Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives via an Au-π-allene intermediate

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives; the reaction mechanism involves alkyne attack on a gold π-allene to yield a vinyl gold carbene.


Introduction
The advent of gold catalysis has greatly promoted the synthetic utility of alkynes. Apart from the functionalizations of alkynes with O, N and C based nucleophiles, gold catalysts also accelerate the development of new alkyne annulations 1 with p-bond motifs. Isoxazoles are readily available aromatic heterocycles; interest in their gold-catalyzed alkyne annulations 2,3 is rapidly growing because of the easy generation of a-imino gold carbenes (eqn (1)). Ye and coworkers reported the rst [3 + 2]annulations of ynamides with isoxazoles to deliver pyrrole derivatives via a-imino gold carbenes In-1 (eqn (1)). 3a-c The use of electron-decient alkynes also afforded pyrrole products with similar carbene intermediates. 3d We employed 1,4-diyn-3-ols to seek other azacycles, 4 but still producing pyrrole derivatives via a 1,2-alkyne migration to a-imino gold carbenes (eqn (2)). Despite intensive efforts, the strong preference toward pyrrole products limits the utility of these isoxazole/alkyne annulations. Similar p-alkyne routes were observed for the anthranil/alkyne annulations, yielding indole derivatives. 5 We sought to achieve the synthesis of other azacyclic compounds beyond pyrrole or indole derivatives; generation of intermediates other than aimino gold carbenes is a viable route. This work reports goldcatalyzed bicyclic annulations of 4-methoxy-1-allenyl-5-ynes with isoxazoles to form 8-and 7-formylindolizines 3 and 5; the structural rearrangement of products is noted here (eqn (3)). We postulate an atypical mechanism for these bicyclic annulations via a 1,4-alkyne migration, activated by a gold p-allene intermediate; the resulting vinyl gold carbene In-3 is trapped by an isoxazole to enable initial sequential cyclizations before delivering indolizine products. This new annulation rationalizes the carbon source of indolizines 3 and 5 from the two reactants well.

(5)
We performed a series of experiments to elucidate the mechanisms of formation of 8-and 7-formylindolizines 3 and 5. We prepared 13 C-enriched 1a and 4e; each contained 10% 13 C content in the CH-OMe carbon. Their resulting products 13 C-3a and 13 C-5e were found to have the enrichment at the aldehyde carbons (eqn (6) and (7)). We prepared d 2 -1a bearing ]CD 2 at the allene C(1)-carbon; its resulting indolizine d 2 -3a comprised equal deuterium content (X ¼ Y ¼ 0.72 D) at the two pyrrolyl carbons. We also performed a crossover experiment involving d 2 -1a and d 0 -1b; this mixture only produced d 2 -3a and d 0 -3b according the mass analysis. The entire 1,2-dienyl-5-yne skeleton 1 remained completely on the resulting indolizine molecule. (6) (7) (8) (9) According the structural analysis of the resulting indolizines 3 and 5, we postulate a mechanism involving an alleneactivation route. This mechanism rationalizes the deuterium and crossover experiments well (eqn (8) and (9)). We use d 2 -1a (R ¼ H) as a tool to verify the mechanism. In the N-attack of isoxazole 2a with Au-p-alkyne a, the resulting intermediate b has a highly aromatic isoxazole ring that is difficult to cleave. We postulate an alternative path involving nucleophilic attack of an alkyne at its tethered Au-p-allene A to form vinyl cation B. An alkyne as a nucleophile to attack an electrophilic Au-p-allene is noted in gold catalysis. 12 We conceive that this vinyl cation induces a subsequent C-C bond cleavage of species B to form phenylalkyne species C bearing an allyl cation C, as stabilized by the gold and methoxy group. This species has a resonance form of vinyl gold carbene that reacts smoothly with isoxazole to yield a 3imino-2-en-1-al D with Z-conguration. 13 An amination on the alkyne of species D is expected to form an azacyclic intermediate E which leads to the desired pyrrole intermediate F. For mono-substituted allenes 1 (R ¼ H), a further carbonyl-ene reaction of species F yields pyrrole-fused sixmembered species G, which loses MeOH to yield 8-formyl indolizine 3a. In the case of a 3,3-disubstituted allene 4 (R ¼ alkyl), a 1,2-formyl shi to the neighboring carbocation occurs preferentially to give 7-formyl indolizine derivative 5a (Scheme 2).
This postulated mechanism rationalizes a small loss of deuterium content of the indolizine product d 2 -3a (X ¼ Y ¼ 0.72 D), as depicted in eqn (8). In the hot DCE solution (65 C 12 h), an imine-enamine tautomerization, as shown by species D and H, results in a deuterium loss of species D because of an exchange with residual water. In this mechanism, a major concern is the cleavage of the sigma C-C bond of species B to yield vinyl gold carbene C.
Calculations with density functional theory (B3LYP) were performed to support our proposed mechanism. Attention was paid to the transformations of the gold p-allene intermediate A (Fig. 1) to gold pyrrolium (F), since the last few steps are well known in organic reactions. 1,4-Alkyne migration of A to form C is a stepwise process: transformation A / B occurs with DH ‡ /DH ¼ 11.0/À0.7 kcal mol; cleavage of the C-C bond of species B results in the formation of intermediate C with DH ‡ /DH ¼ 5.7/À7.3 kcal mol À1 . Species C is subsequently attacked by an isoxazole to generate C 0 with DH ‡ /DH ¼ 11.1/1.0 kcal mol À1 . Next, the ligation of another IPrAu + to species C 0 is expected to form a digold species C 00 with DH ¼ À13.4 kcal mol; this process is accompanied by a N-O cleavage of the isoxazole moiety of species C 00 to generate D 0 with DH ‡ /DH ¼ 5.7/À21.8 kcal mol À1 . Finally, a release of IPrAu + from species D 0 eventually yields a gold-palkyne D with DH ¼ À4.2 kcal mol; an intramolecular cyclization of species D generates gold-containing pyrrolium species F with no kinetic barrier and DH ¼ À21.1 kcal mol À1 . In this D / F step, the electronic barrier is 0.01 kcal mol À1 , which disappears aer correction for zero-point energy. Overall, all the kinetic barriers are less than 11.1 kcal mol À1 with all the steps being thermodynamically downhill except the step C / C 0 (DH ¼ +1.0 kcal mol À1 ). The entire reaction (A / F) releases an enthalpy À67.5 kcal mol À1 . Our calculations thus show that the entire process is kinetically facile and thermodynamically favorable, verifying the proposed mechanism.
We also perform the calculation on a competitive reaction involving gold p-alkyne intermediates a, which has energy 1.3 kcal mol À1 greater than that of the gold p-allene (A). The attack of an isoxazole on p-alkyne a generated alkenylgold species b with DH ‡ /DH ¼ 13.0/3.5 kcal mol À1 . This was followed by a ring-opening reaction to form a-imino gold carbene g with DH ‡ /DH ¼ 4.9/À8.9 kcal mol À1 . Notably, the barrier for formation and the energy state of intermediate b are greater than those of all intermediates in the p-allene route. We conclude that this p-alkyne route is unlikely to play an important role in the reaction.

Conclusions
In summary, we report new gold-catalyzed bicyclic annulations between 4-methoxy-1,2-dienyl-5-ynes and isoxazoles to form 7and 8-formyl indolizine derivatives. 13 This reaction process does not follow a typical p-alkyne route; a-imino gold carbenes 14,15 do not form here. Instead, the mechanism involves p-allene intermediates to induce a 1,4-alkyne shi, yielding a vinyl gold carbene C that is trapped with an isoxazole to generate an a-imino-2en-1-al. Gold-catalyzed sequential cyclizations of this imine intermediate enable the construction of an indolizine skeleton. This mechanism rationalizes the isotope labeling and crossover experiments well. New versions for these gold-catalyzed annulations will be helpful for the design of new catalysis.

Conflicts of interest
There are no conicts of interest to declare.