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KOtBu: A Privileged Reagent for Electron Transfer Reactions?!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!6/18/16!
Mike Frasso !
Mike Frasso @ Wipf Group Page 1 of 22 6/19/2016
Transition Metal Free Couplings!
IR
ArH (80 eq.), KOtBu
100 oC26-89%
ArR
Nat. Chem. 2010, 2, 1044-1049.
ArI (1 eq.), KOtBu
50 oC33-98%
Org. Lett 2008, 10 , 4673-4676.
N-Het N-Het Ar
40 eq.
N N
IR
ArH (90 eq.), KOtBu
100 oC26-89%
ArR
J. Am. Chem. Soc. 2010, 132 , 16737-16739.
NH HN • Extensive purification/trace metal analysis performed!
• All suggest radical mechanisms!• KH/KD = 1.29 !
Mike Frasso @ Wipf Group Page 2 of 22 6/19/2016
Possibilities Following Radical Addition!
• Proton Transfer (PT) most likely favored due to strongly basic conditions!
!Angew. Chem. Int. Ed. 2011, 50, 5018-5022.!
!
H R
H R
RET
PT
PT
ET
R
Mike Frasso @ Wipf Group Page 3 of 22 6/19/2016
“Base-Promoted Homolytic Aromatic Substitution”!
R
I Benzene, KOtBu
additive, ! R
Ph
R
Initiation
RH
R
KOtBuBenzene
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Angew. Chem. Int. Ed. 2011, 50, 5018-5022.!
!
Mike Frasso @ Wipf Group Page 4 of 22 6/19/2016
“Base-Promoted Homolytic Aromatic Substitution”!
R
I Benzene, KOtBu
additive, ! R
Ph
R
Initiation
RH
R
KOtBuBenzene
Reduces another ArI!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Angew. Chem. Int. Ed. 2011, 50, 5018-5022.!
!
Mike Frasso @ Wipf Group Page 5 of 22 6/19/2016
A Different Proposal for Initiation !
N NK OtBu
I
N NK OtBu
+ I+ +
N NK
N
NN N
NN
H
KOtBu
N
NN
N
K
2K
N
NN
N
I2
+60 kcal/mol
+15.8 kcal/molbarrierless
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Sci. 2014, 5, 476-482.!
!
Mike Frasso @ Wipf Group Page 6 of 22 6/19/2016
A Different Proposal for Initiation !
N NK OtBu
I
N NK OtBu
+ I+ +
N NK
N
NN N
NN
H
KOtBu
N
NN
N
K
2K
N
NN
N
I2
+60 kcal/mol
+15.8 kcal/molbarrierless
I ”…pyrophoric reminiscent of our!previous organic electron donors.”! ΔG: -30 kcal/mol!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Sci. 2014, 5, 476-482.!
!
Mike Frasso @ Wipf Group Page 7 of 22 6/19/2016
A Different Proposal for Initiation !
N NK OtBu
I
N NK OtBu
+ I+ +
N NK
N
NN N
NN
H
KOtBu
N
NN
N
K
2K
N
NN
N
I2
+60 kcal/mol
+15.8 kcal/molbarrierless
ΔG: -30 kcal/mol!
Isolable!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
Chem. Sci. 2014, 5, 476-482.!!
Mike Frasso @ Wipf Group Page 8 of 22 6/19/2016
EPR Evidence!
• In DMF, 100 °C!• Black trace is not symmetric!• May be a superposition of 2
similar radicals!!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Commun. 2015, 51, 545-548.!
!
Mike Frasso @ Wipf Group Page 9 of 22 6/19/2016
Proposed Explanation of EPR Spectrum!
N N N NLei, et. al.
Ered = -2.06 V
OtBu OtBu++
Eox = +0.10 V
N N N NMurphy, et. al.
Ered = -2.06 V
++
Eox = +2.19 V
N N
N
N
N N
N
N
Endergonic
Exergonic
• Potentials measured by cyclic voltametry in DMF vs SCE • Demonstrate that t-butoxide does not directly reduce aryl halides
• Ered = -2.0 V for PhI • Electrochemical reduction of phenanthroline inhibited by KOtBu • Conclusion: KOtBu acts as a base
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Commun. 2015, 51, 545-548.!
!
Mike Frasso @ Wipf Group Page 10 of 22 6/19/2016
Is Phenanthroline Needed?!
IR
PhH, KOtBu
160 oC21-77%
PhR
• Direct electron transfer from KOtBu to ArI proposed
O OCH3
OH+ +
Presence confirmed by Janovsky test
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Commun. 2014, 50, 2575-2578.!
!
• Ketone detected by MS • Samples were in THF
Mike Frasso @ Wipf Group Page 11 of 22 6/19/2016
Janovsky Test!
NO2
NO2 Et
O
NO2
NO2
Et
O
Wilden et. al.KOtBu, phen
THF
NO2
NO2
O
KOtBu, phenTHF
552 nm
KOtBu + phenthen 1,3 DNB
THF554 nm
NO2
NO2
O
KOtBu
THF490 nm
then 1,3 DNB
THF558 nmKOtBu
NO2
NO2RO H
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Commun. 2014, 50, 2575-2578.!
!
Mike Frasso @ Wipf Group Page 12 of 22 6/19/2016
Janovsky Test!
NO2
NO2 Et
O
NO2
NO2
Et
O
Wilden et. al.KOtBu, phen
THF
NO2
NO2
O
KOtBu, phenTHF
552 nm
KOtBu + phenthen 1,3 DNB
THF554 nm
NO2
NO2
O
KOtBu
THF490 nm
then 1,3 DNB
THF558 nmKOtBu
NO2
NO2RO H
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Chem. Commun. 2014, 50, 2575-2578.!
!
Mike Frasso @ Wipf Group Page 13 of 22 6/19/2016
Another Alternative Proposal!I
PhH, KOtBu, !
organic additive
PhPhH, KOtBu, !
No Product
!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
!
• Conclusion: KOtBu acts as a base in additive free reaction
Mike Frasso @ Wipf Group Page 14 of 22 6/19/2016
Another Alternative Proposal!
R
I
R
Ph
R
PhH, KOtBu, !PhH, KOtBu, !
Initiation
R
PhH
HR HR RKOtBu
R
e
Propagation
IPhH, KOtBu, !
organic additive
PhPhH, KOtBu, !
No Product
!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
!
Mike Frasso @ Wipf Group Page 15 of 22 6/19/2016
α-Arylation of Ketones!
Ar
O
R
XR'
KOtBu
DMF, 40-120 oC29-99%
Ar
O
R
R'• Proceeds using 2:1 ketone to ArX!• X = I, Br, Cl!• DMF required (no dimer detected)!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Angew. Chem. Int. Ed. 2015, 54, 10587-10591.!
!
O
NMe2HKOtBu
O
NMe2K
I
R O
NMe2 R+
OK
Ar
R
Ar
OR
Ar
O
ArI
Mike Frasso @ Wipf Group Page 16 of 22 6/19/2016
Proposed Dimeric Dianion as Electron Donor!
O
NMe2HKOtBu
O
NMe2K
O
NMe2H O
NMe2Me2N
OH
KKOtBu
O
NMe2Me2N
O
K
K
O
NBu2Bu2N
O
Li
Li
MeIO
Bu2N
ONBu2
J. Org. Chem. 2000, 65, 1629-1635
!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
!!
Mike Frasso @ Wipf Group Page 17 of 22 6/19/2016
Proposed Dimeric Dianion as Electron Donor!
O
NMe2HKOtBu
O
NMe2K
O
NMe2H O
NMe2Me2N
OH
KKOtBu
O
NMe2Me2N
O
K
K
O
NBu2Bu2N
O
Li
Li
MeIO
Bu2N
ONBu2
J. Org. Chem. 2000, 65, 1629-1635
!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
!!
Mike Frasso @ Wipf Group Page 18 of 22 6/19/2016
Investigating the Role of DMF!I
PhH
KOtBu, 130 oC
Ph Ph
Entry Additive A + B (%)
1
2
3
4
5
6
7
8
none 0.5
DMF
Amount
---
1% v/v 2.6
A B
C
DMF 0.1 mmol 0.6
0.05 mmol 8.0
D 0.05 16.1
DMF 1% v/v 0.4
C 0.5% v/v 19.6
D 0.5% v/v 31.6
+
N
N
O
OC
N
N
O
OD
!J. Am. Chem. Soc. 2016, 138, 7401-7410.!
!!
Mike Frasso @ Wipf Group Page 19 of 22 6/19/2016
Photo-induced Cleavage of Dithiane!
S S
Ph Ph
KOtBu, h!
DMSO Ph Ph
OSK
h!
Ph Ph
SS
Ph Ph
SS
Ph Ph
OSK
h!
• Authors propose transfer from KOtBu • “charge transfer” complex observed at 466 nm in UV/Vis
spectrum • Murphy et. al. can reproduce with KH as a base
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Tetraheron Lett. 2013, 54, 1515-1518.!
!
Mike Frasso @ Wipf Group Page 20 of 22 6/19/2016
Photo-induced Cleavage of Dithiane!
S S
Ph Ph
KOtBu, h!
DMSO Ph Ph
OSK
h!
Ph Ph
SS
Ph Ph
SS
Ph Ph
OSK
h!
J. Am. Chem. Soc. 2016, 138, 7401-7410.!Tetraheron Lett. 2013, 54, 1515-1518.!
!
Mike Frasso @ Wipf Group Page 21 of 22 6/19/2016
Conclusion!
• In all examined cases, KOtBu acts as a base • Electron transfer from KOtBu is possible using CBr4 as
electron acceptor (Ered = -0.31 V)
Mike Frasso @ Wipf Group Page 22 of 22 6/19/2016
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