2024年5月20日发(作者：图门飞驰)

NOTE

/joc

OrganocatalyticAsymmetricDominoAza-MichaelÀMannich

Reaction:SynthesisofTetrahydroimidazopyrimidineDerivatives

HongLi,

†

JunlingZhao,*

,†

LiliZeng,

†

andWenhuiHu*

,†,‡

†

GuangzhouInstituteofBiomedicineandHealth,ChineseAcademyofSciences,GuangzhouSciencePark,Guangdong510530,

People’sRepublicofChina

‡

StateKeyLaboratoryofRespiratoryDisease,Guangzhou,Guangdong510120,People’sRepublicofChina

S

SupportingInformation

b

ABSTRACT:Highlysubstitutedtetrahydroimidazopyrimidine

derivativeswiththreechiralcentershavebeensynthesizedfor

thefirsttimeusinganorganocatalyticasymmetricdominoaza-

MichaelÀMannichreactionofR,β-unsaturatedaldehydesand

fficientapproachfur-

nishestheproductsingoodyields(42À87%)withexcellent

stereoselectivities(>20:1dr,upto>99%ee).

T

hetetrahydroimidazopyrimidineringsystemisfoundin

manynaturallyoccurringproductsthathaveattracted

attentionduetothebroadscopeoftheirbiologicalactivities.

1,2

Differentclassesoftetrahydroimidazopyrimidinecompounds

haveshownantidepressant

2a,b

andantihypertonia

2c

activities

r,syntheses

oftetrahydroimidazopyrimidinederivativesarenotverywell

documentedintheliterature.

2b,3

Thetraditionalmethodsfor

theirsynthesisoftenrequiremanysyntheticmanipulationsand

purifications,edevel-

opmentofnovel,concisemethodologiesthatallowtherapid

constructionofthesetetrahydroimidazopyrimidineskeletons,

preferablyinasingleoperation,ishighlydesired.

Organocatalyticdominoreactions

4À6

allowthesequential

formationofseveralnewbondsandchiralcentersinjustone

vebeenproventobepowerfultoolsforthe

efficientandstereoselectivesynthesisofcomplexmolecules

7

that

arediffi-Michael

addition

8

participateddominoreactionprovidesasimpleand

directwayforthesynthesisofnitrogen-containingheterocycles.

Forexample,theasymmetricsynthesesof1,2-dihydroquin-

olines,

9

pyrrolidines,

10

tetrahydro-1,2-oxazines,

11

andiso-

indolines

12

,wereportthefirst

asymmetricsynthesisofenantioenrichedtetrahydroimidazopyr-

imidinederivativesthroughanorganocatalyticdominostrategy

usingR,β-unsaturatedaldehydesandN-arylidene-1H-imidazol-

2-aminesasstartingmaterials(Scheme1).

Thereactionsof2-carbonyl-substitutedindoles

13

and

pyrroles

14

withenalshavebeenrealizedforthesynthesesof

r,theasymmetricsynth-

esisofsix-memberedring-fusedheterocycles,suchasbiologically

interestingtetrahydroimidazopyrimidines,throughaza-Michael

tetrazole,triazole,andothernitrogenheterocycles,

15

theNÀH

r

2011AmericanChemicalSociety

Aza-MichaelÀMannichReactionofr,β-

UnsaturatedAldehydeandN-Arylidene-1H-imidazol-2-

amine

groupofimidazoleisnotacidicenoughtoparticipateinN-

roductionofelectron-withdrawing

groups,suchascarbonylorcyano,canreducethepK

a

valueofthis

NÀHgroup,makingitpossibleforN-alkylationreactions

13,14,15b

nicgroupisaweakelectron-withdrawinggroup

sagedthatthe

N-arylidene-1H-imidazol-2-amines(1)andtheR,β-unsaturated

aldehydes(2)mightbesuitablesubstratesforthedominoaza-

MichaelÀMannichreactionandthattheywouldgeneratethe

highlysubstitutedtetrahydroimidazopyrimidinederivatives(3).

Totestourhypothesis,thereadilyavailable

L

-proline-derived

secondaryamines(IÀIV),whicharecapableofbothiminium

16

andenamine

17

catalysis,wereexploredascatalystsforthis

dominoreaction.

ThereactionofN-benzylidene-1H-imidazol-2-amine(1a)

andcinnamaldehyde(2a)wasselectedasamodelreaction.

Wefirststudiedcatalysisofthedominoreactionwithdiphenyl

prolinolsilylether(I)ctionpro-

ceededwithhighstereoselectivity(97%ee,>20:1dr)butinlow

yield(30%,Table1,entry1).Therewasnosignificantimprove-

mentinyieldwhenusingavarietyofdifferentsolvents,most

Received:June22,2011

Published:August10,2011

8064

/10.1021/jo201301p

|

.2011,76,8064–8069

TheJournalofOrganicChemistry

zingoftheReactionConditions

a

entrycatalystsolventtime(h)yield

b

(%)dr

c

ee

d

(%)

1IDCM2430>20:197

2ITHF2430>20:195

3Itoluene24traceNDND

4Iether24traceNDND

5ICHCl

3

2420>20:198

6IMeOH655>20:196

7IDCM/MeOH(9:1)1673>20:199

8IDCM/MeOH(1:1)1277>20:198

9

e

IDCM/MeOH(9:1)1680>20:1>99

10

f

IDCM/MeOH(9:1)1273>20:198

11

e

IIDCM/MeOH(9:1)2442>20:199

12

e

IIIDCM/MeOH(9:1)24NR

13

e

IVDCM/MeOH(9:1)24traceNDND

a

(0.13

Reactions

(0.02

mmol),

was

cinnamaldehyde

performedwith

(0.1

N-benzylidene-1

mmol),

H-imidazol-2-amine

c

mmol)insolvent(0.5mL)atroomtemperature.

andsecondary

b

Isolated

amine

analysis

Determinedby

1

HNMRoftheproducts.

d

DeterminedbyHPLC

yield.

additive.

with

f

With

the

20%

corresponding

NaOAcasadditive.

alcohol.

e

With20%PhCOOHas

r,

highstereoselectivitieswereretained(Table1,entries2À5).

Whenmethanolwasusedassolvent,thestartingmaterial1awas

completelyconsumedinjust6htoprovidetheproduct3ain

55%yieldand96%ee(Table1,entry6).Thearylaldehydeand

2-aminoimidazolederivedfromthedecompositionof1aalso

esultssuggestedthat1awasmoreactivein

methanolandthattheuseofamixtureofdichloromethaneand

methanolmightimprovetheeffi-

xtensivescreening,

thebestresultsintermsofyield(73%)andenantioselectivity

(99%)wereobtainedusinga9:1ratioofdichloromethaneand

methanol(Table1,entry7).Theyieldwasimprovedto80%by

theadditionofbenzoicacidwhileretaininghighenantioselec-

tivity(>99%ee,Table1,entry9).Incontrast,theadditionof

sodiumacetatehadalmostnoinfluenceonthereaction(Table1,

entry11).Othersecondaryaminecatalystsalsowereexamined

ascatalysts:thereactionproceededin42%yieldand99%ee

whencatalystII(Table1,entry12)wasused,andtherewereno

dominoreactionproductdetectedin24hwhencatalystsIIIand

IVwereemployed(Table1,entries13and14).

Withtheoptimalreactionconditionsinhand,thesubstrate

scopeofthisdominoaza-MichaelÀMannichreactionwasex-

plored,s

ectron-with-

drawingandelectron-donatinggroupsonthearomaticringwere

ateScopeoftheDominoAza-MichaelÀ

MannichReaction

a

entryR

1

R

2

yield

b

(%)dr

c

ee

d

(%)

1Ph(1a)Ph(2a)803a>20:1>99

2Ph(1a)3-MeC

6

H

4

(2b)713b>20:199

3Ph(1a)3-OMeC

6

H

4

(2c)503c>20:1>99

4Ph(1a)3-ClC

6

H

4

(2d)603d>20:199

5Ph(1a)3-BrC

6

H

4

(2e)683e>20:1>99

6Ph(1a)3-NO

2

C

6

H

4

(2f)703f>20:199

7

e

Ph(1a)4-MeC

6

H

4

(2g)583g>20:199

8Ph(1a)4-MeOC

6

H

4

(2h)543h>20:1>99

9

e

Ph(1a)4-ClC

6

H

4

(2i)763i>20:198

10

e

Ph(1a)4-BrC

6

H

4

(2j)723j>20:198

11

e

Ph(1a)4-NO

2

C

6

H

4

(2k)763k>20:1>99

12Ph(1a)piperonyl(2l)663l>20:199

13Ph(1a)2-furyl(2m)493m>20:199

14Ph(1a)2-thiophene(2n)423n>20:199

154-OMeC

6

H

4

(1b)4-ClC

6

H

4

(2i)603o>20:198

164-OMeC

6

H

4

(1b)4-NO

2

C

6

H

4

(2k)623p>20:197

17

e

4-CF

3

C

6

H

4

(1c)Ph(2a)853q>20:199

184-CF

3

C

6

H

4

(1c)4-ClC

6

H

4

(2i)873r>20:199

19

e

4-CF

3

C

6

H

4

(1c)4-NO

2

C

6

H

4

(2k)753s>20:199

a

mmol),

Reactionswasperformedwith

PhCOOH

R,β

temperature.

(20

-unsaturated

N-arylidene-1H-imidazol-2-amine(0.13

b

mol%)

aldehyde(0.1mmol),I(0.02mmol),and

d

Isolatedyield.

in

c

DCM/MeOH

Determinedby

(9:1,

1

HNMR

0.3

of

mL)

theproducts.

atroom

e

DCM/MeOH

Determinedby

(1:1)

HPLC

assolvent.

analysiswiththecorrespondingalcohol.

tolerated,yieldingtheexpectedproductsinmoderatetohigh

yields(54À80%)andexcellentstereoselectivities(>97%ee,

>20:1dr,Table2,entries1À12).Thereactionof2-furyland

2-thiopheneenalledtotheformationof3mand3nin49and42%

yields,respectively,bothin99%ee(Table2,entries13and14).

Theelectronicnatureofthesubstituentonthearomaticringof

1hadlittleinflionsofthisstrategy

tousethelessreactivealiphaticenalswereunsuccessful;no

reactionoccurredwhencrotonaldehydewasused.

Theabsoluteconfigurationofthethreenewchiralcentersof

3nwasassignedas5S,6S,and7RbyX-raycrystallographic

analysisof4n(thealcoholcorrespondingto3n,Figure1).On

thebasisofthisobservation,aplausiblecatalyticcycleforthe

ctionstartswiththe

iminiumactivationof2byI,followedbyaza-Michaeladditionof

mineofA

catalystisregeneratedforthenextcatalyticcyclethrough

hydrolysisofB:Bthenhydrolyzestogivetetrahydroimidazo-

pyrimidine3.

Insummary,wehavedevelopedanovelorganocatalytic

dominoaza-MichaelÀMannichreactionofN-arylidene-1H-imi-

dazol-2-aminesandR,β-unsaturatedaldehydesforuseinthe

synthesisofhighlysubstitutedtetrahydroimidazopyrimidine

8065

/10.1021/jo201301p|.2011,76,8064–8069

2024年5月20日发(作者：图门飞驰)

NOTE

/joc

OrganocatalyticAsymmetricDominoAza-MichaelÀMannich

Reaction:SynthesisofTetrahydroimidazopyrimidineDerivatives

HongLi,

†

JunlingZhao,*

,†

LiliZeng,

†

andWenhuiHu*

,†,‡

†

GuangzhouInstituteofBiomedicineandHealth,ChineseAcademyofSciences,GuangzhouSciencePark,Guangdong510530,

People’sRepublicofChina

‡

StateKeyLaboratoryofRespiratoryDisease,Guangzhou,Guangdong510120,People’sRepublicofChina

S

SupportingInformation

b

ABSTRACT:Highlysubstitutedtetrahydroimidazopyrimidine

derivativeswiththreechiralcentershavebeensynthesizedfor

thefirsttimeusinganorganocatalyticasymmetricdominoaza-

MichaelÀMannichreactionofR,β-unsaturatedaldehydesand

fficientapproachfur-

nishestheproductsingoodyields(42À87%)withexcellent

stereoselectivities(>20:1dr,upto>99%ee).

T

hetetrahydroimidazopyrimidineringsystemisfoundin

manynaturallyoccurringproductsthathaveattracted

attentionduetothebroadscopeoftheirbiologicalactivities.

1,2

Differentclassesoftetrahydroimidazopyrimidinecompounds

haveshownantidepressant

2a,b

andantihypertonia

2c

activities

r,syntheses

oftetrahydroimidazopyrimidinederivativesarenotverywell

documentedintheliterature.

2b,3

Thetraditionalmethodsfor

theirsynthesisoftenrequiremanysyntheticmanipulationsand

purifications,edevel-

opmentofnovel,concisemethodologiesthatallowtherapid

constructionofthesetetrahydroimidazopyrimidineskeletons,

preferablyinasingleoperation,ishighlydesired.

Organocatalyticdominoreactions

4À6

allowthesequential

formationofseveralnewbondsandchiralcentersinjustone

vebeenproventobepowerfultoolsforthe

efficientandstereoselectivesynthesisofcomplexmolecules

7

that

arediffi-Michael

addition

8

participateddominoreactionprovidesasimpleand

directwayforthesynthesisofnitrogen-containingheterocycles.

Forexample,theasymmetricsynthesesof1,2-dihydroquin-

olines,

9

pyrrolidines,

10

tetrahydro-1,2-oxazines,

11

andiso-

indolines

12

,wereportthefirst

asymmetricsynthesisofenantioenrichedtetrahydroimidazopyr-

imidinederivativesthroughanorganocatalyticdominostrategy

usingR,β-unsaturatedaldehydesandN-arylidene-1H-imidazol-

2-aminesasstartingmaterials(Scheme1).

Thereactionsof2-carbonyl-substitutedindoles

13

and

pyrroles

14

withenalshavebeenrealizedforthesynthesesof

r,theasymmetricsynth-

esisofsix-memberedring-fusedheterocycles,suchasbiologically

interestingtetrahydroimidazopyrimidines,throughaza-Michael

tetrazole,triazole,andothernitrogenheterocycles,

15

theNÀH

r

2011AmericanChemicalSociety

Aza-MichaelÀMannichReactionofr,β-

UnsaturatedAldehydeandN-Arylidene-1H-imidazol-2-

amine

groupofimidazoleisnotacidicenoughtoparticipateinN-

roductionofelectron-withdrawing

groups,suchascarbonylorcyano,canreducethepK

a

valueofthis

NÀHgroup,makingitpossibleforN-alkylationreactions

13,14,15b

nicgroupisaweakelectron-withdrawinggroup

sagedthatthe

N-arylidene-1H-imidazol-2-amines(1)andtheR,β-unsaturated

aldehydes(2)mightbesuitablesubstratesforthedominoaza-

MichaelÀMannichreactionandthattheywouldgeneratethe

highlysubstitutedtetrahydroimidazopyrimidinederivatives(3).

Totestourhypothesis,thereadilyavailable

L

-proline-derived

secondaryamines(IÀIV),whicharecapableofbothiminium

16

andenamine

17

catalysis,wereexploredascatalystsforthis

dominoreaction.

ThereactionofN-benzylidene-1H-imidazol-2-amine(1a)

andcinnamaldehyde(2a)wasselectedasamodelreaction.

Wefirststudiedcatalysisofthedominoreactionwithdiphenyl

prolinolsilylether(I)ctionpro-

ceededwithhighstereoselectivity(97%ee,>20:1dr)butinlow

yield(30%,Table1,entry1).Therewasnosignificantimprove-

mentinyieldwhenusingavarietyofdifferentsolvents,most

Received:June22,2011

Published:August10,2011

8064

/10.1021/jo201301p

|

.2011,76,8064–8069

TheJournalofOrganicChemistry

zingoftheReactionConditions

a

entrycatalystsolventtime(h)yield

b

(%)dr

c

ee

d

(%)

1IDCM2430>20:197

2ITHF2430>20:195

3Itoluene24traceNDND

4Iether24traceNDND

5ICHCl

3

2420>20:198

6IMeOH655>20:196

7IDCM/MeOH(9:1)1673>20:199

8IDCM/MeOH(1:1)1277>20:198

9

e

IDCM/MeOH(9:1)1680>20:1>99

10

f

IDCM/MeOH(9:1)1273>20:198

11

e

IIDCM/MeOH(9:1)2442>20:199

12

e

IIIDCM/MeOH(9:1)24NR

13

e

IVDCM/MeOH(9:1)24traceNDND

a

(0.13

Reactions

(0.02

mmol),

was

cinnamaldehyde

performedwith

(0.1

N-benzylidene-1

mmol),

H-imidazol-2-amine

c

mmol)insolvent(0.5mL)atroomtemperature.

andsecondary

b

Isolated

amine

analysis

Determinedby

1

HNMRoftheproducts.

d

DeterminedbyHPLC

yield.

additive.

with

f

With

the

20%

corresponding

NaOAcasadditive.

alcohol.

e

With20%PhCOOHas

r,

highstereoselectivitieswereretained(Table1,entries2À5).

Whenmethanolwasusedassolvent,thestartingmaterial1awas

completelyconsumedinjust6htoprovidetheproduct3ain

55%yieldand96%ee(Table1,entry6).Thearylaldehydeand

2-aminoimidazolederivedfromthedecompositionof1aalso

esultssuggestedthat1awasmoreactivein

methanolandthattheuseofamixtureofdichloromethaneand

methanolmightimprovetheeffi-

xtensivescreening,

thebestresultsintermsofyield(73%)andenantioselectivity

(99%)wereobtainedusinga9:1ratioofdichloromethaneand

methanol(Table1,entry7).Theyieldwasimprovedto80%by

theadditionofbenzoicacidwhileretaininghighenantioselec-

tivity(>99%ee,Table1,entry9).Incontrast,theadditionof

sodiumacetatehadalmostnoinfluenceonthereaction(Table1,

entry11).Othersecondaryaminecatalystsalsowereexamined

ascatalysts:thereactionproceededin42%yieldand99%ee

whencatalystII(Table1,entry12)wasused,andtherewereno

dominoreactionproductdetectedin24hwhencatalystsIIIand

IVwereemployed(Table1,entries13and14).

Withtheoptimalreactionconditionsinhand,thesubstrate

scopeofthisdominoaza-MichaelÀMannichreactionwasex-

plored,s

ectron-with-

drawingandelectron-donatinggroupsonthearomaticringwere

ateScopeoftheDominoAza-MichaelÀ

MannichReaction

a

entryR

1

R

2

yield

b

(%)dr

c

ee

d

(%)

1Ph(1a)Ph(2a)803a>20:1>99

2Ph(1a)3-MeC

6

H

4

(2b)713b>20:199

3Ph(1a)3-OMeC

6

H

4

(2c)503c>20:1>99

4Ph(1a)3-ClC

6

H

4

(2d)603d>20:199

5Ph(1a)3-BrC

6

H

4

(2e)683e>20:1>99

6Ph(1a)3-NO

2

C

6

H

4

(2f)703f>20:199

7

e

Ph(1a)4-MeC

6

H

4

(2g)583g>20:199

8Ph(1a)4-MeOC

6

H

4

(2h)543h>20:1>99

9

e

Ph(1a)4-ClC

6

H

4

(2i)763i>20:198

10

e

Ph(1a)4-BrC

6

H

4

(2j)723j>20:198

11

e

Ph(1a)4-NO

2

C

6

H

4

(2k)763k>20:1>99

12Ph(1a)piperonyl(2l)663l>20:199

13Ph(1a)2-furyl(2m)493m>20:199

14Ph(1a)2-thiophene(2n)423n>20:199

154-OMeC

6

H

4

(1b)4-ClC

6

H

4

(2i)603o>20:198

164-OMeC

6

H

4

(1b)4-NO

2

C

6

H

4

(2k)623p>20:197

17

e

4-CF

3

C

6

H

4

(1c)Ph(2a)853q>20:199

184-CF

3

C

6

H

4

(1c)4-ClC

6

H

4

(2i)873r>20:199

19

e

4-CF

3

C

6

H

4

(1c)4-NO

2

C

6

H

4

(2k)753s>20:199

a

mmol),

Reactionswasperformedwith

PhCOOH

R,β

temperature.

(20

-unsaturated

N-arylidene-1H-imidazol-2-amine(0.13

b

mol%)

aldehyde(0.1mmol),I(0.02mmol),and

d

Isolatedyield.

in

c

DCM/MeOH

Determinedby

(9:1,

1

HNMR

0.3

of

mL)

theproducts.

atroom

e

DCM/MeOH

Determinedby

(1:1)

HPLC

assolvent.

analysiswiththecorrespondingalcohol.

tolerated,yieldingtheexpectedproductsinmoderatetohigh

yields(54À80%)andexcellentstereoselectivities(>97%ee,

>20:1dr,Table2,entries1À12).Thereactionof2-furyland

2-thiopheneenalledtotheformationof3mand3nin49and42%

yields,respectively,bothin99%ee(Table2,entries13and14).

Theelectronicnatureofthesubstituentonthearomaticringof

1hadlittleinflionsofthisstrategy

tousethelessreactivealiphaticenalswereunsuccessful;no

reactionoccurredwhencrotonaldehydewasused.

Theabsoluteconfigurationofthethreenewchiralcentersof

3nwasassignedas5S,6S,and7RbyX-raycrystallographic

analysisof4n(thealcoholcorrespondingto3n,Figure1).On

thebasisofthisobservation,aplausiblecatalyticcycleforthe

ctionstartswiththe

iminiumactivationof2byI,followedbyaza-Michaeladditionof

mineofA

catalystisregeneratedforthenextcatalyticcyclethrough

hydrolysisofB:Bthenhydrolyzestogivetetrahydroimidazo-

pyrimidine3.

Insummary,wehavedevelopedanovelorganocatalytic

dominoaza-MichaelÀMannichreactionofN-arylidene-1H-imi-

dazol-2-aminesandR,β-unsaturatedaldehydesforuseinthe

synthesisofhighlysubstitutedtetrahydroimidazopyrimidine

8065

/10.1021/jo201301p|.2011,76,8064–8069