Aromatic Rings and the Diels-Alder Reaction

OSEM
O
O
Claisen
Diels-Alder
O
O
O
HO
O
HO
O
O
OH
Aromatic Rings and the Diels-Alder Reaction
O
OH
MeO2C
HO2C
OMe
H
H
Oxidation
Diels-Alder
Me
MeO2C
Me
O
OMe
O
Blake Greene
Monday, May 12th
After Group Meeting
Outline
I. Review of the Diels-Alder Reaction
A. Mechanism
B. Types of Diels-Alder Reactions
C. Regioselectivity
II. Background on Aromatic Compounds
A. Stability of Benzene
B. Molecular Orbital Theory
III. Examples of Diels-Alder Reactions of Aromatic Compounds
A. Benzene
B. Cyclohexatriene Equivalents
C. Polycyclic Aromatic Hydrocarbons
D. Tandem Claisen/Diels-Alder Reactions
i. General Reactivity
ii. Garcinia Natural Products
iii. Salvadione A
E. Tandem Oxidation/Diels-Alder Reactions
i. Wessely Oxidation
ii. MOB's
1
Review of the Diels-Alder Reaction
Two mechanisms for the Diels-Alder reaction have been proposed:
One-step (concerted):
b
c
a
e
b
f
c
d
Two-step (nonconcerted):
a
d
e
b
f
c
a
d
e
b
f
c
a
d
e
b
f
c
a
d
e
f
or
b
c
a
d
e
b
f
c
a
e
f
d
biradical or zwitterionic
Concerted mechanism supported by chemical evidence:
--syn stereospecificity of the reaction
--Low solvent effects on the reaction rate
--Kinetic isotope effect research
--Large negative values of activation entropy and activation volume
Frontier molecular orbital (FMO) theory dictates that the Diels-Alder reaction is controlled by the interaction between
the two HOMO-LUMO molecular orbitals closest in energy
HOMO
O
O
H
O
A
B
H
H
A
O
LUMO
Endo Transition State
A: Bonding Interaction
B: Secondary Orbital Interaction
Brian's class notes
Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.
Review of the Diels-Alder Reaction
There are three general types (normal, inverse, and neutral electron demand) of Diels-Alder reactions, depending upon
the arrangements of the HOMO and LUMO molecular orbitals:
E
Diene
Dienophile
Diene
Dienophile
Diene
Dienophile
LUMO
HOMO
Normal
Inverse
Neutral
Factors that lower the HOMO-LUMO distance (i.e. substituent effects) increase the reaction rate due to the fact that the
smaller energy difference allows for a greater contribution to the stabilization of the transition state
E
LUMO
D
D
W
W
HOMO
W= Electron withdrawing group
D = Electron donating group
Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.
2
Review of the Diels-Alder Reaction
Regioselectivity: ortho/para Rule:
O
ortho:
O
OR
ortho/endo
product
favored
OR
longer
interaction
O
OR
O
OR
OR
largely
+ lobe
largely
- lobe
closer
interaction
O
para:
O
O
OR
O
OR
para/endo
product
favored
O
OR
OR
Brian's notes
Brief Background on Aromatic Compounds: A Look at Benzene
Aromatic compounds are unsaturated cyclic molecules containing additional stability caused by the arrangement of !electrons in the ring system
Aromaticity accounts for the fact that benzene is 151kJ/mol more stable than cyclohexatriene
3H2
predicted energy
for cyclohexatriene
aromatic
stabilization
2H2
151kJ/mol
3H2
Energy
360kJ/mol
H2
232kJ/mol
209kJ/mol
120kJ/mol
Hepworth, J. D. ; Waring, D. R.; Waring, M. J. Aromatic Chemistry. The Royal Society of Chemistry: Cambridge, 2002.
3
Molecular Orbital Theory of Benzene
Six carbons of benzene are sp2 hybridized
Three sp2 orbitals on each carbon overlap with those on two adjacent carbons and with the s orbital of hydrogen-compose the planar !-bonded skeleton of benzene
The p orbital (perpindicular to the plane of the ring) of each carbon contains one electron
Six p orbitals of benzene combine to form six molecule orbitals--three bonding and three anti-bonding
"6
anti-bonding
"4
"5
"2
"3
Energy
bonding
"1
Molecular Orbitals
Atomic Orbitals
Six overlapping p orbitals comprise a delocalized p-electron cloud, which result in the aromaticity of benzene
Hepworth, J. D. ; Waring, D. R.; Waring, M. J. Aromatic Chemistry. The Royal Society of Chemistry: Cambridge, 2002.
Diels-Alder Reactions with Benzene
A 20-40kcal/mol thermodynamic barrier must be overcome to induce [4+2] reactivity in benzene
Due to its aromaticity, benzene is a weak diene in [4+2] cycloadditions reactions--very few successful cases have been
reported with benzene as a diene in a Diels-Alder reaction
Successful Cases:
X
X
X
X
Very active dienophiles
X = CN (14%)
X = CF3 (8%)
O
OH
O
O
OH
O
O O
neat
200oC, 1.5h
Destabilize aromatic ring by adding
substituents
O
O
X
X
X
PTAD
20oC, 138h
X
Destabilize aromatic ring by
increasing ring strain
PTAD
(99%)
O
X X
Cossu, S.; Garris, F.; DeLucchi, O. Synlett 1997, 12, 1327.
Chordia, M. D. et al. JACS 2001, 123, 10756.
X-X =
N
N
NPh
O
4
Diels-Alder Reactions with Polycyclic Aromatic Hydrocarbons
Anthracene and its derivatives yield Diels-Alder reactions at diene sites C-9 and C-10, where the lowest benzenoid
character exists
R
R
R
COOH
COOH
COOH
R
ortho
meta
CN
COOH
CHO
NO2
OMe
65%
44%
100%
19%
100%
35%
56%
0%
81%
0%
R1
R
R
R1
R
R
R
R
R1
R
R1
Cl
CO2Me
CO2Me
CN
Me
Me
CO2Me
CO2Me
75%
69%
24%
1%
25%
31%
76%
99%
Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.
Diels-Alder Reactions with Polycyclic Aromatic Hydrocarbons
Diels-Alder rate constants of polycyclic aromatic hydrocarbons with maleic anhydride increase on linear annulation
and decrease on angular annulation
Acene
krel
Acene
1
krel
6 x 10-3
20.3
3 x 10-3
722.5
1447
1.5 x 10-3
= most reactive diene sites
The above can be explained by Clar's sextet theory, which states that the increasing reactivity going from anthracene to
hexacene is a result of a gradual loss of benzenoid character of the aromatic hydrocarbon, whereas the decreasing
reactivity with the angular annulation is due to the formation of a new !-sextet with each angular benzene addition.
Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.
5
Bicyclo[2.2.2]octene Skeleton Synthesis via Cyclohexatriene Equivalents
Y
Z
Y
X
Y
Z
X
-WZ
X
W
W
cyclohexatriene
equivalent
Success of the above reaction requires the "temporary interruption" of the aromaticity of the benzene ring followed by
the reinstallation of the double bond via the elimination of the W and Z functionalities
This is not a trivial point due to the fact that the easier it is to add and/or remove the functional groups, the easier it is
to aromatize. Because of this, the energy needed for the cycloaddition reaction is usually much greater than the
energy of aromatization. This results in the aromatization of the substrate and no Diels-Alder product.
Cossu, S.; Garris, F.; DeLucchi, O. Synlett 1997, 12, 1327.
Example: Barrelene Synthesis
SO2Ph
PhO2S
PhO2S
PhH
O
WCl6/n-BuLi
80oC, 48h
(96%)
SO2Ph
PhO2S
PhO2S
THF, RT, 24h
(90%)
O
Na/Hg
buffered MeOH
(90%)
Barrelene
Cossu, S.; Battaggia, S.; De Lucchi, O. JOC 1997, 62, 4162.
Rhenium Promoted Diels-Alder Reaction with Benzene
CH3
CH3
N
N
N
N
Re
N
HB
N
Br
N
N
Br
CO
Nao
N
O
O
CO
N
Re
N
N
N
CH3
N
PhH, THF, 25oC
(65%)
N
HB
N
N
O
CH3
N CH3
N
O
N CH3
N
N
N
Re
N
HB
O
CO
O
[O]
and/or
N
N
O
N CH3
N
O
single diastereomer
O
Crystal structure of dihapto complexation shows dearomatization to the extent that the uncoordinated portion of the
benzene ring resembles cyclohexadiene
Note: Re complex dictates the stereochemistry of the cycloaddition and prevents retrocycloaddition by hindering one
of the !-bonds
Chordia, M. D. et al. JACS 2001, 123, 10756.
6
Tandem Claisen/Diels-Alder Reactions of Aromatic Compounds
General Reactivity:
R
R
R
R
O
R
O
R
O
The Claisen rearrangement results in the simultaneous formation of the activated diene and the activated dienophile
Some Examples:
H
N
Cl
i-BuOH, H2SO4
O
100oC, 1h
(30%)
Cl
F
F
F
F
N
F
185oC
(81%)
O
N
F
F
O
F
Neuschutz, K.; Velker, J.; Neier, R. Synthesis 1998, 227.
Synthesis of the Bridged Tricyclic Core of Garcinia Natural Products
O
OH
H
O
O
O
O
O
O
O
O
O
O
Other products of this class are bractatin,
1-O-methylbractatin, 1-Omethyneolbractatin, forbesione, 1-Omethylforbesione, morellic acid,
scortechinone A, and scortechinone B
O
O
Morellin
OH
Biologically natural products isolated
from the genus Garcinia of the Guttiferae
family of plants
Biological activity includes antibacterial
and cytotoxic activities
Lateriflorone
Tandem Claisen/Diels-Alder:
OSEM
OSEM
O
O
O
O
O
O
110oC
1h
O
O
O
O
O
O
(85%)
O
O
OSEM
O
Electron donating alkoxides expedite dearomatization via the tandem Claisen/Diels-Alder reactions
Nicolaou, K.C.; Li, J. Angew. Chem. Int. Ed. 2001, 40(22), 4264.
Tisdale, E. J. et al. Org. Lett. 2003, 5(9), 1491.
7
Tandem Claisen/Cope/Diels-Alder in the Stoltz Lab
HO
HO
O
OH
Claisen
OH
HO
O
OH
Cope
OH
OH
HO
OH
OH
O
HO
OH
OH
Diels-Alder
O
O
O
Salvadione A
Tandem Oxidation/Diels-Alder Reactions
Wessely Oxidation:
(AcO)3Pb
OH
t-Bu
t-Bu
O
O
t-Bu
Pb(OAc)4
t-Bu
OH
OR
t-Bu
ROH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
OR
Harrison, M. J.; Norman, R. O. C. J. Chem. Soc. 1970, C, 728.
Examples:
OMe
O
OH
Pb(OAc)4
Et
O
OMe
OH
CO2Et
Pb(OAc)4
AcOH
(72%)
O
(82%)
H2C=CHCO2H
CO2Et
O
80oC
O
OMe
OAc
Et
OMe
MeO
OMe
O
O
140oC
(89%)
EtO2C
Et
OAc
O
Tisdale, E. J. et al. Org. Lett. 2002, 4(6), 909.
Bhamare, N. K. et al. J. Chem. Soc., Chem. Commun.. 1990, 739.
8
Masked o-benzoquinones (MOBs)
Masked o-benzoquinones (MOBs) are a highly reactive species of 6,6-dialkoxycyclohexa-2,4-dienones
MOBs can be formed in situ via the oxidation of the corresponding 2-methoxyphenols with hypervalent iodine
reagents in MeOH--diacetoxyiodobenzene (DAIB) or phenyliodonium (III) bis(trifluoroacetate) (PIFA)
OMe
O
Rn
OR'
Rn
O
Rn
O
o-benzoquinones
R' = alkyl
Type I
O
OAc
OR'
O
O
Rn
O
O
R' = Ac, alkyl
Type II
Type III
MOBs
o-benzoquinones are generally unstable and undergo numerous reactions including dimerization
MOBs are relatively stable compared to the corresponding o-benzoquinones
MOBs can participate in cycloaddition and nucleophilic additions reactions
The double bonds of the diene are electronically different (due to their positioning between carbonyl and acetal
functionalities), thus making regioselective reactions possible
The acetal functionality can act as monoprotection for the vicinyl carbonyl group
Limited methods for the synthesis of MOBs
Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
Lin, K. C. et al. JOC 2002, 67, 8157.
Masked o-benzoquinones (MOBs)
Masked o-benzoquinones (MOBs) are a highly reactive species of 6,6-dialkoxycyclohexa-2,4-dienones
MOBs can be formed in situ via the oxidation of the corresponding 2-methoxyphenols with hypervalent iodine
reagents in MeOH--diacetoxyiodobenzene (DAIB) or phenyliodonium (III) bis(trifluoroacetate) (PIFA)
OMe
O
Rn
OR'
Rn
O
o-benzoquinones
O
R' = alkyl
Type I
O
OAc
Rn
OR'
O
O
Rn
O
R' = Ac, alkyl
Type II
O
Type III
MOBs
o-benzoquinones are generally unstable and undergo numerous reactions including dimerization
MOBs are relatively stable compared to the corresponding o-benzoquinones
MOBs can participate in cycloaddition and nucleophilic additions reactions
The double bonds of the diene are electronically different (due to their positioning between carbonyl and acetal
functionalities), thus making regioselective reactions possible
The acetal functionality can act as monoprotection for the vicinyl carbonyl group
Limited methods for the synthesis of MOBs
Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
Lin, K. C. et al. JOC 2002, 67, 8157.
9
Intramolecular Diels-Alder (IMDA) Reactions with MOBs
Two important advantages of intramolecular vs. intermolecular Diels-Alder reactions
--IMDA reactions can usually proceed under milder conditions with higher reactions rates due to lower entropic
demands
--IMDA reactions usually result in greater selectivities due to the reduction in the degrees of freedom of the transition
state (unimolecular vs. bimolecular)
Replacing methanol with an alkenol or a dienol in the oxidation of 2-methoxyphenols yields MOBs which can undergo
IMDA reactions to form tricyclic ring systems
R4
OMe
R'
R4
OH
n
DAIB
OH
R'
R4
OMe
n
R3
n
O
R3 R'
O
R3
OMe
O
(15-80%)
R2
R2
R2
O
n = 1, R' = H, Me, Ph
n = 2, R' = H
R2 = R3 = H, R4 = H, Me, CO2Me
R2 = R4 = H, R3 = CO2Me
R2 = OMe, R3 = H, R4 = Me, CO2Me
While the intermolecular Diels-Alder reaction of MOBs yields ortho, anti products, the IMDA reaction of MOBs yields
meta, syn products--both with respect to the carbonyl group
X
n
X
OMe
Rn
O
OMe
Rn
OMe
Rn
OMe
O
O
ortho, anti
meta, syn
OMe
O
Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
Diels-Alder Reactions with MOBs in Total Synthesis
cis-clerodane diterpenic acid:
OH
O
OMe
PIFA
OH
3 steps
O
IMDA
OMe
OMe
O
O
OBn
11 steps
oxy-Cope
OH
H
4 steps
Br
MeO2C
Br
OMe
OMe
MeO2C
R = Bn
R = Ac
CO2H
MeO2C
OMe
OMe
Bu3SnH
7 steps
OMe
AIBN
O
O
OH
10 steps
oxy-Cope
H
Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
O
H
OMe
O
BnO
O
OR
O
OBn
H
O
CO2H
10