Homogeneous Organic Electron Donors in Nickel-Catalyzed Reductive Transformations

Abstract

Many contemporary organic transformations, such as Ni-catalyzed cross-electrophile coupling (XEC), require a reductant. Typically, heterogeneous reductants, such as Zn⁰ or Mn⁰, are used as the electron source in these reactions. Although heterogeneous reductants are highly practical for preparative-scale batch reactions, they can lead to complications in performing reactions on process scale and are not easily compatible with modern applications, such as flow chemistry. In principle, homogeneous organic reductants can address some of the challenges associated with heterogeneous reductants and also provide greater control of the reductant strength, which can lead to new reactivity. Nevertheless, homogeneous organic reductants have rarely been used in XEC. In this Perspective, we summarize recent progress in the use of homogeneous organic electron donors in Ni-catalyzed XEC and related reactions, discuss potential synthetic and mechanistic benefits, describe the limitations that inhibit their implementation, and outline challenges that need to be solved in order for homogeneous organic reductants to be widely utilized in synthetic chemistry. Although our focus is on XEC, our discussion of the strengths and weaknesses of different methods for introducing electrons is general to other reductive transformations.

Figure 1.

General depiction of cross-coupling (top) and XEC (bottom) reactions.

Figure 2.

Methods for the introduction of electrons in XEC. Homogeneous organic reductants are the focus of this Perspective. In electrochemically- and photocatalytically-driven systems, electrons are provided by various reagents, such as trialkylamines.

Figure 3.

Homogeneous organic reductants that have been utilized as electron sources in Ni-catalyzed XEC with two or more distinct classes of electrophiles. Outersphere reductants transfer electrons but do not directly interact with the catalyst, while innersphere reductants likely form bonds with the catalyst during the reaction.

Figure 4.

Reductive coupling of alkenyl bromides with aldehydes. TMSCl = chlorotrimethylsilane.

Figure 5.

XEC of aryl halides with alkyl halides using TDAE. Ts = toluenesulfonyl; Pin = pinacolato; TBS = tert-butyldimethylsilyl.

Figure 6.

Proposed mechanism for XEC of aryl halides with alkyl halides using TDAE in CH₃CN or propylene carbonate.

Figure 7.

Ni/Co dual catalyzed XEC of aryl halides with alkyl halides. ^a2-iodo-1,3-dimethoxybenzene with 2 equiv of alkyl substrate and 160 mol% TDAE for 48 h. ^b1.6 equiv of alkyl substrate and 140 mol% TDAE. ^c36 h.

Figure 8.

Proposed mechanism for the XEC of aryl and alkyl halides in the presence of a Ni catalyst, Co^II(Pc) co-catalyst, and TDAE.

Figure 9.

XEC of alkenyl bromides with 2° benzylic NHP esters. PMP = 4-methoxyphenyl; TMSBr = bromotrimethylsilane; Bn = benzyl; DMAc = N,N-dimethylacetamide.

Figure 10.

a) Intermolecular reductive arylalkylation of electron-deficient olefins with aryl iodides and 3° alkyl iodides. Glyme = dimethoxyethane; Ac = Acetyl; Py = pyridine; FG = functional group. b) Intermolecular reductive arylalkylation of unactivated terminal olefins with aryl iodides and 3° alkyl iodides. ^aaryl iodide (1 equiv), alkene (3 equiv).

Figure 11.

Asymmetric intermolecular reductive arylalkylation of electron-deficient terminal olefins with aryl iodides and 3° alkyl iodides. ^a100 mol% LiBF₄. Pin = Pinacolato; FG = functional group.

Figure 12.

a) Newly synthesized homogeneous reductants with variable E° and enhanced air stability in comparison to TDAE. Potentials are reported relative to ferrocene (Fc) in DMF. b) XEC reactions between aryl iodides and benzylic Katritzky salts facilitated by TME. DMAc = N,N-dimethylacetamide.

Figure 13.

General depiction of a mechanism for XEC in which an alkyl electrophile is generated independently of Ni^I. The key to using this strategy is to ensure that Ni^I does not react with the alkyl electrophile by increasing the rate of reduction of Ni^I to Ni⁰.

Figure 14.

Carboxylation of aryl halides and pseudohalides using DMAP-OED. ^a(dppf)Ni^IICl₂ (2.5 mol%) at 25 °C. ^b(PCy₃)₂Ni^IICl₂ (10 mol%) instead of (dppf)Ni^IICl₂.

Figure 15.

Reductive arylation of arylaldehydes using Ni aNPs generated from Si-Me₄-DHP.

Figure 16.

Ni-catalyzed cyanation of aryl halides and aryl triflates using Si-Me₄-DHP as the electron source. ^a15 mol% of [Ni^II(MeCN)₆](BF₄)₂ and 1,10-phenanathroline at 100 °C. TBS = tertbutyldimethylsilyl. CBz = Benzyloxycarbonyl.

Figure 17.

a) XEC of aryl triflates with alkyl halides. b) XEC of aryl triflates with aryl bromides. OTf = trifluoromethanesulfonate; COD = 1,5-cyclooctadiene.

Figure 18.

a) Ni-catalyzed XEC reactions between two alkyl electrophiles using B₂Pin₂ as the reductant. Pin = pinacolato; Ts = tosyl; NMP = N-methyl-2-pyrrolidone. b) Proposed mechanism for the reaction.

Figure 19.

Ni-catalyzed reductive methylation reactions using B₂Pin₂ as the reductant. Pin = pinacolato; NMP = N-methyl-2-pyrrolidone.

Figure 20.

Ni-catalyzed defluorinative reductive coupling reactions using B₂Pin₂ as the reductant. Pin = pinacolato; COD = 1,5-cyclooctadiene; DMAc = N,N-dimethylacetamide.

Figure 21.

Ni-catalyzed monofluoroalkylation reactions using B₂neo₂ as the reductant. Ac = acetyl; DME = dimethoxyethane; neo = neopentyl glycolato; TBAI = tetra-n-butylammonium iodide; NMP = N-methyl-2-pyrrolidone.

Figure 22.

Products derived from reduction of a metal complex using a) TDAE and b) 2,3,5,6-tetramethyl-1,4-bis(trimethylsilyl)-1,4-dihydropyrazine. X = Cl, Br, or I. Resonance structures omitted for clarity.

Figure 23.

Redox states that are readily accessible from TDAE. Resonance structures omitted for clarity.

Figure 24.

Seven-kilogram scale XEC of an aryl and alkyl chloride using Mn⁰ powder as the reductant. DMF = N,N-dimethylformamide; TESCl = chlorotriethylsilane.

Figure 25.

XEC of aryl iodides with NHP esters in continuous flow using a Zn⁰ column.

Figure 26.

Representative classes of organic electron donors and examples of known compounds with potentially catalytically relevant reduction potential in transition metal-catalyzed reductive coupling reactions. Reduction potentials reported vs Fc/Fc⁺ in ^aDMF, ^bTHF, and ^cMeCN.