Solvent and in situ catalyst preparation impacts upon Noyori reductions of aryl-chloromethyl ketones: application to syntheses of chiral 2-amino-1-aryl-ethanols

As part of medicinal chemistry efforts we found it necessary to develop general syntheses of highly enantiomerically enriched 1-aryl-2-chloroethanols and 1-aryl-2-methylaminoethanols. A survey of literature methods suggested that a truly general approach had not yet been reported, encouraging us to undertake the development of such a methodology. This study describes the design, development, and reduction to practice of a general synthesis of chiral 1-aryl-2-chloroethanols and the transformation of these entities to highly enantiomerically enriched 1-aryl-2-methylaminoethanols. Of particular importance were observations of the impact of solvent and the method of catalyst preparation on the yield and enantiomerical excess of chlorohydrins prepared via Noyori transfer hydrogenations of aryl-chloromethyl ketones.

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(R)-3-(1-Hydroxy-2-chloroethyl)-pysidineC7H8ClNOEe = 96%[α]D25=-42 (c 0.81, methanol)Absolute configuration: R

(R)-2-(1-Hydroxy-2-chloroethyl)-pyridineC7H8ClNOEe = 96%[α]D25=-39 (c 0.94, CH2Cl2)Absolute configuration: R

(S)-2-(1-Hydroxy-2-chloroethyl)-pyridineC7H8ClNOEe = >99%[α]D25=+62 (c 0.94, methanol)Absolute configuration: S

(R)-2-(1-Hydroxy-2-chloroethyl)-furanC6H7ClO2Ee = 98%[α]D25=-18 (c 0.97, methanol)Absolute configuration: R

(R)-2-(1-Hydroxy-2-chloroethyl)-thiopheneC6H7ClOSEe = 98%[α]D25=-31 (c 0.91, methylene chloride)Absolute configuration: R

(R)-3-(1-Hydroxy-2-chloroethyl)-thiopheneC6H7ClOSEe = 96%[α]D25=-40 (c 0.85, methylene chloride)Absolute configuration: R

(R)-2-(1-Hydroxy-2-chloroethyl)-benzofuranC8H9ClOEe = 98%[α]D25=-31 (c 1.03, chloroform)Absolute configuration: R

(R)-2-(1-Hydroxy-2-chloroethyl)-thiazoleC5H6ClNOSEe = 97%[α]D25=-33 (c 0.92, methylene chloride)Absolute configuration: R

(R)-2-(1-Hydroxy-2-chloroethyl)-pyrazineC6H7ClN2OEe = 76%[α]D25=-40 (c 1.16, methylene chloride)Absolute configuration: R

(R)-2-Chloro-1-phenylethanolC8H9ClOEe = >99%[α]D25=-50 (c 0.87, methylene chloride)Absolute configuration: R

(R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyridineC8H12N2OEe = >96%[α]D25=+49 (c 0.36, methylene chloride)Absolute configuration: R

(R)-1-(2-Furyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO3Ee = 98%[α]D25=-102 (c 0.98, chloroform)Absolute configuration: R

(5S)-3-Methyl-5-(2-furyl)-2-oxazoldinoneC8H9NO3Ee = 97%[α]D25=+109 (c 0.97, methylene chloride)Absolute configuration: R

(S)-N-Methyl-1-(2-furyl)-2-aminoethanolC8H9NO3Ee = >96%[α]D25=-32 (c 0.91, ethanol)Absolute configuration: S

(R)-1-(3-Pyridyl)-2-chloroethanol–N-methylcarbamateC9H11ClN2O2Ee = 94.6%[α]D25=-33 (c 0.92, chloroform)Absolute configuration: R

(5R)-3-Methyl-5-(3-pyridyl)-2-oxazoldinoneC9H10N2O2Ee = 97.6%[α]D25=-39 (c 1.00, chloroform)Absolute configuration: R

(R)-N-Methyl-1-(3-pyridyl)-2-aminoethanolC8H12N2OEe = >96%[α]D25=-67 (c 0.93, methylene chloride)Absolute configuration: R

(R)-1-(2-Thienyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO2SEe = 92.4%[α]D25=-61 (c 0.73, methylene chloride)Absolute configuration: R

(5S)-3-Methyl-5-(2-thienyl)-2-oxazoldinoneC8H9NO2SEe = 98.4%[α]D25=+90 (c 0.96, methylene chloride)Absolute configuration: S

(S)-N-Methyl-1-(2-thienyl)-2-aminoethanolC7H11NOSEe = >98%[α]D25=-24 (c 1.06, methylene chloride)Absolute configuration: S

(R)-1-(3-Thienyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO2SEe = 92.8%[α]D25=-59 (c 0.86, methylene chloride)Absolute configuration: R

(5R)-3-Methyl-5-(3-thienyl)-2-oxazoldinoneC8H9NO2SEe = >99%[α]D25=+13 (c 0.99, chloroform)Absolute configuration: R

(R)-N-Methyl-1-(3-thienyl)-2-aminoethanolC7H11NOSEe = >99%[α]D25=-48 (c 1.07, chloroform)Absolute configuration: R

(R)-1-(2-Benzofuranyl)-2-chloroethanol–N-methylcarbamateC12H12ClNO3Ee = 98%[α]D25=-110 (c 0.95, chloroform)Absolute configuration: R

(5S)-3-Methyl-5-(2-benzofuranyl)-2-oxazoldinoneC12H11NO3Ee = 92%[α]D25=+37 (c 1.00, chloroform)Absolute configuration: S

(S)-N-Methyl-1-(2-benzofuranyl)-2-aminoethanolC11H13NO2Ee = 92%[α]D25=-30 (c 1.02, chloroform)Absolute configuration: S

(R)-1-(2-Thiazolyl)-2-chloroethanol–N-methylcarbamateC7H9ClN2O2SEe = >99%[α]D25=-17 (c 1.10, methylene chloride)Absolute configuration: R

(R)-1-(2-Pyrazinyl)-2-chloroethanol–N-methylcarbamateC8H10ClN3O2Ee = 82%[α]D25=-29 (c 1.01, methylene chloride)Absolute configuration: R

(R)-1-Phenyl-2-chloroethanol–N-methylcarbamateC10H12ClNO2Ee = 98%[α]D25=-15 (c 0.93, methylene chloride)Absolute configuration: R

(5R)-3-Methyl-5-phenyl-2-oxazoldinoneC10H11NO2Ee = >98%[α]D25=-41 (c 0.90, chloroform)Absolute configuration: R

(R)-N-Methyl-1-phenyl-2-aminoethanolC9H13NOEe = >98%[α]D25=-38 (c 0.66, EtOH)Absolute configuration: R

(S)-1-(3-Pyridyl)-2-chloroethanol–N-methylcarbamateC9H11ClN2O2Ee = 96.6%[α]D25=+33 (c 0.96, chloroform)Absolute configuration: S

(5S)-3-Methyl-5-(3-pyridyl)-2-oxazoldinoneC9H10N2O2Ee = 96.6%[α]D25=+40 (c 0.91, chloroform)Absolute configuration: S

(S)-N-Methyl-1-(3-pyridyl)-2-aminoethanolC8H12N2OEe = 97.4%[α]D25=+39 (c 0.83, EtOH)Absolute configuration: S

(S)-1-(2-Furyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO3Ee = 98%[α]D25=+94 (c 1.02, methylene chloride)Absolute configuration: S

(5R)-3-Methyl-5-(2-furyl)-2-oxazoldinoneC8H9NO3Ee = 98%[α]D25=+106 (c 1.01, methylene chloride)Absolute configuration: R

(R)-N-Methyl-1-(2-furyl)-2-aminoethanolC7H11NO2Ee = >96%[α]D25=+32 (c 0.96, EtOH)Absolute configuration: R

(S)-1-(2-Thienyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO2SEe = 97%[α]D25=+58 (c 0.97, methylene chloride)Absolute configuration: S

(5R)-3-Methyl-5-(2-thienyl)-2-oxazoldinoneC8H9NO2SEe = >98%[α]D25=-94 (c 1.04, methylene chloride)Absolute configuration: R

(R)-N-Methyl-1-(2-thienyl)-2-aminoethanolC7H11NOSEe = >98%[α]D25=+26 (c 1.05, methylene chloride)Absolute configuration: R

(S)-1-(3-Thienyl)-2-chloroethanol–N-methylcarbamateC8H10ClNO2SEe = 97%[α]D25=+57 (c 0.73, methylene chloride)Absolute configuration: S

(5S)-3-Methyl-5-(3-thienyl)-2-oxazoldinoneC8H9NO2SEe = 97%[α]D25=-14 (c 1.05, chloroform)Absolute configuration: S

(S)-N-Methyl-1-(3-thienyl)-2-aminoethanolC7H11NOSEe = >99%[α]D25=+48 (c 0.86, chloroform)Absolute configuration: S

(S)-1-(2-Benzofuranyl)-2-chloroethanol–N-methylcarbamateC12H12ClNO3Ee = 98%[α]D25=+101 (c 0.85, chloroform)Absolute configuration: S

(5R)-3-Methyl-5-(2-benzofuranyl)-2-oxazoldinoneC12H11NO3Ee = 92%[α]D25=-38 (c 0.95, chloroform)Absolute configuration: S

(R)-N-Methyl-1-(2-benzofuranyl)-2-aminoethanolC11H13NO2Ee = 92%[α]D25=+31 (c 1.05, chloroform)Absolute configuration: R

(S)-1-Phenyl-2-chloroethanol–N-methylcarbamateC10H12ClNO2Ee = 97%[α]D25=+13 (c 1.01, methylene chloride)Absolute configuration: S

(5S)-3-Methyl-5-phenyl-2-oxazoldinoneC10H11NO2Ee = 96%[α]D25=+39 (c 1.03, chloroform)Absolute configuration: S

(S)-N-Methyl-1-phenyl-2-aminoethanolC9H13NOEe = 97%[α]D25=+39 (c 0.83, EtOH)Absolute configuration: S

(S)-2-(1-Hydroxy-2-N-methylamino-ethyl)-thiazoleC6H10N2OSEe = >98%[α]D25=-19 (c 1.02, methylene chloride)Absolute configuration: S

(R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-thiazoleC6H10N2OSEe = >98%[α]D25=+31 (c 1.02, DMSO)Absolute configuration: R

(R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyrazineC7H11N3OEe = 77%[α]D25=+58 (c 1.02, methanol)Absolute configuration: R

(5R)-3-Methyl-5-(2-pyrazinyl)-2-oxazoldinoneC8H9N3OEe = >96%[α]D25=+20 (c 0.95, methylene chloride)Absolute configuration: R

(R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyrazineC7H11N3OEe = >93%[α]D25=+66 (c 0.95, methanol)Absolute configuration: R