Chapter Chapter Tandem Conjugate Addition-Elimination Reaction of Cyclic Activated Allylic Bromides 11 Chapter 2.1 Reaction between 2-(bromomethyl)cyclopent-2-enone and dimethyl malonate 2.1.1 Preliminary studies As a starting point, a MBH allylic bromide was prepared by an imidazole promoted Baylis-Hillman reaction between 2-cyclopentenone and formaldehyde followed by bromination2 using PBr3 (Scheme 2.1). We subsequently chose this allylic bromide as the target of initial studies, which focused on standardizing reaction conditions. To the best of our knowledge, this MBH allylic bromide has never been investigated as an electrophile for any nucleophilic substitution or conjugate addition reaction before. H N O + HCHO O N (1.0 eq) PBr3 Br ether, 0o C THF-H 2O (1:1, v/v), rt O OH Scheme 2.1 Synthesis of cyclic MBH allylic bromide 3. We found that with equivalents of triethylamine, the reaction between 2-(bromomethyl)cyclopent-2-enone (3) and dimethyl malonate completed in 24 hrs at room temperature in CH2Cl2. Stoichiometric base was needed for this reaction as HBr could be generated during the nucleophilic reaction process. It is worth noting that SN2’ product was obtained in an isolated yield of 85% while SN2 type product was not observed (Scheme 2.2). Other dialkyl malonates such as diethyl malonate and di-isopropyl malonate were also subjected to the reaction condition. However, the SN2′ type products were obtained only in moderate yields. Thus we focused on the reaction between and dimethyl malonate, which could be used as a model reaction for S. Luo, B. Zhang, J. He, A. Janczuk, P. G. Wang and J-P. Cheng, Tetrahedron Lett., 2002, 43, 7369-7371. H.-K. Yim, Y. Liao and H. N. C. Wong, Tetrahedron, 2003, 59, 1877-1884. 12 Chapter asymmetric studies. O O O Br CO2 Me + CO2 Me CO2 Me CH2 Cl2 , rt CO 2Me eq. Et3N CO2Me MeO 2C SN2 type product SN2' type product 24hrs, 85% yield Scheme 2.2 Reaction between and dimethyl malonate. To better understand how the SN2′ type product was formed, we particularly looked at the mechanistic aspects of this reaction. Based on the results obtained and Lee’s proposed mechanism3, we postulated that the reaction may proceed through a tandem conjugate addition-elimination (C-AE) process (Scheme 2.3). Model reaction: O O O NEt3 Br Br O NEt3 - Et N Et N CO2 Me Et N CO2Me CO2 Me H MeO2 C MeO2 C CO2 Me SN 2' product Asymmetric version: O O Br * NR3 chiral amine NR * O Nu Br * Nu Scheme 2.3 Proposed mechanism of tandem CA-E process. In Scheme 2.3, an initial nucleophilic substitution by triethylamine on the bromide of resulted in the formation of an ionic intermediate. Deprotonation of dimethyl malonate H.-Y. Chen, L. N. Patkar, S.-H. Ueng, C.-C. Lin, A. S.-Y. Lee, Synlett, 2005, 13, 2035-2038. 13 Chapter by triethylamine generated the carbon nucleophile. Subsequently, nucleophilic attack of dimethyl malonate anion onto the β-carbon of the α,β-unsaturated double bond led to the formation of the enolate 5. Finally, the elimination of the promoter would give rise to the SN2′ type product 4. In contrast, the formation of the SN2 type product would be via the direct nucleophilic substitution on the carbon adjacent to the leaving group. Based on the results obtained from the model reaction between and dimethyl malonate, we are keen to develop an asymmetric tandem conjugate addition-elimination (CA-E) reaction using chiral leaving group strategy (Scheme 2.3). Using a chiral tertiary amine as the promoter, enantioselectivity could be achieved through a tandem CA-E fashion. 2.1.2 Cinchona alkaloids promoted tandem CA-E reactions Nowadays, Cinchona alkaloid and its derivatives have attracted lots of chemists’ attention and have been widely used as organocatalysts for various kinds of reactions such as Michael reaction4, Henry reaction5, Mannich reaction6, Friedel-Crafts7 reaction, Diels-Alder reaction8 and so forth. With various kinds of commercially available Cinchona alkaloids (Figure 2.1), we embarked on the study of asymmetric tandem CA-E reaction between and dimethyl malonate (Table 2.1). When equivalents alkaloids such as quinidine and quinine were employed, the reaction could reach 100% conversion according to TLC9 after several Selected examples of Michael reactions catalyzed by cinchona alkaloids: a) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M. Foxman and L. Deng, Angew. Chem. Int. Ed., 2005, 44, 105-108. b) M. Bella and K. A. Jørgenson, J. Am. Chem. Soc., 2004, 126, 5672-5673. c) B. Vakulya, S. Varga, A. Csámpai and T. Soós, Org. Lett., 2005, 7, 1967-1969. H. Li, B. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 732-733. a) J. Song, Y. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 6048-6049. b) A. Ting, S. Lou and S. E. Schaus, Org. Lett., 2006, 8, 2003-2006. Y.-Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156-8157. Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman and L. Deng, J. Am. Chem. Soc., 2007, 129, 6364-6365. When the substrate spot on TLC disappeared on TLC, it was considered as 100% conversion. However, a big spot was observed on the baseline (not corresponds to alkaloid), which was suspected to be the salt intermediate 6. 14 Chapter hours at room temperature (entries and 2). However, reaction yields were very poor along with moderate enantioselectivities. It was deduced that the majority of substrate remained as an ionic intermediate (Scheme 2.3, intermediate 6) after the initial nucleophilic substitution of chiral promoter to the substrate. In addition, it was observed that cinchonidine and cinchonine only promoted the reaction at very slow reaction rates. Table 2.1 Cinchona alkaloid and its derivatives promoted tandem CA-E reactions. O O Br CO2 Me + CH2 Cl2 , rt CO2 Me eq. promoter a * CO 2Me MeO 2C Entry Promoter Time(hr) Yield/%a ee/%b quinidine 1.5 52 25 quinine 34 36 hydroquinine 41 25 A 29 99 39 B 29 77 10 C 29 66 38 D 29 61 E 29 55 23 F 29 92 10 No reaction G Isolated yield. bDetermined by chiral HPLC analysis. - Subsequently, the effects of several other commercially available alkaloids hydroquinine and A-F (entries 3-9) were explored. As expected, these alkaloids did not provide decent enantioselectivities although there was an improvement on the yield of the reaction. The best results (99% yield and 39% ee) were obtained with a quinidine derivative A as the promoter. It is interesting to note that when promoter G was employed, 15 Chapter no product was observed. H H N HO N HO MeO H MeO MeO N N quinidine N hydroquinine quinine CH H 3C R R N N N O N O N MeO N HO O N OMe N MeO O N N N OMe N N R=CH 2CH3 A (DHQD)2 Pyr B (DHQ) 2Pyr CH H3 C N O O N N N Cl O OMe N D C (DHQ) 2PHAL O Cl H H CH3 H N H OMe N H H 3C N O MeO N MeO N H 3C H O MeO N H H 3C NH N HN O S MeO N E N F F3C CF3 G Figure 2.1 Cinchona alkaloid and its derivatives. Furthermore, we surveyed the reaction between substrate and dimethyl malonate under a phase-transfer condition (Scheme 2.4). With 10 mol% N-benzylcinchonidinium chloride as the phase-transfer catalyst (PTC) and 1M NaHCO3 aqueous solution as the 16 Chapter stoichiometric base, reacted smoothly with dimethyl malonate in a very good yield but with almost no enantioselectivity. H O O Br CH2 Cl2 1M NaHCO3 , rt CO2Me + 10mol% PTC CO2Me N HO * CO 2Me Ph MeO 2C Cl 14 hrs, 99% yield 6% ee N PTC Scheme 2.4 Tandem CA-E reaction under PTC condition. 2.1.3 Other chiral tertiary amines as promoters In order to find a suitable promoter for this tandem CA-E reaction, we also attempted other chiral tertiary amines (Table 2.2), which are either commercially available or synthesized molecules. However, chiral imidazoline (entry 1)10 and a (-)-pseudoepherin derivative (entry 2)11 were proved to be ineffective promoters. Other two chiral tertiary amines (entries 3, 4) could only promote this reaction at very slow reaction rate with very poor enantioselectivies. Table 2.2 Several chiral tertiary amines promoted tandem CA-E reaction. O O Br CO2 Me + CH2 Cl2 , rt CO2 Me eq. promoter * MeO 2C 10 11 CO 2Me J. Xu, Y. Guan, S. Yang, Y. Ng, G. Peh, C.-H. Tan, Chemistry: An Asian Journal 2006, 1, 724-729. Compound was prepared by the following procedures: O O Ph OH N H + Ph CH 2Cl2, Et3 N Cl oC-rt Ph N OH 95% yield Ph LiAlH4 THF, reflux Ph N Ph OH 79% yield 17 Chapter Entry Promoter Time(hr) Yield/%a ee/%b - Poor conversion - - No reaction 24 33 24 41 N N Ph Ph N Ph OH N N (S)-(-)-Nicotine a Ph N Isolated yield. bDetermined by chiral HPLC analysis. 2.2 Chiral pyrrolidinyl sulfonamide (CPS). 2.2.1 Introduction From the above results, we concluded that an efficient and highly selective promoter was desirable for this tandem CA-E reaction. Therefore, we designed a class of bi-functional promoters, chiral pyrrolindinyl sulfonamide (CPS) (Figure 2.2). This promoter contains a tertiary amine which can undergo nucleophilic substitution with MBH allylic bromide to form the salt intermediate 6. In addition, the acidic -NH group might activate the carbonyl group of the substrate via hydrogen-bonding. Nucleophilic amine R1 O NH O S R2 N n Hydrogen-bonding donor Figure 2.2 Chiral pyrrolidinyl sulfonamide (CPS). 18 Chapter As organocatalysts, simple and versatile chiral sulfonamides available for various catalytic asymmetric reactions have been developed recently. Wang and co-workers reported that a chiral sulfonamide (Figure 2.3), which resembles L-proline, could be utilized as an organocatalyst for enantioselective Michael addition reaction of aldehydes and ketones towards nitroolefins12 . also serves as an effective organocatalyst for promoting direct, highly enantioselective Aldol reactions of α,α-dialkylaldehydes with aromatic aldehydes13. In addition, can catalyze α-selenenylation and α-sulfenylation reactions in which L-proline shows poor catalytic activity14. The enhanced catalytic activity and enantioselectivity for these reactions promoted by are due to the acidic and sterically bulky properties of the trifluoro-methanesulfonamide group11b. Another bifunctional chiral sulfonamide (Figure 2.3) was firstly reported by Nagao to achieve a highly enantioselective thiolysis of prochiral cyclic dicarboxylic anhydride15. Impressively, only mol% catalyst was required for the reaction between cyclic anhydride and 1.2 equivalents benzyl mercapten (BnSH). i CF3 NHTf F 3C N H iPr S O2 H N i Ph t N Ph Pr O2 S NHTf N NH Pr Bu N NH O Si Ph Ph 10 Figure 2.3 Various sulfonamides as organocatalysts. Ishihara also disclosed that an L-histidine derived chiral sulphonamide acted as an 12 a) W. Wang, J. Wang and H. Li, Angew. Chem. Int. Ed., 2005, 44, 1369-1371. b) J. Wang, H. Li, B. Lou, L. Zu, H. Guo and W. Wang, Chem. Eur. J., 2006, 12, 4321-4332. 13 W. Wang, H. Li and J. Wang, Tetrahedron Lett., 2005, 46, 5077-5079. 14 J. Wang, H. Li, Y. Mei, B. Lou, D. Xu, D. Xie, H. Guo and W.Wang, J. Org. Chem., 2005, 70, 5678-5687. 15 T. Honjo, S. Sano, M. Shiro and Y. Nagao, Angew. Chem. Int. Ed., 2005, 44, 5838-5841. 19 Chapter artificial acylase for the kinetic resolution of racemic alcohols16. Polymer-bound catalyst was also prepared and reused more than cycles without loss of activity. This could be a practical method to prepare chiral diols or chiral amino alcohols. An attractive direct Mannich reaction catalyzed by an axially chiral amino sulfonamide 10 was recently reported by Maruoka for the synthesis of anti-β-amino aldehyde17. Excellent enantioselectivities (>99%) with high anti-selectivies could be achieved by employing only mol% chiral catalyst. Sulfonamide 10 has also been found to catalyze the syn-selective direct asymmetric cross-aldol reactions between aldehydes. Similarly, with the use of mol% of catalyst 5, excellent levels of enantioselectivities (92 to 99%) and syn/anti ratios (up to >20/1) were obtained for the rare example of a syn-selective direct cross-aldol reaction via an enamine intermediate 18 . The use of catalyst loadings as low as mol% or lower makes organocatalysts almost as competent as the traditional organometallic catalysts, which are well known for their low catalysts loading. Inspired by these chiral sulfonamides catalyzed highly enantioselective reactions; we were keen to utilize our designed chiral pyrrolidinyl sulphonamide (CPS) on the tandem CA-E reaction. 2.2.2 Synthesis of chiral pyrrolidinyl sulfonamide (CPS) The CPS promoters could be prepared via two different routes as presented in Scheme 2.5 and 2.6. In Scheme 2.5, N-sulfonyl aziridines were readily prepared from their corresponding commercially available chiral amino alcohols19. The regioselective 16 K. Ishihara, Y. Kosugi and M. Akakura, J. Am. Chem. Soc., 2004, 126, 12212-12213. T. Kano, Y. Yamaguchi, O. Tokuda and K. Maruoka, J. Am. Chem. Soc., 2005, 127, 16408-16409. 18 T. Kano, Y. Yamaguchi, Y. Tanaka and K. Maruoka, Angew. Chem. Int. Ed., 2007, 46, 1738-1740. 19 a) W. Ye, D. Leow, S. L. M. Goh, C.-T. Tan, C.-H. Chian and C.-H. Tan, Tetrahedron Lett., 2006, 47, 1007-1010. b) B. M. Kim, S. M. So, H. J. Choi, Org. Lett., 2002, 4, 949-952. 17 20 Chapter Entry Time(hr) Yield%b Product 17 22 SN2′ type 23 SN2′ type - - No reaction O 2.5 65 SN2 type O 1.5 67 SN2 type O 1.5 19 SN2 type 0.5 51 SN2 type Nucleophile O O NH O NH O O O F3 C N H O CF3 N H S 7c N H O 9c N H H N O S S 10 TsNH2 24 SN2′ type 11 TsNHPh 20 SN2 type 12 MsNHPh 15 57 SN2 type a Two equivalents of the nucleophile were used to react with one equivalent of 3. bIsolated yield. cNucleophilic center could be sulfur. Table 2.12 Asymmetric reaction between and N-containing nucleophiles. O O Br + Nu CH 2Cl2, rt 2eq 11h Entry 1c * Nu 28a-d Nucleophile Time(hr) Yield%a ee%b H N 19 - 22 O O 36 Chapter Entry Nucleophile Time(hr) Yield%a ee%b H N 24 65 24 - - 18 - O O O 3c O NH O 4c NH O TsNH2 53 38 a b c Isolated yield. Determined by chiral HPLC analysis. Very slow reaction. Subsequently, we examined the possibility of asymmetric tandem CA-E reactions between and those N-nucleophiles which successfully gave SN2′ type products (Table 2.12). With equivalents CPS 11h, substrate reacted very slowly with various N-nucleophiles with poor enantioselectivities. Therefore, we focused on searching other heteroatom containing compounds as nucleophiles for the tandem CA-E reaction. 2.3.4 Reaction between 2-(bromomethyl)cyclopent-2-enone and P-nucleophiles. Recently, our group developed a chiral bicyclic guanidine catalyzed enantioselective phospha-Michael reaction between phosphine oxides to nitroalkenes23. Thus, we were interested to utilize phosphine oxides as the nucleophiles for the tandem CA-E reaction. The same reaction condition as that of N-nucleophiles was applied between substrate and P-containing compounds. As shown in Table 2.13, several different phosphine oxides (entries 1-4) were investigated as donors for this reaction. We found that with equivalents triethylamine, diaryl phosphine oxides (entry 1,2 and 5) could undergo tandem CA-E reaction slowly. However, when bulky phosphine oxide 29c was employed, very low conversion was 23 X. Fu, Z. Jiang and C.-H. Tan, Chem. Comm., 2007, 5058-5060. 37 Chapter observed after 24 hours (entry 3). Similar results were obtained when hindered phosphonates such as 29j and 29k were utilized as the nucleophiles. Dialkyl phosphine oxide 29d was also evaluated and considered as an ineffective donor. Other phosphonates or thio-phosphonates 29f-i could react smoothly with the substrate and yield the SN2′ type products. The isolated yields of these reactions were generally low because the SN2′ type products are very polar compounds which may be trapped by silica gel during column chromatography. With the model reactions in hand, we were keen to develop the asymmetric version of the tandem CA-E reaction between and P-nucleophiles. Table 2.13 Reaction between and P-containing compounds 29a-k in an achiral environment.a O O Br + R R P X H X = O,S CH 2Cl2, rt 2eq Et 3N 29a-k R O R P X P X R R SN2' type SN2 type Entry 29, R X Time (hr) Yield%b Product 29a, Ph O 17 SN2′ type 29b, p-FPh O 23 SN2′ type 29c, Mes O 24 - - 4c 29d, Cy O 24 - - 29e,1-Naphthyl O 0.5 23 SN2′ type 29f, OPh O 1.5 12 SN2′ type 29g, OBn O 1.5 26 SN2′ type 29h, OMe O 18 16 SN2′ type 29i, OMe S 18 SN2′ type 10c 29j, OiPr O 24 - - c 11c 29k, OtBu O 24 a Two equivalents of the nucleophile were used to react with one equivalent of 3. bIsolated yield. cVery slow reaction or no reaction after 24 hours. 38 Chapter It was observed that with equivalents CPS 11h in CH2Cl2, the tandem CA-E product 30a was obtained in 43% isolated yield and 90% ee. In order to improve the yield of this reaction, we tried to change the solvent to a polar one and increase the reaction temperature (Table 2.14, entry 2). However, there was no improvement on the yield and the enantioselectivity compromised. Same results were obtained when more equivalents of donor was employed. Diaryl phosphine oxides with an electron withdrawing group 29b and di-1-Naphthyl phosphine oxide 29e gave rise to similar results as 29a. Subsequently, we investigated the reaction of different phosphonates which could participate in the tandem CA-E reaction. Table 2.14 Asymmetric reaction between and P-containing nucleophiles O O Br R R P O + H CH2 Cl2 , rt 2eq 11h 29 O * P R R 30 Entry 29 Time(hr) Product Yield%a ee%b 29a 24 30a 43 90 29a 24 30a 47 85 29b 22 30b 55 90 29e 53 30e 53 91 29f 65 30f 46 58 6d 29f 30f 88 56 29g 43 30g 17 61 29g 30g 59 55 c d d e 43 29h 30h b c Isolated yield. Determined by chiral HPLC analysis. Reaction in CH3CN, at 40oC. d Reaction in CH3CN at reflux temperature. eVery slow reaction. a Generally, the reaction between and phosphonates (entries 5-8) afforded the 39 Chapter products with better isolated yield than that of diaryl phosphine oxide. By increasing temperature, the reaction could complete in several hours but the enantioselectivities slightly decreased (entries 6,8). In addition, we have attempted the reaction between other cyclic MBH allylic bromides/chlorides such as 22a and 22b. No tandem CA-E product was observed even when the reaction was conducted in CH3CN at reflux temperature. 2.4 Utilization of tandem CA-E products In order to demonstrate the usefulness of this reaction, the tandem CA-E products were further modified to generate a variety of interesting compounds via simple transformations. Firstly, chiral tandem CA-E product 17f was subjected to the Luche reduction condition (Table 2.15, entry 1)24. According to Luche and co-worker’s observations, lanthaniod chlorides are efficient catalysts for the regioselective 1,2 reduction of α-enones. When NaBH4 was utilized as the reducing reagent, protic solvents such as methanol would be the best choice as it provides the highest selectivity accompanied by a very high reaction rate. Under the Luche reduction condition, a chiral allylic alcohol 31a was obtained in 78% isolated yield with diastereomeric ratio 3:1 in only minutes. The optical purity of Luche reduction product was maintained. We envisioned that higher diastereoselectivity could be achieved by increase the steric hindrance of the substrate. Thus, tandem CA-E products 21a and 21b were tested under the same condition (entries 2,3). Although alcohols were known to be good solvents for Luche reduction, a solvent mixture of MeOH/CH2Cl2 1:1 was used as 21b was only partially soluble in MeOH. The reaction of 21b was slightly faster than that of 21a and provide better diastereomeric ratio. The yield and the diastereoselectivity were further improved to 10:1 by lowering the 24 A. L. Gernal and J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454-5459. 40 Chapter reaction temperature to 0oC (entry 4). We envisaged that this could be an alternative way of preparing enantiomerically enriched substituted allylic alcohols. Table 2.15 Luche reduction of tandem CA-E products. OH O NaBH , CeCl3 7H 2O solvent, temp. COR COR ROC 31a-c ROC Entry Substrate, R Solvent Temperature (oC) Product 17f, StBu MeOH rt 31a 78 3:1 MeOH rt 31b 30 57 3:1 MeOH/CH2Cl2 1:1 rt 31c 10 71 7:1 21a, 21b, S S Time Yield%a d.r.b (min) MeOH/CH2Cl2 1:1 30 86 10:1 21b, S 31c a b Isolated yield, including both diastereomers. Diastereomeric ratio was determined by calculating the isolated yields of both diastereomers. The relative stereochemistry of Luche reduction products was determined by NOE studies (Figure 2.7). In compound 31c, NOE (1%) was observed between Ha and Hb, which indicates that Ha is in cis position relative to Hb. 3% Ha OH Hc Hd 1% R Hb O R 3% R= S Figure 2.7 NOE of 31c. Lewis acid catalyzed Diels-Alder reaction25 between tandem CA-E products and 25 For Yb(OTf)3 catalyzed Diels-Alder reactions, see: S. Kobayashi, I. Hachiya, T. Takahori, M. Araki and H. Ishitani, Tetrahedron Lett., 1992, 33, 6815-6818. 41 Chapter cyclopentadiene can lead to chiral spiro-compounds such as 32a-b in good yield and diastereoselectivities (Table 2.16, entries 1,2). The yield could be further improved to 97% by stirring the reaction mixture for a longer time at lower temperature to prevent the dimerization of cyclopentadiene (entry 3). We have also investigated Diels-Alder reaction between tandem CA-E products and other commonly used dienes under various conditions (Figure 2.8). In addition to the Diels-Alder reactions described in Table 2.16, 2,3-dimethylbuta-1,3-diene provided positive results with a less hindered tandem CA-E product 17b (Scheme 2.11). No reaction was observed when the other dienes were employed even at reflux temperature. Interestingly, phospha-tandem CA-E product 30a could also serve as a dienenophile for the Yb(OTf)3 catalyzed Diels-Alder reaction of cyclopentadiene in THF (Scheme 2.11). Table 2.16 Diels-Alder reaction of tandem CA-E products. O O 10mol% Yb(OTf)3 COR CH 2Cl2, temp ROC COR ROC 32a-b Entry Substrate, R Temperature (oC) Product 17f, StBu rt 32a 48 70 10:1 rt 32b 29 80 10:1 21b, S Time Yield%a (hr) d.r.b 48 97 20:1 21b, S 32b Isolated yield, including both diastereomers. bDiastereomeric ratio was determined by 1H NMR analysis. a MeO O MeO Figure 2.8 Other dienes. 42 Chapter O O COSEt toluene, ref lux COSEt EtSOC 32c 24 hrs, 33%, d.r. 2:1 EtSOC 17b O O 10mol% Yb(OTf) O THF, rt O P Ph Ph 30a P Ph Ph 32d 24hrs, 58%, d.r. 10:1 Scheme 2.11 Diels-Alder reaction of tandem CA-E product 17b and 30a. The stereochemistry of Diels-Alder product 32b was confirmed by single crystal X-ray analysis. It was observed that the exo adduct26 is preferred, indicating secondary orbital interactions between the carbonyls of dithiomalonate and the developing π bond of cyclopentadiene (Scheme 2.12). O O H ROC R= S COR COR ROC Scheme 2.12 Approach of cyclopentadiene to 21b in the Diels-Alder reaction. The α,β-unsaturated moiety of the tandem CA-E product was also suitably for conjugate addition reactions (Scheme 2.13). Hetero-Michael reactions using amine or thiol27 as the nucleophiles gave products with high diastereoselectivites (d.r.>20:1). No catalyst is required for this aza-Michael reaction. The reaction was carried out by mixing 17f and pyrazole in CH2Cl2 at room temperature. The relative stereochemistry of Michael 26 We assigned the exo stereochemistry according to the following report: R. R. Sauers and T. R. Henderson, J. Org. Chem., 1974, 39, 1850-1853. 27 S. Cabrera, J. Alemán, P. Bolze, S. Bertelsen and K. A. Jørgensen, Angew. Chem. Int. Ed., 2008, 47, 121. 43 Chapter addition products 33 and 34 was assigned by 1H NMR analysis and comparing with literature value28. The coupling constant of adjacent protons Ha and Hb was determined to be 3J = 10.1 Hz, which indicates a trans geometry. O N N H N O O N O O O StBu SPh CH 2Cl2, rt O t S Bu 33 41 hrs, 64%, d.r. >20:1 PhSH, Et 3N StBu S Bu O CH 2Cl2, rt t 17f O StBu t S Bu 34 21 hrs, 70%, d.r. > 20:1 Scheme 2.13 Michael reaction of tandem CA-E product. O N Ha N O Hb O StBu t S Bu J a-b = 10.1 Hz Figure 2.9 Assignment of relative stereochemistry of 33 and 34. Palladium catalyzed hydrogenation reaction could also be applied to the tandem CA-E product 17f. An α-methyl ketone 35 was generated with a moderate diastereomeric ratio with 30% (w/w) Pd/C catalyst and H2 gas (Table 2.17). We have investigated several solvents such as MeOH (entry 1), THF (entry 2) and ethyl acetate (entries 3,4), which are commonly used solvents for palladium catalyzed hydrogenation. Among them, ethyl acetate was the most suitable solvent in terms of diastereoselectivity. Interestingly, the diastereomeric ratio was improved when the product 35 was kept in the fridge for a long time. A possible explanation to this phenomenon could be due to the thermo-stability of 28 M. I. Donnoli, P. Scafato, M. Nardiello, D. Casarini, E. Giorgio and C. Rosini, Tetrahedron, 2004, 60, 4975-4981. 44 Chapter the trans diastereomer. As a result, cis diastereomer may slowly transform to trans through enolate intermediate. Table 2.17 Hydrogenation of tandem CA-E product. O O O Pd/C(30%w/w), H O solvent, temp. StBu O StBu O t t S Bu S Bu 35 17f Entry Solvent MeOH Temperature (oC) rt THF Time(hr) Yield%a d.r.b 24 60 2:1 rt 19 74 3:2 EtOAc rt 19 67 3:1 EtOAc 24 81 4:1 Isolated yield, including both diastereomers. bDiastereomeric ratio was determined by 1H NMR analysis. a We have also developed conjugate addition of Gilman reagent towards tandem CA-E product (Scheme 2.14)29. With equivalents TMSCl, which was reported to strongly promote the reaction between Gilman reagent and α,β-unsaturated ketones, the reactions shown in Scheme 2.14 could complete within 30 minutes at -78oC. The product 36a was obtained with 65% yield and excellent diastereomeric ratio (>20:1). Since the tandem CA-E product 20e was a mixture of two diastereomers (1:1), the corresponding product 36b was obtained in 1:1 diastereomeric ratio with mainly trans stereochemistry. 29 E. Nakamura, S. Matsuzawa, Y. Horiguchi and I. Kuwajima, Tetrahedron Lett., 1986, 27, 4029-4032. 45 Chapter O O O O n BuLi, CuI, TMSCl THF, StBu O -78 oC O t S Bu StBu S Bu t 36a, 65%, d.r. >20:1 17f O O O n O BuLi, CuI, TMSCl THF, -78o C O StBu 20e , d.r. 1:1 O StBu 36b, t rans, 74%, d.r. 1:1 Scheme 2.14 Conjugate addition reaction between Gilman reagent and tandem CA-E products. 2.5 Efforts to develop polymer supported promoter and catalytic version of tandem CA-E reaction 2.5.1 Polymer supported chiral pyrrolidinyl sulfonamide (PS-CPS) We are keenly aware that the key weakness in this methodology is the high amount of CPS required, albeit that they are recoverable. In order to easily and effectively recover the promoter, we have prepared polystyrene-supported chiral pyrrolidinyl sulfonamide (PS-CPS) (Scheme 2.15). Chiral diamine 15 was synthesized from its corresponding amino acid, which has been discussed in 2.2.2. After shaking polystyrene bound sulfonyl chloride (1.5-2.0 mmol/g) with equivalents chiral diamine 15 for days, the beads were washed with several organic solvents and pumped dry. The PS-CPS was obtained as yellow beads and utilized for the tandem CA-E reaction. N N NH 15 + O CH2 Cl2 , rt S Cl Et 3N O O NH S O 37 46 Chapter Scheme 2.15 Synthesis of PS-CPS. As shown in Table 2.18, the synthesized PS-CPS 37 could promote tandem CA-E reactions between and various 1,3-dicarbonyl compounds with decent ee values. This PS-CPS could be easily recovered via a simple filtration followed by rinse with organic solvents. The enantioselectivities of these reactions were obtained as same level as that of 11f, which is structurally similar as 37. Table 2.18 PS-CPS promoted tandem CA-E reaction a. O O Br COR CH 3CN, rt COR2 1.5-2 eq 37 + COR R 2OC Entry Donor, [R1,R2] Product Time(hr) Yield%b eec 16f [StBu, StBu] 17f 42 64 75 2d 16f [StBu, StBu] 17f 96 29 78 18b [Ph, Ph] 19b 48 60 65 20c [Ph, StBu] 21c 45 30 70,64 O O 5e 20f 50 69,62 21f a Two equivalents donor were used to react with 3. PS-CPS was estimated as 1.5-2 equivalents according to the polystyrene supported sulfonyl chloride. bIsolated yield. c Determined by chiral HPLC analysis. dRecovered 37, 2nd cycle. eVery slow reaction. We have also investigated the possibility of preparing a PS-CPS which resembles the best promoter 11h for the tandem CA-E reaction. Since the polymer supported 2,4,6-trimethylbenzenesulfonyl chloride is not commercially available, we need to conduct polymerization reaction or modify the current available polymer bound sulfonyl chloride. Studies are still on-going to make this polymer supported promoter more useful. 2.5.2 Strong bases as “proton sponge”. 47 Chapter As HBr acid is generated in the tandem CA-E reaction, the use of stronger bases as additives or stoichiometric base to neutralize the acid may promote the reaction and allow a catalytic amount of CPS to be used. Figure 2.10 shows some super bases, BTPP30, Verkada’s base31 and BEMP32, which are well known for their high pKa values. N N P N tBu N i N P i BTPP Bu N N Bu N N t Bu P N N N i Bu Verkada's base BEMP Figure 2.10 Various strong and non-nucleophilic organic bases. Table 2.19 11h promoted tandem CA-E reaction with various bases. O O Br t COS Bu CH3 CN, rt COStBu 11h,base + O COStBu COStBu COStBu t 16f BuSOC 17f SN2 type product O COStBu COStBu COSt Bu t BuSOC double addition product Entry Equiv of 11h Base (equiv) Time(hr) Yield%a eeb 1.0 17 76 69 1.0 17 80 74 1.0 BTPP (0.1)c Verkada’s base (0.1) BEMP (0.1) 17 90 50 0.5 BTPP (1.0) 1.5 56d - 1.5 d - 0.2 BTPP (1.0) 47 30 R. Schwesinger, C. Hasenfratz, H. Schlemper, L. Walz, E.-M. Peters, K. Peters and H. G. V. Schnering, Angew. Chem. Int. Ed., 1993, 32, 1361-1363. 31 a) J. You and J. G. Verkade, Angew. Chem. Int. Ed., 2003, 42, 5051-5053. b) J. You, J. Xu and J. G. Verkade, Angew. Chem. Int. Ed., 2003, 42, 5054-5056. 32 R. Schwesinger and H. Schlemper, Angew. Chem. Int. Ed., 1987, 11, 1167-1169. 48 Chapter 0.5 K2CO3 (1.0) 59 35 0.1 NaOAc (2.0) 14 90 b c Isolated yield. Determined by chiral HPLC analysis. BTPP is slightly insoluble in CH3CN. dYield of SN2 type product. The other side product is double addition product. a We first examined the reaction between and S,S'-di-tert-butyl dithiomalonate 16f in the presence of 1.0 equivalent CPS 11h accompanied with 0.1 equivalent super bases (Table 2.19, entries 1-3). The enantioselectivies of these reactions decreases dramatically though the yields were maintained at a satisfactory level. Although with increased amount of BTPP, the reaction could complete in 1.5 hours, only SN2 type product was obtained (entries 4,5). We have also attempted combining CPS with weak inorganic bases such as K2CO3 (entry 6) and NaOAc (entry 7). Only moderate or no enantioselectivity was obtained with catalytic amount of CPS and stoichiometric these bases. Similarly, we have applied the condition (1.0 equivalent 11h with 0.1 equivalent BTPP) on the reaction between other cyclic MBH allylic bromides/chlorides such as 22a and 22b (Table 2.20). While the reaction of 22a could proceed at room temperature with 65% ee, the reaction of 22b was extremely slow even with increased amount of BTPP. Table 2.20 11h promoted tandem CA-E reaction of other substrates with BTPP. O X O t COS Bu CH3 CN, rt COStBu 11h (1.0 eq) BTPP (0.1 eq) + R R 22a R=H, X=Cl 22b R=Me, X=Br O 16f R StBu R O StBu 23a-b Entry Substrate Product Time(hr) Yield%a eeb 22a 23a 120 37 65 c a 120 22b 23b b c Isolated yield. Determined by chiral HPLC analysis. Very slow reaction. We deduced that the enantioselectivity might be improved by lowering the reaction 49 Chapter temperature with the influence of super bases such as BTPP. However, no improvement was observed when these reactions were conducted at 0oC or -20oC. As discussed in Scheme 2.3, the tandem CA-E reaction may proceed through a substitution of chiral tertiary amine followed by the addition of the nucleophile. The replacement of Br in the allylic bromides by CPS to form an ammonium salt 38 was a fairly rapid reaction (Scheme 2.16). The structure of 38 was determined by 1H NMR and further confirmed by single crystal X-ray analysis. When the ammonium salt 38 was also used to react with 1,3-dicarbonyl compounds in the presence of catalytic amount of achiral bases such as Et3N, the enantioselectivity of the tandem CA-E product maintained. However, when Et3N salt of substrate was subjected to the tandem CA-E reaction condition with catalytic amount of CPS 11h, no enantioselectivity was obtained. These results indicated that the formation of ionic intermediate 38 is essential to the enantioselectivity of the reaction. Br Br N MesO2 S NH CH 3CN + 11h N O MesO2 S NH O 38 Scheme 2.16 formation of 38. Thus, we speculated that when super bases was employed, the deprotonated dithiomalonate anion could make a competitive nucleophilic attack to the α,β-unsaturated ketone to yield the achiral SN2′ type product (Scheme 2.17). This may cause the decrease of the enantioselectivity of the reaction. 50 Chapter O Br O COStBu COStBu Br O COStBu COStBu t BuSOC tBuSOC achiral tandem CA-E product Scheme 2.17 Postulated explanation of decreased enantioselectivity. We envisioned that the selectivity of the reaction might be improved by using a more nucleophilic chiral promoter in conjunction with strong bases. For example, the nitrogen nucleophilic center in CPS promoters could be replaced by phosphorus as phosphines are generally more nucleophilic and less basic than similarly substituted amines33. Therefore, the promoter may not be easily destroyed by the protonation of HBr generated in the reaction, which may interrupt the reaction cycle. The studies towards this kind of promoters are still underway. In conclusion, in this chapter, we have disclosed a chiral pyrrolidinyl sulfonamides (CPS) promoted tandem conjugate addition-elimination (CA-E) reaction between cyclic activated allylic bromides and 1,3-dicarbonyl compounds with high enantioselectivities. When amine or phosphorus donor was employed as the nucleophile, only moderate yield was obtained accompanied with moderate to good enantioselectivity. The highly functionalized products can be used to generate a variety of interesting enantiomerically enriched compounds via simple transformations. Future work may involve broadening substrate scope and develop a catalytic version of tandem CA-E reaction. 33 J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346, 1035-1050. 51 [...]... type 29 c, Mes O 24 - - 4c 29 d, Cy O 24 - - 5 29 e,1-Naphthyl O 0.5 23 SN2′ type 6 29 f, OPh O 1.5 12 SN2′ type 7 29 g, OBn O 1.5 26 SN2′ type 8 29 h, OMe O 18 16 SN2′ type 9 29 i, OMe S 3 18 SN2′ type 10c 29 j, OiPr O 24 - - 2 3 c 11c 29 k, OtBu O 24 a Two equivalents of the nucleophile were used to react with one equivalent of 3 bIsolated yield cVery slow reaction or no reaction after 24 hours 38 Chapter 2. .. reactions Table 2. 9 11h promoted tandem CA-E reaction between cyclic MBH allylic bromides and S,S'-di-tert-butyl dithiomalonate O X O t n COS Bu + COStBu R R 22 a n=1, R=H, X=Cl 22 b n=1, R=Me, X=Br 22 c n =2, R=H, X=Br 11h (2 equiv.) O n CH3 CN, reflux StBu R 16f R O StBu 23 a-c Entry Substrate Product Time(hr) Yield/%a ee/%b 1 22 a 23 a 11 40 74 2 22b 23 b 20 37 88 22 c 23 c 29 46 94 3c a b c Isolated yield... Table 2. 11 Reaction between 3 and N-containing compounds in an achiral environment.a O O + Nu Nu CH 2Cl2, rt 2eq Et 3 N 3 Entry O Br Nu SN2' type SN2 type Nucleophile Time(hr) Yield%b Product 1 O H N O 4 64 SN2′ type 2 O H N O 2 90 SN2′ type 35 Chapter 2 Entry Time(hr) Yield%b Product 17 22 SN2′ type 3 23 SN2′ type - - No reaction O 2. 5 65 SN2 type O 1.5 67 SN2 type O 1.5 19 SN2 type 0.5 51 SN2 type... Yield/%a ee/%b 21 a 16 83 94 2c 20 a 21 a 21 74 94 3d 20 a 21 a 21 87 95 4e 20 b[R1= R2= 21 b 44 77 97 S ] 5 20 c[Ph, StBu] 21 c 26 91 94,94 6 20 d[4-MeOPh, StBu] 21 d 23 89 98,95 7 20 e[Me, StBu] 21 e 43 76 94,94 21 f 29 60 98,95 O 8 a d 20 f O Isolated yield bDetermined by chiral HPLC analysis cRecovered 11h, 2nd cycle Recovered 11h, 3rd cycle eReaction in CH2Cl2 Other 1,3-dicarbonyl compounds such as keto-thioesters... (entries 2, 3) This could be a milestone as less amounts of CPS are needed for developing a number of tandem CA-E reactions Table 2. 8 11h promoted tandem CA-E reaction between 3 and 1,3-dicarbonyl compounds under optimized conditions 29 Chapter 2 O O Br COR1 CH 3CN, rt + 1.5 eq 11h COR2 3 Entry 1 20 a-e 20 [R1, R2] 20 a[R1= R2= S COR 1 R 2OC 21 a-e Product ] Time(hr) Yield/%a ee/%b 21 a 16 83 94 2c 20 a 21 a 21 ... TsNH2 2 24 SN2′ type 11 TsNHPh 3 20 SN2 type 12 MsNHPh 15 min 57 SN2 type a Two equivalents of the nucleophile were used to react with one equivalent of 3 bIsolated yield cNucleophilic center could be sulfur Table 2. 12 Asymmetric reaction between 3 and N-containing nucleophiles O O Br + Nu CH 2Cl2, rt 2eq 11h 3 Entry 1c * Nu 28 a-d Nucleophile Time(hr) Yield%a ee%b H N 19 - 22 O O 36 Chapter 2 Entry 2. .. the ee decreased to 28 % Table 2. 5 Optimization of tandem CA-E reaction between 3 and S,S'-di-tert-butyl dithiomalonate 16f O O Br COStBu + COStBu 3 solvents, rt 2 eq promoter COStBu t 16f BuSOC 17f Time(hr) Yield/%a ee/%b toluene 48 15 44 2 CH2Cl2 18 74 54 3 CHCl3 24 88 46 4 THF 21 74 42 5 DMSO 2. 5 85 28 6 CH3CN 16 88 59 11f (2. 0) 14 97 73 11g (2. 0) 20 74 70 11h (2. 0) 12 97 90 11h(1.5) 12 97 90 Entry Solvent... S,S'-di-tert-butyl dithiomalonate gave pure SN2 type product 32 Chapter 2 O O THF, rt X + (HCHO) n O OH PBr 3 X ether, 0 oC 1 eq DABCO Br X 24 , X= O 25 , X= S O O N Ph 1 Ph3 P, AcOH N Ph 2 (HCHO)n , reflux, 1h O O Br 2, CH 2 Cl2 0 oC-rt Br O Br O Et 3 N N Ph O Br N Ph CH 2Cl2, rt 26 O Scheme 2. 9 Synthesis of other cyclic allylic bromides 24 -26 Table 2. 10 Reaction between 26 and S,S'-diethyl dithiomalonate (16b),... model reactions in hand, we were keen to develop the asymmetric version of the tandem CA-E reaction between 3 and P-nucleophiles Table 2. 13 Reaction between 3 and P-containing compounds 29 a-k in an achiral environment.a O O Br + 3 R R P X H X = O,S CH 2Cl2, rt 2eq Et 3N 29 a-k R O R P X P X R R SN2' type SN2 type Entry 29 , R X Time (hr) Yield%b Product 1 29 a, Ph O 1 17 SN2′ type 29 b, p-FPh O 1 23 SN2′... (20 a) or ethyl benzoylacetate (18c) Br O O COR 1 N Ph + COR 2 CH 2Cl2, rt promoters N Ph R 1OC O COR 2 27 O 26 Entry Donor Promoter (equiv.) Time(hr) Yield/%a 1 16b DABCO (2. 0) 2 min 16b 2 16b Et3N (2. 0) 0.5 31 3c 16b Et3N(1.5) 2 20 4d 16b 11h (1.5) - - 5 20 a Et3N(1.5) 1 43 6 18c Et3N(1.5) 3 57 a Isolated yield b100% conversion after 2min, white precipitate formed during the reaction cReaction at -20 oC . 21 a 21 74 94 3 d 20 a 21 a 21 87 95 4 e 20 b[R 1 = R 2 = S ] 21 b 44 77 97 5 20 c[Ph, S t Bu] 21 c 26 91 94,94 6 20 d[4-MeOPh, S t Bu] 21 d 23 89 98,95 7 20 e[Me, S t Bu] 21 e 43. 48 15 44 2 CH 2 Cl 2 18 74 54 3 CHCl 3 24 88 46 4 THF 21 74 42 5 DMSO 2. 5 85 28 6 CH 3 CN 11a (2. 0) 16 88 59 7 11f (2. 0) 14 97 73 8 11g (2. 0) 20 74 70 9 CH 3 CN 11h (2. 0) 12 97 90 10. 2 30 O Br + COR 2 COR 1 3 CH 3 CN, rt 1.5 eq 11h O R 2 OC COR 1 20 a-e 21 a-e Entry 20 [R 1 , R 2 ] Product Time(hr) Yield/% a ee/% b 1 20 a[R 1 = R 2 = S ] 21 a 16 83 94 2 c 20 a 21 a