Letter pubs.acs.org/OrgLett
Catalytic Asymmetric Cycloadditions of Silyl Nitronates Bearing α‑Aryl Group Minghui Jiang, Lifei Feng, Juanjuan Feng, and Peng Jiao* Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China S Supporting Information *
ABSTRACT: 1,3-Dipolar cycloadditions of 2-alkylacroleins or atropaldehyde with triisopropylsilyl nitronates bearing an α-aryl group produced 3-aryl-2-isoxazolines having a chiral quaternary center in up to 94% ee and up to 88% yield with the aid of Corey’s oxazaborolidine catalyst. Specifically, the TIPS nitronate with an α-(p-methoxyphenyl) group gave mainly the 2isoxazolines having an all-carbon quaternary center.
R
attempts, the triisopropylsilyl nitronate prepared from pmethoxyphenyl nitromethane was used as a 1,3-dipole in the catalytic cycloaddition with N-acryloyl-1,3-oxazolidin-2-one.2b Unexpectedly, the TIPS nitronate reacted in a dipole form of δ+ CN−Oδ− instead of δ−CN−Oδ+, though the 2-isoxazoline was obtained in only 7% ee (Scheme 1b). This preliminary result indicated the TIPS nitronates bearing an α-aryl group could be quite different from those bearing an α-alkyl group and prompted us to test the reactions of the TIPS nitronates bearing an α-aryl group. Here, we report the preparation of a series of relatively more stable (E)-aryl O-triisopropylsilyl acinitromethanes and disclose their asymmetric reactions with 2alkylacroleins and atropaldehyde catalyzed by Corey’s oxazaborolidine catalyst. Aryl O-TIPS aci-nitromethanes were prepared from aryl nitromethanes and triisopropylsilyl chloride using DBU as the base.9 Aryl nitromethanes were prepared through Pd(0)catalyzed coupling reactions of aryl bromides with nitromethane according to Kozlowski’s method (Scheme 2).10 In comparison, these TIPS nitronates are more stable than nitroalkane-derived ones and could be normally purified by chromatography on silica gel. The crystal structure of p-
ecently, our group reported catalytic asymmetric syntheses of 3-alkyl-2-isoxazolines from triisopropylsilyl (TIPS) nitronates of nitroalkanes using chiral oxazaborolidine1 or a “Cu(II)-bisoxazoline” complex as the catalyst (Scheme 1).2 Scheme 1. (a) Chiral Lewis Acid Catalyzed Cycloadditions of Alkyl O-Silyl aci-Nitromethanes;2 (b) Unexpected Reversed Cycloaddition of Aryl O-Silyl aci-Nitromethane2b
Scheme 2. (a) Preparations of (E)-Aryl O-TIPS aciNitromethanes; (b) Crystal Structure of TIPS Nitronate 1i
Different from the traditional use of nitrile oxides in asymmetric cycloadditions,3,4 we accomplished the synthesis of enantiomerically pure isoxazolines from achiral nitronates and achiral dipolarophiles.5,6 Various chiral 2-isoxazolines bearing different substituents were prepared in good to excellent yields and enantioselectivities. Isoxazolines as useful intermediates were further demonstrated in an efficient synthesis of (R)Tanikolide2a and isoxazolinyl group-directed and Pd(OAc)2catalyzed C−H acetoxylations.7 Unlike the alkyl nitronic esters,8 the silyl nitronates are stable enough to possess a definite configuration, which is essential to ensure good stereoselectivity in the cycloaddition reactions. In our initial © 2017 American Chemical Society
Received: February 23, 2017 Published: April 24, 2017 2210
DOI: 10.1021/acs.orglett.7b00558 Org. Lett. 2017, 19, 2210−2213
Letter
Organic Letters ethoxycarbonylphenyl O-TIPS aci-nitromethane clearly indicated the E-configuration of these silyl nitronates as well as the coplanarity of the phenyl ring with the nitronate unit in a solid state.11 Similar crystal structures of (E)-O-(tert-butyl)dimethylsilyl aci-nitromethanes were reported by Seebach et al. in the 1980s.12 With the optimal catalyst previously screened out,2a we conducted the 1,3-dipolar cycloaddition reactions of pmethoxyphenyl O-triisopropylsilyl aci-nitromethane (1e) with 2-ethylacrolein (2b) (Table 1). When using 10 mol % of
Scheme 3. Asymmetric 1,3-Dipolar Cycloadditions of Aryl O-TIPS Nitromethanesa,b,c
Table 1. Optimization of the Reaction Conditionsa,b
entry
x (mol %)
y (equiv)
t (°C)
time (h)
yield (%)
1 2c 3 4 5 6d 7e 8f
0 10 10 10 15 15 15 15
1.5 1.5 1.5 1.5 1.5 1.5 3.0 1.5
−60 −60 −50 −50 −50 −50 −50 −50
12 12 12 24 16 48 16 16
0 24 43 46 86 80 87 71
a
All yields were isolated ones for both regioisomers. Regioisomeric ratio was 85:15. bEe of 3be′ was 90%. The abs. configuration was tentatively assumed. cRegioisomeric ratio was >95:5. dThe nitronate in toluene was added over 4 h via syringe pump. e1.5 equiv nitronate was recovered. fCH2Cl2 was the solvent.
Corey’s oxazaborolidine catalyst, the reaction of 1e proceeded at −60 °C but at a slower rate than nitroalkane-derived nitronates.2a The reaction was quenched after 12 h, and the Ntriisopropylsiloxy-2-isoxazolidine product was in situ reduced with NaBH4 to give [4-ethyl-3-(p-methoxyphenyl)-2-isoxazolin4-yl]methanol (3be′) as the major isomer in 90% ee. A 24% isolated yield with a regioisomeric ratio of >95:5 was obtained (Table 1, entry 2). Raising the temperature to −50 °C gave a yield of 43% and a 85:15 regioisomeric ratio (entry 3). Extension of the reaction time to 24 h slightly improved the yield (entry 4). To exclude the possible influence of contaminating DBU to the catalyst, the TIPS nitronate was repeatedly purified before use. The yield was almost the same. The slow reaction rate stemmed from the intrinsic low reactivity of the nitronate. We attribute the low isolated yield of the isoxazoline to the deleterious influence of the TIPS nitronate to the active oxazaborolidine catalyst. Therefore, the loading of the catalyst was raised to 15 mol %. When 15 mol % of the catalyst and 1.5 equiv of 1e were reacted with 2b at −50 °C in one pot, the isoxazolines were isolated in 86% yield (entry 5). Slow addition of the TIPS nitronate solution via a syringe pump gave an even lower yield of the isoxazolines (entry 6). Excess (3 equiv) nitronate was unnecessary. The products were isolated in the same yield, and 1e was recovered (entry 7). When CH2Cl2 was used instead of toluene as the solvent, a lower yield (71%) was obtained (entry 8). The optimal conditions were applied to the cycloadditions of four 2alkylacroleins (2a−2d) and ten TIPS nitronates (1a−1j) bearing different substituents in the aryl group. The results are shown in Scheme 3.
a
All yields were isolated yields for both regioisomers. bRegioisomeric ratios were determined by 1H NMR integration. cEe was determined by chiral HPLC analysis of the corresponding benzoate. dAbs. configuration was determined by comparison of the specific rotation with literature data. eAbs. configuration was tentatively assumed. fEe was for the minor regioisomer. gEe was determined by chiral HPLC analysis of the mixture of 3aj and 3aj′. hEe was for the isoxazoline with diaryl ketone group.
Obviously, nitronate 1e with a p-methoxy group turned out to be specific. Nitronate 1e gave the isoxazolines 3ae′, 3be′, and 3ce′ bearing an all-carbon chiral quaternary center as the major isomers in essentially the same ee (90%) and similar regioisomeric ratios, and atropaldehyde 2d gave 3da′ as the only regioisomer in 94% ee (Scheme 3). Otherwise, the isoxazolines with an oxygen-substituted chiral quaternary center were obtained as the major regioisomers. Generally, the TIPS nitronates bearing an α-aryl group gave the 2-isoxazoline products in 74−94% ee and 20−88% yields, which are lower 2211
DOI: 10.1021/acs.orglett.7b00558 Org. Lett. 2017, 19, 2210−2213
Letter
Organic Letters
why nitronate 1e prefers to react in a dipole form of δ+CN− Oδ− when using the oxazaborolidine as the catalyst and in a form of δ−CN−Oδ+ when using BF3·Et2O as the catalyst. Based on the results of oxazaborolidine-catalyzed asymmetric Diels−Alder reactions of 2-alkylacroleins1 and the absolute configuration of 3aa, we assume the 2-alkylacrolein dipolarophile is activated by the oxazaborolidine catalyst in a uniform manner: the acrolein adopts a s-trans configuration, and the nitronate approaches mainly in an endo way and from the Re face of the 2-alkylacrolein (Figure 1). The production of 3ae′,
than the TIPS nitronates bearing an α-alkyl group.2a Two regioisomers were observed for most isoxazolines, which was in sharp contrast to the instances of the TIPS nitronates bearing an α-alkyl group.2a An electron-donating substituent (Me, MeO) in the aryl group led to higher yields of the isoxazolines compared with an electron-withdrawing one (Cl, CF3, Bz, CO2Et). p-Acetylphenyl O-TIPS aci-nitromethane (1k) did not react under the optimized conditions (eq 1). This was due to
deactivation of the boron Lewis center by the carbonyl group. In hopes of using the isoxazoline product for the synthesis of vitamin E, we prepared the nitro compound and the corresponding TIPS nitronate (1l) from 1,4-dimethoxy-2,3,5trimethylbenzene.13 Unfortunately, no cycloaddition was observed even when the temperature was raised to rt (eq 2). The absolute configuration of 3aa was determined to be (R) by comparison of the specific rotation with literature data.3f,13,14 To figure out the different regioselectivities observed for the isoxazolines listed in Scheme 3, we used BF3·Et2O to catalyze the reactions between 1a−1j and 2a−2d. To our surprise and with no exception, the racemic 2-isoxazolines having a quaternary center at C5 were obtained with complete regioselectivities, and no 2-isoxazolines having a quaternary center at C4 were observed (Scheme 4).13 These results
Figure 1. (a) Suggested TS for production of isoxazoline having allcarbon quaternary center. (b) Suggested TS for production of isoxazoline having oxygen-substituted quaternary center.
3be′, and 3ce′ as the major regioisomers is a result of the transition state structure shown in Figure 1a. As for 3da′, possible π−π stacking between the nitronate (1a) and atropaldehyde (2d) facilitated the cycloaddition to proceed through a transition state similar to that shown in Figure 1a. Except for the above isoxazolines having a quaternary center at C4, all the other isoxazolines were produced mainly through a transition state similar to that shown in Figure 1b.2a In the cases of ortho-tolyl O-TIPS aci-nitromethane (1b) as the dipole, an extra high regioselectivity was observed for the three isoxazolines (3ab, 3bb, and 3cb) bearing an oxygen-substituted chiral quaternary center (Scheme 3). The high regioselectivity as well as the low yields of 3bb and 3cb could be ascribed to the steric hindrance caused by the ortho-methyl group (Figure 1b). As for the nitronate (1l) with a phenyl group bearing two orthosubstituents, the reactivity was totally lost due to severe steric hindrance in both transition states (eq 2). For the approximately 1:1 regioisomeric ratio of the resulting isoxazoline products 3aj and 3bj (Scheme 3), we suggest nitronate 1j reacted through two transition states competitively due to the steric effect of the 2-naphthyl group. In summary, we disclosed asymmetric cycloadditions of silyl nitronates bearing an α-aryl group catalyzed by Corey’s oxazaborolidine catalyst. Chiral 2-isoxazolines bearing a quaternary center were obtained in high enantioselectivities. The nitronates bearing an α-aryl group were less reactive than those bearing an α-alkyl group and usually gave two regioisomers of the isoxazolines. Both steric and electronic effects influenced the reactivity of the nitronates as well as the regioselectivity.
Scheme 4. BF3-Catalyzed Cycloadditions of Aryl O-TIPS Nitromethanes
completely agreed with those of α-alkyl O-TIPS aci-nitromethanes.2a We believe BF3-catalyzed cycloadditions of α-alkyl or α-aryl O-TIPS aci-nitromethanes with α-alkylacroleins proceeded in the same mechanism. When Corey’s oxazaborolidine was used as the catalyst, α-alkyl or α-aryl O-TIPS acinitromethanes behaved differently.2a While α-alkyl O-TIPS acinitromethanes gave exclusively the cycloadducts having a quaternary center at C5, α-aryl O-TIPS aci-nitromethanes, generally, gave the cycloadducts having a quaternary center at C5 or C4 in various ratios. We suspect this is due to both the steric and electronic influences caused by an α-aryl group in the TIPS nitronate. Sibi et al. studied the regioselectivity problem of the cycloadditions of mesitylnitrile oxide with dipolarophiles having varying steric hindrance.3d They concluded that as the steric hindrance brought by the dipolarophiles increased, mesitylnitrile oxide preferred to react in a dipole form of δ− CN−Oδ+ rather than in a form of δ+CN−Oδ−, resulting in 99:1 regioselectivity. In our case, the steric factor could be excluded out when comparing the regioselectivity of 1e with that of the other nitronates in their cycloadditions catalyzed by the oxazaborolidine. At present, it is difficult for us to explain
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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.7b00558. Experimental procedures and compound characterization data (PDF) 2212
DOI: 10.1021/acs.orglett.7b00558 Org. Lett. 2017, 19, 2210−2213
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Organic Letters
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(7) Geng, C.; Jiang, M.; Feng, L.; Jiao, P. RSC Adv. 2016, 6, 56971− 56976. (8) (a) Kornblum, N.; Brown, R. A. J. Am. Chem. Soc. 1964, 86, 2681−2687. (b) Gree, R.; Tonnard, F.; Carrie, R. Tetrahedron 1976, 32, 675−682. (9) For the preparation of silyl nitronates using DBU, see: (a) Aizpurua, J. M.; Oiarbide, M.; Palomo, C. Tetrahedron Lett. 1987, 28, 5361−5364. (b) Martin, O. R.; Khamis, F. E.; Prahlada Rao, S. Tetrahedron Lett. 1989, 30, 6143−6146. (c) Tishkov, A. A.; Lyapkalo, I. M.; Kozincev, A. V.; Ioffe, S. L.; Strelenko, Y. A.; Tartakovsky, V. A. Eur. J. Org. Chem. 2000, 2000, 3229−3233. (d) Tishkov, A. A.; Lyapkalo, I. M.; Ioffe, S. L.; Strelenko, Y. A.; Tartakovsky, V. A. Tetrahedron 2001, 57, 2221−2230. (e) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11332−11334. (10) (a) Walvoord, R. R.; Berritt, S.; Kozlowski, M. C. Org. Lett. 2012, 14, 4086−4089. (b) Walvoord, R. R.; Kozlowski, M. C. J. Org. Chem. 2013, 78, 8859−8864. (c) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106−111. (d) Xu, J.; Li, X.; Wu, J.; Dai, W.-M. Tetrahedron 2014, 70, 3839−3846. (e) Xu, J.; Li, X.; Wu, J.; Dai, W.M. Tetrahedron 2014, 70, 6384−6391. (11) CCDC 1526483: 1i. (12) (a) Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz, J. D. Helv. Chim. Acta 1980, 63, 697−710. (b) Colvin, E. W.; Beck, A. K.; Seebach, D. Helv. Chim. Acta 1981, 64, 2264−2271. (13) See Supporting Information for details. (14) Tripathi, C. B.; Mukherjee, S. Org. Lett. 2015, 17, 4424−4427.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peng Jiao: 0000-0003-4039-8300 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The research reported in this publication was supported by the National Natural Science Foundation of China (21002008). We thank Prof. Jiaxin Zhang (College of Chemistry, Beijing Normal University) for assistance with NMR experiments and Prof. Haoling Sun (College of Chemistry, Beijing Normal University) for XRD analysis.
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