Ring opening of 2-(bromomethyl)-1-sulfonylaziridines towards 1,3-heteroatom substituted 2-aminopropane derivatives

Article abstract of DOI:10.1016/j.tet.2005.06.036

1,3-Heteroatom substituted 2-aminopropane derivatives have been prepared from 2-(bromomethyl)-1-sulfonylaziridines for the first time using sodium azide or different potassium phenoxides in water in the presence of silica gel. The applicability of 1-arenesulfonyl-2-(bromomethyl)aziridines for the synthesis of functionalized sulfonamides has also been demonstrated towards different 1,3-dialkoxy-2-(tosylamino)propanes and 1,3-dialkylthio-2-(tosylamino)propanes upon treatment with the appropriate sodium alkoxide or sodium alkylthiolate in the corresponding alcohol or in methanol, respectively.

Full text of DOI:10.1016/j.tet.2005.06.036

Tetrahedron 61 (2005) 8746–8751
Ring opening of 2-(bromomethyl)-1-sulfonylaziridines towards
1,3-heteroatom substituted 2-aminopropane derivatives
*
Matthias D’hooghe, Mario Rottiers, Inge Kerkaert and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 12 April 2005; revised 10 June 2005; accepted 13 June 2005
Available online 25 July 2005
Abstract—1,3-Heteroatom substituted 2-aminopropane derivatives have been prepared from 2-(bromomethyl)-1-sulfonylaziridines for the
first time using sodium azide or different potassium phenoxides in water in the presence of silica gel. The applicability of 1-arenesulfonyl-2-
(bromomethyl)aziridines for the synthesis of functionalized sulfonamides has also been demonstrated towards different 1,3-dialkoxy-2-
(tosylamino)propanes and 1,3-dialkylthio-2-(tosylamino)propanes upon treatment with the appropriate sodium alkoxide or sodium
alkylthiolate in the corresponding alcohol or in methanol, respectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
processes has become an important element in the design of
new synthetic methodologies. From an ecological point of
view, organic reactions in aqueous media constitute an
attractive alternative for the use of classical solvents. The
present report describes an efficient approach towards
1,3-difunctionalized 2-aminopropane derivatives in water
as a solvent in the presence of silica gel, starting from
2-(bromomethyl)-1-sulfonylaziridines, a versatile but fairly
unknown class of substrates in organic synthesis. The
molecular diversity of these aziridines originates from the
presence of two electrophilic moieties, namely two carbon
atoms of the aziridine ring on the one hand and the halo-
genated carbon atom on the other hand, which enables a
variety of different synthetic transformations towards cyclic
and acyclic target compounds. It has already been demon-
strated in the literature that the closely related 1-tosyl-2-
(tosyloxymethyl)aziridines suffer from ring opening upon
treatment with organocuprate reagents by attack at the least
hindered carbon atom of the aziridine moiety, immediately
followed by ring closure by displacement of the tosylate in a
straightforward manner.10 Also for N,O-bis(diphenylphos-
phinyl)-2-(hydroxymethyl)aziridine, an aziridine with a
different electron-withdrawing substituent at nitrogen, com-
parable results were published.11
A key element present in a whole range of physiologically
active natural products and their synthetic analogues
comprises a 1,2,3-heteroatom substituted three-carbon unit
1 (Fig. 1; X, Y, ZZO, N, S). Many drugs accommodate
such a moiety in their structure, hence the interest in the
development of new entries towards compounds bearing a
1,2,3-trisubstituted propane skeleton. Aryloxypropanol-
amines (XZOAr, YZOH, ZZNHR, Fig. 1) are used as
b-blockers for the treatment of hypertension, angina
pectoris, glaucoma, obesity, and arrhythmia,1 but also as
antidiabetic,2 antihypertensive and vasorelaxing agents.3
Sphingolipids (XZZZOH, YZNH2, Fig. 1), membrane
compounds of essentially all eukaryotic cells, comprise a
2-amino-1,3-dihydroxypropane subunit as part of a longer
(unsaturated) carbon chain.4 Also 2-[(arylmethyl)amino]-
propanediols (XZZZOH, YZNHR, Fig. 1) or shortly
AMAP’s have been reported as antitumor DNA inter-
calators with promising prospects in medicine.5 Moreover,
compounds containing a 2-amino-1,3-propanediol subunit
are important constituents of broad-spectrum antibiotics
such as thiamphenicol and florfenicol.6 Finally, also some
sulfur containing analogues are known for their biological
activity, especially in agriculture as pest control agents
(acaricides and insecticides).7–9
In recent years, the demand for environmentally benign
Keywords: 2-(Bromomethyl)aziridines; 2-Aminopropanes; Water; Ring
opening; Nucleophiles.
*
Corresponding author. Tel.: C32 92645951; fax: C32 92646243;
e-mail: norbert.dekimpe@ugent.be
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.036

M. D’hooghe et al. / Tetrahedron 61 (2005) 8746–8751
8747
1-Arenesulfonyl-2-(bromomethyl)aziridines can be applied
successfully as synthetic equivalents for the
2-aminopropane dication synthon upon treatment with
lithium cuprate reagents towards a-branched N-tosyl-
amides.12 In the present report, the 2-aminopropane dication
synthon equivalency of 2-(bromomethyl)-1-sulfonylaziri-
dines will be further evaluated upon treatment with
heteroatom centered nucleophiles. In the literature, a limited
number of reports dealing with ring opening reactions of
2-(alkoxymethyl)aziridines and 2-(hydroxymethyl)aziri-
dines towards 2-amino-1,3-dioxypropanes have been
reported up to now.13 Only one example of the conversion
of an aziridine into a 1,3-dialkylthio-2-aminopropane
derivative has been published, in which N,O-bis(diphenyl-
phosphinyl)-2-(hydroxymethyl)aziridine was treated with
3 equiv of lithium thiophenoxide in THF at K42 8C, giving
rise to 2-(diphenylphosphinamido)-1,3-bis(thiophenyl)pro-
pane in 70% yield.11
obtained upon treatment of aziridine 3a with 2 equiv of
sodium methoxide, respectively, sodium ethoxide, in the
corresponding alcohol (2 N) after reflux for 3 h (Table 1).
Similarly, N-(2-(2-propenyloxy)-1-((2-propenyloxy)methyl)
ethyl)-4-methylbenzenesulfonamide 4c was prepared in
64% yield utilizing 2 equiv of sodium allyloxide in
refluxing allyl alcohol (1 N). The sulfur analogues 5a,b of
the former dialkoxypropane derivatives were synthesized by
treatment of 2-(bromomethyl)-1-tosylaziridine 3a with
2 equiv of sodium isopropylthiolate or sodium allylthiolate
in methanol (0.3 N) at room temperature for 6–8 h, afford-
ing N-(2-((1-methylethyl)thio)-1-(((1-methylethyl)thio)
methyl)ethyl)-4-methylbenzenesulfonamide 5a and N-(2-(2-
propenylthio)-1-((2-propenylthio)methyl)ethyl)-4-methyl-
benzenesulfonamide 5b in high yields (Table 1).
Very recently, a new protocol for the synthesis of
1-tosylaziridines in water as a solvent in the presence of
silica has been reported, exploiting the adsorptive nature of
silica gel.16 Also the ring opening of 1-tosyl-2-hexylaziri-
dine with sodium azide in water in the presence of silica was
mentioned in the same reference. This reaction did not
proceed in the absence of silica. The applicability of this
approach using 2-(bromomethyl)-1-tosylaziridines 3, how-
ever, has not been investigated up to now.
2. Results and discussion
2-(Bromomethyl)-1-sulfonylaziridines 3 are very easily
accessible, and thus very attractive starting materials in
organic synthesis.14 2-(Bromomethyl)-1-(4-methylbenzene-
sulfonyl)aziridine 3a and 2-(bromomethyl)-1-(methanesul-
fonyl)aziridine 3b were prepared from allylamine 2 in a
very efficient two-step procedure adapted from the literature
(Scheme 1).15
An attempt to prepare 2-(azidomethyl)-1-tosylaziridine 6
selectively by reaction of 1-tosyl-2-bromomethyl)aziridine
3a with 1 equiv of sodium azide in water failed, since this
aziridine 6 was further consumed as a substrate in a ring
opening reaction with azide, probably due to activation of
the aziridine ring by silica. In this way, a mixture of unreacted
2-(bromomethyl)-1-tosylaziridine 3a (44%), 2-(azido-
methyl)-1-tosylaziridine 6 (25%) and tosylamide 7a (31%)
was obtained (Scheme 3).
Consequently, the diazido compounds 7a–b were obtained
very easily and in high yields after treatment of 2-(bromo-
methyl)aziridines 3 with 2 equiv of sodium azide in water in
the presence of silica (0.5 g for 1 mmol of substrate)
(Caution: the azido compounds should be handled with care,
utilizing a safety shield). After heating for 16–20 h at 80 8C,
N-(2-azido-1-(azidomethyl)ethyl)-4-methylbenzenesulfon-
amide 7a and N-(2-azido-1-(azidomethyl)ethyl)-4-metha-
nesulfonamide 7b were isolated as the sole reaction
products (Scheme 4).
Scheme 1.
When 2-(bromomethyl)-1-tosylaziridine 3a was treated
with 2 equiv of an alkoxide or an alkylthiolate, the
corresponding ring opened 1,3-dialkoxy- or 1,3-dialkylthio-
propanamines 4 and 5 were isolated in high yield
(Scheme 2). N-(2-Methoxy-1-(methoxymethyl)ethyl)-4-
methylbenzenesulfonamide 4a and N-(2-ethoxy-1-(ethoxy-
methyl)ethyl)-4-methylbenzenesulfonamide 4b were
Scheme 2.
Table 1. Ring opening reactions of 2-(bromomethyl)-1-tosylaziridine 3a with alkoxides and alkylthiolates
Entry
Conditions
Product
R
Yield (%)
1
2
3
4
5
2 equiv NaOMe/MeOH (2 N), 6, 3 h
2 equiv NaOEt/EtOH (2 N), 6, 3 h
2 equiv NaOCH2CH]CH2/allyl alcohol (1 N), 6, 2 h
2 equiv NaSiPr/MeOH (0.3 N), rt, 6 h
2 equiv NaSCH2CH]CH2/MeOH (0.3 N), rt, 8 h
4a
4b
4c
5a
5b
Me
Et
72
77
64
80
86
CH2CH]CH2
iPr
CH2CH]CH2

8748
M. D’hooghe et al. / Tetrahedron 61 (2005) 8746–8751
Scheme 3.
A stepwise approach based on this methodology enables the
synthesis of 2-aminopropane derivatives with a different
substitution pattern at C1 and C3. 2-(Bromomethyl)-1-
tosylaziridine 3a was converted into the corresponding 2-
(methoxymethyl)aziridine 8 upon reaction with 1.05 equiv
of NaOMe in MeOH (2 N) after stirring at room temperature
for 5 h (Scheme 5). This reaction proceeds through ring
opening and subsequent ring closure of the resulting
b-bromosulfonamide. Treatment of the latter aziridine 8
with 2 equiv of sodium azide in water in the presence of
silica gel afforded N-(2-azido-1-(methoxymethyl)ethyl)-4-
methylbenzenesulfonamide 9 after heating for 20 h at 80 8C
(Scheme 5).
clearly extends the scope of the presented water–silica based
methodology towards a large variety of possible target
compounds, and water can be used as a suitable green
alternative for other solvents in ring opening reactions
of 2-(bromomethyl)-1-sulfonylaziridines with heteroatom
centered nucleophiles.
In summary, the versatility of 2-(bromomethyl)-1-sulfonyl-
aziridines 3 as substrates in organic synthesis has been
demonstrated by the development of a straightforward
approach towards different 1,3-heteroatom substituted
2-aminopropane derivatives using water as a solvent in
the presence of silica gel. In this way, monoazido- and
diazidopropane derivatives have been synthesized using
sodium azide in water, as well as 1,3-diaryloxypropane
sulfonamides by means of different potassium phenoxides
as reagents. The potential of 2-(bromomethyl)-1-sulfonyl-
aziridines has been further demonstrated by the synthesis of
1,3-dialkoxy-2-(tosylamino)propanes and 1,3-dialkylthio-2-
(tosylamino)propanes upon treatment with the appropriate
sodiumalkoxideorsodiumalkylthiolate. Asplentiful methods
areavailableforN-detosylationofsulfonamides, thepresented
methodology offers a suitable access to the synthesis of the
corresponding amines.
Furthermore, also other water-compatible nucleophiles
besides sodium azide have been evaluated using this
water–silica based methodology. Oxygen-centered nucleo-
philes such as potassium phenoxides were applied success-
fully towards 1,3-diaryloxy-2-aminopropane derivatives 10
in good yields upon treatment of 2-(bromomethyl)aziridines
3 with 2.2 equiv of a substituted phenol in water in the
presence of silica (0.5 g for 1 mmol of substrate) and
5 equiv of potassium carbonate after heating for 16–20 h
at 80 8C (Scheme 6). When the same reactions were
performed with less then 5 equiv of K2CO3 (e.g. 2 equiv),
the intermediate 2-(aryloxymethyl)aziridines were also
isolated (25%), besides the desired 1,3-diaryloxy-2-amino-
propane derivatives 10 (75%). The use of phenoxides
3. Experimental
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
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
Scheme 4.
Scheme 5.
Scheme 6.

M. D’hooghe et al. / Tetrahedron 61 (2005) 8746–8751
8749
Spectrum One FT-IR spectrophotometer. Dichloromethane
was distilled over calcium hydride, other solvents were used
as received from the supplier.
13C NMR (68 MHz, CDCl3): d 21.49 (CH3Ar); 52.60
(CHN); 68.62 (2!NCHCH2); 71.98 (2!CH2CH]CH2);
117.05 (2!CH]CH2); 127.08 and 129.58 (2!HCortho and
2!HCmeta); 134.23 (2!CH]CH2); 137.73 (CH3C);
143.30 (Carom,quat). IR (NaCl, cmK1): nZ3296 (NH),
1647, 1598, 1485, 1456, 1329, 1161, 1092. MS (70 eV)
m/z (%): 325 (MC, 0.3); 254 (100); 195 (16); 170 (6); 155
(60); 91 (96); 82 (19); 71 (4); 65 (13). Anal. Calcd for
C16H23NO4S (%): C, 9.05; H, 7.12; N, 4.30. Found (%): C,
58.83; H, 7.28; N, 4.21.
3.1. Synthesis of 1,3-dialkoxy-2-(tosylamino)propanes
4a–c
As a representative example, the synthesis of N-(2-ethoxy-
1-(ethoxymethyl)ethyl)-4-methylbenzenesulfonamide 4b is
described. To 2-(bromomethyl)-1-(4-methylbenzenesulfo-
nyl)aziridine 3a (0.29 g, 1 mmol) was added sodium
methoxide in methanol (1.0 mL, 2 equiv, 2 N in MeOH),
and the resulting mixture was heated under reflux for 4 h.
The reaction mixture was poured into water (20 mL),
extracted with CH2Cl2 (3!10 mL) and dried (K2CO3).
Filtration of the drying agent and evaporation of the solvent
afforded N-(2-ethoxy-1-(ethoxymethyl)ethyl)-4-methyl-
benzenesulfonamide 4b (0.23 g, 77%). These compounds
were purified by means of column chromatography:
(EtOAc/Hexane 1:4). Purity (NMR) O95%.
3.2. Synthesis of 1,3-dialkylthio-2-(tosylamino)propanes
5a,b
As a representative example, the synthesis of N-(2-((1-
methylethyl)thio)-1-(((1-methylethyl)thio)methyl)ethyl)-4-
methylbenzenesulfonamide 5a is described. To sodium
methoxide (12 mL, 4 mmol, 2 equiv, 0.33 N in MeOH) was
added propane-2-thiol (0.46 g, 6 mmol, 3 equiv), and the
mixture was stirred for 30 min at room temperature.
Subsequently, a solution of 2-(bromomethyl)-1-(4-methyl-
benzenesulfonyl)aziridine 3a (0.58 g, 2 mmol) in methanol
(2 mL) was added to the mixture. After stirring for 6 h at
room temperature, the reaction mixture was poured into
water (50 mL), extracted with CH2Cl2 (3!25 mL) and
dried (MgSO4). Filtration of the drying agent and
evaporation of the solvent afforded the crude N-(2-((1-
methylethyl)thio)-1-(((1-methylethyl)thio)methyl)ethyl)-4-
methylbenzenesulfonamide 5a, which was purified by
means of column chromatography (EtOAc/Hexane 1:4,
RfZ0.43).
3.1.1. N-(2-Methoxy-1-(methoxymethyl)ethyl)-4-methyl-
benzenesulfonamide 4a. Yie1d 72%, colorless liquid. H
1
NMR (270 MHz, CDCl3): d 2.41 (3H, s, CH3Ar); 3.21 (6H,
s, 2!CH3O); 3.23–3.38 (4H, m, 2!CH2O); 3.40–3.47 (1H,
m, CHN); 5.35 (1H, s(broad), NH); 7.30 and 7.78 (2!2H,
2!d, JZ8.3 Hz, C6H4). 13C NMR (68 MHz, CDCl3): d
21.49 (CH3Ar); 52.36 (CHN); 58.87 (2!CH3O); 71.18
(2!CH2O); 127.08 and 129.58 (2!HCortho and 2!
HCmeta); 137.93 (CH3C); 143.30 (Carom,quat). IR (NaCl,
cmK1): nZ3270 (NH), 1609, 1452, 1330, 1165. MS (70 eV)
m/z (%): 273 (MC, 1); 229 (81); 171 (31); 155 (44); 139
(81); 91 (100); 73 (67); 65 (27); 45 (60). Anal. Calcd for
C12H19NO4S (%): C 52.73; H 7.01; N 5.12. Found (%): C
52.90; H 7.19; N 4.90.
3.2.1. N-(2-((1-Methylethyl)thio)-1-(((1-methylethyl)
thio)methyl)ethyl)-4-methylbenzenesulfonamide 5a.
Yie1d 80%, colorless liquid. Flash chromatography on
silica gel: EtOAc/Hexane 1:4, RfZ0.43. 1H NMR
(270 MHz, CDCl3): d 1.13 and 1.17 (12H, 2!d, JZ
6.6 Hz, 2!CH(CH3)2); 2.41 (3H, s, CH3Ar); 2.62 (2H, d!
d, JZ13.7, 6.8 Hz, 2!(HCH)S); 2.69 (2H, sept, JZ6.6 Hz,
2!CH(CH3)2); 2.82 (2H, d!d, JZ13.7, 5.4 Hz, 2!
(HCH)S); 3.35 (1H, m, CHN); 5.42 (1H, d, JZ6.6 Hz,
NH); 7.31 and 7.80 (2!2H, 2!d, JZ8.3 Hz, C6H4). 13C
NMR (68 MHz, CDCl3): d 21.47 (CH3Ar); 23.18 and 23.23
(2!CH(CH3)2); 34.21 (2!CH2S); 35.74 (CHS); 52.88
(CHN); 127.24 and 129.61 (2!HCortho and 2!HCmeta);
137.10 (CH3C); 143.47 (Carom,quat). IR (NaCl, cmK1): nZ
3276 (NH), 1598, 1495, 1452, 1337, 1160. MS (70 eV) m/z
(%): 361 (MC, 4); 360 (18); 319 (8); 272 (100); 230 (25);
190 (27); 157 (32); 155 (49); 139 (31); 117 (47); 105 (27);
91 (52); 89 (24); 74 (35); 65 (15); 43 (24). Anal. Calcd for
C16H27NO2S3(%): C, 53.15; H, 7.53; N, 3.87. Found (%): C,
53.31; H, 7.70; N, 3.70.
3.1.2. N-(2-Ethoxy-1-(ethoxymethyl)ethyl)-4-methylben-
zenesulfonamide 4b. Yie1d 77%, colorless liquid. 1H NMR
(270 MHz, CDCl3): d 1.11 (6H, t, JZ7.3 Hz, 2!CH3CH2);
2.43 (3H, s, CH3Ar); 3.29–3.48 (9H, m, 4!CH2O and
CHN); 5.05 (1H, s(broad), NH); 7.30 and 7.79 (2!2H, 2!
d, JZ8.0 Hz, C6H4). 13C NMR (68 MHz, CDCl3): d 14.99
(2!CH3CH2); 21.49 (CH3Ar); 52.61 (CHN); 66.58 (2!
CH3CH2O); 69.00 (2!CH3CH2OCH2); 127.13 and 129.56
(2!HCortho and 2!HCmeta); 137.84 (CH3C); 143.29
(Carom,quat). IR (NaCl, cmK1): nZ3277 (NH), 2978, 2878,
1598, 1457, 1423, 1332. MS (70 eV) m/z (%): 302 (MC, 7);
245 (26); 244 (50); 243 (94); 215 (21); 210 (12); 186 (17);
185 (80); 157 (38); 156 (23); 155 (90); 146 (11); 141 (16);
140 (32); 139 (94); 133 (12); 117 (16); 107 (11); 106 (13);
105 (10); 102 (52); 100 (13); 92 (57); 91 (100); 87 (92); 86
(87); 77 (21); 65 (83). Anal. Calcd for C14H23NO4S (%): C
55.79; H 7.69; N 4.65. Found (%): C 55.96; H 7.88; N 4.48.
3.2.2. N-(2-(2-Propenylthio)-1-((2-propenylthio)methyl)
ethyl)-4-methylbenzenesulfonamide 5b. Yie1d 86%,
colorless liquid. Flash chromatography on silica gel:
EtOAc/Hexane 1:4, RfZ0.25. 1H NMR (270 MHz,
CDCl3): d 2.44 (3H, s, CH3Ar); 2.62 and 2.71 (4H, 2!
d!d, JZ13.8, 6.6, 5.2 Hz, 2!NCH(HCH)); 2.89–3.00
(4H, m, 2!SCH2CH]CH2); 3.36–3.45 (1H, m, NCH);
5.02–5.12 (5H, m, 2!CH]CH2 and NH); 5.60–5.75 (2H,
m, 2!CH]CH2); 7.33 and 7.78 (2!2H, 2!d, JZ8.4 Hz,
C6H4). 13C NMR (68 MHz, refZCDCl3): d 21.44 (CH3Ar);
3.1.3. N-(2-(2-Propenyloxy)-1-((2-propenyloxy)methyl)
ethyl)-4-methylbenzenesulfonamide 4c. Yie1d 64%, color-
less crystals. Mp 42 8C. Flash chromatography on silica gel:
EtOAc/Hexane 1:4, RfZ0.25. 1H NMR (270 MHz, CDCl3):
d 2.42 (3H, s, CH3Ar); 3.30–3.36 (2H, m, 2!NCH(HCH));
3.46–3.49 (3H, m, 2!NCH(HCH) and CHN); 3.86 (4H, d,
JZ5.3 Hz, 2!CH2CH]CH2); 5.07 (1H, s(broad), NH);
5.12–5.21 (4H, m, 2!CH]CH2); 5.71–5.86 (2H, m, 2!
CH]CH2); 7.29 and 7.77 (2!2H, 2!d, JZ8.1 Hz, C6H4).

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M. D’hooghe et al. / Tetrahedron 61 (2005) 8746–8751
34.67 and 35.11 (4!CH2S); 52.06 (CHN); 117.68 (2!
CH]CH2); 127.21 and 129.60 (2!HCortho and 2!
HCmeta); 133.64 (2!CH]CH2); 137.22 (CH3C); 143.52
(Carom,quat). IR (NaCl, cmK1): nZ3279 (NH), 1635, 1598,
1495, 1407, 1331, 1160. MS (70 eV) m/z (%): 357 (MC, 1);
202 (4); 201 (54); 155 (74); 91 (100); 65 (21). Anal. Calcd
for C16H23NO2S3 (%): C, 53.75; H, 6.48; N, 3.92. Found
(%): C, 53.96; H, 6.63; N, 3.81.
143.74 (Carom,quat). IR (NaCl, cmK1): nZ3257 (NH), 2102
(N3), 2935, 2898, 2832, 1596, 1416, 1326, 1162, 1086,
983, 820, 682. MS (70 eV) m/z (%): no MC; 239
(MCKCH2OMe, 9); 228 (28); 155 (49); 139 (30); 91 (100);
65 (20); 45 (19). Anal. Calcd for C11H16N4O3S (%): C 46.47;
H 5.67; N 19.70. Found (%): C 46.61; H 5.83; N 19.59.
3.3.4. 2-(Methoxymethyl)-1-(4-methylbenzenesulfonyl)
aziridine 8. To 2-(bromomethyl)-1-(4-methylbenzenesul-
fonyl)aziridine 3a (0.29 g, 1 mmol) was added sodium
methoxide in methanol (0.53 mL, 1.05 equiv, 2 N in
MeOH), and the resulting mixture was stirred for 5 h at
room temperature. The reaction mixture was poured into
water (20 mL), extracted with CH2Cl2 (3!10 mL) and
dried (MgSO4). Filtration of the drying agent and
evaporation of the solvent afforded the crude 2-(methoxy-
methyl)-1-(4-methylbenzenesulfonyl)aziridine 8, which
was purified by means of column chromatography
(EtOAc/Hexane 1:4, RfZ0.08).
3.3. Ring opening of 1-tosylaziridines with sodium azide
in water
As a representative example, the synthesis of N-(2-azido-1-
(azidomethyl)ethyl)-4-methylbenzenesulfonamide 7a is
described. 2-(Bromomethyl)-1-(4-methylbenzenesulfonyl)
aziridine 3a (1.45 g, 5 mmol), sodium azide (0.66 g,
2 equiv) and silica gel (2.5 g) were suspended in water
(7.5 mL) and stirred at 80 8C for 16 h. The reaction mixture
was filtered over Celite and the filter cake was washed with
CH2Cl2 (2!20 mL). Isolation of the organic phase,
extraction of the water phase with CH2Cl2 (20 mL), drying
of the combined organic extracts (MgSO4), filtration and
evaporation of the solvent afforded the crude N-(2-azido-1-
(azidomethyl)ethyl)-4-methylbenzenesulfonamide 7a,
which was recrystallized from methanol, yielding pure 7a
(1.27 g, 86%).
Yie1d 52%, colorless liquid. Flash chromatography on silica
gel: EtOAc/Hexane 1:4, RfZ0.08. 1H NMR (270 MHz,
CDCl3): d 2.20 (1H, d, JZ4.3 Hz, (HtransCH)N); 2.43 (3H,
s, CH3Ar); 2.61 (1H, d, JZ7.2 Hz, (HCHcis)N); 2.92–3.01
(1H, m, CHN); 3.29 (3H, s, CH3O); 3.38 and 3.53 (2H, 2!
d!d, JZ6.9, 4.3, 1.4 Hz, (HCH)O); 7.32 and 7.81 (2!2H,
2!d, JZ8.1 Hz, C6H4). 13C NMR (68 MHz, CDCl3): d 21.
62 (CH3Ar); 30.85 (CH2N); 38.40 (CHN); 58.92 (CH3O);
71.21 (CH2O); 128.01 and 129.68 (2!HCortho and 2!
HCmeta); 134.79 (CH3C); 144.65 (Carom,quat). IR (NaCl,
cmK1): nZ2253, 1916, 1596, 1490, 1448, 1322, 1290,
1226. MS (70 eV) m/z (%): 241 (MC, 4); 211 (3); 155 (25);
91 (79); 65 (33); 56 (97); 45 (100). Anal. Calcd for
C11H15NO3S (%): C 54.75; H 6.27; N 5.80. Found (%): C
54.93; H 6.44; N 5.64.
3.3.1. N-(2-Azido-1-(azidomethyl)ethyl)-4-methylbenze-
nesulfonamide 7a. Yie1d 86%, colorless crystals. Mp
77.8 8C. Recrystallized from methanol. 1H NMR (300 MHz,
CDCl3): d 2.45 (3H, s, CH3Ar); 3.27–3.50 (5H, m, 2!
CH2N3 and CHN); 5.06 (1H, s(broad), NH); 7.33–7.36 and
7.76–7.80 (2!2H, 2!m, C6H4). 13C NMR (75 MHz,
CDCl3): d 21.57 (CH3Ar); 51.91 (2!CH2N3); 52.23
(CHN); 127.11 and 129.98 (2!HCortho and 2!HCmeta);
137.24 (CH3C); 144.09 (Carom,quat). IR (NaCl, cmK1): nZ
3262 (NH), 2106 (N3), 2936, 2863, 1597, 1449, 1328, 1162,
1093, 733. MS (70 eV) m/z (%): 296 (MCC1, 54); 239
(56); 225 (39); 155 (100). Anal. Calcd for C10H13N7O2S
(%): C, 40.67; H, 4.44; N, 33.20. Found (%): C, 40.85; H,
4.67; N, 33.47.
3.4. Synthesis of diaryloxysulfonamides 10
As a representative example, the synthesis of N-(2-(3-chloro-
phenoxy)-1-((3-chlorophenoxy)methyl)ethyl)methane-
sulfonamide 10a is described. 2-(Bromomethyl)-1-(4-
methanesulfonyl)aziridine 3b (0.54 g, 2.5 mmol) was
added to a mixture of 3-chlorophenol (0.70 g, 2.2 equiv),
K2CO3 (1.73 g, 5 equiv) and silica gel (1.25 g) and stirred at
80 8C for 16 h. The reaction mixture was filtered over Celite
and the filter cake was washed with CH2Cl2 (2!20 mL).
Isolation of the organic phase, extraction of the water phase
with CH2Cl2 (20 mL), drying of the combined organic
extracts (MgSO4), filtration and evaporation of the solvent
afforded the crude N-(2-(3-chlorophenoxy)-1-((3-chloro-
phenoxy)methyl)ethyl)methanesulfonamide 10a, which
was recrystallized from methanol/CH2Cl2 (1:1), yielding
pure 10a (0.79 g, 81%).
3.3.2. N-(2-Azido-1-(azidomethyl)ethyl)methanesulfon-
amide 7b. Yie1d 81%, colorless liquid. 1H NMR
(300 MHz, CDCl3): d 3.07 (3H, s, CH3); 3.53–3.55 (4H,
m, 2!CH2N3); 3.64–3.68 (1H, m, CHN); 5.04 (1H,
s(broad), NH). 13C NMR (75 MHz, CDCl3): d 41.73
(CH3); 52.78 (2!CH2N3); 52.97 (CHN). IR (NaCl, cmK1):
nZ3277 (NH), 2106 (N3), 2936, 2874, 1443, 1319, 1154,
993. MS (70 eV) m/z (%): no MC, 218 (7), 149 (30); 87
(63). Anal. Calcd for C4H9N7O2S (%): C, 21.91; H, 4.14; N,
44.72. Found (%): C, 22.07; H, 4.01; N, 44.93.
3.3.3. N-(2-Azido-1-(methoxymethyl)ethyl)-4-methyl-
benzenesulfonamide 9. Yie1d 74%, colorless crystals.
Mp 67–68 8C. Flash chromatography on silica gel: EtOAc/
Hexane 1:4, RfZ0.14. 1H NMR (300 MHz, CDCl3): d 2.43
(3H, s, CH3Ar); 3.18–3.51 (5H, m, CH2N3, CH2O and
CHN); 3.24 (3H, s, CH3O); 5.15–5.27 (1H, m, NH); 7.29–
7.33 and 7.74–7.84 (2!2H, 2!m, C6H4). 13C NMR
(75 MHz, CDCl3): d 21.55 (CH3Ar); 51.74 (CH2N3);
52.51 (CHN); 58.97 (CH3O); 71.05 (CH2O); 127.09 and
129.80 (2!HCortho and 2!HCmeta); 137.54 (CH3C);
3.4.1. N-(2-(3-Chlorophenoxy)-1-((3-chlorophenoxy)
methyl)ethyl)methanesulfonamide 10a. Yie1d 81%, color-
less crystals. Mp 99.7–100.7 8C. Recrystallized from
methanol/CH2Cl2 (1:1). 1H NMR (300 MHz, CDCl3): d
3.09 (3H, s, CH3); 4.13–4.21 (5H, m, 2!CH2O and CHN);
5.12–5.14 (1H, m, NH); 6.77–6.81, 6.90–6.91, 6.96–6.99
and 7.19–7.26 (8H, 4!m, HCarom). 13C NMR (75 MHz,
CDCl3): d 41.93 (CH3); 52.49 (CHN); 67.71 (2!CH2O);
112.85, 115.06, 121.90 and 130.50 (HCarom); 135.15 (2!

M. D’hooghe et al. / Tetrahedron 61 (2005) 8746–8751
8751
CCl); 158.65 (2!OCquat). IR (NaCl, cmK1): nZ3351 (NH),
3071, 3011, 2962, 2931, 1597, 1486, 1311, 1251, 1151, 770.
MS (70 eV) m/z (%): 389/91/93 (MC, 16); 261/3 (10); 167
(22); 153/5 (100); 134 (15); 111 (23); 96 (24). Anal. Calcd
for C16H17Cl2NO4S (%): C 49.24; H 4.39; N 3.59. Found
(%): C 49.41; H 4.52; N 3.44.
27, 2061. (f) Bevinakatti, H. S.; Banerji, A. A. J. Org. Chem.
1992, 57, 6003. (g) Aubriot, S.; Nicolle, E.; Lattier, M.; Morel,
C.; Cao, W.; Daniel, K. W.; Collins, S.; Leclerc, G.; Faure, P.
Bioorg. Med. Chem. Lett. 2002, 12, 209. (h) Narimatsu, S.;
Watanabe, T.; Masubuchi, Y.; Horie, T.; Kumagai, Y.; Cho,
A. K.; Imaoka, S.; Funae, Y.; Ishikawa, T.; Suzuki, T. Chem.
Res. Toxicol. 1995, 8, 721. (i) Narimatsu, S.; Arai, T.;
Watanabe, T.; Masubuchi, Y.; Horie, T.; Suzuki, T.; Ishikawa,
T.; Tsutsui, M.; Kumagai, Y.; Cho, A. K. Chem. Res. Toxicol.
1997, 10, 289. (j) Teerlink, J.; Massie, B. Am. J. Cardiol. 1999,
84, 94.
3.4.2. N-(2-(4-Fluorophenoxy)-1-((4-fluorophenoxy)
methyl)ethyl)-4-methylbenzenesulfonamide 10b. Yie1d
84%, colorless crystals. Mp 154.4–155.5 8C. Recrystallized
from Hexane/CH2Cl2 (1:1). 1H NMR (300 MHz, CDCl3): d
2.40 (3H, s, CH3Ar); 3.84–3.96 (3H, m, 2!(HCH)O and
CHN); 4.05–4.09 (2H, m, 2!(HCH)O); 5.41 (1H, d, JZ
7.4 Hz, NH); 6.66–6.73 and 6.87–6.96 (8H, 2!m, 4!
OHCorthoHCmeta); 7.25 and 7.78 (4H, 2!d, JZ8.3 Hz, 2!
SHCorthoHCmeta). 13C NMR (75 MHz, CDCl3): d 21.51
(CH3Ar); 51.91 (CHN); 66.92 (2!CH2O); 115.54 (d, JZ
8.1 Hz, 4!OHCortho); 115.93 (d, JZ23.1 Hz, 4!
OHCmeta); 127.20 and 129.78 (2!SHCorthoHCmeta);
137.55 (CH3C); 143.75 (SC); 154.10 (2!OCquat); 157.64
(d, JZ238.8 Hz, 2!CF). IR (NaCl, cmK1): nZ3360 (NH),
3057, 2930, 8875, 1506, 1220, 831, 810. MS (70 eV) m/z
(%): 434 (MCC1, 100). Anal. Calcd for C22H21F2NO4S
(%): C, 60.96; H, 4.88; N, 3.23. Found (%): C, 61.13; H,
5.01; N, 3.09.
2. Ashwell, M. A.; Solvibile, W. R., Jr.; Han, S.; Largis, E.;
Mulvey, R.; Tillet;, J. Bioorg. Med. Chem. Lett. 2001, 11,
3123.
3. Wang, L.-W.; Kang, J.-J.; Chen, I.-J.; Teng, C.-M.; Lin, C.-N.
Bioorg. Med. Chem. 2002, 10, 567.
4. (a) Hakomori, S. J. Biol. Chem. 1990, 5, 878. (b) Van Meer,
G.; Burger, K. N. J. Trends Cell Biol. 1992, 2, 332. (c) Howell,
A. R.; So, R.C.; Richardson, S.K. Tetrahedron 2004, 60,
11327.
5. (a) Bair, K. W.; Tuttle, R. L.; Knick, V. C.; Cory, M.; McKee,
D. D. J. Med. Chem. 1990, 33, 2385. (b) Bair, K. W.; Andrews,
C. W.; Tuttle, R. L.; Knick, V. C.; Cory, M.; McKee, D. D.
J. Med. Chem. 1991, 34, 1983.
6. (a) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
(b) Giordano, C.; Cavicchioli, S.; Levi, S.; Villa, M. J. Org.
Chem. 1991, 56, 6114. (c) Clark, J. E.; Fischer, P. A.;
Schumacher, D. P. Synthesis 1991, 891. (d) Schumacher, D. P.;
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55, 5291.
3.4.3. N-(2-(4-Methoxyphenoxy)-1-((4-methoxyphenoxy)
methyl)ethyl)-4-methylbenzenesulfonamide 10c. Yie1d
72%, colorless crystals. Mp 91.1–92.3 8C. Recrystallized
from methanol. 1H NMR (300 MHz, CDCl3): d 2.41 (3H, s,
CH3Ar); 3.75 (6H, s, 2!CH3O); 3.85–3.94 (3H, m, 2!
(HCH)O and CHN); 4.05–4.09 (2H, m, 2!(HCH)O); 5.25–
5.28 (1H, m, NH); 6.69–6.80 (8H, m, 4!OHCorthoHCmeta);
7.26 and 7.78 (4H, 2!d, JZ8.4 Hz, 2!SHCorthoHCmeta).
13C NMR (75 MHz, CDCl3): d 21.53 (CH3Ar); 52.02
(CHN); 55.70 (2!CH3O); 66.97 (2!CH2O); 114.68 and
115.47 (4!MeOHCorthoHCmeta); 127.18 and 129.75 (2!
SHCorthoHCmeta); 137.57 (CH3C); 143.61 (SC); 152.15 and
154.28 (2!CH2OCquat and 2!MeOCquat). IR (NaCl, cmK1):
nZ3307 (NH), 2940, 2834, 1508, 1228, 1162, 1039, 818.
MS (70 eV) m/z (%): no MC, 333 (MCKMeOC6H4OH,
42); 210 (45); 155 (100); 123 (32); 91 (99). Anal. Calcd for
C24H27NO6S (%): C 63.00; H 5.95; N 3.06. Found (%): C
63.19; H 6.11; N 2.90.
7. (a) Sakai, M.; Kato, M.; Hagiwara, H.; Konishi, K. Jpn.
Tokkyo Koho JP 51,042,177, Nov 13, 1976; Chem. Abstr.
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Fujioka, S.; Kanno, H. Eur. Pat. Appl. EP 1,006,107 A2, June
7, 2000; Chem. Abstr. 2000, 133, 17278.
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Food Chem. 2004, 52, 95.
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Chem. Abstr. 1997, 127, 61838.
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12. D’hooghe, M.; Kerkaert, I.; Rottiers, M.; De Kimpe, N.
Tetrahedron 2004, 60, 3637.
13. (a) Sugiyama, S.; Watanabe, S.; Inoue, T.; Kurihara, R.; Itou,
T.; Ishii, K. Tetrahedron 2003, 59, 3417. (b) Buijnsters, P. J. J.
A.; Feiters, M. C.; Nolte, R. J. M.; Sommerdijk, N. A. J. M.;
Zwanenburg, B. Chem. Commun. 2001, 269. (c) Choi, S.-K.;
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Acknowledgements
The authors are indebted to the ‘Fund for Scientific
Research—Flanders (F.W.O.-Vlaanderen)’ (Belgium) and
Ghent University (GOA) for financial support.
References and notes
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