Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions Vincent Le Fouler, Yu Chen, Vincent Gandon, Vincent Bizet, Christophe Salomé, Thomas Fessard, Fang Liu, K. Houk, Nicolas Blanchard To cite this version: Vincent Le Fouler, Yu Chen, Vincent Gandon, Vincent Bizet, Christophe Salomé, et al.. Ac- tivating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2- Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions. Journal of the American Chem- ical Society, American Chemical Society, 2019, 141 (40), pp.15901-15909. 10.1021/jacs.9b07037. hal-02323378 HAL Id: hal-02323378 https://hal.archives-ouvertes.fr/hal-02323378 Submitted on 6 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Activating pyrimidines by pre-distortion for the general synthesis of 7-aza-indazoles from 2-hydrazonylpyrimidines via intramolecular Diels-Alder reactions Vincent Le Fouler,⫦ Yu Chen,⫧ Vincent Gandon,⫨ Vincent Bizet,⫦ Christophe Salomé,⫩ Thomas Fes- sard,⫩ Fang Liu,⫪* K. N. Houk, ⫫* Nicolas Blanchard⫦* ⫦ Université de Haute-Alsace, Université de Strasbourg, CNRS, LIMA, UMR 7042, 68000 Mulhouse, France ⫧ State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. ⫨ Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France and Laboratoire de Chimie Moléculaire, CNRS UMR 9168, Ecole Polytechnique, IP Paris, route de Saclay, 91128 Palaiseau cedex, France ⫩ SpiroChem AG Rosental Area, WRO-1047-3, Mattenstrasse 24, 4058 Basel, Switzerland ⫪ College of Sciences, Nanjing Agricultural University, Nanjing 210095, China ⫫ Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States Supporting Information Placeholder ABSTRACT: Pyrimidines are almost unreactive partners Diels-Alder cycloaddition of azines 13-5 is of great inter- in Diels-Alder cycloadditions with alkenes and alkynes, est as it generates nitrogen-containing heterocycles 2, a and only reactions under drastic conditions have previ- privileged scaffold in life-science research and industry ously been reported. We describe how 2-hydrazonylpy- (Scheme 1a).6-8 High reactivity is generally observed with rimidines, easily obtained in two steps from commer- an increasing number of nitrogen atoms in the azine, cially available 2-halopyrimidines can be exceptionally which reduces the aromaticity of the 6p system and also activated by trifluoroacetylation. This allows a Diels-Al- favorably influences both distortion and interaction ener- der cycloaddition under very mild reaction conditions, gies required to reach the transition state of the Diels-Al- leading to a large diversity of aza-indazoles, a ubiquitous der cycloaddition.9 The 1,2,4,5-tetrazines are prototypical scaffold in medicinal chemistry. This reaction is general, example of highly reactive aza-diene that reacts with a scalable and has an excellent functional group tolerance. diversity of dienophiles, especially electron-rich, under A straightforward synthesis of a key intermediate of mild conditions.5 This rapid Diels-Alder reaction is cen- Bayer’s Vericiguat illustrates the potential of this cycload- tral to numerous chemical biology studies and drug acti- dition strategy. Quantum mechanical calculations show vation chemistries.10-12 Triazines can also be reactive as how the simple N-trifluoromethylation of 2-hydra- aza-dienes as demonstrated by studies by Boger,13,14 and zonylpyrimidines distorts the substrate into a transition applications in chemical biology by Prescher.15 state-like geometry that readily undergoes the intramolec- ular Diels-Alder cycloaddition. By contrast, near the other end of the azine spectrum, pyrimidines stand as unreactive 4p partners.9,16,17 Seminal studies by Neunhoeffer18 and van der Plas19,20 demon- Introduction strated some decades ago that the lack of reactivity of py- rimidines 3 in inter- or intramolecular Diels-Alder cy- cloadditions has to be overcome by an exceptionally re- 18,21-23 Cycloaddition reactions are unique tools that enable the active dienophile (e.g. ynamines ) or harsh reaction 24 rapid elaboration of complex scaffolds with control over conditions (up to 280 °C in batch and 310 °C in contin- 25 regio- and stereochemistry. Applications of these pericy- uous flow ) and long reaction times (up to several days) 26 clic reactions, and in particular the Diels-Alder cycload- (Scheme 1b). The scope of these early studies remained dition, can be found in natural products synthesis and the very limited, and only a handful of applications were re- 26 preparation of pharmaceutically relevant molecules.1,2 ported. From a strategic standpoint, the inverse electron-demand Scheme 1. Diels-Alder cycloadditions of 2-hydrazinyl-pyrimidines: an entry to relevant N-containing heterocycles. a) Diels-Alder reactions of azines Reactivity of azines in Diels-Alder cycloaddition 1 2 R1 N N N N Replacement of C by N: A R R N N N N N N ■ Reactivity increases B N ■ Distortion energy decreases -A B 2 N N N N N R ■ Orbital interaction energy is stronger 1 2 pyridine pyrimidine pyridazine pyrazine 1,2,4-triazine 1,2,4,5-tetrazine b) State-of-the-art Diels-Alder reactions of pyrimidines d) Reaction design based on distortion into a transition state-like geometry condensation N then domino- R R N Diels-Alder/retro-Diels-Alder N N N 3 4 N NHNH2 N Activating group N 12 H ■ Safety issues ■ High temperature (up to 280 °C) 8 ■ Long reaction times (up to days) ■ Limited scope retro-Diels-Alder c) This work, Diels-Alder of 2-hydrazonylpyrimidines under mild conditions then H2O 6 O then activation Hydrazine N then N Activation N N N N N X N N 20 or 60 °C N N N H H N N N Diels-Alder N N 5 6 7 8 N O N N N ■ Pyrimidines 5 are commercially available, ■ Gram scale inexpensive, structurally diverse ■ Synthetic application s-trans,Z-7 s-cis,Z-7 13 ■ Activation of 7 occurs under mild conditions ■ Outstanding activation of 7 [unreactive conformer] [reactive conformer] ■ Broad functional group tolerance revealed by quantum ■ Amenable to a one-pot process from 12 mechanical calculation ■ Pre-organization of 7 via s-cis and s-trans ■ Spontaneous retro-Diels- conformational equilibria Alder of 13 R2 ■ Activating group imposes distortion of 7 into a ■ Activating group is removed CO Me N 2 Cl transition state-like geometry upon hydrolysis H2N NH2 CF N 3 e) Classical reactions of (hetero)arylhydrazone with 6 lead to pyrazoles N R1 NC N F N 6 N N O N N N Ph N N H H N N N NHNH2 N N N N 12 14 15 HO ■ 9, Adempas® (Riociguat), R1 = H, R2 = Me ■ 11, BMT-145027 ■ Potential formation of pyrazoles ■ 10, Vericiguat, R1 = F, R2 = H (Bayer) (Bristol-Myers Squibb) Because of their low reactivity, the potential of the structurally diverse chemicals. 7-Aza-indazoles 8 are rel- Diels-Alder cycloadditions of pyrimidines remains un- evant nitrogen-containing heterocycles27 that can be tapped. If the reactivity challenge posed by pyrimidines found in the marketed drug Adempas® (9, Bayer28), Ver- could be met, it would be of high significance in terms of iciguat (10, Bayer and Merck & Co.29) actually in phase heterocyclic chemistry and would constitute a fertile III clinical trials and BMT-145027 (11, Bristol-Myers ground for theoretical explanation. Indeed, pyrimidines Squibb30). This conceptually new synthetic approach of are small building blocks that possess key advantages; a 7-aza-indazoles 8 has a very wide scope, is amenable to a large collection of structurally diverse pyrimidines is ac- one-pot procedure and could be performed on a gram cessible at low price, which stands in sharp contrast with scale. We also report quantum mechanical calculations of the triazines or tetrazines (see Supporting Information). this Diels-Alder reaction that shed light on the excep- tional activation of the 2-hydrazonopyrimidines 7. Indeed, this phenomenon can be explained by the formation of an We have discovered that 2-hydrazonopyrimidines 7 can activated conformer s-cis,Z-7 that is distorted into a tran- be activated towards Diels-Alder cycloaddition under sition state-like geometry (Scheme 1d). After Diels-Alder mild conditions (20 or 60 °C, microwave irradiation or cycloaddition, a spontaneous retro-Diels-Alder and hy- classical heating, Scheme 1c) in sharp contrast with pre- drolysis of the activating group delivers the desired 7-aza- vious observations about pyrimidine reactivity. The cor- indazole 8. The nature of the activating group is thus cen- responding cycloadducts are aza-indazoles 8, obtained in tral to prevent N-cyclization to the corresponding pyra- a straightforward three-step sequence from 2-halopyrim- zole 15 (Scheme 1e),31,32 to pre-organize the system idines 5 that are commercially available, inexpensive and through conformational equilibria and