Synthesis of chiral, non-racemic ferrocene derivatives by ortho-metallation and partial reductive removal of ortho-directing amino groups

Chiral, non-racemic 1,2-disubstituted ferrocenes have been prepared from monosubstituted ferrocene derivatives by amine-mediated ortho-directed reactions and subsequent partial reductive removal of the stereogenic ortho-directing group. It was found that the ortho-directing amino group of 2-substituted derivatives of N,N-dimethylaminoethyl-ferrocene and similar compounds can, after quaternisation with methyl iodide, be reductively removed with sodium borohydride to give 2-substituted methyl- or ethylferrocenes. In most cases the substituents I, Br, COOEt, P(O)Ph2 and CN tolerate the reaction conditions used. In addition, a few examples are reported that show how the use of LiTMP allows 2-bromo- and especially 2-cyano-substituted derivatives to be further ortho-lithiated and reacted to give 1,2,3-trisubstituted ferrocenes.

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(R,Sp)-N-1-(2-Cyano-ferrocenyleth-1-yl)-N,N-dimethylamineC15H18FeN2Ee >99%[α]D20=-33.9 (c 0.280, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (R,Sp)

(Sp)-2-Ethyl-1-iodo-ferroceneC12H13FeIEe >99%[α]D20=-5.2 (c 0.484, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)

(Sp)-1-Bromo-2-ethyl-ferroceneC12H13BrFeEe >99%[α]D20=-2.5 (c 0.485, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)

(Sp)-1-Ethoxycarbonyl-2-ethyl-ferroceneC15H18FeO2Ee >99%[α]D20=-15.5 (c 0.252, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)

(Sp)-1-Diphenylphosphinyl-2-ethyl-ferroceneC24H23FeOP2Ee >99%[α]D20=-115.7 (c 0.281, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)

(Sp)-1-Cyano-2-ethyl-ferroceneC13H13FeNEe >99%[α]D20=+24.3 (c 0.485, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)

(1R,2S,Rp)-N-(2-Ethoxycarbonyl-ferrocenylmethyl)-N-methyl-1-methoxy-1-phenylprop-2-ylamineC25H31FeNO3Ee >99%[α]D20=-22.9 (c 0.808, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1R,2S,Rp)

(1R,2S,Rp)-N-(2-Diphenylphosphinyl-ferrocenylmethyl)-N-methyl-1-methoxy-1-phenylprop-2-ylamineC34H36FeNO2PEe >99%[α]D20=+45.0 (c 1.230, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1R,2S,Rp)

(1R,2S,Rp)-N-(2-Cyano-ferrocenylmethyl)-N-methyl-1-methoxy-1-phenylprop-2-ylamineC23H26FeN2OEe >99%[α]D20=-32.6 (c 0.298, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1R,2S,Rp)

(R,Rp)-N-(2-Cyano-ferrocenylmethyl)-2-methoxymethyl-pyrrolidineC18H22FeN2OEe >99%[α]D20=+79.6 (c 0.690, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (R,Rp)

(Rp)-1-Iodo-2-methyl-ferroceneC11H11FeIEe >99%[α]D20=+29.9 (c 0.708, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Rp)

(Rp)-1-Bromo-2-methyl-ferroceneC11H11BrFeEe >99%[α]D20=+26.6 (c 0.957, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Rp)

(Rp)-1-Ethoxycarbonyl-2-methyl-ferroceneC14H16FeO2Ee >99%[α]D20=+22.1 (c 0.521, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Rp)

(Rp)-1-Diphenylphosphinyl-2-methyl-ferroceneC23H21FeOPEe >99%[α]D20=+118.9 (c 0.996, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Rp)

(Sp)-1-Bromo-2-hydroxycarbonyl-5-methyl-ferroceneC12H11BrFeO2Ee >99%[α]D20=+9.8 (c 0.654, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (Sp)