DOI: 10.1002/chem.201405847
Communication
& Synthetic Methods
Asymmetric anti-Selective Michael Reaction of Imidazole-Modified Ketones with trans-b-Nitroalkenes Dongxu Yang,[a, b] Linqing Wang,[b] Dan Li,[b] Fengxia Han,[b] Depeng Zhao,[a] and Rui Wang*[a, b] through enolate chemistry. To date, the site selectivity for the a-alkylation of linear ketones with nitroalkenes is not realized. On the other hand, there are few reports of anti-selective catalytic asymmetric reactions of simple ketones with nitroalkenes;[4] a successful example has been realized by Jacobsen and co-workers by employing a bifunctional primary-amine catalyst.[5] The Zhao group reported an ionic catalyst for the asymmetric reaction of ketones to nitroalkenes with only one successful example of an anti-selective adduct.[6] Other strategies, such as ketones equipped with an a-hydroxyl functionality, are prone to form anti-adducts.[7] Therefore, the development of complementary asymmetric anti-selective reactions between ketones and nitroalkenes is still highly desirable. Herein, we describe the successful application of imidazolemodified ketones[8] in asymmetric anti-selective Michael reactions with trans-b-nitroalkenes. The corresponding conjugate adducts are to be subjected to further transformations with Grignard reagents to solve the a/a’-site-selective problem of simple ketones. Additionally, the anti-selective adduct can be turned to the syn-selective product by treatment with a simple base. Thus, the site-specific products for both diastereomers can be obtained by using our strategy (Figure 2).
Abstract: The successful application of imidazole-modified ketones in asymmetric anti-selective Michael reactions with trans-b-nitroalkenes is presented by employing a newly developed 3-bromothiophene-modified chiral diamine ligand. The corresponding conjugate adduct was submitted to further transformations with Grignard reagents to solve the problem of a-site selectivity of simple linear ketones. Additionally, the syn-selective product was obtained by treating the anti-selective adduct with a simple base. In this way, the site-specific products for both diastereomers in the asymmetric conjugate addition of simple ketones to nitroalkenes can be obtained.
The direct asymmetric conjugate addition of ketones to nitroalkenes represents a fundamental methodology and particularly attractive approach to obtain optically active bifunctional products. Tremendous efforts have been devoted to realize the asymmetric version of this fundamental reaction and there are over 300 published papers documented in this research area.[1] At the same time, the Michael addition of ketones to b-nitroalkenes constitutes a classic template reaction in developing and testing various types of chiral catalysts in recent years.[2] However, for such a well-studied model reaction, there are still obvious unresolved problems, especially when simple linear ketones act as nucleophiles: as shown in Figure 1, the regioselectivity for linear ketones[3] is hard to control because both the a- and a’-position of the carbonyl group can be activated
Figure 2. The application of imidazole-modified ketones in asymmetric antiselective Michael reactions with trans-b-nitroalkenes and further transformations with Grignard reagents.
We began the initial optimization study by evaluating a diamine/Ni(OAc)2 catalyst[9] prepared from L1 and Ni(OAc)2 in a 1:1 ratio in the Michael reaction of N-methylimidazole-modified ketone 1 a and nitroalkene 2 a (Table 1). The reaction proceeded smoothly and furnished the desired anti-selective product (full conversion, > 20:1 d.r.), but with low enantioselectivity (Table 1, entry 1). N-phenylimidazole-modified ketone 1 aa proved to be a more promising candidate in the conjugate reaction, leading to 76 % ee without losing reactivity and diastereoselectivity (entry 2). To improve the enantioselectivity, we optimized the reaction conditions by screening chiral diamine ligands (Scheme 1). Ordinary modifications on the phenyl
Figure 1. Unresolved challenges in the asymmetric conjugate addition of simple linear ketones to nitroalkenes.
[a] D. Yang, Dr. D. Zhao, Prof. Dr. R. Wang School of Pharmaceutical Sciences, Sun Yat-sen University Guangzhou, 510006 (P.R. China) E-mail: [email protected] [b] D. Yang, L. Wang, D. Li, F. Han, Prof. Dr. R. Wang Key Laboratory of Preclinical Study for New Drugs of Gansu Province Lanzhou University, Lanzhou, 730000 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405847. Chem. Eur. J. 2014, 20, 1 – 6
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Communication Table 1. Optimization studies of the anti-selective conjugate reaction.[a]
Entry [c]
1 2 3 4 5 6 7 8 9
L
ee [%][b]
Entry
L
ee [%][b]
L1 L1 L2 L3 L4 L5 L6 L7 L8
31 76 75 83 81 84 87 81 87
10 11 12[d] 13[e] 14[f] 15[f, g] 16[f, g] 17[f, g, h] 18[f, g, h]
L9 L10 L10 L10 L10 L10 L10 (5 %) L10 (1 %) L10 (0.5 %)
85 94 85 80 95 97 95 92 92
[a] Reactions were performed with imidazole-modified ketone (0.10 mmol) and nitroalkene (0.11 mmol) in solvent (0.4 mL) in the presence of L/Ni (10 mol %). All reactions were carried out at RT for 18 h. [b] The ee values were analyzed by chiral stationary-phase HPLC. [c] Performed with 1 a. [d] Reaction in iPrOH. [e] Reaction in CH2Cl2. [f] Reaction in dioxane. [g] 4 MS (100 mg) was added. [h] TEA (20 mol %) was added.
Scheme 1. Development and screening of chiral diamine ligands. Scheme 2. Substrate scope of the anti-selective conjugate reaction. Reactions were performed with imidazole-modified ketones (0.10 mmol) and nitroalkenes (0.11 mmol) in solvents (0.4 mL) in the presence of L10/Ni (10 mol %) and 4 MS (100 mg) at RT for 24 h. Yields of isolated product are given. Diastereomeric ratios were determined by 1H NMR spectroscopy (300 MHz) of the crude mixture. The ee values were analyzed by chiral stationary-phase HPLC. [a] Reaction performed for 72 h. [b] Reaction performed for 48 h. [c] Triethylamine (TEA; 20 mol %) was added.
group of the diamine (L) only slightly enhanced the enantioselectivity (entries 3–5). Then, we synthesized a series of heterocycle- and halogenated-heterocycle-modified diamine ligands to improve the results based on our previous work in introducing these substituents in chiral ligands (Scheme 1, L5–L10, entries 6–11).[10] To our delight, the best selectivity was achieved by using ligand L10 with a 3-bromothiophene-modified diamine unit (entry 11, 94 % ee). Changing the solvent from THF to CH2Cl2 and iPrOH gave less satisfactory results (entries 12 and 13). Using dioxane improved the result and the addition of molecular sieves further enhanced the enantioselectivity (entries 14 and 15, 95 and 97 % ee). Additionally, the reaction also proceeded smoothly with 0.5 mol % catalyst with the assistance of 20 mol % triethylamine, which resulted in a lower enantioselectivity (entries 16–18, 92 % ee). The substrate generality of the anti-selective conjugate reaction[11] of N-phenylimidazole-modified ketones with b-nitroalkenes was investigated under the optimized conditions. As &
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shown in Scheme 2, a series of representative substrates were tested. With a b-naphthyl-substituted nitroalkene, excellent yield, diastereo-, and enantioselectivity could be obtained (3 b). An electron-donating group was tolerable, while retaining the high efficiency and enantioselectivity (3 c). With heterocyclic substrates, such as furanaldehyde- and thenaldehyde-derived nitroalkenes, the corresponding products were obtained in excellent yields and ee values (3 d and 3 e), and 2-indolyl nitroalkene required a longer reaction time and resulted in a lower ee value (3 f). Moreover, b-cinnamyl and b-tiglic nitroalkenes were also good substrates with respect to the chemical yield, 2
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Communication diastereo-, and enantioselectivity (3 g and 3 h). Finally, when applying the optimized conditions to some representative aliphatic substrates, excellent yields and good ee values were obtained, while the reaction of isopropyl nitroalkene needed compensatory addition of 20 mol % Et3N (3 I, 3 j, and 3 k). Next, the scope of N-phenylimidazole-modified ketones was investigated under the optimized conditions. Different linear aliphatic substituents were tolerable in the reaction and lead to the anti-selective conjugate adducts in high yields and excellent diastereo- and enantioselectivities (Scheme 2, 3 l, 3 m, 3 n, and 3 o). When the same conditions were applied to an isopropyl-substituted ketone, a lower diastereo- and enantioselectivity was obtained (3 p). A phenyl-substituted ketone was also subjected to the conjugate reaction and the product was obtained in good yield (85 %) but with low enantioselectivity (3 q, 33 %). Considering the value of the practical application of the current anti-selective conjugate reaction of N-phenylimidazolemodified ketones with b-nitroalkenes, we performed the reaction on a larger scale with a lower catalyst loading (0.5 mol %, 3.2 mg for 1.0 mmol scale) with the assistance of 20 mol % Et3N (Scheme 3). The reactions proceeded smoothly under the current conditions and, to our delight, the pure products could
be easily obtained in good yields and excellent diastereo- and enantioselectivities with only one filtration step,[12] which is a more concise and practical method for the separation of the products without the use of column chromatography. Furthermore, in light of previous reports indicating that synselective adducts are prone to be generated in conjugate reactions of simple ketones with nitroalkenes, we speculated that in the present transformation the syn-selective products might also be more stable under thermodynamic conditions. Therefore, we believe that the syn-selective products could be generated through enolation and protonation by treating the corresponding anti-selective adducts with an appropriate base. After an initial screening, MeONa and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proved to be relatively effective reagents in promoting the reverse process of diastereoselectivity, while other bases, such as Et3N, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, and K2CO3, were not very effective in this reaction (Table 2). To our delight, the syn-selective product 3 a
Table 2. Reversal process of diastereoselectivity.[a]
Base [b]
d.r.
Et3N 0:1
DABCO 1:11
tBuOK –
[c]
MeONa
K2CO3
DBU
1:1.6
1:7.5
2.4:1 (64 %)[d]
[a] Reactions were performed with anti-3 a (0. 20 mmol) in THF (1.0 mL) in the presence of a corresponding base (0.60 mmol, 3.0 equiv) at 40 8C for 24 h. [b] Diastereomeric ratios were determined by 1H NMR spectroscopy (300 MHz) of the crude mixture. [c] Results of decomposition. [d] Yield of the pure product syn-3 a; other unseparated mixtures and anti-3 a were recovered together (31 %).
could be easily separated by column chromatography, which might be owing to the strong polarity contributed by the imidazole group. The syn-selective adduct 3 a was obtained in 64 % yield with a slight decrease in enantioselectivity (95 % ee), and other unseparated mixtures of 3 a were recovered in 31 % yield. In this way, both the syn- and anti-selective products of the conjugate reaction of N-phenylimidazole-modified ketones with b-nitroalkenes could be obtained by employing our aforementioned method. The next stage of our studies was to implement our initial plan of solving the a/a’-site-specific selectivity problem by incorporating Grignard reagents into the corresponding products. As shown in Scheme 4, the right combination of different N-phenylimidazole-modified ketones and Grignard reagents led to the desired products with site-specific selectivity.[13] For example, the difficulty of the a/a’-site-selective reaction of 3-hexanone could be overcome by using our strategy, and both of the corresponding diastereomers could be obtained in three steps with excellent enantioselectivities but in lower yields (Scheme 4 a). The discrimination of a propyl and butyl group was also attempted by employing our strategy, which resulted in the formation of 5 in 24 % yield in two
Scheme 3. Practical process without column chromatography. Reactions were performed with imidazole-modified ketones (1.0 equiv) and nitroalkenes (1.05 equiv) in THF (0.5 m, 0.5 mmol mL 1) in the presence of L10/Ni (0.5 mol %) and Et3N (20 mol %) at RT for 24 h. Then, the reaction was cooled to 0 8C and cold petroleum ether was added under stirring or ultrasound conditions, and the products precipitated as white solids. Chem. Eur. J. 2014, 20, 1 – 6
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Communication mothiophene-derived chiral diamine ligand. The conjugate adducts were successfully applied to solve the regio- and diastereoselectivity problem of simple linear ketones. Additionally, the adducts could be further transformed into chiral esters with excellent enantioselectivity, which could act as important precursors of various types of pyrrolidines. Further applications of other types of N-phenylimidazole-modified ketones in asymmetric synthesis are currently underway.
Acknowledgements This work was supported by NSFC (21432003, 81473095, 21202071); National S&T Major Project of China (2012ZX09504001-003). Keywords: diamines · diastereoselectivity · ligand design · linear ketones · site selectivity [1] For pioneering works, see: a) B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423; b) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260; c) D. Enders, A. Seki, Synlett 2002, 0026; d) A. Alexakis, O. Andrey, Org. Lett. 2002, 4, 3611. [2] For selected examples, see: a) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw, S. V. Ley, Chem. Commun. 2004, 1808; b) T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem. Soc. 2004, 126, 9558; c) P. Kotrusz, S. Toma, H.-G. Schmalz, A. Adler, Eur. J. Org. Chem. 2004, 1577; d) W. Wang, J. Wang, H. Li, Angew. Chem. Int. Ed. 2005, 44, 1369; Angew. Chem. 2005, 117, 1393; e) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 4966; f) S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu, J. Cheng, Angew. Chem. Int. Ed. 2006, 45, 3093; Angew. Chem. 2006, 118, 3165; g) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901; h) Y.-M. Xu, A. Crdova, Chem. Commun. 2006, 460; i) D. Almas¸i, D. A. Alonso, C. Njera, Tetrahedron: Asymmetry 2006, 17, 2064; j) S. V. Pansare, K. Pandya, J. Am. Chem. Soc. 2006, 128, 9624; k) X. Jiang, Y. Zhang, A. S. C. Chan, R. Wang, Org. Lett. 2009, 11, 153; l) Y.-F. Ting, C. Chang, R. Reddy, D. Magar, K. Chen, Chem. Eur. J. 2010, 16, 7030; m) A. Lu, T. Liu, R. Wu, Y. Wang, G. Wu, Z. Zhou, J. Fang, C. Tang, J. Org. Chem. 2011, 76, 3872. [3] For our previous work on a/g-site specific selective reactions of linear ketones, see: a) D. Yang, L. Wang, F. Han, D. Zhao, R. Wang, Chem. Eur. J. 2014, 20, 8584; b) D. Yang, L. Wang, F. Han, D. Zhao, B. Zhang, R. Wang, Angew. Chem. Int. Ed. 2013, 52, 6739; Angew. Chem. 2013, 125, 6871. [4] Other anti-selective catalytic asymmetric reactions of carbonyl compounds are usually limited to ketoesters, see: a) W. Raimondi, O. Basl, T. Constantieux, D. Bonne, J. Rodriguez, Adv. Synth. Catal. 2012, 354, 563; b) O. Basl, W. Raimondi, M. Sanchez Duque, D. Bonne, T. Constantieux, J. Rodriguez, Org. Lett. 2010, 12, 5246; c) A. Nakamura, S. Lectard, R. Shiizu, Y. Hamashima, M. Sodeoka, Tetrahedron: Asymmetry 2010, 21, 1682; for a syn-selective asymmetric reaction of ketoanilides, see: d) Y. Xu, S. Matsunaga, M. Shibasaki, Org. Lett. 2010, 12, 3246. [5] H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170. [6] T. Mandal, C. G. Zhao, Angew. Chem. Int. Ed. 2008, 47, 7714; Angew. Chem. 2008, 120, 7828. [7] a) O. Andrey, A. Alexakis, G. Bernardinelli, Org. Lett. 2003, 5, 2559; b) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003; c) S. Moss, A. Alexakis, Org. Lett. 2006, 8, 3577. [8] For selected examples of imidazole-modified ketones in asymmetric reactions, see: a) D. A. Evans, K. R. Fandrick, H. J. Song, J. Am. Chem. Soc. 2005, 127, 8942; b) D. Coquire, B. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2007, 46, 9308; Angew. Chem. 2007, 119, 9468; c) A. J. Boersma, B. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2009, 48, 3346; Angew. Chem. 2009, 121, 3396; d) X.-Y. Guan, L.-P. Yang, W.-H. Hu, Angew. Chem. Int. Ed. 2010, 49, 2190; Angew. Chem. 2010, 122, 2236; e) A. J. Boersma, D. Coquire, D. Geerdink, F. Rosati, B. L. Feringa, G. Roelfes, Nat. Chem. 2010, 2, 991; f) X. Xu, W.-H. Hu, M. P. Doyle, Angew. Chem. Int. Ed. 2011,
Scheme 4. Strategy to solve site-specific and diastereoselective problems. Details of the experiments are summarized in the Supporting Information.
steps with excellent enantioselectivity (Scheme 4 b). A benzylic Grignard reagent was also incorporated into the reaction to discriminate between a phenyl and a methyl or ethyl group, resulting in slightly lower ee values (Scheme 4 c). Finally, the conjugate adduct could be further transformed into esters by treatment with corresponding alcohols. As shown in Scheme 5, esters 7 a and 7 b could be obtained in high yields and excellent enantioselectivities. The diastereomer 7 c could be accessed in two steps with moderate yield and high enantioselectivity. Importantly, the syn-selective isomer deriving from the conjugate adduct can serve as a useful precursor to construct various types of pyrrolidines (8 a–d), as has been reported previously.14] In summary, a highly enantioselective conjugate reaction between N-phenylimidazole-modified ketones and b-nitroalkenes has been described by employing a newly developed 3-bro-
Scheme 5. Straightforward transformations of adduct 3 a to important pyrrolidine precursors.
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Communication 50, 6392; Angew. Chem. 2011, 123, 6516; g) E. L. Tyson, E. P. Farney, T. P. Yoon, Org. Lett. 2012, 14, 1110; h) M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134, 11896; i) J. Wang, E. Benedetti, L. Bethge, S. Vonhoff, S. Klussmann, J. J. Vasseur, J. Cossy, M. Smietana, S. Arseniyadis, Angew. Chem. Int. Ed. 2013, 52, 11546; Angew. Chem. 2013, 125, 11760; j) B. M. Trost, K. Lehr, D. J. Michaelis, J. Xu, A. K. Buckl, J. Am. Chem. Soc. 2010, 132, 8915; k) B. M. Trost, T. M. Lam, J. Am. Chem. Soc. 2012, 134, 11319; l) M. B. Andrus, M. A. Christiansen, E. J. Hicken, M. J. Gainer, D. K. Bedke, K. C. Harper, S. R. Mikkelson, D. S. Dodson, D. T. Harris, Org. Lett. 2007, 9, 4865; m) M. A. Christiansen, M. B. Andrus, Tetrahedron Lett. 2012, 53, 4805. [9] For selected examples of utilizing benzylated diaminocyclohexane– Ni(OAc)2 catalyst in asymmetric reactions, see: a) H. Zhang, L. Hong, H. Kang, R. Wang, J. Am. Chem. Soc. 2013, 135, 14098; b) W. Li, X. Liu, Z. Mao, Q. Chen, R. Wang, Org. Biomol. Chem. 2012, 10, 4767; c) Q.-H. Deng, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2011, 17, 14922; d) A. Nakamura, S. Lectard, D. Hashizume, Y. Hamashima, M. Sodeoka, J. Am. Chem. Soc. 2010, 132, 4036.
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[10] a) D. Zhao, L. Wang, D. Yang, Y. Zhang, R. Wang, Angew. Chem. Int. Ed. 2012, 51, 7523; Angew. Chem. 2012, 124, 7641; b) D. Zhao, L. Mao, D. Yang, R. Wang, J. Org. Chem. 2010, 75, 6756; see also ref. [3]. [11] CCDC 1025306 (anti-3 a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [12] Details of the separation process are included in the Supporting Information. [13] See the Supporting Information for the detailed procedure. [14] T. A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtius, P. Beak, J. Am. Chem. Soc. 2002, 124, 11689.
Received: October 28, 2014 Published online on && &&, 0000
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Communication
COMMUNICATION & Synthetic Methods
Site-selectivity: A successful strategy was designed to solve the a/a’-regioselectivity problem in Michael reactions of simple ketones with nitroalkenes (see scheme). anti-Selective conjugate adducts were obtained in the reaction of phenylimidazole-modified ketones and nitroalkenes by employing a newly developed 3-bromothiophene-modified chiral diamine ligand.
D. Yang, L. Wang, D. Li, F. Han, D. Zhao, R. Wang* && – && Asymmetric anti-Selective Michael Reaction of Imidazole-Modified Ketones with trans-b-Nitroalkenes
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Communication
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Asymmetric anti-Selective Michael Reaction of Imidazole-Modified Ketones with trans-b-Nitroalkenes Dongxu Yang,[a, b] Linqing Wang,[b] Dan Li,[b] Fengxia Han,[b] Depeng Zhao,[a] and Rui Wang*[a, b] through enolate chemistry. To date, the site selectivity for the a-alkylation of linear ketones with nitroalkenes is not realized. On the other hand, there are few reports of anti-selective catalytic asymmetric reactions of simple ketones with nitroalkenes;[4] a successful example has been realized by Jacobsen and co-workers by employing a bifunctional primary-amine catalyst.[5] The Zhao group reported an ionic catalyst for the asymmetric reaction of ketones to nitroalkenes with only one successful example of an anti-selective adduct.[6] Other strategies, such as ketones equipped with an a-hydroxyl functionality, are prone to form anti-adducts.[7] Therefore, the development of complementary asymmetric anti-selective reactions between ketones and nitroalkenes is still highly desirable. Herein, we describe the successful application of imidazolemodified ketones[8] in asymmetric anti-selective Michael reactions with trans-b-nitroalkenes. The corresponding conjugate adducts are to be subjected to further transformations with Grignard reagents to solve the a/a’-site-selective problem of simple ketones. Additionally, the anti-selective adduct can be turned to the syn-selective product by treatment with a simple base. Thus, the site-specific products for both diastereomers can be obtained by using our strategy (Figure 2).
Abstract: The successful application of imidazole-modified ketones in asymmetric anti-selective Michael reactions with trans-b-nitroalkenes is presented by employing a newly developed 3-bromothiophene-modified chiral diamine ligand. The corresponding conjugate adduct was submitted to further transformations with Grignard reagents to solve the problem of a-site selectivity of simple linear ketones. Additionally, the syn-selective product was obtained by treating the anti-selective adduct with a simple base. In this way, the site-specific products for both diastereomers in the asymmetric conjugate addition of simple ketones to nitroalkenes can be obtained.
The direct asymmetric conjugate addition of ketones to nitroalkenes represents a fundamental methodology and particularly attractive approach to obtain optically active bifunctional products. Tremendous efforts have been devoted to realize the asymmetric version of this fundamental reaction and there are over 300 published papers documented in this research area.[1] At the same time, the Michael addition of ketones to b-nitroalkenes constitutes a classic template reaction in developing and testing various types of chiral catalysts in recent years.[2] However, for such a well-studied model reaction, there are still obvious unresolved problems, especially when simple linear ketones act as nucleophiles: as shown in Figure 1, the regioselectivity for linear ketones[3] is hard to control because both the a- and a’-position of the carbonyl group can be activated
Figure 2. The application of imidazole-modified ketones in asymmetric antiselective Michael reactions with trans-b-nitroalkenes and further transformations with Grignard reagents.
We began the initial optimization study by evaluating a diamine/Ni(OAc)2 catalyst[9] prepared from L1 and Ni(OAc)2 in a 1:1 ratio in the Michael reaction of N-methylimidazole-modified ketone 1 a and nitroalkene 2 a (Table 1). The reaction proceeded smoothly and furnished the desired anti-selective product (full conversion, > 20:1 d.r.), but with low enantioselectivity (Table 1, entry 1). N-phenylimidazole-modified ketone 1 aa proved to be a more promising candidate in the conjugate reaction, leading to 76 % ee without losing reactivity and diastereoselectivity (entry 2). To improve the enantioselectivity, we optimized the reaction conditions by screening chiral diamine ligands (Scheme 1). Ordinary modifications on the phenyl
Figure 1. Unresolved challenges in the asymmetric conjugate addition of simple linear ketones to nitroalkenes.
[a] D. Yang, Dr. D. Zhao, Prof. Dr. R. Wang School of Pharmaceutical Sciences, Sun Yat-sen University Guangzhou, 510006 (P.R. China) E-mail: [email protected] [b] D. Yang, L. Wang, D. Li, F. Han, Prof. Dr. R. Wang Key Laboratory of Preclinical Study for New Drugs of Gansu Province Lanzhou University, Lanzhou, 730000 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405847. Chem. Eur. J. 2014, 20, 1 – 6
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Communication Table 1. Optimization studies of the anti-selective conjugate reaction.[a]
Entry [c]
1 2 3 4 5 6 7 8 9
L
ee [%][b]
Entry
L
ee [%][b]
L1 L1 L2 L3 L4 L5 L6 L7 L8
31 76 75 83 81 84 87 81 87
10 11 12[d] 13[e] 14[f] 15[f, g] 16[f, g] 17[f, g, h] 18[f, g, h]
L9 L10 L10 L10 L10 L10 L10 (5 %) L10 (1 %) L10 (0.5 %)
85 94 85 80 95 97 95 92 92
[a] Reactions were performed with imidazole-modified ketone (0.10 mmol) and nitroalkene (0.11 mmol) in solvent (0.4 mL) in the presence of L/Ni (10 mol %). All reactions were carried out at RT for 18 h. [b] The ee values were analyzed by chiral stationary-phase HPLC. [c] Performed with 1 a. [d] Reaction in iPrOH. [e] Reaction in CH2Cl2. [f] Reaction in dioxane. [g] 4 MS (100 mg) was added. [h] TEA (20 mol %) was added.
Scheme 1. Development and screening of chiral diamine ligands. Scheme 2. Substrate scope of the anti-selective conjugate reaction. Reactions were performed with imidazole-modified ketones (0.10 mmol) and nitroalkenes (0.11 mmol) in solvents (0.4 mL) in the presence of L10/Ni (10 mol %) and 4 MS (100 mg) at RT for 24 h. Yields of isolated product are given. Diastereomeric ratios were determined by 1H NMR spectroscopy (300 MHz) of the crude mixture. The ee values were analyzed by chiral stationary-phase HPLC. [a] Reaction performed for 72 h. [b] Reaction performed for 48 h. [c] Triethylamine (TEA; 20 mol %) was added.
group of the diamine (L) only slightly enhanced the enantioselectivity (entries 3–5). Then, we synthesized a series of heterocycle- and halogenated-heterocycle-modified diamine ligands to improve the results based on our previous work in introducing these substituents in chiral ligands (Scheme 1, L5–L10, entries 6–11).[10] To our delight, the best selectivity was achieved by using ligand L10 with a 3-bromothiophene-modified diamine unit (entry 11, 94 % ee). Changing the solvent from THF to CH2Cl2 and iPrOH gave less satisfactory results (entries 12 and 13). Using dioxane improved the result and the addition of molecular sieves further enhanced the enantioselectivity (entries 14 and 15, 95 and 97 % ee). Additionally, the reaction also proceeded smoothly with 0.5 mol % catalyst with the assistance of 20 mol % triethylamine, which resulted in a lower enantioselectivity (entries 16–18, 92 % ee). The substrate generality of the anti-selective conjugate reaction[11] of N-phenylimidazole-modified ketones with b-nitroalkenes was investigated under the optimized conditions. As &
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shown in Scheme 2, a series of representative substrates were tested. With a b-naphthyl-substituted nitroalkene, excellent yield, diastereo-, and enantioselectivity could be obtained (3 b). An electron-donating group was tolerable, while retaining the high efficiency and enantioselectivity (3 c). With heterocyclic substrates, such as furanaldehyde- and thenaldehyde-derived nitroalkenes, the corresponding products were obtained in excellent yields and ee values (3 d and 3 e), and 2-indolyl nitroalkene required a longer reaction time and resulted in a lower ee value (3 f). Moreover, b-cinnamyl and b-tiglic nitroalkenes were also good substrates with respect to the chemical yield, 2
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Communication diastereo-, and enantioselectivity (3 g and 3 h). Finally, when applying the optimized conditions to some representative aliphatic substrates, excellent yields and good ee values were obtained, while the reaction of isopropyl nitroalkene needed compensatory addition of 20 mol % Et3N (3 I, 3 j, and 3 k). Next, the scope of N-phenylimidazole-modified ketones was investigated under the optimized conditions. Different linear aliphatic substituents were tolerable in the reaction and lead to the anti-selective conjugate adducts in high yields and excellent diastereo- and enantioselectivities (Scheme 2, 3 l, 3 m, 3 n, and 3 o). When the same conditions were applied to an isopropyl-substituted ketone, a lower diastereo- and enantioselectivity was obtained (3 p). A phenyl-substituted ketone was also subjected to the conjugate reaction and the product was obtained in good yield (85 %) but with low enantioselectivity (3 q, 33 %). Considering the value of the practical application of the current anti-selective conjugate reaction of N-phenylimidazolemodified ketones with b-nitroalkenes, we performed the reaction on a larger scale with a lower catalyst loading (0.5 mol %, 3.2 mg for 1.0 mmol scale) with the assistance of 20 mol % Et3N (Scheme 3). The reactions proceeded smoothly under the current conditions and, to our delight, the pure products could
be easily obtained in good yields and excellent diastereo- and enantioselectivities with only one filtration step,[12] which is a more concise and practical method for the separation of the products without the use of column chromatography. Furthermore, in light of previous reports indicating that synselective adducts are prone to be generated in conjugate reactions of simple ketones with nitroalkenes, we speculated that in the present transformation the syn-selective products might also be more stable under thermodynamic conditions. Therefore, we believe that the syn-selective products could be generated through enolation and protonation by treating the corresponding anti-selective adducts with an appropriate base. After an initial screening, MeONa and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proved to be relatively effective reagents in promoting the reverse process of diastereoselectivity, while other bases, such as Et3N, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, and K2CO3, were not very effective in this reaction (Table 2). To our delight, the syn-selective product 3 a
Table 2. Reversal process of diastereoselectivity.[a]
Base [b]
d.r.
Et3N 0:1
DABCO 1:11
tBuOK –
[c]
MeONa
K2CO3
DBU
1:1.6
1:7.5
2.4:1 (64 %)[d]
[a] Reactions were performed with anti-3 a (0. 20 mmol) in THF (1.0 mL) in the presence of a corresponding base (0.60 mmol, 3.0 equiv) at 40 8C for 24 h. [b] Diastereomeric ratios were determined by 1H NMR spectroscopy (300 MHz) of the crude mixture. [c] Results of decomposition. [d] Yield of the pure product syn-3 a; other unseparated mixtures and anti-3 a were recovered together (31 %).
could be easily separated by column chromatography, which might be owing to the strong polarity contributed by the imidazole group. The syn-selective adduct 3 a was obtained in 64 % yield with a slight decrease in enantioselectivity (95 % ee), and other unseparated mixtures of 3 a were recovered in 31 % yield. In this way, both the syn- and anti-selective products of the conjugate reaction of N-phenylimidazole-modified ketones with b-nitroalkenes could be obtained by employing our aforementioned method. The next stage of our studies was to implement our initial plan of solving the a/a’-site-specific selectivity problem by incorporating Grignard reagents into the corresponding products. As shown in Scheme 4, the right combination of different N-phenylimidazole-modified ketones and Grignard reagents led to the desired products with site-specific selectivity.[13] For example, the difficulty of the a/a’-site-selective reaction of 3-hexanone could be overcome by using our strategy, and both of the corresponding diastereomers could be obtained in three steps with excellent enantioselectivities but in lower yields (Scheme 4 a). The discrimination of a propyl and butyl group was also attempted by employing our strategy, which resulted in the formation of 5 in 24 % yield in two
Scheme 3. Practical process without column chromatography. Reactions were performed with imidazole-modified ketones (1.0 equiv) and nitroalkenes (1.05 equiv) in THF (0.5 m, 0.5 mmol mL 1) in the presence of L10/Ni (0.5 mol %) and Et3N (20 mol %) at RT for 24 h. Then, the reaction was cooled to 0 8C and cold petroleum ether was added under stirring or ultrasound conditions, and the products precipitated as white solids. Chem. Eur. J. 2014, 20, 1 – 6
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Communication mothiophene-derived chiral diamine ligand. The conjugate adducts were successfully applied to solve the regio- and diastereoselectivity problem of simple linear ketones. Additionally, the adducts could be further transformed into chiral esters with excellent enantioselectivity, which could act as important precursors of various types of pyrrolidines. Further applications of other types of N-phenylimidazole-modified ketones in asymmetric synthesis are currently underway.
Acknowledgements This work was supported by NSFC (21432003, 81473095, 21202071); National S&T Major Project of China (2012ZX09504001-003). Keywords: diamines · diastereoselectivity · ligand design · linear ketones · site selectivity [1] For pioneering works, see: a) B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423; b) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260; c) D. Enders, A. Seki, Synlett 2002, 0026; d) A. Alexakis, O. Andrey, Org. Lett. 2002, 4, 3611. [2] For selected examples, see: a) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw, S. V. Ley, Chem. Commun. 2004, 1808; b) T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem. Soc. 2004, 126, 9558; c) P. Kotrusz, S. Toma, H.-G. Schmalz, A. Adler, Eur. J. Org. Chem. 2004, 1577; d) W. Wang, J. Wang, H. Li, Angew. Chem. Int. Ed. 2005, 44, 1369; Angew. Chem. 2005, 117, 1393; e) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 4966; f) S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu, J. Cheng, Angew. Chem. Int. Ed. 2006, 45, 3093; Angew. Chem. 2006, 118, 3165; g) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901; h) Y.-M. Xu, A. Crdova, Chem. Commun. 2006, 460; i) D. Almas¸i, D. A. Alonso, C. Njera, Tetrahedron: Asymmetry 2006, 17, 2064; j) S. V. Pansare, K. Pandya, J. Am. Chem. Soc. 2006, 128, 9624; k) X. Jiang, Y. Zhang, A. S. C. Chan, R. Wang, Org. Lett. 2009, 11, 153; l) Y.-F. Ting, C. Chang, R. Reddy, D. Magar, K. Chen, Chem. Eur. J. 2010, 16, 7030; m) A. Lu, T. Liu, R. Wu, Y. Wang, G. Wu, Z. Zhou, J. Fang, C. Tang, J. Org. Chem. 2011, 76, 3872. [3] For our previous work on a/g-site specific selective reactions of linear ketones, see: a) D. Yang, L. Wang, F. Han, D. Zhao, R. Wang, Chem. Eur. J. 2014, 20, 8584; b) D. Yang, L. Wang, F. Han, D. Zhao, B. Zhang, R. Wang, Angew. Chem. Int. Ed. 2013, 52, 6739; Angew. Chem. 2013, 125, 6871. [4] Other anti-selective catalytic asymmetric reactions of carbonyl compounds are usually limited to ketoesters, see: a) W. Raimondi, O. Basl, T. Constantieux, D. Bonne, J. Rodriguez, Adv. Synth. Catal. 2012, 354, 563; b) O. Basl, W. Raimondi, M. Sanchez Duque, D. Bonne, T. Constantieux, J. Rodriguez, Org. Lett. 2010, 12, 5246; c) A. Nakamura, S. Lectard, R. Shiizu, Y. Hamashima, M. Sodeoka, Tetrahedron: Asymmetry 2010, 21, 1682; for a syn-selective asymmetric reaction of ketoanilides, see: d) Y. Xu, S. Matsunaga, M. Shibasaki, Org. Lett. 2010, 12, 3246. [5] H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170. [6] T. Mandal, C. G. Zhao, Angew. Chem. Int. Ed. 2008, 47, 7714; Angew. Chem. 2008, 120, 7828. [7] a) O. Andrey, A. Alexakis, G. Bernardinelli, Org. Lett. 2003, 5, 2559; b) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003; c) S. Moss, A. Alexakis, Org. Lett. 2006, 8, 3577. [8] For selected examples of imidazole-modified ketones in asymmetric reactions, see: a) D. A. Evans, K. R. Fandrick, H. J. Song, J. Am. Chem. Soc. 2005, 127, 8942; b) D. Coquire, B. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2007, 46, 9308; Angew. Chem. 2007, 119, 9468; c) A. J. Boersma, B. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2009, 48, 3346; Angew. Chem. 2009, 121, 3396; d) X.-Y. Guan, L.-P. Yang, W.-H. Hu, Angew. Chem. Int. Ed. 2010, 49, 2190; Angew. Chem. 2010, 122, 2236; e) A. J. Boersma, D. Coquire, D. Geerdink, F. Rosati, B. L. Feringa, G. Roelfes, Nat. Chem. 2010, 2, 991; f) X. Xu, W.-H. Hu, M. P. Doyle, Angew. Chem. Int. Ed. 2011,
Scheme 4. Strategy to solve site-specific and diastereoselective problems. Details of the experiments are summarized in the Supporting Information.
steps with excellent enantioselectivity (Scheme 4 b). A benzylic Grignard reagent was also incorporated into the reaction to discriminate between a phenyl and a methyl or ethyl group, resulting in slightly lower ee values (Scheme 4 c). Finally, the conjugate adduct could be further transformed into esters by treatment with corresponding alcohols. As shown in Scheme 5, esters 7 a and 7 b could be obtained in high yields and excellent enantioselectivities. The diastereomer 7 c could be accessed in two steps with moderate yield and high enantioselectivity. Importantly, the syn-selective isomer deriving from the conjugate adduct can serve as a useful precursor to construct various types of pyrrolidines (8 a–d), as has been reported previously.14] In summary, a highly enantioselective conjugate reaction between N-phenylimidazole-modified ketones and b-nitroalkenes has been described by employing a newly developed 3-bro-
Scheme 5. Straightforward transformations of adduct 3 a to important pyrrolidine precursors.
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[10] a) D. Zhao, L. Wang, D. Yang, Y. Zhang, R. Wang, Angew. Chem. Int. Ed. 2012, 51, 7523; Angew. Chem. 2012, 124, 7641; b) D. Zhao, L. Mao, D. Yang, R. Wang, J. Org. Chem. 2010, 75, 6756; see also ref. [3]. [11] CCDC 1025306 (anti-3 a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [12] Details of the separation process are included in the Supporting Information. [13] See the Supporting Information for the detailed procedure. [14] T. A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtius, P. Beak, J. Am. Chem. Soc. 2002, 124, 11689.
Received: October 28, 2014 Published online on && &&, 0000
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Communication
COMMUNICATION & Synthetic Methods
Site-selectivity: A successful strategy was designed to solve the a/a’-regioselectivity problem in Michael reactions of simple ketones with nitroalkenes (see scheme). anti-Selective conjugate adducts were obtained in the reaction of phenylimidazole-modified ketones and nitroalkenes by employing a newly developed 3-bromothiophene-modified chiral diamine ligand.
D. Yang, L. Wang, D. Li, F. Han, D. Zhao, R. Wang* && – && Asymmetric anti-Selective Michael Reaction of Imidazole-Modified Ketones with trans-b-Nitroalkenes
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