PdCl2 and N-hydroxyphthalimide co-catalyzed c sp 2 -H hydroxylation by dioxygen activation

Article abstract of DOI:10.1002/anie.201300957

Rad transition: The combination of transition-metal-catalyzed C-H activation and a NHPI-initiated radical process is essential for the title transformation. The neutral conditions and the ideal oxidant, molecular oxygen, make this hydroxylation environmen

Full text of DOI:10.1002/anie.201300957

Angewandte
Chemie
DOI: 10.1002/anie.201300957
ꢀ
C H Activation
ꢀ
PdCl2 and N-Hydroxyphthalimide Cocatalyzed Csp2 H Hydroxylation
by Dioxygen Activation**
Yuepeng Yan, Peng Feng, Qing-Zhong Zheng, Yu-Feng Liang, Jing-Fen Lu, Yuxin Cui, and
Ning Jiao*
ꢀ
Direct functionalization of C H bonds has been developed as
ditions (15 atm O2, 15 atm CO, 1808C). To control the
selectivity and improve the efficiency, Yu and co-workers
used a carboxyl group as the directing group and realized the
direct hydroxylation of arenes with molecular oxygen (1 atm)
in the presence of a benzoquinone oxidant (1.0 equiv) and
base (1.0 equiv; Scheme 1b).[6] Nevertheless, for substrates
with other directing groups, the transition-metal-catalyzed
direct hydroxylation is still difficult (Scheme 1c). Alterna-
tively, a hydrolysis process assisted by various stoichiometric
oxidants (potassium persulfates or periodides) for substrates
with carbonyl groups was disclosed by the groups of Rao,[7a]
Dong,[7b] Kwong,[7c] and Ackermann[7d–e] (Scheme 1c). Func-
tionalized 2-(pyridin-2-yl)phenols are useful building blocks
for preparing light-emitting materials[8] and bioactive mole-
cules.[9] Recent development for the synthesis of these
compounds was realized by this hydrolysis strategy through
R-OAc intermediates.[10] Thus, it would be attractive to
synthesize 2-(pyridin-2-yl)phenols by direct hydroxylation of
a powerful strategy to form new chemical bonds.[1] Among
ꢀ
them, transition-metal-catalyzed hydroxylation of C H bonds
has received considerable attention because of the industri-
ally important alcohol or phenol products.[2,3] Despite the
significant development in the past decades,[1,2] catalytic
ꢀ
hydroxylation of Csp2 H bonds still remains a very challenging
task.
With regard to green chemistry, molecular oxygen is
regarded as an ideal oxidant because of its natural, inex-
pensive, and environmental friendly characteritics.[4] In 1990,
Fujiwara and co-workers disclosed a Pd(OAc)2-catalyzed
hydroxylation of benzene with molecular oxygen
(Scheme 1a).[5] However, this reaction is limited by low
efficiency (2.3%), poor selectivity, and harsh reaction con-
ꢀ
a C H bond with O2 under neutral reaction conditions.
Herein, we disclose a novel PdCl2 and NHPI (N-hydroxy-
ꢀ
phthalimide) cocatalyzed, direct Csp2 H hydroxylation of 2-
phenylpyridines (Scheme 1d). The significance of the present
chemistry is threefold: 1) This process is a novel transition
ꢀ
metal and organocatalyst cocatalyzed Csp2 H functionaliza-
tion using a radical process.[11] A unique and reasonable
mechanism is proposed for this reaction, which will probably
ꢀ
promote the development of Csp2 H functionalization by the
combination of a radical process with a transition-metal
catalysis. 2) To the best of our knowledge, this reaction is
a novel pyridyl group directed[12] hydroxylation with O2, thus
leading to useful products for preparing various biologically
active molecules,[9] organic, and light-emitting materials.[8]
3) Molecular oxygen is employed as a reagent and the sole
oxidant under neutral conditions without the addition of any
other stoichiometric oxidant and base, thus making this
protocol very green and practical.
ꢀ
Scheme 1. Hydroxylation of Csp2 H bonds. BQ=benzoquinone,
DG=directing group.
[*] Y. Yan, P. Feng, Q.-Z. Zheng, Y.-F. Liang, J.-F. Lu, Y. Cui, N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
Peking University
Inspired by our previous work on aerobic oxidation by
Xue Yuan Rd. 38, Beijing 100191 (China)
E-mail: jiaoning@bjmu.edu.cn
Homepage: http://sklnbd.bjmu.edu.cn/nj
peroxide radical intermediates,[13] we started our model study
ꢀ
by investigating the direct C H hydroxylation of 2-phenyl-
pyridine (1a). To our delight, when the reaction was
conducted under O2 using PdBr2 and NHPI as cocatalysts at
1008C in toluene, the desired ortho-hydroxylation product 2a
was obtained in 54% yield (Table 1, entry 1). The screening
on different palladium catalysts shows that PdCl2 performed
with high efficiency (entry 5). If TBHP (2.0 equiv) instead of
NHPI was employed, the yield decreased slightly (entry 6),
and the reaction did not work in the presence of TEMPO
(10 mol%; entry 7). The additives such as base, Brønsted
acids, Lewis acids, and ligands did not improve the efficiency
N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
[**] Financial support from the National Basic Research Program of
China (973 Program 2009CB825300), the National Science Foun-
dation of China (No. 21172006), and Peking University are greatly
appreciated. We thank Hang Yin in this group for reproducing the
results for 2j and 2s.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300957.
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Table 1: Screening of hydroxylation conditions.[a]
Entry
[Pd]
Cocatalyst
2a [%][b]
54
1
PdBr2
NHPI
2
3
4
5
Pd(OAc)2
PdTFA2
[Pd(dppf)Cl2]
PdCl2
NHPI
NHPI
NHPI
NHPI
20
44
70 (55)
87 (72)
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
–
PdCl2
TBHP (2.0 equiv)
TEMPO
NHPI
NHPI
NHPI
80 (59)
0
0
0
76 (63)
0
0
8[c]
9[d]
10[e]
11
12
NHPI
–
[a] Reaction conditions: 1a (0.2 mmol), [Pd] (0.01 mmol), NHPI
(0.02 mmol), toluene (3 mL), O2 (1 atm), 1008C, 15 h. [b] Yield as
determined by GC. The value within the parentheses is the yield of the
isolated product. [c] Benzotrifluoride was used as solvent instead of
toluene. [d] The reaction was carried out under Ar (1 atm). [e] The
reaction was carried out under air (1 atm). dppf=1,1’-bis-(diphenyl-
phosphino) ferrocene, TBHP=tert-butyl hydroperoxide, TEMPO=
2,2,6,6-tetramethylpiperidin-N-oxyl, TFA=trifluoroacetate.
of this reaction (see the Supporting Information). The
reaction in benzotrifluoride or under Ar did not work
(entries 8 and 9), and in contrast, the reaction with air
proceeded well but with a slightly lower yield (entry 10).
Notably, the reaction in the absence of a palladium catalyst or
NHPI did not work (entries 11 and 12). We additionally
investigated the experiment with TBHP (2.0 equiv) in the
absence of O2, but no product was observed (see Scheme S1 in
the Supporting Information). When TBHP (2.0 equiv) was
18
employed instead of NHPI under O2, the reaction afforded
Scheme 2. Palladium-catalyzed hydroxylation of 2-phenylpyridine with
O2. Standard reaction conditions: 1 (0.4 mmol), PdCl2 (0.02 mmol),
NHPI (0.04 mmol), toluene (6 mL), 1008C, O2 (1 atm), 15 h. Yields of
isolated products given. [a] PhCHO (0.8 mmol) was added.
[18O]-2a in 55% yield (Scheme S1). These results demon-
strate that the combination of palladium and NHPI (or
TBHP) catalysis, toluene, and O2 were all essential for this
reaction.
With the optimized reaction conditions in hand, the scope
of substituted 2-phenylpyridines was investigated (Scheme 2).
The benzene ring with electron-donating and electron-with-
drawing groups proceeded well. Notably, the substrates
containing a halogen group were also compatible under the
standard reaction conditions (2c, 2 f, 2j and 2k), and allows
additional substrate modification. Substituents at ortho, meta,
or para positions did not affect the efficiency of this trans-
formation (2j–2k, 2l–2p). Moreover, substrates with sub-
stituents on the pyridine ring (at the 3-,4-, or 5-position) also
reacted well (2b–2e, 2q–2t).
Supporting Information]. Furthermore, the
proposed PdII complex A was prepared and
employed in the reaction instead of a PdCl2
catalyst. Interestingly, the desired product
2a was obtained in 74% yield [Eq. (2)].
However the reaction of the A alone did not
produce the desired product 2a [Eq. (3)].
To further probe the mechanism, some control experi-
ments were investigated. The 18O-labeling results proved that
the oxygen atom in the hydroxy group originates from
molecular oxygen [Eq. (1); determined by HRMS. See the
We had hypothesized that the very low solubility of A in
toluene shuts down the reaction, and investigated by running
control experiments. When a stoichiometric amount of PdCl2
was employed in the reaction of 2-phenylpyridine (1a), none
2
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of the desired product 2a formed [Eq. (4)], thus indicating
that the strong chelation between the palladium catalyst and
substrate may prevent the further hydroxylation of 1a.
Interestingly, a similar reaction of A in the presence of
4.0 equivalents of pyridine produced 2a in 31% yield
[Eq. (5)]. Moreover, when A was used as both the catalyst
and substrate, 2a and 2j were obtained in 26 and 28% yield,
respectively [Eq. (6)]. These results suggest that free pyridine
Scheme 3. Proposed mechanism.
hydroxylation product 2a and regeneration of the catalyst
(Scheme 3).
To further prove the proposed mechanism, the reaction
was monitored by EPR (electron paramagnetic resonance
spectroscopy) with DMPO (5,5-dimethyl-1-pyrroline N-
oxide) as the radical trap. Interestingly, when the reaction
was recorded under the standard reaction conditions (Fig-
ure 1A), the signals corresponding to DMPO-OH could be
or 2-arylpyridine may be necessary to break up the PdII
complex A to form a monomeric PdII intermediate.[12p,14]
In addition, a kinetic isotopic effect (KIE) study was also
conducted, and the KIE values (KH/KD = 1.86 for intra-
molecular study and KH/KD = 2.85 forintermolecular study;
see the Supporting Information) suggest that the cleavage of
[15]
ꢀ
a C H bond might be involved in the rate-limiting step.
Similar reactions in the presence of 1.1 equivalents of
mCPBA (3-chloroperbenzoic acid) or NHPI under Ar did
not work [see Eq. (S6) and (S7) in the Supporting Informa-
tion], and may exclude the possibility of a peroxybenzoic acid
as an intermediate. Furthermore, considering that pyridines
can be oxidized to pyridine N-oxides in the presence of
peroxides, 2.0 equivalents of pyridine N-oxide[16] was
employed in the reaction of 1a under Ar and under O2.
However, 2a was not observed under either of these reaction
conditions [Eq. (S8) and (S9) in the Supporting Information].
These results may exclude pyridine N-oxides as a key
intermediate in this transformation.
Figure 1. The EPR spectra (X band, 9.7 GHz, RT): A) A reaction
mixture (1a, PdCl2, NHPI, toluene and O2) in the presence of the
radical trap DMPO (3ꢀ10ꢀ2 m). B) A reaction mixture (NHPI and
toluene) in the presence of radical trap DMPO (3ꢀ10ꢀ2 m).
assigned. The four corresponding peaks are labeled a in
Figure 1). The calculated hyperfine splittings are g0 (2.0053)
and aN = abH = 1.49 mT,[18] which indicates the presence of
hydroxyl radicals during the transformation. Although there
was some overlap, peaks labeled b in this spectrum were
identified as signals corresponding to DMPO-OO(H), and
they disappeared with the addition of superoxide dismutase
(SOD; see the Supporting Information).[18,19] When NHPI
was employed alone in toluene (0.0067m), the hydroxyl
radical and superoxide radical signals were present, though
weak (Figure 1B). These EPR studies (for more details see
the Supporting Information) strongly indicate that hydroxyl
radical F is involved in the NHPI catalytic process in this
transformation.
On the basis of the mechanistic studies, a proposed
reaction pathway is illustrated in Scheme 3. Initially, the
palladium(II) intermediate B[14] is generated by chelate-
ꢀ
directed C H activation. Meanwhile, homolysis of NHPI
affords the PINO radical, which triggers the formation of the
benzyl radical C. The benzyl radical C is then trapped by O2 to
produce the peroxide radical D, which subsequently forms the
hydroxyl radical F and benzaldehyde (E; benzaldehyde can
be oxidized to benzoic acid under O2. Both benzaldehyde and
benzoic acid are detected by GC/MS and TLC; see the
Supporting Information). Then, the reaction of radical F and
B may produce the reactive PdIII G (the palladium complex is
not completely clear yet, and a PdIV intermediate cannot be
excluded).[14a,17] The last step involves carbon–oxygen bond
formation by reductive elimination of G to afford the
ꢀ
To illustrate the synthetic utility of this direct C H
hydroxylation reaction, a variety of transformations of 2-
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(CDCl3, 100 MHz): d = 159.9, 157.8, 145.7, 137.7, 131.4, 126.0, 121.4,
~
119.0, 118.7, 118.5 ppm; IR (neat): n ¼3433.8, 1588.6, 1503.2, 1473.6,
1430.3, 1392.3, 1303.6, 1264.8, 1244.5, 795.6, 753.8, 725.8, 640.9,
626.5 cmꢀ1; MS (m/z, %): 171.10.
Received: February 3, 2013
Revised: March 11, 2013
Published online: && &&, &&&&
ꢀ
Keywords: C H activation · organocatalysis · oxygen ·
palladium · radical reactions
.
ꢀ
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Scheme 4. Transformations of 2-(pyridin-2-yl)phenol.
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yl)phenols with different substituents. Therefore, the present
protocol provides a practical approach to various substituted
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emitting materials.
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3
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In summary, we have demonstrated a novel PdCl2 and
ꢀ
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Experimental Section
NHPI (6.6 mg, 0.04 mmol), PdCl2 (3.6 mg, 0.02 mmol) 2-phenyl-
pyridine (1a, 62.0 mg, 0.4 mmol) toluene (6.0 mL), and a stir bar were
added to a 50 mL Schlenk tube under O2. The mixture was stirred at
1008C under O2 (1 atm) for 15 h as monitored by TLC. The solution
was then diluted with ethyl acetate (15 mL), and evaporated under
vaccum. The crude reaction mixture was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 40:1)
to get product 2a (49.4 mg, 72%). 2a:[10] yellow solid, 1H NMR
(CDCl3, 400 MHz): d = 14.4 (s, 1H), 8.47 (d, J = 4.4 Hz, 1H), 7.88 (d,
J = 8.4 Hz, 1H), 7.80–7.76 (m, 2H), 7.32–7.28 (m, 1H), 7.22–7.19 (m,
1H), 7.03 (d, J = 8.0 Hz, 1H), 6.89 ppm (t, J = 7.4 Hz, 1H); 13C NMR
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
ꢀ
C H Activation
Y. Yan, P. Feng, Q.-Z. Zheng, Y.-F. Liang,
J.-F. Lu, Y. Cui, N. Jiao*
&&&& — &&&&
PdCl2 and N-Hydroxyphthalimide
Rad transition: The combination of tran-
neutral conditions and the ideal oxidant,
molecular oxygen, make this hydroxyl-
ation environmentally friendly and prac-
tical. NHPI=N-hydroxyphthalimide.
ꢀ
ꢀ
Cocatalyzed Csp2 H Hydroxylation by
sition-metal-catalyzed C H activation
Dioxygen Activation
and a NHPI-initiated radical process is
essential for the title transformation. The
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!