Guanylation of Amines by Bis(tert-butoxycarbonyl)thiopseudourea, Polymer-Bound

Chemfiles Volume 5 Article 11

The synthesis of guanidine-containing bioactive molecules is of great interest in medicinal chemistry. The guanidine moiety is fully protonated under physiological conditions due to its strong basicity.1 Introduction of a guanidinyl group can be achieved by the reaction of substituted amines with various guanylation reagents.2,3,4 One such guanylating reagent is bis(tert-butoxycarbonyl)thiopseudourea, polymer-bound.

Typical Experimental Procedure

Synthesis of N,N Disubstituted- N’,N’’-bis(tert-butoxycarbonyl) Guanidine

The amine (1 mmol) and bis(tert-butoxycarbonyl)thiopseudourea, polymer-bound (5 mmol) are mixed in THF (5 mL) and stirred for 40 h at room temperature. The mixture is filtered and the resin washed with THF (2 × 3 mL). The combined washings are evaporated to dryness to give a pure monosubstituted guanidine. The structures are confirmed by 1H NMR and mass spectrometry.

N,N Disubstituted-N’,N’’-bis(tert-butoxycarbonyl) Guanidine

Amine	Yield
propylamine	100%
piperidine	100%

Synthesis of N,N’ Disubstituted-N’,N’’-bis(tert-butoxycarbonyl) Guanidine

Polymer-bound bis(tert-butoxycarbonyl)thiopseudourea (200 mg, 0.2 mmol) and triphenylphosphine (313 mg, 1.2 mmol) were added to a fritted reaction vessel. A solution of benzyl alcohol (108 mg, 1.0 mmol) in THF (3 mL) was added. The mixture was stirred for 20 min, followed by dropwise addition of diisopropyl azodicarboxylate (0.196 mL, 1.0 mmol). The resulting mixture was stirred overnight at room temperature. The reaction solution was drained and the resin washed with several portions of THF and methanol.

Ammonia (2 mmol) or amine (0.6 mmol) in THF (2.5 mL) was added to the reaction vessel. The mixture was agitated overnight at room temperature. The reaction mixture was filtered and the solution collected. The resin was washed with several portions of THF and methanol. The combined reaction solution and washings were evaporated to dryness. The residue was purified by flash chromatography (silica gel, column size: 1.5 × 20 cm). The structures of the isolated products were confirmed by 1H NMR and mass spectrometry. The BOC group can be removed using standard deprotection methods to yield the desired unprotected substituted guanidine.

N,N’ Disubstituted-N’,N’’-bis(tert-butoxycarbonyl) Guanidine

Alcohol	Amine	Yield
benzyl alcohol	ammonia	81%
benzyl alcohol	propylamine	93%
benzyl alcohol	phenethylamine	89%

References

1. Feichtinger K, Sings HL, Baker TJ, Matthews K, Goodman M. 1998. Triurethane-Protected Guanidines and Triflyldiurethane-Protected Guanidines:  New Reagents for Guanidinylation Reactions. J. Org. Chem.. 63(23):8432-8439. https://doi.org/10.1021/jo9814344

2. Dodd DS, Wallace OB. 1998. Solid-phase synthesis of N,N? substituted guanidines. Tetrahedron Letters. 39(32):5701-5704. https://doi.org/10.1016/s0040-4039(98)01197-6

3. Acton JJ, Jones A. 1996. Synthesis and derivatization of a versatile ?-substituted lactam dipeptide isostere. Tetrahedron Letters. 37(25):4319-4322. https://doi.org/10.1016/0040-4039(96)00835-0

4. Dodd DS, Kozikowski AP. 1994. Conversion of Alcohols to Protected Guanidines Using the Mitsunobu Protocol. Tetrahedron Letters. 35(7):977-980. https://doi.org/10.1016/s0040-4039(00)79943-6