Asymmetric Direct Amide Synthesis by Kinetic Amine Resolution: A Chiral Bifunctional Aminoboronic Acid Catalyzed Reaction between a Racemic Amine and an Achiral Carboxylic Acid

Abstract

The formation of amide bonds by direct reaction of amines with carboxylic acids by thermal [1, 2] or catalytic methods [2][3][4][5] is generally a high temperature process. There have been no reports to date of any reactions that involve asymmetric induction during direct amide formation, with the exception of an enzyme-catalyzed process.[6] Lower temperatures are often preferred for any reaction as it can reduce the amount of reagent, reactant, or thermal product degradation. A more important consideration is that asymmetric induction processes are usually more efficient at lower temperatures because small differences in energy between diasteroisomeric transition states are amplified; however, there are an increasing number of examples where this is not the case and improved asymmetric induction can be obtained at higher temperatures. [7] With these considerations in mind, we endeavored to develop a catalytic direct amide formation under mild conditions, though still well above room temperature. The current limiting temperature appears to be 85 8C, the temperature at which reactions can be carried out with bifunctional aminoboronic acid catalysts by using azeotropic water removal in fluorobenzene.[2] Although these reaction conditions are relatively mild compared to all other direct amide formation reactions with boron-derived catalyts, [4,5] they do not completely preclude the thermal direct amide formation with the more reactive carboxylic acid/amine combinations.[2] Though the prospect of developing asymmetric catalysts for amide formation may not look promising, [7] we report herein preliminary results that demonstrate asymmetric processes are possible under elevated temperatures with the development of a planar chiral ferrocenederived bifunctional aminoboronic acid catalyst.Our recent interests in the development of bifunctional aminoboronic acids as potential catalysts [8] led to the development of N,N-di-iso-propylbenzylaminoboronic acid type catalysts [2] such as commercially available 1 and planar chiral ferrocene analogue 2. We recently reported using a (À)-sparteine-directed metallation to provide 2 in 96 % ee.[9]Attempts to prepare other planar chiral aminoboronic acids such as 3 were hindered by the lack of direct access by asymmetric deprotonation methods of ferrocene benzimidazole precursors.[8d] However, this was circumvented by the synthesis of 3 from the known [10] (pS)-bromoferrocene aldehyde 4 (Scheme 1).Coupling aldehyde 4 with diamine 5[8c] in the presence of Oxone gave bromoferrocenylbenzimidazole 6 in 89 % yield and 99 % ee (determined by chiral HPLC methods, see the Supplementary Information), which compares with a literature value of 98 % ee for aldehyde 4.[10] Subsequent lithiumhalogen exchange of 6 provided enantioenriched catalyst 3 (60 % yield).A series of parallel experiments were conducted with catalysts 2 and 3, in which carboxylic acids 7 a-b were reacted with amines 8 a-c in refluxing fluorobenzene by using activated 3-molecular sieves in a Soxhlet (solvent drying system). Th...

Mechanistic Insights into Direct Amide Bond Formation Catalyzed by Boronic Acids: Halogens as Lewis Bases

“…[2] In fact, a study carried out in 1999 showed that about 25 % of known pharmaceuticals contained at least one amide bond. [5][6][7][8] In particular, Hall and co-workers found that using ortho-halophenyl boronic acids as catalysts, the coupling reactions can be carried out at room temperature. The significance and limitations of catalytic approaches to amide bond formation [4a] and to condensations in general [4b] have been recently discussed.…”

“…[5][6][7][8] In particular, Hall and co-workers found that using ortho-halophenyl boronic acids as catalysts, the coupling reactions can be carried out at room temperature. [5][6][7][8] In particular, Hall and co-workers found that using ortho-halophenyl boronic acids as catalysts, the coupling reactions can be carried out at room temperature.…”

“…The significance and limitations of catalytic approaches to amide bond formation [4a] and to condensations in general [4b] have been recently discussed.In this respect, recent studies from different research groups demonstrated that substoichiometric amounts of boronic acids can efficiently promote direct amide bond formation, provided that water is removed from the reaction mixture (Scheme 1). [5][6][7][8] In particular, Hall and co-workers found that using ortho-halophenyl boronic acids as catalysts, the coupling reactions can be carried out at room temperature. [8a] It was proposed that these reactions proceed via formation of a mono- [5a] or diacyloxyboronate species, [7d] which are activated acyl donors capable of reacting with the amine to form the amide product.…”

Catalytic Non‐Enzymatic Kinetic Resolution

“…reported the use of thiourea catalyst 74 combined with DMAP as cocatalyst which allowed various primary benzylic amines to be resolved with selectivity factors of up to 24 through benzoylation with benzoic anhydride (Scheme ) 208. In addition, the KR of primary amines based on N ‐acylation with a carboxylic acid such as benzoic acid was developed by Whiting et al 209. This reaction was catalyzed by a chiral bifunctional aminoboronic acid in fluorobenzene, leading to the corresponding amides in low to moderate enantioselectivities (≤41% ee ).…”

Catalytic Dehydrative Transformations Mediated by Moisture-Tolerant Zirconocene Triflate

“…The use of Lewis acids as catalysts for direct amidation is usually related to boron- and transition-metal-containing compounds. 40 41 42 43 44 45 Group IV metal complexes are well represented in the latter category, 46–50 and their hydrolytic instability typically requires the use of water scavenging techniques such as azeotropic distillation to prevent deactivation of the metal catalyst by the water formed in the dehydrative reaction. For protocols carried out at temperatures below ca.…”