Highly Enantioselective Synthesis of Chiral Benzhydrols via

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Highly Enantioselective Synthesis of Chiral Benzhydrols via Manganese Catalyzed Asymmetric Hydrogenation of Unsymmetrical Benzophenones Using an Imidazole-Based Chiral PNN Tridentate Ligand Fei Ling, Huacui Hou, Jiachen Chen, Sanfei Nian, Xiao Yi, Ze Wang, Dingguo Song, and Weihui Zhong*

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Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China S Supporting Information *

ABSTRACT: A series of Mn(I) catalysts containing imidazole-based chiral PNN tridentate ligands with controllable “side arm” groups have been established, enabling the asymmetrical hydrogenation of unsymmetrical benzophenones with outstanding activity (up to 13 000 TON) and excellent enantioselectivity (up to >99% ee). This protocol uses K2CO3 as an industrially desirable base and features a wide substrate scope and functional group tolerance. Moreover, the imine group in the catalyst is crucial for accessing high activities and good enantioselectivities. he past decades have witnessed great advances in the field of asymmetric hydrogenation of ketones by employing expensive noble metals, such as Ru, Rh, Ir, and Pd, as efficient catalysts, providing various chiral alcohols with up to 99.9% ee in millions of turnover numbers.1 However, the low availability of such metals has encouraged chemists to mine alternative catalysts based on transition metals with essentially indefinitely sustainable sources in the earth crust. Moreover, the removal of scarce metals from the product may cause extra cost, since the first-raw metals have higher metal contamination limitations in pharmaceutical compounds (for example, 250 ppm for manganese compared to 10 ppm for Ru). Based on these considerations, extensive global efforts have been devoted to the development of chiral catalysts with earth abundant, inexpensive, and nontoxic transitions metals,2 like copper,3 nickel,4 iron,5 or cobalt.6 Nevertheless, the activity and/or enantioselectivity of these base metal catalysts still remain a great challenge, severely limiting their further applications. Recently, achiral manganese complexes have been demonstrated as highly active catalysts in the hydrogenation of carbonyl derivatives.7 These fantastic advances stimulated several groups to explore their chiral counterparts for enantioselective ketone hydrogenation (Scheme 1-1). In this field, earlier work by Clarke and co-workers reported the first example of Mn-catalyzed asymmetric hydrogenation of aryl alkyl ketones with up to 97% ee, despite its substrate limitation (a bulky alkyl group is essential for achieving high ee).8 Later, Beller’s group developed a chiral manganese PNP pincer complex for the enantioselective synthesis of chiral benzhydrols with ee’s up to 84%.9 Besides, several other groups also examined the capabilities of chiral Mn species for the

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© XXXX American Chemical Society

asymmetric transfer hydrogenation,10 hydrosilylation,11 and hydroboration12 of ketones, and moderate results were obtained in these cases. Despite these great successes, several restrictions, such as low catalyst activity, moderate enantioselectivity, expensive alkoxide bases, and limited substrate scope, still remain as big problems in ketone hydrogenation using manganese catalysts. On the other hand, optical pure benzhydrols are widely used as intermediates for the commercial synthesis of pharmaceuticals,13 e.g. TAK-475,14 orphenadine,15 and neobenodine16 (Figure 1). Therefore, numerous methodologies have been developed to access enantioenriched benzhydrols.17−22 Among them, the catalytic hydrogenation of unsymmetrical benzophenones is the most captivating which does not produce stoichiometric amounts of metal waste. In this context, methodologies via the noble metal catalyzed asymmetrical hydrogenation of ortho-substituted benzophenones have been successfully established with a maximum of 99% ee (Scheme 12), while the asymmetric synthesis of enantioenriched diaryl methanols with cheap metal catalysts has remained unexplored. As a continuation of our previous work,23 herein, we disclosed a highly enantioselective protocol of Mn-catalyzed asymmetric hydrogenation of unsymmetrical benzophenones with welldefined imidazole-based chiral PNN tridentate ligands containing an imine motif using K2CO3 as an industrially desirable base, producing chiral benzhydrols in up to >99% ee with a 13 000 TON (Scheme 1-3).24 Received: March 25, 2019

A

DOI: 10.1021/acs.orglett.9b01056 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Asymmetrical Hydrogenation of Unsymmetrical Benzophenones

Scheme 2. Synthesis of the Imidazole-Based Chiral PNN Tridentate Ligand L1−L6a

a Reaction conditions: 3 (0.55 mmol) and 4 (0.5 mmol) in 10 mL of MeOH at reflux overnight.

Table 1. Optimization of Reaction Conditionsa

entry

ligands

conversion (%)b

ee (%)c

1 2 3 4 5 6

L1 L2 L3 L4 L5 L6

>99 >99 >99 >99 − >99

56 (R) 70 (R) 91 (R) 96 (R) − −97 (S)

a

Reaction conditions: 1 mmol scale, [substrate] = 0.1 M, 0.1 mol % Mn(CO)5Br, 0.105 mol % ligand L, 5 mol % K2CO3, 10 mL of EtOH, 3 MPa of H2, room temperature (25−30 °C), 14 h. bDetermined by GC analysis. cDetermined by HPLC analysis.

Figure 1. Durgs containing optical pure benzhydrols.

The current developed imine-type PNN tridentate ligands (L) could be easily obtained in 59−75% yield via a one-step condensation reaction starting from commercially available 3 and 4, as shown in Scheme 2. The R2 group on the N atom of the benzo[d]imidazole segment was regarded as a side arm chain,25 regulating the steric hindrance of catalysts. As such, ligands L1−L5 bearing different R2 substituents were prepared to investigate the influence of this side arm. In addition, we also synthesized ligand L6, which is the enantiomer of L4, to investigate the relationship between enantioselectivity and the configuration of the ligand. With these ligands in hand, we began our studies by screening them for the asymmetric hydrogenation of (2bromo-3-methylphenyl)(4-methoxyphenyl)methanone (1a) serving as the model substrate with the catalyst generated in situ by mixing Mn(CO)5Br with ligands L1−L6 (S/C = 1000) in toluene (see the Supporting Information for more details on investigations of solvents, bases, and temperature). As shown in Table 1, 1a was hydrogenated smoothly to the desired chiral alcohol 2a with 56% ee in a full conversion, when using Nisopropyl protected L1 as ligand (Table 1, entry 1). Improved enantioselectivity was achieved when changing the isopropyl group to a phenyl group on the ligand, accessing 2a in 70% ee (Table 1, entry 2). Remarkably, with an increase in steric hindrance of the R1 group, the enantiomeric selectivity of the

reaction was sharply improved up to 91% ee, and L4 gave the best result (Table 1, entry 4, 96% ee, full conversion). These results strongly indicated the great importance of the side arm groups. In contrast, increasing the steric bulk of the substituents on the P-phenyl ring greatly affected the reaction efficiency and enantioselectivity, and L5 failed to produce the corresponding product 2a. As expected, replacing the counterparts from (SC, RFC)-ferrocene to its enantiomer led to a similar enantioselectivity with opposite configuration of the product (L6, −97% ee). Furthermore, the absolute structure of the chiral alcohol (R)-2a was confirmed by X-ray crystallography (CCDC 1902605). After identifying the optimum reaction conditions, we next set out to determine the versatility of this reaction system in the asymmetric hydrogenation of diaryl ketones. Various orthosubstituted benzophenones were reduced to chiral benzhydrols in almost quantitative yields with 76 → 99% ee’s (Scheme 3). The influence of substituents on the nondirected phenyl rings was first investigated. Substrates bearing electron-donating groups (−Me and −OMe) delivered better enantioselectivities than those with electron-withdrawing groups (−Cl, −Br, and −CF3). In addition, disubstituted substrate 1g underwent this hydrogenation smoothly to yield the desired product 2g with B

DOI: 10.1021/acs.orglett.9b01056 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Substrate Scopea

Scheme 4. Gram-Scale Reaction and Further Transformation

method in the formal synthesis of (S)-neobenodine was performed in gram scale through sequential asymmetric hydrogenation/debromination reactions to afford the key intermediate 5z in 82% yield over two steps with 90% ee (Scheme 4-2).26 In order to realize a preliminary understanding of the reaction mechanism, we carried out two control experiments (Scheme 5). Initially, ligand L4 could be converted to the very a

Reaction conditions: 1 mmol scale, [substrate] = 0.1 M, 0.1 mol % Mn(CO)5Br, 0.105 mol % ligand L4, 5 mol % K2CO3, 10 mL of EtOH, room temperature (25−30 °C). Isolated yields.

Scheme 5. Control Experiment

91% ee. Notably, raising the bulk on the phenyl rings did not affect the reaction efficiency, affording 2h and 2j in 93% and 92% ee’s, respectively. It was worth noting that an alkyne group was also tolerated in this transformation, leading to corresponding product 2i in excellent ee, which provided potential for further manipulation. Next, the substituent effect on the directed benzene core was examined. The substituent position had little influence on the reaction outcomes, and all the disubstituted substrates offered good to excellent ee’s. The best result (97% yield with >99% ee) was observed when using 2,6-disubstituted ketone 1p as the substrate. As expected, diminishing the size of the directed group caused a reduction in ee value (2q vs 2r vs 2s; 2t vs 2u). It was delightful to find that the naphthyl group was compatible with this reaction to forge the targeted product 2v in 96% ee. Unfortunately, the chiral manganese catalyst failed to recognize the nondirected diaryl ketones, only giving 2w and 2x in 12% and 15% ee’s, respectively. Remarkably, phenyl(thiophen-2-yl)methanone (1y) could be easily hydrogenated to chiral secondary alcohol 2y in 98% yield, albeit with only moderate enantioselectivity (64% ee). To further exemplify the utility of the developed Mn catalytic system, several gram-scale reactions with a lower catalyst loading were conducted, as shown in Scheme 4. The 30-mmol-scale asymmetric hydrogenation of 1a reacted successfully with S/C = 10000/1, producing the chiral alcohol 2a in 96% ee without any loss of efficiency (Scheme 4-1). Inspiringly, the enantioselectivity was not diminished even when the catalyst loading was decreased to 0.005 mol %, albeit in a relatively lower yield (65%). Next, the application of this

soluble cationic Mn complex by reaction with convenient precursor Mn(CO)5Br in toluene at reflux overnight, affording the Mn−L4 complex A in 80% yield. Although many attempts to solve the crystal structure of A have failed, the data from HRMS and infrared analysis confirmed the hypothetic structure, which was similar that of Clarke’s chiral Mn catalyst (see the Supporting Information). On the other hand, we synthesized ligand L7 from ligand L4 via imine reduction and C

DOI: 10.1021/acs.orglett.9b01056 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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applied it in the asymmetrical hydrogenation of ketone 1a. However, the coordination of L7 and manganese was incomplete, giving a trace amount of the Mn−L7 species and another unknown complex.27 We believe that the great steric hindrance disrupts the coordination process, while the imine group in L4 has a stronger capability of coordinating with manganese than the amino group. Thus, the reaction with L7 turned out to be unsuccessful, indicating that the imine group is indispensable for achievement of high activity and enantioselectivity. Furthermore, the imine group may play a key role in the cleavage of H2 via addition of a molecule of H2 to the CN double bond. Then, the newly formed N−H proton and the Mn−H hydride of the Mn−L4 complex add to the carbonyl group of diaryl ketone via a six-membered ring transition state, thus providing high activity and enantioselectivity.28 The detailed mechanistic investigation is currently underway. In conclusion, we have described a new type of imidazolebased chiral PNN tridentate ligand enabling the manganese catalyzed asymmetrical hydrogenation of unsymmetrical benzophenones with outstanding activity (up to 13 000 TON) and excellent enantioselectivity (up to >99% ee). The utility of this manganese catalytic system has been demonstrated by gram-scale experiments and formal synthesis of (S)neobenodine. Preliminary studies on reaction mechanism revealed that the imine group of the catalyst might play a key role in the cleavage of H2 and the activation of substrate. Further applications of this methodology in asymmetrical reductions of other unsaturated compounds are underway in our lab.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01056. Experimental details, spectra data, copies of 1H and 13C NMR spectra, and HPLC charts (PDF) Accession Codes

CCDC 1902605 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Fei Ling: 0000-0002-4274-912X Weihui Zhong: 0000-0003-0349-2226 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 21676253 and 21706234) and the Natural Science Foundation of Zhejiang Province of China (No. LY19B060011) for financial support. D

DOI: 10.1021/acs.orglett.9b01056 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b01056 Org. Lett. XXXX, XXX, XXX−XXX