BÀI TẬP -BÀI GIẢI TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 2 2021)

BÀI TẬP TỔNG HỢP HÓA HỮU CƠ LUYỆN THI HSG QUỐC GIA (tập 2 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ CHUYÊN NGÀNH HÓA HỌC (tập 2 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ GIÁO VIÊN HÓA HỌC (tập 2 2021)BÀI TẬP TỔNG HỢP HÓA HỮU CƠ BỒI DƯỠNG HỌC SINH GIỎI (tập 2 2021)

BÀI TẬP

TỔNG HỢP HÓA HỮU CƠ

LUYỆN THI HSG QUỐC GIA (tập 2)

Thạc sĩ Phạm Công Nhân

TAXOL

OMeN

H

OH

THF–78 °C;

TMSCl (1.5 eq);

25 °C; HCl aq

0.1 eq PhSH0.1 eq PhSNaTHFreflux

12 hr

1) Me3SiOK toluene, 70 °C;

aq NH4Cl2) Pb(OAc)4

t-BuOH, 50 °C

Ar =

1) Boc2O, DMAP

Et3N, CH2Cl22) TBAF, THF-H2O3) DMSO, H2O, 130 °C

R1CHO +

CrCl2 (8 eq)TMSCl (6 eq)

H2O (1 eq)THF

1) MeAlCl2, CHCl32) NaBH4, MeOH, 63% (2 steps)3) MsCl, Et3N, 94%

4) t-BuOK, THF, reflux, 86%

benzenereflux

67%

MeO

Me4NBH(OAc)3MeCN-AcOH–40 °C

1) Li/NH3

THF, t-BuOH;

TMSCl, Et3N2) Sc(OTf)3

aq HCHO THF

PhSH

aq HCHO

Et3NEtOH

Ph

Ph

OPhOH

PhO

NN

O OHDNs

HO

OOMeMeOHH

MeOTf

2,6-di-t-Bu-pyridine

CH2Cl2, 0 °C;

aq NaHCO355%, >98% ee

Fukuyama Group - Group Meeting Problems

SmI2 (0.1 eq)

PhMe, 80 °C, 4 hr95%

benzenereflux

Hg(OTf)2 1.2 eqtetramethylurea

CH3CNr.t., 5.5 h;

NaCl22%

DMAD (2.0 eq)

Et2O–78 °C to rt

16 hr79%

A

TMSTMS

C26H35NO8Si2

(1.0 eq)

Ph N

TMSTMS

TMSTMS

Ar = p-nitrophenyl

+

hν

Et2O–78 °C to rt

24 hr33%

N3

Ph

ONPh

O

O

O

CO2MeO

Rh2(OAc)4 (1 mol%)

CH2Cl2reflux, 54%

OPd(dba)2, dppp

CO (6 atm)DMF

74%

NO2O

OH

MeO

OMe

NMeCHO

MeO

O

NO2SiMe3

NPMPOTIPS

OMe

O

HTIPSO

HHOH

POCl3, 50 °C86%

i-PrNH2, hυ

NH3, CH3CN-H2O

PMP = p-C6H4OMe

1) ClTi(Oi-Pr)3, c-C5H9MgCl THF, rt, 90%

pentane, 20 °C93%

THF-EtOH (5:1)

20 °C, 69%

1) m-CPBA (1.1 eq)

CH2Cl2, rt, 3 hr 82%

[(COD)RhCl]2

NPh

PhO

OEtMe

N

NH

CO2MeHO

NH2

O

CN

ON

CH3(CH2)14 CH3

OCH3

ON

HCOOHparaformaldehyde

CH3CNreflux, 12 hr85%

TBSOTf (2.1 eq)collidine (4.2 eq)

CH2Cl2

rt, 3 hr61%

S

Li Cl1)

2) HgCl2, H2O

O

OTIPS ;

Br2 (2 eq)

1) BnNH2, Pd2(dba)3, P(o-tolyl) NaOt-Bu

2) Pd-C, HCO2NH4, MeOH reflux

NHMe

OTIPS

3

O

MePentacyclic

compoundO

3) DIBAL, CH2Cl2 –10 °C

CO2EtTBSO

Ti(Oi-Pr)4

2 i-PrMgCl

Et2O

1) FeCl32) AcONa

OTBSO

C12H24O2Si

( racemic )

OCuN N O

t-Bu

t-Bu

toluenereflux

N

CO2Me

Cl cat Cu(bpy)ClClCH2CH2Clreflux, 48 h66%

1) 30% aq HCl reflux, 18 h

2) pH 13

"Olefin"

1) KOH, MeOH

85 °C 2) H3O+, CH2Cl2

ethylene, Na2CO3CCl4, 170 °C

AcO H OAc

H

AcO

NO

HN

Ph

NH2

NHN

O

PhMeO2C

MeO2C

Cl Cl Cl

O OH

OO

OO

H SPh

OMs

OH

CO2HMeO

2 days, 84%

2) dimethyl fumarate

170 °C, 8 h, 84%

1) DBU2)

DMADtoluene

PhO

NPMPSS

PMPN

OAc

OAcMe

OO

CO2Me

P(OEt)2O

Cl

OPhNMe

O OOEt

NMe

Ph

COOEtCl

Fukuyama Group - Group Meeting Problems

* Ti/graphite was prepared from

K + 8C(graphite) + TiCl3

15 eq

NCS, CCl4;MeOH

rt, 40 min

1) t-BuOK

EtCOCl –78 °C2) NaHMDS TBSCl –110 °C

Ph

O

PhO

+

AgNO3MeOH

5 °C, 20 min

1) 10% KOH MeOH-H2O, reflux2) (MeO)3P, EtOH, reflux3) MeSLi, DMF, 0 °C4) (HCHO)n, CSA, Na2SO4 MeCN, reflux

SeO2AcOH

∆

Bu3SnHAIBNbenzene

80 °C

A contains Se atom

Fukuyama Group - Group Meeting Problems

NH2

1) LHMDS (2.2 eq), THF; I22) Cu(OTf)2, CH2Cl23) LiOH, H2O

Ph Ph O

(2.0 eq)xylene

H

Ar

OPh

57 %

O

1) i-amyl nitrite*, HCl

Et2O, 5-15 °C, 1 hr2) NH3*, NaOCl*, NaOH

H2O, 10-20 °C, 1.5 hr 47% (2 steps)

3) hν, Pyrex

MeOH, 3 hr 69%

SO2MeO

OH

t-BuOK, t-BuOH; H+

30 %

SO2Me

OO

Me

CHOMe

NOMe

Me

N H N

N

OH

TsOH, PhH, reflux

CHO Me

n-BuLi, –78 °C;

–78 °C to rt

Ph CN

OH

NHPh

EtOOC HPh

OPh

BTAC: benzyltriethylammonium chloride

IO

C3H7

SmI2benzene-HMPA68%

C3H7Ph

OH

C3H7OHPh

2 : 1+

piperidine, H2O

rt, overnight69%

TMSCHN2, n-BuLi

DME, hexane;

silica gel64%

NO

t-Bu

ON

Ph

NOPh

O OO

OHO

Fukuyama Group - Group Meeting Problems

2) K2CO3, MeOH

3) PDC, CH2Cl24) heat, neat5) Bu3SnH, AIBN benzene-THF

1) TfOH, benzene, 0 °C;

NaOH aq (work up)

82 %2) Pd/C, H2

94 %

Ar = 3,4-(methylenedioxy)phenyl

1) LDA, THF, –78 °C2) HCl/Et2O;

ClCO2i-Bu, NMM

N-Cbz-Gly

3) TsOH, PhMe, ∆

NMM = N-methylmorpholine

1) –80 °C to rt2) NaHMDS;

Davis' oxaziridine3) LTA

MeOH-PhH

OO

O

OO

OMe

H

HH

O

OOO

H

p-TsOH

∆

1) MeMgBr2) POCl3, Pyr3) Pd(PPh3)4 PPh3

hν

OSiMe2t-Bu t-Bu

OLi

TBSOMeO2C

t-Bu CHO

NH

EtO

MeMe

I(OAc)2

MeMe

I

MeMe

ISiMe3

R H

O

NN

RMe

O

NO

NMe

Fukuyama Group - Group Meeting Problems

2) n-PrOH, reflux

2 h, 70%

3) N-methylpiperazine reflux, 4 h, 65%

R=2,4-chlorophenyl-H

O O

N H

CO2H

OI

Fukuyama Group - Group Meeting Problems

2) LiAlH4, THF reflux

3) Al(Oi-Pr)3 N-methyl-4-piperidone

toluene, reflux, Dean-Stark4) aq HF, MeCN

5) NaNO2, H2O, AcOH

CO (2 atm)[Rh(CO)2Cl]2 (5 mol %)

dioxane

60 °C, 24 h;

workup H3O+97%

1) n-BuLi,

THF, –100 °C;

–100 °C to reflux

2) H2O2, NaOH3) Co2(CO)8 DME

3) MeLi

4) Mn(OAc)3•H2O Cu(OAc)2 EtOH, rt

Fukuyama Group - Group Meeting Problems

MeOH, 60 °C95%

Cu(II) ; Copper trifluoroacetylacetonate

NaI, NaOHEtOH, reflux71%

CsF, MeCN4-Methoxybenzaldehyde

71%

1) DBU, 80%

2) TsOH, MeOH refux, quant

3) triphosgene, Et3N THF, –50 °C, 87%

+

NO2MeO2C

MeO2C N O

ON

OO

O O

MeHPhHN

H

A

COCl

N O

CN CO2MeO

OO

O NH

CO2Me

O

NO

Py, rt

4) NBS DMF 0°C;

Et3N;

A, rt

1) PhNCO, Et3N hexane, 50 °C;

2) hν, MeOH, 59%

O O

O

CHOOTBS

N NH

O

NN

TMS

TMS

O

ClPh

MePh

NEt2Me

3) tetralin, 205-208 °C, 52%

PPh3 (2 eq)CCl4 (2 eq)

Et3N (2 eq)

CH2Cl2reflux

1) RCOCl

CH2Cl22) TsCl (20 mol%)

Et3N, CH2Cl2

1) Br2, MeOH-ether –35 °C, 30 min, 73%

LDA; MeITHF–78 °C to rt68%

MeMgI, Et2Oreflux95%

N

SOEt

3) P(OMe)3 reflux

1) NaOEt, MeI2) conc HCl; NaOH3) MeLi

Me OMo(CO)5

NO2

NAc

CO2Me

BuO

OO

O

O

N2

CO2EtOAc

OHO

OHCOOH

OH

HO

Ph CO2HOH

O

CO2MeO

Br

Ph CF3O

OH

O

NH2PhS SnBu3

O

NH2AcO SPh

Fukuyama Group - Group Meeting Problems

3) LHMDS, AcCl THF, –78 °C4) butyl vinyl ether toluene, reflux

BSA = N,O-Bis(trimethylsilyl)acetamide

1) Rh2(OAc)4, solvent2) TFA, EtOH

quant (2 steps)

TFAA, PyPhH, 80 °C

t-BuOK t-BuOH-THF

70%

O3, NaHCO3MeOH-CH2Cl2–770 °C;

Ac2O, Et3N, DMAPbenzene, reflux

1) mCPBA (1 eq), CH2Cl2, rt, 86%

2) AcCl, CH2Cl2, 40 °C, 71%

Fukuyama Group - Group Meeting Problems

ArAr

Ar Ar

Sn(tpp)(ClO4)2 (3 mol%)CDCl3, 20 °C, 2 hr46%

OSArAr

S

S

=S

S

+

1) CHBr3 (>2 eq), t-BuOK

2) MeLi (2 eq), –78 °C3) H2, Pd/C Me

Hdioxane

100 °C

NBn

n-Bu

1)

CSA, CH2Cl2, 0 °C, 15 h2) CH3CHO, Al2O3, CH2Cl2

hν

H2SO4

CH3CN

N MeMe

NH

Me + BF4

BocNHNH2

HN NN

3) Cl3CCHO, toluene, reflux4) Oxone, K2CO3, H2O-CHCl3, 0 °C

Reagent A

1) A, CH2Cl22) TFA3) NIS (2.5 eq)

Ph

HO COPh

ClClO

O

2 eq PhP(SiMe3)2

CH3CN, –15 °C

MeOHreflux, 24 h OMe

OMeO

O

S N

CN

H3C CO2EtO

Si H SiMe2PhPhS

H

HO H SiMe2Ph

1) NaIO42) heat, PhH3) H2O2, KF KHCO3

Cl

OCl

Ph Ph

Ph Br

NMeO

hν

A

76%

HCl (g)MeOH;

I2acetone/H2O

PhMgBr (2.2 eq)THF–42 °C to rt

t-BuO2C

SPh PPh3 BF4

OO

O

NH2OH

Ph

N OO

aq glutaradehyde (2.5eq) pH3.5 , TolSO2Na ; ZnBr2

R : TolSO2

1) CH2N2 (ex.), CH2Cl22) mCPBA, CH2Cl2, – 10 °CCl

OH

Ph

Fukuyama Group - Group Meeting Problems

NO

Tf2O, DTBMPClCH2CH2Cl–20 to 65 °C;

OEt

OTDS

OMOM

CO2EtOMe

R = (CH2)2CO2H

1) 0.03 N HCl MeOH, rt

N

Cl

OMeO

Ph

Fukuyama Group - Group Meeting Problems

H

1) ex EtSH

BF3·Et2O, CH2Cl2, 0 °C2) AlCl3, CH2Cl2, 0 °C3) ex 1,3-cyclohexadiene AlCl3, CH2Cl2, 0 °CN

NN

H

MeO2C PhI(OAc)2

MeOH, 0 °C75%

PhMeO2C

CHCl3, reflux63%

Me

NN

N N

Ph Ph

OMe (OC)5Cr Ph

OHO

C 15 H 10 BrN 4 + •BBr –

O

N Ph

OArHN

NNaH, THF, reflux;

O O

CH3CN

NH2

1) 20 mol% Ni(cod)2

40 mol% PPh3, MVK ClCH2CH2Cl, rt, 18 hr 95%

2) Hg(OAc)2, H2O

40 °C, 40 hr;

NaCl, rt, 16 hr 86%

3) Pb(OAc)4 PhH, 80 °C, 1 hr 91%

4) K2CO3, EtOH

rt, 24 hr 65%

HO

OMeO

t-BuO

Ot-Bu

O

SO2PhO

TsN

SO2Ph

N

H

NOH

H

OOAc

OHAcO

Fukuyama Group - Group Meeting Problems

3) TsCl, Et3N 51% (3 steps)4) BF3•OEt2 76%

1) ClCO2Me

Na2CO3 THF, 80%

2) AcCl, pyridine 77%

3) NaH Pd(OAc)2, Ph3P DMF, 80 ~ 100 °C 56%

0 to 40 °C

2) SmI2, Pd(PPh3)4

THF

AcO

Me

H

HHH

OAcMeOO

Ph IOAcOAc

N

H

NTs

TfOMe2Si CO2 Me

TsO

OHH

H2, Pd(OH)2/CMeOH, rt, 7 days;

O

OH

2

1) hν

CHCl3, rt, 8 h2) PPh3

toluene, reflux, 3 h3) methyl propiolate toluene

140 °C, 12 h

Br

COOH

OOH

n-BuLi (1.1 eq)–20 °C;

DMF (~2.0 eq)–20 °C;

2) ClCO2Me, Na2CO3

CH2Cl2, rt, 84%

3) NaBH4, CeCl3 MeOH, 88%

CH2Cl2, rt 84% (95:5)2) NaN3, DMF3) SnCl2, H2O;

Boc2O, Na2CO3 83% (2 steps)

NHBoc

CO2Me

1) I2, EtOH-H2O 78%

2) Zn, THF3) CH2N2 87% (2 steps)

Amino acidderivative

OH 1) MOMCl, i-Pr2NEt

2) cat t-BuOK 3) n-BuLi

A, –78 °C, 2.5 h;

HCl/EtOH, 0 °CTHF, 75%

OHO

Br

DMF, MeTi(Oi-Pr)3

c-HexMgBr

THF, rt, 14 h63%

decaline, 220 °C, 1 h

90%

NN

O

N NPh

O

NMe2H

Me

MeR

OTIPS

OMe

MeR

OTIPSO

O OH OH HO

air, rt

R =

MeLi (1 eq)THF, –100 °C;

TFAA, –78 °C;

PhNH2, –15 °C

1) NaNHNH2 ether-THF, 0 °C, 2 h

2)

MgSO4, EtOH, rt, 12 h(68% in 2 steps)

3) triisopropylbenzene reflux, 5 h, 80%

MeO

ClO

MeO

CN

Hg(OTf)2, THF

rt, 30 min;

NaBH4, MeOH

0 °C to rt, 14 h47% (α:β = 2:1)

hν, pentane

4) TsOH benzene

reflux 85% in 2 steps

O

OHH

1) aq NaOH PhH, reflux, 3 hr;

CH2N2, Et2O 65-70%

2) tryptamine, MS4A

Et2O, reflux, 24 hr

3) MCPBA, CH2Cl2 –78 °C, 30 min 66% (2 steps)

4) hν

MeCN, quartz tube

6 hr, 60%

NON

BF3•OEt2

CH2Cl2–50 °C

SbCl5

CH2Cl2–50 °C

"tetrahydrofuran"

Bu

O

1) NH2OH•HCl Py-EtOH2) NaBH3CN MeOH, pH 3-4

toluene, reflux N

OBu

TiCl4

CH2Cl2–40 °C71%

OMe

O N2

OMe

OHMe

O N

PhCNNC

CO2Me

H

HOMe

O

·H

Hept Me

Sit-BuMe2

NOMeBrHept

Fukuyama Group - Group Meeting Problems

Py H

(4 eq) ,PhH;

PhCHO (1 eq)90%

(2 eq)

1) cat Ti(Oi-Pr)4

EtMgBr (2 eq) 95%

2) TMSOTf 2,6-lutidine

CH2Cl2, 88%

n-Bu3SnHcat AIBNbenzenereflux95%

NOBF4, CH3CN, –30 °C;

Br2, CCl472%

S

O2HN

NaH; cat CuClacryloyl chloridetoluene, rt, 23 h56%

Fukuyama Group - Group Meeting Problems

OO

compound

OO

O

OEtOEt

CpW(CO)3

TfOHEtOH-CH2Cl265%

1) (CO2H)2, 75%

2) NOBF4, LiCl

CH3CN, 47%

OH

Tungsten-containedethyl ester

Cl

Fukuyama Group - Group Meeting Problems

1) TIPSOTf, i-Pr2NEt

Et2O-Hex

0 °C to rt2) hυ benzene

N

OMe

1)

98%

2) t-BuNC

THF 85%

MeO

1) TFA THF-H2O 85%

2) MeOH

100 °C 92%

THF-DMSOrt

NBu

Cl Pd(PPh3)4

(1 mol%)THF, rt

N

ClBu

85%

Fukuyama Group - Group Meeting Problems

Pd(OH)2/C, H2MeOH

HN

HO OHHO

H

NH2

N OO

97%

S

NS

Me MeO CH2Br

SiMe3

MeMe

MeO CH2SMe

1) BuLi ether, –20 °C;

58%

2) MeOTf benzene, 0 °C 96%

3) CsF DMSO, rt;

aqNaOH, 68%

NMeO

MeO

NMeO

MeO

HOHC

I

1) Bu3SnTMS, CsF DMF, rt

(TMS)3SiHAIBN