Pd(II)-catalyzed C-H iodination using molecular I2 as the sole oxidant

Article abstract of DOI:10.1021/ja4055492

Pd-catalyzed ortho-C-H iodination directed by a weakly coordinating amide auxiliary using I₂ as the sole oxidant was developed. This reaction is compatible with a wide range of heterocycles including pyridines, imidazoles, oxazoles, thiazoles, isoxazoles, and pyrazoles.

Full text of DOI:10.1021/ja4055492

Communication
pubs.acs.org/JACS
Pd(II)-Catalyzed C−H Iodination Using Molecular I2 as the Sole
Oxidant
Xiao-Chen Wang,† Yi Hu,† Samuel Bonacorsi,‡ Yang Hong,‡ Richard Burrell,§ and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
‡Radiochemical Synthesis Group, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543, United States
§Radiochemical Synthesis Group, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States
S
* Supporting Information
Scheme 1. A Practical C−H Iodination Reaction
ABSTRACT: Pd-catalyzed ortho-C−H iodination direc-
ted by a weakly coordinating amide auxiliary using I2 as the
sole oxidant was developed. This reaction is compatible
with a wide range of heterocycles including pyridines,
imidazoles, oxazoles, thiazoles, isoxazoles, and pyrazoles.
auxiliary.8 Therein we observed two turnovers in iodination with
ryl halides (Ar-X, X = Cl, Br, and I) are extensively used in
A
Grignard1 and cross-coupling2 reactions. Directed lithiation
I2 which can be explained by the extensively studied Pd(II)/
Pd(IV) or Pt(II)/Pt(IV) redox chemistry with IX reagents
followed by reaction with a halogen-containing electrophile has
been a major method for the regioselective preparation of aryl
halides.3 In the past decade, Pd(II)-catalyzed C−H halogenation
utilizing electrophilic halogenating reagents has been extensively
studied,4−10 and these collective efforts have significantly
improved the synthetic utility of this potentially powerful
transformation. Notably, the diastereoselective iodination of
both prochiral sp3 and sp2 C−H bonds was demonstrated.8
Protocols to iodinate broadly useful substrates such as carboxylic
acids and protected amines have also been developed.10
including I2 (Figure 1).14 As expected from the redox chemistry
Unfortunately, the use of the Suar
́
ez reagent IOAc11 generated
Figure 1. Redox chemistry of C−H iodination with IX.
by reacting I2 with AgOAc or PhI(OAc)2 is not practical.
Furthermore, noncatalyzed electrophilic iodination of electron-
rich arenes can occur with this highly reactive iodinating reagent,
leading to a scrambling of regioselectivity.12 Recently, Kakiuchi9d
has demonstrated the C−H chlorination of 2-phenylpyridine
using a chloronium species generated in situ via electro-oxidation
of HCl. Alternatively, the use of a combination of metal
chlorides,9b,e NCS10d or NIS,9f and strong co-oxidants to achieve
halogenation is also an improvement in terms of catalysis. A rare
example of Rh(III)-catalyzed iodination of benzamides using
NIS reported by Glorius is also an important advance.13 We
envision that development of a simple catalytic system, using
cheaper and milder molecular I2 as the sole oxidant, will greatly
improve the practicality of Pd-catalyzed C−H iodination
reactions.
Herein we report an efficient and operationally simple Pd-
catalyzed C−H iodination reaction that uses I2 as the sole oxidant
(Scheme 1). For the first time, directed C−H iodination was
successfully applied to a wide range of heterocycles, which
typically inhibit directed C−H activation. The success of this
development hinges upon the combination of an amide auxiliary
for promoting C−H activation and CsOAc as iodide scavenger to
close the catalytic cycle.
shown in Figure 1, unreactive crystalline PdI2 was formed
following two turnovers of iodination when I2 is used.8 We have
previously used IOAc to regenerate Pd(OAc)2 and close the
catalytic cycle.8,10
A single example of Pd-catalyzed iodination of azobenzene
using I2 as the halogen source and CuCl2 as a co-oxidant
indicated the possibility of using molecular I2 as the halogenation
reagent for C−H iodination.5b We envision that an efficient
anionic ligand exchange of PdI(OAc) or PdI2 with other added
metal salts MXn could provide a practical solution to regenerate
PdXn as reactive catalysts. To ensure that the C−H activation
step can proceed under various conditions and with additives that
may be beneficial for the anionic ligand exchange, we attached
one of the most efficient auxiliaries to phenylacetic acid to give
amide 1a (Table 1) as the substrate,15 and began to test
conditions for catalytic C−H iodination with I2.
Considering the poor solubility of PdI2 in organic solvents, we
anticipated that the use of a coordinative solvent could help
solubilize PdI2 and facilitate subsequent anionic exchange. After a
short screening of inorganic salts (see the Supporting
We commenced our study by revisiting our earlier
diastereoselective C−H iodination chemistry using a chiral
Received: June 3, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4055492 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a,b,c,d,e
Table 1. Screening of Iodination Conditions
Table 2. Ortho-iodination of Phenylacetic Amides
b
c
d
e
entry
Pd (II)
base
solvent
DMF
yield (%)
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
none
15
62
<5
CsOAc
CsOAc
CsOAc
DMF
t-AmylOH
DMF/t-AmylOH 80
DMF/t-AmylOH 99
DMF/t-AmylOH 35
f
CsOAc/NaHCO3
f
NaHCO3
g
f
f
f
f
h
7
CsOAc/NaHCO3
CsOAc/NaHCO3
CsOAc/NaHCO3
CsOAc/NaHCO3
none
DMF/t-AmylOH 98 (95% )
DMF/t-AmylOH
8
0
9
PdCl2
DMF/t-AmylOH 83
DMF/t-AmylOH 75
DMF/t-AmylOH <5
10
11
PdI2
PdI2
a
The reactions were run on 0.10 mmol scale in a 25 mL-sealed tube
b
under air. 5 mol % of the Pd(II) catalyst was used unless otherwise
c
d
stated. 1.2 eq of CsOAc was used. Solvent volume = 2.0 mL; DMF/
e
t-AmylOH = 1:1. % yield was determined by the 1H NMR
f
spectroscopy using CH2Br2 as the internal standard. 1.0 eq of
NaHCO3 was added. The reaction was run on 0.30 mmol scale with 2
mol % Pd(OAc)2 in 5.0 mL of solvent. Yield of the isolated product.
g
h
Information), we found that addition of cesium acetate (CsOAc)
effectively improved catalytic turnovers (Table 1, entries 1, 2).
Treatment of 1a with 2.5 equiv of I2 at 65 °C in the presence of 5
mol % of Pd(OAc)2 and 1.2 equiv of CsOAc in DMF produced
the ortho-iodinated product 2a in 62% yield after 20 h (entry 2).
Four Å molecular sieves were added to prevent the hydrolysis of
the amide. While t-amyl alcohol alone is a poor solvent for this
reaction (entry 3), a mixture of DMF and t-amyl alcohol in a 1:1
ratio was found to improve the yield to 80% (entry 4). The use of
NaHCO3 as a coadditive improved yield to 99% (entry 5). The
enhanced reactivity can be attributed to the N−H deprotonation
of the amide to form the imidate structure by using NaHCO3 as a
coadditive as established previously.15g We were pleased to find
that these conditions allowed us to reduce the Pd loading to 2
mol % while maintaining the yield as high as 98% (entry 7). Both
PdCl2 and PdI2 are effective catalysts in the presence of CsOAc,
albeit less effective than Pd(OAc)2 (entries 9, 10). The loss of
reactivity of PdI2 in the absence of CsOAc suggests that the
formation of Pd(OAc)2 or PdI(OAc) via anionic ligand exchange
is essential for catalysis (entry 11). Notably, treatment of 1a with
NIS under these conditions led to full recovery of the starting
material.
With our newly developed iodination method in hand, the
substrate scope of this reaction was investigated. As shown in
Table 2, both electron-donating methyl and methoxy groups
(2a−d) and electron-withdrawing chloro, fluoro, and trifluor-
omethyl groups (2e−h) were well tolerated as demonstrated by
the excellent yields of the iodinated products. Naphthalene was
iodinated at the β-position selectively (2i). Typically only 2 mol
% Pd(OAc)2 was used except for substrates bearing strong
electron-withdrawing groups which required 5 mol % Pd for
obtaining high yields (2g and 2h). When the ortho-positions of
substrates were unsubstituted, di-iodinated products were
formed exclusively (product 2j−n). With substrates bearing
meta-substituents, the hindered ortho-position can still be
iodinated to give the di-iodinated products (2o, 2p) in very
high yields. To secure high conversions of these di-iodinations, 5
mol % of Pd(OAc)2 was used. Interestingly, the α-methyl group
a
b
Ar = (4-CF3)C6F4. Reaction conditions for monoiodination: 0.30
mmol of phenylacetic amide, 2 mol % Pd(OAc)2, 0.75 mmol I2, 0.36
mmol CsOAc, 0.30 mmol NaHCO3, 150 mg of 4 Å molecular sieves,
and 5.0 mL of t-AmylOH/DMF (1:1) in a sealed tube, 65 °C, 20 h.
c
d
For products 2g, 2h, and 2r, 5 mol % Pd(OAc)2 was used. Reaction
conditions for di-iodination: 0.10 mmol of phenylacetic amide, 5 mol
% Pd(OAc)2, 0.50 mmol I2, 0.24 mmol CsOAc, 0.20 mmol NaHCO3,
50 mg 4 Å molecular sieves, and 2.0 mL of t-AmylOH/DMF (1:1) in a
sealed tube, 65 °C, 20 h. Yields of the isolated product. Ratio was
determined by the H NMR spectroscopy.
e
f
1
in the arene substrates derived from ibuprofen and naproxen
hampered the di-iodination (2q, 2r), presumably due to the
steric buttress. The iodination of the latter substrate afforded the
monoiodinated product exclusively in 89% yield. This result
suggests that monoselective iodination of α-substituted phenyl-
acetic amides is possible.
To further demonstrate the advantage of this method, we
carried out gram-scale reactions using o-MeO, CH3, and CF3-
substituted phenylacetic amide substrates in the presence of only
0.5 mol % of Pd(OAc)2 (Scheme 2). The o-Me-substituted
amide was iodinated to give the desired product in 75% yield
(150 turnovers) while the iodination of o-CF3-substituted
substrate afforded a lower yield.
Next, we subjected benzamide 3a to the optimized iodination
conditions (Table 3). Unfortunately, severe decomposition
occurred to give an unidentified mixture. In the absence of
NaHCO3, reaction proceeded to give small amount of the
iodination product 4a (15%) and the dimer 4a′ as the main
Scheme 2. Gram-Scale Iodination with 0.5 mol % Pd(OAc)2
B
dx.doi.org/10.1021/ja4055492 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
,b
,c
,d,
e
a,b,c
Table 3. Ortho-iodination of Benzamides
Table 4. Ortho-iodination of Heterocyclic Compounds
a
Reaction conditions: 0.30 mmol of benzamide, 2 mol % Pd(OAc)2,
0.75 mmol I2, 0.36 mmol CsOAc, 0.06 mmol K2S2O8, 150 mg of 4 Å
molecular sieves, and 4.0 mL DMSO in a sealed tube, 65 °C, 16 h.
a
b
Ar = (4-CF3)C6F4. Reaction conditions: 0.10 mmol substrate, 10
b
For 4a, 5 mol % Pd(OAc)2 was used, the loadings of I2 and CsOAc
mol % Pd(OAc)2, 0.40 mmol I2, 0.24 mmol CsOAc, 0.10 mmol
NaHCO3, 50 mg of 4 Å molecular sieves, and 2.0 mL of solvent in a
sealed tube, 16−48 h. Yields of the isolated product. 0.2 eq K2S2O8
was used in place of NaHCO3.
c
were doubled, and the reaction time was shortened to 5 h. For 4e, 5
d
c
d
mol % Pd(OAc)2 was used. For 4f, 10 mol % Pd(OAc)2 was used and
e
the reaction solvent was changed to DMF. Yields of the isolated
f
product. Trace dimer was formed.
rich pyrazoles can occur at C-4 positions,21 the presence of other
electron-rich arenes within a complex molecule could scramble
the site selectivity under such conditions. We were pleased to
find that pyridine-containing isonicotinic amide and methyl-
nicotinic amide were also suitable substrates for this iodination
reaction (5k, 5l). Although a single example of Pd(0)/PR3-
catalyzed arylation of these pyridine substrates has been
reported,19a this iodination represents the first example of
Pd(II)-catalyzed C−H activation reactions for a broad range of
heterocycles using a directing group. The observed reactivity of
these strongly coordinative heterocycles, especially the thiazole
and pyridine substrates, can be attributed to the following two
factors. First, a strong trans-effect and sterics between the pyridyl
groups in complex I (Scheme 3) can promote formation of a
product (58%). The dimer is likely formed via the C−H arylation
of the monoiodinated product with 4a which could be catalyzed
by the traces of Pd(0) species present in the reaction. Switching
the solvent to DMSO and use of K2S2O8 (0.2 equiv) as an
additive to remove Pd(0) from the system increased the yield of
4a (41%), with only a slight decrease of the formation of 4a′
(48% yield). Nonetheless, monoiodination of ortho-substituted
benzamide substrates under these conditions proceeded to give
the desired products in excellent yields without forming the
dimers (4b−e). To probe the potential of developing a late-stage
iodination method we subjected the complex drug candidate 3f16
to our iodination procedure and obtained the desired iodinated
product 4f in 75% yield. Aryl iodide 4f can potentially react with a
wide range of coupling partners using metal catalysts to provide a
series of analogues for drug discovery. In particular, iodoarenes
are superior substrates over bromo or chloro analogues for the
preparation of tritium labeled compounds in high yield and
radiospecific activity which are of great importance to late-stage
tritio-dehalogenation of drug molecules to facilitate in vivo study
of metabolic processes.17
Scheme 3. Assembly of the Reactive Precursor
Considering the lack of success of directed C−H activation
reactions of heterocycles18,19 and the prevalence of heteroarenes
in drug molecules,20 we were eager to test whether this iodination
protocol is compatible with heterocyclic substrates. Remarkably,
directed ortho-iodination readily occurred with a wide range of
heterocycles under the standard conditions (Table 4). Minor
adjustment of the reaction solvent and the temperature were
needed for obtaining the optimum yields with each substrate. In
general, either N-methylformamide (NMF) or DMSO is the
most effective solvent. Unlike the iodination of benzamides
(Table 3), dimerization did not occur with most of the
heterocyclic substrates. However, additive K2S2O8 (0.2 equiv)
was needed to minimize dimerization with pyrazole 5e and
pyridines 5k and 5l.
small amount complex II,22 in which the moderately
coordinating amide is bound to the Pd center. Second, this
amide directing group is highly effective in promoting C−H
activation: the coordinated amide contains a strongly electron-
withdrawing aryl group [Ar = (4-CF3)C6F4], rendering the
Pd(II) center sufficiently electrophilic for C−H bond cleavage
and the imidate structure enables the assembly of an
approximately coplanar pretransition state with minimum
entropic cost.
In summary, we have developed the first Pd-catalyzed C−H
iodination reaction using molecular iodine as the sole oxidant.
The Pd catalyst loading can be reduced to 0.5 mol % in gram scale
reaction. This reaction also demonstrates broad substrate scope
with respect to a wide range of heterocycles that were previously
incompatible with directed C−H activation. Our collaborators in
Bristol-Myers Squibb Co. are currently applying this reaction for
Notably, various regioisomers of iodinated pyrazoles (5b−e),
oxazoles (5g, 5h) and thiazoles (5i, 5j) can be prepared using
these heterocycles containing the amide directing group at
different positions. Although electrophilic iodination of electron-
C
dx.doi.org/10.1021/ja4055492 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Angew. Chem., Int. Ed. 2010, 49, 8729. (g) Bedford, R. B.; Haddow, M.
F.; Mitchell, C. J.; Webster, R. L. Angew. Chem., Int. Ed. 2011, 50, 5524.
(10) For Pd-catalyzed halogenation of carboxylic acid and amine
derivatives, 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.
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Lett. 2010, 12, 3140. (d) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew.
Chem., Int. Ed. 2013, 52, 4440.
late-stage tritio-deiodination of drug molecules to facilitate in vivo
study of metabolic processes.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
́ ́
(11) Concepcion, J. I.; Francisco, C. G.; Hernandez, R.; Salazar, J. A.;
Suarez, E. Tetrahedron Lett. 1984, 25, 1953.
́
(12) With the conditions previously reported in refs 10a and 10c,
iodination of 2-MeO-substituted benzoic and 2-MeO-substituted
phenylacetic acids with IOAc produced the electrophilic iodination
products as the sole reaction products (5-I-2-MeO-substituted benzoic
acid in 43% yield and 5-I-2-MeO-substituted phenylacetic acid in 83%
yield respectively).
AUTHOR INFORMATION
■
Corresponding Author
yu200@scripps.edu
Notes
The authors declare no competing financial interest.
(13) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
̈
2012, 134, 8298.
ACKNOWLEDGMENTS
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Soc. Chem. Commun. 1986, 1722. (b) Catellani, M.; Chiusoli, G. P. J.
Organomet. Chem. 1988, 346, C27. (c) Canty, A. J.; Denney, M. C.;
Skelton, B. W.; White, A. H. Organometallics 2004, 23, 1122. (d) Yahav,
A.; Goldberg, I.; Vigalok, A. Organometallics 2005, 24, 5654. (e) Yahav-
Levi, A.; Goldberg, I.; Vigalok, A.; Vedernikov, A. N. J. Am. Chem. Soc.
2008, 130, 724.
(15) (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
9886. (b) Wasa, M.; Yu, J.-Q. Tetrahedron 2010, 66, 4811. (c) Wasa, M.;
Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (d) Yoo, E. J.;
Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (e) Wasa, M.;
Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
19598. (f) Chan, K. S. L; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem.,
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(16) Practical synthesis of 6-carboalkoxy-13-cycloalkyl-5H-indolo[2,1-
a] [2] benzazepine-10-carboxylic acid derivatives. Hewawasam, P.; Tu,
Y.; Hudyma, T.; Gentles, R.; Meanwell, N.; Kadow, J.; 240th ACS
National Meeting & Exposition, August 22−26, 2010, Boston, MA.
Abstract ORGN-971.
(17) (a) Voges, R.; Heys, J. R.; Moenius, T. Preparation of Compounds
Labeled with Tritium and Carbon-14; John Wiley & Sons, Inc.: New
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■
We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS 1 R01 GM102265-01)
and Bristol-Myers Squibb Co. for financial support. We wish to
thank Professor James Hendrickson at Brandeis for an
inspirational gift of a bottle of iodine in the spring of 2004,
Phil S. Baran at Scripps for providing TOF LC−MS facilities, and
John Kadow and Martin Eastgate at BMS for helpful discussions.
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