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Diels-Alder Reaction, Lecture notes of Organic Chemistry

diene and dienophile. •. Lewis acid catalysts decrease the activation energy, favoring the endo- cycloaddition and the ortho/para products over.

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Diels-Alder Reaction
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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'
RR
R'
R
[4π + 2π] cyclization of diene and dienophile
dienophiles also include substituted alkynes, benzynes, and allenes
reaction is regioselective and stere ospecific
reaction can be enantioselective using chiral catalysts
with another atom being other than a carbon, reaction is known as hetero Diels-Alder
reaction
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, CO2R, COAr,
NO2, 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
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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

  • may be explained by the

electronic effects from the

substituents R 1

and R 2

creating partial negative or

positive charges on the

diene and dienophile.

  • Lewis acid catalysts

decrease the activation

energy, favoring the endo-

cycloaddition and the

ortho/para products over

meta

  • the percentage of the

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