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TosMIC

TosMIC, or p-toluenesulfonylmethyl isocyanide, is a white crystalline with the molecular formula C₉H₉NO₂S and 36635-61-7, widely recognized as a versatile trifunctional in due to its unique combination of a tosyl , an acidic α-methylene, and a reactive functionality. Developed in the early by chemist Albert M. van Leusen and his group at the , TosMIC enables reactivity at the carbon adjacent to the isocyanide, allowing it to serve as a one-carbon building block for the construction of nitriles, azoles, and other heterocycles. Its stability as a solid and compatibility with base-promoted reactions have made it indispensable in both academic and industrial applications, particularly for multi-component reactions (MCRs) in and synthesis. The of TosMIC generates a that acts as a , facilitating condensations with electrophiles such as aldehydes, ketones, and imines. In the classic van Leusen reaction, TosMIC reacts with aldehydes or ketones under basic conditions (typically or tert-butoxide) to produce nitriles via elimination of the , effectively extending the carbon chain by one unit in a reductive cyanation process. This method, first reported in , offers a cyanide-free alternative to traditional cyanohydrin-based approaches and has been applied in the of alkaloids and pharmaceuticals. TosMIC's utility extends prominently to heterocycle synthesis, where it participates in [3+2] cycloadditions and related cascades. The van Leusen imidazole synthesis, also introduced in 1977, involves the base-induced reaction of TosMIC with aldimines (formed from aldehydes and amines) to yield 1,4-disubstituted , a transformation that proceeds through an intermediate imidazolyl anion followed by protonation and tosyl elimination. This three-component reaction has been extensively utilized for preparing imidazole-based drugs and bioactive molecules, with variations enabling access to fused imidazoles and stereoselective products. Similarly, TosMIC facilitates the synthesis of oxazoles, pyrroles, and thiazoles through reactions with α-halo ketones or other electrophiles, often under mild conditions that tolerate functional groups. Beyond classical applications, recent advances since 2011 have expanded TosMIC's scope to metal-catalyzed processes, tandem reactions, and asymmetric variants, enhancing its role in and complex molecule assembly. For instance, - or copper-catalyzed couplings with TosMIC derivatives allow for C-C and C-N bond formations, while organocatalytic protocols improve enantioselectivity in synthesis. Its commercial availability from suppliers like and its low toxicity relative to isocyanides further underscore its practical value in modern synthetic methodologies.

Structure and properties

Molecular structure

TosMIC, or tosylmethyl isocyanide, possesses the molecular formula C₉H₉NO₂S and a molecular weight of 195.24 g/mol. The molecular structure features a p-toluenesulfonyl moiety (p-CH₃C₆H₄SO₂–), consisting of a ring with a methyl at the position linked to a sulfonyl group, attached to a methylene unit (–CH₂–) that bridges to an functionality (–NC). This arrangement can be depicted as p-CH₃C₆H₄SO₂CH₂NC, where the central methylene carbon serves as the α-position pivotal for subsequent reactivity. As a densely functionalized isocyanide, TosMIC integrates the electron-withdrawing sulfonyl group, which stabilizes the adjacent methylene by delocalizing negative charge, alongside the isocyano group known for its nucleophilic and dipolar properties in synthetic transformations. The sulfonyl acts as a protecting and activating element, while the isocyanide provides versatility in multi-component reactions; together, they render the methylene bridge acidic, with the α-protons exhibiting enhanced reactivity due to this electronic interplay.

Physical properties

TosMIC is typically obtained as a white to pale yellow crystalline solid. The compound has a melting point ranging from 109 to 113 °C. It exhibits low solubility in but is readily soluble in common organic solvents, including , , , 1,2-dimethoxyethane, , and . The density of TosMIC is estimated at approximately 1.27 g/cm³, though detailed physical constants beyond this are not extensively reported in the literature. TosMIC remains stable under ambient conditions but is moisture sensitive; it is typically stored in a cool, dry environment at 2–8 °C to prevent degradation.

Chemical properties

TosMIC functions as a strong carbon acid, characterized by a pKa of approximately 14 for the protons on its α-methylene group. This acidity results from the stabilization of the conjugate carbanion by the electron-withdrawing sulfonyl and isocyano groups, with the isocyano moiety offering particularly effective delocalization of the negative charge. In solid form, TosMIC exhibits good stability, presenting as a colorless and nearly odorless substance that remains intact when stored at . The sulfonyl group contributes to this profile by activating the methylene protons for while also functioning as a , which influences its broader reactivity. The isocyano group endows TosMIC with nucleophilic potential at its carbon atom, a hallmark of isocyanides, though this is tempered by the adjacent sulfonyl's electron-withdrawing influence, which shifts emphasis toward α-carbon reactivity. with bases readily generates the α-carbanion, enabling subsequent electrophilic due to the anion's inherent stability.

Laboratory preparation

The laboratory preparation of tosylmethyl isocyanide (TosMIC) typically proceeds in two steps: first, the synthesis of the precursor N-(p-toluenesulfonylmethyl)formamide from commercially available sodium p-toluenesulfinate, , and in the presence of , followed by of this formamide to TosMIC. The formamide is obtained by heating a mixture of sodium p-toluenesulfinate (1.50 mol), aqueous (ca. 4.4 mol), (15.5 mol), and (5.30 mol) in at 90–95°C for 2 hours, followed by cooling to -20°C and , affording the crude product in 42–47% yield. An alternative route to the formamide precursor involves the reaction of chloromethyl p-tolyl with , or of tosylmethylamine (p-CH₃C₆H₄SO₂CH₂NH₂) derived from chloromethyl p-tolyl and . The key dehydration step converts N-(p-toluenesulfonylmethyl) to TosMIC using a dehydrating agent such as phosphorus oxychloride (POCl₃) in the presence of triethylamine (Et₃N) as a base, typically in solvents like (DCM) or (THF). In a representative procedure, the (0.502 mol) is dissolved in 1,2-dimethoxyethane and with Et₃N (2.52 mol), cooled to -5°C to 0°C, and POCl₃ (0.55 mol) is added over 1 hour with stirring for 30 minutes at 0°C; the reaction is then quenched with ice , extracted with , dried, and purified to yield TosMIC in 76–84%. Variations include the Ugi using excess Et₃N in THF with POCl₃. The reaction can be represented as: \ce{p-CH3C6H4SO2CH2NHCHO ->[dehydrating agent] p-CH3C6H4SO2CH2NC + H2O} Yields for the dehydration step on laboratory scale are typically 70–90%. Recent advances include sustainable methods such as mechanochemical dehydration and in-water micellar conditions at room temperature, offering greener alternatives to traditional solvent-based processes. Purification of TosMIC is achieved by recrystallization from or , yielding a solid with 116–117°C, or by on alumina.

Commercial production

TosMIC is produced commercially on an industrial scale by adapting laboratory-scale methods, typically involving the of a formamide precursor in batch reactors or continuous flow systems to ensure efficiency and consistency. Companies such as Varsal Chemical utilize proprietary processes optimized for large-volume output, supporting applications in pharmaceuticals, agrochemicals, and fine chemicals. The compound is widely available from major chemical suppliers, including , , and , often in quantities ranging from grams to kilograms for research and industrial use. α-Substituted TosMIC analogs, useful for specialized syntheses, are also offered by suppliers like to meet diverse needs in . Commercial TosMIC is typically supplied with >98% purity, verified through standard analytical methods to minimize impurities such as p-toluenesulfinic acid. It is accessible for both academic and applications. Large-scale presents challenges related to TosMIC's , classified as toxic if swallowed, in contact with skin, or if inhaled, necessitating robust safety measures including and controlled environments. Additionally, its moisture sensitivity can lead to degradation or side reactions like cyclodimerization, requiring dry handling protocols and specialized storage to maintain product integrity during and .

Reactions

Van Leusen imidazole synthesis

The Van Leusen imidazole synthesis is a three-component reaction that employs tosylmethyl (TosMIC) as a key reagent to construct from and primary amines. Introduced in 1977, this base-promoted provides efficient access to 1,5-disubstituted , where the contributes the substituent at the 5-position, the amine at the 1-position, and TosMIC furnishes the unsubstituted 4-position carbon. The reaction proceeds via in situ formation of an aldimine intermediate, highlighting TosMIC's role as a versatile C-N=C in heterocyclic chemistry. This method has become a cornerstone for synthesis due to its mild conditions and broad substrate tolerance, enabling the preparation of diverse derivatives in a single pot. Variations using substituted TosMIC derivatives allow access to 1,4,5-trisubstituted . The mechanism begins with deprotonation of TosMIC under basic conditions to generate the tosylmethyl anion, which acts as a nucleophile. This anion adds to the electrophilic carbon of the aldimine (formed from the aldehyde and primary amine), initiating a [3+2] cycloaddition across the C=N bond. The resulting 4-tosyl-2-imidazoline intermediate then undergoes elimination of p-toluenesulfinic acid (TsH), followed by aromatization to afford the imidazole ring. This sequence ensures regioselective substitution, with the tosyl group serving as a leaving group to drive the final tautomerization step. The overall transformation can be represented by the simplified equation: \mathrm{RCHO + R'NH_2 + TsCH_2NC \rightarrow} \quad \text{1-R'-5-R-imidazole} \quad + \quad \mathrm{TsH} where R and R' are alkyl or aryl substituents. Typical reaction conditions involve a base such as (K₂CO₃) in polar aprotic solvents like DMF or protic solvents such as , at temperatures ranging from to . The one-pot procedure often requires 1-4 hours, with yields commonly in the 60-90% range for aromatic and aliphatic substrates, though electron-deficient aldehydes may require optimization to avoid side reactions. Microwave-assisted variants accelerate the process, achieving comparable yields in minutes. Variations of the synthesis include adaptations with secondary amines, which yield 1,5-disubstituted by forming intermediates that participate in modified cycloadditions. Additionally, solid-phase versions have been developed for combinatorial library synthesis, attaching aldehydes or amines to resin supports and performing the reaction under aqueous or DNA-compatible conditions to generate diverse libraries for . These extensions maintain high efficiency while enabling parallel synthesis on scales suitable for .

Van Leusen oxazole synthesis

The Van Leusen oxazole synthesis is a base-promoted reaction that utilizes tosylmethyl isocyanide (TosMIC) as a one-carbon to convert aldehydes or ketones directly into 5-substituted . This method, first reported in , provides a straightforward route to heterocycles, which are prevalent motifs in natural products and pharmaceuticals. The reaction proceeds under mild conditions and tolerates a variety of functional groups, making it a valuable tool in synthetic . The mechanism begins with the of TosMIC at the α-position by a strong base, generating a that acts as a . This anion adds to the of the aldehyde or , forming a β-hydroxy . Cyclization then occurs via intramolecular attack of the oxygen on the isocyanide carbon, generating a 4-tosyl-Δ²-oxazoline , followed by base-promoted elimination of p-toluenesulfinic acid, leading to aromatization and formation of the ring. The overall transformation can be represented as: 
RCHO + TsCH₂NC → 5-R-oxazole + TsH
under base catalysis. Typical reaction conditions involve treatment of the carbonyl compound with TosMIC and a base such as tert-butoxide (t-BuOK) or (NaH) in solvents like (DMSO) or (THF), often starting at low temperatures (-78 °C) and warming to . Yields generally range from 50% to 80%, with the process being particularly effective for α,β-unsaturated carbonyl compounds. The scope of the reaction is broad for both aryl and alkyl aldehydes, affording the corresponding 5-substituted oxazoles in good efficiency. Ketones are also viable substrates, though sterically hindered examples may result in lower yields due to impeded nucleophilic addition.

Cyanation reactions

Tosylmethyl isocyanide (TosMIC) serves as an effective masked cyanide reagent in the reductive cyanation of carbonyl compounds, enabling the conversion of ketones and aldehydes to the corresponding nitriles with incorporation of one additional carbon atom. This one-pot process homologates the carbonyl to an α-cyanoalkane, R₂CHCN, where TosMIC provides the CN unit while the tosyl group acts as a leaving group. The reaction is particularly valuable for its mild conditions and compatibility with hindered substrates, offering a cyanide-free alternative to traditional methods like the Strecker synthesis. The mechanism begins with base-mediated deprotonation of TosMIC at the α-position, generating a that undergoes to the carbonyl carbon of the or , yielding a β-hydroxysulfonyl intermediate. This adduct then eliminates the tosylate anion, facilitated by the electron-withdrawing sulfonyl group, leading to rearrangement of the moiety into a through tautomerization and deformylation steps. Primary alcohols, such as or , play a crucial role by acting as nucleophiles in the deformylation, accelerating the overall process and preventing side reactions like TosMIC cyclodimerization. The general reaction scheme is depicted as follows: \ce{R2C=O + TsCH2NC ->[base] R2CH-CN + Ts- + byproducts} where Ts represents the p-toluenesulfonyl group and the reaction proceeds under basic conditions. Typical conditions involve treatment with a strong base like tert-butoxide in aprotic solvents such as THF or DME at 0–50 °C for ketones, often with 1–2 equivalents of added to enhance rates and yields, which generally range from 70–95%. For aldehydes, lower temperatures (-50 to -20 °C) and excess are employed, followed by to complete the transformation, though yields may be lower without optimization. The process is conducted in a single pot, making it efficient for scale-up. Variations extend the reaction to α,β-unsaturated carbonyl compounds, where conjugate can occur selectively under controlled conditions, preserving the while introducing the cyano group. In the presence of primary alcohols, transient 4-alkoxy-2-oxazoline intermediates may form, particularly with aldehydes, which subsequently decompose to the product, further underscoring the additive's role in pathway selectivity.

Sulfonylation and miscellaneous reactions

TosMIC serves as an effective sulfonylating agent in reactions with α-bromocarbonyl compounds, enabling the efficient synthesis of α-sulfonated ketones, esters, and amides. In this transformation, the functionality of TosMIC undergoes copper-catalyzed to form a intermediate, which fragments under basic conditions to generate a p-toluenesulfinate ; this nucleophilic species then displaces the α-bromo via an SN2 mechanism. The process highlights an unexpected role for TosMIC, where the sulfonyl group is transferred while the moiety acts as a equivalent after modification. Typical conditions involve treatment of the α-bromocarbonyl with TosMIC (1.2 equiv), 2CO3 (2 equiv), and Cu(OTf)2 (5 mol%) in DMF at 80 °C, often with 1 equiv of as an additive to promote . Yields are generally high, ranging from 71% to 96% for a variety of aryl- and alkyl-substituted α-bromoketones and esters. For instance, phenacyl bromide reacts to afford the corresponding α-tosylacetophenone in 92% yield. The general sulfonylation can be outlined as follows: \ce{TsCH2NC ->[Cu(OTf)2][H2O][Cs2CO3] TsSO2^- + HCONHCH2OTs} \ce{TsSO2^- + RCOCH2Br -> RCOCH2SO2Ts + Br^-} Beyond sulfonylation, TosMIC exhibits versatile reactivity in miscellaneous transformations. at the α-position, facilitated by the electron-withdrawing sulfonyl group (a ≈ 24), allows for regioselective C- with electrophiles such as alkyl halides or acceptors. This step is commonly performed using bases like t-BuOK or NaH in THF or DMSO at low temperatures (-78 °C to 0 °C), enabling the synthesis of α-substituted TosMIC derivatives that serve as synthons for further heterocycle ; double alkylation is also feasible, with yields typically exceeding 70% for primary alkyl halides. TosMIC also participates in the synthesis of pyrroles via base-promoted [3+2] with activated alkenes, such as chalcones, where the deprotonated TosMIC acts as a three-atom . For example, reaction with (E)-1,3-diphenylprop-2-en-1-one in the presence of t-BuOK in DMSO at affords 3,4-diphenyl-1H-pyrrole in 82% yield after tosyl elimination. Additionally, TosMIC coordinates to transition metals through its nitrogen, functioning as a in allenyl and propargyl complexes, where it undergoes migratory insertion to form organometallic intermediates useful in coupling reactions. These applications underscore TosMIC's utility as a C1N1 in multicomponent reactions beyond standard heterocycle formations.

Applications

Heterocyclic compound synthesis

TosMIC serves as a versatile in the construction of diverse beyond the core Van Leusen imidazole and oxazole syntheses, particularly through [3+2] cycloadditions and multicomponent reactions (MCRs) that enable the formation of pyrroles, 1,2,4-triazoles, and thiazoles. These methods leverage TosMIC's acidic and functionality to generate reactive intermediates that undergo cyclization, often in a single pot, allowing for the incorporation of various substituents at multiple positions on the heterocyclic ring. In synthesis, TosMIC participates in base-promoted [3+2] cycloadditions with acceptors such as chalcones or other α,β-unsaturated carbonyls, yielding 3,4-disubstituted s after elimination. For instance, the reaction of TosMIC with 3-aryl-1-phenylprop-2-en-1-ones in DMF with tert-butoxide affords the corresponding s in 50–85% yields, providing efficient access to aryl-substituted derivatives suitable for further elaboration. Similar cycloadditions with enamine-derived acceptors extend the scope to multi-substituted s, enhancing product diversity. These approaches highlight TosMIC's utility in generating complex scaffolds with high . For 1,2,4-s, TosMIC reacts with aryldiazonium salts under basic conditions to form 3,5-disubstituted 1,2,4-s via nucleophilic attack and cyclization, often in moderate to good yields (60–80%) using aqueous . This method allows one-pot assembly of rings with aryl groups at the 3- and 5-positions, demonstrating TosMIC's role as a C-N . Variations involving intermediates further diversify the substitution patterns, enabling access to N-substituted s. Thiazole synthesis employs TosMIC in reactions with sulfur-containing electrophiles, such as carboxymethyl dithioates or , leading to 2,4-disubstituted s through thio-Michael addition followed by cyclization and tosyl extrusion. The process facilitates the introduction of thioether or substituents at the 2-position, broadening the range of derivatives available under basic conditions in polar solvents like or DMF. The advantages of these TosMIC-based strategies include streamlined one-pot protocols that minimize synthetic steps and purification needs, while supporting the synthesis of highly substituted heterocycles with control over regiochemistry. Additionally, TosMIC's compatibility with enables combinatorial libraries, as demonstrated by polymer-supported variants that streamline the generation of diverse and arrays for screening applications. These features underscore TosMIC's broad applicability in heterocyclic chemistry, as comprehensively reviewed in the seminal on its synthetic uses.

Medicinal chemistry

TosMIC has emerged as a valuable in , particularly for constructing nitrogen-containing heterocycles that serve as scaffolds in . Its versatility in reactions like the van Leusen imidazole and oxazole syntheses enables the efficient preparation of biologically active compounds with potential therapeutic applications in , infectious diseases, and . By facilitating the introduction of key functional groups such as , , and nitriles, TosMIC supports the development of targeted inhibitors and agents. A prominent example is the synthesis of p38 mitogen-activated protein (MAP) kinase inhibitors, which are imidazole-based compounds used in treating . The van Leusen three-component reaction employing TosMIC has been scaled up industrially, achieving 60-65% isolated yields on a 200-gallon scale for a GlaxoSmithKline (GSK) candidate, demonstrating its practicality for pharmaceutical production. TosMIC has also been utilized in the construction of heterocycles derived from α-formamidomethylation of dithioesters. In applications, TosMIC-derived imidazoles contribute to anti-inflammatory drugs targeting via p38 inhibition, as seen in the GSK analogs that modulate production. Oxazoles synthesized from TosMIC and aldehydes display antibacterial properties, with derivatives showing activity against Gram-positive and , positioning them as leads for novel antibiotics. Additionally, TosMIC's cyanation capability produces intermediates that have been used in the development of inhibitors for antiviral therapies. Recent advances from 2019 to 2025 highlight TosMIC's role in antiviral and anticancer heterocycles, as reviewed in studies emphasizing its use in multicomponent reactions for diverse scaffolds. For instance, TosMIC-tethered imidazo[1,2-a]pyridine derivatives have been developed as agents, with compounds exhibiting superior activity against invasive fungal pathogens compared to standards like . These efforts underscore TosMIC's contribution to related hybrids with broad-spectrum potential. The impact of TosMIC in lies in its ability to enable rapid parallel synthesis of compound libraries for structure-activity relationship () studies, accelerating hit-to-lead optimization in programs. Recent developments include metal-free and mechanochemical variants of TosMIC reactions, promoting sustainable synthesis in pharmaceutical applications as of 2025. As of 2025, it is referenced in over 100 pharmaceutical patents, reflecting its widespread adoption in developing bioactive heterocycles for therapeutic applications.

History

Discovery and development

TosMIC, or p-toluenesulfonylmethyl isocyanide, was introduced in 1972 by Albert M. van Leusen and colleagues at the as a functionalized derivative of , building on the established role of s in multicomponent reactions such as the . The compound derives its name from the p-toluenesulfonyl (tosyl) group attached to the framework, which imparts stability and unique reactivity to the reagent. This initial work focused on the preparation of TosMIC through dehydration of the corresponding precursor and demonstrated its basic reactivity, particularly in reactions with Michael acceptors to form pyrroles and cyanopyrroles. Early development of TosMIC expanded rapidly in the , with van Leusen and co-workers reporting in a base-induced of TosMIC to aldimines, enabling a of 1,4,5-trisubstituted imidazoles. This breakthrough highlighted TosMIC's potential as a for heterocycle construction, leveraging the acidity of its α-methylene group and the nucleophilicity of the moiety. By the , TosMIC had gained recognition as a versatile in , as evidenced by dedicated reviews that emphasized its multifaceted applications beyond initial explorations. The reagent's utility extended to pharmaceutical intermediates during the , where processes involving TosMIC were developed for synthesizing substituted heterocycles and nitriles on preparative scales. This period marked a transition from academic research to practical synthetic tool, solidifying TosMIC's role in efficient construction of complex molecular scaffolds.

Key advancements

The comprehensive review in Organic Reactions Volume 57 detailed the synthetic versatility of TosMIC, encompassing its roles in heterocycle formation, cyanation, and sulfonylation reactions, establishing it as a foundational in . In 2005, a highlight article emphasized the utility of van Leusen multicomponent reactions (MCRs) involving TosMIC in combinatorial chemistry, showcasing its efficiency for generating diverse libraries of imidazoles and oxazoles under mild conditions. Between 2011 and 2019, several reviews highlighted TosMIC's expanded role in MCRs for heterocycle synthesis, with a 2019 RSC publication surveying advances in cyclization strategies and sulfonylations, including polymer-supported variants for solid-phase synthesis that facilitated high-throughput library production. Key developments since 2016 have included refined sulfonylation protocols, such as the 2016 Journal of Organic Chemistry report on TosMIC's unexpected role as a direct sulfonylating agent for α-bromocarbonyls, yielding α-sulfonated products in high efficiency without additional sulfonyl sources. Additionally, a 2019 Organic Letters study introduced TosMIC as a C1N1 two-atom for synthesis via neighboring group assistance in the annulation of aryl methyl ketones and 2-aminobenzyl alcohols. A 2025 Tetrahedron review further consolidated these innovations, positioning TosMIC as a broad for novel cyclizations and sulfonylations beyond traditional van Leusen frameworks. Milestones in TosMIC's practical implementation include large-scale production, as demonstrated in the synthesis of bempedoic acid intermediates using kilogram-scale batches. Integration into flow chemistry systems has enhanced and scalability, particularly for cyanide-free syntheses from ketones. Toxicity profiles, classified under GHS Danger for via oral, dermal, and inhalation routes, have been established through safety data sheets, informing handling protocols in industrial settings.