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Normal Diels-Alder reaction
EWG
EDG
EDG +
EWG
[4+2]
Inverse Electron Demand Diels-Alder reaction
EDG
EWG^ EWG
EDG
[4+2]
Mechanism
R'
R'
R R
R'
R
- [4π + 2π] cyclization of diene and dienophile
- dienophiles also include substituted alkynes, benzynes, and allenes
- reaction is regioselective and stereospecific
- reaction can be enantioselective using chiral catalysts
- with another atom being other than a carbon, reaction is known as hetero Diels-Alder
reaction
- concerted, pericylic reaction with an aromatic transition state
- forms two new σ-bonds
- forms the endo product as shown by the HOMO-LUMO orbital interactions
EDG (electron donating group)
= alkyl, O-alkyl, N-alkyl
EWG (electron withdrawing
group) = COR, CO 2 R, COAr,
NO 2 , etc.
HOMO
LUMO
HOMO
LUMO
or
Reviews:
Nicolaou et al. Angew. Chem. Int. Ed. 2002 , 41, 1668
Kagan, Riant Chem. Rev. 1992 , 92 , 1007
Kurti, Laszlo, Czako Elsevier , 2005 , 140- 141
R 1,4-product ( para ) 1,3-product ( meta )
Ph 80 20
Me 70 30
CF
3
R 1,2-product ( ortho ) 1,3-product ( meta )
Me 90 10
R
1
R
1
R
R 2
2
1,2-product ( ortho )
1,4-product ( para )
R
1
R
1
R
2 R 2
R
R 2
2
1,3-product ( meta )
R
1
R
1
Regioselectivity
- “ ortho ” and “ para ” products
are favored over “ meta ”
products
electronic effects from the
substituents R 1
and R 2
creating partial negative or
positive charges on the
diene and dienophile.
decrease the activation
energy, favoring the endo-
cycloaddition and the
ortho/para products over
meta
“ meta ” product can be
observed with an increase
of electron-withdrawing
groups on the diene
- “ meta ” product ratio is
always less
para-favored
R
1
R
1
CO
2
Me CO 2
Me
CO
2
R Me 1
ortho-favored
R
1
R
1
CO
2
Me CO 2
Me
CO
2
R Me 1
Inukai, Kojima J. Org. Chem., 1971 , 36 , 924
Asymmetric Diels-Alder
BnO
O
N
O
O
N
Al
N
R
R
R
Ph
Ph
CH 2
Cl 2
, -
o C
N
Al
Ph
Ph
R
Me
O
N
O
O
BnO H
endo-TS
O N
O
O
H
BnO
endo adduct
95% ee Corey et al. JACS , 1989 , 111 , 5493
BnO
N
B
O
Ts
H
CH 2
Cl 2
, -
o C
O
HB N
Ts
H
BnO
exo-TS
Br
H
BnO
exo adduct
92% ee
Br CHO
H
N
O
O
Br
O
H
NH
CHO
Corey et al. Tet. Lett. , 1991 , 32 , 7517
Corey et al. JACS , 1992 , 114 , 7938
Lewis acid catalyzed asymmetric Diels-Alder
TBSO
O
O
OMe
Me
(s)-BINOL-TiCl 2
tolune
-60 to -
o C
O
O
Ti
O
OMe
O
OTBS
Me
O
O
H
H
TBSO
OMe
Me
Me
94% ee
Nicolaou et al.
Angew. Chem. , 2001 , 113 , 2543
Angew. Chem. , 2001 , 40 , 2482
O 2 S
SO 2 Tf
Tf
OMe
OTBS
Tf
Tf
SO 2
O 2 S
X =
(s)-catalyst
chiral counterion
OFm
O
Ar
(s)-catalyst (1 mol%)
Et 2 O (0.2M) -
o C
OMe
OTBS
(10 mol%)
Ar
O
OFm
FmO
O
Ar
SiHR 3
X
- silylium ion as lewis acid catalyst
- chirality at the counterion
- Aromatic groups can be electron rich or deficient
90% ee
Gatzenmeier, Gemmeren Science , 2016 , 26 , 949
Hetero Diels-Alder Reaction
X
X = O, S
R
N
R
R
a,b - unsaturated
carbonyls
1 - azabutadienes
N
R
N
NR
R
NR
N
R
NR
NR
R
2 - azabutadienes
1, 2 - diaza
butadienes
1, 3 - diaza
butadienes
1, 4- diaza
butadienes
N
O
a, b - unsaturated
nitroso comp.
a, b- unsaturated
nitro comp.
1, 2 - dicarbonyls
R
N
O
R
O X
X
X = O, S
R
Common Heterodienes:
X
R 1 R 2
X = O, S, Se
carbonyls
NR
R 2
R 1
S
N
R 2
O
imines,
imminium salts
N-sulfinylimines
O
N
R 2
N
N
R 2
S
N
R 2
O
O
S
O
O
C
S
S
R 1
O
R
nitroso comp.
sulfur dioxide
azo comp. (^) N-sulfonylimines
nitriles
diatomic sulfur
Common Heterodienophiles:
- Normal D-A reaction: diene and heterodienophile (electron-deficient); or heterodiene
(electron-rich) and non-heterodienophile can be used
- Inverse D-A reaction: heterodiene (electron-withdrawing) and dienophile; or diene and
heterodienophile (electron-rich) can be used
MeO
OMe
MeO
OMe
N
N N
N
CO 2
Me
CO 2 Me
60
o C
CHCl 3
N
N
N
N
N
N
N
N
OMe
OMe
R
MeO
MeO
R
N
N
CO 2
Me
CO 2
Me
N
N
MeO 2
C
R
R
R
R
MeO 2
C
N
N CO 2
Me
CO 2
Me
N
OMe N
MeO
CO 2
Me
MeO 2
C
Hetero Diels-Alder Reaction
- Double azadiene DA, following
retro-DA to aromatize to final
product
J. Am. Chem. Soc. 1993 , 115 , 11418
Asymmetric hetero-DA
TBSO
OBn
H
TBDPSO
O
salen-type
catalst
Me
N O
O
Cr
H
O
TBDPSO
OBn
TBSO
O
TBSO
OBn
OTBDPS
94% ee
Jacobsen et al. JACS 2001 , 123 , 10 772
