Unexpected formation of o-acylhydroxamate from the oxidation of a dihydroisoquinoline imine

Article abstract of DOI:10.1080/00397911.2011.580882

The reaction of 3,3-dimethyl-7-nitro-3,4-dihydroisoquinoline 1 with m-chloroperbenzoic acid (m-CPBA) mainly yielded oxaziridine and nitrone, with their selectivities being dependent on the solvents. The reaction with 2.5 equivalents of m-CPBA gave small amounts of oxaziridines and hydroxamic acids as well as isolated O-acylhydroxamate compounds.

Full text of DOI:10.1080/00397911.2011.580882

Synthetic Communications1, 42: 3296–3303, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580882
UNEXPECTED FORMATION OF
O-ACYLHYDROXAMATE FROM THE OXIDATION
OF A DIHYDROISOQUINOLINE IMINE
Hassen Ben Saleh,1 Majed Kammoun,1 Besma Hamdi,2 and
Mohamed Damak1
1
´
Laboratoire de Chimie des Substances Naturelles, Universite de Sfax,
´
Faculte des Science, Sfax, Tunisia
Laboratoire de Sciences de Materiaux et d’environnement, Universite de
2
´
´
´
Sfax, Faculte des Sciences, Sfax, Tunisia
GRAPHICAL ABSTRACT
Abstract The reaction of 3,3-dimethyl-7-nitro-3,4-dihydroisoquinoline
1
with
m-chloroperbenzoic acid (m-CPBA) mainly yielded oxaziridine and nitrone, with their
selectivities being dependent on the solvents. The reaction with 2.5 equivalents of m-CPBA
gave small amounts of oxaziridines and hydroxamic acids as well as isolated
O-acylhydroxamate compounds.
Keywords Hydroxamic acid; oxaziridine; oxidation; X-ray diffraction
INTRODUCTION
The development of efficient synthetic methods for the preparation of oxazir-
idines, which have important applications in organic syntheses, is an important
but challenging goal.[1–5] Oxaziridines have long been employed both as nitrogen-
transfer[6,7] and oxygen-transfer[8,9] reagents in synthetic organic chemistry. They
Received March 7, 2011.
Address correspondence to Majed Kammoun, Laboratoire de Chimie des Substances Naturelles,
´
Universite de Sfax, Faculte des Sciences, BP 1171, 3000 Sfax, Tunisia. E-mail: majed_kammoun@yahoo.fr
´
3296

FORMATION OF O-ACYLHYDROXAMATE
3297
have also been extensively used in asymmetric syntheses.[4,5] Oxaziridines are attain-
able through several synthetic methods.
In fact, the electrophilic amination of carbonyl compounds,[6] the double
1,4-conjugate addition of hydroxamic acids to propiolates, and the photoisomeriza-
tion of nitrone[10] represent some of the nonoxidative methods commonly used for
the preparation of a variety of oxaziridines. Other oxidative methods that have been
developed for the oxidation of imines include the use of several oxidizing agents,
such as buffered oxone,[4] tetrabutylammonium oxone,[11] cobalt-mediated oxidation
using molecular oxygen,[12] hydrogen peroxide,[13] urea–hydrogen peroxide,[14] and a
nitrile–hydrogen peroxide system.[15,16] Ultimately, the first method of oxaziridine
preparation, which still continues be to be favored these days, was the oxidation
of an imine with a peracid, usually m-chloroperbenzoic acid (m-CPBA). [4,17] In gen-
eral, the action of peracid with an imine leads to oxaziridine. In some cases, however,
the formation of nitrone can also be observed. The selectivity change with the reac-
tion conditions and imine structures.[18]
In the present article, we describe the results of oxidation of the representative
imine 1 with m-CPBA. We also describe the effects of the solvent as well as the
amount of m-CPBA on the selectivity of the reaction.
RESULTS AND DISCUSSION
The representative imine 1 was synthesized[19] from the commercially available
tertiary alcohol (al) as indicated in Scheme 1. In fact, this imine (im) was previously
used in an earlier work[19] to prepare the corresponding iminium salt, which is a con-
venient catalyst with regard to the oxaziridinium-mediated epoxidation system.
The reaction of imine 1 with m-CPBA gave both oxaziridine and nitrone, with
the selectivity being dependent on the solvent (Scheme 2).
While the oxidation of imine 1 with m-CPBA in a solution of dichloromethane
or acetonitrile gave oxaziridine 2, with a small apparent formation of nitrone 3, the
reaction in the methanol solvent led quantitatively to oxaziridine 2.[20] This reaction
(Scheme 2) shows that the product selectivity depends on the solvents. Oxaziridine
formation is, therefore, predominant and nitrone formation is enhanced in the apro-
tic solvent.
The regioselectivity of oxygen transfer on an imine in these reactions depends
on the steric and electronic factors. It was, for instance, observed that the use of a
protic solvent disfavors the formation of nitrone.
Imine 1 was also oxidized at room temperature in CH2Cl2 with 2.5 equivalents
of m-CPBA. The m-CPBA disappeared after 24 h, and the reaction led to a mixture
of oxaziridine 2 and compound 5, as two minor products, and hydroxamic acid 4 as
the major product. Those products were isolated with the yields of 10%, 25%, and
Scheme 1. Synthesis of the imine 1.

3298
H. BEN SALEH ET AL.
Scheme 2. Reaction of imine 1 with 1 equivalent of m-CPBA.
40%, respectively (Scheme 3). The structure of this hydroxamic acid 4[21] was pre-
viously established by x-ray diffraction. The latter product has always been reported
to be highly required particularly because it has excellent biological activities in a
wide range of organic syntheses and processes[22]
Oxaziridine 2 and nitrone 3[20] were especially sensitive to overoxidation, and
the two major products formed were hydroxamic acid 4 and a new derivative 5,
which were both isolated by column chromatography. Among the methods com-
monly used for the preparation of hydroxamic acid 4, the direct oxidation of imine
1 with 2.5 equivalents of peracid has often been preferred. This is particularly
because it is faster and easier than the oxidation of oxaziridine 2 or nitrone 3 with
1 equivalent of peracid.
Imine 1 was first oxidized to obtain oxaziridine 2. The latter was also oxidized
in situ to the product 6, which was isomerized into the intermediate 7. Two paths
were considered (Scheme 4). In the first path, the resulting 7 led directly to the
ring-opened nitroso compound 8 by rearrangement[23] In contrast to common
nitroso compounds, this exhibited no tendency to dimerize, presumably because of
steric hindrance,[24] but instead by oxidation. Under the conditions described for
similar substrates,[25] it directly led to the nitro intermediate 9.
In the second pathway, the resulting 7 led through rearrangement to the hydro-
xamic acid 4 after two steps. The O-acylhydroxamate compound was eventually pre-
pared through the nucleophilic attack at the intermediate 9 by the hydroxamic acid
compound 4.
Scheme 3. Result of the oxidation of imine 1 with m-CPBA.

FORMATION OF O-ACYLHYDROXAMATE
3299
Scheme 4. Mechanistic hypothesis of compound 5 formation.
Figure 1. Molecular structure of compound 5. (Figure is provided in color online.)

3300
H. BEN SALEH ET AL.
The oxidation mechanism (Scheme 4) presumes the formation and subsequent
fragmentation of intermediate 7, leading to the formation of hydroxamic acid 4 and
O-acylhydroxamate 5.
The structure of the new compound 5 was confirmed by single-crystal x-ray
structure determination. The experimental details of data collection and structure
refinement are summarized in the experimental section. An ORTEP diagram of
the molecular structure of 5 in the crystal form is shown in Fig. 1.
In all subsequent work, the O-acylhydroxamate-derived compounds were
formed from hydroxamic acid by nucleophilic attacks at the acylnitroso carbonyl,[26]
which generally represent transient intermediates in the oxidative cleavage of hydro-
xamic acids with several oxidizing agents[27] or direct acylation.[28]
CONCLUSION
The present study investigated the peracid oxidation of imine 1. This reaction
showed that the product selectivity depended on the operating conditions. The pro-
cess involved the isolation of four interesting products, namely oxaziridine 2, nitrone
3, hydroxamic acid 4, and O-acylhydroxamate 5. The structure of this yet unknown
compound 5 was established by x-ray diffraction. The unexpected formation of
product 5 could open a new pathway for the synthesis of derivatives of imine.
EXPERIMENTAL
Preparation of Compound 5
A solution of the imine 1 (3 mmol) in CH2Cl2 (100 ml) was stirred at rt while a
solution of m-chloroperbenzoic acid 86% (7.5 mmol) in CH2Cl2 (50 ml) was added
slowly. After 24 h, the mixture was washed with saturated aqueous sodium bicarbon-
ate (3 ꢀ 150 ml), dried, and evaporated. An aliquot of the crude product was ana-
1
lyzed by H NMR in CDCl3. A mixture of 2, 4, and 5 in the molar ratio 1:2:4
was detected. These products were separated by chromatography on silica gel
(hexane=ether 4=1) with the yields of 10%, 40%, and 25%, respectively.
Selected Physical Data for Compound 5
Colorless crystals; mp: 147–148 ꢁC; 1H NMR (300 MHz, CDCl3): d ¼ 1.45 (br s
3H), 1.49 (br s 3H), 1.68 (br s 3H), 1.82 (br s 3H), 3.13–4.14 (m, 4H), 7.38 (d,
J ¼ 8.0 Hz, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H), 8.37 (dd, J ¼ 2.5, 8.0 Hz, 1H), 8.41 (dd,
J ¼ 2.5, 8.0 Hz, 1H), 8.54 (d, J ¼ 2.5 Hz, 1H); 8.96 (d, J ¼ 2.5 Hz 1H). 13C NMR
(75 MHz, CDCl3): 27.6, 28.7, 41.7, 43.0, 62.6, 89.1, 124.1, 125.6, 127.3, 127.6,
129.4, 132.9, 128.7, 129.6, 142.9, 144.5, 146.9, 147.6, 159.3, 160.1, 163.4. Anal. calc.
for C22H22N4O9: C, 54.32; H, 4.56; N, 11.52. Found: C, 54.43; H, 4.61; N, 11.58.
Crystal Data for Compound 5
Data were collected at room temperature using a Bruker-APEX II Kappa
˚
CCD diffractometer, M ¼ 486.14, monoclinic, C2=c, a ¼ 26.950 (3) A, b ¼ 7.8778

FORMATION OF O-ACYLHYDROXAMATE
3301
3
ꢁ
˚
˚
˚
(7) A, c ¼ 24.092 (3) A, b ¼ 112.695 (3) , V ¼ 4718.8 (8) A , Z ¼ 8, Dc ¼ 1.369
g=cmꢂ3
,
X-ray source Mo-Ka (radiation), k ¼ 0.71073 A,
F
(000) ¼ 2068,
˚
T ¼ 293 K, colorless prism 0.44 ꢀ 0.31 ꢀ 0.19 mm. The structure solution was
obtained by direct methods and refined with anisotropic thermal parameters using
full-matrix least squares procedures on F2 to give R ¼ 0.113, wR ¼ 0.177 for 5387
independent observed reflections and 316 parameters.
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