T. - S . M E I , D . - H . WA N G , J . - Q . YU * ( T H E S C R I P P S R E S E A R C H I N S T I T U T E , L A J O L L A , U S A )
Expedient Drug Synthesis and Diversification via ortho-C–H Iodination Using Recyclable PdI2 as the Precatalyst
Org. Lett. 2010, 12, 3140-3143.
Synthesis of Diclofenac and Lumiracoxib
C a te go r y
Synthesis of Natural
Products and
Potential Drugs
K e y w ord s
diclofenac
lumiracoxib
NH2
CO2H
CO2H
C (4.0 equiv)
CO2H
DMF, 60 °C, 12 h
92% (0.5 mmol scale)
A
C–H activation
Cl
NH
K2CO3 (2.5 equiv)
CuI (1.0 equiv)
NMP, 100 °C, 12 h
41% (0.5 mmol scale)
I
B
F
Cl
ortho-metalation
2-iodoarylacetic
acids
N-arylation
iodination
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F
Pd(OAc)2 (2 mol%)
PhI(OAc)2 (0.75 equiv)
I2 (0.75 equiv)
Lumiracoxib
palladium
NH2
Cl
CO2H
Pd(OAc)2 (2 mol%)
PhI(OAc)2 (0.75 equiv)
I2 (0.75 equiv)
CO2H
F (4.0 equiv)
CO2H
DMF, 60 °C, 12 h
70% (0.5 mmol scale)
D
Cl
I
E
NH
K2CO3 (2.5 equiv)
CuI (1.0 equiv)
NMP, 100 °C, 12 h
61% (0.5 mmol scale)
Cl
Cl
Diclofenac
Some further examples of 2-iodoarylacetic acids generated using the IOAc/PdX2 catalyst system:
Br
CO2H
CO2H
CO2H
I
82% yield
I
O
65% yield
CO2H
I
72% yield
62% yield
O
CO2H
CO2H
I
F
72% yield
CF3
I
75% yield
CO2H
I
I
83% yield
AcO
PhO
Ph
CO2H
CO2H
I
65% yield
I
75% yield
Significance: Arylacetic acids undergo palladi-
Comment: The active precatalyst is PdI2 which
um(II)-catalyzed ortho-C–H iodination in the presence of IOAc generated in situ by reaction of
PhI(OAc)2 with iodine. The value of the reaction
was illustrated by syntheses of the nonsteroidal
anti-inflammatory drugs lumiracoxib and diclofenac. A selection of the twenty-three substrates
examined shown above illustrates the scope of
the reaction. Methoxy-substituted substrates
react with IOAc non-selectively in the absence of
palladium. The reaction must be shielded from
light to prevent radical decomposition of acyl
hypoiodite intermediates.
can be collected at the end of each reaction and
recycled up to five times with only a slight decrease in yield. In most cases 5–15% of the palladium catalyst was required to achieve acceptable
yields and conversion. In one case (A → B) just
2% of the catalyst was required. None of the reactions was performed on a substantial scale. For
some insight into the possible mechanism of
the reaction, see: T.-S. Mei, R. Giri, N. Maugel,
J.-Q. Yu Angew. Chem. Int. Ed. 2008, 47, 5215.
Philip Kocienski
Synfacts 2010, 10, 1103-1103 Publishedonli e:x .x .201 Published online: 22.09.2010
DOI: 10.1055/s-0030-1258072; Reg-No.: K06710SF © Georg Thieme Verlag Stuttgart · New York
SYNFACTS Contributors:
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