Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

Article abstract of DOI:10.3762/bjoc.12.16

The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine. ICP-MS analysis of the purified reaction products revealed that the base metal impurity was well below the regulatory limit.

Full text of DOI:10.3762/bjoc.12.16

Base metal-catalyzed benzylic oxidation of
(aryl)(heteroaryl)methanes with molecular oxygen
Hans Sterckx, Johan De Houwer, Carl Mensch, Wouter Herrebout,
Kourosch Abbaspour Tehrani and Bert U. W. Maes*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 144–153.
Department of Chemistry, University of Antwerp,
Groenenborgerlaan 171, B-2020 Antwerp, Belgium
doi:10.3762/bjoc.12.16
Received: 09 October 2015
Accepted: 12 January 2016
Published: 27 January 2016
Email:
Bert U. W. Maes* - bert.maes@uantwerpen.be
* Corresponding author
This article is part of the Thematic Series "Sustainable catalysis".
Guest Editor: N. Turner
Keywords:
base metal; benzylic; catalyzed; molecular oxygen; oxygenation
© 2016 Sterckx et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully
oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant.
Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug
Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papa-
verine. ICP–MS analysis of the purified reaction products revealed that the base metal impurity was well below the regulatory limit.
Introduction
Direct oxidation of C(sp3)–H bonds is a useful and fast method [4-7]. Molecular oxygen is considered to be the greenest
to convert fairly unreactive substrates to useful functional oxidant available and it is already widely employed by the
groups for organic synthesis like alcohols, ketones, aldehydes commodity chemical industry [8]. However, when looking at
and carboxylic acids. Classical oxidation protocols rely on the the preparation of more complex molecules, typical for fine
use of (super)stoichiometric quantities of oxyanions of toxic chemicals, the use of aerobic oxidations is more the exception
metals like Mn(VII) and Cr(VI) [1,2]. The amount of waste than the norm [9]. This is partly due to the limited synthetic
these oxidants produce and limitations on their use by new scope and selectivity of the available oxidation methods.
legislation [3] has prompted scientists to search for more sus- Further research into selective and mild aerobic oxidations is
tainable oxidation methods. The use of transition metal- or therefore of vital importance. Of special interest are the transi-
organocatalysis in combination with molecular oxygen has tion metal- and organocatalyzed oxidations of activated methyl-
received a great deal of attention from the scientific community enes such as in benzylic methylenes or their heteroaromatic an-
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Beilstein J. Org. Chem. 2016, 12, 144–153.
Results and Discussion
alogues. Due to the activation, the formation of the correspond-
ing ketones and aldehydes becomes feasible under mild condi- Substrate scope
tions. Oxidations of this kind using Oxone® [10,11], NaOCl In our communication we provided a reaction scope of phenyl-
[12] or especially peroxides [13-19] as the terminal oxidant are substituted 2-benzylpyridines and showed that both, electron-
quite numerous. However, transformations using molecular withdrawing and donating groups are well tolerated. The results
oxygen are rare. Ishii showed that organocatalysts such as additionally indicated that either Cu and Fe catalysts (CuI and
N-hydroxyphthalimide (NHPI) in combination with molecular FeCl2·4H2O) worked equally well for this substrate class [25].
oxygen can be used to perform benzylic oxidations [20]. The In the framework of this work a similar study was executed for
aerobic copper-catalyzed α-oxygenation of 2-arylthioacet- the regioisomeric 4-benzylpyridines using FeCl2·4H2O as the
amides was reported by Moghaddam [21]. In this trans- catalyst. Under the standard conditions previously developed
formation CuCl2 and K2CO3 in DMF were used to produce for 2-benzylpyridines these substrates smoothly oxidized giving
α-ketoarylthioacetamides. The coupling of 2-arylacetaldehydes the corresponding ketones in moderate to good yields (Table 1).
with anilines resulting in the formation of 2-aryl-α-ketoacet- Also in this case electron-donating as well as electron-with-
amides was reported by Jiao [22] and a closely related intramo- drawing substituents on the phenyl ring are well tolerated and
lecular variant leading to isatins has been published by their electronic properties have little influence on the yield of
Ilangovan [23]. A remarkable Cu-catalyzed chemoselective oxi- the reaction. Even substituents that are sensitive to oxidation
dative C–C bond cleavage of methyl ketones was reported by such as NH2 (2b) and SMe (2c) appear to be no problem al-
the group of Liu and Bi [24]. This useful transformation makes though the reaction products were isolated in slightly lower
use of CuI/O2 in DMSO to convert methyl ketones into alde- yields.
hydes in a sustainable manner.
Table 1: Iron-catalyzed aerobic oxidation of phenyl-substituted
Recently our group reported a synthetic protocol for the copper-
and iron-catalyzed aerobic oxidation of the methylene group of
aryl(di)azinylmethanes using acetic acid as a promotor [25].
The resulting ketones are very valuable as they are intermedi-
ates in the synthesis of a variety of pharmaceuticals such as the
antimalarial Mefloquine (Lariam®), the antihistamine Acrivas-
tine, the β2-adrenergic agonist Rimiterol and the anxiolytic
Bromazepam [26]. Furthermore, they can also be used to
synthesize the 1st and 2nd generation antihistamines Carbinox-
amine, Bepotastine and Triprolidine through an alternative syn-
thetic route. In addition to these synthetic examples it has been
shown by Kamijo that 4-benzoylpyridines can act as efficient
organocatalysts in the photoinduced oxidation of secondary
alcohols [27]. Very recently the group of Zhuo and Lei
disclosed an alteration to our reaction conditions to further
extend the substrate scope [28]. Ethyl chloroacetate was used as
the promotor instead of acetic acid, allowing the authors to ad-
ditionally oxidize less reactive alkyl-substituted pyridines. Gao
showed that NH4I can also be used as an organocatalyst in com-
bination with AcOH to facilitate the oxidation of benzyl-
pyridines to benzoylpyridines [29]. Satoh and Miura showed
that when replacing O2 for Na2S2O8 chemoselective methylena-
tion occurred over oxygenation of the methylene with DMA
4-benzylpyridines (1).a
Entry
Substrate
R
Product
Yield (%)b
1
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
70
55
56
67
79
77
85
66
76
61
79
60
2
NH2
SMe
OMe
Me
I
3
4
5
6
7
1g
1h
1i
Br
2g
2h
2i
8
Cl
9
F
10
11
12
1j
CO2Et
CN
NO2
2j
1k
1l
2k
2l
aReactions were performed on a 0.5 mmol scale in 1 mL of solvent
using 1 atmosphere of O2 (balloon). bIsolated yields.
acting as a one-carbon source [30]. An alternative method to Next, pyridine rather than phenyl-substitution was studied. In
synthesize picolinic amides from picolines and ammonium contrast to the phenyl-substituted compounds, substitution on
acetate or amines using a similar oxidation protocol was simul- the pyridine ring exerted a large influence on the rate of the
taneously proposed by the groups of Deng and Yin [31,32]. In reaction (Table 2). This is not surprising when considering the
the current work we study the expansion of the scope of our mechanism of the reaction involving an initial acid catalyzed
previously disclosed method and provide specific examples of imine–enamine tautomerization (the calculation of the equilib-
applications in organic synthesis.
rium constants can be found in Supporting Information File 1,
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Beilstein J. Org. Chem. 2016, 12, 144–153.
Table 2: Iron and copper-catalyzed aerobic oxidation of pyridine-substituted 2-benzylpyridines (3).a
Entry
Catalyst
Substrate
R
Product
Yield 3 (%)b
Yield 4 (%)b
1
FeCl2·4H2O
CuI
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3e
3e
3e
3f
5-CN
4a
4a
4a
4b
4b
4b
4c
4c
4c
4d
4d
4e
4e
4e
4f
19
18
0
67
66
83
73
82
72
15
15
65
69
62
64
56
91
85
88
23
22
87
20
15
92
0
2
5-CN
3
CuI
5-CNc
5-Me
4
FeCl2·4H2O
CuI
9
5
5-Me
9
6
CuI
5-Mec
5-OMe
5-OMe
5-OMed,e
5-CO2Me
5-CO2Me
5-NHCOMe
5-NHCOMe
5-NHCOMec
4-Cl
0
7
FeCl2·4H2O
CuI
65
66
0
8
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
FeCl2·4H2O
CuI
0
0
FeCl2·4H2O
CuI
0
27
0
CuI
FeCl2·4H2O
CuI
0
3f
4-Cl
4f
8
FeCl2·4H2O
CuI
3g
3g
3g
3h
3h
3h
3i
3-Cl
4g
4g
4g
4h
4h
4h
4i
73
71
0
3-Cl
CuI
3-Cld,e
5-Cl
FeCl2·4H2O
CuI
70
69
0
5-Cl
CuI
5-Cld,e
6-Cl
FeCl2·4H2O
CuI
90
91
0
3i
6-Cl
4i
0
CuI
3i
6-Cle, f
4i
59
aReactions were performed on a 0.5 mmol scale in 1 mL of solvent using 1 atmosphere of O2 (balloon). bIsolated yields. c48 h. dAcOH (3 equiv).
e130 °C. fTFA (3 equiv).
Table S1) [33]. As the substituent is now located in the ring While the thermodynamical equilibrium constant between the
where the tautomerization will take place the electronic effect imine and enamine tautomers predicts whether or not a sub-
and the position of this substituent is expected to have a large strate can be oxidized (see Supporting Information File 1), it
effect on it. In general one expects the tautomerization to does not provide an explanation for the incomplete conversion
proceed more efficiently when the pyridine nitrogen becomes that is seen in most cases of the pyridine-substituted 2-benzyl-
more basic and the methylene hydrogen becomes more acidic. pyridines. We attribute the low conversions to the fact that the
In Table 2 the results on pyridine-substituted 2-benzylpyridines pyridine nitrogen becomes less basic and therefore protonation
using both Fe and Cu catalysis are shown. Under the standard by AcOH becomes unfavored. This is supported by the fact that
conditions only a small number of substrates reached full the rate of deuterium incorporation in the benzylic position of
conversion after 24 hours. Based on our findings that placing 16 and 3h through acid-catalyzed imine–enamine tautomeriza-
substituents on the phenyl ring, both in 2- and 4-benzyl- tion is dependent on the strength of the acid used (Figure 1).
pyridines and irrespective of their electronic nature, has little in- The rate of deuterium incorporation in 2-benzylpyridine (16,
fluence on the yield of the reaction the largest substituent effect pKa ≈ 5.2) is much faster when using TFA-d1 than with AcOH-
is expected to be on the basicity of the pyridine nitrogen and not d4 [34,35]. With the less basic 2-benzyl-5-chloropyridine (3h,
that much on the acidity of the methylene hydrogen.
pKa ≈ 3.0) the difference is even more pronounced: Almost no
146

Beilstein J. Org. Chem. 2016, 12, 144–153.
Figure 1: Hydrogen–deuterium exchange through acid-catalyzed imine–enamine tautomerization of 3h (0.5 M) and 16 (0.5 M) using AcOH-d4 (0.5 M)
or TFA-d1 (0.5 M). 1H NMR spectroscopy was used to quantify the monodeuterated species.
147

Beilstein J. Org. Chem. 2016, 12, 144–153.
deuterium incorporation could be detected using AcOH-d4 purpose. The reasoning behind this is reflected in the chemose-
while the reaction ran smoothly using the stronger acid TFA-d1. lectivity experiments (vide infra), where it was shown that CuI
From this we conclude that when the pyridine nitrogen becomes is a slightly more potent catalyst than FeCl2·4H2O. Additional-
less basic and protonation by the acid thus becomes more diffi- ly, comparison of the reaction rate for both catalysts on the
cult, using more equivalents of the acid or a stronger acid standard substrate 2-benzylpyridine (16) further supports this
is needed to reach full conversion. When we compare the (vi,Cu = 1.088 × 10−3 M min−1; vi,Fe = 1.013 × 10−3 M min−1,
different pKa values of substituted pyridines we see that see Supporting Information File 1, Figure S2). For substrates
2-benzylpyridine (16, pKa ≈ 5.2) is one of the most basic that already gave reasonable conversions (>60%) using the stan-
pyridines [34,35]. Substituents in the 5-position generally give dard conditions (Table 2, entries 3, 6 and 14) the reaction time
poor conversion in accordance with their lower pKa values: was doubled to 48 hours which was sufficient to achieve full
5-CN (pKa ≈ 1.3, Table 2, entries 1 and 2), 5-OMe (pKa ≈ 4.9, conversion. For substrates that are harder to oxidize (<60%
Table 2, entries 7 and 8) and 5-Cl (pKa ≈ 3.0, Table 2, entries 20 conversion) due to too low pKa a combination of a higher tem-
and 21) with the exception of 5-CO2Me (pKa ≈ 3.1, Table 2, perature and the addition of more (three) equivalents of acetic
entries 10 and 11). When investigating regioisomeric substrates acid was needed (Table 2, entries 9, 19 and 22). Considering the
featuring chloro substituents in all possible positions of the low basicity of compound 3i, 3 equivalents of the stronger acid
pyridine ring only the 4-Cl (pKa ≈ 3.8, Table 2, entries 15 and TFA were used (Table 2, entry 25).
16) substrate reaches full conversion under the standard condi-
tions. The 3-Cl and 5-Cl regioisomers have a similar pKa value Next, the effect of benzoannulation (quinoline) and C–H for N
(pKa ≈ 2.98) and therefore show similar reactivity (Table 2, substitution (diazines) in the pyridine ring was studied.
entries 17 and 18 and entries 20 and 21) with only limited Scheme 1 provides an overview of the results for these more
conversion. A remarkable case is the 6-Cl-substituted substrate challenging substrates. Interestingly, phenyl(quinolin-2-
(pKa ≈ 0.8, Table 2, entries 23 and 24), which did not react at all yl)methanone (6a) and phenyl(quinolin-4-yl)methanone (6b)
under the standard conditions. The low basicity of the pyridine were formed in moderate yields indicating that larger aromatic
nitrogen is the reason for this lack of reactivity. In addition the systems are compatible with the reaction conditions. In the case
enamine form of this compound is also highly unfavored (see of 2-(4-chlorobenzyl)pyrimidine (5c) the standard conditions
Supporting Information File 1).
allowed smooth oxidation providing the target compound
in an excellent yield. For the regioisomeric diazine, (4-chloro-
To reach full conversion for all substrates we re-optimized the benzyl)pyrazine (5d), no oxidation was observed after 24 h at
reaction conditions. Although similar results for Fe and Cu ca- 100 °C. To our delight, by increasing the reaction temperature
talysis were obtained after 24 h, CuI was selected for this to 130 °C, (4-chlorophenyl)(pyrazin-2-yl)methanone (6d) could
Scheme 1: Benzylic oxygenation of benzoannulated azines and diazines (5).
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Beilstein J. Org. Chem. 2016, 12, 144–153.
be obtained in 92% yield. In contrast to the two former cases, strate. This compound is structurally interesting as it is acti-
4-(4-chlorobenzyl)pyrimidine (5e) could neither be oxidized at vated by both a pyridin-2-yl and a quinolin-4-yl moiety
100 °C nor at 130 °C. Competitive C–H activation of the 2 posi- (Scheme 2, bottom). The synthesis of substrate 12 was accom-
tion is presumed to be the reason for this observation. Blocking plished by a cross-coupling reaction of pyridine alcohol 11 with
this position by a methyl group (5f) delivered the correspond- commercial 4-chloro-2,8-bis(trifluoromethyl)quinoline (7b) ac-
ing ketone 6f, albeit in a poor yield of 40%, thus supporting the cording to a procedure published by Oshima [40]. In this way,
metalation hypothesis. The regioisomer of diazine 5f, 3-benzyl- 12 was obtained in 63% yield and its subsequent Fe-catalyzed
6-methylpyridazine (5g), could be smoothly oxidized to the cor- oxidation provided 10 in 63% isolated yield. In principle sub-
responding ketone in 81% yield. It is worth mentioning that in strate 7a could also be used but the chloro analogue is cheaper.
5f as well as 5g no additional oxidation of the methyl group was The final reduction of 10 into Mefloquine has been described
seen [25].
earlier and can also be achieved in an enantioselective manner
[41].
Applications
An example of an important pharmaceutical which is industri- Human metabolism can produce metabolites of pharmaceuti-
ally prepared from an azinyl benzoazinyl ketone, namely (2,8- cals that possess completely different properties such as for
bis(trifluoromethyl)quinolin-4-yl)(pyridin-2-yl)methanone (10), instance biological activity, toxicity and clearance rates. Rapid
is the antimalarial Mefloquine (13) [36]. This drug is listed on identification and synthesis of potential drug metabolites is
the World Health Organization essential medicines list and therefore of great importance to facilitate the drug discovery
despite numerous side effects it remains one of the most effec- process [42]. For this purpose chemoselective oxidation proto-
tive antimalarial drugs on the market [37,38]. Its classical syn- cols are a valuable tool since they can provide us with metabo-
thesis (Scheme 2, top) is based on the lithiation of 4-bromo-2,8- lites typically generated by cytochrome P450 enzymes. Bearing
bis(trifluoromethyl)quinoline (7a) and quenching with CO2 re- this in mind we attempted to oxygenate the benzylic position of
sulting in the formation of 2,8-bis(trifluoromethyl)quinoline-4- the antispasmodic drug papaverine (14) applying our oxidation
carboxylic acid (8). Reaction of 8 with in situ generated protocol (Scheme 3). The resulting compound is known as
2-pyridyllithium (9) finally yields ketone 10 [39].
papaveraldine (15), a byproduct from the extraction of papa-
verine from Papaver somniferum. Papaverine is a challenging
We considered a new approach based on 4-(pyridin-2- substrate as besides the methylene part it also features two oxi-
ylmethyl)-2,8-bis(trifluoromethyl)quinoline (12) as the sub- dation sensitive veratrole units. Interestingly, a highly chemose-
Scheme 2: Classical (top) and new formal (bottom) synthesis of Mefloquine.
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Beilstein J. Org. Chem. 2016, 12, 144–153.
Scheme 3: Iron-catalyzed aerobic oxidation of papaverine (15).
lective oxidation was observed and compound 15 was isolated tion resulted in 54 ppm of Fe remaining. Omitting the column
in 60% yield.
chromatography step and solely performing the aqueous extrac-
tion provided a much higher value, namely 1097 ppm. Howev-
er, if after the extraction a recrystallization step of the reaction
Trace metal analysis
When using transition metal catalysis in the synthesis of com- product is performed the Fe level can be lowered further to
pounds designated for application (pharmaceuticals, agrochemi- 300 ppm which is well below the legal limit for oral exposure
cals, materials) it is of vital importance to control and deter- (see Supporting Information File 1).
mine any metal impurity in the reaction product. In case the
selected purification methods proved insufficient to get the Alternative solvents
metal contaminations below the maximum allowed threshold A solvent screening was subsequently performed focusing
value set for active ingredients (AIs), an extra treatment might mainly on greener solvents than DMSO with a boiling point
be required. This is especially true if the catalysis is performed above 100 °C in order to allow a direct comparison at the same
in a late stage of a synthesis thus making the method less attrac- reaction temperature [44,45] (Table 4). All reactions were per-
tive and sustainable. While class 1 metals such as Pd and Pt formed in a round-bottomed flask equipped with a reflux
have oral exposure limits of 10 ppm, Cu and Fe are respective- condenser under oxygen atmosphere at a 5 mmol scale to
ly class 2 and class 3 metals with oral exposure limits of be able to reliably quantify remaining starting material.
250 ppm and 1300 ppm [43]. The fact that Cu and Fe are more 2-Benzylpyridine (16) was selected as the substrate for this
abundant, cheaper and benign makes them an interesting choice study. The reaction in anisole and n-BuOAc gave full conver-
as transition metal catalysts. To determine the Cu and Fe sion after 24 hours with excellent yields. With 1,4-dioxane, tol-
contents present in our samples ICP–MS analysis was per- uene, cyclopentyl methyl ether and n-BuOH as the solvent some
formed. Copper contents ranged from 5 to 21 ppm, all well starting product was recovered, however, with a good mass
below the limit of 250 ppm. Iron contents were slightly higher balance suggesting that the reaction is just slower in these sol-
ranging from 29 to 57 ppm but again still well below the regula- vents than in DMSO. From this we can conclude that the reac-
tory maximum value (see Supporting Information File 1, Figure tion is compatible with a variety of other solvents. In addition to
S1). It should be noted that these values pertain to the purified the above results, Kappe et al. successfully applied our protocol
compounds after column chromatography. The influence of the in a flow process [46]. They intensified the process by working
work-up procedure on the remaining metal impurities was in- at 200 °C which allowed them to lower the catalyst loading
vestigated for one of our applications, namely the papaveral- (FeCl3) to 5 mol % and to omit acetic acid as the activator. As
dine (15) synthesis (Table 3). Applying the standard purifica- DMSO degraded and produced repulsive odors at these high
Table 3: The influence of the purification method on the amount of Fe impurities in papaveraldine (15) after oxidation.
Entry
Purification method
Fe impurity in 15 (ppm)
1
2
3
Extractiona + column chromatographyb
Extractiona
54
1097
300
Extractiona + recrystallizationc
aWashing subsequently with sat. aq NaHCO3 and brine, extraction with dichloromethane. bSilica flash cartridge applying a heptane/ethyl acetate
gradient. cRecrystallization from a 2 M HCl solution.
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Beilstein J. Org. Chem. 2016, 12, 144–153.
temperatures the authors switched to propylene carbonate as the benzyl)-2-methylpyrazine (18a). Pyrazine 18a features three
solvent.
possible positions for methylene oxidation: a benzyl,
benzhydryl and a 1,4-diazinylmethyl moiety. When 18a was
submitted to the Cu-catalyzed reaction conditions at 130 °C,
only the bis-oxidation product 6-(4-methylbenzoyl)pyrazine-2-
carbaldehyde (20a) was obtained in 61% (Table 5, entry 1).
Interestingly, when switching to FeCl2·4H2O as the catalyst
in the reaction, only mono-oxidation at the benzhydrylic
methylene occurred, providing (6-methylpyrazin-2-yl)(p-
tolyl)methanone (19a) in 57% yield (Table 5, entry 2). A simi-
lar chemoselectivity was observed for the oxidation of 18b
where Cu catalysis lead to bis-oxidation (20b, Table 5, entry 4)
while Fe catalysis resulted in mono-oxidation (19b, Table 5,
entry 5).
Table 4: An extended solvent screening for the base metal-catalyzed
aerobic oxidation reaction.a
Entry
Solventb
Yield 16 (%)c Yield 17 (%)c
1
2
3
4
5
6
7
DMSOd
0
87
85
89
85
67
80
73
anisolee
0
n-BuOAce
1,4-dioxanef
toluened
CPMEd
0
When the reaction with 18a using Cu catalysis is performed in
n-BuOAc as solvent instead of DMSO only compound 19a was
isolated after 48 hours of reaction (starting material was still
present after 24 hours, Table 5, entry 3). The same trend was
observed in the reaction of 18b. Here under Cu catalysis at
130 °C in n-BuOAc also only benzhydrylic oxidation occurred
and (6-methylpyridin-2-yl)(p-tolyl)methanone (19b) was isolat-
ed in 64% yield as the sole product. These results demonstrate
that the oxidation power of the catalytic system can be tuned by
careful selection of the solvent as well as the base metal.
2
18
5
n-BuOHe
5
aReactions were performed on a 5 mmol scale in 10 mL of solvent
using 1 atmosphere of O2 (balloon). bClassification of solvents as pro-
vided in [44]. cIsolated yields. dProblematic. eRecommended.
fHazardous.
Chemoselectivity
When multiple activated methylene motifs are present the Conclusion
chemoselective oxidation of one of these positions can be This work shows that the oxidation protocol disclosed in 2012
achieved as we previously exemplified for 2-methyl-6-(4- by our group can be applied to a much broader substrate scope
methylbenzyl)pyridine (18b, Table 5, entries 4 and 5). This than originally investigated. Furthermore we have shown that
interesting selectivity was further expanded on 6-(4-methyl- when the nature of the substituents does not permit full conver-
Table 5: Chemoselectivity obtained by selection of catalyst and solvent.a
Entry
Substrate
Catalyst
Solvent
Yield 19 (%)b
Yield 20 (%)b
1
2
3
4
5
6
18a
CuI
DMSO
0
61
0
18a
FeCl2·4H2O
CuI
DMSO
57
78c
0
18a
n-BuOAc
DMSO
0
18bd
18bd
18b
CuI
62
0
FeCl2·4H2O
CuI
DMSO
85
64
n-BuOAc
0
aReactions were performed on a 0.5 mmol scale in 1 mL of solvent using 1 atmosphere of O2 (balloon). bIsolated yields. c48 h. dReported in our com-
munication, see [25].
151

Beilstein J. Org. Chem. 2016, 12, 144–153.
10.Ojha, L. R.; Kudugunti, S.; Maddukuri, P. P.; Kommareddy, A.;
Gunna, M. R.; Dokuparthi, P.; Gottam, H. B.; Botha, K. K.;
Parapati, D. R.; Vinod, T. K. Synlett 2009, 1, 117–121.
doi:10.1055/s-0028-1087384
sion after 24 hours, the standard conditions can be easily
amended to increase the rate of the reaction. ICP–MS analysis
was performed on a representative set of molecules from the
scope disclosed to determine the Cu or Fe impurities remaining
after work-up of the reaction products. This revealed that only
low amounts remained, that are well below the regulatory
limits. In addition, for papaveraldine a comparison between dif-
ferent purification procedures was performed in order to deter-
mine their influence on the amount of metal impurity
remaining. While the reaction is compatible with a large num-
ber of solvents including sustainable ones, DMSO appears to
give the fastest reactions. This is also reflected in the chemose-
lectivity studies where DMSO is the only solvent in which oxi-
dation of a (di)azinylmethyl is possible.
11.Moriyama, K.; Takemura, M.; Togo, H. Org. Lett. 2012, 14, 2414–2417.
doi:10.1021/ol300853z
12.Jin, C.; Zhang, L.; Su, W. K. Synlett 2011, 10, 1435–1438.
doi:10.1055/s-0030-1260760
13.Pan, J.-F.; Chen, K.-M. J. Mol. Catal. A: Chem. 2001, 176, 19–22.
doi:10.1016/S1381-1169(01)00238-2
14.Velusamy, S.; Punniyamurthy, T. Tetrahedron Lett. 2003, 44,
8955–8957. doi:10.1016/j.tetlet.2003.10.016
15.Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson, D. A.; Oldham, J.;
Burton, A. J.; Barrett, A. G. M. Org. Lett. 2005, 7, 4549–4552.
doi:10.1021/ol051765k
16.Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle, M. P.
Org. Lett. 2005, 7, 5167–5170. doi:10.1021/ol0520020
17.Pavan, C.; Legros, J.; Bolm, C. Adv. Synth. Catal. 2005, 347, 703–705.
doi:10.1002/adsc.200404315
Supporting Information
18.Nakanishi, M.; Bolm, C. Adv. Synth. Catal. 2007, 349, 861–864.
doi:10.1002/adsc.200600553
Supporting Information File 1
19.Zhang, J. T.; Wang, Z. T.; Wang, Y.; Wan, C. F.; Zheng, X. Q.;
Wang, Z. Y. Green Chem. 2009, 11, 1973–1978.
doi:10.1039/b919346b
Experimental procedures, compound characterization data
and copies of 1H and 13C NMR spectra of all new starting
materials and reaction products.
20.Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.;
Nishiyama, Y. J. Org. Chem. 1995, 60, 3934–3935.
doi:10.1021/jo00118a002
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-16-S1.pdf]
21.Moghaddam, F. M.; Mirjafary, Z.; Saeidian, H.; Javan, M. J. Synlett
2008, 6, 892–896. doi:10.1055/s-2008-1042925
22.Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2011, 50,
11088–11092. doi:10.1002/anie.201105285
Acknowledgements
This work was supported by the Research Foundation Flanders
(FWO-Flanders), the Agency for Innovation by Science and
Technology (IWT-Flanders), the University of Antwerp (BOF,
IOF) and the Hercules Foundation. The authors thank Philippe
Franck, Heidi Seykens and Norbert Hancke for technical assis-
tance.
23.Ilangovan, A.; Satish, G. Org. Lett. 2013, 15, 5726–5729.
doi:10.1021/ol402750r
24.Zhang, L.; Bi, X.; Guan, X.; Li, X.; Liu, Q.; Barry, B.-D.; Liao, P.
Angew. Chem., Int. Ed. 2013, 52, 11303–11307.
doi:10.1002/anie.201305010
25.De Houwer, J.; Abbaspour Tehrani, K.; Maes, B. U. W.
Angew. Chem., Int. Ed. 2012, 51, 2745–2748.
doi:10.1002/anie.201108540
26.Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances, 4th ed.; Georg Thieme Verlag: Stuttgart, 2001.
27.Kamijo, S.; Tao, K.; Takao, G.; Tonoda, H.; Murafuji, T. Org. Lett. 2015,
17, 3326–3329. doi:10.1021/acs.orglett.5b01550
28.Liu, J.; Zhang, X.; Yi, H.; Liu, C.; Liu, R.; Zhang, H.; Zhuo, K.; Lei, A.
Angew. Chem., Int. Ed. 2015, 54, 1261–1265.
References
1. Shaabani, A.; Mirzaei, P.; Naderi, S.; Lee, D. G. Tetrahedron 2004, 60,
11415–11420. doi:10.1016/j.tet.2004.09.087
2. Rathore, R.; Saxena, N.; Chandrasekaran, S. Synth. Commun. 1986,
16, 1493–1498. doi:10.1080/00397918608056400
3. European chemicals agency (ECHA) website.
doi:10.1002/anie.201409580
http://echa.europa.eu/web/guest/regulations/reach/legislation.
4. Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293–1314.
doi:10.1021/cr100198w
29.Ren, L.; Wang, L.; Lv, Y.; Li, G.; Gao, S. Org. Lett. 2015, 17,
2078–2081. doi:10.1021/acs.orglett.5b00602
30.Itoh, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16,
2050–2053. doi:10.1021/ol500655k
5. Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C.
Chem. Rev. 2013, 113, 6234–6458. doi:10.1021/cr300527g
6. Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381–3430. doi:10.1039/c2cs15224j
31.Xie, H.; Liao, Y.; Chen, S.; Chen, Y.; Deng, G.-J. Org. Biomol. Chem.
2015, 13, 6944–6948. doi:10.1039/C5OB00915D
32.Huang, Y.; Chen, T.; Li, Q.; Zhou, Y.; Yin, S.-F. Org. Biomol. Chem.
2015, 13, 7289–7293. doi:10.1039/C5OB00685F
33.Sterckx, H.; De Houwer, J.; Mensch, C.; Caretti, I.; Tehrani, K. A.;
Herrebout, W. A.; Van Doorslaer, S.; Maes, B. U. W. Chem. Sci. 2016,
7, 346–357. doi:10.1039/C5SC03530A
7. Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105,
2329–2364. doi:10.1021/cr050523v
8. Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851–863.
doi:10.1021/ar2002045
9. Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B.
Chem. Rev. 2006, 106, 2943–2989. doi:10.1021/cr040679f
152

Beilstein J. Org. Chem. 2016, 12, 144–153.
34.The pKa values mentioned are those of the corresponding
monosubstituted pyridines since the benzyl group is the same in every
pyridine and data for the compounds are not available. Tables of Rate
and Equilibrium Constants of Heterolytic Organic Reactions; Palm, V.,
Ed.; VINITI: Moscow-Tartu, 1975–1985.
35.Güven, A. Int. J. Mol. Sci. 2005, 6, 257–275. doi:10.3390/i6110257
36.Adam, S. Tetrahedron 1989, 45, 1409–1414.
doi:10.1016/0040-4020(89)80138-3
37.World Health Organization (WHO) website.
http://www.who.int/medicines/publications/essentialmedicines/en/.
38.Schlagenhauf, P.; Adamcova, M.; Regep, L.; Schaerer, M. T.;
Rhein, H.-G. Malar. J. 2010, 9, 357. doi:10.1186/1475-2875-9-357
39.Lutz, R. E.; Ohnmacht, C. J.; Patel, A. R. J. Med. Chem. 1971, 14,
926–928. doi:10.1021/jm00292a008
40.Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2007, 46,
2643–2645. doi:10.1002/anie.200604472
41.Hems, W. P.; Jackson, W. P.; Nightingale, P.; Bryant, R.
Org. Process Res. Dev. 2012, 16, 461–463. doi:10.1021/op200354f
42.Genovino, J.; Lütz, S.; Sames, D.; Touré, B. B. J. Am. Chem. Soc.
2013, 135, 12346–12352. doi:10.1021/ja405471h
43.Class 1 metals include metals that are known or suspect human
carcinogens or show any other significant toxicity. Class 2 metals
include metals with lower toxicity to man and are typically encountered
with administration of medicinal products. Class 3 metals include
metals with no significant toxicity and are well tolerated up to doses far
exceeding typically encountered with the administration of medicinal
products. European medicines agency, committee for medicinal
products for human use, see
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/gener
al/general_content_000356.jsp&mid=WC0b01ac0580028e8c for a
detailed description.
44.Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.;
Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.;
Curzons, A. D. Green Chem. 2011, 13, 854–862.
doi:10.1039/c0gc00918k
45.Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.;
Abou-Shehada, S.; Dunn, P. J. Green Chem. 2016, 18, 288–296.
doi:10.1039/C5GC01008J
46.Pieber, B.; Kappe, C. O. Green Chem. 2013, 15, 320–324.
doi:10.1039/c2gc36896j
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