Chiral P-Chlorophospholane: A Versatile Building Block for the Synthesis of Ligands

Abstract

The synthesis of enantiomerically pure (R,R)-1-chloro-2,5-dimethylphospholane is described, which can be used for the synthesis of a wide range of phosphine ligands bearing a phospholane moiety.

Keywords

ligands - phosphorus - phosphorylation - stereoselective synthesis

References

• For general reviews, see:
• 1a Brown JM. In Comprehensive Asymmetric Catalysis   Vol. I:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer-Verlag; Berlin: 1999.  p.121-182  
• 1b Ohkuma T. Kitamura M. Noyori R. In Catalytic Asymmetric Synthesis   Ojima I. Wiley-VCH; Weinheim: 2000.  p.1-110  
• 1c Blaser H.-U. Pugin B. Spindler F. J. Mol. Catal. A: Chem.  2005,  231:  1 
• For reviews on chiral phospholanes and other cyclic phosphines and their application in asymmetric catalysis, see:
• 2a Holz J. Gensow M.-N. Zayas O. Börner A. Curr. Org. Chem.  2007,  11:  61 
• 2b Clark PT. Landis CR. Tetrahedron: Asymmetry  2004,  15:  2123 
• 3 Burk MJ. Acc. Chem. Res.  2000,  33:  363 ; and references cited therein
• 4a Holz J. Quirmbach M. Schmidt U. Heller D. Stürmer R. Börner A. J. Org. Chem.  1998,  63:  8031 
• 4b Li W. Zhang Z. Xiao D. Zhang X. J. Org. Chem.  2000,  65:  3489 
• 4c Yan Y.-Y. RajanBabu TV. J. Org. Chem.  2000,  65:  900 
• 5a Holz J. Heller D. Stürmer R. Börner A. Tetrahedron Lett.  1999,  40:  7059 
• 5b Holz J. Stürmer R. Schmidt U. Drexler H.-J. Heller D. Krimmer H.-P. Börner A. Eur. J. Org. Chem.  2001,  4615 
• 5c RajanBabu TV. Yan Y.-Y. Shin S. J. Am. Chem. Soc.  2001,  123:  10207 
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• 8 Fuhrhop J. Penzlin G. Organic Synthesis, Concepts, Methods, Starting Materials   VCH; Weinheim: 1984. 
• For other monophospholane derivatives as possible building blocks for coupling reactions, see:
• 10a Brunner H. Sievi R. J. Organomet. Chem.  1987,  328:  71 
• 10b Brunner H. Limmer S. J. Organomet. Chem.  1991,  413:  55 
• 10c Burk MJ. Feaster JE. Harlow RL. Tetrahedron: Asymmetry  1991,  2:  569 
• 10d Morimoto T. Ando N. Achiwa K. Synlett  1996,  1211 
• 10e Morimoto T. Ando N. Achiwa K. Synlett  1996,  1211 
• 10f Burk MJ. Pizzano A. Marti JA. Organometallics  2000,  19:  250 
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9

Other approaches are based on the cleavage of the P-phenyl bond by lithium or by deprotonation of the P-H bond in relevant phospholanes. The latter methods are frequently accompanied by the epimerization of the adjacent chiral C-atoms or the formation of side products and therefore are not suitable for the construction of optically pure ligands.^10c,f

13

Solvents were dried and freshly distilled under argon before use. All reactions were performed under an argon atmosphere by using standard Schlenk techniques. ¹H, ¹³C and ³¹P NMR spectra were recorded on a Bruker ARX 400 spectrometer at the following frequencies: 400.13 MHz (¹H), 100.63 MHz (¹³C), 161.98 MHz (³¹P), 235 MHz (¹⁹F) with CDCl₃ as solvent.
( R,R )-1-Chloro-2,5-dimethylphospholane (2) A solution of 1-trimethylsilyl-2,5-dimethyl-phospholane (1) (10.0 g, 53.1 mmol) in CH₂Cl₂ (60 mL) was added via cannula to a solution of hexachloroethane (12.6 g, 53.1 mmol) in CH₂Cl₂ (80 mL) under stirring at ambient temperature. Then the mixture was stirred under reflux for 30 min. After cooling, the solvent and tetrachlorethene was removed in vacuo (500 mbar) and the residue was distilled to give chlorophospholane 2 (7.40 g, 93%) as a colorless liquid (bp 100-105 °C/100 mbar).
Verification of the optical purity of chlorophospholane 2 was carried out by reaction with (R)-(+)-N-benzyl-α-methyl-benzylamine. Only the expected (R,R,R)-diastereomer was visible [³¹P NMR (THF-d ₈): δ = 66.5]. The (R,S,S)-diastereomer (δ = 61.5) was not observed.
[α]_D ²⁰ = +96.8 (c = 1.1; CH₂Cl₂). ¹H NMR: δ = 1.22 (d, J = 7.1 Hz, 3 H, CH₃), 1.28 (d, J = 7.1 Hz, 3 H, CH₃), 1.50 (m, 2 H, H_a-CH₂), 2.08-2.36 (m, 4 H, H_b-CH₂, CH-P). ¹³C NMR: δ = 16.2, 35.5, 43.1. ³¹P NMR: δ = 143.3.
Preparation of Phospholane Amides 3a-d To a solution of the monoamine (1 mmol) or diamine (0.5 mmol) in Et₂O (5 mL) was added n-BuLi (1.05 equiv., 1.6 M in hexane, 0.65 mL) at -10 °C. The solution was stirred for 1 h. After the addition of 2 (0.151 g, 1 mmol) in Et₂O (2 mL) the solution was stirred at -10 °C for 1 h and warmed to ambient temperature. After 4 h the solution was filtered and the solvent and byproduct were removed in vacuo to give the phospholanes, which were used without further purification.
( R , R )-1-( N,N -Diethylamino)-2,5-dimethylphospholane (3a) ¹H NMR: δ = 0.94 (t, J = 7.0 Hz, 6 H, CH₃), 1.05 (dd, J = 7.0, 10.0 Hz, 3 H, CH₃), 1.18 (dd, J = 7.1, 18.5 Hz, 3 H, CH₃), 1.10-2.15 (m, 6 H, CH-P, CH₂), 2.91 (m, 4 H, NCH₂). ¹³C NMR: δ = 14.5, 15.2, 18.5, 34.8, 36.2, 37.3, 37.7, 45.2. ³¹P NMR: δ = 86.2.
( R , R )-1-( N,N -Diphenylamino)-2,5-dimethylphospholane (3b) ¹H NMR: δ = 1.13 (dd, J = 7.2, 19.9 Hz, 3 H, CH₃), 1.18 (dd, J = 7.1, 10.4 Hz, 3 H, CH₃), 1.10-2.16 (m, 5 H, CH-P, CH₂), 2.32 (m, 1 H, CH-P), 7.03-7.18 (m, 6 H, arom. H), 7.26-7.35 (m, 4 H, arom. H). ¹³C NMR: δ = 14.7, 19.0, 34.9, 36.1, 36.5, 39.5, 122.6, 124.7, 128.9, 148.8. ³¹P NMR: δ = 78.4.
( R , R )-1-( N,N -Dibenzylamino)-2,5-dimethylphospholane (3c)
¹H NMR (CDCl₃): δ = 1.06 (dd, J = 7.1, 9.9 Hz, 3 H, CH₃), 1.47 (dd, J = 7.0, 18.4 Hz, 3 H, CH₃), 1.12-2.14 (m, 5 H, CH-P, CH₂), 2.29 (m, 1 H, CH-P), 4.06 (dd, J = 9.2 Hz, 15.3 Hz, 2 H, H_a-NCH₂), 4.22 (dd, J = 7.6 Hz, 15.3 Hz, 2 H, H_b-NCH₂), 7.26-7.44 (m, 10 H, arom. H). ¹³C NMR: δ = 15.0, 18.8, 34.7, 37.6, 37.9, 38.6, 55.4, 126.8, 128.1, 128.2, 139.4. ³¹P NMR: δ = 91.5.
N,N′-Bis[( R , R )-2,5-dimethylphospholan-1-yl]- N,N′-dimethylethane-1,2-diamine (3d)
¹H NMR: δ = 1.08 (dd, J = 7.2, 10.2 Hz, 6 H, CH₃), 1.18 (dd, J = 7.2, 18.8 Hz, 6 H, CH₃), 1.02-2.25 (m, 12 H, CH-P, CH₂), 2.58 (d, J = 4.8 Hz, 6 H, NCH₃), 2.95 (m, 4 H, NCH₂). ¹³C NMR: δ = 14.0, 18.8, 35.2, 36.7, 37.5, 38.3, 38.8, 56.6. ³¹P NMR: δ = 88.4.
(2 R ,2" R )-1,1"-Bis[(2′′ R ,5′′ R )-2,5-dimethylphospholan-1-yl]-2,2"-bipyrrolidine (3e)
¹H NMR: δ = 1.09 (dd, J = 7.1, 10.3 Hz, 6 H, CH₃), 1.19 (dd, J = 7.2 Hz, 18.5, 6 H, CH₃), 1.04-2.32 (m, 20 H, CH-P, CH₂), 2.85-3.10 (m, 4 H, NCH₂), 3.74 (m, 2 H, NCH). ¹³C NMR: δ = 14.6, 19.9, 26.4, 27.0, 33.1, 35.7, 37.1, 37.8, 50.6, 67.1. ³¹P NMR: δ = 67.7.
Preparation of Oxazolinephospholanes 5a-d To a solution of oxazoline derivative 4 (2 mmol) and TMEDA (0.29 g, 2.5 mmol) in Et₂O (10 mL) was added n-BuLi (1.6 M in hexane, 1.31 mL) at 0 °C. After stirring for 1 h, the chlorophospholane 2 (0.316 g, 2.1 mmol) dissolved in Et₂O (3 mL) was added. Stirring was continued for 3 h at ambient temperature and degassed H₂O (4 mL) was added. The aqueous phase was extracted with Et₂O (5 mL). The combined organic phases together with traces of n-butyl-phospholane formed were evaporated in vacuo to give oxazoline derivatives 5a-d in yields of 60-75% with a purity of more than 95%. These derivatives were used without further purifications for the preparation of metal complexes.
2-{2-[( R , R )-2,5-Dimethylphospholan-1-yl]phenyl}-4,5-dihydrooxazole (5a)
¹H NMR: δ = 0.72 (dd, J = 7.1, 8.6 Hz, 3 H, CH₃), 1.26 (dd, J = 7.0, 17.6 Hz, 3 H, CH₃), 1.30-1.56 (m, 2 H, CH₂), 2.10 (m, 2 H, CH₂), 2.52 (m, 2 H, CH-P), 4.10 (m, 2 H, NCH₂). 4.37 (m, 2 H, OCH₂), 7.26-7.42 (m, 2 H, arom. H), 7.51 (m, 1 H, arom. H), 7.78 (m, 1 H, arom. H). ¹³C NMR: δ = 17.9, 19.8, 32.4, 33.4, 35.0, 35.4, 55.4, 67.1, 127.5, 129.6, 129.7, 131.6, 133.2, 138.7, 164.7. ³¹P NMR: δ = 10.9. 2-{2-[( R , R )-2,5-Dimethylphospholan-1-yl]phenyl}-4,4-dimethyl-4,5-dihydrooxazole (5b) ¹H NMR: δ = 0.73 (dd, J = 7.1, 8.8 Hz, 3 H, CH₃), 1.25 (dd, J = 7.1, 17.4 Hz, 3 H, CH₃), 1.32-1.51 (m, 2 H, CH₂), 1.37. (s, 6 H, CH₃), 2.09 (m, 2 H, CH₂), 2.47 (m, 2 H, CH-P), 4.07 (AB-system, 2 H, OCH₂), 7.22-7.35 (m, 2 H, arom. H), 7.46 (m, 1 H, arom. H), 7.72 (m, 1 H, arom. H). ¹³C NMR: δ = 17.7, 19.8, 28.1, 28.4, 32.9, 33.6, 35.1, 35.5, 68.0, 78.7, 127.4,, 129.5, 129.5, 131.5, 133.8, 138.6, 162.7. ³¹P NMR: δ = 10.2.( R ) -2-{2-[( R , R )-2,5-Dimethylphospholan-1-yl]phenyl}-4-isopropyl-4,5-dihydrooxazole (5c) ¹H NMR: δ = 0.68 (dd, J = 7.3, 8.4 Hz, 3 H, CH₃), 0.89 (d, J = 7.80 Hz, 3 H, CH₃), 1.01 (d, J = 6.7 Hz, 3 H, CH₃), 1.19 (dd, J = 7.0, 17.2 Hz, 3 H, CH₃), 1.25-1.48 (m, 2 H, CH₂), 1.79 (m, 1 H, CH), 1.94-2.13 (m, 2 H, CH₂), 2.33-2.54 (m, 2 H, CH-P), 3.97-4.05 (m, 2 H, OCH₂), 4.33 (m, 1 H, NCH), 7.19-7.45 (m, 2 H, arom. H), 7.58 (m, 1 H, arom. H), 7.88 (m, 1 H, arom. H). ¹³C NMR: δ = 17.9, 18.6, 19.1, 19.7, 32.6, 33.1, 33.5, 35.0, 35.4, 70.2, 73.5, 127.4, 129.5, 129.5, 131.5, 133.8, 138.6, 163.5. ³¹P NMR: δ = 10.2.
(S) -2-{2-[( R , R )-2,5-Dimethylphospholan-1-yl]phenyl}-4-isopropyl-4,5-dihydrooxazole (5d) ¹H NMR: δ = 0.72 (dd, J = 7.1, 8.5 Hz, 3 H, CH₃), 0.93 (d, J = 6.8 Hz, 3 H, CH₃), 1.02 (d, J = 6.7 Hz, 3 H, CH₃), 1.24 (dd, J = 7.1, 17.3 Hz, 3 H, CH₃), 1.22-1.51 (m, 2 H, CH₂), 1.84 (m, 1 H, CH), 2.01-2.15 (m, 2 H, CH₂), 2.44-2.64 (m, 2 H, CH-P), 4.05-4.19 (m, 2 H, OCH₂), 4.34 (dd, J = 8.0, 9.5 Hz, 1 H, NCH), 7.26-7.39 (m, 2 H, arom. H), 7.51 (m, 1 H, arom. H), 7.80 (m, 1 H, arom. H). ¹³C NMR: δ = 18.2, 18.5, 19.0, 19.4, 32.2, 33.0, 33.0, 34.9, 35.3, 69.9, 73.1, 127.4, 129.5, 129.6, 131.4, 133.1, 138.8, 163.1. ³¹P NMR: δ = +11.1.
Preparation of Phospholane-Substituted Pyridines 7a-e To a solution of pyridine derivative 6a-e (1 mmol) and TMEDA (0.145 g, 1.25 mmol) in Et₂O (5 mL) was added n-BuLi solution (1.6 M in hexane, 0.66 mL, 1.05 mmol) at -78 °C. After stirring for 1 h, chlorophospholane 2 (0.158 g, 1.05 mmol) dissolved in Et₂O (2 mL) was added and the stirring was continued for further 3 h. The reaction mixture was warmed to r.t. and degassed H₂O (3 mL) was added to remove the salts and TMEDA. After extraction of the aqueous phase with Et₂O (3 mL) the solvent from the combined phases was evaporated. Pyridine derivatives 7a-e (80-90% yield) were used without further purifications for the preparation of metal complexes.
2-[( R , R )-2,5-dimethylphospholan-1-yl]pyridine (7a)
As an example, this compound was further purified by column chromatography; R _f = 0.45 heptane : EtOAc, 9:1). ¹H NMR: δ = 0.77 (dd, J = 7.0, 10.7 Hz, 3 H, CH₃), 1.25 (m, 1 H, H_a-CH₂), 1.27 (dd, J = 7.4, 18.6 Hz, 3 H, CH₃), 1.42 (m, 1 H, H_b-CH₂), 1.85 (m, 1 H, H_a-CH₂), 2.10-2.28 (m, 2 H, H_b-CH₂, CH-P), 3.20 (m, 1 H, CH-P), 7.09 (m, 1 H, arom. H), 7.42-7.57 (m, 2 H, arom. H), 8.61 (m, 1 H, arom. H). ¹³C NMR: δ = 15.2, 20.2, 32.6, 36.2, 36.9, 37.0, 122.1, 130.6, 134.3, 149.5, 162.2. ³¹P NMR: δ = 11.8.
2-[( R , R )-2,5-Dimethylphospholan-1-yl]-6-methyl-pyridine (7b)
¹H NMR: δ = 0.75 (dd, J = 7.1, 10.5 Hz, 3 H, CH₃), 1.23 (m, 1 H, H_a-CH₂), 1.24 (dd, J = 7.3, 18.5 Hz, 3 H, CH₃), 1.43 (m, 1 H, H_b-CH₂), 1.82 (m, 1 H, H_a-CH₂), 2.11-2.27 (m, 2 H, H_b-CH₂, CH-P), 2.46 (s, 3 H, CH₃), 3.12 (m, 1 H, CH-P), 6.91 (m, 1 H, arom. H), 7.22 (m, 1 H, arom. H), 7.36 (m, 1 H, arom. H). ¹³C NMR: δ = 15.3, 20.2, 24.7, 32.9, 36.1, 36.8, 37.0, 121.5, 127.0, 134.4, 158.0, 161.3. ³¹P NMR: δ = 10.9.
2-[( R , R )-2,5-Dimethylphospholan-1-yl]-6-methoxy-pyridine (7c)
¹H NMR: δ = 0.78 (dd, J = 7.1, 10.8 Hz, 3 H, CH₃), 1.22 (dd, J = 7.3, 18.7 Hz, 3 H, CH₃), 1.23 (m, 1 H, H_a-CH₂), 1.55 (m, 1 H, H_b-CH₂), 1.82 (m, 1 H, H_a-CH₂), 2.08-2.26 (m, 2 H, H_b-CH₂, CH-P), 3.09 (m, 1 H, CH-P), 3.84 (s, 3 H, OCH₃), 6.51 (m, 1 H, arom. H), 7.04 (m, 1 H, arom. H), 7.34 (m, 1 H, arom. H). ¹³C NMR: δ = 14.8, 20.0, 33.4, 36.2, 36.9, 37.1, 52.8, 109.6, 124.1, 136.9, 159.1, 162.7. ³¹P NMR: δ = 11.8.
8-[( R , R )-2,5-Dimethylphospholan-1-yl]quinoline (7d) ¹H NMR: δ = 0.50 (dd, J = 7.1, 9.2 Hz, 3 H, CH₃), 1.18-1.46 (m, 2 H, CH₂), 1.24 (dd, J = 7.3, 18.5 Hz, 3 H, CH₃), 1.91 (m, 1 H, H_a-CH₂), 2.11 (m, 1 H, H_b-CH₂), 2.46 (m, 1 H, CH-P), 2.64 (m, 1 H, CH-P), 7.20 (m, 1 H, arom. H), 7.34 (m, 1 H, arom. H), 7.55-7.63 (m, 2 H, arom. H), 7.93 (m, 1 H, arom. H), 8.83 (m, 1 H, arom. H). ¹³C NMR: δ = 16.7, 20.4, 30.6, 33.8, 34.8, 35.7, 120.6, 125.6, 127.4, 127.4, 131.3, 135.7, 137.6, 148.7, 150.1. ³¹P NMR: δ = 1.7.
2-{[(2 R ,5 R )-2,5-Dimethylphospholan-1-yl]meth-yl}pyridine (7e) ¹H NMR: δ = 0.90 (dd, J = 7.0, 18.0 Hz, 3 H, CH₃), 1.16 (m, 1 H, H_a-CH₂), 1.12 (dd, J = 7.2, 10.0 Hz, 3 H, CH₃), 1.50 (m, 1 H, H_b-CH₂), 1.90-2.18 (m, 4 H, CH₂, CH-P), 2.86 (doublet of AB-system, 2 H, CH₂P), 7.00 (m, 1 H, arom. H), 7.19 (m, 1 H, arom. H), 7.50 (m, 1 H, arom. H), 8.41 (m, 1 H, arom. H). ¹³C NMR: δ = 14.3, 20.4, 32.8, 34.4, 36.1, 36.5, 36.8, 120.5, 123.4, 136.1, 149.0, 159.5. ³¹P NMR: δ = 8.3.
( S _Fc )-2-[(1 S )-(1- N,N -Dimethylamino)ethyl]-1-[(2′ R ,5′ R )-dimethylphospholan-1-yl]ferrocene (9)
To a solution of (S)-Ugi’s amine (S)-8 (0.28 g, 1.09 mmol) in Et₂O (5 mL) was added t-BuLi (1.7 M solution, 0.70 mL) at -78 °C. The solution was stirred for 1.5 hour at ambient temperature and after cooling to -78 °C the chlorophos-pholane 2 (0.18 g, 1.20 mmol) was added. After 30 min. the solution was allowed to warm and stirred for 1.5 hours. After filtration the solvent was removed and the residue was treated with MeOH (1 mL) to give a yellow precipitate (63%).
¹H NMR: δ = 0.69 (dd, J = 7.1, 10.1 Hz, 3 H, CH₃), 1.22 (m, 1 H, H_a-CH₂), 1.22 (d, J = 6.9 Hz, 3 H, CH₃), 1.12 (dd, J = 7.3 Hz, 18.9 Hz, 3 H, CH₃), 1.38 (m, 1 H, H_b-CH₂), 1.00-2.25 (m, 3 H, CH₂, CH-P), 2.05 (s, 6 H, NCH₃), 2.61 (m, 1 H, CH-P), 3.99 (m, 1 H, H_Cp), 4.05 (m, 1 H, CH-N), 4.09 (s, 5 H, Cp-ring), 4.21 (m, 1 H_Cp), 4.26 (m, 1 H, H_Cp). ¹³C NMR: δ = 8.0, 15.2, 20.3, 34.9, 36.1, 36.4, 37.0, 39.4, 56.1, 67.8, 68.9, 69.0, 71.0, 98.4. ³¹P NMR: δ = 6.8.