Synthesis of 3-methoxyazetidines via an aziridine to azetidine rearrangement and theoretical rationalization of the reaction mechanism

Article abstract of DOI:10.1021/jo102555r

The synthetic utility of N-alkylidene-(2,3-dibromo-2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropylidene)benzylamines was demonstrated by the unexpected synthesis of 3-methoxy-3-methylazetidines upon treatment with sodium borohydride in methanol under reflux through a rare aziridine to azetidine rearrangement. These findings stand in contrast to the known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines, which are easily converted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was provided by both experimental study and theoretical rationalization.

Full text of DOI:10.1021/jo102555r

ARTICLE
pubs.acs.org/joc
Synthesis of 3-Methoxyazetidines via an Aziridine to Azetidine
Rearrangement and Theoretical Rationalization of the Reaction
Mechanism
Sonja Stankoviꢀc,† Saron Catak,‡ Matthias D’hooghe,*,† Hannelore Goossens,‡ Kourosch Abbaspour Tehrani,#,†
Piet Bogaert,† Michel Waroquier,‡ Veronique Van Speybroeck,*,‡ 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
b
ABSTRACT: The synthetic utility of N-alkylidene-(2,3-dibromo-
2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropyli-
dene)benzylamines was demonstrated by the unexpected
synthesis of 3-methoxy-3-methylazetidines upon treatment
with sodium borohydride in methanol under reflux through a
rare aziridine to azetidine rearrangement. These findings stand
in contrast to the known reactivity of the closely related N-
alkylidene-(2,3-dibromopropyl)amines, which are easily con-
verted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was
provided by both experimental study and theoretical rationalization.
Scheme 1
’ INTRODUCTION
Imines carrying halogens in their side chain display a high
intrinsic reactivity, and the selective introduction of halogens in
imino substrates has led to building blocks with high synthetic
potential as shown amply for the useful class of R-haloimines.1
The halogen can be introduced in the aldehyde (or ketone)-
derived part, either before or after imination.1 On the other hand,
examples are known regarding halogenated imines in which the
halogen is present in the amine-derived part.2 The latter type of
imines is usually accessed through imination of carbonyl com-
pounds by means of halogenated (and thus reactive) amines, or
via electrophilic addition of, e.g., bromine across N-alkenylimines.
As a subclass, N-alkylidene- and N-arylmethylidene-(2,3-dibromo-
propyl)amines 1comprise useful intermediates for the preparation of
azaheterocyclic compounds such as aziridines and azetidines.3,4
Within azaheterocyclic chemistry, aziridines and azetidines are
extraordinary classes of strained compounds with diverse syn-
thetic and biological applications. Aziridines are versatile syn-
thetic intermediates for the preparation of a variety of ring-
opened and ring-expanded amines via regio- and stereoselective
ring-opening reactions with nucleophiles.5 Next to their syn-
thetic relevance,6 compounds containing an azetidine moiety
have been shown to possess a wide range of biological activities.7
In particular, 3-alkoxy- and 3-aryloxyazetidines have been de-
scribed as, for example, G-protein-coupled receptor agonists,8
inhibitors of stearoyl-coenzyme d-9 desaturase,9 and antibacterial
agents.10 The present paper describes a hitherto unexploited, yet
remarkable, synthesis of azetidines 3 through formation and
subsequent ring expansion of aziridines as intermediates derived
from N-alkylidene-(2,3-dibromo-2-methylpropyl)amines 1 (R2 =
Me) upon treatment with NaBH4 in methanol under reflux.
These findings stand in sharp contrast to the known reactivity of
the closely related N-alkylidene-(2,3-dibromopropyl)amines 1
(R2 = H), which are easily converted into 2-(bromomethyl)azi-
ridines 23,11 under the same reaction conditions (Scheme 1).
’ RESULTS AND DISCUSSION
Experimental Results. N-Alkylidene- and N-arylmethyli-
dene-(2,3-dibromo-2-methylpropyl)amines 7a-e were formed
by condensation of 2,3-dibromo-2-methylpropylamine hydrobro-
mide 512 with different aldehydes 6a-c in the presence of 1 molar
equiv of triethylamine and magnesium sulfate in dichloromethane
after reflux for 1 h (Scheme 2). The synthesis of 2,3-dibromo-2-
methylpropylamine hydrobromide 5 commenced with the imina-
tion of benzaldehyde using 2-methylallylamine hydrochloride 4 in
Received: December 23, 2010
Published: March 09, 2011
r
2011 American Chemical Society
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Scheme 2
dichloromethane in the presence of triethylamine and magnesium
sulfate, followed by bromination of the alkene moiety in the
resulting N-(2-methyl-2-propenyl)imine in dichloromethane and
subsequent treatment with 2 equiv of hydrogen bromide (48%
solution in water) in dichloromethane (two-phase system). In this
way, the desired 2,3-dibromo-2-methylpropylamine 5 was ob-
tained as the corresponding hydrobromide salt in 62% overall
yield in a short and easy approach (Scheme 2) through a large-
scale synthesis (up to 50 g).
Despite their reactive nature, imines 7c and 7d were purified
through distillation (Scheme 2, yields after distillation), whereas
the other derivatives were judged to be pure enough to be used in
further reactions without prior purification (purity >95% based
on 1H NMR). It should be noted that N-alkylidene-(2,3-dibromo-
2-methylpropyl)amines 7c-e cannot be obtained via bromina-
tion of the corresponding N-alkylidene-(2-methyl-2-pro-
penyl)amines due to the presence of an R-hydrogen atom with
regard to the CdN double bond, as in this case R-bromination
(and further reaction) prevails through imine-enamine tauto-
merism. The condensation of aldehydes 6 bearing an R-hydro-
gen atom with 2,3-dibromo-2-methylpropylamine 5 offers a
convenient alternative in that respect.
In the literature, N-alkylidene- and N-arylmethylidene-(2,3-
dibromopropyl)amines 1 (R2 = H, Scheme 3) have been used as
intermediates for the straightforward preparation of 2-(bromo-
methyl)aziridines 8 via reductive 3-exo-tet-cyclization using so-
dium borohydride in methanol under reflux.3 This convenient
synthesis of 2-(bromomethyl)aziridines 8 has formed the onset
of a very fruitful research area in organic chemistry, leading to the
development of a variety of novel classes of target compounds via
further elaboration.3,11 In analogy, the same methodology was
applied to N-alkylidene-(2,3-dibromo-2-methylpropyl)amines 1
(R2 = Me, Scheme 3) with the intention to prepare 2-bromo-
methyl-2-methylaziridines as a novel class of substrates. Surpris-
ingly, 3-methoxy-3-methylazetidines 9 were obtained instead,
giving rise to a new synthetic methodology toward this type of
compounds. Apparently, the presence of an additional methyl
group (R2 = Me) in imines 1 has a profound influence on the
reaction outcome. In a previous study, treatment of N-alky-
lidene-(2,2,3-tribromopropyl)amines with NaBH4 in methanol
has been reported to furnish 3,3-dimethoxyazetidines via double
methanolysis,4 although in that case the direct formation of
azetidines was foreseen as nucleophilic substitution at the
dibrominated carbon atom toward aziridines is highly unlikely.
The spectral data of 3-methoxyazetidines 9a-b were identical to
those reported in the literature,13 prepared via a totally different
route through NaBH4-mediated cyclization of N-alkylidene-(3-
bromo-2-methoxy-2-methylpropyl)amines.
Scheme 3
From a mechanistic point of view, different pathways can be
considered to explain the observed reactivity (Scheme 4). Re-
duction of imines 7 in methanol via hydride addition across the
imino bond toward amines 10 can either be followed by a 3-exo-
tet-cyclization affording 2-bromomethyl-2-methylaziridines 11
(pathway a) or a 4-exo-tet-cyclization toward 3-bromoazetidines
12 (pathway b). Subsequently, both types of β-bromoamines (11
and 12) can be transformed into bicyclic aziridinium salts 13
through intramolecular displacement of bromide by the nucleo-
philic nitrogen atom, which stand in equilibrium with the
nonbridged carbenium ions 14. Alternatively, the formation of
carbenium species 14 can be the result of spontaneous expulsion
of bromide in 3-bromoazetidines 12. Ring opening of intermedi-
ates 13 by methanol at the more hindered position14 or solvolysis
of carbenium species 14 by methanol finally affords 3-methox-
yazetidines 9.
On the basis of previous findings,15 the 3-exo-tet-cyclization
of amines 10 toward 2-bromomethyl-2-methylaziridines 11
(pathway a) will probably prevail (kinetic effect). The cyclization
of 2-bromomethyl-2-methylaziridines 11 to strained intermedi-
ates 13 stands in contrast with the well-known chemistry of
2-(bromomethyl)aziridines bearing no additional substituent at
the 2-position, as in this case the intramolecular cyclization and
further transformation has never been observed.3,11 The sponta-
neous cyclization of 2-bromomethyl-2-methylaziridines 11 un-
der thermodynamic conditions can be rationalized considering
the Thorpe-Ingold effect due to the gem-disubstitution at the
aziridine carbon atom, resulting in a more favorable geometric
positioning of the nucleophilic nitrogen atom with respect
to the halogenated carbon atom. Alternatively, 2-bromom-
ethyl-2-methylaziridines 11 can first be transformed into 3-bro-
moazetidines 12 via a concerted mechanism, which comprises
simultaneous cleavage and formation of a carbon-nitrogen bond
along with bromide migration. Furthermore, 3-bromoazetidines
12 can be converted into 3-methoxyazetidines 9 either via
bicyclic aziridinium salts 13 or via carbenium ions 14. The
presence and formation of strained intermediates 13 is regarded
as reasonable in a view of various reports involving this type of
intermediates. For example, the formation of a bicyclic
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Scheme 4
Scheme 5
aziridinium intermediate has been suggested in the literature
based on the stereospecific transformation of 3-tosyloxy- and
3-haloazetidines after hydrolysis and substitution reactions, and
ring contraction to aziridinylmethyl derivatives.16 Moreover, it
has been established that the substitution of 3-chloroazetidines
with different nucleophiles occurs via formation of an analogous
bicyclic intermediate which is then regioselectively opened at the
C3 position.17 In light of these reports, the ring opening of
bicyclic aziridinium salts 13 by methanol is expected to proceed
in a regiospecific way at the more hindered carbon atom,
furnishing 3-methoxyazetidines 9. However, the formation of
intermediate carbenium species 14 and their subsequent solvolysis
by methanol should not be completely neglected as an alternative
pathway toward azetidines 9. It is worth mentioning that the
isomerization of 2-(halomethyl)aziridines to 3-haloazetidines has
been observed in the literature in only two cases,18 and that
isolated examples are known in which ring opening of strained
bicyclic intermediates does not occur in a regiospecific way.16c
In the next part, a stepwise experimental approach was applied
in order to shed more light on the underlying reaction
mechanism. At first, a kinetically controlled synthesis of 1-ar-
ylmethyl-2-bromomethyl-2-methylaziridines 19 was envisaged
starting from R,β-dibromoaldimines 18 (Scheme 5). Bromina-
tion of 2-methylpropenal 15 using 1.05 equiv of bromine in
dichloromethane afforded the corresponding 2,3-dibromopro-
panal 16 in nearly quantitative yield, which was subsequently
condensed with 1 equiv of different N-(arylmethyl)amines 17 by
means of 0.6 equiv of titanium(IV) chloride and 3 equiv of
triethylamine in diethyl ether,15 furnishing R,β-dibromoimines
18 in good yields (Scheme 5). The latter imines 18 were reduced
by means of 2 molar equiv of sodium borohydride in methanol,
resulting in 2-bromomethyl-2-methylaziridines 19 after 36 h at
room temperature. Alternatively, imines 18 were reduced toward
aziridines 19a-d utilizing two molar equiv of sodium cyanobor-
ohydride in methanol in the presence of 1 equiv of acetic acid,
however, without providing better yields. In addition, 2-bromo-
methyl-2-methylaziridines 19a,b were also obtained through
reaction of N-arylmethylidene-(2,3-dibromo-2-methylpropyl)-
amines 7a and 7b with 2 molar equiv of NaBH4 in methanol after
36 h at room temperature. The formation of 2-bromomethyl-2-
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Scheme 6
Scheme 7
Scheme 8
methylaziridines 19 from both N-(2,3-dibromo-2-methylpropyli-
dene)amines 18 and N-arylmethylidene-(2,3-dibromo-2-methyl-
propyl)amines 7 is rationalized by the intermediacy of the
same amines 10 (Scheme 4) obtained upon reduction of imines
7 and 18 with NaBH4. From these findings, it is clear that
aziridines 11 are the kinetic and azetidines 9 the thermodynamic
products obtained through NaBH4-mediated reduction of imines
7 and 18 in methanol under reflux (Scheme 4).
Nonactivated 2-bromomethyl-2-methylaziridines 19 repre-
sent a novel class of synthons suitable for further elaboration
to a variety of nitrogen-containing compounds. Under thermo-
dynamic conditions, i.e., treatment of aziridines 19 with sodium
borohydride in methanol under reflux for 48 h, 3-methoxy-3-
methylazetidines 20 were formed in high yields as the sole
reaction products (Scheme 5). This prolonged reaction time
appeared to be necessary in order to drive the reaction to
completion. Again, it should be remarked that applying the same
reaction conditions to 2-(bromomethyl)aziridines 8 without a
2-methyl substituent is known to result in full recovery of the
starting material.
Heating of aziridines 19 in methanol under reflux for 24 h
resulted in a complex reaction mixture, pointing to the necessity of a
basic environment for this aziridine to azetidine rearrangement
process. Furthermore, treatment of aziridines 19 with 1.5 equiv of
NaOMe in MeOH (2 M) furnished azetidines 20, although a
prolonged reaction time was required (72 instead of 48 h).
The above-described synthetic route was also applied for a
straightforward synthesis of chiral 2-bromomethyl-2-methylaziri-
dines. Thus, N-(2,3-dibromo-2-methylpropylidene)-1(S)-pheny-
lethylamine 22 was prepared by imination of 2,3-dibromopropanal
16 with 1 equiv of (S)-R-methylbenzylamine 21 in the presence of
titanium(IV) choride and triethylamine. Next, imine 22 was reduced
utilizing 2 molar equiv of sodium borohydride in methanol, resulting
in a mixture of two diastereomeric 2-bromomethyl-2-methylaziri-
dines 23 and 24 (∼1/1) after 36 h at room temperature (Scheme 6).
After successful separation by column chromatography on silica gel,
chiral aziridines 23 and 24 were separately subjected to 3 molar equiv
of NaBH4 under reflux in methanol for 48 h. As expected, both
reactions provided the same chiral azetidine 25, which can be
explained considering the loss of chirality of the azetidine carbon
atom due to C2-symmetry (Scheme 6).
Once again, it should be stressed that only two reports are
available in the literature describing the ring expansion of
aziridines toward azetidines,18 pointing to the peculiar nature
of this type of rearrangements.
In order to evaluate the intrinsic reactivity of 2-bromo-
methyl-2-methylaziridines 19, aziridine 19b as a selected exam-
ple was heated in acetonitile under reflux for 15 h (Scheme 7),
affording 3-bromoazetidine 26 in 78% yield. The unprecedented
transformation of aziridine 19b into azetidine 26 as the thermo-
dynamic product further illustrates the relevance of this aziridine
to azetidine ring expansion and can be explained by formation of
bicyclic aziridinium salt 13 followed by attack of bromide at the
more hindered carbon atom. Moreover, when this 3-bromoaze-
tidine 26 was treated with NaBH4 in methanol under reflux,
3-methoxy-3-methylazetidine 20b was formed via solvolysis of
the same bicyclic intermediate 13 through ring opening
(Scheme 7).16,17 The replacement of bromide by methanol in
azetidine 26 via an SN2 protocol should be neglected as an
alternative reaction pathway due to the steric hindrance at the
tertiary carbon center, although SN1 reaction through solvolysis
of a tertiary carbenium ion might involve a plausible alternative.
In summary, a novel aziridine to azetidine rearrangement protocol
was established involving the conversion of 2-bromomethyl-2-
methylaziridines 11, obtained via reductive cyclization of halogenated
imines 7 or 18, into 3-methoxy-3-methylazetidines 9 through ring
opening of bicyclic intermediates 13 by methanol upon treatment
with NaBH4 in methanol under reflux (Scheme 8).
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Figure 1. Gibbs free energy profiles for the conversion of N-benzyl-N-(2,3-dibromo-2-methylpropyl)amine 10 (R = Ph) via pathways a and b (kJ/mol,
MPW1B95/6-31þþG**). (B3LYP/6-31þþG** geometries. Critical distances in Å.)
In the next part, a careful theoretical rationalization was
performed for a complete elucidation of the reaction mechanism.
Particular attention was devoted to the nature of the intermedi-
ates in this reaction, in particular the occurrence of bicyclic
aziridinium ions 13 versus nonbridged carbenium ions 14.
Theoretical Rationalization. A thorough computational
analysis was performed on the possible reaction pathways
proposed in Scheme 4 (R = Ph), in order to rationalize the
experimentally observed rearrangement and identify the
reactive intermediates involved. The most plausible path-
way will be determined through comparison of reaction
barriers.
Computational Methodology. Possible pathways were in-
vestigated at the B3LYP/6-31þþG** level of theory.19 Con-
formational analysis was performed on all ground states to
determine the most plausible conformers. Stationary points were
characterized as minima (ground states) or first-order saddle points
(transition states) via frequency calculations. IRC (intrinsic
reaction coordinate) calculations20 followed by full geometry
optimizations were used to locate the corresponding reactant and
product complexes. Energies were refined at the MPW1B95/
6-31þþG** level of theory,21 as previous studies have shown its
efficiency on aziridine species.11o,22 Thermal free-energy correc-
tions were taken from B3LYP/6-31þþG** optimizations at 1
atm and 298 K. The effect of a polar environment was introduced
by the use of self-consistent reaction field (SCRF) theory.23
Solvation free energies in methanol (ε = 32.6) were obtained via
the conductor-like polarizable continuum model (C-PCM).24 All
calculations were carried out with the Gaussian 03 and 09
program packages.25
Since nucleophilic substitution reactions are known to be
influenced by reaction conditions,26 pathways under study were
modeled with a proper solvent environment. Simulation of
reactions in organic solvents can be performed in a continuum
model,24,27 where the solvent is modeled as a continuous medium
characterized by a dielectric constant. However, if explicit solvent
interactions are present, discrete solvent molecules should be
placed around the chemically active species to form a so-called
“supermolecule” structure.22b,22c,28 Nevertheless, since this meth-
od only takes into account short-range interactions to account for
potential long-range interactions with the solvent environment,
the supermolecule can also be placed in a dielectric continuum,
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ARTICLE
leading to a mixed implicit/explicit model.29 A comparative study
has shown that mixed solvation models should be used with
caution as they can give unreliable results with increasing numbers of
explicit solvent molecules, and are highly influenced by their
orientation/alignment.30 Furthermore, a previous study on the
nucleophilic ring opening of aziridines has shown that embed-
ding the supermolecule in a dielectric continuum does not have
an appreciable effect and observed trends are similar to that of the
discrete solvent model.11o Therefore, in this study a discrete
solvent approach, where explicit methanol molecules were used
to build a supermolecule, was adapted.
Cyclization of N-Benzyl-N-(2,3-dibromo-2-methylpro-
pyl)amine 10 (R = Ph). There are two competing pathways in
the first step of the conversion of the N-benzyl-N-(2,3-dibromo-
2-methylpropyl)amine 10 to azetidine 9. Ring closure can lead to
aziridine 11 via pathway a or to azetidine 12 via pathway b. Free
energy profiles and relative energies along the reaction coordi-
nate for pathways a and b are illustrated in Figure 1 and Table 1.
Three explicit methanol molecules, which help to stabilize the
bromide ion through charge-dipole interactions, were used to
solvate the bromide ion, which is expelled during the SN2
reaction. The choice of three methanol molecules is justified
by a former study, which showed that only three acetic acid (also
a polar protic solvent) molecules have explicit contacts with the
bromide ion of an aziridinium-bromide complex.22c Typical
Figure 2. Transition-state geometries for the formation of bicyclic
aziridinium species. (B3LYP/6-31þþG** geometries. Critical distances
in Å.)
Table 2. Relative Gibbs Free Energies (kJ/mol) of Stationary
Points along the Reaction Coordinate for the Formation of
the Bicyclic Aziridinium Ionsa
Br HOMe distances are around 2.4 Å. Free energies of activa-
11b TS (11f13) 13 8b TS (8f27) 27
3 3 3
tion show that pathway a is the kinetically preferred route (ΔGq =
16.2 kJ/mol MPW1B95/6-31þþG**), which is in accordance
with experimental findings. Although the azetidinium ion (denoted
as 12-H in Figure 1) is the thermodynamically preferred product,
thermodynamic equilibration is not feasible as the aziridinium ion
(denoted as 11-H in Figure 1) is immediately deprotonated toward
the neutral, nonactivated aziridine 11 (which is thus not able to
undergo ring opening by bromide at C2). Therefore, aziridine 11 is
the preferred product for the cyclization, as observed experimentally.
Bicyclic Aziridinium Intermediates. As previously described,
aziridine 11 is suggested to undergo further cyclization to yield
the bicyclic aziridinium ion 13, a bicyclic intermediate that will
undergo nucleophilic ring opening to form azetidine 9 (Scheme 9).
However, as discussed previously, applying the same reaction
conditions to imines 1 (Scheme 3) with R2 = H and R2 = Me
resulted in 2-(bromomethyl)aziridines and 3-methoxy-3-methy-
lazetidines, respectively (Scheme 3). In other words, the pre-
sence of an additional methyl group in imines 1 seems to have a
B3LYP/6-31þþG**
0.0
96.0
61.4 0.0
53.4 0.0
120.9
119.1
75.6
61.1
MPW1B95/6-31þþG** 0.0
103.6
a B3LYP/6-31þþG** geometries. b Trans invertomers used for 8
and 11.
profound influence on the reaction outcome. Since intramole-
cular cyclization and further transformation to azetidines was
observed for 2-bromomethyl-2-methylaziridines 11 and not for
2-(bromomethyl)aziridines 8 (Scheme 9), which lack an addi-
tional substituent at the 2-position, cyclization pathways for both
compounds were investigated in detail.
Transition-state geometries and relative energies for the
formation of the bicyclic aziridinium ion 13 and 27 are shown
in Figure 2 and Table 2. The difference in free energies of
activation could explain why 2-bromomethyl-2-methylaziridines
11 undergo cyclization and further transformation as opposed to
2-(bromomethyl)aziridines 8, which lack an additional substitu-
ent at the 2-position. As mentioned earlier, this difference can be
rationalized considering the Thorpe-Ingold effect due to the gem-
disubstitution at the aziridine carbon atom, resulting in a more
favorable geometry for nucleophilic attack.31 Replacement of the
methyl group at the 2-position of aziridine 11 by a hydrogen atom
increases the distance between the nucleophilic nitrogen atom and
the halogenated carbon atom in aziridine 8, as shown in Figure 3,
which in turn gives rise to a reduced reactivity.
As suggested previously, bicyclic aziridinium ion 13 can be in
equilibrium with its nonbridged carbenium ion counterpart 14
(Scheme 10). The free energy profile and relative energies for
this equilibrium are shown in Figure 4 and Table 3, along with
atomic charges, calculated by means of natural population
analysis (NPA).32 The difference in relative stabilities of bicyclic
aziridinium ion 13 and cyclic carbenium ion 14 shows that the
former, where all atoms have full octet structure, is far more
stable than the latter. These results are consistent with earlier
calculations on bicyclic aziridinium intermediates performed at
Table 1. Relative Gibbs Free Energies (kJ/mol) of Stationary
Points along the Reaction Coordinate for the Conversion of
10 via Pathways a and ba
10
TSa
11
TSb
12
B3LYP/6-31þþG**
0.0
0.0
93.3
98.9
56.8
50.6
108.9
115.1
20.2
10.9
MPW1B95/6-31þþG**
a B3LYP/6-31þþG** geometries.
Scheme 9
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Figure 3. Invertomers of 8 and 11.
Table 3. Relative Gibbs Free Energies (kJ/mol) for the 13 to
14 Equilibrationa
13
TS (13f14)
14
B3LYP/6-31þþG**
0.0
0.0
0.0
86.2
108.7
106.5
63.2
84.6
78.3
MPW1B95/6-31þþG**
bMPW1B95/6-31þþG**
a B3LYP/6-31þþG** geometries. b CPCM (ε = 32.6).
Scheme 11
Figure 4. Gibbs free energy profile for the 13 to 14 equilibration (kJ/
mol, CPCM (ε = 32.6) MPW1B95/6-31þþG**). (B3LYP/6-
31þþG** geometries. Critical distances in Å. Atomic charges in italic.)
Scheme 10
MP2/6-311G**//HF/6-31G** level of theory, which showed
that open-ring structures are considerably less stable than the
corresponding bicyclic ions.14
Therefore, the reaction is expected to proceed through the
bicyclic aziridinium ion 13, and the carbenium species 14 is less
likely to be formed or will be short-lived. Next, possible fates of
the bicyclic species 13 were investigated.
Although initially proposed as an alternative route, the direct
transformation of aziridine 11 to azetidine 12 was not compu-
tationally viable. All attempts to locate a concerted transition
state for this transformation, where a simultaneous cleavage and
formation of a carbon-nitrogen bond is accompanied by bro-
mide migration, failed. It has already been established that an
equilibration between 11 and 12 through ring opening/ring
closure is unfeasible as the aziridinium ion (11-H, Figure 1) is
immediately deprotonated toward the neutral aziridine 11.
However, it is possible to obtain 12 via bromide-induced ring
opening of the bicyclic aziridinium 13 (pathway a, Scheme 11).
Figure 5 shows transition states for the transformation of 13 to
12 and 9, respectively. Due to its excessive strain, the bicyclic
intermediate 13 easily undergoes nucleophilic ring opening to
Figure 5. Transition state geometries for the formation of bromide- and
methanol-induced ring-opening reactions of bicyclic aziridinium species
13. (B3LYP/6-31þþG** geometries. Critical distances in Å.)
form azetidines 12 and 9. The transformation of 13 to 12 is
energetically more favorable (ΔΔGq = 38.9 kJ/mol MPW1B95/
6-31þþG**), since the bromide anion—solvated or not—is a
stronger nucleophile than neutral methanol.33 However, it
should be noted that the relative probabilities of these events
are dependent on concentration, and reaction conditions highly
favor the formation of 9 (pathway b, Scheme 11) since the
concentration of methanol is much higher than that of bromide.
However, in the absence of methanol, azetidine 12 would be the
observed product, as was experimentally shown (Scheme 7).
Nonetheless, if 13 is transformed to 12, its transformation to 9
through an SN2 reaction is hindered due to sterics that disable a
backside attack. On the other hand, an SN1 reaction would require
the formation of the highly activated carbenium species 14, which is
also not energetically feasible. It is more likely that azetidine 12 will be
transformed into azetidine 9 through bicyclic aziridinium 13.
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ARTICLE
Table 4. Relative Gibbs Free Energies (kJ/mol) of Stationary
Points along the Reaction Coordinate for the Bromide- and
Methanol-induced Nucleophilic Ring Opening of the Bicyclic
Aziridinium Ion 13.a
equiv) was added in small portions at 0 °C, and the mixture was stirred
for 36 h at room temperature. The reaction mixture was 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-bromomethyl-1-(4-methoxybenzyl)-2-methylaziri-
dine 19d (2.36 g, 87%), which was purified by filtration through silica
gel (hexane/ethylacetate 7:1) in order to obtain an analytically pure sample.
2-Bromomethyl-1-(4-methylbenzyl)-2-methylaziridine
13b TS (13f12) 12c TS (13f9) 9d
B3LYP/6-31þþG**
0.0
10.8
18.8
-78.9
-67.6
42.1
57.7
-49.1
-38.4
MPW1B95/6-31þþG** 0.0
a B3LYP/6-31þþG** geometries. b Reactant-complex of bicyclic azir-
idinium 13 and bromide ion solvated by three methanol molecules.
c Product-complex of azetidine 12 and three methanol molecules.
d Product-complex of azetidine 9 with hydrogen bromide and two
methanol molecules.
1
19b: yellow oil; Rf = 0.16 (hexane/ethyl acetate 9:1); yield 82%; H
NMR (300 MHz, CDCl3) δ 1.43 (3H, s), 1.50 (1H, s), 1.98 (1H, s), 2.33
(3H, s), 3.28 and 3.36 (2H, 2d, J = 9.9 Hz), 3.50 and 3.71 (2H, 2d, J =
13.7 Hz), 7.13-7.15 and 7.24-7.26 (4H, 2m); 13C NMR (75 MHz,
CDCl3) δ 13.6 (CH3), 21.1 (CH3), 40.2 (C), 41.7 (CH2), 44.1 (CH2),
57.1 (CH2), 127.7 and 129.1 (4 ꢀ CH), 136.5 (2 ꢀ C); IR (neat, cm-1
)
Computational analysis of the possible reaction pathways
proposed in Scheme 4 (R = Ph) has revealed that pathway a is
the kinetically preferred route (Figure 1) and aziridine 11 is the
subsequent product for the cyclization, as observed experimen-
tally. Unlike aziridines 8, which lack an additional substituent at
the 2-position, aziridine 11 then undergoes further cyclization to
yield the bicyclic aziridinium ion 13 (Figure 2), a strained
intermediate, which can undergo nucleophile-induced ring
opening to form azetidines 12 or 9, depending on the relative
abundance of the nucleophilic entity (Figure 5).
νmax = 3024, 2962, 2922, 2851, 1671, 1515, 1451, 1384, 1348, 1216,
1167, 1046, 798, 647; MS m/z 254/6 (Mþ þ 1, 100). Anal. Calcd for
C12H16BrN: C, 56.71; H, 6.35; N, 5.51. Found: C, 56.47; H, 6.63;
N, 5.44.
2-Bromomethyl-1-(2-chlorobenzyl)-2-methylaziridine
19c: yellow oil; Rf = 0.24 (hexane/ethyl acetate 9:1); yield 85%; H
1
NMR (300 MHz, CDCl3) δ 1.44 (3H, s), 1.58 (1H, s), 2.07 (1H, s), 3.35
and 3.40 (2H, 2d, J = 10.2 Hz), 3.63 and 3.85 (2H, 2d, J = 15.7 Hz),
7.20-7.36 and 7.66-7.69 (4H, 2m); 13C NMR (75 MHz, CDCl3) δ
13.6 (CH3), 40.2 (C), 42.0 (CH2), 43.9 (CH2), 54.3 (CH2), 126.9,
128.0, 129.0, and 129.1 (4 ꢀ CH), 132.8 (C), 137.3 (C); IR (neat, cm-1
)
’ CONCLUSIONS
νmax = 3035, 2964, 1470, 1443, 1386, 1348, 1218, 1171, 1037, 748, 644;
MS m/z 274/6/8 (Mþ þ 1, 100). Anal. Calcd for C11H13BrClN: C,
48.12; H, 4.77; N, 5.10. Found: C, 48.55; H, 4.92; N, 5.19.
The synthesis of 3-methyl-3-methoxyazetidines starting
from N-alkylidene-(2,3-dibromo-2-methylpropyl)amines
and N-(2,3-dibromo-2-methylpropylidene)benzylamines
through intermediate bicyclic aziridinium species has been
reported for the first time. It was shown that treatment of the
above-mentioned dibromoimines with NaBH4 in methanol
selectively provides 2-bromomethyl-2-methylaziridines at
room temperature and 3-methoxy-3-methylazetidines un-
der reflux, pointing to the conclusion that 3-methoxy-3-
methylazetidines are thermodynamic and 2-bromomethyl-
2-methylaziridines are kinetic products obtained in the
reaction of these imines with NaBH4 in methanol under
reflux through a rare aziridine to azetidine ring expansion.
Furthermore, a careful theoretical rationalization of the
reaction protocol provided a detailed elucidation of possible
mechanistic pathways indicating the initial formation of
2-bromomethyl-2-methylaziridines and subsequent ring ex-
pansion toward azetidines via intermediate bicyclic
aziridinium salts.
2-Bromomethyl-1-(4-methoxybenzyl)-2-methylaziridine
19d: yellow oil; Rf = 0.10 (hexane/ethyl acetate 7:1); yield 87%; H
1
NMR (300 MHz, CDCl3) δ 1.43 (3H, s), 1.50 (1H, s), 1.97 (1H, s), 3.29
and 3.34 (2H, 2d, J = 10.2 Hz), 3.47 and 3.69 (2H, 2d, J = 13.8 Hz), 3.80
(3H, s), 6.86-6.89 and 7.27-7.29 (4H, 2m); 13C NMR (75 MHz,
CDCl3) δ 13.6 (CH3), 40.2 (C), 41.7 (CH2), 44.2 (CH2), 55.3 (CH3),
56.8 (CH2), 113.8 and 129.0 (4 ꢀ CH), 131.7 (C), 158.6 (C); IR
(neat, cm-1) νmax = 3030, 2959, 2933, 2834, 1612, 1511, 1463, 1244,
1172, 1034, 819, 644; MS m/z 270/2 (Mþ þ 1, 100). Anal. Calcd for
C12H16BrNO: C, 53.35; H, 5.97; N, 5.18. Found: C, 53.55; H, 6.27;
N, 5.24.
Synthesis of Optically Active 2-Bromomethyl-2-methyla-
ziridines 23 and 24. N-(2,3-Dibromo-2-methylpropylidene)-1(S)-
phenylethylamine 22 (3.33 g, 10 mmol) was dissolved in methanol
(30 mL), after which NaBH4 (0.76 g, 2 molar equiv) was added in small
portions at 0 °C, and the mixture was stirred for 36 h at room
temperature. The reaction mixture was 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 2(R)-2-bromomethyl-1-[1(S)-phenylethyl]-2-
methylaziridine and 2(S)-2-bromomethyl-1-[1(S)-phenylethyl]-2-
methylaziridine 23 and 24 (2.42 g, 95%), which were separated by silica
gel column chromatography (petroleum ether/ethyl acetate 9:1) in
order to obtain analytically pure samples.
2(R)-2-Bromomethyl-1-[1(S)-phenylethyl]-2-methylaziri-
dine 23 and 2(S)-2-bromomethyl-1-[1(S)-phenylethyl]-2-
methylaziridine 24. 23: light yellow oil; Rf = 0.28 (petroleum
ether/ethyl acetate 9:1); yield 45%; [R]28D = -48.4 (c = 0.05, CDCl3);
1H NMR (300 MHz, CDCl3) 1.38 (1H, s), 1.43 (3H, d, J = 6.6 Hz), 1.51
(3H, s), 1.79 (1H, s), 3.10 (1H, q, J = 6.6 Hz), 3.25 and 3.46 (2H, 2d, J =
9.9 Hz), 7.25-7.40 (5H, m); 13C NMR (75 MHz, CDCl3) δ 13.4
(CH3), 24.6 (CH3), 40.6 (CH2), 41.1 (C), 44.9 (CH2), 61.6 (CH),
127.0 and 128.3 (5 ꢀ CH), 145.0 (C); IR (neat, cm-1) νmax = 3027,
2969, 2927, 2866, 1449, 1348, 1222, 1172, 755, 699, 646; MS m/z 254/6
’ EXPERIMENTAL SECTION
1
General Methods. H 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 in neat form with an ATR
(Attenuated Total Reflectance) accessory. Dichloromethane was dis-
tilled over calcium hydride, while diethyl ether and THF were distilled
from sodium and sodium benzophenone ketyl before use.
Synthesis of 2-Bromomethyl-2-methylaziridines 19. As a
representative example, the synthesis of 2-bromomethyl-1-(4-meth-
oxybenzyl)-2-methylaziridine 19d is described here. N-(2,3-Dibromo-
2-methylpropylidene)-4-methoxybenzylamine 18d (3.49 g, 10 mmol)
was dissolved in methanol (30 mL), after which NaBH4 (0.76 g, 2 molar
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The Journal of Organic Chemistry
ARTICLE
(Mþ þ 1, 100). Anal. Calcd for C12H16BrN: C, 56.71; H, 6.35; N, 5.51.
Found: C, 56.35; H, 6.63; N, 5.44. 24: light yellow oil; Rf = 0.15
127.3, and 128.4 (5 ꢀ CH), 143.8 (C); IR (neat, cm-1) νmax = 2966,
2929, 2825, 1451, 1370, 1235, 1067, 762, 700; MS m/z 206 (Mþ þ 1,
100). Anal. Calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C,
76.15; H, 9.60; N, 6.69.
(petroleum ether/ethyl acetate 9:1); yield 42%; [R]28 = -44.2 (c =
D
0.06, CDCl3); 1H NMR (300 MHz, CDCl3) 1.21 (3H, s), 1.40 (3H, d,
J = 6.6 Hz), 1.48 (1H, s), 2.00 (1H, s), 3.16 (1H, q, J = 6.6 Hz), 3.22 and
3.34 (2H, 2d, J = 9.9 Hz), 7.23-7.39 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 13.6 (CH3), 24.7 (CH3), 40.3 (CH2), 41.0 (C), 43.6 (CH2),
Synthesis of 3-Bromo-1-(4-methylbenzyl)-3-methylazeti-
dine 26. 2-Bromomethyl-1-(4-methylbenzyl)-2-methylaziridine 19b
(2.54 g, 10 mmol) was dissolved in acetonitrile (30 mL), and the mixture
was heated for 15 h under reflux. The reaction mixture was 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-bromo-1-(4-methylbenzyl)-3-methylazetidine 26
(1.98 g, 78%), which was purified by filtration through silica gel
(hexane/ethyl acetate 7:1) in order to obtain an analytically pure sample.
3-Bromo-1-(4-methylbenzyl)-3-methylazetidine 26: light
62.8 (CH), 126.5, 126.8, and 128.3 (5 ꢀ CH), 145.4 (C); IR (neat, cm-1
)
νmax = 3028, 2967, 2926, 2866, 1450, 1349, 1217, 1173, 757, 699, 646;
MS m/z 254/6 (Mþ þ 1, 100). Anal. Calcd for C12H16BrN: C, 56.71; H,
6.35; N, 5.51. Found: C, 56.62; H, 6.55; N, 5.46.
Synthesis of 3-Methoxy-3-methylazetidines 20 from 2-
Bromomethyl-2-methylaziridines 19. As a representative example,
the synthesis of 1-(2-chlorobenzyl)-3-methoxy-3-methylazetidine 20c is
described here. 2-Bromomethyl-1-(2-chlorobenzyl)-2-methylaziridine 19c
(2.76 g, 10 mmol) was dissolved in methanol (30 mL), after which NaBH4
(1.13 g, 3 molar equiv) was added in small portions at 0 °C, and the mixture
was heated for 48 h under reflux. The reaction mixture was 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-(2-chlorobenzyl)-3-methoxy-3-methylazetidine 20c (2.01 g,
89%), which was purified by filtration through silica gel (ether/hexane
10:1) in order to obtain an analytically pure sample.
1
yellow oil; Rf = 0.41 (hexane/ethylacetate 7:1); yield 78%; H NMR
(300 MHz, CDCl3) δ 1.99 (3H, s), 2.33 (3H, s), 3.51 and 3.69 (4H, 2d,
J = 8.2 Hz), 3.67 (2H, s), 7.10-7.18 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 21.2 (CH3), 31.6 (CH3), 52.0 (C), 63.0 (CH2), 70.8 (2 ꢀ
CH2), 128.5 and 129.2 (4 ꢀ CH), 134.6 and 136.9 (2 ꢀ C); IR
(neat, cm-1) νmax = 2922, 2848, 2807, 1514, 1440, 1360, 1244, 1206,
1178, 806, 734; MS m/z 254/6 (Mþ þ 1, 100). Anal. Calcd for C12H16BrN:
C, 56.71; H, 6.35; N, 5.51. Found: C, 56.55; H, 6.54; N, 5.37.
’ ASSOCIATED CONTENT
1-(2-Chlorobenzyl)-3-methoxy-3-methylazetidine 20c:
yellow oil; Rf = 0.15 (ether/hexane 10:1); yield 89%; H NMR (300
1
Supporting Information. Spectra (1H and 13C NMR) of
S
b
MHz, CDCl3) δ 1.51 (3H, s), 3.16 and 3.31 (4H, 2d, J = 8.3 Hz), 3.21
(3H, s), 3.79 (2H, s), 7.14-7.42 (4H, m); 13C NMR (75 MHz, CDCl3)
δ 21.8 (CH3), 50.6 (CH3), 60.2 (CH2), 65.0 (2 ꢀ CH2), 73.0 (C),
126.8, 127.8, 129.3, and 129.4 (4 ꢀ CH), 133.5 and 136.3 (2 ꢀ C); IR
(neat, cm-1) νmax = 2968, 2930, 2827, 1469, 1443, 1371, 1359, 1232,
1067, 1050, 1038, 748; MS m/z 226/8 (Mþ þ 1, 100). Anal. Calcd for
C12H16ClNO: C, 63.85; H, 7.14; N, 6.21. Found: C, 63.72; H, 7.33;
N, 6.44.
19b, 19c, 19d, 20c, 20d, 23, 24, 25 and 26. Cartesian coordinates
and energies of the optimized geometries (B3LYP/6-31þþG**)
of ground states; Cartesian coordinates, energies, imaginary and
low frequencies of the optimized geometries (B3LYP/6-
31þþG**) of transition states. This material is available free of
charge via the Internet at http://pubs.acs.org.
1-(4-Methoxybenzyl)-3-methoxy-3-methylazetidine 20d:
yellow oil; Rf = 0.17 (ether/hexane 10:1); yield 87%; H NMR (300
’ AUTHOR INFORMATION
1
Corresponding Author
*E-mail: matthias.dhooghe@UGent.be; veronique.vanspeybroeck@
UGent.be; norbert.dekimpe@UGent.be.
MHz, CDCl3) δ 1.47 (3H, s), 3.04 and 3.21 (4H, 2d, J = 7.7 Hz), 3.18
(3H, s), 3.60 (2H, s), 3.79 (3H, s), 6.83-6.86 and 7.19-7.22 (4H, 2m);
13C NMR (75 MHz, CDCl3) δ 21.6 (CH3), 50.4 (CH3), 55.2 (CH3),
63.1 (CH2), 64.5 (2 ꢀ CH2), 72.8 (C), 113.7 and 129.6 (4 ꢀ CH),
130.4 and 158.7 (2 ꢀ C); IR (neat, cm-1) νmax = 2933, 2833, 1611,
1511, 1463, 1241, 1173, 1065, 1034, 820; MS m/z 222 (Mþ þ 1, 100).
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.75;
H, 8.83; N, 6.24.
Present Addresses
#Department of Chemistry, Faculty of Science, University of
Antwerp, Middelheimcampus, G.V.211, Groenenborgerlaan
171, 2020 Antwerpen, Belgium.
Synthesis of Optically Pure 3-Methoxy-3-methyl-1-[1(S)-
phenylethyl]azetidine 25. The mixture of 2(R)-2-bromomethyl-
1-[1(S)-phenylethyl]-2-methylaziridine and 2(S)-2-bromomethyl-1-[1(S)-
phenylethyl]-2-methylaziridine 23 and 24 (2.55 g, 10 mmol) was dissolved
in methanol (30 mL), after which NaBH4 (1.13 g, 3 molar equiv)
was added in small portions at 0 °C, and the mixture was heated
for 48 h under reflux. The reaction mixture was 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-methoxy-3-methyl-1-[1(S)-phenylethyl]azetidine 25
(1.97 g, 96%), which was purified by filtration through silica gel (ether/
hexane 10:1) in order to obtain an analytically pure sample.
’ ACKNOWLEDGMENT
This work was supported by the Fund for Scientific Research
Flanders (FWO-Vlaanderen) and the Research Board of the Ghent
University (BOF-GOA). Computational resources and services
used in this work were provided by Ghent University. This work is
supported by the IAP-BELSPO program in the frame of IAP 6/27.
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The Journal of Organic Chemistry
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’ NOTE ADDED AFTER ASAP PUBLICATION
Scheme 3 contained an erroneous compound number and the
name of compound 19b was incomplete in the second to last
paragraph in the version published ASAP March 9, 2011. The
correct version reposted March 11, 2011.
2167
dx.doi.org/10.1021/jo102555r |J. Org. Chem. 2011, 76, 2157–2167