Highly Enantioenriched 2-Azabenzonorbornenes from 7-Azabenzonorbornadienes by Asymmetric Hydroboration-Oxidation and Tandem Deoxygenation-Rearrangement-Electrophile Trapping

Abstract

E n a n t i o e n r i c h e d 2 -A z a n o r b o r n e n e s f r o m 7 -A z a n o r b o r n a d i e n e s Abstract: 3-exo-Substituted 2-azabenzonorbornenes are accessible from 7-azabenzonorbornadienes in good yields and high enantiomeric excess via asymmetric hydroboration-oxidation, followed by tandem deoxygenation-rearrangement-electrophile trapping and also provide access to substituted aminomethylindenes.Radical cascade processes constitute a powerful methodology for the fast assembly of complex molecular frameworks. 1 We previously demonstrated the synthetic utility of nitrogen-directed radical rearrangements, 2 and recently applied this concept in a neophyl-type rearrangement process (4 → 5) to obtain racemic 2-azabenzonorbornenes, e.g. 6, using xanthates 3 of 7-azabenzonorbornenols 2 (Scheme 1). 3 To build on this latter methodology we sought firstly to develop an asymmetric entry and secondly to trap the rearranged radical 5 with an electrophile in tandem with the deoxygenation-rearrangement. Scheme 1 Reagents and conditions: (a) 9-BBN, THF, 20 °C, 24 h, then NaOH, H 2 O 2 , 0 °C → 20 °C, 90 min; (b) KH, THF, then CS 2 , then MeI; (c) (Me 3 Si) 3 SiH, AIBN (slow addition), PhMe, reflux, 2 h.To examine the first objective, initial studies were undertaken screening ligands in rhodium-catalysed asymmetric hydroboration-oxidation 4 for desymmetrisation of 7-azabenzonorbornadiene 1. However, yields and ees for alcohol 2 could not be optimised to synthetically useful levels. 5 Alkene hydroboration-oxidation using organoboranes derived from a-pinene has been shown to be useful for the preparation of alcohols in high ee, 6 and (-)-diisopinocampheylborane [(-)-Ipc 2 BH] has recently been successfully applied to the structurally related tropenone framework. 7 We envisaged that, by analogy, asymmetric hydroboration-oxidation of readily available benzyne/NBoc-pyrrole cycloadduct 1 8 might generate alcohol 2 in good ee. We were pleased to discover that hydroborationoxidation with 1.5 equivalents (-)-Ipc 2 BH, [prepared from commercial (+)-a-pinene of 92% ee according to the method of Brown] 9 furnished alcohol (-)-2 in 84% yield and 95% ee (Equation 1). 10

Radical cascades using enantioenriched 7-azabenzonorbornenes and their applications in synthesis

“…We were encouraged that the best yields of deoxygenated, trapped product relative to directly reduced product were achieved under conditions [refluxing toluene, thermal initiation by AIBN] similar to those we had previously reported for the tandem deoxygenation–rearrangement–reduction of 7-azabenzonorbornenyl xanthates (e.g. 5 to 8 , Scheme 2 ), although the work in our laboratory had employed a syringe pump in order to achieve a slow rate of addition of the radical initiator and reductant [ 21 , 24 ]. Pleasingly, combining these procedures, i.e.…”

“…Ring-opening of this ‘nortricyclyl’ radical species can lead to an overall 1,2-aryl (neophyl) migration [ 20 ]. We have previously communicated our initial findings in the application of tandem radical cascades toward the 2-aza-5,6-benzonorbornenyl system [ 21 ]. We now present our wider investigations of this system and its synthetic utility.…”

Synthesis of azabicyclic systems using nitrogen-directed radical rearrangements

“…Initial efforts to perform rhodium-catalysed asymmetric hydroboration-oxidation 62 did not give ees at a synthetically useful level, 63 however stoichiometric hydroboration-oxidation with (−)-diisopinocampheylborane [(−)-Ipc 2 BH], 45 followed by oxidative workup gave alcohol 46 in 84% yield and 95% ee (Scheme 19). 64 This method was found to be applicable to representative members of the other more substituted 7-azabenzonorbornadienes, with good yields and excellent ees. The absolute sense of asymmetric induction was confirmed in the case of 2-azabenzonorbornadiene 41 by chemical correlation 64 and the others were assigned by analogy.…”

“…64 This method was found to be applicable to representative members of the other more substituted 7-azabenzonorbornadienes, with good yields and excellent ees. The absolute sense of asymmetric induction was confirmed in the case of 2-azabenzonorbornadiene 41 by chemical correlation 64 and the others were assigned by analogy.…”