Copper/Titanium Catalysis Forms Fully Substituted Carbon Centers from the Direct Coupling of Acyclic Ketones, Amines, and Alkynes

Abstract

A wide range of natural products and bioactive compounds contain fully substituted carbon centers. [1] To circumvent the difficulty of creating these hindered CÀN bonds in one step, compounds are commonly synthesized and rearrangement induced. [2] A catalytic system capable of overcoming the barrier to the condensation of a ketone and an amine to a ketimine, while leaving a nucleophile able to attack would lead to the direct formation of tetrasubstituted carbon atoms bearing amines. [3] In contrast to the wide array of threecomponent couplings (3CC) of aldehydes by the in situ formation of aldimines, reactions of ketones as electrophiles require an extra step that costs time, energy, and chemicals to produce and purify the ketimine starting material. [4] Dozens of enantioselective additions to ketimines have appeared without examples of the corresponding 3CC in either asymmetric or racemic form. [1] This situation suggests that the direct 3CC of ketones is more difficult to achieve than the asymmetric addition of nucleophiles to preformed ketimines.The nucleophilic attack on imines by terminal alkynes has been widely studied owing to the intrinsic biological activity and utility of the resulting propargylamines as synthetic building blocks. [5] Aldehyde-amine-alkyne couplings (A 3 ) abound, [6][7][8] but as ketones are 750-times less-active than aldehydes as electrophiles, [9] the corresponding KA 2 procedure for unactivated ketones has not been reported. The three catalytic methods developed for cyclohexanones [10][11][12] rely on the fact that they undergo nucleophilic attack 300-times faster than acyclic ketones. [13] Cyclohexanone is a special case of near aldehyde-like reactivity, [14] and its corresponding ketimines [15] readily react to release torsional strain. [16] Until Van der Eycken and co-workers described their solvent-free KA 2 methodology, [10] the catalytic incorporation of any ketone was an isolated, low-yielding event. [17] By applying microwave conditions in the presence of 20 mol % CuI, cyclohexanones and benzylamines couple with phenylacetylenes in 31-82 % yield. [10] Employing 4 mol % AuBr 3 , Ji and co-workers focused on cyclic amines and phenylacetylenes. [11] With 1 equivalent morpholine and 1.5 equivalents each of 2-pentanone and phenylacetylene, this Au III system produces what they term a quaternary propargylamine in 54 % yield.

Identifying a Highly Active Copper Catalyst for KA2 Reaction of Aromatic Ketones

“…However, in contrast, such three‐component couplings involving ketones, amines and alkynes (KA 2 reaction) are far from being well developed because of the extremely low reactivity observed for ketones . Recently, Larsen and co‐workers utilized CuCl 2 and Ti(OEt) 4 as the catalyst to address the problem for the reaction with alkyl ketones . However, such reactions with aromatic ketones remain a fundamental challenge .…”

Zinc(II)‐Catalyzed Synthesis of Propargylamines by Coupling Aldimines and Ketimines with Alkynes

“…As a preliminary experiment, the reaction of butanone, butylamine, and phenylacetylene was carried out in the presence of 50 mol-% of Ti(OEt 4 ) and 5 mol-% of CuCl 2 in toluene at 110°C for 24 h, according to recent literature. [15] No reaction was observed, and, thus, the catalytic system was changed to 15 mol-% Zn(OTf ) 2 , which also afforded no product besides some trace amounts of the imine and the corresponding tertiary propargylic alcohol. [28] When benzylamine was treated with butanone and phenylacetylene in the presence of 20 mol-% of Zn(OTf ) 2 and 4 Å molecular sieves (MS) or Ti(OiPr) 4 as a drying agent, we were gratified to observe a 15-20 % conversion into the corresponding propargylic amine.…”

“…[13,15] The introduction of electron-withdrawing Scheme 1. Previous approaches for the preparation of tetrasubstituted propargylamines (MW = microwave; OTf = trifluoromethanesulfonate).…”

CuII@PAA/PVC mesoporous fibers: A hybrid wedding as a high‐performance versatile heterogeneous catalyst for A3, KA2, and decarboxylative A3 reactions

“…Examples of homogeneous catalysts which have been employed include CuI, CuBr, Cu (OTf) 2 , AuBr 3 , CuCl 2 /Ti(OEt) 4. The representative heterogeneous catalysts covered Amberlyst A‐21 supported CuI, CuNPs@ZnO–PTh, CuO/Fe 2 O 3 NPs, nano Cu 2 O–ZnO . No matter A 3 or KA 2 couplings, a terminal alkyne is a common reactant partner which occasionally produces the Glaser‐Hay homocoupling by‐product in the presence of some kind of metal catalytic systems resulting in decreasing the yield of the propargylamine product .…”