Synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates as amino acid building blocks

Article abstract of DOI:10.1016/j.tetlet.2008.09.119

A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates was developed involving amination, bromination, and base-induced cyclization of alkyl 2-(bromomethyl)acrylates. These new small ring azaheterocyclic α- and β-amino acid derivatives are promising synthons as demonstrated by their transformation to 2-(aminomethyl)aziridine-2-carboxylates and 3-aminoazetidine-3-carboxylates.

Full text of DOI:10.1016/j.tetlet.2008.09.119

Tetrahedron Letters 49 (2008) 6896–6900
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl
3-bromoazetidine-3-carboxylates as amino acid building blocks
b
b
b
a,
*
Sven Mangelinckx a, , Asta Zukauskaite , Vida Buinauskaite , Algirdas Šackus , Norbert De Kimpe
ˇ
ˇ
˙
˙
a Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Department of Organic Chemistry, Faculty of Chemical Technology, Kaunas University of Technology, Radvilenu pl.19, LT-50270 Kaunas, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-car-
boxylates was developed involving amination, bromination, and base-induced cyclization of alkyl 2-(bro-
momethyl)acrylates. These new small ring azaheterocyclic a- and b-amino acid derivatives are promising
synthons as demonstrated by their transformation to 2-(aminomethyl)aziridine-2-carboxylates and
3-aminoazetidine-3-carboxylates.
Received 16 August 2008
Revised 16 September 2008
Accepted 17 September 2008
Available online 23 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine-2-carboxylates
Azetidine-3-carboxylates
Ring closure
2-(Bromomethyl)aziridines
3-Bromoazetidines
Aziridine-2-carboxylic acid derivatives are biologically and syn-
thetically important amino acid derivatives useful for the prepara-
tion of proteinogenic, non-proteinogenic amino acids, and a variety
of biologically active nitrogen-containing compounds, due to the
fact that these strained heterocycles undergo regio- and stereo-
selective ring opening reactions with nucleophiles.1 On the other
hand, derivatives of azetidine-3-carboxylic acid disclose gameto-
cidal activity,2 and have been used for the preparation of a variety
of pharmaceutically active compounds.3 In view of the biological
and synthetic importance of the aforementioned classes of amino
acids and the continuous need of new lead compounds in agro-
chemical and pharmaceutical industry, the synthesis of new three-
carboxylate or azetidine-3-carboxylate moiety as well as the syn-
thetically important 2-(halomethyl)aziridine or 3-haloazetidine
structural feature. To the best of our knowledge, if trifluorinated
derivatives are excluded, only one report has been published on
the synthesis of related alkyl 2-(halomethyl)aziridine-2-carboxyl-
ates, that is, substituted dialkyl 2-(bromomethyl)aziridine-1,2-
dicarboxylates obtained via addition of diazomethane across
N-protected b-bromo
a
-imino acids.7 1,2,2,4-Tetrasubstituted
3-bromo- and 3-chloroazetidine-3-carboxylic esters have been
prepared via reaction of azomethine ylides derived from aziridines
with sulfur ylides,8 and more interestingly, ring opening of tert-
butyl 1-azabicyclo[1.1.0]butane-3-carboxylate, obtained from the
unstable tert-butyl 1-chloroazetidine-3-carboxylate, with p-tolu-
enesulfonyl chloride resulted in the synthesis of tert-butyl
3-chloro-1-(p-toluenesulfonyl)azetidine-3-carboxylate.9 However,
no further reactivity studies were performed on these aziridines
or azetidines.
and four-membered azaheterocyclic
a- and b-amino acid deriva-
tives is an important research field in modern synthetic chemistry.
As broadly demonstrated by our research group and others, the
presence of a halogenated carbon atom and ring strain in 2-
(halomethyl)aziridines,4,5 and in the related isomeric 3-haloazeti-
dines,5a,6 allows synthetic elaboration of these azaheterocycles
via nucleophilic displacement reactions, ring opening reactions,
and ring transformations. In the present Letter, results are de-
scribed on the synthesis of alkyl 2-(bromomethyl)aziridine-2-car-
boxylates and alkyl 3-bromoazetidine-3-carboxylates, as new
promising azaheterocyclic amino acid derivatives, the structures
of which incorporate the biologically interesting aziridine-2-
Allylamines are suitable substrates for the synthesis of 2-(bro-
momethyl)aziridines and/or 3-bromoazetidines via bromination
to the corresponding b,c-dibromo amines followed by intramole-
cular ring closure,4a–c,10 or via electrophile-induced bromocycliza-
tion.11 This ring closure usually has high selectivity toward the
formation of aziridines instead of azetidines. N-Substituted alkyl
2-(aminomethyl)acrylates are useful functionalized allylamines,
used as monomers for anionic polymerization,12 in case of N-
acyl-substituted derivatives for iodocyclization to the correspond-
ing dihydro-1,3-oxazoles as intermediates in the synthesis of func-
tionalized analogues of N-benzoyl-syn-phenylisoserine,13 and for
* Corresponding author. Tel.: +32 9 264 59 51; fax: +32 9 264 62 43.
E-mail address: norbert.dekimpe@UGent.be (N. De Kimpe).
Postdoctoral Fellow of the Research Foundation—Flanders (FWO).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.119

S. Mangelinckx et al. / Tetrahedron Letters 49 (2008) 6896–6900
6897
the synthesis of b-lactams.14 It was envisaged that the hitherto
Table 2
Bromination of alkyl 2-(aminomethyl)acrylates 2
unreported bromocyclization or bromination of N-substituted
alkyl 2-(aminomethyl)acrylates could provide a convenient entry
toward alkyl 2-(bromomethyl)aziridine-2-carboxylates 6 and alkyl
3-bromoazetidine-3-carboxylates 7.
NHR2
NHR2.HBr
Br
COOR1
NHR2
Br
Br2
or
Br
Br
COOR1
COOR1
(see table)
The synthesis of alkyl 2-(aminomethyl)acrylates 2a–f via sub-
stitution reactions of alkyl 2-(bromomethyl)acrylates 1 with pri-
mary amines was performed under optimized conditions adapted
from literature procedures (Table 1).12,15 Addition of alkyl
2-(bromomethyl)acrylates 1 to 1.02 equiv of primary amine and
1.04 equiv of triethylamine in dichloromethane at 0 °C afforded
ethyl and methyl 2-[(alkylamino)methyl]acrylates 2a–d,f in good
yields (Table 1, entries 1–4 and 6),16 or diesters 3b–c in moderate
yields resulting from undesired N,N-diallylation of the less steri-
cally demanding amines (Table 1, entries 7 and 8). The synthesis
of ethyl 2-[(tosylamino)methyl]acrylate 2e, in which an electron-
withdrawing group is present on nitrogen, was achieved in moder-
ate yield together with the formation of diallylation compound 3a,
through reaction of 2-(bromomethyl)acrylate 1a with p-toluene-
sulfonamide in the presence of 1,4-diazabicyclo[2.2.2]octane
(DABCO) (Table 1, entry 5).
2a-e
4a-c
(84 - 98%)
5a-e
(57 - 98%)
Entry
R1
R2
Reaction time
Result (%)
1
2
3
4
5
6
7
8
Et
Et
Me
Et
Et
Me
Me
Et
t-Bu
t-Amyl
t-Bu
t-Bu
t-Amyl
t-Bu
4 h
14 h
4 h
14 h
14 h
6 h
4a (98)a
4b (86)a
4c (84)a
5a (98)b
5b (97)b
5c (78)b
5d (61)b
5e (57)c
t-Amyl
p-Tos
5 h
4.5 h
a
Reaction conditions: (1) 1.1 equiv HBr, CH2Cl2/H2O, 30 min, 0 °C; (2) 1 equiv
Br2, CH2Cl2, 4–14 h, rt.
b
Reaction conditions: (1) 1.1 equiv HBr, CH2Cl2/H2O, 30 min, 0 °C; (2) 1 equiv
Br2, CH2Cl2, 5–14 h, rt; (3) NaHCO3, EtOAc.
c
Reaction conditions: 1.1 equiv Br2, CH2Cl2, 4.5 h, rt.
Inspired by the aforementioned iodocyclization reaction,13
ethyl 2-[(tert-butylamino)methyl]acrylate 2a was treated with
NBS in chloroform at room temperature, which, unfortunately,
led to a complex reaction mixture. Alternatively, following a typi-
cal procedure for the bromination of allylamines,17 the amino
group of alkyl acrylates 2a–c was protected by treatment with
aqueous hydrobromic acid in dichloromethane to the correspond-
ing hydrobromide salts which were subsequently reacted with
bromine. Bromination at room temperature for 4–14 h efficiently
afforded the desired hydrobromide salts 4a–c in 84–98% yield (Ta-
ble 2, entries 1–3).18 These hydrobromide salts 4 could be spectro-
scopically characterized from the crude reaction mixtures, but they
are hygroscopic, unstable, and bromine elimination was observed
upon heating. In order to obtain more stable reaction products,
the bromination was followed by neutralization of the reaction
mixture with NaHCO3 efficiently affording the desired dibromo-
propanoates 5a–d (entries 4–7).19 Bromination of ethyl 2-[(tosyl-
amino)methyl]acrylate 2f proceeded uneventfully using 1.1 equiv
of bromine in dichloromethane and afforded ethyl dibromopro-
panoate 5e in 57% yield (entry 8). With the targeted dibromo
amino esters 4 and 5 in hand, their ring closure was studied under
different basic conditions (Table 3).
only neutralization to 5a was achieved at room temperature (entry
2), while azetidine 7a could be isolated in 32% yield when the reac-
tion was done under reflux for 24 h (entry 3). The use of Hunig’s
base in acetonitrile under reflux resulted in cyclization of hydro-
bromide salts 4a and 4b allowing the isolation of azetidine 7a after
a reaction time of 4 h (entry 4), and neutralized amine 5b, aziridine
6b and azetidine 7b in low yields after a shorter reaction time (en-
try 5). In view of the moderate results obtained with the hydrobro-
mide salts 4, further optimization of the reaction conditions was
performed on the free dibromo amines 5. The use of harsher reac-
tion conditions (K2CO3, iPrOH, heat or tBuOK, THF, heat) resulted in
decomposition of dibromo amine 5a (entries 6 and 7), while a
clean conversion of dibromo amines 5 was possible under milder
conditions with K2CO3 in acetone or acetonitrile (entries 8–16). A
complete conversion to the aziridines 6 as major products together
with the azetidines 7 as minor compounds was achieved by exten-
sion of the reaction time and by the use of 1.5 equiv of K2CO3 in
acetonitrile at 60 °C. However, the isolated yields of the aziridines
6 and azetidines 7 were low after purification by column chroma-
tography on silica gel as, apparently, these azaheterocycles partly
decompose on column. To our satisfaction, acceptable isolated
yields of the targeted aziridines 6a–d (36–54%) and azetidines
7a–d (17–26%) were obtained via separation by preparative TLC
up to 1 g scale (entries 12–15).20 Interestingly, reaction of the dib-
romopropanoate 5e with an electron-withdrawing substituent
(R2 = p-Tos) on nitrogen resulted in the very efficient and selective
cyclization to aziridine 6e (95% yield, entry 16).
Initial cyclizations were performed on the hydrobromide salts 4
with excess of base. Upon using rather apolar conditions (Et3N,
CH2Cl2) no cyclization of 4a was observed and only the neutralized
amine 5a was isolated (entry 1). In a polar system (KOH, THF/H2O),
Table 1
An attempt was also made to perform the bromination and
cyclization in a one-pot reaction. Bromination of ethyl 2-[(1-
phenylethylamino)methyl]acrylate 2f was executed using the
aforementioned conditions after which dichloromethane was
evaporated and replaced by acetonitrile. Upon adding 2.5 equiv
of K2CO3, a selective cyclization of the intermediate hydrobromide
salt 4f to the aziridines 6f, as an inseparable mixture of diastereo-
mers, occurred without difficulties, resulting in an excellent overall
isolated yield of 81% (Scheme 1). It is worth mentioning that from
the dibromopropanoates 4f and 5e with a sterically demanding
substituent (R2 = PhMeCH) or an electron-withdrawing substituent
(R2 = p-Tos), only the corresponding aziridines 6 were formed in
excellent yields (see Table 3, entry 16 and Scheme 1). This might
be explained by the fact that aziridines 6 are the kinetic cyclization
products, while azetidines 7 result from a thermodynamical equil-
ibration. The isomerization of 2-(halomethyl)aziridines to 3-halo-
azetidines, although only observed in some cases, was explained
Synthesis of alkyl 2-(aminomethyl)acrylates 2
NHR2
R1OOC
+
R2 COOR1
N
R2NH2
Br
COOR1
COOR1
base, CH2Cl2
(see table)
1a-b
2a-f (31 - 97%)
3a-c (42 - 50%)
Entry
R1
R2
Reaction time
Result (%)
1
2
3
4
5
6
7
8
Et
Et
Me
Me
Et
Et
Et
Et
t-Bu
t-Amyl
t-Bu
t-Amyl
p-Tos
PhMeCH
n-Bu
30 min
30 min
30 min
30 min
2 h
1 h
30 min
30 min
2a (97)a
2b (91)a
2c (80)a
2d (91)a
2e (31)b + 3a (50)b
2f (76)a
3b (42)a
Bn
3c (46)a
Reaction conditions: 1.02 equiv R2NH2, 1.04 equiv Et3N, CH2Cl2, 0 °C.
Reaction conditions: 1.2 equiv p-TosNH2, 1.33 equiv DABCO, CH2Cl2, rt.
a
b

6898
S. Mangelinckx et al. / Tetrahedron Letters 49 (2008) 6896–6900
Table 3
Optimization of the ring closure reactions of alkyl 2-[(amino)methyl]-2,3-dibromopropanoates 4 and 5
R2
N
R2
NHR2.HBr
Br
NHR2
Br
base
N
or
+
+
5a-b
Br
COOR1
Br
Br
COOR1
(see table)
COOR1
COOR1
Br
7a-d (0-32%)
4a-b
5a-e
(0-76%)
6a-e (0-95%)
Entry
Substrate
R1
R2
Reaction conditions
3 equiv Et3N, CH2Cl2,
2 equiv KOH, THF/H2O 1/1, r.t., 20 h
2 equiv KOH, THF/H2O 1/1, , 24 h
2.5 equiv iPr2NEt, CH3CN,
2.5 equiv iPr2NEt, CH3CN,
1 equiv K2CO3, i-PrOH, 60 °C, 48 h
1 equiv t-BuOK, THF, 40 °C, 4 h + 55 °C, 3 h
1 equiv K2CO3, acetone, , 18 h
1 equiv K2CO3, CH3CN, 60 °C, 2 h
1.5 equiv K2CO3, acetone, , 39 h
1.5 equiv K2CO3, CH3CN, 60 °C, 19 h
1.5 equiv K2CO3, CH3CN, 60 °C, 19 h
1.5 equiv K2CO3, CH3CN, 60 °C, 12 h
1.5 equiv K2CO3, CH3CN, 60 °C, 8 h
1.5 equiv K2CO3, CH3CN, 60 °C, 18 h
1.5 equiv K2CO3, CH3CN, 60 °C, 1 h
Result (%)a,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4a
4a
4a
4b
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Amyl
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Amyl
t-Bu
D
, 6 d
5a (76)
5a (not isolated)
7a (32)
6a (not isolated)/7a (22) 1:1.3
5b (30)/6b (15)/7b (8)
full decomposition of 5a
partial decomposition of 5a
5a/6a/7a 1:4.3:2.5
5a/6a/7a 1:4:2.1
6a (7)/7a (11)
D
D
, 4 h
D
, 45 min
D
D
6a (19)/7a (13)
6a (36)c/7a (26)c
6b (54)c/7b (24)c
6c (41)c/7c (17)c
6d (54)c/7d (26)c
6e (95)c
t-Amyl
p-Tos
a
Parentheses indicate isolated yields after purification by column chromatography.
Ratio of reaction products determined via 1H NMR (CDCl3, 300 MHz) analysis of the crude reaction mixtures.
Parentheses indicate isolated yields after purification by preparative TLC.
b
c
Me
Ph
NH
1) 1.1 equiv HBr
CH2Cl2/H2O
Me
Ph
NH .
Me
Ph
2.5 equiv
K2CO3
30 min, 0 oC
HBr
N
Br
COOEt
6f (81%, d.r. = 53:47)
Br
COOEt
CH3CN
2 h, 60 oC
Br
2) 1 equiv Br2
CH2Cl2, 3 h, r.t.
COOEt
2f
4f
Scheme 1.
via ionization to the corresponding carbenium ion, followed by ra-
pid isomerization to a bicyclic azonia[1.1.0]bicyclobutane interme-
diate and recombination with the initially expelled halide to give
3-haloazetidines or 2-(halomethyl)aziridines.5a In the assumption
that a strained bicyclic ion is involved in the formation of alkyl
3-bromoazetidine-3-carboxylates 7, a sterically demanding or
electron-withdrawing group at nitrogen destabilizes this bicyclic
ion and therefore stabilizes the initially formed alkyl 2-(bromo-
methyl)aziridine-2-carboxylates 6. Experimental support for this
slow isomerization process was obtained by heating ethyl 1-t-
butyl-2-(bromomethyl)aziridine-2-carboxylate 6a under different
conditions. Heating aziridine 6a in acetonitrile at 60 °C for 3 h gave
no reaction, while prolonged heating in acetonitrile in the presence
of 1 equiv of KBr at 60 °C resulted in decomposition to unidentified
compounds after 24 h. Nevertheless, a rather clean isomerization
of aziridine 6a to azetidine 7a was observed upon heating in
DMSO, giving a mixture of 6a and 7a in a 2:1 ratio (1H NMR anal-
ysis) after 24 h at 55 °C. The latter mixture further isomerized to 6a
and 7a in a 1:2.8 ratio after additional heating at 65 °C for 6 h.
Introduction of new functional groups in aziridines 6 and azeti-
dines 7 would highly enrich the chemistry of these important clas-
attempts to prepare ethyl 2-(azidomethyl)-1-tosylaziridine-2-car-
boxylate under similar conditions (1.1–6 equiv NaN3, DMSO, 3–
72 h, 60 °C) as in the synthesis of aziridines 8a,b,d, by reaction of
N-tosylaziridine 6e failed, leading to inseparable mixtures of azido
compounds resulting from ring opening and substitution, similar
as to the reported failure to synthesize 2-(azidomethyl)-1-tosyl-
aziridine from 1-tosyl-2-(bromomethyl)aziridine.4d Using simple
hydrogenolysis, ethyl 1-tert-pentyl-2-(azidomethyl)aziridine-2-
carboxylate 8b and 1-tert-butyl-3-azidoazetidine-3-carboxylate
9a were converted into the corresponding ethyl 2-(amino-
methyl)aziridine-2-carboxylate 10b and 3-aminoazetidine-3-
carboxylate 11a upon stirring the reaction mixture in ethanol
under hydrogen atmosphere for 3 h in the presence of Pd/C catalyst
at room temperature.22,23 The only reported alkyl 2-(amino-
methyl)aziridine-2-carboxylate entails the N-phthalimidoaziridine
formed via aziridination of methyl 2-[(p-tosylamino)(phenyl)-
methyl]acrylate with N-aminophthalimide.24 N-substituted 3-
aminoazetidine-3-carboxylic acid derivatives are important for
the synthesis of series of active compounds used in SAR, as exem-
plified for EGF receptor tyrosine kinase inhibitors,25 CB1 receptor
antagonists,26 and modulators of the NMDA receptor complex.27
3-Aminoazetidines have been frequently investigated also as anti-
bacterial agents.28
ses of
a- and b-amino acid derivatives as the combination of a
strained ring, functional group, and ester function in the same
molecule could provide access to a broad variety of highly func-
tionalized aziridines and azetidines with a wide range of potential
biological and synthetic applications. Alkyl 2-(azidomethyl)aziri-
dine-2-carboxylates 8a,b,d and 3-azidoazetidine-3-carboxylates
9a–c were prepared in good to excellent yield by reaction with
2 equiv of sodium azide in DMSO at 60 °C (Scheme 2).6a,21 All
In conclusion, several alkyl 2-(bromomethyl)aziridine-2-car-
boxylates and alkyl 3-bromoazetidine-3-carboxylates were syn-
thesized via an unreported stepwise bromocyclization strategy
on alkyl 2-(aminomethyl)acrylates. These novel strained azahet-
erocyclic
a- and b-amino acid derivatives constitute promising
amino acid building blocks as demonstrated by their conversion

S. Mangelinckx et al. / Tetrahedron Letters 49 (2008) 6896–6900
6899
R2
N
R2
t
-Amyl
N
Pd/C, H2
2 equiv NaN3
N
Br
N3
NH2
COOEt
COOR1
COOR1
DMSO
1.5 - 4.5 h, 60 ˚C
EtOH, 3 h, r.t.
R1 = Et
R2 =
t-Amyl
6a,b,d
8a,b,d (58 - 82%)
10b (68%)
R2
N
R2
N
t
-Bu
N
2 equiv NaN3
Pd/C, H2
DMSO
3 h, 60 ˚C
Br
COOR1
7a-c
N3 COOR1
EtOH, 3 h, r.t.
R1 = Et
R2 =
t-Bu
H2N COOEt
9a-c (79-86%)
11a (78%)
Scheme 2.
16. Methyl 2-[(tert-pentylamino)methyl]acrylate 2d. Yellow oil, yield 91%,
Rf = 0.50 (petroleum ether/EtOAc 7:3). 1H NMR (300 MHz, CDCl3): d 0.86 (3H,
t, J = 7.43 Hz, CH2CH3), 1.07 (6H, s, C(CH3)2), 1.44 (2H, q, J = 7.43 Hz, CH2CH3),
3.35 (2H, s, CH2NH), 3.77 (3H, s, OCH3), 5.81 (1H, d  t, J = 1.65 Hz, 1.38 Hz,
C@CH(H)), 6.23 (1H, d, J = 1.38 Hz, C@CH(H)). 13C NMR (75 MHz, CDCl3): d 8.3,
into alkyl 2-(aminomethyl)aziridine-2-carboxylates and alkyl 3-
aminoazetidine-3-carboxylates with potential biological activities.
Acknowledgments
26.7, 33.2, 43.2, 51.9, 52.8, 125.7, 139.9, 167.5. IR (neat, cmÀ1):
m
NH = 3336
(weak),
100).
mC@O = 1718, m
C@C = 1634. MS (ES, pos. mode): m/z (%): 186 (M+H+,
The authors are indebted to the ‘Fund for Scientific Research-
Flanders (Belgium)’ (FWO-Vlaanderen) and to Ghent University
(GOA) for financial support of this research.
17. De Smaele, D.; Dejaegher, Y.; Duvey, G.; De Kimpe, N. Tetrahedron Lett. 2001,
42, 2373–2375.
18. Ethyl 2,3-dibromo-2-[(tert-butylamino)methyl]propanoate hydrobromide salt
4a. Yield 98%, orange viscous oil. 1H NMR (300 MHz, CDCl3): d 1.38 (3H, t,
J = 7.15 Hz, CH2CH3), 1.67 (9H, s, C(CH3)3), 3.72–3.91 (2H, m, NCH2), 4.30 (1H, d,
J = 11.01 Hz, CH(H)Br), 4.52 (1H, d, J = 11.01 Hz, CH(H)Br), 4.35–4.45 (2H, m,
OCH2), 8.94 (2H, br s, NHÁHBr). 13C NMR (75 MHz, CDCl3): d 13.9, 26.4, 34.6,
References and notes
1. (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Mini-Rev. Med. Chem. 2006, 6, 293–
304; (b) Lee, W. K.; Ha, H. J. Aldrichim. Acta 2003, 36, 57–63; (c) Cardillo, G.;
Gentilucci, L.; Tolomelli, A. Aldrichim. Acta 2003, 36, 39–50; (d) Zhou, P.; Chen,
B.-C.; Davis, F. A. Asymmetric Syntheses with Aziridinecarboxylate and
Aziridinephosphonate Building Blocks. In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006; pp 73–115. Chapter 3.
2. (a) Zhang, X.-H.; Takagi, H.; Widholm, J. M. Plant Cell Rep. 2004, 22, 615–622;
(b) Verbrugge, P. A.; DeWaal, J. U. S. Chem. Abstr. 1989, 111, 57527; (c) Orr, A. F.;
Clifford, D. R. Chem. Abstr. 1985, 103, 71181. Brit. UK Pat. Appl. 1984; (d) Devlin,
B. R. Chem. Abstr. 1981, 95, 168969. J. Eur. Pat. Appl. 1981.
47.1, 53.0, 61.9, 64.3, 167.6. IR (NaCl, cmÀ1):
mNH = 3408, mC@O = 1732. MS (ES,
pos. mode): m/z (%): 344/346/348 (MÀHBr+H+, 75).
19. Ethyl 2-((tert-pentylamino)methyl)-2,3-dibromopropanoate 5b. Colorless oil,
yield 97%, Rf = 0.71 (CH2Cl2). 1H NMR (300 MHz, CDCl3): d 0.86 (3H, t, J = 7.4 Hz,
CCH2CH3), 1.04 (3H, s, CCH3(CH3)), 1.05 (3H, s, CCH3(CH3)), 1.34 (3H, t,
J = 7.15 Hz, OCH2CH3), 1.40 (2H, q, J = 7.3 Hz, CCH2CH3), 3.15 (1H, d,
J = 13.76 Hz, NCH(H)), 3.20 (1H, d, J = 13.76 Hz, NCH(H)), 4.06 (1H, d,
J = 9.63 Hz, CBrH(H)), 4.22 (1H, d, J = 9.63 Hz, CBrH(H)), 4.28 (1H, d  q,
J = 7.15 Hz, 10.66 Hz, OCH(H)), 4.32 (1H, d  q, J = 7.15 Hz, 10.73 Hz,
OCH(H)). 13C NMR (75 MHz, CDCl3): d 8.2, 13.9, 26.8, 27.0, 33.6, 34.4, 45.9,
3. Miller, R. A.; Lang, F.; Marcune, B.; Zewge, D.; Song, Z. J.; Karady, S. Synth.
Commun. 2003, 33, 3347–3353.
52.4, 62.4, 62.7, 168.2. IR (NaCl, cmÀ1
pos. mode): m/z (%): 358/360/362 (M+H+, 100).
) mNH = 3327 (weak), mC@O = 1742. MS (ES,
4. (a) Abbaspour Tehrani, K.; Nguyen Van, T.; Karikomi, M.; Rottiers, M.; De
Kimpe, N. Tetrahedron 2002, 58, 7145–7152; (b) De Smaele, D.; Bogaert, P.; De
Kimpe, N. Tetrahedron Lett. 1998, 39, 9797–9800; (c) De Kimpe, N.; De Smaele,
D.; Szakonyi, Z. J. Org. Chem. 1997, 62, 2448–2452; (d) D’hooghe, M.; Rottiers,
M.; Kerkaert, I.; De Kimpe, N. Tetrahedron 2005, 61, 8746–8751; (e) D’hooghe,
M.; De Kimpe, N. Chem. Commun. 2007, 1275–1277; (f) D’hooghe, M.; Vervisch,
K.; De Kimpe, N. J. Org. Chem. 2007, 72, 7329–7332; (g) D’hooghe, M.; Van
Nieuwenhove, A.; Van Brabandt, W.; Rottiers, M.; De Kimpe, N. Tetrahedron
2008, 64, 1064–1070; (h) D’hooghe, M.; De Kimpe, N. ARKIVOC 2008, ix, 6–19;
(i) Karikomi, M.; D’hooghe, M.; Verniest, G.; De Kimpe, N. Org. Biomol. Chem.
2008, 6, 1902–1904.
5. (a) Gaertner, V. R. J. Org. Chem. 1970, 35, 3952–3959; (b) Sheikha, G. A.; La Colla,
P.; Loi, A. G. Nucleosides, Nucleotides Nucleic Acids 2002, 21, 619–635; (c)
Gensler, W. J.; Rockett, J. C. J. Am. Chem. Soc. 1955, 77, 3262–3264; (d) Gensler,
W. J.; Koehler, W. R. J. Org. Chem. 1962, 27, 2754–2762; (e) Gensler, W. J.; Dheer,
S. K. J. Org. Chem. 1981, 46, 4051–4057; (f) Pak, C. S.; Kim, T. H.; Ha, S. J. J. Org.
Chem. 1998, 62, 10006–10010; (g) Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2004, 43, 3952–3954; (h) Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi, T.
Angew. Chem., Int. Ed. 2001, 40, 3865–3867; (i) Kitagawa, O.; Miyaji, S.; Yamada,
Y.; Fujiwara, H.; Taguchi, T. J. Org. Chem. 2003, 68, 3184–3189.
20. Synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates 6 and alkyl 3-
bromoazetidine-3-carboxylates 7. As a representative example, the synthesis
of methyl 1-tert-pentyl-2-(bromomethyl)aziridine-2-carboxylate 6d and
methyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate 7d is described here.
To a solution of methyl 2-[(tert-pentylamino)methyl]-2,3-dibromopropanoate
5d (618 mg, 1.79 mmol, 1 equiv) in CH3CN (30 mL) was added powdered K2CO3
(371 mg, 2.69 mmol, 1.5 equiv) and the reaction mixture was stirred at 60 °C
for 18 h. Then the solvent was removed under reduced pressure and Et2O
(30 mL) was added. The resulting solution was filtered and the filter cake was
washed with small portions of Et2O. Evaporation of the solvent under reduced
pressure and purification by preparative TLC on silica gel (petroleum ether/
Et2O 7:3) afforded analytically pure samples. Methyl 1-tert-pentyl-2-
(bromomethyl)aziridine-2-carboxylate 6d. Light yellow oil, yield 54%,
Rf = 0.48 (petroleum ether/Et2O 7:3). 1H NMR (300 MHz, CDCl3): d 0.90 (3H,
t, J = 7.60 Hz, CH2CH3), 0.94 (3H, s, CCH3), 0.96 (3H, s, CCH3), 1.36–1.58 (2H, m,
CH2CH3), 1.85 (1H, s, NCH(H)), 2.59 (1H, s, NCH(H)), 3.05 (1H, d, J = 9.91 Hz,
BrCH(H)), 3.77 (3H, s, OCH3), 4.07 (1H, d, J = 10.18 Hz, BrCH(H)). 13C NMR
(75 MHz, CDCl3): d 8.8, 24.1, 24.4, 33.9, 36.5, 36.9, 44.3, 52.7, 57.4, 170.4. IR
(neat, cmÀ1): C@O = 1732. MS (ES, pos. mode): m/z (%): 264/266 (M+H+, 100).
m
Methyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate 7d. Yellow oil, yield
26%, Rf = 0.31 (petroleum ether/Et2O 7:3). 1H NMR (300 MHz, CDCl3): d 0.83
(3H, t, J = 7.43 Hz, CH2CH3), 0.88 (6H, s, C(CH3)2), 1.24 (2H, q, J = 7.43 Hz,
CH2CH3), 3.59–3.62 (2H, m, CH(H)NCH(H)), 3.83 (3H, s, OCH3), 3.89–3.92 (2H,
m, CH(H)NCH(H)). 13C NMR (75 MHz, CDCl3): d 8.6, 20.1, 31.6, 45.3, 53.4, 54.8,
6. (a) Van Driessche, B.; Van Brabandt, W.; D’hooghe, M.; Dejaegher, Y.; De Kimpe,
N. Tetrahedron 2006, 62, 6882–6892; (b) Gaertner, V. R. Tetrahedron Lett. 1968,
5919–5922.
7. Danion-Bougot, R.; Danion, D.; Francis, G. Tetrahedron Lett. 1990, 31, 3739–
3742.
59.5, 171.0. IR (neat, cmÀ1):
(M+H+, 100).
mC@O = 1742. MS (ES, pos. mode): m/z (%): 264/266
8. Vaultier, M.; Danion-Bougot, R.; Danion, D.; Hamelin, J.; Carrié, R. J. Org. Chem.
1975, 40, 2990–2992.
21. Ethyl 1-tert-butyl-2-(azidomethyl)aziridine-2-carboxylate 8a. Yellow oil, yield
58%, Rf = 0.47 (petroleum ether/EtOAc 8:2). 1H NMR (300 MHz, CDCl3): d 1.09
(9H, s, C(CH3)3), 1.33 (3H, t, J = 7.15 Hz, CH2CH3), 1.88 (1H, d, J = 1.65 Hz,
NCH(H)), 2.47–2.48 (1H, m, NCH(H)), 3.26 (1H, d, J = 12.66 Hz, CH(H)N3), 3.68
(1H, d, J = 12.66 Hz, CH(H)N3), 4.19 (1H, d  q, J = 10.73 Hz, 7.15 Hz,
OCH(H)CH3), 4.26 (1H, d  q, J = 10.73 Hz, 7.15 Hz, OCH(H)CH3). 13C NMR
(75 MHz, CDCl3): d 14.0, 28.3, 32.0, 43.1, 54.6, 55.8, 61.8, 170.4. IR (neat, cmÀ1):
9. Anderson, A. G., Jr.; Fagerburg, D. R.; Lok, R. J. Heterocycl. Chem. 1974, 11, 431–
435.
10. (a) Hayashi, K.; Ikee, Y.; Goto, S.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2004,
52, 89–94; (b) Gensler, W. J. J. Am. Chem. Soc. 1948, 70, 1843–1846.
11. (a) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099–3114; (b) Robin, S.;
Rousseau, G. Eur. J. Org. Chem. 2000, 3007–3011.
12. (a) Baraki, H.; Habaue, S.; Okamoto, Y. Polym. J. 1999, 31, 1260–1266; (b)
Habaue, S.; Baraki, H.; Okamoto, Y. Polym. J. 1997, 29, 872–874.
13. (a) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Rinaldi, S. Org. Lett. 2004, 6,
2571–2574; (b) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Rinaldi, S.
Tetrahedron 2006, 62, 10450–10455.
m
N3 = 2101, m
C@O = 1734. MS (ES, pos. mode): m/z (%): 227 (M+H+, 100). Anal.
Calcd for C10H18N4O2: C, 53.08; H, 8.02; N, 24.76. Found: C, 52.77; H, 8.17; N,
24.45. Ethyl 1-tert-butyl-3-azidoazetidine-3-carboxylate 9a. Yellow oil, yield
86%, Rf = 0.18 (petroleum ether/Et2O 7:3). 1H NMR (300 MHz, CDCl3): d 0.99
(9H, s, C(CH3)3), 1.34 (3H, t, J = 7.15 Hz, CH2CH3), 3.32 (2H, d, J = 7.43 Hz,
CH(H)NCH(H)), 3.70 (2H, d, J = 7.43 Hz, CH(H)NCH(H)), 4.29 (2H, q, J = 7.15 Hz,
14. Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213–1220.
15. Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571–2573.

6900
S. Mangelinckx et al. / Tetrahedron Letters 49 (2008) 6896–6900
OCH2CH3). 13C NMR (75 MHz, CDCl3): d 14.2, 24.0, 52.2, 54.4, 59.3, 62.4, 170.0.
IR (neat, cmÀ1):
N3 = 2109, C@O = 1737. MS (ES, pos. mode): m/z (%): 227
(M+H+, 100).
(300 MHz, CDCl3): d 0.99 (9H, s, C(CH3)3), 1.31 (3H, t, J = 7.15 Hz, CH2CH3),
m
m
2.37 (2H, br s, NH2), 3.10 (2H, d, J = 8.26 Hz, NCH(H)), 3.72 (2H, d, J = 8.26 Hz,
NCH(H)), 4.22 (2H, q, J = 7.15 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3): d 14.3,
22. Mloston´ , G.; Celeda, M. Helv. Chim. Acta 2005, 88, 1658–1663.
24.0, 52.2, 53.1, 57.7, 61.5, 173.9. IR (neat, cmÀ1): mNH = 3376 (weak),
2
23. Ethyl 1-tert-pentyl-2-(aminomethyl)aziridine-2-carboxylate 10b. Yellow oil,
yield 68%, Rf = 0.27 (CH2Cl2/MeOH 9:1). 1H NMR (300 MHz, CDCl3): d 0.92 (3H,
t, J = 7.60 Hz, CCH2CH3), 0.94 (3H, s, CCH3), 0.98 (3H, s, CCH3), 1.30 (3H, t,
J = 7.15 Hz, OCH2CH3), 1.48 (1H, d  q, J = 13.62 Hz, 7.43 Hz, CCH(H)CH3), 1.51
(1H, d  q, J = 13.35 Hz, 7.43 Hz, CCH(H)CH3), 1.78 (1H, d, J = 1.10 Hz, CH(H)N),
1.86 (2H, br s, NH2), 2.41 (1H, d, J = 1.38 Hz, CH(H)N), 2.87 (1H, d, J = 13.76 Hz,
CH(H)NH2), 2.89 (1H, d, J = 13.76 Hz, CH(H)NH2), 4.16 (1H, d  q, J = 10.73 Hz,
7.15 Hz, OCH(H)CH3), 4.22 (1H, d  q, J = 10.73 Hz, 7.15 Hz, OCH(H)CH3). 13C
NMR (75 MHz, CDCl3): d 8.9, 14.1, 23.8, 24.5, 31.4, 36.7, 46.9, 56.5, 61.3, 172.1.
m
C@O = 1730. MS (ES, pos. mode): m/z (%): 201 (M+H+, 100).
24. (a) Siu, T.; Picard, C. J.; Yudin, A. K. J. Org. Chem. 2005, 70, 932–937; (b)
Krasnova, L. B.; Hili, R. M.; Chernoloz, O. V.; Yudin, A. K. ARKIVOC 2005, iv, 26–
38.
25. Hennequin, L. F. A.; Ballard, P.; Boyle, F. T.; Delouvrié, B.; Ellston, R. P. A.;
Halsall, C. T.; Harris, C. S.; Hudson, K.; Kendrew, J.; Pease, J. E.; Ross, H. S.;
Smith, P.; Vincent, J. L. Bioorg. Med. Chem. Lett. 2006, 16, 2672–2676.
26. Cao, X.; Liang, L.; Hadcock, J. R.; Iredale, P. A.; Griffith, D. A.; Menniti, F. S.;
Factor, S.; Greenamyre, J. T.; Papa, S. M. J. Pharmacol. Exp. Ther. 2007, 323, 318–
326.
IR (neat, cmÀ1): mNH = 3381 (weak),
m
C@O = 1724. MS (ES, pos. mode): m/z (%):
2
215 (M+H+, 100). Ethyl 1-tert-butyl-3-aminoazetidine-3-carboxylate 11a.
27. Kozikowski, A. P.; Fauq, A. H. Synlett 1991, 783–784.
28. See Ref. 6a and references cited therein.
Yellow oil, yield 78%, Rf = 0.10 (petroleum ether/EtOAc 1:1). 1H NMR