Enantioselective tandem conjugate addition elimination reactions 4

Chapter Chapter Asymmetric Baylis-Hillman Reactions Promoted by Chiral Imidazolines 63 Chapter 4.1 Introduction 4.1.1 Baylis-Hillman reaction The coupling of electrophiles with activated alkenes using tertiary amines or phosphines as catalysts is generally known as the Baylis-Hillman reaction.1 It is a useful and atom-economical carbon-carbon bond forming reaction which generates multi-functionalized products such as the α-methylene-β-hydroxycarbonyls. This reaction is notoriously slow; yields are often low and substrate dependent. The development of a methodology that is applicable for a range of substrates is much desired. Many versions of the Baylis-Hillman reaction have been developed. However, asymmetric examples are still limited hence have received considerable attention in the past few years. Barret and co-workers reported a chiral pyrrolizidine catalyzed Baylis-Hillman reaction between aryl aldehydes and ethyl or methyl vinyl ketones in CH3CN (Scheme 4.1).3 Moderate to good ee values were obtained when NaBF4 was utilized as the co-catalyst. O2N H O ArCHO + R2 HO H N OH (10 mol%) NaBF4 , CH 3CN, -40 oC Ar R = Et or Me O R2 18-72% ee Scheme 4.1 Chiral pyrrolizidine catalyzed Baylis-Hillman reaction. (a) D. Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001-8062. ( b) E. Ciganek in Organic Reactions (Ed.: L. A. Paquette et al.), John Wiley & Sons, Inc: New York, 1997, Vol. 51, Chapter 2, 201-350. (c) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811-891. (a) P. Langer, Angew. Chem., 2000, 112, 3177-3180; Angew. Chem. Int. Ed., 2000, 39, 3049-3052. (b) G. Masson, C. Housseman and J. Zhu, Angew. Chem. Int. Ed., 2007, 46, 4614-4628. A. G. M. Barrett, A. S. Cook and A. Kamimura, Chem. Comm., 1998, 2533-2534. 64 Chapter Subsequently,β-isocupreidine (β-ICD or TQO),4 a quinidine derivative, was found to be an effective catalyst for several Baylis-Hillman reactions including that between 1,1,1,3,3,3-hexafluoroisopropyl acrylate and aldehydes or imines (Scheme 4.2). Excellent enantioselectivities were achieved with 10 mol% β-ICD in DMF. OH O N O RCHO + CF3 O CF3 R = aryl or alkyl N OH β-ICD O 10 mol% R CF3 O CF3 DMF, -55 oC 31-58%, 91-99% ee O N O R NHR O CF3 β -ICD (10 mol%) + Ar CF3 O H or Ar CF3 O CF3 NHR O DMF, -55 or -30o C or Ar up to 99% ee Scheme 4.2 β-ICD catalyzed reactions. Chiral phosphines have also been observed to be good catalysts for asymmetric Baylis-Hillman reactions (Scheme 4.3).5 It was first reported by Soai and co-workers that commercially available chiral phosphine (S)-BINAP could catalyze the reaction between pyrimidine-5-carbaldehyde and acrylates. Only moderate enantioselectivities were obtained with 20 mol% catalyst.5a Shi and co-workers have disclosed an effective (a) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. Hatakeyama, J. Am. Chem. Soc., 1999, 121, 10219-10220. (b) S. Kawahara, A. Nakano, T. Esumi, Y. Iwabuchi and S. Hatakeyama, Org. Lett., 2003, 5, 3103-3105. (c) M. Shi and Y.-M. Xu, Angew. Chem., 2002, 114, 4689-4692; Angew. Chem. Int. Ed., 2002, 41, 4507-4510. (d) M. Shi and J.-K. Jiang, Tetrahedron: Asymmetry, 2002, 13, 1941-1947. (e) M. Shi, Y.-M. Xu and Y.-L. Shi, Chem. Eur. J., 2005, 11, 1794-1802. (a) T. Hayase, T. Shibata, K. Soai and Y. Wakatsuki, Chem. Comm., 1998, 1271-1272. (b) M. Shi and L.-H. Chen, Chem. Comm., 2003, 1310-1311. (c) M. Shi, L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc., 2005, 127, 3790-3800. (d) M. Shi and C.-Q. Li, Tetrahedron: Asymmetry, 2005, 16, 1385-1391. (d) M. Shi, L.-H. Chen and W.-D. Teng, Adv. Synth. & Catal., 2005, 347, 1781-1789. (e) Y.-H. Liu, L.-H. Chen and M. Shi, Adv. Synth. & Catal., 2006, 348, 973-979. (f) S. I. Pereira, J. Adrio, A. M. S. Silva and J. C. Carretero, J. Org. Chem., 2005, 70, 10175-10177. 65 Chapter chiral phosphine Lewis base catalyst for the Baylis-Hillman reaction of N-sulfonated imines.5a-e It is interesting to note that ferrocenylphosphines can be used as catalysts for the reaction between aldehydes and acrylates, which are known as one of the slowest reactions.5f Up to 65% ee was observed for the Baylis-Hillman adduct in the presence of 15 mol% chiral ferrocenylphosphine. N R1 OH O CHO (S)-BINAP 20 mol% OR2 + CHCl3 , 20 oC N N R = H or Me R = Me, Et, or i Pr N 8-24%, 9-44% ee OH PPh2 O Ts 10 mol% + Ar H THF, -30 C O O2N NHTsO Ar o Cy P O H OR2 N R1 O + Ph OBn H Fe 49-94%, 61-95% ee NMe H Ph OH O NMe2 PCy 15 mol% THF, rt OBn O 2N 78%, 65% ee Scheme 4.3 Various chiral phosphines catalyzed Baylis-Hillman reactions. Lewis acids,6 thioureas,7 and proline-peptide co-catalysts8 have also been observed to be good catalysts for asymmetric Baylis-Hillman reactions (Figure 4.1). Chen and co-workers reported that a chiral catalyst formed in situ from camphor-derived ligand and La(OTf)3 can catalyze the Baylis-Hillman reactions with good ee values in the presence of DABCO. Thiourea was found to be an efficient catalyst for asymmetric K.-S. Yang, W. D. Lee, J.-F. Pan and K. Chen, J. Org. Chem., 2003, 68, 915-919. (a) I. T. Raheem and E. N. Jacobsen, Adv. Synth. Catal., 2005, 127, 1701-1708. (b) Y. Sohtome, A. Tanatani, Y. Hashimoto and K. Nagasawa, Tetrahedron Lett., 2004, 45, 5589-5592. J. E. Imbriglio, M. M. Vasbinder and S. J. Miller, Org. Lett., 2003, 5, 3741-3743. 66 Chapter Baylis-Hillman reactions as it can activate carbonyl compounds by hydrogen bonding interactions. A proline and peptide catalyzed asymmetric Baylis-Hillman reaction between aldehydes and vinyl ketones was disclosed by Miller and co-workers. It is worth noting that neither praline nor peptide alone is effective for this reaction in terms of rate or enantioselectivity. O BocHN N O HO N OH Peptide O N H Chen's chiral ligand CO2 H N N Me Miller's acid-peptide catalyst CF S S NH N H N H CF3 NH F 3C Nagasawa's bis-thiourea Bn Me N t Bu S O N H N H N HO Jacobsen's thiourea t Bu t Bu CF3 Figure 4.1 Acid catalysts for asymmetric Baylis-Hillman reaction. Recent developments include the use of BINOL derivatives as Brønsted acid catalysts as well as BINOL-amine 10 and amine-thiourea 11 as bifunctional catalysts (Figure 4.2). Schaus and McDougal have developed a highly enantioselective Baylis-Hillman reaction by several kinds of BINOL-derived Brønsted acids. These catalysts were found to be optimum when triethyl phosphine was employed as the nucleophilic co-catalyst. Good yields (up to 88%) and excellent enantioselectivities (up to 96%) can be obtained with 10 mol% of the chiral catalyst. N. T. McDougal and S. E. Schaus, J. Am. Chem. Soc., 2003, 125, 12094-12095. K. Matsui, S. Takizawa and H. Sasai, J. Am. Chem. Soc., 2005, 127, 3680-3681. 11 J. Wang, H. Li, X. Yu, L. Zu and W. Wang, Org. Lett., 2005, 7, 4293-4296. 10 67 Chapter Sasai’s BINOL-amine catalyst was proved to be efficient for the aza-Baylis-Hillman reaction between N-tosyl imines and alkyl vinyl ketones. Another impressive example of asymmetric Baylis-Hillman reaction was reported by Wang and co-workers using BINOL derived amine-thiourea as the catalyst. X OH OH OH OH X= X Schaus's catalyst (R)-BINOL CF3 S N OH OH Sasai's BINOL-amine N N H N H CF3 N Wang's amine-thiourea Figure 4.2 BINOL derived catalysts. In addition, several asymmetric intramolecular Baylis-Hillman reactions have also been reported.12 Alternative approaches to obtain enantiomerically pure adducts include the use of chiral auxiliaries13 and chiral ionic liquids.14 The commonly accepted mechanism of Baylis-Hillman reaction involves the conjugate addition of a nucleophile to generate an enolate, the attack of the enolate onto the aldehyde and subsequent elimination to generate the product. However, the effects of 12 (a) P. R. Krishna, V. Kannan and G. V. M. Sharma, J. Org. Chem., 2004, 69, 6467-6469. (b) C. E. Aroyan, M. M. Vasbinder and S. J. Miller, Org. Lett., 2005, 7, 3849-3851. (c) S.-H. Chen, B.-C. Hong, C.-F. Su and S. Sarshar, Tetrahedron Lett., 2005, 46, 8899-8903. 13 (a) D. Basavaiah, V. V. L. Gowriswari, P. K. S. Sama and P. D. Rao, Tetrahedron Lett., 1990, 31, 1621-1624. (b) A. Gilbert, T. W. Heritage and N. S. Isaacs, Tetrahedron: Asymmetry, 1991, 2, 969-972. (c) A. A. Khan, N. D. Emslie, S. E. Drewes, J. S. Field and N. Ramesar, Chem. Ber., 1993, 126, 1477-1480. (d) L. J. Brzezinski, S. Rafel and J. W. Leahy, J. Am. Chem. Soc., 1997, 119, 4317-4318. (e) P. R. Krishna, R. Sachwani and V. Kannan, Chem. Comm., 2004, 2580-2581. (f) K.-S. Yang and K. Chen, Org. Lett., 2000, 2, 729-731. 14 B. Pégot, G. Vo-Thanh, D. Gori and A. Loupy, Tetrahedron Lett., 2004, 45, 6425-6428. 68 Chapter solvent, the rate determining step, the effects of the pKa of nucleophiles and the role of hydrogen bonding are still under intense investigation for their implication to asymmetric Baylis-Hillman reactions.15 Based on the accepted mechanism, several new extensions of Baylis-Hillman reaction have been developed.16 4.1.2 Chiral imidazolines Chiral imidazolidinones were developed by MacMillan as highly enantioselective catalysts for a number of reactions including Diels-Alder, 1,3-dipolar cycloaddition and Friedel-Crafts reactions.17 Jørgensen reported a novel imidazoline catalyst containing a carboxylic acid. This catalyst has been shown to be an effective catalyst for highly enantioselective Michael reactions.18 O Me N R Me Me N Me H HCl MacMillan's imidazolidinones R2 N R N H CO2 H Jorgensen's imidazoline N R R1 N R4 1,2-disubstituted-4,5-dihydro-1H-imidazoles Figure 4.3 Chiral imidazolidiones and chiral imidazolines. Inspired by these examples, we turned our attention to another class of chiral imidazolines, the 1,2-disubstituted-4,5-dihydro-1H-imidazoles (Figure 4.3). These 15 (a) M. L. Bode and P. T. Kaye, Tetrahedron Lett., 1991, 32, 5611-5614. (b) V. K. Aggarwal, I. Emme and S. Y. Fulford, J. Org. Chem., 2003, 68, 692-700. (c) K. E. Price, S. J. Broadwater, B. J. Walker and D. T. McQuade, J. Org. Chem., 2005, 70, 3980-3987. (d) K. E. Price, S. J. Broadwater, H. M. Jung and D. T. McQuade, Org. Lett., 2005, 7, 147-150. (e) V. K. Aggarwal, S. Y. Fulford and G. C. Lloyd-Jones, Angew. Chem., 2005, 117, 1734-1736; Angew. Chem. Int. Ed., 2005, 44, 1706-1708. (f) P. Buskens, J. Klankermayer and W. Leitner, J. Am. Chem. Soc., 2005, 127, 16762-16763. 16 (a) S. A. Frank, D. J. Mergott and W. R. Roush, J. Am. Chem. Soc., 2002, 124, 2404-2405. (b) Y. Matsuya, K. Hayashi and H. Nemoto, J. Am. Chem. Soc., 2003, 125, 646-647. (c) C. A. Evans and S. J. Miller, J. Am. Chem. Soc., 2003, 125, 12394-12395. (d) M. E. Krafft and T. F. N. Haxell, J. Am. Chem. Soc., 2005, 127, 10168-10169. 17 (a) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243-4244. (b) W. S. Jen, J. J. M. Wiener and D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 9874-9875. (c) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370-4371. 18 (a) N. Halland, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 2002, 67, 8331-8338. (b) N. Halland, P. S. Aburel and K. A. Jørgensen, Angew. Chem., 2003, 115, 685-689; Angew. Chem. Int. Ed., 2003, 42, 661-665. (c) N. Halland, T. Hansen and K. A. Jørgensen, Angew. Chem., 2003, 115, 5105-5107; Angew. Chem. Int. Ed., 2003, 42, 4955-4957. 69 Chapter imidazolines have been developed as possible ligands for enantioselective metal catalyzed reactions.19 Their similarities to oxazolines and the potential to tune their electronic properties with various 2-substitutents make them appealing. The 4,5-dihydro-1H-imidazole is also a privileged structure in which many derivatives exhibit a variety of biological activities. 20 Diversity orientated synthesis using 4,5-dihydro-1H-imidazole as a scaffold has also been attempted.21 Recently, an anionic sulfonated analogue of 4,5-dihydro-1H-imidazole was found to act as a nucleophilic catalyst in a [2+2] cycloaddition between a ketene and imine.22 4.2 Baylis-Hillman reactions promoted by Chiral imidazolines 4.2.1 Chiral imidazoline promoted reaction between various aldehydes and acrylates Chiral imidazoline 53a was readily prepared from the corresponding β-amino alcohol in good yield according to a reported procedure (Scheme 4.4).20 NH2 OH + Ph OH MeOH,Et3 N O Cl rt, 1h O NH Ph 1. SOCl2, reflux 2. NH2 Et2 O, Et N rt, 2days N N Ph 53a 72.3%yield two steps Scheme 4.4 Synthesis of 53a. We envisioned that 53a might be able to catalyze the Baylis-Hillman reaction between aldehydes and acrylates as it contains nucleophilic amines. As far as we know, few examples of the asymmetric Baylis-Hilman reaction between aldehydes and 19 (a) F. Menges, M. Neuburger and A. Pfaltz, Org. Lett., 2002, 4, 4713-4716. (b) A. J. Davenport, D. L. Davies, J. Fawcett and D. R. Russell, J. Chem. Soc., Perkin Trans. 1, 2001, 13, 1500-1503. 20 N. A. Boland, M. Casey, S. J. Hynes, J. W. Matthews and M. P. Smyth, J. Org. Chem., 2002, 67, 3919-3922. 21 V. Sharma and J. J. Tepe, Org. Lett., 2005, 7, 5091-5094. 22 A. Weatherwax, C. J. Abraham and T. Lectka, Org. Lett., 2005, 7, 3461-3463. 70 Chapter unactivated acrylates have been reported5a, 5e, and this reaction is recognized to be one of the slowest due to its combination of substrates. Table 4.1. Reaction of various aldehydes and acrylates in the presence of imidazoline 53a. O H R1 N O + OR2 N 53a Ph OH O eq. neat, r.t. 54 OR2 R1 55 56 R Product Time (days) Yield%a ee%b Entry R 4-NO2 Me 56a 10 90 50 2c 4-NO2 Me 56a 12 89 54 3d 4-NO2 n Bu 56b 14 50 41 4-NO2 Bn 56c 89 48 3-NO2 Bn 56d 73 47 2-NO2 Bn 56e 72 14 4-CN Bn 56f 63 48 2-Cl-5-NO2 Bn 56g 82 31 a Isolated yield. bChiral HPLC analysis, 56a determined to be (R) by comparing with literature data. cRecovered 53a. dIncomplete reaction. It was found that the reaction between 4-nitrobenzaldehyde and methyl acrylate was catalyzed, albeit slowly, by 10 mol% of imidazoline 53a. The product 56a was obtained in 51% enantiomeric excess, giving an isolated yield of 21% after 14 days when no solvent was used. When a series of solvents such as THF, CH3CN, DMSO, MeOH and CH2Cl2 were tested, it was found that these conditions with solvent were inferior in both the yield and enantiomeric excess with respect to neat conditions. However, when toluene 71 Chapter was used, there was a slight improvement in enantioselectivity while the reaction rate decreased. The use of the microwave technique or high pressure did not improve the enantioselectivity or conversion of this reaction. The addition of hydrogen bonding donors as additives such as thioureas and phenols or changes to the temperature of the reaction, both increasing and decreasing, also did not improve the reaction. In order to make the reaction useful, one equivalent of chiral imidazoline 53a was used, which increased the yield of the reaction dramatically to 90% (isolated yield, 100% conversion). The enantiomeric excess was also maintained at a satisfactory level (Table 4.1, entry 1). The use of a stoichiometric amount of the imidazoline did not disadvantage the reaction as it can be easily recovered through a simple acid-base work up for reuse without loss of activity (entry 2). However, the reaction still required a long time to complete. Subsequently, we surveyed various aldehydes and acrylates with one equivalent of the chiral imidazoline 53a under neat conditions. We examined tert-butyl acrylate, n-butyl acrylate (entry 3) and benzyl acrylate (entry 4), which all gave similar levels of enantioselectivity as methyl acrylate. Both tert-butyl acrylate and n-butyl acrylate resulted in much slower reactions while benzyl acrylate allowed the reaction to complete in half the time. Using the benzyl acrylate, it was found that the promoter worked well with electron-deficient aromatic aldehydes (entries 5-8). In general, para and meta substituents led to a slightly better enantioselectivity compared to ortho substituents. Alkyl and aromatic aldehydes with electron donating substituents suffered from a slow rate of reaction. 4.2.2 Various chiral imidazolines promoted reaction between 4-nitrobenzaldehyde and methyl acrylate 72 Chapter Table 4.2. The reaction of 4-nitrobenzaldehyde and methyl acrylate in the presence of imidazolines 53b-j. O OH O O 53b-j eq. H + neat, rt O2N Entry 1c 54a 55a O2N 56a Time (days) Promoter Bn OMe OMe Yield %a ee %b 53b 38 11 53c 100 16 53d 14 no reaction - 53e 14 88 28 Ph 53f 11 90 59 Ph 53g 18 69 55 53h 17 68 58 53i 11 84 60 N N Ph Ph N N Ph N Ph N Ph Ph Ph N N Ph N N Ph N N Ph Ph N N Ph Ph N N Ph 73 Chapter Entry Time (days) Promoter Yield %a ee %b N 9c a N 53j 38 53 Isolated yield. bChiral HPLC analysis. cIncomplete reaction. In order to investigate and understand how various substitutents contribute to the asymmetric induction, we tested various chiral imidazolines (Table 4.2). Modifications at the C4 position from tert-butyl (53a, Table 4.1, entry 1) to benzyl (53b, Table 4.2, entry 1) and phenyl (53c, Table 4.2, entry 2) decreased the enantioselectivity, showing that a bulky substituent was necessary for high level of enantioselectivity. Next, we found that the imidazoline 53e, with a trans-diphenyl configuration at C4 and C5, turned out to be a slightly better promoter than 53c. The effects of various substitutions at C1 were studied through making a collection of chiral imidazolines. An aliphatic group at the C1 position was found to be crucial as the presence of a phenyl group (entry 3) resulted in an ineffective promotor. The usefulness of an isopropyl substitution at C1 led us to install the chiral-methylbenzyl groups (entries and 6) and the methylenediphenyl group (entry 7). The enantioselective improvements by these changes were marginal. These results showed that the configuration of the chiral center of the methyl-benzyl group (entries and 6) did not influence the effectiveness of the imidazolines. However, we observed that by increasing the size of the C1-substituent, the rate of reaction was slower. The use of the chiral-methylnaphthyl group (entry 8) gave the best result of 84 % isolated yield and 60 % enantiomeric excess. Imidazoline 53i were then used to repeat some experiments 74 Chapter (entries 5-8) in Table A.1. In general, the enantioselectivity increased moderately by around 10 % but the reaction time increased by two times. Finally, we modified the aryl group at C2 to a bulkier naphthyl group (entry 9) but no improvement was observed. The introduction of both para- and ortho-phenols at the C2 position in an attempt to provide possible activation of the aldehyde through hydrogen bonding proved futile. We speculated that the protonation of the N3 amino group due to the phenols prevented the initial addition to the acrylate. 4.2.3 Chiral imidazoline promoted reaction between various aldehydes and alkyl vinyl ketones The imidazolines were also suitable promoters for the reaction between aldehydes and alkyl vinyl ketones. This reaction proceeded at a much faster rate and toluene was the most suitable solvent for the reaction. Preliminary studies showed that the imidazoline 53i gave most promising results and thus was used as the promoter in the subsequent survey. With 50 mol% of 53i, the reaction between methyl vinyl ketone and 4-nitrobenzaldehyde was completed in days (Table 4.3, entry 1). Similarly, the reaction with 3-nitrobenzaldehyde was completed in days and gave an isolated yield of 96% and 65% ee of the product (entry 2). The promoter 53i was recovered and reused for the same experiment (entry 3, second cycle). The promotor was recovered and reused again (entry 4, third cycle) and it was found that the enantioselectivity of the product remained unchanged. However, the yields were slightly affected. In both cycles, >95% of the promotor can be recovered. 4-Cyanobenzaldehyde (entry 5) and 4-(trifluoromethyl) benzaldehyde (entry 6) was also attempted and gave moderate yields and ee. The reactions between ethyl vinyl ketone and aldehydes were also examined and they were slightly slower than the corresponding methyl vinyl ketone reactions. However, high 75 Chapter enantioselectivity of 77% ee and yields up to 89% were obtained when the experiments were conducted at -20 oC (entries 7,8). We speculated that bulky alkyl vinyl ketone might improve the enantioselectivity further. Thus we prepare cyclohexyl vinyl ketone, which is previously not explored for Baylis-Hilman reaction. They gave moderate to good ee and yields with several aldehydes including 3-nitrobenzaldehyde, 4-nitrobenzaldehyde and 4-cyanobenzaldehyde (entries 9-11). Table 4.3. The reaction of aldehydes with vinyl ketones in the presence of 50 mol% imidazolines 53i. O R2 H + R1 OH O O 53i 50 mol% toluene, rt 54 R2 R1 57 58 Time (days) Yield %a ee %b 58b 3 75 96 59 65 Me 58b 71 65 3-NO2 Me 58b 79 68 5e 4-CN Me 58c 59 54 6e 4-CF3 Me 58d 71 47 f 4-NO2 Et 58e 13 89 77 f Et Cyg 58f 58g 13 60 75 3-NO2 4-NO2 69 78 10 3-NO2 Cy 58h 63 68 Entry R1 R2 Product 4-NO2 Me 58a 3-NO2 Me c 3-NO2 4d 11 4-CN Cy 10 75 69 58i b 4d c Isolated yield. Chiral HPLC analysis, 58a determined to be (R) . Recovered 53i, second cycle. dRecovered 53i, third cycle. eIncomplete reaction. fReaction at -20oC. g Cyclohexyl. a In conclusion, we have developed a new asymmetric Baylis-Hillman reaction based on a series of chiral imidazolines. The imidazoline promoted reaction between aromatic 76 Chapter aldehydes and unactivated acrylates. However, few examples of this combination of substrates have been reported so far. The reaction between aromatic aldehydes and alkyl vinyl ketones also gave good yields and enantioselectivities. A useful Baylis-Hillman reaction can be developed as the imidazoline can be easily recycled. We are using the benzyl imidazoline hexafluorophosphate salt as a model and are currently attempting to improve the rate as well as the enantioselectivity of this reaction. 77 [...]... including 3-nitrobenzaldehyde, 4- nitrobenzaldehyde and 4- cyanobenzaldehyde (entries 9-11) Table 4. 3 The reaction of aldehydes with vinyl ketones in the presence of 50 mol% imidazolines 53i O R2 H + R1 OH O O 53i 50 mol% toluene, rt 54 R2 R1 57 58 Time (days) Yield %a ee %b 58b 3 3 75 96 59 65 Me 58b 3 71 65 3-NO2 Me 58b 4 79 68 5e 4- CN Me 58c 4 59 54 6e 4- CF3 Me 58d 4 71 47 7 f 4- NO2 Et 58e 13 89 77 8 f...Chapter 4 Table 4. 2 The reaction of 4- nitrobenzaldehyde and methyl acrylate in the presence of imidazolines 53b-j O OH O O 53b-j 1 eq H + neat, rt O2N Entry 1c 54a 55a O2N 56a Time (days) Promoter Bn OMe OMe Yield %a ee %b 53b 9 38 11 53c 4 100 16 53d 14 no reaction - 53e 14 88 28 Ph 53f 11 90 59 Ph 53g 18 69 55 53h 17 68 58 53i 11 84 60 N N Ph 2 Ph N N Ph N Ph 3 N Ph Ph 4 Ph N N Ph 5 N N... cycles, >95% of the promotor can be recovered 4- Cyanobenzaldehyde (entry 5) and 4- (trifluoromethyl) benzaldehyde (entry 6) was also attempted and gave moderate yields and ee The reactions between ethyl vinyl ketone and aldehydes were also examined and they were slightly slower than the corresponding methyl vinyl ketone reactions However, high 75 Chapter 4 enantioselectivity of 77% ee and yields up to... Ph 73 Chapter 4 Entry Time (days) Promoter Yield %a ee %b N 9c a N 53j 5 38 53 Isolated yield bChiral HPLC analysis cIncomplete reaction In order to investigate and understand how various substitutents contribute to the asymmetric induction, we tested various chiral imidazolines (Table 4. 2) Modifications at the C4 position from tert-butyl (53a, Table 4. 1, entry 1) to benzyl (53b, Table 4. 2, entry 1)... 58b 3 71 65 3-NO2 Me 58b 4 79 68 5e 4- CN Me 58c 4 59 54 6e 4- CF3 Me 58d 4 71 47 7 f 4- NO2 Et 58e 13 89 77 8 f Et Cyg 58f 58g 13 60 75 9 3-NO2 4- NO2 8 69 78 10 3-NO2 Cy 58h 9 63 68 Entry R1 R2 Product 1 2 4- NO2 Me 58a 3-NO2 Me c 3-NO2 4d 3 11 4- CN Cy 10 75 69 58i b 4d c Isolated yield Chiral HPLC analysis, 58a determined to be (R) Recovered 53i, second cycle dRecovered 53i, third cycle eIncomplete reaction... between methyl vinyl ketone and 4- nitrobenzaldehyde was completed in 3 days (Table 4. 3, entry 1) Similarly, the reaction with 3-nitrobenzaldehyde was completed in 3 days and gave an isolated yield of 96% and 65% ee of the product (entry 2) The promoter 53i was recovered and reused for the same experiment (entry 3, second cycle) The promotor was recovered and reused again (entry 4, third cycle) and it was... the size of the C1-substituent, the rate of reaction was slower The use of the chiral-methylnaphthyl group (entry 8) gave the best result of 84 % isolated yield and 60 % enantiomeric excess Imidazoline 53i were then used to repeat some experiments 74 Chapter 4 (entries 5-8) in Table A.1 In general, the enantioselectivity increased moderately by around 10 % but the reaction time increased by two times... tert-butyl (53a, Table 4. 1, entry 1) to benzyl (53b, Table 4. 2, entry 1) and phenyl (53c, Table 4. 2, entry 2) decreased the enantioselectivity, showing that a bulky substituent was necessary for high level of enantioselectivity Next, we found that the imidazoline 53e, with a trans-diphenyl configuration at C4 and C5, turned out to be a slightly better promoter than 53c The effects of various substitutions... attempt to provide possible activation of the aldehyde through hydrogen bonding proved futile We speculated that the protonation of the N3 amino group due to the phenols prevented the initial addition to the acrylate 4. 2.3 Chiral imidazoline promoted reaction between various aldehydes and alkyl vinyl ketones The imidazolines were also suitable promoters for the reaction between aldehydes and alkyl vinyl... 3) resulted in an ineffective promotor The usefulness of an isopropyl substitution at C1 led us to install the chiral-methylbenzyl groups (entries 5 and 6) and the methylenediphenyl group (entry 7) The enantioselective improvements by these changes were marginal These results showed that the configuration of the chiral center of the methyl-benzyl group (entries 5 and 6) did not influence the effectiveness . ee% b 1 4- NO 2 Me 56a 10 90 50 2 c 4- NO 2 Me 56a 12 89 54 3 d 4- NO 2 n Bu 56b 14 50 41 4 4-NO 2 Bn 56c 5 89 48 5 3-NO 2 Bn 56d 4 73 47 6 2-NO 2 Bn 56e 4 72 14 7 4- CN Bn. 5 e 4- CN Me 58c 4 59 54 6 e 4- CF 3 Me 58d 4 71 47 7 f 4- NO 2 Et 58e 13 89 77 8 f 3-NO 2 Et 58f 13 60 75 9 4- NO 2 Cy g 58g 8 69 78 10 3-NO 2 Cy 58h 9 63 68 11 4- CN. Y M. Xu, Angew. Chem., 2002, 1 14, 46 89 -46 92; Angew. Chem. Int. Ed., 2002, 41 , 45 07 -45 10. (d) M. Shi and J K. Jiang, Tetrahedron: Asymmetry, 2002, 13, 1 941 -1 947 . (e) M. Shi, Y M. Xu and Y L.