Theoretical evaluation of the carbene-based site-selectivity in gold( III )-catalyzed annulations of alkynes with anthranils †

The gold( III )-catalyzed annulations of alkynes with anthranils were evaluated using DFT calculations. A unified rationale for the Br-migration on a -imino gold( III )-carbene was proposed, from which an unprecedented ‘‘N-donation/abstraction substitution’’ mechanism was established using the substituted anthranils, while direct C–H nucleophilic attack was involved with the unsubstituted anthranils. The controlling factors guiding the site-selectivity were uncovered. These computational studies provide insight for developing new a -imino gold( III )-carbene mediated reactions.

Gold(III)-catalyzed annulations of alkynes 1 with isoxazole derivatives have attracted significant interest since they provide atomand step-economical access to diverse aza-heterocycles found in numerous natural products, organic functional materials and pharmaceuticals. 2 Considerable effort has been devoted to developing gold carbene-promoted reactions 3 for the selective synthesis of azaheterocyclic scaffolds. In this context, three fascinating annulations have recently been developed by the group of Hashmi to construct diverse azacycles through the tuning of nucleophilic sites for gold(III) carbenoid intermediates (Scheme 1) 4,5 Using KAuBr 4 as a catalyst, the reaction of substituted-anthranil 2M with N-benzyl ynamide 1a is proposed to undergo C a -nucleophilic attack to generate the quinoline-fused polyazaheterocycle P a (Scheme 1(1)), 4 while with N-furanylmethyl ynamide 1b undergoes exclusive C b -attack, producing 2-aminopyrrole P b (Scheme 1(2)). 4 Interestingly, the annulation of unsubstituted-anthranil 2N with ynamide 1t under AuBr 3 catalysis, results in the formation of the unprotected 7-acylindole P t , where C t attack is favoured (Scheme 1(3)). 5 The divergence of the nucleophilic site-selectivity at the gold carbene 3 is very interesting but means that access to desired azaheterocycles in a facile and general pattern is challenging. Hence, we decided that it was important to provide an in-depth understanding of the reaction mechanisms and, especially, the inherent origins of the site-selectivity, in order to help generalize these reactions and make them predictable. Mechanistically, according to the general proposal, 6 the reactions in Scheme 1 are assumed to proceed via a direct nucleophilic attack of the C a , C b or C t atom at the carbene C atom. By employing an exhaustive DFT evaluation (see the Computational details in the ESI †), we explored whether the direct attack pathway or other alternative mechanisms could be used to rationalize the observed annulation products. Furthermore, the inherent controlling factors affecting the site-selectivity of these reactions were thoroughly investigated. We anticipate that these results will be informative for the future design of related catalytic reactions. For the 1a system, the DFT-computed free energy profiles are given in Fig. 1. The reaction is initiated by coordination of KAuBr 4 with the CÁ Á ÁC bond of 1a to give AuÁ Á Áp coordinated complex IM1. Then the 2M N atom, acting as a nucleophile, attacks the alkyne internal C atom of IM1 due to the greater electron-deficiency of the internal C over the terminal C, as indicated by the calculated NBO charges (0.385e for the former and À0.443e for the latter). Through TS2-3, the necessary Au(III) carbenoid IM3 can then be formed by cleaving the N-O bond 7,8 with a barrier of 10.9 kcal mol À1 . From IM3, C a nucleophilic attack at carbene C will exclusively produce product P a . Therefore, we firstly evaluated the direct attack mechanism. 9 Unexpectedly, the desired C a -attack denoted as TS3-9 is 3.7 kcal mol À1 less stable than the C t -attack via TS3-4. Therefore, we explored a new mechanism, initiated by one Br(Au) migration. As shown in Fig. 1(black line), one Br(Au) transfers to the carbene C atom to give IM5. The calculations indicate that, through TS3-5, Br-migration occurs with a barrier of only 0.2 kcal mol À1 and is exergonic by 10.8 kcal mol À1 . Subsequently, an unprecedented ''SN2-type N-donation/abstraction substitution'' achieves a formal C b -attack, in which the sp 2 -N atom substitutes with the migrated-Br via TS5-7 (N-donation substitution) and is then replaced by a C b atom via TS7-8 (N-abstraction substitution), affording the five-membered cyclized intermediate IM8. After ring expansion through the C(Au) migration to the C a atom, the target C a -attack complex IM9 is obtained with an energy demand of 14.6 kcal mol À1 relative to IM8. From the formal C a -attack pathway (black line), one can clearly see that three energetically comparable TSs leading to P a , TS3-5, TS5-7, and TS7-8, are lower in energy than TS3-4 (red line) and TS3-9 (blue line). Two crucial factors might be responsible for such energy differences. One is the extremely flat Br-migration due to much smaller structural deformation with slight change of the Br-Au-C(carbene) angle (see Fig. S1 in the ESI †). And the other may be related to the high stability of IM5 after Br-migration, which remarkably reduces the potential energy surface of subsequent processes, making the formation of P a easier. From IM3, other possible reaction scenarios are disfavoured energetically and are given in Fig. S2 of the ESI. † Following IM9, the C a -attached H atom transfers to the sp 2 -N atom resulting in the formation of P a . The calculated results indicate that the (C a )H firstly transfers to one adjacent (S)O atom of the Ts fragment and then is trapped by the sp 2 -N atom with the assistance of KBr. The H-shift step via TS9-10 surmounts an energy demand of 6.5 kcal mol À1 and affords the extremely exergonic intermediate IM10 owning to the formation of the aromatic benzene ring. 10 IM10 then experiences a KBr Br-assisted H-abstraction/donation, smoothly giving rise to the target product P a after dehydration. Along the reaction coordinate, the C b -substitution by the N atom, corresponding to the IM7 -IM8 transformation, is considered as the rate-determining step of the whole reaction and has a barrier of 23.1 kcal mol À1 .
In the case of the 1b annulation, the proposed mechanism of the 1a-system, Au(III)-coordinationanthranil N nucleophilic addition -N-O cleavage -Br-migration -N-donation/abstraction substitution, is applied to rationalize the C b -attack to the C(Au) atom for formation of key intermediate IM18 (1b Cycle, Fig. 2). Then, the reaction is predisposed to chemoselectively cleave the C b -O bond of the furan moiety via TS18-24 to provide IM26. The alternative C(Au)-migration (TS18-21, Fig. S3, ESI †) was also examined and found to be highly unfavourable (À34.7 kcal mol À1 for TS18-21 and À44.9 kcal mol À1 for TS18-24). With the C b -O cleavage, the Br-assisted stepwise H-shift finally produces P b and regenerates the KAuBr 4 active catalyst. Finally, the 1t reaction mechanism was considered (1t Cycle, Fig. 2). After Au(III)coordination, N nucleophilic addition, N-O cleavage and Brmigration, 11 C t -substitution with Br(Au) is selectively favoured, from which the C t -attached H-shift and subsequent dehydration, results in P t formation. The calculated results for other competitive pathways involved in 1b-and 1t-systems are illustrated in Fig. S4 and S5 in the ESI. † We then turned our attention to uncover how the nucleophilic site-selectivity at C a , C b and C t atoms are controlled in these reactions. The relative free energies for the transition states (TSs) of key Br-migration, N-donation substitution and N-abstraction substitution leading to C a /C b selectivity, as well as that of C t -attack resulting in C t -selectivity are summarized in Fig. 3(i). Note that, in 1a-/1b-and 1t-systems, the N-donation substitution TSs (TS5-7/TS16-17 and TS3 0 -5 0 in Fig. 1 and Fig. S4, S5, ESI †) exhibit very similar characteristics for the reaction regions with selected (sp 2 )NÁ Á ÁC(Au) distances of 1.934 Å, C(Au)Á Á ÁBr distance of B3.000 Å and (sp 2 )N-C(N)-C(Au) angle of 89.61. Intriguingly, compared with the N-donation substitution TSs, the competitive C t -attack TSs exhibit almost opposite stability changes (0.2 vs. 3.5 in the 1a-system, À2.9 vs. 7.4 in the 1b-system and 4.9 vs. À2.7 kcal mol À1 in the 1t-system, respectively).
Thus, it is predicted that the site-selectivity is closely related to the geometric constrains of the C t -attack TS. The distinctive degree of the trans-influence of the Br atom is mainly responsible for the bifurcated selectivity at C a /C b and C t atoms. It can be seen in Fig. 3 (ii) that a weaker trans-influence is exhibited in the 1t-system with a Br-C(carbene)-C t bond angle of 151.61 (166.61 in the 1a-system and 166.41 in the 1b-system), which, in turn, makes the interaction of the C t with the C(carbene) atom easier. As a result, smaller energy demand is required for the 1t-system. In contrast, because of the greater Br trans-influence, the resultant larger energy demand forces the 1a-and 1b-systems to follow the N-donation substitution and thus C a /C b selectivity is favoured.
After favourable N-donation substitution followed by N-abstraction substitution in the 1a-/1b-systems, C a -and C b -selectivity was further evaluated. Two selective-determining TSs for the ringexpansion with C a -selectivity and ring-opening with C b -selectivity, TS8-9 vs. TS8-9 0 in the 1a-system and TS18-21 vs. TS18-24 in the 1b-system, were compared and given in Fig. 4. For the 1b-system, the main driving force for the favoured ring-opening might originate from the greater electrostatic OÁ Á ÁC 2 interaction. 12 As shown by the calculated NBO charges, the charges on O and C 2 atoms in TS18-24 are À0.45 and 0.39 e, whereas those of C(Au) and C a in TS18-21 are À0.42 and À0.18 e, respectively. Clearly, the stronger electrostatic attraction involved in TS18-24 is more advantageous to cleave the C b -O bond and thereby generates a relatively lower energy consumption. Nevertheless, significantly different from five-membered ring-opening in the 1b-system, TS8-9 0 in the 1a-system is characteristic of a six-membered ring-opening, in which the C b -C 4 bond rupture will generate a substantially unstable terminal C cation, thereby resulting in a greater energy requirement. Consequently, the reaction is forced to follow a C a -selective ring-expansion via TS8-9.
In summary, the mechanisms and origins of multiple nucleophilic site-selectivity of Au(III)-catalyzed annulations of substituted-anthranil 2M with N-benzyl ynamide 1a and N-furanylmethyl ynamide 1b, as well as that of unsubstituted-anthranil 2N and N-benzyl ynamide 1t, have been elucidated  using DFT calculations. A unified and rational mechanism is presented in Fig. 2. After Au(III) coordination -2M/2N N nucleophilic addition -N-O cleavage to afford gold carbene intermediate C, further Br(Au)-migration affords a common bromide intermediate D. Then, the three competitive reaction sites, C a , C b and C t , selectively attack the Au-attached C atom, resulting in the distinct products. For 1a-/1b-annulations, a common key issue concerning a formal C b -attack is established and involves an unprecedented ''SN2-type N-donation/abstraction substitution'' process. Subsequently, the reaction undertakes either C a -migration -H-shift -Br-assisted H-shiftdehydration to form the C a -attack product P a in the 1a-system or C-O cleavage -Br-assisted H-shift to furnish the C b -attack product P b in the 1b-system. For P t formation in the 1t system, the bromide intermediate, undergoes selective C t -substitution with Br(Au), C t -attached H-shift and dehydration.
For these annulation reactions, the present study indicates that the strength or weakness of the Br(Au) trans-influence dominates the nucleophilic selectivity for the C a /C b or C t atoms. Furthermore, the C a site-selectivity in the 1a-system can be attributed to the rather unstable terminal C cation in the ringopening TS leading to C b -attack, while the strong CÁ Á ÁO electrostatic attraction in the crucial ring-expansion TS is responsible for the preferred C b -selectivity in the 1b-system. In summary, we anticipate that the controlling factors involved in the nucleophilic site-selectivity observed for these reactions can be applied to other transition metal carbene-promoted reactions.
This work was jointly supported by the National Natural Science Foundation of China (21873055)

Conflicts of interest
There are no conflicts to declare.