Amino Acids

, Volume 51, Issue 2, pp 263–272 | Cite as

Ensembling three multicomponent reactions for the synthesis of a novel category of pseudo-peptides containing dithiocarbamate and N,X-heterocylic groups

  • Maryam Khalesi
  • Azim Ziyaei HalimehjaniEmail author
  • Max Franz
  • Marc Schmidtmann
  • Jürgen MartensEmail author
Original Article


Consecutive multicomponent reactions have been applied for the synthesis of novel pseudo-peptides bearing dithiocarbamate and N,X-heterocyclic groups (X = S, O) in only one structure. The first multicomponent reaction includes the synthesis of dithiocarbamates using an amine or amino acid, CS2 and an electrophile. The second MCR is synthesis of Asinger imines using 2-chloroisobutyraldehyde, NaXH (X = S, O), ketone and ammonia. The final MCR is Ugi reaction to afford the corresponding three-dimensional pseudo-peptides. Various Asinger imines, carboxylic acids and isocyanides were applied in this protocol to provide diversities of pseudo-peptides in high to excellent yields.


Consecutive multicomponent reaction Pseudo-peptide Dithiocarbamate Asinger imine Ugi reaction 



We are grateful to the Iran National Science Foundation: INSF, Grant number 95829698, for supporting this work. We also thank the research council of Kharazmi University (Grant number D/2056) for supporting this work. We are thankful to the central analytic section of the University of Oldenburg for retrieving NMR and MS data.

Author contributions

Conceived and designed the experiments: AZH; JM. Performed the experiments and analyzed the data: MK; MF. X-ray data: MS. Wrote the paper: AZH; JM; MK; MF.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical standard

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

726_2018_2661_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1801 kb)
726_2018_2661_MOESM2_ESM.pdf (5.3 mb)
Supplementary material 2 (PDF 5421 kb)
726_2018_2661_MOESM3_ESM.pdf (708 kb)
Supplementary material 3 (PDF 708 kb)
726_2018_2661_MOESM4_ESM.pdf (2.3 mb)
Supplementary material 4 (PDF 2317 kb)
726_2018_2661_MOESM5_ESM.docx (559 kb)
Supplementary material 5 (DOCX 559 kb)


  1. Aboul-Fadl T, El-Shorbagi A (1996) New prodrug approach for amino acids and amino-acid-like drugs. Eur J Med Chem 31:165–169CrossRefGoogle Scholar
  2. Asinger F, Offermans H (1967) Syntheses with ketones, sulfur, and ammonia or amines at room temperature. Angew Chem Int Ed Engl 6:907–919CrossRefGoogle Scholar
  3. Asinger F, Schäfer W, Halcour K, Saus A, Triem H (1964) The course of the Willgerodt-Kindler reaction of alkyl aryl ketones. Angew Chem 68:377Google Scholar
  4. Bacharaju K, Jambula SR, Sivan S, Tangeda SJ, Manga V (2012) Design, synthesis, molecular docking and biological evaluation of new dithiocarbamates substituted benzimidazole and chalcones as possible chemotherapeutic agents. Bioorg Med Chem Lett 22:3274–3277CrossRefPubMedGoogle Scholar
  5. Bathfield M, D’Agosto F, Spitz R, Charreyre MT, Delair T (2006) Versatile precursors of functional RAFT agents. Application to the synthesis of bio-related end-functionalized polymers. J Am Chem Soc 128:2546–2547CrossRefPubMedGoogle Scholar
  6. Berry DJ, de Rosales RTM, Charoenphun P, Blower PJ (2012) Dithiocarbamate complexes as radiopharmaceuticals for medical imaging. Mini-Rev Med Chem 12:1174–1183CrossRefPubMedPubMedCentralGoogle Scholar
  7. Brauch S, van Berkel SS, Westermann B (2013) Higher-order multicomponent reactions: beyond four reactants. Chem Soc Rev 42:4948–4962CrossRefPubMedGoogle Scholar
  8. Cao SL, Feng YP, Jiang YY, Liu SY, Ding GY, Li RT (2005) Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains. Bioorg Med Chem Lett 15:1915–1917CrossRefPubMedGoogle Scholar
  9. Cao SL, Feng YP, Zheng XL, Jiang YY, Zhang M, Wang Y, Xu M (2006) Synthesis of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone and their cytotoxic activity. Arch Pharm 339:250–254CrossRefGoogle Scholar
  10. Cascio G, Lorenzi L, Caglio D, Manghisi E, Arcamone F, Guanti G, Satta G, Morandotti G, Sperning R (1996) Synthesis and antibacterial activity of C-4 thio- and dithiocarbamate monobactam derivatives. Farmaco 51:189–196PubMedGoogle Scholar
  11. Csomos P, Zupko I, Rethy B, Fodor L, Falkay G, Bernath G (2006) Isobrassinin and its analogues: novel types of antiproliferative agents. Bioorg Med Chem Lett 16:6273–6276CrossRefPubMedGoogle Scholar
  12. Das P, Kumar CK, Kumar KN, Innus MD, Iqbal J, Srinivas N (2008) Dithiocarbamate and CuO promoted one-pot synthesis of 2-(N-substituted)-aminobenzimidazoles and related heterocycles. Tetrahedron Lett 49:992–995CrossRefGoogle Scholar
  13. Domling AA (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89CrossRefPubMedGoogle Scholar
  14. Estevez V, Villacampa M, Menendez JC (2014) Recent advances in the synthesis of pyrroles by multicomponent reactions. Chem Soc Rev 43:4633–4657CrossRefPubMedGoogle Scholar
  15. Franz M, Stalling T, Schaper R, Schmidtmann M, Martens J (2017) Facile access to amido (thio-)xanthates under eco-friendly conditions by one-pot three-component reaction (3-CR). Synthesis 49:4045–4054CrossRefGoogle Scholar
  16. Guillaneuf Y, Couturier JL, Gigmes D, Marque SRA, Tordo P, Bertin D (2008) Synthesis of highly labile SG1-based alkoxyamines under photochemical conditions. J Org Chem 73:4728–4731CrossRefPubMedGoogle Scholar
  17. Herrera RP, Marques-Lopez E (2015) Multicomponent reactions: concepts and applications for design and synthesis. John Wiley & Sons, WeinheimGoogle Scholar
  18. Hou XL, Ge ZM, Wang TM, Guo W, Cui JR, Cheng TM, Lai CS, Li RT (2006) Dithiocarbamic acid esters as anticancer agent. Part 1: 4-Substituted-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl esters. Bioorg Med Chem Lett 16:4214–4219CrossRefPubMedGoogle Scholar
  19. Huang W, Ding Y, Miao Y, Liu MZ, Li Y, Yang GF (2009) Synthesis and antitumor activity of novel dithiocarbamate substituted chromones. Eur J Med Chem 44:3687–3696CrossRefPubMedGoogle Scholar
  20. Imamura H, Ohtake N, Jona H, Shimizu A, Moriya M, Sato H, Sugimoto Y, Ikeura C, Kiyonaga H, Nakano M, Hagano R, Abe S, Yamada K, Hashizume T, Morishima H (2001) Dicationic dithiocarbamate carbapenems with anti-MRSA activity. Bioorg Med Chem 9:1571–1574CrossRefPubMedGoogle Scholar
  21. Jiao J, Wei L, Ji XM, Hu ML, Tang RY (2016) Direct introduction of dithiocarbamates onto imidazoheterocycles under mild conditions. Adv Synth Catal 358:268–275CrossRefGoogle Scholar
  22. Keating TA, Armstrong RW (1995) Molecular diversity via a convertible isocyanide in the Ugi four-component condensation. J Am Chem Soc 117:7842–7843CrossRefGoogle Scholar
  23. Kröger D, Franz M, Schmidtmann M, Martens J (2015a) Sequential multicomponent reactions and a cu-mediated rearrangement: diastereoselective synthesis of tricyclic ketones. Org Lett 17:5866–5869CrossRefPubMedGoogle Scholar
  24. Kröger D, Schlüter T, Fischer G, Geibel I, Martens J (2015b) Three-component reaction toward polyannulated quinazolinones, benzoxazinones and benzothiazinones. ACS Comb Sci 17:202–207CrossRefPubMedGoogle Scholar
  25. Lai JT, Shea R (2006) Controlled radical polymerization by carboxyl- and hydroxyl-terminated dithiocarbamates and xanthates. J Polym Sci Part A Polym Chem 44:4298–4316CrossRefGoogle Scholar
  26. Macias B, Villa MV, Chicote E, Martin-Velasco S, Castineiras A, Borras J (2002) Copper complexes with dithiocarbamates derived from natural occurring amino acids. Crystal and molecular structure of [Cu(en)(EtOH)(H2O)3][Cu(dtc-pro)2]. Polyhedron 21:1899–1904CrossRefGoogle Scholar
  27. Maddani M, Prabhu KR (2007) A convenient method for the synthesis of substituted thioureas. Tetrahedron Lett 48:7151–7154CrossRefGoogle Scholar
  28. Malik AK, Rao ALJ (2000) Spectrophotometric determination of ferbam [Iron(III) dimethyl dithiocarbamate] in commercial sample and wheat grains after extraction of its bathophenanthroline tetraphenylborate complex into molten naphthalene. J Agric Food Chem 48:4044–4047CrossRefPubMedGoogle Scholar
  29. Marinovich M, Viviani B, Capra V, Corsini E, Anselmi L, D’Agostino G, Nucci AD, Binaglia M, Tonini M, Galli CL (2002) Facilitation of acetylcholine signaling by the dithiocarbamate fungicide propineb. Chem Res Toxicol 15:26–32CrossRefPubMedGoogle Scholar
  30. Martens J, Offermanns H, Scherberich P (1981) Eine einfache Synthese von racemischem Cystein. Angew Chem 93:680–683. Angew Chem Int Ed Engl 20:668CrossRefGoogle Scholar
  31. McMaster C, Bream RN, Grainger RS (2012) Radical-mediated reduction of the dithiocarbamate group under tin-free conditions. Org Biomol Chem 10:4752–4758CrossRefPubMedGoogle Scholar
  32. Nielsen PE (2004) Pseudo-peptides in drug discovery. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  33. Rotstein BH, Zaretsky S, Rai V, Yudin VAK (2014) Small heterocycles in multicomponent reactions. Chem Rev 114:8323–8359CrossRefPubMedGoogle Scholar
  34. Schlüter T, Ziyaei Halimehjani A, Wachtendorf D, Schmidtmann M, Martens J (2016) A four-component reaction for the synthesis of dithiocarbamates starting from cyclic imines. ACS Comb Sci 18:456–460CrossRefPubMedGoogle Scholar
  35. Scozzafava A, Mastorlorenzo A, Supuran CT (2000) Arylsulfonyl-N, N-diethyl-dithiocarbamates: a novel class of antitumor agents. Bioorg Med Chem Lett 10:1887–1891CrossRefPubMedGoogle Scholar
  36. Stalling T, Martens J (2013) Synthesis of tricyclic lactams from heterocyclic imines. Synthesis 45:355–364Google Scholar
  37. Stalling T, Saak W, Martens J (2013) Synthesis of bicyclic thiazolidinethiones and oxazolidinones by water-mediated multicomponent reactions (MCR) and ring-closing metathesis (RCM). Eur J Org Chem 35:8022–8032CrossRefGoogle Scholar
  38. Tietze LF (1996) Domino reactions in organic synthesis. Chem Rev 96:115–136CrossRefPubMedGoogle Scholar
  39. Trost BM (1991) The atom economy—a search for synthetic efficiency. Science 254:1471–1477CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ugi I (1962) The α-addition of immonium ions and anions to isonitriles accompanied by secondary reactions. Angew Chem Int Ed 4:8–21CrossRefGoogle Scholar
  41. Ugi I, Meyr R, Fetzer U, Steinbrückner C (1959) Versuche mit isonitrilen. Angew Chem 71:386Google Scholar
  42. Ugi I, Werner B, Dömling A (2003) The chemistry of isocyanides, their multicomponent reactions and their libraries. Molecules 8:53–66CrossRefPubMedCentralGoogle Scholar
  43. Weber M, Jakob J, Martens J (1992) Synthese und Reaktivität von 3-Oxazolinen. Liebigs Ann Chem 1992:1–6CrossRefGoogle Scholar
  44. Wong R, Dolman SJ (2007) Isothiocyanates from tosyl chloride mediated decomposition of in situ generated dithiocarbamic acid salts. J Org Chem 72:3969–3971CrossRefPubMedGoogle Scholar
  45. Zhu J, Wang Q, Wang MX (2015) Multicomponent reactions in organic synthesis. Wiley-VCH, WeinheimGoogle Scholar
  46. Ziyaei Halimehjani A, Airamlounezhad S (2014) ZrCl4/TMSCl as an efficient catalyst for synthesis of 4,6-substituted 2-alkylthio-6 H -1,3-thiazines. J Heterocycl Chem 51:1147–1150CrossRefGoogle Scholar
  47. Ziyaei Halimehjani A, Hosseinkhany S (2015) One-pot three-component route for the synthesis of rhodanine derivatives in water. Synthesis 47:3147–3152CrossRefGoogle Scholar
  48. Ziyaei Halimehjani A, Lotfi Nosood Y (2017) Investigation of the reaction of dithiocarbamic acid salts with aromatic aldehydes. Org Lett 19:6748–6751CrossRefPubMedGoogle Scholar
  49. Ziyaei Halimehjani A, Maleki H, Saidi MR (2009) Regiospecific iodocyclization of S-allyl dithiocarbamates: synthesis of 2-imino-1,3-dithiolane and 2-iminium-1,3-dithiolane derivatives. Tetrahedron Lett 50:2747–2750 (And references therein) CrossRefGoogle Scholar
  50. Ziyaei Halimehjani A, Marjani K, Ashouri A, Amani V (2011) Synthesis and characterization of transition metal dithiocarbamate derivatives of 1-aminoadamantane: crystal structure of (N-adamantyldithiocarbamato)nickel(II). Inorg Chim Acta 373:282–285CrossRefGoogle Scholar
  51. Ziyaei Halimehjani A, Ranjbari MA, Zanussi HP (2013) Synthesis of a new series of dithiocarbamate-linked peptidomimetics and their application in Ugi reactions. RSC Adv 3:22904–22908CrossRefGoogle Scholar
  52. Ziyaei Halimehjani A, Hasani L, Alaei MA, Saidi MR (2016) Dithiocarbamates as an efficient intermediate for the synthesis of 2-(alkylsulfanyl)thiazoles in water. Tetrahedron Lett 57:883–886 (And references therein) CrossRefGoogle Scholar
  53. Zou Y, Yu SC, Li RW, Zhao QJ, Li X, Wu MC, Huang T, Chai XX, Hu HG, Wu QY (2014) Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates. Eur J Med Chem 74:366–374CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Organic Chemistry, Faculty of ChemistryKharazmi UniversityTehranIran
  2. 2.Institut für Chemie (IfC), Carl von Ossietzky Universität OldenburgOldenburgGermany

Personalised recommendations