Sonogashira breathes easy: a practical room-temperature homogeneous coupling in continuous flow under air

Abstract

The Sonogashira cross-coupling reaction is a cornerstone of modern organic synthesis, yet its implementation under mild, scalable, and operationally simple conditions remains a challenge. To address this, we developed a homogeneous, room-temperature Sonogashira coupling protocol in continuous flow that operates efficiently at room temperature under air. Using an E-FLOW-10 flow platform, we optimized a catalytic system based on Pd(OAc)₂, CuI, and PPh₃ in a mixed Et₃N/MeOH solvent system. Crucially, separating the palladium and copper catalysts into two distinct feed streams prevented rapid Pd-black formation and significantly enhanced reaction efficiency. This work demonstrates a practical Sonogashira coupling in flow, overcoming previous limitations associated with heterogeneous systems and elevated temperatures.

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Introduction

The discovery of the cross-coupling reaction between terminal alkynes and aryl or vinyl halides – commonly known as the Sonogashira reaction – has profoundly influenced modern organic synthesis. This transformation provides direct access to structurally diverse alkynes, which serve as essential intermediates in pharmaceuticals, fine chemicals, and advanced materials. The reaction's versatility has facilitated major advances across fields such as materials science, organic electronics, and drug discovery, where alkynylated motifs are key building blocks in conjugated systems, bioactive scaffolds, coordination frameworks, and heterocyclic moieties.¹ The industrial impact of Sonogashira coupling is equally noteworthy, underpinning the synthesis of several high-value compounds, including tazarotene (a topical treatment for psoriasis), calicheamicins (enediyne antitumor antibiotics), and erlotinib analogues for cancer therapy. Given its far-reaching importance, continued innovation in Sonogashira chemistry remains an active and essential area of research.^2–5

Despite extensive developments since its inception, conventional Sonogashira protocols still exhibit limitations. Most traditional methods rely on batch reactors, heterogeneous catalysts, or elevated temperatures, often under inert atmospheres. These conditions can hinder scalability, increase energy demand, and pose challenges in controlling reaction selectivity and reproducibility. Moreover, the formation of palladium black and catalyst deactivation – especially in the presence of air or moisture – remain as persistent issues. Addressing these drawbacks requires rethinking both catalyst design and reactor configuration to enable efficient, robust transformations under milder, greener conditions.

Continuous-flow chemistry emerged as a transformative platform for achieving such goals.^6–11 Flow reactors offer precise control over residence time, temperature, and mixing, enabling enhanced mass and heat transfer relative to batch processes. They also provide safer handling of reactive intermediates and hazardous reagents, improved reproducibility and straightforward scalability. Consequently, flow methodologies have been widely adopted in pharmaceutical and fine-chemical manufacturing as a bridge between discovery-scale synthesis and industrial production.^12–16 However, reports of Sonogashira coupling in flow have been largely confined to heterogeneous catalytic systems – typically employing Pd/Cu-packed bed reactors – and often require reaction temperatures above 60 °C.^17–21 These systems can suffer from leaching, channeling, and reduced catalytic turnover due to mass-transfer limitations.

This contribution was aimed to develop a homogeneous, room-temperature Sonogashira coupling protocol in continuous flow that operates efficiently under ambient conditions and in air. Using an E-FLOW-10 flow platform, a catalytic system was optimized based on Pd(OAc)₂, CuI, and PPh₃ in a mixed Et₃N/MeOH solvent system. A crucial design element of our approach was the palladium and copper catalyst segregation into two distinct feed streams, which effectively prevented rapid Pd-black formation and significantly enhanced catalytic performance. This strategy enabled sustained homogeneous catalysis with high reproducibility and minimal fouling.

The resulting process represents a practical and operationally simple Sonogashira coupling in continuous flow, overcoming key limitations of prior heterogeneous and high-temperature systems. It demonstrates that controlled flow conditions can stabilize homogeneous catalysts, reduce by-product formation and ensure consistent reaction performance at room temperature under air. This study thus provides a valuable contribution to sustainable cross-coupling methodologies and highlights the potential of integrated flow systems for developing scalable, energy-efficient, and environmentally benign catalytic transformations.

Results and discussion

Optimization on the E-FLOW-10 flow chemistry platform started using trimethylsilylacetylene 1a and 4-iodotoluene 2a as model substrates (Scheme 1). The main issue with the flow-setup was maintaining Pd- and Cu-species in a solution. As far as we aimed at the most straightforward experimental conditions possible, the cross-coupling proceeding with minimum precautions and the simplest catalysts in non-exotic solvent systems, preferably on air, was pursued. After testing various Pd sources, as well as solvents, it turned out that Pd(OAc)₂ and CuI in Et₃N : MeOH solution with the addition of PPh₃ was the most preferable system to maintain homogeneity.

Scheme 1 The Sonogashira reaction between trimethylsilylacetylene 1a and 4-Iodotoluene 2a.

Indeed, the dissolution of Pd(OAc)₂ and CuI was readily achieved in an Et₃N : MeOH = 1 : 1 (V/V) system, overcoming the limitations for the flow-setup. We first aimed at determining the suitable flow rate for the reaction to proceed. In a typical experiment, two solutions (1st tube and 2nd tube) were mixed in the reactor with the flow rate defined by the means of pumps (Table 1). The first solution (1st tube) contained ArI 2a (0.46 mmol, 1 equiv.), Pd(OAc)₂ (5 mol%) and CuI (10 mol%) in Et₃N : MeOH = 1 : 1 (V/V) system. The second solution (2nd tube) contained PPh₃ (10 mol%) and TMS-acetylene 1a (1.2 equiv.) in Et₃N. The flow rate varied from 1 mL min⁻¹ to 0.1 mL min⁻¹ and the reaction progress was monitored by GCMS – the ratio of the starting iodide 2a and the product 3a was determined. The optimum flow rate to perform the transformation was found to be 0.5 mL min⁻¹ for both tubes (Table 1, entry 2), providing the product 3a in a 60% isolated yield after flash column chromatography.

Table 1 Flow rate optimization for the Sonogashira reaction^a

Entry	Flow rate (both tubes), mL min^−1	2a : 3a ratio^b	Isolated yield
a Reaction conditions: on air; 1st tube – ArI (0.46 mmol, 1 equiv.), Pd(OAc)2 (5 mol%), CuI (10 mol%), Et3N : MeOH (1 : 1, 5 mL); 2nd tube – PPh3 (10 mol%), TMS-acetylene (1.2 equiv.), Et3N (5 mL). b Determined by GCMS. c Not determined.
1	1	1 : 2.8	—^c
2	0.5	1 : 2.8	60
3	0.25	1.1 : 1	—^c
4	0.1	1.9 : 1	21

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A variation of the catalytic system components was subsequently performed (Table 2). Without PPh₃ or CuI, a very low conversion of 2a was obtained (Table 2, entries 1 and 2), with only the 5 : 10 : 10 mol% ratio of Pd(II)/ligand/Cu(I) being optimum (Table 2, entry 3), while the use of different loadings of the catalyst components, as well as different ligands, did not improve the reaction yield (Table 2, entries 4–6). Other Pd-sources were tested for suitability in the Sonogashira reaction (Table 3). Attempting to perform the cross-coupling with tetrakis(triphenylphosphine)palladium(0) required dimethylformamide for the solubilization of the Pd-catalyst (Table 3, entry 1). The extreme instability of Pd(PPh₃)₄ under ambient conditions²² rendered its application ineffective. Switching to another widely employed Pd-source – dichlorobis(triphenylphosphine)palladium(II)²³ – was more productive, however it requires a LiCl additive and a more sophisticated solvent system to achieve complete dissolution (Table 3, entry 2). The previously established “Pd”-source – Pd(OAc)₂ – was found to be optimum in terms of solubility and overall performance (Table 3, entry 3).

Table 2 1a + 2a, Pd(II) + Cu(I) catalysts in the same tube. Further catalytic system optimization^a

Entry	Pd(OAc)2 (mol%)	PPh3 (mol%)	CuI (mol%)	2a : 3a ratio^b	Isolated yield
a Reaction conditions: on air; 1st tube – ArI (0.46 mmol, 1 equiv.), Pd(OAc)2, CuI, Et3N : MeOH (1 : 1, 5 mL); 2nd tube – PPh3, TMS-acetylene (1.2 equiv.), Et3N (5 mL); flow rate for both tubes – 0.5 mL min^−1. b Determined by GCMS. c Not determined. d CyJohnPhos (CAS 247940–06-3) was used instead of Ph3P.
1	5	0	10	27.2 : 1	—^c
2	5	10	0	31.3 : 1	—^c
3	5	10	10	1 : 2.8	60
4	5	15	10	1.7 : 1	—^c
5	5	10^d	10	2.6 : 1	—^c
6	1	2	2	4.6 : 1	9

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Table 3 1a + 2a, “Pd” + Cu(I) catalysts in a same tube. Varying Pd-source^a

Entry	“Pd” (5 mol%)	PPh3 (mol%)	Solvent	2a : 3a ratio^b	Isolated yield
a Reaction conditions: on air; 1st tube – ArI (0.46 mmol, 1 equiv.), CuI (10 mol%), Et3N : MeOH (1 : 1, 5 mL); 2nd tube – Pd(PPh3)4, TMS-acetylene (1.2 equiv.), DMF, 5 mL; flow rate for both tubes – 0.5 mL min^−1. b Determined by GCMS. c Not determined. d Reaction conditions: on air; 1st tube – [Pd(PPh3)2Cl2], LiCl (10 mol%), CuI (10 mol%), MeCN : THF (1 : 1, 5 mL); 2nd tube – ArI (100 mg, 1 equiv.), TMS-acetylene (1.2 equiv.), Et3N (5 mL); flow rate for both tubes – 0.5 mL min^−1. e Standard conditions (Table 1, entry 2).
1^a	Pd(PPh3)4	—	Et3N, MeOH, DMF	Only 2a	—^c
2^d	[Pd(PPh3)2]Cl2	—	Et3N, THF, MeCN	1 : 2.2	—^c
3^e	Pd(OAc)2	10	Et3N, MeOH	1 : 2.8	60

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During regular experiments, mixing Pd(II) and Cu(I) in the same tube still led to the formation of Pd-black in minutes. This fact might disimprove the reaction performance. To prevent the formation of Pd-black, Pd(OAc)₂ was separated from CuI. Indeed, taking Pd(OAc)₂ (5 mol%) and PPh₃ (10 mol%) in the first solution, while having ArI (1 equiv.), TMS-acetylene 1a and CuI (10 mol%) in the second solution, as well as slightly increasing the excess 1a, dramatically ameliorated the conversion (Scheme 2, Table 4). Eventually, the desired product 3a was isolated with 79% yield (Table 4, entry 3).

Scheme 2 The Sonogashira reaction with Pd(II) and Cu(I) catalysts in separate tubes.

Table 4 1a + 2a, Pd(II) and Cu(I) catalysts in separate tubes^a

Entry	Acetylene 1a, equiv.	2a : 3a ratio^b	Isolated yield
a Reaction conditions: on air; 1st tube – Pd(OAc)2 (5 mol%), PPh3 (10 mol%), Et3N : MeOH (1 : 1, 5 mL); 2nd tube – ArI (0.46 mmol, 1 equiv.), TMS-acetylene, CuI (10 mol%), Et3N : MeOH (1 : 1, 5 mL); flow rate for both tubes – 0.5 mL min^−1. b Determined by GCMS. c Not determined. d Ph3P in a 2nd tube. e 1st tube – Pd(OAc)2 (1 mol%), Ph3P (2 mol%); 2nd tube – CuI (2 mol%).
1	1.2	1 : 5.0	—^c
2^d	1.2	1 : 6.0	—^c
3	1.5	1 : 18.2	79
4	2	1 : 15.1	—^c
5^e	1.5	1.8 : 1	—^c

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With the optimized conditions in hand, the scope of the developed methodology was subsequently investigated (Scheme 3). Substrate 2c with a strongly electron-donating OMe group produced the desired coupling derivative 3c with a very good 85% yield. The electron-withdrawing CN group-substituted aryl iodide 2d furnished the corresponding product with almost a quantitative 95% yield. The meta-substituted substrate 2e was converted to the respective product 3e with an analogously excellent 95% yield. As a result of carrying out the Sonogashira reaction with 4-substituted ortho-iodoformamides 2g and 2h, the corresponding alkynes 3g and 3h were obtained in moderate yields. When heteroaryl iodide 2i was introduced into the reaction, product 3i was obtained in moderate yield. Overall, these experiments demonstrate the high versatility of the developed flow methodology for a wide range of aryl iodides.

Scheme 3 Sonogashira flow-reaction scope.

The obtained alkyne 3i is of particular value, serving as a precursor for the synthesis of natural biologically active compounds. In 2024, total synthesis of the β-carboline natural product taraxacine A and its analogues from alkynes 3i and alcohols using silver salts and a base was reported (Scheme 4).²⁴

Scheme 4 Synthesis of taraxacine A from alkyne 3i.

The protocol was also successfully demonstrated to work under scaled-up conditions (4 mmol loadings), producing alkyne 3b with an even improved 77% yield (Scheme 5).

Scheme 5 Scaled-up experiment¹. ¹Reaction conditions: on air; 1st tube – Pd(OAc)₂ (0.2 mmol), PPh₃ (0.4 mmol), Et₃N : MeOH (1 : 1, 50 mL); 2nd tube – ArI (4 mmol), TMS-acetylene (6 mmol), CuI (4 mmol), Et₃N : MeOH (1 : 1, 50 mL); flow rate for both tubes – 0.5 mL min⁻¹. The product was isolated by column chromatography.

Experimental

General information

Solvents were distilled and dried according to standard procedures. The starting materials were purchased from Sigma Aldrich and Alfa Aesar. Column chromatography was performed using silica gel (230–400 mesh); mixtures of pentane with diethyl ether were used as an eluent.

The Sonogashira cross-coupling reaction was performed on an E-FLOW-10 flow chemistry teaching platform (Ou Shisheng Technology Co., Ltd., Beijing, China) equipped with an automatic back pressure valve.

¹H and ¹³C NMR spectra were recorded on Bruker Avance NEO 700 spectrometer at room temperature with an operating frequency of 700 and 176 MHz, respectively. The chemical shifts δ were measured in ppm with respect to solvent (CDCl₃: 1H, δ = 7.26 ppm; 13C δ = 77.16 ppm, DMSO-d₆: 1H, δ = 2.50 ppm; 13C δ = 39.51 ppm). Coupling constants are reported in hertz (J Hz⁻¹). The peak patterns are indicated as follows: s, singlet; d, doublet; dd, double doublet; sept, septet; br., broad.

General procedure for preparation of products 2g and 2h

Sodium carbonate (159 mg, 1.5 mmol) was added to an aqueous solution of the corresponding p-toluidine (1 mmol, 0.15 M). The mixture was stirred for 0.5 hour. Then iodine (508 mg, 2 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC. Upon completion the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium thiosulfate, then dried over anhydrous sodium sulfate. The organic solvent was evaporated to dryness and the residue was used in next step without further purification.

On the next step, formic acid (121 ml, 3.2 mmol) and acetic anhydride (189 ml, 2 mmol) were mixed in a round-bottom flask and stirred under heating (at 60 °C) for 30 minutes. Then the reaction mixture was cooled to 10 °C and crude 2-iodo-4-methylaniline (1 mmol) from the previous step dissolved in 20 ml of THF was added (0.05 M). The reaction mixture was stirred for 3 hours at room temperature. The organic solvent was removed under reduced pressure. The residue was triturated with water. The resulting precipitate was filtered out on a Schott filter and rinsed with water. The product was recrystallized from a mixture of dichloromethane-hexane.

N-(2-Iodo-4-methylphenyl)formamide (2g). This compound is known.²⁵ Brown solid, yield 140 mg (69%). ¹H NMR (DMSO-d₆, 700 MHz, a mixture of rotamers in a ratio of ∼0.75 : 0.25): δ 9.59 (d, ³J = 11.2 Hz, 0.25H), 9.46 (s, 0.75H), 8.30 (d, ³J = 1.7 Hz, 0.75H), 8.26 (d, ³J = 11.0 Hz, 0.25H), 7.74 (s, 0.25H), 7.71 (s, 0.75H), 7.61 (d, ³J = 7.6 Hz, 0.75H), 7.21–7.17 (m, 1.25H), 2.26 (s, 0.75H), 2.24 (m, 2.25H).

N-(4-Chloro-2-iodophenyl)formamide (2h). This compound is known.²⁵ Violet solid, yield 148 mg (66%). ¹H NMR (DMSO-d₆, 700 MHz, a mixture of rotamers in a ratio of ∼0.8 : 0.2): δ 9.70 (d, ³J = 10.3 Hz, 0.2H), 9.59 (s, 0.8H), 8.35 (d, ³J = 17.6 Hz, 1H), 7.97 (s, 0.2H), 7.94 (d, ³J = 2.6 Hz, 0.8H), 7.81 (d, ³J = 8.6 Hz, 0.8H), 7.48–7.45 (m, 1H), 7.36 (d, ³J = 8.6 Hz, 0.2H).

Procedure for the preparation of 3-iodo-1H-indole-2-carbonitrile (2i)

Potassium hydroxide (4.25 g, 75.8 mmol) was dissolved in 15 mL of dry DMF and cooled to 0 °C. Indole-2-carbonitrile 1 (3.0 g, 21.0 mmol) was added and the mixture was stirred for 30 minutes. Then, iodine solution (5.34 g, 21.0 mmol in 10 mL DMF) was added dropwise over 10 minutes. The reaction was stirred at room temperature for 1.5 hours. After completion, the reaction mixture was poured into 300 mL of water and the precipitate was filtered-off, washed with water and vacuum-dried to provide 3-iodo-1H-indole-2-carbonitrile (2i) as a light-beige solid (5.54 g, 95% yield); ¹H NMR (700 MHz, DMSO-d6): δ 12.83 (s, 1H), 7.49 (d, ³J = 8.3 Hz, 1H), 7.44–7.38 (m, 2H), 7.26 (m, 1H).²⁴

General procedure for the flow synthesis of arylacetylenes 3a–3f

In the 1st test tube, palladium(II) acetate (0.05 equiv.) and triphenylphosphine (0.1 equiv.) in a 1 : 1, v/v mixture of methanol (2.5 mL) and triethylamine (2.5 mL) were dissolved upon brief shaking with a rubber cap. In the 2nd test tube, iodoarene 2 (0.41–0.46 mmol, 1 equiv.), copper(I) iodide (0.1 equiv.), and trimethylsilylacetylene 1a (1.5 equiv.) in a 1 : 1, v/v mixture of methanol (2.5 mL) and triethylamine (2.5 mL) were dissolved upon brief shaking with a rubber cap. Both the solutions were introduced in a reactor through separate pumps with a 0.5 mL min⁻¹ flow rate pumping down with pure triethylamine. The total reaction time was ∼80 min at these flows rates. The resulting reaction mixture was analyzed by GCMS in order to control the conversion of the starting iodoarene 2. The resulting reaction mixture (∼40 mL) was diluted with water (120 mL), diethyl ether (30 mL) was added and the biphasic mixture was washed with a 1 N solution of hydrochloric acid (3 × 20 mL). The organic phase was diluted with water (40 mL), the ethereal layer was separated and the aqueous phase was extracted with additional diethyl ether (2 × 30 mL). The combined organic phase was dried with anhydrous Na₂SO₄ and the solvent was removed on a rotary evaporator (r.t., 200 mbar). Products 3 were purified via column chromatography (pentane → pentane – Et₂O = 100 : 1).

Trimethyl(p-tolylethynyl)silane (3a). This compound is known.²⁸ Orange oil, yield 68 mg (79%), ¹H NMR (CDCl₃, 700 MHz): δ 7.37 (d, ³J = 8.0 Hz, 2H), 7.11 (d, ³J = 8.0 Hz, 2H), 2.35 (s, 3H), 0.27 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 138.7, 132.0 (2C), 129.1 (2C), 120.2, 105.5, 93.3, 21.6, 0.2 (3C).

((4-Isopropylphenyl)ethynyl)trimethylsilane (3b). This compound is known.²⁹ Yellow oil, yield 71 mg (80%), ¹H NMR (CDCl₃, 700 MHz): δ 7.39 (d, ³J = 8.1 Hz, 2H), 7.15 (d, ³J = 8.1 Hz, 2H), 2.89 (sept, ³J = 6.9, 1H), 1.23 (d, ³J = 6.9 Hz, 6H), 0.24 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 149.7, 132.1 (2C), 126.5 (2C), 120.6, 105.5, 93.3, 34.2, 23.9 (2C), 0.2 (3C).

((4-Methoxyphenyl)ethynyl)trimethylsilane (3c). This compound is known.³⁰ Yellow oil, yield 76 mg (85%), ¹H NMR (CDCl₃, 700 MHz): δ 7.40 (d, ³J = 8.6 Hz, 2H), 6.82 (d, ³J = 8.6 Hz, 2H), 3.80 (s, 3H), 0.24 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 159.9, 133.6 (2C), 115.4, 113.9 (2C), 105.3, 92.6, 55.4, 0.2 (3C).

4-((Trimethylsilyl)ethynyl)benzonitrile (3d). This compound is known.³⁰ Beige solid, yield 83 mg (95%), ¹H NMR (CDCl₃, 700 MHz): δ 7.58 (d, ³J = 8.0 Hz, 2H), 7.53 (d, ³J = 8.0 Hz, 2H), 0.26 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 132.6 (2C), 132.1 (2C), 128.1, 118.6, 111.9, 103.1, 99.7, −0.1 (3C).

Trimethyl(m-tolylethynyl)silane (3e). This compound is known.²⁹ Yellow oil, yield 83 mg (95%), ¹H NMR (CDCl₃, 700 MHz): δ 7.30 (br. s, 1H), 7.27 (d, ³J = 7.6 Hz, 1H), 7.18 (dd, ³J = 7.9 Hz, ³J = 7.6 Hz, 1H), 7.12 (d, ³J = 7.9 Hz, 1H), 2.32 (s, 3H), 0.25 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 138.0, 132.7, 129.5, 129.2, 128.2, 123.0, 105.5, 93.8, 21.3, 0.1 (3C).

Trimethyl(naphthalen-2-ylethynyl)silane (3f). This compound is known.²⁶ White solid, yield 73 mg (82%), ¹H NMR (CDCl₃, 700 MHz): δ 8.03 (s, 1H), 7.83–7.80 (m, 2H), 7.79 (d, ³J = 7.8 Hz, 1H), 7.54 (dd, ³J = 7.5 Hz, ³J = 7.5 Hz, 1H), 7.52–7.49 (m, 2H), 0.31 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 176 MHz): δ 133.04, 133.01, 132.2, 128.7, 128.0, 127.93, 127.88, 126.9, 126.7, 120.6, 105.6, 94.7, 0.2 (3C).

General procedure for the flow synthesis of arylacetylenes 3g–3i

In the 1st test tube, palladium(II) acetate (0.05 equiv.) and triphenylphosphine (0.1 equiv.) in a 1 : 1, v/v mixture of methanol (2.5 mL) and triethylamine (2.5 mL) were dissolved upon brief shaking with a rubber cap. In the 2nd test tube iodoarene 2 (0.36–0.38 mmol, 1 equiv.), copper(I) iodide (0.1 equiv.), trimethylsilylacetylene 1a (1.5 equiv.) in a 1 : 1, v/v mixture of methanol (2.5 mL) and triethylamine (2.5 mL) were dissolved upon brief shaking with a rubber cap. Both the solutions were introduced in a reactor through separate pumps with a 0.5 mL min⁻¹ flow rate pumping down with pure triethylamine. The total reaction time was ∼80 min at these flows rates. The resulting reaction mixture was analyzed by GCMS in order to control the conversion of the starting iodoarene 2. Upon completion the reaction mass was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the organic solvent was evaporated in vacuo. The products 3g–3i were isolated by column chromatography (eluent : hexane : ethyl acetate = 5 : 1).

N-(4-Methyl-2-((trimethylsilyl)ethynyl)phenyl)formamide (3g). This compound is known.²⁷ Brown solid, yield 55 mg (62%). ¹H NMR (DMSO-d₆, 700 MHz, a mixture of rotamers in a ratio of ∼0.7 : 0.3): ¹H NMR (DMSO-d₆, 700 MHz, a mixture of rotamers in a ratio of ∼0.7 : 0.3): δ 9.65 (d, ³J = 9.6 Hz, 0.3H), 9.35 (s, 0.7H), 8.58 (d, ³J = 8.6 Hz, 0.3H), 8.35 (s, 0.7H), 7.95 (d, ³J = 8.0 Hz, 0.7H), 7.30 (s, 0.3H), 7.27 (s, 0.7H), 7.19 (t, ³J = 7.2 Hz, 1H), 7.14 (d, ³J = 7.1 Hz, 0.3H), 2.25 (s, 0.9H), 2.24 (s, 2.1H), 0.26 (s, 6.3H), 0.22 (s, 2.7H). ¹³C{¹H} NMR (DMSO-d₆, 176 MHz): δ 163.4, 160.4, 136.4, 136.1, 136.7, 134.4, 133.4, 133.2, 132.7, 130.9, 130.3, 122.0, 121.3, 114.9, 113.1, 102.0, 100.6, 100.5, 99.0, 20.02, 19.97, −0.10, −0.24.

N-(4-Chloro-2-((trimethylsilyl)ethynyl)phenyl)formamide (3h). This compound is known.²⁷ Brown solid, yield 60 mg (67%). ¹H NMR (DMSO-d₆, 700 MHz, a mixture of rotamers in a ratio of ∼0.75 : 0.25): δ 9.82 (d, ³J = 11.0 Hz, 0.25H), 9.54 (s, 0.75H), 8.65 (d, ³J = 10.7 Hz, 0.25H), 8.39 (s, 0.75H), 8.14 (d, ³J = 8.6 Hz, 1H), 7.51 (d, ³J = 15.4 Hz, 0.75H), 7.45 (q, ³J = 2.4 Hz, 1H), 7.30 (d, ³J = 8.4 Hz, 0.25H), 0.27 (s, 6.8H), 0.23 (s, 2.2H). ¹³C{¹H} NMR (DMSO-d₆, 176 MHz): δ 163.4, 160.7, 138.1, 137.5, 132.2, 131.7, 130.1, 129.7, 128.7, 127.6, 123.4, 122.7, 116.4, 114.8, 102.7, 101.1, 100.2, 98.7, −0.3, −0.4.

3-((Trimethylsilyl)ethynyl)-1H-indole-2-carbonitrile (3i). This compound is known.²⁴ White solid, yield 42 mg (47%). ¹H NMR (700 MHz, DMSO-d₆) δ ppm 12.80 (s, 1H), 7.64 (d, ³J =8.1 Hz, 1H), 7.51 (d, ³J =8.3 Hz, 1H), 7.42 (t, ³J =7.6 Hz, 1H), 7.27 (t, ³J =7.5 Hz, 1H), 0.29 (s, 9 H). ¹³C {¹H} NMR (176 MHz, DMSO-d6) δ (ppm) 136.2, 126.6 (2C) 122.2, 120.2, 113.1, 113.0, 109.5, 107.3, 101.7, 95.4, 0.1 (3C).

Conclusions

A homogeneous Sonogashira coupling protocol in continuous flow that operates efficiently at room temperature under air was successfully developed, marking a significant step forward in the practical application of this important cross-coupling reaction. By employing a simple catalytic system based on Pd(OAc)₂, CuI, and PPh₃ in an Et₃N/MeOH solvent mixture, we achieved high yields without the need for inert atmospheres or elevated temperatures. A key innovation of this work was the separation of palladium and copper catalysts into two independent feed streams, effectively suppressing Pd-black formation, enhancing catalyst stability, and improving reaction reproducibility. The optimized setup, implemented on an E-FLOW-10 flow platform, delivered robust and scalable performance, demonstrating compatibility with both electron-rich and electron-deficient aryl iodides. The system showed excellent substrate tolerance and provided consistent product yields of up to 95%, confirming its reliability across diverse substrates.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The original contributions presented in this study are included in the supporting information (SI). Further inquiries can be directed to the corresponding authors.

Supplementary information is available. See DOI: https://doi.org/10.1039/d5re00494b.

Acknowledgements

This research was funded by the RUDN University Scientific Projects Grant System, grant number 021411-0-000.

Notes and references

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