Q.

Michaudel

Molybdenum in Organic Synthesis

Baran Lab GM 2012-09-22

Molybdenum (42Mo):

Oxidation processes with heterogeneous Mo catalysts:

* group 6 element
* From neo-latin molybdaenum and greek
molybdos meaning lead, since its ores were
confused with lead ores.
* ground state electron configuration:
[Kr].4d5.5s1
* oxidation levels: 6, 5, 4, 3, 2, 1, -1, -2
* First "discovered" (isolated) by Carl Wilhelm
Scheele in 1778. Metal was isolated in 1781
by Peter Jacob Hjelm.
* abundance: 54th in the Earth's crust, 25th in the oceans, 42th
in the universe
* Does not occur as a free metal on Earth. The principal ore for
its extraction is molybdenite (MoS2). Molybdenum is also an
industrial byproduct of copper and tungstene mining.
* Human abundance: 100 ppb by weight (Mo is a necessary
element in all eukaryotes)

* Partial oxidation of methane by nitrous oxide over molybdenum on silica

MoV + N2O ---> MoVIO + N2
MoVIO + CH4 ---> MoVIOH + CH3
MoVIO2 + CH3 ---> MoVOCH3
MoVOCH3 + H2O ---> MoVOH + CH3OH
MoVIOH + MoVOH ---> MoV + MoVIO2 + H2O

VI

VII

V! Cr Mn
Nb !Mo !Tc
Ta ! W !Re

* Biological role: at least 50 molybdenum-containing enzymes are now known. 2 main

functions: nitrogen fixation (nitrogenase) and redox transformations (xanthine
oxidase...)
*Mo forms hard and stable carbide (Mo2C) in alloys. Around 80% of the Mo world
production is used to make steel type alloys.
Molybdenum blue: name given to some polyoxometalate complexes containing
Mo(V) and Mo(VI) used in analytical chemistry and also MoO3.
Phosphomolybdic acid (12 MoO3 H3PO4) is reduced by unsaturated compounds to
molybdenum blue (Seebach staining reagent).

Other oxidation products are also formed but good selectivity for CH3OH and CH2O
(78%) at low conversion (3%). J. Am. Chem. Soc. 1984, 106, 4117 (kinetics).
* Oxidative dehydrogenation of propane by Mo oxides.
C3H8 + O*
C3H8O* + O*
C3H7O*

C3H8O*

(O* = lattice oxygen)

C3H7O* + OH*
C3H6 + OH*

J. Phys. Chem. B 2000, 104, 1292 (kinetics).

A few prices from Sigma Aldrich catalog 2012:

* Mo(CO)6 = $361.00/100g
* MoO3 = $68.00/100g, 99.5%
* MoCl5 = $186.30/10g, 99.9900%
* (NH4)6Mo7O24 4H2O = $25.00/100g (Strem)
* Pd(OAc)2 = $866.00/25g, 99.9000%
* PdCl2 = $917.00/25g, 99.9000%

PMA is also used in Masson's

trichrome stain that enables to
distinguishing cells from
surrounding connective tissue.

Molybdenum in Organic Synthesis

Q. Michaudel

Biochemistry and Bio-Inspired Chemistry of Molybdenum:

Nitrogenase Enzymes and Analogs:

Reduction of dinitrogen to ammonia:

Schrock, Science 2003, 301, 76.

N
HIPT

Nitrogenases are present in certain bacteria and are responsible for nitrogen
fixation by reduction of atmospheric dinitrogen to ammonia.

First nitrogenase analog:

Mo

Mo

Mo

N'

iPr iPr

iPr

iPr

HIPT

NH3 (12 equiv expected)

rt, 63 %

N'
H+, e Mo(IV) N

NH

H+

Mo(VI) N

NH2

Mo(V) N

NH2

H+

Mo(III)(N2)
N'

Mo
N'

N'

0.5 N2

N'

35 C

N'

N'

N' Mo N
N'

30 C

N'

+N2

N' Mo

N Mo N'

Mo(V) N

NH3
e

NH3

Chatt mechanism:

Mo(III)(NH3)

N'

iPr

HIPT

[HIPTN3N]Mo(N2) (1 equiv)
CrCp*2 (36 equiv)
{LutH}{BAr'4} (48 equiv)

N2 (1 atm)
N'

iPr

HIPT

All nitrogenase enzymes possess a iron-sulfur cluster cofactor that generally contains a
central Mo atom (sometimes replaced by Va or Fe). For a review on Mo cofactors and
enzymes see: Nature 2009, 460, 839.

Cummins, Science 1995, 268, 861.

Baran Lab GM 2012-09-22

Mo(VI) N + NH3

Chem. Rev. 1978, 78, 589.

H+

Synthetic cycle that incorporates N2 into organic nitriles: J. Am. Chem. Soc. 2006, 128, 14036.
Mo(IV)(NH3)

N
1 atm N2
NaH
95%
N'

Mo

N'

Mo
N'

TIPSOTf,
MeC(O)Cl
92%

N'

N'

N'
Cl
Mo
N'

N'

OTMS
0.5 SnCl2
71%

MeCN (99%)

Me

N
N'

Mo
N'

N'

Mo
N'

Mo(V) NH2

H+

Mo(VI) NH2

Mo(V) NH

Another system for the reduction of dinitrogen to ammonia:

Nat. Chem. 2011, 3, 120.

Me

Mg
74%

N'

Mo(IV) NH2

N'

H+

N'

PtBu2
Cl

OTf

1. Mg(anthracene)
2. TMSOTf
82% (2 steps)

Mo

Cl
PtBu2

Cl

N2 (1 atm)
NaHg (6 equiv)
THF, rt, 63 %

catalyst (1 equiv)
reducing agent: CoCp2 (72 equiv)
proton source: {LutH}{OTf} (96 equiv)
49% yield

PtBu2
N2
N

Mo

N2
PtBu2

tBu

2P

N2

N Mo

N2
tBu P
2

active catalyst

Molybdenum in Organic Synthesis

Q. Michaudel

18Olabeled

Biochemistry and Bio-Inspired Chemistry of Molybdenum:

Many different oxotransferase containing Mo have been isolated. Reactions

effected by this family of enzyme is broad, but most of them possess the
molybdopterin moeity in the cofactor:
O
S

molybdopterin

H2N

H H
N

N
O
H H

Mo(VI)

O
P

NH2

H
N

HN

MoIV SH
Ered

18O

N
H

N
H

O
H
N

NH2

or

O Ser

Mo

S.Cys

NH2

or

18O

Mo

OH/OH2

18O

O
H
N

Mo

NH2

A few examples:
S

transfer experiments with xanthine oxidase: J. Biol. Chem. 1966, 241, 4798.
J. Biol. Chem. 1966, 241, 3468.

Oxotransferase Enzymes and Analogs:

HN

Baran Lab GM 2012-09-22

HN

MoVI S
Eox

N
H

N
H

Water is another potential source of oxygen for the oxotransfer as shown in the
postulated xanthine oxidation mechanism : J. Am. Chem. Soc. 2005, 127, 4518.
J. Am. Chem. Soc. 2008, 130, 55.
SH
Mo

O Ser

Mo

O/N

Mo(IV)

O
S

Mo

S Cys
OH/OH2

S
S

S
S

xanthine oxidase
aldehyde oxidoreductase

sulfite oxidase
nitrate reductase

O
Mo
VI

S
O

Moz+2Oa+1Ln + X
2H+

aldehyde oxidoreductase: RCHO + H2O

RCO2H +
sulfite oxidase: SO32 + H2O
SO42 + 2H+ + 2e
nitrate reductase: NO3 + 2H+ + 2e
NO2 + H2O
+

DMSO reductase: Me2SO + 2H + 2e

Me2S + H2O
xanthine oxidase:
O

N
H

xanthine

N
H

O
Mo
V

+ 2H+ + 2e

H
N

N
H

VI

e,

H
N

O
NH

N
H
O

H+

H2O

O
N
H

uric acid,

Mo

S H

e, 2H+

H
N

HN

+ H2O

BH+

2e

O
N

HN

Oxotransfer general reaction: MozOaLn + XO

O
NH

N
H

DMSO reductase

H
N

O
NH

N
H
O

S
S
BH+

O
Mo
IV

SH

H
N

O
NH

N
H
O

(B = Glu)

Other mechanisms cannot be ruled out thus far, for a review, see: Hille, R. Chem. Rev.
1996, 96, 2757.

uric acid

Molybdenum in Organic Synthesis

Q. Michaudel
First oxotransferase analog:

HNR2

CS2, NaOH
then
Na2MoO4 2H2O

R2N

H H
N

Mo
O

NR2

Mo2O3(S2CNR2)4
O2

Application of the system to oxidation and reduction reactions: (for a summary, see Holm,
J. Am. Chem. Soc. 1986, 108, 6992.)

MoO(LNS2)(DMF)

Me

CO2H

BnHN
MoO2(LNS2)

ArSSAr + H2O

Oxotransfer from DMSO to Ph3P or for oxidation of thiol to disulfide:

Me2SO

MoO(LNS2)(DMF)

Ph3PO or PhSSPh + H2O

XO = R2SO, RCO3H, R2NO, Ph3AsO, Ph3SbO, NO2

MoO2(S2CNR2)2 + MoO(S2CNR2)2

CO2H

Reactions proceed at rt, conversion 90%

MoO(S2CNR2)2 + X
X = R3P

Me

ArSH
Tetrahedron Lett. 1972, 1693.

MoO(S2CNR2)2

S
N
H H

CO2H

BnHN

Ph3PO

MoO2(S2CNR2)2 + XO

CO2H

O
Ph3P

H H
N

MoO(LNS2)(DMF)

N
H H

R = Et, nPr, iBu

MoO2(S2CNR2)2

Baran Lab GM 2012-09-22

J. Am. Chem. Soc. 1986, 108, 6992.

J. Am. Chem. Soc. 1988, 110, 2139.

Mo2O3(S2CNR2)4

competing reaction, biologically irrelevant and potentially

decreasing the reactivity of the system.

Me2S

MoO2(LNS2)

Oxotransferase analog second generation:

Ph3P or PhSH

MoO(S2CNEt2)2 (0.3 equiv)

O
PhMe, 130C, 36 h, 92 %
O

S
N

Mo

+X

Mo

O
S

Ph

S
DMF

O
O

PhMe, 80C, 20 h, 92 %

677.

Ph

HO

+
H

Me

[Mo] (2.5 mol %)

tBuOOH (1.5 equiv)

+ XO

Me

MoO(S2CNEt2)2 (0.3 equiv)

Reverse reactions do not

proceed: Inorg. Chem. 1988, 27,

Ph

Me2N

PhMe, 35 C, 18 h

Ph

Ph

OH

Conv.

Ph

MoO2(S2CNEt2)2

6.1

10.6

25.4

42.0

MoO2(NCS)2(bipy)

13.0

4.6

48.8

66.5

Eur. J. Inorg. Chem. 2001, 2001, 10711076.

MoO2(LNS2)

OH

MoO(LNS2)(DMF)

Sterics inhibit formation of -oxo dimers (Mo(V)): Holm, J. Am. Chem. Soc. 1985, 107, 917.
J. Am. Chem. Soc. 1985, 107, 925.

MeO

MoO(S2CNEt2)2 (10 mol %)

tBuOOH,

CHO

, 1030%

MeO
Journal of the Indian Institute of Science 2010, 90, 287.

Molybdenum in Organic Synthesis

Q. Michaudel

A lot of new oxotransferase analogs have been published then, like these
analogs of the sulfite oxidase family using dithiolene ligands:

iPr

iPr

Mo

MoOPh reagent: (see Newhouse 2007 group meeting)

MoOPh = MoO5 Py HMPA (Vedejs J. Am. Chem. Soc. 1974, 96, 5944.)
MoOPH can be prepared from MoO3: Org. Synth. 1986, 64, 127.
O
MoO5 HMPA was first discovered by Mimoun and used as an
O
O
epoxidation reagent: Bull. Soc. Chim. Fr. 1969, 1481.
Mo

Mo

iPr

R = Me, CN

Tetrahedron, 1970, 26, 37.

For a mechanistic discussion on the epoxidation, see

P(NMe2)3 Sharpless, J. Am. Chem. Soc. 1972, 94, 295.

These complexes can catalyze similar redox reactions as depicted before. For reviews
on Mo oxotranferase enzymes and analogs, see Coord. Chem. Rev. 1990, 100, 183.

For oxidations of alcohols to ketones with MoO5 reagents, see

Chem. Rev. 2004, 104, 1175.

Ph

2. MoOPh
70 % overall

S8 (0.25 equiv)
MoO(S2CNEt2)2
(0.07 equiv)
S

acetone, 56 C,
15 h, Ar, 69%

Me

CHO

S
1/4 S8

Et2N

Mo
NEt2

Me

EtO
EtO

S
P
S

S S

NEt2

Et2N

Me

Mo

Mo
S

NEt2

OEt

Ph

(1 equiv)
MoO(S2P(OEt)2)2
(0.01 equiv)
PhH, 80 C,
30 min, Ar, 90%

Me

Me

S
Me

Me

Ph

(1 equiv)
MoO(S2P(OEt)2)2
(0.01 equiv)
PhH, 80 C,
30 min, Ar, > 95%

Me

Me

H
Me
() warburganal
J. Org. Chem. 1988, 53, 855.

R1

Me
R2

Me

Me
R1 = H, R2 = OH 45%
R1 = OH, R2 = H 25%

J. Am. Chem. Soc.

2003, 125, 3871.
Me

Me
S

Me
Me

Synlett. 1994, 337.

O

MeS

MoO(S2P(OEt)2)2

CHO

Me

2. MoOPh
40 C

OEt

H3O+
81%

H
Me

1. LDA, THF,
78 C

Mo

Me

OHC OH
Me
O

Me

8 steps from known

decalone
O

1. LDA, THF,
78 C
2. MoOPh
91% overall

H
Me

O
O

OHC OH O
Me

O
O

Chem. Commun. 2001, 1910

Improvement of the
reaction (yield and scope):

J. Org. Chem. 1979, 44, 921.

O
1. LDA
Ph
HO

Other Oxidations with Mo Complexes:

Episulfidation:

Et2N

Baran Lab GM 2012-09-22

Me

MeS

Epoxidation with Mo(CO)6 and tBuOOH:

OH

1. Mo(CO)6,
tBuOOH, PhH,
2. Jones [O]
Me 74% overall
OH

Me
O

Smith III, J. Am. Chem. Soc. 1991, 113, 4037.

OH O
Me

H
O

26 steps
S

OH

H
Breynolide

Molybdenum in Organic Synthesis

Q. Michaudel

1. Mo(CO)6,
tBuOOH,
PhH, 55 C HO
O
OH
TBSO
1:1 mix
iPr 2. DMP
77% overall Me
3. Deptrotection
Me
Me
steps
(mCPBA gives only the wrong diastereomer)
O

MPMO
Me

Me

For a group meeting on Fisher carbenes, see Chen 2007

O

OH
iPr

Me

Me

octalactin A

PPh3, PTSH,
DEAD, THF, rt

HO
Me

Molybdenum Fisher carbenes:

J. Am. Chem. Soc. 1994,116, 5511.

Oxidation of thioester to sulfone:

Me

then
(NH4)6Mo7O24
H2O2, EtOH,
0 C, 82%

Me

* low oxidation state metals;

* middle and late transition metals Fe(0), Mo(0), Cr(0), W(0);
* -electron acceptor metal ligands;
* -donor substituents on methylene group such as alkoxy and
amino groups.
Fisher carbenes are in the singlet state and the carbene carbonis electrophilic .
Typical synthesis of molybdenum Fisher carbenes:

N
Ph

S
O

Mo(CO)6

ONMe4

1. RLi, Et2O
2. Me4NCl

OH

H2SO4

(OC)5Mo

(OC)5Mo
R

Julia-Kocienski precursor

R
CH2N2

3 steps
OMe

1. RLi, Et2O

OH
HO2C

Fischer carbenes are found with:

OH
Jacobsen, J. Am. Chem. Soc.
2001, 123, 10772.

Baran Lab GM 2012-09-22

(OC)5Mo

Me
2. MeOSO2F or MeOTf

Molybdenum vs chromium carbene in (Wulff)-Dtz reaction:

Me

ambruticin

Me

Me

For other examples, see the synthesis of (+)-azaspiracid-1 (Evans, Angew. Chem. Int. Ed.
2007, 46, 4698.) and C1C52 fragment of amphidinol 3 (Rychnovsky, Org. Lett. 2007, 9, 4757.)
Me

Misc:
Me2Zn, Cu(OTf)2
L*, PhMe, 30C

Me
1. TsNHNH2, MeOH, rt
2. nBuLi, TMEDA,
78 C to rt

Me

then
Br
Me
O
J. Am. Chem. 30 C to rt, 71%,
O
Soc. 2012,
7:1 dr, 91 %ee
134, 13577.
Me
1. (NH4)MoO4 Me
H
H2O2, tBuOH
Me
O
rt, 3 d
O
O
2. PTSA,
H DCM rt, 3 d
H
42%
O
O
Me
13%
yield overall
artemisinin
gram scale
MeO
O

Me

H
Me

OH

OTIPS

Et2AlCl
TIPSO

MeO

M
(CO)4

RS

RL

then air
oxidation

OMe

Me
OTIPS

RS

Me

RL

RS
RL

M(CO)3
OMe

OMe

OMe

H
O

CO

RS

RL

PdCl2
H2O2

OMe

(OC)4M

OMe

Me

61%

RS

Me

3. DMF, 0 C, 1 h
77 % overall
Me

RL

(OC)5M

RS
OMe

RL

OMe

RS
R.E
RL
M
(CO)4

95%
6:2:1:1 dr

Molybdenum in Organic Synthesis

Q. Michaudel
OMe
(OC)5M

OMe

With Mo carbene cyclopropanation is faster than CO insertion. For a study on the effect
of tether length and composition on the cascade see: J. Am. Chem. Soc. 1992, 114, 8424.

OMe

nPr

+
solvent, 80 C
then air/SiO2

OMe
(OC)5M

Et
Et
THF, 50 C or rt

OH

Et

(OC)5Mo

R2

R1
+

nPr
E
R1, R2 = H, Alk
E = CO2Me, CO2Et, CN, PO(OMe)2

nPr

Harvey, J. Am. Chem. Soc. 1991, 113, 5066.

E E
+
J. Org. Chem 2002, 67, 8675.

110 C
40 min

nBu

PhMe
42%, 1:1 dr

OMe

40 C
5h

nBu

PhH
54%

(OC)5Mo

lpc
B

78 C
to rt

Me O
(OC)5Mo

()-lpc2BCl

Me

Ph

Ph

Me

Ph

Me

Me

O
BF3 OEt2

O
Me
Me

Ph
Me

15C
R3

OBF2
(OC)5Mo

up to 80% yield
mixture of 2 diastereomers

1. H2O2
NaOH
2. CH2(OMe)2
PPTS

Barluenga, Org. Lett. 2003, 5, 905.

CHO

O
+

OH
X

R2

R1

R2
X

R1

R2

R1

R1
nBu

E
E

(Et3N)Mo(CO)5
(cat.)

mech?
nBu

Ph
HO

Et3N, Et2O
89%

CHO

OBF2
R1

"Mo(CO)5"

E
OMe

R3
X

[Mo(CO)5BF2]

(OC)5Mo
E

R3

60 C to 20 C
then H2O
CO

BF2

O
Ph

Et2O, 78 C

OMe

OMe
(OC)5Mo

van Halban-White type cyclization

lpc

(OC)5Mo

Mo carbene react faster for cyclopropanations than Cr and W.

Me
Wulff, J. Am. Chem. Soc. 1990, 112, 1645.

Me
OMe

OLi

Tetrahedron Lett. 1990, 31, 2529.

E E

Ph

1%
1%
64%
59%

R2

40%

Me

R1

THF
65 C, 1h

Me OMe

Ph

The following factors favor indene product over phenol product:

* aryl complexes > alkenyl complexes
* Mo > W > Cr
* More coordinating and/or polar solvents
* Higher concentration of alkyne
* Terminal alkynes > internal alkynes
For a complete study, read Wulff, Organometallics 1994, 13, 102.
Cyclopropanation:
OMe

via

Et

60%
75%
6%
8%

X=C
X=O
X=C
X=O

Me

Ph

Et

OH

M = Cr
(C= 0.005 M)
M = Mo
(C= 0.005 M

Me +

(OC)5Mo

+
Et

THF
70 C, 14h

OMe

2%
4%
27%
80%

OMe
X

nPr

84%
64%
12%
3%

then air, HOTs,

H2O/THF

Misc Mo carbenes reaction:

nPr

THF
benzene
THF
benzene

M = Cr
(C= 0.1 M)
M = Mo
(C= 0.005 M)

Baran Lab GM 2012-09-22

Barluenga, Angew. Chem.

Int. Ed. 1999, 38, 3084.

Ph
(OC)5Mo

H O

Et3N

R2

Ph
J. Am. Chem. Soc.
1994, 116, 9363.

Molybdenum in Organic Synthesis

Q. Michaudel
Molybdenum and metathesis at a glance:

Baran Lab GM 2012-09-22

Alkyne metathesis: first report of alkyne disproportionation in 1968 with

heterogeneous catalysts (Chem. Commun. 1968, 1548.)

Alkene metathesis: early reports of olefin disproportionation by the Phillips Petroleum

Company R&D department used heterogeneous catalysts like CoOMoO3Al2O3
(Industrial & Engineering Chemistry Product Research and Development, 1964, 3,
170.) First homogeneous catalysts were also based on Mo complexes:

Mortreux's discovery (J. Chem. Soc., Chem. Commun. 1974, 786):

Mo(CO)6
resorcinol
2

(Ph3P)2Cl2(NO)2MoMe3Al2Cl3

Ph

Tol

Ph
decalin
160C, 3 h

55%

rt, 19 h, 91 wt %

Ph

Tol

Tol

23.5%

21.5%

H2C=CH2 (20 atm)

(Ph3P)2Cl2(NO)2MoMe3Al2Cl3
Me

0 C, 2 h, 18%
J. Am. Chem. Soc. 1970, 92, 528.

(tBuO)3W

Me

Me

Me

Recent Mo alkylidenes for Z-selective olefin cross-metathesis

(Schrock & Hoveyda): Nature 2011, 471, 461.

R'

TBSO

Br

Me
Me
Me Me

Me

OTES

cat. C

Me

Br

R' = Me (cat. A)
or iPr (cat. B)

Mo alkylidyne:
precatalyst, needs to
be activated by CH2X2
like DCM.Tolerates a
lot of functional groups.
Air and water sensitive.

cat. E

Ph
Me

R'

Me
Me

Me

Mo

Me

or

R=

NR

W alkylidyne: highly reactive but

does not tolerate several functional
groups. Air and water sensitive.

Schrock alkylidene catalysts: highly reactive but air and water

sensitive (glove box use only). Generally favor E-alkene
Ph formation.

Mo
RO
RO

Mo
N

Me

cat. D

NAr

Me

1. cat. E, DCM/PhMe
2. Lindlar, H2, DCM
3. aq. HF

Epothilone C
63% (3 steps)
only Z isomer

Chem. Commun. 2001, 1057.

O

OTBS O

For a review on alkyne metathesis, see Frstner, Chem. Commun. 2005, 2307.
Me
TBSO
Me

Ar

Me
Me
O

Me
O

OTBS O
S

Ar =

Me

cat. C

TBSO
Me

22C, 1.5 h
91% conv
Z:E = 9:1

Ar

Me
Me
O

Me

(Tungsten alkylidene gives

a slighty better selectivity)

Me

OTBS O

Ph3SiO Mo
Ph3SiO
N

OSiPh3
N

HF pyr

N
Nature 2011, 479, 88.

New catalysts, more reactive and user friendly (Frstner, J. Am. Chem. Soc. 2010, 132,
11045.)

Me

Epothilone C

Indefinitively stable on
benchtop.
Reaction at 80C

Ph3SiO
Ph3SiO

Mo

Me
MnCl2,

OSiPh3
OEt2

PhMe, 80C
30 min

Air and water sensitive.

Reaction at rt with MS 5
Highest reactivity and
selectivity.

Ph3SiO Mo
Ph3SiO
N

OSiPh3
N

Precatalyst, stable
in air for hours.

Molybdenum in Organic Synthesis

Q. Michaudel
Asymmetric Allylic Alkilations (Trost):

Organometallic Enantiomeric Scaffolding:

CO

O
H

Mo

1. Mo(0)

(R,R)L

AcO

Nu

Ar

NH HN
(R,R)

R
Angew. Chem. Int. Ed. 2002, 41, 1929

1. Boc2O, DCM, Et3N,

DMAP, rt, 98%
2. 10 mol %
Mo(CO)3(C7H8), 15 mol %
(R,R)L, dimethyl
sodiomalonate,

HO

NO2

THF, reflux,
94%, 96% ee.
3. NaCl, 150 C,
20:1 DMSO/H2O,100%.

Tipranavir
MeO2C

J. Am. Chem. Soc. 2002, 124,

14320.
See Michaudel 2011 group
meeting for the full synthesis.

NO2

MeO
O
N
Me

OsO4 NMO
NaIO4
O

THF
98%, 82% ee

Mo(0)L5

Tp

Me

Me

nBuLi

1. NOBF4 HO
2. Na2CO3

OH

OH

49% dr > 98:2

Mo(CO)2Tp
1. OsO4,pyr Me
2. H2S, MeOH
3. KOH

Org. Lett. 2001, 3, 2665.

NMe

MeO

O
62%, 99% ee

H
N

N
Me
O

Ar

J. Am. Chem. Soc.

2006, 128, 4590.

2 recrystallisations

LAH, THF,

H
N
Me

Model for
enantiodiscrimination:

MeNH2, Et3N

CHO

OH

1. NOBF4 HO
CO2H 2. Et3N

OH
Mo(CO)2Tp

O
NH

N
N

CO

Mo
O

R1

Ar
O

NH

N R2
favored

R2 N

nPr

N
R*

CO

60% (5 steps)
dr > 98:2
Mo(CO)2Tp
O

R1

C5H11
disfavored

2 steps

()-adaline O

C5H11
6 steps

O
O

N
Cbz

C4H9

1. allylMgBr
2. HCl
78% (2 steps)
1. KOTMS,
rt

CbzN

J. Org. Chem. 2008, 73, 882.

J. Am. Chem. Soc. 2009, 131, 876.
HN

OH

Me

Mo(CO)2Tp
O

3. chromatography

Mo
O

CO

CO

Ph

1. m-CPBA (name?)
2.(DMF)3Mo(CO)3
then KTp

OH

Me

OH
Mo(CO)2Tp

Me

MeO

()-esermethole

Me

3. H2S,
MeOH 85%
Me (3 steps)

(EtO)2OP

92%

N
Me

O
H

1. DIBAL-H
2. OsO4,pyr.

(racemic)

Me

high Mo(0) concentration

Me
Mo(0)L5
O

N
N H N
N
B
N
N

THF, 78 C, 95%
Mo(CO)2Tp
E = CO2Et

Mo(C7H8)(CO)3,
(R,R)L
MeO
LiOtBu

Me

Mo(CO)2Tp

low Mo(0) concentration

Obtention of inversion or retention
Me
enantiomer can be controlled by the
O Mo(0)L4
chosen set of conditions: temp., solvent
O
(THF vs DCM), slow or fast addition of
(DMF)3Mo(CO)3... Liebeskind, J. Am.

CHO
OtBu

Mo(CO)2Tp

Chem. Soc. 1996, 118, 897.

Me

or

2. KTp

OC
H

Baran Lab GM 2012-09-22

PdCl2
CuCl
DMF:H2O

Mo(CO)2Tp
O O

2. NOPF6
N
C5H11
80% (2 steps) Cbz

Me

93%

Mo(CO)2Tp
O

N
Cbz C5H11

1,5Michael

Molybdenum in Organic Synthesis

Q. Michaudel
O
Mo(CO)2Tp
OMe

CbzN
Me

7 steps
O

Mo(CO)2Tp
Ac

homo-SN2'-like

N
Cbz
SO2Ph

AcO

CbzNHOH
NaIO4

J. Am. Chem. Soc.

2006, 128, 465.

MeOH:H2O
3:1

O
NCbz

Me

NHPh OH
OH

MeCN:H2O
15:1
52% (2 steps)

J. Am. Chem. Soc. 2009, 131, 12546.

NHCbz

N
Cbz

Mo(CO)6

RSH

Reaction temperature can be decreased to rt to 45 C

by using Mo(CO)6 supported on SiO2.

RH

AcOH, 115 C
R = alkyl, aryl

5 steps

J. Chem. Soc., Chem. Commun. 1980, 169.

O

O
O

NH

CO2Et

Et

O2N

Rh(II)

N2

O2N

CO2Et
S

xylene, 180C
83%

CO2Et
Mo(CO)5

R3

R1

NH2

R2

R1

wet MeCN
reflux

N
R3

R2

presumably via:

R1

NH

via:

O
R3

R
Et

Et

R2
J. Chem. Soc. Perkin Trans. I 1985, 1401.

Isoxazoles are good surrogates for 1,3 diketones: see Michaudel 2011 Poly(-carbonyl)s
group meeting.

Mo(CO)6

Et

Reductive Cleavage of NO Bonds:

Mo(CO)6

()-kainic acid
Org. Lett. 2000, 2, 3181.

Other Reductions:

OH

CO2H

N
H

12 steps

Carreira, Angew. Chem. Int. Ed. 2008, 47, 4335.

(+)-isofebrifugine

CO2H

Mo(CO)6

See also the synthesis of 35deoxy amphotericin B methyl ester,

NaH
O
Cu(ethylhex
anoate)2 Me
air
57%
PhO2S
one-pot

aerobic annulative demetalation

Tetrahedron Lett. 1990, 31,

3351.

Me

Ph

wet MeCN
88%

Me

()-bao gong teng A

KOTMS, NaOMe, MeOH

1:10 89%

CO2Me

Mo(CO)6

HN
O

Me

NaH,
MeCOCH2SO2Ph

CO2Me

PhN
Me

Mo(CO)2Tp
O(pNO2Bz)
N
Cbz

CbzN

Ph

OH

Mo(CO)2Tp

EtAlCl2
0 C, 1 min
7:1 (exo:endo)
89%
[5+2]

N
Cbz

Mo(CO)2Tp

Baran Lab GM 2012-09-22

AcOH,
unexpected concomitant reduction of
the nitro group

S
O2N

EtO2C
NBn

HN
S
O
N

EtO2C

EtO2C
1. Mo(CO)6
2. ArSO2N3
3. C4H9N
(91%, 3 steps)

NBn
1. BF3 OEt2 HN

HN
S
O

Me J. Org. Chem. 1985, 50, 425.

N2

2. tBu3P,
then Ac2O
AcO
70% 1:1 mixture

NBn

name
reaction?

Et
NO2

NH

CBr2(COCl)2
Zn
78 C to rt
then 120 C

mech?
Padwa, Org. Lett. 2005, 7, 2925.

3 steps

Et

N
H

N
Et

isoschizozygane
core

10

Molybdenum in Organic Synthesis

Q. Michaudel

Miscanelleous Reactions:
MoCl5 is a strong Lewis acid and oxidizing reagent, often used for the Scholl reaction:

Bu3SnH
TBSO
Mo(CO)3(CNtBu)3 Bu3Sn
2 mol %

TBSO

OC6H13

Me

OC6H13

MoCl5, SiCl4

OC6H13

DCM,
80 C to 20 C
88%

OC6H13

C6H13O

Synthesis 2011, 3801.

MeO

OC6H13

CO2Me

OMe

OMe

1,4dioxane,
w, 130 C

Molybdenum-mediated
carbonylation without Pd and CO
Y

Ar

Mo(CO)6, DMSO
CO2Et
R2

R1

Org. Lett. 2011, 13, 3181.

100 C, 68 %

TMS

MoCl5PPh3 (1:5) (cat.),

CO2 (1 atm)

Me

Angew. Chem., Int. Ed. Engl. 1980, 19, 317.

rt, 7 d, 78 %

MoF6 is a fluorinating reagent (similar reactivity to SF4): mp 17.5 C; bp 35 C

It can be used in normal glassware at room temperature or below.
Br

MoF6
Br
158 C, 64 h, 89%
J. Fluorine Chem. 1979, 13, 375.

CO2H

CF3

RO
R=H
R = THP

Bu3Sn

90 C,
95 %

Me
MeO2C
Me

CbzN

DCE, 40 C, Me
75%
MeO2C

Me
Org. Lett. 2004, 6, 2245.

Internal alkene is generally favored with Mo, but in some cases, sterics can invert the
selectivity.

Study on some
unsaturated propellanes
by Paquette:
SnBu3

+
RO

Me

[Rh(CO)2Cl]2,
PPh3, AgBF4,
Me
CO

CbzN

(DAST generally stops at RCO2F)

Mo(CO)3(CNtBu)3 (MoBI3) a catalyst for hydrostannations of alkyne

Bu3SnH
Mo(CO)3(CNtBu)3
2 mol %
THF, 55 C
81 % (41%)
98 % (68%)

CbzN

Mo(CO)6,
DMSO
Me
MeO2C

Brummond, Tetrahedron Lett.

1995, 36, 2407.

TMS

O
Me

Me

AstraZeneca, Org. Lett. 2010, 12, 4980.

Ar = aryl, heteroaryl
X = Br, I
Y = NR1R2, NHR1, OH, OR, NHSO2R

MeO

mech?

CO2Et

Mo(CO)6 (1 equiv),
Et3NCl (1 equiv)

First allenic Pauson-Khand:

2. R1CH2COR2
Et3N

MeO

CO2Me
major regioisomer (8:2)

MeO

1. MoCl5/TiCl4
MeO

OTBS O

Org. Lett. 2010, 12, 4976.

ArX + HY
(1 equiv) (2 equiv)

MeO

Me

THF, 55 C, 48 h
86 %

OTBS O

C6H13O
OC6H13

Baran Lab GM 2012-09-22

RO
91:9 (55:45)
98:2 (67:33)

J. Am. Chem. Soc. 1974,

96, 1217.
Tetrahedron Lett. 1975,
1145.
J. Am. Chem. Soc. 1975,
97, 3536.

Org. Lett. 1999, 1, 1017.

In brackets are yield and selectivity of the reaction using PdCl2(PPh)3 instead of MoBI3.

Me

(pyrolysis)

Me

Mo(CO)6
benzene,
reflux

Me

mech?

Mo(CO)6
benzene,
reflux

(pyrolysis) or
Mo(CO)6, benzene,
reflux

Me

11