Online citations, reference lists, and bibliographies.
← Back to Search

A Versatile One-Pot Synthesis Of 1,3-substituted Guanidines From Carbamoyl Isothiocyanates

Linton, Carr, Orner, Hamilton
Published 2000 · Chemistry, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Recent advances have demonstrated the importance of the guanidine group in receptors capable of binding molecular anions.1,2 The need for more complex receptors required a new protocol for creating highly substituted guanidines under mild conditions. Several new methods have been developed that use carbamate protection to reduce the basicity of guanidines, simplifying purification.3-8 While these methods permit the mild guanidinylation of amines to form monosubstituted guanidines, most do not allow the formation of highly functionalized guanidines. Synthesis of multisubstituted guanidines has been accomplished primarily with unprotected isothiouronium salts9 or imino carbonates10 or using protocols requiring treatment with strong base.11-13 We wished to take advantage of the benefits of carbamate-protected guanidines, but with a protocol that allowed the formation of 1,3-multisubstituted guanidines from two separate amines. This procedure, shown in eq 1, exploits several advantages of carbamoyl isothiocyanates 1. These reagents provide a protecting group throughout the synthesis, making purification trivial, without the later inclusion of a protection step. The carbamate increases the reactivity of the isothiocyanate, permitting formation of thiourea 2 even with hindered amines. A second amine can be coupled to the carbamoyl thiourea 2 using EDCI,4 forming 1,3-disubstituted and 1,1,3-trisubstituted guanidines through either stepwise or one-pot synthesis. To gauge the steric and electronic limitations of this procedure, amines of varying reactivity (A-G) were investigated for their ability to form protected thiourea 2 and guanidine 3. The synthetic yields for this series of reactions with ethoxycarbonyl isothiocyanate and amines A-G are shown in Table 1. Formation of thiourea 2 proceeded in near quantitative yields for alkylamines (AD), while aromatic amines (E-G) produced slightly lower yields. Each amine has a dual effect on guanidine synthesis: reactivity of the amine with various thioureas as well as coupling efficiency of the thiourea formed from that amine. Both showed a steric effect as yields decreased with bulkier substituents. Most noticeably, both thioureas formed from secondary amines (2C and 2D) failed to form guanidines in detectable yields. It is unclear if this results from increased steric bulk limiting nucleophile attack or from the removal of a reactive proton. Trisubstituted guanidines can be formed, however, through the coupling of unencumbered thioureas with secondary amines, albeit in lower yields than with primary amines. Aromatic amines were also successful in both aspects of guanidinylation, with both phenylamine and the more sterically hindered 2-methoxyphenylamine producing guanidinium in good yields. The electronic nature of the 4-nitrophenylamine reduces the efficiency of the reaction of this amine to form guanidine as well as the coupling with the corresponding thiourea, producing lower yields in each case. The generality of this procedure for other carbamoyl isothiocyanates allows synthetic flexibility in the final † University of Pittsburgh. ‡ Sterling Chemistry Laboratory. § Phone: (203)432-5570.Fax: (203)432-6144.Email: Andrew.Hamilton@ (1) Linton, B.; Hamilton, A. D. Tetrahedron 1999, 55, 6027-6038. (2) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609-1646. (3) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540-1542. Employing Mukaiyama’s reagent in this protocol was unsuccessful, suggesting the singly protected thioureas are less reactive than the bis-carbamoyl thioureas used in the Lipton study. (4) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933-5936. (5) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett. 1993, 34, 3389-3392. (6) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677-7680. (7) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977980. (8) Robinson, S.; Roskamp, E. J. Tetrahedron 1997, 53, 6697-6705. (9) Rasmussen, C. R.; Villani, F. J.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Powell, E. T.; Molinari, A. J. Synthesis 1988, 460-466. Wilson, L. J.; Klopfenstein, S. R.; Li, M. Tetrahedron Lett. 1999, 40, 3999-4002. (10) Schlama, T.; Gouerneur, V.; Valleix, A.; Greiner, A.; Toupet, L.; Mioskowski, C. J. Org. Chem. 1997, 62, 4200-4202. (11) Knieps, S.; Michel, M. C.; Dove, S.; Buschauer, A. Bioorg. Med. Chem. Lett. 1995, 5, 2065-2070. (12) Corelli, F.; Dei, D.; Monache, G. D.; Botta, B.; DeLuca, C.; Carmignani, M.; Volpe, A. R.; Botta, M. Bioorg. Med. Chem. Lett. 1996, 6, 653-658. (13) Of notable exception is the method of Dodd and Wallace (Dodd, D.; Wallace, O. B. Tetrahedron Lett. 1998, 39, 5701-5704) which permits the solid-phase synthesis of N,N′-disubstituted guanidines. Table 1. Reaction of Ethoxycarbonyl Isothiocyanate with Various Amines To Form Thiourea 2 and Guanidine 3

This paper is referenced by
An expedient one-step synthesis of polysubstituted guanidinoglucosides using HgO-4A molecular sieves as catalyst.
Yong-Hua Liu (2008)
Hydrogen bond controlled aggregation of guanidinium-carboxylate derivatives in the solid state
A. Zafar (2002)
Bismuth nitrate pentahydrate: a new and environmentally benign reagent for guanidylation of N-benzoylthioureas
S. Cunha (2002)
SELEX: a tool to study the sequence specific molecular recognition of single stranded nucleic acids
Joseph C. Manimala (2004)
Aromatic bis-N-hydroxyguanidinium derivatives: synthesis, biophysical, and biochemical evaluations.
Amila Kahvedžić (2013)
A versatile synthesis of 2-amino-4H-pyrido[1,2-a][1,3,5]triazin-4-ones from 2-aminopyridines
M. Kopp (2002)
Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN
U. Koehn (2006)
Solid-phase guanidinylation as a diversification strategy of poly-L-proline type II peptide mimic scaffolds.
A. Mamai (2001)
Molecular modeling study and synthesis of novel dicationic flexible triaryl guanidines and imidamides as antiprotozoal agents.
R. Arafa (2011)
Novel thermally stable poly(thiourea–amide–imide)s bearing CS moieties and pyridine units in the backbone: Synthesis and properties
Ayesha Kausar (2010)
High performance segmented polyurethanes derived from a new aromatic diisocyanate and polyol
Ayesha Kausar (2013)
A mild method for the synthesis of carbamate-protected guanidines using the Burgess reagent.
T. Maki (2014)
Synthesis of the hindered N,N,N′-trisubstituted guanidine moiety of martinelline and martinellic acid
B. Snider (2001)
N'-alkylated guanidiniocarbonyl pyrroles: new receptors for amino acid recognition in water.
C. Schmuck (2003)
Synthesis and characterization of novel thermally stable aromatic and semiaromatic polyamides derived from thiourea-based flexible diacid dichlorides
Ayesha Kausar (2011)
A structural study of N,N′-bis-aryl-N′′-acylguanidines
D. O'donovan (2013)
Dimeric self-assembly of pyridyl guanidinium carboxylates in polar solvents.
Muhammad Irfan Ashiq (2010)
Venkatesan Jayakumar (2012)
Synthesis, Characterisation and Crystal Structure of a Novel Pyridyl Urea Macrocycle
S. Perveen (2016)
Peptide heterocycle conjugates: a diverted edman degradation protocol for the synthesis of N-terminal 2-iminohydantoins.
G. Evindar (2003)
Combinatorial approaches towards the discovery of new tryptase inhibitors.
M. del Fresno (2005)
Efficient Room‐Temperature One‐Pot Synthesis of 2‐Amino‐3‐alkyl(3‐aryl)quinazolin‐4(3H)‐ones
Cédric Lecoutey (2011)
A general synthetic method for the formation of substituted 5-aminotetrazoles from thioureas: a strategy for diversity amplification.
R. Batey (2000)
A convenient solution-phase method for the preparation of meta-iodobenzylguanidine in high effective specific activity.
Amanda C. Donovan (2008)
Studies on novel thermally stable segmented polyurethanes based on thiourea-derivative diols
Ayesha Kausar (2010)
Synthesis and thermal behavior of novel poly(thiourea-amide)s derived from 1-(4-aminobenzoyl)-3- (3-aminophenyl) thiourea
Ayesha Kausar (2011)
A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas
A. Saeed (2014)
Efficient introduction of protected guanidines in boc solid phase peptide synthesis.
Y. Zhang (2001)
Solid phase synthesis of mono- or disubstituted arginine containing peptides from an isothiocitrulline precursor
A. Hamze (2005)
Aaron J Haubner (2008)
Guanidines from 'toxic substances' to compounds with multiple biological applications--detailed outlook on synthetic procedures employed for the synthesis of guanidines.
S. Tahir (2015)
Synthesis of 1,3-{Di-[N-bis(dimethylamino)methane]}- benzyl-diamide and its Molecular Recognition of Nucleotides in Aqueous Solution
Haoxiang Gao (2003)
See more
Semantic Scholar Logo Some data provided by SemanticScholar