Organocatalyzed Formal [4+2] Cycloaddition of in situ Generated Azoalkenes with Arylacetic Acids: An Efficient Approach to the Synthesis of 4,5‐Dihydropyridazin‐3(2H)‐ones

Abstract

An unprecedented [4+ +2] cycloaddition of in situ generated azoalkenes with arylacetic acids has been developed under the catalysis of isothiourea. Ther eaction provideda ne fficienta pproacht o the synthesis of 4,5-dihydropyridazin-3(2H)-one derivatives in moderate to good yields(up to 95%).Keywords: 1,2-diaza-1,3-dienes;4 ,5-dihydropyridazin-3(2H)-ones;i sothioureacatalysis Dihydropyridazinones and pyridazinones are important six-membered aza-heterocycles,a nd are present in aw ide range of bioactive compoundsw ith anti-inflammatory, [1] anti-platelet aggregation [2] and anti-congestive heart failurea ctivities (Figure 1). To the best of our knowledge, the reported synthetic strategies for the synthesiso fd ihydropyridazinones are normally limited to the condensation of costly substrate goxo acids andh ydrazine.[3] Therefore,t he development of an ew strategyt hat allowsr apid access to dihydropyridazinones from readily accessible starting materials using ap ractical method is still highly desirable and an enduring goal of organic chemistry.Organocatalysis is now aw elle stablished instrument in the organic chemists tool box due to the generally stability,h igh quality,i nexpensive price, and lower toxicity compared to transitionm etals.I sothioureas, [4] one kind of frequently used organocatalyst, initially introduced by Birman [5] and Okamoto, [6] could promote the in situ generation of ammonium enolates from ac arboxylic acid, introducing functionalization to the carboxylic acid throughaMichaellactonization sequence. [7] 1,2-Diaza-1,3-dienes, generatedf rom the corresponding a-halo hydrazones,h ave recently been identified as ar obust and versatile synthetic building blocks with wide applications in the assembly of various five-, six-,a nd seven-membered heterocyclic ring systems. [8] In 2014, the Glorius group reported the first example of NHC-catalyzedf ormal [4+ +3] and [4+ +1] annulationso f1 ,2-diaza-1,3-dienes with enals, providing ah ighly enantioselective access to the chiral dihydrodiazepinones [9] (Scheme 1a). TheX iao group [10] andt he Luog roup [11] achieved the [4+ +3] and [4+ +2] annulationso ft he in situ generated 1,2-diaza-1,3-dienes with 1,3-dipoles and olefins employinga n inorganic base,l eading to the important building blocks of the tetrazepine and tetrahydropyridazine types (Scheme 1b,c ). Inspired by these works,w ee nvisaged that the possible [4+ +2] cycloadditionb etween a-halo hydrazones and arylacetic acids under the cat- COMMUNICATIONS alysis of isothiourea wouldp rovide an efficienta ccess to dihydropyridazinone derivatives.H erein, we report the first example of isothiourea-catalyzed formal [4+ +2] annulation reactions of in situ generated azoalkenesw ith arylacetic acids,c onstructing 4,5-dihydropyridazin-3(2H)-one derivatives in moderate to excellent yields (Scheme 1d). We started our investigation with the reaction between readilya vailable a-chloro N-Boc-hydrazone 1a and phenylacetic acid 2a.W hen the reactionw as performed in DCE at ambient temperature,c ompound...

Recent Advances in the Chemistry of Conjugated Nitrosoalkenes and Azoalkenes

“…There are a few examples of formal [4 + 2] cycloaddition reactions to obtain highly substituted tetrahydropyridazines that otherwise would not be possible. Thus, reactions of azoalkenes toward dehydroalanine esters, arylacetic acids, and maleimides have been described.…”

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

“…Following seminal work from Romo and co-workers using ammonium enolates generated from carboxylic acids, 16 ourselves and others, 17 have used isothioureas 18 to catalyse a range of formal [2 + 2], 19 [3 + 2] 20 and [4 + 2] 21 cycloaddition processes that employ an ammonium enolate intermediate. 22 Related intramolecular Michael addition-lactonisation cascades from enone-acid substrates have been used to generate simple heterocyclic products such as THFs and pyrrolidines with excellent enantioselectivity.…”

Generation and Reactivity of C(1)‐Ammonium Enolates by Using Isothiourea Catalysis

“… [31] It has been previously demonstrated that azoalkenes can be generated in situ under basic conditions from the corresponding α‐halogeno hydrazone [32] . Inspired by Yao and co‐workers who reported the racemic synthesis of 4,5‐dihydropyridazin‐3(2 H )‐ones using achiral isothiourea DHPB 28 , [33] the authors employed this strategy in the formal [4+2] cycloaddition of carboxylic acids 14 and a range of cyclic α‐chloro N ‐Boc hydrazones 33 , via azoalkene 35 , to furnish the 4,4a,5,6‐tetrahydrobenzo[h]cinnolin‐3(2 H )‐one products 36 in high diastereo‐ and enantioselectivity using pivaloyl chloride as activating agent and ( R )‐ i Pr BTM catalyst 34 .…”