 3.8 (br, 1H, NH).

[0108] .sup.31P NMR (121.5 MHz; CD.sub.3Cl): =5.2 ppm.

2. Complex Synthesis

2.1 Synthesis of Manganese Complexes

[0109] ##STR00032##

[0110] To the suspension of [MnBr(CO).sub.5] (275 mg, 1 mmol) in toluene (20 mL) Bis(2-((2R,5R)-2,5-dimethylphospholanoethyl))amine (331.5 mg, 1.1 mmol, dissolved in 2 mL toluene) was added. The [MnBr(CO).sub.5] was dissolved, the solution was heated up to 100 C. and further stirred for 20 h under argon flow. The reaction mixture was cooled to room temperature and concentrated in vacuo resulting in a yellow solid with red inclusions. The crude solid was washed three times with 5 mL of pentane resulting in a clean yellow/orange solid (359.5 mg, 72.4 mmol, 72% yield).

[0111] .sup.31P{.sup.1H} NMR (122 MHz, C.sub.6D.sub.6): =97.14.

[0112] IR-ATR (solid) [cm.sup.1]: 2009 (s, CO), 1908 (s, CO), 1821 (s, CO).

[0113] EA % ber. (gef) C.sub.17H.sub.38BrMnNO.sub.3P.sub.2, M=520.27 g/mol: C, 43.86 (44.97); H, 6.39 (6.61) N, 2.69 (2.74).

2.2 Synthesis of Iron Complexes

a) Synthesis of the Precursor

[0114] ##STR00033##

[0115] 2.07 g of Bis(2-((2R,5R)-2,5-dimethylphospholanoethyl))amine (6.8 mmol) was dissolved in 30 mL THF. Afterwards a solution of FeBr.sub.2.THF (2.84 g, 6.8 mmol) in 20 mL THF was added. The resulting brown/yellow solution was stirred overnight at room temperature. By reacting with CO over three hours a blue solid was formed. The solvent was removed in vacuo and the resulted crude solid was washed with 5 mL EtOH getting a pure compound with a yield of 63% (2.35 g, 4.3 mmol).

[0116] .sup.1H NMR (400.13 MHz; CD.sub.3Cl): =1.11-1.16 (m, 6H, CH.sub.3); 1.22-1.38 (m, 3H, PCH.sub.2); 1.42-1.52 (m, 2H, PCH.sub.2); 1.59-1.78 (m, 9H, 2CH.sub.3; PCH.sub.2); 1.80-1.90 (m, 1H, PCH.sub.2); 1.99-2.16 (m, 3H, PCH); 2.29-2.36 (m, 1H, PCH); 2.37-2.45 (m, 1H, PCH); 2.54-2.78 (dd, 2H, NCH.sub.2), 2.82-2.92 (m, 1H, NCH.sub.2); 2.94-3.04 (m, 2H, PCH); 3.14-3.26 (m, 1H, NCH.sub.2); 4.32-4.44 (br, 1H, NH).

[0117] .sup.31P{.sup.1H} NMR (122 MHz, C.sub.6D.sub.6): =95.91 (d, J.sub.PP=174.19 Hz), 98.54 (d, J.sub.PP=174.19).

[0118] IR-ATR (solid) [cm.sup.1]: 1935 (s, CO).

b) Synthesis of Iron Complex Ie

[0119] 690 mg of IV (1.27 mmol) was dissolved in 20 mL of benzene or toluene. A freshly prepared solution of NaBH.sub.4 (383 mg, 10.12 mmol, in 20 mL EtOH) was added dropwise to the solution whereas a gas evolution was directly noticeable. After stirring the solution for 3-5 h the solvents were removed and the remaining solid was dried in vacuo. The product was extracted with benzene or toluene (in total 40 mL) and the solvent was afterwards removed in vacuo. The crude solid was washed three times with 10 mL of n-heptane and the expected product was achieved with a yield of 80% (403 mg).

[0120] .sup.1H-NMR (300 K, C.sub.6D.sub.6, 400.13 MHz): =19.20 (t, 1H, FeH, .sup.2J.sub.HP=51.85 Hz, (minor isomer)), 18.80 (t, 1H, FeH, .sup.2J.sub.HP=51.75 Hz, (major isomer)), 2.77 (bs, 4H, HBH.sub.3), 0.95 (m, 3H, CH.sub.3), 1.15 (m, 3H, CHCH.sub.2), 1.25 (m, 5H, CH.sub.3 and PCH.sub.2 and CHCH.sub.2), 1.32 (m, 1H, CHCH.sub.2), 1.41 (m, 3H, CH.sub.3), 1.51 (m, 2H, NCH.sub.2), 1.58 (m, 1H, CH), 1.66 (m, 1H, PCH.sub.2), 1.73 (m, 6H, CH.sub.3, PCH.sub.2 and CHCH.sub.2), 1.91 (m, 4H, CHCH.sub.2 and CH), 2.08 (m, 1H, PCH.sub.2), 2.27 (m, 1H, CH), 2.62 (m, 3H, CH and NCH.sub.2), 3.76 (m, 1H, NH).

[0121] .sup.31P-NMRmajor isomer (300 K, C.sub.6D.sub.6, 100.616 MHz): =109.18 (d, 1P, .sup.2J.sub.PP=122.93 Hz), 107.02 (d, 1P, .sup.2J.sub.PP=120.75 Hz).

[0122] .sup.31P-NMRminor isomer (300 K, C.sub.6D.sub.6, 100.616 MHz): =114.41 (d, 1P, .sup.2J.sub.PP=116.87 Hz), 104.98 (d, 1P, .sup.2J.sub.PP=116.64 Hz).

[0123] IR-ATR (solid) [cm.sup.1]: 1894 (s, CO).

3. Asymmetric Hydrogenation Results

3.1 Hydrogenation of Ketones or Ketoesters with Manganese Complex of Example 2.1

General Procedure:

[0124] All catalytic hydrogenation experiments using molecular hydrogen were carried out in a Parr Instruments autoclave (300 mL) advanced with an internal alloy plate include up to 8 uniform reaction vials (4 mL) equipped with a cap and needle penetrating the septum.

Representative Experiment:

[0125] Under an argon atmosphere, a vial was charged with Manganese Complex of example 2.1 and base which were dissolved in 2 mL of dried solvent. The resulting red solution was stirred briefly before the ketone or ketoester (0.5 or 1 mmol) was added. The vial was placed in the alloy plate which was then placed into the autoclave. Once sealed, the autoclave was purged 5 times with hydrogen, then pressurized to 30 bar and heated to desired temperature. Afterwards, the autoclave was cooled to RT, depressurized, and the reaction mixture was analyzed by GC-FID or HPLC as well as GC-MS. Product isolation was performed via column chromatography using silica gel as stationary phase and n-pentane/ethylacetate or n-pentane/acetone mixture as eluent.

Individual Reaction Conditions:

[0126] [a] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 50 C., EtOH (1.5 mL)
[b] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 70 C., EtOH (1.5 mL)
[c] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 50 C., toluene (1.5 mL)
[d] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 50 C., iPrOH (1.5 mL)
[e] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 50 C., iPrOH (1.5 mL)
[f] 1 mol % cat., 5 mol % KOtBu, 0.5 mmol substrate, 30 bar, 4-5 h, 40 C., tert-amyl alcohol (1.5 mL)
[g] 1 mol % cat., 5 mol % KOtBu, 0.5 mmol substrate, 30 bar, 16 h, 50 C., toluene (1.5 mL)
[h] 2 mol % cat., 5 mol % KOtBu, 0.5 mmol substrate, 30 bar, 8 h, 100 C., dioxan (1.5 mL)
[i] 1 mol % cat., 5 mol % KOtBu, 1 mmol substrate, 30 bar, 4 h, 30 C., 1,4-dioxane (2 mL)
[j] 1 mol % cat., 5 mol % KOtBu, 1 mmol substrate, 30 bar, 4 h, 40 C., tert-amyl alcohol (2 mL)
[k] 1 mol % cat., 5 mol % KOtBu, 1 mmol substrate, 30 bar, 4 h, 80 C., tert-amyl alcohol (2 mL)
[l] 2 mol % cat., 5 mol % KOtBu, 1 mmol substrate, 30 bar, 4 h, 50 C., toluene (2 mL)
[m] 2 mol % cat., 5 mol % KOtBu, 1 mmol substrate, 30 bar, 4 h, 80 C., tert-amyl alcohol (2 mL)
[n] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 3 h, 70 C., iPrOH (1.5 mL)
[o] 2 mol % cat., 5 mol % NaOtBu, 0.5 mmol substrate, 30 bar, 1 h, 50 C., iPrOH (1 mL)
SP=side product (Hydrogenation of double bond)

TABLE-US-00001 TABLE 1 Re- action Con- Ex- Con- version ample Substrate ditions (%) e.e. 3.1.1.a [00034] d 90 (36 SP) 67 3.1.1.b [00035] o 90 (36 SP) 67 (20% for the SP) 3.1.2.a [00036] f 65 69 3.1.2.b [00037] i 76 69 3.1.3.a [00038] a 100 68 3.1.3.b [00039] i >99 70 3.1.4.a [00040] b 99 73 3.1.4.b [00041] i 99 74 3.1.5.a [00042] a 30 79 3.1.5.b [00043] i 70 80 3.1.6a [00044] a 96 84 3.1.6b [00045] i 96 84 3.1.7 [00046] a 87 (13SP) 59 3.1.8.a [00047] f 96 69 3.1.8.b [00048] j 96 70 3.1.9.a [00049] a 42 52 3.1.9.b [00050] j 61 74 3.1.9.c [00051] k 96 74 3.1.10.a [00052] f 100 86 3.1.10.b [00053] j >99 86 3.1.11.a [00054] f 100 70 3.1.11.b [00055] j 96 80 3.1.12 [00056] d 100 (25SP) 50 3.1.13.a [00057] c 100 (7 SP) 64 3.1.13.b [00058] l 94 (6 SP) 62 3.1.14.a [00059] f 44 61 3.1.14.b [00060] j 46 61 3.1.15.a [00061] e 30 51 3.1.15.b [00062] n 30 51 3.1.16 [00063] j >99 76 3.1.17 [00064] j 26 71 3.1.18 [00065] j 23 62 3.1.19 [00066] j >99 50 3.1.20 [00067] m >99 68 3.1.21 [00068] m >99 31 3.1.22 [00069] m 22 29 3.1.23 [00070] k 28 99

3.2 Hydrogenation of Ketones or Ketoesters with Iron Complex of Example 2.2

General Procedure:

[0127] All catalytic hydrogenation experiments using molecular hydrogen were carried out in a Parr Instruments autoclave (300 mL) advanced with an internal alloy plate include up to 8 uniform reaction vials (4 mL) equipped with a cap and needle penetrating the septum.

Representative Experiment:

[0128] Under an argon atmosphere, a vial was charged with Iron Complex of example 2.2 which were dissolved in 2 mL of dried solvent. The resulting yellow solution was stirred briefly before the ketone or ketoester (0.5 or 1 mmol). The vial was placed in the alloy plate which was then placed into the autoclave. Once sealed, the autoclave was purged 5 times with hydrogen, then pressurized to 30 bar and heated to desired temperature. Afterwards, the autoclave was cooled to RT, depressurized, and the reaction mixture was analyzed by GC-FID or HPLC as well as GC-MS. Product isolation was performed via column chromatography using silica gel as stationary phase and n-pentane/ethylacetate or n-pentane/acetone mixture as eluent.

Individual Reaction Conditions:

[0129] [a] 1 mol % cat., 0.5 mmol substrate, 30 bar, 3 h, 30 C., CH.sub.2Cl (1.5 mL)
[b] 3 mol % cat., 0.5 mmol substrate, 30 bar, 3 h, 70 C., iPrOH (1.5 mL)
[c] 2 mol % cat., 0.5 mmol substrate, 30 bar, 2 h, 50 C., EtOH (1.5 mL)
[d] 1 mol % cat., 0.5 mmol substrate, 30 bar, 3 h, 70 C., iPrOH (1.5 mL)
[f] 1 mol % cat., 1 mmol substrate, 30 bar, 22 h, 40 C., n-heptane (1.5 mL)
[g] 1 mol % cat., 1 mmol substrate, 30 bar, 3 h, 30 C., EtOH (2 mL)
[h] 1 mol % cat., 1 mmol substrate, 30 bar, 6 h, 30 C., EtOH (2 mL)
[i] 1 mol % cat., 1 mmol substrate, 30 bar, 6 h, 60 C., EtOH (2 mL)
[j] 1 mol % cat., 1 mmol substrate, 30 bar, 6 h, 30 C., EtOH (2 mL)
[k] 3 mol % cat., 1 mmol substrate, 30 bar, 3 h, 70 C., THF (2 mL)
SP=side product (Hydrogenation of double bond)

TABLE-US-00002 TABLE 2 Re- action Con- Ex- Con- version ample Substrate ditions (%) e.e. 3.2.1.a [00071] b 100 35 3.2.1.b [00072] g >99 35 3.2.2.a [00073] c 96 48 3.2.2.b [00074] g >99 74 3.2.3.a [00075] c 100 32 3.2.3.b [00076] h >99 34 3.2.4.a [00077] b 95 52 3.2.4.b [00078] h >99 60 3.2.5.a [00079] b 100 64 3.2.5.b [00080] h >99 64 3.2.6.a [00081] c 100 45 3.2.6 [00082] h >99 45 3.2.7.a [00083] b 100 (5SP) 48 3.2.7.b [00084] k 97 (3 SP) 48 3.2.8.a [00085] d 98 35 3.2.8.b [00086] i 36 35 3.2.9.a [00087] d 100 30 3.2.9.b [00088] h 17 32 3.2.9.c [00089] i >99 33 3.2.10.a [00090] d 100 40 3.2.10.b [00091] h >99 40 3.2.11.a [00092] f 100 33 3.2.11.b [00093] j >99 33 3.2.12.a [00094] b 100 45 3.2.12.b [00095] k >99 45 3.2.13 [00096] g >99 71 3.2.14 [00097] h 71 70 3.2.15 [00098] h 99 45 3.2.16 [00099] g 97 (6 SP) 56 3.2.17 [00100] h >99 32 3.2.18 [00101] h >99 (2 SP) 48 3.2.19 [00102] g >99 48 3.2.20 [00103] g >99 57 3.2.21 [00104] i 78 32 3.2.22 [00105] h 98 (8 SP) 46 3.2.23 [00106] h 99 55 3.2.24 [00107] h 96 51 3.2.25.a [00108] h 61 >99 3.2.25.b [00109] i >99 >99