Palladium-catalyzed (N-oido-2-pyridinyl)methyl transfer from 2-(2-Hydroxyalkyl)pyridine N-oxide to aryl halides by β-carbon elimination

Full text of DOI:10.1002/asia.200900151

DOI: 10.1002/asia.200900151
Palladium-Catalyzed (N-Oxido-2-pyridinyl)methyl Transfer from 2-(2-
Hydroxyalkyl)pyridine N-Oxide to Aryl Halides by b-Carbon Elimination
Takafumi Suehiro, Takashi Niwa, Hideki Yorimitsu,* and Koichiro Oshima*[a]
Table 1. Pd-catalyzed (N-oxido-2-pyridinyl)methyl transfer to aryl hal-
ides 2 from alcohol 1a.[a]
Pyridine N-oxides are an important class of compounds
found in organic chemistry as oxidants,[1] ligands of transi-
tion metals,[2] organocatalysts,[3] and synthetic intermediates
for substituted pyridines.[4,5] In addition, pyridine N-oxides
and related compounds often show biological activity.[6] De-
velopment of new methods for the synthesis of pyridine N-
oxides is hence important. During the course of our recent
studies on chelation-assisted carbon–carbon bond cleavage
under palladium catalysis,[7] we have discovered the palladi-
um-catalyzed (N-oxido-2-pyridinyl)methyl transfer from 2-
(2-hydroxylalkyl)pyridine N-oxide derivatives to aryl bro-
mides, providing 2-benzylpyridine N-oxide derivatives. Re-
cently Fagnou et al. reported the synthesis of 2-benzylpyri-
dine N-oxides by palladium-catalyzed direct arylation at the
benzylic sp3 carbon atom of 2-methylpyridine N-oxide deriv-
atives.[5e] However, the substrate scope was limited because
of the strongly basic conditions by using sodium tert-butox-
ide. Moreover, this direct route requires a special apparatus
for microwave irradiation. Facile synthetic methods of func-
tionalized pyridine N-oxides hence have to be explored.
Treatment of bromobenzene (2a) with 2-(2-hydroxyalkyl)-
pyridine N-oxide 1a in the presence of potassium carbonate
and a palladium catalyst in refluxing xylene provided 2-ben-
zylpyridine N-oxide (3a) in good yield (Table 1, entry 1).
Palladium(II) acetate as well as palladium(II) trifluoroace-
tate resulted in high efficiency.[8] The choice of the bidentate
phosphine ligand was crucial. DPEphos and rac-binap[9]
acted as effective ligands, while other bidentate ligands or
monodentate ligands exhibited poor to moderate activity for
this reaction.[10] Although the N-oxide may oxidize the phos-
Entry
2
R
t [h]
3
Yield[b] [%]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
H
4-Me
4-OMe
4-F
4-Cl
3
5
11
4
3
7
11
3
5
8
3
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
80
68
68[c]
84[c]
74[c]
78[c]
71
4-CF3
4-COCH3
4-CO2Et
4-CHO
4-CN
75
72
78
100
98
9
10
11
12
13
14
2-Me
2,6-Me2
(1-naphthyl (1Np))
2-COPh
11
2
11
81
74
[a] A mixture of 1a (1.0 mmol),
2
(1.2 mmol), PdACHTUGNTERNNU(G OCOCF3)2
(0.05 mmol), DPEphos (0.05 mmol), and K2CO3 (1.2 mmol) was boiled in
xylene (4.0 mL). [b] Yield of isolated product. [c] rac-binap (0.05 mmol)
was used as a ligand.
phine ligand, no significant formation of phosphine oxide
was observed. The use of chlorobenzene instead of bromo-
benzene provided 3a in 27% yield.
A wide range of p-substituted aryl bromides including
electron-deficient as well as electron-rich ones could be em-
ployed (Table 1, entries 2–10). In some cases, using rac-
binap as a ligand was more effective for the reaction (en-
tries 3–6). It is worth noting that aryl bromides bearing a va-
riety of carbonyl groups such as a formyl group were toler-
ated (entries 7–9). Synthesis of these products should be dif-
ficult by Fagnouꢀs method.[5e] The conventional oxidation of
the parent pyridine would not be applicable to the synthesis
of 3i.[11] Sterically demanding aryl bromides also participat-
ed in the reaction (entries 11–14). Unfortunately, the reac-
tions of alkenyl halides failed to yield the corresponding
[a] T. Suehiro, Dr. T. Niwa, Prof. Dr. H. Yorimitsu, Prof. Dr. K. Oshima
Department of Material Chemistry
Graduate School of Engineering
Kyoto University
Kyoto-daigaku Katsura, Nishikyo, Kyoto 615-8510 (Japan)
Fax : (+81)75-383-2438
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp
oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900151.
Chem. Asian J. 2009, 4, 1217 – 1220
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COMMUNICATION
products. The reaction of iodobenzene afforded a complex
mixture, and 3a was obtained in 27% yield.
Several (2-hydroxyalkyl)pyridine N-oxides were subjected
to the transfer reaction as (N-oxido-2-pyridinyl)methyl sour-
ces (Scheme 1). The two isopropyl groups of 1a were not es-
tion of 1g bearing a methyl group at the 3-position, the cor-
responding product was obtained in lower yield, probably
owing to the steric hindrance. An attempted reaction of the
quinoline N-oxide analogue of 1 gave 2-methylquinoline
quantitatively instead of the desired 2-benzylquinoline.
Notably, (N-oxido-4-pyridinyl)methyl transfer reactions
with 1h yielded no desired product, and a small amount of
starting alcohol was recovered (Scheme 4). This result sug-
Scheme 1. Pd-catalyzed transfer reaction with alcohols 1.
Scheme 4. Unsuccessful Pd-catalyzed transfer reaction with 4-(2-hydroxy-
AHCTUNGTERGaNNUN lkyl)pyridine N-oxide 1h.
sential, and less sterically hindered alcohols were also appli-
cable for the reaction. Alcohols 1b having two methyl
groups and 1c bearing a methyl and a phenyl group could
be employed to afford the corresponding product 3a in
moderate yields. An attempted reaction of 1d gave only a
trace amount of the desired product 3a.[12]
Alcohol 1e would react as an allyl source through retro-
allylation under palladium catalysis (Scheme 2).[13] Selective
carbon–carbon bond cleavage occurred at the pyridinyl-
gests that the coordination of the oxygen atom on the nitro-
gen to the palladium center is essential for the success of
the transfer reaction.
We tentatively assume that the reaction mechanism for
the transfer can be described as follows (Scheme 5). After
Scheme 2. Pd-catalyzed selective (N-oxido-2-pyridinyl)methyl transfer
from homoallyl alcohol 1e. 1Np=1-naphthyl.
Scheme 5. Plausible reaction mechanism.
methyl moiety under the (N-oxido-2-pyridinyl)methyl-
group-transfer conditions to yield 3m. In this reaction, no
allylated product was detected even in using triphenylphos-
phine and cesium carbonate, which are effective for the
retro-allylation.
(2-Hydroxyalkyl)pyridine N-oxides 1 f having a methyl
group at the 6-position on the pyridine ring were also appli-
cable for the reaction (Scheme 3). In contrast, in the reac-
oxidative addition of aryl bromide 2 to the low-valent palla-
dium species,[14] ligand exchange takes place under basic
conditions to afford arylpalladium alkoxide B with intramo-
lecular coordination of the basic oxygen atom on the pyri-
dine ring. Subsequent b-CACHTNUGRTNEUNG
(sp3) elimination[15,16] would pro-
ceed via a four-membered transition state from conforma-
tion B’. Finally, reductive elimination would produce 3 along
with the starting palladium complex to complete the catalyt-
ic cycle.
Transformation of the products was investigated
(Scheme 6). Treatment of 2-benzylpyridine N-oxides 3 with
acetic anhydride provided aryl(2-pyridinyl)methyl acetates 4
in high yield.[17] This method provides a facile route to
highly functionalized aryl(2-pyridinyl)methanols which are
found in some biologically active compounds.[18]
Scheme 3. Scope of the pyridine moiety.
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Palladium-Catalyzed (N-Oxido-2-pyridinyl)methyl Transfer
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Scheme 6. Rearrangement of 3 to aryl(2-pyridinyl)methyl acetates by use
of acetic anhydride.
[4] For recent reports on the synthesis of substituted pyridines from the
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In conclusion, we have discovered an efficient palladium
catalyst system for (N-oxido-2-pyridinyl)methyl transfer
from (2-hydroxyalkyl)pyridine N-oxide derivatives to aryl
bromides. The reaction proceeds via b-carbon elimination
3
which involves cleavage of an unstrained C
bond and provides a facile access to 2-benzylpyridine N-
(sp ) C
(sp3)
À
oxides under mild conditions.
Experimental Section
Typical procedure for palladium-catalyzed (N-oxido-2-pyridinyl)methyl
transfer to aryl bromides: Synthesis of 2-benzylpyridine N-oxide (3a) is
representative (Table 1, entry 1). Potassium carbonate (166 mg,
1.2 mmol), palladium(II) trifluoroacetate (17 mg, 0.050 mmol), and bis[2-
(diphenylphosphino)phenyl] ether (27 mg, 0.050 mmol) were placed in a
20 mL two-necked reaction flask equipped with a Dimroth condenser
under Ar atmosphere. Xylene (4.0 mL), bromobenzene (2a, 0.13 mL,
1.2 mmol), and alcohol 1a (223 mg, 1.0 mmol) were sequentially added at
ambient temperature. The resulting mixture was heated at reflux for 3 h.
After the mixture was cooled to room temperature, a saturated aqueous
ammonium chloride solution (5 mL) was added. The product was extract-
ed with ethyl acetate three times. The combined organic layer was dried
over sodium sulfate and concentrated in vacuo. Silica gel column purifica-
tion (AcOEt/MeOH=10:1) gave 2-benzylpyridine N-oxide (3a, 149 mg,
0.80 mmol) in 80% yield.
[7] T. Niwa, H. Yorimitsu, K. Oshima, Angew. Chem. 2007, 119, 2697–
2699; Angew. Chem. Int. Ed. 2007, 46, 2643–2645.
[8] Product 3a was isolated in 64% yield by using palladium(II) ace-
tate.
Rearrangement of benzylpyridine N-oxides 3 to aryl(2-pyridinyl)methyl
acetates by means of acetic anhydride (Scheme 6): Synthesis of phenyl(2-
pyridinyl)methyl acetate (4a) is representative. A solution of benzylpyri-
dine N-oxide (3a, 93 mg, 0.5 mmol) in acetic anhydride (10 mL) was
placed in a 50 mL flask. After the mixture was heated at 1108C for 3 h,
the mixture was concentrated in vacuo. Silica gel column purification
(hexane/AcOEt=1:1) gave 4a (111 mg, 0.49 mmol) in 98% yield.
[9] DPEphos: bis[2-(diphenylphosphino)phenyl] ether. binap: 2,2’-bis-
AHCTUNGTRENNG(UN diphenylphosphino)-1,1’-binaphthyl.
[10] The effects of the ligands are summarized in the Supporting Infor-
mation.
[11] D. Collado, E. Perez-Inestrosa, R. Suau, J. Org. Chem. 2003, 68,
3574–3584.
[12] Benzophenone (93%) was observed in the crude product.
[13] a) S. Hayashi, K. Hirano, H. Yorimitsu, K. Oshima, J. Am. Chem.
Soc. 2006, 128, 2210–2211; b) S. Hayashi, K. Hirano, H. Yorimitsu,
K. Oshima, J. Am. Chem. Soc. 2007, 129, 12650–12651; c) M. Iwasa-
ki, S. Hayashi, K. Hirano, H. Yorimitsu, K. Oshima, J. Am. Chem.
Soc. 2007, 129, 4463–4469.
Acknowledgements
[14] We prepared a palladium complex, trans-[PdBr(Ph)ACTHUNTRGNE(UNG PPh3)2], and
This work was supported by Grants-in-Aid for Scientific Research and
GCOE Research from JSPS. T.N. acknowledges JSPS for financial sup-
port. H.Y. thanks financial support from Eisai and Kyoto University.
performed the stoichiometric reaction of the arylpalladium complex
with 1a in the presence of 1.2 molar equivalents of potassium car-
bonate in boiling xylene for 5 h. The reaction afforded 3a in 62%
yield.
[15] The b-CACTHNUTRGNEUNG
(sp3) elimination of palladium alkoxides was reported; see:
Keywords: alcohols
· cleavage reactions · palladium ·
H. Wakui, S. Kawasaki, T. Satoh, M. Miura, N. Nomura, J. Am.
Chem. Soc. 2004, 126, 8658–8659.
pyridines
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H. Yorimitsu, K. Oshima et al.
COMMUNICATION
[16] Examples of palladium-catalyzed carbon–carbon bond cleavage of
[18] F. Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem. Soc. Rev.
2006, 35, 454–470.
tertiary alcohols are summarized: J. Muzart, Tetrahedron 2005, 61,
9423–9463.
[17] S. Oae, T. Kitao, Y. Kitaoka, J. Am. Chem. Soc. 1962, 84, 3359–
Received: April 21, 2009
3362.
Published online: June 5, 2009
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Chem. Asian J. 2009, 4, 1217 – 1220