The Mechanism of Nucleophilic Substitution of 1-Alkyl-2-(tosyloxymethyl)- aziridines

Article abstract of DOI:10.1055/s-2003-45001

The stereochemical course of nucleophilic substitution of 1-alkyl-2-(tosyloxymethyl)aziridines has been elucidated by a study using a chiral substrate, which confirmed that no initial ring opening and subsequent ring closure occurred but that instead direct substitution at the exocyclic methylene function took place. Consequently, these N-alkylaziridines exhibit a totally different reactivity towards nucleophiles as compared to the corresponding activated aziridines with an electron-withdrawing group at nitrogen, which has important stereochemical implications.

Full text of DOI:10.1055/s-2003-45001

LETTER
271
The Mechanism of Nucleophilic Substitution of 1-Alkyl-2-(tosyloxymethyl)-
aziridines
N
ucleophilic Substitut
a
ion of 1-Alk
t
yl-2-(t
t
osylox
h
ymethyl)-az
i
i
ridinesas D’hooghe, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 8 October 2003
R
N
R
N
Abstract: The stereochemical course of nucleophilic substitution
of 1-alkyl-2-(tosyloxymethyl)aziridines has been elucidated by a
study using a chiral substrate, which confirmed that no initial ring
opening and subsequent ring closure occurred but that instead direct
substitution at the exocyclic methylene function took place. Conse-
quently, these N-alkylaziridines exhibit a totally different reactivity
towards nucleophiles as compared to the corresponding activated
aziridines with an electron-withdrawing group at nitrogen, which
has important stereochemical implications.
a
LG
Nu
b
1
2
a
Nu
LG = Leaving Group
Nu- = Nucleophile
b
Key words: 2-(bromomethyl)aziridines, nucleophilic substitution,
diastereoselectivity, nitrogen, heterocycles
R
R
N
N
Nu
LG
Nu
3
4
The chemistry of N-tosylaziridines has been explored ex-
tensively in the past.1 1-(Arenesulfonyl)-2-(tosyloxyme-
thyl)aziridines in particular constitute an interesting class
of compounds for further elaboration due to the inherent
reactivity of the constrained heterocycle and the exocyclic
methylene function connected to a good leaving group.2–7
It has already been demonstrated that these aziridines 1
(Scheme 1, R = arenesulfonyl or diphenylphosphinyl,
LG = Tos or diphenylphosphinyloxy ODpp) undergo at-
tack at the least substituted carbon atom of the aziridine
moiety upon reaction with organocuprate reagents.4 The
resulting ring opened intermediates 3 give further ring
closure by displacement of the tosylate or ODpp, furnish-
ing substituted aziridines 4 with the inverted stereochem-
istry as compared to the chirality of the starting aziridine
(Scheme 1, pathway b).4 A different and very promising,
but for the major part yet unexplored field of chemistry
concerns the reactivity of 1-alkylaziridines, functional-
ized at the 2-position with a methylene function connected
to a good leaving group. The absence of an electron-with-
drawing group at nitrogen makes the aziridine moiety less
susceptible towards nucleophiles than the N-(arenesulfo-
nyl) analogues or the corresponding aziridinium salts.
Athough in this case an opposite reactivity can be expect-
ed, no irrefutable proof has been provided up to now.
Therefore, a detailed study concerning the mechanistic
course of the substitution reaction of 1-alkylaziridines 1
urged itself, with particular interest in the stereochemistry
of the substitution product.
Scheme 1
As outlined in Scheme 1, two possible pathways can oc-
cur upon treatment of an aziridine such as 1 (R = alkyl and
LG = arenesulfonyl) with a nucleophile, resulting in ei-
ther an aziridine 2 with the same absolute configuration as
the starting material, or furnishing a substituted aziridine
4 in which the asymmetric carbon atom of the aziridine
ring has the opposite stereochemistry as compared to the
starting compound. In a third possibility both pathways
might be competitive, and a mixture of isomers 2 and 4
would then be formed. To unravel the yet unknown mech-
anism of nucleophilic substitution of 1-alkyl-2-(tosyl-
oxymethyl)aziridines and analogues, we applied a method
based on the comparison of the stereochemistry of an azir-
idine obtained via a substitution reaction with a structur-
ally analogous aziridine of known absolute configuration.
Thus we synthesized an easy accessible racemic aziridine
to evaluate the attainability of this concept, i.e. 1-tert-bu-
tyl-2-(hydroxymethyl)aziridine (6), prepared starting
from methyl acrylate (5), which was converted into meth-
yl (1-tert-butylaziridinyl)-2-carboxylate upon consecu-
tive bromination and aziridination with tert-butylamine
(Scheme 2).8 The reduction of the latter ester was per-
formed using LiAlH4, resulting in the desired alcohol 6 in
good yield.8 When compound 6 was subjected to a Will-
iamson ether synthesis using sodium hydride and io-
domethane in THF, the corresponding methyl ether 7 was
isolated in 90% yield as the single reaction product
(Scheme 2).9 In an alternative pathway, aziridine 6 was
easily tosylated with tosyl chloride in dichloromethane in
the presence of triethylamine and a catalytic amount of
DMAP. The tosylated aziridine 8, thus obtained, was
SYNLETT 2004, No. 2, pp 0271–0274
0
2.
0
2.
2
0
0
4
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-45001; Art ID: G27103ST
© Georg Thieme Verlag Stuttgart · New York

272
M. D’hooghe, N. De Kimpe
LETTER
smoothly converted into 2-(methoxymethyl)aziridine (7)
upon substitution with sodium methoxide in methanol
under reflux in 88% yield (Scheme 2).
N
The same procedures were applied to a similar but enan-
tiomerically pure and commercially available substrate,
i.e. (1R,2S)-1-(a-methylbenzyl)-2-(hydroxymethyl)aziri-
dine (9). In order to discriminate between the different
possible pathways in a nucleophilic substitution with an
aziridine such as 1 (Scheme 1), a substrate was chosen
that contains two chiral centers. Since only one of these
asymmetric carbon atoms might undergo inversion during
the reaction, the substituted product will either be identi-
cal to the reference compound, prepared from the sub-
strate, or a diastereomer of the reference aziridine. Thus,
reference compound 10 was synthesized from aziridine 9
by a Williamson ether synthesis with sodium hydride and
iodomethane in THF in 93% yield (Scheme 3, method a).
Parallel, the chiral aziridine 9 was tosylated with tosyl
chloride in dichloromethane in an excellent yield in the
presence of triethylamine and a catalytic amount of
DMAP, and subsequently subjected to a substitution with
sodium methoxide in methanol resulting in a single reac-
tion product 10 (Scheme 3, method b).10 To distinguish
between both possible pathways for the substitution reac-
tion (Scheme 1), the reference aziridine 10 and the substi-
tution product 10 were compared by means of different
techniques, and judged to be one and the same compound.
Ha
Hb
Hc
OMe
1.5 equiv NaH
1.1 equiv MeI
THF, ∆, 3 h
10
[α]D = +22.0 (c = 1, MeOH)
a
(93 %)
2.0 equiv NaOMe
MeOH (1N)
∆, 4 h
(91 %)
N
OH
b
9
1.05 equiv TosCl
1.1 equiv Et3N
0.1 equiv DMAP
CH2Cl2, 0 °C – r.t., 4 h
N
OTos
11 (98%)
[α]D = +7.5 (c = 1.2, MeOH)
Scheme 3
aziridine carbon atom as compared to the starting aziri-
dine and the reference compound. To confirm the stereo-
chemical identity of the substitution product and the
reference compound, the optical rotation of both com-
pounds was measured and identical values were obtained
{in both cases [a]D +22.0° (c 1, MeOH)}. As a supple-
mentary test, these two compounds were analyzed by gas
chromatography on a chiral column (CYDEX-B), result-
ing in identical retention times. When the mixture of both
compounds was injected, the chromatogram showed only
one single peak.
1
All spectroscopic data, i.e. H NMR, 13C NMR, IR and
MS were identical for both compounds. Furthermore,
chromatographic analysis resulted in identical retention
factors upon column chromatography (SiO2) and identical
retention times upon gas chromatography (HP-5MS).
These observations allowed to conclude that no diastere-
omer of the reference aziridine was formed during the
substitution reaction. In other words, no ring opening oc-
curred and the nucleophilic substitution proceeded via
pathway a (Scheme 1), furnishing a substitution product
with the same absolute configuration at the asymmetric
N
OMe
1.5 equiv NaH, THF
1.1 equiv MeI
∆, 2h
7
(90%)
1) Br2
2) Et3N
2 equiv. NaOMe,
MeOH (1N)
∆, 4 h
OMe
N
(88%)
OH
O
3) tert-BuNH2
4) LiAlH4
CH2Cl2
0° C – r.t., 3 h
6 (76 %)
5
1.1 equiv TosCl
1.1 equiv Et3N
N
OTos
0.1 equiv DMAP
8 (94%)
Scheme 2
Synlett 2004, No. 2, 271–274 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution of 1-Alkyl-2-(tosyloxymethyl)-aziridines
273
(5) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R. J.
Org. Chem. 1995, 60, 1959.
(6) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R.
Tetrahedron Lett. 1993, 34, 6677.
(7) Chiu, I. C.; Kohn, H. J. Org. Chem. 1983, 48, 2857.
(8) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1970, 35, 3424.
(9) The synthesis of 1-tert-butyl-2-(methoxymethyl)aziridine 7,
starting from1-tert-butyl-2-(tosyloxymethyl)aziridine 8, has
been reported in the past.8 This substitution was
The general applicability of this concept in organic syn-
thesis can be derived from the synthesis of some 2-
(alkoxymethyl)aziridines (13) in good yields, prepared
from 2-(bromomethyl)aziridines (12)11 upon treatment
with sodium alkoxides (Scheme 4). This methodology
offers an easy and efficient alternative for the procedure
developed by Deyrup.8
accomplished using methanolic sodium hydroxide (1 N)
upon a prolonged reaction time (2 d). The procedure
reported here with 2 equiv of sodium methoxide in MeOH
(1 N) was much more effective, resulting in the desired
compound in 88% yield after reflux for 4 h. Furthermore, the
reported 1H NMR data are partially incorrect and
1.2 – 5 equiv. NaOR2,
R2OH
R1
R1
N
N
Br
OR2
r.t. / ∆, 1 – 2 h
incomplete,8,12 and for that reason all obtained spectroscopic
data are mentioned here. Spectroscopic data of 1-tert-butyl-
2-(methoxymethyl)aziridine 7: 1H NMR (300 MHz, CDCl3):
d = 0.99 [9 H, s, (CH3)3C], 1.41 (1 H, d, J = 3.0 Hz, Hb), 1.57
(1 H, d, J = 6.3 Hz, Ha), 1.84–1.91 (1 H, m, Hc), 3.31 and
3.37 [2 H, 2 × d × d, J = 10.5, 5.6, 5.2 Hz, (HCH)O]; 3.38 (3
H, s, CH3O). 13C NMR (75 MHz, CDCl3): d = 24.94 (CH2N),
26.52 [(CH3)3C], 30.94 (CHN), 52.67 [(CH3)3C], 58.85
(CH3O), 75.58 (CH2O). IR (NaCl): nmax = 2970, 2930, 2875,
1364, 1110, 734 cm–1. MS (70 eV): m/z (%) = 144 (100)
[M+ + 1], 88(23). TLC: Rf = 0.40 (hexane/EtOAc 1:1).
(10) Method a: To an ice-cooled solution of (1R,2S)-1-(a-
methylbenzyl)-2-(hydroxymethyl)aziridine 9 (0.27 g, 1.5
mmol) in THF (2 mL) was added NaH (0.09 g, 1.5 equiv,
60% dispersion in mineral oil) and the mixture was stirred
for 30 min at r.t. Subsequently, MeI (0.23 g, 1.1 equiv) was
added dropwise to the ice-cooled reaction mixture, which
was then refluxed for 3 h. Extraction with Et2O (3 × 10 mL),
drying (MgSO4), filtration of the drying agent and removal
of the solvent in vacuo afforded (1R,2S)-1-(a-methylbenz-
yl)-2-(methoxymethyl)aziridine 10 (0.27 g, 93%).
12a (R1 = Ph)
13a (R1 = Ph, R2 = Me, 100%)
13b (R1 = Ph, R2 = Et, 81%)
13c (R1 = C(Me)2CH2Ph, R2 = Me, 96%)m
13d (R1 = tBu, R2 = Me, 72%)
13e (R1 = nPr, R2 = Me, 92%)
12b (R1 = C(Me)2CH2Ph)
12c (R1 = tBu)
12d (R1 = nPr)
Scheme 4
In conclusion, it has been demonstrated that 1-alkylaziri-
dines, functionalized at the 2-position with a methylene
function bound to a good leaving group, exhibit a different
reactivity towards nucleophiles than the corresponding 1-
(arenesulfonyl)aziridines. The former aziridines undergo
attack at the exocyclic methylene carbon atom with dis-
placement of the leaving group, instead of an initial ring
opening and subsequent ring closure due to attack at the
aziridine moiety. This implied that the stereochemistry of
the substituted aziridine carbon atom is retained through-
out the reaction. These preliminary results offer new
perspectives in targeted organic synthesis, and extensive
research in this area is currently in progress, about which
will be communicated in due course.
Method b: To a solution of (1R,2S)-1-(a-methylbenzyl)-2-
(tosyloxymethyl)aziridine 11 (0.50 g, 1.5 mmol) in MeOH
(2.25 mL), prepared from the commercially available
(1R,2S)-1-(a-methylbenzyl)-2-(hydroxymethyl)aziridine 9
via a standard tosylation reaction with 1.1 equiv TosCl, 1.1
equiv Et3N and 0.1 equiv DMAP in 98% yield, was added
sodium methoxide in MeOH (0.75 mL, 4 N in MeOH, 2
equiv) at r.t. and the reaction mixture was refluxed for 4 h.
Extraction with CH2Cl2 (3 × 10 mL), drying (MgSO4),
filtration of the drying agent and removal of the solvent in
vacuo afforded (1R,2S)-1-(a-methylbenzyl)-2-(methoxy-
methyl)aziridine 10 (0.26 g, 91%).
Acknowledgment
The authors are indebted to the Fund for Scientific Research-
Flanders (FWO-Vlaanderen) and to Ghent University (GOA
project) for financial support.
References
Spectroscopic data of (1R,2S)-1-(a-methylbenzyl)-2-
(methoxymethyl)aziridine 10: 1H NMR (300 MHz, CDCl3):
d = 1.43 (3 H, d, J = 6.6 Hz, CH3CH), 1.49 (1 H, d, J = 6.6
Hz, Ha), 1.63–1.70 (1 H, m, Hc), 1.86 (1 H, d, J = 3.6 Hz,
Hb), 2.49 (1 H, q, J = 6.6 Hz, CHMe), 3.18 (3 H, s, CH3O),
3.24 and 3.38 [2 H, 2 × d × d, J = 10.6, 5.8, 5.2 Hz,
(HCH)O], 7.22–7.39 (5 H, m, C6H5). 13C NMR (75 MHz,
CDCl3): d = 23.15 (CH2N), 32.07 (CHc), 37.45 (CH3CH),
58.44 (CH3O), 69.80 (CHMe), 74.03 (CH2O), 126.75 (Cpara),
127.02 and 128.28 (2 × Cortho and 2 × Cmeta), 144.49 (Cquat).
IR (NaCl): nmax = 2977, 2927, 1494, 1450, 1109, 701 cm-1.
MS (70 eV): m/z (%) = 191 (1) [M+], 176 (3), 146 (100), 118
(8), 105 (79), 104 (11), 103 (13), 91 (16), 86 (40), 79 (13),
77 (20). [a]D +22.0 (c 1, MeOH). TLC: Rf = 0.28 (hexane/
EtOAc 1/1). Anal. Calcd for C12H17NO: C, 75.35; H, 8.96;
N, 7.32. Found: C, 75.47; H, 9.11; N, 7.20.
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A.; Woolhouse, A. D. In Comprehensive Heterocyclic
Chemistry, Vol. 7; Katritzky, A. R.; Rees, C. W.; Lwowski,
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E. C.; Hassner, A., Eds.; Wiley: New York, 1983, 11–83.
(c) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
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Spectroscopic data of (1R,2S)-1-(a-methylbenzyl)-2-
(tosyloxymethyl)aziridine 11: 1H NMR (300 MHz, CDCl3):
Synlett 2004, No. 2, 271–274 © Thieme Stuttgart · New York

274
M. D’hooghe, N. De Kimpe
LETTER
d = 1.37 (3 H, d, J = 6.6 Hz, CH3CH), 1.52 (1 H, d, J = 6.3
Hz, Ha), 1.66–1.73 (1 H, m, Hc), 1.79 (1 H, d, J = 3.3 Hz,
Hb), 2.43 (3 H, s, CH3Ar), 2.48 (1 H, q, J = 6.6 Hz, CHMe),
3.84 and 3.93 [2 H, 2 × d × d, J = 10.7, 6.2, 6.1 Hz,
(HCH)O], 7.22–7.36 and 7.63–7.66 (7 H and 2 H, 2 × m,
CHarom). 13C NMR (75 MHz, CDCl3): d = 21.74 (CH3Ar),
23.37 (CH2N), 32.33 (CHc), 35.95 (CH3CH), 69.43 (CHMe),
72.17 (CH2O), 126.67, 127.28, 127.98, 128.47 and 129.86
[CH(Me)CHpara, 4 × Cortho and 4 × Cmeta], 133.06 (CCH3),
144.09 and 144.78 (2 × Cquat). IR (NaCl): nmax = 3061, 3030,
2972, 2927, 2869, 1599, 1494, 1450, 1363, 958 cm–1. MS
(70 eV): m/z (%) = 331 (1) [M+], 316 (8), 226 (11), 176 (3),
160 (10), 144 (8), 105 (100), 91 (27), 79 (9), 77 (13), 55 (10).
[a]D +7.5 (c 1.2, MeOH). TLC: Rf = 0.36 (hexane/EtOAc
1:1).
(11) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem.
Commun. 1994, 1221.
(12) Gaertner, V. R. J. Org. Chem. 1970, 35, 3952.
Synlett 2004, No. 2, 271–274 © Thieme Stuttgart · New York