Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 3

Chapter Chapter Chiral Guanidinium Salt Catalyzed Phospha-Mannich Reactions 56 Chapter 3.1 Hydrogen bond donors catalyzed asymmetric reactions. Electrophilic activation by small-molecule hydrogen bond donors has provided an important paradigam for design of enantioselective catalysts.1 Salts of organic bases were shown to be successful in the activation of imines and other anionic intermediates through hydrogen bonds. H H MeO O R O O 151a R = Me 151b R = Et Bis(amidinium) salt 148 H 150a R = Me -70 o C 150b R = Et -22 o C 149 R MeO O R + OH H OH 152a R = Me 152b R = Et MeO a 80% yield 151a 15% ee152a 47% ee 151a/152a 1:22 b quant. yield 151b 48% ee 152b 7% ee 151b/152b 1:11 tBu F3 C F3C H N H N Ph Ph NH Ph CF3 CF3 BAr F-4 = B HN 2BAr F-4 Ph F3C CF3 F3 C 148 CF3 Scheme 3.1. Göbel’s chiral bis(amidinium) salt 148 catalyzed Diels-Alder reaction. Göbel and co-workers reported a chiral bis(amidinium) salt 148 catalyzed Diels-Alder reaction which constituted a key step of the Quinkert-Dane Estrone Synthesis. The hydrogen-bond-mediated association of dienophiles 149 with the chiral salt 148 accelerated the Diels-Alder reaction with diene 7-methoxy-4-vinyl-1,2-dihydronaphthalene (149) by more than three orders of magnitude. In addition, the chemo-selectivities of the adducts were excellent (151a:152a = 1:22 and 151b:152b = 1:11, respectively). However, only moderate enantioselectivities were observed (Scheme 3.1). 57 Chapter The drawback of this type of proton catalyst was that the bisamidine 148 cannot bind a single carbonyl group by two hydrogen bonds simultaneously because of the large distance between the amidinium groups. To expand the scope of amidinium-catalyzed reaction, Göbel and co-workers3 reported an easily synthesized bisamidines 153 derived from malonodinitril. This proton catalyst 153 was found to increase the reaction rate of a series of reactions like Diels-Alder reaction and Friedel-Crafts reaction (Scheme 3.2). Enantioselectivities, however, remained constantly low even at low temperature. H N H N Ph O Ph N N H H Ph Ph BArF-4 bisamidine 153 O mol% 153 + CDCl3 154 NO2 N 156 + + O endo-155 exo- 155 ~12% ee 10 mol% 153 NO2 CDCl3 95a N 157 Scheme 3.2. Göbel’s bisamidines 153 catalyzed asymmetric reactions. Johnston and co-workers reported the use of a chiral proton catalyst 158 to promote enantioselective direct aza-Herry reaction (Scheme 3.3).4 The catalyst can tolerate a range of substituents and substitution patterns on several aldimines 159 and nitroalkanes. Nitroacetic acid easters can afford similar results in which anti-addition products were preferred.5 The catalysts can be easily removed from the final reaction 58 Chapter mixture via a base wash. - OTf H H N H N H N H N N R 1C 6H Boc H NO2 + 159 158 HQuin-BAM .HOTf 158 R 1C 6H -20 oC R2 HN R1 = H, p-NO 2, m-NO2 , o-NO 2, p-CF3 O, p-Cl, p-CF3 R2 = H, Me Boc NO R2 160 50 - 69% yield 59 to 95% ee 7:1 - 19:1 dr (R = Me) -OTf H H N H N H N H N 161 N R C 6H Boc + H 159 Boc 1. H, Quin( ( Anth)2 Pyr)-BAM.HOTf 161 HN toluene, -78 o C CO 2tBu 2. NaBH 4, CoCl2 R 1C 6H NH2 162 69 - 88% yield 78 - 95% ee 5:1 - 11:1 dr CO2 tBu NO Scheme 3.3. Johnston’s chiral proton catalyst catalyzed enantioselective direct aza-Herry reaction. 3.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions The addition of phosphonates to imines (Pudovik reaction or phospha-Mannich reaction) is a widely utilized method for the formation of P-C bonds. However, to best of our knowledge, there were no reports on the use of phosphorus nucleophiles such 59 Chapter as secondary phosphine oxides [R2P(O)H] and H-phosphinates [(RO)P(O)HR] for the addition to imines. The only previous report on the preparation of P-chiral phosphinate esters was through resolution using phosphotriesterase. Yuan and co-workers reported the synthesis of optically pure α-amino-H-phosphinic acids employing chiral ketimines. We aimed to develop an organocatalyst catalyzed phospha-Mannich reaction using secondary phosphine oxides and H-phosphinates. 3.2.1 Synthesis of guanidinium salt 168. 2-Chloro-1,3-dimethylimidazolinium chloride 163 was found to form guanidines easily with appropriate primary amines.8 This type of reaction provided a simple method to prepare guanidines/guanidinium salts (Scheme 3.4). Me Cl MeN Cl Me - NMe + 163 Et3N H 2N DCM N MeN NMe 164 165 Scheme 3.4. Synthesis of guanidines from DMC 163 and amine. Ph Cl BF4- Ph + H 2N N N Et3 N/DCM quantitive yield NH 166 Ph 167 Ph N N N N + +N H H BF4 N BF4 168 . 2HBF4 Scheme 3.5. Synthesis of guanidinium salts Guanidinium 168.2HBF4 was prepared from enantiopure diamine 166 and pyrrolidinium salt 167 in one step with excellent yield (Scheme 3.5). The free base guanidine 168 was obtained after basifying guanidinium salt 168.2HBF4 with 6M NaOH aqueous solution. The absence of 19F signal detected in the 19F NMR indicated 60 Chapter the successful basification of 168.2HBF4. 3.2.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions of phosphine oxides 3.2.2.1 Optimization study of phospha-Mannich reactions of phosphine oxides Table 3.1. Guanidine- and guanidinium-catalyzed phospha-Mannich reactions. R O P R + H 125f R = 1-naphthyl a NTs Ph mol% catalyst oC, THF R O P R Ph NHTs 169a entry catalyst time/ha ee/%b 168 (base) 1.5 33 168.0.5HBF4 1.5 63 168.HBF4 2.5 80 168.1.5HBF4 2.5 47 168.2HBF4 Monitored by TLC. b Determined by HPLC. In preliminary studies, it was found that both the guanidinium salt 168.2HBF4 and guanidine 168 could catalyze the phospha-Mannich reaction between secondary phosphine oxides and imines (Table 3.1, entries and 5). It was surprised that the results in terms of enantioselectivities obtained in the presence of the catalysts basified from K2CO3 were inconsistent. It was proposed that this basification method offered catalysts carrying uncertain numbers of protons and the number of protons on the catalyst had a significant influence on the ees. This effect was evaluated by 61 Chapter employing catalysts 168.xHBF4 (x = 0.5, 1, 1.5) prepared purposely. These catalysts 168.xHBF4 (x = 0.5, 1, 1.5) were obtained by mixing different ratio of the free base 168 and 168.2HBF4 (ratio = 1:3, 1:1, 3:1, respectively). It was discovered the highest ee was obtained with catalyst 168.HBF4, which carried one single proton (entry 3). The results obtained with other catalysts dropped dramatically (entries 1, 2, and 5). MeO Ph Ph N N N N N N N N H N N OMe N H N N N N N H BF 4- BF 4170 .HBF4 iPr N iPr N N Ph N H H iPr iPr BF 4- BF 4- 173.2HBF4 N BF 4- 171 .HBF4 iPr Ph N 172 .HBF4 iPr iPr Ph N iPr iPr N N iPr iPr Ph N N NH H iPr BF 4174 Figure 3.1. A series of guanidinium salts synthesized as catalysts for phospha-Mannich reactions. Following the previous studies, a series of guanidinium salts carrying one proton (Figure 3.1) were synthesized readily from commercially available chiral diamines and corresponding salts under the same conditions. In the case of preparation of 173, only guanidine salt 174 was obtained rather than 173.2HBF4 even under hash conditions (MeCN, reflux). It was likely that the steric effect prevented the formation of the second guanidine. 62 Chapter Table 3.2. The effect of catalyst structure on enantioselectivity. R O P R + H 125f R = 1-naphthyl a NTs mol% catalyst THF Ph R O P R NHTs Ph 169a entry catalyst temp/o C time/ha ee/%b 170.HBF4 -20 16 171.HBF4 -20 14 172.HBF4 -20 24 75 168.HBF4 -50 14 87 168.HPF6 -50 14 80 168.HBArF4 -50 14 92 100% conversion. b Determined by HPLC. These guanidinium salts were also evaluated in the phospha-Mannich reaction of phosphine oxides (Table 3.2). Both the guanidinium salt 170.HBF4 bearing less sterically hindred group (entry 1) and the guanidinium salt 171.HBF4 derived from the dicyclohexyl amine (entry 2) gave poor enantioselectivities. At -20 o C, the guanidinium salt 172.HBF4 gave good enantiomeric excess but worse than 168.HBF4. The reaction temperature was another factor which may be considered to increase the optical purity significantly. Fortunately, decreasing the reaction temperature to -50 oC did not affect the reaction rate much; the reaction catalyzed by 168.HBF4 at -50 oC could complete within 14 h and good result was observed (entry 4). It was reported that different counterions of the chiral salt catalysts could affect the reaction rate and 63 Chapter enantioselectivities.3 In our current research, the guanidinium salts with different weakly-coordinating anions were tested under -50 oC (entries and 6). It was found that the ee increased to 92% when -BArF4 (Figure 3.2), the less coordinating anion, was employed. 3.2.2.2 Highly enantioselective phospha-Mannich reaction between phosphine oxides and imines catalyzed by guanidinium salts. Under the optimum conditions, the phospha-Mannich reaction was investigated with phosphine oxide 125f and different imines (Table 3.3, entries 1-7). Imines bearing electron-donating (entry 1) and electron-withdrawing substituents (entry 2) provided adducts with high ees. The reaction time for completed conversion of the bulky 2-naphthyl imine was also 14h and 92% ee was observed (entry 3). Heterocyclic imine (entry 4) furnished slightly lower ee. Imines derived from aliphatic aldehydes, such as cyclohexanecarbaldehyde, gave adduct with 70% ee (entry 5) while imine derived from pivalaldehyde afforded adduct with 91% ee (entry 6). Imine derived from trans-cinnamyl aldehyde also provided 1,2–addition adduct 169h with high ee (entry 7). Diaryl phosphine oxides 125a and 125g carrying phenyl and ortho-trifluoromethylphenyl groups respectively, afforded adducts with moderate to good ees (entries and 9). The racemic phosphine oxide 125h added to phenyl imine to generate two diastereisomers with a diastereisomeric ratio (dr) of 1:1 and high ees (entry 10). Table 3.3. Guanidinium-catalyzed (168.HBArF4) phospha-Mannich reaction of 64 Chapter di-1-naphthyl phosphine oxide 125 and various imines R1 O P R2 + R1 NTs x mol% 168 .HBAr F4 O P R2 R H 125a R1 = R = Ph 125f R = R = 1-Naphthyl 125g R = R2 = 2-CF3Ph 125h R = Ph, R = 1-Naphthyl THF, -50 or - 60 oC R NHTs 169b-k yield/%a ee/%b entry 125 R 169 X time/h 125f 4-MeC6H5 169b 14 98 92 125f 4-FC6H5 169cc 14 97 90 125f 2-naphthyl 169d 14 98 92 125f 2-furyl 169e 14 92 87 5d 125f Cy 169f 10 16 95 70 125f tBu 169g 10 40 89 91 125f trans-PhCH=CH 169h 36 89 90 8e 125a Ph 169if 20 96 75 56 125g Ph 169jf 20 14 93 82 10 125h Ph 169kg 20 14 90 75;85 a Isolated yield. b Determined by chiral HPLC analysis. c the absolute configuration of 169c was assigned using X-ray crystallographic analysis. d tBuOMe as solvent. e DCM:Et2O 1:1 as solvent. f PG (imine) = 4-phenylbenzenesulfonyl. g PG (imine) = benezenesulfonyl. 3.2.3 Phospha-Mannich reaction of H-phosphinates 3.2.3.1 Optimization study of phospha-Mannich reaction of H-phosphinates and imines 65 Chapter The H-phosphinate such as benzyl benzylphosphinate 179a was another type of phosphorus nucleophile. The H-phosphinates were prepared from the literature reported protocol (Scheme 3.6). Following the reported reagents and conditions9, a mixture of H-phosphinic acids 177 and phosphinic acid 178 were obtained. The phosphinic acid 178 were undesired product and generated from the double attack of the intermediate 176. The modified protocol employed 0.5 eq. of corresponding benzyl bromides rather than eq. of alkylation reagents. The slow dropwise addition of benzyl bromide was the key to increase the selectivities and to improve the yields of H-phosphinic acid 177. The reaction mixture was conducted the next step without further purification after a simple acid-base work-up. H-phosphinate 179a were finally obtained with high yields via Hewitt reaction.10 H 2PO 3.NH3 i TMSO 175 H P OTMS 176 ii OH O P Bn H OH O P Bn Bn 177 178 iii OBn O P Bn H 179a Scheme 3.6. Synthesis of benzyl benzylphosphinate. Reagents and conditions: (i) 1.05 eq. (TMS)2NH, 110 oC, 1-2h; (ii) 0.5 eq. benzylbromide, DCM, oC to rt. (iii) benzyl chloroformate, pyridine, DCM, rt to reflux, 15 min. It was found that the addition of rac-benzyl benzylphosphinate 179a to imines can be catalyzed by 168.HBF4 (Scheme 3.7). However, the reaction was slow at room temperature and low ee was observed ([...]... Table 3. 10 Effects of various protecting groups of phenyl phosphinates on the phospha-Mannich reaction OR O P Ph H NTs + 10mol% 168.HBAr F4 NHTs syn-181 136 [R] OR O P Ph 0 o C, DCM Ph Ph 136 a entrya Ph O P OBn 181 Ph NHTs anti-181 yield/%b ee/%c 74 Chapter 3 1 181a 56 30 ; 25 2 136 b [2-NpCH2] 181b 37 35 ; 15 3 136 c [3, 5-MeOC6H4CH2] 181c 58 32 ; 20 4 136 d [3- NO2C6H4CH2] 181d 58 36 ; 14 5 136 e [Et] 181e 45 38 ;... K2CO 3, -50 o C (S)-179c r ac-179c 63% conversion 87% ee S = 8.2 1 equiv 1 equiv 32 % yield (85% of R = 4-CF3 PhCH2 theoretical yield) CF syn-180j + anti-180j (2) 50% ee 50% ee 52% yield (syn + ant i) dr 1.6:1 3 H N O S O P S O O H N O O O P CF3 O syn-180jA 28.7% [a] syn-180jB 9.6% [a] CF3 O S H N O P O H N O S O O O P CF3 O anti -180jC 18.5%[a] anti -180jD 6 .3% [a] F3 C O P O H O O P H CF3 [a] [a] 2 .3% ... absolute and relative configuration of syn-180 adducts have been determined, the absolute configuration of remaining 179c could be deduced The ee of 78 Chapter 3 remaining 179c was 87% In other words, the enantioselective ratio of remaining 179c was 93. 5:6.5 34 .6% of major enantiomer of remaining 179c and 2 .3% of minor enantiomer were observed based on the 63. 1% conversion (39 .1% x 93. 5% = 34 .6%, 39 .1%... analysis of syn-180m 73 Chapter 3 Table 3. 9 Guanidinium- catalyzed alkylphosphinates 179b-179e OBn O P R H NTs + Ph 179b-e phospha-Mannich reaction with benzyl Bn O P OBn 10mol% 168.HBAr F4 DCM:toluene 1:1 NHTs 10 equiv K2 CO 3, -40 o C Ph syn-180i-m Yield/%a drb ee of syn-180 [%]c entry 179 [R] 1 179b[2-NpCH2] 180i 38 92 6.5:1 94 2 179c[4-CF3Ph CH2] 180j 36 92 16:1 94 3 179d[4-NO2PhCH2] 180k 36 90 5.5:1 89... H NTs 5 mol% 168.HBAr F4 + toluene, -20 oC 10eq K2CO3 Ph 182 Bn O P OR Ph OR O P Bn NHTs NHTs Ph sy n-1 83 anti- 1 83 entrya 1 83 [R] time/hb ee of 1 83/ %c drd 1 183a[2-MeOC6H4CH2] 24 45; 67 2:1 2 183b[2-NO2C6H4CH2] 24 70; 30 2:1 3 183c[2-NpCH2] 24 65; 47 2:1 a Donor : acceptor = 2:1 b Determined by TLC, 100% conversion HPLC d Approximated by 1H NMR and confirmed by HPLC c Determined by A series of benzyl... 168.HBF4 rt . [2-NpCH 2 ] 181b 37 35 ; 15 3 136 c [3, 5-MeOC 6 H 4 CH 2 ] 181c 58 32 ; 20 4 136 d [ 3- NO 2 C 6 H 4 CH 2 ] 181d 58 36 ; 14 5 136 e [Et] 181e 45 38 ; 18 6 136 f [i-Bu] 181f 48 56; 32 a donor. 168 . 2HBF 4 . 3. 2.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions of phosphine oxides 3. 2.2.1 Optimization study of phospha-Mannich reactions of phosphine oxides Table 3. 1. Guanidine- and. NaBH 4 ,CoCl 2 R 1 C 6 H 4 H N Boc 159 + CO 2 tBu NO 2 R 1 C 6 H 4 HN Boc CO 2 tBu NH 2 162 69 - 88% yield 78 - 95% ee 5:1 - 11:1 dr Scheme 3. 3. Johnston’s chiral proton catalyst catalyzed enantioselective direct aza-Herry reaction. 3. 2 Chiral guanidinium salt catalyzed phospha-Mannich