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Revitalizing reformatsky reagent for catalyst-free direct alkylation with unactivated alkyl halides

23 September 2025

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Introduction

Reformatsky reagents (generated from α-halo carbonyl compounds and zinc) have traditionally been primarily employed in reactions with activated electrophiles such as aldehydes, ketones, acyl chlorides, etc. (Figure 1a). These reagents are known for their lower reactivity compared to organolithium or Grignard reagents. Due to their limited nucleophilicity, they generally cannot undergo direct nucleophilic substitution (SN₂) with unactivated alkyl halides (e.g., ethyl bromide) and typically require reliance on transition metal catalysis (e.g., Ni, Fe, Co, etc.) (Figure 1b).

Recently, Professor Qilong Shen and Botao Wu’s team have developed a transition-metal-catalyst-free approach that enables direct cross-electrophile coupling between Reformatsky reagents and unactivated alkyl halides for the construction of C(sp³)–C(sp³) bonds.

Fig.1 Applications of the organozinc reagent.

The researchers significantly enhanced the nucleophilicity of Reformatsky reagents through the following three complementary strategies:

1. Introduction of anionic ligands (e.g., NaI): Promoted the formation of zincate intermediates and elevated the HOMO energy level.

2. Incorporation of alkyl groups at the α-position of the carbonyl group: Increased steric hindrance to facilitate dissociation of dimers into more reactive monomers.

3. Utilization of highly polar solvents (e.g., NMP): Enhanced the formation and stabilization of ionic intermediates.

Reaction discovery and optimizations

Initially, the researchers attempted the reductive cross-electrophile coupling (XEC) between α-bromoamide (1a) and unactivated alkyl bromide (8a) in DMF solvent using zinc powder (Zn) as the reductant and LiBr as the additive. The reaction proceeded smoothly within 2 hours, affording the product with 72% GC yield, demonstrating the fundamental feasibility of this transformation.

Through systematic screening of additives, solvents, and zinc equivalents (see Supplementary Table S1 for details), the optimal conditions were identified. Under the optimized conditions (Zn, NaI, NMP, rt), the reaction achieved complete conversion of starting materials and delivered the target product (9) in 94% yield.

Mechanistic studies

The use of ultra-high-purity zinc powder (99.999%) yielded nearly identical results compared to unpurified zinc powder, effectively ruling out trace transition metal catalysis. Furthermore, complete reaction inhibition was observed when manganese (Mn) was substituted for zinc, confirming zinc's essential role. Radical clock experiments using (bromomethyl)cyclopropane and 6-bromohex-1-ene showed no detection of radical-derived ring-opening or cyclization byproducts. Stereochemical integrity was maintained when optically pure secondary alkyl iodide was employed: only minimal erosion of enantiomeric purity occurred, which was definitively attributed to substrate racemization mediated by iodide anions rather than the coupling process itself. These results collectively demonstrate that the carbon-carbon bond formation proceeds without involving radical intermediates or a single-electron transfer (SET) pathway.

Fig.2 Mechanisticexperiments

Through cross-experimentation and real-time monitoring, the authors confirmed that zinc preferentially inserts into the C–Br bond of activated α-bromo carbonyl compounds to generate Reformatsky reagents. These reagents were identified as the genuine nucleophilic active species, rather than alkylzinc reagents derived from unactivated alkyl halides.

Fig.3 Reaction progress curves.

Substrate scope

The substrate scope demonstrates exceptional breadth in this transition-metal-free Reformatsky coupling protocol. α-Bromo amides, esters, and ketones successfully coupled with diverse unactivated alkyl halides to construct all-carbon quaternary centers. The system tolerates numerous functional groups including alkene, alkyne, silicon ether (TBS), boronyl (Bpin), thioether, alkyl fluoride, chloride, trifluoromethyl, and heterocycles (pyrrole, furan, thiophene). α,α-Dialkyl carbonyl compounds showed optimal reactivity, with steric hindrance significantly influencing yields. Unactivated primary alkyl bromides, chlorides, and iodides all participated effectively, while secondary alkyl iodides required optimized conditions. The methodology enabled intramolecular cyclization to access challenging spirolactones, including 8- and 9-membered rings. Gram-scale and 100-gram-scale reactions proceeded efficiently, and the products underwent diverse derivatizations to carboxylic acids, acyl fluorides, and amides. Late-stage functionalization of natural products (menthol, cholesterol) and drug molecules (paroxetine) further highlighted the synthetic utility of this versatile C(sp³)–C(sp³) bond-forming strategy.

Fig. 4 Substrate scope

AmBeed's Products Support Related Research

Alkyl halides, α-bromo-α-alkyl amides/esters/lactones/ketones were used in the above studies. At AmBeed, we offer a diverse catalog of high-purity reagents to support your research in this field:

References

[1]Lingpu Meng, ZimengLi, Tian Zhang et al. Revitalizing reformatsky reagent for catalyst-free direct alkylation with unactivated alkyl halides. Nat Commun 16, 7627 (2025).

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