Synthesis of spiroindanes by palladium-catalyzed oxidative annulations of non- or weakly activated 1,3- dienes involving C–H functionalization

The site-selective, metal-catalyzed oxidative C−H functionalization of aromatic C(sp)−H bonds with alkynes and activated alkenes, directed by a heteroatom-containing functional group, is now wellestablished for the preparation of diverse heterocycles and carbocycles (Scheme 1A). Despite the impressive advances that have been made, 1,3-dienes have rarely been used as annulation partners in these types of reactions (Scheme 1B). Booker-Milburn, Lloyd-Jones, and co-workers have described the Pd-catalyzed oxidative annulation of N-arylureas with mostly activated 1,3-dienes (R = electron-withdrawing group) to form indolines. Related, but non-oxidative, annulations involving 1,3-dienes have been described by the Glorius group, who recently developed the redox-neutral Rh(III)-catalyzed annulation of aromatic oxime esters with 1,3dienes to give isoquinolines. Nishimura, Hayashi, and co-workers have also described non-oxidative, Ir-catalyzed annulations of cyclic ketimines with 1,3-dienes via C–H functionalization. Although currently limited in number, these processes demonstrate the significant potential of 1,3-dienes as annulation partners in C–H functionalization reactions. The development of new types of annulations involving 1,3-dienes therefore remains an important objective to increase the range of products that can be accessed. Herein, we describe the Pd-catalyzed oxidative annulation of Scheme 1 Directed, catalytic oxidative annulations of aromatic compounds with unsaturated partners by C–H functionalization.

The site-selective, metal-catalyzed oxidative C−H functionalization of aromatic C(sp 2 )−H bonds with alkynes and activated alkenes, directed by a heteroatom-containing functional group, 1 is now wellestablished for the preparation of diverse heterocycles 2-5 and carbocycles (Scheme 1A). 6Despite the impressive advances that have been made, 1,3-dienes have rarely been used as annulation partners in these types of reactions (Scheme 1B).Booker-Milburn, Lloyd-Jones, and co-workers have described the Pd-catalyzed oxidative annulation of N-arylureas with mostly activated 1,3-dienes (R 3 = electron-withdrawing group) to form indolines. 7 Related, but non-oxidative, annulations involving 1,3-dienes have been described by the Glorius group, who recently developed the redox-neutral Rh(III)-catalyzed annulation of aromatic oxime esters with 1,3dienes to give isoquinolines. 8Nishimura, Hayashi, and co-workers have also described non-oxidative, Ir-catalyzed annulations of cyclic ketimines with 1,3-dienes via C-H functionalization. 9Although currently limited in number, these processes demonstrate the significant potential of 1,3-dienes as annulation partners in C-H functionalization reactions.The development of new types of annulations involving 1,3-dienes therefore remains an important objective to increase the range of products that can be accessed.
Herein, we describe the Pd-catalyzed oxidative annulation of Scheme 1 Directed, catalytic oxidative annulations of aromatic compounds with unsaturated partners by C-H functionalization.
A possible catalytic cycle for these reactions, using substrates 1a and 2a for illustrative purposes, is shown in Scheme 4. First, heating PEPPSI-IPr with Cu(OAc) 2 is likely to form a palladium diacetate complex 8, which can then undergo cyclometallation with 1a to give palladacycle 9, liberating two equivalents of acetic acid.Migratory insertion of the 1,3-diene 2a with 9 can then occur to give a new palladacycle 10, containing a π-allylpalladium species.An inner sphere C-C bond-forming reductive elimination 19 of 10 then provides the spiroindane 3a and the palladium(0) species 11, which then undergoes oxidation by Cu(OAc) 2 to regenerate 8. Computational studies on the enantioselective Tsuji allylation of enolates, which proceed via intermediates similar to 10, suggests that in those reactions, reductive elimination by a 3,3' pathway 20 is the lowest in energy. 19However, in the reactions presented herein, where the palladium enolate and allylpalladium components are tethered to each other, the mechanism of reductive elimination may well be different.Alternatively, it is possible that the product could be formed by outer sphere nucleophilic attack of an enol onto a πallylpalladium species such as in 12, 21 which in turn could be formed by protonolysis of 10 by AcOH.Further studies will be required to shed more light on the mechanism.In summary, the synthesis of spiroindanes from the palladiumcatalyzed oxidative annulation of 2-aryl cyclic 1,3-dicarbonyl compounds or 1-aryl-2-naphthols with non-or weakly activated 1,3dienes has been reported.This work demonstrates the broad utility of palladium catalysis in oxidative annulations involving C-H functionalization, and increases the scope of carbocyclic products that can be prepared using these reactions.The development of diastereo-and enantioselective variants of these processes, along with investigations into other types of carbocycle-forming oxidative annulations, are topics for further study in our group.
We thank the ERC, EPSRC, University of Edinburgh, and University of Nottingham for financial support.We are grateful to the EPSRC for a Leadership Fellowship to H.W.L.We thank Dr. William Lewis at the University of Nottingham for assistance with X-ray crystallography.

Table 1
Evaluation of conditions for the synthesis of 3a a d a Using 0.25 mmol of 1a.b Yield of isolated product.c Using degassed DMF.d Without Cu(OAc)2.t-Am = tert-amyl.