Organocatalytic Enantioselective Cross-Aldol Reaction of o

Letter pubs.acs.org/OrgLett

Organocatalytic Enantioselective Cross-Aldol Reaction of o‑Hydroxyarylketones and Trifluoromethyl Ketones Pei Wang,† Hong-Feng Li,† Jia-Zhen Zhao,† Zhi-Hong Du,† and Chao-Shan Da*,†,‡,¶ †

Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China State Key Laboratory of Organic Chemistry, Lanzhou University, Lanzhou 730000, China ¶ Key Lab of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, China ‡

S Supporting Information *

ABSTRACT: The enantioselective cross-aldol reaction between o-hydroxyacetophenones and trifluoromethyl ketones catalyzed by chiral thiourea organocatalysts is reported. Gramscale synthesis of the cross-aldol product was carried out, with no decrease in the yield and enantioselectivity. Furthermore, the cross-aldol products thus prepared were used in the preparation of medicinally interesting 3,5-diaryl-5-trifluoromethyl-2-isoxazoline and β-trifluoromethyl-β-tertiary hydroxy acid ester with high yield and enantiopurity. pplications of fluorinated chemicals are prevalent in medicine, agriculture, and materials science because of the interesting characteristics of fluorine atoms; hence, the search of novel, interesting fluorinated chemicals remains a hot topic in chemistry.1 Among these fluorinated chemicals, a plethora of chiral trifluoromethylated tertiary alcohols such as C-1 to C-4, shown in Figure 1, exhibit various biological and pharmaceutical

A

tertiary alcohols. The asymmetric catalytic direct cross-aldol reaction between o-hydroxyarylketones and trifluoromethyl ketones provides straightforward access to these interesting compounds. To the best of our knowledge, only one racemic case by the reaction between o-hydroxyacetophenone and 2,2,2trifluoromethyl acetophenone has been reported by Hu and coworkers.4 This observation has strongly encouraged us to explore this challenging asymmetric transformation. Catalytic enantioselective aldol reactions have been extensively studied to afford enantioenriched aldols via C−C bond formation, which constitute moieties of bioactive compounds and intermediates for synthesizing chiral drugs.5 Because of the facile access to organocatalysts from commercially available chiral pools, environmental friendliness, and convenient operation, organocatalysis has already emerged as the most developed route for enantioselective direct aldol reactions, especially using alkyl ketones and aldehydes as the aldol donors and acceptors, respectively.6 In this regard, recently, the organocatalytic cross-aldol reaction of acetone and 2,2,2trifluoroacetophenones has been successfully demonstrated, affording highly enantioenriched trifluoromethylated tertiary alcohols.7 However, only Ikemoto’s group has reported direct cross-aldol reactions of arylketones and trifluoromethylketones with limited substrate scope, using 20 mol % of the organocatalyst, with the highest enantioselectivity of 89%.8 Alternatively, Ma and coauthors have reported an indirect organocatalytic decarboxylative aldol reaction of β-ketoacids and trifluoromethyl ketones with the highest enantioselectivity of 90%.9 Typically, arylketones are seldom directly used as efficient aldol donors because of the conjugation effect as well as the delocalization of electrons. In the scarce studies reported for the highly enantioselective organocatalyzed direct aldol reactions,

Figure 1. Compounds with varied biological activities.

activities.2 However, chiral β-tertiary hydroxy o-hydroxyarylketones represent another important framework found in a series of compounds, such as C-5 to C-7 in Figure 1, with important, potent biological and medicinal activities.3 Notably, coupling these two moieties, i.e., chiral α-trifluoromethylated tertiary alcohols and o-hydroxyarylketones, respectively, into a single compound is attractive as it can effectively extend the applications of biologically interesting trifluoromethylated © 2017 American Chemical Society

Received: March 31, 2017 Published: May 8, 2017 2634

DOI: 10.1021/acs.orglett.7b00828 Org. Lett. 2017, 19, 2634−2637

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

arylketones serve as the aldol donors, while only very reactive αketocarbonyl compounds and trifluoroacetaldehyde serve as successful aldol acceptors.10 Thus far, the widely used strategy involves the initial generation of strongly nucleophilic enol anions or metallic enol intermediates from arylketones using very strongly basic modifying reagents or catalysts. This strategy was verified by the extensively utilized Mukaiyama aldol reactions11 and the highly enantioselective direct aldol reaction of arylketones and aldehydes catalyzed by a chiral zincate complex.12 Thus, bifunctional chiral thioureas with tertiary amine as the basic moiety are hypothesized to serve as appropriate organocatalysts, and the tertiary amine moiety comprising N,N-diethyl groups (Et2N-R*) is indispensable because triethylamine (Et3N), as an organic base, typically exhibits higher basicity than most tertiary amine bases; the very strong basic property of the N,N-diethyl-containing tertiary amine moiety in thioureas should effectively help produce enol anions from o-hydroxyacetophenones in high yield. In this study, preliminary results for the unprecedented enantioselective crossaldol reaction of o-hydroxyacetophenones and trifluoromethyl ketones catalyzed by chiral thioureas, with high yield and excellent enantioselectivity, are reported. To prove our hypothesis, a class of chiral tertiary-amine-based thioureas and squaramide organocatalysts 1a−1j (Figure 2) were

entry

1 (mol %)

°C

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

1a (10) 1b (10) 1c (10) 1d (10) 1e (10) 1f (10) 1g (10) 1h (10) 1i (10) 1j (10) 1d (10) 1d (10) 1d (1) 1d (2) 1d (5) 1d (7) 1d (15)

rt rt rt rt rt rt rt rt rt rt 10 0 0 0 0 0 0

67 34 58 92 37 43 84 61 12 22 85 84 14 32 53 84 64

91 84 75 90 83 92 82 62 83 45 93 94 89 92 92 94 90

a

Reaction conditions: 1.25 mmol of 2a, 0.25 mmol of 3a and 0.5 mL of toluene was used, 6 d. bIsolated yield. cDetermined by chiral HPLC.13

% loading of 1d despite the reduced yield (for the optimization of other reaction conditions, see S2 in Supporting Information). With the optimized reaction conditions in hand, the substrate scope was examined (Scheme 1). First, a series of ohydroxyacetophenones with trifluoroacetophenone was examined. Both electron-withdrawing and electron-donating groups in the benzene rings of o-hydroxyacetophenones were well tolerated, with high enantioselectivity and excellent yield. The highest enantioselectivity and yield obtained were up to 94% (4aa, 4ga, and 4ha) and up to 99% (4ea, 4ha), respectively. The positions of the substituted groups in the benzene rings affected the ee and yield. Functional groups at a position para to the hydroxyl (4ba, 4ca, 4ea, 4ga, 4ha, and 4ia) or acetyl group (4da, 4fa) in the benzene ring typically afforded high ee and yield. However, functional groups at a position ortho to the hydroxyl group in the benzene ring afforded dramatically decreased yield and moderately reduced ee (4ja and 4ka). For two o-hydroxy acetonaphthanones (4ka, 4la) and 3-phenyl-2-hydroxyacetophenone (4ja), the extended conjugated effect might contribute to the significantly decreased yield to some extent. Next, the scope of trifluoromethyl ketones was examined (Scheme 1). Typically, electron-donating groups in the benzene rings of trifluoroacetophenones resulted in decreased product yield (4ab, 4ac, 4ad, 4ae, 4af, and 4am). Moreover, electrondonating and electron-withdrawing groups of trifluoroacetophenones afforded similar satisfactory results for ee. In addition, two trifluoromethylenones were investigated, which afforded good product yields, and the sterically bulkier enone afforded higher enantioselectivity (4ao, 4ap). To the best of our knowledge, trifluoromethylenones as substrates are first released in catalytic asymmetric cross-aldol reactions of arylketones. Similar to the aforementioned electron-enriched acetophenones, acetothienone exhibited a similarly good yield, albeit with high enantioselectivity (4aq). Notably, two alkyl trifluoromethyl ketones also afforded good enantioselectivity (4ar, 4as). Finally, two trifluoroacetophenones 3b and 3i reacted with 5-bromo-2-

Figure 2. Organocatalysts used in the cross-aldol reaction.

screened. Initially, widely used thiourea 1a was examined in toluene at room temperature. However, the product was obtained in only 67% yield with high ee (Table 1, entry 1). With the increase in the steric bulk of the acidic moiety of thiourea, the yield and ee of the product decreased (entries 1−3, 1a vs 1b−1c). Gratifyingly, highly basic N,N-diethyl-tertiaryamine-based thiourea 1d afforded excellent yield and ee, as expected (entry 4). When less basic 1e was used, the product yield dramatically decreased, accompanied by a slightly reduced ee (entry 5). Structurally rigid pyrrole-based thiourea 1f exhibited a slightly improved ee of 92%, albeit with a dramatically decreased yield (entry 6). Moreover, using piperidine-based thiourea 1g, the ee decreased again (entry 7). The endeavor to improve ee by decreasing the steric bulk of the acidic moiety of bifunctional catalyst 1h was not successful (entry 8), highlighting the importance of the 3,5-bis(trifluoromethyl)benzyl moiety in thiourea. The ee observed for 1,2-diphenylethylenediaminebased thiourea 1i and squaramide 1j was not greater than that observed for 1d (entries 9−10). Low temperature further improved the ee for 1d (entries 11−12). Considering the catalyst loading, 7 mol % of 1d equivalent to trifluoroacetophenone was optimal, with a slightly improved ee of 94% (entries 13−17). Nevertheless, high ee of 92% was also obtained even with a 2 mol 2635

DOI: 10.1021/acs.orglett.7b00828 Org. Lett. 2017, 19, 2634−2637

Letter

Organic Letters Scheme 1. Direct Organocatalytic Enantioselective CrossAldol Reactiona

Scheme 2. Gram-Scale Asymmetric Cross-Aldol Reaction

Scheme 3. Synthesis of Medicine-Interested Compounds

utility of this method, two compounds, 5-trifluoromethyl-2isoxazoline 6 and β-trifluoromethyl-β-tertiary hydroxy acid ester 8, were readily synthesized from products 4ga and 4aa in high yield and enantiopurity, respectively. In this process, the X-ray analysis of 5, the oxime intermediate of 4ga with hydroxylamine, was utilized to assign the absolute configuration of 4ga (also see S31 in Supporting Information). Based on reported studies,7 two starting materials and thiourea 1d were proposed to favorably generate intermediate 9 in situ (Scheme 4) in which the enol anion from o-hydroxyacetophea

The isolated yield was reported and ee was determined by chiral HPLC. The absolute configuration was assigned by the X-ray analysis of the oxime derivative of 4ga with hydroxylamine (see S31 in Supporting Information). bThe reaction was carried out at room temperature. cTen mol % of 1d was used at room temperature.

Scheme 4. Proposed Reaction Intermediate to (S)-4aa

hydroxy-acetophenone 2g to produce 4gb and 4gi with high yield and enantioselectivity, respectively. Trichloroacetophenone was also observed as an aldol acceptor but the reaction was very sluggish with lower than 5% yield and high enantioselectivity of 86%. In addition, only moderate enantioselectivity of 60% was achieved, while acetophenone was used as an aldol donor to trifluoroacetophenone (see S26 and S27 in Supporting Information). The facile, mild reaction conditions prompted us to successfully extend this protocol for the gram-scale synthesis, with no decrease in the yield and enantioselectivity (Scheme 2). This observation renders this protocol potential for practical applications. 3,5-Diaryl-5-trifluoromethyl-2-isoxazoline A exhibits potent antiparasitic activity against cat fleas and dog ticks (Scheme 3).14 Further studies on the same skeleton are being conducted to search for new agrochemicals and veterinary medicines.15 In addition, β-hydroxy carboxylic acids are typically observed key motifs in pharmaceutical compounds.16 To demonstrate the

none preferentially attacks trifluoroacetophenone in its Re-face and predominantly affords the S-configuration product 4aa. The intramolecular H-bond of o-hydroxyacetophenone leads to the increased acidity of its α-hydrogen and aids in the generation of a strongly attacking enol anion. In summary, the organocatalytic asymmetric cross-aldol reaction of o-hydroxyarylketones and trifluoromethyl ketones was successfully demonstrated for the first time to the best of our knowledge. The strongly basic N,N-diethyl tertiary aminecontaining thiourea 1d was optimum with respect to high yield and enantioselectivity. A number of o-hydroxyarylketones and trifluoromethyl ketones were well tolerated in this method. In addition, even rarely explored trifluoromethyl enones and trifluoromethyl alkylketones afforded good-to-high enantioselectivity. The gram-scale synthesis of the cross-aldol product is 2636

DOI: 10.1021/acs.orglett.7b00828 Org. Lett. 2017, 19, 2634−2637

Letter

Organic Letters

(d) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541. For selected organocatalyzed asymmetric Aldol reactions, see: (e) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395. (f) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (g) Mahrwald, R.; Schetter, B. Org. Lett. 2006, 8, 281. (h) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074. (i) Reis, Ö .; Eymur, S.; Reis, B.; Demir, A. S. Chem. Commun. 2009, 1088. (j) Da, C. S.; Che, L. P.; Guo, Q. P.; Wu, F. C.; Ma, X.; Jia, Y. N. J. Org. Chem. 2009, 74, 2541. (k) Wu, F. C.; Da, C. S.; Du, Z. X.; Guo, Q. P.; Li, W. P.; Yi, L.; Jia, Y. N.; Ma, X. J. Org. Chem. 2009, 74, 4812. (l) Pousse, G.; Le Cavelier, F.; Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582. (m) Lu, Y.; Zheng, C.; Yang, Y.; Zhao, G.; Zou, G. Adv. Synth. Catal. 2011, 353, 3129. (n) Henseler, A. H.; Ayats, C.; Pericas, M. A. Adv. Synth. Catal. 2014, 356, 1795. (7) For organocatalytic asymmetric cross-aldol reactions of acetone and trifluoroacetophenones, see: (a) Qiu, L. H.; Shen, Z. X.; Shi, C. Q.; Liu, Y. H.; Zhang, Y. W. Chin. J. Chem. 2005, 23, 584. (b) Hara, N.; Tamura, R.; Funahashi, Y.; Nakamura, S. Org. Lett. 2011, 13, 1662. (c) Kokotos, C. G. J. Org. Chem. 2012, 77, 1131. (d) Duangdee, N.; Harnying, W.; Rulli, G.; Neudoerfl, J.-M.; Groeger, H.; Berkessel, A. J. Am. Chem. Soc. 2012, 134, 11196. (e) Yang, W.; Cui, Y.-M.; Zhou, W.; Li, L.; Yang, K.-F.; Zheng, Z.-J.; Lu, Y.; Xu, L.-W. Synlett 2014, 25, 1461. (f) Zong, H.; Huang, H.; Bian, G.; Song, L. J. Org. Chem. 2014, 79, 11768. (8) In the process of this work, Ikemoto and co-workers released their preliminary work on catalytic asymmetric cross-aldol reaction of arylketones and trifluoroacetophenones Lutete, L. M.; Miyamoto, T.; Ikemoto, T. Tetrahedron Lett. 2016, 57, 1220. (9) Zheng, Y.; Xiong, H.-Y.; Nie, J.; Hua, M.-Q.; Ma, J.-A. Chem. Commun. 2012, 48, 4308. (10) (a) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed. 2010, 49, 9460. (b) Funabiki, K.; Itoh, Y.; Kubota, Y.; Matsui, M. J. Org. Chem. 2011, 76, 3545. (c) Konda, S.; Guo, Q.-S.; Abe, M.; Huang, H.; Arman, H.; Zhao, J. C.-G. J. Org. Chem. 2015, 80, 806. (11) For reviews on catalytic asymmetric Mukaiyama aldol reactions, see: (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. (b) Matsuo, J.-i.; Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 9109. (c) Averill, D. J.; Allen, M. J. Catal. Sci. Technol. 2014, 4, 4129. (12) For chiral zincate-catalyzed direct asymmetric aldol reactions of arylketones, see: (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (c) Li, H.; Da, C.-S.; Xiao, Y.-H.; Li, X.; Su, Y.-N. J. Org. Chem. 2008, 73, 7398. (13) We also found clear self-disproportionation of the product (S)4aa; details in S3 in Supporting Information. (14) Mita, T.; Kudo, Y.; Mizukoshi, T.; Hotta, H.; Maeda, K.; Takii, S. WO2004018410, 2004. (15) (a) Quan, M. L.; Ellis, C. D.; Liauw, A. Y.; Alexander, R. S.; Knabb, R. M.; Lam, G.; Wright, M. R.; Wong, P. C.; Wexler, R. R. J. Med. Chem. 1999, 42, 2760. (b) Kumar, V.; Aggarwal, R.; Singh, S. P. J. Fluorine Chem. 2006, 127, 880. (16) (a) Krow, G. R. Tetrahedron 1981, 37, 2697. (b) Lavilla, R.; Gullon, F.; Bosch, J. Eur. J. Org. Chem. 1999, 1999, 373. (c) Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2851.

possible without the decrease in the yield and enantioselectivity. The utility of this protocol was successfully explored by the facile preparation of medicinally interesting compounds in high yield and enantiopurity.

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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.7b00828. Selection of optimal solvent and the loading of starting materials, experimental procedures, characterization of compounds, and HPLC and NMR spectra for compounds (PDF) X-ray data for the compound 5 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chao-Shan Da: 0000-0003-1306-4348 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China for its financial support (No. 21072087). REFERENCES

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DOI: 10.1021/acs.orglett.7b00828 Org. Lett. 2017, 19, 2634−2637