Organocatalytic reactions of 3 hydroxy 2 pyrone and n arylsulfonyl 3 hydroxy 2 pyridone 3

Chapter Chapter Reactions of 3-hydroxy-2-pyridone 42 Chapter 3.1 3-Hydroxy-2-pyridone 3-Hydroxy-2-pyridone 4a is a cyclic diene which has the following structure: Figure 3.1 3-Hydroxy-2-pyridone 4a. The main structural difference in pyrone and pyridone lies mainly in that the latter has a nitrogen atom which has the ability to accommodate one more bond (Figure 3.2). With that the structural variety can be stretched to contain more functional groups, which in turn have the ability to tune the chemical properties of the diene core. Being structurally different, their arrangement in space will be different and their physical properties can differ significantly. Most of the chemistry of 4a can be understood by comparison to the oxygen analogue, 1.1 Earlier on, it was mentioned that can be used as a diene in base-catalyzed DA reactions. Thus it should come as no surprise that 4a can also be used as a diene in Diels-Alder reactions. The study of DA reactions of 4a shall occupy a major part of this chapter. 4a, like 4-hydroxycoumarin, can also take part in other reactions like Michael reaction, albeit, to a lesser extent, and to a narrower substrate scope. To match as much of 4a’s chemistry to that of 1, the nitrogen atom is usually protected to prevent hydrogen bonding which may interfere in the course of the reaction. 43 Chapter O O N R O OH carbamate protecting group R = alkyl, aryl N R O OH R = alkyl, aryl R O S N O O NH different groups that can be attached to nitrogen O vs. O OH OH pyridone 4a pyrone O OH sulfonyl protecting group R = alkyl, aryl Figure 3.2 3-hydroxy-2-pyridone 4a versus 3-hydroxy-2-pyrone 1. Compared to the chemistry of 1, the chemistry of 4a is less documented, partly due to the tediousness in preparing the compounds and lack of information on varying the substrates conveniently. There are only a handful of examples in the literature on reactions with using 4a as the substrate. Interestingly, most of the examples made use of 4a with N-sulfonyl protecting group. There is an established synthetic route which puts a sulfonyl protecting group on the nitrogen of the pyridone (Scheme 3.1). The sulfonyl group is chosen mainly because of its robustness to most acidic and alkaline conditions in the reactions. Attempts to put other types of protecting groups on the nitrogen, such as Cbz and Boc, in a bid to vary the chemical reactivity had so far been unsuccessful. 44 Chapter OH N OH TBSCl (1.2 eq.) Imidazole (1.5 eq.) CH2Cl2, rt OTBS n-BuLi (1.5 eq.) ArSO2Cl (1.2 eq.) N H O Et2O, 0oC - rt OTBS OTBS tautomerization OH N ~80% yield OTBS O N SO2Ar N H O OH BF3.Et2O CH2Cl2, rt O N SO2Ar 4b : Ar = 2,4,6-Me3C6H2 ~ 60% overall yield 4c : Ar = 3,5-Me2C6H4 ~ 60% overall yield 4d : Ar = 2,3,4,5,6-Me5C6 ~ 25% overall yield Scheme 3.1 Synthesis of N-arylsulfonyl-3-hydroxy-2-pyridone.2 The synthesis began with the protection of 2,3-pyridinediol with TBSCl using imidazole as a base in CH2Cl2 (Scheme 3.1). ~80% yield can be obtained with a monoprotection product. Subsequently, using n-BuLi and ArSO2Cl under ethereal conditions, the addition of the sulfonyl group can be performed selectively on nitrogen. Deprotection of the TBS group using the standard protocol of BF3.Et2O in CH2Cl2 gave a 60% overall yield of the N-arylsulfonyl-3-hydroxy-2-pyridone product. Compared to the literature protocol which used TsCl as the sulfonyl source, the yield obtained here is lower and a likely reason could be that the sulfonyl chlorides used contained a larger aryl group. When pentamethylphenyl sulfonyl chloride was used, a lower 25% yield of the final pyridone was obtained. Other sulfonyl chlorides which are less bulky can give a yield of around 60% which is still acceptable, giving enough amounts for methodology studies. 45 Chapter Vasella and co-workers synthesized 4e (the protecting group was 2-naphthyl sulfonyl) and it was used in the synthesis of manno-configured isoquinuclidines. The products were tested as glycosidase inhibitors. They developed a methodology using two equivalents of a Cinchona alkaloid to promote the reaction between 4e and methyl acrylate (Table 3.1).2 The product ratio was determined by analytical HPLC of the crude product. The conversion of the pyridone to the product was about 90%. Although the amount of promoter applied was quite high, this was one of the few reports where an asymmetric DA reaction of N-arylsulfonyl-3-hydroxy-2-pyridone was reported. Table 3.1 DA reaction of 4e and methyl acrylate promoted by Cinchona alkaloids. Entry Promoter (eq.) Solvent, temperature and Ratio of (+)-5 reaction time /(-)-5 Quinine (2) Acetone, 40oC, 14h 85:15 Quinine (2) CH2Cl2, 40oC, 14h 79:21 Quinidine (2) Acetone, 24oC, 36h 19:81 Quinidine (2) CH2Cl2, 24oC, 36h 19:81 Cinchonidine (2) CH2Cl2, 40oC, 18h 64:36 46 Chapter Okamura’s group also developed a route for the intermediate leading to the synthesis of oseltamivir phosphate (Tamiflu) using N-nosyl-3-hydroxy-2-pyridone 4f (Scheme 3.2).3 The pyridone was subjected to base catalyzed DA reaction with ethyl acrylate using aqueous sodium hydroxide. A yield of 83% was obtained for the DA product. NaBH4 was used to open up the amide linkage. Following that, iodate oxidation gave the product as a mixture of the two diastereomers and one enol tautomer. Reduction using NaBH4 and removal of the alcohol group by mesylation with MeSO2Cl gave the intermediate product for the synthesis of oseltamivir phosphate. The nosyl group could be removed easily using PhSH and K2CO3. The amido group can be reprotected with Boc group with ease. Using the product obtained, it could be further manipulated with more transformations till oseltamivir phosphate is obtained. The route for the synthesis of oseltamivir phosphate was developed by Corey’s group (Scheme 3.3).4 From the above examples it can be seen that the cycloadducts obtained from the DA reactions of N-sulfonyl-3-hydroxy-2-pyridone can be of great use in synthetic organic chemistry. With such great interest generated, it is important to explore and develop the asymmetric reactions of N-sulfonyl-3-hydroxy-2-pyridone. 47 Chapter OH N Ns O aq. NaOH Ethyl acrylate Ns N O CH2OH NaBH4, THF 83% OH 77% HO 4f XHN CO2Et a : X = Boc b : X = Ns PhSH, K2CO3 MeCN CO2Et 55% O XHN NaIO4, aq. THF CO2Et X = Ns X = Boc unstable mixture of diastereomers and enol tautomer OH XHN 1) NaBH4, EtOH 2) MsCl, NEt3, DMAP, CH2Cl2 CO2Et X = Ns X = Boc XHN 61% from Ns 33% from Boc X = Boc CO2Et Corey's intermediate to synthesis of Tamiflu X = Ns X = Boc Scheme 3.2 Okamura’s route to the synthesis of the intermediate leading to synthesis of oseltamivir phosphate. Scheme 3.3 Corey’s intermediate to Tamiflu. 48 Chapter 3.2 Asymmetric reactions of N-arylsulfonyl-3-hydroxy-2-pyridones As mentioned, using cinchonidine as catalyst, the Diels-Alder reaction of and 2a can be achieved with an enantiomeric excess as high as 77% (Scheme 3.4).5 Scheme 3.4 DA reaction of 1and 2a. With the additional examples by Okamura and Deng, they demonstrated that a molecule containing a hydrogen-bond donor and an acceptor would be a suitable catalyst for the DA reactions of 3-hydroxy-2-pyrone 1. With this lead, we began to search for a suitable catalyst for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridone that can bring about high diastereoselectivity and enantioselectivity. The catalysts that were deemed suitable for the asymmetric DA reactions of were found to be inadequate to complete the reactions of N-sulfonyl-3-hydroxy-2-pyridone. Thus, a new molecular scaffold for the catalyst needed to be evaluated. 49 Chapter Figure 3.3 The CPS catalysts 3a-d. These chiral pyrrolidinyl sulfonamides (CPS) (Figure 3.3) mentioned in the last chapter were evaluated for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridone. They contained hydrogen bond donor and acceptor moieties, thus, it was reasoned that they would be effective as catalysts for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridones. The CPS were applied as catalysts, however, only moderate enantiomeric excesses of 3040 % were achieved. 50 Chapter Table 3.2 Reaction between 4b/4d and N-substituted maleimides catalyzed by CPS. N SO2Ar O + OH O N R O 10 mol% 3b or 3d solvent, temp HO 20h CPS, 3b R, N O R Solvent Yield/%a ee/%b Temp/oC or 3d a O 4d: Ar = 2,3,4,5,6-Me5C6 4b: Ar = 2,4,6-Me3C6H2 (Mes) Entry O SO2Ar N 4d 3b Ph, 2b CH2Cl2, rt 90 40 4d 3d Ph, 2b CH2Cl2, rt 85 4b 3b Ph, 2b CH2Cl2, rt 88 36 4b 3d Ph, 2b CH2Cl2, rt 91 14 4b 3b Ph, 2b CHCl3, rt 92 41 4b 3b Ph, 2b (CH2Cl)2, rt 86 38 4b 3b Ph, 2b Et2O, rt 82 28 4b 3b Ph, 2b THF, rt 80 12 4b 3b Et, 2e CH2Cl2, rt 80 35 10 4b 3b Bn, 2c CH2Cl2, rt 82 43 11 4b 3b 4-MeC6H4, 2f CH2Cl2, rt 81 47 12 4b 3b Ph, 2b CH2Cl2, -40 82 55 Isolated yield. b Chiral HPLC. 51 Chapter Scheme 3.8 Introduction of chlorine and bromine to the 4-position of 4b. Apart from NBS, other reagents attempted for the introduction of halogens into 4b included ICl, NCS and Br2 but they gave a messy reaction profile and no formation of products was clearly observed. O-allyl phenols are known to undergo Claisen rearrangement when heated or when a Lewis acid is added. Thus, the rearrangement reaction was also attempted with 4b.8 Allyl protection of the OH group of 4b was performed using allyl bromide using K2CO3 in refluxing MeCN. The O-allyl product was then refluxed in PhNMe2 at 190oC and it was observed to yield the Claisen rearrangement product after 30 minutes. Only an ortho- product was isolated and the formation of a para- product was not observed. Further transformation of the 4-allyl product could be done by reducing the terminal olefin group. A propyl group was generated without affecting the diene core using Pd/C/H2 hydrogenation (Scheme 3.9). 58 Chapter Scheme 3.9 O-allylation of 4b followed by a Claisen rearrangement. Deng’s group reported the carbon-carbon coupling reaction performed on 4bromo-3-hydroxy-2-pyrone. The Suzuki product was obtained in about 30% yield.9 Applying the same procedure with 9b, only a low yield of the coupled product (~10%) was obtained (Scheme 3.10). Scheme 3.10 Initial scheme for introducing aryl group at the 4-position using Suzuki coupling. In addition, the reaction was not entirely reproducible. Hence, a better synthetic route was required. 59 Chapter Using 9b obtained earlier on, the OH group was protected with TBSCl. Subsequently, the O-protected product was coupled with 4-chloro phenyl boronic acid using Pd(OAc)2/PCy3 as the catalyst system, as described by Fu.10 The TBS group was desilylated with BF3.Et2O smoothly to give 4-aryl-3-hydroxy-2-pyridone 9e (Scheme 3.11). This improved procedure can deliver a higher yield of the coupled product and it was more reproducible. Scheme 3.11 Suzuki coupling of 9b with aryl boronic acid. 60 Chapter 3.4 Asymmetric reactions of N-arylsulfonyl-4-substituted-3-hydroxy2-pyridones We proceeded to use the N-arylsulfonyl-4-substituted-3-hydroxy-2-pyridones for DA reactions. In every case, a DA product was obtained, showing that the character of the diene was not affected by the substituent on the 4-position. After some optimization, high enantioselectivity could also be obtained for the DA products from N-arylsulfonyl-4substituted-3-hydroxy-2-pyridones and various maleimides (Figures 3.7 & 3.8). Scheme 3.12 DA reaction of 9a-e with N-substituted maleimides. 61 Chapter O O S O N O O S O N O O Cl HO Et O 10a, 88% yield, 94% ee O O Br HO N O Cl HO N O O 10c, 89% yield, 92% ee O S O N O O O S O N O O HO N HO N Et O 10d, 95% yield, 94% ee N O 10b, 90% yield, 89% ee O S O N HO O S O N Me O 10e, 92% yield, 94% ee Cl N O 10f, 90% yield, 93% ee Figure 3.7 DA reaction of 9a-e and N-substituted maleimides using 8a as the catalyst. 62 Chapter O O S O N O O S O N O O O Cl HO Br HO N O Br HO N O O Et O S O N 10j, 92% yield, 90% ee O O S O N O O HO N O 10k, 89% yield, 87% ee N O 10h, 91% yield, 90% ee 10g, 90% yield, 92% ee O O S O N HO N O 10m, 93% yield, 83% ee Figure 3.8 DA reaction of 9a-e and N-substituted maleimides using 8a as the catalyst. (cont’d) 63 Chapter To demonstrate the scope of this catalytic system, 4b was reacted with vinyl ketones (Table 3.4). The reactions proceeded smoothly to give the DA products. However, in this case, a mixture of endo and exo products was obtained. The mixture was not well separated on flash column silica gel chromatography. The major distinctive peaks could be observed on 1H NMR. By comparison with similar products previously reported, the endo and exo products could be distinguished (Figure 3.9).11 Figure 3.9 Differentiation of endo and exo products using 1H NMR. Using 1H NOE and 2D NMR analysis, the ratio of the two products could be estimated (See supporting information). The enantioselectivity for both the products was in the range of 85%. This demonstrated that the dienophiles for this reaction need not be restricted to cyclic compounds. 64 Chapter Table 3.4 DA reaction of 4b and alkyl vinyl ketones catalyzed by 8a. a Temp/oC Yield/%a ee/%b Me endo : exo a:b 3:1 rt 85 91,91 Et 3:1 rt 86 90,90 Entry R Combined yield of endo and exo products. b Chiral HPLC. When the same reaction conditions (for DA reaction) were extended to β-nitro styrenes, a DA reaction was not observed. On the other hand, a Michael product was obtained with an alpha attack of 4b (Scheme 3.13). The structure was determined using X-ray analysis. Although a DA adduct was not observed, this experiment demonstrated the dual character of N-sulfonyl-3-hydroxy-2-pyridone to act as a diene (DA reaction) or as an enolate (Michael reaction). 65 Chapter N SO2Mes NO2 O + NO2 OH 4b N 8a 20 mol% NO2 o PhCl, C 48h O OH 13a NO2 N NO2 8a 20 mol% NO2 SO2Mes 75% yield; 96% ee SO2Mes O+ OH 4b N (CH2Cl)2, oC 48h O2N SO2Mes O OH NO2 13b 75% yield; 80% ee Scheme 3.13 Michael reaction of 4b with β-nitro styrenes. In view of the synthetic application of the DA product of N-arylsulfonyl-3hydroxy-2-pyridone with acrylates, an attempt to react 4b with alkyl acrylates was also attempted. Initially, the conditions applied for the DA reactions of 4b and maleimides were adopted, however, it was found to have a slow rate of reaction. Neat conditions were then applied to increase the reaction rate. The reaction yielded the Diels-Alder product as a single isomer. The reactions were carried out using a solvent mixture of CH2Cl2 and ethyl acrylate (Table 3.5). It was observed that when more acrylate was added, the faster the reaction completed. However, the fastest rate (entry 1) still required days to obtain an isolated yield of 95% of the product. On the other hand, the reaction did not complete when the amount of acrylate added was the least even after 14 days of reaction (entry 6). There was an observed inverse relationship between the enantiomeric excess of the product and the amount of acrylate added. When the amount of acrylate added was the least, the best enantiomeric excess was obtained at 53%. Under neat conditions, only a 66 Chapter 29% enantiomeric excess was obtained. However, attempts to conduct the reactions at lower temperatures (similar to previous cases) led to incomplete reactions. Table 3.5 DA reaction of 4b and ethyl acrylate in CH2Cl2. OH N SO2Mes + OEt O 4b OH N 8a 20 mol% CH2Cl2, rt HO O 15 OEt Entry CH2Cl2 : ethyl acrylate Time/days Yield/%a ee/%b : 100 95 29 20 : 80 95 31 40 : 60 10 90 49 60 : 40 12 90 50 80 : 20 13 85 53 91 : 14 75 53 a N SO2Mes O O b Isolated yield. Chiral HPLC. Harano et al. observed the use of an alcoholic solvent would improve the rate of a pericyclic reaction compared to when a non-polar solvent was used.12 Therefore, there is a likelihood that an alcoholic solvent can increase the rate of the DA reaction of 4b with acrylates. Several alcohols were thus tried and some good results were obtained (Table 3.6). The initial screening involved the use of aliphatic alcohols which are liquids at room temperature. The ratio of the liquids was ethyl acrylate:alcohol (3:2). 67 Chapter Table 3.6 DA reaction of 4b and ethyl acrylate using aliphatic alcohols as co-solvents. a Entry Alcohol Time/h ee/%a MeOH 48 38 84 43 96 46 84 35 72 42 84 39 Chiral HPLC. On the other hand, phenolic solvents were also tested as co-solvents in the reactions. Phenol was first tested and did not yield desirable results. Thereafter, phenols containing two or three hydroxyl groups were tested. Most of such phenols are solids at room temperature. They were dissolved in the acrylates before the reaction, however, some remained insoluble in the reaction mixture. 0.25 ml of ethyl acrylate was used and 68 Chapter 15 eq. of the solid phenol was used. The reactions completed in 24-48 hours (Scheme 3.14). OH N SO2Mes O O + OEt O 4b OH N 8a 20 mol% HO O phenol (15 eq.), rt OH OH N SO2Mes 15 OEt OH OH OH phenols: 12% ee 14a OH 46% ee 14b HO OH 58% ee solubility problem in acrylate 14c OH 41% ee 14d Scheme 3.14 DA reaction of 4b with ethyl acrylate with phenols as additives. 14a gave low enantiomeric excess. 14c gave a rather high enantiomeric excess of 58% (room conditions); however, due to its insolubility in ethyl acrylate, the reaction was unable to be repeated at low temperatures. Thus resorcinol 14b was chosen to be the additive for further optimization. The usual DA reactions worked best in chlorinated solvents, so an attempt to increase the enantiomeric excess was performed by adding a chlorinated solvent (Table 3.7). 69 Chapter Table 3.7 DA reaction of 4b with ethyl acrylate with resorcinol as additive. Entry CHCl3 : ethyl acrylate Time/h Yield/%a ee/%b 1:1 36 90 52 5:1 144 80 56 a Isolated yield. bChiral HPLC It seemed that the chlorinated solvent had an effect in increasing the enantiomeric excess of the DA product probably by providing a more conducive environment for the reaction. However, the reaction rate was also affected (became slower) when the concentration of the acrylate was diluted by the addition of CHCl3. The reactions were also conducted at a lower temperature of -20oC (Table 3.8). Since the additional solvent reduced the reaction rate, CHCl3 was excluded. The primary factor that the enantiomeric excess was increased was likely due to the temperature. The amount of additive played less of an effect as the enantiomeric excess was hovering around 65-71%. 70 Chapter Table 3.8 DA reaction of 4b with ethyl acrylate with resorcinol as additive at -20oC. Entry x Time/h Yield/%a ee/%b 30 72 80 65 15 84 76 70 10 96 75 71 a Isolated yield. bChiral HPLC This reaction was important because the DA product can be used as a starting material for the synthesis of oseltamivir phosphate as discussed previously. Thus, efforts to research on improving this methodology are still in progress. The best result obtained is still the following in which 4b is reacted in neat ethyl acrylate with 20 mol% of the catalyst 8a (Scheme 3.15). The reaction was conducted for 48h in -20oC before workup was carried out. 71 Chapter Scheme 3.15 DA reaction of 3-hydroxy-2-pyridone with acrylates. Another problem encountered was that the reaction can work better with the least bulky acrylates. An appreciable amount of DA product could be obtained with methyland ethyl- acrylate. However, as larger groups such as phenyl acrylate and benzyl acrylate were used, the reaction could not proceed. The same problem was encountered when tert-butyl acrylate was used as the dienophile. The reactions of N-sulfonyl-3-hydroxy-2-pyridone were discussed in this chapter. Previously unexplored, 4b could react with N-substituted maleimides and other terminal olefins in the presence of an amino indanol catalyst 8a-d to give Diels-Alder products in high yield and in optical purity. 4b’s dual character to behave like a diene and like an enolate was also displayed when studying its reaction with other substrates. Its diene character was observed when it reacted with olefins to give DA products. It behaves like an enolate when it reacted with β-nitro styrenes to yield Michael products. The addition of different groups on the 4-position of the pyridone was also explored by mapping the reactions of phenol onto 4b and was met with great success. Work is currently in progress to use the products of high optical purity in natural product synthesis. 72 Chapter References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111-9171. Bohm, M.; Lorthiois, E.; Meyyappan, M.; Vasella, A. Helv. Chim. Acta 2003, 86, 3787-3817. Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815-816. Yeung, Y. Y.; Hong, S.; Corey, E. J. J. Am.Chem. Soc. 2006, 128, 6310-6311. Okamura, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M. Chem. Lett. 1996, 3, 193-194. Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995, 36, 3893-3896. Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A. Bull. Chem. Soc. Jpn. 1993, 66, 1576-1579. Moffett, R. B. J. Org. Chem. 1963, 28, 2885–2886. Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364–6365. Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028. Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am.Chem. Soc. 2008, 130, 2422-2423. Jikyo, T.; Eto, M.; Harano, K. Tetrahedron 1999, 55, 6051-6066. 73 [...]... character of N- sulfonyl -3- hydroxy- 2- pyridone to act as a diene (DA reaction) or as an enolate (Michael reaction) 65 Chapter 3 N SO2Mes NO2 O + NO2 OH 4b N 8a 20 mol% NO2 o PhCl, 0 C 48h O OH 13a NO2 N NO2 8a 20 mol% NO2 SO2Mes 75% yield; 96% ee SO2Mes O+ OH 4b N (CH2Cl )2, 0 oC 48h O 2N SO2Mes O OH NO2 13b 75% yield; 80% ee Scheme 3. 13 Michael reaction of 4b with β-nitro styrenes In view of the synthetic... only available site for bond formation between the diene and the dienophile 56 Chapter 3 3 .3 Synthesis of N- arylsulfonyl -3- hydroxy- 2- pyridone derivatives There is little literature on the synthesis of derivatives of 3- hydroxy- 2- pyridone, 4a Most of them are synthesised for biological purposes and the characterization of the compounds is not comprehensive As the molecule itself contains more than one... addition of Br to 4b, Nbromosuccinimide (NBS) was the reagent of choice (Scheme 3. 8) Similarly, a catalytic amount of i-Pr2NH was required for the smooth addition of Br to the 4-position in CH2Cl2 under ambient conditions.7 57 Chapter 3 Scheme 3. 8 Introduction of chlorine and bromine to the 4-position of 4b Apart from NBS, other reagents attempted for the introduction of halogens into 4b included ICl, NCS... using 8a 55 Chapter 3 Figure 3. 6 Working model between the catalyst 8a and pyridone 4b A model for the interaction between the catalyst 8a and the pyridone 4b is proposed (Figure 3. 6) The amino alcohol can form two hydrogen bondings with the pyridone as a result of 8a and 4b each has one H-bond donor and one H-bond acceptor Pi-stacking between the catalyst and the pyridone ring (diene) is also possible... give 4-aryl -3- hydroxy- 2- pyridone 9e (Scheme 3. 11) This improved procedure can deliver a higher yield of the coupled product and it was more reproducible Scheme 3. 11 Suzuki coupling of 9b with aryl boronic acid 60 Chapter 3 3.4 Asymmetric reactions of N- arylsulfonyl- 4-substituted -3- hydroxy2 -pyridones We proceeded to use the N- arylsulfonyl- 4-substituted -3- hydroxy- 2- pyridones for DA reactions In every case,... acrylate:alcohol (3: 2) 67 Chapter 3 Table 3. 6 DA reaction of 4b and ethyl acrylate using aliphatic alcohols as co-solvents Entry Time/h ee/%a 1 MeOH 48 38 2 84 43 3 96 46 4 84 35 5 72 42 6 a Alcohol 84 39 Chiral HPLC On the other hand, phenolic solvents were also tested as co-solvents in the reactions Phenol was first tested and did not yield desirable results Thereafter, phenols containing two or three hydroxyl... incomplete reactions Table 3. 5 DA reaction of 4b and ethyl acrylate in CH2Cl2 OH N SO2Mes + OEt O 4b OH N SO2Mes O O N 8a 20 mol% CH2Cl2, rt HO O 15 OEt Entry CH2Cl2 : ethyl acrylate Time/days Yield/%a ee/%b 1 0 : 100 6 95 29 2 20 : 80 8 95 31 3 40 : 60 10 90 49 4 60 : 40 12 90 50 5 80 : 20 13 85 53 91 : 9 14 75 53 6 a b Isolated yield Chiral HPLC Harano et al observed the use of an alcoholic solvent... the dienophile The reactions of N- sulfonyl -3- hydroxy- 2- pyridone were discussed in this chapter Previously unexplored, 4b could react with N- substituted maleimides and other terminal olefins in the presence of an amino indanol catalyst 8a-d to give Diels-Alder products in high yield and in optical purity 4b’s dual character to behave like a diene and like an enolate was also displayed when studying its... obtained in a similar manner include the following: 52 Chapter 3 Figure 3. 4 Amino Indanol Catalysts 8a-d Initial studies employing the above amino alcohols as catalysts for the Diels-Alder reactions of 4b and 2b gave only moderate results (Table 3. 3, entries 1-4) Good yields of between 85-95% can be obtained but the enantiomeric excess of the cycloadducts was only about 40-60% However, the enantioselectivity... even after 14 days of reaction (entry 6) There was an observed inverse relationship between the enantiomeric excess of the product and the amount of acrylate added When the amount of acrylate added was the least, the best enantiomeric excess was obtained at 53% Under neat conditions, only a 66 Chapter 3 29 % enantiomeric excess was obtained However, attempts to conduct the reactions at lower temperatures . 4b 3b Ph, 2b (CH 2 Cl) 2, rt 86 38 7 4b 3b Ph, 2b Et 2 O, rt 82 28 8 4b 3b Ph, 2b THF, rt 80 12 9 4b 3b Et, 2e CH 2 Cl 2, rt 80 35 10 4b 3b Bn, 2c CH 2 Cl 2, rt 82 43 11 4b 3b. Chapter 3 42 Chapter 3 Reactions of 3- hydroxy- 2- pyridone Chapter 3 43 3. 1 3- Hydroxy- 2- pyridone 3- Hydroxy- 2- pyridone 4a is a cyclic diene. Chapter 3 57 3. 3 Synthesis of N- arylsulfonyl -3- hydroxy- 2- pyridone derivatives There is little literature on the synthesis of derivatives of 3- hydroxy- 2- pyridone, 4a. Most of them are synthesised