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– Hydration R + H2O R (RC2H3) (RC2H5O)

O OH + 2 e– R + 2 H R Reduction

(RC2H3O) (RC2H5O)

O + 0 e– Hydration R H + H2O R

(RC2H) (RC2H3O) O – 2 e– R + H2O R + 2 H 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 H R H – H R H + O R OH

Reduction

H OH O O O

1 H 1 H 1 2 1 2 1 2 R R2 R R2 R R R OR R O OR 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

e

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

NH3 / ROH NH3 / ROH

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

OMe OMe OMe O

Li H H3O

NH3 / EtOH 80%

CO2H CO2 CO2H

Li H3O NH / EtOH 3 90%

9 Pere Romea, 2014 Alkyne Reduction

Alkynes are converted into E-alkenes stereoselectively

H Li or Na 2 1 2 R2 R1 R2 R R R1 NH3 or Z Alkene Lindlar HMPT/ t-BuOH E Alkene

H H M NH or ROH 1) M 1 2 1 2 3 2 R2 R R R R 1 R R1 R 2) NH3 or ROH H

H R1 R2

Na

NH3 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, NH3 liq 2) NH Cl O 4 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 + ICH2I SmI2 + 1/2 H2C=CH2

Sm + ICH2CH2I SmI2 + H2C=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 + SmI2 R H + SmI2X

SmI2 HX R X Sm(II) R R SmI2 R H –SmI2X –SmI2X 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 + SmI2 R1 R2 H

Sm(II) Sm(III) H Sm(III) H O O O O O HX SmI2 HX

H H

R3SiO R3SiO

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 + Bu3SnH Bu3Sn + In–H

Bu3Sn + R–X Bu3SnH + R

R + Bu3SnH Bu3Sn + 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 O SMe 1) NaH, CS2 2) MeI

S S–SnBu3 O SMe O SMe H Bu3Sn Bu3SnH – MeSCOSSnBu 3 15 Radical Reductions

OTIPS OTIPS I

HO HO O O H OMe H Bu3SnH, AIBN 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

Bu3Sn

Br H H Bu3SnH, AIBN PhH, Δ H H 61% – Bu3SnBr Bu3SnH

H H H

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 B are from three elements close in the periodic table: 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 2 1 1 H R1 OR2 R1 OR 2 R1 H R H R H – OR 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 2 3 2 3 R1 NR2R3 R1 NR R R1 H + R R NLi H H AlH Stable? Al 3 H H H AlH 3 2 3 2 3 Li O NR R NR R 2 3 R1 NR R R1 H R1 H H H H Al H H 18 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 1 1 X R R2 O R 1 1 R X R C N R O H OH 1 R1 NR2R3 R R1 R 2 OH H H R1 R1 OH H H H H 1 R1 NR2R3 R NH2

19 Pere Romea, 2014 LiAlH4: A General Reducing Agent?

O

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

O t-Bu O HO H HO H MeO2C LiAlH4 MeO2C HO CO H THF 2 OH H 72% H

MeO MeO LiAlH CN 4 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 LiAlH O 4 t-Bu t-Bu Et2O, ta t-Bu H

t-Bu LiAlH4 O Et O, ta t-Bu t-Bu O 2 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 LiAlH O H2Al O H O H H OH 4 Al R R Al H – H2 H H R H H R H R H

O O OH LiAlH4 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 H i-Bu i-Bu Al Al(i-Bu)2 O O H O O + H3O 2 R1 OR2 R1 OR2 R1 OR 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 + E E B H electron pairs available H H H accept 10e (octet rule) H 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 NaBH4 O O O O HO O H H MeOH, rt H H 90%

I I O OH

O NaBH4 O O O O MeOH, 0 °C O 97%

MeO O MeO O 1) NaBH MeOH NEt2 4, 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 CeCl . 6 H O NaBH O 3 2 O 4 O Ce(III) H H O 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 HO CHO 1) NaBH4/CeCl3.6H2O, EtOH/H2O + 2) H3O

Unsaturated Ketones

N N N NaBH4, CeCl3.6H2O N H H H H H H CH3CN, MeOH H H 78% MeO2C MeO2C O OH

28 Pere Romea, 2014 NaBH4–CeCl3: Reduction of C=O

OTBS OTBS OTBS HO HO HO R R R ClCH2CO2H NaBH4, CeCl3 7H2O DIAD, PPh3 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 CO , MeOH 2 3 92% overall 2) TIPSOTf, lutidine

OTBS OTBS OTBS TIPSO TIPSO TIPSO R R R DMP, pyr H2, Pd(OH)2/C, Al2O3 CH Cl rt OTIPS 2 2, OTIPS EtOAc, 0 °C 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 O N O N OH 2 O CO Me 2 O H 2 LiBH H N OTBS 4 N OTBS N N H THF–Et2O, 0 °C 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 3 4 1 2 + R NHR 1 2 1 H R R R R R R2 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

O

CHO

NMe HO 2 HO O O OH NaBH3CN, MeOH O O O O OMe OH O MeO Et O OH O HN

Tylosine 79% O O N

NMe HO 2 HO O O OH O O O O OMe OH MeO Et O OH O

BnO C CO2Bn CO2Bn 2 BnO2C CO2Bn CO2Bn NaBH CN OHC 3 N OTHP + NH.TFA 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

3 3 R3 3 R OH R OH2 R 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 NHSO Ph CH Cl NHSO Ph MeO 2 2 2 MeO 2 81%

H H O N O N

Et3SiH, TFA

N CH2Cl2 N O O 65% OH

OSiHt-Bu OH H 2 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, OSO2R 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 H Ph 2 Ph Ph Ph Ph + Ph Pd/C Me Me Me racemate

Ph Me Me H Ph 2 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

H H Me 2 H 2 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 CO2Me

dr 94:6 X: OH, CO2Me 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

CH R CH2R 2 Reductive elimination H H π Complex CH2R Complex σ CH R syn Addition H H H H 2

π-Allyl complex – syn Addition H R H – Allyl complexes account for certain rearrangements H 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 1 R1 R2 R R1 R2 Pd/C Pd/CaCO3/Pb(OAc)2

N 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 H Pd/C Ar 2, Ar H2, Pd/C NO2 NH3X O Boc O,AcOEt O Ph Ph 2 EtOH, H2SO4 O O X: HSO4

Acid chlorides: Rosenmund reduction

O O Cl H2 H O O Pd/BaSO NH O 4 NH O

N

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

Easy O O H2 R Cl R H Pd/BaSO4/quinoline rt, 1 atm

H2 RCHO RCH OH Pd, Pt, Rh, Ru rt, 1 atm 2 H 1 2 2 R R 1 2 Lindlar rt, 1 atm R R

2 H2 2 1 R 1 R R Pd, Pt rt, 1 atm R

H2 Ph XR PhCH + RXH Pd rt, 1 –4 atm 3

H2 RN , RNO RNH 3 2 Pd, Pt rt, 1 –4 atm 2

RCN R NH2 H2 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 + H H C C H 2 soluble

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 8 e

Ph3P: 2e x 3 6 e Cl–: 2e x 1 2 e

Total 16 e

13 Pere Romea, 2014 Homogeneous Hydrogenation of Alkenes

Mechanism of the homogeneous hydrogenation with the Wilkinson catalyst

H

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

Reductive H C CH + PPh + H2C CH2 – PPh3 elimination 3 3 3

H H

Cl PPh Cl PPh 16e Rh 3 Rh 3 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

NO2 NO2 H2, [(Ph3P)3RhCl] Benzene, rt MeO MeO 90%

– The less substituted the more easily reduced

H2, [(Ph3P)3RhCl]

OH Benzene, rt OH 90%

– Conjugated olefines react slowly

H2, [(Ph3P)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 OH H2, [(Ph3P)3RhCl] 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

Ph P Cl 1 3 Ph2 Noyori BINAP 3 L L 3 Rh P L M M 2 6 4 Rh (I): 5s 4d Ph3P PPh3 L2 L4 P L 2 4 Ph2 Ru(II): 5s 4d Wilkinson 16 e Rh(I): 5s2 4d6

Ph3P

ClO4

Ph H Ph2 2 O P OMe P O Rh Ru P OMe P O O Ph2 H 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%

H2 (4 atm) CO H 1% [(S)-BINAP]Ru(OAc)2 CO H Ph 2 Ph 2 MeOH, rt NHAc NHAc ee 97% 99%

H2 (135 atm) 0.5% [(S)-BINAP]Ru(OAc) CO2H 2 CO2H

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 Diimide N N KO2C N N CO2K Concerted process: syn addition

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

COOH COOH N2H4, H2O2

O2N 84% O2N

O O KO C N N CO K O 2 2 O AcOH, 45 °C Br Br Pere Romea, 2014 87% 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 BF · OEt Raney nickel 3 2 Thioketal

1) HSCH2CH2SH, BF3·OEt2

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 NNH 2 2 – OH H N N N N N N H N H N H N H N OH H2O OH

H2O H2O H H H O H

25 Pere Romea, 2014 Carbonyl Reductions

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

O H2NNH2

NH N 2

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

O O

O N H2NNH2, 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) NaBH3CN, DMF, 100 °C H 95% HO HO H NNHTs H H H H H ZnCl2, NaBH3CN H MeOH, Δ H H 50% H

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

Shapiro reaction

NHTs O N 1) Base R TsNHNH2 R R R R R 2) H2O Tosylhydrazone Alkene

O H 1) TsNHNH R 2 R R R 2) B

3) H2O TsNHNH2 H2O

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

28 Pere Romea, 2014 Carbonyl Reductions

BnO BnO

1) 2 eq LDA NHTs 2) H O N 2 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 H O HO BzO OAc TBDPSO OBn

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