New multicomponent reactions with phenols and isocyanides Julie Oble PhD. under the supervision of...

New multicomponent reactions with phenols and

isocyanidesJulie Oble

PhD. under the supervision of Dr. Laurence Grimaud and Dr. Laurent El Kaïm

Table of contents

Development of a new multicomponent reaction:

The Ugi-Smiles coupling

Use of Ugi-Smiles coupling for heterocyclic synthesis

Synthesis of aminobenzofurans by a sequence:

Mannich reaction with phenols and [4+1] cycloaddition

with isocyanides

4-CR

-Atom economy

-Step economy

-Simple procedure

+

Muticomponent reactions

The Ugi reaction

R4

O

OH

R3NC

+

R3 NH

O N R2

R1

R1CHO

R2NH2

OR4

-amidoamideI. Ugi:1930-2005

Review: A. Dömling, Chem. Rev. 2006, 106, 1

The Ugi reaction

NR2

R1+ NR2

R1

HR4CO2

R1

HN

N

O

R3

R2

R4CO2H

NR2

R1

H

N

R3

R4CO2

R1CHO R2NH2

O R4

R3NC

R4

O

OH

R3NC

+

R3 NH

O N R2

R1

R1CHO

R2NH2

OR4

-amidoamideI. Ugi:1930-2005


The Ugi reaction

NR2

R1+ NR2

R1

HR4CO2

R1

HN

N

O

R3

R2

R4CO2H

NR2

R1

H

N

R3

R4CO2

R1CHO R2NH2

O R4

R3NC

R4

O

OH

R3NC

+

R3 NH

O N R2

R1

R1CHO

R2NH2

OR4

-amidoamide

MummR1

N

NH

O

R3

R2

O

R4

Final irreversible Mumm rearrangement

I. Ugi:1930-2005


Ugi reaction: variation of the acid component

+R1

HN

N

O

R3

R2

R1CHO R2NH2 +

R4

O

OH Mumm

R1

NHN

OR3

R2

OR4

R3NC

O R4

Ugi (1960), Dömling (2000) Ugi (1961) Ugi (1961)

R4

X

SH

R1

N

NH

S

R3

R2

X

R4

NNN

N

R3 R1

NH

R2

R1

HN

N

S

R3

R2X R4

R1

HN

N

N

R3

R2

NC

XH

C

X

NX

HN

NR3

R1

R2

R1

HN

N

N

R3

R2N

N

NN

NH

X=O, SX=O, S

HeterocyclizationMumm Electrocyclization

+ +

OH

NO2

NR2

R1

H

ArOR1CHO R2NH2

NR2

R1

HArO +

R1

NH

N

O

R3

R2

R3NC

NO2

With NWith Nitrophitropheenolsnols


+ +

OH

NO2

NR2

R1

H

ArOR1CHO R2NH2

NR2

R1

HArO +

R1

NH

N

O

R3

R2

R3NC

NO2

With NWith Nitrophitropheenolsnols

Final irreversible Smiles rearrangement

R1

HN

N

O

R3

R2O2N

R1

NNH

O

R3 R2

O2NO

NR3 R1

NHR2

NO2


New aryl transfert in Ugi-type coupling

OH

NO2

R3NC

+ R3 NH

ON

R2

R1

NO2

R1CHO

R2NH2N-arylaminoamide

OH

NO2 HO NO2

pKa 7.17 pKa 7.15

Ugi-Smiles coupling with nitrophenols

First results

OH

NO2

ClH2N

CyNC+ +

OCyHN

NEtO2N

EtCHO

Cl

MeOH, 40°C, 20h, 74%1M

Toluene, 80°C, 20h, 90%

OH

NO2

O

CyHNN

Et

Cl

NO2

MeOH, 40°C, 20h, 72%

1M

MeOH, W (80°C, 50W), 10min, 100%

El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7165-7169.

Variation of the amine component


CyHNO

N

OMe

O2N

71% (4h at 40°C)

CyHN

O

N

O

O2N

97% (16h at 60°C)

CyHNO

N

O2N

OMe

81% (16h at 60°C)

CyHNO

N

OMe

O2N

OMe

64% (16h at 60°C)

CyHNO

N

NO2

61% (16h at 60°C)

CyHNO

N

NO2

72% (16h at 60°C)

Lower nucleophilicity of aromatic amine

OH

NO2

CyNC+ +EtCHO

NH2

X

O

O2N

NCy

Et

HN



Lower nucleophilicity of aromatic amine

OH

NO2

CyNC+ +EtCHO

NH2

X

O

O2N

NCy

Et

HN

Spiro [6,4] intermediate too much tightened

Et2NH

X O

O2N

N

Et N

Et

Et

Cy

+ + +R1CHO R2NCNHR

R' R2

NO

OR3

R1

NR

R'R2

N

O

R1

NR

R'O

R3

R3COOH



OH

NO2

CyNC+ +EtCHO

NH2

X

O

O2N

NCy

Et

HN


Impossiblility to form a spiro [6,8]

intermediate

HN

NH

X

O

NO2

NCy

Et

N

NH

Et2NH

X O

O2N

N

Et N

Et

Et

Cy


Variation of the amine componentLower

nucleophilicity of aromatic amine

Importance of the Smiles 5-membered transition state

OH

NO2

CyNC+ +EtCHO

NH2

X

O

O2N

NCy

Et

HN


Impossiblility to form a spiro [6,8]

intermediate

HN

NH

X

O

NO2

NCy

Et

N

NH

Et2NH

X O

O2N

N

Et N

Et

Et

Cy


Variation of the amine componentLower

nucleophilicity of aromatic amine


BnHNO

N

O2N

Cl t-BuHNO

N

O2N

Cl

5

NHMeO

MeO

O

NO

NO2

HNO

N

O2N

ClEtOOC

96% (4h, 40°C) 79% (4h, 40°C)

71% (16h, 60°C) 60% (16h, 60°C)


Variation of the isocyanide component

CyHNO

N

Cl

NO2

Cl

35% (40°C, 20h)

80% (60°C, 20h)

CyNH

ON

CF3

ClNO2

81% (20h at 60°C)

Cy

HN

ON

ClO2N

MeO

OMe

71% (70h at 60°C)


Variation of the carbonyl component: with aromatic aldehydes

CyHNO

N

Cl

NO2

Cl

35% (40°C, 20h)

80% (60°C, 20h)

CyNH

ON

CF3

ClNO2

81% (20h at 60°C)

Cy

HN

ON

ClO2N

MeO

OMe

71% (70h at 60°C)


Variation of the carbonyl component: with ketones

CyHN

O

N

ClO2N

33% (7d at 60°C)

CyHN O

N

O

NO2

46% (10d at 60°C)

CyHN

O

N

Cl

NO2

71% (10d at 60°C)


Variation of the carbonyl component: with aromatic aldehydes

ClH2N

CyNC+ +EtCHO

OCyHN

NEt

MeOH60°C, 48h

73%

OH

O2N NO2 O2N

Cl

NO2

MeOH60°C,72h

OCyHN

NEt

Cl

96%

HO Me

Me

O2N

O2NMeOH60°C, 72h

HO

NO2Me

El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169-4180.

Dependence to steric hindrance ?


Variation of the nitrophenol component

ClH2N

CyNC+ +EtCHO

OCyHN

NEt

62%

MeO

Cl

NO2

HO NO2

MeO

MeOH60°C, 16h

OCyHN

NEt

Cl

NO2

Cl

95%

HO NO2

Cl

MeOH60°C, 16h

HO

NO2Me

X



ClH2N

CyNC+ +EtCHO

OCyHN

NEt

62%

MeO

Cl

NO2

HO NO2

MeO

MeOH60°C, 16h

OCyHN

NEt

Cl

NO2

Cl

95%

HO NO2

Cl

MeOH60°C, 16h

MeOH

60°C, 48h

NO2

OH

N

NBn

NO2

N

N

NBn

OCyHN

Cl

88%

HO

NO2Me

X



ClH2N

CyNC+ +EtCHO

OCyHN

NEt

62%

MeO

Cl

NO2

HO NO2

MeO

MeOH60°C, 16h

OCyHN

NEt

Cl

NO2

Cl

95%

HO NO2

Cl

MeOH60°C, 16h

MeOH

60°C, 48h

NO2

OH

N

NBn

NO2

N

N

NBn

OCyHN

Cl

88%

X

O

O2N H

NR3

R1

NR2

HO

NO2Me

X



+MeOH

60°CEtCHO + Cl

NH2

CyNC+

48h

74%

COOMe

OH CyHNO

NCl

MeO2C

Ugi-Smiles coupling with other electron deficient

phenols

With the salicylic acid methyl ester

+MeOH

60°CEtCHO + Cl

NH2

CyNC+

48h

74%

COOMe

OH CyHNO

NCl

MeO2C

CyHNO

NCl

MeO2C

74% (48h, 60°C)

CyHNO

N COOMe

64% (20h, 60°C)

CyHNO

N COOMe

O

63% (16h, 60°C)

CyHNO

N COOMe

47% (48h, 60°C)



phenols


+MeOH

60°CEtCHO + Cl

NH2

CyNC+

48h

74%

COOMe

OH CyHNO

NCl

MeO2C

CyHNO

NCl

MeO2C

74% (48h, 60°C)

CyHNO

N COOMe

64% (20h, 60°C)

CyHNO

N COOMe

O

63% (16h, 60°C)

CyHNO

N COOMe

47% (48h, 60°C)


With the para-hydroxybenzoic acid methyl ester

+MeOH, 60°C or

Toluene, 90°CorW (Toluene, 120°C, 50W)

EtCHO + ClNH2

CyNC+

COOMe

OH

X


phenols


+MeOH

60°CEtCHO + Cl

NH2

CyNC+

48h

74%

COOMe

OH CyHNO

NCl

MeO2C

CyHNO

NCl

MeO2C

74% (48h, 60°C)

CyHNO

N COOMe

64% (20h, 60°C)

CyHNO

N COOMe

O

63% (16h, 60°C)

CyHNO

N COOMe

47% (48h, 60°C)


With the para-hydroxybenzoic acid methyl ester

+MeOH, 60°C or

Toluene, 90°CorW (Toluene, 120°C, 50W)

EtCHO + ClNH2

CyNC+

COOMe

OH

XC

OH

R3N R1

N R2

O

OMe


phenols


Smiles rearrangement of heterocyclic systems

N

OH

CF3

ClCH2CONH2

K2CO3

DMF 50°C

N

OO

NH2

CF3

140°C

DMFN CF3

NH2

48h70%

8h92%

Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Tehrani, K. A.; De Kimpe, N. Tetrahedron 2001, 57, 2051-2055.

Wang, H. Y.; Liao, Y. X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Synlett 2005, 8, 1239-1242.

N

N

MeO

OMe

O

NH

X

R2

R1

N

N

OMe

MeO N

R1

HO

X

R2

R1 = H ou ClX = CH ou N

R2 = amide, ester ou Br

acetic acidactone (1/1)

RT

100%

Ugi-Smiles coupling with heterocyclic phenols

Ugi-Smiles coupling with 2-hydroxypyridine compounds

ClH2N

CyNC+ +EtCHON OH

X

MeOH, 60°C orToluene, 90°C orW(Toluene, 120°C, 50W)

+

With the 2-hydroxypyridine



ClH2N

CyNC+ +EtCHON OH

X

MeOH, 60°C orToluene, 90°C orW(Toluene, 120°C, 50W)

+

With the 2-hydroxypyridine

With the 2-hydroxy-3-nitropyridine and the 2-hydroxy-5-nitropyridine

CyHNO

NN

NO2

Cl

HNO

N

N

NO2

CyHNO

N

N

Cl

NO2

CyHN O

N

N

NO2

Cl

66% (MeOH, 60°C, 16h) 96% (MeOH, 60°C, 72h)62% (MeOH, 60°C, 16h) 25% (MeOH, 60°C, 10d)

El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019-4021.


With the 2-hydroxy-5-chloropyridine and the 2-hydroxy-5-trifluorométhylpyridine

Require higher temperature: use of toluene at 90°C


CyHNO

NN

Cl

Cl

NH

O

N

OMeN

Cl

MeO HN

O

N

N

Cl

CyHN

O

NN

CF3

Cl

HN

O

N

N

CF3

27% (90°C, 72h) 14% (90°C, 16h) 54% (90°C, 16h) 44% (90°C, 72h) 58% (90°C, 16h)




Ugi-Smiles coupling with hydroxypyrimidine compounds

With the 2-hydroxypyrimidine

OMeH2N

CyNC+ + +

MeOH

EtCHO N N

OH.HCl1 eq. MeONa

60°C, 15hCyHN

O

N

N

N

OMe

38%



With the 2-hydroxypyrimidine

OMeH2N

CyNC+ + +

MeOH

EtCHO N N

OH.HCl1 eq. MeONa

60°C, 15hCyHN

O

N

N

N

OMe

38%

ClH2N

CyNC+ + +MeOH

EtCHO

N

N

OH

60°C, 72h CyHN

O

N

N

N

Cl

78%

With the 4-hydroxy-2,6-diméthylpyrimidine


HN

O

N

N

N CyHNO

N

NN

ClF3C

CyHN

O

N

NN

Cl

60% (MeOH, 4d, 60°C) 50% (MeOH, 4d, 60°C) 54% (MeOH, 8d, 60°C)



Preparation of 4-hydroxypyrimidines

Ph

NH

NH2

/HCl +O O

OEt

EtOH/EtONa

reflux1d

N N

Ph

OH64%

Hullar, T. L.; French, W. C. J. Chem. Med. 1969, 12, 424-426.



Preparation of 4-hydroxypyrimidines

Ph

NH

NH2

/HCl +O O

OEt

EtOH/EtONa

reflux1d

N N

Ph

OH64%

Hullar, T. L.; French, W. C. J. Chem. Med. 1969, 12, 424-426.

Ugi-Smiles coupling with disubstitued 4-hydroxypyrimidines

63% (MeOH, 72h, 60°C) 89% (MeOH, 16h, 60°C)

CyHNO

N

NN

Cl

CyHNO

N

NN

Ph

Cl

CyHN

O

N

N

N

MeO

Ph

F3C

51% (MeOH, 72h, 60°C)

CyHNO

N

NN

Ph

Cl

Ph

51% (MeOH, 72h, 60°C)




The new Ugi-Smiles coupling

Z2

Z3

Z1

OH

R3NC

+ R3NH

O

NR2

Z2

Z3

Z1

R1

R1CHO

R2NH2

Z1, Z2, Z3 = C- or N

New Ugi-type-coupling with electron-deficient phenols as acidic

components in place of the traditional carboxylic acids

First example of Smiles rearrangement in Ugi-type-coupling

Extented to 2-hydroxypyridines and 2- or 4-hydroxypyrimidines

Table of contents






with isocyanides

+

Post-condensations

4-CR+

Muticomponent reactions

Ugi-Smiles post-condensations

OH

R3NC

+ R3NH

O

NR2

R1

R1CHO

R2NH2

NO2

NO2

OH

R3NC

+ R3NH

O

NR2

R1

R1CHO

R2NH2

X

X

Functionalization of phenol by halogenation, alkylation ...


Synthesis of quinoxalinone derivatives

1- H2 Pd/C, MeOH

2- APTS, MeOH

Cy

HN

O

R1

NR2

NO2

N

R1

R2 O

NH+ CyNH2


1- H2 Pd/C, MeOH

2- APTS, MeOH

Cy

HN

O

R1

NR2

NO2

N

R1

R2 O

NH+ CyNH2

N

OMe

NH

Et

O

81%

N

NH

O

Cl

Cl

60%

N

OMe

NH

Et

O

OMe

61%

N Et

ONH

Cl

67%

Oble, J.; El Kaïm, L.; Gizzy, M.; Grimaud, L. Heterocycle 2007, 73, 503-517.


1- H2 Pd/C, MeOH

2- APTS, MeOH

Cy

HN

O

R1

NR2

NO2

N

R1

R2 O

NH+ CyNH2

N

OMe

NH

Et

O

81%

N

NH

O

Cl

Cl

60%

N

OMe

NH

Et

O

OMe

61%

N Et

ONH

Cl

67%

2. H2, Pd/C, MeOH

3. APTS, MeOH

EtCHO + + CyNC +

OH

NO2

1. MeOH, 60°CN

OMe

NH

Et

O

47%

H2NOMe


OH

R1CHO R2NH2

R3 NH

O

R1

NR2 N

R1

R2 O

NI

NO2

NO2

I

NO2

R3R3NC

CuI (10 mol%)L-proline (20 mol%)

K3PO4, CH3CN


OH

R1CHO R2NH2

R3 NH

O

R1

NR2 N

R1

R2 O

NI

NO2

NO2

I

NO2

R3R3NC

CuI (10 mol%)L-proline (20 mol%)

K3PO4, CH3CN

Ugi-Smiles coupling with the 2-iodo-4-nitrophenol and the 2-iodo-6-chloro-4-nitrophenol

OH

I

+

Toluene / H2O (9/1)NH4Cl 1eq, 100°C

1 M, 13h

NO2

ONH2 + +

NC

Cl

HNO

N I

Cl

NO264%

HNO

N I

NO2

24%, 20h

HNO

N

ICl

NO2

Cl

Cl

80%, 20h

HNO

N

ICl

NO2

Cl

MeO

74%, 3d


N-arylation of amides under copper catalysis

CuI (10 mol%), L-proline (20 mol%)

K3PO4, CH3CN, 80°CHN

O

N

I

Cl

NO2

N

NO Cl

NO2

20h

65%





O

N

I

Cl

NO2

N

NO Cl

NO2

20h

65%

61%, 16h

N

NO

NO2

N

NO Cl

NO2

Cl

Cl

N

NO

NO2

Cl

Cl

OMe

55%, 18h 45%, 2d






O

N

I

Cl

NO2

N

NO Cl

NO2

20h

65%

Efficient synthesis of quinoxalinone derivatives while maintaining the structural diversity achieved in the coupling

61%, 16h

N

NO

NO2

N

NO Cl

NO2

Cl

Cl

N

NO

NO2

Cl

Cl

OMe

55%, 18h 45%, 2d



OH

R3NC

+ R3NH

O

NR2

R1

R1CHO

R2NH2

X

X

Functionalization of phenol by halogenation, alkylation ...

NH2

HO

R1CHO

R2

HN

O

R1

N

R2NC

Metathesis N

R1

O

R2HN

Ugi-Smiles / RCM strategy



Ugi-Smiles coupling with the 2-allyl-4-nitrophenol

OH

NO2

+ p-ClBnNCMeOH

60°CEt CHO+ + XNH2



OH

NO2

+ p-ClBnNCMeOH

60°CEt CHO+ + XNH2

MCR / RCM with the O-allyl phenol

OH

NO2

ONH2

p-ClBnNC

MeOH, 60°C

72%

CHO

N

NO2

O

p-ClBnHN

O



OH

NO2

+ p-ClBnNCMeOH

60°CEt CHO+ + XNH2

MCR / RCM with the O-allyl phenol

OH

NO2

ONH2

p-ClBnNC

MeOH, 60°C

72%

CHO

N

NO2

O

p-ClBnHN

O

RuClCl

N N MesMes

O

Toluene or CH2Cl2

Ru cat. (10 mol%)

RT or reflux

X

Cat :

No bicyclic product could be isolated from the resulting complex mixture probably because of isomerizations and the allyl ether deprotection under these conditions

MCR / RCM strategy with 4-hydroxypyrimidines substitued by an olefin

Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyrimidines

N

N

OH

X Y

nY

O O

OEt

n

NH.HCl

NH2X+

EtOH, 80°C

NaOEt (1 eq) X = Ph, Y = CH3, n = 2, Rdt=95%X = Ph, Y = CH3, n = 1, Rdt=75%X = Me, Y = CF3, n = 1, Rdt=46%


MCR / RCM strategy with 4-hydroxypyrimidines substitued by an olefin

Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyrimidines

N

N

OH

X Y

nY

O O

OEt

n

NH.HCl

NH2X+

EtOH, 80°C

NaOEt (1 eq) X = Ph, Y = CH3, n = 2, Rdt=95%X = Ph, Y = CH3, n = 1, Rdt=75%X = Me, Y = CF3, n = 1, Rdt=46%

Ugi-Smiles coupling

N

N

OH

Ph

NH2+toluene, 110°C

23 M, 4d

CHO + BnNC +

N

N

N

Ph Me

HN

O

Bn

62%

N

N

N

Ph Me

HN

O

Cy

N

N

N

Ph Me

HN

O

Bn

N

N

N

Ph Me

HN

O

OMe

MeO

N

N

N

Me CF3

HN

O

Cy

59% (4d) 70% (1d) 69% (5d)52% (3d)


MCR / RCM with 4-hydroxypyrimidines substitued by an olefin

Metathesis reaction on the adduct obtained with the 5-homoallyl-4-hydroxypyrimidine

HNO

N

NN

Ph

0.5 Mtoluene, RT

cat. (10 mol%)

x




0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

HNO

N

N

NPh

67%

HNO

N

NN

Ph

0.5 Mtoluene, RT

cat. (10 mol%)

x




0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

HNO

N

N

NPh

67%

toluene, 110°C

cat. (10 mol%)

0.5 M, 3d HNO

N

N

NPh

73%

HNO

N

NN

Ph

0.5 Mtoluene, RT

cat. (10 mol%)

x




0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

HNO

N

N

NPh

67%

toluene, 110°C

cat. (10 mol%)

0.5 M, 3d HNO

N

N

NPh

73%

HNO

N

NN

Ph

0.5 Mtoluene, RT

cat. (10 mol%)

xMetathesis reaction on the adduct obtained with a 5-allyl-4-hydroxypyrimidine

N

N

N

Ph Me

HN

O

Cy

N

N

N

Ph Me

HN

O

Cy

0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

67%

El Kaïm, L.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 5835-5838.




0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

HNO

N

N

NPh

67%

toluene, 110°C

cat. (10 mol%)

0.5 M, 3d HNO

N

N

NPh

73%

HNO

N

NN

Ph

0.5 Mtoluene, RT

cat. (10 mol%)

x

N

N

N

Ph Me

HN

O

Cy

toluene, RTcat. (10 mol%)

0.5 M, 6 h

84%

Metathesis reaction on the adduct obtained with a 5-allyl-4-hydroxypyrimidine

N

N

N

Ph Me

HN

O

Cy

N

N

N

Ph Me

HN

O

Cy

0.5 M, 12 h

toluene, 110°C

cat. (10 mol%)

67%



MCR / RCM / Isomerization

Metathesis reaction on various allyl 4-aminopyrimidines

N

N

N

Ph Me

HN

O

BnN

N

N

Ph Me

HN

O

OMe

MeON

N

N

Me CF3

HN

O

Cy

1j, 53% 1 j, 89%2 j, 47% 2 j, 53%

N

N

N

Ph Me

HN

O

Bn

5


Syntesis of pyrimido-azepines involving the Ugi-Smiles coupling followed by a ring closure metathesis


Conclusion on the applications of Ugi-Smiles

coupling

OH

R3NC

+ R3NH

O

NR2

R1

R1CHO

R2NH2

X

X

N

R1

R2 O

N

NO2

R3

R2HN

O

R1

NN

N

X

Y

n

Quinoxalinones Pyrimido-azepines

Table of contents






with isocyanides

Synthesis of ortho-quinone methides

R1CHO

HO R2

R2

OH

N

R2

O R1

NBnHN

NBn

R1

cycloaddition

Synthesis of ortho-quinone methides

R1CHO

HO R2

R2

OH

N

R2

O R1

NBnHN

NBn

R1

cycloaddition

R"NC

N N

R

O

Ar

NHR"

R'

R

O

NNHAr

R

O

NNHAr

N

NBn

R'

R'CHO

NBnHN

toluene, 80°CR

O

NNHAr

toluene, 110°C

BrBr

NN

R

O

Ar

R'

R'

HN NBnBr Br+

NO

Mannich reaction of hydrazones: synthesis of pyrazoles and pyridazines

Atlan, V.; Bienaymé, H.; El. Kaïm, L.; Majee, A.; J. Chem. Soc., Chem. Commun. 2000, 1585–1586. Atlan, V.; El. Kaïm, L.; Grimaud, L.; Majee, A.; Nirmal, N. K. Synlett, 2002, 2, 352-354.

Mannich reaction with phenols

Mannich reactions with electron deficient phenols

With the formaldehyde

H

O

H

OH

NBnHN+

Toluene 110°C

MeOOCOH

Toluene 110°C

O2NNO2

OH

N

NBn

COOMe

OH

N

NBn

71%92%




H

O

H

OH

NBnHN+

Toluene 110°C

MeOOCOH

Toluene 110°C

O2NNO2

OH

N

NBn

COOMe

OH

N

NBn

71%92%

With aromatic aldehydes

OH

NBnHN

OH

NNBn

+Toluene 110°C

MeOOC

COOMe

CHOOH

Toluene 110°C

O2N

X

80%




H

O

H

OH

NBnHN+

Toluene 110°C

MeOOCOH

Toluene 110°C

O2NNO2

OH

N

NBn

COOMe

OH

N

NBn

71%92%

With aromatic aldehydes

OH

NBnHN

OH

NNBn

+Toluene 110°C

MeOOC

COOMe

CHOOH

Toluene 110°C

O2N

X

80%COOMe

OH

N

NBn

OMe

79%, 5d

COOMe

OH

N

NBn

NO2

71%, 2d

COOMe

OH

N

NBn

CF3

64%, 2d

COOMe

OH

N

NBn

N

66%, 2d

OH

NBnHN OH

NNBn

+Without solvent

140°C, 5h

CHO

OMe

+

OMe

90%

Toluene

110°CX


Mannich reactions with electron enriched phenols

OH

NBnHN OH

NNBn

+Without solvent

140°C, 5h

CHO

OMe

+

OMe

90%

Toluene

110°CX

91%

OH

NBnHN OH

N

NBn

+

Without solvent 140°C, 5h

CHO

OMe

OMe

Without solvent 140°C, 5h

HO

HO

N

NBn

OMe

93%


Mannich reactions with electron enriched phenols

Ortho-quinone methides formation and the trapping by

nucleophiles

OHNBnHN

OH

N

NBn BrBr

toluene110°C

N

+

Toluene 110°CCOOMe

COOMe

(2 eq)

(2 eq)

CHO

NO2

NO2

X

Mannich reaction – alkylation – elimination – nucleophile addition sequence

El Kaïm, L.; Grimaud, L.; Oble, J. Org. Bio. Mol. 2006, 4, 3410-3413.

OHNBnHN

OH

N

NBn BrBr

toluene110°C

LiClO4 (10 mol%)

N

+

Toluene 110°CCOOMe

COOMe

(2 eq)

(2 eq)

CHO

NO2

NO2

OH

N

COOMe

56%

NO2


nucleophiles


New efficient ortho-quinone methides formation under the alkylative elimination of the piperazine from Mannich adducts obtained with the N-benzylpiperazine


OHNBnHN

OH

N

NBn BrBr

toluene110°C

LiClO4 (10 mol%)

N

+

Toluene 110°CCOOMe

COOMe

(2 eq)

(2 eq)

CHO

NO2

NO2

OH

N

COOMe

56%

NO2


nucleophiles


OH

N

NBn

BrBr

toluene110°C

LiClO4 (10 mol%)COOMe

(2 eq)

(2 eq)CyNC

6h

COOMe

O

HN Cy

47%

Synthesis of aminobenzofurans

Ortho-quinone methides formation - [4+1] cycloaddition with isocyanides

OH

N

NBn

BrBr

toluene110°C


(2 eq)

(2 eq)CyNC

6h

COOMe

O

HN Cy

47%


COOMe

O

HN Cy

OMe

61%, 4h

COOMe

O

HN

OMe

COOEt

65%, 6h

COOMe

O

HN Cy

NO2

76%, 1d

COOMe

O

HN Cy

CF3

60%, 5dCOOMe

O

HN Cy

N

55%, 6h

ONH

Cy

OMe

25%, 6h

O

NHCy

OMe35%, 6h



OH

N

NBn

BrBr

toluene110°C


(2 eq)

(2 eq)CyNC

6h

COOMe

O

HN Cy

47%


COOMe

O

HN Cy

OMe

61%, 4h

COOMe

O

HN

OMe

COOEt

65%, 6h

COOMe

O

HN Cy

NO2

76%, 1d

COOMe

O

HN Cy

CF3

60%, 5dCOOMe

O

HN Cy

N

55%, 6h

ONH

Cy

OMe

25%, 6h

O

NHCy

OMe35%, 6h

35%

34%

42%

41%



Conclusion of the sequence: Mannich reaction – [4+1]

cycloaddition

New general efficient three component coupling of phenols with aldehydes and various nucleophiles

Application of this process to [4+1] cycloaddition of isocyanides with transient o-quinone methide: synthesis of aminobenzofurans

OH

R2 O

BnN

NH

OH R2

N

NBn

BrBr

toluene110°C

LiClO4 (10 mol%)

+Toluene 110°C

orWithout solvent

140°CR1 R1

R3NC

R1

O

R2

HN R3

Ackowledgements

Dr Laurence Grimaud Dr Laurent El Kaïm

ENSTA / UCPÉcole polytechnique

Dr Joëlle Prunet

Supervisors

New multicomponent reactions with phenols and isocyanides Julie Oble PhD. under the supervision of...

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Transcript of New multicomponent reactions with phenols and isocyanides Julie Oble PhD. under the supervision of...