Dr.

Pere Romea
Department of Organic Chemistry

Rouen Cathedral
Claude Monet, 1892-94

7. Reductions

Organic Synthesis 2014-2015 Autumn

 Carbon Backbone & Functional Groups

The synthesis of an organic compound must pay attention to ...

Carbon backbone Functional groups

(Chapters 2–4 )
Functional Group Interconversion (FGI)

I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!! III. Oxidations
Pere Romea, 2014 2
 Reductions & Oxidations

Redox: electronic, e–, interchange

Reduction: gain Oxidation: loss

OH
+ 0 e–
R + H2O R
Hydration
(RC2H3) (RC2H5O)

O OH
+ 2 e–
R + 2H R Reduction
(RC2H3O) (RC2H5O)

O
+ 0 e–
Hydration R H + H2O R
(RC2H) (RC2H3O)
O
– 2 e–
R + H2O R + 2H Oxidation
(RC2H3) (RC2H3O)
3 Pere Romea, 2014
 Reductions & Oxidations

Redox: interchange of H or O

Reduction: gain of H/loss of O Oxidation: gain of O/loss of H

H HH
reduction H reduction H
R H R R
+H +H
H HH

OH O O
oxidation oxidation
R H R H R OH
H –H +O

Reduction
H OH O O O

R1 H R1 H R1 R2 R1 OR2 R1O OR2

R2 R2
Alkane 2ary Alcohol Ketone Ester Carbonate

Oxidation
4 Pere Romea, 2014
 Reductions & Oxidations

Standard Reduction Potentials

Remember that ΔGo = – n F ΔEo
Eo(V)

Li+ + e– Li –3.04
Reduction
Na+ + e– Na –2.71
H2 + 2e– 2 H– –2.25
Sm3+ + e– Sm2+ –1.55
Zn2+ + 2e– Zn –0.76
Sn2+ + 2e– Sn –0.13
2 H+ + 2e– H2 0
Cu2+ + e– Cu+ 0.16
Fe3+ + e– Fe2+ 0.77
Ag+ + e– Ag 0.80
Oxidation
Cl2 + 2e– 2 Cl– 1.36
Pere Romea, 2014 5
 Reductions

Reductive processes:

a) Dissolving metal reductions

b) Radical reductions
c) Reductions with hydrides
d) Catalytic hydrogenations
e) Carbonyl deoxigenation reactions

Chap. 23
Different Chaps.
mainly
Pere Romea, 2014 6
 Dissolving Metal Reductions

Lithium or sodium metals give very easily the electron from the valence shell

slow
Li + NH3 Li + e [NH3 ]n NH2 + 1/2 H2
Blue solution Colorless solution

Electrons are the simplest reducing agents and

they reduce any funtional group with a low-energy π* orbital :

BIRCH REDUCTION
ALKYNE REDUCTION
CARBONYL REDUCTION
Pere Romea, 2014 7
 Birch Reduction

Birch reduction converts phenyl groups in 1,4-cyclohexadienes

H H
Li or Na
NH3 / ROH
H H

H H H H
H H H H H H
e ROH

H H H H H H
H H H

H H H H H H
H H H H H H
ROH

H H H H H H
H H H H

8 Pere Romea, 2014

 Birch Reduction

The reduction proceeds with a remarkable regioselectivity ....

EWG EWG EDG EDG

Li Li
NH 3 / ROH NH 3 / ROH

EWG: CO2R, CN, NO2 EDG: OMe, NR2, Alkyl

OMe OMe OMe O

Li H H 3O
NH 3 / EtOH
80%

CO2H CO2 CO2H

Li H 3O
NH 3 / EtOH
90%

9 Pere Romea, 2014

 Alkyne Reduction

Alkynes are converted into E-alkenes stereoselectively

H2 Li or Na
R1 R2 R2
R1 R2 NH3 or R1
Z Alkene Lindlar HMPT/ t-BuOH E Alkene

H H
M NH3 or ROH 1) M
R1 R2 R1 R2 R2 R2
R1 2) NH3 or ROH R1
H

H
R1
R2

Na
NH 3 liq, –33 °C
86%

10 Pere Romea, 2014

 Carbonyl Reduction

Carbonyl groups can be reduced to alcohols

O O O OH OH
M ROH 1) M
2) ROH H
Ketyl radical anion

For a synthetic point of view this procedure is not very important.

It is more useful the reduction of unsaturated carbonyl groups

O O OH
1) 2 M 1) 2 M
2) 2 ROH 2) 2 ROH

H H
1) Li, NH 3 liq
2) NH 4Cl O
O
H
99% trans
11 Pere Romea, 2014
 SmI2 Reductions

Samarium diiodide (SmI2) is a single-electron reducing agent

particularly useful in C-C bond formations and transformations of several functional groups

Nicolaou, K. C. ACIE 2009, 48, 7140; Procter, D. J. ACIE 2012, 51, 9238

Sm + ICH 2I SmI2 + 1/2 H 2C=CH2

Sm + ICH 2CH2I SmI2 + H 2C=CH2

Eo 1.55 V
Sm (II) Sm (III) + e–

The reactivity of SmI2 is significantly affected by the choice of solvent.

It reduces organic halides, aldehydes, ketones and α-functionalized carbonyls

12 Pere Romea, 2014

 SmI2 Reductions

Organic halides can be reduced to hydrocarbons

HX
R X + SmI 2 R H + SmI 2 X

SmI 2 HX
R X Sm(II) R R SmI 2 R H
–SmI2 X –SmI2 X
Sm(III) Sm(III)

SmI2
H H THF / HMPA, i-PrOH, rt H H
Cl
99%
Corey, E. J. JACS 1987, 109, 6187

Br O O
SmI2
O O
THF, HMPA, i-PrOH, rt

99%
13
 SmI2 Reductions

Aldehydes and ketones can be reduced to alcohols

O OH
HX
R1 R2 + SmI 2 R1 R2
H

Sm(II) Sm(III) H Sm(III) H

O O HX O SmI 2 O HX O

H H

R 3SiO R 3SiO

O O
SmI2
PMBO O PMBO O
THF, i-PrOH
O OH
98%

Evans, D. A. JACS 1990, 112, 7001

14 Pere Romea, 2014

 Radical Reductions

Alkyl bromides and iodides are easily reduced to the corresponding alkanes
through a free-radical process with n-Bu3SnH.
In + Bu 3SnH Bu 3Sn + In–H

Bu 3Sn + R–X Bu 3SnH + R

R + Bu 3SnH Bu 3Sn + R–H

A parallel transformation involves a radical-promoted deoxygenation

of O-thiocarbonate derivatives of alcohols in a two-step process
named Barton-McCombie reaction
S

OH 1) NaH, CS2 O SMe

2) MeI

S S–SnBu 3

O SMe O SMe H
Bu 3Sn Bu 3SnH
– MeSCOSSnBu 3
15
 Radical Reductions

OTIPS OTIPS
I

HO HO
O Bu 3SnH, AIBN O
H OMe H H OMe H
TIPSO O THF, Δ TIPSO O
H H
OPMB OTIPS OPMB OTIPS
Cl OPMB 70% Cl OPMB

Kishi,Y. ACIE 1998, 37, 137

The radical generated during the dehalogenation reaction can undergo a tandem radical cyclization
Bu 3Sn

Br HH
Bu 3SnH, AIBN
PhH, Δ
H H
61%
– Bu 3SnBr
Bu 3SnH

H HH

H H H
Curran, D. TL 1985, 26, 4991 16 Pere Romea, 2014
 Hydride Transfer

Formal addition of H– to a double or a simple bond

H
A B + H H A B H A B H

H
A B + H H A + B B H

Hydrides, M–H,
used for the reduction of organic compounds
are from three elements close in the periodic table:
B
boron, aluminum, and silicon

Their reactivity fairly depends on the element: Al Si

aluminium hydrides are more active than the boron counterparts,
and these more than the silicon ones
17
 LiAlH4: A General Reducing Agent?

Lithium aluminum hydride, LiAlH4, the strongest reducing agent?

Li Li Li Li
O O O O OH
+H
R1 OR2 R1 OR2 R1 H R1 H R1 H
H – OR2 H H
H H
Al H Stable? Al H
H H H H

Li Li
O O O R2N– is a very poor leaving group

R1 NR2R3 R1 NR2R3 R1 H + R2R3NLi

H
H Stable?
AlH3
Al H
H H AlH3
Li O NR2R3 NR2R3

R1 NR2R3 R1 H R1 H
H H
H
Al H
18
H H Pere Romea, 2014
 LiAlH4: A General Reducing Agent?

– LiAlH4 is commercially available, very sensitive to water.

– Dry ethereal solvents are required.
– LiAlH4 is a very strong & non chemoselective reductor.

LiAlH4

O
O X
R1 R2 O R1
R1 X R C N R 1

O
H OH
R1 NR2R3 R1
R1 R2
OH
H H
R1
R1 OH H H H H

R1 NR2R3 R1 NH2

19 Pere Romea, 2014

 LiAlH4: A General Reducing Agent?

N N
H LiAlH4 H
MeO MeO
THF
O O
H 70% H
O OH

t-Bu O HO
H HO H
MeO2C LiAlH4
MeO2C HO
CO2H THF
OH
H 72% H

MeO MeO
LiAlH4
CN
MeO MeO NH2
Et2O

85%

20 Pere Romea, 2014

 LiAlH4: A General Reducing Agent?

MsO
O LiAlH4 OH
Et2O, ta

77%

LiAlH4
I
Et2O, ta
94%

O t-Bu OH OH
LiAlH4
O
t-Bu t-Bu Et2O, ta t-Bu
H

t-Bu
LiAlH4
O
t-Bu Et2O, ta
t-Bu O t-Bu OH
H OH
21 Pere Romea, 2014
 LiAlH4: A General Reducing Agent?

LiAlH4 can even be active on propargylic and homopropargylic alcohols …

OH LiAlH4 O H2Al O H O H H OH
R R Al H Al
– H2 H H R H
H R H
R H

O LiAlH4 O OH
OH
THF, ta
Ph Ph
95%

OMe OMe
HO HO
LiAlH4
THF, Δ

85%

22 Pere Romea, 2014

 LiAlH(OR)3: Selective C=O Reduction

LiAlH4 + 3 ROH LiAlH(OR)3 + 3 H2

– Alkoxyde ligands, OR, reduce the reactivity of aluminum hydride:

they become more chemoselective
– The presence of one or two H– permet to tune the reactivity
O O
O O
CHO
LiAlH(Ot-Bu)3 OH
CO2Me THF, –10 °C CO2Me
O O

O O
1) LiAlH(OEt)3, THF, 0 °C
N H
H 2) H+
OH
77%
O OH

O Red-Al™ O
NaAlH2(OCH2CH2OCH3)2
CO2t-Bu CO2t-Bu
Hexà, –70 °C
OTHP OTHP OTHP OTHP
23 Pere Romea, 2014
 i-Bu2AlH: Selective XC=O Reduction

A highly selective reducing agent to aldehydes: i-Bu2AlH (DIBAL or DIBALH)

i-Bu
Al i-Bu i-Bu
i-Bu H
Al Al(i-Bu)2
O O H O O
+ H3O
R1 OR2 R1 OR2 R1 OR2 R1 H
H
Somehow stable at low T

CO2Me DIBAL CHO

O O
N Toluè, –78 °C N
Boc Boc
76%

O O
DIBAL
CN CHO
Et2O, –78 °C
HO t-Bu HO t-Bu
56%

Cl O Cl O
DIBAL
Me
TBSO N TBSO H
CH2Cl2, –78 °C
OMe
Pere Romea, 2014 82% 24
 NaBH4: Reduction of C=O

Sodium borohydride, NaBH4, the mildest agent?

H H
The boron atom has no The boron atom cannot
B H + E E B H
electron pairs available H H H accept 10e (octet rule)
H

H O O OH
H2O o ROH
B H + R H R H R H
H H –BH3 H H

– Sodium borohydride is a solid very easy to handle and commercially available

– The reductions with NaBH4 are carried out in methanol, ethanol, or even water at 0 °C or room temp
– NaBH4 reduces aldehydes and ketones to the corresponding alcohols.
Carboxylic acids, esters, nitriles, epoxides, or nitro compounds are not affected.
NaBH4 is a very chemoselective reductor
25 Pere Romea, 2014
 NaBH4: Reduction of C=O

O Ph O Ph
H MeO MeO
NaBH 4
O O
O O MeOH, rt HO O
H H H H
90%

I I
O OH

O NaBH4 O
O O
O MeOH, 0 °C O
97%

MeO O MeO O
NEt2 1) NaBH4, MeOH
O
2) 6 M HCl
CHO
80%

26 Pere Romea, 2014

 NaBH4–CeCl3: Reduction of C=O

Even more selective with CeCl3 (Luche reduction)

Aldehydes vs Ketones

O O H OH
.
CeCl3 6 H2O NaBH4
O O O
Ce(III)
H HO H
H

Unsaturated Ketones
O OH OH

Reductor
+

NaBH4 59% 41%

NaBH4 / CeCl3.6H2O 99% traces

27 Pere Romea, 2014

 NaBH4–CeCl3: Reduction of C=O

Even more selective with CeCl3 (Luche reduction)

Aldehydes vs Ketones

O CHO 1) NaBH4/CeCl3.6H2O, EtOH/H2O HO CHO

2) H3O+

Unsaturated Ketones

N N
N NaBH4, CeCl3.6H2O N
H H H H H H
CH3CN, MeOH
H H
MeO2C 78% MeO2C
O OH
28 Pere Romea, 2014
 NaBH4–CeCl3: Reduction of C=O

OTBS OTBS OTBS

HO HO HO
R R ClCH 2CO 2H R
NaBH 4, CeCl3 7H2O DIAD, PPh 3 O
–10 °C toluene, 0 °C Cl
O OH O
H H H
97% 90%
BnO BnO BnO
Luche reduction Mitsunobu
See Chap. 5
1) K 2CO3, MeOH
92% overall
2) TIPSOTf, lutidine

OTBS OTBS OTBS

TIPSO TIPSO TIPSO
R R R
DMP, pyr H 2, Pd(OH) 2/C, Al2O3
CH 2Cl 2, rt EtOAc, 0 °C
OTIPS OTIPS OTIPS
H H H
H 96% overall
O HO BnO
Oxidation Selective deprotection
See Chap. 7 See Chap. 1
Nakada, M. OL 2014, 16, 4734

29 Pere Romea, 2014

 LiBH4: Reduction of C=O

... and less selective but more powerful with a different cation: LiBH4

– The substitution of the cation, Li+ instead of Na+, enhances its solubility in organic solvents
– Li+ cation can bind the oxygen of aldehydes, ketones, esters, and epoxides,
which increases their electrophilicity:
LiBH4 reduces aldehydes and ketones as well as esters and epoxides.
– Carboxylic acids, amides, or nitriles are not affected
– Solvents: Et2O,THF > i-PrOH

F F
O2N O2N OH
O CO2Me O
H LiBH4 H
N OTBS N OTBS
N THF–Et2O, 0 °C N
H H
O O
83%

30 Pere Romea, 2014

 NaBH3CN: Reduction of C=N

The mildest agent: sodium cianoborohydride, NaBH3CN

R3 R4
O N NR3R4
pH 6
R1 R2 + R3NHR4 R1 R2 R1 H2
R
H
B H
H CN

R3 R4
NR3R4 O N
H
R1 R2 R1 R2

– The reductive amination of aldehydes and ketones is an important method to synthesize

1ary, 2ary, and 3ary amines
– Iminium cations are prepared in situ in a slightly acid medium and
can be selectively reduced in the presence of the parent carbonyls
31
 NaBH3CN: Reduction of C=N

CHO

NMe2
O HO O OH NaBH3CN, MeOH
HO O
O O O
OMe OH O
MeO Et O OH O
HN

Tylosine 79%
O O
N

NMe2
O HO O OH
HO O
O O O
OMe OH
MeO Et O OH O

CO2Bn CO2Bn BnO2C BnO2C CO2Bn CO2Bn

NaBH3CN
OHC + NH.TFA
N OTHP N N OTHP
pH 6, MeOH
CO2t-Bu CO2t-Bu
59%

32 Pere Romea, 2014

 Et3SiH/TFA: Carbenium Reduction

Protonation of alkenes, alcohols, carbonyls, …produce carbocations

that can be reduced with silicon-based hydrides as Et3SiH

H H
O O O H OH
+H R3SiH
B R1 R2 R1 R2 R1 R2 R1 R2

R3 OH R3 OH2 R3 R3 H
+H R3SiH
Al Si R1 R2 R1 R2 R1 R2 R1 R2

– These ionic hydrogenations are used to proceed in the presence of

a strong acid (TFA) and an organosilicon donator
– Such a combination affects alcohols, ethers, alkenes, and carbonyls.
– Carboxylic acids and their derivatives are not affected
Pere Romea, 2014 33
 Et3SiH/TFA: Carbenium Reduction

O
MeO MeO
OH Et3SiH, TFA OH
NHSO2Ph CH2Cl2 NHSO2Ph
MeO MeO
81%

H H
O N O N
Et3SiH, TFA

N CH2Cl2 N
O O
65%
OH

OSiHt-Bu2 OH
H H
1) TFA, CH2Cl2
2) TBAF

70%

34 Pere Romea, 2014

 Hydride Transfer: A Brief Summary

Hydrides are useful for the reduction of multiple or simple polar bonds

X O O O N O
O
N
H X
X: Halogen, OSO 2R X: Cl, OR, NR2

With the exception of propargylic or homopropargylic alcohols

Reducing power LiAlH4 NaBH4 Et3SiH

+ –
Strong Mild

PAY ATTENTION TO CHEMOSELECTIVITY !!!

35
 Reductions

Reductive processes:

a) Dissolving metal reductions

b) Radical reductions
c) Reductions with hydrides
d) Catalytic hydrogenations
e) Carbonyl deoxygenation reactions

Chap. 23
Different Chaps.
mainly
1 Pere Romea, 2014
 Hydride Transfer vs Hydrogenation

Formal addition of H– to a double or a simple bond

H
A B + H H A B H A B H

H
A B + H H A + B B H

Hydrogenation: addition of H–H catalyzed by a metal

catalyst
A B + H H H A B H

catalyst
A B + H H H A + B H

2 Pere Romea, 2014

 Catalytic Hydrogenations

Catalytic hydrogenations

catalyst
A B + H H H A B H

catalyst
A B + H H H A + B H

Depending on the catalyst, hydrogenations can be ...

– heterogeneous, when the catalyst is a finely dispersed metal on a

solid and inert support (C, Al2O3, …);
then, the hydrogenation occurs on the surface of the catalyst,
– homogeneous, when the catalyst is a metal complex soluble in the
solvent that contains the unsaturated substrate.
3 Pere Romea, 2014
 Heterogeneous Hydrogenation of Alkenes

Alkenes into alkanes

catalyst
C C + H2 H C C H

Catalyst: Pd/C (10%), PtO2, Rh/C, Rh/Al2O3 (5%), Ru/C (5%), Ni–Raney

Hydrogenations with heterogeneous catalysts are very simple reactions.

They are usually been carried out by shaking the reaction mixture under a
hydrogen atmosphere at low(1–5 atm) or high pressure (5–300 atm),
at room temperature or heating.
The catalyst is finally removed by filtration

These hydrogenations are highly stereoselective: syn addition

4 Pere Romea, 2014
 Heterogeneous Hydrogenation of Alkenes

Both hydrogen atoms add to the same face of the π system

H H H
H

H
H H H

Me Me Me
H2
Ph Ph + Ph
Ph Ph Ph
Pd/C
Me Me Me
racemate

Ph Me Me
H2
Ph Ph Ph
Me Ph Ph
Pd/C
Me Me Me
meso form

5 Pere Romea, 2014

 Heterogeneous Hydrogenation of Alkenes

Steric effects usually rule the hydrogenation of the diastereotopic faces of olefines

H2 H H2
Me
H
Me Pd/C Me PtO2
Me major

The stereochemical outcome can be affected by the presence of functional groups as OH or NH2

H O O H O
H2 H2
O O O
MeO Pd/C MeO Pd/C MeO
OH X CO 2Me
dr 94:6 X: OH, CO 2Me dr 85:15

Occasionally, unexpected rearrangements can modify the stereochemical outcome of these reactions

H H H
H2 H2
Pd/C Pd/C Pd/C
H H
21% 79%
6 Pere Romea, 2014
 Heterogeneous Hydrogenation of Alkenes

The mechanism of a heterogeneous hydrogenation is rather complex

H H
Oxidative addition H H

CH2R CH2R
Reductive elimination
H H π Complex
CH2R Complex σ
H H CH2R
syn Addition H H

π-Allyl complex
– syn Addition
H
R H
H
– Allyl complexes account for certain rearrangements H

7 Pere Romea, 2014

 Other Heterogeneous Hydrogenations

Cyclopropanes
H O H O
H2, PtO2

AcOH, 50 °C
H H
82%

R1 R2 R1 R2 R1 R2

gem-Me2 Cyclopropane Alkene

Remember the interesting reactivity of the three–membered rings

O N S

Cyclopropane Epoxide Aziridine Thiirane

8 Pere Romea, 2014

 Other Heterogeneous Hydrogenations

Alkynes into alkenes and alkanes

R2 H2 H2
R1 R1 R2
Pd/C Pd/CaCO3/Pb(OAc)2 R1 R2

Lindlar

OTIPS
COOH

OPMB

H2 Lindlar H2 Lindlar

OTIPS
COOH OPMB
95%
85%
9 Pere Romea, 2014
 Other Heterogeneous Hydrogenations

Benzyl ethers and amines: deprotection

Azides and nitrocompounds

N3 NHBoc
H2, Pd/C H2, Pd/C
Ar Ar NO2 NH3X
O Boc2O,AcOEt O Ph Ph
O O EtOH, H2SO4 X: HSO4

Acid chlorides: Rosenmund reduction

O O
H2
Cl H
O O
Pd/BaSO4
NH O NH O

64%
Pere Romea, 2014 10
 Chemoselectivity of Catalytic Heterogeneous Hydrogenations

Easy
O O
H2
R Cl Pd/BaSO 4 /quinoline rt, 1 atm R H

H2
RCHO RCH2OH
Pd, Pt, Rh, Ru rt, 1 atm
H2
R1 R2
Lindlar rt, 1 atm R1 R2

R2 H2
R2
R1 Pd, Pt rt, 1 atm R1

H2
Ph XR PhCH3 + RXH
Pd rt, 1 –4 atm

H2
RN3 , RNO2 RNH2
Pd, Pt rt, 1 –4 atm

RCN H2 R NH2

Rh, Pt, Ni High T and P

R R

Difficult
11 Pere Romea, 2014
 Homogeneous Hydrogenations of Alkenes

Conversion of alkenes into alkanes

catalyst
C C + H2 soluble
H C C H

Catalysts: Rh (I): [(Ph3P)3RhCl] is known as Wilkinson catalyst

Ir(I): [(cod)Ir(PCy3)pyr] PF6

Homogenous catalysts are organometallic compounds, derived from transition metals,

soluble in common organic solvents as hydrocarbons, ethers, or haloderivatives.
Then, hydrogenations are used to be carried out by stirring the reaction mixture
at room temperature under a 1 atm hydrogen atmosphere.

Hydrogenations with homogeneous catalysts are highly stereoselective: syn addition

Importantly, the development of chiral ligands provides enantioselective hydrogenations
12 Pere Romea, 2014
 Understanding the Catalytic Activity of Transition Metal Complexes

The golden rule: 18 electrons

A complex is particularly stable if the metal reaches the noble gas electronic configuration

1 orbital s + 3 orbitals p + 5 orbitals d = 18 electrons

A complex becomes particularly reactive if the metal has less than 18 electrons

Wilkinson catalyst: [(Ph3P)3RhCl] ?

Rh: 4d7 5s2 Rh (I): 4d6 5s2 8e

Ph3P: 2e x 3 6e
Cl–: 2e x 1 2e

Total 16 e
13 Pere Romea, 2014
 Homogeneous Hydrogenation of Alkenes

Mechanism of the homogeneous hydrogenation with the Wilkinson catalyst

Cl PPh3 + H2 Cl PPh3
16e Rh Rh 18e
Ph3P PPh3 Ph3P H
Oxidative addition
Ph3P

Reductive + H2C CH2 – PPh3

H3C CH3 + PPh3
elimination

H H

Cl PPh3 Cl PPh3
16e Rh Rh 18e
Ph3P CH2CH3 Ph3P H
Insertion
H2C CH2
σ complex π complex

The addition is syn

14 Pere Romea, 2014

 Chemo- and Regioselectivity of Homogeneous Hydrogenation of Alkenes

A highly chemo- and regioselective hydrogenation of alkenes

– Carbonyls, nitroderivatives or benzylic groups are not reduced

NO 2 H 2, [(Ph 3P) 3RhCl] NO 2

Benzene, rt
MeO MeO
90%

– The less substituted the more easily reduced

H 2, [(Ph 3P) 3RhCl]

OH Benzene, rt OH
90%

– Conjugated olefines react slowly

H 2, [(Ph 3P) 3RhCl]

O Benzene, rt O
94%

15 Pere Romea, 2014

 Stereoselectivity of Homogeneous Hydrogenation of Alkenes

A major transformation: Homogeneous hydrogenation of alkenes

– Double and triple bonds are reduced without rearrangements

– π-Facial selectivity of the hydrogenation can be affected by polar groups

OH H2, [(Ph3P)3RhCl] OH

Benzè, ta
H
80% H

H
H
Me
OH
The hydroxyl group directs the hydrogenation
to the lower π-face of the olefin

– Chiral ligands can be attached to the metal, producing enantioselective hydrogenations

16 Pere Romea, 2014

 Knowles, Noyori & Sharpless: Nobel Prize in Chemistry 2001

William S. Knowles Ryoji Noyori Barry S. Sharpless

This year's Nobel Laureates in Chemistry have developed molecules that

can catalyse important reactions
so that only one of the two mirror image forms is produced.
The catalyst molecule, which itself is chiral,
speeds up the reaction without being consumed.
Just one of these molecules can produce millions of molecules
of the desired mirror image form 17
 Stereoselectivity of Homogeneous Hydrogenation of Alkenes

From Rh(I) to Ru(II), from Ph3P to BINAP

Ph3P Cl Ph2 Noyori BINAP

L1 L3
Rh P L3
M M
Ph3P PPh3 L4
Rh (I): 5s2 4d6
L2 L4 P
Ph2 Ru(II): 5s2 4d4
Wilkinson 16 e
Rh(I): 5s2 4d6
Ph3P

ClO4

Ph2 H Ph2
O
P OMe P O
Rh Ru
P OMe P O
Ph2 H O
Ph2

JACS 1980, 102, 7932 JACS 1986, 108, 7117

18 Pere Romea, 2014
 Stereoselectivity of Homogeneous Hydrogenation of Alkenes

BINAP: 1,1’-BINAphtylPhosphines

BINAP is a chiral biphosphine without any chiral center.

The lack of free rotation about the ArC–CAr bond and the resultant chiral axis
are in the origin of the chirality of this biphosphine.
This is a very common ligand in asymmetric synthesis

Chiral axes

PPh2 PPh2

PPh2 PPh2

(R)–BINAP (S)–BINAP
19 Pere Romea, 2014
 Stereoselectivity of Homogeneous Hydrogenation of Alkenes

H2 H2
0.5% [(R)-BINAP]Ru(OAc) 2 0.5% [(S)-BINAP]Ru(OAc) 2
OH
MeOH, rt MeOH, rt

OH OH
ee 96% 99% ee 96% 99%

H 2 (4 atm)
CO 2H 1% [(S)-BINAP]Ru(OAc) 2 CO 2H
Ph Ph
MeOH, rt
NHAc NHAc
ee 97% 99%

H 2 (135 atm)
CO 2H 0.5% [(S)-BINAP]Ru(OAc) 2 CO 2H

MeO MeOH, rt MeO

ee 97% 92%
(S)-Naproxen
20 Pere Romea, 2014
 Other Homogeneous Hydrogenations

Diimide: another hydrogen–transfer agent

H2O2
H2N NH2

HN NH H H – N2 H H
H+ N N
KO2C N N CO2K Diimide
Concerted process: syn addition

– This is a very chemoselective process: it only reduces alkenes and alkynes

COOH N2H4, H2O2 COOH

O2N 84% O2N

O O
KO2C N N CO2K
O O
AcOH, 45 °C
Br
87% Br
Pere Romea, 2014 21
 Reductions

Reductive processes:

a) Dissolving metal reductions

b) Radical reductions
c) Reductions with hydrides
d) Catalytic hydrogenations
e) Carbonyl deoxygenation reactions

Chap. 23
Different Chaps.
mainly
Pere Romea, 2014 22
 Carbonyl Reductions

Carbonyls can be transformed into the corresponding alkanes or alkenes

using different two-step processes

From thioketals

From imine derivatives

– Wolff- Kishner reaction
– Reduction of tosylhydrazones
– Shapiro reaction

23 Pere Romea, 2014

 Carbonyl Reductions

From thioketals

O SH H H
HS S S Ra-Ni
BF3· OEt 2 Raney nickel
Thioketal

1) HSCH 2CH2SH, BF 3·OEt 2

O 2) Ra-Ni, EtOH

81%

O O

OAc OAc
S H
H Ra-Ni H
S H
H H EtOH, Δ H H
AcO 85% AcO

Pere Romea, 2014 Kluge, A. F. JOC 1985, 50, 2359 24

 Carbonyl Reductions

Wolff-Kishner reaction

NH2
O N H H
H2N–NH2 OH
Δ
Hydrazone

O H H
OH
Δ
H 2NNH 2
– OH
H
N N N N N
N H OH N H N H H 2O N H OH N
H 2O H 2O
H H H
O
H

25 Pere Romea, 2014

 Carbonyl Reductions

Unfortunately, this reaction requires harsh experimental conditions ....

O
H 2NNH 2

NH 2
N

KOH
O
HO OH
89% Δ
(193 °C, 4 h) Cargill, R. L. JOC 1979, 72 ,3971

O O
O N H 2NNH 2, KOH O OH
O
HO OH
Ph Ph
O Δ
H
(195 °C, 4 h) Naguib, M. TL 2012, 53, 3316

73%
Pere Romea, 2014 26
 Carbonyl Reductions

Reduction of tosylhydrazones

NHTs
O N H H
H2N–NHTs Reductor

Tosylhydrazone

SO2Ar SO2Ar
N N N
N H N H N H H H
H
H – SO2Ar H – N2

O H
1) TsNHNH2
H H
2) NaBH 3CN, DMF, 100 °C H
95%
HO HO
NNHTs H
H
H H ZnCl2, NaBH 3CN H H

H MeOH, Δ H
H 50% H

Boeckman, R. K. JACS 1989, 111, 2737 27 Ceroplastol I

 Carbonyl Reductions

Shapiro reaction

NHTs
O N
TsNHNH 2 1) Base
R R R
R R R
2) H2O
Tosylhydrazone Alkene

O H
1) TsNHNH2 R
R R
R
2) B
3) H 2O
TsNHNH2
H 2O

Ts Ts
N N N
H N N N
B
R R R R
R R – Ts R – N2 R
H
Base: MeLi, BuLi, LDA
B

28 Pere Romea, 2014

 Carbonyl Reductions

BnO BnO

1) 2 eq LDA
NHTs 2) H 2O
N
98%

The final anion can be trapped with other electrophiles ....

O
N Li O
TBSO NHTs n-BuLi TBSO O
THF, –78 °C to rt H

TBDPSO OBn

Taxol AcO O OH O
O Ph O HO
H O
N O TBSO
H
OH O
H
HO BzO
OAc TBDPSO OBn

82%
Pere Romea, 2014 Nicolaou. K. C. Nature 1994, 367, 630 29