Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 2

Chapter Chapter Chiral bicyclic guanidine-catalyzed enantioselective Phospha-Michael reaction 28 Chapter 2.1 Guanidine catalyzed achiral phosphorus-carbon formation reactions Guanidine (Figure 2.1) is one of the most basic forms of neutral nitrogen compounds and guanidine derivatives are widely used as strong bases in synthetic organic chemistry.1 Due to its high pKaH, guanidine is basic enough to catalyze the Michael addition of a R2P(O)H or (RO)2P(O)H group. R3 R1 N N H N H R2 Figure 2.1. General structure of guanidine. O HO Me (EtO) 2P(O)H Me NH cat. 84 Me2 N OEt H2 C P OEt O 85 (54%) NMe2 TMG, 83 O O O Me OEt O 87 (88%) O O R (EtO) 2P(O)H 90 CH OEt OEt O 89a (71%) 89b (51%) TMG (EtO) 2P(O)H TMG R P MeO 88a: R= H 88b: R= Me NC OEt Me 86 MeO Me P TMG Me O (EtO) 2P(O)H OEt NC P O OEt 91 Scheme 2.1. Tetramethylguanidine (TMG) catalyzed the addition of dialkyl phosphonates to α,β-unsaturated carbonyl compounds. Tetramethylguanidine (TMG, 83) was found to be a good catalyst for the addition of dialkyl phosphonates to α,β-unsaturated carbonyl compounds (Scheme 2.1). But-3-en-2-one (84) was employed as the acceptors to furnish the 1,2 adduct 85, 29 Chapter whereas 86 underwent the Michael addition exclusively. α,β-Unsaturated esters (88a,b) and nitriles (90) can also be used to give the addition products 89a,b and 91 in moderate yields. O O (PhO) 2P(O)H N Ph O cat. N N Ph PhO PhO P O N N H TBD, 92 93 CN Ph CN (PhO) 2P(O)H TBD PhO PhO P O 97 (85%) Ph CN O CN 98 (88%) 94 Ph NO2 Ph (PhO) 2P(O)H TBD PhO PhO EtO2C N CO2 Et (PhO) 2P(O)H TBD 96 O 99 (90%) 95a N NO P CO 2Et N CO 2Et N P PhO H O 100 (86%) PhO Scheme 2.2A. TBD catalyzed phospha-Michael reactions of diphenyl phosphonate. Our group reported that 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 92) provided a mild, rapid and efficient protocol to generate phosphorus–carbon bonds. The convenient procedure allowed a series of dialkyl alkylphosphonates (Scheme 2.2A) and trisubstituted phosphine oxides (Scheme 2.2B) to be prepared in high yields (from 70 to 99%). The addition of phosphonates to various activated alkenes, including maleimide (93a), 2-arylidene malononitrile (94), nitrostyrene (95a) and azodicarboxylate (96) processed smoothly. The phosphonates tolerated the substituents ranging from alkyl to aryl substitutes. Cyclic substrates such as maleimide, as well as linear activated alkenes (102) and 2-cyclopenten-1-one (104a) 30 Chapter were employed in the reaction with diphenyl phosphine oxide to gave good to excellent yields. The phosphine oxide was also under further investigation resulted in a convenient one-pot, three-component reaction containing aldehyde (106) and malononitrile (107) (Scheme 2.2C). O O N Ph Ph2P(O)H N Ph Ph TBD Ph P O 93 O 101 (99%) R2 R1 O R1 Ph2P(O)H Ph Ph TBD R2 P O 103a : R 1=R 2=CN (80%) 103b: R1=R2=CO 2Me (98%) 103c: R 1=R 2=COPh (99%) 103d : R1=Ph; R 2=CN (97%) 103e : R 1=Ph; R2 =COPh (80%) 102a : R 1=R 2=CN 102b: R1=R2 =CO 2Me 102c: R 1=R 2=COPh 102d : R1=Ph; R 2=CN 102e : R 1=Ph; R2 =COPh O O Ph2 P(O)H TBD Ph Ph P 104a O 105 (84%) Scheme 2.2B. TBD catalyzed phospha-Michael reactions of phosphine oxide. R R O + NC CN + Ph 2P(O)H TBD 107 106a: R = Et t 106b: R = Bu 106c: R = Ph 106d: R = Cinnamyl 106e: R = (CH 2) Ph Ph CN P O CN 108a: R = Et (96%) 108b: R = tBu (76%) 108c: R = Ph (97%) 108d: R = Cinnamyl (70%) 108e: R = (CH 2) (93%) Scheme 2.2C. TBD catalyzed three-component phospha-Michael reactions of diphenyl phosphine oxide. 2.2 Synthesis of chiral bicyclic guanidines and their application in enantioselective reactions It is anticipated that chiral guanidine derivatives can function as asymmetric 31 Chapter catalysts by utilizing the great basicity of the guanidine group and the special hydrogen bonding pattern of the guanidinium ion. This research topic has increasingly attracted great interest and the asymmetric catalytic ability of chiral guanidine or guanidinium salt has been demonstrated in several reactions such as Henry reaction4, Strecker synthesis of α-amino acids5, Michael reaction6, asymmetric silylation of secondary alcohols7, and electrophilic amination8. t tBu OH Bu 109 t Bu t N H NHTs Bu t t v N H t Bu NHTs NH N H Bu NH 113 N Bu NH NHTs 111 112 vi Bu N Ts 110 NH iv t iii i, ii t N H I114b.HI Bu vii t Bu N t Bu N N H 114b (base) Scheme 2.3. Synthesis of symmetrical chiral bicyclic guanidines. Reagents and conditions: (i) TsCl, Et3N, MeCN; (ii) MsCl, Et3N, DMAP, DCM, rt; (iii) NH3/MeOH, oC to rt; (iv) MeCH, 90 oC, days; (v) Na/NH3, -78 oC; (vi) (MeS)2C=S, MeI/AcOH, MeNO2, reflux; (vii) K2CO3 column. Our group employed the TBD as the template to synthesize a series of chiral bicyclic guanidines via steps of aziridine-based synthesis and an overall yield of 70% was achieved.9 The synthetic route was modified from Corey’s work.10 Bicyclic chiral guanidine catalyst 114b was prepared according to the reported procedure as shown in Scheme 2.3. N-Tosyl aziridine 110 was readily prepared from its corresponding commercially available α-amino alcohol 109. Triamine unit 112 was easily obtained by treating 110 with NH3 bubbled into its MeOH solution. The 32 Chapter nucleophilic attack occurs preferentially at the sterically least hindered carbon atom. The subsequent triamine 113 was prepared by using sodium in liquid ammonia to remove tosyl groups without further purification. The crude triamine 113 was then subjected to the final cyclization step, leading to the guanidine 114b.HI in 71% total yield from its amino alcohol. The guanidine catalyst was obtained from filtration through K2CO3 column. O O R1 N tBu O Bu N N Et N H 114b (1-20 mol%) N Et R2 O 93b t o O toluene, -50 C 116O R2 R1 O O OEt Ph O Ph 115a 116a 99% yield, 92% ee (20 mol% cat) O Ph 115b 116b 99% yield, 88% ee (20 mol% cat) O O S-t-Bu Ph S O 115c 116c 99% yield, 94, 95% ee (2 mol% cat) Ph 115d 116d 90% yield, 96, 96% ee (1 mol% cat) O O S S O O s O 115 O H S 115e 116e 98% yield, 95% ee (10 mol% cat) O S 115f 116f 99% yield, 96% ee (2 mol% cat) Scheme 2.4. Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide and 1, 3-diketones, β-keto esters, dithiomalonates. The guanidine 114b was found to be a catalyst for asymmetric Michael reactions (Scheme 2.4).11 The initial investigation revealed that 1,3-diketones 115a and β-keto 33 Chapter ester 115b added to maleimides with high enantioselectivity. The Michael adducts 116a-b were obtained in high yields and high ees. However, these reactions were slow and required 20 mol% of catalyst. To improve the reaction rate, β-keto thioesters 115c-d and dithiomalonate 115e-f were tested, and the reaction rate was considerably enhanced. Using guanidine 114b as the catalyst, adducts 116c-f were obtained in high yields and excellent ees with diastereomeric ratios of approximately 1:1 (116c-d). The catalyst loading of 114b can be decreased to mol% for substrate 115d. O O O R X R2 n O 104a x = C n = 104b x = C n = 115 104c x = O n = O t Bu N t Bu N N H 114b (1-20 mol%) toluene, -50 oC O R H S O O R H R2 O 117 R O R O H S O S S 117a 96% yield, 95% ee (10 mol% cat) X 117b 91% yield, 97% ee (5 mol% cat) O O O O R R S H O S 117c 86% yield, 90% ee (20 mol% cat) O H S O S 117d 85% yield, 96% ee (20 mol% cat) Scheme 2.5. Chiral bicyclic guanidine catalyzed Michael reactions of cyclic enones and furanone and 1, 3-diketones, β-keto esters, dithiomalonates. Other cyclic substrates, such as cyclic enones 104a and furanone 104b were also explored as substrates for this reaction (Scheme 2.5). In general, these reactions were 34 Chapter slow. The reactions with various thioesters gave adducts 117a-d in excellent enantioselectivities and high yields. To extend the scope of this reaction, it was found that ethyl trans-4-oxo-4-phenylbut-2-enoate 118 was a useful acyclic Michael acceptor (Scheme 2.6). With mol% of guanidine 114b, dialkyl dithiomalonate 115f reacted smoothly to give adduct 119 in high yields and high ees. O N H R OEt Ar O 118 t Bu N 114b (5 mol%) O CO 2Et COR Ar toluene, -50 oC 10-24 h R O S COR 119 115f O N tBu O R= CO 2Et COR S COR 119a 99% yield, 92% ee S O MeO CO 2Et COR S COR 119b 99% yield, 94% ee Scheme 2.6. Chiral bicyclic guanidine catalyzed Michael reactions of ethyl trans-4-oxo-4-phenylbut-2-enoate and 1, 3-diketones, β-keto esters, dithiomalonates. The guanidine catalyst 114a was also found to be a good catalyst for a highly enantioselective guanidine-catalyzed Diels-Alder reaction between anthrones 120 and activated olefins (Scheme 2.7).12 High yields and ee values were obtained with various anthrones in combination with maleimides. In many examples, the ees were more than 98%. Excellent regioselectivities were also observed when 1,5-dichloro-9-anthrine and 4-(N-methylamino)-9-anthrone were used as the dienes. However, prolonged stirring or treatment of base led to ring-opening products with significant racemization (121d, 121e). 35 Chapter N Bn R O R O N R5 R3 O N O O2 N s s s s R R3 CH Cl2, -20 C, 4-8 hrs OH s s Cl Cl OH R2 R1 121 O s N Ph s O O N O OH OH 121a 87% yield, 98% ee O s N Ph s O Cl O N R5 O o O 93 R4 120 Bn N N H 114a (10 mol%) Cl Cl 121c 92% yield, 99% ee 121b 88% yield, 98% ee O N Et O s s OH OH Cl 121d 87% yield, 99% ee 121e 95% yield, 98% ee Scheme 2.7. Chiral bicyclic guanidine catalyzed Diels-Alder reactions of anthrones. OH O OH OH O OH O 114a (10 mol%) N Ph CH2 Cl2 , -20 o C O 93a 122 H S O N O Ph 124 80% yield, 99% ee OH O OH OH R1 R2 122 MeOC O R2 124 OH H CO2 Me 124a 92% yield 98% ee OH PhOC OH 114a (10 mol%) CH 2Cl2, -20 oC OH O O OH H CO2 Et OH NC H R1 O OH H CN 124b 92% yield 95% ee 124c 90% yield 94% ee Scheme 2.8. Chiral bicyclic guanidine catalyzed Michael reactions of dithranol. 36 Chapter When dithranol 122 was employed, the Michael addition adducts 124 were obtained exclusively. Using 10mol% of guanidine, the reaction performed well with maleimides and other activated olefins (Scheme 2.8). Excellent enantioselectivities and regioselectivities were obtained in all examples. 2.3 Bicyclic guanidine-catalyzed phospha-Michael enantioselective reactions The phospha-Michael reactions employing phosphorus nucleophiles such as phosphonates were investigated by many groups,13 especially the excellent research work done by Terada.14 However, to the best of our knowledge, there was no report on the enantioselective phospha-Michael reactions catalyzed by small molecular using secondary phosphine oxides. We aimed to develop an organocatalyst catalyzed phospha-Michael reaction using secondary phosphine oxides. 2.3.1 The effects of the catalyst structure on the enantioselectivities It was found that without any catalyst, the phospha-Michael reaction ofS diphenyl phosphine oxide 125a and β-nitrostyrene 95a could occur at room temperature (3 h, 50% conversion by NMR). To reduce the effect of this background reaction, the reaction was studied at oC. In order to find an efficient catalyst, two categories of catalysts were tested (Table 2.1). O2 S R1 N H N Tertiary amine as weak base Hydrogen-bonding donor Figure 2.2. Chiral pyrrolidinyl sulfonamides (CPS). 37 easing the reaction temperature. However, when the temperature was lowered to -50 oC, the ee only slightly increased to 20%. 48 Chapter N tBu R R P O H 125f N N H 114b (10 mol%) O + Ph Ph 139 tBu Et2 O O R R P OO Ph Ph * O R = 1-naphthyl 140 -20 o C 15% ee -50 o C 20% ee Scheme 2.16. Phospha-Michael reaction (E)-1,4-diphenylbut-2-ene-1,4-dione 139. of phosphine oxide 125f to The reaction of (E)-methyl 4-oxo-4-phenylbut-2-enoate (141a) and (E)-tert-butyl 4-oxo-4-phenylbut-2-enoate (141b) with phosphine oxide also gave phospha-Michael products with high yield (Scheme 2.17). Low enantioselectivities were observed for both the less sterically hindered (141a) and the more sterically hindered substutents (141b). Decreasing the reaction temperature also did not affect the ee of the product. Employing more sterically hindered groups such as adamantyl could increase the optical purity but still yielding disappointed result. t Bu O R R P O + H 125f OR Ph t Bu N N H 114b (10 mol%) R R P OO RO Et 2O O R = 1-naphthyl N 141a R = Me 141b R = tBu R R P OO Ph 142 R R P OO t MeO * O Ph O 142a -20 oC 2.5h 99% yield 2% ee -50 oC 18h 99% yield 2% ee BuO Ph O 142b -20 oC 22h 99% yield 10% ee -50 oC 22h 87% yield 10% ee Scheme 2.17. Phospha-Michael reaction of phosphine oxide 125f to activated olefins 141. 2.3.6 Proposed mechanism of phospha-Michael reactions 49 Chapter From the experimental results obtained, we can postulate some facts about the mechanism of the phospha-Michael reaction of phosphine oxide to β-nitrostyrene. (a) Guanidine catalyst was basic enough to activate the phosphine oxide to the reactive species and; (b) the nitro group played an essential role in the asymmetric induction, since the linear substrates without a nitro group attached could not provide high ee; Based on these points, the mechanism of phospha-Michael reaction was proposed (Scheme 2.18). N Ph Ph P O N H N H O P Ph Ph H 125a 143 N N N N N H 114b H O P GuanidinePh Ph hydroxyphosphine complex 144 N N H Ph Ph P O Ph 126a NO2 N H O P N OH N Ph NO 95a O 145 Scheme 2.18. Proposed catalytic cycle of the phospha-Michael reaction to nitrostyrene. In the first step, the phosphine oxide was tauomerised to the unstable but reactive nucleophilic form in the presence of guanidine catalyst. The hydroxylphosphine could form stable inter-molecular hydrogen bond with guandinine. The nitrostyrene 50 Chapter approached the guanidine-hydroxylphosphine complex 144 to build a three component intermediate. The phospha-Michael reaction occurred and released the catalyst to give the product. 2.3.7 Synthesis of chiral β-aminophosphine. The highly enantioselective phospha-Michael reaction povided an attractive strategy for the synthesis of optically active α-substituted β-aminophosphines as potential P,N-ligands 18 for metal-catalyzed reactions. These ligands will be complementary to the α-aminophosphines, which are readily prepared from amino acids.19 The phosphine oxide 127c was easily prepared through the filtration protocol. The β-aminophosphine oxide 146 can be obtained by the selective reduction of the nitro group using zinc in acidic conditions (Scheme 2.19). The optical activity was found to remain at >99% ee. The reaction mixture can be easily purified through a simple acid-base wash without further purification. R R P O R R P O NO2 Zn/HCl NH MeOH/THF Cl 75 oC Cl 127a R = 1-naphthyl 146 R = 1-naphthyl 89% yield, >99% ee Scheme 2.19. Synthesis of chiral aminophosphine oxides. Another synthetic application can be achieved when β-aminophosphine oxide 146 is reduced to β-aminophosphine 147 (Scheme 2.20). DIBAL-H20 and a methylation reagent like MeI followed by LiAlH421 were proven to be superior methods for the 51 Chapter reduction of phosphine oxide. However, these methods were not successful in the application for the reduction of β-aminophosphine oxide 146. The use of trichlorosilane with eq. of PPh3 was reported as an efficient tool to complete deoxygenation of phosphine oxides.22 Due to the low boiling point of HSiCl3 and the high reaction temperature, the seal tube was used in this reaction. The reaction yield without any optimized experiments can reach 70% and there was no loss in optical activity (determined by converting 147 back to 146 using H2O2). It was to our surprise that the aminophosphine was stable in air at least for a few hours. R R P O R P HSiCl3, Ph3 P NH2 R NH toluene, Et3N reflux, seal tube Cl Cl 147 R = 1-naphthyl 70% yield, >99% ee 146 R = 1-naphthyl >99% ee Scheme 2.20. Synthesis of chiral aminophosphines. 2.4 Conclusion and future research In this chapter, we have discovered the first catalytic asymmetric phospha-Michael reaction between diaryl phosphine oxides and nitroalkenes. This is a direct and atom economical method to synthesize chiral α-substituted β-phosphine oxides and β-aminophosphines. Those novel animophosphines may be potentially useful as organocatalysts and ligands in metal-catalyzed reactions. The limitation of this method is the narrow reaction scope. In this chapter, only nitroalkenes were found to react as phospha-Michael acceptors to obtain the products with high yield and enatioselectivies. Expanding the reaction scope to other Michael 52 Chapter acceptors is a challenge for future study. Furthermore, only di(1-naphthyl) phosphine oxide were proven to afford excellent results. Improving the enantioselectivities of other aryl substitutions could be another target for future research. 53 Chapter Reference: Yamamoto, Y.; Kojima, S., the Chemistry of Amidines and Imidates. S. Patai, Z. Rappoport, Eds, John Wiley & Sons Inc.: New York, 1991; Vol. 2. Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.; Pollini, G. P., Tetrahedron Lett. 1998, 39, 7615–7618. Jiang, Z.; Zhang, Y.; Ye, W.; Tan, C.-H. Tetrahedron Lett. 2007, 48, 51–54. (a) Chinchilla, R.; Nájera, C.; Sánchez-Agulló, P., Tetrahedron: Asymmetry 1994, 5, 1393–1402. (b) Ma, D.; Pan, Q.; Han, F., Tetrahedron Lett., 2002, 43, 9401–9403. (c) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K., Adv. Syn. Catal. 2005, 347, 1643–1648. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M., J. Am. Chem. Soc. 1996, 118, 4910–4911. (a) Ma, D.; Cheng, K., Tetrahedron: Asymmetry 1999, 10, 713–719. (b) Terada, M.; Ube, H.; Yaguchi, Y., J. Am. Chem. Soc. 2006, 128, 1454–1455. Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T., Chem. Commun. 2001, 243–244. Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044–16045. Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H., Tetrahedron Lett. 2006, 47, 1007–1010. 10 Corey, E. J.; Grogan, M. J., Org. Lett. 1999, 1, 157–160. 11 Ye, W.; Jiang, Z; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y.-T.; Tan, C.-H., Adv. Synth. Catal. 2007, 349, 2454–2458. 12 Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H., J. Am. Chem. Soc. 2006, 128, 13692–13693. 54 Chapter 13 See chapter references 27-30. 14 See chapter reference 31. 15 Xu, J.; Fu, X.; Low, R.; Goh, Y.-P.; Jiang, Z.; Tan, C.-H., Chem. Commun. 2008, 5526–5528. 16 Kassaee, M. Z.; Vessally, E., J. Photoch. Photobio. A 2005, 172, 331–336. 17 Uraguchi, D.; Ito, T.; Ooi, T., J. Am. Chem. Soc. 2009, 131, 3836–3837. 18 Guiry, P. J.; Saunders, C. P., Adv. Syn. Catal. 2004, 346, 497–537. 19 (a) Hayashi, T.; Fukushima, M.; Konishi, M.; Kumada, M., Tetrahedron Lett. 1980, 21, 79–82. (b) Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M., J. Org. Chem. 1983, 48, 2195–2202. 20 Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Hrapchak, M.; Latli, B.; Lee, H.; Sabila, P.; Saha, A.; Sarvestani, M.; Shen, S.; Varsolona, R.; Wei, X.; Senanayake, C. H., Org. Lett. 2005, 7, 4277–4280. 21 Imamoto, T.; Kikuchi, S.; Miura, T.; Wada, Y., Org. Lett. 2001, 3, 87–90. 22 Wu, H.-C.; Yu, J.-Q.; Spencer, J. B., Org. Lett. 2004, 6, 4675–4678. 55 [...]... 125 , with a variety of substituents were investigated (Table 2. 4) 41 Chapter 2 Table 2. 4 Chiral bicyclic guanidine- catalyzed phospha-Michael reactions with various diaryl phosphine oxides t R R P O NO2 + Ph H 95a 125 Bu N t Bu N N H 114b (10 mol%) Et2 O, 0 oC R R P O NO2 Ph 126 entry adduct time/h yield/%a ee/%b 1 125 a [Ph] 126 a 13 64 60 (96) 2 125 b [4-FC6H4] 126 b 14 92 60 (>99) 3 125 c [4-PhC6H4] 126 c... phospha-Michael reactions of aryl nitroalkenes tBu R R P O + Ar H 125 f R = 1-naphthyl NO 2 N tBu N N H 114b (10 mol%) Et2O, -40 o C R R P O NO2 Ar 95a-i 127 R = 1-naphthyl entry adduct time/h yield/%a ee/%b 1 Ph (95a) 126 f 36 94 91 (95) 2 4-ClC6H4 (95b) 127 a 12 94 96 (>99) 3 3-ClC6H4 (95c) 127 b 12 96 90 (95) 4 2- ClC6H4 (95d) 127 cc 12 98 93 (99) 5 4-BrC6H4 (95e) 127 d 12 99 93 (>99) 6 3-NO2C6H4 (95f) 127 e 12 95... mol%) R R P OO RO Et 2O O R = 1-naphthyl N 141a R = Me 141b R = tBu R R P OO Ph 1 42 R R P OO t MeO * O Ph O 142a -20 oC 2. 5h 99% yield 2% ee -50 oC 18h 99% yield 2% ee BuO Ph O 142b -20 oC 22 h 99% yield 10% ee -50 oC 22 h 87% yield 10% ee Scheme 2. 17 Phospha-Michael reaction of phosphine oxide 125 f to activated olefins 141 2. 3.6 Proposed mechanism of phospha-Michael reactions 49 Chapter 2 From the experimental... toluene and furnished 82% yield and 40% ee within 30 min (entry 3) Table 2. 2 Solvent effects on the phospha-Michael reaction of phosphine oxides 125 a and trans-β-nitro styrene 95a tBu Ph Ph P O NO 2 + Ph H 95a 125 a N tBu N N H 114b (10 mol%) solvent, 0 oC Ph Ph P O NO2 Ph 126 a entrya solvent time/h yield/%b ee/%c 1 CH3CN 1 91 12 2 CH2Cl2 4 54 30 3 Toluene 0.5 82 40 4 THF 1 85 45 5 Et2O 1 87 53 6 t-BuOMe...Chapter 2 Table 2. 1 Various chiral catalysts in catalytic phospha-Michael reaction of phosphine oxide 125 a with trans-β-nitro styrene 95a Ph Ph P O H 125 a N N TsHN N Bn 3 20 mol% t N Bu N H t N H 62 15 84 25 25 min 82 40 3h 59 11 114b OBn N 7 114a Bu N N BnO N 47 5 min Bn N H ee/%b 19 h 126 b yield/%a 19 h 126 a tBu 2 a time Bn TsHN NO2 Ph 126 a catalyst 1 5 toluene, 0 oC 95a Entry 4 10 mol% catalyst NO 2 +... excellent ee (>99%) and yield of 70–90% can be obtained by simple filtration and no further purification was required t Bu R R P O Cy + H NO2 N Bu N N H 114b (10 mol%) Et2O, 0o C 128 125 a R = Ph 125 f R = 1-naphthyl Scheme 2. 9 Phospa-Michael (E)- (2- nitrovinyl)cyclohexane t R R P O Cy NO 2 129 a 50% yield, 23 % ee 129 b 15% yield, 71% ee reaction between phosphine oxide and Nitroalkene 128 derived from alkyl... conformation The conformation A was determined to be the major diastereoisomer Similar, the conformation B was determined to be the minor diastereoisomer Ha R2 (O)P R2 (O)P 2. 9Hz Ph Ha 8.2Hz Ph Hb O2 N NO2 Hb Me A Me B Minor diastereoisomer Major diastereoisomer a H δ 4.86 (dd, J = 8 .2, 10 .2 Hz, 1H) H δ 5.10 (dd, J = 2. 9, 11.7 Hz) Scheme 2. 12 The determination of the relative configuration of 133a a 2. 3.4... obtained Di (2- naphthyl )and di(1-naphthyl)phosphine oxides, 125 e and 125 f (entries 5 and 6) were also evaluated; enanioselectivities of 65% and 82% were obtained respectively All adducts except 126 d are crystalline and the optical purity of all adducts were able to 42 Chapter 2 improve to >90% ee after a single recrystallization from MeOH or tBuOMe-DCM Table 2. 5 Chiral bicyclic guanidine- catalyzed phospha-Michael... 95a + NO2 Ph 1 eq Et3 N THF 95a OPh PhO P O NO2 Ph 135 90% yield OBn Ph P O NO2 Ph 137 90% yield Scheme 2. 13 Achiral phospha-Michael reaction of phosphonate and H-phosphinate with nitrostyrene t Bu OPh NO2 PhO P O Ph + H 95a 134 H 136 + NO2 Ph t Bu N N H 114b (10 mol%) Et2 O OPh PhO P O NO2 Ph 135 t OBn Ph P O N Bu N t Bu N N H114b (10 mol%) Et2 O 95a OBn Ph P O NO2 Ph 137 Scheme 2. 14 Bicyclic guanidine. .. freezing point and 40% ee was observed (entry 10) In summary, the optimum solvent for the phospha-Michael reaction was determined to be Et2O (53% ee, entry 40 Chapter 2 5) Table 2. 3 Effect of phosphine oxide/nitrostyrene ratio on the phospha-Michael reactions tBu Ph Ph P O NO 2 + Ph H 95a 125 a N tBu N N H 114b (10 mol%) Et2O, 0 o C Ph Ph P O Ph 126 a NO2 entry time/h yield/%a ee/%b 1 3:1 24 n.d n.d 2 1:3 1 . mol%) CH 2 Cl 2 , -2 0 o C 122 124 OOH OH CO 2 Me H MeOC 124 a 92% yield 98% ee OOH OH CO 2 Et H PhOC 124 b 92% yield 95% ee OOH OH CN H NC 124 c 90% yield 94% ee Scheme 2. 8. Chiral bicyclic guanidine catalyzed. [4-FC 6 H 4 ] 126 b 14 92 60 (>99) 3 125 c [4-PhC 6 H 4 ] 126 c 40 85 50 (91) 4 c 125 d [ 2- EtC 6 H 4 ] 126 d 40 77 75 d 5 125 e [ 2- naphthyl] 126 e 6 92 65 (99) 6 125 f [1-naphthyl] 126 f 8. P O Ph Ph N O O Ph Ph 2 P(O)H N O O Ph 93 101 (99%) TBD R 1 R 2 Ph 2 P(O)H TBD P O Ph Ph R 1 R 2 102a :R 1 =R 2 =CN 102b:R 1 =R 2 =CO 2 Me 102c:R 1 =R 2 =COPh 102d :R 1 =Ph; R 2 =CN 102e :R 1 =Ph; R 2 =COPh 103a :R 1 =R 2 =CN (80%) 103b:R 1 =R 2 =CO 2 Me (98%) 103c:R 1 =R 2 =COPh