Transformation of trans -4-aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones into 3-aryl-2-(ethylamino)propan-1-ols via intermediate 1-(1-aryl-2-chloro-3- hydroxypropyl)aziridines and trans -2-aryl-3-(hydroxymethyl)aziridines

Article abstract of DOI:10.1021/jo1020932

trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were unexpectedly transformed into 3-aryl-2-(ethylamino) propan-1-ols using LiAlH₄

Full text of DOI:10.1021/jo1020932

pubs.acs.org/joc
Transformation of trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-
2-ones into 3-Aryl-2-(ethylamino)propan-1-ols via Intermediate
1-(1-Aryl-2-chloro-3-hydroxypropyl)aziridines and trans-2-Aryl-
3-(hydroxymethyl)aziridines
Karen Mollet,† Matthias D’hooghe,* and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering,
Ghent University, Coupure links 653, B-9000 Ghent, Belgium. Aspirant of the Fund for Scientific
Research-Flanders (FWO-Vlaanderen).
†
matthias.dhooghe@UGent.be; norbert.dekimpe@UGent.be
Received October 22, 2010
trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones, prepared through cyclocondensation of chloro-
ketene and the appropriate imines in a diastereoselective way, were unexpectedly transformed into
3-aryl-2-(ethylamino)propan-1-ols using LiAlH4 in THF under reflux. A stepwise analysis showed
that the initially formed 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines were converted into trans-2-aryl-
3-(hydroxymethyl)aziridines, most probably via N-spiro bis-aziridinium intermediates, which were
subsequently prone to undergo ring opening by LiAlH4 to afford 3-aryl-2-(ethylamino)propan-1-ols.
Introduction
and timolol 3 are used for treating abnormal heart rhythm,
high blood pressure, heart failure, and angina.2
The synthesis of β-amino alcohols merits considerable
attention since these compounds play an important role in
synthetic organic chemistry, for example, as auxiliaries and
ligands in asymmetric synthesis.1 The two heteroatoms allow
great flexibility, as one or both can be bound to a Lewis acid,
transition metal, or achiral starting material.1 In addition, a
variety of β-amino alcohols exhibits various pharmacological
properties, and the β-amino alcohol moiety is present as a key
structural unit in different biologically active compounds.
For example, the β-blockers propranolol 1, metoprolol 2,
Apart from their relevance as potential β-lactam anti-
biotics,3 azetidin-2-ones have also been recognized as valu-
able and flexible synthons for further elaboration toward a
large variety of nitrogen-containing compounds (“β-lactam
synthon method”).4 In particular, azetidin-2-ones bearing
(1) (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
2000, 100, 2159. (b) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467.
(c) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767.
(d) Sutcliffe, O. B.; Bryce, M. R. Tetrahedron: Asymmetry 2003, 14, 2297.
(e) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
(f) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151.
264 J. Org. Chem. 2011, 76, 264–269
Published on Web 12/06/2010
DOI: 10.1021/jo1020932
r
2010 American Chemical Society

Mollet et al.
JOCArticle
SCHEME 1
TABLE 1. Synthesis of N-(Arylmethylidene)-(2-chloroethyl)amines 5
and trans-4-Aryl-3-chloro-1-(2-chloroethyl)-β-lactams 6
halogenated side chains are very useful starting materials for
rearrangements as a result of their high intrinsic reactivity, which
is based on the combination of a strained four-membered
ring, a nucleophilic nitrogen (after elaboration), and a halo-
genated carbon atom. In that respect, intensive research on
the synthetic applicability of the mainly unexplored class of
4-(haloalkyl)azetidin-2-ones has resulted in the efficient and
diastereoselective preparation of a broad variety of functio-
nalized azaheterocycles, including aziridines, azetidines, piper-
idines, pyrrolidines, azepanes, pyrrolidin-2-ones, oxolanes,
bicyclic β-lactams, and bicyclic γ-lactams.5
entry
R
compound 5 (yield) compound 6 (yield)a cis/trans (6)b
1
2
3
4
4-Me
H
4-Cl
3-OMe
5a (79%)
5b (87%)
5c (79%)
5d (84%)
6a (75%)
6b (60%)
6c (69%)
6d (66%)
3/97
3/97
5/95
5/95
aAfter purification by column chromatography (SiO2). bBased on 1H
NMR analysis of the reaction mixture.
SCHEME 2
One of the most straightforward transformations of β-lactams
comprises their reductive ring opening toward γ-amino alcohols.6
The presence of halogenated carbon atoms in these sub-
strates is of synthetic relevance, as this can lead to further
rearrangements toward azaheterocyclic compounds. In pre-
vious work, we have demonstrated the applicability of
halogen-containing β-lactams for the construction of stereode-
fined aziridines upon treatment with LiAlH4, e.g., the conversion
of N-(2-chloroethyl)azetidin-2-ones into 1-(3-hydroxypropyl)-
aziridines6e and the reductive ring contraction of 3-chloro-
β-lactams into 3-(hydroxymethyl)aziridines.6g However, up to
now, the reactivity of halogenated β-lactams bearing a halo-
genated side chain toward LiAlH4 has not been explored.
TABLE 2. Transformation of trans-4-Aryl-3-chloro-1-(2-chloroethyl)-
β-lactams 6 into 3-Aryl-2-(ethylamino)propan-1-ols 7
entry
R
compound (yield)a
1
2
3
4
4-Me
H
4-Cl
3-OMe
7a (61%)
7b (70%)
7c (65%)
7d (68%)
aAfter recrystallization from hexane/EtOAc (1/30).
(2) (a) Hansteen, V.; Moinichen, E.; Lorentsen, E.; Andersen, A.; Strom,
O.; Soiland, K.; Dyrbekk, D.; Refsum, A. M.; Tromsdal, A.; Knudsen, K.;
Eika, C.; Bakken, J.; Smith, P.; Hoff, P. I. Brit. Med. J. 1982, 284, 155.
(b) Narimatsu, S.; Arai, T.; Watanabe, T.; Masubuchi, Y.; Horie, T.; Suzuki,
T.; Ishikawa, T.; Tsutsui, M.; Kumagai, Y.; Cho, A. K. Chem. Res. Toxicol.
1997, 10, 289. (c) Aubriot, S.; Nicolle, E.; Lattier, M.; Morel, C.; Cao, W.;
Daniel, K. W.; Collins, S.; Leclerc, G.; Faure, P. Bioorg. Med. Chem. Lett.
2002, 12, 209. (d) Dasbiswas, A.; Shinde, S.; Dasbiswas, D. J. Indian Med.
Assoc. 2008, 106, 259.
(3) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr. Med.
Chem. 2004, 11, 1837. (b) De Kimpe, N. In Comprehensive Heterocyclic
Chemistry II; Pergamon: Oxford, 1996; Vol. 1B, p 507. (c) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. In Comprehensive Heterocyclic Chemistry III;
Elseviere Science: New York, 2008; Vol. 2, p 1.
(4) (a) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377. (b) Alcaide,
B.; Almendros, P. Synlett 2002, 381. (c) Fisher, J. F.; Meroueh, S. O.;
Mobashery, S. Chem. Rev. 2005, 105, 395. (d) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437. (e) Ojima, I. Acc. Chem. Res.
1995, 28, 383. (f) Singh, G. S. Tetrahedron 2003, 59, 7631.
(5) (a) D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe, N. Pure
Appl. Chem. 2010, 82, 1749. (b) Lee, E.; Kim, S. K.; Kim, J. Y.; Lim,
J. Tetrahedron Lett. 2000, 41, 5915. (c) Dekeukeleire, S.; D’hooghe,
In this paper, the applicability of trans-4-aryl-3-chloro-
1-(2-chloroethyl)azetidin-2-ones regarding their treatment
with lithium aluminum hydride was evaluated for the first
time. The chemistry of 3-chloro-β-lactams comprises a mainly
unexplored field in the literature, although these compounds
are very useful substrates for further elaboration due to their
unique synthetic properties, e.g., dehalogenation toward
3-unsubstituted azetidinones7 and conversion into different
3-substituted azetidines.8 In addition, the use of N-(ω-haloalkyl)-
β-lactams has been studied to a very limited extent, for
example, toward the synthesis of 1,4-diazepan-5-ones,9 bicyclic
β-lactams,5a,10 and aziridines.6e In this work, both structural
features were combined into a new type of substrate, i.e.,
3-chloro-1-(2-chloroethyl)-β-lactams, which were unexpectedly
transformed into 2-(ethylamino)propan-1-ols upon treat-
ment with LiAlH4 in THF under reflux through a number
of rearrangements.
€
M.; Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2010, 75, 5934.
(d) Van Brabandt, W.; De Kimpe, N. J. Org. Chem. 2005, 70, 3369.
(e) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett.
2006, 8, 1105. (f) Van Brabandt, W.; Dejaegher, Y.; Van Landeghem, R.;
De Kimpe, N. Org. Lett. 2006, 8, 1101.
(6) (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita, M.;
Abe, R. J. Org. Chem. 1991, 56, 5263. (b) Alcaide, B.; Aly, M. F.; Sierra,
M. A. Tetrahedron Lett. 1995, 36, 3401. (c) Speeter, M. E.; Maroney, W. H.
J. Am. Chem. Soc. 1954, 76, 5810. (d) Sammes, P. G.; Smith, S. J. Chem. Soc.,
Chem. Commun. 1983, 682. (e) D’hooghe, M.; Dekeukeleire, S.; De Kimpe,
N. Org. Biomol. Chem. 2008, 6, 1190. (f) D’hooghe, M.; Dekeukeleire, S.;
Mollet, K.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. J. Med.
Chem. 2009, 52, 4058. (g) D’hooghe, M.; Mollet, K.; Dekeukeleire, S.;
De Kimpe, N. Org. Biomol. Chem. 2010, 8, 607.
(7) Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Piersanti, G. Org.
Lett. 2000, 2, 1077.
(8) Van Driessche, B.; Van Brabandt, W.; D’hooghe, M.; Dejaegher, Y.;
De Kimpe, N. Tetrahedron 2006, 62, 6882.
(9) (a) Begley, M. J.; Crombie, L.; Haigh, D.; Jones, R. C. F.; Osborne, S.;
Webster, R. A. B. J. Chem. Soc., Perkin Trans. 1 1993, 2027. (b) Crombie, L.; Jones,
R. C. F.; Osborne, S.; Mat-Zin, A. R. J. Chem. Soc., Chem. Commun. 1983, 959.
(10) Van Brabandt, W.; Vanwalleghem, M.; D’hooghe, M.; De Kimpe,
N. J. Org. Chem. 2006, 71, 7083.
J. Org. Chem. Vol. 76, No. 1, 2011 265

Mollet et al.
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SCHEME 3
SCHEME 4
Results and Discussion
TABLE 3. Treatment of 1-[3-Hydroxy-1-(3-methoxyphenyl)-2-phenoxy]-
aziridine 12 with LiAlH4
The synthesis of trans-4-aryl-3-chloro-1-(2-chloroethyl)-
β-lactams, in which the two halogen atoms reside in both
cases in the β-position with respect to the nitrogen atom, was
accomplished by Staudinger’s ketene-imine cycloaddition
reaction. Thus, treatment of N-(arylmethylidene)-(2-chloro-
ethyl)amines 5, prepared via imination of different benzal-
dehydes 4 in dichloromethane in the presence of MgSO4 and
Et3N utilizing 1 equiv of 2-chloroethylamine hydrochloride,
with 1.5 equiv of chloroacetyl chloride and 3 equiv of 2,6-
lutidine in benzene gave the premised trans-4-aryl-3-chloro-
1-(2-chloroethyl)-β-lactams 6 (Scheme 1, Table 1).
molar equiv
LiAlH4
entry
solvent
temp time (h)
result
1
2
2
4
THF or Et2O rt
THF or Et2O reflux
48
48
no reaction
no reaction
followed by conrotatory ring closure will mostly afford the
thermodynamically more stable trans-β-lactams, while the use of
e.g. Bose-Evans ketenes (alkoxy ketenes) generally results in the
diaseteroselective formation of cis-β-lactams.12
In previous work, the reductive ring opening of azetidin-2-
ones by means of LiAlH4 has been described as an efficient
approach toward β- and γ-aminoalcohols.6 In analogy, trans-
4-aryl-3-chloro-1-(2-chloroethyl)-β-lactams 6 were treated
with 3 molar equiv of LiAlH4 in THF under reflux for 48 h,
resulting in full conversion of the starting material. Spectro-
scopic analysis of the obtained reaction products revealed
their molecular structure to be 3-aryl-2-(ethylamino)propan-
1-ols 7, quite unexpectedly (Scheme 2, Table 2). It should be
noted that although this class of β-amino alcohols is known
in the literature,13 the above-described methodology for the
selective preparation of these amino alcohols 7 is totally
different from the synthesis reported in the literature.13
In order to elucidate the mechanistic background of this
intriguing transformation, β-lactam 6a was subjected to dif-
ferent reaction conditions, involving variation of the reaction
time, solvent, and number of molar equivalents of LiAlH4.
First, trans-3-chloro-1-(2-chloroethyl)-4-(4-methylphenyl)-
β-lactam 6a was treated with 2 molar equiv of lithium aluminum
In accordance with previous results on β-lactam synthesis,6g,8
the latter β-lactams 6 were obtained stereoselectively (cis/
trans 3-5/95-97) after a reflux period of 15 h, and separa-
tion of both isomers was performed by means of column
chromatography on silica gel. The trans-selectivity could be
deduced on the basis of the 1H NMR spectra of β-lactams 6,
as the observed coupling constants between the 3-H and 4-H
protons varied between 1.1 and 2.0 Hz (CDCl3), which
corresponds well with those reported in the literature for
trans-β-lactams.11 It should be noted that dichlorinated
β-lactams 6 represent a novel class of substrates suitable
for further elaborations.
The stereochemical outcome of this Staudinger reaction
can be rationalized as follows. It is well-known that the specific
ketene substituent plays an important role in the diastereos-
electivity of the Staudinger reaction. When the ketene, in situ
generated from an acid chloride in the presence of a base, is
substituted with a chloro atom (Moore ketene), E/Z-isomeriza-
tion across the iminium bond of the zwitterionic intermediates
(12) (a) Xu, J. Arkivoc 2009, No. ix, 21. (b) Jiao, L.; Liang, Y.; Xu, J. X.
J. Am. Chem. Soc. 2006, 128, 6060.
(11) (a) Barrow, K. D.; Spotswood, T. M. Tetrahedron Lett. 1965, 6, 3325.
(b) Decazes, J.; Luche, J. L.; Kagan, H. B. Tetrahedron Lett. 1970, 11, 3361.
(13) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568.
266 J. Org. Chem. Vol. 76, No. 1, 2011

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SCHEME 5
SCHEME 6
hydride in diethyl ether under reflux for 2 h.6e This process
resulted in 1,2-fission of the amide bond, followed by intra-
molecular displacement of the chloride at the primary carbon
atom by the nucleophilic nitrogen, giving rise to the initially
expected 1-[2-chloro-3-hydroxy-1-(4-methylphenyl)]aziridine 9a.
Interestingly, next to the latter aziridine 9a, a substantial
amount of trans-1-ethyl-3-hydroxymethyl-2-(4-methylphenyl)-
aziridine 10a was observed in the crude reaction mixture as
well (Scheme 3, ratio 9a/10a = 70/30).6g
TABLE 4. Reduction of trans-3-Chloro-1-(2-chloroethyl)-4-(4-methyl-
phenyl)-β-lactam 6a in THF at Room Temperature
molar equiv
LiAlH4
entry
solvent
temp
time (h)
result
1
2
3
1
1
1
THF
THF
THF
rt
rt
rt
6
19
91
16a/9a = 55/45
16a/9a = 25/75
16a/9a = 13/87
TABLE 5. Transformation of trans-4-Aryl-3-chloro-1-(2-chloroethyl)-
β-lactams 6a,b into 1-(1-Aryl-2-chloro-3-hydroxypropyl)aziridines 9a,b
The unexpected formation of N-ethylaziridine 10a can be
rationalized in two ways. In a first approach, the nucleophilic
nitrogen in intermediate 8a, formed after cleavage of the amide
bond of β-lactam 6a, displaces the chloride at the secondary
carbon atom to afford aziridine 10a in a direct way (followed
by reductive removal of the chloro atom to furnish the
N-ethyl group). Since a primary electrophilic carbon atom is
more likely to be attacked than a secondary, this competition
could not explain the observed ratio (70/30). Alternatively, the
presence of the latter aziridine 10a can be explained by a possible
ring transformation of aziridine 9a. Considering the in situ
activation of the aziridine moiety by the Lewis acid character
of aluminum, aziridine 10a can be formed either by hydride-
induced aziridine ring opening followed by intramolecular
substitution of the chloro atom or by initial formation of a
N-spiro bis-aziridinium intermediate, which is subsequently
prone to undergo ring opening by hydride.
In order to shed light on the underlying mechanism, cis-
1-(2-chloroethyl)-4-(3-methoxyphenyl)-3-phenoxyazetidin-
2-one 11, prepared in 78% overall yield via imination followed
by the Staudinger reaction, was transformed into 1-[3-hydroxy-
1-(3-methoxyphenyl)-2-phenoxy]aziridine 12 upon treatment
with 2 molar equiv of LiAlH4 in diethyl ether under reflux.6e
Treatment of the latter aziridine 12 with LiAlH4 (2 or 4 molar
equiv) did not result in any conversion, and the starting material
was recovered completely after every attempt (Scheme 4,
Table 3). Obviously, aziridine 12 is highly reluctant to undergo
hydride-induced ring opening to furnish 3-(N-ethylamino)-
3-(3-methoxyphenyl)-2-phenoxypropan-1-ol 13, pointing to
a reaction mechanism involving the formation and consecu-
tive ring opening of N-spiro bis-aziridinium salt 14a for the
entry substrate
R
reaction conditions
compound (yield)a
1
2
6a
6b
4-Me 1 molar equiv LiAlH4,
THF, rt, 91 h
H
9a (40%)
1 molar equiv LiAlH4,
THF, rt, 91 h
9b (55%)
aAfter purification by column chromatography (SiO2).
conversion of aziridine 9a to aziridine 10a (Scheme 5). It
should be noted that although reaction mechanisms consistent
with the formation of bicyclic aziridinium salts are well-
known,5a,14 the occurrence of 1-azoniaspiro[2.2]pentanes 14
as such has not been described before in the literature, apart
from one paper in which the N-spiro bis-aziridinium ion is
suggested to be a stable and isolable molecule on the basis of
ab initio studies.15 Nonetheless, an alternative reaction mecha-
nism involving initial epoxide formation, followed by either
N-spiro bis-aziridinium formation and consecutive hydride-
induced ring opening, or hydride-promoted aziridine and epoxide
ring opening in a concerted manner, should not be excluded.
In order to prevent hydride-induced ring transformation
of aziridine 9a toward aziridine 10a, milder reaction condi-
tions were applied for the reduction of β-lactam 6a. Thus,
treatment of β-lactam 6a with 1 molar equiv of LiAlH4 in
THF at room temperature for 6-91 h afforded a mixture of
γ-aminoalcohol 16a and aziridine 9a in varying amounts
(14) (a) Durrat, F.; Sanchez, M. V.; Couty, F.; Evano, G.; Marrot, J. Eur.
J. Org. Chem. 2008, 19, 3286. (b) Graham, A.; Wadsworth, A. H.; Thornton-
Petta, M.; Rayner, C. M. Chem. Commun. 2001, 11, 966. (c) Abbaspour
Tehrani, K.; Van Syngel, K.; Boelens, M.; Contreras, J.; De Kimpe, N.;
Knight, D. W. Tetrahedron Lett. 2000, 41, 2507.
(15) Martinez, A.; Elguero, J.; Mo, O.; Yanez, M. J. Mol. Struct. 1994,
115, 45.
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SCHEME 7
SCHEME 8
TABLE 6. Reduction of trans-3-Chloro-1-(2-chloroethyl)-4-(4-methylphenyl)-β-lactam 6a under Different Reaction Conditions
entry
molar equiv LiAlH4
solvent
temp
time (h)
Resulta
yield (%)
1
2
3
4
5
6
7
8
1
2
2
2
2
2
2
2
2
2
3
3
3
3
4
THF
THF
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
THF
THF
reflux
reflux
rt
rt
rt
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
2
2
18
20
100
1
2
3
4
7
1
5
20
48
1
16a/9a/10a = 45/45/10
9a/10a = 72/28
9a/10a = 67/33
9a/10a = 62/38
9a/10a = 67/33
9a/10a = 73/27
9a/10a = 70/30
9a/10a = 62/38
9a/10a/7a = 48/33/19
10a/7a = 50/50
9a/10a = 71/29
9a/10a/7a = 58/22/20
10a/7a = 25/75
7a
80
85
81
82
75
68
72
87
83
65
69
79
82
82
73
9
10
11
12
13
14
15
10a/7a = 58/42
aBased on 1H NMR analysis of the reaction mixtures
(Scheme 6, Table 4). From a mechanistic point of view, these
results can be rationalized considering the conversion of
β-lactam 6a into aziridine 9a via intermediate γ-aminoalcohol
16a, as mentioned before. In this way, 1-(1-aryl-2-chloro-3-
hydroxypropyl)aziridines 9a,b were isolated in pure form
and in good yields after purification by column chromatog-
raphy on silica gel (Table 5). Interestingly, all four hydrogen
atoms of aziridines 9a,b were observed as separate doublets
of doublets with characteristic aziridine chemical shifts (1.05-
2.20 ppm, CDCl3). Also, spectroscopic analysis by 13C NMR
revealed different δ-values for the two aziridine carbon atoms
(25.22-25.28 ppm and 31.62-31.64 ppm, CDCl3). These
findings are in accordance with analogous results reported in
the literature for C-unsubstituted aziridines.6e,16
In the next stage, different attempts were made to tune
the reaction selectivity toward aziridine 10a starting from
β-lactam 6a upon treatment with LiAlH4 (Scheme 7, Table 6).
From the presented results, it can be deduced that although
complete conversion of aziridine 9a into aziridine 10a was
achieved by establishing more forcing reaction conditions,
the inherent reactivity of the intermediate 2-arylaziridine 10a
toward LiAlH4 resulted in fast ring opening toward β-amino
alcohol 7a at higher temperatures. In this transformation,
LiAlH4 is responsible for both the activation of the aziridine
ring, resulting in a considerable weakening of the C2-N bond
due to benzylic stabilization of the developing carbeniumion,
(16) Kim, H. Y.; Talukdar, A.; Cushman, M. Org. Lett. 2006, 8, 1085.
268 J. Org. Chem. Vol. 76, No. 1, 2011

Mollet et al.
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SCHEME 9
trans-3-Chloro-1-(2-chloroethyl)-4-(4-methylphenyl)azetidin-
2-one 6a. (75%) Yellow oil. Rf = 0.10 (hexane/EtOAc 6/1). 1H
NMR (CDCl3): δ 2.39 (3H, s); 3.20 (1H, ddd, J=14.6, 7.4, 5.2 Hz);
3.51-3.68 (2H, m); 3.84 (1H, ddd, J = 14.6, 6.1, 5.2 Hz); 4.54
and 4.70 (2H, 2ꢀd, J=1.6 Hz); 7.20-7.28 (4H, m). 13C NMR
(CDCl3): δ 21.2 (CH3); 41.3 (CH2); 42.7 (CH2); 63.3 (CH); 66.9
(CH); 126.7 (CH); 130.0 (CH); 131.6 (C); 139.8 (C); 164.1 (C).
IR (cm-1): νCdO =1767. MS: m/z (%) 258/60/2 (Mþ þ 1, 100).
Anal. Calcd for C12H13Cl2NO: C 55.83; H 5.08; N 5.43. Found:
C 55.70; H 5.46; N 5.47.
Synthesis of 1-(1-Aryl-2-chloro-3-hydroxypropyl)aziridines 9.
As a representative example, the synthesis of anti-1-[2-chloro-
3-hydroxy-1-(4-methylphenyl)propyl]aziridine 9a is described
here. To an ice-cooled solution of trans-3-chloro-1-(2-chloro-
ethyl)-4-(4-methylphenyl)azetidin-2-one 6a (8 mmol) in THF
(50 mL) was added LiAlH4 (8 mmol, 1 molar equiv) in small
portions. Subsequently, the resulting suspension was stirred at
room temperature for 91 h, after which water (10 mL) was added
cautiously at 0 °C in order to neutralize the excess of LiAlH4.
Afterward, the mixture was filtered through a pad of Celite, and
the filtrate was dried over MgSO4. Removal of the drying agent
through filtration and evaporation of the solvent in vacuo
afforded anti-1-[2-chloro-3-hydroxy-1-(4-methylphenyl)propyl]-
aziridine 9a, which was purified by column chromatography
on silica gel (hexane/EtOAc 3/2).
anti-1-[2-Chloro-3-hydroxy-1-(4-methylphenyl)propyl]aziridine
9a. (40%) White crystals. Mp=68.7 °C. Rf=0.06 (hexane/EtOAc
3/2). 1H NMR (CDCl3): δ 1.05 (1H, dd, J=6.5, 4.4 Hz); 1.76 (1H,
dd, J=5.7, 4.1 Hz); 1.80 (1H, dd, J=6.5, 4.1 Hz);2.18 (1H, dd, J=
5.7, 4.4 Hz); 2.36 (3H, s); 3.00 (1H, d, J=4.4 Hz); 3.77-3.84 (1H,
m); 4.08 (1H, d, J = 12.7 Hz); 4.16-4.22 (2H, m); 7.18 and 7.28
(4H, 2 ꢀ d, J = 8.2 Hz). 13C NMR (CDCl3): δ 21.2 (CH3); 25.2
(CH2); 31.6 (CH2); 63.8 (CH2); 66.1 (CH); 76.9 (CH); 127.7 (CH);
129.2 (CH); 136.5 (C); 137.8 (C). IR (cm-1): νOH =3188. MS: m/z
(%) 226/8 (Mþ þ 1, 100). Anal. Calcd for C12H16ClNO: C 63.85; H
7.14; N 6.21. Found: C 63.62; H 7.54; N 6.41.
TABLE 7. Transformation of 1-(1-Aryl-2-chloro-3-hydroxypropyl)-
aziridines 9a,b into 3-Aryl-2-(ethylamino)propan-1-ols 7a,b
entry
R
compound (yield)
1
2
4-Me
H
7a (91%)
7b (93%)
and for the delivery of the nucleophilic hydride, which subse-
quently induces ring opening in a regioselective manner.6g
Moreover, an additional activation by an internal hydrogen
bond between the hydroxyl group and the aziridine nitrogen
atom facilitates the ring opening toward β-amino alcohol 7a.17
These detailed experiments finally culminated in a straight-
forward and efficient synthesis of 3-aryl-2-(ethylamino)propan-1-
ols 7 from trans-4-aryl-3-chloro-1-(2-chloroethyl)-β-lactams 6
upon treatment with 3 molar equiv of LiAlH4 in THF under
reflux for 48 h (Table 6, entry 14) through formation and sub-
sequent conversion of intermediates 8, 17, 14, and 15 (Scheme 8).
To provide additional evidence for this reaction mecha-
nism, 3-aryl-2-(ethylamino)propan-1-ols 7a,b were synthe-
sized in excellent yields by reduction of 1-(1-aryl-2-chloro-3-
hydroxypropyl)aziridines 9a,b using 3 molar equiv of LiAlH4 in
THF under reflux for 48 h (Scheme 9, Table 7).
In conclusion, a number of 3-aryl-2-(ethylamino)propan-
1-ols were synthesized in an efficient way by reduction of
the corresponding trans-4-aryl-3-chloro-1-(2-chloroethyl)-
β-lactams using LiAlH4 in THF under reflux. This reaction
proceeded through an unexpected conversion of the initially
formed 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines into
trans-2-aryl-1-ethyl-3-(hydroxymethyl)aziridines via N-spiro
bis-aziridinium salts. The intermediacy of N-spiro bis-
aziridinium salts was thus reported for the first time. Alter-
natively, reduction of the starting compounds by LiAlH4
in THF at room temperature afforded 1-(1-aryl-2-chloro-
3-hydroxypropyl)aziridines in good yields.
Synthesis of 3-aryl-2-(ethylamino)propan-1-ols 7. As a repre-
sentative example, the synthesis of 2-(N-ethylamino)-3-(4-methyl-
phenyl)propan-1-ol 7a is described here. To an ice-cooled solution
of trans-3-chloro-1-(2-chloroethyl)-4-(4-methylphenyl)azetidin-2-
one 6a (2 mmol) in THF (30 mL) was added LiAlH4 (6 mmol,
3 molar equiv) in small portions. Subsequently, the resulting
suspension was heated under reflux for 48 h, after which water
(5 mL) was added cautiously at 0 °C in order to neutralize the excess
of LiAlH4. Afterward, the mixture was filtered through a pad of
Celite, and the filtrate was dried over MgSO4. Removal of the drying
agent through filtration and evaporation of the solvent in vacuo
afforded 2-(N-ethylamino)-3-(4-methylphenyl)propan-1-ol 7a, which
was purified by recrystallization from EtOAc/hexane (1/30).
2-(N-Ethylamino)-3-(4-methylphenyl)propan-1-ol 7a. (61%)
White crystals. Mp=102.3 °C. Recrystallization from EtOAc/
Experimental Section
Synthesis of trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-
2-ones 6. As a representative example, the synthesis of trans-3-
chloro-1-(2-chloroethyl)-4-(4-methylphenyl)azetidin-2-one 6a is
described here. To a solution of N-(4-methylphenylmethylidene)-
(2-chloroethyl)amine 5a (10 mmol) in dry benzene (50 mL) was
added 2,6-lutidine (30 mmol, 3 equiv), and the resulting mixture
was heated under reflux. Immediately thereafter, chloroacetyl
chloride (15 mmol, 1.5 equiv) was added to the boiling mixture,
followed by a reflux period of 15 h. Afterward, the resulting
suspension was filtered in order to remove 2,6-lutidine hydro-
chloride, after which the filtrate was washed with an aqueous
solution of 1 M HCl (2ꢀ15 mL). The organic phase was dried over
MgSO4, followed by removal of the drying agent and evapora-
tion of the solvent in vacuo. Purification by means of column
chromatography on silica gel (hexane/EtOAc 6/1) afforded pure
trans-3-chloro-1-(2-chloroethyl)-4-(4-methylphenyl)azetidin-2-one 6a.
1
hexane (1/30). H NMR (CDCl3): δ 1.05 (3H, t, J = 7.2 Hz);
1.80 (2H, s(broad)); 2.33 (3H, s); 2.59-2.78 (4H, m); 2.84-2.92
(1H, m); 3.29 and 3.60 (2H, 2ꢀdd, J=10.5, 5.5, 3.9 Hz); 7.06 and
7.11 (4H, 2ꢀd, J=8.0 Hz). 13C NMR (CDCl3): δ 15.6 (CH3); 21.0
(CH3); 37.7 (CH2); 41.2 (CH2); 60.0 (CH); 62.4 (CH2); 129.0 (CH);
129.3 (CH); 135.5 (C); 135.9 (C). IR (cm-1): νOH,NH =3254. MS:
m/z (%) 194 (Mþ þ 1, 100). Anal. Calcd for C12H19NO: C 74.57; H
9.91; N 7.25. Found: C 74.24; H 10.26; N 7.09.
Acknowledgment. The authors are indebted to Ghent
University (GOA) and the Fund for Scientific Research-
Flanders (FWO-Vlaanderen) for financial support.
Supporting Information Available: Spectral data of com-
pounds 6b-d, 9b, and 7c,d and 1H NMR and 13C NMR spectra
of compounds 6a-d, 9a,b, and 7a,c,d. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Lee, K.-D.; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, H. G.; Park, C. S.;
Chang, J. W.; Lee, W. K.; Dong, Y.; Yun, H. Tetrahedron 2001, 57, 8267.
J. Org. Chem. Vol. 76, No. 1, 2011 269