Amberlyst-15 in organic synthesis

Commercially available Amberlyst-15 has played an important role in organic synthesis. This review summarizes the versatile synthetic applications of Amberlyst-15 in different chemical transformations. Reactions include esterification, transesterification, Michael addition, aza-Michael addition, Prins cyclization, Friedel-Crafts alkylation, acylation, metal free hydro-arylation, hydroalkylation, halogenation, protection of carbonyls, amines, deprotection of acetals, acetates, Boc-protected amines, cleavage of epoxides, crossed-aldol condensation, synthesis of quinolines, pyrazolines, indolinones


Introduction
In the past decade, the chemistry of Amberlyst-15 has experienced a rapid development.This growing interest in Amberlyst-15 is mainly due to its mild and highly selective properties, combined with its environmentally benign character and commercial availability.Amberlyst-15 is now routinely used in organic synthesis as other heterogeneous reusable acid catalysts 1a-d for various selective transformations of simple and complex molecules.The purpose of the present review is to summarize the utility of Amberlyst-15 1e-i with emphasis on recent synthetic applications; literature coverage is through the end of 2011.

General Information and Structural Features of Amberlyst-15
Amberlyst-15 is brown-grey solid having the following physical properties 2a Ionic form as shipped : hydrogen Concentration of active sites: ≥ 1.7 eq/L; ≥ 4.7 eq/kg Moisture holding capacity : 52 to 57% (H + form) Shipping weight : 770 g/L Particle size : 0.600 to 0.850 mm Average pore diameter : 300Å Total pore volume : 0.40 mL/g Maximum operating temperature: 120 ºC (250 ºF) Figure 1 (left) shows an SEM of Amberlyst-15 resin.2b It is a macro reticular polystyrene based ion exchange resin with strongly acidic sulfonic group (Figure 1, right).Thus, it serves as an excellent source of strong acid.It has been used in various acid catalyzed reactions.It is easy to measure, safe to use, and readily removed at the end of the reaction.An additional advantage is that the catalyst can be regenerated and can be used several times.

Esterification and Transesterification Reaction
Amberlyst-15 is a powerful and selective acid catalyst for esterification reactions.Petrini et al. have reported a mild and selective methyl esterification of aliphatic carboxylic acids using Amberlyst-15 in methanol at room temperature in excellent yield (Scheme 1).3a No racemisation, epimerization and ketalization products have been observed with this method.Excellent results are obtained in the esterification of bile acids.However, aromatic carboxylic acid such as 5methylfuroic acid and conjugated carboxylic acid such as trans-aconitic acid do not react with methanol at room temperature.They can be transformed into esters only by refluxing the mixture for a long time.

Scheme 1
Amberlyst-15 has also been used for production of biodiesel (BD).Talukder and coauthors reported that palm fatty acid distillate (PFAD), a byproduct from the palm oil refinery process, has been utilized as an alternative feedstock for biodiesel production via Amberlyst-15 catalyzed esterification.3b The BD yield obtained using Amberlyst-15 is 97%.Transesterification of esters with alcohols has been accomplished using Amberlyst-15.Chavan and co-workers reported that Amberlyst-15 acts as a Bronsted acid catalyst for transesterification of various β-ketoesters with different alcohols including allylic alcohols and sterically hindered secondary and primary alcohols in refluxing conditions.In a specific example, the transesterified β-ketoester 4 can be prepared from β-ketoesters 3 using Amberlyst-15 under refluxing in toluene.(Scheme 2).3c Pappu et al. 3d  reported that methyl stearate, a model biodiesel compound undergoes transesterification with higher alcohol n-butanol using Amberlyst-15 as acid catalyst.

Michael Addition Reaction
Michael addition of pyrroles to α,β-unsaturated ketones has been accomplished in presence of Amberlyst-15 in acetonitrile at room temperature to obtain the corresponding 2-alkyl and 2,5dialkyl pyrroles in good to excellent yields (65-91%) without polymerization.The method can thus be used to produce C-alkylated pyrroles 6 and 7 from pyrroles and 5 (Scheme 3).4a Acetonitrile was found to be the best solvent in this reaction.

Aza-Michael Addition Reaction
Aza-Michael reaction of a series of amines with α,β-unsaturated carbonyls and nitriles to produce β-amino carbonyls and nitrile compounds 12 in good to excellent yields, using Amberlyst-15 under solvent-free conditions was reported by Das and Chowdhury (Scheme 5).5a

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© ARKAT-USA, Inc. Esteves et al., however, used primary and secondary aliphatic amines as substrates with methyl vinyl sulfone 13a and vinyl p-aminophenylsulfone 13b in presence of Amberlyst-15 (30%, w/w) at room temperature to produce the corresponding aza-Michael addition product 14 in moderate to high yield (Scheme 6).5b

SN2' Reaction
Nucleophilic substitution reaction in allylic alcohols was also studied using Amberlyst-15 as catalyst.The Baylis-Hillman adduct 15 which contains allylic alcohol functionality are highly useful in various chemical transformation and in synthesis of several bioactive compounds.

Scheme 7
Das and co-workers utilized these adducts for the stereoselective synthesis of a series of (E) and (Z) allyl amides 16 through SN2' reaction of 15 and MeCN, using Amberlyst-15 as acid catalyst (Scheme 7).7a (E)-cinnamyl alcohols 18 7b were also synthesized from the isomerization of Baylis-Hillman adduct 15 using Amberlyst-15 as a heterogeneous reusable catalyst (Scheme 8).The plausible mechanism for the formation of allyl primary acetates 17, from 15 is similar to that in Scheme

Prins Reaction
The acid catalyzed condensation of olefins with carbonyl compounds known as Prins reaction is an important carbon-carbon bond forming reaction.8a,b The tetrahydropyran ring is a part of the backbone of various important carbohydrates and natural products.9a,b Yadav et al. reported that Amberlyst-15 catalyses the synthesis of tetrahydropyranols through the Prins-type cyclization.Thus, when 1-phenyl-3-buten-1-ol 19 and benzaldehyde was stirred in refluxing 1,2-dichloroethane in presence of Amberlyst-15 for 2 hrs.2,6-Diphenyl-4hydroxytetrahydropyran 21 was produced in 88% yield with high diastereoselectivity.The formation of 21 may be explained by Prins-type cyclization of the intermediate hemi-acetal 20 (Scheme 9). 10 Scheme 9

Friedel-Crafts Reaction
Friedel-Crafts reaction of aromatic and heteroaromatic compounds is one of the fundamental reactions for forming carbon-carbon bond.Friedel-Crafts alkylation and acylation reactions have been studied by using Amberlyst-15 as acid catalyst.

Alkylation
Kadam et al. demonstrated that Amberlyst-15 can act as a powerful catalyst for the alkylation of activated arenes or heteroarenes and α-amido sulfones.Friedel-Crafts alkylation by various αamido sulfones 22 was achieved on treatment with 1,2,4-trimethoxybenzene using Amberlyst-15 in refluxing CH2Cl2 to give the products 23 in very good yield (Scheme 10).11a The reaction of N-benzyloxycarbonylaminophenyl-p-tolylsulfones with indoles (heteroarenes) afforded C-3 alkylation of indoles in moderate yield.

Scheme 10
Alkylated phenols are widely used as additives in gasolines, lubricants, and a host of consumer products.11b Various alkylated phenols 24 was synthesized by Ma and co-workers from phenol and olefins using eco-friendly heterogeneous catalyst Amberlyst-15 (Scheme 11).11c The mechanism involves an exothermic reaction between olefin and benzene sulphonic acid (from Amberlyst-15) to form an ester followed by three reaction pathways leading to direct Oalkylation, o-C-alkylation and p-C-alkylation.

Scheme 11
Regioselective alkylation at the C-1 position of 2-naphthol using Amberlyst-15 was reported by Das et

Scheme 13
A series of N-sulfonamides 29 were synthesized from sulfonamides 28 and acid anhydrides by Friedel-Crafts acylation reaction using Amberlyst-15 under solvent-free conditions at room temperature (Scheme 14).13b Wu et al. reported that Amberlyst-15 is the best catalyst amongst the previously reported catalyst for the same reaction.Various 1,3-keto-esters can be selectively halogenated at the 2-position with N-halosuccinimides using Amberlyst-15 as a heterogeneous solid catalyst.The 2-halogenated products 34 can be prepared from β-ketoesters 33 in good yields under mild conditions (Scheme 16).15a Cyclic ketones can also be directly halogenated at the α-position by NXS under the same reaction conditions.

Scheme 16
Amberlyst-15 can also be used for the iodination of primary, secondary allylic and benzylic alcohols using NaI.p-Methoxybenzylalcohol 35 is selectively iodinated with NaI/Ambeylyst-15 in acetonitrile at room temperature to give 36 in good yield (Scheme 17).15b Electron donating groups attached to the benzene ring accelerate the iodination reaction and electron-withdrawing group retard the transformation.

Protection and Deprotection Reactions
Protection and deprotection reactions are very important and widely used strategy for organic synthesis.Reactions involving selective protection of functional groups such as carbonyl, hydroxyl carboxylic acids and amines in presence of other functional groups, and their deprotection, are of common importance in the multi-step synthesis of complex natural products 16a,b .
Page 582 © ARKAT-USA, Inc.A survey of the literature revealed that Amberlyst-15 has been efficiently used for the protection of carbonyl and amine functional groups.

Acetalization reaction
Patwardhan and Dev reported that carbonyl group can be protected by acetalization process using catalytic amount of Amberlyst-15.Thus, when benzaldehyde was treated with triethyl orthoformate in presence of Amberlyst-15, the corresponding acetal 37 was obtained in excellent yield (Scheme 18).22a In case of ketones the reaction produced the corresponding ketals and in some cases the enol ethers was directly formed in good yield under similar conditions.

Thioacetalization reaction
Chemoselective thioacetalization of carbonyl group with Amberlyst-15 was reported by Perni et al. when benzaldehyde and acetophenone was allowed to react with one equivalent of ethanedithiol and Amberlyst-15 in chloroform overnight at room temperature, a high yield of 38 was obtained and the ketone recovered in unchanged condition (Scheme 19).22b However, ketones can be protected by this method by refluxing the reaction mixture.

Acyloxy-acylation reaction
Reddy et al. demonstrated that Amberlyst-15 works as an efficient catalyst for chemoselective acyloxy-acylation of aldehydes.Thus, when a mixture of benzaldehyde and acetophenone in (1:1) ratio was reacted with acetic anhydride in presence of Amberlyst-15 catalyst in dichloromethane at room temperature, the 1,1-diacetate of benzaldehyde was exclusively formed (Scheme 20).22c Scheme 20

N-tert-butoxycarbonylation reaction
Chemoselective N-tert-butoxycarbonylation of amines in presence of Amberlyst-15 was reported by Kumar et al.A variety of primary, secondary and aryl amines were reacted with di-tert-butyl dicarbonate (Boc)2O in presence of Amberlyst-15 in CH2Cl2 at room temperature to produce the corresponding N-tert-butylcarbamates in good to excellent yields.However, 2-aminophenol 39 and proline 41 reacted slowly with (Boc)2O in comparison with the other amines, to yield 40 and 42 respectively (Scheme 21).22d This method was found to be selective for the protection of amines as the hydroxyl and carboxylic acid groups were not affected during the reaction.

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© ARKAT-USA, Inc. to their corresponding functional groups in multi-step organic synthesis can not be overstated.Amberlyst-15 has been shown to catalyze such reactions efficiently to give good yields of the deprotected products.

Deacetalization reaction
Coppola demonstrated that Amberlyst-15 can be used as an excellent catalyst for the hydrolysis of acetals or ketone acetals to the corresponding carbonyl derivatives (Scheme 22).27a Thus, when a solution of acetal 43 in acetone, containing water is added to Amberlyst-15 and the mixture is stirred at room temperature for 10 min the corresponding carbonyl compounds 44 was produced in high yield.

Dethioacetalization reaction
Ballini and Petrini reported a new procedure for dethioacetalization via equilibrium exchange with aqueous acetone, paraformaldehyde and Amberlyst-15 as acidic catalyst at 80 ºC (Scheme 23).27b p-Methoxybenzaldehyde 46 was regenerated from corresponding ethanediyl S,S-acetals 45 under the experimental conditions in good yields.The presence of ester, ether and hydroxyl groups in thioacetal or thioketal compounds do not interfere with the deprotection process.The author previously also demonstrated that Amberlyst-15 is an excellent and far superior catalyst for regeneration of carbonyl compounds from nitrogeneous derivatives, 27c like tosylhydrazones, oximes, 2,4-dinitrophenylhydrazones and semicarbazones when wet acetone is used as exchange reagent.

Hydrolysis of aromatic acetates
Aromatic acetates of the type 47 were selectively deprotected to the corresponding phenols 48 using Amberlyst-15 as catalyst in methanol at room temperature (scheme 24).27d Alkyl acetates were unaffected by the catalyst.Ethers, esters and lactones functionality present in acetate compounds also remained unchanged under this reaction condition.

Deprotection of Boc-protected amines
Lu and his groups demonstrated that the strongly acidic ion-exchange resin Amberlyst-15, effectively deprotects, purifies, and isolates BOC-protected amine compounds.Both primary and The epoxide ring-opening occurs in a high regioselective manner with the attacking of nucleophile either at the more hindered carbon or the terminal carbon of the epoxide.

Scheme 26
Various β-alkoxy alcohols were synthesized in good to excellent yields using Amberlyst-15 catalyzed regioselective ring opening reaction of epoxide by primary, secondary and tertiary alcohols under ultrasound irradiation (Scheme 27).29b The likely role of Amberlyst-15 is to act as a Bronsted acid in this case for the activation of epoxide and render the epoxide more susceptible to nucleophilic attack by alcohols.Methanol gave the best yield among the alcohols used for this reaction.As the alkyl group of alcohol becomes bulkier, the yield of the ring-opening reaction gradually decreases.

Scheme 27
Solladie-Cavallo and his group demonstrated that Amberlyst-15 can act as an effective acid catalyst for regio-and stereoselective ring opening of 2,3-diaryl oxiranes by LiBr (Scheme 28).29c In the case of symmetrical trans-stilbene oxide, the synversus anti-bromohydrins ratio ranged between 88/12 and 30/70, by varying the reaction temperature from 20 to -30 ºC.In the case of nonsymmetrical para-substituted trans-2,3-diaryloxiranes 49, the regioselectivity is

Condensation Reaction
Cross-aldol condensation of aldehydes with ketones is an important synthetic reactions for the synthesis of α,β-unsaturated carbonyl compounds, which are known to show diverse biological activities.30a-c These types of compounds are used as intermediates for synthesis of various pharmaceuticals, agrochemicals and perfumes.31a,b On the other hand condensation of carbonyls and indoles give bis(3-indolyl)methanes that show a wide variety of biological activities. 32It was found that Amberlyst-15 effectively catalyses both types reactions.

Crossed-aldol condensation reaction
Pal and his co-workers showed that Amberlyst-15 can act as an efficient heterogeneous acid catalyst for the cross-aldol condensation reaction under solvent free conditions.Thus, when various aldehydes and ketones were mixed thoroughly with Amberlyst-15 and neutral alumina, and the mixture were subjected to microwave irradiation, the condensation products 52 and 53 were produced smoothly in very good yields (Scheme 29 and 30).33a ,-Bis(arylmethylene)cycloalkanones 52, -cinnamylideneacetophenones 53a and chalcones 53b were produced in this process.

Condensation of carbonyl compounds and indoles
Ramesh and coworkers observed that of Amberlyst-15 can be utilized for the condensation of indoles with carbonyl compounds for the synthesis of bis-and tris(1H-indol-3-yl)methanes 56.Thus, when Amberlyst-15 was added to a stirring solution of indole and carbonyl compounds in CH2Cl2 at room temperature, 56 was formed in high yield within 2-3 hrs.(Scheme 33).34a The same condensation reaction was reported by Ke et al. 34b using acetonitrile as solvent.
Tri(heteroaryl)methanes were synthesized by Farhanullah and his group by the condensation of indoles with 4-formyl pyrazoles 57 and bis-(4-formylphenoxy)alkanes 59 separately, in CHCl3 at room temperature using Amberlyst-15 to give indole-pyrazole 58 and indole-oxyaryl 60 respectively (Figure 2).34c The method is concise and economic at the same time.

Multicomponent Reaction
Multicomponent reactions have recently gained much practical importance due to their speed, diversity and efficiency.35a-c Das and Reddy reported an efficient one-pot multicomponent synthesis of β-acetamido ketones 61 from aromatic aldehydes, enolizable ketones or keto esters and both acetyl chloride (AcCl) and acetonitrile (MeCN) at room temperature using Amberlyst-15 as catalyst (Scheme 34).36a Aromatic aldehydes containing either electron-donating orwithdrawing groups underwent the conversion smoothly.Several functional groups such as halogen (Cl, Br), NO2, ester and ether moieties were found to be stable under the reaction condition.Compared with the other methods for multicomponent synthesis of β-acetamido ketones, this new method using Amberlyst-15 offers better yields, shorter reaction times and economic viability.A similar single-step multicomponent reaction has been reported for the coupling of anthranilic acid, orthoesters and amines to their corresponding 4(3H)-quinazolines 62, using a catalytic amount of Amberlyst-15 under solvent-free conditions (Scheme 35).36b Scheme 35

Formation of Nitrogen Heterocycles
Nitrogen heterocycles form the backbone for a host of biologically active molecules.Quinoline 37a,b and pyrazoline 38a-c systems are known to be important constituents of many pharmaceutical and agrochemical products.Indoline-3-ones have been used for chromogenic detection of esterase activity.39a,b Acridine derivatives are interesting chemotherapeutic having antibacterial and antiparasite properties.40 Calix [4]pyrroles are conformationally flexible macrocycles 41a of significant importance due to their binding property with anions, 41b neutral substrates 41c and metal ions 41d under different reaction conditions.These important nitrogeneous heterocycles have efficiently been synthesized using heterogeneous solid acid catalyst, Amberlyst-15.

Synthesis of quinolines
A series of substituted quinolines 63 were synthesized by Das et al. from the reaction between 2aminoaryl ketones and α-methylene carbonyl compounds using Amberlyst-15, a heterogeneous solid acid catalyst (Scheme 42a The catalyst was found to be most effective for the synthesis of quinolines in terms of reaction times, yields and reusability, over the other heterogeneous solid acid catalysts like NaHSO4-SiO2, H2SO4-SiO2 and HClO4-SiO2.

Scheme 36
Hou and coauthors reported a simple and reliable method for the direct synthesize of quinolines 64 from 2-aminobenzophenone and arylketones in ionic liquid [Bimn][PF6] using Amberlyst-15 as catalyst (Scheme 37).42b

Synthesis of pyrazolines Scheme 39
Pyrazolines, a biologically active and an important constituent of many pharmaceutical and agrochemical products were synthesized by Hola and his groups using Amberlyst-15.Thus, when chalcones were treated with hydrazine or substituted hydrazines in presence of Amberlyst-15 in refluxing toluene the substituted pyrazolines 68 were produced in good yields (Scheme 39).43 The proposed reaction mechanism involves a 5-endo-trig cyclization of the intermediate 67.

Synthesis of indolin-3-ones
2'-Aminochalcone 69 derived from 4-pyridinecarboxaldehyde undergoes intramolecular cyclization in presence of Amberlyst-15/AcOH media.Unexpectedly, the reaction proceeded through a 5-exo process thus providing an alternative approach for the synthesis of 2-(pyridinylmethylene)indolin-3-one 73 (Scheme 40).44 The key step is the formation of resonant species 70, where the ipso carbon atom of the pyridine ring, rapidly acquire a positive charge after the protonation of the basic pyridine nitrogen atom.This species 70 is also stabilized via an exocyclic allylic type cation, which favors the 5-exo attack of the amino group towards the αposition of 70 producing the species 71 which rapidly tautomerizes to structure 72.A subsequent dehydration of the intermediate 72 generated 73.Scheme 40

Synthesis of 1,8-dioxodecahydroacridines
Das and co-workers have reported that Amberlyst-15 acts as an excellent catalyst for the synthesis of 1,8-dioxodecahydroacridines 74, a class of tricyclic nitrogeneous heterocyclic compounds.When amines and 5,5-dimethyl-1,3-cyclohexedione were refluxed in CH3CN in presence of Amberlyst-15 for a specified time, 74 was furnished in excellent yields (Scheme 41).45 Aromatic and aliphatic amines underwent the conversion with same efficiency.On the other hand benzopyrans form the backbone of many natural products and is also present in the recently discovered HIV inhibitory class of benzotripyrans.49a,b Moreover, theaspiranes form the aroma components in tea and functionalized furan derivatives are the structural moieties in many bioactive natural products and important These oxygen heterocycles may be synthesized by using Amberlyst-15 as catalyst.

Synthesis of xanthenes
Ko and Yao developed a simple and reliable method for the direct construction of biologically active 14-substituted-14H-dibenzo [a,j]xanthenes 77 in high yield from a one-pot condensation of β-naphthol with aldehydes in presence of Amberlyst-15 under solvent-free conditions (Scheme 43).51 The mechanism of this reaction includes the initial generation of the carbocation, followed by the formation of aryl-or alkyl-methanebisnaphthols, which then undergo dehydration to give the final product.

Synthesis of theaspirane
Young et al. demonstrated that the route for Amberlyst-15 catalyzed intramolecular oxaspirocyclization of secondary allylic alcohol 85, can be applied to the synthesis of theaspirane 86, an allylic oxaspirocycles, to give high yields of the product (Scheme 49). 56 Page 599 © ARKAT-USA, Inc.

Synthsis of furan derivatives
Amberlyst-15 has also been used for the synthesis of furan derivatives.sulphonamido-phosphonates, 61a-c and alkyl/aryl/heteroaryl phosphonates 62 are the pentavalent phosphorus compounds of considerable synthetic interest due to their utility as reagents in several reactions, and also for their applications in bioorganic and pharmacological fields.

Synthesis of α-hydroxy phosphonates
Tajbakhsh and coauthors have developed an efficient procedure for synthesis of α-hydroxy phosphonates 92 from aldehydes and trimethyl phosphite using Amberlyst-15 in water (Scheme 52).63 Probably, the solid acid catalyst, Amberlyst-15 generates a hydronium ion in water that activates the carbonyl group, which consequently undergoes nucleophilic attack by trialkyl phosphite.Water was found to be the most appropriate solvent over the other organic solvents such as diethyl ether, CH2Cl2, CHCl3, MeCN, THF and MeOH, in respect of yields.

Synthesis of alkyl/aryl/allyl/heteroaryl phosphonates
A new and convenient procedure for the synthesis of alkyl/aryl/allyl/heteroaryl phosphonates 94 using Amberlyst-15 under solvent-free conditions was developed by Kundu et al. (Scheme 54). 65 This solvent-free protocol is highly efficient and affords the product in excellent yields with high purity.

Synthesis of β-Enaminones and β-Enaminoesters
The β-enaminone derivatives are very useful synthons for the synthesis of various active heterocyclic compounds which exihibits a wide range of biological activities.66a-d Narsaiah et al. reported that Amberlyst-15 can be used for the synthesis of β-enaminones and β-enamino esters.Thus, when various β-keto carbonyls and β-keto esters were treated with different amines in presence of Amberlyst-15 at room temperature β-enaminones and β-enamino esters respectively were produced in excellent yields (Scheme 55).67 Scheme 55

Conclusions
This review demonstrates an active current interest in synthetic applications of Amberlyst-15 catalyst.This growing interest of Amberlyst-15 is mainly due to their very useful acidic properties, combined with benign environmental character, reusability and commercial availability.There has been a major surge of catalytic activity in several areas of the Amberlyst-15 chemistry.These areas include the application of Amberlyst-15 acid catalysts in various organic transformations such as formation of C-C, C-N, C-P and C-S bonds in different synthetically important compounds.We anticipate that these areas of Amberlyst-15 chemistry will continue to attract significant research activity in the future.

Protection of carbonyls and amines
BOC-protected aliphatic amines can be deprotected effectively with reaction times that ranged from 4 to 29 hours at ambient temperature.The presence of other functional groups such as alcohols esters and carboxylic acids do not interfere with the deprotection process.However, BOC-protected aromatic amines react slowly than the aliphatic ones (Scheme 25).27e © ARKAT-USA, Inc. secondary Epoxides are versatile and important intermediates in organic synthesis.They undergo ringopening reactions to give β-substituted alcohols with a variety of nucleophilic species.28a-d Vijender et.al. reported that epoxides undergo rapid ring-opening reaction with 46]ile and efficient protocol was reported by Chauhan et al. for the synthesis of calix[4]pyrroles 75, and N-confused calix[4]pyrroles 76 in moderate to excellent yields by reaction of dialkyl or cycloalkyl ketones, catalyzed by Amberlyst-15 under eco-friendly conditions (Scheme 42).46 © ARKAT-USA, Inc.A