Expedient drug synthesis and diversification via ortho-C-H iodination using recyclable PdI2 as the precatalyst

Article abstract of DOI:10.1021/ol1010483

(Figure Presented) Pd(II)-catalyzed ortho-C-H iodination reactions of phenylacetic acid substrates have been achieved using recyclable PdI₂ as the precatalyst. This class of substrates is incompatible with the classic amide formation/ortho-lithiation/iodination sequence. The power of this new technology is demonstrated by facile drug functionalization and drastically shortened syntheses of the drugs diclofenac and lumiracoxib.

Full text of DOI:10.1021/ol1010483

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3140-3143
Expedient Drug Synthesis and
Diversification via ortho-C-H Iodination
using Recyclable PdI2 as the Precatalyst
Tian-Sheng Mei, Dong-Hui Wang, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
yu200@scripps.edu
Received May 7, 2010
ABSTRACT
Pd(II)-catalyzed ortho-C-H iodination reactions of phenylacetic acid substrates have been achieved using recyclable PdI2 as the precatalyst.
This class of substrates is incompatible with the classic amide formation/ortho-lithiation/iodination sequence. The power of this new technology
is demonstrated by facile drug functionalization and drastically shortened syntheses of the drugs diclofenac and lumiracoxib.
Palladium-catalyzedcouplingreactions,suchasMizoroki-Heck
olefination, Tsuji-Trost allylation, Suzuki-Miyaura cou-
pling, Negishi coupling, Hiyama coupling, and Buchwald-
Hartwig amination, are among the most useful tools for
constructing carbon-carbon and carbon-heteroatom bonds.1
The remarkable power of these reactions stems from the
widespread availability and diverse reactivity of the aryl and
alkyl halide starting materials and from advances made in ligand
design. Nevertheless, a potential hurdle that remains in applying
one of these methods as a step in a particular synthetic sequence
is the position-selective installation of the halide onto the arene
precursor. In this context, two classical approaches to prepare
halogenated arenes are particularly useful: (i) eletrophilic
aromatic substitution (EAS)2 and (ii) directed ortho-lithation
(DoL) with a subsequent halogen quench.3 Following the early
reports of both stoichiometric4 and catalytic C-H halogenation,
Pd(II)-catalyzed halogenation methods for both sp2 and sp3
C-H bonds have recently been developed, including a dias-
tereoselective version.5-11 However, the majority of these
reactions compare unfavorably with conventional DoL
methods in terms of practicality and versatility, particularly
for applications in large-scale syntheses. With these consid-
erations in mind, we set out to design a truly enabling C-H
iodination reaction using phenyl acetic acid substrates that
are incompatible with DoL methods (Scheme 1).3a
Scheme 1
.
Directed ortho-Lithation (DoL) Follwed by a
Halogen Quench
(1) For reviews, see: (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544. (b) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
Moreover, we endeavored to achieve a high level of
operational simplicity and practicality by developing a recy-
(2) For electrophilic halogenation reactions, see: (a) Taylor, R. Elec-
trophilic Aromatic Substitution; John Wiley: New York, 1990. (b) Prakash,
G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.;
Olah, G. A. J. Am. Chem. Soc. 2004, 126, 15770. (c) Barluenga, J.; Alvarez-
Gutierrez, J. M.; Ballesteros, A.; Gonzalez, J. M. Angew. Chem., Int. Ed.
2007, 46, 1281.
(3) For DoL reactions see: (a) Beak, P.; Snieckus, V. Acc. Chem. Res.
1982, 15, 306. (b) Schlosser, M.; Mongin, F. Chem. Soc. ReV. 2007, 36,
1161.
10.1021/ol1010483  2010 American Chemical Society
Published on Web 06/15/2010

clable catalytic system. Herein, we report a Pd-catalyzed ortho-
C-H iodination reaction of phenylacetic acid substrates, a class
of substrates that is incompatible with classic DoL conditions
because the chelating functional group is remote from the
targeted C-H bond and also because these compounds contain
acidic protons at the R-position. The iodinated phenylacetic acid
products can easily be converted to 3-phenylpropionic acids
through the Arndt-Eistert homologation, which allows for
convenient access to another major class of ortho-iodinated
carbon skeletons (Scheme 2).12 In addition, the resulting
potassium-promoted C-H activation reactions in conjunction
with a mechanistic hypothesis and characterization of reaction
intermediates.10a,15 These findings have prompted us to focus
on a new strategy of using chemical functional groups that
exhibit weak coordination with Pd to direct C-H insertion
(e.g., the carbonyl of a CO2X moiety), including commonly
encountered, synthetically useful compounds such as car-
boxylic acids16 and alcohols.17 Not only does this philosophy
open up a convenient pool of starting materials but also we
have found significantly broader scope in the types of
carbon-carbon and carbon-heteroatom bond-forming reac-
tions that can be performed due to the fact that the resulting
palladated intermediates are highly reactive in the functional-
ization step. While some carboxyl-directed C-H activation
reactions have been extended to phenylacetic and 3-phenyl-
propionic acids, our iodination reaction protocol has been limited
to benzoic acids, a shortcoming that has hampered broad
applications of the protocol when alternative carbon skeleton
are desired. Considering the fact that the traditional amide
formation/ortho-lithiation/iodination sequence (DoL) is unsuit-
able for phenylacetic acids, a Pd-catalyzed ortho-C-H iodina-
tion method for these substrates will be especially valuable.
We began our investigation by optimizing previously
developed catalytic systems, but unfortunately, the iodination
products were obtained in very low yields, despite extensive
efforts (Table 1, entries 1-4). Upon further analysis, we
Scheme 2
.
Pd(II)-Catalyzed ortho-Iodination of Phenylacetic
Acid
iodinated products can be readily converted to a wide range of
highly valuable synthons through subsequent cross-coupling or
Buchwald-Hartwig amination.13 The potential power of this
technology is demonstrated through remarkably short syntheses
of two multibillion dollar drugs.
Recently, we discovered that the presence of a wide range
of cations including organic cations in the reaction medium
drastically promotes ortho-iodination of benzoic acid
substrates.10a Although sodium and potassium countercations
had been present in a number of earlier Pd- and Pt-catalyzed
C-H activation reactions,6,14 the significant effects of cations
on carboxyl-directed C-H insertion had not been realized
prior to the extensive development of various sodium- and
Table 1. Iodination in the Absence of Light
(4) For stoichiometric halogenation, see: (a) Carr, K.; Sutherland, J. K.
J. Chem. Soc., Chem. Commun. 1984, 1227. (b) Baldwin, J. E.; Jones, R. H.;
Najera, C.; Yus, M. Tetrahedron 1985, 41, 699.
1H NMR yield (%)
entry IOAc (equiv) t (°C)
1a
1b
s.m. (%)
(5) For a pioneering catalytic ortho-halogenation of azobenzene, see:
(a) Fahey, D. R. J. Organomet. Chem. 1971, 27, 283. (b) Andrienko, O. S.;
Goncharov, V. S.; Raida, V. S. Russ. J. Org. Chem. 1996, 32, 89.
(6) For the use of NIS and NCS as the halogenation sources in a single
example of ortho-iodination of o-toluic acid, see: Kodama, H.; Katsuhira,
T.; Nishida, T.; Hino, T.; Tsubata, K. Patent WO 2001083421 A1, 2001;
Chem. Abstr. 2001, 135, 344284. Unfortunately, these conditions are not
effective for other aromatic substrates including simple benzoic acid.
(7) For the observation of halogenation of 2-phenylpyridine with NBS
and NCS, see: Dick, A. L.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300.
1
3
100
80
60
40
60
60
60
60
19
14
17
13
26
51
74
58
0
3
17
34
34
20
0
2
3
3
4
3
4
3
4
5b
6b
7b
8b
3
41
36
12
6
2
0
1.5
1.0
12
35
a IOAc was generated in situ from PhI(OAc)2 and I2. b The reaction
was carried out in the dark.
(8) For Pd-catalyzed asymmetric halogenation of sp3 C-H bonds, see:
Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(9) For Pd-catalyzed halogenation of acetanilides and 2-phenylpyridines,
see: (a) Wan, X. B.; Ma, Z. X.; Li, B. J.; Zhang, K. Y.; Cao, S. K.; Zhang,
S. W.; Shi, Z. J. J. Am. Chem. Soc. 2006, 128, 7416. (b) Kalyani, D.; Dick,
A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (c) Zhao, X.;
Dimitrijeviæ, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466. (d)
Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato,
M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131, 11310.
(10) For Pd-catalyzed halogenation of benzoic acids and phenethylamines
see: (a) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 5215. (b) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 6452.
found that substantial decarboxylation of the substrate was
taking place, giving a mixture of benzaldehydes, toluenes,
(14) (a) Kao, L.-C.; Sen, A. J. Chem. Soc., Chem. Commun. 1991, 1242.
(b) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123,
8149. (c) Lee, J. M.; Chang, S. Tetrahedron Lett. 2006, 47, 1375
.
(15) (a) Giri, R.; Maugel, N. L.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Giri, R.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082
.
(11) For Pd-catalyzed fluorination of the C-H bond, see: (a) Hull, K. L.;
Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (b) Wang,
X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520.
(12) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091.
(13) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, B. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31,
852.
(16) (a) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 17676. (b) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 6097. (c) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
14654. (d) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010,
327, 315.
(17) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 5916.
Org. Lett., Vol. 12, No. 14, 2010
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Table 2. Screening of Pd Catalysts and Oxidants
entry
Pd
oxidant
yield (%)
entry
Pd
PdI2
Pd(OAc)2
Pd(OTFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
oxidant
yield (%)
1
2
3
4
5
6
7
8
Pd(CH3CN)2(OTs)2
Pd(OTf)2 ·2H2O
[Pd(CH3CN)4](OTf)2
Pd2(dba)3
IOAc
IOAc
IOAc
IOAc
IOAc
IOAc
IOAc
IOAc
86
84
86
30
20
30
75
88
9
10
11
12
13a
14
15
16
IOAc
IOAc
IOAc
NIS
90
92
85
75
55
10
20
50
Pd(PPh3)4
NIS
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
PdCl2
ICl
NBS
NCS
a The reaction was carried out in the presence of light.
as well as other unknown compounds, presumably through
the formation of PhCH2COOI. Although decarboxylation of
this type has previously been reported with alkyl carboxylic
acids under irradiation with 100 W tungsten-filament lamps,18
phenylacetic acid appears to be particularly prone to such a
reaction because of the stability of the resulting benzylic
radical. We were delighted to find that this decomposition
pathway could be suppressed by performing the iodination
in the dark. Under these new conditions, the efficiency of
this catalytic system was also significantly improved; hence,
the iodination reaction proceeded to give the product in 74%
yield (entry 7). It is worth noting that 1a and other
R-hydrogen-containing substrates are substantially less reac-
tive in C-H activation, in accordance with the Thorpe-Ingold
effect.19
useful yields (2i and 2k-2o). The different reactivity profiles
between iodides and other halides offer convenient handles
Scheme 3. Pd-Catalyzed C-H Iodination of Phenylacetic
Acidsa
Next, various Pd(II) catalysts were screened (Table 2). In
general, most Pd(II) sources were found to be effective, and
commonly used ligands that stabilize Pd(0) (dba, PPh3) were
found to inhibit the reaction (entries 4-6). As anticipated,
the anions of the Pd(II) precatalyst did not have a significant
influence on the reaction because IOAc (generated instantly
from PhI(OAc)2/I2) converts PdX2 to Pd(OAc)2 in a highly
efficient manner (eq 1).20 Other commonly used electrophilic
halogenating reagents were not as effective (entries
12-16).10 The use of PhI(OAc)2 or I2 alone results in
recovery of starting material.
PdI2 IOAc8 Pd(OAc)2 + I2
(1)
To establish the scope of this newly developed iodination
protocol, we subjected a wide range of commonly used
phenylacetic acids to the standard conditions (Scheme 3).
Simple arenes were iodinated smoothly with excellent
monoselectivity (2a, 2c, 2d, and 2h). With meta-substituted
arenes, the less-hindered ortho position was iodinated
exclusively (2b, 2j, 2m, and 2o). This reaction was also
found to tolerate an acetate group on the arene (2j). Arenes
containing halides could also be iodinated in synthetically
a General reaction conditions: 5 mol % of Pd(OAc)2, 0.75 equiv of
PhI(OAc)2, 0.75 equiv of I2, DMF, 60 °C, 12 h, no light. 2c, 2h, 2j-2k,
2m, 2o, and 2q were isolated as methyl esters following treatment of the
crude reaction mixture with CH2N2. b 2 mol % of Pd(OAc)2. c 10 mol % of
Pd(OAc)2, 24 h. d 2.0 equiv of PhI(OAc)2, 2.0 equiv of I2, 36 h. e 15 mol
% of Pd(OAc)2, 2.0 equiv of PhI(OAc)2, 2.0 equiv of I2, 36 h.
(18) Concepcio´n, J. I.; Francisco, C. G.; Freire, R.; Herna´ndez, R.;
Salazar, J. A.; Sua´rez, E. J. Org. Chem. 1986, 51, 402.
(19) Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.
3142
Org. Lett., Vol. 12, No. 14, 2010

for subsequent differential functionalization. Strongly electron-
withdrawing groups such as trifluoromethyl and acetyl groups
were found to reduce the yield to 75% and 65%, respectively,
even in the presence of 15 mol % of Pd(OAc)2 (2p and 2q).
It should be noted that the MeO-substituted aryl ring reacts
with IOAc nonselectively in the absence of Pd catalyst. The
efficiency of this catalytic iodination transformation was also
demonstrated by running the reaction on gram-scale using 2
mol % of Pd(OAc)2 (2b).
Position-selective iodination of existing bioactive drug
scaffolds is a potentially powerful tool for expedient drug
diversification. Thus, we found that a series of nonsteroidal
anti-inflammatory drugs (NSAIDs),21 including ibuprofen,
flurbiprofen, ketoprofen, fenoprofen, and indoprofen, could
be smoothly converted into the corresponding ortho-iodinated
products in good yields and with excellent positional
selectivity (Scheme 4). It is worth noting that electrophilic
Table 3. Catalyst Recycling Experiment with Substrate 1ba
run
1
2
3
4
5
yield (%)
92
90
88
85
80
a Reaction conditions: Pd(OAc)2 (2 mol %), PhI(OAc)2 (0.75 equiv), I2
(0.75 equiv), DMF, 60 °C, 12 h.
the iodinated products 2a and 2b through a modified Ullmann
coupling furnishes the commercial drugs diclofenac and
lumiracoxib in a single step, which compares favorably with
multistep procedures (Scheme 5).25
Scheme 5. Synthetic Applications and Drug Syntheses
Scheme 4.
Site-Selective Functionalization of Drug Scaffoldsa
In summary, we have developed a highly versatile C-H
iodination reaction of phenylacetic acids. ortho-Iodinated
3-phenylpropionic acids could also be accessed through
subsequent homologation. Facile drug functionalization and
concise drug syntheses showcase the synthetic utility of this
iodination reaction.
Acknowledgment. We gratefully acknowledge The Scripps
Research Institute and the U.S. National Science Foundation
(NSF CHE-1011898) for financial support, the Camille and
Henry Dreyfus Foundation for a New Faculty Award, and
A. P. Sloan Foundation for a Fellowship (J.-Q. Y.). We thank
China Scholarship Council for Oustanding Self-Financed
Students Abroad Award (T.-S. Mei & D.-H. Wang).
a General reaction conditions: 10 mol % of Pd(OAc)2, 0.75 equiv of
PhI(OAc)2, 0.75 equiv of I2, DMF, 60 °C, 24 h, no light. 2r and 2t-2v
were isolated as methyl esters following treatment of the crude reaction
mixture with CH2N2. b 15 mol % of Pd(OAc)2, 2.0 equiv of PhI(OAc)2, 2.0
equiv of I2, 36 h. c The temperature was 40 °C.
Supporting Information Available: Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
iodination of relatively electron-rich 2u did not occur in the
absence of Pd catalyst. Interestingly, the amide group in 2v
is not effective in directing the iodination as shown by the
lack of reactivity with the corresponding ester substrate.
Furthermore, we found that PdI2 could conveniently be
reused as a precatalyst at least five times without substantial
erosion of the product yield. After completion of the reaction,
the PdI2 precipitate could be recycled from the solution by
centrifugation.8 With substrate 1b, five reaction cycles
starting with only 44.8 mg (0.2 mmol) of Pd(OAc)2 produced
12.01 g (43.5 mmol) of the iodinated product (Table 3).
Finally, the broad synthetic utility of these ortho-iodinated
products was demonstrated by carrying out subsequent
amination, cyanation,22 acetylenation,23 and homologation
following established procedures.24 Notably, amination of
OL1010483
(20) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett. 1994,
35, 1003.
(21) Acemoglu, M.; Allmendinger, T.; Calienni, J.; Cercus, J.; Loiseleur,
O.; Sedelmeier, G. H.; Xu, D. Tetrahedron 2004, 60, 11571.
(22) (a) Wang, D.; Kuang, L.; Li, Z.; Ding, K. Synlett 2008, 69. (b)
Ma, D. W.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(23) Wessig, P.; Glombitza, C.; Mu¨ller, G.; Teubner, J. J. Org. Chem.
2004, 69, 7582.
(24) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403.
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