Pentanidium catalyzed enantioselective phase transfer reactions 3

Chapter Chapter Pentanidium Catalyzed Enantioselective Phase-Transfer Amination Reaction 69 Chapter 3.1 Introduction to asymmetric C-N bond formations A recent report about the potential drug candidates indicates that 90% of these molecules contain nitrogen and 54% are chiral.1 Furthermore, in this report, it is shown that 19% of the reactions utilized carbon–heteroatom bond-forming reactions. This is the reason why new stereoselective carbon–heteroatom bond forming reactions are very important. Various C-N bond formation reactions were developed so that diverse structures can be readily accessed. Generally, classic asymmetric C-N bond formation reactions include amination of ketones, aldehyde, esters and Mannich reactions of imines.1 3.1.1 Mannich reaction with nitrogen nucleophiles Asymmetric additions of carbon nucleophiles to imines have been a popular area of study by many research groups.2 Catalytic asymmetric Mannich reactions have been well investigated during the last two decades, including Brønsted base catalysis, Brønsted acid catalysis, transition metal catalysis, enamine catalysis, phase-transfer catalysis and thiourea catalysis. As a new approach to catalytic imine addition chemistry, utilizing nitrogen nucleophiles to imines to produce protected aminals, has rarely been investigated with limited examples. In 2005, Antilla’s group developed Brønsted acid catalyzed imine amidation4, which was inspired by the addition of nitrogen nucleophile to enone mediated by metals or Brønsted acid. Previous works required doubly activated imine which contains electron-withdrawing groups at the imine nitrogen and the carbon. 70 Chapter This is the first report of general catalytic addition of amine to imine (Scheme 3.1). Under Brønsted acid S-VAPOL conditions, sulfonamide attacks various Boc-protected imines to afford excellent yields and ee, up to 99%. Scheme 3.1 Asymmetric imine amidation with TsNH2 catalyzed by 117 S-VAPOL However, this reaction was limited to sulfonamide nucleophiles, with other amides affording lower enantioselectivities. Later in the same year, Antilla group5 broadened the substrate scope by applying phthalimide as nucleophile for the addition of imide to imines (Scheme 3.2). Scheme 3.2 Asymmetric imine amidation with phthalimide catalyzed by 117 S-VAPOL Although possibly considered metabolically unstable, cyclic aminals and acetals are relatively common structural elements of diverse commercial pharmaceuticals. Realizing the ubiquitous occurrence of stereogenic cyclic aminals and similar 71 Chapter structures in drugs and other compounds of use and the lack of available enantioselective routes toward their preparations, asymmetric synthesis of chiral aminals shows great importance. Protected aminals have been incorporated into many peptide chains, which is so called retro-inverso mimic.6 These retro-inverso peptide mimics was first popularized by Goodman, due to the applications as proteinase inhibitors, neurotensins, somatostatins, glycosidase inhibitors, amino acid based sweeteners.7 Previously, methodologies to synthesize aminal products have normally been through Curtius or Hoffman-type rearrangements6 of protected amino acid derivatives or by a benzotriazole-mediated approach by Katritzky.8 Figure 3.1 shows several gem-diamine containing pharmaceuticals, which include Aquamox and Thiabutazide, two members of the benzo(thia)diazine class of cyclic aminals used for the treatment of high blood pressure.9a Other examples include S, O-acetal Cevimeline,9b O, O-acetal Pipoxolan,9c N, N-acetal Physostigmine,9d which are all useful pharmaceuticals. Figure 3.1 Gem-diamine containing pharmaceuticals List’s group10 also developed a direct synthesis of chiral aminals from aldehydes 72 Chapter using chiral phosphoric acid 123 as catalyst. After screening various phosphoric acids including VAPOL, high ee was obtained with 123 was as catalyst, affording up to 99% ee (Scheme 3.3). Aliphatic aldehydes provide excellent results, while benzaldehyde only gave moderate ee value. Furthur more, the substrate sulfonamides could also give corresponding cyclic products with excellent enantioselectivities. This methodology has also been applied to synthesize pharmaceutically relevant compounds 124a-e as shown in Figure 3.2.10 Scheme 3.3 Synthesis of chiral aminals from aldehydes using 123 as catalyst Figure 3.2 Pharmaceutically relevant compounds 3.1.2 Amination reaction with azodicarboxylate 73 Chapter Stereoselective C-N bonds formation reaction through the direct amination of substrates is also an important synthetic strategy for organic synthesis. One of the most important amination methodologies is α-amination of carbonyl compounds through the use of azodicarboxylates, which was developed by Evans via a chiral catalyst, magnesium bis(sulfonamide) complex.11 Many classes of carbonyl compounds, such as aldehyde, ketone, α-keto esters, oxindoles and α-cyano esters had been used in amination reactions with azodicarboxylates. A large amount of works have appeared in this area, so several representative examples were chosen to be presented here. Early in 2002, Jørgensen’s group had developed direct asymmetric α-amination of aldehyde with L-proline, providing α-amino aldehyde 127, α-amino alcohols 128a and α-amino acids 128b.12 Excellent yields and enantioselectivities were obtained (Scheme 3.4). Scheme 3.4 Enantioselective α-amination of aldehyde by L-proline Recently, Lu’s group applied cinchona alkaloid derived primary amine 130 as catalyst to furnish the asymmetric amination of α-branched aldehyde (Scheme 3.5).13 CSA was required to form the chiral ion pair, which shows to be the real catalyst in the catalytic cycle. 74 Chapter Scheme 3.5 Enantioselective amination of α-branched aldehyde by 130 Also, cinchona alkaloid derived primary amine 134 could also be applied in the asymmetric amination of aromatic ketones. Chen’s group realized the transformation by using 134 as catalyst, achieving excellent results (Scheme 3.6).14 Scheme 3.6 Enantioselective amination of aromatic ketone by 134 Our group have also developed C-N bonding formation by using fluorinated aromatic ketones as nucleophiles.15 Chiral bicycic guanidine 138 was basic enough to abstract the double activated H. This methodology provides a facile route to the construction of fluorinated quaternary stereogenic centers (Scheme 3.7). Scheme 3.7 Enantioselective amination of fluorinated aromatic ketone catalyzed chiral bicycic guanidine 138 75 Chapter Lu’s group applied the similar strategy, using fluorinated compound as nucleophile, to achieve highly enantioselective amination of fluorinated β-keto ester by novel chiral guanidine 139 derived from cinchona alkaloids (Scheme 3.8).16 Fluorinated products could be transformed to fluorinated Penicillin derivatives easily. Scheme 3.8 Enantioselective amination of fluorinated keto ester by chiral guanidine 139 In the area of guanidine catalysis, Terada’s group developed binaphthyl derived axially chiral guanidine as catalyst for the highly enantioselective amination of 1, 3dicarbonyl compounds.17 Due to the high reactivity and efficience, catalyst loading could lower down to 0.05 mol% (Scheme 3.9). Scheme 3.9 Enantioselective amination of 1, 3-dicarbonyl compounds by axially chiral guanidine 144 Amination of 1, 3-dicarbonyl compounds could also be easily achieved by 76 Chapter phase-transfer catalysis. Maruoka’s group reported a new binaphthyl-derived quaternary phosphonium salt as chiral phase-transfer catalyst, which shows excellent reactivity and enantioselectivity towards the asymmetric amination of β-keto eters.18 Scheme 3.10 Enantioselective amination of β-keto eters by phase-transfer catalyst 147 Shibasaki’s group realized the enantiofacial selectively amination of oxindoles by using bimetallic and monometallic Schiff base catalysis.19 When Z is OH, two Ni atoms would coordinate to the ligand, which leads to R enantiomer selectively. While Z is protected by methyl group, only one Ni atom could coordinate with the ligand, which leads to S enatiomer selectively (Scheme 3.11). Scheme 3.11 Enantiofacial selectivity switch in bimetallic vs monometallic Schiff base catalysis In the amination of α-substituted α-cyanoacetates reactions, Deng’s group also could 77 Chapter tune R and S enantiomer selectively by using quinine and quinidine catalyst 152 (Scheme 3.12).20 Products containing nitrogen-substituted quaternary stereocenters are potential chiral building blocks, such as α, α-disubstituted α-amino acids. Scheme 3.12 Amination of α-substituted α-cyanoacetates by quinine and quinidine catalyst 152 Besides reaction Mannich reaction and amination, there many other reactions could also generate C-N bond, such conjugate addition of azides, siloxyamine, for amination in particular, not only azodicarboxylate, but nitrosobenene type compounds were reported for hydroxylamination reaction. Despite the great success of amination reactions, few groups have investigated the α-amination of glycinate Schiff bases, to obtain asymmetric gem-diaminal glycine derivatives. Such derivatives can be easily modified to obtain chiral α, α-diamino carbonyl compounds, which provided an alternative synthetic route to the chiral aminal subunits found in pharmaceutical drugs. In 2009, Zhou et al. utilized a bifunctional AgOAc catalyst for the α-amination of glycinate Schiff bases to obtain adducts with enantioselectivity up to 98% ee (Schem 3.13).21 However, to date, no report has been described the use of asymmetric phase-transfer catalysis for the synthesis of these optically active α-amino acid derivatives, by emulating the approach of phase-transfer reactions. 78 Chapter Scheme 3.13 Enantioselective α-amination of glycinate Schiff bases with 154 Our pentanidium 80a shows excellent reactivity toward conjugate addition reaction of glycinate Schiff bases. So similarly, it might also show similar reactivity toward α-amination reaction of glycinate Schiff bases. Herein, we describe the enantioselective α-amination of glycinate Schiff bases by pentanidium with good yield and enantioselectivity. 3.2 Pentanidum catalyzed asymmetric α-amination of glycinate Schiff base Similarly, α-amination of glycinate Schiff base proceeded via a nucleophilic conjugate addition pathway. was first deprotonated by base to form an anionic enolate species, which attacked the electrophilic N=N double bond in 126c. A preliminary screening for α-amination of glycinate Schiff base was done using 126c under phase-transfer conditions to determine whether asymmetric induction by pentanidium was present. Using NaOH(s) at room temperature and toluene as solvent, an enantioselectivity of 33% ee was obtained. With this promising lead, further optimization was pursued, in an attempt to further improve enantioselectivity using pentanidium as a chiral phase-transfer catalyst. 79 Chapter Scheme 3.14 Enantioselective α-amination of glycinate Schiff bases by pentanidium 80a 3.2.1Optimization studies Initial optimization studies were done at room temperature using weak bases in toluene, which included carbonates and fluoride salts. Increasing the basicity of carbonates had a positive effect on the enantioselective outcome. This was indicated by an increase in ee from sodium (28% ee) to potassium (48% ee) and cesium (50% ee) carbonate, which correlated with the increase in size of the metal ion on going down the group (Table 3.1, entries 1-3). Stronger carbonates also improved in conversion rates, and higher yields could be obtained within shorter times. The effect of water on enantioselectivity was next studied by using saturated Cs2CO3 (aq) as base. Unfortunately, enantioselectivity decreased slightly to 43% ee, and the reaction took twice as long to complete (entry 4). This was probably due to the hydration of carbonate anions by water molecules leading to a reduction in basicity and diminished ability to deprotonate the acidic proton in 1. Other carbonates used such as Zn2CO3 and Ag2CO3 either gave poorer yields or ee values, and hence not suitable for use in further optimization. A similar trend could be observed for fluoride salts, and enantioselectivity was increased when the base was changed from KF (46% ee) to CsF (60% ee) (entries and 8), this corresponded to an increase in the base strength due to the larger metal counter cation. CsF was thus promising as a potential base for the α-amination reaction. On the other hand, stronger bases such as sodium hydroxide increased reaction rate, but led to side products due to hydrolysis of the labile ester group in and gave a reduced ee value of 33% at room temperature. The enhanced reaction rate for hydroxides encouraged us to lower the temperature further to determine if 80 Chapter enantioselectivity could be improved. Table 3.1 Investigation on the effect of base on α-amination reaction entrya a baseb t (h) yield (%)c ee (%)d Na2CO3 96 52 28 K2CO3 24 87 48 Cs2CO3 18 82 50 Cs2CO3(Sat.aq.) 40 77 43 Zn2CO3 120 - Ag2CO3 15 85 11 KF 24 91 46 CsF 18 88 60 NaOH 0.2 54 33 Reactions conducted using 0.01 mmol of and 126c in 0.5 mL toluene for indicated time. b Solid base used, unless otherwise stated. c Yield of isolated product. d Determined by chiral HPLC using Chiralpak AD-H column. Since Cs2CO3 and CsF gave relatively high ee values (50% and 60%, entries 3,8 respectively) at room temperature with moderately fast reaction rates, further optimization was conducted at a reduced temperature of 0oC. Unfortunately, the reaction proceeded extremely slowly for Cs2CO3 and an almost equivalent ee value of 51% (Table 3.2, entry 1) was obtained (as compared to room temperature). Furthermore, the reaction did not proceed for CsF, and no product was observed after days (entry 2). Thus, stronger bases were subsequently investigated at 0oC, and 81 Chapter reaction rate was greatly enhanced, with the exception of LiOH·H2O and Ca(OH)2, which gave either poor ee values or no product at all (entries and 11). When temperature was reduced to 0oC for NaOH, enantioselectivity increased from 33% to 55% ee (entry 4). However, further reduction in temperature to -20oC reversed the trend, and enantioselectivity dropped to 40% ee (entry 5). This could possibly be due to a greater negative effect of the temperature reduction on the rate of the catalyzed Table 3.2 Investigation on the effect of temperature on α-amination reaction entrya a baseb T (oC) t (h) yield (%)c ee (%)d Cs2CO3 72 64 51 CsF 48 - LiOH·H2O 96 52 20 NaOH 83 55 NaOH -20 2.5 85 40 10 % NaOH (aq.) 41 32 10 % NaOH (aq.) -20 76 35 25 % NaOH (aq.) -20 1.5 80 38 KOH 81 48 10 CsOH·H2O 0.5 70 11 Ca(OH)2 48 - 12 Ba(OH)2 80 40 Reactions conducted using 0.01 mmol of and 126c in 0.5 mL toluene for indicated time. b Solid base used, unless otherwise stated. c Yield of isolated product. d Determined by chiral HPLC using Chiralpak AD-H column. 82 Chapter reaction as compared to the background reaction. The use of aqueous NaOH at different concentrations also led to a decrease in enantioselectivity to 38% ee (entries 6-8), indicating that aqueous base was not favorable for the reaction. Stronger bases such as KOH and CsOH·H2O were also attempted at 0oC, but could not improve enantioselectivity further, giving poorer ee values of 48% and 5% respectively (entires 9-10). Although NaOH gave the highest ee value of 55% as compared to the other hydroxides, enantioselectivity did not match the level attained for CsF at room temperature (60% ee). From these results, it was established that the type of base used had a major impact on enantioselective outcome, and it was surprising to note that lower temperatures were not necessarily favored for this amination reaction. A decision was thus made to use CsF(s) as the base, with further optimization studies conducted at room temperature. The solvent used was next varied and the general trend indicated that increasing the solvent polarity led to a drop in enantioselectivity, as shown in Figure 3.2, and Table 3.3. Enantioselectivity was also disfavoured when the solvent was too low in polarity which might not dissolve catalyst at all. When cyclohexane was used as solvent ee dropped to 48% (Table 3.3, entry 1). On the other hand, aromatic solvents gave favourable ee values, with 60% ee obtained in toluene as reported previously. It was found that increasing the number of methyl substituents present in the aromatic ring had a positive effect, and enantioselectivity increased when the solvent system was changed from benzene (44% ee) to toluene (60% ee), p-xylene (64% ee), mesitlene 83 Chapter (66% ee) (entries 2-5). Increasing the chain length of the substituent from toluene to ethylbenzene, however, gave a comparable ee value of 60%. It was also noted that using other ethereal solvents with similar polarity as toluene such as diethylether and tert-butyl methyl ether gave comparable ee values of 60%, the advantage being that the reaction took a much shorter time of hours to complete (entries 7, 8). Table 3.3 Investigation on the effect of solvent on α-amination reaction a relative entrya solvent t (h) yield (%)b ee (%)c cyclohexane 82 48 0.6 benzene 12 85 44 11.1 toluene 18 88 60 9.9 p-xylene 10 91 64 7.4 mesitylene 15 86 66 5.4 ethylbenzene 20 85 60 - Et2O 88 60 11.7 TBME 90 60 12.4 chlorobenzene 90 38 11.1 10 THF 95 20 20.7 11 CH2Cl2 18 78 30.9 polarityd Reactions conducted using 0.005 mmol of and 125c in 0.1 mL solvent for indicated time. b Yield of isolated product. c Determined by chiral HPLC using Chiralcel AD-H column. d The values for relative polarity were normalized from measurements of solvent shifts of absorption spectra, with polarity of water set to 100 22. 84 Chapter The effect of electron withdrawing substituents present in the aromatic solvent was also investigated, and it was observed that chlorobenzene gave a much poorer enantioselectivity of 38% ee (entry 9). This could be explained by an increase in polarity of the solvent system, allowing for better stabilization of the enolate anion in the organic media without the mediating effects of pentanidium. In this way, the enolate could react directly with the electrophile after being generated at the interface and this enhanced the rate of the uncatalyzed background reaction. Since this did not involve the formation of the configurational ion pair between positively charged pentanidium and the enolate anion, no chiral induction occurred and a greater proportion of substrate reacted to form racemic products. This effect could be also observed when tetrahydrofuran was used as solvent, and the reaction took the shortest time of hours to complete, possibly due to the acceleration of background reactions, with the ee value dropping drastically to 20%. When polarity of the solvent was increased further in dichloromethane, no enantioselectivity was observed, and a racemic mixture was obtained as shown in entry 11. This could be due to the solvation of pentanidium by the polar aprotic solvent, thus shielding the amount of positive charge around pentanidium making it unavailable to interact with the enolate to form configurational ion pair. The higher dielectric constant of dichloromethane provided better solvation and stabilization of electrostatic charges in the reaction mixture. Thus, this caused a decrease in catalyst-substrate interactions, which correlated to the drop in enantioselectivity. Optimization studies indicated that the solvent used had a direct impact on 85 Chapter enantioselectivity, and non-polar aromatic solvents which did not favour charge separation were most favourable, possibly due to the formation of a stronger configurational ion-pair leading to more effective chiral induction by pentanidium. 80 ee (%)/ 70 Polarity 60 Solvent polarity ee (%) 50 40 30 20 10 Solvent Figure 3.2 Effect of solvent polarity on enantioselectivity The effect of base loading on enantioselectivity was next investigated. When large amount of base was used, higher ee was obtained. Further increase in CsF loading to 10 equiv. allowed the reaction to be completed in hours, with a further increase in ee to 70%. This boost in reaction rate could possibly be due to the increase in surface area of the solid base in contact with the solvent which allowed for greater interfacial transfer via the chiral phase-transfer catalyst. Lower catalyst loading prolongs reaction time significantly and higher loading only provides comparable ee values. Thus mol% was decided as the minimal amount of catalyst required for further optimization studies 86 Chapter Table 3.4 Investigation on the effect of concentration on α-amination reaction a entrya conc. [M] t (h) yield (%)b ee (%)c 0.025 12 70 65 0.05 86 70 0.1 88 74 0.2 86 73 Reactions conducted using 0.01 mmol of and 126c for indicated time. b Yield of isolated product. c Determined by chiral HPLC using Chiralpak AD-H column. The concentration effect was examined by varying the volume of solvent used for this reaction. When concentration was lowered from 0.05 M to 0.025 M, reaction time increased to 12 hours and ee value decreased to 65% (Table 3.4, entry 1). The drop in reaction rate could be rationalized from the decrease in frequency of collisions between the substrates when the amount of reagents present was diluted; prolonged reaction rates were not favored due to the enhancement of background reactions, which corresponded to the trend observed previously. Fortunately, an increase in concentration to 0.1 M accelerated the reaction, allowing complete conversion within hours, with an enhanced enantioselectivity of 74% ee (entry 3). However, a further increase in concentration to 0.2 M did not lead to a further improvement in enantioselectivity (entry 4). Thus 0.1 M was decided as the optimal concentration for this reaction and no further increment was attempted. 3.2.2 Mechanism: Proposed catalytic cycle As mentioned in chapter 1, this reaction belongs to the base catalyzed phase-transfer mechanism (interfacial mechanism), as shown in Figure 3.3. Substrate was deprotonated at the interface by the base from aqueous phase to give the 87 Chapter corresponding metalenolate, which stays at the interface of the two layers. Subsequently, pentanidium would undergo ion-exchange process to generate lipophilic chiral onium enolate. Since the enolate entered into organic phase, it would react with the electrophile 126c very fast to afford the optically active amination product 155. Pentanidium 80a provided effective shielding of one of the two enantiotopic faces of the enolate anion. Figure 3.3 Proposed catalytic cycle in asymmetric α-amination of glycinate Schiff base by pentanidium 80a 3.2.3 Enantiomer enriment Pentanidium catalyzed enantioselective α-amination of glycinate Schiff base affords product 155 with 74% ee after optimization. However, product with moderate ee may show limited application, thus enantiomer enrichment is highly required. However, 155 is oil liquid, recrystalization is not suitable for 155 in ee enrinchment. After deprotection of amino group by citric acid and reprotection by benzoyl group, liquid product 156 was obtained. It was observed that 156 is solid state in racemic form, but liquid in chiral 88 Chapter form. After re-crystallization in hexane, optical active 156 was obtained with 96% ee in the residue solutions. Solid 156 from the re-crystallization gives lower ee, 45% (Scheme 3.15). Scheme 3.15 Enrichment of ee of 155 through 156 3.3 Summary Pentanidium has been successfully employed as a chiral phase-transfer catalyst in the asymmetric amination of glycinatae Schiff base. Good yield and moderate ee could be achieved for the α-amination of tert-butyl-glycinate-benzophenone Schiff base with di-tert-butyl azodicarboxylate. Reaction conditions were investigated and optimized to obtain the best results, 80% yield, 74% ee. Finally, α-amination product was transformed to Bz protected chiral aminal with 96% ee after ee enrichment. 89 Chapter Reference 1. Carey, J. 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Reichardt, c.; Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003. 92 [...]... value of 33 % at room temperature The enhanced reaction rate for hydroxides encouraged us to lower the temperature further to determine if 80 Chapter 3 enantioselectivity could be improved Table 3. 1 Investigation on the effect of base on α-amination reaction entrya baseb t (h) yield (%)c ee (%)d 1 96 52 28 2 K2CO3 24 87 48 3 Cs2CO3 18 82 50 4 Cs2CO3(Sat.aq.) 40 77 43 5 Zn2CO3 120 0 - 6 Ag2CO3 15 85 11... under phase- transfer conditions to determine whether asymmetric induction by pentanidium was present Using NaOH(s) at room temperature and toluene as solvent, an enantioselectivity of 33 % ee was obtained With this promising lead, further optimization was pursued, in an attempt to further improve enantioselectivity using pentanidium as a chiral phase- transfer catalyst 79 Chapter 3 Scheme 3. 14 Enantioselective. .. K A Angew Chem.Int Ed 2002, 41, 1790-17 93 13 Liu, C.; Zhu, Q.; Huang, K-W.; Lu, Y Org Lett 2011, 13, 2 638 -2641 14 Liu, T.; Cui, H.; Zhang, Y.; Jiang, K.; Du, W.; He, Z Chen, Y Org Lett 2007, 9, 91 Chapter 3 3671 -36 74 15 Zhao, Y.; Pan, Y.; Liu, H.; Yang, Y.; Jiang, Z.; Tan, C-H Chem Eur J 2011, 17, 35 71 -35 74 16 Han, X.; Zhong, F.; Lu, Y Adv Synth.Catal 2010, 35 2, 2778-2782 17 Terada, M.; Nakano, M.;... electrophile 126c very fast to afford the optically active amination product 155 Pentanidium 80a provided effective shielding of one of the two enantiotopic faces of the enolate anion Figure 3. 3 Proposed catalytic cycle in asymmetric α-amination of glycinate Schiff base by pentanidium 80a 3. 2 .3 Enantiomer enriment Pentanidium catalyzed enantioselective α-amination of glycinate Schiff base affords product 155... in racemic form, but liquid in chiral 88 Chapter 3 form After re-crystallization in hexane, optical active 156 was obtained with 96% ee in the residue solutions Solid 156 from the re-crystallization gives lower ee, 45% (Scheme 3. 15) Scheme 3. 15 Enrichment of ee of 155 through 156 3. 3 Summary Pentanidium has been successfully employed as a chiral phase- transfer catalyst in the asymmetric amination of... reaction entrya baseb T (oC) t (h) yield (%)c ee (%)d 1 0 72 64 51 2 CsF 0 48 0 - 3 LiOH· 2O H 0 96 52 20 4 NaOH 0 2 83 55 5 NaOH -20 2.5 85 40 6 10 % NaOH (aq.) 0 3 41 32 7 10 % NaOH (aq.) -20 2 76 35 8 25 % NaOH (aq.) -20 1.5 80 38 9 KOH 0 1 81 48 10 CsOH· 2O H 0 0.5 70 5 11 Ca(OH)2 0 48 0 - 12 a Cs2CO3 Ba(OH)2 0 6 80 40 Reactions conducted using 0.01 mmol of 1 and 126c in 0.5 mL toluene for indicated...Chapter 3 Scheme 3. 13 Enantioselective α-amination of glycinate Schiff bases 1 with 154 Our pentanidium 80a shows excellent reactivity toward conjugate addition reaction of glycinate Schiff bases So similarly, it might also show similar reactivity toward α-amination reaction of glycinate Schiff bases Herein, we describe the enantioselective α-amination of glycinate Schiff bases by pentanidium with... (interfacial mechanism), as shown in Figure 3. 3 Substrate 1 was deprotonated at the interface by the base from aqueous phase to give the 87 Chapter 3 corresponding metalenolate, which stays at the interface of the two layers Subsequently, pentanidium would undergo ion-exchange process to generate lipophilic chiral onium enolate Since the enolate entered into organic phase, it would react with the electrophile... Ag2CO3 15 85 11 7 KF 24 91 46 8 CsF 18 88 60 9 a Na2CO3 NaOH 0.2 54 33 Reactions conducted using 0.01 mmol of 1 and 126c in 0.5 mL toluene for indicated time b Solid base used, unless otherwise stated c Yield of isolated product d Determined by chiral HPLC using Chiralpak AD-H column Since Cs2CO3 and CsF gave relatively high ee values (50% and 60%, entries 3, 8 respectively) at room temperature with moderately... Table 3. 3 Investigation on the effect of solvent on α-amination reaction relative entrya t (h) yield (%)b ee (%)c 1 cyclohexane 4 82 48 0.6 2 benzene 12 85 44 11.1 3 toluene 18 88 60 9.9 4 p-xylene 10 91 64 7.4 5 mesitylene 15 86 66 5.4 6 ethylbenzene 20 85 60 - 7 Et2O 5 88 60 11.7 8 TBME 5 90 60 12.4 9 chlorobenzene 5 90 38 11.1 10 THF 2 95 20 20.7 11 a solvent CH2Cl2 18 78 0 30 .9 polarityd Reactions . Chapter 3 69 Chapter 3 Pentanidium Catalyzed Enantioselective Phase-Transfer Amination Reaction Chapter 3 70 3. 1 Introduction to asymmetric. derivatives, by emulating the approach of phase-transfer reactions. Chapter 3 79 Scheme 3. 13 Enantioselective α-amination of glycinate Schiff bases 1 with 154 Our pentanidium 80a shows excellent. enantioselectivity using pentanidium as a chiral phase-transfer catalyst. Chapter 3 80 Scheme 3. 14 Enantioselective α-amination of glycinate Schiff bases 1 by pentanidium 80a 3. 2.1Optimization