Synthesis and reactivity study of two new dihydroisoquinoline-derived oxaziridines

Article abstract of DOI:10.1080/00397911.2010.487175

The N-alkyl oxaziridines may be used as reagents for the oxidation of sulfides in acid-promoted reactions. The present work describes the behavior of two newly synthesized dihydroisoquinoline-derived oxaziridines with respect to methanesulfonic acid. An isomerization reaction was observed in the absence of sulfide.

Full text of DOI:10.1080/00397911.2010.487175

Synthetic Communications1, 41: 1520–1528, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.487175
SYNTHESIS AND REACTIVITY STUDY OF TWO NEW
DIHYDROISOQUINOLINE-DERIVED OXAZIRIDINES
Majed Kammoun, Hassen Ben Salah, and Mohamed Damak
´
Laboratoire de Chimie des Substances Naturelles, Faculte des Sciences,
Sfax, Tunisia
GRAPHICAL ABSTRACT
Abstract The N-alkyl oxaziridines may be used as reagents for the oxidation of sulfides in
acid-promoted reactions. The present work describes the behavior of two newly synthesized
dihydroisoquinoline-derived oxaziridines with respect to methanesulfonic acid. An isomeri-
zation reaction was observed in the absence of sulfide.
Keywords Hydroxamic acid; methanesulfonic acid; nitrone; oxaziridine; oxygen transfer
INTRODUCTION
The oxaziridine function, discovered in 1956 by Emmons,[1] contains a small
three-element cycle involving a carbon atom, an oxygen atom, and a nitrogen atom.
It has been extensively investigated and contains the presence of a relatively weak
N-O bond into a strained ring, which endows its components with remarkably great
reactivity.
Oxaziridines are usually known for their ability to react as aminating or, in
some cases, oxygenating agents with nucleophiles. In fact, ordinary oxaziridines,
whether (N-H oxaziridines),[2] (N-alkyl oxaziridines),[3] or (N-alkoxycarbonyl
oxaziridines),[4] are electrophilic amination reagents.[5] The nitrogen transfer is thus
the normal reaction of oxaziridines with nucleophiles. Nevertheless, oxygen transfer
Received February 2, 2010.
Address correspondence to Majed Kammoun, Laboratoire de Chimie des Substances Naturelles,
´
Faculte des Sciences, BP 1171, 3000 Sfax, Tunisia. E-mail: majed_kammoun@yahoo.fr
1520

DIHYDROISOQUINOLINE-DERIVED OXAZIRIDINES
1521
Scheme 1. Reactivity of oxaziridine 1.
may occasionally result from hindered oxaziridines and hindered nucleophiles.[6]
Sulfoxidation has been performed with oxaziridines having electron-withdrawing
substituents on the nitrogen atom or on both the nitrogen and the carbon atoms
of the three-membered ring.[7–9]
In this respect, the nonsubstituted dihydroisoquinoline-derived oxaziridine 1
has been reported to be an excellent agent for the transfer of oxygen on organosul-
fides, which are weakly basic nucleophilic substrates, if the oxygen transfer is
promoted by an acid.[10] In this case, the N-protonated oxaziridine 2 plays the role
of the active oxidizing species and renders the simultaneous presence of acid and
sulfide necessary. Indeed, in the absence of sulfide, oxaziridine 3, which is equally
O-protonated, isomerizes into nitrone 4 (Scheme 1).
In the asymmetric field, acid-catalyzed oxidation of prochiral sulfides by a
chiral N-alkyl oxaziridine has been reported.[11] More recently, acid-catalyzed enan-
tioselective sulfoxidations using N-alkyl binaphthyl-derived oxaziridines have also
been reported.[12] Also, Lewis acid–catalyzed enantioselective sulfoxidations using
an otherwise inert oxaziridine have been recently reported.[13]
In the present paper, we describe the synthesis of two new ordinary oxaziri-
dines 5 and 6 from the dihydroisoquinoline-derived family. Using this new oxidizing
system, described in Scheme 1, the latter was investigated for potential reactivity to
organosulfides as well as isomerization by the action of methanesulfonic acid.
RESULTS AND DISCUSSION
Synthesis of the Oxaziridines 5 and 6
The two new models presented in the current study were synthesized starting
from commercial tertiary alcohol 7 (Scheme 2). The formamide 8 from step (a)[14]
was cyclized to form imine 9[15,16] after a three-step sequence.[17] The nitration of this
Scheme 2. Reagents and conditions : (a) KCN; SO4H2-AcOH; rt; (b) oxalyl chlorid; CH2Cl2; (c) FeCl3;
(d) MeOH; H2SO4; (e) KNO3-H2SO4; rt 2 h, 60 ꢀC 4 h; (f) m-CPBA; MeOH.

1522
M. KAMMOUN, H. B. SALAH, AND M. DAMAK
imine under soft conditions[18,19] selectively led to the derived 10. The oxidation of
imines 9 and 10 under conditions (f) rapidly led to oxaziridines 5 and 6, respectively.
They were isolated with overall yields of 49% and completely characterized
(Scheme 2).
Oxygen-Atom Transfer onto Sulfides
The oxidation of sulfides with 5 and 6 were first performed under the
conditions previously[10] described at room temperature in the presence of methane-
sulfonic acid (MsOH) in dichloromethane (Table 1).
It can be noted from Table 1 that both oxaziridines 5 and 6 have equivalent
behavior in the reactions under investigation, oxidize quantitatively and quickly at
room temperature, and give good sulfoxide conversion with no overoxidation to
sulfones. The reaction times were significantly shortened with oxaziridine 6. The
presence of an electron-withdrawing group (NO2) increased the electrophile of
oxaziridine and thus notably accelerated the transfer of the oxygen atom.
The reaction of oxygen transfer was slowest for both oxaziridines with
diphenylsulfide (entry 3); this is attributed to the resonance effect of this reagent.
Moreover, the oxidation of diphenylsulfide with oxaziridine 5 is not total; a conver-
sion of only 80% into the corresponding sulfoxide was observed.
Table 1. Oxidation of sulfidesa with 5 and 6 in the presence of methanesulfonic acidb
Timec (min)
Yield of sulfoxides (%) (conversions)d
=
=
=
=
R H
Entry
1
Sulfides
R
NO2
R
H
R
NO2
<2
9
82e (100)
79e (100)
84e (100)
77e (100)
2
<2
10
3
4
12
5
40
10
78e (100)
(100)
65e (80)
(100)
aReaction performed at room temperature in CH2Cl2.
b0.5 mmol of sulfide (0,16 M), 2 equivalent of MsOH, and 1 equivalent of oxaziridine.
cDetermined by TLC.
dDetermined by 1H NMR spectroscopy in CDCl3.
eIsolated product.

DIHYDROISOQUINOLINE-DERIVED OXAZIRIDINES
1523
Scheme 3. Chiral oxaziridine 11.
The oxidation of this same reagent by oxaziridine 6 was, however, faster and
more quantitative. In fact, a noticeable increase in the electrophile of oxaziridine 6
was observed. Consequently, an active oxygen loss through the isomerization of
the oxaziridine into nitrone was noted with the least reactive oxaziridine 5. In fact,
and in this case, the oxygen transfer reaction was not fast enough to mask the
acid-catalyzed isomerization reaction. This is consistent with a previously reported
result in the literature[11] stipulating that if the nucleophilic substrate presents a steric
effect, 15–20% of the chiral oxaziridine 11 of the dihydroisoquinoline-derived family
isomerize into the corresponding nitrone 12 under acid catalysis.
The isomerization reaction of oxaziridine 11 by a methanesulfonic acid excess
in the absence of nucleophilic substrate led, rapidly and quantitatively, to nitrone 12
(Scheme 3).
The acid-catalyzed isomerization reaction of new oxaziridines 5 and 6 under
these conditions is shown in Scheme 4.
With oxaziridine 5, unsubstituted in position 7, it was found that when the
latter was made to react with 2 equivalents of MsOH acid, the reaction would lead
to the corresponding nitrone 13 after 30 min, with a conversion rate of 100%. The
nitrone obtained, already described in the literature data,[20] was isolated in 80%
yield.
With the oxaziridine 6, the reaction was very slow. It was only after 30 h that
the reagent disappeared and the reaction led to a mixture of nitrone 14 (50% of
conversion), hydroxamic acid 15 (25% of conversion), and protonated imine 16
(25% of conversion). Those products were isolated with yields of 32%, 16%, and
16%, respectively. The structure of this already unknown compound (hydroxamic
acid 15) was established by x-ray diffraction[21] (Fig. 1).
It is worth noting in this respect that the oxaziridines 1, 5, and 11 of the
dihydroisoquinoline-derived family, unsubstituted in position 7, isomerized quickly
and quantitatively to their corresponding nitrones whereas nitrone 14, formed by
Scheme 4. Oxaziridines 5 and 6 under the action of methanesulfonic acid.

1524
M. KAMMOUN, H. B. SALAH, AND M. DAMAK
Figure 1. Molecular structure of hydroxamic acid 15.
the isomerization of the protonated oxaziridine 6 into oxygen by the methanesulfo-
nic acid at room temperature, was accompanied by the hydroxamic acid 15
(Scheme 4). In fact, it was previously reported[22] that the action of a peracid on
steroidic oxaziridines can lead to the formation of hydroxamic acid in addition to
the compounds that result from the ring opening of the oxaziridine. The action of
a peracid on an oxaziridine was previously explained by an oxaziridine nucleophilic
attack onto the oxidation agent.
By analogy, the present study propose that the hydroxamic acid 15 most prob-
ably came from the oxidation of the oxaziridine 6 by the N-protonated oxaziridine 6
(intermediate 17, Scheme 5). In fact, it was noted that the introduction of the attrac-
tor grouping (nitro) in position 7 onto the dihydroisoquinoline skeleton of the func-
tion brought about a significant variation in terms of oxaziridine 6 reactivity so that
the N-protonated intermediary 17 became able to oxidize oxaziridine 6, which would
play the role of a nucleophile (Scheme 5). This therefore can be considered as the first
time a protonated oxaziridine is shown to be able to oxidize its precursor and to
bring about a hydroxamic acid formation. The latter have always been reported as
highly required products with excellent biological activities particularly in a wide
range of organic syntheses and processes.[23,24]
Scheme 5. Mechanistic hypothesis of hydroxamic acid 15 formation.

DIHYDROISOQUINOLINE-DERIVED OXAZIRIDINES
1525
CONCLUSION
The findings of the present study demonstrate the effectiveness of the new
oxaziridine 6 as an oxygen-transfer agent for sulfides in acidic media and the high
potential of the N-protonated intermediary to oxidize an oxaziridine and form the
hydroxamic acid. This reactivity, which is actually novel for both ordinary and
activated oxaziridine functions, can be considered promising because it offers
interesting possibilities for future applications.
EXPERIMENTAL
Solvents were purified by standard methods. Melting points (mp) were deter-
mined under microscope with a Leitz Wetzlair device and are uncorrected. Mass spec-
tra (MS) were obtained by electronic impact (EI) (70 eV) on a AEI MS-50 spectrometer
and in high resolution (HR) on a Kratos MS-80 spectrometer. NMR spectra were
recorded at 250 or 300 MHz for 1H and 62.5 or 75 MHz for 13C. Chemical shifts (d)
are given in parts per million relative to tetramethylsilane (TMS), and coupling con-
stants (J) are given in hertz (Hz). All reactions were monitored by TLC using commer-
cial silica-gel plates and visualization was accomplished by ultraviolet (UV) light or
stained with Draggendorf reagent. The presence of oxidizing species in the reaction
mixtures was determined by potassium iodide test. All sulfides were commercially
available. Formamide 8[14] and imine 9[15,16] were synthesized by a known procedure.
Preparation of the Imine 10
The imine 9 (6.8 g, 43 mmol) was added to 25 ml of concentrated sulfuric acid
through maintaining the temperature of the reaction mixture lower than ꢁ5 ꢀC. A
solution of potassium nitrate (5.2 g, 52 mmol) in 20 ml of sulfuric acid (98%) was
progressively added. The reaction mixture was stirred at room temperature for 2 h
and then at 60 ꢀC for 4 h. After returning to room temperature, the reaction mixture
was poured on ice and then alkalized (ammonia). The organic phase was extracted with
dichloromethane, washed with a saturated solution of sodium chloride, and dried on
sodium sulfate. Removal of solvent left a solid residue. By recrystallization (hexane),
1
the imine 10 was obtained with a yield of 90%. Mp: 105–106 ꢀC (hexane). H NMR
(CDCl3, 300MHz, d): 1.25s (6H 2CH3), 2.83s (2H CH2 H-4), 7.32 d (1H arom H-5,
J ¼ 9 Hz), 8.15 d (1H arom H-8, J ¼ 2.1 Hz), 8.22 dd (1H H-6, J ¼ 2.1 Hz, J ¼ 9 Hz),
8.30s (1H H-1). 13C NMR (CDCl3, 75MHz, d): 28.01 [C(CH3)2], 37.99 (CH2 C-4),
55.15 (CMe2 C-3), 121.77, 125.80, and 129.20 (CH arom.), 127.96, 143.06, and
147.28 (C arom.), 155.30 (CH C-1). MS (IE): 204 (Mþ., base peak). Anal. calcd. for
C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.73; H, 6.05; N, 13.51%.
Preparation of the Oxaziridine 5
m-Chloroperbenzoic acid (357 mg, 1.78 mmol, 1 equiv of active oxygen) was
added in small portions to a solution of imine 9 (283 mg, 1.78 mmol) in 10 ml of meth-
anol under magnetic stirring. The solvent was evaporated, and the residue was taken
up in dichloromethane and washed with a sodium bicarbonate solution and then with

1526
M. KAMMOUN, H. B. SALAH, AND M. DAMAK
water. The collected organic phase were dried over Na2SO4, filtered, and concen-
trated. The resulting pale yellow oil was purified by chromatography on silica gel
(eluent CH2Cl2=Et2O 95=5) and distilled (75–80 ꢀC, 0.05 mmHg) to give 238 mg of
1
colorless oil of oxaziridine 5 (yield: 76%). H NMR (CDCl3, 300 MHz, d): 0.90 s
(3H CH3), 1.50 s (3H CH3), 2.36 d (1H H-4, J ¼ 15.30 Hz), 2.74 d (1H H-4,
J ¼ 15.30), 4.93 s (1H H-1) 7.10 m (1H arom.), 7.29 m (1H arom.), 7.36 m (1H arom.),
7.51 m (1H arom.); 13C NMR (CDCl3, 75 MHz, d): 22.67 (CH3 C-3), 28.70 (CH3 C-3),
36.28 (CH2 C-4), 56.94 (CMe2 C-3), 75.42 (CH C-1), 126.5, 134.88 (C arom.), 126.5,
128.42, 129.73 (CH arom.). MS (EI): 175 (Mþ., 76%), 160 [(Mþ. ꢁ 15), 87%], 159
[(Mþ. ꢁ 16), 87%], 143 (base peak). Anal. calcd. for C11H13NO: C, 75.4; H, 7.48;
N, 7.99; O, 9.13. Found: C, 75.61; H, 7.58; N, 8.16; O, 9.07%.
Preparation of the Oxaziridine 6
m-Chloroperbenzoic acid (2.75 g, 13.7 mmol, 1 equiv of active oxygen) was
added in small portions to a solution of imine 10 (2.8 g, 13.7 mmol) in 100 ml of meth-
anol. The reaction was monitored by thin-layer chromatography (TLC). TLC that
was performed after the end of peracid addition indicated that the reaction was com-
plete. The solvent was evaporated, and the white solid residue was taken up in dichlor-
omethane and washed with a sodium bicarbonate solution and then with water. The
organic phase was dried (Na2SO4), filtered, and concentrated. The resulting yellow
solid was purified by recrystallization (ether) to give 2.57 g of yellow crystals of oxa-
ziridine 6 (yield 85%). Mp 80–82 ꢀC. 1H NMR (CDCl3, 250 MHz, d): 0.91 s (3H CH3),
1.53 s (3H CH3), 2.5 d (1H H-4, J ¼ 19.25 Hz), 2.8 d (1H H-4, J ¼ 19.25 Hz), 5.04 s (1H
H-1), 7.3 d (1H arom. H-5, J ¼ 10 Hz), 8.24 dd (1H H-6, J ¼ 3, J ¼ 10 Hz), 8.43 d (1H
arom H-8, J ¼ 3 Hz). 13C NMR (CDCl3, 62.5 MHz, d): 22.74 (1 CH3 C-3), 28.68
(1 CH3 C-3), 36.49 (CH2 C-4), 57.30 (CMe2 C-3), 74.44 (CH C-1), 124.85, 124.88,
129.66 (CH arom.), 130.5, 142.62 and 146.95 (C arom.). MS (IE): 220 (Mþ., 67%),
204 [(M ꢁ 16)þ., base peak], 174 (27%), 159 (47%). Anal. calcd. for C11H12O3N2: C,
59.99; H, 5.49; N, 12.72; O, 21.79. Found: C, 59.78; H, 5.73; N, 12.59; O, 21.91%.
Oxygen Transfer to Sulfides with Oxaziridines 5 and 6
A solution of the oxaziridine 5 or 6 (0.50 mmol) in methylene chloride (2 ml)
was added to a solution of sulfide (0.50 mmol) and methanesulfonic acid (1 mmol)
in methylene chloride (2 ml). The reaction mixture was stirred at room temperature
until the disappearance of the active oxygen, monitored by TLC and potassium
iodide test, and then was diluted with methylene chloride and washed with an aque-
ous sodium bicarbonate solution. The organic phase was dried with Na2SO4 and
concentrated in vacuo. The sulfoxides were purified by chromatography on silica
gel. The sulfoxides obtained are compared and identified with commercial samples.
The various results that were obtained are presented in Table 1.
Action of the Methanesulfonic Acid on the Oxaziridine 6
Methanesulfonic acid (2.7 mmol) were added to a solution of oxaziridine 6
(300 mg, 1.35 mmol) in dichloromethane (6 ml), and the mixture was stirred at room
temperature. A control of the reaction mixture by TLC indicated the disappearance

DIHYDROISOQUINOLINE-DERIVED OXAZIRIDINES
1527
of the oxaziridine after 30 h with appearance of three products, nitrone 14, imine 10
and another product of Rf ¼ 0.73 (ether elution), which with acid iron (III) chloride
solution gave a violet blue spot, a distinguishing attribute of the hydroxamic acid.[25]
The reaction mixture was diluted with dichloromethane and was washed with
an aqueous sodium bicarbonate solution and with a saturated sodium chloride
solution. The organic phase was then dried (sodium sulfate), and the solvent was
1
evaporated. An aliquot of the crude product was analyzed by H NMR in CDCl3.
A mixture of (14, 15, and 10) in the molar ratio 2:1:1 was detected. These products
were separated by chromatography on silica gel (ether) with the yields of 32%, 16%,
and 16%, respectively.
Selected Data
Nitrone 14. Mp: 152–154 ꢀC. 1H NMR (CDCl3, 300 MHz, d): 1.47 s (6H
2CH3), 3.19 s (2H CH2 H-4), 7.4 d (1H arom. H-5, J ¼ 8.2 Hz), 7.79 s (1H H-1),
7.97 d (1H arom. H-8, J ¼ 2 Hz), 8.10 dd (1H H-6, J ¼ 2, J ¼ 8.2 Hz); 13C NMR
(CDCl3, 75 MHz, d): 24.82 [C(CH3)2], 41.73 (CH2 C-4), 67.49 (CMe2 C-3), 119.10,
123.46 and 128.65 (CH arom.), 129.73, 131.17, 136.59 (C arom.) and 148 (CH
C-1). MS (EI): 221 [(M þ H)þ., base peak]. Anal. calcd. for C11H12N2O3: C, 59.99;
H, 5.49; N, 12.72; O, 21.79. Found: C, 60.07; H, 5.76; N, 12.59; O, 21.65%.
Acide hydroxamique 15. Mp: 175–176 ꢀC. 1H NMR (CD3SOCD3,
300 MHz, d): 1.26 s (6H 2CH3), 3.23 s (2H CH2 H-4), 7.58 d (1H arom H-5,
J ¼ 8 Hz), 8.33 dd (1H H-6, J ¼ 2.4, J ¼ 8 Hz), 8.55 d (1H arom H-8, J ¼ 2.4 Hz).
13C NMR (CD3SOCD3 75 MHz, d): 25.24 [C(CH3)2], 41.80 (CH2 C-4), 60.66
(CMe2 C-3), 122.02, 126.87 and 130.41 (CH arom.), 129.91, 144.05 and 147.21
(C arom.), 160.08 [-C(O) C-1]. MS (IE): 236 (Mþ.), 221 [(M ꢁ 15)þ., base peak];
MS (HR): found mass: 236.0844 mass calculated for C11H12N2O4: 236.0875.
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