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
Carboxylates in Intramolecular C-H InsertionCarboxylates in Intramolecular C-H Insertion
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
Carboxylates in Intramolecular C-H InsertionCarboxylates in Intramolecular C-H Insertion
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
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.
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
Understanding the Utility of Carboxamidate as LigandsUnderstanding the Utility of Carboxamidate as Ligands
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
Aryldiazoacetate in Intermolecular C-H Insertion ReactionsAryldiazoacetate in Intermolecular C-H Insertion Reactions
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
Aryldiazoacetate in Intermolecular C-H Insertion ReactionsAryldiazoacetate in Intermolecular C-H Insertion Reactions
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
Aryldiazoacetate in Intermolecular C-H Insertion ReactionsAryldiazoacetate in Intermolecular C-H Insertion Reactions
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
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.
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
Intermolecular C-H Insertion – Cope RearrangementIntermolecular C-H Insertion – Cope Rearrangement
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