A.G. Doyle, Chem 253 C-H Insertion -300- Week of Dec. 14, 2004people.fas.harvard.edu/~chem253/notes/2004-12-14.pdf · A.G. Doyle, Chem 253 C-H Insertion -304- Week of Dec. 14, 2004

A.G. Doyle, Chem 253 C-H Insertion -300- Week of Dec. 14, 2004

The Holy Grail of Catalysis

R CH2

R CH2

X[M]

NH

H

H

OH

H

GephyrotoxinDaly Helv. Chim. Acta 1977, 60, 1128-1140

H3C H + 1/2 O2 NH

H

H

H

H

[M] [M]

Bergman Acc. Chem. Res. 1995, 28, 154

H

H3C OH

O

HOCH3

O∗

HOCH3

NH2

[M]*

H[M]

L - Valine

OH3COH3C

HH

MusconeEschenmoser Helv. Chim. Acta. 1971, 54, 2896


C-H Activation C-H Insertion

LnM

C MLn

H

C H C XH

(1) (2)

(1) Process where a strong C-H bond (90-105 kcal/mol) undergoes substitution to produce a weaker C-M bond (50-80 kcal/mol)

(2) The C-M bond is then functionalized to a C-X bond where X = anything but H, regenerating an active catalyst

The challenge lies in finding ways to selectively form the high energy C-M intermediate under mild conditions that enable functionalization and catalyst renewal.

MH

C

Reactivity: Methods have been identified that proceed with (1) late, nucleophilic complexes, where π-backbonding >> σ-donation or (2) late electrophilic complexes in acidic media where σ donation >> π backbonding allowing for effective deprotonation of a complexed C-H bond.

Selectivity: Recall that there is both a kinetic and thermodynamic preference to form the less sterically hindered 1° C-M intermediate.

LnMLG A

C HLG

C AH

LnM A

(1) (2)

(1) Process where a transition-metal promotes extrusion of an irreversible leaving group to generate a M=A species.

Reactivity: Electrophilic metal complexes are most active at decomposing substrates to generate M=A species.

(2) Metal mediated insertion of A: into a C-H bond.

Reactivity: Most successful examples involve dirhodium catalysts where the more electron rich the ligands are, the more chemoselective the C-H insertion event is.

Selectivity: (a) There is a strong preference for insertion into more electron rich C-H bonds. (b) C-H insertion is a stereospecific process.

The challenge lies in harnessing the reactivity of a super-active and unselective intermediate

A = CR2: Carbene NR: Nitrene O: Oxo

LG = N2 IPh IPh, ROH


Carbenes

Concerted two electron processes of carbenes:C

H

H "the most indiscriminate reagent in organic chemistry" Doering JACS 1956, 78, 3224

CHH RR

RY H

RY

R

R R

RY H

RY

R

Marchand Chem. Rev. 1974, 74, 541O

ORH

O

ORH

Carbalkoxycarbenes: by substituting an α carbonyl group, the carbene is both more stabilized and more reactive than methylene.

CarbenoidsCarbenoid: the term was orginally applied to the divalent carbon species generated from organolithium reagents. The term is now used to denote a metal-

complexed carbene as differentiated from a non-complexed or "free" carbene.Closs and Moss JACS 1964, 86, 4042

(OC)5CrPh

OMe

Fischer Carbenes Schrock Carbenes

Tat-Bu

t-Bu

t-Bu

t-Bu

Carbenoids

LnMX

O

R

Unlike Fischer and Schrock carbenes, a metal carbenoid has never been isolated

H

HC C

H

H

Carbenes can exist in either singlet or triplet forms. Triplet carbenes behave as diradicals whereas singlet carbenes undergo concerted two electron processes

singlet carbene triplet carbene


Carbenoid Formation

O

C17H35N2

copper bronze

EtOH

O

C17H35OC2H5

Yates JACS 1952, 74, 5376

Since no metal carbenoid has ever been isolated or characterized, the first report of carbenoid formation in the context of insertion chemistry was a report on metal mediated diazo decomposition and subsequent reaction of the "carbenoid" with an alcoholic solvent.

C17H35OC2H5

O

expected

observed

O

C17H35Cu

O

C17H35H

COC17H35

-or-

Cu

Wolff Rearrangement

EtOH

Insertion into O-H bond

EtOH

The first report:

O

ZR

N2

Z

OR

MLn- N2

Thermal or photolytic carbene generation occurs using precursors such as diazo carbonyl compounds, iodonium ylides, phosphonium ylides, and sulfonium ylides.

N

R2R1

NRO

O

OR

O

IPhPh N

NaN

SO O

Me

Catalytic methods for carbenoid chemistry have been shown to be most effective when diazo carbonyl compounds are employed.

Carbenoid precursors:

The following studies were some of the first to lend support to the existence of a metal carbenoid intermediate

PhHC N2 2N22

Shechter Tet. Lett. 1982, 23, 2277NagaiTet. Lett. 1980, 21, 1251

MLn PhPh

Ph

Ph MLn =

Cu(ClO4)2

Rh2(OAc)4

1.5 : 1

4.0 : 1

Z / E ratio

Carbene dimer formation continues to be a major undesired side reaction of many methods involving carbenoid formation.


The Birth of Asymmetric Catalysis

PhO

OEtN2

O

NPh

CuN

O

PhMe

Me

CO2EtPh

Ph

CO2Et

6% ee

6% ee Noyori Tet. Lett. 1966, 7, 523960 °C

72% yield of a 1:2.3 mixture of cis/trans cyclopropanes

Asymmetric Intermolecular Cyclopropanation

N2CHCH2CO2t-Bu

Ph CO2t-Bu

CO2t-BuPh

93% ee

93% ee

81: 19

NNRR

CN

CuII

L L

Ph N2

MeOO

Ph

Ph

MeO

O

Ph

90% eeDavies Tet. Lett. 1993, 34, 7243

Pfaltz ACIEE 1986, 25, 1005

RhO

RhO

NArO2S

Ph

Asymmetric Intramolecular Cyclopropanation

RhO

RhN

O

CO2MeH

O

N2HCO

R

OO

HH

R

H

> 94% ee

R = Et, i-Pr, i-Bu, Ph,Ch2Ph, Bu3Sn, I

O

O

O

CHN2

MeOO

O

Me

90% ee

N

O

N

OH3C CH3

tBuBut

Doyle ACIEE 1996, 35, 1334

Doyle Chem. Rev. 1998, 98, 911

CuPF6

Jacobsen: Chem153 Notes


Copper and Rhodium

Rh

O

O

O

O

OO

O

H3C

CH3

H3C

CH3

Rh

O

Rh2(OAc)4

σ

πδ

π*δ*

σ* σ−interaction

ncarbene σ* Rh-Rh(dz2)

π back-bonding

π*Rh-Rh(dxz) pcarbene

CH

OR

CH

OR

Rhodium complexes are Lewis acidic and bind additional ligands at two open axial sites. Binding of a second ligand after addition of a first to an axial site is less favorable and catalysis is thought to occur only at a single Rh center.

Cu(I)

CH

ROOCO

O

O O

Reactive Conformer:

looking down the Rh-Rh axis:

Diazo Decomposition:

Based on their unique molecular and electronic structure, Rh(II) dimers have proven the most effective for catalysis of C-H insertion reactions.

Carbene Rh-Rh

Based on its affinity for olefin binding, Cu has proven most effective for functionalization of π−bonds after diazo decomposition.

CuOTf CuOTf

Cu(R2CN2)TfO

CuOTfR2C

R2CN2 N2

R R

Kochi JACS 1973, 95, 3300

Espino, C. G. Stanford PhD Thesis 2004

Molecular and Electronic Structure:


Rh Carbenoids: Intramolecular C-H Insertions

Rh2(OAc)4

CH2Cl2

Evidence for a singlet carbenoid species: 3-centered, 2-electron transition state.C-H Insertion is Stereospecific

O

H3C

CO2CH3

CH396% ee96% ee

OCO2CH3

N2

H3C

CH3

Taber J. Am. Chem. Soc, 1985, 107, 196

Evidence for a highly electrophilic intermediate.Adjacent electron withdrawing groups deactivate C-H bonds and electron donating groups activate C-H bonds.

Me

O

CO2Me

N2

H

Me CO2Me

O

exclusive product

H

MeO

O

N2

Stork Tet. Lett. 1988, 29, 2283

83%

H

MeO

O

Rh(II)

Rh(II)

> 95:5

CH3

CH3

HRH3C

CH3 AgO

MeOH

CH3

CH3

CH3

HO

R = COCHN2

Davis J. Am. Chem. Soc. 1968, 90, 3870

The first report of metal catalyzed C-H insertion:

22% yield (plus Wolff rearrangement products)

Rhodium catalysis: Chemoselectivity

OCO2Me

N2nC8H17

O

CO2MeRh2(OAc)4

CH2Cl2

OCO2Me

N2

O

CO2Me

68%

77%

OCO2Me

N2

O

CO2Me

55%

Rh2(OAc)4

CH2Cl2

Rh2(OAc)4

CH2Cl2

Pellicciari J. Org. Chem. 1982, 47, 3242Taber J. Org. Chem. 1982, 47, 4808


Intramolecular C-H Insertions: Catalyst Imposed Chemoselectivity

Ph

O

CHN2O

Ph

O

Rh2L4

CH2Cl2

L = OAc

L= C3F7CO2

L=

N

O

48 52

0 100

100 0

Padwa JACS 1993, 115, 8669

Metal controlled chemoselectivity: Evidence for Rhodium association to thecarbene intermediate:

RhL4Rh CH2

Charge and HOMO and LUMO energies calculated for the hypothetical Rh carbenoid:

L charge HOMO, eV LUMO, eV

trifluoroacetateacetateacetamidate

0.1170.0880.090

-10.888-10.884-10.784

-9.300-9.292-9.364

OO

CO2MeO

N2OO

OO

CO2Me

O

O

CO2Me

Rh2L4

CH2Cl2

L = OAc

L = HNAc

L = O2CCPh3

1

1

24

:

:

:

2

6

1

Increased selectivities are observed with more electron rich ligands as a result of the greater π back-bonding capability of the Rh complex to the carbene. More electron rich complexes, however, are slower to decompose the diazo substrate.

Increased carbene stabilization as well as increased sterics surrounding the metal carbene lead to more discriminating species.

Doyle Prog. Inorg. Chem., Ed., 2001, 49, 113-168.

Recall Hammond's Postulate which uses transition statetheory to explain structure-reactivity relationships by suggesting that along a reaction coordinate, species with similar energies also have similar structures.


Mechanism of C-H Functionalization

ON2 R

O

N H OR

H

HO

R

H

Rh2L4

O

R

N

Rh2L4

Rh2L4

Rh

OO O

H3C

CH3

Rh

O

(OAc)2

H

R

HO Rh

OO O

H3C

CH3

Rh

OH

R

OH (OAc)2

rds

-N2

path A

path B

Path A:

* Rh-Rh core structure is maintained and no oxidation chemistry takes place at the metal centers

* C-H activation through a three centered-two electron transtion state.

Path B:

* Rh(II)-Rh(II) core dissociates to provide a Rh(I) Rh(III) dimer.

* One metal center is involved in C-H oxidative addition and then C-H reductive elimination to provide product.


Mechanistic Analysis

W

H3CO

N2

OMe

O

X

O

CO2Me

CH3

X O

CO2Me

X

Rh2(OAc)4

CH2Cl2

Wang J. Org. Chem. 1998, 63, 1853

Hammett Studies: Suggests a concerted C-H insertion

Chemoselectivity: Suggests a mechanism distinct from C-H activationRecall:

OC COOC B

O

O

BCat'Cat'B

55%/ W 2%/ W

hv

Hartwig Science 1997, 277, 211

OCO2Me

N2

O

CO2Me

77%

Rh2(OAc)4

CH2Cl2

Pellicciari J. Org. Chem. 1982, 47, 3242

Rh2L4 ρ value

Rh2(OAc)4

Rh2(O2CCF3)4

Rh2(acam)4

-1.26

-0.66

-1.39


Mechanistic Analysis

HD

MeO

MeO Me

ON2 O

MeD

MeO

MeO

HO

Me

MeO

MeO

Rh2(OAc)4

CH2Cl2kH/kD = 1.2

Wang J. Am. Chem. Soc. 1994, 116, 3296

RhMe3P DC2D5

RhMe3P

RhMe3P

RhMe3P

C2D5

D

C2D6 toluene-d8

-30 °CkH/kD = 1.2observed

kH/kD = 2.5not observed

kH/kD = 0.5observed

Bergman J. Am. Chem. Soc. 1986, 108, 7332Jones Acc. Chem. Res. 2003, 36, 140-146

Oxidative addition of C-H bonds shows small but normal KIEs because it involves rate determining C-H precoordination to the metal. Reductive elimination in a single step should show large normal KIEs. Inverse KIEs are observed when rapid preequilibria occur where a transient intermediate possesses increased zero point energy relative to its precursor.

KIEs for C-H activation: (intermolecular)

Rh2(cap)4 kH/kD = 2.0

KIEs for C-H insertion:


Evidence for a slipped ligand complex?

RhO

R

RhO

Rh Rh OAc

R

Rh RhOAc

REtO2C

H

Rh RhOAc

EtO2C

RH

R H

CO2EtHH R

N2CHCO2Et

H R N2CHCO2Et

R H

CO2EtH0.5 mol% 1

CH2Cl2, rt

Corey J. Am. Chem. Soc. 2004, 126, 8916

1 = Rh2L3(OAc)

L =NHTfN

O

Ph Ph

Proposed Mechanism:

H3C(H2C)5 H

CO2EtH 1: 90% yield, 93% ee

10: 91% ee

O

N2

CO2Me

Ph

0.5 mol% 1

CH2Cl2, rtO

Ph

CO2Me

51% yield96% ee

Is this relevant to C-H Insertion?


Chiral Rhodium Catalysts

RhO

RhN

X

CO2MeH

RhO

RhO

O OP

O ORhRh

RhO

RhO

HN SO2C6H4R

Doyle catalystsX = CH2: Rh2(MEPY)4

X = O: Rh2(MEOX)4

X = NC(O)CH2Bn: Rh2(MPPIM)4

McKervey/Davies proline-derived

catalystsR = C6H5: Rh2(BSP)4

R = p-(C12H25)C6H4: Rh2(DOSP)4

N

O

O

H R

Ikegami/ Hashimotophalimido catalysts

McKervey dirhodium phosphate catalyst

γ-Butyrolactone synthesis

O

ON2

R

O

O

R

Rh2(MPPIM)4

CH2Cl2, 40 °C

R = benzyl, ethyl, methoxy56-98% yield91-97% ee

Doyle J. Org. Chem. 1996, 61, 9146

γ-lactam synthesis

RN

ON2

OC2H5

RN

O

OC2H5

Rh2(MEOX)4

CH2Cl2, 40 °C

97% yield, 78% ee

Doyle Tet. Lett. 1992, 33, 7819

Chromanone synthesis

OMe

N2O

HO

OMe

Rh2(BSP)4

CH2Cl2, 40 °C

97% yield86% de, 60% ee

McKervey J. Chem. Soc., Chem. Comm. 1992, 823For reviews, see:

Davies Chem. Rev. 2003, 103, 2861Sulikowski Tet: Asy. 1998, 9, 3145



Intermolecular C-H InsertionsIntermolecular reactions were historically plagued by problems of chemoselectivity, functional group tolerance, and carbene dimerization.

N2

HOEt

O HOEt

O

CuSO4 OEtO

OOEt

40%24%

Hornemann J. Am. Chem. Soc. 1974, 96, 322

"Acceptor" substituted

"Donor/Acceptor"substituted

N2

EDG EWG

EWG = CO2R, COR

EDG = vinyl, aryl, heteroarylalkynyl

N2

XOR

O XOR

O

ORO

OOR

X

X

Rh2(OPiv)4

X R yield (%) yield (%)

CH=CHCO2Et Et 67 0

0

0

67

94

65

10

Me

Me

Et

Ph

COMe

H

Davies Tet. Lett. 1998, 39, 4417

First "successful" example of an intermolecular C-H insertion:

Studies on the effect of diazo structure on intermolecular C-H insertions:

N OBOC

1 0.66 0.078 0.011

1700 2700 28,000

Chemoselectivity: relative rates of C-H insertion

Davies J. Am. Chem. Soc. 2000, 122, 3063

Donor/Acceptor susbstituted carbenoids are uniquely capable of catalytic asymmetric intermolecular C-H insertions. While these reagents broaden the scope of C-H insertion chemistry, they are also, by definition, limiting.

Note that the C-H donor functions as solvent under these conditions.


Asymmetric Intermolecular C-H Insertions

NBoc

NH

Br

CO2Me

H1. Rh2(R-DOSP)4

2. TFA

38% yield, >94% de90% ee

N2

XOR

O XOR

O

Rh2(S-DOSP)4

X R yield (%) ee (%)

CH=CHPh Me 50 83

351MeCOMeH Et 34


N2p-BrC6H4

MeO2C

Davies J. Am. Chem. Soc. 2003, 125, 6462-6368

Mannich Surrogate:

Aldol Reaction Surrogate:

2.0 equiv.

(H3CH2CO)3SiO CH3Rh2(R-DOSP)4

MeO2CCH3

Ph

OSi(OCH2CH3)3N2

Ph

MeO2C

(0.5 equiv) 70% yield, >90% de95% ee

Davies J. Org. Chem. 2003, 68, 6126

Michael Addition Surrogate:

OTBDPS

Ph

TBDPSO

PhCO2Me

Ar

CH3

N2p-BrC6H4

MeO2C

(2.0 equiv)65% yield, >90% de

84% ee


Rh2(S-DOSP)4

Note: TBDPS is crucial in order to prevent intermolecular cyclopropanation from occurring.

Donor/ Acceptor substituents and enantioselectivity:

N2

O

OCl

S

O

OCl

S

O

ON

S

Rh2(R-DOSP)4hexane, rt

55% yield, 88% ee

(+)-cetidilK+ channel blocker

CO2H

S HOCl

DCC, DMAP92% yield O

OCl

S

S

NH

O ON3O

DBU88% yield

An application in the synthesis of (+)-cetidil:

Davies Tet. Lett. 2002, 43, 4981


Other Transformation with M Carbenoids

H

N2

CO2Me

Ar

Rh2(S-DOSP)4Hexanes, rt

CO2Me

Ar

Ar = 4-MeOC6H458% yield99% ee

Davies Org. Lett. 1999, 1, 233

Combined C-H Insertion/ Cope Rearrangement:

N2

CO2Me

Ph

Me

H

Ph

Me

MeO2C

CO2Me

PhMeRh2(S-DOSP)4pentane, -78°C


Combined Cyclopropanation/ [3,3] Sigmatropic Rearrangment:

Rh-Catalyzed [3+2] Cycloaddition:

MeO

R2

N2

CO2Me

R1

MeO

R2

R1

CO2Me

70-99% eeR1 = alkyl, R2 = aryl, vinyl


Rh2(S-DOSP)4

NAr

HPhN2CHCO2Et

N

CO2EtPh

Ar

4:1 cis/ transcis: 67% eetrans: 32% ee

CuPF6(CH3CN)4

L, CH2Cl2

N

O

N

O

Ph Ph

L =

Jacobsen ACIEE 1995, 34, 677

Enantioselective Aziridination:

R O

O

N2

MeO2C CO2Me

O

CO2MeMeO2C

R

O

Hashimoto J. Am. Chem. Soc. 1999, 121, 1417

Rh cat

CF3C6H55 min

80-92% ee

RhO

RhO

N

O

O

Hi-Pr

Rh-Catalyzed Dipolar Cycloaddition via Carbonyl Ylides:

OR

O

Rh cat =via: how is the catalystassociated?


Aziridination

NR'

HR

HN

XH

R++ "NX"N2CHR'

X

R

H

H

R'

O

N3R1

SN3

O O

PO

ORN3RO

SN

O OIPh

Nitrene Precursors

acyl azide sulfonyl azide

phosphoryl azide iminoiodinane

Yamada Chem. Lett. 1975, 361

PhI(OAc)2 SNH2

OO S

N

OO

PhI

2 AcOHKOH

Iminoiodinanes as nitrene precursors:

Metal poryphrin catalyzed aziridination with tosylimidoiodobenzene:Mansuy JCS, Chem. Comm. 1984, 1161

RC

R1

M

N

M

RO

M

Evans J. Am. Chem. Soc. 1994, 116, 2742

CO2Me

ArPhI=NTs

TsN

CO2MeAr

Cu(OTf) (5 mol%)ligand (6 mol%)

C6H6(2 eq.)94-97% ee

60-76% yield

ligand =

R"

R'R

ArPhI=NTs

TsN

Ar R"R'R

66 - 98% ee50-84% yield

(1.1 eq.)

CuOTf or CuPF6(5 - 10 mol%)

ligand (6-12 mol%)

CH2Cl2, 4 Ä sieves–40 to –78 °C

N NCl

Cl Cl

Clligand =

Jacobsen J. Am. Chem. Soc. 1993, 115, 5326

Asymmetric Aziridination by Nitrene transfer:

Asymmetric Aziridination by Nitrene transfer:

N

O

N

O

Ph Ph


Mechanism of Aziridination

L*Cu+ PF6-

[L*Cu=NTs]+

PF6-

PhI=NTs

PhI

NTs

R'

HR

H

R

H

H

R'

L*Cu+ PF6-

R'

HR

H

NTs

R

H

H

R' PhI=NTs

+ PhI

*LCu NTs

I+PhPF6

-

Redox Mechanism Lewis Acid Mechanism

TsN3 [TsN]

PhNTs

PhPhI=NTsL* CuPF6

10 °C

L* CuPF6

10 °C

hυ

-N2

41% ee

ee (%)

ee (%)Jacobsen J. Am. Chem. Soc. 1993, 115, 5326J. Am. Chem. Soc. 1995, 117, 5889

Review: Jacobsen in CACVol 2, Chapter 17

CHCO2Et

NTs

With a given ligand*,eeaziridination ∝ eecyclopropanation

··· ··· ·· ·

·· · ··

(1)

(2)

Evidence for the intermediacy of Cu=NR:

NNAr Ar


Intramolecular C-H Insertions by M=NR

i-Pr i-Pr

SO2

NIPh

H3C CH3 H3C CH3

i-Pr

SO2

NHH3CCH3

i-Pr

SO2NH2

H3C

Fe(TPP)Cl (5 mol%)

CH3CN

85% 1.5% 13%

SO2NH2

i-Pr

H3C CH3

SO2NH2

Breslow and Gellman J. Am. Chem. Soc. 1983, 105, 6728

KOH/ MeOH

PhI(OAc)2

First example of an intramolecular C-H Amination:

N

NH HNN

Ph

Ph Ph

Ph

TPP =

R1 R2

OS

H2N

OO

R1 R2

OS

HN

OO

syn product favored

6-membered ring strongly favored for sulfamate insertions. 5-membered ring strongly favored for carbamate insertions.

MgO is essential for conversion, proposed to scavenge acetic acid in solution

Rh2(OAc)4 (2 mol%)PhI(OAc)2, MgO

RO NH2

OOHN

O

R

Rh2(OAc)4 (2 mol%)PhI(OAc)2, MgO

Espino and Du Bois Angew. Chem., Int. Ed. 2001, 40, 598

Du Bois J. Am. Chem. Soc. 2001, 123, 6935

CBzHN

R1 R2

X

X = OH, NR2, SR, N3

Development of a synthetically useful C-H Amination protocol with in situ formation of the aminoindinane:


C-H Insertion by M=NR

O NH2

O

MeMe OHN

MeMe

O

100% ee OSO2NH2

D H Rh2(OAc)4

PhI(OAc)2

(D)HN OS

D(H)

O O

kH/kD = 1.9

H X

OSO2NH2

σp

product ratioPh: Arx

-0.27

-0.17

0.54

0.78

1.0: 3.0

1.0: 1.7

1.5: 1.0

3.0: 1.0

OCH3

CH3

CF3

NO2

ρ = -0.8

Mechanistic Probes:

Stereospecificity Deuterium Labeling

Hammett Studies

OS

H2N

O O

HN OS

O O

50% enantiomeric excesswith Rh2(L-ATO)4 catalyst

O ORh Rh

NO

Me

O

O

Me

Rh2(L-ATO)4

cat. Rh2(L*)4

PhI(OAc)2, MgOCH2Cl2

Asymmetric Catalytic Intramolecular C-H Insertions:

O

H2N O

nPrMe

Me

Me OHN NHO

O O

MeMe Me Me nPr

MeMenPr

3° C-H Insertion 2° C-H InsertionRh(II) catalyst

Rh2(OAc)4

Rh2(O2CCPh3)4

3° / 2°8 : 1

1: 1

Effect of Catalyst Structure on Selectivity

Espino, C. G. Stanford PhD Thesis, 2004

X


Intermolecular C-H Insertions by M=NR

HO2C CO2H

Me MeMe MeRh

O

O

RhO

O

OO

OO

MeMe

Me

Me

MeMe

MeMeRh2(O2CCF3)4

125 °C

Rh2(esp)2

H2NS

O

O O

Me

HN OS

O O

MeMe

Me

0.15 mol%catalyst

PhI(OAc)2MgO, CH2Cl2

catalystRh2(O2CtBu)4Rh2(esp)2

yield20%92%

A better catalyst for intramolecular insertions:

Rh2L4 catalysts were observed to decompose byligand loss. Rh2(esp)4 is much more robust bycomparison. Does this lend support to Corey's ligand dissociation hypothesis?

OMe

Me

OMe

Me NHSO3CH2CCl3

2 mol% catalyst

PhI(OAc)2H2NSO3CH2CCl3

catalystRh2(O2CtBu)4Rh2(esp)2

yield30%70%

Intermolecular C-H insertions:


NHTs

PhI NTsMn(TPP)

N

NH HN

N

Ph

Ph Ph

Ph

6.8% yield

Breslow and Gellman Chem. Comm. 1982, 1400; J. Am. Chem. Soc. 1983, 105, 6728

TPP =

First example of an intermolecular C-H amination:


Applications in Total Synthesis

+HN

NH

OO

O –

OH

CH2OH

OH

OHH2N HO

tetrodotoxin

CO2Et

NHNO

MeO

NH

Br

manzacidin A

Rh2(OAc)4 (2 mol%)Ph(OAc)2, MgO

85%


CO2Et

OS

NH2

O O

TBDPSOMe

CO2Et

OS

HN

OO

TBDPSOMe

1. Boc2O, pyr

2. NaN3, DMF92%

CO2Et

N3BocHNTBDPSO

Me


O

O

O

N2

OCMe2O

PivO

OTBS

O

O

O

OCMe2O

PivO

OTBSRh2(HNCOCPh3)4(1.5 mol%)

>75%

OCMe2O

OCMe2

O

OC(O)NH2HO

O

Cl

Rh2(HNCOCCF3)4(10 mol%)

PhI(OAc)2, MgO

77%

OCMe2O

OCMe2

O

ONHO

O

Cl

O


A.G. Doyle, Chem 253 Olefin Oxidation -322- Week of Dec. 14, 2004

M=O Species

N

N NN

HO2C

HO2C

Fe

Protoporphyrin IX

FeIII

SCy

FeIII

SCy

(RH)

RH

FeII

SCy

(RH)

FeIII

SCy

(RH)O2

OOFeIII

SCy

(RH)OO

e-

FeV

SCy

(RH)O

2H+

H2O

ROH

e-

SHUNTPhIO, ROOH, NaOCl

H

H

MeMeMe

O

H

OH

MeMeMe

Op450CAM

Ringe, Petsko, Sligar Science 2000, 287, 1615Collman Science 1993, 261, 1404

Biological Oxidation: Cytochrome P-450

N

NH HNN

Ph

Ph Ph

Ph

TPP =O

FeIII(TPP)ClPhI=O

CH2Cl2, rt

Groves J. Am. Chem. Soc., 1979, 101, 1032

Recall that C-H insertion of M=N was first reported with the same complex and PhI=NTs as the nitrene source.

FeO

RR

Stereoelectronically favored side-on approach:

HOMOLUMO

Groves J. Am. Chem. Soc. 1983, 105, 5791

Relative rates: R1

R2R1 R2

R1<< ~

LnMO

MLnO

MLnO

MLnO

[2+2] end-on side-on e- transfer

Possible Approaches:

P-450 Mimic Systems: Fe porphyrin complexes


Chiral Porphyrin Complexes and Salen Ligands

Asymmetric porphyrin complexes:

How do you induce asymmetry when the metal is in a sp2 framework and when the substrate does not preassociate with the catalyst?

Examples: Groves J. Org. Chem. 1990, 55, 3628; Halterman J. Org. Chem. 1991, 56, 5253; Naruta Bull. Chem. Soc. Jpn. 1993, 66, 158; Collman J. Am. Chem. Soc. 1993, 115, 3834.

O1 mol% 1, PhIO

1,5-Cy2imidazoleCH2Cl210x excess 86% yield (based on PhI=O)

69% ee

These complexes are difficult to synthesize and have a propensity towards oxidative degradation of the ligand framework.

1

Cl

N

NN

NFe

O

OO O

OO

OO

O O

H

H

O

OMe

N N

O

MeO

MnIII

+ PF6_

4 mol%

PhIO (1eq), CH3CN

O

2 eq

+ PhI

56%

The first report of epoxidation activity:

Bleach as the terminal oxidant:

Kochi J. Am. Chem. Soc. 1968, 108, 2309

O

N N

ONiII

NaOCl (pH 13)/ CH2Cl2Bu3NBz+ Br-

84%

O

Radical intermediate is envoked to account for exclusive formation of the E-epoxide from the Z olefin

Burrows J. Am. Chem. Soc. 1988, 110, 4087

(salen)Metal catalyzed epoxidation:

A.G. Doyle, M.C. White, Chem 253 Olefin Oxidation -324- Week of Dec. 14, 2004

Jacobsen EpoxidationThe Jacobsen epoxidation:

H

HN

NO

OMn

O

MePh

All trajectories to the Mn(oxo) are sterically blocked except for

over the diimine backbone

Jacobsen J. Org. Chem. 1991, 56, 6497

Rationale for enantioselection:

O

O

Cis-disubstituted Trisubstituted

88% ee90% yield

93% ee69% yield

Substrate Scope:

Br

O

O Cy

TMS

Cy

TMS

O

Tetrasubstituted Cis-enynes give trans-epoxides:

96% ee84% yield

Jacobsen Tet. Lett. 1995, 36, 5123Jacobsen J. Am. Chem. Soc. 1991, 113, 7063

Trans disubstituted and all aliphatic cis-disubstituted olefins undego epoxidation with low rates and low ee

N N

O O

t-Bu

t-Bu

t-Bu

t-BuMn

Cl

Ph MePh

O

Me

NaOCl, CH2Cl2, pyridine N-Oxide (20 mol%)

(0.1-4 mol%)

84% yieldcis: trans (11.5:1)

92% eeJacobsen J. Am. Chem. Soc. 1990, 112, 2801Jacobsen J. Am. Chem. Soc. 1991, 113, 6703

Jacobsen J. Org. Chem. 1991, 56, 2296Jacobsen Tet. Lett. 1996, 37, 3271

cis-disubstituted substrates with at least one sp2 hybridized substituent give optimal yields and ee's


Epoxidation of terminal olefins

N

N

Fe

OH2O

O

H2O

N

N

Fe O

O

OO

OH

O

O

(III) (III)

H147

E114

H246

E209

E144

E243MMO catalyzed olefin epoxidation

RR

O

R = H, CH3, CH2CH3

soluble MMOM. Capsulatus

12 min,

MMO active site

N

N N

N

Fe(II)(CH3CN)2 (SbF6-)2

(3 mol %)

CH3CO2H, CH3CN, H2O2 (1.5 eq), 4 οC, 5 min

R RO

63-90% yield

Active catalyst analogous to MMO active site (forms in situ):

Jacobsen J. Am. Chem. Soc. 2001, 123, 7194

Lippard Nature 1993, 366, 537

A MMO functional mimic:

ReO

OCH3

O

pyridine (12 mol%)

CH2Cl2, rt

(0.5 mol%)

Sharpless J. Am. Chem. Soc. 1997, 119, 6189

HOOHR RO

>90% yield

+ H2O

Na2WO4 ( 2mol%)[MeN(n-oct)3]HSO4

NH2CH2PO3H2

90 °C, rapid stirring

HOOHR RO

+ H2O

>85% yield

Noyori J. Org. Chem. 1996, 61, 8310

Polyoxometalate

MTO

MnTACN

N NN

TACN (0.1mol%), Mn(OAc)2 (0.08 mol%)

Ascorbic acid (0.04 mol%)Na ascorbate (0.17 mol%)

CH3CN, H2O, 0 °CHOOHR R

O+ H2O

Tet. Lett. 1999, 7965 TACN =

A.G. Doyle, M.C. White, Chem 253 Olefin Oxidation -326- Week of Dec. 14, 2004

Directed Epoxidation

VIVO

O OO O

VVO

OOR

Ot-Bu

O

V

O

O

OO

ORV

Ot-Bu

O

OO

OR

t-Bu

OH

OHO

t-BuOOH (TBHP)

Sharpless Aldrichimica Acta 1979, 12, 63Early transition metals and the lanthanides are capable of "directed" epoxidation based on their high oxophilicity. Bystander oxo ligands, present in many early d0 metals, occupy potentially useful binding sites for potential chiral ligands

V

O

O

OO

OR

t-Bu

V

O

OO

OR

t-Bu

ORMeO

Sharpless Chem. Br. 1986, 22, 38

1000 x faster

Vanadium(acac)2 catalyzed epoxidations:

t-BuOH

2 open coordination sites are required for effective catalysis. A chiral ligandoccupies these sites resulting in ligand deaccelerated catalysis

O

OM

R

O

OM

R

LUMO

HOMO LUMO

Spiro orientation favored, where the plane defined by the lone pair of the oxygen of the η2-peroxo is parallel to the plane defined by the olefin π-orbital.

Stereoelectronic effects:

Ph

Ph

OH

VO

ORRO OR

1 mol%

TBHP (2 eq)

tol, -20 °C, 4 days

N

F3C O

N

O

HO

Ph 3 mol%

PhOH

PhO

90%, 80% ee

Asymmetric catalysis:

M.C. White, Chem 253 Olefin Oxidation -327- Week of Dec. 14, 2004

The Sharpless epoxidation

OHMn+(OR)n cat.

TBHP OH

O

For all metals capable of effecting catalytic epoxidation of allylic alcohols with TBHP, only Ti displayed ligand accelerated catalysis. All other systems were strongly inhibited or entirely deactivated with addedtartrate ligand.

Sharpless ACIEE 2002 (41) 2024.

"For years, right up until January of 1980, when the asymmetric epoxidation was discovered, every expert in asymmetric synthesis and catalysis advised me that what we sought- a catalyst that was both selective and versatile- was simply impossible." K.B. Sharpless Chem. Br. 1986 (22) 38.

R OH

Oi-Pr

Oi-PrTiIV

i-PrOi-PrO

(+)-DET or (+)-DIPT�TBHP, 3 MS,

CH2Cl2, -20oC

R OHO

Uniformly >90% ee, 60-70% yields

HO

HO

O

OR'

O

OR'R' = Et : (+)-DET i-Pr: (+)-DIPT

C2-symmetric ligand

note: no bystander oxo ligand

H15C7

OHAll olefin substitution patterns result in high ee's and good yields, with theexception of cis-disubstituted olefinsthat generally react slowly and givemoderate ee's (80's)

C7H15OH

95% ee88% yield

Unsymmetrical disubstituted Trisubstituted

Ph

Me

OH

>98% ee79% yield

Tetrasubstituted

94% ee90% yield

86% ee74% yield

cis-disubstituted

OH

Sharpless JACS 1987 (109) 5765.Sharpless In Asymmetric Synthesis, Morrison, Ed.; Academic Press: New York, 1986 (5) 247.


Mechanism

R OH

Oi-Pr

Oi-PrTiIV

i-PrOi-PrO

(+)-DET or (+)-DIPT�TBHP, 3 MS,

CH2Cl2, -20oC

R OHO

Uniformly >90% ee, 60-70% yields

HO

HO

O

OR'

O

OR'R' = Et : (+)-DET i-Pr: (+)-DIPT

C2-symmetric ligand

note: no bystander oxo ligand

OTiIV

RORO

OTiIV

O O

O

R'(O)C

R'OR

OR'

OR

C(O)R'

The catalyst self-assembles under the reaction conditions to give predominantly a dimeric species that epoxidizesallylic alcohols with high levels of ee. The dimericspecies is significantly more active than Ti tetraalkoxidealone or Ti-tartrates of other than 1:1 stoichiometrywhich lead to zero or low ee products (respectively).

Oi-Pr

Oi-PrTiIVi-PrO

i-PrOO

TiIVRO

RO

OTiIV(OR)3

O

OR' C(O)R'

Major species in solution and kinetically most active. Leads to high ee products.

R OHO

high ee's

rel. rate: 1.0

R OHO

low ee's

rel. rate: 0.28rel. rate: 0.38

R OHO

0 ee

OTiIV

ROOR

OTiIV

O O

R'(O)C

CO2RO

OR'

O

O

t-Bu

R

C(O)R'

proposed intermediate

Sharpless JACS 1991 (113) 106, 113.


Sharpless Dihydroxylation

OH

OH

OsVI

O

O

HO OHHO OH

2- +K2

0.2 mol%(DHQD)2-PHAL (1 mol%)

K3Fe(CN)6 (3 eq)K2CO3 (3 eq)

t-BuOH: H2O (1:1)98% ee

>90% yieldCommercially available as a mix:AD-mix-α uses the ligand (DHQ)2-PHALAD-mix-β uses the ligand (DHQD)2-PHAL

N

H

N

MeO

ONN

O

N

H

N

OMe

(DHQD)2-PHAL

N

MeO

NEt

H ONN

O

NEt

N

OMeH

(DHQ)2-PHAL

pseudo-enantiomericWorks well for all olefin substitution

patterns with the exception ofcis-disubstituted and tetrasubstituted.

OsVI

O

O

HO OHHO OH

+K22-

General mechanism: Sharpless Chem. Rev. 1994 (94) 2483.

OsVIII

O

O

O OHO OH

+K22-

Sharpless JOC 1992 (57) 2768.

2 K3Fe(CN)62 OH-

2 K4Fe(CN)62 H2O

OsVIIIO

OOO

OsVI

O

O

R

R

L

O

O

OsVIII

L

OO O

O

2 OH-2 H2O

R

R

HO OH

R R

Evidence favors the [3+2] mechanism vs. [2+2]:Corey TL 1996 (28) 4899.Houk, Sharpless, Singleton JACS 1997 (119) 9907.

The enzyme-like binding cleft is especially well suited for π-stacking with aromatic substrates. Large rate accelarations are observed for aromatic substrates with the phalazine class of ligands.

ligand accelarated catalysis:although OsO4 is capable ofdihydroxylating olefins, the ligand bound complex does so at a muchgreater rate. Corey JACS 1993 (115) 2861, 12579.

Sharpless JACS 1994 (116) 1278.

Os

O

OO

L

O RR

[3+2]

Documents

A.G. Doyle, Chem 253 C-H Insertion -300- Week of Dec. 14, 2004people.fas.harvard.edu/~chem253/notes/2004-12-14.pdf · A.G. Doyle, Chem 253 C-H Insertion -304- Week of Dec. 14, 2004