Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.

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(S)-2-(Pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonitrileC10H17N3[α]Drt=-50.2 (c 2.95, CHCl3)Source of chirality: (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidineAbsolute configuration: 2S

(S)-2-(Morpholin-4-ylmethyl)-pyrrolidine-1-carbonitrileC10H17N3O[α]Drt=-40.5 (c 2.37, CHCl3)Source of chirality: 4-(pyrrolidin-(S)-2-ylmethyl)morpholineAbsolute configuration: 2S

(S)-2-(Piperidin-1-ylmethyl)-pyrrolidine-1-carbonitrileC11H19N3[α]Drt=-50.8 (c 2.71, CH2Cl2)Source of chirality: 1-(pyrrolidin-(S)-2-ylmethyl)piperidineAbsolute configuration: 2S

C-Pyrrolidin-1-yl-C-(2-(pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl)-methylenamineC14H26N4[α]Drt=-22.2 (c 2.47, CH2Cl2)Source of chirality: (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidineAbsolute configuration: 2S

C-(2-(Morpholin-4-ylmethyl)-pyrrolidin-1-yl)-C-pyrrolidin-1-yl-methylenamineC14H26N4O[α]Drt=-18.9 (c 3.49, CH2Cl2)Source of chirality: 4-(pyrrolidin-(S)-2-ylmethyl)morpholineAbsolute configuration: 2S

C-(2-(Piperidin-1-ylmethyl)-pyrrolidin-1-yl)-C-pyrrolidin-1-yl-methylenamineC15H28N4[α]Drt=-21.5 (c 3.08, CH2Cl2)Source of chirality: 1-(pyrrolidin-(S)-2-ylmethyl)piperidineAbsolute configuration: 2S

C-Morpholin-4-yl-C-(2-(pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl)-methylenamineC14H26N4O[α]Drt=+27.7 (c 2.60, CH2Cl2)Source of chirality: (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidineAbsolute configuration: 2S

C-Morpholin-4-yl-C-(2-(morpholin-4-ylmethyl)-pyrrolidin-1-yl)-methylenamineC14H26N4O2[α]Drt=+26.2 (c 2.60, CH2Cl2)Source of chirality: 4-(pyrrolidin-(S)-2-ylmethyl)morpholineAbsolute configuration: 2S

C-Morpholin-4-yl-C-(2-(piperidin-1-ylmethyl)-pyrrolidin-1-yl)-methylenamineC15H28N4O[α]Drt=+23.1 (c 2.60, CH2Cl2)Source of chirality: 1-(pyrrolidin-(S)-2-ylmethyl)piperidineAbsolute configuration: 2S

C-Piperidin-1-yl-C-(2-(pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl)-methylenamineC15H28N4[α]Drt=+54.2 (c 2.40, CH2Cl2)Source of chirality: (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidineAbsolute configuration: 2S

C-(2-(Morpholin-4-ylmethyl)-pyrrolidin-1-yl)-C-piperidin-1-yl-methylenamineC15H28N4O[α]Drt=+51.7 (c 2.32, CH2Cl2)Source of chirality: 4-(pyrrolidin-(S)-2-ylmethyl)morpholineAbsolute configuration: 2S

C-Piperidin-1-yl-C-(2-(piperidin-1-ylmethyl)-pyrrolidin-1-yl)-methylenamineC16H30N4[α]Drt=+34.3 (c 3.45, CH2Cl2)Source of chirality: 1-(pyrrolidin-(S)-2-ylmethyl)piperidineAbsolute configuration: 2S

C-[Bis-(2-(pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl)]-methylenamineC19H35N5[α]Drt=-40.8 (c 3.19, CH2Cl2)Source of chirality: (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidineAbsolute configuration: 2S

C-[Bis-(2-(morpholin-4-ylmethyl)-pyrrolidin-1-yl)]-methylenamineC19H35N5O[α]Drt=-49.3 (c 2.23, CH2Cl2)Source of chirality: 4-(pyrrolidin-(S)-2-ylmethyl)morpholineAbsolute configuration: 2S

C-[Bis-(2-(piperidin-1-ylmethyl)-pyrrolidin-1-yl)]-methylenamineC21H39N5[α]Drt=-40.4 (c 3.66, CH2Cl2)Source of chirality: 1-(pyrrolidin-(S)-2-ylmethyl)piperidineAbsolute configuration: 2S