Solvent-controlled selective transformation of 2-bromomethyl-2- methylaziridines to functionalized aziridines and azetidines

Article abstract of DOI:10.1021/jo202637a

The reactivity of 2-bromomethyl-2-methylaziridines toward oxygen, sulfur, and carbon nucleophiles in different solvent systems was investigated. Remarkably, the choice of the solvent has a profound influence on the reaction outcome, enabling the selective formation of either functionalized aziridines in dimethylformamide (through direct bromide displacement) or azetidines in acetonitrile (through rearrangement via a bicyclic aziridinium intermediate). In addition, the experimentally observed solvent-dependent behavior of 2-bromomethyl-2-methylaziridines was further supported by means of DFT calculations.

Full text of DOI:10.1021/jo202637a

Article
pubs.acs.org/joc
Solvent-Controlled Selective Transformation of 2-Bromomethyl-2-
methylaziridines to Functionalized Aziridines and Azetidines
Sonja Stankovic,† Hannelore Goossens,‡ Saron Catak,‡ Meniz Tezcan,† Michel Waroquier,‡
́
Veronique Van Speybroeck,*,‡ Matthias D’hooghe,*,† and Norbert De Kimpe*,†
†Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
‡Center for Molecular Modeling, Ghent University, Technologiepark 903, B-9052 Zwijnaarde, Belgium, Member of QCMM-Alliance
Ghent-Brussels
S
* Supporting Information
ABSTRACT: The reactivity of 2-bromomethyl-2-methylazir-
idines toward oxygen, sulfur, and carbon nucleophiles in
different solvent systems was investigated. Remarkably, the
choice of the solvent has a profound influence on the reaction
outcome, enabling the selective formation of either functional-
ized aziridines in dimethylformamide (through direct bromide
displacement) or azetidines in acetonitrile (through rearrange-
ment via a bicyclic aziridinium intermediate). In addition, the
experimentally observed solvent-dependent behavior of 2-
bromomethyl-2-methylaziridines was further supported by
means of DFT calculations.
Scheme 1. Reactivity of 1-Alkyl-2-(bromomethyl)aziridines 1
with Respect to NaBH4 in MeOH
INTRODUCTION
■
Aziridines display an uncommon combination of reactivity,
atom economy and synthetic utility related to the ring strain of
this class of nitrogen-containing heterocycles.1 As a conse-
quence, aziridines are frequently deployed as versatile synthetic
intermediates for the preparation of a variety of ring-opened
and ring-expanded amines via regio- and stereoselective ring-
opening reactions with nucleophiles.2 Azetidines, the higher
homologues of aziridines, have acquired a prominent position
in organic chemistry as well. Next to their synthetic relevance,3
compounds containing an azetidine moiety have been shown to
possess a wide range of biological activities.4 For example, 3-
alkoxy- and 3-aryloxyazetidines have been described as G-
protein coupled receptor agonists,5 inhibitors of stearoyl-
coenzyme d-9 desaturase6 and antibacterial agents.7
Within the class of 2-substituted, nonactivated aziridines, the
use of 2-(bromomethyl)aziridines 1 (R2 = H) as substrates for
ring-opening reactions and nucleophilic substitutions has found
great application in synthetic chemistry. In particular, these
compounds have been used as suitable synthons for the
preparation of cyclopropanes,8 morpholines,9 pyrrolizidines,10
pyrrolidines,10 2-imino-1,3-thiazoli(di)nes11 and piperidine
derivatives.12 In addition, the nucleophilic substitution of
bromide in 2-(bromomethyl)aziridines 1 (R2 = H) with various
heteroatom nucleophiles9,11,13 and carbon nucleophiles8,14 has
provided a convenient access toward a variety of 2-substituted
aziridines. Furthermore, it should be stressed that these
aziridines 1 (R2 = H) are not susceptible to a ring expansion
process upon heating with NaBH4 in methanol to afford the
corresponding 3-methoxyazetidines 2 (Scheme 1).15 On the
other hand, we recently reported that structurally similar 2-
bromomethyl-2-methylaziridines 1 (R2 = Me) readily rearrange
into 3-methoxy-3-methylazetidines 3 under the same reaction
conditions (NaBH4, MeOH, reflux).16 In the same paper, a
single example of the ring rearrangement of a 2-bromomethyl-
2-methylaziridine into the corresponding 3-bromo-3-methyl-
azetidine has been described as well upon heating in acetonitrile
for 15 h. The isomerization of 2-(halomethyl)aziridines to 3-
haloazetidines has been observed in the literature in only a few
exceptional cases,17 pointing to the peculiar nature of this type
of rearrangement.
The limited number of reports regarding aziridine to
azetidine ring expansions and the mainly unexplored synthetic
potential of 2-bromomethyl-2-methylaziridines prompted us to
investigate the chemistry of this class of aziridines in more
detail. Thus, the present study deals with the reactivity of 2-
bromomethyl-2-methylaziridines 1 (R2 = Me) toward different
oxygen, sulfur and carbon nucleophiles in different solvent
Received: December 21, 2011
Published: February 21, 2012
© 2012 American Chemical Society
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systems, providing an unexpected solvent-mediated synthesis of
substituted aziridines and azetidines selectively. The exper-
imentally observed results were further investigated and
supported by high-level molecular modeling.
few precedents in the chemical literature and might provide a
window of opportunities for the selective synthesis of novel 3-
substituted azetidines.
Thus, the intrinsic reactivity of 2-bromomethyl-2-methylazir-
idines 4 to undergo a ring rearrangement was further
investigated utilizing a variety of different nucleophiles such
as thiocyanate, cyanide, phenoxide and acetate to assess the
scope of this transformation with respect to carbon and
heteroatom nucleophiles.
First, aziridines 4a−c were treated with 1 equiv of KSCN in
acetonitrile at reflux temperature for 2−4 h, furnishing mixtures
of 3-methyl-3-thiocyanatoazetidines 7a−c and 2-methyl-2-
(thiocyanatomethyl)aziridines 8a−c, with azetidines 7a−c
being the major products (ratio 7/8 = 50−67/50−33, entry
1−3, Table 1) (Scheme 3). From these mixtures, azetidines
RESULTS AND DISCUSSION
■
Experimental Results. The synthesis of 2-bromomethyl-2-
methylaziridines 4 through NaBH4-mediated reduction of α,β-
dibromoaldimines, obtained by bromination and subsequent
imination of 2-methylpropenal, has recently been reported.16
To provide a general access to novel 3-bromoazetidines as
versatile synthons, 2-bromomethyl-2-methylaziridines 4a−c
were subjected to heating in acetonitrile at reflux temperature
for 15 h. These reactions resulted in the selective formation of
3-bromo-3-methylazetidines 6a−c, obtained through bromide
attack at the more-hindered carbon atom of the intermediate
bicyclic aziridinium species 5 (Scheme 2). The broad synthetic
Scheme 3. Transformation of 2-Bromomethyl-2-
methylaziridines 4 to Functionalized Azetidines 7 and
Aziridines 8
Scheme 2. Transformation of 2-(Bromomethyl)aziridines 4
to 3-Bromoazetidines 6a−c
7a−c were isolated in pure form by preparative TLC
chromatography on silica gel. Several experiments were
performed to optimize the reaction conditions. Surprisingly,
when aziridines 4a−c were treated with 1 equiv of KSCN in
DMF at 60−70 °C for 15−20 h aziridines 8a−c were obtained
as the sole reaction products (entry 10−12, Table 1), giving rise
to a new and straightforward synthetic methodology for the
selective preparation of either aziridines in DMF and azetidines
in acetonitrile. Aziridines 8a−c were then successfully purified
by means of column chromatography on silica gel to obtain
potential of 3-haloazetidines has been demonstrated in the
literature in terms of their nucleophilic substitution with
different nucleophiles.18 The intermediacy of bicyclic aziridi-
nium species 5 in this peculiar aziridine to azetidine
rearrangement protocol has previously been studied and was
confirmed by means of high level molecular modeling
calculations.16 It should be stressed that this thermodynami-
cally-controlled aziridine to azetidine rearrangement has very
Table 1. Transformation of 2-Bromomethyl-2-methylaziridines 4 to Functionalized Azetidines 7 and Aziridines 8
a
entry
R
Nu
reaction conditions
1 equiv KSCN, 2 h, Δ, MeCN
1 equiv KSCN, 3 h, Δ, MeCN
1 equiv KSCN, 4 h, Δ, MeCN
2 equiv KCN, 26 h, Δ, MeCN
ratio 7/8
yield 7 or 8
1
H
SCN
SCN
SCN
CN
50/50
57/43
67/33
100/0
100/0
57/43
67/33
100/0
100/0
0/100
0/100
0/100
0/100
0/100
10/90
0/100
20/80
25/75
7a (45%)
7b (55%)
7c (65%)
7d (96%)
7e (95%)
7f (47%)
7g (65%)
7h (95%)
7i (92%)
8a (94%)
8b (95%)
8c (90%)
8d (85%)
8e (89%)
8f (85%)
8g (90%)
8h (72%)
8i (45%)
2
Me
3
OMe
Me
4
5
OMe
Me
CN
2 equiv KCN, 26 h, Δ, MeCN
6
OPh
OPh
OAc
OAc
SCN
SCN
SCN
CN
2.2 equiv PhOH, 5 equiv K2CO3, 20 h, Δ, MeCN
2.2 equiv PhOH, 5 equiv K2CO3, 24 h, Δ, MeCN
1.1 equiv NaOAc, 24 h, Δ, MeCN
7
OMe
Me
8
9
OMe
H
1.1 equiv NaOAc, 22 h, Δ, MeCN
10
11
12
13
14
15
16
17
18
1 equiv KSCN, 15 h, 60−70 °C, DMF
1 equiv KSCN, 15 h, 60−70 °C, DMF
1 equiv KSCN, 20 h, 60−70 °C, DMF
1 equiv KCN, 16 h, 50−60 °C, DMF
1 equiv KCN, 16 h, 50−60 °C, DMF
2.2 equiv PhOH, 5 equiv K2CO3, 17 h, 50 °C, DMF
2.2 equiv PhOH, 5 equiv K2CO3, 14 h, 50 °C, DMF
1.1 equiv NaOAc, 5 days, r.t., DMSO
1.1 equiv NaOAc, 3 days, r.t., DMSO
Me
OMe
Me
OMe
Me
CN
OPh
OPh
OAc
OAc
OMe
Me
OMe
a
1
Determined based on H NMR.
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analytically pure samples. Aziridines 8a−c were susceptible to
partial decomposition during the chromatographic purification
process.
Bearing in mind the different reactivity profile of aziridines 4
toward KSCN in different solvents (MeCN versus DMF), 2-
bromomethyl-2-methylaziridines 4b,c were then treated with
other nucleophiles such as cyanide, phenoxide and acetate both
in MeCN and DMF as the solvent medium (Scheme 3, Table
1).
After treatment of aziridines 4b,c with 2 equiv of KCN in
MeCN for 26 h at reflux temperature, only 3-cyano-3-
methylazetidines 7d,e were obtained (entry 4−5, Table 1),
whereas the same reaction in DMF gave exclusively 2-
cyanomethyl-2-methylaziridines 8d,e after 16 h at 50−60 °C
(entry 13−14, Table 1). As in the case of thiocyanate (Nu =
SCN), the reaction outcome was shown to be dictated by the
solvent used in these reactions, providing an efficient method
for the synthesis of new functionalized aziridines and azetidines
in a selective way. Azetidines 7d,e and aziridines 8d,e were
purified by means of column chromatography on silica gel to
provide analytically pure samples.
of azetidines 7h,i and small amounts of some side products
(10−15%).
The ratio 7/8 was determined by spectroscopic analysis (1H
NMR) of the crude reaction mixtures. After purification, the
structures of the azetidines 7 and aziridines 8 were confirmed
by means of different characterization methods (1H NMR, 13C
NMR, IR, MS).
The selective transformation of aziridines 4 toward either
azetidines 7 in acetonitrile or aziridines 8 in dimethylformamide
(Scheme 4) provides interesting opportunities for further
elaboration to valuable azaheterocycles.
Scheme 4. Selective Transformation of 2-Bromomethyl-2-
methylaziridines 4 to Functionalized Azetidines 7 and
Aziridines 8
The reaction of aziridines 4b,c with 2.2 equiv of phenol and
5 equiv of K2CO3 in MeCN for 20−24 h was not so
straightforward and gave mixtures of 3-methyl-3-phenoxyazeti-
dines 7f,g and 2-methyl-2-(phenoxymethyl)aziridines 8f,g, in
which azetidines 7f,g were present as the major isomers (ratio
7/8 = 57−67/43−33, entry 6−7, Table 1). These compounds
were separated and isolated by means of column chromatog-
raphy (SiO2) to obtain analytically pure samples. On the other
hand, treatment of aziridines 4b,c with 2.2 equiv of phenol and
5 equiv of K2CO3 in DMF for 14−17 h at 50 °C provided 2-
methyl-2-(phenoxymethyl)aziridines 8f,g as the major products
(entry 15−16, Table 1), and only small amounts (∼10%) of
azetidine 7f were observed. However, the purification by silica
gel column chromatography did not provide completely pure
products due to coelution of an unidentified side product in
small quantities (10−15%). Finally, when aziridines 4b,c were
subjected to 1.1 equiv of NaOAc in MeCN for 22−24 h at
reflux temperature, 3-acetoxy-3-methylazetidines 7h,i were
produced without traces of the corresponding aziridines
(entry 8−9, Table 1). On the other hand, the reaction of the
same aziridines 4b,c with 1.1 equiv of NaOAc in DMF for 16−
20 h resulted in complex mixtures, in which the presence of 2-
acetoxymethyl-2-methylaziridines 8h,i (30−40%) as well as 3-
acetoxy-3-methylazetidines 7h,i (10−20%) was acknowledged
by means of 1H NMR analysis. It should be mentioned that the
reaction with NaOAc provided a unique case of noteworthy
amounts of azetidine formation in DMF as the solvent, while in
all other cases (except in the case of a small amount of azetidine
7f) the formation of azetidines using DMF as the solvent was
not observed. After several attempts to optimize the reaction
conditions in different solvents (DMF and DMSO), at different
temperatures (r.t. to 100 °C), and by using additional reagents
(such as AgBF4), aziridines 8h,i were finally obtained as the
major compounds (ratio 7/8 = 20−25/80−75) after treatment
of aziridines 4b,c with 1.1 equiv of NaOAc in DMSO at room
temperature for 3−5 days. Higher temperatures (>30 °C)
yielded complete conversion of the starting aziridines 4b,c only
after a few hours, however at the expense of selectivity of this
reaction (ratio 7/8 = 40−50/60−50). From these mixtures,
aziridines 8h,i could not be isolated in completely pure form by
means of column chromatography on silica gel due to coelution
From a mechanistic point of view, different pathways can be
considered to explain the synthesis of functionalized aziridines
and azetidines starting from 2-bromomethyl-2-methylaziridines
4. An overview of possible reactivity profiles of aziridines 4 in
MeCN is presented in Scheme 5. Bearing in mind the
Scheme 5. Possible Synthetic Routes for the Formation of
Azetidines 7 and Aziridines 8 from Aziridines 4 in MeCN-
mediated Reactions
previously reported intermediacy of bicyclic aziridinium ions in
the synthesis of 3-methoxy-3-methylazetidines starting from 2-
bromomethyl-2-methylaziridines,16 the nucleophilic attack at
the more hindered carbon atom of the strained intermediates 5
(path b, Scheme 5) is considered to be the most plausible route
for the formation of 3-substituted azetidines 7 in MeCN,
possibly through the less stable nonbridged carbenium ion.
This fact is also in accordance with the ring transformation of 2-
bromomethyl-2-methylaziridines 4a−c in MeCN at reflux
temperature (Scheme 2). It should be noted that in some
cases (entries 1−3, 6, 7, Table 1) the formation of aziridines 8
was observed as well (33−50%). The presence of aziridines 8 in
these MeCN-mediated reactions can be attributed to
nucleophilic attack at the less-hindered carbon atom of the
bicyclic aziridinium ions 5 (path a, Scheme 5), taking into
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account a few isolated literature examples on the ring opening
of strained bicyclic intermediates.19 However, direct nucleo-
philic displacement of bromide in 2-bromomethyl-2-methyl-
aziridines 4 by the nucleophile (path c, Scheme 5) will most
probably prevail as the pathway toward substituted aziridines 8.
The proposed mechanistic pathways for the selective
formation of aziridines 8 in DMF are depicted in Scheme 6.
characterized as minima (ground states) via frequency
calculations. The B3LYP functional has been proven to
produce good geometries, but is less accurate for energy
calculations.23 Therefore energies were refined with the
MPW1K functional, which has shown its utility for energy
calculations.24 Previous computational studies have demon-
strated the necessity of d and f polarization functions on the
sulfur basis set,25 hence, the MPW1K functional was used in
conjunction with the 6-311+G(3df,2p) basis set for sulfur and
the 6-31++G(d,p) basis set for all other atoms, since this
method was shown to be adequate for calculations on sulfur-
containing systems.24e All thermal free energy corrections
reported were taken from B3LYP/6-31+G(d,p) optimizations
at 1 atm and 298 K. All computations were performed with the
Gaussian 09 program packages.26
Scheme 6. Possible Synthetic Routes for the Formation of
Aziridines 8 from Aziridines 4 in DMF-mediated Reactions
Coordination Solvation Energies. As briefly mentioned
earlier, a different close-packing of the nucleophiles (CN− and
SCN−), the nucleophuge Br− or even the bicyclic aziridinium
intermediate 5 by DMF and MeCN could be very important
for the relative reactivity of these ions. To investigate the close-
packing, the convergence behavior of the energy of
coordination solvation was inspected by means of systemati-
cally increasing the number of explicit solvent molecules
around the ions, and the corresponding coordination solvation
energies (CSE’s) and coordination solvation free energies
(CSG’s) were calculated.24e,f,27 CSG’s are known to converge
before CSE’s, which is merely caused by entropic effects. CSE’s
are listed in the Supporting Information.
It has recently been reported that rearrangement of 2-
bromomethyl-2-methylaziridines 1 (R2 = Me) with NaBH4 in
MeOH toward 3-methoxy-3-methylazetidines 3 (Scheme 1)
takes place via a bicyclic aziridinium ion.16 Free energies of
activation for the formation of the bicyclic intermediate were
found to be reasonable and the bicyclic intermediate was found
to be far more stable than its nonbridged counterpart.
Therefore, it is likely that the rearrangement of aziridines 4
toward azetidines 7 takes place via a bicyclic aziridinium species
5 (Scheme 5).
Coordination of the bicyclic aziridinium species 5 by DMF
and MeCN is shown in Figures 1 and 2, respectively. From
experimental data, it is clear that this intermediate was formed
in MeCN (Table 1) but not in DMF (Table 1). A possible
explanation is a better stabilization of intermediate 5 in MeCN
than in DMF. From the coordination solvation energies,
stabilization of 5 does not seem to cause the difference in
reactivity in DMF and MeCN, since coordination at the most
accessible places by both solvents gives rise to a stronger
coordination with DMF than with MeCN (CSGMPW1K = −49.7
and −34.6 kJ/mol for DMF and MeCN, respectively, Figures 1
and 2). This is understandable, since the DMF oxygen and the
MeCN nitrogen interact with the hydrogen atoms of 5, and
oxygen is more electronegative than nitrogen. This can also be
seen in the distances between the hydrogen atoms of 5 and
both the DMF oxygen atoms (2.29−2.65 Å) and the MeCN
nitrogen atoms (2.50−2.84 Å). Moreover, coordination
solvation energies for both solvents converge with 3 solvent
molecules, thus coordination with more solvent molecules is
not expected to make a substantial difference. The close-
packing of 5 by DMF could avoid it from getting attacked by a
nucleophile to give azetidine 7, while 5 is more readily available
for nucleophilic attack in MeCN.
Herein, two different routes can be considered, involving either
direct displacement of bromide by the approaching nucleophile
via a SN2 protocol (path a, intermediate 9, Scheme 6) or via the
formation of primary carbenium ions 10 (SN1 mechanism, path
b, Scheme 6), which might be stabilized by the nitrogen lone
pair through anchimeric assistance. The formation of aziridines
8 via nucleophilic attack at the less-substituted carbon atom of
bicyclic aziridinium intermediates 5 (path a, Scheme 5) in DMF
should not be completely neglected, although the fact that
aziridines 4 do not rearrange into azetidines 6 upon heating in
DMF for several hours suggests that no bicyclic aziridinium
species 5 are formed in these reactions.
To shed more light on the remarkable preference for the
formation of azetidines in MeCN and aziridines in DMF
(Schemes 5 and 6), some computational analyses were
performed.
Theoretical Rationalization. The solvent-dependent
reactivity of different nucleophiles toward 2-bromomethyl-2-
methylaziridines was further investigated by means of DFT
calculations. The difference in the observed selectivity in DMF
and MeCN was unexpected, since both solvents are polar and
aprotic, and have very similar dielectric constants (36.71 and
35.94, respectively). However, they have different densities
(943.87 and 776.49 kg m−3, respectively), molar volumes
(77.442 and 52.870 cm3 mol−1, respectively), shapes and
dipoles. The latter properties of DMF and MeCN can influence
the way they solvate ions, and ion solvation is known to be
correlated with rate constants of chemical reactions.20 Free
energies of solvation of relevant ions in DMF and MeCN are
quite similar, e.g. 251 and 256 kJ mol−1 for Br−, 243 and 248 kJ
mol−1 for CN− and 213 and 217 kJ mol−1 for SCN−,
respectively,21 but the difference in close-packing can be crucial
for their relative reactivities, i.e. this can influence how free the
nucleophiles are to attack and how willing the nucleophuge is
to leave. This notion will be investigated with computational
methods.
Computational Methodology. The B3LYP/6-31+G(d,p)
level of theory was used for geometry optimizations of clusters
of ions and solvent molecules.22 Stationary points were
The difference in observed regioselectivity in DMF and
MeCN can alternatively be due to a stronger coordination and
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Figure 3. Coordination of CN− by an increasing number of DMF
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). CN− with
4 DMF molecules shown in figure. Distances between the hydrogen
atoms of DMF and the CN− nitrogen and carbon are 2.40−2.67 and
2.57−2.89 Å, respectively.
Figure 1. Coordination of the bicyclic aziridinium 5b by an increasing
number of DMF molecules. MPW1K/6-31++G(d,p)//B3LYP/6-
31+G(d,p). 5b with 3 DMF molecules shown in figure. Distances
between the hydrogen atoms of 5 and the DMF oxygen atoms are
2.29−2.65 Å.
Figure 4. Coordination of CN− by an increasing number of MeCN
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). CN− with
4 MeCN molecules shown in figure. Distances between the hydrogen
atoms of MeCN and the CN− nitrogen and carbon are 2.14−2.17 and
2.36−2.51 Å, respectively.
MeCN, respectively). Furthermore, MeCN molecules can pack
more closely than DMF molecules, as seen in the relative
distances between the hydrogen atoms of the solvent and the
CN− nitrogen (2.40−2.67 and 2.14−2.17 Å in DMF and
MeCN, respectively) and the CN− carbon (2.57−2.89 and
2.36−2.51 Å in DMF and MeCN, respectively). Coordination
solvation energies for DMF and MeCN converge after
coordination with three and four molecules, respectively, and
two hydrogen atoms of each DMF molecule can coordinate
with CN− while only one hydrogen atom of MeCN coordinates
with CN−, but the bulky DMF methyl groups prevent the DMF
molecules from packing closely. The stronger coordination and
better stabilization of CN− by MeCN can point to a lower
reactivity, hence allowing the formation of azetidine 7 via
formation of the bicyclic intermediate 5. Since CN− is less
stabilized in DMF, it will be more reactive and hence,
nucleophilic substitution in aziridine 4 will lead to aziridine 8.
In the case of the nucleophile SCN−, a mixture of both 7 and
8 is experimentally observed. Hence, the difference between the
Figure 2. Coordination of the bicyclic aziridinium 5b by an increasing
number of MeCN molecules. MPW1K/6-31++G(d,p)//B3LYP/6-
31+G(d,p). 5b with 3 MeCN molecules shown in figure. Distances
between the hydrogen atoms of 5 and the MeCN nitrogen atoms are
2.50−2.84 Å.
better stabilization of the nucleophile by MeCN and hence, a
higher probability for the formation of the bicyclic intermediate
5 in MeCNwith subsequent formation of azetidine 7over
the direct replacement of Br− by the nucleophile in aziridine 4
and formation of aziridine 8 (Scheme 4). Coordination of the
nucleophile CN− by DMF and MeCN is shown in Figures 3
and 4, respectively. Coordination of CN− with three explicit
DMF or MeCN molecules shows that CN− is strongly
coordinated and thus better stabilized by MeCN than by
DMF (CSGMPW1K = −41.0 and −56.3 kJ/mol for DMF and
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coordination solvation of CN− and SCN− can illustrate the
reasoning behind this experimental observation. Coordination
of SCN− by DMF and MeCN is shown in Figures 5 and 6,
and SCN− nitrogen are 2.14−2.17 and 2.22−2.72 Å,
respectively, and distances between the hydrogen atoms of
MeCN and the CN− carbon and SCN− sulfur are 2.36−2.51
and 2.93−3.07 Å, respectively). This, together with the
difference between the coordination solvation energies of
CN− and SCN− in MeCN (CSGMPW1K = −56.3 and −32.1,
respectively) could explain why both the formation of the
bicyclic intermediate 5 and nucleophilic substitution in aziridine
4 are possible for SCN− in MeCN.
For completeness, coordination of Br− by DMF and MeCN
is shown in Figures 7 and 8, respectively. Like CN−, Br− is
Figure 5. Coordination of SCN− by an increasing number of DMF
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). SCN−
with 3 DMF molecules shown in figure. Distances between the
hydrogen atoms of DMF and the SCN− nitrogen and sulfur are 2.40−
2.64 and 3.03−3.11 Å, respectively.
Figure 7. Coordination of Br− by an increasing number of DMF
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). Br− with
4 DMF molecules shown in figure. Distances between the hydrogen
atoms of DMF and Br− are 2.76−2.87 Å.
Figure 6. Coordination of SCN− by an increasing number of MeCN
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). SCN−
with 3 MeCN molecules shown in figure. Distances between the
hydrogen atoms of MeCN and the SCN− nitrogen and sulfur are
2.22−2.72 and 2.93−3.07 Å, respectively.
respectively. Coordination of SCN− with two explicit DMF or
MeCN molecules shows that SCN− is strongly coordinated and
thus better stabilized in MeCN as the solvent as compared to
DMF as the solvent (CSGMPW1K = −13.5 and −30.4 kJ/mol for
DMF and MeCN, respectively). Coordination solvation
energies for SCN− with DMF and MeCN converge after
coordination with two and three molecules, respectively.
However, in this case the packing distances of MeCN and
DMF molecules are not strikingly different. On the other hand,
MeCN molecules pack more closely to CN− than to SCN−
(distances between the hydrogen atoms of MeCN and the CN−
Figure 8. Coordination of Br− by an increasing number of MeCN
molecules. MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p). Br− with
4 MeCN molecules shown in figure. Distances between the hydrogen
atoms of MeCN and Br− are 2.60 Å.
strongly coordinated and thus better stabilized by MeCN than
by DMF (CSGMPW1K = −64.0 and −78.1 kJ/mol for three
explicit DMF and MeCN molecules, respectively). The
stronger coordination of Br− by MeCN can improve its leaving
group capacity and thus help in the formation of the bicyclic
intermediate 5.
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70.7 (2× CH2), 113.8 (2× CH), 129.7 (2× CH), 129.1 (C), 158.9
(C); IR (neat, cm−1) νmax = 2930, 2835, 1612, 1511, 1243, 1171, 1034,
819, 738, 696; MS m/z (%) 240/2 (M+ + 1, 100).
Thus, stabilization of 5 does not seem to cause the difference
in reactivity in DMF and MeCN but the close-packing of 5 by
DMF could avoid it from getting attacked by a nucleophile.
Furthermore, the stronger coordination and better stabilization
of CN− by MeCN can point to a lower reactivity, hence
allowing the formation of azetidine 7 via formation of the
bicyclic intermediate 5. Since CN− is less stabilized in DMF, it
will be more reactive, and hence, nucleophilic substitution of
aziridine 4 will lead to aziridine 8. The weaker coordination of
SCN− by MeCN, compared to CN−, could explain why both
the formation of the bicyclic intermediate 5 and nucleophilic
substitution in the aziridine 4 are possible for SCN− in MeCN.
Finally, the stronger coordination of Br− by MeCN can
improve its leaving group capacity and thus help in the
formation of the bicyclic intermediate 5.
In summary, the reactivity of 2-bromomethyl-2-methylazir-
idines 4 with regard to different carbon, oxygen and sulfur
nucleophiles was investigated, providing an efficient strategy
toward the selective synthesis of a large variety of functionalized
aziridines and azetidines. The reaction outcome was proven to
be controlled by the choice of the solvent, showing DMF to be
a suitable solvent for the synthesis of the corresponding
aziridines 8 and MeCN for the synthesis of the corresponding
azetidines 7 as major compounds via strained bicyclic
intermediates. To account for the experimentally observed
results, DFT calculations were employed to elucidate the
extraordinary preference for the formation of azetidines in
MeCN and aziridines in DMF.
Synthesis of 3-Methyl-3-thiocyanatoazetidines 7a−c. As a
representative example, the synthesis of 1-(4-methoxybenzyl)-3-
methyl-3-thiocyanatoazetidine 7c is described here. 2-Bromomethyl-
1-(4-methoxybenzyl)-2-methylaziridine 4c (1.35 g, 5 mmol) was
dissolved in acetonitrile (30 mL), after which KSCN (0.49 g, 1 equiv)
was added and the mixture was heated at reflux temperature for 4 h.
The reaction mixture was cooled to room temperature, poured into
water (20 mL) and extracted with CH2Cl2 (3 × 20 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 a mixture of 1-(4-methoxybenzyl)-
3-methyl-3-thiocyanatoazetidine 7c and 2-methyl-2-
(thiocyanatomethyl)aziridine 8c (7c/8c = ratio 67/33), from which
1-(4-methoxybenzyl)-3-methyl-3-thiocyanatoazetidine 7c (0.94 g,
65%) was isolated in pure form by preparative thin layer
chromatography on silica gel (hexane/ethyl acetate/triethylamine 1/
1/0.01) to obtain an analytically pure sample.
1-Benzyl-3-methyl-3-thiocyanatoazetidine 7a. Yellow oil; Rf =
0.20 (hexane/ethyl acetate/triethylamine 1/1/0.01); Yield, 45%;
isolated yield, 36% (after purification); 1H NMR (300 MHz,
CDCl3) δ 1.79 (3H, s), 3.35 (2H, d, J = 8.8 Hz), 3.47 (2H, d, J =
8.8 Hz), 3.69 (2H, s), 7.24−7.35 (5H, m); 13C NMR (75 MHz, ref =
CDCl3) δ 26.4 (CH3), 47.5 (C), 62.5 (CH2), 66.3 (2× CH2), 111.5
(C), 127.5 (CH), 128.5 (2× CH), 128.6 (2× CH), 137.2 (C); IR
(neat, cm−1) νSCN = 2151; MS m/z (%) 219 (M+ + 1, 100).
3-Methyl-1-(4-methybenzyl)-3-thiocyanatoazetidine 7b. Yellow
oil; Rf = 0.22 (hexane/ethyl acetate/triethylamine 1/1/0.01); Yield,
1
55%; isolated yield, 47% (after purification); H NMR (300 MHz,
CDCl3) δ 1.78 (3H, s), 2.33 (3H, s), 3.33 (2H, d, J = 8.8 Hz), 3.46
(2H, d, J = 8.8 Hz), 3.64 (2H, s), 7.11−7.18 (4H, m); 13C NMR (75
MHz, ref = CDCl3) δ 21.2 (CH3), 26.4 (CH3), 47.5 (C), 62.3 (CH2),
66.2 (2× CH2), 111.5 (C), 128.5 (2× CH), 129.2 (2× CH), 134.1
(C), 137.1 (C); IR (neat, cm−1) νSCN = 2151; MS m/z (%) 233 (M+ +
1, 100).
EXPERIMENTAL PART
■
General. 1H NMR spectra were recorded at 300 MHz with CDCl3
as solvent and tetramethylsilane as internal standard. 13C NMR spectra
were recorded at 75 MHz with CDCl3 as solvent. Mass spectra were
recorded using either a direct inlet system (electron spray, 4000 V) or
LC-MS coupling (UV detector). IR spectra were recorded on a FT-IR
spectrometer. All compounds were analyzed in neat form with an ATR
(Attenuated Total Reflectance) accessory. Dichloromethane was
distilled over calcium hydride, while diethyl ether and THF were
distilled from sodium and sodium benzophenone ketyl before use.
Synthesis of 3-Bromo-3-methylazetidines 6a,c. As a repre-
sentative example, the synthesis of 1-benzyl-3-bromo-3-methylazeti-
dine 6a is described here. 1-Benzyl-2-bromomethyl-2-methylaziridine
4a (1.20 g, 5 mmol) was dissolved in acetonitrile (30 mL), and the
mixture was heated at reflux temperature for 15 h. The reaction
mixture was cooled to room temperature, poured into water (20 mL)
and extracted with CH2Cl2 (3 × 20 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 in vacuo afforded 1-benzyl-3-bromo-3-methylazetidine 6a
(0.86 g, 72%), which was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 7/1) to obtain an analytically pure
sample.
1-(4-Methoxybenzyl)-3-methyl-3-thiocyanatoazetidine 7c. Yel-
low oil; Rf = 0.18 (hexane/ethyl acetate/triethylamine 1/1/0.01);
1
Yield, 65%; isolated yield, 52% (after purification); H NMR (300
MHz, CDCl3) δ 1.78 (3H, s), 3.32 (2H, d, J = 9.4 Hz), 3.44 (2H, d, J =
9.4 Hz), 3.62 (2H, s), 3.80 (3H, s), 6.84−6.87 and 7.18−7.20 (4H, 2 ×
m); 13C NMR (75 MHz, ref = CDCl3) δ 26.4 (CH3), 47.5 (C), 55.4
(CH3), 61.9 (CH2), 66.1 (2× CH2), 111.5 (C), 113.9 (2× CH), 129.2
(C), 129.8 (2× CH), 159.0 (C); IR (neat, cm−1) νSCN = 2151; MS m/
z (%) 249 (M+ + 1, 100); HRMS m/z (ESI) calculated for
C13H16N2OS [MH]+ 249.1062, found 249.1059.
Synthesis of 2-Methyl-2-(thiocyanatomethyl)aziridines 8a−
c. As a representative example, the synthesis of 2-methyl-1-(4-
methylbenzyl)-2-(thiocyanatomethyl)aziridine 8b is described here. 2-
Bromomethyl-2-methyl-1-(4-methylbenzyl)aziridine 4b (1.27 g, 5
mmol) was dissolved in DMF (30 mL), after which KSCN (0.49 g,
1 equiv) was added and the mixture was stirred at 60−70 °C for 15 h.
The reaction mixture was cooled to room temperature, poured into
water (20 mL) and extracted with CH2Cl2 (3 × 20 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 2-methyl-1-(4-methylbenzyl)-2-
(thiocyanatomethyl)aziridine 8b (0.91 g, 95%), which was purified by
silica gel column chromatography (hexane/ethyl acetate/triethylamine
1/1/0.1) to obtain an analytically pure sample. It should be mentioned
that aziridines 8a−c showed to be rather unstable on silica gel column
during the purification process.
1-Benzyl-3-bromo-3-methylazetidine 6a. Yellow oil; Rf = 0.30
(petroleum ether/ethyl acetate 7/1); Yield, 72%; isolated yield, 62%
(after purification); 1H NMR (300 MHz, CDCl3) δ 2.00 (3H, s), 3.52
(2H, d, J = 9.1 Hz), 3.69 (2H, d, J = 9.1 Hz), 3.71 (2H, s), 7.21−7.33
(5H, m); 13C NMR (75 MHz, ref = CDCl3) δ 31.6 (CH3), 51.9 (C),
63.2 (CH2), 70.9 (2× CH2), 127.3 (2× CH), 128.5 (3× CH), 137.8
(C); IR (neat, cm−1) νmax = 2924, 2844, 1495, 1453, 1362, 1245, 1208,
1181, 746, 696; MS m/z (%) 240/2 (M+ + 1, 100).
1-Benzyl-2-methyl-2-(thiocyanatomethyl)aziridine 8a. Light yel-
low oil; Rf = 0.43 (hexane/ethyl acetate/triethylamine 1/1/0.1); Yield,
94%; isolated yield, 41% (after purification); H NMR (300 MHz,
CDCl3) δ 1.47 (1H and 3H, s), 2.08 (1H, s), 3.02 (H, d, J = 12.9 Hz),
3.14 (H, d, J = 12.9 Hz), 3.53 (H, d, J = 13.8 Hz), 3.78 (H, d, J = 13.8
Hz), 7.26−7.35 (5H, m); 13C NMR (75 MHz, ref = CDCl3) δ 14.0
(CH3), 38.8 (C), 40.3 (CH2), 45.1 (CH2), 57.1 (CH2), 113.1 (C),
3-Bromo-1-(4-methoxybenzyl)-3-methylazetidine 6c. Yellow oil;
1
Rf = 0.22 (petroleum ether/ethyl acetate 7/1); Yield, 70%; isolated
1
yield, 59% (after purification); H NMR (300 MHz, CDCl3) δ 1.99
(3H, s), 3.49 (2H, d, J = 9.1 Hz), 3.67 (2H, d, J = 9.1 Hz), 3.64 (2H,
s), 3.79 (3H, s), 6.83−6.86 and 7.18−7.20 (4H, 2 × m); 13C NMR (75
MHz, ref = CDCl3) δ 31.6 (CH3), 52.0 (C), 55.3 (CH3), 62.6 (CH2),
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127.2 (CH), 128.0 (2× CH), 128.6 (2× CH), 139.3 (C); IR (neat,
cm−1) νSCN = 2152; MS m/z (%) 219 (M+ + 1, 100); HRMS m/z
(ESI) calculated for C12H14N2S [MH]+ 219.0956, found 219.0952.
2-Methyl-1-(4-methylbenzyl)-2-(thiocyanatomethyl)aziridine 8b.
Light yellow oil; Rf = 0.44 (hexane/ethyl acetate/triethylamine 1/1/
acetate 1/1) to obtain an analytically pure sample. It should be
mentioned that aziridines 8d,e showed to be rather unstable on silica
gel column during the purification process.
2-Cyanomethyl-2-methyl-1-(4-methylbenzyl)aziridine 8d. Yellow
oil; Rf = 0.29 (hexane/ethyl acetate 1/1); Yield, 85%; isolated yield,
36% (after purification); 1H NMR (300 MHz, CDCl3) δ 1.39 (1H, s),
1.43 (3H, s), 1.96 (1H, s), 2.33 (3H, s), 2.40 (H, d, J = 16.8 Hz), 2.49
(H, d, J = 16.8 Hz), 3.52 (H, d, J = 13.8 Hz), 3.69 (H, d, J = 13.8 Hz),
7.13−7.25 (4H, m); 13C NMR (75 MHz, ref = CDCl3) δ 14.8 (CH3),
21.2 (CH3), 29.4 (CH2), 36.7 (C), 39.4 (CH2), 56.7 (CH2), 117.8
(C), 127.7 (2× CH), 129.3 (2× CH), 136.4 (C), 136.8 (C); IR (neat,
cm−1) νCN = 2250; MS m/z (%) 201 (M+ + 1, 100); HRMS m/z
(ESI) calculated for C13H16N2 [MH]+ 201.1392, found 201.1386.
2-Cyanomethyl-1-(4-methoxybenzyl)-2-methylaziridine 8e. Yel-
low oil; Rf = 0.21 (hexane/ethyl acetate 1/1); Yield, 89%; isolated
1
0.1); Yield, 95%; isolated yield, 64% (after purification); H NMR
(300 MHz, CDCl3) δ 1.46 (1H and 3H, s), 2.05 (1H, s), 2.34 (3H, s),
3.02 (H, d, J = 12.7 Hz), 3.13 (H, d, J = 12.7 Hz), 3.49 (H, d, J = 13.2
Hz), 3.73 (H, d, J = 13.2 Hz), 7.13−7.24 (4H, m); 13C NMR (75
MHz, ref = CDCl3) δ 14.0 (CH3), 21.2 (CH3), 38.8 (C), 40.2 (CH2),
45.2 (CH2), 56.8 (CH2), 113.1 (C), 127.9 (2× CH), 129.2 (2× CH),
136.3 (C), 136.8 (C); IR (neat, cm−1) νSCN = 2151; MS m/z (%) 233
(M+ + 1, 100); HRMS m/z (ESI) calculated for C13H16N2S [MH]+
233.1112, found 233.1110.
1-(4-Methoxybenzyl)-2-methyl-2-(thiocyanatomethyl)aziridine
1
8c. Light yellow oil; Rf = 0.36 (hexane/ethyl acetate/triethylamine 1/
yield, 42% (after purification); H NMR (300 MHz, CDCl3) δ 1.39
1
1/0.1); Yield, 90%; isolated yield, 37% (after purification); H NMR
(1H, s), 1.44 (3H, s), 1.96 (1H, s), 2.41 (H, d, J = 17.1 Hz), 2.49 (H, d,
J = 17.1 Hz), 3.49 (H, d, J = 13.5 Hz), 3.68 (H, d, J = 13.5 Hz), 3.81
(3H, s), 6.86−6.90 and 7.26−7.28 (4H, 2 × m); 13C NMR (75 MHz,
ref = CDCl3) δ 14.8 (CH3), 29.4 (CH2), 36.7 (C), 39.4 (CH2), 55.4
(CH3), 56.4 (CH2), 114.0 (2× CH), 117.8 (C), 128.9 (2× CH), 131.5
(C), 158.8 (C); IR (neat, cm−1) νCN = 2249; MS m/z (%) 217 (M+ +
1, 100); HRMS m/z (ESI) calculated for C13H16N2O [MH]+
217.1341, found 217.1344.
Synthesis of 3-Methyl-3-phenoxyazetidines 7f,g. As a
representative example, the synthesis of 1-(4-methoxybenzyl)-3-
methyl-3-phenoxyazetidine 7g is described here. 2-Bromomethyl-1-
(4-methoxybenzyl)-2-methylaziridine 4c (1.35 g, 5 mmol) was added
to a mixture of phenol (1.04 g, 2.2 equiv) and K2CO3 (3.46 g, 5 equiv)
dissolved in acetonitrile (30 mL), and the resulting suspension was
heated at reflux temperature for 24 h. The reaction mixture was cooled
to room temperature, poured into a NaOH solution (30 mL, 0.5M)
and extracted with CH2Cl2 (3 × 20 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 a mixture of 1-(4-methoxybenzyl)-3-methyl-3-
phenoxyazetidine 7g and 1-(4-methoxybenzyl)-2-methyl-2-
(phenoxymethyl)aziridine 8g (7g/8g = ratio 67/33), from which 1-
(4-methoxybenzyl)-3-methyl-3-phenoxyazetidine 7g (0.93 g, 65%) was
isolated in pure form by silica gel column chromatography (petroleum
ether/ethyl acetate 4/1).
(300 MHz, CDCl3) δ 1.46 (1H and 3H, s), 2.04 (1H, s), 3.00 (H, d, J
= 12.9 Hz), 3.12 (H, d, J = 12.9 Hz), 3.45 (H, d, J = 13.2 Hz), 3.71 (H,
d, J = 13.2 Hz), 3.81 (3H, s), 6.86−6.89 and 7.25−7.28 (4H, 2 × m);
13C NMR (75 MHz, ref = CDCl3) δ 14.0 (CH3), 38.8 (C), 40.2
(CH2), 45.2 (CH2), 55.4 (CH3), 56.5 (CH2), 113.1 (C), 114.0 (2×
CH), 129.2 (2× CH), 131.4 (C), 158.8 (C); IR (neat, cm−1) νSCN
=
2153; MS m/z (%) 249 (M+ + 1, 100); HRMS m/z (ESI) calculated
for C13H16N2OS [MH]+ 249,1062, found 249.1058.
Synthesis of Azetidine-3-carbonitriles 7d,e. As a representative
example, the synthesis of 1-(4-methoxybenzyl)-3-methylazetidine-3-
carbonitrile 7e is described here. 2-Bromomethyl-1-(4-methoxyben-
zyl)-2-methylaziridine 4c (1.35 g, 5 mmol) was dissolved in
acetonitrile (30 mL), after which KCN (0.64 g, 2 equiv) was added
in small portions and the mixture was heated at reflux temperature for
26 h. The reaction mixture was cooled to room temperature, poured
into water (20 mL) and extracted with CH2Cl2 (3 × 20 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-(4-methoxybenzyl)-3-methyl-
azetidine-3-carbonitrile 7e (0.96 g, 95%), which was purified by silica
gel column chromatography (dichloromethane/methanol 10/1) to
obtain an analytically pure sample.
3-Methyl-1-(4-methylbenzyl)azetidine-3-carbonitrile 7d. Yellow
oil; Rf = 0.28 (dichloromethane); Yield, 96%; isolated yield, 88% (after
1
3-Methyl-1-(4-methylbenzyl)-3-phenoxyazetidine 7f. Yellow oil;
purification); H NMR (300 MHz, CDCl3) δ 1.64 (3H, s), 2.33 (3H,
Rf = 0.25 (petroleum ether/ethyl acetate 4/1); Yield, 47%; isolated
s), 3.19 (2H, d, J = 6.9 Hz), 3.48 (2H, d, J = 6.9 Hz), 3.58 (2H, s),
7.04−7.24 (4H, m); 13C NMR (75 MHz, ref = CDCl3) δ 21.2 (CH3),
22.9 (CH3), 27.1 (C), 62.5 (CH2), 63.4 (2× CH2), 123.5 (C), 128.4
(2× CH), 129.2 (2× CH), 133.9 (C), 137.1 (C); IR (neat, cm−1) νCN
= 2238; MS m/z (%) 201 (M+ + 1, 100); HRMS m/z (ESI) calculated
for C13H16N2 [MH]+ 201.1392, found 201.1389.
1
yield, 37% (after purification); H NMR (300 MHz, CDCl3) δ 1.60
(3H, s), 2.33 (3H, s), 3.29 (2H, d, J = 8.3 Hz), 3.55 (2H, d, J = 8.3
Hz), 3.66 (2H, s), 6.67−6.70, 6.91−6.95 and 7.11−7.31 (9H, 3 × m);
13C NMR (75 MHz, ref = CDCl3) δ 21.2 (CH3), 22.0 (CH3), 63.4
(CH2), 66.3 (2× CH2), 73.6 (C), 116.8 (2 × CH), 120.9 (CH), 128.5
(2× CH), 129.1 (2× CH), 129.5 (2× CH), 136.8 (C), 137.0 (C),
155.3 (C); IR (neat, cm−1) νmax = 2927, 2838, 1599, 1587, 1514, 1494,
1456, 1241, 1223, 1170, 1034, 959, 803, 752, 692; MS m/z (%) 268
(M+ + 1, 100); HRMS m/z (ESI) calculated for C18H21NO [MH]+
268.1701, found 268.1698.
1-(4-Methoxybenzyl)-3-methyl-3-phenoxyazetidine 7g. Yellow
oil; Rf = 0.07 (petroleum ether/ethyl acetate 4/1); Yield, 65%;
isolated yield, 42% (after purification); 1H NMR (300 MHz, CDCl3) δ
1.67 (3H, s), 3.28 (2H, d, J = 8.3 Hz), 3.53 (2H, d, J = 8.3 Hz), 3.63
(2H, s), 3.79 (3H, s), 6.67−6.70, 6.84−6.95 and 7.20−7.26 (9H, 3 ×
m); 13C NMR (75 MHz, ref = CDCl3) δ 22.0 (CH3), 55.3 (CH3), 63.0
(CH2), 66.2 (2× CH2), 73.6 (C), 113.8 (2× CH), 116.8 (2× CH),
121.0 (CH), 129.5 (2× CH), 129.8 (2× CH), 130.2 (C), 155.3 (C),
158.9 (C); IR (neat, cm−1) νmax = 2932, 2834, 2364, 1611, 1586, 1511,
1493, 1242, 1223, 1204, 1171, 1034, 958, 818, 752, 693; MS m/z (%)
284 (M+ + 1, 100); HRMS m/z (ESI) calculated for C18H21NO2
[MH]+ 284.1651, found 284.1645.
1-(4-Methoxybenzyl)-3-methylazetidine-3-carbonitrile 7e. Yellow
oil; Rf = 0.60 (dichloromethane/methanol 10/1); Yield, 95%; isolated
1
yield, 89% (after purification); H NMR (300 MHz, CDCl3) δ 1.64
(3H, s), 3.18 (2H, d, J = 7.2 Hz), 3.48 (2H, d, J = 7.2 Hz), 3.56 (2H,
s), 3.80 (3H, s), 6.84−6.87 and 7.16−7.19 (4H, 2 × m); 13C NMR (75
MHz, CDCl3) δ 22.7 (CH3), 27.0 (C), 55.3 (CH3), 62.1 (CH2), 63.2
(2× CH2), 113.8 (2× CH), 123.4 (C), 128.9 (C), 129.6 (2× CH),
158.9 (C); IR (neat, cm−1) νCN = 2238; MS m/z (%) 217 (M+ + 1,
100); HRMS m/z (ESI) calculated for C13H16N2O [MH]+ 217.1341,
found 217.1340.
Synthesis of 2-Cyanomethyl-2-methylaziridines 8d,e. As a
representative example, the synthesis of 2-cyanomethyl-2-methyl-1-(4-
methylbenzyl)aziridine 8d is described here. 2-Bromomethyl-2-
methyl-1-(4-methylbenzyl)aziridine 4b (1.27 g, 5 mmol) was dissolved
in DMF (30 mL), after which KCN (0.33 g, 1 equiv) was added and
the mixture was stirred at 50−60 °C for 16 h. The reaction mixture
was cooled to room temperature, poured into water (20 mL) and
extracted with Et2O (3 × 20 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 2-
cyanomethyl-2-methyl-1-(4-methylbenzyl)aziridine 8d (0.85 g, 85%),
which was purified by silica gel column chromatography (hexane/ethyl
Synthesis of 2-Methyl-2-(phenoxymethyl)aziridines 8f,g. As
a representative example, the synthesis of 1-(4-methoxybenzyl)-2-
methyl-2-(phenoxymethyl)aziridine 8g is described here. 2-Bromo-
methyl-1-(4-methoxybenzyl)-2-methylaziridine 4c (1.35 g, 5 mmol)
was added to a mixture of phenol (1.04 g, 2.2 equiv) and K2CO3 (3.46
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g, 5 equiv) in DMF (30 mL), and the resulting suspension was heated
at 50 °C for 14 h. The reaction mixture was cooled to room
temperature, poured into a NaOH solution (30 mL, 0.5M) and
extracted with Et2O (3 × 20 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-
(4-methoxybenzyl)-2-methyl-2-(phenoxymethyl)aziridine 8g (1.27 g,
76%), which was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 4/1) to obtain an analytically pure
sample.
2-Methyl-1-(4-methylbenzyl)-2-(phenoxymethyl)aziridine 8f. Yel-
low oil; Rf = 0.17 (petroleum ether/ethyl acetate 4/1); Yield, 85%;
isolated yield, 70% (after purification); 1H NMR (300 MHz, CDCl3) δ
1.42 (1H, s), 1.44 (3H, s), 2.00 (1H, s), 2.34 (3H, s), 3.60 (H, d, J =
14.0 Hz), 3.73 (H, d, J = 14.0 Hz), 3.75 (H, d, J = 9.8 Hz), 3.90 (H, d,
J = 9.8 Hz), 6.88−6.96 and 7.11−7.30 (9H, 2 × m); 13C NMR (75
MHz, ref = CDCl3) δ 13.0 (CH3), 21.2 (CH3), 38.9 (CH2), 39.2 (C),
56.3 (CH2), 75.8 (CH2), 114.7 (2× CH), 120.8 (CH), 127.7 (2×
CH), 129.1 (2× CH), 129.5 (2× CH), 136.4 (C), 137.0 (C), 159.1
(C); IR (neat, cm−1) νmax = 3030, 2922, 1599, 1586, 1495, 1456, 1241,
1171, 1034, 1020, 798, 752, 691; MS m/z (%) 268 (M+ + 1, 100);
HRMS m/z (ESI) calculated for C18H21NO [MH]+ 268.1701, found
268.1689.
Synthesis of 2-Acetoxymethyl-2-methylaziridines 8h,i. As a
representative example, the synthesis of 2-acetoxymethyl-2-methyl-1-
(4-methylbenzyl)aziridine 8h is described here. 2-Bromomethyl-2-
methyl-1-(4-methylbenzyl)aziridine 4b (1.27 g, 5 mmol) was dissolved
in DMSO (30 mL), after which NaOAc (0.45 g, 1.1 equiv) was added
and the mixture was stirred at room temperature for 5 days. The
reaction mixture was poured into water (20 mL) and extracted with
Et2O (3 × 20 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 a mixture of
3-acetoxy-3-methyl-1-(4-methylbenzyl)azetidine 7h and 2-acetoxy-
methyl-2-methyl-1-(4-methylbenzyl)aziridine 8h (7h/8h = ratio 20/
80), from which 2-acetoxymethyl-2-methyl-1-(4-methylbenzyl)-
aziridine 8h could not be isolated in completely pure form by silica
gel column chromatography (petroleum ether/ethyl acetate 4/1). No
accurate elemental analyses or HRMS analyses could be performed on
2-(acetoxymethyl)aziridines.
2-Acetoxymethyl-2-methyl-1-(4-methylbenzyl)aziridine 8h. Yel-
low oil; Rf = 0.22 (petroleum ether/ethyl acetate 4/1); 1H NMR (300
MHz, CDCl3) δ 1.31 (3H, s), 1.35 (1H, s), 1.95 (1H, s), 2.07 (3H, s),
2.33 (3H, s), 3.64 (2H, s), 3.89 (H, d, J = 11.3 Hz), 4.01 (H, d, J = 11.3
Hz), 7.12−7.15 and 7.25−7.27 (4H, 2 × m); 13C NMR (75 MHz, ref
= CDCl3) δ 12.9 (CH3), 21.0 (CH3), 21.2 (CH3), 38.3 (C), 38.6
(CH2), 56.3 (CH2), 71.9 (CH2), 127.6 (2× CH), 129.1 (2× CH),
136.4 (C), 136.9 (C), 171.1 (C); IR (neat, cm−1) νCO = 1737; MS m/
z (%) 234 (M+ + 1, 100).
1-(4-Methoxybenzyl)-2-methyl-2-(phenoxymethyl)aziridine 8g.
Yellow oil; Rf = 0.31 (petroleum ether/ethyl acetate 4/1); Yield,
1
90%; isolated yield, 76% (after purification); H NMR (300 MHz,
2-Acetoxymethyl-1-(4-methoxybenzyl)-2-methylaziridine 8i. Yel-
low oil; Rf = 0.21 (petroleum ether/ethyl acetate 1/1); 1H NMR (300
MHz, CDCl3) δ 1.31 (3H, s), 1.34 (1H, s), 1.94 (1H, s), 2.07 (3H, s),
3.61 (2H, s), 3.80 (3H, s), 3.88 (H, d, J = 11.3 Hz), 4.00 (H, d, J = 11.3
Hz), 6.85−6.88 and 7.26−7.31 (4H, 2 × m); 13C NMR (75 MHz, ref
= CDCl3) δ 12.9 (CH3), 21.0 (CH3), 38.3 (C), 38.5 (CH2), 55.4
(CH3), 56.0 (CH2), 71.8 (CH2), 113.8 (2× CH), 128.8 (2× CH),
132.1 (C), 158.6 (C), 171.1 (C); IR (neat, cm−1) νCO = 1736; MS m/
z (%) 250 (M+ + 1, 100).
CDCl3) δ 1.41 (1H, s), 1.45 (3H, s), 2.00 (1H, s), 3.56 (H, d, J = 13.8
Hz), 3.71 (H, d, J = 13.8 Hz), 3.76 (H, d, J = 9.4 Hz), 3.81 (3H, s),
3.89 (H, d, J = 9.4 Hz), 6.84−6.96 and 7.24−7.33 (9H, 2 × m); 13C
NMR (75 MHz, ref = CDCl3) δ 13.0 (CH3), 38.9 (CH2), 39.2 (C),
55.4 (CH3), 56.0 (CH2), 75.9 (CH2), 113.9 (2× CH), 114.8 (2× CH),
120.8 (CH), 128.9 (2× CH), 129.5 (2× CH), 132.2 (C), 158.6 (C),
159.1 (C); IR (neat, cm−1) νmax = 3038, 2930, 2835, 1599, 1586, 1511,
1496, 1463, 1300, 1241, 1172, 1033, 819, 753, 691; MS m/z (%) 284
(M+ + 1, 100); HRMS m/z (ESI) calculated for C18H21NO2 [MH]+
284.1651, found 284.1659.
ASSOCIATED CONTENT
* Supporting Information
Synthesis of 3-Acetoxy-3-methylazetidines 7h,i. As a
representative example, the synthesis of 3-acetoxy-3-methyl-1-(4-
methylbenzyl)azetidine 7h is described here. 2-Bromomethyl-2-
methyl-1-(4-methylbenzyl)aziridine 4b (1.27 g, 5 mmol) was dissolved
in acetonitrile (30 mL), after which NaOAc (0.45 g, 1.1 equiv) was
added and the mixture was heated at reflux temperature for 24 h. The
reaction mixture was cooled to room temperature, poured into water
(20 mL) and extracted with CH2Cl2 (3 × 20 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 3-acetoxy-1-(4-methylbenzyl)-3-methylazeti-
dine 7h (1.10 g, 87%), which was purified by silica gel column
chromatography (petroleum ether/ethyl acetate 4/1) to obtain an
analytically pure sample.
■
S
Spectra (1H and 13C NMR) of 6a, 6c, 7a−i, 8a−i. Cartesian
coordinates and energy of the optimized geometries (B3LYP/
6-31+G(d,p)) for coordination of the bicyclic aziridinium 5,
CN−, SCN− and Br− by an increasing number of DMF or
MeCN molecules. Coordination solvation energies (CSE’s)
(MPW1K/6-31++G(d,p)//B3LYP/6-31+G(d,p)) for coordi-
nation of the bicyclic aziridinium ions 5, CN−, SCN− and Br−
by an increasing number of DMF or MeCN molecules. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3-Acetoxy-3-methyl-1-(4-methylbenzyl)azetidine 7h. Yellow oil;
AUTHOR INFORMATION
Corresponding Author
*veronique.vanspeybroeck@UGent.be; matthias.dhooghe@
UGent.be; norbert.dekimpe@UGent.be
■
Rf = 0.11 (petroleum ether/ethyl acetate 4/1); Yield, 95%; isolated
1
yield, 87% (after purification); H NMR (300 MHz, CDCl3) δ 1.64
(3H, s), 2.01 (3H, s), 2.32 (3H, s), 3.13 (2H, d, J = 9.1 Hz), 3.46 (2H,
d, J = 9.1 Hz), 3.61 (2H, s), 7.09−7.17 (4H, m); 13C NMR (75 MHz,
ref = CDCl3) δ 21.2 (CH3), 21.6 (CH3), 22.7 (CH3), 63.3 (CH2), 65.8
(2× CH2), 74.3 (C), 128.5 (2× CH), 129.1 (2× CH), 135.0 (C),
136.8 (C), 169.7 (C); IR (neat, cm−1) νCO = 1737; MS m/z (%) 234
(M+ + 1, 100); HRMS m/z (ESI) calculated for C14H19NO2 [MH]+
234.1494, found 234.1490.
3-Acetoxy-1-(4-methoxybenzyl)-3-methylazetidine 7i. Yellow oil;
Rf = 0.06 (hexane/ethyl acetate 2/1); Yield, 92%; isolated yield, 84%
(after purification); 1H NMR (300 MHz, CDCl3) δ 1.64 (3H, s), 2.02
(3H, s), 3.12 (2H, d, J = 9.4 Hz), 3.45 (2H, d, J = 9.4 Hz), 3.59 (2H,
s), 3.79 (3H, s), 6.83−6.86 and 7.17−7.20 (4H, 2 × m); 13C NMR (75
MHz, ref = CDCl3) δ 21.6 (CH3), 22.6 (CH3), 55.3 (CH3), 62.9
(CH2), 65.6 (2× CH2), 74.2 (C), 113.8 (2× CH), 129.7 (2× CH),
130.0 (C), 158.8 (C), 169.8 (C); IR (neat, cm−1) νCO = 1736; MS m/
z (%) 250 (M+ + 1, 100); HRMS m/z (ESI) calculated for C14H19NO3
[MH]+ 250.1443, found 250.1444.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Foundation-Flanders
(FWO-Vlaanderen), the Research Board of Ghent University
(BOF-GOA) and the IAP-BELSPO program in the frame of
IAP 6/27. Computational resources and services used in this
work were provided by Ghent University.
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