Pyridine-directed palladium-catalyzed phosphonation of C(sp2)-H bonds

Article abstract of DOI:10.1002/anie.201305202

Follow the guide: The palladium-catalyzed phosphonation of a C(sp ²)-H bond occurs through the use of a pyridyl group as the directing group. α-Hydroxyalkylphosphonate is used as the phosphonating reagent (see scheme). Copyright

Full text of DOI:10.1002/anie.201305202

Angewandte
Chemie
DOI: 10.1002/anie.201305202
À
C H Phosphonation
2
À
Pyridine-Directed Palladium-Catalyzed Phosphonation of C(sp ) H
Bonds**
Changkun Li, Takaaki Yano, Naoki Ishida, and Masahiro Murakami*
À
Direct functionalization of carbon–hydrogen (C H) bonds
provides a straightforward means of molecular transforma-
tion, and thus has been extensively investigated in the past
two decades.[1,2] Although a wide variety of transition-metal-
À
catalyzed reactions for functionalizing C H bonds are
currently available, examples of carbon–phosphorus bond
formation are significantly limited, presumably owing to the
strong coordinating character of phosphorus reagents.[3,4]
Existence of an excess amount of coordinative phosphorus
over metal in a reaction media would hamper a process to
À
activate less coordinative C H bonds. Very recently, Yu and
À
co-workers reported a pyridine-directed C H phosphonation
reaction catalyzed by palladium, in which H-phosphonates
À
Scheme 1. C H phosphonation of 1a.
were directly used.[5] Expeditious deactivation of the catalyst
was avoided by adding H-phosphonate slowly with a syringe
pump. Herein, we describe our independent study of the
analogous phosphonation reaction of 2-arylpyridines; an a-
hydroxyalkylphosphonate generates H-phosphonate upon
treatment with a base,[6] which serves as the masked
phosphonating reagent[7] to save the catalyst from deactiva-
tion. Furthermore, step-by-step stoichiometric reactions
clearly delineate the mechanistic features.
2-Phenylpyridine (1a) was treated with commercially
available H-phosphonate 2 in the presence of palladium(II)
acetate (10 mol%), N-methylmaleimide (NMMI, 40 mol%),
silver(I) acetate (2.5 equiv), and K2HPO4 (4.5 equiv) at 1208C
nating reagent. The use of oxidants such as Cu(OAc)2 and
Ag2CO3 were less effective. Stronger bases such as K3PO4
gave inferior results. Reaction in other solvents, including
toluene, dioxane, and acetonitrile, also gave the phospho-
nated products, but the yields were lower.[10]
Variously substituted 2-arylpyridines were phosphonated
using phosphonating reagent 3 (Scheme 2). The substrate 2-
(o-tolyl)pyridine (1b) allowed the isolation of monophospho-
nated product 4b in 66% yield. The m-tolyl group was site-
selectively phosphonated on the sterically less-hindered side
to afford 4c in 82% yield. Methoxy (4d) and chloro (4e)
groups were tolerated on the phenyl ring. Benzothiophene
(4 f) and alkene (4g) were also phosphonated in good yields.
Not only pyridine, but also quinoline (4i) and pyrimidine (4k)
were suitable as directing groups.
A proposed mechanism is shown in Scheme 3. Initially,
cyclopalladation of 1a with palladium(II) acetate gives
palladacycle A.[11] The a-hydroxyalkylphosphonate 3 gradu-
ally releases acetone under the reaction conditions to
generate a small amount of H-phosphonate 2, which reacts
with palladacycle A to displace the acetate ligand on
palladium. The resulting palladium(II) complex B undergoes
reductive elimination with the aid of NMMI (see below).
Arylphosphonate 4a is thus produced, along with a palla-
dium(0) species, which is oxidized back into palladium(II) by
silver(I) acetate.[12]
We carried out some stoichiometric reactions to corrob-
orate the steps constituting the proposed catalytic cycle.
Complex A was prepared by treatment of 1a with palladiu-
m(II) acetate (1.0 equiv) in MeOH and isolated in a form of
the dimer 5.[11] Next, a dioxane solution containing complex 5,
phosphonate 3 (2.0 equiv), and K2HPO4 (2.2 equiv) was
heated at 1208C (Scheme 4). The acetate ligand of A was
displaced with a phosphonate ligand to afford complex B,
which was isolated in the dimeric form 6. Single crystals of 6,
À
for 48 h (Scheme 1). The ortho C H bond was phosphonated
to give product 4a in only 12% yield. Next, H-phosphonate 2
was replaced by a-hydroxyalkylphosphonate 3, which was
easily prepared from 2 and acetone in one step according to
the reported procedure.[8] To our surprise, 4a was obtained in
70% yield, together with a small amount of diphosphonated
product (6%). Thus, a-hydroxyphosphonate 3 proved to be
superior to 2 as the phosphonating reagent, probably because
it gradually generated H-phosphonate 2.[9] Other reaction
conditions were examined using 3 as the masked phospho-
[*] Dr. C. Li, T. Yano, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510, (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
[**] We thank Dr. Y. Nagata (Kyoto Univ.) for his assistance with X-ray
crystallographic analysis. This work was supported in part by
a Grant-in-Aid for Scientific Research on Innovative Areas “Molec-
ular Activation Directed toward Straightforward Synthesis” and
a Grant-in-Aid for Scientific Research (B) from MEXTand The Asahi
Glass Foundation. C.L. thanks the Japan Society for the Promotion
of Science for a Research Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305202.
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Scheme 4. Ligand exchange.
Figure 1. Crystal structure of 6. Thermal ellipsoids set at 50%. Hydro-
gen atoms and three carbon atoms of the n-butyl groups are omitted
for clarity. Selected bond lengths (ꢀ) and angles (8): Pd(1)–P(1)
2.227(1), Pd(1)–C(1) 1.998(2), C(1)-Pd(1)-P(1) 96.00(6), O(2)-Pd(1)-
P(1)-O(1) 3.54, Pd(1)-P(1)-O(1)-Pd(2) 55.85.
Scheme 2. Palladium-catalyzed phosphonation of 1. Reaction condi-
tions: 1 (0.20 mmol), 3 (1.5 equiv), Pd(OAc)2 (10 mol%), NMMI
(40 mol%), AgOAc (2.5 equiv), K2HPO4 (4.5 equiv), tBuOH (1.5 mL),
1208C, 48 h. Yields shown are of isolated products.
Pd(2) was 55.858. The phosphorus atom was located cis to the
phenyl carbon, for which stronger trans influence was
expected than for the pyridine nitrogen.[14]
suitable for X-ray crystallographic analysis, were obtained by
recrystallization from an ether/hexane solution. The six-
membered dinuclear palladacycle is bridged with the phos-
phonate ligand through its oxygen and phosphorus atoms
(Figure 1).[13] It assumes a boat-like form; the O(2), Pd(1),
P(1), O(1) atoms are located on a plane [O(2)-Pd(1)-P(1)-
O(1) = 3.548] and the torsion angle of the Pd(1)-P(1)-O(1)-
The following reductive elimination step was also exam-
ined.[15] No reaction was observed upon heating a CD3CN
solution of 6 at reflux. On the contrary, reductive elimination
occurred when heated at reflux (bath temperature: 1208C) in
the presence of NMMI (2.0 equiv), resulting in the isolation of
arylphosphonate 4a in 97% yield (Scheme 5). The use of
benzoquinone and maleic anhydride instead of NMMI was
equally effective in inducing reductive elimination. Triphe-
nylphosphine less effectively accelerated reductive elimina-
tion (60% after 48 h). These results suggested that electron-
accepting ligands are required to facilitate reductive elimi-
nation of arylphosphonate 4a from palladacycle B.[16]
The reductive elimination giving 4a from 6 was accom-
panied by the formation of black precipitates, presumably an
aggregate of palladium(0). The formation of a palladium(0)
Scheme 3. Proposed mechanism.
Scheme 5. Reductive elimination.
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Chemie
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À
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deactivation.
À
[4] For phosphonation of aromatic C H bonds using a stoichiomet-
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Palladium-catalyzed phosphonation of 1a: Pd(OAc)2 (4.5 mg,
0.02 mmol), N-methylmaleimide (8.8 mg, 0.08 mmol), AgOAc
(84 mg, 0.5 mmol), and K2HPO4 (156 mg, 0.9 mmol). tBuOH
(1.5 mL), a-hydroxyalkylphosphonate 3 (75 mg, 0.30 mmol), and 2-
phenylpyridine 1a (31 mg, 0.20 mmol) were added by syringe into
a 25 mL screw-capped tube equipped with a magnetic stir bar. The
reaction tube was capped in the air and heated at 1208C for 48 h.
After cooling to room temperature, the reaction mixture was filtered
through a short pad of celite, using ethyl acetate as the eluent. The
solvent was removed under reduced pressure and the residue was
then purified by chromatography to afford 4a (48.6 mg, 70%).
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Received: June 17, 2013
Published online: July 23, 2013
À
Keywords: C H activation · palladium catalysis ·
phosphonation · synthetic methods · transition metals
.
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À
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