Amide Synthesis from Alcohols and Amines Catalyzed by Ruthenium N‐Heterocyclic Carbene Complexes

Abstract

The direct synthesis of amides from alcohols and amines is described with the simultaneous liberation of dihydrogen. The reaction does not require any stoichiometric additives or hydrogen acceptors and is catalyzed by ruthenium N-heterocyclic carbene complexes. Three different catalyst systems are presented that all employ 1,3-diisopropylimidazol-2-ylidene (IiPr) as the carbene ligand. In addition, potassium tert-butoxide and a tricycloalkylphosphine are required for the amidation to proceed. In the first system, the active catalyst is generated in situ from [RuCl(2)(cod)] (cod=1,5-cyclooctadiene), 1,3-diisopropylimidazolium chloride, tricyclopentylphosphonium tetrafluoroborate, and base. The second system uses the complex [RuCl(2)(IiPr)(p-cymene)] together with tricyclohexylphosphine and base, whereas the third system employs the Hoveyda-Grubbs 1st-generation metathesis catalyst together with 1,3-diisopropylimidazolium chloride and base. A range of different primary alcohols and amines have been coupled in the presence of the three catalyst systems to afford the corresponding amides in moderate to excellent yields. The best results are obtained with sterically unhindered alcohols and amines. The three catalyst systems do not show any significant differences in reactivity, which indicates that the same catalytically active species is operating. The reaction is believed to proceed by initial dehydrogenation of the primary alcohol to the aldehyde that stays coordinated to ruthenium and is not released into the reaction mixture. Addition of the amine forms the hemiaminal that undergoes dehydrogenation to the amide. A catalytic cycle is proposed with the {(IiPr)Ru(II)} species as the catalytically active components.

Atom-economic dehydrogenative amide synthesis via ruthenium catalysis

“…In addition, the reaction could be performed under neutral conditions without any additive. [25][26][27][28][29][30][31][32][33][34][35][36][37][38] Hong and co-workers reported Ru-NHC complexes 4a-4e for this reaction (as shown in Fig. 3b).…”

Ruthenium-Catalyzed Amide-Bond Formation

“…Ruthenium complexes, and especially NHC-compounds, have been the most widely studied [94], albeit highly efficient processes promoted by rhodium or silver have also been described [112,113]. In regard to ruthenium, both in-situ-generated catalytic systems (Table 1) [114][115][116][117][118][119][120][121][122][123] as well as well-defined catalysts 38-44 ( Figure 10) [124][125][126][127][128][129][130][131] have been reported. In most of the cases, high metal loadings (usually 5 mol%) and an excess of a strong base (10-40 mol% of NaH or KO-t-Bu) were required to achieve satisfactory yields in the amides.…”

“…As a consequence, substrates like anilines usually lead to low or moderate conversions, even at elevated temperatures or after long reaction periods, and large amounts of the corresponding esters by-products are formed. In this context, the ruthenium catalysts have conduced, in general, to quite disappointing results [114,115,117,124]. In fact, only gold nanoparticles have proven to be useful with this type of amines [132].…”

An efficient N-heterocyclic carbene based ruthenium-catalyst: Application towards the synthesis of esters and amides

“…Most recently, the Hong- [20][21][22], the Madsen- [23][24][25], and several other groups [26], have developed phosphine-free in situ generated NHC based ruthenium catalysts. The active catalyst 2 was prepared either from imidazolium salts, a base, pyridine and [Ru(p-cymene)Cl 2 ] 2 [27] or by transmetalation of a silver carbene complex with [Ru(p-cymene)Cl 2 ] 2 [20].…”