Three‐Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o‐Terphenyls

Abstract

An unprecedented organocatalytic three-component domino Knoevenagel/vinylogous Michael reaction starting from simple enolizable aldehydes, malononitrile, and nitroolefins is reported. This facile two-step domino process provides a straightforward stereoselective route to multifunctional vinyl malononitrile products (up to 82 % yield, 85:15 d.r.) containing a nitroalkane moiety, and contributes to the development of sustainability and atom economy. The application of the obtained domino products for synthesis of highly functionalized o-terphenyls (of high interest for materials science and medicinal chemistry) through subsequent new three-step domino reaction involving cyclization-tautomerization-aromatization steps, has been demonstrated.

Facile Access to Challenging ortho‐Terphenyls via Merging Two Multi‐Step Domino Reactions in One‐Pot: A Joint Experimental/Theoretical Study

“…1 a – SR and 1 a – RR are formed with a Gibbs energy of reaction of −1.9 and −0.9 kcal mol −1 , respectively (see Figures b, 3b, 4a). 1 a – SR is therefore slightly more stable by ∼1 kcal mol −1 than 1 a – RR in agreement with the experimentally found ratio of 83 : 17 …”

“…We started our investigation by exploring a selected three-step domino reaction of α,α-dicyanoolefin 1 a towards orthoterphenyl 2 a (Table 1). Initially we applied triethylamine, which we reported for cyclisation step in our previous work, [19] and CuBr 2 co-catalyst as it was recently demonstrated for efficient aromatization of cyclohexene derivatives. [20] To our delight the domino product was obtained in 53 % yield ( This may additionally give a hint on formation of a copperamine complex: If the free amine was completely bound to the metal, lack of base catalyst (required for cyclization step) may be responsible for the suppressed reaction.…”

“…1 a-SR is therefore slightly more stable by~1 kcal mol À 1 than 1 a-RR in agreement with the experimentally found ratio of 83 : 17. [19] In order to study the role of the kinetics on the observed ratio we studied the vinylogous Michael reaction (8 + 3 a to 1 a), which is the only possible diastereoselective step in imidazole catalyzed formation of 1 a. We calculated for both the formation of the SR (see Figure 2a for optimized structures and 2b for the reaction profile) as well as the RR diastereomer (see Figure 3a for structures and 3b for the reaction profile) low lying transition states (TS) (see Supporting Information for details) for the deprotonation of 8, CÀ C-bond formation yielding deprotonated 1 a and the protonation step to 1 a.…”

“…Recently we reported an organocatalyzed three-component domino Knoevenagel/vinylogous Michael reaction and demonstrated a potential application of isolated domino products α,αdicyanoolefins for the synthesis of ortho-terphenyl derivatives via a base/Cu-co-catalyzed three-step domino (cyclization/ tautomerization/ aromatization) reaction (Scheme 1c). [19] Based on these preliminary results, we envisioned to combine these two domino reactions in a one-pot process to avoid timeconsuming and waste-producing isolation and purification of product intermediates (Scheme 1c). Herein we report development of such an efficient and straightforward one-pot five-step synthetic strategy to access a broad scope of highly functionalized ortho-terphenyls starting from easily available compounds.…”

Kinetics Studies on a Multicomponent Knoevenagel−Michael Domino Reaction by an Automated Flow Reactor

“…[15][16][17] In this work, the described combination of a plug-flow catalytic microreactor and an automated flow system allows us to resolve in a fast and convenient manner the kinetics of a primary-amine catalyzed KnoevenagelÀ Michael domino reaction to tetrahydrochromene derivatives (Scheme 1). The importance of multicomponent domino reactions, in general, as well as of the chosen reaction system, in particular, have been broadly covered over the years and in recent reports, [18][19][20][21][22][23] so that we will not discuss further details here. However, even with a wide variety of catalysts and a large number of proposed reaction mechanisms reported, a systematic investigation on how a catalyst is capable of catalyzing simultaneously two different reactions is missing.…”