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

■ Dialkyldisulfides: around 65 kcal mol-1 ■ Diaryldisulfides: around 50 kcal mol-1

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

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

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

CF3

OH SH

Si CF3 t-Bu Bu

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. Tetrahedron Lett. 2000, 41, 3261. HO Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449. V. Addition of Thiols to Alkynes

■ Addition of Thiyl Radical to Alkynes k add 1 1 + 2 R S R S R R2 ■ Addition to alkynes is more exothermic than to alkenes as replacing a very weak π-bond by a stronger Csp2−S σ-bond compensates for the energetic cost of generating a vinyl radical

■ The reverse reaction that releases the triple bond is rather slow, and fragmentation of the thiyl radical is generally not observed due to the rapid decay of the resulting highly reactive vinyl radical

■ Very few intermolecular trappings of β-sulfanylalkenyl radicals in a new C−C bond-forming reaction have been reported because it's very hard to compete with the hydrogen atom abstraction from thiols

H 1 R S + R1SH 1 + 1 R2 R S R S R2

SR1 1 R S + R1SH 1 R2 R S Thiol-Yne Coupling R2 branched

■ Intramolecular trapping by C=C, C=N bonds SPh PhSH (slow addition)

AIBN, TMTHF, reflux 70%

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. V. Addition of Thiols to Alkynes

■ Intramolecular Chalcogenation: SH2 at Sulfur

PhS SH2 S S + Y S Y Y PhS PhS

Y = alkyl, acyl, carbamoyl, Ph2P(O), (EtO)2P(O), (EtO)2P(S), (N(Me)CH2)2P(O)

Me PhSH, AIBN N N N benzene, reflux S O O

O 80% yield 4% yield

■ Translocation Reactions: 1,n-Hydrogen Transfer

O O H PhSH, AIBN H cyclohexane, 25 °C, hv SPh

Me Me cis/trans = 8:1 Me Me

via O O H

SPh SPh H Me Me Me Me Lachia, M.; Denes, F.; Beaufils, F.; Renaud, P. Org. Lett. 2005, 7, 4103. VI. Addition of Thiols to Isonitriles

■ Intermolecular Trapping versus Fragmentation R1 = primary alkyl H Ar C N R2 R1 S

R1 S 2 C N R2 C N R R1 = tertiary alkyl R1 S Bn R1 + HS C N R2

O O t-Bu-NC, AIBN, 80 °C SH + OAc OAc O O 79% yield

■ Intramolecular Trapping by Alkenes or Alkynes

Me Me Me HO Me OTBS OTBS SH AIBN, toluene, 80 °C CO Et O N 2 CN CO2Et H

Me Me via Me Me Me OTBS OTBS Me OTBS S S CO2Et CO Et S N CO2Et N N 2 O H OH OH

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587. VII. Addition of Thiols to C=S bonds

■ Barton Reductive Decarboxylation

O O N N O R + R O R S S t-BuS t-BuS

OH N S O 1. ,pyridine Me H Me 95% yield 11 Cl 11 2. t-BuSH, toluene, reflux

■ Barton Reductive Deoxygenation of Tertiary Alcohols

O Cl Me OH Me H OH Me Me O Me O O Me N S Me Cl Me Cl Me Me , DMAP Me O Me t-BuSH, toluene, reflux AcO AcO AcO

Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901. Barton, D. H. R.; Crich, D. J. Chem. Soc., Chem. Commun. 1984, 774.