Catalyst‐Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones

Abstract Medicinally relevant spirocyclic indolenines, carbazoles and quinolines can each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed by an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl–metal species, which then rearranges selectively by careful choice of catalyst and reaction conditions.

Abstract: Medicinally relevant spirocyclic indolenines, carbazolesa nd quinolinesc an each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed by an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl-metals pecies, which then rearranges selectively by careful choice of catalysta nd reaction conditions. The synthesis of structurally diverse compounds is central to the discovery of pharmaceutical lead compounds. [1] However, the formation of distinct compound sets usually requiresm ultiple synthetic routes, which is time-consuming and labour-intensive; therefore, strategies capable of selectively forming multiple products from common startingm aterialsa re of high value. The concept underpinningo ur approach is the formation of ac ommon reactive intermediate( from as imple, inexpensive starting material), which depending on the catalyst used can rearrange into differents caffolds( e.g.,s pirocycles, aromatics and heterocycles/carbocycles;F igure 1). This approach has the potentialt os ignificantly streamline existing synthetic methods, and lead to ab roader understanding of catalysis and reactionm echanisms.A lthough there have been numerous examples of catalyst variation leading to different products in recenty ears, [2,3] such methods have mainly focusedo nt he formationo fp roductsw ith similar frameworks( e.g.,r edox isomers,r egioisomers or stereoisomers). In this work, our aim was to develop as eries of divergent processes capable of selectively delivering multiple products with the level of scaffold diversity outlined in Figure1.
To demonstrate the synthetic potential of our scaffold-diversity approach, we chose to explore the formation and subsequentr eactiono fs pirocyclic vinyl-metal intermediates of the form 2 (Scheme 1). Previous work in our research group has demonstratedt hat the dearomatising spirocyclisation [4] of ynones 1 into spirocyclic indolenines 3 can be catalysed by AgOTf, with vinyl-silver species 2 ([M] = Ag) as likely intermediates. [5] Ak ey design feature of our strategy was the idea that varyingt he catalystw ould alter the nature and reactivity of the vinyl-metal intermediate 2 in ap rogrammablew ay,s uch that alternative products could be formed by different rearrangementr eactions.H erein, we report the successful realisation of this approach. Notably,b yj udiciousc hoice of catalyst, simple, inexpensive ynone startingm aterials 1 can be converted into spirocyclic indolenines [6] 3 using Ag I ,c arbazoles 5 using Au I and quinolines 7 using Ag I /Al III in high yield, each by as imple, catalytic and atom-economical process. Furthermore, in suitable cases, tetracyclic scaffolds 8 can be formed with complete diastereoselectivity,b yatelescoped spirocyclisation/ nucleophilic addition sequence, which was performed using ac hiral Ag I salt to furnish an enantiopure product.
The spirocyclisation of 1a using AgOTff ormed indolenine 3a in quantitative yield (Scheme2); [5] the mild reactionc onditions are believed to play ak ey role in this process, stabilising the spirocycle with respect to further reactions. However, in the proposed scaffold diversity approach, in whicht he synthesis of carbazole 5a was an initial goal, the challenge was to deliberately promote 1,2-migration [7] in ac ontrolled manner. [8] A Ph 3 PAuNTf 2 catalyst was chosen based on the prediction that the p-acidic gold(I)c atalyst would effectively promote the initial spirocyclisation reaction and that the intermediate vinylgold species (2a-Au)w ould be prone to 1,2-migration, based on known reactivity of relatedv inyl-gold and gold-carbenoid species. [9] This idea was validated (94 %y ield of 5a)w ith al ikely reaction mechanism depicted in Scheme 3; the ring enlargement is believed to proceed either via cyclopropanei ntermediate 9a,o rb yadirect 1,2-migration reaction (2a-Au! 10 a)b ased on related precedent. [7,9] The importance of vinylgold intermediate 2a-Au in the 1,2-migration is evidenced by the fact that no reactiont akes place when spirocycle 3a is treated with Ph 3 PAuNTf 2 under the same conditions. We next examined whether we could initiate an alternative rearrangement commencing from ynone 1a,b ys eeking to promote cyclopropanation of an enolatef rom the lesss ubstituted branch of the cyclopentenone;m ore oxophilic catalysts were chosen for this task, as it was thought that they would better promote the necessary enolate formation.W ew ere unable to uncover ac atalystthat could successfully initiate spirocyclisation and subsequent rearrangement on its own.H owever,f irst performing the spirocyclisation using 2mol %o f AgOTf as catalysti ni sopropanol, followed by the addition of 5mol %o fA lCl 3 ·6H 2 Oa nd subsequent heating in am icrowave gave quinoline 7a in high yield (Scheme 4). [10] Following Ag Imediated spirocyclisation, it is thought that the Al III catalyst promotes enolatef ormation and subsequent cyclopropanation to form 12 a,w hich can then fragment to form 13 a and aromatise to give quinoline 7a (either by simple proton shuttling, or by aseries of 1,5-sigmatropic H-transfer reactions).
Supporting evidence fort his unprecedentedr earrangement was obtained:t reatment of spirocycle 3a with LHMDS in THF (i.e. conditions which almost certainly would result in enolate formation)a lso led to the formation of quinoline 7a,i n8 1% yield. Furthermore,t he importance of the carbonyl group was shownb yt he fact that treatment of known cyclopentenol 14 [11] with AlCl 3 ·6H 2 Od id not result in quinoline formation. Instead,1 ,2-migration of the alkenyl group took place, furnishing carbazole 15 following tautomerisation andd ehydration (Scheme5).
Scheme3.Formation of carbazole 5a;[Au] = Ph 3 PAuNTf 2 ,L= ligand. Chem.E ur.J.2016, 22,8777 -8780 www.chemeurj.org methodology,s ubstrates 1a-1m were cleanly convertedi nto the correspondings pirocyclic indolenines 3a-3m,a ll in excellent yields (Table 1, conditions A). The Ph 3 PAuNTf 2 -mediated carbazole-forming reaction was similarly broad in scope (conditions B);s ome reactions were less efficient than the analogous spirocycle formations, and ynone 1d did not produce any of the desired product( insteads talling at the formation 3d), but the majority of the carbazole products 5a-j werei solated in very good yields. [13] Finally,t he quinoline-formingr eaction sequencew as also found to be very general (conditions C). For ynones 1a-1e,1g,1k-1l,t he sequential AgOTfs pirocyclisation and AlCl 3 ·6 H 2 Om ediated rearrangements teps could both be performed in iPrOH in one-pot as described, whereas for ynones with more sensitivef unctional groups (1f, 1h, 1i, 1j, 1m), the process benefited from as olvent swap,w ith the spirocyclisation first being performed in CH 2 Cl 2 before concentration and addition of iPrOH prior to the AlCl 3 ·6 H 2 Os tep. The AlCl 3 ·6 H 2 Or eactions were typicallyp erformed under microwave irradiation at 100 8C, but they were also shown to proceed well on ag ram scale with conventional heating, albeit with al onger reaction time being required. [14] The structure of quinoline 7fwas confirmed by X-ray crystallography. [15] Another strand of scaffold diversity starting from more functionalised ynones 1h-1j was briefly explored. Tetracyclic scaffolds 8h-j,e quipped with additional complexity, were easily obtained following reactiono fy nones 1h-1j with AgOTf and subsequenta cid-mediated protecting group cleavage in one pot (Scheme 6, and see the Supporting Information for de-tails). [16] The tetracycles were formed as the singled iastereoisomers shown, and in addition, (S)-8 h was prepared in enantioenriched form (89:11e .r.) by utilising( R)-CPAs ilver(I)s alt 16 in place of AgOTf. [17] The e.r.o f(S)-8 h could be increased to % 100:0 by recrystallisation from ethanol, and its structure was confirmed by X-ray crystallography (see the Supporting Information). [15] In summary,r eadily available indolyl ynones have been shownt obeversatile startingmaterials for the synthesis of spirocyclic indolenines 3a-m,c arbazoles 5a-j,q uinolines 7a-m and tetracyclic compounds 8h-j using ac atalyst-driven scaf-Scheme6.One-potspirocyclisation/trapping to form tetracycles 8h-8j.  fold diversity approach. The reactions are typically high yielding, work on aw ide range of indolyl ynone substrates, are operationally simple and can all be performed with no effort to exclude air or moisture. All of the procedures are thought to proceedb ya ni nitial dearomatising spirocyclisation to form ak ey vinyl-metal intermediate before diverging at this point depending on the nature of the catalyst used. The synthetic methods are expected to be of value both in target synthesis projects [18] and to enablet he rapid generationo fc ompound librariesfor biological screening.