New Methods of Imidazole Functionalization - From Imidazole to Marine Alkaloids

Hongwang Du; Yong He; Rasapalli Sivappa; Carl J. Lovely

doi:10.1055/s-2006-939720

ACCOUNT

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;

Abstract

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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

Full Text

References

References and Notes

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We have generally found that these sulfonyl urea derivatives are very convenient to work with many of the substrates can be assembled in good yields and with minimal purification (no chromatography), thus much of chemistry is done with this protecting group. There are some drawbacks with its use, however. It has been found that the DMAS group can migrate to the sterically least encumbered nitrogen in several derivatives during prolonged heating during Diels-Alder reaction. Although this can be circumvented by using less labile groups, the construction of precursors can be complicated with S_N2′-type processes particularly in the Bn-series (see Scheme 39 and Table 10). For related observations, see:

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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.

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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.

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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.

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 S_N2 pathway.

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

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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.

The free alcohols were poor substrates due to benzylic oxidation.

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.

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.

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

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

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Attempts to employ a direct Curtius rearrangement using diphenylphosphoryl azide and the carboxylic acid were unsuccessful in our hands, although it has been employed previously in a few limited cases with imidazoles; see:

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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.

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<A NAME="RA39505ST-91D">91d</A> Pandit UK. Overkleft HS. Borer BC. Bieräugel H. Eur. J. Org. Chem. 1999, 959

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<A NAME="RA39505ST-92A">92a</A> D’Ambrosio M. Guerriero A. Debitus C. Ribes O. Pusset J. Leroy S. Pietra F. J. Chem. Soc., Chem. Commun. 1993, 1305

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<A NAME="RA39505ST-92B">92b</A> Anderson GT. Chase CE. Koh Y. Stien D. Weinreb SM. J. Org. Chem. 1998, 63: 7594

<A NAME="RA39505ST-92C">92c</A> Stien D. Anderson GT. Chase CE. Koh Y. Weinreb SM. J. Am. Chem. Soc. 1999, 121: 9574

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<A NAME="RA39505ST-92J">92j</A> Davis FA. Deng J. Org. Lett. 2005, 7: 621

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<A NAME="RA39505ST-97A">97a</A> Gracias V. Gasiecki AF. Djuric SW. Org. Lett. 2005, 7: 3183

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<A NAME="RA39505ST-99A">99a</A> Tsuji J. Palladium Reagents and Catalysts Wiley; New York: 1996. Chap. 4. p.290-440

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<A NAME="RA39505ST-99C">99c</A> Handbook of Organopalladium Chemistry for Organic Synthesis Negishi E.-I. Wiley-Interscience; New York: 2002.

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

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