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Synlett 2006(7): 0965-0992  
DOI: 10.1055/s-2006-939720
ACCOUNT
© Georg Thieme Verlag Stuttgart · New York

New Methods of Imidazole Functionalization - From Imidazole to Marine Alkaloids

Hongwang Du, Yong He, Rasapalli Sivappa, Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA
Fax: +1(817)2723808; e-Mail: lovely@uta.edu;
Further Information

Publication History

Received 5 October 2005
Publication Date:
24 April 2006 (online)

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Abstract

The pyrrole-imidazole family of marine alkaloids, the so-called oroidin natural products, exhibits an impressive diversity of structural motifs. The majority of these natural products contain one or more imidazole moieties intricately embedded within a polycyclic framework and thus present significant challenges to extant synthetic methods. Our approach to this problem has centered on the development of methods for the elaboration of simple imidazoles. This Account describes the results of these efforts leading to the development of a variety of methods, including cycloadditions, oxidative and transition-metal-catalyzed reactions.

  • 1 Diels-Alder Chemistry of Vinylimidazoles

  • 1.1 Substitution of 4(5)-Iodoimidazole

  • 1.2 Selective Deiodination of 4,5-Diiodoimidazoles

  • 1.3 Isomerization of 4/5-Iodoimidazoles

  • 2 Substituent Effects

  • 2.1 Vinyl Substituents

  • 2.2 Substituents at the 2-Position

  • 3 Intramolecular Variants

  • 4 Fused to Spiro Systems

  • 4.1 Regiochemistry and Mechanism

  • 5 Ring-Closing Metathesis

  • 6 Pd-π-Allyl Chemistry of Imidazole Derivatives

  • 7 Summary

Key words

cycloaddition - cross-coupling - heterocycles - oxidation - rearrangement

16

This biosynthetic proposal was suggested by a reviewer of ref. 1a.

28

These authors did not report the isolation (or observation) of the initial adduct.

29

Since the enamine is effectively locked in an s-trans conformation it cannot react further at least as a diene in a Diels-Alder reaction.

41

The bis-Diels-Alder adduct was not obtained from reactions involving the N-methyl derivative. We do not have an unequivocal explanation for this outcome; however, it may be related to differences in the size of the N-substituent (methyl vs. benzyl). With the smaller methyl group, reduced steric compression is experienced on aromatizing the enamine adduct 62f and thus this occurs faster to provide either 54f or 55f before oxidation can occur.

42

The bis-Diels-Alder adduct was not obtained in the presence of a radical scavenger (BHT).

49

We knew by the time that this chemistry was being investigated that reactions with electrophiles occurred predominantly from the β-face, and thus the chloro moiety would be endo, precisely that required for palau’amine.

52

In addition to the desired methyl ester a small quantity (ca. 12%) of a diimidazolyl ketone was obtained.

56

By the time that these studies were underway, we knew already that direct rearrangement of the enamine was not feasible, but the aromatic Diels-Alder adducts could be rearranged.

58

The initial use of trityl moiety as a protecting group was largely dictated by the ready accessibility of the corresponding protected urocanic acid derivative, where the preparation of 4-isomer was described in the literature. When we commenced this aspect of the study, effective methods for the selective preparation of the 4-isomer were lacking. Further, we expected from the preliminary intermolecular results that these substrates would be viable.

64

In these cases inseparable mixtures of the two cycloadducts were obtained. Reduction of the lactam to the amine was accomplished with LiAlH4 leading to a single product, indicating the regiochemical relationship between the two cycloadducts. He, Y.; Pasupathy, K.; Lovely C. J. unpublished results.

65

Attempted reductive cleavage of the amide to the corresponding amino alcohol was compromised by cleavage of the DMAS group under the forcing conditions required.

67

In fact given the results obtained subsequently with the benzhydryl analogue, it is quite reasonable to assume that both isomers are formed, but that the significant decomposition precluded isolation of the minor isomer.

70

We have found that the magnitude of this coupling constant (J = 10-12 Hz) falls into a very narrow range for both the lactams and oxazine systems prepared in the course of this study and is indicative of a trans ring fusion.

71

While it is conceivable that some of the endo-chloride was formed it would not have been sufficient to account for the diastereomeric ratios of the ethers observed via a purely SN2 pathway.

72

The Romo group has encountered a similar stereochemical problem in their Diels-Alder/rearrangment approach to palau’amine. See ref. 20.

76

This substrate was chosen for purely pragmatic reasons and not by design. As a result of deconvoluting events related to the reaction of 60e with NPM described in Scheme [15] , we had accumulated a large supply of 64e.

77

The free alcohols were poor substrates due to benzylic oxidation.

78

At least to date, it has been difficult to incorporate other classes of protecting groups on this hydroxyl group, although the silylation can be accomplished easily.

79

During the course of this investigation we have prepared a large number of spiro-fused imidazolones and have not observed any significant differences in the spectroscopic properties as a function of stereochemistry.

80

Tetrahydrobenzimidazole can be readily obtained through the partial reduction of benzimidazole.

81

This assignment is based on the chemical shift of the imidazolone carbonyl in the 13C NMR spectrum which falls in a very narrow range (δC=O = 180.1-185.8 ppm) and is substantially different from the 4-isomer of 189 (δC=O = 197.4 ppm).

87

Initial attempts to trigger this rearrangement using conditions that generate DMDO catalytically have not been successful. This is unfortunate since the use of the more reactive fluorinated variants of DMDO and asymmetric variants are more cost effective when conducted with catalytic loadings of the ketone.

89

Rasapalli, S.; Devine, T.; Koswatta, P.; Lovely, C. J. unpublished results.

101

Krishnamoorthy, P.; Sivappa, R.; Lovely, C. J. Tetrahedron, submitted.