Catalytic aerobic photooxidation of primary benzylic amines using hindered acridinium salts

Article abstract of DOI:10.1016/j.tetlet.2005.04.133

Hindered acridinium cations, simply prepared by the addition of primary amines to the known methylium tris(2,6-dimethoxyphenyl) cation, catalyze the aerobic photooxidation of primary benzyl amines into benzylimines. A mechanistic rationale for the electron-transfer process is proposed.

Full text of DOI:10.1016/j.tetlet.2005.04.133

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Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4605–4608
Catalytic aerobic photooxidation of primary benzylic amines
using hindered acridinium salts
*
´ ˆ
Cyril Nicolas, Christelle Herse and Jerome Lacour
´ ´ ` `
Departement de Chimie Organique, Universite de Geneve, quai Ernest Ansermet 30, CH-1211 Geneve-4, Switzerland
Received 4 April 2005; revised 27 April 2005; accepted 29 April 2005
Available online 23 May 2005
Abstract—Hindered acridinium cations, simply prepared by the addition of primary amines to the known methylium tris(2,6-
dimethoxyphenyl) cation, catalyze the aerobic photooxidation of primary benzyl amines into benzylimines. A mechanistic rationale
for the electron-transfer process is proposed.
Ó 2005 Elsevier Ltd. All rights reserved.
The functional group transformation of activated
amines to imines has been strongly studied in synthetic
organic chemistry.1,2 Quite a few of the oxidative pro-
cesses that have been developed are photochemical reac-
tions that use molecular oxygen (O2) as a stoichiometric
oxidant and photoactive dyes as catalysts. Acridinium
salts, which have been studied over the years as cellular
stains with biological and diagnostic purposes as well as
in various fluoroionophores,3 have been particularly
used in the above-mentioned context as these com-
pounds possess a keen ability to promote photoinduced
electron transfer and to be reduced under irradiation.4
Herein, we confirm this trend and report the catalytic
aerobic photooxidative behavior of hindered acridinium
cations of type 1, which are able to transform primary
benzylic amines into imines.
derivatives adopt a twisted helical conformation. As
such, compounds of type 2 may be regarded as [4]het-
erohelicenium derivatives with P or M configura-
tion. Recently, these derivatives were shown to be
highly configurationally stable, more than [6]helicene,
and a general resolution protocol was reported.6
OMe
MeO
R
R
N
N
MeO
MeO
RNH2
ð1Þ
O
80 - 110 °C
O
MeO
OMe
[2][BF4]
[3[BF4]
Recently, the synthesis of the cation 2a derived from
benzylamine was attempted (Eq. 2). To our surprise,
only a moderate yield of 25% was obtained for salt
[2a][BF4] whereas yields in the range of 70–85% are rou-
tinely achieved with linear primary amines as nucleo-
philes (R = n-alkyl chains).6 1H NMR analysis of the
Previously, 1,13-dimethoxyquinacridinium cations of
type 2 have been reported.5 These cationic moieties are
prepared in one step and good yield by the reactions
of primary alkyl amines with the readily available salts
of cation 3 (Eq. 1); the synthesis occurring through
sequential aromatic substitution (SNAr) of four MeO
substituents by nitrogen containing residues. The mole-
cular framework of cations 2 contains four ortho-con-
densed aromatic rings. Due to the steric repulsions
between the two remaining methoxy substituents, these
O
H O
BnN
NBn
BnNH2
BnN
[3][BF4]
O
O
O
25 equiv.
NMP
ð2Þ
O
110 °C
[2a][BF4]
(25%)
4a (60%)
Keywords: Amine; Imine; Photooxidation; Acridinium; Electron
transfer.
+ large excess of benzylimine
*
Corresponding author. Tel.: +41 22 379 6062; fax: +41 22 379
3215; e-mail: jerome.lacour@chiorg.unige.ch
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.133

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C. Nicolas et al. / Tetrahedron Letters 46 (2005) 4605–4608
crude mixture revealed an essentially complete transfor-
mation of the benzylamine 5 in excess (25equiv) into
benzylimine 6; benzyl-tetramethoxyphenyl-acridine 4a
being isolated from the crude mixture (60%).7
80
70
60
50
40
30
20
10
(a)
(b)
In view of the literature precedents on the aerobic pho-
tooxidation catalyzed by acridinium derivatives,4 the in
situ formation of compound [1a][BF4]5b was considered
(Fig. 1). This species would catalyze the oxidation of 5
into 6. Acridine 4a would then be the result from the
necessary reduction of cation 1a.
(c)
(d)
(e)
(f)
O
O
0
5
10
15
20
25
30
R N
Time (h)
O
-
O
BF4
Figure 2. Synthesis of benzylimine 6 (yield, %) under irradiation as a
function of time (h); reactions catalyzed with (a) [1a][BF4], 70 °C; (b)
[1b][BF4], 70 °C; (c) [1a][BF4], 50 °C; (d) [1b][BF4], 50 °C; (e) [2b][BF4],
70 °C; (f) [2b][BF4], 50 °C.
ð3Þ
[1a][BF4] or [1b][BF4]
(2 mol%)
NH2
NH
hν
5
6
these and other experiments. Figure 2 represents the for-
mation of benzylimine (yield, %) under irradiation as a
function of time (hours).
To test this hypothesis and see whether a synthetically
useful process could result from the observation, two
different acridinium salts were prepared, compounds
[1a][BF4] and [1b][BF4] (Fig. 1, R = Bn, n-Pr), by the
room temperature reaction of [3][BF4] with benzylamine
and n-propylamine (83% and 81%, respectively).5,8 Solu-
tions of these derivatives (2 mol %) in benzylamine 5,
used both as reagent and as solvent, were prepared
and subjected to photoirradiation (600 W lamp, Eq.
3).9 An in situ formation of benzylimine 6 was observed,
Rather strong temperature dependence was observed as
the rate of photooxidation is ꢀ3.5times faster at 70 °C
than at 50 °C; little reaction being observed at room
temperature. After about 20 h, yields of 22% and 71%
were obtained for 6 at 50 and 70 °C, respectively, using
salt [1a][BF4] (Table 1, entries 1 and 3). Similar results
were obtained for [1b][BF4] (entries 2 and 4). As it could
be expected, essentially no formation of 6 was observed
when the reaction was performed without irradiation at
50 °C (entries 5and 6). More surprisingly, a significant
amount of 6 was afforded at 70 °C in the absence of light
(entries 7 and 8). This result can be rationalized by the
fact that some acridinium cations can undergo thermal
electron transfer in the absence of light.11
1
of which the yield was measured by H NMR spectro-
scopy using an internal standard (mesitylene, 2 mol %).10
Table 1 summarizes the results that were obtained in
O
O
[1a][BF4]
[1b][BF4]
R = Bn
R = n-Pr
Care was taken not to increase the reaction temperature
above 70 °C as to limit the formation of dimethoxyquin-
acridinium salts of type [2][BF4], which arise at elevated
temperature from the nucleophilic addition of primary
amines onto [1][BF4] salts.6 Although unlikely at 50 or
70 °C, the presence of such cationic species 2 in minor
amount was nevertheless feasible, thus rendering a test
of their aerobic photooxidative behavior necessary.
The oxidation reaction was thus tested in the presence
of 2 mol % of [2b][BF4]. Much lower yields of 6 were ob-
R
N
O
O
-
BF4
Figure 1. Hindered acridinium salts of type [1][BF4].
Table 1. Catalytic photooxidation of benzylamine 5 in the presence of
acridinium salts [1a][BF4] and [1b][BF4]
Entry Catalysta Temperature Irradiation Time Yield
(°C)
(h)
(%)b
Table 2. Catalytic photooxidation of benzylamine 5 in the presence of
acridinium salt [2b][BF4]
1
2
3
4
5
6
7
8
[1a][BF4]
[1b][BF4]
[1a][BF4]
[1b][BF4]
[1a][BF4]
[1b][BF4]
[1a][BF4]
[1b][BF4]
50
50
70
70
5
Yes
Yes
Yes
Yes
20
20
19
24
22
20
71
74
Entry Catalysta Temperature Irradiation Time Yield
(°C)
(h)
(%)b
0
0
No
No
20
20
1
3
1
2
3
4
[2b][BF4]
[2b][BF4]
[2b][BF4]
[2b][BF4]
50
70
50
70
Yes
Yes
No
No
30
22
30
23
3
15
0.2
1
5
70
70
No
No
23
23
19
27
a 2 mol %.
a 2 mol %.
b As measured by 1H NMR spectroscopy using mesitylene as internal
reference.
b As measured by 1H NMR spectroscopy using mesitylene as internal
reference.

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C. Nicolas et al. / Tetrahedron Letters 46 (2005) 4605–4608
4607
pound A (D* ! A to give D+ and Aꢁ, Fig. 3, path a).
The second, which seems to be favored by acridinium
derivatives, is the reaction of an acceptor molecule in
its excited stateꢁ(A*) with a donor moiety (D ! A* to
give D+ and A , Fig. 3, path b).12 In the latter case,
one then expects that the presence of electron-rich sub-
stituents on the donor molecule, in our case the amine,
raises the level of the HOMO orbital of the donor D
and thus limit the efficiency of the electron transfer to
15
Table 3. Catalytic aerobic photooxidation of substituted benzylamines
7, 8, and 9 in the presence of acridinium salt [1a][BF4] (2 mol %) and
light irradiation
OMe
NH2
NH2
NH2
MeO
Me
7
8
9
Entry
Aminea Temperature (°C) Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
7
8
9
5
0
0
0
19
19
19
the excited acceptor moiety A*. As this is observed for
11
electron-rich amines, pathway b seems indeed to be
18
favored.
5
5
70
70
70
17
17
17
33
39
39
In conclusion, hindered acridinium cations of type 1 are
catalysts for the aerobic photooxidation of primary benz-
ylamines into benzylimines making them interesting
NAD+ analogues.
a 1 equiv.
b As measured by 1H NMR spectroscopy using mesitylene as internal
reference.
hν
Acknowledgements
D+
A-
D
A
D+
A-
e-
e-
D
D
A
D*
A
hν
We are grateful for financial support of this work by the
Swiss National Science Foundation.
A*
(a)
(b)
References and notes
hν
hν
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245 °C; IR (film): m = 2996, 2931, 2829, 1616, 1587, 1496,
1470, 1452, 1434, 1387, 1360, 1322, 1286, 1240, 1253, 1227,
1162, 1104, 1082, 1056, 1018, 943, 905, 885, 852, 812, 786,
;
769, 760, 737, 721, 697 cmꢁ1 1H NMR (400 MHz,