有机化学官能团相互转化

5-f

H 3O

+

C=C-ORH 3O +

OCH 3

C=C-SR

Hg 2+ / CHHg 2+

3CN (aq)

SCH 33

O

5-g

a very common protecting group, deprotect back to ketone

OR OR H 3O + / solv (aq)OR H 3O + / solv (aq)OH OR

OH

SR

+SR Hg 2 / H3O +O O H 3O + / solv (aq)O O

H 3O +S 3S

Hg 2+ / H3O +

S

S

Hg 2+OEt H 3O H

C OEt OEt

RMgX / H3O +

OEt O

H

C OEt RMgX

OEt

R

H

5-h 1st alcohol

O R H

i. PCCii. PDC

OCH 3

AcO OAc

O Pfitzner-Moffatt oxidation

JOC, 1985, 50, 1332.

N OH

O

O

O

O Br

O DMSO

3H

60 %

Synth. Commun., 1986, 16, 1343.

O

2nd alcohol

R R

i. PCC

ii. PDC

ix. K2

O

1st alcohol

R OH

O R OH

PCC (pyridinium chlorochromate) (Py-HCl-CrO3)

most widely used

PDC (pyridinium dichormate)

(H2Cr 2O 7 + 2 Py)

use 1 - 1.2 eq.

. CrO 3

aldehyde

HCl

H

2

Cr 2O 7-2

Collins reagent: (CrO3 - 2 Py)Swern oxidation: (DMSO, oxalyl chloride, Et3N) 1. drawback: use 6 equivalent, a messy reactiondrawback: react at low TSynthesis, 1981, 165. 2. must be very dry, fire easily; purify by CaH23. an old oxidizing material, isolated by Collin.

JOC, 1977, 42, 1991.

Ag 2O:

1. a mild oxidizing agent

2. must be freshly prepared: NaOH into AgNO3 (aq)3. may involve surface change, react with CO2, light

5-i

5-i. 1O

O

Ph Ph

O

i. Corey approach: subtituted-quinone // H3O +ii. Watt approach

a. PhCHO // MCPBA // H3O + b. ArPhO // MCPBA // H3O + c. NBS // KOH // H3O +

// H3O +O

Ph Ph

NH 2

H 3O +O H Ph

O

NH 2

5-i. 2i. Et3N // H3O +

Nef reaction

Chem. Rev. 1955, 55, 137.

ii. TiCl3 / pH 1 or 6iii. SiO2 / NaOH // H3O +

McMurray reaction

pH 6: weak acid buffer, avoid interfere with ketal group

JACS, 1977, 99, 3861.

iv. LDA / MoO5-Py -v. NaOH // CH3vi. KMnO4 / KOH

5-j

indrect: change to RC-OH followed by oxidationdirect:

1. DMAPO / DBU / CH3CN 2. NaIO4 / DMF

a new method3. DMSO reagents:

i. DMSO / AgBF4ii. DMSO / ZnS

THL, 1974, 917. JACS, 2003, 68, 2480.

RCHBrMe

OH Br

Bull Soc. Jpn., 1981, 54, 2221.

O Br

RC(O)Me

OH O

Br R

DMSO / AgBF4- Me2S

R

O

5-k 1. SeO2

JCS, 1932, 1875.

2. DDQ / TFA.

O

3.

I

(3 eq.)O

OH O

Synthesis, 1979, 537.

Ph-F / DMSOa select oxidant

JACS, 2001, 123, 3183.

CH 3

CHO

C C

6-a RC CH

b RCH 2-SO 2Ph d C C

e RCH(CO2H)-CH 3g h O X

O

O

c C C

f -C(O)-CH3

6-a

i. n-BuLi / RX

n -BuLi: not MeLi, or t -BuLi, fire easilyRX: R-Br, R-TOS, RCHO, RC(O)R

ii. (Ph3P) 2PdCl 2, CuI, Et2NH / PhI

Cl

iii.

N Li

OMe

steric base, prevent Nu attackiv. CuI, NaI, Na2CO 3, R

C C CH 2Cl

6-b

n -BuLi / R'CHO // Ac2O // KOt Bu

i

CRR'=CHX

R C C H

R C C R' R C C H

R C C CHOH

R

R C C H

R C C Ph

THL, 1975, 4467.

R C C H

R C C Ar

Cl CH 2C C R'

R C C H

R

C

C

CH 2C

C

R'

Synthesis, 2000, 691.

sulfonic acid: PhSO3H; sulfinic acid: PhSO2H; sulfenic acid: PhSOH

6-c

JACS, 1975, 97, 891.

i. move to terminaluse: KAPA

2ii. protect - deprotect

use: Co (CO)8 // Fe(NO3) 3, EtOH

Fe(NO3) 3: weak oxidizing agent

6-d

use: i. Br2 / CCl4 // KOt Bu

ii. Br2 // KOH

Ph

Ph

Ph

Ph

JA CS, 1941, 63, 1180.

6-e

use: Pb(OAc)4, LiCl // KOt Bu // Br2/CCl4 // KOt in fact: convert to C=C firstly

6-f

i. NaBH4, H3O +, Br2, KOtBu

ii. NH2OH, NaNO2 / H2SO 4 // Ac2O / DMAP

O

N

N

iii. LDA, ClPO(OEt)2

O

DMAP:

4-N,N-D i m ethyl a minop y ridine

German invention, as acylating agent

CH 3

mixture of

Ac2O / DMAP:

LDA: Li N(iPr)2, ignored a long time, re-introduced by Michigan State U. became famous, appeared every week

6-g

THL, 1967, 3943.

use: TsNHNH2 / EtOH, heat

CH 3CH CH 2

(MVK)

3(l)

O

Robinson AnnulationO

6-h

LiNH 2 / NH3 (l)

use: LiNH / NH (l) / R-X

Cl

HO

236-i.

i. NaOEt (when X = Br)

ii. BuLi (when X = -OSO2CF 3)

O RX

R

JA CS, 1955, 77, 3293.JA CS, 1958, 80, 4599.

Ar

Br NaOEt

Ar C C Ar'

Ar' H Me OSO 2CF 3Ph

H

Me C C Ph

Me via:

Br Ph

C

via:

Ar Ar'

?

JOC, 1978, 43, 364.

C C

7-a CH-CX b CH-CH 7-a

C C C C C C C C C C c CX-CY d

X C

C

f g

C O C C

i C C j

C-OH

e -C(O)-CH3

h C CH

C

i. p-TSOH.H2O or CSAuse:

ii. weak acid: HOAc; HCO2H; H2C 2O 4use: heat

use: heat

OH Ph

(CO2H) 2 / benzene

applied for reactions: without rearrangement;

no regiosiomer

C Ph

minor

use base: DBN

C C 2

i. CH3I / Ag2ii. HCHO / HCO2227-b i. DDQii. chloronail

NC NC

O

Cl Cl Cl

Cl

O O

Cl Cl

MeO

OAc

2Se

N

MCPBA MeO OAc 2Me

mechanism:

Ph-Se-CN

:PBuPh-Se-PBu

3RCH 2CH 2-OH

MeO 22Me

MeO 2RCH 2CH 2-O-PBu

3

RCH=CH2

iii. Pd-C; or Ni; Pt, Rh

7-c

C

C

OR OR

i. CSCl2

/

OH OH

P ii. CSCl2 / P(OMe)3

C Br

C Br

i. Zn / acetone

ii. In / MeOHJCS.CC, 1998, 2113.

application: i. protect alkene: via Br2 // Zn

ii. purify compound

CCCCC 36 o C CCCC=C 31 o C CCCC C 148 o C

C C

OMs OMs C

C

NaI / Zn (Cu)

C via:

C OAc

AcO AcO

AcO

Br

O

Zn OAc OAc

OAc

O

OH I

POCl 3 / py // Sn

JOC, 1978, 43, 364.

C Br

C OAc

Zn / HOAc

7-

d

7-d.

i. WCl6 / RLiii. LiPPh2 / CH3I iii. Na

product retentionproduct inversion

Cl

Na O

(special structure):

R

H

R C C CH 2CH 2CH 2OH 7-d. use: (EtO)3P

S R 1

R 2

(EtO)3P

R 1

R 2

Synthesis , 1977, 1134.

7-

e

7-f

not

CO 2Me

O H CN

H 7-f. +Ph 3P CH CO 2Me

not

O

PPh 3+H C CO 2Me difficult to prepare

i. Wittig Reaction1953 discover(olefination reaction)ii. Phosphonate Wittig Reaction (Horner-Emmons Modification)iii. Silyl Wittig Reaction (Peterson Reaction)

THL, 1981, 2751. JOC, 1968, 33, 780.

use: Ph3P-CHR' use: (RO)2PO-CHR'

via : betaine, oxaphosphetane (NMR)RO = MeO-, EtO-

+Ph 3P CH Et

CN

3+O

Et

expensive

unstable ylid gives cis (Z)stable ylid gives trans (E)

water soluble, removed by extraction

(comparison: O=PPh3 highly soluble in organic solvent)

+

3

Synthesis, 1984, 384. Me 3SiCHR -Li +

Ph 3SiCH 2-Li + === Ph3SiCH 2Br + n-BuLi (exchange)Me 3SiC -H-MgBr === Me3SiCH 2Cl + Mg (metal reduction)

Ph 3SiC -HCH 2Ph 3SiCH=CH2 + PhLi (addition to vinylsilane)Me 3SiC -HCO 2Et === Me3SiCH 2CO 2Et + Li (metalation)Me 3SiCH=PPh3 === Me3SiCH 2PPh 3+ X- + KH

not good for Ph3P=CH2function as base:

iv. CH2(ZnI)2

Synlett, 1988, 12, 1369.

CH 2(ZnI)22

v. CH2CHBr 2, Sm, SnI2 / CrCl3, THF

Chem. Lett, 1995, 259.

R

O

O R

vi. Sulfoximide (Johnson C.)vii. Grignard reagent:

use:Ph CH 2Li

// Al (Hg)

1. TMSCH2MgCl

Me

use: TMSCH2MgCl

THL, 1988, 4339. THL, 1973, 3497.

2. NaOAc, AcOH

via:

H R

R'

3

methylenation

advantages over the Wittig:

1. by-products are more easily removed, 2. reaction suffers less from steric effects.

7-f. 2

i. use: N2H 4 / H2S / Pb(OAc)4

ii. McMurry Coupling

not for Wittig, ylid unstable

N O

O

2H 4

1. HO

O

1. H2. Pb(OAc)2S

. Pb(OAc)2S

424

P(OEt)TiCl 33S

N S

N Zn-Cu

N

N

N S

O O

via:

N N

S

O

TiCl 3-LiAlH 4 / THFJACS, 1974, 96, 4706.

TiCl 3 / MgBASF, 1973, 2147. TiCl 4 / ZnTiCl / KChem. Lett, 1973, 1041. 4JOC, 1978, 43, 3253.

7-g

not use H2 / Pt: might convert to alkane

form trans alkene:

i. Li / NH3; or other IA metalsii. Li / EtNH2

iii. LiAlH4 / THF

form cis alkene:

i. H2 / Ni2B (P-2 catalyst)

ii. H2 / Pd-CaCO3 (Lindlar catalyst)iii. H2 / Pd-BaSO4

iv. B2H 6 / HOAc (Diborane)v. N2H 2

vi. HCHO / Pd-C / Et3N

7-h

all form trans alkene:

H

C CH

R H

i. R2BH / Br-CN (hydroboration)

ii. DIBAL / n-BuLi / CH3I (hydroalumination)

iii. Cp2ZrClH / RX (hydrozirconation)

7-i application: protecting group

not for

C C double bond might move

via dihalide

C=C

C C X X

C=Cvia halohydrinvia epoxide

C=C

C=C

C C H X O C

C C C

C=CC=CC=C

via diene-olefin additionvia diradical

Ph

Ph

JA CS, 1998, 100, 877.

7-j

N N N 3

MnO 2 / Ph3P CH 3 Br- / MTBD

MTBD

C-X

8-a C-OH b C-NH 2

8-a 8-a. 1

c C=Od C(O)Ze C-H

O O

Chem. Rev., 1996, 96, 1737.N F S

JOC, 1993, 58, 3800.O O

1.

CHCl 2O

N

1. CF3CHFCF 2NEt 2OH 2. HOAc / i PrOH

2. F3S-NEt 2(DAST)$ 500 / 125 g

CH 3

CH 3S

F

2

8-a. 2

8-a. 3

CH I

JCS, 1905, 87, 1592.

8-a. 4

1. HI

CH OH

PBr 3

2. PI3

2. PPh3 / I2

$ 35 / 1000 g$ 65 / 500 g$ 80 / 50 g

3. TsCl / C6PBr 3PI 3

8-b

NaNO2 / HCl / HBF4 /

8-c CF2Br 2 / Zn

8-d

8-d. 8-d. 2

F

JCS.PT I, 1993, 335.

O

Cl

Cl

RhCl(PPh3)

3

O R

OH

1. AgNO3/KOHR Br Chem Rev., 1956, 56, 219.

Ber. 1942, 75

, 296.

2

8-e

i.

N O F

8-e.

1

Chem. Rev., 1996, 96, 1737.

PhCH 2C(O)CH3

+PhCHC(O)CH3

F

S

ii. F-TEDA-BF 4iii. iv. v.

JCS.CC, 1994, 149.

JOC, 1988, 53, 2803.

R

F

1.4-1.6 V

R

33

90 %

1. regioselective fluorination at the more substituted positions2. electrophilic in nature

F 2-N 2 / CFCl3-CHCl 3

HF / electrolysis

already industrilizedNF 3O / TBAH / CH3CN

R = CH3CO, COCF3, CCl3, NO2 THL, 2003, 44, 2799.

TBHA: Tetrabutylammoniumhydroxide

8-e. 2

X = Cl, Br, I

O

O

R H

R 2

R 3

Mg(ClO4) 2

R 1

X

R 2

R 3

NBX:

N

X

O O

O

NBX / Mg(ClO4)

2

JOC, 2002, 67, 7429.

X = Cl, Br, I

8-e. 3

I 2 / HNO3

JACS, 1917, 39

, 437.

I / HNOI

86 %

C-CH 3

9-a C-X 9-a

CH 2Cl 2

98 %

(CH3) 3Al

bridgehead methylation

Organomet. Chem. Rev., 1996, 4, 47.

4-e

reductive amination!

1. RNH2 // NaBH3CN

most general

2. Me3SiN 3 // LiAlH4

3. NH3 (excess) // RaNi / H2

4. PhNHNH2 // Al (Hg)

via: hydrazone

5. NH4+HCO 2-Leuckart reaction

6. RNH2 / n -Bu 2SnClH / HMPA

Synthesis, 2000, 789.

4-f

C=C

C-C-NH 2

B 2H 6 / NH2Cl B 2H 6 / H2NO B 2H 6 / H2NOSO 3H

C-C-NHCOCH 3

CH 3CN / H3O +

4-g

R C NH 2R C NH 2R'

AlH 3 / THFR'Li // NaBH4

Br

TH, 1989, 30, 5137.JOC, 1993, 58, 4313.JOC, 1987, 52, 3901.TH, 1989, 30, 5139.

1. LiAlH4

2. NaBH3(OCOR)

3. B2H 6

4. Et3O + BF4- // NaBH45. P4S 10 // RaNi

C N

AlH 3Br NH 2

JOC, 2000, 65, 8152.

4-g.a form 4-g.b form

R'MgX // NaBH4R'MgX // Li/NH3(l)R' 2CuLi // NaBH4

R C N

R R'

C NH 2

4-h

4-i

4-i. 2NH 2O R

NH 2

PhI(OAc)O R

N

I

PhI(OAc)23R

NH

O OCH 3

JOC, 1993, 58, 2478.

CH 3OH

O

R NH OCH 3

RCH NH 2

PhI(OAc)2 // KOH / CH3OH

Ph OAc

R

N C O

C=O

5-a C=Og C(OR)

2d C C b C=Se C N C(SR)

2c C=N-OHf C=C-ORh C-OH C=N-HC=C-SR5-a

O R

CR

i C-NH 2

C-NO 2j C-Br k C-H

O

R

CH 2O

4

-

i. via: α-CO 2H

SOCl CrO Zn

H 3O +

23O

R

ii. via: α-haloketone

iii. via: aldol process

PhCHO

NaBH 3

H 3O +

O

HgCl 3O

R

CH 2

R

O

24

R

CH 2

R

iv. via: thioenol ether

O R

CH 2R

KOtBu

v. via: epoxysilane

O R

CH 2R

TsNHNH 2

MeLi

TMSCl MCPBA LAH

drawback: require simple structure, use many powerful agents: MeLi, LAH, MCPBA

5-b i. hydrolysis

ii. MCPBA

5-c 5-c.1

i. RaNiC=N-OH

ii. TiCl3

iii. KMnO4 / Al2O 3THL, 2001, 42, 4775.

5-c.2

C=N-H

H 3O +

JOC, 1972, 37, 2138.

5-d

Hg 2+ / H2O HgSO 4 / H2O / H2O

5-e

N

O

-CH 2-C H

R -CH 2-C 5-e.1

1. DIBAL / H3O +

2. HCl./ SnCl2 / Et2O 3.

H O +

Stenphen reduction

mostly for

J.Org.Syn, 1925, 3, 1874.

O

5-e.2

R --C H R' R --C 5-e.3

R"

R' X / n -BuLi

OH OH

CH 3I R''MgBr H 3O +

3

4-e

reductive amination!

1. RNH2 // NaBH3CN

most general

2. Me3SiN 3 // LiAlH4

3. NH3 (excess) // RaNi / H2

4. PhNHNH2 // Al (Hg)

via: hydrazone

5. NH4+HCO 2-Leuckart reaction

6. RNH2 / n -Bu 2SnClH / HMPA

Synthesis, 2000, 789.

4-f

C=C

C-C-NH 2

B 2H 6 / NH2Cl B 2H 6 / H2NO B 2H 6 / H2NOSO 3H

C-C-NHCOCH 3

CH 3CN / H3O +

4-g

R C NH 2R C NH 2R'

AlH 3 / THFR'Li // NaBH4

Br

TH, 1989, 30, 5137.JOC, 1993, 58, 4313.JOC, 1987, 52, 3901.TH, 1989, 30, 5139.

1. LiAlH4

2. NaBH3(OCOR)

3. B2H 6

4. Et3O + BF4- // NaBH45. P4S 10 // RaNi

C N

AlH 3Br NH 2

JOC, 2000, 65, 8152.

4-g.a form 4-g.b form

R'MgX // NaBH4R'MgX // Li/NH3(l)R' 2CuLi // NaBH4

R C N

R R'

C NH 2

4-h

4-i

4-i. 2NH 2O R

NH 2

PhI(OAc)O R

N

I

PhI(OAc)23R

NH

O OCH 3

JOC, 1993, 58, 2478.

CH 3OH

O

R NH OCH 3

RCH NH 2

PhI(OAc)2 // KOH / CH3OH

Ph OAc

R

N C O

C=O

5-a C=Og C(OR)

2d C C b C=Se C N C(SR)

2c C=N-OHf C=C-ORh C-OH C=N-HC=C-SR5-a

O R

CR

i C-NH 2

C-NO 2j C-Br k C-H

O

R

CH 2O

4

-

i. via: α-CO 2H

SOCl CrO Zn

H 3O +

23O

R

ii. via: α-haloketone

iii. via: aldol process

PhCHO

NaBH 3

H 3O +

O

HgCl 3O

R

CH 2

R

O

24

R

CH 2

R

iv. via: thioenol ether

O R

CH 2R

KOtBu

v. via: epoxysilane

O R

CH 2R

TsNHNH 2

MeLi

TMSCl MCPBA LAH

drawback: require simple structure, use many powerful agents: MeLi, LAH, MCPBA

5-b i. hydrolysis

ii. MCPBA

5-c 5-c.1

i. RaNiC=N-OH

ii. TiCl3

iii. KMnO4 / Al2O 3THL, 2001, 42, 4775.

5-c.2

C=N-H

H 3O +

JOC, 1972, 37, 2138.

5-d

Hg 2+ / H2O HgSO 4 / H2O / H2O

5-e

N

O

-CH 2-C H

R -CH 2-C 5-e.1

1. DIBAL / H3O +

2. HCl./ SnCl2 / Et2O 3.

H O +

Stenphen reduction

mostly for

J.Org.Syn, 1925, 3, 1874.

O

5-e.2

R --C H R' R --C 5-e.3

R"

R' X / n -BuLi

OH OH

CH 3I R''MgBr H 3O +

3

5-f

H 3O

+

C=C-ORH 3O +

3

C=C-SR

2+ / CH

Hg 2+

Hg 3CN (aq)

SCH 33

O

5-g

a very common protecting group, deprotect back to ketone

OR OR H 3O + / solv (aq)OR H 3O + / solv (aq)OH OR

OH

SR

+SR Hg 2 / H3O +O O H 3O + / solv (aq)O O

H 3

O +

3Hg 2+ / H3O +

S

S

Hg 2+OEt H 3O H

C OEt OEt

RMgX / H3O +

OEt O

H

C OEt RMgX

OEt

R

C

H

5-h 1st alcohol

O R H

i. PCCii. PDC

OCH 3

AcO OAc

O Pfitzner-Moffatt oxidation

JOC, 1985, 50, 1332.

N OH

O

O

O

O Br

O DMSO

3H

60 %

Synth. Commun., 1986, 16, 1343.

O

2nd alcohol

R R

i. PCC

ii. PDC

ix. K2

O

1st alcohol

R OH

O R OH

PCC (pyridinium chlorochromate) (Py-HCl-CrO3)

most widely used

PDC (pyridinium dichormate)

(H2Cr 2O 7 + 2 Py)

use 1 - 1.2 eq.

. CrO 3

aldehyde

HCl

H

2

Cr 2O 7-2

Collins reagent: (CrO3 - 2 Py)Swern oxidation: (DMSO, oxalyl chloride, Et3N) 1. drawback: use 6 equivalent, a messy reactiondrawback: react at low TSynthesis, 1981, 165. 2. must be very dry, fire easily; purify by CaH23. an old oxidizing material, isolated by Collin.

JOC, 1977, 42, 1991.

Ag 2O:

1. a mild oxidizing agent

2. must be freshly prepared: NaOH into AgNO3 (aq)3. may involve surface change, react with CO2, light

5-i

5-i. 1O

O

Ph Ph

O

i. Corey approach: subtituted-quinone // H3O +ii. Watt approach

a. PhCHO // MCPBA // H3O + b. ArPhO // MCPBA // H3O + c. NBS // KOH // H3O +

// H3O +O

Ph Ph

NH 2

H 3O +O H Ph

O

NH 2

5-i. 2i. Et3N // H3O +

Nef reaction

Chem. Rev. 1955, 55, 137.

ii. TiCl3 / pH 1 or 6iii. SiO2 / NaOH // H3O +

McMurray reaction

pH 6: weak acid buffer, avoid interfere with ketal group

JACS, 1977, 99, 3861.

iv. LDA / MoO5-Py -v. NaOH // CH3vi. KMnO4 / KOH

5-j

indrect: change to RC-OH followed by oxidationdirect:

1. DMAPO / DBU / CH3CN 2. NaIO4 / DMF

a new method3. DMSO reagents:

i. DMSO / AgBF4ii. DMSO / ZnS

THL, 1974, 917. JACS, 2003, 68, 2480.

RCHBrMe

OH Br

Bull Soc. Jpn., 1981, 54, 2221.

O Br

RC(O)Me

OH O

Br R

DMSO / AgBF4- Me2S

R

O

5-k 1. SeO2

JCS, 1932, 1875.

2. DDQ / TFA.

O

3.

I

(3 eq.)O

OH O

Synthesis, 1979, 537.

Ph-F / DMSOa select oxidant

JACS, 2001, 123, 3183.

CH 3

CHO

C C

6-a RC CH

b RCH 2-SO 2Ph d C C

e RCH(CO2H)-CH 3g h O X

O

O

c C C

f -C(O)-CH3

6-a

i. n-BuLi / RX

n -BuLi: not MeLi, or t -BuLi, fire easilyRX: R-Br, R-TOS, RCHO, RC(O)R

ii. (Ph3P) 2PdCl 2, CuI, Et2NH / PhI

Cl

iii.

N Li

OMe

steric base, prevent Nu attackiv. CuI, NaI, Na2CO 3, R

C C CH 2Cl

6-b

n -BuLi / R'CHO // Ac2O // KOt Bu

i

CRR'=CHX

R C C H

R C C R' R C C H

R C C CHOH

R

R C C H

R C C Ph

THL, 1975, 4467.

R C C H

R C C Ar

Cl CH 2C C R'

R C C H

R

C

C

CH 2C

C

R'

Synthesis, 2000, 691.

sulfonic acid: PhSO3H; sulfinic acid: PhSO2H; sulfenic acid: PhSOH

6-c

JACS, 1975, 97, 891.

i. move to terminaluse: KAPA

2ii. protect - deprotect

use: Co (CO)8 // Fe(NO3) 3, EtOH

Fe(NO3) 3: weak oxidizing agent

6-d

use: i. Br2 / CCl4 // KOt Bu

ii. Br2 // KOH

Ph

Ph

Ph

Ph

JA CS, 1941, 63, 1180.

6-e

use: Pb(OAc)4, LiCl // KOt Bu // Br2/CCl4 // KOt in fact: convert to C=C firstly

6-f

i. NaBH4, H3O +, Br2, KOtBu

ii. NH2OH, NaNO2 / H2SO 4 // Ac2O / DMAP

O

N

N

iii. LDA, ClPO(OEt)2

O

DMAP:

4-N,N-D i m ethyl a minop y ridine

German invention, as acylating agent

CH 3

mixture of

Ac2O / DMAP:

LDA: Li N(iPr)2, ignored a long time, re-introduced by Michigan State U. became famous, appeared every week

6-g

THL, 1967, 3943.

use: TsNHNH2 / EtOH, heat

CH 3CH CH 2

(MVK)

3(l)

O

Robinson AnnulationO

6-h

LiNH 2 / NH3 (l)

use: LiNH / NH (l) / R-X

Cl

236-i.

i. NaOEt (when X = Br)

ii. BuLi (when X = -OSO2CF 3)

O R

HO

JA CS, 1955, 77, 3293.JA CS, 1958, 80, 4599.

Ar

Br NaOEt

Ar C C Ar'

Ar' H

Me OSO 2CF 3BuLi

Ph

H

Me C C Ph

Me

via:

Ar Br

Ph

C

via:

Ar'

?

JOC, 1978, 43, 364.

C C

7-a CH-CX b CH-CH 7-a

C C C C C C C C C C c CX-CY d

X C

C

f g

C O C C

i C C j

C-OH

e -C(O)-CH3

h C CH

C

i. p-TSOH.H2O or CSAuse:

ii. weak acid: HOAc; HCO2H; H2C 2O 4use: heat

use: heat

OH Ph

(CO2H) 2 / benzene

applied for reactions: without rearrangement;

no regiosiomer

C Ph

minor

use base: DBN

C C 2

i. CH3I / Ag2ii. HCHO / HCO2227-b i. DDQii. chloronail

NC NC

O

Cl Cl Cl

Cl

O O

Cl Cl

MeO

OAc

2Se

N

MCPBA MeO OAc 2Me

mechanism:

Ph-Se-CN

:PBuPh-Se-PBu

3RCH 2CH 2-OH

MeO 22Me

MeO 2RCH 2CH 2-O-PBu

3

RCH=CH2

iii. Pd-C; or Ni; Pt, Rh

7-c

C

C

OR OR

i. CSCl2

/

OH OH

P ii. CSCl2 / P(OMe)3

C Br

C Br

i. Zn / acetone

ii. In / MeOHJCS.CC, 1998, 2113.

application: i. protect alkene: via Br2 // Zn

ii. purify compound

CCCCC 36 o C CCCC=C 31 o C CCCC C 148 o C

C C

OMs OMs C

C

NaI / Zn (Cu)

C via:

C OAc

AcO AcO

AcO

Br

O

Zn OAc OAc

OAc

O

OH I

POCl 3 / py // Sn

JOC, 1978, 43, 364.

C Br

C OAc

Zn / HOAc

7-

d

7-d.

i. WCl6 / RLiii. LiPPh2 / CH3I iii. Na

product retentionproduct inversion

Cl

Na O

(special structure):

R

H

R C C CH 2CH 2CH 2OH 7-d. use: (EtO)3P

S R 1

R 2

(EtO)3P

R 1

R 2

Synthesis , 1977, 1134.

7-

e

7-f

not

CO 2Me

O H CN

H 7-f. +Ph 3P CH CO 2Me

not

O

PPh 3+H C CO 2Me difficult to prepare

i. Wittig Reaction1953 discover(olefination reaction)ii. Phosphonate Wittig Reaction (Horner-Emmons Modification)iii. Silyl Wittig Reaction (Peterson Reaction)

THL, 1981, 2751. JOC, 1968, 33, 780.

use: Ph3P-CHR' use: (RO)2PO-CHR'

via : betaine, oxaphosphetane (NMR)RO = MeO-, EtO-

+Ph 3P CH Et

CN

3+O

Et

expensive

unstable ylid gives cis (Z)stable ylid gives trans (E)

water soluble, removed by extraction

(comparison: O=PPh3 highly soluble in organic solvent)

+

3

Synthesis, 1984, 384. Me 3SiCHR -Li +

Ph 3SiCH 2-Li + === Ph3SiCH 2Br + n-BuLi (exchange)Me 3SiC -H-MgBr === Me3SiCH 2Cl + Mg (metal reduction)

Ph 3SiC -HCH 2Ph 3SiCH=CH2 + PhLi (addition to vinylsilane)Me 3SiC -HCO 2Et === Me3SiCH 2CO 2Et + Li (metalation)Me 3SiCH=PPh3 === Me3SiCH 2PPh 3+ X- + KH

not good for Ph3P=CH2function as base:

iv. CH2(ZnI)2

Synlett, 1988, 12, 1369.

CH 2(ZnI)22

v. CH2CHBr 2, Sm, SnI2 / CrCl3, THF

Chem. Lett, 1995, 259.

R

O

O R

vi. Sulfoximide (Johnson C.)vii. Grignard reagent:

use:Ph CH 2Li

// Al (Hg)

1. TMSCH2MgCl

Me

use: TMSCH2MgCl

THL, 1988, 4339. THL, 1973, 3497.

2. NaOAc, AcOH

via:

H R

R'

3

methylenation

advantages over the Wittig:

1. by-products are more easily removed, 2. reaction suffers less from steric effects.

7-f. 2

i. use: N2H 4 / H2S / Pb(OAc)4

ii. McMurry Coupling

not for Wittig, ylid unstable

N O

O

2H 4

1. HO

O

1. H2. Pb(OAc)2S

. Pb(OAc)2S

424

P(OEt)TiCl 33S

N S

N Zn-Cu

N

N

N S

O O

via:

N N

S

O

TiCl 3-LiAlH 4 / THFJACS, 1974, 96, 4706.

TiCl 3 / MgBASF, 1973, 2147. TiCl 4 / ZnTiCl / KChem. Lett, 1973, 1041. 4JOC, 1978, 43, 3253.

7-g

not use H2 / Pt: might convert to alkane

form trans alkene:

i. Li / NH3; or other IA metalsii. Li / EtNH2

iii. LiAlH4 / THF

form cis alkene:

i. H2 / Ni2B (P-2 catalyst)

ii. H2 / Pd-CaCO3 (Lindlar catalyst)iii. H2 / Pd-BaSO4

iv. B2H 6 / HOAc (Diborane)v. N2H 2

vi. HCHO / Pd-C / Et3N

7-h

all form trans alkene:

H

C CH

R H

i. R2BH / Br-CN (hydroboration)

ii. DIBAL / n-BuLi / CH3I (hydroalumination)

iii. Cp2ZrClH / RX (hydrozirconation)

7-i application: protecting group

not for

C C double bond might move

via dihalide

C=C

C C X X

C=Cvia halohydrinvia epoxide

C=C

C=C

C C H X O C

C C C

C=CC=CC=C

via diene-olefin additionvia diradical

Ph

Ph

JA CS, 1998, 100, 877.

7-j

N N N 3

MnO 2 / Ph3P CH 3 Br- / MTBD

MTBD

C-X

8-a C-OH b C-NH 2

8-a 8-a. 1

c C=Od C(O)Ze C-H

O O

Chem. Rev., 1996, 96, 1737.N F S

JOC, 1993, 58, 3800.O O

1.

CHCl 2O

N

1. CF3CHFCF 2NEt 2OH 2. HOAc / i PrOH

2. F3S-NEt 2(DAST)$ 500 / 125 g

CH 3

CH 3S

F

2

8-a. 2

8-a. 3

CH I

JCS, 1905, 87, 1592.

8-a. 4

1. HI

CH OH

PBr 3

2. PI3

2. PPh3 / I2

$ 35 / 1000 g$ 65 / 500 g$ 80 / 50 g

3. TsCl / C6PBr 3PI 3

8-b

NaNO2 / HCl / HBF4 /

8-c CF2Br 2 / Zn

8-d

8-d. 8-d. 2

F

JCS.PT I, 1993, 335.

O

Cl

Cl

RhCl(PPh3)

3

O R

OH

1. AgNO3/KOHR Br Chem Rev., 1956, 56, 219.

Ber. 1942, 75

, 296.

2

8-e

i.

N O F

8-e.

1

Chem. Rev., 1996, 96, 1737.

PhCH 2C(O)CH3

+

PhCHC(O)CH3

F

S

O

ii. F-TEDA-BF 4iii. iv. v.

JCS.CC, 1994, 149.

JOC, 1988, 53, 2803.

R

F

1.4-1.6 V

R

F -N 33

adamantane

90 %

1. regioselective fluorination at the more substituted positions2. electrophilic in nature

F 2-N 2 / CFCl3-CHCl 3

HF / electrolysis

already industrilizedNF 3O / TBAH / CH3CN

R = CH3CO, COCF3, CCl3, NO2 THL, 2003, 44, 2799.

TBHA: Tetrabutylammoniumhydroxide

8-e. 2

X = Cl, Br, I

O

O

R H R 2

R 3

Mg(ClO4) 2

R 1

X R 2

R 3

NBX:

N X

O O

O

NBX / Mg(ClO4) 2

JOC, 2002, 67, 7429.

X = Cl, Br, I

8-e. 3

I 2 / HNO3

JACS, 1917, 39

, 437.

I / HNOI

86 %

C-CH 3

9-a C-X 9-a

(CH3) 3

Al

CH 2Cl 2

98 %

bridgehead methylation

Organomet. Chem. Rev., 1996, 4, 47.

5-f

H 3O

+

C=C-ORH 3O +

OCH 3

C=C-SR

Hg 2+ / CHHg 2+

3CN (aq)

SCH 33

O

5-g

a very common protecting group, deprotect back to ketone

OR OR H 3O + / solv (aq)OR H 3O + / solv (aq)OH OR

OH

SR

+SR Hg 2 / H3O +O O H 3O + / solv (aq)O O

H 3O +S 3S

Hg 2+ / H3O +

S

S

Hg 2+OEt H 3O H

C OEt OEt

RMgX / H3O +

OEt O

H

C OEt RMgX

OEt

R

H

5-h 1st alcohol

O R H

i. PCCii. PDC

OCH 3

AcO OAc

O Pfitzner-Moffatt oxidation

JOC, 1985, 50, 1332.

N OH

O

O

O

O Br

O DMSO

3H

60 %

Synth. Commun., 1986, 16, 1343.

O

2nd alcohol

R R

i. PCC

ii. PDC

ix. K2

O

1st alcohol

R OH

O R OH

PCC (pyridinium chlorochromate) (Py-HCl-CrO3)

most widely used

PDC (pyridinium dichormate)

(H2Cr 2O 7 + 2 Py)

use 1 - 1.2 eq.

. CrO 3

aldehyde

HCl

H

2

Cr 2O 7-2

Collins reagent: (CrO3 - 2 Py)Swern oxidation: (DMSO, oxalyl chloride, Et3N) 1. drawback: use 6 equivalent, a messy reactiondrawback: react at low TSynthesis, 1981, 165. 2. must be very dry, fire easily; purify by CaH23. an old oxidizing material, isolated by Collin.

JOC, 1977, 42, 1991.

Ag 2O:

1. a mild oxidizing agent

2. must be freshly prepared: NaOH into AgNO3 (aq)3. may involve surface change, react with CO2, light

5-i

5-i. 1O

O

Ph Ph

O

i. Corey approach: subtituted-quinone // H3O +ii. Watt approach

a. PhCHO // MCPBA // H3O + b. ArPhO // MCPBA // H3O + c. NBS // KOH // H3O +

// H3O +O

Ph Ph

NH 2

H 3O +O H Ph

O

NH 2

5-i. 2i. Et3N // H3O +

Nef reaction

Chem. Rev. 1955, 55, 137.

ii. TiCl3 / pH 1 or 6iii. SiO2 / NaOH // H3O +

McMurray reaction

pH 6: weak acid buffer, avoid interfere with ketal group

JACS, 1977, 99, 3861.

iv. LDA / MoO5-Py -v. NaOH // CH3vi. KMnO4 / KOH

5-j

indrect: change to RC-OH followed by oxidationdirect:

1. DMAPO / DBU / CH3CN 2. NaIO4 / DMF

a new method3. DMSO reagents:

i. DMSO / AgBF4ii. DMSO / ZnS

THL, 1974, 917. JACS, 2003, 68, 2480.

RCHBrMe

OH Br

Bull Soc. Jpn., 1981, 54, 2221.

O Br

RC(O)Me

OH O

Br R

DMSO / AgBF4- Me2S

R

O

5-k 1. SeO2

JCS, 1932, 1875.

2. DDQ / TFA.

O

3.

I

(3 eq.)O

OH O

Synthesis, 1979, 537.

Ph-F / DMSOa select oxidant

JACS, 2001, 123, 3183.

CH 3

CHO

C C

6-a RC CH

b RCH 2-SO 2Ph d C C

e RCH(CO2H)-CH 3g h O X

O

O

c C C

f -C(O)-CH3

6-a

i. n-BuLi / RX

n -BuLi: not MeLi, or t -BuLi, fire easilyRX: R-Br, R-TOS, RCHO, RC(O)R

ii. (Ph3P) 2PdCl 2, CuI, Et2NH / PhI

Cl

iii.

N Li

OMe

steric base, prevent Nu attackiv. CuI, NaI, Na2CO 3, R

C C CH 2Cl

6-b

n -BuLi / R'CHO // Ac2O // KOt Bu

i

CRR'=CHX

R C C H

R C C R' R C C H

R C C CHOH

R

R C C H

R C C Ph

THL, 1975, 4467.

R C C H

R C C Ar

Cl CH 2C C R'

R C C H

R

C

C

CH 2C

C

R'

Synthesis, 2000, 691.

sulfonic acid: PhSO3H; sulfinic acid: PhSO2H; sulfenic acid: PhSOH

6-c

JACS, 1975, 97, 891.

i. move to terminaluse: KAPA

2ii. protect - deprotect

use: Co (CO)8 // Fe(NO3) 3, EtOH

Fe(NO3) 3: weak oxidizing agent

6-d

use: i. Br2 / CCl4 // KOt Bu

ii. Br2 // KOH

Ph

Ph

Ph

Ph

JA CS, 1941, 63, 1180.

6-e

use: Pb(OAc)4, LiCl // KOt Bu // Br2/CCl4 // KOt in fact: convert to C=C firstly

6-f

i. NaBH4, H3O +, Br2, KOtBu

ii. NH2OH, NaNO2 / H2SO 4 // Ac2O / DMAP

O

N

N

iii. LDA, ClPO(OEt)2

O

DMAP:

4-N,N-D i m ethyl a minop y ridine

German invention, as acylating agent

CH 3

mixture of

Ac2O / DMAP:

LDA: Li N(iPr)2, ignored a long time, re-introduced by Michigan State U. became famous, appeared every week

6-g

THL, 1967, 3943.

use: TsNHNH2 / EtOH, heat

CH 3CH CH 2

(MVK)

3(l)

O

Robinson AnnulationO

6-h

LiNH 2 / NH3 (l)

use: LiNH / NH (l) / R-X

Cl

HO

236-i.

i. NaOEt (when X = Br)

ii. BuLi (when X = -OSO2CF 3)

O RX

R

JA CS, 1955, 77, 3293.JA CS, 1958, 80, 4599.

Ar

Br NaOEt

Ar C C Ar'

Ar' H Me OSO 2CF 3Ph

H

Me C C Ph

Me via:

Br Ph

C

via:

Ar Ar'

?

JOC, 1978, 43, 364.

C C

7-a CH-CX b CH-CH 7-a

C C C C C C C C C C c CX-CY d

X C

C

f g

C O C C

i C C j

C-OH

e -C(O)-CH3

h C CH

C

i. p-TSOH.H2O or CSAuse:

ii. weak acid: HOAc; HCO2H; H2C 2O 4use: heat

use: heat

OH Ph

(CO2H) 2 / benzene

applied for reactions: without rearrangement;

no regiosiomer

C Ph

minor

use base: DBN

C C 2

i. CH3I / Ag2ii. HCHO / HCO2227-b i. DDQii. chloronail

NC NC

O

Cl Cl Cl

Cl

O O

Cl Cl

MeO

OAc

2Se

N

MCPBA MeO OAc 2Me

mechanism:

Ph-Se-CN

:PBuPh-Se-PBu

3RCH 2CH 2-OH

MeO 22Me

MeO 2RCH 2CH 2-O-PBu

3

RCH=CH2

iii. Pd-C; or Ni; Pt, Rh

7-c

C

C

OR OR

i. CSCl2

/

OH OH

P ii. CSCl2 / P(OMe)3

C Br

C Br

i. Zn / acetone

ii. In / MeOHJCS.CC, 1998, 2113.

application: i. protect alkene: via Br2 // Zn

ii. purify compound

CCCCC 36 o C CCCC=C 31 o C CCCC C 148 o C

C C

OMs OMs C

C

NaI / Zn (Cu)

C via:

C OAc

AcO AcO

AcO

Br

O

Zn OAc OAc

OAc

O

OH I

POCl 3 / py // Sn

JOC, 1978, 43, 364.

C Br

C OAc

Zn / HOAc

7-

d

7-d.

i. WCl6 / RLiii. LiPPh2 / CH3I iii. Na

product retentionproduct inversion

Cl

Na O

(special structure):

R

H

R C C CH 2CH 2CH 2OH 7-d. use: (EtO)3P

S R 1

R 2

(EtO)3P

R 1

R 2

Synthesis , 1977, 1134.

7-

e

7-f

not

CO 2Me

O H CN

H 7-f. +Ph 3P CH CO 2Me

not

O

PPh 3+H C CO 2Me difficult to prepare

i. Wittig Reaction1953 discover(olefination reaction)ii. Phosphonate Wittig Reaction (Horner-Emmons Modification)iii. Silyl Wittig Reaction (Peterson Reaction)

THL, 1981, 2751. JOC, 1968, 33, 780.

use: Ph3P-CHR' use: (RO)2PO-CHR'

via : betaine, oxaphosphetane (NMR)RO = MeO-, EtO-

+Ph 3P CH Et

CN

3+O

Et

expensive

unstable ylid gives cis (Z)stable ylid gives trans (E)

water soluble, removed by extraction

(comparison: O=PPh3 highly soluble in organic solvent)

+

3

Synthesis, 1984, 384. Me 3SiCHR -Li +

Ph 3SiCH 2-Li + === Ph3SiCH 2Br + n-BuLi (exchange)Me 3SiC -H-MgBr === Me3SiCH 2Cl + Mg (metal reduction)

Ph 3SiC -HCH 2Ph 3SiCH=CH2 + PhLi (addition to vinylsilane)Me 3SiC -HCO 2Et === Me3SiCH 2CO 2Et + Li (metalation)Me 3SiCH=PPh3 === Me3SiCH 2PPh 3+ X- + KH

not good for Ph3P=CH2function as base:

iv. CH2(ZnI)2

Synlett, 1988, 12, 1369.

CH 2(ZnI)22

v. CH2CHBr 2, Sm, SnI2 / CrCl3, THF

Chem. Lett, 1995, 259.

R

O

O R

vi. Sulfoximide (Johnson C.)vii. Grignard reagent:

use:Ph CH 2Li

// Al (Hg)

1. TMSCH2MgCl

Me

use: TMSCH2MgCl

THL, 1988, 4339. THL, 1973, 3497.

2. NaOAc, AcOH

via:

H R

R'

3

methylenation

advantages over the Wittig:

1. by-products are more easily removed, 2. reaction suffers less from steric effects.

7-f. 2

i. use: N2H 4 / H2S / Pb(OAc)4

ii. McMurry Coupling

not for Wittig, ylid unstable

N O

O

2H 4

1. HO

O

1. H2. Pb(OAc)2S

. Pb(OAc)2S

424

P(OEt)TiCl 33S

N S

N Zn-Cu

N

N

N S

O O

via:

N N

S

O

TiCl 3-LiAlH 4 / THFJACS, 1974, 96, 4706.

TiCl 3 / MgBASF, 1973, 2147. TiCl 4 / ZnTiCl / KChem. Lett, 1973, 1041. 4JOC, 1978, 43, 3253.

7-g

not use H2 / Pt: might convert to alkane

form trans alkene:

i. Li / NH3; or other IA metalsii. Li / EtNH2

iii. LiAlH4 / THF

form cis alkene:

i. H2 / Ni2B (P-2 catalyst)

ii. H2 / Pd-CaCO3 (Lindlar catalyst)iii. H2 / Pd-BaSO4

iv. B2H 6 / HOAc (Diborane)v. N2H 2

vi. HCHO / Pd-C / Et3N

7-h

all form trans alkene:

H

C CH

R H

i. R2BH / Br-CN (hydroboration)

ii. DIBAL / n-BuLi / CH3I (hydroalumination)

iii. Cp2ZrClH / RX (hydrozirconation)

7-i application: protecting group

not for

C C double bond might move

via dihalide

C=C

C C X X

C=Cvia halohydrinvia epoxide

C=C

C=C

C C H X O C

C C C

C=CC=CC=C

via diene-olefin additionvia diradical

Ph

Ph

JA CS, 1998, 100, 877.

7-j

N N N 3

MnO 2 / Ph3P CH 3 Br- / MTBD

MTBD

C-X

8-a C-OH b C-NH 2

8-a 8-a. 1

c C=Od C(O)Ze C-H

O O

Chem. Rev., 1996, 96, 1737.N F S

JOC, 1993, 58, 3800.O O

1.

CHCl 2O

N

1. CF3CHFCF 2NEt 2OH 2. HOAc / i PrOH

2. F3S-NEt 2(DAST)$ 500 / 125 g

CH 3

CH 3S

F

2

8-a. 2

8-a. 3

CH I

JCS, 1905, 87, 1592.

8-a. 4

1. HI

CH OH

PBr 3

2. PI3

2. PPh3 / I2

$ 35 / 1000 g$ 65 / 500 g$ 80 / 50 g

3. TsCl / C6PBr 3PI 3

8-b

NaNO2 / HCl / HBF4 /

8-c CF2Br 2 / Zn

8-d

8-d. 8-d. 2

F

JCS.PT I, 1993, 335.

O

Cl

Cl

RhCl(PPh3)

3

O R

OH

1. AgNO3/KOHR Br Chem Rev., 1956, 56, 219.

Ber. 1942, 75

, 296.

2

8-e

i.

N O F

8-e.

1

Chem. Rev., 1996, 96, 1737.

PhCH 2C(O)CH3

+PhCHC(O)CH3

F

S

ii. F-TEDA-BF 4iii. iv. v.

JCS.CC, 1994, 149.

JOC, 1988, 53, 2803.

R

F

1.4-1.6 V

R

33

90 %

1. regioselective fluorination at the more substituted positions2. electrophilic in nature

F 2-N 2 / CFCl3-CHCl 3

HF / electrolysis

already industrilizedNF 3O / TBAH / CH3CN

R = CH3CO, COCF3, CCl3, NO2 THL, 2003, 44, 2799.

TBHA: Tetrabutylammoniumhydroxide

8-e. 2

X = Cl, Br, I

O

O

R H

R 2

R 3

Mg(ClO4) 2

R 1

X

R 2

R 3

NBX:

N

X

O O

O

NBX / Mg(ClO4)

2

JOC, 2002, 67, 7429.

X = Cl, Br, I

8-e. 3

I 2 / HNO3

JACS, 1917, 39

, 437.

I / HNOI

86 %

C-CH 3

9-a C-X 9-a

CH 2Cl 2

98 %

(CH3) 3Al

bridgehead methylation

Organomet. Chem. Rev., 1996, 4, 47.

4-e

reductive amination!

1. RNH2 // NaBH3CN

most general

2. Me3SiN 3 // LiAlH4

3. NH3 (excess) // RaNi / H2

4. PhNHNH2 // Al (Hg)

via: hydrazone

5. NH4+HCO 2-Leuckart reaction

6. RNH2 / n -Bu 2SnClH / HMPA

Synthesis, 2000, 789.

4-f

C=C

C-C-NH 2

B 2H 6 / NH2Cl B 2H 6 / H2NO B 2H 6 / H2NOSO 3H

C-C-NHCOCH 3

CH 3CN / H3O +

4-g

R C NH 2R C NH 2R'

AlH 3 / THFR'Li // NaBH4

Br

TH, 1989, 30, 5137.JOC, 1993, 58, 4313.JOC, 1987, 52, 3901.TH, 1989, 30, 5139.

1. LiAlH4

2. NaBH3(OCOR)

3. B2H 6

4. Et3O + BF4- // NaBH45. P4S 10 // RaNi

C N

AlH 3Br NH 2

JOC, 2000, 65, 8152.

4-g.a form 4-g.b form

R'MgX // NaBH4R'MgX // Li/NH3(l)R' 2CuLi // NaBH4

R C N

R R'

C NH 2

4-h

4-i

4-i. 2NH 2O R

NH 2

PhI(OAc)O R

N

I

PhI(OAc)23R

NH

O OCH 3

JOC, 1993, 58, 2478.

CH 3OH

O

R NH OCH 3

RCH NH 2

PhI(OAc)2 // KOH / CH3OH

Ph OAc

R

N C O

C=O

5-a C=Og C(OR)

2d C C b C=Se C N C(SR)

2c C=N-OHf C=C-ORh C-OH C=N-HC=C-SR5-a

O R

CR

i C-NH 2

C-NO 2j C-Br k C-H

O

R

CH 2O

4

-

i. via: α-CO 2H

SOCl CrO Zn

H 3O +

23O

R

ii. via: α-haloketone

iii. via: aldol process

PhCHO

NaBH 3

H 3O +

O

HgCl 3O

R

CH 2

R

O

24

R

CH 2

R

iv. via: thioenol ether

O R

CH 2R

KOtBu

v. via: epoxysilane

O R

CH 2R

TsNHNH 2

MeLi

TMSCl MCPBA LAH

drawback: require simple structure, use many powerful agents: MeLi, LAH, MCPBA

5-b i. hydrolysis

ii. MCPBA

5-c 5-c.1

i. RaNiC=N-OH

ii. TiCl3

iii. KMnO4 / Al2O 3THL, 2001, 42, 4775.

5-c.2

C=N-H

H 3O +

JOC, 1972, 37, 2138.

5-d

Hg 2+ / H2O HgSO 4 / H2O / H2O

5-e

N

O

-CH 2-C H

R -CH 2-C 5-e.1

1. DIBAL / H3O +

2. HCl./ SnCl2 / Et2O 3.

H O +

Stenphen reduction

mostly for

J.Org.Syn, 1925, 3, 1874.

O

5-e.2

R --C H R' R --C 5-e.3

R"

R' X / n -BuLi

OH OH

CH 3I R''MgBr H 3O +

3

4-e

reductive amination!

1. RNH2 // NaBH3CN

most general

2. Me3SiN 3 // LiAlH4

3. NH3 (excess) // RaNi / H2

4. PhNHNH2 // Al (Hg)

via: hydrazone

5. NH4+HCO 2-Leuckart reaction

6. RNH2 / n -Bu 2SnClH / HMPA

Synthesis, 2000, 789.

4-f

C=C

C-C-NH 2

B 2H 6 / NH2Cl B 2H 6 / H2NO B 2H 6 / H2NOSO 3H

C-C-NHCOCH 3

CH 3CN / H3O +

4-g

R C NH 2R C NH 2R'

AlH 3 / THFR'Li // NaBH4

Br

TH, 1989, 30, 5137.JOC, 1993, 58, 4313.JOC, 1987, 52, 3901.TH, 1989, 30, 5139.

1. LiAlH4

2. NaBH3(OCOR)

3. B2H 6

4. Et3O + BF4- // NaBH45. P4S 10 // RaNi

C N

AlH 3Br NH 2

JOC, 2000, 65, 8152.

4-g.a form 4-g.b form

R'MgX // NaBH4R'MgX // Li/NH3(l)R' 2CuLi // NaBH4

R C N

R R'

C NH 2

4-h

4-i

4-i. 2NH 2O R

NH 2

PhI(OAc)O R

N

I

PhI(OAc)23R

NH

O OCH 3

JOC, 1993, 58, 2478.

CH 3OH

O

R NH OCH 3

RCH NH 2

PhI(OAc)2 // KOH / CH3OH

Ph OAc

R

N C O

C=O

5-a C=Og C(OR)

2d C C b C=Se C N C(SR)

2c C=N-OHf C=C-ORh C-OH C=N-HC=C-SR5-a

O R

CR

i C-NH 2

C-NO 2j C-Br k C-H

O

R

CH 2O

4

-

i. via: α-CO 2H

SOCl CrO Zn

H 3O +

23O

R

ii. via: α-haloketone

iii. via: aldol process

PhCHO

NaBH 3

H 3O +

O

HgCl 3O

R

CH 2

R

O

24

R

CH 2

R

iv. via: thioenol ether

O R

CH 2R

KOtBu

v. via: epoxysilane

O R

CH 2R

TsNHNH 2

MeLi

TMSCl MCPBA LAH

drawback: require simple structure, use many powerful agents: MeLi, LAH, MCPBA

5-b i. hydrolysis

ii. MCPBA

5-c 5-c.1

i. RaNiC=N-OH

ii. TiCl3

iii. KMnO4 / Al2O 3THL, 2001, 42, 4775.

5-c.2

C=N-H

H 3O +

JOC, 1972, 37, 2138.

5-d

Hg 2+ / H2O HgSO 4 / H2O / H2O

5-e

N

O

-CH 2-C H

R -CH 2-C 5-e.1

1. DIBAL / H3O +

2. HCl./ SnCl2 / Et2O 3.

H O +

Stenphen reduction

mostly for

J.Org.Syn, 1925, 3, 1874.

O

5-e.2

R --C H R' R --C 5-e.3

R"

R' X / n -BuLi

OH OH

CH 3I R''MgBr H 3O +

3

5-f

H 3O

+

C=C-ORH 3O +

3

C=C-SR

2+ / CH

Hg 2+

Hg 3CN (aq)

SCH 33

O

5-g

a very common protecting group, deprotect back to ketone

OR OR H 3O + / solv (aq)OR H 3O + / solv (aq)OH OR

OH

SR

+SR Hg 2 / H3O +O O H 3O + / solv (aq)O O

H 3

O +

3Hg 2+ / H3O +

S

S

Hg 2+OEt H 3O H

C OEt OEt

RMgX / H3O +

OEt O

H

C OEt RMgX

OEt

R

C

H

5-h 1st alcohol

O R H

i. PCCii. PDC

OCH 3

AcO OAc

O Pfitzner-Moffatt oxidation

JOC, 1985, 50, 1332.

N OH

O

O

O

O Br

O DMSO

3H

60 %

Synth. Commun., 1986, 16, 1343.

O

2nd alcohol

R R

i. PCC

ii. PDC

ix. K2

O

1st alcohol

R OH

O R OH

PCC (pyridinium chlorochromate) (Py-HCl-CrO3)

most widely used

PDC (pyridinium dichormate)

(H2Cr 2O 7 + 2 Py)

use 1 - 1.2 eq.

. CrO 3

aldehyde

HCl

H

2

Cr 2O 7-2

Collins reagent: (CrO3 - 2 Py)Swern oxidation: (DMSO, oxalyl chloride, Et3N) 1. drawback: use 6 equivalent, a messy reactiondrawback: react at low TSynthesis, 1981, 165. 2. must be very dry, fire easily; purify by CaH23. an old oxidizing material, isolated by Collin.

JOC, 1977, 42, 1991.

Ag 2O:

1. a mild oxidizing agent

2. must be freshly prepared: NaOH into AgNO3 (aq)3. may involve surface change, react with CO2, light

5-i

5-i. 1O

O

Ph Ph

O

i. Corey approach: subtituted-quinone // H3O +ii. Watt approach

a. PhCHO // MCPBA // H3O + b. ArPhO // MCPBA // H3O + c. NBS // KOH // H3O +

// H3O +O

Ph Ph

NH 2

H 3O +O H Ph

O

NH 2

5-i. 2i. Et3N // H3O +

Nef reaction

Chem. Rev. 1955, 55, 137.

ii. TiCl3 / pH 1 or 6iii. SiO2 / NaOH // H3O +

McMurray reaction

pH 6: weak acid buffer, avoid interfere with ketal group

JACS, 1977, 99, 3861.

iv. LDA / MoO5-Py -v. NaOH // CH3vi. KMnO4 / KOH

5-j

indrect: change to RC-OH followed by oxidationdirect:

1. DMAPO / DBU / CH3CN 2. NaIO4 / DMF

a new method3. DMSO reagents:

i. DMSO / AgBF4ii. DMSO / ZnS

THL, 1974, 917. JACS, 2003, 68, 2480.

RCHBrMe

OH Br

Bull Soc. Jpn., 1981, 54, 2221.

O Br

RC(O)Me

OH O

Br R

DMSO / AgBF4- Me2S

R

O

5-k 1. SeO2

JCS, 1932, 1875.

2. DDQ / TFA.

O

3.

I

(3 eq.)O

OH O

Synthesis, 1979, 537.

Ph-F / DMSOa select oxidant

JACS, 2001, 123, 3183.

CH 3

CHO

C C

6-a RC CH

b RCH 2-SO 2Ph d C C

e RCH(CO2H)-CH 3g h O X

O

O

c C C

f -C(O)-CH3

6-a

i. n-BuLi / RX

n -BuLi: not MeLi, or t -BuLi, fire easilyRX: R-Br, R-TOS, RCHO, RC(O)R

ii. (Ph3P) 2PdCl 2, CuI, Et2NH / PhI

Cl

iii.

N Li

OMe

steric base, prevent Nu attackiv. CuI, NaI, Na2CO 3, R

C C CH 2Cl

6-b

n -BuLi / R'CHO // Ac2O // KOt Bu

i

CRR'=CHX

R C C H

R C C R' R C C H

R C C CHOH

R

R C C H

R C C Ph

THL, 1975, 4467.

R C C H

R C C Ar

Cl CH 2C C R'

R C C H

R

C

C

CH 2C

C

R'

Synthesis, 2000, 691.

sulfonic acid: PhSO3H; sulfinic acid: PhSO2H; sulfenic acid: PhSOH

6-c

JACS, 1975, 97, 891.

i. move to terminaluse: KAPA

2ii. protect - deprotect

use: Co (CO)8 // Fe(NO3) 3, EtOH

Fe(NO3) 3: weak oxidizing agent

6-d

use: i. Br2 / CCl4 // KOt Bu

ii. Br2 // KOH

Ph

Ph

Ph

Ph

JA CS, 1941, 63, 1180.

6-e

use: Pb(OAc)4, LiCl // KOt Bu // Br2/CCl4 // KOt in fact: convert to C=C firstly

6-f

i. NaBH4, H3O +, Br2, KOtBu

ii. NH2OH, NaNO2 / H2SO 4 // Ac2O / DMAP

O

N

N

iii. LDA, ClPO(OEt)2

O

DMAP:

4-N,N-D i m ethyl a minop y ridine

German invention, as acylating agent

CH 3

mixture of

Ac2O / DMAP:

LDA: Li N(iPr)2, ignored a long time, re-introduced by Michigan State U. became famous, appeared every week

6-g

THL, 1967, 3943.

use: TsNHNH2 / EtOH, heat

CH 3CH CH 2

(MVK)

3(l)

O

Robinson AnnulationO

6-h

LiNH 2 / NH3 (l)

use: LiNH / NH (l) / R-X

Cl

236-i.

i. NaOEt (when X = Br)

ii. BuLi (when X = -OSO2CF 3)

O R

HO

JA CS, 1955, 77, 3293.JA CS, 1958, 80, 4599.

Ar

Br NaOEt

Ar C C Ar'

Ar' H

Me OSO 2CF 3BuLi

Ph

H

Me C C Ph

Me

via:

Ar Br

Ph

C

via:

Ar'

?

JOC, 1978, 43, 364.

C C

7-a CH-CX b CH-CH 7-a

C C C C C C C C C C c CX-CY d

X C

C

f g

C O C C

i C C j

C-OH

e -C(O)-CH3

h C CH

C

i. p-TSOH.H2O or CSAuse:

ii. weak acid: HOAc; HCO2H; H2C 2O 4use: heat

use: heat

OH Ph

(CO2H) 2 / benzene

applied for reactions: without rearrangement;

no regiosiomer

C Ph

minor

use base: DBN

C C 2

i. CH3I / Ag2ii. HCHO / HCO2227-b i. DDQii. chloronail

NC NC

O

Cl Cl Cl

Cl

O O

Cl Cl

MeO

OAc

2Se

N

MCPBA MeO OAc 2Me

mechanism:

Ph-Se-CN

:PBuPh-Se-PBu

3RCH 2CH 2-OH

MeO 22Me

MeO 2RCH 2CH 2-O-PBu

3

RCH=CH2

iii. Pd-C; or Ni; Pt, Rh

7-c

C

C

OR OR

i. CSCl2

/

OH OH

P ii. CSCl2 / P(OMe)3

C Br

C Br

i. Zn / acetone

ii. In / MeOHJCS.CC, 1998, 2113.

application: i. protect alkene: via Br2 // Zn

ii. purify compound

CCCCC 36 o C CCCC=C 31 o C CCCC C 148 o C

C C

OMs OMs C

C

NaI / Zn (Cu)

C via:

C OAc

AcO AcO

AcO

Br

O

Zn OAc OAc

OAc

O

OH I

POCl 3 / py // Sn

JOC, 1978, 43, 364.

C Br

C OAc

Zn / HOAc

7-

d

7-d.

i. WCl6 / RLiii. LiPPh2 / CH3I iii. Na

product retentionproduct inversion

Cl

Na O

(special structure):

R

H

R C C CH 2CH 2CH 2OH 7-d. use: (EtO)3P

S R 1

R 2

(EtO)3P

R 1

R 2

Synthesis , 1977, 1134.

7-

e

7-f

not

CO 2Me

O H CN

H 7-f. +Ph 3P CH CO 2Me

not

O

PPh 3+H C CO 2Me difficult to prepare

i. Wittig Reaction1953 discover(olefination reaction)ii. Phosphonate Wittig Reaction (Horner-Emmons Modification)iii. Silyl Wittig Reaction (Peterson Reaction)

THL, 1981, 2751. JOC, 1968, 33, 780.

use: Ph3P-CHR' use: (RO)2PO-CHR'

via : betaine, oxaphosphetane (NMR)RO = MeO-, EtO-

+Ph 3P CH Et

CN

3+O

Et

expensive

unstable ylid gives cis (Z)stable ylid gives trans (E)

water soluble, removed by extraction

(comparison: O=PPh3 highly soluble in organic solvent)

+

3

Synthesis, 1984, 384. Me 3SiCHR -Li +

Ph 3SiCH 2-Li + === Ph3SiCH 2Br + n-BuLi (exchange)Me 3SiC -H-MgBr === Me3SiCH 2Cl + Mg (metal reduction)

Ph 3SiC -HCH 2Ph 3SiCH=CH2 + PhLi (addition to vinylsilane)Me 3SiC -HCO 2Et === Me3SiCH 2CO 2Et + Li (metalation)Me 3SiCH=PPh3 === Me3SiCH 2PPh 3+ X- + KH

not good for Ph3P=CH2function as base:

iv. CH2(ZnI)2

Synlett, 1988, 12, 1369.

CH 2(ZnI)22

v. CH2CHBr 2, Sm, SnI2 / CrCl3, THF

Chem. Lett, 1995, 259.

R

O

O R

vi. Sulfoximide (Johnson C.)vii. Grignard reagent:

use:Ph CH 2Li

// Al (Hg)

1. TMSCH2MgCl

Me

use: TMSCH2MgCl

THL, 1988, 4339. THL, 1973, 3497.

2. NaOAc, AcOH

via:

H R

R'

3

methylenation

advantages over the Wittig:

1. by-products are more easily removed, 2. reaction suffers less from steric effects.

7-f. 2

i. use: N2H 4 / H2S / Pb(OAc)4

ii. McMurry Coupling

not for Wittig, ylid unstable

N O

O

2H 4

1. HO

O

1. H2. Pb(OAc)2S

. Pb(OAc)2S

424

P(OEt)TiCl 33S

N S

N Zn-Cu

N

N

N S

O O

via:

N N

S

O

TiCl 3-LiAlH 4 / THFJACS, 1974, 96, 4706.

TiCl 3 / MgBASF, 1973, 2147. TiCl 4 / ZnTiCl / KChem. Lett, 1973, 1041. 4JOC, 1978, 43, 3253.

7-g

not use H2 / Pt: might convert to alkane

form trans alkene:

i. Li / NH3; or other IA metalsii. Li / EtNH2

iii. LiAlH4 / THF

form cis alkene:

i. H2 / Ni2B (P-2 catalyst)

ii. H2 / Pd-CaCO3 (Lindlar catalyst)iii. H2 / Pd-BaSO4

iv. B2H 6 / HOAc (Diborane)v. N2H 2

vi. HCHO / Pd-C / Et3N

7-h

all form trans alkene:

H

C CH

R H

i. R2BH / Br-CN (hydroboration)

ii. DIBAL / n-BuLi / CH3I (hydroalumination)

iii. Cp2ZrClH / RX (hydrozirconation)

7-i application: protecting group

not for

C C double bond might move

via dihalide

C=C

C C X X

C=Cvia halohydrinvia epoxide

C=C

C=C

C C H X O C

C C C

C=CC=CC=C

via diene-olefin additionvia diradical

Ph

Ph

JA CS, 1998, 100, 877.

7-j

N N N 3

MnO 2 / Ph3P CH 3 Br- / MTBD

MTBD

C-X

8-a C-OH b C-NH 2

8-a 8-a. 1

c C=Od C(O)Ze C-H

O O

Chem. Rev., 1996, 96, 1737.N F S

JOC, 1993, 58, 3800.O O

1.

CHCl 2O

N

1. CF3CHFCF 2NEt 2OH 2. HOAc / i PrOH

2. F3S-NEt 2(DAST)$ 500 / 125 g

CH 3

CH 3S

F

2

8-a. 2

8-a. 3

CH I

JCS, 1905, 87, 1592.

8-a. 4

1. HI

CH OH

PBr 3

2. PI3

2. PPh3 / I2

$ 35 / 1000 g$ 65 / 500 g$ 80 / 50 g

3. TsCl / C6PBr 3PI 3

8-b

NaNO2 / HCl / HBF4 /

8-c CF2Br 2 / Zn

8-d

8-d. 8-d. 2

F

JCS.PT I, 1993, 335.

O

Cl

Cl

RhCl(PPh3)

3

O R

OH

1. AgNO3/KOHR Br Chem Rev., 1956, 56, 219.

Ber. 1942, 75

, 296.

2

8-e

i.

N O F

8-e.

1

Chem. Rev., 1996, 96, 1737.

PhCH 2C(O)CH3

+

PhCHC(O)CH3

F

S

O

ii. F-TEDA-BF 4iii. iv. v.

JCS.CC, 1994, 149.

JOC, 1988, 53, 2803.

R

F

1.4-1.6 V

R

F -N 33

adamantane

90 %

1. regioselective fluorination at the more substituted positions2. electrophilic in nature

F 2-N 2 / CFCl3-CHCl 3

HF / electrolysis

already industrilizedNF 3O / TBAH / CH3CN

R = CH3CO, COCF3, CCl3, NO2 THL, 2003, 44, 2799.

TBHA: Tetrabutylammoniumhydroxide

8-e. 2

X = Cl, Br, I

O

O

R H R 2

R 3

Mg(ClO4) 2

R 1

X R 2

R 3

NBX:

N X

O O

O

NBX / Mg(ClO4) 2

JOC, 2002, 67, 7429.

X = Cl, Br, I

8-e. 3

I 2 / HNO3

JACS, 1917, 39

, 437.

I / HNOI

86 %

C-CH 3

9-a C-X 9-a

(CH3) 3

Al

CH 2Cl 2

98 %

bridgehead methylation

Organomet. Chem. Rev., 1996, 4, 47.


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