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Asymmetric Synthesis of Agrochemically Attractive Trifluoromethylated Dihydroazoles and Related Compounds under Organocatalysis Hiroyuki Kawai and Norio Shibata*[a] Department of Nanopharmaceutical Science and Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555 (Japan) E-mail: [email protected]

[a]

Received: March 22, 2014 Published online: ■■

ABSTRACT: The unique, partially saturated, fluorinated five-membered heterocyclic compounds, trifluoromethylated dihydroazoles, and their derivatives, have emerged as a new class of heterocycles with remarkable biological activities in the 21st century. Despite their small molecular structures, a single sterically demanding tetrasubstituted trifluoromethylated stereogenic carbon center has prevented chemists from achieving the asymmetric synthesis of these compounds. In this account, we describe our recent progress in the catalytic asymmetric synthesis of a series of trifluoromethylated heterocycles, such as isoxazolines and pyrrolines having a stereogenic carbon center, based on organocatalysis. Our protocols have advantages in terms of employing inexpensive reagents and organocatalysts and they would be useful for industrial production. DOI 10.1002/tcr.201402023 Keywords: asymmetric synthesis, fluorine, heterocycles, organocatalysis, trifluoromethylation

Introduction As represented by the registered trademark of the American Chemical Society, “Chemistry for Life” is indeed a key phrase of life science in the 21st century. The chemistry of medicine, agriculture and energy is highly related to our lives and has been continuously developed to sustain and improve our lifestyles. Organofluorine compounds are one of the most powerful contributors in this respect.[1] Of the top 200 drug sales in 2012, 33 pharmaceuticals contained fluorine or fluorinated functional groups in their structures, and 25% of commercially available pharmaceuticals are currently related to fluorine chemistry.[2] In addition to medicines, foods are another essential aspect of human life. In order to cope with the population growth worldwide, it is absolutely essential to produce foods effectively, in large quantities, anywhere around the world.

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Agrochemicals such as pesticides and herbicides can help agroproductivity. The contribution of fluorine chemistry to pesticides is much more pronounced than to pharmaceuticals, and it is estimated that fluorine or fluorinated functional groups are contained in almost half of them.[1,3] Among the various families of fluorinated functional groups, the trifluoromethyl (CF3) group has attracted a great deal of attention in the last few decades as the most venerable discovery among biologically active molecules.[1,2a–c,4] In particular, heterocycles containing a trifluoromethyl group are a major contribution to agricultural and medicinal chemistry markets.[5] Thus, the development of an efficient and flexible method to generate a novel trifluoromethylated heterocyclic system has received much attention. Although the aromatic heterocycles

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Fig. 1. Structures of trifluoromethylated dihydroazoles.

are a well-known group of heterocycles, we are interested in the partially saturated heterocyclic compounds. The most obvious aspect that differentiates partially saturated heterocyclic compounds from aromatic heterocycles is the existence of chirality in their cyclic framework. The chiral drug industry has soared in recent years as a result of leading progress in asymmetric synthesis,[6] making the partially saturated fluorinated heterocycles containing chiral center(s) very attractive. Recently, trifluoromethylated dihydroazoles (Figure 1; X=O, isoxazoline; X=CH2, pyrroline; X=NR, pyrazoline) have become promising pharmacophores with remarkable biological activities, which makes them a competitive synthetic topic in life science

Norio Shibata (born July 3, 1965) has been a Professor of Chemistry at the Nagoya Institute of Technology since 2008. He received his Ph.D. (1993) in pharmaceutical sciences from Osaka University underthe direction of Prof. Yasuyuki Kita. He worked at Dyson Perrins Laboratory (Prof. Sir Jack. E. Baldwin), Oxford University (JSPS fellow, 1994– 1996), and Sagami Chemical Research Institute (Dr. Shiro Terashima, 1996), after which he was a lecturer at Toyama Medical & Pharmaceutical University (1997–2003), and an associate professor at Nagoya Institute of Technology (2003– 2008). He also acted as a visiting professor (2008, 2012) at the University of Rouen with the support of Dr. Dominique Cahard. He received the Takeda Pharmaceutical Company Award in Synthetic Organic Chemistry, Japan (2000), the Fujifilm Award in Synthetic Organic Chemistry, Japan (2003), the Incentive Award in Synthetic Organic Chemistry, Japan (2004), the RSC Fluorine Prize (inaugural prize, 2005), the 20th Lecture Award for Young Chemists in Chemical Society of Japan (2005), the Fluorine Chemistry Research Incentive Award in Research Foundation ITSUU Laboratory (inaugural prize, 2009), the Pharmaceutical Society of Japan Award for Divisional Scientific Promotions (2010), and Prizes for Science and Technology, the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology (2014). His research interests cover a wide range of synthetic and medicinal fluorine chemistry.

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industries.[1a,c,5] Particularly, since the original report of trifluoromethylated partially saturated heterocycles, 3,5-diaryl5-trifluoromethyl-2-isoxazoline derivatives 1 (X=O), which show pest control activities, by Nissan Chemical Industries in 2004,[7] the search for new agrochemicals and veterinary medicines has simultaneously focused largely on this partially saturated heterocyclic skeleton.[8] So far, more than 27,000 compounds 1,[9] 8600 compounds 2[10] and 7500 compounds 3[9e,10d,11] have been registered in the SciFinder database and most of them are protected as patents by chemical and pharmaceutical industries. Based on these plentiful compound libraries, many promising drug candidates have been disclosed including antiparasitics.[9–11] More interestingly, a recent biological study of enantioenriched 5-trifluoromethyl-2-isoxazoline 1 obtained by chiral HPLC resolution revealed that only one enantiomer is the biologically active component.[12] Accordingly, it is apparently necessary to synthesize these compounds as enantiopure forms in modern organic synthesis such as in the pharmaceutical industry; however, no reports of asymmetric

Hiroyuki Kawai was born in 1984 in Aichi, Japan. He received his bachelor degree of chemistry in 2008 and his Ph.D. in 2012 from the Nagoya Institute of Technology (NIT) under the direction of Prof. Norio Shibata. He continued working in NIT as a JSPS postdoctoral fellow during 2012–2013. He then moved to the University of California, Berkeley, and he is currently working as a postdoctoral fellow (JSPS) with Prof. F. Dean Toste. His research interests are in the development of new synthetic reactions enabled by gold catalysis.

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synthetic methodologies for trifluoromethylated dihydroazoles have appeared despite their importance. Our group has been engaged in the research of organofluorine chemistry for nearly two decades, in particular the development of novel methodologies for the enantioselective synthesis of organofluorine compounds via direct late-stage fluorinations/ trifluoromethylation reactions[13] and a fluorinated building block strategy.[14] Here we report our recent success on the development of asymmetric synthesis of these agrochemically important molecules based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes.

Asymmetric Synthesis of TrifluoromethylSubstituted 2-Isoxazolines by Cascade Reactions First, we set our sights upon the asymmetric synthesis of 3,5diaryl-5-trifluoromethyl-2-isoxazolines 1. So far, optically active 2-isoxazolines are known to be accessible mainly by the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to olefins.[15] There are also other strategies,[16] but these methods were not applicable to the synthesis of 1 due to limitations in substrate specificity. We hypothesized that a tandem reaction between hydroxylamine and β-aryl-β-trifluoromethyldisubstituted enones 4 consisting of conjugate addition– cyclization–dehydration reactions in the presence of a phasetransfer catalyst would provide the desired compounds 1 with high stereoselectivities. We achieved this objective by using cinchona alkaloid derived phase-transfer catalyst 5a or 5b under basic conditions with a broad substrate range.[17] Our devised reaction system provides 1 with high yields and enantioselectivities, and a variety of substituents at their aromatic rings are tolerated (Table 1). Opposite enantiomers are also accessible by using the pseudo-enantiomer ammonium bromides derived from quinine 5c or 5d (Table 1, entries 2 and 20). It is noteworthy that a multiply substituted substrate is also suitable for this transformation to afford a chiral key intermediate leading to the final target structure with potent biological activity (Table 1, entries 19 and 20).[9a,e] Two possible reaction pathways could be considered for this isoxazoline formation reaction: route A, consisting of an intermolecular Michael addition, then intramolecular imine formation; and route B, consisting of an intermolecular imine formation, then an intramolecular Michael addition, as shown in Scheme 1. To confirm the mechanism, isolable oxime 7 was individually synthesized. Cyclization was attempted under the same reaction conditions in a separate experiment but no isoxazoline 1 formed. This result was also supported by Baldwin’s rules for ring-closing reactions, in which 5-endo-trig is disfavored.[18] On the other hand, the ring-closing reaction in route A occurs in the second step through a favored 5-exo-trig process.

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Synthesis of 5-Trifluoromethyl-2-isoxazolines by Trifluoromethylation of Isoxazoles The foremost strategies for the construction of 5-trifluoromethyl-2-isoxazoline frameworks 1 are: (i) a building block approach using fluorinated substrates with a hydroxylamine–enone tandem reaction (as shown in Scheme 1) or the 1,3-dipolar cycloaddition of nitrile oxides with trifluoromethylated styrenes,[7,9,17] and (ii) straight addition of a CF3 anion into aromatic isoxazoles (Scheme 2). A number of building block methods have been reported. However, no examples of the direct trifluoromethylation of aromatic isoxazoles have appeared. The direct addition of nucleophiles into the 5-position of isoxazoles is a challenge,[19] apparently due to the inherent aromatic character of isoxazoles.[20] We achieved the previously unknown trifluoromethylation of aromatic 3,5-diarylisoxazoles by introducing a strong electron-withdrawing nitro group at the 4-position of the isoxazole ring, which should alter the aromaticity of isoxazoles to improve the reactivity of the 5-position.[21] Under our optimized conditions, using trifluoromethyltrimethylsilane, the Ruppert–Prakash reagent (Me3SiCF3), with NaOAc in the presence of a catalytic amount of achiral phase-transfer catalyst, a range of 4-nitro-3,5diarylisoxazoles 8 were very nicely converted into the corresponding trifluoromethylated isoxazolines 9, which were isolated as single isomers in excellent yields without being affected by the functional groups on the aromatic ring (Table 2). The next challenge was the direct nucleophilic trifluoromethylation of 4-nitro-5-styrylisoxazoles 10. It was considered that this might be problematic, since the 4-nitro5-styrylisoxazoles 10 have two electrophilic centers and both parts could be reactive towards nucleophiles.[22] Previously, Adamo and co-workers reported that 10 reacted with nucleophiles selectively via 1,6-addition to yield conjugated Michael adducts in good yields, while the addition of carbon nucleophiles at the 4-position of 10 is uncommon.[19e,f ] To our great delight, the reaction of 10 with Me3SiCF3 under our optimum conditions afforded trifluoromethylation product 11 entirely, in high yields as a single isomer. The direct regioand diastereoselective trifluoromethylation of 4-nitro-5styrylisoxazoles 10 was found to show high generality to a wide variety of substrates (Table 3). It should be noted that the nitro group at the 4-position is crucially important for successful transformation. No reaction was observed in the case of 3,5-diphenylisoxazole 12, the non-nitro analogue of 8a, under the same reaction conditions (Scheme 3). The nitro group of 9a was easily removed under radical reduction conditions to provide 5-trifluoromethyl-2isoxazolines 1.[23]

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Table 1. Enantioselective synthesis of trifluoromethyl-2-isoxazolines 1 by an asymmetric hydroxylamine–enone cascade reaction.

Entry

Cat. 5

1 2 3 4[b] 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

5a 5c 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5a 5b 5b 5a 5a 5b 5d

[a]

Ar

R

Ph Ph 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl Ph Ph Ph Ph Ph Ph Ph Ph Ph 3,5-Cl2C6H3 3,5-Cl2C6H3

Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-MeC6H4 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl cyclohexyl 3-Me-4-BrC6H3 3-Me-4-BrC6H3

Yield (%)[a]

ee (%)

88 89 83 83 99 92 97 99 94 92 96 99 88 91 96 99 99 80 99 99

92 88(S) 92 94 92 91 91 90 92 82 91 93 91 88 90 91 91 91 88 81(S)

Isolated yield. [b](CH2Cl)2 was used as solvent.

Scheme 2. Synthetic strategies for 5-trifluoromethyl-2-isoxazolines 1.

Scheme 1. The possible reaction routes, A and B.

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Table 2. Stereoselective trifluoromethylation of 4-nitro-3,5-diarylisoxazoles 8.

Entry 1 2 3 4 5 6 7 8 9 10 [a]

R Ph Ph Ph 3-MeC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl 4-ClC6H4 Me Me

Yield (%)[a]

Ar Ph 4-MeC6H4 4-ClC6H4 Ph Ph Ph Ph 4-BrC6H4 Ph 4-MeC6H4

95 85 90 90 99 92 90 97 72 67

Isolated yield.

Table 3. Regio- and diastereoselective trifluoromethylation of 4-nitro-5-styrylisoxazoles 10.

Entry 1 2 3 4 5 6 7 8 9 10 11 12[b] 13 14 15 16 [a]

Ar Ph 4-MeC6H4 4-MeOC6H4 2-ClC6H4 3-ClC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-Cl-4-NO2C6H3 1-naphthyl 2-naphthyl 2-furanyl Ph Ph 4-MeC6H4 4-ClC6H4

R Me Me Me Me Me Me Me Me Me Me Me Me Ph 4-MeC6H4 Ph Ph

Yield (%)[a] 87 84 82 87 89 96 80 90 67 86 85 93 90 95 90 96

Isolated yield. [b]Me3SiCF3 (4.0 equiv), NaOAc (3.0 equiv) and [CH3(CH2)15N(CH3)3]Br (50 mol %) were used.

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Scheme 3. The importance of the nitro group and its removal.

Fig. 2. Biologically potent trifluoromethyl isoxazolines 1 and highly functionalized isoxazoline triflones 14.

Trifluoromethylation/Halogenation of Isoxazole Triflones: Access to All-Carbon-Functionalized Trifluoromethyl Isoxazoline Triflones Our success with the stereoselective trifluoromethylation of 4-nitro-3,5-diarylisoxazoles 8 (Table 2) led us to extend our devised synthetic strategy to prepare 4-functionalized 3,5diaryl-5-trifluoromethyl-2-isoxazoline derivatives, that is, previously unknown 4-functionalized triflone derivatives 14 as novel lead candidates for drug discovery in a future market (Figure 2). The potential of the 1-, 2-, 3- and 5-positions on this small ring has been well investigated. On the other hand, research on functionalization at the 4-position of the skeleton is rather immature.[24] The trifluoromethanesulfonyl (triflyl, SO2CF3, Tf ) moiety has an electron-withdrawing property and it is as strong as the nitro group (Hammett substituent constants: SO2CF3, σp = 0.83, σm = 0.96; NO2, σp = 0.71, σm = 0.78). On the other hand, the lipophilicities of the triflyl and nitro groups are opposite (SO2CF3, πp = 0.55; NO2, πp = −0.28).[5e,25] Thus, replacement of hydrogen or any other group in an organic molecule with the triflyl group is a useful way to markedly change the chemical properties of the original molecule without altering the molecular complexity.[25] We proposed that the triflyl group can: (i) affect the aromaticity of

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isoxazoles, (ii) encourage additive nucleophilic reaction at the 4-position, and (iii) have a potential biological function. As expected, isoxazole triflones 13 were converted into 14 with high yields and high diastereoselectivities under our newly optimized reaction conditions, that is, with Me3SiCF3 at ambient temperature in DMSO in the presence of KOAc (Table 4). The resulting isoxazoline triflones were efficiently halogenated (fluorination with Selectfluor, chlorination with NCS, bromination with NBS) under ambient conditions to provide all-carbon-functionalized isoxazoline triflones 14a-X (X=F, Cl, Br) in high diastereoselectivities (Scheme 4), or in a one-pot tandem protocol from isoxazole triflones 13a (Scheme 5). Interestingly, the reactivity of triflone 14a is rather different from that of nitro analogue 9a (Scheme 4). This is presumably due to the strongly lipophilic nature of the triflyl group, while the nitro group is not lipophilic.[26] Specifically, the attempted fluorination of nitro analogue 9a under the same reaction conditions failed to provide the fluorination product.

Asymmetric Synthesis of TrifluoromethylSubstituted Diarylpyrrolines via Enantioselective Conjugate Cyanation After accomplishing the asymmetric synthesis of trifluoromethyl-substituted 2-isoxazolines 1,[17] we next turned our attention to the asymmetric synthesis of the carbon variant of 1, trifluoromethyl-substituted diarylpyrrolines 2.[10] The challenge with this target was obviously the enantioselective construction of sterically very demanding trifluoromethylated all-carbon quaternary stereocenters.[27] To realize the first asymmetric synthesis of 2, we hypothesized that enantioselective conjugate cyanation of β-aryl-β-trifluoromethyl-disubstituted enones 4, followed by cyano-reduction/cyclization/

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dehydration would provide enantiopure compounds 2. Several conjugate additions of cyanide to β-monosubstituted substrates leading to β-tertiary stereocenters have been reported, although there are few reports of asymmetric conjugate cyanation to β,β-disubstituted enones and related compounds that result in good to high enantioselectivities.[28] We achieved highly stereocontrolled conjugate cyanation of 4 using inex-

Table 4. Stereoselective trifluoromethylation of isoxazole triflones 13.

Entry

R

Ar

dr[a]

Yield (%)[b]

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

Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl 2-furanyl PhCH=CH Me Ph Ph Ph Ph Ph Ph 3,5-Cl2C6H3

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl 4-MeOC6H4

94:6 93:7 95:5 97:3 96:4 97:3 96:4 99:1 100:0 100:0 93:7 93:7 94:6 94:6 95:5 96:4 95:5

91 85 96 88 90 80 93 85 80 64 87 89 89 89 92 99 98

[a] Determined by 19F NMR. [b]Isolated yield. [c]The reaction was carried out with Me3SiCF3 (4.0 equiv) and KOAc (3.0 equiv).

pensive acetone cyanohydrin as the cyanating reagent, catalyzed by an ether-type cinchona alkaloid 5e (Table 5). In all cases, 1,4-addition was selectively observed over 1,2-addition. The conversion (49%) of 15a into partially saturated diarylpyrroline 2a, the target, was achieved with Raney nickel in MeOH at ambient temperature in one step involving three successive reactions (cyano-reduction/cyclization/ dehydration), without losing the enantiopurity of the starting substrate (Scheme 6). Fully saturated pyrrolidine derivative 16a was also obtained (56%) from 15a under a hydrogen atmosphere in one step consisting of four sequential reactions (cyano-reduction/cyclization/dehydration/imine hydrogenation).[29]

Asymmetric Synthesis of TrifluoromethylSubstituted Diarylpyrrolines via Enantioselective Conjugate Addition of Nitromethane Despite our success with the first asymmetric synthesis of trifluoromethyl-substituted diarylpyrroline 2,[29] there are several bottlenecks in practical synthesis that should be overcome. Firstly, the cyano-reduction step requires harsh reaction conditions with Raney nickel, resulting in moderate yields (around 50%) of 2. Secondly, it is difficult for the halogen group on aromatics to survive under the Raney nickel treatment. These are critical drawbacks for agrochemical synthesis, since a fundamental structure of biologically active 2 is a 3,5dichlorophenyl group at the 5-position of the pyrroline ring. Therefore, a different strategy was required. We expected that optically active nitromethane adduct 17 resulting from 4 would provide access to diarylpyrroline 2 under mild reduction conditions. Although numerous papers have appeared on the enantioselective conjugate addition of nitroalkanes to β-monosubstituted α,β-unsaturated carbonyl compounds, examples of enantioselective conjugate addition to β,βdisubstituted substrates are very difficult and this remains one

Scheme 4. Halogenation of trifluoromethylated adduct 14a to 14a-X.

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Scheme 5. Sequential trifluoromethylation/halogenation of 13a to 14a-X.

Scheme 6. Transformations of 15a to pyrroline 2a and pyrrolidine 16a.

of the challenges in synthetic organic chemistry.[30] We found that the ether type of cupreidinium salt 5f is crucial for the effective enantioselective conjugate addition of nitromethane to 4, affording conjugated adduct 17 with excellent yields and ee values (Table 6). The high-yielding one-step conversion of 17a into desired diarylpyrroline 2a was achieved using an Fe/AcOH system in high yield (92%) without any loss of enantiopurity (Scheme 7a, top). The polar isostere N-oxide[10b,e,31] 18a was also synthesized with high chemical yield by treatment of 17a with NaBH4 in the presence of a stoichiometric amount of NiCl2 in THF/MeOH (1:2) at 0°C (Scheme 7a, bottom). We next focused on the transformation of multiply substituted compound 17b (Scheme 7b). As expected, halogens on the aromatic ring were well tolerated under these conditions, and multiply substituted diarylpyrroline 2b and N-oxide 18b were successfully synthesized with high yields of 86% and 80%, respectively.[32]

One-Pot Asymmetric Synthesis of β-Monosubstituted β-Trifluoromethylated Pyrrolines and Their Carboxylates Diarylpyrrolines 2 are well reported in the literature;[10] however, the β-trifluoromethyl pyrrolines without any additional substituent in the β-position are very rare (19, Figure 3).[33] Furthermore, there was no asymmetric synthetic

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approach to 19 despite their potential attractiveness as drug candidates. As part of our ongoing research programs directed at the development of asymmetric synthesis of trifluoromethylated dihydroazoles, we became interested in the asymmetric synthesis of β-monosubstituted β-trifluoromethylated pyrrolines 19 and their carboxylates 20 in a one-pot procedure (Figure 3). One-pot sequential synthesis has recently attracted much attention as a means for temporal integration of chemical reactions.[34] Enantioenriched β-trifluoromethylated pyrrolines 19 were successfully synthesized by cinchonidine-derived thiourea 22 catalyzed enantioselective conjugate addition of nitromethane to β-monosubstituted trifluoromethylated enone 21,[35] followed by an iron-mediated reduction/ cyclization/dehydration system in a one-pot procedure in excellent yields with enantioselectivities up to 98% ee (Table 7).[36] Asymmetric synthesis of β-trifluoromethylated pyrroline carboxylates 20 was also achieved by diastereo- and enantioselective conjugate addition of 1-adamantyl glycinatebenzophenone Schiff base[37] 23 to β-monosubstituted trifluoromethylated enone 21, catalyzed by a phase-transfer catalyst 5g derived from cinchona alkaloid, followed by an acid-mediated deprotection/cyclization/dehydration sequence in excellent yields, excellent diastereoselectivities and high enantioselectivities in a one-pot procedure (Table 8).[38] It should be noted that the steric bulkiness of 23 was necessary for achieving high enantiocontrol.

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Table 5. Enantioselective conjugate cyanation of β-aryl-βtrifluoromethyl-disubstituted enones 4.

Ar1

Ar2

Yield (%)[a]

ee (%)

Entry

Ar1

Ar2

Yield (%)[a]

ee (%)

Ph 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl Ph Ph Ph Ph Ph Ph Ph 3,5-Cl2C6H3 3,5-Cl2C6H3

Ph Ph Ph Ph Ph Ph Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 3-BrC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl 2-Me-3-BrC6H3 2-MeC6H4

90 99 99 93 96 92 92 92 98 99 99 99 99 99 99 94

92 91 91 90 90 90 90 92 94 96 90 95 91 94 95 92

1 2 3 4[b] 5 6 7[c] 8[c,d] 9 10 11[b] 12 13 14 15[c,e] 16 17[c,f ]

Ph 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl Ph Ph Ph Ph Ph Ph Ph Ph 3,5-Cl2C6H3

Ph Ph Ph Ph Ph Ph Ph Ph 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl 3-Me-4-BrC6H3

90 91 99 92 80 85 86 92 91 90 87 90 94 99 86 92 80

92 91 92 90 91 90 91 90 91 93 90 90 92 92 93 90 91

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 [a]

Table 6. Enantioselective conjugate addition of nitromethane to β-aryl-β-trifluoromethyl-disubstituted enones 4.

Isolated yield.

Methylhydrazine-Induced Non-Metallic Aerobic Epoxidation of β,β-Disubstituted Enones During our research program directed at the asymmetric synthesis of trifluoromethylated pyrazoline 3,[11] we encountered an unexpected enantioselective epoxidation of β,βdisubstituted enones 4 that occurred with excellent diastereoselectivity and enantioselectivity. Our initial target was trifluoromethylated pyrazoline 3a, which we attempted to synthesize by the cascade reaction of (E)-4,4,4-trifluoro1,3-diphenylbut-2-en-1-one (4a) with methylhydrazine (H2NNHMe, 3.0 equiv) in the presence of cinchona alkaloid 5a (10 mol %) and Cs2CO3 (3.0 equiv) in iPr2O (0.017 M) at ambient temperature. Astonishingly, instead of 3a, enantioenriched epoxide (2S,3S)-24a with a trifluoromethylated quaternary stereogenic center was obtained, in 99% yield with excellent diastereoselectivity and an excellent enantioselectivity of over 99% ee (Scheme 8).

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[a] Isolated yield. [b]The reaction was carried out at 50°C. [c]The reaction was carried out at ambient temperature. [d]30 mol % of 5f was used. [e]The concentration was 0.04 M. [f ]10.0 equiv of MeNO2 was used.

Ever since the asymmetric epoxidation of allylic alcohols milestone in the early 1980s by Sharpless,[39] the catalytic enantioselective epoxidation of alkenes has been one of the most powerful, well-explored and reliable transformations in organic synthesis to provide enantiomerically enriched epoxides.[40] Catalytic enantioselective epoxidations under a variety of systems have been reported over the last 30 years. Based on the combination of catalysts and oxidants used, the methods are categorized into three classes: (i) metal species/active oxidizing agent,[39,41] (ii) metal species/molecular oxygen,[42] and (iii) organocatalyst/active oxidizing agent.[43] However, as far as we know, the aerobic/organocatalytic oxidation system does not fall into a known category of catalytic epoxidation. A full investigation of this unusual epoxidation reaction determined that methylhydrazine and base (catalytic to

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Scheme 7. Transformations of 17 to diarylpyrrolines 2 and N-oxides 18.

Fig. 3. Structure of β-monosubstituted β-trifluoromethylated pyrrolines 19 and their carboxylates 20.

stoichiometric) are crucial for aerobic epoxidation and this phenomenon would not have been discovered if we had used other hydrazine derivatives. Our devised H2NNHMe/ Cs2CO3/5a system is crucially effective for asymmetric aerobic epoxidation of β-trifluoromethyl β,βdisubstituted enones 4 and has a broad substrate scope (Table 9).[44] We determined that the epoxide oxygen originates from molecular oxygen in air by carrying out 18O tracer experiments (Table 10). Epoxidation did not occur under oxygenfree conditions, i.e., an argon atmosphere without exposure to oxygen (entry 2), even in the presence of H218O (entry 4),

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while the epoxidation of 4a under an 18O2 atmosphere quantitatively gave epoxide 24a with 90% of 18O incorporation (entry 3). These results clearly indicate that the epoxide oxygen originates from molecular oxygen in air, but not from a trace amount of water (i.e., moisture). Our next interest was the identification of the actual oxidant generated from H2NNHMe and molecular oxygen under the reaction conditions. Radical species are generated from hydrazine compounds through the formation of diazenes in the presence of oxidants, and this reaction also involves the formation of hydrogen peroxide via a radical process.[45] Hence, it seems that H2NNHMe is initially oxidized by molecular oxygen via a single-electron transfer in the presence of a base. We next examined the reaction using 50% hydrogen peroxide under a nitrogen atmosphere instead of the H2NNHMe/air system, to mimic the effect of in situ generation of hydrogen peroxide (entry 5). Excitingly, the reaction progressed similarly to afford 24a with the same enantioselectivity, while the chemical yield slightly decreased (66%), probably due to the purity of H2O2, since our H2NNHMe/air system generates highly reactive, pure H2O2 in situ.

Chem. Rec. 2014, ••, ••–••

© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim

A s y m m e t r i c S y n t h e s i s o f Tr i f l u o r o m e t h y l a t e d D i h y d r o a z o l e s

Table 7. One-pot asymmetric synthesis of β-trifluoromethylated pyrrolines 19.

Entry

Ar

1 2 3 4 5 6[b] 7 [a]

Yield (%)[a]

ee (%)

89 92 97 94 91 85 95

98 98 98 98 98 98 97

Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl

Isolated yield. [b]4-(3-trifluoromethyl-3,4-dihydro-2H-pyrrol-5-yl)aniline (Ar=4-NH2C6H4) was obtained.

Table 8. One-pot asymmetric synthesis of β-trifluoromethylated pyrroline carboxylates 20.

Entry 1 2 3 4 5 6 7 8 9 10 [a]

Ar Ph 3-MeC6H4 4-MeC6H4 3-MeOC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl 2-furanyl

Yield (%)[a]

dr[b]

ee (%)

95 72 95 74 94 94 93 96 81 96

98:2 99:1 99:1 98:2 99:1 99:1 99:1 99:1 98:2 99:1

86 84 87 84 88 84 78 77 72 80

Isolated yield. [b]Determined by 19F NMR.

Chem. Rec. 2014, ••, ••–••

© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim

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THE CHEMICAL RECORD

Scheme 8. Unexpected asymmetric aerobic epoxidation of β-trifluoromethyl β,β-disubstituted enone 4a.

Table 9. Methylhydrazine-induced aerobic asymmetric epoxidation of 4.

Ar1

Entry 1 2[c] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 [a]

Ph Ph 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 2-naphthyl Ph Ph Ph Ph Ph Ph Ph Ph

Ar2

Yield (%)[a]

dr[b]

ee (%; major, minor)

Ph Ph Ph Ph Ph Ph Ph Ph 2-MeC6H4 3-MeC6H4 4-MeC6H4 4-MeOC6H4 4-ClC6H4 4-BrC6H4 4-NO2C6H4 2-naphthyl

91 99 95 92 91 90 97 99 99 99 91 98 92 91 98 99

95:5 95:5 93:7 94:6 94:6 95:5 95:5 96:4 96:4 93:7 93:7 93:7 93:7 93:7 94:6 94:6

99, 98 −97, −98 99, 99 99, 98 98, 99 98, 99 98, 97 99, 99 96, 96 98, 98 98, 98 98, 98 98, 99 97, 98 96, 97 98, 98

Isolated yield. [b]Determined by 19F NMR. [c]5c was used instead of 5a.

Enantioselective Synthesis of 5-Trifluoromethyl-2-isoxazolines and Their N-Oxides by Oxidative N–O Coupling Since the discovery that 3,5-diaryl-5-trifluoromethyl-2isoxazoline derivatives 1 exhibit potent antiparasitic activity against cat fleas and dog ticks in 2004,[7] the exploration of these compounds as novel veterinary medicines and agrochemicals has attracted much attention. Thus, a large number of derivatives of 1 have been synthesized. Based on this background, we were fascinated by trifluoromethylated isoxazoline

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N-oxides 25 as future candidates for pharmaceuticals and agrochemicals (Figure 4). However, no report on the synthesis of trifluoromethylated 3,5-diarylisoxazoline N-oxides 25 had appeared in spite of their potential as veterinary drugs and agrochemicals. We achieved the first synthesis of 5-trifluoromethyl-2isoxazoline N-oxides 25 via [hydroxy(tosyloxy)iodo] benzene (HTIB)-mediated oxidative N–O coupling[46] of β-trifluoromethyl-hydroxy-β-ketoximes 26 derived from β-keto-trifluoromethylalcohols 27[47] and hydroxylamine (Table 11).

Chem. Rec. 2014, ••, ••–••

© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim

A s y m m e t r i c S y n t h e s i s o f Tr i f l u o r o m e t h y l a t e d D i h y d r o a z o l e s

Table 10.

Entry 1 2 3 4 5[c]

18

O tracer experiments.

Table 11. Synthesis of 5-trifluoromethyl-2-isoxazoline N-oxides 25.

18

O content[b]

ee (%; major, minor)

Conditions

Yield (%)[a]

air argon 18 O2 Argon + H218O (10 equiv) 50% H2O2 (1.2 equiv)

90

Asymmetric synthesis of agrochemically attractive trifluoromethylated dihydroazoles and related compounds under organocatalysis.

The unique, partially saturated, fluorinated five-membered heterocyclic compounds, trifluoromethylated dihydroazoles, and their derivatives, have emer...
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