c-h insertion of rhodium-carbene using diazo compounds

1

C-H Insertion of Rhodium-Carbene C-H Insertion of Rhodium-Carbene Using Diazo CompoundsUsing Diazo Compounds

Presented by Pascal Cérat

Litterature Meeting6 april 2010

2

CarbenesCarbenes

Typical reactivity of free carbenes:

R RR R

Cyclopropanation

RnX

Ylides reaction

R3C H C-H insertion

R

RR3C H

R R

XRn

Metal Carbenes in Organic Synthesis; Dörwald, F. G., Ed.; Wiley-VCH: Weinheim, 1999.Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39.

Free carbenes are electron-deficient intermediates that possess two electrons distributedin 2 different orbitals:

Energyp

pC

Most of carbenes are in abent-form (sp2 hybridation)

Degeneratethe two orbitals ( and p

p

more stable ground state

(1A1)

p

less stable ground state

p(1A1)

p

excited state

p(1B1)

p

Triplet state:diradicals

p(3B1)

Carbenes can be in a singulet or a triplet state:

Singulet state:ambiphilic ability

3

Metal-CarbenesMetal-CarbenesTo modulate the reactivity of the free carbene, a complexation with a metal lead to different types of carbenoids:

R R

free carbenes

R R

MInteraction between the metal

and the carbene is weak(carbene-like reactivity)

M

R R

Fischer-type:

Electrophilic carbenecomplex

M = Rh, Cu, Pd, Pt M

R R

Schrock-type:Nucleophilic carbene

complex

back-donation from metal to carbon increases

nucleophilicity of the carbene C-atom increases

Synthetic approaches to generate a carbene complexe by a-abstraction:

LnMR

RLnM

R

R

abstraction of an electrophile

LnMX

RR

X+ = H+, SiR3+

Ln-1MR

R

From ylidesLnM +

R R

X

LnMR

RX

reductiveelimination

LnMR

RLnM

R

Rabstraction of a nucleophileX- = H-, RO-, SR2, halide, N2

- X+

- X-

Metal Carbenes in Organic Synthesis; Dörwald, F. G., Ed.; Wiley-VCH: Weinheim, 1999.

4

Synthesis of Diazo CompoundsSynthesis of Diazo CompoundsBecause of their vast utility and their relative stability, diazo compounds are the preferable substrate for manyreactions such as C-H insertion.

H

N2

R Cl

CH2N2 (2 eq.), Et3NArdnt-Eistert

R

O

O

Et2O, 0oC

Some examples have been extended to other diazoalkane then diazomethane (but very few)

Direct diazo transfert

REWG

O i) TsN3

ii) Et3N REWG

O

N2

Restricted to synthesis of diazo bearing two electron withdrawing groups

Regizt (Deformylating diazo transfert)

RR'

O i) Base

ii) HCO2Et RR'

OH

i) TsN3

ii) Et3N RR'

O

N2

Versatile methodology for compound with a single carbonyl group

Activation Diazo transfert

O

Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-VCH: New York, 1998.

5

Reactivity of Diazo CompoundsReactivity of Diazo CompoundsRelative reactivity of diazo compound toward decomposition:

R H

N2

R = alkyl, aryl, H

DiazoalkanesAryldiazomethanes

>H

N2

R

O

Diazoacetates

>Ar

N2

R

O

Aryldiazoacetates

>N2

R

O

Vinyldiazoacetates

>N2

R

O

Diazoacetoacetates

R' OR'

O

>N2

RO

O

Diazomalonates

OR'

O

Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-VCH: New York, 1998.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Decomposition of diazo in presence of a metal:

LnM

RCHN2

ElectrophilicAddition

LnM CHRN2

N2

DinitrogenExtrusion

LnM CHR

SSCHR

CarbeneTransfert

RCHN2

LnM CHRRHC N2

N2

CarbeneDimerization

RHC CHR

-diazocarbonyl compounds are quite stable:

OH

O

N2

Ethyldiazoacetate (EDA)

< 120 oCNo decomposition

CH3CO2H

r.t.No decomposition

6

C-H Insertion by CarbenesC-H Insertion by Carbenes

Doering, W. v. E.; Buttery, R. G.; Laughlin, R. G.; Chaudhuri, N. J. Am. Chem. Soc. 1956, 78, 3224. Doering, W. v. E.; Knox, L. H. J. Am. Chem. Soc. 1956, 78, 4947. Greuter, F.; Kalvoda, J.; Jeger, O. Proc. Chem. Soc. 1958, 348.Yates, P.; Danishefsky, S. J. Am. Chem. Soc. 1962, 84, 879.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

O

N2

Cu(Zn)

Benzene

O

Yield: 53%

Danishefsky (1962)

Except only a few exemples of intramolecular reactionsin geometrically rigid systems in presence of copper.

Discovery of C-H insertion with free carbenes:

CHRN2

h or CHR

Me MeRH2C +

CH2R+

CH2R

O

N2Me

HH

H

Me H

First exemple of the use of a transition metal (1958)

CuO

TolueneHH

H

Me H

O

48 35 17

statistical ratio: 50 33 17If R = H

38 42 20If R = COMe

MeMe

Me

Me

RH2C +RH2C

statistical ratio: 86 1483 17If R = H77 23If R = COMe

No practical selectivity was observed for free carbenes for distinguishing between 1o, 2o and 3o aliphatic C-H bounds

7

Introduction of Rhodium C-H InsertionIntroduction of Rhodium C-H Insertion

Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssié, P. J. Chem. Soc. Chem. Commun. 1981, 688.Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssié, P. Bull. Soc. Chim. Belg. 1984, 93, 945.Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; Da Silva, R. R.; Shulman, S.; Warnet, R. J. J. Org. Chem. 1982, 47, 3242.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Major breakthrough into carbon-hydrogen insertion reactions was the applicability of dirhodium(II)tetraacetate as a catalyst for the reaction of ethyl diazoacetate with alkanes.

Et

OH

N2

Rh2(OAc)4

Me Me

4

63

33

MeMe

5

8

Me 90

MeMe

Me

Me1

5

95

Greater selectivity:

RhO

OO

ORhO

O

CH3

CH3

O

H3C

O

CH3

RH

Metal-carbene C-H insertion step for intramolecular process:

O

C-H insertion is said to be concertedPreference of the formation of 5 members ring

Better reactivity than copper:

AcOMeAcO

H

Me

ON2 MLn

AcOMeAcO

H

Me

O

H H

HCuSO4 : poor yield

Rh2(OAc)4 : 59% yield

8

Propreties of RhodiumPropreties of Rhodium

Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Group 9 (VIII)

Rh(0) : [Kr] 4s2 4p6 4d8 5s1

Oxidation state:Rh(I) : - d8 configuration - planar complex or trigonal bipyramidal - Wilkinson catalyst

[Rh(PPh3)3]Cl

Rh(III) : - d6 configuration - trigonal-bipyramidal, square-pyramidal or octahedral - RhCl3 . 3 H2O

Rh(I) and Rh(III) have been shown to decompose diazo compounds, but neveras efficient as Rh(II)

Rh(II): - d7 configuration with the ability to form dimer complex Rh-Rh - octahedral - First rhodium dimer is Rh2(OAc)4

Rhodium price: 80,000$ / kg

Rhodium(II) carboxylates Rhodium(II) carboxamides Rhodium(II) ortho metalatedaryl phosphine

RhRh

OOO

O

O

O

L

LO

RO

R

R

R

RhRh

ONR'R'N

O

O

R'N

L

LO

RNR'

R

R

R

RhRh

OO

P

P

O

L

LO

R

R

R'''R''

R'

R'

R'''R''

9

C-H Insertion vs C-H ActivationC-H Insertion vs C-H Activation

Davies, H. M.; Manning, J. R. Nature 2008, 451, 417.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Intramolecular C-H insertion:- Regioselectivity: Steric and Electronic Effects- Chemioselectivity (C-H insertion vs cyclopropanation vs aromatic C-H insertion vs aromatic cycloaddition)- Developpement of enantioselective process (effect of ligands)

Intermolecular C-H insertion:- C-H insertion with aryldiazoacetates

- Use of vinyldiazoacetates in C-H insertion-Cope rearrangement

C-H insertion differ from the C-H activation process in which the metal activate the C-H bound by complexationbefore being funtionnalize.

R1

R2

N2

N2

LnM

R1

R2

MLn

LnM

H C

CR2

H

R1

Metal carbenoidC-H insertion

C H

C MLn

H

X

C XH

C-H activation

Complex on the C-H by the metal (oxydative addition)

No interaction between the metaland the C-H bound

10

General Mechanism of C-H InsertionGeneral Mechanism of C-H Insertion

Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.

The transition state of this second step decide the regioselectivity, the diastereoselectivity and theenantioselectivity of the C-H insertion.

O O

RhI RhIII

CH3

CEH

HC

Hydride transfert to the electrophilicmetal carbene

O O

RhI RhIII

CH3

CEH

H C

Formation of the C-C bound

Steps needed for the C-H insertion step:

(1) (2)

A recent DFT calculation confirmed that the formation of the C-C and the C-H bound with the carbenetake place as a single concerted step.

H = 16.4 ± 1.4 kcal/mol

Catalytic cycle of rhodium tetracarboxylate-catalysed C-H bond insertion:

Rate-limiting step

Rh2L4 N2

H

CO2Et

L4Rh2

H

CO2Et

N2

Fast step

R' H

R'H

CO2EtH

11

General Mechanism of C-H InsertionGeneral Mechanism of C-H Insertion

The reaction proceeds through a late transition state where the Rh-carbene bond cleavage is involved:compare to cyclopropanation where the transition state is earlier

Even if they in their calculation they see an impact on the variation of charge distribution for each rhodium atomduring the reaction, but the lengh of the Rh-Rh never dramatically change during the process.

Rh-Rh in free dimer: 2.400 ARh-Rh link to carbene: 2.482 A

o

o

Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.

RhII

O O

RhII

H

N

N

CEt H

Mechanism from DFT calculation:

The second rhodium act as a bifunctionnal electron pool and enchanced the electrophilicity of the carbene

O O

H

RhI RhIII CN

EH

N

N2

RhI

O O

RhIII C

H

E

H

HR'

RhI

O O

RhIII C

H R'

H

Concerted but not-synchrenous process

The regeneration of the complete Rh-Rh bound facilitatethe cleavage of the Rh-C bound

Rh CHH

Rh

Rh Rh CHH

EH

12

Intramolecular C-H insertion: RegioselectivityIntramolecular C-H insertion: Regioselectivity

Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808.Taber, D. H.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108, 7686.

Rhodium(II) catalyst has shown great regioselectivity, but what is his normal trend?

5 members ring cycles are normally prefered in absence of rigidity in the system

OCO2Me

N2

R

Rh2(OAc)4

CH2Cl2, r.t.

O

CO2Me

R

1o C-H insertion vs 2o C-H insertion:O

CO2Me

N2

1o

2o

Rh2(OAc)4

CH2Cl2, r.t.

O

CO2Me

3

O

CO2Me

+

1

Methylene C-H boundsare more reactive than methyl

OCO2Me

N2

2o

2o C-H insertion vs 3o C-H insertion:3o

Rh2(OAc)4

CH2Cl2, r.t.

O

CO2Me

O

CO2Me+

4.6 1

Methine C-H boundsare more reactive than

methylene

On electronic factor only, the C-H bound having the more electronic density is more reactive in C-H insertion with metal-carbene:

3o C-H > 2o C-H > 1o C-HOrder of reactivity:

13

Regioselectivity Modulated by Electronic Effect of the C-HRegioselectivity Modulated by Electronic Effect of the C-H

Stork, G.; Nakatani, K. Tet. Lett. 1988, 29, 2283.Spero, D. M.; Adams, J. Tet. Lett. 1992, 33, 1143.Davies, H. M.; Manning, J. R. Nature 2008, 451, 417.

O

ON2

6 4Rh2(OAc)4

CH2Cl2, r.t. OX

O

X+

O

O

X

C-H in 6 C-H in 4

Activation of a C-H bound by the presence in a of an O (or a protected N): X Ratio 6 : 4

H

OH

OMe

OAc

> 99 : 1

5.9 : 1

24 : 1

> 99 :1

An electon donating group facilitates the process of an "hydride transfer"and an electron withdrawing gropu produces the opposite effect

EDG EWG

CH3

1o sterically favoured, but electronically disfavoured

3o sterically disfavoured, but electronically favoured

2o sterically favoured and electronically favoured

2o sterically favoured, butelectronically disfavoured

Further electronic effect of the C-H bound:O

CO2Me

H

N2

Rh2(OAc)4

CH2Cl2, r.t.

OH

N2

CO2Et83 %

O

CO2Me

Rh2(OAc)4

CH2Cl2, r.t.

O

CO2Et

The presence of an electron withdrawing group desactivate the C-H in (and sometime even in such as in the presence of an ester)

14

Changing the Changing the -Group of the Diazo-Group of the Diazo

Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org. Lett. 2001, 3, 3539.Gois, P. M. P.; Afonso, A. M. Eur. J. Org. Chem. 2003, 3798.

X

N2

N

O

Ph

Rh2(OAc)4N

OX

Ph

+ N

O

Ph

X

A B

CH2Cl2, reflux

X Yield Ratio B : A

MeCO 94 % 1 : 1

PhSO2 95 % > 99 : 1

(EtO)2PO 81 % > 99 : 1

More electronwithdrawingability

Less selectivity

LnM CYXGeneral observation: Electron withdrawl by Y or X increases reactivity,

but decreases selectivity (carbene too electrophilic)

Changing the nature of the diazo, change is reactivity and so his selectivity.

If the reactivity is the diazo is too low, the insertion will not occur and dimerization will be the major product.A good balance between reactivity and selectivity need then to be found.

15

Impact of the Ligands on RegioselectivityImpact of the Ligands on Regioselectivity

Doyle, M. P.; Tauton, J.; Pho, H. Q. Tet. Lett. 1989, 30, 5397.Doyle, M. P.; Bagheri, V.; Pearson, M. M.; Edwards, J. D. Tet. Lett. 1989, 30, 7001.Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958.Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797.

O O

CF3

Rh Rh

tfa :O O

CH3

Rh Rh

OAc:

O N

CH3

Rh Rh

acm :O O

CPh3

Rh Rh

tpa :

Proprieties of the ligand (steric and electronic) can be modulated for controling the desired selectivity

O

CO2MeN2

RhII

O

CO2Me

+

OO

OO O

O

O

CO2Me2o C-H 3o C-H

Rh2(acm)4 14 : 86 Better selectivity withless EWG on ligand

Rh2(tpa)4 96 : 4 Selectivity basedon steric factor

RhII 2o : 3o

Rh2(OAc)4 37 : 63

Rh2(tfa)4 56 : 44

OH

N2

O RhII

OO +

OO

3o C-H 1o C-H

RhII 3o : 1o

Rh2(OAc)4 53 : 47

Rh2(pfb)4 32 : 68

Rh2(acm)4 99 : 1

16

Impact of the Ligands on ChemioselectivityImpact of the Ligands on Chemioselectivity

Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669.Estevan, F.; Lahuerta, P.; Pérez-Prieto, J.; Sanau, M.; Stiriba, S.-E.; Ubeda, M. A. Organometallics 1997, 16, 880.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

O O

C3F7

Rh Rh

pfb :O O

CH3

Rh Rh

OAc:O NRh Rh

cap :Rh

RhO

OP

P

OO

R

R

R'R'

R'R'

R = C3F7 or CH3;R' = Ph

1 :

C-H insertion versus Cyclopropanation:

CHN2

O

Rh2L4

CH2Cl2O

+ O

A B

Rh2L4 A : B

Rh2(OAc)4 44 : 56

Rh2(pfb)4 0 : 100

Rh2(cap)4 100 : 0

Yield

1 (R = CH3)

97%56%

76%

85% 100 : 0

C-H insertion versus Aromatic substitution:

PhCHN2

O

Rh2L4

CH2Cl2+ O

Ph

A B

Rh2L4 A : B

Rh2(OAc)4 65 : 35

Rh2(pfb)4 100 : 0

Rh2(cap)4 59 : 41

Yield

1' (R = C3F7)

96%96%

64%

95% 0 : 100

O

Rh2(pfb)4 : Aromatic substitution > C-H insertion > CyclopropanationRh2(cap)4 : Cyclopropanation > Aromatic substitution ~ C-H insertion

17

Influence of Ligand on Dirhodium(II) CarbeneInfluence of Ligand on Dirhodium(II) Carbene

Lloret, J.; Carbo, J. J.; Bo, C.; Lledos, A.; Pérez-Prieto, J. Organometallics 2008, 27, 2873.

Increasing the electron-withdrawing ability of the ligand = increases the electrophilic character of the carbene

Selectivity of the carbene for more nucleophilic substrate

Rh2Rh1

OOO

O

O

OL

O

HO

H

H

H

Rh2Rh1

ONHHN

O

O

HNL

O

RNH

R

R

R

Rh2Rh1

OO

PH2

H2P

OL

O

H

H

H

H

HH

L = CH(CO2Me)

tetracarboxylate (1a) tetracarboxamidate (1b) ortho-metalated phosphines (1c)

DFT analysis of the different families of ligand on dirhodium in presence of the carbene:

1a 1b 1c

qNPA (Rh1, Rh2) 0.92, 0.72 0.84, 0.59 0.45, 0.24

d (Rh-Ccarbene) 1.940 1.917 1.901Eint (kcal/mol) - 46.2 - 51.5 - 54.4Estab (kcal/mol)Rh(d) p() 39.4 52.5 59.0

Larger donation capability of the ortho metalated phosphine ligand by more electron density at the metal center.The rhodium-carbene bond distance which shorten when going to the ortho-metalated phosphines is in correlation with the energy of the same bond. The Rh-carbene bond is more stable in this case.In the case of 1b and 1c more back-donation of the density of the metal to the carbene stabilizes this specieand render it less reactive (so more selective).

18

Diastereoselectivity in C-H insertionDiastereoselectivity in C-H insertion

Taber, D. F.; You, K. K.; Rheingold, A. J. Am. Chem. Soc. 1996, 118, 547.

Taber has used modeling to predict the diastereoselectivity of the formation of cyclopentane:

Hypothetical transition state:

H

Me HRh

EH

Me HRh

EH

MeRh

E

H

E

MeThe presence of a C-H equatorial is needed for insertion

HCO2Me

Ph

H

Ph

CO2Me

Me

Possible T.S.Relative energy

of T.S. (kcal/mol) Product formed

0.0 Ph

Me

CO2Me

Possible T.S.Relative energy

of T.S. (kcal/mol) Product formed

6.1

Me HRh

HCO2Me

H

Ph

Me HRh Ph

CO2Me

Me5.3

MeCO2Me

Ph

H

H HRh

Ph

Me

CO2Me7.4Me

CO2MeH

Ph

H HRh

Ph

CO2MeN2

Ph

Me CO2Me

Rh2(Oct)4

CH2Cl2

Single diastereoisomer

19

Chiral Dirhodium Catalyst in C-H InsertionChiral Dirhodium Catalyst in C-H Insertion

Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Chiral dirhodium carboxylate catalyst

O ORh Rh

NH S

O O

C12H25

Rh2(S-DOSP)4

O ORh Rh

NRH

O

O

R = t-Bu, Rh2(S-PTTL)4R = PhCH2, Rh2(S-PTPA)4

Rh

Rh

O

OO

O

N

NH

H

Ar Ar

O

OO

O

N

NH

H

ArAr

Rh2(S-biDOSP)2

Used in cyclopropanation,intramolecular C-H insertion

and intermolecular C-H insertion

Used mainly in intermolecular C-H insertion of donor-acceptor diazo compounds

Ortho-metalated arylphosphines (as seen previously)

Chiral dirhodium carboxamidate catalyst

O NRh Rh

R'

CO2R

R'

H

Chiral pyrrolidinates:

(5S)-MEPY (R = Me, R' = H)

O NRh Rh

N

CO2RH

Chiral imidazolidinates:

(4S)-MACIM (R = R' = Me)

O

R'

(4S)-MPPIM (R = Me R' = PhCH2CH2)

O NRh Rh

O

CO2RH

Chiral oxazolidinates:

(4S)-MEOX (R = Me, R' = H)

R'H

O NRh Rh

Chiral azetidinates:

(4S)-MEAZ (R = Me, R' = H)(4S)-IBAZ (R = iBu, R' = H)

R'R'

CO2RH

Carboxamidate ligands are used mainly in intramolecular C-H insertion and sometime in intramolecular cyclopropanation.

20

Carboxylates in Intramolecular C-H InsertionCarboxylates in Intramolecular C-H Insertion

Anada, M.; Kitagaki, S.; Hashimoto, S. Heterocycles 2000, 52, 875.

Diastereoselective model (with Rh2(OAc)4):

Rh

CO2Me

O

N

Me

RR

O

Ha

Hb

(0 kcal/mol)

ONO

MeO2CHa Hb

R R

Rh

CO2Me

O

NMe

RR

O

(+10.9 kcal/mol)

ONO

MeO2CHb Ha

R R

Hb

Ha

boat-like T.S.

Rh

MeO2C

O

N

Me

R R

O

Hb

Ha

(+3.3 kcal/mol)

ONO

MeO2CHb Ha

R R

Rh

MeO2C

O

N

R R

O

(+7.1 kcal/mol)

ONO

MeO2CHa Hb

R R

Ha

Hb

boat-like T.S.

Me

ON

O

N2

MeO2C

Formation of -lactam by double stereodifferentiation

ONO

MeO2CH H

Rh2L4 (5 mol%)

CH2Cl2, 23 oC

ONO

MeO2CH H

+

Rh2L4 Time (h) Yield (%) A : B

Rh2(OAc)4 18 75 25:75

Rh2(R-PTPA)4 18 77 2:98

Rh2(S-PTPA)4 24 47 85:15

A B

O ORh Rh

NPhthHPhH2C

Rh2(S-PTPA)4 =

21


Anada, M.; Kitagaki, S.; Hashimoto, S. Heterocycles 2000, 52, 875.

IIIII

IIVRh

CO2Me

ON

Me

RR

O

Ha

Hb

Rh2(S-PTPA)4

IIIII

IIVRh

MeO2C

ON

Me

R R

O

Hb

Ha

E

F

F is less disfavored than E

ONO

MeO2CH H

A

ONO

MeO2CH H

B

85

15

IIIII

IIVRh

CO2Me

ON

Me

RR

O

Ha

Hb

IIIII

IIVRh

MeO2CO

N

Me

R R

O

Hb

Ha

G

H

Rh2(R-PTPA)4

G is a lot more stable than H

98

2

Rh

Enantioselective model proposed by Hashimoto:

IIIII

IIV

Rh2(S-PTPA)4

RhIIIII

IIV

Rh2(R-PTPA)4

Based on the X-rayof Rh2(S-PTPA)4 with

bis(4-tert-butylpyridine)

22


Davies, H. M.; Grazini, M. V. A.; Aouad, E. Org. Lett. 2001, 3, 1475.Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. 2002, 4, 3887.Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437.

Synthesis of Dihydrobenzofurans via C-H Insertion

N2

CO2Me

O Ar

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

Toluene, -78 oC OAr

CO2Me

63 - 79% yield92 - 99% d.e.91 - 96% e.e.

5 exemples

For Ar = Ph :

O ORh Rh

NPhthRH

R = Me: Rh2(S-PTA)4R = i-Pr: Rh2(S-PTV)4R = Bn: Rh2(S-PTPA)4R = Ph: Rh2(S-PTPG)4R = t-Bu: Rh2(S-PTTL)4

R = Adamantyl: Rh2(S-PTAD)4

R group yield (%) d.r. ee (%)

Me

i-Pr

Bn

Ph

t-Bu

Adamantyl

84

86

86

83

87

79

4 : 1

9 : 1

2.3 : 1

> 30 : 1

> 30 : 1

> 30 : 1

61

61

70

71

90

95Increasing the bulky of the R group on the ligandincrease the selectivity.

N2

CO2Me

OMe

Me

Example of the use of Rh2(DOSP)4 in asymetric intramolecular C-H insertion of aryldiazoacetates:

Rh2(S-DOSP)

hexanes, -50 oC, 72 h

Very limited examples of good enantioselectivity

O

CO2Me

Me

Me

98% yield, 94% ee

23

Carboxamidates in Intramolecular C-H InsertionCarboxamidates in Intramolecular C-H Insertion

Doyle, M. P.; Oeveren, A. v.; Westrum, L. J.; Protopopova, M. N.; Clayton, T. W., Jr. J. Am. Chem. Soc. 1991, 113, 8982.Doyle, M. P.; Dyatkhin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; Basten, A. v. J. Am. Chem. Soc. 1994, 116, 4507.Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

CHN2O

O

OR

Rh2(5R-MEPY)4 (0.1 mol%)

CH2Cl2O

O

OR

Rh2(5S-MEPY)4 (0.1 mol%)O

O

OR

CH2Cl2

R = Me, Et, Bn 64 - 73% yield87 - 91% ee

Asymmetric synthesis of lactones with rhodium(II) carboxamidates:

CHN2N

O

Z

Rh2(4S-MEOX)4N

O

OR

CH2Cl2

Z = Et, i-Pr, OEt 82 - 97% yield69 - 78% ee

Formation of -lactame with medium enantioselectivity:

t-Bu t-Bu

Diastereocontrol for enantioselective C-H insertion for the formation of bicyclic systems:

OCHN2

O

n

Rh2(4S-MPPIM)4(0.5 mol%)

CH2Cl2 O

H

H

O

n = 0 - 3n

62 - 75% yield> 99:1 (cis:trans)

up to 93% ee

24

Understanding the Utility of Carboxamidate as LigandsUnderstanding the Utility of Carboxamidate as Ligands

Doyle, M. P.; Oeveren, A. v.; Westrum, L. J.; Protopopova, M. N.; Clayton, T. W., Jr. J. Am. Chem. Soc. 1991, 113, 8982.Yoshikai, N.; Nakamura, E. Adv. Synth. Catal. 2003, 345, 1159.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

N

O

N O

E

E

How is the asymetric induction of the ligand affecting the C-H insertion enantioselectivity?

Rh

N O

NOH

CO2Me

CO2MeH

HO

O

OMeH H

A

B

Side view: Rh-Rh view:CO2R

HB

A

CHN2O

O

OMe

Rh2((5S)-MEPY)4

CH2Cl2, reflux

O

O

OMe62% yield91% ee

O NRh Rh

CO2MeH

(5S)-MEPY

(S)

N

O

N O

E

E

H

OO

H OMe

B-cis

N

O

N O

E

E

SH

OO

H OMe

B-trans

N

O

N O

E

E

HO

O

H

MeOA-cis

S

N

O

N O

E

E

HO

O

H

MeOA-trans

R

25


Doyle, M. P.; Oeveren, A. v.; Westrum, L. J.; Protopopova, M. N.; Clayton, T. W., Jr. J. Am. Chem. Soc. 1991, 113, 8982.Yoshikai, N.; Nakamura, E. Adv. Synth. Catal. 2003, 345, 1159.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Rh

N O

NOH

CO2Me

CO2MeH

O

O

H

H

HOMe (H)

(OMe)

Selectivity between the face A and B:

A

Rh

N O

NOH

CO2Me

CO2MeH

B

H

O

OMe

HH

(OMe)

(H)

O

The attack from face A is favored

Rh

N O

NOH

CO2Me

CO2MeH

O

O

H

H

HO

Selectivity cis- and trans-T.S. from the approach A:

cisThe T.S. with the cis configuration is favored

Rh

N O

NOH

CO2Me

CO2MeH

O

O

H

H

OH

trans

MeMe

For R-enantiomer of the catalyst, the steric inhibition force the reaction to occur ina clockwise reaction for intramolecular C-H insertion. (S-enantiomer: conterclockwise)

26


Doyle, M. P.; Morgan, J. P.; Fettinger, J. C.; Zavalij, P. Y.; Colyer, J. T.; Timmons, D. J.; Carbucci, M. D. J. Org. Chem. 2005, 70, 5291.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Chiral N-acyl groups on imidazolidinone ligands were also used to investigad the stereoenchancement ofcarboxamidates in C-H insertion reactions by reinforcing the stereocontrol in the cadran form.

Rh

N

O

NO

E ER

RUse of catalyst withachiral N-acyl group

O NRh Rh

N

CO2MeH

O

R Rh

N

O

NO

E E

R RMatched design withchiral N-acyl group

Rh

N

O

NO

E E

Mismatched design withchiral N-acyl group

R

R

O NRh Rh

N

CO2MeH

OPh

O NRh Rh

N

CO2MeH

O

O NRh Rh

N

CO2MeH

O

NSO

O

Ph

Rh2(4S-MPPIM)4 Rh2(4S,2'S,3'S-MCPIM)4Match

Rh2(4S,2'S-BSPIM)4Match

O CHN2

O

Rh2L4 (1 mol%)

CH2Cl2

OH

H

O

Rh2L4 Yield (%) cis/trans ee (%)

Rh2(4S-MPPIM)4 71 100/0 92

Rh2(4S,2'S,3'S-MCPIM)4 78 99/1 97

Rh2(4S,2'R,3'R-MCPIM)4 63 80/20 72

Rh2(4S,2'S-BSPIM)4 88 97/3 99

Rh2(4S,2'R-BSPIM)4 89 98/2 74

27

Diastereoselectivity with Dirhodium CarboxamidatesDiastereoselectivity with Dirhodium Carboxamidates

Doyle, M. P.; Morgan, J. P.; Fettinger, J. C.; Zavalij, P. Y.; Colyer, J. T.; Timmons, D. J.; Carbucci, M. D. J. Org. Chem. 2005, 70, 5291.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

OMe

O

H

H

Rh2L4

Counter-clockwise forR-catalystO

OMe

H

Rh2L4

Clockwise forS-catalyst

Me

O

O

CHN2

racemic

Rh2(5S-MEPY)4

CH2Cl2

Enantiomer differentiation from racemic mixture:

O

Me

O + O

Me

O45% (91% ee) 49% (98% ee)

75 %

Preference of the insertion into a equatorial C-H bond over an axial

When forming diastereoselective bicyclic system, the use of a chiral carboxamidate ligand leads tosignificant ligand-dependent stereocontrol.

Me

O

O

N2

Rh2(5S-MEPY)4

CH2Cl2

Rh2(5R-MEPY)4

CH2Cl2O

Me

O

Me

O

O

91 %94 %

28

Use of Othometalated Aryl Phosphine LigandsUse of Othometalated Aryl Phosphine Ligands

Estevan, F.; Herbst, K.; Lahuerta, P.; Barberis, M.; Perez-Prieto, J. Organometallics 2001, 20, 950.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

Even if they are not a chiral ligand, the otho-metalated aryl phosphine ligands induce an asymmetryin their arrangement around the dirhodium(II).

As previously seen, they are one of the most regioselective ligand and they are the most recent of the ligandfor C-H insertion.

ZN2

O

ClZ = O

CH2Cl2, 40 oC

O NRh Rh

N

CO2MeH

OPh

Rh2(4S-MPPIM)4

Cl

O

O

81% yield95% ee

Rh

Rh

O

OO

O

PR2PR2F3C

F3C

Me

MeR = m-MePh

Z = CCH2Cl2, 40 oC

Cl

O

87% yield73% eeBest enantiocontrol level from

the C-H insertion of a diazoketone

O Rh

P

O

Ar Ar

Side-view:Open

quadrantOpen

quadrant

O Rh

P

O

Ar Ar

Rh

HH

R

O

A

O Rh

P

O

Ar Ar

R

O

HH B

Proposed transition states:

29

Intermolecular C-H Insertion ReactionsIntermolecular C-H Insertion Reactions

Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

The main problem with intermolecular C-H insertion is their lack of chemioselectivity and regioselectivity.The success of intermolecular process is found in the balance between activation and stabilization of the intermediate metal carbene.

The use of donor-acceptor-stabilized carbenoids (aryl- and vinyldiazoacetates) demonstrate a highlyregioselective insertion.

Rh2(OAc)4CO2R

A+ N2

A

CO2R CO2R

A+

R = Et, A = H 20 80

R = Me, A = CO2Me 38 62

R = Me, A = Ph 75 25

The usual ligand on the dirhodium catalyst for intermolecular C-H insertion is the DOSP.

Rh2L4CO2Me

Ph+ N2

Ph

CO2Me CO2Me

Ph+

Rh2(5S-MEPY)4 93 (45% ee) 7

Rh2(S-PTPA)4 50 (53% ee) 50

80 (75% ee) 20Rh2(S-DOSP)4

RhO

RhONSO2Ar

Ar = (Ph-C12H25)Rh2(DOSP)4

30

Aryldiazoacetate in Intermolecular C-H Insertion ReactionsAryldiazoacetate in Intermolecular C-H Insertion Reactions

Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

n

Asymetric C-H insertion of cycloalkanes by aryldiazoacetates:

+Ar CO2Me

N2

n = 1 or 2

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

-10 oCn

Ar

CO2Me

11 exemples47 - 81% yield90 - 96% ee

only Ar without electron donor groups: low yield for p-OMePh

The relative rates of the insertion of the phenyldiazoacetate for various substrates:

R1H

R3

R2 +R4

HR6

R5

Ph

CO2MeN2

Rh2(DOSP)4 (1 mol%)Ph

R1

R3R2

CO2Me

+ PhR4

R6R5

CO2Me

1 0.66 0.078 0.011

NBOC

1700

O

2700

Ph2tBuSi H

24 000 28 000

Sterically crowded C-H bonds are defarvorised for the attack

Presence of an heteroatom in a position or allylic C-H are favorised

31


Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc. 1999, 121, 6509.Davies, H. M. L.; Venkatarmani, C. Angew. Chem. Int. Ed. 2002, 41, 2197.Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

N

Enantioselective C-H insertion of methyl aryldiazoacetates into N-Boc pyrrolidynes

Boc

Ar CO2Me

N2+

Rh2(S-DOSP)4 (1 mol%)hexane, -50 oC

1)

TFA2)NH

Ar

CO2Me

H(2 eq.) 49 - 72% yield

92 - 94% de93 - 94% ee

Ar = Ph, p-Cl-Ph, p-Me-Ph, 2-Naphtyl

Asymetric C-H insertion of tetrahydrofuran

OAr CO2Me

N2+ Rh2(S-DOSP)4 (1 mol%) O

Ar

CO2Me

H(2 eq.) 49 - 72% yield

low (< 4:1) d.r95 - 98% ee

Ar = Ph, p-Cl-Ph, p-Me-Ph, 2-Naphtyl, p-MeO-Ph

hexane, -50 oC

Asymetric C-H insertion of allyl tert-butyldimethylsilyl ethers

Ar CO2Me

N2+

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

hexane, 24 oCTBSO R R

MeO2C

Ar

OTBS(2 eq.) 35 - 72% yield

96 - 98% de74 - 92% ee

R = alkyl, aryl, vinyl, ester

Ar = Ph, p-Cl-Ph, p-Br-Ph

32


Davies, H. M. L.; Venkatarmani, C. Angew. Chem. Int. Ed. 2002, 41, 2197.Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126.

The speed of insertion depends on the steric of the protecting group and the electronic

OTBS

OR

+Ph CO2Me

N2

Rh2(R-DOSP)4MeO2C

Ph

OTBS

+ MeO2C

Ph

OR

Relative rateRTMS 102TES 39TBS 14TIPS 1.7

TBDPS 1

1

1 (2 eq.)TBSO

OAc MeO2C

Ph

OTBSOAc

93% yield, >94% de, 62% ee

Rh2(S-DOSP)4

Insertion on the more nucleophilic C-H bond

Enantioselective synthesis of -amino acids by C-H insertion of aryldiazoacetate in N-protected amines

NPhBoc

+Ar CO2Me

N2

(2 eq.)

Rh2(S-DOSP)4 (1 mol%)2,2-dimethylbutane, 23 oC

1)

TFA2)

Ph NH

Ar

CO2Me55 - 67% yield87 - 96% ee

favored by electronic

favoredby steric

NPhCbz

+Ar CO2Me

N2

(2 eq.)

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

Ar

CO2Me2,2-dimethylbutane,23 oC

Cbz77% yield, 93% ee

1) LiOH.H2O, THF

2) HCO2NH4,10% Pd/C, MeOH

H2NAr

CO2Me66% yield on 2 steps

33


Davies, H. M. L.; Hedley, S. J.; Bohall, B.R. J. Org. Chem. 2005, 70, 10737.

MeO

OTBS

+Ph CO2Me

N2 Rh2(R-DOSP)4 (1 mol%)

2,2-DMB, 23 oCMeO

OTBSCO2Me

Ph

85% yield88% de35% ee

Limitation of the DOSP ligand for benzylic position:

Two solutions to improve this methodology:

Use of a chiral auxiliary derived from (S)-lactate

R1

OTBS

+

N2 Rh2(OOct)4 (1 mol%)2,2-DMB, 23 oC

R1

OTBS

63 - 85% yield79 - 88% de76 - 86% ee

OHO

OOEtO

H1)

2) DIBAL, 0 oCR2

R2

Use of the Rh2(S-PTTL)4 as the chiral catalyst

R1

OTBS

+

N2Rh2(S-PTTL)4 (1 mol%)

R1

OTBSCO2Me

78 - 95% yield89 - 95% de86 - 97% ee

Me

OR2

R2

2,2-DMB, 50 oC

34

Vinyldiazoacetate in Intermolecular C-H Insertion ReactionsVinyldiazoacetate in Intermolecular C-H Insertion Reactions

Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.

The first mechanism to explain this transformation would be an allylic C-H insertion followed bya Cope rearrangement. If this is the case:

N2

CO2Me

Ph

Rh2L4Hexane, 23 oC MeO2C Ph

Product of allylicC-H insertion

Ph

CO2MeProduct of the

Cope-rearrangement

Thermodynamicallynot favorised

Rh2L4

Hexane, reflux

The driving force for the Cope rearrangement is in the reverse direction which indicates that theprocess can not be step-wise.

First exemple of intermolecular C-H insertion with a vinyldiazoacetate:

N2

CO2Me

Ar

Rh2(DOSP)4Hexane, 23 oC

Ar

CO2Me

+

CO2Me

Ar

H

17 - 63% yield84 - 98% ee

Side-product

35

Intermolecular C-H Insertion – Cope RearrangementIntermolecular C-H Insertion – Cope Rearrangement

Davies, H. M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126, 10862.Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.

NHMe

ClCl

(+)-sertaline

Proposed concerted mechanism for the C-H insertion/Cope rearrangement:

+

CO2MeN2

Cl

Cl

Rh2(S-DOSP)4

Hexanes Cl

Cl

HRhMeO2C

60% yield99% ee

This concerted, ordered transition stateleads to higher stereoselectivity than

normal direct C-H insertion

CO2Me

ClCl

This concerted mechanism can be exploited by the possibility of a retro-Cope so favorable that theapparent product would be from a direct C-H insertion.

+

CO2MeN2

Ph

Rh2(S-DOSP)4

2,2-DMB, 23 oC

CO2MeMePh

retro-Cope Ph

HCO2Me

92% yield> 98% de98% ee

36


Davies, H. M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126, 10862.Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.

1,2-Dihydronaptalenes are perfect substrate for such C-H insertion/Cope rearrangement followed by aretro-Cope rearrangement.

OTBS

+

CO2MeN2

Ph

Rh2(DOSP)4

2,2-DMB, 0 oC

OTBSPh

HCO2Me

48% HF

78% yield> 98% de95% ee

OPh

HCO2Me

84% yield

OAcRh2(S-DOSP)4

2,2-DMB, 23 oC

CO2MeAcO

Ph

85% yield> 99% ee

CO2MeN2

Ph

+- HOAc

CO2MePh

Proposed mechanism:

RhRh

CO2Me

R1

R2HH

approachfrom the front

C-H/Cope R1

H

R2CO2Me Retro-Cope R1 R2

H H

CO2MeH

37


Davies, H. M. L.; Walji, A. M. Angew. Chem. Int. Ed. 2005, 44, 1733.Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 1996, 128, 2485.Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.

Use of the C-H insertion/Cope rearrangement in a parallel kinetic enantiodifferentiating step:

Me

Me Me CO2Me

N2

Rh2(R-DOSP)4 (2 mol%)

(2 eq.)

2,2-DMB, 23 oCMe

Me

MeO

O

MeH

+Me

Me

MeO2CMeH

H

48% yield90% ee

48% yield

H2/PdLiAlH4

Me

Me

HOMeH

62% yield

1) PCC(89% yield)

2) Ph3P=C(CH3)2(82% yield)

Me

Me

MeH

MeMe(+)-ergorgiaene

Also synthezise by this approach:

Me

TBSOMeO

OTBS

Me Me

CO2MeN2

+

OMe

HMe

OHO

Me

HMe

elisapterosin B

38

Intermolecular C-H Insertion – Cope RearrangementIntermolecular C-H Insertion – Cope RearrangementEnantiodivergent transition states:

Me

Me+Me

CO2MeN2

RhRh

CO2MeR2

MeH

H

Attack from front

Me

RhRh

CO2MeR2

MeH

H

Me

Interaction between the methyl andthe steric group from the catalyst

Me

Me

RhRh

CO2MeR2

Me

Me

RhRh

CO2MeR2

Interaction between the methyl andthe steric group from the catalystDavies, H. M. L.; Walji, A. M. Angew. Chem. Int. Ed. 2005, 44, 1733.

Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 1996, 128, 2485.Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.

39

ConclusionConclusion

Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.

With the developpement of new rhodium catalyst, the regioselectivity and chemioselectivity of C-H insertionis a lot more understood even in the case of intermolecular reactions.

Interamolecular provided excellent diastereoselectivity and enantiocontrol in reaction with diazoactates and diazoacetamides. They are than a great tool nowday to selectively synthesize C-C bonds for the construction of complex molecules.

OH

O

O

OHenterolactone

OO

O

O

O

O hinokinin

O

OO

MeOOMe

OMe

O

isodeoxypodophylotoxin

Cl

H3N COOHClH

(R)-(-)-baclofen

Rh2(4S-MPPIM)4 : 93% eeRh2(4S-MPPIM)4 : 95% ee Rh2(MPPIM)4 : 99% ee

Rh2(4S-MPPIM)4 : 95% ee

Even if they are using expensive rhodium catalyst, the loading for most of the reactions are not more than1 mol% to 0.1 mol%.

Diazocarbonyl compounds are in general relatively stable to decomposition and can be made in a variouspossible way.

Developpement for a lot of class of diazocompounds, such as diazoketone in intramolecular and any acceptor-acceptor for intramolecular need to be made to achieve a massive pratical way for construction of any C-C bonds.

40

ConclusionConclusion

LnRhAr

CO2Me

MeO2CR

R

Ar

R R 2-substituted ester(enolate alkylation product)

Summary for intermolecular C-H insertions with aryldiazoactates (by Davies):

MeO2CR

OSiR'3R OSiR'3

Ar

protected -hydroxy ester(aldol reaction product)

H R

OO

MeO2CR

Ar

OO protected -keto ester(Claisen condensation product)

R2N R MeO2CR

NR2

Ar

protected -amino ester(Mannich reaction product)

R MeO2CR'

Ar

,-unsaturated carbonyl(Claisen condensation product)

OSiR''3 MeO2CR'

Ar

protected 1,5-dicarbonyl(Michael addition product)

R'

R

R' R

OSiR''3

R

c-h insertion of rhodium-carbene using diazo compounds

Documents

ch insertion of rhodium

intramolecular ch insertion

h insertionnakamura

general mechanism of

diazo compounds wileyvch

organic synthesis drwald

diazo compoundspresented

modern catalytic methods