Organometallics in Organic Synthesis

1. So who cares (i.e., why?)

-Pattern of reactivity of organic compounds is imposed on

molecule by existing functional groups
OMe
O
δ+ δ−
δ−
δ−
δ+ OMe
δ−
- By default, this limits what you can do with the compound

- Coordination of a metal fragment can change this completely

i.e., can render – an electrophilic species nucleophilic

- a nucleophilic species electrophilic
- can make a normally unstable molecule stable
- can make a stable molecule reactive
- can make impossible reactions possible
1
 The (Very) Basics of Organometallics

-The 18 Electron Rule

Most (middle) transition metal complexes prefer having

18 valence electrons (2s + 6p + 10d)

For transition metal complexes in the 0 oxidation state

4e 5e 6e 7e 8e 9e 10e

Ti V Cr Mn Fe Co Ni

Zr Nb Mo Rc Ru Rh Pd

Hf Ta W Re Os Ir Pt
2
-The 18 e rule is followed most closely in complexes of middle
transition metals (Cr to Co)

-As for early transition metal complexes, it’s usually too difficult
to get enough ligands around the metal to get it to 18 e (i.e., Ti)

Cl
Ti (16 e) (Cp2TiCl2)
Cl

- As for late transition metal complexes (Ni, Pd, Pt), particularly

the square planar MIIL4 complexes
- tend to be very stable as 16 e- complexes

- energy gap to 9th orbital is quite big; molecule is

quite willing not to fill that orbital
3
To count to 18 (or 16), need e-’s from ligands
- I’ll adopt a ‘radical approach’ – not only valid one

A) Inorganic Ligands

1e- -X -H -R

2e- R3P: (RO)3P: R-C≡N: R-N≡C:

R3N: R2S: R2O:

3e- NO (usually) nitrosyl complexes

4
 Organic Ligands - Part 1

η1 ( 1 e - ) -R (alkyls) -Ph (aryls) M (σ -allyls)

C C
η2 ( 2 e-) M (alkenes) M (alkynes)
C C
R
- R N
+ M
η1 (2e-) M C O M C O M C
N
R R
(carbonyl ligands) (carbenes, alkylidenes)

η3 (3e-)
M (π -allyls)

η1 (3e-) M C R (carbynes)
5
 Organic Ligands, Cont'd.

(trimethylenemethanes)
η4 (4e-) M = M (dienes) (TMM)
M

η5 (5e-)
(dienyls) (cyclopentadienyls)
M M

η6 (6e-) (arenes, trienes)

M

η7 (7e-) (trienyls)

M
(cyclotetraenes) - rarely, usually η4
η8 (8e-)
6
 So.....

The number of electrons on the free metal

+ sum of the η number of the hydrocarbon ligands + sum of the electrons donated by other ligands

+ any negative charge on the complex - positive charge on the complex

Should = 18 normally

Many exceptions with early or late transition metals ; works best with middle transition metals

Fe Cr Mo+
OC OC
C C N
O O
O
6 (Cr) + 6 (Ph) + (3x2) = 18 e- 6 (Mo) + 5 (Cp) + 2 + 3 +3 -1 = 18 e-
8 (Fe) + (2x5) = 18e-

Ph3P Cl
Pd 10 (Pd) + (2x2) + (2x1) = 16 e-
8 + 4 (TMM) + (3x2) = 18 e-
Fe
OC Ph3P Cl
C C
O 7
O
 Bonding of Hydrocarbon Ligands

- In its simplist form, bonding of the π- system to a transition metal fragment is based on the

Dewar-Chatt-Duncanson Model

C
Consider - There are two contributions to bonding
M
C

C
1) Ligand to Metal Donation M Note: this is not a π- bond, but
rather a σ- bond
C

2) Metal to Ligand Back Donation

C Note: this is a π- bond

M
C

Dewar, M. J. S. Bull. Chim. Soc. Fr. 1951, C71. Chatt, J.; Duncanson, L. A. J. Chem. Soc. 1953, 2939.

For higher level descriptions:

8
η3, η4, η5 - see Yamamoto, A., p. 58-72 η6 - see Collman, Hegedus, Norton, Finke p. 43-47
 Consequences of Bonding of Hydrocarbon Ligands

1) - In the alkene, the C=C bond is made weaker by complexation

2) - The ligand may be made more or less electron rich by complexation

-depends on case

3) - The organic fragment often loses its only plane of symmetry

-for example

and are the same compound

But.......

These are not the same compound

- the plane of symmetry is destroyed

Fe Fe No non-superimposable mirror images

OC CO Enantiomers
C C C C
O O
O O

mirror image 9
Other examples

+ +
OMe MeO
Ph Ph

Cr Cr Pd Pd
OC CO
C C Ph2P PPh2 Ph2P PPh2
C O O C
O O

Same situation: Each pair is enantiomeric

10
Basic Organometallic Reactions

There are several additional fundamental types of reactions in organometallic chemistry

The more complex reactions are normally some combination of these fundamental ones

1) Lewis Acid Dissociation

- many transition metal compounds, especially hydrides, can lose as Lewis acid
(i.e., deprotonate)

-Co(CO)
H Co(CO)4 H+ + 4

change in number of metal valence e-'s 0

change in formal metal oxidation state -2

change in coordination number at the metal -1

This may be a surprise, but many transition metal hydrides are quite acidic
-notice that making the metal more electron rich decreases acidity

HCo(CO)4 (pKa = 8.3, CH3CN) H2Fe(CO)4 (11.4) HCo(CO)3PPh3 (15.4)

Winkler, J. R. et al (Gray, H. B.) J. Am. Chem Soc. 1986, 108, 2263.

SH OH O
(pKa = 10.3, (24.4) 11
(18.0) H2O (32.0)
CH3S(O)CH3) H3 C CH3
 2) Lewis Base Dissociation

Very, very, very..........common process

18e 16e
Fe(CO)5 Fe(CO)4 + CO
16e 14e
Pd(PPh3)4 Pd(PPh3)3 + PPh3

change in number of metal valence e-'s -2

change in formal metal oxidation state 0

change in coordination number at the metal -1

-Reverse reaction: Lewis base Association

Obvious application are in ligand substitution processes,

which may be dissociative ('SN1 like')

slow
L
Ni(CO)4 Ni(CO)3 + CO LNi(CO)3
fast

v = k [ Ni(CO)4] 1st order

12
Most common for 18 e- systems
 - Alternatively, this can be associative, i.e., "SN2 like"
-more common fo 16 e-, d8 square planar complexes (i.e., NiII, PdII, PtII
RhI, IrI)

Y Lc
Lc X
Pt + Y Pt X
Lt Lc Lc X Lt Pt
Lt Lc Y
Lc
square pyramidal trig. bipy
rate v = 2nd order

Lc Y Lc Y
X + Pt Lt Lc
Lt Lc Pt
square pyramidal trig. bipy
X

13
3) Oxidative Addition

- represented by

n+2
A
LnMn + A-B Ln M
B
change in number of metal valence e-'s +2 (14 - 16 e)

change in formal metal oxidation state -+2 (0 - +2)

change in coordination number at the metal +2

for more details, see: R Yamamoto pp. 222-239

R Collman & Hegedus pp. 279-321

-Overall reaction is cleavage of the A-B bond with bonding to the metal
O
- Most common A-B is R3C-X X = halogen or pseudohalogen O S CF3 triflate
O

-Classic 'organic' example is Grignard reagent formation

II
Br MgBr
+ Mgo 14
 - Most common example in this course will be of the following type:
0 Br
Pd(PPh3)4 Pd(PPh3)2 + II Br
2 PPh3 +
Pd
Ph3P PPh3
- the 2nd step is the oxidative addition

Therefore, system needs: a) 2 available oxidation states i.e., Pdo/PdII , Feo/FeII, IrI/IrIII

b) open coordination site

- Reverse reaction: Reductive Elimination

Mechanism

- Most is known about late transition metals (such as Ir, Ni groups)

A) If the R of R-X is alkyl (especially 1o or 2o), the reaction is believed to (usually) occur
via an SN2 substitution
+
CH3 CH3
Cl .. PPh3 rds fast
PPh3
Ir Cl
Ir Cl PPh3 Ir
Ph3P CH3-I Ph3P CO
CO Ph3P CO
I
- Inversion at alkyl carbon has been observed

- Kinetics are overall 2nd order v = k [IrI] [CH3I]

15
B) Vinyl (and perhaps aryl) halides go via π - complex formation,
with ultimate direct insertion

slow Ph3P PPh3

Pt Ph3P X
"Pt(PPh3)2" fast
X X Pt
PPh3

- Goes with retention of configuration of C=C configuration

- Also believed to be mechanism for addition of H2

B') Aryl halides go via direct insertion into C-X bond (clearly related to B)

i.e., P P
M Could result in retention of
Pd C configuration in some cases
X X

C) - Now defrocked - Nucleophilic Aromatic Substiution - was an old proposal for aryl cases,
to rationalized that cases with electron withdrawing groups "always" go faster

X X PdL2X
rds
+ "L2Pd"
EWG - PdL
EWG + 2 EWG 16
C)' - much more likely and often detected in calculations is initial formation of an η2-benzene complex

R
R
N R
N Cl N
Pd N
R Cl Pd
N Cl
Pd R Pd N
R R
N N R
+
Cl N R N R

transition state

Green, J. C. J. Organomet. Chem. 2005, 690, 6054.

D) - Electron transfer, radical mechanisms do exist (Ni, Mg)

rds
i.e. Ln + RX [ LnM+ RX-.]

X
[ LnM+ RX-.] LnM
R

17
 H
Rh + Rh
Me3P Me3P
H

Bi, S. Chem. Phys. Lett. 2006, 431, 385.

Aside: One electron oxidative additions also exist

I I
2 Ln Mo + A-B LnM-A + LnM-B

Conventional organic example - Lithium-Halogen exchange

Br Li
+ 2 Li LiBr +

Many new opinions on these matters:

R Hartwig, J. F. Synlett 2006, 1283.

R Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed. Engl. 2004, 43, 4704.
R Jutand, A. Eur. J. Inorg. Chem. 2003, 2017.
Alcazar-Roman, L. M.; Luis, M.; Hartwig, J.F.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A.
J. Am. Chem. Soc. 2000, 122, 4618. (chelate PR3)
Hartwig, J. F.; Paul, P. J. Am. Chem. Soc. 1995, 117, 5373 (monodentate PR3)
R Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
Lersh,M.; Tilset, M. J. Am. Chem. Soc. 2005, 127, 2471 (C-H activation). 18
 4) Reductive Elimination - reverse of oxidative addition

II A
LnM LnMo + A-B
B
change in number of metal valence e-'s -2 (16e - 14e)

change in formal metal oxidation state -2 (+2 - 0)

change in coordination number at the metal -2

Ph3P
Pt Ph3P
Ph3P Pt + "Pt(PPh3)2"
Ph3P

transition state
-not an intermediate
19
In 'normal' cases, the reaction goes by a concerted mechanism
 -and, importantly for organic chemists.......

Ph CH3 Ph retention of configuration

H Pd PPh3 H CH3 at carbon
D PPh3 D
Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981

Note: Whether the precursor is square planar or trigonal bipyramidal,

it's the cis groups which reductively eliminate

- Again, need two accessible oxidation states

Other notes on reductive elimination: - Non 18 e- situations must be accessible

- Ni group (Ni, Pd, Pt) are the usual synthetic choices

Since metal becomes more electron rich during the reaction,

the reaction is sometimes accelerated by addition of a ligand
which is electron withdrawing

R R R
N R
O O
Ni O
N
R R R
R
More details in general: Yamamoto, pp. 240-5 20
Collman, Hegedus pp 322-33
5) Insertion (Migration)
-There is more than one type possible

A B M A
M-R is a
B R Metal-C or
M R Metal-H bond
or

M R*
M A R*
A B
B

A B is R'2C CR'2 R'2C O R'2C NR'

:A B is :C O :C NR' :CR'2

Most common :A-B is CO

21
-The reaction is a concerted migration of R*, with retention of
configuration at R* and the metal, if they are chiral

H3C CH3
CH3 L
rds OC C O L OC O
OC CO
Mn Mn Mn
OC CO OC CO OC CO
CO CO CO

Change in # of valence electron at the metal -2 (18 to 16e)

Change in metal oxidation state 0 (+1 to +1)

Change in coordination number -1 (6 to 5)

22
Note: Reverse reaction is deinsertion

Most common A=B in this case are alkenes or alkynes

-for example, the intermediate step in hydrogenation

O
O insertion
H Ni O H Ni O
Ph2P PPh2 deinsertion Ph2P PPh2

- The reverse reaction in this case (β-elimination) is one of the most common reactions
of alkylmetals - main mode of decomposition

-again, if inserting group is alkyl, generally there is retention of configuration at R*

see R Cross, R. J., in "Chemistry of the Metal-Carbon Bond", Hartley and Patai, 1982, V.2

R Yamamoto, p. 246-272
23
6) Oxidative Coupling

Oxidative coupling occurs when two 'π-bound' ligands on the metal react with each other
to form (usually) a C-C σ bond

L M L M

One of the best known examples is....

R R
III
I empty coordination site ultimately
Co Co
filled by a ligand
R
R

-This has become increasingly important with a variety of metals and transformations

Change in number of valence electrons at metal -2 (18 to 16e)

Change in metal oxidation state +2 (+1 to +3)

Change in metal coordination number 0 ('3' to '3')

24
Note: There are several other fundamental mechanisms, but they have a close 'organic' analogy
η2-Olefin/Acetylene Complexes

a) Preparation
i) -most common method - ligand exchange (with CO, CH3CN, alkenes)

i.e., with Feo it is almost always as follows

CO2Et hν CO2Et
+ CO
+ Fe(CO)5
Fe(CO)4

CO2Et
CO2Et ether solvents + Fe(CO)5
+ Fe2(CO)9
Fe(CO)4
Weiss et al Helv. Chim. Acta. 1963, 46, 288

Note: The departing ligand doesn't need to be CO - some other examples

60oC +
Fe+ + OC Fe +
OC OC R
OC or R
R
R
25
-sterically hindered alkene Cutler, M. et al (M. Rosenblum) J. Am. Chem. Soc. 1976, 98, 3495
 R
Co + 2 R R R
Co + C2H4
R

-volatile alkenes
R
Jonas, K. et al Angew. Chem. Int. Ed. Engl. 1983, 22, 716.

OPr-i R R R
OPr-i OPr-i
Ti + Ti Ti
OPr-i OPr-i OPr-i
R
R R
R Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343, 759.

ii) Synthesis by Displacement of Halide

Cl- may be displaced by an alkene, either on its own or with an assisting Lewis acid
(SN1 like reactivity)

Cl
+ Pd
PdCl42- 2 Cl- + Cl

PPh3 R Ag+ PPh3

Pt + AgCl(s) + Pt
Cl
R
Schultz, R. G. J. Organomet. Chem. 1966, 8, 435 26
Davies, S. G. et al J. Organomet. Chem. 1986, 188, C41.
iii) -by hydride abstraction (also called σ-bond metathesis)
- this type is common for the preparation of alkene and alkyne early
transition metal complexes

Cp
Cp -CH4(g) Cp Cp
Zr
CH3 Zr Zr
H Cp Cp

accessible from the organolithium benzyne complex

iPrO β-elimination iPrO

Ti(OiPr)4 + BrMg Ti Ti +
2
iPrO Lewis base iPrO H
H dissociation

iPrO CH3 iPrO CH3

H reductive elimination
Ti Ti +
iPrO H
iPrO Lewis base association

Buchwald, S.L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047.

see also Sato review

iv) - By intramolecular nucleophilic substitution

27
-often for alkyne complexes, with a wider variey of metals than hydride abstraction
 Br
Na/Hg Na
PR3 PR3 PR3
Ni PR3 Ni Ni
PR3 Ni PR3
Cl PR3 PR3
Cl

R Bennett, M. A. Chem. Ber./Receuil 1997, 130, 1029.

R Bennett, M. A. Pure Appl. Chem. 1989, 61, 1695.
R Bennett, M. A. Angew. Chem. Int. Ed. Engl. 1989, 28, 1296.

b) Getting Rid of Them (Decomplexation)

-most organic chemists want the metal removed from the organic 'ligand' at the
end of the process

i) Competitive ligand association

R R
(CO)4Fe + L: (CO)4Fe L +

most common L include another alkene or alkyne, R3P, CO, N

+
Cp Cp
Fe CO I- Cp Cp
+ Fe CO
I 28
ii) oxidation of the metal
-very often, if one oxidizes the metal, it no longer bond very well to the organic
ligand, and it simply falls off
-several very common oxidants include.....
FeCl3, Ce+4 ((H4N)2Ce(NO3)6), others
Me3N+-O- (trimethylamine N-oxide, N-methylmorpholine N-oxide)
Shvo, Y.; Hazum, E. J. Chem. Soc., Chem. Commun. 1974, 336 (for iron diene compelxes)

O O
Me3NO
Fe(CO)4
acetone-CH2Cl2
CO2Et CO2Et
Green, J. R.; Carroll, M. K. Tetrahedron Lett. 1991, 32, 1141.

O O
Co2(CO)6 Me3NO

SiMe3 SiMe3
R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.

c) Uses of η2- Metal Complexes

i) as a protecting group

-recall the intro.....that olefin coordination changes the electron density of 29

that alkene
 -can make the alkene more or less reactive than the uncomplexes alkene,
depending upon the case

Consider......
O
O
C C CO2H
Fe CO2H
C Fe(CO)4
O C
O
-therefore, very slightly overall electron donating (essentially the same)

but
+
charge on complex almost unboubtedly renders η2-complex
less electron rich
OC Fe
OC -as a result, the alkene is less reactive to attack by E+, and to
hydrogenation
-but(!), the alkene is more reative to attack by Nu-
Note:

+ = Fp+
OC Fe
OC 30
 +
Fp
BF4- Fp + Fp +
H2, Pd/C

CF3CO2H

+
Fp
BF4-

Fp+
Fp+

+ Br2 + Hg(OAc)2 +
Br
Fp Fp Fp HgOAc

90% 82%
Br OAc

OH OH OH OH
OMe OMe Br2 Br OMe NaI, acetone Br OMe
CH2Cl2, 90% 80%

+ +
Fp Fp

31
-Fp+ alkene complexes are air stable, water stable, and you can store them at 0oC
Alkynes
-many alkyne complexes known
PR3
Ph3P PPh3 Cp Cp Ni PR3
Fp + Pt Mo
R R R R R R

But Co complexes are especially robust

Co2(CO)6
-2CO
Co2(CO)8 + R R R R not real structure, of course
R Co
OC CO
OC Co Co CO or -bonding is called μ−η2 (μ2-η2)
OC CO
Co
R
-these are in general very stable complexes
-since p- bonds are used in bonding to metals as well, they are not available to
electrophiles, like most other alkynes are
Co2(CO)6
H-N=N-H
Co2(CO)6
Co2(CO)8 Co2(CO)6
1) BH3

2) H2O2 32
R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
 η2-Complexes as Electrophiles

a) Cationic Complexes (Fp+)

-just as the '+' charge, nominally on Fe, ultimately withdraws electron density
from the alkene and reduces its reactivity to electrophiles (E+)....

-so it by contrast increased reactivity of alkenes to nucleophiles (Nu-)

The stoichiometric chemistry is dominated by chemistry of +

OC Fe = Fp+
OC
Thus, Cp Nu: Cp
+
OC Fe or OC Fe Nu
OC Nu- OC

-list of Nu- 's hat do this is pretty large

OLi OSiMe3
Carbon based - R'
EtO2C CO2Et R2CuLi R or R' + F-
R
in some cases
Cp Cp
enamines OC Fe OC Fe
R2N OC OC
+
R2N O 33
Heteroatom based
RnNH3-n ; ROH (+Na2CO3); RSH (+Na2CO3); R3P
(amines) (alcohols) (thiols) (phosphines)

Stereochemistry of Addition

-The addition of Nu: or Nu- is stereospecifically trans to the metal. So.....

H + Bn [Fe]
+ H Ph NH2
OC Fe CH3 NH2 H Me
OC Nu: OC Fe
H OC H H Me
CH3 NH Bn
+ 2

+ H [Fe]
Fe H + Bn
OC Ph NH2 Me H
OC Nu: NH2
OC Fe H Me
H OC H NH Bn
+ 2
Regiochemistry
If you draw various resonance forms of the Fp+-alkene cation complex, the
nucleophile ends up attacking the carbon atom where the 'traditional' organic
34
cation would be most highly stabilized (i.e., 'SN1 like') reactivity
 + + CH
Fp OC Fe CH3 Fp 3
OC
CH2 more contributing resonance form
+

Li(CH(CO2Et)2 Li(CH(CO2Et)2

Fp CH3 EtO2C CO2Et

EtO2C minor Fp major
CH3
CO2Et

Note: Unfortunately, with simple alkyl substutuents (like above), the regioselectivity
is pretty poor.
However, with strong cation stabilizing or detsabilizing (electron withdrawing) groups,
the outcome is much more decisive

+ LiCH(CO2Et)2 EtO2C CO2Et

Fp Ph + Ph
Fp
Fp
Ph

δ+ β
Fp + Fe(CO)2Cp
α
+
O 35
OLi O O
 So what do you do with the products?
-there are very few natural products with covalent Fe-C bonds in them, so it's
generally desired to turn these into something 'all organic'

1) -the alkyl-Fp compounds may be transformed into several functional groups, i.e....

I2 Br2
Fp R R I Fp R R Br
CS2
-normally, this occurs with inversion of configuration at the carbon being attacked.

But......

HCl or

}
Fp R R H with retention of configuration
CF3CO2H at the carbon attacked!
HgCl2
Fp R R HgCl
if a good Nu- is present
(I-, Br-) R-Nu
Why this dichotomy? +
SN2 attack on R
+ E+ OC Fe
OC Fe OC E R
OC R (Lewis acid, if no strong Nu- present
or electrophile)
reductive elimination of ER R-E
36
(retention of configuration)
2) Oxidation

In the presence of an oxidant, migratory insertion of CO occurs before the metal

is lost. The 17 e- species does this very rapidly
-common oxidants are CeIV, FeIII, CuII, O2

This is most often done in methanol solvent, so that the final product is a methyl ester.
+
D Cp Cp O O
[O] D L D D
Cp
t-Bu
Fe
CO Fe +. t-Bu
III
MeOH t-Bu CO Fe t-Bu OMe
D CO CO
D D CO D
L
17e- 17e-

notice the retention of configuration

This includes Br2 and Cl2 as oxidants

O O
Br2 Cl2
Fp-R R Fp-R R
MeOH OMe Cl
notice difference when solvent is CS2

3) Elimination

If the is a H atom b- to the iron, which can assume an antiperiplanar conformation,

37
it can be abstracted as H-, usually by Ph3C+
 R Ph3C+ +
Fp
Fp
H R
H

Rules for abstraction:

-if there is a choice between forming a terminal alkene and an internal one, one
normally gets the terminal alkene - probably a steric accessibility argument

Fp + Fp
Ph3C+ BF4+ Fp +
CH3
H H CH2Cl2

-if internal alkenes must be made, one gets mostly the (Z)- isomer
-no one really knows why....perhaps a greater stability of the complex

Fp Ph3C+ BF4+
major
Fp +

References:
R Pearson, A. J. 'Iron Compounds in Organic Synthesis', 1994, Ch.2
R Rosenblum, M. J. Organomet. Chem. 1986, 300, 191.
R Rosenblum, M. Pure Appl. Chem. 1984, 56, 129.
R Rosenblum, M. Acc. Chem. Res. 1974, 7, 122.
R Green, J.R.; Donaldson, W. A. in 'Encyclopedia of Inorganic Chemistry' 1994, V. 2, p.1735.
Enantiomerically pure versions 38
Turnbull, M. M.; Foxman, B.M.; Rosenblum, M. Organometallics 1988, 7, 200.
Begum, M. K. et al (Rosenblum) J. Am. Chem. Soc. 1989, 111, 5252.
 -some similar chemistry is known for the corresponding alkyne complexes, i.e.,

Fp+ It is not nearly as well explored

R R see Reger, D.L. Organometallics 1984, 3, 135 & 1759.

Use in synthesis (M. Rosenblum)

Cp O
+ 1) Cl2 +. O
Ph NH2 OC Fe reduct.
Fp
Fp HBnN N
NHBn Me3N elim?
Bn

+ O NH3 + :NH R Fp
Fp Fp
R R N N NaBH4

Fp R

H Fp
Ag2O O Δ
N
R Fe N N
O 72% Cp CO
CO R
migration R
Wong, P. K. (Rosenblum) J. Am. Chem. Soc. 1977, 99, 2823. 39
Berryhill, S. R. (Rosenblum) J. Org. Chem. 1980, 45, 1984; 1983, 48, 158.
 Synthesis of stereochemically defined alkenes from enol ethers

MeO OMe MeO OMe EtOH EtO OEt

+
Fp +
Fp + Fp + R2CuLi
(anti to Fe)

R OEt OEt
anti EtO H HBF4
R R
O Fp Fp
EtO Fp + departure of Fp Et O+ (-EtOH) OEt
EtOH R H Et

This can be repeated, using other ether function, with modification to get either alkene isomer

R
1) Nu- Nu R I-
Nu R
EtO Fp + 2) HBF4 Fp +

1) Nu- R R
EtO R I-
2) HBF4 Nu Fp + Nu 40
Fp +
PdII Complexes of Alkenes
-probably the other major choice in alkene-TM complexes

Early Chemistry
-Pd II forms comlexes with alkenes; an amine ligand is usually added to
break up dimer and make a more reactive species
R R
R Li2PdCl4 Cl Cl R'3N
Cl
+ or Pd Pd Pd
(MeCN)2PdCl2 Cl Cl
Cl NR'3
R
-susceptible to attack by nucleophiles on the more substituted C
-can sometimes reduce Pd off at low T, but mostly get β-H elimination
O O O
Nu:/Nu- = R2NH, H2O (ROH), - R ) amines, water, alcohols,
R ( R -
enolates

R
Nu- R Nu
Cl -L R Nu L -HCl, -Pdo R Nu
Pd or L
Pd Pd H
Cl NR'3 Nu:
Cl NR'3 Cl 41
 BUT......This is stoichiometric in Pd, and PdCl2 1g, $102; 25g, $1155

see, R Hegedus p.188-201

R Handbook of Organopalladium Chemistry for Organic Synthesis V2, Ch V3
Holton, R.A. J. Am. Chem. Soc. 1985, 107, 2127 (chelating amines/sulphides)

However, if one has a stoichiometric oxidant present to oxidize the Pdo back to PdII,
the could in principle be catalytic

- this can work: oxidant is most often O2 or benzoquinone (BQ), or CuII

Earliest Successes

- is with oxygen based nucleophiles (H2O, ROH)

-perhaps because oxygen nucleophiles don't displace the alkene ligand
R
O Pd and R O Pd are not tremendously strong interactions
R'

-traditional version, with water as nucleophile, is called the Wacker process

OAc PdCl OH OAc O OAc

2(cat)

CuCl(cat)
O2, H2O actually not true 42
species
-reaction is selective for terminal alkenes; in fact intermolecular reactions for
internal alkenes work poorly in most cases (except strong EWG substituted ones)

-Markovnikov addition - Nu: attacks most substituted side of the alkene normally
-this can be overridden by coordinating groups within the substrate

-CuCl2 oxidizes Pdo back to PdII; O2 oxidizes CuI back to CuII

Alcohols and phenols can do this type of chemistry too, usually as an intramolecular
addition

PdCl2 isomerization

OH DMSO, H2O O
KHCO3, air O

-normal tendency is to form 5- membered ring over 6- membered ring;

this tendency can be overriden in some cases

- first work was with PdCl2 as the PdII source, but now it is often replaced with
other PdII salts
-Reason - with Cl- salts, attack of Nu is anti to Pd; whereas with Pd(OAc)2, Pd(OCOCF2)2,
attack is syn to Pd 43
-syn attack allows/forces β-H elimination away from ring
 R R
H H
H R H
R R R R R
PdCl2 anti O H Pd Cl R O
R OH R OH R
or
R R

R O H
R
H R
R H R
R R
PdX2 syn O H Pd X R O H
R OH R
usually

Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.

( )n ( )n
5 mol% Pd(OAc)2
90-96%
HO DMSO, O2, rt O

-this even allows asymmetric synthesis at the newly formed chiral centre
ligand
10 mol%
Pd(OCOCF3)2
O
20mol% ligand O N
OH BQ, MeOH, 60o N
75%, 96% ee O
44
Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071
N Nucleophiles -sometimes called aza-Wacker

-problem with amine ligands - these are generally too basic/nucleophilic; tend to
displace alkene as ligand

-as a result, in the vast majority of successful cases, the lone pair on N is deactivated

H H O H H
N N N N
{ { S = { Ts or even { Ar
O
O

- with this restriction, this has become an increasingly important way of making
heterocycles; especially possible for indole type systems
OTBDMS
OTBDMS
10% PdCl2(MeCN)2
77%
1.5 equiv BQ CH3
NH 3 equiv K2CO3, THF, rt N
CH3 CH3

Ts
5 mol% Pd(OAc)2 N
NH
Ts O2, 2 equiv NaOAc,
DMSO, rt
45
R Minatti, A.; Munoz, K. Chem. Soc. Rev. 2007, 36, 1142.
 Carbon Nucleophiles
-success in these nucleophilic attack reactions has even been extended to carbon
based nucleophiles such as silyl enol ethers, enolizable β-dicarbonyls, electron rich
aromatics and heterocycles - there are even some intermolecular cases

10mol% Pd(OAc)2
MeO O R' 1 equiv BQ MeO O
R' 54-77%
20 mol% ethyl nicotinate
t-AmOH-AcOH, 20 mol% NaOAc
OMe OMe

10mol% Pd(OAc)2
O2 82%
40 mol% ethyl nicotinate
N t-AmOH-AcOH, 80o N

Ferreira, E. M.; Stoltz, B. M.* J. Am. Chem. Soc. 2003, 125, 9578.

7 mol% Pd(OAc)2,
S OEt 1 mol% H4PMo11VO40 CO2Et
+ S 86%
O 7 mol% acetylacetone,
4 mol% NaOAc, EtCO2H, O2

O O O O
OH O
5 mol% PdCl2(MeCN)2
R R
R 64-97%
2.5 equiv CuCl2,
CuCl2, rt 46
 even organometallics, i.e., Ar-HgOAc (ancient history), ArB(OH)2, ArSnR'3
dmphen=
i.e. O Pd(OAc)2, O
B(OH)2
+ OBu-n dmphen(cat) OBu-n
N N
NMM, MeCN,
O2, 50o

exhaustive review R Becalli, E. M.; Broggini, G.; Martinelli, M.; Sottocomola, S. Chem. Rev. 2007, 107, 5318.

We have been hiding an important point for a bit now, though

Some of these (the organometallics, syn attack cases) are probably going through
a different intermediate than has been presented L
L L H Pd X
L
X Pd R 'insertion' X Pd R X Pd H β-elimin. R
reaction A HH H A HH R A
A
A
Nu bound to metal

A
-much more common way to get at the intermediates A
-by oxidative addition of Pdo to organic halides/triflates
-called Heck reaction 47
Reveiws - many

R Heck, R.F. Org, React. 1982, 27, 345; Acc. Chem. Res. 1979, 12, 146.
R Larock, Adv. Met-Org. Chem. 1994, 3, 97.
R Jefery, T. Adv. Met. Org. Chem. 1996, 5, ch.4.
R Crisp, G. T. Chem. Soc. rev. 1998, 27, 427. (mechansitic detail)
R Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31 mechanistic detail
R De Vries, J. G. Dalt. Trans. 2006, 421 (mechanistic discussion)
R lonso, F.; Beletskaya, I. P.; Yus, M.. Tetrahedron 2005, 61, 11771.
R Miyaura, N. Adv. Synth. Catal. 2004, 346, 1522.
R Jutand, A. Pure Appl. Chem. 2004, 76, 565 (mechanistic detail)
R Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945 (asymmetric synthesis)
R Link, J. T. Org. React. 2002, 60 157 (intramolecular rxns)

I
Pd(OAc)2
+ Br CO2Me
CO2Me CO2Me
Et3N Pd(OAc)2,
Br 68% 63%
P(o-tol)3, Et3N

So now we need Pdo, but we added PdII

Not a typo; PdII complexes often used and reduced in situ

H AcO
Pd(OAc)2 + HOAc + + "Pdo"

X " " -HX

β-elim X Pd H "Pdo"
X2Pd + NEt3 X Pd NEt2 n picked up
-X-
+ by NEt3
H
H + Et
n N
48
Et
Regiochemistry
-somewhat different than intermolecular cases
-some tendency to go away from EWG's and towards EDG's, but sterics now
(apparently) dominates
-Nu: goes 'towards' the less substituted site
100
4 H3C Ph O
i.e.
CO2Me CO2Me N
96 93 7 100
40

60

Stereochemistry
-resulting alkene is usually the most thermodynamically stable one, meaning trans
......all else being equal

Nature of the Organic Halide

R-X (usually) can't have β-hydrogens on an sp3 carbon atom, because of β-elimination

HH Br "Pdo" H H L L β-elimination
R
Pd H-Br + Pdo +
R R Br
49
β-elimination takes place before any coupling can occur

X X
Thus X
(aryl) X (vinyl)
(allyl) (benzyl)

Halides -Br is most common choice

-I faster at oxidative addn, but more side rxns

(sometimes better, sometimes worse)
O
-triflates are excellent pseudohalides { S CF3
O

-Cl historically sluggish, but coming along nicely with new catalysts,
including sterically hindered phosphines, carbenes as ligands, and
ortho- metallated palladacycles
O PPr-i2
O O
i.e., PtBu3 Pd Cl
N N
Cy2P ..
O PPr-i2

R Whitcome, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.

R Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. Engl. 2002, 41, 4176. 50
R Christmann, U.; Vilar, R.* Angew. Chem. Int. Ed. 2005, 44, 366
 A cute but increasingly irrelevant variation - acid chlorides
-aryl chlorides are very reactive to oxidative addition, and may be accessibe
when the halides are not

L
O "Pdo" (Pd(OAc)2) O migratory
Br Cl Br Pd Cl
Br
Cl Pd deinsertion
Ph NMe2 Cl L L
-CO

Br
X
-can occur under very mild conds, in some cases - being made obsolete by improvements
to aryl chloride Heck reactions
Spenser, A. J. Organomet. Chem. 1983, 247, 113; 1984, 265, 273.
Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
Tetrahedron Lett. 1985, 26 2667.

The Alkene
R' R3 R1 R3 R1
R R' and >>>
> >> R4 R2
X R R2
monosub disubst. trisubst tetrasubst.
-forget it
51
only practical ones
 -ligands generally stabilize palladium intermediates, but are't always added
-inorganic base is often used (instead of amine) to consume H-X
O
O

I PdCl2(MeCN)2

O HCOOH
O
O O
Br O
Note what happens to
Pd(OAc)2
+ β-elimination process
S OH
S
Et3OSi Et3OSi
H H
Pd(dba)2 CO2Me
OTf + CO2Me
N K3PO4 N
O O
CO2PMP CO2PMP

In some cases, other things can be done to the alkylpalladium

Pdo R'
R-X +
R' R PdX 52
 a) Trap with organometallics

Ph
I 10% Pd(OAc)2
+ PhZnCl 60%
N 20% PPh3
N
H Et2O-THF, rt

Grigg, R. et al Tetrahedron Lett. 1990, 31, 6573 & refs therein

b) Further cyclopalladation

EtO2C 3% Pd(PPh3)4, EtO2C

EtO2C 76%
EtO2C Et3N, CH3CN,Δ

I Yang, Y. et al (E.-i. Negishi) J. Am. Chem. Soc. 1990, 112, 8590.

For still more reviews, see...

R Handbook of Organopalldium Chemistry for Organic Synthesis V1, Ch IV 2.4-2.6
R Naso, F.; Marchese, G., in The Chemistry of Halides, Pseudo Halides, and Azides;
Patai, S; Rappoport, Z. eds Ch. 26, Wiley 1983,
R Green, J. R. in The Chemistry of Halides, Pseudo Halides, and Azides, Supplement D2, Ch 25, Wiley 1995
R Shibasaki, M. Soden, C. D. Kojima, A. Tetrahedron 1997, 53, 7371
R Balme, G. Bouyssi, D.; Lomberget, T. Monteiri, N. Synthesis 2003, 2115 53
 η3- Hydrocarbon Metal Complexes

i.e. type complexes Note: We will discuss

these here, too;
MLn even though they're Fe
OC
η1 OC
Preparation of η3-allyl Complexes

i) From olefins (alkenes) with allylic leaving groups

Na2PdCl4
Cl + CO2 +2 HCl + 2 NaCl
CO, H2O, MeOH Pd
(Pdo generated in situ) Cl
2
I
I Fe(CO)5 or Fe2(CO)9 Fe CO
CO
Δ, -CO C
O
+
(CO)4Fe Fe(CO)4
Fe2(CO)9 HBF4 BF4-
OH OH
Et2O, -H2O

OR
Ni(cod)2
OR Ni + 2
PPh3 PPh3 54
R = Ph, Ac
 Cp Cp
hν
CpFe-(CO)2 + Cl Fe CO Fe CO
CO -CO
η1 η3
Fish, R. W. et al (Rosenblum) J. Organomet. Chem. 1976, 105, 101.

O
O O- C O
Fe(CO)5 + O C
Fe(CO)3
Fe(CO)3

ii) From Metal-Diene Complexes

+ +
Fe(CO)3 Fe(CO)3 Fe(CO)4
HBF4 BF4- BF4-
CO
Salzer, A.*; Hafner, A. Helv. Chem. Acta 1983, 66, 1774.

Y
Cl
+ PdCl2 + Y-
Pd Pd Y- = Cl-, RO-,
Cl AcO-, PhHgCl
Y
55
Trost, B. Tetrahedron 1977, 33, 2615.
iii) Activation of allylic C-H Bonds
-most applicable for Pd complexes
" "
NaOAc -HCl
+ PdCl2
HOAc H
H Pd
Cl Cl Pd
Cl L
i.e.,
PdCl2
Trost, B. M. Tetrahedron Lett. 1974, 2603.
Cl
Pd
2
Huttl, R. Chem. Ber. 1968, 101, 252.
CO2H
CO2H PdCl2
CO2H Chrisope, D. R.; Beak, P.; Saunders, W. H.,
Cl J. A. Chem. Soc. 1988, 110, 230
CO2H AcOH Pd
2

iv) Propargyl (di)Co complexes

Co2(CO)6 Co2(CO)6
Co2(CO)6 H+ (-ROH) or +
R' CH2OR R' CH2OR R' CH2
BF3 (-ROBF3-) 56
 Allyl/Propargyl η3- Complexes as Electrophiles

a) Cationic allyl tetracarbonyl complexes

Nu: R Nu
R

+Fe(CO) Fe(CO)4
4

-complexes react with a pretty wide range of nucleophiles to give η2-alkene complexes
as immediate products

-these η2-alkene complexes are not all that stable, easily decomplexed by mild oxidant
-allyl attack is presominantly at less substituted side of allyl unit (more later)

Nu: can be... R3N (amines), Ph3P (phosphines), R2Cd (RMgBr), RCu(CN)ZnI
O O OSiMe3 M
electron rich arenes, H- (Et3SiH), , R' ,
MeO OMe R - R R
O
(M = Me3Si, Bu3Sn, R2B)

R Pearson, A. J. "Iron Compounds in Organic Synthesis", Academic Press, 1994, Ch.3

R Green, J. R.; Donaldson, W. A., in "Encyclopedia of Inorganic Chemistry", Lukehart, C. M.,
ed., Wiley 1994, V 4, p. 1735.
57
Regiochemistry
-Site of attack is normally at the less substituted end of the allyl unit

-C2 attack has never been observed

N
Fe(CO)3 Fe(CO)3
HBF4 +
CO N
PPh3
O O
1)
O - OMe +
O 2) HO-, H+ PPh3
+ 3) air
68% 17%

-Site of attack is away from electron withdrawing group

OSiMe3 Fe(CO)4
CO2Et CO2Et Me3NO CO2Et

Fe(CO)4 O O
+ CH2Cl2

58
Green, J. R.*; Carroll, M. K. Tetrahedron Lett. 1991, 32, 1141.
Why care?
-allyl cations are very highly reactive; either too unstable to prepare or too reactive
to be isolated or control their reactivity

-site γ-to carbonyl is normally nucleophilic; therefore this is umpolung reactivity

-iron allyls are geometrically stable

R de Koning, H.; Hiemstra, H.; Moolenar, M. J.; Speckamp, W. N. Eur. J. Org. Chem. 1998, 1729.
R Enders, D.; Jandeleit, B.; von Berg, S. Synlett 1997, 421.

b) AllylpalladiumII Complexes Hegedus, p. 245 start

Tsuji, p. 116-168

-by FAR, the most widely used η3-allylmetals

-like the Pd alkene complexes, the chloro- bridged dimers usually aren't reactive enough

-reactivity is enhanced in one of two ways

+
THF -AgCl
Pd BF4-
AgBF4
Pd THF THF
Pd Cl O Cl

2 PPh3 +

-halide displacement by
Pd Cl-
good ligands
Ph3P PPh3 59
-can also be activated by other ligands (esp. phosphines), dimethyl sulphoxide (DMSO),
hexamethylphosphoric triamide (HMPA)

- once 'activated', these can undergo nucleophilic attack by several reagents

O O OSnR'3 OLi OSiMe3
O O
AcO-, R2NH,
- OR , Ph S , R R R
OR
O - R" R" R"
less reliable

-attack superficially similar to allylirons

-i.e., normally at the less substituted allyl terminus
-this can, however, be affected by choice of phosphine ligand

-rationale - more electron rich C-Pd bond shouold be the stronger one - this is the
more substituted one
- therefore the less substituted one is more weakly held, so Nu- attacks there

-BUT , with a bigger ligand (i.e., (o-tol)3P), there is a steric repulsion between PdL2 and
the more substituted C - makes that bond weaker, more easily attacked

Consider..... 60
 SO2Me
Pd Cl -
L, Me-SO2-CH-CO2Me CO2Me SO2Me
2
DMSO, RT + CO2Me

PPh3 62 38

n-Bu3P 100 0
P
3 18 82

Trost, B. M. et al J. Am. Chem. Soc. 1978, 100, 3416.

-electron withdrawing groups direct attack to the end site remote to the group
-electron donating groups direct attack to the end near the EDG

EtO2C CO2Et CO2Et

CO2Et -
Pd Cl EtO2C CO2Et

2
EtO2C CO2Et EtO2C CO2Et
O OAc O -
Cl NHAc O NAc
Pd
2 61
-there are rare cases of attack at the central carbon of the allyl unit - C-2 attack

-usually observed for Nu- with high pKa's (20-30), or where the central carbon has
a leaving group
-C-2 attack has very limited use in synthetic organic chemistry so far

- CO2Me -Pdo
+ CO2Et CO2Et
Pd +
Et3N NEt3
Pd(NEt3)2

-for a good discussion and lead refs, see...

Aranyos, A., et al (Backvall, J. R.) Organometallics 1997, 16, 1058.
Organ, M. et al J. Am. Chem. Soc. 1998, 120, 9283.

Stereochemistry of Attack

-recall - oxidative addition to for π- allyl is on a alkyl centre, and therefore goes with
inversion of configuration

OAc Me
H PPh3
H "Pdo(PPh3)2" Pd +
PPh3 62
 -now, nucleophilic attack on the allylpalladium normally occurs away from the
palladium (it could be called backside attack, too), so overall there is a
retention of configuration at carbon

SO2Ph
O - H3C
Me CO2Me
H PPh3 Ph S CH-CO2Me H
Pd + O
PPh3

Note: This is the normal (and ideal) situation

non-stabilized carbanions are not usually good for attack on these species;
when the do work, the mechanism is different....

- then, the initial attack step is on the metal, which is followed by reductive
elimination to give retention for this step
2
Pd Cl Pd CH3 reductive
CH3MgI CH3
elimination H

Nu- = MeMgX, MgX SnBu3 PhMgBr ClCp2Zr

a) b) c)

Tetrahedron Lett. 1979, 3221 J. Organomet. Chem. 1975, 102, 359

J. Chem. Soc., Chem. Commun. 1984, 107 a) J. Am. Chem. Soc. 1984, 106, 5028. 63
b) Organometallics, 1985, 4, 417 c) J. Am. Chem. Soc. 1982, 104, 1310 and 5028.
-Acetate/carboxylate will attack with retention under special conditions, or if forced by
the constraints of the molecule
"PdCl"
Larock, R.C. J. Org. Chem. 1984, 49, 3662.
O
( )n OH ( )n
O
H O
Cl H Cl

The best news is that many, many, many of these reactions can be done as
catalytic reactions

for example, allylic oxidation McMurry, J. R.; Kocovsky, P. Tetrahedron Lett. 1984, 25, 4187.
O O
O Pd(OC(O)CF3)2(cat)
+
HOAc, O
(solvent) O O
O O OMe O O

or most commonly.....
+
L L
Nu-
X Pd X Pd X- Nu + L2Pd
+ L4Pd
L L

O O O
X = -OAc, -OC-R -OC-OR -OPh, -OH, -SO2Ph, -NO2, 64
so......
OAc Godleski, S. A.;Valpey, R. S.
NaH, THF, Δ CO2Et 66% J. Org. Chem. 1982, 47, 381.
CO2Et
CO2Et
7% Pd(PPh3)4
CO2Et

Me2NH, Pd(acac)2 Backvall, J. R. J. Org. Chem. 1981, 46, 3479.

N dppe, THF NMe2

Ar OAc
Ar

(Ph3P)34Pd(cat)
AcO O HN O
N dppb(cat)
H2N O N
THF, Δ O
HAcN HAcN
Trost, B.M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881.

O OH
O 40o, Pd(PPh3)4
85%
CH2(SO2Ph)2
+
Pd PPh
Ph3P 3 SO2Ph SO2Ph

65
 Notes on that last one: 1) Allylic substituent, CHR-OH is electron withdrawing and sterically
blocking 'proximal' attack - therefore, attack is on remote (distal) end of allyl unit

2) Oxidative addition goes with inversion

Nucleophilic attack is from backside of Pd allyl = inversion
so overall retention

Question: How about the other possible regiochemical outcome, i.e., attack at more
substituted end?

If you instead use Co group catalysts, particularly RhI and IrI, and use less donating
ligands (phosphites, esp. P(OPh)3), it is clear that allyl more 'electrophilic', so
location of '+' resonance for more critical - attack on more substituted end.

n-Bu [Ir(cod)Cl2]2
n-Bu + n-Bu 90%
OAc 4 P(OPh)3, THF, RT Nu Nu
NaCH(CO2Et)2 97:3
R Takeuchi, R. Synlett 2002, 1954 (Ir)

RhCl(PPh3)3,P(OPh)3 + 89%
Nu Nu
OAc
NaCH(CO2Me)2, THF, 30o >99:1
R Leahy, D. K.; Evans, P. A. Modern Rh-Catalyzed Organic Reactions, Ch. 10

-Other metal systems such as IrIII, MoII can do similar substitutions

R Krska, S. W. et al (+Trost, B. M.); Pure Appl. Chem. 2004, 76, 625.(Mo) 66
 Enantioselectivity
-most of the work has been done on allyls with symmetrical substitution patterns,
using a chiral ligand

H3C CH3 H3C CH3

Nu- H3C CH3 +
Pd
+
Nu H H Nu
L* L*
Most recent reviews
Nu- = -CH(CO2Et)2 especially
R Trost, B. M. J. Org. Chem. 2004, 69, 5813.
R Trost, B. M. Chem. Rev. 2003, 103, 2921.
R Graening, T.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2003, 42, 2580.

This still can be a very tricky process, as there are many isomerization processes possible
OAc L*
OAc Pd +
Nu
L* Pd k1
PdL2 *
+ L* L*

A
OAc
OAc L*
Pd + Nu
PdL2* Pd
L* L* k2
+ L*
B
1) Under normal reaction conditions (high phosphine to Pd ratios), nucleophilic displacement
is slow relative to π-allyl interconversion 67
-therefore, the product can depend of stabilities of A and B
2) Acyclic systems can racemize by an η3 - η1 - η3 mechanism
Y X
X Pd H
H Pd Y
X Pd
X Pd Y
Y
-same process can also result in anti / syn- isomerization of allyl Pd's

Pd X Pd
X X Pd
Y Y
Y
syn,syn- syn,anti- anti,anti-

Nevertheless, there has been considerable success in this enantioselective transformation,

especially using ......

O O where O O
X X HX XH N N most common
H H
PPh2 Ph2P is a symmetrical diol P P
diamine Ph2 Ph2
DPPBA ligands
see Trost reviews listed on last page
R Trost. B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
68
 Other successful ligands

H Me Me
X= R = iPr, tBu
X N OH MeO
PPh2 O
Fe PPh2 OH
Me Ph2P N
PPh2 OH R
N
MOP (Monophosphine
OH ( )n
ligands)
BPPF-X
N OH R Hayashi, T. J. Organomet. N N
Chem. 1999, 576, 195. R R
BOX (Bis-oxazoline ligands)
R Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.

NaCH(EWG)2
Ar Ar Ar * Ar
up to 96% ee with (R)- or (S)- BPPFX
OAc (π-C3H5)PdCl/L*, 40o CH(EWG)2 Hayashi, T. et al Tetrahedron Lett. 1986, 27, 191.

O
PdCl/2 BzO conduramine A-1
Bz O
O benzamide
O

O TMSN3, DPPBA O pancratistatin

Bz O N3
= OBz
O 83% yield, >98% ee from Trost (1996) review 69
 π-Allylnickel Halides

Preparation R X Hegedus, p.278

R benzene Ni Ni
X + Ni(cod)2 X R

or Ni(CO)4
X = Br
usually

-These are isostructural, isoelectronic with the corresponding allylpalladium compounds

-Reactivity can be different, however

These can behave as if they are nucleophiles themselves, and will allylate organic halides
(X = Br, usually)

R Br
DMF + NiBrX
Ni + R'X R'
R
2 25o

-ketones and aldehydes are often tolerated (i.e., they survive this rxn at RT)
-esters are tolerated well

Regiochemistry - reaction occurs at less substituted allyl terminus

Br I DMF
Ni α-santelene 70
+ 25o
2
So who cares?
Look carefully at the above; the centre that's being attacked is neopentyl (i.e., R3C-CH2-X)
-neopentyl centres are normally forbidden for nuceophilic (SN2) substitution
-works just fine here

-Generally true - rxn works well in cases where SN2 is impossible (i.e., aryl halides)
OAc OAc O
Br
HMPA
+ Ni
Br 2
OAc OAc O
and if you want to do... vitamin K analogue

O Br
- -this is very tough directly
+
CH2
O

But..
O O
O Br
MeO DMF H3O+ OMe
OMe Ni OMe
+ N
2 N
N Br
O CH3
OMe
Hegedus, L. S.; Stiverson, R. K. J. Am. Chem. Soc. 1974, 96, 3250.
Hegedus, L. S. et al J. Org. Chem. 1977, 42, 1329.

71
Works with aryl, vinyl, 1o, 2o, 3o alkyl bromides and iodides
However, allyl halides 'scramble'

Br Br Br
+
Ni + + Ni +
Br
2 2
Other points
-like allylPd's the allyl fragment loses its stereochemical integrity

Br 1) Ni(cod)2 R R
+
2) R-X

-chiral (and enantiomerically pure) 2o alkyl halides racemize

MeO Br
CH3 Ni CH3
1) racemic
I H 2 H
2) H3O+
O
-while vinyl (alkenyl) halides retain their stereochemical integrity

O OEt Br
O DMF O O OEt
I + Ni
2

Hegedus believes that this is all due to the interventional of NiI and NiIII as well as NiII
Hegedus, L. S.; Thompson, D.H.P. J. Am. Chem. Soc. 1985, 107, 5663. 72
Initiation

IIBr II hν or Δ Br I
III
allyl Ni Ni allyl allyl Ni Ni allyl allyl-NiI + allyl-NiIII
Br Br
?
Oxidative addition/reductive elimination
III R
allyl-NiI + R-X allyl-R + NiI-X
allyl Ni
Br

Scarmbling of R
* III R
III R III R allyl-NiI allyl Ni
allyl Ni + allyl-NiII-Br allyl-NiII-Br + allyl Ni * Br
* Br * Br +
allyl-NiI
Chain carrying step

NiI-X + allyl-NiII-Br NiIIBrX + allyl-NiI

Scrambling of R goes with inversion, i.e., SN2 like - therefore occurs with alkyls, but
not alkenyls

The rest is like you expect - for alkyls, oxidative addition is with inversion,
reductive elimination with retention
- for alkenyls, oxidative addition with retention, 73
reductive elimination with retention
 Other electrophiles
-although organic halides react preferentially, these allylnickel species will react
with aldehydes and the more reactive ketones at ca. 50oC
-ordinary acyclic aliphatic and α,β-unsaturated ketones only react sluggishly
Br O DMF R
Ni + R R' 50o R'
OH
2
-example of use in spirocyclic α-methylene-γ-butyrolactones

O
Br O OH
EtO + ( )n O O
Ni
O ( )n
2 ( )n
OEt
Billington, D. C. Chem. Soc. Rev. 1985, 14, 93.

π-Allylnickels as Electrophiles
PPh3
+
With two phosphine ligands Ni does pretty much the same chemistry
PPh3 as α π-allylpalladium complexes
-what's unusual? - successful coupling of Grignard reagents, i.e.,

X + Nio (or NiII) + RMgX + 2 PR'3 R

-large variety of X, including -Br, -Cl, -Oalkyl, -OAr, -OSiR3, -OH, -OTHP, -SR
-the R of RMgX is suprising....R = Ar, or 2o or 1o alkyl
-β-hydride elimination is apparently a lesser problem in alkyl-Ni 74
 β-elimination step for R = alkyls is often slow enough that one can get reasonable amounts
of C-C bond formation

PhMgBr 95%
PhS OMe PhS
Cl2Ni(dppp)(cat),
benzene, 0o Sugimura, H.; Takei, H.
Chem. Lett. 1984, 351
( )6 MgBr
OEt EtO ( )7 74%
CH3
OEt Cl2Ni(dppp)(cat),
THF, 0o
Hayashi, T., et al J. Organomet. Chem. 1985, 285, 259.
for work with chiral phosphine ligands, see: Cansiglio, G., et al Tetrahedron 1986, 42, 2043.

-Work in this area has slowed drastically since the mid 1980's

π-Allyliron Tetracarbonyl Lactone Complexes

-this area is almost entirely the work of S. V. Ley
-recall.... O
O O
O C O
hν, Fe(CO)5 Fe(CO)3 90%
Fe(CO)3
benzene
75
 hν, Fe(CO)5
O Fe(CO)3 + Fe(CO)3
benzene
O O
O syn, 64% O anti, 11%
-Note: Photochemical conditions usually give retention (completely) - in above case, one
can actually separate the diastereomers chromatographically

-when one attempts the typical oxidative metallation, it causes reductive elimination
and therefore C-C bond formation - with two possible outcomes

CAN O O CAN O
O β-lactone
δ-lactone Fe(CO)3 (major)
high T or [(NH4)2Ce(NO3)6], O
O
under CO CH3CN, RT

Note: The stereochemical nature of the reductive elimination step is retention

retention of configuration
CAN O
Fe(CO)3 51% + 29%
CH3CN, RT O O O
O H
O
76
while, conversely
 CAN likely because the trans fused
Fe(CO)3 β-lactone would be impossibly
O CH3CN, RT O O strained
O
Examples of the use of this in the synthesis of δ-lactones
O
O Fe2(CO)9 195o, 60 atm CO
O Fe(CO)3 parasorbic acid
THF benzene, 73% lactone (racemic)
O O -naturally occurring
lactone from sorbus
carpenter bee acucupara
malyngolide
O O pheromone O O
OH Ley, S.V. et al J. Organomet. Chem. 1985, 285, C17.

The two routes to C-C brond formation

O O O
O O [O] reductive
CO Fe(CO)
+.
3
? Fe(CO)3 elimin. O
O O
Fe(CO)3
?
O [O] O reductive
[O] O
CO, Δ, O O
high O Fe(CO)3 Fe(CO)3 elimin. O
+. 77
π-Allyltricarbonyl Lactam Complexes
-these have had a larger impact than the corresponding lactone complexes
Preparation - less common
O
(CO)3Fe Δ
hν, (CO)3Fe
N-CO2Me N-CO2Me
N-CO2Me Fe(CO)5 RT, CO

-but, vinyl aziridines aren't all that readily accessible, so....

-can be made more readily from the lactone complexes, through Lewis acid mediated
substitution
1 Ph
RT, Al2O3, PhH 1
N O
2 Fe(CO)3 or 2
+ PhNH2 Fe(CO)3
3
O ZnCl2, RT, Et2O 3
4 O
4
-this goes with transposition of the allylic fragment via the following mechanism
(E = Lewis acid) Ph
H2PhN+ + -
H2N+ O-E
..
H2NPh intramolecular
Fe(CO)3 - O
Fe(CO)3
+ E- oxidative addition Fe
O
O E-
+
O O (CO)3
Ph
Ph HN: O-E+ - -H+,
N O -H2O +H+
Fe(CO)3 OH
Fe 78
-E (CO)3
 -when these compounds are oxidized, the reductive elimination is more highly selective
for the β-lactam

O β-lactam
(CO)3Fe -30o - RT
(azetidinone)
N Ph CAN, EtOH, 72% N
O Ph

-these 3-alkenyl-2-azetidinones are not so readily accessible for other methods

-example of synthetic use (+)-thienamycin CH3
NH2
OCH3 Ph
O hν, Fe(CO)5 O Fe(CO)3 H ZnCl2-TMEDA,
OCH3 OCH3 Et2O/THF
benzene, RT
O OCH3

O
(CO)3Fe Ph O Fe(CO)3
-can separate the two diastereomers N CH3 H3C
chromatographically H + N
H
Ph
OCH3 H

OCH3 H3CO OCH3

79
 O
(CO)3Fe Ph OCH3
CAN, MeOH
N CH3
OCH3
H H -30o - RT N
O Ph
OCH3 H CH3
OCH3

O Fe(CO)3 OCH3 O
CAN, MeOH OCH3
H3C 1) O3, -78o
N OCH3 OCH3
-30o - RT N N
Ph O Ph 2) Me2S Ph
H O
H CH3 H CH3
H3CO OCH3

spontaneous
epimerization OH
NH2+
R Ley, S.V. Cox, L. R. Chem. Rev. 1996, 96, 423
R Ley, S. V. Pure Appl. Chem. 1994, 66, 1416. S
R Cox, L.R.; Ley, S.V. Chem. Soc. Rev. 1998, 27, 301 N
O
CO2-
80
(+)-thienamycin
Propargyl Cation-Dicobalt Hexacarbonyl Complexes
R Green, J. R. Curr. Org. Chem. 2001, 5, 809. R Caffyn, A.J.M.; Nicholas, K. M. in Comprehensive Organo-
R Teobald, B. J. Tetrahedron 2002, 58, 4133. metallic Chemistry II, 1995, V.12, Ch. 7.1
R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 208.

(Di)Cobalt alkyne complexes form cations at the propargylic site very easily

HO " "
OH HBF4 or + R2
R' R' R2 R'
R2 R3 R3
R
(CO)6Co2 3 HPF6 (CO)6Co2
(CO)3Co Co(CO)3

thermally stable, dark red/beet/brown structure is a lie

solids

-as cations go, these are very stable

Consider KR+
R + 2 H2O
+
ROH + H3O+ -log KR+ = pKR+
i.e., the less negative (more positive) the number, the more stable

Consider Ph3C+ = pKR+ = -6.8 - -7.4

+ R2 or -5.5
R' depending on reference
+ R3
pKR = -6.6
+ (CO)6Co2 81
meaning, about the same
-best estimation of structure Schreiber, S. L.; et al J. Am. Chem. Soc. 1987, 109, 5749.

-X-Ray of cation Melikyan, G. G. et al Angew. Chem. Int. Ed. Engl. 1998, 37, 161.

R2 R2
R3 R3 -both antarafacial and supra-
facial migrations going on,
(CO)3Co Co(CO)3 (CO)3Co along with epimerization
+ Co(CO)3
+
R' R'
-actually pretty complicated

R3
R2
R2
R2
(CO)3Co Co(CO)3
(CO)3Co Co(CO)3 +
+
R'
R'

-these are much more electrophilic than allylpalladiums, so they are electrophilic
enough to react with several types of nucleophiles
82
 X
electron rich -arene needs one or more activating groups, i.e.,
aromatics
-OCH3, -OH, -NMe2
O
O
O O O-SiMe3 O-BR'2 SiMe3
O
OMe R R R SnBu3
β-dicarbonyls silyl enol ethers allylsilanes or
enol borinates enol
silyl ketene acetals allyltins
acetates

NaBH4 R2NH Et2AlCN R3Al R2Cu(CN)ZnI ???

or
Et3SiH + CF3COOH amines cyanation alkylation

reduction

A couple of examples

CH2Cl2 pretty high syn

OSiMe3
R' R' O stereoselection
+ + -78o
Ph
Co2(CO)6 (CO)6Co2 Ph 83
-the cations can be generated in several related ways, such as from ethers or acetates,
halides, alkenes, epoxides, etc.
OCH3 BF3 AgBF4 Cl
R' R' + R'
CH2Cl2, -78o CH2Cl2, -20o
(CO)6Co2 (CO)6Co2 (CO)6Co2
O
O
R Cl +
R' R C O R' + R
AlCl3
(CO)6Co2 (CO)6Co2

( )n
( )n H+ R' +
R Smit, W.A.; Caple, R.; Smoliakova, I.P.
R' Chem. Rev. 1994, 94, 2359.
O (CO)6Co2 OH
(CO)6Co2

-intramolecular variants of this reation are certainly viable

R BF3-OEt2 R

Me3Si Co2(CO)6 CH2Cl2 Co2(CO)6

OMe 84
 OMe OMe
OMe BF3-OEt2 OMe
MeO MeO
iPr NEt, MeO MeO
2
MeO Co2(CO)6 CH Cl MeO
2 2
MeO Co2(CO)6 NHAc
AcO 70% MeO
NSC 51046
-notice stabilization of 7 membered ring alkyne

in general, the cobalt carbonyl unit can be removed as before (Ce+4, Fe+3, Me3N+-O-)
Importance - in traditional organic chemistry, SN2' reactions are a major competitive
problem in substitutions of propargyl-X
SN2' R
i.e., R C CH2 allenes
X Nu- Nu

-this never, ever, ever happens with Co propargyl cations (Nicholas reactions)

Other Nucleophilic Allyls

-η1-allyl Fp [CpFe(CO)2] complexes

X or
Fe + Fe Fp
OC OC
CO CO 85
 -behave as modestly reactive nucleophiles to a pretty wide range of E+

E+ +
Fp E Fp E
Fp +
O
R Cl + HgCl2 +
O Fp
Fp Fp
Fp HgCl
AgSbF6 R

+ +
Me3O+ Fp H+
CH3 Fp
Fp Fp HBF4 CH3
O
+
R R' OH Br2 +
Fp
Fp Fp
Fp BF3 R Br
R'

R Rosenblum, M. J. Organomet. Chem. 1986, 300, 191.

-even Fp+-alkene complexes will react with these η1-Fp-allyls

H+ + H
+ Fp Fp'
Fp' + Fp+ Fp'
NaI
Fp
86
 η1-propargyls do analogous chemistry H
Fp

η1-allyls react with electron poor alkenes by initial nucleophilic attack, followed by electrophilic
attack back onto the iron containing unit - this is ultimately a 3+2 cycloaddition resulting
E + R Br2
+ Fp R Br R
Fp Fp -
R E E E E CS2 E
E E
Ce+4
E = CO2R, CN
(normally need 2) EtOH EtO2C R
E
E
-to be sufficiently reactive, the alkene usually needs two electron withdrawing
groups, although some cyclic alkenones work with a Lewis acid added (AlBr3)
AlBr3 O
O + Fp
Fp

-several more obscure electron deficient X=X systems do this [3+2] cycloaddition, but they
aren't as important so we'll just list them
δ− δ+ δ− δ+ δ+ δ−
Ts N C O MeO2C N SO2 H2C SO2

-one further [3+2] cycloaddition partner that is interesting enough to show is specialized;
cycloheptadienyl iron cation with an included alkene
87
 R R R
+ +
Fp Fp Fp
+ +
(CO)3Fe (CO)3Fe
(CO)3Fe
if R = O-SiMe3
O
Rosenblum, M. J. Am. Chem. Soc. -"SiMe3+"
functionalized
1990, 112, 6316 and refs therein. Fp
hydoazulene
ring system +
(CO)3Fe

R Ruck-Braun, K.; Mikulas, M/; Amrhein, P. Synthesis 1999, 727.

η3 (?), η4 (?) Complexes - The Iron Oxyallys

some magical species which Noyori proposed
O has never been isolated
Fe2(CO)9
R R OFeLn
R Noyori, R. Acc. Chem. Res. 1979, 12, 61.
Br Br R Noyori, R. Org. React. 1983, 29, 163. R R
R Mann, J. Tetrahedron 1986, 42, 4611. +

But....the following have been isolated at various times

O OR
(CO)3Fe O
S
Fe(CO)3 O Fe(CO)3 M(PPh3)2
Fe(CO)3X Fe(CO)3
X = Br, Cl M = Pd, Pt
see later Frey,M.; Jenny
R = H, TMS Ando, W. Albright, T.A. Organometallics
Organometallics 1990, J. Am. Chem. Soc.
9, 1806. J. Organomet. Chem. 1990, 112, 4574. 1989, 8, 199.
1991, 421, 257. Emerson, G.I. J. Am. Chem. Soc.
1966, 88, 3172.
88
 -therefore, the most likely structures for these iron oxyallyls are....

or perhaps a dimer
O O η3 or
or O η4
+Fe(CO) Fe(CO)3
3 called oxyallyl cations
Br Fe(CO)3
L

-the iron oxyallys react with simple alkenes to give either [3+2] cycloaddition products or
ene reaction products
O
O O O
R R
PhH, Δ R R R R
R R + Fe2(CO)9 +
R' R'
Br Br + CH 3
FeLn
CH3 R'

-the [3+2] cycloadditions work best when the alkene has some carbocation stabilizingg groups
O OFeLn
O Fe2(CO)9
65% via
60o, PhH
Br Br +
Ph Ph Ph
-i.e., with enamines
O O
O Fe2(CO)9
RT - 30o 83%
Br Br N N
O O 89
 OFeLn O
O Fe2(CO)9
51%
RT, O
O O
Br Br
NMe2
NMe2

-nitriles also react in a few cases

Regiochemistry
-on the oxyallyl - the major product results from initial reaction at the least substituted
end of the allyl (to give the most substituted Fe enolate)

-on the alkene - the major product is the one that goes through the most stable carbo-
cationic intermediate
O OFeLn O
O
Fe2(CO)9
major product
Br Br +FeLn +
Ph
Ph

Stereochemistry - normally, one gets retention of stereochemistry about the alkene

-does not mean concertedness; apparently, the intermediate cation is (very) short-lived
-not enough time for bond rotation
O O
Fe2(CO)9 O (D)
+ (D)
D
Br Br benzene, 90
Ph D Ph D 55%
-reaction is certainly not restricted to intermolecular cases; intramolecular ones work as well
+
Br Fe2(CO)9 + other products
110o, PhH
O OFeLn O
Br Camphor
(major)
4+3 Cycloadditions
-probably more imortantly than the [3+2] cycloadditions, these oxyallyl cations react
with dienes ti give 7- membered rings

O O
O Fe2(CO)9 R1 R3
R1 R3 R4
R2 R4 R2
Br Br + FeLn

-a couple of examples
O
ca. 60o 80%
+ Fe2(CO)9 + O
Br Br

O
O O
32o
+ + Fe2(CO)9 35%
O 91
excess
Limitations on Reagents in [4+3] - on the dibromoalkene

O O O O O
Br Br Br R R
R Br
Br Br Br Br R
Br Br Br Br Br Br
can't use
unsubstituted used tribromo used (except R = Ph) is even used
one instead instead of.... sometimes

O O O
Fe2(CO)9 Br Br Zn-Cu
Br Br 63%
O O O
Br Br

-in cases with pyrroles, N-alkyl cases give electrophilic aromatic substitution
N-acyl cases usually give the [4+3]

O Fe2(CO)9 O
N CH3 + + O N CO2Me
N N
Br Br works, though
CH3 CH3
Mechanism
-allyl cation is a 3C, 2π electron system; diene is a 4π electron system
-could this be a concerted [4π + 2π] cycloaddition?
-Noyori thinks yes
-Hoffmann thinks only sometimes, but mostly no 92
(Angew. Chem. Int. Ed. Engl. 1984, 23, 1)
 Regiochemistry
-behaves as if it is a concerted reaction
-therefore, it is controlled by HOMO-LUMO interactions
Consider O if we leave out the iron O LUMO
Ph
Ph
+ FeLn
larger smaller orbital
coefficients
and
EtO2C O
EtO2C O HOMO

-frontier molecular orbital arguments require that atoms with larger orbital coefficients,
and smaller with smaller
O
-therefore, frontier molecular orbital (FMO) arguments would predict Ph
O
EtO2C
-but if stepwise, one would predict....
OFeLn OFeLn O
Ph Ph Ph
+ O would be
+ O CO Et O
CO2Et favoured
EtO2C bad good 2

O O
Ph Ph
-the actual result is....
O 90 : 10 O
EtO2C CO2Et 93
 Stereochemical consequences
-ordinary dienes
O O
Fe2(CO)9
+
+
Br Br O O
+ FeLn
presumed usually major usually minor
configuration (endo) (exo)
-aromatic dienes
O
X X X
+
Fe2(CO)9 X
O O
Br Br O
X = O, N-EWG pretty much a random mixture
-it is the presence of these types of products that makes Hoffmann think that the reaction
is not concerted

-use - pretty good way of making 7-membered ring containing natural products
O
O O O O
i.e., Pd/C, H2 F S OH
DDQ
O
O NH4Cl, PhH O
CH2Cl2
nezukone

-also, in tropane alkaloid synthesis... 94

 O
i-Bu2AlH H3C H3C
E N N
N + 6,7-dihydrotropone
THF, -78o
OH
E = CO2Me HO
H3C
N
1-hyoscyamine
H3C H3C
N N Ph
O
O HO teloidine
HO OH
H HO H HO O
H H
many other natural product syntheses
for reviews, see R Noyori, R. Acc. Chem. Res. 1979, 12, 61.
R Noyori, R. Org. React. 1983, 29, 162.
R Mann, J. Tetrahedron 1986, 42, 4611.
part of R Rigby, J. H. Pigge, F. C. Org. React. 1997, 51, 351
R Harmata, M. Tetrahedron 1997, 53, 6235

η4- Complexes
η4-Trimethylenemethane Complexes

-predominantly used with palladium, due to use of metal in catalytic amounts

-iron also known and used some, but it is stoichiometric

-consider the following substrate that looks like a precursor to an η3-allylpalladium

95
 SiMe3 AcO-
PdoLn SiMe3 -
O CH3
i.e., O CH3
O Pd(PPh3)4 + PdL PdL2
+PdL O 2
2

- in these cases, the Pd is coordinated to all 4 carbon atoms

- this is a trimethylenemethane complex
-excellent reagent for 3+2 cycloaddition reactions
O
SiMe3 PdoLn EWG EWG = -CO2R, -CN, -SO2R, R
OAc
EWG
-mechanism
EWG
-
+ EWG EWG
- +
L2Pd L2Pd

-stereochemical considerations
-about alkene - get mostly retention of configuration, but not perfectly so

CO2Me Pd(PPh3)4(cat), Δ
( )5
OAc
( )5 CO2Me 96
SiMe3
 Pd(PPh3)4(cat), Δ
major minor
Ph CO2Me +
OAc
Ph CO2Me Ph CO2Me
SiMe3

-intramolecular reactions also work well +

PdL2
SiMe3
Pd(dppe)2 H
CO2Me - CO2Me
OAc MeO2C H

-other aspects of the stereochemistry (i.e., diastereoselectivity) have been well established,
but are beyond the course's scope
Regiochemistry
OAc R OAc OAc
R = alkyl
R or or R electron withdrawing
electron donating
SiMe3 SiMe3 SiMe3
-regardless, it doesn't matter (much),
-the produc is as if......
+ + EWG
L2Pd -
L2Pd EWG
R EWG
-
R R
97
-no real mechanistic explanation for this result
-example of use in synthesis - loganin
H O H CO Me
O Pd(OAc)2 2
SiMe3 1) O3
+ (iPrO)3P 2) MeOH, H+
OAc H H
1:1 ratio 3) NaOMe

H CO2Me H CO2Me
racemic loganin O
(key intermediate
in alkaloid biosynthesis) O O
H H
O-beta-D-glu OCH3

-there is some work on reacting TMM-Pd complexes with C=O and C=N-EWG in the
presence of R3Sn-X co-catalysts
-see Trost, B. M. et al J. Am. Chem. Soc. 1990, 112, 408.
Trost, B. M. et al J. Am. Chem. Soc. 1993, 115, 6636.

For reviews in the area see:

Trost R Angew. Chem. Int. Ed. Engl. 1986, 25, 1.
R Pure Appl. Chem. 1988, 60, 1615.
R 'Comprehensive Organic Synthesis' V. 5, p. 271 (1991)
R Org. React. 2002, 61, 1.

Iron tricarbonyl - trimethylenemethane complexes also known

see Donaldson, W.A. J. Org. Chem. 1995, 60, 1611. 98
Frank-Neumann, M. Tetrahedron: Asymm. 1996, 7, 3193. Fe(CO)3
R Green, J. R.; Donaldson, W.A. 'Encyclopedia of Inorganic Chemistry, Vol. 4, 1994
 η4-Diene Complexes
Fe(CO)3
-absolutely dominated by iron tricarbonyl complexes
Preparation

Me3NO or Δ
+ Fe(CO)5 Fe2(CO)9 +
hν, or Δ
Fe(CO)3
-more subtle reagents
(CO)3Fe Δ low T
+ Fe(CO)3
Ph
2
O Fe(CO)3
Fleckner, H.; Grevels, F.W.; Hess, D.
J. Am. Chem. Soc. 1984, 106, 2027.
Me3NO mediated transfer Shvo, Y.; Hazum, E. J. Chem. Soc. Chem. Commun. 1975, 829

-the Fe(CO)3 unit is unusually stable; even in cases where it could lose more CO ligands,
it normally does not
Ph Ph (CO)3Fe Ph Ph
Ph
Fe2(CO)9 R O
O R O
Δ R
Fe(CO)3 R (CO)3Fe
Note: esters, amides only form η2-Fe(CO)4 complexes
Reviews
R Pearson, A.J. 'Iron Compounds in Organic Synthesis, Ch. 4, 1994.
R Green., J. R,; Donaldson, W. A. 'Encyclopedia of Inorganic Chemistry, 1994, Vol. 4
R Gree, R. Lellouche, J. P. Adv. Met.-Org. Chem. 1995, 4, Ch.4
R King, R.B. 'The Organic Chemistry of Iron', Vol. 1, 1978. 99
 Rare/specialty methods

Fe(CO)5 Agar, J.; Kaplan, F.; Roberts, B. W. J. Org. Chem. 1974, 39, 3451.
O
hν, -CO2 Very stable complex
R O R Fe(CO) -by contrast, free cyclobutadiene is not at all stable
3
MeO2C
Fe2(CO)9 rare: ring opening is actually stereospecific
Fe(CO)3
MeO2C MeO2C Whitesides, T.H. J. Organomet. Chem. 1974, 67, 99.
CO2Me

Molybdenum dienes complexes +

CpMo(CO)2 Ph3C+ BF4- CpMo(CO)2
Na[(CO)3MoCp] hν
Br (CO)3Mo or
NO+ PF6+
+
Br BrMo(CO)2(MeCN)2 CpMo(CO)2 CpMo(CO)2
Mo(CO)3(MeCN)3

Δ Na+ Cp- Ph3C+

R
+ R
Mo(CO)2(MeCN)2 Green, M. et al
+ J. Chem. Soc., Chem.
BF4- + Commun. 1985, 18.
(CO)2Mo

R Comprehensive Organometallic Chemistry, V.3, Ch 27.2

R Pearson, A. J. Adv. Met-Org. Chem. 1989, 1, 1. 100
 Early Transition Metal Complexes
R
Cp2MCl2 + Cp2M Cp2M
* Mg C C n*
M = Ti, Zr H2 H2

R Yasuda, H.; Nakamura, A. Angew. Chem. Int. Ed. Engl. 1987, 26, 723.
Cp2M

2. Decomplexation of η4-Diene Complexes

a) Oxidation of Iron-Diene Complexes
CH(CO2Et)2 CH(CO2Et)2
Me3NO FeCl3

OMe OMe
Fe(CO)3 RO RO
Fe(CO)3
Shvo, Y.; Hazum, E. J. Chem. Soc., Chem. Commun.
1974, 336.

Other oxidants such as CeIV, CuCl2, AgI work also

b) Early Transition Metal Dienes

-have reactivity like..... (D)
- H
and therefore H2O
Cp2Zr
Cp2Zr (D2O)
101H (D)
-
notice regiochemistry
3. Use as Protecting/Stabilizing Groups

a) Protection of Dienes
-although coordination of a diene by Fe(CO)3 is inductively a slight electron donor,
the reactivity of dienes to electrophiles is reduced

therefore
1) "BH3" FeCl3
OH
OH
2) H2O2 Fe(CO)3
Fe(CO)3
OH

a b HO

RO RO RO
Fe(CO)3
a. i., H2, PtO2, PhCH2SiMe2H b. i.,OsO4
ii., FeCl3 ii., FeCl3

-Carbenes - normally prefer to add to conjugated dienes over isolated C=C 's, but....
Cl Cl

CHCl3 Cl CuII Cl
tBuO- Cl
Fe(CO)3 :C Fe(CO)3
102
Cl
 -and acylation*
O
H3C Cl
Fe(CO)3 H3C(O)C Fe(CO)3
AlCl3, -78o
* - diene-Fe(CO)3 complexes will also react, but more slowly
-one can even do cycloadditions on free double bonds in the presence of
Fe(CO)3 complexes
O
O
[4+2] PtO2 N
N N-CH3
CH3 N-CH3 N
N H2 Fe(CO)3
(CO)3Fe O N O Fe(CO)3 O
O
N N H Me
H
+ NN Me H
Δ H Me3NO H
N N H
O O
75% O 84% O >90%
(CO)3Fe
(CO)3Fe (CO)3Fe

-also stable to Wittig reaction, aldol condensations, osmylation (dihydroxylation)

-exception (sort of) - let's say 'controlled' reactivity

O
consider v. non-selective reaction/oligomerization
Cl 103
a mess
AlCl3
 -conversely,..
O + Fe(CO)3 (CO)3Fe O
(CO)3Fe O -H+
(CO)3Fe Cl CH3 +
AlCl3 CH3
O
CH3
stabilized intermediate depending upon conditions

-the reactivity is lower, but much more controlled

PPh3 PPh3
+
Fe(CO)2PPh3 O (CO)2Fe
1) AlCl3, -78o O (CO)2Fe
O
Cl
CH3
-H+ CH3 96%
2) H2O H H

b) Stabilization of (overly) Reactive Species

i) consider cyclobutane
Fe(CO)3 Fe(CO)3
-classic antiaromatic compound
-'cannot' be isolated -very stable compounds

hν R
O Fe2(CO)9 Cl

O Fe(CO)5 R
Fe(CO)3 Cl
-stable enough to allow standard aromatic functionalization reactions - behaves pretty
104
much like benzene
-these cyclobutadiene-Fe(CO)3 complexes are stable enough to allow standard aromatic
functionalization reaction - they behave pretty much like benzene

OH
O
O
O H

Cl Fe(CO)3
Fe(CO)3 NaBH4
AlCl3 Fe(CO)3
POCl3 O
D Ph
D+ N H
CH3 HO
Fe(CO)3 Fe(CO)3
CH2O, CH2O,
Fe(CO)3
HCl
Me2N Me2NH Hg(OAc)2,
NaCl Cl

Fe(CO)3
ClHg Fe(CO)3

Fe(CO)3
Rosenblim, M.; et al J. Am. Chem. Soc. 1972, 94, 1239
Emerson, G.F.; Pettit, R., et al J. Am. Chem. Soc. 1975, 97, 3255. 105
R Green, J. R.; Donaldson, W.A. 'Encyclopedia of Inorganic Chemistry', Vol. 4, 1735, 1994.
Note: Decomplexation of Fe leads to free cyclobutadiene, which can be trapped by other
reagents

CeIV, FeIII, R R' R

Δ R
or Me3NO R'
Fe(CO)3 R'

Pettit, R. J. Am. Chem. Soc. 1965, 87, 3253.

Snapper, M.

ii) Dienols
H
not unstable R O
R OH
per se, but...

Fe(CO)3 coordinates more strongly to the π-system of a C=C relative to a C=O, so....
Fe2(CO)9 1) MeLi does not
R O R O R OH
CH3 CH3 tautomerize
2) H2O to aldehyde
O (CO)3Fe O (CO)3Fe

HO R O
R R OH Ph
(CO)3Fe O
(CO)3Fe (CO)3Fe

is similar, except it 106

isomerizes to....
iii) OMe O
H2O OH

+ Fe(CO)
3 Fe(CO)3 Fe(CO)n

-almost nothing has been done with this, but it has much potential....
see Birch, A.J. Tetrahedron Lett. 1975, 119 (Org. Synth. VI, 996)

iv) Other examples

O (CO)3Fe
Landesberg, J.M.; Roth, W.R.; Neier, J.D.
Sieczkowski, J. Tetrahedron Lett. 1967, 2053.
J. Am. Chem. Soc. 1971, 93, 972

Fe(CO)3

4. η4 Diene Iron Complexes as Electrophiles

-iron diene complexes will react with nucleophiles, although the pathways are a bit complex
-
Nu - Fe(CO)
Nu H
+
Nu Nu - 3

- thermod, A
R R Fe(CO) kinetic,
3 0o R Fe(CO) -78o R Nu
3
H+
Nucleophiles are restricted CO2Et -
CN -
to things like.......... - Ph Ph S S
-
Semmelhack, M.F. J. Am. Chem. Soc. 1984, 106, 2715. R Nu
107
-in cyclohexadiene complexes, species like A do further chemistry

CF3CO2H
R- R
+ R R R
+ +
Fe(CO)3 -
Fe(CO)3
major
E O
CO E+
R R

O E = H, OH (O2), or ROSO2R
- Fe(CO)
3
-see R Pearson, A.J. 'Iron Compounds in Organic Synthesis, p. 67-97.

in acyclic dienes, get related but more complicated reaction pathway

-see Semmelhack, M. F. Organometallics 1983, 2 1385 ; J. Am. Chem. Soc. 1985, 107, 1455.
Yeh, M.C.P.; Hwu, C.C. J. Organometal. Chem. 1991, 419, 341.
Chang, S. et al (M. Brookhart) J. Am. Chem. Soc. 1994, 116, 1869.

b) Molybdenum Diene Complexes

-these complexes are cationic, so that they obviously are a good choice for being more
reactive as electrophiles

+
CpMo(CO)2 CpMo(CO)2
Nu- C-1 attack
108
Nu
-range of nucleophiles should start looking familiar

-enamines highly stabilized enolates -CH(CO Et) Grignards, or better

2 2
NR2 still, cuprates
RMgBr, R2CuLi, R(CN)CuZnI

+ O Cp(CO)2Mo
Mo(CO)2Cp 1) N O
H
2) workup

+ O
Mo(CO)2Cp Mo(CO)2Cp
E, E' = -CO2Me, -SO2Ph, CH3
-CH(E)(E') E
E'
Note:
Mo(CO)2Cp
Mo(CO)2Cp
Na/Hg
CO2Me
CO2Me
SO2Ph
109
 +
Mo(CO)2Cp Mo(CO)2Cp
MeMgBr

CH3 CH3

Mo(CO)2Cp H3C CH3

+ Note: Cp* =
Mo(CO)2Cp* C5H11 H3C CH3
LiCu 2
C5H11 can be a ligand on Mo
instead of Cp
Stereochemistry
-it is apparent from the above examples that the addition is routinely anti to Mo

Regiochemistry
-the nucleophile's attack is generally at the less substituted end of the diene

+ O
Mo(CO)2Ind
H3C 1) N Ind(CO)2Mo
O
H3C
2) workup H
H3C
(CO)2Mo(MeCN)2
+
η5-indenyl can be a ligand instead of Cp 110
Note; product allylMo has anti stereochemistry at addition site
 -tandem reactions are also feasible
sterically available
H Ph3C+ CH3 CH3
MeMgBr
MeMgX H CH3 CH3
(-H-) H H
H CpMo(CO)2 H
CpMo(CO)2 CpMo(CO)2 + CpMo(CO)2
+
not sterically available

Decomplexation Reactions of molybdenum Complexes

-straight oxidative decomplexation does occur for diene complexes

Me3NO
C5H11 C5H11
MeCN
(CO)2MoCp*
+

-oxidative decomplexation of allylMo's with nucleophilic attack

Nu I2 Nu attack trans I Nu

H H to Mo H H
CpMo(CO)2 CpMo(CO)2
+.
111
-oxidative decomplexation can occur with nucleophilic addition
 Mo(CO)2Cp I2 or
KOH Mo(CO)2Cp
O
NOPF6 O
CO2Me
CO2H
-note stereochemistry
R Pearson, A.J. Adv. Met. Org. Chem. 1989, 1, 1.
R Backvall, J.-E. Adv. Met. Org. Chem. 1989, 1, 135. (mostly Pd catalyzed addns)

asymmetric addns Pearson, A.J. et al Tetrahedron Lett. 1987, 28, 2459

c) we will not discuss this in detail, but PdII catalyzed additions to dienes is known

Nu- Nu
R R
R R
PdII, oxidant
Nu

Nucleophile is usually R2N- or AcO-; oxidant is usually benzoquinone

some cases of C-C bond formation
-see Backvall review

112
 η4-Diene Complexes as Nucleophiles

-early transition metal diene complexes don't really behave like dienes
-dominated by Cp2Zr complexes
-

Cp2Zr behaves like

Cp2Zr
-

-therefore, the zirconium dienes are reactive as nucleophiles, especially with oxygen
containing electrophiles, where =O: coordination to Zr can increase the electrophilicity
of C=O

1) E+
Cp2Zr E
2) workup

Regiochemistry
-if a substituent is at the 2-position of the diene, the rxn occurs at the more substituted end
O R R'
H+ OH
O notice difference in

}
R R'
Cp2Zr Cp2Zr R R' product isomer
dependence on acid vs.
NH base cleavage
or OH
NH R R'
113
-in acid, the allylZr cleaves via SE2' (remote end, much like allylsilanes)
-in base, the product is the result of direct C-Zr bond cleavage

-other oxygen bearing E+'s include......

esters (or nitriles), and epoxides

O
1) 2) H+
R OR' R
Cp2Zr or O
1) RCN 2) H+
Note: Rxn is at the more substituted
O end of the epoxide
1) R M -
M
OH O O
Cp2Zr R +
2) H+ R R
R = aryl, vinyl

-that is evidence of SN1 - type reactivity

-further evidence is the loss of stereochemical integrity of the epoxide, i.e.,

O Ph Ph
+
Ph Me O
O
Cp2Zr O Cp2Zr - Cp2Zr
or
Ph Me both epoxides give
same isomeric mixture 114
 α, β-unstaurated carbonyls -give high 1,2-addition
R
OR' 1)
1)
Cp2Zr Cp2Zr O OH
O
O
2) H+
2) H+

Other electrophiles
CO2
H+
CO2
Cp*2Zr Cp*2Zr
Cp*2Zr O O O O HO O
But in many cases, further reaction can't be stopped
Isocyanates
NR

R-N=C=O O
Cp2Zr Cp2Zr

Photochemical Reactions

-with carbonyl compounds and alkenes/alkynes, a photochemical reaction occurs at

much lower T (-70o) 115
-one big difference - the reaction now occurs away from a 2-substitutent
 carbonyls
O R R
R R R
R2C=O oxidative O R H+
Cp2Zr R Cp2Zr R O HO
Cp2Zr hν Cp2Zr
coupling

alkenes/alkynes

R3
Cp2Zr hν Cp2Zr R3 Cp2Zr R3
Metal carbonyls
M(CO)6 O O
C Cp2Zr M(CO)5
Cp2Zr Cp2Zr M(CO)5
M = Cr, W, Mo Cp2Zr
O M(CO)5
CpCo(CO)2 is similar

Finally, at least for some products, the allylZr products themselves can be reacted with carbonyls
R R
O carbonyl, metal carbonyl adducts do this to
R2C=O
Cp2Zr -always get 9-membered ring with trans C=C
Cp2Zr

see R Yasuda, H.; Nakamura, H. Angew. Chem. Int. Ed. Engl. 1987, 26, 723.
R Taber, D. F. et al Curr. Org. Chem. 2000, 4, 809.

other Fe diene review R Gree, R. Synthesis 1989, 342. 116

η5-Dienyl Complexes

-dominated by and to a much lesser extent by

R
complexes
-
Cr(CO)3
(CO)3Fe+
we will cover this under η6- complexes

authors -dominated by A.J. Birch initially

-more recently by A.J. Pearson (Case Western)
W.A. Donaldson (Marquette) (acyclics)

Generation of η5-Cationic Complexes

-most commonly made by hydride abstraction from diene complexes, normally by
trityl cation

Ph + Ph H- source
C BF4 Ph3C-H
Ph
triphenylmethyl (trityl) cation
-thus....
+ -works very well for cyclic dienes,
Fe(CO)3 as adjacent substituent must
Ph3C+BF4- be cis
Fe(CO)3 BF4-
117
 -with acyclc dienes, one can normally abstract H- is the source is cis
i.e.,
Ph3C+
+
(CO)3Fe (CO)3Fe

-but, if the "H- source' can only be trans, the abstraction usually fails

Ph3C+ PF6- + PF6-

Ph3C+ Fe(CO)3 Fe(CO)3
(CO)3Fe no rxn

Regiochemistry of Hydride Abstraction

-this abstraction s usually pretty selective, but not that readily predictable. It does not
correspond to the most stable cation

-Pearson has made an orbital interaction based explanation - for those interested, see.
Pearson, A.J. et al Organometallics 1984, 3, 1150.

-examples
1 OMe MeO +Fe(CO) MeO
2 3
Hb +
Hb Fe(CO)3
+
Fe(CO)3
Ha Ha R R
R 3
Hb abstraction Ha abstraction 118
4
 R Hb abstraction Ha abstraction

H 20 80
3-CH3 0 100
4-CH3 90 10
3-OCH3 N O 56 44
4-morpholino 100 0
+
1 2 Fe(CO)3
Hb OMe OMe
Hb OMe
Fe(CO)3 +
Fe(CO)3 +
R Ha R
Ha
R 3
Ha abstraction Hb abstraction
4

R ro Ha abstraction Hb abstraction
H 90 10
1-CO2Me 100 0
4-CO2Me 0 100
4-CH3 0 100
4-OCH3 56 44

-the most common method for formation of acyclic pentadienyliron complexes is by

119
protonation of an η4−dienyl alcohol complex by a strong acid
 Fe(CO)3 + + Fe(CO)
H+ Fe(CO)3 3
HO
R R
R
see R Donaldson, W.A. Aldrichim. Acta 1997, 30, 17.
also Magyar, E.S. et al Inorg. Chem. 1978, 17, 1775.
Beihl, E.R. et al J. Organomet. Chem. 1979, 174, 297.

-there are related methods for preparation of dienylirons, from carbonyls, alkenes (trienes)

Fe(CO)3 + + Fe(CO)
H+ Fe(CO)3 -28o 3
O HO
R R
H H HO R

Fe(CO)3 + Fe(CO)
HBF4 + 3
Fe(CO)3
R propionic
anhydride R
H3C R
H3C

D
CF3CO2D notice the stereochemistry of attack
D +
D Fe(CO)3 -78 , CH2Cl2
o
Fe(CO)3 J. Chem. Soc., Dalton Trans. 1977, 794120
and 2340
-from alkoxy-substituted diene complexes and strong acid

OMe OMe OMe

Fe(CO)5 or 1) H2SO4
+ Fe(CO)3 +
Fe(CO)3 Fe(CO)3
Fe2(CO)9 2) NH4PF6

Birch redn 2:1

This goes via....

OMe MeO D MeO D

D
D2SO4 -H+ +H+, -MeOH +
Fe(CO)3 Fe(CO)3
+
H Fe(CO)3
Fe(CO)3
-and
MeO H H
OMe OMe -MeOH
Fe(CO)3 Fe(CO)3 D D +
D Fe(CO)3
+ +
D2SO4 Fe(CO)3
H

-by cation rearrangement

OH H
+
H+ hydride +
or Fe(CO)3
Fe(CO)3 Fe(CO)3 Fe(CO)3 transfer
121
 Reactions as Electrophiles
Nucleophilic Attack on η5-Complexes

-these cations readily react (normally) with nucleophiles to give C-C or C-heteroatom
bond formation

-attack is from the exo- face (stereoselective, away from iron)

-'normal' mode of attack is at C-1 terminus
Nucleophiles: C-C bonds O
O enolates work
OSiMe3 N - only
EtO2C CO2Et R' R' sometimes
R enamines
- R
stabilized enolates silyl enol ethers
silyl ketene acetals

SiMe3 RLi, RMgBr usually fail

allylsilanes
SnBu3 allyltins R2Cd, R2Zn, R2CuLi, RCu(CN)ZnI usually better

C-X bonds
R2NH (amines), H2O, MeO-, R3P (phosphines), (RO)3P (phosphites), R3As (arsines)
NaBH4, Et3SiH, NaBH3CN (hydride sources)

Regiochemistry, part II
-attack of the nucleophiles is at less substituted terminus
-MeO as a substitutent is particularly powerful in this respect 122
 OMe -enamine example
OMe O Fe(CO)3
+ 1) N -regiochem away from OMe
Fe(CO)3 -sterochem exo (away from iron)
2) H2O O

CH3 NaCH(CO2Me)2 CH3

+ Fe(CO)3
MeO2C
Fe(CO)3
MeO2C

CO2Me
CO2Me
+ NaCH(CO2Me)2
Fe(CO)3 Fe(CO)3
MeO2C
MeO2C

+ MeO2C
Fe(CO)3
Fe(CO)3 NaCH(CO2Me)2
MeO2C Fe(CO)3 +
OMe OMe OMe
MeO2C CO2Me
82:18
123
counterion dependent
 OR OMe
OSiMe3
+ Fe(CO)3
Fe(CO)3 OMe
CO2Me

R = Me, iPr

see R Pearson, A.J., in Comprehensive Organometallic Chemistry, Vol. 8, p 939-1011

R Comprehensive Organic Synthesis, 1991, Vol. 4, p. 663-694
R Iron Compounds in Organic Synthesis, 1994, Ch.5
R Adv. Met-Org. Chem. 1989, 1, 1

R Harrington, P.J. Transition Metals in Total Synthesis, Ch. 4

The acyclic cases have also been studied fairly extensively

+ (CO)3Fe
Fe(CO)3 R' CuLi2 R = Me, Ph, CO2Me
3

R Et2O/THF, -65o R
R'
(CO)3Fe
PhCH2CH2Cu(CN)ZnBr
Donaldson, W. A. et al
Tetrahedron Lett. 1989, 30, 1339.
R = Me H3C

Also, RNH2, H2O, R2Cd, R'-CC-SiMe3 + F-, NaBH3CN, 124

silyl enol ethers, allylsilanes (give trans products), and NaCH(CO2Et)2 in many cases
 There are, though, at least a few regiochemical exceptions....
+
Fe(CO)3 LiCH(CO2Et)2 CO2Me CeIV (MeO2C)2CH
MeO2C
RO2C MeOH
RO2C RO2C
H Fe(CO)3
C-2 attack
see Donaldson reviews....most recent.. R Donaldson, W. A. Curr. Org. Chem. 2000, 4, 837
R Donaldson, W. A. Aldrichim. Acta 1997, 30, 17

-geometry of pentadienyl thermodynamically prefers a "U" shape, but if it's generated

with an "S" shape, it will keep that conformation (configuration?) until about -30o

OAc BF3-OEt2 Nu
R1
R1 Nu-, -78o R
(CO)3Fe R2 (CO)3Fe R2 (CO)3Fe R2 1
+
-reacts before isomerization occurs, therefore retention
Uemura, M. et al Tetrahedron Lett. 1987, 28, 641; Roush, W.R. et al Tetrahedron Lett. 1994, 35, 7347 and 7351.
+ +
Fe(CO)3 Fe(CO)2(P(OPh)3
doesn't work; Pearson's solution
nucleophiles -see book
deprotonate 125
instead
 Synthetic Utility -widely used by Pearson's and Knolker's groups
R Synlett 1992, 371 R Chem. Soc. Rev. 1999, 28, 151. R Pearson, A.J. Acc. Chem. Res. 1980, 13, 463.

Example: as equivalent of cyclohexenone γ-cation O +

OMe OMe OMe

OMe 1) HO-
Fe(CO)5 1) Ph3C+BF4- +
2) MeLi Fe(CO)3 Fe(CO)3
Fe(CO)3
Δ 3) NaH, 2) NH4+PF6-
( )3 O
CO2Me ( )3 CO Me CO2Me
2
CO2Me
MeO OMe O O

OMe O
Et3N, CH2Cl2
Fe(CO)3 1) Me3NO
-78o 2) H3O+(dilute) CO2Me
CO2Me

O O

and
OPr-i
OPr-i 1) p-TsOH OPr-i +
Ph3C+BF4- Fe(CO)3 KH(CO2Me)2
Fe(CO)3
2) Fe2(CO)9, CH2Cl2 THF
OMe
OMe 30
o
OMe
126
 OPr-i 1) KCN, DMSO, OPr-i OPr-i
1) p-TSCl, Fe(CO)3
Fe(CO)3 Δ, -CO2 Fe(CO)3
pyridine
CO2Me 2) iBu2AlH, THF 2) NaCN, CN
OH
-78o - RT HMPA
CO2Me MeO
MeO MeO
major

OPr-i O
1)oxalic
1) Me3NO HH
acid(aq) O N
benzene
2) LiAlH4 2) NaHCO3
NH2 NH2 OMe
MeO MeO

OH (+/-)-limaspermine

N H

Other Pearson reviews:

R Science 1984, 223, 895; R Pure Appl. Chem. 1983, 55, 1767;
R Chem. Ind. 1982, 741; R Knolker, H.J. Chem. Soc. Rev. 1999, 28, 151. 127
 Acyclics - synthesis of 5-HETE methyl ester
+
(CO)3Fe PF6- H11C5 C Li (CO)3Fe
H2
H2, Lindlar cat.
MeO2C + CuBr-Me2S, Et2O/THF, MeO2C 90o
>92%ee -45o
60%
O
(CO)3Fe 1) CuLi2
(CO)3Fe OO
1) DIBAL-H, 92%
3
H
2)MnO2, 65% 2) pTsOH, H2O/THF
MeO2C O
3)MeOH, K2CO3

(CO)3Fe
H (R)-HETE methyl ester
H Ce+4
HO HO >93% ee
86%
MeO2C MeO2C
5-hydroxyeicosatrienoic acid (HETE)
+ diastereomer (S) enantiomer
Tao, C.; Donaldson, W.A. J. Org. Chem. 1993, 58, 2134.

For other metal pentadienyls, see:

R Ernst, R.D. Chem. Rev. 1988, 88, 1255.

R Powell, P. Adv. Organomet. Chem. 1986, 26, 125. 128
η6-Triene Metal Complexes
-dominated by h6-benzene metal complexes
-very extensively developed; many, many complexes known
Order of Utility

>>> >
+ 2+
Cr(CO)3 Fe Mn + Fe
OC CO L

Preparation of Complexes
Chromium
a) Standard method - Arene + Cr(CO)6 + heat
R
R Bu2O:THF (10:1)
+ Cr(CO)6 + 3CO
Δ
Cr(CO)3

b) milder conditions - arene +L3Cr(CO)3

L = is often acetonitrile - requires only ca. 70o
R
R THF
+ (MeCN)3Cr(CO)6 + 3 MeCN
Δ
Cr(CO)3 129
c) by arene exchange - one of the most weakly bound arenes is naphthalene, so
R
R Δ
+ +

Cr(CO)3 Cr(CO)3

equilibrium is well to the right, normally Kundig, E.P. et al J. Organomet.Chem. 1985, 286, 183.

d) Photolysis
R R
hν, RT
+ Cr(CO)6 + 3CO
Cr(CO)3

e) last resort, from Cr(CO)(4-picoline)3 + Lewis acid

R R often works in the most
BF3-OEt2 sensitive cases
+ (CO)3Cr N
3 Cr(CO) 3
Br I
i.e., don't work at all under normal conditions,
, due to oxidative addition

They do complex under these conditions, although the yields are poor 130
Ofele, K. Chem. Ber. 1966, 99, 1732.
Complexes of Mn
Cl 100o Cl
+ (CO)5MnBr + AlCl3 4h
or Mn(CO)8Cl2 +Mn(CO)
+ HBF4/TFA 3

Cl Cl
+ TFA
Mn2(CO)10 + HBF4
Δ +Mn(CO)
3

+Mn(CO)
3

R Sun. S.; Dullaghan, C.A.; Sweigart, D. A. J. Chem. Soc., Dalton Trans. 1996, 4493.

Complexes of Iron

a) Ligand exchange with ferrocene

R 2 AlCl3 H2O HPF6

Fe + Fe + AlCl4- Fe + Cl- Fe + PF6-
Al R
R R 131
b)using the metal Cp-halides
AlCl3
R
Fe
+ Fe + AlCl4-
OC Cl
CO R

original prep, but not used much any more for Cp complexes
-for Cp* complexes, though, it's the default way
R Astruc, D.Tetrahedron 1983, 39, 4027.
R Kündig, E.P. Top. Organomet. Chem. 2004, 7, 3.
AlCl3
R
Fe
+ Fe+ AlCl4-
OC ca. 90o
Br R
CO

Electronic Effects in η6-Complexes

-complexation of the arene by Cr(CO)3 clearly results in a net withdrawal of π-electron density

is a weaker base than

NH2 NH2

Cr(CO)3

and
CO2H pKa 4.77 CO2H pKa 5.52 CO2H pKa 5.68

Cr(CO)3 (MeO)3PCr(CO)2 132

Consider O2N CO2H pKa 4.48

Therefore, is often considered electronically O2N

equal to.......
Cr(CO)3
-this inductive lectron withdrawing ability, as well as resonance electron donating and
resonance electron withdrawing ability, contributes to the reactions that arene-Cr(CO)3
will undergo
-we will discuss these as we encounter them

Nucleophilic Additions to Arene-M

R Pape, A.; Kaliappan, K.P.; Kundig, E.P. Chem. Rev. 2000, 100, 2917.
R Top. Organometal. Chem. 2004, 7, Ch.4

background Nu
+ Nu- H
-

is not normally a commonly feasible reaction, unless the arene has some strongly
electron withdrawing group(s) on it...
But.... Nu
H
+ Nu- further reaction

Cr(CO)3 - Cr(CO)
3
133
is absolutely viable A
-in 'normal' cases, nucleophiles which work in this process are limited to ones whose
conjugate acid (i.e., Nu-H+) has a pKa > 20

-therefore, successful nucelophiles include...

LiCH2CO2R, LiCH2CN, KCH2CO2tBu, LiCHCN(OR), LiCH2SPh, PhLi, ,

S S
Li H
Li R , Li , tBuLi

Unsuccessful ones..
R R
LiCH(CO2R)2, Li , Grignards, Me2CuLi
O O
Li
Note: nBuLi, MeLi, sBuLi do different reactions

So what does one do with the reaction intermediates, i.e., A ?

Chem. Eur. J. 1998, 4, 251;
Helv. Chem. Acta 1997, 80, 2023. R
R H I2
R
Cr(CO)3
- Cr(CO)
several instances 3

not that reliable

1) CF3CO2H
E+
O 2) I2
E R R
in some
cases 134
R Kundig, E.P.; Pape, A. Top. Organomet. Chem. 1994, 7, CH5
 Regiochemistry of Nucleophilic Attack
R Nu R R
Nu- I2 R
R H Nu

Cr(CO)3 - Cr(CO) Nu Nu
3
o- m- p-

-do get mixtures under these conditions, but the general rules are......

R = electron donating (-OCH3, -CH3, -NMe2) meta (major)

R = electron donating and large (-SiMe3, -tBu, -CH(tBu)2) para (major)
R = electron withdrawing (i.e, CF3) para (major)
R = electron withdrawing and coordinating ortho
-considerable variation with size of nucleophile
-sterically smaller nucleophiles, such as -CH2SPh,
S S
give substantial ortho substitution -
-Note: these are under kinetic conditions (-78o)
Why this regiochemistry?
-best guess - a combination of charge and orbital control
-charge control - charge induced by preferred M-CO conformation
-arene C's eclipsed by Cr-CO are attacked preferentially
EDG EWG Bulky

135
Frontier Orbital Control
-attack occurs at the lowest unoccupied arene centred M.O. (LUMO)

EDG EWG
LUMO coefficients

-the argument is that if there is a good energy match between the LUMO of the arene-Cr(CO)3
and the HOMO of the nucleophile, then orbital control is favoured
-in the absence of this match, charge control operates
see Semmelhack, M.F. et al Organometallics 1983, 2, 467.

Thermodynamic Control

-it was later realized that this addition to the arene-Cr(CO)3 is reversible in many cases; this
has a couple of consequences

1) if there is a leaving group present, one should be able to.....

Nu Nu
X H Nu- -X-
Nu- X Nu
X
- Cr(CO) Cr(CO)3 - Cr(CO) Cr(CO)3
3 3

-this is possible, especially for X = F X = F > Cl, OPh >> others 136
 2) some nucleophiles which don't give noticeable amounts of additionin non-X bearing cases
now work well

i.e, NaOMe,, R2NH, -CN, -CH(CO2Et)2 now work

thus -CH(CO Et)

2 2 CO2Et
Cl Semmelhack, M.F. et al
J. Am. Chem. Soc. 1974, 96, 7091, 7092.
25o, 20h CO2Et
Cr(CO)3 Cr(CO)3
-another consequence
-difference in regiochemistry of addition at different T
-apparent that methoxy still prefers to be meta- to nucleophile under thermodynamic
conditions
-other substituents are much less predictable
CN
Examples
1) LiC(Me)2CN -70o, 1 min 35:64
+
NC -70o, 8.6 h 02:97
N 2) I2 N N
(CO)3Cr

NC
1) N
-78o, THF 72:28
Li + 0o, THF 03:97
CN
Cr(CO)3 2) H+
3) I2 NC
137
Semmelhack, M.F. et al J. Am. Chem. Soc. 1977, 99, 959; Ohlsson, B.; Ullenius, C. J. Organomet. Chem. 1984, 267, C34
Note: A couple of nucleophiles that do add kinetically do not undergo reversible reaction

Kundig, E.P. et al J. Am. Chem. Soc. 1989, 111, 1804.

S S , -CH2SPh, PhLi, tBuLi R Kundig, E.P. Pure Appl. Chem. 1985, 57, 1855.
-

Reaction with protic workup

-if a careful work is done using a proton source instead of I2, one gets reduced arene
complex which then loses Cr easily - since the transient complex is coordinatively
unsaturated (16e-) Cr, hydride shifts occur readily and one gets diene rearrangement

1) Li CN CN CN
CN H+ H shift
H HH
2) H+
Cr(CO)3 (CO)3Cr H (CO)3Cr
- Cr(CO)
3
B I2
predominant substitution regiochemistry CN

-except NC
same conds methoxy has very high preference
OCH3
for 1-position
Cr(CO)3 OCH3
Alkylation of anionic intermediates

S S , PhLi, BuLi
-if the incorporated Nu- is one of the irreversible ones t

-then the anionic intermediate B can be alkylated with 1o alkyl,

- allylic, benzylic, propargylic
iodides, bromides, or sulphonates, 138
BUT(!), the reaction usually goes with CO insertion (there are exceptions)
S
S S S S 1) CH3I, CO
- notice stereochemistry
S E+ attacks from same
H 2) I2 or PPh3 CH3 side as the metal
Cr(CO)3
B O -therefore, trans addn
- Cr(CO)
3
-conversely, nucleophiles which add reversibly fail

CN Br
- CN CN
H
+ +
- Cr(CO) Cr(CO)3 Cr(CO)3
3

-another successful example

MeO O CH3
MeO Kundig, E.P. J. Org. Chem. 1994, 59, 4773.
1) PhLi Ph Top. Organomet. Chem. 2004, 7, ch 5

2) MeI, CO
MeO 3) I2
Cr(CO)3
MeO

Improving Reactivity - Other Metals

-definite limits on the nucelophilic attack on arene-Cr(CO)3 139
-therefore, there is some use for other, more electrophilic, M-arene complexes here
 The relative rates of reaction of many of the complexes are known

+ 2+ 2+
Cr(CO)3 Fe Mn + Ru Fe
OC CO CO

v. small
1 11,000 6 x 106 2 x 108

Consider arene-Mn+(CO)3
Nu
Nu- Nu- = MeLi, PhLi, RMgBr, H-,
H NaCH(CO2Et)2, O O
Mn + -
Mn(CO)3 R R
OC CO CO
Note: -CN and :PPh3 add, but are reversible
-so what now?
Nu
Nu CF3CO2H CrO3, H2SO4 Nu
H
(MeCN)3Mn+(CO)3 +
acetone
MeCN
Mn(CO)3
-other chemistry is possible with the intermediate dienyls, but it's beyond the scope of the course

R Pike, R. D.; Sweigart, D.A. Synlett 1990, 565; J. Chem. Soc. Dalton Trans 1996, 4493. 140
-and if there is a leaving group on the arene, the concept is the same, but the reversible
nucleophiles are a different group

Nu-
X Nu -nucleophiles which can add reversibly and
or NuH therefore do this include
Mn + Mn + MeO-, PhO-, PhS-, N3-, R2NH
OC CO CO OC CO CO

X = Cl, Br, F but not H-, R-, Ph-

-the regiochemistry of kinetic substitutions are not as thoroughly studied, but what's available
shows the same general trends
i.e., EWG directs ortho- attack (para is usually blocked in Mn studies)
EDG directs meta- attack
H H
X = Cl 69:37
LiAlH4
X + X
X X = NMe2 3:97
Mn Mn
Mn +
OC CO CO OC CO CO
OC CO CO

Pauson, P.L. et al J. Chem. Soc., Dalton Trans. 1975, 1677 and 1683
Kane-Maguire, L.A.P.; Sweigart, D.A. Inorg. Chem. 1979, 48, 700.
Pearson, A.J. Tetrahedron 1992, 48, 7527
J. Org. Chem. 1991, 56, 7092. 141
And the Cp-Fe+-arenes?
R
H DDQ
R
+ RLi O
+ Cl CN
Fe Fe
Cl CN
O R = Me, Et, Ph, PhCH2MgBr

-here, there are more examples of successful examples of hydride abstraction to get back
the complex
R with the exception of benzyl
H Ph3C+ Ph
R
Ph3C+
+ H
Fe Fe + PhCH2CPh3
+
Fe Fe

R Astruc, D. Tetrahedron 1983, 39, 4027.

R Adb-El Aziz, A.S.; Bernardin, S. Chem. Soc. Rev. 2000, 203, 219.

A similar reaction pattern for substitutions are observed with the haloarenes

X MeO- OMe
+ +
Fe Fe Nu- = PhO-, RO-, RS-, R2NH, NaCH(EWG)2
142
 -fairly analogous trend is seen in the kinetic regiochemistry
EWG - ortho attack EDG - meta attack
H H
H- H H- MeO H
CO2Me OMe
+ +
Fe CO2Me
Fe Fe Fe

McGreer, J . F.; Watts, W.E. J. Organomet. Chem. 1976, 110, 103

Clack, D.W.; Kane-Maguire, L.A.P. J. Organomet. Chem. 1979, 174, 199.

Reactions on are very similar

2+ -see Astruc review if interested
Fe

Effect #2 of electron withdrawing effect of arene-Cr(CO)3

-enahanced acidity of arene ring protons
Li reaction is feasible, but.....pKa's are 38-42
Consider
R v. strong base R the pKa's of arene-Cr(CO)3 are
6-7 pKa units more acidic

C(O)NPr-i2 pKa = 31.1

pKa = 34.8 OMe pKa = 33.0
Cr(CO)3 Cr(CO)3 Cr(CO)3

pKa = 41.2 pKa = 39.0 pKa = 37.8

OMe C(O)NPr-i2
143
 pKa associated with LDA is 35.7; LiTMP 37.1, so these can now be used as bases

-excellent for ortho- functionalization of aromatics; and

-one gets a change in some of the relative abilities to direct ortho- lithiation

for free arene -CONR2 > -SO2NR2 > -NHCOR > -CH2NR2 > -OMe > -NR2 = -F

for Cr complexes -F > -C(O)NHR > -CH2NR2 = -OMe >> -CH2OMe > -NR2, -SR
So

O O O
O NHR
NHR 1) 2 LDA, THF, -78o NHR
1) 2 BuLi, TMEDA Me3Si NHR
F F 2) Me3SiCl F
2) Me3SiCl F
Cr(CO)3
(CO)3Cr SiMe3

DMG
can be trapped by a wide to give
Li range of E+
DMG DMG DMG
Cr(CO)3 CH3I, Me3SiCl, CO2, Ph2PCl,
CH3 SiMe3 CO2H
O
, Br Br
R R' Cr(CO)3 Cr(CO)3 Cr(CO)3
DMG DMG DMG
OH
PPh2 Br
R R'
Cr(CO)3 (CO)3Cr Cr(CO)3 144
 further
OSi(i-Pr)3 OSi(i-Pr)3
1) t-BuLi, THF, -78o

2) MeI H3C
this meta metallation is unheard of
Cr(CO)3 Cr(CO)3 in chemistry of free arenes

NSi(i-Pr)3 1) BuLi, THF

NSi(i-Pr)3 Widdowson, D.A. J. Chem. Soc., Chem. Commun.
1983, 955.
Fukui, M., et al Tetrahedron Lett. 1982, 23, 1605.
2) E+ E
Cr(CO)3
Cr(CO)3
most recent review: R Semmelhack, M. F.; Chlenov, A. Top. Organomet. Chem. 2004, 7, CH 3
Effect #3 of Cr(CO)3 on arenes
CH2R
benzylic site also has enhanced acidity relative to CH2R pKa ca. 40

-so benzylic deprotonation is quite easy

Cr(CO)3 -never seen pKa measured by I guess it's about 25

-as a result, one can often do benzylic deprotonation reactions which fail with the free arene

R2 R2
R3 KOtBu, DMSO R3 Jaouen, G. et al
R1 R1 J. Chem. Soc. Chem. Commun. 1984, 602, 475
EtO OEt CO2Et J. Chem. Soc. Chem. Commun. 1981, 1264
Cr(CO)3 O O (CO)3Cr HO J. Organomet. Chem. 1984, 102, C37.

R1, R2, R3 not acidifying groups

(i.e., H, simple alkyl) 145
 R'
R' R' E
-
R2- E+
R2 R2

Cr(CO)3
Cr(CO)3 Cr(CO)3
O
R2 = - CN - CO2Bu-t
, nBu-, Ph-, S S E+ = H+, CH3I, Ph Cl
-
Semmelhack, M. F. Seufert, W.; Keller, L. J. Am. Chem. Soc. 1980, 102, 6586.
Uemura, M.;Minami, T.; Hayashi, Y. J. Chem. Soc., Chem. Commun. 1984, 1193.

-appears to be both a kinetic and a thermodynamic effect

R Davies, S. G. et al Adv. Met. Org. Chem. 1991, 2, 1.

Effect #4 Stabilization of Benzylic Cations

-recall our discussion of pKR+ values....

+
PhCH2+ < -17.3 Ph2CH+ -13.4 CH2 -11.8 Ph3C+ -6.6

less Cr(CO)3 more

stable stable

Cl Cl
also, the SN1 solvolyses of are 103 - 105 times faster than
and the corresponding
Ph
Cr(CO)3 Cr(CO)3 non-complexed arenes 146
-makes the following reactions possible
OH HPF6 + HNR2 NR2
Y Y CH2 Y
CH2Cl2
Cr(CO)3 Cr(CO)3 Cr(CO)3
-20o

H O
OH H2SO4 N
Y + RCN Y R

Cr(CO)3 Cr(CO)3
-this Ritter reaction only works with 3o benzylic halides
R Davies, S.G. Synlett 1993, 323.

Other Effests in Cr(CO)3-Arene Complexes

R1
-stereochemistry
σ- plane is gone
R1 R2 Chiral
is flat, achiral
σ- plane of symmetry Cr(CO)3
R2

-so what is R- and what is S- ??

Consider
O
O
H
CH3 H CH3
(CO)3Cr 147
(CO)3Cr
 H O
-at position 1 we have C H counterclockwise
O C 4 CH3
Cr 2
C Cr C -therefore,
C C 3
H H Cr (S)-enantiomer
Cr Cr
CH3 Cr
1

-at position 2 we have CHO

C
C 4CH3 CH
Cr 3 3 clockwise
CH3 HOC C
C C 2 -therfore,
Cr Cr
Cr Cr (R)-enantiomer
H Cr
1

-this is (1S,2R)-2-methylbenzaldehyde chromium tricarbonyl

Note: Davies just uses the label at position 1, as the 2-position is then defined automatically

-chiral centre (or plane); therfore should be able to do asymmetric reactions

-will give a sampling, as this is a fairly new and developing area

NaBH4 1) base
CO2Me
H 2) R-X
Cr(CO)3 R
Cr(CO)3 O Cr(CO)3 OH Cr(CO)3 CO2Me
O O
CH3
1) NaH H
2) CH3I
Cr(CO)3 Cr(CO)3 148
 Acyclic cases
R disfavoured
R R'Li or R'MgBr R
O rotamer
H R'
or NaCH2NO2 H
OH Cr(CO)3 H
Cr(CO)3 O Cr(CO)3

X X
X R'MgBr R' R
O
OH
R Cr(CO)3 O
Cr(CO)3 R Cr(CO)3

X = CH3, OR2 R = Me, Et, alkyl

SiMe3

TiCl4 +

(CO)3Cr HO CH3 (CO)3Cr CH3 (CO)3Cr H3C

OH H HNCOMe
H H2SO4 1) MeCN
Me H
Me Me
2) H2O
Cr(CO)3 +
Cr(CO)3 Cr(CO)3 149
 R R R
Cr(CO)3-naphthalene
OH H
OH
H OH
OMe OMe OMe
Cr(CO)3 Cr(CO)3
major
because
R H
H R
favoured disfavoured
X O X O
LnCr LnCr

R Solladie-Cavallo, A. Adv. Met.-Org. Chem. 1989, 1, 99.

R Uemura, M. Adv. Met.-Org. Chem. 1991, 2, 99.
R Davies, S. et al Adv. Met.-Org. Chem. 1991, 2, 1.

-many of these are done on racemic material

-so how does one get enantiomerically pure complexes?
R O O
R *
1) O H2N N R hydrolyze
H O
Ph N-NH-}
H H
H
Cr(CO)3 Cr(CO)3
Cr(CO)3
racemic
separate diastereomers enantomerically
pure 150
Classical Resolution
2) kinetic resolution
OH lipase OH O
pseudomonas sp. O
X X +
O
X
Cr(CO)3 O Cr(CO)3
85-100% ee Cr(CO)3 84-98% ee
Uemura, M. et al Tetrahedron Lett. 1990, 31, 3603; Jaouen, G. et al J. Chem. Soc., Chem. Commun. 1984, 1284.

3) chiral auxiliaries
MeO MeO
1) 2 nBuLi,
O -30o O H+
O CHO
OMe 2) E+ O OMe (E = Me)

E E
Cr(CO)3 Cr(CO)3 Cr(CO)3
90% de
Kondo, Y.; Green, J.R.; Ho, J. J. Org. Chem. 1993, 58, 6182.

4) enantioselective functionalization
O MeO
OMe CONPr-i2
X X X= OMe
1)Ph N Ph O
Li
SiMe3
or Kundig,E.P. at al Tetrahedron Lett. 1994, 35, 3497
Li Simpkins, N.S. et al J. Org. Chem. 1994, 59, 1961
Cr(CO)3 N Cr(CO)3 Siwek, M.J.; Green, J.R. J. Chem. Soc., Chem. Commun,
Ph
1996, 2359.
up to >90%ee
2) Me3SiCl 151
 Other η6-Cycloalkatriene-Cr(CO)3 Complexes

X Cr(CO)6, 100o X X = N-CO2Me, C=O, SO2, CH2, CH(Me)

or (MeCN)3Cr(CO)3, unlike Fe complexes, this is η6

Cr(CO)3
THF, Δ

X 1) R R2 hν, RT [6+4] cycloaddition

1
R1 R2
X good yields
Cr(CO)3 2) P(OMe)3 or O2 H H

Notes: rates unchanged if R's = EWG or EDG

-if there are substituents on remote sites of triene, regiochemistry is 1:1

Mechanism(?) - not concerted

oxid
Cr(CO)2
hν, -CO
Cr(CO)3 Cr(CO)2 coupling Cr(CO)2

-this is stepwise in nature, so there is no 'concertedness' reason why the [6+2] should fail, so...
CO2Et
CO2Et 1) hν, RT, hexanes H H
+
92%
Cr(CO)3 2) O2
152
 -both of these can be catalytic in Cr - often in the presence of Mgo
CO2Me MeO2C CO2Et
N CO2Et 9% (CO)3Cr-naphth
+ H N H
77%
nBu O, 150o
2

R Rigby, J.H. Adv. Met-Org. Chem. 1985, 4, 89.

R Rigby, J.H. Tetrahedron 1999, 55, 4251.
R Rigby, J.H. Org. React. 1997, 49, 331.

Multistep Reactions
The [2+2+2] Cycloaddition
- important method of making six membered rings
-also, many of the other multistep processes are based on this reaction

-consider 3 H H -feasible reaction

-requires 400o; many side reactions
-not synthetically useful as such
-there are several transition metal fragments which allow this type of reaction to occur at
much lower temperatures, including...
R
N
FeCl3 + EtMgBr ; (Ph3P)3RhCl ; (CpCo(CO)2) ; (CpCo(ethene)2)
N Co Co
R Grigg, R. OC CO
R Modern Rhodium
Catalyzed Reactions Vollhardt, K.P.C.
Ch 7.3.1 153
 This reaction proceeds by a combination of fundamental steps we have seen before
CO R
hν or Δ
CpCo(CO)2 + R R CpCo R R
-CO CpCo R
R R
R R
16e R R
oxidative L Cp L = solvent in many cases
CpCo Co L = PPh3 isolated often by
coupling
R L R
R Yamazaki group
R
(Tetrahedron Lett. 1974, 4549; J. Organomet. Chem. 1977, 139, 157;
-then J. Am. Chem. Soc. 1983, 105, 1907.)
R R
Cp R R R Cp R
Co Co now comes uncertainty.......
R -the next step is undecided between
L R R
R R two possibilities
R
Possibility #1 - concerted cycloaddition
Cp
R R
Co
Cp R concerted R - "Cp-Co" R R
Co R R
R 'Diels-Alder
R R R R R R
R like'
R R

"CpCo" regenerated; therefore possible to be catalytic in Co 154

 Possibility #2 - Alkyne insertion/reductive elimination

R R R
Cp R R R
insertion reductive R R
Co + "CpCo"
R' CpCo R elimination
R R' R
R R' R'
R' R'

Personal opinion - there are instances where the concerted cycloaddition mechanism is
operating
- more often, it is the insertion/elimination mechanism that is operating

Regiochemistry
-if one has R(big) R(small) , what happens?

Rb Rb Rs
Rs Cp Rb
Cp major a minor
Rs + Co
CpCo Co product amount of this
Rs Rs
L Rs L
Rb Rb
Rb
-simply from sterics

Rb Rs Rs
Rs Rb Rb
CpCo fast CpCo slower CpCo Rb no way
Rs Rs
155
Rb Rb Rs
-if one has R(EDG) R(EWG) , what happens?

Rw Rw Rw
Rd Cp Rd
Cp major a minor
Rd + Co
CpCo Co product amount of this
Rd Rw
L Rd L
Rw Rd
Rw

-reason - oxidative coupling step proposed to operate under orbital control

- HOMO of complex dominates, and it is domonated by the π* of the alkene

-therefore, C-C bond formation to give metallacycle occurs at the

EWG EDG carbon β- to the EWG

-if sterics and electronic effects compete, the steric effect overwhelm
Ph Ph MeO2C
CO2Me Cp CO2Me Cp Ph
CpCo Ph Co + Co 5%
43%
Ph3P Ph Ph3P Ph
Ph Ph Ph
-there is still a third alkyne to participate in 2+2+2, so often one gets further regiochemical
mixtures
-reaction becomes synthetically useful when BTMSA Me3Si SiMe3
is used as the third alkyne, as it only reacts with itself very slowly
156
-particularly synthetically useful reaction when the two other alkynes are joined
i.e., L
H Me3Si SiMe3 SiMe3
( )n ( )n Co
Cp ( )n
H CpCo(CO)2, hν
SiMe3
n = 0, 1, 2 A good yields

SiMe3 SiMe3 SiMe3

( )n
SiMe3 SiMe3 SiMe3
SiMe3
Note; in this case,
the rxn goes through instead of A
Co SiMe3
L Cp

H
-fortunately, silyl groups are removable from arenes
SiMe3 H H
H+ or
( )n ( )n ( )n
SiMe3 F- SiMe3 H

-reactions tolerate a pretty good range of substituents, such as... -CO2R, -CH2OH, -CH2OR',
-NR'2, -SR', O , N-OR'
R H
-reaction may be carried out thermally or photochemically (or both) 157
-reaction is often (but not always) catalytic in cobalt
examples
xs BTMSA SiMe3 CF3CO2H SiMe3
CpCo(CO)2(cat) SiMe3 72%
SiMe3
hν, Δ 96%
Berris, B.C.; Vollhardt, K.P.C. J. Chem. Soc.,
SiMe3 Chem. Commun. 1982, 953.
Me3Si
xs BTMSA
SiMe3 36%
CpCo(CO)2
Dierks, R.; Vollhardt, K.P.C.
Δ SiMe3 J. Am. Chem. Soc. 1983, 39, 3150.

Me3Si
SiMe3
MeO Vollhardt, K.P.C. et al
xs BTMSA N Tetrahedron 1983, 39, 905.
N MeO
MeO CpCo(CO)2(cat)
MeO SiMe3
hν
96%
SiMe3
Other cyclization partners
-the 'third alkyne' does not have to be an alkyne per se - for example, it can be an alkyne

1 equiv CpCo
CpCo(CO)2 H CuCl2-Et3N
H
SiMe3 Δ, isooctane 0o, CH3CN
SiMe3 SiMe3
158
Sternberg, E.D.; Vollhardt, K.P.C. J. Org. Chem. 1984, 49, 1564.
 CpCo(CO)2 CoCp CuCl2-Et3N
Me Me
hν, Δ, 0o, or silica gel
m-xylene

60% 61%
Vollahrdt, K.P.C. et al J. Org. Chem. 1984, 49, 5010; Angew. Chem. Int. Ed. Engl. 1981, 20, 802.

-in these cases, there must be at least one equivalent of Co

-must subsequently decomplex the Co-diene complex
-normally, the alkene is the 'third' partner

-the 'third' partner can also be a nitrile

Vollhardt, K.P.C. et al Tetrahedron 1983, 39, 905.

H N CpCo(CO)2 N
( )n
( )n +
H R
R
n = 1-3

-or an isocyanate
CpCo(CO)2(cat) R
H R N
( )n N C O ( )n Earl, R.A.; Vollhardt, K.P.C.
H xylene, hν, Δ O J. Org. Chem. 1984, 49, 4786.

n = 1-2
R R R
R " " R2
H ca. 45%
+ R2 R1 N
N C O R1
O 159
 -again, these are, in almost all circumstances, the 3rd partner in the cycloaddition

i.e.
R2 R
R R2R R R
R R1 R1 R R N
Co not Co R Co N Co R
Cp Cp not
R Cp R Cp
R R
R R R R
Use in estrone synthesis O

O O Me3Si
Me3Si Δ
BTMSA
CpCo(CO)2 Me3Si Me3Si

O
O
O H 71%
CF3CO2H Me Si
Pb(OC(O)CF3)4 H 3
H H H
H H Me3Si
H H Me3Si
HO
estrone Funk, R.L.; Vollhardt, K.P.C. J. Am. Chem. Soc. 1977, 99, 5483; 1979, 101, 215; 1980, 102, 5253.

-using the CoI / CoIII systems are not the only transition metal complexes capable of these
cycloaddition - certainly the most popular, especially in early days, but other systems have
been used effectively 160
 -a survey of literature, early 2000's

RhI/RhIII 20 Rh(PPh3)3Cl, [RhCl(cod)2]2 IrI/IrIII 2

Pdo/PdII 15 Pd(PPh3)4 TiII/TiIV 2
Nio/NiII 14 Ni(cod)2, (+ PPh3) Feo/FeII 1
Coo/CoII 9 Co2(CO)8 TaIII/TaV 1
RuII/RuIV 5
Moo/MoII 3 Mo(CO)6

O
O OH
OH 2% (Ph3P)3RhCl
86%
EtOH, 25o, 12h HO
HO
MeO MeO
OMe OMe MeO
SiMe3 Pd(PPh ) 81% OMe
3 4 +
OTf CsF, CH3CN
MeO
MeO 93:7
Many, many reviews on this
R Tanaka, K. Synlett 2007, 1977. (Rh catalysts)
R Chopade, P.R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (all metals)
R Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209 (Co)
R Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741 (all metals, small)
R Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901 (all metals)
R Grotjahn, D.B. Comprehensive Organometallic Chemistry II, Vol12, p741, 1995 (library)
R Boese, R.; Sickle, A.P.; Vollhardt, K.P.C. Synthesis 1994, 1374. (indoles)
R Schore, N. Comprehensive Organic Synthesis, Vol 5, p 1129, 1991
R Vollhardt, K.P.C. Angew. Chem. Int. Ed. Engl. 1984, 23, 539.
161
3. Interrupting the 2+2+2
-there are a number of reactions that start to follow this 2+2+2 pathway, getting to the
metallacyclopentdiene or metallacyclopentene, and then go differently
-only a time to look at a couple, but there are many more in synthesis
see: Topics in Organometallic Chemistry 2006, 19 entire issue

The Pauson-Khand Reaction

-two of the side products from the 2+2+2 are:

R R R
Cp Cp R
Co O Co CoCp
CO CO
R R R R

(Fe : Knolker, H.J.)

-cyclopentadienones are not very stable compounds, but if one of the C=C's is reduced,
you have very useful cyclopentenones
-this type of material is often obtained by using and alkyne, and alkene, and Co2(CO)6
(or an alkyne-Co2(CO)6 complex)
O
i.e., R Δ
+ Co2(CO)8 R' R
+ R'

Intermolecular Cases
-no particular constraints on the alkyne 162
-if you have an unsymmetrical alkyne, larger groups end up next to C=O, as in
Alkene Partner

-simple alkenes don't work especially well, unless present in huge excess
(Note: this is making progress)
-strained alkenes, "non β-hydride" alkenes (bridged bicyclic akenes),
and alkenes with ligands attached (X = NR2, SR, O?) give better yield, high regioselectivity
O
Ph H Ph Ph Ph
+ 15% ordinary alkene
Co2(CO)6
CH3 SMe
SMe
O
Ph H + coordinating substit.
Ph 73%
Co2(CO)6
(note: trans)
Krafft,M. et al J. Am. Chem. Soc. 1991, 113, 1693 CH3
NMe2 O arrow is where
NMe2 R2 1st C-C bond
S+ O Ph
R1 forms
Si
1 O
Krafft
Carretero Kerr Yoshida (with Ru3(CO)12)
-also chiral -loses benzoate -loses Si

H H + Δ bridged bicyclic alkene

Co2(CO)6
Ph (non β-hydride)
O H
Ph

high % 163
 2 ( )n
( )n even n = normal
C 1
with mild conditions
PhMe2Si especially
n = small "no β-H"
Cazes (no β-H)

Reviews focussing on intermolecular reactions R Gibson, S.E. et al Angew. Chem. Int. Ed. 2005, 44, 3022.
R Laschat, S. Synlett 2005, 2547.

-except for sulphoxides, alkenes with EWG's rarely work

Intramolecular Cases
-reaction works much better when alkene and alkyne are in the same molecule
Co2(CO)6
O +N O (NMO) O 85%
O O
CH2Cl2, RT

Co2(CO)8 60% (old conds)

95% O

-often particularly good for all carbon bridges when there is a gem dialkyl in the bridge
Co2(CO)8 H gem dimethyl or Thorpe-Ingold
effect
Δ, 82% O
SiMe3 TBDMSO
TBDMSO SiMe3 164
 -there are subtle stereochemical matters which are beyond this course's scope
-many recent advances have increased yields and allowed reactions under milder conditions

i.e., polar aprotic solvents (CH3CN, DME )

MeO OMe
-use of 1o amines (CyNH2) and mercaptans (nBuSMe) R Sugihara Chem, Eur. J. 2001, 7, 1589

-photolysis O
-3o amine oxides (Me3N+-O-, TMANO), (NMO) O +N and room temp

Catalysis
-the new holy Grail - to use catalytic amounts of metal and CO gas (under as low a pressure
as possible), or a CO substitute (some aldehydes)

MeO2C Co2(CO)8 (5 mol%) MeO2C

O 83%
MeO2C MeO2C
CO (1 atm), DME (60o)

-other metals (other than Co) now are common, especially for catalytic chemistry; I think
that RhI is gradually replacing Co

RhI 25 [RhCl(CO)2]2 ZrII 4

Moo 12 Mo(CO)6 -allenes(Brummond) Fe , hν
o 4
Ruo 8 Ru3(CO)12 Co nanoparticles 2
CoI 1
IrI 4
W 1
TiII 7

Most recent reviews: R Shibata,T. Adv. Synth. Catal. 2006, 348, 2328.
R Pérez-Castells, J. Top Organomet Chem 2006, 19, 207
R Strübing, D.; Beller, M. Top Organomet Chem 2006, 18, 165 165
 Mechanism of Pauson-Khand
-unnaturally complex looking, because presence of second metal, which is just 'along for
the ride'
OC CO
(CO)3Co Co(CO)3 Co Co(CO)3
Rb Rs R
+ R
Co2(CO)6 Rs Rb Rs Rb

oxidative
(CO)3 coupling +L
L2Co(CO) Co (CO)3
Co(CO)3 insertion Co
Rs Rb Rs Rb
CoCO +L Rs Rb
O
LL Co (CO)2
R R O H L
R
same as L2Co(CO)
Co(CO)3 Rs Rb
Rs Rb
+ LnCo-CoLn
O
O
R
Reviews R
R Chung, Y.K. et al Synlett 2005, 545 (Co nanoparticles) R Brummond, K. Tetrahedron 2000, 56, 3262 (allenes)
R Krafft, M.E. Tetrahedron 2004, 66, 9795. (Interrupted P.-K.) R Geis, G.; Schmalz, H.-G. Angew. Chem. Int. Ed. Engl.
R Alcaide, J.C.; Almendros, P. Eur. J. Org. Chem. 2004, 3377 (allenes) 1998, 37, 911
R Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32. R Schore, N.E. Comprehensive Organometal. Chem. II
R Gibson, S.E. Angew. Chem. Int. Ed. Engl. 2003, 42, 1800 (catalytic) 1992, Vol 12, Ch 7.2
R Carretero, J.C. Eur. J. Org. Chem. 2002, 288 R Schore, N.E. Org. React. 1991, 40, 1.
R Carretero, J.C. Synlett 2001, 26. R Schore, N.E. Chem. Rev. 1988, 88, 1081.
166
-so how about alkyne only cases, i.e. + + CO O
-sort of - uses Feo and product is the iron complex

SiMe3 Fe(CO)5 R Knolker, H.-J. Chem. Soc. Rev.

( )n ( )n O ca. 80%
1999, 28, 151
SiMe3 glyme, 140o
n = 1,2 Fe(CO)3
-decomplexation is not straight-forward, because cyclopentadienone is unstable (anti-aromatic)

The [2+2+????] Reactions of Zirconium Alkyne Complexes

R
-compounds like R
ZrCp2 ZrCp2
R
R
-also react with alkynes, alkenes, nitriles, to form C-C bonds by oxidative coupling process,
similar to the 'first half' of the 2+2+2 R
R R -can be isolated as
R R' R Cp
PMe3 the PMe3 adduct
Zr Cp
ZrCp2 + ZrCp2 PMe3
R R' R'
R' R' R'
-the zirconocene alkyne complexes themselves are made differently than in Co case
-most usual method Cp Cp
Δ R
R Br nBuLi R Li Cp2ZrCl(Me) R ZrCH
3 ZrCp2
R -CH4 R
R R

R cannot be H, Cp2Zr , Cp2Zr ( )n also made this way

167
Reactions Encountered
-many of them quite analogous to Co complexes R R
R
R R' R ZrCp2 R ZrCp2
ZrCp2 R' N
H +
N H R' R' H
R' R
ZrCp2
R R H2C=CH2
O R
R ZrCp2
H R' R ZrCp2
O
R'
R R
and unlike Co
R Cp2Zr
ZrCp2
R
-are further reaction possible? - YES -most common is hydrolysis

R R R
R
R H3O+ R H3O+ R
ZrCp2 R ZrCp2
CH3
R' R' R' R'

R R R R
R H3O+ R R ZrCp2 H3O+ R
ZrCp2
N O O OH 168
R' R' R' R'
 -due to electronegativity difference between
C and Zr, there's a tendency for these to react like -
-
R'
-other reactions -with sulphur monochloride or dichloride R'

R' R' SCl2 S

Cp2Zr Cp2Zr benzothiophenes
R'
R'
R'
R'
R' N S2Cl2 S benzothiazoles
Cp2Zr
N N

R' R'
-reactions with iodine
R R R R R
tBuLi
I2
Cp2Zr I Li
Cp2Zr
I I
R
I2 R R
H3O+
Cp2Zr
I I
N I
N O
R' Cp2Zr
R' R' 169
 Regiochemistry in benzyne reactivity

R R
R' R' ZrCp2 Rs Rb ZrCp2
ZrCp2 R' ZrCp2 Rb
R' Rs
analogous to cobalt

Intramolecular cases - E.I. Negishi

2 nBuLi β-elimin reductive
Cp2ZrCl2 Cp2Zr "Cp2Zr" + butane
Cp2Zr elimin
- H

R R
"Cp2Zr" CO
( )n Pauson-Khand
( )n ZrCp2 ( )n O
R

R
( )n "Cp2Zr" same reactions as
R R' ( )n ZrCp2
intermolecular cases
R'

see R Negishi, E.; Takahashi, T. Bull. Chem. Soc. of Jpn. 1998, 71, 755.
R Majoral, J.-P. et al Coord. Chem. Rev. 1998, 178-80, 145 (main group elements)
R Negishi, E. Acc. Chem. Res. 1994, 27, 124.
R Buchwald, S.L.; Nielsen, R.B. Science 1993, 261, 1696.
R Buchwald, S.L. Chem. Rev. 1988, 88, 1047.
170
 Carbenes

LnM=CH2 (carbenes or alkylidenes)

-structurally discrete carnes 'officially' fall into two types, characterized by their reactivity
-I will arbitrarily add a third class

Fischer Type Carbenes Schrock Type Carbenes Methesis Carbenes

(alkylidenes) PCy3
OMe Ph
δ+ δ− Cl
(CO)5Cr
R
Ti CH2 Cl Ru
PCy3
-mostly Cr group (Cr, Mo, W),
or Fe group -early transition metal - early development by Schrock,
-stabilized by heteroatom (O here) -electron rich at carbon so often lumped in with Schrock
-reactivity - electron poor at C carbenes for convenience
-mid- or late transition metals
-no great M-C bond polarity,
so C electronically neutral
-mostly cycloaddition processes
Fischer Carbenes
R de Meijere, A. et al Angew. Chem. Int. Ed. Engl. 2000, 39, 3964
R Barluenga, J. J. Organomet. Chem. 2005, 690, 539.

Bonding
R1 R1 : R1 R1
LnM : C LnM C LnM C LnM C
R2 R2 R2 R2
171
Preparation
O O OMe
PhLi - Me3O+
W(CO)6 (CO)5W C (CO)5W C (CO)5W C
Ph Ph Ph
-nucleophiles mostly alkyllithiums, but don't absolutely have to be C based
Li(NiPr2) Et3O+ BF4- OEt
Cr(CO)6
(CO)5M C
NPr2-i
Reactions of Fischer Carbenes
-for many reactions, it's useful to think of these carbenes as having parallel reactivity
to carboxylic esters

OR CAN OR -can actually do the transformation with CeIV

(CO)5M C = O C
R R

a) Nucleophilic Attack at Carbene Carbon

-calculations show that the LUMO of these species is localized at the carbene carbon
(Blick, T.F.; Fenske, R.F.; Casey, C.P. J. Am. Chem. Soc. 1976, 98, 143)

-attack of nucleophile, orbital controlled, is at that site

OMe OMe Nu
Nu-Li+ - -MeO-
(CO)5Cr C (CO)5Cr C Nu (CO)5Cr C
R R R

nucleophiles include organolithiums amines mercaptans

172
RLi R'2NH RSH
 OMe H
N
(CO)5Cr C + H2N CO2Me (CO)5Cr C CO2Me
Ph Ph

b) Generation of α-Anion and Electrophile capture

OMe very acidic O O O

pKa = 10 pKa = 25
(CO)5Cr C pKa = 8 OEt H3C OEt
CH3 H H

OMe nBuLi, OMe OMe OMe

-78o - E+
(CO)5Cr C (CO)5Cr C (CO)5Cr C (CO)5Cr C
CH3 CH2 CH2 CH2
- E

-anion is so stabilized that it's a fairly weak nucleophile; therefore only captures more
reactive electrophiles
O O
O (Michael acceptor)
Br CO2Et Cl OR R R' R X
-epoxides give further reaction

OMe OMe O
(CO)5Cr C 1) nBuLi, -78o (CO)5Cr C (CO)5Cr C
CH3 2) O
O
Casey, C.P. et al J. Organomet. Chem. 1974, 73, C28.

-aldehydes and ketones don't eliminate immediately, but the alcohols can be made to
eliminate 173
 OMe 1) nBuLi, -78o pyridine OMe
OMe
(CO)5Cr C (CO)5Cr C
(CO)5Cr C OH
2) PhCHO, TiCl4
Ph
3) workup Ph
Wulff, W.D. et al J. Am. Chem. Soc. 1985, 107, 503.

-can make the anion less stable, more reactive, by exchanging one CO ligand for a phosphine;
the anion will then react with (less electrophilic) alkyl halides/triflates
Wulff, W.D. et al J. Org. Chem. 1987, 52, 3263.

Michael Addition to Vinyl Carbenes

-since the α-anions are so stabilized, it's not suprising that reactions that give such an anion
go well.......
OMe OLi OMe
1)
(CO)5Cr C R2 (CO)5Cr C
2) workup Nakamura, E. J. Am. Chem. Soc.
R1 R2 R1 O 1993, 115, 9015.

-can be highly stereoselective

Note: some anions add to carbene carbon, to give other products

Diels Alder Reaction of Vinyl Carbenes

- due to the strongly EWG nature of carbene, vinyl carbenes are more reactive (104 x) more
reactive as dienophiles in 4+2 cycloadditions

OMe Cr(CO)5
(CO)5Cr C H endo exo
Cr(CO)5 OMe
94:6 H
MeO 174
 OMe Wulff, W.D. et al J. Am. Chem. Soc. 1983, 105, 6726
also
C partcicpate Dotz, K.H. et al Angew. Chem. int. Ed. Engl. 1986, 25, 812
(CO)5Cr Wulff, W.D. et al J. Am. Chem. Soc. 1984, 106, 756.
H
Cyclopropanation with Alkenes R'
R'
-typical reaction of carbenes in organic chemistry :CR2 + R
R R'
R'
-may also be done with discrete organometallic complexes, with either electron poor or
electron rich alkenes - probably by two different mechanisms

electron poor alkenes

OMe L OMe reduct. MeO Ph
OMe ca. 100o (CO)4Cr C [2+2]
(CO)4Cr Ph
(CO)5Cr C Ph elimin. RO C
2
Ph CO2R RO C RO2C
2
+ "(CO)4Cr"
O O EWG EWG
CN and disubstituted
-works with NMe2 P (OMe)2 cases, i.e., R R
R Reibig, H.-U. "Organometallics in Organic Synthesis", V2, 1987, p.31
R Dotz, K.H. Angew. Chem. Int. ed. Engl. 1984, 23, 587.
R Wu, Y,-T., Kurahashi, T., De Meijere, A. J. Organomet. Chem. 2005, 690, 5900.
R Barluenga, J.; Rodríguez, F.; Fañanás, F.J.; Flórez, J. Top. Organomet. Chem. 2004, 13, 59.

-with electron rich alkenes, rxns are at lower temperature, different mechanism 175
 R + Ph
CO reduct
(CO)5Cr C N N N
Ph elimin Ph
OMe N R R
- (CO)5Cr
(CO)5Cr OMe MeO R
Ph OMe

-reaction done under CO atmosphere to suppress alkene metathesis

R R
N (CO)5Cr C +
Ph OMe
R N
(CO)5Cr
OMe
+ Δ H2
-with normal alkenes, it's more useful to use
-see R Helquist, P. Adv. Met. Org. Chem. 1991, 2, 143 OC Fe CH2 made OC Fe C
OC
in situ
OC +SMe2
Carbene-Alkyne Cycloaddition
-probably most important type of rxn of Fischer carbenes; many uses in organic synthesis
-vinyl and aryl carbenes do a 2+2+1+1 cycloaddition reaction to give very specific types of arenes
OMe
OH
ca. 45o R
(CO)5Cr C + R R Cr(CO)3
R
OMe
reaction is essentially
R R
MeO Cr O
MeO C: :C O 176
 -this process also occurs on aryl substituted carbenes
OH
OMe
R'
(CO)5Cr C + R' R'
R Cr(CO)3
R R'
OMe

-mechanism is not obvious; it is generally accepted to be

OMe
OMe Rb Rs
[2+2] metathesis
(CO)4Cr C
(CO)5Cr C (CO)4Cr OMe
Rb (CO)4Cr
-CO OMe
Rs Rb Rs Rb Rs
CO
insertion

Dotz HO tautomerism O electrocyclic O

C
rearrangement
Rb OMe Rb OMe OMe
Rs Cr(CO) Rs Cr(CO) Rb Rs
3 3 Cr(CO)3
-easy to decomplex Chromium from arene
HO O HO
Rb Rb sometimes get Rb
FeCl3- DMF

Rs or CeIV/H2O Rs Rs
OMe
Cr(CO)3 OMe O
177
-aromatic heterocycles participate as well

OMe n-Pr OH
H X = O, S
(CO)5Cr Pr-n
Cr(CO)3
X X
OMe
-use in daunomycinone synthesis
Rs
H O
Rb O O OH FeIII/DMF
45o O
O + O 76%
(CO)5Cr THF O 2 steps
MeO O MeO
OMe
(CO)3Cr OMe
O
O OH O O OH
O
CH3
OH O
MeO
MeO O OMe OMe
daunomycinone
-many, many other synthetic examples -see
R Wulff, W.D. Adv. Met. Org. Chem. 1989, 1, 209.
R Minatti, A.; Dötz, K.H. Topics Organomet Chem 2004, 13, 123.

-other major ring formation reactions of Fischer carbenes is β-lactam synthesis 178
 OMe hν
OMe O
[2+2] OMe CO OMe
(CO)5Cr C (CO)4Cr C
R2 L(CO)4Cr CH3 (CO)nCr CH3
CH3 CH insertion
N N R2 3 N R2 N R
R3 R1 R3 R3 R1 R3 R 2
1
R1

O OMe reductive
CH3
N R2 elimination
-for example R3 R
1

OMe S hν
H Me
(CO)5Cr C + MeO S one isomer
CH3 N H CH2Cl2 penam derivative
N
CO2Me O H (related to thienamycin)
MeO2C
R Hegedus, L.S. Topics Organomet Chem 2004,13, 157

Schrock Carbenes (alkylidenes)

-somewhat newer - earliest version is....
low T > -40o
** Cp2TiCl2 + 2 AlMe3 Me Cp2Ti CH2
Cp2Ti Al
Cl Me
Tebbe reagent
or
Δ
Cp2Ti CH2
Cp2Ti 179
 -however one makes it....it is good at converting carbonyls into alkenes
O R'
"Cp2Ti=CH2" + CH2
R R' R
O R
CH2
R OR' R'O not feasible with
O phosphorus ylide (Wittig)
R chemistry
CH2
R N
N

-also works with carbonyls that are highly enolizable, whereas the Wittig reagent
would simply deprotonate
R Hartley, R.C.; McKiernan, G.J. J. Chem. Soc., Perkin Trans. 1 2002, 2763
-alternative set of conditions, see:
R Grubbs, R.H.; Pine, S.H. "Comprehensive Organic Synthesis" 1991, vol 5, Ch 9.3 (p1115)

Problems - replacing =CH2 with =CHR' gives a selectivity problem

Nico Petasis (USC)
=C=CR2, =CHPh, =CHTMS do work, however

"Cp2Ti=CH2" CH2
-acid chlorides do give enolates O
R O-TiCp2Cl
R Cl

R Pine, S.H. Org. React. 1993, 43, 1.

R Petasis, N.A. Pure. Appl. Chem. 1996, 67, 667.
180
 Mechanism - a metathesis type mechanism
X H2 X = H, CR'3,
2+2 CH2
Cp2Ti=CH2 + O Cp2Ti C OR', NR'2 Cp2Ti +
R O X retro 2+2 O R X
R
if X = Cl, it's a better leaving group, so...
H2 + X- Cl
Cp2Ti C Cp2Ti Cp2Ti CH2
CH2
O X O O
R R R

Metathesis of Alkenes
-these 2+2 / retrograde 2+2 cycloadditions become the dominant reaction pathway with
several transition metal carbenes/alkylidenes
N N Mes
Ph PCy3 Mes N N Mes Mes
PCy3 Ph
Cl Ph Cl
N Cl Ru Cl Ru
Ru Ph Ru Cl
Cl Cl Cl
O Mo Ph PCy3 PCy3 O
PCy3
F3C O
CF3 CF3 1 2 3 1st generation 4 2nd generation 5
CF3
Grubbs-Hoveyda
Schrock (pre)catalyst Grubbs' (pre)catalysts
-higher reactivity -more easily handled
-less stable, less easily -much more functional group tolerant
handled -less reactive (4 is close)
-not that functional group tolerant 181
 -use in organic synthesis - Ring Closing Metathesis (RCM)
true (living) catalyst
R
R R R R R H2C M
2+2 retro M 2+2
+ M
M M
2+2

-has enormous synthetic utility

-can close rings of many sizes: normal to large - the 8-12 sizes are the toughest
6 mol% MeO O
MeO O
94% -this poor control over
O 2 O alkene stereochemistry
PCy3 Ph MeO is common
MeO Cl Ru Ph
Cl
PCy3

10 mol%
3
HO OSiPh2Bu-t HO OSiPh2Bu-t 82%
PCy3
Ph
Cl Ru
O Cl O
PCy3
O O Grubbs 1 O O
5-10 mol%
1 Schrock cat.
95%
F3C N F3C N
O N
O
OTBDMS O Mo Ph OTBDMS
F3C O 182
CF3 CF3
CF3
 -one alkyne can be used in these ring closing metathesis reactions; get a diene as product
H2C M
R' R' R'
retro M 2+2
2+2 M
M M R'
2+2 R'

R Maifeld, S.V.; Lee, D. Chem. Eur. J. 2005, 11, 6118

R Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919.
R Mori, M. Adv. Synth. Catal. 2007, 349, 121. (in fact entire issue is on metathesis)
R Villar, H.; Frings, M.; Bolm, C. Chemical Society Reviews 2007, 36, 55.

3 CH3
O O 73%
H N
PCy3
Ph
H3C 1st gen Cl N
Grubbs cat Cl
Ru H
PCy3

R Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919.
R Mori, M. Adv. Synth. Catal. 2007, 349, 121 (entire issue is on metathesis)
R Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55.
R Maifeld, S. V.; Lee, D. Chem.-Eur. J. 2005, 11, 6118.
Cross Metathesis - Intermolecular
-metathesis of two alkenes can be intermolecular, but there is normally a problem with selectivity
-in some cases, an alkene can be chosen such that metathesis with itself is slowed down to
almost zero
-in these cases, it is possible to do cross-metathesis with a second, unhindered alkene
-the 'slow' alkene is normally either H2C=CH-EWG or H2C=CH-BIG

OEt SiR3
CN R P O
O O OEt O 183
R
 OBz
CH2Cl2, 3 mol% OBz
+ CO2Me CO2Me
Mes N N Mes
Ph 4
Cl Ru
91%, 4.5:1 E/Z
Cl
PCy3
2nd gen Grubbs

R Connon, S.J.; Blechert, S. Angew. Chem. int. Ed. Engl. 2003, 42, 1900.

Note: There is much work and progress in the RCM of diynes, using alkylidyne (carbyne)
intermediates

R Furstner, A.; Davies, P.W.

(t-BuO)3W or Mo(CO)6(cat) + Cl OH Chem. Commun. 2005, 2307.

Ring Closing Metathesis reviews - many, many, many - selected ones include..
R Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
R Conrad, J. C.; Fogg, D. E. Current Organic Chemistry 2006, 10, 185.
R Grubbs, R. H.; Trnka, T. M. 'Ruthenium in Organic Synthesis' 2004,153
R Mulzer, J.; Oehler, E. Top. Organomet. Chem. 2004, 13, 269
R Grubbs, R. H Tetrahedron 2004, 60, 7117
R Hoveyda, A.H.; Schrock, R.R, Angew. Chem. Int. Ed. Engl. 2003, 42, 4592 (Mo)
R Hoveyda, A.H.; Schrock, R.R Chem.-Eur. J. 2001, 7, 945 (asymmetric)
R Furstner, A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3012.
R Jafarour, L.; Nolan, S.P. J. Organomet. Chem. 2001, 617-618, 17.
R Tanka, T.M.; Grubbs, R.H. Acc. Chem. Res. 2001, 34, 18.
R Schrock, R.R., Tetrahedron 1999, 55, 8141. (Mo)

184