Zn(OAc)2-Catalyzed C3-Carbonylacetylation of Indoles with α

Letter Cite This: Org. Lett. 2018, 20, 6140−6143

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Zn(OAc)2‑Catalyzed C3-Carbonylacetylation of Indoles with α-Diazoketones Involving Wolff Rearrangement Xinwei Hu, Fengjuan Chen, Yuanfu Deng, Huanfeng Jiang, and Wei Zeng* China Key Laboratory of Functional Molecular Engineering of Guangdong Province, Guangdong Engineering Research Center for Green Fine Chemicals, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China

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S Supporting Information *

ABSTRACT: Zn(OAc)2-catalyzed highly regioselective carbonylacetylation of indoles and pyrroles with α-diazoketones has been developed. This transformation involves a combination of Wolff rearrangement/cross-coupling relay and provides an efficient approach to versatile 3-carbonylacetylindoles and 2-carbonylacetylpyrroles with a broad range of functional group tolerance.

I

Scheme 1. C3-Functional Acylation Strategies of Indoles

ndole skeleta are commonly encountered in many natural products, biological compounds, and pharmaceutical molecules and also play a prominent role as a source of versatile synthons to assemble complex molecules (Figure 1).1

Figure 1. Selected examples of functional and bioactive indolecontaining molecules.

Among the various indole libraries, 3-acylindoles have aroused special interest due to these compounds often being capable of being conveniently transformed into polycyclic scaffolds.2 Traditionally, 3-acylindoles have been made via Friedel−Crafts reactions,3 Vilsmeier−Haack reactions,4 and Grignard reactions.5 However, these methods only furnish structurally simple 3-aroyl- and 3-fatty acylindoles because most functional acyl sources are sensitive to acids, bases, and nucleophiles.6 To surmount the substrate limitation, Su and Davies successively employed N-methylanilines7 and N-sulfonyltriazoles8 as acyl sources to enable a highly regioselective C3-formylation and C3-aminoacylation of indoles in the presence of Ru(III) catalysts and Amberlyst 15 (Scheme 1a), respectively. It thus can be seen that developing C3-functional acylation strategies for indoles that use diverse coupling reagents is synthetically valuable and desirable. Diazo compounds belong to a very important class of synthons in organic chemistry. Transition-metal-catalyzed cross-coupling reactions involving diazo compounds provide a powerful platform to construct C−X bonds (X = C, N, O, S, and Si) through X−H bond carbenoid insertion and electrophilic addition.9 Among them, the carbene-transfer reaction between diazo compounds and indoles has been © 2018 American Chemical Society

widely explored using different metal catalysts; in these, the alkylation generally occurs regioselectively at the C3-position of the indoles under noble metal catalytic systems (Scheme Received: August 15, 2018 Published: September 20, 2018 6140

DOI: 10.1021/acs.orglett.8b02613 Org. Lett. 2018, 20, 6140−6143

Letter

Organic Letters 1b).10 In comparison, the acylation between these two coupling partners is rarely reported. However, we recently developed a cobalt-catalyzed coupling cyclization of aryl C−H bonds with α-diazoketones that allowed the efficient construction of quaternary 2-oxindoles (Scheme 1c).11 The subsequent control experiments demonstrated that transient ketenes are involved, which are derived from the αdiazoketones via Wolff rearrangement, and these are trapped by the cobaltacycle species. This work stimulated us to envision that the acceptor/acceptor diazo compounds could also possibly be employed as a special acyl source to couple with indoles. To test this hypothesis, herein we describe the first example of a Lewis acid catalyzed cross-coupling of indoles with α-diazo ketones in which ketene species could possibly be generated under Lewis acid catalysis or thermal conditions, followed by nucleophilic addition to indoles for the rapid assembly of C3-carbonylacetylindoles (Scheme 1d). Considering that the previous mechanism studies11 have disclosed that both a cobalt-catalyzed Wolff rearrangement and a thermal Wolff rearrangement could lead to the formation of active ketenes,12 the cross-coupling between N-methylindole (1a) and α-benzoyl-α-diazoester (2a) was first performed in the presence of Co(acac)2 (50 mol %) in toluene at 120 °C under an Ar atmosphere for 12 h (Table 1). Gratifyingly, we

reaction between 1a and 2a also produced a 28% yield of 3a even in the absence of the Lewis acid Zn(OAc)2 (entry 7 vs entry 8). This result also implied that the acceptor ketenes could form under thermal conditions. Finally, additional solvent screening revealed that 1,2-dichloroethane (DCE) could increase the yield of 3a from 69% to 84% (compare entries 9−14 with 15), and other solvents such as CH3CN and 1,1,2,2-tetrachloroethane (TCE) gave inferior results. Meanwhile, decreasing the loading of Zn(OAc)2 (20 mol %) still afforded a 85% yield of 3a (entry 15 vs entry 16). Encouraged by the above optimized conditions, we then applied them to a range of both indoles and diazo compounds to investigate the substrate scope. The scope of indoles was initially explored by employing α-benzoyl-α-diazoester (2a) as a coupling partner. As summarized in Scheme 2, except for the Scheme 2. Substrate Scopea,b

Table 1. Optimization of the Reaction Parametersa

entry

Lewis acids

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Co(acac)2 Y(OTf)3 La(OTf)3 Sc(OTf)3 FeCl3 Cu(OAc)2 Zn(OAc)2

toluene toluene toluene toluene toluene toluene toluene toluene CH3CN 1,4-dioxane DMF DMSO CF3CH2OH TCE DCE DCE

31 30 35 39 0 62 69 28 19 0 0 0 0 55 84 85c

Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2

a

Unless otherwise noted, all the reactions were performed using Nmethylindole (1a) (0.20 mmol) and α-diazo ketonester (2a) (0.25 mmol) with Lewis acid (50 mol %) in solvent (1.0 mL) at 120 °C for 12 h under Ar in a sealed reaction tube. Followed by flash chromatography on SiO2. bIsolated yield. c20 mol % of Zn(OAc)2 was used under 120 °C.

soon found Co(acac)2 gave the desired product 3a in 31% yield (entry 1), in which the carbonylacetylation regioselectively occurred at the C3-position of the indole 1a. Subsequently, different Lewis acid catalysts, such as Y(OTf)3 and Sc(OTf)3, were screened for further increasing the reaction conversion, and Zn(OAc)2 was proven to be the most efficient catalyst (compare entries 2−6 with 7), providing 69% yield of 3a (entry 7). It should be noted that this coupling

a All of the reactions were performed using indoles 1 (0.20 mmol) and diazo compound 2 (0.25 mmol) with Lewis acid catalyst Zn(OAc)2 (20 mol %) in DCE (1.0 mL) at 120 °C for 12 h under Ar in a sealed reaction tube. Followed by flash chromatography on SiO2. bIsolated yield. cIsolated yield on the 1.0 mmol scale.

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DOI: 10.1021/acs.orglett.8b02613 Org. Lett. 2018, 20, 6140−6143

Letter

Organic Letters N-(2-pyridyl)indole (3e, 0%), various N-alkyl-, N-phenyl-, and N-benzylindoles produced 3-ethoxycarbonylacetyl indoles 3a− d in 85−88% yield. Meanwhile, 2-methyl- and 2- phenylsubstituted indoles were also tolerated in this reaction, providing the desired C3-carbonylacetylation products 3f and 3g in excellent yields (82−86%). Notably, the X-ray crystal structure of methoxycarbonylacetyl-substituted indole 3h further indicated that the transformation did indeed occur at the C3-position of the N-methylindole. Satisfyingly, both electron-donating group-substituted indoles (3i−l) and electron-withdrawing group substituted indoles (3m−o) could be efficiently transformed into 3-alkoxylcarbonylacetylindoles in 65−87% yield, and different types of substituents and substitution at various positions on the phenyl ring did not significantly affect the reaction conversions (3i−o). Subsequently, we evaluated the coupling reaction of Nmethylindole (1a) with different α-benzoyl-α-diazoesters and found the carbene transfer reaction of electron-rich and electron-deficient α-benzoyl-substituted diazoesters proceeded smoothly to furnish the desired products (3p−u) in 70−88% yield, regardless of the electronic properties and substitution position of the different substituents. In addition, the α-(2naphthalenyl)-α-diazoester could also couple with N-methylindole (1a) to allow for the regioselective installation of the carbonylacetyl group into the target compound 3v in 76% yield. The α-aroyl-substituted α-diazoesters (3p−v) and the αpropionyl-substituted α-diazoesters and even various α-acylsubstituted α-diazoketones also afforded the diverse C3carbonylacetylindoles (3w−z) in 54−75% yield.13 Most interestingly, this C3-carbonylacetylation protocol for indoles could also be applied to N-substituted pyrroles (Scheme 3), and the highly regioselective C2-carbonylacety-

α-diazoacetone was subjected to the reaction system, we simultaneously obtained C2-methylcarbonylacetylation pyrrole 4k and C2-phenylcarbonylacetylation pyrrole 4l (4k/4l = 1:2), which are possibly derived from ketene isomerization. C3-Ethoxycarbonylacetyl indole 3d could be transferred into 3-(3-indolyl)-2-bromo-3-oxo-2-phenylpropionic ester 5 (87%) through regioselective bromination under CuBr2/blue LED irradiation conditions.14 Moreover, the coupling cyclization of the ethoxylcarbonylacetyl moiety of indole 3d with hydrazine hydrate could also efficiently produce C5-indolyl-substituted 1,2-dihydropyrazol-3-one 6 in 89% yield (Scheme 4).15 These compounds could be further employed to assemble more complex biological molecules in synthetic and medicinal chemistry.16

Scheme 3. Substrate Scopea,b

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Scheme 4. Synthetic Application for This Transformation

In conclusion, we present a Lewis acid catalyzed regioselective C3-carbonylacetylation of indoles and C2carbonylacetylation pyrroles employing acceptor/acceptor diazo compounds as coupling partners. The carbonylacetylation proceeds through a combination of Wolff rearrangement/ electrophilic addition and shows excellent functional group compatibility. The postsynthetic transformations of C3carbonylacetyl indoles could provide easy access to many important building blocks.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02613. Detailed experimental procedures, characterization data, 1 H NMR and 13 C NMR spectra for all isolated compounds, and X-ray data for compounds 3h and 4g (PDF) Accession Codes

CCDC 1850518 and 1862116 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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a

All of the reactions were performed using N-benzylpyrroles 1o (0.20 mmol) and diazo compound 2 (0.25 mmol) with Lewis acid catalyst Zn(OAc)2 (20 mol %) in DCE (1.0 mL) at 120 °C for 12 h under Ar in a sealed reaction tube. Followed by flash chromatography on SiO2. b Isolated yield.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yuanfu Deng: 0000-0002-2460-7224 Huanfeng Jiang: 0000-0002-4355-0294 Wei Zeng: 0000-0002-6113-2459

lation of N-benzylpyrroles was found to be successful for most of the α-diazoesters and α-diazoketones investigated (4a−l, 58−80%). The reaction site of pyrroles was confirmed by the X-ray crystal structure of 4g (Scheme 3). But when α-benzoyl-

Notes

The authors declare no competing financial interest. 6142

DOI: 10.1021/acs.orglett.8b02613 Org. Lett. 2018, 20, 6140−6143

Letter

Organic Letters

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Chem. Soc. 2014, 136, 6904. (j) Yu, Z.; Li, Y.; Shi, J.; Ma, B.; Liu, L.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 14807. (10) (a) Gao, X.; Wu, B.; Huang, W.-X.; Chen, M.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2015, 54, 11956. (b) Singh, R. R.; Liu, R.-S. Chem. Commun. 2017, 53, 4593. (c) Delgado-Rebollo, M.; Prieto, A.; Perez, P. ChemCatChem 2014, 6, 2047. (11) Hu, X.; Chen, X.; Shao, Y. X.; Xie, H. S.; Deng, Y. F.; Ke, Z. F.; Jiang, H. F.; Zeng, W. ACS Catal. 2018, 8, 1308. (12) For selected examples, see: (a) Pierrot, D.; Presset, M.; Rodriguez, J.; Bonne, D.; Coquerel, Y. Chem. - Eur. J. 2018, 24, 11110. (b) Arora, R.; Kashyap, K.; Kakkar, R. Comput. Theor. Chem. 2018, 1134, 30. (c) Krout, M. R.; Henry, C. E.; Jensen, T.; Wu, K.-L.; Virgil, S. C.; Stoltz, B. M. J. Org. Chem. 2018, 83, 6995. (13) 3-Diazo-1-phenylbuta-2,4-dione could possibly generate 2methyl-3-phenylprop-1-ene-1,3-dione and 2-phenylbut-1-ene-1,3dione through Wolff rearrangement. Therefore, when N-benzylpyrrole reacted with 3-diazo-1-phenylbuta-2,4-dione under the standard conditions, C2-functionalized pyrroles 4k and 4l (Scheme 3) were simultaneously formed. However, when N-methylindole was treated with 3-diazo-1-phenylbuta-2,4-dione, only product 3x (Scheme 2) was observed, possibly because indoles possess rather strong nucleophilicity compared with pyrroles; see: Prajapati, D.; Gohain, M.; Gogoi, B. Tetrahedron Lett. 2006, 47, 3535. This leads to the formation of regioisomeric 2-methyl-3-phenylprop-1-ene-1,3-dione through polar induction. (14) (a) Marigo, M.; Kumaragurubaran, N.; Jorgensen, K. A. Chem. Eur. J. 2004, 10, 2133. (b) Yang, T.; Fan, X.; Zhao, X.; Yu, W. Org. Lett. 2018, 20, 1875. (c) Khan, A. T.; Ali, M. A.; Goswami, P.; Choudhury, L. H. J. Org. Chem. 2006, 71, 8961. (15) (a) Krylov, I. B.; Paveliev, S. A.; Shelimov, B. N.; Lokshin, B. V.; Garbuzova, I. A.; Tafeenko, V. A.; Chernyshev, V. V.; Budnikov, A. S.; Nikishin, G. I.; Terent’ev, A. O. Org. Chem. Front. 2017, 4, 1947. (b) Mahajan, S. S.; Scian, M.; Sripathy, S.; Posakony, J.; Lao, U.; Loe, T. K.; Leko, V.; Thalhofer, A.; Schuler, A. D.; Bedalov, A.; Simon, J. A. J. Med. Chem. 2014, 57, 3283. (16) (a) Liu, L.; Rozenman, M.; Breslow, R. Bioorg. Med. Chem. 2002, 10, 3973. (b) Brana, M. F.; Gradillas, A.; Ovalles, A. G.; Lopez, B.; Acero, N.; Llinares, F.; Mingarro, D. M. Bioorg. Med. Chem. 2006, 14, 9.

ACKNOWLEDGMENTS The authors thank the National Key Research and Development Program of China (No. 2016YFA0602900), Guangdong Province Science Foundation (No. 2017B090903003), and the Guangdong Natural Science Foundation (No. 2018B030308007) for financial support.

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DOI: 10.1021/acs.orglett.8b02613 Org. Lett. 2018, 20, 6140−6143