Additive controlled, stereoselective benzylation of 2-thioxotetrahydropyrimidin-4(1H)-ones via chiral induction from a remote stereocenter

Stereoselective alkylation reactions of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-one derivatives were studied. The reaction conditions were optimized to obtain the monobenzylated adduct with improved diastereoselectivity by regulating the reaction kinetics using HMPA as the additive and chiral ethyl lactate as the quencher. The absolute configuration of the product was established by NMR experiments, computational calculations, and single crystal X-ray analysis.

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(R)-3-(4-Chlorophenyl)-1-(1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC18H17ClN2OS[α]D20=+240.6 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R)

(R)-3-(3-Chloro-4-fluorophenyl)-1-(1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC18H16ClFN2OS[α]D20=+232.5 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R)

(R)-3-(3-Chloro-4-cyanophenyl)-1-(1-phenylethyl)-2-thioxo tetrahydropyrimidin-4(1H)-oneC19H16ClN3OS[α]D20=+259.7 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R)

(R)-3-(4-Chloro-3-(trifluoromethyl) phenyl)-1-(1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC19H16ClF3N2OS[α]D20=+234.6 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R)

(R)-3-(4-Cyano-3-(trifluoromethyl) phenyl)-1-(1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC20H16F3N3OS[α]D20=+240.05 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R)

(R)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC25H22Cl2N2OS[α]D20=+266.75 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5R)

(S)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC25H22Cl2N2OS[α]D20=+266.55 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5S)

(R)-3-(3-Chloro-4-flurophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC25H21Cl2FN2OS[α]D20=+424.6 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5R)

(S)-3-(3-Chloro-4-flurophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC25H21Cl2FN2OS[α]D20=+224.2 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5S)

(R)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC26H21Cl2N3OS[α]D20=+130.4 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5R)

(S)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC26H21Cl2N3OS[α]D20=+139.4 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5S)

(R)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC26H21Cl2F3N2OS[α]D20=+228.6 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5R)

(S)-3-(4-Chloro-3-(trifluormethyl)phenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC26H21Cl2F3N2OS[α]D20=+439.5 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5S)

(R)-3-(4-Cyano-3-(trifluormethyl)phenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC27H21ClF3N3OS[α]D20=+140.4 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5R)

(S)-3-(4-Cyano-3-(trifluormethyl)phenyl)-5-(4-chlorobenzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-oneC27H21ClF3N3OS[α]D20=+107.4 (c 1.0, CHCl3)Source of chirality; (R)-α-methyl benzylamineAbsolute configuration: (1R,5S)