Chapter Chapter Fluorocarbon Nucleophiles in Organocatalysis Introduction 1.1 Introduction The emergence of asymmetric organocatalysis as a reliable strategy for the development of asymmetric reactions represents a remarkable advance in synthetic organic chemistry. For enamine catalysis, iminium catalysis, general acid/base catalysis, nucleophilic catalysis and phase-transfer catalysis, most of these orgnic catalysis systems are electrophile-nucleophile reactions. The nucleophiles in such reactions are very important for the asymmetric transformation by the interaction between the hydrogen bond donor catalyst and substrates. Generally, a chiral acid or a chiral base catalyst can promote an enantioselective nucleophile-electrophile reaction. However, the development of a broadly useful platform for the activation of nucleophiles via base catalysis represented a major challenge in asymmetric catalysis. Recent research efforts have mainly focused on di-carbonyl compounds, which are easily activated and widely used in many asymmetric conjugated addition reactions. Most aliphatic ketone and acetophenone nucleophiles used in organocatalytic asymmetric transformations rely on the formation of highly reactive enamine intermediates.1 On the other hand, Brønsted bases are seldom used as catalysts in reactions of simple carbonyls due to the relatively lower basicity of most organobases, thus its inability to activate the carbonyl through enolization. Successful examples typically employ strategies to increase the acidity of the -proton. For example, activated esters, such as trifluoroethyl Chapter thioesters,2 -cyanothioacetates,3 -substituted cyanoacetates,4 and -nitroacetate5 are valuable nucleophiles for organic base-catalyzed reactions because of their enhanced acidity. Activated aromatic ketones could be also used as nucleophiles for Brønsted base catalyzed reactions, while much more efforts were donated to -cyano ketones.6 This chapter reviews the progress on fluorocarbon nucleophiles used in organocatalysis, and some related transitional metal catalyzed asymmetric reaction of fluorocarbons are also included . 1.2 Fluorocarbon nucleophiles in organocatalysis 1.2.1 Fluoroacetone as nucleophile Using fluoroacetone as the most promising fluorocarbon nucleophile in asymmetric aldol reaction, the methodology provides a useful route for the synthesis of optically active -fluoro-β-hydroxy ketones. Barbas and his coworkers7 reported the first amino alcohol catalyzed direct asymmetric aldol reactions of fluoroacetone with aldehydes using chiral prolinol as catalyst. The formation of more reactive enamine of fluoroactone with L-prolinol made the reaction proceed, although a long reaction time was required in presence of 35 mol% catalyst. In most cases, both aromatic aldehydes and aliphatic aldehydes were tolerated, and the products were formed with high regioselectivities. The anti--fluoroaldol products were obtained in unsatisfactory yields with Introduction moderate enantioselectivities (up to 87% ee) (Scheme 1.1). O O + R H OH O 35 mol% L-prolinol F DMSO 1- d R = Ar, alkyl OH O + R F F R dr: 7:3-10:1 4/5 = 1:4-43:3 yield: 29-82% ee: 79-87% Scheme 1.1 Aldol reaction of aldehydes with fluoroacetone catalyzed by prolinol Direct asymmetric aldol reaction between aldehydes and fluoroacetone provides convenient access to chiral -fluoro-β-hydroxy ketones. However, it is not easy to control the selectivity and generate a single isomer because six isomers were produced in this reaction. Recently, Gong’s group8a has developed a highly enantioselective aldol reaction with fluoroacetone catalyzed by L-proline amide 6. The reaction predominantly afforded with regiomeric ratios of 4/5 ranging from 83/17 to 98/2 and excellent enantioselectivities ranging from 94% to 98%, although the aromatic aldehydes with strong electron-withdrawing group were required as the aldol acceptor (Scheme 1.2 Eq 1). Similarly, Guillena et al.9 also reported a solvent-free asymmetric direct aldol reaction between fluoroacetone and 4-nitrobenzaldehyde catalyzed by (S)-binam-L-prolinamide 8. The anti aldol product was obtained with 80% ee. The anti diastereomers were provided predominantly by the second amine-based organocatalysts, so the highly enantioselective syn-direct aldol reaction remained an important challenge.10 Gong and his coworkers8b designed a Chapter new organocatalyst 7, which was easily synthesized from primary amino acids and β-amino alcohols. The nitro substituted aromatic aldehydes were used as aldol acceptors, and the highly enantioselective syn aldol adducts (up to 99% ee) were achieved with good yields (Scheme 1.2 Eq 2). O O + Ar H OH O 20 mol% THF, 0oC F F O Ar = 4-NO2C6H4 3,5-F2C6H3 3,5-Br2C6H3 NH N H CO2Et CO2Et F Ar OH O + Ar dr: 2:1-4:1 4/5 = 83:17-98:2 yield: 89-96% ee: 95-98% OH O O + Ar H F Ar = 4-NO2C6H4 2-NO2C6H4 3-NO2C6H4 OH O 20 mol% m-xylene, rt F dr: 5:1-15:1 yield:45-82% ee: 93-99% NH O NH2 Ar N H HO H N N H O (S)-Binam-L-prolinamide O NH Scheme 1.2 Aldol reaction of aldehydes with fluoroacetone 1.2.2 Fluorinated 1,3-dicarbonyl compounds as nucleophile Fluorinated 1,3-dicarbonyl compounds are much more reactive fluorocarbon nucleophiles for some asymmetric transformations in the presence of chiral metal complexes or organocatalysts. Introduction O O O R1 R2 N N + BnO F O OBn 0.5 mol% [Cu((S,S)-Ph-Box)](OTf) 11 R1 DCM, RT F O 10a 9a: R1 = Me, R2 = OEt 9b: R1 = Me, R2 = OMe 9c: R1 = Ph, R2 = OEt 9c: R1 = t-Butyl, R2 = OEt 9e: R1 = Me, R2 = O(-)-Menthyl 9f: R1 = Me, R2 = N(Ph)2 O O R1 + R2 Boc N N 10b R2 N COOBn HN COOBn 12 yield: 73-95% ee: 81-94% O Boc mol% cat 14 O OEt N F Boc HN Boc 13 R1 = Ar, yield: 81-84% ee: 61-74% R1 = alkyl, yield: 85% ee: 20%-47% R1 toluene, rt F 9: R1 = Ar, alkyl R2 = OEt O R R NH X HN Ni NH X HN R R 14: R = 4-fluorophenyl, X = Br Scheme 1.3 Asymmetric amination of β-keto esters and amide with azodicarboxylates Togni and co-workers11 reported the first asymmetric amination of β-keto esters 9a-9e and β-keto amide 9f with azodicarboxylates 10a catalyzed by a copper-bisoxzoline catalyst 11. -Fluoro--hydrazino β-keto esters 12, which are also potential precursors for -fluoro--amino acids, could be obtained in good yield with ee up to 94%. However, the preliminary experiments dealing with the cleavage of the N-N bond failed. Subsequently, NMR studies about the N-CO and N-N bonds rotation were examined in their research (Scheme 1.3 Eq 1.). Similar work has also been reported by Kim and his co-worker.12 The air and moisture stable chiral nickel complex 14 was used as a catalyst for the amination reaction between -fluoro-β-ketoesters and azodicarboxylates 10b. The desired products Chapter 13 were obtained with good yields, but the enantioselectivities were moderate (up to 78% ee) (Scheme 1.3 Eq 2). Maruoka et al.13 reported one single entry about asymmetric amination of -fluoro-β-ketoester by the binaphthyl-modified quaternary phosphonium salts, with 73% ee obtained. In contrast to the chiral metal complexes, such fluorinated methane nucleophiles were more efficient under chiral organic base catalyzed conditions. More recently, Lu and his co-workers14a documented the enatioselective amination reactions of β-keto esters and azodicarboxylates 10b catalyzed by a chiral guanidines derived from cinchona alkaloids (G-C-a and G-C-b). The ee values of adducts 13 (up to 92% ee) were higher than the results from Kim’s work (Scheme 1.4). Scheme 1.4 Asymmetric amination of β-keto esters with azodicarboxylates Recently, Lu14b and Wang15a reported highly enantioselective Michael reaction of -fluoro-β-ketoesters and nitroalkenes catalyzed by cinchona alkaloid-derived Introduction organocatalysts, respectively. Lu and co-workers examined -fluoro-β-ketoesters with a wide range of aryl and alkyl nitroolefins 16 catalyzed by cinchona alkaloid-based thiourea bifunctional organocatalyst QD-1. Quantitative yields and excellent enantioselectivities were achieved, although the diastereoselectivities were moderate in most of the cases (Scheme 1.5). The Michael adducts containing fluorinated quaternary carbons can be converted into useful chiral structural scaffolds with three contiguous stereogenic centers 19 and 20 after one or two steps from adduct 18 (Scheme 1.6). Scheme 1.5 Asymmetric Michael reaction of -fluoro-β-ketoesters and nitroalkenes Pioneering work was reported by Wang and his co-workers.15a The alkyl -fluoro-β-ketoesters used as Michael donor reacted with various nitroolefins 16 catalyzed by cinchona alkaloid derivative QD-2 with a low catalyst loading (1 Chapter mol%). The reaction afforded the Michael adducts with moderate diastereoselectivities and excellent enantioselectivities. The adduct 21 was converted to synthetically useful chiral ∆1-pyrrolidine 22 by a simple hydrogenation reaction (Scheme 1.6). O F OH O F O Ph OEt NO2 Ph3SiH, AlCl3 Ph O OEt NO2 DCM, 86% 18 HN Ph EtO Ph F O 19 NiCl2/NaBH4 CH3OH 91% OH 21 80% O O OEt NO2 Cl 1. Fe/CH3COOH 2. NaCNBH3 90% F Raney Ni atm H2 EtOH, 12h Cl Ph F Ph NH 20 CO2Et F 22 ee: 98%, 95% dr: 2.5/1 N Scheme 1.6 Modification of Michael adducts 18 and 21 Another similar work in this area was also done by them.15b They discovered an efficient Michael addition of nitroolefins using commercially available -fluoromalonate as nucleophile. Highly enantioselective Michael adducts 23 (up to 98% ee) were obtained with high yields in presence of QD-2 (Scheme 1.7). Scheme 1.7 Asymmetric Michael reaction of -fluoromalonate and nitroalkenes Introduction Inspired by previous work, Kim and co-workers16 reported this kind of Michael reaction using bifunctional thiourea-type organocatalyst bearing both central and axial chiral elements 17. The Michael adducts were obtained in high yields with moderate diastereoselectivities and excellent enantioselectivities (up to >99% ee) (Scheme 1.5). Scheme 1.8 Asymmetric Michael reaction between -fluoro-β-ketoesters and N-alkyl maleimides Our group17 also developed a highly enantioselective and diastereoselective Michael addition reaction of -fluoro-β-ketoesters (R1 = Ar) with N-alkyl maleimides 24 catalyzed by chiral guanidine 25. Aryl -fluoro-β-ketoesters performed as nucleophiles in this Michael reaction in presence of mol% chial guanidine catalyst. The adducts 26 were afforded with high yields, excellent diastereoselectivities (dr: >99/1) and ee values up to 99% (Scheme 1.8 Eq 1). Aryl -fluoro-β-ketoesters were also found to be good nucleophiles for Michael addition with linear Michael acceptors such as trans-4-oxo-4-arylbutenamides 27. 10 Chapter With 10 equivalents triethylamine as an additive and 20 mol% catalyst loading, the adducts 28 were obtained in excellent eantioselectivities (up to 96%), diastereoselectivities (99:1) (Scheme 1.8 Eq 2). Figure 1.1 Optimized (B3LYP/6-31G*) geometries of the four transition states leading to the (S,R)-, (S,S)-, (R,S)-, and (R,R)-products. Calculated related energies were given in square brackets in KJmol-1 and the bond lengths are given in Ǻ. Side view of the calculated face-on pre-transition state complex was also given. To understand the mechanism, density functional theory (DFT) calculations at the B3LYP/6-31* level were performed. An ion-pair complex between guanidinium cation and -fluoro-β-ketoester was formed, before the maleimide approaches the complex to form a pretransition-state complex. Two possible structures for the pretransition-state complex were hypothesized: face-on or side-on. The side-on TS was strongly preferred over the face-on TS because of the stronger hydrogen bond association with the maleimide carbonyl group. For the 11 Introduction four plausible side-on transition states, the calculated preference for the (S,R)-stereoisomer was in agreement with the observed high enantioselectivity and diasteroselectivity (Figure 1.1). O O O O OH 10 mol% 32a 10 mol% p-NO2C6H4CO2H R3 OR2 + R3 R1 F CO2R2 33 + O CHCl3, RT F NHR' 30: R3 = Ar 29: R1 = Ar R2 = tBu, Et R1 R3 NH2 N H F CO2R2 R1 trans-31 trans-31/33: 1/1-6/1 dr: 6/1->99:1 yield: 44-80% ee: 98->99% 32a: R' = CH2CH2CH3 32b: R' = C(CH3)3 O O R3 O fast OH R1 F R3 CO2R2 I intramolucular aldol reaction O R3 F I' CO2R2 trans-31 R1 dehydration O very slow R1 33 F cis-31 CO2R2 II Scheme 1.9 Asymmetric Robinson annulations of -fluoro-β-ketoesters 29 Most recently, Zhao and co-workers18 reported asymmetric Robinson annulation reaction of -fluoro-β-ketoesters 29 catalyzed by primary-secondary diamine catalysts 32. The multiply substituted fluorinated chiral cyclohexenones trans-31 and 33 were synthesized by the combination of Michael addition, 12 Chapter intramolecular aldol reaction and dehydration. The highly enantioselective products trans-31 (up to >99% ee) were achieved with good yields by the diamine catalyst 32a in presence of 10 mol% p-nitrobenzoic acid as additive (Scheme 1.9). Besides the major products, there was also undehydrated product 33 obtained in the reaction. The ratio of trans-31/33 ranged from 1/1 to 6/1. They proposed a probable mechanism for the observed transformation. Intermediates I and II were achieved by Michael reaction between -fluoro-β-ketoesters 29 and ,β-unsaturated ketones 30. This was followed by intramolecular aldol reaction which gave I’ and 33 respectively. The intermediate I’ underwent the dehydration step quickly to deliver the product trans-31, while dehydration of 33 was very slow due to the intramolecular hydrogen bond interaction between the hydroxyl group and the ester’s carbonyl group (Scheme 1.9). O mol% (S,S)-35 10 equiv. CsOH O OR2 + R1 R3X O R1 mesitylene, 0oC F OR2 F R3 34: R3 = alkyl X = Br, I 9: R1 = Ph, Me R2 = tBu O 35 yield: 68-89% ee: 65-88% R' Br R' = 3,4,5-F3C6H2 N (S,S)-35 R' Scheme 1.10 Asymmetric alkylation of -fluoro-β-ketoesters Maruoka and co-workers19 reported asymmetric alkylation of -fluoro-β-ketoesters and alkyl halide 34 with N-spiro chiral quaternary 13 Introduction ammonium bromide (S,S)-35. Under phase-transfer conditions, fluorocarbon nucleophiles exhibited good reactivity towards various alkyl halides such as allylic and simple alkyl halides. The best enantioselectivity achieved was 89% ee (Scheme 1.10). O O O NBoc OR2 + R1 R3 F S Ph OH F O toluene, -50oC OR2 R3 NHBoc 37 dr: 1/1->19/1 yield: 70-96% ee: 81-99% Trp-a: Ar = 3,5-CF3C6H3 Trp-b: Ar = p-FC6H4 Trp-c: Ar = p-NO2C6H4 N F R1 36: R3 = Ar, alkyl 9: R1 = Ar, alkyl R2 = Et HN 10 mol% Trp-a N H N H O Ph Ar Cl O O O Ph OEt OEt NHBoc NHBoc dr: 1/1 41 yield: 95% ee: 97%/92% 40 dr: 6/1 yield: 92% ee: 82% O O O NH 37 Ph F NHBoc R1 = Ph R2 = Et 38: -fluoro- -lactam 39: -fluoro- -lactone Scheme 1.11 Asymmetric Mannich reaction of -fluoro-β-ketoesters Fluorocarbon nucleophile are also excellent nucleophiles for Mannich reaction under chiral organic base catalysts. Lu and co-workers20 reported asymmetric Mannich reaction of -fluoro-β-ketoesters and N-Boc imine 36 with a tryptophan-derived bifunctional thiourea catalyst Trp-a. High enantioselective Mannich products 37 were observed with a wide range of aromatic and alkyl 14 Chapter -fluoro-β-ketoesters in good diastereoselectivities. -Fluoro-β-lactam 38 and -fluoro-β-lactone 39 were prepared by three steps from the Mannich products 37. The Mannich product 40 was achieved using -chloro-β-ketoester as nucleophile, but slightly lower enantioselectivity was obtained (82% ee, 17% ee lower than the fluorinated one). For the nonfluorinated β-ketoester, the product 41 was obtained with high enantioselectivities for both diastereomers although the dr value was one to one (Scheme 1.11). tBu O O O R1 O N O F 42: R1 = Ar, alkyl + R2 N N O tBu N N H 10 mol% 25 OCEt3 NH O Et3OC DCM, RT 24-36h 43: R2 = Ar N-Eoc imine F N R2 O R1 NH O O Br NH O K2CO3 (2.0 equiv) OEt H Br 45 yield: 65% dr: 4/1 ee: 95% F O 44 dr: 92:8-99:1 yield: 90-99% ee: 95->99% O Et3OC Et3OC O 50% (w/w) NaOH (aq.) + toluene, H2O,RT Et3OC O H F 46a 44 EtOH, -20oC R1 = Me R2 = p-BrC6H4 NH O F H 46b Br yield: 60% 46a/46b: 1/1 ee: 96%, 96% Scheme 1.12 Asymmetric Mannich reaction of β-keto acetyloxazolidinones Pioneering work was also reported by our group.21 β-Keto acetyloxazolidinones were used as fluorocarbon nucleophiles in asymmetric Mannich reaction with N-Eoc imines 43 catalyzed by our chiral guanidine catalyst 25. Excellent diastereoselectivities (up to 99/1) and enantioselectivities (up to 99% ee) were 15 Introduction achieved for the Mannich adducts 44. When the Mannich product was treated with two equivalents potassium carbonate, the -fluoro-β-amino ester 45 was obtained after deacylation, protonation and transesterification steps. When it was treated with sodium hydroxide, -fluoro-β-amino ketone 46a and 46b were generated by decarboxylation and protonation steps (Scheme 1.12). 1.2.3 FBSM and FSM derivatives as nucleophile 1-Fluoro-bis(phenylsulfonyl)methane methane (FSM) derivatives are (FBSM) effective and fluoro(phenylsulfonyl) synthetic equivalent of monofluoromethide species in asymmetric catalysis. With electron withdrawing sulfonyl or nitro functionalities in the molecule, the fluorocarbon is much more acidic. SO2Ph SO2Ph F OAc R1 + R1 PhO2S SO2Ph F 47 L1 or L2 (5 mol%) [{Pd(C3H5)Cl}2] (2.5 mol%) Cs2CO3 (1.1-1.5 equiv) DCM, 0oC FBSM R1 * R1 50 yield: 22-92% ee: 91-97% R1 = Ar OAc AcO OAc O O O OAc SO2Ph SO2Ph 52 51 yield: 87% ee: 95% yield: 75% ee: 96% NH HN N iPr F PhO2S 49 48 F SO2Ph PPh2 Ph2P L1 = PHOX L2 = (R,R)-DPPBA Scheme 1.13 Palladium-catalyzed asymmetric allylic substitution reaction of FBSM 16 Chapter Shibata and his co-workers22a reported the first highly enantioselective allylic substitution reaction between FBSM and allylic acetates (47-49), which was conducted in the presence of chiral palladium complex. For the acyclic and cyclic electrophiles, the FBSM nucleophile showed efficient reactivity using different chiral ligands in the reaction (acyclic: L1; cyclic: L2). The best enantioselectivity obtained was 97% ee (Scheme 1.13). NHBoc R PhO2S SO2Ph + CsOH H2O (1.2 equiv) DCM, -80oC F FBSM 54 NHBoc SO2Ph R SO2Ph yield: 70-98% F ee: 87-99% 55 53 (5 mol%) SO2Ph MeOH, 0oC Mg or Na(Hg),Na2HPO4 Cl N HO H MeO NHBoc Ph 53 R CH2F 56 yield: 74-92% ee: 83-99% N Scheme 1.14 Asymmetric Mannich-type reaction of FBSM Inspired by the initial work, they reported a Mannich-type reaction of FBSM catalyzed by phase-transfer catalyst.22b The in situ generated imines from -amido sulfones 54 reacted with FBSM in the presence of a catalytic amount of N-benzylquinidinium chloride 53. The highly enantioselective Mannich products 55 (up to 99% ee) were obtained with good yields. The removal of the two phenylsulfonyl groups from Mannich products 55 under Mg/MeOH or Na(Hg)/Na2HPO4/MeOH conditions generated the corresponding monofluoromethylated amines 56 with good yields and enantioselectivities 17 Introduction (Scheme 1.14). Scheme 1.15 Asymmetric Mannich reaction of FSM derivatives Our group21 also reported asymmetric Mannich reactions between fluoro(phenylsulfonyl)methane (FSM) derivatives (57 and 58) and N-Eoc imine 43 catalyzed by the chiral guanidine catalyst 25. The Mannich products were achieved with good ee values (59: 90% ee; 60: 85% ee) and diastereoselectivities (59: 86:14; 60: 85:15) (Scheme 1.15). As described above, FBSM and FSM derivatives are efficient fluorocarbon nucleophiles in asymmetric Mannich reaction, hence it should be a Michael-type donor for some common Michael acceptors. Shibata and his coworkers23c demonstrated that FBSM was well performed as nucleophile in the catalytic enantioselective Michael addition of chalcone derivatives 62 in presence of cinchona alkaloids salt 61. The Michael adducts 63 were afforded in good yields with ee values ranging from 82% to 98% under the phase-transfer conditions. Large amounts of base (Cs2CO3, equiv) were, however, required and the 18 Chapter reaction was carried out at much lower temperature (-40 oC) (Scheme 1.16). Ar R1 + F 61, mol% CsCO3 (3 equiv) O FBSM O 63 62 R1 yield: 56-91% ee: 82-98% CF3 R1 = Ar, alkyl SO2Ph Ar DCM, -40oc SO2Ph R' = OMe CF3 OH Br N N H 61 R' F3C CF3 Scheme 1.16 Asymmetric Michael reaction of FBSM Simultaneously, Prakash and co-workers23 reported a Michael reaction between FSM derivatives (FNSM) and chalcone derivatives with cinchona-based bifunctional chiral catalyst QD-1 (structure see Scheme 1.5). The bifunctional catalyst is capable of deprotonating the FNSM into the corresponding carbanion, which can attack the chalcone derivatives without the need for additional base. The Michael adducts 64 were achieved with high diastereomeric ratios (up to 8/1) and excellent enantiomeric excesses (up to enantiopure). They also pointed out that the resulting FNSM carbanion containing fluorine in the -position assumes a tetrahedral structure rather than a planar one which was suggested for nonfluorinated -nitromethane derivatives. This helped to enhance the diasteroselectivity by a possible inversion. The presence of an inversion step between S-FNSM and R-FNSM after deprotonation, indicated that the 19 Introduction stereoselectivity on the -carbon did not originate from the deprotonation step, but from the interaction between FNSM and the chalcone-QD-1 complex (Scheme 1.17). O O Ar S NO2 + R1 O O F 62: R1 = Ar H O F O S NO2 O O S R1 Toluene, -20 c F NO2 O S O S-FNSM anion O S Ph FO NO2 64: yield: 83% dr: 4.5/1-8/1; ee: 92->99% ee (major) 90->99% ee (minor) R3NH+ "inversion" R3NH+ Ar o FNSM R3N S-FNSM QD-1, 10 mol% O S O R3N F NO2 F NO2 H R-FNSM R-FNSM anion Scheme 1.17 Enantioselective Michael addition of FNSM to chalcones Based on Shibata and Prakash’s work, Córdova et al.24 reported another Michael addition of FBSM with ,β-unsaturated aldehydes 65. However, the reaction required acceleration via an additional base additive TEA although 20 mol% of diarylprolinol 66 was used as catalyst. The final products 68 were obtained after a simple in situ reduction of Michael adduct 67 with high ee values (Scheme 1.18). O R1 H + 65: R1 = Ph, alkyl FNSM 66, 20 mol% TEA, 10% Toluene, 6-50oC Ph PhO2S F SO2Ph O R1 67 H F SO2Ph NaBH4 MeOH 0oC PhO2S R1 68: yield: 57-84% ee: 84-95% ee Ph NH OTMS 66 Scheme 1.18 Asymmetric Michael addition between FNSM and ,β-unsaturated aldehydes 20 OH Chapter F O O 69, 10 mol% Ar R1 + FBSM MTBE, RT, 5d 63 OMe N n 70: n = 1,0 R1 For 62: yield: 85-92% ee: 80-93% R1 = alkyl O SO2Ph Ar 62 SO2Ph For 70: yield: 87-93% ee: 86-89% NH2 N 69 Scheme 1.19 Asymmetric Michael reaction of FBSM and ,β-unsaturated ketones Kim and his co-workers25 reported the asymmetric Michael reaction of active methane FBSM and ,β-unsaturated ketones 62 in the presence of bifunctional catalyst 69. Not only linear ,β-unsaturated ketones 62 but also cyclic ones were effective acceptor to the fluorocarbon nucleophile FBSM under organocatalyzed approach. The desired products 63 and 70 were achieved with high yields and good to high enantioselectivities (Scheme 1.19). 1.2.4 Fluorinated aromatic ketone as nucleophile The study of fluorinated aromatic ketones in asymmetric organocatalysis received less attention, although there were some reports about using fluorinated silyl enol ethers derived from -fluorinated cyclic ketones as nucleophile in enantioselective transitional-metal catalyzed reactions.26 21 Introduction 73, 10 mol% equiv KOH 75: 10 mol% 21 equiv KOH O F + R2 F R Br Toluene -10oc or -20oC 74 yield: 33-83% ee: 70-91% 72a: R2 = Ar 72b: R2 = alkyl 71 O R2 = Ph, yield: 73% ee: 62% OH OH Br N N N H 73 I N R1 R1 = 2,3,4,5,6-Me5 H 75 CH2 n n = 4,6,8 R = H, Me Scheme 1.20 Asymmetric alkylation of -fluorotetralone The first report about using -fluorotetralone as nucleophile in asymmetric alkylation reaction was demonstrated by Shioiri and his coworkers in 1999.27 The reaction was conducted between -fluorotetralone 71 and various aryl methyl bromides 72a and alkyl methyl bromides 72b catalyzed by phase-tranfer catalyst 73 in presence of strong base KOH. The desired alkylated adducts 74 were obtained with moderate to high ee values, but the yields were much lower. Recently, Cahard and his co-workers28 reported one single entry of asymmetric alkylation reaction between -fluorotetralone 71 and benzyl bromide (72a: R2 = Ph) using a polymer-supported phase-transfer catalyst 75. The reaction was carried out in presence of 21 equivalents KOH and afforded 2-benzyl-2-fluoro-1-tetralone in 73% yield and 62% ee (Scheme 1.18). 22 the Chapter 1.3 Summary The development of a simple and efficient strategy to introduce fluorine into organic molecules has attracted much attention. During the past few years, organocatalytic approaches employing fluorocarbon compounds as nucleophile in asymmetric C-C bond forming reactions have been well developed. However, most of efforts focus on to the more reactive fluorocarbon nucleophiles such as fluorinated dicarbonyl compounds, FBSM and FSM derivatives. For the -fluorinated ketone nucleophiles, some progress has been made by utilizing fluoroacetone as donor in asymmetric aldol reaction, which mainly depend on the formation of reactive enamine intermediate. Fluorinated aromatic ketone nucleophile is less studied in asymmetric catalysis, although there are two examples reported under much stronger basic phase-transfer conditions. We will describe the asymmetric H/D exchange reaction, C-N and C-C bonds formation reactions catalyzed by our guanidine catalysts in the following chapters. 23 Introduction References: (1) Berkessel, A.; Groger, H. asymmetric organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH Verlag GmbH &Co. KGaA: Weinheim, Germany, 2005. (2) (a) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F., III. Angew. Chem. Int. Ed. 2008, 47, 4588. (b) Utsumi, N.; Kitagaki, S.; Barbas, C. F., III. Org. Lett. 2008, 10, 3405. (c) Kohler, M. C.; Yost, J. M.; Garnsey, M. R.; Coltart, D. M. Org. Lett. 2010, 12, 3376. (3) Terada, M.; Tsushima, D.; Nakano, M. Adv. Synth. Catal. 2009, 351, 2817. (4) (a) Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem. Int. Ed. 2008, 47, 3414. (b) Marini, F.; Sternativo, S.; Verme, F. D.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2009, 351, 103. (c) Liu, T.-Y.; Li, R.; Chai, Q.; Long J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem. Eur. J. 2007, 13, 319. (d) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (e) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. (f) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 1038. (g) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948. (5) (a) Wang, J.; Zu, L.; Jiang, W.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (b) Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2010, 51, 2906. (n) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897. (c) Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878. (6) (a) Wang, B.; Wu, F.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (b) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (c) Lee, J.-H.; Kim, D. Y. Adv. Synth. Catal. 2009, 351, 1779. (d) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659. (d) Zhao, S.-L.; Zheng, C.-W.; Wang, H.-F.; Zhao, G. Adv. Synth. Catal. 2009, 351, 2811. (7) Zhong, G.; Fan, J.; Barbas, C. F. III. Tetrahedron Lett. 2004, 45, 5681. 24 Chapter (8) (a) Xu, X.-Y.; Wang, Y.-J.; Cun, L.-F.; Gong, L.-Z. Tetrahedron: Asymmetry 2007, 18, 237. (b) Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z. Org. Lett. 2007, 9, 4247. (9) Guillena, G.; Hita, M. C.; Najera, C.; Viózquez, S. F. J. Org. Chem. 2008, 73, 5933. (10) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 1998, 120, 2768. (11) Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658. (12) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. J. Fluorine Chem. 2009, 130, 259. (13) He, R.; Wang, X.; Hashimoto, K.; Maruoka, K. Angew. Chem. Int. Ed. 2008, 47, 9466. (14) (a) Han, X.; Zhong, F.; Lu. Y. Adv. Synth. Catal. 2010, 352, 2778.(b) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009, 2044. (15) (a) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Chem. Commun. 2009, 2136. (b) Li, H.; Zu, L.; Xie, H.; Wang, W. Synthesis 2009, 9, 1525. (16) Oh, Y.; Kim, S. M.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4674. (17) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K.-W.; Wang, M. W.; Tan, C.-H. Angew. Chem. Int. Ed. 2009, 48, 3627. (18) Cui, H.-F.; Yang, Y.-Q.; Chai, Z.; Li, P.; Zheng, C.-W.; Zhu, S.-Z.; Zhao, G. J. Org. Chem. 2010, 75, 117. (19) Ding, C.; Maruoka, K. Synlett 2009, 4, 664. (20) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem. Int. Ed. 2009, 48, 7604. (21) Pan, Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem. Eur. J. 2009, 16, 779. (22) (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973. (b) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394. 25 Introduction (c) Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed. 2008, 47, 8051. (23) Prakash, G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4090. (24) Ullah, F.; Zhao, G.-L.; Deiana, L.; Zhu, M.; Dziedzic, P.; Ibrahem, I.; Hammar, P.; Sun, J.; Córdova, A. Chem. Eur. J. 2009, 15, 10013. (25) Moon, H. W.; Cho, M. J.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4896. (26) (a) Bėlanger, Ė.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007, 129, 1034. (b) Liu, W.-B.; Zheng, S.-C.; Zhao, X.-M.; Dai, L-X.; You, S.-L. Chem. Commun. 2009, 6604. (27) Arai, S ; Oku, M.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999, 40, 6785. (28) Thierry, B.; Perrard, T.; Audouard, C.; Plaquevent, J.-C.; Cahard, D. Synthesis 2001, 11, 1742. 26 [...]... Fluorinated aromatic ketone nucleophile is less studied in asymmetric catalysis, although there are two examples reported under much stronger basic phase-transfer conditions We will describe the asymmetric H/D exchange reaction, C- N and C- C bonds formation reactions catalyzed by our guanidine catalysts in the following chapters 23 Introduction References: (1) Berkessel, A.; Groger, H asymmetric organocatalysis:... out in presence of 21 equivalents KOH and afforded 2-benzyl-2-fluoro-1-tetralone in 73% yield and 62% ee (Scheme 1.18) 22 the Chapter 1 1.3 Summary The development of a simple and efficient strategy to introduce fluorine into organic molecules has attracted much attention During the past few years, organocatalytic approaches employing fluorocarbon compounds as nucleophile in asymmetric C- C bond forming... forming reactions have been well developed However, most of efforts focus on to the more reactive fluorocarbon nucleophiles such as fluorinated dicarbonyl compounds, FBSM and FSM derivatives For the  -fluorinated ketone nucleophiles, some progress has been made by utilizing fluoroacetone as donor in asymmetric aldol reaction, which mainly depend on the formation of reactive enamine intermediate Fluorinated. .. bifunctional catalyst 69 Not only linear ,β-unsaturated ketones 62 but also cyclic ones were effective acceptor to the fluorocarbon nucleophile FBSM under organocatalyzed approach The desired products 63 and 70 were achieved with high yields and good to high enantioselectivities (Scheme 1.19) 1.2.4 Fluorinated aromatic ketone as nucleophile The study of fluorinated aromatic ketones in asymmetric organocatalysis... 96% Scheme 1.12 Asymmetric Mannich reaction of β-keto acetyloxazolidinones Pioneering work was also reported by our group.21 β-Keto acetyloxazolidinones were used as fluorocarbon nucleophiles in asymmetric Mannich reaction with N- Eoc imines 43 catalyzed by our chiral guanidine catalyst 25 Excellent diastereoselectivities (up to 99/1) and enantioselectivities (up to 99% ee) were 15 Introduction achieved... Simultaneously, Prakash and co-workers23 reported a Michael reaction between FSM derivatives (FNSM) and chalcone derivatives with cinchona-based bifunctional chiral catalyst QD-1 (structure see Scheme 1.5) The bifunctional catalyst is capable of deprotonating the FNSM into the corresponding carbanion, which can attack the chalcone derivatives without the need for additional base The Michael adducts 64... F cis-31 CO2R2 II Scheme 1.9 Asymmetric Robinson annulations of -fluoro-β-ketoesters 29 Most recently, Zhao and co-workers18 reported asymmetric Robinson annulation reaction of -fluoro-β-ketoesters 29 catalyzed by primary-secondary diamine catalysts 32 The multiply substituted fluorinated chiral cyclohexenones trans-31 and 33 were synthesized by the combination of Michael addition, 12 Chapter 1 intramolecular... excellent nucleophiles for Mannich reaction under chiral organic base catalysts Lu and co-workers20 reported asymmetric Mannich reaction of -fluoro-β-ketoesters 9 and N- Boc imine 36 with a tryptophan-derived bifunctional thiourea catalyst Trp-a High enantioselective Mannich products 37 were observed with a wide range of aromatic and alkyl 14 Chapter 1 -fluoro-β-ketoesters in good diastereoselectivities... asymmetric Mannich reaction, hence it should be a Michael-type donor for some common Michael acceptors Shibata and his coworkers2 3c demonstrated that FBSM was well performed as nucleophile in the catalytic enantioselective Michael addition of chalcone derivatives 62 in presence of cinchona alkaloids salt 61 The Michael adducts 63 were afforded in good yields with ee values ranging from 82% to 98% under... were achieved with high diastereomeric ratios (up to 8/1) and excellent enantiomeric excesses (up to enantiopure) They also pointed out that the resulting FNSM carbanion containing fluorine in the -position assumes a tetrahedral structure rather than a planar one which was suggested for nonfluorinated -nitromethane derivatives This helped to enhance the diasteroselectivity by a possible inversion The . efforts have mainly focused on di-carbonyl compounds, which are easily activated and widely used in many asymmetric conjugated addition reactions. Most aliphatic ketone and acetophenone nucleophiles. development of asymmetric reactions represents a remarkable advance in synthetic organic chemistry. For enamine catalysis, iminium catalysis, general acid/base catalysis, nucleophilic catalysis and. in most of the cases (Scheme 1.5). The Michael adducts containing fluorinated quaternary carbons can be converted into useful chiral structural scaffolds with three contiguous stereogenic centers