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
NH 2
86 kcal mol -1
87 kcal mol -1
SH
88 kcal mol -1
■ Thiophenols: weaker S−H BDEs due to the stabilization by resonance of the corresponding arenethiyl radical
F
SH
SH
SH
H 2N
O2N
F
SH
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, (PhCO 2)2, (t-BuO)2, Et 3B/O 2
■ One-electron oxidation by Mn(OAc) 3, O2
− eRS
H
RS
− H+
■ One-electron reduction of disulfides
+ eRS
SR
RS
+ RS H
RS
+
+ H+
■ Homolytic cleavage by radiolysis or light irradiation
< 300 nm
RS
H
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 (E e0) and the enthalpy of the reaction of interest (ΔH e)
■ Different interactions in the transition state such as polar effects, antibonding (triplet repulsion), or neighboring
π-electrons may influence E e0, which is particularly low for the reactions of alkyl radicals with thiols
RS
+ R'H 2C
H
RS
S-H BDE = 87 kcal mol -1
n-Bu3Sn
H
+
RH 2C
k 298K = 2 × 10 7 M -1 s-1
+ R'H 2C
+
n-Bu3Sn
Sn-H BDE = 79 kcal mol -1
H
RH 2C
H
k 298K = 2 × 10 6 M -1 s-1
Me
Me
Me
OH
Me
Me
+ R'H 2C
Me
α-tocopherol
O
Me
Me
Me
Me
Me
Me
O-H BDE = 77 kcal mol -1
O
Me
+
Me
O
RH 2C
H
Me
Me
k 298K =6 × 10 5 M -1 s-1
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
R1 O
C
R2
H
R3
OR1
C
R3
the absence of charge-transfer stabilization of
the symmetrical transition state, in which the
incoming and outgoing α-alkoxyalkyl radicals
have the same electronegativity
δ-
RS
Me
O
Me
Me
Me
OOt-Bu
Me
5 mol%
nonane, 125 °C, 3 h
Me
Me
O
O
Me
Me
Me
t-BuOO
Me
O
O
O
Me
+
Me
100%
Me
C
benefits from charge-transfer stabilization
because the electronegativities of he nucleophilic
α-alkoxyalkyl radical and the electrophilic thiyl
radical are significantly different
favored
t-BuOO
O
H
OR1
R3
disfavored
Me
R2
δ+
Me
O
high activation energy
0%
OOt-Bu
Me
5 mol%
Me
Me
Me
nonane, 125 °C, 2.5 h
(t-BuO)3SiSH 5 mol%
Me
Me
O
O
16%
Me
Me
Me
O
Me
+
Me
Me
O
thermodynamic equilibrium
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
entry
+
PhS
radical
C
kH/[M-1 s-1] (T/K)
ΔH/[kcal mol-1]
1
n-C3H7-CH2⋅
1.3 × 10 8 (298)
-17
2
(CH3)2CH⋅
1.0 × 10 8 (298)
-15
3
(CH3)3C⋅
10 8
(298)
-12
4
n-C6F13 -CF2⋅
2.8 × 10 5 (303)
-20
5
ROCH2CH2⋅
7.6 × 10 7 (353)
-18
6
PhCH2⋅
3.0 × 10 5 (298)
-5
1.4 ×
H
■ Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiol
kH
RCH 2S
H
+
C
k-H
entry
radical
kH/[M-1 s-1] (T/K)
1
R-CH2⋅
2 × 10 7 (298)
RCH 2S
+
k-H/[M-1 s-1] (T/K)
C
H
ΔH/[kcal mol-1]
-13
2
R3C⋅
3
R-CH(OMe)⋅
2 × 10 7 (298)
-4
4
R-C(=O)⋅
7 × 10 6 (353)
-1
5
Ph-CHR⋅
7 × 10 2 (333)
6
Ph-CH(OMe)⋅
4×
10 6
(303)
2×
10 4
(353)
1 × 10 6 (353)
2×
10 7
(353)
-8
+2
+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
Et 2N
NH 2
Me
Me
Me
O
(cat.)
C11H 23
AIBN, C11H 23CO2Et, Novozym 435
heptane, 80 °C
Me
81% yield, >99% ee
0% ee
NH 2
Me
Me
Me
(R)
(S)
lipase
acyl donor
lipase
acyl donor
O
C11H 23
Me
NH 2
RSH, initiator
Me
NH
O
NH
RSH, initiator
Me
Me
(R)
C11H 23
NH
Me
Me
(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
O
i-Pr
MeO 2C
N
OAc
O
PhSH (cat.), Et 3B/O 2
Benzene, rt
O
N
O
OAc
48% yield, dr = 13:1
NHBoc
i-Pr
NHBoc
O
NHBoc
CO2Me
N
Me
N
Me
OAc
MeO 2C
O
CO2Me
PhS
PhSH
PhSH
NHBoc
i-Pr
NHBoc
O
N
Me
N
Me
OAc
MeO 2C
O
CO2Me
i-Pr
Me
O
O
N
OAc
N
Me
NHBoc
MeO 2C
CO2Me
Guin, J.; Frohlich, R.; Studer, A. Angew. Chem. Int. Ed. 2008, 47, 779.
II.Thiyl-Mediated Hydrogen Atom Transfer
■ Hydrogen Abstraction from Silane
OAc
Ph
OAc
O
AcO
AcO
Ph
O
Ph
SH
Ph
(5 mol%)
Ph 3Si
Ph 3SiH,TBHN
Hexane/dioxane, 60 °C
O
O
O
90% ( 95% ee)
Ph
Ph
Ph 3Si
O
O
Ph 3SiH
*RS
*RSH
*RSH
Ph
Ph 3Si
Ph
Ph 3Si
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
R1 S
+
R3
k add
R3
R4
R1 S
k frag
R4
R2
R2
■ Thiol-Ene Coupling (TEC)
R3
R1 S
R3
R4
+
R1 S
R1SH
R2
R4
+
RS
R2
■ Thiol-Olefine Cooxidation (TOCO)
O
R3
R1 S
R4
+
R1 S
O2
R2
O
inter R1SH
intra R1SR
R3
products
R4
intra C=C
R2
■ Ring-Openning of Vinyl Cyclopropane
R3
R1 S
R3
EWG
R2
R1 S
EWG
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
AcO
OH
AcO
(1 equiv)
Cl
O
S
O2, hexane, hv
Cl
SH
Me
O
(1 equiv)
Me
V2O5 (cat.)
S
Me
O2, hexane/EA, hv
OH
Me
OH
Me
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
1) PhSH, O2, DTBPO(cat.)
O
OH
Me
O
O
Me
SPh
O
6-exo-trig
30%
O
Me
SPh
O
Me
SPh
Me
2) PPh 3
via:
Me
O
PhSH
Me
O
O2
O
SPh
Me
HO
Me
Me
O
OH
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
CO2Bn
CO2Bn
CO2Bn
thiophenol (3 mol%)
+
t-BuO
BPO (6 mol%), toluene, 0 °C, 2 h
hv (100 W Hg lamp or sunlight)
CO2Bn
t-BuO
95% yield, 19:1 dr, 86% ee
Bu
CF3
OH
SH
Si
CF3
t-Bu
Bu
Me
via:
RS
CO2Bn
CO2Bn
RS
CO2Bn
t-BuO
CH2O2Bn
RS
CO2Bn
t-BuO
CO2Bn
RS
CO2Bn
t-BuO
CO2Bn
Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nature Chem. 2014, 6, 702.
IV. Fragmentation of β-Sulfanyl Radicals
■ Isomerization of Alkenes
R2
+
PhS
R1
R2
R1 S
R2
PhS
+
R1
R1
■ Fragmentation of Allyl Sulfides
R2
R1
+
R2
SPh
R1
R2
SPh
R1
■ Fragmentation of Vinyl Sulfides
R
R
SPh
SPh
R
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
MeO
Mn(OAc) 3 (1 equiv.)
O
N
Bn
via
MeO
N
AcOH, 70 °C
SPh
Me
O
Me
Bn
43% yield
trans only
O
O
Me
MeO
SPh
MeO
O
N
SPh
Bn
N
O
Me
Bn
■ Fragmentation of Vinyl Sulfides
MeO
MeO
OH
O
SPh
Br
N
Bu 3SnH, AIBN
Benzene, 130 °C
Me
O
H
N
Ts
Me
35% yield
H
Ts
HO
via
MeO
O
H
SPh
N
Me
HO
Ts
Cerreti, A.; D'Annibale, A.; Trogolo, C.; Umani, F. Tetrahedron Lett. 2000, 41, 3261.
Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449.
V. Addition of Thiols to Alkynes
■ Addition of Thiyl Radical to Alkynes
+
R1 S
R2
k add
R1 S
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
R1 S
R2
+
R1SH
R1 S
+
R1 S
R2
SR1
R1 S
R2
+
R1SH
R1 S
R2
branched
Thiol-Yne Coupling
■ 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: SH 2 at Sulfur
PhS
S
S
Y
S
SH 2
+
Y
PhS
Y
PhS
Y = alkyl, acyl, carbamoyl, Ph 2P(O), (EtO) 2P(O), (EtO) 2P(S), (N(Me)CH 2)2P(O)
Me
PhSH, AIBN
N
benzene, reflux
S
N
N
O
O
80% yield
O
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
via
O
Me
Me
O
H
SPh
Me
Me
SPh
Me
Me
H
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
Ar
H
C
R1
R1 S
C
N
C
R2
R1
R2
N
R1 = tertiary alkyl
Bn
S
O
R2
N
S
R1
+ HS
C
N
R2
O
SH
O
OAc
+
t-Bu-NC, AIBN, 80 °C
OAc
O
79% yield
■ Intramolecular Trapping by Alkenes or Alkynes
Me
Me
Me
HO
Me
SH
OTBS
OTBS
AIBN, toluene, 80 °C
CN
Me
via
O
CO2Et
Me
N
H
CO2Et
Me
Me
OTBS
Me
OTBS
Me
OTBS
S
S
OH
N
S
CO2Et
OH
N
CO2Et
O
N
H
CO2Et
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
N
O
O
N
R
S
t-BuS
t-BuS
R
+
O
S
R
OH
N
O
Me
1.
S
,pyridine
Me
H
Cl
11
11
95% yield
2. t-BuSH, toluene, reflux
■ Barton Reductive Deoxygenation of Tertiary Alcohols
O
Me OH
Me
Me
Me
Cl
Me H
OH
O
Me O
Cl
Cl
Me
O
Me
N
Me
S
Me
, DMAP
O
Me
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.