Tetrahedron Letters 54 (2013) 2472–2475
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Asymmetric cyclopropanation of chalcones using chiral phase-transfer catalysts Richard Herchl, Mario Waser ⇑ Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstraße 69, Linz 4040, Austria
a r t i c l e
i n f o
Article history: Received 22 January 2013 Revised 25 February 2013 Accepted 27 February 2013 Available online 7 March 2013 Keywords: Cyclopropanes Organocatalysis Phase-transfer catalysis Bifunctional Cinchona alkaloids
a b s t r a c t The ﬁrst phase-transfer catalyzed cyclopropanation reaction of chalcones using bromomalonates as the nucleophiles in a Michael Initiated Ring Closing reaction (MIRC) was developed. Key to success was the use of a free OH-containing cinchona alkaloid ammonium salt catalyst and carefully optimized liquid/liquid reaction conditions. The reaction performed well for electron neutral and electron deﬁcient chalcones giving the products in yields up to 98% and with enantiomeric ratios up to 91:9. Ó 2013 Elsevier Ltd. All rights reserved.
Results and discussion
Chiral cyclopropanes are highly versatile organic molecules. Their importance is a result of their unique reactivity which makes them outstanding synthons to access complex molecular scaffolds1 and because of their presence in different biologically active compounds.2 Although a variety of versatile strategies for the stereoselective syntheses of chiral cyclopropanes have been reported,1–3 the development of novel strategies to access these important compounds is a worthwhile goal. Asymmetric phasetransfer catalysis has proven its potential in numerous demanding applications4–7 and a variety of carefully ﬁne-tuned catalysts have been reported in the past.4–9 Surprisingly, the use of (chiral) phase-transfer catalysts (PTCs) to facilitate (stereoselective) cyclopropanation reactions has so far been limited to a few examples only.10–12 Based on our recent success in developing novel TADDOL-derived PTCs9 and the knowledge gathered therein we have now undertaken systematic investigations concerning the PT-catalyzed Michael Initiated Ring Closing (MIRC) reaction of bromomalonates 1 with trans-chalcones (2) to furnish cyclopropanes 3 in the presence of a variety of known chiral quaternary ammonium salt PTCs (Scheme 1). The asymmetric cyclopropanation of chalcones with malonates is an unprecedented reaction and should therefore broaden the application scope of asymmetric phase-transfer catalysis toward such interesting chiral moieties.
Table 1 gives an overview of the most signiﬁcant results obtained in the course of a thorough and systematic screening. Initial studies were carried out using diethyl bromomalonate (1a) as the nucleophile in the presence of differently substituted cinchona alkaloid catalysts 4 and 5 under liquid/solid conditions (entries 1–9). The ﬁrst challenge to be addressed was the identiﬁcation of reaction conditions suppressing the rapid base-catalyzed dimerization of 1.13 Although the combination of different solvents with solid Cs2CO3 furnished the targeted product 3 in reasonable yields only very low selectivities were obtained. Out of different other solvent/solid base combinations only the use of K3PO4/toluene in combination with the free OH-containing quinidine-derived catalyst 4c furnished 3 in moderate selectivity at room temperature (entry 9). During the course of our investigations the Adamo group reported the ﬁrst PT-catalyzed cyclopropanation of highly electrophilic 4-nitro-5-styrylisoxazoles using cinchona alkaloid-derived PTCs under liquid/liquid (toluene/aq K3PO4) conditions.11 Interestingly, applying analogous conditions to our reaction (entries 10–18), the presence of the free sec-9-OH-group in the cinchona alkaloid catalyst was found to be crucial to achieve reasonable selectivities. Whereas O-alkylated derivatives (e.g., 4a) as well as
⇑ Corresponding author. Tel.: +43 732 2468 8748; fax: +43 732 2468 8747 E-mail address: [email protected]
(M. Waser). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.02.095
Scheme 1. Targeted phase-transfer catalyzed MIRC-reaction of bromomalonates with chalcones.
R. Herchl, M. Waser / Tetrahedron Letters 54 (2013) 2472–2475 Table 1 Identiﬁcation of the most-active catalyst and optimum reaction conditions in the phase-transfer catalyzed MIRC-reaction of bromomalonates 1 with 2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
CH2Cl2 THF Toluene THF
K3PO4 (10) K3PO4 (50%) (10)
70 77 30 45 40 41 14 55 45 84 36 48 57 44 67 30 45 57 43 7 35 54 n.r. 63 10 54 83 82 39 61
51:49 43:57 44:56 46:54 44:56 51:49 52:48 57:43 31:69 50:50 38:62 26:74 40:60 31:69 50:50 70:30 73:27 47:53 24:76 21:79 24:76 22:78 — 17:83 17:83 15:85 15:85 13:87 10:90 75:25
4b 4c 5a 5c 5d 4c 4a 4b 4c 4d 4e 4f 5b 5d 6 4c
Li2CO3 (50%) (10) K2CO3 (50%) (10)
Mesitylene 1b 1c
Bc Cc Dc Ec Fc Ec
Isolated yield. Determined by HPLC using a chiral stationary phase. c A: 3 equiv 2, rt, 22 h, 0.15 M; B: 3 equiv 1a, RT, 22 h, 0.15 M; C: 3 equiv 2, rt, 46 h, 0.075 M; D: 6 equiv 2, rt, 46 h, 0.075 M; E: 6 equiv 2, 0 °C, 46 h, 0.075 M; F: 6 equiv 2, 20 °C, 46 h, 0.075 M. b
our standard TADDOL-based catalyst 6 gave racemic 3 only, the bifunctional quinidine and quinine-derived catalysts 4c and 5d were found to be the most active ones, giving 3 with enantiomeric ratios up to 74:26 at room temperature (entries 12, 17). Compared to the corresponding cinchonine and cinchonidine based catalysts 4b and 5b the 60 -OMe group of 4c and 5d has a beneﬁcial effect on yield and selectivity. In sharp contrast, a 9-O-protected free 60 -OH based catalyst (4f, entry 15) was found to be absolutely nonselective.14 Further investigations using 4c under liquid/liquid biphasic conditions (entries 19–22) allowed us to identify the combination of mesitylene and aqueous K2CO3 as the most promising one with respect to yield and enantioselectivity (entry 22). Testing the inﬂuence of different ester-groups we found that the t-butyl ester 1b did not give any product at all whereas the methyl ester 1c performed reasonably well at room temperature already (entry 24). To improve yield and enantioselectivity different ratios of reagents, temperature, reaction time, and dilution were investigated (entries
24–29). Initially we employed an excess of 2 which could easily be recovered after the reaction. As the dimerization of 1 was found to be the major yield-limiting side reaction,13 the use of an excess of 1 was tested next. However, the yield dropped signiﬁcantly under a variety of conditions (e.g., entry 25) and besides vast amounts of the unwanted dimer various decomposition products were observed. Test reactions revealed that product 3 undergoes further (most presumably ring opening) reactions with an excess of 1 under the reaction conditions. Thus, ensuring a permanent excess of the Michael acceptor 2 was found to be crucial to warrant good yields (entry 27). In addition, higher dilution and prolonged reaction time combined with a slightly reduced reaction temperature allowed us to isolate ()-3 in high yields and with good enantioselectivities up to 90:10 (entries 28 and 29).15 Surprisingly, where the pseudoenantiomeric 4c and 5d performed similarly under Adamo’s conditions (entries 12 and 17), the quinine-derived 5d was found to be less selective than 4c under our optimized conditions (entry 30 vs 28).
R. Herchl, M. Waser / Tetrahedron Letters 54 (2013) 2472–2475
Table 2 Scope of the phase-transfer catalyzed MIRC-reaction of 1c with different chalcones
a b c
1 2 3 4 5 6 7 8 9 10 11
2 7 9 11 13 15 17 19 21 23 25
Ph 4-ClC6H4 Ph Ph 3-NO2C6H4 4-NO2C6H4 Ph 4-OH-C6H4 Ph 4-MeO-C6H4 Ph
Ph Ph 4-ClC6H4 4-FC6H4 Ph Ph 4-MeC6H4 Ph 4-OH-C6H4 Ph 4-MeO-C6H4
3c 8 10 12 14 16 18 20 22 24 26
82 98 91 72 59 58 72 Nrc Nrc Nrc Nrc
13:87 12:88 11:89 13:87 9:91 10:90 16:84 Nd Nd Nd Nd
Isolated yield. Determined by HPLC using a chiral stationary phase. Only dimerization of 1c.
Having identiﬁed suitable high-yielding and selective conditions for the cyclopropanation of the parent chalcone 2, a series of differently substituted chalcone derivatives was screened next (Table 2). Where electron neutral and electron deﬁcient chalcones were well-tolerated (no matter which aryl group was modiﬁed) (entries 1–7), more electron rich electrophiles did not undergo the cyclopropanation reaction. Instead the main product in these experiments was the dimerization of bromomalonate 1c, thus illustrating again the high dependence of this reaction on the electrophilicity of the Michael acceptor and seemingly small changes in the electronic nature of the reagents have a dramatic inﬂuence on the outcome of the reaction.
added to a solution of catalyst (10 mol %) in mesitylene (assuring a dilution of 0.075 M based on the amount of 1 used in the reaction). After ﬂushing the solution with Argon, the corresponding chalcone derivative (6 equiv) was added. The vigorously stirred solution (>1200 rpm) was cooled to 0 °C (Ar-atmosphere). Subsequently, the bromomalonate was added in 3 portions (3 0.33 equiv over 24 h). The biphasic mixture was stirred for a total of 46 h at 0 °C. After extraction with CH2Cl2/H2O, the combined organic phases were dried over Na2SO4, evaporated to dryness and puriﬁed by column chromatography using heptanes/ EtOAc = 40:1–10:1 as the eluent. The excess chalcone could easily be recovered hereby.
Summarizing, the ﬁrst phase-transfer catalyzed cyclopropanation reaction of bromomalonates and chalcones proceeding via a Michael Initiated Ring Closing (MIRC) reaction has been developed. Key to success was the use of a free OH-containing cinchona alkaloid ammonium salt catalyst and carefully optimized liquid/liquid reaction conditions. The exact role of the free-OH group is not clear yet. However, based on recent reports two possible modes of action seem reasonable.5 The free OH-group can either cause an additional coordination of the bromomalonate nucleophile thus achieving a better control of the orientation of the nucleophile compared to the standard ion pair formation achieved with classical chiral PTCs or an activation/coordination of the chalcone, thus resulting in a highly ordered transition state during the reaction.5 The reaction performed well for electron neutral and electron deﬁcient chalcones giving the products in yields up to 98% and with enantiomeric ratios up to 91:9. In contrast, electron rich chalcones could not be successfully employed yet due to the lower reactivity of these Michael acceptors. Further investigations to expand this methodology toward other starting materials are currently undertaken and will be reported in due course.
Obtained as a colorless oil in 82% yield (136 mg, 0.40 mmol) and with er = 87:13 upon reacting chalcone 2 (615 mg, 2.96 mmol) with bromomalonate 1c (104 mg, 0.49 mmol) in 6.4 mL mesitylene with 0.82 mL aqueous K2CO3 solution (50% w/w). Analytical data are in accordance with those reported in the literature.16 ½a20 D 25.9 (c 0.44, CHCl3); 1H NMR (300 MHz, d, CDCl3, 298 K): 3.55 (s, 3H), 3.72 (s, 3H), 3.88 (d, J = 7.7 Hz, 1H), 4.14 (d, J = 7.7 Hz, 1H), 7.27–7.34 (m, 5H), 7.48–7.56 (m, 2H), 7.59–7.66 (m, 1H), 8.07–8.13 (m, 1H) ppm; 13C NMR (75 MHz, d, CDCl3, 298 K): 35.1, 36.6, 46.0, 53.0, 53.1, 127.8, 128.4, 128.5, 128.6, 128.8, 133.4, 133.8, 136.7, 166.1, 166.6, 193.9 ppm; IR (ﬁlm): m = 3064, 3032, 2995, 2953, 2916, 2846, 2358, 2341, 1735, 1678, 1597, 1581, 1449, 1437, 1352, 1267, 1219, 1178, 1117, 1024, 1010, 943, 916, 739 cm1; The enantioselectivity was determined by HPLC (Chiralcel OD-R, eluent: H2O/AcN = 55:45, 0.7 mL/min, 10 °C, retention times: (+)-enantiomer 36.4 min, ()-enantiomer 39.6 min); HRMS (ESI): m/z calcd for C20H18O5: 339.1227 [M+H]+; found: 339.1227.
Experimental section General procedure for the phase-transfer catalyzed cyclopropanation using bromomalonates and chalcones Reactions were usually carried out using less than 0.5 mmol bromomalonate (1). First 10 equiv K2CO3 (50% aq solution) was
Acknowledgments This work was supported by the Austrian Science Funds (FWF): Project No. P22508-N17. Richard Herchl is recipient of a DOC-fellowship of the Austrian Academy of Sciences at the Institute of Organic Chemistry, JKU Linz. The used NMR spectrometers were acquired in collaboration with the University of South Bohemia (CZ) with the ﬁnancial support from the European Union through the EFRE INTERREG IV ETC-AT-CZ programme (project M00146, ‘RERI-uasb’).
R. Herchl, M. Waser / Tetrahedron Letters 54 (2013) 2472–2475
Supplementary data Supplementary data (analytical data and experimental details can be found in the supporting material) associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.tetlet.2013.02.095. References and notes 1. For selected reviews and recent reports about the applications of cyclopropanes to access complex molecules see: (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196; (b) Baldwin, J. E. Chem. Rev. 2003, 103, 1197– 1212; (c) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103, 1213–1270; (d) Simone, F. D.; Waser, J. Synthesis 2009, 3353–3374; (e) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447–457; (f) Tang, D.; Qin, Y. Synthesis 2012, 44, 2969–2984; (g) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Angew. Chem., Int. Ed. 2012, 51, 11153–11156; (h) Kaschel, J.; Schmidt, C. D.; Mumby, M.; Kratzert, D.; Stalke, D.; Werz, D. B. Chem. Commun. 2013. http://dx.doi.org/10.1039/C2CC37631H; (i) Benfatti, F.; de Nanteuil, F.; Waser, J. Chem. Eur. J. 2012, 18, 4844–4849; (j) Benfatti, F.; de Nanteuil, F.; Waser, J. Org. Lett. 2012, 14, 386–389. 2. (a) Pietruszka, J. Chem. Rev. 2003, 103, 1051–1070; (b) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433–442; (c) Waser, M.; Moher, E. D.; Borders, S. S. K.; Hansen, M. M.; Hoard, D. W.; Laurila, M. E.; LeTourneau, M. E.; Miller, R. D.; Phillips, M. L.; Sullivan, K. A.; Ward, J. A.; Xie, C.; Bye, C. A.; Leitner, T.; HerzogKrimbacher, B.; Kordian, M.; Müllner, M. Org. Process Res. Dev. 2011, 15, 1266– 1274. 3. (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–1050; (b) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596– 5605; (c) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341–2372. 4. For reviews about asymmetric phase-transfer catalysis: (a) Maruoka, K. Asymmetric Phase Transfer Catalysis; WILEY-VCH: Weinheim, 2008; b O’Donnell, M. J. In Catalytic Asymmetric Syntheses; Ojima, I., Ed., 2nd ed.; WILEY-VCH: New York, 2000; pp 727–755; (c) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028; (d) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506–517; (e) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222–4266. 5. For a review about bifunctional chiral quaternary ammonium salt catalysts see: Novacek, J.; Waser, M. Eur. J. Org. Chem. 2013, 637–648. 6. For a review about phosphonium-based catalysts see: Enders, D.; Nguyen, T. V. Org. Biomol. Chem. 2012, 10, 5327–5331.
7. For recent impressive examples see: (a) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301–1304; (b) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2011, 50, 10565–10569; (c) Maciver, E. E.; Knipe, P. C.; Cridland, A. P.; Thompson, A. L.; Smith, M. D. Chem. Sci. 2012, 3, 537–540; (d) Bernardi, L.; Indrigo, E.; Pollicino, S.; Ricci, A. Chem. Commun. 2012, 48, 1428–1430; (e) Shirakawa, S.; Liu, K.; Ito, H.; Maruoka, K. Chem. Commun. 2011, 47, 1515–1517; (f) Kano, T.; Yamamoto, A.; Song, S.; Maruoka, K. Chem. Commun. 2011, 47, 4358–4360; (g) Shirakawa, S.; Terao, S. J.; He, R.; Maruoka, K. Chem. Commun. 2011, 47, 10557–10559; (h) Lan, Q.; Wang, X.; Shirakawa, S.; Maruoka, K. Org. Process Res. Dev. 2010, 14, 684– 686; (i) Shirakawa, S.; Liu, K.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 916–919; (j) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794–801; (k) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4564–4567; (l) Johnson, K. M.; Rattley, M. S.; Sladojevich, F.; Barber, D. M.; Nunez, M. G.; Goldys, A. M.; Dixon, D. J. Org. Lett. 2012, 14, 2492–2495; (m) Moss, T. A.; Barber, D. M.; Kyle, A. F.; Dixon, D. J. Chem. Eur. J. 2013, 19, 3071–3081. 8. (a) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76, 4260–4336; (b) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76, 4337–4357. 9. (a) Waser, M.; Gratzer, K.; Herchl, R.; Müller, N. Org. Biomol. Chem. 2012, 10, 251–254; (b) Gratzer, K.; Waser, M. Synthesis 2012, 44, 3661–3670. 10. For the asymmetric phase-transfer catalyzed cyclopropanation by addition of nucleophiles to a-bromocycloalkenones see: Arai, S.; Nakayama, K.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999, 40, 4215–4218. 11. Fiandra, C. D.; Piras, L.; Fini, F.; Disetti, P.; Moccia, M.; Adamo, M. F. A. Chem. Commun. 2012, 48, 3863–3865. 12. For racemic phase-transfer catalyzed cyclopropanation reports see: (a) McIntosh, J. M.; Khalil, H. Can. J. Chem. 1978, 56, 2134–2138; (b) Singh, R. K.; Danishefsky, S. J. Org. Chem. 1975, 40, 2969–2970; (c) Kozhushkov, S. I.; Leonov, A.; de Meijere, A. Synthesis 2003, 956–958; (d) Kryshtal, G. V.; Zhdankina, G. M.; Zlotin, S. G. Russ. Chem. Bull. Int. Ed. 2011, 60, 2286–2290. 13. Base-catalysed dimerization of 1 is the only reaction taking place in the absence of any catalyst and was also the main side reaction in the course of all these investigations. 14. A free 60 -OH group was found to be crucial to obtain high selectivities employing cinchona alkaloid-derived PTCs for enantioselective Darzens reactions (Ref. 7a) and conjugate additions of cyanides (Ref. 7b). 15. Lowering the catalyst loading to 5 mol % did result in signiﬁcantly reduced yields and selectivities. 16. (a) Kingsbury, C. A.; Durham, D. L.; Hutton, R. J. Org. Chem. 1987, 43, 4696– 4700; (b) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156–3159.