A General and Highly Selective Palladium‐Catalyzed Hydroamidation of 1,3‐Diynes

Abstract

Ac hemo-, regio-, and stereoselective mono-hydroamidation of (un)symmetrical 1,3-diynes is described. Keyfor the success of this novel transformation is the utilization of an advanced palladium catalyst system with the specific ligand Neolephos.T he synthetic value of this general approach to synthetically useful a-alkynyl-a, b-unsaturated amides is showcased by diversification of several structurally complex molecules and marketed drugs.C ontrol experiments and density-functional theory (M06L-SMD) computations also suggest the crucial role of the substrate in controlling the regioselectivity of unsymmetrical 1,3-diynes.

Palladium-Catalyzed Domino Aminocarbonylation of Alkynols: Direct and Selective Synthesis of Itaconimides

“…In general, for palladium-catalyzed coupling processes, the choice of ligand is crucial and allows for controlling the selectivity and activity. − Thus, to achieve the desired target product 3aa , we investigated the effect of different bidentate and monodentate phosphines (2 or 4 mol %, respectively) for the carbonylation of 1a in the presence of 1 mol % Pd­(MeCN) 2 Cl 2 , in dichloromethane at 40 bar CO, 120 °C. Using the classic ligand Xantphos L1 , itaconimide 3aa was obtained in only 7% yield; nevertheless, this demonstrated the feasibility of a double carbonylation process.…”

A General and Highly Selective Palladium‐Catalyzed Hydroamidation of 1,3‐Diynes

“…Specifically,the reactions of arylamines bearing Me,F ,Cl, Ac, CN,CO 2 Et, MeO and MeS substituents proceeded smoothly, providing the corresponding products 3ab-3ae, 3ah-3ak in good isolated yields. [19] Notably,b romine-and even iodinesubstituted arylamines,w hich are known to be sensitive to palladium catalysis,a lso worked well and afforded the corresponding products (3af-3ag). Thep osition of substituents on the phenyl ring has no influence on the reaction outcome.Hence,arylamines 2n-2p afforded 3an-3ap in 81-89 %y ields.I nterestingly,t he 2-aminophenol (2q)a nd 2aminobenzamide (2r), which contain two nucleophilic positions,also reacted selectively to give the amides 3aq and 3ar in 84 %a nd 90 %y ield, respectively.F urthermore,t he heterocycle-substituted amine 2s proved to be av iable coupling partner and gave 3as in 73 %yield.…”

Catalytic Hydrofunctionalization Reactions of 1,3-Diynes

“…In the first one, published by Huang and colleagues in 2018, a small family of symmetrically substituted aromatic 1,3-diynes was smoothly converted into the primary amides 36 under 20 atm CO pressure, employing NH 4 Cl as the amine source (Scheme 21) [46]. In the second one, Beller and colleagues reported the hydroaminocarbonylation of both symmetrically and unsymmetrically substituted 1,3-diynes with primary and secondary amines and CO, employing a catalytic system composed of the palladium(II) complex [Pd(acac) 2 ] (acac = acetylacetonate), the diphosphine ligand Neolephos, and triflic acid (Scheme 22) [47]. The reactions proceeded in this case under milder conditions (toluene/40 • C), with mechanistic studies revealing that the pyridyl groups of Neolephos act as proton shuttles, facilitating the nucleophilic attack of the amine on the corresponding acyl-palladium intermediates.…”

“…In all the cases, the final amide products 37 were obtained with complete stereocontrol on the C=C bond formed. As illustrated in Figure 5, in which different amides containing biologically or pharmaceutically relevant skeletons are shown, the molecular complexity achieved by applying the Beller's hydroaminocarbonylation reaction was very high [47]. It should also be noted at this point that, by combining Neolephos with Pd(OAc) 2 and (+)-10-camphorsulfonic acid (CSA), the group of Beller was also able to develop a wide-scope procedure for the monoalkoxycarbonylation of 1,3-diynes, allowing the access to functionalized 1,3-enynes of type 38 in good yields and with excellent chemoselectivity (Scheme 23) [48].…”