Palladium- and Copper-Catalyzed Highly Selective Mono-Coupling Between 2,6-Diiodoanisoles and Terminal Alkynes in the Production of Alkynylated Anisoles as Potential Precursors of Benzo[b]furans

The coupling reaction between 2,6-diiodoanisoles and terminal alkynes using Pd(PPh3)2Cl2 and CuI as catalysts and diisopropylamine as base in toluene at room temperature for 12 h produced selectively alkynylated 2-iodoanisoles, in good to excellent yields (52-95%), which are useful building blocks with potential application in the synthesis of functionalized benzo[b]furans.


Introduction
Palladium-catalyzed cross-coupling reactions can be considered powerful transformations for the construction of carbon-carbon and carbon-heteroatom bonds, [1][2][3][4] including, for example, Sonogashira, 1 Stille, 2 Suzuki 3 and Buchwald-Hartwig 4 reactions.The mentioned transformations have been often employed in total syntheses of complex molecules, 5 in the preparation of functional materials 6 and for the production of polymers of importance in materials science. 7Furthermore, palladiumcatalyzed reactions are in agreement with some principles of green chemistry. 8][3][4][5][6][7] However, a critical evaluation of this active area of the organic chemistry indicates that methodologies for siteselective couplings, 9 involving selective mono-couplings, 10 are still required in organic synthesis, constituting a vast field for investigation.0][11] Among them, we can mention advances achieved for selective Sonogashira mono-couplings. 11espite the advances mentioned, to the best of our knowledge, there is no methodology employing palladium as a catalyst for the selective mono-coupling between 2,6-diiodoanisoles and terminal alkynes, in order to produce alkynylated 2-iodoanisoles, which are useful intermediates in organic synthesis.Accordingly, aiming to enrich the literature, we wish to present in this manuscript results which conducted to the development of a selective mono-coupling between 2,6-diiodoanisoles (1) and terminal alkynes (2) using palladium and copper as catalysts in the presence of a nitrogen-containing base, in order to produce exclusively alkynylated 2-iodoanisoles (3) in good to excellent yields, which are useful building blocks with potential application in the synthesis of functionalized benzo[b]furans, that compose a class of aromatic heterocyclic compounds with an extensive number of pronounced biological activities, comprising, for example, anticancer, 12 antiviral 13 and anti-inflammatory 14 activities.
Afterwards, we focused on the optimization of the conditions for the reaction shown in entry 4 of Table 1, performing variations in the stoichiometry of reagents, temperature and time of reaction, envisioning the production of 1-iodo-2-methoxy-3-(phenylethynyl)benzene (3a) in a higher yield.Thus, as can be seen in Table 2, the best result was achieved when we carried out the reaction between 2,6-diiodoanisole (1a) and 2 equiv. of phenylacetylene (2a) in the presence of 5 mol% of Pd(PPh 3 ) 2 Cl 2 and 15 mol% of CuI using 2 equiv. of DIPA as base and toluene as solvent at room temperature for 12 h, producing the alkynylated 2-iodoanisole 3a in a very good yield of 82% (Table 2, entry 4).In this case, we did not observe the formation of the di-alkynylated product.However, we observed by GC/MS the formation of the alkyne-alkyne homo-coupling as a byproduct.
For entries 5 and 6 we did not observe the formation of di-alkynylated products.In addition, transformations carried out with functionalized terminal alkynes 2c-f produced the mono-coupling products 3g-k in good yields (52-85%) (entries 7-11).Allowing the reaction between 1-iodo-2-methoxy-3-(phenylethynyl)benzene (3a) and 2 equiv. of 1-hexyne (2b) in the presence of 5 mol% of Pd(PPh 3 ) 2 Cl 2 and 15 mol% of CuI using 2 equiv. of DIPA as base and toluene as solvent at room temperature for 12 h, we obtained the unsymmetrical dialkyne 3l in a good yield of 78% (entry 12).It is noteworthy that when we carried out the coupling reaction between 1,4-diiodobenzene and phenylacetylene (2a), employing the optimal conditions shown in Table 2, entry 4, by the addition of DIPA all at once, we observed the prompt formation of a viscous mixture and the exclusive production of the di-coupled product after 12 h, according to GC/MS analysis.Performing the same transformation, however, by the addition of DIPA in portions, we did not notice the formation of a viscous mixture and we observed the production of the mono-coupled product along with the di-coupled product in a ratio of 1 to 1.25 after 12 h, according to GC/MS analysis.The highly selective formation of alkynylated 2-iodoanisoles (3a-k) was not completely rationalized until this moment, however, having in mind that iodinated aromatic compounds were employed, the transmetalation reaction can be considered the rate-determining step for the Sonogashira coupling. 1In this sense, the transition states for the transmetalation step when we consider the catalytic cycle with alkynylated 2-iodoanisoles (3a-k) are substantially more sterically crowded and presumably present higher energies than the transition states for the transmetalation step when we consider the catalytic cycle involving 2,6-diiodoanisoles (1a-c).All these assumptions can be supported by the almost exclusive formation of alkynylated 2-iodoanisoles (3a-k) in good to excellent yields (52-95%).
The structures of the compounds 3a-l and 4 have been assigned on the basis of a variety of spectroscopic techniques, namely, according to their mass spectra (MS), infrared (IR), 1 H and 13 C nuclear magnetic resonance (NMR) spectra.All compounds (3a-l and 4) provided highresolution mass spectra (HRMS) that are in agreement with the proposed structures.

Experimental
General methods 1 H and 13 C NMR spectra were recorded on spectrometers operating at 300 or 200 MHz and 75 or 50 MHz, respectively. 1H NMR spectra were taken in CDCl 3 and the chemical shifts of the signals are given in ppm with respect to tetramethylsilane (TMS) used as an internal standard.

13
C NMR spectra were taken in CDCl 3 and the chemical shifts of the signals are given in ppm with respect to the central peak of the deuterated solvent adjusted to 77.00 ppm and used as a reference.Infrared spectra were obtained using attenuated total reflectance (ATR) or KBr pellets in the 4000-400 cm -1 region.Mass spectra were registered on a mass spectrometer connected to a gas chromatograph using electron impact ionization at 70 eV.High-resolution mass spectra were performed on a time-of-flight mass spectrometer.All melting point values are uncorrected.Column chromatography separations were carried out using 70-230 mesh silica gel.Catalysts, reagents and solvents were used as obtained commercially.2,6-Diiodoanisoles (1a-c) were prepared according to literature procedures. 20neral procedure for preparation of mono-coupling products (3a-k) and unsymmetrical dialkyne 3l To a solution of the appropriate 2,6-diiodoanisole (1a-c) or compound 3a (1 mmol), Pd(PPh 3 ) 2 Cl 2 (0.0351 g, 0.05 mmol) and CuI (0.0285, 0.15 mmol) in toluene (5 mL) under nitrogen atmosphere were added the appropriate terminal alkyne (2a-f) (2 mmol) and diisopropylamine (0.2020 g, 2 mmol).After that, the mixture was stirred at room temperature for 12 h.Then, brine (20 mL) was added to the reaction, which was extracted with ethyl acetate (3 × 20 mL).The organic phase was dried over MgSO 4 .After filtration, the solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel using hexane as eluent, unless otherwise indicated, affording mono-coupling products (3a-k) and the unsymmetrical dialkyne 3l.

Table 1 .
Preparation of compound 3a a entry Palladium catalyst (mol%) CuI / mol% Terminal alkyne 2a / equiv.Base (equiv.)Solvent Temperature / o C time / h Isolated yield / % a Reaction conditions: 1 mmol of compound 1a, the indicated amount of palladium catalyst, the indicated amount of CuI, the presented amount of 2a, the presented amount of base and 5 mL of solvent were stirred at the shown temperature for the time presented under nitrogen atmosphere.r.t.: room temperature.Vol.25, No. 11, 2014

Table 2 .
Optimization of conditions for the preparation of compound 3a a Reaction conditions: 1 mmol of compound 1a, 5 mol% of Pd(PPh 3 ) 2 Cl 2 , 15 mol% of CuI, the indicated amount of 2a, the indicated amount of DIPA and 5 mL of toluene were stirred at the shown temperature for the presented time under nitrogen atmosphere.r.t.: room temperature.

Table 3 .
Coupling between iodoanisoles (1 or 3a) and terminal alkynes (2) in the preparation of alkynylated anisoles (3) using Pd(PPh 3 ) 2 Cl 2 and CuI as catalysts and diisopropylamine as base in toluene at room temperature a