Download PDF
CC BY 4.0 · Synthesis 2023; 55(06): 977-988
DOI: 10.1055/s-0042-1751382
paper

The Synthesis of Novel 7-(Substituted benzyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones via Tandem Ugi–Huisgen Reactions

Nazariy T. Pokhodylo  ∗
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya, 6, Lviv, 79005, Ukraine
,
Mykola A. Тupychak
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya, 6, Lviv, 79005, Ukraine
,
Evgeny A. Goreshnik
b   Department of Inorganic Chemistry and Technology, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
,
Mykola D. Obushak
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya, 6, Lviv, 79005, Ukraine
› Author AffiliationsThe authors are grateful to the Ministry of Education and Science of Ukraine for financial support of this project (Grant No. 0121U107777).
› Further Information
   Permissions and Reprints All articles of this category


Abstract

A convenient method for the synthesis of 2-azido-3-arylpropanoic acids via the Meerwein halogenoarylation reaction of acrylic acid esters with diazonium salts, subsequent nucleophilic substitution of the halogen by an azide, and saponification is developed. The newly formed 2-azido-3-arylpropanoic acids react under the conditions of non-catalytic four-component Ugi reactions, leading to the formation of α-azidoamides in good yields. The use of propargylamine as the amine component allows the formation of Ugi adducts with azide and acetylene motifs ready for intramolecular 1,3-dipolar Huisgen cycloaddition to give the [1,2,3]triazolo[1,5-a]pyrazine annulated system. The Ugi reaction is found to give 2-azido-3-aryl-N-(2-oxo-1,2-disubstituted ethyl)-N-(prop-2-yn-1-yl)propanamides at room temperature without azide–alkyne cycloaddition. These dipeptides are converted into 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones in near quantitative yields by heating in toluene. However, when the Ugi reaction is carried out by heating, it results in a one-pot Ugi–Huisgen tandem reaction leading to 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones in excellent yields. Moreover, the possibility of the incorporation of a bromovinyl fragment (the synthetic equivalent of an acetylene fragment) via the aldehyde component of the Ugi reaction is demonstrated in an alternative preparation of the [1,2,3]triazolo[1,5-a]pyrazine system.

Key words

azides - 1,2,3-triazoles - [1,2,3]triazolo[1,5-a]pyrazines - Ugi reaction - Huisgen cycloaddition - one-pot - Meerwein reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751382.
  • Supporting Information


Publication History

Received: 02 September 2022

Accepted after revision: 27 September 2022

Article published online:
09 November 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

    • 1a Pokhodylo N, Shyyka O, Matiychuk V. Sci. Pharm. 2013; 81: 663
      CrossrefPubMed
    • 1b Pokhodylo N, Shyyka O, Matiychuk V. Med. Chem. Res. 2014; 23: 2426
      Crossref
    • 1c Pokhodylo N, Manko N, Finiuk N, Klyuchivska O, Matiychuk V, Obushak M, Stoika R. J. Mol. Struct. 2021; 1246: 131146
      Crossref
    • 2a Shyyka OY, Pokhodylo NT, Finiuk NS. Biopolym. Cell 2019; 35: 321
      Crossref
    • 2b Pokhodylo N, Shyyka O, Finiuk N, Stoika R. Ukr. Biochem. J. 2020; 92: 23
      Crossref
  • 3 Tupychak M. А, Obushak MD. Chem. Heterocycl. Compd. 2021; 57: 1164
    CrossrefPubMed
  • 4 Cuevas-Cordobes F, Pericas-Brondo MA. EP Patent 2963041, 2016
    PubMed
  • 5 Oehlrich D, Peschiulli A, Tresadern G, Van Gool M, Vega JA, De Lucas AI, Alonso de Diego SA, Prokopcova H, Austin N, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Rombouts FJ. R, Macdonald G, Moechars D, Gijsen HJ. M, Trabanco AA. ACS Med. Chem. Lett. 2019; 10: 1159
    CrossrefPubMed
  • 6 Cumming JN, Dykstra KD, Hruza A, Li D, Liu H, Tang H, Taoka BM, Verras A, Walsh SP, Wu WL. WO Patent 2018034918, 2018
    PubMed
  • 7 Li X, He W, Chen Y, He F, Tao W. WO Patent 2019020070, 2019
    PubMed
  • 8 Han X, Lin X, Shen H, Hu T, Zhang Z. WO Patent 2018011163, 2018
    PubMed
  • 9 Nekkanti S, Pooladanda V, Veldandi M, Tokala R, Godugu C, Shankaraiah N. ChemistrySelect 2017; 2: 7210
    Crossref
  • 10 Akritopoulou-Zanze I, Gracias V, Djuric SW. Tetrahedron Lett. 2004; 45: 8439
    Crossref
  • 11 Asgari MS, Sepehri S, Bahadorikhalili S, Ranjbar PR, Rahimi R, Gholami A, Kazemi A, Khoshneviszadeh M, Larijani B, Mahdavi M. Chem. Heterocycl. Compd. 2020; 56: 488
    CrossrefPubMed
    • 12a Angelo NG, Arora PS. J. Am. Chem. Soc. 2005; 127: 17134
    • 12b Paul A, Bittermann H, Gmeiner P. Tetrahedron 2006; 62: 8919
      Crossref
  • 13 Kolb HC, Walsh JC, Kasi D, Mocharla V, Wang B, Gangadharmath UB, Duclos BA, Chen K, Zhang W, Chen G, Padgett HC, Karimi F, Scott PJ. H, Gao Z, Liang Q, Collier TL, Zhao T, Xia C. WO Patent 2008124703, 2008
    PubMed
  • 14 Geurink PP, Liu N, Spaans MP, Downey SL, van den Nieuwendijk AM. C. H, van der Marel GA, Kisselev AF, Florea BI, Overkleeft HS. J. Med. Chem. 2010; 53: 2319
    CrossrefPubMed
  • 15 Ingham OJ, Paranal RM, Smith WB, Escobar RA, Yueh H, Snyder T, Porco JA, Bradner JE, Beeler AB. ACS Med. Chem. Lett. 2016; 7: 929
    CrossrefPubMed
  • 16 Casimiro-Garcia A, Bigge CF, Davis JA, Padalino T, Pulaski J, Ohren JF, McConnell P, Kane CD, Royer LJ, Stevens KA, Auerbach B, Collard W, McGregor C, Song K. Bioorg. Med. Chem. 2009; 17: 7113
    CrossrefPubMed
  • 17 Lundquist JT. IV, Pelletier JC. Org. Lett. 2001; 3: 781
    CrossrefPubMed
  • 18 Pokhodylo NT, Martyak RL, Rogovyk MP, Matiychuk VS, Obushak MD. Russ. J. Org. Chem. 2021; 57: 532
    CrossrefPubMed
  • 19 Pokhodylo NT, Savka RD, Obushak MD. Russ. J. Org. Chem. 2017; 53: 734
    CrossrefPubMed
  • 20 Fouad MA, Abdel-Hamid H, Ayoup MS. RSC Adv. 2020; 10: 42644
    CrossrefPubMed
  • 21 Váradi A, Palmer TC, Notis Dardashti R, Majumdar S. Molecules 2015; 21: 19
    CrossrefPubMed
  • 22 Mei H, Han J, Fustero S, Medio-Simon M, Sedgwick DM, Santi C, Ruzziconi R, Soloshonok VA. Chem. Eur. J. 2019; 25: 11797
    CrossrefPubMed
    • 23a Song GT, Qu CH, Lei J, Yan W, Tang DY, Li HY, Chen ZZ, Xu ZG. Adv. Synth. Catal. 2020; 362: 4084
      Crossref
    • 23b Ghoshal A, Ambule MD, Yadav A, Srivastava AK. Asian J. Org. Chem. 2021; 10: 315
      Crossref
    • 23c Bariwal J, Kaur R, Voskressensky LG, Van der Eycken EV. Front. Chem. 2018; 6: 557
      CrossrefPubMed
    • 23d Tripolitsiotis NP, Thomaidi M, Neochoritis CG. Eur. J. Org. Chem. 2020; 6525
      Crossref
  • 24 Patil P, Ahmadian-Moghaddam M, Dömling A. Green Chem. 2020; 22: 6902
    CrossrefPubMed
  • 25 Balducci E, Bellucci L, Petricci E, Taddei M, Tafi A. J. Org. Chem. 2009; 74: 1314
    CrossrefPubMed
  • 26 Single-crystal X-ray diffraction data for compound 9g (A) (CCDC 2194707): C24H26BrN5O2, monoclinic crystal system, space group C2/c, Z = 8, unit cell dimensions: a = 20.3612(6), b = 21.6139(7), c = 10.6307(3) Å, β = 93.042(2)°, V = 4671.8(2) Å3 at 150 K; ρ calcd = 1.412 g/cm3, R[F 2 > 2σ(F 2)] = 0.0369 for 4035 reflections, wR(F 2) = 0.1051 for all 4511 reflections. Diffraction data were collected on a Gemini+ diffractometer with Cu Kα radiation (λ = 1.54184 Å) and an Atlas CCD detector. Single-crystal X-ray diffraction data for compound 9g (B) (CCDC 2194708): C24H26BrN5O2, orthorhombic crystal system, space group Pbcn, Z = 8, unit cell dimensions: a = 27.1556(6), b = 10.9436(2), c = 15.6823(3) Å, V = 4660.43(17) Å3 at 150 K; ρ calcd = 1.415 g/cm3, R[F 2 > 2σ(F 2)] = 0.0395 for 3695 reflections, wR(F 2) = 0.1060 for all 4561 reflections. Diffraction data were collected on a Gemini+ diffractometer with Cu Kα radiation (λ = 1.54184 Å) and an Atlas CCD detector. CCDC 2194707 and 2194708 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures