Direct Access to Trifluoromethyl-Substituted Carbamates from

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

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Direct Access to Trifluoromethyl-Substituted Carbamates from Carbon Dioxide via Copper-Catalyzed Cascade Cyclization of Enynes Lu Wang,† Chaorong Qi,*,†,‡ Ruixiang Cheng,† Hongjian Liu,† Wenfang Xiong,† 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 cascade cyclization of enynes with Togni’s reagent, carbon dioxide, and amines has been successfully developed. The reaction provides a direct and efficient route to a range of trifluoromethyl-substituted carbamates, which are difficult to access using existing methods. Mild reaction conditions, good functional tolerance, and wide substrate scope are the feactures of the protocol.

be potent anti-HIV therapeutic drugs, γ-secretase inhibitors, or cathepsin K inhibitors, respectively (Figure 1).4c,11

C

onversion of carbon dioxide (CO2) into valuable chemicals or fuels is of great significance, because it may provide a solution for both the global climate change and energy issues.1 However, due to its thermodynamical and kinetic stability, the utilization of CO2 as a raw material in organic synthesis always suffers from drawbacks such as hard reaction conditions, the need for expensive transition-metal catalysts, and/or sensitive organometallic reagents. Therefore, the development of new and efficient methods for the chemical fixation of CO2 under mild conditions is still highly desirable.2 Organic carbamates constitute an important class of bioactive compounds, which widely exist in many natural products,3 pharmaceuticals,4 and agrochemicals.5 They could also serve as versatile building blocks in organic synthesis.6 Recently, CO2 has emerged as an attractive alternative to phosgene for the synthesis of carbamates because of its advantages such as nontoxicity, natural abundance, and renewability.7 Many multicomponent reactions involving the use of halohydrocarbons, alcohols, unsaturated hydrocarbons, or other compounds as the coupling partners have been reported for the assembly of carbamates.8 In recent years, our group has also developed several novel multicomponent reactions for the synthesis of organic carbamates.9 On the other hand, it is commonly accepted that the incorporation of fluorine or fluorine-containing functional groups into organic compounds could substantially alter their physical and chemical properties, which may be beneficial for improving their biological activities.10 However, the synthetic access to carbamates substituted by fluorine or fluorinecontaining functional groups remains largely underdeveloped, which is very important in view of the growing demand for fluorinated carbamates in medicinal chemistry. For example, carbamates A−C containing a trifluoromethyl group proved to © XXXX American Chemical Society

Figure 1. Representative carbamate-based pharmaceuticals containing CF3 group.

1,n-Enynes have been recognized as highly versatile substrates for the construction of functionalized molecules with structural diversity and complexity.12 However, to the best of our knowledge, they have not yet been applied to the assembly of organic carbamates with CO2. As part of our ongoing interest in developing efficient methods for the conversion of CO2 into organic carbamates,9 herein, we wish to report a coppercatalyzed radical cascade cyclization of enynes with Togni’s reagent in the presence of CO2 and amines, providing a direct and efficient protocol for the synthesis of a diverse range of trifluoromethylated carbamates, which are difficult to access using existing methods (Scheme 1). Received: July 31, 2019

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DOI: 10.1021/acs.orglett.9b02698 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

low yields of 4aa, whereas THF or toluene almost shut down the reaction (entries 5−9). Both increasing the reaction temperature and the amount of 2a decreased the yield of 4aa due to the formation of a large amount of unidentified byproducts (entries 10 and 11). Screening of other CF3 reagents showed that the Togni’s reagent 3b could also furnish 4aa in 60% yield (entry 12), but Umemoto’s reagent (3c) and Langlois’ reagent (CF3SO2Na) were ineffective (entries 13 and 14). Finally, control experiments showed that the copper catalyst is essential for the transformation (entry 15); when the reaction was carried out in the absence of CO2, only 4aa′ was obtained in 10% yield, and a large amount of substrate 1a could be recovered unchanged (entry 16). With the optimized reaction conditions in hand, a variety of 1ethynyl-2-(vinyloxy)benzene derivatives 1 were employed as substrates to react with CO2, 2a, and 3a (Scheme 2).

Scheme 1. Cyclization of Enynes with Togni’s Reagent, CO2, and Amines

Initially, we investigated the reaction of 1-(phenylethynyl)-2(vinyloxy)benzene (1a), CO2, diethylamine (2a), and Togni’s reagent 3a under different conditions (Table 1). To our delight, Table 1. Optimization of Reaction Conditionsa

Scheme 2. Scope of 1,6-Enynesa

entry 1 2 3 4 5 6 7 8 9 10 11d 12e 13f 14g 15 16i

catalyst CuSO4 Cu(OAc)2 CuI [Cu(MeCN)4]BF4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 CuSO4 − CuSO4

solvent DMSO DMSO DMSO DMSO DMF MeCN CH2Cl2 THF toluene DMSO DMSO DMSO DMSO DMSO DMSO DMSO

temp (°C) c

rt rt rt rt rt rt rt rt rt 50 rt rt rt rt rt rt

yield (%)b 73 (71) 47 52 57 21 46 16 5 trace 34 40 60 6 n.d.h n.d. n.d.

a

Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), 3a (0.12 mmol), CO2 (1 atm, balloon), catalyst (20 mol %), solvent (dry, 2 mL), 10 h. bYields were determined by 19F NMR analysis with PhCF3 as internal standard; number in parentheses is the yield of isolated product. crt = room temperature. d2a (0.3 mmol). eThe reaction was conducted with 3b as CF3 source. f3c was used as CF3 source. g CF3SO2Na as CF3 source. hn.d. = not detected. iIn the absence of CO2.

a

Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), 3a (0.12 mmol), CO2 (1 atm, balloon), CuSO4 (20 mol %), DMSO (dry, 2 mL), rt, 10 h. Isolated yields based on 1. All of the Z/E values are greater than 20:1, except for 4ma (Z/E = 7:1, as determined by 19F NMR analysis); the number in parentheses is the yield obtained on a 1 mmol scale.

when the reaction was carried out in dry DMSO with CuSO4 as the catalyst under 1 atm of CO2 at room temperature for 10 h, the desired product 4aa was obtained in 71% yield upon isolation (entry 1). A trace amount of compound 4aa′ was also detected by GC-MS in this case, together with some unidentified byproducts. The Z-configuration of 4aa was unambiguously confirmed by means of X-ray crystallographic analysis. Notably, no regioisomer and only trace amount of E isomer of 4aa was dectected (Z/E > 20:1), revealing the reaction proceeded with excellent regio- and stereoselectivity. Other copper salts such as Cu(OAc)2, CuI, and [Cu(MeCN)4]BF4 were also examined, but they gave inferior results (entries 2−4). A dramatic solvent effect was observed. DMSO was the most suitable solvent for the reaction; the use of DMF, MeCN, or CH2Cl2 as the media led to

Gratifyingly, various 1,6-enynes 1 with substituted aryl groups attached at the terminal alkyne underwent the reaction smoothly to give the corresponding products (4aa−4ja) in moderate to high yields. Both electron-donating or electron-withdrawing groups at the ortho, meta, or para positions of the benzene ring, including methyl, methoxy, halide (F, Cl and Br), trifluoromethyl, nitrile, and nitro groups, could be well tolerated. The substrates containing a fused aryl ring or heterocycle also worked well, as exemplified by 1k and 1l, which afforded the desired trifluoromethylated carbamates 4ka and 4la in 59% and 60% yields, respectively. Moreover, the cyclopentyl-substituted 1,6-enyne 1m was also capable of delivering the desired product B

DOI: 10.1021/acs.orglett.9b02698 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 4ma albeit in a lower yield. The structure of product 4ma was also characterized by X-ray diffraction analysis. Moreover, the substrates 1n and 1o were applicable to the reaction, giving rise to the corresponding products (4na and 4oa) in good yields with excellent stereoselectivities. It should be noted that the reaction could be performed on a 1 mmol scale for 1a, affording the desired product 4aa in a satisfactory yield under standard conditions. Then, the scope of amines was examined. As can be seen from Scheme 3, different dialkylamines, including symmetric and

Scheme 4. Synthesis of Trifluoromethyl-Substituted Carbamates with 1,7-Enynes

Scheme 3. Scope of Aminesa

Scheme 5. Mechanism Studies

spectroscopy when TEMPO was added. These results suggested that a CF3 radical should be involved in the present reaction (Scheme 5a). Moreover, 1a could react with Togni’s reagent 3a and Cu(O2CNBz2)2(NHBz2)2 (6),13 a CuII carbamato complex, under a N2 atmosphere, giving the desired product 4af in 26% yield (Scheme 5b), indicating that a carbamato complex of copper(II) might be generated in situ and act as the active species for the reaction. Based on the aforementioned observations and previous reports,8,9,12,14 two plausible pathways are proposed as depicted in Scheme 6. In path a, the CF3 radical is initially generated from

a

Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), 3a (0.12 mmol), CO2 (1 atm, balloon), CuSO4 (20 mol %), DMSO (dry, 2 mL), rt, 10 h. Isolated yields based on 1a. All of the Z/E values are greater than 20:1 as determined by 19F NMR analysis.

Scheme 6. Plausible Mechanism for the Transformation

unsymmetric ones, underwent the copper-catalyzed cascade cyclization with 1a, CO2, and Togni’s reagent 3a, furnishing the corresponding products (4ab−4ag) in 36−78% yields. Moreover, various cyclic secondary amines, such as pyrrolidine, piperidine, azepane, morpholine, and thiomorpholine, could also enter into the reaction without difficulty, giving the desired products (4ah−4al) in satisfactory yields. Unfortunately, primary amines such as n-butylamine (2m) failed to yield the desired carbamate products but led to the formation of a complex mixture under our conditions. To further evaluate the substrate scope of the new reaction, we also investigated the reactivity of 1-(allyloxy)-2-ethynylbenzene derivatives under the standard conditions (Scheme 4). Pleasingly, both of the two 1,7-enynes, 1p and 1q, could readily take part in the multicomponent reaction and gave the target products 4pa and 4qa in moderate yields with good-to-excellent stereoselectivities. To obtain insight into the mechanism of the reaction, several control experiments were carried out as shown in Scheme 5. It was found that the reaction was completely suppressed by the radical scavengers 2,2,6,6-teramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), and the radical trapping product 5 could be detected by 19F NMR

3a in the presence of Cu(I) species, which may be formed in situ from Cu(II) via reduction by amine 2a as an electron donor. Then, addition of the CF3 radical to 1a will lead to the formation of species D, followed by cyclization to give radical E. Subsequently, the interaction of intermediate B with Cu(II) carbamato complex F, which is formed from the reaction of CO2, 2a, and a Cu(II) ion, affords Cu(III) species G. Finally, reductive elimination of G delivers product 4aa. Alternatively, the reaction might proceed through path b, in which the CF3 radical is first derived from 3a through the action of Cu(II) species. Then, radical E will be formed via intermediate D. Subsequent oxidation of E by Cu(III) will give cation H, which C

DOI: 10.1021/acs.orglett.9b02698 Org. Lett. XXXX, XXX, XXX−XXX

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can be readily trapped by carbamate anion I formed in situ from CO2 and 2a to yield the final product 4aa. In summary, we have developed a copper-catalyzed cascade cyclization of enynes with Togni’s reagent, carbon dioxide, and amines, providing a straightforward and efficient route to a wide range of trifluoromethyl-substituted carbamates, which are difficult to access using existing methods. The reaction could proceed under very mild reaction conditions with good functional tolerance and wide substrate scope. Further investigations on the mechanism of this transformation and the application of this strategy to assemble other fluorinecontaining carbamates are currently 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.9b02698. Experimental procedures, characterization data, and copies of NMR spectra for all products (PDF) Accession Codes

CCDC 1940477 and 1940484 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.

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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.9b02698 Org. Lett. XXXX, XXX, XXX−XXX