Tetrahedron: Asymmetry 22 (2011) 1325–1327
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Highly enantioselective asymmetric direct aldol reaction catalyzed by amine-functionalized tridentate sulﬁnyl ligands Michał Rachwalski a,⇑, Stanisław Les´niak a, Piotr Kiełbasin´ski b a b
Department of Organic and Applied Chemistry, University of Łódz´, Tamka 12, 91-403 Łódz´, Poland Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódz´, Poland
a r t i c l e
i n f o
Article history: Received 23 May 2011 Accepted 12 July 2011 Available online 10 August 2011
a b s t r a c t Enantiomerically pure, diastereomeric tridentate ligands bearing hydroxyl, sulﬁnyl, and amino moieties as nucleophiles have proven to be highly efﬁcient catalysts in the enantioselective asymmetric direct aldol reaction giving the desired products in very high yields (up to 98%) and with ee’s of up to 97%. The inﬂuence of the stereogenic centers located on the sulﬁnyl sulfur atom, and on the amino moiety, on the stereochemical course of the reaction is also discussed. Ó 2011 Elsevier Ltd. All rights reserved.
2. Results and discussion
The direct aldol reaction constitutes a fundamental C–C bond forming reaction in organic chemistry.1,2 Its enantioselective version has become a very important tool for asymmetric synthesis. This transformation relies on the carbonyl compound acting as a nucleophile by itself or with another carbonyl group (electrophile) to give the appropriate product of a condensation (aldol).1 There are many examples in the literature which describe the enantioselective direct aldol reaction catalyzed by proline,3–6 its derivatives7–10, or by other amino derivatives.11–14 Previously, we synthesized a series of chiral tridentate catalysts, containing hydroxyl, sulﬁnyl, and amine moieties, with two stereogenic centers, one located on the sulﬁnyl sulfur atom and the other on the carbon atom in the amine moiety.15 These ligands were found to very efﬁciently catalyze various enantioselective reactions of asymmetric carbon–carbon bond formation. Thus, the catalysts with chiral acyclic amine moieties turned out to be particularly useful in the stereoselective nitroaldol (Henry) reaction16 and aza-Henry reaction17 while those bearing chiral aziridinyl substituents were useful for the enantioselective diethylzinc and phenylethynylzinc additions to aldehydes18,19 and enantioselective conjugate Michael addition of diethylzinc to enones.20 Moreover, it was possible to obtain each enantiomer of the products of the above reactions using easily available enantiopure diastereomeric catalysts. On the basis of all the aforementioned results, we have decided to study the catalytic activity of our tridentate catalysts in the enantioselective direct aldol reaction.
2.1. Screening of the ligands
⇑ Corresponding author. E-mail address: [email protected]
(M. Rachwalski). 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.07.008
Seven chiral tridentate catalysts, containing aziridines 1a–d, ()-(S)- and (+)-(R)-1-phenylethylamine 1e,f and ()-(S)-1-(10 naphthyl)-ethylamine 1g were tested, since each of them proved to be efﬁcient as a catalyst for the aforementioned reactions (Scheme 1). To check the catalytic activity of these ligands in the enantioselective direct aldol reaction, we chose the condensation of acetone with benzaldehyde as a reference transformation. The reactions were performed at room temperature in acetone and no additional solvent was used (Scheme 2). The results are shown in Table 1. The results of Table 1 show that the stereogenic sulﬁnyl group exerts moderate asymmetric induction. This is visible in the case of catalyst 1a bearing an achiral aziridine moiety (entry 1), in which the sulﬁnyl group is the only source of chirality. Ligands bearing chiral acyclic amines 1e–g proved to be much more efﬁcient catalysts (entries 5–7) than those obtained from chiral aziridines 1b,c,d (entries 2, 3, and 4). Interestingly, a similar relationship was found in the Henry and aza-Henry reactions.16,17 Moreover, the decisive role in stereocontrol of the aldol reaction was caused by the stereogenic centers located in the amine moieties; the effect, which was again the same as in the case of the Henry and aza-Henry reactions. This can be seen in entries 2 and 3, and 5 and 6 where the use of diastereomeric catalysts 1b and 1c, and 1e and 1f, respectively, which have the same absolute conﬁguration at the sulﬁnyl sulfur atom (R) and the opposite conﬁguration on the carbon atom in the amine moieties [(S) and (R), respectively], led to opposite enantiomers of product 2 with similar ee’s. The small differences in the ee values of the product may be explained in terms of ‘matched’ and ‘mismatched’ interactions with the stereogenic sulﬁnyl center.
M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1325–1327
HO O S
1 amines Pri
a 2,2`-dimethylaziridine b (-)-(S)-2-isopropylaziridine c (+)-(R)-2-isopropylaziridine d (-)-(S)-2-methylaziridine e (-)-(S)-1-phenylethylamine f (+)-(R)-1-phenylethylamine g (-)-(S)-1-(1`-naphthyl)ethylamine Scheme 1. Ligands for the asymmetric aldol reaction.
Ligand 1g rt
Scheme 3. Asymmetric aldol condensation of acetone with various aldehydes promoted by catalyst 1g.
Scheme 2. Screening of ligands 1.
Table 1 Screening of catalysts 1 Entry
1 2 3 4 5 6 7 a b c
1a 1b 1c 1d 1e 1f 1g
Product 2 a
36 56 54 45 92 89 98
+17.05 +29.24 30.45 +22.54 +57.25 54.80 +59.08
28 48 50 37 94 90 94
(R) (R) (S) (R) (R) (S) (R)
In chloroform, c 1. Determined using chiral HPLC. Taken from the literature.2
2.2. Asymmetric aldol reaction in the presence of catalyst 1g Having obtained the best results with ligand 1g, we then decided to determine the scope of its activity. To this end, it was used to catalyze the title transformation performed with a series of aldehydes (Scheme 3). The results are shown in Table 2. The results shown in Tables 1 and 2 clearly indicate that the selected ligand 1g and the two diastereomeric ligands 1e and 1f are very effective catalysts for the title reaction, with all leading to the appropriate chiral aldols in high chemical yields and with high enantiomeric excesses. Both aryl and alkyl aldehydes are suitable
for the reaction while the absolute conﬁgurations of the resulting adducts are the same in each case. As mentioned above, each diastereomeric catalyst is easily accessible and leads to the formation of the opposite enantiomer of the addition product. This means that the desired enantiomer of the product can be obtained by choosing the appropriate enantiomeric amine to synthesize a diastereomeric catalyst starting from the same chiral precursor previously described.15 3. Conclusion Chiral tridentate catalysts, which contain two stereogenic centers, one located on the sulﬁnyl sulfur atom, and the other on the carbon atom in the amine moiety, were found to be very efﬁcient catalysts for the enantioselective direct aldol reaction. The stereogenic centers located in the amine moieties exerted a decisive inﬂuence on the stereochemistry of the reaction and the absolute conﬁguration of the products. Each enantiomer of the product may be obtained by using easily available diastereomeric catalysts. 4. Experimental 4.1. General Unless otherwise speciﬁed, all reagents were purchased from commercial suppliers. Acetone, benzaldehyde, 2-chlorobenzaldehyde, and isobutyraldehyde were distilled before use. 4-Nitroand 4-bromobenzaldehyde were crystallized before use. NMR
M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1325–1327 Table 2 Asymmetric aldol condensation of acetone with various aldehydes in the presence of catalyst 1g Entry
1 2 3 4 5 6 a b c
C6H5 4-BrC6H4 2-ClC6H4 4-NO2C6H4 4-MeOC6H4 i-Pr
Product 3 ]Da
a b c d e f
98 89 82 85 96 95
+59.1 +57.2 +52.0 +52.7 +66.8 +7.3
eeb (%) 94 85 91 87 92 96
Absolute conﬁgurationc (R) (R) (R) (R) (R) (R)
In chloroform, c 1. Determined using chiral HPLC. Taken from the literature.2,22,23
spectra were recorded on a Bruker instrument at 600 MHz with CDCl3 as a solvent and relative to TMS as an internal standard. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and b = broad. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter with a sodium lamp at room temperature (c 1). Melting points were measured on a MELTEMP apparatus and are uncorrected. Column chromatography was carried out using Merck 60 silica gel. TLC was performed on Merck 60 F254 silica gel plates. Visualization was accomplished with UV light or iodine vapor. The enantiomeric excess (ee) values were determined by chiral HPLC (Knauer, Chiralcel OD). Chiral tridentate catalysts were obtained using the previously described procedure.15,18 4.2. General procedure for the asymmetric direct aldol reaction A round-bottomed ﬂask was charged with catalyst 1 (0.2 mmol) and acetone (25 mL). The mixture was cooled to 0 °C, after which the corresponding aldehyde (1 mmol) was added and the mixture was stirred at room temperature for 24 hours. After this time, acetone was evaporated and the crude mixture was puriﬁed via column chromatography (hexane: ethyl acetate in gradient) to obtain optically active products 3a–f. The yields, speciﬁc rotations, and enantiomeric excess values are shown in Tables 1 and 2. 4.2.1. (R)-4-Hydroxy-4-phenylbutan-2-one 3a Yellow oil; 1H NMR (CDCl3): d = 2.19 (s, 3H), 2.82 (dd, J = 3.0, 18.0 Hz, 1H), 2.89 (dd, J = 9.0, 18.0 Hz, 1H), 3.25 (br s, 1H), 5.15 (dd, J = 3.0, 9.0 Hz, 1H), 7.27–7.37 (m, 5H). Other spectroscopic data of compound 3a are in agreement with those reported in the literature.2,21 4.2.2. (R)-4-Hydroxy-4-(4-bromophenyl)butan-2-one 3b White solid, mp 56 °C. 1H NMR (CDCl3): d = 2.19 (s, 3H), 2.78 (dd, J = 3.5, 18.0 Hz, 1H), 2.83 (dd, J = 9.0, 18.0 Hz, 1H), 3.36 (br s, 1H), 5.10 (dd, J = 3.5, 9.0 Hz, 1H), 7.22–7.31 (m, 2H), 7.46–7.48 (m, 2H). Other spectroscopic data of compound 3b are in agreement with those reported in the literature.22 4.2.3. (R)-4-Hydroxy-4-(2-chlorophenyl)butan-2-one 3c Yellowish oil, 1H NMR (CDCl3): d = 2.21 (s, 3H), 2.68 (dd, J = 2.5, 18.0 Hz, 1H), 2.98 (dd, J = 2.5, 9.0 Hz, 1H), 3.52 (br s, 1H), 5.50 (dd, J = 2.5, 9.0 Hz, 1H), 7.20–7.22 (m, 1H), 7.28–7.33 (m, 2H), 7.61–7.62 (m, 1H). Other spectroscopic data of compound 3c are in agreement with those reported in the literature.23 4.2.4. (R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one 3d Yellow solid, mp 61 °C. 1H NMR (CDCl3): d = 2.22 (s, 3H), 2.81– 2.90 (m, 2H), 3.53 (br s, 1H), 5.24–5.28 (m, 1H), 7.53–7.55 (m, 2H), 8.20–8.22 (m, 2H). Other spectroscopic data of compound 3d are in agreement with those reported in the literature.22
4.2.5. (R)-4-Hydroxy-4-(4-methoxyphenyl)butan-2-one 3e Colorless oil. 1H NMR (CDCl3): d = 2.21 (s, 3H), 2.81 (dd, J = 3.0, 18.0 Hz, 1H), 2.91 (dd, J = 9.0, 18.0 Hz, 1H), 3.21 (br s, 1H), 3.82 (s, 3H), 5.03 (dd, J = 3.0, 9.0 Hz, 1H), 6.89–6.92 (m, 2H), 7.29–7.31 (m, 2H). Other spectroscopic data of compound 3e are in agreement with those reported in the literature.22 4.2.6. (R)-4-Hydroxy-5-methylhexan-2-one 3f Yellow oil. 1H NMR (CDCl3): d = 0.93 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 1.62–1.73 (m, 1H), 2.21 (s, 3H), 2.43–2.65 (m, 2H), 3.80–3.86 (m, 1H). Other spectroscopic data of compound 3f are in agreement with those reported in the literature.2 Acknowledgments Financial support provided by the Polish Ministry of Science and Higher Education, Grant no. N N204 131140 for PK, is gratefully acknowledged. References 1. Guillena, G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249– 2293. 2. Raj Vishnumaya, M.; Singh, V. K. J. Org. Chem. 2009, 74, 4289–4297. 3. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395– 2396. 4. Izquierdo, I.; Plaza, M. T.; Robles, M. T.; Mota, A. J.; Franco, F. Tetrahedron: Asymmetry 2001, 12, 2749–2754. 5. Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510–9512. 6. Sekiguchi, Y.; Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotaki, H. Synlett 2003, 1655–1658. 7. Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911–4914. 8. Chen, J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198–8202. 9. Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657–4660. 10. Mecˇiarová, M.; Toma, Š.; Berkessel, A.; Koch, B. Lett. Org. Chem. 2006, 3, 437– 441. 11. Amedjkouh, M. Tetrahedron: Asymmetry 2005, 16, 1411–1414. 12. Enders, D.; Gries, J. Synthesis 2005, 3508–3516. 13. Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127, 14566–14567. 14. Kano, T.; Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738–1740. 15. Rachwalski, M.; Kwiatkowska, M.; Drabowicz, J.; Kłos, M.; Wieczorek, W. M.; Szyrej, M.; Sieron´, L.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2008, 19, 2096– 2101. 16. Rachwalski, M.; Les´niak, S.; Sznajder, E.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2009, 20, 1547–1549. 17. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P., Tetrahedron: Asymmetry 2011, submitted. 18. Les´niak, S.; Rachwalski, M.; Sznajder, E.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2009, 20, 2311–2314. 19. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2010, 21, 2687–2689. 20. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2010, 21, 1890–1892. 21. Acetti, D.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Eur. J. Org. Chem. 2010, 142–151. 22. Singh, P.; Bhardwaj, A.; Kaur, S.; Kumar, S. Eur. J. Med. Chem. 2009, 44, 1278– 1287. 23. 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, 4812–4818.