Unexpected reduction of N-hydroxyphthalimides to phthalimides-orthogonal reduction of functionalized N-hydroxyphthalimides

Article abstract of DOI:10.1055/s-0030-1258039

A chemoselective reduction of N-hydroxyphthalimides to phthalimides under mild conditions has been discovered. It involves reaction of an N-hydroxyimide with bis(pinacolato)diboron in the presence of a base. Other easily reducible functional groups, such as iodo, nitro, or azido groups are unaffected. Alternatively, such functional groups may be selectively reduced without affecting the N-hydroxyimide moiety using a set of classical conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258039

LETTER
2263
Unexpected Reduction of N-Hydroxyphthalimides to Phthalimides –
Orthogonal Reduction of Functionalized N-Hydroxyphthalimides
R
eduction
é
of
N
-Hydr
r
oxyphtha
ô
limides to P
m
hthalimides e Jacq, Florian Berthiol,* Cathy Einhorn, Jacques Einhorn*
Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, Université Joseph Fourier,
301 Rue de la Chimie, BP 53, 38041 Grenoble Cedex 9, France
Fax +33(4)76514836; E-mail: Jacques.Einhorn@ujf-grenoble.fr
Received 17 June 2010
87% yield (Scheme 1). A similar reaction was observed
with NHPI, which was smoothly reduced to phthalimide
under the same conditions.
Abstract: A chemoselective reduction of N-hydroxyphthalimides
to phthalimides under mild conditions has been discovered. It in-
volves reaction of an N-hydroxyimide with bis(pinacolato)diboron
in the presence of a base. Other easily reducible functional groups,
such as iodo, nitro, or azido groups are unaffected. Alternatively,
such functional groups may be selectively reduced without affect-
ing the N-hydroxyimide moiety using a set of classical conditions.
Intrigued by this result, we investigated the reaction con-
ditions more in detail. Without palladium catalyst, the re-
action proceeded equally well. No reaction occurred when
potassium acetate was omitted, but potassium acetate
could be replaced effectively by other bases such as sodi-
um acetate, sodium hydrogenocarbonate, or potassium
triphosphate. Finally, DMSO could be advantageously re-
placed by methanol. Under the new set of conditions (1.1
equiv B2Pin2, 3 equiv KOAc, in MeOH at 50 °C for 2 h)
NHPI was reduced to phthalimide in 88% isolated yield
(Table 1, entry 1). Under such conditions, many easily re-
ducible functional groups are unaffected, as shown by the
chemoselective reduction of NHPI analogues bearing io-
do, nitro, or azido functional groups (Scheme 2, Table 1).
As expected, iodinated NHPI analogues 1e and 1f gave
the corresponding phthalimides 2e and 2f in 81% and 56%
isolated yields (Table 1, entries 4 and 5). Periodinated
NHPI analogue 1h was found to be hardly soluble in
methanol, so the reaction was performed in DMSO at
80 °C, giving the expected phthalimide 2h in good yield
(Table 1, entry 7). In the case of the nitro analogue 1c the
reaction was slower, and 2c was obtained in only 13%
yield (Table 1, entry 2). Nevertheless, other nitro NHPI
analogues, including polycyclic compounds 1i–l, gave
medium to high yields of the corresponding imides
(Table 1, entries 3 and 8–11). Finally, even the fragile azi-
Key words: chemoselective reduction, bis(pinacolato)diboron,
N-hydroxyphthalimides, phthalimides, mild conditions
N-Hydroxyphthalimide (NHPI) is a valuable organocata-
lyst allowing aerobic oxidation reactions to be performed
under mild conditions.1 A broad variety of NHPI ana-
logues has also been prepared, with the aim of developing
more effective or more selective catalysts.2 Moreover, we
found recently that some functionalized polycyclic NHPI
analogues posses promising biological activities.3 In order
to prepare rapidly functionally diverse NHPI analogues,
we became interested in synthetic methods allowing func-
tional-group transformations to be performed in the pres-
ence of an unprotected N-hydroxyimide moiety. Thus, C-
borylation of iodinated NHPI analogue 1a was attempted,
using conditions developed by Miyaura et al.: Compound
1a was reacted with bis(pinacolato)diboron (B2Pin2) in
the presence of potassium acetate and a catalytic amount
of PdCl2dppf in DMSO at 80 °C.4 Unexpectedly, no C-bo-
rylated product was obtained but compound 2a, still iodi-
nated but having lost its hydroxy group, was isolated in
O
O
I
I
B
O
O
O
B2Pin2 (1.1 equiv)
PdCl2dppf (3 mol%)
N
OH
N
H
N OH
KOAc (3 equiv)
DMSO, 80 °C, 4 h
O
O
O
Ph
Ph
Ph
1a
2a
87%
3
(not observed)
Scheme 1 Unexpected reduction of the N-hydroxyphthalimide function to the phthalimide
SYNLETT 2010, No. 15, pp 2263–2266
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258039; Art ID: D15410ST
© Georg Thieme Verlag Stuttgart · New York

2264
J. Jacq et al.
LETTER
O
O
Table 1 Selective Reduction of the N-Hydroxyphthalimide 1 Func-
tion to the Phthalimide 2
B2Pin2 (1.1 equiv)
KOAc (3 equiv)
N
OH
N H
Yield (%)a
MeOH
Entry
1
Reactant
1b
1c
Product
2b
2c
50 °C, 2 h
R
R
O
O
88
13
56
81
56
50
80
90
56
68
82
2b–h
1b–h
1b R = H
1c R = 3-NO2
2b
3
1f
1g
1h
R = 4-I
R = 4-N3
R = 3,4,5,6-tetraiodo
1d
1e
2d
2e
1d
1e
R = 4-NO2
R = 3-I
4c
5
1f
2f
R2
R2
B2Pin2 (1.1 equiv)
KOAc (3 equiv)
6
1g
2g
O
O
7d
8
1h
1i
2h
2i
MeOH
50 °C, 2 h
R1
N
OH
R1
N
H
O
O
Ph
Ph
2i–l
9
1j
2j
R1 = H, R2 = 2-NO2
R1 = H, R2 = 3-NO2
R1 = H, R2 = 4-NO2
R1 = 3-NO2, R2 = H
1i
1j
10
11
1k
1l
2k
2l
1k
1l
a Reaction conditions: 1 (0.1–0.5 mmol), B2Pin2 (1.1 equiv), KOAc (3
equiv), MeOH (0.017 M), 50 °C, 2h; isolated yields.
b Reaction time was 5 h.
Scheme
function to the phthalimide
2
Selective reduction of the N-hydroxyphthalimide
c Reaction time was 3.5 h.
d Reaction performed in DMSO at 80 °C.
do NHPI analogue 1g could be transformed into the cor-
responding azidophthalimide 2g in a satisfactory isolated
yield (Table 1, entry 6).
ditions by the method disclosed above, this bond proved
to be quite resistant to a set of other reductive conditions.
Thus, it was also possible to perform the selective reduc-
tion of some of the previous functional groups without af-
fecting the N-hydroxyimide moiety (Scheme 4, Table 2).
The selective reduction of 4-nitro NHPI 1d into 4-amino
NHPI 4a has already been reported using palladium on
charcoal under pressure of hydrogen (Table 2, entry 1).7
We found that in this case, it is important to control the
amount of hydrogen consumed during the reaction, to
avoid complete reduction into 4-aminophthalimide. We
also applied the catalytic hydrogenation procedure to
polycyclic NHPI analogues bearing nitro groups 1i–l, ob-
taining good isolated yields of the corresponding amino
NHPI analogues 4b–e (Table 2, entries 3–6). In these
cases no fully reduced compounds were obtained. When
The mechanism of this reduction may tentatively be asset
as follows (Scheme 3): owing to their low pKa (pKa of
NHPI itself in water is 6.1)5, NHPI analogue can be depro-
tonated even by weak bases such as potassium acetate.
This deprotonation can in fact be easily visualized by the
formation of a deeply red colored NHPI anion. This an-
ionic species could add to one of the boron atom of B2Pin2
to give intermediate A. Nitrogen–oxygen bond cleavage,
accompanied by boron migration from boron to oxygen,
would then furnish deprotonated phthalimide along with
boron species B.6 The progress of the reaction can be
monitored by progressive fading of the deeply red colored
reaction medium.
Although the nitrogen–oxygen bond cleavage of N-
hydroxyphthalimides occurs under particularly mild con-
O
O
O
O
B
B
O
O
O
O
O
B
B
KOAc
N
O
N
OH
N
O
O
R
R
R
O
O
O
O
A
O
O
AcOH
O
B
O
B
+
N
N H
O
O
O
R
R
O
O
B
Scheme 3 Proposed mechanism of the B2Pin2 reduction of N-hydroxyphthalimides to phthalimides
Synlett 2010, No. 15, 2263–2266 © Thieme Stuttgart · New York

LETTER
Reduction of N-Hydroxyphthalimides to Phthalimides
2265
applied to 4-azido-N-hydroxyphthalimide (1g) catalytic Supporting Information for this article is available online at
hydrogenation procedure led only to the fully reduced 4- http://www.thieme-connect.com/ejournals/toc/synlett.
aminophthalimide. Nevertheless 1g could smoothly be
transformed into 4-amino NHPI 4a, using the Staudinger
reaction (Table 2, entry 2).
Acknowledgment
The financial support from CNRS, Université Joseph Fourier, and
Cluster de Recherche Chimie de la Région Rhône-Alpes are duly
acknowledged.
O
O
Ph3P (1.5 equiv)
N
OH
N OH
MeOH
80 °C, 1 h
N3
H2N
References
O
O
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Scheme 4 Selective reduction of the function on the N-hydroxy-
phthalimide
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phthalimide 1 to give N-Hydroxyphthalimide 4
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1a
Reactant
Product
4a
Time (h)
Yield (%)
1d
1g
1i
0.75
70
74
88
72
55
64
2b
4a
1
4
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In summary we developed the first selective reduction of
N-hydroxyphthalimides to phthalimides under very mild
conditions. This reaction is tolerant toward many fragile
functional groups like iodo, nitro, or azido groups. We
also showed that it is possible to reduce selectively some
functional groups present on the N-hydroxyphthalimide
backbone, keeping the N-hydroxyimide moiety un-
changed. Such orthogonal functional-group manipulation
could find interesting applications, as phthalimide and N-
hydroxyphthalimide moieties can be found in many bio-
logically active compounds.3,8
Synlett 2010, No. 15, 2263–2266 © Thieme Stuttgart · New York

2266
J. Jacq et al.
LETTER
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