unit 2

imidazole as LG, activation of caboxy acid scheme

carboxy acid + carbonyldiimidazole (CDI) + Nu-H —> carbonyl - Nu

activation of carboxy acid steps

-imidazole N grabs OH proton

-O- attacks CDI carbonyl, e swing, kick off one imidazole group

-same imidazole group attacks carbonyl of carboxy acid

-intramolecular PT from one imidazole to other

-O- e swing, breaks into CO2 and imidazole

-carbonyl O grabs H from Nu, Nu- attacks carbonyl

-proton transfer to imidazole, e swing to make product

Indole structure /properties

pyrrole attached to benzene ring

C3 for protonation and SeAr

vilsmeier rxn

indole + Me2NCOH + POCl3 —> aldehyde at C3

mannich rxn

indole + Me2NH + aldehyde + HOAc/H2O —> CH2-NMe2 at C3

aclyation rxn

indole + Cl-CO-CO-R —> diketone at C3

fischer indole syn scheme

arylhydrazine + ketone + H+ —> indole

fischer indole steps

-NH2 of arylhydrazine attacks ketone carbonyl

-PT from NH2 to O-

-N LP swing, kick off OH-, OH- removes H from N

-taut then [3,3] to attack benzene ring

-taut, then NH2 attcks double bond to form ring

-PT from NH2 to NH, N LP swing to removes NH2

-NH2- grabs H near R group to restore aromaticity

Leimgruber batcho scheme

ortho-CH3-NO2 benzene + (MeO)2-C-NMe2 —> ortho-NO2-NM2 alkene benzene + Zn/HCl —> indole

Leimgruber batcho steps

-N LP swing, kick off OMe, MeO- removes H from ortho methyl

-LP attacks C=N, N LP swing kick off OMe

-MeO- removes proton, e swing onto N

-Zn donates one e to nitro carbonyl, double bond swings onto N'

-O- grabs H from HCl, single electron forms bond w ZnCl

-O-Zn bond grabs H from HCl, ZnCl2 leaves

-lose water to generate R-N=O, N Lp grabs H from HCl

-Zn gives one e to oxygen, e swing, O e forms bond with Zn

-O-Zn bond grabs H from HCl, N LP grabs H from HCl

-N-O bond grabs to form N radical and ZnOH, Zn gives another e to N, ZnOHCl leaves

-NH2 LP grabs H from HCl

-ortho N LP swing, alkene grabs H from NH3, NH2 LP attacks double bond to close ring

-PT from NH2 to NMe2, N LP swing to kick off NMe2

-NMe2 remove benzlyic proton to restore aromaticity

Bischler Indole syn scheme

analine + Br - CH2-Ketone → substituted indole

Bischler indole steps

-NH2 Lp attacks and kicks off Br

-PT from NH2 to carbonyl, 2nd eq of analine attacks carbonyl

-PT from NH2 to OH, N Lp swing, removes H2O

-Br removes alpha proton, e swing back onto N

-taut to imine, N LP push towards benzene, benzene attacks imine double bond to ring close

-N- grabs H from benzene, e swing back onto other N

-N LP swing towards benzene to kick off other NHPh

-NHPh removes H next to R group

Larock indole syn scheme

bezene w/ ortho NHR and I + alkyne + Pd + MCl —> indole

larock indole steps

-ox add of Pd between benzene and I

-complexation with alkyne with Pd

-migratory insertion, benzene-Pd bond attacks alkyne, alkyne attacks Pd

-Pd-I bond grabs H from N, H-N bond attacks Pd

-red elim to lose Pd, generates indole

bartoli indole syn scheme

ortho-R-NO2 benzene + alkene-MgBr (3 eq), H+ —> indole

bartolie indole steps

-MgBr-alkene bond attacks O, forms O-alkene bond

-O e swing, kick off O-alkene

-MgBr-alkene bond attacks O, e swing

-[3,3] with benzene ring to form =N and aldehyde

-taut imine to NH, N Lp attacks aldehyde to form ring

-PT from NH to O-

-N Lp kicks off OH-, OH- removes proton, N- protonates from H+

Furan structure/reactivity

five membered ring with O

reactive at C2

friedel crafts furan

furan + Ac2O + ZnCl2 —> ketone at C2

1,4 addition furan

furan + Br2 + MeOH —> OMe at C2 and C4

metallation furan

furan + BuLi —> Li at C2 + E —> E at C2

nitration furan

furan + AcONO2 + AcOH —> NO2 at C2

sulfonation furan

furan + 2eq pyridine-SO3 + DCE —> SO3H at C2 and C4

Achmatowicz scheme

furan-(CHR)-OH + Br2, Et2O/MeOH —> intermediate + H2SO4/H2O —> six membered O ring with carbonyl

achmatowicz steps

-furan O Lp swing, double bond grabs Br

-MeOH attacks C4, Br- removes H from MeOH

-O e swing, kick off Br, MeOH attack C2, Br- remvoes H from MeOH

-MeO Lp removes H from H3O+

-other MeO Lp swing, furan bond pushes to ring open

-MeOH removes Me from carbonyl

-carbonyl grabs H+, OH Lp attack carbonyl to form ring

oxidative reactivity w furan scheme

furan - alc/amine + mCPBA —> six membered ring w/ O or N

oxidative reactivity steps

-mCPBA reacts with double bond of furan to make epoxide

-epoxide O grabs H from carboxy acid

-furan O Lp swing, open epoxide

-epoxide OH Lp swing, open furan

-PT from carbonyl to other carbonyl

-one OH attacks activated carbonyl to form ring

directed lithiation of furan

furan + BuLi —> furan-Li at C2

furan with strong acids

decomposes back into 1,4 dicarbonyl

paal knorr furan syn scheme

1,4 dicarbonyl + H+ —> furan

paal knorr furan mech

-carbonyl protonates

-base removes alpha proton, e swing to make enolate

-2nd carbonyl protonate

-OH LP attack carbonyl

-PT to make water, O LP swing to kick off water

-base removes proton to restore aromatic

Feist Benary furan syn scheme

a-halo aldehyde/ketone + b-keto-ester + base —> furan

feist benary furan aldehyde mech

-base removes alpha proton form ester

-O LP swing, enolate attacks ald carbonyl

-PT of alpha proton to O-, taut carbonyl to O-

-O- attack X carbon, kick off X, closes ring

-OH grabs H+, lose water to make furan

fiest benary furan ketone mech

-base removes alpha proton from ester

-enolate e swings, kicks off X

-taut to OH, OH attacks ketone carbonyl

-PT, remove water to make furan

gold catalysis - allene

ketone w allene + Au+ X- + DCM —> furan

allene mech

-Au coordinated to allene

-carbonyl O LP attack further allene carbon, double bond grabs Au

-furan forms, PT to swap Au with H, leave e- on carbon

-e swing to restore aromaticity

gold catalysis - double alkyne scheme

ketone w double alkyne + Cl2 N-Oxide + ROH + AuX —> furan with ester

double alkyne mech

-O- attacks first alkyne, bond grabs Au

-e on Au swing, make double bond, e swing to make carbonyl, kick off pyr

-alc attack new carbonyl

-PT to carbonyl, O LP swing back to Au

-Au breaks bond, e swing back up, AuX leaves

-taut between OH and carbonyl, draw arrows

-OH attacks alkyne, bond grabs Au

-PT from OH to Au to form furan

gold catalysis - alkyne/alkene carbonyl

carbonyl w alkene and alkyne + Me2N-(CH2)-OR + AuX —> furan w alc and NMe2

alkyne/alkene carbonyl mech

-N LP swing, kick off OR to make -OR and NMe2+

-carbonyl LP attack far carbon in alkyne, bond swing to grab Au

-new double bond swings, e swing onto O, creates carbocation

-OR- attacks carbocation

-Au bond attacks carbon=NMe2

pd catalyst furan syn

dicarbonyl w ester + PdX2 + O2/NaOAc —> furan w ester

pd cat mech

-alkene corrdinate w pd, taut ketone carbonyl

-OH LP attack alkene, bond grabs Pd

-b-H elim to remove Pd, X- removes H from O

-[1,3] shift to restore aromaticity

copper catalyst furan syn

cyclopropane-allene-ketone + carbonyl alkyne + CuX —> furan w alkyne and ketone

copper catalyst mech

-Cu coordinates to far double bond in allene

-carbonyl O LP attack far double bond, bond grabs Cu

-Cu LP swing, e swing onto O

-[1,2] shift of cyclopropane, swing e back onto Cu, forms catio n

-Cu bond breaks, e swing down to cation

-[4,2] with furan and alkyne

-retro [4,2] to make product

lewis acid furn synth - cyclobutane w Bi (OTf)3

ketone with cyclobutane and OH + Bi(OTf)3 —> furan with CH2-OH

Bi(OTf)3 furan mech

-Bi coordinates to cyclobutane O

-carbonyl O LP attacks cyclo, e swing to grab Bi

-O-Bi bond grabs alpha H, e swing to enolate

-alc LP attacks Bi

-OTf- grabs H to restore aromatic and kick off HO-Bi

lewis acid furan synth - Ti(OiPr)4

ketone + halo-ketone + Ti(OiPr)4 —> mix of furan products

sulfur ylide furan syn

ester w alkyne + ketone w sulfure ylide —> furan w ester

sulfure ylide mech

-LP on carbon in ylide attacks alkyne, e swing up to carbonyl

-O LP swing down, puts LP on middle allene carbon

-LP attack carbonyl of ylide

-4pi ring open, O Lp attacks double bond, push e onto carbon

-LP swing to kick off SMe2

robinson gabreiel oxazole syn

dicarbonyl amide + H2SO4 or POCl3 —> oxazole

robinson gabriel mech

-N Lp swing, carbonyl bond attacks P, kick off Cl

-Cl- attack carbonyl carbon

-N LP swing, kick off O-P

-PO- removes H from N, e swing to kick off Cl

-taut other carbonyl

-OH LP attack alkyne, e swing onto N

-Cl - removes H from OH

van leusen oxazole syn

TosMIC + aldehyde + base —> oxazole

van leusen mech

-base removes H from tosmic

-LP attacks alde

-O- attacks C-

-PT to move H to C-, leaves LP on carbon

-LP swing to kick off tos

diazo oxazole syn

diazo-ketone + hv + RCN —> oxazole

diazo oxazole mech

-resoance between two N in diazo ketone

-hv removes N2, leaves carbene

-N in RCN attacks carbene

-LP swings, carbonyl bond swings to close ring