Experimental and mechanistic insights into copper(ii)-dioxygen catalyzed oxidative: N -dealkylation of N -(2-pyridylmethyl)phenylamine and its derivatives

Article abstract of DOI:10.1039/c7ob02192e

A di-(2-pyridylmethyl)phenylamine ((PyCH₂)₂NPh) supported Cu(ii)/O₂ catalytic system was explored with the synthesis of pyridylmethyl-based compounds of carboxylate (PyCOOH), amide (PyC(O)NHPh), and imine (PyCHNPh) from the oxidative N-dealkylation of N-(2-pyridylmethyl)phenylamine (PyCH₂NHPh) and its derivatives, by means of controlling the addition of a base and/or water to the reaction system under a dioxygen atmosphere at room temperature. Experimental studies showed that the imine and amide species could be precursors in succession in the way to the final oxidation state of carboxylates. A cyclic catalytic mechanism was proposed including the base triggered C-H bond activation of the 2-pyridylmethyl group (PyCH₂-) and the intermolecular Cu-OOH α-hydrogen atom abstraction from the coordinated imine substrate (PyCHNPh).

Full text of DOI:10.1039/c7ob02192e

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Experimental and mechanistic insights into
copper(II)–dioxygen catalyzed oxidative
N-dealkylation of N-(2-pyridylmethyl)phenylamine
and its derivatives†
Cite this: DOI: 10.1039/c7ob02192e
Yang Wang,‡ Haixiong Liu,‡ Xiaofeng Zhang, Zilong Zhang and Deguang Huang
*
A di-(2-pyridylmethyl)phenylamine ((PyCH2)2NPh) supported Cu(II)/O2 catalytic system was explored with
the synthesis of pyridylmethyl-based compounds of carboxylate (PyCOOH), amide (PyC(O)NHPh), and
imine (PyCHvNPh) from the oxidative N-dealkylation of N-(2-pyridylmethyl)phenylamine (PyCH2NHPh)
and its derivatives, by means of controlling the addition of a base and/or water to the reaction system
under a dioxygen atmosphere at room temperature. Experimental studies showed that the imine and
amide species could be precursors in succession in the way to the final oxidation state of carboxylates.
A cyclic catalytic mechanism was proposed including the base triggered C–H bond activation of the
2-pyridylmethyl group (PyCH2–) and the intermolecular Cu–OOH α-hydrogen atom abstraction from the
coordinated imine substrate (PyCHvNPh).
Received 31st August 2017,
Accepted 9th October 2017
DOI: 10.1039/c7ob02192e
rsc.li/obc
ability of raw materials. Directed by these motivations, we have
undertaken investigations into a copper(II)-mediated amino
Introduction
Enzymatic copper–dioxygen reactive species1 play an important N-dealkylation reaction via the catalytic oxidation process, and
role as oxidative intermediates in many biological report herein the synthesis of 2-picolinic acid (PyCOOH),
oxidation processes such as those of dopamine N-phenylpicolinamide (PyC(O)NHPh) and N-(pyridin-2-yl-
β-monooxygenase,
hemocyanin
and
peptidylglycine methylene)phenylimine (PyCvNPh) from the same starting
α-amidating monooxygenase,2 concerning aliphatic C–H bond material N-(2-pyridylmethyl)phenylamine (PyCH2NHPh), by
deprotonation and thereafter hydroxylations.3 Recently, the controlling the addition of different bases and/or water to the
study of N-dealkylation has been of interest to chemists with catalytic molecular systems at room temperature.
the development of drug synthesis for the treatment of HIV,
cardiovascular diseases, hypertension and high blood
pressure.4 However, the application of enzymatic copper–
dioxygen adducts for the catalytic N-dealkylation of amines is
Results and discussion
still rarely reported,5 and the oxidation of alkyl amines to the
corresponding amides6 was limited to the use of rigorous reac-
tion conditions such as Ru(OH)x/Al2O3 at high temperature
and high pressure,7 or the strong oxidant t-BuOOH8 and/or
RuO4.9 Efficient molecular catalytic methods are required for
the progress of oxidative N-dealkylation including reactions
that are both chemo-selective and economical in the avail-
Complex [CuII(LN)(H2O)(OTf)](OTf) 1a (LN = (PyCH2)2NPh) was
readily prepared by the stirring of LN and Cu(OTf)2 in a moist
MeCN solution followed by the diffusion of Et2O into the fil-
trate over 3 days. The reaction of the complex 1a, PyCH2NHPh,
Et3N and trace of water in MeCN under a dioxygen atmosphere
generated
a
thermodynamic air-stable complex {[CuII(LN)
(PyCOO)](OTf)}n 1b in 53% yield (Scheme 1), which has been
structurally characterized by X-ray crystallography (Fig. 1).
Treatment of 1b with concentrated hydrochloric acid (37%)
followed by the extraction of organic species in CH2Cl2
afforded a carboxylate product (PyCOOH) as a white solid.
Modification of the experimental conditions by the absence of
copper salt, ligand (LN), base, dioxygen or water confirmed
that all these species were necessary for a successful trans-
formation from PyCH2NHPh to PyCOOH. The study showed
that the formation of the [CuII(LN)] moiety was crucial for the
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.
E-mail: dhuang@fjirsm.ac.cn
†Electronic supplementary information (ESI) available. CCDC 1560832, 1560849,
1560850, 1560839 and 1561119. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7ob02192e
‡These authors contributed equally to this work and should be considered co-
first authors.
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Table 1 Optimization studies for the formation of amide
En Cu(II)
Base
Oxi
T
Ligand Solv
Yield
1
2
3
4
5
6
7
8
Cu(OTf)2 t-BuOK
Cu(OAc)2 t-BuOK
O2
O2
O2
O2
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
60 °C LN
80 °C LN
RT
RT
RT
RT
LN
LN
LN
LN
LN
LN
LN
LN
LN
LN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
THF
92%
56%
81%
0
76%
0
CuCl2
None
t-BuOK
t-BuOK
Cu(OTf)2 t-BuONa O2
Cu(OTf)2 K2CO3
Cu(OTf)2 NaOH
Cu(OTf)2 None
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
Cu(OTf)2 t-BuOK
O2
O2
O2
N2
Air
O2
O2
O2
O2
O2
O2
0
0
0
Scheme 1 Routine and examination of substrates for the synthesis of
2-picolinic acid in the presence of O2 and water.
9
10
11
12
13
14
15
16
62%
88%
86%
0
60%
0
None
LN
LN
LN
CH2Cl2
0
Reaction conditions: amine (0.1 mmol), Cu(II) salts (10 mol%), ligand
(15 mol%), base (0.2 mmol), O2 (1 atm), solvent (1 mL). En = entry; Oxi
= oxidant; Solv = solvent.
obtained, it was shown that the reaction of (PyCH2)NH(PhCH3)
with Cu(OTf)2 (10 mol%), LN (15 mol%) as the supported
ligand, dioxygen as the oxidant, and t-BuOK as the base in
DMF solution at room temperature gave the best result to yield
the product, 4-methyl-N-phenylpicolinamide in a 92% yield.
Modification of the experimental conditions by the absence of
catalyst, base, oxidizing agent, or supported ligand (LN),
Fig. 1 Crystal structures of the complexes 1a (a) (CCDC 1560832†) and
1b (b) (CCDC 1560849†) showing a 50% probability ellipsoid.
process of highly efficient oxidative catalysis accompanied by respectively, confirmed that these species played critical roles
the addition of dioxygen as an oxidant. Other copper sources in this N-dealkylation reaction (entries 4, 8, 9 and 13). The pre-
such as Cu(BF4)2·6H2O and Cu(ClO4)2·6H2O provided the same sented results also indicated that the OTf− anion coordinated
product in similar yields. For the purpose of exploring the [CuII(LN)] moiety worked as a highly efficient molecular catalyst
scope of substrates acceptable for our reaction, seven likely in the process of oxidation of N-(2-pyridylmethyl)phenylamine
analogues L1–L7 were chosen as substrates on trial derivatives to amides together with dioxygen. The coordination
(Scheme 1), but no sign of 1b was found from the experiments. of the OTf− anion and/or H2O as the terminal groups led to a
In contrast, the bis-ligand coordinated complexes 1c and 1d relatively weak ligand field at the central copper atom and the
(Fig. S1†) were obtained instead of 1b when tridentate sub- attendant tendency to form a {CuII(LN)[(PyCH2)NH(PhCH3)]}
strates di-(2-pyridylmethyl)amine (L6) and N-methyl-N,N-di(2- (Fig. S2†) intermediate heading for the oxidative molecular
pyridylmethyl)amine (L7) were used as substrates for the reac- catalytic reaction. Other copper sources such as Cu(OAc)2
tions. It is shown that the phenyl, pyridyl and the aromatic sec- (entry 2) and CuCl2 (entry 3) provided the product in much
ondary amine groups are indispensable for the selection of lower yields, probably due to the presence of the strong ligand
reactive substrates suitable for this copper-mediated oxidative field of the OAc− and Cl− anions, respectively. Different sol-
N-dealkylation activation.
vents of DMF, MeCN, THF and CH2Cl2 were tried for the reac-
In order to better understand the formation and reactivity tion (entries 1 and 14–16). It appeared that the polarity of the
of copper–dioxygen adducts, we successfully repeated this oxi- solvents would have a large effect on the reaction with yields
dation reaction by means of organometallic catalysis methodo- of 92% in DMF down to 60% in MeCN and 0% in THF and
logy and isolated the product as amides analogously. CH2Cl2. Meanwhile, it was found that higher temperature had
We commenced the investigation by choosing 4-methyl-N-(2- a negative effect on the formation of the amide products
pyridylmethyl)phenylamine (PyCH2)NH(PhCH3) as a model (entries 1, 11 and 12). Finally, the reaction time was explored
substrate and explored the reaction by changing different ingre- at the points of 8 h, 16 h, 24 h and 36 h under the reaction
dients including the copper(II) salt, ligand, oxidant, base, solvent condition of entry 1 in Table 1. The reactions yielded the
and the reaction temperature to find out the most suitable con- product of (PyC(O))NH(PhCH3) in 87% (8 h), 91% (16 h), 92%
dition (Table 1). Based on the amount of experimental data (24 h) and 92% (36 h) after isolation. A suitable reaction time
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of 24 h was determined with the consideration of other bulky demonstrated that the bulky groups on the pyridine ring
substrates for a unified reaction condition, since bulky groups would inhibit the reactions with yields down to 70% (2k), 61%
on the phenyl and pyridyl rings of substrates might slow down (2m), and 46% (2n), in contrast to the pyridine-only substrate
the reaction rates dynamically.
which afforded a yield of 92% (2b). In addition, no product
Encouraged by the above results, we started to examine the species was detected when the 2-pyridylmethylamine deriva-
scope of the reaction as to other amine substrates for the cata- tives of L1–L7 (Scheme 1) were used as reaction substrates for
lytic reaction (Table 2). Firstly, alkyl substituted phenylamine the catalytic reaction, which was consistent with the result
derivatives (2b–2f) were employed for the study of the steric deduced from the inorganic section presented in Scheme 1.
effect on the reaction, and the experimental results showed
Interestingly, the catalytic products were found as imine
that 4-toluidine, 3-toluidine and 2-toluidine substituted species rather than amides when the base of Et3N was used for
phenylamine reactants yielded the desired amide products in the deprotonation of substrates instead of t-BuOK (Table 3(a)).
92% (2b), 68% (2c) and 51% (2d), respectively, with the 2,6-di- Traces of amides were also isolated as by-products with the
methylaniline substituted reactant giving only a 38% yield yield as low as 3–5% based on the amount of substrates used
(2e). Obviously, the steric effect would reduce the yield drasti- for the reaction. The exploration of suitable substrates for the
cally from the para-position to the meta- and/or ortho-position. generation of the imine products was carried out from the
The slightly larger ethyl group in the para-position (2f) could viewpoints of steric effect and electronic effect as well, and it
also lead to the decrease of yield over 20% by comparison of was found that the imine generation reaction was very sensitive
the methyl group at the same site (2b). Secondly, the electronic to the steric effect with the products yielding in 88% (3b), 60%
effect of substituents on the phenyl group was examined by (3c) and 28% (3d) for methyl substituted phenylamine sub-
employing variable substituents (2g–2j) in the para-position. strates in the para-, meta- and ortho-positions, respectively.
The results indicated that the electron-donating groups (2g2h) However, the study of the electronic effect failed due to unsuc-
showed positive effects on the reaction, but the use of elec- cessful attempts to isolate the corresponding imine products
tron-withdrawing groups on the phenyl group only gave pro- from major substrates, except for one sample that held an elec-
ducts at around 60–70% yield (2i2j). Finally, the investigation tron-donating group of methoxyl in the ortho-position of the
of the steric effect on the pyridine site of the substrates phenyl ring and produced the imine in low yield (40%, 3g).
Perhaps the generated imine species were too reactive to be
isolated for those ineffective reactions, since it has been
reported that the oxidation of imine to amides was possible in
10
the presence of strong oxidants KMnO4 and NaBO3/TFA11 or
Table 2 Scope of the reactions with respect to amides
by cyanide-mediated aerobic oxidation.12 Moreover, the
obtained imine was found in our lab able to be catalytically
Table 3 Scope of the reactions with respect to imines
All the reactions were performed on a 0.1 mmol scale under O2 All the reactions were performed on a 0.1 mmol scale under O2
(1 atm): Cu(OTf)2 (0.01 mmol), LN (0.015 mmol), amines (0.1 mmol), (1 atm): Cu(OTf)2 (0.01 mmol), LN (0.015 mmol), Et3N (0.1 mL), amine
t-BuOK (0.2 mmol), DMF (1 mL), RT, 24 h. Isolated yields were derivatives (0.1 mmol), DMF (1 mL), RT, 24 h. Isolated yields were
indicated.
indicated.
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oxidized to amide in the presence of the copper(II) catalyst, the
base of t-BuOK and dioxygen as well (Table 3(b)). This work
indicated that the imine could be the intermediate in the oxi-
dation reaction of N-(2-pyridylmethyl)phenylamine to the
corresponding amide.
On the basis of the above results, a catalytic mechanism is
proposed in Scheme 2. Mixing of the tridentate ligand LN with
Cu(OTf)2 generates the complex (A), which reacts with the
chelate ligand of PyCH2NHPh to produce the complex (B). In
the presence of a base, the proton of the secondary amine of
(B) is attacked to leave via the N–H bond cleavage to form an
intermediate (C). The species of (C) executes an intermolecular
two-electron reduction together with a joint (B) molecule to
afford the dicopper(I) species (D), which turns into a μ-peroxo
dicopper(II) intermediate (E) under two-electron oxidation in a
dioxygen atmosphere. In path A, the intermediate (E) receives
a proton from the base H+ (Et3N-H+) and divides into two
species of (F) and (G). The HOO− group prefers to stay at the
amine coordinated copper(II) side rather than the imine side
possibly due to less electron donation from the amine donor
than the imine donor. Thus, the imine product is released
Scheme 3 Summary of the controlled N-dealkylation of PyCH2NHPh in
the Cu(II)/O2 molecular system under mild conditions.
from (F) by the substrate of a triflate anion together with the
regeneration of the starting catalyst (A). Meanwhile, the
complex (G) can be protonated by a second portion of Et3N-H+
followed by the release of O2 and H2O to afford the complex
(B). In path B, the intermediate (E) may undergo nucleophilic
attack by the t-BuO− group at the amine coordinated copper(II)
side to form two species of (H) and (I), since the Cu(II) species
at the amine side shows stronger electrophilicity to the strong
electron donating group t-BuO− compared to the imine side.
The complex (H) may transfer to the species (B) after a substi-
tution reaction with the triflate anion. The copper(II) moiety
[Cu(II)–OOH] (I)13 shows high reactivity towards the elimin-
ation of water via hydrogen atom transfer (I → J) and oxygen
rebound to the carbon atom of the imine group (J → K) leads
to the formation of the intermediate (K),13,14 which accepts a
proton from the solution and performs an intramolecular
rearrangement reaction to produce the intermediate (L).
Pyridyl amide is released as the second catalytic product. In
path C, the species of (L) undergoes a hydrolysis reaction to
afford the coordination complex (M) when a trace of water is
present in the activation reaction (Scheme 1).
Conclusions
In summary, we have developed a simple and safe Cu(II)/O2-
catalytic molecular system for the oxidative N-dealkylation of
N-(2-pyridylmethyl)phenylamine (PyCH2NHPh) and its deriva-
tives to synthesize pyridylmethyl-based analogous compounds
of carboxylate (PyCOOH), amide (PyC(O)NHPh), and imine
(PyCHvNPh), by controlling the addition of bases and/or
water to the solution (Scheme 3). Experimental and mechanis-
tic studies showed that the imine and amide species could be
precursors in succession in the way to the final oxidation state
of carboxylate. This work shows a successful example regard-
ing the study of small molecule activation from the view of
bioinorganic chemistry, coordination chemistry and catalytic
chemistry, and offers an economic and efficient method for
the catalytic oxidation of the methylene groups of amines by
using an environmentally friendly catalyst, and a green oxidant
under mild reaction conditions, and might provide a chance
Scheme 2 Proposed catalytic process for the oxidative N-dealkylation
of N-(2-pyridylmethyl)phenylamine to imine, amide and carboxylate.
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to access the enzymatic copper–dioxygen system that could
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Experimental section
Cu(OTf)2 (3.6 mg, 0.01 mmol), N,N-bis(pyridin-2-ylmethyl)
phenylamine (LN) (4.1 mg, 0.015 mmol), t-BuOK (22.4 mg,
0.2 mmol) or (Et3N, 0.1 mL) and N-(2-pyridylmethyl)phenyl-
amine derivatives (0.1 mmol) were mixed in dried DMF (1 mL)
in a 35 mL Teflon screw-cap sealed tube. The tube was charged
with O2 (1 atm) and the mixture was vigorously stirred at RT for
24 h. After the reaction was completed, the reaction mixture was
diluted with dichloromethane (20 mL), filtered through a pad of
silica gel and concentrated under reduced pressure. The crude
product was purified on a silica gel column.
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Conflicts of interest
There are no conflicts of interest to declare.
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (Grant No. 21371171) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
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