Palladium-catalyzed asymmetric iodination of unactivated C-H bonds under mild conditions

Article abstract of DOI:10.1002/anie.200462884

(Chemical Equation Presented) Specific, asymmetric, and mild: Oxazoline (Oxa), a removable chelating chiral auxiliary, assists in the asymmetric activation of C(sp³)-H bonds at the β position and C(sp ²)-H bonds at the γ position. Pd-(OAc)₂ is an effective catalyst for the selective and asymmetric iodination of methyl, cyclopropyl, and aryl groups at room temperature (see formulae).

Full text of DOI:10.1002/anie.200462884

Communications
Asymmetric Catalysis
Palladium-Catalyzed Asymmetric Iodination of
À
Unactivated C H Bonds under Mild Conditions**
Ramesh Giri, Xiao Chen, and Jin-Quan Yu*
Dedicated to Professor E. J. Corey
3
2
À
À
The catalytic activation of C(sp ) H and C(sp ) H bonds in
readily available, inexpensive starting materials would pro-
vide a valuable array of new transformations for organic
chemistry research and the fine chemical industry.[1] Activa-
tion of C(sp ) H bonds in benzene and ortho-substituted
arenes has been successfully exploited in the development of
2
À
À
catalytic C C bond-forming reactions by coupling to ole-
3
fins.[2,3] The selective activation of C(sp ) H bonds under mild
À
conditions could be an attractive strategy for the development
of catalytic reactions with wide applicability. Despite exten-
sive efforts that have focused mainly on carbene and nitrene
insertions, metathesis, Shilov chemistry, and biomimetic
approaches, the catalytic and asymmetric functionalization
of C(sp ) H bonds remains a significant challenge.
We report herein an auxiliary approach for the chemo-
selective and asymmetric room-temperature iodination of
3
[4]
À
[*] R. Giri, Dr. X. Chen, Prof. Dr. J.-Q. Yu
Department of Chemistry, Brandeis University
Waltham, MA 02454-9110 (USA)
Fax: (+1)781-736-2516
E-mail: yu200@brandeis.edu
[**] We thank Brandeis University for financial support, and the Camille
and Henry Dreyfus Foundation for a New Faculty Award.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2112
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462884
Angew. Chem. Int. Ed. 2005, 44, 2112 –2115

Angewandte
Chemie
Table 1: Monoiodination of methyl groups catalyzed by Pd(OAc)2.[a]
methyl groups located at the a position of saturated aliphatic
acids.[5] This protocol also applies to the activation of cyclo-
À
À
propanes (C H bond b to the carboxy group) and arenes (C
H bond g to the carboxy group). Our strategy involves the
installation of a s-chelating auxiliary, such as oxazoline,[6] to
facilitate the assembly of the pre-transition state for cyclo-
metallation through a square-planar complex as illustrated by
compound 1 (Scheme 1). One of the earliest observed
Entry
Substrate
Yield [%]
1
2
3
4
5
6
5a
6a
7a
8a
9a
10a
R1 =R2 =Me
92
R1 =Me; R2 =Et
R1 =R2 =Et
n=1
91[d]
88[e]
90[e]
97[e]
81
n=2
n=3
7
11a
67[f]
8
9
12a
13a
98
32
[a] Reaction conditions: Pd(OAc)2 (10 mol%), I2 (1 equiv), PhI(OAc)2
(1 equiv), CH2Cl2, 248C, 48–72 h. [b] Entries 1–3. [c] Entries 4–6.
[d] 63:37 d.r. (NMR spectroscopy). [e] PdI2 precipitated at 36–48 h,
PhI(OAc)2 (1 equiv) was added, and stirring continued for another 48 h.
[f] PhI(OAc)2 (2 equiv), 508C, 48 h.
A single isomer of the trinuclear palladium alkyl species
2a (Scheme 1) was obtained in 60% yield (determined by Pd
recovery) by simply stirring substrate 5a with Pd(OAc)2
(1 equiv) in CH2Cl2 at 248C for 36 h (Supporting Informa-
tion).[11] The syn geometry of 2a was tentatively assigned by a
steric argument: the bulky tert-butyl group must avoid the
concave face. This complex was instantly converted into the
iodinated product 5b when I2 was added.
À
Scheme 1. Proposed catalytic cycle of C H-bond activation.
Following these experimental observations, we proposed a
À
stoichiometric C H bond-activation pathway that involves
steps a) and b) shown in Scheme 1. From the known structure
of the cyclic trimer Pd3(OAc)6 crystallized from CH2Cl2[12] and
the isolated complex 2a, we assumed the trinuclear bis-m-
acetatopalladium complex 1 is formed as the reactive
À
examples of C H bond activation was cyclometallation
promoted by agostic interactions or sigma chelation.[7] The
À
activation of ortho aryl C H bonds to give cyclopalladation
À
by the pre-coordination of a nitrogen atom has been reviewed
extensively.[8] Inspired by the remarkable discovery of, and
recent progress in the Shilov oxidation cycle,[9] we searched
for an oxidation system that would render the cyclopallada-
tion reaction catalytic in a similar manner. Notably, Sanford
and co-workers recently reported an efficient PdII-catalyzed
acetoxylation reaction with O-methyl oxime as a directing
group at the time our work was in progress.[10]
precursor. First, electrophilic cleavage of the C H bond
occurs to give the trinuclear square-planar PdII complex 2.
Next, I2 reacts with complex 2, presumably by oxidative
addition[13] and reductive elimination, to form the iodinated
product 3 and PdI2 (isolated as a powder in quantitative yield
and characterized by X-ray powder diffraction).[14] The
kinetic isotope effect (KIE) of the iodination reaction of
substrate 9a into 9b, in which the methyl group was
À
Trimethylacetic acid was selected for an initial test, owing
to its structural simplicity. Oxazoline 5a and other substrates
were readily prepared from their corresponding carboxylic
acids and (S)-tert-leucinol (Table 1). We found that Pd(OAc)2/
I2 was an effective stoichiometric reagent for the iodination of
a methyl group in 5a. Stirring 5a with Pd(OAc)2 and I2
(1 equivalent each) in CH2Cl2 at 248C for 24 h gave exclusive
iodination of the methyl group to provide the monoiodide in
80% yield. Reactions of other oxazolines that were prepared
from trimethylacetic acid and ethanolamine, 2-methyl-2-
aminopropanol, or valinol were either very slow or did not
proceed under the same conditions.
deuterated (kH/kD = 4.7), is also consistent with C H bond
cleavage as the rate-limiting step.[15]
PdI2 was unreactive with substrate 5a. Therefore, IOAc
generated[16] in situ from AgOAc and I2 was used to convert
PdI2 into Pd(OAc)2 to close the catalytic cycle, as shown in
step c) (Scheme 1). PhI(OAc)2 was more effective for this
catalytic reaction.[17] Control experiments showed that PhI-
(OAc)2 alone does not react directly with PdI2. However, PdI2
was converted into Pd(OAc)2 by stirring with PhI(OAc)2 and
I2 (1 equiv each) in CH2Cl2 at 248C for 1 h (Supporting
Information). Thus, substrate 5a was stirred with I2, PhI-
(OAc)2 (1 equiv each), and Pd(OAc)2 (10 mol%) in CH2Cl2 at
Angew. Chem. Int. Ed. 2005, 44, 2112 –2115
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2113

Communications
À
248C for 64 h to afford the iodination product in 92% yield
(Table 1).
The highly selective activation of primary over secondary
The scope of this C H bond-activation reaction was
further examined with the arene-containing substrate 17a.
À
Interestingly, the arene C H bond was iodinated with high
À
C H bonds was conclusively demonstrated with substrates 6a
selectivity in the presence of a methyl group. The monoiodi-
nated product 17b was isolated in 98% yield (> 99:1 d.r.;
NMR spectroscopy, GC–MS, Table 2).[19] We reasoned that if
the reaction proceeds by cyclometallation of the trinuclear
complex 1, the hydrogen atom cleaved from the methyl group
is the one that affords 2 with the larger group on the convex
face (R2) (Scheme 1). This model explains the high diaster-
eoselectivity attained, even though the stereogenic center in
the oxazoline ring is far removed from the reaction site.
Unfortunately, confirmation of this model through the assign-
ment of the absolute configuration of the products has proven
difficult, and is still in progress.
and 7a. The oxazoline prepared from triethylacetic acid does
not react under the same conditions. These observations are
consistent with the unfavorable steric interactions between
coordinated ligands and branched alkyl groups in a cyclo-
metalation step. Cyclic substrates (8a–10a) were also exam-
À
ined, and the methyl C H bonds were consistently selectively
iodinated in high yields. Substrate 11a, which bears a polar
ketal group, was also iodinated in 67% yield at 508C
(Table 1). The striking rate difference (ktrans/kcis = 5.7)
between isomeric substrates 12a and 13a is particularly
intriguing. A detailed understanding of this observation
À
requires further mechanistic exploration of the C H bond-
cleavage processes.
A clear advantage of this catalytic system is the ease with
which the palladium catalyst can be recycled (Table 3). As
The moderate diastereoselectivity (63:37 d.r.) observed
with substrate 6a prompted us to test asymmetric iodination
with various prochiral substrates. Iodination of substrate 14a
exhibited drastically improved diastereoselectivity relative to
the reaction of 6a. The two diastereomers were isolated as a
mixture (d.r. = 91:9) (Table 2). We were pleased to find that
the reaction conditions were also compatible with a TBS-
protected hydroxy group in substrate 15a.
Table 3: Catalyst recycling experiments with substrate 17a.[a]
Run
1
2
3
4
5
Yield [%]
98
97
93
88
84
[a] Reaction conditions: Pd(OAc)2 (10 mol%), I2 (1 equiv), PhI(OAc)2
(1 equiv), CH2Cl2, 248C, 13–20 h.
Table 2: Asymmetric iodination.[a]
PdI2 precipitates from solution toward the completion of the
reaction, it can be isolated by centrifugation. After decanting
the supernatant, PdI2 is recycled with a fresh supply of I2 and
PhI(OAc)2. With 17a, five reaction cycles starting with only
22.4 mg (0.1 mmol) of Pd(OAc)2 produced 1.99 g (4.6 mmol)
of the iodinated product 17b with high diastereoselectivity
(> 99:1 d.r.).
In summary, the combination of a hindered oxazoline
auxiliary, Pd(OAc)2, I2, and PhI(OAc)2 was shown to be a
powerful protocol for the catalytic and asymmetric iodination
Entry
Substrate
Product
Yield [%] d.r.
1
14a
15a
16a
14b
15b
16b
83[b]
62[c]
65[d]
91:9
2
3
93:7
99:1
4
17a
17b
98[e]
99:1
À
of inactivated C H bonds of methyl, cyclopropyl and aryl
groups under mild conditions.
[a] Reaction conditions: Pd(OAc)2 (10 mol%), I2 (1 equiv), PhI(OAc)2
(1 equiv), CH2Cl2. [b] 248C, 30 h. [c] 508C, 48 h. [d] 248C, 96 h. [e] 248C,
13 h. TBS=tert-butyldimethylsilyl.
Received: December 10, 2004
Published online: February 23, 2005
Keywords: asymmetric catalysis · C-H activation · chiral
auxiliaries · iodine · palladium
The well-documented amide-directed lithiation reactions
of cyclopropanes[18] prompted us to determine if this newly
developed catalytic system could functionalize the secondary
.
À
cyclopropyl C H bond in the presence of a methyl group.
[1] a) N. Chatani, T. Asaumi, S. Yorimitsu, Y. Ishii, F. Kakiuchi, S.
Murai, J. Am. Chem. Soc. 2000, 122, 12882; b) G. Dyker, Angew.
Chem. 1999, 111, 1808; Angew. Chem. Int. Ed. 1999, 38, 1699;
c) H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science 2000,
287, 1995; d) J. Y. Cho, M. K. Tse, D. Holmes, R. E. Male-
czka, Jr., M. R. Smith III, Science 2002, 295, 305; e) R. H.
Crabtree, J. Chem. Soc. Dalton Trans. 2001, 2437.
[2] a) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34,
633; b) F. Kakiuchi, M. Yamauchi, N. Chatani, S. Murai, Chem.
Lett. 1996, 2, 111; c) C. P. Lenges, M. Brookhart, J. Am. Chem.
Soc. 1999, 121, 6616; d) Y. G. Lim, Y. H. Kim, J. B. Kang, J.
Chem. Soc. Chem. Commun. 1994, 2267; e) R. K. Thalji, K. A.
Ahrendt, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2001,
123, 9692; f) C. H. Jun, C. W. Moon, J. B. Hong, S. G. Lim, K. Y.
Chung, Y. H. Kim, Chem. Eur. J. 2002, 8, 485.
Cyclopropane substrate 16a was subjected to the same
conditions as described. Indeed, the selectivity was com-
À
pletely reversed from primary to secondary C H bonds. Of
particular importance is the excellent stereochemical control
À
in the exclusive iodination of the cyclopropyl C H bond.
Reaction of 16a afforded iodinated product 16b as a single
isomer in 65% yield. The cis geometry of 16b was established
by NOE experiments. The enantiomer of 16b was also
obtained with oxazoline substrate prepared from (R)-tert-
leucinol. Both 16b and its enantiomer were hydrolyzed by
treatment with H2SO4/dioxane (1:1, 4m) at reflux for 8 h to
give the corresponding carboxylic acids with > 99% ee as
determined by HPLC analysis.
2114
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2112 –2115

Angewandte
Chemie
À
[3] For enantioselective aromatic C H coupling to olefins, see:
a) R. K. Thalji, J. A. Ellman, R. G. Bergman, J. Am. Chem. Soc.
2004, 126, 7192; b) K. Mikami, M. Hatano, M. Terada, Chem.
Lett. 1999, 1, 55.
[4] a) H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103,
2861; b) P. Muller, C. Fruit, Chem. Rev. 2003, 103, 2905; c) C. G.
Espino, J. D. Bois, Angew. Chem. 2001, 113, 618; Angew. Chem.
Int. Ed. 2001, 40, 598; d) A. E. Shilov, G. B. Shulꢀpin, Chem. Rev.
1997, 97, 2879; e) J. T. Groves, P. J. Viski, J. Am. Chem. Soc.
1989, 111, 8537; f) R. Breslow, A. B. Brown, R. D. McCullough,
P. W. White, J. Am. Chem. Soc. 1989, 111, 4517.
[5] For a recent example of a chiral auxiliary in the dehydrogenation
of an ethyl group involving stoichiometric amounts of PtMe2L2,
see: J. A. Johnson, N. Li, D. Sames, J. Am. Chem. Soc. 2002, 124,
6900.
[6] A. I. Meyers, Acc. Chem. Res. 1978, 11, 375.
[7] a) M. A. Bennett, D. L. Milner, J. Am. Chem. Soc. 1969, 91,
6983; b) J. A. Ibers, R. Dicosimo, G. M. Whitesides, Organo-
metallics 1982, 1, 13; c) for various examples of stoichiometric
cyclopalladation reactions, see: A. J. Canty in Comprehensive
Organometallic Chemistry II: A Review of the Literature 1982–
1994 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Perga-
mon, New York, 1995.
[8] a) A. D. Ryabov, Synthesis 1985, 233; b) K. Carr, J. K. Suther-
land, J. Chem. Soc. Chem. Commun. 1984, 1227; c) J. E. Baldwin,
R. H. Jones, C. Najera, M. Yus, Tetrahedron 1985, 41, 699.
[9] a) N. F. Golꢀdshleger, M. B. Tyabin, A. E. Shilov, A. A. Shtein-
man, Zh. Fiz. Khim. (Engl. Transl.) 1969, 43, 1222; b) S. S. Stahl,
J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc. 1996, 118, 5961;
c) U. Fekl, K. I. Goldberg, J. Am. Chem. Soc. 2002, 124, 6804;
d) R. A. Periana, D. J. Taube, S. Gamble, H. Taube, T. Satoh, H.
Fujii, Science 1998, 280, 560; e) B. D. Dangel, J. A. Johnson, D.
Sames, J. Am. Chem. Soc. 2001, 123, 8149.
[10] a) A. R. Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004,
126, 2300; b) L. V. Desai, K. L. Hull, M. S. Sanford, J. Am. Chem.
Soc. 2004, 126, 9542.
[11] The predominant formation of a dimeric complex by combining
Pd(OAc)2 and 2-tert-butyl-4,5-dihydro-4,4-dimethyloxazole in
HOAc at reflux was previously reported. Trinuclear Pd alkyl
species at a syn/anti ratio of 2:3 were also observed as minor
products, and determined by crystallographic analysis to be
stacked in a head-to-tail orientation: G. Balavoine, J. C. Clinet, J.
Organomet. Chem. 1990, 390, C84.
[12] For the crystallographic structure of the trinuclear Pd acetate
obtained from CH2Cl2, see: F. A. Cotton, S. Han, Rev. Chim.
Miner. 1985, 22, 277.
[13] For the oxidative addition of I2 to organoplatinum(ii) complexes,
see: J. C. Muijsers, J. W. Niemantsverdriet, I. C. M. Wehman-
Ooyevaar, D. M. Grove, G. van Koten, Inorg. Chem. 1992, 31,
2655.
[14] Acetoxylation product from the reductive elimination of acetate
was not observed under our reaction conditions.
[15] For the measurement of KIE in stoichiometric oxime-directed
palladation, see: A. P. Wells, W. Kitching, Organometallics 1992,
11, 2750.
[16] G. M. Rubottom, R. C. Mott, J. Org. Chem. 1979, 44, 1731.
[17] For the early use of PhI(OAc)2 as an oxidant for the acetox-
ylation of benzene, see: T. Yoneyama, R. H. Crabtree, J. Mol.
Catal. A 1996, 108, 35; for activation of alkanes upon reaction
with PhI(OAc)2/I2, see: J. Barluenga, F. Gonzales-Bobes, J. M.
Gonzalez, Angew. Chem. 2002, 114, 2668; Angew. Chem. Int. Ed.
2002, 41, 2556; for recent work with PhI(OAc)2 as an oxidant for
À
C H bond activation, see reference [10].
[18] P. E. Eaton, R. G. Daniels, D. Casucci, G. T. Cunkle, J. Org.
Chem. 1987, 52, 2100.
[19] Oxazoline 17b was also hydrolyzed to give the iodo acid in
> 99% ee.
Angew. Chem. Int. Ed. 2005, 44, 2112 –2115
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2115