Rhodium-catalyzed asymmetric arylation of N- and O-containing cyclic aldimines: facile and efficient access to highly optically active 3,4-dihydrobenzo[1,4]oxazin-2-ones and dihydroquinoxalinones

Abstract

A highly enantioselective rhodium-catalyzed arylation of benzoxazinones and quinoxalinones with arylboroxines was realized for the first time by employing a simple sulfur-olefin as the ligand. This protocol provides an efficient access to chiral 3,4-dihydrobenzo[1,4]oxazin-2-ones and dihydroquinoxalinones with exceptionally high enantiomeric purity (up to 99.9% ee).

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3,4-Dihydrobenzo[1,4]oxazin-2-ones and dihydroquinoxalinones are two intriguing classes of nitrogen-containing heterocycles.¹ These heterocycles are not only important intermediates for the synthesis of many pharmaceutical compounds, but also widely used in the agro-industry.² As reported, optically active compounds containing these core structural units often show a wide range of biological activities. For example, compound I is a pyruvate kinase activator and can increase the lifetime of red blood cells (Fig. 1).³ Compound II possesses potent activity against retroviruses such as HIV.⁴ Dihydroquinoxalinone derivative III is a newly developed CETP inhibitor and is expected to be utilized in the treatment of atherosclerosis.⁵ Besides, other interesting bioactivities of such benzo-fused heterocycles are also demonstrated, including 5-HT2c agonist binding activity,⁶ antibacterial and anticancer effects,⁷ and euglycemic and hypolipidemic activities.⁸ Therefore, highly enantioselective synthesis of these chiral heterocycle structural motifs has been a compelling research topic.

Fig. 1 Bioactive 3,4-dihydrobenzo[1,4]oxazin-2-one and dihydroquinoxalinone derivatives.

Over the past decade, several asymmetric approaches including chiral auxiliary⁹ and chiral pool¹⁰ strategies have been developed to construct enantiomerically enriched 3,4-dihydrobenzo[1,4]oxazin-2-one and dihydroquinoxalinone scaffolds. The most frequently used method to construct these chiral heterocycles is asymmetric reduction of aryl-substituted benzoxazinones and quinoxalinones mainly via transfer hydrogenation,^11a–c hydrosilylation^11d,e and biomimetic hydrogenation,^11f–h catalyzed by Brønsted acids (chiral phosphoric acids) or Lewis base organocatalysts.¹¹ⁱ Although asymmetric addition to imines is an efficient and direct method to furnish nitrogen-containing chiral organic molecules, there is only limited success involving the chiral Brønsted acid-catalyzed Friedel–Crafts reaction of indoles and pyrroles in which ester- or trifluoromethyl-substituted benzoxazinones were employed for the construction of highly enantiomerically enriched dihydrobenzoxazinones.¹² In the case of a reaction with pyrrole,^12b a sole example of addition to non-substituted benzoxazinone was described, however, giving only 45% yield and 9% ee without the activation and stereoeffect of the CF₃-group. While the transition-metal-catalyzed asymmetric addition approach has been widely applied, surprisingly, successful examples of the synthesis of these heterocycles remain scarce,^13,14 and enantioselective 1,2-addition of organoboron reagents to benzoxazinones and quinoxalinones has not yet been successfully developed. Therefore, there is still an unmet need for highly efficient asymmetric synthesis of these appealing heteroaromatic compounds. Herein, we report the first rhodium-catalyzed highly enantioselective arylation of cyclic benzoxazinones and quinoxalinones with arylboroxines using a simple sulfur-olefin as the ligand.

In recent years, our laboratory has been exploring the design of new chiral olefin ligands and successfully introduced a series of sulfur- and phosphorus-based olefins as well as bisolefins for transition-metal-catalyzed asymmetric reactions.¹⁵ We found that readily available, sulfinamide-based branched olefin ligands showed great promise in the Rh-catalyzed asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines, typically exhibiting excellent efficiency and the ideal enantioselectivity.^16,17 On the basis of these results, we presumed that these simple sulfur-olefins might also act as effective ligands for asymmetric organoboron addition to the C=N bond of benzoxazinones and quinoxalinones for the construction of chiral 3,4-dihydrobenzo[1,4]oxazin-2-one and dihydroquinoxalinone scaffolds (Scheme 1).

Scheme 1 Asymmetric arylation strategy under rhodium catalysis.

We initiated our studies by evaluating the reaction of cyclic aldimine benzoxazinone 1a with 4-methoxyphenylboronic acid (2a) in KF (1.5 M)/toluene at 60 °C using branched sulfur-olefin L1 as the ligand in the presence of the [Rh(COE)₂Cl]₂ catalyst (1.5 mol%) (Table 1, entry 1). To our delight, the reaction gave the desired addition product 3b with the expected excellent enantioselectivity (97% ee), albeit in a relatively low yield (39%). In contrast, sulfur-olefin L2 with a linear structure could only afford moderate enantioselectivity (64% ee) with a similar low yield (27%) (entry 2). Encouraged by this result, the effects of solvent and additive were carefully examined. The employment of KHF₂ would largely promote the substrate conversion (entry 6), while utilization of bases such as K₂CO₃, K₃PO₄ and KOH led to an apparent decrease of yield due to the decomposition of the substrate (entries 3–5). Adding Et₃N resulted in moderate yield but a dramatic decrease in enantioselectivity (entry 7). To avoid hydrolysis of the imine substrate, we examined the use of a solid salt as the additive (entries 8–10). Gratifyingly, we found that the reaction could afford the product in 70% yield with an outstanding enantioselectivity (99% ee) under the conditions of solid K₃PO₄ (1 equiv.)/dioxane (entry 9). Inspired by this result, the corresponding more reactive boroxine (1.2 equiv.) instead of boronic acid was employed with the addition of an alcohol (4 equiv.) as the proton source. Through further evaluation of the new reaction conditions, we were pleased to discover that the yield could be substantially improved to over 90% (entries 11–12). Notably, when the reaction was performed in the solid K₃PO₄/dioxane in the presence of methanol, a surprisingly high 98% yield and 99.9% ee were obtained (entry 11).

Table 1 Optimization of reaction conditions for addition to 1a ^a

Entry	Ligand	Solvent	Additive	Yield^b (%)	ee^c (%)
a Conditions: 1a (0.1 mmol), 2a (2 equiv.), [Rh(COE)2Cl]2 (1.5 mol%), ligand (3.3 mol%) and base (1.0 equiv.) in 1.0 mL of solvent at 60 °C for 2 h unless otherwise noted. b Isolated yields. c Determined by chiral HPLC analysis. d  2b (1.2 equiv.) was used. e Solid salt (1.0 equiv.) was used. f 4.0 equiv. of alcohol were used.
1	L1	Toluene	KF (1.5 M)	39	97
2	L2	Toluene	KF (1.5 M)	27	64
3	L1	Toluene	K2CO3 (1 M)	23	97
4	L1	Toluene	K3PO4 (1 M)	25	95
5	L1	Toluene	KOH (1 M)	Trace	—
6	L1	Toluene	KHF2 (1 M)	68	99
7	L1	Toluene	Et3N	66	65
8	L1	Dioxane	KHF2 ^e	19	97
9	L1	Dioxane	K2CO3 ^e	66	98
10	L1	Dioxane	K3PO4 ^e	70	99
11^d	L1	Dioxane	K3PO4 ^e/MeOH ^f	98	99.9
12^d	L1	Dioxane	K3PO4 ^e/t-amyl alcohol ^f	94	99

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With the optimal conditions established, we proceeded to investigate the substrate scope of the reaction. As shown in Table 2, regardless of the substitution pattern, a wide variety of arylboroxines reacted smoothly with benzoxazinone 1 and gave all nearly enantiopure 3-aryl-3,4-dihydrobenzo[1,4]oxazin-2-ones (with 99.3–99.9% ee). The electronic effect of the para-substituent on the phenyl ring of boroxine barely showed the influence on the reactivity and enantioselectivity (3b–d). However, while electron donating group substituted phenylboroxines gave addition products in great yields (3e, 3f, 3h), the utilization of boroxines possessing phenyl rings with electron-withdrawing groups at the ortho- and meta-position showed an obvious decrease in yields (3g, and 3i). The reaction can be extended to heteroaryl boroxine and a 3-thieny-group could be introduced to form product 3j in 99% yield with 99.3% ee. It is particularly notable that great yield and enantiomeric control were obtained with the use of more sterically hindered arylboroxines (3h, 3i, and 3l). To our knowledge, these results are otherwise difficult to be achieved by the known hydrosilylation or hydrogenation reactions. Benzoxazinone substrates bearing substitutents on the benzene ring can be well tolerated to furnish the corresponding products 3m–3p in equally excellent yields and enantioselectivities. Besides, it is also interesting to find that the reaction gave a promising enantioselectivity (95% ee) with challenging styrylboroxine, although the yield was low (25%, 3q).

Table 2 Rhodium-catalyzed asymmetric addition of benzoxazinones 1 ^a,b,c

a Conditions: 1 (0.10 mmol), 2 (1.2 equiv.), [Rh(COE)₂Cl]₂ (1.5 mol%), L1 (3.3 mol%), and K₃PO₄ (1.0 equiv.)/MeOH (4 equiv.) in 1.0 mL of 1,4-dioxane at 60 °C for 2–4 h. b Isolated yields. c Determined by chiral HPLC.

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Encouraged by the above success, the current catalytic system was extended to the asymmetric addition of quinoxalinones 4 for construction of dihydroquinoxalinones (Table 3). Generally, the para-substituted phenylboroxines displayed a good reactivity as well as high enantioselectivity irrespective of the electronic nature of substituents (5b–d). Nevertheless, the use of arylboroxines bearing the electron-withdrawing group at the ortho- and meta-position of the phenyl ring failed to afford the product (5f, and 5g). Fortunately, satisfactory yields and enantioselectivities were obtained with sterically hindered 2-methylphenylboroxine and 1-naphthylboroxine (5h, 5i). Changing the N-substituent of substrate 4 from methyl to benzyl and p-methoxybenzyl did not affect the reaction enantioselectivity (5j, 5k). Finally, a difluoro-substituted quinoxalinone substrate was employed, and the same high level of enantiocontrol was observed (5l).

Table 3 Rhodium-catalyzed asymmetric arylation of quinoxalinones 4 ^a,b,c,d

a Conditions: 4 (0.10 mmol), 2 (1.2 equiv.), [Rh(COE)₂Cl]₂ (1.5 mol%), L1 (3.3 mol%), and K₃PO₄ (1.0 equiv.)/MeOH (4 equiv.) in 1.0 mL of dioxane at 60 °C for 12 h. b Isolated yields. c Determined by chiral HPLC. d 5d and 5i were prepared at 80 °C.

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To demonstrate the practicality of this conversion, we conducted the reaction on a larger scale (3.42 mmol, 500 mg) under standard conditions, which furnished product 3b in 92% yield and 99% ee. The stereochemistry of the newly formed chiral center of product 3g was determined to be R by single-crystal X-ray diffraction analysis.¹⁸ Assuming the same stereoinduction pathway, the configuration of the other 3,4-dihydrobenzo[1,4]oxazin-2-one products as well as dihydroquinoxalinones was assigned by analogy. Based on this reaction stereochemical outcome, an empirical transition state model is proposed. As depicted in Fig. 2, the arylrhodium species prefer a specific geometry, in which the aryl group is in the trans-position to the olefin ligand. To avoid unfavorable steric interaction with the bulky R group on the double bond, the cyclic imine substrate could only coordinate to rhodium from the re-face of C=N (B) to furnish the (R)-product.

Fig. 2 Proposed transition-state model and the X-ray crystallographic structure of 3g.

Finally, we set out to investigate the transformation of the highly enantiomerically enriched 3,4-dihydrobenzo[1,4]oxazin-2-ones and dihydroquinoxalinones into other useful molecules. As revealed in Scheme 2a, treatment of 3,4-dihydrobenzo[1,4]oxazin-2-one 3b with LiAlH₄ at 0 °C, followed by the Mitsunobu reaction can give rise to benzomorpholine 6 in 83% yield without the loss of optical purity (99% ee). Accordingly, dihydroquinoxalinones can be readily converted into useful tetrahydroquinoxalines under the conditions of BH₃·THF (2.5 equiv.) in refluxing THF with quantitative yield, as exemplified in Scheme 2b. It is worth noting that benzomorpholines and tetrahydroquinoxalines are also valuable heterocycles that often possess interesting biological activities.¹⁹ In another case, dihydrobenzoxazinone 3c was subjected to ring opening and transformed to aryl glycine amide 8 in the presence of pyridin-2-ol and benzyl amine in THF.

Scheme 2 Transformation of addition products.

In summary, we have developed an efficient and highly enantioselective Rh-catalyzed arylation of benzoxazinones and quinoxalinones with arylboroxines. This protocol provides a facile method to achieve chiral 3,4-dihydrobenzo[1,4]oxazin-2-ones and dihydroquinoxalinones with excellent stereocontrol (up to 99.9% ee) in the presence of a simple sulfur-olefin ligand. Moreover, the work reveals new opportunities to access other important heterocycles such as chiral benzomorpholines and tetrahydroquinoxalines through operationally simple procedures. It should find future applications in medicinal chemistry and organic synthesis.

Acknowledgements

We thank the National Natural Science Foundation of China (21325209, 21472205, 81521005) and the Shanghai Municipal Committee of Science and Technology (Program of Shanghai Academic Research Leader, 14XD1404400) for financial support.

Notes and references

1. (a) D. D. Andrea and E. J. John, (Warner Lambert Co., USA), U.S. Patent6410536(B1), 2002; (b) D.-S. Su, M. K. Markowitz, R. M. DiPardo, K. L. Murphy, C. M. Harrell, S. S. O'Malley, R. W. Ransom, R. S. L. Chang, F. J. Hess and D. J. Pettibone, J. Am. Chem. Soc., 2003, 125, 7516; (c) P. E. Mahaney, M. B. Webb, F. Ye, J. P. Sabatucci, R. J. Steffan, C. C. Chadwick, D. C. Harnish and E. J. Trybulski, Bioorg. Med. Chem., 2006, 14, 3455; (d) H. Daniel and P. William, (P & H Therapeutics Inc., USA), U.S. Patent2009311318, 2009.
2. (a) S. X. Cai, S. M. Kher, Z.-L. Zhou, V. Ilyin and S. A. Espitia, J. Med. Chem., 1997, 40, 730; (b) M. Patel, R. J. McHugh, B. C. Cordova, R. M. Klabe, S. Erickson-Viitanen and G. L. Trainor, Bioorg. Med. Chem. Lett., 2000, 10, 1729; (c) L. A. Cruz, E. Estébanez-Perpiña, S. Pfaff, S. Borngraeber, N. Bao, J. Blethrow and R. J. Fletterick, J. Med. Chem., 2008, 51, 5856; (d) D. V. Smil, S. Manku, Y. A. Changtigny, S. Leit, A.-M. Lmieuz and A. NIcolescuz, Bioorg. Med. Chem., 2009, 19, 688.
3. S. S.-S. Michael, (Agios Pharm. Inc.), Patent WO2012151440, 2012.
4. M. Rosner, U.-M. Billhardt-Troughton, R. Kirsh, J.-P. Kleim, C. Meichsner, G. Riess and I. Winkler, U.S. Patent, 5723461, 1998.
5. R. Anand, V. Colandrea, J. M. Reiter, P. Vachal, A. Zwicker, J. E. Wilson, F. Zhang and K. Zhao, Patent WO2013028382, 2013.
6. G. Yoon, H. J. Jeong, J. J. Kim and S. H. Cheon, Arch. Pharm. Res., 2008, 31, 989.
7. (a) I. V. Mashaevskaya, R. R. Makhmudov, G. A. Aleksandrova, A. V. Duvalov and A. N. Maslivets, Pharm. Chem. J., 2001, 35, 69; (b) X. K. Li, N. Liu, H. N. Zhang, S. Knudson, R. A. Slayden and P. J. Tonge, Bioorg. Med. Chem. Lett., 2010, 20, 6306; (c) M. Y. Abu Shuheil, M. R. Hassuneg, Y. M. Al-Hiari, A. M. Qaisi and M. M. El-Abadelah, Heterocycles, 2007, 71, 2155; (d) S. Tanimori, T. Nishimira and M. Kirihata, Bioorg. Med. Chem. Lett., 2009, 19, 4119.
8. D. Gupta, N. N. Ghosh and R. Chandra, Bioorg. Med. Chem. Lett., 2005, 15, 1019.
9. Y. M. Lee and Y. S. Park, Heterocycles, 2009, 78, 2233.
10. S. Luo and J. K. De Brabander, Tetrahedron Lett., 2015, 56, 3179.
11. For selected examples, see: (a) R. I. Storer, D. E. Carrera, Y. K. Ni and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 84; (b) M. Rueping, A. P. Antonchick and T. Theissmann, Angew. Chem., Int. Ed., 2006, 45, 6751; (c) F. Shi, W. Tan, H.-H. Zhang, M. Li, Q. Ye, G.-H. Ma, S.-J. Tu and G.-G. Li, Adv. Synth. Catal., 2013, 355, 3715; (d) A. V. Maikov, K. Vrankova, S. Stoncius and P. Kocovsky, J. Org. Chem., 2009, 74, 5839; (e) Z.-Y. Xue, Y. Jiang, X.-Z. Peng, W.-C. Yuan and X.-M. Zhang, Adv. Synth. Catal., 2010, 352, 2132; (f) Q.-A. Chen, M.-W. Chen, C.-B. Yu, L. Shi, D.-S. Wang, Y. Yang and Y.-G. Zhou, J. Am. Chem. Soc., 2011, 133, 16432; (g) Q.-A. Chen, K. Gao, Y. Duan, Z.-S. Ye, Y. Yang and Y.-G. Zhou, J. Am. Chem. Soc., 2012, 134, 2442; (h) L.-Q. Lu, Y.-H. Li, K. Junge and M. Beller, J. Am. Chem. Soc., 2015, 137, 2763. Only limited success was achieved in the standard asymmetric hydrogenation, for a recent report using a chiral iridium complex as the catalyst, see: (i) J. L. Núňez-Rico and A. Vidal-Ferran, Org. Lett., 2013, 15, 2066.
12. (a) T. Kano, R. Takechi, R. Kobayashi and K. Maruoka, Org. Biomol. Chem., 2014, 12, 724; (b) H. Lou, Y. Wang, E. Jin and X. Lin, J. Org. Chem., 2016, 81, 2019.
13. H. Miyabe, Y. Yamaoka and Y. Takemoto, J. Org. Chem., 2006, 71, 2099.
14. For a Pd-catalyzed non-asymmetric addition of arylboronic acids to quinoxalinones, see: A. Carrër, J.-D. Brion, M. Alami and S. Messaoudi, Adv. Synth. Catal., 2014, 356, 3821 . For an oxidative arylation example, see: A. Carrër, J.-D. Brion, S. Messaoudi and M. Alami, Org. Lett., 2013, 15, 5606.
15. (a) C.-G. Feng, M.-H. Xu and G.-Q. Lin, Synlett, 2011, 1345; (b) Y. Li and M.-H. Xu, Chem. Commun., 2014, 50, 3771; (c) Y.-N. Yu and M.-H. Xu, Org. Chem. Front., 2014, 1, 738; (d) H.-Q. Dong, M.-H. Xu, C.-G. Feng, X.-W. Sun and G.-Q. Lin, Org. Chem. Front., 2015, 2, 73; (e) D. Chen, X. Zhang, W.-Y. Qi, B. Xu and M.-H. Xu, J. Am. Chem. Soc., 2015, 137, 5268.
16. (a) H. Wang, T. Jiang and M.-H. Xu, J. Am. Chem. Soc., 2013, 135, 971; (b) H. Wang, Y. Li and M.-H. Xu, Org. Lett., 2014, 16, 3962; (c) T. Jiang, Z. Wang and M.-H. Xu, Org. Lett., 2015, 17, 528.
17. For recent examples of Rh-catalyzed arylation of cyclic imines using other chiral ligands, see: (a) T. Nishimura, A. Noishiki, Y. Ebe and T. Hayashi, Angew. Chem., Int. Ed., 2013, 52, 1777; (b) Y. Luo, H. B. Hepburn, N. Chotsaeng and H. W. Lam, Angew. Chem., Int. Ed., 2012, 51, 8309; (c) Y. Li, Y.-N. Yu and M.-H. Xu, ACS Catal., 2016, 6, 661 and references cited therein.
18. CCDC 1478345 (3g) contains the supplementary crystallographic data.
19. (a) R. Pauwels, K. Andries, Z. Debyser, P. V. Daele, D. Schols, P. Stoffels, K. D. Vreese, R. Woestenborghs, A. M. Vandamme and E. D. Clercq, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 1711; (b) E. Perola, J. Med. Chem., 2010, 53, 2986; (c) H. J. Sanganee, A. Baxter, S. Barber, A. J. H. Brown, D. Grice, F. Hunt, S. King, A. Laughton, G. Pairaudeau, B. Thong, R. Weaver and J. Unitt, Bioorg. Med. Chem. Lett., 2009, 19, 1143.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1478345. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00191b

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