Synthesis of 4-alkyl-1-benzhydryl-2-(methoxymethyl)azetidin-3-ols by regio- and stereoselective alkylation of 1-benzhydryl-3-(N-alkyl)imino-2-(methoxymethyl)azetidine

Article abstract of DOI:10.1016/S0040-4020(02)00178-3

The regio- and stereoselective alkylation at the position C-4 of 1-alkyl-2-substituted azetidin-3-ones was investigated. Imination of 1-benzhydryl-2-methoxymethylazetidin-3-one, followed by alkylation under kinetic conditions and final hydrolysis of the imino group, gave 4-alkyl-1-benzhydryl-2-methoxymethylazetidin-3-ones in which the susbstituents at C-2 and C-4 had the cis stereochemistry. The reduction of the carbonyl group afforded the corresponding 4-alkyl-1-benzhydryl-2-methoxymethylazetidin-3-ols. The structure and the stereochemistry of the azetidinols were confirmed by single crystal X-ray diffraction analysis.

Full text of DOI:10.1016/S0040-4020(02)00178-3

TETRAHEDRON
Pergamon
Tetrahedron 58 :2002) 2763±2775
Synthesis of 4-alkyl-1-benzhydryl-2-ꢀmethoxymethyl)azetidin-
3-ols by regio- and stereoselective alkylation of 1-benzhydryl-3-
ꢀN-alkyl)imino-2-ꢀmethoxymethyl)azetidine
Antonio Salgado,a Mark Boeykens,a Christine Gauthier,a Jean-Paul Declercqb
and Norbert De Kimpea,p
aDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
B-9000 Gent, Belgium
 Â
Unite CSTR, Laboratoire de Cristallographie, Universite Catolique de Louvain, 1 Place Louis Pasteur, B-1348 Louvain-la-Neuve, Belgium
b
This article is dedicated to Professor R. Sheldon on the occasion of his 60th birthday
Received 29 November 2001; revised 29 January 2002; accepted 18 February 2002
AbstractÐThe regio- and stereoselective alkylation at the position C-4 of 1-alkyl-2-substituted azetidin-3-ones was investigated. Imination
of 1-benzhydryl-2-methoxymethylazetidin-3-one, followed by alkylation under kinetic conditions and ®nal hydrolysis of the imino group,
gave 4-alkyl-1-benzhydryl-2-methoxymethylazetidin-3-ones in which the susbstituents at C-2 and C-4 had the cis stereochemistry. The
reduction of the carbonyl group afforded the corresponding 4-alkyl-1-benzhydryl-2-methoxymethylazetidin-3-ols. The structure and the
stereochemistry of the azetidinols were con®rmed by single crystal X-ray diffraction analysis. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
alkaloids, all of them having the common structural pattern
of 2,4-disubstituted azetidin-3-ols 1, have been reported by
some groups.1,2 It must be said that the absolute con®gu-
ration of C-16 of Penazetidin A is still unknown.2f
Azetidin-3-ols are found in nature as the sphingosine type
alkaloids Penaresidines A and B and Penazetidin A :Fig. 1).
Penaresidines A and B were ®rstly isolated fromthe
Okinawan marine sponge Penares sp.1 Syntheses of these
These compounds possess remarkable pharmacological
Figure 1.
Keywords: azetidine; azetidinone; alkylation.
Corresponding author. Tel.: 132-9-264-59-51; fax: 132-9-264-62-43; e-mail: norbert.dekimpe@rug.ac.be
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020:02)00178-3

2764
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
Scheme 1.
properties. Penaresidine A and B are known for their
actomyosine-ATPase activating properties,1 whereas
Penazetidine A is a strong inhibitor of protein kinase C.3
In other cases, azetidin-3-ols have been also incorporated
as active moieties of some pharmaceutical drugs.4,5 Due to
their potential applicability, much effort has been recently
dedicated to develop synthetic methods for this important
class of compounds, either as racemates or in enantiopure
form.1,2
The results of the synthesis of azetidin-3-one 4 and those of
our alkylation attempts are described below.
2. Results and discussion
2.1. Preparation of 1-benzhydryl-2-ꢀmethoxymethyl)-
azetidin-3-one 4
The synthetic route leading to azetidinone 4 is shown in
Scheme 2. The synthesis started from the commercially
available methyl 4-chloro-3-oxobutanoate 5, which was
converted into methyl 4-chloro-3-methoxy-2-butenoate 6
by acetalization and elimination of methanol, utilizing
subsequently hydrogen chloride in methanol and methane-
sulfonic acid.11 Methyl 4-chloro-3-methoxy-2-butenoate 6
was then reacted with sodiumazide in acetonitrile under
re¯ux,12 to give methyl 4-azido-3-methoxy-2-butenoate
7. Alkoxybromination of 7 with N-bromosuccinimide
in methanol13 afforded methyl 4-azido-2-bromo-3,3-
dimethoxy butanoate 8, the azido group of which was
reduced with tin:II) chloride in dry methanol,14 resulting
in the amine hydrochloride derivative of methyl 4-amino-
2-bromo-3,3-dimethoxybutanoate 12 in moderate yield. At
this stage, the cyclization to the azetidine systemcould be
attempted by intramolecular displacement of the bromine
Azetidin-3-ols were ®rst prepared by Gaertner, who studied
the ring transformation of primary amines with epichloro-
hydrin.6 A reportedly improved version of this method
consisted of the reaction of epichlorohydrin with bis:tri-
methylsilyl)methylamine :BSMA), followed by desilyl-
ation.7 Other methods are based on the ring closure of
conveniently functionalized 3-amino-1,2-propanediol
precursors,6b,8 the addition of amines to 2-O-benzyloxy-
methyl-1,3-bis:O-methanosulfonyl)glycerol,4e the regio-
selective halogenation of 2,3-epoxyamines,9 or the
reduction of azetidin-3-ones.4e In the case of the structurally
more complex penaresidines and penazetidines, to the best
of our knowledge, all the reported syntheses are based on
the preparation of a suitable 3-amino-1,2-diol precursor, and
the subsequent ring closure.1,2 A synthetic strategy of this
kind requires that the substituents at positions C-2 and C-4
of the azetidin ring have to be present in the acyclic pre-
cursor prior to the ring closure step. This implies that long
and tedious synthetic protocols have to be devised for each
single compound. In order to obtain several penaresidin-like
derivatives, with which extensive and thus reliable struc-
ture±activity studies can be carried out, a more ¯exible
method for these compounds and their stereoisomers
would be desirable. We present here a protocol for the
synthesis of 2,4-disubstituted azetidin-3-ols 1 via selective
alkylation of an azetidin-3-one precursor 2,10 and subse-
quent reduction of the carbonyl group of 3. :Scheme 1).
atomof compound
12 by the amino group. However,
neutralization of 9 in a biphasic mixture of dichloromethane
and aqueous sodiumbicarbonate gave 3-broom-4,4-
dimethoxypyrrolidin-2-one 15 as the sole product after
one hour :Scheme 3).15 This ®nding was in agreement
with the reported propensity of N-unsubstituted g-amino-
butanoates to cyclize to the ®ve-membered ring.16
It was reasoned that a N-substituted g-amino-2-bromo-
butanoate would be a better precursor for the cyclization
to the four-membered azetidine system. Such precursor
should be readily obtained fromthe reduction with hydride
of the corresponding imine. Therefore, the amine hydro-
chloride 9 was reacted with benzophenone imine, i.e.
N-diphenylmethylideneamine, which gave rise to methyl
2-bromo-3,3-dimethoxy-4-:diphenylmethyleneamino)butano-
ate 10.17 This precursor was thought to be amenable to
afford an azetidine by reduction with hydride, according
to the expertise gained in our group with N-:alkylidene)-
or N-:arylidene)-3-haloalkylamines.18 It must be taken
into account that the comparable bulky diphenylmethylene
group may conformationally assist the ring closure step to
the azetidine, in the same way as in some reported syntheses
of azetidin-3-ols.8 Although it did not work out well in the
case of the formation of an azetidine from g-bromoamine 9,
the geminal dimethoxy effect19 may favorably contribute in
substrate 10 to produce the corresponding azetidine.
In this work, 1-benzhydryl-2-methoxymethylazetidin-3-one
4 was chosen as the substrate for the alkylation reactions
because of the importance of 2-alkyl-3-hydroxy-4-:hydroxy-
methyl)azetidines 1 :Fig. 2).
Figure 2.

A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
2765
Scheme 2.
Scheme 3.

2766
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
Scheme 4.
The reduction of the imine group of 10 was tried under
several experimental conditions.20 The best results were
encountered when sodiumcyanoborohydride was used as
the reducing agent. The reaction of the N-:diphenylmethyl-
idene)-3-bromoamine 10 with sodiumborohydride in
methanol gave complex reaction mixtures and resulted in
lower yields of azetidine 11. The reaction of the functional-
ized imine 10 with sodiumcyanoborohydride in methanol in
the presence of acetic acid, and followed by addition of an
equivalent amount of triethylamine and heating under
re¯ux, afforded methyl 1-benzhydryl-3,3-dimethoxyazeti-
dine-2-carboxylic acid 11, mixed with the g-lactam1-benz-
hydryl-3-bromo-4,4-dimethoxypyrrolidin-2-one 12 in a
ratio of ca. 2.5 to 1. As discussed above, the latter is a
consequence of the ring closure on the ester group of 10.
This reaction was carried out under various experimental
conditions, and in every case lactamization occurred to
some extent. The highest azetidine ratio was obtained
when the reaction was performed at high temperature.
More g-lactamresulted if the temperature was lowered
:08C). These ®ndings can be rationalized on the basis that
cyclization to a four-membered ring is a priori a kinetically
and thermodynamically unfavored process when compared
to the formation of a ®ve-membered cycle,21 even though
the presence of a bulky substituent at the nitrogen atomof
:10) would probably destabilize to some extent the tran-
sition state to the pyrrolidin-2-one system, thus favoring
the formation of the azetidin-3-one derivative.
graphic conditions tried :TLC, silica gel). Nevertheless, the
azetidine 11 and the pyrrolidone 12 were successfully sepa-
rated by fractional crystallization fromdiethyl ether at
2208C, as the pyrrolidin-2-one 12 crystallized in the ®rst
place and could be then removed completely this way by
®ltration.
The reduction of methyl 1-benzhydryl-3,3-dimethoxyazeti-
dine-2-carboxylate 11 with lithiumaluminiumhydride in
diethyl ether gave 1-benzhydryl-3,3-dimethoxy-2-:hydroxy-
methyl)azetidine 13. Its hydroxy group was protected by
methylation with methyl iodide and sodium hydride in tetra-
hydrofuran,22 resulting in 1-benzhydryl-3,3-dimethoxy-2-
:methoxymethyl)azetidine 14. Final hydrolysis of the acetal
function with concentrated sulfuric acid23 furnished 1-benz-
hydryl-2-:methoxymethyl)azetidin-3-one 4.
2.2. Alkylation of 1-benzhydryl-2-methoxymethyl-
azetidin-3-one 4
It is known that the use of imines in the a-alkylation of
ketones is often advantageous as compared to the direct
alkylation of carbonyl compounds because of some striking
chemical properties of 1-azaenolates.24 The addition at low
temperature of a relatively sterically bulky base, such as
lithiumdiisopropylamide, allows to deprotonate regio-
selectively the least sterically hindered a-position of the
imine, whereas an increase of the temperature would favor
an equilibriumshifted to the most stable 1-azaenolate. It
was therefore attempted to alkylate the N-isopropylimine
derived fromazetidin-3-one 4, using lithiumdiisopropyl-
amide and an alkyl halide in tetrahydrofuran at 2208C,
The mixture of azetidin 11 and g-lactam 12 could not be
separated by ¯ash chromatography, as it happened that both
components had the same Rf values under all the chromato-

A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
2767
Scheme 5.
with the aimto selectively achieve the conversion to the less
hindered 1-azaenolate :Scheme 4).
freshly prepared lithiumdiisopropylamide in THF, followed
by the alkylating agent, i.e. iodoethane or iodopropane.
These conditions exclusively furnished the C-4 alkylated
imines 17a and 17b. Conventional hydrolysis of the imino
groups of compounds 17a and 17b with aqueous hydro-
chloric acid in a two phase systemwith dichloromethane,
respectively gave 1-benzhydryl-4-ethyl-2-:methoxymethyl)-
azetidin-3-one 18a and 1-benzhydryl-2-:methoxymethyl)-
4-propyl-azetidin-3-one 18b in 19 and 22% yield after the
chromatographic puri®cation. These yields, albeit modest,
were in fact the combined yield of three sequential steps
The ®rst step was the almost quantitative conversion of
the 1-benzhydryl-2-:methoxymethyl)azetidin-3-one 4 to
the corresponding N-isopropylimino derivative 16. This
reaction was performed by reacting azetidine 4 with iso-
propylamine and titanium:IV) chloride in diethyl ether,
affording N-:1-benzhydryl-2-:methoxymethyl)-3-azetidinyl-
idene)isopropylamine 16 in 96% yield.25 The alkylation
itself was done by sequential addition of the imine 16 to

2768
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
Scheme 6.
:azaenolization, alkylation and acidic imine hydrolysis).
Therefore, an overall yield of ca. 20% can be seen as the
result of three 60% yield steps, moderate but acceptable.
hybridation of that carbon atomin the azaenolization step
would condition that the methoxymethyl group clearly is
pointed outwards, therefore laying too distant to effectively
coordinate with the metal counterion, and giving rise to a
less stable transition state. Consequently, a plausible
mechanism for the alkylation of the 3-iminoazetidine 15 is
shown in Scheme 5. It was presumed that the preferred
conformation of the benzhydryl substituent at the 1-position
was trans to the 2-methoxymethyl group due to steric
considerations. It is clear also that the kinetic deprotonation
of the 3-iminoazetidine 16 by LDA favors the alkylation of
the least substituted position, i.e. the methylene group at the
4-position.
1
All the collected H, 13C and DEPT NMR data of 18a and
18b supported the proposed structures. The 13C NMR spec-
trum:CDCl ) of 18a showed two signals at 83.77 and
3
86.04 ppm, which were unambiguously assigned to the
methine carbon atoms C-2 and C-4, respectively. The fact
that, according to the DEPT experiment, the C-2 and C-4
carbon atoms of 18a were methines completely demon-
strated that the alkylation of 16 had exclusively occurred
at the C-4 position. The same result was observed with
18b, as the two signals :13C NMR, CDCl3) at 84.37 and
84.96 ppmwere also attributed to the two methine carbons
C-2 and C-4, thus proving the regioselectivity of the
method.
In order to prove the cis stereochemistry of 18a and 18b,
some nOe experiments were carried out. Unfortunately,
these experiments were unsuccessful because the 1H signals
assigned to H-2 and H-4 were too close together. No
W-pattern coupling was observed between H-2 and H-4,
positioned on the same side of the ring. It has been reported
that a W-coupling constant of ca. 4.4 Hz could be expected
in such a four-membered ring.10c
Analytical GC and the fact that the signals in the 1H and 13
C
NMR spectra were not doubled indicated that uniquely one
compound had been obtained. This implied that, under the
given reaction conditions, not only alkylations did proceed
regioselectively, but also stereoselectively, and only one
stereoisomer of each azetidinone 18a and 18b was obtained.
In relation to the relative stereochemistry of the azeti-
dinones 18a and 18b, it was concluded that the substituents
at C-2 and C-4 were cis to each other. This fact is in agree-
ment with the reported mechanism of asymmetric alkylation
of ketones using b-:alkoxy)amines as chiral auxiliaries, in
which imines are used as intermediates.26 According to that
mechanism, an alkoxy group coordinates with the metal
counterion in the enolization step. This process leads to a
favoring of the cis approximation of the alkylating agent, as
the halogen atomwould also coordinate with the metal
counterion, resulting in a more compact, and thus more
stable, transition state.27 In the case of an hypothetical alkyl-
ation at the C-2 position of the 3-iminoazetidine 16, the sp2
2.3. Reduction of 4-alkyl-1-benzhydryl-2-ꢀmethoxy-
methyl)azetidin-3-ones 18
The reduction of 1-benzhydryl-4-ethyl-2-:methoxymethyl)-
azetidin-3-one 18a and 1-benzhydryl-2-:methoxymethyl)-
4-propylazetidin-3-one 18b with sodiumborohydride
gave, in each case, the corresponding azetidin-3-ols 19
and 20 as mixtures of two epimers. Each epimeric pair
was successfully resolved by ¯ash chromatography :silica
gel, hexane±ethyl acetate 5:1). The all cis epimer 19b was
also selectively prepared in 25% yield by reduction of 18b
with a bulky reducing agent, such as potassiumtrisiamyl-
borohydride :KS Selectride) in diethyl ether at 08C.28
Reagents of this kind are used in the stereoselective

A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
2769
Figure 3. X-Ray crystallographic structure of 1-benzhydryl-2-:methoxymethyl)-4-propylazetidin-3-ol 19b.
reduction of ketones when steric factors are controlling.29 It
was therefore expected that KS Selectride would add
hydride by attack fromthe less hindered diastereotopic
face of the carbonyl group of the 3-azetidinone 18b,
uniquely affording the all cis 1-benzhydryl-2-methoxy-
methyl-4-propylazetidin-3-ol 19b :Scheme 6).
The all cis isomers 19a and 19b showed coupling constants
between H-2 and H-3, and H-3 and H-4 of 6.3 Hz. Their
epimers 20a and 20b gave a little smaller :5.6 Hz) trans
vicinal coupling constants. These ®ndings are consistent
with the reported coupling constants of other azetidine
derivatives, as it has been reported that trans vicinal coupling
gave rise to smaller coupling constants.32 For instance, the 1H
NMR spectrum:60 MHz) of the cis and trans isomers of
1-tertbutyl-2-methylazetidin-3-ol, gave vicinal coupling
constant values of 6.2 and 6.0 Hz, respectively.33 Also, trans
1-benzyl-2-phenylazetidin-3-ol gave a coupling constant
value of 5.4 Hz,34 while cis :2S,3S) 1-tert-butoxycarbonyl-2-
methylazetidin-3-ol showed J2,3ˆ 6.5 Hz.10c These values are
virtually identical to those measured for 20a and 20b.
The relative stereochemistry of the substituents at positions
C-2 and C-4 of the azetidin-3-ols 19 and 20 could not be
either proved with mono- and bidimensional nOe NMR
1
experiments, due to the proximity of the H-2 and H-4 H
NMR signals. No W-coupling between H-2 and H-4 was
observed. However, the cis relative con®guration of the
substituents at C-2, C-3 and C-4 of 19 and, therefore also
that of the azetidinone precursors 18, was unambiguously
demonstrated from the X-ray diffraction analysis of 1-benz-
hydryl-2-:methoxymethyl)-4-propylazetidin-3-ol 19b :Fig.
3).30 This result con®rmed the assumption that the a-alkyl-
ation of azetidin-3-ones via the corresponding imine 16
proceeded in a regio- and stereoselective way. In addition,
these results determined the stereochemistry of the isomeric
azetidinols 20.
3. Experimental
3.1. General
NMR spectra were recorded on Jeol JNM EX270 or Bruker
AM500 spectrometers, with TMS as internal standard. IR
spectra were recorded on a Perkin±Elmer PE 1310 FTIR
spectrophotometer. Melting points were recorded on a
BuÈchi 535 melting point apparatus. Boiling and melting
points are uncorrected. Gas chromatographic analyses
were carried out with a DELSI Instersmat IGC 120 ML
gas chromatograph, ®tted with a RSL 150 silica capillary
column :20 m, 0.53 mm internal diameter), and using
hydrogen as carrier gas. Flash chromatographic separations
were performed on Merck Kieselgel 60 :230±400 mesh
ASTM). Analytical TLC was performed on Merck Kiesel-
gel 60 F254 precoated TLC plates :0.25 mm thickness).
Dichloromethane was distilled over calcium hydride prior
to use. Diethyl ether was distilled over lithiumaluminium
Once fully determined the con®guration of both epimeric
azetidinols 19 and 20, the accurate measuring of the chemi-
1
cal shifts and coupling constants in the H NMR spectrum
was performed as it should be useful in the structural deter-
mination of other 2,4-dialkylated azetidinols. To the best of
our knowledge, the preparation of all cis 2,4-disubstituted
azetidin-3-ol derivatives has been reported only once,31
although no accurate NMR data on these compounds were
provided. Detailed NMR data on disubstituted azetidinols
are very scarce in the literature.1,2i,3,10c,31±34 The chemical
shifts and coupling constants of the 2,4-disubstituted
azetidin-3-ols 19a±b and 20a±b are summarized in Table 1.
Table 1. Selected 1H NMR data of 2,4-disubstituted azetidin-3-ols 19 and 20 :CDCl3, 270 or 500 MHz)
Compound
Con®guration
R
d H-2 :ppm)
d H-3 :ppm)
d OH :ppm)
d H-4 :ppm)
J2,3 :Hz)
J3,4 :Hz)
J3,OH :Hz)
19a all cis
19b all cis
20a trans,trans
20b trans,trans
2RS,3SR,4SR
2RS,3SR,4SR
2RS,3RS,4SR
2RS,3RS,4SR
Et
n-Pr
Et
3.09
3.12
2.95
2.93
4.46
4.44
3.80
3.80
3.55
3.53
1.90
1.90
3.01
3.08
2.85
2.85
6.6
6.3
5.6
5.7
6.3
6.3
5.6
5.7
7.9
7.9
Not observed
Not observed
n-Pr

2770
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
hydride before use. Tetrahydrofuran was distilled over
sodiumbenzophenone ketyl before use. All other chemicals
and solvents were used as supplied. Experiments with the
azides 7 and 8 were carried out behind a safety shield.
three-necked round-bottomed ¯ask, provided with a
magnetic stirrer, a side-arm dropping funnel and nitrogen
inlet, thionyl chloride :71.4 g, 0.61 mol) was added drop-
wise and very cautiuosly to anhydrous methanol :300 mL)
at 2108C over 20 min. The solution was stirred further at
this temperature for another 20 min and methyl 4-azido-2-
bromo-3,3-dimethoxybutanoate :8, 77.5 g, 0.27 mol) was
added dropwise at 2108C over a period of 10 min. Then,
tin:II) chloride :78.0 g, 0.41 mol) was added portionwise
under a nitrogen streamat 2108C. The resulting suspension
was stirred at roomtemperature for 15 h, ®ltered and evapo-
rated. The residue was diluted with diethyl ether :450 mL)
and stirred for one hour at 08C. A white solid precipitated,
which was ®ltered, washed with fresh diethyl ether :20 mL)
and dried in vacuo over calciumchloride :25 8C/10 mmHg).
Methyl 4-amino-2-bromo-3,3-dimethoxybutanoate hydro-
chloride :9, 35.6 g, 0.12 mol, 45.2%) was obtained as an
3.1.1. Preparation of ꢀE)-methyl 4-chloro-3-methoxy-2-
butenoate 6.11 In a 500 mL two-necked round-bottomed
¯ask, provided with a magnetic stirrer, a side-arm dropping
funnel and nitrogen inlet, thionyl chloride :169.9 g,
1.43 mol) was carefully added dropwise to anhydrous
methanol :124.0 g, 3.90 mol). After cooling to 2108C,
methyl 4-chloro-3-oxobutanoate :5, 196.0 g, 1.30 mol)
was added at this temperature over a period of 20 min. It
was stirred at roomtemperature for 17 h and then excess
methanol and thionyl chloride were evaporated in vacuo.
The residue was transferred to a 250 mL round-bottomed
¯ask ®tted with a fractional distillation set, methanesul-
phonic acid :1.26 g, 13.0 mmol) was added and the mixture
was heated at ca. 1508C :oil bath temperature) at reduced
pressure. First, methanol was distilled off :ca. 248C/
15 mmHg), while afterwards a main fraction of :E)-methyl
4-chloro-3-methoxy-2-butenoate :6, 205.6 g, 1.25 mol,
96.4%) was obtained as a colorless liquid. Bp: 1248C/15±
16 mmHg :95±978C/11±12 mmHg).11 1H NMR :270 MHz,
CDCl3): d 5.15 :s, 1H, CHv); 4.66 :s, 2H, CH2Cl); 3.73 and
3.71 :each s, each 3H, OCH3 and COOCH3).
1
amorphous white solid. Mp: 1358C :decomp.). H NMR
:270 MHz, D2O): d 4.87 :s, 1H, CHBr); 3.76 :s, 3H,
COOCH3 or :OCH3)2); 3.58 and 3.64 :each d, Jgem
14.5 Hz, AB system, 1H, CH2N); 3.30 and 3.31 :each s,
ˆ
each 3H, COOCH3 or :OCH3)2). 13C NMR :67.5 MHz,
D2O):
d
168.59 :CvO); 97.25 :C:OMe)2); 53.19
:COOCH3); 48.39 and 49.54 :O:CH3)2); 43.92 :C±Br);
39.43 :CH2N). IR :KBr, cm21): 3190 :N±H, broad); 1725
:CvO). No correct elemental analytical data could be
obtained, probably due to the adventituous water present
due to hygroscopicity.
3.1.2. Preparation of ꢀE)-methyl 4-azido-3-methoxy-2-
butenoate 7. In a 1 L two-necked round-bottomed ¯ask,
provided with a magnetic stirrer and re¯ux condenser,
:E)-methyl 4-chloro-3-methoxy-2-butenoate :6, 49.2 g,
0.30 mol) and sodium azide :39.0 g, 0.60 mol) were dis-
persed in acetonitrile :600 mL). The mixture was re¯uxed
for 5 h, cooled down to roomtemperature and residual
sodiumazide was ®ltered. The ®ltrate was evaporated and
then diluted with n-pentane and stirred at 08C for one hour.
More sodiumazide precipitated, which was ®ltered off.
The ®ltrate was evaporated to afford :E)-methyl 4-azido-
3-methoxy-2-butenoate :7, 49.8 g, 0.29 mol, 97.1%) as a
reddish liquid, which was used without further puri®cation
:purity.96%). 1H NMR :270 MHz, CDCl3): d 5.18 :s, 1H,
CHv); 4.42 :s, 2H, CH2N3); 3.72 and 3.71 :each s, each 3H,
OCH3 and COOCH3).
3.1.5. Preparation of methyl 2-bromo-4-ꢀdiphenylmethyl-
ene)amino-3,3-dimethoxybutanoate 10. In a 500 mL
round-bottomed ¯ask, provided with a magnetic stirrer,
methyl 4-amino-2-bromo-3,3-dimethoxybutanoate hydro-
chloride :9, 10.63 g, 36.4 mmol) and diphenylketimine
:6.59 g, 36.4 mmol) were dissolved in dichloromethane
:200 mL). The solution was stirred at room temperature
for 20 h, ®ltered and 10% sodiumbicarbonate :200 mL)
was added to the ®ltrate. After stirring for 15 min, the result-
ing emulsion was ®ltered through a celite layer. The organic
phase was decanted and the aqueous phase was extracted
with dichloromethane :2£50 mL), the combined organic
phases were washed with water :100 mL), dried :K2CO3),
®ltered and the solvent was evaporated in vacuo. Methyl
2-bromo-4-:diphenylmethylene)amino-3,3-dimethoxybutano-
ate :10, 14.61 g, 34.78 mmol, 95.6%) was obtained as a
caramel-like solid residue. Rf: 0.40 :silica gel, hexane±
AcOEt 4:1). Mp: 868C :white prisms from MeOH,
3.1.3. Preparation of methyl 4-azido-2-bromo-3,3-
dimethoxybutanoate 8. In a 1 L round-bottomed ¯ask,
provided with a magnetic stirrer, :E)-methyl 4-azido-3-
methoxy-2-butenoate :7, 49.8 g, 0.29 mol) was dissolved
in methanol :600 mL). To this solution, N-bromosuccini-
mide :53.4 g, 0.30 mol) was added portionwise and the
mixture was stirred at room temperature and under subdued
light for 90 min. The solvent was evaporated in vacuo and
n-pentane :500 mL) was added. The resulting suspension
was stirred at 2158C for one hour and was then ®ltered.
The ®ltrate was evaporated to afford methyl 4-azido-2-
bromo-3,3-dimethoxybutanoate :8, 77.5 g, 0.27 mol, 93.1%)
as a pale yellow liquid, which was used directly in the next
1
2208C). H NMR :270 MHz, CDCl3): d 7.10±7.70 :m,
10H, Ph2); 5.01 :s, 1H, CHBr); 3.76 :d, Jgemˆ16.5 Hz, AB
system, 1H, H-4); 3.71 :s, 3H, COOCH3 or :OCH3)2); 3.61
:d, Jgemˆ16.5 Hz, AB system, 1H, H-4); 3.27 and 3.28 :each
s, each 3H, COOCH3 or :OCH3)2). 13C NMR :67.5 MHz,
CDCl3): d 168.05 and 169.38 :CvO and CvN); 136.48 and
139.40 :Ar Cquat); 127.49, 127.98, 128.64 and 130.20 :Ar);
101.27 :C:OMe)2); 54.64 :CH2N); 53.05 :COOCH3); 49.52
and 50.48 ::OCH3)2); 49.31 :CHBr). IR :NaCl, cm21): 1758
:CvO); 1630 :CvN). Elemental analysis :C20H22BrNO4)
calculated C 57.15%, H 5.28%, N 3.33%; found C 57.29%,
H 5.14%, N 3.26%.
1
step. H NMR :270 MHz, CDCl3): d 4.52 :s, 1H, CHBr);
3.80 :s, 3H, COOCH3 or :OCH3)2); 3.75 :s, 2H, CH2N3);
3.41 and 3.35 :each s, each 3H, COOCH3 or :OCH3)2).
3.1.6. Preparation of methyl 1-benzhydryl-3,3-dimethoxy-
azetidine-2-carboxylate 11. In a 250 mL round-bottomed
¯ask, provided with a magnetic stirrer and nitrogen
3.1.4. Preparation of methyl 4-amino-2-bromo-3,3-
dimethoxybutanoate hydrochloride 9. In a 500 mL

A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
2771
inlet, methyl 2-bromo-4-:diphenylmethylene)amino-3,3-
dimethoxybutanoate :10, 12.67 g, 30.17 mmol) was dis-
persed in dry methanol :180 mL). After cooling to 2178C
with an ice±salt bath, sodiumcyanoborohydride :3.79 g,
60.34 mmol, 2.0 equiv.) and acetic acid :1.81 g, 30.17 mmol,
1.0 equiv.) were carefully added in this order. The reaction
mixture was left stirring to warm up to room temperature
over two and a half hours. A re¯ux condenser was then ®tted
and triethylamine :9.14 g, 90.51 mmol) was added. The
mixture was re¯uxed for 4 h, cooled down to room tempera-
ture, poured into water :250 mL) and extracted with
dichloromethane :3£100 mL). The combined organic
phases were washed with water :100 mL), dried :MgSO4),
®ltered and the solvent was evaporated in vacuo. The resi-
due was chromatographed :silica gel, column dimensions
45.0 cm£2.4 cm, hexane±AcOEt 4:1). Pooling of the appro-
priate fractions and evaporation in vacuo afforded a residue
containing methyl 1-benzhydryl-3,3-dimethoxyazetidine-2-
carboxylate 11 and 1-benzhydryl-3-bromo-4,4-dimethoxy-
pyrrolidin-2-one 12. After crystallization fromdiethyl ether
at 2208C, 1-benzhydryl-3-bromo-4,4-dimethoxypyrrolidin-
2-one :12, 2.99 g, 7.69 mmol, 26%) was obtained as white
prisms, which were ®ltered off. Evaporation of the mother
liquors afforded methyl 1-benzhydryl-3,3-dimethoxyazeti-
dine-2-carboxylate :11, 6.55 g, 19.20 mmol, 64%) as a
colorless oil. 1-Benzhydryl-3-bromo-4,4-dimethoxypyrro-
lidin-2-one 12: Rf: 0.20 :silica gel, hexane±AcOEt 4:1).
Mp: 147±1488C :white prisms from Et2O, 2208C). 1H
NMR :270 MHz, CDCl3): d 7.34±7.37 and 7.20±7.26
:each m, 4H and 6H, respectively, Ph2); 6.64 :s, 1H,
CHPh2); 4.27 :s, 1H, CHBr); 3.28 :s, 3H, OCH3); 3.25
and 3.16 :each d, Jˆ11 Hz, each 1H, AB system, H-4);
3.13 :s, 3H, OCH3). 13C NMR :67.5 MHz, CDCl3): d
168.95 :CvO); 137.55 and 137.89 :Ar Cquat); 127.85,
127.90, 128.08, 128.39, 128.46, 128.66 and 128.71 :Ar);
102.28 :C:OMe)2); 58.29 :CHPh2); 50.10 and 50.47
::OCH3)2); 47.33 :CHBr); 47.17 :CH2N). IR :NaCl,
cm21): 3010, 3004 :C±H Ar); 2842 :OMe); 1709 :CvO).
MS :EI, 70 eV), :m/z, %): 389/391 :M1, 1), 310 :21), 309
:100), 168 :5), 167 :33), 166 :6), 165 :15), 152 :8), 149 :6),
147 :4), 146 :6), 129 :7), 115 :20), 101 :4), 99 :4), 89 :27),
88 :84), 71 :5), 70 :5), 69 :4), 59 :4), 58 :17), 57 :9), 55 :4),
45 :5), 44 :8), 43 :16), 41 :4), 40 :60). Elemental analysis
:C19H20BrNO3): calculated C 58.47%, H 5.17%, N 3.59%;
found C 58.30%, H 5.10%, N 3.44%. Methyl 1-benzhydryl-
3,3-dimethoxyazetidine-2-carboxylate 11: Rf: 0.20 :silica
aluminium hydride :0.83 g, 22.0 mmol) was added to dry
diethyl ether :25 mL) and cooled to 08C. To this suspension,
methyl 1-benzhydryl-3,3-dimethoxyazetidine-2-carboxyl-
ate :11, 3.74 g, 0.011 mol, dissolved in 25 mL of diethyl
ether) was added dropwise over 10 min at 08C. A re¯ux
condenser was ®tted and the mixture was re¯uxed for two
hours, cooled down to roomtemperature and all residual
hydride was destroyed by dropwise addition of ethyl acetate
:30 mL). The mixture was poured into water :50 mL) and
was extracted with ethyl acetate :3£40 mL). The combined
organic phases were dried :MgSO4), ®ltered and the solvent
was evaporated in vacuo. The residue was crystallized from
diethyl ether at 2208C. Successive crops gave 1-benz-
hydryl-3,3-dimethoxy-2-:hydroxymethyl)azetidine 13 as
white needles :1.79 g, 5.73 mmol, 52.1%). Rf: 0.09 :silica
gel, hexane±AcOEt 4:1). Mp: 90.4±90.88C :white prisms
fromEt O, 2208C). H NMR :270 MHz, CDCl3): d 7.41±
1
2
7.51 and 7.19±7.32 :each m, 4H and 6H, respectively, Ph2);
4.55 :s, 1H, CHPh2); 3.66 :d, Jgemˆ9.2 Hz, 1H, H-4); 3.23±
3.35 :m, 3H, H-2 and CH2OH); 3.24 and 3.21 :each s, each
3H, :OCH3)2); 2.82 :d, Jgemˆ9.2 Hz, 1H, H-4). 13C NMR
:67.5 MHz, CDCl3): d 142.62 and 142.24 :Ar Cquat);
128.57, 128.51, 128.12, 127.76, 127.33 and 127.15 :Ar);
99.31 :C:OMe)2); 77.23 :CHPh2); 72.77 :C-2); 61.85
:CH2OH), 60.68 :C-4); 49.23 and 48.93 ::OCH3)2). IR
:NaCl, cm21): 3515 :OH); 3078, 3019 :C±H Ar); 2877,
2833 :OMe). Elemental analysis :C19H23NO3): calculated
C 72.82%, H 7.40%, N 4.47%; found C 73.25%, H
7.48%, N 4.40%.
3.1.8. Preparation of 1-benzhydryl-3,3-dimethoxy-2-
ꢀmethoxymethyl)azetidine 14. In a 100 mL two-necked
round-bottomed ¯ask, provided with a magnetic stirrer
and nitrogen inlet, sodiumhydride :0.33 g of a 60% suspen-
sion in mineral oil, 8.32 mmol) was dispersed in dry tetra-
hydrofuran :15 mL). To this slurry was added dropwise
1-benzhydryl-3,3-dimethoxy-2-:hydroxymethyl)azetidine
:13, 1.53 g, 4.88 mmol, dissolved in 15 mL of dry tetra-
hydrofuran) at room temperature over a period of 10 min.
The mixture was stirred for one hour at room temperature,
after which iodomethane :2.23 g, 15.70 mmol, dissolved in
10 mL of dry tetrahydrofuran) was then added dropwise at
room temperature over 10 min. After stirring at room
temperature for 6 h, additional iodomethane :1.0 mL,
excess) was added in one portion. The reaction mixture
was stirred for another 14 h and was then poured into
water :150 mL) and extracted with diethyl ether
:4£50 mL). The combined organic phases were dried
:MgSO4), ®ltered and the solvent was evaporated in
vacuo. Column chromatography :silica gel, column dimen-
sions 21 cm£2.4 cm, hexane±AcOEt 4:1) afforded 1-benz-
hydryl-3,3-dimethoxy-2-:methoxymethyl)azetidine 14 as a
pale yellow solid :1.40 g, 4.28 mmol, 88%). It was puri®ed
by crystallization from dichloromethane±methanol. Rf: 0.30
:silica gel, hexane±AcOEt 4:1). Mp: 88±898C :white
prisms from CH2Cl2±MeOH). 1H NMR :270 MHz,
CDCl3): d 7.37±7.45 and 7.19±7.31 :each m, 4H and 6H,
1
gel, hexane±AcOEt 4:1). H NMR :270 MHz, CDCl3, d):
7.44±7.54 and 7.14±7.32 :each m, 4H and 6H, respectively,
Ph2); 4.55 :s, 1H, CHPh2); 3.87 :s, 1H, H-2); 3.74 :d, Jˆ
8.9 Hz, 1H, H-4); 3.49 :s, 3H, COOCH3); 3.29 and 3.20
:each s, each 3H, :OCH3)2); 2.88 :d, Jˆ8.9 Hz, 1H, H-4).
13C NMR :67.5 MHz, CDCl3, d): 168.97 :CO2CH3); 141.28
and 140.48 :Ar Cquat); 128.39, 128.36, 128.25, 127.96 and
127.33 :Ar); 98.09 :C:OCH3)2); 77.39 :CHPh2); 73.39
:C-2); 60.34 :C-4); 51.48 :COOCH3); 49.47 and 49.38
::OCH3)2). IR :NaCl, cm21): 3081, 3058, 3023 :C±H
Ar); 2853 :OMe); 1715 :CvO). Elemental analysis
:C20H23NO4): calculated C 70.36%, H 6.79%, N 4.10%;
found C 70.18%, H 6.85%, N 4.02%.
respectively, Ph2); 4.48 :s, 1H, CHPh2); 3.59 :dd, Jgem
ˆ
9.0 Hz, Jˆ0.6 Hz, 1H, CH2OCH3); 3.45 :d, Jˆ9.5 Hz, 1H,
H-4); 3.35 :m, 1H, H-2); 3.25 and 3.19 :each s, each 3H,
:OCH3)2); 3.00 :s, 3H, CH2OCH3); 2.73 :d, Jˆ9.5 Hz, 1H,
C
3.1.7. Preparation of 1-benzhydryl-3,3-dimethoxy-2-
ꢀhydroxymethyl)azetidine 13. In
bottomed ¯ask, provided with a magnetic stirrer, lithium
a
100 mL round-
H-4); 2.34 :dd, Jgemˆ9.0 Hz, Jˆ3.0 Hz, 1H, CH2OCH3). 13
NMR :67.5 MHz, CDCl3): d 142.12 :Ar Cquat); 128.48,

2772
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
128.41, 128.28, 127.42 and 127.03 :Ar); 98.67 :C:OMe)2);
77.92 :CHPh2); 72.36 :CH2OCH3), 70.30 :C-2); 60.58
:C-4); 58.55 :CH2OCH3); 49.45 and 49.33 ::OCH3)2).
IR :NaCl, cm21): 3073, 3023 :C±H Ar); 2868
:OMe). Elemental analysis :C20H25NO3): calculated C
73.37%, H 7.70%, N 4.28%; found C 73.53%, H 7.74%,
N 4.27%.
128.59, 128.55, 128.50, 128.46, 128.37 and 128.25 :Ar);
98.71 :CHPh2); 72.24 :CH2OCH3), 62.75 and 59.23 :C-2
and C-4); 52.97 :CH2OCH3); 49.29 :CvNCHMe2); 23.67
and 23.60 :CvNCH:CH3)2). IR :NaCl, cm21): 3061 :C±H
Ar), 1725 :CvN).
3.1.11. Preparation of cis-1-benzhydryl-4-ethyl-2-ꢀmeth-
oxymethyl)azetidin-3-one 18a. In
a 50 mL round-
3.1.9. Preparation of 1-benzhydryl-2-ꢀmethoxymethyl)-
azetidin-3-one 4. In a 100 mL round-bottomed ¯ask,
provided with a magnetic stirrer and nitrogen inlet, 1-benz-
bottomed ¯ask, provided with a magnetic stirrer and nitro-
gen inlet, N-:1-benzhydryl-2-:methoxymethyl)-3-azetidinyl-
idene)isopropylamine :16, 278 mg, 0.863 mmol, dissolved
in 6 mL of dry tetrahydrofuran) was added dropwise at
2208C over 5 min to a solution of lithium diisopropylamide
:0.95 mmol), freshly prepared from diisopropylamine
:0.15 mL, 1.036 mmol) and n-butyllithium:0.34 mL of a
2.5 M solution in hexane, 0.95 mmol) in 3 mL of tetra-
hydrofuran. The reaction mixture was stirred at 2208C for
3 h, after which iodoethane :269 mg, 1.726 mmol, dissolved
in 3 mL of tetrahydrofuran) was added at 2208C over ®ve
minutes. After this addition, the ice±salt bath was removed
and the reaction mixture was left stirring to warm up to
roomtemperature for 15 h. Then it was poured into 1 M
sodiumhydroxide :30 Lm). The aqueous phase was
extracted with diethyl ether :3£20 mL) and the combined
organic phases were dried :K2CO3), ®ltered and the solvent
was evaporated in vacuo. A yellow oil :282 mg), mostly
containing N-:1-benzhydryl-4-ethyl-2-:methoxymethyl)-3-
azetidinylidene)isopropylamine 17a :mixture of isomers)
was obtained and used as such. It was dissolved in dichloro-
methane :10 mL) and was then vigorously stirred with 2 M
hydrochloric acid :4.0 mL) for one hour at room tempera-
ture. The mixture was then carefully neutralized with 1 M
sodiumhydroxide :ca. 10 mL), transferred to a separating
funnel and the aqueous phase was extracted with dichloro-
methane :2£20 mL). The combined organic phases were
dried :K2CO3), ®ltered and the solvent was evaporated in
vacuo. The residue was puri®ed by column chromatography
:silica gel, column dimensions 16.0 cm£2.4 cm, hexane±
AcOEt 5:1). cis-1-Benzhydryl-4-ethyl-2-:methoxymethyl)-
azetidin-3-one :18a, 49.5 mg, 0.160 mmol, 19%) was
obtained as a yellow oil after pooling and evaporation of
the appropriate fractions. Rf: 0.46 :silica gel, hexane±
hydryl-3,3-dimethoxy-2-:methoxymethyl)azetidine
:14,
0.736 g, 2.25 mmol) was stirred with 36N sulfuric acid
:1.25 mL, 22.5 mmol) for 17 h at room temperature The
mixture was then carefully neutralized with 1 M sodium
hydroxide under ice cooling and extracted with diethyl
ether :4£30 mL). The combined organic phases were
washed with water :20 mL), dried :K2CO3), ®ltered and
the solvent was evaporated in vacuo. The residue was
column chromatographed :silica gel, column dimensions
12 cm£2.4 cm, hexane±AcOEt 4:1). Pooling and evapo-
ration of the appropriate fractions gave 1-benzhydryl-2-
:methoxymethyl)azetidin-3-one :4, 0.545 g, 1.94 mmol,
86.2%) as a solid yellow residue. Rf: 0.29 :silica gel,
hexane±AcOEt 4:1). 1H NMR :270 MHz, CDCl3): d
7.48±7.53 and 7.22±7.34 :each m, 4H and 6H, respectively,
Ph2); 4.67 :s, 1H, CHPh2); 4.23 :dd, Jgemˆ16.2 Hz, J2±4
ˆ
4.0 Hz, 1H, H-4); 4.11 :ddd, Jˆ4.3 Hz, J2±4ˆ4.0 Hz, Jˆ
3.3 Hz, 1H, H-2); 3.73 :d, Jˆ16.2 Hz, 1H, H-4); 3.25 :s,
3H, CH2OCH3); 3.22 :dd, Jgemˆ10.9 Hz, Jˆ3.3 Hz, 1H,
CH2OCH3); 3.05 :dd, Jgemˆ10.9 Hz, Jˆ3.3 Hz, 1H,
CH2OCH3). 13C NMR :67.5 MHz, CDCl3): d 201.96
:CvO); 142.14 :Ar Cquat); 128.34, 128.18, 127.82 and
126.99 :Ar); 84.58 :CHPh2); 76.80 :C-2); 72.92
:CH2OCH3), 70.30 :C-4); 58.96 :CH2OCH3). IR :NaCl,
cm21): 3061 :C±H Ar); 1810 :CvO).
3.1.10. Preparation of N-ꢀ1-benzhydryl-2-ꢀmethoxy-
methyl)-3-azetidinylidene)isopropylamine 16. In a 50 mL
round-bottomed ¯ask, provided with a magnetic stirrer and
nitrogen inlet, 1-benzhydryl-2-:methoxymethyl)azetidin-3-
one :4, 325 mg, 1.159 mmol) and isopropylamine :0.6 mL,
6.94 mmol, 6.0 equiv.) were dissolved in dry diethyl ether
:15 mL). To this solution was added dropwise titanium:IV)
chloride :132 mg, 0.694 mmol, dissolved in 2.0 mL pen-
tane) at room temperature over ®ve minutes. After stirring
for 17 h at room temperature, the reaction mixture was
added to 1 M sodiumhydroxide :15 mL). The aqueous
phase was extracted with diethyl ether :3£20 mL) and the
combined organic phases were dried :K2CO3), ®ltered and
the solvent was evaporated in vacuo. N-:1-Benzhydryl-
2-:methoxymethyl)-3-azetidinylidene)isopropylamine :16,
mostly E isomer, 359 mg, 1.114 mmol, 96.2%) was
obtained as a yellow residue and was used without further
puri®cation because of its lability. Rf: 0.53 :silica gel,
CH2Cl2±MeOH±conc. NH3 80:1:0.05). 1H NMR :270
MHz, CDCl3): d 7.43±7.50 and 7.17±7.31 :each m, 4H
and 6H, respectively, Ph2); 4.62 :s, 1H, CHPh2); 4.21 :dd,
Jgemˆ14.2 Hz, Jˆ3.6 Hz, 1H, H-4); 4.02±4.10 :m, 1H,
H-2); 3.45±3.58 :m, 1H, H-4); 3.28 :m, 2H, CH2OCH3
and CH:CH3)2); 3.19 :s, 3H, CH2OCH3); 3.13 :m, 1H,
CH2OCH3); 1.11 :d, Jˆ6.7 Hz, 6H, CH:CH3)2). 13C NMR
:67.5 MHz, CDCl3): d 161.62 :CvN); 142.69 :Ar Cquat);
1
AcOEt 4:1). H NMR :270 MHz, CDCl3): d 7.53±7.59
and 7.22±7.34 :each m, 4H and 6H, respectively, Ph2);
4.65 :s, 1H, CHPh2); 3.94 :dd, Jˆ4.9, 3.96 Hz, 1H, H-2);
3.86 :dd, Jˆ7.6, 4.6 Hz, 1H, H-4); 3.18±3.30 :m, 2H,
CH2OCH3); 3.23 :s, 3H, CH2OCH3); 1.39 :m, 2H,
CH2CH3); 0.84 :t, Jˆ7.6 Hz, 3H, CH2CH3). 13C NMR
:67.5 MHz, CDCl3, d): 207.02 :CvO); 142.42 and 142.30
:Ar Cquat); 128.42, 128.39, 128.17, 127.69 and 127.49
:Ar); 86.04 :C-4); 83.77 :C-2); 78.74 :CHPh2); 70.78
:CH2OCH3), 59.28 :CH2OCH3); 23.92 :CH2CH3); 9.42
:CH2CH3). IR :NaCl, cm21): 3059, 3024 :C±H Ar);
2961, 2850 :C±H); 1801 :CvO). Elemental analysis
:C21H25NO2): calculated C 77.99%, H 7.79%, N 4.33%;
found C 77.81%, H 7.91%, N 4.20%.
3.1.12. Preparation of cis-1-benzhydryl-2-methoxy-
methyl-4-propylazetidin-3-one 18b. In a 50 mL round-
bottomed ¯ask, provided with a magnetic stirrer and nitro-
gen inlet, N-:1-benzhydryl-2-:methoxymethyl)-3-azetidinyl-
idene)isopropylamine :16, 359 mg, 1.114 mmol, dissolved
in 12 mL tetrahydrofuran) was added dropwise at 2208C

A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
2773
over a period of 10 min to a solution of lithium diisopropyl-
amide :1.225 mmol), freshly prepared from diisopropyl-
amine :0.19 mL, 1.34 mmol) and n-butyllithium:0.49 mL
of a 2.5 M solution in hexane, 1.225 mmol) in 2 mL of dry
tetrahydrofuran. The reaction mixture was stirred at 2208C
for 3 h, after which iodopropane :380 mg, 2.23 mmol,
dissolved in 5 mL of dry tetrahydrofuran) was added at
2208C over ®ve minutes. After this addition, the ice±salt
bath was removed and the reaction mixture was left stirring
to warmup to roomtemperature for 18 h. It was then poured
into 1 M sodiumhydroxide :15 mL), the aqueous phase was
extracted with diethyl ether :3£20 mL) and the combined
organic phases were dried :K2CO3), ®ltered and the solvent
was evaporated in vacuo. A yellow oil :318 mg), mostly
containing N-:1-benzhydryl-2-:methoxymethyl)-4-propyl-
3-azetidinylidene)-isopropylamine 17b, as a mixture of
isomers, was obtained. It was dissolved in dichloromethane
:10 mL) and it was vigorously stirred with 2 M hydrochloric
acid :4.5 mL) for one hour at room temperature, after which
it was carefully neutralized with 1 M sodiumhydroxide :ca.
10 mL). The aqueous phase was extracted with diethyl ether
:2£20 mL). The combined organic phases were dried
:K2CO3), ®ltered and the solvent was evaporated in vacuo.
The residue was puri®ed by column chromatography :silica
gel, column dimensions 15.0 cm£2.4 cm, hexane±AcOEt
5:1). cis-1-Benzhydryl-2-:methoxymethyl)-4-propylazeti-
din-3-one :18b, 78 mg, 0.241 mmol, 22%) was obtained
as a yellow oil. Rf: 0.46 :silica gel, hexane±AcOEt 4:1).
1H NMR :270 MHz, C6D6): d 7.40±7.50 and 6.95±7.16
:each m, 4H and 6H, respectively, Ph2); 4.26 :s, 1H,
CHPh2); 3.68±3.64 :m, 2H, H-2 and H-4); 3.19 :dd,
Jgemˆ10.6 Hz, Jˆ3.3 Hz, 1H, CH2OCH3); 3.09 :dd,
Jgemˆ10.6 Hz, Jˆ4.3 Hz, 1H, CH2OCH3); 3.02 :s, 3H,
CH2OCH3); 1.54 :m, 2H, CH2CH2CH3); 1.33 :m, 2H,
CH2CH2CH3); 0.70 :t, Jˆ7.0 Hz, 3H, CH2CH2CH3). 13C
NMR :67.5 MHz, C6D6): d 205.16 :CvO); 143.09 and
142.97 :Ar Cquat); 132.04, 130.17, 129.22, 128.93 and
128.86 :Ar); 84.96 and 84.37 :C-2 and C-4); 78.58
:CHPh2); 71.04 :CH2OCH3), 58.87 :CH2OCH3); 33.39
:CH2CH2CH3); 18.62 :CH2CH2CH3); 14.17 :CH2CH2CH3).
IR :NaCl, cm21): 3061, 3027 :C±H Ar); 2958, 2872 :C±H);
1804 :CvO). MS :CI, NH3, m/z): C21H25NO2 requires
323.1885; found 323.1892 :M1, 0.45%); 278 :100%).
hexane): 115±116.58C. 1H NMR :270 MHz, CDCl3): d
7.49±7.44 and 7.15±7.29 :each m, 4H and 6H, respectively,
Ph2); 4.46 :ddd, Jˆ7.9 Hz, J2,3ˆ6.6 Hz, J3,4ˆ6.3 Hz, 1H,
H-3); 4.38 :s, 1H, CHPh2); 3.55 :d, Jˆ7.9 Hz, 1H, OH);
3.26 :s, 3H, CH2OCH3); 3.16 :m, 1H, CH2OCH3); 3.09
:m, 2H, H-2 and CH2OCH3); 3.01 :m, 1H, H-4); 1.70 and
0.75 :each m, each 1H, CH2CH3); 0.59 :t, Jˆ7.6 Hz, 3H,
CH2CH3). 13C NMR :67.5 MHz, CDCl3): d 143.04 :Ar
Cquat); 128.41, 128.25, 128.14, 128.05, 127.33 and 127.26
:Ar); 78.44 :CHPh2); 72.04 :CH2OCH3); 73.28 :C-3); 67.55
and 66.04 :C-2 and C-4); 59.16 :CH2OCH3); 22.21
:CH2CH3); 9.97 :CH2CH3). IR :NaCl, cm21): 3440 :broad,
O±H); 1638 :CvC, Ar). MS :EI, m/z): C20H25NO2 requires
311.1885; found 311.1896. The second eluting compound
was :trans,trans)-1-benzhydryl-4-ethyl-2-methoxymethyl-
azetidin-3-ol :20a, 11.0 mg, 0.035 mmol, 27.4%). Rf: 0.11
:silica, hexane±AcOEt 4:1). 1H NMR :270 MHz, CDCl3): d
7.47±7.42 and 7.18±7.29 :each m, 4H and 6H, respectively,
Ph2); 4.45 :s, 1H, CHPh2); 3.80 :dd, J2±3ˆ J3,4ˆ5.6 Hz, 1H,
H-3); 3.17 :s, 3H, CH2OCH3); 3.04 :dd, Jgemˆ9.0 Hz, Jvicˆ
7.4 Hz, 1H, CH2OCH3); 2.95 :m, 1H, H-2); 2.85 :m, 2H,
H-4 and CH2OCH3); 1.30±1.05 :m, 2H, CH2CH3); 0.73 :t,
Jˆ7.6 Hz, 3H, CH2CH3). 13C NMR :67.5 MHz, CDCl3): d
142.69, 142.37 :Ar Cquat); 128.37, 128.28, 128.16, 128.05,
127.37, 127.28 :Ar); 79.03 :CHPh2); 74.63 and 74.23 :C-3
and CH2OCH3); 71.59 and 71.02 :C-2 and C-4); 59.03
:CH2OCH3); 26.97 :CH2CH3); 8.82 :CH2CH3). IR :NaCl,
cm21): 3438 :broad, O±H); 1635 :CvC, Ar). MS :EI, m/z):
C20H25NO2 requires 311.1885; found 311.1868.
3.1.14. Preparation of 1-benzhydryl-2-ꢀmethoxymethyl)-
4-propylazetidin-3-ol 19b and 20b. In a 50 mL round-
bottomed ¯ask, provided with a magnetic stirrer and nitro-
gen inlet, cis-1-benzhydryl-2-:methoxymethyl)-4-propyl-
azetidin-3-one :18b, 65 mg, 0.201 mmol) was dissolved in
absolute ethanol :7 mL) and cooled to 08C. To this solution,
sodium borohydride :15 mg, 0.397 mmol) was added in
small portions. After this addition, the ice bath was removed
and the reaction mixture was left stirring at room tempera-
ture for one hour. Water :15 mL) was added and stirring was
continued for one more hour. Then the reaction mixture was
extracted with diethyl ether :3£20 mL). The combined
organic phases were dried :MgSO4), ®ltered and the solvent
was evaporated in vacuo. The residue was puri®ed by
column chromatography :silica gel, column dimensions
20 cm£2.4 cm, hexane±AcOEt 5:1). Pooling and evapo-
ration of the solvent in vacuo afforded two compounds,
i.e. 19b and 20b, as colorless oils. The ®rst eluting
compound was :all cis)-1-benzhydryl-2-methoxymethyl-4-
propylazetidin-3-ol :19b, 18.4 mg, 0.057 mmol, 28.2%). Rf:
0.22 :silica, hexane±AcOEt 3:1). Mp :CH2Cl2/hexane):
119±1218C. 1H NMR :500 MHz, CDCl3): d 7.43±7.50
and 7.18±7.29 :m, 4H and 6H, respectively, Ph2); 4.44
:ddd, J2±3ˆJ3±4ˆ6.3 Hz, JH±OHˆ7.9 Hz, becomes a triplet
upon shaking with D2O, 1H, H-3); 4.39 :s, 1H, CHPh2); 3.53
:d, JH±OHˆ7.9 Hz, disappears upon shaking with D2O, 1H,
OH); 3.27 :s, 3H, CH2OCH3); 3.16 :m, 1H, CH2OCH3); 3.12
:m, 1H, H-2); 3.09 :dd, Jˆ10.6, 4.3 Hz, 1H, CH2OCH3);
3.08 :m, 1H, H-4); 1.65 :m, 2H, CH2CH2CH3); 1.14 and
0.72 :each m, each 1H, CH2CH2CH3); 0.67 :t, Jˆ7.2 Hz,
3H, CH2CH2CH3). 13C NMR :67.5 MHz, CDCl3): d 143.01,
142.71 :Ar Cquat); 128.48, 128.25, 127.83, 127.31, 127.28
:Ar); 78.42 :CHPh2); 72.08 :CH2OCH3); 69.38, 67.80,
3.1.13. Preparation of 1-benzhydryl-4-ethyl-2-ꢀmethoxy-
methyl)azetidin-3-ol 19a and 20a. In a 50 mL round-
bottomed ¯ask, provided with a magnetic stirrer and nitro-
gen inlet, cis 1-benzhydryl-4-ethyl-2-:methoxymethyl)-
azetidin-3-one :18a, 40 mg, 0.129 mmol) was dissolved in
absolute ethanol :5 mL) and cooled to 08C. Sodiumboro-
hydride :10 mg, 0.260 mmol) was then added portionwise.
After addition, the ice bath was removed and the reaction
mixture was stirred at room temperature for 4 h. Water
:10 mL) was added and the reaction mixture was extracted
with dichloromethane :3£20 mL). The combined organic
phases were dried :MgSO4), ®ltered and the solvent was
evaporated in vacuo. Puri®cation by column chroma-
tography :silica gel, column dimensions 9 cm£2.4 cm,
hexane±AcOEt 4:1) of the residue gave two compounds,
i.e. compounds 19a and 20a, each as a colorless oil. The
®rst eluting compound was :all cis)-1-benzhydryl-4-ethyl-
2-methoxymethylazetidin-3-ol :19a, 23.7 mg, 0.076 mmol,
59.1%). Rf: 0.20 :silica, hexane±AcOEt 4:1). Mp :CH2Cl2±

2774
A. Salgado et al. / Tetrahedron 58 42002) 2763±2775
66.25 :C-2, C-3 and C-4); 59.16 :CH2OCH3); 31.16
:CH2CH2CH3); 18.83 :CH2CH2CH3); 14.00 :CH2CH2CH3).
IR :NaCl, cm21): 3438 :broad, O±H); 1637 :CvC, Ar). MS
:EI, m/z): C21H27NO2 requires 325.2042; found 325.2036
:M1, 3%). The second eluting compound was :trans,
trans)-1-benzhydryl-2-methoxymethyl-4-propylazetidin-3-ol
:20b, 25.4 mg, 0.078 mmol, 39%). Rf: 0.12 :silica gel, hex-
ane±AcOEt 3:1). 1H NMR :500 MHz, CDCl3): d 7.46±7.43
and 7.17±7.29 :each m, 4H and 6H, respectively, Ph2); 4.44
:s, 1H, CHPh2); 3.80 :dd, J2±3ˆJ3,4ˆ5.7 Hz, 1H, H-3); 3.17
:s, 3H, CH2OCH3); 3.04 :dd, Jgemˆ9.6 Hz, Jvicˆ7.4 Hz, 1H,
CH2OCH3); 2.93 :ddd, J2±3ˆ5.7 Hz, Jˆ7.4, 3.8 Hz, 1H,
H-2); 2.85 :ddd, J3±4ˆ5.7 Hz, Jˆ9.3, 3.7 Hz, 1H, H-4);
2.83 :dd, Jgemˆ9.6 Hz, Jvicˆ3.8 Hz, 1H, CH2OCH3);
0.95±1.30 :m, 4H, CH2CH2CH3); 0.73 :t, Jˆ7.3 Hz, 3H,
CH2CH2CH3). 13C NMR :67.5 MHz, CDCl3): d 142.28
:Ar Cquat); 128.43, 128.30, 128.16, 127.35, 127.30 :Ar);
79.03 :CHPh2); 74.23, 73.28, 71.70, 71.48 :C-2, C-3, C-4
and CH2OCH3); 59.05 :CH2OCH3); 36.48 :CH2CH2CH3);
17.93 :CH2CH2CH3); 14.11 :CH2CH2CH3). IR :NaCl,
cm21): 3440 :broad, O±H); 1636 :CvC, Ar). MS :EI, m/z):
C21H27NO2 requires 325.2042; found 325.2039 :M1, 2%).
for the 1919 observed re¯ections and wR2ˆ0.1787 for all
data.
Acknowledgements
We thank the Fund for Scienti®c Research :FWO-Vlaanderen)
for ®nancial support.
References
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