Recent update on synthesis of spiro-heterocycles in alcohol using malononitrile as a building block

Spiro-heterocycles represent an important class of heterocyclic compounds with diverse area of application. These types of heterocycles are found in nature and also available synthetically. Especially, pyran based spiro heterocycles are one such important class of heterocycles among others. Here, in our review we have tried to focus on the recent developments in the synthesis of spiro-heterocycles using malononitrile as a simple and effective building block. We have also focused on alcohol mediated reactions as in most of the cases, the organic compounds are soluble in alcohol. Most of the alcohols are cost effective, easily available and easy to handle.


Introduction
2][3] Heterocycles are sought after by the synthetic chemists due to its overwhelming applications in medicinal and other applied arenas.Various methodologies have been developed to access interesting heterocyclic motifs and to further modify them.0][11][12] Apart from that, some naturally isolated spiro-heterocycles are also used as remedy for food-poisoning and poisonous snake bites. 12Several spiroheterocycles show properties like photo-initiated ring closure 13 and also some spiro-bezopyrans have been found to help in the prevention of myocardial ischemia. 14The two forms of spiro-heterocycles which are generated under photochemical influence can be utilized to develop 3D-optical storage memory device as shown by two eminent researchers Parthenopoulos and Rentzepis. 15This type of molecules can also act as chemosensors. 16The ring opening tendency of spiro-heterocycles has also been utilized for other synthetic purpose. 17Therefore, due to such versatile application of such spiro-heterocycles, it has become important to synthesize new types of spiro-heterocycles as well as the development of new methodologies.9] As a starting material it is comparatively cheaper and easy to handle.Malononitrile itself also incorporates a nitrile group in the product.A number of pharmaceutically active moieties contain nitrile as a substituent. 20The nitrile group being a good π-acceptor, often helps to design electronic devices. 21Therefore, synthesis of a diverse range of spiro-heterocycles using malononitrile as a useful tool has attracted chemists far and wide.3][24][25][26] Among other solvents, alcohols are comparatively less harmful towards human health as well as environment.The alcohols also dissolve a large number of organic compounds.Therefore, in our review, we have tried to focus on recent developments on the synthesis of spiro-heterocycles in alcohol as solvent using malononitrile as one of the reagents.

Synthesis of Spiro-heterocycles with a Pyran Core
An efficient multi-component reaction protocol for the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] system 3 has been developed 27  derivatives.A triclinic crystal system was found with space group P-1 upon X-ray crystallography of its selected derivative.
Synthesis of an interesting spiroacenaphthylene heterocycles containing a pyran ring 5 was achieved 28 by Elinson et al. in 2012.This multi component reaction methodology involved the heating of a mixture of three components namely malononitrile, acenaphthenequinone and a cyclic active methylene carbon containing compound 4 at 80 o C in alcohol solvent.The reaction is also achievable in water (Scheme 2) as solvent.A broad range of active C-H containing compounds has been studied.Ultimately, this new methodology is a good example of a noncatalytic green procedure.Scheme 2. Synthesis of spiro acenaphthylene type of heterocycles containing a pyran ring.
Bez et al. developed 29 a methodology to synthesize spirocyclic dihydropyrano[2,3-c]pyrazole derivatives using Amberlyst A21 as the catalyst in ethanol medium (Scheme 3).The methodology involved a four-component reaction involving malononitrile, hydrazine hydrate, ethyl acetoacetate and cyclic ketone 6.In this methodolgy they have shown a green approach for the synthesis of spiro-substituted dihydropyrano[2,3-c]pyrazoles 7. Amberlyst A21 here, acted as an efficient reusable catalyst and the methodology also didn't involve hazardous organic solvent or high temperature.Scheme 3. Synthesis of spiro-substituted dihydropyrano[2,3-c]pyrazoles using Amberlyst A21 as the catalyst.
Spiro[4H-pyran-oxindole] derivatives 10 were synthesized 30 by the magnesium perchlorate catalyzed methodology involving malononitrile, isatins 8 and 1, 3-dicarbonyl compounds 9. Ethyl cyano acetate was also used in place of malononitrile for the synthesis of other derivatives (Scheme 4).The reactions were performed in 50% aqueous ethanol medium and the reaction completed within 30 min.to 60 min.The described protocol is simple, eco-friendly and easy to carry out.The Mg(ClO4)2 catalyst is non-toxic, inexpensive and readily available also.Scheme 4. Synthesis of spiro[4H-pyran-oxindole] derivatives using magnesium perchlorate as catalyst.
Synthesis of methyl 6'-amino-5'-cyano-1,3-dihydro-1,3-dioxo-1'H-spiro[indene-2,4'-pyrano[2,3c]pyrazole]-3'-carboxylate 14 has been achieved 31 by Alizadeh and Bayat in 2014.They developed a one-pot methodology involving dimethyl acetylenedicarboxylate (11), ninhydrin (12), hydrazine derivatives and malononitrile.This reaction occurred at room temperature.This four component methodology was carried out in ethanol medium.On the other hand, derivatives of 6'-amino-1,3-dioxo-1,3-dihydro-1'H-spiro[indene-2,4'-pyrano[2,3-c]pyrazole]-5'-carbonitrile 15 were obtained when β-keto ester 13 was used instead of the dimethyl acetylenedicarboxylate under refluxing condition.The reactions completed within a short span of time (1 hour) and good yields were obtained and the protocol also had operational simplicity (Scheme 5).The mechanism of the reaction is shown in Scheme 6.  16) and malononitrile were employed for the synthesis in presence of DABCO.Phenanthrene-9, 10-dione was also used in place of isatin.Some other active methylene groups like methyl cyanoacetate or ethyl cyanoacetate was also used to obtain different derivatives.The reaction completed within 12h under refluxing condition (Scheme 7).The mechanism of the reaction is shown in Scheme 8. Spiropyrans 19 have been synthesized 33 using poly (styrene-co-maleic anhydride) based N-sulfonic acid containing solid catalyst by Heravi et al. in 2014.The methodology was based on multicomponent procedure involving isatin, malononitrile and 3-methyl-1H-pyrazol-5-one 18 and the three components were allowed to react together to produce the desired spiro-pyran (Scheme 9).Heravi et al. have extended the methodology using acenaphthenequinone or ninhydrin in place of isatin.And, 4-hydroxy coumarin or dimedone was also used in place of pyrazole derivatives for the synthesis of spiro-pyran derivatives.The catalyst was reusable up to six times without any notable loss in activity.The reaction proceeded at room temperature in ethanol medium.This straightforward one-pot synthetic route was effective for both mono and bis-spirooxindole systems.The use of toxic catalyst was avoided in this methodology.Malononitrile, isatins and 3-methyl-1H-pyrazole-5(4H)-one derivatives 18 or dimedone (9) were the ingredients for this one-pot, multicomponent methodology (Scheme 13).Excellent yields were obtained in a short span of time (10-15 min.).The solid product was obtained by filtration and the ionic liquid catalyst was recovered from the ethanol filtrate and it was also recyclable up to five times.Darvish, Mirza and Makarem established an electrolytic green methodology for the synthesis of pyran containing spiro oxindole 36 derivatives. 39In this protocol, malononitrile, isatin 35 and dimedone 9 were taken in an undivided cell using NaBr as electrolyte.In this protocol, propanol played the dual role as the solvent and the base as alkoxide anion as well (Scheme 15).The alkoxide anion is generated via cathode reduction.The reaction proceeded at 50 o C. Nanoparticles of spiro oxindoles were obtained in excellent yields under this protocol.
Another one-pot multicomponent reaction methodology was developed 41 by Xu et al. by using DABCObased ionic liquid in ethanol solvent.The reaction involved malononitrile, isatin and dialkyl acetylene dicarboxylate.These three components when combined with a primary aromatic amine 39, produced spiro 1,4-dihydro pyridine compounds 41 and when combined with hydrazine derivatives 40 spiro pyrano[2,3c]pyrazole systems 42 was produced (Scheme 17).This protocol was also extended to carbonyl compounds apart from isatin, like ninhydrin and acenaphthylene-1, 2-dione.A number of DABCO based ionic liquid was screened for optimization and the catalyst could be recycled up to 5 times without loss of much reactivity.Scheme 17. Synthesis of spiro 1,4-dihydro pyridine and spiro pyrano[2,3-c]pyrazole systems using DABCObased ionic liquid.
An ultrasound promoted multi-component reaction methodology for the synthesis of spiro-4H-pyrans 43-44 was developed 42 by Naeimi and Lahouti (Scheme 18).The reactions were performed in aqueous ethanol medium at room temperature.Malononitrile, 1, 3-dicarbonyl compounds and isatin or acenaphthoquinone were involved in this three-component methodology.The reaction was catalyzed by a recyclable chitosan encapsulated magnetic Fe3O4 nanoparticles (Fe3O4@CS-SO3H NPs).A range of 1, 3-dicarbonyl compounds were studied under this methodology.Scheme 18. Ultrasound promoted multi-component reaction methodology for the synthesis of spiro-4Hpyrans.
Another multi-component methodology for the synthesis of spiro-pyran derivatives 45-46 as well as spiro-acenaphthylenes was developed 43 by Safari and Nasab using magnetic NiFe2O4@SiO2@Melamine nanoparticles as an effective and reusable catalyst (Scheme 19).Different 1,3-dicarbonyl compounds were allowed to react with ninhydrin/acenaphthoquinone and malononitrile/ethyl cyanoacetate under this one-pot multi-component methodology.The reactions proceeded under reflux in ethanol solvent.The magnetic nanoparticle catalyst was easily separated from the reaction mixture by using an external magnet.Scheme 19.Synthesis of spiro-pyran derivatives and spiro-acenaphthylenes using magnetic NiFe2O4@SiO2@Melamine nanoparticles as an effective and reusable catalyst.
Pawar et al. also independently developed 44 a multi-component methodology to synthesize pyran containing spiro-oxindole derivatives using malononitrile, enolizable ketones and isatins in (1:1) aqueous ethanol solvent under the catalytic influence of Cu nanoparticles embeded on carbon microsphere under reflux.

Scheme 20. CsF promoted multi component synthesis of spiro oxindole based heterocycles.
Spirooxindole based heterocycles 48 have been synthesized 45 by the CsF promoted multi component reaction methodology involving isatin and malononitrile along with different 1, 3-dicarbonyl compounds or its equivalent compounds 47 as the third component (Scheme 20).4-hydroxycoumarin or barbituric acid or pyrazolone was used as the third component in this one-pot three component methodology in ethanol at room temperature.The methodology also worked with bis-isatins.

Synthesis of Spiro-heterocycles without a Pyran Core
An ultrasound promoted methodology for the synthesis of spiro [indoline-3,1'-pyrazolo [1,2b]phthalazine]systems 52 has been developed 47 were also synthesized using meta-phenylene diamine (53), isatin and malononitrile as starting materials. 16In this methodology Pramanik et al. illustrated one-pot multicomponent reaction which was performed in ethanol medium under reflux.The reaction completed within one hour (Scheme 24).

Scheme 24. Synthesis of isatin based spiro heterocycles from meta-phenylene diamines.
A one-pot multicomponent reaction methodology was developed 48 for the synthesis of spiro-2,4diaminopyrimidines 57 by Balalaie et al. in 2013.The methodology involved guadinium carbonate (56), cyclic ketones 55 and malononitrile/methylcyanoacetate.The reaction proceeded in methanol solvent under reflux (Scheme 25).The reaction progressed via Knoevenagel reaction followed by Michael reaction and cyclization.The unique feature of the synthesized compounds is that they are capable of earning extra stability by virtue of having hydrogen bonding property.Moreover, the careful study of antibacterial activity of these spiro aminopyrimidines revealed notable results.The mechanism is shown in Scheme 26.© AUTHOR(S) Scheme 25.One-pot multicomponent synthesis of spiro-2,4-diaminopyrimidines.Scheme 26.Mechanism for one-pot multicomponent synthesis of spiro-2-aminopyrimidines.
A multi-component synthetic methodology of spiro[indoline-3,4'-pyrrolo [3,4-b]pyridine] derivatives 59 was achieved 49 using triethylamine as base by Yan et al.Malononitrile or ethyl cyanoacetate was chosen as a building block along with isatins and 3-arylamino-1-methyl-1H-pyrrole-2,5-dione (58).A range of spiro oxindole systems were obtained under this methodology.The reaction proceeded under reflux in ethanol solvent (Scheme 27).This protocol is very simple to handle with respect to easy purification, short span of reaction time (1 hour), easily available starting material.
Scheme 30.Synthesis of spirocyclopropylbarbiturates using arylidenemalononitriles.Scheme 31.Mechanism for the synthesis of spirocyclopropylbarbiturates using arylidenemalononitriles.
A DABCO (1,4-  programme.Department of Chemistry, University of Kalyani for providing necessary facilities.We also extend our thanks to RUSA 10 Component (CH & E).
by Shi et al.They involved malononitrie, hydrazine, β-keto ester 2 and isatin 1 in the four component reaction methodology.The reaction was performed in ethanol solvent under the catalytic influence of piperidine and ultrasound irradiation.The reaction completed in one hour at room temperature (Scheme 1).The reactions follow the non-hazardous ultra-sound driven green procedure.No traditional column chromatography was required for purification of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]

Table of Contents 1 .
Introduction 2. Synthesis of Spiro-heterocycles with a Pyran Core 3. Synthesis of Spiro-heterocycles without a pyran core 4. Conclusion 52azabicyclo[2.2.2]octane) catalyzed methodology for the synthesis of spiro oxindole derivatives 66 has been developed52by Pore et al. in aqueous ethanol at room temperature (Scheme 32).This one-pot, three component methodology involved malononitrile, isatin and cyclohexanone 65.This methodology was further improvised by this group to prepare bis spiro compounds 68 (Scheme 33) by using bis-isatins 67.Scheme 32.DABCO catalyzed synthesis of spiro oxindole derivatives.