REPRINT Reviews ChemistrySelect doi.org/10.1002/slct.202001344 z Organic &Supramolecular Chemistry TosMIC: APowerful Synthon for Cyclization and Sulfonylation Kapil Kumar[a] p-tosylmethyl isocyanide (TosMIC) which is also known as van focused on synthetic utility of TosMIC in diverse range of Leusen’s reagent hold the three functionalized groups includ- heterocycles like five membered heterocycles, fused hetero- ing the isocyanide and sulfonyl group and an alpha carbon cycles, linked or tethered heterocycles, spiro compounds etc. It which is acidic by nature. Tosyl set of this fortunate reagent is also utilized for regio, chemo and stereoselective synthesis acts as agood leaving group and assist the alpha carbon to and production of sulfones and sulfinates. It serves as an contribute in arange of cyclization strategies. Exceptionally, important building block in various synthetic methodologies TosMIC was also proved as agood sulfonylating and sulfometh- like multi component reaction, cyclization, domino, cascade ylating reagent. TosMIC has proved as apowerful and versatile and cycloaddition and metal catalysedreactions. Various new synthon and betrothed in the synthesis of broad range of catalyst and novel methodologies were explored due to heterocycles having pharmacological interest. This review is enormous use of this wonderful reagent. 1. Introduction Isocyanide has been crowned as imaginative reagent by medicinal chemist due to their synthetic utility and pharmaco- logical applications.Abroad range of isocyanides are reported in literature but p-tosylmethyl isocyanide attracted the syn- thetic chemists because of its applicability in diversified reaction categories. p-toluenesulfonylmethyl isocyanide, gener- ally abbreviated as TosMIC, has drawn attention of researchers due to its astonishing structural features, constancy and reactivity. TosMIC is powerful and versatile synthon and Figure 1. Structure of TosMIC representing various functionalities. employed in affording diverse range of organic compounds having altered functionalities. It contains three densely func- tionalized groups, namely the isocyanide and sulfonyl function- oxazole, triazole can be easily constructed using this reagent. ality and an alpha carbon between them having acidic nature. TosMIC is also explored to produce various fused heterocycles The sulfonyl group serves as agood leaving group augmenting like β-carboline, pyrrolo-quinoline, imidazo-quinoline, pyrrolo- the strength of acidity of the α-carbon. TosMIC is also reported pyrimidine, imidazo- β-carboline and achoice of linked hetero- for unanticipated synthesis of sulfones and sulfinates. It has cycles like indole linked with oxazole, imidaole etc. TosMIC is also been proved that TosMIC involvedinchemo, regio and also utilized for affording the spiro compounds using mild stereoselective synthesis without disturbing the selectivity. reaction conditions. It is widely accepted reagent due to ease Mono- and disubstitutions at the α-position derive the sundry of preparation, functional group tolerance and good tosyl functionalized molecules.TosMIC was introduced and exten- leaving group preceding the cycloaddition mechanism.[1] sively applied in organic synthesis by the Dutch professor van Leusen. Due to establishment the applicability of TosMIC in 2. Synthetic applications heterocyclic synthesis by van Leusen, it is now recognized as van Leusen’s reagent 1 as shown in Figure 1. TosMIC is very The chemistry of TosMIC is very well understood and has been reactive due to less steric hindrance and increased electrophilic explored in the past few decades. TosMIC also showed nature. It is very well explored in past decades for construction competent reactivity in yielding new molecules of various of heterocyclesbut various new methodologies, novel reactions categories like five membered heterocyclic such as pyrrole, using this powerful synthon are always demanding. Various oxazole, thiazole, imidazole, triazole, indole, oxazolidine, fused five membered heterocycles like pyrrole, imidazole, indole, heterocycle, tetheredorlinked heterocycle and spiro hetero- cyclic compounds. [a] Dr. K. Kumar School of Pharmacy and Technology Management, SVKM’s NMIMS, Hyderabad,Telangana-509301, India. ChemistrySelect 2020, 5,10298–10328 10298 ©2020 Wiley-VCH GmbH Wiley VCH Mittwoch, 02.09.2020 2033 /177182 [S. 10298/10328] 1 Reviews ChemistrySelect doi.org/10.1002/slct.202001344 2.1. Synthesis of five membered heterocycles nucleophilic attack of ethoxide on carbonyl group of C producing the ortho-substituted ethyl ester D.The ethyl ester D 2.1.1. Synthesis of pyrrole scaffold afforded the final substituted pyrrole derivatives after elimina- Pyrrole is afive membered heterocycle containing one nitrogen tion of toluenesulfinate anion and subsequent isomerization. atom and available in colorless volatile liquid. It was extracted Nair et al developed an efficient protocol for synthesis of from the pyrolysate of bone. Substituted derivatives of pyrrole 3,4-disubstituted pyrrole derivatives 10 by the van Leusen are called pyrroles. In five membered heterocyclic compounds, method.LiOH.H2O 8 in ethanol was found to be an effective pyrroles are the most significant heterocycles and present in reagent for this strategy by in situ formation of chalcones from various biological products, natural alkaloids, and pharmaceut- aromatic aldehydes 7 and enolisable ketones 9 and their icals. There are several methodsreported for the preparation of subsequent reaction with tosylmethyl isocyanide resulted in pyrroles using tosylmethyl isocyanide. Pyrroles might be the formation and precipitation of desired products in good isolated or can be fused with aromatic carbocyclic or other yields. The solvation effect of the polar medium facilitates the heterocyclic molecule. reaction. The base, LiOH.H2O, has significant covalent character Dell Erba et al reported the synthesisofpyrrole derivatives due to the small size of the Li+ ion. The low solvation leads to using alkene and butadiene 2 with TosMIC in presence of base. the precipitation of the products from the solution. Thisfavours Michael approach was utilized for synthesis of pyrrole 3 and the equilibrium towards the completion of reaction and dipyrrole derivative with good to excellent yield using DBU as a facilitates the isolation of the product without further purifica- base and tetrahydrofuran as asolvent. The structure of tion. Apart from solvation, dynamic solvent effects also play a prototypecompound was ascertained using X-ray crystallo- significant role to accelerate the reaction rate and afforded the graphic study and all derivatives were further characterized by desired products.[4] The developed procedure offer advantages spectroscopic analysis.[2] Detailed synthetic approach is illus- like atom economy, escape of column purification, easy work trated in Scheme 1. up, reduce solvent wastage, high purity etc. as illustrated in Yennam and his group synthesized avariety of 3,4- Scheme 4. disubstituted pyrroles 6 from readily available aromatic The plausible mechanism suggest that the base abstract α- aldehydes 4,1,3-Indanedione 5 and tosylmethylisocyanide acidicproton to generate Carbanion, which undergo aMichael (TosMIC) by aone-pot protocol in high yields using cesium addition over α, β-unsaturated compound along with electro- carbonate as abase and ethanol as agreener reaction medium philic attack of electron deficient carbon of isocyanide group. as shown in Scheme 2. The reaction yield depends on the These successive additions complete [2 +3] cycloaddition nature of substituent present on aromatic aldehyde. The reaction between Michael acceptor and TosMIC. The intermedi- substituted aryl aldehydes containing electron-neutral and ate formed has been short lived and the tosyl group, in -donating groups such as methyl and methoxy at the para presence of base, has undergo elimination; leading to position afforded the desired products in high yields. While, formation of 3H-pyrrole derivative and lithium p-tolunesulfi- electron attracting substituent like fluoro, chloro, trifluorometh- nate. Finally, 1, 3-hydrideshift route it to desired 1H-pyrrole yl and nitro groups atthe para or meta position were also derivative as illustrated in Scheme 5. tolerated and afforded desired products in good yields. This Kumar et al further unmitigated similar protocol by switch- novel methodology features operationally simple, tolerated ing the aromatic aldehyde to aliphatic counterpart. In this with broad substrate scope and usage of easy to handle protocol aliphatic aldehyde like trimethylacetaldehyde or reagents. The one-pot sequential reactions proposed to pivaldehyde was used as astandard one keeping the other proceeds through atandem in situ generated chalcones and reaction condition unchanged. Author consummated one-pot [3+ 2]-cycloaddition/ring cleavage process.[3] synthesis by comprising acetophenone 8,trimeth- Based on the result obtained, aplausible mechanism for ylacetaldehyde 11,lithium hydroxide monohydrate 9 in round formation of substituted pyrrole derivatives was proposed as bottom flask using ethanol as reaction medium at ambient shown in Scheme 3. It starts from 1,4-conjugate addition of temperature. This led to the formation of unsaturated carbonyl tosylmethyl isocyanide anion to Michael acceptor 1,3-Indane- intermediate to which equimolar tosylmethylisocyanide was dione followed by intramolecular cyclization of the enolate introduced and the reaction completion was determined