Oxidative deamination of benzylamine by electrogenerated quinonoid systems as mimics of amine oxidoreductases cofactors

Article abstract of DOI:10.1021/jo000478l

The reactions of a new type of quinonoid system with benzylamine have been investigated in methanol in order to mimic the reactions occurring in the course of the enzymatic oxidation of amines by quinone cofactors. Under strictly anaerobic conditions, unstable quinonoid species 1_OX-4_OX have been selectively electrogenerated using anodic-controlled potential electrolysis. Thus, we have demonstrated that 3,4-quinone 1_OX is incapable of deaminating benzylamine, while 3,4-iminoquinone species 3_OX and 4_OX act as efficient catalysts for the autorecycling oxidation of benzylamine: the reaction efficiency reached 64 turnovers. Additional mechanistic investigations reveal that the oxidation of benzylamine by our quinonoid model cofactors proceeds unambiguously via a transamination mechanism, as suggested for many enzymatic systems.

Full text of DOI:10.1021/jo000478l

8874
J . Org. Chem. 2000, 65, 8874-8881
Oxid a tive Dea m in a tion of Ben zyla m in e by Electr ogen er a ted
Qu in on oid System s a s Mim ics of Am in e Oxid or ed u cta ses Cofa ctor s
Martine Largeron and Maurice-Bernard Fleury*
Laboratoire de Chimie Analytique et Electrochimie, UMR 8638 CNRS - Universite´ Rene´ Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire,
75270 Paris Cedex 06, France
Received March 29, 2000
The reactions of a new type of quinonoid system with benzylamine have been investigated in
methanol in order to mimic the reactions occurring in the course of the enzymatic oxidation of
amines by quinone cofactors. Under strictly anaerobic conditions, unstable quinonoid species 1ox
-
4ox have been selectively electrogenerated using anodic-controlled potential electrolysis. Thus, we
have demonstrated that 3,4-quinone 1ox is incapable of deaminating benzylamine, while 3,4-
iminoquinone species 3ox and 4ox act as efficient catalysts for the autorecycling oxidation of
benzylamine: the reaction efficiency reached 64 turnovers. Additional mechanistic investigations
reveal that the oxidation of benzylamine by our quinonoid model cofactors proceeds unambiguously
via a transamination mechanism, as suggested for many enzymatic systems.
In tr od u ction
far involve a carbinolamine intermediate (Scheme 1). The
most popular pathway is akin to the transamination
reaction of pyridoxal phosphate with amino acids. This
involves a tautomerization of the benzyliminoquinone
species to the product Schiff base, which is then hydro-
lyzed to yield the aldehyde product and the aminophenol.
The latter is autoxidized to the iminoquinone species,
which is in turn hydrolyzed to the quinone and ammonia.
The alternative is an addition-elimination mechanism
proposed first for PQQ, in which the carbinolamine is
directly converted into the quinol and benzylimine with-
out generating an aminophenol intermediate.5 The quinol
is then autoxidized to regenerate the quinone. The
observation of catalytic turnover did not permit a distinc-
tion between transamination and addition-elimination
mechanisms. Furthermore, attempts to distinguish under
anaerobic single-turnover between these two mechanisms
through product analysis (aminophenol from transami-
nation or quinol from addition-elimination) were thwarted
by the occurrence of redox interchange reactions that
scrambled the initial cofactor reduction product.7 None-
theless, in the case of the TPQ- and TTQ-catalyzed amine
oxidation reaction, solutions were found to circumvent
these problems, allowing the demonstration of a preferred
transamination mechanism.10,11
Copper amine oxidases and bacterial amine dehydro-
genases are enzymes containing a covalently bound
quinone cofactor. These enzymes catalyze the oxidative
deamination of a primary amine to produce the corre-
sponding aldehyde and ammonia, concomitant with a
two-electron reduction of dioxygen to hydrogen peroxide.1
For instance, the active carbonyl cofactor used by mam-
malian copper amine oxidases is the quinone form (TPQ)
of an active site 2,4,5-trihydroxyphenylalanine (TOPA)
residue.2 Likewise, the bacterial methylamine dehydro-
genase has been shown to contain an active site tryp-
tophan tryptophylquinone (TTQ). It is also well-known
that pyrroloquinoline quinone (PQQ) behaves as a cata-
lyst of amine oxidation, although PQQ is now recognized
not to be the cofactor of amine oxidases.3
The design of artificial catalysts that begin to approach
the reactivity of amine oxidoreductases cofactors is a
challenging problem that could provide further insight
into the function of the quinonoid cofactors in amine
oxidation. Several synthetic models of naturally occurring
quinones have been developed, and model reactions of
amine oxidoreductases were examined.4-9 In particular,
substantial information has been obtained through cata-
lytic aerobic deamination of benzylamine mediated by
model cofactors, providing relevant insight into the
enzyme catalysis. All the ionic mechanisms proposed so
In the course of our search for new neuroprotective
agents, we recently reported the one-pot electrochemical
syntheses of two novel classes of derivatives exhibiting
potent neuroprotective activities close to that of standard
R-tocopherol.12,13 The key step consisted of the reactivity
of the highly electrophilic electrogenerated 3,4-quinone
1ox (Chart 1) with amino alcohols. Depending on the
nature of the condensed amino alcohols, attack at the
2-position led to 3-substituted-1,4-benzoxazin-8-one de-
rivatives, while attack at the 3-position gave substituted
(1) Stubbe, J . A.; Van der Donk, W. A. Chem. Rev. 1998, 98, 705.
(2) Klinman, J . P. Chem. Rev. 1996, 96, 2541.
(3) J anes, S. M.; Mu, D.; Wemmer, D.; Smith, A. J .; Kaur, S.; Maltby,
D.; Burlingame, A. L.; Klinman, J . P. Science 1990, 248, 981.
(4) Rodriguez, E. J .; Bruice, T. C. J . Am. Chem. Soc. 1989, 111, 7947.
(5) Itoh, S.; Mure, M.; Ogino, M.; Ohshiro, Y. J . Org. Chem. 1991,
56, 6857.
(6) Itoh, S.; Takada, N.; Ando, T.; Haranou, S.; Huang, X.; Ue-
noyama, Y.; Ohshiro, Y.; Komatsu, M.; Fukuzumi, S. J . Org. Chem.
1997, 62, 5898.
(7) Lee, Y.; Sayre, L. M. J . Am. Chem. Soc. 1995, 117, 3096 and
references therein.
(8) Mure, M.; Klinman, J . P. J . Am. Chem. Soc. 1995, 117, 8707
and references therein.
(10) Lee, Y.; Sayre, L. M. J . Am. Chem. Soc. 1995, 117, 11823.
(11) Itoh, S.; Takada, N.; Haranou, S.; Ando, T.; Komatsu, M.;
Ohshiro, Y.; Fukuzumi, S. J . Org. Chem. 1996, 61, 8967.
(12) Largeron, M.; Lockhart, B.; Pfeiffer, B.; Fleury, M.-B. J . Med.
Chem. 1999, 42, 5043.
(9) Kano, K.; Nakagawa, M.; Takagi, K.; Ikeda, T. J . Chem. Soc.,
Perkin Trans 2 1997, 1111.
(13) Larget, R.; Lockhart, B.; Pfeiffer, B.; Neudorffer, A.; Fleury, M.-
B.; Largeron, M. Bioorg. Med. Chem. Lett. 1999, 9, 2929.
10.1021/jo000478l CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/01/2000

Mimics of Amine Oxidoreductases Cofactors
J . Org. Chem., Vol. 65, No. 26, 2000 8875
Sch em e 1
Ch a r t 1
tages derive from the possibility of realizing selective
oxidation by varying the potential applied to the working
anode, we will endeavor to demonstrate that 3,4-quinone
1ox is incapable of deaminating benzylamine, while 3,4-
iminoquinone species 3ox and 4ox act as a new type of
efficient cofactor for the autorecycling oxidation of ben-
zylamine.
Resu lts a n d Discu ssion
Rea ction of th e Electr ogen er a ted 3,4-Qu in on e 1ox
w ith Ben zyla m in e. The cyclic voltammogram of com-
pound 1r ed (2 mM), in deaerated CH3OH containing
LiClO4 as the supporting electrolyte and an excess of
benzylamine (100 mM) at a dropping mercury electrode,
showed an oxidation peak Pa1, due to a diffusion-
controlled two-electron process, at - 140 mV vs SCE, the
sweep rate v being 0.5 V s-1. As can be seen in Figure 1
(curve a), a cathodic peak Pc1 appeared on the reverse
sweep, at - 190 mV vs SCE, illustrating the partial
reversibility of the two-electron transfer that could be
assigned to the 3,4-quinol 1r ed /3,4-quinone 1ox redox
couple. However, the redox potential E′0 could not be
accurately evaluated, under our experimental conditions,
as the system (Pa1, Pc1) did not fulfill all the diagnostic
criteria required for a reversible process, at least when
v was e500 V s-1: the ratio of the height of Pa1 over that
alkylaminophenols.14,15 The C(3) reactivity of the elec-
trogenerated 3,4-quinone 1ox was further extended to
amines. At the outset, we believed that 3,4-quinone 1ox
efficiently catalyzed the oxidative deamination of ben-
zylamine, in deaerated CH3OH, in a way reminiscent of
that reported for PQQ, TTQ, and TPQ model cofactors.
This paper describes our efforts to provide an unam-
biguous conclusion based on an electrochemical approach.
Through controlled potential electrolysis, whose advan-
of Pc1 never reached unity (iPc /iPa
0.8) and the value
∼
1
1
of EPa - EPc (E being the peak potential) was found to
1
1
be higher than 30 mV. Note that, in the reverse sweep,
a second reduction peak was recorded at a more negative
potential (-1720 mV vs SCE), due to the irreversible two-
electron reduction of the carbonyl group of the benzophen-
(14) Largeron, M.; Fleury, M.-B. Tetrahedron Lett. 1998, 39, 8999.
(15) Largeron, M.; Neudorffer, A.; Fleury, M.-B. Tetrahedron Lett.
1998, 39, 5035.

8876 J . Org. Chem., Vol. 65, No. 26, 2000
Largeron and Fleury
F igu r e 1. Progress of the cyclic voltammogram in the course of anodic controlled potential electrolysis of 1r ed (2 mM) at a mercury
working electrode (E ) - 180 mV vs SCE), in deaerated CH3OH containing LiClO4 (200 mM) and benzylamine (100 mM). Curve
a (s), before electrolysis; curve b (---), after consumption of 1 F mol-1 of substrate; curve c (-‚-), after exhaustive electrolysis (2.1
F mol-1). Arrowheads indicate the direction of the potential sweep; v ) 0.5 V s-1. The vertical arrow indicates the initial potential
point.
Ch a r t 2
due to a partially reversible two-electron transfer. The
lack of peak Pc1 in the voltammogram of the oxidized
solution clearly indicated that the electrochemical oxida-
tion of 1r ed was followed by a chemical reaction involving
the produced 3,4-quinone 1ox. The height of Pa2 was
found to be roughly identical to that of the initial peak
Pa1, and the voltammogram of the oxidized solution
exhibited a well-defined cathodic peak Pc3 at -1300 mV
vs SCE (Figure 1, curve c). This corresponded to the
reduction of N-benzylidenebenzylamine (PhCHdNCH2-
Ph), as further confirmed after recording the cyclic
voltammogram of an authentical sample. The progress
of the electrolysis was simultaneously followed by moni-
toring the UV-vis absorption spectrum. After applying
the potential E, no spectral changes were observed: the
UV-vis spectrum shown by the oxidized solution was
nearly identical with that of the monoanionic form of the
quinol 1r ed with λmax at 348 nm, suggesting a similarity
in their chromophoric groups. The preparative electroly-
sis was stopped after consumption of 2.1 faraday (F)
mol-1, when a negligible value of the current was
recorded, allowing the isolation of two benzylaminophe-
nols, 2r ed (16% yield) and 3r ed (5% yield), as the minor
products, along with aminophenol 4r ed (62% yield) as the
major product (see Experimental Section). The structure
of products 2r ed -4r ed justified, in the cyclic voltammo-
gram of the oxidized solution, the presence of the system
of peaks (Pa2, Pc2) that could be assigned to the oxidation/
reduction of the aminophenol/iminoquinone redox couples.
These structures were also consistent with the analogy
existing between the UV-vis absorption spectrum of the
one skeleton.16 From the results of preparative electroly-
ses, two different anodic behaviors could be distinguished,
depending on the selected potential.
Wh en th e con tr olled p oten tia l E of th e m er cu r y
p ool w a s fixed a t -180 m V vs SCE, i.e., at a potential
for which the quinol 1r ed could be oxidized exclusive of
the reaction products 2r ed -4r ed (Chart 2), a coulometric
value of 2.1 ( 0.1 was found for the number of electrons
(n) involved in the oxidation of one molecule of 1r ed . As
the electrolysis proceeded, a decrease in the Pa1 and Pc1
intensities was observed, while a new system of peaks
(Pa2, Pc2) developed at a 100 mV more positive potential,
(16) Largeron, M.; Dupuy, H.; Fleury, M.-B. Tetrahedron 1995, 51,
4953.
oxidized solution and that of the starting quinol 1r ed .

Mimics of Amine Oxidoreductases Cofactors
J . Org. Chem., Vol. 65, No. 26, 2000 8877
F igu r e 2. Progress of the cyclic voltammogram in the course of anodic controlled potential electrolysis of 1r ed (0.4mM) at a
mercury working electrode (E ) + 100 mV vs SCE), in deaerated CH3OH containing LiClO4 (40 mM) and benzylamine (20 mM).
Curve a (s), before electrolysis; curve b (---), after consumption of 2 F mol-1 of substrate; curve c (-‚-), after consumption of 10 F
mol-1; curve c is superimposed on curve b in the anodic domain. Arrowheads indicate the direction of the potential sweep; v ) 0.5
V s-1. The vertical arrow indicates the initial potential point.
At that point it could be deduced that, when the
controlled potential E of the mercury working electrode
was fixed at -180 mV vs SCE, i.e. at a potential for which
the quinol 1r ed could be electrochemically oxidized but
the reaction products 2r ed -4r ed remained nonoxidizable,
no catalytic behavior was observed. Accordingly, PhCHd
NCH2Ph (quantified in terms of benzaldehyde phenyl-
hydrazone obtained upon workup of the oxidized solution
with phenylhydrazine) was isolated in equimolar amount
of the anodic electrolysis (n > 40) a new cathodic peak
Pc4 developed at a more negative potential (-1550 mV
vs SCE), which could be assigned to the reduction of
PhCHO, as corroborated after recording the cyclic vol-
tammogram of an authentical sample; (b) the voltammo-
gram given by the exhaustively oxidized solution no
longer exhibited the pair of peaks (Pa2, Pc2).
As benzylamine was present in large amounts com-
pared with the quinonoid forms, these results supported
the suggestion that benzylamine suffered catalytic oxida-
tion. The turnover yield was first determined in terms
of the benzaldehyde phenylhydrazone, which was isolated
in 2600% turnover yield, based on 1r ed initial concentra-
tion (Table 1). To quantify more accurately the products
of benzylamine anodic oxidation, these were isolated after
subsequent electrochemical reduction of the exhaustively
oxidized solution conducted at a potential fixed at -1600
mV vs SCE, i.e. at a potential immediately following the
peak Pc4. The results of the exhaustive cathodic elec-
trolyses are summarized in Table 2. They indicated that
the main product of benzylamine oxidation was PhCHd
NCH2Ph, whereas PhCHO was present as a minor
product. As earlier reported,17 dibenzylamine 5 resulted
from a two-electron reduction process, while dimers 6 and
7, isolated as meso and (D,L) forms, arose from a one-
electron reduction mechanism. The formation of imida-
zolidine 8 could be reasonably regarded as proceeding
through a tandem two-electron oxidation-cyclization
based on the initial concentration of 1r ed
.
These results demonstrated that, under our experi-
mental conditions, the electrogenerated quinone 1ox was
incapable of deaminating benzylamine, whatever the
nature of the mechanism (path A or path B in Scheme
1). Consequently, the primary identification of 1ox as an
efficient catalyst for benzylamine oxidation proved to be
unfounded.
In contrast, w h en E w a s fixed a t +100 m V vs SCE,
i.e. at a potential following the peak Pa2 for which the
reaction products 2r ed -4r ed could be oxidized to the
iminoquinone forms 2ox-4ox, a different anodic behavior
was observed. After the consumption of 2 F mol-1, the
system of peaks (Pa2, Pc2) remained unchanged over a
long time, a result in agreement with a steady-state
catalytic behavior, while a significant increase in the
cathodic peak Pc3 intensity was observed (Figure 2). At
the same time, a new absorption band at 250 nm
markedly increased, its height being much higher than
the absorption band at 348 nm. The electrolysis pro-
ceeded further until a coulometric value of 55 ( 1 was
found for n. It could be noted that (a) during the last part
(17) Horner, L.; Skaletz, D. H. Liebigs Ann. Chem. 1975, 1210 and
references therein.

8878 J . Org. Chem., Vol. 65, No. 26, 2000
Largeron and Fleury
Ta ble 1. Yield s of Ca ta lytic Dea m in a tion of
Ben zyla m in e Med ia ted by Electr ogen er a ted Mod el
Qu in on oid Cofa ctor s in Dea er a ted CH3OHa
Sch em e 2
yield (%)
substrate
(a)
(b)
1r ed
2r ed
3r ed
4r ed
2600
800
3200
3200
53
16
64
64
a
Electrochemical oxidation of the substrate was performed at
a mercury pool (E ) +100 mV vs SCE), [substrate] ) 2 mM,
[PhCH2NH2] ) 100 mM, under N2, in CH3OH. Control studies
indicated that the amount of PhCHO produced either from simple
autoxidation or from electrochemical oxidation of benzylamine in
the absence of catalyst was negligible. Yields represent mol % of
isolated benzaldehyde phenylhydrazone based on the initial
concentration of substrate (a) and on the initial concentration of
PhCH2NH2 (b).
Ta ble 2. P r od u cts a n d Yield s of Ca th od ic Con tr olled
P oten tia l Electr olysis Con secu tive to Ca ta lytic
Electr och em ica l Oxid a tion of Ben zyla m in e in Dea er a ted
CH3OHa
noquinone derivatives 3ox and 4ox, which proved to be
equivalent.
Rea ction of th e Electr ogen er a ted 3,4-Ben zylim i-
n oqu in on e 3ox w ith Ben zyla m in e. The cyclic voltam-
mogram of 3r ed (2 mM), in deaerated CH3OH containing
LiClO4 as the supporting electrolyte and an excess of
benzylamine (100 mM), at a dropping mercury electrode,
exhibited an oxidation peak Pa1 at -70 mV vs SCE, in
agreement with the two-electron oxidation of 3r ed to 3ox
.
a
Ean ) 100 mV vs SCE; Ecath ) 1600 mV vs SCE. Yields
The partial reversibility of the two-electron transfer was
illustrated by the appearance of a cathodic peak Pc1, on
the reverse sweep, at -120 mV vs SCE.
When E was fixed at +100 mV vs SCE, a decrease in
the Pa1 and Pc1 intensities was observed simultaneously,
while a new system of peaks (Pa2, Pc2) developed at a 30
mV more positive potential, due to a partially reversible
two-electron transfer. Simultaneously, the cathodic peak
Pc3, characteristic of the reduction of PhCHdNCH2Ph,
developed at -1300 mV vs SCE.
In the first procedure, the anodic electrolysis was
allowed to go to completion. As the electrolysis proceeded,
the system of peaks (Pa2, Pc2) remained unchanged for a
long time, consistent with a steady-state catalytic be-
havior, while the cathodic peak Pc3 continuously in-
creased. Finally, a coulometric value of 70 ( 1 was found
for n, and benzaldehyde phenylhydrazone was isolated
in 3200% turnover yield (Table 1).
represent mol % of isolated product based on the initial concentra-
tion of PhCH2NH2; [substrate] ) 2 mM, [PhCH2NH2] ) 100 mM,
under N2, in CH3OH. (a) 1red was used as the substrate; (b) 4r ed
was used as the substrate.
reaction of a dimer form, during isolation or upon column
chromatography (Scheme 2). Interesting enough, the
isolation of mixed dimer 9 constituted a proof of the
presence, in the exhaustively oxidized solution, of ben-
zaldehyde as the minor product. Mixed dimer 9 resulted
obviously from the condensation reaction of radicals
formed consecutively to the one-electron reduction of both
PhCHO and PhCHdNCH2Ph.17
Therefore, we were encouraged to think that one of the
iminoquinone systems 2ox-4ox could be effective in
benzylamine oxidative deamination. Consequently, to
clarify the substantial role of each iminoquinone form in
supporting the catalytic efficiency, the electrochemical
oxidation of compounds 2r ed -4r ed was separately per-
formed, in deaerated CH3OH, in the presence of benzyl-
amine excess. With 2r ed as the starting material, the
catalytic process ceased after 16 turnovers, and the yield
of benzaldehyde phenylhydrazone did not exceed 800%
(Table 1). As a consequence, 2ox could not be considered
as responsible for the potent catalytic efficiency (2600%
turnover yield) in deaminating benzylamine. So, we
focused our attention on the catalytic potential of imi-
In the second procedure, the anodic electrolysis was
spontaneously stopped after consumption of 2 F mol-1
.
Then, 3,4-aminophenol 4r ed was isolated in 70% yield
along with 6% of the recovered starting material 3r ed , a
result in agreement with a transamination mechanism,
which implied the 3,4-iminoquinone species 4ox as the
efficient catalyst in deaminating benzylamine.
The hypothesis that 4ox might play a crucial role in
the oxidative deamination of benzylamine was further

Mimics of Amine Oxidoreductases Cofactors
J . Org. Chem., Vol. 65, No. 26, 2000 8879
Sch em e 3
substantiated when considering the specific behavior of
4r ed , under the same experimental conditions.
associated with enzymatic systems: (a) the reaction
seems to be enhanced through the participation of
neighboring substituents, here, the benzoyl and 2-hy-
droxyl substituents, as they prevented the competing
formation of Michael adducts and (b) the presence of an
active hydroxyl proton at the 2-position very probably is
an essential component of the catalytic activity. It can
be remembered that similar active hydrogens (pyrrole
proton 1-NH of PQQ and hydroxyl proton 2-OH of TPQ)
were found to be essential for optimal catalytic activity.5,7
In this connection, further analogues development would
be useful to confirm the substantial role of both the
benzoyl and 2-hydroxyl groups in enhancing the reactiv-
ity of the iminoquinone ring.
Reaction of th e Electr ogen er ated 3,4-Im in oqu in o-
n e 4ox w ith Ben zyla m in e. The cyclic voltammogram of
4r ed (2 mM), in deaerated CH3OH containing LiClO4 as
the supporting electrolyte and an excess of benzylamine
(100 mM) at a dropping mercury electrode, showed an
oxidation peak Pa at - 40 mV vs SCE, characteristic of
the two-electron oxidation of 4r ed to 4ox.When E was fixed
at +100 mV vs SCE, the intensity of the anodic peak at
-40 mV vs SCE remained unchanged, in agreement with
steady-state catalytic behavior. When the electrolysis was
stopped after consumption of 2 F mol-1, 76% of the
starting material 4r ed was recovered without evidence of
other products. When the controlled potential electrolysis
was pursued beyond 2 F mol-1, the catalytic efficiency
was identical to that previously described from 3r ed . The
results of these experiments are collected in Tables 1 and
2.
Mech a n ism of Ben zyla m in e Oxid a tion . On the
basis of the results given by the controlled potential
electrolyses, we can formulate the following assumptions
about the mechanism of benzylamine oxidative deami-
nation. Electrogenerated 3,4-iminoquinone species 3ox
and 4ox turned out to be efficient catalysts in deaminating
benzylamine, producing 3200% turnover yield. The fact
that, starting from 3r ed , 4r ed was isolated in 70% yield
after a single turnover (2 F mol-1) clearly demonstrated
that the oxidative catalytic deamination of benzylamine
proceeded via a transamination mechanism. This in-
volved R-proton abstraction and the subsequent electron
flow from the R-carbon to the quinone moiety, to produce
the Schiff base intermediate 3′ox, the driving force being
the tendency to restore aromaticity within the 3,4-
iminoquinone ring. The proposed mechanism (Scheme 3)
is the analogue of path B in Scheme 1, which is the
accepted mechanism for catalytic deamination by quinon-
oid cofactors.
Con clu d in g Rem a r k s
In this paper, the catalytic efficiency of a new type of
quinonoid cofactor was investigated toward the oxidation
of benzylamine. Contrary to previous studies on related
redox cofactors, in our work the unstable quinonoid
species were electrogenerated. Under strictly anaerobic
conditions, the use of controlled potential electrolysis
enabled us to modulate the oxidative strength by a simple
variation of the potential applied to the working anode.
On this basis, we have established that electrogenerated
3,4-quinone 1ox was incapable of deaminating benzy-
lamine, while electrogenerated 3,4-iminoquinone species
3ox and 4ox behaved as effective catalysts. Under our
experimental conditions, the reaction efficiency reached
64 turnovers.
Finally, using 3r ed as the starting material, we were
led to conclude that the deamination mechanism of
benzylamine was akin to the transamination reaction
reported earlier for quinone cofactors of amine oxi-
doreductases. We are currently conducting experiments
to explore the ability of our model system 4ox to catalyze
the oxidative deamination of unactivated aliphatic pri-
mary amines.
Although the structure of our model compounds mark-
edly differs from that of naturally occurring quinones,
the reaction displays two features that are most often

8880 J . Org. Chem., Vol. 65, No. 26, 2000
Largeron and Fleury
hydroalcoholic solution was concentrated to remove CH3OH
and extracted with CH2Cl2 (100 mL). After the extract was
dried over MgSO4, evaporation of the solvent gave a pale
yellow oil from which pure dimer product 6 (meso form) was
isolated after washing with ethanol in 12% yield, based on the
initial concentration of PhCH2NH2. The resulting ethanolic
layer was concentrated to remove ethanol, leading to a crude
product which was purified by flash column chromatography
(SiO2, toluene-acetone gradient of 100:0 for 200 mL, 95:5 for
200 mL, and 90:10 for 200 mL. Dibenzylamine 5, dimer 7 (D,L
form), imidazolidine 8, and mixed dimer 9 were then isolated
in 11%, 10%, 5%, and 2% yields, respectively.
Exp er im en ta l Section
Chemicals were commercial products of the highest avail-
able purity and were used as supplied. All apparatus, cells,
and electrodes were identical with those described previously.18
P r epar ation of 4-Ben zylam in o-2,3-dih ydr oxyben zoph e-
n on e (2r ed ), 3-Ben zyla m in o-2,4-d ih yd r oxyben zop h en on e
(3r ed ), a n d 3-Am in o-2,4-d ih yd r oxyben zop h en on e (4r ed
)
fr om Electr och em ica l Oxid a tion of 1r ed in th e P r esen ce
of Ben zyla m in e. Meth od A. A solution of 2,3,4-trihydroxy-
benzophenone (1r ed ) (115 mg, 0.5 mmol), LiClO4 (5.30 g, 50
mmol), and benzylamine (2.67 g, 25 mmol) in CH3OH (250 mL)
was oxidized under N2, at room temperature, at a mercury
pool working electrode (E ) -180 mV vs SCE). After exhaus-
tive oxidation (2 F mol-1), i.e., when a negligible value of the
current was recorded, the methanolic solution was poured into
a molar citric acid buffered aqueous solution of pH ∼ 3 (100
mL). The resulting hydroalcoholic solution was concentrated
to remove CH3OH and extracted with ether (100 mL). After
the extract was dried over MgSO4, evaporation of the solvent
Diben zyla m in e 5: colorless oil. Spectroscopic data of
dibenzylamine have been reported earlier.21
N,N′-Diben zyl-1,2-d ip h en yl-1,2-d ia m in oeth a n e 6 (m eso
for m ): white solid recrystallized from ethanol, mp 149-151
°C; 1H NMR (300 MHz, CDCl3) δ 1.70 (s, br, 2H), 3.30 (d, 2H,
J ) 14 Hz), 3.55 (d, 2H, J ) 14 Hz), 3.75 (s, 2H), 7.00-7.35
(m, 20H); 13C NMR (75 MHz, CDCl3) δ 50.9, 67.1, 126.6, 127.6,
127.8, 128.1, 128.3, 128.5, 140.2, 140.7; MS DCI m/z 393
(MH+). Anal. Calcd for C28H28N2 C, 85.71; H, 7.14; N, 7.14.
Found: C, 85.77; H, 7.19; N, 7.11.
gave a dark yellow residue from which aminophenols 2r ed , 3r ed
,
and 4r ed were isolated in 16%, 5%, and 62% yields, respectively,
by flash column chromatography (SiO2, toluene-acetone gra-
dient from 100:0 to 95:5).
N,N′-Dib en zyl-1,2-d ip h en yl-1,2-d ia m in oet h a n e 7 (D,L
1
1
for m ): colorless oil; H NMR (300 MHz, CDCl3) δ 2.40 (s, br,
2r ed (recrystallized from ether): mp 124-126 °C; H NMR
2H), 3.50 (d, 2H, J ) 13 Hz), 3.75 (d, 2H, J ) 13 Hz), 3.80 (s,
2H), 7.10-7.40 (m, 20H); 13C NMR (75 MHz, CDCl3) δ 51.3,
68.3, 126.7, 126.9, 127.9, 128.0, 128.3, 140.6, 141.1; MS DCI
m/z 393 (MH+).
(300 MHz, DMSO-d6) δ 4.45 (d, 2H, J ) 5 Hz), 6.10 (d, 1H, J
) 9 Hz), 6.85 (d, 1H, J ) 9 Hz), 6.90 (t, 1H, J ) 5 Hz), 7.20-
7.35 (m, 5H), 7.40-7.55 (m, 5H), 8.95 (s, br, 1H), 12.70 (s, br,
1H); 13C NMR (75 MHz, DMSO-d6) δ 46.2, 103.1, 110.0, 127.8,
128.0, 128.3, 129.3, 129.5, 131.9, 130.4, 139.2, 140.8, 146.0,
3-Ben zyl-2,4,5-tr ip h en ylim id a zolid in e 8: colorless oil;
1H NMR (600 MHz, CDCl3) δ 2.05 (1H, broad s, NH, D2O
exchanged), 3.65 (2H, AB, J ) 16 Hz, CH2-N), 3.80 (1H, d, J
) 8 Hz, H-4), 4.42 (1H, d, J ) 8 Hz, H-5), 4.88 (1H, s, H-2),
6.95 (2H, broad d, J ) 8 Hz, ortho Ph-3), 7.20 (2H, broad d, J
) 8 Hz, ortho Ph-5), 7.25-7.40 (12H, m, aromatic proton), 7.45
(2H, broad d, J ) 8 Hz, ortho Ph-4), 7.70 (2H, broad d, J ) 8
Hz, ortho Ph-2); 13C NMR (150 MHz, CDCl3) δ 53.5 (CH2-N),
69.8 (C-5), 75.6 (C-4), 81.3 (C-2), 127.2-130.4 (CH, aromatic
carbon), 136.3, 140.5 and 142.7 (CQ, aromatic); HRMS (LC
TOF, reserpine as the lock mass) m/z 391.2185 (MH+) calcd
for C28H27N2 391.2174.
151.5, 197.0; MS DCI m/z 320 (MH+). Anal. Calcd for C20H17
-
NO3 C, 75.23; H, 5.33; N, 4.39. Found: C, 74.97; H, 5.37; N,
4.36.
3r ed (recrystallized from ether): mp 149-151 °C dec; 1H
NMR (300 MHz, DMSO-d6) δ 4.50 (d, 2H, J ) 5 Hz), 6.40 (d,
1H, J ) 9 Hz), 6.85 (d, 1H, J ) 9 Hz), 7.20-7.35 (m, 5H), 7.50-
7.65 (m, 5H), 12.80 (s, br, 1H); 13C NMR (75 MHz, DMSO-d6)
δ 50.1, 108.8, 113.1, 125.1, 126.9, 127.6, 128.5, 129.2, 129.4,
129.7, 132.4, 139.2 and 142.6, 155.3, 155.7, 201.0; MS DCI m/z
320 (MH+). Anal. Calcd for C20H17NO3 C, 75.23; H, 5.33; N,
4.39. Found: C, 74.93; H, 5.35; N, 4.37.
4r ed (recrystallized from CH2Cl2): mp 186-188 °C dec;
Spectroscopic data for product 4r ed have been reported ear-
lier.15
The relative stereochemistry of the three asymmetric cen-
ters was determined through a 2D NOESY experiment (mixing
time ) 250 ms). NOE cross-peaks were observed between H-2
and H-4, ortho Ph-5, on one hand, while correlations were
obtained between H-5 and ortho Ph-4, ortho Ph-2, on the other.
The carbon type (methyl, methylene, methide, or quaternary)
was determined by DEPT experiments.
Ca ta lytic Oxid a tion of Ben zyla m in e fr om Electr ogen -
er a ted 3,4-Qu in on e 1ox. Meth od B. A solution of 2,3,4-
trihydroxybenzophenone (1r ed ) (115 mg, 0.5 mmol), LiClO4
(5.30 g, 50 mmol), and benzylamine (2.67 g, 25 mmol) in CH3-
OH (250 mL) was oxidized under N2, at room temperature, at
a mercury pool working electrode (E ) +100 mV vs SCE). After
exhaustive oxidation (55 F mol-1), phenylhydrazine (2.70 g,
25 mmol) and 100 mL of a molar acetic buffered aqueous
solution of pH ∼ 4.5 were added to the reaction mixture. The
resulting hydroalcoholic solution was concentrated to remove
CH3OH and allowed to come to room temperature. The solid
was collected by filtration, washed with H2O, and dried in a
vacuum desiccator. Benzaldehyde phenylhydrazone was then
isolated as a colorless solid in 53% yield, based on PhCH2NH2
initial concentration, mp 156-158 °C (recrystallized from
toluene). Spectroscopic data of benzaldehyde phenylhydrazone
have been reported earlier.19,20
Meth od C. A solution of 2,3,4-trihydroxybenzophenone
(1r ed ) (115 mg, 0.5 mmol), LiClO4 (5.3 g, 50 mmol), and
benzylamine (2.67 g, 25 mmol) in CH3OH (250 mL) was
oxidized using method B. After exhaustive oxidation (55 F
mol-1), the resulting methanolic solution was immediately
reduced after the potential of the mercury pool was switched
to -1600 mV vs SCE. After exhaustive cathodic electrolysis,
the solution was poured into H2O (100 mL). The resulting
N-Ben zyl-1,2-d ip h en yl-a m in oeth a n ol 9: white solid re-
crystallized from ethanol, mp 156-158 °C; 1H NMR (300 MHz,
CDCl3) δ 1.70 (s, 1H), 3.00 (s, 1H), 3.55 (d, 1H, J ) 13 Hz),
3.75 (d, 1H, J ) 13 Hz), 3.95 (d, 1H, J ) 13 Hz), 4.85 (d, 1H,
J ) 6 Hz), 7.10-7.35 (m, 15H); 13C NMR (75 MHz, CDCl3) δ
51.0, 67.8, 76.7, 126.8, 126.9, 127.6, 127.7, 127.8, 128.0, 128.2,
128.3, 128.4, 139.1 139.8 and 140.3; MS DCI m/z 304 (MH+).
Anal. Calcd for C21H21NO C, 83.17; H, 6.93; N, 4.62. Found:
C, 82.87; H, 6.97; N, 4.60.
Ca ta lytic Oxid a tion of Ben zyla m in e by Electr ogen -
er a ted 4,3-Ben zylim in oqu in on e 2ox. The above-described
method A, replacing 1r ed by 2r ed , with E ) +100 mV vs SCE
and n ) 2, led, after flash column chromatography (SiO2,
toluene-acetone 98:2), to the recovered starting material in
75% yield.
The above-described method B, replacing 1r ed by 2r ed
,
allowed, after consumption of 18 F mol-1, the isolation of
benzaldehyde phenylhydrazone in 16% yield, based on the
initial concentration of PhCH2NH2.
Ca ta lytic Oxid a tion of Ben zyla m in e by Electr ogen -
er a ted 3,4-Ben zylim in oqu in on e 3ox. The above-described
method A, replacing 1r ed by 3r ed , with E ) +100 mV vs SCE
(18) Largeron, M.; Neudorffer, A.; Fleury, M.-B. J . Chem. Soc.,
Perkin Trans 2 1998, 2721.
(19) Yao, H. C.; Resnick, P. J . Org. Chem. 1965, 30, 2832.
(20) Barchiesi, E.; Bradamante, S.; Carfagna, C.; Ferriaccioli, R. J .
Chem. Soc., Perkin Trans 2 1988, 1565.
(21) Katrizky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi,
L. J . Chem. Soc., Perkin Trans 2 1989, 225.

Mimics of Amine Oxidoreductases Cofactors
J . Org. Chem., Vol. 65, No. 26, 2000 8881
and n ) 2 afforded, after flash column chromatography (SiO2,
toluene-acetone 90:10), compound 4r ed in 70% yield, along
The above-described method B, replacing 1r ed by 3r ed ,
allowed, after consumption of 70 F mol-1, the isolation of
benzaldehyde phenylhydrazone in 64% yield, based on the
initial concentration of PhCH2NH2.
with 6% of the recovered starting material 3r ed
.
The above-described method B, replacing 1r ed by 3r ed
,
allowed, after consumption of 70 F mol-1, the isolation of
benzaldehyde phenylhydrazone in 64% yield, based on the
initial concentration of PhCH2NH2.
The above-described method C, replacing 1r ed by 4r ed
,
afforded dibenzylamine 5 (13% yield), dimer compounds 6 (12%
yield, meso form) and 7 (10% yield, D,L form), imidazolidine
8 (4% yield), and mixed dimer 9 (2% yield).
Ca ta lytic Oxid a tion of Ben zyla m in e by Electr ogen -
er a ted 3,4-Im in oqu in on e 4ox. The above-described method
A, replacing 1r ed by 4r ed , with E ) +100 mV vs SCE and n )
2, led, after flash column chromatography (SiO2, toluene-
acetone 90:10), to the recovered starting material 4r ed in 76%
yield.
Ack n ow led gm en t. The authors are indebted to
Marc Vuilhorgne for HRMS and stereochemical attribu-
tion of compound 8.
J O000478L