methodsanddesigninorganicsynthesis

2018-19Master Course

PereRomea

inOrganicChemistry

4.3.Functionalgroups

Rubik’scube

JustONEfunctionalgroupdisconnectionR X

NR2

Amine

OR

AlcoholEther

SR

ThiolThioether

N3

Azide

NR

Imine

O

AldehydeKetone

N

Nitrile

Asingleheteroatomboundtothebackbone

R

OH

R

O

H R

O

OH

oxidation oxidation

reductionreduction

primaryalcohol aldehyde carboxylicacid

R R

OH

R R

O

R OR

Ooxidation oxidation

reductionreduction

secondaryalcohol ketone ester

alcohols?

OHNH2

amines?

OHNaturalchargedistribution

Alkylad0

OHOH

Alkylda3

OH OHR

Alkylad2

OH OHAlkylda1

OHOH

OHNaturalchargedistribution

OHOH

X

X:halide,sulfonate

OH OR

OH O X

X:halideEnolate

OHO

HHM

X:Li,MgCl

SN2

IonicAdditionstoCarbonyls

AlkylationofEnolates(orEnamines)

Michael

OHNaturalchargedistribution

OHOH

X

X:halide,sulfonate

OH OR

OH O X

X:halideEnolate

OHO

HHM

X:Li,MgCl

SN2

IonicAdditionstoCarbonyls

AlkylationofEnolates(orEnamines)

Michael

?Ph HN O O PhJabbatheHuttStarWars

ICI-D7114 intermediate anti-obesity treatment

SeeChapter2.Concepts(II)

route A

problem

Chemoselectivity

PhHN O

O Ph

PhHN O

O Pha

SN2

PhHN

O

OH

PhHN

O

O

PhHN

O

O Ph

Base

Br Ph

route B

PhHN O

O Ph

PhHN O

O Phb

StabilityChemoselectivity

problem(s)

SN2

OH

HO HO

O PhBr Ph

Base O

O PhBr Ph

Base

PhHN

O

O Ph

PhHN

Cl

route C

PhHN O

O Phc

Ph NH O

O Ph

Polyalkylation?

OH

HO HO

O PhBr Ph

Base Base

BrBr

PhHN

O

O Ph

BrO

O Ph

Ph NH2

route D

PhHN O

O Phd

Ph HN O

O Ph

O

O PhNH3BECAREFUL!LONGWAY

Aminesarealwayssensitivefellows

REVIEW: Synthesis of Amines

Apparently,SN2MEDIATEDALKYLATION

ofammonia,primary,secondary,ortertiaryamines

isthemostappropriatewaytoprepareamines.

HOWEVER,POLYALKYLATIONHAMPERSSUCHANAPPROACH

HN

HH

HN

HR

HN

RR

RN

RR

RN

R RR

– HX

R X

– HX

R X

– HX

R X

– HX

R X

SN2 SN2 SN2 SN2

So,keepinminddifferentoptions…

REVIEW: Synthesis of Amines

PRIMARYAMINES

Alkyl azidesAlkyl halides Primary aminesSN2

R XN3 R N3

H2 R NH2

Reduction

N

O

OR X N

O

O

R R NH2N2H4 or OH

Alkyl halides SN2 Hydrolysis Primary amines

GabrielSynthesis

R NO2H2 R NH2

LiAlH4 R CH2NH2R C N

Reduction Reduction Primary aminesNitrilesPrimary aminesNitro

REVIEW: Synthesis of Amines

SECONDARYAMINES

R R

ORNH2

R R

N RNaBH4

R R

N RH

ReductionImines Secondary Amines

R Cl

ORNH2 LiAlH4

R N

OR

HR N R

H

ReductionAmides Secondary Amines

TERTIARYAMINES

R Cl

OR2NH LiAlH4

R N

OR

RR N R

R

ReductionAmides Tertiary Amines

?Ocfentanil (or A-3217) painkiller NNMeO OF Ph

Don’tdisconnectthisnitrogen:heterocycleBUILDINGBLOCK

N

NMeOO

F

Ph

N

NMeOO

F

PhN

HNF

PhClMeO

O

N

NF

Ph

FGA

NH2F

N

O

PhN-Phenylethylpiperidone

a1 d0

N

H2N

F PhHowever,payattentiontotheBuchwald-Hartwigreaction

OHNaturalchargedistribution

OHOH

X

X:halide,sulfonate

OH OR

OH O X

X:halideEnolate

OHO

HHM

X:Li,MgCl

SN2

IonicAdditionstoCarbonyls

AlkylationofEnolates(orEnamines)

Michael

?Terfenadine derivative treatment of allergyHO PhPh N OH CO2H

Thedisconnectionofthisalcoholproducestwofragmentsofsimilarcomplexity:

TWOOPTIONS

NHO

PhPh

OH

CO2H

a b

NHO

PhPh

OH

CO2H

a

NHO

PhPh

H

O

CO2H

b

NHO

PhPh

H

O CO2H

FourindependentFG

HO

PhPh

NOH

CO2H

HO

PhPh

NOH

CO2H

HO

PhPh

N H

O

CO2H

Br

CN

Br

Br

CN

HO

PhPh

NH Cl O

O

NH

O

EtO2 x Ph

NH

O

EtO Protection

NCbz

O

EtO 2 PhMgBr HO

PhPh

NCbz

Cl O

O

NHO

O

O

PhPh

HO

PhPh

NH

Deprotection

Br

CN1) Base

2) MeI

Br

CNNaOH

Br

CO2H1) NaH

2) BuLi

Li

CO2Na

Li

CO2Na HO

PhPh

NOH

CO2H

NHO

H

O

PhPh

H3O+

OHNaturalchargedistribution

OHOH

X

X:halide,sulfonate

OH OR

OH O X

X:halideEnolate

OHO

HHM

X:Li,MgCl

SN2

IonicAdditionstoCarbonyls

AlkylationofEnolates(orEnamines)

Michael

?trans-Clerodane diterpenoids

antibacterial, antitumor, antifeedant activity

H

OO

H

OO

OH

H

O

Annonene Solidagolactone PL3

a5

Alkyl-d

H

OO

H

OO

: ORGANOCUPRATES

1) LDDB, THF, –78 °CSPhH2) CuBr·SMe2, –78 °C

3) TMSCl,O

O

4) DBU, CH2Cl2, rt,

–78 °C to rt

H

OO

43%

Overman,L.E.JACS2015,137,660

Non-Naturalchargedistribution

d1

OH

UMPOLUNG

a1

OHX

S

S S S

d1 aldehyde

S

S

OH

OH

OH

S SO

X:halide,sulfonate

d1epoxide

OOHOHS SS

S OH

Smith,A.B.III,ACR1998,31,35;2004,37,365

Non-Naturalchargedistribution

d1

OH

UMPOLUNG

a1

d1epoxide

d1 aldehyde

OHX

S

S S S

S

S

OH

OH

OH

S SO

X:halide,sulfonate

OOHOHS SS

S OH

Smith,A.B.III,ACR1998,31,35;2004,37,365

?Mycoticin A antifungi agent

OH OH OHOH OH OH

HO

HO

O

O

Theconstructionofthepolyolfragmenttakesadvantageofthesymmetry

OH OH OHOH OH OH

HO

HO

O

O

OHOH OH OHOH OH OH

HO

…andTACTICSmaybebasedontheUMPOLUNGconcept

S S

TBS

S S

TBSTBS OBn

SS Ot-BuLiEt2O Et2O

OBnO

Et2O, HMPA

O O

BnO OBnTBSO OHOHSS SS OTBS

59%

Brookrearrangement

S OBnOTBSS

HO OTBSO OO OO O

Smith,A.B.,III.OL1999,1,2001;JACS2003,125,14445

FournewC–Cbondsinoneflask

Non-NaturalchargedistributionOH

UMPOLUNG

a2d2organocuprate

OH O O

OH O OX

a3 d3 X:#halide,#sulfonate

TWOfunctionalgroupswhichdisconnection?Y Cn X

one-groupdisconnection

R O R R O R

d0 alkyl-a

two-groupdisconnection

R O R

OH

R OR

OHd0 a2

Relationshipsbetweentwoheteroatoms

1,1-RelationshipX

O

1

YX

1

X

Y

O

Y

O

O1

21

21

21,2-Relationship

X Y

1 3

O Y

1 3

O O

1 31,3-Relationship

X

Y

O

Y

O

O1

41

41

41,4-Relationship

1,1-relationship?esters?

X

O

ORRO

acetals?

Consonantrelationship

X:halide,OR,NR2,SR

X

O

d0a1

ORROOR

OR

OR

O

OR

O

d0a1

Consonantrelationship

X:halide,OR,NR2,SR

X

O

Cl

O

O

O O

SR

O

OR

O

N3

O

NH

+ N

O

1,2-relationship?1,2-diols?

α-hydroxyketones?OH

OH1

2

O

OH12

Dissonantrelationship

X,Y:halide,OR,NR2

X

Y

OH

OH

O

O

OBr

Br

OsO4oxidationPinacolcoupling

EpoxideopeningSN2

Epoxidesplayacrucialroleinthesynthesisof1,2-diols

Dissonantrelationship

X,Y:halide,OR,NR2

X

Y

OH

OH

O

O

OBr

Br

OsO4oxidationPinacolcoupling

EpoxideopeningSN2

Epoxidesplayacrucialroleinthesynthesisof1,2-diols

?O OHO

OH

RouteAone-groupdisconnection

OOH

RouteBtwo-groupdisconnection

OOH

RouteA

problem

Siteselectivity

HOOH

Br

RouteB

OH OTACTICReactivityofepoxides

?Propranolol high blood pressure O NOH

O NOH

O OH N

1,2-di

O O

C–X

OHCl O

Payattentiontothissystem

Cl O

Threeelectrophilicsites

13

2

C1isthemostreactiveone

HO O

O O O O

O OH

PAYNEREARRANGEMENT

OOCl O O OCl

O

X

OXOH

Theconfigurationofthechiralcentercanbedramaticallyaffected

Cl O O OO

X

OXOH

Dissonantrelationship

X,Y:halide,OR,NR2

X

Y

OHO

BrO O

BrominationSN2

Inageneralway,

O OOH

O

Oxidationofenolates,enols,orenamines

1,3-relationship?ß-hydroxycarbonyl?

ß-aminocarbonyl?

O OH

12

3

O NH21

23

Consonantrelationship

X,Y:O,N

YX

O OH O OH

d2 a1

O OH OOR

a3 d0

Consonantrelationship

X,Y:O,N

YX

Aldol

O OH O O

Enolate Aldehyde

O OH OOR Oxa-Michael

?Doxpicomine analgesic ON O

N O

N

O

N OH

N

OH

ACETALasourceofinstability

N O

N

ORO

OR

SYMMETRYtakeadvantage

N O

ORO

OROH

FGI

N O

ORO

OR

1,3-ConsonantAZAMICHAEL

13

Conversionofanalkeneintoanalcoholisveryuseful

FGI

O

ORO

ORN H

O

ALDOL

1,3-Consonant1

3

? Atropine treatment of certain nerve agents and pesticide poisoningN OO OH

N

O

O

OH

N

HO

HO

O

OH

ON

3

31

3

31

AHIGHLYSYMMETRICALß-aminoketone

N

O

FGI

HO

O

O

H H

1

3

ACHIRALß-HYDROXYACID

1,3-Consonant

ON ON

CO2H

CO2H

ON

CO2H

CO2H

1

3

3

a1 d2

FGI

Keepinmindbidirectionalsyntheses

CHO

CHO+ MeNH2

Mannichreactioncouplingofanenolizablecarbonylwithformaldehydeanda1aryor2aryamine

R

OR

R

OR

R2N

H

O

HR2NH

ß-AminocarbonylSeeChapter7

CHO

CHO+ MeNH2 N

OH

CO2H

CO2H

OH

N

CO2H

HO2COH

N

HO

CO2H

HO2CO

N

CO2H

HO2CO

ON

1,4-relationship?1,4-dicarbonylcompounds?

O

O1

2

34

HO OHOH

HOOHHO

HO OHO

OHO OH

O

Osuccinic acid fumaric acid

OHO

Olevulinic acid

O OO

maleic anhydride

O

furan

DissonantrelationshipX

Y

O

O

O

CH2

FGI

O

CH2d2alkyla

O

NO2

FGI

O

NO2a3d1

X,Y:O,N

?from Gymnomitrion obtusumOH O

O O O

OH

FGI

13

1

4

BrBr

O

1) LDA, –78 to 0 °C

2) BrBr

OBr

OO

Hg(OAc)2

HCOOH

1,3-Consonant

OOO

O1,4-Dissonant

a2

Ot-BuOK

t-BuOHO

Me2CuLi

1,5-relationship?1,5-dicarbonylcompounds?

O O

12

3

45

Consonantrelationship

X,Y:O,N

X Y

O O O O

d2 a3

Enolate

OMichael

?Rogletimide sedative N NHOO

N

NH

O

O NCO2Et

CO2Et

1

5

1,5-consonantN

CO2Et

CO2Et

a3

d2

NCO2Et

NCN

FGI

NBr

CN

d1a1

NCO2Et

CO2Et

?Steroid skeletonO ROH

H

H HO

testosterone

H

H HO

O

progesterone

H

H HHO

Hcholesterol

HO

H

Hlanosterol

O

R

O

O

RobinsonannulationMichaeladditionofacarbonyltoanenone

followedbyanintramolecularaldolcondensation

O

BaseO

O

Wieland-MiescherKetoneOHO

O

1 5

1,3-consonant

O

OO

1 3

O

OO

1,5-consonant