Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions 4a

Chapter Chapter Enantioselective C-C bond formation reactions of catalyzed by chiral bicyclic guanidine 69 Enatioselective C-C bond formation 4.1 Introduction Asymmetric C-C bond formation reactions are important reactions in organic synthesis. Among the various asymmetric organic reaction, asymmetric Mannich and Michael reactions are much more useful reactions for preparation of chiral functionalized organic molecules. Recently, more efforts were donated to the development of efficient chiral organocatalysts for pre-formed enolates and more reactive methlenes,1 but the highly enantioselective Mannich and Michael reactions of aromatic ketones were still rarely reported. O N R2 R1 Boc + O R1 toluene, -78oC CN 141 NHBoc cat.143 10 mol% Ph R2 CN 144 142 N HN cat. 143 O HN CF3 141a dr: 100/0 yield: 75-81% ee: 90->99% O CN CN 144a: F3C O O R 144b n 141b dr: 86/14-99/1 yield: 75-84% ee: 94-95% CN 141c 144c: dr: 59/41 yield: 80% ee: 98/98% Scheme 4.1 Asymmetric Mannich reaction of -cyano ketones. Kim et al. reported the asymmetric Mannich reaction between -cyano ketones 141 and N-Boc-aldimines 142 in presence of chiral bifunctional 70 Chapter organocatalyst 143. The desired Mannich products 144 were obtained with excellent ee values and good yields. The best enantioselectivities were achieved with cyclic aliphatic ketones 141a. Moreover, cyclic aromatic ketones 141b and acyclic ketone 141c reacted with 142 to afford products with high ee values (up to 98% ee) (Scheme 4.1). Deng et al. reported the highly enantioselective and diastereoselective tandem conjugate addition and protonation of -cyano ketones 145 and -chloroacrylonitrile 146. The -cyano ketones 145 of different ring size were tolerated under the reaction conditions in presence of organocatalyst QD-1 or QD-2 (Scheme 4.2). O CN Cl cat.QD-1or QD-2 (10 mol%) CN toluene, RT + n n = 0, 1, 145 O CN CN Cl n 147 146 OH OMe N OR4 H N HN HN F3C H S N N 9/1-16/1 CF3 dr: yield: 94-99% QD-1 ee: 97-99% R4 = dr: 8/1-25/1 yield: 87-95% QD-2 ee: 91-96% Scheme 4.2 Asymmetric conjugated addition reaction of -cyano ketones. Zhao et al. reported a Michael addition of -substituted cyano ketones to -keto esters using bifunctional thiourea-tertiary amine catalyst 150. The 71 Enatioselective C-C bond formation 3-oxo-3-phenylpropanenitrile 148 reacted with -keto esters 149 to afford the chiral dihydropyrans 151 with high enantioselectivities (up to 95% ee) (Scheme 4.3). O O 150, 2.0 mol% CN + R1 CO2R2 Et2O, RT 149 148 H N R H N CF3 O OH CO2R2 NC 151 N 150 Ph R1 yield: 70-95% ee: 87-95% S R = 4-BnO-C6H4-CH2- CF3 Scheme 4.3 Asymmetric Michael reaction of -substituted cyano ketones This chapter will present the -fluorinated aromatic ketones in the asymmetric Mannich and Michael reactions. 4.2 Asymmetric Mannich reaction of -fluorinated aromatic ketones 4.2.1 Synthesis of imines and pentanidines; Pentanidines catalyzed asymmetric Mannich reaction The imines 154a-154k were prepared according the reported procedures.5 Under neat conditions, they were easily obtained in presence of Si(OEt)4 at high temperature as 160 o C, and the crude products could be purified by recrystallization over Hexane and EA (Scheme 4.4). The purified imines should be kept in the -4 oC fridge. 72 Chapter N O O R2 S NH O R1 Si(OEt)4 SO2R2 R1 160oC 154 yield: 50-90% 153 152 154a: R1 = H, R2 = 3,5-Me2C6H4 154b: R1 = p-Cl, R2 = p-CH3C6H4 154c: R1 = p-Cl, R2 = Me 154d: R1 = p-Cl, R2 = 2-napthyl 154e: R1 = p-Cl, R2 = Bn 154f : R1 = H, R2 = p-ClC6H4 154g: R1 = p-CH3O, R2 = Me 154h: R1 = o-CH3, R2 = Me 154i: R1 = p-Br, R2 = Me 154j: R1 = p-Br, R2 = Et 154k: R1 = p-CH3O, R2 = Bn Scheme 4.4 Synthesis of imines 154 Ar CS2 Ar Ar EtOH/H2O H2N NH2 concd. HCl reflux 155a: Ar = Ph HN H2N RBr K2CO3 Ar Ar 155a: Ar = Ph 155b: Ar = p-CH3OC6H4 Ar Ar RHN NH2 DMF, RT toluene 80oC S 161 Ph N N Ph MeI MeOH, 0oC 1. NH3 (g) MeOH days Ar CH2Cl2 Ar Ar R N N R Ar Ar Lawessen' reagent RHN NR o-xylene 145oC Ar Ar 4Å MS, MeCN reflux Ar R N 158 Cl Cl 162 imidazoline salt Ar HN NH NH 2. NaOH(5 M) HI NH THF, RT SMe 158 157 O 160 N R N N N H HCl Ar 163 Cl Ph N N N 159 Ar NR Ar triphosgene/Et3N NHR (COCl)2 RN NH Ar S 156 155b: Ar = p-CH3OC6H4 Ar Ar N H Ph 163a: Ar = Ph, R = Bn 163b: Ar = Ph, R = Me 163c: Ar = p-CH3OPh, R = Bn 163d: Ar = p-CH3OPh, R = 2-napthyl 163e Scheme 4.5 Synthesis of pentanidines (163a and 163e by Fu xiao; 163b by Dr Chen jie). The chiral pentanidines 163a-163d were prepared from commercial diamine 155 via multi-steps.6 The thiourea 156 was easily prepared from the starting material diamines with excellent yields, by treatment with MeI to afford 73 Enatioselective C-C bond formation compound 157. Then, the guanidine intermediates 158 were obtained from 157 after treatment of 157 with ammonia gas in MeOH solution for three days and basification with NaOH solution. The N-protected 159 were prepared from the same starting material 155, followed by the reaction with triphosgene to give urea 160. Because of the poor reactivity of urea 160, they should be transformed into thiourea 161 by Lawessen’s reagent. Then, the air and moisture sensitive imidazoline salts 162 were prepared form thiourea 161. The pentanidine salts were achieved by the reaction between 162 and 158, followed by basification with K2CO3 to give pure pentanidine catalysts 163a-163d. Pentanidine 163e was prepared by Fuxiao by the modificated procedure of others (Scheme 4.5). Table 4.1 Various pentanidines catalyzed asymmetric Mannich reaction O O N F S O + 154a 82d Entry Pentanidines Reaction time/h a O 10 mol% Pentanidines THF, RT 5-24 h F H O O N S 164a Product Convn/%a drb ee/%c 163a 164a 70 4/1 50/81 163b 15 164a 80 1/3 69/47 163c 15 164a 80 1/3 72/52 163d 24 164a 70 1/5.5 75/50 163e 164a 60 9/1 4/2 Monitored by TLC bMonitored by 1H NMR; c Chiral HPLC analysis The initial asymmetric Mannich reaction was carried out between -fluorinated 74 Chapter aromatic ketone 82d and imine 154a with 10 mol% pentanidine 163a. The desired product 164a was achieved with moderate enantioselectivity and diastereoselectivity (Table 4.1, entry 1). Other pentanidines 163b-163d were also effective for this asymmetric Mannich reaction, and similar results were obtained under the same reaction conditions. The reaction did not show any enantioselectivity in presence of pentanidine 163e although the best diastereoselectivity 1/9 was obtained. Table 4.2 Asymmetric Mannich reaction of various imines a Reaction time/h Product Convn./%a drb ee/%c 164a 70 4/1 50/81 154b 164b 100 1/4 78/56 154c 164c 100 1/2 3/52 154d 24 164d 60 1/1 20/78 154e 15 164e 80 1/4 73/58 154f 24 164f 60 1/4 68/49 Entry Imines 154a Monitored by TLC bMonitored by 1H NMR; c Chiral HPLC analysis Different N-protected imines 154a-154f were examined in the asymmetric reaction in the presence of 10 mol% pentanidine 163a at room temperature. The imines 154b and 154c showed good reactivity with -fluorinated aromatic ketone 75 Enatioselective C-C bond formation 82d, but lower enantio- and diastereoselectivity of product 164c were obtained due to lowered steric effect (Table 4.2 entry 3). The much bulky imine 154a and 154d reacted with 82d slowly and afforded one diastereomer with better enantioselectivities (Table 4.2 entries and 4). 4.2.2 Chiral bicyclic guanidine catalyzed asymmetric Mannich reaction From the results of pentanidines catalyzed asymmetric Mannich reactions, the enantioselectivities and diastereoselectivities were not excellent for all the cases. Table 4.3 Asymmetric Mannich reaction of various imines a T/oC Product Convn./%a drb ee/%c RT 164b 40 3.2/1 28/50 154c RT 164c 70 3/2 82/24 154g RT 164b 80 3/2 92/11 154h RT 164h 30 1/1 83/0 154i -20 164i 60 2/1 89/10 154j -20 164j 60 2/1 90/0 154k -10 164k 80 1.2/1 91/30 Entry Imines 154b Monitored by TLC. bMonitored by 1H NMR. c Chiral HPLC analysis. We examined this reaction by using chiral bicyclic guanidine. And it was 76 Chapter proven to be a good catalyst for the asymmetric Mannich reaction of -fluorinated aromatic ketones. The effect of different protecting groups on imines was investigated in the preliminary study. The reaction between aryl sulfonyl imine 154b and 82d was sluggish with 40% conversion and low enantioselectivity (Table 4.3 entry 1). When the protecting group of imine was replaced by alkyl sulfonyl group, all of the Mannich products (164c-164b, 164h-164k) showed good ee values for one diastereoisomer although the diastereoselectivities were moderate (Table 4.3, entries 2-7). Fortunately, the major diastereosiomers gave the better ee values than their minor counterparts. Table 4.4 Solvent and temperature effect on the asymmetric Mannich reaction of -fluorinated aromatic ketone 82d a T/oC Time/h Convn./%a drb ee/%c RT 18 70 3/2 82/24 DCM RT 18 80 2/1 86/0 toluene RT 18 NR / / TBME RT 18 70 2/1 78/27 DCE -10 66 >90 1.8/1 89/0 DCE -20 96 >90 3.0/1 96/5 Entry Solvent THF Determined by TLC. bDetermined by1H NMR. c Chiral HPLC analysis. 77 Enatioselective C-C bond formation With these results in hand, we took the asymmetric Mannich reaction between 82d and 154c as model reaction for solvents and temperature screening. It was found that chlorinated solvents such as DCM and DCE resulted in much better conversion (Table 4.4 entries and 5). Other common solvents such as THF and TBME were also suitable for this reaction but the ee values decreased slightly (Table 4.4 entries and 4). Toluene was not effective for this reaction. When the reaction temperature decreased to -20 o C, the best enantio- and diastereoselectivity were obtained in DCE after 96 hours (Table 4.4 entry 6). A series of -fluorinated aromatic ketones was investigated in this asymmetric Mannich reaction (Scheme 4.6). We noticed a significant amount of aldehydes arising from the decomposition of imines 154c and 154g, so 4Å molecular sieves was added to reduce this side product. The Mannich products 165 were obtained with excellent ee values and moderate dr values from the -fluorinated aromatic ketones regardless of the electronic and steric properties of their aromatic ring. The five-member ring fluorocarbon nucleophile 82r gave the enantiopure adduct with good yield. Ketones 82h-82k, which were derived from 4-chromanones, were also found to be suitable for this Mannich reaction, providing the enantioselectivities up to 98%. When the imine 154g bearing electron-donating group on its aromatic ring exhibited relatively lower reactivity, the reaction should be carried out at -5 oC with 20% chiral guanidine 25. But fortunately, the enatioselectivity is still high as others with 79% yield. 78 Chapter tBu NMs O F + X R1 R2 82a-82g: X = C 154c R = Cl 82h-82k: X = O 154g R2 = 4-MeO O Br F N N H O tBu F NHMs N 25 (10 mol%) ClCH2CH2Cl, -20 oC 4Å MS, 60-96h R1 X R2 165a,b O O F Cl F 82c 82b TsO 165c: yield: 90%; dr: 3.0/1; 165a: yield: 87%; dr: 5.2/1; 165b: yield: 92%; dr: 3.4/1; ee: 95%/9% ee: 95%/6% ee: 96%/8% O O O F F F 82a 82e 82d 82h O 165d: yield: 78%; dr: 3.0/1; 165e: yield: 70%; dr: 3.3/1; 165h: yield: 88%; dr: 3.0/1; ee: 96%/5% ee: 96%/14% ee: 98%/14% O O O F Cl F F F 82k O 165ic: yield: 94%; dr: 4.6/1; 165j: yield: 88%; dr: 3.0/1; 165k: yield: 90%; dr: 2.4/1; ee: 95%/8% ee: 97%/8% ee: 97%/8% O O F F 82d 82r O 82i 165l: yield: 87%; dr: 3.4/1; ee: >99%/25% O 82j 165md : yield: 79%; dr: 1.8/1; ee: 96%/33% Scheme 4.6 Asymmetric Mannich reaction of -fluorinated aromatic ketones. a Isolated yield. bdr determined by 1H NMR. c20 mol% catalyst was used. dReacted with imine 154g. Moreover, the Mannich adducts was shown to consist mainly of syn-isomers. Although enantioselectivities of the minor anti-isomers were less than 33% ee, the two isomers were easily seperated by flash chromotography for most of examples. The methodology described a simple approach to prepare -fluoro-β-amino carbonyl compounds. The absolute configuration of this Mannich adducts was determined by single-crystal X-ray structural analysis based on the product 165i 79 Enatioselective C-C bond formation (Figure 4.1). Figure 4.1 X-Ray crystallographic structure of 165i. 4.3 Asymmetric Michael reaction of -fluorinated aromatic ketones Inspired by the asymmetric Mannich reaction of fluorocarbon nucleophiles, we examined this kind of nucleophiles for asymmetric Michael reaction with different Michael donors. Scheme 4.7 Asymmetric Michael reaction of -fluorinated aromatic ketone 82d. Conversion was determined by TLC. bdr and ee values were determined by chiral HPLC. a In the preliminary study, N-ethyl maleimide 166a was used as Michael acceptor in the presence of 10 mol% chiral bicyclic guanidine catalyst 25. The Michael adduct 167a was obtained with 50% conversion over 66 hours, moderate ee 80 Chapter values and high dr value (dr: 98/2; ee: 40%/10%) (Scheme 4.7). Table 4.5 Asymmetric Michael reaction of -fluorinated aromatic ketone 82d and N-substituted maleimides 166. Convn./%a drb ee/%c RT 66 50 98/2 40/10 RT 18 20 / / 166c:CH2CH(CH3)2 -50 24 50 92/8 67/50 166:R 166a:Et 166b:Bn 3d T/oC Time/h Entry 166d:Ph RT 18 NR / / 166e:tBu RT 25 NR / / 166f:Me -50 48 50 99/1 86/NA 7d 166f:Me -50 48 50 97/3 85/48 Determined by TLC. bDetermined by1H NMR. c Chiral HPLC analysis.d1.0 equiv. Et3N was added. a With this result in hand, we tried to find a much better acceptor by screening various N-substituted maleimides. In presence of 10 mol% chiral bicyclic guanidine catalyst 25, -fluorinated aromatic ketone 82d and various N-alkyl maleimides 166a-166c and 166f underwent conjugate addition to afford adducts, and the best enantio- and diastereoselectivity of 167f were achieved at -50 oC with 86% ee (dr: 99/1). For the bulky N-tBu maleimide and N-phenyl maleimide, the reactions did not occur even over one day. We tried to add 1.0 equivalent Et3N as 81 Enatioselective C-C bond formation additive, the enantioselectivity was remained and the diastereoselectivity droped slightly with no change of conversion. We took the reaction between 82d and N-methyl maleimide 166f as model reaction for the solvent screening. We found that chlorinated solvents such as DCM and DCE resulted in much better conversion and excellent enantio- and diastereoselectivities (Table 4.6 entries and 4). Other common solvents such as THF were not suitable for this reaction. The ee values decreased slightly when m-xylene was used as the solvent (Table 4.6 entry 3). 7.0 equivalents of Et3N was added to the reaction, the conversion was not improved (Table 4.6 entry 5). Table 4.6 Solvent effect on the asymmetric Michael reaction of -fluorinated aromatic ketone 82d Time/h Convn./%a drb ee/%c / 44 [...]... ee: 72% Scheme 4.8 Asymmetric Michael reaction of  -fluorinated aromatic ketone 82d a Isolated yield bdr and ee values were determined by chiral HPLC cThe reaction was carried out at -50 oC in presence of 1.0 equiv Et 3N Other Michael acceptors such as β-nitro styrenes, chalcones and acrylates were examined in the Michael reaction using  -fluorinated aromatic ketone as nucleophile, no reaction occurred... and C- C bonds formation reactions should be tested by this kind of  -fluorinated aromatic ketone nucleophiles 84 Chapter 4 c) The scope of fluorinated aromatic ketones is limited to cyclic aromatic ketones It is difficult to achieve high conversion and enantioselectivity for the linear aromatic ketones Trying to find a better catalystic system for this kind of nucleophiles is the key solution in the... Summary and future work A series of new pentanidines was prepared over 10 steps synthesis The application of these catalysts in the asymmetric Mannich reaction with  -fluorinated aromatic ketones were examined, moderate enantioselectivities and diastereoselectivities were achieved for most of cases We also have developed 83 Enatioselective C- C bond formation the  -fluorinated aromatic cyclic ketone nucleophiles... presented in this chapter Although the enantioselectivities and diastereoselectivities were excellent, the yields were not satisfactory due to the incomplete reactions Fluorinated quaternary carbon centers, which is one of the most challenging tasks in organic synthesis, were achieved by the asymmetric C- C bond formation reactions of fluorocarbon nucleophiles The future study should focus on the following... by single-crystal X-ray structural analysis based on the product 165i 79 Enatioselective C- C bond formation (Figure 4.1) Figure 4.1 X-Ray crystallographic structure of 165i 4.3 Asymmetric Michael reaction of  -fluorinated aromatic ketones Inspired by the asymmetric Mannich reaction of fluorocarbon nucleophiles, we examined this kind of nucleophiles for asymmetric Michael reaction with different Michael... nucleophiles in asymmetric Mannich reaction catalyzed by chiral bicyclic guanidine The syn-adducts 165 were obtained in high yields (70-95%) with excellent enantioselectivities (94-99% ee) These substrates derived from chromanones 82h-82k were also suitable for this Mannich reaction, providing enantioselectivities of up to 98% ee Asymmetric Michael reaction between  -fluorinated aromatic ketones and N- substituted... Michael donors Scheme 4.7 Asymmetric Michael reaction of  -fluorinated aromatic ketone 82d Conversion was determined by TLC bdr and ee values were determined by chiral HPLC a In the preliminary study, N- ethyl maleimide 166a was used as Michael acceptor in the presence of 10 mol% chiral bicyclic guanidine catalyst 25 The Michael adduct 167a was obtained with 50% conversion over 66 hours, moderate ee 80 Chapter... Determined by TLC bDetermined by1H NMR c Chiral HPLC analysis.d1.0 equiv Et 3N was added a With this result in hand, we tried to find a much better acceptor by screening various N- substituted maleimides In presence of 10 mol% chiral bicyclic guanidine catalyst 25,  -fluorinated aromatic ketone 82d and various N- alkyl maleimides 166a-16 6c and 166f underwent conjugate addition to afford adducts, and the... reaction between 82d and N- methyl maleimide 166f as model reaction for the solvent screening We found that chlorinated solvents such as DCM and DCE resulted in much better conversion and excellent enantio- and diastereoselectivities (Table 4.6 entries 2 and 4) Other common solvents such as THF were not suitable for this reaction The ee values decreased slightly when m-xylene was used as the solvent (Table... following aspects: a) More pentanidines of structural and electronic diversity should be prepared, which may donate a lot for the improvement for the Mannich reaction’s enantioselectivity and diastereoselectivity of  -fluorinated aromatic ketones Moreover, this kind of catalyst should be useful for other asymmetric reactions b) Although the asymmetric Mannich and Michael were developed well, other C- X and . 4.1 Introduction Asymmetric C- C bond formation reactions are important reactions in organic synthesis. Among the various asymmetric organic reaction, asymmetric Mannich and Michael reactions. reaction of -substituted cyano ketones This chapter will present the  -fluorinated aromatic ketones in the asymmetric Mannich and Michael reactions. 4.2 Asymmetric Mannich reaction of  -fluorinated. entries 1 and 4). 4.2.2 Chiral bicyclic guanidine catalyzed asymmetric Mannich reaction From the results of pentanidines catalyzed asymmetric Mannich reactions, the enantioselectivities and