Highly efficient Ir-catalyzed asymmetric hydrogenation of benzoxazinones and derivatives with a Brønsted acid cocatalyst† †Electronic supplementary information (ESI) available: See DOI: 10.1039/c8sc05797d

The Ir-catalyzed highly efficient asymmetric hydrogenation of benzoxazinones and derivatives was successfully developed with N-methylated ZhaoPhos L5 as the ligand, affording various chiral dihydrobenzoxazinones and derivatives with excellent results.


Introduction
Chiral dihydrobenzoxazinones and derivatives are important and unique building blocks in the biologically active molecule discovery process (Fig. 1). 1 Chiral dihydrobenzoxazinone derivatives A are potential IgE/IgG receptor modulators for the treatment of autoimmune diseases. 2 Chiral 1,2,3,4-tetrahydroquinoxaline compounds B-C and 2, 3-dihydro-3,8-diphenylbenzo[1,4]oxazine D are disclosed as active and promising cholesteryl ester transfer protein inhibitors. [3][4][5][6] Taking into account the growing importance of these compounds, great attention had been paid to the development of efficient enantioselective synthetic methodologies. Among various synthetic approaches for the construction of these chiral dihydrobenzoxazinones and derivatives, 7 the direct asymmetric hydrogenation of prochiral benzoxazinones and derivatives was paid great attention with the advantages of high atom economy, a relatively simple procedure and easy work-up. Zhou and co-workers realized Ru-catalyzed biomimetic asymmetric hydrogenation of benzoxazinones and derivatives in the presence of chiral phosphoric acid through the NAD(P)H mode. 7c In 2015, Beller and co-workers described asymmetric hydrogenation of benzoxazinones via a relay iron/chiral Brønsted acid catalysis with good to excellent enantioselectivities. 7e However, the reactivity of most catalytic systems is not very high with less than 2000 TON (turnover numbers). It is well known that the substrate activation strategy with noncovalent interactions has been widely used in the eld of asymmetric organic catalysis, which played an important role in greatly improving the reactivity and stereoselectivity. 8, 9 The thiourea motif as the hydrogen bonding donor can recognize suitable guest molecules, which usually works on the direct activation of neutral substrates bearing hydrogen bonding acceptor groups. 10 Compared with the hydrogen bonding interaction, the anion-binding ion-pairing strategy did not draw much attention until recent development in organocatalysis. 9b-d,11 In 2013, our group successfully developed a series of bifunctional bisphosphine-thiourea ligands, which extended the powerful hydrogen-bonding and anion-binding activation strategy in organocatalysis to transition-metal-catalyzed asymmetric hydrogenation, and a variety of functionalized substrates had been hydrogenated well. 12 Herein, we successfully realized Ircatalyzed highly enantioselective hydrogenation of prochiral benzoxazinones and derivatives using N-methylated ZhaoPhos L5 as the ligand, which may exhibit a single anion-binding activation mode among the substrate, cocatalyst Brønsted acid hydrochloric acid and ligand. A variety of hydrogenation products, chiral dihydrobenzoxazinones and derivatives, can be obtained with excellent results (>99% conversion, 88-96% yields, 91->99% ee), and our catalytic system displayed extremely high activity with up to 40 500 TON (Scheme 1). In addition, a highly efficient synthetic route was successfully developed to prepare the important intermediate for the potential IgE/IgG receptor modulator with our asymmetric hydrogenation methodology as the key reaction step.
A series of bisphosphine-(thio)urea ligands ( Fig. 2) were then applied to this Ir-catalyzed asymmetric hydrogenation of 3phenyl-2H-benzo[b] [1,4]oxazin-2-one 1a in THF. Full conversions and excellent enantioselectivities can be obtained in the presence of ZhaoPhos L1 and N-methylated ZhaoPhos L5, and N-methylated ZhaoPhos L5 provided higher enantioselectivity (>99% conversion, 98-99% ee, Table 2, entries 1 and 5). The ligand L2 containing one triuoromethyl group and ligand L3 without any triuoromethyl group on the phenyl ring provided poor conversions and excellent enantioselectivities (33-45% conversions, 97% ee, Table 2, entries 2 and 3). The ligand L4 displayed very poor reactivity and enantioselectivity, which changed the thiourea motif to the urea motif (11% conversion, 13% ee, Table 2, entry 4). In addition, no reaction was observed in the presence of ligand L6 without the thiourea motif (Table 2, entry 6). This indicated that the thiourea motif may make Scheme 1 Ir-catalyzed asymmetric hydrogenation of benzoxazinones and derivatives, and the possible activation mode. a great contribution to activate our substrate through anionbinding interactions. When the catalyst loading is decreased from 1.0 mol% to 0.2 mol%, full conversion and excellent enantioselectivity can be obtained with ligand L5 (>99% conversion, 99% ee, Table 2, entry 8). Interestingly, it is better than ZhaoPhos L1 (65% conversion, 98% ee, Table 2, entry 7 vs. entry 8). It is possible that a single anion-binding interaction in a precise position is sufficient in this asymmetric reaction, which is different from previous reports. 11,12b,d,e,g A series of representative Brønsted acids were then deeply inspected in this Ir/ligand L5-catalyzed asymmetric hydrogenation of 3-phenyl-2H-benzo[b] [1,4]oxazin-2-one 1a, and we found that there is a signicant correlation between the reactivity, enantioselectivity and acid strength of the Brønsted acid. When hydrochloric acid, HCl (4 M in dioxane), was switched to a strong acid, CF 3 SO 3 H, this hydrogenation proceeded smoothly to provide the same result with full conversion and 99% ee ( Table 3, entries 1 and 7). CF 3 COOH and H 3 PO 4 gave high conversions and good enantioselectivities (95->99% conversions, 81-84% ee, Table 3, entries 2 and 3). As expected, the weaker acids HCOOH and AcOH afforded poor reactivities and enantioselectivities (21-30% conversions, 57-58% ee, Table  3, entries [4][5]. In addition, the amount of Brønsted acid HCl was further investigated in this asymmetric hydrogenation. We found that the amount of HCl had little effect on the reactivity and enantioselectivity, and the reaction results remained excellent, when the amount of HCl was gradually reduced from 2.0 equiv. to 0.01 equiv. (>99% conversion, 95-99% ee, Table 3, entries 6-10). However, no reaction was observed in the absence of the cocatalyst HCl (Table 3, entry 11), which showed that HCl was involved in this transformation with great importance. These results also displayed that the acid strength of the Brønsted acid cocatalyst is very important to achieve excellent results in this asymmetric hydrogenation, which may affect the formation of anion-binding activation among the substrate, Brønsted acid and ligand. To our delight, this asymmetric hydrogenation still proceeded smoothly with the same result even when catalyzed by only the 0.1 mol% [Ir(COD)Cl] 2 /ligand L5 catalyst with 1.0 equiv. HCl (4 M in dioxane) ( Table 3, entry  12).
The deuterium-labeling experiment was conducted to verify the hydrogen atom source of the hydrogenation product dihydrobenzoxazinone. As shown in Scheme 2, the asymmetric hydrogenation of 3-phenyl-2H-benzo[b] [1,4]oxazin-2-one 1a Table 4 Substrate scope study of Ir-catalyzed asymmetric hydrogenation of benzoxazinones a a Unless otherwise noted, all reactions were carried out with a [Ir(COD) Cl] 2 /ligand L5/substrate 1 (0.05 mmol) ratio of 0.5 : 1.1 : 1000 in 1.0 mL THF with 1.0 equiv. HCl (4 M in dioxane) at room temperature under 30 atm H 2 for 16 h. Conversion was determined by 1 H NMR analysis, ee was determined by HPLC with a chiral stationary phase, and the yield was isolated yield.   [1,4]oxazin-2-one 1a were performed using ligand L5 with varying ee values. As shown in Fig. 3, there is no nonlinear effect in this transformation, which indicated that there should be no catalyst self-aggregation or ligand-substrate agglomeration in this catalytic system. 13 IgE/IgG is one of the most important immunoglobulins, which are associated with the release of vasoactive amines stored in basophils and tissue mast cell granules to cause allergic effects. Our catalytic hydrogenation methodology showed great synthetic application. As shown in Scheme 3,amino)-3-methyl-2H-benzo[b] [1,4]oxazin-2-one 1q was efficiently obtained within four steps using the easily commercially available 2-amino-5-nitrophenol as the starting material. 14 The Ir-catalyzed asymmetric hydrogenation of compound 1q was efficiently accomplished to obtain the chiral compound 2q with 92% yield and 91% ee, which is the key intermediate to construct the potential IgE/IgG receptor modulator for the treatment of autoimmune diseases. 2

Conclusions
In summary, the Ir-catalyzed asymmetric hydrogenation of benzoxazinones and derivatives was successfully developed with N-methylated ZhaoPhos L5 as the ligand through a new anion-binding activation strategy. A series of chiral dihydrobenzoxazinones and derivatives were obtained with excellent results (88-96% yields, 91->99% ee, up to 40 500 TON). The utilization of a strong Brønsted acid, such as hydrochloric acid even at a small catalytic amount, as the cocatalyst is very important to form a single anion-binding interaction with the substrate and ligand L5, which strongly improved the reactivity. Moreover, a highly efficient synthetic route was developed to construct the key intermediate to synthesize a potential IgE/IgG receptor modulator through our catalytic methodology system.

Conflicts of interest
There are no conicts to declare.