Abstracts
Chiral β-hydroxy-2-oxazolines were synthesized and evaluated as catalysts for the addition of diethylzinc to aldehydes. All oxazolines proved effective in obtaining the addition products. The best enantiomeric excesses (69-78%) were obtained using the chiral β-hydroxy oxazoline derived from (−)-menthone and the amino alcohol 2-amino-2-methylpropan-1-ol.
(−)-menthone; chiral β-hydroxy-2-oxazolines; catalysts; diethylzinc; aldehydes
β-Hidroxi-2-oxazolinas quirais foram sintetizadas e avaliadas como catalisadores na adição de dietilzinco a aldeídos. Todas as oxazolinas se mostraram eficientes na obtenção dos produtos de adição. Os melhores excessos enantioméricos (69 a 78%) foram obtidos quando se empregou a β-hidroxi oxazolina quiral derivada da (−)-mentona e do amino álcool 2-amino-2-metilpropan-1-ol.
Introduction
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Oxazolines have been extensively used in asymmetric catalysis, especially
2-oxazolines.5555 Gant, T. G.; Meyers, A. I.; Tetrahedron
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catalysts used in the addition of organozinc reagents to carbonyl compounds, most of
them employing α-hydroxy-2-oxazolines.2828 Pastor, I. M.; Adolfsson, H.; Tetrahedron Lett.
2002, 43, 1743.,5959 Bauer, M.; Kazmaier, U.; J. Organomet. Chem.
2006, 691, 2155.
60 Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I.;
Synthesis
2004, 2173.
61 Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O.; Org.
Lett.
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Herein we describe the synthesis of some β-hydroxy-2-oxazolines derived from (–)-menthone, and their application as chiral ligands in the enantioselective addition of diethylzinc to aldehydes.
Results and Discussion
To obtain the oxazolines derived from 2-amino-2-methylpropan-1-ol we used the method proposed by Meyers, in which a carboxylic acid, in this case acetic acid, is reacted with an amino alcohol under heating.6363 Meyers, A. I.; J. Org. Chem. 2005, 70, 6137. The 2-oxazoline derivatives from (+) or (–)-valinol were obtained by another method, also developed by Meyers, in which an amino alcohol reacts with an orthoester, in this case triethyl orthoacetate, under reflux.6464 Kamata, K.; Agata, I.; Meyers, A. I.; J. Org. Chem. 1998, 63, 3113.
With the 2-oxazolines in hand, we performed the addition of their anions, generated by reaction with n-butyllithium,6565 Meyers, A. I.; Knaus, G.; Tetrahedron Lett. 1974, 15, 1333. to (–)-menthone, affording the chiral β-hydroxy-2-oxazolines outlined below (Figure 1).
Ligand 1 was obtained as a mixture of diastereomers in a 75:25 ratio (Figure 2a), the same stereoselectivity observed in the synthesis of the other two ligands.
Chromatogram obtained with a fused silica column coated with Chirasil-Dex CB-β-cyclodextrin (30 m × 0.25 mm × 0.25 μm) showing the area of elution of ligand 1 in (a) 75:25 diastereomeric ratio and (b) after diastereomeric purification, at 95:5 diastereomeric ratio.
Using ligand 1 as a model, we determined the stereoselectivity of the major addition product obtained by nuclear Overhauser effect (NOE) experiment. The CH2 (2.74 ppm) alpha to the hydroxyl group was strongly correlated with Ha and Hb (2.09 and 2.19 ppm), as shown in Figure 3. This confirmed that the oxazoline anion attacked the carbonyl moiety mainly via an equatorial approach, in accordance with previous reports.3838 Kwong, H. L.; Lee, W. S.; Tetrahedron: Asymmetry 1999, 10, 3791.,4444 Xu, Q.; Wang, G.; Pan, X.; Chan, A. S. C.; Tetrahedron: Asymmetry 2001, 12, 381.
In order to evaluate the effect of the stereochemistry of the generated stereocenters of
the new ligands on the stereoselective course of the addition of diethylzinc to
aldehydes, the diastereomeric mixture was enriched in the major diastereomer by column
chromatography, reaching a 95:5 diastereomeric ratio (Figure 2b). The addition of diethylzinc to
p-chlorobenzaldehyde was performed with both diastereomeric mixtures in
the same conditions (entry 1a, using the 75:25 and entry 1b, using the 95:5
diastereomeric ratio, Table 1). The results showed
that the products were obtained with the same enantiomeric excess. This is probably a
consequence of a non-linear effect between the diastereomeric ratio of the chiral ligand
and the enantioselectivity obtained in the addition process catalyzed by the ligand, as
has been described elsewhere.6666 Page, P. C. B.; Allin, S. M.; Maddocks, S. J.; Elsegood, M. R. J.;
J. Chem. Soc., Perkin Trans. 1
2002, 2827.
67 Kitamura, M.; Okada, S.; Suga, S.; Noyori, R.; J. Am. Chem.
Soc.
1989, 111, 4028.
68 Long, J.; Ding, K.; Angew. Chem., Int. Ed.
2001, 40, 544.-6969 Girard, C.; Kagan, H. B.; Angew. Chem., Int. Ed.
1998, 37, 2922.
Screening of the conditions to perform the addition of diethylzinc to p-chlorobenzaldehyde using 1 as catalyst
aYield of isolated product; bdetermined by chiral GC (column: β-cyclodextrin-CB); cabsolute configuration determined by comparison of the optical rotation with published data;7070 Kang, J.; Lee, J. W.; Kim, J. I.; J. Chem. Soc., Chem. Commun. 1994, 2009. dligand used in a 95:5 diastereomeric mixture.
Ligand 1, in a 75:25 diastereomeric ratio, was chosen in order to evaluate the influence of the solvent, temperature and amount of the catalyst in the stereoselective addition of diethylzinc to aromatic aldehydes, using p-chlorobenzaldehyde as a model (Table 1).
After the reaction conditions were optimized, all β-hydroxy-2-oxazolines prepared were tested, without diastereomeric purification, as chiral ligands to perform the stereoselective addition of diethylzinc to p-chlorobenzaldehyde (Table 2).
Addition of diethylzinc to p-chlorobenzaldehyde using chiral β-hydroxy-2-oxazolines as catalystsa a The reaction was carried out using hexane as solvent, 5% molar ratio of ligand, 0 °C, for 2 h;
Interestingly, the ligand with the fewest stereogenic centers showed the best result. We assumed that the stereogenic center present in the oxazoline portion could improve the stereoselectivity, if acting in synergism with the steric hindrance provided by the menthane portion; however, both ligands 2 and 3 led to lower stereoselectivities.
Since ligand 1 showed the best results, it was used in the addition to other aromatic aldehydes (Table 3).
Addition of diethylzinc to benzaldehydes using ligand 1 as catalyst
aYield of isolated product; bdetermined by chiral GC (column: CB-cyclodextrin-β); cabsolute configuration determined by comparison of the optical rotation with published data.7070 Kang, J.; Lee, J. W.; Kim, J. I.; J. Chem. Soc., Chem. Commun. 1994, 2009.
The best enantiomeric excess (e.e.) (78%) was achieved using 3-methoxybenzaldehyde. This result is probably related to the lower steric hindrance caused by the methoxy group when located at the 3-position, compared to the starting material with the methoxy group at the 2-position.
The e.e. achieved employing the other aldehydes were compared to those obtained using benzaldehyde.
This is the first report dealing with the use of chiral β-hydroxy-2-oxazolines as
catalysts in the addition of diethylzinc to aldehydes; in the literature there are a few
reports of the use of chiral α-hydroxy-2-oxazolines as catalysts in this reaction.2828 Pastor, I. M.; Adolfsson, H.; Tetrahedron Lett.
2002, 43, 1743.,5959 Bauer, M.; Kazmaier, U.; J. Organomet. Chem.
2006, 691, 2155.
60 Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I.;
Synthesis
2004, 2173.
61 Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O.; Org.
Lett.
2001, 3, 4259.-6262 Zhang, X. M.; Zhang, H. L.; Lin, W. Q.; Gong, L. Z.; Mi, A. Q.; Cui, X.;
Jiang, Y. Z.; Yu, K. B.; J. Org. Chem.
2003, 68, 4322. Although some e.e.
obtained when using α-hydroxy-2-oxazolines are better than those reported herein,
β-hydroxy-2-oxazolines are much easier to prepare, using less-expensive, commercially
available materials. The results obtained in this study are being used by our group in
order to synthesize other chiral β-hydroxy-2-oxazolines, aiming to improve the
stereoselectivity of this process.
Conclusions
We describe herein the synthesis of new chiral β-hydroxy-2-oxazolines, and their application in the asymmetric addition of diethylzinc to aromatic aldehydes. The best ligand 1, which was readily synthesized from inexpensive and commercially available materials, showed good catalytic activity (up to 93% yield and 78% e.e.). Other chiral β-hydroxy-2-oxazolines are being synthesized in our laboratory, aiming at applications beyond the organozinc additions to aldehydes, such as in the asymmetric addition of alkynes to carbonyl compounds,7171 Trost, B. M.; Weiss, A. H.; Adv. Synth. Catal. 2009, 351, 963. and in the asymmetric addition of boronic acids to carbonyl compounds.7272 Braga, A. L.; Paixao, M. W.; Westermann, B.; Schneider, P. H.; Wessjohann, L. A.; J. Org. Chem. 2008, 73, 2879.
Experimental
Oxazolines
All three oxazolines (2,4,4-trimethyl-2-oxazoline and (S) and (R)-4-isopropyl-2-methyl-2-oxazoline) were synthesized, and afforded spectral data according with the literature.6363 Meyers, A. I.; J. Org. Chem. 2005, 70, 6137.,6464 Kamata, K.; Agata, I.; Meyers, A. I.; J. Org. Chem. 1998, 63, 3113.
General procedure for the preparation of β-hydroxy-2-oxazolines 1-3
In a 25 mL flask equipped with magnetic stirring, a solution of n-butyllithium (1.31 mL, 2.1 mmol) in hexane was added at –78 ºC to a solution of the corresponding 2-oxazoline (2 mmol) in tetrahydrofuran (THF) (4 mL). The reaction mixture was stirred for 30 min and then a solution of menthone (308 mg, 2 mmol) in THF (4 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was stirred for 2 h at 25 ºC. The reaction mixture was quenched with aqueous saturated NH4Cl solution (10 mL), and extracted with diethyl ether (3 × 30 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration and evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography using a mixture of hexane/ethyl acetate (9:0.5) as eluent to give the corresponding chiral β-hydroxy-2-oxazolines.
(1R,2S,5R)-1-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)methyl)-2-isopropyl-5-methylcyclohexanol (1): Yield 91% (486 mg); [α]D25 –34.97 (c 1.25, CHCl3, 90% e.e.); IR (KBr) ν/cm–1 3046, 2957, 1742, 1653, 1558, 1457, 1406, 1242, 1191, 982; 1H NMR (200 MHz, CDCl3) δ 0.85 (d, 3H, J 6.5 Hz, CH3), 0.90 (d, 3H, J 6.9 Hz, CH3), 0.93 (d, 3H, J 6.8 Hz CH3), 0.96 (m, 1H, CH), 1.00 (dd, 1H, J 13.4 Hz, 1.1, CH), 1.02 (ddd, 1H, J 12.1 Hz, 3.9, 1.8, CH), 1.27 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.52 (m, 2H, CH2), 1.66 (ddd, 1H, J 13.4 Hz, 3.3, 2.5, CH2), 1.77 (m, 1H, CH2), 1.79 (m, 1H, CH2), 2.09 (qqd, 1H, J 6.9 Hz, 6.8, 1.4, CH), 2.19 (d, 1H, J 14.9 Hz, CH2), 2.74 (d, 1H, J 14.9 Hz, CH2), 3.89 (d, 1H, J 8.1 Hz, CH2), 3.93 (d, 1H, J 8.1 Hz, CH2); 13C NMR (50 MHz, CDCl3) δ 18.2, 20.9, 22.4, 23.8, 26.3, 27.8, 28.3, 28.5, 35.3, 38.5, 47.7, 50.4, 67.1, 73.4, 78.6, 164.7; HRMS (ESI-TOF) m/z, calcd. for C16H29NO2 [M + H]+: 268.2271, found 268.2266.
(1R,2S,5R)-2-isopropyl-1-(((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)methyl)-5-methylcyclohexanol (2): Yield 67% (342 mg); [α]D25 –34.34 (c 1.15, CHCl3, 98% e.e.); IR (KBr) ν/cm–1 3413, 2957, 2925, 1742, 1660, 1603, 1451, 1362, 1261, 1160, 1046, 982, 881, 780, 698; 1H NMR (200 MHz, CDCl3) δ 0.80 (d, 3H, J 6.9 Hz, CH3), 0.85 (d, 3H, J 6.4 Hz, CH3), 0.90 (d, 3H, J 6.8 Hz, CH3), 0.97 (d, 3H, J 6.7 Hz, CH3), 0.98 (d, 3H, J 7.0 Hz, CH3), 1.08 (m, 2H, CH2), 1.29 (m, 2H, CH2), 1.45 (m, 1H, CH2), 1.65 (m, 1H, CH2), 1,78 (m, 1H, CH), 1.80 (m, 1H, CH), 1,82 (m,1H, CH), 2.23 (qqd, 1H, J 6.9 Hz, 6.8, 1.9, CH), 2.47 (dt, 1H, J 15.3 Hz, 1.6, CH2), 2.62 (d, 1H, J 15.3 Hz, CH2), 3.90 (m, 2H, CH2), 4.26 (m, 1H, CH); 13C NMR (50 MHz, CDCl3) δ 18.5, 18.9, 19.2, 22.4, 23.5, 24.8, 24.9, 30.3, 31.5, 32.8, 35.0, 48.4, 51.7, 69.8, 72.0, 73.8, 166.2; HRMS (ESI-TOF) m/z, calcd. for C17H32NO2 [M + H]+ 282.2428, found 282.2437.
(1R,2S,5R)-2-isopropyl-1-(((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)methyl)-5-methylcyclohexanol (3): Yield 65% (365 mg); [α]D25 6.73 (c 1.22, CHCl3, 97% e.e.); IR (KBr) ν/cm–1 3447, 2935, 2901, 1842, 1650, 1633, 1479, 1352, 1252, 1147, 1081, 978, 869, 802, 678; 1H NMR (400 MHz, CDCl3) δ 0.84 (d, 3H, J 6.5 Hz, CH3), 0.89 (d, 3H, J 7.1 Hz, CH3), 0.90 (d, 3H, J 7.2 Hz, CH3), 0.93 (d, 3H, J 6.9 Hz, CH3), 0.98 (d, 3H, J 6.7 Hz, CH3), 1.03 (ddd, 1H, J 12.1 Hz, 4.2, 1.9, CH), 1.48 (m, 1H, CH2), 1.55 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.75 (m, 1H, CH), 1,77 (m, 1H, CH) 1.83 (m, 1H, CH), 2.10 (qqd, 1H, J 7.2 Hz, 6.9, 1.9, CH), 2.20 (d, 1H, J 15.1 Hz, CH2), 2.79 (dd, 1H, J 15.1 Hz, 1.2, CH2), 3.90 (m, 2H, CH2), 4.24 (m, 1H, CH); 13C NMR (50 MHz, CDCl3) δ 18.41, 18.44, 19.0, 20.9, 22.4, 23.8, 26.4, 27.8, 32.8, 35.3, 38.3, 47.6, 50.4, 69.7, 72.1, 166.2; HRMS (ESI-TOF) m/z, calcd. for C17H32NO [M + H]+ 282.2428, found 282.2437.
General procedure for the addition of diethylzinc to aldehydes
The chiral β-hydroxy-2-oxazoline (0.05 mmol) was dissolved in the desired solvent (1 mL) then a solution of diethylzinc was added (2.5 mL, 2.5 mmol, 1 mol L–1 in hexane) at 25 ºC. The mixture was stirred for 20 min and then cooled to 0 ºC. A solution of the aldehyde (2 mmol in 3 mL of solvent) was added dropwise. After 2 h, the cooling bath was removed and the reaction was quenched with an aqueous saturated solution of NH4Cl (5 mL), extracted with a mixture of hexane (2 mL) and diethyl ether (2 mL).The organic layer was dried over anhydrous Na2SO4, and after filtration, the solvent was eliminated under reduced pressure. The product was purified by flash chromatography using hexane/ethyl acetate 9:1 as eluent leading to the corresponding secondary alcohol. The enantiomeric excess was determined by chiral gas chromatography.
1-phenylpropan-1-ol: The reaction was performed as described above to give the product as a colorless oil (255 mg, 94% yield); [α]D25 +32.6 (c 1.00, CHCl3). The NMR data match those previously reported.7373 Yue, H.; Huang, H.; Bian, G.; Zong, H.; Li, F.; Song, L.; Tetrahedron: Asymmetry 2014, 25, 170.
1-(2-methoxyphenyl)propan-1-ol: The reaction was performed as described above to give the product as a colorless oil (298 mg, 90% yield); [α]D25 +21.2 (c 1.00, CHCl3). The NMR data match those previously reported.7373 Yue, H.; Huang, H.; Bian, G.; Zong, H.; Li, F.; Song, L.; Tetrahedron: Asymmetry 2014, 25, 170.
1-(3-methoxyphenyl)propan-1-ol: The reaction was performed as described above to give the product as a colorless oil (305 mg, 92% yield); [α]D25 +39.1 (c 1.00, toluene). The NMR data match those previously reported.7474 Zhang, A.; Yang, N.; Yang, L.; Peng, D.; Chem. Lett. 2014, 43, 462.
1-(4-methoxyphenyl)propan-1-ol: The reaction was performed as described above to give the product as a colorless oil (309 mg, 93% yield); [α]D25 +21.9 (c 1.00, toluene). The NMR data match those previously reported.7373 Yue, H.; Huang, H.; Bian, G.; Zong, H.; Li, F.; Song, L.; Tetrahedron: Asymmetry 2014, 25, 170.
1-(4-chlorophenyl)propan-1-ol: The reaction was performed as described above to give the product as a colorless oil (316 mg, 93% yield); [α]D25 +27.0 (c 1.00, toluene). The NMR data match those previously reported.7373 Yue, H.; Huang, H.; Bian, G.; Zong, H.; Li, F.; Song, L.; Tetrahedron: Asymmetry 2014, 25, 170.
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Supplementary InformationExperimental detail and supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.
Acknowledgments
The authors thank CNPq-INCT "Controle Biorracional de Insetos Pragas", CAPES and Fundação Araucária for financial support.
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Data availability
Publication Dates
-
Publication in this collection
Jan 2015
History
-
Received
24 July 2014 -
Accepted
03 Oct 2014