Protocol for iron-catalyzed cross-electrophile coupling of aryl chlorides with unactivated alkyl chlorides

Summary

Organochlorides are a crucial class of electrophiles in organic synthesis. Here, we present a protocol for the cross-electrophile coupling of aryl chlorides with unactivated alkyl chlorides, facilitated by an iron/B₂pin₂ catalytic system. We describe steps for the coupling of aryl chlorides with alkyl chlorides, followed by purification of products. This protocol can produce alkylated products with up to 81% yield.

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

Graphical abstract

Highlights

• •Coupling reaction of aryl chlorides with unactivated alkyl chlorides under iron catalysis
• •B₂pin₂ promoted cross-electrophile coupling reaction
• •Compatible with diverse functional groups

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

Organochlorides are a crucial class of electrophiles in organic synthesis. Here, we present a protocol for the cross-electrophile coupling of aryl chlorides with unactivated alkyl chlorides, facilitated by an iron/B₂pin₂ catalytic system. We describe steps for the coupling of aryl chlorides with alkyl chlorides, followed by purification of products. This protocol can produce alkylated products with up to 81% yield.

Before you begin

Organochlorides are a significant class of electrophiles due to their abundance, diverse structures, and ready accessibility. Despite these advantages, they are less frequently employed as coupling partners in cross-electrophile coupling reactions, mainly due to the high dissociation energy of the C-Cl bond. In recent years, efforts have been made to explore the use of organochlorides in such reactions. In 2018, Zhang and colleagues reported a nickel-catalyzed reaction involving aryl chlorides and HCF₂Cl, showcasing high efficiency and a broad substrate scope.² The Weix group, using an unconventional PyBCam^CN ligand, achieved the cross-coupling of aryl chlorides with primary alkyl chlorides under nickel catalysis, in which only one example involving a secondary alkyl chloride was presented with low efficiency.³ Subsequently, MacMillan reported a similar study using photoredox/nickel catalysis. In this approach, a superior silane reagent induced the formation of alkyl radicals under mild photocatalytic conditions, thereby broadening the utilization of organochlorides.⁴

Iron catalysis has received increasing attention due to its abundance, non-toxicity, and cost-effectiveness.^5,6,7 The functionalization of inert bonds under iron catalysis presents a significant challenge, often encountering difficulties in oxidative addition reactions with electrophiles when using iron-based complexes for cross-electrophilic reactions.^8,9 However, our recent investigation has revealed that iron/B₂pin₂ catalytic systems can overcome this challenge, enabling the borylation and alkylation of the inert C-O bond.^{10,11,12,13,14} Notably, the active iron species in these catalytic systems may be in-situ generated. This finding leads us to anticipate that these resulting active iron species could play a crucial role in achieving the cross-electrophilic coupling of organochlorides. Therefore, inspired by these advances, there is significant merit in developing a general method for iron-catalyzed cross-electrophile coupling reaction of aryl chlorides with alkyl chlorides, especially for the secondary alkyl chlorides. The outlined protocol showcases the steps for the synthesis of alkylated compounds through an iron-catalyzed cross-electrophile coupling reaction between aryl chlorides and alkyl chlorides (Scheme 1). Additionally, this protocol is suitable for gram-scale synthesis and late-stage functionalization of biomolecules. For the same experiment performed in batch, please see Zhang et al. (2023).¹

Scheme 1.

General scheme of iron-catalyzed cross-electrophile coupling reaction of organochlorides

Preparation of the reagents and equipment

A complete list of reagents and equipment can be found in the “key resources table” part.

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Chemicals, peptides, and recombinant proteins
4-Chloro-1,1′-biphenyl (aryl chloride)	Energy Chemical	Cat#D051465
1-Chloro-4-methoxybutane (alkyl chlorine)	Bidepharm	Cat#BD57841
FeBr2	Meryer	Cat#M58644
MeOLi	Adamas	Cat#87055A
Dry methyl tert-butyl ether (MTBE)	Adamas	Cat#28130O
Tetramethylethylenediamine (TMEDA)	J&K Scientific	Cat#255989
Sodium iodide (NaI)	Bidepharm	Cat#BD40879
B2pin2	Adamas	Cat#79736B
3-Chloropyridine (hetero aryl chloride)	Bidepharm	Cat#BD34390
Chlorocyclopentane (alkyl chlorine)	Adamas	Cat#90496A
CataCXium AHI	Bidepharm	Cat#BD234433
FeCl2	Bidepharm	Cat#BD130332
Other
Silica gel for chromatography, 200–300 mm	Bidepharm	Cat#BD01115913
Chromatography column (Ø 17 mm, 305 mm)	Synthware Glass	Cat#C189173C
5 mL syringe	J&K Scientific	Cat#972645
Glass vial	Synthware Glass	Cat#F580825D
Electronic balance	Mettler Toledo	Cat#ME204
Heating module	Boost	Cat#DZ-AHB-PRL
Magnetic stirrer	IKA	Cat#RTC basic
Thin-layer chromatography (TLC-plates 0.25 mm)	Nuo Tai	Cat#GF 254
Rotary evaporator	IKA	Cat#RV 10 basic
Vacuum pump	Yong Hao	Cat#2XZ-4
400 MHz NMR spectrometer	Agilent	Cat#400-MR DD2
Glove box	DELLIX	Cat#GP25S

Step-by-step method details

Note: Protocol steps in this section have been partially modified from our previous work, Bai et al., (2022).¹⁵

Part 1: Procedure for the cross-electrophile coupling of (hetero)aryl chlorides with unactivated alkyl chlorides

Timing: 15 h

Timing: 20 h (for step 2)

In this step, the setup of the coupling reaction using (hetero)aryl chlorides as substrates has been accomplished. The full scope of the transformation is described in Zhang et al. (2023).¹

• 1.
  The coupling reaction of aryl chlorides with alkyl chlorides (Table 1; Scheme 2).

  • a.
    In one 8 mL of glass vial equipped with a magnetic stir bar.
  • b.
    Add FeBr₂ (3.1 mg, 0.014 mmol, 7 mol %), B₂pin₂ (126.9 mg, 0.5 mmol, 2.5 equiv), LiOMe (41.8 mg, 1.1 mmol, 5.5 equiv), NaI (40.5 mg, 0.27 mmol, 1.35 equiv), and alkyl chloride (42.9 mg, 0.35 mmol, 1.75 equiv), aryl chlorides (37.7 mg, 0.2 mmol, 1.0 equiv), TMEDA (9.7 mg, 0.084 mmol, 42 mol %), freshly distilled MTBE (0.3 mL) in the glove box.
  • c.
    Seal the glass vial with a cap containing a polytetrafluoroethylene (PTFE)-lined silicone septum and move it out from the glove box.
  • d.
    Heat the reaction mixture in a heating module at 80°C for 15 h.

CRITICAL: Seal the top of the glass vial with parafilm.

Note: LiOMe proves irreplaceable by alternative bases like t-BuOLi, t-BuONa, t-BuOK, MeONa, and MeOK in this reaction. DFT calculations suggested a mechanistic cycle involving a dilithium-iron complex. Furthermore, the synergistic interaction between iron and lithium may enhance the generation of alkyl radicals facilitated by the formation of a Li-Cl interaction. A Li cation-assisted single electron transfer (CASET) mechanism is likely involved in the catalytic cycle.

• 2.
  The coupling reaction of heteroaryl chlorides with alkyl chlorides (Table 2; Scheme 3).

  • a.
    In one 8 mL of glass vial equipped with a magnetic stir bar.
  • b.
    Add FeCl₂ (2.5 mg, 0.02 mmol, 10 mol %), cataCXium AHI (9.7 mg, 0.02 mmol, 10 mol %), B₂pin₂ (126.9 mg, 0.5 mmol, 2.5 equiv), LiOMe (41.8 mg, 1.1 mmol, 5.5 equiv), alkyl chlorides (20.9 mg, 0.2 mmol, 1.0 equiv), chloropyridines (34.1 mg, 0.3 mmol, 1.5 equiv), freshly distilled MTBE (1.5 mL) in the glove box.
  • c.
    Seal the glass vial with a cap containing a PTFE-lined silicone septum and move it out from the glove box.
  • d.
    Heat the reaction mixture in a heating module at 80°C for 20 h.

CRITICAL: Seal the top of the glass vial with parafilm.

Table 1.

Quantification of reagents, solvent, and product

Reagent	Mw (g/mol)	m (mg)	n (mmol)	Equiv.	V (mL)	Conc (M)	Yield (%)
FeBr2	215	3.1	0.014	0.07
B2pin2	253	126.9	0.5	2.5
LiOMe	37	41.8	1.1	5.5
NaI	149	40.5	0.27	1.35
1-Chloro-4-methoxybutane	122	42.9	0.35	1.75
4-Chloro-1,1′-biphenyl	188	37.7	0.2	1		0.66
TMEDA	116	9.7	0.084	0.42
Dry MTBE					0.3
4-(4-Methoxybutyl)-1,1′-biphenyl (1)	240	38	0.16				81

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 6.8 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 2 H), 3.41 (t, J = 6.4 Hz, 2 H), 3.34 (s, 3 H), 2.68 (t, J = 7.2 Hz, 2 H), 1.84–1.55 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃) δ 141.7, 141.2, 138.8, 129.0, 128.8, 127.2, 127.1, 72.8, 58.8, 35.5, 29.5, 28.1.

Scheme 2.

Cross-electrophile coupling reaction of 4-chloro-1,1′-biphenyl with 1-chloro-4-methoxybutane

Table 2.

Quantification of reagents, solvent, and product

Reagent	Mw (g/mol)	m (mg)	n (mmol)	Equiv.	V (mL)	Conc (M)	Yield (%)
FeCl2	126	2.5	0.02	0.1
cataCXium AHI	486	9.7	0.02	0.1
B2pin2	253	126.9	0.5	2.5
LiOMe	37	41.8	1.1	5.5
3-Chloropyridine	113	34.1	0.3	1.5
Chlorocyclopentane	104	20.9	0.2	1		0.14
Dry MTBE					1.5
3-Cyclopentylpyridine (2)	147	23	0.16				80

¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H), 8.41 (d, J = 4.8 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.19 (dd, J = 8.0, 4.8 Hz, 1 H), 3.04–2.93 (m, 1 H), 2.20–2.00 (m, 2 H), 1.91–1.77 (m, 2 H), 1.76–1.65 (m, 2 H), 1.64–1.47 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 149.2, 147.3, 141.7, 134.4, 123.4, 43.4, 34.5, 25.6.

Scheme 3.

Cross-electrophile coupling reaction of 3-chloropyridine with chlorocyclopentane

Part 2: Purification of the crude products

Timing: 2 h

In this step, the purification of desired products using (hetero)aryl chlorides as substrates has been accomplished.

• 3.
  After completing the reaction, cool the mixture to 25°C, then quench it with saturated aqueous ammonium chloride (sat. aq. NH₄Cl, 1 mL).

  • a.
    Dilute the resulting mixture with 2 mL ethyl acetate.
  • b.
    Wash it with 2 mL saturated brine, and vigorously shake the separatory funnel.
  • c.
    Release pressure and allow the aqueous and organic phases to fully separate.
• 4.Transfer the separated organic and aqueous phases into two 20 mL flasks.
• 5.Pour the aqueous phase back into the separatory funnel and add 2 mL ethyl acetate for extraction again.
• 6.
  Shake the separatory funnel vigorously, and allow the aqueous and organic phases to fully separate.

  • a.
    Transfer each organic and aqueous phases into their corresponding flasks.
• 7.Repeat steps 3 and 4 two times.
• 8.
  Transfer the organic layer to an Erlenmeyer flask and add Na₂SO₄.

  • a.
    Slowly shake the flask and filter the solution in a 25 mL round bottom flask.
• 9.Remove the solvent by rotatory evaporation (45°C, 152 mmHg, ∼15 min) to obtain the dried crude product.
• 10.
  Dissolve the dried crude product in 2 mL of dichloromethane and add 50 mg of silica into it.

  • a.
    Carefully swirl the flask and remove the solvent under vacuum (45°C, 235 mmHg, ∼15 min).
• 11.Purify the crude product by flash column chromatography (8 cm of silica, Ø of the column = 17 mm) using a 50:1 (by volume) mixture of PE/EA (∼100 mL).
• 12.
  Monitor the fractions by thin layer chromatography (TLC).

  • a.
    Collect the combined fractions containing the pure product.
  • b.
    Concentrate them under vacuum to deliver the desired alkylated compounds.

Note: These coupling products are stable for half a year at 25°C–30°C.

Expected outcomes

A colorless oil, 4-(4-methoxybutyl)-1,1′-biphenyl 1 was obtained in 81% yield, totaling 39 mg.

A colorless oil, 3-cyclopentylpyridine 2 was obtained in 80% yield, totaling 24 mg.

Quantification and statistical analysis

Analytical data

4-(4-Methoxybutyl)-1,1'-biphenyl 1.¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 6.8 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 2 H), 3.41 (t, J = 6.4 Hz, 2 H), 3.34 (s, 3 H), 2.68 (t, J = 7.2 Hz, 2 H), 1.84-1.55 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃) δ 141.7, 141.2, 138.8, 129.0, 128.8, 127.2, 127.1, 72.8, 58.8, 35.5, 29.5, 28.1.3-Cyclopentylpyridine 2.¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H), 8.41 (d, J = 4.8 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.19 (dd, J = 8.0, 4.8 Hz, 1 H), 3.04-2.93 (m, 1 H), 2.20-2.00 (m, 2 H), 1.91-1.77 (m, 2 H), 1.76-1.65 (m, 2 H), 1.64-1.47 (m, 2 H).¹³C NMR (100 MHz, CDCl₃) δ 149.2, 147.3, 141.7, 134.4, 123.4, 43.4, 34.5, 25.6.

Limitations

The protocol exhibits good efficiency with primary and secondary alkyl chlorides, while tertiary alkyl chlorides are not suitable for this protocol.

Troubleshooting

Problem 1

Step 1b & 2b: Can the yield of the reaction be improved by increasing the amount of catalyst?

Potential solution

Increasing the amount of catalyst has a negative impact on the efficiency of this reaction, resulting in an increased production of by-products from borylation and hydrogenation of organochlorides. Occasionally, for some substrates, reducing the catalyst loading will give the comparable results.

Problem 2

Step 1b & 2b: What are the possible reasons for the poor reproducibility of this reaction?

Potential solution

This reaction is slightly sensitive to both air and water. It is crucial to use freshly distilled MTBE as the solvent. Additionally, prolonged storage of MeOLi may result in a diminished yield.

Problem 3

Step 1b & 2b: After the reaction, the system will become very viscous or even dry. How to do workup of this reaction?

Potential solution

After quenching this reaction with a saturated ammonium chloride solution, add ethyl acetate to dilute the mixture, and stir quickly with a magnetic stirrer to facilitate layer separation.

Problem 4

Step 1b & 2b: How to store the catalysts and additives?

Potential solution

Catalysts and additives should be stored in the glove box.

Problem 5

Step 12a: What are the potential difficulties in the purification of the desired products?

Potential solution

Borylation side reaction always occurs during this transformation, and the corresponding by-products are difficult to separate from the desired alkylated products. These crude products could be purified by flash column chromatography, and then separated by thin-layer chromatography to get the high-purity products. Typically, borylated by-products exhibit higher polarity than the desired alkylation products, causing them to appear at the bottom of the TLC plate and facilitating easy separation.

Resource availability

Lead contact

Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Zhang Feng (fengzh@cqu.edu.cn).

Technical contact

Further information and requests for procedure should be directed to and will be fulfilled by the technical contact, Pengjie Xian (xianpengjie@126.com).

Materials availability

All other data supporting the finding of this study are available within the article, 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.
• •Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.