Catalytic aerobic oxidation of substituted 8-methylquinolines in Pd II-2,6-pyridinedicarboxylic acid systems

Article abstract of DOI:10.1039/b803156h

The ability of Pd^II complexes derived from 2,6- pyridinedicarboxylic acids to catalyze homogeneous regioselective aerobic oxidation of 5- and 6-substituted 8-methylquinolines in AcOH-Ac₂O solution to produce corresponding 8-quinolylm

Full text of DOI:10.1039/b803156h

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Catalytic aerobic oxidation of substituted 8-methylquinolines
in PdII-2,6-pyridinedicarboxylic acid systemsw
Jing Zhang, Eugene Khaskin, Nicholas P. Anderson, Peter Y. Zavalij and
Andrei N. Vedernikov*
Received (in Cambridge, UK) 25th February 2008, Accepted 8th May 2008
First published as an Advance Article on the web 16th June 2008
DOI: 10.1039/b803156h
The ability of PdII complexes derived from 2,6-pyridinedicar-
boxylic acids to catalyze homogeneous regioselective aerobic
oxidation of 5- and 6-substituted 8-methylquinolines in AcOH–
Ac2O solution to produce corresponding 8-quinolylmethyl acet-
ates in high yield was demonstrated; corresponding 8-quinoline
carboxylic acids are minor reaction products.
acid (H2hpda)–aceticacid–Ac2O system leading to the corre-
sponding 8-quinolylmethyl acetates in high yield (eqn (1)):
Selective CH functionalization of organic substrates is an
important problem of synthetic chemistry.1 A number of
reports on heteroatom-directed catalytic CH functionalization
have appeared recently.2,3 The use of the PdII complexes in
combination with strong oxidants such as PhI(OAc)2,
NaHSO5, IOAc or alkyl peroxocarboxylates was especially
fruitful.2 Still, the use of dioxygen for selective CH functiona-
lization remains challenging and constitutes an attractive prac-
tical goal.3–5 Given the fact that facile aerobic conversion of
monoalkyl platinum(II) complexes to corresponding alcohols6,7
can be promoted by the dpms ligand8 (Scheme 1), we were
interested to find out whether the reactivity of the systems
including monohydrocarbyl palladium(II) complexes and di-
oxygen can be enhanced with the help of suitable ligands. One
of the useful routes to various organopalladium(II) species is via
selective CH activation and cyclopalladation of suitable or-
ganic substrates with PdII complexes such as Pd(OAc)2 or
Pd(acac)2 (acac = acetylacetonate) in AcOH or some other
solvents.9 The resulting palladacycles that contain Pd–C(sp3)
or Pd–C(sp2) bonds are typically unreactive towards O2,10 and
even H2O2.10b Therefore, the effect of added ligands on their
reactivity towards O2 could be readily established.
ð1Þ
Since the tridentate anionic pyridine-containing motif present
in dpms turned out to be useful in promoting aerobic oxidation
of various monoalkyl PtII complexes in water,6,7 a lipophilic
dpms ligand, t-Bu-dpms was tested in this work along with
dianionic tridentate 2,6-pyridinedicarboxylates (L, Scheme 1).
We anticipated that H2pda-derived PdII carboxylates would be
active in CH activation of HQ, similar to PdII acetate itself. A
tert-butyl group present in some ligands was needed to increase
solubility of the derived metal complexes in acetic acid. The
ability of Li(t-Bu-dpms) and H2hpda to promote aerobic
oxidation of palladacycles 3a and 3d (Scheme 2) was tested first.
Complexes 3a and 3d were prepared according to standard
procedures.w No reaction between 3a and O2 in acetic acid at
20 1C was seen after 1 day. Combination of yellowish complex 3a
with 1 equivalent of Li(t-Bu-dpms) in acetic acid quantitatively
produced a B1 : 1 mixture of colorless cis- and trans-4a that were
characterized by NMR spectroscopy and elemental analysis.
When the solution of 4a in AcOH was stirred under air at
20 1C, a fast reaction occurred, leading to the clean formation
of a B1 : 1 mixture of 8-quinolylmethanol (5a) : 8-quinolyl-
methyl acetate (2a) (86% combined NMR yield after 15 min),
and complex [(t-Bu-dpms)Pd(OAc)]2, 6 (eqn (2); R = H):
In this work, we report selective catalytic aerobic oxidation
of various substituted 8-methylquinolines (HQ) in
Pd(OAc)2 or Pd(acac)2–4-hydroxopyridine-2,6-dicarboxylic
a
ð2Þ
Scheme 1 Anionic chelating pyridine-derived ligands.
When the same reaction was carried out under O2 in the
presence of 5 equivalents of Ac2O, a mixture of 2a and 5a that
formed initially slowly produced 2a as the only organic product
(97% NMR yield after 8 h at 20 1C). Volumetric experiments
allowed us to establish that 0.5 mol O2 was consumed per mole
of 4a. Hence, no sacrificial substrate was required for dioxygen
activation and oxidation of this palladacyclic complex.
Department of Chemistry and Biochemistry, University of Maryland,
College Park, MD 20742, USA. E-mail: avederni@umd.edu
Fax: +1-301-314-9121; Tel: +1-301-405-2784
w Electronic supplementary information (ESI) available: Experimental
and computational details. CCDC 679231. For ESI and crystallo-
graphic data for 7a in CIF format see DOI: 10.1039/b803156h
ꢀc
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Scheme 2 8-Methylquinoline derivatives.
Fig. 1 ORTEP plots (50% probability ellipsoids) for complex 7a
Fluoro analogue 4d could also be oxidized with O2 in
AcOH–Ac2O solution but due to its poorer solubility at
ambient temperature a higher temperature of 60 1C was used.
Solid 4d dissolved after 5 h to produce 2d as the only organic
(disordered methyl groups are omitted for clarity). Selected bond
lengths (A) and angles (1): Pd1–C10, 2.022(2); Pd1–N1, 2.003(1);
Pd1–N2, 2.085(1); Pd1–O1, 2.132(1); N1–Pd1–N2, 172.51(5),
O1–Pd1–C10, 176.45(6).
1
product detected by H and 19F NMR spectroscopy in 98%
a ligand (entry 5). Finally, the use of less lipophilic H2pda
resulted in a slightly lower yield of 2a (66%, entry 6).
yield. No oxidation of 3d could be observed under the same
reaction conditions.
Oxidation of other quinolines 1b–1i was performed in a
Pd(acac)2–H2hpda system (Table 1, entries 7–14). Acetoxyla-
tion of 5,8-dimethylquinoline 1b (entry 7) was regiospecific; no
trace of a 5-acetoxymethyl derivative was detected by NMR
spectroscopy. The electron-releasing MeO group (entry 8),
halogens (entries 9–12), electron-withdrawing NO2 group
(entries 13–14) are all tolerated. Corresponding acetates 2
were obtained in moderate to high yield.
Along with acetates 2, formation of poorly soluble PdII
bis(8-quinolinecarboxylate)s was detected at the end of all
reactions. As a result of catalyst degradation the reaction rates
slowed and conversion of HQ could not be increased after
24 h.14 In the case of fluorinated quinoline 1d the yield of acid
9d was 7%, according to the 19F NMR spectrum. Importantly,
catalytic oxidation of 2-p-tolylpyridine or pinacolone oxime,w
substrates that form palladacycles as a result of C(sp2)–H or
non-activated C(sp3)–H bond cleavage, respectively, was not
successful. Though palladation of 2-p-tolylpyridine with
Pd(hdpa)(DMF) in AcOH was facile, the product of its
oxidation, 2-(20-acetoxy-p-tolyl)pyridine was detected in low
Similarly, palladacycles 7 and 8 derived from H2-t-Bu-pda
and H2hpda, respectively (Scheme 2) were prepared in high
yield by reacting 3 with 1 equivalent of the appropriate dicar-
boxylic acid, H2-t-Bu-pda or H2hpda, in DMF or AcOH.
Complexes 7a and 8a were isolated in analytically pure form
and the former was characterized by X-ray diffraction (Fig. 1).w
As in the case of complexes 4, oxidation of 7a, 8a or 8d with O2
in AcOH–Ac2O system was efficient, but it was less selective. For
instance, in the reaction of 8d, according to the 19F NMR
spectrum, after 5 h at 60 1C acetate 2d formed in 87% yield
along with 9% 5-fluoro-8-quinoline carboxylic acid 9d. Since
acetate 2d was proven to be inert towards O2 in the presence of
5% Pd(OAc)2–H2hpda under the conditions employed, we sug-
gest that a Pd-catalyzed aerobic oxidation of alcohol 5d con-
tributed to the formation of 9d.11 Consistent with these
observations, as established by volumetric measurements, oxida-
tion of 1.0 mol 7a at 20 1C required 0.6 mol of O2 accounting for
over-oxidation of a small part of alcohol 5a. Importantly, the
presence of Hg metal in the mixtures did not affect the rates of
reaction above suggesting that they were homogeneous.12
With the results of aerobic oxidation of 3a and 3d in the
presence of Li(t-Bu-dpms) and H2hpda in hand, we tested the
ability of the derived PdII complexes, 6 and Pd(hpda)(DMF),13
to catalyze aerobic oxidation of free amines 1a–1i (Table 1).
Heating 1a with 5 equivalents of Ac2O, 5 mol% 6 under
ambient pressure of O2 in AcOH solution at 80 1C for 24 h led
to the formation of 2a (4.5% by NMR, 24 h; Table 1, entry 1).
A control experiment with Pd(OAc)2 in the absence of Li(t-Bu-
dpms) showed an only slightly lower yield of 2a, 2.5%. The result
observed in the presence of 6 is consistent with its poor ability to
cyclopalladate HQ as established in a separate experiment.w
The use of Pd–pda complexes proved more effective.
PdII(hpda)(DMF) dissolved in AcOH containing 5 equivalents
of 1a at room temperature produced, in the course of few
hours, a palladacyclic product 8a.
Table 1 Oxidation of 1 with O2 in AcOH solution in the presence of 5
equivalents of Ac2O and 5 mol% PdII–L (80 1C, 24 h) (NMR yields)
Conversion
of 1 (%)
Entry
R
L
Pd source 2a (%)
1
2
H
H
t-Bu-dpms
Pd(OAc)2 4.5 (2.5) 7.0
H2hpdab
Pd(hpda)
(DMF)
Pd(OAc)2 72 (2.5)
79 (2.5)
85
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
Me
H2hpda
H2hpda
H2-t-Bu-pda Pd(acac)2
H2pda
H2hpda
81
85
81
75
82
70
70
89
80
69
80
60
Pd(acac)2
78 (2.5)
74 (2.5)
Pd(OAc)2 66 (2.5)
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
73 (3)
57 (3)
48 (2.5)
79 (1)
73 (1)
63 (1.5)
70 (3.5)
53 (3.5)
OMe H2hpda
I
Br
Cl
F
NO2 H2hpda
6-
NO2
H2hpda
H2hpda
H2hpda
H2hpda
Importantly, catalytic oxidation of free 8-methylquinoline
1a in the presence of 5 mol% of Pd(hpda)(DMF) at 80 1C was
efficient (79%, entry 2). When the Pd(hpda) complex was
prepared in situ from H2hpda and Pd(OAc)2 (entry 3), or
Pd(acac)2 (entry 4), virtually indistinguishable results were
observed. Similar results were obtained with H2-t-Bu-pda as
H2hpda
a
Yield determined in the absence of L is given in parentheses.
Pd(hpda)(DMF) was used as a catalyst.
b
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5% yield only when the temperature of the reaction mixture
was raised to 110 1C. Pinacolone oxime did not undergo CH
activation with Pd(hdpa)(DMF). As in the case of stoichio-
metric oxidation, no Pd black was detected in either of these
experiments; an additive of Hg metal in the mixtures did not
affect the yields of the catalytic reactions. Hence, the reported
catalytic aerobic CH functionalization is homogeneous and is
currently limited to substrates with benzylic C–H bonds.15
Two plausible mechanisms of Pd(hpda)-catalyzed oxidation
of HQ with O2, involving Pd0/PdII (Scheme 3a) or PdII/PdIV
couple (Scheme 3b) were analyzed.16 DFT calculations were
used to estimate the thermodynamic accessibility of presumed
key intermediates. According to the mechanism given in
Scheme 3a, quinoline complex A13 undergoes fast cyclometal-
lation to give intermediate B, which was confirmed in this
work. The slowest reaction step might be subsequent nucleo-
philic attack of acetic acid at the benzylic carbon in B leading
to postulated Pd0 transient C, which is consistent with the
observed poor reactivity of arylpalladium intermediates. Very
low steady-state concentration of C may be responsible for the
lack of accumulation of palladium black in the reaction
mixtures and for the remarkable tolerance of C(sp2)–I and
C(sp2)–Br groups present in some substrates. An H2hpda-
enabled reaction of C with O2 leading to a stable dichelate F
via a PdII peroxo complex D4a,c and a hydroperoxo inter-
mediate E might be the driving force for the CH functionaliza-
tion reaction that does not occur under an inert gas
atmosphere. Dichelate F liberates an acetoxy-functionalized
quinoline ligand 2 and forms A. Finally, H2O2 formed in a
reaction of E is responsible for the oxidation of B leading to an
alcohol 5 which was established in separate experiments.w A
Pd-mediated aerobic oxidation of 5 can lead to an acid 9.11
An alternative oxidation mechanism in Scheme 3b involving
PdII/PdIV couple is similar to that suggested for reaction of
(dpms)PtII(OH)Alk with O2.6 Reductive elimination of an
alcohol 5 or an acetate 2 (not shown in Scheme 3b) from PdIV
intermediate Y is responsible for the formation of these major
reaction products. Though transient PdIV complexes X and Y
are surprisingly low-energy, transformation of W to X might be
a substrate dependent high-barrier reaction. More extensive
computational study is required to theoretically support or rule
out the viability of this PdII/PdIV couple mediated mechanism.
In summary, we have developed a simple homogeneous system
that allows facile selective N-heteroatom directed organopalla-
dium mediated aerobic benzylic CH acetoxylation of 8-methyl-
quinolines. A detailed mechanistic study and work on other
applications of the catalytic system developed are underway.
We thank the University of Maryland, the Donors of the
American Chemical Society Petroleum Research Fund, and
NSF (CHE-0614798) for financial support.
Notes and references
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13 Complexes Pd(pda)L (L = H2O, MeCN, quinoline etc.) were
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´
14 Consistent with that result, 2-pyridinecarboxylic acid, producing
similar poorly soluble PdII dicarboxylates, was not efficient as a
ligand in the catalytic oxidation of HQ.
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benzenes see the review: B. Lucke, K. V. Narayana, A. Martin and
K. Jahnisch, Adv. Synth. Catal., 2004, 346, 1407.
16 For a discussion of alternative mechanistic possibilities including
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ger oxidants, IIII compounds, see: N. R. Deprez and M. S. Sanford,
Inorg. Chem., 2007, 46, 1924.
Scheme 3 Two plausible mechanisms for the reaction in eqn (2).
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