有机所许杏祥考博讲义(中)

第二章自由基反应

(一)概述

1.RadicalChainMechanism

InitiationRX+In---------►R-+InX

AdditionR-+.CH2=CHR'--------►RCH2CHR'

ChaintransferRCH2CHR'+RX--------►RCH2cH—R+R-

.X

orRCH2dHR+InH--------►RCH2CH2R'+In-

(1)Formationofradical

Thehomolysis,thefirststepofradicalreaction,couldbeachievedbyphotolysis

andthermolysisofthemoleculeswithaweakbond,orbyaredoxsystem.

(i)Peroxide

Y|—O—O—Y2--------►YiO-+-OY2

Y|O-(orY2O-)+R-H--------►R-+Y^HCorY2OH)

OO

IIII

PhCOOCPhtBuOOBut

(ii)Azocompound

R、

N=N、----►2R«+N2

、R

Me2(CN)C-N=N-C(CN)Me2(AIBN)

(iii)Organometalliccompound

(A)trialkyltinhydride

Bu3SnH8()oc>Bu3Sn«

BU3ST+R-X--------►R-+Bu3SnX

X=halogen,SePh,SPh

(B)alkylmercurysalt

NaBKi

RHgX►RHgH--------►RHg*--------►R-+Hg

(iv)Redoxsystem

R—X——a|R—X广----►R.+X+

R-X+(；>[R-X广----►R-+X

(2)Transformationofoneradicalintoanother

Itisthisstepwheretherequiredproductsareformed.

R-+--------►

a-fragmentation

.P——-------------►x—Y：+・A-B

/YCB

XOA，一

P-fragmentationXA

2.Radicalcyclization:

Radicalcyclizationsconsistofintramolecularadditionstodoubleortriplebonds.

Thecyclizationsarefasterfortheformationof5-memberedringsthanforanyotherring

size.

(i)Theregioselectivityfor5-exocyclizationsisoftenoutstanding.

exoendo

(ii)Thecyclizationgiving5-memberedringcanbehighlystereoselective.

(iii)Theconstructionofbicycliccompoundgoesmainlythecis-junction.

(二)Thechainadditionreaction

1.Thetinhydridemethod

Tnbutyltinhydrideisthereagentmostcommonlyusedtoconductfree-radical

reaction.

例

CN

8812

例3

例4

例5

Bu3SnH

AIBN

PhH,ref.

70%

例6

例8

例9

例10

XY1,5-cis/trans

OBnH0/100

HH77/23

HOBn99/1

2.TheMercurichydridemethod

例2

例3

3.Thefragmentationmethod

例1

例2

例3

例4

PhS，^

OBn

（三）Thechainatom/grouptransferreaction

1.Carbon-halogenatomtransfer

例i

/x.CuCl

Cl3CCOOEt+------------->

5CH3CN

140℃

79%

例2

58%

2.Heteroatom-halogenatomtransfer

Heteroatom-halogenbondsareveryweakandareeasilyhomolyticallycleaved.

Theresultingheteroatomcenteredradicalreactviathreepathways.

Thehydrogenatomabstrationshavebeenusedintheintroductionoffunctional

groupatunactivatedC-Hbond.

例1

OAcOAc

CH3CH3

Pb(OAc)4,12

hv,CCI4

AcO

例2

TheP-fragmenttionoccurswithoxygen-centeredradicaltogiveacarbonylgroup.

Thistransformationisusedinringenlargementprocesses.

例1

例2

3.Grouptransfer

RCOOHARCOCl

例1

RCOOH

例2

（四）Thenon-chainredoxreaction

1.Reductivemethod

ee;H

R—X—►R-+X

Reactioninvolvingketylisthemostpopularapplicationofthereductive

technique.

1.e-

------>

2.H+

例1

例2

MEMO

2.Oxidationmethod

例1

例2

o

例3

第三章协同型反应

（一）电环化反应

立体化学选律

兀-电子数热反应光反应

4n顺旋对旋

4n+2对旋顺旋

H3cCH3

例1

例2

<100oc

-----------A

例3

hv

-----A

（二）Diels-Alder反应

TheDiels-Alderreactionisthemostatom-economicalandreliablesix-membered

ringformingmethodsknowninorganicchemistry.

/R3

、R4

R2

(a)Itaccomplishestheunionofa47T-electronsystemwitha2兀-electronsystem,

creatingtwonewC-Cbondsanduptofourcontiguousstereocentersinoneefficient

step.

(b)ByvaryingtheNatureofthedieneandthedienophilemanydifferenttypeofring

structurescanbebuiltup.

(c)Highregio-andstereo-selectivityandtheirpredictability.

(d)TheintramolecularD-Areactionhasshownwidespreaduseintheconstructionof

polycyclicringsystems.

1.反应的选择性

(1)区域选择性:

Additionofanunsymmetricaldienetoanunsymmetricaldienophilecould

apparentlytakeplaceintwowaystogivetwostructurallyisomericproducts.Itisfound

inpractice,however,thatformationofoneoftheisomersisstronglyfavored.

(A)1-取代双烯

Proportionsofstructuralisomersformedinadditionofacrylicacidderivativesto

1-substitutedbutadienes

℃

RiR2RTRatioofproducts

1,2-1,3-

N(C2H5)2HC2H5201,2-only--

CH3HCH320181

CO2HHH701,2-only-

CO2NaHNa22011

C(CH3)3C(CH3)3CH32000.91

CH2OHHCH319011

(B)2-取代双烯

Proportionsofstructuralisomersformedinadditionofmethylacrylateto2-

substitutedbutadienes

1,4-1,3-

RiT℃Ratio1,4-to1,3-

OC2H51601,4-only

1504.5to1

C6H5

CN951,4-only

(C)1,3-二取代双烯

Thedirectiveinfluenceofthesubstituentsisadditive.

(D)1,2-和2,3•二取代双烯

Thestructureoftheadductswilldependonthenatureanddispositionofthe

substituents.

例1

例2

CO2Et

ElOjC-c三CH

,2o°cryu+

83：17

DBU

COzEtNO2

liooc/x^/X^^COzEt

「「+「

O2N

0：100

例3

oo

H

+1BF血。a

11

CH2Cl2,-80OC

OROR

例4

0

T+IL

—A1+1

\<ci40J

0

toluene,120℃,nocatalyst5941

benzene,25℃SnCl4-5H9O96:4

⑵立体选择性:

Thestereochemistryoftheadductcanbeselectedonthebasisoftwoempirical

rulesforthekineticallycontrolledreaction.

(i)Thecisprinciple

Accordingtothe麽isprinciple',whichisverywidelyfollowed,therelative

stereochemistryofsubstituentsinboththedienophileandthedieneisretainedinthe

adduct.

H

尸H

CO2CH3

(ii)Theendoadditionrule

Intheadditionofmaleicanhydridetocyclopentadiene,twodifferentproducts,the

endoandtheexo,mightconceivablybeformeddependingonthemannerinwhichthe

dieneandthedienophilearedisposedinthetransitionstate.AccordingtoAlderjflendo

additionrule,inadieneadditionreactionthetwocomponentsarrangethemselvesin

parallelplanes,andthemoststabletransitionstatearisesfromtheorientationinwhich

thereis惚aximumaccumulationofdoublebonds\Notonlythedoublebondswhich

actuallytakepartintheadditionaretakenintoaccount,butalsotheK-bondsofthe

activatinggroupsinthedienophile.

(A)Theadditionofcyclicdienophilestocyclicdiene

(B)Theadditionofacyclicdienetocyclicdienophiles

(C)Theadditionofopen-chaindienophilestocyclicdiene

R尸H,R2=CH3,R3=H84:16

R产H,R2=H,R3=H80:20

R1=H,R2=H,R3=H0℃,47%AICI3OEt293:7

Ri=H,R2=H,R3=H-70℃,47%AlCl3OEt297:3

R产CH3,R2=H,R3=H62:38

R)=H,R2=H,R3=CH329:71

(D)Theadditionofopen-chaindieneanddienophiles

Effectoftemperatureonratioofcis-andtrans-adductsformedinreactionof

trans-butadiene-1-carboxylicacidwithacrylicacid

Temperature℃7590100110130

Ratiocis:transcisonly7:14.5:12:11:1

2.反应的可变性：

2.1亲双烯体：

ManydifferentkindsofdienophilecantakepartintheD-Areaction.

(1)Thederivativeofethyleneoracetylene

Themostcommonlyencounteredactivatingsubstituentsforthe"normal"D-A

reactionareCO,COOR,CNandNO2.

例1

例2

例3

+R。/^

例4

200℃6hr346673%

100℃16hr51:4991%

BF3H2O,苯伸苯,・15OC5min9010100%

例5

OCH3

5Kbar

+--------A

72hr

CH380%

例6

A1C13

R=CH39010

919

1000

973

R=CH3

,Pr928

lBu919

例7

Indirectmethodshavebeendevelopedforengagingunactivatedalkeneas

dienophilesinD-Areaction.

例1

Na-Hg

1350c

l.LDA

2.RCH2Br

SO2Ph

CH2R

例2

,CO2cH3

800c

c

II

CO2cH3

CO2CH3

,P+PhBr

3CH3CN

1500C

LDA

CHoO

例3

(2)Heterodienophiles:

Oneorbothofthecarbonatomsofthedienophilemultiplebondmaybereplaced

byaheteroatomwithoutsignificantlossofreactivity.

(A)C=O

例1

O

II

HC—CO处

例2

(B)C=Nimino-Diels-Alderreaction

例1

例2

例3

Me3SiO

O

H

cH/

/C

E2C

to

例4

CO2cH3

2150c

-------->

toluene

(C)N=O

例1

C6H5NO

Aliphaticnitrosocompoundswithanelectron-withdrawinggrouponthea-carbon

atom,suchasa-chloro-ora-cyanonitrosocompoundreactreadilywithdienein

alcoholicsolventsinaninterestingway.

R'OH

R2c(0R')2+

例2

(D)双氧原子取代的亲双烯体:

例1

例2

2.2双烯体:

Thedienecomponentmusthaveormustbeabletoadoptthecisoidconformation

beforeitcantakepartinD-Areactions.

(1)Heterosubstituteddienes.

(A)Oxy-substituteddiene

例1

/COCH3

Me3SiO^^^^SOPh

例2

benzene

ref.

/

Me3SiO^

COOCH3

例3

CH3CH3

例4

EtO2c飞

4?/

\/CC^Et

?、+PhB(OH)2f

J'PhH,90OC

。丫|(-H2O)

OHOH

,Ph

HO八OH

f

OH

EtO2c%,,IX

Hr]

<VH

of

o

(B)Acylamino-substituteddiene

例

CH3

//CH3

彳<110℃

+----------►

\OHa”"NHCO2cH2Ph

NHCO2cH2Ph

AW/

H1

H

H

215OC

(C)Thio-substituteddiene

例

、

770OC.

/+x

S0C

CH3CN1(

〃s、CH

C)/、Ph3,、"CH3

0/Ph

Na2S/CH3OH

vA

H0弁

N、

CH3

(2)Heterodienes.

例1

BF3.El2O,CH2Q2

例2

,N、

H、CHO

+

(3)1,2-dimethylenecycloalkanesandrelateddienes.

例1

Anovelroutetoortho-xylyleneisprovidedbythediscoverythathexa-1,5-diynes

maybeco-cyclizedwithsubstitutedacetylene,particularlywithbis(trimethyl-

silyl)acetylene,inthepresenceofthecobalt(I)catalysttogivesubstituted

benzocyclobutene.

例2

例3

例4

SiMe3

3.不对称的D-A反应

Ingeneral,thebestresultshavebeenobtainedinreactionscatalyzedbyLewis

acidsatlowtemperatures.Thestereochemistryofthepredominantisomercouldbe

predictedfromthechiralstartingcomponentandaknwoledgeoftheorientationofthe

transitionstate.

例1

.广^+金^

R*OH--------►

oCH2C-20OCAOOR*COOR*

:R=H96%endo

99%ee

95%endo

；R=H

99%ee

例2

R◎_f^YR厂\

R*N、/

R*NH--------►

1.5eqEt2AlCl*+

-78oc1

0^NR*

R*N、O

\7

96%endo

H;R=CH398%ee

y

98%endo

；R=CH394%ee

例3

例4

OCH3

-

R*=C川”H

C6H5

例5

Me

95%ee

4.分子内D-A反应(IMDAreaction)

TheIMDAreactionhasbeenwidelyusedintheconstructionofmulticyclic

systeminoneoperation.

AvaluablefeatureoftheIMDAreactionistheirstereoelectivityandtwoormore

chiralcentersarestepupselectively.Butthestereochemistryofthecyclizationis

determinedbyacomplexinterplayofconformational,stericandelectroniceffectwhich

mayvaryindependently.

4.1Carbocyclicsystems:

(1)Bicyclo[4.3.0]nonanes:1,3,8-nonatrienesmaycyclizeviathreealternative

transitionstatestoformtrans-orcis-fusedproducts.

Atrans-fused

acis-fused

Acis-fused

例1

150OC,24hr,65%60

ElAlCb，CH2C12,23OC,36hr,60%100

NO2

91

例2

例3

例4

00

(2)Bicyclo[4.4.0]decanes:IMDAreactionsof1,3,9-decatrienesmayproceedvia

fourdistincttransitionstates,givingrisetoproducttypesasdepictedbelow.

—trans-fused

acis-fused

例1

例2

例3

180oC,24hr

89%

例4

例5

4.2Heterocyclicsystem

(1)Nitrogen-containingheterocycles:

例1

HCOOCH3

190oc,16hr

------:----->

59%

例2

X=COOEt,Y=O0℃1000

X=Ph,Y=O90℃,lOhr81

X=H,Y=O110℃,8hr11

例3

例4

例5

(2)Oxygen-containingheterocycles:

例1

例2

（三）其它类型的环加成反应

1.Theenereaction

Thisisalsoa6兀.electronelectrocychcreaction,butherethetwoelectronsofthe

allylicC-Hobondtaketheplaceoftwo^-electronsofthedieneintheD-Areaction.

X=Y:C=C,C=O,C=N,etc.

例1

COOCH3

170-190℃

---------->

IC4H9/、COOCH3

COOCH3

例2

例3

(1)Intramolecularene-reaction

Intramolecularene-reactionhasshowngreatpotentialforthesynthesisofcyclic

compound,particularlyforthesynthesisoffive-memberedringsfrom1,6-dienes.

例1

1300C

toluene

例2

2500c

---------------►

toluene

例3

例4

COCF3CO(下3COCF3

NCOOEtNCOOEtNCOOEt

JNoOEt--------»ku

COOEt+\_AcOOEt

—《COOR-

S—COOR—/“’—COOR

R=Et180℃31

R=(-)-8-phenylmenthylEtAlCl2,-78℃95(5%isomer)

Thermalcyclisationof5,6-ethylenicketonesprovidesausefulrouteto

cyclopentanonesandcyclopentylketones.

例1

\^O\.O-H

350OCH产

H

例2

60%

(2)Metal-catalyzedintramolecularene-typereaction.

ThePd-catalyzedcycloisomerizationofenynesconstitutesapowerfulring

formingprocess.

例1

(BBEDA)Pd(OAc)2

C1CH2CH2C1,50OC

then

TBAF,THF

Thisreactionwasalsoanefficientstrategyforsynthesisof1,3-diene.

例2

(TOTP)2Pd(OAc)2

PhH,80OC

OTBDMS

例3

TBDMSOTBDMSO

(dba)3Pd2cHeI3.TOTP_

HOAc,Et3SiH

/~=—COOCH3

COOCH3

例4

H

(dba)3Pd2CHCI3.TOTP

(Me2SiH)2O,PhCH3*\/J\

HOv/

(3)Magnesio-enereaction

彳JRI

+

一»

、MgClIlll

R2ClMg^^R^

例1

1.Mg,E(2O

2.02

例2

l.Mg,THF

60℃

2.C02

例3

LMg,EtO

-------------2----A

2.400C

(4)Carbonyl-enereaction:

CarbonylcompoundcanactasenophilesunderthermalorLewisacid-catalyzed

conditiontogivethehomoallylicalcohol.

例1

MeAICl

+CH3cH0——2:------►

25oc

例2

例4

7

withoutSiMej72

Me9AlCl

----------->

2.1,3-Dipolarcycloadditionreaction:

Thisreactionprovideaversatileroutetoawidevarietyoffive-membered

heterocycliccompounds.

a人飞

d二二二e

The47t-electroncomponent,calledthe1,3-dipole,isathreeatomsystemabc

containingatleastonehetero-atomandrepresentedbyazwitterionicoctetstructure.

+-/+-/

C=N-C——c三N—CN三N一C

\\

AzomethineylideNitrileylideDiazoalkane

\++-+-

C=N-0—C三N-0N=N-0

/1

NitroneNitrileoxideNitrousoxide

\++-+-

C=N-N——C三N-N—N三N-N—

/1

AzomethineimineNitrileimi