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368GARBRECHTVOL.24[CONTRIBUTIONFROMTHEDEPT.OFORQANICCHEMICALDEVELOPMENT,ELILILLYANDCo.]SynthesisofAmidesofLysergicAcid*WILLIAML.GARBRECHTReceivedSeptember15,1958Althoughinterestinthechemistryandpharmacologyoflysergicacidderivativeshasremainedhighformanyyears,untilrecentlyonlyoneusefulmethodforconvertinglysergicacidintoitsamidederivativeshasbeenrecorded.ThismethodasdescribedbyA.Stol12consistsofcleavingergotalkaloidswithhydrazine.Theresultinrlysergicacidhydrazideontreat-mentwithnitrousacidisconvertedintotheazidewhichmaybeusedtopreparethedesiredamidebyacylationofanappro-priateamine.I1111HN-JIAlthoughthisprocedureisfrequentlycapableofproducingamideproductingoodyields,certaininherentdifficultiesreduceitspracticalvalue.Ofthese,themostimportantisthatthenecessaryreactionconditionsforpreparinglysergicacidhydrazideresultinaracemizedandisomerizedmaterial,nL-isolysergicacidhydrazide.Further,themethodleavesmuchtobedesiredintermsofoperationaleasesincetheazidemustbecollectedinarelativelylargevolumeofetherandseveralhoursarerequiredtocarryouttheacylationstep.Becauseopticallyactive+-lysergicacidisreadilyavailablethroughaqueousalkalinecleav-ageofergotalkaloid^,^amethodwhichutilizedthefreeacidandcausednoracemizationwasdesired.Theclassicalmethodsforpreparingamidesbyacylationofamineswithestersoracidchloridesfailwhenappliedtolysergicacid.Thus,whilethemethyl3andethyl4estersoflysergicacidareknown,theyfailtoundergoaminolysisexceptinthespecialcasealreadymentionedinvolvingtheuseofhydrazine.Ontheotherhand,attemptsto(1)PresentedinpartbeforethcDivisionofOrganicChemistry,AmericanChemicalSociety,NewYork,N.Y.,September,1957.(2)A.StollandA.Hofmann,Helv.Chim.Acta,26,911(1943).(3)W.A.JacobsandL.C.Craig,J.Rid.Chern.,104,547(1934).(4)A.StollandTh.I’etrzilka,Helv.Chim.Acta,140,1125(1953).____-preparelysergicacidchlorideyieldonlydecompo-sitionproducts.Xumerousnewamide-formingtechniques,chieflyarisingfromworkinthepeptidefield,haveap-pearedintherecentliterature.Manyofthesewereinvestigatedwithrespecttolysergicacidamidesynthesis.Amethodtobesuitableforthisappli-cationmustoperateundermildnon-acidiccondi-tionsbecauseofthesensitivenatureconferreduponlysergicacidderivativesbytheirindolecon-tainingstructure.Mostofthenewermethodsinvolvetheappli-cationofcertainmixedanhydrides.Suchtech-niquesfrequentlysufferfromoneormoreofthefollowingdisadvantages:(a)Thereactionfailstogotocompletion.(b)Thereactionrequireshighertemperaturesthanarecompatiblewiththestabilitiesofthesematerials.(c)Thereacionsystemdecomposeslysergicacidoritsamideproductbecauseoftheacidiccharacter.(d)Themixedanhydrideundergoesdispro-portionationwhichcontributestoreactionin-completionand/ornonspecificacylation:00II2R-ii-0--R’&(R-b)nO+(It’-C)*O(e)Themixedanhydrideacylatesinanoii-specificmanner,resultinginamixtureofacylatedproductsincludingesters,aswellasamideswherepossible:00CHzI//II0CH3ItIR-C-0-C-R’+HdY-CH-CH20II--+R-C--i\jH-CH-CH,OEI+0CH,/IIR~-&-NH-CH-CH,OH+R-C-O-cH2--CH-KH,+etc.Also,twonewdehydrationreactionsappliedtopeptidebondformationhavebeendescribedre-cently,whereinanacidandanaminearecausedtocoiidenseundertheinfluenceofthepowerfuldehydrationreagents,dicyclohexylcarbodiimideandethoxyacetylene.MARCH195!)AMIDESOFLYSERGICACID369Mostofthemethodsexamined,togetherwiththegeneralresultsobtained,arelistedinTableI.TABLEIREACTIONSYSTEMSAPPLIEDTOLYSERGICACIDAMIDESYNTHESISAIlIivrdAnhydrideSystemsMixedAnhydrideValueofSystemR-COXaa(11)Poor.Requiredstartingmatc-rialwasracemizedinprep-arationRCOCIbSone.Lysergicaciddecom-posedRCOZCOCF?'Good.Non-specificacylationdRCOzC0zC:H:None.YieldedethyllysergateRCO~POGH,~Poor.Lowyield~ithdecom-~c~~so~c~~~~c~~~~None.DecomposedlysergicRCOiSO,CHj''Fair.hIodrratevieldithRC0~SOJZExcellentinallrespectspositionacidsomederompoqitionI31)chydrationSystcms/I-HnO/R1'R2RCO:H+H--S-RCONReagentReagentC6Hs-N=C=S-c6HajNone.VerypooryieldC,H~O-CEZCHICNone.VerypooryieldaA.StollandA.Hofmann,Helv.Chim.Acta,26,944(1943).A.StollandA.Hofmann,U.S.Pat.2,090,430(1937).E.J.Bourne,S.H.Henry,C.E.M.Tatlow,andJ.C.Tatlow,J.Chem.SOC.,4014(1952).R.1'.Pioch,U.S.Pat.2,736,728(1956).eR.A.Boissonnas,Hrlv.Chim.Acta,34,874(1951).fG.W.AndersonandIt.W.Young,b.Am.Chem.SOC.,74,5307(1952).J.H.Brewster,J.Am.Chem.Soc.,77,6214(1955).Nopreviousreferencefound.G.W.KennerandR.J.Stedman,J.Chem.SOC.,2069(1952).fJ.C.SheehanandG.P.Hess,J.Am.Chem.Soc.,77,1067(1955).'J.F.Arens,Rec.trav.chim.,74,769(1955).Ofthemethodsstudied,theuseofthemixedanhydrideofsulfuricacidandlysergicacidprovedmostpracticablebecausethedifficultiesinherentintheothermethodmereabsent.Thus,assaysfortotalamideproducedindicatedthatthisreactionproceededtocompletion,Therewasnodecompo-sitionobservedwhichcouldbeascribedtothereaction,sinceittookplacereadilyatlowtempera-tureandatnotimemasthesystemacidicincharacter.Ilisproportionationmasnotencounteredandnoevidenceofesterificationwasobserved.Theamideproductsmereobtainedfreefromrace-mization.Further,theprocesswascarriedoutrapidlyandwithconsiderableexperimentalease.However,theyicldsofamideproductisolatedbythismethodwereoftencons