Thiyl Radicals in Organic Synthesis - Princeton University · PDF fileThiyl Radicals in...

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Thiyl Radicals in Organic Synthesis When burned, sulfur melts to a blood-red liquid and emits a blue flame that is best observed in the dark. Jian Jin MacMillan Group Meeting November 6, 2014

Transcript of Thiyl Radicals in Organic Synthesis - Princeton University · PDF fileThiyl Radicals in...

Thiyl Radicals in Organic Synthesis

When burned, sulfur melts to a blood-red liquid and emits a blue flame that is best observed in the dark.

Jian JinMacMillan Group Meeting

November 6, 2014

I. Generalities

II.Thiyl-Mediated Hydrogen Atom Transfer

III. Addition of Thiols to C=C bonds

IV. Fragmentation of β-Sulfanyl Radicals

V. Addition of Thiols to Alkynes

VI. Addition of Thiols to Isonitriles

VII. Addition of Thiols to C=S bonds

I. Generalities

■ S-H Bond Dissociation Energies in Thiols

■ Alkanethiols: similar S−H BDEs around 87 kcal mol-1 regardless of the structure of the alkyl residue

86 kcal mol-1

HO SHNH2

O O

SHMe

O

SH

87 kcal mol-1 88 kcal mol-1

■ Thiophenols: weaker S−H BDEs due to the stabilization by resonance of the corresponding arenethiyl radical

SHSH

H2N

SH

O2N

70 kcal mol-1 79 kcal mol-1 82 kcal mol-1

■ S-S Bond Dissociation Energies in Disulfides

■ Dialkyldisulfides: around 65 kcal mol-1 ■ Diaryldisulfides: around 50 kcal mol-1

SH

84 kcal mol-1

FF

FF

F

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

I. Generalities

■ Generation of Thiyl Radicals

■ Hydrogen atom abstraction by the other radicals having a corresponding higher X−H BDEs

■ One-electron oxidation by Mn(OAc)3, O2

■ Homolytic cleavage by radiolysis or light irradiation

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

RS H X+ RS X+ H

Initiator: AIBN, (PhCO2)2, (t-BuO)2, Et3B/O2

RS H RS− e-

− H+

■ One-electron reduction of disulfides

RS SR RS RS+ H+ e-

+ H+

RS H RS + H< 300 nm

PhS SPh 2PhS355 nm

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Rate of Hydrogen Atom Transfer■ The reactivity of a class of radicals toward a given hydrogen atom donor is well described by two parameters: the activation energy of the thermoneutral reaction (Ee0) and the enthalpy of the reaction of interest (ΔHe)

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

RS H R'H2C+ RS RH2C+ H

S-H BDE = 87 kcal mol-1 k298K = 2 × 107 M-1 s-1

n-Bu3Sn H R'H2C+ n-Bu3Sn RH2C+ H

Sn-H BDE = 79 kcal mol-1 k298K = 2 × 106 M-1 s-1

Me

O

MeMe

Me

Me

MeMe

Me

OH

α-tocopherol

R'H2C+

RH2C+ H

O-H BDE = 77 kcal mol-1 k298K =6 × 105 M-1 s-1

Me

O

MeMe

Me

Me

MeMe

Me

O

■ Different interactions in the transition state such as polar effects, antibonding (triplet repulsion), or neighboring π-electrons may influence Ee0, which is particularly low for the reactions of alkyl radicals with thiols

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Polar Effect in Hydrogen Atom Transfer■ In hydrogen atom transfers between two radicals of different electronegativity, charge transfer configurations may contribute to the character of the transition state, such polar effects resulting in a lowering of the activation barrier

Dang, H.-S.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 , 2001, 2452.

R1O CR2

R3

H CR2

R3

OR1

disfavored

RS H CR2

R3

OR1δ- δ+

favored

the absence of charge-transfer stabilization ofthe symmetrical transition state, in which theincoming and outgoing α-alkoxyalkyl radicalshave the same electronegativity

benefits from charge-transfer stabilization because the electronegativities of he nucleophilicα-alkoxyalkyl radical and the electrophilic thiylradical are significantly different

O

O

MeMe

Me

MeMe

Met-BuOO OOt-Bu

5 mol%

nonane, 125 °C, 3 h O

O

MeMe

Me

Me

O

O

MeMe

Me

Me+

100% 0%

O

O

MeMe

Me

MeMe

Met-BuOO OOt-Bu

5 mol%

nonane, 125 °C, 2.5 h O

O

MeMe

Me

Me

O

O

MeMe

Me

Me+

16% 84%

thermodynamic equilibrium

(t-BuO)3SiSH 5 mol%

high activation energy

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Rate Constants for the Reduction of Various Alkyl Radicals by Thiophenol

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

1.3 × 108 (298)

1.0 × 108 (298)

1.4 × 108 (298)

2.8 × 105 (303)

7.6 × 107 (353)

3.0 × 105 (298)

entry

123456

radical kH/[M-1 s-1] (T/K)

n-C3H7-CH2⋅

(CH3)2CH⋅(CH3)3C⋅

n-C6F13-CF2⋅

ROCH2CH2⋅

PhCH2⋅

-17-15-12-20-18-5

PhS H C+ PhS C+ HkH

ΔH/[kcal mol-1]

■ Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiol

2 × 107 (298)

4 × 106 (303)

2 × 107 (298)

7 × 106 (353)

7 × 102 (333)

entry

123456

radical kH/[M-1 s-1] (T/K)

R-CH2⋅

R3C⋅R-CH(OMe)⋅

R-C(=O)⋅Ph-CHR⋅

Ph-CH(OMe)⋅

-13-8-4-1+2+2

RCH2S H C+ RCH2S C+ HkH

ΔH/[kcal mol-1]

k-H

2 × 104 (353)

1 × 106 (353)

2 × 107 (353)

k-H/[M-1 s-1] (T/K)

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Dynamic Kinetic Resolution of α-Chiral Amines

Gastaldi, S.; Escoubet, S.; Vanthuyne, N.; Gil, G.; Bertrand, M. P. Org. Lett. 2007, 9, 837.

MeMe

NH2

0% ee

Et2NSH

O

Me

AIBN, C11H23CO2Et, Novozym 435heptane, 80 °C Me

MeNH

81% yield, >99% ee

C11H23

O

MeMe

NH2

(R)

MeMe

NH2

(S)

MeMe

NH

(R)

MeMe

NH

(S)

C11H23

O

C11H23

O

RSH, initiator

lipaseacyl donor

lipaseacyl donor

RSH, initiator

(cat.)

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Hydrogen Abstraction from Benzylic Positions

Guin, J.; Frohlich, R.; Studer, A. Angew. Chem. Int. Ed. 2008, 47, 779.

NOAc PhSH (cat.), Et3B/O2

Benzene, rt 48% yield, dr = 13:1

O

i-Pr

O

NNHBoc

Me Me

MeO2C CO2MeN

OAcO

i-Pr

O

NHBoc

PhS

NNHBoc

Me Me

MeO2C CO2Me

NHBoc

NOAc

O

i-Pr

O

NHBoc

NNHBoc

Me Me

MeO2C CO2Me

NMe Me

MeO2C CO2MeN

OAcO

i-Pr

O

PhSH

NOAc

O

i-Pr

O

NHBoc

PhSH

II.Thiyl-Mediated Hydrogen Atom Transfer

■ Hydrogen Abstraction from Silane

Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 , 2002, 1376.

Ph3SiH,TBHN Hexane/dioxane, 60 °C

90% ( 95% ee)

*RS

*RSH *RSH

O O

PhPh

O O

PhPh

Ph3Si

OAcO

AcO

OAc

SH

OAc

(5 mol%)

Ph3SiH

Ph3Si

O O

PhPh

Ph3Si

O O

PhPh

Ph3Si

O O

PhPh

III. Addition of Thiols to C=C bonds

■ anti-Markovnikov Addition of Thiyl Radicals to Olefins

■ Thiol-Ene Coupling (TEC)

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

+R1Skadd

kfragR4

R2

R3

R4

R2

R3

R1S

R4

R2

R3

R1S R1SH RS+R4

R2

R3

R1S+

■ Thiol-Olefine Cooxidation (TOCO)

R4

R2

R3

R1S O2 R4

R2

R3

R1S+

OO

products

inter R1SHintra R1SR

■ Ring-Openning of Vinyl Cyclopropane

R2

R3

R1S

R2

R3

R1SEWG EWG

intra C=C

III. Addition of Thiols to C=C bonds

■ Thiol-Olefine Cooxidation (TOCO)

Iriuchijima, S.; Maniwa, K.; Sakakibara, T.; Tsuchihashi, G. J. Org. Chem. 1974, 39, 1170.

O2, hexane, hv

AcO Cl

SH

(1 equiv) AcO SOH O

Cl

O2, hexane/EA, hv

Me

SH

(1 equiv)S

O

Me

Me

OH

MeV2O5 (cat.)

SOH

Me

Me

O

III. Addition of Thiols to C=C bonds

■ Thiol-Olefine Cooxidation (TOCO)

Szpilman, A. M.; Korshin, E. E.; Rozenberg, H.; Bachi, M. D. J. Org. Chem. 2005, 70, 3618.

Me

Me

1) PhSH, O2, DTBPO(cat.)

2) PPh3

OO

OH

Me

MeSPh

30%

via:

Me

MeSPh

OO 6-exo-trig

OO

Me

MeSPh O2

OO

Me

MeSPh

PhSH

OHO

OO

Me

MeOH

Me

OHMe

Yingzhaosu A

III. Addition of Thiols to C=C bonds

■ Ring-Openning of Vinyl Cyclopropane

Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nature Chem. 2014, 6, 702.

BPO (6 mol%), toluene, 0 °C, 2 hhv (100 W Hg lamp or sunlight)

thiophenol (3 mol%)

CO2BnCO2Bn t-BuO

t-BuO

CO2Bn

CO2Bn

Me

SHSit-Bu

CF3

CF3

OH

Bu

Bu

+

CO2BnCO2Bn

RS

via:CO2Bn

CH2O2Bn

RS

t-BuO t-BuO

CO2Bn

CO2Bn

RS

t-BuO

CO2Bn

CO2Bn

RS

95% yield, 19:1 dr, 86% ee

IV. Fragmentation of β-Sulfanyl Radicals

■ Isomerization of Alkenes

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

■ Fragmentation of Allyl Sulfides

R1 +R2

SPhR2

SPhR1

R2

R1

+PhS R2

R1R2

R1

R1S+PhS

R1

R2

■ Fragmentation of Vinyl Sulfides

SPh

R

SPh

R R

IV. Fragmentation of β-Sulfanyl Radicals

■ Fragmentation of Allyl Sulfides

Cerreti, A.; D'Annibale, A.; Trogolo, C.; Umani, F. Tetrahedron Lett. 2000, 41, 3261.

■ Fragmentation of Vinyl Sulfides

SPhNMeBn

O

O

MeO

SPhNMeBn

O

O

MeO

NO Bn

MeO

O MeSPh

NO Bn

MeO

O Me

Mn(OAc)3 (1 equiv.)

AcOH, 70 °C

OHO

43% yieldtrans only

MeO

BrSPh

NMe

Ts

Bu3SnH, AIBN

Benzene, 130 °C

MeO

OH

HOH

NMe

Ts

35% yield

MeO

OH

HO

NMe

Ts

SPh

via

via

Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449.

V. Addition of Thiols to Alkynes

■ Addition of Thiyl Radical to Alkynes

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

+R1S R2R1S

■ The reverse reaction that releases the triple bond is rather slow, and fragmentation of the thiyl radical is generally not observed due to the rapid decay of the resulting highly reactive vinyl radical

R2kadd

■ Addition to alkynes is more exothermic than to alkenes as replacing a very weak π-bond by a strongerCsp2−S σ-bond compensates for the energetic cost of generating a vinyl radical

■ Very few intermolecular trappings of β-sulfanylalkenyl radicals in a new C−C bond-forming reaction havebeen reported because it's very hard to compete with the hydrogen atom abstraction from thiols

R2R1S R1SH+

R2R1S

H+ R1S

R2R1S +

R2R1S

SR1

R1SH

branched

Thiol-Yne Coupling

■ Intramolecular trapping by C=C, C=N bonds

PhSH (slow addition)

AIBN, TMTHF, reflux

SPh

70%

V. Addition of Thiols to Alkynes

■ Intramolecular Chalcogenation: SH2 at Sulfur

Lachia, M.; Denes, F.; Beaufils, F.; Renaud, P. Org. Lett. 2005, 7, 4103.

SY

PhS SY

PhS

SH2 S

PhS

+ Y

Y = alkyl, acyl, carbamoyl, Ph2P(O), (EtO)2P(O), (EtO)2P(S), (N(Me)CH2)2P(O)

S

O

NPhSH, AIBN

benzene, refluxN

Me

O

N

O80% yield 4% yield

■ Translocation Reactions: 1,n-Hydrogen Transfer

Me Me

OH

cis/trans = 8:1

PhSH, AIBN

cyclohexane, 25 °C, hv

Me Me

OH

SPh

Me Me

O

SPhH

Me Me

O

H

SPh

via

VI. Addition of Thiols to Isonitriles

■ Intermolecular Trapping versus Fragmentation

Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114 , 2587.

■ Intramolecular Trapping by Alkenes or Alkynes

R2NCR1 S R2NCSR1

R1 = primary alkyl Ar

R1 = tertiary alkyl Bn

R2NCSR1

H

R1 R2NCHS+

O

O

SHt-Bu-NC, AIBN, 80 °C

O

O

OAcOAc

79% yield

+

Me Me

OTBS

CO2EtCN

Me Me

OTBS

CO2EtNSOH

N

OTBS

CO2Et

MeMe

SOH

NH

OTBS

CO2Et

MeMe

S

O

NH

OTBS

CO2Et

MeMe

O

SHHO

AIBN, toluene, 80 °C

via

VII. Addition of Thiols to C=S bonds

■ Barton Reductive Decarboxylation

Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901.

■ Barton Reductive Deoxygenation of Tertiary Alcohols

RON

O

S

t-BuS

N

St-BuS

RO

OR+

MeCl11

O 1.NOH

S

,pyridine

2. t-BuSH, toluene, reflux

Me11

95% yield

AcO

Me

MeMe

Me OH

ClCl

O

O

AcO

Me

MeMe

Me ONOH

S

, DMAP

t-BuSH, toluene, reflux

ClO

O

AcO

Me

MeMe

Me H

H

Barton, D. H. R.; Crich, D. J. Chem. Soc., Chem. Commun. 1984, 774.