Divergent Synthesis of Polycyclic Indolines: Copper-Catalyzed

Letter pubs.acs.org/OrgLett

Divergent Synthesis of Polycyclic Indolines: Copper-Catalyzed Cascade Reactions of Propargylic Carbamates and Indoles Tian-Ren Li,† Liang-Qiu Lu,*,† Ya-Ni Wang,† Bao-Cheng Wang,† and Wen-Jing Xiao*,†,‡ †

Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, P. R. China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P. R. China S Supporting Information *

ABSTRACT: Polycyclic indolines are the common and core structural motif of many indole alkaloids that usually exhibit biological activities. Here, we describe two copper-catalyzed cascade reactions between propargylic carbamates and indoles. By doing so, one-step and divergent synthesis of structurally distinct polycyclic indolines, quinoline-fused indolines, C(3a)-indolyl furoindolines, and pyrroloindolines was achieved in high synthetic efficiency and selectivity.

M

any indole alkaloids that commonly exhibit significant biological activities consist of structurally diverse polycyclic indoline scaffolds.1 As illustrated in Figure 1,

Recently, it has been shown that copper-catalyzed propargylation reactions are useful for the construction of complex molecules.5,6 For example, in 2010 a Cu-catalyzed cascade transformation involving a propargylic amination/ Diels−Alder reaction was developed by Nishibayashi and coworkers,6a which efficiently converted propargylic acetates and N-(E)-2,4-pentadienylaniline to unsaturated isoindoles. In 2012, an elegant Cu-catalyzed cascade reaction between propargylic esters and enamines was disclosed by the Hu group, affording bicyclo[n.3.1] products with high efficiency and selecivity.6b With the aim of efficient heterocyclic synthesis via transition-metal-catalyzed cyclizations,7 we designed a new propargylic carbamate reagent in 2016, which has been used for construction of indolines/indoles by us,7c,d as well as 3,4dihydroquinolin-2-ones recently by Gong.8 As a thematic extension, we herein plan to develop two copper-catalyzed cascade reactions of this reagent with 3-substituted indoles, enabling the efficient, selective, and divergent synthesis of quinoline-fused indolines, C(3a)-indolyl furoindolines, and pyrroloindolines. As outlined in Scheme 1, we proposed that a Cu-catalyzed decarboxylative propargylation of indole 2 might proceed smoothly to generate intermediate A.6e,9 Subsequent addition of tosyl amide to the iminium component would deliver quinoline-fused indoline 3 (path a). When the R substituent contains a nucleophilic group XH, an alternative addition of XH to the iminium unit in intermediate A would occur to give intermediate B. Finally, a Cu-catalyzed intramolecular hydroamination would result in C(3a)-indolyl furoindoline or

Figure 1. Selected examples of polycyclic indoline alkaloids.

communesin F and perophoramidine,2 which show important anticancer and insecticidal activities, are two structurally related indole alkaloids incorporated with a quinoline-fused indoline core. Moreover, furoindoline (i.e., physvenine) and pyrroloindoline (i.e., gliocladin B) are also widespread in many bioactive natural alkaloids.3 Their structural complexity and diversity, as well as promising bioactivities, make polycyclic indolines a particularly important target to inspire methodology development. Although a number of elegant strategies have been developed, there are still few approaches to simultaneously access polycyclic indoline scaffolds from the same starting materials with high efficiency and selectivity.4 © 2017 American Chemical Society

Received: June 21, 2017 Published: July 25, 2017 4098

DOI: 10.1021/acs.orglett.7b01903 Org. Lett. 2017, 19, 4098−4101

Letter

Organic Letters

desired quinoline-fused indoline 3a was produced in excellent yield and stereoselectivity (97% yield and >95:5 dr). Further experiments revealed that the copper catalyst was necessary for this transformation (Table 1, entry 2: 0% yield) and CuI was a better catalyst precursor than Cu(OTf)2 (Table 1, entry 1 vs 3). It might be the result of a stronger coordination of Cu(I) with terminal alkynes than that of Cu(II).10 Ligands have a profound influence on the reaction efficiency. For example, the Cucatalyzed cascade process was very slow with reduced diastereoselectivity in the absence of ligand (Table 1, entry 4: 72% yield and 80:20 dr). Other ligands, such as box ligand L2, pybox ligand L4, and diphosphine ligand L5 were also suitable for the present transformation, albeit in relatively lower yields (Table 1, entries 5, 7, and 8). The dipyridine ligand L3 and racemic diphosphine ligand L6 only gave a complex reaction mixture with trace product 4a observed (Table 1, entries 6 and 9). In addition, the solvent effect was studied and dioxane also gave good results (Table 1, entry 10:91% yield and >95:5 dr). With the optimal conditions in hand, we next probed the generality of Cu-catalyzed cascade reactions for the divergent synthesis of polycyclic indolines. As highlighted in Scheme 2, a wide range of structurally diverse quinoline-fused indolines were obtained in high yields and in excellent stereoselectivities

Scheme 1. Divergent Synthesis of Polycyclic Indolines

pyrroloindoline 4. The focus of this research was to determine whether a general and practical strategy could be developed that enable the simultaneous construction of structurally distinct polycyclic indoline scaffolds. Given the diversity of nucleophilic components (i.e., C(3) of indole, TsNH, OH or NHCO2Me) and electrophilic components (i.e., alkyne, iminium) in intermediate species, the challenge associated with this study is the extent of selectivity control during the cascade transformation. Initially, propargylic carbamate 1a and 1,3-dimethyl indole 2a were chosen to examine the feasibility of Cu-catalyzed cascade reactions. We were pleased that this reaction proceeded well in the presence of 5 mol % of copper catalyst consisting of CuI and box ligand L1 and with 2 equiv of iPr2NEt and MeOH as the base and solvent. As indicated in entry 1 of Table 1, the

Scheme 2. Representative Quinoline-Fused Indolinesa

Table 1. Selected Condition Optimizationa

entry

variation of the standard conditions

yieldb (%)

drc

1 2 3 4 5 6 7 8 9 10

none without CuI Cu(OTf)2 instead of CuI without L1 L2 instead of L1 L3 instead of L1 L4 instead of L1 L5 instead of L1 L6 instead of L1 dioxane instead of MeOH

97 0 77 72 94 trace 60 97 trace 91

>95:5 ND 90:10 80:20 >95:5 ND >95:5 87:13 ND >95:5

a Standard condition 1: 1a (0.2 mmol), 2a (0.24 mmol), CuI (5 mol %), L1 (6 mol %), and iPr2NEt (0.4 mmol, 2.0 equiv) in MeOH (2 mL) at ambient temperature for 0.5 h. bIsolated yield. cMajor isomer: ∑(minor isomers) determined by 1H NMR. ND: not determined. Racemic ligands were used here.

a

Standard conditions 1. bln dioxane. cGram-scale reaction: 1 mol % of CuI and 1.2 mol % of L1. 4099

DOI: 10.1021/acs.orglett.7b01903 Org. Lett. 2017, 19, 4098−4101

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Organic Letters through a Cu-catalyzed propargylation/aza-Mannich reaction cascade. The variation of electronic character and substitution position on the benzene ring of propargylic carbamates 3a−e and indoles 3f−j were proven compatible for this cascade reaction; the corresponding quinoline-fused indolines were afforded in 87−96% yields and 87−92% yields, respectively. The reaction with tetrahydrocarbazole was also performed. It has been found that the reaction can form a bridged polycyclic indoline 3k in 81% yield and >95:5 dr. In addition to the substrate diversity, good functional group tolerance at the 3position of indole was observed. For example, indoles having linear or branched aliphatic groups and an unsaturated allylic group can be used as efficient substrates, generating the desired products 3l−n in 84−96% yields and >95:5 dr.11 Moreover, indoles possessing other functional groups, such as ketone, ester, amide and protected alcohol, were suitable for the present transformation, approaching the functionalized polycyclic indolines 3o-3r in 75−97% yields and >95:5 dr. Additionally, with 3r as example, this cascade reaction can be implemented on a gram scale and with a reduced catalyst loading, affording the desired product with a similar results. Furthermore, we turned our attention to the Cu-catalyzed propargylation/hetero-Mannich reaction/hydroamination cascade. As shown in Scheme 3, many propargylic carbamates with

yield and >95:5 dr. Notably, further treatment with 2 equiv of Cs2CO3 at 65 °C for 2 h in one-pot could efficiently promote the rearrangement reaction to give C(3a)-indolyl pyrroloindoline 4g. In addition, replacement of methyl carbamate (2m) with formamide (2q) of indole substrates proved successful, providing the corresponding C(3a)-indolyl furoindoline products 4h and 4i in 78% yield and 73% yield, respectively. Given the significance of chirality in natural products and drugs, we briefly probed the asymmetric process of these Cucatalyzed cascade transformations. When an enantioenriched box ligand L1 was used, two preliminary but encouraging results were observed, producing enantioenriched quinolinefused indoline 3a and C(3a)-indolyl furoindoline 4a in excellent yields with >95:5 dr and moderate enantioselectivities (3a: 73:27 er; 4a: 72:28 dr, see the SI for detail).12 Further endeavors toward the improvement of enantiocontrol are ongoing in our laboratory. The possible reaction pathways to produce quinoline-fused indolines and C(3a)-indolyl furoindolines/pyrroloindolines from propargylic carbamates and indoles are illustrated in Schemes S1−3 in SI. The mechanism profile for the formation of C(3a)-indolyl furoindoline was investigated with control experiments using quinoline-fused indoline 3r. As shown in Scheme 4a, treatment of 3r with TBAF (tetrabutylammonium

Scheme 3. Representative C(3a)-Indolyl Pyrroloindolines and Furoindolines

Scheme 4. Mechanism Studies

Standard conditions 2: same as standard conditions 1, but at 60 °C for another 0.5 h. bStandard conditions 3: same as standard conditions 1, but at 65 °C for another 2 h in the presence of Cs2C03 (2.0 equiv). a

fluoride) in THF (tetrahydrofuran) at low temperature initially afforded the OH-containing quinoline-fused indoline 5 in 99% yield. Then, subjecting 5 to different reaction conditions I−IV gave distinct results, which supported that copper catalysis are crucial for the generation of C(3a)-indolyl furoindolines and base was helpful in accelerating the rearrangement process. Thus, a proposed mechanism is illustrated in Scheme 4b. The retro-aza-Mannich reaction of amine acetal 5 would generate intermediate C in the presence of copper catalyst, which was readily converted into furoindoline intermediate D through an oxa-Mannich reaction. Subsequently, a hydroamination reaction

different substitution on the benzene ring readily reacted with 3-hydroxyethylindole 2o under similar reaction conditions, but at 60 °C (standard conditions 2). Indeed, a series of C(3a)indolyl furoindolines were synthesized efficiently in high yields and excellent diastereoselectivities (Scheme 3, 4a−f: 89−97% yields and >95:5 dr).11 Importantly, the success of the cascade reaction can be extended to 3-amidoethylindoles using a modified procedure. For example, when propargylic carbamate 1a and 3-amidoethylindole 2m were subjected to the copper catalyst system (standard conditions 3), we were pleased to find that C(3a)-indolyl pyrroloindoline 4g was generated in 71% 4100

DOI: 10.1021/acs.orglett.7b01903 Org. Lett. 2017, 19, 4098−4101

Letter

Organic Letters of D would result in the final C(3a)-indolyl furoindoline 4a with the help of the copper catalyst and iPr2NEt. In summary, we have successfully designed and realized two novel Cu-catalyzed cascade reactions of propargylic carbamates with indoles. These transformations enable a one-step, divergent synthesis of multiple types of polycyclic indolines, quinoline-fused indolines, C(3a)-indolyl furoindolines, and pyrroloindolines from readily available staring materials under environmentally friendly conditions. Importantly, the reactions feature simple operation, high reaction efficiency, and selectivity as well as excellent substrate diversity and 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.7b01903. Experimental procedures; spectral data; X-ray crystallographic files for 3l and 4a (PDF) X-ray data for compound 3l (CIF) X-ray data for compound 4a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Liang-Qiu Lu: 0000-0003-2177-4729 Wen-Jing Xiao: 0000-0002-9318-6021 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21232003, 21472057, and 21572074), the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019), and other foundations (Nos. 201422, CCNU15A02007, and 2015CFA033) for support of this research.

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DOI: 10.1021/acs.orglett.7b01903 Org. Lett. 2017, 19, 4098−4101