2011/04/06 (Wed)Noriaki Takasu (D2)

Literature Seminar (D2 Part)

Diazo-mediated Metal Carbenoid Chemistry~Recent Developments of Variety Bond Formation Methods~

Cyclopropanation
C-H Insertion

R1[ 4+3] Cyclization

R2
N2

R1
LnM

LnM

R2

[ 3+2] Cyclization

Metal
Carbenoid

Y lide Formation

Coupling
N-H, O-H Insertion

Recently, many metal catalyzed C-H activation reactions have been reported, but many reactions have not
become reaction using wide range (selectivity, functional group tolerance). The metal-carbenoid intermediates
are capable of undergoing a range of unconventional reactions, and due to their high energy, they are ideal for
initiating cascade sequences leading to the rapid generation of structural complexity. These species are using
for many type C-H activated reactions, C-C or C-heteroatom bond formations, and skeletal constructions.
In this seminar, I talk about many type metal-carbenoid reactions from various metal.

Contents
1. Carbenoid (P.1-2)
2. Rhodium Carbenoid Induced Reaction (P.3-10)
3. Copper Carbenoid Induced Reaction (P.11-12)
4. Palladium Carbenoid Induced Reaction (P.13-14)
5. Other Metal Carbenoid Induced Reaction (P.15-16)
6. Summary & Perspective (P.17)

1. Carbenoid
1-1. Carbene
Carbene is a molecule containing a neutral carbon with a 2 valencesand 2 unshared electrons.
Carbenes are classified as either singlets or triprets depending upon theirCelectronic structure.
R'
Most carbenes are very short lived, although persistent carbenes are
known (example of stable carbene: N-Heterocyclic carbene; NHC).
pp
R
R
Singlet
Triplet

R N

R

R'

N R

NHC
ref.) Nojiri's Lit(M1 Part)R'• unshared electron pair ( orbital) and empty p orbital• resembles carbocation and carboanion united on samecarbon, so have nucleophilicity and electrophilicity(reactivity depends on substituted groups).
• many R and R' groups can stabilize singlet carbene(more than triplet carbene).
• Typical angle (calculated) : 100~110°• 2 electron was shared with p orbital and• resembles biradical• Typical angle (calculated) : 130~150°

orbital

One of the typical carbene formation : diazo decompositionNNor h or Metal

CO2R

- N2

H

CO2R
H

C-H Insertion
1,2-migration of alkyl
Cyclopropanylationand other reaction...

Diazo compounds readily decompose thermally or photochemicallydriving force : formation of N2 bond and generation of N2 gas
Generated carbene is high reactivity.
In the case of using transition metal to generated carbene
Metal-Carbenoid species is generated

1-2. Metal-Carbenoid
Carbenoid is a vague term used for a molecule in which all carbons are tetravalent but still has properties resembling
those of a carbene, typically the carbene-like carbon has multiple bonds with a metal. Carbene is stabilized by
Metal.
Carbenoid has unique reactivity that carbene has not, keeping the reactivity of free carbene.
Carbenoid is structurally related to singlet carbenes and posses similarly reactivity.

R
MLn
R'

Carbenoids can be formed by reacting salts of transition metals.
e.g. Cu, Rh, Pd, etc... many metals can be formed.
These are formed by metal with carbenoid precursor, typically diazo compound.

Kind of Diazo Compound (Carbenoid Precursor)
Carbenoid can be controled carbene reactivity through substituent (acceptors and donors).
Not enough electrophilicity causes less reactivity, and too much electrophilicity causes side-reaction,
so control of electrophilicity is important.
Metal-carbenoid reaction requires appropriate level of electrophilic ability at the carbenoid carbon center.
AcceptorO
HX
N2
X = R, OR, NR2

Acceptor/Acceptor
O
O
X

Y
N2
X, Y = R, OR, NR2

Acceptor/DonorOYXN2
X = R, OR, NR2
Y = vinyl, Aryl

• Acceptor/Acceptor and Acceptor/Donor types stabilize
diazo compound (so more active catalyst needed fordecomposition).
• Donor substituent stabilized carbenoid through resonance.
• Almost metal-carbenoids have electrophilicity.
• Carbenoids formed from Acceptor/Acceptor compounds
has high electrophilicity.

too much electrophilicity causes side-reaction, so control of electrophilicity is important.

Electron Feature of This Type Metal-CarbenoidR

M

Clone pair on carbon to M : strong C-M bondd electrons to p orbital on carbon : weak~moderate bond, stabilize carbene a littleR'
but still maintain its enough electrophilicity

desired metal : bind to the carbene through strong -acceptor interactions and weak (appropriate) back donationinteraction.
1/17

Observation of Carbenoid
Cu-Carbenoid

P. Hofmann et al., ACIE, 2001, 40, 1288.

TMS
N
Bu
P
Cu
t
Bu
N
TMS

TMS
CO2Me
N
Bu
+ N2
P
Cu
t
Bu
N
Ph
Ph
TMS
Cu-Carbenoid
In toliene-d8 or benzene-d6 at rt, 15-25% Cu-complex was detected.
Caractarization from 1H NMR (Figure 2), 13C NMR (229.9 ppm(C=N2), 177.9 ppm (C=O), MS (FAB; 531.2, [M +]).
(At -33 C, this comoplex was maintained for several hours without
significant evolution of nitrogen.)
CO2Me

t

Rh2-Carbenoid

2

t

5

atropisomerof 5

J. P. Snyder et al., JACS, 2001, 123, 11318.
t

O
N
Rh2(OCOtBu)4 +Otoluene
rt

N

Rh

Bu
t Bu

O O
Rh

O

O
t
MeN
Bu O
O

Me
N

X-ray structuret Bu

1-3. Early Example of Metal-Carbenoid Reaction
Insertion

P. Yate, JACS, 1952, 74, 5376.
:NuH
O
O
Cu
- N2
H
H
Nu = RO, RS, R2N R
R(complex with Cu)
Nu

O
N2

R

Cyclopropanyration
Cl

Metal

Cl

A. F. Noels et al., Tetrahedron, 1983, 39, 2169.

Cl
Cl

N2HC CO2R
CO2R

Metal;
Rh2(OAc)4 : 54%
Cu(OTf)2 : 42%
Pd(OAc)2 : 12%

In this paper, other example,
reactivity is [Rh] > [Cu] > [Pd]Dimerization (Homometathesis)
O
O
Cu
O
O

Ph
N2

+
Ph

toluene

Ph

Ph

Ph

Ph

86%
R. Noyori et al., TL, 1966, 1, 59.
general metal of metal-carbenoid reaction : Rh, Cu, Pd ; most useful metal is Rhodium.

Dirhodium carboxylate (Rh2L4) H. Reimlinger et al., TL, 1973, 24, 2233.
First example of Rhodium carbenoid generation from diazo decomposition.
R OH + N2

CO2Et

catalyst
25 C

RO

CO2Et

Reactivity using Rh2(OAc)4 (Rh(II)) was higher than Rh(I), Rh(III).

Catalyst diazo/Catalyst R
Rh2(OAc)4600
Eti
Rh2(OAc)4600
Prt
Rh2(OAc)4
600
Bu
Rh2(OAc)4600
H
Rh2(OAc)4600
Ac
RhCl3•3H2O
125
Et
t
RhCl3•3H2O
Bu
125
RhCl(PPh3)3
Et
125

Yield
88
83
82
80
93
64
58
49

2/17

2. Rhodium Carbenoid Induced Reaction
2-1. C-H Insertionref.) Yamaguchi's Lit (M1 Part)

Trend in Selectivity
In simple case, Reactivity is determined with both electric effect and steric effect.
D. F. Taver et al., JACS, 1986, 108, 7686.
O

O

R1

CO2Et Rh2(OAc)4
2

R

O
CO2Et

R3

N2

1

R
R2

R3

CO2Et

R1
R2

R3

23 : 1
R1= Me, R2= Me, R3= Me (3 vs 2 )1
2
3 t
R = Me, R = H, R = Bu (2 vs 2 bulky) 34 : 1
steric effecttertially > secondary > primary (electric effect; electron density in the C-H bond)
G. Stork et al., TL, 1988, 29, 2283.
COCHN2OO

Rh2(OAc)4
CO2Et

CH2Cl2 (0.01 M)
rt

COCHN2Rh2(OAc)4
CO2Me

CO2Et
81%

CH2Cl2 (0.01 M)
rt

CO2Me
0%
dimer : 33%

O
COCHN2O

Rh2(OAc)4
CO2Me

CH2Cl2 (0.01 M)
rt

COCHN264%

CO2Me

Rh2(OAc)4

CO2Me

CH2Cl2 (0.01 M)
rt

CO2Me
0%
dimer : 31%• electron-withdrawing groups inhibit adjacent C-H bondMechanism
M. P. Doyle et al., JACS, 1993, 115, 958.

D. F. Taber et al., JACS, 1996, 118, 547.

C-Rh-Rh is 180
from calculation.

They didn't perfom DFT calculation, but they expected fromalinedligand (L) effect of C-H insertion.
This mechanism was expected from experiments results,
low EWG : general selectivity
and ZINDO calculation was performed to ylide intermediate.
high EWG : selectivity is decreased (attack low steric barrier)
These mechanisms were plausible and widely accepted, but additional analysis of mechanism was performed for further
development of the C-H activation chemistry.

Proposed mechanism from DFT calculation E. Nakamura et al., JACS, 2002, 124, 7181.
DFT using B3LYP on Rh2(O2CR)4 C-H activation/C-C bond formation reaction.
calclated for [Rh2(O2CH)4 - CH2N2 - metane or propane]and [Rh2(O2CH)4 - N2CHCO2Et - metane or propane]-Donation

Rh2

Rh1

Rh Carbenoid
Formation• carboxylate groups serves as anchors of the Rh2 atom
• electron-withdrawing group (E) enhances the electrophilicityof the carbene carbon center• Rh1 has positive charge which increases the electrophilicity
of carbon center• electron donation from Rh2 to Rh1 assist the C-C bondformation and catalyst regeneration.
• If chiral ligand was used, it also serves as the site to harness
chirarity.

C-H
Activation

Activated energy is decreased, so C-H Insertion is enhanced.
C-H
Insertion
Dissociationof
Rh-Catalyst
C-C Bond
Formationcompared to Cu-carbenoid and Ru-carbenoid, energy of C-H
insertion to carbenoid is lower (diazomethane-methane).
H
NH
Cl
N Ru
Cl
NH
H

O
Cu
O

H
H

27.6 kcal/mol>

HH

15.6 kcal/mol(HCO2)4Rh2>

CH2

5.7 kcal/mol 3/17

Review; H. M. L. Davies et al., Chem. Rev., 2003, 103, 2861.
H. M. L. Davies, ACIE, 2006, 45, 6422.
H. M. L. Davies et al., Nature, 2008, 451, 417.
H. M. L. Davies et al., Chem. Soc. Rev., 2009, 38, 3061.

Stereo-/Chemo-Selective Reaction
Intramolecular reaction
M. P. Doyle et al., JACS, 1996, 118, 8837.

M. P. Doyle et al., JOC, 2005, 70, 5291.

1.0 mol%

I

II

10
53
62
87

7
19
23
trace

Rh2(5S-MEPY)4

Rh2(4S-MEOX)4Rh2(OAc)4
Rh2(4S-MPPIM)4
Rh2(5S-MEPY)4
Rh2(4S-MEOX)4

Rh2(4S-MPPIM)4

In this type reaction, it was thought that Rh-carbenoid reacts
with equatrial C-H, because access to axial C-H is prevented
by crowding of the cyclohexane ring.
Proposed mechanism;stericallyhinderedRh2(4S-MPPIM)41

additional chiral attachment, so ee was increased.
• 12, 16 : direction of additional chiral attachment is mismatched.
• diastereoselectivity;

react withMe of i Pr

H
MeH
L*4Rh2H
O
O

conformation should be locked as all the substituents areplaced at equatrial position• Equilibrium depends on the ligand (catalyst)(whether the substituent is at axial or equatrial).
• Small ligand leads to low diastereoselectivity.
(L=OAc, 40:60 ; JACS, 1994, 116, 4507.)• Rh-carbenoid reacts with equatrial C-H, so inappropriate ligand, reaction is cis selectivity.

insertion toequatrial C-H• Model for aymmetric induction with Doyle's catalysts;

O
Rh

N
Rh

H
CO2Me

ester

Rh2(5S-MEPY)4O

Doyle's catalyst

N2

O

(4R)

R

In the cases of other type ligands, they are expected by similarly catalysit model.

4/17

S. Hashimoto et al., Synlett, 1994, 12, 1031.
H. M. L. Davies et al., Chem. Rev., 2003, 103, 2861.

• lactam formation

Ar=tBuC6H4 Rh2(S-TBSP)4• In the case of R2 is alkyl group, -lactam is obtained, but in R2 is Aryl groups, -lactam is obtained.
Electron density of nitrogen atom is important.
When N has electron-enough, C-H insertion at adjacent to N is enhanced (in insertion mechanism, C-H insertion
process is activated by push of unshared-electron pair).
When N has electron-withdraing group (Ar, carbonyl), -lactam cyclization is inactivated, and -lactam is obtained.
• This is acceptor/acceptor type, reactivity is so high. So enantioselectiviry is low, but R1 = Ar, selectivity is increased.
Benzyl position is slightly lower reactivity than saturated aliphatic C-H because of electron-withdrawing nature of
Ph group, so reactivity is controlled, and enantioselectivity is increased.
• Model for aymmetric induction in -lactam formation with Hashimoto's catalyst.
phthalimide
O
H

N
O Bn

O

Rh

4O

Rh

Rh2(S-PTPA)4

Hashimoto's catalyst

Intermolecular reaction• Simple reaction system and chemoselectivity
O

H. M. L. Davies et al., JACS, 2000, 122, 3063.
H. M. L. Davies et al., JACS, 1999, 121, 6509.
H. M. L. Davies et al., JACS, 1997, 119, 9075.

Rh

N
O
Rh
SO2Ar
4
Ar = p-C12H25C6H4
Rh2(S-DOSP)4

Mannich type products.
Newmann model of intermolecularreaciton (Rh2(S-DOSP)4).

a 3 mol% of catalyst was used.

H. M. L. Davies et al., JOC, 2009, 74, 6555.

At 80 C, 85%, 67%ee.

• enantioselective reaction• electron-donating groups on Ar decrease reactivity,
probably because of the lower electrophilicity.
• adjacent to heteroatom, reactivity is increased.

diastereoselectivity is depended on size of substituents.
5/17

Relative rates of reaction various substrates.

H
0.66

1

0.078

OL, 2001, 3, 3587.

JACS, 2001, 123, 2070.

Boc
N
2700

O
1700

Ph
24000

28000

cyclopropane

reaction rate is so defferent with respect tosubstrates (functional groups), so selective
reaction is possible.
C-H activationat
adjacent to N

C-H activationat
adjacent to O

Intermolecular metal-carbenoid C-H insertion
can replace with classical C-C bond formation,
in high stereoselectivity.

JOC, 2005, 70, 10737.
C-H activation as a surrogate of classic reactions of organic synthesis.

C-H Insertion/Cope Rearrangement
previous work

H. M. L. Davies et al., JACS, 2004, 126, 10862.
Ph

R

R
+

N2

Ar

6

Rh2(S-DOSP)4

CO2Et

normal C-C bond formation

Ar
H

CO2Me
morerate yieldhigh eemoderate dr

H. M. L. Davies et al., OL, 2001, 3, 3587.
Ph

Et

+ N2

R
7

X

CO2Et

Rh2(S-DOSP)4(0.5 mol%)
2,2-dimethylbutane
0C

Ph
R1
X

1

H

CO2Me

R = H, X = CH2 : 95%, >98%de, 99.5%ee
R = 6-OMe, X = CH2 : 77%, >98%de, 99.3%ee
R = 7-OMe, X = CH2 : 90%, >98%de, 98.9%ee
R = H, X = O : 75%, >98%de, 95.1%eehigh ee and deother mechanism??

• first step: C-C bond formation of benzyl position (olefin side) (3)high stereoselective reaction by Rh2(S-DOSP)4
C-H activation/Cope rearrangement• second step: cope rearrangement

Proposed mechanism

consecutive 2 steps reaction, apparent direct C-H activation• using diazo 4, second retro cope rearrangement is unfavored,sohigh temperature is required.
Et
Ph, because of cunjugated with Ph after rearrantement,so retro cope rearrangement undergo low temperature.
• Aromatization• surrogate of Michael addtion
OTBS
OTBS
Rh2(S-DOSP)4
1.1 eq 1
DMB, 0 C

H

O
Ph

Ph

CO2Me

H
CO2Me
78%, >98%de, 95.2%ee

6/17

2-2. Cyclopropanation
diastereoselective cyclopropanation
Ph
+

Ph

CO2Me

Rh2(OAc)4(1 mol%)N294%, E/Z = >20:1

R

CO2Me

Ph

H. M. L. Davies et al., TL, 1989, 30, 5057.
enantio/diastereoselective cyclopropanation
Ph
Rh2(S-DOSP)4(1 mol%)+R

N2penetane, -78 C

CO2Me
R

CO2Me

Ph

R

% ee

yield (%)

C6H5
p-ClC6H4
p-MeOC6H4
EtO

98
97
90
93

68
70
41
65

model of diastereoselectivity• R1 is saturated alkyl group (not shown, TL paper) :diastereoselectivity is decreased.
intermediate is not stabilized??
(but when bulky ligand is used, it is improved (JACS paper).)• R2 is donor group (Ar, allyl)
diastereoselectivity is increase.
(R2 = acceptor(e.g. ester) : selectivity is decreased,
acceptor/acceptor type carbenoid is too much reactivity)• using chiral Rh catalyst, high ee was obtained.

H. M. L. Davies et al., JACS, 1996, 118, 6897.

Enantioselective Cyclopropanation of Allenes
CO2Me

H. M. T. M. Gregg et al., OL, 2009, 11, 4434.
CO2Me

Rh2(S-DOSP)4+ N2

Rh2(S-DOSP)4

+ N2
Br

Br

2

2

positive charge• In toluene solvent, trace procuct is obtained. Maybe cyclopropanation of aromatic rings and methyl C-H insertion is proceeded, so it is suggested that cyclopropanation of allene is slowly.
• Reaction is proceeded at only indicated no substituted olefin.
• Aryl allene and aliphatic allene are succeeded moderate~good yield and ee.
• Disubstituted allenes are decreased reactivity because of sterically barrier (see TS).
• In TS, there is positive carbon on the central carbon of the allene, so stabilized substituents givehigh reactivity (e.g. silyl).
TS from DFT calc.

Buchner ring expansion
R

A. R. Maguire et al., Chem. Comm., 1996, 2595.
R

R

O
Rh2(OAc)4Ph

CH2Cl2, heat

N2

O
O

in NMR, rapidly equilibrating mixture
major (>97%) : trans
R = H, Et, Pr, Pr, Bu, Bu, allyl
intallyl : 49% (byproduct : cyclopropanation of allyl olefin,
other alkyl substrate : 59-79%• Benzen ring is reacted with metal-carbenoid species.
• In this case, R groups stericallyblock, diastereoselectivity isappearred.
steric effect of cyclization

7/17

H. M. L. Davies et al., JACS, 2010, 132, 17211.

Enantioselective Cyclopropenation of Alkyne
H. M. L. Davies et al., OL, 2004, 6, 1233.
R
Rh2(S-DOSP)4(1 mol%)

N2
Ar

CO2Me

hexane, rtAllyldiazoester

CO2Me
R

Ar

R = alkyl, aryl, allyl : 48-74%, 84-92%ee
Ar = EWG, heteroaromatic : moderate yield and high ee
EDG : low yield and moderate ee
lower reacivity of p-methoxyphenyl carbenoid.
allylic : not obtained (can't isolate)unstable
Predictive model with Rh2(S-DOSP)4
from result and DFT calculation
unstable, tentatively assigned on the basis of NOE

Formation of furan• At low temperature, cyclopropen is generally obtained in highenantioselectivity.
• When Ar has EDG, cyclopentadiene is generated.
• At reflux, cyclopropene is not observed, cyclopentadiene is obtained.
• Disubstituted alkynes are no reaction sterically barrier (in TS)

Mechanistic hypothesis of cyclopentadiene[4+3] Cyclization : Tandem Cyclopropanatin/Cope Rearrangement (for diene)
With heteroaromaticWith simple diene

H. M. L. Davies et al., JACS, 2007, 129, 10312.

H. M. L. Davies et al., JACS, 2009, 131, 8329.

tolueneProposed mechanism of stereoselective [4+3]cyclopropanation[3.3]
pyrrole + N2
substrate

CO2Me
OTBS

Rh2(S-PTAD)4(1 mol%)product;
Boc
N

CO2Me

Boc
N

CO2Me

1)
O

OTBS
(3.0 eq)

TBSO

OMe
N2

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

Ph
N

CO2Me
OTBS

64%, 97%ee

Boc
N
CO2Me
OTBS MeO2C

OTBS
69%, 96%ee

bicycloproduct

DMB, 50 C

72%, 98%ee
p-tol
N

OTBS
68%, 94%ee

OTBS

71%, 89%ee
Boc
N

CO2Me

CO2Me

CO2Me
OTBS

76%, 91%eetoluene, -10 C
2) reflux, 4 h67%, 90%eeless substituted olefin is preferentially proceeded first cyclopropanation

8/17

2-4. Other C-C Bond Formaiton

2-methylindole[3+2] Annulation of Indole

H. M. L. Davies et al., JACS, 2010, 132, 440.
2- substituted or
3-substituted indole

exo
endo
In simple N-methylindole, 2 isomers are obtained.
initial reaction at C2 or C3 position of indole??
reactivity of substituted indols• 2-methylindole : endo compound is obtained.
• 3-methylindole : exo compound is obtained.
• Reactivity is stability of 2 or 3-position? So author's said, this reaction is
step-by-step reaction, stable 3 carbocation is generated in transition state,maybe not concerted reaction.

Proposed mechanism;3-methylindole

Ylide Formation

H. M. L. Davies et al., JACS, 2009, 131, 1101.
Carbenoid can generate ylide with appropriate carbonyls or imines.
R3

epoxide

H
R3

R1

R4

H
O

R1

CO2R2

H
N

H

R5

O CO2R2
N2
O-YlideM. P. Doyle et al., OL, 2001, 3, 933.

3

R

R1
N CHO2R4
R5
N-Ylideaziridine

reaction rate of intermolecular reaction;
epoxidation of benzaldehyde >cyclopropanation of styrene

Three-Component Cycloaddition

proposed model of reaction.

• Rh2Piv4 is most suitable.
• Rh2(OAc)4, yield is decreased.
• regioselective reaction• endo selective reaction

9/17

2-5. Heteroatom-H InsertionN-H Insertion

Si-H Insertion

F. A. Davis et al., OL, 2004, 6, 4523.

H. M. L. Davies et al., TL, 1998, 38, 1741.
Me2PhSiH
Rh2(S-DOSP)4R
N2

CO2Me pentane, -78 C

Me2PhSi

Me2PhSi

CO2Me

O
P(OMe)2O

Rh2(OAc)2(4 mol%)P(OMe)2
CH2Cl2, 35 C R
N
Boc O
N2
R = Ph : 68% (cis/trans = 81:19)
CH=CH2 : 65% (cis/trans = 92:8)
Me : 88% (cis/trans = 96:4)
nBu : 79% (cis/trans = 95:5)
t
Bu : 84% (cis/trans = 99:1)

Ph
Me2PhSi

CO2Me
64%, 95%ee

50%, 85%ee

NH O

R

CO2Me
Me

Ph
Me2PhSi

Boc

R

CO2Me
76%, 91%ee

Ph
Me2PhSi

Me2PhSi
CO2Me
68%, 77%ee

CO2Me

O-H Insertion

Me2PhSi

63%, 85%ee

CO2Me
77%, 92%ee

Y. Landais et al., JOC, 1997, 62, 1630.
R2

N2

R1

Rh2(OAc)4
CO2R3

OR
CO2Et

ROH

R = H, Me, Et, Ph; R1 = Ar, vinyl, alkyl; R2 = H, Me;
R3 = Me or Et.
40-77%.

2-6. Total Synthesis using Rhodium Carbenoid
T. Fukuyama et al., JACS, 2008, 130, 16854.

(0.3 mol%)

Combined chiral auxiliary andchiral ligand (S-DOSP) provided
an excellent result.

stereoselective intramolecular C-H insertion.
T. Fukuyama et al., OL, 2011, 13, 1089.

R*O2C

R

Rh2(R-DOSP)4(0.2 mol%) ,N2

CH2Cl2
R = H, 88%, >95%de
OMe, 63% >95%de

R
R

R*O2C

CO2H
CO2H
N
H
R = H : Phenylkainic Acid
R = OMe : Methoxyphenylkainic Acid

R* = PhN

HO

O

stereoselective intermolecular C-H insertion.
R. Sarpong et al., ACIS, 2009, 48, 2398.
When racemic SM was employed,
41 and 44 (diastereomer) was
mainlyobtained (depend of chiral ligand).
Although they have inverse absoluteconfiguration at reactive site, using
Rh2(R-DOSP)4, [4+3] cyclization
wasproceeded in 'same' stereochemistry
so diastereomers are obtained.
'pallarel kinetic resolution'
diastereoselective intermolecular [4+3] to diterpenes.

10/17

3. Copper Carbenoid Induced Reaction
Copper carbenoid is shown the similar reaction for Rhodium carbeoid reaction.
But to manipulate reagents and condtions, higher reactivity and selectivity can be afforded.
Copper carbenoid can be proceeded main metal-carbenoid reaction, C-H insertion and cyclopropanation, and total
synthesis was performed by copper carbenoid induced reaction.
ex) Y. Qin et al., JACS, 2007, 129, 13794.
O

Br

O

Br

O

O

CuOTf
N2

88%
N3

N
Me

PBu3
THF aq.
83%

Br

N N3
Me

O

N
Me

1.6:1.0 drONH( )-communesin F

Reactivity of many C-H insertion or cyclopropanation using Copper carbenoid is lower or same for Rhodium carbenoid.
But heteroatom(N, O, Si, S)-H insertion reaction is significantly improvement of ee compared for Rhodium carbenoid.

N-H Insertion

Q.-L. Zhou et al., JACS, 2007, 129, 5834.
-amino acid derivative (N-Ar) synthesis.
Ph
Ph(Sa,S,S)-1a

F3C

CF3

F3C

CF3
B

F3C

CF3
F3C

CF3
BASF-

• Counter anion effect is so high, the smaller and slightly coordinating OTf is inferior to the PF6 in the enantiocontrol.
• with the larger and non-coordination ion BARF-, reactivity and enantioselectivity is significantly increased.
• steric-hindrance diazoacetate (Entry 17), secondary amine (Entry 18), amide (Entry 19)
enantioselectivity is so low.

O-H Insertion
OH
N2
CO2R

Q.-L. Zhou et al., JACS, 2010, 132, 16374.

5 mol% CuOTf•1/2toluene
6 mol % (Sa,S,S)-1b
6 mol% NaBASF
CH2Cl2, 25 C

OH
*

CO2R

(Sa,S,S)-1b : R = t Bu
(Sa,S,S)-1b : R = i Pr

high yield and high selective
reaction for pyran rings andfuran rings.
In seven-menbered ring,
reactivity is so decreased, butusing ligand 1c, good yield andselectivity is obtained.

11/17

○Calculated Study for O-H Insertion into Water, Cu vs. Rh
Z.-X. Yu et al., JACS, 2009, 131, 17783.
Ph

CO2Me
N2

Cu(I)

+

H

O

MLn*
H

Ph

CO2Me

HO H

Rh(II)• TS-O : 2 H2O and metal-coordinated TS before product
TS-F : only 2 H2O cordinated TS before product• In DFT calculation;
Cu : TS-3-O is more favor than TS-3-F (Figure 1)
Rh : TS-7-O is more unfavor than TS-7-F (Figure 2)• Scheme 4 , FY : metal is not coordinated at protonation step
MY : metal is coordinated at protonation stepG(FY-MY) ( G'solTS-(FY-MY))> 0
Ligand affects protonation step determining ee.
in Rh2L4, G(FY-MY)< 0, so ligand effect is decreased.
in CuLn, G(FY-MY)> 0, so ligand effect is significantly
obtained.
in O-H insertion Cu prefers to Rh.

S-H Insertion

Q.-L. Zhou et al., Chem. Comm., 2009, 5362.
Ph
Ph(Sa,S,S)-4amoderate~good yield was obtained,
but enantioselectivity was moderate.

other heteroatom-H insertion;
Si-H : high yield and high enantioselectivity for the similar ligand ;Q.-L. Zhou et al., ACIE, 2008, 47, 8496.
12/17

4. Palladium Carbenoid Induced Reaction

Review : Y. Zhang et al., EurJOC, 2011, 1015.

Palladium carbenoid shows different behavior for other metal carbenoid.
L. Wang et al., TL, 2008, 6781.

Early report

D. F. Taber et al., JOC, 1986, 51, 3382.
OO

Pd(PhCN)2Cl2(1.5 mol%)

CO2Me
N2

O
CO2Me

CO2Me +

PhCN, reflux, 5 h

14%

34%
O

O
CO2Me

CO2Me
PdLn

PdLn

palladocyclobutane ??

Authors believed to proceed through a palladocyclobutane
whitch partitions to the enone or the cyclopropane.

in reactive olefin, even Rh2(OAc)4 was not reacted.
Mechanism is different from other metal carbenoid.
In after report, enantioselective reaction was failed.
S. E. Denmark et al., JOC, 1997, 62, 3375.

Pd-Carbenoid can perform other type reaction ??

Insertion of Palladium Carbenoid
Pd2dba3CHCl3(2.5 mol%)
AsPh3
SiMe3
(15 mol%)

Br+

D. L. V. Vranken et al., TL, 1999, 40, 1617.
D. L. V. Vranken et al., Tetrahedron, 2001, 57, 5219.

N2

Oxidative addition
Migratory insertion-Hydride elimination
Insertion to olefin
Elimination of TMS and regeneration of Pd(0)DIPEA, DCE
refluxMeO

MeO

Proposed mechanism;
Pd(0) reacts with diazo compounds to rapidly form a
Pd-carbenoid, and Pd(II) can be formed in situ from
Pd(0).

Nucleophilic Addition

Cross-Coupling with Diazoacetate

D. L. V. Vranken et al., OL, 2007, 9, 2047. X = TMSCH2N2
D. L. V. Vranken et al., ACIE, 2009, 48, 3677. X = CO2Et

J. Wang et al., JACS, 2007, 129, 8708.

HNR2 +

R1

X

IH+

R2
R3

N

Pd2dba3CHCl3(2.5 mol%)
PPh3(15 mol%)
THF, heat

N2

TMS

80%

Bn
91%

O

94%

TMS

Bn

N Me
55%

TMS

O

N
Bn

R3

N

TMS Bn

27%

X

R2 N

O
N

Bn

R1 R2

N
CO2Et

Bn
55%

N
CO2EtNC

91%

CO2Et

Proposed mechanism
attack from low stericbarrier position.
In X=CO2Et,
product is stableconjugated ester.

This substituent ishydrogen, thisreaction is occurred.
In other groups,
coupling ofcarbenoid with Aryl
halide.
(I show next.)
maybe this routeis plausible.

Tsuji-Trost

Migratry
insertion

13/17

Cross Coupling with Aryl GroupJ. Wang et al., JACS, 2008, 130, 1566. PhB(OH)2

J. Wang et al., JACS, 2010, 49, 1139.

Using CuCl (10 mol%) & O2, reaction was proceeded.
(From tosylhydrazone; shown below.)
J. Wang et al., Chem. Comm., 2010, 46, 1724.

CO Insertion

Et3SiH is hydrogen source, halogen-hydrogen exchange
process promotes reaction.

Coupling of tosylhydrazone
NNTs
R3

R1

+

Ar X
(X = Cl, Br)

Pd2dba (1 mol%)
Xphos (2 mol%)
LiOt Bu (2.2 eq)

ArR

dioxane

R2

R2
OMe

Ph

p-tol

R3

1

CN

Ph
70 C, 4 h98%Ph
90 C, 4 h
98%

S

p-tol
90 C, 16 h99%
(Pd:2 mol%, L:4 mol%)

90 C, 10 h
68%

t

N
90 C, 17 h
50%Bu
100 C, 16 h90%

in situ, diazo intermediate is generated from tosylhydrazone with base,and next carbenoid generation, migratory-elimination.

14/17

5. Recent Other Metal Carbenoid Induced Reaction
Iridium Carbenoid
Recently, Iridium-salen complexes are employed for metal-carbenoid
reactions, by Katsuki's group.

Cyclopropanation ; ACIE, 2007, 46, 3889.
JACS, 2008, 130, 10327.
ACIE, 2009, 48, 3121.
C-H Insertion ; JACS, 2009, 131, 14218.
Si-H Insertion ; JACS, 2010, 132, 4510.
Cyclopropenation ; JACS, 2011, 133, 170.

ACIE, 2007, 46, 3889 ; Cyclopropanation

Ph Ph

L = p-MeC6H4• at -78 C, in THF, high yields and high stereoselectivity.
• cis selective reaction.

JACS, 2010, 132, 4510 ; Si-H Insertion• in aryldiazozcetate, nomal salen complex (R=C6H5) gives
high yiled and enantioselectivity• in alkyldiazozcetate, salen complex 4 (R=p-TBDPSC6H4)
gives high yiled and enantioselectivity.
(the complexes having a higher molecular recognition
ability would serve as an efficient catalyst for thisreaction.)

15/17

Cobalt Carbenoid

There are a few examples.
X. P. Zhang et al., ACIE, 2008, 47, 8460.
CO2Et
R'

+ N2
NO2
(1.2 eq)[Co(P1)] (1 mol%)hexane, rt, 24 h
N2

R

CO2R
NO2

• [h] 5 mol% catalyst.
• enantioselective cyclopropanationof acceptor/acceptor type
(Hydrogen bond of N-H of amide vsNO2 and ester of diazosubstrate,
reactive face is determined.)

Iron Carbenoid

Ruthenium Carbenoid

Iron is so cheap metal, but reaction example is not enough...

Y. Tang et al., JACS, 2010, 12, 604.

Y. Tang et al., JACS, 2009, 131, 4192.

sterically barrieris criticallyaffected.
Entry 10, 13, 14.

Cl

N Cl N
Fe
N
N

Cl

Cl

tandem carbenoid reaction/ Wittig.
good E/Z selectivity for Wittig
reaction.
Cyclopropanation

Fe(TCP)Cl
Cl

CO2Me
Bu3P

+

CO2Me
CO2Me

(PCT)Fe
CO2Me
Aldehyde
R

PPh3

Ph3P

CO2Me
CO2Me

CO2Me
CO2Me

Other example of iron carbenoid, asymmmeric cyclopropanation
using porphyrin complex, moderate yield (up to 67%), good
diastereoselectivity (up to 96:4) and moderate enantioselectivity(up to 80%ee), further improvements are required...
G. Simonneaux et al., TL, 2009, 50, 5149.

Ruthenium is the similar reactivity for Rhodium, many high efficient
examples of Ruthenium are reported, but enantioselective reaction
is a few report. (See Review ; Enantioselective Rutheniumporphyrin-carbenoid ; C.-M. Che et al., Synlett, 2010, 2681.)

16/17

6. Sammury & Perspective
Metal-carbenoid-mediated-reactions are so useful reactions for several type bond formation and skeletal construction.
C-H Insertion, cyclopropanation, ylide formation, and others....
These reaction was used for several total syntheses.
N2
R1

MLn

MLn
R2

R1

Various Bond Formations

f urther transf ormations

Natural Products

stereoselective

R2

Futher Improvement• Main metal of carbenoid reaction is Rhodium, that is so expensive.
We would like to use other cheap and available metal ; Cu, Fe, Co, Ni, Mn, ....
Recently, several cheap metals is used for metal-carbenoid reaction (further improvements were required).

• Usually, many type diazo compounds are thermally and photochemically unstable, and diazo precursor is unstable,
explosive, and toxic.
ex) Most available diazo preparation method ; Regitz diazo transfer
O

O

R1

O
R2

H

R1
:Base

O

N
R2

N

O O
S
Ar
N

O

O

1

O
R2

R

H

N
N N

TsN3 or p-ASBA
Ar

O

R1

O
R2

N
N

NHAc

O

R1

R2
N
N

N3
p-ASBA

Carbenoid generation method not using diazo precursor ??
available substrate and useful addtitive, easy conditons...
e.g.)
substrate (dihalogen, monohalogen, active methylene (benzylic, allylic, -position of carbonyl), directing group,
alkene, or alkane), additive (base, oxidant), ligand effect of metal (steric, other several character), and the otheraddtivie and conditions...
If these reactions will be achieved, metal-carbenoid reactions is sure to become more general and conventional reaction.

17/17