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

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Presentation on theme: "New multicomponent reactions with phenols and isocyanides Julie Oble PhD. under the supervision of Dr. Laurence Grimaud and Dr. Laurent El Kaïm."— Presentation transcript:

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 [4+1] 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 [4+1] cycloaddition with isocyanides

4 4-CR -Atom economy -Step economy -Simple procedure + Muticomponent reactions

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

6 The Ugi reaction I. Ugi: 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

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

9 With Nitrophenols Ugi reaction: variation of the acid component

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

11 New aryl transfert in Ugi-type coupling

12 Ugi-Smiles coupling with nitrophenols First results

13 El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, Variation of the amine component Ugi-Smiles coupling with nitrophenols

14 Lower nucleophilicity of aromatic amine Ugi-Smiles coupling with nitrophenols Variation of the amine component

15 Lower nucleophilicity of aromatic amine Spiro [6,4] intermediate too much tightened Ugi-Smiles coupling with nitrophenols Variation of the amine component

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

17  Importance of the Smiles 5-membered transition state Spiro [6,4] intermediate too much tightened Impossiblility to form a spiro [6,8] intermediate Ugi-Smiles coupling with nitrophenols Variation of the amine component Lower nucleophilicity of aromatic amine

18 El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, Ugi-Smiles coupling with nitrophenols Variation of the isocyanide component

19 Ugi-Smiles coupling with nitrophenols Variation of the carbonyl component: with aromatic aldehydes

20 El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, Variation of the carbonyl component: with ketones Ugi-Smiles coupling with nitrophenols Variation of the carbonyl component: with aromatic aldehydes

21 El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72,  Dependence to steric hindrance ? Ugi-Smiles coupling with nitrophenols Variation of the nitrophenol component

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

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

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

29 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, Ugi-Smiles coupling with heterocyclic phenols

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

31 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, Ugi-Smiles coupling with heterocyclic phenols

32 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, Ugi-Smiles coupling with heterocyclic phenols Ugi-Smiles coupling with 2-hydroxypyridine compounds

33 Ugi-Smiles coupling with heterocyclic phenols Ugi-Smiles coupling with hydroxypyrimidine compounds

34 With the 2-hydroxypyrimidine Ugi-Smiles coupling with heterocyclic phenols Ugi-Smiles coupling with hydroxypyrimidine compounds

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

36 Preparation of 4-hydroxypyrimidines Hullar, T. L.; French, W. C. J. Chem. Med. 1969, 12, Ugi-Smiles coupling with heterocyclic phenols Ugi-Smiles coupling with hydroxypyrimidine compounds

37 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, Ugi-Smiles coupling with heterocyclic phenols Ugi-Smiles coupling with hydroxypyrimidine compounds

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 [4+1] cycloaddition with isocyanides

40 + Post-condensations 4-CR + Muticomponent reactions

41 Ugi-Smiles post-condensations

42

43 Functionalization of phenol by halogenation, alkylation... Ugi-Smiles post-condensations

44 Synthesis of quinoxalinone derivatives

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

49 N-arylation of amides under copper catalysis Synthesis of quinoxalinone derivatives

50 N-arylation of amides under copper catalysis Synthesis of quinoxalinone derivatives Oble, J.; El Kaïm, L.; Gizzy, M.; Grimaud, L. Heterocycle 2007, 73,

51 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, Synthesis of quinoxalinone derivatives

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

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

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

58 MCR / RCM with 4-hydroxypyrimidines substitued by an olefin Metathesis reaction on the adduct obtained with the 5-homoallyl-4-hydroxypyrimidine Ugi-Smiles / RCM strategy

59 MCR / RCM with 4-hydroxypyrimidines substitued by an olefin Metathesis reaction on the adduct obtained with the 5-homoallyl-4-hydroxypyrimidine Ugi-Smiles / RCM strategy

60 MCR / RCM with 4-hydroxypyrimidines substitued by an olefin Metathesis reaction on the adduct obtained with the 5-homoallyl-4-hydroxypyrimidine Ugi-Smiles / RCM strategy

61 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, Ugi-Smiles / RCM strategy

62 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, Ugi-Smiles / RCM strategy

63 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 Ugi-Smiles / RCM strategy

64 Conclusion on the applications of Ugi-Smiles coupling QuinoxalinonesPyrimido-azepines

65 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 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 El Kaïm, L.; Grimaud, L.; Oble, J. Org. Bio. Mol. 2006, 4, Ortho-quinone methides formation and the trapping by nucleophiles Mannich reaction – alkylation – elimination – nucleophile addition sequence

75 New efficient ortho-quinone methides formation under the alkylative elimination of the piperazine from Mannich adducts obtained with the N-benzylpiperazine El Kaïm, L.; Grimaud, L.; Oble, J. Org. Bio. Mol. 2006, 4, Ortho-quinone methides formation and the trapping by nucleophiles Mannich reaction – alkylation – elimination – nucleophile addition sequence

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

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

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

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


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