官能团相互转换 by jackson jackson

FunctionalG roup Interconversion C-OH

C-OR

C-H 1- a b c d e f g h i j

C-OH C-X C-NH2 C-S C=O C=C C-CN C-CO2H C-CHO

2- a C-OH b C-(OR)2 c C(O)OR d C-H e C=C f C-CN

C(O)X C=C

C C 6- a

RC CH

b c d e

RCH2-SO2Ph C C C=C RCH(CO2H)-CH3

f g

-C(O)-CH3 O

h i

O X

CRR'=CHX

3- a b c d e f g h i j

C-H C-OR C-X C-NH2 C-OCH2OR C-OC(O)R C---OH C=O C O C=C C-X

7- a CH-CX b CH-CH c CX-CY X

d e

-C(O)-CH3

f C=O g C C h C CH i C=C j C-OH

C=O

C-N

8- a C-OH b C-NH2 c C=O d C(O)Z e C-H

4- a b c d e f g h

C-H C-N C-X C-OH C=O C=C C-C(O)Z C N

C-CH3 9- a C-X

5- a b c d e f g h i j k

C=O C=S C=N-OH, C=N-H C C C N C=C-OR; C=C-SR C(OR)2; C(SR)2 C-OH C-NH2; C-NO2 C-Br C-H

C-H 1- a b c d

C-OH C-X C-NH2 C-S

e C=O f C=C g C-CN h C-CO2H

C-CHO C(O)X

i j

J. Org. Chem. 2000, 65, 6179

1-a C-OH

C-H

RCH2 O S CH3 O O

(1). for 1', 2' alcohol: i. p-TsCl // LiAlH4

CH3

S Cl O

RCH2OH

LiAlH4

RCH2 O S CF3 O

RCH2-H

dry Py

ii. Ph2SiHCl / InCl3

Ph2SiHCl / InCl3

Cl2In

CH3

OH CH3

JOC, 2000, 65, 6179.

C O Ph

SiPh2

InCl3

CH3 i. ClC(S)OPh // n-Bu3SnH

mesylate

methanesulfonyy chloride (l) ~ $ 30 / Kg

triflate

purification textbook dry pyridine: from CaH2 and distilled

H O

JOC, 2001, 66, 7741.

(2). for 3' alcohol:

toluenesulfonyl chloride (s) ~ $ 30 / Kg

Ph via:

CHCl2 rt, 3 hr

tosylate

ii. Et3SiH / Lewis acid

CH3

RCH2 O S O O

CH3 n-Bu3SnH CH 3

H CH3

via:

indium trichloride a unique Lewis acid catalyst, acceleratedeoxgyenation

S O C O Ph

thiocarbonate (an ester) steric OK

SnBu3 S O C O Ph

1-b

C-X

C-H Br i n-Bu3SnH / AlBN

n-Bu3SnH AIBN

(1). free radical reduction ii NaBH4 / InCl3 / CH 3CN

JACS, 2002, 124, 906.

i LiAlH4 (2). hydride reduction

Bu3SnH: (l), easy to remove Ph3SnH: (s), hard to remove Me3SnH: too volatile, toxic

radical reagent

JACS, 1972, 94, 8905. JOC, 1969, 34, 3923.

ii NaBH4 iii NaBH3CN

THL, 1969, 3095.

hygroscopic, dried self, suggest: buy small amount each time unstable in acid, form H2 gas; stable in weak base

NaBH3CN: stable at pH 5-6

iv LiBHEt3 (super hydride)

(3). metal reduction

JOC, 1976, 41, 3064.

i Na / NH3; Li / NH3; Na / EtOH ii Zn; Fe; Sn; Mg

Mg / Et2O

H2O

(Grignard reagent) Br

n-BuSnH N

- N2 CN CN (AIBN) azobisisobutyronitrile radical initiator

H R

n-BuSn n-BuSnBr

n-BuSnH

n-BuSn

1-c C-NH2

C-H p-TsCl

(1).

BuLi

RCH2NH2

LiAlH4

ArSO2Cl RCH2NH2 Hinsberg's test

RCH2NH

RCH2-H

(2).

NaH

Ar-NH2

NaH

p-TsCl

SO2Ar

LiAlH4 RCH2-H SO2Ar tosylimide weaker C-N bond

Ar-H

NH2Cl (3). Ar-NH2

NaNO2 H3PO2 HCl

via:

1-d

C-S

C-H

Ag2O

radical mechanism

RCH2NMe3 OH-

SO2Ar

Ar-H

RCH2NMe3 X

(4). RCH2NH2

RCH2

S Cl

CH3

RCH2N SO2Ar

- BuH

tosylamide

p-TsCl

BuLi

SO2Ar

R=CH2

NaH NH2 - ArSO H 2

(2). Li / NH3

Ar-H

JOC, 2001, 66, 8293.

R-CH3

JOC, 1985, 50, 427.

EtO2C

(1). Raney Ni

N O

MeO2C

CH2Ph

Raney Ni

Raney Nickel: Ni - Al alloy, suspension HN

N CH2Ph

S MeO2C

(3). LiAlH4 / CuCl2 JCS Perkin Trans I, 1973, 654. NaBH4 / NiCl2 NaBHEt3 / FeCl2 (or CoCl2, VCl3) Chemistry:

R-SH R-S-R R-SS-R remove: Hg+; Ni

burn filter paper if dry mechanism uncertain, probably radical

R2SO R2SO2

1-e

C=O

C-H

HS best suitable for aryl ketone (ArCOR); not good for conjugate ketone OH O preparation: HgCl2 into Zn (1). Clemmensen reduction: Zn-Hg / HCl

C6H13

acidic

Ra(Ni) S H S thioketal

BF3, CH2Cl2

thioketal: inert to LAH; react with RaNi; smell terrible and stay long; discard shoses

similar: Sn / HCl SH (2). thioketal:

/ BF3, CH2Cl2 // RaNi

(3). Wolff-Kishner reduction:

neutral

N2H4, OH-, heat

basic O

(4). Pd-C / HCO2NH4: mild, efficient

N NH2

O N2H4 Pd-C

(5). Tosylhydrazone reduction (Shapiro reaction): (modified Wolff-Kishner reduction):) TsNHNH2 // RED

NN H

OH-

OHN N H - N2

N N Ph

major side-product: drawback of the reaction

HCO2NH4

Synthesis, 2001, 16, 2370.

N N Ts

for acyclic, may C=C side product

H(6). enol derivatives:

Tf2O /

limit: for Îą-H compd.

// H2 / PtO2

B H

RED choice: MeLi; NaBH3CN (good) LAH, NaBH4: 2 group compete at Stanford U. B2H6: very flamable, fire if shoot out from syringe

O (7). Et3SiH / CF3COOH

NO2

Et3SiH Ph

NO2

CF3COOH JOC, 1973, 38, 2675.

Ph H O C C

CF3 S O O

S CF3 O

OTf C C

H H H2 PtO2

PtO2 + H2 = Pt

C C H

H H

1-f

C-C-H

C=C

catalyst: Pd-C PtO2 Rh-C; Rh-Al2O3; RhCl(PPh3)3 Ni

(1). H2 / cat

H2 R

PtO2 HO

H2 , PtO2

R N R = NHAc , NH2

TFA , 60 â&#x201E;&#x192;

HO H H OH OH stereoselcetive: same side as OH (due to H bond)

in acetic condition JOC, 2002, 67, 7890.

(2). HN=NH (diimide) JOC, 1993, 58, 4979. (3). B2H6 // RCO2H, heat

RhCl(PPh3)3

O RhCl(PPh3)3

benzene 12 hr

O (4). n-Bu2SnI / MgBr2-Et2O // H3O+ O O Wilkinson's catalyst: regioselective, prefer isolated double bond soluble in org solvent, 9 Ph group $ 50 / 25 g via:

CO2Me

JACS, 1979, 101, 7020.

H H

CH3CO2D B R R

N2H2: unstable; generated in situ from "DEAD" (diethyl azodicarboxylate) or from: N2H4 + H2O2; N2H4 + Cu(II) + O2; NH2OH + NH2OSO3

JCS, PT1, 1986, 546.

prepare isotope EtO2C N N CO2Et

OEt O

OH-

HO2C N N CO2H H O H O N N O O

OEt n-Bu2SnI

JOC, 2001, 66, 8690.

- 2 CO2

R R

syn-addition

OEt not radical mech.

via: O

- N2

OEt

H3O+

MgBr2-Et2O

H N N H

R C C

O Sn

H R R

O Sn R

R C C R H H

1-g C C N

C-H CN: ~ X (pseudo halogen), form KCN, NaCN with IA elements not quite same: not for H-

(1). K / Al2O3 JOC, 1980, 45, 3227 K / HMPA

characteristcs: IR, CMR

R C C N

which is δ+ ?

(2). Na / NH3

toxic?

HMPA: hexamethylphosphoramide (Me2N)3P=O b.p. ~ 230 C = HMPT: hexamethylphosphoric triamide (Me2N)3P=O highly toxic, cancer suspected agent? modified to: N N yes for white mouse, uncertain for human O

1-h C CO2H

C-H

solvent

(1). particular structure: β-CO2

other Cl sources: PCl5; (COCl)2 oxalyl chloride (3). organic electrochemistry CO2H

CO2H

N R

(2). normal structure: SOCl2 // PhSeH // n-Bu3SnH

O Ph CO2

- CO2

O RCH2

C OH

O SOCl2

RCH2

C Cl

PhSeH RCH2

Ph H

R pyridinium betaine

C SePh

n-Bu3SnH

RCH2 H

(radical mechanism?) organoselenium chemistry

1-i

CHO

C-H O

O Cl (1). RhCl(PPh3)3 (Wilkinson's cat) (2).

PPh3

- PPh3

Rh(DPPD)2+ ClDPPD = Ph2P-CH2CH2-PPh2

1-j

C(O)X

C O

oxidative addition

Cl R H

PPh3

reductive elimination

R Cl

R C H

PPh3

O R

PPh3 PPh3

-CH3

HSiEt3 / B(C6F5)3

PPh3 PPh3

rearrangement

R C

CH3

JOC, 2001, 66, 1672.

C O

PPh3 PPh3

RC-OR 2- a b c

RC-OH RC-(OR)2

d e

RC-H RC=C

RC(O)OR

RC-CN

2-a RC-OH

RC-OR

trimethyloxonium tetrafluoroborate generate H2, or butane gas JOC, 1988, 53, 2985. JCS, 1930, 2166. base: NaH, n-BuLi, Ag2O + CH3-X: CH3I; CH3OSO2R; (CH3)3O BF4 , (CH3)2SO4

application: for protecting group (1). Me: base / CH3-X RC-OCH3

PhCH2-Cl PhCH2-X: PhCH2-Br: reactivity good PhCH2-I: reactivity better than PhCH2Br, RC-OCH2Ph = RC-OBZl = RC-OBn generated in situ, PhCH2Br + NaI Br (3). allyl: base /

Me group: i. Williamson ether synthesis, SN2 type ii. not a good protecting group, too stable to convert back to alcohol Benzyl- group: i. abbreviation: benzyl = PhCH2 = Bzl = Bn ii. deprotecting: H2 / Pd-C

(2). PhCH2-: base / PhCH2-X

RC-OCH2CH=CH2 t-Butyl group:

acid: H2SO4 H3PO4 BF3-Et2O

(4). t-Bu: acid cat / RC-OtBu

Willianson synthesis (base, SN2) not work: elimination side-product with base CH3 CH3

(5). trityl: py // Ph3C-Br RC-OCPh3 = RC-OTr (6). silyl: Et3N / R3SiCl RC-OSiR3

Si CH3

Et3N / TMS-Cl

CH3

/ TBDMS-Cl N H

(8). ArF / CsF

ROH

CsF

RC-OR

OR O

activator / hydride source

R O

(1). hÎ˝ / HSiCl3 (2). HCl / NaBH3(CN) (3). AlCl3 / LiAlH4

Ph Si

Silyl group: i. Willianson synthesis OK: Si - Cl bond long ii. stability of silyl in acid/base: RC-O-TBDPS > RC-O-TBDMS >> RC-O-TBS iii. abbrev.: TBDMS = tert-butyl-dimethylsilyl = TBS =

NO2 RO

2-b RC-(OR)2

NO2

TBDPS-Cl

CH3 Si

(7). acetal / ketal: (see 3e)

Br base Trityl group: (tirphenylmethyl) i. SN1 reaction ii. abbreviation: triphenylmethyl = trityl = -CPh3 = -Tr (RO-Tr) iii. advantage: high MW, easy to handle (small amount become large amount)

RCH2 RCH2

aromatic substitution reaction usually contain NO2, F as leaving group

OR OCH2CH2OH

OCH3

HCl

OCH3

OCH3 O O

AlCl3 LiAlH4

OCH3

2-c

O R C OR

RC-OR

SiCl3 t-BuO RaNi with C=S

radical mechanism:

(1). hv / HSiCl3

(2). HCl / tBu-OO-tBu

HCl

JOC, 1974, 39, 2470.

tBu-OO-tBu (3). Lawesson reagent / RaNi (4). BF3 / NaBH4

limit for: lactone

Lawesson reagent

P CH3O

OCH3

~ P4S10 Lawesson reagent JOC, 1983, 48, 1127.

NaBH4

see mech-13 O I

RC-OR

I2 / Pb(OAc)4

(1). I2 / Pb(OAc)4 / hv Angew Chem Int Eng., 1964, 8, 525. limit: for 5~6 ring neighboring OH group

e / Pt (2). Organoelectro Chemistry:

BF3

2-d RC-H

RaNi

e- /

Pt, R4NOTs

H N O N H

R'MgBr

R4NOTs Ph

Ph (3). NCS / MeOH JOC, 2002, 67, 4498. limit: for allylic alcohol

NH2

NCS MeOH

R' OH

(79 %)

H H

H N O N H

OCH3 NH2

2-e

C-C-OR

C C

O C

2-e.1 C C

C=C-OR

Hg(O C CF3)2

+ O Hg

peracid:

EtOH

C CF3

OEt

NaBH4

CF3CO3H

C-C-OR CO2H CO3H

i. Hg(OCOCF3)2, ROH // NaBH4 ii. HCHO Prins Rxn

H2O

HCHO (aq)

Synthesis, 1980, 871.

O C

trans-diaxial attack!

stereoselective

iv. t-BuOOH, Mo(CO)6 HO

v. KHSO5 potassium hydrogen preoxide convenient, inexpensive, powerful.

JOC, 1980, 45, 4758.

JOC, 1982, 47, 2670.

conversion: O OH O

HOAc

OAc OAc

C=C-OR

OSO2Me

O O

Heterocyclic Chem, 1990, 27, 583.

via:

C-C-OR Et

ROH / HCl

JOC, 2001, 66, 521.

HO2C

Br2

2-f C C N

CO2Et H OH (+)-diethyl tartrate HO H chiral source CO2Et

JACS, 2001, 123, 2933.

HO2C

Br2 / ROH

vi. H2O2, t-BuOH, MnSO 4 // NaHCO 3, pH 8 new, cheap,, simple, green chemistry

HOBr generation: NBS + H2O + DMSO

racemic products Sharpless O

O racemic products

HOBr H2O

ii. via halohydrin: HOBr, H2O // K2CO3 iii. Sharpless asymmetric epoxidation: t-BuOOH, Ti(OiPr)4 // (+)-diethyl tartrate

mCPBA

i. peracid

2-e.3 C C

MCPBA (m-chloroperoxybenzoic acid) stable solid, 85 % (contain MCBA) for safety

limit for allyl alcohol, high e.e.

peroxybenzoic acid

HCHO CO3H

via:

2-e.2 C C

good result

CO3H

EtOH HCl

Et C

OEt OEt OEt

JACS, 1942, 64, 1825.

OH OSO2Me

C-OH 3- a C-H b C-OR c C-X

g C---OH h C=O i C O j C=C

d C-NH2 e C-OCH2OR f C-OC(O)R C-OH

3-a C-H

NH2

NO2

[PhI(OAc)-O]2-Mn(TPP)

JACS, 1983, 105, 2920.

3-a.1

H2O

JACS, 1983, 105, 3515. H

OH R

(1). [PhI(OAc)-O]2-Mn(TPP) Se

indirect

O R

3-a.2

SeO2

for allyl H:

SeO2

H HO

OSiMe3

Me3SiCl

MCPBA

O H

1. Me3SiCl Ph

(1) Me3SiCl // MPCBA//H3O+

Ph OH

O 2. MCPBA

Ph OH

RO (2). O2, LDA, (EtO)3P

JACS, 1975, 97, 6909.

O2, LDA, CO2R

(EtO)3P

via:

RO OH CO2R

OSiMe3

H3O

JOC, 1975, 40, 3427.

Ph O

OSiMe3

3-a.3

Se(OH)2

JACS, 1972, 94, 7154.

H2O

(2). organic electrochemistry (3). X2 / hv // OH-

O P

OEt OEt

3-b C-OR

C-OH RCH2-O-CH3

i. TMSI ii. BF3-Et2O // R-SH (or HS-CH2CH2-SH)

application: deprotecting

Me3Si-I - I-

iii. BBr3 / CH2Cl2, 0-10 C (1). Me: RC-OCH3

iv. AlCl3 / RSH v. N H

(2). PhCH2RC-OCH2Ph = RC-OBZl = RC-OBn

RCH2-O-CH3

THL, 2001, 42, 9207. vi.

Cl- / heat

/ LiI, heat N

BF3 RCH2

SiMe3

I-

CH3

- CH3I

ii.

O Cl

RCH2-OH

- RSCH3

CH3

CO2Me OCH3 OH

- toluene

O CH2

OCH3

O O C

[O]

heat N H Cl- - CH3Cl

H2 / Pd-C

O CH2

CN , OH-

RCH2-OH

RCH2-O-SiMe3

RSH

BF3

AlCl3 CO2Me HO CH3(CH2)11 SH odorless

MeO

RC-OCH2CH=CH2

i. H2 / Pd-C

(3). allyl:

RCH2

OCH3

OH-

RhCl(PPh3)3, H3O+ JOC, 1973, 38, 3224. RhCl(PPh3)3

(4). t-Bu:

(5). trityl:

RC-OtBu

i. TFA (CF3CO2H) ii. HBr / HOAc iii. TMS-I

RC-OCPh3 = RC-OTr triphenylmethyl

need stronger acid

H O

H3O+

CF3CO2H

H O

- EtCHO

O OH

- Me3C i. HOAc: weak acid: good leaving group ii. H2 / Pd-C: reserve, too strong, might affect other group

+ OCOCF3

H O CPh3 HOAc

H OH

- Ph3C (6). silyl:

RC-OSiR3 -SiMe3 -SiBuMe2 -SiBuPh2

i. F- : HF, Py-H+ F-; n-Bu4N+ F-

Si - F: 140 Kcal/mol

ii. mild base: not for TBDPS organic base: TMG Organic Letters, 2003, 5, 209. iii. mild acid: only for TMS, not for TBDMS, TBDPS if HOBr: OK for TMDMS

JOC, 1987, 52, 4973.

TMG

NH OH

CH3CN 1h R = TBDMS, TBDPS, Ac

TMG:

1,1,3,3-Tetramethylguanidine

3-c C-X

not practically useful: R-OH cheaper than R-X

C-OH

(1). OH(2). KO2 / DMSO

JOC, 1975, 40, 1678.

THL, 1975, 3183.

(3). Ag2O / H2O

3-d

C-NH2

C-OH

NH2

N2+X-

NO+

OH H3O+

(1). HNO2 // H3O+ NH2

(2). Na2[Fe(CN)5(NO)] / K2CO3 / H2O

RO2C (CH2)3CHR

Na2[Fe(CN)5(NO)]

JOC, 1986, 51, 3913.

RO2C (CH2)3CHR

K 2CO3 / H2O

H3O+ O

3-e

R-OC(O)R

R-OH

O O

OMe OMe

H3O+

MeOH

(1). Symmetry: H3O+

ketal: use H3O+

RO-CH2OCH3

acetal: use H3O+

RO-CH2OCH2CH2OCH3 (2). unsymetry: RO-MOM RO-MEM RO-MTM RO-THP

JOC, 1984, 49, 3912. i. H3O+; ii. HCl / MeOH; iii. BBrMe2

p-TsOH / MeOH

actually, acetal exchange rather than hydrolysis

H3O+ CH3OCH2CH2OCH2Cl

H3O+

RO-CH2SCH3

RO-MOM highly toxic, world top 10 killer, discard RO-H

not toxic not dangerous

RO-H

CH3SCH2Cl

i. H3O+; ii. ZnBr2 / CH2Cl2; iii. BBrMe2 HgCl2 / CH3CN (aq.)

RO-H

CH3OCH2Cl

R O

H3O+ O O

p-TSOH or CSA

RO-H

p-TSOH

CH3

(p-toluenesulfonic acid) THP: tetrahydropyran

SO3H

SO3H O

CSA (camphorsulfonic acid)

3-f

R OH

R' C O R

common esters: formate = HCO2R ------------------------ KHCO3 (or K2CO3, or NH3) / MeOH trifluoroacetate = CF3CO2R ------------ KHCO3 (or K2CO3, or NH3) / MeOH acetate = CH3CO2R = ROAc --------- KHCO3 (or K2CO3, or NH3) / MeOH

(1). base: KHCO3 (or K2CO3, NH3) / MeOH; NaOH (1 %, or 0.5 N)

benzoate = PhCO2R = ROBz -------- NaOH (1 %) / MeOH

(2). acid: H3O+

pivalate = tBu-CO2R = ROPv ------ NaOH (0.5 N) / EtOH

Na / NH3 (3). RED: electron: i hydride: LiAlH4 ii. NaAlH2(OCH2CH2OCH3) CO2CH3

AGIEE, 2002, 41, 3028. OH

NaAlH2(OCH2CH2OCH3)2

CH3O2C

HCl

selectivity:

MeOH

C6H6, r.t.

3-g

C OH Mitsunobu inversion

LAH

C OH

(or K2CO3 / MeOH)

JOC, 1987, 52, 4235.

Synthesis, 1981, 1.

PPh3 / DEAD / RCO2H // OH-

P-TsOH

O O

MeOH

PPh3 / DEAD * PhCO2H

PPh3

EtO2C N

CO2Et

HO*

EtO2C N NH CO2Et PPh3

ROH

EtO2C N NH Ph

P O R

Ph Ph

CO2Et

* PhCO2H

O Ph

* OR

* R-O-H

3-h C O (1). regioselective:

C OH O

LAH ------------ almost all: ald, ketone, acie, ester, acyl X, anhydride (but LiBH4 work for ester) NaBH4 --------------- not for acid, ester B2H6 --------------- not for ester, acyl X, anhydride; solvent: THF, SMe2

BH3 / THF

99.5 % trans

reflux 5 d

JOC, 2001, 66, 7514.

O Ph

H O

Synthesis, 1994, 1007. from bottom: Al (OiPr)3 / iPrOH ----------- Meerwein-Pondorf-Verley rxn IrCl4 / iPrOH / P(OMe)3 ------ Henbest rxn LiBH(secBu)3 ------------------ H. C. Brown JACS, 1972, 94, 7159. (3). HCHO reagent: JACS, 1935, 511, 903. HCHO / KOH HCHO / Ca(OH)2 Org.Syn, 1925, 4, 53. HCHO Me CHO Me KOH HCHO CH3 CHO

LAH

O Al(OiPr)2

O OiPr Al OiPr O

IrCl4

IrCl3

JCS, 1969, 1653.

JCS, 1970, 785.

JACS, 1978, 100, 2226.

[H]

THL, 2000, 41, 5631. 49% trace

51% 99%

Luche Reduction

influence of the lanthanide on the regiochemistry

3-i

C OH

R3B C

R3B, HOCH2CH2OH // H2O2 // NaOH JOC, 1986, 51, 4925.

R C

O O

R3C

B O

O O

H2O2 R3C

B O O

HOCH2CH2OH R

R3C

O H

O R3C

generate acetone opposite to Oppenauer oxidation

NaBH4 NaBH4 / CeCl3

C O

C(CH2OH)4

Ca(OH)2

regioselectivity determined by reactivity. reactivity: ald > ketone > ester

O Al(OiPr)3

JOC, 2003, 68, 2030.

(2). stereoselective: from top: LiAlH4; NaBH4; Na / NH3

H OH NO2

BH3 / SMe2

NO2

B O

H2O

R3C

C OH

C C

3-j

RCH C

Hg(OAc)2

R CH C

NaBH4

R CH C

Hg OH OAc

H2O oxymercuration - demercuration:

Hg (OAc)2: toxic, hard to remove

H2O2: dangerous, skin whiten, metal decompose

C OH

3-j.1 C C

B2H6

hydration:

(1). H3O+

hydroboration:

(2). Hg(OAc)2, H2O // NaBH4

(40%-60%) H H2O2 B OH

H B

(3). B2H6, H2O2 / OH-, H2O

C C OH OH

3-j.2 C C

(1). KMnO4 / NaOH cis cis (2). OsO4 tran (3). H2O2/HCO2H cis

(4). Na / EtOH

OH JCS, 1946, 2988.

tran

Ann, 1949, 561, 165.

e c i t c a r p

OH O

3-k

JACS, 1945, 67, 1786.

JOC, 1967, 32, 3452. OH

OH O

OH MeOH

H+

OMe PhCH2-Br OH

BnO

OBn O

OBn

BnO

H2 Pd-C

OH OH

OBn O BnO

O OBn

BnO OBn

OBn

OTr OBn

chemistry: hemiacetal ROH

O OH

OBn

H OH

OBn

OH OH OH

OBn OBn

OH O

BnO

CrO3

OBn

H3O+

OBn

Ph3C-Cl

LAH BnO

OMe

OBn OH OTr

OBn OH OH

OBn

ROH

1', 2' alcohol ROBn ROTr

ROH ROH

O O H R

H2O OBR2

C-N Compare nomenclature class:

4- a b c d e 4-a

C-H C-N C-X C-OH C=O

C-H

R3C NH2

f C=C g C N h C(O)X i C-C(O)X

primary

R C NH2

RC OH

secondary

R C NHR

R2C OH

R C NR2

R3C OH

tertiary

N N

TPP

N N Ph

SO2NH2 Ph I OAc OAc

C-N

O S N I Ph O

O S NH2 O

Fe (TPP)Cl

not a very useful reaction

NH S O O (insertion)

(1). nitrene insertion process: PhI(OAc)2 / Fe (TPP)Cl (2). PhI=NTs

NHTs

PhI NTs JOC, 2000, 65, 7858. Ru cat

(3). nitrogen cation radical (via Hofmann - Loeffler - Freytag) H

JACS, 1959, 81, 5209. NH2

COOH

N NCS H2SO4 hν

Me2N

AcO H

Me2N O C N N N

COOH 1. SO2Cl2

N C O H2O

HOAc

O N C OH

2. NaN3

AcO

NHCHO

Me2NH

NHCH3 NCS

2. H2 / Pt

Me2N

Cl N CH3 H

N Cl

Cl N CH3 H

N CH3 H

Me2N

O C

CH3

K2CO3

TsCl

MeOH TsO

N CH3 H+

N C

NHCHO

N CH3

1. LAH

DMF TsO

O C

CO2

NHCHO HOAc

NH2

N CH3 H hν

N CH3 H

4-b C-N

special case, limit for axial to equitorial NH2

C-NH2

CF3CO3H

C NH2

4-b.1

C NH2

NH2

CF3CO3H // Fe / HOAc NH2

4-b.2

RC N Z

NH2

RC NH2 RC NH2

RC NO2

Fe/HOAc

NO2

1. Fe3(CO)12 / CH3OH

JOC, 1972, 37, 930. 2. NaBH4 / Pd-C Vogel's 12.57 3. Na2S Vogel's 12.58 Vogel's 12.59 4. Sn / HCl

1. many reducing agents

5. H2 / Pt (S)-C 2. organic electrochemistry

NH2

RC N3

RC NH2

NO2

RC N iii RC N RC N

NH2

CPh

RC NH2

DMF rt. 15 hr

C OPh

RC NH2

BF4 Ph

CO2H H

N R

Ph CO2Et

NaN3

- TPP (SN2)

CO2Et 1. reduction N3 H

2. hydrolysis

CO2H NH2 H

D -α-amino acid .

H O N C OtBu

N CH3 NH2

TFA

NH2

BOC-ON

N CH3

H2/cat

O Ac2O

N CH3

OH N

N-oxide

O NH C OH CO2

NH CH2Ph NH2

NH-BOC CO2Et

CO2Et H O N C OCPh

1. H2O2 2. Ac2O 3. H2O

[BOC-OFF]

BOC-ON [58632-95-4]: 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile

Cl C O CH2Ph

RCH2 NH2

H2 / Pd-C

O Ph (CH3)3C O C O N C CN

H R C NH N N Ph H -

L -α-amino acid

BOC ON

NH2

1. HOAc; 2. H2 / Pd-C

RC NH2 1. TFA; 2. HCl

$ 300 / 100 g

H + R C N N N H

OCH3

application:

C OtBu O

THL, 1975, 4393.

JACS, 1965, 87, 2767.

Eg-Ni: electrogenerated nickel

H2 / Pd-C

RC NH2

CPh3 O

Fe3(CO)12 / CH3OH reflux 8 hr

Eg-Ni

OCH3 RC N

NH2

NO2

NH2

1. NaBH4; 2. Al (Hg)

RC NH2 H2O2 // Ac2O, heat / H3O+

RC N Me

NH2

sulfided platium not affect: aromatic rings, ketones, halides, nitriles, amide, easters

JOC, 1999, 64, 2301.

+N O

NO2

NH2

H2 / Pd-C

- HCHO NH2

N CH2

OCH3

4b.3 R C N Z

R C N R'

i RC NH 2 R C N

1. HCHO / HCO2H

2. HCHO // H2 / Pd-C

CO2Et

NaBH4

R NH2

COOH

HC(OEt)3

OEt R NH

OEt

NMe2 NH2 HCHO

CO2Et

HCO2H

NH2

CH3 N

CH3

H N C H H

O H C H

OEt R NH CH2

N N N

R C N

O H C O-

R N CH3 H

NH CH3 O H C H

R-BCl2

N N N B Cl Cl R

BCl2

NO2 MeO2C

B Cl Cl

N - N2

NaBH4 CoCl2-6H2O (cat) rt

mild condition NO2 MeO2C

NH2

CH3 N CH3

O H C OCO2

1. RBCl2 / base

CoCl2-6H2O

H CH3

R' N3

2. NaBH4 /

R N CH2

CO2

HCOOH

R N CH OEt

COOH

HCHO

- + R C N N N

new: p-TsOH / HC(OEt)3 / EtOH, reflux 5 hr

OEt O

H N CH3

HC(OEt)3

CO2Et

JACS, 1933, 55, 4579.

NH2

about HC(OEt)3: ethyl orthoformate ($ 25 / 1 L), may function as dehydrating agent HC(OEt)3 becomes HCO2Et 原甲酸三乙酯 O CO2Et O OEt old: FeCl3, MgSO4 in Soxhlet extract, reflux 40 hr CH3COCH3 H OH

1. HC(OEt)3 // NaBH4; 2. R2CO // NaBH3CN

RC NC

Synthesis, 1979, 537. high yield not affect:: NO2, C=C, CN, COOR, COOH

H R

4-c

C-N

C-X

Ph CH2Br

1. NH3

PhCH2NH2 + (PhCH2)2NH + O

O N K

2. Gabriel:

N K

N2H4

Ph CH2Br

3. Delepine

H2O

commercial available, tetramer of Me3N

N N

Ph CH2Br

N N

Ph CH2NH2

O N

Gabriel amine synthesis

NHNH2 NHNH2

N2H4

N CH2Ph

N N

not good, usually contain polyalkylation products

(PhCH2)3N

Ph CH2NH2

内服后遇酸分解出 HCHO, 可做尿道消毒剂, 治膀胱炎 urotropine (乌洛托品) methenamine (六甲烯胺) hexamethylenetetramine (环六亚甲基四胺) N

Br-

4. NaN3 / RED

5. Unpolung

i. LAH, NaBH4 ii. H2 / cat iii Zn / HCl; Al (Hg)

CH2Ph

R Br

i. Mg // NH2Cl ii. Mg // PhSCH2-N3 // KOH

OMe

R MgBr

NH2Cl

R NH2

OCH3

OMe Br

PhS

MgBr

OCH3 N

SPh OMe

CH2Ph

OCH3 NH2

H SPh

-N2

OMe

OCH3

6. CH3NH2 (aq) / EtOH // HCl / Et2O JOC, 1988, 53, 2918.

CH3NH2 / EtOH O

4-d

C-OH

HCl / Et2O Cl

C-N

NHMe

O NK

in fact: C-OH C- OTs C-NH2 OH

TSCl

1. Gabriel:

NH2

N2H4

2. Delepine 3. NaN3 / RED

4. CBr4, PPh3, NaN3, DMF // PPh3 / THF JOC, 2000, 65, 7110.

CBr4 PPh3

NaN3

N N N N

PPh3 THF

NH2 N

4-e

C-N

C=O

N CH3

CH3NH2

reductive amination!

NH CH3 NaBH3CN

acid

1. RNH2 // NaBH3CN most general

PH 6

O SiMe3

Me3SiN3

SiMe3

N N N

N N

N N N

LiAlH4

2. Me3SiN3 // LiAlH4 via: acetal / ketal type exchange

H N

NH2

RaNi / H2

4. PhNHNH2 // Al (Hg)

H O

PhNHNH2

N NHPh

H N

N NHPh Al (Hg)

(radical)

Leuckart reaction O O

6. RNH2 / n-Bu2SnClH / HMPA

NH2

NH3

NH2

Synthesis, 2000, 789. immonium salt

4-f

C=C

NHPh

n-Bu2SnClH HMPA

N H Sn

via:

Ph By

By P(NMe2)3

C-C-N C-C-NH2

NH2Cl B

B2H6 / NH2Cl B2H6 / H2NO

B2H6 / H2NOSO3H H+

C=C

PhNH2

CHO

CO2

B2H6

C=C

NH2 LiAlH4

NH3

catalytic reductive amination

5. NH4+HCO2-

H N N H

3. NH3 (excess) // RaNi / H2

via: hydrazone

C-C-NHCOCH3 CH3CN / H3O+

B RR

CH3CN

R N B R H

N Cl H

N C CH3

H2O

OH N C CH3

NH2

O NH C CH3

CH3CN: bp 81-2, mp -48; polar solvent, for UV, HPLC, NMR (CMR very high field 0.86 ppm, ring current)

R C NH2 4-g

R C N

R C NH2 R'

4-g.a form

R C NH2

4-g.b form

R C NH2 R'

AlH3 / THF

NH2

TH, 1989, 30, 5137.

R'MgX // NaBH4

JOC, 1993, 58, 4313.

R'MgX // Li/NH3(l)

JOC, 1987, 52, 3901.

R'2CuLi // NaBH4

O R C NHR

JOC, 2000, 65, 8152.

THF

R'Li // NaBH4

4-h

AlH3

C N

R'M // H

NH2

TH, 1989, 30, 5139.

R CH2 NHR

CO2H

LiAlH4 N

1. LiAlH4

JOC, 1985, 50, 1711.

THF

O 2. NaBH3(OCOR) O

B2H6

CH3 C NH

3. B2H6

CO2CH3

CH3 CH2 NH

CO2CH3

4. Et3O+ BF4- // NaBH4 1. Et3O+BF4-

5. P4S10 // RaNi NH

6. Lawesson's reagent // RaNi

not for B2H6, affect C=C

2. NaBH4

NH NH

1. Et3O+BF4O

Et3O+BF4-

OEt

- Et2O

2. NaBH4

N OEt H

- EtOH

Et3O+: Et source, convert to good leaving group; not use EtBr different from: HC(OEt)3 dehydrating agent; H2C(OEt)2 (ketal agent) NH O

[Sulfide]

NH S

RaNi

4-i

RCH2

4-i.1

O C Z

RCH2

R CH2 NH2 R CH2 NHR'

O C Z

R CH2 NH2

O RCH2 C OH

NH3

R CH2 C Cl NaN3

HN3

Schmidt

O RCH2 C NH2

O SOCl2 R CH2 C OH

1. Hofmann: SOCl2, NH3, Br2 / OH- / heat not good, lots of side-products, Br2 strong oxidant toxic, Schmidt died of it 2. Schmidt: HN3 // H2O

Beckmann

R CH2 C CH3

R CH2 C N N N

R CH2 C CH3

Application:

most useful O

CO2Et CO2Et

OH-

CO2Et

R CH2 N C CH3

R CH2 C CH3 anti-migration

H2O

R CH2 NH2

H2O

O R CH2 N C CH3

H2O from outside CO2H

CO2H

CO2Et

R CH2 N C O

OTs

O RCH2 C Cl Curtius: NaN3 // H2O

O R CH2 C N-Br

Curtius

O R CH2 C N N N

Hofmann (see below)

Hofmann O O Br2 R CH2 C NH2 R CH2 C NH-Br OH-

CO2H

H2 / Pd-C - CO2

RCH2 C CH3

Beckmann: NH2OH // TsCl / H2O JACS, 1981, 103, 7368.

2.TsCl

R CH2 NHR'

Pr- source

4-i.2 RCH2

Bu2AlH

n-Pr3Al 。 80 C

1.NH2OH O

O C Z

H- source

N H

O PhI(OAc)2

NH2

O RCH2 C NH2

OCH3

KOH / CH3OH

JOC, 1993, 58, 2478.

PhI(OAc)2 // KOH / CH3OH O R

PhI(OAc)2 NH2

O R

Ph OAc

KOH

O R

CH3OH

Ph OAc

R PhI, OAc

O R NH C

OCH3

C=O 5- a C=O g C(OR)2 d C C b C=S e C N C(SR)2 c C=N-OH f C=C-OR h C-OH C=N-H C=C-SR 5-a

C=O

i C-NH2 C-NO2 j C-Br k C-H

NaNH2

CO2

C OH

H3O+

camphor

Ac2O

NaBH4

C NHNH2

O R

NaNH2

NaBH4

Ac2O

CO2 / H3O

SOCl2

H3O+

HNO2

CH2

O OO

OH-

Br2

KOH

CeCl3

H 3O

CH2R

LDA

limit for: 6 ring, with 1 α-position blocked

TsNHNH2 CH2R

MeLi

1. in the presence of CeCl3, H- attack C=O; otherwise may attack β-C . and give mixture; mechanism: form Ce-H, follow by H- transfer other choice: use Al(OiPr)2 / iPrOH (MPV)

KOtBu

HgCl2

MsCl

CH2

KOH

TMSCl MCPBA LAH

O CrO3

CH2

PhCHO

OH-

NaBH4

CeCl3

H O

H+

Ph OH

R O

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

LDA O TsNHNH2

N N Ts

Li N N Ts H

MeLi

SiMe3 O MCPBA

Li into structure

LAH

SiMe3 OH

CrO3

SiMe3 O

OMs

O LAH SPh

PhSSPh Li

SPh

HgCl2 CH3CN (aq)

N2, Ts-

thioenol ether OH

KOtBu

SiMe3 TMSCl

MeLi

SPh H

MsCl

O O3 Zn

H2SO4

H N N Ts

C O O O C

2. need Zn, convert to C=O; other choice Me2S

aqCH3CN

v. via: epoxysilane O

O3 Zn

LAH

Br2

O CrO3

HBr

iv. via: thioenol ether O

O OH

iii. via: aldol process NaBH4

corticosteroid

NaBH4

PhCHO

epicamphor O

NaBH4

hecogenin acetate CrO3

HBr

OH OH

HO O

N2H4

ii. via: α-haloketone

NH2

not use NaN3 directly, avoid attack β-C

O O

N2H4

H3O+

N C O

C N N N

i. via: α-CO2H

COOH

H 3O +

HNO2

C=O

SO2Cl OAc COOH

OH COOH

5-b

C=S

C=O

i. hydrolysis

ii. MCPBA

5-c

C=N-Z

5-c.2

5-d

C=N-OH

C=N-H

C C

MCPBA

OH H

CH3O O

NMe2

NOH

C=O N OH

5-c.1

OH H

CH3O

RaNi

i. RaNi ii. TiCl3 iii. KMnO4 / Al2O3 THL, 2001, 42, 4775.

H3O+

C=O Hg2+ / H2O HgSO4 / H2O / H2O

O KMnO4 / Al2O3 acetone rt, 5 min

C(CH3)3 O

NH H3O+

C(CH3)3

JOC, 1970, 35, 858.

NH2

JOC, 1972, 37, 2138.

Hg2+ Hg

not certain of which mechanism

H2O

HgX

HgX OH H

5-e

C N

C=O CN

Ph R-CH2-C

N O R-CH2-C H

5-e.1

O 5-e.2

5-e.3

R-CH-C H R' O R-CH-C R" R' R' X / n-BuLi OH OH

CH3I R''MgBr H3O+

1. DIBAL /

Al (iBu)2H

H3O+

C N Al

C H

H3O+

2. HCl./ SnCl2 / Et2O 3. OH OH

Stenphen reduction mostly for Ar

H3O+

OH OH

R CH2 C N

H R' X O

CH3I

n-BuLi

H JOC, 1973, 38, 2129.

O C

R R

O H

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

R''MgBr O

N R''

H3O+

H R'

R' H3O+

R R

H3O+

R''

5-f

C=C-X

C=O H+

H3O+

C=C-OR C=C-SR

H3O+

OCH3

OCH3 Hg2+

Hg2+ / CH3CN (aq)

H2O

tpye:

CH3CN (aq) SCH3

reactivity:

SR thioenol ether

OR >>

Cl O

5-g

C(OR)2

OR OR

H3O+ / solv (aq)

SR SR

Hg2+ / H3O+

O O

H3O+ / solv (aq)

OEt C OEt OEt

vinyl chloride

SR >>

O R

C=O preparation: acid catalyst TsOH CSA (camphorsulfonic acid) Amberlite resin

a very common protecting group, deprotect back to ketone

S S

enamine

OH OR

- CH3OH

OR enol ether

use:

CH3O

+OCH3

H3O+ / solv (aq)

OR OR

OH OH

acid catalyst

O O

RMgX / H3O+

OR OR

ketal

Hg2+ O

via:

RMgX R

OEt H

R OEt

C H

RMgX

OEt C OEt H

H R

OR OH

hemiacetal

R R

OR OH hemiketal

unstable: only in aqueous acid stable in: basic solution: LDA, NaOMe RED: LiAlH4, NaBH4 organoMetal: RMgX, RLi

H3O+ OEt C OEt OEt

O O

acid cat

CH3CN

Hg2+ / H3O+

CH3O OCH3

HOCH2CH2OH

H3O+

acetal

CH3OH acid cat

Type: H OR

O R

5-h C-OH

O 1st alcohol

THL, 1979, 5, 399.

C=O R C H

AcO OAc I OAc O O

O R C R

N+ O

alcohol

R C OH

H DMSO

PhCH2OH

PhCHO

HCl

via: PhCH2

DMSO

SynLett, 2002, 2041. H

CH3

PhC

S CH3

Synth. Commun., 1986, 16, 1343.

DMSO

Ac2O

+ Me2S

OH R C R

O C CH3

O O C C OH O

H3C S CH3 O

DMSO

R C R ClCO-CO2H

+ HOAc

Moffatt oxidation

Et3N

Swern oxidation

MeO

OH DDQ

i. Jones reagent ii. KMnO4

JOC, 1985, 50, 1332.

N OH

TH, 1975, 2647. i. PCC TH, 1978, 2771. ii. PDC iii. Jones reagent (Na2Cr2O7-H2SO4 / acetone) iv. Moffatt oxidation (DMSO / Ac2O) v. Swern oxidation vi. DDQ / dioxane JOC, 1997, 62, 5246. vii. MnO2 / CHCl3 viii. Oppenauer zoidation Al(OiPr)3, acetone ix. K2Cr2O7 (s), rt solvent free THL, 2002, 43, 8843.

CHO

Pfitzner-Moffatt oxidation

R C H

S OH DMSO S DCC Can. J. Chem, 1978, 56, 1268.

NaHCO3 / NaI H 60 %

H11C5

OCH3

N O+

RCH2OH

DMSO

PDC CH2OH 70 %

H11C5

OCH3

O 1st

CHO

OCH3

92 %

CH2Cl2, rt, 30 min JACS, 1991, 113, 7277.

2nd alcohol

i. PCC ii. PDC iii. Collins reagent CrO3 - 2 Py iv. N-oxide v. DMSO / DCC vi. DMSO / HCl vii. DMSO / NHCO3 / NaI viii. Dess-Martin Reagent

OH PDC

H3C S CH3

C R

DDQ:

dioxane JOC, 1980, 45, 1596.

Cl O

O aldehyde

R C OH

Al(OiPr)3

Ag2O HO

PCC (pyridinium chlorochromate) (Py-HCl-CrO3) most widely used PDC (pyridinium dichormate) (H2Cr2O7 + 2 Py) use 1 - 1.2 eq.

. N CrO3 HCl

N+ H

Cr2O7- 2 2

acetone

+ Me2S + Cl, CO, CO2 + Et3NHCl

Synthesis, 1979, 537. O

Collins reagent: (CrO3 - 2 Py) Swern oxidation: (DMSO, oxalyl chloride, Et3N) 1. drawback: use 6 equivalent, a messy reaction drawback: react at low T Synthesis, 1981, 165. 2. must be very dry, fire easily; purify by CaH2 3. an old oxidizing material, isolated by Collin. JOC, 1977, 42, 1991. Ag2O: 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

C-NX2

C=O O

5-i.1 C-NH2

C=O

i. Corey approach: subtituted-quinone //

H3O+

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

Ph Ph

// H3O+

H3 O+

NH2

C H

PhCHO

NH2

Ph Ph

NH2

MCPBA

PhCHO

N C Ph

C=O Nef reaction Chem. Rev. 1955, 55, 137.

i. Et3N // H3O+

ii. TiCl3 / pH 1 or 6

H O

McMurray reaction O

iii. SiO2 / NaOH // H3O+

JACS, 1977, 99, 3861.

iv. LDA / MoO5-Py- / HMPT // H3O+

v. NaOH // CH3OH / H2SO4 //

H3O+

TiCl3 pH6

NO2

THL, 1981, 5235.

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

NO2

OMe

1. NaOH

S Synthesis, 1988, 379.

2.CH3OH H2SO4

H3O+

OMe

Ph O

vi. KMnO4 / KOH

H3 O+

N O O

TiCl3 pH1

N C Ph

- PhCHO

O NO2

H3 O+

H3O+ Ph Ph

MCPBA

Et3N

NO2

N C Ph

5-i.2 C-NO2

Ph Ph

JOC, 1969, 34, 2438.

KOH NO2

KMnO4 N

OO-

O O

O Mn

O O

- MnO2 - NO3-

5-j

C-Br

C=O

direct:

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

1. DMAPO / DBU / CH3CN 2. NaIO4 / DMF a new method

NaIO4 / DMF

N O

ii. DMSO / ZnS

5-k C-H

RCHBrMe OH Br

JACS, 2003, 68, 2480.

N,N-Dimethylaminopyridineoxide

84 %

3. DMSO reagents: THL, 1974, 917.

via:

DMAPO

THL, 2003, 44, 1375.

150 C, 40 min

i. DMSO / AgBF4

NMe2

indrect: change to RC-OH followed by oxidation

Ph DMSO AgBF4

RC(O)Me Br

OH O

DMSO

DMSO / AgBF4

- AgBr

ZnS

- Me2S

C=O JCS, 1932, 1875.

1. SeO2

2. DDQ / TFA.

I 3. (3 eq.) O

H DDQ

CH3

TFA Ar

OH O

CH3

Synthesis, 1979, 537.

SeO2

JACS, 2001, 123, 3183.

N H

CF3 O

Ph-F / DMSO a select oxidant

CH2

CH3

CHO

H3O+

DDQ N O

CF3 O

N H

CHO

C C g

dC C

6- a RC CH b RCH2-SO2Ph c C C

e RCH(CO2H)-CH3

f -C(O)-CH3

O X

CRR'=CHX n-BuLi

R C C H

6-a

RC CR'

RC CH

R C C R'

R C C H

R C C CHOH R C C H

R i. n-BuLi / RX

R Br

O R C H R C C Li

n-BuLi

OH R C C C H R

R C C Ph

R C C H

Pd I

Ph-I

THL, 1975, 4467.

R C C H

N Li

OMe

R C C Ar

R C C H

iv. CuI, NaI, Na2CO3, R

RCH2-SO2Ph

CH2Cl

RC CR'

Cl CH2 C R

Pd C C R

R C C Ph

addition steric δ-

C C R

R C C Li

OCH3

OMe

n-BuLi

R CH2SO2Ph sulfone

n-BuLi / R'CHO // Ac2O // KOtBu

δ+

N H

OMe

steric base, prevent Nu attack

Pd Ph

6-b

LiBr

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

ii. (Ph3P)2PdCl2, CuI, Et2NH / PhI

iii.

RCHO

CH2 C

SO2Ph R C C R' OH

Ac2O

Synthesis, 2000, 691.

SO2Ph R C C R' OAc

SO2Ph -HOAc

R C C R' H

KOtBu

R C C R' - PhSO2H

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

6-c

KAPA

C C

C H

JACS, 1975, 97, 891.

K+N-HR

R H

use: KAPA

i. move to terminal

ii. protect - deprotect

limit: continueous CH2, not branch

R C C C CH2 CH2-CH2 CH2 CH3 H allene

propargylic

NH2 NHK

H R C C C C H

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

R C C C C

CH2 CH2 CH3

R C C C C

CH2 C CH

HO C CH CO

HO C

use: i. Br2 / CCl4 // KOtBu

JACS, 1941, 63, 1180.

6-e

R CH CH3 CO2H

Fe(NO3)3 EtOH H

Ph R CH

R C C H

CH3

CO2H

Pb(OAc)4, LiCl Br2/CCl4 R CH CH2 KOtBu KOtBu CH3

use: Pb(OAc)4, LiCl // KOtBu // Br2/CCl4 // KOtBu Cl-

in fact: convert to C=C firstly

OAc R C C O Pb OAc OAc O

LiCl Pb(OAc)4

O CO2H

R C C H

Cl R C CH3 - CO2, - Pb (OAc)2, -OAc1.NaBH4

H Cl

2.HOAc

C CH

1.B2H6

CO Co Co CO CO CO CO CO

ii. Br2 // KOH

choose B2H6, not H2/cat: Co poison cat

C C

CO CO CO CO CO

Co2(CO)8

C C

irreversible at the final step

Fe(NO3)3: weak oxidizing agent

6-d

CH2C C

2.KOtBu

1.Br2/CCl4 HO

involved: reduction NaBH4, oxidation CrO3.Py, prevent α-H attacked by Br2

2.KOtBu O 3.CrO3.2Py

6-f

O R C CH3

R C C H O R C CH3

i. NaBH4, H3O+, Br2, KOtBu

ii. NH2OH, NaNO2 / H2SO4 // Ac2O / DMAP

NaBH4

O R C CH3

OH R C CH3

H3O+

R C CH2

H2SO4

NH2OH R C N OH

Br2

RCHBrCH2Br

R C N OH2

NaNO2

CH3

KOtBu

R C CH

O R C N N O C H H H

JOC, 1979, 44, 4116.

OAc

Ac2O

R C N N

DMAP

C H

R C CH O

N O

iii. LDA, ClPO(OEt)2

R C CH3

OPO(OEt)2

LDA

R C CH

ClPO(OEt)2

JOC, 1980, 45, 2526.

R C CH

vinyl phosphate

N DMAP: 4-N,N-Dimethylaminopyridine German invention, as acylating agent

N C O

CH3

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

TsNHNH2

use: TsNHNH2 / EtOH, heat

NH Ts

THL, 1967, 3943. H2O2

N N

Ts-

Na / NH3(l)

CH3 CH CH2 (MVK) O

Robinson Annulation O

6-h

LiNH2 / NH3 (l) use: LiNH2 / NH3 (l) / R-X

6-i.

C C

JACS, 1955, 77, 3293.

R C C R'

JACS, 1958, 80, 4599.

Ar i. NaOEt (when X = Br)

Ar'

via:

OSO2CF3

ii. BuLi (when X = -OSO2CF3)

NaOEt

Ph BuLi

via:

JOC, 1978, 43, 364.

Ar Ar'

Br ?

C C

C O

i C C

C C

c CX-CY X

7- a CH-CX

C C

use:

H OH

C-OH

h C CH

e -C(O)-CH3

b CH-CH 7- a

i. p-TSOH.H2O or CSA ii. weak acid: HOAc; HCO2H; H2C2O4 iii strong acid: H2SO4; HCl iv. ArSeCN, PBu3 // MCPBA

Dean-Stark

MsCl

H OMs

use base: i. RONa; ii. KOtBu

C C C C

MsO

S O

iii. CH3I N

heat

NMe2

HCHO

H i. DDQ ii. chloronail iii. Pd-C; or Ni; Pt, Rh

OAc

MeO O NC

NO2 Se

MeO N

H H2O2

NC O

heat

Cl Cl

MeO2C

O Cl

DDQ

Pd-C

MeO

RCH2CH2-O-PBu3 TBDMS O H . O

DDQ

RCH2CH2-OH Ph-Se-PBu3

:PBu3

CO2Me

OAc CO2Me

heat

mechanism:

OAc

heat

Ph-Se-CN MeO2C

NMe2

MCPBA

NMe3 OH

Ag2O

HCO2H

heat CH3

H2SO4

NMe3I

NH2

minor

syn elimination

compare:

i. CH3I / Ag2O // heat (Hoffman elimination) ii. HCHO / HCO2H // H2O2 // heat (Cope elimination)

CH3I (excess)

7- b C

p-TSOH major

SMe

I DBN

C C

use base: DBN

H NH2

applied for reactions: without rearrangement; no regiosiomer

use: heat

or KOtBu

i. n-BuLi ii. CS2

H OC(S)SMe C C

RONa

use: heat

H OAc

C C

(CO2H)2 / benzene

MCPBA

MeO

RCH=CH2

heat TBDMS O .

23oC, 14h, 88%

O .

THL, 1991, 3679.

7- c

C C

CSCl2

C C

base C C

i. CSCl2 /

P Ph

OH OH

thiophosgene

ii. CSCl2 / P(OMe)3

i. Zn / acetone

ii. In / MeOH JCS.CC, 1998, 2113.

NaI / Zn (Cu)

OMs OMs C

OH I

via:

CSCl2

Et H3C

OR S P

OR OR

CCCCC 36 oC CCCC=C 31 oC CCCC C 148 oC

ii. purify compound

H I

OR OR

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

CH3

POCl3 / py // Sn

P(OMe)3

Cl Cl

or: ?

S P

thionocarbonate

HCO3H

OH OH

POCl3 Py

Cl P Cl O H CH3

Et H3C

OAc

AcO AcO AcO Br

Zn HOAc

OAc OAc

JOC, 1978, 43, 364. C

OAc

Zn / HOAc

OAc O

7- d

C H

7-d.1

O C

i. WCl6 / RLi

product retention

ii. LiPPh2 / CH3I

product inversion

LiPPh2

CH3I

H PPh2

PPh2

oxaphosphetane

(EtO)3P R2

O C

Synthesis, 1977, 1134.

N NH

TsNHNH2

n-BuLi

C Br

HO HO

use: TsNHNH2 // n-BuLi

Pregnenolone (a female hormone)

Li O

N NH Ts

N N Ts

H2O Br2 CH3-S-S-CH3

JACS, 1972, 94, 7748.

TsNHNH2 O

EtOH

use: (EtO)3P

C CH3

SN2

CH3

OH H

H R C C CH2 CH2 CH2 OH H

7- e

CH3

(special structure):

7-d.2

WCl6 RLi

C H

iii. Na

n-BuLi TsNHN

JOC, 1977, 42, 1079.

S CH3

7-f

7-f.1 RC

C O

C RC

CR' O PPh3 + H C CO2Me

not CO2Me

i. Wittig Reaction 1953 discover (olefination reaction)

RO = MeO-, EtO-

JOC, 1968, 33, 780.

stable ylid gives trans (E)

PPh3

not good for Ph3P=CH2 function as base:

Me3SiC-H-MgBr H O

THL, 1973, 3947. C

N2H4

iv. CH2(ZnI)2

PPh3 + O Et expensive unstable ylid gives cis (Z)

+ Ph3P CH Et

water soluble, removed by extraction (comparison: O=PPh3 highly soluble in organic solvent)

Synthesis, 1984, 384. Me3SiCHR-Li+ + === Ph3SiCH2Br + n-BuLi (exchange) Ph3SiCH2 Li Me3SiC-H-MgBr === Me3SiCH2Cl + Mg (metal reduction) Ph3SiC-HCH2Ph === Ph3SiCH=CH2 + PhLi (addition to vinylsilane) === Me3SiCH2CO2Et + Li (metalation) Me3SiC-HCO2Et Me3SiCH=PPh3 === Me3SiCH2PPh3+ X- + KH R

THL, 1981, 2751.

not O

use: (RO)2PO-CHR'

ii. Phosphonate Wittig Reaction (Horner-Emmons Modification) iii. Silyl Wittig Reaction (Peterson Reaction)

difficult to prepare

via: betaine, oxaphosphetane (NMR)

use: Ph3P-CHR'

Ph3P CH CO2Me

R2CO

C NHNH2

SiMe3

C N

N C

H2S

N C

Ph(OAc)4

CH2(ZnI)2

Synlett, 1988, 12, 1369.

CH2

PPh3

C S

v. CH2CHBr2, Sm, SnI2 / CrCl3, THF

Ph O

Chem. Lett, 1995, 259.

N N C PPh3

O CH2 OH

N Me

use: Ph

PPh3

S C

N. R. if use: Ph3P-CHR' due to steric hindrance

// Al (Hg)

N Me

vii. Grignard reagent:

1. TMSCH2MgCl

use: TMSCH2MgCl

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

O H

2. NaOAc, AcOH

SiMe3

H O H

via:

C R

methylenation advantages over the Wittig: 1. by-products are more easily removed, 2. reaction suffers less from steric effects.

R C

NMe Al (Hg)

CH2 Li

Ph S

vi. Sulfoximide (Johnson C.)

7-f.2

CR R C

N2H4

R2CO

C NHNH2

R not for Wittig, ylid unstable

C S

O N2H4

PPh3

3. H3O+

N N C

C PPh3

1. H2S 2. Pb(OAc)4

N C

R C

O TiCl3

Zn-Cu Ti (II) O O

commercial available butene side product (trimer)

Ph(OAc)4

N N

C R

P(OEt)3 S

N N

R S C

1. H2S 2. Pb(OAc)4

TiCl3-LiAlH4 / THF JACS, 1974, 96, 4706. TiCl3 / Mg BASF, 1973, 2147. TiCl4 / Zn Chem. Lett, 1973, 1041. TiCl4 / K JOC, 1978, 43, 3253.

PPh3

H N

H2S

i. use: N2H4 / H2S / Pb(OAc)4

ii. McMurry Coupling

N C

C N

via:

R C

7- g

form trans alkene:

form cis alkene:

not use H2 / Pt: might convert to alkane

i. Li / NH3; or other IA metals ii. Li / EtNH2 iii. LiAlH4 / THF

i. H2 / Ni2B (P-2 catalyst) ii. H2 / Pd-CaCO3 (Lindlar catalyst) iii. H2 / Pd-BaSO4 iv. B2H6 / HOAc (Diborane) v. N2H2 vi. HCHO / Pd-C / Et3N

R H

R C C R

C C

H R

C C Me

C C H H H

Ph C C

CHO

HCHO Pd-C Et3N

Ph C C

C R

C CH

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

iii. Cp2ZrClH / RX (hydrozirconation)

i. R2BH / Br-CN (hydroboration)

DIBAL

H C

R C

R CN

n-BuLi

Cp2ZrClH

B CN

C H

Syn elimination

ZrCP2 Cl

R H

H C

C R'

H CH3

C B R

CH3I

R'X

C H

CN-

B R

C C

AlR2

Br-CN

B R

all form trans alkene:

C H

CH R BH 2 (Syn)

7- h

JOC, 1980, 45, 4926.

CHO

CN R

7-i C

application: protecting group

not for

via dihalide

via halohydrin via epoxide

C C

C=C

double bond might move

C=C

X X C C

C=C

H X O

C=C

via diene-olefin addition

CO2Et

7-j

C-OH

C NO2

MnO2 / Ph3P CH3 Br- / MTBD

JACS, 1998, 100, 877.

CO2H 180C

C=C Ph

MnO2 Ph3P CH3 BrMTBD

NO2

in situ alcohol oxidition Wittig rxn

PhSO2Cl

COOH

1. OH2. H3O+

RONa

C=C

LAH

NaBr CO2Et CO2Et

CO2Et

C=C

200 oC

CH2

C=C

C C

via diradical

CO2Et CO2Et

EtO2C CO2Et

N N CH3

Synlett, 2002, 215.

MTBD

CH2

C-X c C=O d C(O)Z e C-H

8- a C-OH b C-NH2 8-a

C-X

C-OH

8-a.1

C-OH

C-F

O O Chem. Rev., 1996, 96, 1737. S N F S JOC, 1993, 58, 3800. O O O

CHCl2 O

1. CF3CHFCF2NEt2

CH3

2. F3S-NEt2 (DAST) $ 500 / 125 g

OH 2. HOAc / iPrOH

CH3 S O 3. CF3CHFCF2NEt2 (Ishikawa reagent) Cl

1. SOCl2

8-a.2

C-OH

C-Cl

2. HCONMe2 /

N Cl

3. COCl2 / DMF

Me N

HCONMe2

JOC, 1983, 48, 2625.

F NHCOCHCl2 NMe2

O S O

via:

N N

Org.Lett, 2002, 4, 553.

4. CCl4 / PPh3 CCl4

5. HCl / ZnCl2

PPh3

6. HCl fit for 3rd alc, directly

Can.J.Chem, 1968, 46, 86. HCl

8-a.3

C-OH

C-Br fit for

1. HBr 2 PBr3

Can. J. Research, 1932, 7, 464.

3. TMS-Br (HMDS / PyH Br3)

8-a.4

C-OH

C-I

1. HI PI3 CH3OH CH3I 2. PI3 2. PPh3 / I2 JACS, 2003, 125, 1458.

1st

TMSBr

ZnCl2

alc

JACS, 1938, 60, 2497.

good for 3rd alc

OH OH

Si Si

prepare in situ

JOC, 1980, 45, 1638.

(HMDS)

JCS, 1905, 87, 1592.

3. TsCl / C6H6 // NaI Intermediate. Org. Chem, 1988.

OTBS BnO

PPh3 / I2 OH

96 %

OTBS BnO

I Me

N + Br3 H

(PyH Br3)

TMS-Br

PBr3

$ 35 / 1000 g

PBr3 PI3

$ 65 / 500 g $ 80 / 50 g

C-X

8-b C-NH2

NH2 Cl

C-F

C-NH2

NaNO2

N2BF4 Cl

F Cl

HCl, HBF4

NaNO2 / HCl / HBF4 /

for aromatic amine

C-X

8-c C=O

C-F

C=O

CF2Br2 / Zn

F F JCS.PT I, 1993, 335.

58 %

8-d C(O)Z

C-X O

8-d.1 8-d.2

C(O)Z

C-Cl

C-Br

Cl RhCl(PPh3)3

O OH

1. AgNO3/KOH 2. Br2

Chem Rev., 1956, 56, 219.

Ber. 1942, 75, 296.

8-e C-H 8-e.1

C-X

C-H

C-F

F+

PhCH2C(O)CH3

Chem. Rev., 1996, 96, 1737.

N F

iii. F2-N2 / CFCl3-CHCl3

Ar F

JCS.CC, 1994, 149.

ii. F-TEDA-BF4

CFCl 3-CHCl3

JOC, 1988, 53, 2803.

HF / electrolysis already industrilized

v. NF3O / TBAH / CH3CN

F electrolysis 1.4-1.6 V anode: Pt or Ni O

R = CH3CO, COCF3, CCl3, NO2 O

O THL, 2003, 44, 2799.

R' TBAH / CH3CN rt, 12h

R '' H

R' R '' F

NBX R1

R3 H R2

Mg(ClO4)2

C-I I2 / HNO3

X R2

X = Cl, Br, I

I JACS, 1917, 39, 437.

N X

NBX:

JOC, 2002, 67, 7429.

C-H

TBHA: Tetrabutylammoniumhydroxide

X = Cl, Br, I

NBX / Mg(ClO 4)2

8-e.3

Ar Me-CN, R TEDA=triethylenediamine

C-X

CH3

F 55-90 %

90 % 1. regioselective fluorination at the more substituted positions 2. electrophilic in nature

NF3O

C-H

F2-N2 adamantane

8-e.2

F-TEDA-BF4

iv.

PhCHC(O)CH3

I2 / HNO3 86 %

C-CH3 9- a C-X

9-a C-X

C-CH3

Me3Al (CH3)3Al Br

CH2Cl2

bridgehead methylation 98 %

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