Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki–Miyaura cross-coupling reactions

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki–Miyaura cross-coupling reactions.

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes and were evaluated in the Suzuki–Miyaura cross-coupling reactions.

Palladium-catalyzed cross-coupling methodologies have become common themes in modern organic synthesis.^1–5 A decade before his death, Snieckus presented in his 2010 Nobel Prize review that privileged ligands represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst – the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.⁶ In the last two decades, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions. The overall rate of the reaction was increased with bulky trialkylphosphine or N-heterocyclic carbene ligands, which facilitated the oxidative addition processes of electron-rich, unactivated substrates like aryl chlorides.^7,8 Monophosphine ligands have found wide-spread use in metal-catalyzed cross-coupling reactions.^9–13 Privileged ligands such as Buchwald''s biarylphosphines,^14–17 Stradiotto''s biaryl P–N phosphines,^18–21 Fu/Koie/Shaughnessy''s trialkylphosphines,^7,8,22 Hartwig''s ferrocenes,^23,24 Ackermann''s diaminochlorophosphines,^25,26 Beller''s bis(adamantyl)phosphines²⁷ and N-aryl(benz)imidazolyl- or N-pyrrolyl-monophosphines,^28–30 Kwong''s indolyl-based monophosphines,^31–35 Zhang''s ClickPhos ligands,^36,37 Singer''s bippyPhos ligands,^38,39 Rodriguez/Tang''s oxaphospholes,^40,41 and Verkade''s proazaphosphatranes^42,43 have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonagashira, carbon–heteroatom cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized in cross-coupling methodologies.^44,45Open in a separate windowFig. 1Representative monophosphine ligands for palladium-catalyzed cross-coupling reactions.Our group is interested in a long-standing research program directed at the use of unexplored heterocyclic potential phosphorus ligands for cross-coupling reactions. Our first entry into the use of new heterocyclic phosphorus ligands was our previously developed complementary synthetic routes for the preparation of 3-aryl-2-phosphino[1,2-a]pyridine ligands 2 from 2-aminopyridine (1) (Fig. 2).⁴⁶ In this current work, we have developed synthetic protocols to access 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands 4 from 2-aminomethylpyridine (3) as our starting material.Open in a separate windowFig. 2Our previous and current syntheses of imidazopyridine phosphorus ligands.The parent 1-phosphinoimidazo[1,5-a]pyridine ligands 7a–c were synthesized from imidazo[1,5-a]pyridine (5). Imidazo[1,5-a]pyridine (5), which is commercially available, was conveniently prepared in a two-step sequence via formylation and cyclization with phosphorus oxychloride from 2-aminomethylpyridine (3, Scheme 1).⁴⁷ Reaction of imidazo[1,5-a]pyridine (5) with N-iodosuccinimide (NIS) afforded 1-iodoimidazo[1,5-a]pyridine (6),⁴⁸ which underwent palladium-catalyzed reactions with different phosphines in the presence of 1,1′-bis(diisopropylphosphino)ferrocene (DIPPF) to deliver our 1-phosphino imidazo[1,5-a]pyridine 7a–c ligands.⁴⁹Open in a separate windowScheme 1Preparation of 1-phosphinoimidazo[1,5-a]pyridine ligands 7a–c from 2-aminomethylpyridine (3).We were then interested in the preparation of various methoxy-substituted aryl imidazo[1,5-a]pyridine phosphorus ligands. 2-Aminomethylpyridine (3) reacted in with various mono-, di, and trimethoxy-substituted benzoyl chlorides, prepared from the corresponding benzoic acids with oxalyl chloride, to afford N-[(pyridin-2-yl)methyl]arylamides 8c–i in excellent yields (Scheme 2, Route A).⁵⁰ The arylamides 8c–i were then cyclized to generate 3-arylimidazo[1,5-a]pyridines 9c–i in the presence of phosphorus oxychloride under reflux in good yields, which were very pure and carried onto the next step without further purification.⁵¹ Route B showed that 2-methoxy-, 3-methoxy- and 3,4,5-trimethoxybenzaldehydes were reacted with 2-aminomethylpyridine (3) in the presence of TBHP and I₂ in DMF at 70 °C to afford 3-arylimidazo[1,5-a]pyridines 9a–b/j in moderate yields.⁵² We found that Route A was more convenient compared to Route B in terms of yields, time, and purification.Open in a separate windowScheme 2Preparation of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands 4a–s from 2-aminomethylpyridine (3) via Routes A and B.With intermediates 9a–j obtained from Routes A and B in hand, two different conditions to iodinate at the C-1 position were explored. Substrates 9a–j were successfully iodinated at the C-1 position using either NIS in acetonitrile⁴⁸ at room temperature or I₂ in THF under reflux to give 1-iodo-3-arylimidazo[1,5-a]pyridines 10a–j in low to excellent yields.⁵³ It was noted that mono- and dimethoxy substrates must be iodinated with NIS in acetonitrile within 3 h. Otherwise, the compounds would be over-iodinated on multiple carbons. However, the trimethoxy substrates were unsuccessful with NIS in acetonitrile within 3 h, but successful with I₂ in THF under reflux to give moderate yields. The trimethoxy substrates could be iodinated with NIS in acetonitrile but the time of the reaction needed to be 24 h at room temperature as shown for compound 9h (46 Iodo substrates 10a–j were successfully phosphinated at the C-1 position via the palladium-catalyzed reaction with diphenylphosphine and dicyclohexylphosphine to give new ligands 4a–s in low to moderate yields.⁴⁹ Many attempts to attach a di-tert-butylphosphine group to the iodo intermediates met with complete failure. Our early attempts to perform the metal–halogen exchange of the iodo intermediates followed by trapping with disubstituted chlorophosphines failed to yield any trace of phosphinated products.Iodination and palladium-catalyzed phosphination sequence reactions of 2-iodoimidazo[1,5-a]pyridines 9 and 10