N-Mesityl-Substituted Triazolium Salts

Egor Chirkin was born in Moscow, Russia, in 1986. He studied pharmacy at Peoples’ Friendship University in Moscow and medicinal chemistry at the Université d’Auvergne in Clermont-Ferrand, France. After a six-month research internship in the group of Professor Klaus T. Wanner at Ludwig Maximilians University of Munich, Germany, he started to pursue doctoral studies under the supervision of Dr. François-Hugues Porée at Université René Descartes in Paris. His research interests include the total synthesis of bioactive natural products and semi-synthetic modifications of their structure for medicinal applications.

Introduction

Metal-free organocatalysis employing N-heterocyclic carbenes (NHCs) has attracted great interest because of its use in the construction of intricate molecular architectures from simple starting materials under mild reaction conditions.[1] The catalytic pathway of NHCs mimics that of thiamine-dependent enzymatic processes and passes through discrete reactive species, such as acyl anions and enolate or homoenolate equivalents.[2] This enables the selective generation of a set of versatile electrophilic (acyl azoliums) and nucleophilic (enolates, homoenolates) intermediates and makes NHCs efficient catalysts in such various reactions as acylation, cycloaddition, β-borylation, and elimination.

N-Mesityl substituted imidazolium (cat. A) and triazolium (cat. B) salts were introduced by Bode and co-workers as stable NHC precursors.[3] The imidazolium derivative favors the homoenolate pathway, whereas the triazolium precursor promotes almost all NHC-catalyzed transformations, except for benzoin and Stetter reactions. Chiral pre-catalysts like C and its enantiomer are also commercially available.[4]

It should be noted that the N-substituent is of crucial importance; for example, an N-phenyl substituents might not provide any product, while the Bode (N-mesityl) or Rovis (N-pentafluorophenyl)[5] catalysts are highly catalytically active.

Figure 1 N-Mesityl-substituted imidazolium (cat. A) and triazolium (cat. B and C) carbene precursors. Chiral pre-catalyst C is commercially available (Mes = 1,3,5-trimethylphenyl).

Abstracts

(A) Bode catalysts were first found to be efficient for the esterification of aldehydes via the activated carboxylates generated from α,β-epoxyaldehydes, enals, and cyclopropanes. You et al. used a similar methodology for the ring expansion of formylcyclopropanes to afford 3,4-dihydro-α-pyrones.[6] Although in situ generated acyl azoliums did not react directly with amines, amidation was possible using a co-catalyst with additives such as imidazole, triazole, hydroxamic acid, HOBt, HOAt, or pentafluorophenol.[7a] This approach was successfully in the catalytic kinetic resolution of cyclic amines using the chiral hydroxamic acid 1 or 2 as co-catalyst.[7b] [c] Recent development includes the use of a polymer-supported histidine-bound NHC precursor in which the histidine moiety acts as co-catalyst.[7d]
(B) Ester enolate equivalents generated from α-halo- and α,β-unsaturated aldehydes underwent enantioselective oxa- and aza-Diels–Alder reactions.[1a] Strikingly, bench-stable bisulfite adducts of α-halo aldehydes could be directly used for this transformation. ­Kobayashi et al. reported the synthesis of 1β-methylcarbapenem antibiotic intermediates using vinylogous amides as dienes.[8]
(C) Although imidazolium-derived catalysts are generally superior to triazolium precursors in γ-lactonization and γ-lactamization reactions, triazolium salts also efficiently promote the annulation of highly reactive electrophiles via the homoenolate pathway.[9] In 2013, Chi et al. developed a selective β-protonation of homoenolate equivalents.[10] This enabled the synthesis of previously inaccessible enolate products by the reaction of enals with chalcones.
(D) In course of their work on kojic acids, Bode and co-workers discovered a new enantioselective azolium-catalyzed annulation of ynals via a Coates–Claisen rearrangement. The reaction pathway was different from enolate, homoenolates, and acyl anion activation.[11a] [b] Further, the substrate scope of the reaction was extended to enals. Mechanistical insights into this transformation led to the NHC-catalyzed aza-Claisen rearrangement of enals with vinylogous amides.[11c]
(E) The NHC-promoted addition of enals to imine electrophiles represents a particular reactivity. Ketimines derived from saccharine were found to be excellent electrophiles in annulation reactions proceeding via homoenolate and acyl azolium pathways.[12] In the latter case, the pre-catalyst C ensured the first annulation of α- and β,β′-substituted enals with a high enantio- and diastereoselectivity.
(F) Recently, Alexakis and co-workers reported the stereoselective annulation between α-cyano-1,4-diketones and ynals.[13] Starting from achiral material and in the presence of achiral pre-catalyst B, this transformation furnished a functionalized bicyclic scaffold possessing three contiguous stereogenic centers with a good diastereo­selectivity.

• References


For recent reviews see:
• 1a Chiang P.-C, Bode JW. TCI MAIL 2011; 149: 2
• 1b Grossmann A, Enders D. Angew. Chem. Int. Ed. 2012; 51: 314

Book chapters:
• 1c Mahatthananchai J, Bode JW In Contemporary Carbene Chemistry. Moss RA, Doyle MP. Wiley; Hoboken: 2013: 237
• 1d Mahatthananchai J, Bode JW In Asymmetric Synthesis: The Essentials II. Christmann M, Bräse S. Wiley; Weinheim: 2012: 67
• 1e Gondo CA, Bode JW In Science of Synthesis: Houben Weyl Methods of Molecular Transformations Vol. 13.33. List B. Georg Thieme Verlag; Stuttgart, New York: 2012: 199
• 1f Chiang P.-C, Bode JW In Science of Synthesis: Asymmetric Organocatalysis Vol. 1. List B. Georg Thieme Verlag; Stuttgart, New York: 2012: 639
• 2 For a review on the mechanism of NHC-catalyzed reactions, see: Mahatthananchai J, Bode JW. Acc. Chem. Res. 2014; 47: 696
• 3 Sohn SS, Bode JW. Org. Lett. 2005; 7: 3873
• 4 He M, Struble JR, Bode JW. J. Am. Chem. Soc. 2006; 128: 8418
• 5 Kerr MS, Rovis TJ. J. Am. Chem. Soc. 2004; 126: 8876
• 6 Li G.-Q, Dai L.-X, You S.-L. Org. Lett. 2009; 11: 1623
• 7a Chiang P.-C, Kim Y, Bode JW. Chem. Commun. 2009; 30: 4566
• 7b Hsieh S.-Y, Binanzer M, Kreituss I, Bode JW. Chem. Commun. 2012; 48: 8892
• 7c Binanzer M, Hsieh S.-Y, Bode JW. J. Am. Chem. Soc. 2011; 133: 19698
• 7d Gondo CA, Bode JW. Synlett 2013; 24: 1205
• 8 Kobayashi S, Kinoshita T, Uehara H, Sudo T, Ryu S. Org. Lett. 2009; 11: 3934
• 9 For the recent review on the homoenolates see: Nair V, Menon RS, Biju AT, Sinu CR, Paul RR, Jose A, Sreekumar V. Chem. Soc. Rev. 2011; 40: 5336
• 10 Fu Z, Sun H, Chen S, Tiwari B, Li G, Chi YR. Chem. Commun. 2013; 49: 261
• 11a Mahatthananchai J, Kaeobamrung J, Bode JW. ACS Catal. 2012; 2: 494
• 11b Kaeobamrung J, Mahatthananchai J, Zheng P, Bode JW. J. Am. Chem. Soc. 2010; 132: 8810
• 11c Wanner B, Mahatthananchai J, Bode JW. Org. Lett. 2011; 13: 5378
• 12a Rommel M, Fukuzumi T, Bode JW. J. Am. Chem. Soc. 2008; 130: 17266
• 12b Kravina AG, Mahatthananchai J, Bode JW. Angew. Chem. Int. Ed. 2012; 51: 9433
• 13 Romanov-Michailidis F, Besnard C, Alexakis A. Org. Lett. 2012; 14: 4906