Article pubs.acs.org/joc
Chemoselective α‑Methylenation of Aromatic Ketones Using the NaAuCl4/Selectfluor/DMSO System Hongbo Zhu,† Xin Meng,† Yanhui Zhang,† Guang Chen,†,‡ Ziping Cao,*,†,‡ Xuejun Sun,†,‡ and Jinmao You*,†,‡ †
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong 273165, China Shandong Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu, Shandong 273165, China
‡
S Supporting Information *
ABSTRACT: Gold-catalyzed chemoselective α-methylenation of aromatic ketones was developed through the use of Selectfluor as a methylenating agent. A variety of useful 1,2-disubstituted propenone derivatives can be prepared in good yields via the present protocol. This reaction features a simple operation, good functional group tolerance, and broad scope of substrates.
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INTRODUCTION 1,2-Disubstituted propenone derivatives exist in many natural products and possess various kinds of biological activities. For instance, compounds 1−5 have the propenone substructure with significant drug activities (Figure 1).1 Ethacrynic acid 1 is a
synthesis of 1,2-disubstituted propenones has attracted extensive attention.7 The classic dehydrative aldol condensation is a direct and efficient method to prepare the propenone products.8 The oxidation of allyl alcohols is another excellent route.9 Palladium dehydrogenation,10 hydroacylation of alkynes,11 and isomerization of propargylic alcohols12 can achieve the synthesis of enones.13 However, these methods suffer from a series of limitations: the reaction conditions are sensitive; the functional group scope is not broad, and the substrates are not readily available. As a result, the new synthetic methods to this class of structure would be of great interest.14 Following our continuing interest in gold-catalyzed reactions,15−17 herein we would like to provide a direct way to 1,2-disubstituted propenone derivatives through the NaAuCl4-catalyzed chemoselective α-methylenation of aromatic ketones using Selectfluor as a methylenating agent. To the best of our knowledge, this reactivity of the Selectfluor reagent is not yet reported.18−20
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RESULTS AND DISCUSSION Initially, the reaction of 1-tetralone (6a, 0.5 mmol) with Selectfluor (7, 3 equiv) in the presence of catalytic gold trichloride (8a, 5 mol %) was carried out to access the αfluorinated product 10. Unexpectedly, the α-methylene ketone 9a was obtained when the reaction was heated at 100 °C for 1.5 h, whereas the fluorinated tetralone (10) could not be found (Table 1, entry 1). In view of the importance of αmethylenation of ketones, we further optimized the reaction conditions to improve the yield of 9a. First, the various Lewis and Brϕnsted acids were screened. As shown in Table 1, the catalysts containing NaAuCl4·2H2O (8b), Pd(OAc)2 (8c), and AgOTf (8d) can promote the formation of the desired product
Figure 1. Natural and bioactive molecules with the propenone substructure.
loop diuretic that can treat high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure, and kidney failure;1a Oridonin 2, a diterpenoid isolated from Rabdosia rubescens, displays anti-inflammatory, antibacterial, and antitumor effects and has been used for the treatment of human esophageal carcinoma,1b and penicillic acid 3 is a polyketide mycotoxin used to study the genotoxicity of hepatocytes.1c Moreover, these types of compounds are important intermediates for many organic reactions such as Diels−Alder reaction,2 Michael addition,3 Morita−Baylis− Hillman reaction,4 Heck coupling,5 etc.6 Therefore, the © 2017 American Chemical Society
Received: July 18, 2017 Published: October 27, 2017 12059
DOI: 10.1021/acs.joc.7b01790 J. Org. Chem. 2017, 82, 12059−12065
Article
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entry 1 2
catalyst
x (equiv)
solvent
temp (°C)
time (h)
yield 9a (%)b
3 3
DMSO DMSO
100 100
1.5 1.5
70 87
3 4 5 6 7 8c 9c 10 11 12 13 14 15
AuCl3 (8a) NaAuCl4·2H2O (8b) Pd(OAc)2 (8c) AgOTf (8d) In(OTf)3 (8e) Cu(OTf)2 (8f) Sc(OTf)3 (8g) TfOH (8h) TFA (8i) 8b 8b 8b 8b 8b 8b
3 3 3 3 3 3 3 3 3 3 3 3 3
100 100 100 100 100 100 100 100 100 100 100 100 100
4 2.5 4 4 4 4 4 4 4 4 4 4 3
45 65
