The utilization of NH-1,2,3-triazoles as easily accessible building blocks in denitrogenative ring cleavage transformations with electrophiles to provide multifunctionalized nitrogen heterocycles and N-alkenyl compounds is reviewed. Leveraging the ready availability of NH-1,2,3-triazoles, these processes provide a convenient route to a range of pharmaceutically relevant heterocyclic cores and N-alkenyl compounds. The synthetic usefulness of in situ acylated NH-1,2,3-triazoles as viable alternatives to widely explored N-sulfonyl-1,2,3-triazoles in ring cleavage processes is highlighted.

Institute of Orgranic Chemistry and Biochemistry Academy of Sciences Flemingovo nám 2 160 00 Prague 6 Czech Republic

Zobrazit více v PubMed

Chemistry of 1,2,3-triazoles, in Topics in Heterocyclic Chemistry, ed. W. Dehaen and V. A. Bakulev, Springer, 2015, vol. 40

Davies H. M. Alford J. S. Reactions of metallocarbenes derived from N-sulfonyl-1,2,3-triazoles. Chem. Soc. Rev. 2014;43:5151. doi: 10.1039/C4CS00072B. PubMed DOI

Li W. Zhang J. Synthesis of Heterocycles through Denitrogenative Cyclization of Triazoles and Benzotriazoles. Chem. – Eur. J. 2020;26:11931. doi: 10.1002/chem.202000674. PubMed DOI

Kumar S. Sharma B. Mehra V. Kumar V. Recent accomplishments on the synthetic/biological facets of pharmacologically active 1H-1,2,3-triazoles. Eur. J. Med. Chem. 2021;212:113069. doi: 10.1016/j.ejmech.2020.113069. PubMed DOI

Tornøe C. W. Christensen C. Meldal M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002;67:3057. doi: 10.1021/jo011148j. PubMed DOI

Rostovtsev V. V. Green L. G. Fokin V. V. Sharpless K. B. A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem., Int. Ed. 2002;41:2596. doi: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4. PubMed DOI

Akter M. Rupa K. Anbarasan P. 1,2,3-Triazole and Its Analogues: New Surrogates for Diazo Compounds. Chem. Rev. 2022;122:13108. doi: 10.1021/acs.chemrev.1c00991. PubMed DOI

Chattopadhyay B. Gevorgyan V. Transition-Metal-Catalyzed Denitrogenative Transannulation: Converting Triazoles into Other Heterocyclic Systems. Angew. Chem., Int. Ed. 2012;51:862. doi: 10.1002/anie.201104807. PubMed DOI PMC

Anbarasan P. Yadagiri D. Rajasekar S. Recent Advances in Transition-Metal-Catalyzed Denitrogenative Transformations- of 1,2,3-Triazoles and Related Compounds. Synthesis. 2014;46:3004. doi: 10.1055/s-0034-1379303. DOI

Xu Z.-F. Dai H. C. Shan L. H. Li C.-Y. Metal-Free Synthesis of (E)-Monofluoroenamine from 1-Sulfonyl-1,2,3-triazole and Et2O·BF3via Stereospecific Fluorination of α-Diazoimine. Org. Lett. 2018;20:1054. doi: 10.1021/acs.orglett.7b04014. PubMed DOI

Yang D. Shan L. Xu Z.-F. Li C.-Y. Metal-free synthesis of imidazole by BF3·Et2O promoted denitrogenative transannulation of N-sulfonyl-1,2,3-triazole. Org. Biomol. Chem. 2018;16:1461. doi: 10.1039/C8OB00083B. PubMed DOI

Motornov V. Markos A. Beier P. A rhodium-catalyzed transannulation of N-(per)fluoroalkyl-1,2,3-triazoles under microwave conditions – a general route to N-(per)fluoroalkyl-substituted five-membered heterocycles. Chem. Commun. 2018;54:3258. doi: 10.1039/C8CC01446A. PubMed DOI

Motornov V. Beier P. Chemoselective Aza-[4+3]-annulation of N-Perfluoroalkyl-1,2,3-triazoles with 1,3-Dienes: Access to N-Perfluoroalkyl-Substituted Azepines. J. Org. Chem. 2018;83:15195. doi: 10.1021/acs.joc.8b02472. PubMed DOI

Motornov V. Košťál V. Markos A. Taffner D. Beier P. General approach to 2-fluoroalkyl 1,3-azoles via the tandem ring opening and defluorinative annulation of N-fluoroalkyl-1,2,3-triazoles. Org. Chem. Front. 2019;6:3776. doi: 10.1039/C9QO01104H. DOI

Bakhanovich O. Khutorianskyi V. Motornov V. Beier P. Synthesis of N-perfluoroalkyl-3,4-disubstituted pyrroles by rhodium-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles with terminal alkynes. Beilstein J. Org. Chem. 2021;17:504. doi: 10.3762/bjoc.17.44. PubMed DOI PMC

Markos A. Voltrová S. Motornov V. Tichý D. Klepetářová B. Beier P. Stereoselective Synthesis of (Z)-β-Enamido Triflates and Fluorosulfonates from N-Fluoroalkylated Triazoles. Chem. – Eur. J. 2019;25:7640. doi: 10.1002/chem.201901632. PubMed DOI

Markos A. Janecký L. Chvojka T. Martinek T. Martinez-Seara H. Klepetářová B. Beier P. Haloalkenyl Imidoyl Halides as Multifacial Substrates in the Stereoselective Synthesis of N-Alkenyl Compounds. Adv. Synth. Catal. 2021;363:3258. doi: 10.1002/adsc.202100009. DOI

Opsomer T. Dehaen W. Metal-free syntheses of N-functionalized and NH-1,2,3-triazoles: an update on recent developments. Chem. Commun. 2021;57:1568. doi: 10.1039/D0CC06654K. PubMed DOI

Parambil C. P. Veethil S. P. Dehaen W. The Synthesis of Five-Membered N-Heterocycles by Cycloaddition of Nitroalkenes with (In)Organic Azides and Other 1,3-Dipoles. Synthesis. 2022;54:910. doi: 10.1055/a-1547-0196. DOI

Prakash R. Opsomer T. Dehaen W. Triazolization of Enolizable Ketones with Primary Amines: A General Strategy toward Multifunctional 1,2,3-Triazoles. Chem. Rec. 2021;21:376. doi: 10.1002/tcr.202000151. PubMed DOI

John J. Thomas J. Dehaen W. Organocatalytic routes toward substituted 1,2,3-triazoles. Chem. Commun. 2015;51:10797. doi: 10.1039/C5CC02319J. PubMed DOI

Motornov V. A. Ioffe S. L. Tabolin A. A. [3+ 2]-Annulation reactions with nitroalkenes in the synthesis of aromatic five-membered nitrogen heterocycles. Targets Heterocycl. Syst. 2019;23:237.

Jin T. Kamijo S. Yamamoto Y. Copper-Catalyzed Synthesis of N-Unsubstituted 1,2,3-Triazoles from Nonactivated Terminal Alkynes. Eur. J. Org Chem. 2004:3789. doi: 10.1002/ejoc.200400442. DOI

Hui R. Zhao M. Chen M. Ren Z. Guan Z. One-Pot Synthesis of 4-Aryl-NH-1,2,3-Triazoles through Three-Component Reaction of Aldehydes, Nitroalkanes and NaN3. Chin. J. Chem. 2017;35:1808. doi: 10.1002/cjoc.201700367. DOI

Wu L. Wang X. Chen Y. Huang Q. Lin Q. Wu M. 4-Aryl-NH-1,2,3-Triazoles via Multicomponent Reaction of Aldehydes, Nitroalkanes, and Sodium Azide. Synlett. 2016;27:437.

Hu Q. Liu Y. Deng X. Li Y. Chen Y. Aluminium(III) Chloride-Catalyzed Three-Component Condensation of Aromatic Aldehydes, Nitroalkanes and Sodium Azide for the Synthesis of 4-Aryl-NH-1,2,3-triazoles. Adv. Synth. Catal. 2016;358:1689. doi: 10.1002/adsc.201600098. DOI

Garg A. Hazarika R. Dutta N. Dutta B. Sarma D. Bio-waste Derived Catalytic Approach Towards NH-1,2,3-Triazole Synthesis. ChemistrySelect. 2021;6:7266. doi: 10.1002/slct.202101347. DOI

Garg A. Sarma D. Ali A. A. Curr. Res. Green Sustainable Chem. 2020;3:100013. doi: 10.1016/j.crgsc.2020.100013. DOI

Sultana J. Garg A. Kulshrestha A. Rohman S. S. Dutta B. Singh K. Kumar A. Guha A. K. Sharma D. Catal. Lett. 2023;153:3516. doi: 10.1007/s10562-022-04248-0. DOI

Phukan P. Chetia R. Boruah R. Konwer S. Sharma D. Adv. Mater. 2021;2:6996. doi: 10.1039/D1MA00700A. DOI

Bagheri S. Nejad M. J. Pazoki F. Miraki M. K. Heydari A. ChemistrySelect. 2019;4:11930. doi: 10.1002/slct.201902205. DOI

Jankovic D. Virant M. Gazvoda M. Copper-Catalyzed Azide–Alkyne Cycloaddition of Hydrazoic Acid Formed In Situ from Sodium Azide Affords 4-Monosubstituted-1,2,3-Triazoles. J. Org. Chem. 2022;87:4018. doi: 10.1021/acs.joc.1c02775. PubMed DOI PMC

Hu L. Muck-Lichtenfield C. Wang T. He G. Gao M. Zhao J. Reaction between Azidyl Radicals and Alkynes: A Straightforward Approach to NH-1,2,3-Triazoles. Chem. – Eur. J. 2016;22:911. doi: 10.1002/chem.201504515. PubMed DOI

Roshandel S. Suri S. C. Marcischak J. C. Rasul G. Prakash G. K. S. Catalyst and solvent free microwave-assisted synthesis of substituted 1,2,3-triazoles. Green Chem. 2018;20:3700. doi: 10.1039/C8GC01516C. DOI

Benzaldehydes are by the order of magnitude less expensive than corresponding aryl acetylenes according to price lists of common chemical suppliers. Also, nitroalkanes are very inexpensive large scale industrial products. See: Ono N., The Nitro Group in Organic Synthesis, John Wiley & Sons, New York, 2002

Kwok S. W. Zhang L. Grimster N. P. Fokin V. V. Catalytic Asymmetric Transannulation of NH-1,2,3-Triazoles with Olefins. Angew. Chem., Int. Ed. 2014;53:3452. doi: 10.1002/anie.201306706. PubMed DOI PMC

Motornov V. Pohl R. Klepetářová B. Beier P. N-Acyl-1,2,3-triazoles – key intermediates in denitrogenative transformations. Chem. Commun. 2023;59:9364. doi: 10.1039/D3CC00987D. PubMed DOI

Wang T. Tang Z. Luo H. Tian Y. Xu M. Lu Q. Li B. Access to (Z)-β-Substituted Enamides from N1-H-1,2,3-Triazoles. Org. Lett. 2021;23:6293. doi: 10.1021/acs.orglett.1c02087. PubMed DOI

Lu Q. Wang T. Wu Q. Cheng L. Luo H. Liu L. Chu G. Wang L. Li B. C–H heteroarylation of aromatics via catalyst free SN2′ coupling cycloaromatization. Green Chem. 2022;24:4399. doi: 10.1039/D2GC00467D. DOI

Chvojka T. Markos A. Voltrová S. Pohl R. Beier P. Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates. Beilstein J. Org. Chem. 2021;17:2657. doi: 10.3762/bjoc.17.179. PubMed DOI PMC

Motornov V. Beier P. Access to Fluoroalkylated Azoles and 2-Acylaminoketones via Fluorinated Anhydride-Mediated Cleavage of NH-1,2,3-Triazoles. Org. Lett. 2022;24:1958. doi: 10.1021/acs.orglett.2c00359. PubMed DOI

Motornov V. Beier P. One-pot synthesis of 4-substituted 2-fluoroalkyloxazoles from NH-1,2,3-triazoles and fluoroalkylated acid anhydrides. New J. Chem. 2022;46:14318. doi: 10.1039/D2NJ02461F. DOI

Singh A. S. Mishra N. Kumar D. Tiwari V. K. Lewis-Acid-Mediated Benzotriazole Ring Cleavage (BtRC) Strategy for the Synthesis of 2-Aryl Benzoxazoles from N-Acylbenzotriazoles. ACS Omega. 2017;2:5044. doi: 10.1021/acsomega.7b00965. PubMed DOI PMC

Dong B. Liu Y. Yang P. Sang D. Tian J. Li L. Long S. Denitrogenative cleavage of benzotriazoles and benzotriazinones, and selective N-desulfonylation of benzotriazoles by aluminum halides. Tetrahedron Lett. 2022;103:153965. doi: 10.1016/j.tetlet.2022.153965. DOI

Motornov V. Beier P. Synthesis of N-vinyl isothiocyanates and carbamates by the cleavage of NH-1,2,3-triazoles with one-carbon electrophiles. Org. Biomol. Chem. 2023;21:1147. doi: 10.1039/D2OB02115C. PubMed DOI

Xu M. Liu L. Wang T. Luo H. Hou M. Du L. Xin X. Lu Q. Li B. Acid-catalyzed ring-expansion of 4-(1-hydroxycyclobutyl)-1,2,3-triazoles. Org. Chem. Front. 2022;9:1065. doi: 10.1039/D1QO01747K. DOI

Synthesis of 1-Fluoroalkyl-5-Substituted-1,2,3-Triazoles from Carbonyl-Stabilized Phosphonium Ylides