Protocol for Sonogashira coupling of alkynes and aryl halides via nickel catalysis

Summary

Alkynes are widely present in natural products and pharmaceutical compounds. Here, we present a protocol for nickel-catalyzed cross-coupling of terminal alkynes with aryl iodides or bromides for constructing a C(sp²)-C(sp) bond. We describe steps for reagent preparation, reaction setup, purification process, and product characterization. We also detail procedures for obtaining a single crystal of 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b). The application of this protocol is limited to aryl bromide and iodide.

For complete details on the use and execution of this protocol, please refer to Chen et al.¹

Graphical abstract

Highlights

• •Steps for Sonogashira reactions to form C(sp²)-C(sp) bonds without using a co-catalyst
• •Steps for Ni-catalyzed C(sp²)-C(sp) coupling of terminal alkynes and aryl halides
• •Steps for purification and recrystallization of product

Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Alkynes are widely present in natural products and pharmaceutical compounds. Here, we present a protocol for nickel-catalyzed cross-coupling of terminal alkynes with aryl iodides or bromides for constructing a C(sp²)-C(sp) bond. We describe steps for reagent preparation, reaction setup, purification process, and product characterization. We also detail procedures for obtaining a single crystal of 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b). The application of this protocol is limited to aryl bromide and iodide.

Before you begin

The alkyne is a functional moiety that is important for many natural products and pharmaceutical compounds.^{2,3,4,5,6,7,8,9,10,11} It is widely applied for bio-orthogonal labeling, often referred to as 'click chemistry', as well as materials science.^{12,13,14,15,16,17,18} In addition, sp carbons of alkynes introduced via C-C(sp) cross-couplings, could be readily converted into sp³ and sp² carbons under many known mild conditions. Accordingly, C-C(sp) cross-couplings serve as a valuable complementary approach to C-C(sp³)/(sp²) couplings for constructing the carbon-carbon backbones of products.^{19,20,21,22,23}

The Sonogashira reaction, regarded as the most widely used C-C(sp) cross-coupling methods, traditionally combine a palladium catalyst with a copper co-catalyst to enable the coupling of terminal alkynes with electrophiles. In recent years, there has been a growing interest in the development of Sonogashira-type reactions catalyzed by a single transition metal. The state-of-the-art work reported by Buter, Feringa and co-workers presents a Pd-catalyzed cross-coupling of lithium acetylides with aryl bromides. Their innovative approach requires the preparation of air- and moisture-sensitive lithium acetylides in advance.²⁴ The conditions for single copper-catalyzed Sonogashira reactions to form C(sp²)-C(sp) bonds can be quite harsh.²⁵ Elevated reaction temperatures are required to facilitate oxidative addition of copper catalyst with aryl halides. In contrast, nickel owns an advantage of facile oxidative addition with C(sp²) partners, in which some coupling reactions could occur at mild conditions.²⁶

In this protocol, we depict an efficient and practical nickel-catalyzed C(sp²)-C(sp) Sonogashira coupling reaction for unactivated terminal alkynes and aryl halides without using a co-catalyst. This protocol demonstrates good functional group tolerance since strong bases are avoided. This strategy opens up new avenues for preparing a broad array of acetylenes, including those with applications in optoelectronic materials, pharmaceuticals, and fundamental chemical biology building blocks. Additionally, this protocol can achieve selective alkynylation for multi-halide substituted arenes by careful tuning of the reaction conditions. For the details, please refer to Chen et al.¹

Preparation of the reagent and equipment

A complete list of reagents and equipment can be found in the ‘‘key resources table’’ and ‘‘materials and equipment’’.

Preparation of active zinc powder

Timing: 4 h

• 1.Introduce commercial zinc powder (10 g), 200 mesh, obtained from Acros, into a stirring 250 mL single-neck round-bottomed flask, which contains 100 mL of 2% hydrochloric acid (with a weight ratio of HCl to H₂O at 2:98).
• 2.Stir vigorously until the surface of the zinc becomes bright and no bubbles are generated from it (10 min).

Note: Conduct stirring under nitrogen protection.

• 3.Transfer the activated zinc powder to a suction filter. The obtained zinc powder is washed with distilled water (50 mL × 3), ethanol (50 mL × 3), acetone (50 mL × 3) and ether (50 mL × 3).
• 4.Transfer the washed zinc powder into a single-neck round-bottomed flask and dried at 25°C under vacuum for 3 h. This process yields 8.2 g of activated zinc.

CRITICAL: Filtration and washing should be accomplished as rapidly as possible to shorten the exposure time of zinc to air (within 10 min). If necessary, the obtained zinc powder could be filtrated by 200 mesh sieve and stored under N₂.

Note: Gloves are required since hydrochloric acid is corrosive.

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Chemicals, peptides, and recombinant proteins
Nickel chloride, anhydrous, powder (99.99%)	Acros	CAS: 7718-54-9
1,10-Phenanthroline, anhydrous, powder (99+%)	Acros	CAS: 66-71-7
4-Cyano pyridine N-oxide (98%)	TCI	CAS: 14906-59-3
Potassium fluoride (99.99%)	Alfa Aesar	CAS: 7789-23-3
Zinc powder (99.995%)	Acros	CAS: 7440-66-6
N,N-dimethylacetamide, 99.5%, super dry, with molecular sieves, water ≤ 30 ppm	J&K Scientific	CAS: 127-19-5
4-Iodobiphenyl (97%)	Alfa Aesar	CAS: 1591-31-7
Phenylacetylene (98+%)	Alfa Aesar	CAS: 536-74-3
6-Bromo-1-(phenylsulfonyl)-1H-indole (98%)	Adamas-Beta	CAS: 679794-03-7
1,4-Diiodobenzene (98%)	Alfa Aesar	CAS: 624-38-4
(Triethylsilyl)acetylene (97%)	Adamas-Beta	CAS: 1777-03-3
4-Ethynylanisole (98%)	TCI	CAS: 768-60-5
3-Bromoiodobenzene (97%)	TCI	CAS: 591-18-4
4-Ethynyltoluene (98+%)	Adamas-Beta	CAS: 766-97-2
4-Tert-butylphenylacetylene (98%)	Adamas-Beta	CAS: 772-38-3
4-Iodophenyl acetate (99%)	Adamas-Beta	CAS: 33527-94-5
Sodium hydroxide (98%)	Acros	CAS: 1310-73-2
Sodium chloride (98%)	Shanghai Titan Scientific Co., Ltd.	CAS: 7647-14-5
Methanol (99.5%)	J&K Scientific	CAS: 67-56-1
Hydrochloric acid (37%)	Fisher Scientific	CAS: 7647-01-0
Ethyl acetate	General reagent	CAS: 141-78-6
Petroleum ether	General reagent	CAS: 8032-32-4
Anhydrous sodium sulfate	General reagent	CAS: 7757-82-6
Dichloromethane	General reagent	CAS: 75-09-2
n-Hexane	General reagent	CAS: 110-54-3
Deuterated chloroform, 99.8 atom % D	Energy Chemical	CAS: 865-49-6
Nitrogen (>99.9999%)	Air Liquide	CAS: 7727-37-9
Critical commercial assays
Structure of compound 3b	This paper; Cambridge Crystallographic Data Center	CCDC: 2068369
Software and algorithms
GCMS-analysis	Shimadzu	https://www.shimadzu.com
MestReNova	Mestrelab Research	https://mestrelab.com
ChemBioDraw Ultra 14.0	PerkinElmer	https://www.perkinelmer.com/category/chemdraw
Other
Magnetic stirrer	IKA	https://www.ika.com
Electronic balance	Mettler Toledo	Cat# AL104
Magnetic stir bar	Synthware Glass	Cat# SA1758
Vacuum pump	VALUE	Cat# VRD 12
Syringe needle	Synthware Glass	Cat# YCKJ-KSM-2-007353
Rubber plug	Shanghai Titan Scientific Co., Ltd.	Cat# 02024583
Vial (2 mL)	Shanghai Titan Scientific Co., Ltd.	Cat# 02041214
Tube (φ 12 × 75 mm)	Shanghai Titan Scientific Co., Ltd.	Cat# 02036870
Round-bottom flask	Synthware Glass	Cat# F304250
Filter funnel	Synthware Glass	Cat# F366019M
Chromatography column	Synthware Glass	Cat# C371720
Suction filter	Synthware Glass	Cat# F664500R
Absorbent cotton	Innochem (Beijing) Technology	Cat# C124537-50g
Booster pump	Zhipu	Cat# zhipu-12L
Thin-layer chromatography (TLC-plates 0.25 mm)	XUBO	Cat# HSGF254
Separatory funnel	Synthware Glass	Cat# F472925A
Oven	Keelrein	Cat# DHG-9240A
Rotary evaporator	EYELA	Cat# N-1100D-WB
400 MHz NMR spectrometer	Bruker	Cat# AVANCE III
X-ray single crystal diffractometer	Rigaku	Cat# XtaLAB PRO 007HF(Mo)
Silica gel (200–300 mesh)	Shanghai Titan Scientific Co., Ltd.	Cat# DG72651C
Gloves	Ammex	Cat# APFNCHD100
Gas chromatography-mass spectrometer (GC-MS)	Shimadzu	Cat# GCMS-QP2010-SE
Glovebox	Vigor	Cat# LG1200/750TS-F

Materials and equipment

Materials examples

Reagent	Final concentration	Amount
4-Iodo-1,1′-biphenyl (1a)	N/A	140 mg
Phenylacetylene (2a)	N/A	77 mg
Nickel chloride (NiCl2)	N/A	6.5 mg
1,10-Phenanthroline	N/A	13.5 mg
4-Cyanopyridine N-oxide	N/A	90 mg
Potassium fluoride (KF)	N/A	44 mg
Zinc powder (Zn)	N/A	38 mg
N,N-dimethylacetamide (DMAc)	N/A	5 mL

Store at 4°C for up to 2 years.

Step-by-step method details

Part 1: Set up Ni-catalyzed C(sp²)-C(sp) coupling of terminal alkynes and aryl iodides

Timing: 48 h

In this part, 4-(phenylethynyl)-1,1′-biphenyl (3a) is prepared with nickel catalysis (Scheme 1). Twenty-three analogs have been produced via this method. The full scope of the transformation is described in Chen et al.¹

• 1.
  Set up reaction (Scheme 1; Figure 1):

  • a.
    Add nickel(II) dichloride (0.05 mmol, 10 mol %) to a solution of 1,10-phenanthroline (0.075 mmol, 15 mol %) in degassed N,N-dimethylacetamide (DMAc) (2.00 mL).

    Note: This results in a mixture in a 15 mL single-neck flask.

  • b.
    Stir the solution in a glovebox filled with N₂ at 25°C for 30 min.
  • c.
    Add 4-iodo-1,1′-biphenyl (1a) (0.50 mmol, 1.0 equiv), phenylacetylene (2a) (0.75 mmol, 1.5 equiv), 4-cyanopyridine N-oxide (0.75 mmol, 1.5 equiv), KF (0.75 mmol, 1.5 equiv), zinc powder (0.60 mmol, 1.2 equiv) and DMAc (3.00 mL) to the mixture successively. The reaction mixture is subsequently heated under N₂ at 60°C for 48 h (Figures 1A and 1B).

    CRITICAL: The reaction is sensitive to oxygen. We suggest conducting the reaction in glovebox filled with nitrogen. If Schlenk operation techniques are applied, please replace the air in tube with nitrogen for many times to ensure the inert gas atmosphere.

Scheme 1.

Ni-catalyzed Sonogashira coupling for preparation of 3a

Figure 1.

Reaction and appearance of 3a and 3b at different stages

Part 2. Purification of the crude material 4-(phenylethynyl)-1,1′-biphenyl (3a)

Timing: 1.5 h

• 2.
  Work up reaction (30 min):

  • a.
    Pour the reaction mixture into water (100 mL).
  • b.
    Extract the water layer with ethyl acetate (3 × 25 mL) (Figure 1C).
  • c.
    Wash the combined extracts with brine (1 × 25 mL).
  • d.
    Dry the ethyl acetate layer with anhydrous sodium sulfate (Figure 1D).
  • e.
    Filter off sodium sulfate and pour the filtrate into a 250 mL round-bottom flask.
  • f.
    Concentrate the filtrate under reduced pressure with a rotary evaporator to afford the crude product (-0.1 MPa, 35°C, 80 rmp) (Figures 1F–1H).
• 3.
  Purification by column chromatography (1 h) (Figures 1F–1J).

  • a.
    Dilute the crude product with 10 mL dichloromethane, and add silica gel (3 gram, 200–300 mesh).
  • b.
    Evaporate the solvent under reduced pressure to afford a dry mixture of product with silica gel (-0.1 MPa, 35°C, 80 rmp) (Figures 1F and 1G).

    Note: Cotton is stuffed into the splash guard in case of silica splashing during rotary evaporation.

  • c.
    Add 25 g silica gel (200–300 mesh) to chromatography column (φ 17 mm, length 305 mm) and add petroleum ether subsequently.
  • d.
    Use air booster pump to accelerate the flow velocity to wet silica gel.
  • e.
    Load the crude product into chromatography column and add quartz sand (1 cm) subsequently.
  • f.
    Use petroleum ether (100%) to elute product (Figure 1I).
  • g.
    Use TLC (100% petroleum ether) combined with UV-light detection (254 nm and 365 nm) to analyze the fractions (Figure 1E).
  • h.
    Apply GC-MS to identify each fraction.
  • i.
    Collect the fractions containing product and remove the solvent by rotary evaporation (-0.1 MPa, 35°C, 80 rmp) to afford coupling product (Figure 1J).
  • j.
    Characterize the product by ¹H-NMR,¹³C-NMR, MS and HRMS.

Part 3. Set up Ni-catalyzed C(sp²)-C(sp) coupling of terminal alkynes and aryl bromides

Timing: 48 h

In this part, 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b) is prepared with nickel catalysis (Scheme 2). Twenty analogs have been produced via this method. The full scope of the transformation is described in Chen et al.¹

Scheme 2.

Ni-catalyzed Sonogashira coupling for preparation of 3b

The method on nickel-catalyzed coupling of 6-bromo-1-(phenylsulfonyl)-1H-indole (1b) with phenylacetylene (2a) is same to the coupling of 4-(phenylethynyl)-1,1′-biphenyl (3a) with phenylacetylene (2a). The only difference is the temperature is elevated to 70°C (refer to Part 1).

Compound 3b is synthesized following the procedure outlined for compound 3a (vide supra, Part 1). However, the reaction temperature is increased to 70°C instead of 60°C.

Part 4. Purification of the crude material 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b)

Timing: 1.5 h

The operational procedure for purification of 3b is the same as for 3a (refer to Part 2). The difference is elution solvents are petroleum ether and ethyl acetate (30:1).

Part 5. Recrystallization

Timing: 4 days

In this section, a procedure for obtaining crystals of 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b) is described.

• 4.
  Set-up for recrystallization.

  • a.
    Weigh 3b (8 mg) on the electronic balance.
  • b.
    Dissolve 3b with dichloromethane (200 μL) in a 2 mL vial.
  • c.
    Add 1.5 mL n-hexane to the vial and ensure no 3b precipitate.

    Note: If 3b is precipitated when adding n-hexane, add as much DCM until 3b is again dissolved completely.

  • d.
    Fill another tube (φ 12 × 75 mm) with 2 mL n-hexane.
  • e.
    Transfer the vial with 3b into the tube (Figure 1K).
  • f.
    Seal the tube and keep them standing still in a shelf at 25°C.

    Note: The sample should be placed on a flat surface where it is not moved.

  • g.
    After evaporation slowly for 4 days, the colorless crystals are obtained (Figure 1L).

Expected outcomes

4-(phenylethynyl)-1,1′-biphenyl (3a) is obtained as white powder in 65% yield. 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b) is obtained as pale yellow powder in 74% yield. 3b is recrystallized to afford the colorless solid (Figure 1L).

Quantification and statistical analysis

Analytical data

4-(phenylethynyl)-1,1′-biphenyl (3a).

¹H NMR (400 MHz, CDCl₃) δ 7.61–7.53 (m, 8H), 7.45 (t, J = 8.0 Hz, 2H), 7.36–7.33 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 141.1, 140.5, 132.2, 131.8, 129.0, 128.5, 128.4, 127.8, 127.1, 123.4, 122.3, 90.2, 89.5.

EI-MS m/z calculated for [M]⁺ 254.11, found 254.15.

6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b).

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.62–7.59 (m, 3H), 7.53–7.49 (m, 2H), 7.46–7.37 (m, 6H), 6.67 (d, J = 3.6 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃) δ 138.2, 134.7, 134.1, 131.7, 130.7, 129.5, 128.5, 128.4, 127.6, 127.1, 126.8, 123.3, 121.5, 119.6, 116.8, 109.4, 90.1, 89.5.

EI-MS m/z calculated for [M]⁺ 357.08, found 357.00.

HRMS m/z calculated for [M + H]⁺ 358.0902, found 358.0902.

Limitations

Aryl halides are limited to aryl iodide and bromide. When aryl chloride is employed as substrate, the reaction temperature is required to be elevated to 120°C, generating coupling product in an extremely low yield (< 5% yield). Although aryl triflates are tolerated, coupling products are obtained in low yield (< 20% yield).

Troubleshooting

Problem 1

Nickel chloride (anhydrous) is sensitive to water (step 1).

Potential solution

• •Store NiCl₂ in a vacuum desiccator with allochroic silica gel as the desiccant. Use a vacuum pump to keep the desiccator under vacuum before use.
• •Store NiCl₂ in nitrogen-filled glovebox if available.

Problem 2

Zinc powder is sensitive to air (step 1).

Potential solution

• •Store Zn in a vacuum desiccator with allochroic silica gel as the desiccant. Use a vacuum pump to keep the desiccator under vacuum before use.
• •Store Zn in nitrogen-filled glovebox if available.
• •Store Zn in a flame dried Schlenk flask under argon or nitrogen.

Problem 3

N,N-dimethylacetamide (DMAc) is sensitive to water (step 1).

Potential solution

• •Add activated 3Å molecular sieve to the super dry DMAc and store the solvent in a sealed bottle.
• •Store DMAc in nitrogen-filled glovebox if available.

Problem 4

N,N-dimethylacetamide (DMAc) is need to be degassed (step 1).

Potential solution

• •A 250 mL single-neck flask is charged with 230 mL of DMAc. The solvent can be degassed by repeated sonication under vacuum. Subject the flask to vacuum conditions while sonicating for 5 min and then replenishing the flask with N₂. After 5–10 cycles, degassed DMAc is achieved. Transfer and store the solvent in a sealed bottle.

Problem 5

N,N-dimethylacetamide cannot be removed completely (step 2).

Potential solution

• •When the reaction is quenched, pour the mixture into ethyl acetate (100 mL). Use water (25 mL × 2) and brine (25 mL × 2) to wash the organic layer, respectively.

Problem 6

Yields are lower than expected (step 3).

Potential solution

• •This protocol is water and air sensitive; therefore, ensure the solvent is extra dry (water < 50 ppm).
• •When the reaction is conducted in glovebox, ensure the content of water and oxygen of it is lower than 10 ppm.

Resource availability

Lead contact

Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Xuebin Liao (liaoxuebin@mail.tsinghua.edu.cn).

Technical contact

Further information and requests for technical support will be fulfilled by technical contact, Xuebin Liao (liaoxuebin@mail.tsinghua.edu.cn).

Materials availability

All other data supporting the finding of this study are available within the article reported by Chen et al.¹ or from the lead contact upon reasonable request.

Data and code availability

All data reported in this paper will be shared by the lead contact upon request.

This paper does not report the original code.

Any additional information required to analyze the data reported in this paper is available from the lead contact upon reasonable request.