A new approach to the synthesis of N-alkylated 2-substituted azetidin-3-ones

Article abstract of DOI:10.1002/ejoc.200500987

We report a one-pot methodology for the synthesis of N-alkylated 2-substituted azetidin-3-ones based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates, obtained in tu

Full text of DOI:10.1002/ejoc.200500987

FULL PAPER
DOI: 10.1002/ejoc.200500987
A New Approach to the Synthesis of N-Alkylated 2-Substituted Azetidin-3-ones
Stéphane Gérard,[a] Marion Raoul,[a] and Janos Sapi*[a]
Keywords: Azetidin-3-ones / Small ring systems / Levulinic acid / Domino nucleophilic substitution-addition
We report a one-pot methodology for the synthesis of N-al-
kylated 2-substituted azetidin-3-ones based on a tandem nu-
cleophilic substitution followed by intramolecular Michael
reaction of primary amines with alkyl 5-bromo-4-oxopent-2-
enoates, obtained in turn in three steps from levulinic acid.
A mechanistic interpretation of these reactions and an at-
tempted enantioselective approach are also described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
starch, cellulose-containing waste materials, recycled paper,
or agricultural residues.[10]
Since the azetidin-3-one core has been used as a precur-
sor for the synthesis of the natural sphingosine-type alka-
loids penaresidines A and B and penazetidin A,[1] or as an
Beside its conversion into methyltetrahydrofuran, a fuel
extender, or into δ-aminolevulinic acid, a biodegradable
broad spectrum herbicide,[11] levulinic acid (1) also offers a
great number of other synthetic transformations,[12] such as
the synthesis of fused heterocycles prepared from norbor-
nane amino acids and diamines[13] or the synthesis of the
antibiotic lissoclinolide.[14]
For a recent synthetic endeavour we needed ethyl 5-
bromo-4-oxopent-2-enoate (3a) as key intermediate. This le-
vulinic acid derivative appeared to be an even more versatile
intermediate for further transformations such as Diels–Al-
der reactions, coupling reactions, nucleophilic substitutions
and conjugate additions, and it was speculated that nucleo-
philic substitution combined with intramolecular Michael
reaction should open a new approach for the synthesis of
small-ring aza-heterocycles. Here we describe a simple syn-
thesis for the preparation of N-alkyl-2-substituted azetidin-
3-ones.
intermediate in the synthesis of polyoxin antibiotics,[2,3]
a
number of different methodologies to obtain these four-
membered heterocycles have previously been described.[4]
Cyclisation based on rhodium carbenoid intramolecular
NH insertion has been developed by Seebach for the prepa-
ration of some azetidine-containing amino alcohol and
amino acid derivatives[5] and by Vederas et al. for the syn-
thesis of keto-glutamine analogues,[6] while De Kimpe has
recently reported the synthesis of 4-alkyl-1-benzhydryl-2-
(methoxymethyl)azetidin-3-ol as the result of stereoselective
alkylation at the C-4 position of the corresponding azeti-
din-3-one obtained through a high-temperature reaction of
an N-(diphenylmethylidene)-3-bromoamine precursor.[7]
Azetidin-3-ones could also be obtained from the corre-
sponding azetidin-3-ol precursors by use of pyridinium di-
chromate or Swern-type oxidation conditions.[8]
As part of a recently started program aiming at the trans-
formation of non-food/non-feed agricultural products, by-
products and waste materials into commodity chemicals we
were interested in fine chemistry application of polyfunc-
tionalised building blocks. One such derivative is 4-oxopen-
tanoic acid or levulinic acid (LA; 1), traditionally obtained
through the controlled degradation of hexose sugars by
mineral acids.[9] The increasing number of patents directed
towards the production of levulinic acid demonstrates its
potential as an important basic chemical that could now be
cost-efficiently produced from raw materials such as wood,
Results and Discussion
Alkyl 5-bromo-4-oxopent-2-enoates 3a–b were obtained
from levulinic acid (1) by
a three-step procedure
(Scheme 1). After esterification, unsaturation was intro-
duced by bromination, followed by base-catalysed elimi-
nation.[15] 3-Acetylacrylates 2a–b were directly brominated
with the recyclable triphenylphosphonium perbromide[16] to
afford the unsaturated bromo esters (E)-3a–b in about 50%
overall yield after chromatographic purification. Although
both methyl and ethyl esters (3a) have already been re-
ported,[17] the selective direct bromination of the 3-acetyl-
acrylates 2a–b or related compounds proved unprecedented.
[a] FRE CNRS 2715 “Isolement, Structure, Transformations et
Synthèse de Substances Naturelles”, Université de Reims-
Champagne-Ardenne, Faculté de Pharmacie, IFR 53 “Biomolé-
cules”
51 rue Cognacq-Jay, 51096 Reims, Cedex, France
2440
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2440–2445

New Approach to the Synthesis of N-Alkylated 2-Substituted Azetidin-3-ones
FULL PAPER
Introduction of an electron-withdrawing or electron-do-
nating group in the para position of the aromatic amine
modified the yield profoundly, while p-bromobenzylamine
was used since it offers the possibility of further transfor-
mation through cross-coupling reactions.
1
In their H NMR spectra each isolated 2-substituted az-
etidin-3-one showed a typical ABX pattern for protons H2,
H5, and H5Ј, appearing at δ = 3.8–4.0 ppm (J Ϸ 5.5 and
7.5 Hz) and at δ = 2.5–2.7 and 2.7–2.9 ppm (JAB Ϸ 18 Hz)
respectively. In the 13C NMR spectra, ketone and ester car-
bonyl signals were found at δ = 210–212 and 170–172 ppm,
respectively.
In the last part of our study we extended this sequential
reaction to chiral amines (Scheme 3 and Table 2). (R)-1-
Phenylethylamine and (R)-1-naphthylethylamine were
added to ethyl 5-bromo-4-oxopent-2-enoate (3a) under our
optimized conditions. The yield of the corresponding iso-
lated azetidin-3-one was acceptable, but only poor dia-
stereoselectivity was observed (Entries 1 and 2, Table 2).
Similarly, addition onto benzylbromo derivative 3b proved
to be inefficient in terms of both yield and diastereoselectiv-
ity (de 18%), and addition of different magnesium salts or
titanium() isopropoxide to the solution did not increase
the selectivity.
Scheme 1.
The reactivities of these polyfunctional synthons were
then studied, since treatment of 3a–b with nucleophiles
could potentially give rise to 1,2- or 1,4-additions or to nu-
cleophilic substitution. Treatment of ethyl 5-bromo-4-oxop-
ent-2-enoate (3a) with benzylamine in THF at room tem-
perature in the presence of triethylamine gave a moderate
yield (37%) of a major product that was unambiguously
identified, on the basis of H-13C HMBC correlations, as
azetidin-3-one 4a (Scheme 2 and Table 1).
1
Scheme 2.
Scheme 3.
Preliminary optimisation, carried out by variation of sol-
vents, temperature and base, showed that the best yield of
From a mechanistic point of view, the formation of the
4a was obtained by treatment of benzylamine with two azetidin-3-one skeleton involves conjugate addition to the
equivalents of brominated compound 3a in the presence of double bond and nucleophilic substitution in a well defined
potassium carbonate in a CH2Cl2/water biphasic system manner. If the first, rate-determining step is the conjugate
(Table 1). To explore the scope and limitations further, we addition, by analogy with the findings of David or Berkes,
tested other amines under the optimized reaction condi- the aza-Michael reaction should occur regioselectively at
tions. As shown in Table 1, formation of azetidin-3-ones position C-2 to afford pyrrolidin-3-one 5 as the result of
proceeded in moderate to good yields with both primary subsequent cyclisation.[18,19] In our hands this same C-2 se-
aliphatic and alkylarylamines.
lectivity was confirmed by the regioselective reaction of
Table 1. Synthesis of N-substituted azetidin-3-ones.
R1
R2
Solvent
T [°C]
Base
Yield [%]
4a
Ph
Ph
Ph
Ph
Ph
Ph
propyl
propyl
Bn
cyclohexyl
4-MeOPh
4-NO2Ph
4-BrPh
4-BrPh
Et
Et
Et
Et
Et
Bn
Et
Bn
Et
Et
Et
Et
Et
Bn
THF
THF
DMF
CH2Cl2
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
room temp.
50
60
Et3N
Et3N
K2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
37
46
12
43
76
50
74
86
53
51
63
37
57
63
4a
4a
4a
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
4a
4b
6a
6b
7a
8a
9a
10a
11a
11b
Eur. J. Org. Chem. 2006, 2440–2445
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2441

S. Gérard, M. Raoul, J. Sapi
Yield [%] (de)[a]
FULL PAPER
Table 2. Diastereoselective approach.
Entry
R1
R2
Conditions
1
2
3
4
5
6
7
12a
13a
12a
12a
12a
12a
12b
Ph
1-naphthyl
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Bn
K2CO3/CH2Cl2–H2O/room temp.
K2CO3/CH2Cl2–H2O/room temp.
Mg(OAc)2/K2CO3/CH2Cl2–H2O/room temp.
MgCl2/K2CO3/CH2Cl2–H2O/room temp.
MgCl2/K2CO3/CH2Cl2–H2O/–10 °C
Ti(OiPr)4/K2CO3/CH2Cl2
56 (20)
45 (10)
75 (8)
48 (24)
36 (23)
29 (17)
39 (18)
MgCl2/K2CO3/CH2Cl2–H2O/room temp.
1
[a] Ratio determined by H NMR.
benzylamine with ethyl 3-acetylacrylate (2a). From this ob-
servation, path a (Scheme 4) implying C-3 regioselectivity
can therefore be discarded.
In path b, the first step is a nucleophilic displacement of
bromine followed by an intramolecular 4-exo-trig ring clo-
sure to afford azetidin-3-one 4a rather than pyrrolidin-3-
one 5, which would be the result of a disfavoured 5-endo-
trig cyclisation (Scheme 4).
Conclusion
In summary, we present a quite simple and direct method
for the preparation of N-substituted azetidin-3-ones by
treatment of primary amines with alkyl 5-bromo-4-oxo-
pent-2-enoates 3a–b, derived from levulinic acid. The
mechanism of this reaction probably involves an SN2
displacement of bromine from 3a–b, followed by 4-exo-trig
ring closure to afford azetidin-3-ones. Studies aimed at
further exploration of the scope of the reaction, in particu-
lar for the synthesis of biologically active compounds, are
currently underway.
Experimental Section
General Remarks: All solvents were dried and purified by standard
literature methods prior to use. Melting points were determined on
a Reichert Thermovar hot-stage apparatus and are uncorrected. IR
spectra (film or KBr) were measured with a Bomem FTIR instru-
ment. Mass spectra were recorded with a VG Autospec apparatus.
Elemental analyses were carried out by the Microanalysis Service
of the University of Reims. Reactions were monitored with Merck
Scheme 4.
TLC aluminium sheets (Kieselgel 60F254
) and preparative
Similar reaction behaviour has been observed by Carlson
et al. on treatment of 1-bromobut-3-en-2-one with a pri-
mary amine. By NMR spectroscopy they observed that the
nucleophilic displacement of bromine seems to take place
in the first step, resulting in pyrrolidinone formation.[20] Pri-
mary amino compounds have been found to participate in
similar reactions to yield nitrogen-containing heterocy-
cles.[21] In the synthesis of simple five- and six-membered
nitrogen and sulfur heterocycles, Bunce established, by GC
monitoring, higher reactivity of benzylamine with halide
than with crotonate and isolated isothiouronium salts, dem-
onstrating that halide displacement is the initial step of the
sequence in the sulfur heterocyclisation.[22] A reaction with
N-methylbenzylamine could have definitively established
chromatography was carried out with silica gel 60 (70–230 mesh
1
ASTM) supplied by Merck. H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were acquired on a Bruker AC 300 spectrometer
in CDCl3, with TMS as internal standard.
General Procedure for the Preparation of Brominated Levulinates
3a–b: Triphenylmethylphosphonium perbromide (1 equiv.) was
added at room temperature to a solution of a 3-acetylacrylate 2a–
b (1 equiv.) in THF (2 mLmmol–1). After 1 hour, the mixture was
filtered. The filtrate was concentrated, washed with a saturated
solution of NaHCO3, extracted with CH2Cl2 and dried with
MgSO4. After concentration under vacuum, the crude products
were purified by column chromatography on silica gel (eluent
CH2Cl2/petroleum ether, 50:50) to furnish the corresponding bro-
minated derivatives.
the nature of the first step of this sequence, but unfortu- Ethyl 5-Bromo-4-oxopent-2-enoate (3a): This compound was pre-
pared by the general procedure from 2a (1.00 g, 7.4 mmol) and tri-
phenylmethylphosphonium perbromide (3.64 g, 7.4 mmol) to give
3a as a yellow solid after purification and recrystallisation from
hexane (794 mg, 51%). M.p. 34–36 °C. 1H NMR (CDCl3): δ = 1.33
(t, J = 7.1 Hz, 3 H, CH2CH3), 4.07 (s, 2 H, BrCH2), 4.29 (q, J =
7.1 Hz, 2 H, CH2CH3), 6.80 (d, J = 16.0 Hz, 1 H, CHvinyl), 7.28
(d, J = 16.0 Hz, 1 H, CHvinyl) ppm. 13C NMR (CDCl3): δ = 14.1
(CH3), 32.7 (BrCH2), 61.6 (CH2CH3), 133.3 135.6 (CHvinyl), 164.8
nately this reaction only generates polymerisation products.
With regard to the reactions with chiral amines (Table 2),
similar diasteroselectivities have been observed in some re-
lated reactions. Whilst Urbach, for example, described the
regioselective addition between (S)-alanine benzyl ester and
ethyl (E)-4-oxo-4-phenylbut-2-enoate with a de of 54%,
Knollmüller et al. obtained low selectivity (de 30%) on
treating (S)-phenylethylamine with ethyl (E)-4-oxo-4-phen-
ylbut-2-enoate.[23,24] These observed poor diastereoselectivi-
ties are in accordance with our proposed mechanism.
(CO Et), 190.2 (CO) ppm. IR (film): ν = 2982, 1721, 1701, 1381,
˜
2
1300, 988 cm–1. C7H9O3Br (220.06): calcd. C 38.20, H 4.12; found
C 38.58, H 4.44.
2442
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2440–2445

New Approach to the Synthesis of N-Alkylated 2-Substituted Azetidin-3-ones
FULL PAPER
Benzyl 5-Bromo-4-oxopent-2-enoate (3b): This compound was pre-
pared by the general procedure from 2b (3.47 g, 17 mmol) and tri-
phenylmethylphosphonium perbromide (8.79 g, 17 mmol), to give
= 13.8 [CH3(CH2)3N], 14.2 (CH3), 20.3 [CH3CH2(CH2)2N], 30.0
(CH3CH2CH2CH2N), 41.6 (C-5), 53.4 (CH3CH2CH2CH2N), 59.1
(C-4), 61.0 (CO2CH2CH3), 62.9 (C-2), 172.0 (CO2Et), 211.5
1
3b as a white oil (2.27 g, 47%). H NMR (CDCl3): δ = 4.04 (s, 2
(COazetidin.) ppm. IR (film): ν = 2992, 2934, 1763, 1732, 1258,
˜
H, BrCH2), 5.26 (s, 2 H, PhCH2), 6.86 (d, J = 15.8 Hz, 1 H,
1182 cm–1. MS (CI): m/z (%) = 214 (13) [M + H], 172 (21), 144
CHvinyl), 7.29 (d, J = 15.8 Hz, 1 H, CHvinyl) ppm. 13C NMR
(25), 83, 42. C11H19NO3 (213.27): calcd. C 61.95, H 8.98, N 6.57;
(CDCl3): δ = 32.7 (BrCH2), 67.1 (PhCH2), 128.1 128.3 128.5 (Ar found C 61.62, H 8.53, N 6.84.
CH), 134.9 (Ar Cq), 132.6 136.0 (CHvinyl), 164.5 (CO2Bn), 189.9
2-(Benzyloxycarbonylmethyl)-1-butylazetidin-3-one (6b): This com-
(CO) ppm. IR (film): ν = 3025, 2988, 1726, 1718, 1297, 1027 cm–1.
C12H11O3Br (282.13): calcd. C 51.08, H 3.93; found C 50.88, H
4.19.
˜
pound was synthesized from 3b (283 mg, 1 mmol) and butylamine
1
(0.50 mL, 0.5 mmol), to yield 6b (118 mg, 86%) as a yellow oil. H
NMR (CDCl3): δ = 0.88 [t, J = 7.3 Hz, 3 H, CH3(CH2)3N], 1.31
[m, 2 H, CH3CH2(CH2)2N], 1.45 (m, 2 H, CH3CH2CH2CH2N),
2.41–2.72 (m, 4 H, CH3CH2CH2CH2N, H-5, H-5Ј), 3.02 (d, J =
17.2 Hz, 1 H, H-4), 3.39 (d, J = 17.2 Hz, 1 H, H-4Ј), 3.80 (dd, J =
7.6 Hz, J = 5.5 Hz, 1 H, H-2), 5.18 (s, 2 H, OCH2Ph), 7.34–7.41
(m, 5 H, CHarom) ppm. 13C NMR (CDCl3): δ = 13.8 [CH3-
(CH2)3N], 20.2 [CH3CH2(CH2)2N], 29.9 (CH3CH2CH2CH2N),
41.5 (C-5), 53.3 (CH3CH2CH2CH2N), 59.0 (C-4), 62.7 (C-2), 66.7
(CO2CH2Ph), 128.4 128.5 128.6 (Ar CH), 135.3 (Ar Cq), 171.8
General Procedure for the Preparation of N-Substituted Azetidin-3-
ones (4–11): Amine (1 equiv.), an aqueous solution of K2CO3
(0.5 mL, 2 equiv.) and tetrabutylammonium hydrogen sulfate
(0.1 equiv.) were successively added, at room temperature, to a solu-
tion of the brominated compound (3a–b, 2 equiv.) in CH2Cl2
(2.5 mLmmol–1). The mixture was stirred for 4 h at room tempera-
ture and was then poured into water. Extraction with CH2Cl2, dry-
ing over MgSO4 and concentration under vacuum gave the crude
products, which were purified by column chromatography on silica
gel (eluent CH2Cl2/AcOEt, 95:5) to furnish the corresponding azet-
idin-3-one.
(CO2Bn), 211.3 (COazetidin.) ppm. IR (film): ν = 3155, 3015, 1919,
˜
1793, 1757, 1560, 1474, 1378 cm–1. MS (CI): m/z (%) = 276 (100)
[M + H], 242 (12), 184, 57. C16H21NO3 (275.34): calcd. C 69.79, H
7.69, N 5.09; found C 69.51, H 7.95, N 5.01.
1-Benzyl-2-(ethoxycarbonylmethyl)azetidin-3-one (4a): This com-
pound was synthesized from 3a (442 mg, 2 mmol) and benzylamine
(0.11 mL, 1 mmol), to yield 4a (188 mg, 76%) as a dark oil. 1H
NMR (CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H, CH3), 2.56 (dd, J =
18.1 Hz, J = 5.7 Hz, 1 H, H-5), 2.72 (dd, J = 18.1 Hz, J = 7.7 Hz,
1 H, H-5Ј), 3.02 (d, J = 17.2 Hz, 1 H, H-4), 3.37 (d, J = 17.2 Hz,
2-(Ethoxycarbonylmethyl)-1-phenethylazetidin-3-one (7a): This
compound was obtained from 3a (221 mg, 1 mmol) and phen-
ethylamine (63 µL, 0.5 mmol): 69 mg (53%) as a dark oil. 1H NMR
(CDCl3): δ = 1.29 (t, J = 7.1 Hz, 3 H, CH3), 2.58 (dd, J = 18.0 Hz,
J = 5.2 Hz, 1 H, H-5), 2.69 (dd, J = 18.0 Hz, J = 7.8 Hz, 1 H, H-
1 H, H-4Ј), 3.73 (d, J = 13.0 Hz, 1 H, NCH2Ph), 3.83 (dd, J = 5Ј), 2.86 (m, 2 H, NCH2CH2Ph), 3.01 (m, 2 H, NCH2CH2Ph), 3.12
7.7 Hz, J = 5.7 Hz, 1 H, H-2), 3.95 (d, J = 13.0 Hz, 1 H, NCH2Ph),
4.22 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 7.25–7.40 (m, 5 H,
CHarom.) ppm. 13C NMR (CDCl3): δ = 14.2 (CH3), 41.7 (C-5), 57.3
(d, J = 17.1 Hz, 1 H, H-4), 3.45 (d, J = 17.1 Hz, 1 H, H-4Ј), 3.82
(dd, J = 7.8 Hz, J = 5.2 Hz, 1 H, H-2), 4.20 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 7.15–7.35 (m, 5 H, CHarom.) ppm. 13C NMR
(CH2Ph), 58.8 (C-4), 61.1 (CO2CH2CH3), 62.2 (C-2), 127.6 (CDCl3):
128.4 128.8 (Ar CH), 136.6 (Ar Cq), 171.7 (CO2Et), 210.5 (NCH2CH2Ph), 59.0 (C-4), 61.1 (CO2CH2CH3), 62.6 (C-2), 126.2
(COazetidin.) ppm. IR (film): ν = 2928, 2872, 2801, 1763, 1732, 1198, 128.4 128.5 (Ar CH), 139.3 (Ar Cq), 171.9 (CO2Et), 211.1
δ = 14.2 (CH3), 34.6 (CH2Ph), 41.5 (C-5), 55.0
˜
1177, 1030 cm–1. MS (EI): m/z (%) = 247 [M]+·, 174 (100), 149, 137, (COazetidin.) ppm. IR (film): ν = 2980, 2949, 2897, 2864, 1771, 1732,
˜
130, 115, 106. C14H17NO3 (247.29): calcd. C 68.00, H 6.93, N 5.66;
found C 68.23, H 6.99, N 5.41.
1650, 1432, 1065 cm–1. MS (CI): m/z (%) = 262 [M + H], 170, 157
(100), 105, 91. C15H19NO3 (261.32): calcd. C 68.94, H 7.33, N 5.36;
found C 69.35, H 7.68, N 5.18.
1-Benzyl-2-(benzyloxycarbonylmethyl)azetidin-3-one (4b): This
compound was synthesized from 3b (283 mg, 1 mmol) and benzyl-
amine (55 µL, 0.5 mmol), to yield 4b (77 mg, 50%) as a yellow oil.
1H NMR (CDCl3): δ = 2.55 (dd, J = 18.3 Hz, J = 5.5 Hz, 1 H, H-
1-Cyclohexyl-2-(ethoxycarbonylmethyl)azetidin-3-one (8a): This
compound was obtained from 3a (221 mg, 1 mmol) and cyclohex-
ylamine (57 µL, 0.5 mmol): 60 mg (51%) as a colourless oil. 1H
5), 2.69 (dd, J = 18.3 Hz, J = 7.7 Hz, 1 H, H-5Ј), 3.01 (d, J = NMR (CDCl3): δ = 1.20 [m, 6 H, NCH(CH2CH2)2CH2], 1.30 (t, J
17.2 Hz, 1 H, H-4), 3.31 (d, J = 17.2 Hz, 1 H, H-4Ј), 3.71 (d, J =
13.1 Hz, 1 H, NCH2Ph), 3.81 (m, 2 H, H-2, NCH2Ph), 5.18 (s, 2
= 7.0 Hz, 3 H, CH3), 1.52–1.98 [m, 4 H, NCH(CH2CH2)2CH2],
2.47 [m, 2 H, NCH(CH2CH2)2CH2, H-5], 2.71 (dd, J = 17.9 Hz, J
H, OCH2Ph), 7.18–7.49 (m, 10 H, CHarom.) ppm. 13C NMR = 8.1 Hz, 1 H, H-5Ј), 3.31 (m, 2 H, H-4, H-4Ј), 4.02 (dd, J = 8.1 Hz,
(CDCl3): δ = 41.6 (C-5), 57.2 (NCH2Ph), 58.7 (C-4), 62.0 (C-2), J = 4.6 Hz, 1 H, H-2), 4.23 (q, J = 7.0 Hz, 2 H, CO2CH2CH3) ppm.
66.8 (CO2CH2Ph), 127.5 128.4 128.5 128.6 128.7 128.8 (Ar CH), 13C NMR (CDCl3): δ = 14.2 (CH3), 24.4 24.5 25.8 29.5 31.9
135.2 136.7 (Ar Cq), 171.7 (CO2Bn), 210.8 (COazetidin.) ppm. IR
[NCH(CH2CH2)2CH2], 41.7 (C-5), 56.1 (C-4), 58.8 59.1
[NCH(CH2CH2)2CH2, C-2], 60.7 (CO2CH2CH3), 172.8 (CO2Et),
(film): ν = 2980, 2954, 2901, 1765, 1736, 1254, 1233, 1198 cm–1. MS
˜
(EI): m/z (%) = 309 [M]+·, 218 (100), 202, 135, 107, 91. C19H19NO3 212.2 (COazetidin.) ppm. IR (film): ν = 2897, 2864, 2802, 1765, 1728,
˜
(309.36): calcd. C 73.77, H 6.19, N 4.53; found C 73.51, H 6.38, N
4.81.
1528, 1280, 1165, 1058 cm–1. MS (CI): m/z (%) = 240 [M + H], 194,
166, 156 (100), 83. HRMS (EI): 239.1506. C13H21NO3 [M]+ re-
quires 239.1521.
1-Butyl-2-(ethoxycarbonylmethyl)azetidin-3-one (6a): This com-
pound was synthesized from 3a (447 mg, 2 mmol) and butylamine
(0.10 mL, 1 mmol), to yield 6a (159 mg, 74%) as a yellow oil. H This compound was synthesized from 3a (221 mg, 1 mmol) and p-
NMR (CDCl3): δ = 0.94 [t, J = 7.2 Hz, 3 H, CH3(CH2)3N], 1.30 methoxybenzylamine (65 µL, 0.5 mmol), to yield 9a (87 mg, 63%)
(t, J = 7.1 Hz, 3 H, CH3), 1.36 [m, 2 H, CH3CH2(CH2)2N], 1.50
(m, 2 H, CH3CH2CH2CH2N), 2.53–2.70 (m, 4 H, CH3CH2- H, CH3), 2.57 (dd, J = 18.1 Hz, J = 5.8 Hz, 1 H, H-5), 2.75 (dd, J
CH2CH2N, H-5, H-5Ј), 3.03 (d, J = 17.2 Hz, 1 H, H-4), 3.42 (d, J = 18.1 Hz, J = 7.6 Hz, 1 H, H-5Ј), 3.03 (d, J = 17.2 Hz, 1 H, H-
2-(Ethoxycarbonylmethyl)-1-(p-methoxybenzyl)azetidin-3-one (9a):
1
as a colourless oil. 1H NMR (CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3
= 17.2 Hz, 1 H, H-4Ј), 3.75 (dd, J = 7.5 Hz, J = 5.8 Hz, 1 H, H-2), 4), 3.39 (d, J = 17.2 Hz, 1 H, H-4Ј), 3.73 (d, J = 12.9 Hz, 1 H,
4.22 (q, J = 7.1 Hz, 2 H, CO2CH2CH3) ppm. 13C NMR (CDCl3): δ NCH2Ph), 3.78–3.90 (m, 4 H, H-2 OCH3), 3.92 (d, J = 12.9 Hz, 1
Eur. J. Org. Chem. 2006, 2440–2445
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2443

S. Gérard, M. Raoul, J. Sapi
FULL PAPER
H, NCH2Ph), 4.26 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 6.92 (d, J nium() isopropoxide (2 equiv.) were used before the addition of
= 10.5 Hz, 2 H, CHarom), 7.24 (d, J = 10.5 Hz, 2 H, CHarom) ppm. amine.
13C NMR (CDCl3): δ = 14.2 (CH3), 41.7 (C-5), 55.2 (OCH3), 56.6
2-(Ethoxycarbonylmethyl)-1-[(R)-1-phenylethyl]azetidin-3-one (12a):
(CH2Ph), 58.8 (C-4), 61.1 (CO2CH2CH3), 62.0 (C-2), 113.7 130.1
This compound was synthesized from 3a and (R)-1-phenylethyl-
(Ar CH), 128.7 (Ar Cq), 159.0 (MeOCq), 171.9 (CO2Et), 211.0
amine to yield the diastereoisomeric mixture 12a as a colourless
1
(COazetidin.) ppm. IR (film): ν = 2921, 2853, 1771, 1717, 1259,
˜
oil. H NMR (CDCl3) (minor isomer): δ = 1.26 (t, J = 7.1 Hz, 3
H, CH3) (1.20), 1.40 (d, J = 6.6 Hz, 3 H, CHCH3), 2.44 (dd, J =
18.5 Hz, J = 2.4 Hz, 1 H, H-5) (2.38), 2.78 (dd, J = 18.5 Hz, J =
8.4 Hz, 1 H, H-5Ј) (2.62), 2.97 (d, J = 17.5 Hz, 1 H, H-4) (3.39),
3.20 (d, J = 17.5 Hz, 1 H, H-4Ј) (3.48), 3.79 (q, J = 6.6 Hz, 1 H,
CHCH3) (3.87), 4.10–4.28 (m, 3 H, H-2 CO2CH2CH3), 7.20–7.31
(m, 5 H, CHarom.) ppm. 13C NMR (CDCl3) (minor isomer): δ =
14.0 (CH3), 20.6 (CHCH3) (22.3), 41.8 (C-5), 57.3 (C-4) (56.2), 59.5
61.2 (C-2 CHCH3) (59.7 60.5), 60.8 (CO2CH2CH3) (60.7), 126.8
127.3 128.3 (Ar CH), 143.4 (Ar Cq) (141.7), 172.4 (CO2Et), 211.7
1163 cm–1. MS (CI): m/z (%) = 278 (70) [M + H], 262, 241, 121.
HRMS (ESI): 278.1387. C15H20NO4 [M + H]+ requires 278.1392.
2-(Ethoxycarbonylmethyl)-1-(p-nitrobenzyl)azetidin-3-one
(10a):
This compound was prepared by the general procedure from 3a
(221 mg, 1 mmol) and p-nitrobenzylamine hydrochloride (95 mg,
0.5 mmol), to give 10a as a pale yellow oil (54 mg, 37%). 1H NMR
(CDCl3): δ = 1.31 (t, J = 7.3 Hz, 3 H, CH3), 2.58 (dd, J = 18.1 Hz,
J = 5.3 Hz, 1 H, H-5), 2.79 (dd, J = 18.1 Hz, J = 7.8 Hz, 1 H, H-
5Ј), 3.03 (d, J = 16.9 Hz, 1 H, H-4), 3.38 (d, J = 16.9 Hz, 1 H, H-
4Ј), 3.85 (d, J = 13.9 Hz, 1 H, NCH2Ph), 3.92 (dd, J = 7.8 Hz, J
= 5.3 Hz, 1 H, H-2), 4.13 (d, J = 13.9 Hz, 1 H, NCH2Ph), 4.28 (q,
J = 7.3 Hz, 2 H, CO2CH2CH3), 7.55 (d, J = 8.6 Hz, 2 H, CHarom),
8.21 (d, J = 8.6 Hz, 2 H, CHarom) ppm. 13C NMR (CDCl3): δ =
14.2 (CH3), 41.6 (C-5), 56.6 (CH2Ph), 58.7 (C-4), 61.3
(CO2CH2CH3), 62.2 (C-2), 123.8 129.1 (Ar CH), 144.9 147.4 (Ar
(COazetidin.) ppm. IR (film): ν = 2949, 2897, 1768, 1732, 1206 cm–1.
˜
MS (EI): m/z (%) = 261 [M]+·, 246, 219, 188, 105 (100). HRMS
(EI): 261.1372. C15H19NO3 [M]+ requires 261.1365.
2-(Benzyloxycarbonylmethyl)-1-[(R)-1-phenylethyl]azetidin-3-one
(12b): This compound was synthesized from 3b (283 mg, 1 mmol)
and (R)-1-phenylethylamine (65 µL, 0.5 mmol), to yield the dia-
stereoisomeric mixture 12b (61 mg, 39%) as a colourless oil. 1H
NMR (CDCl3) (minor isomer): δ = 1.48 (d, J = 6.6 Hz, 3 H, CH3)
(1.46), 2.48 (dd, J = 18.0 Hz, J = 2.4 Hz, 1 H, H-5) (2.39), 2.75
(dd, J = 18.0 Hz, J = 8.4 Hz, 1 H, H-5Ј) (2.68), 2.92 (d, J = 17.5 Hz,
1 H, H-4) (3.37), 3.19 (d, J = 17.5 Hz, 1 H, H-4Ј) (3.55), 3.71 (q,
J = 6.6 Hz, 1 H, CHCH3) (3.85), 4.27 (dd, J = 8.4 Hz, J = 2.4 Hz,
Cq), 171.6 (CO2Et), 210.1 (COazetidin.) ppm. IR (film): ν = 3147,
˜
2931, 1760, 1724, 1603, 1524, 1344 cm–1. MS (CI): m/z (%) = 293
(28) [M + H], 292 (100), 241, 218, 136. HRMS (ESI): 293.1137.
C14H17N2O5 [M + H]+ requires 293.1137.
1-(p-Bromobenzyl)-2-(ethoxycarbonylmethyl)azetidin-3-one (11a):
This compound was synthesized from 3a (221 mg, 1 mmol) and p-
bromobenzylamine (93 mg, 0.5 mmol), to yield 11a (91 mg, 57 %)
1
H, H-2), 5.15 (m, 2 H, CH2Ph), 7.15–7.38 (m, 10 H,
CHarom.) ppm. 13C NMR (CDCl3) (minor isomer): δ = 20.8 (CH3)
(22.5), 41.8 (C-5), 57.4 (C-4) (56.3), 59.6 60.8 (C-2 CHCH3) (59.7
60.2), 66.5 (CO2CH2Ph), 126.9 127.4 127.5 128.4 128.5 128.8
(Ar CH), 135.3 143.6 (Ar Cq) (141.9), 172.3 (CO2Bn), 211.6
1
as an orange oil. H NMR (CDCl3): δ = 1.29 (t, J = 7.3 Hz, 3 H,
CH3), 2.51 (dd, J = 17.9 Hz, J = 5.8 Hz, 1 H, H-5), 2.68 (dd, J =
17.9 Hz, J = 7.7 Hz, 1 H, H-5Ј), 2.99 (d, J = 17.2 Hz, 1 H, H-4),
3.41 (d, J = 17.2 Hz, 1 H, H-4Ј), 3.67 (d, J = 13.0 Hz, 1 H,
NCH2Ph), 3.72 (dd, J = 7.7 Hz, J = 5.8 Hz, 1 H, H-2), 3.89 (d, J
= 13.0 Hz, 1 H, NCH2Ph), 4.22 (q, J = 7.3 Hz, 2 H, CO2CH2CH3),
7.21 (d, J = 8.3 Hz, 2 H, CHarom), 7.47 (d, J = 8.3 Hz, 2 H,
CHarom) ppm. 13C NMR (CDCl3): δ = 14.2 (CH3), 41.6 (C-5), 56.6
(CH2Ph), 58.7 (C-4), 61.0 (CO2CH2CH3), 62.1 (C-2), 121.3 (CBr),
130.3 131.6 (Ar CH), 136.0 (Ar Cq), 171.7 (CO2Et), 210.5-
(COazetidin.) ppm. IR (film): ν = 3079, 3034, 2949, 2864, 1765, 1728,
˜
1405, 1067 cm–1. MS (CI): m/z (%) = 324 (100) [M + H], 261, 220,
105. HRMS (ESI): 324.1594. C20H22NO3 [M + H]+ requires
324.1600.
2-(Ethoxycarbonylmethyl)-1-[(R)-1-(naphth-1-yl)ethyl]azetidin-3-one
(13a): This compound was prepared by the general procedure from
3a (111 mg, 0.5 mmol) and (R)-1-(1-naphthyl)ethylamine (41 µL,
0.25 mmol), to give 13a as a dark oil (35 mg, 45%). 1H NMR
(CDCl3) (minor isomer): δ = 1.33 (t, J = 7.5 Hz, 3 H, CH3) (1.25),
1.55 (d, J = 6.6 Hz, 3 H, CHCH3) (1.48), 2.55 (dd, J = 18.0 Hz, J
= 2.6 Hz, 1 H, H-5) (2.48), 2.83 (dd, J = 18.0 Hz, J = 8.4 Hz, 1 H,
H-5Ј) (2.72), 3.05 (d, J = 17.0 Hz, 1 H, H-4) (3.39), 3.18 (d, J =
17.0 Hz, 1 H, H-4Ј) (3.48), 3.92 (q, J = 6.6 Hz, 1 H, CHCH3), 4.15–
4.35 (m, 3 H, H-2 CO2CH2CH3), 7.32–7.78 (m, 7 H, CHarom.) ppm.
13C NMR (CDCl3) (minor isomer): δ = 14.2 (CH3), 20.3 (CHCH3)
(21.9), 41.5 (C-5), 56.9 (C-4) (56.0), 60.1 61.8 (C-2 CHCH3), 61.2
(CO2CH2CH3), 126.8 127.2 127.3 128.3 128.4 (Ar CH), 143.3 (Ar
(COazetidin.) ppm. IR (film): ν = 2942, 2810, 1762, 1727, 1484, 1308,
˜
1251 cm–1. MS (CI): m/z (%) = 327 [M + H], 212, 209, 171 (100),
130. C14H16BrNO3 (326.19): calcd. C 51.55, H 4.94, N 4.29; found
C 51.38, H 5.02, N 4.43.
2-(Benzyloxycarbonylmethyl)-1-(p-bromobenzyl)azetidin-3-one
(11b): This compound was synthesized from 3b (283 mg, 1 mmol)
and p-bromobenzylamine (93 mg, 0.5 mmol), to yield 11b (122 mg,
63%) as a yellow oil. 1H NMR (CDCl3): δ = 2.55 (dd, J = 18.1 Hz,
J = 5.3 Hz, 1 H, H-5), 2.71 (dd, J = 18.1 Hz, J = 7.8 Hz, 1 H, H-
5Ј), 2.98 (d, J = 17.1 Hz, 1 H, H-4), 3.31 (d, J = 17.1 Hz, 1 H, H-
4Ј), 3.62 (d, J = 13.2 Hz, 1 H, NCH2Ph), 3.84 (d, J = 13.2 Hz, 1
H, NCH2Ph), 3.91 (dd, J = 7.8 Hz, J = 5.3 Hz, 1 H, H-2), 5.17
(AB, J = 13.4 Hz, 2 H, CO2CH2Ph), 7.11 (d, J = 10.5 Hz, 2 H,
CHarom), 7.35–7.49 (m, 7 H, CHarom) ppm. 13C NMR (CDCl3): δ
Cq) (141.9), 172.5 (CO2Et), 211.7 (COazetidin.) ppm. IR (film): ν =
˜
3085, 3024, 2949, 2868, 1760, 1735, 1342, 1208 cm–1. MS (CI):
m/z (%) = 312 [M + H], 210, 155 (100), 129. C19H21NO3 (311.37):
calcd. C 73.29, H 6.80, N 4.50; found C 73.58, H 6.99, N 4.78.
=
41.6 (C-5), 56.4 (CH2Ph), 58.6 (C-4), 61.9 (C-2), 66.8
(CO2CH2Ph), 121.3 (CBr), 128.2 128.4 128.6 130.3 131.5 (Ar CH),
135.1 136.0 (Ar Cq), 171.6 (CO2Bn), 210.5 (COazetidin.) ppm. IR
Acknowledgments
(film): ν = 3147, 2937, 1757, 1724, 1488, 1373, 1174 cm–1. MS (CI):
˜
The authors thank the University of Reims and the CNRS for fin-
ancial support. Spectroscopic measurements by C. Petermann
(NMR), and P. Sigaut (MS) are gratefully acknowledged.
m/z (%) = 389 (100) [M + H], 370, 276, 218, 170, 91. HRMS (ESI):
388.0556. C19H19NO3Br [M + H]+ requires 388.0548.
General Procedure for the Preparation of the Chiral N-Substituted
Azetidin-3-ones 12, 13: The previously described reaction condi-
tions and treatment were maintained, but complexing salts or tita-
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Eur. J. Org. Chem. 2006, 2440–2445

New Approach to the Synthesis of N-Alkylated 2-Substituted Azetidin-3-ones
FULL PAPER
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Received: December 19, 2005
Published Online: March 16, 2006
Eur. J. Org. Chem. 2006, 2440–2445
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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