Mild and convenient one pot synthesis of N-hydroxyimides from N-unsubstituted imides

Article abstract of DOI:10.1081/SCC-100103264

A new, one pot synthesis of various N-hydroxyimides from N-unsubstituted imides is described. Imides are first transformed into their N-Boc derivatives, which are next reacted with aqueous hydroxylamine, providing crystalline hydroxylammonium salts of the corresponding N-hydroxyimides. Filtration and acidic workup affords pure N-hydroxyimides.

Full text of DOI:10.1081/SCC-100103264

This article was downloaded by: [Fordham University]
On: 07 July 2013, At: 10:57
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number:
1072954 Registered office: Mortimer House, 37-41 Mortimer Street,
London W1T 3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
MILD AND CONVENIENT
ONE POT SYNTHESIS OF N-
HYDROXYIMIDES FROM N-
UNSUBSTITUTED IMIDES
a
a
Cathy Einhorn , Jacques Einhorn & Céline
a
Marcadal-Abbadi
a
Université Joseph Fourier, Laboratoire de Chimie
Biomimétique, LEDSS/UMR CNRS 5616, Grenoble,
BP 53 – 38041, France
Published online: 16 Aug 2006.
To cite this article: Cathy Einhorn , Jacques Einhorn & Cline Marcadal-Abbadi
2001) MILD AND CONVENIENT ONE POT SYNTHESIS OF N-HYDROXYIMIDES FROM N-
(
UNSUBSTITUTED IMIDES, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:5, 741-748, DOI: 10.1081/
SCC-100103264
To link to this article: http://dx.doi.org/10.1081/SCC-100103264
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions

and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(5), 741–748 (2001)
MILD AND CONVENIENT ONE POT
SYNTHESIS OF N-HYDROXYIMIDES FROM
N-UNSUBSTITUTED IMIDES
Cathy Einhorn,* Jacques Einhorn, and Ce
Marcadal-Abbadi
´
line
´
Laboratoire de Chimie Biomimetique, LEDSS/UMR
CNRS 5616, Universite Joseph Fourier, BP 53 – 38041
´
Grenoble, France
ABSTRACT
A new, one pot synthesis of various N-hydroxyimides
from N-unsubstituted imides is described. Imides are first
transformed into their N-Boc derivatives, which are next
reacted with aqueoushydroxylamine, providing cry tsa lline
hydroxylammonium salts of the corresponding N-hydroxy-
imides. Filtration and acidic workup affords pure N-hydroxy-
imides.
N-Hydroxyimides are very useful and versatile intermediates in
organic synthesis. For example, N-hydroxysuccinimide has been used in
1
racemisation-free peptide coupling procedures. N-Hydroxyphthalimide
isu es ful asan N,N diprotected form of hydroxylamine, allowing the
2
synthesis of O-substituted hydroxylamines. N-hydroxyphthalimide has
been recognized asa valuable cataly st for the oxidation of variousorganic
3
compoundsunder mild condition.s
We have also reported recently the
* Corresponding author. Fax: 33 4 76 51 48 36; E-mail: Cathy.Einhorn@ujf-
grenoble.fr
7
41
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

7
42
EINHORN, EINHORN, AND MARCADAL-ABBADI
electrocatalytic properties of variously substituted N-hydroxyphthalimi-
4
a
des, aswell asthe ys nthe is sof the fir ts axially chiral
4
N-hydroxyimides,
promising asymmetric catalysts. N-Hydroxyphthalimide mediated oxida-
b
tionsinvolve the corre ps onding phthalimide
highly reactive, nitroxide-type, free radical.
Whereas sterically crowded amines can easily be oxidized to hydroxyl-
N-oxyl, a fairly stable but
5
aminesor even directly to nitroxide,s
N-unsubstituted imides cannot be
oxidized to N-hydroxyimidesnor to N-oxyl radicals. Therefore, the imide
functional group hasgenerally not been con si dered asa convenient precur-
sor of the corresponding N-hydroxyimide. We report herein a non-oxidative
synthesis of N-hydroxyimidesfrom N-unsubstituted imides. Our approach
isrelated to a procedure known for a long time and de sc ribed by Nefkens
who prepared N-hydroxyphthalimide by reaction of N-(ethoxycarbonyl)-
6
phthalimide with hydroxylamine and triethylamine in refluxing ethanol.
N-(Ethoxycarbonyl)-phthalimide (NefkensReagent) wasprepared in a
first step by reacting ethyl chloroformate in DMF with potassium phthali-
7
mide or with phthalimide and triethylamine. Asour aim wasto develop a
one pot procedure, operating under mild conditions, we first investigated the
transformation of phthalimide into various N-carbamoyl- or N-sulfonyl-
imides. The preparation of N-(tert-butoxycarbonyl)-phthalimide waspar-
ticularly simple and efficient using di-tert-butyldicarbonate and a small
amount of 4-N,N-dimethylaminopyridine (DMAP) in acetonitrile at room
temperature. A 97% of N-Boc derivative 1 was isolated alter a very simple
8
workup (Scheme l).
Scheme 1.
Gratifyingly, 1 wasan excellent precur so r of N-hydroxyphthalimide 2:
when an acetonitrile solution of 1 wastreated with a commercial aqueous
solution of hydroxylamine at room temperature, the solution rapidly
turned orange. After stirring overnight an orange precipitate formed
which wasprobably the hydroxylammonium as lt of N-hydroxyphthal-
9
imide. Filtration and acidic workup of the precipitate furnished pure 2.
Soluble tert-butylcarbamate 3 byproduct waseliminated in the filtrate
(
Scheme 2).

N-HYDROXYIMIDES
743
Scheme 2.
The whole synthesis was easily amenable to a straightforward one pot
procedure: after completion of the first step, hydroxylamine was directly
added to the reaction medium and the final product isolated as its hydroxyl-
ammonium salt without the need of any purification step. It proved to be
fairly general, provided that the amountsof di- tert-butyldicarbonate and of
DMAP were adapted to each case (TLC control for the completion of the
first step): variously substituted N-hydroxyphthalimideshave been obtained
in very good yields(Table, entries1–5). N-hydroxyimideswith heterocyclic
or naphtalenic fused rings have also been synthetised with nearly quantita-
tive yields(entries6,7). Although the procedure failed in the ca se of male-
imide (entry 8), it seems efficient for the synthesis of aliphatic or six
membered ring N-hydroxyimides(entries9 and 10).
In summary, this procedure offers a new and straightforward access to
N-hydroxyimidesfrom N-unsubstituted imides. Its mildness and efficiency
should render it of great value in the case of stereochemically labile com-
4
b
pounds or of compounds with sensitive functionalities that do not allow
the use of more classical methods.
EXPERIMENTAL
Imides, di-tert-butyldicarbonate, 4-N,N-dimethylaminopyridine and
hydroxylamine (50 wt % in water) were commercial grade and were used
˚
without purification. Acetonitrile wasdried over 4 A molecular sieve prior to
use. Analytical thin layer chromatography (TLC) was performed using
Merck 60F 254 plates. Visualisation of the developed chromatogram was
performed by UV absorbance or ethanolic phosphomolybdic acid. Infrared
spectra were recorded on a Perkin Elmer IR 397 or a Nicolet Impact 400

7
44
EINHORN, EINHORN, AND MARCADAL-ABBADI
Table.
Boc O
2
DMAP
(mol %) Yield
a
Entry
1
Imide
(eq)
mp
(mp litt)
b
1.1
1
1
92
232–233
(233)
1
0
2
3
2
1.5
100
198–200
252–254
(195–197)
1
1
3
4
5
2.2
1.1
1.1
10
5
97
99
94
(254)
1
167–169.5 (168–170)
159–162
5
1
6
7
8
1.5
1.1
1.1
2
1
1
100
94
–
233
248–249
–
(232–233)
b
9
1.1
1.5
1
83
80
95–96
(95–98)
b
1
0
10
281–283
(284)
a
Yield of isolated N-hydroxyimide.
Melting point of a commercial sample.
b

N-HYDROXYIMIDES
745
1
spectrometer. H NMR spectra were recorded on a Bruker AC200 or a
Bruker WM250 spectrometer (200 and 250 MHz respectively). Chemical
shifts are reported in ppm on the ꢀ scale relative to tetramethylsilane
1
3
(
TMS) asan internal st andard. C NMR spectra were also recorded on a
Bruker AC200 or a Bruker WM250 (50 and 62.5 MHz respectively) with
complete proton decoupling. Chemical shifts are reported in ppm relative to
tetramethylsilane on the ꢀ scale. Mass spectra were obtained on a Nermag
mass spectrometer. Melting points have been determined on a Buchi 530
¨
apparatusand are uncorrected. Elemental analy se swere performed at the
Service Central d’Analyses of the C.N.R.S. in Vernaison.
N-(tert-Butoxycarbonyl)-phthalimide 1
To a suspension of phthalimide (1.47 g, 10 mmol) in 5 ml of anhydrous
acetonitrile, at room temperature, were added di-tert-butyldicarbonate
(
2.29 g, 10.5 mmol), followed by DMAP (12 mg, 1 mol%). Fast CO evolu-
2
tion was accompanied by progressive dissolution of the phthalimide. After
0 min at room temperature an homogeneous so lution wasobtained. TLC
dichloromethane-ethyl acetate 9:1) indicated no remaining starting
3
(
material. Solvent wasremoved under reduced pr eus re. The remaining
solid was recrystallized from hexane-ethyl acetate (9:1). Compound 1
(
9
2.4 g, 97%, in two crops) was obtained as slightly beige plates; mp
ꢀ
ꢀ
8
1
7–98 C (litt 97.4 C). H NMR (CDCI ) ꢀ 7.95–7.80 (m, 4H) 1.63 (s, 9H).
3
N-Hydroxyphthalimide 2
To a solution of 1 (1.235 g, 5 mmol) in 5 ml of acetonitrile at room
temperature wasadded an aqueous so lution of hydroxylamine (0.61 ml of a
0 wt % aqueous so lution, 10 mmol). An orange colour developed rapidly.
5
After stirring the mixture overnight at room temperature, an orange pre-
cipitate had formed. Addition of 10 ml of ether allowed the precipitation of
all the orange material, which wasfiltered, wa sh ed with ether and dried. A
yellowish-orange powder (843 mg) was obtained, which corresponds to a
9
5% yield of hydroxylammonium salt of 2. This salt was dispersed in
5 ml of water and diluted HCl wasadded until pH 1. The aqueous
9
1
medium wasextracted with ethyl acetate (3 ꢁ 20 ml). The combined organic
extractswere dried over Na SO and the solvent removed under reduced
2
4
pressure, leaving an almost colourless solid (712 mg, 100% from the hydro-
ꢀ
xylammonium salt), mp 232–233 C. Usual spectroscopic data were identical
to those of a commercial sample.

7
46
EINHORN, EINHORN, AND MARCADAL-ABBADI
General One Pot Procedure for the Synthesis of N-Hydroxyimides
To a suspension of imide (10 mmol) in 5 ml of acetonitrile at room
temperature were added di-tert-butyldicarbonate (1.1–2.2 eq, see table)
followed by DMAP (1ꢂ10 mole%, see Table). Evolution of CO was
2
accompanied by the dissolution of the imide. In some cases, the N-Boc
derivative crystallized from the reaction medium. Progress of the reaction
wasmonitored by TLC. When no st arting material remained, an aqueous
solution of hydroxylamine (0.61 ml of a 50 wt % aqueous solution, 10 mmol)
wasadded. After st irring the mixture overnight at room temperature, addi-
tion of 10 ml of ether led to the precipitation of most of the hydroxyl-
ammonium salt of the N-hydroxyimide. The solid was filtered, washed
thoroughly with ether and dried. It was next dispersed in 15 ml of water
and diluted HCl wasadded until pH 1. N-Hydroxyimidesof low so lubility
in aqueousmedia were filtered, wa sh ed with water and dried. In the ca se of
more water-soluble N-hydroxyimides, the aqueous phase was saturated with
NaCl and extracted several times with ethyl acetate. The combined organic
extractswere dried over Na SO and the solvent removed under reduced
2
4
pressure. N-Hydroxyimides so obtained were generally of sufficient purity
for most synthetic purposes. Analytically pure samples were obtained after
recrystallisation from the suitable solvent or sublimation in vacuum.
4
,5-Dichloro-N-hydroxyphthalimide
ꢀ
Pale yellow powder, 2.32 g, 100%; mp 198–200 C after sublimation
ꢀ
1
0
1
(
1
(
litt 195-197 C). H NMR (200 MHz) ꢀ (DMSO d6) 8.10 (s, 2H), 11.03 (s,
H); C NMR (62.5 MHz) ꢀ (DMSO d6) 125.2, 128.8, 137.2, 162.4; IR
1
3
-1
KBr) cm 3514, 3453, 1715, 1384.
3
,4,5,6-Tetrachloro-N-hydroxyphthalimide
ꢀ
11
Orange powder, 2.76 g, 97%; mp 252–254 C after sublimation (litt
1
ꢀ
13
54 C). H NMR (200 MHz) ꢀ (DMSO d6) 11.22 (s, 1H); C NMR
62.5 MHz) ꢀ (DMSO d6) 125.8, 127.9, 166.1, 171.2; IR (KBr) cm 3586,
2
(
ꢂ1
3
494, 1734, 1370.
4
-Nitro-N-hydroxyphthalimide
ꢀ
Yellow crystals, 2.06 g, 99%; mp 167-169.5 C, after recrystallisation
ꢀ
1
2
1
from ethanol (litt 168–170 C). H NMR (200 MHz) ꢀ (DMSO d6)

N-HYDROXYIMIDES
747
1
3
8
1
1
.01–8.66 (m, 3H), 11.14 (s, 1H); CNMR (62.5 MHz) ꢀ (DMSO d6) 117.6,
ꢂ1
24.4, 129.6, 130.3, 133.8, 151.3, 162.4, 162.5; IR (KBr) cm 3147, 1727,
545, 1347.
3
-Nitro-N-hydroxyphthalimide
ꢀ
1
Yellow powder, 1.95 g, 94%; mp 159–162 C, after sublimation. H
1
3
NMR (200 MHz) ꢀ (DMSO d6) 7.98–8.27 (m, 3H), 11.11 (s, 1H);
C
NMR (62.5 MHz) ꢀ (DMSO d6) 120.7, 126.7, 128.3, 130.7, 136.1, 143.9,
ꢂ1
1
59.7, 162.1; IR (KBr) cm 3147, 1717, 1545, 1547; MS (DCI, NH þ
3
þ
isobutane) m/z 226 (MH þ NH , 100%). Anal. Calcd. for C H N O :
3
8
4
2
5
C, 46.16; H, 1.94; N, 13.46. Found: C, 45.94; H, 1.96; N, 13.57.
N-Hydroxy-3,4-pyridinedicarboximide
ꢀ
Pale yellow crystals, 1.64 g, 100%; mp 233 C, after recrystallisation
ꢀ
1
3
1
from ethanol (litt 232–233 C). H NMR (200 MHz) ꢀ (DMSO d6)
.81–8.08 (m, 3H), 11.04 (s, 1H); C NMR (50 MHz) ꢀ (DMSO d6) 116.5,
23.1, 136.6, 143.2, 156.1, 162.8, 163.3; IR (KBr) cm 3500, 1721, 1431.
1
3
7
1
ꢂ1
N-Hydroxy-2,3-naphtalenedicarboximide
ꢀ
Pale yellow crystals, 2 g, 94%; mp 248–249 C, after recrystallisation
1
from ethanol. H NMR (200 MHz) ꢀ (DMSO d6) 7.72–8.43 (m, 6H), 10.97
1
3
(
1
s, 1H); C NMR (50 MHz) ꢀ (DMSO d6) 124.3, 124.7, 129.3, 130.3, 134.9,
ꢂ1
63.6; IR (KIBr) cm 3450, 1708, 1448; MS (DCI, NH þ isobutane) m/z
3
þ
þ
2
C, 67.59; H, 3.31; N, 6.57. Found: C, 67.37; H, 3.29; N, 6.59.
15 (MH , 100%), 231 (MH þ NH , 93%). Anal. Calcd. for C H NO :
2
3
12
2
5
N-Hydroxysuccinimide
ꢀ
Colourless crystals, 0.95 g, 93%; mp 95–96 C, after recrystallisation
from ethyl acetate. Usual spectroscopic data identical to those of a com-
mercial sample.
N-Hydroxy-1,8-naphtalenedicarboximide
ꢀ
Yellows crystals, 1.71 g, 80%; mp 282–284 C, after recrystallisation
from ethanol. Usual spectroscopic data identical to those of a commercial
sample.

7
48
EINHORN, EINHORN, AND MARCADAL-ABBADI
REFERENCES AND NOTES
1
2
. (a) Anderson, G.W.; Zimmerman, J.E.; Callahan, F.M. J. Am. Chem.
Soc. 1964, 86, 1839–1842. (b) Zimmerman, J.E.; Anderson, G.W.
J. Am. Chem. Soc. 1967, 89, 7151–7152.
. See for example: (a) Rougny, A.; Daudon, M. Bull. Soc. Chim. 1976,
8
33–838. (b) Ace, K.W.; Hussain, N.; Lathbury, D.C.; Morgan, D.O.
Tetrahedron Lett. 1995, 36, 8141–8144. (c) Bonaccorsi, F.; Giorgi, R.
Synthetic Commun. 1997, 27, 1143–1147.
3
. (a) Einhorn, C.; Einhorn, J.; Marcadal, C.; Pierre, J.L. Chem,
Commun. 1997, 447–448 and referencescited therein. (b) Iwahama, T.;
Sakaguchi, S.; Ishii, Y. Chem Commun. 1999, 727–728. (c) Matsunaka,
K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1999, 40,
2
1
165–2168. (d) Eikawa, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
999, 64, 4676–4679.
4
. (a) Gorgy, K.; Lepretre, J.C.; Saint-Aman, E.; Einhorn, C.; Einhorn, J.;
Marcadal, C.; Pierre, J.L. Electrochemica Acta. 1998, 44, 385–393. (b)
Einhorn, C.; Einhorn, J.; Marcadal-Abbadi, C.; Pierre, J.L. J. Org.
Chem. 1999, 64, 4542–4546.
5
. Aurich, H.G. In Nitrones, Nitronates and Nitroxides, Patai, S.;
Rappoport, Z. Eds; John Wiley & Sons : New York, 1989, p. 318.
. Nefkens, G.H.L.; Tesser, G.I. J. Am. Chem. Soc. 1961, 83, 1263.
. Nefkens, G.H.L. Nature, 1960, 185, 309–310.
6
7
8
. N-Boc pthalimide has recently been described, see: Tavecchia, P.;
Marazzi, A.; Dallanoce, C.; Trani, A.; Ciciliato, I.; Ferrari, P.; Selva,
E.; Ciabatti, R. J. Antibiot. 1996, 49, 1249–1257. In our procedure
acetonitrile wasu es d in the place of dioxane and no triethylamine
was necessary.
9
. This as lt hasnot been characterized. It may be in equilibrium with
o-(N-hydroxycarbamoyl)-benzohydroxamic acid; see: Khan, M.N.
J. Chem. Sec. Perkin Trans. II 1988, 213–219.
1
1
1
1
0. Villiger, V. Chem. Ber. 1909, 3529–3549.
1. Orndorff, W.R. J. Am. Chem. Soc, 1912, 48, 495–498.
2. Chan, C.L.; Lien, E.J.; Tokes, Z.A. J. Med. Chem. 1987, 30, 509–514.
3. Hurd, C.R.; Bethurne, V.G. J. Org. Chem. 1970, 35, 1471–1475.
Received in the U.K. March 15, 2000