Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via

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

Synthesis of Densely Functionalized N‑Alkenyl 2‑Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2‑Pyridones Pardeep Singh,† Andrew G. Cairns,† Dan E. Adolfsson,† Jörgen Ådeń , Uwe H. Sauer, and Fredrik Almqvist* Department of Chemistry, Umeå University, 90187 Umeå, Sweden

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ABSTRACT: We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

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he reactivity of arynes with sulfides has attracted considerable attention due to the potential to access scaffolds not easily prepared by other methods. This reactivity was initially demonstrated by Mertz and others1 and more recently further investigated in other laboratories.2 Specific developments include Studer and coworkers’ report of the stereoselective synthesis of alkenes via the [3 + 2] cycloaddition of vinyl sulfides with arynes2e and Hoye2a and Tan and Xu’s2b−d ring opening of cyclic sulfides to obtain functionalized thioethers. Although this pioneering work has demonstrated the potential synthetic power of the transformation, the application of these methods to complex, druglike scaffolds with varied and competing reactivities has not yet been investigated. N-Alkenyl and alkyl 2-pyridones are core structural components in many natural products and pharmacologically active compounds. They have also been used as substrates in cycloadditions and polymerization reactions.3 There are a number of synthetic methods available for the synthesis of Nalkenyl 2-pyridones (Figure 1);4a−h however, all of these methods are more applicable to simple substrates, and the outcome is very substrate-dependent. Therefore, new strategies to access N-alkenyl 2-pyridones as a part of functionalized scaffolds are desirable. In our previous research, we have made use of the biologically active thiazolino-fused 2-pyridone scaffold5 to build fluorescent and nonfluorescent polyheterocycles of biological interest.6 We judged this system to be ideal for assessing the applicability of aryne-mediated ring opening to complex molecules, as the cyclic thioether of the thiazolino ring must compete with the aryne [4 + 2] cycloaddition across the pyridone ring system.7 The ring-opening reaction would result in the N- and C-6 substitution of the 2-pyridone ring. © XXXX American Chemical Society

Figure 1. Previous work and our new strategy.

Furthermore, the resulting compounds would access new functionalities and spatial arrangements while retaining the characteristics of bicyclic 2-pyridones associated with previously observed biological activity. Herein we report our investigation of the aryne reactivity with thiazolino-fused 2-pyridone systems and our efforts to develop substrates and conditions to efficiently produce complex, densely functionalized 6-arylthio-substituted-N-alkenyl 2-pyridones. Our investigations started with 2-(trimethylsilyl)phenyl triflate 28 and a set of diversely substituted 2-pyridones, 1a− h, to identify the substrates that could provide ring-opened products 3 in preference to the formation of [4 + 2] adducts 4 (Scheme 1). The combination of KF/18-crown-6 at −10 °C was found to give good results with selected substrates. Received: July 22, 2019

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DOI: 10.1021/acs.orglett.9b02549 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

products is theoretically possible; however, from the analysis by 1H NMR, it is clear that a single diastereomer was formed. The crystal structure of 4h (Figure S2) confirmed that benzyne approaches from the least hindered side, opposite to the methyl carboxylate. To investigate the biological activity of ring-opened analogues of bioactive 2-pyridones, we tested the ring opening of 2-pyridone 1i, which is a precursor to a promoter of α-synuclein amyloid formation.6b Unfortunately both ring-opened product 3i and 4 + 2 cycloaddition adduct 4i were isolated in low yield. Given the low to moderate yields of ring-opened products, we next introduced conjugated electron-donating and -withdrawing substituents at position C-6 of the 2-pyridone scaffold, investigating whether cycloaddition can be avoided to afford N-alkenyl 2-pyridones selectively. We synthesized a number of C-6 aryl/alkyl-substituted 2-pyridones, 7a−j, and tested their reactivity with benzyne and 3-methoxy benzyne (Schemes 2 and 3).

Scheme 1. Treatment of Various 2-Pyridones with in Situ Generated Benzynee

Scheme 2. Treatment of 2-Pyridones 7 with in Situ Generated Benzynea

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92% complete. bReaction was carried out at rt (17 h). c2.0 equiv of 2 and 3.0 equiv of 18-crown-6 in acetonitrile at rt (16 h). d3.0 equiv of 18-crown-6. The concentration of 1i was 0.3 M, and the reaction mixture was stirred at 0 °C. e2-Pyridone of general structure 1 was treated with 2.5 equiv each of 2-(trimethylsilyl)phenyl-trifluoromethanesulfonate 2, KF, and 18-crown-6 in dry THF. The mixtures were stirred at −10 °C until the complete consumption of 1 was indicated by TLC (1−5 days). The concentration of 1 was 0.07 M.

Notably, lowering the reaction temperature from room temperature to −10 °C improved the selectivity for ringopened product 3 in preference to [4 + 2] cycloaddition product 4. The substituents on the 2-pyridone ring had a pronounced effect on the reaction outcome. The reactions of 1a and 1d with benzyne under established conditions gave conversion to ring-opened products 3a and 3d. The C-7- or C-8-substituted 2-pyridones 1b, 1c, and 1e afforded mixtures of ring-opened and [4 + 2] cycloaddition products. Substitution with a strongly electron-withdrawing C-6 nitro group (1f) reduces the nucleophilicity of the sulfur, resulting in [4 + 2] cycloaddition. The loss of conjugation increases the sulfur nucleophilicity toward a second equivalent of benzyne, giving 5f. Additionally, a ring-expanded product 6f was observed. (The structure was established by 1D and 2D NMR experiments and was further supported by a crystal structure of the analogous compound V (Figure S1).) No reaction was observed upon the addition of benzyne to trisubstituted 2-pyridone 1g at −10 °C. Repeating at rt yielded the [4 + 2] cycloaddition product exclusively. We therefore believed that increasing the reaction temperature would favor [4 + 2] cycloaddition. We treated compound 1h at rt using acetonitrile as solvent. Gratifyingly, bridged product 4h was isolated in 50% yield along with 17% of the ringopened product 3h. A mixture of [4 + 2] cycloaddition

a

2-Pyridone of general structure 7 was treated with 2-(trimethylsilyl)phenyl-trifluoromethanesulfonate 2 (1.4 equiv), KF (2.0 equiv), and 18-crown-6 (2.5 equiv) in dry THF at 0 °C until confirmed complete by TLC analysis (8.5 h to 2 days). The concentration of 7 was 0.3 M.

Initial tests of 7a with benzyne precursor 2 carried out under our established conditions showed a very slow reaction. However, the reaction time was vastly reduced by increasing the concentration and the temperature. The excess benzyne precursor and potassium fluoride could also be reduced without negatively affecting the isolated yield. 7a was found to give good conversion to ring-opened product 8a, suggesting that these substrates are more prone to react via the desired nucleophilic attack. Subsequent reactions with analogues 7b−h confirmed a trend of high sensitivity to conjugated electronwithdrawing substituents (7f and 7g), although in some cases (notably 7h), low yields reflect a very slow reaction rather than the competitive formation of other products. C-8 methoxysubstituted 2-pyridone 7d reacted to give a mixture of ringopened 8d and cycloaddition product 9d, likely due to the B

DOI: 10.1021/acs.orglett.9b02549 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

enhanced electrophilicity at C-1 of 3-methoxy benzyne.10 As before, the electronic properties of the R3 substituents had a pronounced effect on the yields of ring-opened products. 2pyridones 7a−d substituted at C-6 with phenyl groups, with or without C4′ electron-donating groups, furnished the desired products 11a−d in excellent yield, irrespective of the substituents in C-8. In contrast with our previous tests with unsubstituted benzyne, 7e reacts exclusively through sulfur attack on 3-methoxybenzyne and provides 11e in excellent yield. As previously observed, electron-withdrawing substituents at C-6 have a negative impact on the reaction yields, and the alkyl-substituted 2-pyridone 7i reacted cleanly to give an excellent yield of ring-opened product 11i. Finally, we applied our ring-opening protocol to tricyclic 2pyridone 12 and polycyclic 14, which are precursors to an αsynuclein fibril binder6f and an aggregation inhibitor,6c respectively. To our delight, the corresponding ring-opened products 13 and 15 were isolated in excellent yield (Scheme 4A,B).

Scheme 3. Treatment of 2-Pyridones 7 with in Situ Generated 3-Methoxybenzyneb

Scheme 4. (A,B) Ring Opening of Multiring Fused 2Pyridones with in Situ Generated 3-Methoxybenzyne and (C) Hydrolysis of Methyl Ester a Reaction was performed on a 1.4 mmol scale. b2-Pyridone of general structure 7 was treated with 3-methoxy-2-(trimethylsilyl)phenyltrifluoromethanesulfonate 10 (1.4 equiv), KF (2.0 equiv), and 18crown-6 (2.5 equiv) in dry THF. The mixtures were stirred at 0 °C until confirmed complete by TLC analysis (7−17 h). The concentration of 7 was 0.3 M.

activation of the diene by the methoxy group. The reaction of C-6-thienyl 2-pyridone 7e with benzyne did not go to completion, presumably due to competition with reactions between benzyne and the thiophene ring.9 From the mixture, cycloaddition product 9e was isolated in 11% yield, in addition to the 23% of desired ring-opened product 8e and 13% of unreacted 7e. We also considered mildly donating (7i) and withdrawing (7j) substituents directly attached to the C-6 position. The efficient reaction of 7i shows the extended C-6 conjugation previously tested to be unnecessary for good conversion, and the cleaner conversion observed in Scheme 2 compared with that in Scheme 1 is mainly due to the electronic effects of the C-6 substituent, which is also consistent with the unfavorable effect of C-6-I substitution (7j). The presence of a phenyl substituted with a C4′ electron-withdrawing group at position C-6 reduces the reactivity of the 2-pyridone both toward ring-opening and cycloaddition reactions. For instance, the 2-pyridones 7f and 7g slowly reacted with benzyne, reducing the yields of N-alkenyl 2-pyridones and cycloaddition products. The electrophilicity and regioselectivity of 3-substituted arynes have been investigated in computational studies by Garg and Houk et al., and an angle distortion model has been proposed as an explanation for the large differences in electrophilicity.10a,b On the basis of this work, the reactivity of 3-methoxy benzyne would be biased toward nucleophilic attack, with a [4 + 2] cycloaddition less likely.10a Although 3-methoxy benzyne has also been shown to participate in cycloaddition reactions,11 it reacted cleanly with all pyridones 7a−j, providing the desired ring-opened products 11a−j exclusively (Scheme 3) in moderate to excellent yield. The reactions were regioselective, presumably due to the

To investigate the biological activity of the ring-opened products, we selected 2-pyridones 3i, 13, and 15 and hydrolyzed them to the corresponding carboxylic acids 16, 17, and 18 in low yield (22−26%) (Scheme 4C). The carboxylic acids were evaluated for their ability to modulate the α-synuclein amyloid formation and fibril binding by a fluorescence assay with amyloidophilic dye Thioflavin T (ThT) (Figure 2). Compound 16 was observed to accelerate the α-synuclein amyloid formation, although not as efficiently as the previously reported accelerator FN075.6b Compound 17 (Figure 2B), which is the ring-opened analogue of a tricyclic amyloid fibril binder,6f retained this biological activity, as indicated by low ThT fluorescence signals. Compound 18 was also observed to promote the α-synuclein amyloid formation, as indicated by the short lag phase compared with wild-type αsynuclein. The observed activity is of great interest because previous ring-opened analogues have proven inactive,12 and as C

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pyridones 12 and 14 in excellent yield. The preliminary in vitro biological data showed that ring-opened compounds 16 and 17 have the ability to modulate α-synuclein amyloid formation and bind to amyloid fibrils, respectively. On the basis of this initial data, we believe that our methodology produces a scaffold worthy of further investigation and anticipate that both the methodology and the products described will be proven valuable as probe molecules or in medicinal chemistry investigations.

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Figure 2. Effect on α-synuclein aggregation.

ASSOCIATED CONTENT

S Supporting Information *

such, these are the first examples demonstrating that this structural motif can be replaced without a loss of activity. To better understand the ring opening that follows electrophilic attack on the sulfur, we conducted experiments with deuterium-labeled substrate, water, and THF (Scheme S2). On the basis of our mechanistic experiments, we propose the following mechanism (Scheme 5). Sulfur attacks the aryne

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02549. Experimental procedure and spectroscopic and analytical data for all new compounds (PDF) Accession Codes

CCDC 1945502 and 1945580 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.

Scheme 5. Proposed Mechanism for the Ring Opening of Thiazolino-Fused 2-Pyridones upon Thioether Attack on Aryne

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Fredrik Almqvist: 0000-0003-4646-0216 Author Contributions †

P.S., A.G.C., and D.E.A. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS F.A. is grateful to the Swedish Research Council (2017-02339, 2017-00695, and 2018-04589), the Knut and Alice Wallenbergs Foundation (KAW 2013.0031), the Göran Gustafsson Foundation, the Kempe Foundation (SMK-1755), the Swedish Foundation for Strategic Research (SB12-0070), the National Institutes of Health (R01AI134847-01A1), the Erling-Perssons Stiftelse, and the Michael J. Fox foundation for financial support.

to give a zwitterionic intermediate A, which undergoes 1,4intramolecular proton transfer (path a) to deliver the sulfonium ylide B. The sulfonium ylide picks up an acidic C3 proton from unreacted 2-pyridone, from intermediates, or from traces of water present in the reaction mixture; then, elimination furnishes the ring-opened product. The unusual case of the ring expansion, 6, would therefore seem to result from the competition of intramolecular nucleophilic substitution (path b) with proton transfer in intermediate A. To confirm that acidic C-3 proton is necessary for opening of the ring, we treated 2-pyridone 23 with 3-methoxy benzyne precursor 10 (Mechanistic Experiment F, Scheme S2). No ring-opened product was detected. In summary, we have used bicyclic thiazolino-2-pyridones to explore the reactivity of arynes generated in situ to synthesize highly functionalized N-alkenyl-2-pyridones. To make use of this transformation, it is necessary to consider alternative reactivity, notably the [4 + 2] cycloaddition of 2-pyridones with benzyne and the further ring opening of these adducts. Understanding the effect of different substituents and choosing a more electrophilic precursor allowed us to achieve good selectivity with highly reactive intermediates. Several examples were isolated in >90% yield. Furthermore, to extend the scope of the methodology, we ring-opened polycyclic bioactive 2-

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