BÀI TẬP -BÀI GIẢI TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)

BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3 2021)

Trang 1

BÀI TẬP

TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 3) Thạc sĩ Phạm Công Nhân

TAXOL

Trang 2

Ph OEt

O NHMe

OO

NH

OO

NH

PhPh

O

HN

NH2

N

HNNHAc

N

PhO2S

NO

NPhO2S

NH

BrCN, Et2O, 0 °C;

AcCl, Et3N55%

diphenyl ether

190 °C, 2.5 h76%

1) KOt-Bu, O2, P(OEt)3 HOt-Bu, DME, 79%

2) NaBH4, THF, 76%

3) NaIO4, 53%

O NEt

SMe

OHNHEt

1) I2, THF, 69%

2) Na2CO3 THF/dioxane/H2O, reflux, 71%

3) 0.5 N NaOH EtOH/H2O, reflux, 64%

(racemic)

Trang 3

O

Br Br

1) n-Bu3P, DMF, 0 °C then

47%

2) 1,2,2,6,6-pentamethyl- piperidine (cat) toluene, reflux, 72%

OO

OH

O

SS

O

MeOO

CO2Me

CO2MeNHt-Bu

Fukuyama Group - Group Meeting Problems

t-BuNC, DMAD

CH2Cl2, rt, 24 h94%

NO2

O

SnCl2 (5 eq)EtOHreflux, 2 h98%

NH

SS

CO2Et

OHOH

NH2OH

(NH4)2SO3·H2O

NH3·H2O

200 °C, 5 d91%

Trang 4

NOO

NH4Cltoluene

CO2Me

NH2

OHC C6H13

N C6H13OMeO2C N

SnBu3

NHTsMeO

OMOMPh

n-Bu

PhOH

2) KF on Al2O3 (under air)

OO

1) t-BuOLi, –60 °C2) DDQ

3) toluene, reflux

OO

O

+

Trang 12

NaOH, acetone, ~60%

O2N Cl

OMe

MeO2C

O

HOO

MeO

18OHhn

dioxane/H218O

1) mCPBA, CHCl32) CHCl3, reflux3) 20% aq KOH

O

OH

DBU, NIS

CH2Cl2, rt73%

OH

H

O

"tricyclic compound"

Bu3SnH, AIBNt-BuOH, reflux50%

Trang 13

O

Me

OHMeO

MeO

MeOMeO

OMe

OMeO

OO

Me

N

SO2CF3Me

N

OH

N

NH

N,N-diethylaniline

225 °C, 12 h

1) PIDA, MeOH2) p-TsOH, MeOH reflux, 1.5 h PIDA = phenyliodonium diacetate

Cy2BH, THF

0 ° C to rt, 12 h;

MeOH85%

NH

NO2

O

NH

NH2O

S

Lawesson's rgt (1.1 eq)toluene, 100 °C, 15 min

68%

OOPh

NH 2

Trang 18

OOHO

Mo(CO)5

Bu OMebenzene

40 °C54%

OO

N2NO

Ph

NO

HO

O Ph

W W

Bu

WW

NO2

Me OMe

ON

O2N

O

ClCl

10 min, 94%

2) xylene, 145 °C

13 hr, 68%

[Rh(II) = Rh2(pfb)4]

W = CO2Me

(0.5 eq : theoretical amount)

CHCl3 - MeNO2

rt, 10 min

2 : 3 mixture+

1) n-BuLi, –78 °C

2) n-BuLi, 0 °C

Trang 19

OMe

OO

Me

1) PhNMe2

180 °C, 6 h, 87%

2) cat Zr(acac)4, TBHP (2 eq)

Me

OO

NHCbz

PhCbz-L-Phe

CH3CN

rt, 19 h83%

OH

NHBn

OH 1) BrCH i-Pr 2CO2Ph

2NEt, MeCN

2) TIPSOTf, Et3N benzene3) LiAlH4

NBn

OHTIPSO

CO2MeCl

NO

1) CH2Cl2, rt

5 days, 70%

2) DMSO, 100 °C

3 hr, 73%

CO2MeO

Trang 25

–78 °C to reflux2) toluene, 80 °C3) EtAlCl2, CH2Cl2

DMF, rt54%

OH

H

OOH

[CF3CO2ReO3·2MeCN]

TFAA

CH2Cl2-MeCN (9:1 v/v)–40 °C, 1.5 hr, 84%

1) TsNCO, Et3N THF, rt, 94%

2) Pd(OAc)2 (5 mol%) P(o-tol)3 (11 mol%)

Na2CO3, n-Bu4NCl

CH3CN, 90 °C, 77%

Br

COClClOC

+

1) benzene, rt overnight, 93%

2) CH2N2, overnight 34%

3) benzene, 170 ºC 85%

OH

H

Trang 26

xs KCNDMSO

120 °C71%

i-Pr

N CN

H2NEt

H

N

NH2 OO

, EtONa

EtOH

Raney Ni, H2EtOH

ONa

O Me OEt O

OEtO

Me

NCScat pyridine CHCl3

N

HNO

NNMe

MeO

O

N

H NH2O

C 13 H 19 NO 4 FVP*

15 minFVP*: 520 °C, ca 10-4 Torr

N

OO

Trang 27

NHCCl3 4) n-BuLi

> 96% ee

O N3AcO

AcO

OAcOAc

OAcO

AcO

OAcOAc

HNOPhPPh3, MS4A;

O S Ph

N

a (exclusive)

O

MeO(–)-CSA

1) LAH2) NaH; Me2SO43) O2, photosensitizer, hn

Ac2O, Py, DMAP

substituted cyclopentene

H+

O

SnCl4,

CH2Cl2 –78 °C 73%

O

MeO

OMeO

OHOMe

OMe

Trang 37

2) PPh3, NaHCO3, CCl4, reflux3) LDA (5 eq.), THF, –30 °C to rt

OH HH

H

HO

OH

1) BH3·NEt3 (1 eq : theoretical) diglyme, D

2) CO (70 atm), THF, 150 °C3) aq H2O2-NaOH

2) Et3N, CH2Cl2, 89%

3) Me3S(O)I, NaH, DMSO, 76%

4) Pb(OAc)4, AcOH, benzene reflux, 45%

AcO

OAcO

CO2i-PrO

OH

CO2i-PrRacemic

1) LDA, THF –78 °C to 25 °C

2) decane, D

180 °C

Trang 38

2) BF3·OEt2; allyltrimethylsilane –78 °C

3) Ba(OH)2·8H2O MeOH, 0 °C 64% (2 steps) O O

CsF (3-4 eq.), PhNTf2 (2-3 eq.),DME, 23 °C, 4 h72%

(Sealed reactor)

O

OTfTfO

O

OH

Mg (activated)THFrt

AcOEt–78 °C

CO2Me

1) NaBH4 (2 eq) MeOH, rt

2) MsCl (1 eq), Et3N

CH2Cl2, –15 °C

3) NaOMe MeOH, rt

hnacetone, rt92%

O

H H MeO OMe O

OMe

OH

O

cyclopentadienePhI(OAc)2MeOH, rt79%

Li

Trang 44

N2

O

1) , K2CO3, MeOH, 88%

2) TBAF, THF3) Swern oxdn., 76% (in 2 steps)

OH

H

CO2t-Bu

OMe

1) decalin, 215 °C, 1h2) HCl, EtOH, rt3) NaOH, H2O2, H2O/MeOH 68% (3 steps)

CO2t-Bu

A

TsNH-NH2AcOH, CH2Cl272%

OTBS

t-BuMOMO

Ot-BuO

MePh

O N Ph

Me O

n-BuLi (2 eq), THF, –40 °C;

–78 to –40 °C;

aq KH2PO4 74%

cat Hg(OCOCF3)2TFA

CH2Cl2

rt, 36 h71%

LiBF4 benzene, rt 82%

3) NaOMe

MeOH reflux 74%

O

CO2MeMeO2C

MeO2C

Trang 45

92%

C 8 H 6 N 2 OS K2CO3, BzCl

acetone, reflux91%

OSBz

TMS

1) toluene

110 ºC, 70%

2) Ag2O

K2CO3 benzene

3) TFA

CH2Cl2 90% (2 steps)

O

OMeOHMeOMeO

O

HN

3) NaNO2, FeSO4 AcOH-H2O

•

OAc

Pd (PPh3)4COAcOH, 75 °C22%

H

OH

O

racemic

Trang 46

BnSiMe3 A

NMeN

MeO2C CO2MePh

1) NBS, CCl4 (hn)2) MeNH2, MeOH3) NaNO2, H+

DMADtoluene, reflux83%

cat p-nitrobenzonitrile, KOHDMSO, rt, 5 hr, 79%

Pb(OAc)4THF74%

NO

4) Zn, AcOH, 82%

CO2Et O

Me

OHPhMe2Si MeOH

1) SeO2, TBHP, CH2Cl22) AllylBr, NaH, THF3) DBU (2 eq), toluene, 220 °C4) TPAP, NMO, MS4A, CH2Cl2

dr > 98%

Trang 58

2) mCPBA (1 eq), CH2Cl2

25 °C, 47% (2 steps)

1) A, 60 °C

2) t-BuOK THF, 0 °C57% (2 steps) 85% (2 steps)

1) A, 60 °C

2) t-BuOK THF, 0 °C

Br

OHOBr

A

LiN O

Li OMOM

–78 °C, THF;

isobutylaldehyde, reflux

73%

O Li

H O SiEt3

c)

–78 °C d) I

IHO

H O

OTESMeO

1) PhCH2N3

BF3·OEt2 47%

2) Rh2(OAc)4 90%

NOPh

acetone, reflux82%

SiEt3

Trang 59

I 3) hv (Pyrex)

acetone/MeCN

0 °C 4) p-TsOH (0.1 eq) MeOH, reflux 80% in 2steps

OH

OMs

1) BnNH2 toluene, reflux*;

EtSCH2COCl 73%

2) NaIO4 MeOH-H2O, rt 90%

*Dean-Stark trap

TsOHbenzenereflux61%

N

MeO

Bn Me

CO2MeEtS

Ph S

OPh

TIPSO Me 1) lithium dispersion t-Bu2SiCl2, THF

0 °C to rt

Trang 60

1) PhOPh reflux, 60 min 90%

2) SeO2 (2 eq) HCO2H (2 eq) dioxane, 90 ºC

4 hr, 68%

NCbz OHMeO2C

MsCl

Et3N

CH2Cl2

rt, 2 h74%

DBUbenzene

80 ºC, 70 h

61 %

O

NHPMPO

racemic

1) acetylene, hn2) p-TsOH, benzene reflux

BnO

OSiPh3

SiMe3O

OSiMe3OPhMeTiCl4;

CH2Cl2, –78 °C

1)

TsOHbenzene, 40 °C80% (2 steps) O O

Me

OH

Me3SiBnO2)

MePh

1) Rh2(OAc)4 (1 mol%)

130 °C2) Me2AlCl

CO2Me

Trang 70

1) HCl·H2NOH, Na2CO3, EtOH reflux, 21 hr

3 days, 92%

Bz SThe intermediate is the Rh-carbenoid complex

N

O

OHPh

hνbenzene88%

NN

NNOH

PhO

MeO

O

N NN

MeOO

A

CH2Cl2

25 °C, 10 min78%

1) N2CHCO2Et, Pd(OAc)2

Et2O, 60%

2) CH3ONa, CH3OH, 92%

(single isomer)3) LAH, Et2O, 96%

SOCl2CHCl374%

CH2Cl2, rt;

work up71%

Trang 71

Me CN NaOMe (1 eq)

MeOH

5 °C, 24 h86%*

(2 eq)

A

(C13H16N4O)

xylenereflux, 3 h99%

NMe

NC

NH2CNOMe

* Yield is based on NaOMe

TMSO

OTMS

n-Bu3SnH, AIBNPhH, 80 °C;

SiO2;

1 N HCl, MeOH49%

1) PhSeCH(CO2Me)2 hν

2) Bu3SnH, AIBN

hν, 10 °C

1) mCPBA2) Bu4NI, BBr33) CH2N2

O

C11H14O6(bicyclic compound)

Trang 76

S SHNO

NH

OPOCl3, Δ ;

1) acrylonitrile Triton B THF, 96%

2) mCPBA

CH2Cl2, rt 88%

1 h

SiMe3

C6H13

I60%

CO2MeN

O

hνbenzene50%

NHO

O

CO2HPh

Trang 77

2) n-BuLi, I23) Na2CO3 MeOH 83% (2 steps)

3) TMSCN cat ZnI2; TBAF 59%

OSn-Bu

LDMAN =

NMe2 Li

NPh

+ OTf–

1) Ph2Cu(CN)Li2 THF, –40 °C to rt2) toluene, Δ

O

O OMe1) O3, CH2Cl2

–78 °C2) FeSO4 Cu(OAc)2

OOHC

toluenereflux

OOOO

OOOO+

110 ºC68%

H

Trang 78

2) CAN, NaHCO3, MS4A Cl(CH2)2Cl-MeCN (3:1 v/v)

40 °C, 10 min; TBAF 91%

On-C8H17

SN

, CH2Cl2;

O

O1)

CO2H

PhOPPh3

CO2Me 1) TMSN3, NBS, CH2Cl2

2) heptane, reflux

A

HN

Ph CO2Et

A

toluenereflux

N

NPh

CO2MePh

O

H

OTMS

1) mesitylene, 190 °C (in a sealed tube), 63%

2) NaBH4(2 eq), MeOH rt

3) Collins oxidation 92% (in 2 steps)4) FVT (470 °C, 1.5 torr) 75%

Trang 87

2) benzoyl chloride, toluene reflux, 83%

A

OPh

BF3·OEt2

CH2Cl2–78 °C to rt45%

1) LDA (1 eq), THF; MeI –78 °C to 0 °C, 95%

2) toluene, reflux3) LDA (1 eq), THF;

–78 to 0 °C, 90%

4) MeI, LiF, Li2CO3 DMF, rt (in the dark), 80%

Br

(all trans)

O

OO

HO HHO

C13H19NO3

1) TsOH•H2O MeOH-H2O reflux, 70%

2) toluene, reflux 64%

3) K2CO3, MeOH reflux, 88%

4) SmI2, THF

rt, 64%

racemic

S EtO

NEt2O

Ac2O, DMADcat TsOHxylene, reflux

OH

CO2Me

CO2MeNEt2

Trang 88

; wet SiO278%

PhO

MgX

THF

KHMDStoluene, 50 °C79%

KHMDSdiglyme, 100 °C67%

OPh

Ts-N=S=O

1) pyridine, benzene

rt, 1 h;

rt, 15 h 43%

2) PhMgBr, THF –60 °C, 1.5 h3) (MeO)3P, MeOH reflux, 30 min 83% (2 steps)

NHTsNHTs

O

N3 BF3•OEt2

CH2Cl2

rt, 2 min92%

OHC

O2N

OMeMe

OMeOMe

N

OMeMeO

MeOMe

OOMe

HO

OMe Li

1) 80%

2) hν MeOH 45%

Trang 89

N Ph

Me

2) NaBH4 glyme 70%

ONH

MeMe

PhPh

Ph

MeO

OMe

1) PhLi(workup H3O+)

2) TsOH, H2O

O

OHMe

SSS

S

O hυ, Pyrex

benzene76%

SS

S

TsOHbenzenerefluxDean-Stark

+ n-BuLi

NNN

Bn

n-BuLi; PhCNTHF–78 °C to rt

toluenereflux

Silica gel, 4 N HCl

N O MeS

Trang 90

HMe

2) POCl3, pyridine

3) NaOH, H2O2 n-Bu4NHSO44) 3N HCl reflux

N O Ph

benzene, 406 °C

HNPh

O

NPh

SOO

Trang 100

A

NaNO2FeSO4AcOH-H2O87%

Ph

OHPh

HNI

HO

Ph

Pd(PPh3)2Cl2CuI, Et3N99%

1) POCl3 iPr2NH2) tBuOK tBuOH

N

PhSe

H

HO

H

O30% H2O2

EtOHreflux

CCl4

CO2HCl

Cl

O Cl

C8H10OCl4 aq NaOH

rt to 100 °C73%

Trang 101

OH

1) I(coll)2ClO4

CH2Cl2 –78 °C to rt, 77 %2) LAH, THF 72%

3) toluene, rt 86%

4) Ca, NH3 –78 °C, 92%

mediummemberedring compound

NNN

CO2Et

CO2EtEtO2C

NH2NH•HCl

DMF, 90 °C, 24 h85%

70 °C

Ph

OPh

NHCOCHCl2NHTs

heterocyclic compound

N

CO2H

COCF3COAr

TFAA (5 eq)

Py (10 eq)benzene

12 h, rt55%

Ar =

Me Me Me

Trang 102

, BuSSBuhν

1) m-CPBA, CH2Cl22) H2SO4, MeOH 79% (2 steps)64%

NH2

OMe

NH

Me

CO2Et

MeO1) NaNO2, aq HCl, 0 °C;

KOH,

Me O Et

2) (PhCO2)2

CH3CN reflux 67%

3) K 18-crown-6 toluene 90%

MeMeO

MeMe

CO2Me

NO2(C10H11NO4)

OO

2) hν, Et3N MeCN, 78%

OTBSH

Trang 113

TBSO

H H

COSEtO

10 °C, 1 hr, 57%

4) DIPEA, LiCl, MeCN

25 °C, 17 hr, 88%

NO

, Et3N

SeMe Li

ether-pentane

1) AgBF4, Al2O3, CCl42) TsOH, benzene, 80 °C3) hυ

PhHN

PhHN NO2

NHPhS

Br

HO2C HO2C

Br+

Trang 114

HHO

1) hν (pyrex) acetone

5 °C, 88%

2) 4% aq KOH

rt, 100%

1) Al(Oi-Pr)3, i-PrOH reflux, 91%

2) TsCl (1.3 eq) pyridine, rt, 89%

3) i-PrLi (5 eq) pentane, rt, 55%

Ph S

+

O

CHOR

R = n-Bu

Et2NH (2 eq)AcOH (0.5 eq)propanenitrile*

rt, 6 h82%

(2 eq)+

OR

OH

* Used as a solvent

O–

OCOOMe

OMeMeO

I

Bu3SnH, AIBN74%

OCOOMeMeO

MeOPhMe,

TESO

OHO

R

O

OTESO

OR

R =

OTf

Pd(PPh3)4

CO (800 psi)i-Pr2NEtPhCN

65 to 110 °C56%

Tricyclo Compound

OO

OHEtOHH

Ti(Oi-Pr)4i-PrMgCl (2 eq)

Et2O, –78 to 0 °C

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Dung lượng	3,04 MB