A new selective free radical synthesis of aromatic aldehydes by aerobic oxidation of tertiary benzylamines catalysed by -hydroxyimides and Co(II) under mild conditions. Polar and enthalpic effects

Article abstract of DOI:10.1016/S0040-4039(02)00474-4

Tertiary benzylamides are easily and selectively converted into aldehydes by molecular oxygen; the reaction is catalysed by N-hydroxyamides and Co(II).

Full text of DOI:10.1016/S0040-4039(02)00474-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3605–3607
A new selective free radical synthesis of aromatic aldehydes by
aerobic oxidation of tertiary benzylamines catalysed by
N-hydroxyimides and Co(II) under mild conditions.
Polar and enthalpic effects
Andrea Cecchetto,a Francesco Minisci,a,* Francesco Recupero,a Francesca Fontanab and
Gian Franco Pedullic
aDipartimento di Chimica, Materiali e Ingegneria Chimica ‘G.Natta’, Politecnico di Milano, via Mancinelli 7,
20131 Milano, Italy
bDipartimento di Ingegneria, Universita` di Bergamo, viale Marconi 5, 24044 Milano, Italy
cDipartimento di Chimica Organica ‘A.Mangini’, Universita` di Bologna, via S.Donato, 15, I-40127 Bologna BO, Italy
Received 25 January 2002; accepted 8 March 2002
Abstract—Tertiary benzylamides are easily and selectively converted into aldehydes by molecular oxygen; the reaction is catalysed
by N-hydroxyamides and Co(II). © 2002 Published by Elsevier Science Ltd.
Recently we have developed simple, selective and conve-
nient syntheses of aromatic aldehydes by aerobic oxida-
tion of primary benzyl alcohols under N-oxyl radical
catalysis. We have utilised tetramethylpiperidine-N-oxyl
(TEMPO, a persistent radical)1 and phthalimide-N-oxyl
(PINO), generated in situ from N-hydroxyphthalimide
(NHPI).2 Both these N-oxyl radicals catalyse the selective
aerobic oxidation of primary benzyl alcohols to the
corresponding aromatic aldehydes in combination with
transition metal salt catalysis (Co(II), Mn(II), Cu(II))
under mild conditions (room temperature and atmo-
spheric pressure) (Eq. (1)), but with quite different
mechanisms.
which occurs in the absence of TEMPO under the same
conditions.1
PINO acts as a hydrogen abstracting species from CꢀH
bonds in free-radical chains.2,3
We ascribed the different behaviour of the two N-oxyl
radicals to the values of the bond dissociation energies
(BDE) of the OꢀH bonds, which we2 have evaluated as
at least 16 kcal mol−1 higher for NHPI (>86 kcal mol−1)
than for N-hydroxypiperidine (70 kcal mol−1).4 Thus,
hydrogen abstraction from CꢀH bonds by PINO is
justified on enthalpic grounds, while it is too endothermic
to occur by TEMPO, which is a well-known inhibitor of
free-radical chains.4 This inhibition makes oxidation to
aldehydes quite selective and general for benzylic and
non-benzylic primary alcohols,1 while the free-radical
oxidation, catalysed by PINO, is strongly affected by
polar and enthalpic effects.2 In this latter case, the
oxidation of benzylic alcohols is governed by the polar
Ar-CH2OH+1/2O2“Ar-CHO+H2O
(1)
TEMPO, in the presence of the Mn(II)–Co(II) or Mn(II)–
Cu(II) couples as cocatalysts, has a twofold function: it
determinestheformationofanoxoammoniumsalt, which
is the actual oxidant of the alcohol, and it inhibits the
further free-radical oxidation of the aldehyde by O2,
(2)
* Corresponding author. Fax: +39 02 2399 3080; e-mail: francesco.minisci@polimi.it
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00474-4

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A. Cecchetto et al. / Tetrahedron Letters 43 (2002) 3605–3607
(3)
effect, which makes the alcohols much more reactive than
the corresponding aldehydes, which are therefore
obtained with very high selectivity. With non-benzylic
alcohols, the enthalpic effect is dominant in hydrogen
abstraction by PINO (BDE values for RCHOH-H are 6–8
kcal mol−1 higher than RCO-H) and it makes the
aldehydes much more reactive than the starting alcohols,
leading selectively to carboxylic acids, even at very low
conversions of the alcohols.
Tertiary benzylamines cannot react with NHPI according
to Eq. (3) and we report in this letter a new, simple and
selective oxidation by O2 to the corresponding aldehydes
under mild conditions.
The mechanism of the oxidation involves a superimposi-
tion of a redox chain to a free-radical chain (Eqs. (4–8))
(4)
(5)
The amino group is a more effective electron-releasing
substituent than the hydroxy group and therefore we
wouldexpectahigherreactivityandastrongerpolareffect
(Eq. (2)) for the oxidation of alkylamines by O2 and NHPI
catalysis compared to the corresponding alcohols.
However, primary and secondary benzylamines are com-
pletely inert towards the oxidation by O2 and NHPI
catalysis under the same conditions in which primary and
secondary alcohols are easily oxidised. We soon realised
that this behaviour was related to the reaction of amines
with NHPI according to Eq. (3), which deactivates the
catalyst.
(6)
(7)
(8)
Table 1. Oxidation of benzyldimethylamines X-C6H4-CH2-N(CH3)2 to the aldehydes X-C6H4-CHO by O2 catalysed by NHSI
and NHPIa
Entry
X
Catalyst (%)
T (°C)
t (h)
Conv. (%)
Select. (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
m-Cl
m-Cl
p-Cl
p-Cl
p-OMe
p-CN
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
NHSI (7)
NHSI (7)
NHSI (10)
NHPI (7)
NHSI (7)
NHPI (10)
NHSI (7)
NHPI (7)
NHSI (10)
NHPI (10)
NHPI (7)
NHSI (10)
NHSI (10)
NHSI (10)
NHPI (7)
NHSI (7)
NHSI (7)
NHPI (10)
35
35
50
35
35
50
35
35
50
50
40
50
50
50
35
35
35
50
2
8
2.5
2
8
9
7
7
7
7
3
4
2
9
2
7
10
9
42
100
100
75
80
90
100
90
100
90
96
100
37
91
78
88
81
78
70
78
68
86
86
84
86
92
80
88
82
76
60
9
10
11
12
13
14
15
16
17
18
90
64
72
75
83
a Standard experimental procedure: a solution of 7 mmol of benzylamine, NHSI or NHPI in the amounts reported in Table 1, 0.07 mmol of
Co(OAc)2 in 15 mL of acetonitrile was stirred at the temperatures and for the times reported in Table 1 in the presence of O2 at atmospheric
pressure. The catalysts were separated by flash chromatography on silica gel and the reaction products were analysed by GLC and GC–MS and
comparison with authentic samples.

A. Cecchetto et al. / Tetrahedron Letters 43 (2002) 3605–3607
3607
Co(III), formed in Eq. (7), can be reduced to Co(II) either
by the hydroperoxide (Eq. (9)) or by NHPI (Eq. (10)),
generating a redox chain.
The hydroxyamine is more reactive than the starting
benzylamine in hydrogen abstraction by the N-oxyl
radicals for both polar and enthalpic effects.
+
’
R-OOH+Co(III)“R-OO +H +Co(II)
(9)
Since the selectivity of the oxidation is determined by
hydrogen abstraction, the high selectivity in aldehydes
and the absence of carboxylic acids reflect a much higher
rate of hydrogen abstraction from benzylamines than
from the corresponding aromatic aldehydes. This appears
as the result of a high sensitivity to the polar effect for
hydrogen abstraction by the N-oxyl radicals (Eq. (2)),
since the enthalpic effect is substantially similar for the
benzylamines and the corresponding aldehydes (BDE
values for the CꢀH bond in benzylamines and the
corresponding aldehydes are similar, about 87 kcal
mol−1). In this sense we have verified our hypothesis that
benzylamines should be more reactive than the benzyl
(10)
The overall stoichiometry is given by Eq. (11):
ArCH2N(CH3)2+1/2O2“Ar-CHO+HN(CH3)2
(11)
The results are reported in Table 1. N-Hydroxysuccin-
imide (NHSI, entries 1–3, 7, 9, 12–14 in Table 1) appears
to give even better results than NHPI. The latter is a more
effective catalyst (entries 4–6, 8, 10, 11, 15–18 in Table
1), but it has two main drawbacks compared to NHSI:
itcatalyses fastertheinitial oxidationofthebenzylamines,
but it is deactivated before the completion of the oxida-
tion, particularly with the less reactive benzylamines, such
as the nitro-substituted ones (entries 13–18 in Table 1).
With NHSI the reaction is slower, but it goes to
completion without deactivation of the catalyst, which is
due to the formation of Me2NH (Eq. (11)), according to
Eq. (3); competitive experiments with NHPI and NHSI
with Me2NH have shown that the former reacts faster
than the latter. Moreover, the faster oxidation by NHPI
catalysis makes the reaction somewhat less selective
compared to the slower NHSI catalysis, the main by-
product being the benzamide, ArCONMe2, which is
formed by the further oxidation of the hydroxyamine (Eq.
(12)) before the hydrolysis according to Eq. (8).
alcohols;
a competitive experiment between ben-
zyldimethylamine and m-methylbenzyl alcohol leads to
the formation of 75% of benzaldehyde and only traces
of m-methylbenzaldehyde when 80% of the amine has
reacted (no substantial oxidation of the alcohol occurs).
In the absence of the benzylamine the benzyl alcohol is
substantially oxidised to aldehyde under the same condi-
tions.
References
1. Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F.
Tetrahedron Lett. 2001, 42, 6651.
2. Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.; Pedulli,
G. F. Chem. Commun., in press.
3. Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal.
2001, 343, 393.
4. Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U. J. Am.
Ar-CHOH-NMe2+1/2O2“Ar-CO-NMe2+H2O
Chem. Soc. 1973, 95, 8610.
(12)