Abstract
An unprecedented ZnCl2-catalyzed formal [2 + 2 + 1] annulation of 1,2-diaza-1,3-dienes (DDs) with hexahydro-1,3,5-triazines (HTs) has been accomplished, which provides imidazolidine frameworks with quaternary carbon centers. Thus, a new opportunity bypassing the use of hazardous diazo reagents is made possible by a unique carbene-like reactivity (C1 synthon) of readily available and safe 4-alkoxycarbonyl-1,2-diaza-1,3-butadienes. Besides, this noncarbenoid transformation can be implemented into a two-step three-component approach by utilizing the aromatic amine, 1,2-diaza-1,3-dienes and 1,3,5-triazines to synthesize differently substituted 1,3-diaryl imidazolidines.
Imidazolidines are prevalent motifs in pharmaceutical, agrochemical, and (bio)organic chemistry, such as chaetominine (strong cytotoxic against K562 human leukemia and SW1116 colon cancer cells), alchorneine with spasmolytic activity, cannabinoid CB2 receptor agonist, and chiral ligands/catalyst (MacMillan’s catalyst). This type of heterocycle is also useful as an organic synthon for various transformations.
The application of bench-stable hexahydro-1,3,5-triazines (HTs) has had a profound impact recently, which is attributed to their different reaction modes. HTs have been employed not only in aminomethylation but also in various annulation reactions, where two, three, or four atoms (i.e., C–N, C–N–C, N–C–N, and C–N–C–N) can be incorporated into the final products. On the other hand, 1,2-diaza-1,3-dienes (DDs) have been recognized as versatile building blocks in organic synthesis, which could undergo a wide array of chemical transformations. Owing to their various possible reactivities as both heterodienes and electrophiles, they have frequently been employed for the assembly of various N-heterocyclic compounds.
Although much effort has been spent for the efficient constructions of imidazolidines, there is limited literature about building this framework bearing a quaternary stereocenter at the 4- or 5-position. ,,− Among the developed strategies, [4 + 1]-cycloadditions of diazocarbonyl precursors with hexahydro-1,3–5-triazines are the most straightforward and convenient methods. In particular, the gold-, copper- and iron-catalyzed cycloadditions have been reported by groups of Lu/Wang, Sun, , and others. Metal-free visible light and base-induced synthesis of imidazolidine scaffolds have also been described by groups of Wang/Xuan and Sun (Scheme a). However, the development of a reliable protocol that circumvents direct human exposure to toxic and explosive diazo reagents remains a significant challenge.
1. Previous Reports and Our Utilization of 1,3,5-Triazines.
Recently, 1,2-diaza-1,3-dienes [azoalkenes], formed in situ from α-halo hydrazones in the presence of a base, have been employed as efficient dienes in inverse electron-demand aza-Diels–Alder (IEDDA) reaction with 1,3,5-triazinanes to synthesize tetrahydro-1,2,4-triazine derivatives (Scheme b). Inspired by these reports and as a continuation of our studies on the chemistry of DDs, we envisioned that a different reactivity of 4-alkoxycarbonyl-1,2-diaza-1,3-butadienes might occur upon the presence of a suitable catalyst. Herein, we report the unprecedented zinc-catalyzed [2 + 2 + 1] annulation between 1,2-diaza-1,3-dienes (DDs) and hexahydro-1,3,5-triazines (HTs) providing imidazolidine scaffolds (Scheme c). Notably, a rarely reported carbene-like C1 activity of 1,2-diaza-1,3-dienes is exhibited by the presence of an ester group (CO2R3) at the 4-position of the azoene system. Besides, different from Fang and Wang’s protocol in which the triazines acted as active imine intermediates undergoing [4 + 2] cycloadditions, we herein employ these as formal 1,4-dipoles under ZnCl2 catalysis to realize the synthesis of five-membered N-heterocycles.
At the outset, we selected 1,2-diaza-1,3-diene (1a) and commercially available 1,3,5-triphenyl-1,3,5-triazinane (2a) as the model substrates. When the reaction was performed in the presence of ZnCl2 (20 mol %) in DCM at room temperature by using a molar ratio of 1:1.3 between 1a and 2a, the imidazolidine 3a was obtained in 33% yield (entry 1, Table ). After a series of screenings (entries 1–6), the 2:1 molar ratio of 1a:2a was found to be optimal delivering the desired product 3a in nearly quantitative yield. Adding activated 4Å MS (entry 7) or decreasing the catalyst loading to 10 mol % (entry 8) was not beneficial. In the absence of Lewis acid, the reaction did not occur (entry 9). Other Lewis acid catalysts were also investigated, including ZnBr2, FeCl2, FeCl3, Cu(OTf)2, Bi(OTf)3, CuCl, CuCl2; however only inferior results were obtained (entries 10–16). A further solvent screen revealed that DMSO, acetonitrile, and THF could not improve the reaction efficiency (entries 17–19). Finally, no improvement was observed when the reaction was performed in DCE at 80 °C (entry 20).
1. Optimization Studies .
| entry | ratio 1a:2a | catalyst | solvent | yield (%) |
|---|---|---|---|---|
| 1 | 1:1.3 | ZnCl2 | DCM | 33 |
| 2 | 1:1 | ZnCl2 | DCM | 67 |
| 3 | 1.3:1 | ZnCl2 | DCM | 72 |
| 4 | 1.5:1 | ZnCl2 | DCM | 82 |
| 5 | 1.8:1 | ZnCl2 | DCM | 92 |
| 6 | 2:1 | ZnCl2 | DCM | 96 |
| 7 | 2:1 | ZnCl2 | DCM | 72 |
| 8 | 2:1 | ZnCl2 | DCM | 89 |
| 9 | 2:1 | – | DCM | 0 |
| 10 | 2:1 | ZnBr2 | DCM | 84 |
| 11 | 2:1 | FeCl2 | DCM | 0 |
| 12 | 2:1 | FeCl3 | DCM | 0 |
| 13 | 2:1 | Cu(OTf)2 | DCM | 24 |
| 14 | 2:1 | Bi(OTf)3 | DCM | 15 |
| 15 | 2:1 | CuCl | DCM | 0 |
| 16 | 2:1 | CuCl2 | DCM | 0 |
| 17 | 2:1 | ZnCl2 | DMSO | 0 |
| 18 | 2:1 | ZnCl2 | CH3CN | 39 |
| 19 | 2:1 | ZnCl2 | THF | 77 |
| 20 | 2:1 | ZnCl2 | DCE | 86 |
Reactions performed at 0.1 M solution of 2a (0.15 mmol) unless otherwise noted.
Determined by crude 1H NMR analysis using 2,5-dimethylfuran as the internal standard.
Isolated yields.
With activated 4 Å MS.
10 mol % of ZnCl2 was used.
Performed at 80 °C.
With optimal conditions established, the scope of this [2 + 2 + 1] cycloaddition was explored. As shown in Scheme , a wide range of differently substituted azoalkenes (1a–l) (R1 = Me, n-Pr; R2 = OMe, OEt, t-Bu, OBn, NH2, NHPh; R3 = Me, Et, t-Bu, Bn, (CH2)2OMe) participated in the reaction to afford desired imidazolidines 3 in moderate to good yields (35–97%). Then a series of N-phenyl triazinanes (2a–e) bearing an electron-donating (methyl, methoxy), or electron-withdrawing (chloro), group were surveyed in the reaction. While para-methoxy and para-chloro/fluoro as substituents worked well, a significant effect on the yield was observed when using trimethylbenzyl-1,3,5-triazine (3p, 21%).
2. Synthesis of Imidazolidines 3 from 1,2-Diaza-1,3-dienes 1 and 1,3,5-Triaryl-1,3,5-triazinanes 2 ,
a Reactions performed with 1 (0.6 mmol), 2 (0.3 mmol) and ZnCl2 (20 mol %) in CH2Cl2 (3 mL) at rt for 12 h.
b Isolated yields.
c On a 1.0 mmol reaction scale. PMP = p-methoxyphenyl; Bn = benzyl.
Disappointingly, the use of 1,3,5-tri(p-nitrophenyl)-1,3,5-triazinane (2g), 1,3,5-tri(pyridin-2-yl)-1,3,5-triazinane (2h) and 1,3,5-tri(benzyl)-1,3,5-triazinane (2i) delivered no identifiable imidazolidine products. For deactivated 2g it was found that the reaction could only furnish a trace (5% yield) of Michael adduct III (vide infra) along with the recovery unreacted triazinane (92%) despite heating at 60 °C in DCE for 24 h.
The LCMS detection of α-aminohydrazone species III (vide infra) as s potential intermediate for the generation of cyclic imidazolidine 3a prompted us to consider the assembly of differently substituted 1,3-diaryl imidazolidine compounds. To check our hypothesis, we carried out a sequential protocol where the α-aminohydrazone was preformed and employed to couple with 1,3,5-triazinanes. Attempts started with the ZnCl2-catalyzed 1,4-conjugate addition reaction between 1,2-diaza-1,3-diene (1a) and aniline (A) to form a Michael adduct (30 min, TLC monitoring), which was subsequently subjected to reaction with 1,3,5-triphenyl-1,3,5-triazinane 2b. To our delight, desired imidazolidine 3Ab was obtained in 84% yield. Thus, the possibility of reacting different α-aminohydrazone intermediates with various 1,3,5-triazinanes was explored to determine the scope of the tandem reaction to produce differently substituted 1,3-diaryl imidazolidines 3. Various primary aromatic amine/N-aryltriazinane combinations worked well in this three-component telescopic reaction with DDs to provide the desired product 3 in good yields.
Interestingly, with this protocol, it is possible to reverse the aromatic substituents on the nitrogen atoms of imidazolidines by a judicious choice of the two N-components, namely amines 1 and triazinanes 2 (3Ab vs 3Ba, 3Ac vs 3Ca, 3Ad vs 3Da, 3Ae vs 3Ea, 3Bc vs 3Cb, and 3Bd vs 3Db; Scheme ).
3. Synthesis of Differently Substituted 1,3-Diaryl Imidazolidines 3 from 1,2-Diaza-1,3-diene 1a, Aromatic Amines A–F and 1,3,5-Triaryl-1,3,5-triazinanes 2 ,
a Reactions performed with 1 (0.3 mmol), A–F (0.3 mmol) and ZnCl2 (20 mol %) in CH2Cl2 (3 mL) at rt for 30 min.; then 2 (0.3 mmol) at rt for 12 h.
b Isolated yields.
On the basis of the results described above, a possible pathway for the assembly of imidazolidine is proposed (Scheme ). Upon the ZnCl2 catalysis, it is hypothesized that N-aryl amine disassembling from 1,3,5-triazinane (ArNCH2)3 would react with azoalkene 1 to provide an α-aminohydrazone intermediate III. The LCMS peak for III is consistent with the hypothesis that the aza-Michael addition step is likely to have a rate faster than those of other pathways. Subsequently, a formaldimine unit might react to give intermediate IV. Then, a further condensation of IV with a formaldehyde molecule followed by proto abstraction/intramolecular five-ring cyclization takes place to provide the final products 3. Alternatively, the direct participation of imine monomer I, ,, the dimeric intermediate (1,4-dipole) II, or triazine itself , (the latter not shown) in the reaction with 1 to give the intermediate V should be excluded.
4. a) Possible Reaction Mechanism; b) Crossover Experiment; c) Control Experiments.
A crossover experiment between DD 1a, N-Ph triazinane 2a and N-PMP triazinane 2b provided a mixture of 3a, 3m, 3Ba, which were confirmed by both LCMS and 1H NMR analysis (Scheme b). The formation of these inseparable cross cycloaddition products suggests that both 1,3,5-triazinanes 2a and 2b depolymerize under the reaction conditions into amine and formaldimine to participate in the transformation to final products. Our control experiments (Scheme c) also highlighted that both the terminal disubstituted azoalkene 1l and the cyclic DD 1m did not furnish the imidazolidine products under the standard conditions, indicating the need for an acidic proton in the C4 position of the starting DD.
Hydrolytic cleavage of hydrazone product 3a was performed to further demonstrate the utility of the present approach (Scheme ). By treatment of 3a with Amberlyst-15H and formaldehyde in acetone/H2O (9:1) solution the conversion of 3a into the corresponding ketone 4a proceeded in good yield.
5.
In conclusion, we have developed a formal [2 + 2 + 1] annulation of 1,2-diaza-1,3-dienes (DDs) with hexahydro-1,3,5-triazines (HTs) leading to 1,3-diaryl imidazolidines with quaternary carbon centers. Under the catalysis of a simple Lewis acid (ZnCl2) catalyst, 4-alkoxycarbonyl-DDs demonstrated unique carbene-like reactivity (C1 synthon), offering a safe alternative to the use of explosive/hazardous α-diazo compounds. The preliminary mechanistic studies indicate that the amine and formaldehyde (or formaldimine) derived in situ from depolymerization of the trimer (ArNCH2)3, instead of 1,3,5-triazine itself, are involved in the transformation. Meanwhile, this approach could be implemented in a three-component reaction by utilizing the aromatic amine, 1,2-diaza-1,3-dienes (DDs) and hexahydro-1,3,5-triazines (HTs) to reach differently substituted 1,3-diaryl imidazolidines. Further investigations based on this chemistry are currently underway.
Supplementary Material
Acknowledgments
The authors thank Prof. Michele Menotta for HRMS characterization of the new compounds. The authors also acknowledge for the support from the Research Projects of Significant National Interest (PRIN) of the Italian Ministry of University and Research (MUR) funded by the European Union – NextGenerationEU, Project Code P2022ACY8P, Concession Decree n. 1386 of 01-09-2023 adopted by the Italian Ministry of University and Research (MUR), CUP H53D23007770001, “A Multicomponent Solar Energy Conversion System with Extended Spectral Collection 4H9-onesand Improved Efficiency (MUSES)”.
The data underlying this study are available in the published article and its .
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c01387.
§.
V.C. and S.C. contributed equally to this work.
The authors declare no competing financial interest.
References
- Jiao R. H., Xu S., Liu J. Y., Ge H. M., Ding H., Xu C., Zhu H. L., Tan R. X.. Chaetominine, a Cytotoxic Alkaloid Produced by Endophytic Chaetomium sp. IFB-E015. Org. Lett. 2006;8:5709–5712. doi: 10.1021/ol062257t. [DOI] [PubMed] [Google Scholar]
- Buchi G., Rodriguez A. D., Yakushijin K.. Syntheses of (±)-Alchorneme and (±)-Isoalchorneine. J. Org. Chem. 1989;54:4494–4496. doi: 10.1021/jo00280a009. [DOI] [Google Scholar]
- a Hopkinson M. N., Richter C., Schedler M., Glorius F.. An Overview of N-heterocyclic Carbenes. Nature. 2014;510:485–496. doi: 10.1038/nature13384. [DOI] [PubMed] [Google Scholar]; b Allen A. E., MacMillan D. W. C.. Enantioselective α-Arylation of Aldehydes via the Productive Merger of Iodonium Salts and Organocatalysis. J. Am. Chem. Soc. 2011;133:4260–4263. doi: 10.1021/ja2008906. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Arai T., Mishiro A., Yokoyama N., Suzuki K., Sato H.. Chiral Bis(imidazolidine)pyridine-Cu(OTf)2: Catalytic Asymmetric Endo-Selective [3 + 2] Cycloaddition of Imino Esters with Nitroalkenes. J. Am. Chem. Soc. 2010;132:5338–5339. doi: 10.1021/ja100265j. [DOI] [PubMed] [Google Scholar]; d Prieto A., Halland N., Jørgensen K. A.. Novel Imidazolidine-Tetrazole Organocatalyst for Asymmetric Conjugate Addition of Nitroalkanes. Org. Lett. 2005;7:3897–3900. doi: 10.1021/ol051301m. [DOI] [PubMed] [Google Scholar]
- a Liu Y., Liu X., Gao S., Liu Y., Lang M., Peng S.. Gold(I)-Catalyzed Asymmetric Heterocyclization/(5 + 3) Cycloaddition of Yne-enones with Imidazolidines: Access to Cycloocta[c]furan Frameworks. Org. Lett. 2025;27:5128–5134. doi: 10.1021/acs.orglett.5c01267. [DOI] [PubMed] [Google Scholar]; b Cheng Z., Chen J., Zhang Y., Shao Y., Sun J., Tang S.. Decarboxylative cyclization of ethynyl benzoxazinanones with imidazolidines to access 2,3-indole-fused 1,4-diazocines. Org. Lett. 2024;26:4863–4867. doi: 10.1021/acs.orglett.4c01279. [DOI] [PubMed] [Google Scholar]; c Yang L., Wang H., Lang M., Wang M., Peng S.. B(C6F5)3-Catalyzed Formal (n + 3) (n = 5 and 6) Cycloaddition of Bicyclo[1.1.0]butanes to Medium Bicyclo[n.1.1]alkanes. Org. Lett. 2024;26:4104–4110. doi: 10.1021/acs.orglett.4c01219. [DOI] [PubMed] [Google Scholar]; d Zhu Y., Yang L., Zhang X., Xu W., He J., Wang H., Lang M., Peng S.. Copper-Catalyzed Cycloadditions of Diazo Compounds with Imidazolidines/Hexahydropyrimidines for the Syntheses of N-Heterocycles. Org. Lett. 2022;24:6443–6448. doi: 10.1021/acs.orglett.2c02561. [DOI] [PubMed] [Google Scholar]; e He J., Yang L., Zhang X., Xu W., Wang H., Lang M., Wang J., Peng S.. Stereodivergent Syntheses of N-heterocycles by Catalyst-Controlled Reaction of Imidazolidines with Allenes. ACS Catal. 2022;12:14647–14653. doi: 10.1021/acscatal.2c04775. [DOI] [Google Scholar]; f Guarnieri-Ibánez A., de Aguirre A., Besnard C., Poblador-Bahamonde A. I., Lacour J.. Regiodivergent synthesis of pyrazinoindolines vs. triazocines via α-imino carbenes addition to imidazolidines. Chem. Sci. 2021;12:1479–1485. doi: 10.1039/D0SC05725H. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liang D., Xiao W.-J., Chen J.-R.. Recent Advances of 1,3,5-Triazinanes in Aminomethylation and Cycloaddition Reactions. Synthesis. 2020;52:2469–2482. doi: 10.1055/s-0040-1707160. [DOI] [Google Scholar]
- a De Crescentini L., Mari G., Santeusanio S., Favi G., Mantellini F.. 1,2-Diaza-1,3-dienes as a Multifaceted Synthon for the Synthesis of Heterocycles: A Fifteen-Years Update. Eur. J. Org. Chem. 2024;27:e202400716. doi: 10.1002/ejoc.202400716. [DOI] [Google Scholar]; b Wei L., Shen C., Hu Y.-Z., Tao H.-Y., Wang C.-J.. Enantioselective synthesis of multi-nitrogen-containing heterocycles using azoalkenes as key intermediates. Chem. Commun. 2019;55:6672–6684. doi: 10.1039/C9CC02371B. [DOI] [PubMed] [Google Scholar]; c Lopes S. M. M., Cardoso A. L., Lemos A., Pinho e Melo T. M. V. D.. Recent Advances in the Chemistry of Conjugated Nitrosoalkenes and Azoalkenes. Chem. Rev. 2018;118:11324–11352. doi: 10.1021/acs.chemrev.8b00375. [DOI] [PubMed] [Google Scholar]; d Attanasi O. A., De Crescentini L., Favi G., Filippone P., Mantellini F., Perrulli F. R., Santeusanio S.. Cultivating the Passion to Build Heterocycles from 1,2-Diaza-1,3-dienes: the Force of Imagination. Eur. J. Org. Chem. 2009;2009:3109–3127. doi: 10.1002/ejoc.200900243. [DOI] [Google Scholar]
- a Tian J., Zhao L., Yang C., Yang C., Guo L., Xia W.. Four-Component Synthesis of Spiro-Imidazolidines Enabled by Carbon Nitride Photocatalysis. ACS Catal. 2023;13:866–876. doi: 10.1021/acscatal.2c04453. [DOI] [Google Scholar]; b Viso A., Fernández de la Pradilla R., García A., Guerrero-Strachan C., Alonso M., Tortosa M., Flores A., Martínez-Ripoll M., Fonseca I., André I., Rodríguez A.. Highly Diastereoselective [3 + 2] Cycloadditions between Nonracemic p-Tolylsulfinimines and Iminoesters: An Efficient Entry to Enantiopure Imidazolidines and Vicinal Diaminoalcohols. Chem.Eur. J. 2003;9:2867–2876. doi: 10.1002/chem.200204674. [DOI] [PubMed] [Google Scholar]; c Chen Z., Zhou Y., Hu T., Xiong H.-Y., Zhang G.. Merging Imidazolidines with a Trifluoromethylated Tetrasubstituted Carbon through Tungsten Catalyzed 1,3-Dipolar Cycloaddition. J. Org. Chem. 2021;86:7714–7724. doi: 10.1021/acs.joc.1c00676. [DOI] [PubMed] [Google Scholar]; d Zhang J., Li Y.-F., Jia F.-C., Gao Y., Hu X.-Q.. Strain-release enabled [3 + 2] annulation of 3-aminooxetanes with simple CN bonds: facile synthesis of imidazolidines. Org. Chem. Front. 2021;8:6616–6621. doi: 10.1039/D1QO01164B. [DOI] [Google Scholar]; e Tarannum S., Sk S., Das S., Wani I. A., Ghorai M. K.. Stereoselective Syntheses of Highly Functionalized Imidazolidines and Oxazolidines via Ring-Opening Cyclization of Activated Aziridines and Epoxides with Amines and Aldehydes. J. Org. Chem. 2020;85:367–379. doi: 10.1021/acs.joc.9b02278. [DOI] [PubMed] [Google Scholar]; f Tu L., Li Z., Feng T., Yu S., Huang R., Li J., Wang W., Zheng Y., Liu J.. Access to Imidazolidines via 1,3-Dipolar Cycloadditions of 1,3,5-Triazinanes with Aziridines. J. Org. Chem. 2019;84:11161–11169. doi: 10.1021/acs.joc.9b01959. [DOI] [PubMed] [Google Scholar]; g Sengoden M., Bhowmick A., Punniyamurthy T.. Stereospecific Copper-Catalyzed Domino Ring Opening and sp3 C–H Functionalization of Activated Aziridines with N-Alkylanilines. Org. Lett. 2017;19:158–161. doi: 10.1021/acs.orglett.6b03458. [DOI] [PubMed] [Google Scholar]
- a Cheng X., Cai B.-G., Mao H., Lu J., Li L., Wang K., Xuan J.. Divergent Synthesis of Aziridine and Imidazolidine Frameworks under Blue LED Irradiation. Org. Lett. 2021;23:4109–4114. doi: 10.1021/acs.orglett.1c00979. [DOI] [PubMed] [Google Scholar]; b Zhou Y., Ma F., Lu P., Wang Y.. Preparation of spiro[imidazolidine-4,3′-indolin]-2′-imines via copper(I)-catalyzed formal [2 + 2+1] cycloaddition of 3-diazoindolin-2-imines and triazines. Org. Biomol. Chem. 2019;17:8849–8852. doi: 10.1039/C9OB01767D. [DOI] [PubMed] [Google Scholar]; c Liu P., Zhu C., Xu G., Sun J.. Iron-catalyzed intermolecular cycloaddition of diazo surrogates with hexahydro-1,3,5-triazines. Org. Biomol. Chem. 2017;15:7743–7746. doi: 10.1039/C7OB02115A. [DOI] [PubMed] [Google Scholar]; d Liu P., Xu G., Sun J.. Metal-Free [2 + 1 + 2]-Cycloaddition of Tosylhydrazones with Hexahydro-1,3,5-triazines To Form Imidazolidines. Org. Lett. 2017;19:1858–1861. doi: 10.1021/acs.orglett.7b00600. [DOI] [PubMed] [Google Scholar]; e Zhu C., Xu G., Sun J.. Gold-Catalyzed Formal [4 + 1]/[4 + 3] Cycloadditions of Diazo Esters with Triazines. Angew. Chem., Int. Ed. 2016;55:11867–11871. doi: 10.1002/anie.201606139. [DOI] [PubMed] [Google Scholar]
- Wang C., Fang L., Wang Z.. Base-induced inverse-electron-demand aza-Diels-Alder reaction of azoalkenes and 1,3,5-triazinanes: Facile approaches to tetrahydro-1,2,4-triazines. Tetrahedron Lett. 2021;79:153303. doi: 10.1016/j.tetlet.2021.153303. [DOI] [Google Scholar]
- For representative examples of sequential multicomponent reactions initiated by a Michael addition of amines on DDs, see:; a Mari G., De Crescentini L., Favi G., Santeusanio S., Mantellini F.. Straightforward Access to Pyrazine-(2,3)-diones through Sequential Three-Component Reaction. Eur. J. Org. Chem. 2023;26:e202201080. doi: 10.1002/ejoc.202201080. [DOI] [Google Scholar]; b Attanasi O. A., Bartoccini S., Favi S., Giorgi G., Perrulli F. R., Santeusanio S.. Powerful Approach to Heterocyclic Skeletal Diversity by Sequential Three-Component Reaction of Amines, Isothiocyanates, and 1,2-Diaza-1,3-dienes. J. Org. Chem. 2012;77:1161–1167. doi: 10.1021/jo2021949. [DOI] [PubMed] [Google Scholar]; c Preti L., Attanasi O. A., Caselli E., Favi G., Ori C., Davoli P., Felluga F., Prati F.. One-Pot Synthesis of Imidazole-4-Carboxylates by Microwave-Assisted 1,5-Electrocyclization of Azavinyl Azomethine Ylides. Eur. J. Org. Chem. 2010;2010:4312–4320. doi: 10.1002/ejoc.201000434. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Attanasi O. A., Berretta S., De Crescentini L., Favi S., Giorgi G., Mantellini F.. Lewis Acid-Catalyzed Synthesis of Functionalized Pyrroles. Adv. Synth. Catal. 2009;351:715–719. doi: 10.1002/adsc.200800807. [DOI] [Google Scholar]
- a Chen F., Duan Y., Guo Y., Liu Y., Lang m., Peng J., Peng S.. An unexpected Lewis acid-catalyzed cascade reaction of bicyclo[1.1.0]butanes with triazinanes toward biscyclobutenyl amines. Org. Chem.Front. 2025;12:1815–1820. doi: 10.1039/D4QO02245A. [DOI] [Google Scholar]; b Zheng D., Zhang R., Chen W., Yang P., Yang G., Chai Z.. Lewis Acid-Catalyzed Annulations of Geminally Disubstituted Cyclopropanes with Aldehydes or 1,3,5-Triazinanes. Org. Lett. 2023;25:2577–2581. doi: 10.1021/acs.orglett.3c00511. [DOI] [PubMed] [Google Scholar]; c Tian Y., Chen Z., Su K., Zheng Y., Liu J.. [2 + 2+1 + 1] Cycloaddition Reaction of 1,3,5-Triazinanes with Methylene Compounds: Approach to Hexahydropyrimidines. Adv. Synth. Catal. 2023;365:3909–3914. doi: 10.1002/adsc.202300490. [DOI] [Google Scholar]; d Liu X., Wang Y., Zheng H., Huang J., Su Z., Zhao L., Cao H.. Construction of Diverse N -Heterocycles by Formal (3 + 3) Cycloaddition of Naphthol/Thionaphthol/Naphthylamine and 1,3,5-Triazinanes. J. Org. Chem. 2023;88:75–85. doi: 10.1021/acs.joc.2c01822. [DOI] [PubMed] [Google Scholar]; e Ruan P., Tang Q., Yang Z., Liu X., Feng X.. Enantioselective formal [2 + 2+2] cycloaddition of 1,3,5-triazinanes to construct tetrahydropyrimidin-4-one derivatives. Chem. Commun. 2022;58:1001–1004. doi: 10.1039/D1CC06549A. [DOI] [PubMed] [Google Scholar]; f Wang T., Zhang B., Hu L., Sun H., Wang Y., Zhai H., Cheng B.. Synthesis of Chromeno[2,3-d]pyrimidin-5-one Derivatives from 1,3,5-Triazinanes via Two Different Reaction Pathways. J. Org. Chem. 2022;87:1348–1356. doi: 10.1021/acs.joc.1c02649. [DOI] [PubMed] [Google Scholar]; g Zheng Y., Chi Y., Bao M., Qiu L., Xu X.. Gold-Catalyzed Tandem Dual Heterocyclization of Enynones with 1,3,5-Triazines: Bicyclic Furan Synthesis and Mechanistic Insights. J. Org. Chem. 2017;82:2129–2135. doi: 10.1021/acs.joc.6b02947. [DOI] [PubMed] [Google Scholar]
- Likely, an intramolecular OH-assisted proto abstraction or an intermolecular (such as water as a proton shuttle) proto abstraction for the formation of 3 could be operative.
- Zhao H.-W., Pang H.-L., Zhao Y.-D., Liu Y.-Y., Zhao L.-J., Chen X.-Q., Song X.-Q., Feng N.-N., Du J.. Construction of 2,3,4,5-tetrahydro-1,2,4-triazines via [4 + 2] cycloaddition of α-halogeno hydrazones to imines. RSC Adv. 2017;7:9264–9271. doi: 10.1039/C6RA27767E. [DOI] [Google Scholar]
- Miles D. H., Guasch J., Toste F. D.. A Nucleophilic Strategy for Enantioselective Intermolecular α-Amination: Access to Enantioenriched α-Arylamino Ketones. J. Am. Chem. Soc. 2015;137:7632–7635. doi: 10.1021/jacs.5b04518. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Data Availability Statement
The data underlying this study are available in the published article and its .