Reaction Optimization.
We commenced our studies by investigating the reaction of indole-2-carbaldehyde 1a and 2,2,2-trifluoroacetophenone 2a as the model substrates, K2CO3 as the base, DQ as the oxidant, tetrahydrofuran (THF) as the solvent, and the results are briefly summarized in Table 1. When L- phenylalanine-derived triazolium NHC precatalyst A was exploited, the expected cycloadduct 3a was not observed. Replacing mesitylene group with pentafluorophenyl group triazolium NHC precatalyst B gave desired product 3a in 40% yield and 0% ee, whereas the use of precatalyst C and D resulted in almost no reaction. To our delight, when indanol-derived triazolium catalyst E was tested, the [10+2] cycloadduct 3a was successfully formed in 61% yield with 35% ee and implies that this highly enantioselective [10+2] annulation can be achieved in the presence of ideal conditions. The catalytic performance could be further improved by changing the X group of precatalyst E from H to NO2 (entry 6). After evaluating bases and solvents, we found that a combination of PhCO2Na as the base and hexane as the solvent gave the product 3a in 80% yield and 88% ee (entry 10). Improvements in yield and enantioselectivity were found when thiourea was used as the additive to form 3a (entry 12, 85% yield, 91% ee).
Substrate Scope.
With the optimal catalytic system in hand, we moved our attention to explore the generality of this asymmetric higher order [10+2] annulation. As illustrated in Scheme 2, by reacting with indole-2-carbaldehyde 1a, an array of aryl trifluoromethyl ketones 2 were examined firstly. In the reactions to generate the [10+2] cycloadducts 3, yields and enantioselectivities were found to be independent on the electronic properties of the substituents on aryl group in 2 (3b-i). When the heteroaryl trifluoromethyl ketones were reacted with indole-2-carbaldehyde 1a under optimal conditions, an [10+2] annulation was efficiently realized in all cases (3j-n). Reactions attempted using the alkyl trifluoromethyl ketones gave their corresponding [10+2] cycloadducts in good yields with high ee values (3o and 3p). Whereas the alkenyl trifluoromethyl ketone 2q was reacted with 1a, product 3q was also obtained in a good yield (73%) but with a slightly diminished enantioselectivity (72% ee). Switching the fluorinated substituent from CF3 to CF2H, ClCF2 or C2F5 in ketones, synthetic useful yields and high to excellent enantioselectivities were still obtained under current conditions (3r-t).
Next, we turned our focus to investigate the scope of substrate 1. Different substituents and substitution patterns on the indole skeleton were examined comprehensively. Electron- withdrawing substituents such as halo (4a and 4b) units on the phenyl ring of the aldehyde substrates were well tolerated. Electron-releasing groups such as methyl (4c, 4e, 4f and 4g) and methoxyl unit (4d) could also be installed on the indole scaffold of the aldehyde substrates. It is worth to noting that this [10+2] protocol could be extended to a higher order [14+2] cycloaddition, affording their corresponding cycloadducts (4h and 4i) in good enentioselectivities albeit with acceptable but dropped yields under the current standard conditions. The absolute configuration of 3e (CCDC 1961662) was determined by single-crystal X-ray analysis and other products were assigned by analogy.
Postulated Mechanism:
A postulated catalytic mechanism of [10+2] annulation is summarized in Fig. 4. The addition of NHC precatalyst F to aldehyde 1 in the presence of base generates Breslow intermediate I67,68, which is subsequently oxidized to the key NHC-bounded aza-benzofulvene intermediate II. A mass correlating to intermediate II was observed via high-resolution mass spectrometry (See SI (supplementary information) for details). This critical intermediate II can promote a cascade Michael /acylation sequence, a C-O bond is formed via II to form intermediate III, which undergoes N-acylation to release the NHC catalyst F for next catalytic cycle. At current stage, the concerted [10+2] pathway for this reaction can’t be ruled out in the absence of evidences (for more detalis ,please see SI).
To further reveal the enantioselectivity of this [10+2] annulation, density functional theory (DFT) calculation was performed to study the key step of nucleophilic attack of intermediate II onto trifluoroacetophenone. As shown in Figure 1, two transition states named TS(II-III)R and TS(II-III)S was located, where the re- or si-face of trifluoroacetophenone was attacked respectively. The calculated relative free energy of transition state TS(III-IV)R is 5.0 kcal/mol lower than that of TS(II-III)S, which predicts that the generation of R-configuration product 4a is favorable. The calculated result is consistent with experimental observations. The geometry of those two transition states are also given in Figu. 5. After the absorption of indole reactant onto NHC catalyst, a strong π-π stacking between indolyl moiety and the aryl in NHC catalyst can significantly stabilize the deprotonated indolyl moiety. The π-π attraction is clearly shown in calculated noncovalent interaction (NCI) maps (we also carried our kinetic experiment to prove it, please see SI). When the nucleophilic attack occurs, trifluoromethyl of trifluoroacetophenone appears at the more bulky inner side in transition state TS(II-III)R. It is more favorable than the case in transition state TS(II-III)S that phenyl group is set to inner side. The NCI map of transition state TS(II-III)R clearly reveals that the repulsion between phenyl group of trifluoroacetophenone and the NHC catalyst leads to instability of transition state TS(III-IV)S, while this repulsion is absent in transition state TS(II-III)R.
Synthetic transformations and applications:
Our protocol is amenable for large-scale preparation. For example, the use of standard conditions was sufficient to produce 4d (1.29 g) in 92% yield and with 90% ee (Fig. 6a). A facile Pd-catalyzed Suzuki coupling of 3d with 4-methoxyphenylboronic acid 5 led to product 6 in a 72% yield and with a remained enantioselectivity (Fig. 6b).