Pr

1
New multicomponent reactions with phenols and
isocyanides
Julie Oble
PhD. under the supervision of Dr. Laurence
Grimaud and Dr. Laurent El Kaïm
2
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 41
  cycloaddition with isocyanides

3
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 41
  cycloaddition with isocyanides

4
Muticomponent reactions

• Atom economy
• Step economy
• Simple procedure

4-CR

5
The Ugi reaction
I. Ugi1930-2005
Review A. Dömling, Chem. Rev. 2006, 106, 1
6
The Ugi reaction
I. Ugi1930-2005
Review A. Dömling, Chem. Rev. 2006, 106, 1
7
The Ugi reaction
I. Ugi1930-2005
Review A. Dömling, Chem. Rev. 2006, 106, 1
8
Ugi reaction variation of the acid component
9
Ugi reaction variation of the acid component
With Nitrophenols
10
Ugi reaction variation of the acid component
With Nitrophenols
11
New aryl transfert in Ugi-type coupling
12
Ugi-Smiles coupling with nitrophenols
First results
13
Ugi-Smiles coupling with nitrophenols
Variation of the amine component
El Kaïm, L. Grimaud, L. Oble, J. Angew. Chem.,
Int. Ed. 2005, 44, 7165-7169.
14
Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
15
Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
16
Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
Spiro 6,4 intermediate too much tightened
17
Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
Spiro 6,4 intermediate too much tightened

• Importance of the Smiles 5-membered transition
  state

18
Ugi-Smiles coupling with nitrophenols
Variation of the isocyanide component
El Kaïm, L. Grimaud, L. Oble, J. Angew. Chem.,
Int. Ed. 2005, 44, 7165-7169.
19
Ugi-Smiles coupling with nitrophenols
Variation of the carbonyl component with
aromatic aldehydes
20
Ugi-Smiles coupling with nitrophenols
Variation of the carbonyl component with
aromatic aldehydes
21
Ugi-Smiles coupling with nitrophenols
Variation of the nitrophenol component

• Dependence to steric hindrance ?

El Kaïm, L. Gizolme, M. Grimaud, L. Oble,
J. J. Org. Chem. 2007, 72, 4169-4180.
22
Ugi-Smiles coupling with nitrophenols
Variation of the nitrophenol component
23
Ugi-Smiles coupling with nitrophenols
Variation of the nitrophenol component
24
Ugi-Smiles coupling with nitrophenols
Variation of the nitrophenol component
25
Ugi-Smiles coupling with other electron deficient
phenols
With the salicylic acid methyl ester
26
Ugi-Smiles coupling with other electron deficient
phenols
With the salicylic acid methyl ester
27
Ugi-Smiles coupling with other electron deficient
phenols
With the salicylic acid methyl ester
28
Ugi-Smiles coupling with other electron deficient
phenols
With the salicylic acid methyl ester
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Ugi-Smiles coupling with heterocyclic phenols
Smiles rearrangement of heterocyclic systems
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.
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Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with 2-hydroxypyridine
compounds
With the 2-hydroxypyridine
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Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with 2-hydroxypyridine
compounds
With the 2-hydroxypyridine
32
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with 2-hydroxypyridine
compounds
With the 2-hydroxy-5-chloropyridine and the
2-hydroxy-5-trifluorométhylpyridine

• Require higher temperature use of toluene at
  90C

El Kaïm, L. Gizolme, M. Grimaud, L. Oble, J.
Org. Lett. 2006, 8, 4019-4021.
33
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine
compounds
34
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine
compounds
35
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine
compounds
36
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine
compounds
Preparation of 4-hydroxypyrimidines
Hullar, T. L. French, W. C. J. Chem. Med. 1969,
12, 424-426.
37
Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine
compounds
Preparation of 4-hydroxypyrimidines
Hullar, T. L. French, W. C. J. Chem. Med. 1969,
12, 424-426.
38
The new Ugi-Smiles coupling

• 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

39
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 41
  cycloaddition with isocyanides

40
Muticomponent reactions
Post-condensations
4-CR


41
Ugi-Smiles post-condensations
42
Ugi-Smiles post-condensations
43
Ugi-Smiles post-condensations
Functionalization of phenol by halogenation,
alkylation ...
44
Synthesis of quinoxalinone derivatives
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Synthesis of quinoxalinone derivatives
Oble, J. El Kaïm, L. Gizzy, M. Grimaud, L.
Heterocycle 2007, 73, 503-517.
46
Synthesis of quinoxalinone derivatives
Oble, J. El Kaïm, L. Gizzy, M. Grimaud, L.
Heterocycle 2007, 73, 503-517.
47
Synthesis of quinoxalinone derivatives
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Synthesis of quinoxalinone derivatives
49
Synthesis of quinoxalinone derivatives
N-arylation of amides under copper catalysis
50
Synthesis of quinoxalinone derivatives
N-arylation of amides under copper catalysis
Oble, J. El Kaïm, L. Gizzy, M. Grimaud, L.
Heterocycle 2007, 73, 503-517.
51
Synthesis of quinoxalinone derivatives
N-arylation of amides under copper catalysis

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

Oble, J. El Kaïm, L. Gizzy, M. Grimaud, L.
Heterocycle 2007, 73, 503-517.
52
Ugi-Smiles post-condensations
Functionalization of phenol by halogenation,
alkylation ...
Ugi-Smiles / RCM strategy
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Ugi-Smiles / RCM strategy
Ugi-Smiles coupling with the 2-allyl-4-nitrophenol

54
Ugi-Smiles / RCM strategy
Ugi-Smiles coupling with the 2-allyl-4-nitrophenol

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Ugi-Smiles / RCM strategy
Ugi-Smiles coupling with the 2-allyl-4-nitrophenol

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Ugi-Smiles / RCM strategy
MCR / RCM strategy with 4-hydroxypyrimidines
substitued by an olefin
Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyri
midines
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Ugi-Smiles / RCM strategy
MCR / RCM strategy with 4-hydroxypyrimidines
substitued by an olefin
Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyri
midines
58
Ugi-Smiles / RCM strategy
MCR / RCM with 4-hydroxypyrimidines substitued by
an olefin
Metathesis reaction on the adduct obtained with
the 5-homoallyl-4-hydroxypyrimidine
59
Ugi-Smiles / RCM strategy
MCR / RCM with 4-hydroxypyrimidines substitued by
an olefin
Metathesis reaction on the adduct obtained with
the 5-homoallyl-4-hydroxypyrimidine
60
Ugi-Smiles / RCM strategy
MCR / RCM with 4-hydroxypyrimidines substitued by
an olefin
Metathesis reaction on the adduct obtained with
the 5-homoallyl-4-hydroxypyrimidine
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Ugi-Smiles / RCM strategy
MCR / RCM with 4-hydroxypyrimidines substitued by
an olefin
Metathesis reaction on the adduct obtained with
the 5-homoallyl-4-hydroxypyrimidine
62
Ugi-Smiles / RCM strategy
MCR / RCM with 4-hydroxypyrimidines substitued by
an olefin
Metathesis reaction on the adduct obtained with
the 5-homoallyl-4-hydroxypyrimidine
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Ugi-Smiles / RCM strategy
MCR / RCM / Isomerization
Metathesis reaction on various allyl
4-aminopyrimidines
El Kaïm, L. Grimaud, L. Oble, J. J. Org. Chem.
2007, 72, 5835-5838.

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

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Conclusion on the applications of Ugi-Smiles
coupling
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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 41
  cycloaddition with isocyanides

66
Synthesis of ortho-quinone methides
67
Synthesis of ortho-quinone methides
68
Mannich reaction with phenols
Mannich reactions with electron deficient phenols
With the formaldehyde
69
Mannich reaction with phenols
Mannich reactions with electron deficient phenols
With the formaldehyde
70
Mannich reaction with phenols
Mannich reactions with electron deficient phenols
With the formaldehyde
71
Mannich reaction with phenols
Mannich reactions with electron enriched phenols
72
Mannich reaction with phenols
Mannich reactions with electron enriched phenols
73
Ortho-quinone methides formation and the trapping
by nucleophiles
Mannich reaction alkylation elimination
nucleophile addition sequence
74
Ortho-quinone methides formation and the trapping
by nucleophiles
Mannich reaction alkylation elimination
nucleophile addition sequence
El Kaïm, L. Grimaud, L. Oble, J. Org. Bio. Mol.
2006, 4, 3410-3413.
75
Ortho-quinone methides formation and the trapping
by nucleophiles
Mannich reaction alkylation elimination
nucleophile addition sequence
El Kaïm, L. Grimaud, L. Oble, J. Org. Bio. Mol.
2006, 4, 3410-3413.

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

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Synthesis of aminobenzofurans
Ortho-quinone methides formation - 41
cycloaddition with isocyanides
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Synthesis of aminobenzofurans
Ortho-quinone methides formation - 41
cycloaddition with isocyanides
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Synthesis of aminobenzofurans
Ortho-quinone methides formation - 41
cycloaddition with isocyanides
79
Conclusion of the sequence Mannich reaction
41 cycloaddition

• New general efficient three component coupling
  of phenols with aldehydes and various
  nucleophiles
• Application of this process to 41
  cycloaddition of isocyanides with transient
  o-quinone methide synthesis of aminobenzofurans

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Ackowledgements
Supervisors
Dr Laurence Grimaud Dr Laurent El Kaïm
ENSTA / UCP École polytechnique
Dr Joëlle Prunet