Au(I)-Catalyzed Cycloisomerizations Terminated by sp³ C−H Bond Insertion

Abstract

The gold(I)-catalyzed cycloisomerization 1,5-enynes and 1,4-allylallenes to tetracyclododecane and tetracyclotridecane derivatives is reported. Complexation of the cationic gold(I) complex to either the alkyne or the allene moiety induces an intramolecular addition of the alkene leading to gold(I)-stabilized carbenoid intermediate. This intermediate undergoes a formal sp 3 -C-H insertion to generate the tertacyclic adduct. A series of deuterium labeling experiments show that the C-H functionalization step proceeds with an inverse kinetic isotope effect.Cationic gold(I) complexes have emerged as powerful π-acids capable of promoting a diverse range of enyne cycloisomerization reactions. 1 In these reactions, the gold catalyst not only serves to activate the alkyne towards nucleophilic addition,2 but also plays a role in stabilizing the cationic intermediates produced in the cyclization event.3 In many of these cases, the stabilization arises from interaction of the gold catalysts with the directly bonded carbocation. 4 Thus, transformations in which these intermediates display reactivity that is reminiscent of electrophilic metal-stabilized carbenes have been developed. 5,6 However, in contrast to other electrophilic metal-carbenoid species, insertion of the gold-stabilized cationic intermediates into sp 3 -C-H bonds is rare. 7,8 We envisioned that access to such a transformation might provide horino@eng.u-toyama.ac.jp, fdtoste@berkeley.edu. With the aim of examining the potential of cationic gold(I)-carbenoid intermediates to participate in this class of reactions, we revisited the gold-catalyzed cycloisomerization of 1,5-enynes A. 10 While we had previously observed that gold-catalyzed cycloisomerizations of cyclobutane and -pentane derived enynes (A, n=1,2) were terminated by a ring expansion to afford C ,10b we postulated that larger more flexible rings might allow for an intramolecular C-H insertion via gold-carbenoid intermediate B (eq 1). NIH Public Access(1)In order to explore this hypothesis, 1,5-enyne 1a possessing cycloheptyl skeleton at the C4 position was allowed to react under our standard conditions (2% (Ph 3 P)AuCl/AgSbF 6 ) for cycloisomerization of 1,5-enynes (eq 2). We were pleased to find that the reaction proceeded smoothly to provide tetracyclic compound 2a in 75% yield after one hour. On the basis the observation that electron donating ligands are preferred for reactions involving trapping of the gold(I)-carbenoid intermediates, we examined N,N-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and tri(tert-butyl)phosphinegold(I)chloride as catalysts. Gratifyingly, both of these complexes showed improved reactivity (10-15 minutes) in the cycloisomerization reaction and produced 2a in better yield. Notably, in all cases, neither competing deprotonation from gold-carbenoid intermediate B to afford spiro[5.6]dodeca-1,4-diene nor 1,2-alkyl shift to provide ring expansion product (C) were observed.Under these optimized reactions conditions, a number of cycloheptyl or cyclooctyl-substitu...

Theoretical Elucidation of Au(I)-Catalyzed Cycloisomerizations of Cycloalkyl-substituted 1,5-Enynes: 1,2-alkyl Shift versus C−H Bond Insertion Products

“…From the discussion above, it is clear that our present study has provided theoretical validation for Toste's experimental findings 23 that the cycloisomerizations product of cycloalkylsubstituted 1,5-enynes depends on the size of cycloalkyl substituents: the small ones (n ) 1, and 2) result in the ringexpanded three-cyclic product (C) and the large one (for example n ) 4) favors the ring-closed four-cyclic product (D). Furthermore, at a molecular level we have shown the mechanism details of the catalytic rearrangements of 1,5-enynes.…”

Complexity via Gold-Catalyzed Molecular Gymnastics

“…Enynes 25c-d react with catalyst A gave 32a-c and 33a-c by 1,5-migration followed by a formal C-H insertion (Scheme 7). Related formal C-H insertions have been observed in other reaction proceeding through Au or Pt carbenes [83][84][85][86][87][88][89][90]. These results are consistent with a mechanism in which the intermediate a,b-unsaturated gold carbene/allyl-gold cation 34 abstracts a hydride from the ArCH 2 O group to form a g 1 -allyl-gold(I) 35, which reacts at C-1 or C-3 with the oxonium cation to give 32a-c or 33a-c, respectively.…”

C–C bond migration in the cycloisomerization of 1,6-enynes

“…24 Though this variance in reactivity may simply be catalyst- or substrate-dependent, both transformations are thought to proceed through similar carbenoid intermediates. Perhaps, in the oxygen-tethered cases here, stabilization by the adjacent oxygen atom through oxocarbenium formation promotes the alkyl migration for the larger ring substrates.…”