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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

O

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

C

-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

O

C-H

RCH2 O S CH3 O 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

Ph

ii. Ph2SiHCl / InCl3

Ph2SiHCl / InCl3

Ph

Ph

OH

H

Cl2In

CH3

OH CH3

JOC, 2000, 65, 6179.

Cl

C O Ph

SiPh2

InCl3

Cl

S

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

Ph

Ph

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

H

JOC, 1976, 41, 3064.

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

Br

Mg / Et2O

H

H2O

(Grignard reagent) Br

n-BuSnH N

N

- N2 CN CN (AIBN) azobisisobutyronitrile radical initiator

CN

R

H R

n-BuSn n-BuSnBr

n-BuSnH

n-BuSn

R


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

O

NH2Cl (3). Ar-NH2

NaNO2 H3PO2 HCl

via:

-

1-d

C-S

C-H

Ag2O

radical mechanism

RCH2NMe3 OH-

N

SO2Ar

Ar

Ar-H

RCH2NMe3 X

(4). RCH2NH2

RCH2

S Cl

CH3

RCH2N SO2Ar

- BuH

tosylamide

O

p-TsCl

BuLi

SO2Ar

R=CH2

N

NaH NH2 - ArSO H 2

Ar

N

(2). Li / NH3

N

N

Ar-H

JOC, 2001, 66, 8293.

R-CH3

JOC, 1985, 50, 427.

EtO2C

EtO2C

(1). Raney Ni

Ar

NH

HN

N O

MeO2C

CH2Ph

Raney Ni

Raney Nickel: Ni - Al alloy, suspension HN

N CH2Ph

S MeO2C

H

(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

SH

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

O

H

H

H

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

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

SH

/ 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

Ph

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

Ph

NN H

OH-

H

OHN N H - N2

N N Ph

major side-product: drawback of the reaction

Ph

HCO2NH4

Synthesis, 2001, 16, 2370.

H

N N Ts

H

for acyclic, may C=C side product

H(6). enol derivatives:

Tf2O /

N

O

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

O (7). Et3SiH / CF3COOH

NO2

Et3SiH Ph

NO2

CF3COOH JOC, 1973, 38, 2675.

O

Ph H O C C

O

CF3 S O O

S CF3 O

OTf C C

H H H2 PtO2

N

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 ℃

N

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

O

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

CO2Me

O

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

D

JCS, PT1, 1986, 546.

prepare isotope EtO2C N N CO2Et

OEt O

R

OH-

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

OEt n-Bu2SnI

JOC, 2001, 66, 8690.

- 2 CO2

R R

I

R

syn-addition

I

OEt not radical mech.

via: O

R

- N2

OEt

H3O+

MgBr2-Et2O

H N N H

R C C

O Sn

H

H R 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

Ph

1-h C CO2H

C-H

R

H

solvent

O

(1). particular structure: β-CO2

Ph

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

CO2H

N R

O

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

Ph

O Ph CO2

- CO2

Ph

O RCH2

C OH

O SOCl2

RCH2

C Cl

R

O

PhSeH RCH2

Ph H

R

R pyridinium betaine

e-

N

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

Rh

PPh3

PPh3

- PPh3

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

Rh

1-j

C(O)X

C O

oxidative addition

Rh

Cl

Cl

Cl R H

PPh3

reductive elimination

R Cl

R C H

PPh3

O R

PPh3 PPh3

-CH3

HSiEt3 / B(C6F5)3

Rh

PPh3 PPh3

H

R

rearrangement

Cl

H

R C

CH3

JOC, 2001, 66, 1672.

Rh

+

C O

PPh3 PPh3


RC-OR 2- a b c

RC-OH RC-(OR)2

d e

RC-H RC=C

RC(O)OR

f

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

F

CsF

RC-OR

R

OR O

activator / hydride source

R O

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

Ph Si

Cl

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

OR

2-b RC-(OR)2

Cl

Ph

NO2

TBDPS-Cl

CH3 Si

N

(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)

Cl

RCH2 RCH2

aromatic substitution reaction usually contain NO2, F as leaving group

OR OCH2CH2OH

OCH3

HCl

OCH3

OCH3 O O

OH

AlCl3 LiAlH4

O

H

OCH3


2-c

O R C OR

RC-OR

SiCl3 t-BuO RaNi with C=S

radical mechanism:

O

(1). hv / HSiCl3

O

(2). HCl / tBu-OO-tBu

O

HCl

JOC, 1974, 39, 2470.

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

S

O

limit for: lactone

Lawesson reagent

O

S

S

P CH3O

OCH3

S

O

O

P

Ar

O

S

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

Ar

O

Ar

NaBH4

O

Ar

O

O

see mech-13 O I

RC-OR

HO

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

hv

e / Pt (2). Organoelectro Chemistry:

O

BF3

OH

2-d RC-H

RaNi

O

e- /

OH

N

Pt, R4NOTs

O

H N O N H

R'MgBr

R4NOTs Ph

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

N

NH2

NCS MeOH

R' OH

Ph

(79 %)

H H

N

H N O N H

OCH3 NH2

I

HO


2-e

C-C-OR

C C

O

O C

2-e.1 C C

C=C-OR

C

O

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

O

OH

O

OH

trans-diaxial attack!

Br

stereoselective

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

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

O

OSO2Me

O O

O

OH

O

Heterocyclic Chem, 1990, 27, 583.

via:

Br

H

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

Br

O

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

O

HOBr generation: NBS + H2O + DMSO

racemic products Sharpless O

OH

O racemic products

O

HOBr H2O

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

O

mCPBA

i. peracid

2-e.3 C C

O

OH

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

Cl

limit for allyl alcohol, high e.e.

C

peroxybenzoic acid

HCHO CO3H

via:

2-e.2 C C

good result

CO3H

C

N

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

OH

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

e-

JACS, 1983, 105, 2920.

3-a.1

H2O

JACS, 1983, 105, 3515. H

OH

OH R

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

indirect

O R

3-a.2

SeO2

H

OH

for allyl H:

R

SeO2

H HO

O

OH

Se

OH

OSiMe3

Me3SiCl

MCPBA

Ph

O H

O

OH

1. Me3SiCl Ph

(1) Me3SiCl // MPCBA//H3O+

Ph OH

O 2. MCPBA

Ph OH

OH

Ph

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

JACS, 1975, 97, 6909.

RO

O2, LDA, CO2R

(EtO)3P

O

via:

RO OH CO2R

RO

O

OSiMe3

O

H3O

JOC, 1975, 40, 3427.

Ph O

OSiMe3

3-a.3

Se(OH)2

OH

JACS, 1972, 94, 7154.

OH

H

O

Se

O

Ph

O

R

H2O

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

R

R

O P

OEt OEt

OH


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

O

SiMe3

I-

CH3

- CH3I

ii.

O Cl

RCH2-OH

- RSCH3

CH3

CO2Me OCH3 OH

- toluene

CN

O CH2

OCH3

O O C

[O]

OH

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

O

RC-OCH2CH=CH2

O

i. H2 / Pd-C

Cl

(3). allyl:

RCH2

OCH3

OH-

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+

O

H

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

H

+ 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.

OR

TMG

NH OH

CH3CN 1h R = TBDMS, TBDPS, Ac

TMG:

N

N

1,1,3,3-Tetramethylguanidine

OH


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

OH

Na2[Fe(CN)5(NO)]

JOC, 1986, 51, 3913.

RO2C (CH2)3CHR

K 2CO3 / H2O

H3O+ O

H

3-e

R-OC(O)R

+

O

R-OH

HO

OH

O O

OMe OMe

H

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)


O

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:

OH

MeOH

HO

C6H6, r.t.

O

3-g

C OH Mitsunobu inversion

O

LAH

C OH

O

(or K2CO3 / MeOH)

JOC, 1987, 52, 4235.

OH

HO

O

Synthesis, 1981, 1.

PPh3 / DEAD / RCO2H // OH-

O

HO

O

P-TsOH

O O

MeOH

PPh3 / DEAD * PhCO2H

HO

PPh3

EtO2C N

N

CO2Et

HO*

EtO2C N NH CO2Et PPh3

ROH

EtO2C N NH Ph

P O R

Ph Ph

CO2Et

* PhCO2H

O Ph

C

* OR

OH

-

* 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

OH

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

H

O

IrCl4

O

H

IrCl3

JCS, 1969, 1653.

JCS, 1970, 785.

OH

OH

OH

O

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

R

R3B C

O

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

R

B

R C

B

O O

R3C

B O

OH

O O

H2O2 R3C

R

C

R

R

R

R

B O O

O

B

C

HOCH2CH2OH R

R3C

B

O

O H

O R3C

H

generate acetone opposite to Oppenauer oxidation

OH

NaBH4 NaBH4 / CeCl3

C O

OH

H

OH

C(CH2OH)4

Ca(OH)2

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

OH

O Al(OiPr)3

JOC, 2003, 68, 2030.

Ph

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

H OH NO2

BH3 / SMe2

NO2

O

B O

H2O

R3C

OH


R

C OH

C C

3-j

RCH C

Hg(OAc)2

R

R CH C

R

R

NaBH4

R

R CH C

Hg OH OAc

H2O oxymercuration - demercuration:

H

R

Hg (OAc)2: toxic, hard to remove

OH

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

R

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

C C OH OH

3-j.2 C C

B

OH

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

(4). Na / EtOH

+

OH JCS, 1946, 2988.

tran

OH

Ann, 1949, 561, 165.

e c i t c a r p

OH

OH O

3-k

OH

JACS, 1945, 67, 1786.

OH

O

JOC, 1967, 32, 3452. OH

OH

OH

OH

OH

OH

OH

OH O

O

OH MeOH

HO

H+

OH

HO

OMe PhCH2-Br OH

BnO

OH

OH

OBn O

OBn

OBn

BnO

H2 Pd-C

OH

OH OH

Py

OBn O BnO

O OBn

BnO OBn

OBn

OTr OBn

chemistry: hemiacetal ROH

O OH

OBn

H OH

OBn

OH OH OH

OH

OBn OBn

OH O

BnO

CrO3

OBn

OH

O

H3O+

OBn

Ph3C-Cl

LAH BnO

OMe

OBn OH OTr

OBn OH OH

OBn

OBn

ROH

1', 2' alcohol ROBn ROTr

ROH ROH

O O H R

H2O OBR2

OH


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

Cl

O

O C

CH3

K2CO3

TsCl

MeOH TsO

N CH3 H+

N C

NHCHO

Cl

N CH3

1. LAH

DMF TsO

H

O C

CO2

NHCHO HOAc

NH2

H

N CH3 H hν

H

H

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

ii

RC N3

RC NH2

NO2

RC N iii RC N RC N

NH2

CPh

RC NH2

DMF rt. 15 hr

C OPh

RC NH2

R

BF4 Ph

CO2H H

N2

N R

Ph CO2Et

NaN3

R

- TPP (SN2)

CO2Et 1. reduction N3 H

R

2. hydrolysis

H

CO2H NH2 H

D -α-amino acid .

H O N C OtBu

N CH3 NH2

TFA

NH2

BOC-ON

N CH3

H2/cat

N

H

O

O Ac2O

N CH3

O

H

OH N

N

N-oxide

O NH C OH CO2

NH CH2Ph NH2

N

H

N

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

O

H R C NH N N Ph H -

L -α-amino acid

BOC ON

NH2

H

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

H

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

JOC, 1999, 64, 2301.

+N O

NO2

NH2

H

i

O

H

H2 / Pd-C

- HCHO NH2

N CH2

OCH3

NH


4b.3 R C N Z

R C N R'

i RC NH 2 R C N

1. HCHO / HCO2H

C

2. HCHO // H2 / Pd-C

HO

H

O

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

H

-

OEt R NH CH2

N N N

R C N

O H C O-

H

-

R N CH3 H

H

NH CH3 O H C H

N

R-BCl2

N N N B Cl Cl R

BCl2

NO2 MeO2C

N3

B Cl Cl

N - N2

R

NH

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

ii

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.

C

NH2

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

N

H R


4-c

C-N

C-X

Ph CH2Br

1. NH3

PhCH2NH2 + (PhCH2)2NH + O

O N K

2. Gabriel:

N K

N2H4

O

O

Ph CH2Br

3. Delepine

O

O

N

N

H2O

commercial available, tetramer of Me3N

N N

Ph CH2Br

N

N N

N N

Ph CH2NH2

O

O N

Gabriel amine synthesis

NHNH2 NHNH2

N2H4

N CH2Ph

N N

not good, usually contain polyalkylation products

(PhCH2)3N

N

N

N

Ph CH2NH2

N

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

N

Br-

4. NaN3 / RED

5. Unpolung

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

CH2Ph

Mg

R Br

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

OMe

R MgBr

NH2Cl

R NH2

OCH3

OMe Br

PhS

MgBr

N

N

N

N

N

OCH3 N

N

SPh OMe

N

N

CH2Ph

OCH3 NH2

H SPh

-N2

OMe

OCH3

OCH3

OCH3

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

CH3NH2 / EtOH O

4-d

C-OH

O

HCl / Et2O Cl

C-N

NHMe

O NK

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

TSCl

1. Gabriel:

O

NH2

N2H4

2. Delepine 3. NaN3 / RED

OH

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

N

R

Br

CBr4 PPh3

N

R

NaN3

N N N N

R

PPh3 THF

NH2 N

R


4-e

C-N

C=O

O

N CH3

CH3NH2

reductive amination!

NH CH3 NaBH3CN

acid

1. RNH2 // NaBH3CN most general

O

PH 6

O SiMe3

Me3SiN3

SiMe3

O

N N N

N N

N N N

LiAlH4

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

H N

N

NH2

RaNi / H2

4. PhNHNH2 // Al (Hg)

H

H O

PhNHNH2

N NHPh

H N

N NHPh Al (Hg)

H

(radical)

H

Leuckart reaction O O

6. RNH2 / n-Bu2SnClH / HMPA

NH2

NH3

H

O

-

NH2

Ph

Synthesis, 2000, 789. immonium salt

4-f

C=C

Ph

NHPh

n-Bu2SnClH HMPA

N H Sn

via:

O

Ph By

Cl

By P(NMe2)3

C-C-N C-C-NH2

NH2Cl B

B2H6 / NH2Cl B2H6 / H2NO

3

B2H6 / H2NOSO3H H+

C=C

Ph

PhNH2

CHO

CO2

B2H6

C=C

NH2 LiAlH4

NH3

O

catalytic reductive amination

5. NH4+HCO2-

H N N H

3. NH3 (excess) // RaNi / H2

via: hydrazone

N

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

H

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

Br

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

Br

R'Li // NaBH4

4-h

AlH3

C N

R

C

R'M // H

N

R

C

NH2

R'

TH, 1989, 30, 5139.

R CH2 NHR

CO2H

H

LiAlH4 N

1. LiAlH4

OH

H

JOC, 1985, 50, 1711.

THF

N

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

O

NH NH

NH

1. Et3O+BF4O

N

H

H

N

Et3O+BF4-

OEt

O

H

N

- 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

NH

H

N

H


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

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

O

Beckmann

R CH2 C CH3

O

N

R CH2 C N N N

OH

R CH2 C CH3

Application:

most useful O

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

CO2H

CO2Et

R CH2 N C O

OTs

N

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

CO2H

CO2H

H2 / Pd-C - CO2

RCH2 C CH3

O

O

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

2.TsCl

N

R CH2 NHR'

N

+

N

Pr- source

Ts

4-i.2 RCH2

Bu2AlH

n-Pr3Al 。 80 C

1.NH2OH O

O C Z

H

H- source

N H

O PhI(OAc)2

NH2

O RCH2 C NH2

NH

OCH3

KOH / CH3OH

O

JOC, 1993, 58, 2478.

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

C

PhI(OAc)2 NH2

O R

C

N

I

Ph OAc

KOH

O R

C

N

I

CH3OH

Ph OAc

R PhI, OAc

N

C

O

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

O

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

NaNH2

O

CO2

C OH

H3O+

camphor

Ac2O

NaBH4

O

C NHNH2

O

O R

C

NaNH2

CR

NaBH4

Ac2O

CO2 / H3O

SOCl2

H3O+

HNO2

CH2

R

C

O OO

OH-

Br2

KOH

CeCl3

O

H 3O

Br

OH

-

R

C

CH2R

LDA

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

+

Ph

S

S

Ph

O

R

C

TsNHNH2 CH2R

MeLi

Br

Br

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

O

HgCl2

MsCl

R

CH2

C

R

KOH

TMSCl MCPBA LAH

O

O CrO3

R

CH2

C

PhCHO

HO

OH-

Ph

NaBH4

Ph

CeCl3

O

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

SPh

HgCl2 CH3CN (aq)

N2, Ts-

thioenol ether OH

O

KOtBu

H

SiMe3 TMSCl

MeLi

SPh H

MsCl

O

H

O

C

O O3 Zn

Ph

H2SO4

H N N Ts

C O O O C

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

O

O

aqCH3CN

v. via: epoxysilane O

Zn

O3 Zn

LAH

Br2

O

O CrO3

HBr

iv. via: thioenol ether O

O

OH

O OH

iii. via: aldol process NaBH4

O

corticosteroid

O

Zn

NaBH4

PhCHO

epicamphor O

NaBH4

hecogenin acetate CrO3

HBr

OH OH

O

HO O

O

NH

R

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

O

i. via: α-CO2H

COOH

H 3O +

HNO2

C=O

SO2Cl OAc COOH

OH COOH

O

Ce

Cl


5-b

C=S

C=O

i. hydrolysis

S

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

NMe2

NOH

C=O N OH

5-c.1

OH H

CH3O

RaNi

O

NH

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

H3O+

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

C

O KMnO4 / Al2O3 acetone rt, 5 min

C(CH3)3 O

OH

NH H3O+

C(CH3)3

JOC, 1970, 35, 858.

H

NH2

JOC, 1972, 37, 2138.

Hg2+ Hg

not certain of which mechanism

H2O

O

OH

H2O

HgX

HgX OH H

O


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 /

O

Al (iBu)2H

H3O+

C N Al

Ph

C H

Ph

H3O+

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

Stenphen reduction mostly for Ar

H3O+

OH OH

R CH2 C N

H R' X O

N

O

Ar

N

N

H

CH3I

n-BuLi

H JOC, 1973, 38, 2129.

O C

R R

O H

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

H

R''MgBr O

N

O

N R''

R'

R

H3O+

R

C

O

N

R

H R'

R' H3O+

R R

O

R'

H

R'

H3O+

R

O

R'

R''


5-f

C=C-X

C=O H+

H3O+

C=C-OR C=C-SR

H3O+

OCH3

O

OCH3 Hg2+

Hg2+ / CH3CN (aq)

H2O

tpye:

CH3CN (aq) SCH3

O

X

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)

H

OEt C OEt OEt

OR

>>

OH

R

H

SR

OR

vinyl chloride

OR

O

OR

SR

SR >>

SR

O

R

O R

H

H

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

R

- CH3OH

OR enol ether

NR

use:

OH

CH3O

+OCH3

H3O+ / solv (aq)

OR OR

OH OH

acid catalyst

O O

O

S

S

RMgX / H3O+

H

OR OR

ketal

Hg2+ O

via:

O

RMgX R

OEt H

C

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

O

H3O+ OEt C OEt OEt

R

OR

O O

acid cat

CH3CN

Hg2+ / H3O+

CH3O OCH3

HOCH2CH2OH

H3O+

R

R

acetal

CH3OH acid cat

Type: H OR

O R

C

H


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

O

N+ O

O

alcohol

R C OH

+

O

H DMSO

O

PhCH2OH

PhCHO

HCl

via: PhCH2

DMSO

SynLett, 2002, 2041. H

CH3

PhC

O

S CH3

H

Synth. Commun., 1986, 16, 1343.

DMSO

OH

O

Ac2O

+ Me2S

OH R C R

O C CH3

O O C C OH O

H3C S CH3 O

O

DMSO

R C R ClCO-CO2H

O

+ HOAc

Moffatt oxidation

Et3N

Swern oxidation

MeO

MeO

OH DDQ

i. Jones reagent ii. KMnO4

JOC, 1985, 50, 1332.

N OH

Ph

O

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

O

N O+

RCH2OH

S

DMSO

PDC CH2OH 70 %

H11C5

OCH3

O 1st

CHO

OCH3

S

Ph

O

92 %

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

Br

2nd alcohol

O

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

O

OH PDC

HO

H3C S CH3

H

C R

O

O

CN

Cl

DDQ:

HO

CN

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

H

O

+ 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

R


5-i

C-NX2

C=O O

5-i.1 C-NH2

O

C=O

i. Corey approach: subtituted-quinone //

H3O+

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

O

Ph

O

O

Ph Ph

// H3O+

Ph

O

H3 O+

NH2

C H

PhCHO

NH2

Ph Ph

NH2

Ph

O

NH2

O

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

N

O

O

O

O

McMurray reaction O

iii. SiO2 / NaOH // H3O+

JACS, 1977, 99, 3861.

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

v. NaOH // CH3OH / H2SO4 //

H3O+

O

O

TiCl3 pH6

NO2

THL, 1981, 5235.

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

O

NO2

OMe

1. NaOH

S Synthesis, 1988, 379.

O

2.CH3OH H2SO4

Ph

H3O+

O

OMe

S

S

Ph

Ph O

vi. KMnO4 / KOH

Ph

H3 O+

N O O

O

TiCl3 pH1

NH

N C Ph

- PhCHO

H

O

O NO2

H3 O+

H3O+ Ph Ph

o

MCPBA

Et3N

NO2

Ph

OH

Ph

N C Ph

5-i.2 C-NO2

N

Ph

Ph

O

Ph

N

Ph

Ph Ph

O

Ph

Ph

N

O

JOC, 1969, 34, 2438.

KOH NO2

N

KMnO4 N

OO-

O O

O

O

N

O Mn

O

O O

O O

Mn

O

- MnO2 - NO3-

O

O


5-j

C-Br

C=O

direct:

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

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

Br

NaIO4 / DMF

N O

ii. DMSO / ZnS

5-k C-H

RCHBrMe OH Br

JACS, 2003, 68, 2480.

N

N,N-Dimethylaminopyridineoxide

84 %

3. DMSO reagents: THL, 1974, 917.

via:

DMAPO

O

THL, 2003, 44, 1375.

O

o

150 C, 40 min

i. DMSO / AgBF4

NMe2

NMe2

indrect: change to RC-OH followed by oxidation

H

Ph DMSO AgBF4

RC(O)Me Br

OH O

DMSO

O

DMSO / AgBF4

R

- AgBr

ZnS

S

O

H

R

R

- Me2S

C=O JCS, 1932, 1875.

1. SeO2

2. DDQ / TFA.

I 3. (3 eq.) O

Ph

Ph

H DDQ

Ar

N

CH3

TFA Ar

N

H

OH O

O

Se

CH3

Synthesis, 1979, 537.

O

O

SeO2

O

JACS, 2001, 123, 3183.

Ar

Ar

N H

O

CF3 O

Ph-F / DMSO a select oxidant

CH2

CH3

CHO

H3O+

DDQ N O

CF3 O

Ar

N H

CHO


C C g

dC C

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

O

e RCH(CO2H)-CH3

h

f -C(O)-CH3

i

O X

O

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

H

O R C H R C C Li

n-BuLi

OH R C C C H R

II

Pd

R C C Ph

R C C H

Pd I

Ph-I

THL, 1975, 4467.

R C C H

Ph

N Li

OMe

Cl

R C C Ar

R C C H

iv. CuI, NaI, Na2CO3, R

RCH2-SO2Ph

C

C

CH2Cl

RC CR'

Cl CH2 C R

C

C

C

II

Pd C C R

R C C Ph

addition steric δ-

C C R

R C C Li

OCH3

OMe

R'

H

R

n-BuLi

R CH2SO2Ph sulfone

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

δ+

N H

OMe

steric base, prevent Nu attack

Pd Ph

Cl

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.

R

Li

RCHO

C

C

CH2 C

SO2Ph R C C R' OH

Ac2O

C

R'

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 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

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

H

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

H

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

O

H Cl

2.HOAc

C CH

HO

Ph

1.B2H6

HO

HO

Ph

Co

C

CO Co Co CO CO CO CO CO

Ph

Co

H

HO

ii. Br2 // KOH

C

choose B2H6, not H2/cat: Co poison cat

HO

C C

C

CO CO CO CO CO

Co2(CO)8

C C

K

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

O

OH R C CH3

H3O+

R C CH2

H2SO4

NH2OH R C N OH

Br2

RCHBrCH2Br

R C N OH2

NaNO2

CH3

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

H

N

N O

iii. LDA, ClPO(OEt)2

R C CH3

O

OPO(OEt)2

LDA

LDA

R C CH

ClPO(OEt)2

JOC, 1980, 45, 2526.

R C CH

H

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

O

O

O

O

use: TsNHNH2 / EtOH, heat

N

O

O

NH Ts

THL, 1967, 3943. H2O2

O

N N

O

N2

O

Ts-

Ts

Na / NH3(l)

CH3 CH CH2 (MVK) O

Robinson Annulation O

OH


6-h

Cl

O

HO

R

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

R

6-i.

R'

C C

X

Cl

O

HO

R

JACS, 1955, 77, 3293.

R C C R'

JACS, 1958, 80, 4599.

Ar i. NaOEt (when X = Br)

RX

Ar'

Br

Ar

C

C

Me

Ar'

via:

H

Me

OSO2CF3

Ph

H

ii. BuLi (when X = -OSO2CF3)

NaOEt

Ph BuLi

Me

C

C

Ph

C

via:

JOC, 1978, 43, 364.

Ar Ar'

Br ?


C C

f

C O

i C C

g

C C

j

c CX-CY X

7- a CH-CX

d

C

C

H

X

C C

C

use:

H OH

C

C-OH

h C CH

e -C(O)-CH3

b CH-CH 7- a

C

C

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

Ph

Dean-Stark

MsCl

H OMs

use base: i. RONa; ii. KOtBu

C C C C

MsO

S O

iii. CH3I N

O

heat

-

NMe2

HCHO

H

OH

C

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

Cl

DDQ

O

Pd-C

O

O

MeO

RCH2CH2-O-PBu3 TBDMS O H . O

DDQ

RCH2CH2-OH Ph-Se-PBu3

:PBu3

CO2Me

OAc CO2Me

Cl

heat

mechanism:

OAc

OAc

heat

O

Ph-Se-CN MeO2C

-

NMe2

MCPBA

Cl

NMe3 OH

Ag2O

HCO2H

C

heat CH3

H2SO4

OH

NMe3I

NH2

H

minor

syn elimination

compare:

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

C

+

N

CH3I (excess)

7- b C

p-TSOH major

SMe

I DBN

C C

Ph

O

OH

use base: DBN

H NH2

applied for reactions: without rearrangement; no regiosiomer

H

use: heat

I

OH

or KOtBu

i. n-BuLi ii. CS2

H OC(S)SMe C C

C

H

RONa

HO

use: heat

H OAc

C

OH

C C

H

OH

(CO2H)2 / benzene

MCPBA

MeO

RCH=CH2

heat TBDMS O .

23oC, 14h, 88%

.

O .

THL, 1991, 3679.


7- c

C

C

X

X

C

C C

CSCl2

C C

C

O

base C C

O

C

N

i. CSCl2 /

C

P Ph

OH OH

N

thiophosgene

ii. CSCl2 / P(OMe)3

S

C

C

i. Zn / acetone

Br

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

C

C

NaI / Zn (Cu)

OMs OMs C

C

OH I

via:

C

C

I

I

O

CSCl2

O

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

O

OH

O

or: ?

OH

Br

S P

thionocarbonate

OH

HCO3H

OR

O

OH OH

POCl3 Py

Cl P Cl O H CH3

Et H3C

I

Sn

Et

OAc

H

O

AcO AcO AcO Br

Zn HOAc

OAc OAc

JOC, 1978, 43, 364. C

C

Br

OAc

Zn / HOAc

OAc O


X

7- d

C

C

C

C H

7-d.1

O C

C

C

O

i. WCl6 / RLi

product retention

ii. LiPPh2 / CH3I

product inversion

O

R

C

C

C

LiPPh2

H

CH3I

O

H PPh2

PPh2

Ph

P

H

Ph

O

H

H

oxaphosphetane

(EtO)3P R2

R1

O C

R1

Synthesis, 1977, 1134.

R2

O

N NH

TsNHNH2

n-BuLi

Ts

C Br

HO 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

H

C

use: (EtO)3P

C CH3

H

SN2

CH3

OH H

H R C C CH2 CH2 CH2 OH H

Na

S

7- e

H

CH3

(special structure):

S

H

OH

H

Cl

7-d.2

WCl6 RLi

C H

iii. Na

H

n-BuLi TsNHN

JOC, 1977, 42, 1079.

S CH3


7-f

C

O

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-

Et

JOC, 1968, 33, 780.

CN

CN

O

stable ylid gives trans (E)

PPh3

+

not good for Ph3P=CH2 function as base:

Me3SiC-H-MgBr H O

O

THL, 1973, 3947. C

O

N2H4

R

R

iv. CH2(ZnI)2

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

+ Ph3P CH Et

H

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

H

via: betaine, oxaphosphetane (NMR)

use: Ph3P-CHR'

+

O

Ph3P CH CO2Me

R

R2CO

C NHNH2

SiMe3

C N

O

N C

R

R

R

H2S

R

N C

S

R

R

N C

R

Ph(OAc)4

R

CH2(ZnI)2

Synlett, 1988, 12, 1369.

R

CH2

O

N

R

PPh3

R

R

R

R

O

R

O

C S

R

v. CH2CHBr2, Sm, SnI2 / CrCl3, THF

N

C

Ph O

Chem. Lett, 1995, 259.

S

N N C PPh3

O CH2 OH

N Me

S

use: Ph

S

R

R

R

PPh3

+

R

R

R

R

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

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

C

Ph S

O

vi. Sulfoximide (Johnson C.)

R

C

C

R


7-f.2

RC

O

RC

CR R C

N2H4

O

R

R

R

R2CO

C NHNH2

R not for Wittig, ylid unstable

O

N

C S

R

O N2H4

O

N

C

O

O

R

PPh3

R

R

3. H3O+

N

S

N N C

R

R

R

C PPh3

S

R

R

O

O

1. H2S 2. Pb(OAc)4

N

R

R

N C

O

O

S

R

R

R

R C

C

R

O TiCl3

N

Zn-Cu Ti (II) O O

N

S

N

N

O

commercial available butene side product (trimer)

Ph(OAc)4

N

N N

O

C R

P(OEt)3 S

N N

+

S

R

R S C

O

1. H2S 2. Pb(OAc)4

N

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

N

N

O

C

H N

H

H2S

R

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

ii. McMurry Coupling

R

N C

R

R

O

C N

via:

R

C

C

R

R C

C

R

N

S

N

O

O


7- g

C

C

form trans alkene:

form cis alkene:

C

C

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

Et

C C

H R

Me

Et

C C Me

H

C C H H H

Ph C C

CHO

HCHO Pd-C Et3N

Ph C C

C

C

CH

C

C R

H

H

R

C CH

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

iii. Cp2ZrClH / RX (hydrozirconation)

H

C

C

H

R

H

i. R2BH / Br-CN (hydroboration)

C

C

H

DIBAL

R

H C

H

R C

B

R CN

R

n-BuLi

C

H

Cp2ZrClH

B CN

C

C

C H

C

H

Syn elimination

R

ZrCP2 Cl

C

H

R H

R

H C

C R'

C

H CH3

H

C B R

H

CH3I

R'X

C H

H

Li

H

Br

CN-

R

H

R

H

H

B R

Br

C C

R

C

H

R

H

AlR2

C

Br-CN

B R

C

R

Br

all form trans alkene:

Br

C H

C

CH R BH 2 (Syn)

7- h

JOC, 1980, 45, 4926.

CHO

CN R


7-i C

C

C

application: protecting group

C

not for

via dihalide

via halohydrin via epoxide

C

C

H

OH

C C

C=C

double bond might move

C=C

X X C C

C=C

H X O

C=C

C

C

via diene-olefin addition

CO2Et

7-j

C-OH

C

C NO2

MnO2 / Ph3P CH3 Br- / MTBD

-

Ph

JACS, 1998, 100, 877.

OH

CO2H 180C

C=C Ph

MnO2 Ph3P CH3 BrMTBD

N

NO2

in situ alcohol oxidition Wittig rxn

Br

PhSO2Cl

COOH

1. OH2. H3O+

RONa

C=C

Ph

OH

LAH

NaBr CO2Et CO2Et

CO2Et

C=C

Br

OH

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

1.

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

N

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

N

Et

OH

HCONMe2

Cl

N

JOC, 1983, 48, 2625.

Cl

F NHCOCHCl2 NMe2

H

Me

Cl

H

OH

O S O

via:

Et

Cl

Me

O

Et

H

Cl

N N

Org.Lett, 2002, 4, 553.

Cl

4. CCl4 / PPh3 CCl4

OH

5. HCl / ZnCl2

Cl

PPh3

6. HCl fit for 3rd alc, directly

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

8-a.3

C-OH

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

Cl

ZnCl2

alc

JACS, 1938, 60, 2497.

good for 3rd alc

OH OH

Br

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

Me

96 %

OTBS BnO

I Me

N + Br3 H

(PyH Br3)

Si

Br

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

Cl

NaNO2

Cl

N2BF4 Cl

F Cl

HCl, HBF4

NaNO2 / HCl / HBF4 /

for aromatic amine

C-X

8-c C=O

C-F

C=O

O

CF2Br2 / Zn

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(O)Z

Cl

C-Cl

C-Br

Cl RhCl(PPh3)3

R

C

O OH

1. AgNO3/KOH 2. Br2

R

Br

Chem Rev., 1956, 56, 219.

Ber. 1942, 75, 296.

Cl


8-e C-H 8-e.1

C-X

C-H

C-F

i.

S

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

R

HF

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

R = CH3CO, COCF3, CCl3, NO2 O

O

O THL, 2003, 44, 2799.

R' TBAH / CH3CN rt, 12h

R '' H

R

R' R '' F

O

O

O

O

O

NBX R1

R3 H R2

Mg(ClO4)2

R1

C-I I2 / HNO3

X R2

O

X = Cl, Br, I

I JACS, 1917, 39, 437.

N X

NBX:

R3

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

R

R

C-X

CH3

F 55-90 %

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

NF3O

C-H

R

OH

F2-N2 adamantane

8-e.2

F-TEDA-BF4

F

O

O

iv.

OH

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.


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