Multi‐component reactions (MCRs), where three or morereactants are combined into a one‐pot process, represent anincreasingly important and attractive area of research in or‐ganic synthesis because they provide high levels of efficiencyvia the combination of several operational steps, as well asallowing foroperational steps involving the isolationof inter‐mediatesor changingof reactionconditions tobeavoided. Intermsoftheadvantagesthattheyoffer,MCRsaregeneraleffi‐cientproceduresthatprovidehighlevelsofatomeconomyandsignificant cost savings. The discovery and development ofnovel andknownMCRshave consequentlybecomeapopularareaofresearchinorganicchemistry.
ase inhibitors [1,2], such as ritonavir and liponavir [3,4].1‐Amidoalkyl‐2‐naphthol derivatives can be converted to1‐aminomethyl‐2‐naphthols via an amide hydrolysis reaction.Thesecompoundsareimportantsyntheticbuildingblocksandexhibita rangeofbiologicalactivity, includingdepressiveandbradycardiaeffectsinhumans[4,5].
1‐Amidoalkyl‐2‐naphthols can be prepared by the multi‐
component condensation of aryl aldehydes with 2‐naphtholandacetamideor thioacetamide in thepresenceof an appro‐priate catalyst such as RuCl2(PPh3)3 [6], sulfamic acid [7,8],Ce(SO4)2 [9], [FemSILP]‐L‐prolinate [10], Bi(NO3)3·5H2O [11],K5CoW12O40·3H2O [12], Hf(NPf2)4 [13], H3PW12O40 [14],Yb(OTf)3 [15],Fe(HSO4)3 [16],montmorilloniteK10clay [17],p‐TSA[18],H4SiW12O40[19],zeolite[20],2,4,6‐trichloro‐1,3,5‐
trizine [21], iodine [22], PFPAT [23], and poly(4‐vinylpyri‐diniumbutanesulfonicacid)hydrogensulfate[24].
Inmostcases,however,theapplicationofthesemethodsislimited by their requirement for prolonged reaction time, ul‐
trasonic or microwave irradiation, and the use of stoichio‐metricquantitiesoftoxicandcorrosivecatalysts.Furthermore,the existing procedures generally provide low yields of thedesiredproducts.Therefore, thediscoveryof anew, inexpen‐sive, and readily available catalystwith high catalytic activityand short reaction time for the preparation of amidoalkylnaphthols is strongly desired. Tribromo‐melamine (mela‐mine‐Br3)isahomogeneousandnon‐hygroscopicsolidcatalystthatcanbereadilypreparedbyreactionofmelaminewithBrunderalkaliconditions(Scheme1)[25].
Melamine‐Br3isstableunderavarietyofdifferentreactionconditions,includingacidicandbasicconditions.Itisnotewor‐thy thatmelamine‐Br3 isproducedviaa facile and cleanpro‐cess that does not require a complicatedwork‐up procedure.Melamine‐Br3hasbeenusedinavarietyofdifferentreactions,including the synthesis of 2‐aryl thiazolines [25] and the tri‐methyl silylation of hydroxyl groupswith 1,1,1,3,3,3‐hexame‐thyldisilazane(HMDS)[26].Herein,wereportamelamine‐Br3‐
catalyzed one‐potMCR for the synthesis of biologically inter‐esting1‐amidoalkyl‐2‐naphthols.
AllofthechemicalsusedherewerepurchasedfromFluka,Merck, and Aldrich chemical companies. The products werecharacterizedbycomparisonoftheirspectral(1Hand13CNMR)andphysicaldatawiththoseofauthenticsamples.
Melamine‐Br3(0.054g,0.15mmol)wasaddedtoamixtureofaldehyde(1mmol),2‐naphthol(1mmol)andacetamideorthioacetamide (1.5 mmol), and the resulting mixture wasstirredat130°Cinanoilbathfortheappropriatetime.Uponcompletionofthereaction,asdeterminedbyTLC,themixturewascooledtoroomtemperature,andpurifieddirectlybycol‐umn chromatography over silica gel using a mixture of ace‐tone/n‐hexane (3:7, v/v) as the eluent to give the desiredproduct.
Amixtureof terephthaldehyde (0.134g, 1mmol),2‐naph‐thol (0.36 g, 2.5 mmol), acetamide (0.22 g, 3.75 mmol), andmelamine‐Br3(0.054g,0.15mmol)wasstirredat130°C for the appropriate time. Uponcompletionofthe reaction,asdetermined by TLC, the mixture was cooled to room temperature and purifieddirectly by column chromatography over silica gel using amix‐tureofacetone/n-hexane (1:1,v/v) astheeluent to give thede‐
Ina continuationofourongoing research towards thede‐velopmentofnovel transformation inorganic synthesisusinghalogenating agents [26,28,29],we have developed a processfor the construction of 1‐amidoalkyl‐2‐naphthols usingmela‐mine‐Br3asanefficientcatalyst.Thereactionofbenzaldehydewith2‐naphtholandacetamidewasinitiallyselectedasamod‐eltransformation(Scheme2)tooptimizedthereactioncondi‐tions.
As shown in Table 1,when the reactionwas initially con‐ductedintheabsenceofthecatalyst,onlyasmallamountoftheproductwasformedoveralongreactiontime.Theadditionof0.05mmolofcatalyst ledtoasignificant increase in theyield(70%)withthereactiontimebeingreducedto6.5h.Increasingthe catalyst amount from0.05 to 0.15mmol continously, theproduct yield was increased, and the reaction time was re‐ducted. Further increasing the catalyst amount to0.20mmol,however,ledtoareductionintheproductyieldandanincreasein the reaction time.0.15mmolof catalyst thereforegave thebestresults.
Todeterminetheeffectoftemperatureonthereaction,weevaluated the condensation reaction of 2‐naphtholwith acet‐amideandbenzaldehydeinthepresenceofmelamine‐Br3atavarietyofdifferenttemperatures.AsshowninFig.1,whenthereaction temperature was varied from room temperature to130°C,theproductyieldgraduallyincreased,withthehighestyieldbeingobtainedat130°C.
ceeded smoothly under the optimized conditions to give thedesiredproductsingoodyields.Aromaticaldehydesbearinganelectron‐donating group, however, gave a slightly lower yieldandrequiredlongerreactiontime(Table2,entries7–10).Theoptimized method also proceeded successfully when thio‐acetamidewasusedinsteadofacetamideinthereaction(Table2,entries11–16).
The presence of an electron‐withdrawing group on thebenzaldehyde led toan increase in therateof the1,4‐nucleo‐philic addition reaction of the o‐quinone methide (o‐QM) in‐termediates because the electron‐withdrawing group led to areduction in the energy of the lowest unoccupied molecularorbitalofthealkene.
Basedonourresultsandrelatedreportsfromtheliterature[25], we have proposed amechanism for the transformationwhichisshowninScheme3.
Thereactionisbelievedtoproceedviatheformationofano‐QMintermediate.Nucleophilicconjugateadditionoftheam‐idetotheo‐QMintermediatewouldleadtotheformationoftheamidoalkylnaphtholproductinexcellentyields.Inthisreaction,the melamine‐Br3 could act as a bifunctional catalyst[27,30,31],inthatitwouldactivateboththecarbonyloxygeninthe aldehyde and the acidic hydrogen in 2‐naphthol. Sincemelamine‐Br3containsBratomsthatareattachedtoNatoms,itislikelythatBr+wouldbereleasedinsitu,andthatthisspe‐cieswouldactasacatalystinthereactionmedium;leadingtoaconsiderable increase in the electrophilicity of the aldehyde.The reactionwouldproceedvia the formationof ano‐QM in‐termediate,whichwouldbe formedvia thenucleophilicaddi‐tion of 2‐naphthol to the aldehyde. The o‐QM intermediatewouldthenreactwithacetamideorthioacetamidetoproducethedesired1‐amidoalkyl‐2‐naphtholproduct.
The reaction was also studied using the bis‐aldehyde ter‐ephthalaldehydewith2‐naphtholandacetamide(Scheme4).
When the 2‐naphthol (2.5 mmol) and the aldehyde (1
mmol)werereactedwithacetamide(3.75mmol) in thepres‐enceofmelamine‐Br3(0.15mmol)at130°Cfor2h,bis‐1‐am‐idoalkyl‐2‐naphthol(A)wasobtainedin95%.
Theresultsofthecurrentstudywerecomparedwiththoseof severalotherreportedprocedures fromthesametransfor‐mation to demonstrate the effectiveness of our newly devel‐opedmethod(Table3).Itrevealedthatmelamine‐Br3wassu‐periortoothercatalystsintermsoftheproductyieldsand/orthereactiontime.
0
10
20
30
40
50
60
70
80
90
100
25 35 45 55 65 75 85 95 105 115 125 135
Yie
ld (
%)
Temperature (oC)
Fig. 1.The effect of temperature on the reaction of 2‐naphthol withacetamideandbenzaldehyde.
Table2Synthesis of 1‐amido or thio alkyl‐2‐naphthols catalyzed by mela‐mine‐Br3.
2‐naphthol derivatives via the one‐potmulti‐component con‐densationof2‐naphtholwitharomaticaldehydesandacetam‐ide/thioacetamide under solvent‐free conditions was devel‐oped using melamine‐Br3 as an efficient catalyst. There areseveraladvantagestothisprocedurecomparedwiththeexist‐
ing methodologies, including good yield and short reactiontime. Furthermore, the catalytic system is environmentallybenignandhighlyefficient,aswellasbeingeasytoprepare.
