Gold-catalyzed (4+3)-annulations of 2-alkenyl-1-alkynylbenzenes with anthranils with alkyne-dependent chemoselectivity: skeletal rearrangement versus non-rearrangement

Two distinct (4+3)-nitroxy annulations between 1,5-enynes and anthranils have been developed to access tetrahydro-1H-benzo[b]azepine derivatives.


Introduction
Cyclic nitroxy species (N-O) are widespread functionalities in numerous bioactive molecules and natural products. 1 Tetrahydro-1H-benzo [b]azepines bearing a hydroxyl (I-IV) represent a family of privileged seven-membered azacycles, 2 possessing potent activities in antiparasitic disease, antidiuretic hormone receptors and b 2 adrenergic agonists. 3 Synthetic procedures for compounds I-IV are generally long and tedious. 2 A short route to construct tetrahydrobenzo [b]azepine cores involves the development of stereoselective (4+3)-annulations between anthranils and allcarbon 1,3-dipoles (eqn (1)), but only donor-acceptor cyclopropanes were shown to be applicable substrates. 4 We are aware of no p-bond motifs that can serve as effective 1,3-dipoles. 5 Synthetic interest in isoxazoles and anthranils is rapidly growing in Au-and Pt-catalysis because of their various annulations with alkynes. 6,7 Nevertheless, these hetero-aromatics serve as nucleophiles that attack p-alkynes via a N-or O-attack route, inevitably cleaving the N-O bonds; selected examples are provided in eqn (2) and (3). We sought the rst (4+3)-nitroxy annulations using alkyne-based 1,3-dipoles and anthranils. This work reports two distinct (4+3)-annulations of 1,5-enynes with anthranils; interestingly, the chemoselectivity varies with the alkynes. Terminal 1,5-enynes 1 (R ¼ H) afford seven-membered nitroxy heterocycles 3 via an unprecedented rearrangement in gold catalysis; 8 the mechanism of this novel rearrangement has been elucidated. Annulation products 5 derived from internal alkynes 4 are not skeletally rearranged, but are elaborated into various benzo [b]azepine frameworks (Fig. 1).
Annulations with N-O cleavages
We performed the reductive N-O cleavage of compounds 3a and 5a to manifest their synthetic utility. Treatment of species 3a with Zn in AcOH/MeOH/H 2 O 10 gave compound 6a in 89% yield while the reaction with Pd/H 2 gave compound 6b efficiently. Alternatively, compound 5a was hydrolyzed with HCl/ water to yield ketone derivative 7b that was convertible to 1amino-5-ol 7c with Zn/AcOH reduction, and to the diol derivative 7d with Pd/H 2 reduction. An imine reduction of species 5a was achieved with Pd/H 2 to afford species 7a. Unexpectedly, Znreduction of species 5a in HOAc/MeOH/water led to a structural rearrangement to form compound 7e in 81% yield. The imine moiety of the initial 5a was incorporated into the structural skeleton of product 7e, but the mechanism is not clear at this stage. Molecular structures of compounds 7a and 7e were veri-ed by X-ray diffraction. 9 The mechanism for the transformation of 5a into 7e will be elucidated in a future study (Scheme 1).
Among the two nitroxy annulations, the mechanism for terminal 1,5-enynes 1a is difficult to deduce because its cycloisomerization product 1a 0 is not skeletally rearranged. We prepared 13 C-1a containing 12% 13 C at only the ]C-H carbon, and its resulting product 3a contained the 13 C-content only at Table 3 Reactions with internal 1,5-enynes and anthranils a 4/2 ¼ 1 : 2.1, [4] 0.20 M. b Yields of the products were reported aer isolation on a silica gel column. the alkyl C-H carbon (eqn (6)). Isobenzofulvene species In 1 was unlikely to occur here although it was observed in a rutheniumcatalyzed cycloisomerization. 11 In the presence of D 2 O, we found that the resulting d 1 -3a contained deuterium (X ¼ 0.29D) only at its alkenyl C-H moiety (eqn (7)). Accordingly, goldcontaining isobenzofulvene In 2 is compatible with these 13 C and 2 H-labeling experiments.
(6) (7) Scheme 2 depicts the mechanisms of the two annulations. Internal 1,5-enynes 4 react with LAu + to form cyclopropyl gold carbenes B (or B 0 ) in two resonance forms; exo-(4+3)-annulations of species B 0 with anthranils 2a likely yield goldcarbene species C that subsequently capture a second anthranil to yield products 5. This mechanism is essentially the same as that of their annulations with nitrosoarenes. 12 Herein, a stepwise mechanism for the annulation of anthranils with 1,3dipoles B/B 0 is also likely to occur. Terminal 1,5-enyne 1a also generates cyclopropylgold carbene E because its cycloisomerization product 1a 0 is also a 1-vinylindene derivative. We envisage that the cyclopropyl C-H proton of gold carbene E is acidic because of its proximity to the gold carbene functionality; the deprotonation with anthranil 2a generates cyclopropylidenylgold species F that undergoes a "methylenecyclopropane-trimethylenemethane" rearrangement, 13 further generating gold-containing isobenzofulvene species In 2. An exo-(3+4)-annulation between fulvene In 2 and anthranil 2a affords the observed product 3a. The intermediacy of organogold species G is supported by 2 H and 13 C-labeling experiments.
Density functional theory calculations were then performed to investigate the feasibility for the key steps D / G. Four possible paths 1-4 are considered; Path 1 is our proposed mechanism in Scheme 2. The energy prole is provided in Scheme 4. The formation of cyclopropylgold carbenes E from palkyne D has a low barrier of 9.1 kcal mol À1 ; the anionpromoted deprotonation of gold carbene E to form Scheme 1 Reductive cleavage of the N-O bonds.
Scheme 2 Plausible mechanisms for rearrangement and nonrearrangement. cyclopropylidenylgold species F is operable as the enthalpy cost is 16.9 kcal mol À1 ; the energy of species F is slightly higher than that of p-alkyne D by only 6.6 kcal mol À1 . The remaining steps F / In 2 and In 2 / G are also operable as the transition states TS-F-In2 and TS-In2-G are close to p-alkyne D energy levels. One notable feature is that the enthalpy of transition state TS-F-ln2 is surprisingly smaller than that of species F by À0.3 kcal. This atypical case has similar precedents in the literature. 14 This is because TS-F-In2 has less zero-point vibration energy than F, due to the loss of one degree of freedom in the transition state. This also means that F / In2 is a barrierless process. We next examined the energy proles in the (4+3) annulations (Path 2) between cyclopropyl gold carbenes E and anthranil 2a. The reaction proceeds in a stepwise manner. As shown in Scheme 5, the N-attack of anthranil 2a at gold carbene E produces species E step by an endothermic process (H ¼ 13.6 kcal mol À1 ); its activation energy is as high as 25.4 kcal mol À1 . In the next step involving E step / GH, the energy level of TS-E step -GH is higher than that of 1,5-enyne D by 18.1 kcal mol À1 . We conclude that Path 2 is not as feasible as Path 1 according to Scheme 5. We also considered the remaining Paths 3 and 4, as depicted in Scheme 3. In Path 3, the deprotonation and ring rearrangement take place simultaneously (E / In2), in contrast to a stepwise process in Path 1 (E / F / In2). Despite multiple attempts, we were unable to locate the transition state for the direct E / In2 step, suggesting that Path 3 probably does not exist. In Path 4, a ring opening takes place initially (E / In2-H), followed by deprotonation (In2-H/In2). However, our calculations show that this pathway is unlikely to occur as we are unable to locate In2-H; all geometry optimizations lead to E.

Conclusions
Before this work, Au-and Pt-catalyzed annulations of anthranils with alkynes typically produced azacyclic products that cleaved the N-O bonds. To develop new (4+3)-annulations of alkyne-derived 1,3-dipoles 15 with anthranils, we achieve stereoselective synthesis of two classes of tetrahydrobenzo [b]azepines using 1,5enynes, anthranils and a gold catalyst. Internal 1,5-enynes deliver these cyclic nitroxy species without skeletal rearrangement while their terminal alkyne analogues afford distinct annulation products with skeletal rearrangement. To elucidate the mechanism of this rearrangement, 2 H and 13 C-labeling experiments were performed to identify the intermediates of gold-containing isobenzofulvene species, the formation of which is dependent on the presence of anthranils.

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