Academia / Industry Collaborations towards the Functionalization of Aryl Azoles.

Aryl azoles can be found in numerous active pharmaceutical ingredients (APIs). Milvexian is a Factor Xia inhibitor currently in phase III for the treatment of thrombotic events containing an ortho-substituted 1-aryl-1H-1,2,3-triazole moiety. During the process development of Milvexian, we assessed multiple approaches for the preparation of 4-chloro-1,2,3-triazole, intermediate 1. In this review article, we will detail how we initiated several academic collaborations to speed up the selection of the best synthesis for commercial manufacturing. Ultimately, those results not only helped us to achieve our goal but yielded general methodologies for the functionalization of azoles that extended even beyond our initial scope.

Directed regioselective ortho,ortho'-magnesiations of aromatics and heterocycles using sBu2Mg in toluene.

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base sBu2Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several double ortho,ortho'-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes.

Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets.

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

Formation of XPhos-Ligated Palladium(0) Complexes and Reactivity in Oxidative Additions.

Understanding the nature of the intermediate species operating within a palladium catalytic cycle is crucial for developing efficient cross-coupling reactions. Even though the XPhos/Pd(OAc)2 catalytic system has found numerous applications, the nature of the active catalytic species remains elusive. A Pd0 complex ligated to XPhos has been detected and characterized in situ for the first time using cyclic voltammetry and NMR techniques. In the presence of XPhos, Pd(OAc)2 initially associates with the ligand to form a complex in solution, which has been characterized as PdII (OAc)2 (XPhos). This PdII center is then reduced to the Pd0 (XPhos)2 species by an intramolecular process. This study also sheds light on the formation of PdI -PdI dimers. Finally, a kinetic study probes a dissociative mechanism for the oxidative addition with aryl halides involving Pd0 (XPhos) as the reactive species in equilibrium with the unreactive Pd0 (XPhos)2 . Remarkably, the reportedly poorly reactive PhCl reacts at room temperature in the oxidative addition, which confirms the crucial role of the XPhos ligand in the activation of aryl chlorides.

Mapping the substrate scope of monoamine oxidase (MAO-N) as a synthetic tool for the enantioselective synthesis of chiral amines.

A library of 132 racemic chiral amines (α-substituted methylbenzylamines, benzhydrylamines, 1,2,3,4-tetrahydronaphthylamines (THNs), indanylamines, allylic and homoallylic amines, propargyl amines) was screened against the most versatile monoamine oxidase (MAO-N) variants D5, D9 and D11. MAO-N D9 exhibited the highest activity for most substrates and was applied to the deracemisation of a comprehensive set of selected primary amines. In all cases, excellent enantioselectivity was achieved (e.e. >99%) with moderate to good yields (55-80%). Conditions for the deracemisation of primary amines using a MAO-N/borane system were further optimised using THN as a template addressing substrate load, nature of the enzyme preparation, buffer systems, borane sources, and organic co-solvents.

Asymmetric bromine-lithium exchange: on the importance of both the diamine ligand and the organolithium reagent.

The asymmetric bromine-lithium exchange on a series of prochiral biphenyls was investigated. As in many asymmetric organolithium reactions, the chiral ligand (here a diamine) was considered to be the enantiocontrolling element. We show here that the organolithium reagent also plays an important role.

α-C-Glycosides via syn Opening of 1,2-Anhydro Sugars with Organozinc Compounds in Toluene/n-Dibutyl Ether.

The diastereoselective addition of organozinc species to 1,2-anhydro sugars in toluene/n-dibutyl ether solvent is reported. Compared to the existing methods, the reaction proceeds at 0 °C, and only a slight excess of nucleophile is required to achieve good yields. Scope was assessed with different O-protected glycals along with various nucleophiles (aryl, alkynyl). This methodology was applied to the synthesis of the α-anomer of canagliflozin.

Pyrrolo[2,3-d]pyrimidine synthesis through activation of N-benzyl groups by distal amides.

A new activation mode of CH2-benzylamino groups has been observed during the preparation of pyrrolopyrimidines from Ugi-Smiles adducts of hydroxypyrimidines. The cyclization proceeds via a formal deprotonation of the N-benzyl group followed by trapping of the resulting anion by the alkyne moiety. The key role of the vicinal amide function during the process was pointed out.

Palladium catalyzed ring opening of furans as a route to α,ß-unsaturated aldehydes.

Furans may be ring opened via pallado-catalyzed reactions leading to α,ß-unsaturated aldehydes and ketones tethered to indole and isoquinoline moieties. Besides their synthetic interest, these fragmentations bring interesting elements into the discussion around the reaction mechanisms involved in palladium C-H activations of electron-rich heterocycles.

Toward pyrrolo[2,3-d]pyrimidine scaffolds.

Herein, we present a new route to highly substituted pyrrolo[2,3-d]pyrimidines featuring a Ugi-Smiles/Sonogashira cascade followed by an efficient base-catalyzed intramolecular cyclization. When formaldehyde is chosen as input in the Ugi-Smiles step, aromatic fused systems are eventually obtained through the isomerization of an exo-alkylidene intermediate.