Aerobic oxidative N-dealkylation of secondary amines in aqueous solution catalyzed by rhodium porphyrins

Article abstract of DOI:10.1142/S108842461450076X

N-dealkylation demonstrates an important biochemical oxidation reaction by cytochrome P450 and other monooxygenases. In this article, catalytic oxidative N-dealkylation of secondary amines was achieved using rhodium(III) tetra (p-sulfonato-phenyl) porphyrin ((TSPP)Rh^III) in aqueous solution with oxygen as the sole oxidant. Addition of benzaldehyde to trap primary amine product inhibited catalyst deactivation and dramatically increased reaction turnover numbers (TONs). Substrate scope examination suggested the reaction was performed with a preference for bulkier secondary amines. Kinetic study exhibited first-order kinetics with regard of (TSPP)Rh^III catalyst. Results from the Hammett study gave a σ value of -1.38, suggesting formation of an iminium ion intermediate in the rate determining step.

Full text of DOI:10.1142/S108842461450076X

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2014; 18: 1–7
DOI: 10.1142/S108842461450076X
Published at http://www.worldscinet.com/jpp/
Aerobic oxidative N-dealkylation of secondary amines
in aqueous solution catalyzed by rhodium porphyrins
LinYun, Ling Zhen, Zikuan Wang and Xuefeng Fu*◊
Beijing National Laboratory for Molecular Sciences, State Key Lab of Rare Earth Materials Chemistry and
Applications, Colleage of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
Dedicated to Professor Nagao Kobayashi on the occasion of his 65th birthday
Received 12 August 2014
Accepted 2 September 2014
ABSTRACT: N-dealkylation demonstrates an important biochemical oxidation reaction by cytochrome
P450 and other monooxygenases. In this article, catalytic oxidative N-dealkylation of secondary amines
III
was achieved using rhodium(III) tetra (p-sulfonato-phenyl) porphyrin ((TSPP)Rh ) in aqueous solution
with oxygen as the sole oxidant.Addition of benzaldehyde to trap primary amine product inhibited catalyst
deactivation and dramatically increased reaction turnover numbers (TONs). Substrate scope examination
suggested the reaction was performed with a preference for bulkier secondary amines. Kinetic study
III
exhibited first-order kinetics with regard of (TSPP)Rh catalyst. Results from the Hammett study gave
a ρ value of -1.38, suggesting formation of an iminium ion intermediate in the rate determining step.
KEYWORDS: oxidative N-dealkylation, secondary amines, rhodium porphyrin, iminium ion, water.
Werner-type complexes with the metal center. In addition,
the reported substrate scopes are, in most cases, limited
to N,N-dialkylaniline or tetrahydroisoquinoline motifs.
Recently, our group developed a green and general
INTRODUCTION
Amine moieties commonly occur as active groups in
drugs and other xenobiotics ingested into the body which
are conveniently metabolized through cytochrome P450
and other monooxygenase systems. N-dealkylation of
protocol for catalytic aerobic oxidative N-dealkylation
of tertiary amines in aqueous solution [7]. The substrate
amines represents an important oxidation type of this
scope was largely expanded to a variety of aliphatic
biochemical process and functions as the major pathway
tertiary amines and anilines.
for xenobiotic metabolism [1, 2]. A large number of
Despite a large number of studies on catalytic systems
studies are devoted to this transformation and two
alternative mechanisms were proposed: single electron
and mechanisms of N-dealkylation of tertiary amines [3],
onlyafewgroupsreportedsecondaryamineN-dealkylation
transfer (SET) [1b, 3, 5h] and hydrogen atom transfer
processes [8, 9]. However, this transformation is of equal
(
HAT) [4]. Generally, there are two commonly used
importance for converting secondary amines to more
polar primary amines in order to be easily excreted from
the body due to enhanced solubility. The reason for the
lack of literature reports largely lies on: (1) the stronger
coordination affinity of secondary amines towards
electrophilic metal center compared with tertiary amines,
the former of which forms stable metal-amine complex
that subsequently hampers C–N bond cleavage process
strategies for the cleavage of the C–N bond of amines:
by oxometal (M=O) complexes [5] or by low-valence
transition metal complexes [6] (Scheme 1). However,
high-valence transition metal complexes (non-oxo) are
rarely reported to catalyze this process probably due
to the strong coordination ability of amines to form
◊SPP full member in good standing
[10]; (2) the resulting primary amines inclined to poison
*
Correspondence to: Xuefeng Fu, email: fuxf@pku.edu.cn,
the metal center with facile formation of Werner-type
complexes which shut down the catalytic cycle [11]. With
tel: +86 10-6275-6035, fax: +86 10-6275-1708
Copyright © 2014 World Scientific Publishing Company

2
L. YUN ET AL.
R1
R3
R2
R4
R1
R2
O
III
5-
[
(TSPP)Rh (OH) ] + ((CH ) CH) NH
N
[O]
N
H
2
3
2
2
+
I
5-
R3
R4

→ [(TSPP)Rh ] + ((CH ) CH)NH
(2)
3
2
2
+
CH COCH + H O
3
3
2
Scheme 1. Aerobic oxidative N-dealkylation of tertiary amines
1
H NMR analysis at the end of the reaction showed that
one molecule of isopropylamine product coordinated to
rhodium complex (Fig. 1). Inhibiting product coordination
thus seemed crucial for improving reaction efficiency.
The same problem was encountered in our previous work
on the N-dealkylation of tertiary amines [7]. The small
TON of tertiary amine was subtly improved by addition
of acid to trap the resulting comparatively more basic
secondary amine product. However, since the basicity
of the secondary amine is, instead, stronger than that of
the corresponding primary amine [12], addition of acid
failed to improve the reaction TON (Table S2). In this
case, benzaldehyde was introduced to selectively trap
the resulting primary amine by immediate formation
of corresponding imine. As a result, the TON increased
dramatically to 410 (Table 1, entry 2). A higher TON
was obtained by running the reaction in a mixed
an interest in further extending the substrate scope, we
turned to study the oxidative N-dealkylation of secondary
amines. In this work, we describe a general method for
aerobic oxidative N-dealkylation of secondary amines
catalyzed by electrophilic metal complex (TSPP)Rh
in aqueous solution by in situ trapping of the resulting
III
primary amines.
RESULTS AND DISCUSSION
Optimization and substrate scope
The N-dealkylation of diethylamine was first
examined as the model reaction in aqueous solution
at 100°C under an atmosphere of oxygen. However,
the expected product ethylamine was not observed.
Instead, diethylamine coordinated Rh(III) complex
solvent MeOH-H O (9/1) to increase the solubility of
2
benzaldehyde (Table 1, entry 3). Screening reaction time
and temperature gave the optimum reaction condition at
1
was observed by H NMR, suggesting that the catalyst
1
00°C for 6 h (Table 1, entry 7). Optimization of (TSPP)
was poisoned by irreversible coordination of amine
substrates (Equation 1, Fig. S1). On the contrary, when
using diisopropylamine as the substrate, which binds
weaker towards rhodium than diethylamine, 80 TON
of isopropylamine was observed (Equation 2; Table 1,
entry 1), implying that steric bulk was a key factor on the
reactivity of secondary amines.
III
Rh mediated N-dealkylation of dicyclohexylamine also
gave the same reaction condition (Table S1).
The reactivity difference between diethylamine
and diisopropylamine allowed further understanding
of N-dealkylation of tertiary amines. Previously, we
proposed that the deactivation of catalytic systems of
tertiary amines was caused by irreversible coordination
of secondary amine products towards rhodium center
[6]. However, it now seems that for some substrates such
as N-ethyl-N-isopropylpropan-2-amine, which reacted
III
5-
[
(TSPP)Rh (OH) ] + (CH CH ) NH
2
3
2 2
(1)
III
4-

→ [(TSPP)Rh (OH)(HNEt )]
2
1
Fig. 1. Low field and high field H NMR spectrum of the catalyst form at the end of catalytic N-dealkylation of diisopropylamine
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J. Porphyrins Phthalocyanines 2014; 18: 2–7

AEROBIC OXIDATIVE N-DEALKYLATION OF SECONDARY AMINES IN AQUEOUS SOLUTION
3
III
a
Table 1. Optimization of (TSPP)Rh mediated N-dealkylation
of diisopropylamine
Table 2. Scope of secondary amines
a
b
Entry
Substrate
Product
TON Yield,
%
III
H
N
TSPP Rh
O
(
)
+
Ph
N
c
1
C H CHO
6
5
1
95
9.8
31.2
22.0
b
c
d
Entry
Solvent
C H CHO Time, h Temp.,°C TON
6
5
2
3
4
d
d
e
625
1
H O
0
2
2
100
100
100
100
100
100
100
100
80
80
410
564
452
607
683
777
842
606
245
2
2
3
4
5
6
7
8
9
H O
2
2
2
1
3
2
2
2
2
2
4
41
MeOH/H O
2
2
MeOH/H O
2
2
MeOH/H O
2
160
8.0
2
MeOH/H O
4
2
5
MeOH/H O
6
de
d
2
3
62
18.1
MeOH/H O
11
6
2
MeOH/H O
6
7
2
5
1
2.1
24.5
11.3
1
0
MeOH/H O
6
60
2
a
III
Reaction conditions: (TSPP)Rh (1.00 mmol), diisopropylamine
2.00 mmol), solvent(1.00 mL), benzaldehyde, under1 baroxygen.
MeOH/H O (9/1). Equivalence to the amount of amine. GC
491
226
(
b
c
d
2
8
9
e1
results. H NMR result.
1
17
5.8
8.5
further with the catalyst to generate primary amines,
the deactivation was actually due to primary amine
poisoning (Fig. S2). Therefore addition of acid not only
inhibited amine product coordination, but also, for some
tertiary amines, shut down the following N-dealkylation
of secondary amine products.
A series of aliphatic amines and aniline substrates
were investigated under the optimum condition (Table 2).
The formed imine was easily and quantitatively con-
verted back to primary amine by addition of HCl at
the end of the reaction followed with basic treatment,
thus the TON was measured on primary amine product
1
0
1
70
a
III
Reaction conditions: (TSPP)Rh (1.00 mmol), substrates
(2.00 mmol), MeOH (0.90 mL), H O (0.10 mL), benzaldehyde
2
b
(4.00 mmol), 100°C, 6 h, under 1 bar oxygen. GC results.
c
d1
e
imine product was measured. H NMR result. 228 TONs of
N-isopropylamine was formed.
groups were favored for N-dealkylation process (Table 2,
entries 6 and 7). In our previous work, tricyclohexylamine
remained inert towards N-dealkylation reaction, whereas in
this work, cyclohexylamine was produced with 226 TON
from oxidation of dicyclohexylamine (Table 2, entry 8).
Substituted N-isopropylaniline also showed decent TON in
the catalytic transformation, indicating good tolerance of
methyl and methoxy groups on the phenyl ring (Table 2,
entries 9 and 10).
(
Table S3). However, since the N-dealkylation product of
N-ethylisopropylamine was difficult to measure by either
1
H NMR or GC method, the corresponding imine product
was used to calculate TON. 195 TON was observed
which is far less than that of diisopropylamine (Table 2,
entry 1). 441 TON of tert-butylamine was produced upon
N-dealkylation of N-tert-butylisopropylamine (Table 2,
entry 3). Comparison with the result of diisopropy-
lamine (Table 1, entry 2) implied that C–N bond was
more easily cleaved with sterically bulkier alkyl groups
on the nitrogen atom [13]. Aromatic amine substrate
N-isopropylanilinewasalsoconvertedtoanilineexclusively
with 160 TON (Table 2, entry 4). For asymmetric
N-benzylisopropylamine that had two possible products,
isopropylaminewasthemainproductformed(Table2,entry
Kinetic study
The kinetics of the stoichiometric N-dealkylation
III
reaction of N-ethylisopropylamine by (TSPP)Rh in
the absence of dioxygen was studied in D O at room
2
1
5
). Both N-benzylaniline and N-benzyl-tert-butylaniline
temperature through H NMR. The progress of the
were N-debenzylated to form 51 TON of aniline and 491
TON of tert-butylamine respectively, which suggested that
secondary amines with steric bulkier N-alkyl or N-aryl
reaction was conveniently monitored by the disappearance
of the pyrrole H signal of (TSPP)Rh at 9.0 ppm (Fig. 2).
The reaction rate was obtained from the ratio of
III
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J. Porphyrins Phthalocyanines 2014; 18: 3–7

4
L. YUN ET AL.
1
III
Fig. 2. H NMR spectra of the kinetics of (TSPP)Rh catalyzed oxidative N-dealkylation of ethylisopropylamine (t = 0 min, t = 22
1
2
III
I
min, t = 47 min, t = 64 min). a: (TSPP)Rh , b: (TSPP)Rh , c: external standard benzaldehyde. d: ethylamine coordinated rhodium
species
3
4
Fig. 4. Hammett Plot for N-dealkylation of secondary anilines
III
Fig. 3. Kinetic study of (TSPP)Rh catalyzed oxidative
N-dealkylation of secondary amines. Concentration changes
III
by (TSPP)Rh . k and k represent product yields of N-isopropyl-
H
X
aniline and meta or para-substituted N-isopropylaniline
III
of (TSPP)Rh upon reaction with ethylisopropylamine,
i
[
NHEt Pr] = 50 mM at 298 K
pathways: Iminium cation and neutral carbinol species
[1, 3]. In order to gain some mechanistic understandings
intensity integration compared with an external standard
benzaldehyde.With the concentration of diisopropylamine
remained approximately constant throughout the reaction,
the first-order reaction rate of (TSPP)Rh was obtained
which was similar with rhodium porphyrin mediated
of the secondary amine N-dealkylation, the electronic
character of the transition state of the rate-determining
step was measured by conducting Hammett study. A
series of competition experiments using an equimolar
mixture of N-isopropylaniline and meta or para-
substituted N-isopropylaniline in one pot were carried out
at 100°C for 10 h [14] under an atmosphere of oxygen.
The relative rate constants k /k , which were expressed
III
N-dealkylation of tertiary amines (Fig. 3) [7].
X
H
Hammett study
as the ratio of the respective reaction yields TON /TON ,
X
H
During the mechanism studies for N-dealkylation of
amines, key intermediates were proposed in SET and HAT
correlated well with the substituent constant (s) values
of the Hammett linear free energy relationship (Table S4,
Copyright © 2014 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2014; 18: 4–7

AEROBIC OXIDATIVE N-DEALKYLATION OF SECONDARY AMINES IN AQUEOUS SOLUTION
5
R1
(
TSPP)RhIII
R2
H
N
H
H
R1
R2
R NH
R1
R2
1
2
N
C
H O
N
2
R3
- H+
c
O
C
R3
1
R3
a
b
R2
R3
2
NH R
2
1
H
e
H+
-
(TSPP)RhIII
(TSPP)RhI
(
TSPP)RhIII
(TSPP)Rh
R NH
1
2
PhCHO
f
d
PhCH=NR1
O2
III
Scheme 2. Proposed mechanism of (TSPP)Rh catalyzed oxidative N-dealkylation of secondary amines
Fig. 4) [15]. The ρ value of this reaction was -1.38,
suggesting positive charge build up in the transition
state, which was ascribed to the formation of iminium
ion intermediate in our system. The ρ value obtained was
larger than that of the ruthenium catalysed oxidation with
t-BuOOH (-0.84) by Murahashi’s group and smaller that
obtained in a RuCl ·nH O catalyzed oxidation with H O
molecular oxygen. Irreversible coordination of product
towards catalyst reduced reaction efficiency (Step e)
whereas Step f trapped the newly formed primary amine
immediately to inhibit deactivation of catalyst and
improved catalyst TON (Scheme 2).
3
2
2
2
EXPERIMENTAL
in the presence of methanol (-3.26). Follow-up study
using the ruthenium catalyst led to an aerobic oxidative
cyanation reaction of tertiary amines, with a ρ value of
Chemicals and apparatus
-3.35. Iminium ion intermediates were proposed in the
TSPPH ligand was purchased from Tokyo Chemical
2
rate determining step of both reactions [16]. In order to
trap the in situ formed iminium ion, oxidative cyanation
of tertiary amines was developed using TMSCN as the
nucleophile. Preliminary studies led to catalytic formation
of a-aminonitrile product with up to 107 TON (Table S5).
The results highly suggest generation of iminium ion
intermediate in N-dealkylation of amines.
Previously, Collman and co-workers reported an
unusual stoichiometric C–N bond activation of tertiary
amines by rhodium(III) corroles. They proposed that
bC–H elimination was involved in the mechanism [17].
Chan and co-workers reported a stoichiometric activation
of aC–H bond of amines to form rhodium alkyl complex
by rhodium porphyrin chloride in neat amine conditions
Industry (TCI); [Rh(CO) Cl] from Strem Chemical Inc.;
2
2
andallotherchemicalswerepurchasedfromAldrichorAlfa
1
Aesar unless otherwise noted. Room temperature H NMR
spectra were recorded on a Bruker AV-400 spectrometer.
The chemical shifts were referenced to 3-trimethylsilyl-1-
propanesulfonic acid sodium salt (DSS). GC-MS results
were obtained by the Agilent 7980A/5975C GC/MSD
system. GC results were obtained by Agilent 7890A GC
with a flame ionization detector (FID). The rhodium
III
porphyrin species Na [(TSPP)Rh (H O) ] was synthe-
3
2
2
sized by literature methods ofAshley [20]. The equilibrium
III
-3
III
distribution of [(TSPP)Rh (D O) ] , [(TSPP)Rh (D O)
2
2
2
-4
III
-5
(
OD)] and [(TSPP)Rh (OD) ] were reported in the
2
previously published paper [19].
[
18]. The reaction yields of secondary amines were
rather low due to stronger ligand coordination. However,
for our aqueous system, the rapid oxidation of (TSPP)
General procedure for reaction condition
optimization
I
III
Rh to (TSPP)Rh by O gave this system the capability
2
to undergo catalytic oxidation processes [7, 19]. Based
on the proposed mechanism of oxidation of tertiary
amines and Hammett study, we proposed that the aerobic
catalytic oxidative N-dealkylation of secondary amines
III
(TSPP)Rh (1.00mmol),diisopropylamine(2.00mmol,
2000 equiv.), 1.00 mL solvent and benzaldehyde were
added into a 25 mL Schlenk flask sealed with a Teflon
cap. The mixture was stirred at different temperatures
for several hours after the flask was pressurized with
molecular oxygen (1 atm). The reaction mixture was then
cooled down to room temperature followed by addition
of 1 mL water and then extracted with ethyl ether. The
organic layer was washed with deionized water, dried
III
by (TSPP)Rh proceeded through a four-step cycle
III
involving: (a) amine coordination to (TSPP)Rh to
form complex 1; (b) bC–H elimination to give iminium
ion 2 and rhodium hydride species; (c) hydrolysis of 2
to produce N-dealkylation product and corresponding
III
carbonyl compound; (d) regeneration of (TSPP)Rh by
Copyright © 2014 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2014; 18: 5–7

6
L. YUN ET AL.
over NaSO and diluted to 10 mL in a volumetric flask.
is rarely reported but challenging and biologically
important. Addition of benzaldehyde into the system
served as a delicate solution for the product poisoning
problem. Combining Hammett study and peer work,
together with the feature of rhodium porphyrin system,
the reaction mechanism was proposed with bC–H
elimination as the rate determining step and iminium
ion as the key intermediate. Rapid hydrolysis of the
iminium ion in protic solvent as well as fast oxidation
of Rh(I) species by molecular oxygen might be the key
factors that contribute to the realization of this oxidation
reaction. Follow-up studies focusing on in situ trapping
and functionalization of the iminium ion is ongoing.
4
The resulting imines and aldehydes (or ketones) were
detected by GC-MS and the conversion was determined
1
by GC or H NMR.
General procedure for aerobic oxidative
N-dealkylation of secondary amines
III
(
TSPP)Rh (1.00mmol),secondaryamine(2.00mmol),
0
.9 mL methanol, 0.1 mL water, and benzaldehyde
(
4.00 mmol, 0.407 mL) was added into a 25 mL Schlenk
flask sealed with a Teflon cap. The mixture was stirred
at 100°C for 6 h after the flask was pressurized with
molecular oxygen (1 atm). Excess HCl solution was
added and the mixture was stirred at 80°C for several
hours until hydrolysis of imines to form primary amines
was complete. Then, the mixture was poured into NaOH
aqueous solution and extracted with ethyl ether. The
organic layer was washed with deionized water, dried
Acknowledgements
This work was supported by National Science
Foundation of China (21171012).
over NaSO and diluted to 10 mL in a volumetric flask.
Supporting information
4
The resulting primary amines were detected by GC-MS
and the conversion was determined by GC or H NMR.
Tables S1–S5 and Figs S1–S2 are given in the
supplementary material. This material is available free of
charge via the Internet at http://www.worldscinet.com/
jpp/jpp.shtml.
1
General procedure for Hammett study
1
.00 mL 1 mmol/L methanol solution of (TSPP)
III
Rh , 0.407 mL benzaldehyde, 1.00 mmol meta or
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of secondary amines in aqueous solution by rhodium
porphyrins. This system is not only a steady expansion
of N-dealkylation of amines, but also offers insights
into catalytic transformation of secondary amines which
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