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Empowering a Transition-Metal-Free Coupling Between Alkyne and Alkyl Iodide with Light in Water

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Empowering a Transition-Metal-Free Coupling Between Alkyne and Alkyl Iodide with Light in Water ARTICLE Received 5 Oct 2014 | Accepted 5 Feb 2015 | Published 10 Mar 2015 DOI: 10.1038/ncomms7526 Empowering a transition-metal-free coupling between alkyne and alkyl iodide with light in water Wenbo Liu1,LuLi1 & Chao-Jun Li1 Methods to assemble alkynes are essential for synthesizing fine chemicals, pharmaceuticals and polymeric photo-/electronic materials. Using light as a clean energy form and water as a green solvent has the potential to make synthetic chemistry more environmentally friendly. Here we present a transition-metal-free coupling protocol between aryl alkyne and alkyl iodide enabled by photoenergy in water. Under ultraviolet irradiation and in basic aqueous media, aryl alkynes efficiently couple with a wide range of alkyl iodides including primary, secondary and tertiary ones under mild conditions. A tentative mechanism for the coupling is also proposed. 1 Department of Chemistry, FRQNT Center for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 0B8. Correspondence and requests for materials should be addressed to C.-J.L. (email: [email protected]). NATURE COMMUNICATIONS | 6:6526 | DOI: 10.1038/ncomms7526 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms7526 he ongoing pursuit of synthetic efficiency combined with the pharmaceutical and electronic industries. Transition-metal the increasing emphasis on sustainability inspires chemists (depleting and precarious)3,4-free couplings in water (a greener Tto explore novel approaches to construct chemical solvent)5 enabled by photoenergy (a cleaner energy input)6 products more efficiently, cleanly, under milder conditions and provide great opportunities towards more sustainable synthetic in an environmentally benign manner1,2. Although the past chemistry. several decades have witnessed tremendous successes of Alkynes are fundamental structural motifs and are versatile transition-metal catalysis in organic chemistry, the difficulty intermediates in chemical transformations7–11. Research towards associated with metal residues has led to concerns in, for example, the synthesis of alkynes has been pivotal throughout the history of organic chemistry. Methods to synthesize alkyne compounds consist of two types: the first is the direct formation of the triple a 12 Previous work: bond such as the Corey–Fuchs reaction and the Seyferth– 13 X R Gilbert homologation ; and the second involves modifications R Pd, Cu, ligand on the basis of a pre-existing triple bond14,15. Diverse metal- + Base organic solvent catalysed alkyne couplings, including the Glaser–Hay coupling, the Cadiot–Chodkiewicz coupling, the Eglinton coupling, the (X=Cl, Br, I) Castro–Stephens coupling and the Sonogashira coupling, have found wide applications in the synthesis of pharmaceuticals, fine 14 b R chemicals and polymeric materials . Discovered in 1975, the R R R Pd or Ni, Cu, ligand 16 1 2 + R Sonogashira coupling , owing to its efficiency and robustness, Base 1 X organic solvent is one of the most reliable reactions to couple terminal alkynes R (X=Br, I) 2 with vinyl/aryl halides or vinyl/aryl pseudohalides. However, the c reaction protocol in Sonogashira’s seminal paper is not applicable to the coupling of alkynes with unactivated alkyl halides (Fig. 1a). This work: 17 Ar In 2003, Fu et al. pioneered a method of coupling terminal R R 3 R R alkynes with unactivated primary bromides and iodides by using 1 2 Ar Ultraviolet light, base, H2O R 3 + 1 catalytic amounts of both palladium and copper salts combined X R with N-heterocyclic carbene ligands (Fig. 1b). Although this (X=I) 2 method is only suitable for primary bromides and iodides, it Figure 1 | Methods for direct alkyne homologation. (a) Classical inspired chemists to explore other metal/ligand systems to couple Sonogashira coupling reaction between an alkyne and an aryl halide. more challenging secondary alkyl halides. In ref. 18, a different (b) Transition-metal-catalysed coupling of an alkyne with an alkyl halide. protocol was reported, expanding the scope to unactivated (c) Transition-metal-free coupling of an aryl alkyne and an alkyl iodides secondary bromides and iodides (Fig. 1b). Besides palladium, under ultraviolet in water. nickel catalysts were also utilized to couple alkynes with a Control experiment: H R1 Weak nucleophile R2 R2 R2I Weak electrophile b Classical method for the alkylation of alkyne: H LDA or n-BuLi R1 R1 R2 Weak nucleophile Strong nucleophile R1 R2I R2=methyl and Weak electrophile primary carbon c Our proposed strategy: H R2 Weak nucleophile R2 R UV light + 1 • or R R2I R2 2 R = primary, secondary Weak electrophile Radical Strong electrophile 2 and tertiary carbon Figure 2 | Research design. (a) A regular alkyne cannot react with an alkyl halide; (b) the classical coupling of terminal alkyne with the primary halide via metal acetylide; (c) proposed strategy to increase the reactivity of the alkyl halide via radical or carbocation. 2 NATURE COMMUNICATIONS | 6:6526 | DOI: 10.1038/ncomms7526 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms7526 ARTICLE Table 1 | Model reaction for the evaluation of different conditions*. H I NaOt Bu, water 50°C, hv, 2 h, Ar O ‘standard conditions’ 1 equiv 10 equiv O Entry Variation from standard conditions Yieldw 1 No change 79% (74%) 2NoUVat50°C0% 3 No UV at 120 °C0% 4 No solvent (neat) 0% 5 NaOH instead of NaOtBu 60% t 6Na2CO3 instead of NaO Bu 0% t 7K3PO4 instead of NaO Bu 63% t 8K2CO3 instead of NaO Bu 0% z 9 LiClO4 as an additive 59% 10 8 Equiv CyI 70% y 11 TFE instead of H2O o10% 12 Triethylamine 65% 13 0.6 mmol NaOtBu 70% 14|| Distilled CyI 76% 15 CH3CN instead of H2O 27% 16 MeOH instead of H2O 31% 17 t-BuOH instead of H2O 37% 18 Dimethylformamide instead of H2O0% 19 0.5 ml H2O 63% 20 2.5 ml H2O 67% 21 1 Equiv CuI 28% 22 320 nm Optical filter 72% 23 360 nm Optical filter 0% 24 Under O2 atmosphere 42% 25 CCl4 instead of H2O o1% *Reaction conditions unless otherwise noted: 4-methoxyphenylacetylene 10 ml (0.077 mmol, 1 equiv), cyclohexyl iodide 100 ml (0.775 mmol, 10 equiv), 1.5 ml water, NaOtBu 80 mg (0.83 mmol, 10.8 equiv). wYield was determined using the 1H NMR analysis on the basis of two experiments; isolated yield is given in parentheses. zWater (0.2 ml) and saturated lithium perchlorate solution (1.3 ml) were used in the reaction. yTFE: 2,2,2-trifluoroethanol. ||Commercially available alkyl iodides are stabilized by copper. unactivated alkyl halides. In 2009, Hu et al.19 developed a halides could provide a reasonable yield23. Besides the limited Ni/pincer ligand-based catalyst system to couple terminal alkynes substrate scope (vide supra), the classical alkylation method also with unactivated primary iodides. By using a catalytic amount of requires a strong base such as n-BuLi or lithium diisopropylamide NaI, in situ formation of primary iodides from primary bromides to pre-generate the metal acetylide24 (Fig. 2a,b). Inspired by also renders this system applicable to primary bromides (Fig. 1b). Kropp’s seminal work25–28 on the heterolytical cleavage of alkyl By further modifying the ligand, Liu et al.20 reported a protocol C–I bond to form carbocations under ultraviolet irradiation in capable of coupling alkynes with secondary bromides and iodides highly polar solvents, we hypothesized that by harmonizing the under mild conditions (Fig. 1b). Along with the Sonogashira-type rate of C–I bond cleavage (related to the light intensity) and the coupling, other transition-metal-based couplings in the literature nucleophilicity of the terminal alkyne, the coupling between such as the Kumada coupling21,22 also allow to synthesize alkyne alkynes and alkyl iodides can be accomplished directly via radical compounds. However, among all the reports up to now, no or carbocation intermedates, in the absence of any transiton known method is available to couple alkynes with unactivated metals (Fig. 2c). tertiary alkyl halides (whether via classical metal acetylides or modern coupling reactions). Herein, we wish to report the coupling of terminal alkynes with Optimization of reaction conditions. To test our hypothesis, the various unactivated alkyl iodides in the absence of any transition coupling between 4-methoxyphenylacetylene and cyclohexyl metal, assisted by ultraviolet light in water. Most importantly, the iodide was selected as the model reaction. Extensive investigations method allows the successful coupling of terminal alkynes with were made to optimize the reaction conditions (Table 1). Control tertiary unactivated iodides for the first time (Fig. 1c). experiments (Table 1, entries 2 and 3) clearly demonstrated that ultraviolet irradiation is essential for this reaction, as no coupling product was observed without ultraviolet light. Sodium t-butyl Results oxide as a base was superior to other inorganic and organic bases Designing strategy. Before the use of transition metals in syn- tested (Table 1, entries 5–8 and 12). Addition of inorganic salts thetic organic chemistry, alkylation of terminal alkynes with alkyl (Table 1, entry 9) decreased the yield dramatically. Decreasing the halides via an SN2 substitution was the traditional technique to amount of cyclohexyl iodide also reduced the yield (Table 1, entry construct complex alkyne compounds, in which only primary 10). Different polar solvents were examined and water was found NATURE COMMUNICATIONS | 6:6526 | DOI: 10.1038/ncomms7526 | www.nature.com/naturecommunications 3 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms7526 I t secondary alkyl iodides provided the highest yields (52–87%). + NaO Bu, H2O, R It should be noted that alkene side products (B50% as Ultraviolet light R 1 ‘standard conditions’ determined by H NMR) due to elimination was also observed 1 equiv 10 equiv with secondary and tertiary iodides.
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