Synthesis and reactivity of trans-2-aryl-3-chloroazetidines

Article abstract of DOI:10.1016/j.tet.2006.04.104

Several trans-2-aryl-3-chloroazetidines were synthesized in a stereoselective way by reduction of the corresponding β-lactams, which were formed by a Staudinger reaction using different benzaldimines and chloroketene. The resulting chloroazetidines proved to be excellent building blocks for the synthesis of different 3-substituted azetidines through nucleophilic substitution of the chlorine by different carbon, nitrogen, sulfur and oxygen nucleophiles in good to high yields. Since these substitution reactions took place with retention of stereochemistry, the intermediacy of bicyclic azonio[1.1.0]bicyclobutanes is proposed.

Full text of DOI:10.1016/j.tet.2006.04.104

Tetrahedron 62 (2006) 6882–6892
Synthesis and reactivity of trans-2-aryl-3-chloroazetidines
Berten Van Driessche, Willem Van Brabandt, Matthias D’hooghe,
*
Yves Dejaegher and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 24 March 2006; revised 20 April 2006; accepted 27 April 2006
Available online 5 June 2006
Abstract—Several trans-2-aryl-3-chloroazetidines were synthesized in a stereoselective way by reduction of the corresponding b-lactams,
which were formed by a Staudinger reaction using different benzaldimines and chloroketene. The resulting chloroazetidines proved to be
excellent building blocks for the synthesis of different 3-substituted azetidines through nucleophilic substitution of the chlorine by different
carbon, nitrogen, sulfur and oxygen nucleophiles in good to high yields. Since these substitution reactions took place with retention of
stereochemistry, the intermediacy of bicyclic azonio[1.1.0]bicyclobutanes is proposed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
straightforward synthetic method for the synthesis of
3-haloazetidines compromises ring opening of the peculiar
and difficultly accessible 1-azabicyclo[1.1.0]butanes. Open-
ing of the bridging 1,3-bond with p-toluenesulfonyl chlo-
ride,24–26 hydrogen halides25,27–29 or acid chlorides25,30
resulted in a broad group of different 3-haloazetidines.
3-Haloazetidines, such as 1-tert-butyl-3-chloroazetidine,
have already been used in different reactivity studies with
various nucleophiles. Although moderate to good yields
were reported, the reaction procedures required long reac-
tion times (up to 11 days) and extreme reaction conditions
(heating in steel bombs).22,31
Within azaheterocyclic chemistry, azetidines are an extra-
ordinary class of strained compounds because of their wide
range of known biological activities.1–4 In the literature,
several 3-substituted azetidines with known physiological
effects have been reported. 1-Cyclohexyl-3-guanidinylazeti-
dine has an antihypertensive activity,5 3-carbamoyl sub-
stituted azetidines exhibit a tranquilizing effect on the
central nervous system6 and azetidine-3-carboxylic acid is
a known gametocide.7 Invarious recent patents, 3,3-difluoro-
azetidines have been described as therapeutically active
and selective inhibitors of the dipeptidyl peptidase-IV
enzyme (DPP-IV)8–12 making them potential drugs for the
treatment of type 2 diabetes.13 Indeed, 3-haloazetidines form
an important subclass within the azaheterocycles because
of their potential physiological activities and their use as
substrates towards the synthesis of 3-substituted azetidine
derivatives.
In this report, a straightforward and efficient synthesis of
trans-2-aryl-3-chloroazetidines is disclosed as versatile sub-
strates in organic chemistry. The scope of these synthons for
the preparation of a large variety of 3-substituted azetidines
was demonstrated by means of different nucleophiles in an
efficient and elegant way.
Various reports on the synthesis of 3-haloazetidines can be
found in the literature. 2-Aryl-3-bromoazetidinyl-1-tosylates
were prepared by electrophile-induced cyclization of
N-cinnamyl tosylamine with bis(collidine)bromine(I) hexa-
fluorophosphate as electrophile.14 Furthermore, azetidinyl-
3-tosylates and -mesylates are known precursors for
3-haloazetidine formation by substitution reactions,15–20 and
azetidin-3-ols also underwent substitution reactions at the
C3 carbon atom upon treatment with triphenylphosphine
dibromide or triphenylphosphine in tetrachloromethane
towards 3-bromo- and 3-chloroazetidines.21–23 Another
2. Results and discussion
trans-2-Aryl-3-chloroazetidines 4a–g were prepared by con-
densation of different aromatic aldehydes 1 with a variety of
amines in dichloromethane in the presence of magnesium
sulfate as drying agent, and the corresponding aldimines 2
were isolated in excellent yield after reflux for 1 h. In the
next step, the latter imines 2 underwent a Staudinger
[2+2]-cycloaddition using chloroacetyl chloride as a ketene
precursor and 2,6-lutidine as base, affording trans-4-aryl-3-
chloro-b-lactams 3a–g (Scheme 1).32 The stereoselectivity
of this reaction was confirmed by literature data regarding the
coupling constants of cis- and trans-3-hydroxy-2-methyl-1-
tert-butylazetidine between the protons at C3 and C4.33,34
Keywords: b-Lactams; Azetidines; Azonio[1.1.0]bicyclobutanes.
* Corresponding author. Tel.: +32 92645951; fax: +32 92646243; e-mail:
norbert.dekimpe@UGent.be
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.104

B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
6883
R1
R1
R1
For a cis configuration, coupling constants of 5–6 Hz have
been reported, and for a trans configuration a J-value of
0–2 Hz.33,34 All the synthesized b-lactams 3a–g had a cou-
pling constant of 1.7 or 1.8 Hz between the protons at C3
and C4, indicative of a trans configuration of the chlorine
atom with respect to the aromatic substituent (Scheme 1).
H
Cl
C
H
H
R2
H
H
R2
+
Cl
O
Cl
N
H
R2
+
N
N
-
-
O
O
5
2
6
7
R1
J = 1.7-1.8 Hz
R1
R2
O
N
1.05 equiv. R2NH2
H
H
H
Cl
Cl
H
H
R2
H
1.5 equiv. MgSO4
CH2Cl2, ∆, 1h
+
N
-
R1
N
O
R1
O
R2
1
2
3a-g
8
Scheme 2.
1.5 equiv. chloroacetyl chloride
3 equiv. 2,6-lutidine
C6H6, ∆, 4h
R1
The retention of the trans configuration of the formed 2-aryl-
3-chloroazetidines 4a–g was confirmed by comparing the
coupling constants of the protons at the C2, C3 and C4
carbon atoms with literature data.37–39 According to the
literature, cis-3-hydroxy-2-methyl-1-tert-butylazetidine has
coupling constants of 6.6 and 1.8 Hz between the protons
at C3 and C4, whereas trans-3-hydroxy-2-methyl-1-tert-
butylazetidine has coupling constants of 6.7 and 6.4 Hz.
The coupling constants between the C2 and C3 protons
were about 6 Hz in both cases.37–39 Upon analysis of
the spectral data of azetidines 4a–g, the coupling constants
of the azetidine ring protons were observed to be larger
than 5 Hz, indicating the trans-configuration. The proton
at the C3 carbon atom was distinguished as a quadruplet-
R1
3 equiv. AlH2Cl
Cl
Cl
Et2O, ∆, 4h
N
O
N
R2
R2
4a-g (69-99%)
Scheme 1.
3a-g (75-90%)
The use of monochloroalane has already been proven to be
an efficient method for the reduction of b-lactams towards
their corresponding azetidines.35 Also in this case, the use
of 3 equiv of monochloroalane in diethyl ether proved to
be an efficient method for the stereoselective reduction of
the 4-aryl-3-chloroazetidin-2-ones 3a–g, affording trans-2-
aryl-3-chloroazetidines 4a–g in high yield after reflux for
4 h without the formation of undesired ring opening prod-
ucts (Scheme 1, Table 1).
1
like multiplet in the H NMR spectra, which exists of a
dꢀdꢀd system with similar coupling constants. The protons
at the C4 carbon have a triplet like appearance since
both coupling constants are about the same size (6.6–7 Hz)
(Fig. 1).
The mechanism of the stereochemical outcome of this Stau-
dinger reaction has been studied thoroughly in the past
(Scheme 2).36 The ketene 5, formed by dehydrochlorination
of the acid chloride with 2,6-lutidine as a base, is attacked by
the nitrogen lone pair of the imine 2 at the less hindered side
of the ketene with the plane of the imine perpendicular to
the ketene. When using N-(alkylidene)amines, the formed
zwitterionic intermediate 7 undergoes ring closure in the
thermodynamic less stable cis isomer in a conrotatory way.
In this case however, using aromatic aldimines 2, isomeriza-
tion of the imine bond is possible as the positive charge,
which occurs during this isomerization, can be stabilized
at the benzylic position, allowing rotation of the nitrogen–
carbon double bound towards intermediate 8. Hence, by con-
rotatory ring closure, the b-lactams 3a–g are formed in the
thermodynamic more stable trans-configuration.36
Insertion of new functional groups on azetidine rings is a
challenging synthetic topic within organic chemistry because
of the interesting biological and chemical properties of
substituted azetidines. Since no systematic study of nucleo-
philic substitution reactions of 3-haloazetidines has been
performed up to now and the known methods are very labo-
rious, 2-aryl-3-chloroazetidines 4a–g were treated with
different nucleophiles in dimethylsulfoxide (DMSO) and
methanol, resulting in several 3-substituted azetidines
(Scheme 3). trans-2-Aryl-3-chloroazetidines 4a–g reacted
with 4 equiv of sodium azide, potassium cyanide, sodium
acetate and potassium thiocyanate, respectively, in dimethyl-
sulfoxide resulting in trans-2-aryl-3-azidoazetidines 9a–g,
trans-2-aryl-3-cyanoazetidines 9h–j, trans-3-acetoxy-2-
arylazetidines 9k–n and trans-2-aryl-3-thiocyanoazetidines
9o–p, respectively, as substitution products in good yields
after overnight heating at 80–120 ꢁC (Table 2).
Table 1. Synthesis and yield of 4-aryl-3-chloroazetidin-2-ones 3a–g and
2-aryl-3-chloroazetidines 4a–g
Compound
R1
R2
Yield of 3 (%)
Yield of 4 (%)
R1
a
b
c
d
e
f
H
Cl
H
Cl
H
H
Me
Allyl
Allyl
Benzyl
Benzyl
iPr
85
82
75
90
77
86
81
73
80
87
69
83
79
86
H2 H1
JH1-H2 = 6.9 - 7.0 Hz
JH2-H3 = 6.6 - 7.0 Hz
JH2-H4 = 6.6 - 7.0 Hz
Cl
H3
N
R2
H4
4a-g
cHex
iPr
g
Figure 1.

6884
B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
R1
R1
R1
Table 3. Reaction of trans-2-aryl-3-chloroazetidines 4a and 4d with sodium
methoxide towards trans-2-aryl-3-methoxyazetidines 9q–r
4 equiv.
4 equiv.
KSCN
Cl
NCS
N3
Starting
compound 4
Temperature
(ꢁC)
Reaction
time (h)
Isolated
compound 9
Yield
(%)
NaN3
DMSO
N
N
N
DMSO
R2
4a-g
R2
R2
4a
4d
Reflux, D
Reflux, D
22
72
9q
9r
49
45
9o-p (31-43%)
9a-g (45-76%)
4 equiv.
NaOAc
4 equiv.
KCN
DMSO
DMSO
R1
R1
number of different carbon, sulfur, oxygen and nitrogen
nucleophiles. In an efficient, straightforward and simpleway,
several potentially bioactive compounds can be synthesized,
which broaden the already significant azetidine chemistry.
AcO
NC
N
N
R2
9k-n (15-73%)
R2
9h-j (54-76%)
It should be stressed that all substitution reactions took place
with retention of stereochemistry, and only trans substituted
azetidines were detected in the reaction mixtures. This
behaviour can be explained by the formation of a bicyclic
azonia[1.1.0]bicyclobutane intermediate 11, followed by
attack of the nucleophile at C3 (Scheme 5). The same inter-
mediate has already been suggested in literature, based on
stereospecific retention after hydrolysis and substitution
reactions, and ring contraction to aziridinylmethyl deriva-
tives.40–42 Further investigation of this intermediate by
ab initio calculations stated that this bicyclic intermediate
is indeed the most stable one, in comparison with other pos-
sible intermediates.43 Moreover, 1-azabicyclo[1.1.0]butanes
have been converted into 3-haloazetidines and vice versa
via intermediate azonia[1.1.0]bicyclobutane derivatives
such as 11.44 The fact that thiocyanates 9o–p are obtained,
instead of the corresponding isothiocyanates, after reaction
of 3-chloroazetidines 4a–g with potassium thiocyanate is
in accordance with literature data, as in most cases substitu-
tion proceeds via attack of the sulfur atom.45 The preferen-
tial attack of the sulfur atom of the thiocyanate nucleophile
can be rationalized considering the soft acid character of
the intermediate bicyclic azonia[1.1.0]bicyclobutane inter-
mediate 11.
Scheme 3.
Table 2. Substitution reactions of trans-2-aryl-3-chloroazetidines 4a–g
towards 3-substituted azetidines 9a–p
Starting
compound 4 MX
Reagent Temperature Reaction Isolated
(ꢁC)
Yield
time (h) compound 9 (%)
4a
4b
4c
4d
4e
4f
4g
4a
4b
4d
4a
4b
4c
4d
4a
4b
NaN3
80
90
22
22
22
22
18
18
18
22
46
22
22
72
22
21
22
22
9a
9b
9c
9d
9e
9f
47
62
45
63
62
70
76
54
62
65
52
73
52
15
31
43
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
KCN
KCN
KCN
NaOAc
NaOAc 100
NaOAc 110
NaOAc 125
KSCN
KSCN
90
110
80
80
80
90
90
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
120
90
90
90
DMSO has proven to be the most suitable solvent for this
type of substitution reactions. Treatment of trans-2-aryl-3-
chloroazetidines 4a–g with potassium cyanide in acetonitrile
or methanol at reflux did not result in substitution, and the
starting material was recovered. The required reaction tem-
perature had to be above 80 ꢁC, since a reaction temperature
below 80 ꢁC did not result in substitution reactions.
Nu-
R1
R1
R1
Cl
Nu
R2C6H4
N
N
N
R2C6H4
11
R2C6H4
10
12
Only for the synthesis of 3-methoxyazetidines 9q–r, a differ-
ent solvent had to be chosen. Treatment of trans-2-aryl-3-
chloroazetidines 4a–d with 4 equiv of sodium methoxide
in methanol (4 N) afforded the corresponding trans-2-aryl-
3-methoxyazetidines 9q–r in moderate yields (Scheme 4,
Table 3).
Scheme 5.
trans-2-Aryl-3-chloroazetidines 4a–g proved to be stable
in refluxing methanol for 24 h, and no isomerization to the
corresponding isomeric 2-(chloromethyl)aziridines was ob-
served. It should be remarked that upon treatment with
nucleophiles the intermediate azonia[1.1.0]bicyclobutanes
11 are opened in a regioselective way at C3 towards
3-substituted azetidines instead of attack at C2 or C4 towards
the corresponding aziridine derivatives. However, it has been
reported previously that treatment of the analogous trans-
1-cyclohexyl-3-mesyloxy-2-phenylazetidine with sodium
hydroxide resulted in a mixture of the corresponding 3-
hydroxyazetidine and both isomers of 1-cyclohexyl-2-(a-
hydroxybenzyl)aziridine in a 1:1:1 ratio.42 The same result,
i.e., formation of the corresponding 3-methoxyazetidines
and2-(a-methoxybenzyl)aziridines,wasobtainedupontreat-
ment of trans-1-cyclohexyl-3-mesyloxy-2-phenylazetidine
R1
R1
4 equiv. NaOMe
MeOH (4N)
MeO
Cl
N
N
R2
9q-r (45-49%)
R2
4a, 4d
Scheme 4.
The method developed for the stereospecific substitution
of trans-2-aryl-3-chloroazetidines 4a–d can be used for a

B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
6885
with sodium methoxide in methanol, which can only be
explained by ring opening of the intermediate azonia[1.1.0]-
bicyclobutanes at C2. Only when sodium methanethiolate
and sodium benzenethiolate were used, no isomerization
towards the corresponding aziridines took place.42
trans-3-Acetoxy-2-arylazetidines 9k–l were stable in reflux-
ing methanol, whereas treatment with 1 equiv of sodium
bicarbonate in refluxing methanol for 1 h resulted in trans-
2-arylazetidin-3-ols 19a–b (Scheme 8). Azetidin-3-ols
have been studied intensively in the literature since they
form interesting synthons towards azetidinyl tosylates and
mesylates.15,21
The opposite reactivity has also been reported, i.e., the con-
version of a 2-(tosyloxymethyl)aziridine into an azetidine
derivative via the intermediacy of an azonia[1.1.0]bicyclo-
butane salt. These authors described the ring expansion of
1-tert-butyl-2-(tosyloxymethyl)aziridine 13 into a mixture
of 3-hydroxyazetidine 14 (38%), azetidine 15 (4%) and
2-(hydroxymethyl)aziridine 16 (5%) via the formation of
an intermediate bicyclic aziridinium salt 17 after heating
for 6 days at 25 ꢁC in 5% EtOH/H2O in the presence of
1 equiv of Et3N.15 As this result seemed to be doubtful in
view of our recent study of the reactivity of 2-(bromomethyl)-
aziridines, we decided to repeat the solvolysis of aziridine
13. However, careful repetition of this reaction did not result
in the formation of azetidines 14 and 15, and the starting
material was recovered completely (Scheme 6).
R1
R1
AcO
HO
1 equiv. NaHCO3
N
N
MeOH, ∆, 1h
R2
R2
9k R1= H, R2= allyl
9l R1= Cl, R2= allyl
19a R1= H, R2= allyl (47%)
19b R1= Cl, R2= allyl (79%)
Scheme 8.
Efforts towards acidic or basic conversion of trans-2-aryl-3-
cyanoazetidines 9h–j to the corresponding methyl esters or
carboxylic acids as analogues of the gametocide azetidine-
3-carboxylic acid7 by using 2–6 N hydrochloric acid or sul-
furic acid in water or methanol only resulted in complex
reaction mixtures, while treatment with 6 N aqueous sodium
hydroxide yielded the starting compounds 9h–j.
HO
EtO
5% EtOH/H2O
+
+
X
N
N
N
N
1 equiv. Et3N
25°C, 6d
OTos
OH
15 (4%)
16 (5%)
14 (38%)
13
3. Conclusion
N
Several trans-2-aryl-3-chloroazetidines were synthesized
in a stereoselective way by reduction of the corresponding
b-lactams, which were, on their turn, formed by a Staudinger
reaction between different benzaldimines and chloroketene.
The formed chloroazetidines were subjected to a variety of
substitution reactions with nitrogen, carbon, sulfur and
oxygen nucleophiles in DMSO. Since these substitution
reactions took place with retention of stereochemistry, the
occurrence of a bicyclic azonio[1.1.0]bicyclobutane inter-
mediate is proposed. These substitution reactions resulted
in several trans-2-aryl-3-substituted azetidines as valuable
new compounds with potential biological activities and as
substrates for further elaboration towards e.g., 3-amino-
and 3-hydroxyazetidines.
17
Scheme 6.
Although the desired substitution of 3-chloroazetidines 4a–g
was attained by reaction with sodium azide, potassium cya-
nide, sodium acetate and potassium thiocyanate in DMSO,
treatment of trans-2-aryl-3-chloroazetidines 4a–g with
sodium bicarbonate, potassium cyanate, potassium fluoride
and potassium iodide using the same reaction conditions
(overnight heating in DMSO) resulted only in complex reac-
tion mixtures, probably due to the less nucleophilic character
of the first three nucleophiles compared to chloride. In the
latter case, the higher leaving capacities of iodide in com-
parison to chloride can be responsible for the failure of the
substitutions.
4. Experimental
4.1. General
In recent years, 3-aminoazetidines have received a lot of at-
tention because of their antibacterial activities.46–50 Reduc-
tion of trans-2-aryl-3-azidoazetidines 9e–g with 2 equiv of
lithium aluminium hydride in ether yielded unprecedented
3-aminoazetidines 18a–c after reflux for 2 h, which could be
purified by performing an acid–base extraction (Scheme 7).
1H NMR spectra were recorded at 270 MHz (JEOL JNM-EX
270) or at 300 MHz (JEOL ECLIPSE+) with CDCl3 as sol-
vent and tetramethylsilane as internal standard. 13C NMR
spectra were recorded at 68 MHz (JEOL JNM-EX 270)
or at 75 MHz (JEOL ECLIPSE+) with CDCl3 as solvent.
Mass spectra were obtained with a mass spectrometer
(VARIAN MAT 112), 70 eVusing a GC–MS coupling (RSL
200, 20 m glass capillary column, i.d. 0.53 mm, He carrier
gas) or AGILENT 1100, 70 eV. IR spectra were measured
with a Spectrum One FT-IR spectrophotometer. Melting
R1
R1
N3
H2N
2 equiv. LiAlH4
N
N
Et2O, ∆, 2h
R2
R2
9e R1= H, R2= iPr
18a R1= H, R2= iPr (70%)
18b R1= H, R2= cHex (82%)
18c R1= Me, R2= iPr (92%)
points were measured using a Buchi B-540 apparatus and
¨
9f R1= H, R2= cHex
9g R1= Me, R2= iPr
are uncorrected. Elemental analysis was performed on a
Perkin–Elmer 2400 Elemental Analyzer. Dichloromethane
was distilled over calcium hydride, while diethyl ether
Scheme 7.

6886
B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
and THF were freshly distilled over sodium benzophenone
ketyl. Other solvents were used as received from the
supplier.
and 134.68 (2ꢀCC5H5), 163.61 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1777. MS (70 eV): m/z (%): 274/2 (M++1, 100), 91
(14). Anal. Calcd for C16H14ClNO (%): C, 70.72; H, 5.19;
N, 5.15. Found (%): C, 70.94; H, 5.29; N, 5.01.
4.1.1. Synthesis of trans-4-aryl-3-chloro-b-lactams 3a–g.
The synthesis of trans-1-allyl-3-chloro-4-phenylazetidin-
2-one 3a is given as a representative example. N-(Benzyl-
idene)allylamine (7.23 g, 0.05 mol) was dissolved in
benzene (150 ml) and 2,6-lutidine (16.05 g, 0.15 mol,
3 equiv) was added, after which the solution was heated to
reflux. Chloroacetylchloride (8.48 g, 0.075 mol, 1.5 equiv)
was added dropwise to this refluxing solution. The resulting
solution was kept at reflux temperature for 22 h. After cool-
ing, the precipitated 2,6-lutidine hydrochloride was filtered
off and the filtrate was washed twice with 1 N hydrochloric
acid. Drying over magnesium sulfate, filtration and evapora-
tion of the solvent yielded trans-1-allyl-3-chloro-4-phenyl-
azetidin-2-one (10.85 g, 49 mmol, 97%). Although the
obtained b-lactams were pure enough for direct use in the
next step, further purification was performed by flash chro-
matography on silica gel.
4.1.1.4. trans-1-Benzyl-3-chloro-4-(4-chlorophenyl)-
azetidin-2-one 3d. Yield 90%, light yellow oil. Hexane/
EtOAc 3:1, Rf ¼0.44. Mp: 83 ꢁC. 1H NMR (300 MHz,
CDCl3): d 3.84 (1H, d, J¼15.0 Hz, C(H)HC6H5), 4.35 (1H,
d, J¼1.7 Hz, CHCl), 4.52 (1H, dꢀd, J¼1.7 Hz, J¼0.7 Hz,
CHC6H4Cl), 4.84 (1H, d, J¼15.0 Hz, C(H)HC6H5), 7.29–
7.38 (9H, m, CH2C6H5 and CHC6H4Cl). 13C NMR
(75 MHz, CDCl3): d 45.04 (CH2C6H5), 63.15 and 64.61
(CHCl and CHC6H4Cl), 128.01, 128.18, 128.45, 128.97
and 129.47 (CC4H4CCl and CC5H5), 133.28, 134.07
and 135.34 (CC4H4CCl and CC5H5), 163.40 (C]O). IR
(KBr, cmꢂ1): nC]O¼1765. MS (70 eV): m/z (%): 310/08/
06 (M++1, 100). Anal. Calcd for C16H13Cl2NO (%):
C, 62.76; H, 4.28; N, 4.57. Found (%): C, 62.91; H, 4.18;
N, 4.74.
4.1.1.5. trans-3-Chloro-1-isopropyl-4-phenylazetidin-
2-one 3e. Yield 77%, light yellow oil. Hexane/EtOAc 3:2,
4.1.1.1. trans-1-Allyl-3-chloro-4-phenylazetidin-2-one
3a. Yield 85%, light yellow oil. Hexane/EtOAc 3:1,
Rf ¼0.3. 1H NMR (300 MHz, CDCl3): d 3.41 (1H, dꢀdꢀd,
J¼15.5 Hz, J¼7.2 Hz, J¼0.8 Hz, NC(H)H), 4.21 (1H,
dꢀdꢀt, J¼15.5 Hz, J¼5.0 Hz, J¼1.6 Hz, NC(H)H), 4.54
(1H, dꢀd, J¼1.8 Hz, J¼0.8 Hz, CHC6H5), 4.58 (1H, d,
J¼1.8 Hz, CHCl), 5.08–5.21 (2H, m, CH]CH2), 5.66–
5.78 (1H, m, CH]CH2), 7.28–7.47 (5H, m, C6H5).
13C NMR (75 MHz, CDCl3): d 43.54 (CH2N), 63.06
(CHC6H5), 65.73 (CHCl), 119.53 (CH]CH2), 126.63,
129.28 and 129.49 (CC5H5), 130.30 (CH]CH2), 134.83
(CC5H5), 163.84 (C]O). IR (NaCl, cmꢂ1): nC]O¼1772.
MS (70 eV): m/z (%): 224/2 (M++1, 100), 186 (45). Anal.
Calcd for C12H12ClNO (%): C, 65.02; H, 5.46; N, 6.32.
Found (%): C, 65.28; H, 5.22; N, 6.44.
1
Rf ¼0.64. H NMR (270 MHz, CDCl3): d 1.07 and 1.31
(2ꢀ3H, 2ꢀd, J¼6.9 Hz, CH(CH3)2), 3.75 (1H, septet, J¼
6.9 Hz, CH(CH3)2), 4.46 and 4.53 (2ꢀ1H, 2ꢀd, J¼1.7 Hz,
NCH and CHCl), 7.35–7.47 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 19.80 and 20.74 (CH(CH3)2), 45.63
(CH(CH3)2), 62.23 and 64.75 (NCH and CHCl), 126.42,
128.86 and 129.08 (CC5H5), 136.24 (CC5H5), 163.13
(C]O). IR (NaCl, cmꢂ1): nC]O¼1765. MS (70 eV): m/z
(%): no M+, 139 (57), 137 (100), 102 (46). Anal. Calcd for
C12H14ClNO (%): C, 64.43; H, 6.31; N, 6.26. Found (%):
C, 64.21; H, 6.43; N, 6.34.
4.1.1.6. trans-3-Chloro-1-cyclohexyl-4-phenylazetidin-
2-one 3f. Yield 86%, light yellow oil. Hexane/EtOAc 3:2,
1
Rf ¼0.65. H NMR (270 MHz, CDCl3): d 0.96–2.04 (10H,
m, (CH2)5), 3.33–3.45 (1H, m, NCH), 4.44 and 4.54
(2ꢀ1H, 2ꢀd, J¼1.7 Hz, NCH and CHCl), 7.34–7.46 (5H,
m, C6H5). 13C NMR (68 MHz, CDCl3): d 24.95, 25.01,
30.21, 31.15 and 32.80 ((CH2)5), 53.75 (NCH), 62.85
and 65.15 (NCH and CHCl), 126.95, 129.20 and 129.31
(CC5H5), 136.71 (CC5H5), 163.82 (C]O). IR (NaCl,
cmꢂ1): nC]O¼1769. MS (70 eV): no M+, 140/38 (100).
Anal. Calcd for C15H18ClNO (%): C, 68.30; H, 6.88; N,
5.31. Found (%): C, 68.51; H, 7.01; N, 5.19.
4.1.1.2. trans-1-Allyl-3-chloro-4-(4-chlorophenyl)aze-
tidin-2-one 3b. Yield 82%, light yellow oil. Hexane/EtOAc
3:1, Rf ¼0.3. 1H NMR (300 MHz, CDCl3): d 3.39 (1H, dꢀd,
J¼15.6 Hz, J¼7.3 Hz, NC(H)H), 4.10–4.20 (1H, m,
NC(H)H), 4.50–4.52 (2H, m, CHCl and CHC6H4Cl), 5.09–
5.22 (2H, m, CH]CH2), 5.65–5.79 (1H, m, CH]CH2),
7.23–7.40 (4H, m, C6H4Cl). 13C NMR (75 MHz, ref¼
CDCl3): d 43.72 (CH2N), 63.22 and 65.11 (CHC6H4Cl
and CHCl), 119.88 (CH]CH2), 128.08 and 129.61
(CC4H4CCl), 130.29 (CH]CH2), 130.99 and 135.51
(CC4H4CCl), 163.50 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1774. MS (70 eV): m/z (%): 258/6 (M++1, 100),
116 (37). Anal. Calcd for C12H11Cl2NO (%): C, 56.27; H,
4.33; N, 5.47. Found (%): C, 56.08; H, 4.51; N, 5.39.
4.1.1.7. trans-3-Chloro-1-isopropyl-4-(4-methylphenyl)-
azetidin-2-one 3g. Yield 81%, light yellow oil. Hexane/
1
EtOAc 3:2, Rf¼0.53. H NMR (270 MHz, CDCl3): d 1.06
and 1.30 (2ꢀ3H, 2ꢀd, J¼6.6 Hz, CH(CH3)2), 2.38 (3H, s,
CqCH3), 3.74 (1H, septet, J¼6.6 Hz, CH(CH3)2), 4.44 and
4.49 (2ꢀ1H, 2ꢀd, J¼1.7 Hz, NCH and CHCl), 7.23–7.25
(2ꢀ2H, 2ꢀd, J¼9.0 Hz, C6H4). 13C NMR (68 MHz,
CDCl3): d 20.09, 21.08 and 21.22 (CH(CH3)2 and CqCH3),
45.80 (CH(CH3)2), 62.53 and 64.92 (NCH and CHCl),
126.63 and 129.79 (CCcH4C), 133.48 and 139.37
(CC4H5C), 163.57 (C]O). IR (NaCl, cmꢂ1): nC]O¼1769.
MS (70 eV): m/z (%): 238/6 (M+, 1), 154/2 (100), 118
(44), 117 (82), 115 (75), 91 (58), 70 (42). Anal. Calcd for
C13H16ClNO (%): C, 65.68; H, 6.78; N, 5.89. Found (%):
C, 65.49; H, 6.86; N, 6.02.
4.1.1.3. trans-1-Benzyl-3-chloro-4-phenylazetidin-2-
one 3c. Yield 75%, light yellow oil. Hexane/EtOAc 3:1,
Rf ¼0.32. 1H NMR (300 MHz, CDCl3): d 3.82 (1H, d,
J¼15.1 Hz, C(H)HC6H5), 4.38 and 4.55 (2ꢀ1H, 2ꢀd,
J¼1.8 Hz, CHCl and CHC6H5), 4.86 (1H, d, J¼15.1 Hz,
C(H)HC6H5), 7.10–7.42 (10H, m, CH2C6H5 and CHC6H5).
13C NMR (75 MHz, ref¼CDCl3): d 44.90 (CH2C6H5),
63.19 and 65.26 (CHCl and CHC6H5), 126.65, 128.05,
128.42, 128.89, 129.24 and 129.43 (2ꢀCC5H5), 134.30

B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
6887
4.1.2. Synthesis of trans-2-aryl-3-chloroazetidines 4a–g.
The reduction of trans-1-allyl-3-chloro-4-phenylazetidin-
2-one 3a to trans-2-aryl-3-chloroazetidine 4a is given as
a representative example. To a solution of aluminium(III)
chloride (12.13 g, 0.09 mol, 3 equiv) in dry diethyl ether
(150 ml) was added carefully lithium aluminium hydride
(3.44 g, 0.09 mol, 3 equiv) at 0 ꢁC. This reaction mixture
was stirred at 0 ꢁC for 10 min, and subsequently refluxed
for 30 min. trans-1-Allyl-3-chloro-4-phenylazetidin-2-one
(6.64 g, 0.03 mol) in dry diethyl ether (100 ml) was added
slowly and after addition was complete, reflux was main-
tained for 4 h. The reaction was cooled and water (200 ml)
was added carefully. The aqueous phase was extracted with
dichloromethane and dried over magnesium sulfate. After
filtration and evaporation of the solvent and further purifica-
tion by flash chromatography on silica gel, trans-2-aryl-3-
chloroazetidine (4.57 g, 0.022 mol, 73%) was obtained as
a light yellow oil.
(36). Anal. Calcd for C16H16ClN (%): C, 74.55; H, 6.26;
N, 5.43. Found (%): C, 74.70; H, 6.38; N, 5.31.
4.1.2.4. trans-1-Benzyl-3-chloro-2-(4-chlorophenyl)-
azetidine 4d. Yield 69%, light yellow oil. 1H NMR
(300 MHz, CDCl3): d 2.97–3.02 (1H, m, C(H)HCHCl),
3.48 (1H, d, J¼12.7 Hz, C(H)HC6H5), 3.67–3.75 (1H, m,
C(H)HCHCl), 3.82 (1H, d, J¼12.7 Hz, C(H)HC6H5), 3.97–
4.03 (1H, m, CHCl), 4.10 (1H, d, J¼6.6 Hz, CHC6H4Cl),
7.22–7.37 (9H, m, CH2C6H5 and CHC6H4Cl). 13C NMR
(75 MHz, CDCl3): d 52.81 (CHCl), 60.80 (CH2C6H5),
61.88 (CH2N), 77.84 (CHC6H4Cl), 127.27, 127.90, 128.13,
128.30 and 128.60 (CC4H4CCl and CC5H5), 133.73,
137.02 and 137.90 (CC4H4CCl and CC5H5). MS (70 eV):
m/z (%): 120 (100), 91 (38). Anal. Calcd for C16H15Cl2N
(%): C, 65.77; H, 5.17; N, 4.79. Found (%): C, 65.89; H,
5.36; N, 4.61.
4.1.2.5. trans-3-Chloro-1-isopropyl-2-phenylazetidine
4e. Yield 83%, light yellow oil. 1H NMR (270 MHz, C6D6):
d 0.60 and 0.77 (2ꢀ3H, 2ꢀd, J¼6.0 Hz, CH(CH3)2), 2.24
(1H, septet, J¼6.0 Hz, CH(CH3)2), 2.74 (1H, dꢀd, J¼
6.6 Hz, J¼6.6 Hz, NCH(H)), 3.51 (1H, dꢀdꢀd, J¼6.6 Hz,
J¼6.6 Hz, J¼1.0 Hz, NCH(H)), 3.79 (1H, q, J¼6.6 Hz,
CHCl), 3.93 (1H, d, J¼6.6 Hz, NCHC6H5), 7.06–7.20
and 7.42–7.45 (5H, m, C6H5). 13C NMR (68 MHz, C6D6):
d 20.09 and 20.84 (CH(CH3)2), 52.99 (CHCl), 59.64 and
59.93 (CH(CH3)2 and NCH2), 78.83 (NCHC6H5), 126.95–
128.62 (NCHCC5H5), 141.96 (NCHCC5H5). MS (70 eV):
m/z (%): 211/09 (M+, 27), 196/4 (MꢂMe+, 25), 132 (100).
Anal. Calcd for C12H16ClN (%): C, 68.73; H, 7.69; N, 6.68.
Found (%): C, 68.89; H, 7.60; N, 6.82.
4.1.2.1. trans-1-Allyl-3-chloro-2-phenylazetidine 4a.
Yield 73%, light yellow oil. Hexane/EtOAc 4:1, Rf ¼0.40.
1H NMR (300 MHz, CDCl3): d 2.97–3.01 (1H, m,
C(H)HCHCl), 3.06 (1H, dꢀd, J¼13.4 Hz, J¼6.9 Hz,
C(H)HCH]CH2), 3.32 (1H, dꢀdꢀt, J¼13.4 Hz, J¼
5.5 Hz, J¼1.4 Hz, C(H)HCH]CH2), 3.83–3.89 (1H, m,
C(H)HCHCl), 4.05–4.12 (2H, m, CHCl and CHC6H5),
5.02–5.20 (2H, m, CH]CH2), 5.65–5.80 (1H, m,
CH]CH2), 7.19–7.44 (5H, m, C6H5). 13C NMR (75 MHz,
CDCl3): d 52.69 (CHC6H5), 60.80 (CH2CHCl), 61.10
(CH2CH]CH2), 78.72 (CHCl), 117.66 (CH]CH2),
126.59, 128.05 and 128.45 (CC5H5), 133.81 (CH]CH2),
139.55 (CC5H5). MS (70 eV): m/z (%): 210/8 (M++1,
100). Anal. Calcd for C12H14ClN (%): C, 69.39; H, 6.79;
N, 6.74. Found (%): C, 69.11; H, 6.95; N, 6.70.
4.1.2.6. trans-3-Chloro-1-cyclohexyl-2-phenylazeti-
dine 4f. Yield 79%, light yellow oil. H NMR (270 MHz,
1
4.1.2.2. trans-1-Allyl-3-chloro-2-(4-chlorophenyl)aze-
tidine 4b. Yield 80%, light yellow oil. Hexane/EtOAc 4:1,
Rf ¼0.60. H NMR (300 MHz, CDCl3): d 2.98–3.03 (1H,
C6D6): d 0.75–1.57 (10H, m, (CH2)5), 2.00–2.04 (1H, m,
NCH), 2.79 (1H, dꢀd, J¼7.0 Hz, J¼7.0 Hz, NCH(H)),
3.59 (1H, dꢀd, J¼7.0 Hz, J¼7.0 Hz, NCH(H)), 3.85 (1H,
q, J¼7.0 Hz, CHCl), 3.99 (1H, d, J¼7.0 Hz, NCHC6H5),
7.07–7.20 and 7.45–7.48 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 24.29, 24.37, 25.77, 30.03 and 30.87
((CH2)5), 52.90 (CHCl), 59.44 (NCH2), 67.94 (NCH),
78.62 (NCHC6H5), 126.66, 127.87 and 128.34
(NCHCC5H5), 141.15 (NCHCC5H5). MS (70 eV): m/z
(%): 252/0 (M+H+, 100). Anal. Calcd for C15H20ClN (%):
C, 72.13; H, 8.07; N, 5.61. Found (%): C, 72.28; H, 8.22;
N, 5.80.
1
m, C(H)HCHCl), 3.07 (1H, dꢀd, J¼13.4 Hz, J¼6.9 Hz,
C(H)HCH]CH2), 3.29 (1H, dꢀdꢀt, J¼13.4 Hz, J¼
5.6 Hz, J¼1.0 Hz, C(H)HCH]CH2), 3.84–3.88 (1H, m,
C(H)HCHCl), 4.00–4.07 (2H, m, CHC6H4Cl and CHCl),
5.03–5.21 (2H, m, CH]CH2), 5.64–5.77 (1H, m, CH]
CH2), 7.29–7.39 (4H, m, C6H4Cl). 13C NMR (75 MHz,
CDCl3): d 52.71 (CHCl), 60.80 (CH2CHCl), 61.09
(CH2CH]CH2), 78.72 (CHC6H4Cl), 117.94 (CH]CH2),
127.99 and 128.66 (CC4H4CCl), 133.70 (CH]CH2),
133.82 and 138.19 (CC4H4CCl). MS (70 eV): m/z (%):
246/4/2 (M++1, 50), 116 (23). Anal. Calcd for C12H13Cl2N
(%): C, 59.52; H, 5.41; N, 5.78. Found (%): C, 59.68; H,
5.36; N, 5.71.
4.1.2.7. trans-3-Chloro-1-isopropyl-2-(4-methylphenyl)-
azetidine 4g. Yield 86%, light yellow oil. 1H NMR
(270 MHz, C6D6): d 0.64 and 0.78 (2ꢀ3H, 2ꢀd, J¼
6.3 Hz, CH(CH3)2), 2.11 (3H, S, CqCH3), 2.26 (1H, septet,
J¼6.3 Hz, CH(CH3)2), 2.75 (1H, dꢀd, J¼7.0 Hz, J¼
7.0 Hz, NCH(H)), 3.53 (1H, dꢀd, J¼7.0 Hz, J¼7.0 Hz,
NCH(H)), 3.83 (1H, q, J¼7.0 Hz, CHCl), 3.94 (1H, d, J¼
7.0 Hz, NCHC6H4), 7.00 and 7.37 (2ꢀ2H, 2ꢀd, J¼7.9 Hz,
4.1.2.3. trans-1-Benzyl-3-chloro-2-phenylazetidine 4c.
Yield 87%, light yellow oil. H NMR (300 MHz, CDCl3):
1
d 3.00 (1H, t, J¼7.2 Hz, C(H)HCHCl), 3.47 (1H, d,
J¼12.9 Hz, C(H)HC6H5), 3.71–3.75 (1H, m, C(H)HCHCl),
3.89 (1H, d, J¼12.9 Hz, C(H)HC6H5), 4.03–4.10 (1H, m,
CHCl), 4.16 (1H, d, J¼6.9 Hz, CHC6H5), 7.22–7.33 (10H,
m, CH2C6H5 and CHC6H5). 13C NMR (75 MHz, CDCl3):
d 52.92 (CHCl), 60.86 (CH2CHCl), 61.93 (CH2C6H5),
78.52 (CHC6H5), 126.56, 127.20, 128.05, 128.28, 128.45
and 128.63 (2ꢀCC5H5), 137.29 and 139.37 (2ꢀCC5H5).
MS (70 eV): m/z (%): 260/58 (M++1, 23), 120 (100), 91
C6H4). 13C NMR (68 MHz, CHCl3):
d 20.09 and
20.79 (CH(CH3)2), 21.11 (CqCH3), 52.56 (CHCl), 59.68
(CH(CH3)2 and NCH2), 78.58 (NCHC6H5), 126.61 and
129.04 (NCHCC4H4C), 137.32 and 138.47 (NCHCC4H4C).
MS (70 eV): m/z (%): 225/3 (M+, 22), 210/08 (MꢂMe+, 22),
146 (100). Anal. Calcd for C13H18ClN (%): C, 69.79; H,
8.11; N, 6.26. Found (%): C, 69.62; H, 8.19; N, 6.11.

6888
B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
4.1.3. Synthesis of 3-substituted azetidines 9a–p. The
transformation of trans-3-chloro-2-phenylazetidine 4a into
trans-3-azido-2-phenylazetidine 9a is given as a representa-
tive example of substitution reactions of 3-chloroazetidines.
trans-3-Chloro-2-phenylazetidine (1 g, 4.8 mmol) was dis-
solved in DMSO (40 ml). To this solution, sodium azide
(1.25 g, 19.28 mmol, 4 equiv) was added carefully. This
mixture was stirred overnight at 80 ꢁC. After cooling, the
reaction mixture was poured into water (40 ml) and the mix-
ture was extracted with diethyl ether. The combined organic
extracts were washed with water and brine. After drying over
magnesium sulfate and evaporation of the solvent, crude
trans-3-azido-2-phenylazetidine (1 g, 4.7 mmol, 98%) was
obtained. Further purification was performed by flash chro-
matography on silica gel, yielding trans-3-azido-2-phenyl-
azetidine (0.48 g, 2.3 mmol, 47%).
3.55–3.60 (1H, m, C(H)HCHN3), 3.67–3.76 (1H, m,
CHN3), 3.88 (1H, d, J¼12.8 Hz, C(H)HC6H5), 4.01 (1H,
d, J¼6.6 Hz, CHC6H5), 7.18–7.47 (10H, m, CH2C6H5
and CHC6H5). 13C NMR (75 MHz, CDCl3): d 56.42
(CH2CHN3), 58.48 (CHN3), 61.39 (CH2C6H5), 74.63
(CHC6H5), 126.59, 127.15, 127.90, 128.25, 128.51 and
128.63 (2ꢀCC5H5), 137.32 and 138.80 (2ꢀCC5H5). IR
(NaCl, cmꢂ1): nN3¼2102. MS (70 eV): m/z (%): 265
(M++1, 22), 120 (100) and 91(20). Anal. Calcd for
C16H16N4 (%): C, 72.70; H, 6.10; N, 21.20. Found (%): C,
72.96; H, 6.01; N, 21.02.
4.1.3.4. trans-3-Azido-1-benzyl-2-(4-chlorophenyl)-
azetidine 9d. Yield 63%, light yellow oil. Hexane/EtOAc
1
3:2, Rf ¼0.76. H NMR (300 MHz, CDCl3): d 2.81–2.85
(1H, m, C(H)HCHN3), 3.45 (1H, d, J¼12.8 Hz,
C(H)HC6H5), 3.58–3.63 (1H, m, C(H)HCHN3), 3.66–3.73
(1H, m, CHN3), 3.83 (1H, d, J¼12.8 Hz, C(H)HC6H5),
3.98 (1H, d, J¼6.6 Hz, CHC6H4Cl), 7.21–7.42 (9H, m,
CH2C6H5 and CHC6H4Cl). 13C NMR (75 MHz, CDCl3):
d 56.52 (CH2CHN3), 58.64 (CHN3), 61.48 (CH2C6H5),
74.14 (CHC6H4Cl), 127.34, 128.02, 128.36 and 128.73
(CC4H4CCl and CC5H5), 133.67, 137.09 and 138.36
(CC4H4CCl and CC5H5). IR (NaCl, cmꢂ1): nN3¼2102. MS
(70 eV): m/z (%): 120 (100), 91 (18). Anal. Calcd for
C16H15ClN4 (%): C, 64.32; H, 5.06; N, 18.75. Found (%):
C, 64.13; H, 5.24; N, 18.60.
The same procedure was executed with potassium cyanide,
sodium acetate and potassium thiocyanate. The reaction
times and temperatures for the other derivatives are listed
in Section 2.
Caution: All reactions with sodium azide were performed
behind a safety shield. No (violent) decomposition of the
organic azides was observed throughout.
4.1.3.1. trans-1-Allyl-3-azido-2-phenylazetidine 9a. Yield
47%, light yellow oil. Hexane/EtOAc 7:1, Rf ¼0.18. 1H NMR
(300 MHz, CDCl3): d 2.78–2.82 (1H, m, C(H)HCHN3), 3.00
(1H, dꢀd, J¼13.2 Hz, J¼6.9 Hz, C(H)HCH]CH2), 3.30
(1H, dꢀd, J¼13.2 Hz, J¼5.5 Hz, C(H)HCH]CH2), 3.67–
3.77 (2H, m, C(H)HCHN3 and CHN3), 3.92 (1H, d, J¼
5.6 Hz, CHC6H5), 5.04–5.20 (2H, m, CH]CH2), 5.67–5.80
(1H, m, CH]CH2), 7.22–7.43 (5H, m, C6H5). 13C NMR
(75 MHz, CDCl3): d 56.54 (CH2CHN3), 58.34 (CHN3),
60.75 (CH2CH]CH2), 74.97 (CHC6H5), 117.63 (CH]
CH2), 126.69, 127.95 and 128.55 (CC5H5), 133.93 (CH]
CH2), 139.99 (CC5H5). IR (NaCl, cmꢂ1): nN3¼2101. MS
(70 eV): m/z (%): 215 (M++1, 23). Anal. Calcd for C12H14N4
(%): C, 67.27; H, 6.59; N, 26.15. Found (%): C, 67.49; H,
6.71; N, 26.40.
4.1.3.5. trans-3-Azido-1-isopropyl-2-phenylazetidine
9e. Yield 62%, light yellow oil. Hexane/EtOAc 3:1,
Rf ¼0.3. 1H NMR (270 MHz, CDCl3): d 0.72 and 0.77
(2ꢀ3H, 2ꢀd, J¼6.3 Hz, CH(CH3)2), 2.48 (1H, septet,
J¼6.3 Hz, CH(CH3)2), 2.76 (1H, t, J¼7.0 Hz, NCH(H)),
3.61 (1H, q, J¼7.0 Hz, CHN3), 3.68 (1H, q, J¼7.0 Hz,
NCH(H)), 3.87 (1H, d, J¼7.0 Hz, NCHC6H5), 7.22–7.40
and 7.43–7.47 (5H, m, C6H5). 13C NMR (68 MHz,
CDCl3): d 20.04 and 20.75 (CH(CH3)2), 55.40 (NCH2),
57.68 (CHN3), 59.23 (CH(CH3)2), 74.77 (NCHC6H5),
126.74, 127.71 and 128.62 (NCHCC5H5), 141.79
(NCHCC5H5). IR (NaCl, cmꢂ1): nN3¼2106. MS (70 eV):
m/z (%): 201 (MꢂMe+, 25), 173 (MꢂN3ꢂMe+, 48) 161
(100), 119 (69), 91 (100). Anal. Calcd for C12H16N4 (%):
C, 66.64; H, 7.46; N, 25.90. Found (%): C, 66.91; H, 7.59;
N, 25.78.
4.1.3.2. trans-1-Allyl-3-azido-2-(4-chlorophenyl)azeti-
dine 9b. Yield 62%, light yellow oil. Hexane/EtOAc 3:1,
1
Rf ¼0.33. H NMR (300 MHz, CDCl3): d 2.78–2.85 (1H,
m, C(H)HCHN3), 3.02 (1H, dꢀd, J¼13.2 Hz, J¼6.7 Hz,
C(H)HCH]CH2), 3.26 (1H, dꢀd, J¼13.2 Hz, J¼5.8 Hz,
C(H)HCH]CH2), 3.66–3.74 (2H, m, CHN3 and
C(H)HCCN3), 3.88 (1H, d, J¼5.5 Hz, CHC6H4Cl), 5.04–
5.25 (2H, m, CH]CH2), 5.65–5.78 (1H, m, CH]CH2),
7.31–7.39 (4H, m, C6H4Cl). 13C NMR (75 MHz, CDCl3):
d 56.52 (CH2CHN3), 58.45 (CHN3), 60.71 (CH2CH]CH2),
74.36 (CHC6H4Cl), 117.82 (CH]CH2), 128.08 and 128.76
(CC4H4CCl), 133.76 (CH]CH2), 133.76 and 138.59
(CC4H4CCl). IR (NaCl, cmꢂ1): nN3¼2103. MS (70 eV):
m/z (%): 251/49 (M++1, 100). Anal. Calcd for C12H13ClN4
(%): C, 57.95; H, 5.27; N, 22.53. Found (%): C, 57.66; H,
5.42; N, 22.69.
4.1.3.6. trans-3-Azido-1-cyclohexyl-2-phenylazetidine
9f. Yield 70%, light yellow oil. Hexane/EtOAc 3:1,
1
Rf ¼0.3. H NMR (270 MHz, CDCl3): d 0.68–1.77 (10H,
m, (CH2)5), 2.11–2.21 (1H, m, NCH), 2.77 (1H, t,
J¼7.0 Hz, NCH(H)), 3.61 (1H, q, J¼7.0 Hz, CHN3), 3.69
(1H, q, J¼7.0 Hz, NCH(H)), 3.90 (1H, d, J¼7.0 Hz,
NCHC6H5), 7.23–7.36 and 7.40–7.46 (5H, m, C6H5). 13C
NMR (68 MHz, CDCl3): d 24.35, 24.40, 25.84, 30.08 and
30.94 ((CH2)5), 55.08 (NCH2), 58.17 (CHN3), 67.53
(NCH), 74.64 (NCHC6H5), 126.65, 127.65 and 128.39
(NCHCC5H5), 141.88 (NCHCC5H5). IR (NaCl, cmꢂ1):
nN3¼2101. MS (70 eV): m/z (%): 257 (M+H+, 100).
4.1.3.7. trans-3-Aazido-1-isopropyl-2-(4-methylphe-
nyl)azetidine 9g. Yield 76%, light yellow oil. H NMR
1
4.1.3.3. trans-3-Azido-1-benzyl-2-phenylazetidine 9c.
Yield 45%, light yellow oil. Hexane/EtOAc 5:1, Rf ¼0.53.
1H NMR (300 MHz, CDCl3): d 2.80 (1H, t, J¼6.9 Hz,
C(H)HCHN3), 3.42 (1H, d, J¼12.8 Hz, C(H)HC6H5),
(300 MHz, C6D6):
J¼6.3 Hz, CH(CH3)2), 2.33 (3H, S, CqCH3), 2.45 (1H, sep-
d
0.72 and 0.98 (2ꢀ3H, 2ꢀd,
tet, J¼6.3 Hz, CH(CH3)2), 2.74 (1H, t, J¼7.0 Hz, NCH(H)),

B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
6889
3.69 (1H, q, J¼7.0 Hz, J¼7.0 Hz, NCH(H)), 3.83 (1H, q,
J¼7.0 Hz, CHN3), 3.84 (1H, d, J¼7.0 Hz, NCHC6H4),
7.15 and 7.34 (2ꢀ2H, 2ꢀd, J¼8.3 Hz, C6H4). 13C NMR
(75 MHz, CHCl3): d 20.07 and 20.79 (CH(CH3)2), 21.13
(CqCH3), 55.36 (NCH2), 57.77 (CHN3), 59.30
(CH(CH3)2), 74.68 (NCHC6H4), 126.70 and 129.14
(NCHCC4H4C), 137.36 and 138.87 (NCHCC4H4C). IR
(NaCl, cmꢂ1): nN3¼2105. MS (70 eV): m/z (%): No M+,
175 (100), 133 (65), 105 (83). Anal. Calcd for C13H18N4
(%): C, 67.80; H, 7.88; N, 24.33. Found (%): C, 67.98; H,
7.70; N, 24.47.
4.1.3.11.
trans-3-Acetoxy-1-allyl-2-phenylazetidine
9k. Yield 52%, light yellow oil. 1H NMR (300 MHz,
CDCl3): d 2.05 (3H, s, CH3C]O), 2.75–2.80 (1H, m,
C(H)HCHO), 3.05 (1H, dꢀd, J¼13.4 Hz, J¼6.9 Hz,
C(H)HCH]CH2), 3.33 (1H, dꢀdꢀt, J¼13.4 Hz, J¼
5.6 Hz, J¼1.4 Hz, C(H)HCH]CH2), 3.85 (1H, dꢀdꢀd,
J¼7.3 Hz, J¼6.5 Hz, J¼1.1 Hz, C(H)HCHO), 3.99 (1H, d,
J¼6.3 Hz, CHC6H5), 4.83–4.90 (1H, m, CHOC]O),
5.03–5.29 (2H, m, CH]CH2), 5.68–5.80 (1H, m, CH]
CH2), 7.25–7.47 (5H, m, C6H5). 13C NMR (75 MHz,
CDCl3): d 20.73 (CH3), 57.91 (CH2CHO), 61.03 (CH2CH]
CH2), 70.68 (CHOC]O), 74.62 (CHC6H5), 117.52
(CH]CH2), 127.11, 127.84 and 128.34 (CC5H5), 134.04
(CH]CH2), 139.86 (CC5H5), 170.00 (C]O). IR (NaCl,
cmꢂ1): nC]O¼1745. MS (70 eV): m/z (%): 232 (M++1,
89), 190 (83) and 172 (84). Anal. Calcd for C14H17NO2
(%): C, 72.70; H, 7.41; N, 6.06. Found (%): C, 72.91; H,
7.26; N, 5.94.
4.1.3.8. trans-1-Allyl-3-cyano-2-phenylazetidine 9h.
Yield 54%, light yellow oil. Hexane/EtOAc 5:1, Rf ¼
0.36. 1H NMR (300 MHz, CDCl3): d 2.95–3.09 (3H,
m, C(H)HCH]CH2, CHC^N and C(H)HCHC^N),
3.27 (1H, dꢀdꢀt, J¼13.4 Hz, J¼5.5 Hz, J¼1.4 Hz,
C(H)HCH]CH2), 3.65–3.70 (1H, m, C(H)HCHC^N),
4.21 (1H, d, J¼8.0 Hz, CHC6H5), 5.04–5.25 (2H, m,
CH]CH2), 5.62–5.77 (1H, m, CH]CH2), 7.22–7.48
(5H, m, C6H5). 13C NMR (75 MHz, CDCl3): d 27.51
(CHC^N), 53.50 (CH2CHC^N), 60.17 (CH2CH]CH2),
71.93 (CHC6H5), 118.05 (CH]CH2), 118.97 (C^N),
126.57, 128.56 and 128.68 (CC5H5), 133.15 (CH]CH2),
139.25 (CC5H5). IR (NaCl, cmꢂ1): nC^N¼2241. MS
(70 eV): m/z (%): 176 (25). Anal. Calcd for C13H14N2 (%):
C, 78.75; H, 7.12; N, 14.13. Found (%): C, 78.61; H, 7.01;
N, 14.29.
4.1.3.12. trans-3-Acetoxy-1-allyl-2-(4-chlorophenyl)-
azetidine 9l. Yield 73%, light yellow oil. Hexane/EtOAc
5:2, Rf ¼0.48. H NMR (300 MHz, CDCl3): d 2.04 (3H, s,
1
CH3C]O), 2.80–2.84 (1H, m, C(H)HCHO), 3.09 (1H,
dꢀd, J¼13.2 Hz, J¼6.9 Hz, C(H)HCH]CH2), 3.29 (1H,
dꢀd, J¼13.2 Hz, J¼6.1 Hz, C(H)HCH]CH2), 3.83–3.88
(1H, m, C(H)HCHO), 3.97 (1H, d, J¼6.3 Hz, CHC6H4Cl),
4.83–4.90 (1H, m, CHOC]O), 5.14–5.20 (2H, m,
CH]CH2), 5.65–5.78 (1H, m, CH]CH2), 7.26–7.42 (4H,
m, C6H4Cl). 13C NMR (75 MHz, CDCl3): d 20.73 (CH3),
57.61 (CH2CHO), 60.94 (CH2CH]CH2), 70.52 (CHOC]
O), 74.14 (CHC6H4Cl), 117.90 (CH]CH2), 128.51 and
128.59 (CC4H4CCl), 133.61 (CH]CH2), 133.72 and
138.27 (CC4H4CCl), 169.98 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1746. MS (70 eV): m/z (%): 268/6 (M++1, 100).
Anal. Calcd for C14H16ClNO2 (%): C, 63.28; H, 6.07; N,
5.27. Found (%): C, 63.40; H, 6.10; N, 5.16.
4.1.3.9. trans-1-Allyl-2-(4-chlorophenyl)-3-cyanoaze-
tidine 9i. Yield 62%, light yellow oil. Hexane/EtOAc 3:1,
1
Rf ¼0.3. H NMR (300 MHz, CDCl3): d 2.93–3.06 (2H,
m, CHC^N and C(H)HCH]CH2), 3.10 (1H, dꢀd,
J¼9.2 Hz, J¼6.5 Hz, C(H)HCHC^N), 3.24 (1H, dꢀdꢀt,
J¼13.5 Hz, J¼5.6 Hz, J¼1.5 Hz, C(H)HCH]CH2), 3.67–
3.72 (1H, m, C(H)HCHC^N), 4.19 (1H, d, J¼8.3 Hz,
CHC6H4Cl), 5.02–5.22 (2H, m, CH]CH2), 5.61–5.77
(1H, m, CH]CH2), 7.27–7.47 (4H, m, C6H4Cl). 13C
NMR (75 MHz, CDCl3): d 27.62 (CHC^N), 53.45
(CH2CHC^N), 60.19 (CH2CH]CH2), 71.23 (CHC6H4Cl),
118.33 (CH]CH2), 118.77 (C^N), 128.01 and 128.89
(CC4H4CCl), 133.15 (CH]CH2), 134.65 and 137.78
(CC4H4CCl). IR (NaCl, cmꢂ1): nC^N¼2242. MS (70 eV):
m/z (%): 235/3 (M++1, 66). Anal. Calcd for C13H13ClN2
(%): C, 67.10; H, 5.63; N, 15.23. Found (%): C, 67.30; H,
5.54; N, 15.39.
4.1.3.13. trans-3-Acetoxy-1-benzyl-2-phenylazetidine
9m. Yield 52%, light yellow oil. Hexane/EtOAc 5:2,
Rf ¼0.59. 1H NMR (300 MHz, CDCl3): d 2.03 (3H, s,
CH3C]O), 2.77–2.82 (1H, m, C(H)HCHO), 3.49 (1H, d,
J¼13.1 Hz, C(H)HC6H5), 3.73–3.78 (1H, m, C(H)HCHO),
3.91 (1H, d, J¼13.1 Hz, C(H)HC6H5), 4.08 (1H, d,
J¼5.0 Hz, CHC6H5), 4.87–4.91 (1H, m, CHOC]O),
7.19–7.48 (10H, m, CH2C6H5 and CHC6H5). 13C NMR
(75 MHz, CDCl3): d 20.78 (CH3), 57.90 (CH2CHO), 61.62
(CH2C6H5), 70.97 (CHOC]O), 74.34 (CHC6H5), 127.09,
127.87, 128.25, 128.34, 128.50 and 128.74 (2ꢀCC5H5),
137.46 and 139.69 (2ꢀCC5H5), 169.99 (C]O). IR (NaCl,
cmꢂ1): nC]O¼1744. MS (70 eV): m/z (%): 282 (M++1,
12), 120 (100) and 91(20). Anal. Calcd for C18H19NO2
(%): C, 76.84; H, 6.81; N, 4.98. Found (%): C, 76.99; H,
6.70; N, 4.88.
4.1.3.10. trans-1-Benzyl-2-(4-chlorophenyl)-3-cyano-
azetidine 9j. Yield 65%, light yellow oil. Hexane/EtOAc
1
3:1, Rf ¼0.43. H NMR (300 MHz, CDCl3): d 2.92–3.01
(1H, m, CHC^N), 3.12 (1H, dꢀd, J¼9.2 Hz, J¼6.4 Hz,
C(H)HCHC^N), 3.49 (1H, d, J¼12.9 Hz, C(H)HC6H5),
3.56–3.61 (1H, m, C(H)HCHC^N), 3.81 (1H, d, J¼
12.9 Hz, C(H)HC6H5), 4.28 (1H, d, J¼8.3 Hz, CHC6H4Cl),
7.22–7.42 (9H, m, CH2C6H5 and CHC6H4Cl). 13C NMR
(75 MHz, CDCl3): d 27.83 (CHC^N), 53.55 (CH2CHC^
N), 61.10 (CH2C6H5), 71.18 (CHC6H4Cl), 118.72 (C^N),
127.57, 127.98, 128.47, 128.68 and 128.92 (CC4H4CCl
and CC5H5), 134.44, 136.27 and 137.54 (CC4H4CCl and
CC5H5). IR (NaCl, cmꢂ1): nC^N¼2242. MS (70 eV): m/z
(%): 120 (100), 91 (40). Anal. Calcd for C17H15ClN2 (%):
C, 72.21; H, 5.35; N, 9.91. Found (%): C, 72.36; H, 5.48;
N, 9.73.
4.1.3.14. trans-3-Acetoxy-1-benzyl-2-(4-chlorophenyl)-
azetidine 9n. Yield 15%, light yellow oil. Hexane/EtOAc
1
10:3, Rf ¼0.43. Yellow oil. H NMR (300 MHz, CDCl3):
d 2.04 (3H, s, CH3C]O), 2.29–2.84 (1H, m, C(H)HCHO),
3.50 (1H, d, J¼12.9 Hz, C(H)HC6H5), 3.74 (1H, t,
J¼6.3 Hz, C(H)HCHO), 3.86 (1H, d, J¼12.9 Hz,
C(H)HC6H5), 4.02 (1H, d, J¼6.1 Hz, CHC6H4Cl), 4.79–
4.85 (1H, m, CHOC]O), 7.22–7.42 (9H, m, CH2C6H5
and CHC6H4Cl). 13C NMR (75 MHz, CDCl3): d 20.75

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B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
(CH3), 57.74 (CH2CHO), 61.67 (CH2C6H5), 70.95
(CHOC]O), 71.49 (CHC6H4Cl), 127.21, 127.99, 128.28,
128.44 and 128.71 (CC4H4CCl and CC5H5), 137.29,
138.34 and 169.96 (CC4H4CCl and CC5H5), 184.16
(C]O). IR (NaCl, cmꢂ1): nC]O¼1745. MS (70 eV): m/z
(%): 318/6 (M++1, 14), 120 (100).
C(H)HCH]CH2), 3.70 (1H, t, J¼6.3 Hz, C(H)HCHO),
3.79–3.83 (1H, m, CHO), 3.86 (1H, d, J¼5.5 Hz,
CHC6H5), 5.00–5.20 (2H, m, CH]CH2), 5.67–5.80 (1H,
m, CH]CH2), 7.22–7.48 (5H, m, C6H5). 13C NMR
(75 MHz, CDCl3): d 55.35 (OCH3), 56.62 (CH2CCHO),
59.95 (CH2CH]CH2), 75.35 (CHC6H5), 77.00 (CHO),
116.06 (CH]CH2), 125.84, 126.30 and 127.17 (CC5H5),
133.28 (CH]CH2), 140.12 (CC5H5). MS (70 eV): m/z
(%): 204 (M++1, 100). Anal. Calcd for C13H17NO (%): C,
76.81; H, 8.43; N, 6.89. Found (%): C, 76.96; H, 8.56; N,
6.80.
4.1.3.15. trans-1-Allyl-2-phenyl-3-thiocyanoazetidine
9o. Yield 31%, light yellow oil. Hexane/EtOAc 2:1, Rf ¼
1
0.48. H NMR (300 MHz, CDCl3): d 3.08 (1H, dꢀd, J¼
13.3 Hz, J¼6.6 Hz, C(H)HCH]CH2), 3.11–3.16 (1H, m,
C(H)HCHSC^N), 3.32 (1H, dꢀd, J¼13.3 Hz, J¼5.5 Hz,
C(H)HCH]CH2), 3.37–3.44 (1H, m, CHSC^N), 3.85–
3.90 (1H, m, C(H)HCHSC^N), 4.18 (1H, d, J¼7.7 Hz,
CHC6H5), 5.06–5.38 (2H, m, CH]CH2), 5.65–5.80
(1H, m, CH]CH2), 7.25–7.48 (5H, m, C6H5). 13C NMR
4.1.4.2. trans-1-Benzyl-2-(4-chlorophenyl)-3-methoxy-
azetidine 9r. Yield 45%, light yellow oil. Hexane/EtOAc
1
5:2, Rf ¼0.33. H NMR (300 MHz, CDCl3): d 2.73–2.77
(1H, m, C(H)HCHO), 3.21 (3H, s, OCH3), 3.46 (1H, d,
J¼12.8 Hz, C(H)HC6H5), 3.59–3.60 (1H, m, C(H)HCHO),
3.70–3.76 (1H, m, CHO), 3.82 (1H, d, J¼12.8 Hz,
C(H)HC6H5), 3.92 (1H, d, J¼5.8 Hz, CHC6H4Cl), 7.18–
7.41 (9H, m, C6H5 and C6H4Cl). 13C NMR (75 MHz,
ref¼CDCl3): d 56.73 (OCH3), 57.97 (CH2CHO), 61.92
(CH2C6H5), 75.69 (CHC6H4Cl), 78.67 (CHO), 127.24,
128.37, 128.46, 128.63 and 128.87 (CC4H4CCl and
CC5H5), 133.22, 137.88 and 139.87 (CC4H4CCl and
CC5H5). MS (70 eV): m/z (%): 290/88 (M++1, 20), 120
(100). Anal. Calcd for C17H18ClNO (%): C, 70.95; H,
6.30; N, 4.87. Found (%): C, 70.79; H, 6.45; N, 4.99.
(75 MHz, ref¼CDCl3):
d 42.88 (CHSC^N), 57.80
(CH2CHSC^N), 60.58 (CH2CH]CH2), 75.94 (CHC6H5),
110.57 (CH]CH2), 118.18 (SC^N), 126.84, 128.60 and
128.80 (CC5H5), 133.65 (CH]CH2), 139.24 (CC5H5). IR
(NaCl, cmꢂ1): nC^N¼2156. MS (70 eV): m/z (%): 231
(M++1, 100). Anal. Calcd for C13H14N2S (%): C, 67.79;
H, 6.13; N, 12.16. Found (%): C, 67.96; H, 6.30; N, 12.05.
4.1.3.16. trans-1-Allyl-2-(4-chlorophenyl)-3-thiocyano-
azetidine 9p. Yield 43%, light yellow oil. Hexane/EtOAc
1
10:3, Rf¼0.45. H NMR (300 MHz, CDCl3): d 3.12 (1H,
dꢀd, J¼13.2 Hz, J¼6.6 Hz, C(H)HCH]CH2), 3.11–3.17
(1H, m, C(H)HCHSC^N), 3.28 (1H, dꢀdꢀt, J¼13.2 Hz,
J¼5.8 Hz, J¼1.4 Hz, C(H)HCH]CH2), 3.32–3.40 (1H,
m, CHSC^N), 3.85–3.90 (1H, m, C(H)HCHSC^N), 4.16
(1H, d, J¼7.4 Hz, CHC6H4Cl), 5.05–5.24 (2H, m, CH]
CH2), 5.63–5.77 (1H, m, CH]CH2), 7.26–7.43 (4H, m,
C6H4Cl). 13C NMR (75 MHz, CDCl3): d 42.87 (CHSC^N),
57.60 (CH2CHSC^N), 60.41 (CH2CH]CH2), 75.20
(CHC6H4Cl), 118.22 (CH]CH2), 128.10 and 128.89
(CC4H4CCl), 133.38 (CH]CH2), 110.21 and 134.27
(CC4H4CCl), 137.74 (SC^N). IR (NaCl, cmꢂ1):
nC^N¼2157. MS (70 eV): m/z (%): 267/5 (M++1, 100).
Anal. Calcd for C13H13ClN2S (%): C, 58.97; H, 4.95; N,
10.58. Found (%): C, 59.19; H, 4.74; N, 10.50.
4.1.5. Synthesis of trans-3-amino-2-arylazetidines 18a–c.
The synthesis of trans-3-amino-1-isopropyl-2-phenylazeti-
dine 18a is described as a representative example.
To trans-3-azido-1-isopropyl-2-phenylazetidine (1 g, 4.6
mmol) in diethyl ether (10 ml) at 0 ꢁC was added lithium
aluminium hydride (0.35 g, 9.2 mmol, 2 equiv). This reac-
tion mixture was refluxed for 2 h and after cooling, water
was added until all remaining lithium aluminium hydride
had decomposed. The resulting suspension was poured into
water and the aqueous layer was extracted three times with
dichloromethane. The combined organic layers were dried
(magnesium sulfate) and, after filtration and evaporation of
the solvent in vacuo, trans-3-amino-1-isopropyl-2-phenyl-
azetidine (0.62 g3.22 mmol, 70%) was obtained. Purification
was performed by an acid–base extraction.
4.1.4. Synthesis of 3-methoxyazetidines 9q–r. The reaction
of trans-1-allyl-3-chloro-2-phenylazetidine 4a to afford
trans-1-allyl-3-methoxy-2-phenylazetidine 9q is given as
a representative example for the substitution reactions of
the 3-chloroazetidines with sodium methoxide. Sodium
methoxide (4 N) (5 ml, 20 mmol, 4 equiv) in methanol was
added to trans-3-chloro-2-phenylazetidine (1 g, 4.8 mmol)
and the resulting mixture was refluxed overnight (22 h).
After cooling, water (10 ml) was added and the mixture
was extracted with diethyl ether and dried over magnesium
sulfate. After evaporation of the solvent in vacuo, trans-3-
methoxy-2-phenylazetidine (0.69 g, 3.4 mmol, 71%) was
obtained. After flash chromatography (Hexane/EtOAc 3:2)
on silica gel, pure trans-3-methoxy-2-phenylazetidine
(0.48 g, 2.35 mmol, 49%) was isolated.
4.1.5.1. trans-3-Amino-1-isopropyl-2-phenylazetidine
18a. Yield 70%, yellow oil. H NMR (270 MHz, CDCl3):
1
d 0.71 and 0.98 (2ꢀ3H, 2ꢀd, J¼6.3 Hz, CH(CH3)2), 1.66
(2H, br s, NH2), 2.32 (1H, septet, J¼6.3 Hz, CH(CH3)2),
2.48 (1H, t, J¼7.0 Hz, NCH(H)), 3.18 (1H, q, J¼7.0 Hz
CHNH2), 3.43 (1H, d, J¼7.0 Hz, NCHC6H5), 3.76 (1H, q,
J¼7.0 Hz, NCH(H)), 7.21–7.48 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 20.31 and 21.02 (CH(CH3)2), 52.96
(CHNH2), 59.62 (CH(CH3)2), 60.07 (NCH2), 80.88
(NCHC6H5), 126.57, 127.08 and 128.19 (NCHCC5H5),
142.98 (NCHCC5H5). IR (NaCl, cmꢂ1): nNH ¼3379, 3306.
2
MS (70 eV): m/z (%): 147 (MꢂiPr+, 48), 106 (56). Anal.
Calcd for C12H18N2 (%): C, 75.74; H, 9.53; N, 14.72. Found
(%): C, 75.99; H, 9.27; N, 14.94.
4.1.4.1. trans-1-Allyl-3-methoxy-2-phenylazetidine 9q.
Yield 49%, light yellow oil. Hexane/EtOAc 3:2, Rf ¼0.48.
1H NMR (300 MHz, CDCl3): d 2.73 (1H, t, J¼6.3 Hz,
C(H)HCHO), 3.01 (1H, dꢀd, J¼13.3 Hz, J¼7.0 Hz,
C(H)HCH]CH2), 3.23 (3H, s, OCH3), 3.24–3.32 (1H, m,
4.1.5.2.
trans-3-Amino-1-cyclohexyl-2-phenylazeti-
dine 18b. Yield 82%, yellow oil. 1H NMR (270 MHz,
CDCl3): d 0.95–1.97 (10H, m, (CH2)5), 2.00–2.12 (1H, m,

B. Van Driessche et al. / Tetrahedron 62 (2006) 6882–6892
6891
NCH), 2.48 (1H, t, J¼7.0 Hz, NCH(H)), 3.18 (1H, q,
J¼7.0 Hz, CHNH2), 3.45 (1H, d, J¼7.0 Hz, NCHC6H5),
3.76 (1H, q, J¼7.0 Hz, NCH(H)), 7.21–7.45 (5H, m,
C6H5). 13C NMR (68 MHz, CDCl3): d 24.49, 24.56, 25.93,
30.33 and 31.25 ((CH2)5), 53.58 (CHNH2), 59.75 (NCH2),
68.10 (NCH), 80.90 (NCHC6H5), 126.54, 127.10 and
128.21 (NCHCC5H5), 143.11 (NCHCC5H5). IR (NaCl,
CDCl3): d 2.68–2.73 (1H, m, C(H)HCHOH), 3.01 (1H,
dꢀd, J¼13.2 Hz, J¼6.9 Hz, C(H)HCH]CH2), 3.23 (1H,
dꢀd, J¼13.2 Hz, J¼5.8 Hz, C(H)HCH]CH2), 3.66–3.70
(1H, m, C(H)HCHOH), 3.73 (1H, d, J¼6.1 Hz, CHC6H4Cl),
4.03–4.09 (1H, m, CHOH), 5.00–5.21 (2H, m, CH]CH2),
5.62–5.75 (1H, m, CH]CH2), 7.26–7.33 (4H, m,
C6H4Cl). 13C NMR (75 MHz, CDCl3):
d
60.11
cmꢂ1): nNH ¼3379, 3307. MS (70 eV): m/z (%): 231
(CH2CHOH), 60.12 (CH2CH]CH2), 70.10 (CHOH),
77.96 (CHC6H4Cl), 117.84 (CH]CH2), 128.24 and
128.51 (CC4H4CCl), 133.29 (CC4H4CCl), 133.81
(CH]CH2), 138.89 (CC4H4CCl). IR (NaCl, cmꢂ1):
nOH¼3343. MS (70 eV): m/z (%): 226/4 (M++1, 100).
Anal. Calcd for C12H14ClNO (%): C, 64.43; H, 6.31; N,
6.26. Found (%): C, 64.65; H, 6.43; N, 6.12.
2
(M+H+, 72), 112 (100). Anal. Calcd for C15H22N2 (%): C,
78.21; H, 9.63; N, 12.16. Found (%): C, 78.47; H, 9.41; N,
12.32.
4.1.5.3. trans-3-Amino-1-isopropyl-2-(4-methylphenyl)-
azetidine 18c. Yield 92%, yellow oil. H NMR (270 MHz,
1
CDCl3): d 0.71 and 0.97 (2ꢀ3H, 2ꢀd, J¼6.3 Hz,
CH(CH3)2), 2.32 (3H, S, CqCH3), 2.41 (1H, septet,
J¼6.3 Hz, CH(CH3)2), 2.41 (1H, t, J¼7.0 Hz, NCH(H)),
3.14 (1H, q, J¼7.0 Hz, CHNH2), 3.37 (1H, d, J¼7.0 Hz,
NCHC6H4), 3.73 (1H, t, J¼7.0 Hz, J¼7.0 Hz, NCH(H)),
7.12 and 7.32 (2ꢀ2H, 2ꢀd, J¼7.9 Hz, C6H4). 13C NMR
(68 MHz, CHCl3): d 20.34 and 21.08 (CH(CH3)2) and
(CqCH3), 53.06 (CHNH2), 59.68 (CH(CH3)2), 60.02
(NCH2), 80.86 (NCHC6H4), 126.56 and 128.91
(NCHCC4H4C), 136.62 and 140.11 (NCHCC4H4C). IR
Acknowledgements
The authors are indebted to the Institute for the Promotion
of Innovation through Science and Technology in Flanders
(IWT-Vlaanderen), the Fund for Scientific Research-
Flanders (Belgium) (FWO-Vlaanderen) and Ghent Univer-
sity (GOA) for financial support.
(NaCl, cmꢂ1): nNH ¼3376. MS (70 eV): m/z (%): No M+,
2
175 (MꢂNH2ꢂMe+100), 133 (66), 106 (93), 84 (66).
Anal. Calcd for C13H20N2 (%): C, 76.42; H, 9.87; N,
13.71. Found (%): C, 76.66; H, 9.71; N, 13.79.
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47%, light yellow oil. Hexane/EtOAc 3:2, Rf ¼0.15.
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4.98–5.13 (2H, m, CH]CH2), 5.59–5.72 (1H, m,
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CDCl3): d 60.06 (CH2CHOH), 61.23 (CH2CH]CH2),
69.84 (CHOH), 78.69 (CHC6H5), 117.67 (CH]CH2),
126.91, 127.60 and 128.36 (CC5H5), 133.99 (CH]CH2),
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