Periselectivity in the aza-Diels–Alder Cycloaddition between α-Oxoketenes and N-(5-Pyrazolyl)imines: A Combined Experimental and Theoretical Study

Abstract

The thermal 6π aza-Diels−Alder cycloadditions between α-oxoketenes, in situ derived from a thermally induced Wolff rearrangement of 2-diazo-1,3-diketones, and N-(5-pyrazolyl)imines as prototypical electron-rich 2-azadienes lead to two distinct sets of products, essentially as a function of the nature of the α-oxoketenes involved. For instance, cyclic five-membered α-oxoketenes lead preferentially to spiro hydropyridin-4-ones, which involves the α-oxoketenes as the 2π partners at their CC double bond and the N-(5-pyrazolyl)imines as the 4π partners at their 2-azadiene moiety. In contrast, other cyclic and acyclic α-oxoketenes lead preferentially to 1,3-oxazin-4-ones, which now involves the α-oxoketenes as the 4π partners at their 1-oxadiene moiety and the N-(5pyrazolyl)imines as the 2π partners at their CN double bond. A computational modeling study using DFT methods allowed rationalizing this change of periselectivity: the formation of spiro hydropyridin-4-ones is under thermodynamic control while the formation of 1,3-oxazin-4-ones is kinetically controlled, and slightly thermodynamically disfavored in the five-membered ring series. The competing cyclodimerization of the α-oxoketenes is also studied in detail.

Periselectivity in the Aza-Diels–Alder Reaction of 1-Azadienes with α-Oxoketenes: A Combined Experimental and Theoretical Study

“…However, the actual aza-Diels–Alder thermodynamic product of the reaction was computationally identified as iso-3j (the diastereomer of 3j ) with a relative free Gibbs energy determined at −75.8 kJ/mol, that is more stable than 3j by a tiny but meaningful −2.4 kJ/mol; modeling its formation indicated a relative activation energy of ΔG ≠ = 73.9 kJ/mol at 298 K and 100.5 kJ/mol at 413 K plausible with its formation under the actual reaction conditions ( Figure 1 c). Because the diastereoselectivity in the model molecule iso-3j has never been reported experimentally in cycloadditions of α-oxoketene 1e with any 4π reaction partner [ 11 , 16 , 17 ], a competing process is certainly at hand. Actually, the formation of iso-3j through TS6 was found kinetically outcompeted by the cyclodimerization of α-oxoketene 1e ( Figure 1 c) that occurs with a significantly lower relative activation energy through TS7 to give dimer-1e , a molecule itself amenable to further thermodynamically driven transformations under the reaction conditions [ 11 ].…”

“…Since, α-oxoketenes have revealed as versatile chemical intermediates for synthetic applications, ranging from the preparation of simple β-oxocarbonyl derivatives [ 8 ] to the total synthesis of complex natural products [ 4 , 5 ]. However, and with few exceptions [ 9 , 10 ], α-oxoketenes are not stable species because of their propensity to react with a number of chemicals, including themselves [ 11 ], at significant rates at ambient temperature; thus, they must be generated in situ immediately before use. The most common and practical methods for the generation of α-oxoketenes are the thermal decomposition of dioxinones with concomitant extrusion of acetone [ 12 ], and the thermal or photochemical Wolff rearrangement of 2-diazo-1,3-dicarbonyl compounds extruding nitrogen gas [ 13 , 14 ].…”

“…However, when α,β-unsaturated imines 2 are employed, another formal aza-Diels–Alder process becomes possible, involving the α,β-unsaturated imines as 4π reaction partners (1-azadienes) and the α-oxoketenes as the 2π reaction partners to give hydropyridin-2-ones of type 3 [ 16 ]. Periselectivity, the selectivity in formation of the pericyclic products, in the formal aza-Diels–Alder cycloadditions between α-oxoketenes and some electron rich 2-azadienes was recently examined and found to be dependent on kinetic and thermodynamic factors, as well as the nature of the α-oxoketene employed [ 11 ]. For the present study, the periselectivity in the reactions of α-oxoketenes with α,β-unsaturated imines as prototypical 1-azadienes was further investigated and rationalized by a combination of experimental and computational studies.…”

Revealing the Origin of Π‐facial and Regioselectivity in the Diels‐Alder Reaction of Unsymmetrical, Cage‐annulated 1,3‐Cyclohexadiene with Ethyl Propiolate Dienophile: a DFT Study

“…Diels-Alder (DA) reactions are one of the most widely studied reactions in organic chemistry due to their range of utility for the formation of six-membered rings with considerable diastereo-and regioselectivity. [1][2][3][4][5][6][7] The Diels-Alder reaction has been utilized for the formation of various agrochemicals, natural products, biomaterials, and other hetero-aromatic compounds. [8][9][10][11][12][13][14][15][16] The Diels-Alder reactions of π-facially differentiated cage-annulated 1,3-dienes are well-studied and have received attention from organic chemists.…”

“…Diels‐Alder (DA) reactions are one of the most widely studied reactions in organic chemistry due to their range of utility for the formation of six‐membered rings with considerable diastereo‐ and regioselectivity [1–7] . The Diels‐Alder reaction has been utilized for the formation of various agrochemicals, natural products, biomaterials, and other hetero‐aromatic compounds [8‐16] .…”