Synthesis of 1-alkyl-2-methylazetidin-3-ones and 1-alkyl-2-methylazetidin-3-ols

Article abstract of DOI:10.1016/S0040-4020(03)00241-2

Several 1-alkyl-2-methylazetidin-3-ones were prepared in good yield by the hydride-induced cyclization of the corresponding β-bromo-α,α-dimethoxyketimines, the resulting 3,3-dimethoxyazetidines being hydrolyzed by acid. Imination of these 1,2-disubstituted azetidin-3-ones, followed by alkylation under kinetic control conditions resulted in regioisomeric mixtures of 2,4- and 2,2-dialkylated compounds. Analytical samples of the major 2,4-disubstituted derivatives were obtained after extensive chromatographic separation. The cis stereochemistry of the major 2,4-dialkylated isomer was demonstrated on the basis of NMR data.

Full text of DOI:10.1016/S0040-4020(03)00241-2

Tetrahedron 59 (2003) 2231–2239
Synthesis of 1-alkyl-2-methylazetidin-3-ones
and 1-alkyl-2-methylazetidin-3-ols
Antonio Salgado, Yves Dejaegher, Guido Verniest, Mark Boeykens, Christine Gauthier,
*
Christelle Lopin, Kourosch Abbaspour Tehrani and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
B-9000 Gent, Belgium
Received 4 December 2002; revised 15 January 2003; accepted 7 February 2003
Abstract—Several 1-alkyl-2-methylazetidin-3-ones were prepared in good yield by the hydride-induced cyclization of the corresponding
b-bromo-a,a-dimethoxyketimines, the resulting 3,3-dimethoxyazetidines being hydrolyzed by acid. Imination of these 1,2-disubstituted
azetidin-3-ones, followed by alkylation under kinetic control conditions resulted in regioisomeric mixtures of 2,4- and 2,2-dialkylated
compounds. Analytical samples of the major 2,4-disubstituted derivatives were obtained after extensive chromatographic separation. The cis
stereochemistryofthemajor2,4-dialkylatedisomerwasdemonstrated on the basisof NMRdata. q 2003 ElsevierScienceLtd. Allrightsreserved.
1. Introduction
penazetidine A (Fig. 1).4 The synthetic protocol that was
developed consisted of the regio- and stereoselective
alkylation of 1-benzhydryl-2-(methoxymethyl)azetidin-3-
one 3, followed by the hydride reduction of the carbonyl
group. In order to gain insight into the mechanism that rules
the stereoselectivity of the alkylation protocol, and to fully
exploit the synthetic possibilities of this method, it was
decided to prepare 2-substituted azetidin-3-one derivatives,
and to study their alkylation. Of prime importance was the
In our research group, we have been engaged in the
development of versatile synthetic methods for the prepa-
ration of small-size heterocyclic compounds, such as
some azetidine derivatives.1,2 In a previous research, we
described a general method to prepare 2,4-disubstituted
azetidin-3-ones 1 and azetidin-3-ols 2,3 as related structural
motifs of the alkaloids penaresidine A, penaresidine B and
Figure 1.
Keywords: azetidin-3-ones; azetidin-3-ols; azetidines; bromoimines.
*
Corresponding author. Tel.: þ32-(0)9-2645951; fax: þ32-(0)9-2646243; e-mail: norbert.dekimpe@ng.ac.be
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00241-2

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A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
Scheme 1.
development of an efficient and straightforward synthesis of
more azetidin-3-ones because such procedures are lacking
until now.5
conventional acid hydrolysis after the cyclization step
(Scheme 1).
The key step for this synthesis would be the cyclization
induced by the addition of hydride to an a,a-dimethoxy-b-
bromoketimine 4. One of the most relevant features of the
azetidine synthesis from b-haloimines is that different
functionalities could be introduced via appropriate sub-
stituents in the haloimine precursor.2b Consequently, if an
acetal moiety was conveniently placed like in the haloimine
precursor 4, it could be converted into a carbonyl group by
2. Results and discussion
2.1. Preparation of 1-alkyl-2-methylazetidin-3-ones 6
The synthetic route which was followed to prepare 1-alkyl-
2-methylazetidin-3-ones 6 is described below (Scheme 2).
Butane-2,3-dione 7 was converted into 3,3-dimethoxy
Scheme 2.

A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
2233
2-butanone 8 by selective protection of one of the two
carbonyl groups with methyl orthoformate in the presence
of a catalytic amount of sulfuric acid.6 Pyrolysis of the
ketoacetal 8 with diisopropylethylammonium tosylate as
cracking catalyst7 gave 3-methoxy-3-buten-2-one 9,8 which
could only be partially purified by distillation. This resulted
in a mixture of 3-methoxy-3-buten-2-one 9 and unreacted 8
in a 2.6:1 ratio (1H NMR). This mixture was reacted with
N-bromosuccinimide in methanol at room temperature9 to
afford 4-bromo-3,3-dimethoxy-2-butanone 10 in 80% yield
after distillation in vacuo.
Figure 2.
The rigid conformation associated to the planar W-arrange-
ment of the hydrogen atoms H-2 and H-4 would necessarily
imply that these two hydrogen atoms adopted a pseudo-
equatorial disposition, the methyl group at position C-2
being pseudoaxial. It must be quoted that, for four-
membered cyclic compounds like 6a–c, long distance
coupling between equatorial H-2 and axial H-4, where a
planar W disposition would not be observed, would give rise
to smaller values of the coupling constant (J2,4¼0.7 Hz, 6a),
also this being in accordance to the literature.12 These
results strongly support the conformation of 6a–c shown in
Figure 2.
The b-bromoketone 10 was reacted with different aliphatic
and aromatic amines in the presence of titanium(IV)
chloride at room temperature.10 The E isomers of the
corresponding imines 4a–d were in each case exclusively
obtained with good yield (88–95%) and pure enough
(.96%) to be used as such in the following step. Only when
the less reactive aniline was used, harsher reaction
conditions were required to bring the reaction to com-
pletion. For the less sterically hindered imines 4a–c,
reaction with 2 equiv. of sodium borohydride in methanol
at reflux afforded the desired 1-alkyl-2-methyl-3,3-di-
methoxyazetidines 11a–c in good yield (70–96%). The
phenyl derivative 11d, however, could only be obtained
after attempted activation (protonation) of the Schiff base
4d to the corresponding iminium ion.11 Reflux of 4d with
sodium cyanoborohydride in methanol in the presence of
1 equiv. of acetic acid gave 3,3-dimethoxy-2-methyl-1-
phenylazetidine 11d in excellent yield (91%).
2.2. Alkylation of 1-isopropyl-2-methylazetidin-3-one 6a
In a previous work, it was found that 1-benzhydryl-2-
(methoxymethyl)azetidin-3-one 3 could be regio- and
stereoselectively alkylated via the corresponding N-iso-
propylimine.3 Therefore, and as part of our research on the
synthesis of penaresidin-like alkaloids, it was decided to
study the possibilities of 1-alkyl-2-methylazetidin-3-ones
4a–c as substrates for the synthesis of 2,4-disubstituted
azetidin-3-ols 11.
As a model reaction, only the alkylation of 1-isopropyl-2-
methylazetidin-3-one 6a was attempted (Scheme 3).
Compound 6a was reacted with isopropylamine in the
presence of titanium(IV) chloride in diethyl ether, which
afforded E-N-isopropyl-3-[(N-isopropyl)-imino]-2-methyl-
azetidin-3-one 12 in 70% yield. This compound was
converted to its 1-azaenolate anion under kinetic control
conditions, i.e. by addition of lithium diisopropylamide in
anhydrous THF at 2208C. This was followed by the
addition of the alkylating agent, also at 2208C, and finally
by acidic hydrolysis of the imino group at room
temperature.
The following step concerned the acidic hydrolysis of the
protecting ketal functionality of the dimethoxyazetidines
11a–d. Stirring the azetidines 11a–c in 6N hydrochloric
acid and under reflux resulted in the complete hydrolysis
to the desired azetidin-3-ones 6a–c, which were obtained
in high purity after alkaline workup. However, these
conditions proved unsuccessful with the N-phenylazetidine
11d, as no hydrolysis was observed to occur and only
unreacted 11d was recovered. This apparent lack of
reactivity of 11d could not be improved by the use of
stronger acidic conditions, such as 10 equiv. of sulfuric acid,
which also led at room temperature to unreacted 11d. When
this reaction mixture was heated at reflux, complete
decomposition was observed and no azetidin-3-one could
be isolated.
Under these conditions, the alkylation of N-isopropyl-3-[(N-
isopropyl)imino]-2-methylazetidin-3-one 12 with alkyl
iodides always afforded mixtures of the desired 2,4-di-
alkylated azetidinones 13a–d and their regioisomeric
2,2-dialkylated analogues 14a–d. In every case, the ratio
between both regioisomers 13 and 14 was determined by
The structure of the 2-methylazetidin-3-ones 6a–c was
determined on the basis of their spectroscopic data. The
presence of the carbonyl group was in each case demon-
strated by the 13C NMR spectra (204.74 ppm, CDCl3,
67.5 MHz, 6a) and by the strong absorptions in the IR
1
comparing the relative intensity of the signals in the H
NMR spectrum of the crude reaction mixture. In the case of
the 2,4-dialkylated compounds 13a–d, only one stereo-
isomer was obtained in each case, as evidenced by
1
spectra (1809 cm21, NaCl, 6a). The H NMR spectra of
1
compounds 6a–c with the remarkably comparatively large
coupling constants between the protons at positions C-2
and C-4 (J2,4¼4.3 Hz, 6a) are consistent with a four-
membered cyclic structure. The magnitude of these
coupling constants has been associated to a planar W
geometry of the molecule, in which the hydrogen atoms at
positions C-2 and C-4 were on the same side of the
molecule, as shown in Figure 2.12 These findings were in
agreement with some reported data of other 2-substituted
azetidin-3-one derivatives.5b
analytical GC and by the fact that the signals in the H
and 13C NMR spectra were not doubled. The structure of the
minor isomers 14a–d was demonstrated by the DEPT NMR
spectrum of the reaction crudes. These NMR experiments
proved that, for compounds 14a–d, C-2 were quaternary
carbons and C-4 were methylenic. In addition to this lack
of regioselectivity, the two different regioisomers proved
very difficult to separate, and extensive chromatographic
treatment was required, in every case, to obtain analytical
samples of each 2,4-dialkylated compound 13a–d. In our

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A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
Scheme 3.
Scheme 4.
Table 1. Selected 1H NMR data of 2-methyl azetidin-3-ols 15a and 15b (CDCl3, 270 MHz)
Compound
Configuration
d H-2 (ppm)
d H-3 (ppm)
d OH (ppm)
d H-4 (ppm)
J2,3 (Hz)
J3,4 (Hz)
J3,OH (Hz)
15a (cis, cis)
15b (trans, trans)
2RS,3RS,4SR
2RS,3SR,4SR
3.25
2.95
4.23
3.48
1.91
2.10
3.17
2.77
Not observed
5.4
Not observed
5.4
7.9
Not observed
hands, only the benzyl derivative 13c could be completely
purified by flash chromatography.
(2RS,3SR,4SR) 2-benzyl-1-isopropyl-4-methyl azetidin-3-
ol 15b by comparison of its NMR data with those of 2a and
2b.3 The measured value of the coupling constant
(J2,3¼J3,4¼5.4 Hz) proved the trans relationship of the
hydroxy group with the substituents at C-2 and C-4.
Likewise, the second eluting isomer was identified as the
all cis (2RS,3RS,4SR) 2-benzyl-1-isopropyl-4-methylazeti-
din-3-ol 15a on the basis of the J3,OH constant (7.9 Hz).
These findings were supported by a nOe experiment of the
minor isomer 15b (CDCl3, 270 MHz, rt). Irradiation of the
signal due to the methyl group at C-4 lead to a 1.3% nOe
interaction with the hydrogen at C-3 (Fig. 3). This implied
that these two groups lie on the same side of the molecule,
which can only be explained by the trans relationship
2.3. Reduction of 2-benzyl-1-isopropyl-4-methylazetidin-
3-one 13c
In order to elucidate the relative stereochemistry of the
2,4-disusbtituted azetidin-3-ones 13a–c, the corresponding
azetidin-3-ol derivatives 15 were prepared. Accurate
measuring of the coupling constants in the 1H NMR
spectrum of 15 and direct comparison with published
data3 would thus provide information on the stereo-
chemistry of the precursor azetidin-3-ones 13a–c. Due to
the above mentioned difficulty with the isolation of
reasonably large amounts of the pure 2,4-disubstituted
azetidin-3-ones 13a–c, only the reduction of the benzyl
derivative 13c was attempted (Scheme 4).
The reduction of azetidinone 13c with sodium borohydride
in a 9:1 mixture of ethanol and dichloromethane afforded
two epimeric azetidinols 15a and 15b which were separated
by flash chromatography. The most relevant NMR data of
these two azetidin-3-ols are summarised below (Table 1).
The first eluting isomer was identified as the trans epimer
Figure 3.

A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
2235
between H-3 and H-4 of 15b, as discussed before. No long
range W-coupling for 15a and 15b was observed.
(270 MHz, CDCl3, d): 5.22 and 4.53 (each s, 1H, H-4); 3.66
(s, 3H, OCH3); 2.34 (s, 3H, H-1).
All these facts concluded that the alkylation of N-iso-
propylimine 12, although not completely regioselective,
occurred with some degree of stereoselectivity, and only
one of the two possible diastereoisomers of the 2,4-di-
alkylated azetidin-3-ones 13a–d were obtained in each
case. Further research to improve the encountered regio-
selectivity in the alkylation step and the asymmetric
reduction of the imine functionality13 in order to prepare
enantiomerically pure azetidinols is currently being done.
3.1.3. Preparation of 4-bromo-3,3-dimethoxy-2-buta-
none 10. In a 250 ml round-bottomed flask, provided with
a magnetic stirrer and an air condenser, a solution of
3-methoxy-3-buten-2-one (9, 8.78 g, 87.8 mmol) and
3,3-dimethoxy-2-butanone (8, 4.91 g, 3.7 mmol) in metha-
nol (60 ml) was prepared. N-Bromosuccinimide (18.75 g,
105.4 mmol) was added and the mixture was stirred for 3 h
at room temperature under subdued light. The solvent was
evaporated, the residue was diluted in carbon tetrachloride
(150 ml) and succinimide was filtered off. 4-Bromo-3,3-
dimethoxy-2-butanone (10, 14.90 g, 70.6 mmol, 80.2%)
was obtained as a pale yellow liquid after evaporation of
the solvent and distillation in vacuo. Bp 95–978C/19–
3. Experimental
3.1. General
1
20 mm Hg. H NMR (270 MHz, CDCl3, d): 3.51 (s, 2H,
H-4); 3.29 (s, 6H, OCH3); 2.34 (s, 3H, H-1). 13C NMR
(67.5 MHz, CDCl3, d): 206.23 (C-2); 101.42 (C-3); 50.01
(OCH3); 29.49 (C-4); 28.37 (C-1). IR (NaCl, cm21): 1732
(CvO). Elemental analysis C6H11BrO3; calculated 34.14%
C, 5.25% H; found 34.05% C, 5.14% H.
1H and 13C NMR spectra were recorded on a JEOL JNM-
EX270 NMR spectrometer, operating at 270 and 67.5 MHz,
respectively. GC analytical and preparative separations
were done with a DELSI Intersmat IGC 120 ML gas
chromatograph. FT-IR spectra were recorded on a Perkin–
Elmer model 1310 spectrophotometer. The Electron Impact
(EI) mode mass spectra were obtained with a Varian MAT
112 mass spectrometer, operating at 70 eV. Boiling points
are uncorrected. Tetrahydrofuran was distilled over sodium
benzophenone ketyl prior to use. Dichloromethane was
distilled over calcium hydride prior to use. Diethyl ether was
dried and distilled over sodium wire. Chromatographic
separations were done using Merck Kieselgel 60 (230–400
mesh ASTM). Reactions were monitored with Merck
Kieselgel 60 F254 precoated tlc plates (0.25 mm thickness).
All other solvents and chemicals were used as supplied.
3.1.4. General preparation of the N-(4-bromo-3,3-
dimethoxy-2-butylidene)amines 4a–d. The preparation
of N-(4-bromo-3,3-dimethoxy-2-butylidene)isopropylamine
4a is representative. In a 250 ml three-necked round-
bottomed flask, provided with a magnetic stirrer and
nitrogen inlet, 4-bromo-3,3-dimethoxy butanone (10,
6.86 g, 32.5 mmol) and isopropylamine (11.15 ml,
130.0 mmol) were dissolved in dry diethyl ether (100 ml).
The mixture was cooled to 08C and titanium(IV) chloride
(2.14 ml, 19.5 mmol) dissolved in 5 ml of pentane was
added dropwise over 5 min at 08C. After stirring at room
temperature for 6 h the reaction mixture was poured onto
0.5N sodium hydroxide (150 ml) and stirred for 5 min. Then
it was filtered through celite and the filtrate was extracted
with diethyl ether (3£40 ml), the combined organic phases
were dried over potassium carbonate, filtered and the
solvent was evaporated. N-(4-Bromo-3,3-dimethoxy-2-
butylidene)isopropylamine (4a, 7.29 g, 28.9 mmol, 89%)
was obtained as a yellow liquid. Bp 47.5–50.08C/0.15–
3.1.1. Preparation of 3,3-dimethoxy-2-butanone 8.6 In a
500 ml round-bottomed flask, provided with a magnetic
stirrer and reflux condenser, 2,3-butadione (7, 86.0 g,
1.0 mol) and methyl orthoformate (106.0 g, 1.0 mol) were
placed. Concentrated sulfuric acid (ca. 0.2 ml) was added
and the mixture was refluxed for 5 h, cooled down to room
temperature and neutralised by slow and careful addition of
10% sodium bicarbonate (100 ml). The reaction mixture
was extracted with chloroform (3£100 ml), the combined
organic phases were dried over magnesium sulfate, filtered
and the solvent was evaporated. The residue was distilled to
give 3,3-dimethoxy-2-butanone (8, 80.44 g, 0.609 mol,
60.9%) as a pale yellow liquid. Bp 568C/24 mm Hg; (lit.6
1
0.20 mm Hg. H NMR (270 MHz, CDCl3, d): 3.78 (hepta-
plet, J¼6.2 Hz, 1H, CH(CH3)2); 3.66 (s, 2H, H-4); 3.25 (s,
6H, OCH3); 1.93 (s, 3H, H-1); 1.16 (d, J¼6.2 Hz, 6H,
CH(CH3)2). 13C NMR (67.5 MHz, CDCl3, d): 164.72 (C-2);
101.29 (C-3); 51.05 (CH(CH3)2); 49.33 (OCH3); 32.96
(C-4); 23.09 (CH(CH3)2); 14.93 (C-1). IR (NaCl, cm21):
1669 (CvN). Elemental analysis C9H18BrNO2; calculated
42.87% C, 7.20% H, 5.55% N; found 42.70% C, 7.31% H,
5.45% N.
1
588C/28 mm Hg). H NMR (270 MHz, CDCl3, d): 3.26 (s,
6H, OCH3); 2.24 (s, 3H, H-1); 1.38 (s, 3H, H-4).
3.1.2. Preparation of 3-methoxy-3-buten-2-one 9.8 In a
250 ml round-bottomed flask, provided with a magnetic
stirrer and a fractional distillation set, 3,3-dimethoxy-2-
butanone (8, 54.37 g, 0.446 mol) and diisopropylethyl-
ammoniun tosylate7 (1.56 g, 5.18 mmol) were heated at
ca. 1658C (oil bath temperature), when a yellowish liquid
distilled (1108C). A main fraction (38.4 g) was collected,
which contained 3-methoxy-3-buten-2-one, (9, 19.26 g,
0.214 mol, 48%), unreacted 3,3-dimethoxy-2-butanone (8,
14.26 g, 0.117 mol, 26%) and methanol, according to the
3.1.5. N-(4-Bromo-3,3-dimethoxy-2-butylidene)isobutyl-
amine 4b. Yellow liquid (yield 88%). Bp 49–518C/
0.07 mm Hg. H NMR (270 MHz, CDCl3, d): 3.67 (s, 2H,
1
H-4); 3.25 (s, 6H, OCH3); 3.23 (m, 2H, CH2CH(CH3)2);
2.05 (m, 1H, CH2CH(CH3)2); 1.92 (s, 3H, H-1); 0.95 (d,
J¼6.5 Hz, 6H, CH2CH(CH3)2). 13C NMR (67.5 MHz,
CDCl3, d): 166.23 (C-2); 104.05 (C-3); 56.10 (CH2CH(CH3)2);
48.46 (OCH3); 31.66 (C-4); 28.57 (CH2CH(CH3)2); 19.86
(CH2CH(CH3)2); 14.25 (C-1). IR (NaCl, cm21): 1655
(CvN). MS (EI, m/z, %): no Mþ; 234 (5); 186 (2); 99
(7); 98 (77); 89 (5); 88 (12); 73 (6); 58 (9); 57 (100); 43 (10);
1
relative integration in the 1H NMR spectrum. H NMR

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A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
42 (71); 41 (21). Elemental analysis C10H20BrNO2;
calculated 45.12% C, 7.57% H, 5.26% N; found 45.02%
C, 7.71% H, 5.08% N.
1H, H-4); 3.16, 3.26 (each s, 3H, OCH3); 3.09 (q, J¼6.6 Hz,
1H, H-2); 2.69 (d, Jgem¼8.2 Hz, 1H, H-4); 2.43 (dd, Jgem
11.5 Hz, Jvic¼6.6 Hz, 1H, CH2CH(CH3)2); 2.16 (dd, Jgem
¼
¼
11.5 Hz, Jvic¼7.6 Hz, 1H, CH2CH(CH3)2); 1.64 (m, 1H,
CH2CH(CH3)2); 1.18 (d, J¼6.3 Hz, 3H, CH3); 0.87, 0.89
(each d, J¼6.5 Hz, 3H, CH2CH(CH3)2). 13C NMR
(67.5 MHz, CDCl3, d): 99.06 (C-3); 70.28 (C-2); 67.53
(CH2CH(CH3)2); 61.33 (C-4); 48.48 and 49.15 (OCH3);
27.74 (CH2CH(CH3)2); 21.02 and 21.17 (CH2CH(CH3)2);
15.54 (CHCH3). MS (EI, m/z, %): 187 (Mþ, 2); 172 (7); 156
(7); 144 (9); 102 (45); 101 (5); 100 (6); 89 (26); 88 (100); 72
(17); 58 (43); 57 (30); 56 (40); 55 (8); 45 (5); 43 (33); 42
(17); 41 (13). Elemental analysis C10H21NO2; calculated
64.13% C, 11.30% H, 7.48% N; found 64.04% C, 11.49%
H, 7.35% N.
3.1.6. N-(4-Bromo-3,3-dimethoxy-2-butylidene)benzyl-
amine 4c. Yellow liquid (yield 86%). Bp decomp. 1H
NMR (270 MHz, CDCl3, d): 7.30 (m, 5H, Ph); 4.69 (s, 2H,
H-4); 3.27 (s, 6H, OCH3); 2.15 (s, 3H, H-1); 2.03 (s, 2H,
CH2Ph). 13C NMR (67.5 MHz, CDCl3, d): 168.77 (C-2);
139.19 (Ph -ipso-); 127.24, 127.89 (Ph-2, Ph-3); 126.18
(Ph-4); 101.15 (C-3); 54.81 (CH2Ph); 49.15 (OCH3); 32.15
(C-4); 15.24 (C-1). IR (NaCl, cm21): 1665 (CvN). MS (EI,
m/z, %): no Mþ; 271 (1); 270 (1); 269 (1); 268 (1); 220 (1);
169 (10); 167 (10); 132 (31); 92 (9); 91 (100); 88 (21); 73
(14); 65 (9); 58 (5); 43 (19). Elemental analysis
C13H18BrNO2; calculated 52.01% C, 6.04% H, 4.67% N;
found 52.15% C, 5.95% H, 4.59% N.
3.1.10. 1-Benzyl-3,3-dimethoxy-2-methylazetidine 11c.
Yellow liquid (yield 82%). Bp decomp. Rf: 0.39 (silica
gel, hexane–AcOEt 60:40). 1H NMR (270 MHz, CDCl3, d):
7.3 (m, 5H, Ph); 3.60, 3.75 (each d, Jgem¼12.5 Hz, 1H, AB
system, CH2Ph); 3.57 (dd, Jgem¼8.4 Hz, Jvic¼1 Hz, 1H,
H-4); 3.26 (q, J¼6.6 Hz, 1H, H-2); 3.17, 3.24 (each s, 3H,
OCH3); 2.80 (d, Jgem¼8.6 Hz, 1H, H-4); 1.05 (d, J¼6.3 Hz,
3H, CH3). 13C NMR (67.5 MHz, CDCl3, d): 138.13 (Ph
-ipso-); 128.19 and 129.00 (Ph-2 and Ph-3); 127.35 (Ph-4);
99.06 (C-3); 69.77 (C-2); 62.39 (CH2Ph); 60.16 (C-4); 48.75
and 49.29 (OCH3); 15.34 (CHCH3). MS (EI, m/z, %): no
Mþ; 206 (6); 191 (1); 190 (4); 130 (1); 102 (47); 92 (5); 91
(51); 89 (42); 88 (100); 72 (14); 59 (6); 58 (39); 57 (21); 56
(10); 43 (31). Elemental analysis C13H19NO2; calculated
70.56% C, 8.65% H, 6.33% N; found 70.44% C, 8.60% H,
6.24% N.
3.1.7. N-(4-Bromo-3,3-dimethoxy-2-butylidene)phenyl-
amine 4d. Yellow liquid (yield 95%). Bp 95–988C/
0.4 mm Hg. 1H NMR (270 MHz, CDCl3, d): 6.70–7.30
(m, 5H, Ph); 3.74 (s, 2H, H-4); 3.36 (s, 6H, OCH3); 1.92
(s, 3H, H-1). 13C NMR (67.5 MHz, CDCl3, d): 166.58
(C-2); 146.74 (Ph -ipso-); 125.25 (Ph-2); 119.91 (Ph-4);
115.08 (Ph-3); 97.58 (C-3); 45.91 (OCH3); 28.63 (C-4);
14.41 (C-1). IR (NaCl, cm21): 1670 (CvN). MS (EI, m/z,
%): 285/287 (Mþ, 2); 257 (1); 256 (1); 255 (1); 254 (1); 206
(1); 192 (2); 119 (10); 118 (100); 88 (19); 77 (32); 51 (8).
Elemental analysis C12H16BrNO2; calculated 50.37% C,
5.64% H, 4.89% N; found 50.53% C, 5.71% H, 4.82% N.
3.1.8. General preparation of 1-substituted 3,3-di-
methoxy-2-methylazetidines 11a–d. The preparation of
3,3-dimethoxy-1-isopropyl-2-methylazetidine 11a is repre-
sentative. In a 100 ml round-bottomed flask, provided with
a magnetic stirrer and nitrogen inlet, N-(4-bromo-3,3-di-
methoxy-2-butylidene)isopropylamine (4a, 3.77 g, 14.96
mmol) was dissolved in methanol (40 ml). After cooling to
08C, sodium borohydride (1.13 g, 29.92 mmol) was added
portionwise over 5 min at 08C. A reflux condenser was then
fitted and the mixture was refluxed for 2 h and cooled down
to room temperature. The reaction mixture was poured into
ice-water (ca. 100 g) and was then extracted with dichloro-
methane (3£70 ml). The combined organic phases were
dried over potassium carbonate, filtered and the solvent was
evaporated. 3,3-Dimethoxy-1-isopropyl-2-methylazetidine
(11a, 1.80 g, 10.41 mmol, 70%) was obtained as a yellow
liquid after distillation. Bp 68–748C/8–9 mm Hg. Rf: 0.32
(silica gel, hexane–AcOEt 60:40). 1H NMR (270 MHz,
CDCl3, d): 3.63 (d, Jgem¼8.2 Hz, 1H, H-4); 3.26 (s, 3H,
OCH3); 3.19 (q, J¼6.6 Hz, 1H, H-2); 3.17 (s, 3H, OCH3);
2.70 (d, Jgem¼8.2 Hz, 1H, H-4); 2.42 (heptet, J¼6.3 Hz,
1H, CH(CH3)2); 1.25 (d, J¼6.6 Hz, 3H, CH3); 0.95, 1.02
(each d, J¼6.3 Hz, 3H, CH(CH3)2). 13C NMR (67.5 MHz,
CDCl3, d): 97.79 (C-3); 68.41 (C-2); 59.00 (C-4); 58.56
(CH(CH3)2); 48.61 and 49.15 (OCH3); 20.56 and 21.33
(CH(CH3)2); 17.23 (CHCH3). MS (EI, m/z, %): C9H19NO2
requires 173.1416, found 173.1419 (Mþ, 3).
3.1.11. 3,3-Dimethoxy-2-methyl-1-phenylazetidine 11d.
Yellow liquid (yield 95%). Bp 69–718C/0.01 mm Hg. Rf:
0.19 (silica gel, hexane–AcOEt 97:3). 1H NMR (270 MHz,
CDCl3, d): 6.5–7.3 (m, 5H, Ph); 4.10 (q, J¼6.2 Hz, 1H,
H-2); 3.54, 4.07 (each d, Jgem¼8.2 Hz, 1H, H-4); 3.21, 3.32
(each s, 3H, OCH3); 1.44 (d, J¼6.3 Hz, 3H, CH3). 13C NMR
(67.5 MHz, CDCl3, d): 151.07 (Ph -ipso-); 128.82 (Ph-2);
117.80 (Ph-4); 112.09 (Ph-3); 98.87 (C-3); 68.18 (C-2);
59.62 (C-4); 48.66 and 49.38 (OCH3); 16.12 (CHCH3). MS
(EI, m/z, %): 207 (Mþ, 21); 192 (3); 176 (13); 169 (3); 159
(1); 132 (6); 119 (100); 102 (76); 88 (40); 77 (35); 57 (24);
43 (19). Elemental analysis C12H17NO2; calculated 69.54%
C, 8.27% H, 6.76% N; found 69.42% C, 8.39% H, 6.65% N.
3.1.12. General preparation of 1-alkyl-2-methylazetidin-
3-ones 6a–c. The preparation of 1-isopropyl-2-methyl-
azetidin-3-one 6a is representative. In a 50 ml round-
bottomed flask, provided with a magnetic stirrer, reflux
condenser and nitrogen inlet, 3,3-dimethoxy-1-isopropyl-2-
methylazetidine (11a, 1.80 g, 10.41 mmol) was cooled to
08C and to this 6N hydrochloric acid (17.3 ml, 104 mmol,
precooled to 08C) was added in one portion. The mixture
was refluxed for 12 h, cooled down to room temperature and
then it was carefully poured into ice-cooled 2N sodium
hydroxide (150 ml). After stirring for 5 min, it was
transferred to a 250 ml separatory funnel and extracted
with diethyl ether (3£40 ml). The combined organic phases
were dried over potassium carbonate, filtered and the
solvent was evaporated. 1-Isopropyl-2-methylazetidin-3-
one (6a, 1.20 g, 9.47 mmol, 91%) was obtained as a pale
3.1.9. 3,3-Dimethoxy-1-isobutyl-2-methylazetidine 11b.
Yellow liquid (yield 96%). Bp 90–948C/17 mm Hg. Rf:
0.20 (silica gel, hexane–AcOEt 80:20). 1H NMR
(270 MHz, CDCl3, d): 3.64 (dd, Jgem¼8.2 Hz, Jvic¼1 Hz,

A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
2237
yellow liquid. Rf: 0.22 (silica gel, Et2O). 1H NMR
1.37 (d, J¼6.6 Hz, 3H, CH3); 1.12, 1.13 (each d, J¼6.3 Hz,
3H, CvNCH(CH3)2); 1.02, 1.08 (each d, J¼6.3 Hz, 3H,
NCH(CH3)2). 13C NMR (67.5 MHz, CDCl3, d): 165.03
(C-3); 72.74 (C-2); 61.06 (C-4); 58.33 (NCH(CH3)2); 52.60
(CvNCH(CH3)2); 23.58 (CvNCH(CH3)2); 21.19 and
21.38 (NCH(CH3)2); 18.81 (CHCH3). IR (NaCl, cm21):
1740 (CvN). MS (EI, m/z, %): C10H20N2 requires
168.1626, found 168.1631 (Mþ, 2).
(270 MHz, CDCl3, d): 4.19 (dd, Jgem¼15.8 Hz, J2–4
¼
4.3 Hz, 1H, H-4); 3.92 (dq, J¼6.9 Hz, J2–4¼4.3 Hz, 1H,
H-2); 3.74 (dd, Jgem¼15.8 Hz, J2–4¼0.7 Hz, 1H, H-4); 2.62
(heptet, J¼6.3 Hz, 1H, CH(CH3)2); 1.33 (d, J¼6.9 Hz, 3H,
CH3); 1.08, 1.12 (each d, J¼6.3 Hz, 3H, CH(CH3)2). 13C
NMR (67.5 MHz, CDCl3, d): 204.74 (C-3); 80.38 (C-2);
71.46 (C-4); 58.99 (CH(CH3)2); 21.65 and 21.71
(CH(CH3)2); 16.82 (CHCH3). IR (NaCl, cm21): 1809
(CvO). MS (EI, m/z, %): C7H13NO requires 127.0997,
found 127.1011 (Mþ, 2).
3.1.16. General preparation of (2RS,4SR) 2-alkyl-1-
isopropyl-4-methylazetidin-3-ones 13a–d. The prepa-
ration of (2RS,4SR) 2-ethyl-1-isopropyl-4-methylazetidin-
3-one 13a is representative. In a 25 ml round-bottomed
flask, provided with magnetic stirrer and nitrogen inlet,
1-isopropyl-3-[(N-isopropyl)imino]-2-methylazetidine (12,
223 mg, 1.33 mmol), dissolved in 6 ml of tetrahydrofuran,
was added dropwise at 2208C over 5 min to a solution of
diisopropyl amine (161 mg, 1.59 mmol, 1.2 equiv.) and
n-butyllithium (0.58 ml of a 2.5 M solution in hexane,
1.46 mmol, 1.1 equiv.) in 2 ml of tetrahydrofuran. After
stirring at 2208C for 3 h, ethyl iodide (414 mg, 2.65 mmol,
dissolved in 2.0 ml of tetrahydrofuran, was added dropwise
at 2208C. The mixture was left stirring to warm up to room
temperature for 16 h, poured into 1N sodium hydroxide
(25 ml) and extracted with diethyl ether (2£25 ml). The
combined organic phases were dried over potassium
carbonate, filtered and the solvent was evaporated. The
obtained residue was dissolved in dichloromethane (20 ml)
and to this solution was added 2N hydrochloric acid
(6.5 ml). The two-phase system was vigorously stirred for
2.5 h at room temperature and then was carefully neutralised
with ice-cooled 1N sodium hydroxide (ca. 25 ml). Then, the
aqueous phase was extracted with fresh dichloromethane
(2£20 ml). The combined organic phases were dried over
potassium carbonate, filtered and the solvent was evapo-
rated. The residue was chromatographed (silica gel, column
dimensions 13.0 cm£2.5 cm, hexane–AcOEt 10:1). Appro-
priate fractions were pooled and evaporated. A yellow
residue (84 mg, 0.54 mmol, 41%) containing (2RS,4SR)
2-ethyl-1-isopropyl-4-methylazetidin-3-one 13a and 2-ethyl-
1-isopropyl-2-methylazetidin-3-one 14a in a ca. 9:1 ratio,
respectively, was obtained. An analytical sample of
(2RS,4SR) 2-ethyl-1-isopropyl-4-methyl azetidin-3-one
13a was obtained after preparative GC. Rf: 0.25 (silica,
hexane–AcOEt 5:1). 1H NMR (270 MHz, CDCl3, d): 3.75–
3.83 (m, 2H, H-2 and H-4); 2.68 (heptaplet, J¼6.3 Hz, 1H,
CH(CH3)2); 1.65–1.76 (m, 2H, CH2CH3); 1.28 (d, J¼
6.9 Hz, 3H, CH3); 1.08, 1.10 (each d, J¼6.3 Hz, 3H,
CH(CH3)2); 0.99 (t, J¼7.6 Hz, 3H, CH2CH3). 13C NMR
(67.5 MHz, CDCl3, d): 209.34 (C-3); 84.15 (C-2); 78.18
(C-4); 58.94 (CH(CH3)2); 25.39 (CH2CH3); 21.92 and 22.03
(CH(CH3)2); 16.80 (CHCH3); 9.97 (CH2CH3). IR (NaCl,
cm21): 1809 (CvO). MS (EI, m/z, %): 155 (Mþ, 2); 141
(1); 140 (7); 127 (26), 112 (14); 98 (7); 85 (14); 84 (100); 70
(29); 56 (20); 43 (15); 42 (10); 41 (33). Elemental analysis
C9H17NO; calculated 69.63% C, 11.04% H, 9.02% N; found
69.70% C, 11.21% H, 8.90% N.
3.1.13. 1-Isobutyl-2-methylazetidin-3-one 6b. Yellow
liquid (75% yield). Bp 65–678C/25 mm Hg. Rf: 0.22 (silica
gel, Et2O). 1H NMR (270 MHz, CDCl3, d): 4.19 (dd,
Jgem¼15.7 Hz, J2–4¼4.5 Hz, 1H, H-4); 3.85 (m, 1H, H-2);
3.70 (dd, Jgem¼15.7 Hz, J2–4¼0.5 Hz, 1H, H-4); 2.59 (dd,
Jgem¼11.3 Hz, Jvic¼6.9 Hz, 1H, CH2CHMe2); 2.43 (dd,
Jgem¼11.3 Hz, Jvic¼7.3 Hz, 1H, CH2CHMe2); 1.65 (m, 1H,
CH2CHMe2); 1.27 (d, J¼6.9 Hz, 3H, CH3); 0.94, 0.96 (each
d, J¼6.3 Hz, 3H, CH2CH(CH3)2). 13C NMR (67.5 MHz,
CDCl3, d): 204.85 (C-3); 82.05 (C-2); 73.03 (C-4);
67.82 (NCH2CHMe2); 28.30 (CHMe2); 20.56 and 20.69
(CH(CH3)2); 15.10 (CHCH3). IR (NaCl, cm21): 1810
(CvO). MS (EI, m/z, %): 141 (Mþ, 2); 126 (3); 113 (13);
99 (9); 98 (100); 84 (3); 71 (29); 70 (31); 69 (10); 68 (8); 58
(13); 57 (37); 56 (49); 55 (10); 42 (60); 41 (34); 39 (9).
Elemental analysis C8H15NO; calculated 68.04% C, 10.71%
H, 9.92% N; found 67.89% C, 10.85% H, 9.87% N.
3.1.14. 1-Benzyl-2-methylazetidin-3-one 6c. Yellow liquid
1
(yield 85%). Rf: 0.38 (silica, hexane–AcOEt 60:40). H
NMR (270 MHz, CDCl3, d): 7.30 (m, 5H, Ph); 4.18 (dd,
Jgem¼15.8 Hz, J2–4¼4.3 Hz, 1H, H-4); 4.02 (m, 1H, H-2);
3.88, 3.92 (each d, Jgem¼12.7 Hz, 1H, AB system, CH2Ph);
3.82 (dd, Jgem¼15.8 Hz, J2–4¼0.8 Hz, 1H, H-4); 1.15 (d,
J¼6.6 Hz, 3H, CH3). 13C NMR (67.5 MHz, CDCl3, d):
204.37 (C-3); 137.77 (Ph -ipso-); 128.28 and 128.63 (Ph-2
and Ph-3); 127.33 (Ph-4); 81.47 (C-2); 72.26 (CH2Ph);
62.54 (C-4); 14.95 (CHCH3). IR (NaCl, cm21): 1805
(CvO). MS (EI, m/z, %): C11H13NO requires 175.0997,
found 175.1003 (Mþ, 3).
3.1.15. Preparation of (E)-1-isopropyl-3-[(N-isopropyl)-
imino]-2-methylazetidine 12. In a 50 ml round-bottomed
flask, provided with magnetic stirrer and nitrogen inlet,
N-isopropyl-2-methylazetidin-3-one (6a, 747 mg, 5.88 mmol)
and isopropylamine (3.0 ml, 35.3 mmol) were dissolved in
dry diethyl ether (15 ml). To this titanium(IV) chloride
(0.38 ml, 3.53 mmol) was added at room temperature under
nitrogen. The mixture was stirred at room temperature for
3 h, then it was poured into 1N sodium hydroxide (50 ml),
stirred for five more minutes and extracted with diethyl
ether (3£20 ml). The combined organic phases were
dried over potassium carbonate, filtered and the solvent
was evaporated. (E)-1-Isopropyl-3-[(N-isopropyl)imino]-2-
methylazetidine (12, 693 mg, 4.12 mmol, 70%) was
obtained as
a
caramel coloured liquid. 1H NMR
(270 MHz, CDCl3, d): 4.24 (dd, Jgem¼13.8 Hz, J2–4
¼
3.1.17. (2RS,4SR) 1-Isopropyl-4-methyl-2-propylazeti-
din-3-one 13b. Yellow liquid (yield 48%, 85:15 mixture
of 13b and 14b, analytical sample of 13b obtained after
preparative GC). Rf: 0.43 (silica gel, hexane–AcOEt 5:1).
1H NMR (270 MHz, CDCl3, d): 3.74–3.82 (m, 2H, H-2 and
3.6 Hz, 1H, H-4); 3.86 (ddq, J¼6.6 Hz, J2–4¼3.6 Hz,
J2–4¼2.0 Hz, 1H, CHCH3); 3.56 (dd, Jgem¼13.8 Hz,
J2–4¼2.0 Hz, 1H, H-4); 3.35 (heptaplet, J¼6.3 Hz, 1H,
CvNCH(CH3)2); 2.54 (heptet, J¼6.3 Hz, 1H, NCH(CH3)2);

2238
A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
H-4); 2.67 (heptaplet, J¼6.3 Hz, 1H, CH(CH3)2); 1.50–
1.70 (m, 4H, CH2CH2CH3); 1.29 (d, J¼6.9 Hz, 3H, CH3);
1.08, 1.11 (each d, J¼6.3 Hz, 3H, CH(CH3)2); 0.92
(t, J¼7.6 Hz, 3H, CH2CH2CH3). 13C NMR (67.5 MHz,
CDCl3, d): 209.37 (C-3); 82.96 (C-2); 78.11 (C-4); 59.08
(CH(CH3)2); 34.66 (CH2CH2CH3); 21.89 and 22.07
(CH(CH3)2); 18.98 (CH2CH2CH3); 16.99 (CHCH3); 14.12
(CH2CH2CH3). IR (NaCl, cm21): 1803 (CvO). MS (EI,
m/z, %): 169 (Mþ, 4); 154 (10); 141 (37); 136 (5); 126 (43);
112 (45); 98 (100); 85 (16); 84 (37); 71 (20); 70 (64); 69
(11); 44 (36); 43 (41); 42 (34); 41 (44). Elemental analysis
C10H19NO; calculated 70.96% C, 11.31% H, 8.28% N;
found 70.78% C, 11.19% H, 8.22% N.
was evaporated in vacuo. The residue was chromatographed
(silica, column dimensions 13£2.5 cm, hexane–AcOEt 4:1).
Two compounds were isolated after pooling and evapo-
ration of the appropriate fractions.
First eluting compound. (2RS,3SR,4SR) 2-Benzyl-1-isopro-
pyl-4-methylazetidin-3-ol (15b, 87.5 mg, 0.40 mmol, 17%).
Rf: 0.31 (silica, AcOEt–hexane–MeOH 83:12:5). 1H NMR
(270 MHz, CDCl3, d): 7.15–7.31 (m, 5H, phenyl); 3.48 (t,
J2–3¼J3,4¼5.4 Hz, 1H, H-3); 3.07 (dd, Jgem¼12.8 Hz,
Jvic¼4.0 Hz, 1H, CH2Ph); 2.95 (m, 1H, H-2); 2.80 (m, 1H,
CH2Ph); 2.77 (m, 1H, H-4); 2.55 (heptet, J¼6.3 Hz, 1H,
CHMe2); 2.10 (s, 1H, OH); 1.28 (d, J¼6.3 Hz, 3H, CH3–
C-4); 1.01, 1.06 (each d, J¼6.3 Hz, 3H, CHMe2). 13C NMR
(67.5 MHz, CDCl3, d): 138.29 (Ph -ipso-); 128.89, 128.50
(Ph-2 and Ph-3); 126.27 (Ph-4); 74.37 (C-3); 72.28 (C-2);
66.76 (C-4); 58.87 (CHMe2); 42.73 (CH2Ph); 21.01 and
21.46 (CHMe2); 14.20 (Me–C-2). MS (EI, m/z, %):
C14H21NO requires 219.1623, found 219.1631 (Mþ, 3).
3.1.18. (2RS,4SR) 2-Benzyl-1-isopropyl-4-methylazeti-
din-3-one 13c. Yellow liquid (yield 51.1%, 3:1 mixture of
13c and 14c, considerable amount of pure 13c was obtained
after flash chromatography, silica, hexane–AcOEt 9:1). Rf:
1
0.20 (silica gel, hexane–AcOEt 9:1). H NMR (270 MHz,
CDCl3, d): 4.02 (dd, J¼7.6, 4.6 Hz, 1H, H-2); 3.80 (q,
J¼6.9 Hz, 1H, H-4); 3.04 (dd, Jgem¼14.3 Hz, Jvic¼7.6 Hz,
1H, CH2Ph); 2.90 (dd, Jgem¼14.3 Hz, Jvic¼4.6 Hz, 1H,
CH2Ph); 2.69 (heptaplet, J¼6.3 Hz, 1H, CH(CH3)2); 1.14
(d, J¼6.9 Hz, 3H, CH3); 1.06, 1.08 (each d, J¼6.3 Hz, 3H,
CH(CH3)2). 13C NMR (67.5 MHz, CDCl3, d): 207.96 (C-3);
137.72 (Ph -ipso-); 127.30, 128.40 and 129.50 (Ph); 83.52
(C-2); 77.95 (C-4); 58.56 (CH(CH3)2); 38.74 (CH2Ph);
21.74 and 22.16 (CH(CH3)2); 16.82 (CHCH3). IR (NaCl,
cm21): 1802 (CvO). MS (EI, m/z, %): no Mþ; 202 (3); 190
(4); 189 (22); 174 (4); 160 (1); 146 (14); 126 (100); 105 (6);
91 (12); 84 (39); 70 (10); 65 (4); 56 (19); 43 (16). Elemental
analysis C14H19NO; calculated 77.38% C, 8.81% H, 6.45%
N; found 77.32% C, 8.69% H, 6.58% N.
Second eluting compound. (2RS,3RS,4SR) 2-Benzyl-1-iso-
propyl-4-methyl azetidin-3-ol (15a, 159 mg, 0.73 mmol,
31%). Rf: 0.18 (silica gel, AcOEt–hexane–MeOH 83:12:5).
1H NMR (270 MHz, CDCl3, d): 7.00–7.20 (m, 5H, phenyl);
4.22 (m, 1H, H-3); 3.25 (m, 2H, H-2 and CH2Ph); 3.17 (m,
1H, H-4); 2.72–2.79 (m, 1H, CH2Ph); 2.51 (heptet, J¼
6.3 Hz, 1H, CHMe2); 1.91 (d, J¼7.9 Hz, 1H, OH); 1.20 (d,
J¼6.3 Hz, 3H, CH3–C-4); 1.01, 1.07 (each d, J¼6.3 Hz,
3H, CHMe2). 13C NMR (67.5 MHz, CDCl3, d): 139.32
(Ph-ipso-); 128.46 and 128.96 (Ph-2 and Ph-3); 126.07
(Ph-4); 68.52 (C-2); 66.36 (C-3); 62.12 (C-4); 58.45
(CHMe2); 36.39 (CH2Ph); 21.53 and 21.92 (CHMe2);
15.83 (Me–C-2). MS (EI, m/z, %): C14H21NO requires
219.1623, found 219.1637 (Mþ, 4).
3.1.19. (2RS,4SR) 2-Allyl-1-isopropyl-4-methylazetidin-
3-one 13d. Yellow residue (yield %, 4:1 mixture of 13d and
14d, analytical sample of 13d was obtained after preparative
1
GC). Rf: 0.42 (silica gel, hexane–AcOEt 5:1). H NMR
References
(270 MHz, CDCl3, d): 5.82–5.94 (m, 1H, CH2vCH);
5.06–5.14 (m, 2H, CH2vCH); 3.78–3.89 (m, 2H, H-2 and
H-4); 2.70 (heptet, J¼6.3 Hz, 1H, CH(CH3)2); 2.41–2.49
(m, 2H, CH2vCHCH2); 1.29 (d, J¼6.9 Hz, 3H, CH3); 1.09,
1.11 (each d, J¼6.3 Hz, 3H, CH(CH3)2). 13C NMR
(67.5 MHz, CDCl3, d): 208.15 (C-3); 133.87 (CH2vCH);
117.39 (CH2vCH); 83.52 (C-2); 78.24 (C-4); 58.78
(CH(CH3)2); 36.75 (CH2vCHCH2); 21.85 and 22.17
(CH(CH3)2); 16.89 (CHCH3). IR (NaCl, cm21): 1804
(CvO). MS (EI, m/z, %): C10H17NO requires 167.1310,
found 167.1316 (Mþ, 3).
1. De Kimpe, N. In Azetidines, Azetines and Azetes: Monocyclic.
Comprehensive Heterocyclic Chemistry II, Three and Four-
Membered Rings, with All Fused Systems Containing Four-
Membered Rings; Padwa, A., Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 1B.
Chapter 1.18.
2. (a) De Kimpe, N.; Sulmon, P.; Schamp, N. J. Chem. Soc.,
Chem. Commun. 1985, 715–716. (b) De Kimpe, N.; Sulmon,
P.; Schamp, N. Tetrahedron 1988, 44, 3653–3670. (c) De
Kimpe, N.; Sulmon, P.; Schamp, N. J. Org. Chem. 1989, 54,
2587–2590. (d) De Kimpe, N.; Sulmon, P.; Schamp, N.
Tetrahedron 1989, 45, 2937–2955. (e) De Kimpe, N.;
Stevens, C. Synthesis 1993, 89–91. (f) De Kimpe, N.;
De Smaele, D. Tetrahedron Lett. 1994, 35, 8023–8026.
(g) Aelterman, W.; De Kimpe, N.; Declercq, J.-P. J. Org.
Chem. 1998, 63, 6–11. (h) De Smaele, D.; Dejaegher, Y.;
Duvey, G.; De Kimpe, N. Tetrahedron Lett. 2001, 42,
2373–2375.
3.1.20. Reduction of (2RS,4SR) 2-benzyl-1-isopropyl-4-
methylazetidin-3-one 13c. In a 50 ml round-bottomed
flask, provided with a magnetic stirrer and nitrogen inlet,
sodium borohydride (223 mg, 5.88 mmol) was added
dropwise to an ice-cooled solution of (2RS,4SR) 2-benzyl-
1-isopropyl-4-methyl azetidin-3-one (13c, 510 mg, 2.35 mmol)
in dichloromethane (2 ml) and absolute ethanol (18 ml).
This mixture was stirred while warmed up to ambient
temperature for 2 h, water (4 ml) was then added, and the
stirring was continued for another hour. Ethyl acetate
(10 ml) was added, and the aqueous phase was extracted
with ethyl acetate (2£5 ml). The combined organic phases
were dried over magnesium sulfate, filtered and the solvent
3. Salgado, A.; Boeykens, M.; Gauthier, C.; Declercq, J.-P.; De
Kimpe, N. Tetrahedron 2002, 58, 2763–2775.
¨
4. (a) Kobayashi, J.; Cheng, J.; Ishibashi, M.; Walchli, M. R.;
Yamamura, S.; Ohizumi, Y. J. Chem. Soc., Perkin Trans. 1
1991, 1135–1137. (b) Takikawa, H.; Maeda, T.; Seki, M.;
Koshino, H.; Mori, K. J. Chem. Soc., Perkin Trans. 1 1997,

A. Salgado et al. / Tetrahedron 59 (2003) 2231–2239
2239
97–111. (c) Knapp, S.; Dong, Y. Tetrahedron Lett. 1997, 38,
3813–3816.
8. Feuerer, A.; Severin, T. J. Org. Chem. 1994, 59, 6026–6029.
9. Grady, G. L.; Chokshi, S. K. Synthesis 1972, 483–484.
10. De Kimpe, N.; Rocchetti, M. T. J. Agric. Food Chem. 1998,
46, 2278–2281.
5. For previous syntheses of azetidin-3-one derivatives, see:
(a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem.
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´
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