Complimentary and personal copy www.thieme.com SYNTHESIS Reviews and Full Papers in Chemical Synthesis This electronic reprint is provided for non- commercial and personal use only: this reprint may be forwarded to individual colleagues or may be used on the author’s homepage. This reprint is not provided for distribution in repositories, including social and scientific networks and platforms. Publishing House and Copyright: © 20 by Georg Thieme Verlag KG Rüdigerstraße 14 70469 Stuttgart ISSN 0039-7881 Any further use only by permission of the Publishing House 2387 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany J. A. Cabezas, N. Ferllini PaperSyn thesis Regiospecific Palladium-Catalyzed Cross-Coupling Reactions Using the Operational Equivalent of 1,3-Dilithiopropyne Jorge A. Cabezas* 0000-0002-7571-6914 Natasha Ferllini Escuela de Química, Universidad de Costa Rica, San José, 11501-2060, Costa Rica jorge.cabezas@ucr.ac.cr Cl Cl 1. Mg, THF 2. n-BuLi (2 equiv.) Pd(PPh3)4 1. CuI (1 equiv.) 9 examples up to 97% yield Pd(PPh3)2Cl2 or Li Li IR R 2. Tolerance to functional groups in R Regiospecific cross-coupling Highly efficient (0.8 equiv.) S I R or (0.7 equiv.) S R Received: 05.03.2020 Accepted after revision: 26.03.2020 Published online: 07.04.2020 DOI: 10.1055/s-0039-1690895; Art ID: ss-2020-m0129-op Abstract A regiospecific palladium-catalyzed cross-coupling reaction using the operational equivalent of the dianion 1,3-dilithiopropyne, with aromatic iodides is reported. This reaction gives high yields of 1- propyn-1-yl-benzenes and 2-(propyn-1-yl)thiophenes in the presence of catalytic amounts of palladium(0) or (II) and stoichiometric amounts of copper iodide. No terminal alkyne or allene isomers were detected. Reaction conditions were very mild and several functional groups were tolerated. Key words 1,3-dilithiopropyne, cross coupling, 1-propynylbenzenes, 2-(propyn-1-yl)thiophenes, 2-phenyl-5-(propyn-1-yl)thiophene The alkynylation of halogenated aromatic rings is one of the most general methods for the synthesis of aromatic alkynes.1 A seminal work was the 1963 Stephens–Castro synthesis of diarylacetylenes, prepared by treatment of aryl iodides with cuprous acetylides in refluxing pyridine.2 In 1975, Heck reported3 the preparation of disubstituted acet- ylenes by reaction of the corresponding mono-substituted acetylenes with aryl (or heterocyclic) bromides and iodides, at 100 °C, in the presence of an amine under Pd(II) catalysis. At the same time, Cassar reported4 a catalytic system, based on the use of tetrakis(triphenylphosphine)palladium(0), to prepare disubstituted acetylenes by reaction of aryl and vi- nyl halides with monosubstituted acetylenes, using sodium methoxide as a base, and temperatures between 40 and 100 °C. Currently, the method most extensively used for the synthesis of mono- and disubstituted acetylenes is the So- nogashira reaction, originally reported in 1975.5 In this pro- tocol, an aromatic (or vinyl) halide is treated with the corre- sponding acetylene, in the presence of catalytic amounts of Pd(0) or Pd(II) triphenylphosphine complexes, an amine (e.g., Et2NH) and catalytic amounts of CuI at room tempera- ture. Thereafter, Negishi reported a similar palladium-cata- lyzed cross-coupling reaction employing alkenyl halides6 and aryl halides7 with alkynylzincs. This alkynylation has also been reported with alkynyl metals bearing magne- sium,8 boron,9 and aluminum.10 However, it has been re- ported that alkynyllithium reagents are as reactive as the corresponding alkynylzincs only if the corresponding palla- dium complex is used stoichiometrically; they fail to pro- duce the expected alkynylation product in the presence of catalytic amounts of palladium.1 Negishi later found11 that ethynylation of aromatic iodides proceeded best with ethynyl metals such as magnesium and zinc and ethynyl- lithium gave very poor results (≤3% yield).12 It has been suggested that this cross-coupling reaction is difficult to achieve with lithium acetylides using catalytic amounts of palladium, because the highly nucleophilic alkynyllithiums may displace the ligands (e.g., PPh3, Cl–) from the palladium complexes, forming lithium palladates that do not exhibit any catalytic activity.13 O-Substituted arylalkynes are very useful intermediates in the synthesis of heterocyclic compounds14 such as phtha- lides and isocoumarins,15 furocoumarins,16 2-substituted benzofurans,17 indoles,18 1,2-benzothiazine 1,1-dioxides,19 benzoisothiazoles, benzofluorenones,20 dihydroisobenzo- furanes,21 and isoquinolones.14 Specifically, 1-propynylarenes that can be obtained by the above alkynylation protocols using prop-1-yne, are not only very valuable synthetic intermediates, but are also present as key motifs in a wide number of natural prod- ucts,22 many of which have important biological activity.22e Some interesting pharmaceutical examples are a series of 1-propyn-1-yl-benzenes 2, which have been used at Eli Lilly as important building blocks for the synthesis of a se- quence of dibenzoxapines bearing tetrasubstituted exo- cyclic alkenes that act as modulators of selective nuclear SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X © Georg Thieme Verlag Stuttgart · New York 2020, 52, 2387–2394 paper en 2388 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis hormone receptors.23 The synthesis of the key intermediate 1 was performed by a palladium-catalyzed carbometalla- tion of 1-prop-1-ynylbenzene 2 (Scheme 1). Scheme 1 Palladium-catalyzed carbometallation of alkyne 2 A common structural framework found in many natu- rally occurring thiophenes is a 1-propynyl group attached to an -carbon of the thiophene ring. Examples of these are 2-phenyl-5-(propyn-1-yl)thiophene (3), isolated from Core- opsis grandiflora24 and Coreopis lanceolata,25 methyl cis- - (5-propynyl-2-thienyl)acrylate (4), isolated from the roots of Chrysanthenum vulgare,26 and 2-(propyn-1-yl)-5-form- ylthiophene (junipal; 5), isolated from Daedalia juniperi- na22a (Figure 1). The former compound, 3, exhibited nemat- icidal activity.25 Figure 1 Some naturally occurring thiophenes bearing a propynyl group We report herein an unprecedented regiospecific, palla- dium-catalyzed, cross-coupling reaction of the operational equivalent of dianion 1,3-dilithiopropyne 6, with aromatic iodides. This alkynylation reaction proceeds in the presence of catalytic amounts of palladium(0) or (II), and stoichio- metric amounts of copper iodide, leading exclusively to 1- propyn-1-yl-benzenes and 2-(propyn-1-yl)thiophenes, in very good yields. We previously reported27 the preparation, on a 1-liter scale, of the operational equivalent of propargyl dianion 6, obtained from the treatment of allene 7 with two equiva- lents of n-BuLi28 (Scheme 2, Method A). Later we showed that dianion 6 reacted regiospecifically with aromatic alde- hydes and ketones to produce, after protonolysis, the corre- sponding homopropargyl alcohols, without contamination with the allenic isomers, in very good yields.29 Since the high price of allene 7 considerably discourages the use of this methodology, we later developed a more economical procedure30 to prepare 1,3-dilithipropyne dianion 6 by treatment of propargyl bromide 8 with n-BuLi in the pres- ence of TMEDA (Scheme 2, Method B). Treatment of dianion 6 with aldehydes and ketones produced the corresponding homopropagyl alcohols in excellent yields.30 Moreover, we have used dianion 6 to develop new protocols for the syn- thesis of bishomopropargylic alcohols31 and 1,5-diynes.32 The latter methodology was fundamental to establish a short and efficient synthesis of the cocoa pod borer moth pheromone.32 Scheme 2 Preparation of dianion 6, under different reaction condi- tions One of our goals was to develop experimental condi- tions to perform regioselective palladium-catalyzed cross- coupling chemistry with species 6. Thus, we started execut- ing reactions of dianion 6, generated from propargyl bro- mide 8 (Scheme 2, Method B) with iodobenzene (10), in the presence of Pd(0) or Pd(II) complexes, and CuI. All of these attempts failed to produce any cross-coupling product (Scheme 3). When dianion 6 was first treated with ZnCl2 (1 or 2 equivalents) to form the corresponding alkynylzinc re- agents and then reacted with aryl iodide 10, under palladi- um catalysis, the reaction was also unsuccessful (Scheme 3). Scheme 3 Initial reactions of dianion 6 with PhI (10) We considered that a highly coordinating species such as TMEDA, used to prepare dianion 6, might strongly coor- dinate with palladium, inhibiting its catalytic function. In fact, several stable chelate complexes between palladium and TMEDA (and its derivatives) have been reported.33 Moreover, the palladium(II) chloride complex with TMEDA, dichloro (N,N,N′,N′-tetramethylethylenediamine) palladi- um(II), is commercially available. 1,3-Dilithiopropyne (6) (or its synthetic equivalent) can also be prepared by reaction of 1-propyne with n-BuLi, but this reaction also requires the presence of one equivalent of TMEDA.34 We envisioned that 2,3-dichloropropene (9) might be a starting material for the preparation of dianion 6, avoiding the use of TMEDA.35 Thus, treatment of 9, with magnesium in THF formed the corresponding allyl Grignard reagent, which spontaneously decomposed to generate allene gas 7,35 which was bubbled into a cold (–78 °C) ether/hexane36 O I R1 R2 NO2 B(OH)2 + NO2 O R1 R2 12 Pd(OAc)2 S S O H 3 5 S 4 CH3O O H • H H H n-BuLi (2 equiv.) –78 °C Li Li Brn-BuLi (2 equiv.) TMEDA, –78 °C67 8 Cl Cl 1. Mg 9 2. n-BuLi (2 equiv.), –78 °C 7 Method A Method B Method C Li Li6 PhI (10) Pd(PPh3)4 CuI 1. ZnCl2 2. PhI (10), Pd(PPh3)4 N.R. N.R. 2389 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis solution of n-BuLi. After warming the reaction mixture to – 15 °C, dianion 6 was obtained as a white precipitate (Scheme 2, Method C). The dianion 6, thus prepared, not only reacted with aldehydes and ketones, producing the corresponding homopropargyl alcohols in very good yields, the lithium-acetylide intermediates, obtained in these reac- tions, also gave palladium-catalyzed cross coupling reac- tions with aromatic halides.35 We later used this methodol- ogy to convert aldehydes and ketones into 1,4-disubstituted 1,3-enynes in a ‘one-pot’ reaction.37 Having a TMEDA-free method for the preparation of dianion 6, in our hands, we were prompted to attempt its direct palladium-catalyzed cross-coupling reaction with aromatic iodides. Initial reactions of 6 (0.90 mmol) with o-iodoanisol 11 (0.80 mmol) in the presence of catalytic amounts of Pd(PPh3)4 (7 mol%) and CuI (5–10 mol%) gave the desired coupling product 12, in variable yields from 0 to 30% (Table 1, entry 1). When dianion 6 (0.90 mmol) was treated first with an ethereal solution of ZnCl2 (1.80 mmol) to form the corresponding zinc species, then treated with iodide 11, under palladium catalysis (with or without CuI), the corresponding coupling product 12 was not obtained and unreacted starting material was recovered (entries 2 and 3). Table 1 Cross-Coupling Reaction of Dianion 6 with o-Iodoanisole (11) under Different Reaction Conditionsa The reaction of 6 (0.90 mmol) with iodide 11 was re- peated using palladium(0) catalysis (7 mol%) but, in this case, higher amounts of CuI were used (0.45 mmol). After stirring the mixture at room temperature overnight, GC-MS analysis of an aliquot taken from the reaction flask revealed the presence product 12, albeit in low yield (20–25%; Table 1, entry 4). Surprisingly, when an additional amount of CuI (0.45 mmol) was added and the reaction was stirred for four additional hours at room temperature, the yield of 12 increased to 50% (entry 5). We interpreted this result as sig- naling that species 6 remained active for several hours at room temperature under nitrogen, and also that its partici- pation in this cross-coupling was highly dependent on the Entry Catalyst (0.06 mmol) Amount of CuI (mmol) Additive (mmol) Yield (%)b 1 Pd(PPh3)4 0.04–0.08 – 0–30 2 Pd(PPh3)4 0.04–0.08 ZnCl2 (1.8) 0 3 Pd(PPh3)4 – ZnCl2 (1.8) 0 4 Pd(PPh3)4 0.45 – 20–25 5 Pd(PPh3)4 additional 0.45 – 50 6 Pd(PPh3)4 0.90 – 96 7 – 0.90 – 0 8 Pd(PPh3)2Cl2 0.90 – 95 a In all the cases, reactions were allowed to warm from –15 °C to r.t. over 18 h. b Yield calculated based on GC-MS analysis. Li Li OCH3 I 11 6 + (0.80 mmol) (0.90 mmol) OCH3 12 Table 2 Palladium-Catalyzed 1-Propynylation of Aromatic Iodidesa Entry Starting iodide Product Isolated yield (%)b 1 95 2 90 3 76 4 97 5 82 6 85 7 68 8 86 9 97 a In all these cases Pd(PPh3)2Cl2 was used as catalyst. Reactions were allowed to warm from –20 °C to r.t. over 18 h. b In all cases, GC-MS analysis of the crude reaction mixtures indicated complete consumption of the corresponding starting material. OCH3 I 11 OCH3 12 I 13 14 I 15 O2N 16 O2N I 17 HN S O O 18 HN S O O O I 19 O 20 I O OCH3 21 22 O OCH3 I O H 23 24 O H S I 25 S 26 S I 28 S 3 2390 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis amount of CuI. The foregoing led us to consider that the ac- tive species was an acetylenic cuprate rather than a lithium acetylide. Acetylide groups have long been used as nontransfer- able, or ‘dummy’, ligands in mixed organocuprate reagents of type R1R2CuLi, to allow selective group transfer, specifi- cally in substitutions and addition reactions. This concept was introduced by Corey in 1972,38 and since then alkynyl groups such as 1-pentynyl,38 tert-butylacetylide,39 and 3- methoxy-3-methyl-1-butynyl40 have been successfully used as nontransferable or residual ligands. These alkynyl ligands are usually not transferred because they are tightly bound to copper. It has been shown that the ease of the li- gand transfer follows the order n-Bu ~ s-Bu > t-Bu >> Ph > alkynyl41 and vinyl > Me >> alkynyl.42 It is well known that a sp3-carbon ligand transfers selectively over a sp-carbon li- gand from copper. Thermodynamic and kinetic control fac- tors have been proposed for this selectivity.43 Because a ni- trile is electronically similar to an alkyne, it has also been successfully used as a residual ligand in higher order cyano- cuprates of the type R1R2Cu(CN)Li2.44 If an acetylenic cuprate is the active intermediate spe- cies in our 1,3-dilithiopropyne, palladium-catalyzed, cross- coupling protocol, the acetylene moiety (propyn-1-yl) acts as a transferable ligand, and not as a residual or ‘dummy’ ligand,38–44 in the transmetalation step of the palladium- catalytic cycle. Moreover, it is very interesting to note that, under the reaction conditions developed, the acetylide sp carbon of dianion 6 transfers regiospecifically over its sp3 carbon-terminus, contrary to expectations.38–44 In another reaction, a suspension of dianion 6 (0.90 mmol) at –15 °C was treated with a THF solution of iodide 11 (0.80 mmol) and Pd(PPh3)4 (0.06 mmol) and, after stir- ring for about 5 minutes, it was reacted with one equivalent of CuI (0.90 mmol) and allowed to stir overnight. After this time, GC-MS analysis of an aliquot revealed that acetylene 12 was obtained quantitatively. After purification by col- umn chromatography, the product was isolated in 96% yield (Table 1, entry 6). To verify the requirement of palladium catalysis in our new coupling protocol, the latter reaction (entry 6) was repeated but without Pd(PPh3)4 and, in this case, only the starting material was recovered (entry 7). Finally, it was confirmed that use of the more stable Pd(II) complex Pd(PPh3)2Cl2 was as effective as Pd(PPh3)4 catalyzing this coupling reaction (Table 1, entry 8). The use of aromatic bromides in this cross-coupling reaction was unsuccessful and the starting material was always recov- ered. We note that, in this reaction, the best and most repro- ducible results were obtained when dilithium species 6 was first treated with one equivalent of CuI, to presumably form the corresponding cuprate, which then reacts with the aro- matic iodide in the presence of catalytic amounts of Pd. To demonstrate the wide applicability of this new pro- tocol and tolerance to diverse functional groups, several alkynylation products were prepared (Table 2). Thus, di- anion 6 was reacted under the above conditions with o-iodotoluene (13) and p-iodonitrobenzene (15), to pro- duce high yields of the corresponding propyn-1-yl benzene derivatives 14 and 16, respectively (entries 2 and 3). We elucidated the crystal structure for 1-nitro-4-(propyn-1- yl)benzene (16).45 Particularly relevant was the synthesis of the biological- ly active N-[3-(propyn-1-yl)phenyl]benzenesulfonamide (18) in 97% yield from iodide 17 (Table 2, entry 4). In addi- tion to elucidating its crystal structure,46 we tested the anti- bacterial activity of sulfonamide 18 against Staphylococcus aureus and Escherichia coli, and obtained minimum inhibi- tory concentrations (MIC) of 12.5 g/mL and 25.0 g/mL, respectively.47,48 To explore functional group compatibility, we further used 4-iodoacetophenone (19) as a substrate. We were pleased to observe that the coupling product, 4-(propyn-1- yl)acetophenone (20), was isolated in 82% yield (Table 2, en- try 5), and no reaction at the carbonyl group was observed. Under similar conditions, methyl 2-iodobenzoate (21) gave 85% yield of methyl 2-(propyn-1-yl)benzoate (22) (entry 6). Under our propynylation protocol, even the extremely la- bile 2-iodobenzaldehyde (23) gave the corresponding cou- pling product 24 in 68% isolated yield (entry 7). Finally, pro- pynylation of 2-iodothiophene (25) gave 2-(propyn-1- yl)thiophene (26; entry 8), which could be a useful synthet- ic intermediate in the synthesis of natural products such as 3, 4, and 5. Synthesis of Natural Product 3 We decided to apply this methodology to the synthesis of natural product 3. Thus, we started treating commercial- ly available 2-phenylthiophene (27) with n-BuLi-TMEDA at –78 °C, followed by warming to room temperature. After cooling the reaction mixture back to –78 °C, it was reacted Scheme 4 Synthesis of natural product 3 S 1. n-BuLi-TMEDA 2. I2 S I Cl Cl 1. Mg, THF 2. n-BuLi CuI Li Li S Pd(PPh3)2Cl2 27 28 9 6 3 91% 97% 88% overall yield 2391 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis with a THF solution of iodine and allowed to warm to room temperature. After aqueous work-up and purification, io- dide 28 was obtained in 91% yield (Scheme 4). 1-Propynyla- tion of 28, under the above reaction conditions, yielded nat- ural product 3 in 97% isolated yield (Scheme 4; Table 2, en- try 9), and with an overall yield of 88% from 27. To our knowledge,22b,c,49 this is the shortest and highest yielding synthesis reported for this compound to date. A specific advantage of this 1-propynylation reaction over the Sonogashira reaction is that in the former protocol the propynylation reagent used is 1,3-dilithiopropyne 6 (or its equivalent), which is easily prepared from 2,3-dichloro- propyne (9; bp 94 °C), whereas in the latter the propynyla- tion is performed with propyne gas which, due to its low boiling point (–23 °C), has to be bubbled in a large excess into a reaction mixture, at room temperature, over a long time (ca. 6 h).5 To compare both methods, we prepared47 sulfone 18 from iodide 17 and propyne under Sonogashira reaction conditions, and the product was isolated in 70% yield (compare to Table 2, entry 4). In summary, we have developed a new palladium-cata- lyzed cross-coupling 1-propynylation method for aromatic iodides, using the operational equivalent of 1,3-dilithiopro- pyne. The method is regiospecific and, contrary to expecta- tions,38–44 only coupling reaction through the sp-carbon of dianion 1,3-dilithiopropyne 6 was observed. No terminal alkynes or allenyl isomers, as by-products, were observed in any of the reactions performed. The method is very mild and tolerates reactive functional groups such as aldehydes, ketones, and esters. The cross-coupling products were ob- tained in very good yields and with high purity. This 1-pro- pynylation reaction gave better yields than the Sonogashira reaction and, due to the nature of the starting materials, it is easier to perform (2,3-dichloropropyne vs. propyne). All glassware and syringes were dried in an oven overnight at 140 °C, assembled while hot, flushed, and cooled under nitrogen immediately prior to use. Transfers of reagents were performed with syringes equipped with stainless-steel needles. All reactions were carried out under a positive pressure of nitrogen. Nitrogen was passed through a Drierite gas-drying unit prior to use. Diethyl ether and tetrahydrofu- ran were heated at reflux and freshly distilled from sodium and potassium/benzophenone ketyl, respectively, under nitrogen atmo- sphere. Hexane was distilled from sodium and collected and kept over activated molecular sieves. Pd(PPh3)4, Pd(PPh3)2Cl2 and CuI were weighed in a glove box under nitrogen. n-Butyllithium was titrated according to the method of Watson and Eastham.50 1H and 13C NMR spectra were recorded with 600 and 400 MHz Bruker NMR spectrom- eters. Low-resolution mass spectra were obtained with an Agilent Technologies 7820A GC coupled to a mass spectrometer 5977E unit operated using electron impact at 70 eV. High-resolution mass was determined with a Waters Synapt HMDS G1, Q-TOF. Infrared spectra were recorded with a Perkin Elmer FT-IR Spectrum 1000. The melting points were determined with a Fisher Scientific apparatus and are re- ported without correction. Preparation of 1,3-Dilithiopropyne (6) An oven-dried, 100 mL, three-necked, round-bottomed flask was equipped with a magnetic stirring bar and a Liebig condenser bearing a glycerin-bubbler at the top. The exit of the bubbler, bearing a sep- tum, was punctured with a double-tipped needle, the other end of which was inserted, through a rubber septum, into a two-necked flask equipped with a magnetic stirring bar, and capped by a rubber septum bearing a needle attached to a balloon. All joints were greased and secured with parafilm. The three-necked flask was charged with magnesium turnings (1.55 g, 64 mmol), a small crystal of iodine and THF (25 mL). A small amount (ca. 0.5 mL) of a THF solution (5 mL) of 2,3-dichloropropene (2.22 g, 20 mmol) was added to the magnesium, the mixture was stirred for about 10 min and a very exothermic reac- tion ensued after slightly warming the reaction flask. The allene gas that was generated was bubbled into a solution of n-BuLi (0.70 mL, 1.80 mmol) in anhydrous diethyl ether (5 mL) and anhydrous hexane (4.30 mL),36 at –78 °C, contained in the two-necked flask, under nitro- gen atmosphere. The remaining THF solution of 2,3-dichloropropene was added in small portions, in order to maintain a vigorous genera- tion of allene. It is important to keep a positive pressure of allene throughout the process. A drop in pressure in the three-necked flask produces a vacuum in the second flask. To avoid loss of material during the process of generation of allene, the valve connected to the manifold, in the second flask containing the n-BuLi, was kept closed, and the allene was collected in a balloon. After generation of allene stopped, the cannula was removed from the second flask, and the n-BuLi-allene solution was allowed to warm gradually (over a 3-hour period) to –20 °C, during which time a white precipitate was ob- tained. After the suspension reached –20 °C it was stirred for 30 addi- tional minutes. Cross-Coupling of 1,3-Dilithiopropyne (6) with Aromatic Iodides To the 1,3-dilithiopropyne solution, prepared as above, was added CuI (0.175 g, 0.92 mmol) in one portion and the reaction mixture was stirred for 5 minutes at –20 °C, followed by the addition of THF (5 mL) and stirred for 30 additional minutes. A THF (7 mL) solution of Pd(PPh3)2Cl2 (0.045 g, 0.06 mmol) and the aromatic iodide (0.80 mmol) was added, via cannula under nitrogen, and the reaction mix- ture was stirred overnight. The reaction was quenched by addition of a saturated ammonium chloride solution and extracted with ether. The extracts were dried (MgSO4) and concentrated in vacuo, with the exception of product 26, which was concentrated by distillation using a Vigreaux column. All the products were purified by column chro- matography. Synthesis of 2-Phenyl-5-iodothiophene (28) [CAS Reg. No. 13781-37-8] To a cold (–78 °C) solution of n-BuLi in hexanes (0.63 mL, 1.5 mmol) and TMEDA (0.22 mL, 1.5 mmol) was added a THF solution (5 mL) of 2-phenylthiophene (27) (0.250 g, 1.5 mmol) and the mixture was al- lowed to reach r.t. in about 30 min. The reaction mixture was cooled to –78 °C and treated with a THF solution (10 mL) of iodine (0.436 g, 1.72 mmol) and allowed to warm to r.t. The mixture was treated with an aqueous solution (10 mL) of Na2S2O3 (1.56 g), extracted with ether, and dried over MgSO4. The crude material was filtered through a small pad of silica gel and concentrated in vacuo to obtain 28. Yield: 0.404 g (91%); brownish solid. 1H NMR (CDCl3, 400 MHz): = 7.53 (m, 2 H), 7.38 (br dd, J = 7.8, 7.2 Hz, 2 H), 7.30 (dddd, J = 7.4, 7.4, 1.2, 1.2 Hz, 1 H), 7.22 (d, J = 3.8 Hz, 1 H), 6.98 (d, J = 3.8 Hz, 1 H). 2392 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis 13C NMR (CDCl3, 100 MHz): = 150.4, 137.9, 133.6, 129.0, 128.0, 125.8, 124.5, 72.3. MS (EI): m/z (%) = 39 (4), 51 (5), 63 (8), 79 (15), 102 (10), 115 (85), 127 (5), 143 (10), 158 (8), 184 (3), 286 (100) [M]+, 288 (12) [M+2]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C10H8SI: 286.9391; found: 286.9394. 1-Methoxy-2-(propyn-1-yl)benzene (12) [CAS Reg. No. 66021-98-5] Yield: 0.112 g (95%); colorless liquid; Rf 0.41 (hexane/ether, 8:2). 1H NMR (CDCl3, 600 MHz): = 7.37 (dd, J = 7.5, 1.7 Hz, 1 H), 7.24 (ddd, J =8.3, 7.5, 1.7 Hz, 1 H), 6.88 (ddd, J = 7.5, 7.5, 0.9 Hz, 1 H), 6.85 (br d, J = 8.3 Hz, 1 H), 3.88 (s, 3 H), 2.12 (s, 3 H). 13C NMR (CDCl3, 150 MHz): = 160.0, 133.8, 129.0, 120.5, 113.2, 110.6, 90.1, 75.9, 55.9, 4.91. MS (EI): m/z (%) = 39 (2), 51 (8), 63 (6), 77 (28), 91 (8), 103 (18), 115 (22), 131 (50), 146 (100) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C10H11O: 147.0810; found: 147.0812. 1-Methyl-2-(propyn-1-yl)benzene (14) [CAS Reg. No. 57497-13-9] Yield: 0.094 g (90%); colorless liquid. 1H NMR (CDCl3, 600 MHz): = 7.37 (br d, J = 7.4 Hz, 1 H), 7.18 (m, 2 H), 7.11 (m, 1 H), 2.43 (s, 3 H), 2.11 (s, 3 H). 13C NMR (CDCl3, 150 MHz): = 140.3, 132.2, 129.6, 127.8, 125.7, 124.1, 89.9, 78.9, 21.0, 4.8. MS (EI): m/z (%) = 39 (8), 51 (9), 63 (13), 77 (10), 89 (10), 102 (7), 115 (87), 130 (100) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C10H11: 131.0861; found: 131.0862. 1-Nitro-4-(propyn-1-yl)benzene (16) [CAS Reg. No. 28289-83-0] Yield: 0.098 g (76%); yellow solid; mp 105–106 °C. 1H NMR (CDCl3, 600 MHz): = 8.15 (m, J = 8.8 Hz, 2 H), 7.51 (m, J = 8.8 Hz, 2 H), 2.10 (s, 3 H). 13C NMR (CDCl3, 150 MHz): = 146.6, 132.2, 131.1, 123.5, 92.2, 78.5, 4.5. MS (EI): m/z (%) = 39 (7), 51 (7), 63 (20), 77 (20), 89 (39), 103 (17), 115 (55), 131 (22), 161 (100) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C9H8NO2: 162.0555; found: 162.0552. N-[3-(Propyn-1-yl)phenyl]benzenesulfonamide (18) Yield: 0.212 g (97%); colorless solid; mp 124–125 °C; Rf 0.30 (hex- ane/EtOAc, 75:25). 1H NMR (CDCl3, 600 MHz): = 7.79 (m, 2 H), 7.53 (dd, J = 7.5, 7.5 Hz, 1 H), 7.44 (dd, J = 7.5, 7.5 Hz, 2 H), 7.11 (m, 3 H), 7.01 (m, 1 H), 2.01 (s, 3 H). 13C NMR (CDCl3, 150 MHz): = 138.8, 136.4, 133.1, 129.2, 129.1, 128.5, 127.2, 125.3, 124.3, 120.6, 86.9, 78.9, 4.3. IR (KBr): 3253, 3067, 2955, 2929, 2856, 1603, 1581, 1470, 1330, 1257, 1159, 1091, 836, 785 cm–1. MS (EI): m/z (%) = 39 (5), 51 (20), 77 (90), 103 (65), 115 (4), 130 (100), 141 (10), 165 (10), 180 (10), 192 (7), 206 (47), 207 (25), 271 (90) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C15H14NSO2: 272.0745; found: 272.0748. 1-(4-(Propyn-1-yl)phenyl)ethanone (20) [CAS Reg. No. 112921-88-7] Yield: 0.104 g (82%); colorless solid; mp 57–59 °C. 1H NMR (CDCl3, 400 MHz): = 7.86 (m, 2 H), 7.44 (m, 2 H), 2.57 (s, 3 H), 2.07 (s, 3 H). 13C NMR (CDCl3, 100 MHz): = 197.5, 135.8, 131.7, 129.2, 128.3, 89.9, 79.4, 26.7, 4.6. IR (KBr): 2251, 1678, 1599, 1355, 1258, 1181, 956, 842, 595 cm–1. MS (EI): m/z (%) = 39 (8), 43 (10), 63 (18), 89 (23), 115 (90), 143 (100), 158 (68) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C11H11O: 159.0810; found: 159.0809. Methyl 2-(Propyn-1-yl)benzoate (22) [CAS Reg. No. 172508-28-0] Yield: 0.119 g (85%); colorless liquid; Rf 0.53 (hexane/ether, 75:25). 1H NMR (CDCl3, 400 MHz): = 7.88 (dd, J= 7.7, 0.9 Hz, 1 H), 7.51 (br d, J = 7.7 Hz, 1 H), 7.42 (ddd, J = 7.7, 7.5, 1.2 Hz, 1 H), 7.30 (ddd, J = 7.7, 7.5, 1.2 Hz, 1 H), 3.91 (s, 3 H), 2.12 (s, 3 H). 13C NMR (CDCl3, 100 MHz): = 166.9, 134.3, 131.8, 131.6, 130.1, 127.2, 124.6, 91.5, 78.3, 52.1, 4.8. IR (film): 3056, 2950, 2915, 2244, 1731, 1434, 1293, 1252, 1132, 1084, 758, 743, 694, 453. MS (EI): m/z (%) = 39 (15), 63 (25), 89 (35), 103 (37), 115 (85), 143 (90), 159 (100), 174 (67) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C11H11O2: 175.0759; found: 175.0758. 2-(Propyn-1-yl)benzaldehyde (24) [CAS Reg. No. 176910-65-9] Yield: 0.078 g (68%); colorless solid; mp 37–38 °C; Rf 0.51 (hexane/ ether, 7:3). 1H NMR (CDCl3, 400 MHz): = 10.51 (s, 1 H), 7.87 (br d, J = 7.7 Hz, 1 H), 7.50 (m, 2 H), 7.36 (m, 1 H), 2.12 (s, 3 H). 13C NMR (CDCl3, 100 MHz): = 192.2, 136.1, 133.7, 133.3, 127.9, 127.8, 126.9, 93.5, 75.5, 4.5. IR (KBr): 3063, 2916, 2849, 2746, 2240, 2210, 1694, 1594, 1476, 1435, 1249, 1193, 1011 cm–1. MS (EI): m/z (%) = 39 (4), 50 (4), 63 (36), 74 (8), 89 (18), 101 (8), 115 (100), 116 (52), 129 (3), 144 (72) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C10H9O: 145.0653; found: 145.0654. 2-(Propyn-1-yl)thiophene (26) [CAS Reg. No. 23229-66-5] Yield: 0.083 g (86%); colorless solid. In this case a 6/25 ratio of 1.5 had to be used in order to consume all the starting material 25. 2393 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis 1H NMR (CDCl3, 400 MHz): = 7.17 (dd, J = 5.2, 1.1 Hz, 1 H), 7.11 (br d, J = 3.6 Hz, 1 H), 6.93 (dd, J = 5.2, 3.6 Hz, 1 H), 2.08 (s, 3 H). 13C NMR (CDCl3, 100 MHz): = 130.7, 126.5, 125.6, 124.0, 89.8, 72.7, 4.4. MS (EI): m/z (%) = 39 (8), 51 (13), 63 (15), 77 (21), 96 (28), 121 (97), 122 (100) [M]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C7H7S: 123.0268; found: 123.0267. 2-Phenyl-5-(propyn-1-yl)thiophene (3) [CAS Reg. No. 1204-82-6] Yield: 0.126 g (97%); yellow solid. 1H NMR (CDCl3, 400 MHz): = 7.60 (br d, J = 7.9 Hz, 2 H), 7.41 (br dd, J = 7.9, 7.3 Hz, 2 H), 7.32 (dddd, J = 7.3, 7.3, 1.2, 1.2 Hz, 1 H), 7.18 (d, J = 3.8 Hz, 1 H), 7.12 (d, J = 3.8 Hz, 1 H), 2.13 (s, 3 H). 13C NMR (CDCl3, 100 MHz): = 144.2, 133.7, 131.8, 128.7, 127.5, 123.3, 122.6, 90.6, 73.0, 4.5. MS (EI): m/z (%) = 39 (4), 51 (5), 63 (5), 77 (8), 99 (5), 121 (8), 139 (5), 152 (10), 165 (30), 198 (100) [M]+, 200 (27) [M+2]+. HRMS (ESI, V+): m/z [M + H]+ calcd for C13H11S: 199.0581; found: 199.0582. Funding Information We thank the University of Costa Rica and Vicerrectoría de Investi- gación for financial support. () Acknowledgment We thank Lorena Hernández of CIPRONA-UCR for high-resolution mass determination, and Prof. Cam Oehlschlager and Dr. Albán Pereira for reading the manuscript and for useful suggestions. Supporting Information Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690895. 1H and 13C NMR spectra of all compounds prepared in Table 2 are provided. Supporting InformationSupporting Information References (1) For a review on palladium-catalyzed alkynylation see: Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979. (2) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313. (3) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259. (4) Cassar, L. J. Organomet. Chem. 1975, 93, 253. (5) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (6) King, A. O.; Okukado, N.; Negishi, E. I. J. Chem. Soc., Chem. Commun. 1977, 683. (7) King, A. O.; Negishi, E. I. J. Org. Chem. 1978, 43,02 358. (8) Dang, H. P.; Linstrumelle, G. Tetrahedron Lett. 1978, 191. (9) (a) Soderquist, J. A.; Matos, K.; Rane, A.; Ramos, J. Tetrahedron Lett. 1995, 36,14 2401. (b) Soderquist, J. A.; Rane, A. M.; Matos, K.; Ramos, J. Tetrahedron Lett. 1995, 36,38 6847. (10) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21,26 2531. (11) Negishi, E. I.; Kotora, M.; Xu, C. J. Org. Chem. 1997, 62, 8957. (12) For a historical review on palladium-catalyzed cross-coupling reactions, see: Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062. (13) Negishi, E. I.; Akiyoshi, K.; Takahashi, T. J. Chem. Soc., Chem. Commun. 1987, 477. (14) For a review on the synthesis of heterocyclic compounds through substituted alkynes, see: Pal, M. Synlett 2009, 2896. (15) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem. Commun. 1993, 86. (16) Chen, L.; Li, Y.; Xu, M. H. Org. Biomol. Chem. 2010, 8, 3073. (17) (a) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc., Chem. Commun. 1992, 41. (b) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815. (c) Arcadi, A.; Blesi, F.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. Tet- rahedron Lett. 2011, 52, 5149. (18) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Luo, Y. G.; Basha, R. S.; Reddy, D. M.; Xue, Y. J.; Chen, T. H.; Lee, C. F. Org. Lett. 2018, 20, 6872. (c) Lessing, T.; Müller, T. J. J. Chem. Hetero- cycl. Compd. 2018, 54, 334. (19) Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.; Tatini, L. K.; Babu, J. M.; Pal, M. Tetrahedron 2007, 63, 1775. (20) Yan, B.; Fu, Y.; Zhu, H.; Chen, Z. J. Org. Chem. 2019, 84, 4246. (21) Zhao, Y.; Zhang, Z.; Liu, X.; Wang, Z.; Cao, Z.; Tian, L.; Yue, M.; You, J. J. Org. Chem. 2019, 84, 1379. (22) (a) Birkinshaw, J. H.; Chaplen, P. Biochem. J. 1955, 60, 255. (b) Atkinson, R. E.; Curtis, R. F.; Taylor, J. A. J. Chem. Soc. C 1967, 578. (c) Carpita, A.; Lezzi, A.; Rossi, R.; Marchetti, F.; Merlino, S. Tetrahedron 1985, 41,03 621. (d) Christensen, L. P.; Lam, J. Phy- tochemistry 1991, 30,01 11. (e) Zhang, L.; Chen, C. J.; Chen, J.; Zhao, Q. Q.; Li, Y.; Gao, K. Phytochemistry 2014, 106, 134. (23) (a) Yu, H.; Richey, R. N.; Mendiola, J.; Adeva, M.; Somoza, C.; May, S. A.; Carson, M. W.; Coghlan, M. J. Tetrahedron Lett. 2008, 49, 1915. (b) Richey, R. N.; Yu, H. Org. Process Res. Dev. 2009, 13, 315. (24) Sörensen, J. S.; Sörensen, N. A. Acta Chem. Scand. 1958, 12, 771. (25) Kimura, Y.; Hiraoka, K.; Kawano, T.; Fujioka, S.; Shimada, A. Z. Naturforsch., C: J. Biosci. 2008, 63, 843. (26) Guddal, E.; Sörensen, N. A. Acta Chem. Scand. 1959, 13, 1185. (27) Hooz, J.; Cabezas, J.; Musmanni, S.; Calzada, J. Org. Synth. 1990, 69, 120. (28) For the original report on this preparation, see: Hooz, J.; Calzada, J. G.; McMaster, D. Tetrahedron Lett. 1985, 26,03 271. (29) Cabezas, J. A.; Alvarez, L. X. Tetrahedron Lett. 1998, 39, 3935. (30) Cabezas, J. A.; Pereira, A. R.; Amey, A. Tetrahedron Lett. 2001, 42, 6819. (31) Vásquez, S.; Cabezas, J. A. Tetrahedron Lett. 2014, 55, 1894. (32) Pereira, A. R.; Cabezas, J. A. J. Org. Chem. 2005, 70,07 2594. (33) (a) Bandi, S.; Debata, N. B.; Ramkumar, V.; Chand, D. K. Inorg. Chem. Commun. 2014, 39, 75. (b) Hughes, R. P.; Overby, J. S.; Williamson, A.; Lam, K. C.; Concolino, T. E.; Rheingold, A. L. Organometallics 2000, 19,24 5190. (c) Gogoll, A.; Oernebro, J.; Grennberg, H.; Baeckvall, J. E. J. Am. Chem. Soc. 1994, 116, 3631. (d) Meek, D. W. Inorg. Chem. 1965, 4,02 250. (34) (a) Bhanu, S.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1975, 817. (b) Bhanu, S.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1979, 1218. (35) Umaña, C. A.; Cabezas, J. A. J. Org. Chem. 2017, 82, 9505. (36) A solvent ratio (v/v) of ether/hexane of 1:1 was used, as previ- ously reported.27 (37) Cabezas, J. A.; Poveda, R. R.; Brenes, J. A. Synthesis 2018, 50, 3307. (38) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210. (39) House, H. O.; Umen, M. J. Org. Chem. 1973, 38, 3893. 2394 © 2020. Thieme. All rights reserved. Synthesis 2020, 52, 2387–2394 J. A. Cabezas, N. Ferllini PaperSyn thesis (40) Corey, E. J.; Floyd, D.; Lipshutz, B. H. J. Org. Chem. 1978, 43, 3418. (41) Mandeville, W. H.; Whitesides, G. M. J. Org. Chem. 1974, 39, 400. (42) House, H. O.; Chu, C. Y.; Wilkins, J. M.; Umen, M. J. J. Org. Chem. 1975, 40, 1460. (43) Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697. (44) (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984, 40, 5005. (b) Lipshutz, B. H. Synthesis 1987, 325. (45) Campos-Fernández, C. S.; Pineda, L. W.; Cabezas-Pizarro, J. IUCrData 2019, 4, x191585. (46) Pineda, L. W.; Cabezas, J. A. IUCrData 2019, 4, x191176. (47) Cabezas, J. A.; Arias, M. L. Int. J. Curr. Res. 2019, 11, 5224. (48) The presence of the propynyl group in sulfonamide 18 consider- ably increased its antibacterial activity when compared to iodo- sulfonamide 17. Propynylbenzenesulfonamide 18 was found to be 20.5 times more active than iodofulfonamide 17 against Staphylococcus aureus, and 5 times more active against Escherichia coli.47 (49) Schulte, K. E.; Bohn, G. Arch. Pharm. 1964, 297, 179. (50) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.