Silica Gel as a Promoter of Sequential Aza‐Michael/Michael Reactions of Amines and Propiolic Esters: Solvent‐ and Metal‐Free Synthesis of Polyfunctionalized Conjugated Dienes

Abstract

We present an efficient, simple, metal- and solvent-free silica-gel-promoted synthesis of functionalized conjugated dienes by sequential aza-Michael/Michael reactions by starting from commercially available primary amines and propiolic esters. The scope and usefulness of the method is demonstrated for 31 examples, including a range of propiolic esters, aliphatic amines, and differently substituted aromatic amines. For aliphatic amines, the products were obtained within 0.5 to 4 h in 52 to 85 % yield, compared with 3.5 to 22 h under classical solution-phase synthesis, which proceeds with similar or lower yields. The method was found to be particularly useful for weakly nucleophilic aromatic amines, which provided products in 21 to 73 % yield over 2.5 to 9.5 h compared with yields of 0 to 49 % over 1 to 6 d under standard solution-phase conditions, and for more hydrophobic esters that gave products in yields of 47 to 79 % over 1 to 3 h compared with 0 to 45 % over 4 to 114 h in solvent.

Synthesis of 2,3-Dihydro-4-pyridones and 4-Pyridones by the Cyclization Reaction of Ester-Tethered Enaminones

“…While intermediates 5 are easily obtainable from aliphatic amines, this is not the case with aromatic amines, which is due to their inherent weak nucleophilicity, making them as poor Michael donors . Even though the addition of an aromatic amine onto an activated alkyne is made possible under solvent-free conditions in a planetary ball mill, with ZrO 2 milling balls and SiO 2 added, our experiments showed that the solvent-free, silica gel-mediated reaction is accompanied by the formation of diene 4 (Table ), which can become the ultimate product with both aliphatic and aromatic amines . Furthermore, since the nucleophilicity of the nitrogen atom decreases further in enaminones due to the extended electron delocalization involving the aromatic ring and the double bond, we did not expect that 5 would show any tendency to react with ethyl acrylate even under basic conditions.…”

“…30 Even though the addition of an aromatic amine onto an activated alkyne is made possible under solventfree conditions in a planetary ball mill, with ZrO 2 milling balls and SiO 2 added, 31 our experiments showed that the solventfree, silica gel-mediated reaction is accompanied by the formation of diene 4 (Table 1), which can become the ultimate product with both aliphatic and aromatic amines. 22 Furthermore, since the nucleophilicity of the nitrogen atom decreases further in enaminones due to the extended electron delocalization involving the aromatic ring and the double bond, we did not expect that 5 would show any tendency to react with ethyl acrylate even under basic conditions. Therefore, we envisioned another strategy to obtain precursor 2 from aromatic amines to reverse the abovedescribed reaction sequence.…”

“…It should be noted that compounds of structure 4 were used as substrates for cyclization reactions that yielded biaryl-2carbaldehydes, 18 1,2-dihydropyridines, 19 2-pyridinones, 20 and pyrroles, 21 and we recently reported metal-free and solventfree conditions for their synthesis from aliphatic amines and weakly nucleophilic aromatic amines. 22 However, structure 1 is less common. A few examples involve N-trimethylsilyloxy derivatives (R = Me 3 SiO) obtained by silylation of βsubstituted aliphatic nitro compounds, 23 N-heteroaryl derivatives formed by the reaction of annelated 2-aminothiophene with methyl propiolate in refluxing toluene, 24 bis-(chlorodifluoromethyl)keto derivatives (ClF 2 CO instead of CO 2 Et in 1) formed by the self condenzation of the corresponding enamino ketone under basic conditions, 25 and mixed keto−ester derivatives obtained by the reaction of enamino ketone with ethyl propiolate in the presence of a base.…”

“…It should be noted that compounds of structure 4 were used as substrates for cyclization reactions that yielded biaryl-2-carbaldehydes, 1,2-dihydropyridines, 2-pyridinones, and pyrroles, and we recently reported metal-free and solvent-free conditions for their synthesis from aliphatic amines and weakly nucleophilic aromatic amines . However, structure 1 is less common.…”

“…To accelerate the reactions, both steps were performed on the surface of silica gel, with no solvent added (Table ; for details, see the Experimental Section). Such conditions were primarily chosen on the basis of our previous results, showing that silica gel activates amine and activated alkyne toward the Michael addition reaction, although there are also reports on the use of silica gel as a promoter of Michael additions of amines to electron-poor alkenes. , Since silica gel is nontoxic, inexpensive, and present in almost every organic chemistry laboratory, it gains popularity as a promoter of various kinds of reactions . The applied reaction sequence afforded compounds 2 (Table ) from activated aromatic amine ( p -methoxyaniline), unsubstituted one (aniline), and deactivated aromatic amine ( p -chloroaniline).…”