Research Article Insight into the Willgerodt-Kindler ...downloads.hindawi.com/archive/2014/486540.pdf · is paper reports e orts aimed at tuning up the synthesis of a compound library

Research ArticleInsight into the Willgerodt-Kindler Reaction of120596-Haloacetophenone Derivatives Mechanistic Implication

Urbain C Kasseacutehin12 Fernand A Gbaguidi1 Coco N Kapanda3

Christopher R McCurdy3 and Jacques H Poupaert2

1Laboratoire de Chimie Pharmaceutique Organique Ecole de Pharmacie Faculte des Sciences de la SanteUniversite drsquoAbomey-Calavi Campus du Champ de Foire 01 BP 188 Cotonou Benin2Medicinal Chemistry Louvain Drug Research Institute UCL 73 Bte B17310 Avenue E Mounier 1200 Bruxelles Belgium3Department of BioMolecular Sciences School of Pharmacy University of Mississippi 419 Faser Hall PO Box 1848University MS 38677-1848 USA

Correspondence should be addressed to Urbain C Kassehin comlankassehinstudentuclouvainbe

Received 16 September 2014 Accepted 25 November 2014 Published 10 December 2014

Academic Editor Joseph E Saavedra

Copyright copy 2014 Urbain C Kassehin et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

This paper reports efforts aimed at tuning up the synthesis of a compound library centered on the general template 2-amino-1-phenyl-2-thioxoethanone taking the condensation of 120596-haloacetophenone octasulfur and morpholine as pilot reactionConsiderations about atomic economywere found extremely precious in selecting the best starting halo-reagent Aone-pot practicalmethod based on use of 2-bromo-1-phenylethanone as substrate and NN-dimethylformamide as solvent can be easily scaled up togram amounts (72 yield) Based on this synthetic approach some more specific examples are reported

1 Introduction

Thioamides and related structure are ever more becomingessential building blocks for preparing biologically usefulprobes [1] Along this line a plethora of methods has longbeen reported in the literature to synthesize thioamides [2 3]In spite of the fact that this one-pot process is a long-knownreaction (which was first reported by Kindler in 1923) [4]the three-component condensation of an aldone (aldehyde-ketone) 1 cyclooctasulfur (ie cyclo-S

8) and an amine 2mdash

either primary or secondarymdash(Figure 1) termed nowadaysin the literature as the Willgerodt-Kindler (WK) reactionhas received over the last ten years considerable attentionfrom the point of view of the combinatorial chemistry [56] There has been indeed a revival of interest for thisrelatively old reaction as it allows for a straightforwardintroduction of chemical diversity around the C(=S)ndashNHbackbone by variation of the aldone (R1) and amine (R2 andR3) components in a one-pot single condensation step [7] Asa wide variety of aldones and primarysecondary amines are

nowadays readily commercially accessible as a consequence awide variety of pharmacologically useful thioamides can thusbe potentially prepared in a single-step procedure using thismethod [2 8 9] It is also noteworthy that the WK reactionallows for a form of ldquoumpolungrdquo which involves the reversalof polarity in the sense that starting from the acetophenonesubstrate for example the carbonyl is reduced while theterminal methyl group is oxidized

In this connection and particularly in the context of thesynthesis of a compound library our group became interestedin generating a collection of 2-oxo-2-phenylethanethioamidederivatives as potential inhibitors of the endocannabinoidMAGL (monoacylglycerol lipase) enzyme for high through-put screening [10ndash14] The general structure of the targetedmolecules is shown in Figure 2 This paper thus reports ourefforts aimed at tuning up amodel reaction in the elaborationof a compound library centered on the general template 2-amino-1-phenyl-2-thioxoethanone taking into considerationthe condensation of 120596-haloacetophenone octasulfur andmorpholine as pilot reaction For obvious reasons the fluoro

Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2014 Article ID 486540 5 pageshttpdxdoiorg1011552014486540

2 Organic Chemistry International

O

X

N

XS

R

n

nCH3

S8 HNRR998400 R998400

minusH2O

Figure 1 General equation of the WK reaction (where X is asubstituent on the aryl group 119899 is a variable number of methylenegroups and R and R1015840 are alkyl aryl or (hetero)cycloalkyl groups)

N

O

S

R

XR998400

Figure 2 General template of 120572-ketothioamides reaction (where Xis a substituent on the aryl group and R and R1015840 are alkyl aryl or(hetero)cycloalkyl groups)

term was not considered in this study because of its too lowintrinsic reactivity the iodo termwas also eliminated becauseof its chemical instability As a matter of fact many syntheticalternatives refering to 120572-ketothioamides were already pub-lished in the literature However these approaches mostlynot generally employ hazardous and expensive reagents andnecessitate long reactions times Nevertheless some of themost recent literature references demonstrate the contem-porary relevance of this class of molecules Some of theserecent contributions capitalize on arylglyoxal derivatives asstartingmaterials which are synthetized from acetophenonesexploiting selenium dioxide as oxidizing agent This reagenthowever is toxic as well as the selenious acid found in theeffluents after working up the reaction mixture to isolatethe glyoxal derivatives This can be alleviated by using ourhalogenation procedure herein described [15ndash17]

2 Results and Discussion

Increasingly stringent environmental and economic consid-erations along with paradigms generated a pressing need forcleaner and more efficient methods of chemical synthesiswhich reduce amounts of waste and avoid the use of toxicand potentially hazardous reagents and solvents [18ndash20]Thistrend toward ldquogreen chemistryrdquo [21 22] requires a formof separation from the traditional concepts which focusseson chemical yields to one that drastically aims at limitingunuseful wastes Along this line was introduced the conceptof ldquoatomic economyrdquo

Atomic economy (AE) can be written as in the followingequation

AE () =MW (end product)Σ (MW reactants)

times 100 (1)

The atom economy (AE) concept [19] is an extremely usefultool for rapid assessment of the amount of waste generatedin the synthesis of a reaction product It is calculated by

Table 1 Atomic economy for the model WK reaction

Entry R Atomeconomy ()

Yield()

Overallefficiency

(Number 1) CH3 98 27 26(Number 2) CH2Cl 86 40 34(Number 3) CHCl2 76 65 49(Number 4) CH2Br 74 72 53(Number 5) CHBr2 59 70 41

dividing the molecular weight of the end product by the sumof the molecular weights (MW) of all reactants involved inthe stoechiometric equation for the reaction(s) consideredthis ratio being multiplied by 100 (1) Typically catalytichydrogenation of an alkene for instance reduction of styreneto ethylbenzene using dihydrogene has got an AE of 100Diels-Alder reaction is another example also that has gota 100 AE Calculation of the atom economy has beenperformed for various pertinent model reactions of the WKreaction and the results are shown in Table 1 (cfr Figure 3)

Clearly the best AE figure is reached with acetophenone(entry number 1) whereas the less efficient option is obtainedfor 22-dibromo-1-phenylethanone (entry number 5) How-ever this aspect must be tempered by the actual yield ofthe reaction In our hands preliminary results indicated that2-bromo-1-phenylethanone (entry number 4) was the bestsubstrate for the reaction in terms of yield and also ease ofreaction In effect if we multiply the AE value by the actualyield to obtain the overall efficiency entry number 4 appearsas the best practical option The dibromo (entry number 5)substrate is too reactive and requires cooling at the beginningof the reaction For all these reasons we therefore endeavourto obtain a one-pot practical method that could be easilyscaled up to gram scale amounts

After carrying out directly the bromination of acetophe-none in a traditional manner (see Section 41) in chloroformthe resulting product was engaged in theWKprocess withoutany further purification Following stepwise optimizationingredients necessary to perform the WK reaction wereintroduced into the reaction medium in the following orderDMF octasulfur (15 equivalents) and finally morpholine(3 equivalents) The reaction proceeded to completion atroom temperature in 24 h Using excess sulfur does not createa problem with regard to the purity of the final productas far as the amine is also used in sufficient excess (here3 equivalents) and therefore these side-products are easilyremoved during the work-up The reactive intermediatesinvolved in the WK reaction are indeed in great part polarwater-soluble nitrogen-sulfur species formed by ring openingof octasulfur by the nucleophilic attack of the amine [23]DMF (at room temperature) was found greatly beneficial asreaction in refluxing diethyl ether (sim35∘C) required a ratherlong reaction time typically 36 h

At this point the question arose as to the genesis of com-pound (5) starting from acetophenone (1) According to Liuet al [24] therewould be apparently a spontaneous formationof 2-morpholino-1-phenylethanone (6) (cfr Figure 5) from

Organic Chemistry International 3

O

R

O

S

N

OS8

HN(CH2CH

2)2O

Figure 3 WK pilot reaction

O O

H

S

O

H

N

O

O

SH

N

OO

S

N

O(1) (2) (3)

(4)(5)

Figure 4 Mechanism proposed for the generation of 2-oxo-2-phenylethanethioamide (5) from acetophenone (1)

O

N

O

(6)

Figure 5

acetophenone by direct substitution on the methyl groupThis seems very unlikely as this process (SN2 nucleophilicsubstitution) would formally involve the release of a hydrideanion and a strong base and therefore represents a prettybad ldquoleaving grouprdquo We therefore sought for an alternativemechanistic explanation which is shown in Figure 4 Inthis mechanism proposal 1 is thionated to a thioaldehydespecies (2) which is transformed to an immonium species (3)by nucleophilic attack and condensation with morpholineFurther thionation of (3) leads to (4) which after loss ofa hydron yields final compound (5) It should be notedthat thionation of active methylene moieties is classicallyinvoked in the WK reaction and other related chemicalsituations [23] Moreover it is worth mentioning that inthis reaction in which (5) is produced there is a massiveproduction of the normal WK product which is the expectedphenylthiomorpholide [4 8]

As to the possibility that at the level of compound(2) there would be potentially a concurrent nucleophilicattack of the secondary amine onto the carbonyl in 2-position a possibility that cannot be theoretically excludedwe performed various attempts to react this carbonyl at thelevel of compound (5) using primary and secondary amines

without any success In this connection it should be pointedout that 4-phenylthiosemicarbazide is a reagent well knownfor its high nucleophilicity and affinity for carbonylated com-pounds Furthermore (5) remained inert towards 4-phenyl-thiosemicarbazide even under strong conditions We cantherefore state that this carbonyl group is strongly deactivatedpresumably due to the neighbouring thiocarbonyl group

To further substantiate our approach we report thesynthesis of a few terms of the projected library whichwere obtained in good yield (typically 70 yield) Furtherwork is now being devoted to create a compound libraryof 120572-ketothioamides in the antitrypanosomal (Trypanosomabrucei brucei) axis

3 Conclusion

In this paper we report efforts aimed at tuning up thesynthesis of a series of 2-amino-1-phenyl-2-thioxoethanonebased on the condensation of 120596-haloacetophenone octasul-fur and morpholine with special consideration about atomiceconomy and efficiency A one-pot practical method basedon use of 2-bromo-1-phenylethanone as substrate and DMFas solvent has been set up It is noteworthy that this syntheticmethod proceeds in good yield at room temperature incontrast with the need for high temperatures in most WKprocesses Hendrickson defined such a synthesis in 1975stating that ldquoThe ideal synthesis creates a complex moleculein a sequence of only construction reactions involving nointermediary refunctionalizations leading directly to thetarget not only its skeleton but also its correctly placedfunctionalityrdquo [25] In this connection we truly believe prag-matically that theWK reaction applied to haloacetophenones


is a remarkable example of a reaction to be included amongideal syntheses

4 Experimental

Melting points were determined using an electrothermalmelting point apparatus and are uncorrected IR spectrawere recorded on a Perkin-Elmer 457 spectrometer usingKBr pellets Wave numbers are expressed in cmminus1 1H- and13C-NMR spectra were recorded at ambient temperatureon a Brucker 400 spectrometer Compounds were dissolvedin CDCl

3or DMSO-d6 to obtain a 01 molar solution

Chemical shifts are expressed in the 120575 scale with TMS(tetramethylsilane) as internal standard Thin layer chro-matography (TLC) analyses were performed on Merck TLCplates (silica gel 60 F 254 EMerckDarmstadt ref 5735) ForTLC all the compounds reported were routinely checked intwo standard solvents that is acetonetoluenecyclohexane(solvent A 5 2 3 vvv) and ethyl acetaten-hexane (solventB 4 6 vv) The reverse-phase thin layer chromatographyconditions were HPTLC plates RP-18 F-254 S (Merck) andmethanol water (7525 vv) All compounds reported werefound homogenous under such TLC and HPLC conditionsAll reagents were purchased from Aldrich All solvents wereof the ACS reagent grade (Aldrich)

41 2-Morpholino-1-phenyl-2-thioxoethanone (5) To a mag-netically stirred solution of acetophenone (120 g 01mol)in ethanol-stabilized chloroform (50mL) was added drop-wise over 30min a solution of dibromine (192 g 012mol)in chloroform (25mL) The reaction vessel was partiallyimmersed in a water bath (sim20∘C) to cool down someheat evolution After 2 h the solvent was evaporated invacuo to give a crude yellowish oil consisting mainly of 2-bromo-1-phenylethanone along with trace amounts of 22-dibromo-1-phenylethanone according to 13C-NMR analysisTo this oily residue were added at room temperature insequence DMF (15mL) cyclooctasulfur (48 g 015mol)and vacuum-redistilled morpholine (261 g 03mol) Somemoderate heat evolutionwas notedThe reactionmixture wasstirred magnetically and kept at room temperature for 24 hquenched with distilled water (250mL) to give a semisolidprecipitate which was further washed twice with distilledwater (100mL) The resulting hard cake was crystallizedfrom absolute ethanol using a Soxhlet solid-liquid extractionapparatus to remove any unreacted sulfur and give TLCpure (solvent B Rf 065) pure 2-morpholino-1-phenyl-2-thioxoethanone (182 g 72 yield) mp 112-113∘C 1H NMR(CDCl

3 400MHz) 120575 802ndash748 (m Ph 5H) 438ndash433 (m

OCH2 2H) 396ndash390 (m OCH

2 2 H) 373ndash368 (m NCH

2

2H) 364ndash359 (m NCH2 2H) IR (KBr) ] 3060 2971 2855

1667 (]C=O) 1594 1579 1450 (]C=S) 1106 701 688 cmminus113C-NMR DMSO-d6 1006MHz 120575 4477 4958 6401 641212661 12747 13091 13209 18552 (C=O) 19332 (C=S) MSmz () 235 (M+ 35) 221 (5) 177 (20) 150 (4) 130 (91) 105(84) 86 (100) 77(62) 43 (31)

42 N-Benzyl-N-methyl-2-oxo-2-phenylethanethioamide (6)mp 107ndash18∘C TLC (solvent B Rf 060) IR (KBr) ]3062 2933 1667 (]C=O) 1595 1579 1450 (]C=S) 1HNMR(CDCl

3) 120575(ppm) 724ndash803 (m 10H) 337 (s 2H) 306 (s

3H) 13CNMR (CDCl3) 120575(ppm) 19595 (C=S) 18668 (C=O)

13319 13231 13200 12889 12880 12864 12776 1275312685 4587 3825

43 2-(4-Benzhydrylpiperazin-1-yl)-1-phenyl-2-thioxoetha-none (7) mp 125ndash127∘C 1HNMR (CDCl

3) 120575(ppm) 789ndash

722 (m 15H) 422 (s 1H) 351 (t 2H J = 484Hz) 349 (t2H J = 476Hz) 256 (t 2H J = 484Hz) 235 (t 2H J =476Hz)13CNMR (CDCl

3) 120575(ppm) 19505 (C=S) 18800 (C=O)

14160 13427 13334 12983 12889 12878 12775 127447558 5175 5168 5112 4699 MSmz = 401166

44 2-(4-Benzhydrylpiperazin-1-yl)-1-(4-nitrophenyl)-2-thiox-oethanone (8) mp 105ndash107∘C 1HNMR (CDCl

3) 120575(ppm)

829 (d 2H 119869 = 852Hz) 812 (d 2H 119869 = 852Hz) 741ndash722 (m 10H) 527 (s 1H) 430 (t 2H 119869 = 444Hz) 360(t 2H 119869 = 448Hz) 244 (t 2H 119869 = 472Hz) 265 (t 2H119869 = 472Hz) 13CNMR (CDCl

3) 120575(ppm) 19308 (C=S) 18457

(C=O) 15069 14141 13847 13077 12882 12774 1275212398 7555 5191 5176 5110 4721 MSmz = 446151

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] J Bostrom R I Olsson J Tholander et al ldquoNovel thioamidederivatives as neutral CB1 receptor antagonistsrdquo Bioorganic ampMedicinal Chemistry Letters vol 20 no 2 pp 479ndash482 2010

[2] O I Zbruyev N Stiasni and C O Kappe ldquoPreparationof thioamide building blocks via microwave-promoted three-component kindler reactionsrdquo Journal of Combinatorial Chem-istry vol 5 no 2 pp 145ndash148 2003

[3] Z Kaleta B T Makowski T Soos and R Dembinski ldquoThiona-tion using fluorous Lawessonrsquos reagentrdquo Organic Letters vol 8no 8 pp 1625ndash1628 2006

[4] K Kindler ldquoStudien uber den Mechanismus chemischer Reak-tionen Erste Abhandlung Reduktion von Amiden und Oxyda-tion von Aminenrdquo Justus Liebigs Annalen der Chemie vol 431pp 187ndash230 1923

[5] K Okamoto T Yamamoto and T Kanbara ldquoEfficient synthesisof thiobenzanilides by Willgerodt-Kindler reaction with basecatalystsrdquo Synlett no 17 pp 2687ndash2690 2007

[6] F A Gbaguidi C N Kapanda A L Ahoussi et al ldquoGeneralacid-base catalysis in the Willgerodt-Kindler reactionrdquo Journalde la Societe Ouest-Africaine deChimie vol 029 pp 89ndash94 2010

[7] H R Darabi K Aghapoor Y Balavar E Mobedi HFarhangian and F Mohsenzadeh ldquoSynthesis of 1n-acyloxythioamides by the Willgerodt-Kindler reaction chemoselectiv-ity of 13-ketoesters over 13-diketonesrdquo Zeitschrift fur Natur-forschung vol 63 no 8 pp 993ndash997 2008


[8] J H Poupaert S Duarte E Colacino P Depreux C RMcCurdy andD L Lambert ldquoWillgerodt-kindlerrsquos microwave-enhanced synthesis of thioamide derivativesrdquo Phosphorus Sul-fur and Silicon and the Related Elements vol 179 no 10 pp1959ndash1973 2004

[9] J H Poupaert P Carato and C R McCurdy ldquoA simple andeffective method for the thionation of amides to thioamidesusingAl

2O3-supported P

4S10rdquoLetters inOrganic Chemistry vol

2 no 4 pp 330ndash333 2005[10] C N Kapanda J H Poupaert and D M Lambert ldquoInsight

into themedicinal chemistry of the endocannabinoid hydrolaseinhibitorsrdquo Current Medicinal Chemistry vol 20 no 14 pp1824ndash1846 2013

[11] C N Kapanda J Masquelier G Labar G G Muccioli J HPoupaert and D M Lambert ldquoSynthesis and pharmacologi-cal evaluation of 24-dinitroaryldithiocarbamate derivatives asnovel monoacylglycerol lipase inhibitorsrdquo Journal of MedicinalChemistry vol 55 no 12 pp 5774ndash5783 2012

[12] C N Kapanda G G Muccioli G Labar N Draoui DM Lambert and J H Poupaert ldquoSearch for monoglyceridelipase inhibitors synthesis and screening of arylthioamidesderivativesrdquo Medicinal Chemistry Research vol 18 no 4 pp243ndash254 2009

[13] G Labar C Bauvois GGMuccioli JWouters andDM Lam-bert ldquoDisulfiram is an inhibitor of human purified monoacyl-glycerol lipase the enzyme regulating 2-arachidonoylglycerolsignalingrdquo ChemBioChem vol 8 no 11 pp 1293ndash1297 2007

[14] G Labar and C Michaux ldquoFatty acid amide hydrolase fromcharacterization to therapeuticsrdquo Chemistry and Biodiversityvol 4 no 8 pp 1882ndash1902 2007

[15] J E Valdez-Rojas H Rıos-Guerra A L Ramırez-Sanchezet al ldquoA study of the Willgerodt-Kindler reaction to obtainthioamides and 120572-ketothioamides under solvent-less condi-tionsrdquoCanadian Journal of Chemistry vol 90 no 7 pp 567ndash5732012

[16] B Eftekhari-Sis S V Khajeh and O Buyukgungor ldquoSynthesisof 120572-ketothioamides via willgerodt-kindler reaction of arylgly-oxals with amines and sulfur under solvent-free conditionsrdquoSynlett vol 24 no 8 pp 977ndash980 2013

[17] H Saeidian S Vahdati-Khajehi H Bazghosha and Z Mir-jafary ldquoNa2S-mediated thionation an efficient access to sec-ondary and tertiary 120572-ketothioamides via WillgerodtndashKindlerreaction of readily available arylglyoxals with aminesrdquo Journalof Sulfur Chemistry vol 35 no 6 pp 700ndash710 2014

[18] G Labar F V Vliet J Wouters and D M Lambert ldquoA MBP-FAAH fusion protein as a tool to produce human and ratfatty acid amide hydrolase expression and pharmacologicalcomparisonrdquo Amino Acids vol 34 no 1 pp 127ndash133 2008

[19] R A Sheldon ldquoAtom efficiency and catalysis in organic synthe-sisrdquo Pure and Applied Chemistry vol 72 no 7 pp 1233ndash12462000

[20] R A Sheldon ldquoCatalysis and zeolites fundamentals and appli-cationsrdquo Journal of Molecular Catalysis A vol 107 pp 75ndash2581996

[21] R A Sheldon ldquoGreen chemistry and catalysisrdquo Chemistry andIndustry pp 903ndash906 1992

[22] R A Sheldon ldquoGreen Chemistry for Environmental Sustain-ability Catalysis the key to waste minimizationrdquo Journal ofChemical Technology and Biotechnology vol 68 no 4 pp 381ndash388 1997

[23] M Carmack ldquoThe Willgerodt-Kindler reactions the mecha-nismrdquo Journal of Heterocyclic Chemistry vol 26 no 5 pp 1319ndash1323 1989

[24] W-W Liu Y-Q Zhao R-B Xu L-J Tang and H-W HuldquoAn unexpected discovery in the Willgerodt-Kindler reac-tion of acetophenonemdashthe formation of the 4-(benzoylthio-carbonyl)morpholinerdquoChinese Journal of Chemistry vol 24 no10 pp 1472ndash1475 2006

[25] J B Hendrickson ldquoSystematic synthesis design III The scopeof the problemrdquo Journal of the American Chemical Society vol97 no 20 pp 5763ndash5784 1975

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


O

X

N

XS

R

n

nCH3

S8 HNRR998400 R998400

minusH2O

Figure 1 General equation of the WK reaction (where X is asubstituent on the aryl group 119899 is a variable number of methylenegroups and R and R1015840 are alkyl aryl or (hetero)cycloalkyl groups)

N

O

S

R

XR998400

Figure 2 General template of 120572-ketothioamides reaction (where Xis a substituent on the aryl group and R and R1015840 are alkyl aryl or(hetero)cycloalkyl groups)

term was not considered in this study because of its too lowintrinsic reactivity the iodo termwas also eliminated becauseof its chemical instability As a matter of fact many syntheticalternatives refering to 120572-ketothioamides were already pub-lished in the literature However these approaches mostlynot generally employ hazardous and expensive reagents andnecessitate long reactions times Nevertheless some of themost recent literature references demonstrate the contem-porary relevance of this class of molecules Some of theserecent contributions capitalize on arylglyoxal derivatives asstartingmaterials which are synthetized from acetophenonesexploiting selenium dioxide as oxidizing agent This reagenthowever is toxic as well as the selenious acid found in theeffluents after working up the reaction mixture to isolatethe glyoxal derivatives This can be alleviated by using ourhalogenation procedure herein described [15ndash17]

2 Results and Discussion

Increasingly stringent environmental and economic consid-erations along with paradigms generated a pressing need forcleaner and more efficient methods of chemical synthesiswhich reduce amounts of waste and avoid the use of toxicand potentially hazardous reagents and solvents [18ndash20]Thistrend toward ldquogreen chemistryrdquo [21 22] requires a formof separation from the traditional concepts which focusseson chemical yields to one that drastically aims at limitingunuseful wastes Along this line was introduced the conceptof ldquoatomic economyrdquo

Atomic economy (AE) can be written as in the followingequation

AE () =MW (end product)Σ (MW reactants)

times 100 (1)

The atom economy (AE) concept [19] is an extremely usefultool for rapid assessment of the amount of waste generatedin the synthesis of a reaction product It is calculated by

Table 1 Atomic economy for the model WK reaction

Entry R Atomeconomy ()

Yield()

Overallefficiency

(Number 1) CH3 98 27 26(Number 2) CH2Cl 86 40 34(Number 3) CHCl2 76 65 49(Number 4) CH2Br 74 72 53(Number 5) CHBr2 59 70 41

dividing the molecular weight of the end product by the sumof the molecular weights (MW) of all reactants involved inthe stoechiometric equation for the reaction(s) consideredthis ratio being multiplied by 100 (1) Typically catalytichydrogenation of an alkene for instance reduction of styreneto ethylbenzene using dihydrogene has got an AE of 100Diels-Alder reaction is another example also that has gota 100 AE Calculation of the atom economy has beenperformed for various pertinent model reactions of the WKreaction and the results are shown in Table 1 (cfr Figure 3)

Clearly the best AE figure is reached with acetophenone(entry number 1) whereas the less efficient option is obtainedfor 22-dibromo-1-phenylethanone (entry number 5) How-ever this aspect must be tempered by the actual yield ofthe reaction In our hands preliminary results indicated that2-bromo-1-phenylethanone (entry number 4) was the bestsubstrate for the reaction in terms of yield and also ease ofreaction In effect if we multiply the AE value by the actualyield to obtain the overall efficiency entry number 4 appearsas the best practical option The dibromo (entry number 5)substrate is too reactive and requires cooling at the beginningof the reaction For all these reasons we therefore endeavourto obtain a one-pot practical method that could be easilyscaled up to gram scale amounts

After carrying out directly the bromination of acetophe-none in a traditional manner (see Section 41) in chloroformthe resulting product was engaged in theWKprocess withoutany further purification Following stepwise optimizationingredients necessary to perform the WK reaction wereintroduced into the reaction medium in the following orderDMF octasulfur (15 equivalents) and finally morpholine(3 equivalents) The reaction proceeded to completion atroom temperature in 24 h Using excess sulfur does not createa problem with regard to the purity of the final productas far as the amine is also used in sufficient excess (here3 equivalents) and therefore these side-products are easilyremoved during the work-up The reactive intermediatesinvolved in the WK reaction are indeed in great part polarwater-soluble nitrogen-sulfur species formed by ring openingof octasulfur by the nucleophilic attack of the amine [23]DMF (at room temperature) was found greatly beneficial asreaction in refluxing diethyl ether (sim35∘C) required a ratherlong reaction time typically 36 h

At this point the question arose as to the genesis of com-pound (5) starting from acetophenone (1) According to Liuet al [24] therewould be apparently a spontaneous formationof 2-morpholino-1-phenylethanone (6) (cfr Figure 5) from


O

R

O

S

N

OS8

HN(CH2CH

2)2O


O O

H

S

O

H

N

O

O

SH

N

OO

S

N

O(1) (2) (3)

(4)(5)


O

N

O

(6)

Figure 5





3 Conclusion




4 Experimental








2




3) 120575(ppm) 724ndash803 (m 10H) 337 (s 2H) 306 (s


13319 13231 13200 12889 12880 12864 12776 1275312685 4587 3825


3) 120575(ppm) 789ndash


3) 120575(ppm) 19505 (C=S) 18800 (C=O)

14160 13427 13334 12983 12889 12878 12775 127447558 5175 5168 5112 4699 MSmz = 401166


3) 120575(ppm)


3) 120575(ppm) 19308 (C=S) 18457

(C=O) 15069 14141 13847 13077 12882 12774 1275212398 7555 5191 5176 5110 4721 MSmz = 446151



References











2O3-supported P




























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

R

O

S

N

OS8

HN(CH2CH

2)2O


O O

H

S

O

H

N

O

O

SH

N

OO

S

N

O(1) (2) (3)

(4)(5)


O

N

O

(6)

Figure 5





3 Conclusion




4 Experimental








2




3) 120575(ppm) 724ndash803 (m 10H) 337 (s 2H) 306 (s


13319 13231 13200 12889 12880 12864 12776 1275312685 4587 3825


3) 120575(ppm) 789ndash


3) 120575(ppm) 19505 (C=S) 18800 (C=O)

14160 13427 13334 12983 12889 12878 12775 127447558 5175 5168 5112 4699 MSmz = 401166


3) 120575(ppm)


3) 120575(ppm) 19308 (C=S) 18457

(C=O) 15069 14141 13847 13077 12882 12774 1275212398 7555 5191 5176 5110 4721 MSmz = 446151



References











2O3-supported P




























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



4 Experimental








2




3) 120575(ppm) 724ndash803 (m 10H) 337 (s 2H) 306 (s


13319 13231 13200 12889 12880 12864 12776 1275312685 4587 3825


3) 120575(ppm) 789ndash


3) 120575(ppm) 19505 (C=S) 18800 (C=O)

14160 13427 13334 12983 12889 12878 12775 127447558 5175 5168 5112 4699 MSmz = 401166


3) 120575(ppm)


3) 120575(ppm) 19308 (C=S) 18457

(C=O) 15069 14141 13847 13077 12882 12774 1275212398 7555 5191 5176 5110 4721 MSmz = 446151



References











2O3-supported P




























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




2O3-supported P




























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Insight into the Willgerodt-Kindler ...downloads.hindawi.com/archive/2014/486540.pdf · is paper reports e orts aimed at tuning up the synthesis of a compound library