Kinetic studies show that the direct formation of amides from amines and carboxylic acids without catalyst does occur under relatively low temperature conditions, but is highly substrate dependent. Boric and boronic acid-based catalysts improve the reaction, especially for less reactive acids, and initial results indicate that bifunctional catalysts show even greater potential.
Three new derivatives of N,N-di-isopropylbenzylamine-2-boronic acid have been prepared by directed metallation-borylation methods, to derive the 3-fluoro, 3-methoxy and 5-trifluoromethyl systems. The addition of an electron withdrawing group does increase the reactivity of such systems to act as improved direct amide formation catalysts under the most ambient conditions employed to date. In contrast, an electron donating group does result in considerable lowering of catalyst reactivity. DoE studies have been used to identify the ideal reaction conditions under which these types of catalysts should be used, typified by the parent system N,N-diisopropylbenzylamine-2-boronic acid. This shows best performance at a 5 mol% loading and under higher dilution conditions, which most likely reflect the drying capacity of the solvent.
(-)-Sparteine directed lithiation of N-Boc-pyrrolidine, alkylation with chloromethylboronate pinacol ester and acid-based deprotection provides homoboroproline HX salt in 94% ee, which is then an efficient enamine-type pyrrolidine catalyst in an asymmetric aldol reaction when neutralised and especially when esterified in situ with a tartrate ester, for example, providing 90% ee of the aldol adduct derived from acetone and p-nitrobenzaldehyde.
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...
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