Reactivity of N-(ω-haloalkyl)-β-lactams with regard to lithium aluminium hydride: Novel synthesis of 1-(1-aryl-3-hydroxypropyl)aziridines and 3-aryl-3-(N-propylamino)propan-1-ols

Article abstract of DOI:10.1039/b719686e

The reactivity of 4-aryl-1-(2-chloroethyl)azetidin-2-ones and 4-aryl-1-(3-bromopropyl)azetidin-2-ones with regard to lithium aluminium hydride has been evaluated for the first time. 4-Aryl-1-(2-chloroethyl)azetidin-2-ones were transformed into novel 1-(1-

Full text of DOI:10.1039/b719686e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Reactivity of N-(x-haloalkyl)-b-lactams with regard to lithium aluminium
hydride: novel synthesis of 1-(1-aryl-3-hydroxypropyl)aziridines and
3-aryl-3-(N-propylamino)propan-1-ols†
Matthias D’hooghe, Stijn Dekeukeleire‡ and Norbert De Kimpe*
Received 20th December 2007, Accepted 5th February 2008
First published as an Advance Article on the web 3rd March 2008
DOI: 10.1039/b719686e
The reactivity of 4-aryl-1-(2-chloroethyl)azetidin-2-ones and 4-aryl-1-(3-bromopropyl)azetidin-2-ones
with regard to lithium aluminium hydride has been evaluated for the first time.
4-Aryl-1-(2-chloroethyl)azetidin-2-ones were transformed into novel
1-(1-aryl-3-hydroxypropyl)aziridines through an unprecedented conversion of b-lactams into
2,3-unsubstituted aziridine derivatives. Unexpectedly, 4-aryl-1-(3-bromopropyl)azetidin-2-ones
underwent dehalogenation towards 3-aryl-3-(N-propylamino)propan-1-ols upon treatment with
LiAlH4. 1-(1-Aryl-3-hydroxypropyl)aziridines were further elaborated by means of ring opening
reactions using benzyl bromide in acetonitrile towards
3-aryl-3-[N-benzyl-N-(2-bromoethyl)amino]propan-1-ols and using aluminium(III) chloride in diethyl
ether, affording 3-aryl-3-[N-(2-chloroethyl)amino]propan-1-ols.
ing azetidines, resulting in the unexpected formation of 3-(N-
propylamino)propan-1-ols instead.
The chemistry of N-(x-haloalkyl)azetidin-2-ones comprises an
2-ones have acquired a prominent place in organic chemistry as
unexplored field of research, although the combination of the
Introduction
Besides their biological relevance as potential antibiotics, azetidin-
synthons for further elaboration, which led to the introduction
of the term “b-lactam synthon method” in 1997.1 Since then, the
constrained azetidin-2-one ring has been employed successfully in
a large variety of different synthetic methodologies towards all
kinds of nitrogen-containing target compounds.2 One of these
reactive b-lactam ring and the halogenated carbon atom allows
the design of a variety of transformations towards relevant target
compounds. To date, only two approaches involving the use of
N-(x-haloalkyl)-b-lactams are available, the first describing the
transformation of 1-(x-haloalkyl)-4-phenylazetidin-2-ones into
7-phenyl-1,4-diazepan-5-ones7 and the second dealing with the
synthesis of 1-(2- and 3-haloalkyl)azetidin-2-ones as precursors
for novel piperazine-, morpholine-, and 1,4-diazepane-annulated
b-lactams.8
useful transformations involves the ring transformation of b-
lactams into C-substituted aziridine derivatives, which are in their
turn interesting synthetic intermediates for further syntheses.3
Despite the synthetic and biological relevance of 2,3-unsubstituted
1-alkylaziridines,4 no convenient transformations of b-lactams
into this type of aziridine derivatives are available in the literature
as an alternative for the use of the parent aziridine via N-alkylation.
The need for alternative methods is justified by the severe acute
toxicity, explosion hazard, decomposition during storage and
instability towards violent polymerization of aziridine itself.5 In a
recent study, an elegant synthesis of 1-(2-hydroxyethyl)aziridines
has been described involving ring opening of epoxides by in
situ generated aziridine.6 In the present report, a convenient and
straightforward approach towards 1-(3-hydroxypropyl)aziridines
is disclosed through conversion of 1-(2-chloroethyl)azetidin-2-
ones upon treatment with lithium aluminium hydride. Further-
more, also the reactivity of 1-(3-bromopropyl)-b-lactams towards
LiAlH4 was evaluated for the synthesis of the correspond-
Results and discussion
N-(2-Chloroethyl)imines 2a–e (n = 1), N-(3-bromopropyl)imines
2f–j (n = 2) and N-(3-chloropropyl)imine 2k (n = 2) were prepared
in good yields via imination of different benzaldehydes 1 in
dichloromethane in the presence of MgSO4 and Et3N utilizing
1 equivalent of the appropriate amine hydrohalide salt (Scheme 1,
Table 1). Subsequently, the obtained imines 2 were used as
substrates for a Staudinger reaction upon treatment with 1.1
equivalents of phenoxy-, methoxy- or benzyloxyacetyl chloride in
the presence of triethylamine in dichloromethane, affording the
corresponding novel 1-(2-chloroethyl)azetidin-2-ones 3a–e and
3l,m (n = 1), 1-(3-bromopropyl)azetidin-2-ones 3f–j (n = 2) and
1-(3-chloropropyl)azetidin-2-one 3k (n = 2) after 15 hours at room
temperature (Scheme 1, Table 1). The relative stereochemistry of
b-lactams 3 was assigned as cis based on the coupling constants
between the protons at C3 and C4 in 1H NMR (4.4–4.7 Hz, CDCl3)
in accordance with literature data.9
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000, Ghent, Belgium
† Electronic supplementary information (ESI) available: Characterisation
data of compounds 2c–e,h–j, 3b–e,g–k, 4b–e, 7b,c,e, 8b–e and 9b–e. See
DOI: 10.1039/b719686e
In the next stage, 1-(2-chloroethyl)azetidin-2-ones 3a–e,l–m
were transformed into novel 1-(1-aryl-3-hydroxypropyl)aziridines
4a–g upon treatment with 2 equivalents of lithium aluminium
‡ Aspirant of the Fund for Scientific Research – Flanders (FWO-
Vlaanderen).
1190 | Org. Biomol. Chem., 2008, 6, 1190–1196
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Scheme 1
Table 1 Synthesis of N-(x-haloalkyl)imines 2a–k and Staudinger reac-
tion thereof towards N-(x-haloalkyl)-b-lactams 3a–m
with 1.5 equivalents of sodium hydride followed by the addition
of 1.1 equivalents of iodomethane in THF, affording methyl
ether 6 in 88% yield after reflux for 3 hours (Scheme 2). NMR
analysis of the latter compound 6 revealed that the hydrogen
bonding in aziridines 4 cannot be responsible for the observed
difference in chemical shift values in NMR for the aziridine
carbon and hydrogen atoms, as the same observations were
made for this aziridine 6. These findings are in accordance
with analogous results reported for 1-(2-hydroxyethyl)aziridines
and the corresponding TMS ethers, as in both cases the four
aziridine proton atoms also exhibited separate signals for each
proton in 1H NMR.6 In the literature, non-activated 1-(3-
hydroxypropyl)aziridines have been reported only sporadically,
e.g. for the synthesis of 1,3-disubstituted propanones11 and 2-
amino-4-aryl-3-(1-aziridinylmethyl)quinolines,12 and thus com-
prise an interesting class of substrates for further elaboration.
Attempts were made to induce intramolecular ring opening of
the aziridine ring—activated in situ by a Lewis acid (BF3·Et2O,
BF3·THF, Me3Al)—by the nucleophilic hydroxyl group. However,
all these attempts were unsuccessful, resulting in either recovery
of the starting material or the formation of complex reaction
mixtures.
Aziridines are generally recognized as versatile synthetic inter-
mediates in organic chemistry due to their intrinsic reactivity
and their usefulness in the synthesis of nitrogen-containing
bioactive compounds.13 A characteristic feature of the aziridine
ring comprises its reactivity towards a variety of reagents, as this
ring system is susceptible to ring cleavage because of the favourable
release of strain energy involved. A very useful application of
aziridine ring opening reactions comprises the synthesis of b-
halo amines, an extensive class of reactive organic compounds
with plentiful applications as synthons in organic chemistry14
and as anticancer agents (nitrogen mustards) in medicinal
chemistry.15,16
Imines 2
(yield)
b-Lactams 3
(yield)
Entry
R1
X
n
R2
1
2
3
4
5
6
7
8
H
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Cl
Cl
Cl
1
1
1
1
1
2
2
2
2
2
2
1
1
2a (90%)
2b (89%)
2c (91%)
2d (95%)
2e (90%)
2f (78%)
2g (71%)
2h (73%)
2i (77%)
2j (83%)
2k (83%)
2a (90%)
2a (90%)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bn
3a (75%)
3b (70%)
3c (63%)
3d (67%)
3e (82%)
3f (83%)
3g (89%)
3h (93%)
3i (81%)
3j (74%)
3k (91%)
3l (93%)
3m (88%)
4-Cl
4-Me
4-OMe
3-OMe
H
4-Cl
4-Me
4-OMe
3-OMe
H
9
10
11
12
13
H
H
hydride in refluxing diethyl ether for 2 hours (Scheme 2). This
reaction proceeds through reduction of the b-lactam moiety by
hydride towards an intermediate b-chloro lithio-amide 5, followed
by intramolecular displacement of the chlorine by the nucleophilic
nitrogen. In this way, 1-substituted aziridines 4 were obtained in
high yields and purity in an elegant and straightforward approach.
Remarkably, all four hydrogen atoms of aziridines 4 were
observed as separate signals in 1H NMR and appeared as doublets
of doublets with characteristic aziridine chemical shifts (1.08–
2.03 ppm, CDCl3). Also in 13C NMR, both aziridine carbon
atoms resonated at different d-values (26.0–26.3 ppm and 30.2–
30.4 ppm, CDCl3). It is known in the literature that c-amino
alcohols are characterized by an intramolecular hydrogen bonding
between the hydroxyl group and the basic nitrogen atom, resulting
in a chair-like conformation.10 In order to evaluate the effect
of this intramolecular hydrogen bonding, a Williamson ether
synthesis was performed by treatment of aziridine alcohol 4b
Scheme 2
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Scheme 3
In order to demonstrate the synthetic potential of non-activated
aziridines 4, and to prove their presence, two different types of
ring opening reactions were evaluated towards the synthesis of
functionalized b-halo amines. The first approach involved the
ring opening of aziridines 4 upon treatment with 1 equivalent
of benzyl bromide in acetonitrile, affording b-bromo amines
7 in excellent yields after heating under reflux for 24 hours
(Scheme 3). In this transformation, benzyl bromide is responsible
for both the activation of the aziridine ring towards an aziridinium
intermediate and for the delivery of the nucleophilic bromide
anion which induces ring opening of the aziridinium ion. This
methodology was applied previously for the ring opening of 1-
(arylmethyl)aziridines upon reflux for 5 hours.17 The presence of
an a-branched 1-arylmethyl group in aziridines 4 can account for
the longer reaction times (24 hours) due to steric hindrance, as
the starting material was recovered when shorter reaction times
were used. For aziridine 4d (R1 = 4-OMe), only complex reac-
tions mixtures were obtained, even upon shorter reaction times
(5 hours).
An alternative approach comprised the reactivity of aziridines 4
with regard to the Lewis acid aluminium(III) chloride. Treatment
of aziridines 4 with 1 equivalent of AlCl3 in refluxing diethyl ether
for 4 hours afforded the corresponding b-chloro amines 8 in good
yields after purification by column chromatography on silica gel
(Scheme 3). The use of aluminium(III) chloride offers a new and
easy approach towards the synthesis of secondary b-chloro amines
through ring opening of non-activated aziridines, as there are no
systematic studies available with regard to this methodology.18
Based on the reactivity of 1-(2-chloroethyl)azetidin-2-ones 3a–
e, the same reductive ring opening and consecutive intramolecular
ring closure of 1-(3-bromopropyl)-b-lactams 3f–j was envisaged
towards the corresponding azetidine derivatives. Surprisingly,
treatment of 1-(3-bromopropyl)azetidin-2-ones 3f–j with lithium
aluminium hydride in diethyl ether did not afford the anticipated
1-substituted azetidine derivatives 10, but resulted in the formation
of c-amino alcohols 9a–e instead (Scheme 4). The presence of an
N-propyl group in the latter c-amino alcohols 9 was unexpected,
in contrast with the intramolecular substitution by the nitrogen
anion in lithium N-(2-chloroethyl)amides 5 towards the formation
of aziridines 4, and can be the result of nucleophilic displacement
of the bromine by hydride or, more likely, the result of a radical
protocol through SET (single electron transfer).19 In order to
exclude a possible influence of the halogen atom (bromine versus
chlorine), the same method was applied starting from 1-(3-
chloropropyl)-3-phenoxy-4-phenylazetidin-2-one 3k, furnishing
N-propylamine 9a in 71% yield. Thus, the higher reactivity of
bromoalkanes as compared to chloroalkanes did not correspond
to the observed substitution by hydride.
In order to prove the formation of 3-aryl-2-phenoxy-3-(N-
propylamino)propan-1-ols 9, an independent synthesis was per-
formed. 1-Propylazetidin-2-one 11 was prepared in 83% over-
all yield via a standard procedure involving imination of 4-
chlorobenzaldehyde with propylamine in CH2Cl2, followed by
Staudinger reaction with phenoxyacetyl chloride in CH2Cl2
in the presence of Et3N. Reductive ring opening of b-lactam
11 by means of 2 equivalents of LiAlH4 in refluxing diethyl
Scheme 4
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1
ether afforded the expected 3-(4-chlorophenyl)-2-phenoxy-3-(N-
propylamino)propan-1-ol 9b in 76% yield (Scheme 5), which was
identical to the compound obtained from 1-(3-bromopropyl)-b-
lactam 3g.
chloroethylamine 2c in high purity (> 90% based on H NMR),
which was used as such in the next step due to its instability.
(E)-N-(phenylmethylidene)-2-chloroethylamine 2a and (E)-N-
(phenylmethylidene)-3-halopropylamines 2f,k have been reported
previously in the literature.20
(E)-N-[(4-Chlorophenyl)methylidene]-2-chloroethylamine
2b.
Light-yellow oil. Yield 89%. 1H NMR (300 MHz, CDCl3): d
3.79–3.83 and 3.87–3.92 (2 × 2H, 2 × m, NCH2CH2Cl); 7.35–7.39
=
and 7.64–7.69 (2 × 2H, 2 × m, CHarom); 8.23 (1H, s, HC N).
13C NMR (75 MHz, ref = CDCl3): d 44.3 (CH2Cl); 62.6 (NCH2);
129.0 and 129.6 (4 × HCarom); 134.3 and 137.0 (2 × Cquat); 162.2
−1
=
(C N). IR (NaCl, cm ): mC= = 1651; mmax = 2879, 2825, 1596,
N
Scheme 5
1487, 1436, 1295, 1087, 1047, 843, 828, 656. MS (70 eV): m/z (%)
202/4/6 (M+ + 1, 100).
Conclusion
(E)-N-[(4-Chlorophenyl)methylidene]-3-bromopropylamine 2g.
Light-yellow oil. Yield 71%. 1H NMR (300 MHz, CDCl3): d 2.26
(2H, quint, J = 6.3 Hz, CH2CH2Br); 3.49 (2H, t, J = 6.3 Hz,
CH2Br); 3.75 (2H, t × d, J = 6.3, 1.4 Hz, NCH2); 7.36–7.41 and
In summary, the reactivity of 1-(2-chloroethyl)- and 1-
(3-bromopropyl)azetidin-2-ones with regard to lithium alu-
minium hydride has been evaluated for the first time.
4-Aryl-1-(2-chloroethyl)azetidin-2-ones were transformed into
novel 1-(1-aryl-3-hydroxypropyl)aziridines, whereas 4-aryl-1-
(3-bromopropyl)azetidin-2-ones underwent ring opening and
dehalogenation towards 3-aryl-3-(N-propylamino)propan-1-ols.
This is the first report of a conversion of b-lactams into 2,3-
unsubstituted aziridine derivatives as an elegant alternative for the
use of the parent aziridine. 1-(1-Aryl-3-hydroxypropyl)aziridines
were further elaborated by means of ring opening reactions using
benzyl bromide or aluminium(III) chloride, affording novel 3-aryl-
3-[N-benzyl-N-(2-bromoethyl)amino]propan-1-ols and 3-aryl-3-
[N-(2-chloroethyl)amino]propan-1-ols, respectively.
7.64–7.70 (2 × 2H, 2 × m, CHarom); 8.30 (1H, s, HC N). 13C
=
NMR (75 MHz, ref = CDCl3): d 31.7 and 33.3 (CH2CH2Br); 58.9
(NCH2); 129.0 and 129.4 (HCarom); 134.6 and 136.8 (2 × Cquat);
−1
=
160.8 (C N). IR (NaCl, cm ): mC= = 1646; mmax = 2844, 1596,
N
1489, 1276, 1250, 1088, 1014, 822. MS (70 eV): m/z (%) 260/2/4
(M+ + 1, 100).
Synthesis of 4-aryl-1-(x-haloalkyl)azetidin-2-ones 3
As a representative example, the synthesis of cis-1-(2-chloroethyl)-
3-phenoxy-4-(4-methylphenyl)azetidin-2-one 3c is described here.
To an ice-cooled solution of (E)-N-[(4-methylphenyl)methyli-
dene]-2-chloroethylamine 2c (45.5 mmol, 1 equiv) and triethyl-
amine (136.6 mmol, 3 equiv) in dichloromethane (100 mL) was
added dropwise a solution of phenoxyacetyl chloride (50 mmol,
1.1 equiv) in CH2Cl2 (30 mL). After stirring for 15 hours at room
temperature, the reaction mixture was poured into water (125
mL) and extracted with CH2Cl2 (2 × 50 mL), and the combined
organic extracts were dried (MgSO4). Filtration of the drying
agent and removal of the solvent afforded cis-1-(2-chloroethyl)-3-
phenoxy-4-(4-methylphenyl)azetidin-2-one 3c, which was purified
by recrystallization from absolute ethanol.
Experimental
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 obtained with a mass
spectrometer AGILENT 1100, 70 eV. IR spectra were measured
with a Spectrum One FT-IR spectrophotometer. Elemental anal-
yses were performed with a PerkinElmer Series II CHNS/O An-
alyzer 2400. Dichloromethane was distilled over calcium hydride,
while diethyl ether was dried over sodium benzophenone ketyl.
Other solvents were used as received from the supplier.
cis-1-(2-Chloroethyl)-3-phenoxy-4-phenylazetidin-2-one
3a.
Yellow crystals. Recrystallization from EtOH. Yield 75%. Mp.
◦
1
137.4 C. H NMR (300 MHz, CDCl3): d 3.28 (1H, d × d × d,
J = 14.6, 7.1, 5.1 Hz, (HCH)N); 3.54 (1H, d × d × d, J = 11.6,
6.4, 5.1 Hz, (HCH)Cl); 3.66 (1H, d × d × d, J = 11.6, 7.1, 5.0 Hz,
(HCH)Cl); 3.91 (1H, d × d × d, J = 14.6, 6.4, 5.0 Hz, (HCH)N);
5.11 (1H, d, J = 4.4 Hz, NCH); 5.51 (1H, d, J = 4.4 Hz, OCH);
6.71–6.75, 6.85–6.91, 7.09–7.16 and 7.26–7.37 (2H, 1H, 2H and
5H, 4 × m, CHarom). 13C NMR (75 MHz, ref = CDCl3): d 41.5
(CH2Cl); 42.2 (NCH2); 63.3 (NCH); 82.3 (OCH); 115.6 (2 ×
O(HC)ortho); 122.2 (O(HC)para); 128.5, 128.7, 129.0 and 129.3 (2 ×
Synthesis of (E)-N-arylmethylidene-N-(x-haloalkyl)amines 2
As
a representative example, the synthesis of (E)-N-[(4-
methylphenyl)methylidene]-2-chloroethylamine 2c is described
here. To a solution of 2-chloroethylamine hydrochloride (50 mmol,
1 equiv) and magnesium sulfate (100 mmol, 2 equiv) in
dichloromethane (125 mL) was added 4-methylbenzaldehyde 1c
(50 mmol, 1 equiv) and triethylamine (150 mmol, 3 equiv). The
resulting mixture was stirred for 1 hour at room temperature,
followed by filtration of MgSO4 and evaporation of the solvent.
Diethyl ether (125 mL) was then added to the residue, and
the precipitated hydrochloride salt was removed by filtration
and washed with diethyl ether (2 × 30 mL). Evaporation
of the solvent afforded (E)-N-[(4-methylphenyl)methylidene]-2-
O(HC)meta and 5 × (HC)arom); 132.8 (NCHCquat); 156.9 (OCquat);
−1
=
166.3 (C O). IR (KBr, cm ): mC= = 1758; mmax = 3012, 1597,
O
1494, 1412, 1242, 752. MS (70 eV): m/z (%) 302/4 (M+ + 1, 100).
Anal. Calcd for C17H16ClNO2: C 67.66, H 5.34, N 4.64. Found: C
67.78, H 5.51, N 4.77.
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−1
=
cis-1-(3-Bromopropyl)-3-phenoxy-4-phenylazetidin-2-one
3f.
(C O). IR (KBr, cm ): mC= = 1748; mmax = 2959, 1599, 1495,
O
Yellow crystals. Recrystallization from EtOH. Yield 83%. Mp.
89.3 ◦C. 1H NMR (300 MHz, CDCl3): d 1.97–2.19 (2H, m,
CH2CH2Br); 3.09–3.23 (1H, m, (HCH)N); 3.40 (2H, t, J =
6.6 Hz, CH2Br); 3.53–3.67 (1H, m, (HCH)N); 4.95 (1H, d,
J = 4.4 Hz, NCH); 5.45 (1H, d, J = 4.4 Hz, OCH); 6.70–6.74,
6.85–6.99, 7.09–7.16 and 7.24–7.43 (2H, 1H, 2H and 5H, 4 ×
m, CHarom). 13C NMR (75 MHz, ref = CDCl3): d 30.3 and 30.5
(CH2CH2Br); 39.7 (NCH2); 62.9 (NCH); 82.0 (OCH); 115.6 (2 ×
O(HC)ortho); 122.1 (O(HC)para); 128.4, 128.7, 129.0 and 129.3 (2 ×
1408, 1241, 1090, 825, 749, 688. MS (70 eV): m/z (%) 316/8 (M+
+ 1, 100). Anal. Calcd for C18H18ClNO2: C 68.46, H 5.75, N 4.44.
Found: C 68.52, H 5.84, N 4.57.
Synthesis of 1-(1-aryl-3-hydroxypropyl)aziridines 4
As a representative example, the synthesis of 1-[3-hydroxy-
1-(4-methoxyphenyl)-2-phenoxypropyl]aziridine 4d is described
here. To an ice-cooled solution of cis-1-(2-chloroethyl)-4-(4-
methoxyphenyl)-3-phenoxyazetidin-2-one 3d (20 mmol) in dry
diethyl ether (125 mL) was added lithium aluminium hydride
(40 mmol, 2 equiv) in small portions. After reflux for 2 hours,
the reaction mixture was cooled to 0 ◦C and water was added
in order to quench the excess of LiAlH4. The resulting suspen-
O(HC)meta and 5 × HCarom); 133.0 (NCHCquat); 156.9 (OCquat);
−1
=
166.3 (C O). IR (KBr, cm ): mC= = 1749; mmax = 2944, 1598,
O
1495, 1457, 1417, 1244, 749. MS (70 eV): m/z (%) 360/2 (M+ +
1, 100). Anal. Calcd for C18H18BrNO2: C 60.01, H 5.04, N 3.89.
Found: C 60.17, H 5.21, N 4.02.
R
sion was filtered over Celiteꢀ and washed with diethyl ether
(40 mL), and the filtrate was poured into water (100 mL) and
extracted with Et2O (3 × 30 mL). Drying (MgSO4), filtration of
the drying agent and removal of the solvent in vacuo afforded
1-[3-hydroxy-1-(4-methoxyphenyl)-2-phenoxypropyl]aziridine 4d,
which was purified by means of column chromatography on silica
gel (hexane/EtOAc 4/1).
cis-1-(2-Chloroethyl)-3-methoxy-4-phenylazetidin-2-one
3l.
Yellow crystals. Recrystallization from EtOH. Yield 93%. Mp.
61.8 ◦C. 1H NMR (300 MHz, CDCl3): d 3.12 (3H, s, OMe); 3.23
(1H, d × d × d, J = 14.6, 7.2, 5.2 Hz, (HCH)N); 3.50 (1H, d ×
d × d, J = 11.3, 6.3, 5.2 Hz, (HCH)Cl); 3.62 (1H, d × d × d,
J = 11.3, 7.2, 5.3 Hz, (HCH)Cl); 3.83 (1H, d × d × d, J = 14.6,
6.3, 5.3 Hz, (HCH)N); 4.77 (1H, d, J = 4.5 Hz, OCH); 4.91
(1H, d, J = 4.5 Hz, NCH); 7.34–7.44 (5H, m, CHarom). 13C NMR
(75 MHz, ref = CDCl3): d 41.4 and 41.9 (NCH2CH2Cl); 58.3
1-(3-Hydroxy-2-phenoxy-1-phenylpropyl)aziridine 4a. Color-
less crystals. Rf = 0.07 (hexane/EtOAc 4/1). Yield 65%. Mp.
106.2 ◦C. 1H NMR (300 MHz, CDCl3): d 1.11 (1H, d × d,
J = 7.2, 4.4 Hz, (HCH)N(HCH)); 1.62 (1H, d × d, J =
7.2, 4.2 Hz, (HCH)N(HCH)); 1.75 (1H, d × d, J = 5.7,
4.2 Hz, (HCH)N(HCH)); 2.02 (1H, d × d, J = 5.7, 4.4 Hz,
(HCH)N(HCH)); 2.87 (1H, d, J = 5.8 Hz, NCH); 3.15 (1H,
broad s, OH); 3.52 and 3.71 (2H, 2 × d × d, J = 11.6, 5.8, 4.7 Hz,
(HCH)OH); 4.73–4.79 (1H, m, OCH); 6.96–7.06 and 7.26–7.45
(3H and 7H, 2 × m, CHarom). 13C NMR (75 MHz, ref = CDCl3):
d 26.2 and 30.2 (2 × NCH2); 61.9 (CH2OH); 75.0 (NCH); 80.0
(OCH); 116.1 (2 × O(HC)ortho); 121.5 (O(HC)para); 127.9, 128.3,
128.4 and 129.8 (2 × O(HC)meta and 5 × HCarom); 138.6 (NCHCquat);
158.2 (OCquat). IR (KBr, cm−1): mOH = 3206; mmax = 2931, 2844, 1596,
1585, 1492, 1242, 1012, 763, 695. MS (70 eV): m/z (%) 270 (M+
+ 1, 100). Anal. Calcd for C17H19NO2: C 75.81, H 7.11, N 5.20.
Found: C 75.39, H 7.19, N 5.35.
(OMe); 62.9 (NCH); 85.9 (OCH); 128.5, 128.6 and 129.0 (5 ×
−1
=
HCarom); 133.5 (NCHCquat); 167.5 (C O). IR (KBR, cm ): mC=
=
O
1744; mmax = 2948, 1399, 1364, 1202, 1100, 998, 881, 702. 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 60.31, H 6.08 N 5.70.
cis-3-Benzyloxy-1-(2-chloroethyl)-4-phenylazetidin-2-one 3m.
Yellow crystals. Recrystallization from EtOH. Yield 88%. Mp.
◦
1
106.4 C. H NMR (300 MHz, CDCl3): d 3.23 (1H, d × d ×
d, J = 14.6, 7.1, 5.2 Hz, (HCH)N); 3.49 (1H, d × d × d, J =
11.4, 6.4, 5.2 Hz, (HCH)Cl); 3.61 (1H, d × d × d, J = 11.4, 7.1,
5.3 Hz, (HCH)Cl); 3.83 (1H, d × d × d, J = 14.6, 6.4, 5.3 Hz,
(HCH)N); 4.16 (1H, d, J = 11.2 Hz, (HCH)O); 4.30 (1H, d, J =
11.2 Hz, (HCH)O); 4.90 (1H, d, J = 4.4 Hz, NCH); 4.95 (1H, d,
J = 4.4 Hz, OCH); 6.91–6.94, 7.19–7.22 and 7.35–7.41 (2H, 3H
and 5H, 3 × m, CHarom). 13C NMR (75 MHz, ref = CDCl3): d
41.4 and 42.0 (NCH2CH2Cl); 63.1 (NCH); 72.4 (OCH2Ar); 83.9
1-(3-Hydroxy-2-methoxy-1-phenylpropyl)aziridine 4f. Colour-
less oil. Rf = 0.03 (hexane/EtOAc 3/1). Yield 70%. 1H
NMR (300 MHz, CDCl3): d 1.09 (1H, d × d, J = 7.0,
4.3 Hz, (HCH)N(HCH)); 1.59 (1H, d × d, J = 7.0, 4.3 Hz,
(OCH); 128.1, 128.3, 128.4, 128.7 and 129.0 (10 × HCarom); 133.7
−1
=
(NCHCquat); 136.4 (OCH2Cquat); 167.4 (C O). IR (KBR, cm ):
mC= = 1761; mmax = 2905, 1400, 1365, 1171, 1099, 1008, 880, 752,
O
(HCH)N(HCH)); 1.73 (1H,
(HCH)N(HCH)); 2.07 (1H,
d
d
×
×
d,
d,
J
J
=
=
5.9, 4.3 Hz,
5.9, 4.3 Hz,
700. MS (70 eV): m/z (%) 316/8 (M+ + 1, 100). Anal. Calcd for
C18H18ClNO2: C 68.46, H 5.75 N 4.44. Found C 68.26, H 5.94 N
4.29.
(HCH)N(HCH)); 2.66 (1H, d, J = 5.7 Hz, NCH); 3.06 (1H,
broad s, OH); 3.33–3.39 (1H, m, (HCH)OH); 3.53 (1H, d × d,
J = 11.5, 5.7 Hz, (HCH)OH); 3.60–3.66 (1H, m, OCH); 7.27–
7.40 (5H, m, CHarom). 13C NMR (75 MHz, ref = CDCl3): 26.0
and 30.2 (2 × NCH2); 58.9 (OMe); 61.6 (CH2OH); 75.5 (NCH);
84.1 (OCH); 127.7, 128.2 and 128.3 (5 × HCarom); 139.2 (Cquat). IR
(NaCl, cm−1): mOH = 3301; mmax = 2928, 1452, 1362, 1261, 1116,
1066, 752, 700. MS (70 eV): m/z (%) 208 (M+ + 1, 100). Anal.
Calcd for C12H17NO2: C 69.54, H 8.27, N 6.76. Found C 69.75, H
8.42, N 6.52.
cis-4-(4-Chlorophenyl)-3-phenoxy-1-propylazetidin-2-one
11.
Yellow crystals. Recrystallization from EtOH. Yield 89%. Mp.
102.1 ◦C. 1H NMR (300 MHz, CDCl3): d 0.91 (3H, t, J = 7.4 Hz,
CH3); 1.43–1.59 (2H, m, CH2CH3); 2.89–2.98 and 3.40–3.50 (2 ×
1H, 2 × m, (HCH)N); 4.91 (1H, d, J = 4.4 Hz, NCH); 5.43 (1H, d,
J = 4.4 Hz, OCH); 6.71–6.75, 6.87–6.98, 7.10–7.17 and 7.23–7.28
(2H, 1H, 2H and 4H, 4 × m, CHarom). 13C NMR (75 MHz, ref =
CDCl3): d 11.7 (CH3); 20.9 (CH2CH3); 42.4 (NCH2); 61.7 (NCH);
81.8 (OCH); 115.5 (2 × O(HC)ortho); 122.2 (O(HC)para); 128.6,
129.4 and 130.0 (2 × O(HC)meta and 2 × Cl(HC)ortho(HC)meta);
132.0 and 134.7 (NCHCquat and ClCquat); 156.8 (OCquat); 165.9
1-(2-Benzyloxy-3-hydroxy-1-phenylpropyl)aziridine
4g.
Colourless oil. Rf
=
0.05 (hexane/EtOAc 3/1). Yield
72%. 1H NMR (300 MHz, CDCl3): d 1.08 (1H, d × d,
1194 | Org. Biomol. Chem., 2008, 6, 1190–1196
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J = 7.1, 4.3 Hz, (HCH)N(HCH)); 1.55 (1H, d × d, J =
7.1, 4.3 Hz, (HCH)N(HCH)); 1.72 (1H, d × d, J = 5.9,
4.3 Hz, (HCH)N(HCH)); 2.05 (1H, d × d, J = 5.9, 4.3 Hz,
(HCH)N(HCH)); 2.67 (1H, d, J = 5.8 Hz, NCH); 3.00 (1H,
broad s, OH); 3.35–3.41 (1H, m, (HCH)OH); 3.53 (1H, d × d,
J = 11.4, 5.8 Hz, (HCH)OH); 3.88 (1H, q, J = 5.8 Hz, OCH);
4.67 (1H, d, J = 11.6 Hz, O(HCH)Ar); 4.82 (1H, d, J = 11.6 Hz,
O(HCH)Ar); 7.27–7.42 (10H, m, CHarom). 13C NMR (75 MHz,
ref = CDCl3): d 26.0 and 30.4 (2 × NCH2); 62.0 (CH2OH);
73.1 (OCH2Ar); 75.9 (NCH); 82.0 (OCH); 127.7, 127.9, 127.9,
128.3 and 128.6 (10 × HCarom); 138.5 and 139.3 (2 × Cquat). IR
(NaCl, cm−1): mOH = 3306; mmax = 2868, 1453, 1355, 1260, 1110,
1055, 735, 697. MS (70 eV): m/z (%) 284 (M+ + 1, 100). Anal.
Calcd for C18H21NO2: C 76.29, H 7.47, N 4.94. Found C 76.48, H
7.67, N 4.79.
of the solvent afforded 3-[N-benzyl-N-(2-bromoethyl)amino]-2-
phenoxy-3-phenylpropan-1-ol 7a, which was purified by means of
column chromatography on silica gel (hexane/EtOAc 9/1).
3-[N-Benzyl-N-(2-bromoethyl)amino]-2-phenoxy-3-phenylpro-
pan-1-ol 7a. Yellow oil. Rf = 0.07 (hexane/EtOAc 9/1).
1
Yield 86%. H NMR (300 MHz, CDCl3): d 2.67–2.76 (1H, m,
N(HCH)CH2Br); 3.07–3.24 (2H, m, CH2Br); 3.28–3.38 (1H, m,
N(HCH)CH2Br); 3.43 (1H, d, J = 13.7 Hz, N(HCH)Ar); 3.56
and 3.86 (2H, 2 × d × d, J = 11.9, 4.6, 4.4 Hz, (HCH)O); 3.93
(1H, d, J = 13.7 Hz, N(HCH)Ar); 4.09 (1H, d, J = 6.3 Hz,
NCH); 4.78–4.83 (1H, m, OCH); 6.89–7.10 and 7.19–7.59 (3H
and 12H, 2 × m, CHarom). 13C NMR (75 MHz, ref = CDCl3):
d 30.7 (CH2Br); 53.7 (NCH2CH2Br); 56.6 (NCH2Ar); 62.6
(CH2OH); 65.2 (NCH); 79.1 (OCH); 116.2 (2 × O(HC)ortho); 121.6
(O(HC)para); 127.5, 128.1, 128.6, 128.7, 129.0, 129.5 and 129.9
(2 × O(HC)meta and 10 × HCarom); 136.3 and 139.4 (NCHCquat and
NCH2Cquat); 158.2 (OCquat). IR (NaCl, cm−1): mOH = 3271; mmax
=
Synthesis of 1-[1-(4-chlorophenyl)-3-methoxy-2- phenoxypropyl]-
aziridine 6
3029, 2959, 2874, 1597, 1494, 1454, 1233, 1048, 756, 696. MS
(70 eV): m/z (%) 360 (M+ − Br, 100). Anal. Calcd for C24H26-
BrNO2: C 65.46, H 5.95, N 3.18. Found: C 65.69, H 6.14, N 2.99.
To an ice-cooled solution of 1-[1-(4-chlorophenyl)-3-hydroxy-2-
phenoxypropyl]aziridine 4b (0.25 g, 0.8 mmol) in THF (5 mL)
was added NaH (0.05 g, 1.5 equiv, 60% dispersion in mineral oil)
and the mixture was stirred for 30 minutes at room temperature.
Subsequently MeI (0.13 g, 1.1 equiv) was added dropwise to the
ice-cooled reaction mixture, which was then refluxed for 3 hours.
Extraction with Et2O (3 × 10 mL), drying (MgSO4), filtration of
the drying agent and removal of the solvent in vacuo afforded 1-[1-
(4-chlorophenyl)-3-methoxy-2-phenoxypropyl]aziridine 6 (0.23 g,
88%), which was purified by means of column chromatography on
silica gel (hexane/EtOAc 6/1).
Synthesis of 3-aryl-3-[N-(2-chloroethyl)amino]-2-phenoxypropan-
1-ols 8
As
a
representative example, the synthesis of 3-[(2-
chloroethyl)amino]-3-(4-methoxyphenyl)-2-phenoxypropan-1-ol
8d is described here. To a suspension of AlCl3 (15 mmol, 1
equiv) in dry diethyl ether (120 mL) was added 1-[3-hydroxy-
1-(4-methoxyphenyl)-2-phenoxypropyl]aziridine 4d (15 mmol,
1 equiv), and the resulting mixture was heated under reflux
for 4 hours. Afterwards, the reaction mixture was poured into
water (100 mL), extracted with Et2O (3 × 50 mL), and the
combined organic extracts were dried (MgSO4). Filtration of
the drying agent and removal of the solvent afforded 3-[(2-
chloroethyl)amino]-3-(4-methoxyphenyl)-2-phenoxypropan-1-ol
8d, which was purified by column chromatography on silica gel
(hexane/EtOAc 6/1).
1-[1-(4-Chlorophenyl)-3-methoxy-2-phenoxypropyl]aziridine 6.
Colorless oil. Rf = 0.14 (hexane/EtOAc 6/1). Yield 88%.
1H NMR (300 MHz, CDCl3): d 1.02 (1H, d × d, J =
7.0, 4.3 Hz, (HCH)N(HCH)); 1.64 (1H, d × d, J = 5.6,
4.3 Hz, (HCH)N(HCH)); 1.70 (1H, d × d, J = 7.0, 4.3 Hz,
(HCH)N(HCH)); 1.97 (1H,
d
×
d,
J
=
5.6, 4.3 Hz,
(HCH)N(HCH)); 2.79 (1H, d, J = 6.5 Hz, NCH); 3.12 (1H, d ×
d, J = 10.4, 5.0 Hz, (HCH)OMe); 3.26 (3H, s, OMe); 3.65 (1H,
d × d, J = 10.4, 3.2 Hz, (HCH)OMe); 4.64 (1H, d × d × d, J =
6.5, 5.0, 3.2 Hz, OCH); 6.94–7.05 and 7.26–7.40 (3H and 6H, 2 ×
m, CHarom). 13C NMR (75 MHz, ref = CDCl3): d 25.3 and 30.5
(2 × NCH2); 59.3 (OMe); 71.6 and 73.7 (CH2OMe and NCH);
81.9 (OCH); 116.5 (2 × O(HC)ortho); 121.5 (O(HC)para); 128.6 and
129.7 (2 × O(HC)meta and 2 × Cl(HC)ortho(HC)meta); 133.5 and 138.4
3-[(2-Chloroethyl)amino]-2-phenoxy-3-phenylpropan-1-ol
8a.
1
Light-yellow oil. Rf = 0.13 (hexane/EtOAc 4/1). Yield 51%. H
NMR (300 MHz, CDCl3): d 2.77 (2H, t, J = 5.7 Hz, NCH2);
3.26 (2H, broad s, NH and OH); 3.42–3.62 (3H, m, CH2Cl and
(HCH)OH); 3.80 (1H, d × d, J = 11.8, 3.4 Hz, (HCH)OH); 4.13
(1H, d, J = 6.0 Hz, NCH); 4.35 (1H, d × t, J = 6.0, 3.4 Hz,
OCH); 6.92–7.08 and 7.20–7.42 (4H and 6H, 2 × m, CHarom). 13
C
NMR (75 MHz, ref = CDCl3): d 44.8 (CH2Cl); 48.4 (NCH2); 62.2
(CH2OH); 64.0 (NCH); 82.3 (OCH); 116.9 (2 × O(HC)ortho); 122.0
(O(HC)para); 128.2, 128.9, 129.8 and 129.9 (5 × HCarom and 2 ×
O(HC)meta); 139.4 (NCHCquat); 158.2 (OCquat). IR (NaCl, cm−1):
mOH, NH = 3338; mmax = 3063, 2929, 1597, 1587, 1493, 1455, 1235,
1040, 754, 693. MS (70 eV): m/z (%) 306/8 (M+ + 1, 100). Anal.
Calcd for C17H20ClNO2: C 66.67, H 6.59, N 4.58. Found: C 66.89,
H 6.82, N 4.62.
(ClCquat and NCHCquat); 158.6 (OCquat). IR (NaCl, cm−1): mmax
=
2923, 1597, 1489, 1234, 1088, 1013, 752, 691. MS (70 eV): m/z (%)
318/20 (M+ + 1, 100). Anal. Calcd for C18H20ClNO2: C 68.03, H
6.34, N 4.41. Found: C 68.21, H 6.55, N 4.58.
Synthesis of 3-aryl-3-[N-benzyl-N-(2-bromoethyl)amino]-2-pheno-
xypropan-1-ols 7
As a representative example, the synthesis of 3-[N-benzyl-
N-(2-bromoethyl)amino]-2-phenoxy-3-phenylpropan-1-ol 7a is
described here. To a solution of 1-(3-hydroxy-2-phenoxy-1-
phenylpropyl)aziridine 4a (1 mmol) in acetonitrile (10 mL) was
added benzyl bromide (1 mmol, 1 equiv), and the resulting
mixture was heated under reflux for 24 hours. Evaporation
Synthesis of 3-aryl-2-phenoxy-3-(N-propylamino)propan-1-ols 9
3-Aryl-2-phenoxy-3-(N-propylamino)propan-1-ols 9 were pre-
pared starting from 4-aryl-3-phenoxy-1-(3-bromopropyl)azetidin-
2-ones 3f–j applying the same procedure as described above for the
synthesis of 1-(1-aryl-3-hydroxy-2-phenoxypropyl)aziridines 4.
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2-Phenoxy-3-phenyl-3-(N-propylamino)propan-1-ol 9a. Light-
yellow oil. Rf = 0.12 (hexane/EtOAc 4/1). Yield 37%. 1H NMR
(300 MHz, CDCl3): d 0.80 (3H, t, J = 7.4 Hz, CH3); 1.34–1.49
(2H, m, CH2CH3); 2.31–2.41 (2H, m, NCH2); 3.65 and 3.82 (2 ×
1H, 2 × d × d, J = 12.0, 3.6, 2.8 Hz, (HCH)O); 4.02 (1H, d, J =
4.4 Hz, NCH); 4.22–4.28 (1H, m, OCH); 6.70–6.92 and 7.04–7.32
(3H and 7H, 2 × m, CHarom). 13C NMR (75 MHz, ref = CDCl3):
d 11.9 (CH3); 23.2 (CH2CH3); 49.2 (NCH2); 63.1 (CH2OH); 65.2
(NCH); 81.1 (OCH); 117.0 (2 × O(HC)ortho); 121.9 (O(HC)para);
127.9, 128.0, 128.7 and 129.7 (2 × O(HC)meta and 5 × HCarom);
139.9 (NCHCquat); 158.0 (OCquat). IR (NaCl, cm−1): mOH, NH = 3351;
mmax = 2958, 2930, 2873, 1598, 1588, 1494, 1455, 1239, 1041, 753,
701, 692. MS (70 eV): m/z (%) 286 (M+ + 1, 100). Anal. Calcd for
C18H23NO2: C 75.76, H 8.12, N 4.91. Found: C 75.92, H 8.29, N
5.14.
1970, 11, 3365; (c) B. K. Banik, K. J. Barakat, D. R. Wagle, M. S.
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14 For a few recent examples, see: (a) G. A. Holloway, J. B. Baell, A. H.
Fairlamb, P. M. Novello, J. P. Parisot, J. Richardson, K. G. Watson
and I. P. Street, Bioorg. Med. Chem. Lett., 2007, 17, 1422; (b) J. L.
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Gu, M. Ahmadian, D. E. Baty, M. R. Etling, C. H. Al-Anzi, T. M.
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Acknowledgements
The authors are indebted to the “Fund for Scientific Research –
Flanders (Belgium)” (F.W.O.-Vlaanderen) and to Ghent Univer-
sity (GOA) for financial support.
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