2020-02-20 15:11:02
Lu Ding, Run-Duo Gao, and Shu-Li You
Fused indolenines are important structural cores of natural products and frequently appear in biologically active mole- cules (Figure 1).[1] Accordingly, extensive efforts have been de- voted to developing efficient methods for the construction of these scaffolds in a highly chemo- and enantioselective manner. In this regard, the recently emerging catalytic asym- metric dearomatization (CADA) reactions provide a large array of methods allowing for efficient access to fused indolenines from readily available indole derivatives.[2] Notably, transition- metal-catalyzed allylic dearomatization reactions of indoles have witnessed significant progresses in the past decade.[3,4,5] Recently, we realized the construction of fused indolenine skeletons in a cascade fashion.[6] In 2014, the Rawal group and we independently reported an intermolecular cascade dearo- matization reaction of indole-based bisnucleophiles with prop- argyl carbonate, leading to a series of spiroindolenines and spi- roindolines. Moderate enantioselectivity (, 77 % ee) was ach- ieved for limited substrates (Scheme 1, reaction 1).[6a,7,8] Rawal and co-workers found that the indole N@H moiety could par- ticipate in the cyclization process when the nucleophilic side chain was decorated at the C2 position of the C3 methyl sub- stituted indole (Scheme 1, reaction 2).[7,9] Herein, we report a chemo- and enantioselective synthesis of multisubstituted fused indolenines by Pd-catalyzed cascade dearomatization of indoles bearing a nucleophile at the C2 position with proparg- yl carbonate (Scheme 1, reaction 3).
We began our studies by examining the reaction of dimethyl 2-[(3-benzyl-1H-indol-2-yl)methyl]malonate (1 a) with methyl prop-2-yn-1-yl carbonate (2) in dimethylacetamide (DMA) in the presence of a Pd catalyst derived from Pd2dba3. Firstly, sev- eral commercially available chiral phosphorus ligands were tested (Scheme 2). The desired product 3a was obtained in moderate yields when Feringa ligand (S,S,Sa)-L1, BINAP (R)-L2, or Synphos (R)-L3 were used. However, the Pd complex de- rived from PHOX ligand (S)-L4 could hardly promote this reac- tion. It is worth noting that the reaction with L1 led to 3a in excellent enantioselectivity and good chemoselectivity (94 % ee, 10:1 3 a/4 a). Encouraged by these results, phosphora- midite ligands L5-L9 were investigated, however, no better re- sults were obtained. Next, further optimization of the reaction conditions was carried out using L1 (Table 1). Reactions in vari- ous solvents, such as DMF, CH2Cl2, and THF, afforded compara- ble yields and enantioselectivity albeit with lower 3 a/4a ratios (entries 2–4), whereas MeOH and PhMe led to almost no reac- tion (entries 5–6). Further evaluation of the concentration (entries 7–11) of 1a revealed that c = 0.2 mol L@1 was optimal in terms of yield (entry 8). Pd2(4-OMe-dba)3 was a better palladium source than Pd2dba3 and [Pd(allyl)Cl]2 (entries 12 and 13).[10] Furthermore, some additives were tested. To our delight, both yield and 3 a/4a ratio were improved remarkably when 4 a molecular sieves were used (82 % yield, 95 % ee, > 19:1 3 a/4 a, entry 15). Finally, the optimized reaction conditions were es- tablished as the following: Pd2(4-OMe-dba)3 (2.5 mol%), L1 (11 mol%), 4 a MS (100 mg) in DMA (1 mL) at 80 8C (entry 15). Notably, 4a could not be converted to 3a under the optimized conditions, suggesting the formation of C@N is likely an irreversible process here.
With the optimized conditions in hands, we then explored the substrate scope of this reaction (Scheme 3). Firstly, sub- strates with different substituents on the benzyl group were examined. Both electron-donating (3b: 4-OMe; 3c: 4-Me; 3d: 3-Me) and electron-withdrawing (3e: 4-F; 3 f: 4-Cl) groups were found to be well tolerated. The corresponding products were obtained in good to excellent yields, with excellent chemo- and enantioselectivities (3 b–3 f, 78–82 % yields, 16.2 :1 to > 19:1 3/4, 93–95 % ee). When the benzyl group was changed to 2-thienyl or 2-naphthyl, the desired products could also be obtained with gratifying re- sults (3g: 79% yield, 15.6:1 3 g/4 g, 96% ee; 3h: 85% yield, > 19:1 3 h/4 h, 96% ee). Next, substrates with different substituents on the indole ring were investi- gated. The dearomatized products were afforded in excellent yields, chemo- and enantioselectivities when an electron-donating group (3i: 5-OMe, 3j: 5- Me) was installed on the indole ring (3i: 84% yield, > 19:1 3 i/4 i, 96% ee ; 3j: 86% yield, > 19:1 3 j/4 j, 92 % ee). Remarkably, when an electron-withdrawing group was introduced on the indole ring (3k: 5-F; 3l: 5-Cl; 3m: 5-Br; 3n: 6-F; 3o: 6-Cl), good to excel- lent yields, C/N ratios and excellent enantioselectivity were obtained (3 k–3o: 73–77 % yields, 4.2:1 to 11.7:1 3/4, 92–94 % ee). Notably, the formation of al- lylic amination products was more favorable when stronger electron-withdrawing group was introduced (from 5-F to 5-Br, 6-F to 6-Cl). These are probably due to the increased acidity of the indole N@H and more easily formed N nucleophiles caused by the electron-withdrawing substituent. When the elec- tron-withdrawing group on substrate 1 was changed from methyl carbonate to ethyl carbonate, the desired product could also be obtained in good results (3p: 71% yield, 18.3 :1 3 p/4 p, 91% ee). Furthermore, when an aliphatic group was in- stalled at the C3 position, all substrates were well tolerated (3 q–3v: 71–85 % yields, > 19:1 3/4 in all cases, 92–94 % ee). The structure and absolute configuration of product 3r were confirmed by an X-ray crystallographic analysis of an enantio- pure example (see the Supporting Information for details). Moreover, substrate 1w bearing a nucleophilic chain at the C3 position underwent the reaction smoothly, affording the bridged indoline 3w in 71 % yield and 96 % ee.
To demonstrate the utility of the current method, a gram-scale reaction and several transformations of the product were carried out (Scheme 4). The asymmetric cascade dearomatization reaction of 1a with 2 on a 3.0 mmol scale provided product 3a in 84 % yield and 95 % ee. Under Pd/C hydrogena- tion conditions, the exocyclic double bond of product 3a was reduced and the benzyl group was also removed at the same time likely due to the driving force of aromatiza- tion, giving 5 in 92 % yield. The imine moiety in 3a could be reduced by NaBH3CN in acetic acid to afford 6 in 91 % yield. The relative configuration of 6 was determined by NOE analysis (for details, see the Sup- porting Information). Treatment of 6 with acetyl chloride and NaH produced 7 in quantitative yield. Finally, the double bond in 7 was oxidized with ozone to give ketone 8 in 64 % yield.
A proposed catalytic cycle is depicted in Scheme 5. The propargyl carbonate is acti- vated by Pd0 to give intermediate. Then, the nucleophilic side chain attacks intermediate to generate p-allyl palladium species. Upon the deprotonation of indole N@H, the C3 position of indole in III attacks p-allyl palla- dium moiety to deliver IV. Finally, product 3 is provided upon the liberation of palladium catalyst.
In conclusion, we have achieved an efficient palladium(0)-catalyzed intermolecular asymmetric cascade dearomatization reac- tion of indole derivatives with propargyl car- bonate. A series of multiply substituted fused indolenines were obtained in good to excellent yields, excellent chemo- and enan- tioselectivities. This method features mild reaction conditions and broad substrate scope. Further studies on the reaction mechanism are currently underway in our laboratory.
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