Alkynes and imines have long been staples in the chemist's toolkit because they combine structural versatility with high reactivity. Alkynes provide a linear, rigid, electron-deficient triple bond scaffold, allowing precise placement of two π-systems at the molecular scale. Imines, on the other hand, act like a molecular "wrench," offering both the lone pair of the sp2 nitrogen and the polarity of the C=N bond for chemical manipulation. Together, they equip molecules with dual capabilities: "vectorial growth" and "polarity switching."
Vectorial growth: from linear to three-dimensional
Alkynes can be converted into 1,2,3-triazoles through copper-catalyzed azide-alkyne cycloaddition (CuAAC), bending a linear bond angle of 180° to around 108° and introducing a metabolically stable, high-dipole fragment capable of forming multiple hydrogen bonds. Extending the linear scaffold is also possible by introducing silyl or boron groups at the alkyne terminus. Subsequent coupling reactions can append aromatic rings, alkenes, or even sugars, effectively creating a "molecular ruler" spanning 10–15 Å—ideal for probing protein–protein interaction surfaces.
Polarity switching: reversible and irreversible states of imines
The C=N bond in imines has an intermediate bond length and dipole moment, making it capable of acting both as a hydrogen-bond donor and acceptor. Its reversible nature allows hydrolysis under specific conditions, while reduction fixes it as a stable amine, altering polarity and membrane permeability. This dual property enables strategies such as temporary covalent binding, molecular pre-organization, and controllable locking of reactive intermediates.
Synergistic spatial design: alkynes and imines together
Combining alkynes and imines in a single molecule can trigger tandem cyclization reactions. One end undergoes copper-catalyzed azide-alkyne cycloaddition, while the other undergoes imine-alkyne cyclization, generating complex fused ring systems in a single pot. Such scaffolds occupy rare chemical space, offering both shape diversity and unique architectures for novel molecular design.
Heterocycles are central to small molecule design, and alkynes and imines serve as highly efficient "cyclization engines," transforming linear precursors into five-, six-membered, or even spirocyclic systems under mild conditions. Moreover, they retain functional handles for further derivatization.
Five-membered nitrogen heterocycles: from click chemistry to multicomponent reactions
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) can rapidly generate 1,2,3-triazoles, with variants including thio-click, seleno-click, and photocatalytic click reactions. These enable scalable synthesis from milligram to gram quantities without protective groups. Coupling imines or isocyanides with alkynes in multicomponent reactions allows one-pot construction of imidazoline-2-carboxamides, providing versatile scaffolds for structure optimization.
Six-membered nitrogen heterocycles: polarity inversion and stereodivergence
Imines and alkynes can undergo [4+2] nitrogen hetero-Diels-Alder reactions to form dihydropyridines. Modern photocatalytic methods allow these reactions to proceed at room temperature with high E/Z selectivity. Introducing chiral ligands enables stereocontrol, yielding cis- or trans-tetrahydroquinolines with high diastereomeric ratios, offering flexibility in conformational optimization of active molecules.
Spirocycles and bridged rings: escaping planarity
Tandem cyclization of alkynes and imines can generate high-fsp3 spiro- or bridged ring systems, increasing three-dimensionality and enhancing protein binding selectivity. Cyclic imines reacting with diynes under Rh(I)-catalyzed [2+2+2] cycloaddition yield integrated bridged lactam scaffolds that lock aromatic rings in optimal angles, mimicking α-helices while keeping molecular weight low—ideal for multitarget designs.
Programmable late-stage functionalization
Even after ring formation, the residual reactivity of alkynes and imines remains valuable. Triazoles can undergo C-H functionalization to introduce sulfonyl, cyano, or fluorine groups. Imines can participate in Chan-Lam coupling to append aryl, alkenyl, or PEG chains, simultaneously improving solubility and stability. This enables efficient late-stage diversification, simplifying synthetic routes while preserving biological activity.
Alkynes and imines represent essential structural motifs in organic synthesis, and the development of efficient and highly selective methods for their construction has remained a focal point in contemporary chemistry. With continuous advancements in synthetic concepts and techniques, a range of modern strategies has emerged, enhancing reaction efficiency and expanding the scope of alkynes and imines in complex molecule assembly. This review systematically presents recent developments in modern synthetic strategies for alkynes and imines, emphasizing coupling and condensation reactions, catalyst-driven efficiency improvements, and the integration of electrochemical methodologies.
Among the numerous approaches for forming carbon-carbon and carbon-heteroatom bonds, coupling and condensation reactions occupy a central position due to their efficiency and atom economy. Particularly for the transformation of alkynes and imines, several innovative strategies have been developed in recent years.
Reductive coupling reactions represent a significant advancement in this domain. Traditional carbonyl and imine vinylation processes often rely on stoichiometric vinyl metal reagents or Nozaki-Hiyama-Kishi (NHK) reactions. Modern approaches, however, utilize alkynes as direct vinylmetal nucleophiles, enabling intermolecular enantioselective metal-catalyzed reductive couplings of carbonyls and imines. This strategy efficiently constructs allylic alcohol and allylic amine frameworks. By employing a convergent synthetic approach, these processes enable high-efficiency conversion from simple starting materials to complex molecules.
Multicomponent reactions, notably the classic A3 coupling (amine-aldehyde-alkyne three-component reaction), have long served as a powerful method for assembling propargylamines. Recently, an innovative variant termed the redox A3 reaction has emerged. Unlike conventional A3 couplings, the redox A3 approach incorporates an ammonium ion isomerization step, enabling α-alkynylation of amines. This transformation combines reductive N-alkylation with oxidative C–H functionalization in an overall redox-neutral process, eliminating the need for external oxidants or reductants.
Beyond alkyne participation, imine reactions with various metal reagents have shown broad applicability. For example, in the presence of catalytic In(OTf)3 (10 mol%), a range of aldehyde-derived imines react with tetraallyltin in a 2:1 molar ratio, providing the corresponding polyallylic amines in good yields. This methodology achieves high atom efficiency under mild conditions and offers a novel approach for the allylation of simple imines.
Catalyst design and selection are pivotal in achieving high efficiency and selectivity in alkyne and imine synthesis and transformations. Advances in catalysis, from traditional metal complexes to emerging single-atom catalysts, continue to drive progress in this field.
Nickel catalysts have demonstrated remarkable performance in intramolecular imine hydrovinylation. By employing large bite-angle diphosphine ligands in combination with Brønsted acids, researchers have developed highly efficient nickel-catalyzed systems capable of cyclizing imines with unactivated alkenes, yielding five- and six-membered cyclic allylic amines in high yields. Preliminary investigations into asymmetric variants suggest significant potential for synthesizing enantioenriched cyclic allylic amines, providing new avenues for chiral amine synthesis.
In the domain of hydroboration, n-butyllithium (n-BuLi) has proven effective as a simple, commercially available catalyst for hydroboration of imines and alkynes with HBpin. This catalytic system exhibits good functional group tolerance and short reaction times under mild conditions, with high chemoselectivity favoring imines over alkynes, providing a practical route to selective borylation. Computational studies have suggested plausible mechanistic pathways for n-BuLi-catalyzed imine hydroboration, offering insights for further optimization.
Platinum single-atom catalysts (Pt-SACs) represent the forefront of catalyst design. Pt-SACs supported on graphite carbon nitride nanosheets, synthesized via microwave-assisted methods, enable 1,2-diboration of sterically hindered alkenes and 1,2,2-triboration of alkynes with B2pin2. In the diboration of styrene, the catalyst achieves 99% yield with 95% selectivity, turnover numbers (TON) up to 3711, and turnover frequencies (TOF) of 247 h-1. Moreover, the catalyst promotes regioselective hydroboration of alkenes and alkynes, producing anti-Markovnikov alkylboranes and vinylboranes, respectively. Computational analyses indicate that enhanced reactivity on Pt-SACs arises from adsorption-induced weakening of key bonds (C=C and B–H), significantly lowering activation barriers.
Electrochemical synthesis has emerged as a green and sustainable strategy, offering unique advantages for alkyne and imine transformations. By using electrons as clean oxidants or reductants, electrochemical approaches avoid conventional chemical oxidants or reductants and reduce waste generation.
For constructing five-membered nitrogen heterocycles via alkyne cyclization, electrochemical methods provide multiple efficient routes. Indole frameworks can be assembled through electrochemical intramolecular cyclization of ureas with ethynyl groups, ortho-arylethynyl aniline cyclization, 2-ethynylaniline cyclization, selenation with 2-ethynylaniline, and C–H indolization of 2-ethynylaniline with 3-functionalized indoles. These strategies offer environmentally friendly routes to bioactive indole derivatives.
Isoindolinone synthesis is achieved via electrochemical cyclization of benzamide with terminal alkynes, 5-exo-dig nitrogen cyclization of 2-ethynylbenzamides, and reductive cascade cyclization of ortho-alkynyl benzamides. For pyrrole and imidazole synthesis, electrochemical cyclization of alkynes with enamides and tandem Michael addition/azidation/cyclization of alkynes, amines, and azides efficiently constructs these heterocycles.
In imine chemistry, electrochemical methods also demonstrate significant potential. Electro-generated acids (EGAs) have been used to synthesize imine-linked covalent organic frameworks (COFs). EGAs, formed via electrochemical oxidation of precursors on the electrode surface, act as effective Brønsted acid catalysts, facilitating imine bond formation between amine and aldehyde monomers. This process simultaneously deposits highly crystalline, porous COF films in situ.
Electrochemical strategies also facilitate the construction of 1,2,3-triazole systems. Electrochemical oxidative [3+2] cycloaddition of secondary propargyl alcohols provides a simple and efficient route to 1,2,3-triazoles. A defining feature of these electrochemical cyclizations is the use of electrons as clean reagents, eliminating the need for chemical oxidants or reductants and aligning with principles of green chemistry.
Alkynes and imines are essential intermediates and functional units in modern organic chemistry, widely applied in the construction of drug lead molecules, material chemistry, and the synthesis of high-value fine chemicals. BOC Sciences is dedicated to providing comprehensive custom organic synthesis services to research institutions and industrial clients, supporting the development of innovative synthetic pathways for these key compounds. Leveraging an extensive reaction library, advanced laboratory platforms, and deep technical expertise, BOC Sciences offers tailored solutions based on the structural characteristics of the target molecules. From initial route design to process optimization, the company provides end-to-end support to meet both research and industrial development needs efficiently and reliably.
Reaction route design and optimization are crucial in the synthesis of alkynes and imines. BOC Sciences provides systematic support in this area, including precursor selection, strategic planning of key intermediates, reaction sequencing, and condition screening. For example, in the synthesis of alkyne derivatives, strategies can be chosen based on the electronic and steric properties of the substrates, such as Sonogashira cross-coupling, C–H activation alkynylation, or direct introduction of terminal alkynes. For imine compounds, selecting appropriate carbonyl precursors and amine substrates, combined with acid-catalyzed or Lewis acid-assisted strategies, allows for high selectivity and yield.
Optimization is further supported by high-throughput reaction screening and analytical platforms, enabling rapid evaluation of catalysts, solvents, temperatures, and other parameters affecting product yield and selectivity. Through systematic data analysis, reaction condition models can be established to enhance efficiency and minimize by-product formation. This integrated approach, combining route design with experimental optimization, provides clients with high-confidence experimental plans, significantly reducing the time from concept to practical synthesis.
Table.1 BOC Sciences Process R&D and Optimization Service Portfolio.
| Services | Inquiry |
| Process R&D | Inquiry |
| Route Scouting and Development | Inquiry |
| Reaction Condition Optimization | Inquiry |
| Tech Transfer Services | Inquiry |
| Scale-up | Inquiry |
Catalytic and electrochemical methodologies have expanded the possibilities for alkyne and imine synthesis. BOC Sciences operates specialized catalytic platforms, including transition metal catalysis, metal-organic framework (MOF)-assisted catalysis, and photocatalytic systems. For instance, copper-, palladium-, and nickel-catalyzed cross-coupling reactions enable efficient construction of complex alkynes, while photocatalytic conditions facilitate imine formation with minimized side reactions compared to conventional acid catalysis.
Electrochemical platforms provide a green and efficient alternative for synthetic challenges, allowing selective formation of alkynes and imines without the need for external oxidants or reductants. By controlling applied potential and current density, terminal alkynes or imine structures can be synthesized with high selectivity while reducing energy consumption and environmental impact. These specialized platforms offer chemists increased flexibility and control when designing complex molecules, supporting innovation and exploration in synthetic chemistry.
Table.2 BOC Sciences Targeted Functionalization & Catalysis Services.
BOC Sciences emphasizes project-based collaboration, providing customized technical services tailored to specific molecular design requirements. From small-scale laboratory verification to multi-step synthesis, comprehensive technical support is offered throughout the project lifecycle. The company works closely with clients to develop optimized reaction plans and experimental protocols based on molecular structure, reaction feasibility, and yield requirements.
In addition, BOC Sciences engages in technical collaboration by sharing catalytic strategies, reaction optimization experience, and innovative synthetic methodologies to accelerate molecular innovation and process development. For example, in the development of complex alkyne derivatives, multi-step combined catalytic strategies and controlled electrochemical conditions were applied to improve product yield and purity, significantly shortening the timeline from molecular concept to material production. This project-based customization and collaborative approach not only reduces development risk but also provides reliable technical support for clients pursuing innovation in organic synthesis.
Table.3 BOC Sciences Custom Synthesis Services for drug development.
In the forefront of innovative drug discovery and advanced materials science, alkynes and imines represent two pivotal classes of chemical building blocks. Their efficient and precise synthesis directly impacts the success of core projects. Leveraging deep expertise in synthetic chemistry, BOC Sciences provides clients with comprehensive, end-to-end solutions encompassing route design, reaction development, and scale-up preparation. The following case studies highlight our capabilities in addressing complex synthetic challenges with tailored approaches.
Project Overview
A client focused on a novel protein-targeting molecule required the introduction of sulfonamide functionality onto a sterically demanding aromatic scaffold to enhance solubility and molecular interactions. Conventional sulfonylation strategies posed two major challenges: the use of highly corrosive reagents with difficult work-up procedures, and low yields due to steric hindrance at the reactive site. The client sought a milder, highly efficient, and selective alternative.
Synthetic Strategy
BOC Sciences developed an innovative electrochemical approach. The method employed the target aromatic substrate and sulfonamide reactant under controlled electrolysis conditions, facilitating direct C–N bond formation at the anode to construct the sulfonamide moiety in a single step. No additional chemical oxidants were required; precise control of current and voltage was sufficient to drive the transformation.
Technical Highlights
Oxidant-free system: The electrochemical process uses electrons as a clean reagent, eliminating side products and metal residues associated with conventional oxidants, simplifying downstream processing.
Precise potential control: Fine-tuning the working electrode potential allows preferential oxidation of the sulfonamide precursor, generating a nitrogen-centered radical that selectively reacts with the aromatic substrate, overcoming steric challenges.
Substrate compatibility: Customized electrolyte systems, such as acetonitrile/water mixtures with supporting salts, demonstrated excellent tolerance toward complex aromatic substrates provided by the client, ensuring reaction efficiency.
Outcome
The electrochemical synthesis provided a robust and scalable process. Conducted under ambient conditions, the reaction exhibited a significant increase in efficiency, enabling large-scale material preparation while minimizing environmental impact. This approach established a practical and reliable route for further development of advanced intermediates.
Project Overview
A materials science company aimed to produce novel conjugated alkyne-based polymers for advanced optoelectronic applications. Their objective was the synthesis of asymmetric diaryl alkynes with bulky substituents, which presented challenges under standard coupling conditions, including excessive homocoupling, purification difficulties, and instability of sensitive functional groups in palladium/copper catalytic systems.
Synthetic Strategy
BOC Sciences designed a stepwise assembly route. Initially, a silyl-protected terminal alkyne was coupled with a halogenated aryl derivative to form a stable intermediate. After selective deprotection under mild conditions, the freed terminal alkyne underwent a second optimized coupling with a structurally distinct aryl halide to yield the target asymmetric alkyne.
Technical Highlights
Functional group protection: The use of triisopropylsilyl as a protecting group ensured stability during the first coupling and allowed mild, quantitative deprotection without affecting other functional moieties.
Catalyst optimization: Screening of high-activity Pd PEPPSI-type precatalysts in combination with tailored phosphine ligands enabled efficient coupling of sterically hindered aryl bromides, facilitating C(sp)–C(sp2) bond formation.
Process monitoring and purification: Real-time HPLC-MS analysis ensured precise tracking of intermediates and side products. Customized chromatographic methods guaranteed high chemical integrity of the final products.
Outcome
A reliable and reproducible synthetic protocol was established, enabling the production of multiple previously inaccessible asymmetric diaryl alkynes. The process supported subsequent polymerization and material characterization, fulfilling the client's requirements for advanced optoelectronic applications.
Project Overview
An agrochemical client encountered limitations in producing a critical imine intermediate for a herbicidal agent. The existing method, using toluene as a solvent and employing azeotropic water removal, was time-consuming, required excess amine, and generated large volumes of amine-containing wastewater, increasing both operational costs and environmental impact.
Synthetic Strategy
BOC Sciences introduced molecular sieves as an in situ dehydrating agent and systematically evaluated alternative reaction solvents. After testing various non-protic solvents, dichloromethane was selected, combined with 4Å molecular sieves, allowing the reaction to proceed under ambient or mildly elevated temperatures with stirring.
Technical Highlights
In situ water removal: Molecular sieves selectively adsorb reaction water, shifting the equilibrium toward imine formation, enabling near-stoichiometric amine usage.
Solvent engineering: Dichloromethane's lower boiling point compared to toluene facilitates solvent recovery, reduces energy requirements, and simplifies downstream removal.
Process parameter refinement: Optimized conditions included reactant concentration, sieve loading, stirring rate, and reaction endpoint monitoring (e.g., TLC or online IR), ensuring reproducible and controllable outcomes.
Outcome
The optimized process reduced reaction time from over 24 hours to under 6 hours, lowered amine consumption, and decreased waste generation. The approach proved scalable and reliable, supporting multi-kilogram production while significantly reducing operational costs and environmental impact.
Alkynes and imines, as key structural units in modern organic synthesis, not only demonstrate exceptional reactivity and versatility in constructing complex molecular frameworks but also provide highly controllable means for spatial and polarity modulation in molecular design. Through diverse contemporary synthetic strategies, including copper catalysis, nickel catalysis, single-atom catalysis, and electrochemical methods, the efficiency, selectivity, and functionalization potential of alkynes and imines have been significantly enhanced. Leveraging an extensive reaction library, advanced laboratory platforms, and deep technical expertise, BOC Sciences offers comprehensive, end-to-end customized services ranging from route design and reaction development to process scale-up. Whether for complex alkyne-based polymers, finely functionalized intermediates, or key imine precursors, systematic optimization strategies enable efficient and controllable synthesis, providing reliable support for the development of novel drug molecules and high-end materials, and driving continuous advancement in molecular innovation and industrial applications.
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