Thiyl Radicals in Organic Synthesis - Princeton University · PDF fileThiyl Radicals in...
Transcript of Thiyl Radicals in Organic Synthesis - Princeton University · PDF fileThiyl Radicals in...
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 JinMacMillan 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
86 kcal mol-1
HO SHNH2
O O
SHMe
O
SH
87 kcal mol-1 88 kcal mol-1
■ Thiophenols: weaker S−H BDEs due to the stabilization by resonance of the corresponding arenethiyl radical
SHSH
H2N
SH
O2N
70 kcal mol-1 79 kcal mol-1 82 kcal mol-1
■ S-S Bond Dissociation Energies in Disulfides
■ Dialkyldisulfides: around 65 kcal mol-1 ■ Diaryldisulfides: around 50 kcal mol-1
SH
84 kcal mol-1
FF
FF
F
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
■ One-electron oxidation by Mn(OAc)3, O2
■ Homolytic cleavage by radiolysis or light irradiation
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
RS H X+ RS X+ H
Initiator: AIBN, (PhCO2)2, (t-BuO)2, Et3B/O2
RS H RS− e-
− H+
■ One-electron reduction of disulfides
RS SR RS RS+ H+ e-
+ H+
RS H RS + H< 300 nm
PhS SPh 2PhS355 nm
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)
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
RS H R'H2C+ RS RH2C+ H
S-H BDE = 87 kcal mol-1 k298K = 2 × 107 M-1 s-1
n-Bu3Sn H R'H2C+ n-Bu3Sn RH2C+ H
Sn-H BDE = 79 kcal mol-1 k298K = 2 × 106 M-1 s-1
Me
O
MeMe
Me
Me
MeMe
Me
OH
α-tocopherol
R'H2C+
RH2C+ H
O-H BDE = 77 kcal mol-1 k298K =6 × 105 M-1 s-1
Me
O
MeMe
Me
Me
MeMe
Me
O
■ 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
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
Dang, H.-S.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 , 2001, 2452.
R1O CR2
R3
H CR2
R3
OR1
disfavored
RS H CR2
R3
OR1δ- δ+
favored
the absence of charge-transfer stabilization ofthe symmetrical transition state, in which theincoming and outgoing α-alkoxyalkyl radicalshave the same electronegativity
benefits from charge-transfer stabilization because the electronegativities of he nucleophilicα-alkoxyalkyl radical and the electrophilic thiylradical are significantly different
O
O
MeMe
Me
MeMe
Met-BuOO OOt-Bu
5 mol%
nonane, 125 °C, 3 h O
O
MeMe
Me
Me
O
O
MeMe
Me
Me+
100% 0%
O
O
MeMe
Me
MeMe
Met-BuOO OOt-Bu
5 mol%
nonane, 125 °C, 2.5 h O
O
MeMe
Me
Me
O
O
MeMe
Me
Me+
16% 84%
thermodynamic equilibrium
(t-BuO)3SiSH 5 mol%
high activation energy
II.Thiyl-Mediated Hydrogen Atom Transfer
■ Rate Constants for the Reduction of Various Alkyl Radicals by Thiophenol
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
1.3 × 108 (298)
1.0 × 108 (298)
1.4 × 108 (298)
2.8 × 105 (303)
7.6 × 107 (353)
3.0 × 105 (298)
entry
123456
radical kH/[M-1 s-1] (T/K)
n-C3H7-CH2⋅
(CH3)2CH⋅(CH3)3C⋅
n-C6F13-CF2⋅
ROCH2CH2⋅
PhCH2⋅
-17-15-12-20-18-5
PhS H C+ PhS C+ HkH
ΔH/[kcal mol-1]
■ Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiol
2 × 107 (298)
4 × 106 (303)
2 × 107 (298)
7 × 106 (353)
7 × 102 (333)
entry
123456
radical kH/[M-1 s-1] (T/K)
R-CH2⋅
R3C⋅R-CH(OMe)⋅
R-C(=O)⋅Ph-CHR⋅
Ph-CH(OMe)⋅
-13-8-4-1+2+2
RCH2S H C+ RCH2S C+ HkH
ΔH/[kcal mol-1]
k-H
2 × 104 (353)
1 × 106 (353)
2 × 107 (353)
k-H/[M-1 s-1] (T/K)
II.Thiyl-Mediated Hydrogen Atom Transfer
■ Dynamic Kinetic Resolution of α-Chiral Amines
Gastaldi, S.; Escoubet, S.; Vanthuyne, N.; Gil, G.; Bertrand, M. P. Org. Lett. 2007, 9, 837.
MeMe
NH2
0% ee
Et2NSH
O
Me
AIBN, C11H23CO2Et, Novozym 435heptane, 80 °C Me
MeNH
81% yield, >99% ee
C11H23
O
MeMe
NH2
(R)
MeMe
NH2
(S)
MeMe
NH
(R)
MeMe
NH
(S)
C11H23
O
C11H23
O
RSH, initiator
lipaseacyl donor
lipaseacyl donor
RSH, initiator
(cat.)
II.Thiyl-Mediated Hydrogen Atom Transfer
■ Hydrogen Abstraction from Benzylic Positions
Guin, J.; Frohlich, R.; Studer, A. Angew. Chem. Int. Ed. 2008, 47, 779.
NOAc PhSH (cat.), Et3B/O2
Benzene, rt 48% yield, dr = 13:1
O
i-Pr
O
NNHBoc
Me Me
MeO2C CO2MeN
OAcO
i-Pr
O
NHBoc
PhS
NNHBoc
Me Me
MeO2C CO2Me
NHBoc
NOAc
O
i-Pr
O
NHBoc
NNHBoc
Me Me
MeO2C CO2Me
NMe Me
MeO2C CO2MeN
OAcO
i-Pr
O
PhSH
NOAc
O
i-Pr
O
NHBoc
PhSH
II.Thiyl-Mediated Hydrogen Atom Transfer
■ Hydrogen Abstraction from Silane
Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 , 2002, 1376.
Ph3SiH,TBHN Hexane/dioxane, 60 °C
90% ( 95% ee)
*RS
*RSH *RSH
O O
PhPh
O O
PhPh
Ph3Si
OAcO
AcO
OAc
SH
OAc
(5 mol%)
Ph3SiH
Ph3Si
O O
PhPh
Ph3Si
O O
PhPh
Ph3Si
O O
PhPh
III. Addition of Thiols to C=C bonds
■ anti-Markovnikov Addition of Thiyl Radicals to Olefins
■ Thiol-Ene Coupling (TEC)
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
+R1Skadd
kfragR4
R2
R3
R4
R2
R3
R1S
R4
R2
R3
R1S R1SH RS+R4
R2
R3
R1S+
■ Thiol-Olefine Cooxidation (TOCO)
R4
R2
R3
R1S O2 R4
R2
R3
R1S+
OO
products
inter R1SHintra R1SR
■ Ring-Openning of Vinyl Cyclopropane
R2
R3
R1S
R2
R3
R1SEWG EWG
intra C=C
III. Addition of Thiols to C=C bonds
■ Thiol-Olefine Cooxidation (TOCO)
Iriuchijima, S.; Maniwa, K.; Sakakibara, T.; Tsuchihashi, G. J. Org. Chem. 1974, 39, 1170.
O2, hexane, hv
AcO Cl
SH
(1 equiv) AcO SOH O
Cl
O2, hexane/EA, hv
Me
SH
(1 equiv)S
O
Me
Me
OH
MeV2O5 (cat.)
SOH
Me
Me
O
III. Addition of Thiols to C=C bonds
■ Thiol-Olefine Cooxidation (TOCO)
Szpilman, A. M.; Korshin, E. E.; Rozenberg, H.; Bachi, M. D. J. Org. Chem. 2005, 70, 3618.
Me
Me
1) PhSH, O2, DTBPO(cat.)
2) PPh3
OO
OH
Me
MeSPh
30%
via:
Me
MeSPh
OO 6-exo-trig
OO
Me
MeSPh O2
OO
Me
MeSPh
PhSH
OHO
OO
Me
MeOH
Me
OHMe
Yingzhaosu A
III. Addition of Thiols to C=C bonds
■ Ring-Openning of Vinyl Cyclopropane
Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nature Chem. 2014, 6, 702.
BPO (6 mol%), toluene, 0 °C, 2 hhv (100 W Hg lamp or sunlight)
thiophenol (3 mol%)
CO2BnCO2Bn t-BuO
t-BuO
CO2Bn
CO2Bn
Me
SHSit-Bu
CF3
CF3
OH
Bu
Bu
+
CO2BnCO2Bn
RS
via:CO2Bn
CH2O2Bn
RS
t-BuO t-BuO
CO2Bn
CO2Bn
RS
t-BuO
CO2Bn
CO2Bn
RS
95% yield, 19:1 dr, 86% ee
IV. Fragmentation of β-Sulfanyl Radicals
■ Isomerization of Alkenes
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
■ Fragmentation of Allyl Sulfides
R1 +R2
SPhR2
SPhR1
R2
R1
+PhS R2
R1R2
R1
R1S+PhS
R1
R2
■ Fragmentation of Vinyl Sulfides
SPh
R
SPh
R R
IV. Fragmentation of β-Sulfanyl Radicals
■ Fragmentation of Allyl Sulfides
Cerreti, A.; D'Annibale, A.; Trogolo, C.; Umani, F. Tetrahedron Lett. 2000, 41, 3261.
■ Fragmentation of Vinyl Sulfides
SPhNMeBn
O
O
MeO
SPhNMeBn
O
O
MeO
NO Bn
MeO
O MeSPh
NO Bn
MeO
O Me
Mn(OAc)3 (1 equiv.)
AcOH, 70 °C
OHO
43% yieldtrans only
MeO
BrSPh
NMe
Ts
Bu3SnH, AIBN
Benzene, 130 °C
MeO
OH
HOH
NMe
Ts
35% yield
MeO
OH
HO
NMe
Ts
SPh
via
via
Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449.
V. Addition of Thiols to Alkynes
■ Addition of Thiyl Radical to Alkynes
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
+R1S R2R1S
■ 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
R2kadd
■ Addition to alkynes is more exothermic than to alkenes as replacing a very weak π-bond by a strongerCsp2−S σ-bond compensates for the energetic cost of generating a vinyl radical
■ Very few intermolecular trappings of β-sulfanylalkenyl radicals in a new C−C bond-forming reaction havebeen reported because it's very hard to compete with the hydrogen atom abstraction from thiols
R2R1S R1SH+
R2R1S
H+ R1S
R2R1S +
R2R1S
SR1
R1SH
branched
Thiol-Yne Coupling
■ Intramolecular trapping by C=C, C=N bonds
PhSH (slow addition)
AIBN, TMTHF, reflux
SPh
70%
V. Addition of Thiols to Alkynes
■ Intramolecular Chalcogenation: SH2 at Sulfur
Lachia, M.; Denes, F.; Beaufils, F.; Renaud, P. Org. Lett. 2005, 7, 4103.
SY
PhS SY
PhS
SH2 S
PhS
+ Y
Y = alkyl, acyl, carbamoyl, Ph2P(O), (EtO)2P(O), (EtO)2P(S), (N(Me)CH2)2P(O)
S
O
NPhSH, AIBN
benzene, refluxN
Me
O
N
O80% yield 4% yield
■ Translocation Reactions: 1,n-Hydrogen Transfer
Me Me
OH
cis/trans = 8:1
PhSH, AIBN
cyclohexane, 25 °C, hv
Me Me
OH
SPh
Me Me
O
SPhH
Me Me
O
H
SPh
via
VI. Addition of Thiols to Isonitriles
■ Intermolecular Trapping versus Fragmentation
Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.
■ Intramolecular Trapping by Alkenes or Alkynes
R2NCR1 S R2NCSR1
R1 = primary alkyl Ar
R1 = tertiary alkyl Bn
R2NCSR1
H
R1 R2NCHS+
O
O
SHt-Bu-NC, AIBN, 80 °C
O
O
OAcOAc
79% yield
+
Me Me
OTBS
CO2EtCN
Me Me
OTBS
CO2EtNSOH
N
OTBS
CO2Et
MeMe
SOH
NH
OTBS
CO2Et
MeMe
S
O
NH
OTBS
CO2Et
MeMe
O
SHHO
AIBN, toluene, 80 °C
via
VII. Addition of Thiols to C=S bonds
■ Barton Reductive Decarboxylation
Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901.
■ Barton Reductive Deoxygenation of Tertiary Alcohols
RON
O
S
t-BuS
N
St-BuS
RO
OR+
MeCl11
O 1.NOH
S
,pyridine
2. t-BuSH, toluene, reflux
Me11
95% yield
AcO
Me
MeMe
Me OH
ClCl
O
O
AcO
Me
MeMe
Me ONOH
S
, DMAP
t-BuSH, toluene, reflux
ClO
O
AcO
Me
MeMe
Me H
H
Barton, D. H. R.; Crich, D. J. Chem. Soc., Chem. Commun. 1984, 774.