Acenaphthene

Letter Cite This: Org. Lett. 2018, 20, 954−957

pubs.acs.org/OrgLett

Gold(I)-Catalyzed Formation of Naphthalene/Acenaphthene Heterocyclic Acetals Malina Michalska,* Krzysztof Grudzień, Paweł Małecki, and Karol Grela* Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Ż wirki i Wigury Street 101, 02-089 Warsaw, Poland S Supporting Information *

ABSTRACT: A gold-catalyzed addition/cyclization reaction to form 3-alkoxy-benzo[de]isochromene derivatives was developed. All reactions, performed in mild conditions, exhibited high regioselectivity and good to excellent reaction yields. Additionally, optimized methodology was used in total synthesis of 2-phenylphenalenone, an alleged natural product found in Macropidia f uliginosa plant.

P

The crucial step in their strategy was an intramolecular McMurry coupling. They mostly concentrated on the synthesis of compound III, and yet, after optimization study, the method still has restrictions concerning multiple steps and reagents used. Another very interesting paper was published by Yamamoto and co-workers in 2009.13 The intramolecular cyclization of alkynylketones allowed to synthesize cyclic enones but still required using highly sensitive and toxic TfOH as a catalyst. In the context of our ongoing research on developing an effective method for the generation of new carbon−carbon bonds,14−16 we decided to optimize an alternative, efficient procedure for the synthesis of acenaphtylene-1-carbaldehyde derivatives (Scheme 1 c.). Our inspiration has come from an article published in 2012 by Jana and co-workers (Scheme 1b).17 They have developed an iron(III)-catalyzed intramolecular coupling reaction between alkyne and carbonyl groups in substituted 2′-alkynyl-biphenyl-2carbaldehyds. The advantage of this method is using inexpensive and environmentally friendly FeCl3 under acceptable conditions. The reaction proceeded smoothly with various types of ketones and aldehydes substituted at the triple bond and aryl rings. First, we were curious whether a similar method might also be applied in a more challenging, sterically stressed starting material such as 8-(phenylethynyl)-1-naphthaldehyde (1a). We started our investigation using acenaphthaldehyde 1a as a model substrate and anhydrous FeCl3 in 1,2-dichloroethane solution at reflux. The results are summarized in Table 1. The reaction did not proceed neither in the presence of FeCl3 nor with Fe(acac)3, and nearly all starting material was recovered. Given these results, we decided to adopt another set of transition metals, such as gold and silver complexes, which could be efficient in an intramolecular cyclization reaction. Gold catalysis has become a particularly active area of research within the past decade. The reasons for such an interest are

olycyclic aromatic compounds with an acenaphtylene-1carbaldehydes skeleton have found many potential applications in modern synthesis. They are considered to be building blocks in the synthesis of organic electronics,1 various ligands,2−4 and biologically active substances.5−10 Surprisingly, despite the widespread and potential applications of such products, there is a limited number of known methods for their synthesis, usually requiring harsh reaction conditions and multiple steps.11,12 One of the most interesting contributions was published by Dallavalle and co-workers10 who has optimized an efficient method for the synthesis of benzo[j]fluoranthene from 2bromoacenaphthene-1-carbaldehyde (Scheme 1a). Scheme 1. Background and Initial Aim of the Project

Received: December 10, 2017 Published: February 7, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.7b03856 Org. Lett. 2018, 20, 954−957

Letter

Organic Letters

the cationic gold(I) complex generated in situ by mixing NQIPrAuCl with AgNTf2.26 A strong counteranion effect was observed. SIPrAuX (where X = Cl− and OTs−) was not effective in promoting the reaction. In the end, the simple and air-stable SIPrAuNTf2 complex appeared to be the most efficient in producing 2-phenylphenalenone in 20% yield. To explain formation of the unexpected product 3a, we decided to perform a brief mechanistic study. The most acceptable mechanism to explain gold-catalyzed synthesis of 3a invokes the presence of water or alcohol in the reaction mixture so that acetal/hemiacetal intermediate could be formed. Further transformation involving nucleophilic attack of the hemiacetal to the gold-coordinated alkyne would give the final product.34−36 To investigate this possible scenario, we carried out the reaction in the presence of a stoichiometric amount of water and methanol under tested conditions (Scheme 2). While complex

Table 1. Optimization Study

entry

cat.

time

yield (2a/3a) [%]

1 2 3 4 5 6 7 8 9 10

FeCl3 Fe(acac)3 Ph3PAuNTf2 Bipyr-Au IPrAuNTf2 NQ-IPrAuNTf2 NQ-IPrAuCl/AgNTf2 SIPrAuNTf2 SIPrAuCl SIPrAuOTs

3h 3h 40 min 23 h 2 h 40 min 23 h 1 h 40 min 3h 23 h 23 h

0 0 complex mixture 0 4/15 11/14 24/15 4.5/20 0 traces

Scheme 2. Cyclization Reaction in the Presence of Additives

linked with the singular reactivity of electrophilic gold species, their high Lewis acidity, and the possibility to selectively and efficiently perform a plethora of transformations.18−24 Therefore, we further investigated our testing reaction using cationic gold complexes. Based on the mechanism proposed by Jana and coworkers, we first considered Bipyr-Au catalyst in which gold(III) chloride is coordinated to the 2,2′-bipyridyl ligand. Unfortunately, no reaction took place, and all starting material was recovered. Therefore, we next tested a set of cationic gold(I) complexes coordinated to various ligands. In the reaction performed with Ph3PAuNTf2, a complex mixture was observed within only 40 min (Table 1, entry 3). Thus, we prepared a series of slightly less electrophilic, air stable (NHC)AuNTf2 complexes25−27 with different electronic and steric properties (Table 1).28 In the reaction catalyzed by IPrAuNTf2, product 2a was synthesized together with unexpected 2-phenylphenalenone (3a) in a 1:3.75 ratio. Compound 3a belongs to phenylphenalenones, natural products that are mainly used as plants’ defense against phytopathogenic fungi and nematodes.29,30 Additionally, pharmacological and antimicrobial activities have also been reported.31,32 Finally, 3a is an alleged natural product found in the Australian endemic plant Macropidia f uliginosa. A recent study by Urban et al. showed that an actual structure of naturally occurring product is different (2-hydroxyphenalenone).33 We found these results very interesting, and therefore, in the next step of our investigation, we sought to understand the influence of the NHC ligand on the selectivity of the reaction. (We wished to find conditions in which one of two products could be selectively obtained.) Based on the results presented in Table 1, the electrophilic nature of gold(I) salts stabilized by NHC-ligand was found to be crucial: in the reaction catalyzed by complexes possessing less electrophilic SIPr ligand gave product 3a as a major product while using more electrophilic IPr or NQIPr ligands changed the ratio; product 2a was obtained in excess. A very interesting result was observed in the reaction catalyzed by

mixture was obtained in the presence of water, in the reaction with methanol, one product was selectively obtained within only 1 h. Full analysis of the product indicated formation of the acetal 4a in 92% yield. Decreasing the temperature from reflux to room temperature in 1,2-dichloroethane and also catalyst loading from 5 to 2 mol % gave the single product in quantitative yield (Scheme 2). To the best of our knowledge, this is the first example of application of gold(I) complexes in the synthesis of 3alkoxy-benzo[de]isochromenes, and only transformations of ortho-alkynylbenzaldehydes have been reported.36−40 It is worth emphasizing the simplicity and mildness of these conditions. This unexpected addition/cycloisomerization reaction underwent regioselectively to 6-exo-dig cyclization product, which could be very efficiently purified through a short pad of silica gel. With these encouraging results in hand, this addition/ cycloisomerization strategy has been investigated using various alcohols to form a diverse range of functionalized acetals under optimized reaction conditions (Scheme 3). We have found that, under presented conditions, the acetal 4j with an acenaphthaldehyde skeleton was also smoothly produced within only 10 min in quantitative yield, as well as a series of alcohols possessing a sterically demanding group such as isopropanol and 9-fluorenylmethanol (4b and 4g, 87% and 88% yields). In the reaction with racemic menthol, the product 4e was obtained in 87% yield after 30 min. The presented methodology can also be expanded to propargylic (4m, 98% yield) and allyl (4n, 80% yield) alcohols, trifluoroethanol (4w, 55% yield), and benzyl alcohols possessing various substituents on the aryl ring. Benzyl alcohols possessing electron withdrawing groups such as −NO2 as well as electron-donating −OCH3 groups reacted smoothly and gave the expected products 4c and 4k in good yields (96% and 63%, respectively). To our delight, in the reaction with 7-ethyltryptophol, the product 4x was smoothly obtained in 95% yield after 30 min; the product 4y with N955

DOI: 10.1021/acs.orglett.7b03856 Org. Lett. 2018, 20, 954−957

Letter

Organic Letters

These results strongly suggest that the amine group is the inhibitor for the reaction. This topic is under further investigation in our group. It should be noted that the presented methodology can be easily scaled-up and still produce the 4a in a quantitative yield. In some cases, the product could not have been isolated by simple filtration through a short pad of silica gel and needed to be purified by regular column chromatography; resulting products were obtained in lower yields.41 We suspect that 3-alkoxybenzo[de]isochromene is not very stable under chromatographic purification conditions, as partial decompositions of the products were observed, possibly due to the presence of an acetal group sensitive to the acidic nature of silica. We performed the addition/cycloisomerization reaction, and after completion (10 min), 0.2 equiv of p-TSA was added to the solution; the reaction was further carried at 50 °C for 140 min to complete. The product 3a was isolated in 78% yield (Scheme 4).

Scheme 3. Scope of the Gold(I)-Catalyzed Synthesis of 3Alkoxy-benzo[de]isochromene

Scheme 4. One-Pot Formation of Ketone 3a

This result confirmed our hypothesis and also allowed to obtain 2-phenylphenalenone in a good yield, nearly four times better than using the procedure presented in Table 1. Furthermore, the methodology allows to obtain it in four steps in 34% total yield (unoptimized) from commercially available starting material, 1,8-diaminonaphthalene.42 To conclude, we have developed an efficient method for the synthesis of 3-alkoxy-benzo[de]isochromene derivatives. The presented method offers high regioselectivity, mild conditions, and good to excellent reaction yields. It is also important to emphasize that one of the advantages of the method is the simplicity of the process, which in most cases allows isolation of the pure product by a simple filtration through a short pad of silica gel and can be scaled-up. Additionally, optimized methodology allows to synthesize the 2-phenylphenalenone under acceptable reaction conditions.

1. The reaction was carried out in 0.5 mol % SIPrAUNTf2. 2. The reaction was carried out in a mixture of DCE/CH3CN solution 1/1.

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ASSOCIATED CONTENT

S Supporting Information *

hydroxyphthalimide group was also obtained after 48 h in 60% yield; however, due to poor solubility of the substrate, a mixture of DCE/acetonitrile was required. We have also investigated a variety of substituents at the triple bond. Alkynes bearing an alkyl chain such as hexyne and also having an ester or ether group in the structure were well tolerated; thus, products such as 4h, 4l, and 4f can be isolated in good yields. Nevertheless, we have observed a limitation of our methodology in the case of amines. For example, the reaction did not proceed in the presence of allylamine and naphthalen-1amine. No conversion of the starting materials was observed at room temperature, while heating to reflux resulted in the formation of complex mixtures. Surprisingly, the reactions with ethanolamine derivative possessing primary, secondary, and tertiary amines and with choline chloride did not convert the desired product (4o−4t).

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03856. Experimental procedures and characterization data, mechanistic proposal, and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Karol Grela: 0000-0001-9193-3305 Notes

The authors declare no competing financial interest. 956

DOI: 10.1021/acs.orglett.7b03856 Org. Lett. 2018, 20, 954−957

Letter

Organic Letters

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(31) Rosquete, L. I.; Cabrera-Serra, M. G.; Piñero, J. E.; MartínRodríguez, P.; Fernández-Pérez, L.; Luis, J. G.; McNaughton-Smith, G.; Abad-Grillo, T. Bioorg. Med. Chem. 2010, 18 (12), 4530. (32) Brkljača, R.; Urban, S. J. Nat. Prod. 2015, 78 (7), 1486. (33) Brkljača, R.; Schneider, B.; Hidalgo, W.; Otálvaro, F.; Ospina, F.; Lee, S.; Hoshino, M.; Fujita, M.; Urban, S. Molecules 2017, 22 (2), 211. (34) The proposition of the mechanism is presented in the Supporting Information. (35) Asscher, Y.; Agranat, I. J. Org. Chem. 1980, 45 (16), 3364. (36) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69 (15), 5139. (37) Dell’Acqua, M.; Castano, B.; Cecchini, C.; Pedrazzini, T.; Pirovano, V.; Rossi, E.; Caselli, A.; Abbiati, G. J. Org. Chem. 2014, 79 (8), 3494. (38) Ruch, A. A.; Kong, F.; Nesterov, V. N.; Slaughter, L. M. Chem. Commun. 2016, 52 (98), 14133. (39) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem. Eur. J. 2007, 13 (19), 5632. (40) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E. Synthesis 2010, 2010 (14), 2367. (41) The similar observation was also described by Dell’Acqua, M.; Castano, B.; Cecchini, C.; Pedrazzini, T.; Pirovano, V.; Rossi, F.; Caselli, A.; Abbiati, G. J. Org. Chem. 2014, 79 (8), 3494. (42) First two steps in the synthesis of 1a leading to 8iodonaphthalenecarbaldehyde were carried out following the procedure described by Grudzień, K.; Ż ukowska, K.; Malińska, M.; Woźniak, K.; Barbasiewicz, M. Chem. - Eur. J. 2014, 20, 2819 Third step: Sonogashira coupling with phenylacetylene was 92% yield.

ACKNOWLEDGMENTS Authors are grateful to the National Science Centre (Poland) for the NCN MAESTRO Grant No. DEC-2012/04/A/ST5/00594 as well as Polpharma Company for the kind donation of 7ethyltryptophol compound. The study was carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project cofinanced by European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007−2013.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03856 Org. Lett. 2018, 20, 954−957