Chemistry 206 Advanced Organic Chemistry Handout–22A A Survey of "Soft Enolization" Techniques Mark Bilodeau Evans Group Seminar, March 10, 1993 Matthew D. Shair FridayNovember 8, 2002 Sasai, Suzuki, Arai, Arai, Shibasaki J. Am. Chem. Soc. 1992, 114, 4418-4420. PhCHO + Catalyst THF Ti(Ot-Bu) 4 - No coupling product La 3 (Ot-Bu) 9 (3.3 mol%), -72° C, 30 h, 74% yield Y 3 (Ot-Bu) 8 Cl (3.3 mol%), -43° C, 3.5 h, 50% yield Zr(Ot-Bu) 4 (140 mol%), -50° C, 2.5 h, 86% yield La 3 (Ot-Bu) 9 (3.3 mol%) (S)-Binaphthol (15 mol%) + THF, rt 2 h 1 H NMR shows absence of a t-Butoxy group on the catalyst RCHO, 1 equiv MeNO 2 , 10 equiv LiCl, 20 mol% H 2 O, 1 equiv R = c-C 6 H 11 , 91% yield, 90% ee R = i-Pr, 80% yield, 85% ee R = PhCH 2 CH 2 CHO, 79% yield, 73% ee a73 Catalytic Enantioselective Aldol Reactions of Nitroalkanes Sasai, Itoh, Suzuki, Shibasaki Tetrahedron Lett. 1993, 34, 855-858. Tetrahedron Lett. 1993, 34, 851-854. 1 equiv + MeNO 2 50 equiv Catalyst -50° C, 60 h LaCl 3 ?7H 2 O (10 mol%) (R)-(+)-binaphthoxide (10 mol%) NaOt-Bu (10 mol%) H 2 O (10 mol%) Catalyst prepared from: 80% yield 92% ee Alkoxides of Lanthanum and Yttrium Mark Bilodeau Evans Group Meeting 3/10/93 A Survey of 'Soft' Enolization Techniques D. Boron Enolates - Enolate Stereochemistry I. Metal Alkoxides II. Lewis Acid/ Amine Base Enolizations A. Horner-Emmons Reactions B. Glycine Enolates C. Methods for General Carbonyl Substrates M. Bilodeau, D.A. Evans Chem 115A Survey of 'Soft' Enolization Techniques O Me Cl Me O Ph HO Cl NO 2 R HO α?NaphtO NO 2 OH α?NaphtO CHO 22A-01 Ketone Acidity 11/1/01 3:41 PM R 3 N ML n + ML n R 3 N a73 Many reactions surveyed here don't rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate. pKa 19.2 (DMSO), K + counterion pKa 12.2 (Diglyme), Li + counterion LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN rt 1.2 equiv Horner-Wadsworth-Emmons Reaction. Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Above conditions using DIPEA 24 h, rt 85% + 10% recovered aldehyde Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). R= i-Pr, 40% yield R= n-C 6 H 13 , 100% yield 1 equiv MgBr 2 , 1.2 equiv Et 3 N, 1.1 equiv RCHO, 1 equiv THF rt Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. El+ a73 Acidity of a-protons enhanced by coordination of Lewis acid. a73 This allows the use of mild bases to depronate substrate. a73 A critical issue in the success of procedure of enolization is the reversible Lewis acid/amine base association. Lewis Acid - Tertiary Amine Enolizations ML n + R' 3 N R' 3 N-ML n R' 3 N - + Chem 115M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques R O Me Me O R ML n O ML n-1 R Me O R Me El O OEt (EtO) 2 P O ROEt O O OEt (EtO) 2 P O OEt O Me Me NHCbz CHO Me Me NHCbz OEt O 22A-02 Ketone Acidity 11/1/01 3:41 PM M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 77% yield, single isomer 1 equiv 1 equiv + LiBr, 1.1 equiv DBU, 1.0 equiv THF, rt NaI, MgBr 2 ?OEt 2 , ZnI 2 , Et 2 AlCl employed in related reactions (Bull. Chem. Soc. Jpn. 1989, 62, 869-874). 82% yield AgOAc, THF, 90% yield, 1:>9 ZnBr 2 , THF, 90% yield, 1:2.7 Formation of Glycine Enolates. Tsuge, Kanemasa, Yoshioka J. Org. Chem. 1988, 53, 1384-1391. Kanemasa, Tatsukawa, Wada, Tsuge Chem. Lett. 1989, 1301-1304. Kanemasa, Uchida, Wada J. Org. Chem. 1990, 55, 4411-4417. LiBr, 1.5 equiv Et 3 N, 1.2 equiv THF, rt + + Grigg et al Tetrahedron 1988, 44, 557-570; 1989, 45, 4649-4668. Tetrahedron Lett. 1989, 30, 4727-4730; 1990, 31, 6569-6572. 1 equiv 1 equiv 1 equiv 2 equiv Ti(Oi-Pr) 3 Cl, 1.5 equiv Et 3 N, 1 equiv CH 2 Cl 2 , rt 80% yield 1.2:1 R=Me/R=i-Pr Note: Regiochemistry of addition opposite to that above. + + Lewis Acid Et 3 N Solvent rt LiBr, MeCN, 89% yield, 1:6 Related reactions have been conducted with MnBr 2 , MgBr 2 ?OEt 2 , TlNO 3 , CoCl 2 ? Cu(I) catalyzes the reaction but with no enantioselectivity. This has been rationalized on the basis of Cu(I)'s strong preference for N coordination. ? Ag(I) has recently been optimised to provide moderate-to-good enantioselectivity . Hayashi, Ito et. al. Tet. Lett. 1991, 32, 2799-2802. CH 2 Cl 2, 25 °C [Au(c-HexNC) 2 ] + BF 4 - / 1 (1 mol%) i-PrCHO + 1a : R=Et 1b : R=Me Ito, Sawamura, Hayashi J. Am. Chem. Soc., 1986, 108, 6405-6406. (R)-(S) Ito Tet. Lett. 1985, 5781. + RCHO CuCl, 5 mol% Et 3 N, 5 mol% THF, RT ? When only Et 3 N is employed - complex mixtures, low yields R= Me, 100% yield, 2:1 trans/cis R=Et 2 CH, 75% yield, trans only 99% yield, 98:2 trans/cis 92% ee Glycine Enolates NCO 2 MePh CO 2 Me H N Ph CO 2 Me MeO 2 C N OOMe O Li MeO Ph CO 2 Me N CO 2 Me Ph N CO 2 Me CO 2 Me CO 2 RPh H N Ph Me CO 2 Me MeO 2 CMeO 2 C CO 2 MePh H N H N Ph CO 2 Me MeO 2 C CO 2 Me CO 2 Me Me Me Me Me Me N Me t-Bu CO 2 Me CO 2 Me Me CO 2 Me t-Bu N CO 2 Me CN O Fe OMe O PPh 2 N PPh 2 NCH 2 CH 2 NR 2 Me H Me i-Pr CO 2 Me CN CO 2 Me ON CO 2 MeR 22A-03 Ketone Acidity 11/1/01 3:41 PM Rathke A Survey of 'Soft' Enolization Techniques M. Bilodeau, D.A. Evans Chem 115 16:1 ratio of isomers 3M LiClO 4 Et 3 N Et 2 O Harmata, Elahmad Tetrahedron Lett. 1993, 34, 789-792. 70% yield + LiClO 4 Et 3 N Et 2 O Kaiser, Fohlisch Helv. Chim. Acta. 1990, 73, 1504-1514. "Reaction can be brought about with less than 1 equiv of LiI." 76%, 60:40 ratio of diastereomers LiI TMSCl, Et 3 N Et 2 O, reflux PhCHO R= Ph, 77% R= n-C 6 H 11 , 85% slow addn of: RCHO Et 2 O reflux 4 equiv LiI+ 1 equiv Lithium Halide Enolizations Kelleher, McKervey, Vibuljan Chem. Comm. 1980, 486-488. - Evans, Bilodeau unpublished results. 73% yield, 93:7 diastereomer ratio Magnesium Enolates Deuterium quench indicates 25% enolization of N-propionyloxazolidinone MgBr 2 ?OEt 2 Et 3 N CH 2 Cl 2 , 0° C 75% yield MVK EtOH MgCl 2 , 2 equiv Et 3 N, 4 equiv CO 2 MeCN rt 70 % yield MgCl 2 , 2 equiv NaI, 2 equiv Et 3 N, 4 equiv CO 2 MeCN rt Ketone Carboxylation 85% yield MgCl 2 , 1 equiv Et 3 N, 2 equiv MeCN, rt Diethylmalonate acylations J. Org. Chem. 1985, 50, 2622-2624. J. Org. Chem. 1985, 50, 4877-4879. Syn. Comm. 1986, 16, 1133-1139. Me O Me Me O R Me O Me Me O Me Ph OH O O Cl Cl Cl O O O O Cl O O Cl O O O EtO O OEt Me O Cl OEt O EtO O OMe O O COOH O O O O Mg O Me O ON Bn O Me O CO 2 Me O Me N O Bn O CO 2 Me 22A-04 Ketone Acidity 11/1/01 3:42 PM A Survey of 'Soft' Enolization Techniques M. Bilodeau, D.A. Evans Chem 115 70% enolization (Deuterium Quench) AlCl 3 Et 3 N CH 2 Cl 2 , 0° C Miscellaneous Metals Nelson, Howells, DeLullo, Landen J. Org. Chem. 1980, 45, 1246-1249. 90% yield Ni(acac) 2 (1 mol%) dioxane 85° C, 19 h + a73 Bis(2,4-pentanedionato)nickel(II) - Employing TMSCl and Et 3 N alone provide no enol ether. 68% yield ZnCl 2 , 3 mol % Et 3 N TMSCl C 6 H 6 , 40° C Danishefsky, Kiahara J. Am. Chem. Soc. 1974, 96, 7807-7808. a73 Zinc chloride a73 Dialkylaluminumphenoxide Tsuji, Yamada, Kaito, Mandai Tetrahedron Lett. 1979, 2257-2260. i-Bu 2 AlOPh Pyridine THF reflux 85% a73 Aluminum trichloride Evans, Bilodeau unpublished results. Mukaiyama, Iwasawa Chem. Lett. 1982, 1903. 95% yield, >97:3 syn/anti i-PrCHO Sn(OTf) 2 N-ethylpiperidine CH 2 Cl 2 , -78° C a73 Methyl ketones readily self-condense (Chem. Lett. 1982, 1459). a73 Amine and Sn(OTf) 2 are pre-mixed followed by addition of carbonyl substrate. This indicates that Lewis acid-amine association is reversible. Tin(II) triflate Mukaiyama, Stevens, Iwasawa Chem. Lett. 1982, 353. Sn(OTf) 2 R 3 N CH 2 Cl 2 , -45° C Ph(CH 2 ) 2 CHO Base = Et 3 N, 50% yield (15% self-condensation) N-Methylmorpholine, 22% yield (65%) N-Ethylpiperidine, 80% (trace) Pyridine, 0% DBU, 0% Sn(OTf) 2 N-ethylpiperidine CH 2 Cl 2 , -78° C i-PrCHO R = Et, 73% yield, 93:7 syn/anti R =Ph, 80% yield, 91:9 syn/anti a73 Cannot quantitatively enolize simple esters or amides. However, using standard enolization protocol on esters in the presence of PhCHO resulted in a "good" yield of aldol adduct. Employing enolizable aldehydes provides polymerized product. There is some equilibrium enolization of esters. ? Sn(OTf) 2 unsuitable for enolization of N-propionyloxazolidinone (Evans, Weber). Me TMSO OMe OMe O O Me n-C 6 H 11 O n-C 6 H 11 Me n-C 5 H 11 Me Me OO Me O OO MeMe Me O ON Bn O Me O Ph O Me O Ph Me OH Ph Me O R R O Me OH Me Me SN S Me O O N S S Me MeMe OH 22A-05 Ketone Acidity 11/1/01 3:42 PM The Early Literature 10-15:1 Z/E TiCl 4 DIPEA THF -40° C a73 Brocchini, Eberle, Lawton J. Am. Chem. Soc. 1988, 110, 5211-5212. 91% yield 95:5 syn/anti TiCl 4 Et 3 N CH 2 Cl 2 , 0° C 30 min PhCHO+ Ketone and aldehyde combined followed by sequential addn of TiCl 4 and then amine a73 Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135-4138. 75% yield TiCl 4 Pyridine THF Titanium Enolates a73 Lehnert, W. Tetrahedron Lett. 1970, 4723-4724. No diamine: 60% yield, 61:39 syn/anti Diamine= TMEDA, 65% yield, 9:91 anti/syn i-PrCHO Sn(OTf) 2 N-ethylpiperidine [Diamine] Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 1. Sn(OTf) 2 Et 3 N 2. i-PrCHO Evans, Weber J. Am. Chem. Soc. 1986, 108, 6757. i-PrCHO Sn(OTf) 2 N-ethylpiperidine CH 2 Cl 2 , -78° C Tin Enolates Chem 115 M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques 79% Diastereoselection >95:5 Sn(OTf) 2 Et 3 N Evans, Sheppard J. Org. Chem. 1990, 55, 5192. ON O O NCS Bn Bn O N O O Me O Me Me O ON O Bn HN O N O O O O H Me Me O Bn Me MeMe OH SN S OBn O O N S S Me MeBnO OH Et Et O EtO OEt OO O OEtEtO O EtEt Ph Me O Ph Ph O Me OH NO 2 O S OH CHO N S O NO 2 OH O Me OH Me Me H O MeMe Me O CH 2 Me X P OO Me CH 2 OO OO Me O Me Me MeMe Bn O Me 22A-06 Ketone Acidity 11/1/01 3:42 PM A Survey of 'Soft' Enolization Techniques M. Bilodeau, D.A. Evans Chem 115 R=Ar, R<i-Pr a73 Substrates Which present problems: a73 Enolizable substrates: Titanium Enolates Irreversible Complexation -+ R 3 N-TiCl 4 TiCl 4 +R 3 N a73 Order of addition of reagents is important for TiCl 4 . a73 For Titanium: Enolization process not responsive to tertiary amine structure a73 DIPEA, Et 3 N, N-Ethylpiperidine all suitable bases . a73 DBU and tetramethylguanidine do not provide enolate. a73 CH 2 Cl 2 is the only suitable solvent for these enolizations. a73 Order of addition of reagents is not important for i-PrOTiCl 3 or (i-PrO) 2 TiCl 2 . R 3 N + i-PrOTiCl 3 -+ R 3 N-TiCl 3 (OiPr) Reversible Complexation TiCl 4 R 3 N N-Propionyloxazolidone (1) Lewis Acid % Enolization TiCl 4 i-PrOTiCl 3 (i-PrO) 2 TiCl 2 (i-PrO) 3 TiCl 100 100 70 ~10 80TiCl 4 ?2THF Ethylisopropylketone Lewis Acid % Enolization TiCl 4 i-PrOTiCl 3 (i-PrO) 2 TiCl 2 100 80 50 Reactions of Titanium Enolates 1. TiCl 4 DIPEA 2. i-PrCHO Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 86% yield, >99:1 99%, >99:1 BOMCl 93%, 97:3 PhSCH 2 Cl 89%, 97:3 ClCH 2 NHCOPh MeOCH 2 NHCbz 91%, 96:4 93%, 99:1 HC(OMe) 3 99%, >99:1 88%, >99:1 78%, 98:2 H 2 C=CHCOEt H 2 C=CHCO 2 Me J. Am. Chem. Soc. 1990, 112, 8215-8216.; J. Org. Chem. 1991, 56, 5750-5752. 1 Reactions with Representative Electrophiles MeO OMe O R O Me PhS O t-Bu Me Me O MeO O Me O RMe O O Me N O Bn O ON Bn O Me O O Me N O Bn O Ti Cl Cl Cl Cl Ti Cl n Bn O N O O Me O Me Me O ON O O Bn Me Me OH Me O Me N O Bn O Ti Cl n X p CH 2 OBn O Me Me O CH 2 SPh X p X p CH 2 NHCOPh O Me Me O CH 2 NHCBz X p X p CH 2 OH O Me O OO Me O CH(OMe) 2 X p X p (CH 2 ) 2 COEt O Me OMe O Me O X p 22A-07 Ketone Acidity 11/1/01 3:42 PM M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 96% yield, 96:4 diastereomer ratio 1. TiCl 4 DIPEA CH 2 Cl 2 , -78° C 2. i-PrCHO R = Et, 95% yield, 92:8 syn/anti R = i-Pr, 95%, 93:7 syn/anti 1. TiCl 4 DIPEA CH 2 Cl 2 , -78° C 2. i-PrCHO Aldol Reactions of Titanium Enolates J. Am. Chem. Soc. 1991, 113, 1047-1049. ? Order of addition is crucial, Lewis acid and amine irreversibly associate. ? Including PhCHO in reaction solution affords no aldol product. 72% yield TiCl 2 (OTf) 2 , 1.5 equiv Et 3 N, 2.2 equiv CH 2 Cl 2 , 0° C 4? M.S. Tanabe, Mukaiyama Chem. Lett. 1984, 1867-1870. Titanium Enolization of Esters Xiang, Olivier, Ouimet Tetrahedron Lett. 1992, 33, 457-460. TiCl 4 (1.05 equiv) Et 3 N (2.1 equiv) PhCHO CH 2 Cl 2 , -40° C 70:30 ratio of diastereomers 94% combined yield When PhCHO is pre-complexed with an equimolar amount of TiCl 4 a syn diastereomer predominates (90:10). Tanabe Bull. Chem. Soc. Jpn. 1989, 62, 1917-1924. Cinquini, Cozzi et. al. Tetrahedron 1991, 47, 8767-8774. 1991, 47, 7897-7910. 65% yield, 89:11 syn/anti 1. TiCl 4 , 1 equiv Et 3 N, 1 equiv CH 2 Cl 2 , -78° C 2. i-PrCHO 64% yield, 84:16 syn/anti Titanium Enolates of Thioesters 80% yield, >96% de 2 equiv 1 equiv TiCl 4 , 2 equiv Et 3 N, 2 equiv CH 2 Cl 2 , -78° C R = Bn, 95% yield, 98:2 syn/anti R = TBS, 98% yield, 10:90 syn/anti i-PrCHO, 1 equiv TiCl 4 , 2 equiv Et 3 N, 2 equiv CH 2 Cl 2 , -78° C 2 equiv Cinquini, Cozzi et. al. J. Org. Chem. 1992, 57, 4155-4162. 1992, 57, 6339-6342. OTsHN Me O Me Ph O X c Ph Me OH Me O OEt OEt O Me O Me R O Me O R Me MeMe OH OH Me Me Me O Me O Me Me Me TBSO Me Me HO Me PhS O Me O PhS Me MeMe OH SPh O EtO OH PhS Me Me EtO O PhS O OR PhS O Me MeRO OH Me O PhS Me N Me PMP OBn NPMP O Me OBn Me Me 22A-08 Ketone Acidity 11/1/01 3:42 PM A Survey of 'Soft' Enolization Techniques M. Bilodeau, D.A. Evans Chem 115 (-)-(Ipc) 2 BOTf a73 Chiral dialkylboron triflates Masamune, S. et. al. Tetrahedron Lett. 1979, 2225, 2229, 3937. Masamune, S. et. al. J. Am Chem. Soc. 1981, 103, 1566-1568. a73 Diastereoselective Aldol Reactions of Boron Enolates. a73 Di-n-butylboron triflate Evans, Vogel, Nelson J. Am. Chem. Soc. 1979, 101, 6120. Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Evans, Bartroli, Shih J. Am. Chem. Soc. 1981, 103, 2127. Dialkylboron Triflates Enolizes ketones with 2,6-lutidine or DIPEA in ethereal solvents. Mukaiyama, Inoue Chem. Lett. 1976, 559-562. Bull. Chem. Soc. Jpn. 1980, 53, 174-178. Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281. Paterson, I. et. al. Tetrahedron 1990, 46, 4663-4684. Tetrahedron Lett. 1989, 30, 997-1000. Tetrahedron Lett. 1986, 27, 4787-4790. a73 Borane and lutidine or DIPEA form 1:1 complex. Complexation reversible as enolization will occur upon addition of ketone. a73 Less hindered nitrogen bases - pyridine, Dabco, DBU, and tetramethylguanidine innefective in the enolization. Attributed to irreversible amine-borane complexation. a73 The more hindered triflate - enolization must be carried out at 0° C. R=Et: Z:E = >97:3 R= i-Pr: Z:E = 45:55 R= t-Bu: Z:E = 25:75 n-Bu 2 BOTf DIPEA Ether, -78° C R 2 BOTf DIPEA Ether, -78° C R= n-Bu: Z:E = >97:3 R= c-C 5 H 11 : Z:E = 82:18 DIPEA: Z:E = >97:3 Lut: Z:E = 69:31 n-Bu 2 BOTf Base Ether, -78° C Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Dialkylboron Triflates + L 2 BOTf + - + - NR' 3 NR' 3 (A) E and Z enolates derived from deprotonation of syn and anti complexes respectively. (B) Deprotonation is rate determining step rather than complexation. (C) All factors being equal anti deprotonation preferred over syn deprotonation. 1. n-Bu 2 BOTf Et 3 N 2. n-BuLi, TMSCl Polniazek, R. Research Report 94:6 Z:E TfOB Me Me BOTf O MeMe Me Me O Me R O O R Me H Me H RO BL 2 OTf O BL 2 OTf R MeH H Me R Me OBL 2 R OBL 2 O Me Et O HH O Et Me TMSO 22A-09 Ketone Acidity 11/1/01 3:43 PM M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 Coordination to a Lewis Acid lowers rotational barriers moderately , still a preference for eclipsed methyl. LePage, Wiberg J. Am. Chem. Soc. 1988, 110, 6642-6650. Raber, D. J.; Raber, N. K.; Chandrasekhar, J.; Schleyer, P. von R. J. Organomet. Chem. 1984, 23, 4076-4080. 13 C NMR study of 2-butanone with BF 3 shows Lewis acid predominantly on one side of carbonyl group. Shielded by 2.0 ppmDeshielded by 2.2 ppm Hartman, J. S.; Stibbs, P.; Forsen, S. Tetrahedron Lett. 1975, 3497-3500. a73 Poor regioselectivity of deprotonation by R 2 BOTf (vide infra) a73 Electronic as well as steric impetus for trans deprotonation. + Calculations on cationic complex: 6-31G*//3-21G If OTf- dissociates from ketone-R 2 BOTf complex structure could be anticipated to become linear. Allene-like structure resulting from rehybridization of O lone pairs and overlap of resulting p-orbital with empty p orbital on boron. R = H, Me: Methyl group eclipsing carbonyl preferred conformation. Lewis Acid-Ketone complexation: Theory & NMR - + + a73 Enolization could occur through a linear boron-carbonyl complex. R 2 BCl Et 3 N Et 2 O R =Chx, Z:E = 20:80 R = Bco, Z:E = 3:97 Bco = Bicyclo[2.2.2]oct-2-ane Esters, N,N-disubstituted amides could not be enolized. Thioesters could be quantitatively enolized. Z:E ratio as a function of Lewis acid and base. Propiophenone Reagent Base Z:E 9-BBN-Cl Et 3 N 52:48 DIPEA >99:1 Chx 2 BCl Et 3 N 1:>99 DIPEA 51:49 9-BBN-OTf Et 3 N >99:1 DIPEA >99:1 Chx 2 BOTf Et 3 N 67:33 DIPEA >99:1 R = Ph, Z:E = >97:3 R = Et, Z:E = >97:3 R = i-Pr, Z:E = 65:35 R = Ph, Z:E = <3:97 R = Et, Z:E = 20:80 R = i-Pr, Z:E = <3:97 R = t-Bu, Z:E = <3:97 9-BBN-Cl DIPEA Et 2 O Chx 2 BCl Et 3 N Et 2 O H. C. Brown J. Am. Chem. Soc. 1989, 111, 3441-3442. J. Org. Chem. 1992, 57, 499-504. J. Org. Chem. 1992, 57, 2716-2721. J. Org. Chem. 1992, 57, 3767-3772. J. Org. Chem. 1993, 58, 147-153. Dialkylboron chlorides BF 3 O Me Me O H H B H H O Me Me B OTf O B Me R Me R RR R Me O HH O R Me Me R OB-9-BBN OBChx 2 R Me Me Et OBR 2 Me Et O 22A-10 Ketone Acidity 11/1/01 3:43 PM M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 a73 For 9-BBN-Cl, greater Z:E with DIPEA. Smaller R - greater Z:E. a73 For Chx 2 BCl, greater E:Z with Et 3 N. Larger R - greater E:Z. a73 2-Butanone regioselectively deprotonated at methyl group. a73 Diethylketone poor ratio (4:1 E:Z). Increasing the size of L 2 increases E:Z ratio (97:3). Boron Chloride - Cis Deprotonation? H. C. Brown Tetrahedron Lett. 1992, 33, 3421-4. Chx 2 BI Et 3 N CCl 4 , 0° C X = OEt, 96% yield ( 1 H NMR) X = NMe 2 , 96% yield ( 1 H NMR) Enolization also achieved in hexane or CH 2 Cl 2 . a73 Chx 2 BI enolizations of esters and amides. 6-31G*//3-21G level Gung, Wolf J. Org. Chem. 1992, 57, 1370-1375. Goodman Tetrahedron Lett. 1992, 7219-7222. MO Calculations on C=O-Boron Lewis Acid Complexes a73 Strong preference for F to eclipse the C=O bond. Generalized anomeric effect. Gaussian82 MP2/6-31G*//3-21G level F-H separation of only 2.06 ? Van der Walls radii: H 1.2 ?, F 1.35 ? a73 Calculation on 2-butanone with H 2 BF show Lewis acid adjacent to methyl group by 3.8 kJ/mol. a73 Methyl group staggered is 16 kJ/mol higher in energy. a73 Formaldehyde: For Me 2 BF preference for staggered is 19kJ/mol For H 2 BCl complex has preference of 14 kJ/mol O Me Me BL 2 Cl O BL 2 Cl Me O R R Me ClL 2 B O BL 2 Cl Me Me O ClL 2 B X Me Me O Me OBChx 2 Me X O HH B F HHHH HH F B H F H H O H HH F 22A-11 Ketone Acidity 11/1/01 3:44 PM A Survey of 'Soft' Enolization Techniques M. Bilodeau, D.A. Evans Chem 115 Goodman/Paterson Mechanistic Rationale E:Z = 80:20 Z:E = 97:3 R =Et R = Me Z:E = 97:3 60:40 regioisomers Only isomer L 2 BCl Et 3 N L 2 BCl Et 3 N L 2 BOTf DIPEA L 2 BOTf DIPEA Goodman, Paterson Tetrahedron Lett. 1992, 47, 7223-7226. "The Cl atom is directed towards one of the hydrogens on the cis alkyl group, which induces a partial negative charge on this α-carbon (thus activating the cis over the trans side for enolization by an unhindered base like Et 3 N)." For L 2 BOTf the steric bulk of the triflate is expected to force the X-B-O=C angle to increase thus reducing any electronic preference for the Lewis acid to be cis to the less substituted group. Favored Disfavored Disfavored Favored Proton activated by cis Cl-B Sterically hindered amine (DIPEA) gives Z by trans deprotonation + + + + - - - - Corey, Kim J. Am. Chem. Soc., 1990, 112, 4976-4977. A: Ar= p-MeC 6 H 4 -; B: Ar= 3,5-(F 3 C) 2 C 6 H 3 - B Et 3 N toluene-hex B DIPEA CH 2 Cl 2 c-C 6 H 11 CHO 86% yield, 98:2 syn/anti, 91% ee c-C 6 H 11 CHO 83% yield, 94:6 syn/anti, 75% ee 82% yield, 83% ee 85% yield, 98:2 syn/anti, 95% ee i-PrCHO -90 °C 2 h Et 3 N, 1.5 equiv CH 2 Cl 2 23 °C, 1h A 1 equiv i-PrCHO -78 °C 2 h DIPEA, 2 equiv CH 2 Cl 2 -78 °C, 1h 1 equivA Corey, Imwinkelried, Pikul, Xiang J. Am. Chem. Soc., 1989, 111, 5493-5495. Enantioselective Aldols - Corey O R Me O BL 2 Cl Me OBL 2 OBL 2 Me Me Me OBL 2 OBL 2 Me Me O MeH H RBL 2 OTf R H HMe O HMe H R B TfO L L B L L Cl O R H Me H Me R OBL 2 OBL 2 R Me Me R OBL 2 OBL 2 R Me Me N B Br N Ph Ph SO 2 O 2 S Ar Ar O Me Ot-Bu Ot-Bu O R HO Me SPh Me O Me HO c-C 6 H 11 O SPh O MeMe Me OOH Me O PhS Me O PhS OH Me Me Me Me 22A-12 Ketone Acidity 11/1/01 3:44 PM M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 Rationale for Apparent Enolate Stereochemistry. DIPEA Br - R* 2 BBr DIPEA CH 2 Cl 2 PhCHO R* 2 BBr Et 3 N PhCHO Et 3 N Corey, Kim J. Am. Chem. Soc., 1990, 112, 4976-4977. A similar explanation for Brown's observations in enolizations of propiophenone. + - + TfO- Et 3 N optimal base DIPEA optimal base Formation of Z-enolate from 9-BBNCl a consequence of strong acceleration of the E1 pathway in the 9-BBN pathway regardless of leaving group. R = Et, 87%, 84:16 syn/anti R = i-Pr, 84%, 75:25 syn/anti i-PrCHO BCl 3 , 2 equiv DIPEA, 2 equiv CH 2 Cl 2 -95° C Inability to achieve complete conversion attributed to attack of DIPEA upon Boron of coordinated ketone. Employing 2 equiv of BCl 3 affords complete conversion. Regenerated ketone activated by excess BCl 3 and deprotnated by excess DIPEA. DIPEA R 3 N-BCl 3 DIPEA - + +BCl 3 1 H-NMR shows formation of a 1:1 complex between BCl 3 and DIPEA. Pre-mixing Lewis acid (1 equiv) and DIPEA (3 equiv) followed by addition of ketone leads to little enolization. Addition of ketone to Lewis acid followed by addition of DIPEA leads to conversion of 75% of aldol. Chow, H.-F.; Seebach, D. Helv. Chim. Acta 1986, 69, 604-614. Boron Trichloride Alkoxydichloroboranes BCl 3 + i-PrOH i-PrOBCl 2 + HCl i-PrOBCl 2 , 2 equiv DIPEA, 4→5 equiv CH 2 Cl 2 -95° C i-PrCHO 65%, 95:5 syn/anti Although less Lewis acidic, this Lewis acid irreversible associates with DIPEA O Me Ot-Bu Ot-Bu O R HO Me SPh Me O Me HO R O SPh Me + O Me SPh OBR* 2 S Ph R* 2 B - Br OR* 2 B Me + S Ph OBR* 2 Ot-BuMe + O O MeR* 2 B - t-Bu Br O Ph Me Ph L 2 B Cl O BL 2 Me O MeMe O OH Me R O BCl 2 O MeMe O BCl 3 MeMe R Me MeMe OH Me Me MeMe O O MeMe 22A-13 Ketone Acidity 11/1/01 3:44 PM A Survey of 'Soft' Enolization TechniquesM. Bilodeau, D.A. Evans Chem 115 Gennari, C.; Colombo, L.; Scolastico, C.; Todeschini, R. Tetrahedron 1984, 40, 4051-4058. Ethylenechloroboronate 1.0 equiv DIPEA (1.15 equiv) CH 2 Cl 2 , -78° C R= Et, i-Pr >95:5 Z:E Enolization achieved with 2,6-lutidine as well. Can enolize thioseters (25° C). PhCHO R= Et, 82%, >99:1 syn/anti R= i-Pr, 71%, >99:1 syn/anti t-Butylethylketone or N-propionyloxazolidinone inert at -78° C Phenyldichloroborane Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 1729-1732. R= Et, i-Pr PhBCl 2 , 1.2 equiv CH 2 Cl 2 , -78° C DIPEA, 2.4 equiv i-PrCHO, 1.2 equiv R= Et, 96%, >99:1 syn/anti R= i-Pr, 80%, >99:1 syn/anti Aldehyde and DIPEA must be added together for good conversion. Otherwise self-condensed product of ketone is observed. B O O Cl R O Me Me O R B O O O RPh Me OH O R Me B O B Me R O R Me B O O O O O O Cl Cl Cl Me O R OH Me R O Me Me 22A-14 Ketone Acidity 11/1/01 3:44 PM