Carbon-to-nitrogen single-atom transmutation of azaarenes

Abstract

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom¹. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines², but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis³. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

Fig. 1 |. Introduction.

a, Illustrative examples of ‘necessary nitrogen atom’ effects in drug development, found by replacement of a carbon atom with a nitrogen atom in the discovery process. b, The philosophical framework of single-atom transmutation as summarized by a square scheme. c, Two main pitfalls of existing insertion–deletion approaches. d, C-to-N transmutation of azaarenes delineated in this work. DPP4, dipeptidyl peptidase IV; PDE5, phosphodiesterase-5; ETA/B, endothelin-A/B; Me, methyl; ^tBu, tertiary butyl.

Fig. 2 |. Scope of the C-to-N transmutation of azaarenes.

Conditions: 1 (0.3 mmol), toluene (0.06 M), 390 nm LED, 1–5 h at 25 °C, then ammonium carbamate (7.0 equivalents (equiv.)), pyridine (10.0 equiv.), O₃/O₂ bubbling for 5–20 min at −78 °C, followed by heating at 90 °C for 24 h. Isolated yields are given. ^aHeating for 48 h. ^b12.0 equiv. of ammonium carbamate. ^cAmmoniolysis was carried out with 12.0 equiv. of ammonium acetate in ethanol (0.1 M). ^dIsolated with alternative workup procedure. See Supplementary Information for the details. Ph, phenyl group; OMe, methoxy group; OEt, ethoxy group; mCPBA, meta-chloroperoxybenzoic acid; Tf, triflate; Cp*, 1,2,3,4,5-pentamethylcyclopentadiene; Boc, tert-butyloxycarbonyl.

Fig. 3 |. Synthetic applications of C-to-N transmutation of azaarenes.

a, Scalable synthesis of belumosudil. b, Synthesis of rare triazanaphthalenes using single-atom transmutation logic. c, Editing of talnetant and brequinar. d, Alternative oxidative cleavage mediated by photoexcited nitroarene. Isolated yields from N-oxide substrates. See Supplementary Information for the detailed conditions. BOP, benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; TFA, trifluoroacetic acid; TACR3, tachykinin receptor 3; DHODH, dihydroorate dehydrogenase.

Fig. 4 |. Mechanistic experiments.

a, Tracing of a ¹³C label during the course of the reaction. b, Control experiments for assessing the reactivity of hydrolysed intermediates 10a and 10b.