The Preparation of Rigid Alicyclic Molecules Bearing Effector Groups from Alkene BLOCKs using s-Tetrazines and 1,3,4-Triazines as Stereoselective Coupling Agents

Abstract

Alicyclic alkenes are reacted with s-tetrazines or 1,3,4-triazines to give fused aza or diaza-1,3-dienes which are further reacted with alkenes, thermally or under high pressure conditions (8-14 kbar), to form aza-bridged or diaza-bridged Diels−Alder products of rigid structure, some bearing multifunctionality, eg ligand + chromophore.Developing ways to couple different alicyclic alkenes together as the basis for the production of rigid products lies at the heart of our newly announced building BLOCK approach to ribbon molecule synthesis. The initial work featured the coupling of alkenes with ester-activated cyclobutene epoxides (the ACE reaction). 2 More recently, the aziridine equivalent (the aza-ACE reaction) has been realised and the thermally generated 1,3-dipole used as the cycloaddition reagent to link with alkenes (Scheme 1, top). 3 We now report that s-tetrazines and 1,3,4-triazines can be used to provide a Diels−Alder coupling process as an alternative method for assembling norbornene BLOCKs into rigidly constructed products, this time containing an azabicyclo[2.2.2]octene or diazabicyclo[2.2.2]octene as the rigid linking subunit (Scheme 1, bottom). Scheme 1The present coupling method exploits the ability of inverse electrondemand heterocycles 4 to react with ring-strained alkenes to produce fused aza-1,3-dienes which can be stored (if stable) as BLOCKs and made to react further with the same or other ring-strained dienophiles to produce Diels−Alder coupled products. The success of the reaction with s-tetrazines depended on the suppression of the prototropic rearrangement of 4,5-dihydropyridazines 3 (Diels−Alder active) to their 1,4-isomers 5 (Diels−Alder inactive) (Scheme 2). 5 This was achieved simply by the addition of triethylamine to the reaction mixture. Where the dihydropyridazine BLOCK is produced from norbornenes, the second cycloaddition step is best conducted at room temperature under high pressure conditions. 7 We were not concerned about such rearrangements in our earlier work on fused 3,6-dipyridylpyridazines 6, since both isomers produce the same oxidised ligand. 8Reaction of norbornene 1 (as the prototype A-BLOCK) with 3,6-di(2'-pyridyl)-s-tetrazine 2b (triethylamine, CH 2 Cl 2 , 2h, RT) formed the 3,4-dihydropyridazine 3b (1,3-diene, B-BLOCK). Without isolation, 3b was treated with a variety of dienophiles 7-10 (second dienophilic A-BLOCK, 2-3 equivalents excess) under high pressure (8-14 kbar, 16h) 7 to form the A+B coupled products 11-14 (see Table 1). 9 The stereochemistry of these coupled products was assigned on the basis of two distinctive 1 H NMR probes: the nOe between the endo-protons (cf Ha, Hb in 11) of the central diazabicyclo[2.2.2]octene ring and the upfield shift of the inward-facing methylene bridge proton when it is proximate to the shielding effect of the diazo bridge.The most significant feature of these coupling reactions was the high diastereoselectivity with single products formed in all cases: formation of products with exo-stereochemistry occurred with simple di...

Fundamental Principles of BLOCK Design and Assembly in the Production of Large, Rigid Molecules with Functional Units (Effectors) Precisely Located on a Carbocyclic Framework

“…Here the intermediate aza-1,3-diene formed by the reaction of the norbornene A-BLOCK with triazine is not isolated but is coupled in situ with a second equivalent of the A-BLOCK to afford a rigid aza-bridged product. 24 This process can again be effected under thermal or high pressure conditions. 1,2,4-Triazine coupling affords a new design element, namely the ability to introduce an effector (in the case of 12, this is a bidentate ligand) which is at right angles to the long axis of the rod or curve (Scheme 4) in coupled product 14.…”

Rigid Alicyclic Molecules from Bicyclo[2.2.1]hept‐2‐enes (=8,9,10‐Trinorbornenes) and 1,4‐Dipyridin‐2‐ylphthalazines as Stereoselective Coupling Agents

“…The latter can serve as 1,3-diene for the coupling with another bicyclo[2.2.1]alkene under high pressure, to efficiently produce symmetrical and unsymmetrical polycyclic products (see C, Fig. 1) [3]. In these synthetic protocols, reactions of the triazine and tetrazine produce at the junction a bicyclo[2.2.2] moiety which slightly alters the overall curvature of the polytrinorbornane products [4].…”

Reaction of 2,5-bis-trifluoromethyl-1,3,4-oxadiazole with 7-oxanorbornenes revisited: Experimental and quantum-chemical study of reaction stereoselectivity

“…The results are collected in Table 2. Microwave enhanced reactions were proven to be an efficient entry to a variety of O 3 -[3]-, O 5 -[5]-, and O 7 - [7]polynorbornanes. The individual stereoisomers were isolated and their structures characterized spectroscopically.…”

“…A crucial step in the building BLOCK protocols is the connection of two alkene (norbornene) units utilizing cycloaddition reactions. Either Diels-Alder or 1,3-dipolar cycloadditions of small heterocyclic molecules, such as 1,2,4,5-tetrazine [7,8], 1,2,4-triazine [7], 1,3,4-oxadiazole [9,10], phthalazine [11], bis-epoxide [12], or bis-aziridine [13] were used. Using these protocols, a number of functionalized hetero-bridged and polarofacial [n]polynorbornanes was prepared [3,12,14,15].…”