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Open AccessCCS ChemistryRESEARCH ARTICLES23 Sep 2024

Asymmetric Amination of Primary Alcohols via Dynamic Kinetic Resolution: Enantioconvergent Access to Chiral Benzomorpholines

    https://doi.org/10.31635/ccschem.024.202404559

    We present here a catalytic enantioconvergent amination of alcohols for efficient access to chiral C2- and C3-substituted benzomorpholines. The racemic amino alcohol substrates of different substitution patterns, which are readily available from a common precursor, can be converted to the enantioenriched heterocycles in a highly atom- and step-economical fashion. In particular, an unprecedented asymmetric amination of racemic primary alcohols via dynamic kinetic resolution is achieved under cooperative iridium/iron catalysis, resulting in highly enantioenriched C2-substituted benzomorpholines that are difficult to access otherwise.

    Introduction

    Enantioconvergent transformations via dynamic kinetic resolution (DKR) represents a significant strategy in stereoselective synthesis, offering the powerful capability of converting readily accessible, racemic starting materials to value-added enantioenriched products with high efficiency.1–5 Notably, in the majority of reported DKR processes (Figure 1a), the generation of a new stereogenic center serves as the foundation for setting product stereochemistry; the pre-existing stereocenter in the racemic substrates generally undergoes facile racemization and is converted to one major isomer based on diastereo-control.

    Figure 1

    Figure 1 | Establishing isolated preexisting stereocenter via DKR and application to N-heterocycle synthesis. (a) Established transformations in dynamic kinetic resolution. (b) Rarely reported transformations in dynamic kinetic resolution. (c) Selected benzomorpholine-based drugs and bioactive compounds. (d) This work: enantioconvergent access to C3- & C2-substituted benzomorpholines.

    In sharp contrast, the construction of enantioenriched products by fixing the isolated stereocenter originating from the substrate remains a formidable challenge in asymmetric synthesis (Figure 1b). Such molecular structures bearing a stereocenter remote from the functionality are highly intriguing but extremely difficult to access in an enantioenriched form. The key difficulties in achieving high enantioselectivity in these DKR reactions lies in the facts that (a) the high reactivity of the functionalities (such as an aldehyde) requires an extremely facile racemization of preexisting stereocenter and (b) the recognition of stereochemistry has to be established remotely by the reaction site. In fact, only a few examples of this type of DKR process have been reported in the literature from the Zhou group, the List group and others,6–9 who have all focused on asymmetric (transfer) hydrogenation or reductive amination of aldehydes to produce acyclic alcohols/amines bearing α β-stereogenic center. Considering the attractiveness of this strategy to set challenging stereocenters, it is highly desirable to apply it to the preparation of chiral heterocycles with substitution patterns that are difficult to access otherwise (Figure 1b right). These endeavors can dramatically expand the privileged heterocyclic chemical space for medicinal chemistry.10 However, to the best of our knowledge, such an approach has never been documented in the literature.

    Compared with the well-established imine (transfer) hydrogenation11–13 or reductive amination14–16 necessitating stoichiometric reductants, the direct amination of alcohols through borrowing hydrogen attracted a great deal of attention as a powerful strategy to promote green chemical synthesis.17–21 These methods use the alcohol substrates as an inherent reductant, achieve overall redox-neutral C–N bond formation with minimal use of reagents, and generate water as the sole side product. Aiming toward N-heterocycle synthesis, an intramolecular amination can deliver these valuable compounds from simple amino alcohol substrates with high atom and step economy.22 In the past decade, significant advances in enantioselective synthesis have been achieved through borrowing hydrogen catalysis.23–30 In particular, our group and others have achieved enantioconvergent transformations of racemic alcohols to chiral amines,31–38N-heterocycles,39–41 and others.42–58 Yet, it is noteworthy that all these reported examples of heterocycle formation are based on amination of secondary alcohols having an enantiodetermining reduction of the prochiral ketoimine intermediates. An enantioconvergent amination of racemic primary alcohols via DKR still remains elusive.

    During our exploration of enantioconvergent synthesis using the borrowing hydrogen methodology for N-heterocycle synthesis, we were attracted to benzomorpholines that are widely present in bioactive compounds and drugs (Figure 1c).59,60 As exemplified by antiarrhythmics A61 and antibacterial levofloxacin,62 both C2- and C3-substituted benzomorpholines are important backbones in medicine and therefore important targets for stereoselective synthesis. Despite extensive efforts in method development,63–68 achieving high enantiocontrol in the preparation of benzomorpholines, and especially the C2-substituted variants with stereocenter away from the amine moiety,69–71 still represents a significant challenge.

    Herein, we report an unprecedented DKR for achieving enantioconvergent synthesis of C2-substituted benzomorpholines bearing a difficult-to-set stereocenter from readily available racemic amino primary alcohols 1 (Figure 1d, eq. 1). The identification of effective iridium and iron cooperative catalysis with a delicate balance was key to establishing this highly redox- and atom-economical amination of primary alcohols with high enantioselectivity. Intriguingly, the nitro precursor to the amino-primary alcohol substrate 1 was also converted to the alternative amino-secondary alcohols 4 involving a Smiles rearrangement. The enantioconvergent amination of this alternative class of substrates was also established using commercially available iridium catalyst to produce chiral C3-substituted benzomorpholines (Figure 1d, eq. 2). Our method thus represents an overall divergent and enantioconvergent synthesis of C2- and C3-subsituted benzomorpholines.

    Experimental Methods

    General procedure for enantioconvergent synthesis of C2-substituted benzomorpholines 2

    To an 8 mL vial equipped with an oven-dried stir bar were added 1 (0.1 mmol, 1.0 equiv), [Ir(COD)OMe]2 (5 mol %), L5 (10 mol %), Fe(OTf)3 (5 mol%), 3 Å molecular sieves (MS) (40 mg), and o-xylene (0.4 mL) in glovebox. The reaction mixture was removed from the glovebox and allowed to stir at 80 °C for 120 h. The crude reaction mixture was concentrated under reduced pressure and directly purified by silica gel chromatography with hexanes:EtOAc (10:1) as the eluent. The enantiopurity of the purified product was analyzed by chiral high-performance liquid chromatography (HPLC).

    General procedure for enantioconvergent synthesis of C3-aryl substituted benzomorpholines

    To an 8 mL vial equipped with an oven-dried stir bar were added 4 ( 4a–4h) (0.1 mmol, 1.0 equiv), [Ir(COD)OMe]2 (5 mol %), L5 (10 mol %), 3 Å MS (20 mg), and toluene (0.6 mL) in glovebox. The reaction mixture was removed from the glovebox and allowed to stir at 70 °C for 48 h. The crude reaction mixture was concentrated under reduced pressure and directly purified by silica gel chromatography with hexanes:dichloromethane (4:1) as the eluent. The enantiopurity of the purified product was analyzed by chiral HPLC.

    General procedure for enantioconvergent synthesis of C3-alkyl substituted benzomorpholines

    To an 8 mL vial equipped with an oven-dried stir bar were added 4 ( 4i–4u) (0.1 mmol, 1.0 equiv), [Ir(COD)OMe]2 (5 mol %), L3 (10 mol %), 3 Å MS (40 mg), and o-xylene (0.6 mL) in a glovebox. The reaction mixture was removed from the glovebox and allowed to stir at 100 °C for 24 h. The crude reaction mixture was concentrated under reduced pressure and directly purified by silica gel chromatography with hexanes:EtOAc (10:1) as the eluent. The enantiopurity of the purified product was analyzed by chiral HPLC.

    Results and Discussion

    Optimization and scope for enantioconvergent synthesis of C2-substituted benzomorpholines

    We initiated our studies by choosing the readily available racemic 1a as the model substrate for the preparation of C2-substituted benzomorpholine 2a (Figure 2a). Preliminary investigation identified commercially available [Ir(COD)OMe]2 as the most promising choice of redox catalyst. However, minimal efficiency and enantioselectivity was obtained by using chiral iridium catalyst alone (e.g., 17% ee for 2a using L1). Considering that an effective imine-enamine tautomerization is essential for this DKR process that can be influenced by an acid cocatalyst,31,32,72 we decided to examine the effect of various acid cocatalysts. Initial evaluation of chiral phosphoric acids as in our previous studies improved the efficiency of 2a formation, but enantioselectivity of all those attempts remained disappointingly poor (>40% ee for 2a in all cases). At this stage, a series of Lewis acids including B(C6F5)3, Mg(OTf)2, Zn(OTf)2, Fe(OTf)3, and FeCl3 were screened instead, the results of which are illustrated in the graph on the left of Figure 2a. To our delight, we saw improvements in both yield and ee, and in particular, the addition of Fe(OTf)3 led to the formation of 2a in up to 99% yield with 60% ee. Subsequently, different solvents were examined, from which o-xylene was found to be optimal, producing 2a in 78% ee. To further improve the selectivity, a systematic rescreening of chiral ligands identified L5 as the optimal choice (Figure 2a right graph). Furthermore, reducing the reaction temperature from 100 °C to 80 °C improved the enantioselectivity of 2a from 86% ee to 90% ee. With an extended reaction time, 2a was eventually accessed in 81% yield with an excellent 96% ee.

    Figure 2

    Figure 2 | Enantioconvergent synthesis of C2-substituted benzomorpholines via DKR. (a) Optimization of reaction conditions for enantioselective synthesis of 2a. (b) Scope of C2-substituted benzomorpholines. aReaction conditions: 1a (0.1 mmol), [Ir(COD)OMe]2 (5 mol %), L1 (10 mol %), w or w/o acid (5 mol %), 3 Å MS (40 mg) in toluene (0.4 mL) under N2 atmosphere at 100 °C for 24 h. See Supporting Information for details. bo-Xylene was found to be the optimal solvent and used in subsequent screening. cReaction at 80 °C for 120 h. dUsing 5 mol % Zn(OTf)2 as Lewis acid (LA).

    With the optimal conditions in hand, we moved on to explore the scope of this catalytic system to deliver various C2-substituted benzomorpholines (Figure 2b). In general, various aryl substituents of different electronic or steric properties at the C2 position of benzomorphonline were well-tolerated to deliver 2a–2f with good to excellent yield (73–93%) and enantioselectivity (80–96%). Notably, 2-pyridine substituent at the C2 position, which may prove to be a challenge due to catalyst deactivation, was also compatible, delivering 2g with a good 90% ee albeit with a decreased 35% yield. However, alkyl substituent at the C2 position led to the benzomorpholine product in minimal enantiopurity, representing a limitation of the current catalytic system. We hypothesize that the aryl substituent helps stabilize the enamine intermediate and in turn allows for a faster tautomerization, which is required for achieving efficient DKR. For the substitution on the aniline backbone, various 7-substituted benzomorpholines were produced with excellent enantioselectivity (88–96% ee for 2h–2l). For the preparation of benzomorpholines ( 2m– 2o) bearing six- or four-substituents, the corresponding amino alcohol substrates turned out to be less reactive and resulted in minimal conversion to the desired heterocycle products. For these examples, switching Fe(OTf)3 to Zn(OTf)2 as the Lewis acid cocatalyst proved to be beneficial for both the efficiency and enantioselectivity, producing the products in useful yields with excellent enantiocontrol (94–96% ee). Overall, it is noteworthy that substitution on the aniline moiety generally led to reduced efficiency of the catalytic reaction regardless of the reaction’s electronic properties ( 2h–2o). We hypothesize that this is due to a highly congested chiral pocket induced by the bulky chiral ligand, which is required for achieving enantiocontrol in this challenging DKR heterocycle synthesis yet causes a reduction in efficiency for substituted substrates.

    Mechanistic studies for enantioconvergent synthesis of C2-substituted benzomorpholines

    To better understand the mechanism of this unprecedented dynamic kinetic asymmetric amination of primary alcohols, a series of control experiments were carried out (Figure 3). Firstly, the enantiopurity of both product 2a and substrate 1a were monitored at different reaction times. As illustrated in Figure 3a, the enantiopurity of 1a increased gradually as the reaction progressed, suggesting a kinetic resolution in the initial oxidation of 1a. In contrast, the enantiopurity of 2a remained at a high level throughout the reaction (90–96% ee), as the result of an efficient enantioselective reduction of the chiral cyclic imine intermediate. This catalytic system thus operates with two separate enantiodetermining steps (as shown by the proposed reaction pathway in Figure 3e): an overall effective enantioconvergent synthesis of 2a is achieved via DKR with an initial oxidative kinetic resolution of 1a.

    Figure 3

    Figure 3 | Mechanistic insight for the enantioconvergent synthesis of C2-substituted benzomorpholines via DKR. (a) Reaction profile revealed oxidative kinetic resolution of 1 & DKR to form 2. (b) Effect of Lewis acid loading with [Ir-OMe]. (c) Effect of Lewis acid loading with [Ir-OTf]. (d) Analysis of reaction of Ir & Fe using CV. (e) Proposed reaction pathway for 2a synthesis.

    Further control reactions were carried out to explore the nature of the intriguing effect of Fe(OTf)3. Different amounts of Fe(OTf)3 were evaluated under otherwise identical conditions (Figure 3b). In the absence of Fe(OTf)3, the reaction proceeded to only ∼50% conv. to 2a with minimal enantioselectivity (despite at >95% consumption of 1a). When the amount of Fe(OTf)3 was increased from 1 mol %, 2.5 to 5 mol %, the enantioselectivity of 2a dramatically increased from 38%, 82% to 96% ee. The observation of improved enantiopurity with increased loading of iron catalyst was attrituted to a Lewis acid-promoted facile racemization of the imine intermediates Int-II′-a and Int-II′-b (Figure 3e) through the achiral enamine Int-III prior to reduction, which is essential for an effective DKR.

    Notably there was also a surprising turn on the Lewis acid effect. As the amount of Fe(OTf)3 increased from 1 mol % onward, the yield of 2a gradually decreased, and only trace 2a was formed by the use of 7.5 mol % Lewis acid, despite a consistently high enantioselectivity. The recovery of 1a also gradually increased with higher loading of Lewis acid, suggesting inhibition of the initial oxidation of 1a by excess Fe(OTf)3. As illustrated in our previous studies, the combined use of iridium-methoxide with Fe(OTf)3 leads to the formation of iridium triflate by salt metathesis.51 To probe this possibility, we examined the direct use of [Ir(COD)OTf]2 as the precatalyst (Figure 3c), which was indeed more efficient and enantioselective than the methoxide counterpart (73% conv., 74% ee for 2a). The introduction of additional Fe(OTf)3 was also tested under this set of conditions. The use of a small amount of Lewis acid as low as 0.2 mol % was sufficient to enhance the enantioselectivity of 2a; however, the inhibition effect of Fe(OTf)3 was already significant at this low loading with significantly decreased yield of 2a and accordingly higher recovery of 1a.

    To shed some light on this unexpected inhibitory effect of Fe(OTf)3, we examined the interaction of the two metal catalysts using cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) measurements. The redox potential of Fe(OTf)3 and [Ir(COD)OMe]2 from CV measurement hinted at the possibility of redox reaction between these two reagents (Figure 3d top). A more focused CV measurement of Fe(OTf)3 versus a 1:1 mixture of [Ir(COD)OMe]2:Fe(OTf)3 in CH3CN further demonstrated the absence of the Fe(III) signal in the mixture (Figure 3d bottom; see Supporting Information Figures S1 and S2 for more details). Additionally, EPR measurement of the mixture of Fe(OTf)3/[Ir(COD)OMe]2 also identified a complete disappearance of the Fe(III) signal with the formation of a new radical species (see Supporting Information Figure S3). Although the exact nature of this reaction was not clear at this point, the inhibition of catalytic activity of the Ir catalyst by excess Fe(OTf)3 was likely due to an undesired redox reaction between these two metal catalysts. Overall, the control experiments in Figure 3a–d suggested a delicate balance between the beneficial effect of the Lewis acid on the enantioselectivity and inhibition of the amination reaction in this challenging dynamic kinetic asymmetric benzomorpholine synthesis.

    Based on the above mechanistic investigation, a plausible reaction pathway for the enantioconvergent synthesis of 2a from 1a is illustrated in Figure 3e. Iridium-catalyzed dehydrogenation of 1a worked with an effective kinetic resolution. The key racemization was achieved by imine/enamine tautomerization, which was facilitated by the iron Lewis acid cocatalyst. In the final enantiodetermining reduction step, the chiral iridium catalyst effectively recognized the chirality at the C2 position, producing 2a in an overall enantioconvergent fashion by DKR. On the other hand, the proper loading of Fe(OTf)3 proved to be critical, as excess Fe(OTf)3 likely underwent undesired side reaction with the iridium redox catalyst and effectively shut down the whole reaction.

    Divergent synthesis of C3-substituted benzomorpholines from a common precursor

    An intriguing discovery was made during our substrate synthesis. As shown in Figure 4a, amino primary alcohol substrate 1 was produced from 3 by direct nitro reduction. Alternatively, treatment of 3 with a strong base resulted in an effective Smiles rearrangement, which, followed by nitro reduction, led to the formation of amino secondary alcohol 4 instead. Recognizing that this can serve as the substrate for the preparation of C3-substituted benzomorpholines, we decided to explore the enantioconvergent amination of 4 as well. These efforts, together with that in Figure 2 would lead to divergent preparation of both series of benzomorpholines from the common precursor 3.

    Figure 4

    Figure 4 | Divergent access to C2- & C3-substituted benzomorpholines. (a) Divergent synthesis of C2- & C3-substituted benzomorpholines from a common precursor? (b) Enantioconvergent synthesis of C3-substituted benzomorpholines.a (c) Large scale reaction and synthetic transformations of bezomorpholines 2 and 5.

    The optimization of 5a formation from 4a was carried out with an emphasis on the iridium catalyst (Figure 4b). In the screening of a range of chiral ligands at 90 °C, the use of L5 produced 5a with the highest 82% ee and 77% yield. We then tested different solvents including t-amyl alcohol, 1,4-dioxane, and toluene. To our delight, the use of toluene led to the formation of 5a with 84% yield and 84% ee. By reducing the amount of 3 Å MS (20 mg instead of 40 mg), 5a was obtained with a higher 88% ee. Further lowering the reaction temperature to 70 °C led to an improvement of enantioselectivity to 90% ee, albeit with a diminished yield of 60%. Finally, extended reaction time of 48 h at 70 °C was able to produce 5a in 80% yield with 90% ee.

    With the optimal reaction conditions in hand (Condition A), we next investigated the scope and generality of this catalytic synthesis of C3-substituted benzomorpholines. For substrates bearing a benzylic alcohol (Figure 4b top, R2 = aryl), different substituents on the aniline backbone were well-tolerated to produce 5b and 5c in good to high yields and enantioselectivities. Various electron-rich and electron-neutral substituents on R2 were also compatible, producing 5d–5h in 80–94% ee. Notably the current catalytic system did not tolerate electron-deficient substrates, which produced the corresponding heterocyclic products with only moderate enantioselectivities.

    When substrates bearing aliphatic alcohols were examined (Figure 4b bottom, R2 = alkyl), minor adjustment of the reaction conditions and especially replacing L5 with L3 was found to be essential to deliver the products in good yield and excellent enantioselectivity (Condition B). This catalytic system was able to deliver products bearing linear and branched alkyl substituents (e.g., n-butyl or t-butyl) in high enantioselectivity (82–86% ee for 5i and 5j). More desirably, we were delighted to observe higher efficiency and selectivity for functionalized products such as silyl ether 5k. Considering this silyl ether product can be further functionalized, a significant portion of the scope was carried out with substrates containing an tert-butyldimethylsiloxy (OTBS) functionality. In this series, a range of diversely substituted products bearing alkyl ( 5l– 5o, 5t, and 5u), electron-rich ( 5q) as well as electron-deficient groups ( 5r and 5s) were produced in good to excellent yield (54–93%) and ee (73–93%).

    Our divergent synthesis of C2- and C3-substituted enantioenriched benzomorpholine provided highly efficient access to this class of important chemical space in medicinal chemistry. As exemplified in Figure 4c top, 2a bearing a C2-phenyl substituent was converted to an analogue of the antiarrhythmic A (Figure 1b) in two steps with high efficiency and complete retention of the enantiopurity. Furthermore, as shown in Figure 4c bottom, a large-scale synthesis of 5k resulted in comparable yield and enantioselectivity. Following that, Buchwald–Hartwig coupling on the amine unit in 5k produced N-aryl 7 in high excellent yield (89%). Alternatively, tetrabuylammonium fluoride (TBAF) deprotection of 5k produced 8 in high yield (87%). The alcohol unit in 8 was derivatized in different ways, including a conversion to alkyl bromide 9 that opens up more opportunities for various substitutions or cross coupling.

    Conclusion

    In conclusion, we have developed a highly economical preparation of both C2- and C3-substituted chiral benzomorpholines through iridium-catalyzed enantioconvergent intramolecular amination of alcohols. In particular, an unprecedented and highly challenging DKR under cooperative iridium/iron catalysis was achieved for asymmetric amination of racemic primary alcohols, delivering the difficult-to-access C2-substituted benzomorpholines in high efficiency and enantioselectivity. The use of a single commercially available chiral iridium system for highly enantioselective synthesis of C3-substituted benzomorpholines was also noteworthy. Further applications of this powerful enantioconvergent amination via DKR are under investigation.

    Supporting Information

    Supporting Information is available and includes the experimental procedures and characterization of the compounds. All data supporting the findings of this study are available within the article and its Supporting Information.

    Conflict of Interest

    There is no conflict of interest to report.

    Funding Information

    We are grateful for the financial support from the National Natural Science Foundation of China (grant no. 22171208), the Ministry of Education of Singapore (grant no. A-8001893-00-00), the Agency for Science, Technology and Research (grant no. A-8001271-00-00), the National University of Singapore (grant no. A-8001040-00-00), and the Joint School of National University of Singapore and Tianjin University in Fuzhou.

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