Tosmic: Apowerful Synthon for Cyclization and Sulfonylation Kapil Kumar[A]

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 pharmacological applications.Abroad range of isocyanides are reported in literature but p-tosylmethyl isocyanide attracted the synthetic chemists because of its applicability in diversified reaction categories. p-toluenesulfonylmethyl isocyanide, generally 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 functionalized 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 heterocyclic compounds.

[a] Dr. K. Kumar School of Pharmacy and Technology Management, SVKM’s NMIMS, Hyderabad,Telangana-509301, India.

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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 using adduct A,furnishes the spiropyrrolenine anion B,which takes thin layer chromatography. Formation of precipitate was the proton from medium and undergoes ring cleavage by witnessed that desired pyrrole derivative 12 has been formed.[5]

Dr. Kapil Kumar received his M. S. (Pharm)and Ph.D. in Medicinal Chemistry fromNational Institute of Pharmaceutical Education and Research (NIPER) Mohali, India. Currently, He is working as an Assistant Professor at SVKM’s NMIMS (Deemed to be university) Hyderabad campus, India. His research interests involve synthesis and pharmacological studies on anticancer, anti-diabetic and neglected diseases. His research area is focused on heterocyclic synthesis, methodology development, catalytic synthesis, asymmetric synthesis, green chemistry, total synthesis and computer aided drug design etc. His research has resulted in the publication of over 25 peer-reviewed articles. He is in reviewer panel of many top ranked journals.

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Scheme1.Synthesis of pyrrole derivatives from butadiene.

Scheme2.Synthesis of 3,4-disubstitutedpyrrole derivatives from aldehyde and indanedione.

Scheme3.Mechanistic explanation for synthesis of 3,4-disubstituted pyrrole employing indanedione.

using spectral analysis and melting point which revealthat desired pyrrole derivative has been formed as shown in Scheme 6. Dijkstra and co-workers industrialized aseries of 2-(trimeth- ylstannyl)pyrroles 15 having substituents at the 3- and 4- positions, by abase-mediated reaction of novel stannylated reagent 13 and Michael acceptors 14 as illustrated in Scheme 7. In this protocol,stannyl group participated in cyclization Scheme4.Synthesis of pyrrole derivatives using lithium hydroxide mono- process and stannylated pyrroles were found as final novel hydrate. entities. All the synthesized derivatives were afforded with good to excellentyield and characterized by spectral analysis.[6] The reaction mechanism was imaginedstarting from a

The desired precipitate was filtered, washed and further dried. species A TosCLi-NCSnMe3 produced from dilithioTosMIC and The scope of reaction was generalized using assorted range of trimethyl stannyl chloride. This imprudent species A reacts with acetophenone having electron withdrawing and releasing chalcone by aMichael type addition-cyclization strategy group. The structure of solid compounds were characterized

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Scheme5.[2+3] cycloaddition reaction mechanism affording pyrrole derivatives.

Scheme6.Synthesis of pyrrole derivatives using pivaldehyde.

Scheme7.Synthesis of pyrrole derivatives using stannylated TosMIC.

affording pyrrole derivatives asaresult of cycloaddition as illustrated in Scheme 8. Babu and his co-workers reported the tandem strategyfor synthesis of 3,4-disubstituted pyrroles. This procedure involves the three component reaction of aldehydes 16,1,3-dicarbonyls 17 and TosMIC in one pot under metal free conditions using base affording the desired products with moderate to excellent yields as illustrated in Scheme 9. The mechanismofthe reaction involves aKnoevenagel condensationbetween an aldehyde and dicarbonyl substrate to afford unsaturated alkene intermediate which further experience Michael addition with TosMIC to provide desired 3,4-disubstituted pyrroles 18.The scope of the substrate was then explored to realize the Scheme 8. APlausible mechanism for synthesis of trimethylstannylated pyrrole derivatives. diversity of functional group tolerance. In other words,

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Scheme9.Synthesis of pyrrole derivatives using aldehyde and 1,3 dicarbonyl compounds.

products afforded via [3+2] annulation/deacetylation/aromati- Yong ping Yu et al reported anovel synthesis of multi- zation cascade pathway in regioselective manner.[7] substituted pyrroles 22 reactingtrisubstituted olefins 21 and p- Five decadeago, D. van Leusen reported the simple toluenesulfonylmethyl isocyanide (TosMIC) derivatives as synthesis of pyrrole from Michael acceptor and tosylmethyl shown in Scheme 11. The reaction protocol is operationally and isocyanide. TosMIC react with Michael acceptor 19 like α,β- economically simple and utilizes inconsequential reaction unsaturated ketones, esters or nitriles under basic condition to conditions. Optimization study of solvent and bases proved afford the pyrrole derivatives 20 by concomitant loss of p- that the sodium hydride in anhydrous acetonitrile was the best toluene sulfinic acid as depicted in Scheme 10. Scope of the combination to afford the desired product with excellent yield reaction was explored using variety of reagent including in short span of time. The scope of the optimized reaction aliphatic and aromatic group containing Michael acceptor and conditions was investigated using various multisubstituted observedthat yield of reaction is better in compound olefins. Simple and readily available starting materials, excellent containing aryl group.[8] yields of the products, mild reaction environments were the main advantages of this protocol.[9] Based on the desired product formation,aplausible mechanism was proposed as shown in Scheme 12. Initially, in the presence of base the TosMIC reactswith the double-bond of the olefin A leading to the intermediate B.Then intermediate B proceeds for intramolecular cycloaddition of the isocyano group to produce the intermediate C.Then elimination of a tosylsulfinic acid produces the intermediate D.Finally, the Scheme10. Synthesis of pyrrole derivatives using Michael acceptor. ketone or ester group is eliminated with anucleophilic addition to furnish the desired pyrrole product. Pompei and his co-workers reported the synthesis of pyrrolnitrin and it’s related endowed from tosylmethyl isocyanide and nitro compounds. Nitro heterocycles are proves to be aversatile chemotherapeutic agent like antifungal, antiprotozoal and antibacterial activities. Pyrrolnitrin is antifungal antibiotic. Pseudomonas pyrrocinia and other pseudomonas species produce pyrrolnitrin from tryptophan as secondary Scheme11. Synthesis of pyrrole derivatives using trisubstituted olefin. metabolite. In this strategy, different nitropyrroles 24 were

Scheme12. Possible mechanism for synthesis of pyrrole from trisubstituted olefins.

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Scheme13. Synthesis of pyrrolnitrin derivatives against M. tuberculosis.

synthesized from α, β-unsaturated compounds 23 as shown in chromone carbon. At last, loss of the formylinstead thetosyl Scheme 13 and their antimycobacterial activity was also group, the more stable aromatic pyrrole derivatives can be evaluated. Synthesized compounds were found active against formed. This hypothesis was also confirmed using IR and NMR Mycobacterium tuberculosis as well as Mycobacterium avium.[10] spectroscopy. This efficient, simple and economical strategy Stephanatou et al reported that chromone-3-carboxalde- described the synthesis of disubstituted pyrroles with two hydes 25 react with tosylmethylisocyanide(TosMIC) to afford 2- distinct substituents like hydroxybenzoyl and the tosyl. Sub- hydroxy benzoyl pyrrole derivatives 26 with tosyl group as sequent replacement of tosyl group by asuitable substituent is illustrated in Scheme 14. Reaction was optimized varying differ- afavourable method to progress innovative routes to synthe- ent solvent and bases and it was found that using DBU as a size novel pyrrole derivatives.[11] base and tetrahydrofuranasreaction medium afforded the Aplausible mechanism was investigated to understand this desired derivative at ambient temperature and with reasonably unprecedented product formation. The reaction is initiated by good yield. Tosyl group remain at the 2-position of product an attack of the base-activated nucleophilic TosMIC to the CÀ2 which is explained by plausible mechanism. Mechanism double bond chromone carbon A,being aMichael acceptor, suggests that the reaction is most possibly initiated by an followed by ring closure, which gives rise to the intermediate B. attack of the nucleophilic TosMIC to the double bonded Subsequent formation of intermediate C is followed by chromone ring opening to give intermediate D,from which by loss of the formyl instead thetosyl group the more stable aromatic pyrrole derivatives were the final products as depicted in Scheme 15. Hu and co-workers reported aone-pot consecutive procedure for synthesis of multisubstituted pyrroles. In this approach, electron deficient alkenes 27 are reacted with tosylmethyl isocyanide and aryl halide 28 in presence of mixed base and copper iodide to afford N-arylated 3,4-disubstitutedpyrroles 29 as depicted in Scheme 16. Actually, it is avan Leusen pyrrole synthesis followed by aligand-mediated copper-catalyzed N- Scheme14. Synthesis of pyrrole derivatives using chromene-3-carboxalde- arylation of pyrroles. Although both reaction steps are hyde.

Scheme15. Possible mechanism for pyrrole synthesis from chromene-3-carboxaldehyde.

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synthesis as per van Leusen strategy. Plausible mechanism suggested that reaction proceeds via [3+2] cycloaddition of TosMIC with Michael acceptor to provide imidoyl ion intermediate followed by 1,5 sigmatropic hydrogen shift to afford desired cyclopenta[b]pyrrole derivatives with good yield without using any metal catalyst. The similar protocol was further reported by this author taking stoichiometric amount of Scheme16. Synthesis of N-arylated pyrrole derivatives using electron sodium hydroxide as abase and tetrahydrofuran as areaction deficient alkene. medium at ambient temperature.[13] Yu and co-workers developed the copper catalysed protocol to afford multi-substituted pyrrole derivatives from ethyl allenoates 32 and tosylmethyl isocyanide in adifferent fashion promoted by bases, they could not share acommon base as shown in Scheme 18. In this protocol, aryl sulfonyl moiety, because significantly different strengths of bases were required whichfunctions as the electro-withdrawing group in the α- for each of them. Amixture of base namely sodium tert- carbon of the isocyanide, was found to migrate to the γ-carbon butoxide and cesium carbonate was used for sequential of the allenoate in the final pyrrole derivatives 33.The structure reaction with high efficiency and excellent yield. This simple, of this unpredicted product was confirmed by X-ray crystallog- efficient,economical one-pot protocol avoids work up wastage raphy. The reaction condition was optimized after varying of first step affording desired product with wide substrate solvent, temperature and catalyst loading. Out of various scope.[12] solvent screened, 1,4-dioxane gave better result and yield was Liu et al developed the bicyclization protocol from further improved when 1,4-dioxane was mixed with water in a isocyanide to afford cyclopenta[b]pyrrole from acyclic substrate ration of 10:1 at 50 °C. Different copper catalyst was also trying as illustrated in Scheme 17. To optimize the reaction condition, but best result was obtained with copper oxide and 1,10- aprototype reaction was performed using alkenoyl ketene phenanthrolineligand. Reaction scope was also generalized dithioacetal 30 and tosylmethylisocyanide using sodium taking allenoate and isocyanide bearing arange of substituents hydroxideasabase and dimethyl formamide as reaction and found that halogen is more tolerated on isocyanide medium to afford desired cyclopenta[b]pyrrole derivatives 31 compare to methyl substituent. Aplausible mechanism involv- with good to excellent yield in short span of time. Scope of ing an elimination and re-addition of atosyl group was also reaction was also explored using avariety of substrate bearing proposed. All the synthesized derivatives were characterized electron deficient, electron rich, aryl, heteroaryl and alkyl using spectral analysis.[14] substituent to synthesize the exclusively regioselective product. Aplausible mechanism for the copper-catalyzed cyclization Solvent play acrucial role in bicyclization protocol which is between allenoate and tosylmethyl isocyanide was proposed.

evident by changing solventtopolar one leading to pyrrole The mechanism starts with aCÀHbond activation by Cu2O catalyst to give acopper-isocyanide complex A with simulta- neous formation of water. A[3+2] cycloaddition between allenoate starting material and intermediate A takes place to give intermediate B.The intermediate B then undergoes protonolysis leading to the formation of intermediate Cand

the regeneration catalyst. ACu2O-assisted elimination of the 4- methylbenzenesulfinate group (TsÀ)produces an electrophilic species D.Recombination of D with tosyl group affords the pyrrole copper complex E.Protonolysis of compound E leads to the formation of desired pyrrole product and the recovery of the copper catalyst as shown in Scheme 19.

Scheme17. Synthesis of cyclopenta[b]pyrrole from acyclic substrate.

Scheme18. Synthesis of multi-substituted pyrrole derivatives from ethyl allenoatesand TosMIC.

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Scheme19. APlausible mechanism for pyrrole synthesis from allenoates.

Scheme20. Tandem Michael addition for synthesis of 2-acyl pyrroles.

Liu and his team reported the tandem Michael addition/ Tavani and his co-workers established aone-pot protocol formal isocyanide insertion into the acyl CÀCbond to afford for synthesis of imidazole derivatives by reacting arylazosul- polyfunctionalized2-acylpyrroles asillustrated in Scheme 20. A fones 37 with conjugate bases of (tertbutoxycarbonyl)methyl prototypereaction was performed for optimization using (E)-2- 38 and TosMIC. The final imidazole derivatives 39 were benzylidene-3-oxobutanenitrile 34 and tosylmethyl isocyanide afforded with moderate to good yield depending upon the as amodel substrate. 4-phenyl-1H-pyrrole-3-carbonitrile 35 was nature of substituent as illustrated in Scheme 21. All synthe- the exclusive product obtained in presence of sodium sized compounds werecharacterized and mechanistic study hydroxideinDMF. Product was turned to afford 3,4-disubsti- was also explored by authors.[16] tuted 2-acylpyrrole in acetonitrile in the presence of DBU (1,8- Dixon et al reported the synthesis of 2-imidazolines bearing diazabicyclo[5.4.0]undec-7-ene) at room temperature. The re- two adjacent stereocenters using chiral amine as aligand. In action outcome was optimized taking different copper halide this enantioselective protocol, they developed the first enantio- salt and copper chloride was turned to be best catalyst to selective and diastereoselective method reacting ketimines 40 afford 2-acylpyrrole with excellent yield with the small amount with tosylmethyl isocyanide catalyzed by silver oxide and a of 4-phenyl-1H-pyrrole-3-carbonitrile 36.The reaction condition dihydroquinine-derived N,P-ligand to afford 2-imidazolines 41 was also extrapolated on various enones to afford 2-acylpyr- with high yields as depicted in Scheme 22. The scope of role. Both the products were separated using column chroma- reaction was generalized by exploring diverse range of tography and very well characterized using spectroscopic ketimines including aliphatic, aromatic and heteroaromatic techniques.[15]

2.1.2. Synthesis of imidazole scaffold Imidazole is afive-membered heterocyclic compound having

structural formula C3N2H4.Itisalkaline in nature and exists as colourless solid that is soluble in water. It is adiazole in which two nitrogen atoms are not adjacent while they are present at first and third position. Manynatural as well synthetic drugs contain imidazole moiety such as alkaloids, antifungal drugs, antibiotic and sedatives. Scheme 21. Synthesis of imidazole derivativesfrom arylazosulfones.

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Wu and co-workers developed an I2/FeCl3-co-promoted formal [2+2+ 1] annulations protocol to afford imidazoles by

neighboring group (ÀCH2OH) assistance as depicted in Scheme 24. In this novel and unique strategy, tosylmethyl isocyanide acts as aC1N1 “two-atom synthon”. Reaction was optimized for anovel van Leusen-typeimidazole synthesis from aryl methyl ketones 45,2-aminobenzyl alcohols 46 and TosMIC as starting substrate under acidic conditions to produce avariety of 1,4-disubstituted imidazoles 47.After screening of various acids, it was found that ferric chloride gave the excellent yield when combined with 0.8 equivalent of iodine at 110 °Ctemperature using DMSO as reaction medium. Further increase of iodine loading or temperature diminishes the

Scheme22. Synthesis of chiral imidazole derivatives from ketimines. reaction yield. Substrate scope of imidazole synthesis was also explored by varying diverse range of methyl ketones substrates bearing electron rich and electron deficient groups, although 1-naphthyl or 9-anthracene methyl ketones were unable to variant. All compounds were characterized by spectroscopic give product due to steric hindrance. Structure of prototype analysis and stereoselectivity was confirmed by computation compound was determined by X-ray crystallography. The [17] approach and X- ray diffraction method. neighbouring group CH2OH in the target product provided A. M. van Leusen and his co-workers reported the synthesis flexibility for further structural diversification and methodology of imidazole derivatives from aldimine derivative and was scaled up upto gram scale.[19] tosylmethyl isocyanide. Diverse range of aldimines was pre- Based on the product obtained, amechanistic reaction pared from readily available aldehyde and N-dimethylsulfamoyl pathway for this [2+2+ 1] annulation is exemplified in amide in refluxing toluene. In this protocol, reaction of Scheme 25. Initially, Acetophenone 1a undergoes iodination sulfamoyl aldimine 42 was furnished with tosylmethyl and Kornblum oxidation sequences to form 1ab in the isocyanide using potassium carbonate as abase and mixture of presence of iodine and DMSO. Next, the first cyclization occurs methanol and DME as the reaction medium to afford dimethyl to generate intermediate A from the reaction of 1ab with 2a. sulfamoyl substituted imidazole derivatives 43.The dimethyl Meanwhile, intermediate F is produced from 3 via hydrolysis sulfamoyl group was further removed by using 30%hydro- with HI. Subsequently, an intermolecular dehydration conden- bromic acid to afford desired imidazole derivatives 44 with sation occurstoafford intermediate B from active intermedi- good yield as illustrated in Scheme 23. All synthesized com- ates F and A.Intermediate B then undergoes intramolecular pounds were purified by crystallization using isopropanol and nucleophilic addition to form cyclized intermediate C which characterized by spectroscopic analysis and X-ray produce intermediate D through release of tosyl group. crystallography.[18]

Scheme23. Synthesis of imidazole derivatives from sulfamoyl aldimines.

Scheme24. Synthesis of imidazoles by neighbouring group assistance strategy.

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Scheme25. Apossible mechanism for [2+2+ 1] annulations to afford imidazoles.

Subsequently, aring-opening process followed by aromatiza- was supported by cross coupling reaction and HRMS analysis. tion furnished final products under acidic conditions. Methyl ketones serve as the α-dicarbonyl compounds and Anxin Wu and co-workers developed awell-designed aldehydes in this Radziszewski-type reaction. Similar mechanis- molecular fragment assembly to afford trisubstituted imida- tic concept was proposed as illustrated in Scheme 25.[20] zoles via aformal [2+ 1+ 1+1] annulations as illustrated in Scheme 26. Aprototype reaction was conducted using Aceto- 2.1.3. Synthesis of indole scaffold phenone 48, p-toluidine 49 and tosylmethylisocyanide in one- pot in the presence of 1.6 equivalent molecular iodine and Indole is an aromatic heterocyclic compound with molecular

dimethyl sulfoxideasareaction medium at 100 °C. The desired formula C8H7N. In this bicyclic scaffold, pyrrole is fused with trisubstitutedimidazole 50 was obtained with 43%yield only benzene ring. It is widely distributed in natural environment, which demands for further investigation the reaction parame- amino acids and pharmaceuticals. Non-steroidal anti-inflamma- ter. Different Bronsted acids were also tried but nothing was tory drug indomethacin also contains indole as its core part able to improve yield. Product yield was surprisingly increased and responsible for pharmacological profile. when reaction was conducted at 110 °Ctemperature and Campo et al reviewed the synthesis of 3-nitroindole moiety loading of iodine was decreased to 0.8 equivalents. Wide from nitro alkene and tosylmethyl isocyanide derivative. In this substrate scope was also explored including sterically hindered methodologynitrolkene act as aMichael acceptor. For syn- 2-naphthyl methyl ketone as asubstrate, however reaction was thesis ofindole, pyrrole ring is constructed by van Leusen unable to provide product with acetone. The reaction scope method. Michael acceptor 51 is reacted with 1-tosylalk-1-enyl was extended to substituted anilines with electron rich and isocyanide 52 using potassium tertiary butoxide as abase to electron deficient groups. The reaction mechanism was inves- afford indole derivatives 53 with high yield as illustrated in tigated by performing D-labelingand 13C-labeling experiments Scheme 27. Reaction is well explained mechanistically and under the optimized conditions. The investigated mechanism

Scheme26. An elegant molecular fragment assembly for synthesis of trisubstituted imidazoles.

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Scheme27. Synthesis of indole derivatives from Michael acceptor.

Scheme28. Synthesis of chiral oxazoline derivatives from ketone.

concluded that thermal electrocyclization followed by dehydro- genation afforded desired indole derivatives.[21]

2.1.4. Synthesis of oxazole/oxazoline scaffold Oxazole is five-membered aromatic heterocyclic compound containing three carbon atoms, one nitrogen and one oxygen. Scheme 29. Synthesis of oxazole derivatives from solid phase TosMIC. Oxygen and nitrogen atom are present at 1st and 3rd position in this privilegedscaffold. Different strategies for synthesis of oxazolefrom tosylmethyl isocyanide are reported by chemists. ammonium hydroxide afforded the desired product with Cozzi and co-workers developed the stereoselective addi- excellentyield in short span of time.[23] tion of tosylmethyl isocyanide to ketones 54 to afford oxazoline Zhang et al reported an efficient, tandem [3+2] cyclo- 55 as depicted in Scheme 28. Stereoselectivity is imparted by addition/decarboxylationapproach of α-keto acid 59 and

chiral aminoalcohol as aligand. Acombination of Me2Zn and tosylmethyl isocyanide to afford monosubstitutedoxazole 60 aminoalcohol catalyst encouraged the aldol addition/cycliza- as illustrated in Scheme 30. The reaction was promoted by tion reaction to synthesize oxazolines holding afully sub- copper salt, under oxidant-free condition, aseries of mono- stitutedstereocenter using dichloromethane as areaction substituted oxazoles have been created. Reaction was opti- medium with excellent yields. The chiral oxazolines were then mized by varying copper salt, base and solvent and it was used to deliver enantioenriched building blockshaving tertiary concluded that copper chloride with 1,10-phen as acatalyst alcohol motifs like hydroxyl aldehydes, hydroxyl acids, and and potassium hydroxide as abase using dimethyl formamide

hydroxyl esters after acidic hydrolysis. Me2Zn proved to be a as reaction medium afforded the desired product with suitable reagent for the deprotonation and activation of excellent yield in short span of time. The synthesized products nucleophiles in the presence of aminoalcohols. It was proved were characterized using spectroscopic analysis and plausible [24] mechanistically that Me2Zn is the deprotonating reagent that is mechanism was investigated. able to form the corresponding MeZn-TosMIC intermediate. To understand the product formation, aplausible mecha- The capability of the chiral zinc alkoxide to coordinate with nism involving Cu(I)-promoted tandem reactionwas exempli- ketone and MeZn-TosMICyields the stereoselective response. fied as described in Scheme 31. In the prensence of CuCl/1,10- This hypothesis was confirmedbydeuteration experiments.[22] phen and KOH, α-oxocarboxylates A form intermediate B. Ganesan et al reported thesolid phase synthesis of oxazole Similarly, tosylmethylisocyanide form the cuprioisocyanide C. using readily available aromatic aldehyde 56 and tetrabutyl Intermediate B and C experience [3+2] cycloadditionreaction ammonium hydroxide as abase. Asolid phase version of to generate the intermediate D.Subsequently, decarboxylation tosylmethyl isocyanide (PS-TosMIC) 57 was used in this of intermediate D followed by elimination of tosylate anion protocol to afford 5-aryl oxazole derivatives 58 as illustrated in affords the aromatized monosubstituted oxazole products. Scheme 29. Optimization study indicates that tetrabutyl

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Scheme30. Synthesis of oxazole derivatives from α-keto acid.

Scheme31. Aplausible mechanism for synthesis of oxazole derivatives from α-keto acid.

2.1.5. Synthesis of triazole scaffold 2.2. Synthesis of fused heterocycles Triazole is afive-member heterocycle consisting of two carbons Heterocyclic ring systems that are formally derived by fusion

and three nitrogen atoms with molecular formula C2H3N3. with other carbocyclic or heterocyclic rings are called fused Triazole is aprivileged scaffold due to its diverse pharmaco- heterocycles. For example, with the benzo-fused unsaturated logical activities. Triazole is an integral part of natural products nitrogen heterocycles, pyrrole provides indole and isoindole and pharmaceuticals. Copper is widely used catalyst for rings depending on the positioning. The pyridine analog is regioselective formation of triazole. Two types of triazole are called quinoline. For azepine, benzazepine is the preferred possible one is 1,2,3-triazole and another is 1,2,4-triazole. name. Similarly, the compounds with two benzene rings fused Various synthetic strategies are reported for construction of to the central heterocycle are acridine, carbazole and dibenzoa- this priviledged moiety. zepine which are of great pharmaceutical significance. Thieno- Van Leusen and his team reported the synthesis of 1,2,4- thiophene are the fusion of two thiophene rings. Herein, we triazole derivatives 62 from diazonium salts 61 using mild are describing different strategies for synthesis of fused hetero- potassium carbonate as abase as illustrated in Scheme 32. cycle using tosylmethyl isocyanide as one of the active reagent. Diazo compounds contain the nitrogen-nitrogentriple bond. Vaquero et al reported the synthesis of carboline moiety Base is responsible to generate nucleophile in the method- from tosylmethyl isocyanide and its derivatives using hetero- ology. Synthesized compounds were well characterized by cyclization approach. Carbolines are basically pyridine fused spectroscopic analysisand melting point of all compounds with indole so they are also called pyrido-indoles and exist in were also corrected.[25] four isomeric forms. This cyclization takes advantage of the tendency of isocyanides to act both as nucleophiles and electrophiles, which mean that cyclization of aTosMIC derivative by electrophilic aromatic substitution and attack of the isocyanide to the corresponding electrophile would occur as a tandem process. Carboline derivatives 65 were synthesized using acid catalyzed cyclization of corresponding α-indol-2- ylmethyl α-alkyl TosMIC 64 derivatives which was achieved by the addition of respective indole derivatives 63 and two different alkyl groups and in asingle one-pot phase transfer catalyst (PTC) process as illustrated in Scheme 33. This methodology has been successfully applied using protons, aldehydes, Scheme32. Synthesis of triazole derivatives from diazonium salt.

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Scheme33. Synthesis of γ-carboline derivatives from indole and substituted tosylmethylisocyanide.

ketones,epoxides, aziridines, iminium salts, and halogenating afforded the 3-phenyl-1H-benzo[f]indole-4,9-dione with good agents as electrophiles.[26] yields through one-carbon-atom ring extension along with acyl Aplausible mechanism was proposed to understand the 1,2-migration strategy. This innovative procedure features possible formation of azolo-pyridine derivatives asillustrated in operationally simple, economical, accepted with broad sub- Scheme 34. It involves initial nucleophilic substitution of strate scope and high yield.[3] TosMIC to the bromomethylindole followed by intramolecular Bergman et al developed thesynthesis of 4-Oxo-4,5-dihy- transfer of the tert-butoxycarbonyl protectinggroup. Subse- dro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester de- quent cyclization and 1,2-elimination of toluenesulfonate rivatives 68 by reacting TosMIC with 3-methylene-oxindole would afford the azolopyrimidine derivative. acetic acid ethyl ester 67 under basic condition as illustrated in In 2017, Yennam et al synthesized avariety of benzo[f] Scheme 36. The protocol afforded desired product with good indole-4,9-diones 66 from readily available aromatic aldehydes yield using potassium tertiary butoxideasabase in refluxing 4,1,3-Indanedione 5 and tosylmethyl isocyanide (TosMIC) by a tetrahydro furan as reaction medium under inert environment. one-pot protocol using cesium carbonate as abase and All the products were characterized using spectroscopic refluxing 1,4-dioxane as the reaction medium as shown in analysis and mechanistic study was investigated.Mechanism Scheme 35. The reaction yield depends on the nature and type suggests that initially Michael addition would lead to adduct. of substituent present on aldehyde. Although, we have After subsequent loss of p-toluenesulfinate, cleavage of the discussed that in ethanol, pyrrole derivatives wereafforded oxindole moiety and recyclization afforded the desired using same reaction conditions. Surprisingly, the change of the pyrroloquinolone.[27] solvent from EtOH to THF or 1,4-dioxane at reflux temperature

Scheme34. Mechanistic explanation for synthesis of γ-carboline derivatives.

Scheme35. Synthesis of benzo[f]indole-4,9-diones derivatives from 1,3-Indanedione and aldehydes.

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Scheme36. Synthesis of pyrrolo quinolone derivativesfrom oxindole derivatives.

Scheme37. Mechanistic explanation for synthesis of pyrrolo quinolone derivatives.

Ahypothetical mechanism for formation of pyrroloquino- products with good yield in short span of time. Among the

line was predicted as shown in Scheme 37. An initial Michael screenedbases such as Cs2CO3,NaOH, KOH, K2CO3 and DBU, addition would lead to adduct A.Adduct A cyclises to afford sodium hydroxide has turned to be the best choice. The simple, the intermediate B after loss of p-toluenesulfinate. Cleavage of efficient, economical protocol had wide substrate scope and the oxindole moiety, promoted by the basic conditions, results acquiescent to gram scale synthesis.[28] in intermediate C,which recycles to furnish the desired Amechanistic pathway for the domino synthesis of pyrrolo- pyrroloquinolone derivative. quinolines is proposed as shown in Scheme 39. The overall Xu and his co-workers reported atandem formal [3+ 2] process may involvefirst Michael addition of TosMIC to cycloaddition/cyclization reaction of aminochalcones 69 and aminochalcone A under basic conditions to produce carbanion tosylmethyl isocyanide derivatives to afford diverse tricyclic intermediate B which lead to intramolecular cyclization to form pyrrolo[3,4-c]quinolines 70 in high to excellent yields as the imidoyl anion intermediate C followed by hydrogen shift illustrated in Scheme 38. In this domino procedure, three new and elimination of tosylic acid to give the pyrrole intermediate bonds and two rings are successively formed at ambient D as per van Leusen protocol. The ketone group of intermedi- reaction conditions. Optimization study of solvent concluded ate D furnishes final pyrroloquinolines after intramolecular that ethanol has proved the best reaction medium to afforded condensation in this tandem formal [3+2] cycloaddition/ cyclization series. SÀJJiand co-workers reported an efficient and applied synthetic approach to afford 2H-pyrrolo[3,4-c]quinoline derivatives 72 by the reaction of 2-aminoarylacrylates/2-aminochalcones 71 and tosylmethylisocyanide in one pot as depicted in Scheme 40. Optimization study revealthat potassium tertiary butoxide in tetrahydro furan under heating is suitable for reaction. It was found that 60 °Cwas the suitable reaction temperature to afford the products with good to excellent yield. All products were characterized by reported spectroscopic data and melting points were uncorrected. Scheme38. Synthesis of pyrrolo quinolone derivativesfrom amino chal- Mechanism is believed to follow the same sequence as shown cones. in Scheme 39.[29]

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Scheme39. Mechanistic pathway for synthesis of pyrrolo quinolone derivatives.

employed, the reaction productivity was further enriched with 90%yield without the use of any base. An economical, simple, efficientand environment friendly method offer the broad substrates scope including aromatic and heteroaromatic to afford corresponding products in moderate to good yields. The structure of model compound was confirmed by NMR,HRMS and X-ray diffraction method.[30] Ding and co-workers reported anew and efficient synthesis of multisubstituted 1H-imidazo-[4,5-c]quinoline derivatives via Scheme40. Synthesis of pyrrolo quinolone derivativesfrom aminochalcones sequential van Leusen/Staudinger/aza-Wittig/carbodiimide- in THF. mediated cyclization approach as illustrated in Scheme 42. Initially Azides 75,Amine 76 and tosylmethylisocyanide were reacted in presence of potassium carbonate as abase using a Hao et al reported anovel iron chloride catalyzed solvent mixture of methanol and 1,2-dimethoxyethane at 76 °C tosylmethylation of imidazo[1,2-α]pyridines 73 with p- to afford imidazole derivatives 77 via van Leusen approach. toluenesulfonylmethyl isocyanide to afford 3-tosylmethyl imi- These imidazole derivatives were further reacted with triphenyl

dazo[1,2-α]pyridines 74 in asolvent mixture of H2Oand phosphine to yield iminophosphorane 78 via Staudinger PEG400under an argon atmosphere as illustrated in approach. Atandem aza-Wittig reaction of iminophosphorane Scheme 41. This procedure offers afacile synthetic route for with isocyanate created carbodiimide intermediate 79 in the functionalization of the imidazo[1,2-α]pyridine scaffold with moderate to good yield. However, the cyclization of carbodii- diverse substrate compatibility. The reaction was optimized by mideswas successfully realized in refluxing 1,2-dichloroben- varying the effects of solvents, iron resources, and base and it zene at 180 °Cand the 1H-imidazo[4,5-c]quinolines 80 were

was found that the reaction performed in H2Ogave the 62% afforded in moderate to good yields. All the synthesized yield, despite other solvents using iron chloride as acatalyst. products were characterized by spectral analysis and reaction [31] But when amixed solvent of H2Oand PEG400 (7:3)was was generalizedusing broad substrate scope.

Scheme41. Synthesis of imidazo pyridinederivatives via CÀHfunctionalization.

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Scheme42. Synthesis of imidazo quinoline derivatives via van Leusen/Staudinger/Wittig/ cyclization approach.

Minguez et al reported the synthesis of pyrrolo pyrimidine was optimized reactingdihydro β-carboline imines 84 and p- derivatives using cyclocondensation of pyrrole-2-carboxalde- toluenesulfonylmethyl isocyanides to afford substituted N- hyde and tosylmethyl isocyanide as illustrated in Scheme 43. In fused imidazo 6,11-dihydro β-carboline derivatives 85 by this approach, pyrrole-2-carboxaldehyde derivatives 81 were varying base, solvent, temperature and time. It should be noted initially reacted with tosylmethyl isocyanide using DBU as a that the reaction washeterogeneousinnature. When the base to afford 2-tosyl pyrrolo pyrimidine derivatives 82,which reaction temperature was increased there was adecrease in were further desulfonyl in presence of sodium amalgam using the isolatedyield of the product. Optimization study reveals asolvent mixture of tetrahydro furan and methanol and that products were afforded with good yield using water as afforded desired pyrrolo pyrimidine derivatives 83 with good reaction medium without any base at ambient temperature in yield.[32] short span of time. This method also can be generalized to Suresh et al reported abase-free construction of imidazole scale up of the reaction to the gram scale to afford desired nucleus fused with dihydro β-carboline imine under aqueous 6,11-dihydro-5H-imidazo-pyrido[3,4-b]indole derivatives.[33] conditions as illustrated in Scheme 44. Compounds halting Aplausible mechanism for this metal, base-free imidazole from the fusion of imidazole and β-carboline have reported formation has been depicted in Scheme 45. Initially, the with interesting pharmacological profile.Reaction condition starting material dihydro β-carboline imine A itself would act as

Scheme43. Synthesis of pyrrolo[1,2-c]pyrimidine derivatives from pyrrole-2-carboxaldehyde.

Scheme44. Synthesis of imidazo carboline derivatives under aqueous medium.

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Scheme45. Aplausible mechanism for synthesis of imidazo carboline derivatives.

abase to abstract aproton from TosMIC to provide aC- resulted an imine intermediate, which upon treatment with nucleophile B that would add on to the dihydro β-carboline toluenesulfonylmethyl isocyanide in presence of potassium imine followed by cyclization resulting in the formation of carbonate as abase and asolvent mixture of acetonitrile and intermediate C via intermediate B.Another molecule of the dimethyl sulfoxide at 80 °Cgave rise to N-1 substituted nitro starting dihydro β-carboline imine would abstract aproton imidazole derivatives 88.The nitro group of this compound from intermediate C followed by the removal of the tosyl group was further reduced into amine functionality 89 using sodium that could result in the formation of final imidazo carboline borohydride as areducing agent and nickel chloride hexahy- derivative. Later, the product might also act as abase to repeat drate as acatalystinacetonitrile and water. The amino group the same plausible reaction mechanism cycle. containing compound was further reacted with benzaldehyde

Bhattacharya et al reported Yb(OTf)3 catalyzed synthesis of 90 using standard condition to afford desired imidazo 1,4-diaryl substituted imidazo[4,5-c]quinolines via modified quinoline derivatives 91.Reaction condition was optimized for Pictet-Spengler approach as illustrated in Scheme 46. Fused this key step by varying diverse range of lewis or bronsted acid quinoline and imidazole systems are privileged scaffold for catalyst and solvent. Results were fruitful while using yerbium their multitude of pharmacological profile. Prominent examples triflate as acatalyst in nitrobenzene as reaction medium at containing this scaffold are imiquimod and its structural 150 °Ctemperature to afford desired product with good yield. analogue resiquimod, used as immune response modifier are Reaction was generalised by taking various aniline and available in market. The reaction was started reacting 2- benzaldehyde derivatives and all products were characterized nitrobenzaldehyde 86 with aniline derivatives 87 which using spectroscopic analysis. All synthesized compounds were

Scheme46. Synthesis of imidazo quinoline derivativesusing lewis acid.

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also evaluated for anti-cancer activity and few compounds products were afforded in excellentyield when silver acetate were found active, in which the highest activity was exhibited was used as acatalyst and potassium carbonate as abase. by 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline hav- Acetonitrile turned to be the best solvent in this domino [3+ ing IC50: 103.3 μM.[34] 2]-cycloaddition/imidoyl cyclization/ring opening/aromatization The mechanism for yerbium triflate catalysed cyclization is reaction. Reaction was generalizedbyemploying broad shown in Scheme 47. The electrophilic attack of imidazole ring substrate bearing electron donating and electron withdrawing, followed by oxidative aromatization is envisioned as key step in aromatic and heteroaromatic group. This reaction represents a the formation of final product. Given the requirement of high new strategy for the construction of this tricyclic scaffold temperature in the reaction, an alternative CÀHactivation step through one-carbon-atom ring expansion along with acyl 1,2- could also be envisaged. migration. Mechanism is believed to process as same sequence In 2016, Zhang and co-workers reported asilver-catalyzed described in Scheme 3a.[35] tandem reaction for direct synthesis of benzo[f]indole-4,9- Wang et al reported anovel reaction of 3-phenacylidene diones derivatives 93 as depicted in Scheme 48. In this oxindoles 94 with tosylmethyl isocyanide to afford pyrrole protocol, 2-methyleneindene-1,3-dione derivatives 92 were derivatives 95 as illustrated in Scheme 49. Optimization study reacted with tosylmethyl isocyanide in presence of acatalyst of reaction reveals that the products were afforded with good and base. Optimization study of reaction concluded that to excellent yield while using potassium tertiarybutoxide as a base and methanol as reaction medium. The reaction proceeded under mild conditions, providing apowerful synthetic tool for the construction of pyrrole derivatives through carbon- carbon bond cleavage approach. The prototype compound was characterized by NMR spectroscopy and unambiguously demonstrated by X-ray diffraction analysis.[36] Wang et al also developed asimple and convenient synthetic approach to access the 3H-pyrrolo[2,3-c]quinolin- 4(5H)-one derivatives 98 from indoline-2-one derivatives as illustrated in Scheme 50. Initially, 3-phenacylideneoxindole 96 and 1-((cyclohexylidene(isocyano)methyl)sulfonyl)-4-meth- ylbenzene 97 were reacted as the model substrates under basic medium. Reaction was optimized by taking diverse range of base and solvent and concluded that combination of potassium tertiary butoxide as abase and tetrahydro furan as a Scheme47. Plausible mechanism for synthesis of imidazo quinoline deriva- medium afforded the desired products in good to excellent tives.

Scheme48. Synthesis of benzo[f]indole-4,9-diones derivatives using silver acetate.

Scheme49. Synthesis of pyrrole derivatives from phenacylidene oxindoles.

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Scheme50. Synthesis of pyrrolo quinoline derivativesfrom phenacylidene-oxindoles.

yields. The easily available materials, simple, efficient, econom- considerable regioselectivity as shown in Scheme 52. To ical and mild reaction conditions, short reaction time are the optimize the reaction parameter, amodel reaction was advantages of this protocol. All synthesized products were performed using azomethine imine 99 and ethyl isocyanoace- characterized using spectroscopic analysis.[37] tate in the presence of copper iodide as acatalyst and DBU as Based on the formation of final products, aplausible abase in ethanol at room temperature, which furnishes the mechanism for this reaction is exemplifiedinScheme 51. [3+ 2] annulated pyrrole product with low yield only. Switching Initially, the 1-((cyclohexylidene(isocyano)methyl)sulfonyl)-4- to aprotic reaction media substantially decrease the pyrrole methylbenzeneisdeprotonated under basic condition to form product and increased the desired [3+ 3]-cross-cycloaddition an anion on the α-positionoffunctional isocyanide and the product which was confirmed as pyrazolo[1,2-a][1,2,4]triazine- carbon-carbon double bond could migrate to the cyclohexyl 3-carboxylate 100 by X-ray crystallography and spectroscopic ring. Then, anucleophilic addition will occur to the carbon- analysis. Different trial of copper catalyst, base and solvent carbon double bond of oxindole A to give the intermediate B, concluded that reaction afforded desired triazine product when followed by the ring closing with the isocyanide group to form copper iodide is combined with DBU in chloroform at room the intermediate C.The intermediate D could be achieved by temperature. In the absence of copper iodide, reaction did not the elimination of tosyl group from intermediate C.Then the give any sign of desired product which prove the importance intermediate E will be formed by the ring opening of of catalyst in this unique methodology. Wide reaction scope intermediate D by losing aproton ion and the carbon anion of was claimed taking various azomethine imines bearing sub- intermediate E will attack the isocyano group to close the six stituted aryl groups, 2-naphthalenyl and heteroaryl groups and membered rings and the final product was synthesized. substituted tosylmethylisocyanidederivatives.[38] Liu and his team developed [3+ 3]-cross cycloaddition of α- The plausible mechanism suggested based on the product acidic isocyanides to afford 1,2,4-triazine derivatives with formation. Reaction starts with the formation of α-cuprioisocya-

Scheme51. Aplausible mechanism for synthesis of pyrrolo quinoline derivatives.

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Scheme52. Synthesis of 1,2,4-triazine derivatives from azomethine imine and isocyanide.

nide A from tosylmethyl isocyanide in the presence of CuI and available precursors without the use of any metal catalyst as DBU. Then, the nucleophilic addition of α-cuprioisocyanide A illustrated in Scheme 54. To find the best possible reaction on the imine B takes place to form intermediate C.Insertion of parameter, 2-methyleneaminochalcone 101 was reacted with isonitrile into the NÀCu bond generates the imidoyl-copper tosylmethyl isocyanide in the presence of DBU (1,8-diazabicyclo intermediate D followed by protonation to give 1,2,4-triazine [5.4.0]undec-7-ene) in acetonitrile at room temperature. Differ- with regeneration of the catalysts, CuI and DBU, for the next ent base with varying amount was also studies and found that catalytic cycle as shown in Scheme 53. DBU gave the better yield of desired product when used 2.0 Xu et al reported thetandem cyclization-annulation proto- equivalents. Duringthe screeningofvarious protic and aprotic col to deliver pyrrolo[2,3-c]quinoline derivatives from readily solvents, acetonitrile was turned to be better choice. The scope of this domino bicyclization reaction was generalized by using various 2-methyleneaminochalcones bearing various functional groups including electron-deficient aryl, electron-neutral aryl, electron-rich aryl, hetereoaryl and alkyl groups. The reaction was also extrapolated using isocyanoacetate instead of tosylmethyl isocyanide affording the tetrahydro-3H-pyrrolo[2,3- c]quinolines 102 with excellent yield. It was noted that only one of the four possible diastereomers was synthesized in this protocol, indicating that it proceeds in ahighly diastereoselective manner. The relative configurationofprototype compound was confirmed by single crystal X-ray diffraction method.[39]

2.3. Synthesis of tethered/linked heterocycles These are basically heterocyclic compounds. If two heterocyclic moieties are connected to each other by covalent bond, then these are called linked or tethered heterocycle. These types of molecules are generally designed for synergistic pharmacolog- Scheme53. Mechanistic explanation for synthesis of 1,2,4-triazine deriva- ical activity. Herein, we are focusingonsynthetic strategies for tives. tethered heterocycles using tosylmethylisocyanide and its derivatives as an energetic reactant. Chakrabarty and co-workers developed thesynthesis of indole tethered with oxazole scaffold. The reaction was started with 3-formylindole 103 and tosylmethyl isocyanide using potassium carbonate as abase and refluxing methanol as reaction mediumasillustrated in Scheme 55. Two products were afforded in nearly quantitative overall yield, one was 5-(3-indolyl)oxazoles 104,and another was E-2-(3-indolyl)-2-tosylethenamines 105.The reaction was generalized using wide substrate scope and synthesized Scheme54. Synthesis of fused pyrrolo[2,3-c]quinoline from 2-meth- desired compounds and side products werecharacterized yleneaminochalcone. using spectroscopic analysis. The representative compound

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Scheme55. Synthesis of indole linked withoxazole derivatives from TosMIC.

Scheme56. Synthesis of imidazole linked with dihydro oxane derivatives from ketimine.

was also confirmed by the single crystal X-ray crystallographic which suggest that the reaction is believed to involve analysis.[40] realization of an imidazoline intermediate, followed by the Hoffmann et al reported the preparation of aseries of 1,5- methyl group migration and subsequent aromatization to disubstituted-4-methyl imidazoles linked with dihydro oxane afford the imidazole ring derivatives with good to excellent derivatives 108 as illustrated in Scheme 56. The reaction was yield at ambient temperature using methanol as reaction proceeded using an acetimine 106 and tert-butylamine 107 medium.[41] with tosylmethyl isocyanide and its substituted derivatives Aplausible mechanism for formal imidazole synthesis from using catalytic amounts of bismuth(III) triflate. Acetamine ketimine is envisaged in Scheme 57. The mechanism is to be derivatives were prepared from corresponding dehydroacetic the anticipated via imidazoline-carbocation intermediate with- acid and TosMIC. Compounds were characterized using spec- out suitable hydrogens next to the positively charged carbon, troscopic analysis and plausible mechanism was investigating thus leading to migration of the methyl group to the adjacent position, and subsequent aromatization. This intramolecular rearrangementwould explain the formation of 4-methyl imidazole in astraightforward manner. The author further extended the above strategy by modifying ketamine to enaminic tautomerofsecondary ketimine to afford 1,4-disubstituted 5-methylimidazole under similar reaction condition as illustrated in Scheme 58. In this protocol, the reaction of TosMIC with an Aldimine or its enamine tautomer 109,which is formedfrom condensation of an aldehyde with an amine, gives rise to the corresponding imidazole ring through asimilar mechanism, i.e.,cycloaddition

Scheme57. Mechanistic explanation for synthesis of imidazole from keti- of tosylmethyl isocyanide to the aldimine carbon-nitrogen mine. double bond, cyclization, and proton shift to produce an

Scheme58. Synthesis of imidazole sandwiched withthiophene and dihydro oxanederivatives from ketimine.

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imidazoline intermediate, followed by aromatization to 1-carboxaldehyde 115 was reacted with (ethoxycarbonylmeth- imidazole 110 with the affiliated loss of toluenesulfinic acid. ylene)triphenylphosphorane 116 in refluxing benzene to afford The structure of synthesized compounds was confirmedbya corresponding unsaturated ester 117 (72%, only Eisomer). The combination of one- and two-dimensional NMR spectroscopy unsaturated ester was furthersubjected to react with and X-ray diffraction method.[42] tosylmethyl isocyanide and n-butyl lithium in presence of Bojarski et al reported the discovery of 3-(1-ethyl-1H- tetrahydro furan as medium at À78 °Ctoafford pyrrole C- midazol-5-yl)-4-fluoro-5-iodo-1H-indole derivatives, which is a nucleosides 118.Compounds were anomeric mixture, which

highly drug-like, selective 5-HT7Ragonist as illustrated in were separated using column chromatography and thoroughly Scheme 59. These hybrid compounds were synthesized from characterized. indole derivatives 111,which were reacted with the standard Dand L-2-deoxyribo-1-carboxaldehyde 97 was also directly condition of Vilsmer Haak formylation to afford indole 3- reacted with tosylmethyl isocyanide using potassium carbonate carboxaldehydeintermediate 112.These intermediates were as abase and refluxing methanol as amedium to afford further reactedwith amine derivatives 113 and tosylmethyl oxazole-C-ribosides 119 without converting aldehyde into isocyanide using potassium carbonate as abase and methanol unsaturated ester.[44] as reaction medium to afford the desired indole imidazole Padmavathi et al reported anew class of sulfonelinked conjugates 114.Structure activity relationship of synthesized pyrrolyl oxazolines and thiazolines derivatives as illustrated in compounds was established and found that the modifications Scheme 61. The reaction was started from E-arylsulfonyl at the 1, 2and 6positions of indole are forbidden, while the ethenesulfonyl acetic acid methyl ester 120 and 2-amino- only tolerable substitutionofthe 7position is with the fluorine ethanol/2-aminoethanethiol and n-butyllithium using anhy-

atom, which led to asignificant decrease in affinity. Com- drous SmCl3 as catalyst and toluene as reaction medium to pounds were characterized by excellent water solubility, high afford 2-(arylsulfonylethenesulfonylmethyl)-4,5-dihydrooxazole selectivity over related CNS targets, high metabolic stability, derivatives 121 and 2-(arylsulfonylethenesulfonylmethyl)-4,5- oral bioavailability and low cytotoxicity. Compounds were dihydrothiazole 122.The olefin moiety in 121 and 122 was characterized and evaluated for in vitro affinity.[43] used to develop pyrrole ring. Compound 121 and 122 was Krishna and co-workers developed anovel route for the further reacted with tosylmethyl isocyanide in the presence of synthesis of oxazole-C-ribosides/pyrrole C-nucleosides from 2- sodium hydride and asolvent mixture of diethyl ether and deoxy-D- and L-ribose-1-carboxaldehyde as illustrated in dimethyl sulfoxide to afford 2-(40-arylsulfonyl-10H-pyrrol-30- Scheme 60. This aldehyde was synthesis from corresponding sulfonylmethyl)-4,5-dihydrooxazole 123 and 2-(40-arylsulfonyl- alcohol using Swern oxidation approach. Dand L-2-deoxyribo- 10H-pyrrol-30-sulfonylmethyl)-4,5-dihydrothiazole 124.All the

Scheme59. Synthesis of indole-imidazole conjugates from indole derivatives.

Scheme60. Synthesis of oxazole-C-ribosides/pyrrole C-nucleosides from TosMIC.

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Scheme61. Synthesis of sulfone linked pyrrolyl oxazolines and thiazolines from corresponding sulfone.

synthesized compounds were characterized using spectral and afford aromatic heterocyclic styryl amides, (E)-N-(4-aryloxazol-2- elemental analysis and evaluated for in vitro antioxidant and yl)cinnamamide 127a,(E)-N-(4-arylthiazol-2-yl)cinnamamide antimicrobial activity against the Gram-positive bacteria like 127b and (E)-N-(4-aryl-1H-imidazol-2-yl)cinnamamide 127c. Staphylococcus aureus (NCIM No. 5021), Bacillus subtilis (NCIM These heterocyclic styrylamides were further reacted to No. 2063), the Gram-negative bacteria Klebsiella pneumoniae tosylmethyl isocyanide and sodium hydride as abase using (NCIM No. 2957), Proteus vulgaris (NCIM No. 2027) and fungi diethyl ether and dimethyl sulfoxide as reaction medium to Fusarium solani (NCIMNo. 1330), Curvularia lunata (NCIM No. afford 4’-phenyl-N-(4-aryloxazol-2-yl)-1’H-pyrrole-3’-carboxa- 716) and Aspergillus niger (NCIM No. 596) using agar disc- mide 128a,4’-phenyl-N-(4-arylthiazol-2-yl)-1’-pyrrole-3’-carbox- diffusion method and taking chloramphenicol and ketocona- amide 128b and 4’-phenyl-N-(4-aryl-1H-imidazol-2-yl)-1’H- zole as referencedrug. The result of in vitro testing reveals that pyrrole-3’-carboxamide 128c.All the synthesized compounds the compounds having pyrrole with thiazoline possess ex- were characterized using elemental and spectral analysis and cellent antimicrobial activity while the compounds having further evaluated for antimicrobial and antifungal activity using pyrrole with oxazoline exhibited good antioxidant activity.[45] chloramphenicol as reference drug. The result indicated that The author further extended the synthetic strategy to Gram-negative bacteria were more susceptible towards the develop anew class of amido linked bis heterocycles viz., tested compounds than Gram positive ones. All the tested pyrrolyl/oxazoles, thiazoles and imidazoles by 1,3-dipolar cyclo- compounds inhibited the spore germination against tested addition approach as illustrated in Scheme 62. The reaction fungi. In general, most of the compounds exhibited slightly starts with 4-aryloxazol-2-amine 125a,4-arylthiazol-2-amine higher antifungal activity towards Penicillium chrysogenum than 125b and 4-aryl-1H-imidazol-2-amine 125c derivative and Aspergillus niger. The structure activity relationship of the cinnamoyl chloride 126 using toluene as reaction medium to compounds discovered that mono heterocyclic systems with

Scheme62. Synthesis of amido linked bis heterocycles from corresponding amines.

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extended conjugation 127(a–c) are more active than the efficiently when 80 μl(about 8.9 equiv.) water was employed, corresponding bis heterocyclic systems 128(a–c) and it was delivering the corresponding 3,3-bipyrrole derivatives 135 with also observed that the compounds having thiazole ring and good to excellent yield. The reaction was generalized by imidazole ring were more effective compared to compounds keeping wide substrate scope ranging from conformationally having oxazole moiety.[46] restricted dienones bearing, alkyl, aryl and heteroaryl group. Sisko et al reported the synthesis of bis-imidazole as Structure of all synthesized compounds was confirmed by depicted in Scheme 63. In this protocol, 1.0 equivalent of spectroscopic analysis and mechanism was proposed which is a Glutaric dialdehyde 129 and 2.0 equivalent of allylamine 130 is traditional van Leusen pyrrole synthetic strategy followed by reacted to generate corresponding diamine in situ 131,which unusual CÀCbond cleavage.[48] is reacted with tosylmethylisocyanide derivative 132 to afford Based on the synthesized product, aplausible reaction desired bis-imidazole derivatives 133.The multicomponent mechanism was proposed as illustrated in Scheme 65. The base reaction afforded the desired products with good yield and first generates tosylmethyl isocyanide anion which attach on synthesized compounds were very well characterized using carbonyl of dienone. The 1,4-addition of tosylmethyl isocyanide spectral data.[47] anion to dienone in the presence of potassium hydroxidegives Wang et al developed asimple and highly efficient the enolateintermediate A.Asubsequent intramolecular synthetic strategy to construct 3,3-bipyrrole derivatives as cyclization occurs to produce aspirocyclic intermediate B. illustrated in Scheme 64. Reaction condition was optimized by Then, the spirocyclic intermediate C could be formed after performing amodel reaction of (2E,5E)-2,5-dibenzylidenecyclo- furtherelimination of tosyl group from intermediate B.After an pentanone 134 with tosylmethylisocyanide in the presence of iterative process, the bispirocyclic D is generated. In the t-BuOK in DMF. The reaction was further studied varying presence of water and potassium hydroxide, one of the spiro solvent, base and temperature and results concluded that the rings is opened to give intermediate E,affording the desired products were afforded in good yield while using potassium 3,3-bipyrrole derivatives via decarboxylation and protonation hydroxideasabase and dimethyl formamide as asolvent. approach. Undoubtedly, water was involved in the reaction and promoted Zhang and co-workers developed afacile strategy for the reaction kinetics. Delightfully, the reaction worked more synthesis of pyrrole linked with isoxazoles 137 through [3+ 2]

Scheme63. Synthesis of bis imidazoles from dialdehyde and diamines.

Scheme64. Synthesis of 3,3-bipyrrolefrom dienones.

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Scheme65. Aplausible mechanism for synthesis of 3,3-bipyrrole derivatives.

cycloaddition of tosylmethyl isocyanide at ambient temper- anion to (E)-3-methyl-4-nitro-5-(prop-1-en-1-yl)isoxazole, in the

ature as shown in Scheme 66. Initially, the reaction of (E)-5-(4- presence of KOH in CH3CN, leads to the adduct A.Intra- chlorostyryl)-3-methyl-4-nitroisoxazole 136 with tosylmethyl molecular cyclization of the adduct A occurs to generate the isocyanide was tested for the optimization of the reaction intermediate B.Then protontropic shifts gives the intermediate conditions. Screening of different bases and solvents reached C which is further converted into intermediate D by the to the conclusion that potassium hydroxideinacetonitrile was elimination of atoluenesulfinate anion. The final hydrogen shift the best combination to afford product with high yield at room of intermediate D delivers the 3-isoxazole-substituted pyrrole temperature. Avariety of substituent including aromatic, derivatives as the final product. aliphatic and heteroaryl were well tolerated proving the wide substrate scope of the reaction. All the compounds are well 2.4. Synthesis of spiro heterocycles characterized using spectral analysis.[49] Product formation was explained by classical van Leusen Aspiro compound containstwo rings fused at acommon mechanism as exemplified in Scheme 67. Addition of TosMIC point, mostly acarbon atom. Spiro compounds having cyclic

Scheme66. Synthesis of pyrrole linked withisoxazoles via [3+ 2] cycloaddition.

Scheme67. Mechanistic explanation for synthesis of pyrrole linked with isoxazoles.

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structures fused at acentral carbon are the privileged scaffolds was able to produce pyrrole intermediate derivatives which due to their interesting conformational features and their was further stirred with iodine to afford spiro compound 141 structural implications on pharmacological profile. Due to the with good yield. Although solvent play acrucial role in this tetrahedral nature of these compounds, the ring planes are tandem one-pot procedure and it was evident when dichloro- approximately perpendicular. There are various methodologies methane was employed, final product was characterized as to synthesize spiro compounds including alkylation, transition- fused benz-indole derivatives. The amount of base and iodine metal catalysed, rearrangement type approaches,cyclization of was also studies and found suitable as 2.5 and 4.0 equivalent geminally substituted compounds, radical cyclization’s, cleav- respectively. Reaction scope was generalized employing diverse age of bridged ring systemsetc. Herein, we are describing group on cinnamate includingaryl, benzyl, electron rich and synthesis of spirans using tosylmethyl isocyanide as aprevailing deficient groups. The structure of prototype spiro compound reagent. was confirmed by X-ray diffraction study and subsequent Shaabani and co-workers developed avan Leusen type [3+ derivatives were characterized by spectroscopic analysis.[51] 2] cycloaddition reaction from various activated cyclic ketones Aplausible mechanism was proposed based on the spiro as illustrated in Scheme 68. The reactivity and chemo-, regio- product generated. Initially, the formal [3+2]-cycloaddition of and diastreo-selectivity of tosylmethyl isocyanides (TosMIC) cinnamate with TosMIC under basic conditions provides the were investigated in this protocol without the use of any pyrrole intermediate A.Anelectrophilic bisiodination of pyrrole catalyst. The reaction was optimized by reacting 11H-indeno intermediate occurs with elemental iodine to deliver intermedi- [1,2-b]quinoxalin-11-one as acyclic ketone 138 and tosylmethyl ate B,which undergoes iodine promoted 5-endo-dig cyclization isocyanide in the presence of various base and solvent and to generate intermediate C.Finally, spiro[indene-1,3’-pyrrole] results of reaction reveal that the desired spirooxazolines 139 were afforded after deprotonation of intermediate C as were afforded with good to excellentyield while employing an illustrated in Scheme 70. equimolar amount of potassium carbonate and using ethanol as agreener solvent. The products were isolated by filtration 2.5. Miscellaneous uses of TosMIC and washed with water and characterize using NMR spectroscopy. The high chemo,regio and diastereoselectivity in Tosylmethyl isocyanide also serve as powerful synthon for product formation were ascertained by X-ray crystallography of variety of synthetic intermediate. Apart from different catego- model compound.[50] ries of heterocycles, herein we are describing few miscella- Xu et al developed an efficient and novel protocol for the neous uses of tosylmethyl isocyanide. expedient and divergent one-pot synthesis of spiro[indene-1,3- Lamberth discovered the umpolungeffect of tosylmethyl pyrroles]from acyclic precursor at room temperature as isocyanide. He explained that TosMIC can be used as aformyl- illustrated in Scheme 69. Reaction parameters were optimized (di)anion equivalent, whereas mono-substituted TosMIC deriva- reacting alkyne-tethered cinnamate 140 with tosylmethyl tives are versatile acyl-anion equivalents. In peptide synthesis, isocyanide with different combinationofbase and solvent at TosMIC was used as isocyanide component in the Ugi four ambienttemperature. Sodium hydride with tetrahydrofuran component condensation reactions. This one pot conversion combines an aldehyde, an amine, acarboxylic acid and an isonitrile to form an a-acylaminoamide with generation of a new stereocenter derived from the aldehyde moiety. The following example demonstrates the application of TosMIC in the stereoselective solid phase synthesis of pharmacologically important 2,5-diketopiperazines.[52] Shen et al developed an oxidant-directed chemoselective sulfonylation and sulfonyloximation of alkene as illustrated in Scheme 71. Sulfones have inarguably gained widespread attentions throughout the drug development. The reaction was Scheme68. Synthesis of spiro-oxazolines from activated cyclic ketones. started from simple alkenes 142 and tosylmethyl isocyanide in

Scheme69. Synthesis of spiro[indene-1,3-pyrroles] from alkyne-tethered cinnamates.

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Scheme70. Aplausible mechanism for synthesis of spiro[indene-1,3-pyrroles].

Scheme71. Synthesis of sulfonesfrom alkenes.

presence of suitable oxidant, catalyst, base and solvent.

Optimization study reveal that the combination of Co(salen)2, sodium carbonate and perfluorobutyl iodide with tert-butyl hydroperoxide (TBHP) revealed to be capable of promoting the reaction with high performance. Tetrahydro furan was turned to be better solvent comparatively to afford desired sulfone 143 and oxime 144.Perfluoroalkyl iodides are employed as vital hydrogenatom abstractor for assisting triggering of the CÀSbond in tosylmethyl isocyanide by means of the formed reactive and strongly electrophilic radicals. All synthesized compounds were characterized and the strategy was extended for synthesis of vinyl sulfones from diverse range of alkenes.[53] Based on the major product formation, aplausible radical sulfonylation reaction mechanismisproposed as shown in Scheme 72. The sulfonylation reaction for the synthesis of vinyl sulfones is expected to initiate via acobalt salt induced Scheme 72. Mechanistic explanation for synthesis of vinyl sulfones. homolytic cleavage of TBHP to give t-BuO radical and t-BuOO radical. The initial step is the formation of aisocyanide radical B from anion A with the concomitant release of perfluorobutyl and serve an alternate of sulfonyl chloride or sulfinate salts. radical under basic conditions in the presence of Co-catalyst. Reaction condition was optimized using benzamide derivatives Consequently, CÀSbond cleavage of active carbon-centred 145 protected with PyO group, which serve as unique reactivity radical B rapidly takes place, giving the key sulfonyl radical in kinetics and tosylmethyl isocyanide with additives. Cheap species, which readily adds to the unsaturated C=Cbond of copper salts have attracted the attention due to unique alkene and generates the benzylicradical C.Further, elimina- nucleophilic characters and serve as avaluable catalyst in the tion of hydrogen atom with the use of TBHP to reinstate the procedure involving solvent and oxidant. It was concluded unsaturation affording the desired vinyl sulfone. from study that sulfonyl products 146 were afforded in good Niu and Song’s collaborately developed amethod for Cu- yield when copper acetate as acatalyst, sodium bicarbonate as mediated direct ortho-CÀHsulfonylation of protected benza- abase, HFIP as asolvent and Tert butyl hydroperoxide (TBHP) mide derivatives as illustrated in Scheme 73. Generally, sulfonyl as aoxidant were used at 110 °Cinthis protocol. The substrate group of TosMIC acts as aleaving group but here it was scope was investigated using diverse range of benzamide demonstrated that it can also act as atosylmethylating reagent derivatives bearing electron withdrawing and electron donat-

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Scheme73. TosMIC as sulfomethylating agent using benzamidederivatives.

ing group. Surprisingly, the iodo functional group on the sulfinate with excellent yield. Awide substrate scope was benzamides remained intact under the reaction conditions, investigated using various derivatives of benzyl alcohol bearing possessing potential synthetic application. Structure of proto- electron withdrawing and donating and sterically hindered type compound was confirmed by X-ray crystallographic study group. Chiral sulfinate formation with excellent enantioselectiv- and subsequent compounds were characterized using spectral ity was also observedusing chiral benzyl alcohol which prove analysis.[54] that reaction occur by the SN2 mechanism and support the Wu et al developed abismuth (III) bromide-catalysed direct intramolecularring rearrangement. All the compounds were substitution of benzyl alcohols 147 with tosylmethyl isocyanide characterized using spectral analysisand evaluated for anti- to afford unexpected sulfinate derivatives 148 under mild biotic activity against ahuman leukaemia cell line HL-60.[55] acidic conditions as illustrated in Scheme 74. Amodel reaction Neochoritis and co-workers reported the isocyanide-based was performed reacting 3,5-difluorobenzyl alcohol with para- MCRs (IMCRs) to afford a-aminoamides as illustrated in toluenesulfonylmethyl isocyanide as the substrates using Bi Scheme 75. Reaction wasoptimized by performing amodel

(OTf)3 in nitromethane (CH3NO2)at60°Cfor aday and reaction involving p-methyl-benzaldehyde 149, p-methylaniline surprisingly, sulfinate was obtained instead of expected 150,carboxylic acid derivatives 151 with tosylmethyl sulfone.Reaction was further optimizing to afford sulfinate and isocyanide using methanol as reaction medium at ambient it was observed that products were obtained in good yield temperature. Initially, indole acetic acid was employed as while using bismuth bromide as acatalyst and nitromethane as carboxylic acid partner affording aminoamides 152 with poor reaction medium.Fortunately, reaction wasfruitful at room yield while with 2-acetyl indole acetic acid improvedthe yield temperature while using acetic acid as additive to afford drastically. The broad reaction scope was investigated by

Scheme74. Bismuth bromide catalysed unexpected synthesis of suphinate.

Scheme75. Synthesis of α-aminoamides using Ugi multi component reaction.

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employing different derivatives of 2-acetyl indole acetic acid. range of alkyne bearing electron withdrawing, electron donat- Reaction did not afford the product in theabsence of ing, bicyclic, heteroaryl and tetracyclic alkyne. All the synthe- carboxylic acid and gave only Schiff base. Reaction also did not sized compounds were characterizedusing spectral analysis proceed in aqueous medium. Aromatic carboxylic acid was and stereochemicalassignment was proved by X-ray crystallo- found better reactant than aliphatic counterpart. All the graphic data. Plausible mechanism was also investigated which synthesized compounds were characterized using vigorous explain that the active methylene group of TosMIC was spectroscopic analysis includingIR, one and two dimensional oxidizedtogenerate atosyl radical which eventually attacked NMR, HRMS and elemental analysis.[56] the terminal carbon of acetylene to afford an unexpected E- An acid catalysed plausible mechanism was proposed to vinyl sulfone.[57] understand product formation as shown in Scheme 76. Initially, Aplausible mechanism of nano-copper catalyzed synthesis aniline and benzaldehyde react to form imine after dehydra- of E-vinyl sulfone from alkynes and TosMIC is exemplified in tion. Imine reacts with tosylmethyl isocyanide to form Scheme 78. The active methylene of tosylmethyl isocynide A intermediate A which is further reactedwith carboxylate anion gets oxidized to give intermediate B.The intermediate B to afford intermediate B.Anucleophilic addition of water produces tosyl radical C in the presence of copper, which reacts moleculewith intermediate B afforded intermediate C,which with copper acetylide to form intermediate D which ultimately provides the- aminoamides after loss of carboxylate ion. abstract aproton from the solvent to afford the E-vinyl sulfone Tiwari et al reported an exceptional, efficient, simple and as the final product. mild catalytic strategy for stereoselective synthesis of E-vinyl sulfones as illustrated in Scheme 77. In this strategy, tosylmeth- 3. Conclusion yl isocyanide acts as asulfonyl source instead of acting as a typical 1,3 dipole. Reaction was optimized using terminal Based on our interest on synthetic chemistry[58] and medicinal alkynes 153 and tosylmethyl isocyanide (TosMIC) in the chemistry,[59] we reflected that p-tosylmethyl isocyanide has presence of magnetically separable nano-copper (0) stabilized become part and parcel in the construction of diversified

on Fe3O4 under an oxygen atmosphere to afford E-vinyl heterocyclic scaffold and also serve as sulfonylating regent. sulfones 154 with good to excellent yield. The catalyst was Due to excellent reactivity and selectivity, TosMIC facilitated a separated magnetically and washed with diethyl ether, dried broad range of chemical transformations and novel method- and used directly for the next cycle of reaction. The catalyst ologies includingmulticomponent, domino/cascade and cyclo- was reused five times without the loss of catalyticefficiency. addition reactions. TosMIC is greatly attracted by synthetic Broad scope of substrate was generalized employing diverse chemist due to ease of preparation, functional group tolerance,

Scheme76. Aplausible mechanism for synthesis of α-aminoamides via Ugi-MCR.

Scheme77. Synthesis of E-vinyl sulfone from terminal alkyne.

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Scheme78. Mechanistic explanation for the synthesis of E-vinyl sulfone.

[12] R. Zhu, L. Xing, Y. Liu, F. Deng, X. Wang, Y. Hu, J. Organomet. Chem. regioselective transformation and better tosyl leaving group to 2008, 693,3897–3901. enforce cycloaddition to heterocycles having biological poten- [13] a) L. Zhang, X. Xu, W. Xia, Q. Liu, Adv. Synth. Catal. 2011, 353,2619– tial. TosMIC is very well established for synthesis of isolated 2623; b) Y. Li, X. Xu, H. Shi, L. Pan, Q. Liu, J. Org. Chem. 2014, 79,5929– heterocycles like pyrrole, imidazole, indole, triazole, oxazole 5933. and fused heterocycles like -carboline, pyrrolo-quinoline, [14] K. Lu, F. Ding, L. Qin, X. Jia, C. Xu, X. Zhao, Q. Yao, P. Yu, Chem.: An Asian β J. 2016, 11,2121–2125. imidazo-quinoline, pyrrolo-pyrimidine, imidazo-β-carboline as [15] L. Zhang, X. Xu, Q-r. Shao, L. Pana, Q. Liu, Org. Biomol. Chem. 2013, 11, well as for spiro compounds.Hopefully, this review will further 7393–7399. stimulate research in the area of this powerful synthon. [16] C. Dell Erba, M. Novi, G. Petrillo, C. Tavani, Tetrahedron 1997, 53,2125– 2136. [17] A. Franchino, J. Chapman, I. Funes-Ardoiz, R. S. Paton, D. J. Dixon, Chem. Acknowledgements Eur. J. 2018, 24,17660–17664. [18] R. ten Have, M. Huisman, A. Meetsma,A.M.van Leusen, Tetrahedron We acknowledge the faculty members and management of 1997, 53,11355–11368. SVKM’s NMIMS, Universityfor their guidance and support. [19] X. Geng, C. Wang, C.Huang, Y. Bao, P. Zhao, Y. Zhou, Y.-D. Wu, L-l. Feng, A.-X. Wu, Org. Lett. 2020, 22,140–144. [20] J. Zhang, Q. Gao, X. Wu, X. Geng, Y.-D Wu, A. Wu, Org. Lett. 2016, 18, Conflict of Interest 1686–1689. [21] J. Campo, M. G. Valverde, S. Marcaccini, M. J. Rojo, T. Torroba, Org. The authors declare no conflict of interest. Biomol. Chem. 2006, 4,757–765. [22] A. R. Keeri, A. Gualandi, A. Mazzanti, J. Lewinski, P. G. Cozzi, Chem. Eur. J. 2015, 21,18949–18952. Keywords: Cyclization · p-tosylmethyl isocyanide · [23] B. A. Kulkarni, A. Ganesan, Tetrahedron Lett. 1999, 40,5633–5636. imidazopyridine · pyrrolo-quinoline · spiro compound [24] L.-J. Zhang, M.-C. Xu, J. Liu, X.-M. Zhang, RSC Adv. 2016, 6,73450–73453. [25] A. M. van Leusen,B.E.Hoogenboom, H. A. Houwing, J. Org. Chem. 1976, 41,711–713. [26] S. Gutiérrez, D. Sucunza, J. J. Vaquero, J. Org. Chem. 2018, 83,6623– 6632. [1] a) D. van Leusen, A. M. van Leusen, Synthetic uses of tosylmethyl isocyanide (TosMIC), in organic reaction,John Wiley and Sons, Wiley [27] J. Bergman, S. Rehn, Tetrahedron 2002, 58,9179–9185. Online Library, 2001,pp. 417–666; b) T. Kaur, P. Wadhwa, A. Sharma, RSC [28] Z. Hu, Y. Li, L. Pan, X. Xu, Adv. Synth. Catal. 2014, 356,2974–2978. Adv. 2015, 5,52769–52787; c) A. M. van Leusen, B. E. Hoogenboom, H. [29] X.-M. Lu, J. Li, Z.-J. Cai, R. Wang, S.-Y. Wang, S.-J. Ji, Org. Biomol. Chem. Siderius, Tetrahedron Lett. 1972, 23,2369–2372. 2014, 12,9471–9477. [2] C. Dell Erba, A. Giglio, A. Mugnoli, M. Novi, G. Petrillo, P. Stagnaro, [30] S. Lu, X. Zhu, K. Li, Y.-J. Guo, M.-D. Wang, X.-M. Zhao, X.-Q. Hao, M.-P. Tetrahedron 1995, 51,5181–5192. Song, J. Org. Chem. 2016, 81,8370–8377. [3] A. Aitha, N. Payili, S. R. Rekula,S.Yennam, J. S. Anireddy, ChemistrySelect [31] Z.-R. Guan,Z.-M. Liu, M.-W. Ding, Tetrahedron 2018, 74,7186–7192. 2017, 2,7246–7250. [32] J. M. Minguez, J. J. Vanquero, J. L. G-Navio, J. A-Builla, Tetrahedron Lett. [4] R. Sharma, K. Kumar, M. Chouhan, V. Grover, V. A. Nair, RSC Adv. 2013, 3, 1996, 37,4263–6266. 14521–14527. [33] K. Satyam,V.Murugesha, S. Suresh, Org. Biomol. Chem. 2019, 17,5234– [5] R. Kaur, K. Kumar, Chem. Heterocycl. Compd. 2018, 54,700–702. 5238. [6] H. P. Dijkstra, R. ten Have, A. M. van Leusen, J. Org. Chem. 1998, 63, [34] Y. Thigulla, M. Akula, P. Trivedi, B. Ghosh, M. Jhac, A. Bhattacharya, Org. 5332–5338. Biomol. Chem. 2016, 14,876–883. [7] K. L. Manasa, K. N. V. Sastry, Y. Tangella, B. N. Babu, ChemistrySelect 2018, [35] L. Zhang, X. Zhang, Z. Lu,D.Zhang, X. Xu, Tetrahedron 2016, 72,7926– 3,2730–2733. 7930. [8] A. M. van Leusen, H. Siderlus, B. E. Hoogenboom, D. van Lsusen, [36] R. Wang, X.-P. Xu, H. Meng, S.-Y. Wang, S.-J. Ji, Tetrahedron 2013, 69, Tetrahedron Lett. 1972, 52,5337–5340. 1761–1766. [9] F. Qiu, J. Wu, Y. Zhang, M. Hu, F. Yu, G. Zhang, Y. Yu, Lett. Org. Chem. [37] R. Wang, S.-Y. Wang, S.-J. Ji, Tetrahedron 2013, 69,10836–10841. 2012, 9,305–308. [38] J. Du, X. Xu, Y. Li, L. Pan, Q. Liu, Org. Lett. 2014, 16,4004–4007. [10] R. D. Santo, R. Costi, M. Artico, S. Massa, G. Lampis, D. Deidda, R. Pompei, [39] J. Dong,X.Wang, H. Shi, L. Wang, Z. Hu, Y. Li, X. Xu, Adv. Synth. Catal. Bioorg. Med. Chem. Lett. 1998, 8,2931–2936. 2019, 361,863–867. [11] M. Terzidis, C. A. Tsoleridis, J. S. Stephanatou, Tetrahedron 2007, 63, [40] M. Chakrabarty, R. Basak, Y. Harigaya, H. Takayanagi, Tetrahedron 2005, 7828–7832. 61,1793–1801.

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[41] M. Fodili, B. N-Kolli, B. Garrigues, C. Lherbet, P. Hoffmann, Lett. Org. [58] a) S. K. Manjal, S. Pathania, R. Bhatia, R. Kaur, K. Kumar, R. K. Rawal, J. Chem. 2009, 6,354–358. Heterocycl. Chem. 2019, 56,2318–2332; b) R. Kaur, Y. Kapoor, S. K. [42] M. Fodili, B. N-Kolli, M. Vedrenne, N. S-Merceron, C. Lherbet, P. Manjal, R. K. Rawal, K. Kumar, Curr. Org. Synth. 2019, 16,342–368; c) M. Hoffmann, Chem. Heterocycl. Compd. 2015, 51,940–943. Chouhan, K. R. Senwar, K. Kumar, R. Sharma, V. A. Nair, Synthesis 2014, [43] A. S. Hogendorf, A. Hogendorf, K. Popiołek-Barczyk, A. Ciechanowska, J. 46,2,195–202; d) K. Kumar, S. S. More, G. L. Khatik, R. K. Rawal, V. A. Nair, Mika, G. Satała, M. Walczak, G. Latacz, J. Handzlik, K. Kieć-Kononowicz, E. J. Heterocycl. Chem. 2017, 54,2696–2702; e) K. Kumar, D. Konar, S. Goyal, Ponimaskin, S. Schade, A. Zeug, M. Bijata, M. Kubicki, R. Kurczab, T. M. Gangar, M. Chouhan, R. K. Rawal, V. A. Nair, J. Org. Chem. 2016, 81, Lenda, J. Staroń,R.Bugno, B. Duszyńska, B. Pilarski, A. J. Bojarski, Eur. J. 9757–9764; f) K. Kumar, J. Siddique, M. Gangar, S. Goyal, R. K. Rawal, Med. Chem. 2019, 170,261–275. V. A. Nair, ChemistrySelect 2016, 1,2409–2412; g) K. Kumar, D. Konar, S. [44] P. R. Krishna, V. V. R. Reddy, R. Srinivas, Tetrahedron 2007, 63,9871–9880. Goyal, M. Gangar, M. Chouhan, R. K. Rawal, V. A. Nair, ChemistrySelect [45] V. Padmavathi, K. Mahesh, G. D. Reddy, A. Padmaja, Eur. J. Med. Chem. 2016, 1,3228–3231; h) K. Kumar, S. S. More, S. Goyal, M. Gangar, G. L. 2010, 45,3178–3183. Khatik, R. K. Rawal, V. A. Nair, Tetrahedron Lett. 2016, 57,2315–2319; i) K. [46] V. Padmavathi, C. P. Kumari, B. C. Venkatesh, A. Padmaja, Eur. J. Med. Kumar, S. R. Mudshinge, S. Goyal, M. Gangar, V. A. Nair, Tetrahedron Lett. Chem. 2011, 46,5317–5326. 2015, 56,1266–1271; j) S. Goyal, J. K. Patel, M. Gangar, K. Kumar, V. A. [47] J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan,A.Allen, M. A. Olsen, J. Org. Nair, RSC Adv. 2015, 5,3187–3195; k) S. Goyal, B. K. Patel, R. Sharma, M. Chem. 2000, 65,1516–1524. Chouhan, K. Kumar, M. Gangar, V. A. Nair, Tetrahedron Lett. 2015, 56, [48] R. Wang, S.-Y. Wang, S.-J. Ji, Org. Biomol. Chem. 2014, 12,1735–1740. 5409–5412; l) K. Kumar, R. K. Rawal, ChemistrySelect 2020, 5,3048–3051. [49] X. Zhang, X. Xu, D. Zhang, Molecules 2017, 22,1131–1141. [59] a) Y. Kapoor, K. Kumar, Bioorg. Chem. 2020, 94,103351–103375; b) R. [50] A. Shaabani, H. Sepahvand, A. Bazgir, H. R. Khavasi, Tetrahedron 2018, Kaur, S. K. Manjal, R. K. Rawal, K. Kumar, Bioorg. Med. Chem. 2017, 25, 74,7058–7067. 4533–4552; c) S. K. Manjal, R. Kaur, R. Bhatia, K. Kumar, V. Singh, R. [51] X. Zhang, C. Feng, T. Jiang, Y. Li, L. Pan, X. Xu, Org, Lett. 2015, 17,3576– Shankar, R. Kaur, R. K. Rawal, Bioorg. Chem. 2017, 75,406–423; d) M. 3579. Mittal, K. Kumar, D. Anghore, R. K. Rawal, Curr. Drug Discovery Technol. [52] C. Lamberth, J. Prakt. Chem. 1998, 340,483–485. 2017, 14,106–120; e) R. Kaur, S. Choudhry, K. Kumar, M. K. Gupta, R. K. [53] X.-Q. Chu, D. Ge, T.-P. Loh, Z.-L. Shen, Org. Chem. Front. 2019, 6,835– Rawal, Eur. J. Med. Chem. 2017, 132,108–134; f) B. Kumar, V. Singh, R. 840. Shankar, K. Kumar, R. K. Rawal, Curr. Topics. Med. Chem. 2017, 17,148– [54] C.-L. Fan, L.-B. Zhang, J. Liu, X.-Q. Hao, J.-L. Niu, M.-P. Song, Org. Chem. 161; g) P. Talwan, S. Choudhary, K. Kumar, R. K. Rawal, Curr. Bioact. Front. 2019, 6,2215–2219. Compd. 2017, 13,109–120. [55] H.-J. Li, R. Wang, J. Gao, Y.-Y. Wang, D.-H. Luo, Y.-C. Wu, Adv. Synth. Catal. 2015, 357,1393–1397. [56] C. G. Neochoritis, D. Livadiotou,V.Tsiaras, T. Z. Tzitzikas, E. Samatidou, Tetrahedron 2016, 72,5149–5156. [57] M. Phanindrudu, D. K. Tiwari, B. Sridhar,P.R.Likhar, D. K. Tiwari, Org. Submitted: April 2, 2020 Chem. Front. 2016, 3,795–798. Accepted: August 20, 2020

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