Reduction - IIT Bombaykpk/Chap3-R.pdf · aminations (Borsch Reduction) NaBH 3CN reduced iminium ions much more quickly than ketone or aldehyde B H HCN HNa+ At pH 3-4, It reduces aldehydes

CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Reduction

Ø Hydrogenation

Ø  Boron Reagents

Ø Aluminium Reagents

Ø Tin Hydrides

Ø Silanes

Ø Dissolving Metal Reductions

Ø Diimide Reductions

1


Reduction

Catalytic Hydrogenation

Heterogeneous Homogeneous

2


Reduction Heterogeneous Catalytic Hydrogenation

Metal- Pd, Pt, Rh, Ni Support- Charcoal, Alumina, Silica Solvents- MeOH, EtOH, EtOAc, AcOH, Et2O, Hexanes

Decreasing order of activity

H2, Pd-C

H2, Pt-C

H2, Rh/Al2O3

H2, Ra-Ni

Decreasing order of reactivity

Transition metals adsorbed onto a solid support

RNO2 RCOCl

RR R

ORR

RCN

3

Reduction


Reduces olefins & acetylenes to saturated hydrocarbons

Sensitive to steric effects & choice of solvents

Polar functional groups, like hydroxyl groups can sometimes direct the delivery of H2 cis-addition of H2

Catalysts can be poisoned

Properties:

Order of solvent reactivity is-

Hexane < EtOAc < EtOH < HOAc < HOAc/HCl

H2, Catalyst1 - 30 atm

H H

Heterogeneous Catalytic Hydrogenation

4

Reduction


Mechanism:

HH H

H

H H

H

HH

Isomerization

H H

H

H

H

H

H

H H

Catalyst surface


5

Reduction


Decreasing order of Reactivity:

ROCl RCHORNO2 RNH2

RC CR RR

RCHO RCH2OHRR RCH2CH2R

RCOR RCH(OH)RRCN RCH2NH2

RCOOR RCH2OH + ROHRCONHR RCH2NHR

RCOO- INERT

FACILE

DIFFICULT


6


Reduction

CH3

CH3

H2, Pd-CCH3

CH3

CH3CH3+

major minor

Hydrogen will approach from exo side

Equatorial attack is predominant

NN

S (CH2)4COMe

O

AcAc NN

S (CH2)4COMe

O

AcAc

H HPd/ C/ H2

85oC37 bar

H2, Pd-CR OBn R OH H3C+

Pt/ H2

70% 30%


7

Reduction

Directed Heterogeneous Hydrogenation:


O

O

MeO OH

H2/ Pd/ CO

O

MeO OH

H

O

O

CO2Me

H2/ Pd/ CO

O

CO2Me

H

HO

Ni/ H2

HOH

HOH

(95:5)

H2, Pd-C

OH OH

H

OH

H

+

major minor

Hydroxyl group delivers hydrogen from same side


8


Reduction

Reduction of aryl groups:

Rosenmund Reduction: Quinoline is used to poison the catalyst to reduce its activity

RCOClH2, Pd

BaSO4

CHOR

H2/ Raney Ni

150 oC

H2/ Raney Ni200 oC


Raney Nickel Desulfurization:

R

O

HSH SH

S SR

H2, Ra-NiEtOH

R CH3

9

Reduction


Lindlar Catalyst (Pd/CaCO3):

HO OH

LindlarCatalyst

OHHO

8π con

Electrocyclicreaction

HH

HOH

HO

6π dis

Electrocyclicreaction

OHHO


O

MeO2C

O

MeO2C

H2, Pd

CaCO3

R TMSTMSRH2, Pd

CaCO3

10


Reduction Homogeneous Catalytic Hydrogenation

LnM

LnMH

H

H2

MHH

Ln-1

HLnM

H

- L+ L

HH

Mechanism:

Wilkinson's catalyst [(PPh3)3RhCl]

Reactivity:

11


Reduction

OH OHH2, (PPh3)3RhCl

Homogeneous Catalytic Hydrogenation O OH2, (PPh3)3RhCl

OO

H2, (PPh3)3RhCl

NO2NH2 H2/ Pt

EtOH

NO2H2

Wilkinson'scatalyst

SPh SPh

H2(PPh3)3RhCl

12

O

Na/ Liq. NH3

Reduction Homogeneous Catalytic Hydrogenation


Directed Homogeneous Hydrogenation:

KO

(PPh3)3RhCl

H2/ EtOHMeO

KO

HMeO

CO2Me

MeO

(PPh3)3RhCl

H2/ EtOH

CO2Me

HMeO

13

Reduction Hydrogenolysis


ORH2/ Pd or

Pt

H H OR - ROH HH

HO

H2/ Pt

EtOH HOH H54% 46%

Benzyloxy groups:

R OH R OBnH2/ Pd

Na/ NH3

ROH

Allylic ethers:

14

Reduction Hydrogenolysis


Benzyloxy carbonyl groups:

R2N CO

OCH2Ph R2NHH2/ Pd

- Toluene- CO2

Halides: R Br

H2/ PdEtOH

R H

Cl

H2/ PdSO4

Other reactions:

ONH3C

R

OHNHH3C

R

H2/ Pd

NO2 NH2

H2/ Pd-C

15


Reduction Boron Based Reagents

Ø NaBH4

Ø NaCNBH3

Ø NaBH4/CeCl3

Ø Zn(BH4)2

16

Ø NaBH4/ NiCl2

Ø  Boranes

Ø NaB(OAc)3H

Ø Me4NB(OAc)3H

Ø Alkyl borohydrides

Ø  LiBH4



NaBH4

Solvents: EtOH, MeOH, Dimethoxy ethane (DME)

Temperature: 0-25 oC

Substrate: RCHO, RCOR, RCOCl, R2C=NR

Mechanism:

OO HR

H BH

HH

HOR HO H

BH

H OH

R OR

H

17



CeCl3 is a good Lewis acid & highly oxophilic

Selectivity:

NO2

O NaBH4NO2

OH

OH

O

Luche Reduction:

O OH OHNaBH4 80-90% 10-20%

NaBH4 / CeCl3(1:1) MeOH

100% 0%

ONaBH4

CeCl3

OH

18

O

O

0.25 eq NaBH4

0 °C, EtOH

Reduction


Selective reduction of ketones in presence of aldehydes: O

CO2Me

CHO

NaBH4, CeCl3

EtOH, H2O

OH

CO2Me

CHO

O

CO2Me

HOOH

CeCl3, H2O (1) NaBH4, CeCl3(2) Work up

CHOONaBH4, CeCl3

EtOH, H2O

CHOOH

Boron Based Reagents

19

Reduction


Reduction of imines:

OR2

R1 NH2R3

- H2O4Å MS

NR2

R1R3 NH

R2R1

R3H

R C NNaBH4

No Reaction

R CNNaBH4

C NR MeMe3O+BF4-

BF4-NaBH4

NHR

MeC NR Me BF4-

RCH2BrNaBH4

DMSORCH3

NaBH4 can’t reduce RCN unless Meerwein’s salt (Me3O+BF4

-) is used

DMSO

NaHCO3R O

Boron Based Reagents

NaBH4or

H2/ Pd-C

20

H2C O SR



LiBH4

Can reduce esters & lactones efficiently

More reactive than NaBH4 but milder than LiAlH4 in ether

Higher reactivity is due to greater Lewis acid strength of Li+

21

O OC3H7 OH OHC3H7

LiBH4

COCH3

NO2 NO2

CH3HO

LiBH4



NaBH3CN

Electron withdrawing cyano group decreases the ease of hydrogen transfer

Less reactive than NaBH4. Used predominantly in reductive aminations (Borsch Reduction)

NaBH3CN reduced iminium ions much more quickly than ketone or aldehyde

BH

H CNH Na+

At pH 3-4, It reduces aldehydes & ketones At pH 6-8, It reduces iminium ions

Uses:

OR

R

R'2NH, MeOH

NH4OAc,pH=6

NR'

R'R

R

NaCNBH3N

R

HR

R'

R'

22



N

NR

HN R

Reduction of oximes:

R

O O NH4Br

NaCNBH3MeOH

NOHR

R NaCNBH3

pH=3NHOHR

R

α,β-Unsaturated ketones:

N

CHO

O

RNH2, MeOH

NH4OAcNaCNBH3

(1) TsNHNH2, H+

(2) NaCNBH3

O

23



Reduction of tosylhydrazones:

Epoxide openings:

Drawback: Sometimes strong acids can release HCN from NaCNBH3

OH

H

(1) TsNHNH2, H+

(2) NaCNBH3

H

H

OH

OH

OH

ONaCNBH3

BF3.Et2O, THF

24


Reduction

Boranes Boron Based Reagents

Borane is highly electrophilic. So, they attack the most electron rich center

B HHH

HB

HB

H

H H

H

Borane exists as a dimer

HO

O

O

O

1/3 BH3

THF

Similarly between an amide and ester, amide gets reduced first

BHHH

O

BH3.THF

BHHH

SMe2

BH3.SMe2

25



NO

OOMe

Me

1/3 BH3

THF NH

OOMe

MeN

OOMe

Me

1/3 BH3

THF

NO

OOMe

Me

H3B NO

OOMe

Me

H3B

NO

OOMe

Me

H2B

NO

OOMe

Me

B

N

O

OMeO

Me

N

OO

MeOMe

26



Hydroboration: B2H6

H2B H

H2O2

NaOH HO H

R R'B2H6

B

R R'

HH

H

H3O+

R HB2H6 H2O2

NaOHRCH2CHO

R2B H

R2B

R R'

H

R R'

HH

R

B HH

H

R

BR'2H

BH3 reduces carboxylic acids to primary alcohols in the presence of esters, nitro and cyano groups

O O

CO2H BH3. Me2S

THF O O

HO

27


Reduction Boron Based Reagents Other available boranes

B2H6

HB

HB

H

H H

H

9BBN

Thexyl borane

OB

OH

Catechol borane

BH

BH3

Disiamyl borane(Sia2BH)

BH

BH

BH

2

Pinylborane

B

Alpine borane

HB

(Ipc)2BCl

BCl

2

H2B HB

HB

BH3

28



Borolane Oxazaborolidine

BH N B

H

O

PhPhH

Asymmetric reduction of ketones:

Alpine Borane

O Alpine-borane

THF, 0oC

OH

94% ee

H

BO

RS

RL

OH

RLRS

Works best for aryl & acetylenic ketones. Because of steric hindrance it is fairly unreactive

29



Chlorodiisopinylcamphenyl borane (DIP-Cl)

B Cl

2

Chlorine increases the Lewis acidity of boron making it more reactive

Saturated ketones are reduced to chiral alcohols with varying degrees of ee

OIpc2B-ClTHF

OH

> 90% ee

30



Oxazaborolidine

N BH

O

PhPhH

N BO

PhPhH

CH3

BH3

Stoichiometric Catalytic

NH

CO2H

NH

OH

PhPhH

2 StepsN B

O

PhPh

H

Me

(MeBO)3

Toluene

N BO

PhPh

H

MeH3B

BH3

ORS

RL

NO B

Me

O

Ph

PhRS

RLB H

HH

H2BORS

RLHHO RS

RLH

H2O

31



Oxazaborolidine

R

O

R

OH

O OH

O OH

> 90% ee

> 95% ee

> 96% ee

OBr

OHBr

32



NaBH4/ NiCl2 Uses:

NO2Ar NH2Ar

Ar NO NH2Ar

Ar CH

N OH NH2H2CAr

Zn(BH4)2 Preparation:

ZnCl2 (Ether) NaBH4 Zn(BH4)2

Good for base sensitive groups

Chelation control model

33



Zn(BH4)2

R1OR

O

R2 R2

RO

H

O

R1

Zn2+

B

H

H

HH

R1OR

OH

R2

OH

O

OH

OH

Zn(BH4)2

Et2O

O

Zn2+O

HH

Me O Zn2+

O

H

MeH

34



NaB(OAc)3H; Me4NB(OAc)3H

CHO

OBu4NB(OAc)3H

OOH

PhCHO

OBu4NB(OAc)3H

Ph

O OBH

AcO OAc

Ph

OH OH

OH ONa+(OAc)3BH-

OH OH

HBOiPr

OOAc

OAc

H

35

Reduction


Boron Based Reagents Alkyl Borohydrides

Selectrides:

HB3

MM+ = Li (L-Selectride)

= K (K-Selectride)

OMe L- Selectride

THF

OHMe

HO

R2

R1

OL- Selectride

THFHO

R2

R1

OH

O K- Selectride

THF

OO

K- Selectride

Br

O

36



LiBHEt3 (Superhydride):

Alkyl Borohydrides

Very reactive hydride source Reduce ketones, aldehydes, esters, epoxides and C-X bonds

Br

LiEt3BH

Br

O OH

LiEt3BHO OH

LAH 73%LiEt3BH 100%

37



Comparison Between Borohydride and Boranes

Negatively charged

Borohydrides Boranes

Neutral

Nucleophilic Electrophilic

Valence shell of boron completed octet

Boron contains six electrons and a vacant

p-orbital

Hydride transfer occurs intermolecularly

Hydride transfer occurs via a Lewis acid-base

complex

38


Reduction Aluminum-based reagents

Ø DIBAL-H Ø Red-Al

Ø AlH3 Ø  LiAlH4

Lithium aluminum hydride (LiAlH4)

Very powerful reducing reagent

Used as a suspension in ether or THF Reacts violently with water, alcohol Reduces carbonyl, carboxylic acid & ester Reduces nitrile, amide & aryl nitro group to amine Reduces acetylene to olefin Reduces C-X bond, opens epoxide

Available as either powder or pallet

Ø  Li(OtBu)3AlH

39


Reduction

O

R'R

Mechanism:

Al HHH

HLi

OCR R'H

AlH3Li

O

R'R

O CR

R'HAl

4

LiOHCR R'H

O

R'R

OH

R'R

O

OR'RRCH2OH

O

O

OH

OH

O

NRR

R

RCH2NR2

R C N RCH2NH2

R NO2 RNH2

O

R

OH

R

O

RCH3

R

HO

Aluminum-based reagents

N

R'R

OHNH2

R'R

40

Reduction


Reduction of alkyl halides go via radical mechanism Alkyl halides:

This is proved by-

Alkynes: It is complementary to that of partial hydrogenation

R X e R X

R X R + X

ILAH

81%

ROHOHR

H2/PdCaCO3 LAH

R

OH

R + H R H e


41

Reduction


Epoxides:

OH

H LAH

OH

H

H

OH

H

LAHOH

H

H

Axial attack

O OH

OHReduction

LAH 10 90L-Selectride 93 7

CO2Me CO2MeO OH

OHLAH


42

Reduction


RCHO RCH2OHRCOR RCHOHRRCOCl RCH2OHLactone DiolEpoxide Alcohol

Ester AlcoholCarboxylic acid AlcoholCarboxylate Salt Alcohol

Amide AmineNitrile Amine

EASY

DIFFICULT


43

Reduction


Alane (AlH3)

AlCl3 + LAH AlH3 + 3LiCl

It is inert to olefin & nitro group

Br OMe

OAlH3

Br OH

LAHPh OH

AlH3

1,2- selective

Preparation:


Ph H

OPh OH

44

Reduction


Diisobutylaluminium Hydride (DIBAL-H)

AlH

Highly pyrophoric

Under carefully controlled conditions, will partially reduce an ester to an aldehyde

O

O

O

OAl(i-Bu)2

DIBAL-H O

OH

OH

O

Work up

RCOOEt RCH2OHDIBAL-H


RCO2MeR C OMe

O

H

Al

If complex is Unstable

R CHO RCH2OHFast

R CHO

If complex is Stable

45

Reduction


Direct conversion of acids to aldehydes:

Acid chloride to aldehyde using Weinreb’s amide:

O

R OH

TMSCl

Et3N

O

R OTMS

DIBAL-H

DCM, -78oC

O

R H

O

R Cl

HNOMe

MeO

R NOMe

MeWeinreb'samide

DIBAL-H O

NR

Al

OMeH

Me

RCHO

RMgBr


O

RR

46


Reduction

Meerwein – Pondorff - Verley Reduction

Al(OiPr)3 is the reagent Isopropanol is the hydride donor By-product is acetone Reverse process is known as Oppenauer oxidation

O

R R'

Al(OiPr)3

iPrOH

R OAlOiPr

R'OiPrH

OH

R'

R

CHO OHNO2

CHO

NO2

OH

BrO

BrOH


OH

OAl

iPrO

OiPr

R'

R

47


Reduction

Tris-(tert-butoxy) lithium aluminium hydride [LiAlH(OtBu)3] Preparation:

Less reactive than LAH Partial reduction is possible Alternative to Rosenmund reduction

LiAlH4 + 3tBuOH LiAlH(OtBu)3 + 3H2

O2N

Cl

O

Li(OtBu)3AlH

O2N

H

O

Cl

O

Li(OtBu)3AlH H

O

RCO2H

NMe

Me

Cl

Pyridine-30oC

O

OR NMe

Me

Li(OtBu)3AlH

CuI (cat.)-78oC

O

HR


48


Reduction

Sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al)

AlH

H

OMeO

MeO ONa+

Reduces lactones in presence of bulky ester

Opens epoxy alcohols through chelation

O

O

CO2tBu

Red Al O

OH

CO2tBu

O

ROH

DIBAL-HOH

ROH

Red-Al OH OH

RO

RO

Al

OMeMeO

H

Na+


49

O

RO

Al

OMeMeO

H

Na+

Reduction


In case of Red-Al:

OAl

ORO R'OR'

Na+Hydrolysis

OH

OHR

In case of DIBAL-H:

O OAlR

AlH

Hydrolysis

OHHO

R

OAlO

R


50

Reduction


Ph

OH

Ph

OHO

VO(acac)2t-BuOOH

Ph

OH

Sharplessasymmetricepoxidation O OH OH

Ph

Red - Al

DIBAL - H

Ph OHOH

BnOOH

OBnO

OH

OHBnO

OHOH

Red - Al 150 : 1

DIBAL - H 1 : 13


51


Reduction Free Radical Reactions

Used to reduce alkyl halides Usual hydrogen donor is tributyltin hydride

XR

TBTH

AIBNΔ

CH3R

Mechanism:

N NCNNC

Δ

CN2 N2

Bu3SnH

Bu3Sn H

CNBu3Sn

R X

RBu3Sn H

R H Bu3Sn

Tributyltin hydride (TBTH)

52



Barton- McCombie Reaction:

O

OO

OO

HO

NaH, CS2

MeIO

OO

OO

O

MeS

S

n-Bu3SnHAIBN

PhCH3O

OO

OO

TBTHAIBN

SnBu3H SnBu3

R H SnBu3

HO

1. NaH/ CS2 MeI

2. TBTH

RO SMe

SBu3Sn S

O

SMe R

53



Thiocarbonate Modification:

O

OO

OO

HO

PhO Cl

S

Py, DMAP

O

OO

OO

O

S

PhO

O

OO

OOTBTHAIBN

PhCH3

Radical Decarboxylation:

R OH

O (COCl)2

NO

S

R O

ON

S

TBTHAIBN

R H

54



Reduction of Nitroalkanes:

O

O

O2N

TBTHAIBN

TolueneO

O

Tandem Reaction:

OHO2NOH

AIBNTBTH

TolueneΔ

OH

55



Radical Cyclization Reaction:

Br

AIBNTBTH

Br

TBTH, AIBN

Toluene, reflux

OR RO

5-exo-trig

RO

X

nBu3SnH, AIBNToluene, reflux

56


Reduction Baldwin’s Rule

Exo, EndoDig, Trig, Tet

DiagonalTrigonal

Tetrahedral

n-exo-trig n-endo-trig n = ring size

π e- outside - exo

exo-trig exo-dig

π e- inside - endo

57


Reduction

X

+

X

R

R

R

X

R

Baldwin’s Rule

X

RR

H

HCH3

R

H

CH3

R

H

CH3

R

58

X RR H

CH3

R


Reduction Silane Reagents

Most commonly used silane reagents are Et3SiH, i-Pr3SiH

Hydrosilylation:

Reduction Of Lactol Ethers:

O

Et3SiH

(Ph3P)3RhCl OSiEt3 O

H3O+

OOMe

OBF3.Et2O

Et3SiH

59


Reduction Dissolving Metal Reduction

Birch Reduction

M A M A

Li, Na, K, Ca, in Liquid ammonia, Et2NH, EtNH2, ROH, H2O

Partial Reduction Of Aromatic Rings:

e

H H

e

H H

60



Electron Donating Substituents: OMe OMe

Li/ NH3

1e

OMe

H+OMe

1e

OMe

Electron Withdrawing Substituents:

CH3 CH3

CaRNH2

OO OO

1e

CO2HCO2H

Na/ NH3

CO2

1e

61



CO2H

OMe

Na/liq. NH3

OMe

O O OO CO2H

Both Electron Donating And Electron Withdrawing Substituents:

CO2HOMe

CO2

OMeNa

Liq NH3

- CO2O

CO2H

OMe

Na/liq. NH3

CO2H

OMe

H3O

CO2HO

62



Ketones and nitro groups get reduced keeping esters and nitriles untouched

OR

MeO

OR

O

(1) Li, Liq NH3

(2) Oxalic acid

OR

O

(1) Li, Liq NH3

(2) H3O+

MeO

Li

Liq NH3 MeO

Oxalic acid

O

OMe OMe O

H3O

63



α,β-unsaturated compounds are reduced in 1,4-fashion

OLi

Liq NH3

O

Li, Liq NH3

1 eq H2O

OLi OBr

64

O OHtBuOH

OHLi

Liq NH3

TMSCl OTMS

O LiEOE



OO

O

(1) Li, Liq NH3 1 eq. tBuOH

(2) CH2O

OO

O

OH

H

Reduction of Alkynes:

R R'1 e

RR'

RR'

H

H+R

R'1 eR

R'H+

65



Reduction of Phosphates:

R OHNaH

Cl P(OEt)2O

R O P(OEt)2

O Li, EtNH2

tBuOHR H

R1R2

O

H H LDA

Cl P(OEt)2O

R1R2

OP(OEt)2O

Li, EtNH2

tBuOHR1 R2

Asymmetric Birch Reduction:

O N

OMe (1) K, Liq NH3

(2) MeI

ON

OMe

66



Mg in MeOH:

XMg

MeOHX X = CN, COOR, CONR2

MeO2C

Mg

MeOHMeO2C

Mg

MeOHCO2Me CO2Me

67


Reduction

Zn in AcOH:

Dissolving Metal Reduction

R2

OZnX

R1

HOAc H

R2

O

R1

OBr

Zn/MeI

O

Zn/AcOH

O

OBr O

Zn

AcOH

OBr

O

Zn, DMSO

MeI

X

R2

O

R1

Zn

Zn

68



OOAc

Zn/AcOH

O

O

Zn/AcOH

O

Zn in AcOH:

O OH

O

OCl

OH

Zn/AcOH

69

Reduction


Diimide Reduction

N NCOONa

NaOOC

CH3COOHN N

COOH

HOOC

Syn addition

H HN2

- 2CO2N N

H H

N2H2

70

Reduction


N2H2

HN NH

SO O

hν, 16 h

OCO2Me

NO2

OCO2Me

NO2

HN NH

SO O hν NHNH

COS CO

Diimide Reduction

71

Reduction - IIT Bombaykpk/Chap3-R.pdf · aminations (Borsch Reduction) NaBH 3CN reduced iminium ions much more quickly than ketone or aldehyde B H HCN HNa+ At pH 3-4, It reduces aldehydes

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