Photo-induced copper-catalyzed alkynylation and amination of remote unactivated C(sp3)-H bonds

A method for remote radical C–H alkynylation and amination of diverse aliphatic alcohols has been developed. The reaction features a copper nucleophile complex formed in situ as a photocatalyst, which reduces the silicon-tethered aliphatic iodide to an alkyl radical to initiate 1,n-hydrogen atom transfer. Unactivated secondary and tertiary C–H bonds at β, γ, and δ positions can be functionalized in a predictable manner.


Introduction
Direct functionalization of inert C(sp 3 )-H bonds provides an atom-and step-economic strategy for the rapid construction of valuable chemical frameworks. 1 Along with transition-metalmediated processes, 2 radical-mediated hydrogen atom transfer (HAT) has emerged as an appealing and efficient strategy to activate and functionalize C(sp 3 )-H in a selective manner, and signicant progress has been made in this eld. 3 An easily installed and removable hydroxyl protecting group, the (halomethyl)silyl group, has been established as an excellent carbon radical precursor and widely applied in radical-type reactions. 4 Gevorgyan pioneered remote aliphatic C-H functionalization through radical transposition processes initiated with silicontethered carbon radicals. 5 Particularly inspiring is the photoinduced palladium-catalyzed remote C-H Heck reaction, allowing ready access to alkenyl alcohols (Scheme 1, eqn (1)). 5a Benetting from their electronic properties and various methods for further transformations, alkynes have been widely used as pivotal intermediates for the synthesis of complex biologically active or functional molecules. 6 To our knowledge, remote C-H alkynylation at unactivated C-H bonds proceeding via intramolecular HAT has been explored only very recently, dominated by 1,5 transposition. Among the established methods, a polarized alkyne (X-Y) (e.g., X^R) is required and generally needs multistep synthesis (eqn (2)). 7 Approaches allowing the use of a simple terminal alkyne in remote C-H bond alkynylation are limited and therefore highly desired. 8 Photocatalysis using inexpensive and readily available copper complexes experienced a signicant growth, exhibiting highly tunable redox properties and diverse reactivity. 9 Fu pioneered photo-induced copper-catalyzed C-N bond formation using carbazole as the reactant and photocatalyst, 10 while Hwang and Lalic demonstrated that copper could catalyze the coupling of acetylene with aryl 11 and alkyl halides 12 under light irradiation, with copper-acetylide acting as the photo-excitable intermediate.

Results and discussion
Our group recently discovered a photo-catalytic system of copper(I) and realized the three-component carbon Scheme 1 C-H alkynylation and amination of aliphatic alcohols.
functionalization of alkenes (eqn (3)). 13a,b The signicance of this work lies in the following: (1) the identication of in situformed photoactive Cu(I) species with signicantly enhanced reducing capability, 13c,d and (2) the use of simple terminal alkynes and amines as coupling partners. Encouraged by the potential of C-H functionalization in synthesis, it was reckoned that carbon radical formation occurred from (halomethyl)silyl ether through Cu-acetylide photoreduction, followed by the selective 1,n-HAT. The newly formed radical could be recaptured by a Nu-copper species, which then furnished the remotely functionalized products. Herein, the successful implementation of this hypothesis is described. In the presence of a single Cu complex, various mono-substituted alkynes and carbazoles undergo a site-selective radical relay alkynylation and amination reaction of aliphatic alcohols (eqn (4)). The reaction proceeds under mild visible-light-induced conditions at room temperature, producing b-, d-, and g-functionalized products selectively without the use of exogenous photosensitizers or external oxidants.
Our attempt began by allowing a model substrate Si-tethered iodide 1a to react with 1-ethynyl-4-methylbenzene 2a in the presence of the 2,2 0 :6 0 ,2 00 -terpyridine copper catalyst under bluelight irradiation. Aer comprehensive investigation of the reaction conditions, it was pleasing to nd that the translocated Sonogashira product 3a did form. Under the optimized conditions, 1a provided the desired product 3a in 60% yield aer 32 h using CuI as the catalyst and 2,2 0 :6 0 ,2 00 -terpyridine as the ligand under blue-LED (BLED) irradiation (Table 1, entry 1). Under these conditions, the premature alkynylation at the Siauxiliary site is suppressed to approximately 15%.
Control experiments determined that product 3a was not produced in the absence of a copper salt, ligand, or base (entry 2). It was found that a structurally similar ligand with tBu substitution on the terpyridine L2 led to decreased yield (entry 3). Bidentate ligands L3 and L4 proved to be inefficient in this transformation (entry 4). Switching the base from K 2 CO 3 to Cs 2 CO 3 , Na 2 CO 3 , or K 3 PO 4 was detrimental to the reaction, and traces to small amounts of product were observed (entries 5 and 6). The performance of other copper salts such as CuBr and CuTc was also briey examined, but they were less efficient for this reaction (entries 7-9). Further reaction optimization experiments identied MeCN as the best solvent (entries 10-12). The reaction running at lower temperature decreased the yield (entry 13). The use of the Pd catalyst gave no 3a, highlighting the unique role of Cu in this tandem HAT and coupling process (entry 14).
Aer the optimal reaction conditions were established, the substrate scope with respect to alkynes was rst investigated, keeping iodide 1a as the substrate (Table 2). For aryl-substituted alkynes, various electronically different para-substituted phenylalkynes reacted to provide the corresponding C-H alkynylation products 3b-3g in 39%-72% yields. Similar yields were obtained for alkynes bearing ortho-and meta-substituted aryl groups (3h-3i). 3-Ethynylpyridine was a competent substrate as well (3j). Notably, aliphatic and electron-decient alkynes did not provide the desired product under current reaction conditions.
For Si-tethered alcohols (Table 3), although 1,5-HAT is kinetically less favorable than 1,6-HAT, 4d,14 product 4a was isolated in 30% yield. Next, the possibility of achieving a d-  Sonogashira reaction was examined; remarkably, selective dalkynylation of alcohols proceeded well (4b). Substrates containing competitive tertiary C-H sites (b-vs. g-, and gvs. d) were tested, and, as expected, g-functionalized alkenols were obtained as the sole regioisomers (4c and 4d). In Gevorgyan's remote Heck reaction, the g-benzylic C-H alkenylation under Pd catalysis leads to the de-saturated byproduct exclusively; in contrast, Cu-catalyzed g-benzylic C-H alkynylation worked well (4l). Benzylic alcohols are capable substrates, and a range of functional groups were tolerated on the phenyl ring (4m-4r).
This photo-induced Cu-catalyzed remote C-H functionalization strategy could be expanded to C-H amination. The siteselective amination could readily take place at the tertiary and secondary C-H sites using 9H-carbazole as the reactant (5a and 5b). 10,13b A benzylic position could be aminated as well (5c). The functional-group compatibility was investigated briey, and Cl, MeO, and tBu are readily allowed on the carbazole ring (5d-5f) ( Table 4). The carbazole motif frequently occurs in natural products, drug molecules and chiral ligands, and the alkylated carbazoles obtained by this method are not easily accessed through other approaches. 15 In an effort to understand the mechanism of this transformation, some preliminary control experiments were conducted. With addition of TEMPO, the reactions were inhibited and no desired product 3a was observed (Scheme 2, eqn (5)). Furthermore, to identify the possible intermediate, iodide 6 was independently synthesized and smoothly converted into 4h under standard conditions (eqn (6)).
The UV-vis spectra of individual reagents or complexes were recorded at the reaction concentration in MeCN. L1-Cu-alkyne (should form in situ in the reaction) shows absorption in the range 380-500 nm. 13a In addition, the Stern-Volmer experiment indicated that the excited state of the L1-Cu-Nu complex formed in situ could be quenched by Si-iodide. These results suggest that a complex of nucleophile, copper, and base accounts for the photoactive species under BLED irradiation. Moreover, the quantum yield (F ¼ 0.75%) suggested that a radical-chain process might not be involved (see the ESI † for details).
Based on the literature 5c,12,13a and these ndings, a reaction mechanism was proposed ( Fig. 1)   the alkyl halide, leading to [L1Cu(II)(C^CR 00 )] (C) and an alkyl radical (Rc) (D). Subsequently, the latter undergoes a 1,n-HAT process, generating the translocated radical species (E). The radical species E could reversibly form the intermediate F either by a direct atom transfer from the CuI species or by recombination with the Cu complex followed by reductive elimination. Alternatively, instead of iodide, an alkyne could be delivered to afford the alkynylated product and regenerate the Cu catalyst. Related examples of this so-called radical relay strategy have been extensively studied by Liu, 3g Xiao, 16 and Liu. 17 g-Alkynyl alcohols are valuable intermediates in organic synthesis, and they can participate in a wide range of transformations at triple bonds or hydroxyl groups. Thus, it can be shown that the g-alkynylated product can be readily transformed into cis-tetrahydropyran through hydro hydroalkoxylation mediated by a Lewis acid (Scheme 3, eqn (7)). Only one more salicylaldehyde was added under the same conditions, and a cascade hydroalkoxylation-formal [4 + 2] cycloaddition reaction of the alkyne took place to construct tetrahydrofurano/pyrano chromene (eqn (8)). 18

Conclusions
In summary, in this work, a mild approach for visible-lightpromoted, copper-catalyzed remote functionalization of C-H bonds of aliphatic alcohols at b, g, and d via a radical 1,n-HAT process is described. These reactions proceed at low temperature and are compatible with a range of functional groups. This system introduces the idea of merging visible-light photoredox catalysis with copper-catalyzed C-H functionalization. A single copper nucleophile complex serves as the photo-coupling catalyst and reactant as well. It is anticipated that this new methodology will nd application in the C-H functionalization reactions directly using Nu-H.

Conflicts of interest
There are no conicts to declare.