A Unified Strategy for the Synthesis of β-Carbolines, γ-Carbolines, and

Letter Cite This: Org. Lett. 2018, 20, 6336−6339

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A Unified Strategy for the Synthesis of β‑Carbolines, γ‑Carbolines, and Other Fused Azaheteroaromatics under Mild, Metal-Free Conditions Dilipkumar Uredi, Damoder Reddy Motati, and E. Blake Watkins* Department of Pharmaceutical Sciences, College of Pharmacy, Union University, Jackson, Tennessee 38305, United States

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S Supporting Information *

ABSTRACT: An efficient, unified approach for the synthesis of β-carbolines, γ-carbolines, and other fused azaheteroaromatics has been realized under metal-free conditions, from propargylic amines and (hetero)aromatic aldehydes. This unified strategy provides β- and γ-carbolines as well as a range of fused azaheteroaromatics with a broad substrate scope and excellent functional group compatibility. The formal synthesis of oxopropalines D and G has been achieved on gram scale (3a), in a one-pot reaction from commercially available materials (previous shortest reported route to 3a was 5 steps). NMR studies of the conversion of imine intermediate 3aa to β-carboline 3a were conducted and revealed that the reaction proceeded through an allene intermediate.

C

Hence, the development of efficient methodologies for the construction of the carboline skeleton has attracted substantial attention in synthetic chemistry.2 The augmentation of processes that tease new reactivity out of easily accessible precursors continues to spur the chemistry community toward pioneering methodologies that provide rapid access to nitrogen-containing heterocycles. While the Bischler−Napieralski,5 Pictet−Spengler,6 and Graebe−Ullmann7 reactions are the conventional approaches for the synthesis of β- or γ-carboline derivatives, in recent years several new protocols for the synthesis of β- or γ- carboline frameworks have been developed using a range of starting materials and metal catalysts. Examples include the cyclization/ iminoannulation of acetylene derivatives with prefunctionalized indoles;8 metal-catalyzed cyclization/functionalization of various precursors prepared in multiple steps;9 synthesis of 3amino-β-carbolines via gold-catalyzed formal [4 + 2] cycloaddition of azides and ynamides;10 synthesis of either β- or γcarbolines using ruthenium or rhodium catalyzed [2 + 2 + 2] cycloaddition reactions;11 arene-ynamide cyclization via copper catalysis;12 palladium-catalyzed, imidoylative cyclization of tryptophan-derived isocyanides;13 and others.14 In this regard, while much effort has been devoted to the development of metal-catalyzed cyclizations, alternative and/or complementary methods using more practical, environmentally benign and metal-free conditions are limited.15 Reactions employing mild and metal-free protocols are ideal because they circumvent the use of toxic metals, excess oxidant/additive, and the preconstruction of starting materials in multiple steps. A metal-free, domino reaction for the synthesis of complex

arbolines and fused-pyridine heterocycles are ubiquitous structural motifs prevalent in natural products, pharmaceuticals, agrochemicals, materials, and ligand scaffolds among other examples, thus highlighting the significance of such structures.1 Among the isomeric α-, β-, γ-, and δ-carbolines, the most abundant framework in nature is β-carboline.2 βCarbolines possess a wide array of pharmacological properties, including anti-inflammatory, anti-Alzheimer, antimalarial, antibacterial, antitumor, anti-HIV activities, and others (Figure 1).3 The structural similarity of C1-substituted β-carboline alkaloids with 2-substituted pyridines revealed their potential as directing groups for C−H functionalization reactions.4

Figure 1. Representative β-carboline core natural products and bioactive molecules. © 2018 American Chemical Society

Received: July 31, 2018 Published: October 1, 2018 6336

DOI: 10.1021/acs.orglett.8b02441 Org. Lett. 2018, 20, 6336−6339

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Organic Letters

to provide NH-carbolines (3j and 3k), albeit in slightly diminished yield and a comparatively longer reaction time (24 h). The feasibility of the metal-free conditions was further explored with various protecting groups on the indole aldehyde (1c−f) with 2b, affording good to excellent yields of the Nprotected carbolines (3l−o). Moreover, the substituted indole 2-aldehydes (1g−j) were compatible under these conditions and gave the corresponding β-carbolines (3p−s) in good yields. As expected, the reaction of 1,3-dimethyl-1H-indole-2carbaldehyde (1k) with 2a gave the imine intermediate 3ka in 87% yield, with no subsequent cyclization to the β-carboline (see SI for details, Scheme S1). Variously substituted indole 3-aldehydes were also efficient under the current reaction conditions, providing good yields of the corresponding γ-carbolines. N-Methylindole 3-aldehyde (1l) was subjected to the optimal conditions with 2a and 2b independently to give the γ-carbolines (3t in 92% and 3u in 87%), respectively, in good yields. Impressively, 1H-indole-3carbaldehyde (1m) was well-tolerated to give γ-carboline 3v in 69% yield. Bromo (1n) and cyano (1o) substituted NH-indole 3-aldehydes were found to be competent substrates (3w and 3x). Also, fused indole 3-aldehyde (1p) could be subjected to the optimal reaction conditions resulting in a good isolated yield of 3y (77%). This demonstrated that our method could be successfully applied to the synthesis of both β- and γcarbolines. Next, we extended the scope of the reaction with diverse (hetero)aromatic aldehydes (1q−y), using 2a/2b as amine coupling partners (Scheme 2). Benzofuran-2-carbaldehyde

heterocyclic scaffolds is a highly attractive strategy as an atomeconomic and environmentally benign process. To the best of our knowledge, examples of β- or γ-carboline synthesis involving metal-free, mild conditions from easily accessible starting materials in a one-pot operation have not been reported. In continuation of our work on the synthesis of heterocyclic derivatives,16 in this letter, we disclose an efficient and metal-free method in which the combination of a propargylic amine and (hetero)aromatic aldehyde can be used to efficiently produce a series of β- and γ-carbolines as well as a range of fused-azaheteroaromatics which have important pharmacological properties. For the optimization of the reaction parameters, we chose 1methyl-1H-indole-2-carbaldehyde (1a) as a model substrate in combination with propargylamine (2a). The investigation of metal-catalyzed and metal-free conditions with various bases and solvent systems revealed that the reaction proceeded well with NaHCO3 at 80 οC (see Supporting Information (SI) for details, Table S1). Using the optimal reaction conditions, we examined the scope and generality of this base-mediated, metal-free reaction (Scheme 1). First, the effect of changing substitution on the Scheme 1. Synthesis of β- and γ-Carbolines from Indole Aldehydes (1) and Substituted Propargylic Amines (2)a

Scheme 2. Synthesis of Diverse, Fused Pyridines

a Reaction conditions: 1 (0.6 mmol), 2 (0.9 mmol), and base (1.2 mmol). b24 h.

(1q) and benzothiophene-2-aldehyde (1r) gave the corresponding fused-pyridine derivatives in good yields (4a in 79% and 4b in 83%). Pyrrolopyridine aldehyde (1s) also worked well in this conversion (4c). Moreover, pyrrole, furan, and thiophene aldehydes (1t−v) were suitable substrates in this transformation, generating bicyclic compounds in 62−86% yields (4d−f). Pleasantly, quinoline-8-carbaldehyde (1w) reacted smoothly with 2a to afford the phenanthroline (4g) in 63% yield. Remarkably, polycyclic aldehydes (1x and 1y) were easily converted to the corresponding fused-pyridine heterocycles (4h−j) in 82−87% yields, showcasing the promising synthetic generality and utility of the current reaction conditions. After successfully establishing a metal-free process for the synthesis of β-carbolines, γ-carbolines, and fused-nitrogen heterocycles, we extended this protocol to the synthesis of

propargylic amine was explored. To our delight, 3-phenylprop2-yn-1-amine (2b) and 3-(4-methoxyphenyl)prop-2-yn-1amine (2c) were well tolerated under the present conditions, delivering the corresponding carboline moieties in good yields (3b in 87% and 3c in 72%, respectively). Similarly, amines with electron-withdrawing groups (2d−g) were successfully utilized, yielding the appropriate carbolines 3d−g in excellent yields (81−93%). Additionally, 1-naphthyl (2h) and 2-thienyl (2i) propargylic amines could be smoothly converted to carbolines 3h and 3i in synthetically useful yields. Furthermore, Nsubstitution on the indole aldehyde was investigated (3j−o). Interestingly, 1H-indole-2-carbaldehyde (1b) revealed that our reaction conditions were tolerant of N-unsubstituted aldehydes 6337

DOI: 10.1021/acs.orglett.8b02441 Org. Lett. 2018, 20, 6336−6339

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Organic Letters other substituted β-carbolines. Accordingly, the reaction of 1a with 4-phenylbut-3-yn-2-amine (2j) and but-3-yn-2-amine (2k) progressed well, to give 3,4-disubstituted β-carbolines 5a and 5b in 81% and 91% yields, respectively. Additionally, when 4-chlorobut-2-yn-1-amine (2l) was subjected to the present conditions, it provided the dehydrohalogenated carboline 5c in 63% yield and a handle for further structural elaboration (Scheme 3). Scheme 3. Synthesis of Substituted β-Carbolines from 2j/2k and 2l

Figure 2. Kinetic profile of the conversion of imine 3aa to carboline 3a.

Scheme 5. Plausible Reaction Mechanism for the Synthesis of 3a To investigate the scalability of the present conditions, we performed the reaction of 1a and 2a on gram scale (6.29 mmol) to afford 3a in 79% isolated yield after 24 h. Scale-up and the necessary extension of the reaction time resulted in the formation of a minor side product, the carboline-indole alcohol 6 in 5% yield (Scheme 4). It is worth noting that we have Scheme 4. Gram-Scale/Formal Synthesis of Oxopropalines D and G and Synthetic Utility of β-Carboline Derivatives

Cyclization appears to proceed through the allene A via basemediated isomerization of intermediate 3aa. The allene then undergoes a 6π-azacyclization to give intermediate B. Isomerization through a [1,7]-H shift would then establish aromaticity and complete the reaction pathway to β-carboline 3a. In conclusion, we have demonstrated a practical and unified protocol for the synthesis of β-carbolines, γ-carbolines, and diverse fused-azaheteroaromatics starting from propargylic amines and (hetero)aromatic aldehydes via base-mediated, one-pot, and metal-free conditions for the first time. The reaction proceeded smoothly under mild conditions through an imine, 6π-azacyclization strategy. Moreover, the present protocol enables the rapid conversion of abundant feedstock materials into a range of fused azaheterocycles under metal-free conditions. Diverse heteroaromatic, polycyclic aldehydes were compatible with the present approach and provided βcarbolines, γ-carbolines, and diverse azaheterocycles with broad substrate scope and in excellent yields. Additionally, we also extended the applicability of our conditions to the formal synthesis of oxopropalines D and G, by preparing compound 3a on gram scale in a one-pot procedure. The formation of an allene intermediate (A) was demonstrated using NMR analysis in the conversion of amine 3aa to product 3a.

achieved the synthesis of 3a in one step from easily available materials under mild and metal-free conditions.17 Additionally, the reaction of 1z (1 g) with 2a under standard conditions delivered the MOM-protected carboline 3z in 93% yield. βCarbolines 3a and 3z could be converted to oxopropalines D and G.18 Additionally, the reaction of 3a with isovaleraldehyde at room temperature provided the oxopropaline analogue 7 in 87% yield.19 To help establish the mechanistic pathway of the reaction and to identify the intermediates of the reaction, we monitored the conversion of imine 3aa to carboline 3a using 1H NMR analysis of the reaction mixture in DMF-d7 at 2-h intervals (see SI for details, Figure S1). Based on the NMR analysis, a kinetic profile is drawn showing the change in relative concentrations of the reaction species in Figure 2. Based on the literature reports20 and NMR analysis, we propose a plausible reaction mechanism in Scheme 5. Initially, the reaction of 1a with 2a at rt produces the imine intermediate 3aa, which was isolated and fully characterized.

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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.8b02441. 6338

DOI: 10.1021/acs.orglett.8b02441 Org. Lett. 2018, 20, 6336−6339

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Organic Letters

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General experimental procedures and spectroscopic data of all the compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dilipkumar Uredi: 0000-0002-1272-6613 Damoder Reddy Motati: 0000-0002-4000-1548 E. Blake Watkins: 0000-0002-7505-0083 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was funded by Union University. The authors are grateful for the HRMS data provided by D. R. Phillips and C.-W. Chou [Proteomics and Mass Spectrometry (PAMS) Facility, NIH Grant 1S10RR1028859] at the University of Georgia, Department of Chemistry, Athens, Georgia.

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DOI: 10.1021/acs.orglett.8b02441 Org. Lett. 2018, 20, 6336−6339