藥物合成反應(yīng)-第四章縮合

Chapter

4Condenation

Reaction第四章 縮合反應(yīng)第一節(jié)

-羥烷基、鹵烷基、氨烷基化反應(yīng)一、-羥烷基化反應(yīng)1.醇醛縮合反應(yīng)(Aldol縮合)(1)含有-活潑氫的醛或酮的自身縮合堿催化機理:RCH2

CR'

+

BORCHCR'ORCHCR'

+

BHOδδδ

δ

O

R

CH2CR'

+

RCH

CR'ORCH

CR'OR'RCH2

C

OBHOH

HR'RCH2

CRC

CR'OB△R'+OHRCRCH2COCR'BH(62%)CHOOHC

(CH2)3C3H7CH1150CC3H7OH

-

CHO(90%)OCH2COCH3KOHO與含有-活潑氫的醛、酮之間的縮合NaOH(稀)40-420C(45%)HCHO+

CH3COCH32H

C

CHCOCH3-

H2O(90%)K2CO314-200C,

3h2HCHO

+ CH3

CH2

CH2

CHOCH3

CH2CCHOCH2

OH(1)

[H](2)

HCHO+NaOHCH3

CH2

CCH2

OHCH2

OHCH2

OHCH2

OH三羥甲基丙烷催化劑的影響以堿催化劑為主，酸催化劑應(yīng)用較少④應(yīng)用特點定向醇、醛縮合(a)

烯醇鹽法(b)

烯醇硅醚法（2）芳醛與-活性氫的醛、酮的縮合應(yīng)用特點反式芳丙醛COOHNHR

=

Ar, <

78%

ee; R

=

Alkyl,

99%

ee,R

=4-NO2Ph, 78%

eeList,

B.

et

al,

J.

Am.

Chem.

Soc.

2000,

122,

2395OR

HOR'+RR'OH

OCatalystDMSO,

RT手性羥基醛有機小分子脯氨酸催化直接

Aldol

反應(yīng)（3）分子內(nèi)的羥醛縮合Robinson環(huán)化2.不飽和烴的a羥烷基化（Prins反應(yīng)）Mechanism3.安息香縮合影響因素①芳醛結(jié)構(gòu)的影響強吸電子、強供電子對反應(yīng)都不利；自身縮合、交叉縮合②催化劑的影響

劇毒，可用噻唑鎓鹽、咪唑鎓鹽等代替Example4.有機金屬化合物的-羥烷基化(1)Reformatsky反應(yīng):醛或酮與-鹵代酸酯在金屬鋅粉存在下縮合而得-羥基酸酯或脫水得、-不飽和羧酸酯的反應(yīng)：metal:

Zn,

Mg,

Cd,

Ba,

In,

Ge,

Co,Ni,

Ce;

metal

salt:

SmI2,

CrCl2,TiCl2,

CeX3,

Na2Te,

R3SnLi,R3Sb/I2,

Et2AlClmost

often

ether

solvents

are

used

suchas

diethyl

ether,tetrahydrofuran,

1,4-dioxane

and

dimethoxyethane,

butmixtures

of

these

solvents

with

aromatichydrocarbons

and

more

polar

solventssuch

as

acetonitrile,

dimethyl

formamide,andare

alsodimethyl

sulphoxide,hexamethylphosphoric

triamideused;催化劑鋅粉必須活化，常用20%鹽酸處理，再用、乙醚洗滌，真空干燥。亦可用K、Na、Li等還原無水氯化鋅，此法活性較高。Mg,Cd,Ba,In,Ge,

Co,Ni,Ce等。例如:Zn

/

(CH3O)3B

/

THFr.

t.(95%)CH3

CHO

+

Br

CH2

COOC2H5OHCH3CHCH2

COOC2H5加入(CH3O)3B/THF可提高收率(如上)(50%)CHOO+

Br

Zn

CH2

COOC2H5OCHCH2

COOC2H5OH00CTHF（2）Grignard反應(yīng)機理:+乙醚(干)RXMgRMgXOMgXδ

δ-

+OC3H

O+HH

+

RMgXRH

CHRCH2

OH

+

Mg(OH)X③影響因素1)

the

reagents

are

predominantlyprepared

by

reacting

alkyl,

aryl,

or

vinylhalides

with

magnesium

metal

in

aproticnucleophilic

solvents

(e.g.,

ethers,

tertiaryamines);2)

the

reagentsthermodynamically

stableare

usuallybut

air

andpatible

withmoisture

sensitive

andacidic

functional

groups

(e.g.,

alcohols,thiols,

phenols,

carboxylic

acids,

1°,

2°amines,

terminal

alkynes);二、

-鹵烷基化反應(yīng)(Blanc反應(yīng))3.影響因素也可用ZnCl2(干)等Lewis酸。苯環(huán)上供電子基,有利于反應(yīng)進(jìn)行。吸電子基不利于反應(yīng)進(jìn)行。(87%)引入-CH2Cl后，可進(jìn)一步轉(zhuǎn)化成其他官能團(tuán)并增長碳鏈。三、-氨烷基化反應(yīng)Mannich反應(yīng)：有活潑氫的化合物(醛、酮等)與

、胺進(jìn)行縮合，H原子被-氨甲基取代稱為

-氨甲基化反應(yīng)(Mannich反應(yīng))反應(yīng)機理如：抗膽堿藥阿托品的(90%)IntroductionSilicon

EnolatesKetonesMannich

ProductsAldehydes

+

AminesImines

and

Imine

SurrogatesElectrophilesNucleophiles+One-PotAldehydesPreformed

IminesOrganicSol.AqueousMedia1.

Metal

Catalysis2.ProlineCatalysis3.Br?nsted

Acid-Catalysis4.

Protonated

Chiral

Catalysis5.ACDC6.

H-Bond

Catalysis7.PTCTrost,

B.

M.

J.

Am.

Chem.

Soc.2006,

128,

2778-2779.Proline

catalysisBr?nsted

acid-catalysis磷原子的四齒結(jié)構(gòu)磷酸的酸性足以誘捕亞胺雙功能手性催化劑4.

Protonated Chiral

CatalysisJ.

Am.

Chem.

Soc.

2004,

126,

3418-3419Ishihara,

K.

J.

Am.

Chem.

Soc2008,

130,

16858–16860.H-Bond

CatalysisJacobsen,

E.

N.

Angew.

Chem.

Int.

Ed.

2005,

44,466–468.2.

Pictet-Spengler

reactionBaldwin環(huán)化規(guī)則Baldwin環(huán)化規(guī)則SP3

=

tet；SP2

=

trig；SP

=

digSP3:5-6-endo

禁阻SP2:3-5-endo

禁阻SP:

3-4-exo

禁阻其他允許（3）影響因素①

only

β-arylethylamines

with

electron-donating

substituents

afford

high

yields;②

the

reaction

is

usually

carried

out

with

a

slight

excess

of

the

carbonyl

compound

(to

ensure

the

complete

consumption

of

the

amine)

in

either

protic

or

aprotic

medium;3.

Strecker反應(yīng)（1）反應(yīng)通式（2）反應(yīng)機理（3）應(yīng)用-Corey，1999第三節(jié)

-羥烷基、

-羰烷基化反應(yīng)—

-羥烷基化反應(yīng)1.反應(yīng)通式-F-C反應(yīng)2.反應(yīng)機理CH3

CH2

CHCH2

OH> CH3

CH2

CHCH2OH苯環(huán)連在取代基多的C上SnCl2

/

CS2-100C(40%)C6H5OCH3

CH2

CHCH2

OH+

CH3

CH2

CH

CH23.應(yīng)用特點（1）區(qū)域選擇性選擇性（2）構(gòu)型反轉(zhuǎn)（3）環(huán)內(nèi)酯二、-羰烷基化反應(yīng)Michael加成反應(yīng)反應(yīng)機理:+δδ

CH3OCH3HO

OH

H

+OOCH3OOOC

CH3δ

δCH2

CHCH2OHOO3OC

CH2CH3CH

CHH

+OOCH3CH23OC

CH△OCH3-H2OOδ+OOO

CH3O3O

CHCH2OOδCH3CH2OCCH2HOHH（3）影響因素1)

the

nucleophile

(Michael

donor)

can

bederived

by

the

deprotonation

of

CH-activated

compounds

such

as

aldehydes,ketones,

nitriles,

β-dicarbonyl

compounds,etc.

as

well

as

by

the

deprotonation

ofheteroatoms;2)

depending

on

the

type

and

strength

ofthe

electron-withdrawing

group(negativecharge

stabilizing

group),

the

use

of

evenrelatively

weak

bases

is

possible

(e.g.,NEt3);（4）應(yīng)用第四節(jié)亞甲基化反應(yīng)—

羰基烯化反應(yīng)（1）反應(yīng)通式及機理n-C4H8Li

/

EtON2,

250CC6H6025

C(C6H5)3

P

+

CH3

Br (C6H5)3

PCH3

BrR'CH2CH2(C6H5)3

P(C6H5)3

P+

R

COOCH2O(C

H

)6 5

3P

CCH

HRR'OC(C

H

)6 5

3PCH

HRR'RC6 5

3R'

+

(C

H

)

P（2）影響因素the

ylides

are

water

as

well

as

oxygen-sensitive；the

phosphorous

ylides

chemoselectivelyreact

with

aldehydes

(fast)

and

ketones(slow),

other

carbonyl

groups

(e.g.,

esters,amides)

remain

intact

during

the

reaction;the

stereoselectivity,

E-or

Z-selectivity,

isinfluenced

by

many

factors:

type

of

ylide,type

of

carbonyl

compound,

nature

ofsolvent；The

Wittig

reaction

has

several

importantvariants:

HWE

Reaction①the

phosphonate

carbanions

are

morenucleophilic

than

the

correspondingphosphorous

ylides,

so

they

readily

reactwith

practically

all

aldehydes

and

ketonesunder

milder

reaction

conditions；②

the

by-product

dialkyl

phosphates

are

water-soluble,

so

it

is

much

easier

to

separate

them

from

the

alkene

products

than

from

the

water-insoluble

triphenylphosphine

oxide.③

high

(E)-selectivity

for

disubstitutedalkenes

under

mu ilder

conditionsthan

normally

used

in

Wittig

reactions；④

the

(E)-selectivity

is izedbyincreasing

the

size

of

the

alkyl

group

of

theR1

or

R2

substituents⑤

There

are

an

important

modifications

ofthe

HWE

olefination:in

the

Still-Gennari

modificationR1=OCH2CF3

and

the

reaction

affords(Z)-olefins

exclusively；for

base-sensitive

substrates,

the

use

of

ametal

salt

(LiCl

or

NaI)

and

a

weak

aminebase

(e.g.,

DBU)

has

proven

effective

toavoid

epimerization.（4）應(yīng)用二羰基a位的亞甲基化反應(yīng)1.活性亞甲基的亞甲基化Knoevenagel

反應(yīng)（1）反應(yīng)通式（2）反應(yīng)機理（3）影響因素①

the

nature

of

the

catalyst

is

important,usually

primary,

secondary,

and

tertiaryamines

and

their

corresponding

ammoniumsalts,

certain

Lewis

acids

combined

with

atertiary

amine

(e.g.,

TiCl4/Et3N).②the

by-product

of

the

reaction

is

waterand

its

removal

from

the

reaction

mixtureby

means

of

azeotropic

distillation,

theaddition

of

molecular

sieves,

or

otherdehydrating

agents

shifts

the

equilibriumtoward

the

formation

of

the

product;③

the

choice

of

solvent

is

crucial

and

theuse

of

dipolar

aprotic

solvents

(e.g.,

DMF)is

advantageous,

since

protic

solventsinhibit

the

last

1,2-elimination

step;2.Stobbe

反應(yīng)（1）反應(yīng)通式（2）反應(yīng)機理（3）應(yīng)用烯酸3.

Perkin反應(yīng)(1)反應(yīng)通式（2）反應(yīng)機理（3）影響因素①芳香醛結(jié)構(gòu)影響吸電子活性增強，給電子相反碘番酸②催化劑的影響相應(yīng)羧酸的鉀鹽、鈉鹽；銫鹽效果更好（4）應(yīng)用第五節(jié)

、

-環(huán)氧烷基化反應(yīng)(Darzens反應(yīng))1.反應(yīng)通式EWG

=

CO2R,

CN,

SO2R,

CONR2,

C(=O),C(=NR);

Y

=

O,

NR;2.

反應(yīng)機理3.

影響因素Aliphatic

aldehydes

usually

give

loweryields；α-Chloro

esters

are

preferable

to

bromo

oriodo

esters,

since

they

give

higher

yields；α-halo

sulfones,nitriles,ketones,

ketimines,thiol

esters,or

amides,c so

be

used

toobtain

the

corresponding

derivatives；4.

應(yīng)用特點醛、酮同系化C+1布洛芬的第六節(jié)環(huán)加成反應(yīng)EDG

(electron-donating

group)=

alkyl,

O-alkyl,

N-alkyl,

etc.EWG

(electron-withdrawing

group)

=

CN,

NO2,

CHO,COR,

COAr,

CO2H,

CO2R,

COCl

etc.一、D-A反應(yīng)Mechanism（3）影響因素及應(yīng)用特點①共軛二烯雙鍵必需是順型的②順式原理③內(nèi)向加成原理④加成定位規(guī)則Example二、1,3偶極環(huán)加成1.

Azomethine

Ylides2.

Azomethine

Imines3.

Nitrones4.

Azides5.

O3

/

Carbonyl

Oxides三、碳烯、氮烯對不飽和鍵的加成Carbene-電中性二價碳

，