A new approach towards 2-amino-1-aryloxy-3-methoxypropanes from 1-arylmethyl-2-(bromomethyl)aziridines

Article abstract of DOI:10.1016/j.tet.2005.12.006

1-Arylmethyl-2-(bromomethyl)azirdines were converted into the corresponding 2-(aryloxymethyl)aziridines upon treatment with the appropriate potassium phenoxides in DMF/acetone in excellent yields, followed by regioselective ring opening towards N,N-di(ary

Full text of DOI:10.1016/j.tet.2005.12.006

Tetrahedron 62 (2006) 2295–2303
A new approach towards 2-amino-1-aryloxy-3-methoxypropanes
from 1-arylmethyl-2-(bromomethyl)aziridines
*
Matthias D’hooghe, Alex Waterinckx, Tim Vanlangendonck and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 25 October 2005; revised 1 December 2005; accepted 2 December 2005
Available online 27 December 2005
Abstract—1-Arylmethyl-2-(bromomethyl)azirdines were converted into the corresponding 2-(aryloxymethyl)aziridines upon treatment
with the appropriate potassium phenoxides in DMF/acetone in excellent yields, followed by regioselective ring opening towards N,N-
di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines using benzyl bromide in acetonitrile. Treatment of the latter b-bromoamines with
sodium methoxide afforded the desired 2-amino-1-aryloxy-3-methoxypropanes as the major compounds (49–58%) besides the isomeric
3-amino-1-aryloxy-2-methoxypropanes in minor quantities (9–15%).
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Moreover, compounds containing a 2-amino-1,3-propane-
diol subunit are important constituents of broad-spectrum
antibiotics such as thiamphenicol and the fluorine-contai-
ning florfenicol.6
Many important pharmaceutical compounds contain a
1,2,3-trisubstituted three-carbon unit in their structure,
and the synthesis of drugs based on this moiety has become
a key issue in academic research as well as in
pharmaceutical industry. Especially aryloxypropanol-
amines 1 constitute a very popular class of target
compounds in organic synthesis due to the pronounced
physiological activities ascribed to many representatives of
this class of compounds. Propranolol, atenolol and
metoprolol are frequently cited b-blockers containing an
aryloxypropanolamine moiety 1, used for the treatment of
hypertension, angina pectoris, glaucoma, obesity, and
arrhythmia.1 Furthermore, aryloxypropanolamines with a
4-aminopiperidine scaffold exhibit antidiabetic activity2
and those containing a xanthone unit have been reported as
antihypertensive and vasorelaxing agents.3 Synthetic
efforts towards 2-amino-1,3-dioxypropane derivatives,
however, are much more scarce then those towards the
structurally related aryloxypropanolamines, despite of the
biological relevance of the former class of compounds.
Sphingolipids 2, membrane compounds of essentially all
eukaryotic cells, comprise a 2-amino-1,3-dihydroxy-
propane subunit as a part of a longer (unsaturated) carbon
chain.4 Also 2-[N-(arylmethyl)amino]propane-1,3-diols 3
(AMAP’s) have been reported as new antitumor DNA
intercalators with promising prospects in medicine.5
OH
HO
OH
ArO
NHR
NH
HO
R
OH
NH2
Ar
1
2
3
Due to the general biological interest in 2-amino-1,3-
dioxypropanes and the lack of synthetic methods for the
preparation of 2-amino-1-aryloxy-3-alkoxypropanes, a new
approach towards derivatives containing this moiety is
reported here. This communication comprises the first
report of the synthesis of 2-(di(arylmethyl)amino)-1-
aryloxy-3-methoxypropanes as a new class of 1,2,3-
trisubstituted propane derivatives with promising potential
in medicinal chemistry, starting from 1-arylmethyl-2-
(bromomethyl)aziridines.
Although several examples of the synthesis of 2-amino-1,3-
propanediols are known,7 these strategies are less suitable
when aryloxypropane derivatives are contemplated, since an
additional transformation of a hydroxyl group into an
aryloxy group is required. Ring opening reactions of
aziridines bearing an electron-withdrawing group at nitrogen
(activated aziridines) have been well-covered in the
literature, but only a minor part are dealing with the
synthesis of 2-amino-1,3-dioxypropane derivatives,8 for
example, the synthesis of 2-amino-1,3-diaryloxypropane
Keywords: 2-(Bromomethyl)aziridines; 2-Amino-3-alkoxy-1-aryloxypro-
panes; Substitution; Ring opening; Aziridinium salts.
*
Corresponding author. Tel.: C32 92645951; fax: C32 92646243;
e-mail: norbert.dekimpe@UGent.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.006

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M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
derivatives from 1-arenesulfonyl-2-(bromomethyl)aziridines
upon treatment with a substituted phenol in water in the
presence of potassium carbonate and silica.8k These
procedures require the removal of the N-activating group
in a final stage of the synthesis in order to obtain the
corresponding amines. Up to now, only one type of ring
opening reaction of unactivated aziridines, namely 1-alkyl-2-
(alkoxymethyl)aziridines, towards 2-amino-1,3-dioxy-
propanes has been reported in the literature.9 This
transformation involves activation of the aziridine ring by
means of an organic acid (e.g., AcOH or TFA), followed by
ring opening of the aziridinium ion by the nucleophilic
carboxylate anion. Hydrolysis of the resulting ester then
affords the desired 2-amino-1-alkoxy-3-hydroxypropanes.
means of a nucleophilic substitution of the bromo atom of
the aziridines 5 using a phenolate anion as a nucleophile
(Scheme 2). It has already been demonstrated that 1-alkyl-2-
(bromomethyl)aziridines can be easily transformed into the
corresponding 2-(alkoxymethyl)aziridines upon treatment
with alkoxides in alcohol via a direct substitution of the
bromo atom (instead of ring opening ring closure, which
occurs when N-activated aziridines are used).11 Treatment
of aziridines 5 with 2.2 equiv of phenol or, alternatively, a
substituted bromo- or chlorophenol, and 5 equiv of K2CO3
in a mixture of DMF and acetone (1/1) afforded the
corresponding 2-(aryloxymethyl)aziridines 6 in excellent
yields and high purity after reflux for 10–20 h (Scheme 2,
Table 1). These 2-(aryloxymethyl)aziridines 6 can be
considered as synthetic precursors of 2-amino-1-aryloxy-
propanes at the one hand and 3-amino-1-aryloxypropanes at
the other hand, depending on whether ring opening occurs at
the less hindered or the more hindered carbon atom of the
aziridine ring, respectively.
2. Results and discussion
1-Arylmethyl-2-(bromomethyl)aziridines 5 are very easily
accessible substrates suitable for various applications in
organic synthesis, although the synthetic potential of these
b-haloamines has been scarcely evaluated in the literature.
Condensation of benzaldehydes 4a–d with 1 equiv of
allylamine in dichloromethane in the presence of mag-
nesium sulfate afforded the corresponding N-allylimines,
which were subsequently brominated by bromine in
dichloromethane to give N-(arylidene)-2,3-dibromopropyl-
amines in a quantitative yield. The latter dibromoimines
were used as such because of their instability and hence
treated with sodium borohydride in methanol under reflux,
furnishing 1-arylmethyl-2-(bromomethyl)aziridines 5a–d in
high overall yields (Scheme 1).10 These 2-(bromomethyl)-
aziridines 5 are excellent substrates for the synthesis of
1,2,3-trisubstituted propane derivatives since their structure
comprises a three-carbon unit in which the three electro-
philic carbon atoms are structurally differentiated from each
other, allowing the selective preparation of different
substituted amines.
1-Arylmethyl-2-(bromomethyl)aziridines 5 can be trans-
formed regioselectively into N-(2,3-dibromopropyl)amines
upon treatment with benzyl bromide in acetonitrile in a
straightforward reaction.12 When this methodology was
applied to 1-arylmethyl-2-(aryloxymethyl)aziridines 6,
N,N-di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines 7
were isolated in high yields and high purity upon treatment
with 1 equiv of a benzyl bromide in acetonitrile and reflux
for 5 h (Scheme 3, Table 2). Detailed spectral analysis
confirmed the structural identity of these N-(2-bromo-3-
aryloxypropyl)amines 7, excluding the formation of the
corresponding regioisomers. These results confirm the
general regioselectivity with which 2-substituted 1-(aryl-
methyl)aziridines are transformed into N-(2-bromopropyl)-
amines upon ring opening with an arylmethyl bromide. N-
(2-Halo-3-aryloxypropyl)amines such as compounds 7
might be of interest due to their potential biological
activities, since some 2-bromo-1-oxypropane-3-amines
have already been reported as potential antitumor, anti-
microbial and antifungal agents,13 as well as inhibitors of
cytokinine production and secretion.14
b-Bromoamines 7 are suitable substrates for the synthesis of
different 1,2,3-triheteroatom substituted propane deri-
vatives, since only a nucleophilic substitution of the bromo
atom by a heteroatom-centered nucleophile is required.
Consequently, N,N-di(arylmethyl)-N-(2-bromo-3-aryloxy-
propyl)amines 7 were treated with 2 equiv of sodium
methoxide (0.2 N in methanol), yielding a mixture of
2-amino-1-aryloxy-3-methoxypropanes 8 as the major
Scheme 1.
The incorporation of an aryloxy moiety into the desired
three-carbon units can be very efficiently established by
Scheme 2.

M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
2297
Table 1. Synthesis of 2-(aryloxymethyl)aziridines 6
compounds (79–86%) and 3-amino-1-aryloxy-2-methoxy-
propanes 9 as the minor constituents (14–21%) after reflux
for 2 h (Scheme 4, Table 3).
Entry
R1
R2
Compound
(% yield)
1
2
3
4
5
6
7
H
3-Cl
H
H
2-Br
2-Cl
2-Br
4-Cl
6a (92)
6b (95)
6c (91)
6d (90)
6e (90)
6f (93)
6g (93)
In order to obtain analytically pure samples for detailed
spectroscopical analysis, the regioisomers 8 and 9 were
separated by means of column chromatography on silica gel
(hexane/ethyl acetate 98:2), affording the pure major
isomers. The spectral data, thus obtained, confirmed that
the major isomers formed in this reaction were 2-amino-1-
2-Br
2-Cl
2-Br
2-Cl
2-Cl
4-Me
R1
R1
Br
Br
1 equiv.
R3
N
N
O
O
R2
CH3CN, ∆, 5h
R2
R3
R3
6a–g
7a–g (86–94%)
R1
Br
N
O
R2
Scheme 3.
aryloxy-3-methoxypropanes 8, whereas 3-amino-1-aryloxy-
2-methoxypropanes 9 were present as the minor isomers. It
should be noted that the ratio of major versus minor isomer
slightly changes in the benefit of the major regioisomer
when the aryloxy moiety is substituted with a halogen atom
(Table 3).
Table 2. Synthesis of N-(2-bromo-3-aryloxypropyl)amines 7
Entry
R1
R2
R3
Compound
(% yield)
1
2
3
4
5
6
7
H
3-Cl
H
H
2-Br
2-Cl
2-Br
4-Cl
H
H
H
H
H
H
Me
7a (89)
7b (90)
7c (89)
7d (94)
7e (86)
7f (91)
7g (89)
2-Br
2-Cl
2-Br
2-Cl
2-Cl
4-Me
The presence of both regioisomers can be rationalized
considering the formation of an intermediate aziridinium
ion upon heating, which is then attacked by methoxide at the
least hindered carbon atom of the aziridine ring furnishing
R3
R3
OMe
R2
O
R1
2 equiv.
NaOMe
N
N
R1
R2
+
N
R1
R2
MeOH (0.2 N)
∆ , 2 h
O
O
Br
OMe
R3
8
9
7
R3
R1
N
O
R2
MeO
Scheme 4.

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M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
Table 3. Formation of regio-isomers 8 and 9 upon treatment of N,N-di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines 7 with sodium methoxide
Entry
R1
R2
R3
Ratio 8/9a
8 (%)b
9 (%)b
1
2
3
4
5
6
7
2-Br
2-Cl
2-Br
2-Cl
2-Cl
H
H
H
H
H
H
H
H
H
Me
79/21
80/20
85/15
86/14
86/14
86/14
87/13
8a (56)
8b (58)
8c (55)
8d (57)
8e (54)
8f (49)
8g (55)
9a (15)
9b (15)
9c (10)
9d (9)
9e (9)
9f (—)
9g (—)
2-Br
2-Br
2-Cl
3-Cl
4-Cl
4-Me
1
a Based on H NMR.
b Yield after column chromatography.
the major isomers 8, in which the amino moiety has moved
from the terminus of the propane skeleton towards the
central carbon atom. The formation of the minor isomers
9 can be the result of the attack of methoxide at the more
hindered carbon atom of the aziridinium ion or, alter-
natively, the result of a SN2 substitution reaction of
methoxide at CHBr in bromoamines 7.
spectra were recorded at 68 MHz (JEOL JNM-EX 270) or at
75 MHz (JEOL ECLIPSEC) with CDCl3 as solvent. Mass
spectra were obtained with a mass spectrometer VARIAN
MAT 112, 70 eV using 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 points
were measured using a Bu¨chi B-540 apparatus and are
uncorrected. Dichloromethane was distilled over calcium
hydride, other solvents were used as received from the
supplier.
In order to study the effect of the concentration of sodium
methoxide in this transformation, 2-bromoamine 7g was
treated with a 0.2, 1.0, 1.5 and 2.0 N solution of 2 equiv
of sodium methoxide in methanol, respectively. In all
cases, the same ratio of isomers 8g versus 9g was observed
after reaction (87/13). Apparently, the concentration of
methoxide has no influence on the reaction outcome. When
N-(2-bromo-3-aryloxypropyl)amines 7 were heated under
reflux in methanol or ethanol, a mixture of the correspon-
ding 2-amino-1-aryloxy-3-alkoxypropanes and 3-amino-1-
aryloxy-2-alkoxypropanes was obtained, although in these
cases the ratio of both isomers was almost in equilibrium
(55/45 and 54/46, respectively). In isopropanol, however, no
reaction occurred and the starting material was recovered.
Attempts to introduce a hydroxyl group instead of a
methoxy group using sodium hydroxide (3 N in H2O) in
CH2Cl2–H2O (1/1) or in DMF–H2O (3/1) (rt or 80 8C,
30 min–5 h), or using KOH in Et2O (rt, 6 h) were
unsuccessful and the starting material was recovered.
3.2. Synthesis of 1-arylmethyl-2-(aryloxymethyl)aziri-
dines 6
As a representative example, the synthesis of 1-(2-chloro-
phenyl)methyl-2-(phenoxymethyl)aziridine 6c is described
here. 1-(2-Chlorophenyl)methyl-2-(bromomethyl)aziridine
5c (1.30 g, 5 mmol) was added to a mixture of phenol
(1.04 g, 2.2 equiv) and K2CO3 (3.46 g, 5 equiv) dissolved in
50 mL of a solvent mixture containing acetone and DMF (1/1
on volumetric basis) and heated under reflux for 10 h. The
reaction mixture was poured into brine and extracted with
Et2O (3!50 mL). Drying (MgSO4), filtration of the drying
agent and evaporation of the solvent afforded 1-(2-chloro-
phenyl)methyl-2-(phenoxymethyl)aziridine 6c (1.24 g, 91%),
which was purified by means of column chromatography
(hexane/ethyl acetate 4:1) in order to obtain an analytically
pure sample.
In conclusion, a new and attractive synthetic approach
towards 2-amino-1-aryloxy-3-methoxypropanes, valuable
compounds with diverse biological activities, has been
developed in three efficient steps starting from 1-aryl-
methyl-2-(bromomethyl)aziridines. The latter aziridines
were converted into the corresponding 2-(aryloxymethyl)-
aziridines upon treatment with the appropriate phenoxide,
followed by regioselective ring opening using benzyl
bromide towards N,N-di(arylmethyl)-N-(2-bromo-3-aryloxy-
propyl)amines. Treatment of the latter amines with sodium
methoxide in methanol afforded the desired 2-amino-1-
aryloxy-3-methoxypropanes as the major compounds (49–
58%) besides the isomeric 3-amino-1-aryloxy-2-methoxy-
propanes in minor quantities (9–15%).
R1
N
Hb
Ha
Hc
O
R2
3.2.1. 1-Phenylmethyl-2-(3-chlorophenoxymethyl)aziri-
1
dine 6a. H NMR (270 MHz, CDCl3): d 1.51 (1H, d, JZ
6.6 Hz, Hb); 1.79 (1H, d, JZ3.6 Hz, Ha); 1.87–1.93 (1H, m,
NCH); 3.42 and 3.47 (2H, 2!d, JZ13.2 Hz, C6H4CH2);
3.82 and 3.93 (2H, 2!d!d, JZ10.6, 6.6, 4.6 Hz, CH2O);
6.70–6.74, 6.86–6.88, 7.07–7.13 and 7.23–7.36 (1H, 2H, 1H
and 5H, 5!m, CHarom). 13C NMR (68 MHz, CDCl3): d
31.72 (NCH2CH); 37.65 (NCH); 64.22 (PhCH2); 70.40
(CH2O); 113.12 and 115.13 (2!CH2OHCortho); 120.93,
127.17, 128.07, 128.37 and 130.13 (CH2OHCpara, CH2-
OHCmeta, 2!NCH2HCortho, 2!NCH2HCmeta and NCH2-
HCpara); 134.79 and 138.76 (NCH2C and CCl); 159.44
(CH2OC). IR (NaCl, cmK1): nmaxZ3063; 3029; 2986;
2925; 2831; 1594; 1579; 1480; 1230; 1028; 733. MS
3. Experimental
3.1. General
1H NMR spectra were recorded at 270 MHz (JEOL JNM-
EX 270) or at 300 MHz (JEOL ECLIPSEC) with CDCl3 as
solvent and tetramethylsilane as internal standard. 13C NMR

M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
2299
(70 eV): m/z (%): 274/276 (MCC1, 100), 91 (10). Light-
yellow oil. Anal. Calcd for C16H16ClNO: C 70.20, H 5.89, N
5.12. Found: C 70.39, H 6.06, N 4.98.
(3H; 4H and 1H, 3!m, CHarom). 13C NMR (68 MHz,
CDCl3): d 31.57 (NCH2CH); 38.20 (NCH); 60.70
(PhCH2); 71.07 (CH2O); 113.62 (CH2OHCortho); 120.82
and 122.86 (CH2OCCC and CH2OHCpara); 127.06,
127.65, 128.23, 129.29, 129.49, 130.22 (4!NCH2HCarom
and 2!CH2OHCmeta); 132.84 and 135.99 (CClCCH2N
3.2.2. 1-(2-Bromophenyl)methyl-2-(phenoxymethyl)-
aziridine 6b. H NMR (270 MHz, CDCl3): d 1.66 (1H, d,
1
and CCH2N); 158.42 (CH2OC). IR (KBr, cmK1): nmax
Z
JZ6.6 Hz, Hb); 1.96 (1H, d, JZ3.3 Hz, Ha); 2.05–2.10 (1H,
m, Hc); 3.58 and 3.66 (2H, 2!d, JZ15.2 Hz, C6H4CH2); 3.97
and 4.07 (2H, 2!d!d, JZ10.4, 6.6, 4.6 Hz, CH2O); 6.80–
6.83, 6.88–6.94, 7.13–7.36, 7.51–7.54 and 7.74–7.77 (2H, 3H,
2H and 2!1H, 5!m, CHarom). 13C NMR (68 MHz, CDCl3):
d 31.52 (NCH2CH); 38.62 (NCH); 62.60 (PhCH2); 69.06
(CH2O); 114.43 (2!CH2OHCortho); 120.90 (CH2OHCpara);
2896; 1591; 1489; 1446; 1250; 1061; 742; 698. MS
(70 eV): m/z (%): 308/10/12 (MCC1, 100). RfZ0.20;
hexane/ethyl acetate 4:1. Light-yellow crystals; mpZ57.5–
58.6 8C. Anal. Calcd for C16H15Cl2NO: C 62.35, H 4.91, N
4.54. Found: C 62.51, H 5.12, N 4.35.
123.16 (CBr); 127.49; 128.64 and 129.38 (2!BrHCmeta
,
3.2.6. 2-[(2-Bromophenoxy)methyl]-1-(2-chlorophenyl)-
methylaziridine 6f. 1HNMR(300 MHz,CDCl3):d1.66(1H,
d, JZ6.6 Hz, Hb);1.95(1H, d, JZ3.3 Hz, Ha);2.05–2.16 (1H,
m, Hc); 3.57 and 3.67 (2H, 2!d, JZ15.0 Hz, C6H4CH2); 3.98
and 4.16 (2H, 2!d!d, JZ10.5, 6.9, 4.1 Hz, CH2O); 6.80–
6.85, 6.93–6.96, 7.17–7.35, 7.51–7.54 and 7.71–7.74 (2!1H,
4H and 2!1H, 5!m, CHarom). 13C NMR (75 MHz, CDCl3):
d 31.82 (NCH2CH); 38.12 (NCH); 61.09 (PhCH2); 71.60
(CH2O); 112.33 and 113.73 (2!CH2OHCortho); 122.16,
127.18, 128.24, 128.54, 129.14, 133.00 and 133.47 (7!
HCarom and CCl); 136.68 (CCH2N); 155.22 (CH2OC). IR
(KBr, cmK1): nmaxZ2894; 1586; 1484; 1442; 1249; 1033;
743. MS (70 eV): m/z (%): 352/4/6 (MCC1, 100). RfZ0.17;
hexane/ethyl acetate 4:1. White crystals; mpZ78.8–79.7 8C.
Anal. Calcd for C16H15BrClNO: C 54.49, H 4.29, N 3.97.
Found: C 54.66, H 4.52, N 3.81.
BrHCpara and 2!CH2OHCmeta); 132.33 (BrHCortho); 137.19
(NCH2C); 158.27 (CH2OC). IR (NaCl, cmK1): nmaxZ3064;
1664; 1594; 1496; 1472; 1242; 1027; 910; 751; 692. MS
(70 eV):m/z(%): 318/20(MCC1,100); 277/9(55), 256/8(8),
169/71 (15), 121 (16). RfZ0.18; hexane/ethyl acetate 4:1.
Light-yellow oil. Anal. Calcd for C16H16BrNO: C 60.39, H
5.07, N 4.40. Found: C 60.53, H 5.20, N 4.27.
3.2.3. 1-(2-Chlorophenyl)methyl-2-(phenoxymethyl)-
aziridine 6c. H NMR (270 MHz, CDCl3): d 1.65 (1H, d,
1
JZ6.6 Hz, Hb); 1.94 (1H, d, JZ3.3 Hz, Ha); 2.04–2.07 (1H,
m, Hc); 3.60 and 3.37 (2H, 2!d, JZ15.0 Hz, C6H4CH2); 3.96
and 4.06 (2H, 2!d!d, JZ10.3, 6.6, 4.8 Hz, CH2O); 6.80–
6.97; 7.17–7.36 and 7.72–7.75 (5H, 3H and 1H, 3!m,
CHarom). 13C NMR (68 MHz, CDCl3): d 31.59 (NCH2CH);
38.41 (NCH); 60.39 (PhCH2); 69.38 (CH2O); 114.46 (2!
CH2OHCortho); 120.84 (CH2OHCpara); 126.84, 128.26,
129.00 and 129.36 (ClHCpara, 2!ClHCmeta, ClHCortho and
2!CH2OHCmeta); 132.84 and 135.99 (CCl and CCH2N);
158.42 (CH2OC). IR (NaCl, cmK1): nmaxZ3063; 2991; 2925;
1599;1496;1472;1242;1038;910;751;692.MS(70 eV):m/z
(%): 274/6 (MCC1, 100); 231/3 (20). RfZ0.21; hexane/ethyl
acetate 4:1. Light-yellow oil. Anal. Calcd for C16H16ClNO: C
70.20, H 5.89, N 5.12. Found: C 70.42, H 6.03, N 5.26.
3.2.7. 1-(4-Methylphenyl)methyl-2-(4-chlorophenoxy-
methyl)aziridine 6g. H NMR (300 MHz, CDCl3): d 1.55
1
(1H, d, JZ6.6 Hz, Hb); 1.81 (1H, d, JZ3.6 Hz, Ha); 1.91–
1.98 (1H, m, NCH); 2.33 (3H, s, PhCH3); 3.47 and 3.42 (2H,
d!d, JZ13.2, 3.9 Hz, ArCH2); 3.86 and 3.93 (2H, 2!d!
d, JZ10.4, 6.3, 4.8 Hz, HCHO); 6.76–6.81 and 7.11–7.25
(2H and 6H, 2!m, CHarom). 13C NMR (75 MHz, CDCl3): d
21.09 (PhCH3); 31.70 (NCH2CH); 37.67 (NCH); 64.00
(ArCH2); 70.46 (CH2O); 115.88 (OCCHortho); 125.56
(CCl); 128.04, 129.03 and 129.20 (CHarom); 135.67 and
136.71 (CCH3 and CCH2N); 157.28 (CH2OCquat). IR (NaCl,
cmK1): nmaxZ2922; 1757; 1675; 1595; 1581; 1491; 1347;
1286; 1243; 1171; 1094; 1064; 1022; 824; 666. MS (70 eV):
m/z (%): 288/90 (MCC1, 100). RfZ0.24; hexane/ethyl
acetate 7:3. Light-yellow oil. Anal. Calcd for C17H18ClNO:
C 70.95, H 6.30, N 4.87. Found: C 71.18, H 6.51, N 4.72.
3.2.4. 2-[(2-Bromophenoxy)methyl]-1-(2-bromophenyl)-
methylaziridine 6d. H NMR (270 MHz, CDCl3): d 1.66
1
(1H, d, JZ6.6 Hz, Hb); 1.95 (1H, d, JZ3.3 Hz, Ha);
2.10–2.16 (1H, m, Hc); 3.55 and 3.65 (2H, 2!d, JZ
15.1 Hz, C6H4CH2); 3.98 and 4.17 (2H, 2!d!d, JZ10.6,
6.9, 4.1 Hz, CH2O); 6.80–6.86, 6.93–6.96, 7.09–7.37,
7.50–7.55 and 7.73–7.76 (2!1H, 3H, 2H and 1H, 5!m,
CHarom). 13C NMR (68 MHz, CDCl3): d 31.77 (NCH2CH);
38.12 (NCH); 63.56 (PhCH2); 71.61 (CH2O); 112.34 and
113.74 (2!CH2OHCortho); 122.18, 123.22, 127.81, 129.56,
132.40 and 133.48 (7!HCarom and NCH2CCBr); 138.32
(CCH2N); 155.22 (CH2OC). IR (KBr, cmK1): nmaxZ2892;
1587; 1484; 1461; 1441; 1284; 1249; 1015; 742; 670. MS
(70 eV): m/z (%): 396/8/400 (MCC1, 100). RfZ0.20;
hexane/ethyl acetate 4:1. White crystals; mpZ82.4–
82.6 8C. Anal. Calcd for C16H15Br2NO: C 48.39, H 3.81,
N 3.53. Found: C 48.21, H 4.11, N 3.37.
3.3. Synthesis of N-(2-bromo-3-aryloxypropyl)amines 7
As a representative example, the synthesis of N-benzyl-N-(2-
chlorobenzyl)-N-(2-bromo-3-phenoxypropyl)amine 7c is
described here. To a solution of 1-(2-chlorophenyl)methyl-
2-(phenoxymethyl)aziridine 6c (2.73 g, 10 mmol) in 50 mL
acetonitrile was added benzyl bromide (1.71 g, 1 equiv) under
stirring and the resulting mixture was heated for 5 h under
reflux. Evaporation of the solvent afforded N-benzyl-N-(2-
chlorobenzyl)-N-(2-bromo-3-phenoxypropyl)amine 7c
(3.95 g, 89%), which was purified by means of column
chromatography (hexane/ethyl acetate 1:1) in order to obtain
an analytically pure sample.
3.2.5. 2-[(2-Chlorophenoxy)methyl]-1-(2-chlorophenyl)-
methylaziridine 6e. H NMR (300 MHz, CDCl3): d 1.67
1
(1H, d, JZ6.3 Hz, Hb); 1.95 (1H, d, JZ3.6 Hz, Ha);
2.04–2.18 (1H, m, Hc); 3.54 and 3.72 (2H, 2!d, JZ
15.0 Hz, C6H4CH2); 3.96 and 4.17 (2H, 2!d!d, JZ10.5,
7.2, 4.3 Hz, CH2O); 6.80–6.98, 7.10–7.36 and 7.73–7.76
3.3.1. N,N-Di(phenylmethyl)-N-(2-bromo-3-(3-chloro-
phenoxy)propyl)amine 7a. H NMR (270 MHz, CDCl3):
1

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M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
d 2.91 and 3.08 (2H, 2!d!d, JZ13.5, 8.7, 5.1 Hz,
N(HCH)CH); 3.56 and 3.72 (4H, 2!d, JZ13.2 Hz, 2!
PhCH2N); 3.93–3.99 and 4.07–4.19 (1H and 2H, 2!m,
BrCH and (HCH)O); 6.64–6.68, 6.73–6.74, 6.88–6.96 and
7.13–7.43 (1H, 1H, 2H and 10H, 4!m, CHarom). 13C NMR
(68 MHz): d 48.57 (CHBr); 57.50 (NCH2CH); 59.37 (2!
NCH2Ar); 70.06 (CH2O); 113.08 and 114.98 (2!
OHCortho), 121.18, 127.28, 128.34, 128.96, 130.10
(OHCmeta, OHCpara, 4!NCH2HCortho, 4!NCH2HCmeta
and 2!NCH2HCpara); 134.71 (CCl); 138.63 (2!
NCH2C); 158.85 (OCquat). IR (NaCl, cmK1): nmaxZ3064;
3029; 2928; 2805; 1595; 1480; 1454; 1247; 1229; 749; 697.
MS (70 eV): m/z (%): 444/46/48 (MCC1, 12), 396/8 (90),
364/6 (100). Colorless oil. Anal. Calcd for C23H23BrClNO:
C 62.11, H 5.21, N 3.15. Found: C 62.26, H 5.42, N 3.02.
59.71 (3!NCH2); 70.81 (CH2O); 112.58, 113.43, 122.34,
127.44, 128.43, 128.80, 128.89, 129.14, 129.27, 131.31,
132.97 and 133.50 (13!CHarom and 2!CBr); 138.06 and
138.54 (2!NCH2C); 154.68 (COCH2). IR (NaCl, cmK1):
nmaxZ3062; 3028; 2930; 2833; 1586; 1481; 1442; 1278;
1248; 1030; 749; 698. MS (70 eV): m/z (%): 566/68/70/72
(MCC1, 5); 486/88/90 (100). RfZ0.88; hexane/ethyl
acetate 1:1. Colorless oil. Anal. Calcd for C23H22Br3NO:
C 48.62, H 3.90, N 2.47. Found: C 48.79, H 4.03, N 2.30.
3.3.5. N-Benzyl-N-(2-chlorobenzyl)-N-(2-bromo-3-
(2-chlorophenoxy)propyl)amine 7e. 1H NMR (300
MHz, CDCl3): d 2.99 and 3.21 (2H, 2!d!d, JZ13.8,
7.6, 5.4 Hz, N(HCH)CH); 3.62-3.92 (4H, m, 2!PhCH2N);
4.19-4.23 (3H, m, BrCH and (HCH)O); 6.74 (1H, d!d,
JZ8.1, 1.0 Hz, CHarom); 6.86-6.91 and 7.10-7.34 (1H and
3.3.2. N-Benzyl-N-(2-bromobenzyl)-N-(2-bromo-3-
phenoxypropylamine 7b. H NMR (300 MHz, CDCl3): d
10H, 2!m, CHarom); 7.52 (1H, d, JZ7.2 Hz, CHarom). 13
C
1
NMR (75 MHz, refZCDCl3): d 48.91 (CHBr); 56.39,
58.07 and 59.78 (3!NCH2); 70.88 (CH2O); 113.81,
122.05, 123.44, 127.00, 127.56, 127.84, 128.59, 128.70,
129.38, 129.81, 130.57, 131.38, 134.48 (13!CHarom and
2!CCl); 136.55 and 138.72 (2!NCH2C); 154.00
(COCH2). IR (NaCl, cm-1): vmaxZ3064; 3028; 2931;
2833; 1590; 1486; 1445; 1278; 1249; 748; 699. MS (70
eV): m/z (%): 478/80/82/84 (M++1; 5); 399/401/403 (65);
398/400/402 (100). Rf = 0.62; hexane/ethyl acetate 4/1.
Colorless oil. Anal. Calcd for C23H22BrCl2NO: C 57.64, H
4.63, N 2.92. Found: C 57.84, H 4.75, N 2.76.
2.97 and 3.14 (2H, 2!d!d, JZ13.8, 8.3, 5.9 Hz,
N(HCH)CH); 3.75 (2H, d, JZ13.8 Hz, PhCH2N); 3.64
and 3.83 (2H, 2!d, JZ13.6 Hz, PhCH2N); 3.99–4.06 and
4.13–4.27 (1H and 2H, 2!m, BrCH and (HCH)O); 6.76–
6.79, 6.93–6.98, 7.06–7.12, 7.17–7.45 and 7.49–7.68 (2H,
1H, 1H, 8H and 2H; 5!m, CHarom). 13C NMR (75 MHz,
refZCDCl3): d 48.10 (CHBr); 57.99, 59.10 and 59.63 (3!
NCH2); 70.09 (CH2O); 114.78, 121.22, 124.66, 127.48,
128.48, 128.86, 129.26, 129.52, 131.27 and 132.99 (14!
CHarom and CBr); 138.03 and 138.52 (2!NCH2C); 158.29
(COCH2). IR (NaCl, cmK1): nmaxZ3062; 3029; 2926;
2832; 1599; 1496; 1243; 1027; 753; 692. MS (70 eV): m/z
(%): 488/90/92 (MCC1, 10); 409/11 (25); 408/10 (100);
365/7/9 (65). RfZ0.60; hexane/ethyl acetate 4:1. Anal.
Calcd for C23H23Br2NO: C 56.46, H 4.74, N 2.86. Colorless
oil. Found: C 56.62, H 4.95, N 2.97.
3.3.6. N-Benzyl-N-(2-chlorobenzyl)-N-(2-bromo-3-
(2-bromophenoxy)propyl)amine 7f. H NMR (300 MHz,
1
CDCl3): d 2.98 and 3.23 (2H, 2!d!d, JZ11.1, 7.7, 5.5 Hz,
N(HCH)CH); 3.63–3.86 (4H, m, 2!PhCH2N); 4.11–4.20
(3H, m, BrCH and (HCH)O); 6.70 (1H, d!d, JZ8.3,
1.4 Hz, CHarom); 6.82 (1H, d!t, JZ7.43, 1.38 Hz, CHarom);
3.3.3. N-Benzyl-N-(2-chlorobenzyl)-N-(2-bromo-3-
phenoxypropyl)amine 7c. H NMR (270 MHz, CDCl3):
7.19–7.33 and 7.47–7.53 (10H and 1H, 2!m, CHarom). 13
C
1
NMR (75 MHz, refZCDCl3): d 48.65 (CHBr); 56.65, 58.04
and 59.72 (3!NCH2); 70.74 (CH2O); 112.57, 113.38,
122.34, 126.84, 127.41, 128.44, 129.23, 129.68, 131.22,
133.51 and 134.37 (13!CHarom, CCl and CBr); 136.45 and
138.63 (2!NCH2C); 154.68 (COCH2). IR (NaCl, cmK1):
nmaxZ3063; 3028; 2929; 2833; 1586; 1481; 1443; 1278;
1247; 1052; 1031; 749; 698. MS (70 eV): m/z (%): 522/4/6/
8 (MCC1, 5); 443/5/7(20); 442/4/6(100). RfZ0.59;
hexane/ethyl acetate 4:1. Colorless oil. Anal. Calcd for
C23H22Br2ClNO: C 52.75, H 4.23, N 2.67. Found: C 52.88,
H 4.47, N 2.74.
d 2.96 and 3.13 (2H, 2!d!d, JZ13.9, 8.3, 5.6 Hz,
N(HCH)CH); 3.74 (2H, d, JZ14.8 Hz, PhCH2N); 3.62
and 3.84 (2H, 2!d, JZ13.5 Hz, PhCH2N); 3.99–4.06
and 4.13–4.23 (1H and 2H, 2!m, BrCH and (HCH)O);
6.76–6.98, 7.12–7.41 and 7.51–7.55 (5H, 8H and 1H; 3!m,
CHarom). 13C NMR (68 MHz, CDCl3): d 48.97 (CHBr);
56.06, 57.52 and 59.14 (3!NCH2); 69.61 (CH2O); 114.46,
120.95, 126.56, 128.14, 128.53, 128.82, 128.89, 129.23,
129.38, 130.85, 133.92 (14!CHarom and CCl); 136.04 and
138.22 (2!NCH2C); 157.91 (COCH2). IR (NaCl, cmK1):
nmaxZ3063; 3030; 2832; 1598; 1497; 1243; 909; 754; 735;
692. MS (70 eV): m/z (%): 444/6 (MCC1, 10); 364/6 (100);
321 (23); 323 (21). RfZ0.85; hexane/ethyl acetate 1:1.
Colorless oil. Anal. Calcd for C23H23BrClNO: C 62.11, H
5.21, N 3.15. Found: C 62.32, H 5.38, N 2.96.
3.3.7. N,N-Di[(4-methylbenzyl)methyl]-N-[2-bromo-3-
(4-chlorophenoxy)propyl]amine 7g. H NMR (300 MHz,
1
CDCl3): d 2.31 (6H, s, 2!CH3); 2.88 and 3.06 (2H, 2!
d!d, JZ13.6, 8.7, 5.4 Hz, N(HCH)CH); 3.50 and 3.66
(4H, 2!2!d, JZ13.4 Hz, 2!Ar(HCH)N); 3.95–4.00
and 4.10–4.17 (1H and 2H, 2!m, CHBr and (HCH)O);
6.65–6.70 and 7.07–7.29 (2H and 10H, 2!m, CHarom).
13C NMR (75 MHz, CDCl3): d 21.10 (2!CH3); 48.92
(CHBr); 57.52 and 59.12 (2!NCH2Ar); 70.22 (CH2O);
115.93, 128.96, 129.02 and 129.22 (CHarom); 129.47
(CCl); 135.69 and 136.79 (2!CH3C and 2!NCH2Cquat);
156.88 (OCquat). IR (NaCl, cmK1): nmaxZ3021; 2922;
2823; 1596; 1582; 1514; 1491; 1454; 1370; 1286; 1244;
1171; 1092; 1021; 823; 808. MS (70 eV): m/z (%): 392/4
(MCKBr, 100). RfZ0.53; hexane/ethyl acetate 4:1.
3.3.4.
3-(2-bromophenoxy)propyl)amine
N-Benzyl-N-(2-bromobenzyl)-N-(2-bromo-
7d.
1H NMR
(300 MHz, CDCl3): d 3.01 and 3.24 (2H, 2!d!d, JZ
13.8, 7.6, 5.8 Hz, N(HCH)CH); 3.69 and 3.73 (2H, 2!d,
JZ13.6 Hz, PhCH2N); 3.78 and 3.83 (2H, 2!d, JZ
14.2 Hz, PhCH2N); 4.10–4.21 (3H, m, BrCH and
(HCH)O); 6.71 (1H, d!d, JZ8.0, 1.4 Hz, CHarom); 6.83
(1H, d!t, JZ7.4, 1.4 Hz, CHarom); 7.06 (1H, d!t, JZ7.7,
1.7 Hz, CHarom); 7.19–7.34 (10H, m, CHarom). 13C NMR
(75 MHz, refZCDCl3): d 48.62 (CHBr); 58.00, 59.22 and

M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
2301
White crystals; mpZ54.4 8C. Anal. Calcd for C25H27-
BrClNO: C 63.50, H 5.76, N 2.96. Found: C 63.66, H
5.88, N 2.78.
3.75 (2H, d, JZ6.1 Hz, CH2OMe); 3.90 and 3.97 (2H, 2!d,
JZ14.2 Hz, N(HCH)); 4.01–4.09 (2H, m, NCH2);
4.18–4.27 (2H, m, CH2OPh); 6.78–6.90 (2H, m, CHarom);
7.06 (1H, d!t, JZ7.6, 1.7 Hz, CHarom); 7.16–7.33 (5H, m,
CHarom); 7.40–7.60 (4H, m, CHarom); 7.72 (1H, d!d, JZ
7.7, 1.7 Hz, CHarom). 13C NMR (75 MHz, refZCDCl3): d
54.90 and 55.64 (2!NCH2); 56.75 (NCH); 59.22 (OCH3);
67.43 (CH2OPh); 71.25 (CH2OCH3); 112.15, 112.80,
121.84, 124.24, 126.96, 127.44, 128.31, 128.52, 128.80,
130.83, 132.62, 133.44 (13!CHarom and 2!CBr);
139.29 and 140.25 (2!CCH2N); 155.35 (COCH2). IR
(NaCl, cmK1): nmaxZ3062; 2925; 2875; 1587; 1481; 1442;
1277; 1248; 1121; 1030; 961. MS (70 eV): m/z (%): 518/20/
22 (MCC1, 100). RfZ0.04; hexane/ethyl acetate 98:2.
Colorless oil. Anal. Calcd for C24H25Br2NO2: C 55.51, H
4.85, N 2.70. Found: C 55.39, H 5.05, N 2.59.
3.4. Synthesis of 2-amino-1-aryloxy-3-methoxypropanes 8
As a representative example, the synthesis of 2-[N-benzyl-
N-(2-chlorobenzyl)]amino-1-phenoxy-3-methoxypropane
8b is described here. To N-benzyl-N-(2-chlorobenzyl)-N-(2-
bromo-3-phenoxypropyl)amine 7c (1.19 g, 3 mmol) was
added slowly under stirring a solution of sodium methoxide
in methanol (60 mL, 0.2 N, 12 mmol), and the resulting
solution was heated under reflux for 2 h. The resulting
reaction mixture was poured into brine (50 mL) and
extracted with CH2Cl2 (3!50 mL). Drying (MgSO4),
filtration of the drying agent and evaporation of the solvent
afforded a mixture of 2-[N-benzyl-N-(2-chlorobenzyl)]-
amino-1-phenoxy-3-methoxypropane 8b and N-benzyl-N-
(2-chloorbenzyl)-N-(2-methoxy-3-phenoxypropyl)amine 9b
(4/1). Isolation of the major isomer was realized by means
of column chromatography (SiO2) (hexane/EtOAc 49:1).
3.4.4. 2-[N-Benzyl-N-(2-chlorobenzyl)]amino-1-(2-bromo-
phenoxy)-3-methoxypropane 8d. 1H NMR (270 MHz,
CDCl3): d 3.32-3.36 (1H, m, NCH); 3.33 (3H, s, CH3O);
3.75 (2H, d, JZ5.9 Hz, CH2OMe); 3.89 and 3.97 (2!1H,
2!d, JZ14.2 Hz, NCH2); 4.01 and 4.07 (2!1H, 2!d,
JZ15.0 Hz, NCH2); 4.20-4.24 (2H, m, CH2OPh); 6.79-
6.88 and 7.09-7.30 (2H and 7H, 2!m, CHarom); 7.40 (1H,
d, JZ7.3 Hz, CHarom); 7.54 (1H, d!d, JZ7.7, 1.5 Hz,
CHarom); 7.70 (1H, d, JZ7.6 Hz, CHarom). 13C NMR (75
MHz, refZCDCl3): d 52.19 and 55.56 (2!NCH2); 56.68
(NCH); 58.94 (OCH3); 67.37 (CH2OPh); 71.14
(CH2OCH3); 112.02, 112.69, 121.67, 126.60, 126.77,
127.76, 128.12, 128.32, 128.61, 129.16, 130.55, 133.24
and 133.82 (13!HCarom, CBr and CCl); 137.59 and
140.09 (2!CCH2N); 155.20 (COCH2). IR (NaCl, cm-1):
vmaxZ3063; 3027; 2926; 2926; 2877; 1587; 1481; 1442;
1248; 1031; 749; 699. MS (70 eV): m/z (%): 472/4/6
(M+-1; 100). Rf=0.04; hexane/ethyl acetate 98/2. Colorless
oil. Anal. Calcd for C24H25BrClNO2: C 60.71, H 5.31, N
2.95. Found: C 60.93, H 5.43, N 3.05.
3.4.1. 2-[N-Benzyl-N-(2-bromoarylmethyl)]amino-1-
phenoxy-3-methoxypropane 8a. 1H NMR (300 MHz,
CDCl3): d 3.28–3.34 (1H, m, NCH); 3.32 (3H, s, CH3O);
3.63–3.73 (2H, m, CH2OMe); 3.88 (2H, s, NCH2); 3.97 (2H,
d, JZ3.3 Hz, NCH2); 4.11–4.21 (2H, m, CH2OPh);
6.89–6.95 (3H, m, CHarom); 7.03 (1H, d!t, JZ7.7,
1.7 Hz, CHarom); 7.16–7.29 and 7.37–7.40 (6H and 2H,
2!m, CHarom); 7.46 (1H, d!d, JZ8.0, 1.1 Hz, CHarom);
7.68 (1H, d!d, JZ7.7, 1.7 Hz, CHarom). 13C NMR
(75 MHz, refZCDCl3): d 55.03 and 55.70 (2!NCH2);
57.09 (NCH); 59.20 (OCH3); 66.76 (CH2OPh); 71.69
(CH2OCH3); 114.70, 120.83, 124.31, 127.03, 127.44,
128.36, 128.86, 129.59, 130.79, 132.68 (14!CHarom and
CBr); 139.41 and 140.28 (2!CCH2N); 159.00 (COCH2).
IR (NaCl, cmK1): nmaxZ3063; 3029; 2926; 2876; 1600;
1496; 1244; 909; 753; 734; 693. MS (70 eV): m/z (%): 440/2
(MCC1; 100). RfZ0.11; hexane/ethyl acetate 98:2. Color-
less oil. Anal. Calcd for C24H26BrNO2: C 65.46, H 5.95, N
3.18. Found: C 65.62, H 6.14, N 3.08.
3.4.5. 2-[N-Benzyl-N-(2-chlorobenzyl)]amino-1-(2-chloro-
phenoxy)-3-methoxypropane 8e. 1H NMR (300 MHz,
CDCl3): d 3.31–3.90 (1H, m, NCH); 3.33 (3H, s, CH3O);
3.73 (2H, d, JZ6.1 Hz, CH2OMe); 3.88 and 3.96 (2!1H, 2!
d, JZ14.0 Hz, NCH2); 4.01 and 4.05 (2!1H, 2!d, JZ
15.1 Hz, NCH2);4.22(2H, d, JZ5.5 Hz, CH2OPh); 6.84–6.90
and 7.10–7.42 (2H and 10H, 2!m, CHarom); 7.72 (1H, d!d,
JZ7.7, 1.7 Hz, CHarom). 13C NMR (75 MHz, refZCDCl3): d
52.24 and 55.62 (2!NCH2); 56.71 (NCH); 59.20 (OCH3);
67.46 (CH2OPh); 71.33 (CH2OCH3); 112.96, 121.33, 122.91,
126.81, 126.96, 127.77, 127.95, 128.32, 128.32, 128.79,
129.35, 130.35, 130.68 and 133.99 (13!HCarom and 2!
CCl); 137.75 and 140.28 (2!CCH2N); 154.53 (COCH2). IR
(NaCl, cmK1): nmaxZ3064; 3027; 2926; 2877; 1590; 1486;
1446; 1249; 1062; 748; 698. MS (70 eV): m/z (%): 428/30/32
(MCK1, 100). RfZ0.08; hexane/ethyl acetate 49:1. Colorless
oil. Anal. Calcd for C24H25Cl2NO2: C 66.98, H 5.86, N 3.25.
Found: C 67.13, H 6.02, N 3.11.
3.4.2. 2-[N-Benzyl-N-(2-chlorobenzyl)]amino-1-phenoxy-
3-methoxypropane 8b. 1H NMR (300 MHz, CDCl3): d
3.28–3.39 (1H, m, NCH); 3.33 (3H, s, CH3O); 3.64–3.72
(2H, m, CH2OMe); 3.88 (2H, s, NCH2); 3.98 and 4.04 (2!
1H, 2!d, JZ15.4 Hz, NCH2); 4.14–4.22 (2H, m,
CH2OPh); 6.89–6.96, 7.11–7.39 and 7.67–7.69 (3H, 10H
and 1H, 3!m, CHarom). 13C NMR (75 MHz, refZCDCl3):
d 52.26 and 55.62 (2!NCH2); 56.90 (NCH); 59.15 (OCH3);
66.65 (CH2OPh); 71.60 (CH2OCH3); 114.58, 120.73,
126.73, 126.94, 127.91, 128.28, 128.76, 129.33, 129.52,
130.57 and 133.96 (14!CHarom and CCl); 137.75 and
140.25 (2!CCH2N); 158.90 (COCH2). IR (NaCl, cmK1):
nmaxZ3063; 3029; 2925; 2876; 1600; 1496; 1244; 1037;
753; 692. MS (70 eV): m/z (%): 396/98 (MCC1, 100). RfZ
0.10; hexane/ethyl acetate 98:2. Colorless oil. Anal. Calcd
for C24H26ClNO2: C 72.81, H 6.62, N 3.54. Found: C 72.96,
H 6.80, N 3.39.
3.4.6. 2-(N,N-Dibenzyl)amino-1-(3-chlorophenoxy)-3-
methoxypropane 8f. 1H NMR (300 MHz, CDCl3): d
3.27–3.32 (1H, m, CHN); 3.31 (3H, s, OCH3); 3.62 and
3.65 (2H, 2!d!d, JZ9.9, 6.1, 5.8 Hz, (HCH)OCH3);
3.78–3.87 (4H, m, 2!NCH2); 4.10 and 4.13 (2H, 2!d!d,
JZ9.6, 6.3, 5.5 Hz, (HCH)OAr); 6.74–6.78, 6.89–6.93 and
3.4.3. 2-[N-Benzyl-N-(2-bromobenzyl)]amino-1-(2-bromo-
phenoxy)-3-methoxypropane 8c. 1H NMR (300 MHz,
CDCl3): d 3.30–3.39 (1H, m, NCH); 3.33 (3H, s, CH3O);

2302
M. D’hooghe et al. / Tetrahedron 62 (2006) 2295–2303
7.13–7.39 (1H, 2H and 11H, 3!m, CHarom). 13C NMR
(75 MHz, CDCl3): d 55.42 (2!NCH2); 55.96 (NCH); 58.92
(OCH3); 67.21 (CH2OAr); 71.64 (CH2OCH3); 112.97,
115.05, 120.88, 126.94, 128.25, 128.74, 129.21, 130.15
3.5.3. N-Benzyl-N-(2-bromobenzyl)-N-[2-methoxy-3-
(2-bromophenoxy)propyl]amine 9c. H NMR (300 MHz,
1
CDCl3): d 2.72 and 2.79 (2H, 2!d!d, JZ13.6, 6.5, 5.5 Hz,
CH(HCH)N); 3.50 (3H, s, CH3O); 3.65–4.10 (7H, m, OCH,
2!NCH2Ph and CH2OPh); 6.74–7.75 (14H, m, CHarom).
13C NMR (68 MHz, CDCl3): d 54.64 (CH2N); 58.51
(OCH3); 59.03 and 59.82 (2!NCH2Ph); 70.33 (CH2O);
78.47 (OCH); aromatic signals could not be seen separately.
RfZ0.03; hexane/ethyl acetate 49:1. Colorless oil.
and 130.77 (HCarom); 134.96 (CCl); 140.36 (2!NCH2Cquat
)
159.72 (OCquat). IR (NaCl, cmK1): nmaxZ 3063; 3028;
2925; 1595; 1454; 1099; 1072; 745; 698. MS (70 eV): m/z
(%): 396/8 (MCC1, 100). RfZ0.14; hexane/ethyl acetate
97:3. Colorless oil. Anal. Calcd for C24H26ClNO2: C 72.81,
H 6.62, N 3.54. Found: C 73.01, H 6.84, N 3.41.
3.5.4. N-Benzyl-N-(2-chlorobenzyl)-N-[2-methoxy-3-(2-
bromophenoxy)propyl]amine 9d. 1H NMR (270 MHz,
CDCl3): d 2.70 and 2.78 (2H, 2!d!d, JZ13.6, 6.4, 5.3 Hz,
CH(HCH)N); 3.50 (3H, s, CH3O); 3.62–4.06 (7H, m, OCH,
2!NCH2Ph and CH2OPh); 6.73–3.83, 7.10–7.35 and
7.47–7.55 (14H, 3!m, CHarom). 13C NMR (68 MHz,
CDCl3): d 54.75 (CH2N); 56.60 (OCH3); 58.51 and 59.91
(2!NCH2Ph); 70.37 (CH2O); 78.54 (OCH); aromatic
signals could not be seen separately. RfZ0.03; hexane/
ethyl acetate 49:1. Colorless oil.
3.4.7. 2-N,N-Di[(4-methylbenzyl)methyl]amino-1-(4-
chlorophenoxy)-3-methoxypropane 8g. 1H NMR
(300 MHz, CDCl3): d 2.30 (6H, s, 2!CH3); 3.25–3.30
(1H, m, CHN); 3.30 (3H, s, CH3O); 3.59–3.66 (2H, m,
CH2OMe); 3.75 and 3.77 (4H, 2!2!d, JZ14.3 Hz, 2!
N(HCH)); 4.06 and 4.08 (2H, 2!d!d, JZ9.9, 6.1, 5.5 Hz,
(HCH)OAr); 6.74–6.81 and 6.97–7.28 (2H and 10H, 2!m,
CHarom). 13C NMR (75 MHz, CDCl3): d 21.08 (2!CH3);
54.87 (2!NCH2); 55.64 (NCH); 59.00 (OCH3); 67.33
(CH2OAr); 71.53 (CH2OCH3); 115.79 (2!HCortho); 125.38
(CCl); 128.59, 128.86 and 129.21 (CHarom); 136.28 and
137.29 (2!CH3C and 2!NCH2C); 157.48 (OCquat). IR
(NaCl, cmK1): nmaxZ2923; 1596; 1513; 1491; 1242; 1207;
1094; 1019; 910; 823; 734. MS (70 eV): m/z (%): 424/6
(MCC1; 100); 307 (62). RfZ0.15; hexane/ethyl acetate
97:3. Colorless oil. Anal. Calcd for C26H30ClNO2: C 73.65,
H 7.13, N 3.30. Found: C 73.84, H 7.30, N 3.16.
3.5.5. N-Benzyl-N-(2-chlorobenzyl)-N-[2-methoxy-3-
(2-chlorophenoxy)propyl]amine 9e. H NMR (300 MHz,
1
CDCl3): d 2.67 and 2.75 (2H, 2!d!d, JZ13.7, 6.5, 5.5 Hz,
CH(HCH)N); 3.47 (3H, s, CH3O); 3.53–4.12 (7H, m, OCH,
2!NCH2Ph and CH2OPh); 6.58–7.52 (14H, m, CHarom).
13C NMR (68 MHz, CDCl3): d 54.63 (CH2N); 56.59
(OCH3); 58.45 and 59.89 (2!NCH2Ph); 70.37 (CH2O);
78.54 (OCH); aromatic signals could not be observed
separately. RfZ0.06; hexane/ethyl acetate 49:1. Colorless
oil.
3.5. Detectable signals derived from the minor
constituents 9
3.5.1. N-Benzyl-N-(2-bromobenzyl)-N-(2-methoxy-3-
phenoxypropyl)amine 9a. H NMR (300 MHz, CDCl3):
3.5.6. N,N-Dibenzyl-N-[2-methoxy-3-(3-chlorophenoxy)-
propyl]amine 9f. MS (70 eV): m/z (%): no MC; 350 (10);
254 (10); 210 (100); 181 (7); 91 (90).
1
d 2.70 and 2.77 (2H, 2!d!d, JZ13.5, 6.6, 5.2 Hz,
CH(HCH)N); 3.44 (3H, s, CH3O); 3.56–3.79 (5H, m,
OCH and 2!NCH2Ph); 3.85 and 4.01 (2H, 2!d!d, JZ
10.0, 5.6, 3.7 Hz, (HCH)OPh); 6.79–7.57 (14H, m, CHarom).
13C NMR (75 MHz, refZCDCl3): d 54.37 (CH2N); 58.50
(OCH3); 59.17 and 59.95 (2!NCH2Ph); 68.64 (CH2O);
78.55 (OCH); 114.67, 120.77, 120.88, 124.60, 127.23,
127.40, 128.38, 128.57, 129.19, 129.42, 129.51, 131.07 and
132.87 (14!CHarom and CBr); 138.64 and 139.15 (2!
CCH2N); 158.90 (COCH2). IR (NaCl, cmK1): nmaxZ3063;
3029; 2928; 2827; 1600; 1496; 1244; 1027; 752; 734; 692.
MS (70 eV): m/z (%): 440/2 (MCC1, 100). RfZ0.10;
hexane/ethyl acetate 49:1. Colorless oil.
3.5.7. N,N-Di[(4-methylbenzyl)methyl]-N-[2-methoxy-3-
(4-chlorophenoxy)propyl]amine 9g. H NMR (300 MHz,
1
CDCl3): d 2.34 (6H, s, 2!CH3); 2.58 and 2.70 (2H, 2!d!
d, JZ13.5, 7.4, 4.7 Hz, N(HCH)CH); 3.36 (3H, s, OCH3);
3.57–4.05 (7H, m, CHOMe, 2!NCH2Ar and 2!CH2OAr);
6.69–6.72 and 6.97–7.28 (2H and 10H, 2!m, CHarom). MS
(70 eV): m/z (%): no MC; 378/80 (34); 282 (34); 238 (19);
105 (100). Colorless oil.
Acknowledgements
3.5.2. N-Benzyl-N-(2-chlorobenzyl)-N-(2-methoxy-3-
phenoxypropyl)amine 9b. H NMR (300 MHz, CDCl3):
The authors are indebted to the ‘Fund for Scientific
Research—Flanders (Belgium)’ (F.W.O.-Vlaanderen) and
to Ghent University (GOA) for financial support.
1
d 2.69 and 2.77 (1H, 2!d!d, JZ13.5, 6.6, 5.2 Hz,
CH(HCH)N); 3.45 (3H, s, CH3O); 3.58–3.68 and
3.73–3.85 (3H and 2H, 2!m, OCH and 2!NCH2Ph);
3.86 and 4.02 (H, 2!d!d, JZ11.6, 5.6, 3.6 Hz, CH2OPh);
6.81–7.59 (14H, m, CHarom). 13C NMR (75 MHz, refZ
CDCl3): d 54.34 (CH2N); 56.57 (OCH3); 58.04 and 59.97
(2!NCH2Ph); 68.58 (CH2O); 78.53 (OCH); 114.63,
120.75, 126.77, 127.20, 128.26, 128.37, 129.13, 129.41,
129.56, 129.56, 130.94 and 134.28 (14!CHarom and CCl);
137.00 and 139.19 (2!CCH2N); 158.87 (COCH2). IR
(NaCl, cmK1): nmaxZ2928; 1600; 1496; 1245; 752; 692.
MS (70 eV): m/z (%): 396/8 (MCC1, 100). RfZ0.07;
hexane/ethyl acetate 49:1. Colorless oil.
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