Opposite regioselectivity in the sequential ring-opening of 2-(alkanoyloxymethyl)aziridinium salts by bromide and fluoride in the synthesis of functionalized β-fluoro amines

Article abstract of DOI:10.1055/s-2006-947359

1-Arylmethyl-2-(bromomethyl)aziridines were converted into the corresponding 2-(alkanoyloxymethyl)aziridines upon treatment with potassium 2-methylpropanoate or potassium 2-methylbutyrate in DMSO in excellent yields, following regioselective ring-opening

Full text of DOI:10.1055/s-2006-947359

LETTER
2089
Opposite Regioselectivity in the Sequential Ring-Opening of 2-(Alkanoyl-
oxymethyl)aziridinium Salts by Bromide and Fluoride in the Synthesis of
Functionalized b-Fluoro Amines
R
egioselectivity in the
a
Sequential
t
Ring-O
t
pening
h
of 2-(Alkan
i
oyloxy
a
methyl)azi
s
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 27 April 2006
SO2Me
Abstract: 1-Arylmethyl-2-(bromomethyl)aziridines were convert-
ed into the corresponding 2-(alkanoyloxymethyl)aziridines upon
treatment with potassium 2-methylpropanoate or potassium 2-
methylbutyrate in DMSO in excellent yields, following regio-
O
F
OH
F
OH
selective ring-opening towards N-(2-bromo-3-alkanoyloxy-
propyl)amines using allyl bromide or an arylmethyl bromide in
acetonitrile. Treatment of the latter b-bromo amines with tetrabutyl-
ammonium fluoride in acetonitrile afforded 2-amino-1-fluoro-
propanes as the major compounds (72–86%) besides the isomeric 1-
amino-2-fluoropropanes in minor quantities (14–28%). The ring-
opening of the intermediate aziridinium salts by bromide and
fluoride in acetonitrile resulted in a different regioselectivity with a
preferential attack of bromide at the more hindered carbon atom and
of fluoride at the less hindered carbon atom of the aziridinium ion.
HN
NH2
COCHCl2
1
2
Figure 1
In this communication, the synthesis of fluorinated prop-
ylamines is disclosed based on the sequential ring-open-
ing of the same intermediate aziridinium salts by bromide
and fluoride. A comparative study of the ring-opening of
these aziridinium salts in acetonitrile showed a different
regioselectivity depending on the nature of the nucleo-
philic halide ion.
Key words: 2-(bromomethyl)aziridines, aziridinium salts, b-fluoro
amines, ring-opening, substitution
1,2,3-Triheteroatom-substituted propane derivatives
constitute very valuable target compounds in medicinal
chemistry due to the pronounced physiological activities
ascribed to many representatives of this class of com-
pounds.1 In recent years, the introduction of a fluoro atom
in a strategic position of a molecule is emerging as a pow-
erful and versatile tool for the development of effective
drugs and agrochemicals, since fluorine can dramatically
alter both the chemical and the biological properties of
these compounds.2 For example, fluorinated amino acids
– such as 3-fluoro-D-alanine (1) – and other fluoro amines
have received a lot of attention due to their interesting bi-
ological activities.3 Moreover, the incorporation of a b-
fluoro amine moiety into a 1,2,3-triheteroatom-substitut-
ed propane skeleton has led to the discovery of a new class
of powerful antimicrobial agents,4 with florfenicol (2)4a,4b
as an important example (Figure 1). Nevertheless, syn-
thetic approaches towards 2-amino-3-fluoro-1-oxypro-
panes are rather limited and restricted mainly to patent
literature, with only a few exceptions,5 despite of the great
biological potential of compounds bearing such a moiety
in their structure. Therefore, the synthesis of novel 1,2,3-
triheteroatom-substituted propane derivatives bearing a
fluoro atom is of potential interest.
1-Arylmethyl-2-(bromomethyl)aziridines
3 are very
easily accessible substrates suitable for various applica-
tions in organic synthesis, prepared from the correspond-
ing benzaldehydes in a three-step procedure.6 These 2-
(bromomethyl)aziridines 3 are excellent precursors for
the synthesis of 1,2,3-trisubstituted propane derivatives
since their structure comprises a three-carbon unit in
which the three electrophilic carbon atoms are structurally
differentiated from each other, allowing the preparation of
different substituted propylamines.
1-Arylmethyl-2-(bromomethyl)aziridines 3a–d were con-
verted into the corresponding 2-(alkanoyloxymethyl)azir-
idines 4a–d upon treatment with one equivalent of
potassium 2-methylpropanoate or potassium 2-methylbu-
tyrate in DMSO in excellent yields after heating at 80 °C
for 15 hours (Scheme 1).7 In the case of 2-methylbutyrate
(4d), the two diastereomers (ratio 47:53) appeared to be
inseparable by chromatography (GC and flash) and the
mixture was used as such. 2-(Alkanoyloxymethyl)aziri-
dines, mainly 2-(acetyloxymethyl)aziridines, have been
prepared in other ways, usually by (enzymatic) acetyl-
ation of 2-(hydroxymethyl)aziridines8 or by ring-closure
of mesylated or tosylated 1-acetoxy-2-amino-3-hy-
droxypropanes.9 This is the first report of the synthesis of
2-(alkanoyloxymethyl)aziridines starting from 2-(bro-
momethyl)aziridines in a very efficient procedure based
on a simple substitution of the halogen by a nucleophilic
carboxylate anion.
SYNLETT 2006, No. 13, pp 2089–2093
1
7
.0
8
.2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-947359; Art ID: G13806ST
© Georg Thieme Verlag Stuttgart · New York

2090
M. D’hooghe, N. De Kimpe
LETTER
upon attack by bromide, resulting in a stable transition
state,10c followed by ring-opening towards b-bromo
amines 6.
O
R1
R1
1 equiv HO
R2
N
N
O
R2
2 equiv K2CO3
DMSO
Br
Subsequently, the latter b-bromo amines 6a–f were treat-
ed with 1–2 equivalents of tetrabutylammonium fluoride
(TBAF·3H2O) in acetonitrile, affording a mixture of b-
fluoro amines 7 as the major constituents (72–86%) and b-
fluoro amines 8 as the minor compounds (14–28%) after
reflux for 7 hours (Scheme 3, Table 1).12 Only in the case
of allylamines 7a/8a and 7b/8b (R = CH=CH2), both
regioisomers could be separated by means of column
chromatography on silica gel. The presence of the major
regioisomers 7, in which the amino moiety has moved
from the terminus of the propane skeleton towards the
central carbon atom, can only be rationalized considering
the formation of an intermediate aziridinium ion 5 upon
heating (Scheme 3), which is then attacked by fluoride at
the less hindered carbon atom of the aziridine ring. The
formation of the minor isomers 8 can be the result of the
attack of fluoride at the more hindered carbon atom of the
aziridinium ion 5 or, alternatively, the result of an SN2
substitution reaction at the bromomethine moiety in
bromo amines 6.
O
80 °C, 15 h
3a (R1 = 3-Me)
3b (R1 = 2-Cl)
3c (R1 = 4-Me)
3d (R1 = H)
4a (R1 = 3-Me, R2 = H, 85%)
4b (R1 = 2-Cl, R2 = H, 82%)
4c (R1 = 4-Me, R2 = H, 86%)
4d (R1 = H, R2 = Me, 77%)
Scheme 1
1-Arylmethyl-2-(bromomethyl)aziridines and 1-aryl-
methyl-2-(aryloxymethyl)aziridines can be transformed
regioselectively into N-(2-bromopropyl)amines upon
treatment with a benzyl bromide in acetonitrile in a
straightforward reaction.10 Accordingly, 2-(alkanoyl-
oxymethyl)aziridines 4a–d were treated with allyl bro-
mide or an arylmethyl bromide in MeCN and thus
converted into the corresponding N-(2-bromo-3-alkanoyl-
oxypropyl)amines 6a–f in high yields and high purity
after reflux for 6 hours (Scheme 2).11 Detailed spectral
analysis confirmed the structural identity of these novel
N-(2-bromo-3-alkanoyloxypropyl)amines 6, excluding
the formation of the corresponding regioisomers. Obvi-
ously, the intermediate aziridinium salts 5 are opened ex-
clusively at the more hindered aziridine carbon atom by
bromide in MeCN towards b-bromo amines 6. This can be
explained considering the weakening of the C2–N bond
If another fluoride source was used, e.g. potassium fluo-
ride, b-bromo amines 6 were recovered completely upon
treatment with one equivalent of KF in refluxing acetoni-
trile for 7 hours, pointing to the importance of the choice
of the fluoride source. The amount of TBAF used for this
R1
R1
R
1–1.2 equiv
RCH2Br
R
N
O
R1
N
N
O
R2
O
R2
O
R2
MeCN, ∆, 6 h
Br
O
O
Br
6a (R1 = 3-Me, R2 = H, R = CH=CH2, 90%)
6b (R1 = 2-Cl, R2 = H, R = CH=CH2, 92%)
6c (R1 = 3-Me, R2 = H, R = Bn, 89%)
6d (R1 = 4-Me, R2 = H, R = Bn, 90%)
6e (R1 = H, R2 = Me, R = 4-BrC6H4, 82%)
6f (R1 = H, R2 = Me, R = 4-MeC6H4, 85%)
4a–d
5
Scheme 2
R
N
R
F
O
1–2 equiv
TBAF·3H2O
R2
O
N
O
O
R1
R1
R1
+
N
R2
O
R2
O
MeCN, ∆, 7 h
Br
F
R
6a–f
7a–f (72–86%)
8a–f (14–28%)
R1
R
N
O
R2
O
F
5
Scheme 3
Synlett 2006, No. 13, 2089–2093 © Thieme Stuttgart · New York

LETTER
Regioselectivity in the Sequential Ring-Opening of 2-(Alkanoyloxymethyl)aziridinium Salts
2091
Table 1 Conversion of b-Bromo Amines 6 into b-Fluoro Amines 7 and 8 upon Treatment with TBAF in Acetonitrile under Reflux for 7 Hours
Entry
Compounds
7a, 8a
7b, 8b
7c, 8c
7d, 8d
7e, 8e
7e, 8e
7e, 8e
7f, 8f
R1
R2
H
R
TBAF (equiv)
Ratio 7.8a
72:28
78:22
86:14
77:23
77:23
83:17
79:21
74:26
86:14
79:21
1
2
3-Me
2-Cl
3-Me
4-Me
H
CH=CH2
CH=CH2
Ph
2.0
2.0
1.5
1.5
1.0
1.5
2.0
1.0
1.5
2.0
H
3
H
4
H
Ph
5
Me
Me
Me
Me
Me
Me
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
6
H
7
H
8
H
9
7f, 8f
H
10
7f, 8f
H
a Ratio determined by 19F NMR and 1H NMR.
transformation had a peculiar influence on the ratio of the hence the preferential attack at the unsubstituted carbon
major versus the minor isomer, since treatment of b-bro- atom of the intermediate aziridinium salt. The favorable
mo amine 6e with TBAF (1.0, 1.5 and 2 equiv, respective- transition state upon attack of bromide has been acknowl-
ly), gave mixtures of the corresponding fluoro amines 7e edged previously by means of high level ab initio calcula-
and 8e in a 77:23, 83:17 and 79:21 ratio (entries 5, 6 and tions for an analogous substrate.10c The peculiar behavior
7, Table 1). This small shift in favor of the major isomers of ring-opening reactions of aziridinium salts by fluoride
7 utilizing 1.5 equivalents of TBAF was also observed has also been noted before by others, although in these
upon treatment of b-bromo amines 6f with TBAF (1.0, 1.5 cases ring-opening of N–H or N-activated aziridines by
and 2 equiv, respectively, entries 8, 9 and 10, Table 1), al- fluoride (upon treatment with HF or Olah’s reagent) usu-
though in both cases the differences are to small to be sig- ally occurred at the more hindered aziridine carbon atom
nificant. When dichloromethane was used as the solvent instead of at the less hindered carbon atom.14
instead of acetonitrile for the conversion of b-bromo
In conclusion, a novel and easy access towards fluorinated
1-(alkanoyloxy)propylamines has been developed based
on the subsequent ring-opening of intermediate aziridini-
amines 6 into b-fluoro amines 7 and 8 upon treatment with
TBAF, the ratio of 7:8 dropped to 65:35, whereas in THF
similar ratios as compared to the reaction in acetonitrile
um salts by bromide and fluoride with a different regio-
were obtained.
selectivity. Further studies on the ring-opening of 2-
The ring-opening of aziridinium salts by halides consti- substituted aziridinium salt are currently in progress,
tutes a very powerful method towards the preparation of about which will be communicated in due course.
b-halo amines and, consequently, many synthetic efforts
have been devoted to this matter.13 Interestingly, the
Acknowledgment
regioselectivity of these reactions often appears to be
The authors are indebted to the ‘Fund for Scientific Research –
Flanders (Belgium)’ (F.W.O.-Vlaanderen) and to Ghent University
(GOA) for financial support.
dependent on several factors such as the substrate, the
nucleophile and the solvent. Indeed, also in this case, it
should be stressed that the same aziridinium salts 5 are
present as intermediates in both transformations
(Scheme 2 and Scheme 3), although a different regio-
selectivity upon ring-opening by bromide and fluoride has
been observed. Apparently, these aziridinium salts are
opened exclusively at the more hindered aziridine carbon
atom by bromide and mainly at the less hindered aziridine
carbon atom by fluoride, both in acetonitrile. The differ-
ence in polarizability between bromide and fluoride can
account for this behavior, since the high polarizability of
bromide enables the formation of a favorable transition
state, stabilized by acetonitrile, upon attack at the substi-
tuted aziridine carbon atom, whereas the low polariza-
bility of fluoride impede such a stabilizing interaction,
References and Notes
(1) (a) 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. (b) Bair,
K. W.; Tuttle, R. L.; Knick, V. C.; Cory, M.; McKee, D. D.
J. Med. Chem. 1990, 33, 2385. (c) Bair, K. W.; Andrews, C.
W.; Tuttle, R. L.; Knick, V. C.; Cory, M.; McKee, D. D. J.
Med. Chem. 1991, 34, 1983.
(2) Elliott, A. J. In Chemistry of Organic Fluorine Compounds
II: A Critical Review; Hudlicky, M.; Pavlath, A. E., Eds.;
ACS Monograph 187, American Chemical Society:
Washington DC, 1995, 1119–1125.
Synlett 2006, No. 13, 2089–2093 © Thieme Stuttgart · New York

2092
M. D’hooghe, N. De Kimpe
LETTER
(3) (a) Qiu, X. L.; Meng, W. D.; Qing, F. L. Tetrahedron 2004,
60, 6711. (b) Sutherland, A.; Willis, C. L. Nat. Prod. Rep.
2000, 17, 621. (c) Kollonitsch, J. In Biomedicinal Aspects of
Fluorine Chemistry; Filler, R.; Kobayashi, Y., Eds.;
Elsevier: Amsterdam, 1993.
(4) (a) Nagabhushan, T. L. US 4235892, 1980; Chem. Abstr.
1980, 94, 139433. (b) Wu, G.; Schumacher, D. P.; Tormos,
W.; Clark, J. E.; Murphy, B. L. J. Org. Chem. 1997, 62,
2996. (c) Stanek, J.; Frei, J.; Mett, H.; Schneider, P.;
Regenass, U. J. Med. Chem. 1992, 35, 1339.
(9) (a) Chang, J.-W.; Bae, J. H.; Shin, S.-H.; Park, C. S.; Choi,
D.; Lee, W. K. Tetrahedron Lett. 1998, 39, 9193.
(b) Sugiyama, S.; Inoue, T.; Ishii, K. Tetrahedron:
Asymmetry 2003, 14, 2153.
(10) (a) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org.
Chem. 2004, 69, 2703. (b) D’hooghe, M.; Waterinckx, A.;
Vanlangendonck, T.; De Kimpe, N. Tetrahedron 2006, 62,
2295. (c) D’hooghe, M.; Van Speybroeck, V.; Waroquier,
M.; De Kimpe, N. Chem. Commun. 2006, 1554.
(11) As a representative example, the synthesis of 3-[allyl-(3-
methylbenzyl)amino]-2-bromopropyl 2-methylpropanoate
(6a) is described. To a solution of 1-(3-methylbenzyl)-
aziridin-2-ylmethyl 2-methylpropanoate (4a, 2.47 g, 10
mmol) in MeCN (50 mL) was added allyl bromide (1.45 g,
1.2 equiv) under stirring, and the resulting mixture was
heated for 6 h under reflux. Evaporation of the solvent
afforded 3-[allyl(3-methylbenzyl)amino]-2-bromopropyl 2-
methylpropanoate (6a), which was purified by means of
column chromatography (hexane–EtOAc, 49:1) on silica gel
in order to obtain an analytically pure sample.
(d) Hennequin, L. F. A.; Gibson, K. H.; Foote, K. M. PCT
Int. Appl. WO 2003047582 A1, 2003; Chem. Abstr. 2003,
139, 36516.
(5) (a) Bravo, P.; Resnati, G.; Zappala, C. J. Fluorine Chem.
1992, 59, 153. (b) Okada, T.; Tsuji, T.; Tsushima, T.;
Yoshida, T.; Matsuura, S. J. Heterocycl. Chem. 1991, 28,
1061. (c) Foster, A. B.; Jarman, M.; Kinas, R. W.; Van
Maanen, J. M. S.; Taylor, G. N.; Gaston, J. L.; Parkin, A.;
Richardson, A. C. J. Med. Chem. 1981, 24, 1399.
(6) (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc.,
Chem. Commun. 1994, 1221. (b) De Kimpe, N.; De Smaele,
D.; Szakonyi, Z. J. Org. Chem. 1997, 62, 2448.
3-[Allyl(3-methylbenzyl)amino]-2-bromopropyl 2-methyl-
propanoate (6a): colorless liquid; yield 90%; Rf = 0.04
(hexane–EtOAc, 49:1). 1H NMR (300 MHz, CDCl3): d =
1.17 [6 H, d, J = 7.2 Hz, (CH3)2CH], 2.34 (3 H, s, CH3Ar),
2.54 [1 H, sept, J = 7.0 Hz, (CH3)2CH], 2.84 and 2.93 [2 H,
2 × dd, J = 13.7, 8.8, 5.9 Hz, N(HCH)CHBr], 3.06 and 3.17
[2 H, 2 × dd, J = 14.0, 6.9, 6.1 Hz, N(HCH)CH=CH2], 3.53
and 3.67 [2 H, 2 d, J = 13.5 Hz, N(HCH)Ar], 4.07–4.16 (1
H, m, CHBr), 4.27 and 4.50 [2 H, 2 × dd, J = 11.9, 6.3, 3.7
Hz, (HCH)O], 5.15–5.22 (2 H, m, CH=CH2), 5.79–5.92 (1
H, m, CH=CH2), 7.05–7.26 (4 H, m, CHarom). 13C NMR (68
MHz, CDCl3): d = 18.87 and 18.96 [(CH3)2CH], 21.41
(CH3Ar), 33.94 [(CH3)2CH], 48.77 (CHBr), 57.50, 57.67
and 59.12 (3 × CH2N), 65.70 (CH2O), 118.07 (CH=CH2),
125.93, 127.95, 128.25 and 129.61 (HCarom), 135.23
(CH=CH2), 137.90 and 138.70 (2 × Carom,quat), 176.48 (CO).
IR (NaCl): 1736 cm–1 (C=O). MS (70 eV): m/z (%) = 368,
370 (23) [M+ + 1], 288 (100) [M+ – Br]. Anal. Calcd for
C18H26BrNO2: C, 58.70; H, 7.12; N, 3.80. Found: C, 58.91;
H, 7.31; N, 3.66.
(c) Abbaspour Tehrani, K.; Van Nguyen, T.; Karikomi, M.;
Rottiers, M.; De Kimpe, N. Tetrahedron 2002, 58, 7145.
(d) D’hooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org.
Chem. 2005, 70, 227. (e) D’hooghe, M.; Rottiers, M.; Jolie,
R.; De Kimpe, N. Synlett 2005, 931.
(7) As a representative example, the synthesis of 1-(3-methyl-
benzyl)aziridin-2-ylmethyl 2-methylpropanoate 4a is
described. To a solution of isobutyric acid (0.88 g, 1.0 equiv)
in DMSO (15 mL) was added K2CO3 (2.76 g, 2 equiv), and
the resulting suspension was stirred for 30 min at r.t.
Subsequently, 2-(bromomethyl)-1-(3-methylbenzyl)-
aziridine (3a, 2.40 g, 0.01 mol) was added, and the mixture
was heated at 80 °C for 15 h. The reaction mixture was
poured into H2O (20 mL) and extracted with Et2O (3 × 15
mL). The combined organic extracts were washed with H2O
(2 × 15 mL) and brine (20 mL). Drying (MgSO4), filtration
of the drying agent and evaporation of the solvent afforded
1-(3-methylbenzyl)aziridin-2-ylmethyl 2-methylpropanoate
(4a), which was purified by filtration through silica gel
(hexane–EtOAc, 5:3).
1-(3-Methylbenzyl)aziridin-2-ylmethyl2-methylpropanoate
(4a): Rf = 0.25; light-yellow oil; yield 85%. 1H NMR (300
MHz, CDCl3): d = 1.10 and 1.11 [6 H, 2 d, J = 6.9 Hz,
(CH3)2CH], 1.51 [1 H, d, J = 6.3 Hz, (HcisCH)N], 1.77 [1 H,
d, J = 3.3 Hz, (HCHtrans)N], 1.82–1.89 (1 H, m, NCH), 2.34
(3 H, s, CH3Ar), 2.47 [1 H, sept, J = 7.0 Hz, (CH3)2CH], 3.30
and 3.53 [2 H, 2 d, J = 13.3 Hz, N(HCH)Ar], 3.81 and 4.20
[2 H, 2 × dd, J = 11.6, 7.4, 4.5 Hz, (HCH)O], 7.06–7.24 (4
H, m, CHarom). 13C NMR (68 MHz, CDCl3): d = 18.89
[(CH3)2CH], 21.39 (CH3Ar), 31.76 [(HcisCHtrans)N], 33.86
[(CH3)2CH], 37.21 (CHN), 64.40 (NCH2Ar), 66.55 (CH2O),
125.14, 127.87, 128.27 and 128.85 (HCarom), 137.93 and
138.73 (2 × Carom,quat), 176.99 (CO). IR (NaCl): 1733 cm–1
(C=O). MS (70 eV): m/z (%) = 247 (19) [M+], 160 (38), 158
(17), 105 (100), 72 (21), 71 (38). Anal. Calcd for C15H21NO2:
C, 72.84; H, 8.56; N, 5.66. Found: C, 72.97; H, 8.74; N, 5.50.
(8) (a) Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G.
Tetrahedron 2001, 57, 1801. (b) Davoli, P.; Caselli, E.;
Bucciarelli, M.; Forni, A.; Torre, G.; Prati, F. J. Chem. Soc.,
Perkin Trans. 1 2002, 1948. (c) Risberg, E.; Fischer, A.;
Somfai, P. Tetrahedron 2005, 61, 8443. (d) Bilke, J. L.;
Dzuganova, M.; Fröhlich, R.; Würthwein, E.-U. Org. Lett.
2005, 7, 3267.
(12) As a representative example, the synthesis of 2-[allyl(3-
methylbenzyl)amino]-3-fluoropropyl 2-methylpropanoate
(7a) and 3-[allyl(3-methylbenzyl)amino]-2-fluoropropyl 2-
methylpropanoate (8a) is described. To a solution of 3-
[allyl(3-methylbenzyl)amino]-2-bromopropyl 2-methyl-
propanoate (6a, 3.68 g, 10 mmol) in MeCN (50 mL) was
added TBAF·3H2O (4.73 g, 1.5 equiv) under stirring and the
resulting mixture was heated for 7 h under reflux. Extraction
with H2O (40 mL) and Et2O (3 × 30 mL), drying (MgSO4),
filtration of the drying agent and evaporation of the solvent
afforded a mixture of 2-[allyl(3-methylbenzyl)amino]-3-
fluoropropyl 2-methylpropanoate (7a, 72%) and 3-[allyl(3-
methylbenzyl)amino]-2-fluoropropyl 2-methylpropanoate
(8a, 28%). Both isomers were separated by means of column
chromatography (hexane–ethyl acetate, 34:1) in order to
obtain analytically pure samples.
2-[Allyl(3-methylbenzyl)amino]-3-fluoropropyl 2-methyl-
propanoate (7a): colorless liquid; Rf = 0.16 (hexane–EtOAc,
34:1). 1H NMR (300 MHz, CDCl3): d = 1.18 and 1.19 [6 H,
2 d, J = 6.9 Hz, (CH3)2CH], 2.34 (3 H, s, CH3Ar), 2.57 [1 H,
sept, J = 7.0 Hz, (CH3)2CH], 3.20–3.35 (3 H, m, CHN and
NCH2CH=CH2), 3.73 and 3.76 [2 H, 2 d, J = 14.3 Hz,
N(HCH)Ar], 4.20 [1 H, dd, J = 11.4, 6.5 Hz, (HCH)O], 4.30
[1 H, ddd, J = 11.4, 6.5, 1.2 Hz, (HCH)O], 4.50 and 4.66
[2 H, dd, J = 47.5, 5.1 Hz, (HCH)F], 5.09–5.24 (2 H, m,
CH=CH2), 5.73–5.86 (1 H, m, CH=CH2), 7.04–7.32 (4 H, m,
CHarom). 13C NMR (68 MHz, CDCl3): d = 19.06 [(CH3)2CH],
Synlett 2006, No. 13, 2089–2093 © Thieme Stuttgart · New York

LETTER
Regioselectivity in the Sequential Ring-Opening of 2-(Alkanoyloxymethyl)aziridinium Salts
2093
21.52 (CH3Ar), 34.12 [(CH3)2CH], 54.06 and 54.81
(2 × CH2N), 56.85 (d, J = 18.5 Hz, CHN), 61.55 (d, J = 5.8
Hz, CH2O), 82.34 (d, J = 171.9 Hz, CH2F), 117.28
(2 × Carom,quat), 176.80 (CO). 19F (CCl3F): d = –189.50 to
–189.34 (m, CHF). IR (NaCl): 1736 cm–1 (C=O). MS
(70 eV): m/z (%) = 307 (3) [M+], 174 (99), 105 (100). Anal.
Calcd for C18H26FNO2: C, 70.33; H, 8.53; N, 4.56. Found: C,
70.54; H, 8.72; N, 4.32.
(CH=CH2), 125.57, 127.82, 128.26 and 129.22 (HCarom),
136.84 (CH=CH2), 137.94 and 139.87 (2 × Carom,quat), 176.92
(CO). 19F (CCl3F): d = –227.42 (td, J = 46.0, 22.4 Hz,
CH2F). IR (NaCl): 1738 cm–1 (C=O). MS (70 eV): m/z
(%) = 307 (1) [M+], 274 (5) [M+ – CH2F], 206 (45), 174 (40),
105 (100). Anal. Calcd for C18H26FNO2: C, 70.33; H, 8.53;
N, 4.56. Found: C, 70.50; H, 8.70; N, 4.41.
3-[Allyl(3-methylbenzyl)amino]-2-fluoropropyl 2-methyl-
propanoate (8a): colorless liquid; Rf = 0.09 (hexane–EtOAc,
34:1). 1H NMR (300 MHz, CDCl3): d = 1.16 [6 H, d, J = 7.2
Hz, (CH3)2CH], 2.34 (3 H, s, CH3Ar), 2.55 [1 H, sept, J = 7.0
Hz, (CH3)2CH], 2.74 (2 H, dd, J = 19.8, 5.5 Hz, NCH2CHF),
3.15 (2 H, d, J = 6.3 Hz, NCH2CH=CH2), 3.62 (2 H, s,
NCH2Ar), 4.11–4.34 (2 H, m, CH2O), 4.76 (1 H, dddd, J =
48.8, 11.7, 5.8, 3.0 Hz, CHF), 5.14–5.23 (2 H, m, CH=CH2),
5.85–5.93 (1 H, m, CH=CH2), 7.04–7.25 (4 H, m, CHarom).
13C NMR (68 MHz, CDCl3): d = 18.92 [(CH3)2CH], 21.42
(CH3Ar), 33.88 [(CH3)2CH], 53.39 (d, J = 23.1 Hz,
NCH2CHF), 57.82 (NCH2CH=CH2), 59.13 (NCH2Ar),
64.42 (d, J = 21.9 Hz, CH2O), 90.33 (d, J = 173.1 Hz, CHF),
117.96 (CH=CH2), 125.95, 127.89, 128.22 and 129.61
(HCarom), 135.43 (CH=CH2), 137.90 and 138.83
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Synlett 2006, No. 13, 2089–2093 © Thieme Stuttgart · New York