Mason Delacroix
Aryl ether synthesis by etherification (arylation) involves the conversion of aryl alcohols to aryl tertbutoxide. This process is facilitated by transition-metal-catalysed reactions, utilising aryl halides and primary alcohols to yield alkyl aryl ethers. Lithium alkoxide is crucial for successful coupling, either directly or generated in situ, with the corresponding alcohol acting as a solvent. Tert-butoxide, specifically, enables Cu-catalysed alkoxylation of aryl iodides at room temperature, as demonstrated in recent research. Additionally, sodium tert-butoxide serves as the sole activator in the transition-metal-free borylation of aryl halides, resulting in a broad range of organohalide borylation with excellent chemoselectivity.
| Characteristics | Values |
|---|---|
| Synthesis method | Etherification by etherification (arylation) |
| Catalyst | Copper |
| Ligands | Oxalic diamides |
| Reaction type | Cu-catalyzed coupling reaction |
| Reactants | Hetero)aryl halides, ortho-substituted diaryliodonium salts, primary alcohols |
| Products | Alkyl aryl ethers, tertiary alkyl aryl ethers |
| Temperature | Room temperature |
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What You'll Learn
Aryl ether synthesis by etherification (arylation)
Palladium-catalyzed reactions are commonly used in aryl ether synthesis. This method involves the reaction of aryl halides, including activated, non-activated, and (hetero)aryl bromides, as well as aryl chlorides, with primary alcohols. The presence of a bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand is crucial for achieving high yields of the corresponding alkyl aryl ethers. This process demonstrates excellent selectivity when functionalizing primary alcohols in the presence of secondary and tertiary alcohols.
Transition-metal-free arylation is another approach that enables the synthesis of tertiary alkyl aryl ethers with unprecedented steric congestion. This method utilizes ortho-substituted diaryliodonium salts and can be applied to a range of tertiary alcohols, including cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols, as well as primary and secondary fluorinated alcohols.
Copper-catalyzed reactions play a significant role in aryl ether synthesis. Cu-catalyzed alkoxylations of (hetero)aryl halides, specifically aryl iodides, can be facilitated by tert-butoxide at room temperature. Self-assembled octanuclear copper clusters enable the coupling of aryl iodides with alcohols under mild conditions. Additionally, the use of lithium alkoxide, particularly lithium tert-butoxide, is crucial for successful copper-catalyzed ether formation from aryl halides and aliphatic alcohols.
Phenols and vinyl halides can undergo a cross-coupling reaction through a unique Ni/Cu catalytic system, providing access to a library of aryl-vinyl and aryl-styrenyl ethers. This protocol offers an efficient and convenient approach to aryl ether synthesis.
Nucleophilic substitution reactions involving benzyl methyl carbonates and phenols, in the presence of a catalyst, yield aryl benzyl ethers. This method is well-documented in the literature.
Diaryliodonium tosylates and phenols, in the presence of potassium carbonate in acetonitrile, efficiently produce unsymmetrical diaryl ethers with high regioselectivities. This reaction provides access to a range of diaryl ether structures.
In conclusion, aryl ether synthesis by etherification (arylation) encompasses various catalytic methods, including palladium, copper, nickel, and transition-metal-free reactions. The choice of method depends on the specific reactants and desired products, with each technique offering unique advantages and applications in organic synthesis.
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Transition-metal-free arylation of tertiary alcohols
The key to this transition-metal-free arylation process is the use of ortho-substituted diaryliodonium salts as reactive electrophilic arylation agents. These salts enable the synthesis of tertiary alkyl aryl ethers with unprecedented steric congestion, which has been challenging with traditional methods. The scope of this methodology covers a wide range of tertiary alcohols, including cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols, as well as primary and secondary fluorinated alcohols.
One of the critical advantages of this method is its compatibility with a broad range of nucleophiles and aryl groups. The use of diaryliodonium salts facilitates the arylation of nucleophiles, and their reactivity allows for the synthesis of various aryl ethers. This versatility extends to the arylation of the pro-drug mestranol, demonstrating the tolerance of steric bulk within the methodology.
The reaction conditions for transition-metal-free arylation of tertiary alcohols are mild and typically involve low temperatures and short reaction times. For example, a reaction employing diaryliodonium salts and sodium hydroxide in water at low temperature successfully arylates phenols to diaryl ethers with good to excellent yields. This mild and metal-free protocol avoids the use of excess coupling partners, making it a more efficient and cost-effective process.
In conclusion, the transition-metal-free arylation of tertiary alcohols with ortho-substituted diaryliodonium salts provides a powerful tool for synthesizing sterically congested alkyl aryl ethers. This method offers a straightforward and versatile approach to accessing structurally complex molecules, making it a valuable technique in synthetic organic chemistry and drug discovery.
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Palladium-catalyzed reactions of aryl halides
One example of a palladium-catalyzed reaction of aryl halides is the synthesis of aryl tert-butoxide. Tert-butoxide enables a Cu-catalyzed alkoxylation of aryl iodides at room temperature. This reaction can be catalyzed by self-assembled octanuclear copper clusters, which couple aryl iodides with alcohols under mild conditions.
Transition-metal-free arylation of tertiary alcohols with ortho-substituted diaryliodonium salts enables the synthesis of tertiary alkyl aryl ethers with unprecedented steric congestion. Cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols, as well as primary and secondary fluorinated alcohols, can be converted through this method.
Palladium-catalyzed amination of aryl halides with aqueous ammonia and a hydroxide base has also been achieved through ligand development. This reaction has been a long-standing synthetic challenge due to the competing hydroxylation and the high concentration of water, which affects catalyst stability. However, the development of a new ligand (KPhos) based on a bipyrazole backbone has enabled the selective formation of primary arylamines with a broad scope of aryl and heteroaryl halides.
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Potassium tert-butoxide in synthesis
Potassium tert-butoxide (commonly abbreviated to KOt-Bu or KOtBu) is a strong base that is widely used in organic synthesis. It is particularly useful when a strong, bulky, poorly nucleophilic base is required for a reaction.
One of its key advantages is its ability to perform reactions typically carried out using transition metals, but with improved environmental congruence and reduced economic cost. For example, it can be used in the synthesis of substituted phenanthridinones and dibenzoazepinones from N-phenyl-2-halobenzamides or N-phenyl-2-(2-halophenyl)acetamides, respectively, in the presence of a catalytic amount of 1,10-phenanthroline or AIBN. This reaction provides direct access to various biaryl lactams containing six- and seven-membered rings chemoselectively.
Potassium tert-butoxide is also commonly used in the construction of C–C, C–O, C–N, and C–S bonds, as well as in coupling, alkylation, arylation, α-phenylation, cyclization, Heck-type, annulation, photo-arylation, aromatic substitution, amidation, and silylation reactions. Its role in these reactions is to mediate the formation of the desired bonds with good to excellent yields.
In addition, potassium tert-butoxide plays a crucial role in electron transfer reactions. It has been used in studies investigating the coupling reactions of halobenzenes and arenes, reductive cleavages of dithianes, and SRN1 reactions. While direct electron transfer from KOtBu has been observed in certain cases, the literature generally supports the in situ formation of organic electron donors.
Furthermore, potassium tert-butoxide enables Cu-catalyzed alkoxylation of aryl iodides at room temperature. This reaction involves the coupling of aryl iodides with alcohols under mild conditions, demonstrating the versatility of potassium tert-butoxide in organic synthesis.
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Sodium tert-butoxide as an activator
Sodium tert-butoxide, also known as sodium t-butoxide, is a chemical compound with the formula (CH3)3CONa, often abbreviated as NaOtBu. It is a strong, non-nucleophilic base with reactivity similar to the more common potassium tert-butoxide. This compound is moisture-sensitive and flammable, requiring careful handling.
Sodium tert-butoxide serves as an effective activator in organic chemistry, particularly in the activation and discovery of earth-abundant metal catalysts. It enables the use of sustainable first-row transition metals, such as iron, cobalt, nickel, and manganese, as alternatives to precious-metal catalysts. This application offers a more inexpensive and sustainable approach for various reactions.
One notable use of sodium tert-butoxide is in the Buchwald-Hartwig amination, where it acts as a non-nucleophilic base. It is also employed in the synthesis of tert-butoxide complexes, such as hexa(tert-butoxy)ditungsten(III). Additionally, sodium tert-butoxide facilitates Cu-catalyzed alkoxylation of aryl iodides at room temperature, contributing to the formation of aryl ethers.
Furthermore, sodium tert-butoxide plays a crucial role in etherification (arylation) reactions. It promotes the coupling of aryl halides, including aryl bromides and aryl chlorides, with aliphatic alcohols to form alkyl aryl ethers. This process is catalyzed by palladium and can be highly selective, particularly with functionalized primary alcohols in the presence of secondary and tertiary alcohols.
Sodium tert-butoxide's versatility extends to its involvement in transition-metal-free arylation reactions. These reactions enable the synthesis of tertiary alkyl aryl ethers with unprecedented steric congestion. A range of tertiary alcohols, including cyclic and acyclic aliphatic, benzylic, allylic, and propargylic varieties, can undergo this transformation.
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