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

Chapter Chapter Enantioselective C-N bond formation reaction catalyzed by chiral bicyclic guanidine 41 Enatioselective C-N bond formation 3.1 Introduction The catalytic, enantioselective, direct C-N bond formation reaction using carbonyl compounds and nitrogen sources, such as azodicarboxylates, is the simplest strategy for the construction of a stereogenic carbon center attached to a nitrogen atom. It provides a much convenient way to synthesize optically active -amino acid derivatives.1 O HN N O EtO2C + 84 N N O R2 R1 83 R1 = Me, Et R2 = Me, Et, Bn, iPr 87 yield: 67%; 84% ee CO2Et 86 L-proline (10 mol%) CO2Et CO2Et O MeCN, RT R1 HN N O CO2Et + CO2Et R2 HN N CO2Et CO2Et R2 85-major 85-minor for R1 = Me major: minor = 76:24-91:9 major: yield: 77-92%; 94-99% ee Scheme 3.1 L-proline catalyzed asymmetric -amination of aliphatic ketones The direct -amination reaction of aliphatic ketones was developed well under organocatalysis conditions. The first catalytic enantioselective direct -amination reaction of ketones was presented by Jørgensen and his coworkers in 2002.2 The direct -amination of the various aliphatic ketones 83 (R1 = alkyl) by diethyl azodicarboxylate (DEAD) was carried out in the presence of L-proline with excellent enantioselectivities (85-major: up to 99% ee), and the reaction was highly regioselective as the -amination took place at the highest substituted carbon atoms. The -hydrazino ketone 86 derived from cyclohexanone was 42 Chapter obtained in good yield and with 84% ee (Scheme 3.1). O R1 EtO2C R2 + 83 R1 = Ar N N 88 (10 mol%) p-TSA (40 mol%) CO2Et O R1 2-PrOH, 40oC 4Å MS, 72 h CO2Et CO2Et R2 87 O HN N 89 O O R Br R1 83a R = Cl 83d R = Br 83g R = F 83j 83b R = H 83e R = CH3 83h R = Br 83c R = F 83f R = OCH 83i R = CH3 89j: 89a-89f: 89g-89i: yield: 52%; 97% ee yield: 52-77%; 93-98% ee yield: 49-77%; 96-98% ee O O O O S O OMe O Ph Ph Ph 83k 83m 83n 83l 89k: 89l: 89n: 89m: yield: 63%; 96% ee yield: 74%; 90% ee yield: 51%; 88% ee yield: 39%; 96% ee O R3 N O 83o R3 = Br OMe 83p R3 = Cl 89o-89p yield: 63-65%; 91% ee NH2 N 88 Scheme 3.2 Direct asymmetric -amination of aryl ketones In contrast, aromatic ketones are less used as direct nucleophilic donors in the asymmetric organocatalysis due to the difficulty in the formation and poor reactivity of the corresponding enamine intermediates. Chen and his co-workers3 reported the direct enantioselective -amination reaction of aryl ketones 83g-83i (R1 = Ar) with diethyl azodicarboxylate 87. The chiral primary amine catalyst 88 was suitable for the generation of nucleophilic enamines with aryl ketones 83g-83i (R1 = Ar) in presence of 40 mol% p-toluenesulfonic acid (p-TSA). The 43 Enatioselective C-N bond formation linear aromatic ketones 83a-83k, 83m-83p and fused cyclic aromatic ketone 83l were tolerated in this amination reaction. Moreover, the amination products 89 were obtained with high ee values (up to 99% ee), although the yields of all the entries were only moderate (yields of 89: 39%-77%). Long reaction time (72 h) and high temperature (40 oC) were required because of the poor reactivity of enamine intermediates of aromatic ketones (Scheme 3.2). O tBuO2C R Ar + CN 90 N N O 17 (10 mol%) o CO2tBu toluene, RT~-78 C Ar NC R 10b O CN 90a 91a: yield: 77-95%; 97-99% ee CO2tBu CO2tBu 91 CN O O CN R' n HN N R1 R2 90c; R2 = Me, Et 90b : R1 = Ar, allyl 91b: 91c: yield: 92-94%; 87-99% ee yield: 45-93%; 90-96% ee Scheme 3.3 Direct asymmetric -amination of -cyanoketones Recently, Kim and his co-workers4 reported the direct -amination reaction of cyclic and acyclic -cyanoketones 90 catalyzed by bifunctional organocatalyst 17 with azodicarboxylate 10b as the electrophilic nitrogen source (the structure of 17, see Chapter 1). The desired -aminated products 91 were obtained in good to high yields, and excellent enantioselectivities (87-99% ee) were observed for all the entries. Actually, the introduction of cyano group to the aromatic ketones reduced the pKa value of -proton and drove enolate formation, which made the aromatic ketones suitable to the organocatalysis (Scheme 3.3). 44 Chapter 3.2 Enantioselective amination reaction of -fluorinated aromatic ketones 3.2.1 Synthesis of -fluorinated carbonyl compounds 82m-82t, 99a-99c and di-3-ethylpentan-3-yl azodicarboxylate 106. The procedure of -fluorinated cyclic aromatic ketones 82a-82l was shown in Chapter (Scheme 2.4 in Page 31). Other types of -fluorinated aromatic ketones 82n-82o was prepared by the modification of reported procedure.5 Scheme 3.4 Synthesis of linear -fluorinated ketones Linear -fluorinated aromatic ketone 82m was easily prepared according to same procedure as synthesis of 82a (Scheme 3.4 equation 1). For 82n and 82o, the intermediates 94 were obtained by bromonation of starting material 93 catalyzed by AlCl3, followed by halogen substitution between KF and 94. The linear -fluorinated aromatic ketones 82n and 82o were achieved with moderate yields due to the difficulty of chromatography of products and unconsumed starting material (Scheme 3.4 equation 2). 45 Enatioselective C-N bond formation We also prepared some other -fluorinated carbonyl compounds 99a-99c for the initial examination of asymmetric amination reaction.6 From commercially available starting material 2-fluoro-2-phenylacetic acid ethyl 95, 2-fluoro-2-phenylacetate 99b was obtained by esterification reaction under strong acid catalyzed conditions. Starting material 95 could be activated by cyanuric chloride 96 by the conversion of carboxylic acid into more reactive acyl chloride, followed esterification with thiol phenyl to generate 99a. 3-(2-Fluoro-2-pheny lacetyl)oxazolidin-2-one 99c was prepared from 95 via nucleophilic attack of lithium salt of oxazolidin-2-one 98 to in situ generated anhydride between 95 and pivaloyl chloride 97 at -78 oC (Scheme 3.5). Cl 0.3 equiv. N Cl F SPh O 99a yield: 48% N 96 N Cl EtOH F OH equiv. PhSH 1.1 equiv. DCM, 0oC O N O RT 95 1. 1.1 equiv. O F concd. H2SO4 OEt bezene reflux O 99b yield: 47.2% 2. 1.1 equiv. O HN Cl 97 O 98 1.5 equiv. Et3N 1.1 equiv. n-BuLi -78oC -78oC F N O O O 99c yield: 42% Scheme 3.5 Synthesis of -fluorinated carbonyl compounds 99a-99c The new nitrogen source di-3-ethylpentan-3-yl azodicarboxylate 106 was prepared by five-step synthesis according to the modification procedure of 46 Chapter literature.7 reported The bulkier version of azodicarboxylate, di-3-ethylpentan-3-yl azodicarboxylate 106, was designed as we are aware that bicyclic guanidine catalyst responds positively to an increase in steric demand of the substrate. 3-Ethylpentan-3-yl 1H-imidazole-1-carboxylate 102 was synthesized with 82% yield from the much cheaper starting material 1,1’-carbonyldiimidazole (CDI) 100 and 3-ethylpentan-3-ol 101. Under basic condition, 102 reacted with hydrazine hydrate to give 3-ethylpentan-3-yl hydrazinecarboxylate 103 followed treatment by NaNO2 to generate 3-ethylpentan-3-yl carbonazidate 104. The key intermediate 105 was obtained by the reaction between 104 and 103 using pyridine as solvent. After the oxidation with Br2 in pyridine, the product 106 was obtained as yellow solid (Scheme 3.6). O O N N N N + 0.6% KOH Et3COH O Et3CO N H Na2CO3/EtOH NH2 103: yield: 70% Py. rt O NaNO2 Et3CO HOAc, H2O 0oC N3 104 O O Et3CO N 102:yield: 82% NH2NH2 H2O 103 N toluene 60oC 101 100:CDI Et3CO N H H N OCEt3 O 105 Br2, Py. Et CO 0oC to rt N N OCEt3 O 106: yield: 80% two steps yield: 46% Scheme 3.6 Synthesis of di-3-ethylpentan-3-yl azodicarboxylate 106 3.2.2 Initial examination of asymmetric amination reaction with Boc=Boc 10b Firstly, we carried out asymmetric amination between -fluorinated aromatic 47 Enatioselective C-N bond formation cyclic ketone 82d and azodicarboxylate Boc=Boc 10b in presence of 10 mol% chiral bicyclic guanidine catalyst 25 at room temperature. The desired product -hydrozino--fluorinated aromatic cyclic ketone 107d was obtained with high yield and 76% ee (Scheme 3.7). Scheme 3.7 Asymmetric amination reation of -fluorinated aromatic cyclic ketone Scheme 3.8 Other -fluorinated compounds tested in asymmetric amination. a Conversion of corresponding products determined by TLC. bChiral HPLC ananlysis for corresponding products. Inspired by this result, other -fluorinated carbonyl compounds were tested under the same reaction conditions (Scheme 3.8). The linear -fluorinated aromatic ketones 82m-82o showed some reactivity in the asymmetric amination reaction, the best enantioselectivity was obtained with 60% ee and 80% conversion when with electron-withdrawing group in the aromatic ring of 82o was 48 Chapter used as nucleophile. For -fluorinated carbonyl compounds 99a-99c derived from 2-fluoro-2-phenylacetic acid 95, they were less effective in this reaction. 3.2.3 Optimization of asymmetric amination reaction of -fluorinated aromatic cyclic ketones Table 3.1 Optimization study of asymmetric amination of -fluorinated aromatic ketone. a Entry Solvent 10b or106 T[h] T[oC] Yield [%]a Ee [%]b CH2Cl2 10b 24 rt 80 45 hexane 10b 20 rt 81 72 Toluene 10b 20 rt 88 64 acetone 10b rt 92 72 DME 10b rt 80 75 iPr2O 10b rt 80 75 Et2O 10b rt 90 75 THF 10b rt 95 76 THF 10b 15 -20 92 84 10 THF 106 30 86 94 Isolated yields; b Chiral HPLC analysis. Because of the better results obtained from -fluorinated aromatic cyclic 49 Enatioselective C-N bond formation ketone 82d, we took the reaction as model reaction for the further study. 1,5,7-triazabicyclo[4.4.0]dec-1-ene (TBD) was used as catalyst for the achiral version. In our optimization studies with -fluorinated aromatic ketone 82d, we screened different solvents for this asymmetric amination reaction at room temperature or lowered temperatures. The common solvents gave moderate enationselectivities (Table 3.1, entries 1-4). Lewis base type solvents were found to be the best solvent for this asymmetric amination reaction (Table 3.1, entries 5-8). The best result obtained was 84% ee in THF at -20 oC (Table 3.1, entry 9). -Hydrozino--fluorinated aromatic cyclic ketone 108d was obtained in 94% ee with 86% yield when the novel azodicarboxylate 106 (EocN=NEoc) was used as the nitrogen source (Table 3.1, entry 10). However, the reaction was carried out at oC (Table 3.1). 3.2.4 The scope of asymmetric amination reation With the optimal reaction conditions in hand (THF as solvent and reaction temperature less than 0oC), the scope of the direct -amination reaction between -fluorinated aromatic ketones 82a-82k, 82o and azodicarboxylate 106 was investigated. A variety of cyclic ketones 82a-82g with varying substituents on the aromatic ring was prepared from -tetralone derivatives. Excellent yields and high ee values were achieved irrespective of the electronic nature or positions of the substituents on the aromatic ring (Scheme 3.9). Substrate 82e bearing two electron-donating groups underwent direct amination reaction in 94% yield and 50 Chapter The absolute configuration of 108a was determined to be (S) by X-ray crystallographic ananlysis (Figure 3.1). The stereochemistry of other amination products (108b~108k) was 3.2.5 Proposed mechanism of asymmetric amination reation Recently, there was an increased attention for utilizing chiral guanidine molecular as Brønsted base catalyst. The guanidinium intermediate was formed by abstracting one proton from the substrate, which could contribute to the stabilization of anionic reaction intermediates through electrostatic interaction and recognize at the active site through hydrogen bonding.9 R1 R2 E N N H R1 R1 N H R2 R2 Nu N R1 R N H Nu N H E R3 a R3 b Figure 3.2 Previously proposed mechanisms of guanidine There were two previously proposed mechanisms for guanidine catalyzed addition reaction. (a) guanidine molecular act as a dual hydrogen bond donor to form a complex with the deprotonated substrate to attack the electrophile directly; (b) the hydrogen bond formation with the substrate as well as the electrophile to generate a pre-transition-state intermolecular complex (Figure 3.2). Our group reported two crystal structures of guanidine salt: guanidinium 53 Enatioselective C-N bond formation chloride (Figure 3.3) and guanidinium chloride mono hydrate (Figure 3.4). These experimental details supported the model of bifunctional activation between the guanidine catalyst and substrates.10 N N H N H Cl Figure 3.3 X-ray structure of guanidinium chloride. N N N H H Cl H O H Figure 3.4 X-ray structure of guanidinium chloride mono hydrate. The bifunctional mode of the guanidine catalyst was also demonstrated in asymmetric Michael reaction by DFT calculations.11 The Michael reaction was carried out between -fluoro-β-ketoesters and N-substituted maleimides 24 catalyzed by the chiral guanidine catalyst 25 (see, Chapter 1. Scheme 1.8). There were two possible structures for the pretransition-state complex: face-on or side-on. The side-on TS was strongly preferred over the face-on TS because of the 54 Chapter stronger hydrogen bond associated with the maleimide carbonyl group. For the four plausible side-on transition states, the calculated preference for the (S,R)-stereoisomer is in agreement with the observed high enantioselectivity and diasteroselectivity. Interestingly, only one of the two carbonyl oxygens of the -fluoro-β-ketoesters formed a hydrogen bond with a guanidinium NH proton in all cases (see, Chapter Figure 1.1). O CO2R F NH N CO2R O F N tBu 108d N H tBu 82d N 25 tBu tBu RO2C H N N H N N CO2R O H N F N N O N H F tBu tBu I III tBu H N RO2C N N N O H N CO2R F tBu II ion pair complex Figure 3.5 The proposed mechanism of asymmetric -amination From the above experiments and the previous experimental results obtained, we can postulate some facts about the mechanism of this direct asymmetric amination reaction of -fluorinated aromatic ketones (Figure 3.5). Guanidine catalyst 25 was 55 Enatioselective C-N bond formation basic enough to deprotonate fluorinated ketone 82d to form the ion pair complex II from intermediate I, which was also supported by the asymmetric H/D exchange experiments. The bifunctional guanidine would activate the azocarboxylate though hydrogen bonding before it approached the si-face of the enolate (intermediate III). The catalyst would be regenerated after releasing the desired amination product 108d. 3.3 Modification of amination products -Fluoro--amino acid structure A is one kind of special -amino acid in anticipation of the inherent chemical properties and biological activities caused by the introduction of a fluorine atom. However, it is a challenge to achieve this kind of structure due to the instability. F R C CO2 NH3 A In 1991, Takeuchi and his coworkers described the synthetic details of the synthesis of this kind of fluorinated compounds.12 The amino protected compound 109 was treated with CF3CO2D to cleavage the amino protective group, but the defluorinated product 113 was formed, presumably via the oxazolone intermediate 112. Therefore, cleavage of the ester group prior to deprotection of the amino group seemed indispensable to maintain the fluorine atom. The N-protected 56 Chapter compound 110 was accomplished smoothly without defluorination. When it was treated with a catalytic amount of CF3CO2D or HF in CDCl3, one of the two carboxylates was cleaved easily to form the unstable intermediate 111. However, prolonged exposure of compound 111 to an excess of HF in CDCl3, defluorination occurred via N-carboxyimine structure and leaded to decomposed product (Scheme 3.10). F H 5% NaOH CO2Et N(CO2tBu)2 cat. CH3CO2D, or HF F H EtOH COOH N(CO2tBu)2 F H CDCl3 110 yield: 92% 109 111 unstable excess of HF CDCl3 CH3CO2D CDCl3 O F N COOH NHCO2tBu H O OtBu 112 unstable H C COOH NCO2tBu OEt COOEt NHCO2tBu 114 113 decomposition products Scheme 3.10 Dehydrofluorination of 109 under acidic conditions F H CO2Et N(CO2Bn)2 CF3CO2D CDCl3 F H COOH N(CO2Bn)2 O TMSI F CDCl3 116 yield: 49% 115 H2/Pd-C EtOH F H C CO2 NH3 118 N O OBn 117 unstable decomposition products Scheme 3.11 Dehydrofluorination of 109 under neutral conditions In considering unfavorable acidic conditions, they tried neutral conditions for 57 Enatioselective C-N bond formation N-deprotection (Scheme 3.11). Treatment of compound 115 with CF3CO2D in CDCl3, the desired carboxylic acid 116 was obtained with 49% yield. Then, the use of TMSI for carbamate cleavage of compound 116 was attempted, but afforded the oxazolone 117, which decomposed slowly and accompanied by defluorination. The compound 115 was submitted to Pd/C catalyzed hydrogenation, but it was unsuccessful to get desired product 118. Figure 3.6 Computational study by the GAUSSIAN 86 and GAMESS programs. Theoretical studies on the elimination of hydrogen fluoride and its substituent effect was studied by Fang et al.13 Using the RHF/3-21G method, the activation barriers were lowered obviously when the NH2 substituent was introduced into  position, the ,-elimination or ,β-elimination occurred (Figure 3.6 a). Therefore, the lone-pair electron of the N atom in the NH2 group may be involved in F-C-N bonding (Figure 3.6 b and c), as the C-F bond length increased, the C-N bond became a “double bond” at both TSS, and the energies of the two TSS 58 Chapter (,-elimination: 63.0 Kcal/mol; ,β-elimination: 63.8 Kcal/mol) were lowered obviously. Recently, Togni and his coworkers14 demonstrated the cleavage of N-N bond of amination products (-fluoro--hydrazino-β-ketoesters) in their published paper was unsuccessful, but details of the transformation did not present in their paper (structures of products see, Chapter 1. Scheme 1.3). With the amination products in hand, we decided to achieve some useful compounds from our products. Because of the expensive chiral bicyclic guanidine catalyst 25, some racemic amination products were prepared using TBD as catalyst for the coming experiments (Figure 3.7). O Br R F NH N R 107a-R R = Boc 108a-R R = Eoc O Cl R F NH N R 107c-R R = Boc 108c-R R = Eoc O O Eoc F NH N Eoc 108h-R Figure 3.7 Some racemic amination products 3.3.1 Modification of the racemic amination products via N-deprotection, N-N bond cleavage The -fluoro--amino acid derivatives were the target final products. Firstly, we try to develop the synthetic route of preparation this kind of compounds (Figure 3.8). The free amine products would be produced in a two-step synthesis of deprotection of the N-carbamate and reductive cleavage N-N bond of the 59 Enatioselective C-N bond formation racemic amination products. Figure 3.8 Modification of racemic amination products Scheme 3.12 Deprotection of the N-carbamate under acidic conditions: a) HCl (g) in dioxane, oC; b) concd. HCl, rt; c) 10% TFA, DCM, 0oC; d) TsOH, THF, oC. Four acidic conditions were tested in this kind of transformation.15 When the racemic amination product 108a-R was treated with HCl (g) in dioxane, TsOH in THF or 10% TFA in DCM, the unidentified solid 119 or its salt was obtained via the suspicious unstable imine 120 (dehydrofluorinated product) and verified by 19 F NMR (Scheme 3.12 conditions a, c and d). Under condition b, no clear spot could be found on the TLC plate. O O 108h-R Eoc F NH N Eoc O Zn-HOAc acetone, RT Eoc N Eoc N H O 122 convn.: 80% O F NH2 O 121 Scheme 3.13 Reductive cleavage N-N bond by Zn-HOAc/acetone According to the published work, the cleavage of N,N-substituted hydrazines 60 Chapter was easily achieved under Zn/HOAc/acetone system. The racemic amination product 108h-R was used as starting material, but the defluorinated product 122 was obtained with 80% conversion instead of the desired product 121 (Scheme 3.13). From the above experiments, application of acidic conditions for the removal of the N-carbamate group seemed unfavorable. Some mild condition systems16 such as Mg(ClO4)2/CH3CN, TMSI/CH3CN, Ce(NH4)2(NO3)6/MeCN, Yb(OTf)3/DCM and TMSOTf/2,6-lutidine/DCM were tested at the same time, but they were unsuccessful to achieve the wanted product 118. 3.3.2 Modification of the racemic amination products via reduction, cyclization and N-N bond cleavage Figure 3.9 Modification of racemic amination products The initial attempt for the removal of the N-protected group from the amination products was unsuccessful under various conditions. We decided to remove the carbamate group at the final step after formation of a much stable oxazolidinone 61 Enatioselective C-N bond formation derivative, and the final free amine product will be achieved from oxazolidinone derivative. Three steps such as reduction, cyclization and N-N bond cleavage will be involved in this synthetic route (Figure 3.9). O Cl R F NH N R 107c-R R = Boc 108c-R R = Eoc OH reductant solvent Cl H N N R R OH Cl 123a R = Boc 123b R = Eoc F H N R N R 124a R = Boc 124b R = Eoc Scheme 3.14 Reduction of racemic amination products. Reagents and conditions: a) TiCl4 (1.2 equiv.), BH3.SMe2 (1 equiv.), DCM, -20 oC; b) PhMe2SiH(4 equiv.), TBAF (2 equiv.), DMF, oC; c) Ti(OiPr)4 (1.5 equiv.), Et3SiH (4 equiv.), THF, o C; d) AlCl3 (1.5 equiv.), PhMe2SiH (4 equiv.), THF, oC; e) NaBH4 (2 equiv.), THF, oC; f) L-selectride (1.5 equiv.), THF, 4Å MS, -78 oC; g) NaBH4 (0.5 equiv.), THF, oC. Various reductants and conditions were examined for this transformation (a-g). The reduction reactions of 107c-R were sluggish while protocol a and d were chosen, the in situ generation of HCl from TiCl4 and AlCl3 with moisture in the reaction system made the amination products decomposed. For protocol b and c, no reactions occurred, and the starting material 107c-R was recovered. According to the reported work, anti-product was favored under protocol e while syn-product was favored by the protocol f. These two methods were used for the reduction of 108c-R, but the defluorinated product 123b was obtained instead of 124b with the conversion of 50% (determined by TLC and MS ESI). When the amount of NaBH4 was lowered to 0.5 equiv (protocol g) in the reduction reaction of 108c-R, the desired product 124b was obtained with less than 20% conversion, accompanied by 50% conversion of 123b (Scheme 3.14). 62 Chapter Scheme 3.15 Cyclization of reduction product 125. Reagents and conditions: a) NaOH (0.5 M), THF, rt; b) NaHCO3 (sat.), THF, rt; c) SOCl2 (1.5 equiv.), THF, RT; d) TsCl (1 equiv.), DMAP (0.5 equiv.), Et3N (2 equiv.), DCM, oC. Using the 0.6 equivalent NaBH4 as reductant in presence of 10% EtOH in THF, the desired reduction product 125 was achieved with 43% yield. Followed by the cyclization reaction under basic conditions (a: pH = 12; b: Ph = 8), the reactions failed to get the desired product 128. According to the protocol a, the reaction mixture were turn to brown color from colorless solution, no clear spot could be found on the TLC plate. As for protocol b and c, no reactions occurred. In considering the poor leaving ability of hydroxyl group, the Ts protected compound 127 was designed to increase the leaving ability of the hydroxyl group. Unfortunately, the defluorinated product 126 was obtained instead of 127 (Scheme 3.15). 3.3.3 Modification of the racemic amination products via inorganic base or SmI2 promoted and oxidative N-N bond cleavage To circumvent limitations and difficulties related to the strong acidic or basic 63 Enatioselective C-N bond formation conditions of modification of the amination products, a mild and efficient method was required for the transformations. The N-N bond cleavage was key step to get free amines in the transformations. Three more methods such as inorganic base Cs2CO3 promoted17, SmI2 promoted18 and oxidative19 N-N bond cleavage were examined. Scheme 3.16 Inorganic base Cs2CO3 promoted N-N bond cleavage of 108c. Determined by TLC. a The amination product 108c-R was N-alkylated using methyl bromoacetate 130 in DMF in presence of one equivalent inorganic base Cs2CO3 to give 129 with 50% conversion. The compound 129 was treated with three equivalents Cs2CO3 in CH3CN at 50 oC, but we failed to get desired product 131 and by-product 132 although the compound 129 was consumed completely (Scheme 3.16). Another attempt was the introduction an activating acyl group on the nitrogen to promote N-N bond cleavage in presence of SmI2. The acylated compound 133 was easily prepared from 108c-R, but the SmI2-mediated N-N bond cleavage did 64 Chapter not work. The TFA-protected amines are more reactive for N-N bond cleavage by SmI2 due to coordination between samarium (II) and trifluoroacetyl moiety. We attempted to prepare TFA-protected compound 135 using trifluoroacetic anhydride (TFAA) under basic conditions. Unfortunately, the defluorinated compound 134 was obtained (Scheme 3.17). Scheme 3.17 SmI2 promoted N-N bond cleavage of 108c-R. TLC. a Determined by The other method was oxidative N-N bond cleavage promoted by dried meta-chloroperbenzoic acid (mCPBA), which should be a mild condition for the transformation. The N-alkylated compound 136 was prepared from 107a-R and 4-bromobutane 140 under base condition with 20% yield, accompanied with defluorinated compound 137 with 40% conversion. For the oxidative N-N cleavage step, there was no reaction occurred at all (Scheme 3.18). 65 Enatioselective C-N bond formation Scheme 3.18 Oxidative N-N bond cleavage of 107a-R. a Determined by TLC. 3.4 Summary In conclusion, we have developed a series of -fluorinated aromatic cyclic ketone nucleophiles in asymmetric amination reaction catalyzed by chiral bicyclic guanidine. Under the optimal reaction conditions, the chiral -hydrozino--fluorinated aromatic ketone products were achieved with high yields (up to 96% ee). The amination reaction provides a better way to construct nitrogen-containing fluorinated quaternary stereocenter. However, the linear -fluorinated ketone did not show any reactivity for the amination reaction. A more basic chiral catalyst should be used in this kind of this reaction. In order to prepare multifunctional carbon center, the racemic product was used as starting material for this kind of transformation. However, no desired free amine fluorinated compounds were obtained, although various reaction conditions were tested for this transformation. The reason may be the instability of 66 Chapter nitrogen-containing -fluorinated carbon centers. References: 1. (a) Janey, J. M.; Angew. Chem. Int. Ed. 2005, 44, 4292 (b) Nair,V.; Biju, A.; Mathew, S.; Babu, B. Chem. Asian J. 2008, 3, 810. 2. Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. 3. Liu, T.-Y.; Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2007, 9, 3671. 4. Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett. 2008, 17, 2659. 5. (a) Aldous, D. L.; Riebsomer, J. L.; Castle, R. N. J. Org. Chem. 1960, 25, 1151. (b) Tanner, D. D.; Chen, J. J. J. Org. Chem. 1989, 54, 3842 6. (a) Bandgar, B.P.; Pandit, S.S. J. Sulfur chem. 2004, 25, 343. (b) Lee, H. K.; Lee, Y. S.; Roh, E. J.; Rhim, H.; Lee, J. Y.; Shin, K. J. Bioorg. Med. Chem. Lett. 2008, 18, 4424. (c) Feuillet, F. J. P.; Cheeseman, M.; Mahon, M. F.; Bull, S. D. Org. Bio. Chem. 2005, 3, 2976. 7. (a) Little, R. D.; Venegas, R. G. Org. Syn., 61, 1983, 17. (b) Carpino, L. A.; Carpino, B. A.; Giza, C. A.; Terry, P. H. Org. Syn., 44, 1964, 15. (c) Carpino, L. A.; Crowley, P. J. Org. Syn., 44, 1964, 18. 8. (a) The Flavonoids: Advances in Research Since 1980 (Ed.: Harborne, J. B.), Chapman and Hall, New York, 1994; (b) Flavonoid in Biology and Medicine Ⅲ: Proceedings of 3rd International Symposium on Flavonoids in Biology &Medicine Held in Singapore, November 13-17, 1989 (Ed.: Das, N. P.), National University of Singapore, Singapore, 1989. 9. Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem. Int. Ed. 2002, 41, 2832. 10. Lee, R.; Lim, X.; Chen, T.; Tan, G. K.; Tan, C.-H. Tetrahedron Lett. 2009, 50, 1560. 67 Enatioselective C-N bond formation 11. 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. 12. Takeuchi, Y.; Nabetani, M.; Takagi, K.; Hagi, T. Koizumi, T. J. Chem. Soc. Perkin Trans, 1991, 49. 13. Fu, X.-Y.; Li, Q.-M.; Fang, D.-C. International Journal of Quantum Chemistry, 1996, 57, 715. 14. Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658. 15. (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342. (b) Matsubara, R.; Kobayashi, S. Angew. Chem. Int. Ed. 2006, 45, 7993. Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. 16. (a) . Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.; (b) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 5543. 17. Magnus, P.; Garizi, N.; Seibert, K. A.; Ornholt, A. Org. Lett. 2009, 11, 5646. 18. Poulsen, T. B.; Alemparte, C.; Jøgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614. 19. Fernandez, R.; Ferrete, A.; Llera, J. M.; Magriz, A.; Martin, E.; Diez, E.; Lassaletta, J. M. Chem. Eur. J. 2004, 10, 737. 68 [...]... accompanied with defluorinated compound 137 with 40 % conversion For the oxidative N- N cleavage step, there was no reaction occurred at all (Scheme 3.18) 65 Enatioselective C- N bond formation Scheme 3.18 Oxidative N- N bond cleavage of 107a-R a Determined by TLC 3 .4 Summary In conclusion, we have developed a series of  -fluorinated aromatic cyclic ketone nucleophiles in asymmetric amination reaction catalyzed... Enatioselective C- N bond formation racemic amination products Figure 3.8 Modification of racemic amination products Scheme 3.12 Deprotection of the N- carbamate under acidic conditions: a) HCl (g) in dioxane, 0 oC; b) concd HCl, rt; c) 10% TFA, DCM, 0oC; d) TsOH, THF, 0 oC Four acidic conditions were tested in this kind of transformation.15 When the racemic amination product 108a-R was treated with HCl (g) in dioxane,... (108b~108k) was 3.2.5 Proposed mechanism of asymmetric amination reation Recently, there was an increased attention for utilizing chiral guanidine molecular as Brønsted base catalyst The guanidinium intermediate was formed by abstracting one proton from the substrate, which could contribute to the stabilization of anionic reaction intermediates through electrostatic interaction and recognize at the active... by chiral bicyclic guanidine Under the optimal reaction conditions, the chiral -hydrozino- -fluorinated aromatic ketone products were achieved with high yields (up to 96% ee) The amination reaction provides a better way to construct nitrogen-containing fluorinated quaternary stereocenter However, the linear  -fluorinated ketone did not show any reactivity for the amination reaction A more basic chiral... 1983, 17 (b) Carpino, L A.; Carpino, B A.; Giza, C A.; Terry, P H Org Syn., 44 , 19 64, 15 (c) Carpino, L A.; Crowley, P J Org Syn., 44 , 19 64, 18 8 (a) The Flavonoids: Advances in Research Since 1980 (Ed.: Harborne, J B.), Chapman and Hall, New York, 19 94; (b) Flavonoid in Biology and Medicine Ⅲ: Proceedings of 3rd International Symposium on Flavonoids in Biology &Medicine Held in Singapore, November 13-17,... Unfortunately, the defluorinated product 126 was obtained instead of 127 (Scheme 3.15) 3.3.3 Modification of the racemic amination products via inorganic base or SmI2 promoted and oxidative N- N bond cleavage To circumvent limitations and difficulties related to the strong acidic or basic 63 Enatioselective C- N bond formation conditions of modification of the amination products, a mild and efficient method... steps such as reduction, cyclization and N- N bond cleavage will be involved in this synthetic route (Figure 3.9) O Cl R F NH N R 10 7c- R R = Boc 10 8c- R R = Eoc OH reductant solvent Cl H N N R R OH Cl 123a R = Boc 123b R = Eoc F H N R N R 124a R = Boc 124b R = Eoc Scheme 3. 14 Reduction of racemic amination products Reagents and conditions: a) TiCl4 (1.2 equiv.), BH3.SMe2 (1 equiv.), DCM, -20 oC; b) PhMe2SiH (4. .. in DMF in presence of one equivalent inorganic base Cs2CO3 to give 129 with 50% conversion The compound 129 was treated with three equivalents Cs2CO3 in CH3CN at 50 oC, but we failed to get desired product 131 and by-product 132 although the compound 129 was consumed completely (Scheme 3.16) Another attempt was the introduction an activating acyl group on the nitrogen to promote N- N bond cleavage in. .. catalyst should be used in this kind of this reaction In order to prepare multifunctional carbon center, the racemic product was used as starting material for this kind of transformation However, no desired free amine fluorinated compounds were obtained, although various reaction conditions were tested for this transformation The reason may be the instability of 66 Chapter 3 nitrogen-containing  -fluorinated. .. F H CDCl3 110 yield: 92% 109 111 unstable excess of HF CDCl3 CH3CO2D CDCl3 O F N COOH NHCO2tBu H O OtBu 112 unstable H C COOH NCO2tBu OEt COOEt NHCO2tBu 1 14 113 decomposition products Scheme 3.10 Dehydrofluorination of 109 under acidic conditions F H CO2Et N( CO2Bn)2 CF3CO2D CDCl3 F H COOH N( CO2Bn)2 O TMSI F CDCl3 116 yield: 49 % 115 H2/Pd -C EtOH F H C CO2 NH3 118 N O OBn 117 unstable decomposition products . examination of asymmetric amination reaction with Boc=Boc 10b Firstly, we carried out asymmetric amination between  -fluorinated aromatic Enatioselective C- N bond formation 48 cyclic ketone 82d and. amination reation Recently, there was an increased attention for utilizing chiral guanidine molecular as Brønsted base catalyst. The guanidinium intermediate was formed by abstracting one. reaction conditions in hand (THF as solvent and reaction temperature less than 0 o C) , the scope of the direct -amination reaction between  -fluorinated aromatic ketones 82a-82k, 82o and azodicarboxylate