DOI: 10.1002/adsc.200505431 Highly Regioselective DABCO-Catalyzed Nucleophilic Aromatic Substitution (S N Ar) Reaction of Methyl 2,6-Dichloronicotinate with Phenols Yao-JunShi,*GuyHumphrey,PeterE.Maligres,RobertA.Reamer, J.MichaelWilliams DepartmentofProcessResearch,MerckResearchLaboratories,P.O.Box2000,RY800-B361,Rahway,NJ07065,USA Fax:( þ 1)-732-594-5170,e-mail:y-j_shi@merck.com Received:November1,2005;Accepted:December5,2005 Abstract: Exclusive formation of 6-aryloxy ethers 9 fromanS N Arreactionofmethyl2,6-dichloronicoti- nate (2) with phenols 7 catalyzed by 1,4-diazabicy- clo[2.2.2]octane (DABCO) in the presence of stoi- chiometric triethylamine is described. The reaction proceeds via the regioselective formation of an un- precedentedDABCO-pyridineadduct 10a. Keywords: aromaticsubstitution;biarylether;DAB- COcatalysis;nucleophilicsubstitution;pyridines Substitutedpyridinesoftenappearasimportantmotifs inbothbiologicallyactivecompoundsaswellasphar- maceuticals. [1] Readily available 2,6-dichloronicotinic acid(1)anditsderivatives 2 – 4 areusefulstartingmate- rialsforthepreparationofuniquebuildingblocksinthe synthesisofnewdrugcandidates. [2] Selectivesubstitu- tionofoneortwoofthechlorideatomsatthe2-and/ or6-positionofthesecompounds, via aS N Arreaction withdifferentnucleophiles,continuestoreceiveintense interestasamethodtoaccesstherequisitesubstituted pyridines.Forexample,KawatoandNewkomereported thetreatmentofmethyl2,6-dichloronicotinate(2)with sodiumethoxideinxylenetogiveamixtureofmonosub- stituted 5b (2-OEtisomer)and 6b (6-OEtisomer)infa- vor of 5b, the 2-OEt isomer. [3] Recently, Hirokawa, etal.,reportedanewS N Arreactionofdichloronicotinic acid 1 withpotassiummethoxide(KOMe)inrefluxing MeOH to produce 6a (6-OMe isomer) as the major productin66%overallyieldafteresterification. [4] This processwasutilizedinthepreparationofakeyinter- mediateforthesynthesisofapotentserotonin5-HT 3 and dopamine D 2 receptor antagonist. In addition, theyalsoreportedahighlyselectiveS N Arreactionof methyl2,6-dichloronicotinate(2)withsodium4-meth- ylbenzenethiolate (p-MePhSNa) in DMF, providing the6-isomer 6c inbothhighyieldandexcellentselectiv- ity(Scheme1). [5] Toourknowledge,thereactionof2,6- dichloronicotinate derivatives with phenols has not beenreported. Aspartofanongoingprogramtodevelopapractical synthesisforaninvestigationaldrugcandidate,synthesis ofthebiarylether 9a wasrequired.Inthispaper,were- portthediscoveryofanunprecedentedDABCO-pyri- dine adduct 10a, derived from the S N Ar reaction of methyl 2,6-dichloronicotinate (2) with DABCO and the successful development of a highly regioselective, DABCO-catalyzedS N Arreactionofdichloronicotinate 2 withphenols 7 toprovide6-aryloxyethers 9 inhigh yields. InitialexaminationoftheS N Arreactionbetweendi- chloronicotinate 2 and 4-chlorophenol (7a) revealed thatslowadditionof 7a toaslurryof 2 andanexcess ofCs 2 CO 3 inDMFatroomtemperature,providedthe products 8a/9a (1:4)(Scheme2). [6] Additionofwaterdi- rectlytothereactionmixtureledtothecrystallizationof thecrudeproducts.Subsequentrecrystallizationfrom i- PrOHaffordedpure 9a in60%overallyieldfromdi- chloronicotinate 2. [7] Scheme 1. COMMUNICATIONS Adv. Synth. Catal. 2006, 348,309–312 #2006Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim 309