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

2. Development of a new multicomponent reaction: The Ugi-Smiles coupling
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

3. Development of a new multicomponent reaction: The Ugi-Smiles coupling
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. Muticomponent reactions
Atom economy
Step economy
Simple procedure
4-CR +

5. The Ugi reaction I. Ugi:1930-2005
Review: A. Dömling, Chem. Rev. 2006, 106, 1

6. The Ugi reaction I. Ugi:1930-2005
Review: A. Dömling, Chem. Rev. 2006, 106, 1

7. The Ugi reaction Final irreversible Mumm rearrangement
I. Ugi:
Review: A. Dömling, Chem. Rev. 2006, 106, 1
Final irreversible Mumm rearrangement

8. Ugi reaction: variation of the acid component
Ugi (1960), Dömling (2000)
Ugi (1961)

9. Ugi reaction: variation of the acid component
With Nitrophenols

10. Ugi reaction: variation of the acid component
With Nitrophenols
Final irreversible Smiles rearrangement

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,

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
Spiro [6,4] intermediate too much tightened

16. Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
Spiro [6,4] intermediate too much tightened
Impossiblility to form a spiro [6,8] intermediate

17. Ugi-Smiles coupling with nitrophenols
Variation of the amine component
Lower nucleophilicity of aromatic amine
Spiro [6,4] intermediate too much tightened
Impossiblility to form a spiro [6,8] intermediate
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,

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
El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44,
Variation of the carbonyl component: with ketones

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,

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

27. Ugi-Smiles coupling with other electron deficient phenols
With the salicylic acid methyl ester
El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44,
With the para-hydroxybenzoic acid methyl ester

28. Ugi-Smiles coupling with other electron deficient phenols
With the salicylic acid methyl ester
El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44,
With the para-hydroxybenzoic acid methyl ester

29. 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,
Wang, H. Y.; Liao, Y. X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Synlett 2005, 8,

30. Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with 2-hydroxypyridine compounds
With the 2-hydroxypyridine

31. Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with 2-hydroxypyridine compounds
With the 2-hydroxypyridine
With the 2-hydroxy-3-nitropyridine and the 2-hydroxy-5-nitropyridine
El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,

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 90°C
El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,

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
With the 2-hydroxypyrimidine

35. Ugi-Smiles coupling with heterocyclic phenols
Ugi-Smiles coupling with hydroxypyrimidine compounds
With the 2-hydroxypyrimidine
With the 4-hydroxy-2,6-diméthylpyrimidine
El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,

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,

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,
Ugi-Smiles coupling with disubstitued 4-hydroxypyrimidines
El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,

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. Development of a new multicomponent reaction: The Ugi-Smiles coupling
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

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

45. Synthesis of quinoxalinone derivatives
Oble, J.; El Kaïm, L.; Gizzy, M.; Grimaud, L. Heterocycle 2007, 73,

46. Synthesis of quinoxalinone derivatives
Oble, J.; El Kaïm, L.; Gizzy, M.; Grimaud, L. Heterocycle 2007, 73,

47. Synthesis of quinoxalinone derivatives

48. Synthesis of quinoxalinone derivatives
Ugi-Smiles coupling with the 2-iodo-4-nitrophenol and the 2-iodo-6-chloro-4-nitrophenol

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,

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,

52. Ugi-Smiles post-condensations Ugi-Smiles / RCM strategy
Functionalization of phenol by halogenation, alkylation ...
Ugi-Smiles / RCM strategy

53. 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
MCR / RCM with the O-allyl phenol

55. Ugi-Smiles / RCM strategy
Ugi-Smiles coupling with the 2-allyl-4-nitrophenol
MCR / RCM with the O-allyl phenol
No bicyclic product could be isolated from the resulting complex mixture probably because of isomerizations and the allyl ether deprotection under these conditions

56. Ugi-Smiles / RCM strategy
MCR / RCM strategy with 4-hydroxypyrimidines substitued by an olefin
Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyrimidines

57. Ugi-Smiles / RCM strategy
MCR / RCM strategy with 4-hydroxypyrimidines substitued by an olefin
Synthesis of 5-allyl and 5-homoallyl-4-hydroxypyrimidines
Ugi-Smiles coupling

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

61. 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
Metathesis reaction on the adduct obtained with a 5-allyl-4-hydroxypyrimidine
El Kaïm, L.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72,

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
Metathesis reaction on the adduct obtained with a 5-allyl-4-hydroxypyrimidine
El Kaïm, L.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72,

63. 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,
Syntesis of pyrimido-azepines involving the Ugi-Smiles coupling followed by a ring closure metathesis

64. Conclusion on the applications of Ugi-Smiles coupling
Quinoxalinones
Pyrimido-azepines

65. Development of a new multicomponent reaction: The Ugi-Smiles coupling
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

66. Synthesis of ortho-quinone methides

67. Synthesis of ortho-quinone methides
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,

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
With aromatic aldehydes

70. Mannich reaction with phenols
Mannich reactions with electron deficient phenols
With the formaldehyde
With aromatic aldehydes

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,

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

76. Synthesis of aminobenzofurans
Ortho-quinone methides formation - [4+1] cycloaddition with isocyanides

77. Synthesis of aminobenzofurans
Ortho-quinone methides formation - [4+1] cycloaddition with isocyanides
El Kaïm, L.; Grimaud, L.; Oble, J. Org. Bio. Mol. 2006, 4,

78. Synthesis of aminobenzofurans
Ortho-quinone methides formation - [4+1] cycloaddition with isocyanides
El Kaïm, L.; Grimaud, L.; Oble, J. Org. Bio. Mol. 2006, 4,

79. 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

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