Stereospecific synthesis of 2-alkyl-3-aryloxaziridines from prochiral and chiral N-arylidenealkylamines by use of the benzonitrile-hydrogen peroxide system

Article abstract of DOI:10.1081/SCC-100000208

Benzonitrile-hydrogen peroxide oxidation of prochiral and chiral imines 1a-h leads to racemic (E)-oxaziridines (R,R/S,S) and nonracemic (E)-oxaziridines (R,R,R/S,S,R) 2a-h, respectively.

Full text of DOI:10.1081/SCC-100000208

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STEREOSPECIFIC SYNTHESIS OF 2-ALKYL-3-
ARYLOXAZIRIDINES FROM PROCHIRAL AND CHIRAL
N-ARYLIDENEALKYLAMINES BY USE OF THE
BENZONITRILE-HYDROGEN PEROXIDE SYSTEM
Jamil Kraïem , Yakdhan Kacem , Jameleddine Khiari & Béchir Ben Hassine
Published online: 16 Aug 2006.
To cite this article: Jamil Kraïem , Yakdhan Kacem , Jameleddine Khiari & Béchir Ben Hassine (2001) STEREOSPECIFIC
SYNTHESIS OF 2-ALKYL-3-ARYLOXAZIRIDINES FROM PROCHIRAL AND CHIRAL N-ARYLIDENEALKYLAMINES BY USE OF
THE BENZONITRILE-HYDROGEN PEROXIDE SYSTEM, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:2, 263-271, DOI: 10.1081/SCC-100000208
To link to this article: http://dx.doi.org/10.1081/SCC-100000208
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SYNTHETIC COMMUNICATIONS, 31(2), 263–271 (2001)
STEREOSPECIFIC SYNTHESIS
OF 2-ALKYL-3-ARYLOXAZIRIDINES
FROM PROCHIRAL AND CHIRAL
N-ARYLIDENEALKYLAMINES BY USE
OF THE BENZONITRILE-HYDROGEN
PEROXIDE SYSTEM
Jamil Kra¨ıem, Yakdhan Kacem, Jameleddine Khiari,
and Be´chir Ben Hassine∗
Laboratoire de Synthe`se Organique Asyme´trique et de
Photochimie, Faculte´ des Sciences de Monastir,
5000 Monastir, Tunisie-Tunisia
ABSTRACT
Benzonitrile-hydrogen peroxide oxidation of prochiral and
chiral imines 1a–h leads to racemic (E)-oxaziridines (R,R/S,S) and
nonracemic (E)-oxaziridines (R,R,R/S,S,R) 2a–h, respectively.
Oxidation of imines with organic peracids is the most useful method for
preparing oxaziridines (1–4). These reagents convert anti-N-arylidenealkyl-
amines (3,5,6) to a mixture of (E) and (Z)-oxaziridines (3,7–10) according to
a two-step mechanism (11–13). Note that 2-tert-alkyl-3-aryloxaziridines were ob-
tained exclusively in the (E) form because of the bulkiness of the substituents. Until
now, no stereospecific synthesis of 2-alkyl-3-aryl-oxaziridines has been reported.
∗ To whom correspondence should be addressed.
263
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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KRAIEM ET AL.
264
Scheme 1.
The nitrile-hydrogen peroxide system (14) has found good success in syn-
thesis of epoxides from olefins (15–17). It was previously used by Schirmann and
Weiss (18) to prepare N-alkyloxaziridines from imines. Yields were generally less
than 50%; moreover, no information about stereospecificity of this procedure has
been reported.
In this work, anti-imines 1a–h were converted to oxaziridines 2a–h
(Scheme 1) with good to high yields (60–90%), using the benzonitrile-hydrogen
peroxide system. We have found that commercial aqueous hydrogen peroxide of
moderate concentration 35% can be used successfully instead of 70% (18) solution
to prepare oxaziridines 2a–h.
All oxaziridines 2a–f displayed one spot on TLC, and thus appear to consist
ofoneisomer(EorZ). Indeed, (E)and(Z)isomersof2-alkyl-3-aryloxaziridinesare
known to give different 1H and 13C spectra (3,8,9,19–22). The H−3 proton absorbs
at lower field (near 5.2 ppm) in the (Z) compounds than in the (E) compounds
(near 4.6 ppm). A similar structural dependance for the C chemical shifts in
−3
oxaziridines has been observed (21). As indicated in Table 1, the chemical shifts
of the H−3 proton in oxaziridines 2a–f fall in the narrow range of δ 4.46–4.77 ppm,
and indicate that only (E)-oxaziridines (R,R/S,S) were formed (23).
Chiral anti-imines 1g,h, obtained from parasubstituted benzaldehydes and
(R)-(-)-α-cyclohexylethylamine, wereconvertedtooxaziridines2g,h. TheH1NMR
spectra of these oxaziridines show two signals of the H proton, near 4.5 ppm
−3
(Table 2). The MCPBA oxidation of chiral anti-aldimines, having (R) configura-
tion of the substituent linked to the N-atom, yields three or four nonracemic di-
astereoisomers (20,25). Diastereoisomers of (E) configuration [(RRR) and (RSS)]
have two different δH−3, near 4.3 ppm and those of (Z) configuration [(RSR) and
(RRS)] have two different δH−3, near 5.1 ppm. The same results has been observed
when 1g,h were converted to oxaziridines with MCPBA (26) (for oxaziridine from

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PROCHIRAL AND CHIRAL IMINES
265
Table 1. Chemical Shifts of H and C of 2a–f Compared with the Literature Data
−3
−3
Litt. Data
δ(C
δ(H
)
δ(C )
−3
−3
Oxaziridines
ppma
ppma
δ(H
)
)
−3
Ref.
−3
2a (E)
2b (E)
2c (E)
(Z)
2d (E)
(Z)
2e (E)
(Z)
2f (E)
(Z)
4.63
4.77
4.46
—
4.50
—
4.46
—
4.58
—
73.70
72.22
79.71
—
78.40
—
79.79
—
79.11
—
4.63
4.79
4.26b
4.26
4.61
5.36
4.50
5.26
4.63
5.33
73.66
72.32
78.60
78.50
78.10
78.60
—
—
79.32
79.62
19, 24
9, 24
10, 21
9, 21
22
c
aRecorded in CDCl3.
bH1NMR spectra of 2c show two signals of CH3 (iPr); 1.25 (d), 1.30 (d) [Litt. Data (10);
1.13 (d), 1.27 (d) for the (E) compound and 0.68 (d), 1.17 (d) for the (Z) compound].
cChemical shifts releved from spectra of the crude product obtained by oxidation of 1f
with MCPBA, according to Mlochwski procedure (3).
1g: δH = 4.41, 4.53, 5.15, 5.27; for oxaziridine from 1h: δH = 4.55, 4.63,
−3
−3
5.18, 5.33), and the comparison with δH of 2g,h indicates that in every case,
−3
only two (E) dastereoisomers I (RRR) and II (RSS) (Fig. 1), were formed when a
mixture of benzonitrile-hydrogen peroxide is used as oxidant.
The composition of the mixture was determined by integration of the signal
produced by H proton.
−3
Table 2.
Analytical Datad
2g-h Diast. (%)a (ppm)b (ppm)b Yieldsc Required (%) Found (%)
δH
δC
−3
−3
M(62)
4.52
81.88
C(77.92)
H(9.09)
N(6.06)
C(77.86)
H(9.05)
N(6.10)
2g
2h
72
63
m(38)
M(85)
4.41
4.63
78.16
80.42
C(65.21)
H(7.26)
C(65.18)
H(7.17)
m(15)
4.56
77.20
N(10.14)
N(10.21)
aThe major and the minor diastereoisomers were assigned to M and m, respectively.
bRecorded in CDCl3.
cDetermined iodometrically.
dMicroanalytical data for the mixture of diastereoisomers.

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KRAIEM ET AL.
266
Figure 1.
In every case, the H proton and the C carbon of the major diastereo-
−3
−3
isomerabsorbatlowerfield. Thusallpredominantdiastereoisomersseemtoconsist
of the same structure. As described by Belzeki et al. (20), when the substituent
linked to the N-atom of imines has an (R) absolute configuration, this imine will
be attacked preferably from the pro-s face (Fig. 2). Accordingly, the predominant
diastereoisomer should be II (SSR). To confirm this result, we have separated the
diastereoisomers of 2g,h by chromatography (SiO2; hexane-ethyl acetate 97:3) in
order to calculate the difference between the molecular rotation “[ꢀM]” of each
one and the corresponding imine 1a–h. A small positive value of [ꢀM]D was
observed for predominant diastereoisomer and a large positive value was observed
for the other one (Table 3). By analogy (20), the major diastereoisomer is assigned
as II (SSR) and the minor as I (RRR).
From a mechanistic point of view, the two-step mechanism cannot explain
the results obtained in this work, since oxaziridines 2c–f, were formed exclusively
Figure 2.

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PROCHIRAL AND CHIRAL IMINES
267
Table 3.
2g-h Diast.
M
[ꢀM]D
Configuration
+17.8◦
SSR
RRR
2g
m
+269.1◦
M
m
+4.7◦
SSR
RRR
2h
+279.8◦
in (E) isomeric form. A one-step attack of II-bonding electrons on the electrophilic
oxygen atom of the peroxybenzimidic acid 3 can be proposed (Scheme 2).
To conclude, the benzonitrile-hydrogen peroxide system provides the stereo-
specificity and the ease of preparation. This relatively inexpensive oxidant agent
schould provide a practical substitute of MCPBA in many instances.
Scheme 2.

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KRAIEM ET AL.
268
EXPERIMENTAL
Melting points were determined with a Bu¨chi capillary apparatus and are
uncorrected. NMR spectra were recorded on a Bruker 300 spectrometer (1H at
300 MHz and 13C at 75 MHz) with CDCl3 as solvant and TMS as internal stan-
dard reference. IR spectra were recorded on a Perkin-Elmer 197 spectrometer.
Mass spectra (EI) were recorded on a Hewelett Packard 5792 apparatus coupled
to a GC HP-5890 chromatograph. Optical rotations were measured with Perkin-
Elmer 241-MC polarimeter. Elemental analyses were carried out by University
of Claude Bernard Lyon 1. Microanalytical Laboratory. N-arylidenealkylamines
were prepared as described by Mlochwski et al. (3). Oxidation of imines into cor-
responding oxaziridines was carried out as follows. A mixture of 50 mL methanol,
1g sodium bicarbonate, 10 mmol benzonitrile, 10 mmol imine, and 13 mmol 35%
hydrogen peroxide was surrounded by a tap-water bath and allowed to stir at room
temperature for 48 h. At that time the imine had been consumed. The mixture was
diluted with 250 mL of water and extracted with three 50-mL portions of chlo-
roform. Combined solvant was dryed over MgSO4 (anhydrous) and concentrated
on a rotary evaporator (below 40◦C). The crude residue was cooled, diluted with
100 mL hexane, and filtred to remove precipitated benzamide. The solvant was
evaporated and the residue was purified by flash chromatography (SiO2/ hexane-
ethyl acetate 85:15). Diastereoisomers of 2g,h were separated by preparative TLC
(SiO2/ hexane-ethyl acetate 97:3).
(R)-(-)-N-benzylidene-α-cyclohexylethylamine: 1g
Yield 85%; oil; [α]D −109.1◦; MD −234.5◦ (c = 1, EtOH); IR (CCl4, cm−1
)
1
=
=
1645 (C N), 1585 (C CAr); H NMR (ppm) 1.23 (d, 3H, CH3), 1.35 (m, 11H,
=
C6H11), 2.95 (m, 1H, CH at N), 7.51 (m, 5H, Ar), 8.18 (s, 1H, CH N); MS (m/z)
215 (M+), 132 (base peak). Anal. calcd for C15H21N: C, 83.72; H, 9.76; N, 6.51.
Found C, 83.68; H, 9.80; N, 6.50.
(R)-(-)-N-4-nitrobenzylidene-α-cyclohexylethylamine: 1h
Yield 82%; mp 35–37◦C (from EtOH - H2O 80:20); [α]D −72.4◦; MD
1
−188.2◦ (c = 1, EtOH); IR (KBr, Cm−1) 1650 (C N), 1610 (C CAr); H NMR
=
=
(ppm) 1.27 (d, 3H, CH3), 1.37 (m, 11H, C6H11), 3.10 (m, 1H, CH at N), 8.02
(m, 4H, Ar), 8.25 (s, 1H, CH N); MS (m/z) 260 (M ), 177 (base peak). Anal.
calcd for C15H20N2O2: C, 69.23; H, 7.69; N, 10.76. Found C, 69.13; H, 7.71;
N, 10.75.
+.
=

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269
(E)-3-phenyl-2-t-butyloxaziridine: 2a
Oil. Yield 90%. bp 45◦C/0.02 mbar (Lit. (27) bp 61◦C/0.03 mm Hg); AO (28)
98.5%; 1H NMR (ppm) 1.20 (s, 9H, tBu), 4.63 (s, 1H, H−3), 7.45 (s, 5H, Ar); 13
NMR (ppm) 25.36 (3 CH3, tBu), 58.44 (C at N), 73.70 (C−3).
C
(E)-3-p-nitrophenyl-2-t-butyloxaziridine: 2b
1
Yield 87%. mp 63◦–64◦C (Lit. (29) mp 63◦C); AO 99%; H NMR (ppm)
1.25 (s, 9H, tBu), 4.77 (s, 1H, H−3), 7.94 (m, 4H, Ar); 13C NMR (ppm) 25.12
(3 CH3, tBu), 58.83 (C at N), 72.22 (C−3).
(E)-2-isopropyl-3-phenyloxaziridine: 2c
Oil. Yield 71%. bp 48◦C/0.05 mbar (Lit. (27) bp 52.5/0.05 mm Hg for
1
mixture of E and Z); AO 98%; H NMR (ppm) 1.25 (d, 3H, CH3), 1.30 (d, 3H,
CH3), [Lit. (10) 1.13 d, 1.13 d, 1.27 d (E); 0.68 d, 1.17 d (Z)] 2.30 (m, 1H, CH at
N), 4.46 (s, 1H, H−3) 7.37 (s, 5H, Ar); 13C NMR (ppm) 18.61 (CH3, iPr), 21.00
(CH3, iPr) 62.25 (CH at N), 79.71 (C
)
−3
(E)-2-isopropyl-3-p-nitrophenyloxaziridine: 2d
Yield 76%. mp 46–48◦C (Lit. (8) mp 47–48◦C); AO 99%; 1H NMR (ppm)
1.25 (d, 3H, CH3), 1.18 (d, 3H, CH3), 1.32 (d, 3H, CH3), 2.42 (m, 1Hh, CH at
N), 4.50 (s, 1H, H−3) 7.58 (m, 4H, Ar); 13C NMR (ppm) 18.85 (CH3, iPr), 21.27
(CH3, iPr) 22.70 (CH at N), 78.40 (C−3).
(E)-2-cyclohexyl-3-phenyloxaziridine: 2e
Oil. Yield 60%. bp 92◦C/0.01 mbar (Lit. (22) bp 105◦–107◦C/0.13 mmHg);
1
AO 97.5; H NMR (ppm) 1.67 (m, 11H, cyclohex.), 4.46 (s, 1H, H−3), 7.35 (s,
5H, Ar); 13C NMR (ppm) 69.70 (CH, cyclohex.), 79.40 (C−3).
(E)-2-cyclohexyl-3-p-nitrophenyloxaziridine: 2f
Yield65%. mp72–74◦C;AO98%;1HNMR(ppm)1.65(m, 11H, cyclohex.),
4.58 (s, 1H, H−3), 7.87 (m, 4H, Ar); 13C NMR(ppm) 69.23 (CH, cyclohex.), 79.11

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KRAIEM ET AL.
270
(C−3). Anal. calcd for C13H16N2O2: C, 67.24; H, 6.89; N, 12.06. Found C, 67.30;
H, 6.81; N, 12.11. 2-[(R)-α-cyclohexyl]-3-phenyloxaziridine: 2g.
Diastereoisomer Ig (RRR)
Oil; [α]D +15◦; MD +34.6◦ (c = 1.05, EtOH), 1H NMR (ppm) 1.29 (d, 3H,
CH3), 2.01 (m, 1H, CH at N), 4.41 (s, 1H, H−3), 7.36 (s, 5H, Ar); 13C NMR (ppm)
13.65 (CH3), 71.47 (CH at N), 78.76 (C−3).
Diastereoisomer IIg (SSR)
1
Oil; [α]D −93.8◦; MD −216.8◦ (c = 1.13, EtOH), H NMR (ppm) 1.64
(d, 3H, CH3), 1.99 (m, 1H, CH at N), 4.52 (s, 1H, H−3), 7.37 (m, 5H, Ar); 13C
NMR (ppm) 17.04 (CH3), 71.22 (CH at N), 81.88 (C−3). 2-[(R)-α-cyclohexyl]-3-
p-nitrophenyloxaziridine: 2h.
Diastereoisomer Ih (RRR)
Oil; [α]D +33.2◦; MD +91.6◦ (c = 1, EtOH), 1H NMR (ppm) 1.11 (d, 3H,
CH3), 2.06 (m, 1H, CH at N), 4.56 (s, 1H, H−3), 7.91 (m, 4H, Ar); 13C NMR (ppm)
13.84 (CH3), 71.62 (CH at N), 77.20 (C−3).
Diastereoisomer IIh (SSR)
Mp 69–71◦C; [α]D −66.5◦; MD −183.5◦ (c = 1.23, EtOH), 1H NMR (ppm)
1.31 (d, 3H, CH3), 2.05 (m, 1H, CH at N), 4.62 (s, 1H, H−3), 7.90 (m, 4H, Ar);
13C NMR (ppm) 17.17 (CH3), 71.77 (CH at N), 80.42 (C−3).
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Received in the U.S.A. April 6, 2000

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