Copper-Catalyzed Aerobic Oxygenation of Benzylpyridine N-Oxides and Subsequent Post-Functionalization

Article abstract of DOI:10.1002/adsc.201700588

A copper-catalyzed aerobic oxidation of benzylpyridine N-oxides is reported. The N-oxide moiety acts as a built-in activator for the benzylic methylene oxidation, without requirement of additives. Reaction conditions were identified which suppress undesired benzoylpyridine formation via N-deoxygenation involving intermolecular oxygen transfer. The versatility of the N-oxide group of the benzoylpyridine N-oxide reaction products for post-functionalization of the pyridine ring is demonstrated through efficient C–C, C–N, C–O and C–Cl bond forming procedures, with both nucleophiles and electrophiles. Finally, the applicability of the new synthetic methodology is demonstrated in an alternative route towards the antihistaminic drug Acrivastine via three consecutive N-oxide activated C–H functionalization processes, starting from picoline N-oxide. (Figure presented.).

Full text of DOI:10.1002/adsc.201700588

Title: Copper-Catalyzed Aerobic Oxygenation of Benzylpyridine N-
oxides and Subsequent Post-Functionalization
Authors: Hans Sterckx, Carlo Sambiagio, Vincent Médran-Navarrete,
and Bert Maes
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Aerobic Oxygenation of Benzylpyridine N-
oxides and Subsequent Post-Functionalization
Hans Sterckx,‡ Carlo Sambiagio,‡ Vincent Médran-Navarrete, and Bert U. W. Maes *
Organic Synthesis (ORSY), Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp,
Belgium
‡These authors contributed equally. *E-mail: bert.maes@uantwerpen.be
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
copper-catalyzed aerobic oxidation of bond forming procedures, with both nucleophiles and
benzylpyridine N-oxides is reported. The N-oxide moiety electrophiles. Finally, the applicability of the new synthetic
acts as a built-in activator for the benzylic methylene methodology is demonstrated in an alternative route
oxidation, without requirement of additives. Reaction towards the anti-histaminic drug Acrivastine via three
conditions were identified which suppress undesired consecutive N-oxide activated C-H functionalization
benzoylpyridine formation via N-deoxygenation involving processes, starting from picoline N-oxide.
intermolecular oxygen transfer. The versatility of the N-
oxide group of the benzoylpyridine N-oxide reaction
products for post-functionalization of the pyridine ring is
demonstrated through efficient C-C, C-N, C-O and C-Cl
Keywords: C-H functionalization; pyridine-N-oxide;
aerobic oxidation; molecular oxygen; copper catalysis
hydroxyphtalimide (NHPI) by a cobalt catalyst and
O2.[10] From a synthetic point of view, the main
limitation of these important oxidation procedures is
that the acyl-substituted pyridines obtained upon
methylene oxidation are deactivated toward further
functionalization of the pyridine moiety (Scheme 1).
While the electron-withdrawing acyl substituent and
azine nitrogen both inhibit electrophilic aromatic
substitutions, nucleophilic substitutions do not occur
unless a leaving group, e.g. halogen, is present in the
substrate. Pre-installing the substituent in the
substrate upfront is not a solution, as it does not
provide a protocol applicable in library synthesis,
typically involving late stage functionalization.
Moreover, we previously have shown the oxidation
protocol of benzylpyridines to be very sensitive
towards the pyridine substitution pattern requiring
reoptimization.[4b] These aspects prompted us to
develop a new versatile strategy by considering
pyridine N-oxides as alternative substrates for the
oxidation. The N-oxide functionality would have a
double function in the process: 1) act as an
unprecedented built-in activator for the methylene
oxidation without requiring any additive,[11] and 2)
allow further decoration of the pyridine ring via post-
functionalization. Due to its unique electronic
properties, the N-oxide can activate the alpha position
Introduction
Oxidase and oxygenase types of reactions are now
acquiring increasing importance from both an
academic and industrial perspective. These aerobic
oxidation processes do not require the use of
(over)stoichiometric reagents, which result in large
amounts of often toxic waste, and generally produce
only water as by-product.[1],[2] Although safety issues
concerning the use of oxygen as oxidant have
hampered its use at an industrial level for fine
chemicals synthesis, the development of efficient
flow processes have now provided a safe solution to
work with oxygen as reactant or reagent.[3]
In 2012 our group reported the aerobic copper and
iron catalyzed methylene oxidation of substituted
benzylpyridines
and
analogues.[4],[5]
The
aroylpyridine products and their derivatives are
important intermediates in the synthesis of
pharmaceuticals,[6] and the method has found
application in metabolite studies.[7] The methylene
C(sp3)-H bond cleavage in this process is promoted
by stoichiometric acid via N-protonation of the
substrate.[8] In 2015 Zhuo and Lei published an
alternative Cu-catalyzed aerobic oxidation protocol,
which employed ethyl chloroacetate as
a
stoichiometric activator through in situ pyridine N-
alkylation.[9] While this work was in progress, Stahl
reported a procedure using phthalimido N-oxyl
radical (PINO) as co-catalyst (20 mol%) to cleave the
C(sp3)-H bond, generated in situ from N-
of the pyridine ring for reactions with both
12]
nucleophiles and electrophiles[6a,
(Scheme 1).
While in reaction with nucleophiles the N-oxide
moiety is typically removed, reactions with
electrophiles usually leave this moiety intact, which
1
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
can be easily removed at a later stage.[6a] Cheap and
commercially available picoline N-oxides or
(chloro)pyridines N-oxides, obtained from the
corresponding pyridine derivatives by oxidation with
13]
sustainable H2O2 oxidant,[6a,
can be used to
synthesize the required substituted benzylpyridine N-
oxides via directed Pd catalyzed C-H bond
functionalization[11a, b, 14] or cross-coupling reactions[6b,
15]
(Scheme 1). Herein we report the aerobic Cu-
catalyzed oxygenation of substituted benzylpyridine
N-oxides and subsequent post-functionalization on
the pyridine ring with both nucleophiles and
electrophiles.
a)a
b)b
Figure 1. Effect of different Cu sources and additives
on the conversion of 1a versus time (FT-IR).
Reaction conditions: 1a (5 mmol), catalyst (10 mol%),
DMSO (10 mL), O2 (balloon), 100°C; a) 1 eq. of
CsOAc or AcOH added; b) anhydrous CuCl2 was
used.[2i]
With the optimized conditions in hand (5% CuI,
DMSO [1.0M], O2 balloon, 120⁰C, 24h), we then set
out to explore the scope of this methodology. 2-
Benzylpyridine N-oxide (1a) gave in these conditions
64% yield of the corresponding benzoyl product 3a
(Scheme 2, Method 1; vide infra for discussion on
Method 2). The 4-benzyl regioisomer 6a could be
obtained in 71% yield, although a longer reaction
time was required (48h); 3-benzylpyridine N-oxide
8a proved instead not reactive in these conditions.
Both phenyl and pyridine substituted 2-
benzylpyridine N-oxides 1 were then subjected to
these conditions to get an idea on the sensitivity of
the oxidation reaction versus azine substitution
pattern. The benzylic oxidation occurred smoothly in
most cases, however, the formation of the
corresponding aroylpyridines 4 was also observed to
a considerable extent. While N-deoxygenated side-
product 4a was only observed in trace amounts (≤
5%) for the unsubstituted substrate 1a, the ratio of 3/4
for pyridine- and phenyl- substituted substrates
proved strongly substituent-dependent, and fell in the
range of 2/1 to 1/1 (see ESI for details).
Scheme 1. Classical versus new approach towards
benzoylpyridines allowing to perform smooth
pyridine post-functionalization.
Results and Discussion
Optimization and substrate scope. The benzylic
oxidation of the unsubstituted model substrate 2-
benzylpyridine N-oxide 1a proceeded with CuI (10
mol%) as catalyst in DMSO at 100°C using a balloon
of O2. However, while little oxidation of 2-
benzylpyridine (2a) occurred without AcOH,[4] 1a
was smoothly oxidized in the absence of the acid
additive. In fact, addition of either acids or bases
proved to have an inhibiting effect on the oxidation of
1a (Figure 1a). Screening of a number of Cu salts
revealed that CuI is by far the best in terms of
reaction rate (Figure 1b), whereas the use of Fe salts
generally resulted in lower yields and mass-balance.
The oxidation performed well in both DMSO and
BuOAc, although the use of DMSO results in more
homogeneous reaction mixtures and no metal
deposition was observed. This solvent was therefore
chosen for further experiments. A temperature of
120°C was selected to allow the use of a lower
catalyst loading (5%).
2
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
Table 2. Selected optimization results for substrate
1ga
Entry
Solvent [1g]
DMSO [1.0M]
DMSO [1.0M]
DMSO [0.5M]
BuOAc [0.5M]
T (⁰C) % CuI % Yield (3g/4g/1g)
1
2
3
4
120
100
120
120
5
5
10
10
28/33/0
61/<23/0
74/16/0
51/12/0b
a) Yields of isolated products are reported. b) 18% of the corresponding
benzylic alcohol, 5-cyano-2-[hydroxy(phenyl)methyl]pyridine N-oxide,
was obtained
Based on these results, 0.5M concentration, 10 mol%
CuI, and 120°C were selected as new reaction
conditions to suppress, to some extent, N-
deoxygenation. Both DMSO and BuOAc were
employed to evaluate the 2-benzylpyridine N-oxide
scope (Scheme 3). A range of electron-withdrawing
and electron-donating substituents on either the
pyridine or the phenyl ring were well tolerated in the
reaction, and much better selectivity than with the
original conditions was observed (Scheme 3 and ESI).
The amount of deoxygenated products 4 was reduced
to 7-16% for the solvent giving the highest yield,
except for 4-chloropyridine substrate 1k (21% of 4k
in BuOAc). The desired N-oxides 3 were generally
isolated in moderate to good yields (56-81%), apart
from 3d (39%), for which a low mass balance was
noted (see ESI, Figure S1). 6-(4-Methylbenzyl)-2-
methylpyridine N-oxide (1m) was tested to
investigate the chemoselectivity of the oxidation
process as it features three potential reaction sites
(benzyl, benzhydryl and picolinyl). Only benzhydryl
oxidation was observed in our conditions;[16] 3m was
formed in a 48% yield. It is worth noting that the CuI
catalyzed oxidation of 6-(4-methylbenzyl)-2-
methylpyridine using AcOH as an activator resulted
in additional oxidation of the 2-methyl group at the
same reaction temperature in the same solvent.[4a]
Ketone 3n, from 2-benzylquinoline N-oxide, was
obtained in DMSO in 64% yield, together with 28%
of the corresponding deoxygenation product 4n.
Similar results were obtained in BuOAc. Benzo
annulated systems seem to be more sensitive towards
deoxygenation.
Scheme 2. Comparison of the aerobic Cu-catalyzed
and aerobic Co/NHPI-catalyzed[10] oxygenation of
regioisomeric benzylpyridine N-oxides; reactions on
1 mmol scale; a) 48h.
In order to increase the selectivity by reducing the
formation of the undesired deoxygenation product 4,
we performed further optimization studies on both a
phenyl and pyridine substituted model substrate, to
identify the reaction parameters suppressing its
formation. Selected optimization data for 2-(4-
chlorobenzyl)pyridine N-oxide (1b) are reported in
Table 1. While in our initial conditions a 3b/4b ratio
of 2/1 was obtained (entry 1, overall yield 79%),
decreasing the temperature to 100°C improved the
selectivity to 4/1, although with considerably
reduced conversion (entry 2). Reduction of the
substrate concentration from 1.0M to 0.5M, improved
the yield and increased the 3b/4b ratio (5/1). To
keep the concentration of copper constant, 10% CuI
was used in this experiment (entry 3). Reaction in
BuOAc gave a reduced mass balance and slightly
lower yield of target compound 3b (entry 4). On 2-
benzyl-5-cyanopyridine N-oxide 1g the same reaction
conditions as for 1b proved optimal (Table 2, entry 3).
Table 1. Selected optimization results for substrate
1ba
Entry Solvent [1b] T (⁰C) % CuI % Yield (3b/4b/1b)
1
2
3
4
DMSO [1.0M]
DMSO [1.0M]
DMSO [0.5M]
BuOAc [0.5M]
120
100
120
120
5
5
10
10
54/25/0
41/13/22
75/16/0
67/11/0
a) Yields of isolated products are reported
3
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
(see Figure 2), suggesting a considerable difference
in the reaction mechanism for the two substrate types.
Scheme 4. Scope of substituted 4-benzylpyridine N-
oxides 5. Yield of deoxygenated products 7 in round
brackets and remaining 5 in square brackets. Reaction
conditions: 5 (0.5 mmol), CuI (10 mol%), DMSO or
BuOAc (1 mL), O2 (balloon), 120°C, 24h.
Scheme 3. Scope of substituted 2-benzylpyridine N-
oxides 1. Yield of deoxygenated products 4 in round
brackets and remaining 1 in square brackets. Reaction
conditions: 1 (0.5 mmol), CuI (10 mol%), DMSO or
BuOAc (1 mL), O2 (balloon), 120°C, 24h.
The recently published protocol by Stahl and co-
workers was subsequently tested on the
3
regioisomeric benzylpyridine-N-oxides (1a, 5a, 8a)
for comparison (Scheme 2, Method 2).[10] Using
substrate 1a 35% of the 2-benzoyl N-oxide product
3a and also some N-deoxygenated side product 4a
(15%) was isolated. Besides, a considerable amount
of unreacted starting material (35%) remained. This
result did not change when a double amount of Co
catalyst was used. Better results were obtained on
substrate 5a, which gave 67% of the desired 6a,
together with 11% of the N-deoxygenated side
product 7a, and no remaining substrate over a 24h
period. On 3-benzylpyridine N-oxide (8a) a low
conversion and yield but no N-deoxygenation was
observed (Scheme 2). The same reaction conditions
on the corresponding benzylpyridines resulted in full
conversion and 93%, 89% and 92% yield of the
corresponding benzoylpyridine as reported by
Stahl.[10] While these conditions have not been
optimized for N-oxide substrates, the difference in
performance between the two classes of substrates
underpin the challenging nature of the azine N-oxides
versus the corresponding azines for oxygenation, and
the suppression of the N-deoxygenation as a general
challenge.
A range of 4-benzylpyridine N-oxides 5 was
subsequently tested under the optimized conditions
(Scheme 4). Oxidation of the unsubstituted 5a was
slower than its regioisomer 1a, but afforded 6a in
good yield in DMSO over 48h (Scheme 2). Electron-
withdrawing substituents on the phenyl and the
pyridine rings promoted the reaction, furnishing
moderate to good yields (59-88%) of 6b-d, 6f in 24h.
On the other hand, electron-donating substituents
considerably inhibited the process, and products 6e
and 6g were obtained with max. 52% and 24% yield
respectively, with (a large amount of) unreacted
substrate remaining. Increasing the reaction time to
48h was fruitless in these cases, as only lower mass
balance or larger amounts of degradation products
were observed. Finally, 4-benzoylquinoline N-oxide
6h was obtained in 41-47% yield, with about 20% of
the deoxygenated side product. As observed for the 2-
regioisomer benzo annulated systems are more
deoxygenation sensitive.
The generally lower reactivity of 4-benzylpyridine N-
oxides 5 compared to the corresponding 2-benzyl N-
oxide isomers 1 is in contrast with what observed
with analogous benzylpyridines in our previous work
4
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
Finally, Pd-catalyzed directed arylation[11b] with p-
tolyl bromide resulted in product 14 with 59% yield,
Pyridine ring functionalization on benzoylpyridine
N-oxides. As mentioned above, while pyridine ring
functionalization of benzoylpyridines is a non-viable
synthetic approach, the use of the corresponding N-
oxide analogues would allow such decoration, both
with electrophiles and nucleophiles. Compounds 3
(3a, 3e and 3m) and 6a were selected as model
systems to demonstrate the utility of the N-oxide
moiety for post-functionalization. A variety of
functionalization reactions could be efficiently
performed on 2-benzoylpyridine N-oxides (3)
(Scheme 5). Boekelheide rearrangement on 3a using
trifluoroacetic anhydride resulted in 68% of
pyridinone 9.[17] Closely related 6-methylated
substrate 3m gave 77% of the picolinyl alcohol 10.[18]
Amination was possible via reaction of 3a with Ts2O
and t-butylamine followed by de-t-butylation with
TFA (11, 67%).[19] Cyanation and chlorination, using
respectively TMSCN/Me2NCOCl[20] and POCl3,[21]
occurred with 79% and 47% yield (12 and 13). The
formation of 13 is of particular importance, as the
aerobic oxidation of 2-benzyl-6-chloropyridine was
not successful with our initially reported method.[4b]
while
Pd-catalyzed
cross-dehydrogenative
olefination[22],[23] on substrate 3e with methyl acrylate
provided 15 in 53% yield. Complete regioselectivity
at the alpha position of the pyridine was achieved in
all transformations on 3.
Next we turned our attention to regioisomer 4-
benzoylpyridine N-oxide (6a) (Scheme 6). This
proved to be easily functionalized with a range of O-
and
N-nucleophiles
using
PyBroP
(bromotripyrrolidinophosphonium
hexafluorophosphate) as activating reagent in mild
conditions,[24] giving products 16-22 in 45-97% yield.
It is worth noting that this procedure proved
completely ineffective for the 2-benzoyl substrate 3a.
Cyanation, chlorination, directed arylation and cross-
dehydrogenative olefination on 4-benzoylpyridine N-
oxide (6a) were performed under the same conditions
used for the 2-benzoyl regioisomer. Generally higher
yields of the final products (23-26), in comparison
with the 2-benzoyl analogues, were obtained.
a)
b)
Figure 2. Kinetic profiles for the oxidation of a) 2- and 4-benzylpyridine N-oxides, and b) corresponding
benzylpyridines (FT-IR). Reaction conditions: substrate (5 mmol), CuI (10 mol%), DMSO (10 mL), O2
(balloon), 100°C.
5
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
Scheme 5. Functionalization of 2-benzoylpyridine N-oxides 3a, 3e and 3m.
Scheme 6. Functionalization of 4-benzoylpyridine N-oxide (6a); a) Et2NH used as base and reactant.
Apart from functionalization of the pyridine ring,
the removal of the N-oxide moiety can also be easily
performed by reaction with PCl3 as exemplified on 3a
and 6a, giving the corresponding benzoylpyridines 4a
and 7a (Scheme 7).[25] Interestingly, the use of
Zn/NH4Cl[26] results in the formation of benzylic
alcohols 27 and 28.[27] Alcohols of type 27 find
applications in the synthesis of APIs (active
pharmaceutical ingredients) such as Carbinoxamine
and Bepotastine (antihistaminic drugs). To our
knowledge, the direct reduction of aroylpyridine N-
oxides to the corresponding benzhydrilic alcohols has
not been reported before.[28]
N-oxide (1 mmol), Zn (4.5 eq.), NH4Cl (15 mL), THF
(15 mL), r.t., 1h (50°C, 2h for 27).
Acrivastine synthesis. A concrete example of the use
of the N-oxides for oxidation/post-functionalization
processes is the formal synthesis of the antihistamine
Acrivastine (Scheme 8). The classical routes for the
synthesis of Acrivastine start from 2,6-
dibromopyridine using Li-Br exchange with BuLi
and quenching with 4-cyanotoluene to install the 2-
benzoyl moiety. The acrylate moiety is introduced via
formylation, through Li-Br exchange with BuLi and
quenching with DMF, followed by Wadsworth–
Emmons reaction with a phosphonate;[29] alternatively
a Pd-catalyzed Heck coupling with ethyl acrylate can
be used which does not require ketone protection,[30]
obtaining intermediate 29. Here, the synthesis of 29
starts from a much cheaper starting material, 2-
picoline-N-oxide, which was transformed into
intermediate 15 via three consecutive atom-economic,
N-oxide activated C-H functionalization processes
(Pd-catalyzed directed arylation of the picoline
methyl,[11a, b] Cu-catalyzed benzylic oxidation,[31] and
Pd-catalyzed cross-dehydrogenative olefination of the
pyridine C6-H). As expected (Scheme 1), no
functionalization occurred using 2-benzoylpyridines
in the same reaction conditions. Deoxygenation of 15
with PCl3 finally leads to 29. Transformation into
Acrivastine by reaction with triphenyl[2-(pyrrolidin-
1-yl)ethyl]phosphonium bromide has been reported in
the classical routes (Scheme 8).[29-30]
Scheme 7. Reduction of 2- and 4-benzoylpyridine N-
oxides 3a and 6a. Method A: N-oxide (0.5 mmol),
PCl3 (3 eq.), CHCl3 (1.5 mL), 80°C, 1h. Method B:
6
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
Scheme 8. Synthesis of the antihistaminic drug Acrivastine based on our new strategy versus classical
routes.[29-30]
Formation of benzoylpyridines via N-O cleavage.
Intrigued by the unexpected formation of
benzoylpyridine side-products (4 and 7), beside the
desired benzoylpyridine N-oxides (3 and 6), we
performed a series of control experiments on the 2-
regioisomers to ascertain the nature of this
transformation. The reductive cleavage of the N-O
bond in pyridine N-oxides is typically achieved by
reaction with main-group oxophilic species such as
P,[25] Al[32] and B[33] reagents. On the other hand, a
variety of transition metal salts have also been used,
either alone or in combination with reducing
agents,[34] to promote cleavage. Therefore, we
suspected this process to be related to the presence of
the copper catalyst in the reaction. We envisaged two
main pathways which could lead to the
benzoylpyridine side-products 4 under our reaction
Scheme 9. Possible N-deoxygenation pathways (top)
conditions: path a) benzylic oxidation of
and aerobic control experiments (bottom, reactions on
benzylpyridine N-oxide 1, followed by N-
0.5 mmol scale).
deoxygenation of 3; path b) N-deoxygenation of 1,
followed by oxidation of the benzylpyridine
intermediate 2 (Scheme 9). To discriminate between
the two pathways control experiments where
undertaken on 3b and 2b.
When the reaction product 3b was submitted to
the aerobic reaction conditions no deoxygenation was
observed (Scheme 9, eq. 1). Instead, reaction of 2b
under the same conditions furnished 34% of product
4b (eq. 2), suggesting path b as the reaction route.
The formation of only traces of 4a when starting from
unsubstituted N-oxide 1a is in accordance with this,
as 2-benzylpyridine (2a) was previously found to not
give oxidation into 4a in the absence of AcOH.[4a]
7
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
the possibility of an oxygen transfer from the N-oxide
to the benzylic carbon.[12d, 36] An experiment with a
mixture of equal amounts of N-oxide 1b and
benzylpyridine 2a resulted in the formation, among
others, of 4-benzoylpyridine (4a) in 35% yield,
proving the intermolecularity of the process (eq 4).
Importantly, this result also rationalizes the positive
effect of lowering the concentration in inhibiting the
de-oxygenation process (Tables 1 and 2). Further
proof was obtained by the reaction between 2-
benzylpyridine (2b) and pyridine N-oxide, yielding
58% of ketone 4b (eq. 5). Replacement of CuCl2 by
CuI completely suppressed the N-oxide transfer (eq.
5). These results suggest that oxidized Cu(II) species
(formed in-situ during the reaction under oxygen) are
responsible for both N-deoxygenation of substrates 1
and intermolecular oxygen transfer from the N-oxide
moiety to the benzylic carbon, leading to the ketone
side product 4.
Conclusion
In summary, we reported the Cu-catalyzed oxidation
of benzylpyridine N-oxides using molecular oxygen.
This reaction occurs without the use of additives,
typically
required
for
the
corresponding
benzylpyridines. 2-Benzylpyridine N-oxides 1 proved
generally more reactive than their 4-benzyl isomers 5,
although considerable differences are observed
depending on the electronic properties of the
substrate. In particular, differences are observed in
the amount of N-deoxygenation side products 4 and 7
formed, occurring by competitive anaerobic
intermolecular oxygen transfer between the N-oxide
moiety and the benzylic methylene (N-oxide as
oxidant). This anaerobic process could be suppressed
by reducing the concentration of the substrate in the
reaction.
The N-oxide moiety in the substrates has a triple role:
1) it allows smooth synthesis of starting materials 1
from cheap and commercially available pyridine N-
oxide (or derivatives); 2) it promotes the Cu-
catalyzed benzylic oxidation with O2; and 3) its
presence allows smooth post-functionalization of the
pyridine ring in reaction products 3 and 6, which is
not feasible on the corresponding deactivated
benzoylpyridines 4 and 7. A variety of such post-
functionalization procedures with both nucleophiles
and electrophiles (C-C, C-O, C-N and C-Cl bond
formation) was demonstrated. Finally, the triple role
of the N-oxide was demonstrated in a new formal
synthesis of Acrivastine, involving three consecutive
C-H functionalization processes.
Scheme 10. Control experiments under anaerobic
conditions to rationalize N-deoxygenation; anhydrous
CuCl2 was used.[2i] Reactions on 0.5 mmol scale.
To get more insight into the deoxygenation pathway,
the effect of a Cu(I) and a Cu(II) species on
compounds 1b and 3b under anaerobic conditions
(argon atmosphere) was tested. Product 3b again
proved unreactive in the deoxygenation process with
both CuI and CuCl2 (Scheme 10, eq. 1). On the
contrary, compound 1b, although not reactive in
DMSO in the presence of CuI (eq. 2), with CuCl2 led
to a number of compounds (eq. 3). Although
benzylpyridine 2b was not observed, 24% of 2-[1-(4-
chlorophenyl)-1-hydroxymethyl]pyridine
N-oxide
(30) and 11% of 2-(4-chlorobenzoyl)pyridine (4b)
were detected. As DMSO can act as an anaerobic
oxygen donor,[35] the products observed after the
aerobic reaction can be the results of a mixture of two
simultaneous processes. This reaction was therefore
repeated in inert solvents; reactions in BuOAc and
toluene resulted in the formation of 2-benzylpyridine
(2b) in 40-46% yield, and comparable amounts of the
corresponding ketone 4b (eq. 3). The formation of
considerable amount of ketone 4b and the absence of
doubly-oxygenated compound 3b made us consider
Experimental Section
General considerations
8
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
Infrared reaction monitoring experiments were
performed on a ReactIR spectrometer using a custom
made (DST, Ø 6.35 mm) DiComp AgX probe. All
the chemicals used were commercially available.
Crude materials were purified by flash
chromatography on silica gel if not otherwise
specified. NMR spectra were recorded at 400 MHz
(1H), 100 MHz (13C) and 376 MHz (19F) on a Bruker
AVANCE II 400 spectrometer in CDCl3 at ambient
The crude material was purified with silica gel flash
chromatography (Heptane/EtOAc/MeOH) to afford
2-(4-methylbenzoyl)pyridine 1-oxide in 55 % yield
(0.059 g, 0.275 mmol) in DMSO and 81 % yield
(0.086 g, 0.406 mmol) in n-BuOAc. 1H-NMR
(CDCl3, 400 MHz) δH: 8.25 (d, 1H, J = 5.2 Hz), 7.75
(d, 2H, J = 8.0 Hz), 7.46-7.34 (m, 3H), 7.29 (d, 2H, J
= 7.9 Hz), 2.43 (s, 3H). 13C-NMR (CDCl3, 100
MHz) δC: 188.9 [C], 147.3 [C], 145.4 [C], 140.1
[CH], 132.7 [C], 129.6 [CH], 129.5 [CH], 126.8 [CH],
125.6 [CH], 125.5 [CH], 21.8 [CH3]. HRMS (ESI)
for C13H12NO2 [M+H]+, calcd 214.0868, found
214.0874; yellow solid; mp: 124 °C.
13
temperature if not otherwise specified. For C-NMR
spectra descriptions, CH3, CH2 and CH signals were
attributed using DEPT experiments. Chemical shifts
(δ) were reported in parts per million (ppm) from the
residual solvent peak with tetramethylsilane (TMS)
as internal standard. Coupling constants (J) were
expressed in Hz. Melting points were measured on a
Büchi Melting Point B-545 apparatus. Positive ion
mode accurate mass spectra (electrospray) were
acquired using a QTOF II instrument (Waters,
Manchester, UK). The MS was calibrated prior to use
with a 0.1% H3PO4 solution. The spectra were lock
mass corrected using the know mass of the nearest
H3PO4 cluster. LC-MS samples were prepared in
MeCN at a concentration of 10-5M, and injected on a
Waters AcQuity UPLC system equipped with a
HALO C18 column (2.1 x 30 mm, 2.7 µm). The
samples were eluted with H2O/MeCN (gradient:
90/10 to 5/95, flow rate: 0.5 mL/min), and analyzed
with a Waters micromass ZQ (ESI+ and ESI-) with a
Photo Diode Array (PDA) detector. The starting
materials needed for this investigation were prepared
from the corresponding picoline N-oxides, pyridine
N-oxides or 2-chloro- or 4-chloro-pyridine N-oxides
via respectively C(sp3)-H bond arylation,[11a] C(sp2)-
Synthesis of 6-Benzoylpicolinonitrile (12)[20]
An oven dried 10 mL vial was charged with 2-
benzoylpyridine 1-oxide (0.199 g, 1 mmol), 100mg
MS (powder) and 2 mL DCM. Under Ar (balloon),
trimethylsilylcyanide (0.150 ml, 1.200 mmol) and
dimethylcarbamoyl chloride (0.110 ml, 1.200 mmol)
were added to the mixture through syringe. The vial
was sealed with an aluminum crimp cap and a
pressure cap, and the mixture was stirred at 100°C for
24h. At the end of the reaction, the mixture was
diluted with 20 mL DCM, 20 mL NaHCO3 (sat.
solution) were added, and the mixture stirred for 20
min. The mixture was then extracted with DCM
(3x20 mL), organic fractions dried over MgSO4,
filtered and concentrated. The crude material was
purified
using
a
semi-automated
flash
chromatography system on silica gel cartridges (12g)
using mixtures of heptane, EtOAc and MeOH as
eluents (gradient: 100% heptane to EtOAc/MeOH:
80/20 over 30 min, flow rate: 25-30 mL/min). The
product was obtained in 79% yield (165 mg, 0.792
mmol). 1H-NMR (CDCl3, 400 MHz) δH: 8.28 (d, 1H,
J = 8.0 Hz), 8.14 (d, 2H, J = 8.0 Hz), 8.08 (t, 1H, J =
7.9 Hz), 7.90 (d, 1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.4
Hz), 7.53 (t, 2H, J = 7.7 Hz). 13C-NMR (CDCl3, 100
MHz) δC: 191.3 [C], 156.3 [C], 138.4 [CH], 135.1
[C], 133.7 [CH], 132.5 [C], 131.2 [CH], 130.5 [CH],
128.4 [CH], 127.6 [CH], 116.7 [C]. HRMS (ESI) for
C13H9N2O [M+H]+, calcd 209.0715, found 209.0719;
white fluffy solid; mp: 113 °C.
H bond benzylation,[14] and cross-coupling reactions
15]
with benzylzinc derivatives,[6b,
using previously
reported procedures. All reactions were performed
under magnetic stirring.
General procedure for the Cu-catalyzed aerobic
benzylic oxidation
A 10 mL vial was charged with the N-oxide (0.5
mmol), CuI (0.05 mmol, 10mol%) and DMSO (1
mL) or BuOAc (1 mL). The vial was flushed with O2,
capped with an aluminum crimp cap with septum,
and an oxygen balloon was inserted through the
septum. The reaction mixture was stirred for 24 h at
120 °C. After completion the reaction mixture was
transferred to a separation funnel, 20 mL of brine
were added, and the mixture was extracted with DCM
(3 x 20 mL). The combined organic layers were dried
on MgSO4, filtered, and concentrated. The crude
material was purified using a semi-automated flash
chromatography system on silica gel cartridges (12g)
using mixtures of heptane, EtOAc and MeOH as
eluents (gradient: 100% heptane to EtOAc/MeOH:
80/20 over 30 min, flow rate: 25-30 mL/min).
Synthesis
of
(6-Chloropyridin-2-
yl)(phenyl)methanone (13)[21]
A
round-bottom flask was charged with 2-
benzoylpyridine 1-oxide (0.199 g, 1 mmol), then
phosphorusoxychloride (0.918 ml, 10.00 mmol) was
slowly added. The mixture was refluxed (set
temperature oil bath 110⁰C) under Ar for 24h. At the
end, the reaction was placed in an ice bath, and 10
mL of water were slowly added, while stirring. The
resulting solution was slowly poured into a 50 mL aq.
NaHCO3 saturated solution. The mixture was then
extracted with DCM (4x20mL). The combined
organic extracts were dried over MgSO4, filtered and
concentrated. The crude material was purified using a
semi-automated flash chromatography system on
2-(4-Methylbenzoyl)pyridine
Acrivastine synthesis intermediate): The general
method was applied using 2-(4-
methylbenzyl)pyridine 1-oxide (0.100 g, 0.5 mmol).
1-oxide
(3e,
9
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
silica gel cartridges (12g) using mixtures of heptane,
EtOAc and MeOH as eluents (gradient: 100%
heptane to EtOAc/MeOH: 80/20 over 30 min, flow
rate: 25-30 mL/min). The product was isolated in
chromatography system on silica gel cartridges (12g)
using mixtures of heptane, EtOAc and MeOH as
eluents (gradient: 100% heptane to EtOAc/MeOH:
80/20 over 30 min, flow rate: 25-30 mL/min). The
product was obtained in 53% yield (157 mg, 0.53
mmol). 1H-NMR (CDCl3, 400 MHz) δH: 8.00 (d, 1H,
J = 16.2 Hz), 7.70 (d, 2H, J = 8.0 Hz), 7.65 (dd, 1H, J
= 2.8 Hz, 7.1 Hz), 7.39-7.31 (m, 2H), 7.26 (d, 2H, J =
8.3 Hz), 7.09 (d, 1H, J = 16.2 Hz), 3.79 (s, 3H), 2.40
1
47% yield (103 mg, 0.47 mmol). H-NMR (CDCl3,
400 MHz) δH: 8.14-8.10 (m, 2H), 7.96 (dd, 1H, J =
0.6 Hz, 7.6 Hz), 7.87 (t, 1H, J = 7.8 Hz), 7.62 (t, 1H,
J = 7.4 Hz), 7.54-7.48 (m, 3H). 13C-NMR (CDCl3,
100 MHz) δC: 191.8 [C], 155.3 [C], 150.3 [C], 139.6
[CH], 135.6 [C], 133.3 [CH], 131.1 [CH], 128.3 [CH], (s, 3H). 13C-NMR (CDCl3, 100 MHz) δC: 188.6 [C],
127.1 [CH], 123.1 [CH]. HRMS (ESI) for
C12H9NOCl [M+H]+, calcd 218.0367, found
218.0380; green oil.
166.6 [C], 148.2 [C], 145.4 [C], 145.3 [C], 133.4
[CH], 132.6 [C], 129.6 [CH], 129.2 [CH], 126.7 [CH],
125.1 [CH], 125.0 [CH], 124.8 [CH], 52.0 [CH3],
21.8 [CH3]. HRMS (ESI) for C17H16NO4 [M+H]+,
calcd 298.1079, found 298.1087, yellow oil.
Synthesis of 2-Benzoyl-6-(p-tolyl)pyridine 1-oxide
(14)[11b]
A 10 mL vial was charged with 2-benzoylpyridine 1-
oxide (0.797 g, 4.00 mmol), palladium(II)acetate
(0.011 g, 0.05 mmol), potassium carbonate (0.276 g,
2 mmol), tri(tert-butylphosphonium)tetrafluoroborate
(0.044 g, 0.15 mmol), 4-bromotoluene (0.171 g, 1.0
mmol) and 3.33 mL of toluene. The vial was flushed
with Ar, sealed with an aluminum crimp cap with
septum and stirred at 120 °C for 24h. At the end of
the reaction the mixture was cooled to room
temperature, then filtered through celite, washed with
DCM and evaporated. Further purification was
achieved via column chromatography with an
automated chromatography system using a Silica
Flash Cartridge applying a heptane-EtOAc-MeOH
gradient (from 50% heptane to 100% EtOAc in 15
minutes to 80% EtOAc, 20% MeOH in 15 minutes,
30 mL/min). 2-Benzoyl-6-(p-tolyl)pyridine 1-oxide
was obtained in 59% yield (174 mg, 0.601 mmol).
1H-NMR (CDCl3, 400 MHz) δH: 7.84 (d, 2H, J = 7.4
Hz), 7.77 (d, 2H, J = 8.1 Hz), 7.55 (t, 2H, J = 7.8),
7.46-7.36 (m, 3H), 7.29 (dd, 1H, J = 7.6, 1.7 Hz),
7.24 (d, 2H, J = 7.8 Hz), 2.37 (s, 3H). 13C-NMR
(CDCl3, 100 MHz) δC: 189.7 [C], 149.7 [C], 147,9
[C], 140.2 [C], 135.5 [C], 133.8 [CH], 129.3 [CH],
129.1 [CH], 128.9 [CH], 128.8 [CH], 128.6 [C],
127.7 [CH], 125.6 [CH], 123.4 [CH], 21.4 [CH3].
HRMS (ESI) for C19H16NO2 [M+H]+, calcd 290.1181,
found 290.1183; white solid; mp: 154 °C.
Acknowledgements
This work was supported by the Research Foundation Flanders
(FWO-Flanders), the Agency for Innovation by Science and
Technology (IWT-Flanders), UAntwerpen (BOF), the Hercules
Foundation and the COST Action CA15106 (C-H Activation in
Organic Synthesis, CHAOS).
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10.1002/adsc.201700588
Advanced Synthesis & Catalysis
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11
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FULL PAPER
Copper-Catalyzed Aerobic Oxygenation
of Benzylpyridine N-oxides and
Subsequent Post-Functionalization
Adv. Synth. Catal. Year, Volume, Page –
Page
Hans Sterckx,‡ Carlo Sambiagio,‡
Vincent Médran-Navarrete, and Bert U.
W. Maes*
12
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