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Highly efficient conjugate additions of diethylzinc to enones promoted by chiral aziridine alcohols and aziridine ethers
Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Highly efficient conjugate additions of diethylzinc to enones promoted by chiral aziridine alcohols and aziridine ethers Szymon Jarzyn´ski, Michał Rachwalski ⇑, Adam M. Pieczonka, Zuzanna Wujkowska, Stanisław Les´niak Department of Organic and Applied Chemistry, University of Łódz´, Tamka 12, 91-403 Łódz´, Poland
a r t i c l e
i n f o
Article history: Received 28 May 2015 Accepted 14 July 2015 Available online xxxx
a b s t r a c t Chiral heteroorganic N-trityl aziridine alcohols and aziridine ethers have proven to be highly efficient catalysts in enantioselective conjugate diethylzinc additions to enones, namely chalcone and 2-cyclohexen1-one providing the desired chiral adducts in high chemical yields (up to 95%) and with ee’s up to 93%. The change of the absolute configuration of the stereogenic center located at the aziridine moiety on the stereochemical outcome is also discussed. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Asymmetric synthesis constitutes one of the main fields in modern organic chemistry.1–3 The choice of the appropriate chiral catalyst plays a crucial role in the formation of the desired products in good chemical yield and with elevated enantiomeric excess values. Carbon–carbon bond formation in an enantioselective fashion using organometallic reagents is one of the most common and useful synthetic methodologies in stereoselective synthesis.4–6 Among the reactions applied, the enantioselective addition of diethylzinc to carbonyl compounds (1,2-addition) and to enones (1,4-addition) are the basic model reactions that are commonly used for testing the catalytic activity of newly developed chiral ligands.7,8 Previously, we have described a highly enantioselective conjugate Michael addition of diethyl zinc to enones promoted by tridentate sulfinyl aziridine-containing ligands9 and by diast ereomerically pure aziridine alcohols derived from (S)-mandelic acid.10 More recently, we have reported the synthesis of a series of novel chiral catalysts, N-trityl aziridine carbinols,11 and aziridine ethers,12 and their high catalytic activity in the asymmetric addition of diethylzinc and phenylethynylzinc to aldehydes. It is worth noting that small-molecule amine ether ligands are scarcely reported in the chemical literature.13–16 In continuation of our interests in the field of asymmetric synthesis,17–21 and taking all of the aforementioned results into account, we decided to extend the scope of the applicability of aziridine alcohols11 and aziridine ethers12 using them as chiral catalysts for the conjugate Michael additions of diethylzinc to enones.
Aziridine alcohols 1a–d and aziridine ethers 2a–c synthesized as reported previously11,12 were applied (Fig. 1).
⇑ Corresponding author. E-mail address: [email protected] (M. Rachwalski).
OH
R2 O
R
R1
N
N Trt 2a-c
1a-d R = Me 1a R = Ph 1b R = iPr 1c R = Bn 1d
aziridines Pri
Me N H a
H
N H b
H
H N H c
Pr i
a (-)-( S)-2-methylaziridine b (-)-( S)-2-isopropylaziridine c (+)-( R)-2-isopropylaziridine
Figure 1. Catalysts for the asymmetric Michael addition of diethyl zinc to enones.
Since the asymmetric 1,4-addition of diethylzinc to a,b-unsaturated carbonyl compounds (enones) requires the application of a metal catalyst,22–25 nickel acetylacetonate Ni(acac)2 was used and ligands 1a–d and 2a–c were tested for their catalytic activity in the asymmetric addition of diethylzinc to chalcone 3 (Scheme 1) and 2-cyclohexen-1-one 5 (Scheme 2). Some experiments in the absence of Ni(acac)2 were also carried out in order to prove the importance of the metal catalyst. All of the results are summarized in Table 1. From Table 1 it can be seen that all ligands 1a–d and 2a–c can catalyze the title Michael addition to deliver chiral adducts in high chemical yields and with high enantiomeric excess values. The use
http://dx.doi.org/10.1016/j.tetasy.2015.07.010 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jarzyn´ski, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.010
´ ski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx S. Jarzyn
2
O
Et
O
O
Et
O
ligand 1 or 2, Ni(acac)2 Ph
Ph
+ Et2Zn
Ph
Ph
Ph
Ph
Ph
Ph
toluene 4
3
3
O
toluene
O
Scheme 1. Asymmetric conjugate Michael addition of diethylzinc to chalcone.
4
ligand 1d, metal component + Et2Zn
O
O Et
ligand 1 or 2 , Ni(acac) 2 + Et2Zn
6
5
toluene
Et
Scheme 3. Screening of various metal components in the Et2Zn addition to enones 3 and 5.
6
5
Scheme 2. Asymmetric conjugate Michael addition of diethylzinc to 2-cyclohexen1-one.
to both products in low chemical yields (22% and 18%, respectively) and with poor ee values (15% and 13%, respectively). To continue our investigations into the application of aziridine alcohols of type 1 as catalysts in the conjugate Michael addition of diethylzinc to enones, two another ligands 1e and 1f (synthesized as described previously11) were applied (Fig. 2). Ligand 1e was applied in order to check the action of an enantiomerically pure alcohol bearing a primary hydroxyl group at a stereogenic carbon atom, whereas ligand 1f with an opposite absolute configuration at the aziridine carbon atom was introduced in order to examine the influence of the stereogenic center located in the aziridine subunit on the stereochemical outcome of the title reaction. The results are summarized in Table 3. These results reveal that ligand 1e bearing a primary hydroxyl group at a stereogenic carbon atom is prone to catalyze the title reaction to afford the desired products 4 and 6 in good chemical yields and enantiomeric excess values (Table 3, entry 1). More interestingly, the use of ligand 1f bearing an opposite configuration at the aziridine carbon atom led to products with opposite absolute configurations (in comparison with the use of ligand 1d). This may suggest that the stereogenic center located at aziridine subunit has a decisive influence on the stereochemical outcome of the addition reaction. This assumption is in agreement with the literature.9–12 Finally, in order to check the influence of the ether subunit of ligands type 2 on the chemistry and stereochemistry of the asymmetric diethylzinc addition to enones, three novel catalysts bearing (S)-2-isopropylaziridine subunit 2d–f were synthesized (Fig. 3) according to the literature.12 Ligand 2d derived from 2-benzyloxyacetic acid constitutes an aliphatic ether system, whereas ligands 2e–f were tested in order to check the presence and character of the substituents in the phenyl ring. All of the results are summarized in Table 4.
of both enantiomeric ligands 2b and 2c led to the formation of chiral products 4 and 6 with opposite absolute configurations. The same phenomenon was also observed when using other heteroorganic ligands in asymmetric conjugated additions of diethylzinc to enones.9,10 Finally, in the absence of a nickel catalyst (Table 1, entries 5 and 8), the 1,4-addition took place, albeit with significantly lower values of chemical yield and enantiomeric excess. This proves that the metal catalyst plays an important role in terms of efficiency and high stereoselectivity of the title reaction, however the crucial factor influencing the stereochemistry of this process constitutes the presence and the configuration of the aziridine ring. It should be noted that the presence of the oxygen atom is necessary as a second complexing center of the catalyst (we did not observe any catalytic effect of non-functionalized enantiomerically pure aziridine in this reaction), while the substituent on the nitrogen atom as well as the chemical character of the oxygen function did not play any important role. This assumption is in full agreement with our previous observations.11 With the best results in terms of chemical yield and enantiomeric excess for the reaction catalyzed by ligand 1d in hand, further studies involving the application of other metal components were performed. Thus, substrates 3 and 5 were subjected to the diethylzinc addition in the presence of the most effective ligand 1d, using copper(II) acetate, zinc trifluoromethanesulfonate Zn(OTf)2 and tin(II) trifluoromethanesulfonate Sn(OTf)2 (Scheme 3). The results are summarized in Table 2. From Table 2 it can be seen that all of the metal catalysts tested were less effective in comparison with the previously applied nickel acetylacetonate. Additionally, tin(II) trifluoromethanesulfonate proved to be ineffective in the title addition reaction leading
Table 1 Screening of ligands 1a–d and 2a–c Entry
Ligand
Product 4 Yield (%)
1 2 3 4 5 6 7 8 9 a b c d
1a 1b 1c 1d 1dd 2a 2b 2bd 2c
85 90 93 95 46 83 91 44 87
[a]D
a
2.1 2.2 2.3 2.4 1.0 2.1 2.3 0.9 +2.2
b
Product 6
ee (%)
Abs. config.
82 86 90 92 40 82 89 38 86
(R) (R) (R) (R) (R) (R) (R) (R) (S)
Yield (%) 80 84 88 91 42 81 89 40 86
[a
]Da
8.4 9.2 9.5 9.9 4.6 8.2 9.6 4.2 +9.3
eeb (%)
Abs. config.c
79 86 89 93 43 77 90 39 87
(S) (S) (S) (S) (S) (S) (S) (S) (R)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25 No Ni(acac)2 added.
Please cite this article in press as: Jarzyn´ski, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.010
´ ski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx S. Jarzyn
3
Table 2 Screening of various metal components Entry
Metal component
Product 4 [a]D
Yield (%) 1 2 3 a b c
Cu(OAc)2 Zn(OTf)2 Sn(OTf)2
86 52 22
a
Product 6
b
2.1 1.3 0.4
ee (%)
Abs. config.
80 48 15
(R) (R) (R)
[a]D
Yield (%) 82 49 18
a
9.0 4.5 1.4
eeb (%)
Abs. config.c
85 42 13
(S) (S) (S)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
the title addition reaction in terms of chemical yield and enantioselectivity.
OH OH N
N
Trt
Trt
3. Conclusions The chiral aziridine alcohols of type 1 and aziridine ethers of type 2 were found to be highly effective catalysts for the enantioselective conjugate Michael addition of diethylzinc to enones (chalcone and 2-cyclohexen-1-one, respectively). It should be noted that each enantiomer of the designed product should be available by the use of various isomers of ligands 1 and 2.
1f
1e
Figure 2. Aziridine alcohols 1e and 1f for the asymmetric addition of Et2Zn to enones.
From Table 4 it can be seen that the aromatic ether subunit to an aliphatic one led to a decrease in the chemical yields and enantiomeric excess values (Table 4, entry 1). The use of ligand 2e containing an aromatic ether moiety with an electron donating group gave better results (entry 2) in comparison with non-substituted catalyst 2b. Finally, the application of aromatic ether ligand 2f bearing an electron withdrawing group located in the phenyl ring gave the desired adducts 4 and 6 with lower values of chemical yields and ee’s (entry 3) compared with non-substituted ligand 2b. This may suggest that enhancement of electron density on the oxygen atom and thus the complexing properties improves
4. Experimental 4.1. General Unless otherwise specified, all reagents were purchased from commercial suppliers and used without further purification. Toluene was distilled from sodium benzophenone ketyl radical. 1 H NMR spectra were recorded on a Bruker instrument at 600 MHz with CDCl3 as the solvent and relative to TMS as internal
Table 3 Screening of aziridine alcohols 1e and 1f Entry
Ligand
Product 4 Yield (%)
1 2 a b c
1e 1f
82 94
Product 6
[a]Da
eeb (%)
Abs. config.
2.0 +2.4
78 91
(R) (S)
Yield (%) 80 92
[a]Da
eeb (%)
Abs. config.c
8.6 +9.9
81 93
(S) (R)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
Pr i
Pri
H
O
N O
Pri
H O
N
H
N
Cl 2e
2d
2f
Figure 3. Aziridine ethers for enantioselective Michael addition of Et2Zn to enones.
Table 4 Screening of various aziridine ether ligands Entry
Ligand
Product 4 Yield (%)
1 2 3 a b c
2d 2e 2f
70 94 85
[a]Da 1.9 2.4 2.0
Product 6
eeb (%)
Abs. config.
72 92 80
(R) (R) (R)
Yield (%) 69 93 76
[a]Da 8.0 10.1 8.6
eeb (%)
Abs. config.c
75 95 81
(S) (S) (S)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
Please cite this article in press as: Jarzyn´ski, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.010
´ ski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx S. Jarzyn
4
standard. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter with a sodium lamp at room temperature (c 1). 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 (254 nm) or using iodine vapor. The enantiomeric excess (ee) values were determined by chiral HPLC (Knauer, Chiralcel AS). Aziridines a–c were prepared according to the literature.26 Chiral ligands 1a–f and 2a–f were synthesized using the protocols previously described.11,12 4.2. Aziridine ethers 2d–f Aziridines 2d–f were synthesized according to literature.12 4.2.1. (R)-( )-1-(2-Benzyloxyethyl)-2-(propan-2-yl)aziridine 2d Colorless oil; [a]rt 0.4 (c 1, CHCl3); 1H NMR (CDCl3): d = 0.94 D = (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H), 1.21–1.25 (m, 2H), 1.27 (d, J = 6.0 Hz, 1H), 1.60 (d, J = 3.5 Hz, 1H), 2.35 (dt, J = 6.0, 12.0 Hz, 1H), 2.64 (dt, J = 6.0, 12.0 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 4.57 (s, 2H), 7.29–7.39 (m, 5H); 13C NMR (CDCl3): d = 19.6 (CH3), 20.5 (CH3), 31.8 (CHaz), 32.9 (CH2az), 46.6 (CHaz), 60.7 (CH2), 70.2 (CH2), 73.3 (CH2), 127.5 (Car), 127.6 (Car), 127.8 (Car), 128.3 (Car), 128.4 (Car), 138.4 (Cq ar); MS (CI): m/z 220 (M+H); HRMS (CI): calcd for C14H21NO: 219.0121; found: 219.0125. 4.2.2. (R)-( )-1-(2-(4-tert-Butyl)phenoxyethyl)-2-(propan-2-yl)aziridine 2e Colorless oil; [a]rt 0.86 (c 1, CHCl3); 1H NMR (CDCl3): d = 0.97 D = (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.22–1.28 (m, 2H), 1.33 (s, 9H), 1.35 (d, J = 6.0 Hz, 1H), 1.65 (d, J = 3.3 Hz, 1H), 2.45 (dt, J = 6.0, 12.0 Hz, 1H), 2.88 (dt, J = 6.0, 12.0 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 6.87–6.90 (m, 2H); 7.31–7.33 (m, 2H); 13C NMR (CDCl3): d = 19.7 (CH3), 20.6 (CH3), 31.5 (3CH3), 31.7 (CHaz), 32.8 (CH2az), 34.0 (Cq), 46.8 (CHaz), 60.1 (CH2), 67.6 (CH2), 113.2 (2Car), 126.2 (2Car), 143.3 (Cq ar), 156.6 (Cq ar); MS (CI): m/z 262 (M+H); HRMS (CI): calcd for C17H27NO: 261.2715; found: 261.2713. 4.2.3. (R)-( )-1-(2-(4-Chloro)phenoxyethyl)-2-(propan-2-yl)aziridine 2f 1 Colorless oil; [a]rt D = +5.4 (c 1, CHCl3); H NMR (CDCl3): d = 0.91 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.23–1.29 (m, 2H), 1.35 (d, J = 6.0 Hz, 1H), 1.65 (d, J = 3.2 Hz, 1H), 2.46 (dt, J = 5.5, 11.5 Hz, 1H), 2.87 (dt, J = 5.5, 11.5 Hz, 1H), 4.12 (t, J = 5.5 Hz, 2H), 6.86– 6.90 (m, 2H); 7.24–7.30 (m, 2H); 13C NMR (CDCl3): d = 19.6 (CH3), 20.6 (CH3), 31.7 (CHaz), 32.9 (CH2az), 46.7 (CHaz), 59.8 (CH2), 67.9 (CH2), 116.0 (2Car), 129.3 (2Car), 155.9 (Cq ar), 167.4 (Cq ar); MS (CI): m/z 240.5 (M+H); HRMS (CI): calcd for C13H18ClNO: 239.5237; found: 239.5240. 4.3. General protocol for the conjugate Michael addition of diethylzinc to a,b-unsaturated enones using chiral ligands 1a–f, 2a–f and metal component A solution of metal component (0.07 mmol) and chiral ligand 1a–f or 2a–f (0.11 mmol) in 5 mL of freshly distilled toluene was stirred under a nitrogen atmosphere at room temperature for 1 h. After this time, the corresponding enone substrate (1 mmol) was added, the mixture was cooled to 20 °C and a solution of diethylzinc in hexane (1.0 M) (1.65 mL, 1.65 mmol) was added. The mixture was stirred at 20 °C for 1 h and at room temperature
overnight. After complete conversion (TLC), the reaction mixture was poured into 20 mL of 1 M HCl and extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Filtration and evaporation yielded the crude products 4 and 6. After purification via column chromatography on silica gel using hexane and ethyl acetate in gradient as an eluent, pure products 4 and 6 were obtained. Chemical yields, enantiomeric excesses (determined by chiral HPLC) and specific rotations values are shown in Tables 1–4. 4.3.1. (R)-( )-1,3-Diphenyl-pentan-1-one 4 Colorless solid; 1H NMR (CDCl3): d = 0.75 (t, J = 7.3 Hz, 3H), 1.56–1.60 (m, 1H), 1.71–1.74 (m, 1H), 3.16–3.22 (m, 3H), 7.10– 7.34 (m, 5H), 7.35–7.38 (m, 2H), 7.44–7.47 (m, 1H), 7.82–7.83 (m, 2H). Other spectroscopic data of compound 4 are in agreement with the literature.25 4.3.2. (S)-( )-3-Ethylcyclohexanone 6 Colorless liquid; 1H NMR (CDCl3): d = 0.93 (t, J = 7.2 Hz, 3H), 1.28–1.41 (m, 3H), 1.67–1.74 (m, 2H), 1.94–2.39 (m, 6H). Other spectroscopic data of compound 6 are in agreement with the literature.25 Acknowledgement Financial support by the National Science Centre, Poland (NCN), Grant no. 2012/05/D/ST5/00505 for M.R., is gratefully acknowledged. References 1. Ojima, I. Catalytic Asymmetric Synthesis; John Wiley & Sons, 2010. 3rd ed. 2. Christmann, M.; Bräse, S. Asymmetric Synthesis II: More Methods and Applications; Wiley-VCH, 2012. 3. Gawley, R. E.; Aubé, J. Principles of Asymmetric Synthesis, 2nd ed.; Elsevier: Amsterdam, 2012. 4. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69. 5. Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196. 6. Pellissier, H. Tetrahedron 2007, 63, 9267–9331. 7. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824. 8. Łowicki, D.; Bas´, S.; Młynarski, J. Tetrahedron 2015, 71, 1339–1394. 9. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2010, 21, 1890–1892. 10. Rachwalski, M.; Jarzyn´ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 1117–1119. 11. Jarzyn´ski, S.; Les´niak, S.; Pieczonka, A. M.; Rachwalski, M. Tetrahedron: Asymmetry 2015, 26, 35–40. 12. Pieczonka, A. M.; Les´niak, S.; Jarzyn´ski, S.; Rachwalski, M. Tetrahedron: Asymmetry 2015, 26, 148–151. 13. Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y. Tetrahedron: Asymmetry 1995, 6, 2109–2112. 14. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673–1679. 15. Shi, M.; Jiang, J.-K.; Feng, Y.-S. Tetrahedron: Asymmetry 2000, 11, 4923–4933. 16. Liu, Y.; Da, C.-S.; Yu, S.-L.; Yin, X.-G.; Wang, J.-R.; Fan, X.-Y.; Li, W.-P.; Wang, R. J. Org. Chem. 2010, 75, 6869–6878. 17. Rachwalski, M.; Vermue, N.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2013, 42, 9268– 9282. 18. Rachwalski, M.; Jarzyn´ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 421– 425. 19. Rachwalski, M.; Leenders, T.; Kaczmarczyk, S.; Kiełbasin´ski, P.; Les´niak, S.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2013, 11, 4207–4213. 20. Rachwalski, M.; Kaczmarczyk, S.; Les´niak, S.; Kiełbasin´ski, P. ChemCatChem 2014, 6, 873–875. 21. Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219–223. 22. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878. 23. de Vries, A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron: Asymmetry 1997, 9, 1467–1473. 24. Kang, J.; Lee, J. H.; Lim, D. S. Tetrahedron: Asymmetry 2003, 14, 305–315. 25. Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153–4155. 26. Xu, J. Tetrahedron: Asymmetry 2002, 13, 1129–1134.
Please cite this article in press as: Jarzyn´ski, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.010
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Highly efficient conjugate additions of diethylzinc to enones promoted by chiral aziridine alcohols and aziridine ethers Szymon Jarzyn´ski, Michał Rachwalski ⇑, Adam M. Pieczonka, Zuzanna Wujkowska, Stanisław Les´niak Department of Organic and Applied Chemistry, University of Łódz´, Tamka 12, 91-403 Łódz´, Poland
a r t i c l e
i n f o
Article history: Received 28 May 2015 Accepted 14 July 2015 Available online xxxx
a b s t r a c t Chiral heteroorganic N-trityl aziridine alcohols and aziridine ethers have proven to be highly efficient catalysts in enantioselective conjugate diethylzinc additions to enones, namely chalcone and 2-cyclohexen1-one providing the desired chiral adducts in high chemical yields (up to 95%) and with ee’s up to 93%. The change of the absolute configuration of the stereogenic center located at the aziridine moiety on the stereochemical outcome is also discussed. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Asymmetric synthesis constitutes one of the main fields in modern organic chemistry.1–3 The choice of the appropriate chiral catalyst plays a crucial role in the formation of the desired products in good chemical yield and with elevated enantiomeric excess values. Carbon–carbon bond formation in an enantioselective fashion using organometallic reagents is one of the most common and useful synthetic methodologies in stereoselective synthesis.4–6 Among the reactions applied, the enantioselective addition of diethylzinc to carbonyl compounds (1,2-addition) and to enones (1,4-addition) are the basic model reactions that are commonly used for testing the catalytic activity of newly developed chiral ligands.7,8 Previously, we have described a highly enantioselective conjugate Michael addition of diethyl zinc to enones promoted by tridentate sulfinyl aziridine-containing ligands9 and by diast ereomerically pure aziridine alcohols derived from (S)-mandelic acid.10 More recently, we have reported the synthesis of a series of novel chiral catalysts, N-trityl aziridine carbinols,11 and aziridine ethers,12 and their high catalytic activity in the asymmetric addition of diethylzinc and phenylethynylzinc to aldehydes. It is worth noting that small-molecule amine ether ligands are scarcely reported in the chemical literature.13–16 In continuation of our interests in the field of asymmetric synthesis,17–21 and taking all of the aforementioned results into account, we decided to extend the scope of the applicability of aziridine alcohols11 and aziridine ethers12 using them as chiral catalysts for the conjugate Michael additions of diethylzinc to enones.
Aziridine alcohols 1a–d and aziridine ethers 2a–c synthesized as reported previously11,12 were applied (Fig. 1).
⇑ Corresponding author. E-mail address: [email protected] (M. Rachwalski).
OH
R2 O
R
R1
N
N Trt 2a-c
1a-d R = Me 1a R = Ph 1b R = iPr 1c R = Bn 1d
aziridines Pri
Me N H a
H
N H b
H
H N H c
Pr i
a (-)-( S)-2-methylaziridine b (-)-( S)-2-isopropylaziridine c (+)-( R)-2-isopropylaziridine
Figure 1. Catalysts for the asymmetric Michael addition of diethyl zinc to enones.
Since the asymmetric 1,4-addition of diethylzinc to a,b-unsaturated carbonyl compounds (enones) requires the application of a metal catalyst,22–25 nickel acetylacetonate Ni(acac)2 was used and ligands 1a–d and 2a–c were tested for their catalytic activity in the asymmetric addition of diethylzinc to chalcone 3 (Scheme 1) and 2-cyclohexen-1-one 5 (Scheme 2). Some experiments in the absence of Ni(acac)2 were also carried out in order to prove the importance of the metal catalyst. All of the results are summarized in Table 1. From Table 1 it can be seen that all ligands 1a–d and 2a–c can catalyze the title Michael addition to deliver chiral adducts in high chemical yields and with high enantiomeric excess values. The use
http://dx.doi.org/10.1016/j.tetasy.2015.07.010 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jarzyn´ski, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.010
´ ski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx S. Jarzyn
2
O
Et
O
O
Et
O
ligand 1 or 2, Ni(acac)2 Ph
Ph
+ Et2Zn
Ph
Ph
Ph
Ph
Ph
Ph
toluene 4
3
3
O
toluene
O
Scheme 1. Asymmetric conjugate Michael addition of diethylzinc to chalcone.
4
ligand 1d, metal component + Et2Zn
O
O Et
ligand 1 or 2 , Ni(acac) 2 + Et2Zn
6
5
toluene
Et
Scheme 3. Screening of various metal components in the Et2Zn addition to enones 3 and 5.
6
5
Scheme 2. Asymmetric conjugate Michael addition of diethylzinc to 2-cyclohexen1-one.
to both products in low chemical yields (22% and 18%, respectively) and with poor ee values (15% and 13%, respectively). To continue our investigations into the application of aziridine alcohols of type 1 as catalysts in the conjugate Michael addition of diethylzinc to enones, two another ligands 1e and 1f (synthesized as described previously11) were applied (Fig. 2). Ligand 1e was applied in order to check the action of an enantiomerically pure alcohol bearing a primary hydroxyl group at a stereogenic carbon atom, whereas ligand 1f with an opposite absolute configuration at the aziridine carbon atom was introduced in order to examine the influence of the stereogenic center located in the aziridine subunit on the stereochemical outcome of the title reaction. The results are summarized in Table 3. These results reveal that ligand 1e bearing a primary hydroxyl group at a stereogenic carbon atom is prone to catalyze the title reaction to afford the desired products 4 and 6 in good chemical yields and enantiomeric excess values (Table 3, entry 1). More interestingly, the use of ligand 1f bearing an opposite configuration at the aziridine carbon atom led to products with opposite absolute configurations (in comparison with the use of ligand 1d). This may suggest that the stereogenic center located at aziridine subunit has a decisive influence on the stereochemical outcome of the addition reaction. This assumption is in agreement with the literature.9–12 Finally, in order to check the influence of the ether subunit of ligands type 2 on the chemistry and stereochemistry of the asymmetric diethylzinc addition to enones, three novel catalysts bearing (S)-2-isopropylaziridine subunit 2d–f were synthesized (Fig. 3) according to the literature.12 Ligand 2d derived from 2-benzyloxyacetic acid constitutes an aliphatic ether system, whereas ligands 2e–f were tested in order to check the presence and character of the substituents in the phenyl ring. All of the results are summarized in Table 4.
of both enantiomeric ligands 2b and 2c led to the formation of chiral products 4 and 6 with opposite absolute configurations. The same phenomenon was also observed when using other heteroorganic ligands in asymmetric conjugated additions of diethylzinc to enones.9,10 Finally, in the absence of a nickel catalyst (Table 1, entries 5 and 8), the 1,4-addition took place, albeit with significantly lower values of chemical yield and enantiomeric excess. This proves that the metal catalyst plays an important role in terms of efficiency and high stereoselectivity of the title reaction, however the crucial factor influencing the stereochemistry of this process constitutes the presence and the configuration of the aziridine ring. It should be noted that the presence of the oxygen atom is necessary as a second complexing center of the catalyst (we did not observe any catalytic effect of non-functionalized enantiomerically pure aziridine in this reaction), while the substituent on the nitrogen atom as well as the chemical character of the oxygen function did not play any important role. This assumption is in full agreement with our previous observations.11 With the best results in terms of chemical yield and enantiomeric excess for the reaction catalyzed by ligand 1d in hand, further studies involving the application of other metal components were performed. Thus, substrates 3 and 5 were subjected to the diethylzinc addition in the presence of the most effective ligand 1d, using copper(II) acetate, zinc trifluoromethanesulfonate Zn(OTf)2 and tin(II) trifluoromethanesulfonate Sn(OTf)2 (Scheme 3). The results are summarized in Table 2. From Table 2 it can be seen that all of the metal catalysts tested were less effective in comparison with the previously applied nickel acetylacetonate. Additionally, tin(II) trifluoromethanesulfonate proved to be ineffective in the title addition reaction leading
Table 1 Screening of ligands 1a–d and 2a–c Entry
Ligand
Product 4 Yield (%)
1 2 3 4 5 6 7 8 9 a b c d
1a 1b 1c 1d 1dd 2a 2b 2bd 2c
85 90 93 95 46 83 91 44 87
[a]D
a
2.1 2.2 2.3 2.4 1.0 2.1 2.3 0.9 +2.2
b
Product 6
ee (%)
Abs. config.
82 86 90 92 40 82 89 38 86
(R) (R) (R) (R) (R) (R) (R) (R) (S)
Yield (%) 80 84 88 91 42 81 89 40 86
[a
]Da
8.4 9.2 9.5 9.9 4.6 8.2 9.6 4.2 +9.3
eeb (%)
Abs. config.c
79 86 89 93 43 77 90 39 87
(S) (S) (S) (S) (S) (S) (S) (S) (R)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25 No Ni(acac)2 added.
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Table 2 Screening of various metal components Entry
Metal component
Product 4 [a]D
Yield (%) 1 2 3 a b c
Cu(OAc)2 Zn(OTf)2 Sn(OTf)2
86 52 22
a
Product 6
b
2.1 1.3 0.4
ee (%)
Abs. config.
80 48 15
(R) (R) (R)
[a]D
Yield (%) 82 49 18
a
9.0 4.5 1.4
eeb (%)
Abs. config.c
85 42 13
(S) (S) (S)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
the title addition reaction in terms of chemical yield and enantioselectivity.
OH OH N
N
Trt
Trt
3. Conclusions The chiral aziridine alcohols of type 1 and aziridine ethers of type 2 were found to be highly effective catalysts for the enantioselective conjugate Michael addition of diethylzinc to enones (chalcone and 2-cyclohexen-1-one, respectively). It should be noted that each enantiomer of the designed product should be available by the use of various isomers of ligands 1 and 2.
1f
1e
Figure 2. Aziridine alcohols 1e and 1f for the asymmetric addition of Et2Zn to enones.
From Table 4 it can be seen that the aromatic ether subunit to an aliphatic one led to a decrease in the chemical yields and enantiomeric excess values (Table 4, entry 1). The use of ligand 2e containing an aromatic ether moiety with an electron donating group gave better results (entry 2) in comparison with non-substituted catalyst 2b. Finally, the application of aromatic ether ligand 2f bearing an electron withdrawing group located in the phenyl ring gave the desired adducts 4 and 6 with lower values of chemical yields and ee’s (entry 3) compared with non-substituted ligand 2b. This may suggest that enhancement of electron density on the oxygen atom and thus the complexing properties improves
4. Experimental 4.1. General Unless otherwise specified, all reagents were purchased from commercial suppliers and used without further purification. Toluene was distilled from sodium benzophenone ketyl radical. 1 H NMR spectra were recorded on a Bruker instrument at 600 MHz with CDCl3 as the solvent and relative to TMS as internal
Table 3 Screening of aziridine alcohols 1e and 1f Entry
Ligand
Product 4 Yield (%)
1 2 a b c
1e 1f
82 94
Product 6
[a]Da
eeb (%)
Abs. config.
2.0 +2.4
78 91
(R) (S)
Yield (%) 80 92
[a]Da
eeb (%)
Abs. config.c
8.6 +9.9
81 93
(S) (R)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
Pr i
Pri
H
O
N O
Pri
H O
N
H
N
Cl 2e
2d
2f
Figure 3. Aziridine ethers for enantioselective Michael addition of Et2Zn to enones.
Table 4 Screening of various aziridine ether ligands Entry
Ligand
Product 4 Yield (%)
1 2 3 a b c
2d 2e 2f
70 94 85
[a]Da 1.9 2.4 2.0
Product 6
eeb (%)
Abs. config.
72 92 80
(R) (R) (R)
Yield (%) 69 93 76
[a]Da 8.0 10.1 8.6
eeb (%)
Abs. config.c
75 95 81
(S) (S) (S)
In chloroform (c 1). Determined using chiral HPLC. According to literature data.25
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4
standard. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter with a sodium lamp at room temperature (c 1). 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 (254 nm) or using iodine vapor. The enantiomeric excess (ee) values were determined by chiral HPLC (Knauer, Chiralcel AS). Aziridines a–c were prepared according to the literature.26 Chiral ligands 1a–f and 2a–f were synthesized using the protocols previously described.11,12 4.2. Aziridine ethers 2d–f Aziridines 2d–f were synthesized according to literature.12 4.2.1. (R)-( )-1-(2-Benzyloxyethyl)-2-(propan-2-yl)aziridine 2d Colorless oil; [a]rt 0.4 (c 1, CHCl3); 1H NMR (CDCl3): d = 0.94 D = (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H), 1.21–1.25 (m, 2H), 1.27 (d, J = 6.0 Hz, 1H), 1.60 (d, J = 3.5 Hz, 1H), 2.35 (dt, J = 6.0, 12.0 Hz, 1H), 2.64 (dt, J = 6.0, 12.0 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 4.57 (s, 2H), 7.29–7.39 (m, 5H); 13C NMR (CDCl3): d = 19.6 (CH3), 20.5 (CH3), 31.8 (CHaz), 32.9 (CH2az), 46.6 (CHaz), 60.7 (CH2), 70.2 (CH2), 73.3 (CH2), 127.5 (Car), 127.6 (Car), 127.8 (Car), 128.3 (Car), 128.4 (Car), 138.4 (Cq ar); MS (CI): m/z 220 (M+H); HRMS (CI): calcd for C14H21NO: 219.0121; found: 219.0125. 4.2.2. (R)-( )-1-(2-(4-tert-Butyl)phenoxyethyl)-2-(propan-2-yl)aziridine 2e Colorless oil; [a]rt 0.86 (c 1, CHCl3); 1H NMR (CDCl3): d = 0.97 D = (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.22–1.28 (m, 2H), 1.33 (s, 9H), 1.35 (d, J = 6.0 Hz, 1H), 1.65 (d, J = 3.3 Hz, 1H), 2.45 (dt, J = 6.0, 12.0 Hz, 1H), 2.88 (dt, J = 6.0, 12.0 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 6.87–6.90 (m, 2H); 7.31–7.33 (m, 2H); 13C NMR (CDCl3): d = 19.7 (CH3), 20.6 (CH3), 31.5 (3CH3), 31.7 (CHaz), 32.8 (CH2az), 34.0 (Cq), 46.8 (CHaz), 60.1 (CH2), 67.6 (CH2), 113.2 (2Car), 126.2 (2Car), 143.3 (Cq ar), 156.6 (Cq ar); MS (CI): m/z 262 (M+H); HRMS (CI): calcd for C17H27NO: 261.2715; found: 261.2713. 4.2.3. (R)-( )-1-(2-(4-Chloro)phenoxyethyl)-2-(propan-2-yl)aziridine 2f 1 Colorless oil; [a]rt D = +5.4 (c 1, CHCl3); H NMR (CDCl3): d = 0.91 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.23–1.29 (m, 2H), 1.35 (d, J = 6.0 Hz, 1H), 1.65 (d, J = 3.2 Hz, 1H), 2.46 (dt, J = 5.5, 11.5 Hz, 1H), 2.87 (dt, J = 5.5, 11.5 Hz, 1H), 4.12 (t, J = 5.5 Hz, 2H), 6.86– 6.90 (m, 2H); 7.24–7.30 (m, 2H); 13C NMR (CDCl3): d = 19.6 (CH3), 20.6 (CH3), 31.7 (CHaz), 32.9 (CH2az), 46.7 (CHaz), 59.8 (CH2), 67.9 (CH2), 116.0 (2Car), 129.3 (2Car), 155.9 (Cq ar), 167.4 (Cq ar); MS (CI): m/z 240.5 (M+H); HRMS (CI): calcd for C13H18ClNO: 239.5237; found: 239.5240. 4.3. General protocol for the conjugate Michael addition of diethylzinc to a,b-unsaturated enones using chiral ligands 1a–f, 2a–f and metal component A solution of metal component (0.07 mmol) and chiral ligand 1a–f or 2a–f (0.11 mmol) in 5 mL of freshly distilled toluene was stirred under a nitrogen atmosphere at room temperature for 1 h. After this time, the corresponding enone substrate (1 mmol) was added, the mixture was cooled to 20 °C and a solution of diethylzinc in hexane (1.0 M) (1.65 mL, 1.65 mmol) was added. The mixture was stirred at 20 °C for 1 h and at room temperature
overnight. After complete conversion (TLC), the reaction mixture was poured into 20 mL of 1 M HCl and extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Filtration and evaporation yielded the crude products 4 and 6. After purification via column chromatography on silica gel using hexane and ethyl acetate in gradient as an eluent, pure products 4 and 6 were obtained. Chemical yields, enantiomeric excesses (determined by chiral HPLC) and specific rotations values are shown in Tables 1–4. 4.3.1. (R)-( )-1,3-Diphenyl-pentan-1-one 4 Colorless solid; 1H NMR (CDCl3): d = 0.75 (t, J = 7.3 Hz, 3H), 1.56–1.60 (m, 1H), 1.71–1.74 (m, 1H), 3.16–3.22 (m, 3H), 7.10– 7.34 (m, 5H), 7.35–7.38 (m, 2H), 7.44–7.47 (m, 1H), 7.82–7.83 (m, 2H). Other spectroscopic data of compound 4 are in agreement with the literature.25 4.3.2. (S)-( )-3-Ethylcyclohexanone 6 Colorless liquid; 1H NMR (CDCl3): d = 0.93 (t, J = 7.2 Hz, 3H), 1.28–1.41 (m, 3H), 1.67–1.74 (m, 2H), 1.94–2.39 (m, 6H). Other spectroscopic data of compound 6 are in agreement with the literature.25 Acknowledgement Financial support by the National Science Centre, Poland (NCN), Grant no. 2012/05/D/ST5/00505 for M.R., is gratefully acknowledged. References 1. Ojima, I. Catalytic Asymmetric Synthesis; John Wiley & Sons, 2010. 3rd ed. 2. Christmann, M.; Bräse, S. Asymmetric Synthesis II: More Methods and Applications; Wiley-VCH, 2012. 3. Gawley, R. E.; Aubé, J. Principles of Asymmetric Synthesis, 2nd ed.; Elsevier: Amsterdam, 2012. 4. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69. 5. Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196. 6. Pellissier, H. Tetrahedron 2007, 63, 9267–9331. 7. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824. 8. Łowicki, D.; Bas´, S.; Młynarski, J. Tetrahedron 2015, 71, 1339–1394. 9. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2010, 21, 1890–1892. 10. Rachwalski, M.; Jarzyn´ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 1117–1119. 11. Jarzyn´ski, S.; Les´niak, S.; Pieczonka, A. M.; Rachwalski, M. Tetrahedron: Asymmetry 2015, 26, 35–40. 12. Pieczonka, A. M.; Les´niak, S.; Jarzyn´ski, S.; Rachwalski, M. Tetrahedron: Asymmetry 2015, 26, 148–151. 13. Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y. Tetrahedron: Asymmetry 1995, 6, 2109–2112. 14. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673–1679. 15. Shi, M.; Jiang, J.-K.; Feng, Y.-S. Tetrahedron: Asymmetry 2000, 11, 4923–4933. 16. Liu, Y.; Da, C.-S.; Yu, S.-L.; Yin, X.-G.; Wang, J.-R.; Fan, X.-Y.; Li, W.-P.; Wang, R. J. Org. Chem. 2010, 75, 6869–6878. 17. Rachwalski, M.; Vermue, N.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2013, 42, 9268– 9282. 18. Rachwalski, M.; Jarzyn´ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 421– 425. 19. Rachwalski, M.; Leenders, T.; Kaczmarczyk, S.; Kiełbasin´ski, P.; Les´niak, S.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2013, 11, 4207–4213. 20. Rachwalski, M.; Kaczmarczyk, S.; Les´niak, S.; Kiełbasin´ski, P. ChemCatChem 2014, 6, 873–875. 21. Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219–223. 22. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878. 23. de Vries, A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron: Asymmetry 1997, 9, 1467–1473. 24. Kang, J.; Lee, J. H.; Lim, D. S. Tetrahedron: Asymmetry 2003, 14, 305–315. 25. Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153–4155. 26. Xu, J. Tetrahedron: Asymmetry 2002, 13, 1129–1134.
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