Thiyl Radicals in Organic Synthesis When burned, sulfur melts to a blood-red liquid and emits a blue flame that is best observed in the dark. Jian Jin MacMillan Group Meeting November 6, 2014 I. Generalities II.Thiyl-Mediated Hydrogen Atom Transfer III. Addition of Thiols to C=C bonds IV. Fragmentation of β-Sulfanyl Radicals V. Addition of Thiols to Alkynes VI. Addition of Thiols to Isonitriles VII. Addition of Thiols to C=S bonds I. Generalities ■ S-H Bond Dissociation Energies in Thiols ■ Alkanethiols: similar S−H BDEs around 87 kcal mol-1 regardless of the structure of the alkyl residue O O O HO SH SH Me SH NH2 86 kcal mol-1 87 kcal mol-1 88 kcal mol-1 ■ Thiophenols: weaker S−H BDEs due to the stabilization by resonance of the corresponding arenethiyl radical F SH SH SH F SH H2N O2N F F F 70 kcal mol-1 79 kcal mol-1 82 kcal mol-1 84 kcal mol-1 ■ S-S Bond Dissociation Energies in Disulfides -1 -1 ■ Dialkyldisulfides: around 65 kcal mol ■ Diaryldisulfides: around 50 kcal mol Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. I. Generalities ■ Generation of Thiyl Radicals ■ Hydrogen atom abstraction by the other radicals having a corresponding higher X−H BDEs RS H + X RS + X H Initiator: AIBN, (PhCO2)2, (t-BuO)2, Et3B/O2 ■ One-electron oxidation by Mn(OAc)3, O2 − e- RS H RS − H+ ■ One-electron reduction of disulfides + e- RS SR RS + RS H + H+ ■ Homolytic cleavage by radiolysis or light irradiation < 300 nm RS H RS + H 355 nm PhS SPh 2PhS Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Rate of Hydrogen Atom Transfer ■ The reactivity of a class of radicals toward a given hydrogen atom donor is well described by two parameters: the activation energy of the thermoneutral reaction (Ee0) and the enthalpy of the reaction of interest (ΔHe) ■ Different interactions in the transition state such as polar effects, antibonding (triplet repulsion), or neighboring π-electrons may influence Ee0, which is particularly low for the reactions of alkyl radicals with thiols RS H + R'H2C RS + RH2C H -1 7 -1 -1 S-H BDE = 87 kcal mol k298K = 2 × 10 M s n-Bu3Sn H + R'H2C n-Bu3Sn + RH2C H -1 6 -1 -1 Sn-H BDE = 79 kcal mol k298K = 2 × 10 M s Me OH Me Me Me + R'H2C Me O Me Me Me α-tocopherol Me O Me Me Me + RH2C H Me O Me Me Me -1 5 -1 -1 O-H BDE = 77 kcal mol k298K =6 × 10 M s Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Polar Effect in Hydrogen Atom Transfer ■ In hydrogen atom transfers between two radicals of different electronegativity, charge transfer configurations may contribute to the character of the transition state, such polar effects resulting in a lowering of the activation barrier R2 R2 2 the absence of charge-transfer stabilization of R benefits from charge-transfer stabilization 1 1 δ- δ+ R O C H C OR the symmetrical transition state, in which the RS H C OR1 because the electronegativities of he nucleophilic incoming and outgoing α-alkoxyalkyl radicals α-alkoxyalkyl radical and the electrophilic thiyl 3 3 R R have the same electronegativity R3 radical are significantly different disfavored favored t-BuOO OOt-Bu Me O Me Me O Me O Me Me 5 mol% Me Me + high activation energy Me nonane, 125 °C, 3 h Me Me Me O Me O Me O 100% 0% t-BuOO OOt-Bu Me O Me Me O Me O Me Me 5 mol% Me Me + thermodynamic equilibrium Me nonane, 125 °C, 2.5 h Me Me Me O Me O Me O (t-BuO)3SiSH 5 mol% 16% 84% Dang, H.-S.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1, 2001, 2452. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Rate Constants for the Reduction of Various Alkyl Radicals by Thiophenol kH PhS H + C PhS + C H -1 -1 entry radical kH/[M s ] (T/K) ΔH/[kcal mol-1] 8 1 n-C3H7-CH2⋅ 1.3 × 10 (298) -17 8 2 (CH3)2CH⋅ 1.0 × 10 (298) -15 8 3 (CH3)3C⋅ 1.4 × 10 (298) -12 5 4 n-C6F13-CF2⋅ 2.8 × 10 (303) -20 7 5 ROCH2CH2⋅ 7.6 × 10 (353) -18 5 6 PhCH2⋅ 3.0 × 10 (298) -5 ■ Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiol kH RCH2S H + C RCH2S + C H k-H -1 -1 -1 -1 -1 entry radical kH/[M s ] (T/K) k-H/[M s ] (T/K) ΔH/[kcal mol ] 7 1 R-CH2⋅ 2 × 10 (298) -13 6 4 2 R3C⋅ 4 × 10 (303) 2 × 10 (353) -8 3 R-CH(OMe)⋅ 2 × 107 (298) -4 4 R-C(=O)⋅ 7 × 106 (353) -1 5 Ph-CHR⋅ 7 × 102 (333) 1 × 106 (353) +2 6 Ph-CH(OMe)⋅ 2 × 107 (353) +2 Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Dynamic Kinetic Resolution of α-Chiral Amines O SH O Et2N NH2 Me (cat.) Me C11H23 NH Me AIBN, C11H23CO2Et, Novozym 435 Me heptane, 80 °C Me 0% ee 81% yield, >99% ee NH NH 2 RSH, initiator 2 Me Me Me Me (R) (S) lipase lipase acyl donor acyl donor O O C11H23 NH RSH, initiator C11H23 NH Me Me Me Me (R) (S) Gastaldi, S.; Escoubet, S.; Vanthuyne, N.; Gil, G.; Bertrand, M. P. Org. Lett. 2007, 9, 837. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Hydrogen Abstraction from Benzylic Positions NHBoc Me N Me i-Pr i-Pr NHBoc O MeO2C CO2Me O N N OAc OAc PhSH (cat.), Et3B/O2 O Benzene, rt O 48% yield, dr = 13:1 i-Pr NHBoc NHBoc Me N Me O N OAc O MeO2C CO2Me PhS PhSH PhSH i-Pr NHBoc NHBoc Me N Me O N OAc O MeO2C CO2Me i-Pr Me N Me O N OAc NHBoc MeO C CO Me O 2 2 Guin, J.; Frohlich, R.; Studer, A. Angew. Chem. Int. Ed. 2008, 47, 779. II.Thiyl-Mediated Hydrogen Atom Transfer ■ Hydrogen Abstraction from Silane OAc OAc Ph O Ph AcO Ph AcO SH (5 mol%) Ph Ph3Si O O Ph3SiH,TBHN O O Hexane/dioxane, 60 °C 90% ( 95% ee) Ph Ph Ph3Si O O Ph3SiH *RS *RSH *RSH Ph Ph Ph3Si Ph3Si O O Ph Ph O O Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1, 2002, 1376. III. Addition of Thiols to C=C bonds ■ anti-Markovnikov Addition of Thiyl Radicals to Olefins 3 3 R R kadd 1 R1S R S + 4 R4 R kfrag 2 R2 R ■ Thiol-Ene Coupling (TEC) R3 R3 R1S R1S R4 + R1SH R4 + RS R2 R2 ■ Thiol-Olefine Cooxidation (TOCO) O 3 inter R1SH R O 3 R intra R1SR R1S R1S R4 + O2 R4 products intra C=C R2 R2 ■ Ring-Openning of Vinyl Cyclopropane 3 R R3 1 R S EWG R1S EWG 2 R R2 Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. III. Addition of Thiols to C=C bonds ■ Thiol-Olefine Cooxidation (TOCO) SH OH O AcO S (1 equiv) AcO Cl O2, hexane, hv Cl SH OH O (1 equiv) V O (cat.) Me S 2 5 Me Me O2, hexane/EA, hv Me OH O S Me Me Iriuchijima, S.; Maniwa, K.; Sakakibara, T.; Tsuchihashi, G. J. Org. Chem. 1974, 39, 1170. III. Addition of Thiols to C=C bonds ■ Thiol-Olefine Cooxidation (TOCO) Me Me O 1) PhSH, O , DTBPO(cat.) SPh 2 O Me 2) PPh3 OH Me 30% via: Me Me O Me O SPh SPh O O O 6-exo-trig SPh O2 O Me PhSH Me Me O HO OH Me O OH O Me Me Me Yingzhaosu A Szpilman, A. M.; Korshin, E. E.; Rozenberg, H.; Bachi, M. D. J. Org. Chem. 2005, 70, 3618. III. Addition of Thiols to C=C bonds ■ Ring-Openning of Vinyl Cyclopropane thiophenol (3 mol%) CO2Bn CO2Bn + t-BuO CO Bn CO Bn BPO (6 mol%), toluene, 0 °C, 2 h 2 2 hv (100 W Hg lamp or sunlight) t-BuO 95% yield, 19:1 dr, 86% ee Bu CF3 OH SH Si CF3 t-Bu Bu Me via: RS RS RS CO2Bn CO2Bn CO2Bn CO2Bn RS CO Bn CH2O2Bn CO2Bn CO2Bn 2 t-BuO t-BuO t-BuO Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nature Chem. 2014, 6, 702. IV. Fragmentation of β-Sulfanyl Radicals ■ Isomerization of Alkenes R2 R1S R2 2 PhS + R PhS + 1 R R1 R1 ■ Fragmentation of Allyl Sulfides R2 R2 R2 R1 + SPh R1 SPh R1 ■ Fragmentation of Vinyl Sulfides R R R SPh SPh Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. IV. Fragmentation of β-Sulfanyl Radicals ■ Fragmentation of Allyl Sulfides O O Me MeO Mn(OAc)3 (1 equiv.) MeO O N SPh AcOH, 70 °C N 43% yield O Bn Bn Me trans only via O O Me MeO SPh MeO O N SPh N Bn Me O Bn ■ Fragmentation of Vinyl Sulfides MeO MeO OH O SPh Bu3SnH, AIBN Br Benzene, 130 °C O Me H N N H Ts Ts Me HO 35% yield via MeO SPh O H N Ts Me Cerreti, A.; D'Annibale, A.; Trogolo, C.; Umani, F.