Direct Access to α-Oxoketene Aminals via Copper-Catalyzed Formal

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

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Direct Access to α‑Oxoketene Aminals via Copper-Catalyzed Formal Oxyaminalization of Alkenes under Mild Conditions Lu Wang,† Chaorong Qi,*,†,‡ Tianzuo Guo,† and Huanfeng Jiang*,† †

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Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P.R. China ‡ State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, P.R. China S Supporting Information *

ABSTRACT: A copper-catalyzed four-component formal oxyaminalization of alkenes with Togni’s reagent and amines using molecular oxygen as both the oxidant and oxygen source has been developed for the first time, offering a straightforward and efficient method for the synthesis of a range of structurally diverse α-oxoketene aminals. The use of cheap copper catalyst and readily available substrates, excellent functional group tolerance, broad substrate scope, mild conditions, and simple procedure are the attractive features of the strategy. Scheme 1. Synthetic Strategies for α-Oxoketene Aminals

K

etene aminals constitute an important class of biologically active compounds which are frequently found in many pharmaceuticals and agrochemicals.1 More importantly, due to their unique structural characteristics, they have been widely used as versatile building blocks for the construction of a range of medicinally relevant heterocyclic compounds in the past years.2,3 In addition, these molecules can serve as efficient ligands in transition-metal catalysis.4 For the preparation of ketene aminal compounds, many methods based on two-component reactions have been developed.2a However, these methods generally suffer from the use of not easily accessible starting materials and tedious procedures. In particular, α-oxoketene aminals, one of the most important kind of ketene aminals, are often prepared by the condensation reaction between α-oxoketene dithioacetals and amines (Scheme 1A, a), but the corresponding ketene dithioacetals need to be synthesized from ketones in advance via a two-step procedure involving the use of toxic and highly volatile carbon disulfide and methyl iodide as the reagents. Other methods based on C−C bond formation include the acylation of 1,1-diaminoethenes with acyl chlorides (Scheme 1A, b)5a and the condensation between orthocarbonic acid derivatives with ketones (Scheme 1A, c),5b,c both of which also suffer from the drawback of using not easily obtained reagents and rather narrow substrate scope. Therefore, the development of a new strategy for the efficient synthesis of α-oxoketene aminals, especially from readily available starting materials via a simple one-step process, is highly desirable but remains a great challenge. Alkenes are the most abundant and commonly used organic building blocks in large-scale chemical synthesis. Recently, difunctionalization of alkenes has emerged as a powerful tool for making valuable products due to their step and atomeconomy.6 However, the oxyaminalization of simple alkenes, © XXXX American Chemical Society

which would enable the rapid assembly of ketene aminals with great structural diversity, has not been reported yet. As part our continuous interest in oxidative functionalization of unsaturated hydrocarbons with molecular oxygen,7 herein, we wish to report the first copper-catalyzed four-component formal oxyaminalization of alkenes with amines, Togni’s reagent, under aerobic conditions. The novel reaction proceeds by transition-metal-catalyzed oxytrifluoromethylation of alkenes8 and subsequent C−F bond activation process,9,10 which provides an unprecedented route to a variety of structurally Received: February 8, 2019

A

DOI: 10.1021/acs.orglett.9b00518 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Alkenesa

diverse and synthetically useful α-oxoketene aminals (Scheme 1B). We began our study with the synthesis of ketene aminal 4aa by using styrene (1a), Togni’s reagent 2a, and diethylamine (3a) as the model substrates. After scrupulous examination of the reaction parameters, we were glad to find that combining CuS (10 mol %) and 2-methyl-1,10-phenanthroline (L2, 20 mol %) as the ligand under an oxygen atmosphere provided the best result, giving 4a in 72% yield upon isolation.11 It is worth noting that the structure of the ligand has a great impact on the activity of catalyst (Scheme S1, a). Among various pyridine−base bidentate and tridentate ligands screened, monosubstituted 1,10-phenanthroline derivative L2 proved to be the most effective. Different CF3 reagents were also screened for the transformation (Scheme S1, b). Using Togni’s reagent 2b instead of 2a as the trifluoromethyl group source gave lower yield, while other CF3 reagents including Umemoto’s reagent (2c), TMSCF3, and CF3SO2Na failed to provide the desired product. Several other copper salts (Table S1, entries 2−5) and solvents (Table S1, entries 6−9) were examined, but all of them gave 4aa in lower yields. Two control experiments showed that both copper catalyst and molecular oxygen are essential for the reaction to occur (Table S1, entries 17 and 18). With the optimized reaction conditions in hand, we then examined the generality and limitations of the copper-catalyzed process, and the representative results are summarized in Scheme 2. To our delight, a wide range of styrene derivatives could undergo smooth reaction with 2a and 3a to give the corresponding products in moderate to high yields. Both electron-donating and electron-withdrawing substituents at the para positions of the benzene ring, including tert-butyl, methoxyl, phenyl, halide (F, Cl and Br), trifluoromethyl, nitrile, nitro, and ester groups, were well tolerated (4ba−ka), which may be beneficial for further transformations. In general, ortho-substituted substrates gave the corresponding products (4na−qa) in slightly lower yields than their meta- or parasubstituted analogues, which may be due to the steric effect. The multisubstituted substrates, 1,3-bis(trifluoromethyl)-5vinylbenzene (1r) and 1,2,3,4,5-pentafluoro-6-vinylbenzene (1s), worked well to afford the expected products 4ra and 4sa in 71% and 52% yields, respectively. Notably, the reaction of estrone-derived alkene 1u proceeded smoothly with high efficiency. 4-Vinylpyridine and 4-methyl-5-vinylthiazole, which are heteroaromatic alkenes, were also suitable substrates for the reaction to give the products 4va and 4wa in satisfactory yields. Internal alkenes, such as trans-stilbene and 1,2-dihydronaphthalene, could enter into the reaction to give products 4xa and 4ya without difficulty. Moreover, our protocol could be applied to aliphatic alkenes, which are often challenging substrates for difunctionalization reaction. For example, but-3-en-1-ylbenzene could afford the product 4za, albeit in a low yield. Then the scope of amines was studied. As can be seen from Scheme 3, a variety of amines were viable partners for this transformation. Both acyclic and cyclic secondary amines took part in the reaction efficiently, giving the desired products (4ab−rj) in good to high yields. Various primary amines, including those with long or bulky alkyl substituents, also reacted well with 1a and 2a to provide the corresponding products 4ak−ap. The structures of the products 4rj and 4an were unambiguously confirmed by means of X-ray crystallographic analysis. It is worth mentioning that heterocyclic ketene aminals, such as 4aq and 4ar, could be obtained from

a

Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), 3a (0.7 mmol), CuS (10 mol %), L2 (20 mol %), MeCN (1 mL), 60 °C, 10 h, O2 (balloon). Yields of isolated products are given.

the corresponding diamines by the present protocol, but in these cases Cu(OAc)2 was used as catalyst instead of CuS. However, aromatic amines failed to undergo the reaction, and the substrates could be recovered unchanged. To demonstrate the synthetic benefit of our coppercatalyzed protocol, the newly formed 4an was further converted to several useful heterocyclic compounds. As shown in Scheme 4, 4an could undergo Michael addition/ cyclization reaction with dimethyl acetylenedicarboxylate to give the pyridine derivative 5 in 51% yield.12a Product 6 bearing a fused three-ring system could be synthesized with high efficiency by the interaction of 4an with isatin in refluxing toluene.3d The structure of 6 was also characterized by X-ray diffraction analysis. Additionally, treating 4an with benzoyl isothiocyanate or 1,4-benzoquinone could gave 2,5,6-trisubstituted 4-thioxopyrimidine 712b and benzofuran derivative 8,12c respectively, in good yields under metal-free conditions. To gain more insight into the mechanism of the reaction, a series of control experiments were performed. First, the reaction of 1a, 2a, and 3a could be inhibited by the radical scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), and benzoquinone, revealing the reaction might proceed through a radical pathway (Scheme 5, a). Second, when the reaction was conducted in the absence of air, no trace of 4aa was detected. Moreover, the reaction under an 18O2 atmosphere gave the 18O-isotopologue 4aa′ in 71% yield and in 83% isotopic purity (Scheme 5, b). B

DOI: 10.1021/acs.orglett.9b00518 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Scope of Aminesa

Scheme 4. Versatile Transformations of the Ketene Aminal Productsa

a

Reaction conditions: (a) 4an (0.2 mmol), dimethyl acetylenedicarboxylate (1.3 equiv), toluene (2 mL), room temperature, 30 min; (b) 4an (0.5 mmol), isatin (1.1 equiv), toluene (3 mL), reflux, 4 h; (c) 4an (0.2 mmol), benzoyl isothiocyanate (1.25 equiv), THF (2 mL), room temperature, 24 h, N2; (d) 4an (0.4 mmol), 1,4benzoquinone (1.2 equiv), AcOH (3 mL), reflux, 1 h.

Scheme 5. Mechanism Studies

a

Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), 3 (0.7 mmol), CuS (10 mol %), L2 (20 mol %), MeCN (1 mL), 60 °C, 10 h, O2 (balloon). Yields of isolated products are given. bThe reaction was carried out with Cu(OAc)2 as the catalyst instead of CuS.

These results indicated that the carbonyl oxygen atom of products 4 originated from molecular oxygen. Finally, it was found that 1a could react with 2a in the presence of 1 equiv of triethylamine to give 3,3,3-trifluoro-1-phenylpropan-1-one (9) in 16% yield, and the treatment of compound 9 with 7 equiv of 3a in acetonitrile gave 4aa in almost quantitative yield (Scheme 5, c), indicating compound 9 is the reaction intermediate for the transformation. On the basis of the above investigations and previous reports,8,10e−g,13,14 a plausible mechanism for the reaction is postulated in Scheme 6. Initially, the Cu(I) species, generated in situ from Cu(II) via reduction by amine 3a as electron donor,13 undergoes single-electron transfer with Togni’s reagent 2a to give a CF3 radical. The addition of CF3 radical to styrene 1a then yields benzylic radical 10,14 which can be trapped by molecular oxygen to give α-trifluoromethylsubstituted ketone 9 via intermediates 11 and 12. Subsequently, ketone 9 undergoes dehydrofluorination in the presence of 3a as the base to afford gem-difluoro-substituted

vinyl ketone 13.10e−g Nucleophilic substitution of 13 with 3a finally furnishes the target product 4aa via intermediates 14− 16 through two similar addition−elimination processes. In this mechanism, 3a plays triple roles: it serves not only as a coupling partner but also as a reductant and base, which explains why an excess amount of 3a is required to facilitate significant product formation. In conclusion, we have disclosed a copper-catalyzed fourcomponent formal oxyaminalization of alkenes, providing a straightforward and efficient method for the synthesis of a range of synthetically important α-oxoketene aminals. The reaction employs Togni’s reagent as a one-carbon synthon and molecular oxygen as both the oxidant and oxygen source. This C

DOI: 10.1021/acs.orglett.9b00518 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Scheme 6. Plausible Mechanistic Pathway

protocol features the use of cheap copper catalyst and readily available starting materials, excellent functional group tolerance, broad substrate scope, mild conditions, and a simple procedure. Further investigation on the mechanistic details and synthetic applications are now underway 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.9b00518. Experimental procedures, condition screening table, characterization data, and copies of NMR spectra for all products (PDF) Accession Codes

CCDC 1882257, 1882261, and 1882263 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]. uk, 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 Authors

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

Chaorong Qi: 0000-0003-4776-2443 Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Ministry of Science and Technology of the People’s Republic of China (2016YFA0602900), the National Natural Science Foundation of China (21572071), and the Guangdong Natural Science Foundation (2017A030313054) for financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b00518 Org. Lett. XXXX, XXX, XXX−XXX