Studies on the synthesis and some reactions of (S)-proline hydrazides

A convenient synthesis of (S)-proline hydrazide 2a via the reaction of ethyl (S)-N-benzylprolinate with hydrazine hydrate and subsequent deprotection of (S)-N-benzyl proline hydrazide 5 is described. The latter, in methanolic solution, reacted with aromatic aldehydes as well as with cycloaliphatic ketones at room temperature to give the corresponding hydrazones of type 7 in good yields. The structure of the product with furan-2-carbaldehyde 7b, proving the (E)-configuration of the hydrazone, was established by X-ray crystallography. In the case of the unprotected (S)-proline hydrazide 2a, the analogous reaction with aromatic aldehydes led either to the expected hydrazones 7 or the 1H-pyrrolo[1,2-c]imidazol-1-one derivatives 8, depending on the reaction conditions. The latter were formed via a secondary cyclocondensation of the initially formed 7 with a second molecule of the aldehyde. Whereas the reaction of (S)-N-benzyl proline hydrazide 5 with butyl isocyanate and isothiocyanate gave the corresponding semicarbazide and thiosemicarbazide, respectively, of type 9, the unprotected (S)-proline hydrazide 2a yielded the 1:2 adducts 10. Thiosemicarbazide 9b underwent cyclization reactions under basic (NaOH) and acidic (H2SO4) conditions to yield (S)-prolinyl-substituted 1,2,4-triazole-3-thione 11 and 1,3,4-thiadiazole-2-amine 12, respectively.

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(2S)-Pyrrolidine-2-carbohydrazideC5H11N3Oee = 100%[α]D25=-38 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-1-Benzylpyrrolidine-2-carbohydrazideC12H17N3Oee = 100%[α]D25=-70 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-1-Benzyl-N-[(E)-(4-methoxyphenyl)methylidene]pyrrolidine-2-carbohydrazideC20H23N3O2ee = 100%[α]D25=+104 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-1-Benzyl-N-[(E)-2-furylmethylidene]pyrrolidine-2-carbohydrazideC17H19N3O2ee = 100%[α]D25=+121 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-1-Benzyl-N-(cyclohexylidene)pyrrolidine-2-carbohydrazideC18H25N3Oee = 100%[α]D25=-102 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-(2-Adamantylidene)-1-benzylpyrrolidine-2-carbohydrazideC22H29N3Oee = 100%[α]D25=-74 (c 1.00, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-[(E)-(4-Methoxyphenyl)methylidene]pyrrolidine-2-carbohydrazideC13H17N3O2ee = 100%[α]D25=-65 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-[(E)-(4-Nitrophenyl)methylidene]pyrrolidine-2-carbohydrazideC12H14N4O3ee = 100%[α]D25=-57 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-[(E)-2-Furylmethylidene]pyrrolidine-2-carbohydrazideC10H13N3O2ee = 100%[α]D25=-80 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-(Cyclohexylidene)pyrrolidine-2-carbohydrazideC11H19N3Oee = 100%[α]D25=-88 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(2S)-N-(2-Adamantylidene)pyrrolidine-2-carbohydrazideC15H23N3Oee = 100%[α]D25=-63(c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

(7aS)-3-(4-Methoxyphenyl)-2-{[(Z)-(4-methoxyphenyl)methyliden]amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-oneC21H23N3O3ee = 100%[α]D25=-75 (c 1.00, CH2Cl2)Source of chirality: (S)-prolineAbsolute configuration: (S)

(7aS)-3-(4-Nitrophenyl)-2-{[(Z)-(4-nitrophenyl)methyliden]amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-oneC19H17N5O5ee = 100%[α]D25=-51(c 1.00, CH2Cl2)Source of chirality: (S)-prolineAbsolute configuration: (S)

(7aS)-3-(Furan-2-yl)-2-{[(Z)-furan-2-ylmethyliden]amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-oneC15H15N3O3ee = 100%[α]D25=-193 (c 0.44, CH2Cl2)Source of chirality: (S)-prolineAbsolute configuration: (S)

1-{[(2S)-1-Benzylpyrrolidine-2-carbonyl]amino}-3-butylureaC17H26N4O2ee = 100%[α]D25=-18 (c 1.00, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (S)

1-{[(2S)-1-Benzylpyrrolidine-2-carbonyl]amino}-3-butylthioureaC17H26N4OSee = 100%[α]D25=-68 (c 1.00, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (S)

1-Butyl-3-{[(2S)-1-(butylcarbamoyl)pyrrolidine-2-carbonyl]amino}ureaC15H29N5O3ee = 100%[α]D25=-11 (c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

1-Butyl-3-{[(2S)-1-(butylthiocarbamoyl)pyrrolidine-2-carbonyl]amino}thioureaC15H29N5OSee = 100%[α]D25=-54(c 1.00, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (S)

5-[(2S)-1-Benzylpyrrolidin-2-yl]-4-butyl-2H-1,2,4-triazole-3-thioneC17H24N4See = 100%[α]D25=-126 (c 1.00, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (S)

5-[(2S)-1-Benzylpyrrolidin-2-yl]-N-butyl-1,3,4-thiadiazol-2-amineC17H24N4See = 100%[α]D25=-92 (c 1.00, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (S)