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Barbier reaction
Barbier reaction
Barbier reaction
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Barbier reaction
Named after Philippe Barbier
Reaction type Coupling reaction
Reaction
R-X
+
Carbonyl group
+
Metal
↓
Primary, secondary or tertiary alcohol
Identifiers
RSC ontology ID RXNO:0000084
Barbier reaction with samarium(II) iodide

The Barbier reaction is an organometallic reaction between an alkyl halide (chloride, bromide, iodide), a carbonyl group and a metal. The reaction can be performed using magnesium, aluminium, zinc, indium, tin, samarium, barium or their salts. The reaction product is a primary, secondary or tertiary alcohol. The reaction is similar to the Grignard reaction but the crucial difference is that the organometallic species in the Barbier reaction is generated in situ, whereas a Grignard reagent is prepared separately before addition of the carbonyl compound.[1] Unlike many Grignard reagents, the organometallic species generated in a Barbier reaction are unstable and thus cannot be stored or sold commercially. Barbier reactions are nucleophilic addition reactions that involve relatively inexpensive, water insensitive metals (e.g zinc powder) or metal compounds. For this reason, it is possible in many cases to run the reaction in water, making the procedure part of green chemistry.[2] In contrast, Grignard reagents and organolithium reagents are highly moisture sensitive and must be used under an inert atmosphere without the presence of water. The Barbier reaction is named after Philippe Barbier, who was Victor Grignard's teacher.

Scope

[edit]

Examples of Barbier reactions are the reaction of propargylic bromide with butanal with zinc metal (The attached reference details that the reaction goes to completion after the addition of saturated aqueous ammonium chloride):[3]

Barbier reaction
Barbier reaction
With a substituted alkyne instead of a terminal alkyne the allene product is favoured

the intramolecular Barbier reaction with samarium(II) iodide:[4]

Barbier reaction
Barbier reaction

the reaction of an allyl bromide with formaldehyde in THF with indium powder:[5]

Barbier reaction
Barbier reaction
The Barbier reaction is accompanied by an allylic rearrangement to a terminal alkene

The reaction of 3-Bromocyclohexene with benzaldehyde and zinc powder in water:[6]

Barbier reaction
Barbier reaction
The observed diastereoselectivity for this reaction is erythro : threo = 83 : 17

Asymmetric variants

[edit]
Main article: Asymmetric addition of dialkylzinc compounds to aldehydes

The synthesis of (+)-aspicillin, starts first with a hydroboration, then transmetallation to zinc which can then do an addition into the aldehyde substituent.[7]

The total synthesis of (+)-aspicillin involves a Barbier reaction
The total synthesis of (+)-aspicillin involves a Barbier reaction

See also

[edit]
[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Barbier reaction

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from Grokipedia
The Barbier reaction is an organometallic reaction in that facilitates the formation of carbon-carbon bonds through the one-pot coupling of an alkyl, allyl, or benzyl halide with a carbonyl compound—such as an or —in the presence of a low-valent metal like magnesium or , typically yielding homoallylic or other substituted alcohols as products. Discovered in 1899 by French chemist Philippe Barbier during his studies on synthesis, the reaction was first reported as the treatment of methyl iodide and methylheptenone with magnesium to produce dimethylheptenol, marking it as a pioneering example of organomagnesium-mediated synthesis. This one-step process predates and inspired the more controlled two-step developed by Barbier's doctoral student in 1900, offering advantages in simplicity and tolerance to protic solvents like , which renders traditional Grignard reagents unstable. Unlike the , where the organometallic reagent is preformed and isolated before addition to the , the Barbier reaction generates the reactive intermediate in situ, often under aqueous or heterogeneous conditions that enhance by avoiding setups and using inexpensive, abundant metals. The mechanism remains partially debated but is generally understood to involve single-electron transfer from the metal to the , forming an organometallic or radical intermediate that adds to the carbonyl; it is not a free-radical chain process, as evidenced by stereochemical studies and trapping experiments showing rapid reaction even in the absence of preformed organometallics. Key variants include the allyl Barbier reaction for homoallylic alcohols and extensions with or tin for selective additions, with applications in synthesis such as analogs, ipsdienol, and complex pharmaceuticals. Over its 125-year history, the reaction has evolved to incorporate ultrasonic and green solvents, underscoring its enduring role in efficient, diastereoselective carbon-carbon bond formation.

Overview

Definition and Significance

The Barbier reaction is an organometallic coupling process that facilitates the formation of carbon-carbon bonds by reacting an alkyl, allyl, or benzyl halide (RR-X) with a carbonyl compound, such as an aldehyde (R′R'-CHO) or ketone (R′R'-CO-R′′R''), in the presence of a metal, typically zinc or magnesium, to yield a secondary or tertiary alcohol (RR-R′R'-CH-OH or RR-R′R'-R′′R''C-OH$). First described by French chemist Philippe Barbier in 1899, this reaction represents a foundational one-pot method in organic synthesis for constructing alcohols from readily available starting materials. The primary significance of the Barbier reaction stems from its generation of the organometallic reagent, which eliminates the need to isolate and handle air- and moisture-sensitive intermediates, in contrast to multistep procedures like the traditional . This streamlined approach reduces operational complexity, minimizes side reactions, and enhances overall synthetic efficiency, making it particularly valuable for constructing complex molecular frameworks in both academic and industrial settings. Additionally, the Barbier reaction aligns with principles by employing inexpensive, abundant metals and tolerating protic solvents, including aqueous media, which avoids the use of conditions and hazardous organic solvents. It also demonstrates applicability to sensitive substrates and can exhibit diastereoselectivity, such as favorable erythro:threo ratios in allylic systems, further broadening its utility in stereocontrolled synthesis.

General Reaction Scheme

The Barbier reaction involves the one-pot coupling of an organic halide with a carbonyl compound in the presence of a metal, typically zinc, to form a new carbon-carbon bond and yield an alcohol product. The general reaction scheme can be represented as: R-X+R’CHO+M→R-CH(OH)R’+MX\text{R-X} + \text{R'CHO} + \text{M} \rightarrow \text{R-CH(OH)R'} + \text{MX} where R-X is an alkyl, allyl, or similar halide (X = Cl, Br, or I), R' is an aryl or alkyl substituent on the aldehyde, and M is a low-valent metal such as zinc. This extends to ketones as: R-X+R’COR”+M→R-C(OH)(R’)R”+MX\text{R-X} + \text{R'COR''} + \text{M} \rightarrow \text{R-C(OH)(R')R''} + \text{MX} yielding tertiary alcohols when R, R', and R'' are non-hydrogen substituents. A representative example is the reaction of allyl bromide with benzaldehyde using zinc powder in tetrahydrofuran (THF) at room temperature, producing 1-phenylbut-3-en-1-ol as the homoallylic alcohol product along with zinc bromide as the byproduct salt. This process highlights the reaction's simplicity, as all components—halide, carbonyl, and metal—are combined directly without prior organometallic preparation, in contrast to the Grignard reaction which requires stepwise formation of the reagent. Schematically, the Barbier reaction depicts the simultaneous mixing of the organic halide, carbonyl compound, and (e.g., granular or dust ) in a like THF or aqueous media, leading to in situ generation of the organometallic species and its subsequent addition to the carbonyl, with precipitation of the metal halide salt as a byproduct.

Historical Development

Discovery and Early Work

The Barbier reaction was first reported by French Philippe Barbier in 1899 while supervising the PhD work of at the in . In his seminal publication, Barbier described a one-pot organometallic addition using magnesium to couple methyl iodide with the carbonyl compound methylheptenone, producing 2,6-dimethylhept-5-en-2-ol and marking a significant advancement in synthetic . This approach allowed for the direct formation of carbon-carbon bonds without isolating sensitive intermediates, distinguishing it from prior multi-step methods. Barbier's foundational experiment involved the reaction of methyl iodide with methylheptenone in the presence of magnesium turnings in , yielding the tertiary alcohol product 2,6-dimethylhept-5-en-2-ol. The reaction was conducted under conditions in , demonstrating feasibility for organomagnesium-mediated additions. This magnesium-mediated addition represented an accessible alternative to the Wurtz coupling, which relied on sodium to dimerize alkyl halides but offered limited control for incorporating carbonyl functionalities. Initially, the reaction's scope was constrained, showing good efficacy with certain alkyl halides but delivering poor yields with others due to competing side reactions and inefficient organomagnesium formation. These early limitations highlighted the method's preliminary nature, yet it laid the groundwork for subsequent refinements; Grignard later extended similar principles to isolated organomagnesium reagents in his doctoral .

Evolution and Key Milestones

Following the initial one-pot reaction reported by Barbier in 1899 using magnesium, refined the process in 1900 by developing a two-step method involving the preformation of organomagnesium reagents in anhydrous , which improved and shifted widespread attention to magnesium-mediated variants while crediting Barbier's foundational one-pot approach. Although Barbier's original used magnesium, zinc-mediated variants quickly became synonymous with the Barbier reaction, particularly for allylic halides, offering advantages in moisture tolerance. In the mid-20th century, expansions to alternative metals began, with Henri B. Kagan introducing samarium diiodide (SmI₂) in 1977 for intermolecular Barbier reactions, enabling milder conditions and broader functional group tolerance compared to traditional or magnesium systems. The 1980s saw further innovation with Jean-Louis Luche's development of aqueous -mediated Barbier allylations under ultrasonic irradiation, which facilitated water-tolerant conditions and enhanced selectivity for homoallylic alcohols without requiring anhydrous solvents. The 1990s marked the advent of indium-mediated variants, first reported by Li and Chan in 1991, which offered high efficiency in aqueous media and compatibility with sensitive substrates, alongside early asymmetric implementations using chiral ligands to achieve enantioselective additions, as demonstrated in a 1997 catalytic allylation protocol. Into the , a push toward emphasized solvent-free and mechanochemical methods, reducing environmental impact while maintaining yields comparable to classical setups. Post-2010 developments have focused on , including a 2023 mechanochemical adaptation of the magnesium-mediated Barbier reaction that serves as an air- and moisture-stable alternative to traditional Grignard synthesis, enabling efficient coupling of diverse halides and carbonyls under ball-milling conditions. Recent water-compatible variants, such as those incorporating under mechanochemical activation with added water, have advanced sustainable synthesis by minimizing organic solvents and supporting eco-friendly assembly, as highlighted in a 2024 review of Barbier applications in complex construction.

Reaction Mechanism

In Situ Organometallic Generation

The in situ organometallic generation in the Barbier reaction initiates via a single-electron transfer (SET) process, in which the metal—typically or magnesium—donates an to the alkyl (R-X), yielding an alkyl radical (R•) and a anion (X⁻). This SET step is rate-determining for the to the metal, as evidenced by kinetic studies and linear free energy relationships (LFERs) showing structure-reactivity dependencies consistent with rather than a two-electron process. Theoretical modeling using semiempirical calculations on model systems like and supports this pathway, highlighting the formation of a intermediate (R-X^{•-}) that dissociates rapidly to the alkyl radical and . Although the mechanism is generally understood to involve SET and radical intermediates, it remains partially debated, with alternative proposals including two-electron transfers or direct organometallic formation without free radicals. The alkyl radical subsequently reduces a second metal atom, forming the organometallic species (R-M) along with a metal-halide pair (M^+ X^-). For zinc-mediated reactions, this leads to transient organozinc halides (R-ZnX) as the key reactive intermediates, which are generated directly within the reaction mixture without prior isolation or conditions typical of preformed reagents. This approach contrasts with traditional Grignard preparations by enabling a one-pot procedure tolerant to protic solvents. Several factors influence the efficiency of this generation phase, including metal surface activation to facilitate SET. Techniques such as ultrasonic irradiation clean and activate the metal surface, promoting radical processes by effects that enhance electron donation. Additives like metal salts (e.g., CeCl_3) further accelerate the reaction by modifying the metal's . Evidence for the radical pathway includes radical clock experiments showing negligible cyclization products from substrates designed to detect free alkyl radicals, indicating short-lived or caged intermediates.

Nucleophilic Addition and Product Formation

In the Barbier reaction, the second phase of the mechanism involves the of the in situ-generated organometallic species (R-M, where M is typically Zn or Mg) to the electrophilic of an (R'-CHO) or (R'-CO-R''). This addition proceeds via a direct nucleophilic attack at the carbonyl carbon, forming a tetrahedral intermediate, such as R-CH(O⁻M⁺)-R' for aldehydes. The process mirrors classical organometallic additions, with the carbanionic carbon of R-M bonding to the carbonyl carbon while the oxygen coordinates to the metal cation. Upon completion of the addition, the intermediate undergoes during aqueous or in the presence of a , yielding the corresponding alcohol product, R-CH(OH)-R' from aldehydes (secondary alcohols) or R-C(OH)(R')(R'') from ketones (tertiary alcohols). This step is typically rapid and quantitative under standard conditions, ensuring high conversion to the desired homoallylic or alkyl-substituted alcohol. Side reactions, such as pinacol coupling (reductive dimerization of two carbonyl molecules to a 1,2-diol via single-electron transfer pathways) or β-elimination, can compete but are generally minimized by optimized conditions including excess metal, controlled polarity, or mechanochemical activation to favor the desired addition pathway. Stereochemical outcomes of the addition are governed by either control, where an α-coordinating group (e.g., oxygen or ) forms a five- or six-membered ring with the metal, directing nucleophilic approach to the less hindered face (Cram-chelate model), or non-chelated Felkin-Anh control, positioning the largest substituent anti to the incoming for axial attack in rigid systems. These models enable predictable diastereoselectivity, often exceeding 90:10 in chelation-assisted cases with α-alkoxy aldehydes.

Scope and Conditions

Standard Reaction Setup

The standard zinc-mediated Barbier reaction is performed by combining an alkyl or allyl halide, a carbonyl compound (typically an or ), and excess powder in a suitable , allowing for the in situ generation of an organozinc species that undergoes to the carbonyl. This one-pot protocol avoids the need for isolating air-sensitive intermediates, distinguishing it from traditional Grignard methodologies. Typically, 2–5 equivalents of dust relative to the carbonyl substrate are employed, with bromides and iodides preferred as halides due to their superior reactivity compared to chlorides, which often require activated or harsher conditions. Aldehydes generally react more efficiently than ketones, affording higher yields and cleaner product profiles. Common solvents include (THF) mixed with saturated aqueous (e.g., 5:1 THF:H₂O), pure , or ; serves as a mild proton source to facilitate activation without promoting side reactions. The mixture is stirred vigorously at 0–25 °C for 1–24 hours, often under an inert atmosphere to minimize oxidation, though aqueous conditions enhance tolerance to air and moisture. Reaction progress is monitored by (TLC) or (GC), observing the disappearance of starting materials. Upon completion, the reaction is quenched with aqueous or dilute acid, followed by to remove unreacted , extraction with an organic solvent such as or , drying over , and purification via or . Isolated yields for the classic setup typically range from 60% to 90%, depending on substrate compatibility and reaction scale.

Substrate Scope and Selectivity

The Barbier reaction displays a varied substrate scope with respect to organic halides, where reactivity is highest for allylic and benzylic systems due to facilitated organometallic formation and reduced tendency for side reactions. These halides routinely afford addition products in high yields, often 70-95%, as seen in the zinc-mediated coupling of with aliphatic aldehydes in THF. In contrast, simple primary or secondary alkyl halides exhibit lower reactivity, yielding products in 20-50% ranges under standard conditions, primarily because of competing reductions and eliminations that diminish efficiency. Alkyl fluorides are generally incompatible, showing negligible reactivity owing to the inertness of the C-F bond. Carbonyl compounds as electrophiles also show differential compatibility, with aldehydes providing the broadest scope and highest efficiency. Aromatic and aliphatic aldehydes react smoothly to give homoallylic alcohols in 70-95% yields, even with unactivated allylic halides. Ketones are viable but moderately less reactive, delivering 50-80% yields influenced by steric bulk around the carbonyl, as demonstrated in zinc-promoted additions to derivatives. Esters and amides perform poorly, often resulting in low yields (<30%) due to susceptibility to over-addition or hydrolysis under the reaction conditions. Selectivity profiles enhance the utility of the Barbier reaction in stereocontrolled synthesis. For α-alkoxy-substituted carbonyls, diastereoselectivity adheres to the Cram chelate model, coordinating the metal to both the carbonyl oxygen and the α-alkoxy group to direct nucleophilic approach. Allylic halides exhibit regioselectivity favoring the SN2' pathway, particularly with or mediation, to produce branched γ-adducts over linear α-products in ratios up to 90:10 depending on substitution. Key limitations include moisture sensitivity in magnesium variants, which require strictly environments to prevent quenching of the nascent organomagnesium species, whereas zinc-based protocols in THF offer improved tolerance. Additionally, β-elimination can generate byproducts from substrates with β-hydrogens, reducing overall yields by 10-30% in affected cases.

Variations

Asymmetric Barbier Reactions

The asymmetric Barbier reaction extends the classical one-pot allylation protocol to achieve enantioselectivity through the incorporation of chiral auxiliaries or catalysts, enabling the synthesis of enantioenriched homoallylic alcohols from achiral aldehydes and allyl halides. These methods typically involve low-valent metals like or , where the chiral component directs the via coordination or control, often attaining high enantiomeric excesses () while maintaining the reaction's aqueous tolerance and simplicity. Chiral ligands, particularly amino alcohols, have been employed with to promote enantioselective allyl additions to , with reported ee values up to 95% in optimized systems. For instance, β-amino alcohols facilitate , forming a rigid bidentate complex that shields one face of the aldehyde during nucleophilic attack by the in situ-generated allylzinc , thus enforcing selectivity. This mechanism is analogous to that in related organozinc additions and has been demonstrated in THF or aqueous media at mild temperatures. Catalytic variants utilizing transition metals such as or with chiral ligands enable enantioselective allylation under Barbier conditions, building on early developments in asymmetric . Copper-catalyzed systems, for example, promote γ-selective alkyl-allyl couplings with chiral ligands, achieving ee >90% for a range of substrates by stabilizing the allylcopper intermediate and directing through ligand-metal interactions. More recent advancements include ligand-free approaches with chiral-at-metal complexes, such as cobalt-based catalysts, which deliver high ee (up to 99%) in photoredox-assisted variants without additional chiral additives, leveraging inherent metal for control. Representative applications highlight the utility in natural product synthesis, such as the diastereoselective preparation of intermediates for compounds like deoxyelephantopin via zinc-mediated Barbier allylation, yielding single diastereomers in 80% yield through chelate-controlled addition to chiral aldehydes. Recent developments in the 2020s emphasize scalable asymmetric aqueous variants, including cobalt-photoredox systems for allylation with unactivated alkyl iodides, providing tertiary alcohols with ee up to 99% and yields >80% on multigram scales, suitable for industrial applications due to their mild, water-compatible conditions. These advances prioritize broad substrate scope and minimal waste, distinguishing them from earlier stoichiometric methods.

Modified Conditions and Alternative Metals

Adaptations of the Barbier reaction have incorporated alternative metals to enhance compatibility with aqueous environments and expand substrate tolerance. metal, introduced in the early 1990s, facilitates Barbier-type allylations of aldehydes and ketones in , delivering homoallylic alcohols in yields typically ranging from 70% to 95% without requiring anhydrous conditions. This approach leverages 's low reactivity toward , enabling clean C-C bond formation under mild, eco-friendly setups. Samarium diiodide (SmI₂), a versatile single-electron transfer reagent, supports Reformatsky-like variants where α-halo esters add to carbonyl compounds, often achieving high and yields above 80% in THF or solvents. Magnesium, traditionally associated with Grignard chemistry, can be used in ethereal solvents like to perform one-pot Barbier reactions, emulating isolated organomagnesium additions while tolerating the presence of the from the outset. Modified reaction conditions have further broadened the utility of the Barbier reaction toward and efficiency. Mechanochemical methods, employing ball milling, enable solvent-free allylations with or magnesium, as demonstrated in 2023 developments that couple allyl s with carbonyls in yields up to 90%, minimizing waste and avoiding traditional solvents. activation accelerates metal insertion and reduction, a technique established in the late that promotes reactions in aqueous or protic media, often completing in minutes with enhanced yields for unactivated metals like magnesium or . Protic media, such as water-tetrahydrofuran (THF) mixtures, support green syntheses particularly with or , where saturated aqueous in THF facilitates high-yield additions to aldehydes while suppressing side reactions through controlled . These modifications have extended the reaction's scope to specialized applications. Barbier polyaddition reactions, adapted in the and refined in the , utilize dihalide and monomers to synthesize polymers, though challenges such as polydispersity control and molecular weight limitations persist, with recent advances achieving number-average molecular weights up to 10,000 g/mol. Tandem Barbier processes with imines, often generated from aldehydes and amines, enable direct access to α-branched amines via allylation of transient ions, providing yields of 60-85% in multicomponent setups mediated by tin or in aqueous media. Throughout these variants, the core mechanism of organometallic generation and remains consistent with the standard reaction.

Applications and Comparisons

Synthetic Applications

The Barbier reaction has been widely employed in the of complex natural products, particularly and carbohydrates, due to its ability to form carbon-carbon bonds under mild, one-pot conditions. In the synthesis of thuggacin cmc-A, a with potent activity against , an indium-mediated Barbier propargylation served as a key step to install a propargyl unit on an intermediate, delivering the coupled product in 91% yield as a single and enabling the first determination of its absolute structure. Similarly, zinc-mediated Barbier allylation has been utilized in the construction of sugar scaffolds; for example, in a divergent synthesis starting from D-ribose, the reaction of an with a protected ribose-derived enone afforded a cyclohexenyl intermediate in 90% yield, which was further elaborated into allo-inositol and conduritol E, bioactive cyclitols with applications in glycosidase inhibition. In , the Barbier reaction excels at constructing β-hydroxy motifs prevalent in pharmaceutical analogs, offering high diastereoselectivity for chiral drug-like structures. A notable application is the first asymmetric of salinosporamides B and D, marine-derived inhibitors with anticancer potential; here, an indium-mediated Barbier allylation between an α,β-unsaturated and crotyl bromide provided the β-hydroxy core in 70–71% yield over two steps as a single , streamlining access to these analogs for structure-activity studies. Recent In-mediated variants have extended this utility to synthesis; in the 2021 of (–)-arborisidine, a Kopsia , an asymmetric Barbier-type addition of to harmalane generated a quaternary center in 51% yield, facilitating the cage-like pentacyclic framework. The one-pot nature of the Barbier reaction lends itself to scalable pharmaceutical processes, as demonstrated in the development of a continuous-flow variant for producing a benzylic alcohol intermediate in the synthesis of edivoxetine, a for psychiatric disorders; this approach achieved >99% conversion at 1.3 kg/h scale using activation in aqueous media. Its compatibility with water and low metal loadings also supports by minimizing waste in multi-step sequences, reducing process mass intensity by over 30% relative to traditional Grignard methods and avoiding conditions. Asymmetric variants of the Barbier reaction have further enhanced its value for chiral targets in drug and synthesis. The Barbier reaction contrasts with the in its one-pot procedure, where the organic halide, carbonyl , and metal (typically magnesium or ) are combined directly to generate the organometallic species , avoiding the need for preformation under conditions required by the Grignard method. This approach enables the Barbier reaction to proceed in the presence of water and protic solvents, tolerating functional groups that would quench traditional Grignard reagents, and it simplifies operations especially for allylic systems where yields remain comparable. In practice, the Barbier method reduces handling risks and is particularly useful when Grignard reagents prove unstable or incompatible with substrates. Compared to the Reformatsky reaction, another zinc-mediated process, the Barbier reaction offers broader applicability by accommodating a wider range of organic halides and carbonyl compounds for general alcohol synthesis. The Reformatsky reaction, however, is tailored specifically to α-halo esters, forming β-hydroxy esters under milder conditions that suit acid-sensitive substrates, though its scope is narrower and often requires organic solvents rather than the aqueous tolerance of many Barbier variants. The Nozaki-Hiyama-Kishi (NHK) reaction, employing (with catalysis) for allylation or vinylation of aldehydes and ketones, provides superior stereocontrol and diastereoselectivity in complex syntheses, making it preferable for assemblies demanding precise geometry. In contrast, the Barbier reaction uses more economical metals like for similar allylic additions but at the expense of stereochemical precision, prioritizing simplicity and lower cost over advanced selectivity. Overall, the Barbier reaction excels in principles through its simplicity, aqueous compatibility, and use of abundant metals, facilitating sustainable carbon-carbon bond formation. Nonetheless, it faces limitations in tolerance relative to organocopper variants, which offer enhanced selectivity and compatibility with electrophilic moieties in conjugate additions and polyfunctionalized settings.

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