Mild oxidation of benzylic amines into aldehydes using an oxidative Polonovski-like process

Article abstract of DOI:10.1055/s-0031-1290676

A chemoselective and environmentally benign oxidation of benzylic amines into aldehydes mediated by a hypervalent iodine reagent has been developed. This mild oxidative version of the Polonovski process may be selectively carried out in the presence of several functionalities including a free alcohol and provides new synthetic opportunities as a masked aldehyde segment. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290676

LETTER
▌1497
lMetteirld Oxidation of Benzylic Amines into Aldehydes Using an Oxidative
Polonovski-Like Process
Mild Oxidation of Benzylic Amines into Aldehydes
Samuel Desjardins, Guillaume Jacquemot, Sylvain Canesi*
Laboratoire de Méthodologie et Synthèse de Produits Naturels, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal,
H3C 3P8, Québec, Canada
Fax +1(514)9874054; E-mail: canesi.sylvain@uqam.ca
Received: 03.03.2012; Accepted after revision: 02.04.2012
AcO–
Abstract: A chemoselective and environmentally benign oxidation
R2
N
PhI(OAc)2
R2
R1
of benzylic amines into aldehydes mediated by a hypervalent iodine
reagent has been developed. This mild oxidative version of the
Polonovski process may be selectively carried out in the presence of
several functionalities including a free alcohol and provides new
synthetic opportunities as a masked aldehyde segment.
R3
R3
+
N
R1
I
Ph
1
H
O
O
Key words: hypervalent iodine, oxidation, amines, Polonovski,
2
aromatic aldehydes
R2
N
R2
N
AcO–
R3
R3
R3
R1
R1
3
Aromatic aldehydes are important components of several
natural products and are employed as valuable precursors
in various synthetic processes. These common functional-
ities may be obtained using traditional transformations
such as oxidation of an alcohol, but this may require the
use of protecting groups to ensure selective oxidation if
several alcohols are present in the molecule. In this paper,
we describe a mild and chemoselective method for the se-
lective transformation of a benzylic amine into an alde-
hyde even in the presence of a free alcohol. Similar
reactions have been reported in the literature for oxidizing
amines into carbonyl groups through imine or iminium
species, but most of these have required toxic heavy met-
als or multistep processes.1 This new method is promoted
by hypervalent iodine reagents2,3 such as iodobenzene di-
acetate (DIB), a mild and environmentally benign oxidiz-
ing reagent, avoiding the need for poisonous transition
metals. Our method involves the formation of an iminium
species 3 through a route similar to an oxidative Polo-
novski transformation4,5 following the exposure of an
amine to iodobenzene diacetate. A potential mechanism is
described in Scheme 1.
O
O
5
O
4
Scheme 1
etate ion attack occurs mainly at the most accessible
benzylic position without competition from the hindered
tertiary positions neighboring the ammonium ion. It
should be noted that the corresponding starting amines
may be easily and efficiently obtained from their bromo
derivatives 6 using a simple SN2 transformation in the
presence of inexpensive diisopropylamine.6 In addition,
bulky segments such as these may be safely used in syn-
theses as an inert functionality compatible with several
traditionally used transformations (Scheme 2).
N
Br
80 °C, 24 h
R
R
H
N
6
7
84–97%
The process was applied to several benzylic secondary
and tertiary amines to determine the scope of the transfor-
mation, and a summary of representative investigations
appears in Table 1.
Scheme 2
To verify this hypothesis, several hindered amines 7 were
oxidized to produce the aldehydes 8; a summary of repre-
sentative experiments appears in Table 2.7
It appears that the process occurs slowly and in moderate
yields with unhindered amines. However, when a very
bulky amino segment such as a diisopropylamine (entries
1a vs. 1f) was used, a clear improvement was observed in
terms of yield and reaction rate (two hours instead of one
day). We suppose that in the presence of bulky substitu-
ents, formation of the iminium species 3 mediated by ac-
Under these conditions, aldehydes were obtained in useful
to high yields (50–86%). An important aspect of this
transformation is the chemoselectivity, which permits this
reaction to occur in the presence of several spectator func-
tionalities including a free alcohol (Table 2, entry 7). The
method was also attempted using a secondary methyl-aryl
amine derivative to produce a ketone but as expected with
the Polonovsky or Pummerer8 processes, the ketone ad-
duct was not observed, demonstrating that this transfor-
SYNLETT 2012, 23, 1497–1500
Advanced online publication: 25.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290676; Art ID: ST-2012-S0193-L
© Georg Thieme Verlag Stuttgart · New York

1498
S. Desjardins et al.
LETTER
Table 1 Synthesis of Compounds 5
R1
PhI(OAc)2
N
R2
O
R3
R3
CHCl3, 60 °C
NaHCO3
1
5
Time (h)
24
Entry
Yield (%)
55
1
a
I
I
N
O
Br
Br
2
3
4
5
6
b
c
d
e
f
12
24
24
24
2
42
50
5
NMe2
O
N
O
O2N
O2N
N
O
Ph
I
I
N
H
50
75
O
Br
I
Br
I
O
N
mation occurs selectively on a primary center to enable a hindered base such as diisopropylamine, which avoids
almost exclusive formation of aldehyde moieties. This ob- competition at other positions during iminium ion forma-
servation explains why the reaction is more effective with tion (Scheme 1).
Table 2 Synthesis of Aldehydes 8
PhI(OAc)2
N
O
R1
R1
CHCl3, 60 °C
NaHCO3, 2 h
7
8
Entry
1
Yield (%)
75
a
I
I
NR2
NR2
O
2
3
4
b
c
O
69
83
75
MeO
Br
MeO
Br
NR2
O
I
I
d
NR2
O
NR2
5
6
e
f
65
50
O
MeOOC
MeOOC
NR2
O
Synlett 2012, 23, 1497–1500
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mild Oxidation of Benzylic Amines into Aldehydes
1499
Table 2 Synthesis of Aldehydes 8 (continued)
PhI(OAc)2
N
O
R1
R1
CHCl3, 60 °C
NaHCO3, 2 h
7
8
Entry
Yield (%)
65
7
g
NR2
O
HO
HO
MeO
MeO
8
h
86
NR2
O
MeO
MeO
The reaction was also undertaken using alternate hyperva-
lent iodine reagents such as PIFA {[bis(trifluoroacet-
oxy)iodo]benzene} or Koser’s reagent,9 known to be
more reactive oxidants. Yields were generally higher with
DIB, most probably due to the less acidic environment
generated by acetic acid versus the trifluoro homologue
present in PIFA. However, if the desired product is com-
patible with the more rigorous conditions of PIFA, the de-
sired aldehyde 10 may be obtained at room temperature in
83% yield from the secondary amine 9 (Scheme 3).
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Experimental Procedure
To a stirred solution of amine 7 (1 mmol) in CHCl3 (4 mL) was add-
ed NaHCO3 (92 mg, 1.1 mmol, 1.1 equiv) and PhI(OAc)2 (451 mg,
1.4 mmol, 1.4 equiv). The solution was stirred at reflux (60 °C) for
2 h, after which a solution of sat. aq NH4Cl was added. The aqueous
phase was extracted with CH2Cl2, and the combined organic layers
were washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was chromatographically puri-
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We are very grateful to the Natural Sciences and Engineering Re-
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1497–1500

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LETTER
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Synlett 2012, 23, 1497–1500
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