A 1,3-Dipolar Cycloaddition Route to 7-Azanorbornanes: Application to the Synthesis of syn-Facial N-Bridged Polynorbornanes

Abstract

Aziridinocyclobutenes react with electron-deficient or ringstrained alkenes to produce 7-azanorbornenes in a novel 1,3-dipolar cycloaddition reaction suitable for BLOCK assembly protocols. Benzo-7-azanorbornadiene and 7-heterobridged analogues react stereoselectively to produce compounds with syn-facial orientation of their bridges. 7-Azanorbornanes have received much interest following the discovery of the analgesic properties of epibatidine 1 (Scheme 1) and several specialist syntheses of this alkaloid have appeared in the recent literature. 4 Higher norbornalogues of 7-azanorbornanes, on the other hand, are uncommon and one of the rare examples is the doubly Nbridged adduct 2 reported by Sasaki et al. as the minor product (21%) in the cycloaddition of N-t Boc-isoindole with N-t Boc-7-azabenzonorbornadiene. 5 Scheme 1Following the success of our recently described ACE reaction (Scheme 2, equation 1) for the synthesis of 7-oxanorbornenes, 6 we reasoned that the development of an aziridine equivalent (aza-ACE reaction, Scheme 2, equation 2) held much potential for the synthesis of N-bridged alicyclics, especially 7-azanorbornanes. This is the subject of the present letter where we demonstrate the versatility of this new BLOCK reaction by the synthesis of the first examples of syn-facial polynorbornane systems containing multiple N-bridges. 7 Scheme 2The aziridinocyclobutane 8 required to test the potential of the aza-ACE coupling reaction was prepared as outlined in Scheme 3. Conversion of the benzonorbornadiene 3 8 to the cyclobutene-1,2-diester 4 followed the established method of Mitsudo and co-workers, which employs the ruthenium-catalysed addition of dimethyl acetylene dicarboxylate 4 (DMAD). 9 Conversion of cyclobutene 5 to the triazoline 7 10 was achieved by thermal addition of benzyl azide 6 and elimination of dinitrogen to produce aziridine 8 10 was conducted photochemically (Hanovia 450 watt Hg lamp, quartz, benzene, RT). The synthesis of aziridinocyclobutane 8 was achieved in 40% overall yield for the three step process from the readily available benzonorbornadiene 3.The reactivity of the N-benzyl aziridinocyclobutane 8 towards 1,3-dipolar cycloaddition was assessed initially by reaction with excess DMAD 4 (benzene at reflux) which produced the 1:1-adduct 10. 10 The structure of 10 was supported by NMR data and presumed to arise via attack of the DMAD onto the α-face of the 1,3-dipolar intermediate 9, formed by ring-opening of the aziridine (Scheme 3). Support for this proposal is provided by the formation of a yellow colour when aziridine 8 is heated alone in toluene. 11 Colour formation is lost on cooling and regenerated on heating, indicating the reversibility of the ring-opening process; further, the colour is discharged immediately on the addition of dipolarophiles like dimethyl fumarate. Scheme 3High stereoselectivity is observed in the reaction of the aziridine 7 with ethylenic dienophiles, eg maleic anhydride 11 forms a single product, shown to be the exo-fused adduct 12 10 by the existence of ...

Photolysis of Fused Cyclobutatriazolines: An Adventitious Route to 3,6-Di(2-pyridyl)pyridazonorbornadiene

“…10 The triazoline (18a) was prepared as outlined in Scheme 3, starting from dimethyl tricyclo[4.2.1.0 2,5 ]nona-3,7-diene-3,4-dicarboxylate (Smith's diene) 11 (13a). Reaction of s-tetrazine (8) with (13a) occurred site-specifically at the norbornene π-bond to form the dihydropyridazine (14a), which was converted to the dpp ligand (16a) by dehydrogenation with ddq (15).…”

“…10 Reference to Scheme 4 outlines that there are two cleavage pathways, one which involves cleavage of the bond α to the azo chromophore (path I) and the other β to the azo chromophore (path II). These reactions are entirely analogous to the Norrish type 1 and Norrish type 2 cleavages of ketones.…”

“…Dimethyl (1α,8α,9β,10α,12α,13β)-11-benzyl-3,6-di(2-pyridyl)-4,5,11-triazapentacyclo[6.5.1.0 2,7 .0 9,13 .0 10,11 ]tetradeca-2,4,6-triene-10, 12-dicarboxylate (19a …”

Parity Reversal: A New Diels-Alder Strategy for the Synthesis of Sesquinorbornadienes, Including Those with Heterobridges and Those of Unusual Stereochemistry

“…1 Since they are available as stereoisomeric variants, they can be used as either spacers, eg 1, or geometric turn-units, eg 2-4, in the building process. In order to maximise the value of norbornadienes as BLOCK units, it is necessary to have access to a complete range of geometric frameworks 1-4.…”

Microwave-Accelerated Ruthenium-Catalyzed [2π + 2π] Cycloadditions of Dimethylacetylene Dicarboxylate with Norbornenes

“…In this respect, synthesis of a polynorbornane skeleton functionalized at both ends [1,2] has been achieved, utilizing several synthetic strategies, and cycloaddition reactions were shown to be the most effective. In particular, acetylene cyclobutene epoxide (ACE) coupling protocol, [3] its aza-ACE variant, [4] and photochemical [2p þ 2p] dimerisation [5] were employed by Warrener et al These methods were based on cyclobutene diester functionalization, where the Mitsudo reaction has been the cornerstone in the preparation of ester functionalized norbornene cyclobutenes of type 2 (Scheme 1). The Mitsudo reaction is a thermal reaction of norbornenes 1 with dimethylacetylene dicarboxylate (DMAD) in the presence of ruthenium catalyst, RuH 2 CO(PPh 3 ) 3 , [6] with high p-facial selectivity, taking place specifically at the exo-face exclusively.…”