A biomimetic electrocatalytic system for the atom-economical chemoselective synthesis of secondary amines

Article abstract of DOI:10.1021/ol802885b

A facile one-pot oxidation-imine formation-reduction route to secondary amines can be achieved electrolytically from primary amines. This atom-economical 1_ox-mediated sequence, leaving ammonia as the sole byproduct, allows the rapid chemoselect

Full text of DOI:10.1021/ol802885b

ORGANIC
LETTERS
2009
Vol. 11, No. 4
883-886
A Biomimetic Electrocatalytic System
for the Atom-Economical
Chemoselective Synthesis of Secondary
Amines
Martine Largeron* and Maurice-Bernard Fleury
UMR 8638 Synthe`se et Structure de Mole´cules d’Inte´reˆt Pharmacologique,
CNRS-UniVersite´ Paris Descartes, 4 aVenue de l’obserVatoire, 75270
Paris cedex 06, France
martine.largeron@parisdescartes.fr
Received December 15, 2008
ABSTRACT
A facile one-pot oxidation-imine formation-reduction route to secondary amines can be achieved electrolytically from primary amines. This
atom-economical 1ox-mediated sequence, leaving ammonia as the sole byproduct, allows the rapid chemoselective synthesis of secondary
amines, at both ambient temperature and pressure.
Secondary amines are highly versatile building blocks for
various organic substrates and are essential pharmacophores
in numerous biologically active compounds. Hence, the
development of efficient methods for the synthesis of
secondary amines has still been a challenging and active area
of research. Conventional synthetic approaches from primary
amines include reductive alkylation, protection-deprotection
strategy, and direct N-alkylation. However, these methods
suffer disadvantages such as low functional group tolerance,
harsh reaction conditions, lengthy sequences, and overalky-
lation.1
most important, metal-catalyzed N-alkylation of primary
amines with alcohols,4 amines,5 or nitriles6 represents
attractive approaches for the synthesis of secondary amines.
(2) For recent reviews on catalytic hydroamination of alkynes and
alkenes, see: (a) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407–
1420. (b) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. ReV. 2008, 108, 3795–3892.
(3) For recent reviews on metal-catalyzed amination of aryl halides, see:
(a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–
6361. (b) Hartwig, J. F. Nature 2008, 455, 314–322. (c) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534–1544.
(4) For selected recent examples see: (a) Fujita, K.-I.; Yamaguchi, R.
Synlett 2005, 4, 560–571. (b) Tillack, D.; Hollmann, D.; Michalik, R.;
Jackstell, R.; Beller, M. Tetrahedron Lett. 2006, 47, 8881–8885. (c)
Hoolman, D.; Tillack, A.; Michalik, D.; Jackstell, R.; Beller, M. Chem.
Asian J. 2007, 2, 403–410. (d) Hamid, M. H. S. A.; Williams, M. J. Chem.
Commun. 2007, 725–727. (e) Nordstrom, L. U.; Madsen, R. Chem. Commun.
2007, 5034–5036. (f) Fujita, K.-I.; Enoki, Y.; Yamaguchi, R. Tetrahedron
2008, 64, 1943–1954. (g) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita,
K.-I. Org. Lett. 2008, 10, 181–184. (h) Pontes da Costa, A.; Viciano, M.;
Sanau, M.; Merino, S.; Tejeda, J.; Peris, E.; Royo, B. Organometallics 2008,
27, 1305–1309.
To overcome these limitations, various efficient metal-
catalyzed syntheses of secondary amines have been devel-
oped in the past decade. Although the hydroamination of
alkenes or alkynes2 and the amination of aryl halides3 are
(1) For a review on the synthesis of secondary amines, see: Salvatore,
R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785–7811.
10.1021/ol802885b CCC: $40.75
Published on Web 01/27/2009
2009 American Chemical Society

A noteworthy example is the selective ruthenium-catalyzed
N-alkylation of aryl amines using aliphatic amines which
produces the corresponding N-alkyl-aryl amines, in high
yields, leaving ammonia as the only byproduct.5a
tautomeric enamine form of certain in situ generated alky-
limines as the cycloaddition partner in cascade reactions
leading to potent neuroprotective 1,4-benzoxazine deriva-
tives.10
The performance of a metal-free in situ oxidation-imine
formation-reduction sequence, using manganese dioxide in
combination with sodium borohydride or polymer-supported
cyanoborohydride, has also been reported for the conversion
of activated alcohols into secondary amines.7
Related routes to secondary amines could also be achieved
electrolytically from primary amines, but the fact these are
oxidized at relatively high anodic potentials (>+ 1.5 V vs
SCE), and give rise to unstable cation radicals that rapidly
deprotonate and attach to the electrode surface, does not
make it possible directly.8
Recently, we reported that electrogenerated o-imino-
quinone 1ox acted as an effective biomimetic catalyst for the
chemoselective oxidation of primary aliphatic amines, under
metal-free conditions. The mechanism was very close to the
ionic pyridoxal-like transamination process reported for
amine oxidase cofactors (Scheme 1).9 The formation of a
Next, we decided to investigate the utility of the electro-
catalyst 1ox for the synthesis of secondary amines through
the 1ox-mediated catalytic process followed by an electro-
chemical reduction of the extruded alkylimine. However, the
yield of the produced secondary amine could not exceed
50%, because two molecules of primary amine (eqs 2 and
5, Scheme 1) are required to produce one molecule of
alkylimine (eq 6, Scheme 1). Furthermore, secondary amines
possessing different substituents on both sides of the nitrogen
atom could not be prepared by this way.
Thus, we envisioned some modifications of our electro-
catalytic procedure, and we report herein a facile one-pot
metal-free 1ox-mediated oxidation-imine formation-reduction
sequence for the atom-economical chemoselective N-alky-
lation of activated primary amines with amines, under mild
conditions.
As a starting point of our investigations, we chose to
perform the 1ox-mediated catalytic oxidation of an activated
primary amine such as benzylamine, in the presence of a
nonactivated primary amine such as aminomethylcyclopro-
pane, which should serve as the alkylating agent. Upon
optimization, we found that a combination of 2.50 mmol of
benzylamine with 3.75 mmol of aminomethylcyclopropane
and 0.10 mmol of 1red which corresponds to 4 mol %
(relative to benzylamine) of the electrocatalyst 1ox, gave the
best results. Then, the 1ox-mediated catalytic oxidation step
was realized under the previously reported conditions, which
required a platinum anode and methanol as the solvent.9b
When the controlled potential of the Pt anode was fixed at
+ 0.6 V vs SCE, which is at a potential for which 1red could
be oxidized to the iminoquinone form 1ox, the anodic current
remained constant for a long time, and the current efficiency
obtained by electrolysis for 3 h was 100%, indicating that
no side reaction took place under the experimental conditions
used. These results confirmed that the 1ox/1red system behaved
as a redox mediator for the indirect electrochemical oxidation
Scheme 1. Ionic Transamination Mechanism of Catalytic
Oxidation of Primary Aliphatic Amines Mediated by
Electrogenerated o-Iminoquinone Amine Oxidase Mimic 1ox
(5) (a) Hollmann, D.; Ba¨hn, S.; Tillack, A.; Beller, M. Angew. Chem.,
Int. Ed. 2007, 46, 8291–8294. (b) Hollmann, D.; Ba¨hn, S.; Tillack, A.;
Beller, M. Chem. Commun. 2008, 3199–3201. (c) Hollmann, D.; Ba¨hn, S.;
Tillack, A.; Parton, R.; Altink, R.; Beller, M. Tetrahedron Lett. 2008, 49,
5742–5745.
(6) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977–4980.
(7) (a) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637–1639.
(b) Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 7337–7340. (c)
Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38,
851–869.
(8) For recent papers, see: (a) Adenier, A.; Chehimi, M. M.; Gallardo,
I.; Pinson, J.; Vila`, N. Langmuir 2004, 20, 8243–8253. (b) Gallardo, I.;
Pinson, J.; Vila`, N. J. Phys. Chem. B 2006, 110, 19521–19529. (c)
Bourdelande, J. L.; Gallardo, I.; Guirado, G. J. Am. Chem. Soc. 2007, 129,
2817–2821.
highly reactive Schiff base cyclic transition state (eq 4,
Scheme 1), which allowed the activation of the imine
function for further nucleophilic attack by the amine,
constituted the driving force for the overall ionic
mechanism.9b The catalytic cycle produced the reduced
catalyst 1red and an unstable alkylimine as the product of
amine oxidation, at room temperature, leaving ammonia as
the sole byproduct. These conditions were particularly
favorable for using the imine in situ for further reactions.
Accordingly, we recently described the utilization of the
(9) (a) Largeron, M.; Neudo¨rffer, A.; Fleury, M.-B. Angew. Chem., Int.
Ed. 2003, 42, 1026–1029. (b) Largeron, M.; Chiaroni, A.; Fleury, M.-B.
Chem.-Eur. J. 2008, 14, 996–1003.
(10) (a) Largeron, M.; Neudo¨rffer, A.; Vuilhorgne, M.; Blattes, E.;
Fleury, M.-B. Angew. Chem., Int. Ed. 2002, 41, 824–827. (b) Blattes, E.;
Fleury, M.-B.; Largeron, M. J. Org. Chem. 2004, 69, 882–890. (c) Blattes,
E.; Lockhart, B.; Lestage, P.; Schwendimann, L.; Gressens, P.; Fleury, M.-
B.; Largeron, M. J. Med. Chem. 2005, 48, 1282–1286. (d) Xu, D.; Chiaroni,
A.; Fleury, M.-B.; Largeron, M. J. Org. Chem. 2006, 71, 6374–6381.
884
Org. Lett., Vol. 11, No. 4, 2009

of benzylamine to the corresponding N-benzylidenealky-
catalytic anodic process (see Figure 1(a) in the Supporting
Information). Effectively, a UV absorption band at 250 nm
developed which was close to that recorded from a solution
of commercially available related N-benzylidenemethylamine
in methanol. In a control experiment, the chemoselectivity
of the oxidation-imine formation reaction was verified by
converting the unstable in situ generated imine to the 2,4-
dinitrophenylhydrazone (DNPH) by aqueous acidic workup
of the oxidized solution with 2,4-dinitrophenylhydrazine.9b
As expected, only benzaldehyde DNPH was isolated, indi-
cating that no alkylidenealkylamine was formed in the course
of the catalytic anodic process.
Table 1. Electrocatalyzed N-Alkylation of Benzylamine with
Different Primary Aliphatic Aminesa
After exhaustive anodic oxidation, the Pt anode was
replaced by a mercury pool because N-benzylidenealkyl-
amine could not be reduced at the platinum cathode in
methanol. Obviously, the switch to a mercury cathode
constitutes a relative weakness of the process from practical
and environmental points of view. Replacing the Hg cathode
by a graphite carbon cathode, the yield was roughly halved
because of partial loss of the product on the porous graphite
carbon material. Achieving both the oxidative amine alky-
lation and the imine reduction using a single anode/cathode
couple would be a challenge for the future. When the
potential of the mercury pool was fixed at -1.6 V vs SCE,
which is at a potential for which N-benzylidenealkylamine
could be reduced to the corresponding secondary amine, the
UV absorption band at 250 nm disappeared in agreement
with the formation of the secondary amine (see Figure 1(b)
in the Supporting Information). Note the UV-vis absorption
changes recorded in the course of the imine reduction
reaction were almost superimposed with those observed
during the oxidation-imine formation sequence. Accord-
ingly, the two-electron reduction process led to N-benzyl-
N-cyclopropylmethylamine in 80% yield (entry 1, Table 1).
In subsequent studies, we examined the scope of the
process using different alkylating amines. The results are
summarized in Table 1. Various aliphatic primary amines
reacted with benzylamine to give the desired products in
yields ranging from 51 to 80%. In several cases (entries 2-6,
entry 8, entries 11, and 12, Table 1), dibenzylamine was
formed as a byproduct. However, the formation of diben-
zylamine could be limited to 5-10%, through the addition
of an excess of alkylating amine (1.5 equiv).
In some cases (entries 2, 7, 9, and 10, Table 1), diamines
arising from a one-electron reduction mechanism were also
observed as a dimeric byproduct. To minimize the formation
of these compounds, which were produced after a bimo-
lecular dimerization reaction, benzylamine concentration did
not exceed 10 mM. Furthermore, the application of a
sufficiently negative cathodic potential (-1.6 V vs SCE)
favored the electroreduction of the alkylimine intermediate
to the desired secondary amine.11
a Reagents and conditions: (1ox) ) 0.4 mM (4 mol % relative to
benzylamine), (benzylamine) ) 10 mM, (alkylating amine) ) 15 mM,
MeOH, rt. Oxidation-imine formation step: Pt anode (E ) +0.6 V vs SCE),
3 h. Imine reduction step: Hg cathode (E ) -1.6 V vs SCE), 1 h. b Yields
refer to chromatographically pure isolated products and are relative to
benzylamine. c Dibenzylamine was formed as a byproduct (5-10%).
d Diamines were observed as byproduct (5-15%). e Diamine was isolated
in 30% yield and was partly formed during workup.
Interestingly, in the case of ꢀ-aminoalcohols (entries 11
and 12, Table 1), the presence of the alcohol group did not
interfere with the catalytic anodic process indicating a good
tolerance of this functional group. Furthermore, the use of
(R)-(-)-2-amino-1-butanol gave the expected aminoalcohol
with no loss of optical activity {[R]22D -22.0 (c 2.6, EtOH);
lamine (see the equation in Table 1). The in situ presence of
N-benzylidenealkylamine could be evidenced through the
UV-vis absorption changes observed in the course of the
Org. Lett., Vol. 11, No. 4, 2009
885

lit.12 [R]20 -25.6 (c 0.08, EtOH)} as shown in entry 12.
So, the synthesis of various ꢀ-aminoalcohols should be
feasible through this one-pot oxidation-imine formation-
reduction sequence.
In a second series of experiments, we explored the
electrocatalyzed N-alkylation of various activated amine
substrates with phenylpropylamine chosen as the alkylating
agent (Table 2). As expected, activated substituted benzy-
of the phenyl ring (entries 1-4, Table 2). However, in the
case of 1-naphtalenemethylamine, the yield of the desired
secondary amine decreased to 51%, while that of bisnaph-
talen-2-yl-methylamine increased to 25% (entry 5, Table 2).
Probably, the stability of the symmetrical imine species
facilitated its extrusion during the 1ox-mediated catalytic
process at the expense of the unsymmetrical expected imine.
Less activated pyridinemethanamines could be also N-
alkylated with phenylpropylamine by the present biomimetic
electrocatalytic system (entries 6-8, Table 2).
D
Finally, the possibility to apply our methodology to
nonactivated primary amines was briefly examined using
aminomethylcyclopropane as the amine substrate and phe-
nylpropylamine as the alkylating agent (Scheme 2). The yield
Table 2. Electrocatalyzed N-Alkylation of Different Activated
Primary Amines with Phenylpropylaminea
Scheme 2. Electrocatalyzed N-Alkylation of Nonactivated
Aminomethylcyclopropane with Phenylpropylamine
of isolated product (48%) was lower than that expected on
the basis of the high current efficiency (95% for 3 h),9b
probably as a result of the lower stability of the produced
secondary alkylamine during workup. However, this moder-
ate yield is redeemed by the simplicity and the rapidity of
our approach which could be useful for the assembly of
libraries.
In conclusion, we have developed a facile one-pot metal-
free oxidation-imine formation-reduction route to benzylic
secondary amines. The key step of the process consisted of
the chemoselective 1ox-mediated catalytic oxidation of an
activated primary amine, in the presence of a second amine
used as the alkylating agent. This atom-economical sequence,
leaving ammonia as the sole byproduct, at both ambient
temperature and pressure, should allow the synthesis of
various amine derivatives including ꢀ-aminoalcohols. We are
currently expanding the scope of this novel reaction se-
quence.
Supporting Information Available: Figure 1, general
experimental procedure, high-field 1H NMR spectra for
known compounds as a criterion of purity, and characteriza-
1
tion data for new secondary amines, including H and 13C
a Reagents and conditions: (amine substrate) ) 10 mM, (phenylpropy-
lamine) ) 15 mM, (1ox) ) 0.4 mM (4 mol % relative to the amine substrate),
MeOH, rt. Oxidation-imine formation step: Pt anode (E ) +0.6 V vs SCE),
3 h. Reduction step: Hg cathode (E ) -1.6 V vs SCE), 1 h. b Yields refer
to chromatographically pure isolated products and are relative to the amine
substrate. c Substituted dibenzylamine was formed as a byproduct (5-10%).
d Bisnaphtalen-2-yl-methylamine was isolated as a byproduct in 25% yield.
e N-(Pyridinylmethyl)pyridinemethanamine was formed as a byproduct: 4%,
entry 6; 12%, entry 7; 11%, entry 8.
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL802885B
(11) The formation of related diamines has already been observed from
the one-electron cathodic reduction of aldimines. See, for example: (a)
Tanaka, H.; Nakahara, T.; Dhimane, H.; Torii, S. Synlett 1989, 51–52. (b)
Largeron, M.; Fleury, M.-B. J. Org. Chem. 2000, 65, 8874–8881. (c) Siu,
T.; Li, W.; Yudin, A. K. J. Comb. Chem. 2001, 3, 554–558.
(12) (a) Togrul, M.; Turgut, Y.; Hosgoren, H. Chirality 2004, 16, 351–
355. (b) Togrul, M.; Askin, M.; Hosgoren, H. Tetrahedron: Asymmetry 2005,
16, 2771–2777.
lamines were good substrates for this reaction, and the
product yield did not markedly depend on the substitution
886
Org. Lett., Vol. 11, No. 4, 2009