Chemo-enzymatic synthesis of N-alkyloxaziridines mediated by lipases and urea-hydrogen peroxide

Article abstract of DOI:10.1039/b816955a

Chemo-enzymatic oxidation of various N-alkylimines mediated by lipases produced the corresponding E- or a mixture of E- and Z-N-oxaziridines with moderate to very high yields (>99%) and good to excellent selectivities (70-100%) within 30 min to 6 h in var

Full text of DOI:10.1039/b816955a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/greenchem | Green Chemistry
Chemo-enzymatic synthesis of N-alkyloxaziridines mediated by lipases
and urea-hydrogen peroxide†
Thiago Bergler Bitencourt and Maria da Grac¸a Nascimento*
Received 29th September 2008, Accepted 24th October 2008
First published as an Advance Article on the web 19th November 2008
DOI: 10.1039/b816955a
Chemo-enzymatic oxidation of various N-alkylimines mediated by lipases produced the
corresponding E- or a mixture of E- and Z-N-oxaziridines with moderate to very high yields
(>99%) and good to excellent selectivities (70–100%) within 30 min to 6 h in various organic
solvents at room temperature (25 ◦C) with urea-hydrogen peroxide (UHP) or aqueous hydrogen
peroxide (AHP). The E/Z isomer ratio was critically dependent on the stereo-electronic nature of
the substituents in the N-alkylimines. The influence of organic solvents, acyl donor and lipase
mass was evaluated in these reactions.
(Baeyer–Villiger oxidation)18 along with perhydrolysis reactions.
Introduction
Recent applications of lipases include the production of food
The evolution of environmentally acceptable organic synthesis is
additives, chiral intermediates and pharmaceutical products.19
ever present in chemistry today. The most promising approaches
The use of lipases in an organic medium makes many synthetic
to “Green Synthesis” involve the replacement of conventional
reactions that do not occur in the natural media of these enzymes
methods employing toxic/hazardous stoichiometric reagents
possible.20
with biocatalytic processes using enzymes and whole cells.1,2
Moreover, the enzyme is among the most important factors
and the utilization of nonvolatile and recyclable reaction
determining the overall cost of the process.21
media3 Oxaziridines were firstly reported in the late 1950s.4
Herein, peracids, prepared using a method mediated by
They constitute a class of three-membered heterocycles, which
three different lipases with UHP (18%) and/or AHP (30%) as
have received attention as potential antitumour agents5,6 and
analogues of penicillin.7,8 Davis and co-workers reported that N-
oxidizing agents at room temperature, were used in the oxidation
=
of the C N bonds of a series of N-alkylimines in order to obtain
sulfonyloxaziridines are able to oxidise nucleophilic substrates
in the same way as peracids.9 The reactivity of oxaziridines is
generally dependent on the nature of the substituent linked to
the N-atom of the cycle.10 They can be readily prepared from
Schiff bases, through a number of methods including oxidation
in the presence of transition metals, oxidizing agents such as
Oxone,11 or a urea-hydrogen peroxide (UHP)/maleic anhydride
system,12 oxidation with hydrogen peroxide or molecular oxygen
and treatment with sulfonic peracids or in a nitrile/hydrogen
peroxide system.13 Until now, the most used method to form
oxaziridines involves the oxidation of an imine with a peracid
such as m-chloroperbenzoic acid (MCPBA).14
various N-oxaziridines. Other parameters include the influence
of organic solvents, acyl donors, lipase mass and substituent
effects on the N-alkylimines. N-alkyloxaziridines were obtained
in moderated to high product yields under mild conditions
(Scheme 1).
An alternative method to prepare peroxyacids in the presence
of a small amount of free fatty acids mediated by lipases was first
described by Bjo¨rkling15 in the early 1990s. The peracid, which
transfers oxygen to the double bonds, is formed in situ from
hydrogen peroxide and the corresponding fatty acid. Recent
papers have described the preparation of peracids by lipases
with hydrogen peroxide and fatty acids.16,17
Lipases are versatile catalysts as they catalyze many types of
reactions, such as esterification, amidation, transesterification
of esters, and oxidation of cyclic ketones to produce lactone
Department of Chemistry, Universidade Federal de Santa Catarina,
Floriano´polis, SC, Brazil 88040-900. E-mail: graca@qmc.ufsc.br;
Fax: +55-48-3721-6850; Tel: +55-48-3721-6844/238
† Electronic supplementary information (ESI) available: Supplementary
spectra. See DOI: 10.1039/b816955a
Scheme 1
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 209–214 | 209
©

View Article Online
Table 1 Solvent effects on the chemo-enzymatic formation of
Results and discussion
N-oxaziridine 13 using different lipasesa
Oxidant effects
Lipase
Firstly, the effect of the peroxy donor on the formation of the
N-oxaziridine 13 was evaluated. In this study AHP (30%) or
UHP (18%) were used in acetonitrile as the organic solvent
and in the presence of octanoic acid and lipase from Candida
antarctica (CAL-B–Novozymes), which was immobilised in
an anionic resin as the biocatalyst. The results are shown in
Fig. 1.
Conversion (%)b
Solvent
Log Pe
CAL-B
PSL
ROL
Ethanol
-0.31
-0.33
0.83
1.43
1.50
2.00
2.50
3.50
26c
91
26
76
60
61
60
73
n.d.d
16
<5
<5
23
10
<5
<5
n.d.
8
10
<5
<5
<5
<5
<5
Acetonitrile
Diethyl ether
MTBEf
Dichloromethane
Chloroform
Toluene
Hexane
a UHP (0.4mmol) as a peroxide donor, 25 mg of lipases (250 U CAL-B,
750 U PSL and 3750 U ROL), octanoic acid (1 mmol) and 5 mL of
organic solvents. b Evaluated by GC from the crude E/Z isomer mixture,
3 h of reaction, r.t., 200 rpm. c In 24 h. d n.d.—not detected. e Log P—
octanol–water partition coefficient.24 f MTBE = methyl tert-butyl ether.
employed using UHP as the peroxy donor and octanoic acid as
the acyl donor. These lipases (PSL and ROL) were employed
in native form. The results for the degrees of conversion to the
N-oxaziridines 13 are given in Table 1.
These data indicated that there is not a linear relationship
between the N-oxaziridine conversion degrees and the organic
solvent polarity (expressed as log P values).24 Using CAL-B
the highest conversion degrees were obtained when acetonitrile,
methyl tert-butyl ether (MTBE) and hexane were the organic
solvents, these being 91%, 76% and 73% respectively. Using
dichloromethane, chloroform and toluene the conversion de-
grees were 60–61%. Another interesting result was obtained
using ethanol, forming the product in 26% conversion in 24 h of
reaction. However, using PSL the highest degrees of conversion
to N-oxaziridine 13 were 23% and 16% using dichloromethane
and acetonitrile, respectively. Using PSL and ROL in diethyl
ether, toluene or hexane, lower values were obtained, these
being 10% or only <5%. The reactions carried out in diethyl
ether did not give good conversions, probably due to the low
solubility of UHP in this medium. In this study CAL-B was
the best biocatalyst, regardless of the organic solvent, forming
the product 13 in the range of 26% to 91% conversion. Even
though the unit values for PSL and ROL were higher than that
for CAL-B, they proved not to be suitable catalysts for this
oxidation reaction, probably due to the fact that they were used
in a free form and their activities were considerably effected by
the presence of hydrogen peroxide. Thus, based on the results
given above CAL-B was selected for use in all subsequent
experiments.
Fig. 1 Peroxy donor effects on the formation of N-oxaziridine 13
carried out in UHP (18%) (ꢀ) or APH (30%) (●) under the reaction
conditions: acetonitrile (5 mL), CAL-B (25 mg), octanoic acid (1 mmol),
r.t., and 200 rpm.
The conversion to 13 was faster using AHP than UHP during
the first 3 h of reaction, forming the product in 70% and 60%
conversion degrees, respectively. Using UHP, the conversion to
13 continued to increase, reaching at the equilibrium a maximum
of 96% after 5 h of reaction. However, using AHP, a decrease
in the conversion was observed after 3 h of reaction; reaching
values lower than 10%. Through the GC analysis benzaldehyde
was detected as one of the hydrolysis products by comparison
with a standard sample. After 5 h of reaction, the undesirable
product benzaldehyde was formed in 40% conversion. This
problem was minimised by using periodic addition of AHP
(0.1 mmol/h), whereby the imine hydrolysis degree decreased
but was still higher than 15%. Another drawback is that AHP
can denature the lipase due to its high toxicity level.22
However, using UHP benzaldehyde was only formed at con-
versions of <2%. Similar results were obtained by Kra¨ıem et al.
for the synthesis of oxaziridines with a trichloroacetonitrile-
hydrogen peroxide system.10 Thus, to minimise side reactions
and the formation of hydrolysis products, urea-hydrogen per-
oxide was used to replace aqueous hydrogen peroxide in the
subsequent experiments. This reactant is easy to handle and
has low toxicity levels. Using UHP good conversions were also
achieved in the chemo-enzymatic epoxidation of (+)-3-carene.23
Amount of CAL-B
In another study, the influence of the amount of CAL-B
on the conversion of N-oxaziridine 13 was evaluated, in the
range of 0–150 mg (0–1500 U). The results are presented in
Fig. 2, which show that the conversion to 13 increased up to
25 mg (250U) CAL-B, and from this value onwards it can be
observed that there is a plateau with a conversion degree of 93%
(~2.1 ¥ 10-3 mmol.min-1). Thus, this lipase mass was used in the
subsequent experiments.
Solvent effects
In another study, two other commercially available enzymes
were screened in the formation of N-oxaziridine 13 in various
organic solvents. Besides CAL-B, lipases from Pseudomonas sp.
(Amano, PSL) and Rhizopus oryzae (Amano, ROL) were also
210 | Green Chem., 2009, 11, 209–214
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
was detected by GC analysis after 3 h of reaction. The formation
rate of oxaziridine 13 as a function of the amount of octanoic
acid is shown in Fig. 3. These data show that the conversion was
dependent on the acyl donor reaching ~1.7 ¥ 10-3 mmol min-1
using 2 mmol of octanoic acid. Furthermore, under these
conditions, the product was easily recovered.
Fig. 2 Influence of CAL-B units on the chemo-enzymatic oxidation of
N-benzyliden-2-ethylhexylamine 1 with UHP as peroxide donor. (●)
Oxaziridine formation (¥103 mmol min-1) and (ꢀ) Conversion (%).
Reaction conditions as given in Fig. 1.
Amount and type of acyl donor
Fig. 3 Influence of octanoic acid on the chemo-enzymatic oxidation
of N-benzyliden-2-ethylhexylamine 1 with UHP as peroxide donor.
Reaction conditions as given in Fig. 1.
The chemo-enzymatic formation of oxaziridines involves basi-
cally two steps. Firstly, the enzymatic formation of peracids by
the carboxylic acids or esters and hydrogen peroxide, followed
=
by the attack of the double bond C N of an imine on the
electrophilic oxygen of the peracid, resulting in an oxazirane
ring (Scheme 1). Thus, in this study the acyl donor content
and type (carboxylic acid or an ester) were evaluated in the
conversion of the corresponding oxaziridine 13, using CAL-B
as the biocatalyst. The results are shown in Table 2.
The results show that the conversion into oxaziridine 13 was
dependent on the structure of the acyl donor. The conversion
rates were similar using octanoic, lauric, myristic and palmitic
acids. These results are in agreement with those reported by
Moreira et al.23 The enzymatic step involves the stabilisation of
the tetrahedral intermediate acyl-enzyme which was dependent
on the chain length.25 In the reaction using benzoic acid as the
acyl donor, no product was formed. Using ethyl acetate the
oxaziridine 13 was obtained in reasonable conversion (53%).
However, the formation of by-products such as benzaldehyde
Substituent effects on the phenyl ring and nitrogen
After optimising the parameters described above, a series of
N-alkylimines was tested for the formation of oxaziridines. The
results given in Table 3 show the high efficiency (entries 1–6) and
a 100% selectivity (entry 10) for this oxidation system, after 1 h
of reaction. Substrates with electron donating and withdrawing
groups on the aromatic ring had a pronounced effect on the
conversion to the products. For example, in the presence of 4-
OH (entry 2), 4-CH3 (entry 3), 4-OCH3 (entry 4) and 4-N(CH3)2
(entry 5), the conversion degrees were in the range of 87–95%.
These values are similar to that obtained under the same reaction
conditions for substrate 1, which was 91% after 3 h of reaction.
However, in the presence of 2,4,5-OCH3 groups, the conversion
was >99% after only 20 min of reaction, showing the strong
influence of this substituent on the formation of oxaziridine
18. The E:Z ratio remained almost constant regardless of the
nature of the electron donating or withdrawing groups (around
70:30%). Using substrates with electron withdrawing groups
such as, 4-F (entry 7) and 2,4-Cl (entry 8), lower degrees of
conversion to products were observed, these being 50% and
35%, respectively.
The influence of some substituents linked to the nitrogen
was then evaluated (compounds 9–12). In general, good degrees
of conversion to the corresponding N-oxaziridines 21–24 were
obtained, these being in the range of 40–70%. However, the
most interesting feature was that for substrate 10, with a bulky
tert-butyl substituent on the nitrogen, only the E-oxaziridine
isomer was formed. These results are in agreement with those
reported by Mohajer11 et al. for the oxidation of substrate 10
and N-naphthyliden-methylamine with Oxone, achieving 100%
of E-isomer and 86% of Z-2-methyl-3-1-naphthyloxaziridine,
respectively. For substrates 9, 11 and 12 the E:Z ratio remained
Table 2 Influence of the acyl donor chain length on the chemo-
enzymatic formation of oxaziridine 13a
Conversion (%)c
Time (h)
Acyl donorb
0.5
1
3
Rate ¥ 103 (mmol min-1)
Octanoic acid
Lauric acid
Myristic acid
Palmitic acid
Acetic acid
Benzoic acid
Ethyl acetate
20
27
18
43
50
38
40
7
n.d.
28
90
75
70
69
16
n.d.
53
2.00
1.67
1.56
1.53
0.36
0
15
n.d.d
n.d.
3
1.18
a UHP (0.4 mmol) as a peroxide donor and 25 mg of CAL-B. b Acyl
donor (1 mmol). c Evaluated by GC from the crude E/Z mixture, r.t.,
200 rpm. d n.d.—not detected.
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 209–214 | 211
©

View Article Online
Table 3 Chemo-enzymatic oxidation of N-alkylimines 1–12 mediated by CAL-Ba
N.
Alkylimine
Oxaziridine
13
Conv (%)b
43
E:Zc
65:35
dH (ppm)d
1
4.47 (E)
5.25 (Z)
2
3
4
5
14
15
16
17
87
90
95
88
70:30
75:25
75:25
70:30
4.37 (E)
5.19 (Z)
4.44 (E)
5.21 (Z)
4.40 (E)
5.17 (Z)
4.42 (E)
5.11 (Z)
6
7
8
9
18
19
20
21
>99e
50
75:25
71:29
80:20
80:20
3.95 (E)
5.27 (Z)
4.45 (E)
5.23 (Z)
35
4.91 (E)
5.39 (Z)
65
4.59 (E)
5.04 (Z)
10
11
22
23
60
70
100:0
80:20
4.68 (E)
4.48 (E)
5.14 (Z)
12
24
40
70:30
4.47 (E)
5.12 (Z)
1
a Reaction conditions are given in the text. b Conversions determined by GC in a 1 h reaction. c Determined by H NMR and GC. d The chemical
shifts of the oxaziridine ring hydrogen. e 20 minutes reaction.
almost constant, with a predominance of the E-isomer (around
70–80%), as previously observed for substrates 1–8.
The use of UHP minimised the side reactions due to the absence
of water, and the conversion was dependent on the type of
organic solvent and acyl donor. Also, the conversion degrees
and E:Z ratios were found to be strongly dependent on the
substrate structure. No oxidation product was detected in the
blank experiments, that is, in the absence of lipases.
The results show that the E- and Z-oxaziridines can be formed
from anti-imines according to a concerted mechanism (similar
to that of epoxidation by peracids) under mild conditions
forming the corresponding products in good conversions and
with excellent selectivity depending on the substrate structure.
Experimental
Conclusions
General
In conclusion, we have developed a highly efficient chemo-
enzymatic system for the oxidation of N-alkylimines, mediated
by lipases, in comparison to traditional methodologies, e.g.
MCPBA epoxidation. The advantages of this method are the
use of mild conditions (room temperature and neutral pH) and
the absence of strong oxidants such as Oxone or peracetic acid.
All chemicals are commercially available and were used without
purification. All solvents were analytical grade and were dried
˚
by storing over activated 3 A molecular sieves before use. The
lipolytic enzyme preparations from Rhizopus oryzae (Amano—
150 U/mg) and Pseudomonas sp. (Amano—30,000 U/g) were
donated by Amano Pharmaceutical Co. and lipase from
212 | Green Chem., 2009, 11, 209–214
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Candida antarctica B absorbed on a macroporous resin
(Novozym 435—10,000 PLU/g) was donated by Novozymes
Inc.28
(CDCl3) dc 158.5, 129.9, 115.2, 114.0, 78.3, 66.1, 36.1, 32.4, 29.9,
28.4, 21.2, 12.3, 8.61. IR (ZnSe window): cm-1 2979, 1618, 1519,
1400, 1372, 1268, 730.
The reaction progress was measured by GC on a Shimadzu
GC14B instrument equipped with a Shimadzu CBP-5 column
using H2 as the carrier gas, with the flame ionization detector set
at 280 ◦C, an injector set at 270 ◦C, and a column temperature
range of 70–250 ◦C (10 ◦C/min). The characterization of the
products was performed by spectroscopic analysis on a Perkin
2-Ethyl-hexylamine-3-4-methyl phenyl oxaziridine (16). (E)-
isomer: colourless oil (38.4%, 38 mg) 1H NMR (CDCl3): dh 7.76
(2H,d), 7.18 (2H, d), 4.44 (1H, s), 2.75–2.73 (m, 2H), 2.33(s, 3H),
1.62, (1H, m), 1.43–0.86 (14H, m). 13C NMR (CDCl3) dc 136.1,
130.1, 127.3, 125.8, 78.9, 63.7, 37.1, 35.1, 29.9, 27.2, 23.0, 20.7,
12.3, IR (ZnSe window): cm-1 2890, 1620, 1471, 1374, 1305,
1162, 810.
(Z)-isomer: light yellow oil (15%, 15 mg) 1H NMR (CDCl3):
dh 8.13 (2H,d), 7.75 (2H, d), 5.21 (1H, s), 2.73 (m, 2H), 2.33 (s,
3H), 1.62–1.28 (8H, m), 0.87–0.86 (6H, s). 13C NMR (CDCl3) dc
137.6, 128.1, 127.4, 125.8, 77.5, 63.5, 36.9, 29.6, 26.5, 23.0, 21.1,
12.2. IR(ZnSe window): cm-1 2926, 1622, 1460, 1386, 1216, 818.
1
Elmer FTIR 16PC, H (400 MHz) and 13C (100 MHz) nuclear
magnetic resonance on a Varian EM360L spectrometer, using
CDCl3 as solvent.
General procedure for the oxidation of N-alkylimines
The starting N-alkylimines (1–12) were prepared by conven-
tional methods reported in the literature26 with yields in the
range of 82–97%. All N-alkylimines were obtained as single
geometrical E-isomer.27 The chemo-enzymatic reaction for
the preparation of N-alkyl oxaziridine was carried out using
0.4 mmol of N-alkylimines, 0–6.0 mmol of the different acyl
donors, lipases with different masses or unit values, and a
peroxide donor (AHP 30% or UHP 18%) at room temperature
and at 200 rpm. The mixture was washed with distilled water
and then with dichloromethane to remove UHP. The crude
products (13–24) were purified using a small column of SiO2
to obtain separately the E and Z isomers, using hexane:ethyl
acetate (9:1). The organic solvent was evaporated under reduced
2-Ethyl-hexylamine-3-4-methoxy phenyl oxaziridine (17).
(E)-isomer: yellow oil (66%, 70 mg) 1H NMR (CDCl3): dh 7.31
(2H, d), 6.90 (2H, d), 4.40(1H, s), 3.76 (3H, s), 2.77–2.70 (2H,
m), 1.66 (1H, m), 1.26 (8H, m), 0.89–0.84 (6H, m). 13C NMR
(CDCl3) dc 159.4, 129.1, 127.2, 112.1, 78.7, 63.7, 53.5, 36,1, 29.8,
28.3, 23.1, 21.7, 12.3. IR(ZnSe window): cm-1 2929, 1592, 1577,
1506, 1450, 1309, 1257, 1160, 1022, 829.
(Z)-isomer: light yellow oil (23%, 25 mg) 1H NMR (CDCl3):
dh 7.81 (2H, d), 6.96 (2H, d), 5.17(1H, s), 3.76 (3H, s), 2.77–2.70
(2H, m), 1.65 (1H, m), 1.35–1.25 (8H, m), 0.89–0.84 (6H, m). 13
C
NMR (CDCl3) dc 153.4, 130.2, 129.1, 125.2, 112.1, 77.6, 63.6,
53,8, 37,0, 29.8, 29.7, 23.1, 21.7, 12.3. IR(ZnSe window): cm-1
2928, 1603,1570, 1448, 1451, 1313, 1238, 1156, 1026, 829.
◦
pressure at 40 C to give the pure product which was weighed
to obtain the corresponding yields. The products formed were
fully characterised by 1H and 13C NMR and IR spectroscopies.
The IR and NMR spectroscopy data for compounds 21–24
were compared with those reported in the literature.10,11 The data
for compounds 13–20, including both isomers, are described
below.
2-Ethyl-hexylamine-3-4-N,N-dimethyl phenyl oxaziridine (18).
(E)-isomer: dark yellow oil (42.5%, 47 mg) 1H NMR (CDCl3):
dh 7.61(d. 2H), 6.69 (2H, d), 4.42 (1H, s), 3.48–3.45 (2H, m), 2.99
(6H, s), 1.67(1H, m), 1.30(8H, m), 0.90–0.88(6H, s). 13C NMR
(CDCl3) dc 157.4, 126.3, 116.0, 111.2, 72.2, 62.8, 40.0, 34.8, 31.8,
29.3, 25.2, 22.8, 14.3, 11.0. IR(ZnSe window): cm-1 2959, 1600,
1535, 1480, 1374, 1332, 1292, 1237, 1165, 1113, 849, 721, 630.
(Z)-isomer: pale brown oil (27%, 30 mg) 1H NMR (CDCl3):
dh 7.61(d. 2H), 6.69 (2H, d), 5.11(1H, s), 3.46–3.44 (2H, m),
2.99(6H, s), 1.78 (1H, m), 1.44 (8H, m), 0.92 (6H, m). 13C NMR
(CDCl3) dc 157.4, 126.3, 116.0, 111.2, 70.2, 62.3, 40.10, 34.8,
31.8, 29.3, 25.2, 22.8, 14.3, 11.1. IR(ZnSe window): cm-1 2960,
1600, 1459, 1377, 1332, 1289, 1167, 1101, 852, 757, 724, 627.
2-Ethyl-hexylamine-3-phenyl oxaziridine (14). (E)-isomer:
1
yellow oil (26%, 25 mg) H NMR (CDCl3): dh 7.41–7.37 (5H,
m, Ph), 4.47 (1H, s), 2.86–2.75 (2H, m), 1.71 (1H, m), 1.36–
1.26 (8H, m), 0.89 (3H, s), 0.87 (3H, s).; 13C NMR (CDCl3)
dc 130.2, 130.1, 128.7, 127.8, 128.6, 80.9, 65.6, 39.5, 34.3, 31.8,
31.2, 29.3, 29.1, 29.0, 25.0, 14.3, 11.0. IR (ZnSe window): cm-1
2924, 1633,1549, 1459, 1370, 1270, 731.
1
(Z)-isomer: colourless oil (10%, 11 mg) H NMR (CDCl3):
dh 7.41–7.37 (5H, m, Ph), 5.25 (1H, s), 2.84–2.73 (2H, m), 1.70
(1H, m), 1.39–1.26 (8H, m), 0.89 (3H, s), 0.87 (3H, s).; 13C NMR
(CDCl3) dc 133.1, 130.2, 128.7, 127.8, 79.9, 63.4, 42.8, 39.5, 34.2,
31.8, 24.4, 23.2, 22.8, 14.1, 11.0. IR(ZnSe window): cm-1 2962,
1653,1423, 1375, 1297, 756.
2-Ethyl-hexylamine-3-2,4,5-trimethoxy phenyl oxaziridine
(19). (E)-isomer: orange oil (46%, 60 mg) 1H NMR (CDCl3):
dh 7.72 (1H s), 6.47 (1H, s), 3.99 (1H, s), 3.95 (3H, s), 3.90
(3H, s), 3.83 (3H, s), 2.29(2H, m), 1.59 (1H, m) 1.28–1.27(8H,
m),0.88 (6H, m); 13C NMR (CDCl3) dc 151.8, 142.4, 111.7,
96.8, 70.9, 56.5, 36.9, 29.3, 29.1, 25.1, 23.7, 14.3, 10.6. IR(ZnSe
window): cm-1 2980, 1607, 1507, 1459, 1408, 1285, 1224, 1122,
1029, 876.
(Z)-isomer: dark orange oil (29%, 38 mg) 1H NMR (CDCl3):
dh 7.66 (1H s), 6.43 (1H, s), 5.27 (1H, s), 3.90 (3H, s), 3.85 (3H, s),
3.80 (3H, s), 2.25 (2H, m), 1.55(1H, m), 1.26 (8H, m), 0.81(6H,
m); 13C NMR (CDCl3) dc 151.8, 142.5, 109.2, 99.9, 70.9, 56.4,
56.3, 36.9, 34.4, 30.3, 29.3, 28.6, 25.1, 22.8, 14.2, 10.6. IR(ZnSe
window): cm-1 2962, 1608, 1460, 1378, 1332, 1285, 1165, 1100,
848, 757, 722, 618.
2-Ethyl-hexylamine-3-4-hydroxy phenyl oxaziridine (15).
1
(E)-isomer: pale brown oil (15%, 15 mg) H NMR (CDCl3):
dh 7.51 (2H, d, Ph), 6.73 (2H, d), 4.37 (1H, s), 3.45 (2H, m),
1.65 (1H, m), 1.29–1.19 (8H, m), 0.86–0.83 (6H, s), 13C NMR
(CDCl3) dc 153.6, 129.9, 119.9, 114.2, 77.2, 62.1, 33.1, 30.4, 26.6,
23.2, 21.8, 12.3, 8.6. IR (ZnSe window): cm-1 2960, 1620,1509,
1459, 1300, 1292, 728.
(Z)-isomer: pale brown oil (15%, 15 mg) 1H NMR (CDCl3):
dh 8.02 (2H, d, Ph), 6,74 (2H, d), 5.19 (1H, s), 3.64 (2H, m),
1.59 (1H, m), 1.27–1.11 (8H, m), 0.78–0.71 (6H, s), 13C NMR
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 209–214 | 213
©

View Article Online
2-Ethyl-hexylamine-3-4-fluoro phenyl oxaziridine (20). (E)-
isomer: colourless oil (28%, 28 mg) 1H NMR (CDCl3): dh 7.38
(2H, m), 7.04 (2H, m), 4.45 (1H, s), 2.82–2.72 (2H, m), 1.62 (1H,
m), 1.43–0.81 (14H, m).13C NMR (CDCl3) dc 165.3, 155.42,
132.9, 132.8, 131.4, 129.7, 115.6, 80.0, 62.5, 39.1, 31.8, 31.7,
24.8, 23.2, 14.3, 11.0. IR (ZnSe window): cm-1 2932, 1603, 1541,
1480, 1260, 1104, 829, 610.
3 (a) S. L. Jain, J. K. Joseph and B. Sain, Catal. Lett., 2007, 115(1–2),
52–55; (b) M. Kochi, Green Reaction Media for Organic Synthesis,
Blackwell (2005).
4 W. D. Emmons, J. Am. Chem. Soc, 1957, 79, 5739.
5 J. Mlochowski, E. Kubiez, K. Kloc, M. Mordarski, W. Peczy-uska
and L. Syper, Liebigs Ann. Chem., 1988, 455.
6 S. B. Said, J. Molchowski and J. Skarzewski, Liebigs Ann. Chem.,
1990, 461.
7 Marchant-Brynaert, Z. Bounkhala-Khrouz, B. J. Van Keuten, H.
Vanlierde and L. Ghosez, Isr. J. Chem., 1989, 29, 247.
8 J. Marchant-Brynaert, Z. Bounkhala-Khrouz, H. Vanlierde and L.
Ghosez, Heterocycles, 1990, 30, 97.
9 F. Davis and A. C. Sheppard, A., Tetrahedron, 1989, 45, 5709.
10 (a) J. Kra¨ıem, R. B. Othman and B. B. Hassine, C. R. Chim., 2004,
7(10–11), 1119–1126; (b) K. G. Taylor, M. Chi and M. S. Clark,
J. Org. Chem., 1976, 41(7), 1131–5; (c) S. L. Jain, S. Singhal and B.
Sain, J. Organomet. Chem., 2007, 692(14).
1
(Z)-isomer: colourless oil (13%, 13 mg) H NMR (CDCl3):
dh 7.55 (2H,d), 7.15 (2H, d), 5.23 (1H, s), 2.93–2.78 (2H, m),
1.85–1.82 (1H, m), 1.60–0.89 (14H, m). 13C NMR (CDCl3) dc
162.8, 155.4, 162.8, 132.8, 131.5, 131.1, 115.8, 77.6, 62.5, 39.1,
34.3, 31.6, 29.2, 25.0, 14.3, 10.6. IR(ZnSe window): cm-1 2932,
1603, 1541, 1480, 1260, 1104, 829, 610.
11 (a) D. Mohajer, N. Iranpoor and A. Rezaeifard, Tetrahedron Lett.,
2004, 45(3), 631–634; (b) S. Schoumaker, O. Hamelin, S. Te´ti, J.
Pecaut and M. Fontecave, J. Org. Chem., 2005, 70, 301–308; (c) D.
Mostowicz and C. Belzecki, J. Org. Chem., 1977, 42(24), 3917–3921;
(d) J. Chakravarty and P. Truitt, J. Med. Chem., 1969, 12, 961–2.
12 J. A. Damavandi, B. Karami and M. A. Zolfigol, Synlett, 2002, 6,
933–934.
13 Y. M. Lin and M. J. Miller, J. Org. Chem., 2001, 66(24), 8282–8285.
14 Y. Usuki, Y. Wang and J. Aub, J. Org. Chem, 1995, 60, 8028–8035.
15 F. Bjorkling, H. Frykman, S. E. Godtfredsen and O. Kirk, Tetrahe-
dron, 1992, 48(22), 4587–4592.
16 D. Bezbradica, D. Mijin, S. Siler-Marinkovic and Z. Knezevic, J. Mol.
Catal. B: Enzym., 2007, 45(3–4), 97–101.
17 T. B. Bitencourt, M. A. Moreira and M. D. Nascimento, Synth.
Commun., 2005, 35(15), 2107–2114.
18 H. F. Olivo, E. Salazar and M. Y. Rios, J. Mol. Catal. B: Enzym.,
2008, 54, 61–66.
2-Ethyl-hexylamine-3-2,4-dichloro phenyl oxaziridine (21).
◦
1
(E)-isomer: white solid (mp 118 C, 33%, 40 mg) H NMR
(CDCl3): dh 7.44–7.30 (3H, m), 4.91 (1H, s), 2.93–2.70 (2H,
m), 1.64 (1H, m), 1.28–1.26 (8H, m), 0.86 (6H, m). 13C NMR
(CDCl3) dc 134.2, 133.4, 129.3, 127.5, 126.1, 125.4, 75.2, 63.7,
37.4, 30.0, 27.4, 23.3, 21.4, 21.0, 12.1, 9.7. IR(KBr): cm-1 2960,
1608, 1469, 1390, 1258, 1140, 1080, 829, 818.
(Z)-isomer: light green oil (12.5%, 15 mg)1H NMR (CDCl3):
dh 7.74–7.61 (3H, m), 5.39 (1H, s), 2.95–2.73 (2H, m), 1.61 (1H,
m), 1.28 (2H, m), 1.28–0.87 (14H, m). 13C NMR (CDCl3) dc
134.2, 133.4, 129.3, 129.2, 127.5, 126.0, 75.2, 63.7, 37.4, 32.2,
30.1, 27.4, 23.2, 21.4, 12.3, 9.8. IR (ZnSe window): cm-1 2930,
1690, 1503, 1459, 1285, 810.
19 V. Skouridou, H. Stamatis and F. N. Kolisis, J. Mol. Catal. B: Enzym,
2003, 21(1–2), 67–69.
20 A. Ghanem, Tetrahedron, 2007, 63(8), 1721–1754.
21 D. R. Boyd, J. F. Malone, M. R. McGuckin, W. B. Jennings, M.
Rutherford and B. M. Saket, J. Chem. Soc. Perkin Trans., 1988, 2,
1145.
Acknowledgements
This work was supported by the Universidade Federal de Santa
Catarina (UFSC-Brazil) and the Conselho Nacional de Desen-
volvimento Cient´ıfico e Tecnolo´gico (CNPq) which provided
financial support and scholarships (T.B.B. and M.G.N.). We are
grateful to Novozymes Inc. and Amano Pharmaceutical (Japan)
for the donation of the lipases.
22 E. G. Ankudey, H. F. Olivio and T. L. Peeples, Green Chem, 2006, 8,
923–926.
23 M. A. Moreira and M. G. Nascimento, Catal. Commun, 2007, 8,
2049–2053.
24 C. Laane, S. Boeren and C. Veger, Biotechnol. Bioeng., 1987, 30, 81.
25 K. Faber, Biotransformation in Organic Chemistry, Springer, Verlag,
Berin, 1997.
26 E. A. Dikusar, V. I. Potkin, N. G. Kozlov and A. P. Yuvchenko,
Russ. J. Gen. Chem., 2006, 76(9), 1425–1430.
27 (a) Isolated yields of imines: (1) 82%, (2) 84%, (3) 90%, (4) 89%, (5)
95%, (6) 88%, (7) 97%, (8) 92%, (9) 92%, (10) 90%, (11) 96%, (12)
97%, (13) 88%; (b) Determined by 1H-NMR, the signals of E-isomer
are in a range of dH 8.10–8.25 ppm. See reference 26.
28 (a) www.amano.co.jp (acessed 12.08.2008); (b) www.novozymes.com
(accessed 13.08.2008).
References
1 (a) M. Alcalde, M. Ferrer, F. J. Plou and A. Ballesteros, Trends
Biotechnol., 2006, 24(6), 281–287; (b) J. S. Yadav, G. S. Reddy, G.
Sabitha, A. D. Krishna, D. Prasad, H. U-R-Rahaman, K. V. Rao
and A. B. Rao, Tetrahedron Asymm., 2007, 18(6), 717–723.
2 C. Mateo, J. M. Palomo, G. Fernandez-Lorente, J. M. Guisan and
R. Fernandez-Lafuente, Enzym. Microb. Technol., 2007, 40(6), 1451–
1463.
214 | Green Chem., 2009, 11, 209–214
This journal is
The Royal Society of Chemistry 2009
©