Microwave-assisted regioselective ring opening of non-activated aziridines by lithium aluminium hydride

Article abstract of DOI:10.1039/c004960c

A new synthetic protocol for the LiAlH₄-promoted reduction of non-activated aziridines under microwave conditions was developed. Thus, ring opening of 2-(acetoxymethyl)aziridines provided the corresponding β-amino alcohols, which were then used as eligible substrates in the synthesis of 5-methylmorpholin-2-ones via condensation with glyoxal in THF. The same procedure was applied for the preparation of novel 5(R)- and 5(S)-methylmorpholin-2-ones starting from the corresponding enantiopure 2-(hydroxymethyl)aziridines. Additionally, 2-(methoxymethyl)- and 2-(phenoxymethyl)aziridines were treated with LiAlH₄ under microwave irradiation, giving rise to either isopropylamines or 1-methoxypropan-2-amines depending on the reaction conditions.

Full text of DOI:10.1039/c004960c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Microwave-assisted regioselective ring opening of non-activated aziridines by
lithium aluminium hydride
Sonja Stankovic´, Matthias D’hooghe and Norbert De Kimpe*
Received 8th April 2010, Accepted 17th June 2010
DOI: 10.1039/c004960c
A new synthetic protocol for the LiAlH4-promoted reduction of non-activated aziridines under
microwave conditions was developed. Thus, ring opening of 2-(acetoxymethyl)aziridines provided the
corresponding b-amino alcohols, which were then used as eligible substrates in the synthesis of
5-methylmorpholin-2-ones via condensation with glyoxal in THF. The same procedure was applied for
the preparation of novel 5(R)- and 5(S)-methylmorpholin-2-ones starting from the corresponding
enantiopure 2-(hydroxymethyl)aziridines. Additionally, 2-(methoxymethyl)- and
2-(phenoxymethyl)aziridines were treated with LiAlH4 under microwave irradiation, giving rise to
either isopropylamines or 1-methoxypropan-2-amines depending on the reaction conditions.
reduction of suitable substrates, such as a-halo imines,15a,16 vinyl
Introduction
azides,17 oximes18 and azirines,19 by nucleophilic complex hydrides.
The aziridine moiety represents a valuable three-membered ring
Very recently, the reductive ring opening of highly electrophilic
system in organic chemistry due to its versatility as a building block
aziridinium salts by hydrides has been reported to afford 2-
for the preparation of a large variety of ring opened and ring
aminopropanes through regiospecific ring opening at the unsub-
expanded amines.1,2 Aziridines bearing an electron-withdrawing
substituent at the nitrogen (activated aziridines) are known to be
reactive towards a large number of nucleophiles with respect to
ring opening.2 On the other hand, electron-donating groups at the
nitrogen render the aziridine more stable and activation towards
an aziridinium intermediate is, in most cases, required prior to
nucleophilic ring opening.3–7 The resulting electrophilic species is
then attacked by a nucleophile at the more or less substituted
position of the aziridine ring depending on the substrate, the
type of the nucleophile and the solvent, yielding a functionalized
amine.3–11
In comparison to the huge number of reports on the ring
opening of aziridines by other nucleophiles, their ring opening
by hydrides has received very limited interest in the literature
despite the synthetic potential of this approach. The intermediacy
of aziridines in direct, non-regioselective ring opening reactions by
LiAlH4 has been proposed in an early paper, in which the reduction
of N-(1,1-dichloro-2-alkylidene)anilines was investigated,12 and
was also deduced indirectly from the experiments of Suzuki.13
In addition, in one recent report,14 the reduction of 2-methyl-1-
phenylaziridine with LiAlH4 in THF yielded a mixture of ring
opened amines (derived from hydride attack at both the more and
the less hindered aziridine carbon atom in a 1 : 2 ratio, respectively)
yet was shown to be slow and not complete after heating under
reflux for 20 h. Furthermore, the contribution of the electron-
withdrawing effect of the phenyl group at the nitrogen, facilitating
ring opening of the aziridine moiety, should not be neglected.
In addition to the above-mentioned reports, the ring open-
ing of reactive 2-chloroaziridine intermediates by LiAlH4 has
been described.15 It should be stressed that several syntheses
of aziridines have been reported in the literature based on the
stituted position.6c,20 However, up to now, LiAlH4 has been mainly
used to reduce functional groups in compounds incorporating an
aziridine unit without affecting the three-membered ring itself,21–24
and the hydride-promoted ring opening of non-activated aziridines
has not been described in the literature so far.
In the present study, special attention was devoted to the
LiAlH4-promoted ring opening of non-activated 2-substituted
aziridines towards biologically and synthetically relevant species.
The lack of studies concerning the reduction of aziridines by
LiAlH4 is remarkable in view of the large number of papers on
the reductive ring opening of their oxygen counterparts, oxiranes.
In contrast to previous reports, all of the reactions in the present
work proceeded smoothly with high regioselectivity and resulted
in full conversion of the substrate, without requiring the presence
of Lewis acids. In addition, the regio- and stereoselective reduc-
tive ring opening of enantiopure 2-(hydroxymethyl)aziridines by
LiAlH4 towards chiral b-amino alcohols was performed, and the
resulting b-amino alcohols were applied in the synthesis of novel
5-methylmorpholin-2-ones.
Results and discussion
1-Arylmethyl-2-(bromomethyl)aziridines25 1 constitute versatile
substrates for further elaboration,4b,26–28 although their reactivity
towards LiAlH4 has not been evaluated up until now. The reaction
of aziridines 1 with two molar equivalents of LiAlH4 in dry Et2O
under reflux for 3–6 h afforded N-arylmethyl-N-isopropylamines
2 as the sole reaction products quite unexpectedly in high yields
(80–84%) (Scheme 1). The suggested mechanistic pathway for this
transformation consists of an initial reductive debromination of
2-(bromomethyl)aziridines 1 toward 2-methylaziridines 3 through
the action of LiAlH4, either via a nucleophilic or a radical
reaction.29 Subsequently, reductive ring opening takes place via
nucleophilic attack of a hydride ion (from LiAlH4) at the less
substituted carbon atom of the aziridine moiety in intermediates
Department of Sustainable Organic Chemistry and Technology, Faculty
of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000
Ghent, Belgium. E-mail: norbert.dekimpe@UGent.be; Fax: +32-92646243;
Tel: +32-92645951
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2d in 96% yield. The spectral data of amine 2d obtained via both
routes were judged to be identical.
Apart from its use in the preparation of amines 2, which can of
course easily be prepared via other routes, this methodology holds
significant synthetic potential for the preparation of a large variety
of amines in a convenient way through reductive ring opening of
the appropriate aziridine derivatives.
The utility of this LiAlH4-promoted ring opening of non-
activated aziridines was demonstrated by the synthesis of versa-
tile b-amino alcohols starting from 2-(acetoxymethyl)aziridines.
1-Arylmethyl-2-(acetoxymethyl)aziridines 4 were smoothly pre-
pared upon treatment of 2-(bromomethyl)aziridines 1 with an
excess (1.5 equiv) of sodium acetate in DMSO at 100 ◦C for
15 h (Scheme 2). The reaction provided almost pure acetates 4a–d
suitable for further elaboration without prior purification. How-
ever, for full characterization, aziridines 4 were purified by column
chromatography on silica gel column, affording analytically pure
samples.
Further treatment of 2-(acetoxymethyl)aziridines 4 with two
molar equiv of LiAlH4 in Et2O and heating for six hours under
reflux provided crude mixtures containing mainly alcohols 5,
and no traces of ring opened b-amino alcohols 6 were detected.
Increasing the reaction time to 24–62 h led to partial formation of
b-amino alcohols 6 (~50%). It was shown that, in order to obtain b-
amino alcohols 6 in reasonable yields, a reflux time of several days
(4–5) was required. In order to overcome this major drawback,
the reaction mixture was subjected to microwave irradiation.
Gratifyingly, after heating aziridines 4 in THF at 130 ◦C for
two hours (220 Wmax) in the presence of two molar equiv of
LiAlH4, only the corresponding b-amino alcohols 6 were formed
in high purity without traces of 2-(hydroxymethyl)aziridines 5
(Scheme 2). Thus, the nucleophilic attack of hydride at the less
substituted carbon atom of aziridines 5 was confirmed and, as
a result, b-amino alcohols 6 were obtained in high yields after
purification by column chromatography on silica gel. In this way,
2-aminopropan-1-ols 6 were formed selectively through complete
Scheme 1
3. Apparently, the reducing agent acts both as the activator
of the aziridine ring (through coordination of aluminium with
nitrogen5,14) and as the provider of the nucleophile (hydride)
which opens up the ring at the less hindered position (Scheme 1).
However, the alternative mechanistic pathway comprising an
initial hydride attack at the less hindered position of the aziridine
moiety of 2-(bromomethyl)aziridines 1, yielding the ring opened
intermediates, and their subsequent ring closure towards 2-
methylaziridines 3, should not be neglected. Although attempts to
isolate 2-methylaziridines30 3 by column chromatography on silica
1
gel failed, their intermediacy was acknowledged upon H NMR
and 13C NMR analysis of some of the crude reaction mixtures.
Furthermore, the presence of aziridines 3 was confirmed by MS
analysis of these reaction mixtures.
Additionally, in order to confirm the structure of N-
arylmethyl-N-isopropylamines 2, an independent synthesis of N-
(4-methoxybenzyl)-N-isopropylamine 2d was performed. Con-
densation of 4-methoxybenzaldehyde with 1.05 equiv of iPrNH2
in CH2Cl2 in the presence of MgSO4 afforded the corresponding
imine in 75% yield after six hours under reflux, which was then
reduced using two molar equiv of NaBH4 in MeOH for two hours
under reflux, furnishing N-(4-methoxybenzyl)-N-isopropylamine
Scheme 2
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Scheme 3
regioselective conversion of 2-(hydroxymethyl)aziridines 5. Al-
though several useful routes for the synthesis of b-amino alcohols
are available in the literature,31–33 some of these approaches suffer
from (minor) drawbacks such as low regioselectivity, cumbrous
substrate synthesis or low substrate stability. The synthesis of
b-amino alcohols 6 through microwave-assisted ring opening
of aziridines 4 utilizing LiAlH4 satisfies the requirements for a
generally applicable route, i.e. the use of commercially available
starting compounds, complete regio- and stereoselectivity and
high energy efficiency. Thus, the presented methodology can be
regarded as a complementary approach or a worthy alternative
for other known routes. b-Amino alcohols are applied extensively
in organic chemistry as building blocks in designing natural and
biologically active substances,33a,34–44 and their chiral versions are
also used in catalytic asymmetric synthesis.31,45
In the next part, 2-aminopropan-1-ols 6 were shown to be good
substrates for the construction of 5-methylmorpholin-2-ones,46
which are known as useful substrates for the synthesis of biologi-
cally relevant compounds.47,48 Thus, 2-(arylmethylamino)propan-
1-ols 6 were dissolved in THF and treated with three equiv of gly-
oxal. After heating these mixtures for 2–3 h, 5-methylmorpholin-
2-ones 7a–d were obtained in good yields (Scheme 2) and
column chromatography on silica gel provided analytically pure
compounds suitable for full characterization.
Given the intermediacy of 2-(hydroxymethyl)aziridines 5 in
the conversion of acetates 4 into alcohols 6, efforts were de-
voted to the evaluation of chiral 2-(hydroxymethyl)aziridines
as substrates for a LiAlH4-promoted reductive ring opening.
In the literature, only a few studies have been made on ring
opening reactions of non-activated enantiomerically pure 2-
(hydroxymethyl)aziridines.32,49–52 For example, the catalytic hy-
drogenation of aziridine methanols 8a and 8b in EtOH using
Pd(OH)2 has provided b-amino alcohols 9a and 9b in good yields.49
Recently, the preparation of chiral b-amino alcohols via regio-
and stereocontrolled ring opening reactions of chiral aziridines
was examined.53 This approach comprised the reaction of 2-alkyl-
substituted aziridines with acetic acid to yield the ring opened
products with excellent regioselectivity, which were then treated
with LiAlH4 or Pd(OH)2 to provide the corresponding b-amino
alcohols. On the other hand, the reaction of the same chiral
aziridines with acetyl chloride followed by treatment with water
gave isomeric b-amino alcohols through oxazoline intermediates.53
In addition, the reaction of the latter chiral aziridines with benzyl
bromide followed by treatment with sulfuric acid gave secondary
b-amino alcohols via ring opening at the substituted aziridine
carbon atom.
In the present work, the synthesis of enantiopure 2-
aminopropan-1-ols by means of LiAlH4-promoted reduction of
chiral 2-(hydroxymethyl)aziridines 8a and 8b was successfully
examined. After failing to prepare amines 9a and 9b upon
treatment with two molar equiv of LiAlH4 under reflux for
several days in THF and toluene, the mixture of aziridine 8 and
two molar equiv of LiAlH4 in THF was subjected to microwave
conditions (160 ◦C, 220 Wmax, two hours). Fortunately, full and
selective conversion of aziridines 8a and 8b into enantiopure 2-
aminopropan-1-ols 9a and 9b as single stereoisomers was obtained
(Scheme 3).
Again, the mechanism comprises coordination of aluminium
with the aziridine nitrogen atom, enabling C(3)–N cleavage
induced by nucleophilic attack of a hydride ion to furnish the
corresponding ring opened product. The bond cleavage was shown
to be highly regioselective, since hydride attack only occurred
at the less hindered position. Furthermore, the ring opening
reaction of chiral aziridines 8 proceeded not only with high
regio- but also high stereoselectivity, furnishing the corresponding
enantiopure amino alcohols 9a and 9b with full retention of
configuration.
The preparation of enantiopure six-membered oxazaheterocy-
cles has received significant attention, due for example to their high
potential as chiral substrates. In particular, chiral morpholin-2-
ones have been used in the asymmetric synthesis of a-amino acids47
and other natural products.48 In the present study, enantiopure 5-
methylmorpholin-2-ones were prepared by condensation of the
corresponding chiral amino alcohols with glyoxal. Thus, chiral
b-amino alcohols 9a and 9b were treated with three equiv of
glyoxal (40%), furnishing enantiopure morpholin-2-ones 10a and
10b upon reflux for three hours in THF (Scheme 3). The reaction
showed high stereoselectivity since no diastereomers were detected
in the crude 1H NMR spectra, which is in accordance with
previously reported analogous condensation reactions.46
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Scheme 4
Attempts to convert enantiopure amino alcohols 9 into chiral
2-methylaziridines were not successful. For this purpose, b-amino
alcohols 9a and 9b were subjected to Mitsunobu conditions using
1.2 equiv of PPh3 and 1.2 equiv of diisopropyl azodicarboxylate
(or 1.2 equiv of N-bromosuccinimide) in THF for 18 h, or were
treated with 1.05 equiv of MsCl and 1.1 equiv of Et3N (or 1.05
equiv of TsCl and 0.1 equiv of DMAP) in CH2Cl2 for 4 h, although
in all cases only complex mixtures were obtained. Furthermore,
a number of efforts were made towards the N-deprotection
of morpholinones 10a and 10b through hydrogenolysis (10%
Pd(OH)2, EtOAc, r.t., 5 bar H2). However, 1H NMR and GC-MS
analysis of the crude mixtures revealed the presence of deprotected
amines only as minor components (up to 35%) together with the
starting compound, even upon prolonged reaction times (more
than three days).
reaction mixtures. The reaction of 2-(phenoxymethyl)aziridines
11c and 11d, obtained by treatment of 2-(bromomethyl)aziridines
1 with 2.2 equiv of phenol and 5 equiv of K2CO3 under reflux
for 10 h in a mixture of DMF and acetone (1/1),4b with two
equiv of LiAlH4 surprisingly furnished isopropylamines 2 after
6 h at 160 ◦C under microwave irradiation. However, when
these aziridines 11c and 11d were heated at 130 ◦C (or 140 ◦C)
for 10–15 h, 2-methylaziridines 3 were obtained in a mixture
together with starting compounds 11c and 11d. Increasing the
temperature to 160 ◦C led to the full conversion of aziridines
11c and 11d into isopropylamines 2. These observations can be
explained by considering the better leaving group capacities of the
phenoxy substituent as compared to the methoxy group, resulting
in a more rapid formation of intermediate 2-methylaziridines 3.
The unexpected behaviour of the phenoxy group as a leaving
group is remarkable, as no other reports on the conversion of
phenoxyalkanes into the corresponding alkanes using hydride
reagents have been reported in the literature. Thus, attempts were
made to convert n-decylphenylether into n-decane using LiAlH4
under microwave conditions. However, the reaction showed◦ to
be potentially dangerous under microwave irradiation at 160 C,
leading to an explosive reaction outcome. Therefore, this method
cannot be regarded as a general synthetic approach for alkane
formation as such.
In addition to the use of 2-(acetoxymethyl)- and 2-
(hydroxymethyl)aziridines, the LiAlH4-promoted ring opening of
2-(methoxymethyl)- and 2-(phenoxymethyl)aziridines 11a–d was
evaluated applying microwave conditions (Scheme 4).
2-(Methoxymethyl)aziridines 11a and 11b were prepared
through conversion of 2-(bromomethyl)aziridines 1 upon treat-
ment with two equiv of sodium methoxide in methanol (2M) under
reflux for 15 h.54 Remarkably, treatment of these aziridines 11a and
11b with two equiv of LiAlH4 under microwave conditions resulted
in different reaction products depending upon the temperature
used. Indeed, treatment of aziridine 11a and 11b for 2 h at 160 ◦C
yielded isopropylamines 2, whereas mainly b-methoxyamines 12a
and 12b were obtained after 12 h at 130 ◦C. The formation of
isopropylamines 2 can be explained by considering the initial
replacement of the methoxy group by means of LiAlH4 (via a
nucleophilic or radical pathway) furnishing 2-methylaziridines 3,
which subsequently underwent reductive ring opening via nucle-
ophilic attack of a hydride ion (from LiAlH4) at the less substituted
carbon atom of the aziridine moiety. Again, spectroscopic evidence
for the intermediacy of 2-methylaziridines 3 was obtained through
careful analysis of the reaction mixtures. Apparently, at 130 ◦C
nucleophilic aziridine ring opening by hydride took place prior
to replacement of the methoxy group, and b-methoxyamines
12a and 12b were obtained as the major components in the
Conclusion
In conclusion, the microwave-assisted reductive ring opening of
2-substituted non-activated aziridines utilizing LiAlH4 has been
reported for the first time in a highly regio- and stereoselective way.
2-(Acetoxymethyl)aziridines provided b-amino alcohols upon
treatment with LiAlH4 under microwave irradiation, which were
then used to produce synthetically relevant 5-methylmorpholin-2-
ones in a straightforward way. Besides, the microwave-assisted
conversion of chiral aziridine substrates by means of LiAlH4
furnished the corresponding enantiopure b-amino alcohols, which
were then exposed to glyoxal to give chiral 5(R)- and 5(S)-
morpholin-2-ones. In addition, 2-(methoxymethyl)aziridines pro-
vided isopropylamines or b-methoxyamines upon treatment with
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LiAlH4 under microwave irradiation, depending on the tempera-
ture applied. Thus, LiAlH4 can be regarded as a useful reagent for
a new type of reductive aziridine ring opening in a selective way
under microwave conditions, paving the way for a variety of novel
applications in organic chemistry.
171.0. IR (neat, cm-1): nCO = 1737; nmax = 2986; 2832; 1491; 1370;
1231; 1087; 1033; 806. MS (70 eV): m/z (%): 240/2 (M+ + 1, 100).
Anal. Calcd for C12H14ClNO2: C 60.13, H 5.89, N 5.84. Found: C
60.28, H 6.12, N 5.79.
1-(4-Methoxyphenyl)methyl-2-(acetoxymethyl)aziridine
4d.
Yield 79%, light-yellow oil, Rf 0.08 (hexane–ethyl acetate 2 : 1).
1H NMR (300 MHz, CDCl3): d 1.51 (1H, d, J = 6.6 Hz); 1.77
(1H, d, J = 3.3 Hz); 1.79–1.89 (1H, m); 1.97 (3H, s); 3.26 and
3.52 (2H, 2 x d, J = 13.0 Hz); 3.80 (3H, s); 3.86 and 4.17 (2H, 2
x d x d, J = 11.6, 7.7, 4.7 Hz); 6.85–6.88 and 7.25–7.28 (4H, 2 x
m). 13C NMR (75 MHz, CDCl3): d 20.8, 31.8, 36.9, 55.3, 63.6,
66.6, 113.7, 129.3, 131.0, 158.8, 170.9. IR (neat, cm-1): nCO = 1736;
nmax = 2952; 2835; 1511; 1234; 1031; 818. MS (70 eV): m/z (%):
236 (M+ + 1, 100). Anal. Calcd for C13H17NO3: C 66.36, H 7.28,
N 5.95. Found: C 66.45, H 7.57, N 5.81.
Experimental section
General
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent. Mass spectra were recorded on an Agilent
1100 series mass spectrometer using either a direct inlet system
(electron spray, 4000 V) or LC-MS coupling (UV detector). IR
spectra were recorded on a Perkin-Elemer Spectrum BX FT-
IR spectrometer. All compounds were analysed in neat form
with an ATR (Attenuated Total Reflectance) accessory. Melting
points were measured using a Bu¨chi B-540 apparatus and are
uncorrected. Dichloromethane was distilled over calcium hydride,
while diethyl ether and THF were distilled from sodium and
sodium benzophenone ketyl before use. Microwave reactions were
performed in a CEM Discover Microwave Reactor in a 80 ml
sealed vessel using a fiber-optic temperature sensor.
Synthesis of 2-(arylmethylamino)propan-1-ols 6 from
1-arylmethyl-2-(acetoxymethyl)aziridines 4
As
a
representative example, the synthesis of 2-{[(4-
chlorophenyl)methyl]amino}propan-1-ol 6c is described here. 1-
(4-Chlorophenyl)methyl-2-(acetoxymethyl)aziridine 4c (1.20 g, 5
mmol) was dissolved in dry THF (50 ml), after which LiAlH4
(0.38 g, 2 molar equiv) was added in small portions at 0 ◦C.
The resulting mixture was then placed in an 80 ml sealed glass
vessel, provided with appropriate stirrer bar and subjected to
microwave conditions (130 ◦C, 220 Wmax, two hours, CAUTION).
Afterwards, the reaction mixture was poured into water (20 ml)
and extracted with Et2O (3 ¥ 20 ml). Drying (MgSO4), filtration
of the drying agent and evaporation of the solvent afforded 2-
{[(4-chlorophenyl)methyl]amino}propan-1-ol 6c (0.92 g, 92%),
which was purified by filtration through silica gel column
(dichloromethane–methanol 9 : 1) in order to obtain an analyti-
cally pure sample. CAUTION: strict safety measurements have
to be applied for LiAlH4-promoted reactions under microwave
irradiation in order to cover the risk of explosion.
Synthesis of 1-arylmethyl-2-(acetoxymethyl)aziridines 4
As
a
representative example, the synthesis of 1-(4-
chlorophenyl)methyl-2-(acetoxymethyl)aziridine 4c is described
here.
1-(4-Chlorophenyl)methyl-2-(bromomethyl)aziridine
(2.60 g, 10 mmol)25 1c was added to a stirred solution of NaOAc
(1.23 g, 1.5 equiv) in DMSO (20 ml) at room temperature, and
the mixture was heated at 100 C for 15 h. The reaction mixture
◦
was poured into water (20 ml) and extracted with Et2O (3 ¥
20 ml). The combined organic extracts were washed with H2O
(2 ¥ 15 ml) and brine (20 ml). Drying (MgSO4), filtration of
the drying agent and evaporation of the solvent afforded 1-(4-
chlorophenyl)methyl-2-(acetoxymethyl)aziridine 4c (2.16 g, 90%),
which was purified by filtration through silica gel (hexane–ethyl
acetate 2 : 1) in order to obtain an analytically pure sample.
2-{[(4-Methylphenyl)methyl]amino}propan-1-ol
6b. Yield
75%, light-yellow crystals, Rf 0.17 (dichloromethane–methanol
◦
1
9 : 1), Mp = 71.7–72.2 C. H NMR (300 MHz, CDCl3): d 1.07
(3H, d, J = 6.6 Hz); 2.33 (3H, s); 2.74 (2H, br s); 2.77–2.88 (1H,
m); 3.27 and 3.57 (2H, 2 x d x d, J = 11.0, 6.9, 3.9 Hz); 3.68
and 3.83 (2H, 2 x d, J = 12.9 Hz); 7.07–7.25 (4H, m). 13C NMR
(75 MHz, CDCl3): d 16.7, 21.2, 50.5, 53.9, 65.2, 128.4, 129.3,
136.0, 137.1. IR (neat, cm-1): nNH,OH = 3277; nmax = 2846; 1460;
1063; 886; 812. MS (70 eV): m/z (%): 180 (M+ + 1, 100). Anal.
Calcd for C11H17NO: C 73.70, H 9.56, N 7.81. Found: C 73.92, H
9.48, N 9.47.
1-(4-Methylphenyl)methyl-2-(acetoxymethyl)aziridine
4b.
Yield 83%, light-yellow oil, Rf 0.15 (hexane–ethyl acetate 2 : 1).
1H NMR (300 MHz, CDCl3): d 1.51 (1H, d, J = 6.0 Hz); 1.77
(1H, d, J = 3.3 Hz); 1.81–1.89 (1H, m); 1.97 (3H, s); 2.34 (3H, s);
3.30 and 3.54 (2H, 2 x d, J = 13.2 Hz); 3.82 and 4.17 (2H, 2 x d x
d, J = 11.5, 7.2, 4.4 Hz); 7.13–7.25 (4H, m). 13C NMR (75 MHz,
CDCl3): d 20.7, 21.1, 31.8, 36.9, 64.0, 66.6, 128.0, 129.0, 135.7,
136.6, 170.9. IR (neat, cm-1): nCO = 1737; nmax = 2924; 1370; 1230;
1032; 802. MS (70 eV): m/z (%): 220 (M+ + 1, 100). Anal. Calcd
for C13H17NO2: C 71.21, H 7.81, N 6.39. Found: C 71.35, H 8.03,
N 6.44.
2-{[(4-Chlorophenyl)methyl]amino}propan-1-ol 6c. Yield 92%,
light-yellow crystals, Rf 0.19 (dichloromethane–methanol 9 : 1),
Mp = 64.6–65.6 ◦C. 1H NMR (300 MHz, CDCl3): d 1.06 (3H, d,
J = 6.6 Hz); 2.31 (2H, br s); 2.75–2.85 (1H, m); 3.27 and 3.56 (2H,
2 x d x d, J = 10.8, 7.2, 3.8 Hz); 3.68 and 3.83 (2H, 2 x d, J =
13.2 Hz); 7.23–7.33 (4H, m). 13C NMR (75 MHz, ref = CDCl3): d
17.2, 50.4, 53.9, 65.6, 128.7, 129.5, 132.9, 138.8. IR (neat, cm-1):
nNH,OH = 3312; nmax = 2927; 1491; 1256; 1043; 730. MS (70 eV): m/z
(%): 200/2 (M+ + 1, 100). Anal. Calcd for C10H14ClNO: C 60.15,
H 7.07, N 7.01. Found: C 60.05, H 7.18, N 7.10.
1-(4-Chlorophenyl)methyl-2-(acetoxymethyl)aziridine
4c.
Yield 90%, light-yellow oil, Rf 0.12 (hexane–ethyl acetate 2 : 1).
1H NMR (300 MHz, CDCl3): d 1.51 (1H, d, J = 6.6 Hz); 1.79
(1H, d, J = 3.9 Hz); 1.80–1.90 (1H, m); 1.98 (3H, s); 3.26 and
3.56 (2H, 2 x d, J = 13.8 Hz); 3.79 and 4.20 (2H, 2 x d x d, J =
11.6, 7.4, 4.4 Hz); 7.24–7.32 (4H, m). 13C NMR (75 MHz, ref =
CDCl3): d 20.9, 32.0, 37.2, 63.5, 66.6, 128.5, 129.5, 132.9, 137.4,
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mixture was heated for 2.5 h under reflux. The reaction mixture
was then poured into water (20 ml) and extracted with CH2Cl2 (3
¥ 10 ml). The combined organic layers were dried with anhydrous
Na2SO4, filtered and evaporated. The crude product was purified
by column chromatography on silica gel (petroleum ether–ethyl
acetate 7 : 1) in order to obtain an analytically pure sample (0.76 g,
87%).
2-{[(4-Methoxyphenyl)methyl]amino}propan-1-ol
6d. Yield
72%, light-yellow crystals, Rf 0.08 (dichloromethane–methanol
◦
1
9 : 1), Mp = 59.4–60.4 C. H NMR (300 MHz, CDCl3): d 1.02
(3H, d, J = 7.2 Hz); 1.95 (2H, br s); 2.72–2.81 (1H, m); 3.20 and
3.52 (2H, 2 x d x d, J = 10.5, 6.6, 3.9 Hz); 3.61 and 3.74 (2H, 2 x
d, J = 12.9 Hz); 3.72 (3H, s); 6.78–6.81 and 7.15–7.19 (4H, 2 x m).
13C NMR (75 MHz, ref= CDCl3): d 17.1, 50.6, 53.7, 55.4, 65.6,
113.9, 129.4, 132.4, 158.8. IR (neat, cm-1): nNH,OH = 3294; nmax
2834; 1511; 1245; 1034; 819. MS (70 eV): m/z (%): 196 (M+
=
+
4-(4-Methylphenyl)methyl-5-methylmorpholin-2-one 7b. Yield
87%, yellow liquid, Rf 0.07 (petroleum ether–ethyl acetate 7 : 1).
1H NMR (300 MHz, CDCl3): d 1.17 (3H, d, J = 6.1 Hz); 2.34 (3H,
s); 2.82–2.92 (1H, m); 3.11 and 3.43 (2H, 2 x d, J = 18.2 Hz); 3.27
and 3.88 (2H, 2 x d, 12.9 Hz); 4.09 and 4.34 (2H, 2 x d x d, J = 11.0,
7.7, 3.6 Hz); 7.09–7.19 (4H, m). 13C NMR (75 MHz, CDCl3): d
12.4, 21.1, 51.1, 52.5, 57.3, 73.7, 128.8, 129.3, 133.6, 137.3, 168.2.
IR (neat, cm-1): nCO = 1742; nmax = 2923; 1227; 1055; 807. MS (70
eV): m/z (%): 220 (M+ + 1, 100). Anal. Calcd for C13H17NO2: C
71.21, H 7.81, N 6.39. Found: C 71.47, H 8.06, N 6.27.
1, 100). Anal. Calcd for C11H17NO2: C 67.66, H 8.78, N 7.17.
Found: C 67.76, H 8.91, N 7.14.
Synthesis of optically active 2-aminopropan-1-ols 9 from chiral
aziridine alcohols 8
As
a representative example, the synthesis of (S)-[1(R)-
phenylethylamino]propan-1-ol 9a is described here. Aziridine
alcohol 8a (0.88 g, 5 mmol) was diluted in dry THF (50 ml),
and LiAlH4 (0.38 g, 2 molar equiv) was added in small portions at
4-(4-Chlorophenyl)methyl-5-methylmorpholin-2-one 7c. Yield
83%, yellow solid, Rf 0.05 (petroleum ether–ethyl acetate 7 : 1),
0
◦C. The resulting mixture was then placed in an 80 ml sealed
vessel, provided with appropriate stirrer bar and subjected to
microwave conditions (160 ◦C, 220 Wmax, two hours, CAUTION).
The resulting reaction mixture was subsequently poured into water
(15 ml) and extracted with Et2O (3 ¥ 20 ml). Drying (MgSO4), fil-
tration of the drying agent and evaporation of the solvent afforded
2(S)-[1(R)-phenylethylamino]propan-1-ol 9a (0.83 g, 93%), which
was purified by filtration through silica gel (dichloromethane–
methanol 9 : 1) in order to obtain an analytically pure sample.
◦
1
Mp = 55.5–58.5 C. H NMR (300 MHz, CDCl3): d 1.16 (3H,
d, J = 6.0 Hz); 2.84–2.93 (1H, m); 3.11 and 3.41 (2H, 2 x d, J =
17.6 Hz); 3.29 and 3.88 (2H, 2 x d, 13.2 Hz); 4.09 and 4.35 (2H,
2 x d x d, J = 11.0, 7.7, 3.6 Hz); 7.23–7.35 (4H, m). 13C NMR
(75 MHz, ref = CDCl3): d 12.5, 51.4, 52.6, 57.1, 73.7, 128.8, 130.2,
133.4, 135.6, 168.0. IR (neat, cm-1): nCO = 1741; nmax = 2969; 1490;
1227; 1056; 810. MS (70 eV): m/z (%): 240/2 (M+ + 1, 100). Anal.
Calcd for C12H14ClNO2: C 60.13, H 5.89, N 5.84. Found: C 60.27,
H 6.11, N 5.98.
2(S)-[1(R)-Phenylethylamino]propan-1-ol 9a. Yield 93%, col-
orless liquid, Rf 0.18 (dichloromethane–methanol 9 : 1), [a]2D8 = +
115.6 (c = 0.41, CDCl3). 1H NMR (300 MHz, CDCl3): d 0.98 (d x
d, J = 6.9, 1.4 Hz); 1.36 (3H, d, J = 6.6 Hz); 2.51–2.61 (1H, m); 2.55
(2H, br s); 3.16–3.23 (1H, m); 3.40 (1H, d x d, J = 10.8, 4.2 Hz);
3.93 (1H, q, J = 6.6 Hz); 7.19–7.34 (5H, m). 13C NMR (75 MHz,
CDCl3): d 16.6, 25.2, 51.4, 54.9, 66.5, 126.6, 127.1, 128.6, 145.1.
IR (neat, cm-1): nNH,OH = 3292; nmax = 2965; 1452; 1044; 762; 731;
699. MS (70 eV): m/z (%): 180 (M+ + 1, 100). Anal. Calcd for
C11H17NO: C 73.70, H 9.56, N 7.81. Found: C 73.94, H 9.84, N
7.69.
4-(4-Methoxyphenyl)methyl-5-methylmorpholin-2-one
7d.
Yield 74%, yellow solid, Rf 0.05 (petroleum ether–ethyl acetate
◦
1
7 : 1), Mp = 48.3–51.3 C. H NMR (300 MHz, CDCl3): d 1.17
(3H, d, J = 6.6 Hz); 2.82–2.92 (1H, m); 3.11 and 3.43 (2H, 2 x d,
J = 17.6 Hz); 3.26 and 3.86 (2H, 2 x d, J = 12.6 Hz); 3.81 (3H,
s); 4.09 and 4.34 (2H, 2 x d x d, J = 11.0, 7.7, 3.3 Hz); 6.84–6.89
and 7.18–7.25 (4H, 2 x m). 13C NMR (75 MHz, CDCl3): d 12.4,
51.1, 52.4, 55.3, 57.0, 73.7, 114.0, 130.1, 128.6, 161.3, 167.9. IR
(neat, cm-1): nCO = 1739; nmax = 2965; 1511; 1243; 1031; 822. MS
(70 eV): m/z (%): 236 (M+ + 1, 100). Anal. Calcd for C13H17NO3:
C 66.36, H 7.28, N 5.95. Found: C 66.31, H 7.24, N 5.88.
2(R)-[1(R)-Phenylethylethylamino]propan-1-ol 9b. Yield 85%,
white crystals, Rf 0.08 (dichloromethane–methanol 9 : 1), Mp =
49.5–51.1 ◦C, [a]D28 = - 2.3 (c = 0.36, CDCl3). 1H NMR (300 MHz,
CDCl3): d 0.98 (3H, d, J = 6.6 Hz); 1.35 (3H, d, J = 6.4 Hz); 2.30
(2H, br s); 2.68–2.80 (1H, m); 3.20 and 3.59 (2H, 2 x d x d, J =
10.5, 6.1, 3.8 Hz); 3.87 (1H, q, J = 6.4 Hz); 7.22–7.36 (5H, m).
13C NMR (75 MHz, CDCl3): d 18.2, 24.1, 51.6, 55.4, 64.9, 126.4,
127.1, 128.6, 145.9. IR (neat, cm-1): nNH,OH = 3292; nmax = 2965;
1452; 1045; 761; 700. MS (70 eV): m/z (%): 180 (M+ + 1, 100).
Anal. Calcd for C11H17NO: C 73.70, H 9.56, N 7.81. Found: C
73.78, H 9.72, N 7.82.
Synthesis of chiral 5-methylmorpholin-2-ones 10 from chiral
2-aminopropan-1-ols 9
As a representative example, the synthesis of 5(S)-methyl-4-[1(R)-
phenylethyl]morpholin-2-one 10a is described here. To a solution
of 2(S)-[1(R)-phenylethylamino]propan-1-ol 9a (0.72 g, 4 mmol)
in THF (30 ml) an aqueous solution of glyoxal (40%, 1.74 g,
3 equiv) was added, and the resulting mixture was heated for
3 h under reflux. The reaction mixture was then poured into
water (20 ml) and extracted with CH2Cl2 (3 ¥ 10 ml). The
combined organic layers were dried with anhydrous Na2SO4,
filtered and evaporated. The crude product was purified by column
chromatography on silica gel (hexane–ethyl acetate 3 : 1) in order
to obtain an analytically pure sample (0.78 g, 89%).
Synthesis of 5-methylmorpholin-2-ones 7 from
2-(arylmethylamino)propan-1-ols 6
As
a
representative example, the synthesis of 4-(4-
methylphenyl)methyl-5-methylmorpholin-2-one 7b is described
here. To a solution of 2-{[(4-methylphenyl)methyl]amino}propan-
1-ol 6b (0.72 g, 4 mmol) in THF (30 ml) an aqueous solution
of glyoxal (40%, 1.74 g, 3 equiv) was added, and the resulting
5(S)-Methyl-4-[1(R)-phenylethyl]morpholin-2-one 10a. Yield
89%, light yellow solid, Rf 0.25 (hexane–ethyl acetate 3 : 1), Mp =
37.1–40.2 ◦C, [a]D28 = + 25.0 (c = 0.44, CDCl3). 1H NMR (300 MHz,
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CDCl3): d 1.04 (3H, d, J = 6.6 Hz); 1.35 (3H, d, J = 6.8 Hz); 2.82–
2.91 (1H, m); 3.38 and 3.74 (2H, 2 x d, J = 17.9 Hz); 3.66 (1H, q,
J = 6.8 Hz); 4.00 and 4.37 (2H, 2 x d x d, J = 11.0, 3.3, 3.3 Hz);
7.24–7.34 (5H, m). 13C NMR (75 MHz, CDCl3): d 9.0, 21.0, 47.2,
48.3, 60.2, 74.1, 127.3, 127.6, 128.7, 142.7, 168.6. IR (neat, cm-1):
nCO = 1737; nmax = 2973; 1224; 1004; 701. MS (70 eV): m/z (%):
220 (M+ + 1, 100). Anal. Calcd for C13H17NO2: C 71.21, H 7.81,
N 6.39. Found: C 71.27, H 7.93, N 6.33.
C12H19NO2: C 68.87, H 9.15, N 6.69. Found: C 68.61, H 9.48, N
6.47.
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1
[a]2D8 = + 9.6 (c = 0.37, CDCl3). H NMR (300 MHz, CDCl3):
d 1.16 (3H, d, J = 6.6 Hz); 1.34 (3H, d, J = 6.6 Hz); 3.11 and
3.28 (2H, 2 x d, J = 18.2 Hz); 3.26–3.36 (1H, m); 3.74 (1H, q, J =
6.6 Hz); 4.14 and 4.47 (2H, 2 x d x d, J = 10.8, 5.2, 3.6 Hz); 7.22–
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59.1, 73.9, 127.38, 127.44, 128.6, 142.8, 168.8. IR (neat, cm-1):
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As a representative example, the synthesis of N-(4-methyl-
phenyl)methyl-N-(2-methoxy-1-methylethyl)amine
12a
is
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aziridine 11a (0.96 g, 5 mmol) was dissolved in dry THF (25 ml),
after which LiAlH4 (0.38 g, 2 molar equiv) was added in small
portions at 0 ◦C. The resulting mixture was then placed in an
80 ml sealed vessel, provided with appropriate stirrer bar and
subjected to microwave conditions (130 ◦C, 250 Wmax, 12 h).
Afterwards, the reaction mixture was poured into water (20 ml)
and extracted with Et2O (3 ¥ 20 ml). Drying (MgSO4), filtration
of the drying agent and evaporation of the solvent afforded
N-(4-methylphenyl)methyl-N-(2-methoxy-1-methylethyl)amine
12a (0.27 g, 80%), which was purified by filtration through a silica
gel column (dichloromethane–methanol 9 : 1) in order to obtain
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N-(4-Methylphenyl)methyl-N-(2-methoxy-1-methylethyl)amine
12a. Yield 80%, light-yellow oil, Rf 0.23 (dichloromethane–
methanol 9 : 1). 1H NMR (300 MHz, CDCl3): d 1.06 (3H, d, J =
6.1 Hz); 2.33 (3H, s); 2.08 (1H, br s); 2.89–2.99 (1H, m); 3.27 and
3.34 (2H, 2 x d x d, J = 9.4, 7.7, 4.4 Hz); 3.32 (3H, s); 3.69 and 3.86
(2H, 2 x d, J = 12.9 Hz); 7.12–7.26 (4H, m).13C NMR (75 MHz,
CDCl3): d 16.9, 21.1, 50.9, 51.8, 58.9, 77.1, 128.2, 129.1, 136.5,
137.2. IR (neat, cm-1): nNH = 3325; nmax = 2923; 2875; 2826; 1514;
1450; 1373; 1197; 1162; 1106; 805. MS (70 eV): m/z (%): 194
(M+ + 1, 100). Anal. Calcd for C12H19NO: C 74.57, H 9.91, N
7.25. Found: C 74.68, H 9.48, N 7.47.
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amine 12b. Yield 60%, dark-yellow oil, Rf 0.21 (dichloro-
1
methane–methanol 9 : 1). H NMR (300 MHz, CDCl3): d 1.07
(3H, d, J = 6.1 Hz); 2.24 (1H, br s); 2.89–2.99 (1H, m); 3.25–3.36
(2H, m); 3.67 and 3.83 (2H, 2 x d, J = 12.7 Hz); 3.80 (3H, s);
6.85–6.88 (4H, m).13C NMR (75 MHz, CDCl3): d 16.8, 50.7, 51.8,
55.3, 58.8, 77.0, 113.8, 129.4, 132.4, 158.6. IR (neat, cm-1): nNH
=
3324; nmax = 2928; 2877; 2832; 1612; 1511; 1462; 1244; 1105; 1035;
822. MS (70 eV): m/z (%): 210 (M+ + 1, 100). Anal. Calcd for
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