Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji–Trost Process

Abstract A three‐step synthesis of the 2‐azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium‐catalysed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs by acid‐assisted C−N bond cleavage followed by β‐hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off‐cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold.

Abstract: At hree-step synthesis of the 2-azabicyclo[3.3.1]nonaner ing system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad,a llowing the incorporation of aw ider ange of functionalityr elevant to medicinal chemistry.M echanistic studies demonstrate that the processo ccurs by acid-assisted CÀNb ond cleavage followed by b-hydride eliminationt of orm ar eactive diene, demonstratingt hat efficient control of what mightb e considered off-cycle reactionsc an result in productive tandem catalytic processes. This represents as hort and versatile route to the biologically important morphan scaffold.
Since their discovery,p alladium-catalysedc ross-coupling reactions have seen increasing use in the synthesis of bioactive molecules. [1] In particular,d ue to its reliability,t he Suzukic rosscoupling hasb ecomeakey CÀCb ond forming reaction within medicinal chemistry. [2] However,t he resulting compounds are often relatively planar in nature, despite evidence that increasedbioactivity mightresult from increased levels of sp 3 -hybridized carbon. [3] The Ts uji-Trost allylation represents ap alladium-catalysed process with potential to achieve more threedimensional molecules, necessarily connecting fragments via sp 3 -hybridized centres. [4] Recent work has added to this potential with increasingly effective systemsf or performing enantio-selectiveT suji-Trost reactions. [5] The power of such reactions withint andemp rocesses has also been demonstrated, particularly in combination with photochemistry to create complex, three-dimensional molecules from simple substrates (Scheme 1a). [6] Ts uji-Trost reactionsa re also potentially less pronet os ide reactions, such as competing protodehalogenatione ncountered in Suzukic ross-couplings. [7] While competing b-hydride elimination from intermediate p-allyl Pd complexest of orm dienesi sk nown, [8] this process is less reported and potentially reversible. [9] However, dienes themselves frequently serve as usefuls ynthetic intermediates, [11] raising the possibility that their formationc ould form part of ap roductive catalytic cycle. [11] Herein, we report ad iverted Tsuji-Trost process, where b-hydride elimination to form ar eactive diene results in a novelt andemp rocess, forming complex tertiary amines that represent the core of the biologically significant morphan ringsystem(Scheme1b).
Following our recently reported synthesiso fl ycorane alkaloid 4, [12] employing ak ey Heck cyclisation on ap hotochemically-derived substrate, we were led to considerw hether simple homologation of the carbon tether might lead directly to the homologated alkaloid series. However, initial investigation of the Heck reaction of iodide 10 a in fact yieldedd eiodinated material 10 b under the majority of conditions (Table 1). In no case was the desired Heck product detected, with use of previously successful phosphite ligands [13] leading to the unex-Scheme1.Previoussynthetic utility of photochemically synthesized vinyl aziridinesa nd their formation of azabicyclo [3.3.1]nonanes in ad iverted Ts uji-Trost process. [6] pected phosphonate ester 10 c (Entry 4), presumably via reductive elimination to aphosphoniums alt intermediate. [14] However,t he use of triphenylphosphine and dppf (Entries 7a nd 8) led to the formationo fb icyclic amine 11.T his process appeared to result from CÀNb ond cleavage with concurrent amine migration and reduction of the iodide moiety.F urther screening of reaction conditions demonstrated that bicyclic amine 11 was formed in good yield through the use of DPE-Phos (Entry 9), and that iPr 2 NEt was required for this process to occur,w ith either no base or Et 3 Np roving unsuccessful (Entries 10 and1 1).
While this process was found to be relativelyt olerant of variation of the aryl group (see SI for details), the inclusion of a sacrificial iodide moiety (i.e. X = I) provede ssential for reactivity. [15] As noted previously,t he protodehalogenation of aryl halides is well documented within cross coupling reactions. Such ap rocess has the potentialt og enerate stoichiometric quantities of HX,w hich might then facilitate the observed cleavage of the CÀNb ond. [16] Further evidencef or this was obtained from ac ross-over reaction where am ixture of iodinated and non-iodinated substrates led to product formationf rom both (see SI for details). We therefore investigated various additives ( Table 2).
It can be seen that the use of an external electron-rich aryl iodide led to efficient reaction (Entry 2). Howevers toichiometric quantities were required (Entry 3), and the use of simpler, less electron-rich species was less effective (Entries4-6). Use of iodide anion itself, either alone or in the presence of aw eak acid provedi neffective (Entries7 and 8). However,t he use of the HI salt of iPr 2 NEt provedar eal breakthrough, obviating the need for as acrificial aryl iodide (Entry 9). Exploring the required acid and amine stoichiometryl ed to further refinement, with ab uffered system of 1equiv.e ach of methanesulfonic acid and iPr 2 NEt (Entry 12) proving optimal (see SI for complete acid study).
With thesec onditions in hand, we explored the scope of this reaction ( Figure 1), the substrates being easily accessible via as imple two-step processf rom pyrrole 1 (R = CO 2 tBu), involvingp hotochemical conversion to tricyclic aziridine 7 followed by ao ne pot retro-ene reaction/reductive amination sequence(see SI for details). [6a,c] The reactionp roved very general, with ar ange of N-alkyl, Nbenzyla nd N-homobenzyl substrates proceeding in good to moderate yield (17 a-i). Of particular note is the potential to include as imple methyl group (17 h), permitting access to Nmethyl morphan structures, and the medicinally important CF 3 group (17 c). [17] Given the importance of the morphan scaffold to medicinal chemistry, [18] we also explored heterocyclics ubstituents. The reactionp rovedt ot olerate ar ange of electronrich (17 l, o, r)a nd electron-poor( 17 j, n)h eterocycles, albeit in reduced yield. N-tosyl system (17 t)w as also exploredb ut provedunreactive.
The rapidity with which such complex, sp 3 -rich aza-systems can be reached from as ingle parentp yrrole is as ignificant highlight of the methodology,a si st he ability to include reactive functional groups as in 17 p.I mportantly, N-deprotection can be readily achieved to form 19,p ermitting the installation of additional functionality on nitrogen in only two further steps. This could allow ap ractical approach to furthere xpand the range of Rg roups in 17.E xchange of PMB for the more versatile Cbzp rotectingg roup is conveniently achieved in a single step, as shown in the formation of 18.T his could be a significant advantage for am edicinal chemist wishing to pre-  Having established the scope to be relatively broad, we turned our attention to the reactionm echanism. Formally ar earrangement, we considered that the process mostl ikely involved acid-assisted cleavage of the CÀNb ond forming a pallyl Pd intermediate, from which b-hydride elimination formed ad iene. This wast ested by the addition of acetic anhydridet o ar eaction of substrate 12,w here uncyclized acetamide 20 was formed in good yield (Scheme 2). Stoppingt he reaction at an early stage also showed the presence of intermediate 21,c onsistent with intramolecular 1,6-addition to this diene. Re-subjection of 21 to the reaction conditions showed conversion to 13 even in the absence of palladium. Furthermore, brief treatment of 21 to the optimized reaction conditions gave only 13 and no startingm aterial 12 wasd etected. This latter experiment likely indicates that 1,6-addition is not reversible.
We then prepared deuterated compounds 22 and 23 and subjected these to the reaction conditions (Scheme 3). This led to as omewhats urprising results, with both compoundss howing deuterium incorporation within the product;i nf act, compound 24 showed ah igherl evel of deuterium incorporation at the bridgehead (60 %v s. 35 %), despite an anti-addition [19] /synelimination [20] mechanism being expected to result in selective cleavage of the CÀDb ond of 22 and the CÀHb ond of 23.A ssuming addition of palladium occurs anti to nitrogen, such behaviours uggests that facile equilibrationofpalladium between the endo and exo faces occurs within the p-allyl Pd complex (vide infra). Further,acompetition reactionbetween 22 and 12 (see Supporting Information for details) suggested no significant kinetic isotope effect was operating, although as econdary KIE, for instanced uring rate limiting p-allyl complex formation, cannotbee xcluded. [21] Based on theser esults, am echanism is proposed in Scheme4.I nitial acid-promoted cleavage of the CÀNb ond by Pd 0 forms p-allyl Pd complex 25.B ased on the similar H/D ratios in the products of deuterated compounds 22 and 23, this undergoes equilibrationb etween faces, presumably by palladium O-enolate 26, [22] with b-hydride elimination thus Scheme2.Investigationo ftrapping and intermediates.
[a] Substrate 24 contains asecond remote deuterium atom (NCH endo D exo )a saconsequence of the synthetic route,w hich remainedu nchanged in the reaction( seethe Supporting Informationf or full details). Chem.E ur.J.2020, 26,14330 -14334 www.chemeurj.org 2020 The Authors. Published by Wiley-VCH GmbH being possible from either face to form diene 28,a nd occurring somewhat preferentially from the endo face (i.e. from complex 27). The exchange of Pd between the faces of the pallyl complex suggestst his species has as ignificant lifetime, and this combined with the absence of the appreciable primary KIE generally associated with b-hydride elimination, [23] leaves open the possibility that this step to form diene 28 may be reversible. Trapping of this diene is possible through the inclusion of an electrophile such as acetic anhydride (Scheme 2), and otherwiset his dienethen undergoes irreversible 1,6-conjugate addition to form intermediate 29 as am ixture of diastereomers. These species undergo acid/base-promoted isomerization to the observedp roduct. Related conjugateda ddition processesh ave been observed to occur under palladiumc atalysis. [24] In conclusion, we have demonstrated that ad iverted Ts uji-Trost process provides rapid access to biologically important ring systems. This occurs via an unusual Pd-catalysedm echanism, exploiting processes often regarded as unwanted side reactions that is, proto-dehalogenation, b-hydridee limination and Pd O-enolate equilibration. Overall, this methodologyp rovides three-step access to complex, biologically significant molecules from simple aromatic startingm aterials. The versatility of this chemistry could prove useful for medicinal chemists in the constructiono f2 D-libraries based on the morphan scaffold, and once again highlights the power of combining photochemical synthesis with palladium catalysis.