Mild, Stereoselective, and Highly Efficient Synthesis of N -Acylhydrazones Mediated by CeCl 3 ·7H 2...

FULL PAPER

DOI: 10.1002/ejoc.201402609

Mild, Stereoselective, and Highly Efficient Synthesis of N-AcylhydrazonesMediated by CeCl3·7H2O in a Broad Range of Solvents

José Maurício dos Santos Filho*[a]

Keywords: Synthetic methods / Green chemistry / Medicinal chemistry / N-Acylhydrazones / Diastereoselectivity / Cerium

In a mild and practical approach, hydrazides and aldehydesunderwent condensation reactions that were mediated bycerium(III) chloride to be rapidly converted into N-acyl-hydrazones. This method uses a minimal catalytic amount ofcerium(III), is stereoselective, and offers several unique fea-tures, such as compatibility with aryl, heterocyclic, alkenyl,and sensitive functional groups as well as the ability to pre-

Introduction

N-Acylhydrazones serve an important role in medicinalchemistry, as they display biological activity for a wide vari-ety of diseases. In recent years, several reports have demon-strated the importance of N-acylhydrazone derivatives asantitubercular,[1,2] antiviral,[3,4] analgesic, anti-inflamma-tory,[5–7] anticonvulsant,[8,9] and antitrypanosomal[10,11]

agents, amongst others.[12a–12c] This broad spectrum of pos-sible applications has driven the interest of medicinal chem-ists towards the syntheses of new related compounds andhas placed the N-acylhydrazone functionality into a rel-evant position for drug development.

The synthesis of N-acylhydrazone is mainly carried outby a reaction between hydrazides and aryl/alkyl aldehydes.In a few cases, they are prepared by heating ketones at re-flux with a Brønsted–Lowry acid catalyst in a protic polarsolvent.[13a–13c] Under these conditions, the reactions leadto mixtures of (E) and (Z) diastereomers, with the predomi-nant formation of the (E) isomer. Indeed, accurate reportsof this method corroborate this observation.[14a–14d] Theformation of the (Z) isomer is directly related to the heatneeded for the condensation to occur between the hydrazideand the carbonyl compound, and the E/Z ratio is dependenton the structural features of the starting molecules, as ourgroup has previously demonstrated by 1H NMR analysisof two hydrazone series that were obtained by heating thereactants in tetrahydrofuran (THF) without an acid cata-lyst.[15] The steroselective synthesis of the (E) isomer can be

[a] Chemical Engineering Department, Universidade Federal dePernambuco,Av. Prof. Artur de Sá, s/n, Recife, PE, BrazilE-mail: [email protected] information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402609.

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pare N-acylhydrazones from highly hindered substrates.More strikingly, cerium(III) efficiently mediated the reactionwith less reactive substrates such as diaryl and alkyl arylketones, when classical protocols without the catalyst werenot effective. This method enables the synthesis of a structur-ally diverse library of N-acylhydrazones that have applica-tions in synthetic and medicinal chemistry.

achieved by using hydrazides with sufficient reactivity forthe process to succeed at room temperature under acid ca-talysis.[10,11] Because these compounds are often biologicallyevaluated, it is crucial that their stereochemical purity isensured to avoid erroneous results. However, few N-acylhy-drazones can be prepared at room temperature in the ab-sence of a Brønsted–Lowry acid catalyst. Therefore, it isclear that new protocols are needed for the synthesis of thisclass of compounds.

On the basis of the aforementioned challenges in thepreparation of new N-acylhydrazone derivatives that aresought for the development of antiparasitic agents, our ob-jective was to investigate the effect of Lewis acids on thecondensation between hydrazides and aldehydes. One of thesimplest and most efficient examples of a Lewis acid cata-lyst is cerium(III) chloride,[16a,16b] which has been utilizedin various condensation reaction protocols.[17a–17d] The fin-dings indicate that cerium(III) chloride heptahydrate is anefficient catalyst for this synthesis and that it would allowthe condensation reaction to occur under very mild condi-tions with generally short reaction times and good to excel-lent yields. More strikingly, the stereoselectivity for the (E)isomer was observed by using this catalyst. In addition, thisreaction effectively proceeded with functionally sensitiveand sterically hindered reactants, such as carbohydrates,ferrocenyl compounds, and ketones.

Results and Discussion

Benzohydrazide and benzaldehyde were chosen as start-ing materials to establish the optimal reaction conditions toyield (E)-N�-benzylidenebenzohydrazide (1). We observedthat high temperatures led to the formation of the (Z) iso-mer, and, therefore, all reactions were carried out at 20 °C.

J. M. dos Santos FilhoFULL PAPERThe amount of CeCl3·7H2O, the effects of the solvent, andthe reaction time were examined by monitoring for thecomplete consumption of both reagents of the reaction byTLC analysis. In intervals of 10 s, standardized sampleswere removed from the reaction mixture with a capillarytube and dissolved in 0.3 mL of THF, and the sample solu-tion was then applied to the TLC plate. The reaction wasfirst performed in methanol in the absence of a catalyst tovalidate the influence of the cerium(III) chloride hepta-hydrate (see Table 1, Entry 1). After 60 min, the reactionreached completion. The same experiment was carried outin the presence of 10 mol-% of CeCl3·7H2O, and completeconsumption of reactants was observed within 10 s (seeTable 1, Entry 2). When 5 mol-% of the catalyst was em-ployed under the same conditions, we also observed com-plete consumption of both reactants within 10 s. Reducingthe amount of catalyst to 1 mol-% resulted in completionof the reaction after 30 s, which is a significant result (seeTable 1, Entry 4). It is important to highlight that the reac-tion worked well with a catalyst amount of as low as 1 mol-%. Obviously, a reduced quantity of the cerium catalyst isadvantageous, especially when there is no significant re-duction in the reaction rate. Because of this result, furtherinvestigations with regard to the solvent and its effect onthe rate of the reaction were carried out by using 1 mol-%of the catalyst. In all cases, complete conversion of reac-tants was confirmed by TLC and 1H NMR analysis of thecrude product.

Table 1. Optimization of the synthesis of of N-acylhydrazone (1).

Entry Solvent CeCl3·7H2O [mol-%] Time [s] Yield [%][a]

1 MeOH 0 3600 932 MeOH 10 10 963 MeOH 5 10 954 MeOH 1 30 925 EtOH 1 30 936 H2O 1 10 947 H2O 0 –[b] 608 THF 1 50 939 CH2Cl2 1 40 9410 PhCH3 1 5,400 9111 PhCH3 0 –[c] 29

[a] Determined from isolated products. [b] No completion of thereaction after 60 min. [c] Reaction was incomplete after 24 h.

The activity of the cerium catalyst in other polar proticsolvents such as ethanol and water was investigated. Theoutcome for ethanol was similar to that for methanol (seeTable 1, Entry 5), which demonstrated that this less toxicand inexpensive solvent could be used without compromis-ing the efficiency of the reaction. The most promising re-sult, however, was obtained when an aqueous medium was

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used (see Table 1, Entry 6). The reaction reached comple-tion within 10 s, according to TLC analysis. This result isespecially interesting when compared with the same experi-ment under the same conditions but without the catalyst.Although the formation of some N-acylhydrazone was alsoobserved by TLC analysis, the reaction did not reach com-pletion even after 60 min (see Table 1, Entry 7).

The activity of the catalyst in polar aprotic and apolarsolvents was also investigated, and interestingly, the reac-tion proceeded well in aprotic media. Specifically, the timesof the reaction in THF and dichloromethane (see Table 1,Entries 8 and 9) were slightly longer than those of reactionsthat took place in polar protic solvents, which confirms theremarkable performance of the catalyst to promote the con-densation reaction. Finally, the reaction was carried out intoluene for 90 min, whereupon TLC indicated that the reac-tion had reached completion (see Table 1, Entry 10). Thisoutcome shows that the activity of the catalyst depends onits solubility in the solvent. Because CeCl3·7H2O must bein solution to catalyze the reaction efficiently, an apolar sol-vent should be unfavorable to the process. Indeed, this wasthe case, and thus confirmed our observations. In compari-son to ethanol or aqueous media, the catalyzed reaction intoluene was not as effective. However, when the same reac-tion was performed in an apolar medium without the cata-lyst (see Table 1, Entry 11), the formation of the N-acyl-hydrazone did not successfully proceed, even after 24 h. Onthe basis of this result, which shows a remarkable applica-tion of the catalyst, there exists the possibility to work withreactants that are soluble in apolar solvents.

To define the scope and limitations of this method, thecondensation reaction was investigated for a number ofhydrazides and aldehydes in the presence of 1 mol-%CeCl3·7H2O in ethanol. Most of these reactions could alsobe conducted in water, but some of the reactants and theresulting N-acylhydrazones were too insoluble, whichcreated a challenge to maintain a homogeneous reactionmixture and, consequently, slowed or prevented the reac-tion development. The employment of ethanol allowed forthe reaction mixture to be properly stirred, even when theproducts formed a precipitate, and provided for an environ-mental friendly process. The reaction between benzohydra-zide and an aldehyde that contained electron-donatinggroups (EDG), such as 4-hydroxy-3-methoxybenzaldehyde(see Table 2, Compound 2), resulted in a reduced reactiontime than that of the same reaction with benzaldehyde (seeTable 1, Entry 5). Conversely, an electron-withdrawinggroup (EWG) attached to the aromatic ring of the aldehyderesulted in an increased reaction time (see Table 2, com-pound 3).

When benzaldehyde undergoes a reaction with a hydraz-ide that contains either an EWG or EDG, the influence ofthe substituent effects is not always as obvious as in the twoprevious examples. Clearly, solubility plays an importantrole in reaction time. In almost all cases, the N-acylhydraz-one precipitated from the reaction mixture before completeconsumption of both reactants. Procedures that yieldedproducts as thick precipitates had the longest reaction times

Stereoselective Synthesis of N-Acylhydrazones

Table 2. Synthesis of N-acyl-aldohydrazones 2–13.[a]

[a] Yields determined from isolated products.

(see Table 2, Compounds 6, 7, 9, and 12). The end point ofeach reaction was determined by observing the consump-tion of the reactants by TLC analysis. From this, it wasclear that the more easily the reaction mixture could bestirred, the shorter the reaction time. Importantly, the1 mol-% of catalyst that is reported for CeCl3·7H2O, onlyrepresents approximately 0.5 mol-% of actual CeCl3. Con-sequently, the ability of the catalyst to react with the re-maining reactants is limited in cases when the medium isnot sufficiently homogenized. Exceptions include the reac-tions between benzohydrazide and cyclohexylcarbaldehyde

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(see Table 2, Compound 8) and benzo[b][1,3]dioxole-5-carbohydrazide and heptanal (see Table 2, Compound 13),which were pale yellow solutions until the completion ofthe reaction. However, each took more than 100 s to reachcompletion. In these cases, one can assume that a longerreaction time is related to a greater difficulty in the forma-tion of the electrophilic center at the carbonyl group. With-out the stabilization of aromatic ring, the carbonyl groupis not readily available for a nucleophilic attack from thehydrazide, which results in a longer reaction time. Thisstatement is consistent with the proposed mechanism forthe reaction (see Scheme 2).

The reaction between benzohydrazide and ferrocenecarb-aldehyde led to compound 9 and an important result (seeTable 2). Although the syntheses of hydrazones that containa ferrocenyl moiety have been described to occur by heatingat reflux in a polar solvent with or without a protic acid forup to 16 h,[18a,18b] attempts to reproduce these methodshave yielded complex mixtures of products. This was alsoobserved for the preparation of compound 9, which wasisolated as a trace amount in low yield. Under CeCl3·7H2Ocatalysis, the reaction proceeded more effectively with nodecomposition products and with complete conversion inexcellent yield. These results were reproducible throughoutall other experiments.

Other experiments were carried out between benzo-hydrazide and 2,6-dichlorobenzaldehyde (see Table 2, Com-pound 10) and 2,4,6-trimethylbenzaldehyde (see Table 2,Compound 11), which established the applicability of thecatalytic system with regard to any steric hindrance at thecarbonyl group of the aldehyde. When traditional reactionconditions were applied, both reactions required severalhours to reach completion, and partial decomposition ofthe hydrazide was observed.

In addition to TLC analysis for monitoring the conver-sion of the reactants into the products, 1H NMR analysisof the crude reaction mixture, without the workup, was per-formed to confirm the consumption of both the hydrazideand aldehyde. For this process, the stirring was stopped,and the solvent was removed without heat under reducedpressure followed by analysis of the samples. The signals forthe protons of hydrazido group (–CONHNH2) were at δ =9.30–9.80 (–CONH–) and 4.40–5.60 ppm (–NH2), and thesignal for the aldehyde proton was at δ = 9.50–10.5 ppm(–CHO). A detailed inspection of spectra of crude productsrevealed no trace amount of reactants, which supported theTLC analysis (see Supporting Information).

After the structural elucidation, the stereoselectivity ofthe crude products was determined by 1H NMR analysis.To determine the E/Z ratio of isomers, the signals of theimino group (–N=CH–) were considered, as previouslyestablished by our research group using NMR analysis andX-ray crystallography.[15] The signals that were used for theimino group proton were δ = 8.50 ppm [(E) isomer)] and8.10 ppm [(Z) isomer]. The 1H NMR spectroscopic analy-ses for all synthesized N-acylhydrazones by usingCeCl3·7H2O catalysis exclusively displayed signals for the(E) isomer, which confirmed the expected stereochemical

J. M. dos Santos FilhoFULL PAPERoutcome of this procedure. A possible exception was ob-served with compounds 4 and 7 (see Table 2), the 1H NMRspectra of which showed small signals that could be associ-ated to trace amounts of the (Z) isomer. However, the (E)isomer remained the major product (see Supporting Infor-mation). Compound 12 (see Table 2), which was investi-gated in our group,[15] revealed the presence of both (E) and(Z) isomers, as observed by the signals for the imino groupproton (–N=CH–) at δ = 8.53 [(E) isomer] and 8.09 ppm[(Z) isomer] and signals for the methylenedioxy group (–O–CH2–O–) at δ = 6.10 [(E) isomer] and 6.02 ppm [(Z) iso-mer]. 1H NMR analysis of the crude reaction mixture aswell as the isolated compound revealed that the (E) isomerwas predominant, whereas only trace amounts of the (Z)isomer were observed, which confirmed the selectivity ofthis method. Not only were the reactions that were medi-ated by CeCl3·7H2O more selective, but the reaction timeswere substantially reduced. For a comparison, in the caseof compound 12, the reaction without CeCl3·7H2O tookapproximately 4 h to reach completion, whereas the cata-lyzed reaction was done after 4.5 min.

With the investigation of other acid sensitive reactants,similar results were observed, as in the synthesis of 1-β-d-glucosyl-2-benzoylhydrazine (14, see Scheme 1). Attemptsto obtain this product by heating glucose and benzohydraz-ide at reflux in ethanol under acetic acid catalysis, as de-scribed in the literature,[19] repeatedly failed. The initial ex-periments that used 1 mol-% of the CeCl3 catalyst at 20 °Cunder the standard conditions for the syntheses of the N-acyl-aldohydrazones also did not worked properly. An ex-planation for this is that glucose, in its open chain form, ispresent in less than 1%, which results in the hydrazide reac-tion being substantially slow. For this particular case, theoptimal conditions for complete consumption of both reac-tants employed 10% of the CeCl3 catalyst at 40 °C with areaction time of 80 min. This is one of the most importantinvestigational findings described herein, as this shows theapplicability of this protocol to the synthesis of potentiallybioactive hydrazones that contain sugar moieties.

Scheme 1. Synthesis of 1-β-d-glucosyl-2-benzohydrazine (14).

The positive outcomes that resulted from aldehydesprompted our investigation of the reaction with ketones. Asketones are less reactive than aldehydes, their reactions withhydrazides are usually more difficult and require muchharsher conditions, which limits any sensitive functionalgroups in the reactants. A series of ketones were submittedto the CeCl3-catalyzed formation of the N-acylhydrazones


(see Table 3). Because of the reactivity of the ketones, dif-ferent experimental conditions were investigated for thepreparation of their corresponding N-acyl-ketohydrazones.Alkyl ketones underwent the reaction in presence of 1 mol-% of CeCl3·7H2O under very mild conditions to give com-plete conversion of reactants into the products and highyields of the isolated compounds (see Table 3, com-pounds 15–20). A comparison of the results for the synthe-ses of compounds 15–17 shows that the electronic effects ofthe hydrazide have less of an impact on the reaction thanthe solubility of the reactants. The delayed reaction time forthe formation of compound 17 (see Table 3) may be associ-ated with its low solubility in ethanol rather than with theelectron-withdrawing effect of the nitro group on thehydrazide. Because of its high solubility, benzohydrazidewas selected as the standard hydrazide reactant in subse-quent ketone investigations.

Increasing the steric demand around the carbonyl groupwas first investigated, and the reaction of benzohydrazideand butanedione monooxime gave 20. The presence ofbulky substituents strongly affected the reaction time in thepresence of 1 mol-% of the catalyst. Nevertheless, both re-actants were fully converted into the corresponding N-acylhydrazone 20 without affecting the oxime functionality,which is easily affected when conventional Brønsted–Lowryacid-catalyzed methods are applied. The greater the stericdemand around the carbonyl group, the longer the reactiontime and a greater amount of catalyst required. For in-stance, even in the presence of 5 mol-% of CeCl3, the forma-tion of N-acylhydrazone 21 (see Table 3) requires a longerreaction time for the complete consumption of both reac-tants. Next, the effectiveness of the catalyst was investigatedin the reaction between benzohydrazide and camphor, anextremely bulky ketone, to afford product 22. Because cam-phor can easily sublime, the use of high temperatures wasnot desirable, and, thus, the reaction was carried out at60 °C in the presence of 10 mol-% of the CeCl3 catalyst.After 24 h, the reaction had not reached completion, andthis crude mixture was analyzed by 1H NMR spectroscopy.According to the signals attributed to the NH and NH2 ofthe hydrazide moiety, an approximate 1:1 ratio of the reac-tant to the product was calculated. Interestingly, the synthe-sis of 22 was reported in 1911 by using a camphor deriva-tive,[20] but this is the first time that it was achieved by usingthe direct and mild reaction between benzohydrazide andcamphor. Attempts to obtain this same hydrazone underrefluxing conditions in the presence of protic acids havefailed, with the recovery of the reactants and partial forma-tion of ethyl benzoate, which was possibly the result ofalcoholysis of the benzohydrazide.

The influence of mild temperatures on the stereoselectiveformation of the (E) isomer was demonstrated by compar-ing the 1H NMR spectroscopic data of the crude and pureN-acyl-ketohydrazones, which were produced by the reac-tion of benzohydrazide and asymmetric ketones. No split-ting of the 1H NMR signals were observed in most cases,and the 13C NMR spectra of the pure products clearlyshowed the presence of only one molecule. Hydrazones 19


Table 3. Synthesis of N-acyl-ketohydrazones 15–27.[a]

[a] Yields determined from isolated products.

and 21 (see Table 3), however, constitute exceptions to thisgeneral trend. Because both ketones have low steric require-


ments, a mixture of (E) and (Z) isomers was expected. And-rade et al.[21] obtained compound 19 as an approximate4.5:1 (E/Z) mixture of isomers. By observing the splittingof the NH signal at δ = 10.65 (minor) and 10.58 ppm(major) for the isolated product of the CeCl3-catalyzed syn-thesis, we found the ratio of the isomers to be approxi-mately 8.1:1 (E/Z), which is a substantial improvement tothe stereochemical purity.

In the case of compound 21, Andrade[21] reported an iso-meric ratio of approximately 5.6:1 (E/Z). After 1H NMRanalysis of the crude product of the CeCl3-catalyzed synthe-sis, it was possible to identify an approximate 11.3:1 (E/Z)mixture of both compounds, which was determined fromthe splitting of the NH signal at δ = 10.48 (minor) and10.42 ppm (major). After this substance was isolated, the(Z) isomer could no longer be detected by 1H or 13C NMRanalysis, which supports our claim of the decisive role ofthe catalyst in the stereoselective synthesis of the N-acyl-hydrazones. Moreover, our method does not require com-plex equipment such as a microwave reactor, and, therefore,it can be employed in every laboratory.

The alkyl aryl ketones exhibited low reactivity with thehydrazides and required higher temperatures and prolongedreaction times to yield the desired products 23–25 (seeTable 3). In these cases, the effects from the increased bulki-ness of the groups around the carbonyl group and the in-creased stabilization by the substituents exceeded the elec-trophilic character of the carbonyl carbon. Despite the in-creased reaction times and higher temperatures that wereused to obtain compounds 23–25 in the presence of 5% ofthe catalyst, these conditions were milder than those re-ported, which usually include extreme heat, protic acid ca-talysis, and several hours to result in low to moderate yieldsof product. In addition, the stereoselectivity of the reactionsin the presence of the CeCl3 catalyst was maintained. All1H NMR spectroscopic data of the crude products showedno evidence of isomeric mixtures for compounds 23–25.

When less reactive benzophenone was used to preparecompound 26 (see Table 3), the reaction was complete after24 h in the presence of 10 mol-% of the catalyst at 70 °C.Compound 27 (see Table 3) involved an α,β-unsaturatedketone as the starting material, which is an acid-sensitivereactant, the hydrazones of which cannot be synthesized inpresence of protic acids. In this case, the synthetic approachrequired a different strategy, and 27 and its analogues wereprepared through a multistep synthetic route.[22] Using 10%of CeCl3 catalyst, the condensation between benzohydra-zide and benzalacetone easily proceeded under very mildconditions with a good time reaction to give 27 in excellentyield and stereoselectivity. Such α,β-unsaturated N-acyl-hydrazones are important building blocks in the synthesisof nitrogen-containing heterocycles, which are important inboth medicinal and synthetic chemistry.[22]

The proposed mechanism for this CeCl3-catalyzed reac-tion (see Scheme 2) is supported by the established work ofBartoli and co-workers[23] and initially involves a Lewisacid–base interaction between the catalyst and the oxygenof the aldehyde carbonyl group to lead to an electrophilic

J. M. dos Santos FilhoFULL PAPER

Scheme 2. Proposed mechanism for the CeCl3-catalyzed synthesis of N-acylhydrazones.

carbon atom. The rate of the reaction depends upon theease of formation of this electrophilic center and its sta-bility. Consequently, electron-donating groups favor its for-mation, whereas electron-withdrawing substituents exert theopposite effect.

The nucleophilic attack of the hydrazide at the carbonatom of the carbonyl group proceeds, over an ionic transi-tion state, and affords charged intermediates. This is consis-tent with the reaction performing better in polar protic sol-vents, which stabilize this type of species. This mechanismalso explains why the formation of compounds 8 and 13(see Table 2) occurs more slowly. Without the stabilizationof an aromatic ring in both of these cases, the formation ofthe electrophilic center at the carbonyl carbon is unfavor-able, which reduces the concentration of the species avail-able for a nucleophilic attack by the hydrazide. In the caseof ketones, both steric and electronic effects can influencethe reaction rate. Although it is easier to form the electro-philic carbon center, the alkyl and aryl substituents at thecarbonyl group stabilize the positive charge more efficiently,which slows the nucleophilic attack of the hydrazide aminogroup.

Finally, studies towards the scale up of this approachwere investigated and led to similar results as those on amillimole scale. As the model, compound 1 was obtainedwithin a few minutes on a multigram scale by using theestablished standard conditions. The 1H NMR spectrum ofthe crude product was exactly the same as that obtained ona millimole scale. Because the products could be isolated bya simple filtration followed by washing with cold water, thecatalyst could be recovered and recycled by removing thewater under vacuum. The results were the same for up tofour successive catalytic cycles with no excessive loss of ac-tivity. As a result, the synthesis of compound 1 could beachieved on a five gram scale with yields of 94, 92, 93, and91% for the successive cycles.

Conclusions

CeCl3·7H2O proved to be an effective catalyst for thesynthesis of N-acylhydrazones. The method described


herein is considerably simple and clean to lead to the stereo-selective formation of the products in good to excellentyields under mild conditions and in the presence of a smallamount of the catalyst. Sterically demanding, less reactive,and functionally sensitive reactants are suitable for this re-action. In addition, this CeCl3-catalyzed method is particu-larly relevant with regard to green chemistry, as it is suitablefor use with water at room temperature and is atom econ-omic. The catalyst can be recovered from large-scale experi-ments and easily recycled for at least four times withoutthe loss of efficacy. New perspectives on the syntheses ofstructurally diverse N-acylhydrazones are envisaged, whichcan result in a broad spectrum of applications in severalfields of synthetic medicinal chemistry.

Experimental SectionGeneral Procedure for the Synthesis of N-Acylhydrazones 1–13 (Mil-limole Scale): A mixture of benzohydrazide (1 mmol), aldehyde(1 mmol), and cerium(III) chloride heptahydrate (1 mol-%) in eth-anol (2 mL) was stirred at 20 °C. The progress of the reaction wasmonitored by TLC. In intervals of 10 s, standardized samples wereremoved from the reaction mixture with a capillary tube and dis-solved in THF (0.3 mL), and then the sample solution was appliedto a TLC plate (suitable solvent system as eluent). Chromatogramswere visualized under UV light (254 nm) and iodine vapor, and theconsumption of the reactants was determined by the disappearanceof their spots on the TLC plate. The stirring was then stopped, andthe ethanol was removed under reduced pressure without heat. Thecrude product was dried under vacuum and then analyzed by 1HNMR spectroscopy. The completion of the reaction was confirmedby the absence of signals for the hydrazido protons (–CONHNH2),which were at δ = 9.30–9.80 (–CONH–) and at 4.40–5.60 ppm(–NH2), and the aldehyde proton at δ = 9.50–10.5 ppm (–CHO).The crude product was recrystallized from a suitable solvent to givethe pure product, which was characterized by melting point and1H NMR, 13C NMR and IR spectroscopy. The proton and carbonsignals were assigned by comparison with reported NMR spectro-scopic data.

General Procedure for the Synthesis of N-Acylhydrazones 14–27(Millimole Scale): A mixture of the hydrazide (1 mmol) and ketone(1 mmol) in ethanol (2 mL) was stirred in the presence of the opti-mized quantity of cerium(III) chloride heptahydrate at the tem-


perature reported in Table 3. The progress of the reaction was mon-itored by TLC. At appropriate time intervals, standardized sampleswere removed from the reaction mixture with a capillary tube anddissolved in THF (0.3 mL), and then the sample solution was ap-plied to the TLC plate (suitable solvent system as eluent). Chroma-tograms were visualized under UV light (254 nm) and iodine vapor,and the consumption of the reactants was determined by the disap-pearance of their spots on the TLC plate. The stirring was thenstopped, and the ethanol was removed under reduced pressurewithout heat. The crude product was dried under vacuum and thenanalyzed by 1H NMR spectroscopy. The completion of the reactionwas confirmed by the absence (except for compound 21) of signalsfor the hydrazido protons (–CONHNH2), which were at δ = 9.30–9.80 (–CONH–) and at 4.40–5.60 ppm (–NH2). The crude productwas recrystallized from a suitable solvent to give the pure product,which was characterized by melting point and 1H NMR, 13C NMRand IR spectroscopy. The proton and carbon signals were assignedby comparison with reported NMR spectroscopic data.

Procedure for Synthesis of Standard Compound 1 (MultigramScale): A mixture of benzohydrazide (5.0 g, 36.7 mmol), benzalde-hyde (3.90 g, 36.7 mmol), and cerium(III) chloride heptahydrate(0.1368 g, 3.67 mmol, 1 mol-%) in ethanol (10 mL) was stirred at20 °C. After 6.5 min, TLC indicated that the reaction had reachedcompletion. The mixture was cooled and filtered. The crystals werewashed with water (10 mL), dried under vacuum, and then charac-terized. The filtrate was concentrated to dryness under reducedpressure. The resulting solid residue was suspended in dichloro-methane, and the suspension was filtered. The resulting solid wasreused for additional synthetic cycles, and the amounts of the reac-tants were adjusted each time to the recovered amount of CeCl3.The successive yields of (E)-N�-benzylidenebenzohydrazide (1) foreach cycle were 94, 92, 93, and 91%. The 1H NMR spectroscopicdata were the same for each sample.

Supporting Information (see footnote on the first page of this arti-cle): Experimental details, characterization data, and copies of the1H NMR, 13C NMR, and IR spectra of all compounds.

Acknowledgments

The author is grateful to Ms Eliete de Fátima V. B. N. da Silva, MsAbene Silva Ribeiro, and the Analytical Centre of FundamentalChemistry Department, Universidade Federal de Pernambuco, forthe NMR experiments. Additional acknowledgments are given toProf. Savio Moita Pinheiro (UFPB-Brazil) for the helpful dis-cussions and to Dr. Kyan James Allahdadi (Hospital São Rafael-Brazil) for proofreading the manuscript.

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Received: May 20, 2014Published Online: August 29, 2014

Mild, Stereoselective, and Highly Efficient Synthesis of N -Acylhydrazones Mediated by CeCl 3 ·7H 2...

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