Catalytic Functionalization of Allylic C-H · PDF file4 (1 equiv) Pd PPh 3 (2 equiv) NMe 2 ... Chem 153 C-H Activation -33- Week of October 16, 2012 It is not clear if these ... salts

PdCl/2 CO2Et

CO2Et

EtO2C CO2Et

NaEtOH/DMSO

r.t.

+ Pd0+O O

PdCl/2

Pd(TFA)2;Bu4NCl

Acetone, r.t.

Trost, JACS 1980, 102, 3572. Tsuji, TL 1965, 49, 4387.

C-H Cleavage: Functionalization:

Early catalytic oxidations

reaction occurs under heterogeneous Pd0 catalysis

Hegedus, JACS 1978, 100, 7747. EtO2C CO2Et

20 mol% PdCl2(MeCN)240 mol% Et3N

1 equiv LDATHF, rt

+CO2Et

CO2Et

+EtO2C CO2Et

carbopalladation C-H functionalization

18% yield 36% yield

Åkermark, ACIE 1984, 23, 453.

Catalytic Functionalization of Allylic C-H Bonds Early stoichiometric studies

Akermark, Hegedus, JACS 1981, 103, 3037.

AgBF4 (1 equiv)PPh3 (2 equiv) NMe2Pd

Cl

2 Me2NH (10 equiv)THF, rt94%

Alkylation

Amination

Larock, JOC 1996, 61, 3584.

OAc5 mol% Pd(OAc)2

20 mol% BQ

MnO2

60oC 17h 99% yield

NHTsTsNPd(OAc)2 (5 mol%)

NaOAc (2 equiv)

DMSO, O2, 80oC

86% yield

Strong, basic nucleophiles are incompatible with conditions needed for C-H cleavage; prevents catalysis

M.C. White, S.M. Paradine, Chem 153 C-H Activation -33- Week of October 16, 2012

It is not clear if these reactions occur through C-H

cleavage or an olefin insertion event

White, JACS 2004, 126, 1346. White, JACS 2005, 127, 6970.

C-H oxidationolefin oxidation(Wacker)

+ Nuc

Nuc

R R Nuc

R

Pd(OAc)2DMSOBQ

Pd(OAc)2BQ

Chemoselectivity: Site-selectivity:

Catalytic Functionalization of Allylic C-H Bonds M.C. White, S.M. Paradine, Chem 153 C-H Activation -34- Week of October 16, 2012

OAc

Pd(OAc)2

BQ (2 equiv)

40oC, 72h

(10 mol%)

DMSO/AcOH

OO PhHN

O

PhHN

O

64% yield17:1 L/B13:1 E/Z

<1% Wacker

Ligand‐basedcontroloverchemoselec4vityandsite‐selec4vity

C8H17

PdDMSODMSO

—OAc

C8H17

SPd(OAc)2

S PhPhOO

H

C8H17

PdOAc

O

O

C8H17

OAc

C8H17AcO

Pd(OAc)2+

DMSO+ BQ

outer spherefunctionalization

inner spherefunctionalization

Serial Ligand Catalysis

R

AcOH +

R

Nu

R

Pd(OAc)

Pd(OAc)2

bisSO

Ph

OO

Functionalization

C-H CleavageCatalyst

Re-Oxidation

bisSO

BQ

SSPh

O O

AcOH +

NuH

DHQ

2 equiv. AcOH + bisSO

(bisSO)Pd(OAc)2

R

Pd

O

O

OAc

Pd0(BQ)

White, JACS 2005, 127, 6970.

C8H17C8H17

Pd(OAc)L

SPd(OAc)2 cat.

S RROO or S

O

C8H17

Pd(OAc)L

C8H17Nu

C8H17

Nu

!-acids (!A)

S

O

R R

·!ambidentate (O or S)·!" donor (O)·!! acceptor (S)·!supports dicationic Pd (i.e. [Pd(DMSO)4](BF4)2)· activates !-allylPd

Weak, ambidentate ligands

catalytic base

or

O

HO R

O

NH

OMeTs

pKa ~ 3.5 - 5.0

O2N R

Pro-nucleophiles

!A = BQ, DMSO +/- LA

M(OAc)2, DIPEA

1. C-H Cleavage 2. Functionalization


Reaction Acceleration/Activation

PdLn CrLn

krel C—H cleavage B:L ee

+ — 1.01.05------

>20:15:1---2:1

---55%---

29%

+ +

krel C—Obond formation

1.09.7---3.8

+ + (— BQ)+ Cr(salen)OAc

C8H17

Pd

AcO BQ · Cr(F)L*

I.

C8H17

Pd

II.

Ln

BQ

AcO-CrL* C8H17

Pd

AcO BQ · Cr(F)L*

III.AcO-CrL* Three possible scenarios for Lewis acid activation:

1)  Coordination to ligated BQ 2)  Direct delivery of nucleophile by Cr-salen 3)  Combination of 1 & 2 #2 can be eliminated

R

RSPd(OAc)2

S PhPhOO

R

Pd(BQ.LA)

NR2

Lewis acid/BQ

L

50-60%

OO

(11%)

RR

Pd(Nu)

NR2

L

50-80%

OO

(70%)exogenous

catalyticbase

BH+ Nu—

TsHN OMe

O

BQ

S SO O

Ph Ph·Pd(OAc)2

Cr(salen)Cl (6 mol%)

MeOC(O)NHTs (2 equiv.)BQ, TBME, 45oC

C7H14 NTs

O

OMe

59%11:1 L:B19:1 E:Z

C7H14DIPEA (6 mol%)

OR

without activator: 1% yield

O NHNs

O

ONHNs

OSPd(OAc)2

S PhPhOO

THF, 45oC

PhBQ

no additive: 24h, 78% yield10 mol% Cr(salen)Cl: 6 h, 80% yield

Two modes of activation: 1)  Activation of electrophile - pulls electron

density away from Pd-allyl intermediate 2)  Activation of nucleophile – increases

concentration of deprotonated nucleophile

White, JACS 2008, 130, 3316. White, ACIE 2008, 47, 6448. White, Tetrahedron 2010, 66, 4816.


C-H Oxidation: White, JACS 2004, 126, 1346. OL 2005, 7, 223. JACS 2005, 127, 6970. ACIE 2006, 45, 8217. JACS 2006, 128, 9032. ACIE 2008, 47, 6448. JACS 2010, 132, 1133. JACS 2011, 133, 12584. C-H Amination: White, JACS 2007, 129, 7274. JACS 2008, 130, 3316. Guosheng Liu, ACIE 2008, 47, 4733. Poli, Chem. Eur. J. 2009, 15, 3316. White, JACS 2009, 131, 11701. JACS 2009, 131, 11707. Tetrahedron 2010, 66, 4816. C-H Alkylation: White, JACS, 2008, 130, 14090. Zhang-Jie Shi, JACS 2008, 130, 12901. White, ACIE 2011, 50, 6824. C-H Dehydrogenation: White, JACS 2011, 133, 14895.

Scope of Allylic C-H Functionalization M.C. White, S.M. Paradine, Chem 153 C-H Activation -37- Week of October 16, 2012

O NNs

R

O

R O R'

O

S S

O O

Pd(OAc)2RR

NTsO

R

O

R

O

O

R'

RR''

R'

R NTs

CO2R'

R

O

O

O

RO O

R

O

RH

HEWG

EWG

Guosheng Liu, ACIE 2008, 47, 4733. Zhang-Jie Shi, JACS 2008, 130, 12901. White, JACS 2008, 47, 6448.

Examples of Allylic C-H Functionalization

Intramolecular C-H Alkylation

Oxygen as Terminal Oxidant

OMe

NTs

OMe

OMe

OPd(OAc)2 (10 mol%)maleic anhydride (40 mol%)

NaOAc (25 mol%)

4A MS, DMA

O2 (6 atm), 35oC, 48h3 equiv

TsN OMe

O+

1 equiv

75% yield

SPd(OAc)2

SOOPh Ph

O

Ph

O O

Ph

O

BQ, O2 (1 atm)

PhMe

60oC, 60h

88% yield

Asymmetric Allylic C-H Oxidation

7 7

OAc

SPd(OAc)2

S PhPhOO

(R,R)-Cr(salen)F

(10 mol%)

(10 mol%)

AcOH (1.1 equiv.), BQ54% ee5:1 B:L

81%

7

OAc

97% ee>20:1 B

Novozyme 435

O

N

O

N

Me

MeO

Me

MeO

O

N

Me

MeO


White, JACS 2011, 133, 14895.

Applications of Allylic C-H Functionalization

Dehydrogenative Diels-Alder Reaction

Tandem C-H Oxidation/Heck

, BQ

HO

O

(10 mol%)

1.5 equiv.

SPd(OAc)2

S PhPhOO

O

O

NHBoc

Br

n=7n=7NHBoc

B(OH)2

Br2 equiv

75% yield>20:1 E/Z

>20:1 internal/terminal


R R

PdLn

H

C–Hcleavage

!-hydrideelimination

reactiveintermediate

D.A.(KDA)

R

H

H·

Pd(OAc)2

S SR R

O O

DehydrogenativeDiels-Alder

catalyst

EWG

EWG

EWG

EWG

R

(1 equiv.)

(±) NPM (1 equiv.),

2,6Me2BQ (1 equiv.),

solvent, 45oC, 48 h

PhN

O

O

H

H

OAc

74% yield>20:1 d.r.

(10 mol%)

(+/-)

HH

2

AcO

Pd(OAc)2

S SBn Bn

O O

White, JACS 2006, 128, 15076.

White, Nature Chem 2009, 1, 547.

Applications of Allylic C-H Functionalization

LnPd

O O

PMP

OOO

HO

Ha Hb

13

"Chelate"

BQ, 45!C

(56% + 8% r.s.m.,2x recycles)

"Non-chelate"

TBAF, BQ, 45!C

(44% + 36% r.s.m.,2x recycles)(1:1.3 d.r.)

O

O

O

O

O

O

PMP H

13

S S PhPhOO

O

O

O

O

O

O

PMP H

13+ C13

Epimer

PdO

O

OO

(30 mol%)

From F

Pd(OAc)2

(>40:1 d.r.)

OH

O

O

O

OH

OH

6-deoxyerythronolide B

22 steps (7.8% overall yield,

85% avg. yield/step)

136

3 steps

Total synthesis of 6-deoxyerythronolide B

Derivatization of β-Lactam Pharmacophores


NTBS

BocHN

O

OAcSPd(OAc)2

S PhPhOO

BQ, DIPEA NTBS

BocHN

O

OAc

NTs

OBn

O

TsNHCbz

69% yield

White, Tetrahedron 2010, 66, 4816.

Oxidative functionalization of alkanes

overoxidation to CO2 ismajor problem w/methane oxidation

The methane to methanol challenge: Synthesizing "liquid gold":

CH4 (g) + H2O (g)Ni/Al2O3

700oCCO (g) + H2 !Ho = 49.3 kcal/mol

CO (g) + 2 H2 (g) zeolite cat.!

CH3OH !Ho = -21.7 kcal/mol

Current industrial process consumes significant amounts of energy:

Direct oxidation is thermodynamically favorable.

CH4 (g) + 1/2 O2 (g) !Ho = -30.7 kcal/molcatalyst ? CH3OH

Nature does it:

Methane Mono-Oxygenase (MMO):

CH4 + O2 + NADPH + H+ MMOM. Capsulatus

12 min

CH3OH + NADP+ + H2O

84 tof tof = nmol product/min/mg enzyme

Higher hydrocarbons are oxidized with poor regioselectivities

MMO oxidizes methane to methanol with 100% chemoselectivity (no overoxidized product results).

MMOM. Capsulatus

12 minOH

+

OH

1.3 : 1Lipscomb J. Biol. Chem. 1992 (267) 17588.

Pseudomonos Oleovorans Mono-Oxygenase (POM):

Oxidizes linear alkanes with 100% regio- and chemoselectivity

n-alkanes

C6-C12

+ O2 + NADPH + H+ 1-alcohols

+ NADP+ + H2O

1-octanol, 590 tof

POM

Coon Biochem. Biophys. Res. Comm. 1974 (57) 1011.Munck PNAS 1997 (94) 2981.

The Shilov system:

CH4 + H2O

Cl

PtIICl Cl

Cl

(K+)2

cat.

CH3OH + CH3Cl

120oC

K2Pt(IV)Cl6 oxidant

In 1972 Shilov and coworkers demonstrated that a combination of chloroplatinum(II)and (IV) salts in aqueous solutions at elevated temperatures effects the oxidation ofalkanes to mixtures of alcohols and alkyl chlorides. The regio- and chemoselectivity of the Shilov system reflects those of other organometallic systems in that the stronger 1o

methyl hydrogens of propane and even ethanol are more reactive than the methylenehydrogens. Unfortunately only modest selectivites are observed. Some overoxidizedproducts and regioisomeric mixtures of alcohols are observed because the productalcohols are more soluble in the aqueous reaction media than the hydrocarbon.

Shilov Zh. Fiz. Khim. (Engl. Trans.) 1972 (46) 785. regioselectivities: Bercaw JACS 1990 (112) 5628.

A beginning...

M.C. White, Chem 153 C-H Activation -41- Week of October 16, 2012

MMO

N

N

Fe(II)

OH2O

O OO

N

N

Fe(II)

O

O

OO

N

N

Fe(III)

OH2O

O

H2O

N

N

Fe(III)

O

O

OO

OH

O

O

·Hydroxylase Active Site of MMO

H147

E114

E243

H246

E209

E144

MMOHred

H147

E114

H246

E209

E144

MMOHox

E243

Based on crystallographic studies of M. capsulatus(-160oC) Lippard Nature 1993 (366) 537.

CH3

HT

D

CH3

OHT

D

CH3

HO T

DMMO

Key piece of evidence supporting substrate radical intermediate:

(R)-ethane (S)-ethanol (R)-ethanol

+

35%

Lipscomb Chem. Reviews 1996 (96) 2625.

FeIII

O

O

N

N

N

FeIII

O

N

N

N

Cl Cl

2+

(ClO4-)2

cat.

H2O2, CH3CN, air

note: the same yields and selectivities were observed when the reactions were run under an inertatmosphere (Ar) or in air. This indicates that freeradicals, propagated with O2, are not acting as theoxidant.

OH

+

O

4 tn 2 tn

Nishida Chem. Lett. 1995 885.

Attempts to mimic Nature's solution have failed. The key to chemo- and regioselectivity in these radical systems may be MMO and POM's protein suprastructure which thus far havenot been mimicked in solution.

Fe

HO

Fe

·O O·

Fe

HO

Fe

O O

Fe

HO

Fe

O O

H

Fe

HO

Fe

Fe

HO

FeO

Fe

HO

Fe

OH

Fe

HO

Fe

(II)(II)

(III)(III)

(III) (III)

O·

(III)(IV)

(IV) (IV)

(III)(III)

(III)(IV)

H2O2

-H+

H+

H+

-H2OQ

µ-1,2 peroxo

adduct

+R·

"peroxideshunt"

RH

P

2e-

ROH

The second iron in MMO transiently stabilzesintermediate Q by supplying an e- to fill theoxygen atom's octet. This avoids energetically unfavorable Fe(V) intermediates.

Proposed mechanism (thought to be operating for POM as well):


The Shilov System/C-H activation via late, electrophilic complexes

H

C

M M C

!"donation>>

#-backbonding

heterolytic cleavage

!-complex

+ H+

C-H activation processes that occur via heterolytic cleavage result in no oxidation state change at the metal. Generally,electrophilic metal complexes are used that incorporate metals in their highest stable oxidation states. Unlike the Bergman nucleophilic complexes, electrophilic complexes are compatable with oxidants and provide a route to oxidativefunctionalization of hydrocarbons (the most desirable form of functionalization).

Because Pt is a late "soft" metal,the relatively diffuse alkane C-Hbond is able to intermolecularlycompete with the hard oxygen lone pair of H2O for binding to themetal.

Inversion of stereochemistry at

the platinum bound C using

deuteruim labeled substrates

provided strong evidence for

SN2 functionalization pathway

Proposed mechanism:

Bercaw ACIEE 1998 (37) 2180.

The Shilov system:

CH4 + H2O

Cl

PtIICl Cl

Cl

(K+)2

cat.

CH3OH + CH3Cl

120oC

K2Pt(IV)Cl6 oxidant

Cl

PtIICl OH2

OH2

Cl

PtIICl OH2

H

CH3

OH2

Cl-

soft deprotonation

Cl

PtIICl OH2

CH3

note: no oxidation state change to the metal

K+

K2Pt(IV)Cl6Cl

PtIVCl OH2

CH3

Cl

Cl

K+

HCl

Cl

PtIVCl Cl

Cl

CH3

H2O

K+

Cl

PtIICl Cl

Cl

2

(K+)2

2

H2O

2 H2O2 Cl -

K2Pt(II)Cl4 Pt(II) catalyst is regenerated

orCl

PtIVCl OH2

CH3

H Cl-

MeOH

CH4


C-H activation via late, electrophilic complexes in highly acid media

Although the Periana Pt system is unparalleled withrespect to its efficiency at oxidative functionalization ofmethane, the high cost associated with platinum coupledto the operational difficulty in seperating the product fromthe solvent renders this route to methanol non-competitive with traditional reforming.

Proposed mechanism:

N N

N N

PtII

OSO3H

OSO3H

N N

N N

PtIIOSO3H

+

(-OSO3H)

14 e- complex

N N

N N

PtII

OSO3H

+

(-OSO3H)

H

CH3

or

N N

N N

PtIV

OSO3H

CH3

+

(-OSO3H)H

-OSO3H

-OSO3H

N N

N N

PtII

OSO3H

CH3

N N

N N

PtIV

OSO3H

CH3

OSO3H

OSO3H

heterolytic cleavage

CH3OSO3H CH4

SO3 + 2 H2SO4

SO2 + H2O

oxidation

CH4 + 2 H2SO4

N N

N N

PtII

Cl

Cl

500 tn

H2SO4 (ox/solv)

200oC

CH3OSO3H

70% methyl bisulfate(90% conversion/80% selectivity) basedon methane.

note that the product cannot undergo further oxidation.

Periana Science 1998 (280) 560.Heterolytic cleavage directly from the !-complex is clearly operating for Pd(II) and Hg(II) systems where the M(n+2) oxidation state of thealkyl(hydrido)metal intermediate is prohibitively high in energy.

CH4 + 2 H2SO4

Hg(II)(OSO3H)2 cat.

H2SO4 (ox/solv)

200oC

CH3OSO3H

50% yield (based on CH4)

CH4 +Pd(OAc)2 stoic.

CF3CO2H

CF3CO2H (solv)CH3O2CF3 + Pd (0)

Periana Science 1993 (259) 340

Sen JACS 1987 (109) 8109

N N

N N

PtII

OSO3H

OSO3H

H

H

(-OSO3H)2

2+

The ligand may become protonated under the reaction conditions. Protonation willwithdraw electron density from the Ptthrough the !-bonding framework of thebidiazine ligand thereby enhancing itselectrophilicity.


Oxidative functionalization of alkanes: Oxygen M.C. White, S.M. Paradine, Chem 153 C-H Activation -45- Week of October 16, 2012

O

n = 2 n = 2O

n = 2

O

GC ratios:64% 28% 3% (+4% 1-isomer)

7% GC yield (oxidant)0.34% (substrate)

Mn(TDCPP)ClH2O2

n = 2

excess

33 equiv.

Fe(porphyrin) cat.

OH

8% GC yield* (oxidant)0.24% (substrate)

PhIO(1 equiv.)*

AcO

<2%

17%

15%

21%

22%

24%

Groves JACS 1979, 101, 1032. Mansuy JACS 1988, 110, 8462.

Early examples of non-enzymatic aliphatic C-H oxidations used large excesses of substrates, with low yields and poor selectivities when multiple sites of C-H oxidation were possible

CO2H

NH2

K2PtCl4 cat.

CuCl (7 equiv.)

160oC

O O

NHBoc

15% yield

Controlling site-selectivity through directing effects

Sames, JACS 2001, 123, 8149.

Application of the Shilov system for C-H oxidation of amino acids -even with directing group, harsh conditions result in the formation of multiple products, including oxidation of 1o C-H bonds

Development of Site-Selective C-H Oxidations M.C. White, S.M. Paradine, Chem 153 C-H Activation -46- Week of October 16, 2012

Groves JACS 1989, 111, 2900.

A Shape-Selective Oxidation Catalyst

Crabtree, Science 2006, 312, 1941.

Groves synthetically re-created an enzymeʼs active site in order to mimic the high site-selectivities that enzymes achieve for specific substrates in biological settings

ML

L L

L

H2C

CH3O

R hydrophobicshape recognition

cavity

active metal-oxomoiety

HO

O

7

3

HO

O

7

3

HO

O

7

3

O

O

+

Fe cat.1 equiv PhIO

Fe(TPP)Cl 1 : 1 1 1 : 2

1 equiv

Molecular Recognition for Selective Oxidation

HO O

HO O

OO

Mn cat (0.1 mol%)Oxone (5 equiv)

MeCN

1

2

1:2 = 97:3

71% conversion

710 turnovers

Small Molecule Catalysts for C-H Oxidation M.C. White, S.M. Paradine, Chem 153 C-H Activation -47- Week of October 16, 2012

Que Jr. JACS 1997, 119, 5964.

White, Science 2007, 318, 783.

First example of a C-H oxidation reaction using limiting quanities (1 equiv) of substrate with synthetically useful yields (>50%)

1 equiv.

Fe(S,S-PDP) 5 mol%H2O2 (1.2 equiv.)

AcOH (0.5 equiv.) OHH

PivO PivOCH3CN, 30 min

51% isolatedyield

3X

N

N

N

N

Fe

NCCH3

NCCH3

(SbF6)2

Fe(S,S-PDP)(CH3CN)2(SbF6)2

FeN

N NCCH3

NCCH3

N

N

2+

(SbF6)2

[Fe(mep)(CH3CN)2](SbF6)2

Effect of ligand structure on selectivity:

Fe(mep) 62% selectivity Fe(pdp) 90% selectivity

Using limiting substrate with high yields:

Early example of a non-heme catalyst:

FeN

N NCCH3

NCCH3

N

N

2+

(ClO4)2

[Fe(TPA)(CH3CN)2](ClO4)2

excess

Fe(TPA)H2O2 (limiting)

CH3CN, air

OH

3.6-4.6 tn

Hydroxyla)onoccursinastereospecificmanner

Selectivity Trends for Aliphatic C-H Oxidation M.C. White, S.M. Paradine, Chem 153 C-H Activation -48- Week of October 16, 2012

C-H Bond Reactivity Trends

White, Science 2007, 318, 783. White, Science 2010, 327, 566. White, Science 2012, 335, 807.

Site-Selectivity Rules

H

H HH

RH

R = Me or H

EWG

RH

EWG

RH

RH

EAG<< << < <

1o 2o 3o

reactivity

2o, 3o

increasing steric access

increasing electron-rich character

CO2Me

I. electronic

II. steric

IV. directed

OH

Olefin Oxidation C—H Oxidation

I. electronic

EWG

BG

II. steric

IV. directed

DG

OAc

RH

RH

RH

RH

RH

RH

R = C or H

III. stereoelectronic

C3H7n = 3

CO3H

III. stereoelectronic

BG

H

H

H

H

H

H

H

H

H

HH

I. electronics

II. sterics

Fe(PDP)

III. conformational effects

Fe(PDP)t-Bu t-Bu

O3

t-Bu

O

59% 12%

4

[2.5:1]

MeO

O

22%

Fe(PDP)

OAc OAc OAc

OH

HO

50% 4%[11:1]

[2.3:1]

IV. directed

70% <1%

HO

O OO

MeO

O OFe(PDP)

[>20:1]

MeO

O

O

MeO

O O

50%

Selectivity Trends for Aliphatic C-H Oxidation: “Exceptions” M.C. White, S.M. Paradine, Chem 153 C-H Activation -49- Week of October 16, 2012

White, Science 2010, 327, 566. White, JACS 2012, 134, 9721.

Hyperconjugative Activation Groups such as cyclopropanes and oxygen, have lone

pairs that are arranged in space so as to hyperconjugatively activate the adjacent C-H bond,

increasing selectivity for that position (note that these groups are generally inductively withdrawing!)

O

RO

HFe(PDP)

H2O2O

O

starting material

lactone product

isolated yields

R = Me, H

O

HO

HOAc

O

O

OAcester = 26% (52% rsm)acid = 50% (26% rsm)

Electronic effects

Steric effects

t-Bu

H CO2H

t-Bu

O

O

ester = 9% (36%, ketone)acid = 50%

ester = 32% (25%, ketone)acid = 29%

TFDO

Stereoelectronic effects

O H CO2H O O Oester = 2% (22%, 2o)acid = 58%

Fe(PDP)

H2O2/AcOH

Substrate Major ProductIsolated

% Yield (rsm)

MeO

O

62% (17%)[C5:C6 = 6:1]MeO

O O

O

52% (15%)[C1:C2 = 5:1]

56

12

O O O 41% (---)

EAG

H

HEAG

O

MeO

O

O

56

51%[C6:C5 = 3:1]

Directing Group Activation Groups such as carboxylic acids tethered on the substrate will bind to the catalyst, forming five-membered lactones,

even in positions that would otherwise be strongly disfavored according to selectivity rules

Mechanism of Aliphatic C-H Oxidation M.C. White, S.M. Paradine, Chem 153 C-H Activation -50- Week of October 16, 2012

White, Nat. Chem. 2011, 3, 218. White, JACS 2012, 134, 9721.

Over-oxidation from cleavage of a primary C-H bond, especially one adjacent to a lactone, is very strongly disfavored. Experimental controls established that hydroxylactone formation was the result of a desaturation event. This type of desaturation activity is unable to occur if oxidation occurs via a concerted three-centered insertion. This suggests that oxidation with Fe(PDP) involves a radical C-H abstraction/rebound.

FeO2C

O

hydroxylrebound

1 e-

oxidation

HO2C

R'OH

n = 2

n = 2

R'H

OOR'

Lactones 50-60%

HO2C

R'

n = 2

HO2C

R'

n = 2

O OOR'

Hydroxylactones 15-20%

OH

Ln FeO2C

n = 2

R'

Ln

HO

FeO

O2CRLnFeLn Fe

OH

XLn

R'R

H2O2

metal oxo carboxylate

R'R

H

H-abstractioncarbon-centered radical

non-hemeiron catalyst

R'R

HO

R'OH

R

R

Hydroxylase

Hydroxylase

Desaturase

oxidation

rearrgement/rebound

* Only when R = carboxylic acid

rapidhydroxylrebound

R'

OH

FeLn

R'R

HO

R

concerted insertion

Mixed hydroxylase/desaturase activity:

Mechanism of Aliphatic C-H Oxidation M.C. White, S.M. Paradine, Chem 153 C-H Activation -51- Week of October 16, 2012

White, Science 2007, 318, 783. White, Nat. Chem. 2011, 3, 218. White, JACS 2012, 134, 9721.

Taxane-based radical trap

H

HOAc

AcO

AcO

O

O

OAc

O

HOAc

AcO

AcO

O

O

OAc

O

HOAc

OAcAcO

AcOO

OO

HOAc

OAcAcO

AcOO

OO

OH

Fe(PDP) 1

H2O2

C1 = OH no observed nor-taxane

taxane nortaxane21% (29% rsm)

1115

1

11

15

1

I-1 I-2

Fe OLn FeLn OH

First direct evidence for a radical intermediate in aliphatic C-H oxidations

O

MeOH

OO

Fe(S,S-PDP) cat.

H2O2/AcOH

97% ee 97% ee

Fe(S,S-PDP) cat. H2O2/AcOH

62% yieldno olefin detected

O

MeO

O

MeO

O

Stereoretentive: radical lifetime <1x10-10 s No ring-opening: radical lifetime <1x10-11 s

Short-lived radical

Aliphatic C-H Oxidations in Complex Settings M.C. White, S.M. Paradine, Chem 153 C-H Activation -52- Week of October 16, 2012

White, Science 2007, 318, 783. White, Science 2010, 327, 566.

O

HO

AcO

OHO

OAc

H

O

H

O

AcOOAc

H

OO

Fe(S,S-PDP) 15%H2O2

no AcOH

rt, 30 min

52% isolated yield

+ rsm

recycle1X

H H

tetrahydrogibberellic acid

80%

Me

Me

Me

HH

O

O

Me O

Me

Me

Me

HH

O

Me OMe

Me

Me

HH

O

MeFe(PDP) Fe(PDP)

46%sclareolide

1 equiv.

Me

Me

Me

HH

O

Me O

O

28%

+

Oxidative functionalization of alkanes: Nitrogen

FeV

NSO2

R

FeV

OH2O

OH

FeIII+

R'R

HO

R'R

R"HN

oxygenation

amination

alkylation

FeO

XLn

FeLn

FeOH

XLn

R'R

R'R

H

iron catalyst

[O]

[N]

[C]

R'R

C

R1

R2

FeNR

XLn Fe

NHR

XLn

R'R

R'R

H

FeC

XLn Fe

C

XLn

R'R

R'R

HR1

R2

R1R2H

Ron White, JACS 1984, 106, 4922. Breslow, JACS 1985, 107, 6427.

-decreasing reactivity -increasing selectivity -increasing steric demands

Why doesnʼt nature do C-H amination? -C-H amination reactions are not known in nature -M-N bond is readily hydrolyzed by water to form metal oxo species; M-O bonds are shorter -alternate pathways to introduce nitrogen have evolved in nature, including Mannich-type aminations and transamination of carbonyls

Metal-Ligand multiple bond complexes are isoelectronic:



Du Bois, Top. Curr. Chem. 2010, 292, 347.

Concerted asynchronous insertion: -examples: Rh -turnover-limiting step is normally formation of iminoiodane -three-centered transition state -reactivity trends are dictated by the electron density of the reacting site (e.g. more electron-rich C-H bonds, such as 3o, are more reactive)

Radical C-H abstraction/rebound: -examples: Fe, Mn, Cu, Ru, Ag, Co -turnover-limiting step is normally C-H abstraction -carbon-centered radical intermediate; lifetime of intermediate can be tuned by changing metal and ligand environment around metal center -reactivity trends are dictated by the BDE of the reacting site (lower BDE = more reactive)


MLnRN

R2R1

HH

R1 R2

H

R1 R2

H NHRMLn MLn

PhI=NR

R1 R2

NRH

H

MLn

MLn

N

R1 R2

H NHR

H

R

Radical C—H Abstraction/

Rebound Pathway

(FeII/III, RuII, CuI, MnII/III)

Concerted C—H

Insertion Pathway

(RhII)

three-centered

TS

radical

rebound

PhI(CO2R')2 + H2NR


Wigley, Progress in Inorganic Chemistry 1994, 42, 239.

M N R

4 e- ligand if no N (p!) --> M (d) donation

6 e- ligand if N (p!) --> M (d) donation


OO

Rh Rh

R

N

N N

N

Ar

Ar

Ar

Ar M

EvidenceforMetal‐Nitrenes:

NHTsRuVI(Por)(NTs)2

20 equiv 71% yield

Characterized by NMR, UV-Vis, MS, X-ray crystal, CV

RuVI(Por)(NTs)2:

Metal-nitrene species is catalytically competent:

Chi-Ming Che, JACS 1999, 121, 9120. Chi-Ming Che, JACS 2005, 127, 16629.

Still debate in literature about whether this is actually a bis-nitrene

BondingandComplexes

Metal dimers (Rh, Ru)

Stabilization of nitrene through metal-metal bond

Heme-type complexes (Fe, Mn, Ru)

Stabilization of nitrene by distributing charge through

ligand


cat.TsNIPh

~23 equiv(solvent)

1:1 CH2Cl2/CyH

NHTsFe(TPP)Cl: 3.1% based on TsNIPhMn(TPP)Cl: 6.5% based on TsNIPh

Breslow, Chem Comm 1982, 1400. Breslow, JACS 1983, 105, 6729.


SNH

SO2NIPhO

O

catalyst Fe(TPP)Cl: 77% yieldMn(TPP)Cl: 16% yieldRh2(OAc)4: 86% yield

Early studies with iron

Although Mn was more effective than Fe in the intermolecular reaction, the opposite is the case for the intramolecular reaction

Early development with rhodium

Ph

NHNsNHNs

O

NHNs

56% yield18% yield(mix of isomers)

50% yield

benzylic aliphatic ethereal

Substrate scope

Müller, Helv. Chim. Act. 1997, 80, 1087.

*note:yieldsarebasedonNsNIPhaslimi)ngreagent(excessofhydrocarbonsubstratewasusedinallcases)

Rh2(OAc)4 (2 mol%)NsNIPh (1 equiv)

4 MS, CH2Cl2rt, 15h

NHNs

50% yield20 equiv

Early Mechanistic Studies on Rh-catalyzed C-H Amination

Müller, Helv. Chim. Act. 1997, 80, 1087.


Cyclopropane Radical Trap No ring-opened products observed (suggests that any radical intermediate would have a lifetime of <10-12 s)

Stereoretention

Hammett Analysis

Rh2(OAc)4 (2 mol%)NsNIPh (1 equiv)

4A MS, CH2Cl2rt, 15hR R

NHNs

ρ = -0.9 for σ+ suggests a build-up of positive charge in the transition state, consistent with an electrophilic insertion event

Complete preservation of existing stereocenters under C-H insertion conditions (a long-lived radical would planarize the reacting C-H center, resulting in loss of chiral information)

Conclusion: A carbon-centered radical intermediate cannot be excluded, but must have a very rapid rebound (later researchers would conclude that, like Rh-catalyzed carbene insertions, functionalization occurs via a concerted asynchronous insertion)

Intramolecular Aliphatic C-H Amination

Du Bois, ACIE 2001, 40, 598. Du Bois, JACS 2001, 123, 6935.


Intramolecular C-H Amination

HNO

PhPh

O NH2

O

ORh2(OAc)4(5 mol%)PhI(OAc)2

MgO, CH2Cl2

74% yield

BocN BocN

HN OS

O ORh2(OAc)4(2 mol%)PhI(OAc)2

MgO, CH2Cl2

78% yield

OS

H2N

O O

OHN

R2 R1

O

NTcesHN

R2 R1

O

NHHN

R2 R1

NTces

HN OS

R2 R1

O O

HN

NMbs

OS

R2

O O

HN NBocS

R2 R1

O O

R1

R2

X NH2

n = 1,2

R1

R2

X NH2

n = 1,2

PhI(O2CR')2

Rh2(O2CR)4

R1

X NH2

R2n = 0,1

Changing tether increased flexibility in C-H insertion, allowed for a greater expansion of substrate scope:

Intermolecular C-H Amination: Catalyst Development

Multidentate ligand made a more stable catalyst - improved catalyst lifetime and had two main effects: 1)  Significant reduction in catalyst loadings for

intramolecular insertions while maintaining high yields (0.15 mol% vs. 2 mol% in some cases)

2)  Made possible intermolecular insertions using limiting quantities of substrate

Du Bois, JACS 2004, 126, 15378.

Intermolecular Aliphatic C-H Amination

Du Bois, JACS 2007, 130, 562.

3o/benzylic = 7:1

3o/benzylic = 1:7

NH

S p-TolO

NTs

n=1,2,3,4n=1,2,3,4

p-TolS

NH2

O NTs1.2 equiv

3 mol% Rh2[(S)-nttl]4

1.4 equiv PhI(OPiv)2

(Cl2CH)2/MeOH, -35oC48-66% yield1 equiv

Dauban, ACIE 2006, 45, 4641. Dauban, JACS 2008, 130, 343.

Du Bois, JACS 2007, 129, 562.


Ph CO2Me

2 mol% cat.1 equiv TcesNH2

PhI(OPiv)2C6H6, rt

Ph CO2Me

NHTces

Rh2(OPiv)4 <5% yieldRh2(esp)2 70% yield

1 equiv

TcesHNNHTces

25% yield 38% yield

Unactivated hydrocarbons still problematic:

N

OO

Rh Rh

O

ORh2[(S)-nttl]4 =

A chiral catalyst and chiral sulfonimidamide give improved yields for amination of unactivated hydrocarbons:

Reactivity Trends: Intra- vs. Intermolecular

Ph

OS

NH2

O O

Ph

Ph

OS

NH

O O

Ph

NHTces

+

+

Rh2(esp)2TcesNH2

PhI(OPiv)2C6H6, rt

Rh2(esp)2

PhI(OPiv)2C6H6, rt

Ph

OHNS

O O

Ph

TcesHN

Limitation to π-allyl C-H insertions: No internal olefins

NNsO

O

EtNNsO

O

Et

NsN O

O

Et

SSPh Ph

OO

Pd(OAc)2

.

X

Challenges for nitrene-based C-H insertions: Chemoselectivity

R1 R2R1 R2

NHR

R1 R2

RN+

catalyst

"PhI=NR"

C-H insertion olefin addition

Reactivity trends for concerted insertions:

Reactivity trends for stepwise insertions:

bond dissociation energy

more reactiveless reactive

electron density

more reactiveless reactive

White, JACS 2009, 131, 11707.


MgO, CH2Cl2N

OSO

O

OS

HN

O O

+

ins./azir. = 1:1

Rh2(esp)2PhI(OAc)2

OS

H2N

O O

Preference for aziridination is even more pronounced for intermolecular amination: aziridine often sole product from acyclic olefins

Chemoselectivity problematic for Rh-based C-H amination:

Origin of chemoselectivity lies partly in mechanism of insertion:

R1 R2

C-H abstractionolefin addition

R1

NRH

H

MLn

R2R1

RN

MLn

R2

resonance stabilization of radical

R1 R2 R1 R2R1 R2

MLn

NH

R

LnMNR C-H abstractionolefin addition

R1 R2

2o radical - unstable

Nitrene-based Allylic C-H Insertions

Nitrene-based Allylic C-H Insertions M.C. White, S.M. Paradine, Chem 153 C-H Activation -61- Week of October 16, 2012

NHS

p-Tol

OTsN

p-TolS

NH2

O NTs1.2 equiv


1.4 equiv PhI(OPiv)2

3:1 (Cl2CH)2/MeOH, -35oC

>20:1 ins./azir.

N S

p-Tol

ONTs

+p-Tol

SNH2

O NTs

racemic

NHS

p-Tol

OTsN

~1:1 ins./azir.

1.2 equiv


Other factors governing chemoselectivity: sterics of metallonitrene

Dauban, ACIE 2006, 45, 4641.

Effect of metal on chemoselectivity

R1

O

PhI(OPiv)2 (2 equiv.)PhMe/MeCN, rt

R2 R1

OS

HN

O O

R2N

N

N

N

N

N

N

NFe

X

R1 = alkyl, aromatic, H52-72% yield

>20:1 ins./azir.

SH2N

O O

[FePc]Cl (10 mol%)AgSbF6 (10 mol%)

R1

NBnS

N3

O OCo cat.4A MS

C6H6, 40oCR1

NBnS

HN

O O

N

N N

N

HN

O

HN

ONH

O

NH

O

Co

R1 = alkyl, H

>90% yield>20:1 ins./azir.R2 R2

PhI(OPiv)25Å MS, CH2Cl2

R

HN OS

R

O O

ins./azir. = 2:1 to >20:1

R = alkyl, alkyne, aromatic[Ru2(hp)4Cl]OS

H2N

O O

ONRu Ru Cl

Ru2(hp)4Cl = Increasing radical character

Du Bois, JACS 2011, 133, 17207. White, JACS 2012, 134, 2036. Zhang, Chem. Sci. 2011, 2, 2361.

N

OO

Rh Rh

O

ORh2[(S)-nttl]4 =

BnNSNH

O O

R

90% eestarting material: 99% ee

OHNS

O O

n-Pr3

d.r. = 5:95 starting material: d.r. = 5:95

Early Examples of C-H Carbene Insertions

Seminal report on Rh-catalyzed carbene insertions:

Early Cu-catalyzed carbene insertions:


RR

O

N2

RR

O

h!"

Ag, Cu

R1 R2

R1 R2

R C(O)R

The ability for transition metals to decompose diazo compounds to generate carbenes has long been known (e.g. metal-mediated promotion of Wolff rearrangement for ketene synthesis); when this is done in the presence of a hydrocarbon, C-H insertion can occur, although it is an inefficient process that is generally unselective

Maas, Top. Curr. Chem. 1987, 76. Teyssíe, Chem Comm 1981, 688. Teyssie, J. Mol. Cat. 1988, 49, L13.

Rh2(TFA)4

CO2Et

N2+

rt

78% combined yield(based on diazo)

67 equiv 1 equiv

(EtO2C)2C

Advance over Cu: -milder reaction conditions -increased reactivity -ability of catalyst to tune site-selectivity

Rh2(O2CR)4+

60oC

30 equiv 1 equiv

CO2Et

CO2Et

CO2Et

+ +

R = H 14 55 31

CH2Cl 20.5 55.5 24

31 49 20

0.2 52 48

Cl

NO2

Cl

O2N

Fe

CO2Et

N2

Catalytic Cycle & Metal Carbene Structure

Rh2L4C

R2R1

HH

R1 R2

CH

H

Rh2L4

R1 R2

H

concerted asynchronous

TS

R'

R

R

R'

R

R'

RCR'

N2

Rh Rh

N2

rate-limiting

fast

Rh

O

Rh

O

Rh

O

Rh

O

C3F7

Rh

O

Rh

NH

-more stable carbene-less electrophilic-more selective

-less stable carbene-more electrophilic-less selective

< <

O

R"

R'

O

R"

N2

R

RR'

Rh2(OAc)4

CH2Cl2

Rh2(OAc)4 33 63 4 5 8 90 1 5 95Rh2(tfa)4 31 64 5 5 25 66 4 12 88Rh2(9-trp)4 9 61 30 18 18 27 37 33 67

increasing catalyst

electrophilicity

Rh

O

O

Rh

O

OO

O

O

O

CR'

R

strong !-donation stabilizes carbene

weak " back-bonding maintains

electrophilic character

bridged dirhodium disperses positive charge on metal

carbene

Features of dirhodium carbenes:

Types of metal carbenes:

Crabtree, Organometallic Chemistry of the Transition Metals, 2005, Wiley: New Jersey.

Davies, Chem Rev 2003, 103, 2861.

Doyle, Chem Rev 2010, 110, 704.

Catalyst structure affects both reactivity and product selectivity


M C M C

d!

Fischer Carbene Schrock Carbene

-singlet carbene-dative (L) ligand

-triplet carbene-covalent (X) ligand

Carbene Classes & Reactivity Trends

Taber, JACS 1986, 108, 7686. Davies, JACS 2000, 122, 3063.

N2

H

O

R

N2

O

R

N2

O

RO

O

R'

R'

acceptor acceptor-acceptor donor-acceptor

> >

-acceptor carbenes most reactive, but dimerization is problematic -stabilization of carbene with electron-rich groups minimizes dimerization, allows for greater product selectivity – especially enantioselectivity

Classes of carbenes:

Reactivity Trends

N Boc

O

0.078 0.66 1 1700 2700 28000

Intramolecular:

Intermolecular:

-insertion into 3o C-H bonds favored based on electronics -insertion into 2o C-H bonds favored based on sterics -product 2o/3o selectivity dependent on steric requirements of catalyst, carbene source and substrate


O

N2

R

O

N2

R

O

N2

R

O

N2

R

O

N2

R

> > > >>

O

N2

2o/allylic = 3:1

Unusual result: researchers since have found that allylic and benzylic C-H bonds are actually highly reactive

Examples of C-H Carbene Insertions

Doyle, JOC 2002, 67, 2954.

Intramolecular:

Intermolecular:

Rh

O

Rh

N

N

O

OMe

OPh

O O

OMe

PO

N2

OMe

PO O

O1 mol% Rh2L4

CH2Cl2, rt

68% yield93% ee

OH

OMe

HO

OH

OMe

(+)-imperaneneantiinflammatory

Rh2L4 =

P = TBDMS


PhOMe

O

N2

+

Fe(TPP)Cl (2 mol%)

80oC

solvent

CO2Me

Ph

66% yield(based on diazo)

PhOMe

O

N2

+

Rh2(S-DOSP)4(1 mol%)

rt

solvent

CO2Me

Ph

80% yield (based on diazo)92% ee

O NBoc

2 equiv67% yield

2 equiv72% yield

Davies, JACS 1999, 121, 6509. Davies, JACS 2000, 122, 3063. Woo, Organometallics 2008, 27, 637.

Rh catalysts show low intermolecular C-H insertion reactivity for unactivated hydrocarbons; hyperconjugative activation by O or N improves reactivity significantly (2 equiv substrate vs. >100 equiv)

A rare example of iron-catalyzed C-H alkylation:

Oxidative functionalization of alkanes: Halogenation

Groves, JACS 2010, 132, 12847. Groves, Science 2012, 337, 1322.

Chlorination:


O

O

O

O

O

OMn(TMP)Cl(15 mol%)

AgF (3 equiv)

TBAF (cat.)PhIO (10 equiv)

FF

+

42% (1:3 ax/eq) 16% (1:7.8 ax/eq)

Fluorination:

MIII

L

ClO-

MV

O

O

MIV

OH

LMIV

O

L

Cl

R-H

R

ClO-HO-

L = O, OH or OCl

R-Cl

R

Most substrates are in excess (3:1 substrate/oxidant)

Uses limiting quantities of substrate in all cases

Proposed catalytic cycle: (no mechanistic experiments performed yet to

validate the proposed mechanism)

Mn(TMP)Cl (15 mol%)

NaOClO

O

O

O

O

O

ClCl

+

42% 6%

Documents

Catalytic Functionalization of Allylic C-H · PDF file4 (1 equiv) Pd PPh 3 (2 equiv) NMe 2 ... Chem 153 C-H Activation -33- Week of October 16, 2012 It is not clear if these ... salts