ARTICLE https://doi.org/10.1038/s42004-019-0219-z OPEN Unified and practical access to ɤ-alkynylated carbonyl derivatives via streamlined assembly at room temperature Xu-Lu Lv1 & Wei Shu 1,2* 1234567890():,; The development of a unified and straightforward method for the synthesis of ɤ-alkynylated ketones, esters, and amides is an unmet challenge. Here we report a general and practical protocol to access ɤ-alkynylated esters, ketones, and amides with diverse substitution pat- terns enabled by dual-catalyzed spontaneous formation of Csp3–sp3 and Csp3–sp bond from alkenes at room temperature. This directing-group-free strategy is operationally simple, and allows for the straightforward introduction of an alkynyl group onto ɤ-position of carbonyl group along with the streamlined skeleton assembly, providing a unified protocol to syn- thesize various ɤ-alkynylated esters, acids, amides, ketones, and aldehydes, from readily available starting materials with excellent functional group compatibility. 1 Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, 518055 Shenzhen, Guangdong, P.R. China. 2 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, 300071 Tianjin, P.R. China. *email: [email protected] COMMUNICATIONS CHEMISTRY | (2019) 2:119 | https://doi.org/10.1038/s42004-019-0219-z | www.nature.com/commschem 1 ARTICLE COMMUNICATIONS CHEMISTRY | https://doi.org/10.1038/s42004-019-0219-z lkynes and carbonyl derivatives are among the most esters, and amides, from easily available and cost-effective starting Aimportant functional groups since they are ubiquitous in materials is highly desirable. On the other hand, intermolecular organic compounds as well as they serve as useful che- carbo-difunctionalization of alkenes is unarguably an attractive mical handles transformed to other diverse functional groups1–4. alternative to build molecular complexity via simultaneous for- The introduction of alkyne onto a specific remote position to mation of two C–C bonds by backbone assembly 21–35. carbonyl groups is of interest to organic chemists5–14. In parti- Herein, we establish a unified and general protocol for the cular, the alkynylation at ɤ-positon of carbonyl functional group direct synthesis of ɤ-alkynylated aryl or alkyl ketones, aldehydes, is challenging. Yu and Chatani reported a coordination-assisted esters, acids, secondary and tertiary amides using α-bromomethyl strategy for alkynylation of amides via Pd/Rh catalyzed C–H carbonyl precursors with alkynes in the presence of alkenes at activation (Fig. 1a)15,16. This strategy gave only two examples for room temperature (Fig. 1c). Over the past years, reports disclosed ɤ-alkynylation with poor results (<40% yield) and is only that α-halomethyl carbonyl compounds could be converted into applicable to the terminal methyl group of amide with directing alkyl radicals (A)36–46 to initiate coupling with unsaturated sys- group. Recently, Zhu and Studer independently developed an tems, such as alkenes and alkynes, to produce C-centered radical elegant alkynyl migration of propargyl alcohol with a pendant (B) (Fig. 1c). We hypothesize that the direct utilization of the olefin via a radical initiated chain reaction to give ɤ-alkynylated radical intermediate (B) with copper catalysis47–51 by the merger ketones (Fig. 1b)17–19. Despite significant progress in this field20, of photocatalysis52–57 to give desired ɤ-alkynylated carbonyl the existing methods suffer from several major limitations and compounds. However, several highly competitive reactions have drawbacks: (1) Requiring additional steps to synthesize the to be suppressed. First, radical B is facile to undergo atom backbone of sophisticated substrates. (2) Restricted to specific transfer39–42 or single electron oxidation43–46 by transition metal carbonyl functional groups (amide or ketone). (3) Limited sub- or photocatalyst (k = 105−109 M−1 s−1)58,59. Moreover, A would ɤ = stitution patterns at -position (R H, or CnFmCH2). Thus, a directly undergo metal-catalyzed (Pd, Cu) cross-coupling to give general, practical, and straightforward method to introduce ɤ- α-alkynylated carbonyl derivatives C in the presence of alkynylation for diverse carbonyl derivatives, including ketones, alkyne 60,61. a Chatani, Yu et. al. b Zhu, Studer et. al. R1 R1 X R1 3 R3 = NH-DG R = alkyl, aryl + DG R3 R2 = H R2 2 Me NH R = CnFmCH2 + R3 OH DG = directing group O O CnFmX Limited to secondary amide Limited to ketone Directing group required Tedious synthesis of precursor 2 Limited to terminal C–H Limited to perfluoroalkyl group (R ) Tedious synthesis of precursor Low efficiency (<40% yield) c This work: 1 Cu R 3 hv R R4 catal. 2 R ++1 3 4 X X R R R R2 1 O 2 3 O Applicable to esters, ketones, amides Radical cascade in copper and photocatalysis Mild conditions and broad scope Chemoselectivity over alkene and alkyne Challenges: [O] R2 [TM] or hv R2 R2 O 1 X – X 2 -X O B O R A X R1 O R2 O [TM] R1 C Fig. 1 Synthesis of ɤ-alkynylated carbonyl derivatives. a Coordination-assisted strategy for alkynylation of amides via Pd/Rh catalyzed C–H activation. b Alkynyl migration of propargyl alcohols with a pendant olefin by radical initiated chain reaction. c This work 2 COMMUNICATIONS CHEMISTRY | (2019) 2:119 | https://doi.org/10.1038/s42004-019-0219-z | www.nature.com/commschem COMMUNICATIONS CHEMISTRY | https://doi.org/10.1038/s42004-019-0219-z ARTICLE Table 1 Effect of the reaction parametersa TMS CuI (10 mol%) TMS L1 (10 mol%) OEt Ir(ppy)3 (1 mol%) Br + Ph + Si(OMe) Cs CO (2 equiv) OEt O 3 2 3 Ph 1a 2a 3a visible light 4a DCM, rt O R R R L7 N N N N N Me Me N N R = t-Bu, L5 R = 4-MeC H , L1 6 4 R = OMe, L6 L8 R = 4-MeOC6H4, L2 R = Ph, L3; R = H, L4 N N Entry Variation from the “standard” conditions Yield of 4ab 1 None 82% (78%)c 2 No CuI 0% 3 No light Trace 4 No Ir(ppy)3 35% 5 L2 instead of L1 75% 6 L3 instead of L1 70% 7 L4 instead of L1 36% 8 L5 instead of L1 23% 9 L6 instead of L1 28% 10 L7 instead of L1 20% 11 L8 instead of L1 18% 12 CuTc instead of CuI 66% 13 K2CO3 instead of Cs2CO3 Trace 14 t-BuOLi instead of Cs2CO3 5% 15 DCE instead of DCM 40% 16 Chloroform instead of DCM Trace aThe reaction was carried out on 0.1 mmol scale of 2a, using 1a (2 equiv) and 3a (2 equiv) in DCM (3 mL) under the irradiation of 30 W blue LED for 12 h bThe yield was determined by the 1H NMR of crude mixture using mesitylene as internal standard cIsolated yield after flash chromatography Results amount of 4a was detected (entries 13 and 14). The use of other Reaction conditions evaluation. With these concerns in mind, chlorine-containing solvents led to diminished yields (entries 15 we set out to explore the possibility of direct incorporating radical and 16). intermediate B into copper-catalyzed Csp3–sp bond-forming to furnish ɤ-alkynylated carbonyl derivatives using ethyl α-bro- moacetate 1a, styrene 2a, and trimethylsilylacetylene. After some Reaction scope. With the optimal conditions in hand, we turned initial trials, we found the use of alkynyl silicate 3a significantly to test the generality of this reaction. We first evaluated different improve the radical cascade coupling efficiency. Upon intensive types of carbonyl derivatives (Fig. 2a). The reaction is applicable examining a wide range of reaction parameters, we determined to a variety of α-bromomethyl carbonyl functional groups, that CuI (10 mol%), a tridendate ligand L1 (10 mol%) and a affording ɤ-alkynylated esters, ketones, secondary and tertiary photocatalyst Ir(ppy)3 (1 mol%) can accomplish the desired amides, which are inaccessible otherwise. ɤ-Alkynylated esters reaction in the presence of Cs2CO3 using DCM as solvent with with two or one enolizable proton can be obtained in good yields blue LED irradiation, affording ɤ-ethynyl ester 4a in 78% isolated (4a–4e). ɤ-Alkynylated lactone could be isolated in moderate yield (Table 1, entry 1). No desired product was obtained in the yield (4e). Notably, this method is applicable to synthesize α,α- absence of copper or light (entries 2 and 3). The absence of disubstituted ɤ-alkynylated esters in good yields (4f and 4g). It is photocatalyst dramatically decreased the reaction efficiency, albeit delighting that ɤ-alkynylated alkyl or aryl ketones could be delivering 4a in 35% yield (entry 4). The selection of ligand has furnished in good yields (4h–4j). This reaction also tolerates significant impact on the radical cascade process. The employ- secondary and tertiary amides to afford corresponding ɤ-alky- ment of tridentate ligand is crucial for the success (entries 5–7). nylated amides in synthetically useful yields (4k and 4l). This The use of bidentate ligand gave 4a in low yields (entries 8–11). protocol tolerates a wide variety of carbonyl derivatives, providing When CuTc was used, 4a was obtained in 66% yield (entry 12). a unified directing-group-free alternative to access ɤ-alkynylation When the reaction was carried out with other bases, such as of esters, ketones, amides with diverse substitution patterns under potassium carbonate or lithium tert-butoxide, no substantial mild conditions. COMMUNICATIONS CHEMISTRY | (2019) 2:119 | https://doi.org/10.1038/s42004-019-0219-z | www.nature.com/commschem 3 ARTICLE COMMUNICATIONS CHEMISTRY | https://doi.org/10.1038/s42004-019-0219-z a Scope of carbonyl derivatives TMS TMS TMS TMS F Me OEt OEt OMe O Ar Ar Ph Ar O O O O 60% (4c) 77% (4b) 70% (4d) 45% (4e) TMS TMS TMS TMS R Me Me F F OMe OEt Et Ar Ar Ar Ar O O O O 75% (4f) 47% (4g) 51% (4h) R = H, 63% (4i) R = OMe, 60% (4j) TMS Ph F F O F F H N N Ph Ar O O t-Bu 72% (4k) 38% (4l) b Scope of alkynes t-Bu Me OMe Si Me n-Bu t-Bu OEt OEt OEt OEt Ar Ar Ar Ar O O O O 64% (5a) 55% (5b) 72% (5c) 59% (5d) OMe F Ph OEt OEt OEt Ar Ph Ar O O 56% (5g) O 66% (5e) 69% (5f) Fig.