Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of Aryl N‑Heteroaryl Ketones with N‑Oxide as a Removable orthoSubstituent Qixing Liu,†,§ Chunqin Wang,†,§ Haifeng Zhou,*,†,‡ Baigui Wang,† Jinliang Lv,‡ Lu Cao,‡ and Yigang Fu*,‡ †
Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China ‡ Yichang Humanwell Pharmaceutical Co., Ltd., Yichang 443005, China S Supporting Information *
ABSTRACT: A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric synthesis of bepotastine besilate in 51% total yield and 99.9% ee.
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nantiomeric aryl N-heteroaryl alcohols are very important building blocks of numerous pharmaceuticals, agrochemicals, and biologically active compounds.1 Therefore, various asymmetric synthetic strategies, including biocatalytic asymmetric reduction,2 chemocatalytic asymmetric reduction,3−7 as well as asymmetric addition of aryl organometallic reagents to heteroaryl aldehydes,8 have been reported to prepare such chiral alcohols. Among which, the chemocatalytic asymmetric reduction of aryl N-heteroaryl ketones is the most attractive from the atom-economic point of view. For example, chiral Ru/ diphosphine/diamine4-catalyzed asymmetric hydrogenation, chiral Ru/diamine5-catalyzed asymmetric transfer hydrogenation, and copper/diphosphine6-catalyzed asymmetric hydrosilylation have been developed. In all cases, the aryl N-heteroaryl ketones bearing an ortho-substituent on the aryl ring are essential to achieve high enantioselectivity. In fact, drugs like histamine H1 antagonists bepotastine besilate9 and carbinoxamine10 contain a non-ortho-substituted (S)-4-chlorophenylpyridyl methanol moiety (Figure 1), which has been previously produced by hydroborylation of corresponding ketones with chiral oxazaborolidine.3 However, it suffered from tedious nitrogen protection and deprotection processes, and ultralow temperature (−78 °C). In 2015, Zhang and co-workers realized the asymmetric hydrogenation of 2-(4-chlorobenzoyl)pyridine with [Rh(COD)Binapine]BF4 complexes, affording (S)-4-chlorophenylpyridyl methanol in excellent ee.7 Until now, the asymmetric synthesis of non-ortho-substituted aryl N-heteroaryl alcohols is very limited. © XXXX American Chemical Society
Figure 1. Drugs contain an aryl N-heteroaryl alcohol moiety.
It is highly attractive to develop effective, highly enantioselective, and practical methods. Asymmetric transfer hydrogenation is an efficient, safe, and convenient method to prepare chiral alcohols without using hazardous hydrogen gas and a pressure vessel.11 In 1995, Noyori reported a pioneering work about the asymmetric transfer hydrogenation of aromatic ketones with chiral N-toluenesulfonyl-1,2-dipenylethylenediamine ruthenium complexes.12 Since then, various asymmetric transfer hydrogenations of simple aryl ketones and diaryl ketones with chiral diamine-derived Ru, Rh, or Ir complexes as catalysts have been developed.13,14 In contrast, little attention has been focused on the asymmetric reduction of aryl N-heteroaryl ketones with this kind of catalyst.15 Very recently, we have developed an efficient asymmetric transfer hydrogenation of ortho-substituted aryl NReceived: December 13, 2017
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DOI: 10.1021/acs.orglett.7b03878 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
heteroaryl ketones with up to 99.9% ee using a commercially available bifunctional oxo-tethered ruthenium complex [(S,S)Ts-DENEB] as the catalyst. However, the non-ortho-substituted 2-(4-chlorobenzoyl)pyridine was reduced with poor ee under the standard reaction conditions, indicating that the ortho steric effect plays an essential role in achieving high enantioselectivity. By introducing an N-oxide onto 2-(4-chlorobenzoyl)pyridine to increase the steric effect, 2-(4-chlorobenzoyl)pyridine N-oxide could be reduced with 97.8% ee. To further demonstrate this strategy and develop a potential practical method, we reported an asymmetric transfer hydrogenation of aryl N-heteroaryl ketones with N-oxide as a removable ortho-substituent using readily available iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v = 1:1) at ambient conditions, followed by treatment with Zn/ NH4Cl. A variety of chiral non-ortho-substituted aryl Nheteroaryl methanols were obtained with excellent ee. Most importantly, the gram-scale asymmetric synthesis of bepotastine besilate was also realized (Scheme 1). Scheme 1. Asymmetric Transfer Hydrogenation of Aryl NHeteroaryl Ketones
entry
cat
[H] sourceb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
(S,S)-1a (S,S)-1b (S,S)-1c (S,S)-1d (S,S)-1e (S,S)-1f (S,S)-1g (S,S)-1h (S,S)-1i (S,S)-1f (S,S)-1f (S,S)-1f (S,S)-1f (S,S)-1f (S,S)-1f
F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (1.1:1) F/T (5:2) HCOONa HCOONa HCOONa HCOONa HCOONa HCOONa
16 17 18
(S,S)-1f (S,S)-1j (S,S)-1k
HCOONa HCOONa HCOONa
solvent (v/v)
H2O/MeOH (1:1) H2O/DMF (1:1) H2O/DMSO (1:1) H2O/i-PrOH (1:1) H2O/CF3CH2OH (1:1) H2O/HFIP (1:1) H2O/i-PrOH (1:1) H2O/i-PrOH (1:1)
yield (%)
ee (%)
85 78 81 81 80 86 85 80 79 82 88 80 85 90 84
88.2 79.0 31.6 90.2 96.4 97.1 95.6 81.8 83.9 18.2 94.5 97.1 95.8 98.0 89.4
81 87 85
68.4 95.2 95.0
a
Reaction conditions: 2-(4-chlorobenzoyl)pyridine N-oxide (0.2 mmol), catalyst (5 mol %), hydrogen source (2.0 mmol), solvent (2.0 mL), rt, 24 h, isolated yield, the ee values were determined by HPLC analysis. bThe data in brackets are molar ratio of F/T (HCOOH/TEA).
Our initial studies were carried out by examining the reduction of 2-(4-chlorobenzoyl)pyridine N-oxide in the presence of 5 mol % of catalyst with a mixture of HCOOH/TEA (F/T = 1.1:1, molar ratio) as both hydrogen source and solvent at room temperature for 24 h (Table 1). First, the catalysts including ruthenium complexes 1a−1c, rhodium complex 1d, and iridium complexes 1e−1i were screened, and (S,S)-1f was demonstrated to be the best in terms of yield and enantioselectivity (entries 1− 9). However, poor ee was observed when the reaction was conducted under acidic conditions using HCOOH−NEt3 azeotrope (molar ratio F/T = 5/2) as a hydrogen source and solvent (entry 10). Next, the reaction was investigated with HCOONa as a hydrogen source in an aqueous solution, including H2O/MeOH (1:1), H2O/DMF (1:1), H2O/DMSO (1:1), H2O/i-PrOH (1:1), H2O/CF3CH2OH (1:1), and H2O/ HFIP (1:1), and it was found that 4-chlorophenylpyridyl methanol N-oxide was obtained with up to 90% yield and 98% ee in the mixture of H2O/i-PrOH (entries 11−16). Considering that the counteranion effect of this kind of catalyst has been demonstrated in the asymmetric hydrogenation,16 the anion effect of iridium complexes was also evaluated with catalysts (S,S)-1j and (S,S)-1k, but no apparent effect on the results was
found (entries 17 and 18). Based on these results, the optimized reaction conditions were set as follows: 5 mol % of (S,S)-1f, 10 equiv of HCOONa, H2O/i-PrOH (v/v = 1:1), room temperature, and 24 h. Under the optimized reaction conditions, a variety of aryl Nheteroaryl ketone N-oxides were reduced, followed by treatment with Zn/NH4Cl (Scheme 2). The phenyl 2-pyridyl ketone Noxides 2a−2l bearing electron-donating or electron-withdrawing groups at the para- or meta-position on the benzene ring gave the corresponding aryl 2-pyridyl methanols 3a−3l in 78−98% ee and good yields. For example, the asymmetric transfer hydrogenation of 2-(4-chlorobenzoyl)pyridine N-oxide 2d afforded (S)-3d in 90% yield and 98.2% ee after removing the N-oxide moiety.17 By contrast, the meta-disubstituted phenyl 2-pyridyl methanols 3j− 3l were obtained in relatively lower ee. Note that the steric effects not only impact the enantioselectivity but also determine the reactivity. Regarding the sterically hindered 2-tolyl 2-pyridyl ketone N-oxide (2m), α-naphthyl 2-pyridyl ketone N-oxide (2n), and α-naphthyl 2-isoquinolinyl N-oxide (2r), the transfer B
DOI: 10.1021/acs.orglett.7b03878 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scopea
effect plays an essential role in achieving high enantioselectivity.18,19 To demonstrate the practical utility of this protocol, the key intermediate of bepotastine besilate (S)-3d was synthesized successfully in a gram scale, which was then subjected to the reaction with compound 4, followed by hydrolysis, salification, and recrystallization. Finally, the bepotastine besilate (5) was obtained with 51% total yield and up to 99.9% ee (Scheme 3).20 Scheme 3. Asymmetric Synthesis of Bepotastine Besilate in a Gram Scale
In summary, we have developed an effective method for the asymmetric transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones by introducing N-oxide as a removable ortho-substituent with a readily available chiral diamine-derived iridium complex as a catalyst and sodium formate as a hydrogen source in an aqueous solution at ambient conditions. A range of non-ortho-substituted aryl N-heteroaryl methanols were obtained with excellent yields and high enantioselectivities. The great potential of this protocol in practical use was also demonstrated by the gram-scale synthesis of bepotastine besilate.
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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.7b03878. Experimental details and characterization data (PDF)
a
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Reaction conditions: aryl N-heteroaryl ketone N-oxide 2 (0.2 mmol), (S,S)-1f (5 mol %), HCOONa (2.0 mmol), H2O/i-PrOH (2.0 mL, v/ v = 1:1), rt, 24 h; isolated yield; the ee values were determined by HPLC analysis. bThe corresponding substrates without an N-oxide moiety were used. cNR: no reaction.
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
hydrogenation did not occur. For methyl-substituted 2-pyridyl phenyl ketone N-oxides 2o and 2p, both gave excellent ee and yields. In the case of substrates 2q and 2s bearing a bulky isoquinolinyl or quinolinyl moiety, relatively lower ee values were obtained. Finally, substrates 2t and 2u that have substituents on both aromatic and N-heteroaromatic ring moieties were also examined, affording the corresponding alcohols with more than 75% yield and 89% ee. Moreover, the asymmetric transfer hydrogenation of substrates such as 2a, 2d, 2h, 2f, and 2o without an N-oxide proceeded smoothly, giving the corresponding aryl N-heteroaryl methanols in good yield but with no more than 15.1% ee (Scheme 2, data in the brackets). It means that the Noxide moiety acts as an ortho-substituent, and the ortho steric
Haifeng Zhou: 0000-0002-2710-9570 Author Contributions §
Q.L. and C.W. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support by grants from the National Natural Science Foundation of China (21202092), the Project of Scientific Research of Hubei Provincial Education Department (B2016024), China Three Gorges University C
DOI: 10.1021/acs.orglett.7b03878 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters (KJ2014H008, KJ2014B084), and a joint research fund from Yichang Humanwell Pharmaceutical Co., Ltd. (SDHZ2015003).
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REFERENCES
(1) For selected examples, see: (a) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. Chem. Rev. 2006, 106, 2734−2793. (b) Rennison, D.; Bova, S.; Cavalli, M.; Ricchelli, F.; Zulian, A.; Hopkins, B.; Brimble, M. A. Bioorg. Med. Chem. 2007, 15, 2963−2974. (c) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.; Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787−3797. (d) Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.; Lombardi, P. Tetrahedron: Asymmetry 1996, 7, 1263−1266. (2) Truppo, M. D.; Pollard, D.; Devine, P. Org. Lett. 2007, 9, 335−338. (3) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675−5678. (4) (a) Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Xie, X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z. J. Org. Chem. 2012, 77, 612−616. (b) Chen, C.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003, 5, 5039−5042. (c) Maerten, E.; Agbossou-Niedercorn, F.; Castanet, Y.; Mortreux, A. Tetrahedron 2008, 64, 8700−8708. (5) Wang, B.; Zhou, H.; Lu, G.; Liu, Q.; Jiang, X. Org. Lett. 2017, 19, 2094−2097. (6) (a) Lee, C. T.; Lipshutz, B. H. Org. Lett. 2008, 10, 4187−4190. (b) Sui, Y. Z.; Zhang, X. C.; Wu, J. W.; Li, S.; Zhou, J. N.; Li, M.; Fang, W.; Chan, A. S. C.; Wu, J. Chem. - Eur. J. 2012, 18, 7486−7492. (7) Yang, H.; Huo, N.; Yang, P.; Pei, H.; Lv, H.; Zhang, X. Org. Lett. 2015, 17, 4144−4147. (8) Salvi, L.; Kim, J. G.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483−12493. (9) Roszkowski, A. P.; Govier, W. M. Pharmacologist 1959, 1, 60−78. (10) (a) Barouh, V.; Dall, H.; Patel, D.; Hite, G. J. Med. Chem. 1971, 14, 834−836. (b) Casy, A. F.; Drake, A. F.; Ganellin, C. R.; Mercer, A. D.; Upton, C. Chirality 1992, 4, 356−366. (11) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621−6686. (12) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562−7563. (13) (a) Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J. Chem. - Eur. J. 2008, 14, 2209−2222. (b) Bartoszewicz, A.; Ahlsten, N.; Martin-Matute, B. Chem. - Eur. J. 2013, 19, 7274−7320. (c) Malacea, R.; Poli, R.; Manoury, E. Coord. Chem. Rev. 2010, 254, 729−752. (14) Selected examples of iridium-catalyzed asymmetric transfer hydrogenation of ketones: (a) Bartoszewicz, A.; Ahlsten, N.; MartIń Matute, B. Chem. - Eur. J. 2013, 19, 7274−7302. (b) Tian, C.; Gong, L.; Meggers, E. Chem. Commun. 2016, 52, 4207−4210. (c) Liu, W.-P.; Yuan, M.-L.; Yang, X.-H.; Li, K.; Xie, J.-H.; Zhou, Q.-L. Chem. Commun. 2015, 51, 6123−6125. (15) Asymmetric transfer hydrogenation of diheteroaryl ketone: Hems, W. P.; Jackson, W. P.; Nightingale, P.; Bryant, R. Org. Process Res. Dev. 2012, 16, 461−463. (16) Ding, Z.-Y.; Chen, F.; Qin, J.; He, Y.-M.; Fan, Q. H. Angew. Chem., Int. Ed. 2012, 51, 5706−5710. (17) Absolute configuration of 3d was assigned as S on the basis of its HPLC and optical rotation. See refs 8 and 16 and Supporting Information. (18) Stephan, M.; Sterk, D.; Mohar, B. Adv. Synth. Catal. 2009, 351, 2779−2786. (19) The origin of the enantioselectivity of both substrates with and without N-oxide and the related electronic effects could be explained based on Noyori’s outer-sphere mechanism. For the detailed discussion, please refer to our previous work and the references cited therein: Wang, B.; Zhou, H.; Lu, G.; Liu, Q.; Jiang, X. Org. Lett. 2017, 19, 2094−2097. (20) (a) Zhao, Z.; Zhou, Z.; Peng, L. Chin. J. Pharm. 2006, 37, 726− 727. (b) Ha, T. H.; Suh, K.-H.; Lee, G. S. Bull. Korean Chem. Soc. 2013, 34, 549−552.
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DOI: 10.1021/acs.orglett.7b03878 Org. Lett. XXXX, XXX, XXX−XXX
