Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Introduction
• Stable cation radical salts were first isolated in 1879 (Wurster’s
Red and Blue).
• However, it was not until 1926 that the true nature of these salts
as monomeric species possessing both an unpaired electron
and a single unit of positive charge was decisively imputed by
Weitz.
• Weitz also coined the terms ‘cation radical’ and ‘aminium’ ion.
NH2
Me
NMe2
Br3NMe2
N
Br3-
ClO 4-
Blue
Me
Wurster's Salts
Generation of Cation Radicals:
S
Various methods may be applied to facilitate the remove of
one electron from HOMO level: a) Chemical method; b)
Photochemical method; c) Electrochemical oxidation; d)
Radiolytic oxidation.
a) Chemical Method
A chemical one electron oxidant having suitable oxidation
potential to match the potential of the substrate is chosen and
react in inert solvent (e.g. CH2Cl2, MeCN). Due to the radical
chain character of the reaction, only catalytic amount (e.g. 510%) of oxidant is need.
Weitz' Aminium Salt
• In 1963, Labes et. al. surmised that the polymerization of Nvinylcarbazole (NVC) in acetonitrile induced by certain Wurster
salts was, in fact, initiated by the NVC cation radical.
• Dimerization of NVC was disclosed in 1964 by Ellinger.
• The cation radical chain nature of the reaction was definitely
established by Ledwith et al in 1968.
• DA dimerization of 1,3-cyclohexadiene under γ-radiolysis was
disclosed in 1964; the radical chain nature of the reaction was
identified in 1969.
N SbCl6 -
R
N Ar
chloranil, hv
MeOH
Ellinger, 1964
Ar
N SbCl6 - Fe(Phen)3(PF6)3 NO+PF 6-
Br
3
3
Cp2Fe+BF4-
Br
R = H, Me, Br
Half-Wave Oxidation Potentials
+
(Ag/Ag vs SCE, MeCN, Irrev ers ible)
Compound Potential
S
O
1.11
1.36
1.4 2
1.5 5
1.59
1.72
1.7 3
1 .42
1.5 2
O
Ar
N
-e
S
Me
NMe2
Red
Shun Su
1.5 3
N
O
1.60
O
1.62
N
Ar
Nathan L. Bauld Tetrahedron 1989, 45, 5307 and ref there in.
1.70
1 .95
1.9 8
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
b) Photochemical Method:
Shun Su
Radical Cation Diels-Alder Reaction
This process involves the excitation of a suitable sensitizer to its
excited state followed by quenching of excited sensitizer by
substrate leading to the formation of substrate cation radical
and sensitizer anion radical.
Ar3NSbCl6Ar =
+
DCM, 0oC
5 min, 70%
Br
4.5:1
Small amounts (ca 2 %) of the syn and anti
cyclobutane (CB) cyclodimers are also etected.
200 oC, 20h
Sensitized Electron Transfer
30%, 4.0:1
Sens
hν
[Sens]*
S
S
+ [Sens]
BET
S + Sens
Ar3NSbCl 6
+
Electron Transfer by Charge Transfer Excitation
D + A
[D,A]
hν
[D+', A-']
DCM, 0oC
200 oC, 2day
20%
+ EXO + homodimer
4:3
40%
N.R.
c) Electrochemical Oxidation:
Substrate is oxidized at the electrode interface at its oxidation
potential, resulting in the direct formation of the corresponding
cation radical.
d) Radiolytic Oxidation:
Substrate in a cryogenic matrix is exposed to gamma ray
(Normally 60Co as source).
Bauld et. al. JACS 1981, 103, 718.
• A typical DA reaction is not efficient unless the dienophile is
substantially electron deficient.
• Reactivity umpolung of electron rich diene via cation radical
formation provides an effective and direct remedy for the
absence of electron deficiency in the dienic system.
Terminology:
• Caticophile: neutral component which react with cation radical
• Caticogen: neutral component which generate cation radical
• Caticogenicity: the ability to generate cation radical (assumed
to parallel the half-wave potential of the caticogen)
• Caticophilicity: assumed to parallel π basicity or
neucleophilicity.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Regiospecificity & Chemoselectivity:
Stereochemical Outcome:
Ar3NSbCl6-
Ar3NSbCl6+
40%
Br
2:1
Ar3NSbCl6DCM, 0oC
Ar =
+
DCM, 0o C
75%
+
DCM, 0oC
20%
+
Shun Su
+
+
Ar3NSbCl65%
Ar3NSbCl6+
DCM,
0oC
+
+
+
Ar3NSbCl 6+
+
25%
60
24
16
200oC
+
0.5 %
+
Three factors may control the selectivity:
3:1
Complete suprafacial stereospecificity was observed.
It was believed that the cation radical DA inherently has an
extremely high endo stereoselectivity as a consequence of 1)
low reaction temperature; 2) the electron deficient nature of the
dienophile provides strong secondary orbital interaction in the
transition state for endo addition, which closely parallel the
situation exists for the Lewis acid catalyzed DA.
1) Steric effect; 2) Maximum stabilization of the bisallylic
transition state; 3) Charge effect
vs
Bauld et. al. JACS 1982, 104, 2665.
Bauld et. al. JACS 1982, 104, 2665.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Shun Su
Acyclic Diene Components:
Photosensitized Electron Transfer (PET) Initiation:
Dienic component in the cation radical DA need not be cyclic,
CN
CN
Ph
however substantial s-cis contents is necessary. Simple acyclic
diene such as 1,3-butadiene, isoprene, piperylene, and 2,4hexadienes are not efficient as diene component.
Ph
CN
CN
DCB
DCA
O
BF-
Ph
TPP
Compared to aminium salt condition:
• PET condition provides similar results with a wide variety of
45%
substrates.
• Especially advantageous in the case of cycloadditions involving
Reynold Dissertation at the University of Texas Austin 1988
very sensitive functionalities.
Styrene as Dienophiles:
• However, cation radical lifetimes are limited by back electron
Styrenes are often sufficiently caticogenic to participate in the transfer when cycloadditions are exceptionally slow (e.g.
cation radical DA, normally in the dienophilic role. Certain sterically hindered substrate).
substrates can also assume the dienic role in the
cyclodimerization.
TPP+ BF4Ar3N
+
+
RO
Ar3N
+
OR
OR
45%
MeO
OR
RO
R=OMe
R=OAc
70% 2:1
20%
MeO
O
Electron Rich Alkenes:
These substrates are moderately caticogenic but extraordinarily
caticophilic. Cycloaddition to acyclic dienes is predominantly
cyclobutane (CB) periselective.
+
+
Ar3NSbCl6+
DCM
X
O
O
+
O
O
O
O
1.3:1
hv
+
X
hv, LiCO4
Sens
Sens=DCB 0%
Sens=TPP+ 34%
X
X=OPh 75%
X=SPh 68%
Bauld et. al. JACS 1987, 109, 4960;
Matty et. al. J. Chem. Soc. Chem. Commun. 1985, 1088.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Several Issues to be Addressed:
Reaction mechanism
Chemical Initiation:
+ Ar3N+·
Role selectivity:
RH+· + Ar3N
initiation
R
cycloaddition
R+· + R'
P+·
propagation 1
P+· + Ar3N
P
+ Ar3N+·
P
+ R+·
propagation 2
+·
P
+ R
Shun Su
The majority of efficient radical DA cross reactions which had
been observed involved systems in which the dienophile is more
caticogenic than the diene, the extraordinarily high caticophilicity
of cyclic ([4+1] type). However, [3 + 2] cycloadditions are also
well established.
SPh
SPh Ar NSbCl 3
6
SPh
+
+
31%
[3+2]
PET Initiation:
initiation
Sens + hv
Sens*
Sens* + R
Sens-· + R+·
cycloaddition
R+·
+ R'
P+·
propagation
P+·
+ R
P
termination
Sens-· + P+·
+
Ar3N
+
45%
[1+4]
+ R+·
Sens + P
Stepwise vs Concerted Pathway:
Based on extensive stereochemical investigations of various
pericyclic reaction, it’s more likely the reaction proceed in a
concerted manner. However, many exceptions exist.
Direct DA vs Vinylcyclobutane Rearrangement:
Ar3NSbCl6DCM, 0oC
5 min, 70%
Ar = B r
+
+
2%
4.5:1
Bauld et. al. Phy. Org. Chem. 1989, 2, 57.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Direct DA vs Vinylcyclobutane Rearrangement:
H
H
H
H
Shun Su
Synthetic Applications:
Ar3NSbCl6-
CHO
NC
Ph3P=CH2
DCM, 0oC
Ar = B r
H
85%
H
H H
Ar3NSbCl6mCPBA
DCM, 0o C
Ar = B r
Br
Me
H
CH2 MeCuBF3
2)
3)
4)
5)
O
Typical conditions: [Ar3N+ /DCM/0oC] or [2,4,6-triphenylpyrylium fluoroborate/MeCN/Pyrex/rt].
For a successful DA, diene components should either be
cyclic or, if acyclic, have s-cis conformational populations.
The dienophile typically is of one of three basic structural
types : conjugated diene, styrene, orelectron rich alkene.
Utilizing dienophiles which are more caticogenic than the
diene component is preferred for a selective DA.
Caticogenicity can be assessed on the basis of oxidation
potentials or ionization potentials; Caticophilicity is
considered to be affected by ability to stabilize thebisallylic
cation radicaloid transition state, steric hindrance toward
bond formation, s-cis conformationcontent and so on.
●
LDA, -78o C,
MoOPH
H
Ph3P=CH2
Brief Summary:
1)
SPh
MeCN, hv
60%
SPh
Br
H
CN
+
SO2 Ph
then Al2O3
45%
(-)-β-selinene
mo lybd enum pen toxide/pyridine /HMPA co mple x
Bauld et. al. JACS 1989, 111, 1826.
TAP (2 mol%)
hv, AcCl
+
4 -OMe -Ph
N
H
N
Ph-Me O-4
O
Ac
4-OMe -Ph
70% endo/exo = 3.3:1
TAP (2 mol%)
λ >345 nm, DCM
+
N
H
H
4-OM e-Ph
N
H
O
P h- MeO-4
O
H
O
4 -OMe-P h
46% 2:1 anti:syn
Steckhan et. al. Chem. Eur. J. 1995, 5, 2859.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
OMe
+
N
H
Me
TPP+, DCM
OMe
> 345 nm,15 oC,
CN
Me
Ar
N
H
25%
Me
Me
Me
Me
Me
N
CN
Ar3NSbCl6-
Me
CN
N
H
Me2 N
CN
N
H
NO2 DCM, 98% Ar =Br
CN
+
Shun Su
Me
TPP+ , DCM
> 345 nm,15 o C,
N
H
Me
Me
O
O
Me
CN
N
Me
Me
MeCN
electrolysis cell
490 mV, 53%
O
+
N
H
CN
O
Me2N
Ar3NSbCl6DCM, 84%
CN
N
Me2 N
O
Liu et. al. Synlett. 2003, 40, 1707.
Me
Me2N
Tf2O
N
N
H
CO2 Me
N
N
Me
Tf
R
N
O
Canthin-6-one
N
N
N
Steckhan et. al. Tetrahedron Lett. 1999, 40, 7075.
O
Ar
Me
Me
MeCN, 0oC
5 min
+
Ar
R
R
H
tB u
CO2 Me
Ar
Ar3NSbCl6-
NH
O
CO2 Me
Ar
O
H
C
+
Me
MnO2
78%
+
Ar = p-methoxyphenyl 36%
Ar = p-methylphenyl 25%
Na, DME
60%
N
Ar
Me
Me
MeCN, 0oC
5 min
Anode
Tf 87%
CO2 Me
1) HCl
2) Cu/Pyr
50%
Ar
Ar3NSbCl6-
C
+
94%
Br
syn/anti = 2:1
O
N
H
N
H
Ar =
O
Steckhan et. al. ACIEE. 1995, 34, 1900.
N
NO2
syn/anti = 3:2
N
tBu
H
Ar
4-MeOPh
4-MePh
4-MeOPh
R
H
H
Me
Yield(%)
67 13
46 12
63 09
Schmittel et. al. ACIEE. 1991, 30, 999; JACS. 1993, 115, 2165.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Shun Su
Cation Radical Cyclobutanation
S
Me
Me
S
Ph +
Me
Ph
TPP+, MeCN
hv, 91%
S
Me
Ph
0o C
+
An
Me Ar3NSbCl 6An
Miranda et. al. Org. Lett. 2007, 9, 3587.
OAc
OsO4
hv, Ba(ClO 4)3
O
O
Os
O
O
Ac2O
36%
AcO
OAc
OsO4
hv, Ba(ClO4)3
X
AcO
X
52:48
An
An
Bauld et. al. JACS 1986, 108, 6189.
OPh
Cross addition:
TPP+, hv
MeCN, 91%
OAc
+
OPh
OAc
40:60 syn:anti
OAc
OAc
6.2:1
OAc
M eO
Me
+
OAc
OAc
+
then Ac2O
An
Me
An
OAc
OAc
-35oC
Me
+
OAc
X
An=
Me
Ar = B r
OAc
OAc
0oC
Me
An
DCM
43:47
Ar3NSbCl6-
OAc
OAc
X= F 0.6% 4.4:1
Cl 3.4% 5.0:1
Br 2.6% 5.5:1
Farid et. al. J. Chem. Soc., Chem. Commun. 1973, 677.
Cross addition with conjugated dienes:
Motherwell et. al. ACIEE. 1995, 34, 2031.
H
X
X
Ar3NSbCl6-
X
+
+
H
X = NAcMe
OEt
OCH2CH2Cl
OPh
SPh
100
98
97
82
69
0
2
3
18
31
Bauld et. al. ibid 1984, 106, 2730.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
Shun Su
VCB Rearrangement:
+
N
2) KOH, 100o C
NH2NH2
Me
36% for 2 steps
Me
KH, THF
reflux, 91%
Me
H
OMe
NHMe
hv
NHMe
3.2:1
anti/syn
Me
phena nthrene
MeO
OMe
+
N
1) DCB, hv
Ac MeCN, 72h
Me
MeO
Me
OMe
OMe
+
Me
Ar
N
Me
KH, THF
reflux
2) KOH, 100o C
NH2NH2
40% for 2 steps
H
NHMe
Me
H
H
Me
Me
Ar3NSbCl6
H
-
H
+
An
H
Me
PET
Me
An
N2CHCO2Et
Ar3NSbCl 6-
H
Me
EtO2 C
An
+
N2CHCO 2Et
Ar3NSbCl671%
PET or
Ar3NSbCl 6-
2:1 syn:anti
Me
Me
Me
+
An
EtO 2C
MeO
An
Me
Me
Ar
Ar
H
H
Me
2.0%
64%
+
Me
Me
Me
H
Me
H
Me
+
PET or
Direct hv
Pyrex
H
+
Ar Ar
H
Me
Cyclopropanation
Bauld et. al. JACS 1988, 110, 8111.
Me
H
H
6.6%
Kikuchi et. al. Tetrahedron Lett. 1987, 28, 2857.
+
Me
H
NHMe
NHMe
H
Me
12.6% mahnosalin
MeO
mahnoshinin
1:1
anti/syn
H
Ar
Ar
OMe
H
1) DCB, hv
Ac MeCN, 72h
Me
H
+
2.3%
MeCN
KH, THF
reflux
H
2) KOH, 100o C
MeHN
NH2NH2
32% for 2 steps
OMe
Me
Me
Me
1) DCB, hv
Ac MeCN, 72h
An 1:1
Ph
Ph
N2CHCO2Et
An
42% Me
Me
Bauld et. al. Tetrahedron 1986, 42, 6189.
Ar3NSbCl681%
Ph
Ph
Ph
Ph
EtO 2C
Bauld et. al. JACS 1986, 108, 4235.
Cation Radical Cycloadditions
Baran Group Meeting
10/03/2007
VCP Rearrangement
Ar3NSbCl6An
An
MeCN, 22 oC
5 min
86%
Ar3NSbCl6An
MeCN, 59 oC
10 min
An
86%
Colon et. al. ibid 1988, 110, 2324.
E
E
N
N
E
N
N
hv, DCN
MeO2 C
E
NH
HN
CO2Me
E
E
N
N
E
E
Mattay et. al. Chem. Ber. 1993, 126, 543.
O
O
Ar3NSbCl6O
Ph
+
Ph
Me
Ph
Ph
Ph
DCM
Ar = Br
O
Ph
Me
32/33/19/16
O
O
O
Ph
Ph
O
+
An
Ar3NSbCl6- Ph
N
+
Ph
DCM
Ar = B r
65%
O
N
Ph
An
Ph
An
O
N
Ph
12:1
Ph
Ph
Liu et. al. Synlett. 2004, 251; 2005, 161.
Shun Su