Letter Cite This: Org. Lett. 2018, 20, 5696−5699
pubs.acs.org/OrgLett
Palladium-Catalyzed Dual C(sp2)−H Functionalization of Indole-2carboxamides Involving a 1,2-Acyl Migration: A Synthesis of Indolo[3,2‑c]quinolinones Lingkai Kong,†,‡ Zhong Zheng,† Rong Tang,† Mengdan Wang,† Yue Sun,† and Yanzhong Li*,† †
Org. Lett. 2018.20:5696-5699. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/21/18. For personal use only.
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China ‡ School of Chemistry and Chemical Engineering, Linyi University, Shuangling Road, Linyi, Shandong 276000, China S Supporting Information *
ABSTRACT: A novel Pd/Cu catalytic system to construct indolo[3,2-c]quinolinones has been developed starting from indole2-carboxamides. Substrates were transformed into indolo[3,2-c]quinolinones through dual C(sp2)−H functionalization of the indole moiety and arene, in which a carbonyl 1,2-migration was involved. The corresponding products were obtained in moderate to excellent yields with a wide substrate scope.
T
he direct C−H bond functionalization has emerged as a powerful strategy to construct C−C and C−X bonds in organic synthesis using transition metal catalysis.1 This synthetic methodology can contribute to atom- and stepeconomic processes without the requirement for prefunctionalization to synthesize a target molecule.2 On the other hand, the indole structures have received great attention for developing selective C−H bond functionalization reactions because of their utility in the syntheses of bioactive products with diverse pharmaceutical properties.3 Many efforts have been focused on these reactions, leading to a variety of transition-metal-catalyzed direct C−H functionalizations of indole.4 The direct C−H functionalization of indole has also been applied to construct fused indole compounds,5 which are frequently found in a variety of natural products and bioactive molecules (Figure 1).6 Among fused indole cores, indoloqui-
Scheme 1. Intramolecular Cyclization Reactions of Indole2-carboxamides or Indole-3-carboxamides
Figure 1. Some bioactive fused indole compounds.
developed another novel synthetic approach for the synthesis of indolo[3,2-c]quinolinones from N-(o-bromophenyl)-3indolecarboxamide using a Pd-catalyst (Scheme 1b). The bromo group on the N-aryl moiety was crucial for the success of this reaction. In spite of this progress, the development of novel methods through direct C−H activation for the synthesis
nolinone is very important due to their potential biological activities.6c,d There are several elegant reports for the syntheses of indoloquinolinones.7 Zhang’s group8 disclosed an efficient synthesis of indolo[3,2-c]quinolinones by the photocyclization of 2-chloro-N-phenyl-1H-indole-3-carboxamides (Scheme 1a), wherein the −Cl group at the C2-position of indole played an important role in this reaction. Yin and Wang’s groups9 © 2018 American Chemical Society
Received: July 30, 2018 Published: September 5, 2018 5696
DOI: 10.1021/acs.orglett.8b02419 Org. Lett. 2018, 20, 5696−5699
Letter
Organic Letters Table 1. Optimization Studies for the Formation of 2aa
entry
catalyst (mol %)
[O] (equiv)
additive (equiv)
solvent
t (°C)
yield (%)
1b 2b 3c 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Pd(OAc)2 (10) Pd(TFA)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (5) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) −
Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) CuCl2 (3) CuSO4 (3) Cu(OAc)2 (3) Cu(OAc)2 (2) Cu(OAc)2 (1) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (3) − Cu(OAc)2 (3)
− − − − PivOH (4) PivOH (2) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6) PivOH (6)
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DCE toluene DMAc DMF DMF
140 140 140 140 140 140 140 140 140 140 140 140 120 150 140 140 140 140 140
62 65 65 74 84 76 91 trace trace 83 89 74 38 86 trace trace 70 trace NP
Reaction conditions: 1a (0.3 mmol), Pd(OAc)2 (10 mol %), [O] (0.9 mmol), PivOH (1.8 mmol), solvent (1 mL), 140 °C, N2, isolated yields. Solvent (6 mL). cSolvent (3 mL).
a
b
of indolo[3,2-c]quinolinones is still highly desirable. However, selective C2−H or C3−H bond functionalization of simple indole derivatives is difficult.10 Recently, we have reported an efficient method to spiro-pseudoindoxyls via copper-catalyzed C2-functionalization of indole-2-carboxamides using TBHP as the oxidant (Scheme 1c).11 As part of our continued interest in the C−H functionalization chemistry of amidoindoles, we herein report an efficient protocol for the selective synthesis of indolo[3,2-c]quinolinones through C3−H/C−H(arene) functionalization involving a 1,2-acyl migration from indole-2carboxamides (Scheme 1d). Initially, indole-2-carboxamide 1a was chosen as a model substrate to optimize the reaction conditions (Table 1). When the reaction was carried out in the presence of 10 mol % of Pd(OAc)2 using 3.0 equiv of Cu(OAc)2 as the oxidant in DMF (N,N-dimethylformamide) at 140 °C under N2, the desired product 2a was obtained in 62% yield (entry 1). Interestingly, the structure of this product is a 5-methyl-5,11-dihydro-6Hindolo[3,2-c]quinolin-6-one. The result reveals that a rearrangement of the acyl group from C-2 to the C-3 position of the indole ring occurred during the cyclization process. 1,2Acyl migration has been considered as an efficient strategy in organic synthesis toward complex compounds which are difficult to form.12 A slightly higher yield was achieved using Pd(TFA)2 as the catalyst (entry 2). From the point of view of economy, we selected Pd(OAc)2 as the catalyst to further explore the reaction conditions. Decreasing the amount of solvent to 1 mL resulted in a higher yield (74%, entry 4). To our delight, the desired product 2a was formed in 84% yield with the addition of 4.0 equiv of pivalic acid (PivOH) (entry 5).13 Further increasing the amount of PivOH to 6.0 equiv could improve the yield of 2a to 91% (entry 7). Then, other oxidants such as CuCl2 and CuSO4 failed to give the desired product 2a (entries 8−9). Reducing the amount of Pd(OAc)2
to 5 mol % gave a lower yield (83%) of 2a (entry 10). When the amount of Cu(OAc)2 was reduced to 2.0 or 1.0 equiv, the yield of 2a was decreased to 89% and 74%, respectively (entries 11 and 12). The yield of 2a dramatically decreased to 38% at a lower temperature of 120 °C (entry 13). A higher temperature of 150 °C also led to a slightly lower yield of 86% (entry 14). Other solvents were also examined such as DCE (1,2-dichloroethane), toluene, and DMAc (N,N-dimethylacetamide). It was found that DMF was the most effective for this reaction (entry 7 vs entries 15−17). Notably, no desired product was obtained in the absence of Pd(OAc)2 or Cu(OAc)2 (entries 18 and 19). Finally, the optimized reaction conditions were concluded to be 10 mol % Pd(OAc)2, 3.0 equiv of Cu(OAc)2, and 6.0 equiv of PivOH in DMF (1 mL) at 140 °C under N2 (entry 7). With the optimal conditions in hand, a series of indole-2carboxamides were examined to determine the scope of this reaction (Scheme 2). First, the effect of different N-alkyl groups (R1) on the amide moiety was investigated. It was found that, in addition to methyl, N-ethyl- or N-benzyl substituted substrates also worked well under the standard conditions, affording the desired products 2b and 2c in 89% and 75% yields, respectively. Then, we examined the electronic effects of different N-aryl substituents (R2). Both the electrondonating and electron-withdrawing aryl substituents (p-CH3, p-nBu, p-OCH3, p-Cl) were efficiently converted to the expected products 2d−2g in good to high yields ranging from 74% to 87%. In the case of ortho-methyl substituted Naryl of indole-2-carboxamide, the desired product 2h was formed in 40% yield possibly due to steric hindrance. When a substrate bearing a methyl at the meta position of N-aryl was employed, an inseparable mixture of regioisomers (2i and 2i′) was obtained in a combined yield of 85% with a ratio of 6:1 (determined by 1H NMR). In addition, the substrate with -3,55697
DOI: 10.1021/acs.orglett.8b02419 Org. Lett. 2018, 20, 5696−5699
Letter
Organic Letters Scheme 2. Scope of the Indolyl Amide 1a
Scheme 3. Control Experiments
Scheme 4. Proposed Reaction Mechanism
a Reaction conditions: 1 (0.3 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 (0.9 mmol), PivOH (1.8 mmol), DMF (1.0 mL), 140 °C, isolated yields. Under nitrogen. The ratio of regioisomers was determined by 1H NMR.
dimethyl on the N-phenyl ring underwent the reaction smoothly to provide the corresponding product 2j in 80% yield. Remarkably, indole-2-carboxamide bearing a tetrahydroquinoline moiety on the amide moiety also underwent the reaction, affording the highly strained polycyclic indole compound 2k in 42% yield. Finally, we also investigated the substituent (R3) effect on the indole ring. Substrates with electron-deficient (5-COOMe, 5-Cl, 5-F) and electron-rich groups (5-OCH3, 6-OCH3) all gave the desired products 2l− 2p in moderate to good yields ranging from 49% to 83%. To gain further insight into the reaction mechanism, some control experiments were conducted (Scheme 3). When NMe-protected indole 3 or substrate 4 bearing an N−H amide group or substrate 5 containing a −CO2(4-MePh) group was applied to the standard reaction conditions, no desired products were formed, indicating that the presence of the free N−H indole and N-alkyl amide moiety in 1a played an important role in this reaction. Subsequently, a radical trapping experiment was employed. The reaction was not inhibited by addition of 3.0 equiv of TEMPO, and 2a was still obtained in 54% yield (Scheme 3a). The results suggested that a radical pathway was most likely not involved in this reaction. By changing the oxidant from copper acetate to oxygen, 2a could still be obtained in 33% yield (Scheme 3b). However, without palladium acetate, product 2a could not be observed (Scheme 3c). These results indicated that copper acetate might serve only as an oxidant. Based on above experiments and the reported literature,14 a possible reaction mechanism is proposed (Scheme 4). Initially, substrate 1a reacts with Pd(OAc)2 to generate the iminium intermediate A. Then, a nucleophilic attack of the N-aryl to the iminium moiety forms the intermediate B, which is further converted to the intermediate C via a nucleophilic addition
process. Subsequently, the formed C undergoes 1,2-acyl migration to give intermediate D. Finally, the desired product 2a is obtained through protonation and oxidative aromatization.15 In summary, we have developed an efficient method to construct indolo[3,2-c]quinolinones starting from indole-2carboxamides in the presence of a Pd-catalyst. The desired fused indole products were selectively formed through dual C(sp2)−H functionalization and 1,2-acyl migration. The reaction possesses a wide substrate scope with easily accessible starting materials and good functional group tolerance.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02419. Experimental details and spectroscopic characterization of all new compounds (PDF) Accession Codes
Accession Codes
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Lingkai Kong: 0000-0003-4162-2837 Zhong Zheng: 0000-0002-3868-006X 5698
DOI: 10.1021/acs.orglett.8b02419 Org. Lett. 2018, 20, 5696−5699
Letter
Organic Letters
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Yanzhong Li: 0000-0002-2898-3075 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grant Nos. 21272074, 21871087) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) for financial support.
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DOI: 10.1021/acs.orglett.8b02419 Org. Lett. 2018, 20, 5696−5699
