DBU Reagent Reaction Revolutionizes Organic Synthesis

General Description

DBU is an amidine compound with the molecular formula C9H16N2 and a systematic name 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS number: 6674-22-2). Its structure consists of a bicyclic framework formed by two nitrogen atoms in a spiro arrangement bridged by seven carbon atoms.

Molecular Formula of DBU
Molecular Formula of DBU

The chemical structure of DBU not only imparts remarkable stability but also endows it with exceptional basicity as its lone pairs of electrons are highly accessible for coordination with various reactants.

This unique structural feature enables DBU to act as both a nucleophilic catalyst and a strong base in organic reactions.

Its high stability and low vapor pressure make it easy to handle, ensuring safety during large-scale processes. DBU offers an eco-friendly alternative compared to traditional hazardous bases like sodium hydroxide or Sodium tert-butoxide.

Its compatibility with various solvents and reagents further adds to its appeal.

Overview of DBU’s role in various reactions

DBU, or 1,8-diazabicyclo[5.4.0]undec-7-ene, is a compound that plays a pivotal role in a wide range of organic reactions.

Deprotonation Reaction

As a strong base, DBU excels in deprotonation reactions such as carboxylation or esterification reactions where it facilitates the formation of carbanions or enolates, crucial intermediates in the synthesis of pharmaceuticals and natural products.

Elimination Reaction

DBU’s high basicity allows for efficient elimination reactions, such as E2 elimination or Hofmann degradation, leading to the formation of alkenes or alkynes from suitable precursors.

As a Nucleophilic Catalyst

Furthermore, DBU’s role as a nucleophilic catalyst enhances its versatility even further. It functions as a complexing ligand in transition metal-catalyzed reactions, facilitating the activation of substrates and promoting selective bond formations.

Cyclization Reactions

DBU is commonly used in cyclization reactions to form heterocyclic compounds. It can facilitate the formation of pyridines, pyrimidines, quinolines, and other heterocycles through intramolecular reactions.

Its ability to act as a strong base, a nucleophilic catalyst, and a complexing ligand makes it a versatile reagent in organic synthesis.

Application of DBU in Deprotonation Reactions

Deprotonation of Acidic Protons in Organic Compounds

DBU finds significant applications in deprotonating carboxylic acids, alcohols, and amides.

Carboxylic acids are among the most commonly encountered acidic protons in organic chemistry.With DBU as a catalyst, these acids undergo deprotonation reactions efficiently. For example, esterification reactions involving carboxylic acids require their prior deprotonation to form active intermediates that can undergo nucleophilic substitution or addition reactions.

DBU’s ability to efficiently promote this deprotonation step contributes to its success as a catalyst for various synthetic transformations. Similarly, alcohols and amides can also be effectively deprotonated by DBU.

In alcohol-based reactions such as acylation or carbonylation processes, the initial conversion of alcohol into its corresponding alkoxide facilitates subsequent steps involving nucleophilic additions or substitutions. The use of DBU as a catalyst not only accelerates these transformations but also unlocks new prospects for the synthesis of complex molecules.

Factors Affecting DBU Deprotonation

It involves evaluating parameters like solvent polarity, temperature, steric hindrance around the protonated site, and the basicity of DBU itself. Carefully controlling these factors allows chemists to finely tune the deprotonation process, ensuring high yields and selectivity in the synthesis of anionic intermediates.

Deprotonation for the Synthesis of Anionic Intermediates

Harnessing Carbanion Stability One of the remarkable applications of DBU-catalyzed deprotonation is in generating stabilized carbanions as key intermediates for subsequent transformations. Carbanions are highly reactive species that can undergo a variety of reactions, enabling access to diverse molecular structures.

However, their inherent reactivity also renders them challenging to handle and manipulate directly. Therefore, DBU plays a crucial role by facilitating controlled generation of these anionic intermediates.

By serving as a strong base, DBU selectively abstracts acidic protons from appropriate carbon sites, leading to carbanion formation. The resultant stabilized carbanions can then participate in various chemical reactions including nucleophilic additions or substitutions.

For instance, in pharmaceutical synthesis, DBU-catalyzed carbanions often act as key building blocks for constructing complex drug molecules or natural products. Moreover, this synthetic strategy involving carbanion generation finds relevance across diverse fields such as polymer chemistry and fine chemicals production.

In polymerization processes where controlled chain growth is desired, utilizing DBU’s nucleophilic catalyst properties aids in precisely initiating polymerization reactions via well-controlled generation and subsequent reactions with activated monomers. The application of DBU as a catalyst for deprotonation reactions offers tremendous advantages in organic synthesis.

Elimination reactions involving β-hydrogens

E2 elimination, Hofmann elimination

Elimination reactions are fundamental transformations in organic chemistry that involve the removal of certain atoms or groups from a molecule to form a double bond or triple bond. DBU, with its strong basic properties and ability to act as a nucleophile, plays a crucial role in facilitating different types of elimination reactions. One common type of elimination reaction is the E2 (bimolecular) elimination, where the leaving group and a β-hydrogen are eliminated simultaneously.

This process occurs via a concerted mechanism, wherein DBU acts as both a base and nucleophile. E2 eliminations are widely utilized in organic synthesis for the preparation of alkenes or alkynes from appropriate precursors.

For example, in the synthesis of 1-alkenes, DBU can deprotonate a β-hydrogen adjacent to a leaving group (e.g., halide) attached to an alkyl chain. The resulting carbanion is then able to eliminate the leaving group through an E2 mechanism.

This method offers an advantageous route for synthesizing alkenes due to its simplicity and high efficiency. Another notable elimination reaction involving DBU is the Hofmann elimination.

Hofmann elimination: In this case, DBU facilitates the removal of an amine functional group from quaternary ammonium salts by abstracting one of its α-protons adjacent to the nitrogen atom. The resulting carbanion then eliminates one equivalent of amine under basic conditions, leading to Hofmann rearrangement products with one less carbon atom compared to the starting material.

Mechanism and regioselectivity considerations

In both E2 and Hofmann eliminations involving DBU as the catalyst or reagent, several factors influence regioselectivity – which refers to the preferred site at which elimination occurs. For E2 eliminations, the regioselectivity is primarily determined by the accessibility and acidity of the β-hydrogens. Generally, more acidic β-hydrogens are preferentially eliminated over less acidic ones.

Additionally, steric hindrance around the leaving group and the competing groups around the β-carbon also influence regioselectivity. In Hofmann eliminations, regioselectivity is influenced by factors such as electronic effects and steric hindrance.

The nature of substituents on the amine nitrogen affects their basicity, which in turn influences regioselectivity. A more basic nitrogen atom favors elimination of an α-proton closer to it, resulting in a different product distribution compared to less basic nitrogen atoms.

These elimination reactions employing DBU have found extensive use in various industrial applications. For instance, in polymer synthesis, DBU-mediated E2 eliminations provide a practical method for preparing conjugated polymers with π-conjugated systems that exhibit desirable electronic properties.

Moreover, these elimination reactions are also employed in fine chemical synthesis where selective formation of alkenes or alkynes is required as key steps for building complex molecular architectures. By harnessing DBU’s reactivity as a catalyst or reagent in elimination reactions involving β-hydrogens, chemists have unlocked new possibilities for synthesizing valuable compounds with diverse applications across multiple fields.

Application of DBU as a Nucleophilic Catalyst

Addition Reactions Involving Electrophiles

DBU’s unique properties make it an excellent nucleophilic catalyst for addition reactions, where it acts as a powerful base to promote the reaction between electrophiles and nucleophiles.

One example is the Michael addition, where DBU facilitates the addition of a nucleophile to an α,β-unsaturated carbonyl compound. This reaction is widely used in the synthesis of pharmaceuticals and fine chemicals.

Another remarkable application is DBU-catalyzed carboxylation reactions. In this process, DBU activates carbon dioxide and adds it to various electrophilic substrates, such as alkyl halides or aryl halides.

This methodology allows for the efficient synthesis of carboxylic acids under mild conditions and has gained significant attention in recent years due to its environmentally friendly nature. Furthermore, DBU can also catalyze esterification reactions by facilitating the addition of alcohols to carboxylic acid derivatives.

This transformation finds extensive use in organic synthesis for constructing ester bonds efficiently. The advantages of using DBU as a catalyst in these addition reactions lie in its high reactivity, broad substrate scope, and ability to operate under mild reaction conditions without requiring expensive or toxic metals.

Examples

Application of DBU in Synthesis of Amidine Compounds

One notable example showcasing DBU’s versatility as a nucleophilic catalyst is its application in amidine compound synthesis. Amidines are valuable building blocks employed in medicinal chemistry and agrochemical industries due to their broad spectrum of biological activities. By utilizing DBU as a catalyst, researchers have successfully achieved efficient amidine formation through nucleophilic addition reactions between nitriles and primary or secondary amines.

Application of DBU in the Field of Complex Ligands

Another intriguing application lies in the field of complexing ligands. Complexes formed between transition metals and chelating ligands play a vital role in various catalytic processes. DBU has shown promise as a nucleophilic catalyst for the synthesis of ligands that can efficiently coordinate to metal ions, facilitating the formation of stable metal complexes. This has opened up new avenues in designing catalysts for industrial applications such as cross-coupling reactions or asymmetric catalysis.

Application of DBU in Cyclization Reactions

DBU is a strong, nucleophilic base that is commonly used to promote cyclization reactions by deprotonating certain sites on a molecule to generate nucleophilic centers or anions.

DBU is also useful for anionic polycyclization reactions. It can sequentially deprotonate sites on a polyunsaturated compound to generate stabilized carbanions which can cyclize in a domino-like manner. A classic example is the Nazarov cyclization.

– In the Nazarov cyclization, DBU deprotonates the β-position of a divinyl ketone, generating a pentadienyl anion which then cyclizes in an electrocyclization reaction to form a cyclopentenone. The mechanism proceeds through a 4π conrotatory electrocyclic ring closure.

Examples of DBU Organic Responses

Here are some specific examples of organic reactions where DBU is commonly used:

  1. Cyclizations: DBU has been utilized in the synthesis of various heterocyclic compounds through cyclization reactions. For example, it has been employed in the synthesis of pyridines, pyrimidines, and quinolines.
  2. Eliminations: DBU can act as a base in elimination reactions. It has been used in the elimination of hydrogen halides from alkyl halides to form alkenes.
  3. Reductions: DBU has been employed in reduction reactions. It has been used to reduce nitrobenzenes, nitrosobenzene, and phenylhydroxylamine.
  4. Amidations: DBU has been used as an additive in amidation reactions. It has been employed in the amidation of 7-methoxycarbonylpterin, which facilitated the development of new pterins.
  5. β-Lactam Synthesis: DBU has been utilized in the synthesis of β-lactams, which are important structural motifs found in many biologically active compounds.
  6. β-Amino Acid Synthesis: DBU has been used in the synthesis of β-amino acids, which are valuable building blocks in organic synthesis and pharmaceutical chemistry.
  7. α-Amino Phosphonate Synthesis: DBU has been employed in the synthesis of α-amino phosphonates, which are important intermediates in the preparation of bioactive compounds.

Conclusion

The application of DBU as a nucleophilic catalyst has demonstrated remarkable potential in various addition reactions involving electrophiles. Its unique basic properties, such as high reactivity and broad substrate scope, make it an attractive choice for synthetic chemists.

From enabling efficient carboxylation reactions to facilitating esterification and amidine synthesis, DBU provides significant advantages in terms of reaction efficiency and environmental sustainability. As research continues to explore novel applications of DBU as a nucleophilic catalyst, prospects for its utility in diverse chemical transformations are bright.

The development of new methodologies utilizing DBU opens up exciting avenues in organic synthesis, offering safer and more sustainable alternatives to traditional approaches.

References

Lihan Zhu, Hai-Yan Yuan, and Jingping Zhang. “Mechanistic investigation-inspired activation mode of DBU and the function of the α-diazo group in the reaction of the α-amino ketone compound and EDA: [DBU-H]+-DMF-H2O and α-diazo as strong N-terminal nucleophiles.” Organic Chemistry Frontiers 6, no. 15 (2019): 2678-2686.

Boddu, S. K., Najeeb Ur Rehman, Mohanta, T. K., Majhi, A., Avula, S. K., et al. (2022). A review on DBU-mediated organic transformations. Green Chemistry Letters and Reviews, 15(3), 765-795. DOI: 10.1080/17518253.2022.2132836.

IstváN. Hermecz, Chemistry of Diazabicycloundecene (DBU) and Other Pyrimidoazepines, Editor(s): Alan R. Katritzky, Advances in Heterocyclic Chemistry, Academic Press, Volume 42, 1987, Pages 83-202, ISSN 0065-2725, ISBN 978012020642.

Boddu, S.K., Rehman, N.U., Mohanta, T.K., Majhi, A., Avula, S.K., & Al-Harrasi, A. (2022). A review on DBU-mediated organic transformations. Green Chemistry Letters and Reviews, 15(3), 765-795.

1,8-Diazabicyclo(5.4.0)undec-7-ene – Wikipedia

Common Organic Chemistry. “DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) – chemical structure, common uses, and safety.

Microwave-assisted synthesis of hydroxyl-containing isoquinolines by metal-free radical cyclization of vinyl isocyanides with alcoholsDengqi Xue, Hao Chen, Yulong Xu, Haihua Yu, Linqian Yu, Wei Li, Qiong Xie and Liming Shao
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