Toward Acetylene Renaissance: Functionally Rich N-Aminoindoles

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Toward Acetylene Renaissance: Functionally Rich N‑Aminoindoles from Acetylene Gas, Ketones, and Hydrazines in Two Steps Elena Yu. Schmidt, Nadezhda V. Semenova, Inna V. Tatarinova, Igor’ A. Ushakov, Alexander V. Vashchenko, and Boris A. Trofimov* A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia

Org. Lett. Downloaded from pubs.acs.org by UNIV OF ROCHESTER on 05/17/19. For personal use only.

S Supporting Information *

ABSTRACT: A straightforward acetylene-based scalable strategy for the synthesis of highly functionalized N-aminoindoles has been discovered. This pot-, atom-, step-, and energy-economic strategy includes two simple stages: (i) a one-pot multimolecular (2 + 2) diastereoselective assembly of 6,8-dioxabicyclo[3.2.1]octanes (6,8-DOBCOs) from acetylene gas and ketones in the KOH/DMSO two-phase superbase catalytic system and (ii) a mild (rt, CF3COOH) cascade transformation of 6,8-DOBCOs under the action of hydrazines to afford N-(arylamino)-3-(acylpropyl)indoles in good yields.

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amination of indoles.10 Other approaches to these compounds include the reduction of N-nitrosoindoles,11 transition-metalcatalyzed intramolecular cyclizations of 2-chlorophenylacetaldehyde hydrazones,12 enehydrazines,13 and 2-aryl-3-substituted hydrazonoalkylnitriles,14 intermolecular cyclizations of 2haloarylalkynes with hydrazines,15 and 1,2-diaryldiazenes with internal alkynes.16 In addition, N-aminoindoles were synthesized electrochemically from 2-(o-nitrosophenyl)ethylamines.17 Recently, several reports have appeared on the Rh-catalyzed syntheses of N-aminoindoles by the cyclization of acylhydrazines with diazo compounds18 or alkynes,19 arylsubstituted diazenecarboxylates with alkenes,20 and threecomponent annulation of arylhydrazines, diazo compounds, and ketones.21 Eventually, the development of direct and efficient synthetic strategies to build N-aminoindoles, particularly highly functionalized ones, based on the principles of the pot-atomstep-economy (PASE) paradigm22 from available and inexpensive precursors under transition metal-free conditions, is strongly desired. In conjunction with our ongoing interest in the acetylenebased synthetic strategies toward carbo- and heterocycles,23 most recently,24 we have discovered the diastereoselective synthesis of dihydro-1,3,4-oxadiazines 2 by the acid-catalyzed reaction of hydrazine with 6,8-dioxabicyclo[3.2.1]octanes 1 (commonly abbreviated as 6,8-DOBCOs),25 products of the superbase-promoted diastereoselective self-organization of acetylene with ketones (Scheme 1).26 Here, we disclose an unexpected one-pot formation of highly functionalized Naminoindoles 4 through the acid-assisted cascade ring-

n recent years, the application of acetylene and its close derivatives in the design of complex molecular architectures is rapidly growing into one of the main trends in organic chemistry that is supported by an increasing number of publications.1 The prerequisites for this are (i) the industrial availability of acetylene (multithousand ton production of acetylene gas);2 (ii) the attractive character of acetylene as an alternative and renewable (manufactured from lignocelluloses) feedstock;3 (iii) the high and multifaceted reactivity of the triple bond (due to its unique energy capacity); and (iv) the possibility of rendering clean, atom-economic, and energysaving processes owing to most typical addition reactions. Consequently, this is now considered as an acetylene renaissance, i.e., its comeback as a fundamental chemical feedstock, previously moved aside by cheap oil-based ethylene and propylene.4 Acetylene as a reactant especially fits the construction of complex heterocyclic compounds, among which functional indoles attract great attention as a ubiquitous motif in living matter (hormones, neurotransmitters, amino acids, growth regulators)5 and numerous commercial drugs.6 Therefore, synthesis and transformations of the indole systems are of continuous interest and the subject of many original papers and reviews.5,6 One of the most important subfamilies of indoles is N-aminoindoles, whose derivatives exhibit promising biological activities.7 For example, among them is a commercial nootropic drug for the treatment of Alzheimer’s disease, e.g., besipirdine, N-propyl-N-(pyridin-4yl)-1H-indol-1-amine.8 In addition, N-aminoindole derivatives are widely utilized as starting materials to access important nitrogen-containing heterocycles.9 A careful examination of the literature reveals a limited number of methods for the preparation of N-aminoindoles. The most known are the syntheses based on the direct © XXXX American Chemical Society

Received: April 26, 2019

A

DOI: 10.1021/acs.orglett.9b01452 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Scheme 2. Synthesis of N-Aminoindoles 4 from DOBCOs 1a−l and Phenylhydrazine 3aa

Scheme 1. Previous and Present Works

opening/ring-closure of DOBCOs 1 under the action of arylhydrazines 3 (Scheme 1). We began optimization of the N-aminoindole synthesis using DOBCO 1a (assembled from acetylene and acetophenone in the KOH/DMSO system) and phenylhydrazine 3a as model substrates. After a series of experiments, the arbitrarily optimized reaction conditions for the formation of Naminoindole 4aa were selected. Thus, when a mixture of DOBCO 1a and trifluoroacetic acid (TFA) (1a/TFA molar ratio = 1:1) in chloroform, kept at ambient temperature for 1− 2 min, was treated with an equimolar amount of phenylhydrazine 3a at the same temperature (20−25 °C) for 2 h, Naminoindole 4aa was obtained in 78% isolated yield (Scheme 2). No conversion of DOBCO 1a was observed in the absence of TFA. The screening of solvents showed that the acetonitrile could also be used as a suitable medium. It was found that the reaction proceeded slower when 50 or 20 mol % of TFA was used. Thus, having obtained provisionally optimum conditions for implementation of the synthesis, we have investigated the substrate scope of the reaction, first changing the DOBCO 1 structure and retaining phenylhydrazine 3a as a reference (Scheme 2). The reaction tolerates diverse DOBCOs 1 with aromatic and aliphatic substituents in the bicyclic core as well as the representatives having Me, Ph, MeO, and halogen groups in the aryl moieties. Substitution on the benzene rings had no noticeable influence on the outcome of the reaction: electrondonating or electron-withdrawing groups provided similar results (Scheme 2). Naphthyl-substituted DOBCO 1h afforded benzo[g]indole 4ha in 68% yield. Subsequently, the scope of hydrazines 3 was examined for the transformation under the same conditions. As can be seen from Scheme 3, different arylhydrazines, including Me-, F-, Cl-, and NO2-substituted ones, underwent smooth reaction with DOBCO 1 to give rise to the corresponding indoles 4 in 59− 73% yields. The structures of indoles 4 were determined by NMR analysis (COSY, NOESY, 1H−13C HSQC, 1H−13C, and 1 H−15N HMBC experiments, Figure 1) and also finally confirmed by single-crystal X-ray analysis of one of their representatives, 4ia (Figure 2). As for the mechanistic rationale, the cascade sequence of indole 4 formation is likely triggered by the acid-assisted rearrangement of DOBCO 1 to acetyldihydropyran 528 (Scheme 4). Next, the formation of hydrazone 6 takes place followed by addition of a water molecule to the enole double bond to generate unstable semiacetal A. The latter rearranges with ring cleavage to intermediate hydroxy hydrazone B, which is further transformed to carbocation D via the subsequent the hydroxyl protonation/water elimination (via intermediate C). The formation of carbocation D should be thermodynamically

a Reaction conditions: 1 (0.5 mmol), TFA (0.5 mmol), 3a (0.5 mmol), CHCl3 (8 mL), 2 h for 1a−h and 4 h for 1i−l. Isolated yields after column chromatography (basic Al2O3, hexane-diethyl ether with gradient from 1:0 to 0:1) are given. DOBCOs 1i−k were prepared from acetylene and 1,5-diketones by published procedure.27

favorable due to distribution of its positive charge over the benzene ring (benzylic type cation) and hydrazone moiety. Finally, indole ring closure occurs via the attack of the carbocation-like ortho-position of benzene ring at the imine nitrogen atom to give indole 4 (after the release of proton). To gain more insight into the mechanism, control experiments were conducted. Thus, treatment of the intermediate acetyldihydropyran 5a (obtained from DOBCO 1a, TFA, rt, 1−2 min, 95% yield)28 with hydrazine 3a under the elaborated conditions furnished the expected indole 4aa in 81% yield (Scheme 5). Other evidence in favor of the proposed scheme is the trapping of the intermediate hydrazone 6a by a shorter treatment of DOBCO 1a with TFA and hydrazine 3a (rt, 1 h). The further keeping of hydrazone 6a with TFA (rt, 10 min) afforded indole 4aa in almost quantitative yield (Scheme 5). To demonstrate the easy scalability of the discovered strategy, a gram-scale synthesis of indole 4ja and some its transformations were implemented. Under the optimized reaction conditions, DOBCO 1j (7.5 mmol) and phenylhydrazine 3a (7.5 mmol) reacted smoothly to give indole 4ja in 79% isolated yield (Scheme 6). Functionalizations on the B

DOI: 10.1021/acs.orglett.9b01452 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Synthesis of N-Aminoindoles 4 from DOBCOs 1a−i and Arylhydrazines 3b−ea

Figure 1. Main NOESY (↔), 1H−13C ( HMBC correlations for 4aa.

), and 1H−15N (→)

Figure 2. X-ray structure of 4ia (from ethanol).

Scheme 4. Plausible Scheme for the Formation of Indole 4

Scheme 5. Control Experiments

a The reaction conditions were the same as Scheme 2. Isolated yields after column chromatography are given.

carbonyl moiety of indole 4ja were performed by a reaction with phenylhydrazine 3a and hydroxylamine to deliver the corresponding hydrazone 7 (Z-isomer) and oxime 8 (a mixture of E/Z-isomers in 7:3 ratio), respectively (Scheme 6). For the example of indole 4aa, we have shown that synthesis can be realized directly from acetylene gas and ketones in a one-pot manner (without isolation and purification of the intermediate DOBCO 1a) via sequential reaction of ketones with acetylene in the presence of a KOH/DMSO system followed by treatment of the reaction mixture (petroleum ether extract) with TFA and phenylhydrazine 3a to produce 4aa in 63% yield (see the Supporting Information for details).

In summary, we have developed a unique strategy for constructing pharmaceutically oriented functionally rich Naminoindoles. In this reaction, 6,8-DOBCOs, readily synthesized from acetylene gas and ketones in a one-pot manner, react with arylhydrazines under exceptionally mild conditions (room temperature, 2−4 h) to afford a wide variety of highly substituted N-aminoindoles. To the best of our knowledge, such construction of N-aminoindoles from simple, easily available starting materials (in fact, acetylene gas, ketones, C

DOI: 10.1021/acs.orglett.9b01452 Org. Lett. XXXX, XXX, XXX−XXX

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(c) Alabugin, I. V.; Gonzalez-Rodriguez, E. Alkyne Origami: Folding Oligoalkynes into Polyaromatics. Acc. Chem. Res. 2018, 51, 1206− 1219. (d) Alyabyev, S. B.; Beletskaya, I. P. Gold as a Catalyst. Part II. Alkynes in the Reactions of Carbon−Carbon Bond Formation. Russ. Chem. Rev. 2018, 87, 984−1047. (e) Heravi, M. M.; Dehghani, M.; Zadsirjan, V.; Ghanbarian, M. Alkynes as Privileged Synthons in Selected Organic Name Reactions. Curr. Org. Synth. 2019, 16, 205− 243. (2) For examples, see: (a) Schobert, H. Production of Acetylene and Acetylene-based Chemicals from Coal. Chem. Rev. 2014, 114, 1743− 1760. (b) Trotus, I.-T.; Zimmermann, T.; Schüth, F. Catalytic Reactions of Acetylene: A Feedstock for the Chemical Industry Revisited. Chem. Rev. 2014, 114, 1761−1782. (3) (a) Lehmann, J. A. Handful of Carbon. Nature 2007, 447, 143− 144. (b) Li, G.; Liu, Q.; Liu, Z.; Zhang, Z. C.; Li, C.; Wu, W. Production of Calcium Carbide from Fine Biochars. Angew. Chem., Int. Ed. 2010, 49, 8480−8483. (4) (a) Tedeschi, R. J. Acetylene-Based Chemicals from Coal and Other Natural Resources; Marcel Dekker: New York, 1982. (b) Tedeschi, R. J. In Encyclopedia of Physical Science and Technology, 3rd ed.; Meyers, R.A., Ed.; Academic Press: San Diego, 2001. (5) For examples, see: (a) Naim, M. J.; Alam, O.; Alam, J.; Bano, F.; Alam, P.; Shrivastava, N. Recent Review on Indole: A Privileged Structure Scaffold. Int. J. Pharm. Sci. Res. 2016, 7, 51−62. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893−930. (c) Herzon, S. B.; Myers, A. G. Enantioselective Synthesis of Stephacidin B. J. Am. Chem. Soc. 2005, 127, 5342−5344. (d) Somei, M.; Yamada, F. Simple Indole Alkaloids and Those with a Non-rearranged Monoterpenoid Unit. Nat. Prod. Rep. 2005, 22, 73− 103. (e) Kawasaki, T.; Higuchi, K. Simple Indole Alkaloids and Those with a Nonrearranged Monoterpenoid Unit. Nat. Prod. Rep. 2005, 22, 761−793. (f) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Organocatalytic Strategies for the Asymmetric Functionalization of Indoles. Chem. Soc. Rev. 2010, 39, 4449−4465. (g) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010, 110, 4489−4497. (6) For examples, see: (a) Messaoudi, S.; Anizon, F.; Peixoto, P.; David-Cordonnier, M.-H.; Golsteyn, R.; Léonce, S.; Pfeiffer, B.; Prudhomme, M. Synthesis and Biological Activities of 7-Aza Rebeccamycin Analogues Bearing the Sugar Moiety on the Nitrogen of the Pyridine Ring. Bioorg. Med. Chem. 2006, 14, 7551−7562. (b) Brancale, A.; Silvestri, R. Indole, a Core Nucleus for Potent Inhibitors of Tubulin Polymerization. Med. Res. Rev. 2007, 27, 209− 238. (c) Hénon, H.; Conchon, E.; Hugon, B.; Messaoudi, S.; Golsteyn, R.-M.; Prudhomme, M. Pyrrolocarbazoles as Checkpoint 1 Kinase Inhibitors. Anti-Cancer Agents Med. Chem. 2008, 8, 577−597. (d) de Sa Alves, F. R.; Barreiro, E. J.; Manssour Fraga, C. A. From Nature to Drug Discovery: the Indole Scaffold as a ’Privileged Structure’. Mini-Rev. Med. Chem. 2009, 9, 782−793. (e) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. A Review on Recent Developments of IndoleContaining Antiviral Agents. Eur. J. Med. Chem. 2015, 89, 421−441. (7) For examples, see: (a) Andersen, K.; Perregaard, J.; Arn, J.; Nielsen, J. B.; Begtrup, M. Selective, Centrally Acting Serotonin 5HT2 Antagonists. 2. Substituted 3-(4-Fluorophenyl)-1H-indoles. J. Med. Chem. 1992, 35, 4823−4831. (b) Itoh, T.; Miyazaki, M.; Maeta, H.; Matsuya, Y.; Nagata, K.; Ohsawa, A. Radical Scavenging by NAminoazaaromatics. Bioorg. Med. Chem. 2000, 8, 1983−1989. (c) Gurkan, A. S.; Karabay, A.; Buyukbingol, Z.; Adejare, A.; Buyukbingol, E. Syntheses of Novel Indole Lipoic Acid Derivatives and Their Antioxidant Effects on Lipid Peroxidation. Arch. Pharm. 2005, 338, 67−73. (d) Kornicka, A.; Wasilewska, A.; Sączewski, J.; Hudson, A. L.; Boblewski, K.; Lehmann, A.; Gzella, K.; Belka, M.; Sączewski, F.; Gdaniec, M.; Rybczyńska, A.; Bączek, T. 1[(Imidazolidin-2-yl)imino]-1H-indoles as New Hypotensive Agents: Synthesis and in vitro and in vivo Biological Studies. Chem. Biol. Drug Des. 2017, 89, 400−410.

Scheme 6. Gram-Scale Synthesis and Further Transformation of the Indole 4ja

and hydrazines) has not been reported. This strategy offers an attractive alternative method for their preparation, which can easily be adapted for large-scale operations. Noteworthy, this synthesis does not require transition metals, avoiding challenges associated with separation of trace transitionmetal-containing impurities, which is crucial for the pharmaceutical industry.29 Further investigations to extend utility of this reaction and to deepen our mechanistic understanding of this transformation are ongoing in our laboratory.

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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.9b01452. Experimental procedure, compound characterizations, NMR spectra, and crystallographic data (PDF) Accession Codes

CCDC 1904260 contains 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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AUTHOR INFORMATION

Corresponding Author

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

Boris A. Trofimov: 0000-0002-0430-3215 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Baikal Analytical Centre for collective use of the equipment at the Siberian Branch of the Russian Academy of Sciences and Dr. Anton V. Kuzmin (Limnological Institute of SB RAS) for recording the HRMS spectra.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b01452 Org. Lett. XXXX, XXX, XXX−XXX