Copper‐Catalyzed Oxidative Cross‐Coupling of Electron‐Deficient Polyfluorophenylboronate Esters with Terminal Alkynes

Abstract We report herein a mild procedure for the copper‐catalyzed oxidative cross‐coupling of electron‐deficient polyfluorophenylboronate esters with terminal alkynes. This method displays good functional group tolerance and broad substrate scope, generating cross‐coupled alkynyl(fluoro)arene products in moderate to excellent yields. Thus, it represents a simple alternative to the conventional Sonogashira reaction.


Introduction
Functionalized aryl and heteroaryl alkynes are powerful building blocks in chemical synthesis because of their versatility to be transformed into various useful molecules and also their ubiquity in natural product synthesis, pharmaceuticals, and advancedm aterials. [1] Consequently, much effort has been expended to develop efficient methods to install various alkynyl groups.S ome of the strategies which have been established include:1 )Sonogashira palladium/copper-catalyzed sp 2 -sp cross-coupling of aryl halidesw ith terminal alkynes; [2] 2) direct alkynylation of unreactive alkyl and aryl CÀHb onds with prefunctionalized alkynating reagents such as alkynyl halides [3] and hypervalent iodine reagents; [4] 3) alkynylation of tetra-and pentafluoroarenesa nd heteroarenes via CÀHb ond activation; [5,6] and 4) cross-couplingo fc opper(I) acetylides with aryl halides, known as the Castro-Stephens reaction. [7][8][9] However, some drawbacksr emain, such as the use of preciousm etal catalysts including Pd, [2] Rh, [4a,b,h] and Au, [4c,d] strategies that depend on the use of alkynyl halides or hypervalent iodine reagents, which are less readily availablet han the corresponding terminal alkynes, and the fact that copper(I) acetylides can be heat and shock sensitive when isolated.
It is generally acknowledged that polyfluoroarenes are important fluorinated aromaticc ores and key structuralu nits for variousorganic molecules, such as pharmaceuticals, agrochemicals and organic materials. [10] The development of efficient methods to introduce fluorine or fluorinated buildingb locks into organic molecules has been the subject of intense research. Underc ertain conditions, Sonogashira cross-couplings involving highly fluorinated aryl halides can be problematic, giving low yields [11a] and side reactions, that is, hydrodehalogenation accompanied by homocoupling of the terminal alkyne. [11b] The latter problem seems to arise from the slow reductive elimination of the fluoroaryl alkyne from Pd II ,w hich leads to competing reverse transmetalation processes, that is, transfer of aryl groups from Pd to Cu in exchange for as econd alkynyl moiety being transferred from Cu to Pd. Thus,ana lternative approachw ould be useful.I n2 010, Su and co-workers demonstrated the direct functionalization of polyfluoroarene CÀHb onds with terminal alkynes, which has provent ob ea viable method to generate the corresponding alkynylated products (Scheme 1a), [12] but this reactioni sl imited to C 6 F 5 H or 4-RC 6 F 4 Hs ubstrates. Soon after,t he oxidative alkynylation of azoles containing acidic CÀHb onds with terminal alkynes was reported by the groups of Miura, [13] Chang, [14] and others. [15] Recently,S ua nd co-workersr eported ap alladium-catalyzed alkynylation of heterocyclic substrates such as thiophenes and furans. [16] Although these achievements were promising,t hey were restricted by elevated temperatures (> 90 8C) and limited substrate scope. In 2003, the palladium-catalyzed oxidative cross-coupling of terminal alkynes with arylboronic acids was first disclosed by Zou and co-workers (Scheme1b). [17] In the past few years, various modifications of this Pd-catalyzed reaction have been developed. [18] However,p alladium is costly and only af ew electron-withdrawing substituents on the aromatic ring of arylboronic acids were employed. Recently,C heng et al. disclosedacopper-catalyzed oxidative coupling of arylboronic acids with terminal alkynes. [19] However, the reported method suffers from some disadvantages including high reaction temperature, long reactiont ime (36 h), and only moderate yields. From as ynthetic point of view,t he development of an improvedp rocedure employing an inexpensive catalystf or widespread application has remained ah ighly desirable goal.
We reported the CÀFb orylation of fluoroarenes using aNHC (N-heterocyclicc arbene)-ligated Ni complex as ac atalyst to generate fluorinated arylboronic acid pinacol esters (Ar F Bpin) in good to excellent yields. [20a,b] Very recently, we reported optimized conditions for the Suzuki-Miyaura cross-coupling of Ar F Bpin with aryl iodides and bromides using ac ombination of CuI and phenanthroline as ac atalystp recursor to generate cross-coupled products in moderate to excellent yields. [20c] We have recently reported the palladium-catalyzed homocoupling of fluorinated arylboronates, [20d] and the borylation of aryl chlorides, using NHC-stabilized nickel(0) complexes [20e] or a readily prepared NHC-stabilizedC uc atalyst. [20f] Inspired by these results, we attempted to develop aC u-catalyst system for the oxidative cross-coupling of Ar F Bpin compounds with terminal alkynes.

Results and Discussion
We initially investigated the cross-coupling reaction with models ubstrates pentafluorophenyl-Bpin (1a)a nd phenylacetylene (2a), using Ag 2 Oa st he oxidanta nd phenanthroline (Phen)a st he ligand.D uring our initial experiments,n or eaction occurred when CuBr 2 wase mployed as the metal source, with tBuOLi as the base in DMF solution( Ta ble 1, entry 1). However, employing CuCl as catalyst precursor gave rise to compound 3a in 10 %y ield (Table 1, entry 2). The introduction of Cu(OAc) 2 as the catalystp recursor improved the yield to 18 %( Ta ble 1, entry 3). However,l arge amountso fd iyne byproduct 4 and perfluorobiphenyl compound 5 were produced.
We speculated that strong bases, such as tBuOLi, might acceleratet he formation of 5.U nder otherwise identical conditions, replacing the strong base with K 3 PO 4 effectively inhibited the homocoupling of pentafluorophenyl-Bpin (Table 1, entry 4). To our surprise, the addition of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) significantly improved the yield to 58 %a nd suppressed the formation of 4 (Table 1, entry 5). It is possible that DDQ serves as an electron-transfer mediator. [12,21] To optimize the reaction performance, we screened the reaction parameters, including the base andt he solvent. Of the bases examined, K 2 CO 3 proved to be the moste ffective (entry 7). Both KF and Cs 2 CO 3 gave significantly lower yields (entries6and 8).
Scheme1.Selectedoxidativecross-coupling reactionso fa lkynes. In addition, reaction optimization also revealed that the solvent had as ignificant impacto nt his reaction. Lower yields were observed when reactions were performed in other solvents such as 1,2-dichloroethane (DCE),C H 3 CN, THF,D MSO, methyl tert-butyle ther (MTBE), and toluene (entries [9][10][11][12][13][14]. Notably,t he replacement of Ag 2 Ow ith O 2 failed to give any desired product (entry 17), indicating the uniquer oles of Ag 2 Oi n promoting this reaction. Attempts to run the reaction in air resulted in av ery low yield of the desired product (entry 15). Reducing the amount of K 2 CO 3 and Ag 2 Oa lso diminishedt he yield (Table 1, entries 18 and 19).
With the optimized conditions in hand, we focusedo ur attention on investigating the scope and limitations of the oxidative cross-coupling reaction. As shown in Scheme 2, various fluorophenylboronate esters 1 containing 1-4 fluorine atoms were tested. Under the standard conditions (Table 1, entry 7), differentt etrafluorophenylboronate esters and trifluorophenylboronate esters smoothly underwent alkynylation giving good to excellent yields (Scheme 2, 3b-3f). However,t hese reaction conditions were not suitable for Ar F Bpin substrates containing di-or mono-fluorinated arylboronates such as 2,5-or 2,3-difluorophenyl-Bpin (1g and 1i)a nd 3-fluorophenyl-Bpin (1h), perhaps due to the lower Lewis acidity of the boronates which is impacted by the number of fluorines and, especially, orthofluorines ubstituents. We speculated that increasingt he temperature might be crucial for overcoming the barrier to CÀB bond activation and thus to obtaining efficient catalysis. When reactions were performed at 80 8C, the corresponding products 3g and 3i were formed in good yields. It is also noteworthy that replacement of the weak base with as tronger base afforded the corresponding product in good yield (3h).
The substituents of alkynes 2 were then varied in order to explore further the scope of the reaction. As shown in Scheme 3, as eries of alkynes 2 with different electron-withdrawing ande lectron-donatings ubstituents on the aromatic ring were subjected to the optimal conditions. The experimental results showedt hat ab road range of substituents on the arylalkynes 2,i ncluding methyl, methoxy,c hloro, bromo,a nd fluoro groupsatthe ortho-, meta-, and para-positions of the aromatic ring werew ell tolerated, providing the desired compounds in moderate to excellent yields (Scheme 3, 6a-6h). Furthermore, the structures of compounds 6a and 6g were unambiguously confirmed via single crystal X-ray diffraction (see below). An ester group, which may not be tolerated in reactions employing organozinc reagents, is also compatible with this reaction (6i). Importantly,a liphatic alkynes proceeded to give the desired products in moderate to good yields (6j and 6k). With ah ighly electron-withdrawing CF 3 substituent, only moderate yields were observed (6l and 6m). Unfortunately,l ess reactive 4-nitro-phenyl and 4-cyano-phenyl alkynes were not suitable for the reaction under the standard conditions.
To examinet he feasibility of scalingu pt he reaction, ag ramscale coupling of C 6 F 5 -Bpin with phenylacetylene was em-C.T he desired product 3a would be generatedb yC ÀCr eductive elimination. The Cu 0 species formed is reoxidized by DDQ (see above) [12,21] to regenerate A,c ompleting the catalytic cycle.
In compounds 6a and 6g,t he nearly planarm olecules are related by inversion symmetry and are oriented offset face-toface in ah ead-to-tail fashion forming infinite p-stacks (Figure 2). The interplanar separations between the aromatic rings (3.325(3) À3.438(2) ,T able2)a re in the normal range of p-p stacking interactions,w hich are typical of molecules for which the packingi sd ominated by arene-perfluoroarene interactions.T he differences in electronegativity of hydrogen and fluorine atoms with respectt ot he carbon atoms lead to the formation of opposite multipoles for fully fluorinated andn onfluorinated aryl groups and, hence, to attractive multipole forces between these groups. [29] Head-to-tail stackingv ia arene-perfluoroarene interactions, analogous to that observed in 6a and 6g,i sc ommonly found in self-complementary compounds that contain both fluorinated and nonfluorinated aryl groups.E xamples are partially fluorinatedt olans [24] and phenylendcapped polyynes, [26] but also co-crystals of bis(phenylethynyl)benzenes with inverselya lternating fluorinated and nonfluorinated phenyl rings. [25] We conclude that methylation at the 2-, 4-, and 6-positionso ft he phenyl ring in 6a does not alter this common stacking motif and, hence, the influence of arene-perfluoroarene interaction on the molecular packing. Arene-perfluoroarene p-stacking was also observed in the 1:1 co-crystal of mesitylene and hexafluorobenzene. [30] Weak intermolecular CÀH···F,C ···F,a nd F···F interactions exist between adjacents tacks in 6a and 6g (Figure 2, Ta ble S2 in the Supporting Information). Mono-fluorinationa tt he para-position of the phenylr ing in 6g does not have as ignificant influence on the arene-perfluoroarene packing, which is very similar to that of 1-pentafluorophenyl-2-phenylacetylene. [24] This was expected as the mono-chlorination of partially fluorinated tolan at the same para position did not alter the packing motif. [28a] The effect of halogenation with chlorine, bromine, and iodine atoms at the para-positions of partially fluorinated tolans on the presence of arene-perfluoroarene interaction, studied earlier by Marder and co-workers, [28a] revealed the absence of arene-perfluoroarene stacking only for the compounds substituted with the heavierh alogens (Br,I ). This was explained by the prevalence of Br···Br and I···I interactions determining the packing of the molecules. [28a] Also note the larger twist angle between the phenyl rings in these compounds (15.69(8) and 9.4(2)8)w hen compared to those in arene-perfluoroarene pstacked tolans (see discussion above). Similarly,t he substitution of other strong electron-withdrawingg roups such as NO 2 and CN at the para-positiono ft he phenyl ring in partially fluorinatedt olans showed the prevalence of O···O and CÀH···N in-   (3) 3.04(5) centroid-centroidd istance3 .586 (3) 3.629 (3) 3.705 ( (3) [a] The offset shift, also called inter-centroid shift, is the distancew ithina plane of an arylr ing between the centroid of the respective aryl ring and the intersection pointw ith the normal to the plane through the centroid of the other aryl ring.
teractions and the absence of arene-perfluoroarene interactions in their crystal structures. [28b]

Conclusion
In conclusion, we have developed ac opper-catalyzed method for the direct alkynylation of electron-deficient polyfluorophenylboronate esters with terminal alkynes. This reaction features broad functional group tolerance, mild reaction conditions, and simple operation. From as ynthetic point of view,t he present reactionh as the potentialt ob ea pplied widely in organic synthesis because many shelf-stable aryl and alkyl boronate esters are commercially available. The partially fluorinated tolans also displayi nteresting fluoroarene-arene p-stacking interactions in the solid-state as demonstrated by single-crystal X-ray diffraction in two cases.

Crystallographic details
Crystal data collection and processing parameters are given in the Supporting Information. Deposition Numbers 2000968 (6a), and 2000970 (6g)c ontain the supplementary crystallographic data for this paper.T hese data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/ structures.