An Approach to 3-(Indol-2-yl)succinimide Derivatives by Manganese

Letter pubs.acs.org/OrgLett

An Approach to 3‑(Indol-2-yl)succinimide Derivatives by ManganeseCatalyzed C−H Activation Shuang-Liang Liu, Yang Li, Jun-Ru Guo, Guang-Chao Yang, Xue-Hong Li, Jun-Fang Gong,* and Mao-Ping Song* College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450001, P. R. China S Supporting Information *

ABSTRACT: The manganese-catalyzed addition of C-2 position of indoles to maleimides has been achieved under additive-free conditions. The manganese catalyst exhibits excellent chemo- and regioselectivity, good functional group compatibility, and high catalytic efficiency. The substrate scope can also be extended to maleates, ethyl acrylate, 1,4-dihydro-1,4-epoxynaphthalene, pyrroles, and 2-phenylpyridine, which further demonstrates the universality of this straightforward approach.

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C−H functionalization reactions for the construction of valuable succinimide derivatives.4,19 In continuation of our interest in inexpensive metal-catalyzed auxiliary-assisted C−H functionalizations,20 herein we report a manganese-catalyzed addition of the C-2 position of indoles to maleimides under additive-free conditions. This protocol offers a direct and reliable approach to a variety of 3-(indol-2-yl)succinimide derivatives with solely C-2 selectivity and good to excellent yields. Our studies were initiated by employing indole 1a and Nphenylmaleimide 2a as the model substrates (Table 1). Delightedly, the reaction occurred solely at the less nucleophilic C-2 position of indole in the presence of Mn2(CO)10 as the catalyst and hexane as the solvent, giving the 3-(indol-2yl)succinimide 3a in an inspiring isolated yield (71%, entry 1). The molecular structure of 3a was confirmed by X-ray crystallography (CCDC 1551378, see the Supporting Information). No product was observed in the absence of Mn2(CO)10 (entry 2). As a comparison, MnBr(CO)5 gave a lower yield (35%) and the yield was improved to 65% with the assistance of Cy2NH (entry 3). Simple manganese salts, for instance, MnCl2, MnSO4, and Mn(OAc)2, exhibited no catalytic activity (entries 4−6). Screening of some other transition metal catalysts all gave inferior results (entries 7−12). For example, rhenium, a member of the manganese subgroup, delivered 3a in only 33% yield (entry 7). A ruthenium carbonyl catalyst such as Ru3(CO)12 also showed low catalytic efficiency (entry 8). In addition, Fe3(CO)12, Pd(OAc)2, and Ni(COD)2 were all ineffective catalysts (entries 9−11). Further investigation of solvents (entries 12−15 and the SI) revealed that ethyl acetate (EtOAc) led to an excellent yield of 3a (90%, entry 15).

uccinimides not only belong to important natural and pharmaceutical products but also act as versatile precursors for chemical synthesis.1 Likewise, the indole moieties are widely found in natural products and medicinal molecules, and the indole and its derivatives have been used as key precursors in organic synthesis.2 Although the functionalization of indoles has been extensively explored,2d−f installation of the succinimide moiety onto the indole ring has lagged behind. In this regard, the 3-(indol-3-yl)succinimides can be easily prepared through Michael addition of C-3 position of indoles to maleimides under Lewis acid catalysis.3 However, introduction of succinimides on the less nucleophilic C-2 position of indoles using traditional methods seems difficult. Up to now, there have only been two reported examples of addition on the C-2 position of indoles to maleimides where the Ru(II) or Co(III) catalyst was employed.4 In these reports, additives were also needed to achieve a satisfactory conversion rate. In recent years, direct functionalization of inert C−H bonds has emerged as a straightforward, atom- and step-economical tool in organic synthesis.5 Various second-row and even firstrow transition metals including Fe,6 Co,7 Ni,8 Cu,9 Ru,10 Rh,11 as well as Pd12 were employed as catalysts and well-studied in such processes. However, manganese, known as the third most naturally abundant transition metal in earth’s crust, was largely untapped in this realm.13 So far, only sporadic examples contributed by Kuninobu/Takai,14 Wang,15 Ackermann,16 Glorius,17 and others18 were reported, which mainly focused on insertions of polar multiple bonds and nucleophilic additions. For example, Wang et al. have successfully achieved ortho-directed addition of 2-arylpyridines to α,β-unsaturated carbonyls including acrylates and enones through manganese(I)-catalyzed, amine-accelerated C−H functionalization.15b On the other hand, maleimides have been proven to be appropriate partners in Rh-, Ru-, and Co-catalyzed as well as Cu-mediated © 2017 American Chemical Society

Received: June 13, 2017 Published: July 26, 2017 4042

DOI: 10.1021/acs.orglett.7b01795 Org. Lett. 2017, 19, 4042−4045

Letter

Organic Letters

good to excellent yields (3c−p, 46−90%). These substituents include methyl (3c, 3j, 3o), methoxy (3d, 3f, 3p), ester (3e), and cyano (3k) groups. In addition, it is noteworthy that a wealth of halogenated indole substrates reacted smoothly with N-phenylmaleimide to give the corresponding products with halogens intact (3g−i,l−n), which made further elaboration of the products possible. As expected, C-3 substituted substrates showed lower reactivity, largely due to the steric hindrance (3b and 3c).18c Besides indoles, pyrroles were also amenable to this transformation, affording the 3-(pyrrol-2-yl)succinimides in synthetically valuable yields (3q−t, 33−74%). Furthermore, 2phenylpyridine was compatible with the current system, leading to the formation of 3u in an acceptable yield. Next, the range of maleimides was examined. As shown in Scheme 2, the N-4-bromophenyl, N-4-acetylphenyl, and N-4-

Table 1. Optimization of Manganese-Catalyzed C−H Activationa

entry

catalyst

solvent

3a (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Mn2(CO)10

hexane hexane hexane hexane hexane hexane hexane hexane hexane hexane hexane acetone Et2O THF EtOAc

71 0 35/65b 0 0 0 33 30 0 0 0 70 63 69 90

MnBr(CO)5 MnCl2 MnSO4 Mn(OAc)2 Re2(CO)10 Ru3(CO)12 Fe3(CO)12 Pd(OAc)2 Ni(COD)2 Mn2(CO)10 Mn2(CO)10 Mn2(CO)10 Mn2(CO)10

Scheme 2. Substrate Scope of Maleimidesa

a

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol %), solvent (1.0 mL), air, 120 °C, 12 h. Isolated yields. bCy2NH (20 mol %) was added as an additive.

Notably, the succinimidated product at the C-3 position of indole and the Heck-type product were not observed in the present catalytic system. The scope of indoles was then investigated under the optimal reaction conditions (Scheme 1). In general, substituents with both electron-withdrawing and electron-donating properties on the C-3 to C-7 position of indoles were all well tolerated, providing the desired 3-(indol-2-yl)succinimide derivatives in Scheme 1. Substrate Scope of Indolesa a

Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Mn2(CO)10 (10 mol %), EtOAc (1.0 mL), air, 120 °C, 12 h. Isolated yields. bReaction conditions: 1a (0.2 mmol), dimethyl maleate (0.6 mmol), Mn2(CO)10 (10 mol %), Cy2NH (20 mol %), Et2O (0.5 mL), air, 100 °C, 12 h.

hydroxyphenyl maleimides reacted smoothly with indole 1a to give the desired products in good yields (4a−c, 75−80%). The N-alkyl maleimides including methyl, ethyl, and tert-butyl also displayed high reactivity under standard reaction conditions (4d−f, 63−84%). However, slightly lower reactivity was observed in the case of N-benzylmaleimide (4g, 48%). Delightedly, the 3-maleimidopropionic acid substrate exhibited extremely high reactivity, affording the corresponding product 4h in a 96% yield. We were also excited to find that maleimide itself was an appropriate substrate (4i, 66%). Furthermore, the maleimide substrate scope could be extended to maleate esters to deliver the 2-(indol-2-yl)succinic esters in moderate yields (4j,k). Notably, an excellent yield of 4j (95%) was obtained under the modified reaction conditions. Finally, the reactions of ethyl acrylate as well as 1,4-dihydro-1,4-epoxynaphthalene with indole 1a also proceeded efficiently to furnish the expected addition products under the optimal conditions (4l,m), which further demonstrated the wide applicability of our protocol. Succinimide frameworks have been demonstrated to be useful precursors for diverse functional molecules, including γ-

a

Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Mn2(CO)10 (10 mol %), EtOAc (1.0 mL), air, 120 °C, 12 h. Isolated yields. 4043

DOI: 10.1021/acs.orglett.7b01795 Org. Lett. 2017, 19, 4042−4045

Letter

Organic Letters keto amides, diamides, dicarboxylic acids, pyrrolidines, hydroxy lactam rings, etc.21 Furthermore, we found that under the treatment of LAH in THF at room temperature compound 3a could be reduced to form the corresponding pyrrole derivative 5, which gave the compound 6 after depyridination as depicted in Scheme 3.

Scheme 6. C−H Additions with Cyclometalated Complex 7

Scheme 3. Synthetic Application Scheme 7. Proposed Mechanism

A serendipitous cascade addition process was revealed during the course of our study (Scheme 4). When Cy2NH was used as Scheme 4. Cascade Addition

also act as a base in the current catalytic system, see the SI for details) C−H manganesation of 1a with Mn2(CO)10 forms the cyclometalated complex 7.23a Thereafter, coordination of maleimides 2 to 7 leads to the formation of complex 8 along with the release of one binding CO. The subsequent insertion of olefin into the Mn−Caryl bond furnishes the intermediate 9.23b Finally, in the presence of another 1a, 9 undergoes protonative demetalation to produce the desired product 3a or 4 and regenerates the catalytically active manganese complex. In summary, we present herein the manganese-catalyzed addition of C-2 position of indoles to maleimides assisted by a pyridine directing group. This simple and efficient method allows the synthesis of a wide range of synthetically meaningful 3-substituted succinimide derivatives in good to excellent yields under additive-free conditions. Furthermore, maleates, ethyl acrylate, 1,4-dihydro-1,4-epoxynaphthalene, pyrroles as well as 2-phenylpyridine are also suitable substrates, which convincingly demonstrates the universality of our protocol. Notably, with Cy2NH as additive and Et2O as solvent the cascade addition process occurs efficiently to give the compound 3aa which contains two succinimide rings. This type of Mncatalyzed cascade reactions is being pursued in our laboratory.

an additive and Et2O as the solvent, the product 3aa containing two succinimide rings was obtained in 80% isolated yield while only trace amount of 3a was detected. Further investigation indicated that 3aa was generated via the manganese-catalyzed addition of 1a to 2a followed by the Cy2NH-catalyzed addition of 3a to 2a (see the SI for details).22 To gain more insights into the nature of the manganesecatalyzed C−H activation, deuterium-labeling experiments were conducted (Scheme 5). By employing D2O as cosolvent, a Scheme 5. Deuterium-Labeling Experiments

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facile H/D scrambling was observed at the C-2 position of 1a, while no H/D exchange occurred at the C-3 position (Scheme 5a). In addition, the independent kinetic experiments revealed a minor kinetic isotope (KIE) effect (Scheme 5b), which was in good agreement with the H/D scrambling experiment. These observations illustrated a fast and reversible C−H activation step and the exclusive C-2 positional selectivity. Subsequently, to delineate the active manganese species in the catalytic cycle, the cyclometalated complex 7 was prepared16d (see the SI) and applied in both the catalytic and the stoichiometric process (Scheme 6). The high reaction efficiency strongly supported the notion that cyclometalated complex 7 was a key intermediate within the catalytic cycle. Based on the experiments (see above and the SI) and previous reports,15c,16a−c,23 a plausible mechanism is proposed in Scheme 7. Initially, the base-assisted (the maleimides may

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01795. Experimental procedures; spectral data for new compounds (PDF) Single-crystal X-ray diffraction data for compound 3a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 4044

DOI: 10.1021/acs.orglett.7b01795 Org. Lett. 2017, 19, 4042−4045

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Organic Letters ORCID

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Mao-Ping Song: 0000-0003-3883-2622 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21672192, 21472176). REFERENCES

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DOI: 10.1021/acs.orglett.7b01795 Org. Lett. 2017, 19, 4042−4045