Insights into the mechanistic and synthetic aspects of the Mo/P-catalyzed oxidation of N-heterocycles

Article abstract of DOI:10.1039/c4ob00115j

A Mo/P catalytic system for an efficient gram-scale oxidation of a variety of nitrogen heterocycles to N-oxides with hydrogen peroxide as terminal oxidant has been investigated. Combined spectroscopic and crystallographic studies point to the tetranuclear Mo₄P peroxo complex as one of the active catalytic species present in the solution. Based on this finding an optimized catalytic system has been developed. The utility and chemoselectivity of the catalytic system has been demonstrated by the synthesis of over 20 heterocyclic N-oxides.

Full text of DOI:10.1039/c4ob00115j

Volume 12 Number 19 21 May 2014 Pages 2981–3138
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
ISSN 1477-0520
PAPER
Oleg V. Larionov et al.
Insights into the mechanistic and synthetic aspects of the Mo/P-catalyzed
oxidation of N-heterocycles

Organic &
Biomolecular Chemistry
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PAPER
Insights into the mechanistic and synthetic aspects
of the Mo/P-catalyzed oxidation of
N-heterocycles†
Cite this: Org. Biomol. Chem., 2014,
2, 3026
1
Oleg V. Larionov,* David Stephens, Adelphe M. Mfuh, Hadi D. Arman,
Anastasia S. Naumova, Gabriel Chavez and Behije Skenderi
A Mo/P catalytic system for an efficient gram-scale oxidation of a variety of nitrogen heterocycles to
N-oxides with hydrogen peroxide as terminal oxidant has been investigated. Combined spectroscopic
Received 15th January 2014,
Accepted 11th March 2014
and crystallographic studies point to the tetranuclear Mo P peroxo complex as one of the active catalytic
4
species present in the solution. Based on this finding an optimized catalytic system has been developed.
DOI: 10.1039/c4ob00115j
The utility and chemoselectivity of the catalytic system has been demonstrated by the synthesis of over
www.rsc.org/obc
20 heterocyclic N-oxides.
Introduction
Heterocyclic N-oxides have significant synthetic value as inter-
1
mediates en route to diversely functionalized N-heterocycles.
2
In particular, recent examples of regioselective C–H-arylation,
3
4
5
as well syntheses of 2-halo 2-amino, and 2-cyano azines con-
stitute an important domain of modern heterocyclic synthesis
(Fig. 1). In addition, N-oxides have been employed as ligands
and catalysts, as synthetic intermediates in the industrial
syntheses of pharmaceuticals (e.g. pranoprofen and omepra-
zole), as well as new pharmacophores in drug discovery. In the
course of studies aimed at development of new reactions of
6
heterocyclic N-oxides we had to prepare multigram quantities
of various compounds of this class. A survey of the literature
showed that current approaches to heterocyclic N-oxides are
largely limited to stoichiometric oxidations by peroxyacids,
either generated in situ from large excess of hydrogen peroxide
7
in acetic or trifluoroacetic acids at elevated temperatures, or
as a commercially available reagent (e.g. meta-chloroperben-
8
zoic acid). Both methods have significant drawbacks. The
in situ method furnishes impure products that have been
9
reported to detonate shortly after isolation. On the other
hand, stable peroxyacids are more expensive and produce
significant amounts of waste. Other less common methods
1
0
include oxidation with dimethyldioxirane (DMDO)
and
Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas,
USA. E-mail: oleg.larionov@utsa.edu; Fax: +1 210 458 7428; Tel: +1 210 458 6050
†
Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. CCDC 981527, 981529, 981530 and 981531. For
ESI and crystallographic data in CIF or other electronic format see DOI:
Fig. 1 Examples of applications of heterocyclic N-oxides in organic
10.1039/c4ob00115j
chemistry and drug discovery.
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11
HOF·MeCN. There is, therefore, an unmet need for inexpensive methods. Furthermore, while oxidations of pyridines have
and environmentally benign methods of azine and azole been studied to some extent, applicability of polyoxometallate
1
2
N-oxide synthesis based on readily available catalysts.
catalysis to the synthesis of N-oxides of five-membered N-hetero-
Herein, we report a combined mechanistic and synthetic study cycles (azoles) has not been investigated. Although, N-methyl-
of the oxidation of a variety of azines and azoles catalyzed by imidazole is known to undergo uncatalyzed oxidation by H O ,
2
2
molybdenum-phosphate catalysts with hydrogen peroxide as a other less electron-rich imidazoles and thiazoles require use of
3
6
terminal oxidant.
such harsh and non-chemoselective reagents as HOF·MeCN
3
7
Catalytic oxidation reactions with hydrogen peroxide as a and peroxyacids at high temperatures. In addition, most of
terminal oxidant have recently gained significant attention the catalytic systems are based on tungsten that has recently
due to their low environmental impact, as well as low cost been implicated as carcinogen. On the other hand, more
3
8
−
1
(
<0.7 USD kg ) and high atom efficiency (47%) of hydrogen environmentally benign molybdenum catalysis of N-oxidation
1
3
peroxide. In addition, such oxidations are generally carried and the mechanistic aspects thereof remain poorly studied.
out under mild conditions, and require less intensive purifi- Early pioneering studies by Griffith, Galindo and Longo indi-
cation, as the only by-product that stems from the oxidant is cate that H O -mediated N-oxidation of pyridine can be cata-
2
2
2 2
water. Most of the produced H O (3.8 million metric tons per lyzed by molybdate either in stoichiometric or in catalytic
1
4
39
year) is currently used for bleaching and detoxification, but fashion, but little is known about the scope and applicability
the number of industrial synthetic processes utilizing this of this catalytic system.
environmentally benign oxidant has been growing at a fast
pace, e.g. hydrogen peroxide is currently used as an oxidant in
3
the multi-ton scale propylene oxidation and caprolactam pro-
Results and discussion
1
5
duction. Although redox potential of H
2
O
2
+
is relatively high
0
−
5
Initial comparison of catalyst performance in acetonitrile at
0 °C with quinoline as a test substrate has revealed that mol-
(
E = 1.76 V for the half-reaction H
2
O
2
+ 2H + 2e → 2H
2
O),
5
most oxidations of typical organic substrates (alcohols, alde-
hydes, alkenes, sulfides, phenols, etc.) by H are slow and
The O–O-acti-
vation can be effected by Brønsted acids via protonation or for-
ybdenum-based catalysts have consistently outperformed other
catalytic systems. Thus, neither triflic nor trifluoroacetic
acids were catalytically active (Table 1). Interestingly, Sc(OTf)
mediated the oxidation, however the conversion was low.
Fe(III), Cu(II), [Ru(p-cumene)Cl]2 and Na WO were also
2 2
O
1
3a
require some activation of the O–O-bond.
3
1
6
17
mation of peracids, as well as transition metal catalysts
e.g. Fe, Mn, V, Ti, Mo, Re, W) via formation of highly active
oxo and peroxymetal species. While significant progress has
been achieved in the catalytic hydrogen peroxide-mediated oxi-
(
2
4
catalytically inactive. On the other hand, Mimoun’s catalyst,
1
8
19
20
dations of alkenes,
sulfides
and alcohols,
including
a
2
1
Table 1 Catalytic N-oxidation of quinoline
asymmetric modifications, other less readily oxidizable sub-
strates, such as N-heterocycles, have generally been prepared
using stronger oxidants, in part due to substantially higher oxi-
2
2
0
dation potentials (e.g. E = 1.41 V for pyridine N-oxide/pyri-
2
3
24
dine, versus 0.16 V for (CH
catalytic H -based methods include methyltrioxorhenium
MTO)-catalyzed oxidation of azines developed by Sharpless,
3 2 3 2
) SO/(CH ) S ). Examples of
2 2
O
2
5
(
Solvent
(temperature/°C)
2
6
27
Entry
Catalyst (x mol%)
Yield(%)
and Mn(TCDPP)Cl -catalyzed reaction reported by Mansuy.
However, methyltrioxorhenium is expensive and undergoes
Re–C bond cleavage that leads to a decrease in the catalytic
activity and prevents catalyst recycling. On the other hand,
Mn(TCDPP)Cl is not commercially available and can only be
1
2
3
4
5
6
7
8
9
—
—
CH CN (50)
3
0
0
0
0
13
0
0
0
0
22
19
33
13
14
16
39
95
97
99
C H OH (50)
2
5
CF
3
SO
CO
SCF
FeCl (10)
3
H (10)
H (10)
(10)
CH
CH
CH
3
3
3
CN (50)
CN (50)
CN (50)
CF
3
2
Sc(O
3
)
3 3
2
8
prepared in low yields. Hence, more recent approaches have
3
CH CN (50)
3
2
9
CuCl
[Ru(p-cumene)Cl]
Na WO (10)
Mo(O ) O·HMPA (10)
MoO
Na MoO
MoO Cl
2
2
(10)
CH
CH
CH
3
CN (50)
3
CN (50)
3
CN (50)
focused on polyoxometallates as catalysts for the oxidation of
pyridines by H . Some of the catalysts studied include
Na [(WZn (H O) ][(ZnW O ) ],
2
(10)
2 2
O
2
4
3
0
various mixed W/V/Mo- 10
CH CN (50)
1
2
3
2
2
9
34 2
2 2
(10)
3
3
1
32
1
12
1
1
3
CH
CH
CH
3
CN (50)
3
CN (50)
3
CN (50)
based heteropolyacids,
M
8
[BW11
(CH
Notwithstanding this progress, significant 14
O
39H] (M = K or R
4
N),
3
3
34
2
4
(10)
(10)
Δ-Na
K [PW V O ].
8
HPW
9
O
34
3
,
[(C18
H
37
)
2
3 2 7
) N] [PW11O39],
and
3
2
5
6
9
3
40
Mo(CO) (10)
(NH
6
3
CH CN (50)
15
16
17
4
)
2
Mo
7
O
40 (10)
40 (10)
24 (10)
CH
C H
2 5
3
CN (50)
OH (50)
CN (70)
CH CN (50)
problems remain unaddressed. Thus, the synthetic utility and
the scope of these catalytic systems have not been assessed,
and practical procedures amenable to multi-gram preparation 18
H
H
3
PMo12
O
O
3
PMo12
CH
3
b
3
H PMo12O40 (1)
3
1
9
H
3
PMo12O40 (0.5)
3
CH CN (50)
of heterocyclic N-oxides have not been described. These
deficiencies may have contributed to the persistence of the
a
Reaction conditions: csubstrate = 1 mol L−1, except if stated otherwise;
b
−1
substrate = 2 mol L .
less efficient and less environmentally benign N-oxidation 30% aqueous H
O
2 2
.
c
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0
a
oxodiperoxymolybdenum(VI) HMPA complex, provided an Table 2 Substrate scope of the catalytic oxidation of N-heterocycles
encouraging result with 22% yield of quinoline N-oxide 2. Sub-
sequent investigation of catalytic activities of other molyb-
denum compounds has shown that sodium molybdate,
molybdenum(VI) oxide, or several other molybdenum com-
pounds did not offer substantial improvements in catalytic
efficiency. Phosphomolybdic acid, on the contrary, has lead to
clean conversion of 1 to quinoline N-oxide.
Encouragingly, the amount of the phosphomolybdic acid
can be reduced to 0.5 mol% without jeopardizing the yield.
Acetonitrile proved to be the solvent of choice, as neither alco-
hols (ethanol, methanol) nor water led to any improvement.
4
1
Freshly prepared
phosphomolybdic acid has exhibited
higher catalytic activity than a commercially available solution
in ethanol.
With these results we have set out to investigate the scope
of the catalytic process (Table 2).
A variety of substituted quinolines, including 8-hydroxyqui-
4
2
noline, that is prone to phenolic oxidation, have undergone
a smooth and chemoselective transformation to the corres-
ponding N-oxides. Similarly, substituted pyridines are also
viable substrates for the reaction. Less easily oxidizable tri-
cyclic systems, such as phenanthridine and 1,10-phenanthro-
line, readily undergo N-oxidation under these conditions as
well.
In addition, pyrimidine and quinoxaline have furnished the
corresponding N-oxides in high yields. Thiazole undergoes
efficient oxidation, thus eliminating the necessity of using
harsh oxidation conditions, such as HOF·MeCN. In none of
the cases have we observed benzylic oxidation of α-alkyl substi-
tuents. Advantageously, phenols and benzylic alcohols have
also proved resistant to this N-oxidation method. The isolation
of the products is generally accomplished by treatment of the
reaction mixture with aqueous ammonium chloride or manga-
nese dioxide, if aqueous work-up has to be avoided. This oxi-
dation has been routinely performed on gram-scale. Thus,
quinoline N-oxide was prepared on a 10 g scale, and 2-phenyl-
quinoline was oxidized on a 5 g scale. The oxidation reactions
of less reactive substrates proceeded at slower rates than with
quinoline, but could be brought to completion by using
additional amounts of hydrogen peroxide and the catalyst
a
c
b
0
2
.5 mol% catalyst, 1.5 equiv. H
2
O
2
.
1 mol% catalyst, 1.5 equiv. H
2 2
O .
d
mol% catalyst, 3 equiv. H
2 2
O .
3 mol% catalyst, 4.5 equiv. H
2 2
O .
(Table 2).
In an effort to characterize molybdenum-containing peroxo
complexes with heterocyclic N-oxides that can be produced
under the reaction conditions, we have studied products
3
formed in a reaction of heterocyclic N-oxides with MoO ,
hydrogen peroxide and phosphoric acid. Several new peroxo
complexes have been isolated and characterized by means of
single crystal X-ray crystallography (Fig. 2). Thus, two com-
2
plexes 26 and 27 of the type [Mo(η -O ) O]L with quinoline
2
2
2
N-oxide and 4-methylquinoline-N-oxide as monodentate
ligands L, as well as chelate 28 with 2,2′-dipyridyl-N-oxide as a
bidentate ligand (Fig. 2 and 3) exhibit several noteworthy struc-
tural features. The coordination polyhedron of the molyb-
denum atom in 26–28 (Fig. 3a and c) can be described as a
2
pseudotrigonal bipyramid with two η -peroxo ligands in the Fig. 2 Oxo diperoxo Mo(VI) complexes 26–29.
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2
Fig. 3 (a) Molecular structure of (quinoline-N-oxide)
2
[Mo(η -O
2
)
2
O] 26 in the crystal. (b) Two-dimensional hydrogen-bonded layer resulting from
the interlinking of hydrogen-bonding chains in the crystal of 26·H
2
O, viewed down the c-axis. (c) Molecular structure of (4-methylquinoline-N-
2
oxide)
of (κN,κO-2,2’-dipyridyl-N-oxide)[Mo(η -O
structure of (4-methoxyquinoline-N-oxide)·H
2 2 2
[Mo(η -O ) O] 27. (d) Extended chains formed by π–π interactions between molecules of 27, viewed down the b-axis. (e) Molecular structure
2
2 2
) O] 28. (f) Hydrogen-bonded chain of centrosymmetric dimers of 28 viewed down the b-axis. (g) X-ray
2
3
2 2 4
P[OMo(η -O ) O] 29. Thermal ellipsoids are at 50% probability.
equatorial plane and the oxo ligand occupying one of the axial chain which propagates along the b-axis. These chains are
positions. The Mo–O bonds of the Mo–L units trans to the oxo linked to one another through a weak C–H⋯O interaction
ligands in 26 and 27 are consistently longer then the Mo–O between the quinoline moiety in the Mo complex, and the
bonds of the cis ligands due to the trans effect of the oxo ligand water molecule extending along the a-axis. This weak inter-
and in line with the previous observations for the structurally action results in the formation of a 2D hydrogen-bonded layer
39
similar pyridine-N-oxide complex. It is interesting that the (Fig. 3b). In the case of 27 the asymmetric unit comprises the
difference in the lengths of the Mo–Otrans and Mo–Ocis bonds is Mo complex (Fig. 4d). There are no hydrogen-bonding inter-
larger (0.143 Å) for complex 26 (with quinoline-N-oxide) then for actions present due to the absence of a water molecule in the
the pyridine-N-oxide complex reported by Griffith (0.131 Å), but crystal lattice. The packing is dominated by π–π interactions
smaller (0.073 Å) for 27 (with 4-methylquinoline-N-oxide). The (3.53 Å) between 4-methylquinoline moieties which result in
crystals of complexes 26 and 27 are not isostructural. For 26 the the formation of centrosymmetric dimers.
asymmetric unit consists of the complex and a water molecule
These 4-methylquinoline moieties are involved in other π–π
(Fig. 3b). The solvent molecule plays a vital role in the packing interactions (3.61 Å), which link these dimers and form
of this structure by forming strong hydrogen bonds between the extended chains along the c-axis (Fig. 3d). In the structure of
peroxo and the N-oxide ligands of interlinked complexes. These compound 28 the dipyridyl-N-oxide ligand is coordinated to
strong hydrogen bonds result in an extended hydrogen-bonded the Mo atom in a bidentate chelating (N, O) mode (Fig. 3e).
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Fig. 4 (a) Comparison of the P NMR spectra of phosphomolybdic acid in the presence of hydrogen peroxide and during oxidation reaction with
quinoline. (b) Comparison of rates of N-oxidation of quinoline with H (4 equiv.) at 50 °C in acetonitrile in the presence of: 5 mol% of MoO
(Mo/P ratio 4 : 1, red); 5 mol% of MoO –2.5 mol% H PO (Mo/P ratio 2 : 1, green); and 1.25 mol%
} (purple). (c) Dependence of relative reaction rates of N-oxidation of 1 on the pH of the reaction medium in
–1.25 mol% H PO (Mo/P ratio 4 : 1) as a catalyst.
2
O
2
3
(
[
blue); 5 mol% of MoO
3
–1.25 mol% H
3
PO
4
3
3
4
2
(C12 (CH N] {P[OMo(η -O ) O]
H
25
)
2
3
)
2
3
2 2 4
the presence of 5 mol% of MoO
3
3
4
The axial position in the pseudotrigonal bipyramid is occupied not go to completion, faster conversion was observed with the
by the O(1) atom of the N-oxide, and the N(2) atom of the other three catalytic systems. More importantly, both 4 : 1 and
pyridyl moiety is located in the equatorial position. The asym- 2 : 1 MoO
metric unit in the crystal of 28 is made up of the Mo complex {P[OMo(η -O ) O] } exhibited similar catalytic behavior, faster
3
–H
3
PO
4 25 2 3 2 3
catalytic systems, and [(C12H ) (CH ) N] -
2
2
2
4
(Fig. 3f). The packing is dominated by centrosymmetric reaction and achieved >90% conversions within 16 h. It is
dimers through C–H⋯O hydrogen bonding interactions. These interesting that no acceleration was observed when phosphoric
dimers are linked to one another through another weaker C– acid was replaced with boric acid (H BO ), sulfuric acid, sel-
3
3
H⋯O interaction that results in the formation of hydrogen- enium dioxide, or silicic acid (H SiO ) confirming the impor-
4
4
bonded chains. Interestingly, treatment of 4-methoxyquino- tant role of Mo/P complexes in the catalytic cycle.
line-N-oxide with MoO , H O and phosphoric acid led to a for- We have also studied the influence of the pH of the reaction
mation of an adduct of the N-oxide and the tetranuclear media on the reaction rate with 5 mol% of MoO –1.25 mol%
3
2 2
3
2
complex H
3
P[OMo(η -O
2
)
2
O]
4
29. Crystal structures of com-
3 4
H PO (Mo/P ratio 4 : 1) as a catalyst (Fig. 4c). It was observed
pounds containing this PMo4 cluster are exceedingly rare – that the highest reaction rate is achieved at pH 7. The oxi-
only one X-ray structure had been reported in the CCDC data- dation is much slower at lower pH and no reaction is observed
4
3
base to date. The Mo complex and the uncoordinated below pH 2.5, presumably due to protonation of the substrate.
N-oxide ligand occupy the asymmetric unit (Fig. 3g). The phos- However, an even more rapid decline in reaction rates is
phorus atom is situated on a fourfold axis. The hydrogen atom observed between pH 7 and 8. It is possible that the catalytic
that is located on the hydroxide coordinated to molybdenum species that were active below pH 7.5 are unstable at higher
is disordered, only occupying three of the four symmetry pH. Subsequent increase in reaction rates between pH 8 and
related hydroxide ions at any given time. There were no major 9.5 may be due to formation of oxo diperoxo Mo complexes
−
long range interactions present in the packing of this complex. similar to 26 and 27 with L = OH . A rapid deceleration at pH
In order to further optimize the reaction and to investigate > 9.5 may, on the other hand, be due to the accelerated hydro-
the mechanism we have carried out several spectroscopic and lysis of acetonitrile that is mediated by hydroperoxide
3
1
44
kinetic experiments. The P NMR spectroscopic studies of anions.
phosphomolybdic acid (PMA) in the presence of hydrogen per- The influence of the PvO ligands on the reactivity of the
oxide and during the oxidation reaction with quinoline as a Mo catalyst was studied next (Table 3). The catalytic perform-
substrate (Fig. 4a) suggest that PMA dissociates and forms ance of the phosphoric acid-based system generally exceeded
3
−
several phosphorus-containing species. One of them has been that of phosphine oxides, considering that PO4 ligand can
2
3−
identified as P[OMo(η -O
2
)
2
O]
4
with δ 6.0 ppm, which was coordinate up to 4 Mo atoms, and thus a 4 : 1 ratio of M : L can
confirmed by comparison with the NMR data of several qua- be used. Electron rich monophosphine oxides were found to
ternary ammonium salts with this anion synthesized accord- be better ligands (entries 2–6), with tris(p-fluorophenyl)phos-
4
3
ing to the reported procedure. Guided by the indications phine oxide emerging as the best ligand in the set (entry 4).
from our spectroscopic and crystallographic studies that the Steric hindrance on the other hand was detrimental to the
tetranuclear PMo4 complex can be a key catalytic species in catalyst performance, as evidenced by the low activity of the
the N-oxidation, we have compared the catalytic performance tris(o-tolyl)phosphine oxide system (entry 7). Both triaryl-,
of MoO
3
with that of catalytic systems composed of trialkyl-, and triaminophosphine oxides were affective ligands
MoO –H PO in 4 : 1 and 2 : 1 ratios, as well as preformed (entries 2–6, 9, 10). Interestingly, chelating bisphosphine
3
3
4
2
[(C12
H
25
)
2
(CH
3
)
2
N]
3
{P[OMo(η -O
2 2 4
) O] } (Fig. 4b). While the oxides proved far inferior to monophosphine oxides (entries
reaction catalyzed by MoO
3
proved to be relatively slow and did 11–13), presumably due to increased steric hindrance around
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Table 3 Influence of the phosphine oxide ligands on the catalyst per-
a
formance in the N-oxidation of 1
Entry
Ligand
TON
b
1
H
3
PO
Ph PO
(p-FC
[3,5-(CF
Me PhPO
tBuPh PO
(o-Tol) PO
o-C (PPh
Et PO
(Me N)
4
11
12
2
3
4
5
6
7
8
9
0
1
2
3
3
6
H
4
)
3
PO
14.6
6.9
7.5
8.9
1.8
1
12.9
8.1
3.9
2.2
2.1
3 2 6 3 3
) C H ] PO
2
2
3
6
H
4
2 2
O)
3
1
1
1
1
2
3
PO
c
c
c
dppe-dioxide
dppm-dioxide
binap-dioxide
Scheme 1 Synthesis of biorelevant heterocyclic N-oxides 30–32.
a
Reaction conditions: 1 (1.4 mmol), MoO
CN (1 mL), H (30% aq. solution, 4 equiv.), 50 °C, 4 h. O system, whereas Mo/P catalysis afforded the product in an
.25 mol% H PO
ethane, dppm = bis(diphenylphosphino)methane, binap = 2,2′-bis-
3
(5 mol%), ligand (5 mol%)
4
6
CH
3
2 2
O
2
b
c
1
3
4
was used. dppe = 1,2-bis(diphenylphosphino)-
8
9% yield.
(diphenylphosphino)-1,1′-binaphthyl.
Conclusions
2
the η -O ligands, and in line with the similar negative effect In conclusion, synthetic scope and the mechanism of the mol-
2
in the monophosphine oxide series.
ybdenum(VI)-catalyzed N-oxidation of N-heterocycles have been
Based on the aforementioned observations it is therefore investigated. The reaction exhibits high chemoselectivity and
plausible that the Mo P cluster plays a crucial role as an N-oxi- scope with respect to the heterocyclic backbone and is amen-
4
3 3 4
dation catalyst in the MoO –H PO and the PMA systems. able to gram-scale preparations of various heterocyclic
Monomeric Mo/P catalytic species may also contribute to the N-oxides. Thus, thiazoles undergo efficient N-oxidation
overall N-oxidation as evidenced by the results in Table 3. In without the concomitant S-oxidation. Benzylic and phenolic
1
this case complexes of type 26 with L position occupied by oxidations can also be avoided by using this catalytic system.
2
OvPR
3
and L position occupied by a labile pendant ligand, Single crystal X-ray crystallographic studies provided insights
e.g. solvent or the N-oxide product, may act as active catalysts. into the structure of Mo complexes relevant to the catalytic
1
2
Complexes with both L and L positions occupied by OvPR
3
cycle and the role of the PvO ligand on the catalyst activity.
possibly have a very low catalytic activity due to steric hin- Further experimental evidence points to the influence of the
drance, as evidenced by the results with bidentate bispho- steric and electronic properties of the PvO ligands on the cat-
sphine dioxides.
alytic activity.
Heterocyclic N-oxides are emerging new scaffolds in drug
discovery, as exemplified by the structures of the direct Factor
Xa inhibitor otamixaban, CCR5 inhibitor ancriviroc, sedative/
hypnotic chlordiazepoxide and reverse transcriptase inhibitor
BILR 355. Heterocyclic N-oxides are also known to be metabo-
lites of various pharmaceuticals and agrochemicals.
Experimental section
General methods
Anhydrous dichloromethane, toluene, tetrahydrofuran and
We have employed the developed oxidation procedure for ether were collected under argon from an LC Technologies
the synthesis of several N-oxides of such biologically active solvent purification system, having been passed through two
compounds. Thus, N-oxides of selective fungicide quinoxyfen columns packed with molecular sieves. Acetonitrile, ethanol,
(Quintec) 30, as well antimicrobial drugs chlorquinaldol 31 and methanol were dried over 4 Å molecular sieves. All other
and cloxyquin 32 have been prepared in high yields using the chemicals were used as commercially available (Sigma-Aldrich,
optimized 5 mol% MoO
3
–1.25 mol% H
3
PO
4
as a catalyst Acros, Alfa Aesar, Combi-Blocks, Strem). Reactions were moni-
glass plates (Merck Kieselgel 60 F254). Plates were visualized
(Scheme 1). In addition 4-cyanopyridine-N-oxide (33) was pre- tored by TLC until deemed complete using silica gel-coated
pared (86% yield) using this catalytic system.
The Mo/P-catalyzed N-oxidation provided improved yields under ultraviolet light (254 nm). Column chromatography was
of the heterocyclic N-oxides when compared with other performed using CombiFlash Rf-200 (Teledyne-Isco) auto-
methods for some substrates. Thus, N-oxide 4 was previously mated flash chromatography system with RediSep columns.
4
5
1
13
1
prepared in 34% yield using m-chloroperbenzoic acid, while
H, C NMR spectra were recorded at 300 and 500 ( H), and
1% was observed using PMA as a catalyst. Similarly, N-oxide 75.5 and 125 MHz on Varian Mercury VX 300 and Agilent
was prepared in 82% using surfactant-encapsulated Inova 500 instruments in CDCl3 solutions if not otherwise
6
2
[
2
32b
37 2 3 2 8
(C18H ) (CH ) N] [HBW11O39],
and 79% with the Fe(acac)
3
/
specified. Chemical shifts (δ) are reported in parts per million
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1
3
(
(
ppm) from the residual solvent peak and coupling constants 1, 8 Hz), 8.14 (1 H, dd, J = 1.5, 5 Hz) ppm. – C NMR
J) in Hz. Infrared measurements were carried out neat on a (125 MHz): 122.64, 128.12, 138.53, 141.96, 150.04 ppm. – IR:
Bruker Vector 22 FT-IR spectrometer fitted with a Specac 1042, 1270, 1414, 1560, 2998, 3049 cm−
1
.
diamond attenuated total reflectance (ATR) module. Com-
pounds 26–29 have been assigned the following CCDC 6-bromo-2-pentylquinoline (38 mg, 0.137 mmol) was reacted
6-Bromo-2-pentylquinoline 1-oxide (6). According to GP1,
1
3
numbers: 26 (CCDC 981527), 27 (CCDC 981529), 28 (CCDC with hydrogen peroxide (41 μL, 0.411 mmol, 3 equiv., 30% in
9
81530), 29 (CCDC 981531).
H
2
O) and phosphomolybdic acid (25 μL, 0.002 mmol, 2 mol%,
2
0% in EtOH) in acetonitrile (100 μL). The isolated product
General procedure (GP1) for N-oxidation catalyzed by PMA or
1
afforded 6 (25 mg, 62%) as a brown oil. – H NMR (500 MHz):
.93 (3 H, t, J = 7 Hz), 1.37–1.48 (4 H, m), 1.82 (2 H, quin., J =
7 Hz), 3.10 (2 H, t, J = 8 Hz), 7.32 (1 H, d, J = 8.5 Hz), 7.56 (1 H,
substrate) was added hydrogen peroxide (1.5–3 equiv., 30% in d, J = 8.5 Hz), 7.80 (1 H, dd, J = 2, 9 Hz), 7.99 (1 H, d, J = 2 Hz),
MoO –H PO
4
3
3
0
To a solution of azine or azole in acetonitrile (0.5 mL mmol−
1
1
3
water) and phosphomolybdic acid (0.5–3 mol%) or MoO
3
8.66 (1 H, d, J = 9.5 Hz) ppm. – C NMR (125 MHz): 13.99,
(
5 mol%) H PO (4 w/w solution in water, 1.25 mol%) at 50 °C. 22.47, 25.65, 31.45, 31.77, 121.80, 122.03, 123.13, 123.71,
3
4
After 12 h the reaction was diluted with saturated aqueous 129.87, 130.19, 133.48, 130.52, 139.68 ppm. – IR: 1064, 1179,
−
1
−1
ammonium chloride (0.1 mL mmol substrate) and extracted 1336, 1449, 1504, 2858, 2954, 3064 cm . – MS (ESI): 293.0,
+
with dichloromethane. The combined organic layers were HRMS: calcd: 293.0415; found 294.0542 [M + H ].
dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The crude product was purified by column 2-(hydroxymethyl)pyridine (163 mg, 1.53 mmol) was reacted
4
9
2-(Hydroxymethyl)pyridine 1-oxide (7). According to GP1,
chromatography [hexanes–EtOAc] to yield the desired N-oxide.
with hydrogen peroxide (690 μL, 6.88 mmol, 4.5 equiv., 30% in
O) and phosphomolybdic acid (418 μL, 0.045 mmol, 3 mol%,
0% in EtOH) in acetonitrile (750 μL). The isolated product
H
2
2
General procedure (GP2) for kinetic experiments
1
The reactions were carried out as described in GP1. Reaction afforded 7 (124 mg, 65%) as a yellow oil. – H NMR (500 MHz):
medium pH was adjusted by adding appropriate amounts of 4.78 (2 H, s), 7.24–7.27 (1 H, m), 7.37 (1 H, t, J = 7.5 Hz), 7.45
aqueous HBF or NaOH solutions. Aliquots of reaction mix- (1 H, d, J = 7.5 Hz), 8.23 (1 H, d, J = 6 Hz) ppm. – C NMR
4
1
3
tures were drawn at specified times and the conversions were (125 MHz): 60.55, 124.68, 128.13, 139.36, 150.61, 161.10 ppm.
1
−1
determined by H NMR spectroscopy.
– IR: 1064, 1209, 1437, 1491, 1559, 1653, 3049, 3216 cm .
5
0
Quinoxaline 1-oxide (8). According to GP1, quinoxaline
200 mg, 1.53 mmol) was reacted with hydrogen peroxide
Experimental procedures and spectroscopic data
(
3
8
-Methoxyquinoline 1-oxide (3). According to GP1, S1 (230 μL, 2.29 mmol, 1.5 equiv., 30% in H
2
O) and phosphomo-
(
(
340 mg, 2.12 mmol) was reacted with hydrogen peroxide lybdic acid (140 μL, 0.015 mmol, 2 mol%, 20% in EtOH) in
313 μL, 3.18 mmol, 1.5 equiv., 30% in H O) and phosphomo- acetonitrile (700 μL). The isolated product afforded 8 (210 mg,
2
1
lybdic acid (197 μL, 0.21 mmol, 1 mol%, 20% in EtOH) in 94%) as a red solid. – m.p.: 152–155 °C16 – H NMR
acetonitrile (1 mL). The product was isolated to yield oxide 3 (300 MHz): 7.33 (2 H, d, J = 6.5 Hz), 8.18 (2 H, d, J = 5.5 Hz),
1
13
(260 mg, 71%) as a brown solid. – m.p.: 38–41 °C – H NMR 8.45 (2 H, s) ppm. – C NMR (75 MHz): 124.70, 125.86, 126.90,
(
300 MHz): 3.92 (3 H, s), 6.88 (1 H, dd, J = 1.5, 8 Hz), 7.20–7.40 129.37, 135.10, 137.58, 140.36, 149.90 ppm. – IR: 1000, 1169,
−
1
(4 H, m), 7.96 (1 H, dd, J = 1.5, 8 Hz), 8.78 (1 H, dd, J = 1.5, 1305, 1457, 1565, 2990, 3269 cm .
1
3
51
4
1
1
Hz) ppm. – C NMR (75 MHz): 55.84, 107.57, 119.42, 121.57,
Thiazole 3-oxide (9). According to GP1, thiazole (130 mg,
26.72, 129.19, 136.07, 139.66, 148.89, 155.02 ppm. – IR: 910, 1.53 mmol) was reacted with hydrogen peroxide (460 μL,
−
1
090, 1232, 1378, 1467, 1504, 2858, 2954, 3037 cm
Pyrimidine 1-oxide
.
4.59 mmol, 3 equiv., 30% in H
(4). According to GP1, pyrimidine (280 μL, 0.03 mmol, 2 mol%, 20% in EtOH) in acetonitrile
80 mg, 1 mmol) was reacted with hydrogen peroxide (150 μL, (750 μL). The isolated product afforded 9 (96 mg, 62%) as a
2
O) and phosphomolybdic acid
4
7
(
1
(
(
1
.5 mmol, 1.5 equiv., 30% in H
2
O) and phosphomolybdic acid colorless oil. – H NMR (500 MHz): 7.40 (1 H, s), 7.94 (1 H, s),
91 μL, 0.01 mmol, 2 mol%, 20% in EtOH) in acetonitrile 8.86 (1 H, s) ppm. – C NMR (125 MHz): 118.87, 143.28,
500 μL). The isolated product afforded 4 (59 mg, 61%) as a 153.09 ppm. – IR: 909, 1106, 123, 1414, 1560, 3028, 3049 cm
1
3
−1
.
1
52
brown oil. – H NMR (300 MHz): 7.33 (1 H, s), 8.27 (1 H, dd, J =
3,4-Dimethylpyridine 1-oxide (10). According to GP1, 3,4-
0
.5, 2.5 Hz), 8.40 (1 H, d, J = 4 Hz), 9.01 (1 H, s) ppm. – lutidine (500 mg, 4.67 mmol) was reacted with hydrogen per-
1
3
C NMR (75 MHz): 121.23, 144.00, 144.35, 149.94 ppm. – IR: oxide (702 μL, 7 mmol, 1.5 equiv., 30% in H
2
O) and phospho-
molybdic acid (430 μL, 0.046 mmol, 1 mol%, 20% in EtOH) in
-Bromopyridine 1-oxide (5). According to GP1, 2-bromo- acetonitrile (650 μL). The isolated product afforded 10
pyridine (241 mg, 1.53 mmol) was reacted with hydrogen per- (480 mg, 84%) as a colorless solid. – m.p.: 126–128 °C21 –
−1
1
064, 1179, 1244, 1423, 2958, 2954, 3037 cm .
4
8
2
1
oxide (460 μL, 4.59 mmol, 3 equiv., 30% in H
phosphomolybdic acid (279 μL, 0.03 mmol, 2 mol%, 20% in 6.5 Hz), 7.97 (1 H, d, J = 6.5 Hz), 8.02 (1 H, s) ppm. – C NMR
2
O) and
H NMR (300 MHz): 2.19 (3 H, s), 2.23 (3 H, s), 7.01 (1 H, d, J =
1
3
EtOH) in acetonitrile (700 μL). The isolated product afforded 5 (75 MHz): 16.81, 18.40, 126.57, 135.49, 136.24, 137.41,
1
(
249 mg, 95%) as a brown oil. – H NMR (500 MHz): 7.06 (1 H, 138.73 ppm. – IR: 910, 1090, 1209, 1394, 1449, 1554, 2857,
dd, J = 4.5, 7.5 Hz), 7.26 (1 H, dd, J = 1, 8 Hz), 7.36 (1 H, dt, J = 2931, 3135 cm−
1
.
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5
3
56
Phenanthridine 5-oxide (11). According to GP1, phenan-
thridine (50 mg, 0.279 mmol) was reacted with hydrogen per- lutidine (163 mg, 1.53 mmol) was reacted with hydrogen per-
oxide (83 μL, 0.837 mmol, 3 equiv., 30% in H O) and oxide (690 μL, 6.88 mmol, 4.5 equiv., 30% in H O) and phos-
2,3-Dimethylpyridine 1-oxide (17). According to GP1, 2,3-
2
2
phosphomolybdic acid (25 μL, 0.005 mmol, 2 mol%, 20% in phomolybdic acid (418 μL, 0.045 mmol, 3 mol%, 20% in
EtOH) in acetonitrile (200 μL). The isolated product afforded EtOH) in acetonitrile (750 μL). The isolated product afforded
1
1
1
7
9
1
1
1
1 (41 mg, 76%) as a brown oil. – H NMR (500 MHz): 17 (141 mg, 75%) as a yellow oil. – H NMR (500 MHz): 1.91 (3
.25–8.09 (5 H, m), 8.53–8.63 (2 H, m), 8.97 (1 H, d, J = 2 Hz), H, s), 2.05 (3 H, s), 6.65–6.72 (2 H, m), 7.71 (1 H, d, J = 6.5 Hz)
.19 (1 H, d, J = 2 Hz) ppm. – C NMR (125 MHz): 120.67, ppm. – C NMR (75 MHz): 13.21, 18.95, 122.00, 131.86,
1
3
13
22.13, 122.77, 127.06, 128.18, 128.99, 129.53, 129.71, 129.91, 137.84, 144.81, 155.96 ppm. – IR: 1018, 1260, 1457, 1540, 2961,
30.15, 130.46, 133.83, 169.27 ppm. – IR: 1071, 1191, 1473, 3026 cm−
1
.
559, 1647, 3071 cm−
4
1
.
6-Bromoquinoline 1-oxide (18). According to GP1, 6-
3
4
8
-Phenylpyridine 1-oxide
(12). According to GP1, 4- bromoquinoline (50 mg, 0.24 mmol) was reacted with hydro-
2
phenylpyridine (237 mg, 1.53 mmol) was reacted with hydro- gen peroxide (36 μL, 0.36 mmol, 1.5 equiv., 30% in H O) and
gen peroxide (460 μL, 4.59 mmol, 3 equiv., 30% in H O) and phosphomolybdic acid (20 μL, 0.002 mmol, 2 mol%, 20% in
2
phosphomolybdic acid (280 μL, 0.03 mmol, 2 mol%, 20% in EtOH) in acetonitrile (100 μL). The isolated product afforded
1
EtOH) in acetonitrile (750 μL). The isolated product afforded 18 (41 mg, 77%) as a red solid. – m.p.: 110–112 °C – H NMR
1
1
(
1
2 (220 mg, 84%) as a red oil. – H NMR (500 MHz): 7.43–7.67 (300 MHz): 7.31 (1 H, dd, J = 1, 2.5 Hz), 7.63 (1 H, d, J =
1
3
5 H, m), 8.29 (4 H, dd, J = 6 Hz) ppm. – C NMR (125 MHz): 8.5 Hz), 7.79 (1 H, dd, J = 2, 9.5 Hz), 8.02 (1 H, d, J = 2 Hz),
15.58, 123.81, 126.50, 129.39, 129.46, 139.37, 157.21 ppm. – 8.52 (1 H, d, J = 6 Hz), 6.60 (1 H, d, J = 9.5 Hz) ppm. – C NMR
IR: 1043, 1236, 1430, 1592, 2981, 3053 cm
1
3
−
1
.
(75 MHz): 121.72, 122.19, 123.29, 124.98, 130.08, 131.57,
3
4
-Methoxyquinoline 1-oxide (13). According to GP1, 4- 133.83, 135.90, 140.25 ppm. – IR: 1143, 1266, 1421, 1569, 2999,
methoxyquinoline (2.76 g, 17.36 mmol) was reacted with 3026 cm−
hydrogen peroxide (5.3 mL, 52.07 mmol, 3 equiv., 30% in H O) 2-Phenylpyridine 1-oxide
and phosphomolybdic acid (3.16 mL, 0.34 mmol, 2 mol%, phenylpyridine (200 mg, 1.29 mmol) was reacted with hydro-
0% in EtOH) in acetonitrile (9 mL). The isolated product gen peroxide (418 μL, 4.17 mmol, 3 equiv., 30% in H O) and
afforded 13 (2.14 g, 71%) as a red oil. – H NMR (500 MHz): phosphomolybdic acid (235 μL, 0.25 mmol, 2 mol%, 20% in
1
.
4
8
(19). According to GP1, 2-
2
2
2
1
4
7
.00 (3 H, s), 6.74 (1 H, d, J = 6.5 Hz), 7.48 (1 H, dt, J = 1, 7 Hz), EtOH) in acetonitrile (650 μL). The isolated product afforded
.68 (1 H, dt, J = 1, 7 Hz), 8.08 (1 H, d, J = 8.5 Hz), 8.14 (1 H, 19 (210 mg, 78%) as a colorless solid. – m.p.: 150–152 °C12
13
1
dd, J = 1, 8.5 Hz), 8.73 (1 H, d, J = 4.5 Hz) ppm. – C NMR – H NMR (300 MHz): 7.21–7.31 (2 H, m), 7.40–7.49 (4 H, m),
(
1
2
125 MHz): 56.09, 121.96, 122.63, 126.15, 127.31, 128.27, 7.80 (2 H, dd, J = 2.5, 5.5 Hz), 8.32 (1 H, d, J = 5.5 Hz) ppm. –
1
3
30.56, 131.13, 150.11, 163.42 ppm. – IR: 1156, 1394, 1507,
C NMR (75 MHz): 124.51, 125.76, 127.38, 128.27, 129.25,
129.58, 132.59, 140.39, 149.25 ppm. – IR: 995, 1073, 1158,
999, 3125 cm−
1
.
5
4
−1
4
,7-Dichloroquinoline 1-oxide (14). According to GP1, 4,7- 1259, 1416, 1476, 2925, 3032 cm
.
dichloroquinoline (2 g, 10.2 mmol) was reacted with hydrogen
7-Chloro-4-methoxyquinoline 1-oxide (20). According to
peroxide (1.55 mL, 15.30 mmol, 1.5 equiv., 30% in H O) and GP1, S3 (1.6 g, 5.54 mmol) was reacted with hydrogen peroxide
2
phosphomolybdic acid (930 μL, 0.102 mmol, 1 mol%, 20% in (1.7 mL, 16.62 mmol, 3 equiv., 30% in H
2
O) and phosphomo-
EtOH) in acetonitrile (5 mL). The isolated product afforded 14 lybdic acid (1 mL, 0.118 mmol, 2 mol%, 20% in EtOH) in
2
4
1
(
(
1.9 g, 88%) as a tan solid. – m.p.: 164–165 °C – H NMR acetonitrile (2.5 mL). The isolated product afforded 20 (1.12 g,
1
500 MHz): 7.36 (1 H, d, J = 6.5 Hz), 7.68 (1 H, d, J = 9 Hz), 8.13 97%) as a colorless solid. – m.p.: 145–147 °C – H NMR
(
1 H, d, J = 9 Hz), 8.43 (1 H, d, J = 6.5 Hz), 8.77 (1 H, s) ppm. (500 MHz): 4.06 (3 H, s), 6.64 (1 H, d, J = 7 Hz), 7.59 (1 H, d, J =
1
3
–
1
1
3
C NMR (125 MHz): 119.93, 121.22, 121.42, 125.60, 126.52, 2 Hz), 8.15 (1 H, d, J = 9 Hz), 8.46 (1 H, d, J = 7 Hz), 8.77 (1 H,
1
3
26.75, 128.68, 129.85, 130.80, 135.96, 138.22, 142.33, d, J = 2 Hz) ppm. – C NMR (125 MHz): 56.34, 99.84, 119.57,
50.88 ppm. – IR: 829, 1091, 1291, 1367, 1412, 1555, 1609, 120.99, 123.39, 124.28, 129.06, 136.99, 137.88, 154.26 ppm.
025, 3094 cm−
1
1
.
– IR: cm . – MS (ESI): found 212.9. MS (HRMS): calc.
−1
5
5
+
,10-Phenanthroline 1-oxide (16). According to GP1, 1,10- 210.0316, found 213.9937 [M + H ].
5
7
phenanthroline (275 mg, 1.53 mmol) was reacted with hydro-
gen peroxide (690 μL, 6.88 mmol, 4.5 equiv., 30% in H2O) and phenylpyridine (200 mg, 1.29 mmol) was reacted with hydro-
phosphomolybdic acid (418 μL, 0.045 mmol, 3 mol%, 20% in gen peroxide (418 μL, 4.17 mmol, 3 equiv., 30% in H O) and
EtOH) in acetonitrile (750 μL). The isolated product afforded phosphomolybdic acid (235 μL, 0.25 mmol, 2 mol%, 20% in
3-Phenylpyridine 1-oxide
(21). According to GP1, 2-
2
1
1
6 (246 mg, 82%) as a yellow oil. – H NMR (300 MHz): 7.45 EtOH) in acetonitrile (650 μL). The isolated product afforded
(
1 H, t, J = 6.5 Hz), 7.63–7.81 (4, m), 8.22 (1 H, dd, J = 21 (250 mg, 93%) as a colorless solid. – m.p.: 116–118 °C –
1
1
4
1
1
3
.5, 8 Hz), 8.74 (1 H, dd, J = 1, 6.5 Hz), 9.30 (1 H, dd, J = 1.5,
Hz) ppm. – C NMR (75 MHz): 122.85, 123.04, 123.19, 8.5 Hz), 8.34 (1 H, d, J = 3.5 Hz), 8.55 (1 H, dd, J = 1, 8.5 Hz),
H NMR (300 MHz): 7.71–7.84 (5 H, m), 8.11 (1 H, dd, J = 1,
1
3
13
24.64, 126.50, 128.91, 129.04, 133.25, 135.93, 140.75, 149.92, 8.66 (1 H, d, J = 3.5 Hz) ppm. – C NMR (75 MHz): 118.88, 127.95,
50.30 ppm. – IR: 1068, 1249, 1436, 1559, 1653, 2981, 129.24, 129.94, 130.07, 130.24, 131.75, 137.44, 145.92 ppm.
042 cm−
1
.
– IR: 1015, 1131, 1314, 1497, 1575, 1639, 2995, 3079 cm .
−1
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5
8
8
-Hydroxyquinoline 1-oxide
-hydroxyquinoline (221 mg, 1.53 mmol) was reacted with 0.012 mmol, 1.25 mol%) and molybdenum(VI) oxide (7 mg,
hydrogen peroxide (460 μL, 4.59 mmol, 3 equiv., 30% in H O) 0.05 mmol, 5 mol%). The crude reaction mixture was diluted
2
(22). According to GP1, 2.0 mmol, 2 equiv., 30% in H O), phosphoric acid (1.22 mg,
8
2
and phosphomolybdic acid (280 μL, 0.03 mmol, 2 mol%, 20% with saturated aqueous ammonium chloride (5 mL) and
in EtOH) in acetonitrile (750 μL). The isolated product extracted with chloroform (3 × 5 mL), dried over anhydrous
1
afforded 22 (220 mg, 89%) as a red oil. – H NMR (300 MHz): sodium sulfate, and concentrated under reduced pressure to
1
7
8
5
1
1
.05 (1 H, d, J = 5.5 Hz), 7.21–7.27 (2 H, m), 7.48 (1 H, t, J = yield 32 (178 mg, 78%) as a yellow oil. – H NMR (300 MHz):
.5 MHz), 7.80 (1 H, d, J = 8.5 Hz), 8.30 (1 H, dd, J = 0.5, 7.40 (1 H, dd, J = 6, 9 Hz), 7.70 (1 H, s), 8.17 (1 H, d, J = 9 Hz),
.5 Hz) ppm. – C NMR (75 MHz): 115.06, 116.88, 120.41, 8.33 (1 H, d, J = 6 Hz) ppm. – C NMR (75 MHz): 118.89,
28.11, 130.07, 130.60, 134.76, 153.79, 168.71 ppm. – IR: 1047, 118.98, 121.37, 126.96, 128.42, 128.90, 131.39, 135.54,
1
3
13
−
1
153, 1201, 1312, 1436, 1598, 1698, 2950, 3066 cm
4
.
149.68 ppm. – IR: 906, 1068, 1156, 1208, 1320, 1423, 1513,
3
−1
-Methylquinoline 1-oxide (23). According to GP1, lepti- 2995, 3067, 3078 cm
dine (218 mg, 1.53 mmol) was reacted with hydrogen peroxide 4-Cyanopyridine 1-oxide (33). To a solution of 4-cyano-
690 μL, 6.88 mmol, 4.5 equiv., 30% in H O) and phosphomo- pyridine (100 mg, 0.961 mmol) in acetonitrile (500 μL) was
.
5
9
(
2
lybdic acid (418 μL, 0.045 mmol, 3 mol%, 20% in EtOH) in reacted with hydrogen peroxide (150 μL, 1.92 mmol, 2 equiv.),
acetonitrile (750 μL). The isolated product afforded 23 phosphoric acid (1.17 mg, 0.012 mmol, 1.25 mol%) and mol-
1
(
169 mg, 67%) as a brown oil. – H NMR (500 MHz): 2.65 (3 H, ybdenum(VI) oxide (4.5 mg, 0.048 mmol, 5 mol%). The crude
s), 7.11 (1 H, d, J = 6 Hz), 7.66 (1 H, t, J = 7 Hz), 7.76 (1 H, t, J = reaction mixture was diluted with saturated aqueous
7
9
1
–
Hz), 7.96 (1 H, d, J = 7), 8.44 (1 H, d, J = 7 Hz), 8.80 (1 H, t, J = ammonium chloride (5 mL) and extracted with chloroform
1
3
Hz) ppm. – C NMR (125 MHz): 18.38, 120.32, 121.41, (3 × 5 mL), dried over anhydrous sodium sulfate, and concen-
24.73, 128.51, 129.83, 130.18, 135.02, 135.11, 140.86 ppm. trated under reduced pressure to yield 33 (99 mg, 86%) as a
−
1
1
IR: 1058, 1277, 1394, 1473, 1559, 1653, 2949, 3024, 3081 cm
5
.
yellow oil. – H NMR (500 MHz): δ 8.23 (1 H, d, J = 5 Hz), 8.83
6
13
,7-Dichloro-4-(4-fluorophenoxy)quinoline 1-oxide (30). To (2 H, d, J = 8.5 Hz). C NMR (125 MHz): 109.3, 117.8, 130.2,
a solution of quinoxyfen (50 mg, 0.162 mmol) in acetonitrile 140.8 ppm.
80 μL) was reacted with hydrogen peroxide (36 μL,
(
0
0
0
.324 mmol, 2 equiv., 30% in H O), phosphoric acid (0.2 mg,
.002 mmol, 1.25 mol%) and molybdenum(VI) oxide (1 mg,
.008 mmol, 5 mol%). The crude reaction mixture was diluted
2
Acknowledgements
with saturated aqueous ammonium chloride (5 mL) and
extracted with chloroform (3 × 5 mL), dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to
Financial support by the Welch Foundation (AX-1788), the Max
and Minnie Tomerlin Voelcker Fund, the San Antonio Life
Sciences Institute (SALSI) and the University of Texas at San
Antonio is gratefully acknowledged. Mass spectroscopic analy-
sis was supported by a grant from the National Institute on
Minority Health and Health Disparities (G12MD007591).
1
yield 30 (42 mg, 81%) as a yellow oil. – H NMR (500 MHz):
6
1
.57 (1 H, d, J = 6.5 Hz), 7.06–7.12 (4 H, m), 7.63 (1 H, d, J =
.5 Hz), 8.34 (1 H, 6.5 Hz), 8.72 (1 H, s) ppm. – C NMR
13
(125 MHz): 107.70, 117.19 (d, J = 23.5 Hz), 119.26 (d, J = 51 Hz),
1
1
–
1
21.75 (d, J = 8.5 Hz), 128.24, 131.77 (d, J = 74 Hz) 137.03,
43.61, 150.05 (d, J = 2 Hz), 153.01, 158.99, 160.94 ppm.
1
9
F NMR (252 MHz): −116.42 ppm. – IR: 1012, 1091, 1174,
Notes and references
254, 1303, 1415, 1563, 1641, 2988, 3071, 3102 cm−
5
1
.
5
5
,7-Dichloro-8-hydroxy-2-methylquinoline 1-oxide (31). To
solution of 5,7-dichloro-8-hydroxy-2-methylquinoline
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a
(217 mg, 0.961 mmol) in acetonitrile (500 μL) was reacted with
hydrogen peroxide (150 μL, 1.92 mmol, 2 equiv.), phosphoric
acid (1.17 mg, 0.012 mmol, 1.25 mol%) and molybdenum(VI)
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–
1
H NMR (500 MHz): 2.64 (3H, s), 7.32 (1H, d, J = 8.9 Hz), 7.51
1
3
(1H, s), 7.92 (1H, d, J = 8.9 Hz). C NMR (125 MHz): 18.0,
1
18.4, 118.5, 123.6, 125.7, 126.9, 130.0, 130.1, 146.2, 149.3.
−
1
–
IR: 3080, 1535, 1454, 1413 cm
,7-Dichloro-8-hydroxyquinoline 1-oxide (32). To a solution
of 5,7-dichloro-8-quinolinol (214 mg, 1.0 mmol) in acetonitrile
500 μL) was reacted with hydrogen peroxide (225 μL,
.
6
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