ACS Publications. Most Trusted. Most Cited. Most Read
Regio- and Diastereoselective 1,3-Dipolar Cycloadditions of 1,2,4-Triazin-1-ium Ylides: a Straightforward Synthetic Route to Polysubstituted Pyrrolo[2,1-f][1,2,4]triazines
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Omega 2022, 7, 24, 21233-21238
  • Open Access
Article

Regio- and Diastereoselective 1,3-Dipolar Cycloadditions of 1,2,4-Triazin-1-ium Ylides: a Straightforward Synthetic Route to Polysubstituted Pyrrolo[2,1-f][1,2,4]triazines
Click to copy article linkArticle link copied!

  • Juraj Galeta
    Juraj Galeta
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    More by Juraj Galeta
  • Veronika Šlachtová
    Veronika Šlachtová
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    More by Veronika Šlachtová
  • Martin Dračínský
    Martin Dračínský
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    More by Martin Dračínský
    Orcidhttps://orcid.org/0000-0002-4495-0070
  • Milan Vrabel*
    Milan Vrabel
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    *Email: [email protected]
    More by Milan Vrabel
    Orcidhttps://orcid.org/0000-0001-6633-4351
Open PDFSupporting Information (1)

ACS Omega

Cite this: ACS Omega 2022, 7, 24, 21233–21238
Click to copy citationCitation copied!
https://doi.org/10.1021/acsomega.2c02276
Published June 10, 2022

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY-NC-ND 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

A synthetic strategy to pyrrolo[2,1-f][1,2,4]triazines is reported. We show that various synthetically easily accessible 1,2,4-triazines can be efficiently alkylated under mild conditions to provide the corresponding 1-alkyl-1,2,4-triazinium salts. These bench-stable salts serve as precursors to triazinium ylides, which react in 1,3-dipolar cycloadditions with electron-poor dipolarophiles to yield polysubstituted pyrrolotriazines in a single step.

This publication is licensed under

CC-BY-NC-ND 4.0 .
  • cc licence
  • by licence
  • nc licence
  • nd licence
Copyright © 2022 The Authors. Published by American Chemical Society

Subjects

what are subjects

Introduction

Click to copy section linkSection link copied!
The bridgehead pyrrolo[2,1-f][1,2,4]triazine heterocycle is a privileged scaffold found in numerous pharmaceutically important substances. The biological activities of compounds containing the pyrrolotriazine core include inhibition of kinases, anticancer activities, and potent antiviral effects. (1−8)
The first synthesis of the heterocycle based on addition/fragmentation of 1,2,4-triazines (hereafter denoted as triazines) with dimethyl acetylenedicarboxylate (DMAD) was reported by Neuenhoeffer in 1977. (9) Two years later, Migliara and co-workers reported synthesis of the pyrrolotriazine core via an acid-mediated cyclization of semicarbazone onto a pendant α-ketoester, followed by a base-promoted cyclization and decarboxylation. (10) These pioneering studies paved the way for later re-emergence of the heterocycle as a ‘purine-like’ scaffold introduced into a series of C-nucleoside analogues. (11−13) The discovery that C-4-substituted pyrrolotriazines are potent ATP-competitive kinase inhibitors (14) further fueled the research interest in these compounds and led to numerous candidates in late stages of clinical development and to approved drugs (Figure 1). (1,7,15−20)

Figure 1

Figure 1. Examples of biologically active pyrrolo[2,1-f][1,2,4]triazines (and their respective targets).

High Resolution Image
Download MS PowerPoint Slide
A typical synthetic route leading to pyrrolotriazines follows a number of steps depicted in Scheme 1A. Variations in these steps and late-stage modification of the heterocycle by, for example, cross-coupling reactions can provide access to diverse derivatives with a wide range of potential biological activities. (21−23)

Scheme 1

Scheme 1. (A) Example of a Typical Synthetic Route to Pyrrolo[2,1-f][1,2,4]triazines. (B) Single-Step Construction of Pyrrolotriazines via 1,3-Dipolar Cycloadditions
High Resolution Image
Download MS PowerPoint Slide
Despite the pharmacological importance of pyrrolotriazines reflected in numerous literature reports and patent applications, virtually no alternative synthetic procedures to the scaffold exist. Even the most recent examples exploit reactions that have been originally developed decades ago. (24) To the best of our knowledge, the only alternative route to pyrrolotriazines, briefly examined in the early 90s, was based on cycloadditions of 1-alkyl-1,2,4-triazinium ylides generated in situ from the respective triazinium precursors under basic conditions. (25) Despite its great synthetic potential, this methodology has remained largely unexplored and neglected.
Herein, we show that various, previously unknown pyrrolotriazines can be prepared in a single step from readily accessible 1-alkyl-1,2,4-triazinium salts via 1,3-dipolar cycloaddition (DCA) of the in situ generated triazinium ylides with electron-poor dipolarophiles (Scheme 1B).

Results and Discussion

Click to copy section linkSection link copied!
Substituted 1,2,4-triazines are synthetically readily accessible heterocycles. Depending on the substitution pattern, their preparation typically includes a single and usually high-yielding condensation step starting from various commercial glyoxal hydrates and S-alkyl isothiosemicarbazides in the presence of sodium bicarbonate. More recent synthetic routes include regioselective reactions of N-tosyl hydrazones with aziridines, (26) carbene N–H insertion of hydrazides, (27) O–H insertion of rhodium-azavinylcarbenes, (28) Zn-catalyzed hydrohydrazination of propargylamides, (29) cycloaddition of tetrazines, (30) or domino annulation reactions. (31) There are numerous possibilities to further derivatize and decorate the basic heterocyclic core. For example, simple 3-substituted triazines are susceptible to an easy nucleophilic attack at position 5 followed by position 6. (32,33) The S-alkyl substituents can be utilized in cross-coupling reactions (33,34) or after oxidation, used in nucleophilic substitutions. (35,36) Therefore, the substrate scope of the starting triazines is immense, opening an easy access to diverse 1-alkyl-1,2,4-triazinium salts.
The first goal of our study was to optimize the alkylation of the triazine core. For this purpose, we used 3-phenyltriazine 1a (34) and the commercial 3-methylthiotriazine and explored different alkylating agents and reaction conditions (Table S1). These experiments revealed that the alkylation with benzyl bromide and dimethyl sulfate is sluggish, while methyl iodide proved unreactive. In contrast, the use of Meerwein’s salt (Me3O+BF4–) led to clean formation of the N1-alkylated product. (25) Due to difficulties in handling this sensitive compound, we decided to explore triflates as more convenient alkylating agents. To our delight, the alkylation with methyl or ethyl triflate was successful. Interestingly, the simple 3-aryltriazines are alkylated exclusively at position 1, while electronically richer derivatives, such as the commercial 3-methylthiotriazine, led under the same conditions to the formation of products alkylated at both, N1 and N2, as determined by heteronuclear multiple bond correlation nuclear magnetic resonance (NMR) experiments.
The observed differences in the preferred position for the alkylation can be explained, at least in part, by differences in the electrostatic potential of differently substituted triazines in combination with steric effects of the substituent at position 3 (Figure S1).
We also studied the influence of various solvents on the alkylation reaction. Anhydrous toluene was found superior over other solvents with the minor N2 isomer being formed in 15% yield using the methyl triflate and in only 10% using the ethyl triflate. We found that the two N-alkylated isomers can be separated by reversed phase column chromatography. However, the N2 isomer does not interfere with the subsequent DCA step and can be easily removed during purification of the final cycloaddition product. Therefore, we used the crude mixture of the triazinium isomers in all subsequent experiments. Under the optimized conditions, we next prepared a series of triazinium triflates 2a-o-Me(Et) in excellent yields (Scheme 2).

Scheme 2

Scheme 2. Scope of Triazinium Compoundsa
High Resolution Image
Download MS PowerPoint Slide

aStandard conditions: triazine 1a–1o (2 mmol), triflate (2.4 mmol), anhydrous toluene (20 mL), 0 °C to RT, under argon. Note: all compounds are triflate salts.

The alkylation is basically quantitative, and the formed triazinium salt simply precipitates from the reaction mixture in most cases. The reaction can be conveniently performed on a larger scale (hundreds of milligrams), and the 1-alkyltriazinium triflates are surprisingly stable when stored in the crystalline form and even in solution (Figure S2).
With the set of triaziniums in hand, we proceeded to optimize the 1,3-dipolar cycloaddition reaction using DMAD as the dipolarophile and 3-phenyltriazinium methyl triflates 2a-Me and 2b-Me as model substrates. We experimented with different bases, solvents, temperatures, and orders of reagent addition. Unfortunately, all these efforts led only to decomposition of the starting materials and formation of the cycloaddition product in less than 10% yield in the best case.
In contrast to these initial results, we found that the cycloaddition of compounds bearing additional substituents at position 5 is viable. In this case, the reaction with DMAD performed in tetrahydrofuran (THF) in the presence of N,N-diisopropylethylamine (DIPEA) afforded the desired cycloaddition products 3d-m-H(Me) in good to very good yields (up to 84%). The reaction proceeded smoothly, and a wide range of triaziniums bearing various aryl substituents at position 5 were tolerated (Scheme 3). In general, cycloadditions of ethyl triazinium ylides gave higher yields when compared to the methylated analogues. The final pyrrolotriazines form in the reaction as the fully oxidized products especially from the methyl triaziniums. If this was not the case, the dihydro intermediates were converted to the oxidized products by simply opening the reaction flask to the air. By following the reaction progress on high-performance liquid chromatography mass spectrometry, we observed that a small portion of the triazinium compounds undergoes dequarternization at the nitrogen atom to yield the starting triazine. Although the exact mechanism remains unclear, similar dealkylation of N-alkyl triazinium salts has been observed previously. (37) Interestingly, the pyrrolotriazines are fluorescent compounds when irradiated at 365 nm using a standard handheld UV lamp. This property could be potentially exploited in preparation of new fluorophores based on this heterocyclic core.

Scheme 3

Scheme 3. 1,3-Dipolar Cycloaddition of Triazinium Ylides with DMADa
High Resolution Image
Download MS PowerPoint Slide

aStandard conditions: triazinium (0.5 mmol), DMAD (2 mmol), THF (10 mL), DIPEA (1.5 mmol), 0 °C to RT, 5 h.

Encouraged by these results, we decided to explore the possibility of using other dipolarophiles in the reaction (Scheme 4).

Scheme 4

Scheme 4. Scope of Dipolarophiles
High Resolution Image
Download MS PowerPoint Slide
Hence, reaction of 1-methyl-5-phenyl-1,2,4-triazinium triflate 2g-Me with methyl propiolate performed in THF using DIPEA as the base yielded after optimization the desired pyrrolotriazine 4g-H as a single regioisomer in 38% yield. The observed formation of the single regioisomer in the reaction is substantiated by the 5.0 kcal/mol lower energy of the corresponding transition state as evident from density functional theory (DFT) calculations (Figure S3). Even though the cycloaddition was in this case complicated by the competing reaction of the DIPEA base with the electron-poor triple bond, (38) this approach opens the possibility to generate additional pyrrolotriazines in a regioselective manner.
To further expand the scope of dipolarophiles, we performed the reaction with acrylonitrile, N-ethylmaleimide, and N-propargylmaleimide. The reaction with acrylonitrile yielded two diastereomers of a single regioisomer 5g-H in a 2 to 1 ratio and in 54% overall yield. The reaction with maleimide proceeded smoothly and afforded two diastereomeric products 6g-H in an 8 to 1 ratio and 88% overall yield. Based on DFT calculations, the transition state structure leading to the major product has lower calculated energy by 0.9 kcal/mol (Figure S4). Interestingly, only the minor isomer slowly oxidizes to the corresponding pyrrolotriazine. Cycloaddition experiments with N-propargylmaleimide and triaziniums 2g-Me and 2j-Me confirmed the diastereoselectivity of the transformation and yielded pyrrolotriazines 7g-H and 7j-H in 59% (significant dequarternization) and 95% overall yield, respectively.
Finally, to demonstrate the possibility of further derivatization of the pyrrolotriazine scaffold, we performed pilot coupling experiments with cycloadduct 3i-Me (Scheme 5). The thiomethyl substituent at position 3 was successfully utilized in the Liebeskind–Srogl cross-coupling reaction with phenylboronic acid under standard conditions. The corresponding 3-phenyl pyrrolotriazine isolated in 54% yield was used in the next Suzuki–Miyaura cross-coupling reaction, which gave the desired heterocyclic product 8i-Me in excellent 90% isolated yield.

Scheme 5

Scheme 5. Cross-Coupling Modificationsa
High Resolution Image
Download MS PowerPoint Slide

aConditions: 1. Phenylboronic acid (2.5 equiv), copper(I) thiophene-2-carboxylate (2.2 equiv), Pd(PPh3)4 (10 mol %), 1,4-dioxane, 95 °C. 2. Phenylboronic acid (2.0 equiv), PdCl2(dppf)·DCM (10 mol %), K2CO3 (2.0 equiv), 1,4-dioxane/H2O = 3/1, 100 °C.

Conclusions

Click to copy section linkSection link copied!
In conclusion, we show that 1,3-dipolar cycloadditions of electron-poor dipolarophiles with triazinium ylides generated in situ from 1-alkyl-1,2,4-triazinium salts provide a facile access to various pyrrolo[2,1-f][1,2,4]triazines in a single step. The reaction gives differently substituted pyrrolotriazines in good yields, and the resulting compounds can be further elaborated by selective cross-coupling reactions. Our experimental data complemented by DFT calculations demonstrate that the reactions can be regio- and diastereoselective. We believe that the presented methodology will provide an efficient synthetic route to medicinally relevant pyrrolotriazines from readily available starting materials.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02276.

  • General synthetic procedures, optimization details, 1H, 13C NMR and HRMS, and computational details (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
  • Authors
    • Juraj Galeta - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    • Veronika Šlachtová - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic
    • Martin Dračínský - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 16000, Czech Republic;  Orcidhttps://orcid.org/0000-0002-4495-0070
  • Author Contributions

    J.G. and V S. performed the synthetic work and isolated, purified, and characterized the compounds. M.D. performed all computational work and detailed NMR measurements of some compounds. M.V. supervised the work. The manuscript was written through contributions of all authors, and all authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 677465), by the Czech Science Foundation (20-30494L), and by the Academy of Sciences of the Czech Republic (RVO: 61388963). We also appreciate support from the IOCB fellowship for VS.

References

Click to copy section linkSection link copied!

This article references 38 other publications.

  1. 1
    Dzierba Carolyn, D.; Dasgupta, B.; Macor John, E.; Bronson Joanne, J.; Rajamani, R.; Karageorge George, N. Pyrrolotriazine Kinase Inhibitors. WO 2015054358 A1, 2014/10/08, 2015.
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Kim In, W. O. O.; Yoo Ja, K.; Kim Ji, D.; Jun Sun, A. H.; Lee Jun, H. E. Pyrrolotriazine Derivatives As Kinase Inhibitor. WO 2018169373 A1, 2018/03/19, 2018.
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Liang, C.; Jia, M.; Tian, D.; Sun, H. A. N. Synthesis And Medical Application Of Pyrrolo-[2,1-f] [1,2,4] Triazine Mother Nucleus Compound. CN 106432249 A, 2016/09/30, 2017.
    Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Ott, G. R.; Favor, D. A. Pyrrolo[2,1-f][1,2,4] triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle. Bioorg. Med. Chem. Lett. 2017, 27, 4238– 4246,  DOI: 10.1016/j.bmcl.2017.07.073
    Google Scholar
    4
    Pyrrolo[2,1-f][1,2,4]triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle
    Ott, Gregory R.; Favor, David A.
    Bioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4238-4246CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Pyrrolo[2,1-f][1,2,4]triazine, a unique N-N bond-contg. heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chem. until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chem. in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a "privileged" template, and finally reemergence in the C-nucleoside field.
  5. 5
    Yang, C.; Meng, L.; Chen, Y.; Wang, X.; Tan, C. U. N.; Li, J.; Ding, J.; Chen, Y. I. Pyrrolo[2,1-f[1,2,4]Triazine Compounds, Preparation Methods And Applications Thereof. U.S. Patent 9,724,352 B2, 2016/09/19, 2017.
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Tyndall, E. M.; Draffan, A. G.; Frey, B.; Pool, B.; Halim, R.; Jahangiri, S.; Bond, S.; Wirth, V.; Luttick, A.; Tilmanis, D.; Thomas, J.; Porter, K.; Tucker, S. P. Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro. Bioorg. Med. Chem. Lett. 2015, 25, 869– 873,  DOI: 10.1016/j.bmcl.2014.12.069
    Google Scholar
    6
    Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro
    Tyndall, Edward M.; Draffan, Alistair G.; Frey, Barbara; Pool, Brett; Halim, Rosliana; Jahangiri, Saba; Bond, Silas; Wirth, Veronika; Luttick, Angela; Tilmanis, Danielle; Thomas, Jesse; Porter, Kate; Tucker, Simon P.
    Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 869-873CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A no. of prodrugs of HCV-active purine nucleoside analogs 2'-C-Me 4-aza-9-deaza adenosine, 2'-C-Me 4-aza-7,9-dideaza adenosine, 2'-C-Me 4-aza-9-deaza guanosine and 2'-C-Me 4-aza-7,9-dideaza guanosine were prepd. and evaluated to improve potency, selectivity and liver targeting. Phosphoramidate guanosine prodrugs showed insufficient cell activity for further profiling. Striking enhancement in replicon activity relative to the parent was obsd. for phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs I [R1 = H, Me, c-Bu; PhCH2; R2 = H, Me; R3 = Me, Et, PhCH2; X = N], but this was accompanied by an increase in cytotoxicity. Improved or similar potency without a concomitant increase in toxicity relative to the parent was demonstrated for phosphoramidate pyrrolo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs I [R1 = Me, c-Bu; R2 = H, Me; R3 = Me, Et, i-Pr; X = CH]. Carbamate, ester and mixed prodrugs showed mixed results. Selected prodrugs were analyzed for activation to the triphosphate, with most demonstrating much better activation in hepatocytes over replicon cells. The best activation was obsd. for ester II followed by ester III.
  7. 7
    Mesaros, E. F.; Angeles, T. S.; Albom, M. S.; Wagner, J. C.; Aimone, L. D.; Wan, W.; Lu, L.; Huang, Z.; Olsen, M.; Kordwitz, E.; Haltiwanger, R. C.; Landis, A. J.; Cheng, M.; Ruggeri, B. A.; Ator, M. A.; Dorsey, B. D.; Ott, G. R. Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase. Bioorg. Med. Chem. Lett. 2015, 25, 1047– 1052,  DOI: 10.1016/j.bmcl.2015.01.019
    Google Scholar
    7
    Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase
    Mesaros, Eugen F.; Angeles, Thelma S.; Albom, Mark S.; Wagner, Jason C.; Aimone, Lisa D.; Wan, Weihua; Lu, Lihui; Huang, Zeqi; Olsen, Mark; Kordwitz, Emily; Haltiwanger, R. Curtis; Landis, Amy J.; Cheng, Mangeng; Ruggeri, Bruce A.; Ator, Mark A.; Dorsey, Bruce D.; Ott, Gregory R.
    Bioorganic & Medicinal Chemistry Letters (2015), 25 (5), 1047-1052CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The diastereoselective synthesis and biol. activity of piperidine-3,4-diol and piperidin-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivs. showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochem. and pharmacokinetic properties. Furthermore, the stereochem. of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (I) were more potent than the cis diastereomers (II).
  8. 8
    Lim, J.; Altman, M. D.; Baker, J.; Brubaker, J. D.; Chen, H.; Chen, Y.; Kleinschek, M. A.; Li, C.; Liu, D.; Maclean, J. K. F.; Mulrooney, E. F.; Presland, J.; Rakhilina, L.; Smith, G. F.; Yang, R. Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications. Bioorg. Med. Chem. Lett. 2015, 25, 5384– 5388,  DOI: 10.1016/j.bmcl.2015.09.028
    Google Scholar
    8
    Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications
    Lim, Jongwon; Altman, Michael D.; Baker, James; Brubaker, Jason D.; Chen, Hongmin; Chen, Yiping; Kleinschek, Melanie A.; Li, Chaomin; Liu, Duan; MacLean, John K. F.; Mulrooney, Erin F.; Presland, Jeremy; Rakhilina, Larissa; Smith, Graham F.; Yang, Ruojing
    Bioorganic & Medicinal Chemistry Letters (2015), 25 (22), 5384-5388CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    IRAK4 plays a crit. role in the IL-1R and TLR signaling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by c Log D led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.
  9. 9
    Neunhoeffer, H.; Lehmann, B. Cycloadditionen mit Azabenzolen, XI. Cycloadditionen mit Methoxy- und Dialkylamino-1,2,4-triazinen. Justus Liebigs Ann. Chem. 1977, 1977, 1413– 1420,  DOI: 10.1002/jlac.197719770902
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Migliara, O.; Petruso, S.; Sprio, V. Synthesis of a new bridgehead nitrogen heterocyclic system. Pyrrolo [2,1-f]-[1,2,4]-triazine derivatives. J. Heterocycl. Chem. 1979, 16, 833– 834,  DOI: 10.1002/jhet.5570160501
    Google Scholar
    10
    Synthesis of a new bridgehead nitrogen heterocyclic system. Pyrrolo[2,1-f]-1,2,4-triazine derivatives
    Migliara, Onofrio; Petruso, Salvatore; Sprio, Vincenzo
    Journal of Heterocyclic Chemistry (1979), 16 (5), 833-4CODEN: JHTCAD; ISSN:0022-152X.
    1-Ureidopyrroles I (R = OEt, R1 = Et; R = Ph, R1 = Me) were prepd. by treating ClCH2CMe:NNHCONH2 with RCOCH2COCO2R1 and were readily cyclized under basic conditions giving pyrrolo[2,1-f]-1,2,4-triazine-2,4(1H,3H)diones II (R = OH, Ph); II (R = OH) was decarboxylated.
  11. 11
    Maeba, I.; Hayashi, M.; Araki, A. C-Nucleosides A Synthesis of 2-Substituted 7-(β-D-Ribofuranosyl)pyrrolo[2,1-f]-[1,2,4]-triazines. A New Type of “Purine Like” C-Nucleoside. Heterocycles 1992, 34, 569– 574,  DOI: 10.3987/COM-91-5946
    Google Scholar
    11
    C-Nucleosides. 17. A synthesis of 2-substituted 7-(β-D-ribofuranosyl)-pyrrolo[2,1-f]-1,2,4-triazines. A new type of purine like C-nucleoside
    Hayashi, Masanori; Araki, Akemi; Maeba, Isamu
    Heterocycles (1992), 34 (3), 569-74CODEN: HTCYAM; ISSN:0385-5414.
    A versatile intermediate pyranulose glycoside I (R = O) for C-nucleoside synthesis was treated with semicarbazides H2NNHCXNH2 (X = O, S) to give the corresponding semicarbazones I (R = NNHCXNH2) (II) in good yield. Treatment of II with concd. HCl in dioxane followed by heating in AcOH and deblocking, gave C-nucleoside III.
  12. 12
    Patil, S. A.; Otter, B. A.; Klein, R. S. Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles. J. Heterocycl. Chem. 1994, 31, 781– 786,  DOI: 10.1002/jhet.5570310415
    Google Scholar
    12
    Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles
    Patil, Shirish A.; Otter, Brian A.; Klein, Robert S.
    Journal of Heterocyclic Chemistry (1994), 31 (4), 781-6CODEN: JHTCAD; ISSN:0022-152X.
    The synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines is described. Key intermediates 1-aminopyrrole-2-carbonitrile (3) and 1-amino-5-ethylpyrrole-2-carbonitrile (15) were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO → CN conversion with either hydroxylamine-O-sulfonic acid for 3 or O-mesitylenesulfonylhydroxylamine for 15. Cyclization of 3 or 15 with a variety of amidine reagents or, after conversion of 3 to its corresponding amide, base-catalyzed annulation completed the synthesis of the title products.
  13. 13
    Patil, S. A.; Otter, B. A.; Klein, R. S. 4-aza-7,9-dideazaadenosine, a new cytotoxic synthetic C-nucleoside analogue of adenosine. Tetrahedron Lett. 1994, 35, 5339– 5342,  DOI: 10.1016/s0040-4039(00)73494-0
    Google Scholar
    13
    4-Aza-7,9-dideazaadenosine, a new cytotoxic synthetic C-nucleoside analog of adenosine
    Patil, Shirish A.; Otter, Brian A.; Klein, Robert S.
    Tetrahedron Letters (1994), 35 (30), 5339-42CODEN: TELEAY; ISSN:0040-4039.
    The first synthesis of I, the pyrrolo[2,1-f]triazine C-nucleoside congener of adenosine is described. The key intermediate ribofuranosyl pyrrole is obtained by the direct C-ribosylation of pyrrolemagnesium bromide followed by an acid-catalyzed dehydration, Vilsmeier formylation, and N-amination. In vitro growth inhibitory activities of I against leukemic cell lines (0.8-15 nM) are comparable to those of 9-deazaadenosine.
  14. 14
    Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. Discovery of the Pyrrolo[2,1-f][1,2,4]triazine Nucleus as a New Kinase Inhibitor Template. J. Med. Chem. 2004, 47, 4054– 4059,  DOI: 10.1021/jm049892u
    Google Scholar
    14
    Discovery of the Pyrrolo[2,1-f][1,2,4]triazine Nucleus as a New Kinase Inhibitor Template
    Hunt, John T.; Mitt, Toomas; Borzilleri, Robert; Gullo-Brown, Johnni; Fargnoli, Joseph; Fink, Brian; Han, Wen-Ching; Mortillo, Steven; Vite, Gregory; Wautlet, Barri; Wong, Tai; Yu, Chiang; Zheng, Xiaoping; Bhide, Rajeev
    Journal of Medicinal Chemistry (2004), 47 (16), 4054-4059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochem. inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biol. activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochem. properties. Preliminary inhibition studies with varying ATP concns. suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
  15. 15
    Borzilleri, R. M.; Cai, Z.-w.; Ellis, C.; Fargnoli, J.; Fura, A.; Gerhardt, T.; Goyal, B.; Hunt, J. T.; Mortillo, S.; Qian, L.; Tokarski, J.; Vyas, V.; Wautlet, B.; Zheng, X.; Bhide, R. S. Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 1429– 1433,  DOI: 10.1016/j.bmcl.2004.12.079
    Google Scholar
    15
    Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors
    Borzilleri, Robert M.; Cai, Zhen-Wei; Ellis, Christopher; Fargnoli, Joseph; Fura, Aberra; Gerhardt, Tracy; Goyal, Bindu; Hunt, John T.; Mortillo, Steven; Qian, Ligang; Tokarski, John; Vyas, Viral; Wautlet, Barri; Zheng, Xioping; Bhide, Rajeev S.
    Bioorganic & Medicinal Chemistry Letters (2005), 15 (5), 1429-1433CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compds. with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus.
  16. 16
    Cai, Z.-w.; Wei, D.; Borzilleri, R. M.; Qian, L.; Kamath, A.; Mortillo, S.; Wautlet, B.; Henley, B. J.; Jeyaseelan, R.; Tokarski, J.; Hunt, J. T.; Bhide, R. S.; Fargnoli, J.; Lombardo, L. J. Synthesis, SAR, and Evaluation of 4-[2,4-Difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 1354– 1358,  DOI: 10.1016/j.bmcl.2008.01.012
    Google Scholar
    16
    Synthesis, SAR, and evaluation of 4-[2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors
    Cai, Zhen-wei; Wei, Donna; Borzilleri, Robert M.; Qian, Ligang; Kamath, Amrita; Mortillo, Steven; Wautlet, Barri; Henley, Benjamin J.; Jeyaseelan, Robert; Tokarski, John; Hunt, John T.; Bhide, Rajeev S.; Fargnoli, Joseph; Lombardo, Louis J.
    Bioorganic & Medicinal Chemistry Letters (2008), 18 (4), 1354-1358CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
    Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was obsd. with compd. I against L2987 human lung carcinoma xenografts in athymic mice.
  17. 17
    Gavai, A. V.; Fink, B. E.; Fairfax, D. J.; Martin, G. S.; Rossiter, L. M.; Holst, C. L.; Kim, S.-H.; Leavitt, K. J.; Mastalerz, H.; Han, W.-C.; Norris, D.; Goyal, B.; Swaminathan, S.; Patel, B.; Mathur, A.; Vyas, D. M.; Tokarski, J. S.; Yu, C.; Oppenheimer, S.; Zhang, H.; Marathe, P.; Fargnoli, J.; Lee, F. Y.; Wong, T. W.; Vite, G. D. Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases. J. Med. Chem. 2009, 52, 6527– 6530,  DOI: 10.1021/jm9010065
    Google Scholar
    17
    Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases
    Gavai, Ashvinikumar V.; Fink, Brian E.; Fairfax, David J.; Martin, Gregory S.; Rossiter, Lana M.; Holst, Christian L.; Kim, Soong-Hoon; Leavitt, Kenneth J.; Mastalerz, Harold; Han, Wen-Ching; Norris, Derek; Goyal, Bindu; Swaminathan, Shankar; Patel, Bharat; Mathur, Arvind; Vyas, Dolatrai M.; Tokarski, John S.; Yu, Chiang; Oppenheimer, Simone; Zhang, Hongjian; Marathe, Punit; Fargnoli, Joseph; Lee, Francis Y.; Wong, Tai W.; Vite, Gregory D.
    Journal of Medicinal Chemistry (2009), 52 (21), 6527-6530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochem. potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626, I) was selected as a clin. candidate for treatment of solid tumors.
  18. 18
    Schroeder, G. M.; Chen, X.-T.; Williams, D. K.; Nirschl, D. S.; Cai, Z.-W.; Wei, D.; Tokarski, J. S.; An, Y.; Sack, J.; Chen, Z.; Huynh, T.; Vaccaro, W.; Poss, M.; Wautlet, B.; Gullo-Brown, J.; Kellar, K.; Manne, V.; Hunt, J. T.; Wong, T. W.; Lombardo, L. J.; Fargnoli, J.; Borzilleri, R. M. Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase. Bioorg. Med. Chem. Lett. 2008, 18, 1945– 1951,  DOI: 10.1016/j.bmcl.2008.01.121
    Google Scholar
    18
    Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase
    Schroeder, Gretchen M.; Chen, Xiao-Tao; Williams, David K.; Nirschl, David S.; Cai, Zhen-Wei; Wei, Donna; Tokarski, John S.; An, Yongmi; Sack, John; Chen, Zhong; Huynh, Tram; Vaccaro, Wayne; Poss, Michael; Wautlet, Barri; Gullo-Brown, Johnni; Kellar, Kristen; Manne, Veeraswamy; Hunt, John T.; Wong, Tai W.; Lombardo, Louis J.; Fargnoli, Joseph; Borzilleri, Robert M.
    Bioorganic & Medicinal Chemistry Letters (2008), 18 (6), 1945-1951CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
    An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compds. with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallog. revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
  19. 19
    Thieu, T.; Sclafani, J. A.; Levy, D. V.; McLean, A.; Breslin, H. J.; Ott, G. R.; Bakale, R. P.; Dorsey, B. D. Discovery and Process Synthesis of Novel 2,7-Pyrrolo[2,1-f][1,2,4]triazines. Org. Lett. 2011, 13, 4204– 4207,  DOI: 10.1021/ol2015237
    Google Scholar
    19
    Discovery and Process Synthesis of Novel 2,7-Pyrrolo[2,1-f][1,2,4]triazines
    Thieu, Tho; Sclafani, Joseph A.; Levy, Daniel V.; McLean, Andrew; Breslin, Henry J.; Ott, Gregory R.; Bakale, Roger P.; Dorsey, Bruce D.
    Organic Letters (2011), 13 (16), 4204-4207CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    The synthesis of a new kinase inhibitor template 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine is described which includes a late stage orthogonally reactive key intermediate amenable to rapid diversification as well an optimized in situ triflate displacement to install the C2-aniline. Furthermore, an efficient scalable process approach will be highlighted which begins with tert-Bu carbazate to provide the key N-N bond and generates the pyrrolotriazine core through a stable bromoaldehyde intermediate followed by condensation with ammonium carbonate.
  20. 20
    Hodous Brian, L.; Wilson Kevin, J.; Zhang, Y. Compositions Useful For Treating Disorders Related To Kit And Pdfgr. U.S. Patent 20,170,022,206 A1, 2016/07/22, 2017.
    Google Scholar
    There is no corresponding record for this reference.
  21. 21
    Cascioferro, S.; Parrino, B.; Spanò, V.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G. An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds. Eur. J. Med. Chem. 2017, 142, 328– 375,  DOI: 10.1016/j.ejmech.2017.08.009
    Google Scholar
    21
    An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds
    Cascioferro, Stella; Parrino, Barbara; Spano, Virginia; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo
    European Journal of Medicinal Chemistry (2017), 142 (), 328-375CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivs., their N-oxides, N,N'-dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivs. disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivs. having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clin. trials.
  22. 22
    Xin, M.; Zhang, L.; Tang, F.; Tu, C.; Wen, J.; Zhao, X.; Liu, Z.; Cheng, L.; Shen, H. Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors. Bioorg. Med. Chem. 2014, 22, 1429– 1440,  DOI: 10.1016/j.bmc.2013.12.055
    Google Scholar
    22
    Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors
    Xin, Minhang; Zhang, Liandi; Tang, Feng; Tu, Chongxing; Wen, Jun; Zhao, Xinge; Liu, Zhaoyu; Cheng, Lingfei; Shen, Han
    Bioorganic & Medicinal Chemistry (2014), 22 (4), 1429-1440CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compd. with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compds. were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compd. (I), a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.
  23. 23
    Song, Y. n.; Zhan, P.; Zhang, Q.; Liu, X. Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry. Curr. Pharm. Des. 2013, 19, 1528– 1548,  DOI: 10.2174/1381612811319080020
    Google Scholar
    23
    Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry
    Song, Yu'ning; Zhan, Peng; Zhang, Qingzhu; Liu, Xinyong
    Current Pharmaceutical Design (2013), 19 (8), 1528-1548CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivs. with a wide range of biol. activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogen-activated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biol. properties of pyrrolo[2,1-f][1,2,4]triazine derivs. have motivated new studies in searching for novel derivs. with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1-f][1,2,4]triazine derivs. concerning the design of potent drug-like compds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacol. activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.
  24. 24
    Paymode, D. J.; Cardoso, F. S. P.; Agrawal, T.; Tomlin, J. W.; Cook, D. W.; Burns, J. M.; Stringham, R. W.; Sieber, J. D.; Gupton, B. F.; Snead, D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 22, 7656– 7661,  DOI: 10.1021/acs.orglett.0c02848
    Google Scholar
    24
    Expanding access to remdesivir via an improved pyrrolotriazine synthesis: Supply centered synthesis
    Paymode, Dinesh J.; Cardoso, Flavio S. P.; Agrawal, Toolika; Tomlin, John W.; Cook, Daniel W.; Burns, Justina M.; Stringham, Rodger W.; Sieber, Joshua D.; Gupton, B. Frank; Snead, David R.
    Organic Letters (2020), 22 (19), 7656-7661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Pyrrolo[2,1-f][1,2,4]triazine is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.
  25. 25
    Chupakhin, O. N.; Rudakov, B. V.; Alexeev, S. G.; Shorshnev, S. V.; Charushin, V. N. 1-Alkyl-1,2,4-triazinium Ylides as 1,3-Dipoles in a Cycloaddition Reaction with Diethyl Acetylenedicarboxylate. Mendeleev Commun. 1992, 2, 85– 86,  DOI: 10.1070/mc1992v002n03abeh000144
    Google Scholar
    There is no corresponding record for this reference.
  26. 26
    Crespin, L.; Biancalana, L.; Morack, T.; Blakemore, D. C.; Ley, S. V. One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines. Org. Lett. 2017, 19, 1084– 1087,  DOI: 10.1021/acs.orglett.7b00101
    Google Scholar
    26
    One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines
    Crespin, Lorene; Biancalana, Lorenzo; Morack, Tobias; Blakemore, David C.; Ley, Steven V.
    Organic Letters (2017), 19 (5), 1084-1087CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A new, three-step, telescoped reaction sequence for the regioselective conversion of N-tosyl hydrazones and aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines is described. The process involves an efficient nucleophilic ring opening of the aziridine, giving access to a wide range of aminohydrazones, isolated with excellent yields. A "one-pot" procedure, combining the ring opening with a cyclization and an oxidn. step, allows the prepn. of diversified triazines in good yields.
  27. 27
    Shi, B.; Lewis, W.; Campbell, I. B.; Moody, C. J. A Concise Route to Pyridines from Hydrazides by Metal Carbene N–H Insertion, 1,2,4-Triazine Formation, and Diels–Alder Reaction. Org. Lett. 2009, 11, 3686– 3688,  DOI: 10.1021/ol901502u
    Google Scholar
    27
    A Concise Route to Pyridines from Hydrazides by Metal Carbene N-H Insertion, 1,2,4-Triazine Formation, and Diels-Alder Reaction
    Shi, Baolu; Lewis, William; Campbell, Ian B.; Moody, Christopher J.
    Organic Letters (2009), 11 (16), 3686-3688CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A simple, new three-step sequence for the conversion of hydrazides into pyridines is reported in which the key steps are N-H insertion by a copper carbene intermediate derived from α-diazo-β-ketoesters into the hydrazide, reaction with ammonium acetate to give 1,2,4-triazines, followed by Diels-Alder reaction with norbornadiene.
  28. 28
    Meng, J.; Wen, M.; Zhang, S.; Pan, P.; Yu, X.; Deng, W.-P. Unexpected O–H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines. J. Org. Chem. 2017, 82, 1676– 1687,  DOI: 10.1021/acs.joc.6b02846
    Google Scholar
    28
    Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines
    Meng, Jiang; Wen, Min; Zhang, Shiwei; Pan, Peiwen; Yu, Xingxin; Deng, Wei-Ping
    Journal of Organic Chemistry (2017), 82 (3), 1676-1687CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    A practical and efficient method for divergent synthesis of 3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-triazines via unexpected rhodium-catalyzed O-H insertion/rearrangement/conditions-controlled intramol. cyclization and oxidn. reaction under mild conditions has been developed. Notably, it is the first example for the synthesis of 1,2,4-triazines with different substituted-patterns via a common intermediate with excellent chemoselectivities by the reaction of N-acylhydrazones as aze-[3C] or [4C] synthons with N-sulfonyl-1,2,3-triazoles as aze-[2C] synthons. Furthermore, this method allows direct access to di(het)aryl ketone frameworks contg. 1,2,4-triazine moiety for the first time, serving as a versatile building block for the synthesis of other useful heterocyclic skeletons, such as pyridine or pyridazinone-fused triazine in excellent yields.
  29. 29
    Lukin, A.; Vedekhina, T.; Tovpeko, D.; Zhurilo, N.; Krasavin, M. Zn-catalyzed hydrohydrazination of propargylamides with BocNHNH2: a novel entry into the 1,2,4-triazine core. RSC Adv. 2016, 6, 57956– 57959,  DOI: 10.1039/c6ra12664b
    Google Scholar
    29
    Zn-catalyzed hydrohydrazination of propargylamides with BocNHNH2: a novel entry into the 1,2,4-triazine core
    Lukin, Alexey; Vedekhina, Tatiana; Tovpeko, Dmitry; Zhurilo, Nikolay; Krasavin, Mikhail
    RSC Advances (2016), 6 (63), 57956-57959CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    Hydrohydrazination of a variety of propargylamides with BocNHNH2 under Zn(OTf)2 catalysis, unexpectedly, gave dihydro-1,2,4-triazines with a loss of the protecting group. The initial products could be efficiently aromatized in situ with K3[Fe(CN)6]. This provided a new entry into the medicinally important 1,2,4-triazine core.
  30. 30
    Zhu, Z.; Glinkerman, C. M.; Boger, D. L. Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding. J. Am. Chem. Soc. 2020, 142, 20778– 20787,  DOI: 10.1021/jacs.0c09775
    Google Scholar
    30
    Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding
    Zhu, Zixi; Glinkerman, Christopher M.; Boger, Dale L.
    Journal of the American Chemical Society (2020), 142 (49), 20778-20787CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An unprecedented 1,4-cycloaddn. (vs 3,6-cycloaddn.) of 1,2,4,5-tetrazines is described with preformed or in situ generated aryl-conjugated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) that is conducted under mild reaction conditions (0.1 M HFIP, 25°C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddn. across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed by a formal retro [4 + 2] cycloaddn. loss of a nitrile and aromatization to generate a 1,2,4-triazine deriv. The factors that impact the remarkable change in the reaction mode, optimization of reaction parameters, the scope and simplification of its implementation through in situ enamine generation from aldehydes and ketones, the reaction scope for 3,6-bis(thiomethyl)-1,2,4,5-tetrazine, a survey of participating 1,2,4,5-tetrazines, and key mechanistic insights into this reaction are detailed. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines under mild conditions from readily accessible starting materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP) provide products of the conventional 3,6-cycloaddn., the enhanced hydrogen bonding capability of HFIP uniquely results in promotion of the unprecedented formal 1,4-cycloaddn. As such, the studies represent an example of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddn. by hydrogen bonding catalysis but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddn.
  31. 31
    Tang, D.; Wang, J.; Wu, P.; Guo, X.; Li, J.-H.; Yang, S.; Chen, B.-H. Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot. RSC Adv. 2016, 6, 12514– 12518,  DOI: 10.1039/c5ra26638f
    Google Scholar
    31
    Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot
    Tang, Dong; Wang, Jing; Wu, Ping; Guo, Xin; Li, Ji-Hui; Yang, Sen; Chen, Bao-Hua
    RSC Advances (2016), 6 (15), 12514-12518CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    Simple and efficient [4 + 2] domino annulation reactions was developed for the synthesis of 1,2,4-triazine derivs. The strategies exhibited high performance with moderate to high yields, using easily available materials including ketones, aldehydes, alkynes, secondary alcs. and alkenes, representing a powerful tool for the formation of potentially biol. active derivs.
  32. 32
    Yamanaka, H; Konno, S.; Sagi, M.; Yoshida, N.; Yamanaka, H. Studies on as-Triazine Derivatives .X. Addition-Reaction of Phenylmagnesium Bromide with 1,2,4-Triazines. Heterocycles 1987, 26, 3111– 3114,  DOI: 10.3987/R-1987-12-3111
    Google Scholar
    32
    as-Triazine derivatives. X. Addition reaction of phenylmagnesium bromide with 1,2,4-triazines
    Konno, Shoetsu; Sagi, Mataichi; Yoshida, Nobuko; Yamanaka, Hiroshi
    Heterocycles (1987), 26 (12), 3111-14CODEN: HTCYAM; ISSN:0385-5414.
    Triazines I (R1 = H, SMe) were treated with PhMgBr to give dihydrotiazines II. Treatment of II with KFe3(CN)6 gave 5-phenyl-1,2,4-triazines III.
  33. 33
    Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. A General Approach to Selective Functionalization of 1,2,4-Triazines Using Organometallics in Palladium-Catalyzed Cross-Coupling and Addition Reactions. Synthesis 2004, 2893– 2899,  DOI: 10.1055/s-2004-834868
    Google Scholar
    33
    A general approach to selective functionalization of 1,2,4-triazines using organometallics in palladium-catalyzed Cross-coupling and addition reactions
    Alphonse, France-Aimee; Suzenet, Franck; Keromnes, Anne; Lebret, Bruno; Guillaumet, Gerald
    Synthesis (2004), (17), 2893-2899CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
    A selective way to obtain disubstituted 1,2,4-triazines, e.g., I, in good yields by combining addn. reactions and palladium-catalyzed cross-coupling reactions of organometallics with 3-methylsulfanyl-1,2,4-triazine is described.
  34. 34
    Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Unsaturated Tri-n-butylstannane with Heteroaromatic Thioether. Org. Lett. 2003, 5, 803– 805,  DOI: 10.1021/ol027453o
    Google Scholar
    34
    Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Unsaturated Tri-n-butylstannane with Heteroaromatic Thioether
    Alphonse, France-Aimee; Suzenet, Franck; Keromnes, Anne; Lebret, Bruno; Guillaumet, Gerald
    Organic Letters (2003), 5 (6), 803-805CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Palladium-catalyzed cross-coupling of vinyl- and arylstannanes with π-electron-deficient heteroaroms. was performed in good yields. This Stille-type reaction was carried out with a methylthioether function as an electrophile in the presence of a copper(I) bromide-dimethyl sulfide complex.
  35. 35
    Finlay, M. R. V.; Anderton, M.; Bailey, A.; Boyd, S.; Brookfield, J.; Cairnduff, C.; Charles, M.; Cheasty, A.; Critchlow, S. E.; Culshaw, J.; Ekwuru, T.; Hollingsworth, I.; Jones, N.; Leroux, F.; Littleson, M.; McCarron, H.; McKelvie, J.; Mooney, L.; Nissink, J. W. M.; Perkins, D.; Powell, S.; Quesada, M. J.; Raubo, P.; Sabin, V.; Smith, J.; Smith, P. D.; Stark, A.; Ting, A.; Wang, P.; Wilson, Z.; Winter-Holt, J. J.; Wood, J. M.; Wrigley, G. L.; Yu, G.; Zhang, P. Discovery of a Thiadiazole–Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models. J. Med. Chem. 2019, 62, 6540– 6560,  DOI: 10.1021/acs.jmedchem.9b00260
    Google Scholar
    35
    Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models
    Finlay, M. Raymond V.; Anderton, Mark; Bailey, Andrew; Boyd, Scott; Brookfield, Joanna; Cairnduff, Ceri; Charles, Mark; Cheasty, Anne; Critchlow, Susan E.; Culshaw, Janet; Ekwuru, Tennyson; Hollingsworth, Ian; Jones, Neil; Leroux, Fred; Littleson, Mairi; McCarron, Hollie; McKelvie, Jennifer; Mooney, Lorraine; Nissink, J. Willem M.; Perkins, David; Powell, Steve; Quesada, Mar Jimenez; Raubo, Piotr; Sabin, Verity; Smith, James; Smith, Peter D.; Stark, Andrew; Ting, Attilla; Wang, Peng; Wilson, Zena; Winter-Holt, Jon J.; Wood, J. Matthew; Wrigley, Gail L.; Yu, Guoqing; Zhang, Peng
    Journal of Medicinal Chemistry (2019), 62 (14), 6540-6560CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chem. evolution of a series from lipophilic inhibitors with suboptimal physicochem. and pharmacokinetic properties to cell potent examples with reduced mol. wt. and lipophilicity, leading to compds. with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.
  36. 36
    Shi, D.-H.; Harjani, J. R.; Gable, R. W.; Baell, J. B. Synthesis of 3-(Alkylamino)-, 3-(Alkoxy)-, 3-(Aryloxy)-, 3-(Alkylthio)-, and 3-(Arylthio)-1,2,4-triazines by Using a Unified Route with 3-(Methylsulfonyl)-1,2,4-triazine. Eur. J. Org. Chem. 2016, 2016, 2842– 2850,  DOI: 10.1002/ejoc.201600267
    Google Scholar
    36
    Synthesis of 3-(alkylamino)-, 3-(alkoxy)-, 3-(aryloxy)-, 3-(alkylthio)-, and 3-(arylthio)-1,2,4-triazines by using a unified route with 3-(methylsulfonyl)-1,2,4-triazine
    Shi, Da-Hua; Harjani, Jitendra R.; Gable, Robert W.; Baell, Jonathan B.
    European Journal of Organic Chemistry (2016), 2016 (16), 2842-2850CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In our attempts to synthesize 3-(alkylthio)- and 3-(alkoxy)-1,2,4-triazines without substituents at the 5- or 6-position, the synthesis of their anticipated precursor 3-(methylsulfonyl)-1,2,4 triazine was also optimized. The reactivity of 3-(methylsulfonyl)-1,2,4-triazine towards alkyl and aryl thiols, primary and secondary alkylamines, phenols, and alcs. was explored, and the reactions were optimized to maximize the isolation of the corresponding 3-substituted 1,2,4-triazine. Good yields were obtained for the products of the reactions with all of the aforementioned nucleophiles, with the exception of alcs., by using alkali metal carbonates. Higher yields of 3-(alkoxy)-1,2,4-triazines were obtained by using the appropriate magnesium alkoxide as the nucleophile.
  37. 37
    Chupakhin, O. N.; Rudakov, B. V.; McDermott, P.; Alexeev, S. G.; Charushin, V. N.; Hegarty, F. An Unusually Easy Oxidative Dequaternization of N-Alkyl-1,2,4-triazinium Salts. Mendeleev Commun. 1995, 5, 104– 105,  DOI: 10.1070/mc1995v005n03abeh000478
    Google Scholar
    There is no corresponding record for this reference.
  38. 38
    McCulloch, A. W.; McInnes, A. G. The Reaction of Propiolic Acid Esters with Tertiary Amines. Formation of Betaines. Can. J. Chem. 1974, 52, 3569– 3576,  DOI: 10.1139/v74-534
    Google Scholar
    38
    Reaction of propiolic acid esters with tertiary amines. Formation of betaines
    McCulloch, A. W.; McInnes, A. G.
    Canadian Journal of Chemistry (1974), 52 (21), 3569-76CODEN: CJCHAG; ISSN:0008-4042.
    Reaction of HC≡CCO2R with tertiary alkylamines, R13N, in highly aq. media yields betaines, trans-R31N+CH.dbd.CHCO2-. The spectral and chem. properties of these derivs. are discussed as well as the mechanism of their formation. The major byproduct of reaction is trans-ROCH:CHCO2R.

Cited By

Click to copy section linkSection link copied!
Citation Statements
Explore this article's citation statements on scite.ai
powered by  Scite

This article is cited by 5 publications.

  1. Veronika Šlachtová, Simona Bellová, Milan Vrabel. Synthesis of C3-Substituted N1-tert-Butyl 1,2,4-Triazinium Salts via the Liebeskind–Srogl Reaction for Fluorogenic Labeling of Live Cells. The Journal of Organic Chemistry 2024, 89 (20) , 14634-14640. https://doi.org/10.1021/acs.joc.3c02454
  2. Ankur Maji, Aditya Yadav, Shubham Sharma, Rajat Saini, Anshu Singh, Aurobinda Mohanty, Chayan K. Nandi, Kaushik Ghosh. One‐Pot Synthesis of 1, 2‐Dihydro [1,2,4] Triazinium Salt by Copper‐Assisted Unprecedented Cyclization Reaction: Applications in DNA and Protein Interaction Studies. ChemPlusChem 2024, 89 (12) https://doi.org/10.1002/cplu.202400219
  3. Veronika Šlachtová, Simona Bellová, Agustina La‐Venia, Juraj Galeta, Martin Dračínský, Karel Chalupský, Alexandra Dvořáková, Helena Mertlíková‐Kaiserová, Peter Rukovanský, Rastislav Dzijak, Milan Vrabel. Triazinium Ligation: Bioorthogonal Reaction of N 1‐Alkyl 1,2,4‐Triazinium Salts**. Angewandte Chemie 2023, 135 (36) https://doi.org/10.1002/ange.202306828
  4. Veronika Šlachtová, Simona Bellová, Agustina La‐Venia, Juraj Galeta, Martin Dračínský, Karel Chalupský, Alexandra Dvořáková, Helena Mertlíková‐Kaiserová, Peter Rukovanský, Rastislav Dzijak, Milan Vrabel. Triazinium Ligation: Bioorthogonal Reaction of N 1‐Alkyl 1,2,4‐Triazinium Salts**. Angewandte Chemie International Edition 2023, 62 (36) https://doi.org/10.1002/anie.202306828
  5. Pierre Audebert, Vincent Sol. Triazines, tetrazines and fused ring polyaza systems. 2023, 471-491. https://doi.org/10.1016/B978-0-443-21936-8.00013-6
Download PDF
Go to ACS Omega
Get e-Alerts
Get e-Alerts

ACS Omega

Cite this: ACS Omega 2022, 7, 24, 21233–21238
Click to copy citationCitation copied!
https://doi.org/10.1021/acsomega.2c02276
Published June 10, 2022

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY-NC-ND 4.0 .

Article Views

984

Altmetric

-

Citations

5
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Examples of biologically active pyrrolo[2,1-f][1,2,4]triazines (and their respective targets).

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. (A) Example of a Typical Synthetic Route to Pyrrolo[2,1-f][1,2,4]triazines. (B) Single-Step Construction of Pyrrolotriazines via 1,3-Dipolar Cycloadditions
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 2

    Scheme 2. Scope of Triazinium Compoundsa
    High Resolution Image
    Download MS PowerPoint Slide

    aStandard conditions: triazine 1a–1o (2 mmol), triflate (2.4 mmol), anhydrous toluene (20 mL), 0 °C to RT, under argon. Note: all compounds are triflate salts.

    Scheme 3

    Scheme 3. 1,3-Dipolar Cycloaddition of Triazinium Ylides with DMADa
    High Resolution Image
    Download MS PowerPoint Slide

    aStandard conditions: triazinium (0.5 mmol), DMAD (2 mmol), THF (10 mL), DIPEA (1.5 mmol), 0 °C to RT, 5 h.

    Scheme 4

    Scheme 4. Scope of Dipolarophiles
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 5

    Scheme 5. Cross-Coupling Modificationsa
    High Resolution Image
    Download MS PowerPoint Slide

    aConditions: 1. Phenylboronic acid (2.5 equiv), copper(I) thiophene-2-carboxylate (2.2 equiv), Pd(PPh3)4 (10 mol %), 1,4-dioxane, 95 °C. 2. Phenylboronic acid (2.0 equiv), PdCl2(dppf)·DCM (10 mol %), K2CO3 (2.0 equiv), 1,4-dioxane/H2O = 3/1, 100 °C.

  • References

    This article references 38 other publications.

    1. 1
      Dzierba Carolyn, D.; Dasgupta, B.; Macor John, E.; Bronson Joanne, J.; Rajamani, R.; Karageorge George, N. Pyrrolotriazine Kinase Inhibitors. WO 2015054358 A1, 2014/10/08, 2015.
      There is no corresponding record for this reference.
    2. 2
      Kim In, W. O. O.; Yoo Ja, K.; Kim Ji, D.; Jun Sun, A. H.; Lee Jun, H. E. Pyrrolotriazine Derivatives As Kinase Inhibitor. WO 2018169373 A1, 2018/03/19, 2018.
      There is no corresponding record for this reference.
    3. 3
      Liang, C.; Jia, M.; Tian, D.; Sun, H. A. N. Synthesis And Medical Application Of Pyrrolo-[2,1-f] [1,2,4] Triazine Mother Nucleus Compound. CN 106432249 A, 2016/09/30, 2017.
      There is no corresponding record for this reference.
    4. 4
      Ott, G. R.; Favor, D. A. Pyrrolo[2,1-f][1,2,4] triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle. Bioorg. Med. Chem. Lett. 2017, 27, 4238– 4246,  DOI: 10.1016/j.bmcl.2017.07.073
      4
      Pyrrolo[2,1-f][1,2,4]triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle
      Ott, Gregory R.; Favor, David A.
      Bioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4238-4246CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Pyrrolo[2,1-f][1,2,4]triazine, a unique N-N bond-contg. heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chem. until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chem. in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a "privileged" template, and finally reemergence in the C-nucleoside field.
    5. 5
      Yang, C.; Meng, L.; Chen, Y.; Wang, X.; Tan, C. U. N.; Li, J.; Ding, J.; Chen, Y. I. Pyrrolo[2,1-f[1,2,4]Triazine Compounds, Preparation Methods And Applications Thereof. U.S. Patent 9,724,352 B2, 2016/09/19, 2017.
      There is no corresponding record for this reference.
    6. 6
      Tyndall, E. M.; Draffan, A. G.; Frey, B.; Pool, B.; Halim, R.; Jahangiri, S.; Bond, S.; Wirth, V.; Luttick, A.; Tilmanis, D.; Thomas, J.; Porter, K.; Tucker, S. P. Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro. Bioorg. Med. Chem. Lett. 2015, 25, 869– 873,  DOI: 10.1016/j.bmcl.2014.12.069
      6
      Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro
      Tyndall, Edward M.; Draffan, Alistair G.; Frey, Barbara; Pool, Brett; Halim, Rosliana; Jahangiri, Saba; Bond, Silas; Wirth, Veronika; Luttick, Angela; Tilmanis, Danielle; Thomas, Jesse; Porter, Kate; Tucker, Simon P.
      Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 869-873CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A no. of prodrugs of HCV-active purine nucleoside analogs 2'-C-Me 4-aza-9-deaza adenosine, 2'-C-Me 4-aza-7,9-dideaza adenosine, 2'-C-Me 4-aza-9-deaza guanosine and 2'-C-Me 4-aza-7,9-dideaza guanosine were prepd. and evaluated to improve potency, selectivity and liver targeting. Phosphoramidate guanosine prodrugs showed insufficient cell activity for further profiling. Striking enhancement in replicon activity relative to the parent was obsd. for phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs I [R1 = H, Me, c-Bu; PhCH2; R2 = H, Me; R3 = Me, Et, PhCH2; X = N], but this was accompanied by an increase in cytotoxicity. Improved or similar potency without a concomitant increase in toxicity relative to the parent was demonstrated for phosphoramidate pyrrolo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs I [R1 = Me, c-Bu; R2 = H, Me; R3 = Me, Et, i-Pr; X = CH]. Carbamate, ester and mixed prodrugs showed mixed results. Selected prodrugs were analyzed for activation to the triphosphate, with most demonstrating much better activation in hepatocytes over replicon cells. The best activation was obsd. for ester II followed by ester III.
    7. 7
      Mesaros, E. F.; Angeles, T. S.; Albom, M. S.; Wagner, J. C.; Aimone, L. D.; Wan, W.; Lu, L.; Huang, Z.; Olsen, M.; Kordwitz, E.; Haltiwanger, R. C.; Landis, A. J.; Cheng, M.; Ruggeri, B. A.; Ator, M. A.; Dorsey, B. D.; Ott, G. R. Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase. Bioorg. Med. Chem. Lett. 2015, 25, 1047– 1052,  DOI: 10.1016/j.bmcl.2015.01.019
      7
      Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase
      Mesaros, Eugen F.; Angeles, Thelma S.; Albom, Mark S.; Wagner, Jason C.; Aimone, Lisa D.; Wan, Weihua; Lu, Lihui; Huang, Zeqi; Olsen, Mark; Kordwitz, Emily; Haltiwanger, R. Curtis; Landis, Amy J.; Cheng, Mangeng; Ruggeri, Bruce A.; Ator, Mark A.; Dorsey, Bruce D.; Ott, Gregory R.
      Bioorganic & Medicinal Chemistry Letters (2015), 25 (5), 1047-1052CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The diastereoselective synthesis and biol. activity of piperidine-3,4-diol and piperidin-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivs. showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochem. and pharmacokinetic properties. Furthermore, the stereochem. of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (I) were more potent than the cis diastereomers (II).
    8. 8
      Lim, J.; Altman, M. D.; Baker, J.; Brubaker, J. D.; Chen, H.; Chen, Y.; Kleinschek, M. A.; Li, C.; Liu, D.; Maclean, J. K. F.; Mulrooney, E. F.; Presland, J.; Rakhilina, L.; Smith, G. F.; Yang, R. Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications. Bioorg. Med. Chem. Lett. 2015, 25, 5384– 5388,  DOI: 10.1016/j.bmcl.2015.09.028
      8
      Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications
      Lim, Jongwon; Altman, Michael D.; Baker, James; Brubaker, Jason D.; Chen, Hongmin; Chen, Yiping; Kleinschek, Melanie A.; Li, Chaomin; Liu, Duan; MacLean, John K. F.; Mulrooney, Erin F.; Presland, Jeremy; Rakhilina, Larissa; Smith, Graham F.; Yang, Ruojing
      Bioorganic & Medicinal Chemistry Letters (2015), 25 (22), 5384-5388CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      IRAK4 plays a crit. role in the IL-1R and TLR signaling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by c Log D led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.
    9. 9
      Neunhoeffer, H.; Lehmann, B. Cycloadditionen mit Azabenzolen, XI. Cycloadditionen mit Methoxy- und Dialkylamino-1,2,4-triazinen. Justus Liebigs Ann. Chem. 1977, 1977, 1413– 1420,  DOI: 10.1002/jlac.197719770902
      There is no corresponding record for this reference.
    10. 10
      Migliara, O.; Petruso, S.; Sprio, V. Synthesis of a new bridgehead nitrogen heterocyclic system. Pyrrolo [2,1-f]-[1,2,4]-triazine derivatives. J. Heterocycl. Chem. 1979, 16, 833– 834,  DOI: 10.1002/jhet.5570160501
      10
      Synthesis of a new bridgehead nitrogen heterocyclic system. Pyrrolo[2,1-f]-1,2,4-triazine derivatives
      Migliara, Onofrio; Petruso, Salvatore; Sprio, Vincenzo
      Journal of Heterocyclic Chemistry (1979), 16 (5), 833-4CODEN: JHTCAD; ISSN:0022-152X.
      1-Ureidopyrroles I (R = OEt, R1 = Et; R = Ph, R1 = Me) were prepd. by treating ClCH2CMe:NNHCONH2 with RCOCH2COCO2R1 and were readily cyclized under basic conditions giving pyrrolo[2,1-f]-1,2,4-triazine-2,4(1H,3H)diones II (R = OH, Ph); II (R = OH) was decarboxylated.
    11. 11
      Maeba, I.; Hayashi, M.; Araki, A. C-Nucleosides A Synthesis of 2-Substituted 7-(β-D-Ribofuranosyl)pyrrolo[2,1-f]-[1,2,4]-triazines. A New Type of “Purine Like” C-Nucleoside. Heterocycles 1992, 34, 569– 574,  DOI: 10.3987/COM-91-5946
      11
      C-Nucleosides. 17. A synthesis of 2-substituted 7-(β-D-ribofuranosyl)-pyrrolo[2,1-f]-1,2,4-triazines. A new type of purine like C-nucleoside
      Hayashi, Masanori; Araki, Akemi; Maeba, Isamu
      Heterocycles (1992), 34 (3), 569-74CODEN: HTCYAM; ISSN:0385-5414.
      A versatile intermediate pyranulose glycoside I (R = O) for C-nucleoside synthesis was treated with semicarbazides H2NNHCXNH2 (X = O, S) to give the corresponding semicarbazones I (R = NNHCXNH2) (II) in good yield. Treatment of II with concd. HCl in dioxane followed by heating in AcOH and deblocking, gave C-nucleoside III.
    12. 12
      Patil, S. A.; Otter, B. A.; Klein, R. S. Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles. J. Heterocycl. Chem. 1994, 31, 781– 786,  DOI: 10.1002/jhet.5570310415
      12
      Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles
      Patil, Shirish A.; Otter, Brian A.; Klein, Robert S.
      Journal of Heterocyclic Chemistry (1994), 31 (4), 781-6CODEN: JHTCAD; ISSN:0022-152X.
      The synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines is described. Key intermediates 1-aminopyrrole-2-carbonitrile (3) and 1-amino-5-ethylpyrrole-2-carbonitrile (15) were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO → CN conversion with either hydroxylamine-O-sulfonic acid for 3 or O-mesitylenesulfonylhydroxylamine for 15. Cyclization of 3 or 15 with a variety of amidine reagents or, after conversion of 3 to its corresponding amide, base-catalyzed annulation completed the synthesis of the title products.
    13. 13
      Patil, S. A.; Otter, B. A.; Klein, R. S. 4-aza-7,9-dideazaadenosine, a new cytotoxic synthetic C-nucleoside analogue of adenosine. Tetrahedron Lett. 1994, 35, 5339– 5342,  DOI: 10.1016/s0040-4039(00)73494-0
      13
      4-Aza-7,9-dideazaadenosine, a new cytotoxic synthetic C-nucleoside analog of adenosine
      Patil, Shirish A.; Otter, Brian A.; Klein, Robert S.
      Tetrahedron Letters (1994), 35 (30), 5339-42CODEN: TELEAY; ISSN:0040-4039.
      The first synthesis of I, the pyrrolo[2,1-f]triazine C-nucleoside congener of adenosine is described. The key intermediate ribofuranosyl pyrrole is obtained by the direct C-ribosylation of pyrrolemagnesium bromide followed by an acid-catalyzed dehydration, Vilsmeier formylation, and N-amination. In vitro growth inhibitory activities of I against leukemic cell lines (0.8-15 nM) are comparable to those of 9-deazaadenosine.
    14. 14
      Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. Discovery of the Pyrrolo[2,1-f][1,2,4]triazine Nucleus as a New Kinase Inhibitor Template. J. Med. Chem. 2004, 47, 4054– 4059,  DOI: 10.1021/jm049892u
      14
      Discovery of the Pyrrolo[2,1-f][1,2,4]triazine Nucleus as a New Kinase Inhibitor Template
      Hunt, John T.; Mitt, Toomas; Borzilleri, Robert; Gullo-Brown, Johnni; Fargnoli, Joseph; Fink, Brian; Han, Wen-Ching; Mortillo, Steven; Vite, Gregory; Wautlet, Barri; Wong, Tai; Yu, Chiang; Zheng, Xiaoping; Bhide, Rajeev
      Journal of Medicinal Chemistry (2004), 47 (16), 4054-4059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochem. inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biol. activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochem. properties. Preliminary inhibition studies with varying ATP concns. suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
    15. 15
      Borzilleri, R. M.; Cai, Z.-w.; Ellis, C.; Fargnoli, J.; Fura, A.; Gerhardt, T.; Goyal, B.; Hunt, J. T.; Mortillo, S.; Qian, L.; Tokarski, J.; Vyas, V.; Wautlet, B.; Zheng, X.; Bhide, R. S. Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 1429– 1433,  DOI: 10.1016/j.bmcl.2004.12.079
      15
      Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors
      Borzilleri, Robert M.; Cai, Zhen-Wei; Ellis, Christopher; Fargnoli, Joseph; Fura, Aberra; Gerhardt, Tracy; Goyal, Bindu; Hunt, John T.; Mortillo, Steven; Qian, Ligang; Tokarski, John; Vyas, Viral; Wautlet, Barri; Zheng, Xioping; Bhide, Rajeev S.
      Bioorganic & Medicinal Chemistry Letters (2005), 15 (5), 1429-1433CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compds. with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus.
    16. 16
      Cai, Z.-w.; Wei, D.; Borzilleri, R. M.; Qian, L.; Kamath, A.; Mortillo, S.; Wautlet, B.; Henley, B. J.; Jeyaseelan, R.; Tokarski, J.; Hunt, J. T.; Bhide, R. S.; Fargnoli, J.; Lombardo, L. J. Synthesis, SAR, and Evaluation of 4-[2,4-Difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 1354– 1358,  DOI: 10.1016/j.bmcl.2008.01.012
      16
      Synthesis, SAR, and evaluation of 4-[2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors
      Cai, Zhen-wei; Wei, Donna; Borzilleri, Robert M.; Qian, Ligang; Kamath, Amrita; Mortillo, Steven; Wautlet, Barri; Henley, Benjamin J.; Jeyaseelan, Robert; Tokarski, John; Hunt, John T.; Bhide, Rajeev S.; Fargnoli, Joseph; Lombardo, Louis J.
      Bioorganic & Medicinal Chemistry Letters (2008), 18 (4), 1354-1358CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
      Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was obsd. with compd. I against L2987 human lung carcinoma xenografts in athymic mice.
    17. 17
      Gavai, A. V.; Fink, B. E.; Fairfax, D. J.; Martin, G. S.; Rossiter, L. M.; Holst, C. L.; Kim, S.-H.; Leavitt, K. J.; Mastalerz, H.; Han, W.-C.; Norris, D.; Goyal, B.; Swaminathan, S.; Patel, B.; Mathur, A.; Vyas, D. M.; Tokarski, J. S.; Yu, C.; Oppenheimer, S.; Zhang, H.; Marathe, P.; Fargnoli, J.; Lee, F. Y.; Wong, T. W.; Vite, G. D. Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases. J. Med. Chem. 2009, 52, 6527– 6530,  DOI: 10.1021/jm9010065
      17
      Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases
      Gavai, Ashvinikumar V.; Fink, Brian E.; Fairfax, David J.; Martin, Gregory S.; Rossiter, Lana M.; Holst, Christian L.; Kim, Soong-Hoon; Leavitt, Kenneth J.; Mastalerz, Harold; Han, Wen-Ching; Norris, Derek; Goyal, Bindu; Swaminathan, Shankar; Patel, Bharat; Mathur, Arvind; Vyas, Dolatrai M.; Tokarski, John S.; Yu, Chiang; Oppenheimer, Simone; Zhang, Hongjian; Marathe, Punit; Fargnoli, Joseph; Lee, Francis Y.; Wong, Tai W.; Vite, Gregory D.
      Journal of Medicinal Chemistry (2009), 52 (21), 6527-6530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochem. potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626, I) was selected as a clin. candidate for treatment of solid tumors.
    18. 18
      Schroeder, G. M.; Chen, X.-T.; Williams, D. K.; Nirschl, D. S.; Cai, Z.-W.; Wei, D.; Tokarski, J. S.; An, Y.; Sack, J.; Chen, Z.; Huynh, T.; Vaccaro, W.; Poss, M.; Wautlet, B.; Gullo-Brown, J.; Kellar, K.; Manne, V.; Hunt, J. T.; Wong, T. W.; Lombardo, L. J.; Fargnoli, J.; Borzilleri, R. M. Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase. Bioorg. Med. Chem. Lett. 2008, 18, 1945– 1951,  DOI: 10.1016/j.bmcl.2008.01.121
      18
      Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase
      Schroeder, Gretchen M.; Chen, Xiao-Tao; Williams, David K.; Nirschl, David S.; Cai, Zhen-Wei; Wei, Donna; Tokarski, John S.; An, Yongmi; Sack, John; Chen, Zhong; Huynh, Tram; Vaccaro, Wayne; Poss, Michael; Wautlet, Barri; Gullo-Brown, Johnni; Kellar, Kristen; Manne, Veeraswamy; Hunt, John T.; Wong, Tai W.; Lombardo, Louis J.; Fargnoli, Joseph; Borzilleri, Robert M.
      Bioorganic & Medicinal Chemistry Letters (2008), 18 (6), 1945-1951CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
      An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compds. with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallog. revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
    19. 19
      Thieu, T.; Sclafani, J. A.; Levy, D. V.; McLean, A.; Breslin, H. J.; Ott, G. R.; Bakale, R. P.; Dorsey, B. D. Discovery and Process Synthesis of Novel 2,7-Pyrrolo[2,1-f][1,2,4]triazines. Org. Lett. 2011, 13, 4204– 4207,  DOI: 10.1021/ol2015237
      19
      Discovery and Process Synthesis of Novel 2,7-Pyrrolo[2,1-f][1,2,4]triazines
      Thieu, Tho; Sclafani, Joseph A.; Levy, Daniel V.; McLean, Andrew; Breslin, Henry J.; Ott, Gregory R.; Bakale, Roger P.; Dorsey, Bruce D.
      Organic Letters (2011), 13 (16), 4204-4207CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The synthesis of a new kinase inhibitor template 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine is described which includes a late stage orthogonally reactive key intermediate amenable to rapid diversification as well an optimized in situ triflate displacement to install the C2-aniline. Furthermore, an efficient scalable process approach will be highlighted which begins with tert-Bu carbazate to provide the key N-N bond and generates the pyrrolotriazine core through a stable bromoaldehyde intermediate followed by condensation with ammonium carbonate.
    20. 20
      Hodous Brian, L.; Wilson Kevin, J.; Zhang, Y. Compositions Useful For Treating Disorders Related To Kit And Pdfgr. U.S. Patent 20,170,022,206 A1, 2016/07/22, 2017.
      There is no corresponding record for this reference.
    21. 21
      Cascioferro, S.; Parrino, B.; Spanò, V.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G. An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds. Eur. J. Med. Chem. 2017, 142, 328– 375,  DOI: 10.1016/j.ejmech.2017.08.009
      21
      An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds
      Cascioferro, Stella; Parrino, Barbara; Spano, Virginia; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo
      European Journal of Medicinal Chemistry (2017), 142 (), 328-375CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivs., their N-oxides, N,N'-dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivs. disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivs. having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clin. trials.
    22. 22
      Xin, M.; Zhang, L.; Tang, F.; Tu, C.; Wen, J.; Zhao, X.; Liu, Z.; Cheng, L.; Shen, H. Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors. Bioorg. Med. Chem. 2014, 22, 1429– 1440,  DOI: 10.1016/j.bmc.2013.12.055
      22
      Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors
      Xin, Minhang; Zhang, Liandi; Tang, Feng; Tu, Chongxing; Wen, Jun; Zhao, Xinge; Liu, Zhaoyu; Cheng, Lingfei; Shen, Han
      Bioorganic & Medicinal Chemistry (2014), 22 (4), 1429-1440CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compd. with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compds. were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compd. (I), a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.
    23. 23
      Song, Y. n.; Zhan, P.; Zhang, Q.; Liu, X. Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry. Curr. Pharm. Des. 2013, 19, 1528– 1548,  DOI: 10.2174/1381612811319080020
      23
      Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry
      Song, Yu'ning; Zhan, Peng; Zhang, Qingzhu; Liu, Xinyong
      Current Pharmaceutical Design (2013), 19 (8), 1528-1548CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivs. with a wide range of biol. activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogen-activated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biol. properties of pyrrolo[2,1-f][1,2,4]triazine derivs. have motivated new studies in searching for novel derivs. with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1-f][1,2,4]triazine derivs. concerning the design of potent drug-like compds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacol. activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.
    24. 24
      Paymode, D. J.; Cardoso, F. S. P.; Agrawal, T.; Tomlin, J. W.; Cook, D. W.; Burns, J. M.; Stringham, R. W.; Sieber, J. D.; Gupton, B. F.; Snead, D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 22, 7656– 7661,  DOI: 10.1021/acs.orglett.0c02848
      24
      Expanding access to remdesivir via an improved pyrrolotriazine synthesis: Supply centered synthesis
      Paymode, Dinesh J.; Cardoso, Flavio S. P.; Agrawal, Toolika; Tomlin, John W.; Cook, Daniel W.; Burns, Justina M.; Stringham, Rodger W.; Sieber, Joshua D.; Gupton, B. Frank; Snead, David R.
      Organic Letters (2020), 22 (19), 7656-7661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Pyrrolo[2,1-f][1,2,4]triazine is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.
    25. 25
      Chupakhin, O. N.; Rudakov, B. V.; Alexeev, S. G.; Shorshnev, S. V.; Charushin, V. N. 1-Alkyl-1,2,4-triazinium Ylides as 1,3-Dipoles in a Cycloaddition Reaction with Diethyl Acetylenedicarboxylate. Mendeleev Commun. 1992, 2, 85– 86,  DOI: 10.1070/mc1992v002n03abeh000144
      There is no corresponding record for this reference.
    26. 26
      Crespin, L.; Biancalana, L.; Morack, T.; Blakemore, D. C.; Ley, S. V. One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines. Org. Lett. 2017, 19, 1084– 1087,  DOI: 10.1021/acs.orglett.7b00101
      26
      One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines
      Crespin, Lorene; Biancalana, Lorenzo; Morack, Tobias; Blakemore, David C.; Ley, Steven V.
      Organic Letters (2017), 19 (5), 1084-1087CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A new, three-step, telescoped reaction sequence for the regioselective conversion of N-tosyl hydrazones and aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines is described. The process involves an efficient nucleophilic ring opening of the aziridine, giving access to a wide range of aminohydrazones, isolated with excellent yields. A "one-pot" procedure, combining the ring opening with a cyclization and an oxidn. step, allows the prepn. of diversified triazines in good yields.
    27. 27
      Shi, B.; Lewis, W.; Campbell, I. B.; Moody, C. J. A Concise Route to Pyridines from Hydrazides by Metal Carbene N–H Insertion, 1,2,4-Triazine Formation, and Diels–Alder Reaction. Org. Lett. 2009, 11, 3686– 3688,  DOI: 10.1021/ol901502u
      27
      A Concise Route to Pyridines from Hydrazides by Metal Carbene N-H Insertion, 1,2,4-Triazine Formation, and Diels-Alder Reaction
      Shi, Baolu; Lewis, William; Campbell, Ian B.; Moody, Christopher J.
      Organic Letters (2009), 11 (16), 3686-3688CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      A simple, new three-step sequence for the conversion of hydrazides into pyridines is reported in which the key steps are N-H insertion by a copper carbene intermediate derived from α-diazo-β-ketoesters into the hydrazide, reaction with ammonium acetate to give 1,2,4-triazines, followed by Diels-Alder reaction with norbornadiene.
    28. 28
      Meng, J.; Wen, M.; Zhang, S.; Pan, P.; Yu, X.; Deng, W.-P. Unexpected O–H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines. J. Org. Chem. 2017, 82, 1676– 1687,  DOI: 10.1021/acs.joc.6b02846
      28
      Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines
      Meng, Jiang; Wen, Min; Zhang, Shiwei; Pan, Peiwen; Yu, Xingxin; Deng, Wei-Ping
      Journal of Organic Chemistry (2017), 82 (3), 1676-1687CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      A practical and efficient method for divergent synthesis of 3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-triazines via unexpected rhodium-catalyzed O-H insertion/rearrangement/conditions-controlled intramol. cyclization and oxidn. reaction under mild conditions has been developed. Notably, it is the first example for the synthesis of 1,2,4-triazines with different substituted-patterns via a common intermediate with excellent chemoselectivities by the reaction of N-acylhydrazones as aze-[3C] or [4C] synthons with N-sulfonyl-1,2,3-triazoles as aze-[2C] synthons. Furthermore, this method allows direct access to di(het)aryl ketone frameworks contg. 1,2,4-triazine moiety for the first time, serving as a versatile building block for the synthesis of other useful heterocyclic skeletons, such as pyridine or pyridazinone-fused triazine in excellent yields.
    29. 29
      Lukin, A.; Vedekhina, T.; Tovpeko, D.; Zhurilo, N.; Krasavin, M. Zn-catalyzed hydrohydrazination of propargylamides with BocNHNH2: a novel entry into the 1,2,4-triazine core. RSC Adv. 2016, 6, 57956– 57959,  DOI: 10.1039/c6ra12664b
      29
      Zn-catalyzed hydrohydrazination of propargylamides with BocNHNH2: a novel entry into the 1,2,4-triazine core
      Lukin, Alexey; Vedekhina, Tatiana; Tovpeko, Dmitry; Zhurilo, Nikolay; Krasavin, Mikhail
      RSC Advances (2016), 6 (63), 57956-57959CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      Hydrohydrazination of a variety of propargylamides with BocNHNH2 under Zn(OTf)2 catalysis, unexpectedly, gave dihydro-1,2,4-triazines with a loss of the protecting group. The initial products could be efficiently aromatized in situ with K3[Fe(CN)6]. This provided a new entry into the medicinally important 1,2,4-triazine core.
    30. 30
      Zhu, Z.; Glinkerman, C. M.; Boger, D. L. Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding. J. Am. Chem. Soc. 2020, 142, 20778– 20787,  DOI: 10.1021/jacs.0c09775
      30
      Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding
      Zhu, Zixi; Glinkerman, Christopher M.; Boger, Dale L.
      Journal of the American Chemical Society (2020), 142 (49), 20778-20787CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An unprecedented 1,4-cycloaddn. (vs 3,6-cycloaddn.) of 1,2,4,5-tetrazines is described with preformed or in situ generated aryl-conjugated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) that is conducted under mild reaction conditions (0.1 M HFIP, 25°C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddn. across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed by a formal retro [4 + 2] cycloaddn. loss of a nitrile and aromatization to generate a 1,2,4-triazine deriv. The factors that impact the remarkable change in the reaction mode, optimization of reaction parameters, the scope and simplification of its implementation through in situ enamine generation from aldehydes and ketones, the reaction scope for 3,6-bis(thiomethyl)-1,2,4,5-tetrazine, a survey of participating 1,2,4,5-tetrazines, and key mechanistic insights into this reaction are detailed. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines under mild conditions from readily accessible starting materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP) provide products of the conventional 3,6-cycloaddn., the enhanced hydrogen bonding capability of HFIP uniquely results in promotion of the unprecedented formal 1,4-cycloaddn. As such, the studies represent an example of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddn. by hydrogen bonding catalysis but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddn.
    31. 31
      Tang, D.; Wang, J.; Wu, P.; Guo, X.; Li, J.-H.; Yang, S.; Chen, B.-H. Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot. RSC Adv. 2016, 6, 12514– 12518,  DOI: 10.1039/c5ra26638f
      31
      Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot
      Tang, Dong; Wang, Jing; Wu, Ping; Guo, Xin; Li, Ji-Hui; Yang, Sen; Chen, Bao-Hua
      RSC Advances (2016), 6 (15), 12514-12518CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      Simple and efficient [4 + 2] domino annulation reactions was developed for the synthesis of 1,2,4-triazine derivs. The strategies exhibited high performance with moderate to high yields, using easily available materials including ketones, aldehydes, alkynes, secondary alcs. and alkenes, representing a powerful tool for the formation of potentially biol. active derivs.
    32. 32
      Yamanaka, H; Konno, S.; Sagi, M.; Yoshida, N.; Yamanaka, H. Studies on as-Triazine Derivatives .X. Addition-Reaction of Phenylmagnesium Bromide with 1,2,4-Triazines. Heterocycles 1987, 26, 3111– 3114,  DOI: 10.3987/R-1987-12-3111
      32
      as-Triazine derivatives. X. Addition reaction of phenylmagnesium bromide with 1,2,4-triazines
      Konno, Shoetsu; Sagi, Mataichi; Yoshida, Nobuko; Yamanaka, Hiroshi
      Heterocycles (1987), 26 (12), 3111-14CODEN: HTCYAM; ISSN:0385-5414.
      Triazines I (R1 = H, SMe) were treated with PhMgBr to give dihydrotiazines II. Treatment of II with KFe3(CN)6 gave 5-phenyl-1,2,4-triazines III.
    33. 33
      Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. A General Approach to Selective Functionalization of 1,2,4-Triazines Using Organometallics in Palladium-Catalyzed Cross-Coupling and Addition Reactions. Synthesis 2004, 2893– 2899,  DOI: 10.1055/s-2004-834868
      33
      A general approach to selective functionalization of 1,2,4-triazines using organometallics in palladium-catalyzed Cross-coupling and addition reactions
      Alphonse, France-Aimee; Suzenet, Franck; Keromnes, Anne; Lebret, Bruno; Guillaumet, Gerald
      Synthesis (2004), (17), 2893-2899CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
      A selective way to obtain disubstituted 1,2,4-triazines, e.g., I, in good yields by combining addn. reactions and palladium-catalyzed cross-coupling reactions of organometallics with 3-methylsulfanyl-1,2,4-triazine is described.
    34. 34
      Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Unsaturated Tri-n-butylstannane with Heteroaromatic Thioether. Org. Lett. 2003, 5, 803– 805,  DOI: 10.1021/ol027453o
      34
      Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Unsaturated Tri-n-butylstannane with Heteroaromatic Thioether
      Alphonse, France-Aimee; Suzenet, Franck; Keromnes, Anne; Lebret, Bruno; Guillaumet, Gerald
      Organic Letters (2003), 5 (6), 803-805CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Palladium-catalyzed cross-coupling of vinyl- and arylstannanes with π-electron-deficient heteroaroms. was performed in good yields. This Stille-type reaction was carried out with a methylthioether function as an electrophile in the presence of a copper(I) bromide-dimethyl sulfide complex.
    35. 35
      Finlay, M. R. V.; Anderton, M.; Bailey, A.; Boyd, S.; Brookfield, J.; Cairnduff, C.; Charles, M.; Cheasty, A.; Critchlow, S. E.; Culshaw, J.; Ekwuru, T.; Hollingsworth, I.; Jones, N.; Leroux, F.; Littleson, M.; McCarron, H.; McKelvie, J.; Mooney, L.; Nissink, J. W. M.; Perkins, D.; Powell, S.; Quesada, M. J.; Raubo, P.; Sabin, V.; Smith, J.; Smith, P. D.; Stark, A.; Ting, A.; Wang, P.; Wilson, Z.; Winter-Holt, J. J.; Wood, J. M.; Wrigley, G. L.; Yu, G.; Zhang, P. Discovery of a Thiadiazole–Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models. J. Med. Chem. 2019, 62, 6540– 6560,  DOI: 10.1021/acs.jmedchem.9b00260
      35
      Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models
      Finlay, M. Raymond V.; Anderton, Mark; Bailey, Andrew; Boyd, Scott; Brookfield, Joanna; Cairnduff, Ceri; Charles, Mark; Cheasty, Anne; Critchlow, Susan E.; Culshaw, Janet; Ekwuru, Tennyson; Hollingsworth, Ian; Jones, Neil; Leroux, Fred; Littleson, Mairi; McCarron, Hollie; McKelvie, Jennifer; Mooney, Lorraine; Nissink, J. Willem M.; Perkins, David; Powell, Steve; Quesada, Mar Jimenez; Raubo, Piotr; Sabin, Verity; Smith, James; Smith, Peter D.; Stark, Andrew; Ting, Attilla; Wang, Peng; Wilson, Zena; Winter-Holt, Jon J.; Wood, J. Matthew; Wrigley, Gail L.; Yu, Guoqing; Zhang, Peng
      Journal of Medicinal Chemistry (2019), 62 (14), 6540-6560CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chem. evolution of a series from lipophilic inhibitors with suboptimal physicochem. and pharmacokinetic properties to cell potent examples with reduced mol. wt. and lipophilicity, leading to compds. with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.
    36. 36
      Shi, D.-H.; Harjani, J. R.; Gable, R. W.; Baell, J. B. Synthesis of 3-(Alkylamino)-, 3-(Alkoxy)-, 3-(Aryloxy)-, 3-(Alkylthio)-, and 3-(Arylthio)-1,2,4-triazines by Using a Unified Route with 3-(Methylsulfonyl)-1,2,4-triazine. Eur. J. Org. Chem. 2016, 2016, 2842– 2850,  DOI: 10.1002/ejoc.201600267
      36
      Synthesis of 3-(alkylamino)-, 3-(alkoxy)-, 3-(aryloxy)-, 3-(alkylthio)-, and 3-(arylthio)-1,2,4-triazines by using a unified route with 3-(methylsulfonyl)-1,2,4-triazine
      Shi, Da-Hua; Harjani, Jitendra R.; Gable, Robert W.; Baell, Jonathan B.
      European Journal of Organic Chemistry (2016), 2016 (16), 2842-2850CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In our attempts to synthesize 3-(alkylthio)- and 3-(alkoxy)-1,2,4-triazines without substituents at the 5- or 6-position, the synthesis of their anticipated precursor 3-(methylsulfonyl)-1,2,4 triazine was also optimized. The reactivity of 3-(methylsulfonyl)-1,2,4-triazine towards alkyl and aryl thiols, primary and secondary alkylamines, phenols, and alcs. was explored, and the reactions were optimized to maximize the isolation of the corresponding 3-substituted 1,2,4-triazine. Good yields were obtained for the products of the reactions with all of the aforementioned nucleophiles, with the exception of alcs., by using alkali metal carbonates. Higher yields of 3-(alkoxy)-1,2,4-triazines were obtained by using the appropriate magnesium alkoxide as the nucleophile.
    37. 37
      Chupakhin, O. N.; Rudakov, B. V.; McDermott, P.; Alexeev, S. G.; Charushin, V. N.; Hegarty, F. An Unusually Easy Oxidative Dequaternization of N-Alkyl-1,2,4-triazinium Salts. Mendeleev Commun. 1995, 5, 104– 105,  DOI: 10.1070/mc1995v005n03abeh000478
      There is no corresponding record for this reference.
    38. 38
      McCulloch, A. W.; McInnes, A. G. The Reaction of Propiolic Acid Esters with Tertiary Amines. Formation of Betaines. Can. J. Chem. 1974, 52, 3569– 3576,  DOI: 10.1139/v74-534
      38
      Reaction of propiolic acid esters with tertiary amines. Formation of betaines
      McCulloch, A. W.; McInnes, A. G.
      Canadian Journal of Chemistry (1974), 52 (21), 3569-76CODEN: CJCHAG; ISSN:0008-4042.
      Reaction of HC≡CCO2R with tertiary alkylamines, R13N, in highly aq. media yields betaines, trans-R31N+CH.dbd.CHCO2-. The spectral and chem. properties of these derivs. are discussed as well as the mechanism of their formation. The major byproduct of reaction is trans-ROCH:CHCO2R.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02276.

    • General synthetic procedures, optimization details, 1H, 13C NMR and HRMS, and computational details (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.