Stereoselective synthesis of cis -3,4-disubstituted piperidines through ring transformation of 2-(2-Mesyloxyethyl)azetidines

Article abstract of DOI:10.1021/jo201556t

The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding Β-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation

Full text of DOI:10.1021/jo201556t

ARTICLE
pubs.acs.org/joc
Stereoselective Synthesis of cis-3,4-Disubstituted Piperidines through
Ring Transformation of 2-(2-Mesyloxyethyl)azetidines
Karen Mollet,†,§ Saron Catak,‡ 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 (Member of QCMM-Alliance Ghent-Brussels), Technologiepark 903,
9052 Zwijnaarde, Belgium
S Supporting Information
b
ABSTRACT: The reactivity of 2-(2-mesyloxyethyl)azetidines,
obtained through monochloroalane reduction and mesylation
of the corresponding β-lactams, with regard to different nu-
cleophiles was evaluated for the first time, resulting in the
stereoselective preparation of a variety of new 4-acetoxy-,
4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone
to undergo an SN2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational
analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines,
providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-
3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid
hydrolysis.
Scheme 1
’ INTRODUCTION
Substituted six-membered azaheterocycles in general and
piperidines in particular are found in a whole variety of natural
products and pharmaceutical compounds and continue to attract
considerable attention due to their diverse and important bio-
logical activities. The pivotal position of piperidines is illustrated
by the fact that several thousands of piperidine derivatives have
been mentioned in clinical or preclinical studies.1 The biological
importance of this ring system makes short and versatile routes to
substituted piperidines of high interest and value. Therefore, a
continuous interest exists in the development of new methodol-
ogies for the synthesis of biologically active piperidines.2
Within azaheterocyclic chemistry, azetidines are an extraor-
dinary class of strained compounds, which makes them excellent
candidates for nucleophilic ring-opening or ring-expansion reac-
tions yielding highly substituted acyclic amines or higher ring
systems. As a result, substituted azetidines have, for example,
been proven to be suitable starting materials for rearrangements
toward pyrroles, pyrrolidines, pyrrolidinones, imidazolidinones,
isoxazolidines, piperidines, 1,2-oxazines, piperidin-2-ones, 2-imi-
nopiperidines, azepanes, and azepan-2-ones.3 Moreover, the
introduction of a leaving group in one of the substituents of
these small-ring heterocycles enables intramolecular transforma-
tions toward intermediate bicyclic azetidinium ions, which are
subsequently prone to undergo ring opening (mostly implying
ring expansion) by the expelled leaving group or by an additional
nucleophile.4,5
In previous work, we have demonstrated the applicability of
2-(2-bromo-1,1-dimethylethyl)azetidines 2, prepared via mono-
chloroalane reduction of the corresponding β-lactams 1, for the
construction of stereodefined 4-cyano-, 4-azido-, 4-bromo-, 4-fluoro-,
4-acetoxy-, and 4-hydroxypiperidines 3 (Scheme 1).4d,5a The starting
β-lactams 1 were synthesized through Staudinger reaction of N-
(3-bromo-2,2-dimethylpropylidene)amines and the appropriate ke-
tenes. Nonetheless, the incorporation of a 5,5-gem-dimethyl group in
piperidines 3 hampered the further elaboration of this synthetic
methodology, as the corresponding 5,5-nor-dimethyl variants
are usually considered to be more effective in terms of biological
activities.
Received: August 1, 2011
Published: September 14, 2011
r
2011 American Chemical Society
8364
dx.doi.org/10.1021/jo201556t J. Org. Chem. 2011, 76, 8364–8375
|

The Journal of Organic Chemistry
ARTICLE
Scheme 2
Scheme 3
In that respect, the synthesis of analogous piperidines 4, in
which no 5,5-gem-dimethyl group is present (Scheme 1), might
open up interesting possibilities for the development of biologi-
cally and pharmaceutically relevant compounds. To achieve this
goal, a different synthetic route had to be developed, as the
presence of α-protons in the N-(3-bromopropylidene)amines
leads to dehydrobromination as an undesired side reaction. From
a retrosynthetic point of view, the synthesis and ring expansion of
2-(2-mesyloxyethyl)azetidines, prepared via mesylation of the
corresponding alcohols, could offer a convenient alternative and
an easy access to this new class of 5-unsubstituted piperidines.
The present paper will focus on the reactivity of different
nucleophiles with regard to 2-(2-mesyloxyethyl)azetidines 5 to
develop new pathways toward biologically relevant piperidines.
Hereby, it should be noted that the chemistry of 2-(2-hydroxy-
ethyl)azetidines has been explored to a very limited extent
up to now, apart from reports of one type in which the
(unsubstituted) 2-azetidinylethanol moiety was found to con-
tribute significantly to the functional activity of nonpeptide
GnRH (gonadotropin releasing hormone) antagonists, thus
imparting to their clinical efficacy for the treatment of several
diseases including prostate cancer and breast cancer.6
then oxidized to the corresponding aldehyde 9 by means of
a Swern oxidation using oxalyl chloride, DMSO, and Et3N in
CH2Cl2 (Scheme 2).8 Subsequent imination of 3-(tert-butyldi-
methylsilyloxy)propanal 9 with 1 equiv of isopropylamine or
cyclohexylamine in dichloromethane in the presence of MgSO4
as a drying agent led to the formation of (E)-N-[3-(tert-butyldi-
methylsilyloxy)propylidene]alkylamines 10a,b in high yields.
Subsequently, imines 10 were used as substrates for a Staud-
inger reaction upon treatment with 1.3 equiv of two different
acetyl chlorides (i.e., phenoxy- and benzyloxyacetyl chloride) in
the presence of 3 equiv of triethylamine in dichloromethane,
affording the corresponding novel cis-4-[2-(tert-butyldimethylsi-
lyloxy)ethyl]azetidin-2-ones 6 (together with small amounts
(17À33%) of the corresponding N-alkyl-N-[3-(tert-butyldi-
methylsilyloxy)prop-1-enyl]acetamides) after 15 h at room tem-
perature (Scheme 2). This reaction involves a [2 + 2] cyclocon-
densation of imines 10 with the ketenes in situ generated from
benzyloxy- and phenoxyacetyl chloride. The stereochemical
outcome of the Staudinger reaction toward azetidin-2-ones 6
was shown to be cis based on the coupling constants between the
1
protons at C3 and C4 in H NMR (4.1À4.7 Hz, CDCl3).9 It
should be noted that the reported yields are yields obtained after
purification by column chromatography on silica gel.
’ RESULTS AND DISCUSSION
Although the chemistry of β-lactams has been thoroughly
investigated in the past,10 very little is known about the synthetic
applicability of the latter class of 2-azetidinones 6, pointing at the
unexplored nature of this subject. Indeed, β-lactams 6 hold
interesting potential for further elaboration due to the presence
of a strained four-membered ring and an oxygenated carbon
center. Therefore, a thorough investigation was executed to
reveal the synthetic applicability of these new β-lactam scaffolds.
To achieve a selective oxidation and to circumvent difficulties
associated with the presence of a free hydroxyl group during
β-lactam formation, 1,3-propanediol 7 was first monoprotected
as its tert-butyldimethylsilyl ether 8 using a literature protocol,
involving silylation of the monosodium salt (obtained upon
treatment of diol 7 with 1 equiv of NaH in THF) with 1 equiv
of tert-butyldimethylsilyl chloride (TBDMSCl) in THF,7 and
8365
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
Scheme 4
Scheme 5
To perform a selective reduction of the carbonyl moiety
without affecting the four-membered ring system, β-lactams 6
were treated with monochloroalane (AlH2Cl), as this method
had already been proven to be a suitable method for the synthesis
of functionalized azetidines.4,5a,11 Also in the present report,
reductions of highly functionalized β-lactams 6 were performed
successfully in that respect. Treatment of β-lactams 6 with 1
molar equiv of AlH2Cl, prepared in situ from 3 molar equiv of
LiAlH4 and 1 equiv of AlCl3, in Et2O at 0 °C for 2 h furnished the
corresponding 2-(2-hydroxyethyl)azetidines 11 in good yields
after deprotection of the silyl ether using 1.1 equiv of tetra-n-
butylammonium fluoride (TBAF) in THF (Scheme 3). It has to
be noted that in all cases significant amounts of alcohols 11
(40À85%) were present in the crude reaction mixtures after
monochloroalane reduction of the corresponding β-lactams 6
without subsequent introduction of TBAF. Furthermore, it was
necessary to perform an inverse addition by adding β-lactams 6
to 1 molar equiv of AlH2Cl in diethyl ether.
The reductive removal of the carbonyl group in β-lactams 6
proceeded with retention of stereochemistry as defined during
the Staudinger synthesis of these β-lactams 6. The cis stereo-
chemistry of azetidines 11 was unambiguously proven by the
observation that the coupling constants between the protons at
C2 and C3 of the azetidine ring (6.6À7.7 Hz, 1H NMR, CDCl3)
were similar to coupling constants found in the literature for
azetidines with analogous stereochemistry.4d,5,11c
1.05 equiv of mesyl chloride (MsCl) in the presence of a base and
a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in
dichloromethane at 0 °C for 3 h (Scheme 3), as substrates for
ring expansion toward piperidine derivatives was evaluated with
the intention to provide a convenient entry into the biologically
relevant class of 3-oxygenated piperidines. Although the ring
expansion of functionalized azetidines to produce 2-unsubsti-
tuted pyrrolidines is known in the literature,4a,f a similar re-
arrangement of azetidines toward 5,6-unsubstituted piperidines
has not been described before.
It should be stressed that during workup of the obtained
mesylated azetidines 5, careful monitoring of the temperature
proved to be very important, as evaporation of the solvent in
vacuo at temperatures higher than 25 °C led to the spontaneous
formation of reasonable amounts (4À35%) of ring-expanded
4-mesyloxypiperidines 13, which can be explained considering
the formation and subsequent mesylate-induced ring opening of
intermediate 1-azoniabicyclo[2.2.0]hexanes 12. In addition,
small amounts of 2-vinylazetidines 14 (3À12%) were observed
as well (Scheme 4).
In the next part, the deployment of azetidines 5 for the
synthesis of 4-substituted piperidines was examined. Thus,
treatment of 2-(2-mesyloxyethyl)azetidines 5 with 2 equiv of
LiBr in acetonitrile for 15 h under reflux resulted in the selective
formation of cis-4-bromopiperidines 15 in high yields after
column chromatography on silica gel or recrystallization from
absolute ethanol (Scheme 5). The cis stereochemistry of 3-oxy-
genated 4-bromopiperidines 15 was assessed on the basis of the
coupling constants between the protons at position 3 and 4
(3.6À3.9 Hz, 1H NMR, CDCl3), which are in accordance with
those reported in the literature for cis-vicinal substituted
piperidines.5a,14 Furthermore, the fact that dehydrobromination
occurred upon treatment of piperidines 15a,b with dimsylso-
dium (four equiv) in DMSO at 150 °C for 15 h was indicative of
Azetidines are generally recognized as valuable four-mem-
bered ring systems in organic chemistry, both from a synthe-
tic3À5,12 and from a medicinal viewpoint.13 Also, 2-(2-hydro-
xyethyl)azetidines 11 were expected to furnish a broad range of
reactivities, although little has been reported on the synthesis
and reactivity of this type of functionalized azetidines.
Consequently, the aptitude of 2-(2-mesyloxyethyl)azetidines
5, synthesized in high yields by treatment of azetidines 11 with
8366
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
Scheme 6
Scheme 7
a cis relationship between the C3 and C4 substituents, which is
required to obtain an anti-elimination (Scheme 5). The obtained
cyclic enol ethers 16 could be easily hydrolyzed to give 1-iso-
propylpiperidin-3-one 1715 by reaction with aq 2 M HCl at 40 °C
for 40 h (Scheme 5). Piperidin-3-ones constitute a class of
compounds of high biological interest as they are considered as
pharmacophores in medicinal sciences and their synthesis is often
associated with the preparation of biologically relevant compounds.16
From a mechanistic point of view, the observed cis stereo-
chemistry of piperidines 15 can be rationalized considering the
in situ formation and consecutive ring opening of bicyclic
azetidinium intermediates 12 (Scheme 5). This reaction me-
chanism is based on the intramolecular displacement of the
mesyloxy substituent by the nucleophilic nitrogen lone pair of
azetidines 5 toward reactive bicyclic intermediates 12, which are
subsequently prone to undergo ring opening by a nucleophile,
i.e., bromide, at the bridgehead carbon atom in an SN2 fashion to
furnish the thermodynamically more favored six-membered
4-bromopiperidines 15 (Scheme 5). It should be stressed
that the transient generation of 1-azoniabicyclo[2.2.0]hexanes
has been described in only a few exceptional cases in the literature
so far.4d,5a An alternative reaction pathway, involving direct
nucleophilic substitution of the mesyloxy group by bromide
followed by ring expansion via bicyclic azetidinium ions 12,
should not be excluded. The selective formation of 4-bromopi-
peridines 15 over 4-mesyloxypiperidines 13 can be attributed to
the considerably stronger nucleophilicity of bromide in acetoni-
trile as compared to the mesyloxy anion.
Upon detailed spectroscopic analysis, small amounts of 2-vi-
nylazetidines 14 (5À9%) were observed as well in the crude
reaction mixtures, as characteristic azetidine chemical shifts and
typical signals for vinylic protons were detected in the 1H NMR
spectra of these mixtures (CDCl3).
Subsequently, attempts were made to broaden the scope of
this synthetic methodology toward other 4-substituted piperidine
derivatives. The possibility of introducing nucleophiles other than
bromine was first tested through the addition of sodium acetate.
Thus, treatment of azetidines 5 with 2 equiv of NaOAc in acetonitrile
under reflux for 15 h resulted in the selective formation of cis-4-
acetoxypiperidines 18 in good yields (Scheme 6). The relative cis
stereochemistry controlled by the Staudinger synthesis of β-lactams
6 was transferred through the reaction sequence, affording cis-
piperidines 18 in a stereoselective way as demonstrated by the vicinal
coupling constants between the protons at C3 and C4 (2.9À4.0 Hz,
8367
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
Figure 1. Formation of the bicyclic azetidinium ion 12a, solvated by explicit acetonitrile molecules. M06-2X/6-311++G(d,p)//B3LYP/6-31+G(d,p).
Critical distances in Å.
1H NMR, CDCl3), which are in accordance with literature data con-
cerning cis-3,4-dioxygenated piperidines.5a,14 Again, small amounts
of 2-vinylazetidines 14 (2À6%) were present in the crude reaction
mixtures.
Next, the reactivity of 4-acetoxypiperidines 18 was evaluated
with the intention to provide a convenient entry into the bio-
logically relevant class of 4-hydroxylated piperidines,17 yielding
the corresponding cis-4-hydroxy-3-(phenoxy- or benzyloxy)
piperidines 19 via methanolysis of the ester moiety upon treat-
ment with 2 equiv of K2CO3 in methanol under reflux for 1 h
(Scheme 6).
formation of intermediate bicyclic azetidinium ions 12. To assess
the feasibility of this process and the relative stability of these
intermediates, a density functional theory (DFT)-based compu-
tational study was performed on both the formation of the highly
transient intermediate 12a as well as its ring opening by
nucleophiles, acetate in particular (Scheme 6), leading to the
corresponding piperidine 18a.
Computational Methodology. DFT calculations, utilizing
the Gaussian 0918 program package, were carried out to model
both reactions mentioned above. All reactants, transition states,
intermediates, and products were optimized using the hybrid
functional B3LYP19 with the 6-31+G(d,p) basis set.20 Harmonic
vibrational frequencies, computed at the same level of theory,
were used to provide thermal contributions to Gibbs free
energies at 298 K and 1 atm and to confirm the nature of the
stationary points. Intrinsic reaction coordinate (IRC)21 paths
were traced to locate the two associated minima, corresponding
to reactant and product complexes, directly connected to each
transition state on the potential energy surfaces.
In an effort to investigate the influence of the level of theory on
barrier heights, energies were refined with contemporary DFT
functionals, including newly developed range-separated hybrids.
The following functionals were used in conjunction with the
6-311++G(d,p) basis set: Boese and Martin’s τ-dependent
hybrid functional BMK,22 which was especially developed for
reaction kinetics and known to efficiently reproduce activation
barriers;23 Truhlar and Zhao’s meta hybrid functional M06-2X,24
which has double the amount of nonlocal exchange and has
proven to perform well on organic systems with dispersive
effects;25 CAM-B3LYP, Handy’s long-range corrected version
of B3LYP utilizing the Coulomb-attenuating method;26 and
finally ω-B97X-D, Head-Gordon’s latest hybrid functional,
which includes long-range corrections as well as damped atomÀ
atom dispersion corrections,27 found to be one of the most
promising methods in a recent benchmark of density functional
methods for main group thermochemistry, kinetics, and noncovalent
To further assess their intrinsic reactivity, azetidines 5 were
heated in DMF at 80 °C for 3 h. Surprisingly, next to small
amounts of 2-vinylazetidines 14 (3À7%), azetidines 5 were
almost exclusively converted into cis-4-formyloxypiperidines 21
(Scheme 7). A plausible explanation for this transformation
involves the formation of intermediate azetidinium salts 12,
followed by nucleophilic ring opening by dimethylformamide
at the bridgehead carbon atom. Subsequent hydrolysis of inter-
mediates 20 during aqueous workup afforded the corresponding
piperidines 21 in high yields after purification by column
chromatography on silica gel. Again, the relative cis stereochem-
istry obtained during the Staudinger synthesis of β-lactams 6 was
retained, thus affording cis-piperidines 21 as can be derived from
the coupling constants between the protons at C3 and C4
(3.9À4.1 Hz, 1H NMR, CDCl3).5a,14
In addition to the elegant nature of this transformation (no
additional reagents required), 4-formyloxypiperidines thus ob-
tained are valuable compounds due to the combination of a
piperidine moiety and a formyloxy group, which enables the
preparation of a variety of functionalized piperidines through
further modification of the ester functionality.
’ THEORETICAL RATIONALIZATION
The cis stereochemistry observed in piperidines formed from
the ring enlargement of azetidines 5 can be rationalized by the
8368
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
interactions28 and for distance dependent hydrogen-bonded inter-
actions.29
based on full solute electron densities. The molecular cavity was built,
including explicit hydrogen spheres, using atomic radii from the UFF
force field scaled by 1.1.
Ionic species, such as the nucleophile and nucleophuge involved in
nucleophilic substitution reactions, are known to be stabilized by the
solvent environment.30 To properly model the effect of the solvent, a
mixed explicit/implicit solvation scheme31 has been employed in the
current study. Explicit solvation, also known as “microsolvation”,
involves placing discrete solvent molecules around the chemically
active species to form a so-called “supermolecule” structure. How-
ever, this method only takes into account short-range interactions.
To account for potential long-range interactions with the solvent
environment, the supermolecule was also immersed in a dielectric
continuum by means of the self-consistent reaction field (SCRF)
theory.32 Free energies in acetonitrile (MeCN, ε = 36.6) were
obtained via C-PCM, the conductor-like polarizable continuum
model,33 and SMD,34 the newly developed universal solvation model
Formation and Ring Opening of Bicyclic Azetidinium Ion
12a. The formation of bicyclic azetidinium ion 12a (Schemes 4,
5, 6, and 7) occurs via intramolecular nucleophilic attack of the
nitrogen atom of the azetidine 5a (Scheme 3) and simultaneous
displacement of the mesylate ion as depicted in TS1 (Figure 1).
Three explicit acetonitrile molecules were used to stabilize the
nucleophuge, each interacting with one of the mesylate oxygen
atoms through chargeÀdipole interactions. Typical distances
for CH O type interactions between acetonitrile and the
3 3 3
mesylate group are within the range of 2.1À2.3 Å. Ring opening
of the bicyclic azetidinium ion 12a occurs via nucleophilic attack
at the bridgehead carbon atom, resulting in the formation of 18a
(Scheme 6), as shown in TS2 (Figure 2). The incoming acetate
ion is stabilized by explicit interactions with two acetonitrile
molecules. Interactions between acetonitrile molecules and the
acetate ion are similar to those described for the mesylate group.
Relative free energies for the formation of bicyclic intermediate
12a and its ring opening via acetate attack are listed in Table 1.
As mentioned earlier, relative free energies along the reaction
path for the formation and ring opening of bicyclic intermediate
12a were calculated using two different solvation schemes,
namely, microsolvation (explicit solvation) and mixed solvation
(explicit/implicit solvation). For the latter scheme, two different
continuum models (C-PCM and SMD) were employed. For all
three solvation models, energies were refined using five different
DFT methods, two of which are recently developed range-
separated density functionals (CAM-B3LYP and ωB97X-D),
that are particularly chosen to account for the long-range dis-
persive interactions between the substrate and the explicit aceto-
nitrile molecules. Compared to nonsolvated gas-phase results
[relative free energy of TS1 in gas phase =136.6 kJ/mol, BMK/
6-311++G(d,p)//B3LYP/6-31+G(d,p)], explicit solvation lowers
barriers by an average of 15 kJ/mol by means of stabilizing the
forming charge through intermolecular interactions. Results for
Figure 2. Transition state structure (TS2) for the acetate-induced ring
opening of bicyclic azetidinium ion 12a, solvated by explicit acetonitrile
molecules. B3LYP/6-31+G(d,p) geometries. Critical distances in Å.
Table 1. Relative Gibbs Free Energies (kJ/mol, 298 K and 1 atm) for the Formation and the Nucleophilic Ring Opening of Bicyclic
Azetidinium Intermediate 12aa
formation of intermediate 12a
ring opening of intermediate 12a
5a
TS1
12a + mesylate
12a + acetate
TS2
18a
explicit solvation
B3LYP
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
123.2
124.8
121.1
127.2
111.2
104.3
105.9
102.3
108.1
92.2
26.1
1.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
37.6
60.4
52.8
47.6
57.6
43.8
65.4
58.5
53.1
63.3
45.1
66.2
59.2
54.2
64.2
À141.1
À120.3
À142.6
À141.4
À118.6
À134.9
À114.7
À135.3
À135.3
À111.9
À135.3
À116.1
À136.8
À136.2
À113.1
BMK
M06-2X
CAM-B3LYP
ωB97X-D
B3LYP
6.8
17.3
À1.8
3.4
explicit/implicit solvation with C-PCM
explicit/implicit solvation with SMD
BMK
À21.4
À16.9
À5.7
À25.0
À2.7
À26.8
À22.1
À11.6
À30.4
M06-2X
CAM-B3LYP
ωB97X-D
B3LYP
103.3
105.5
102.2
107.3
91.8
BMK
M06-2X
CAM-B3LYP
ωB97X-D
a B3LYP/6-31+G(d,p) optimized structures. Single point energy calculations at all levels of theory with 6-311++G(d,p) basis set. Implicit solvation in
acetonitrile, ε = 36.6.
8369
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
both mixed (explicit/implicit) solvation models, i.e., C-PCM and
SMD, indicate that implicit solvation lowers the barriers by an
additional 20 kJ/mol, bringing the barrier for the formation of
bicyclic intermediate 12a (see relative energy of TS1) down to
∼100 kJ/mol. The consistency among C-PCM and SMD results
is noteworthy. The ωB97X-D functional, considered to be one of
the most promising methods in recent benchmark studies,28,29
produces on average 10 kJ/mol lower relative free energies
compared to other functionals. These results indicate that the
formation of intermediate 12a is a feasible process and, further-
more, its stability is comparable to the starting azetidine 5a.
Nucleophilic ring opening (TS2) of the bicyclic azetidinium ion
12a occurs readily, as illustrated in the small barriers and highly
exergonic nature of this reaction step (Table 1).
The nucleophile (acetate) and nucleophuge (mesyloxy) in-
volved in this computational study both bear highly localized
negative charges on their oxygen atoms. The solvent, acetonitrile,
in return is highly polar (ε = 36.6) yet aprotic and, therefore, is
unlikely to form very strong explicit interactions with the
substrate. However, the dielectric constant of the solvent body
can have a larger stabilizing effect on these charged species, as was
observed in this study. Previous computational studies employ-
ing the mixed explicit/implicit solvent approach have shown that
with protic solvents, such as acetic acid and methanol, micro-
solvation alone gives sufficient solvent stabilization and the effect
of placing the supermolecule in a continuum does not result in
any appreciable stabilization.31d,e This is in line with the fact that
protic solvents give rise to much higher coordination solvation
energies per solvent molecule than polar aprotic solvents, due to
strong intermolecular hydrogen-bonding interactions.31f None-
theless, the results of this study show that in case of a highly polar
aprotic solvent, such as acetonitrile, stabilization caused by the
dielectric continuum can be even higher than that caused by
explicit chargeÀdipole interactions between the solvent and the
substrate. While microsolvation alone is quite satisfactory for
protic solvents, this study has shown that mixed solvation models
are necessary to properly mimic the stabilizing effect of highly
polar aprotic solvents.
analysis. These results show that the bicyclic intermediate could
be localized on the potential energy surface as a stable species.
’ EXPERIMENTAL SECTION
Synthesis of (E)-N-[3-(tert-Butyldimethylsilyloxy)propylidene]
alkylamines 10. As a representative example, the synthesis of (E)-
N-[3-(tert-butyldimethylsilyloxy)propylidene]isopropylamine10a is described
here. To a solution of 3-(tert-butyldimethylsilyloxy)propanal 9 (10 mmol) in
anhydrous CH2Cl2 (40 mL) were added MgSO4 (20 mmol, 2 equiv) and
isoproylamine (10 mmol, 1 equiv). After 2 h of stirring at room temperature,
MgSO4 was removed by filtration. After evaporation of the solvent in vacuo,
(E)-N-[3-(tert-butyldimethylsilyloxy)propylidene]isopropylamine
10a was obtained in 70% yield. Imines 10 were obtained in high purity (>95%
based on 1H NMR) and used as such in the next reaction step due to their
hydrolytic instability.
(E)-N-[3-(tert-Butyldimethylsilyloxy)propylidene]isopro-
pylamine 10a. (70%) Yellow oil. 1H NMR (CDCl3): δ À0.05 (6H,
s); 0.79 (9H, s); 1.05 (6H, d, J = 6.3 Hz); 2.34 (2H, q, J = 5.8 Hz); 3.19
(1H, septet, J = 6.3 Hz); 3.73 (2H, t, J = 5.8 Hz); 7.63 (1H, t, J = 5.8
Hz). 13C NMR (CDCl3): δ À5.4 (CH3); 18.2 (C); 24.1 (CH3); 25.9
(CH3); 38.9 (CH2); 60.5 (CH2); 61.5 (CH); 160.1 (CH). IR (cmÀ1):
νCdN = 1666. MS: m/z (%): 229 (M+, 1); 214 (10); 172 (100); 142
(14); 130 (35); 100 (32); 73 (18); 59 (9); 43(10).
(E)-N-[3-(tert-Butyldimethylsilyloxy)propylidene]cyclohe-
xylamine 10b. (75%) Yellow oil. 1H NMR (CDCl3): δ 0.05 (6H, s);
0.89 (9H, s); 1.09À1.37, 1.40À1.53, 1.61À1.66 and 1.71À1.82 (10H,
4 Â m); 2.44 (2H, q, J = 5.7 Hz); 2.88À2.98 (1H, m); 3.83 (2H, t, J = 5.7
Hz); 7.74 (1H, t, J = 5.7 Hz). 13C NMR (CDCl3): δ À5.3 (CH3); 18.3
(C); 24.9 (CH2); 25.2 (CH2); 25.7 (CH2); 25.9 (CH3); 34.4 (CH2);
36.3 (CH2); 39.2 (CH2); 60.7 (CH2); 69.9 (CH); 160.5 (CH). IR
(cmÀ1): νCdN = 1667. MS: m/z (%): 270 (M+ + 1, 100).
Synthesis of cis-1-Alkyl-4-[2-(tert-butyldimethylsilyloxy)
ethyl]azetidin-2-ones 6. As a representative example, the synth-
esis of cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-isopropyl-3-phenox-
yazetidin-2-one 6a is described here. To an ice-cooled solution of (E)-
N-[3-(tert-butyldimethylsilyloxy)propylidene]isopropylamine 10a (3.6
mmol) and Et3N (10.8 mmol, 3 equiv) in anhydrous CH2Cl2 (25 mL)
was added dropwise a solution of phenoxyacetyl chloride (4.7 mmol, 1.3
equiv). The reaction mixture was stirred for 15 h at room temperature
and was then washed with water (25 mL). Subsequently, the aqueous
phase was extracted with CH2Cl2 (3 Â 25 mL), after which the
combined organic fractions were dried over MgSO4, followed by
removal of the drying agent and evaporation of the solvent in vacuo.
Purification by means of column chromatography on silica gel (hexane/
EtOAc 6/1) afforded pure cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-
isopropyl-3-phenoxyazetidin-2-one 6a.
’ CONCLUSION
In conclusion, the reactivity of 2-(2-mesyloxyethyl)azetidines,
prepared via monochloroalane reduction and mesylation of the
corresponding β-lactams, toward different nucleophiles has been
evaluated for the first time, pointing to a useful transformation of
the former into the biologically relevant class of cis-3,4-disubsti-
tuted piperidines through SN2 ring opening of intermediate
1-azoniabicyclo[2.2.0]hexanes. The latter bicyclic azetidinium
salts, lacking a 5,5-gem-dimethyl group, have not yet been
described in the literature, and the present results allow the
construction of a wide variety of vicinally functionalized six-
membered heterocycles. This approach constitutes a convenient
alternative for the known preparation of 3,4-disubstituted 5,5-
dimethylpiperidines, as the corresponding 5,5-nor-dimethyl var-
iants provide interesting opportunities within the field of drug
development. Furthermore, a new entry into the piperidin-3-one
scaffold is provided through dehydrobromination of 4-bromo-
3-(phenoxy- or benzyloxy)piperidines followed by acid hydro-
lysis. In addition to the experimental results, the intermediacy of
transient 1-azoniabicyclo[2.2.0]hexanes in this transformation
was further validated by means of high-level computational
cis-4-[2-(tert-Butyldimethylsilyloxy)ethyl]-1-isopropyl-3-
phenoxyazetidin-2-one 6a. (47%) Yellow crystals. Mp = 57.2 °C.
1
Rf = 0.14 (hexane/EtOAc 6/1). H NMR (CDCl3): δ 0.02 and 0.04
(2 Â 3H, 2 Â s); 0.89 (9H, s); 1.29 and 1.34 (2 Â 3H, 2 Â d, J = 6.8 Hz);
1.95À2.12 (2H, m); 3.60À3.68 and 3.71À3.78 (2 Â 1H, 2 Â m); 3.85
(1H, septet, J = 6.8 Hz); 4.13 (1H, ddd, J = 8.8, 4.1, 4.1 Hz); 5.16 (1H, d,
J = 4.1 Hz); 6.96À7.11 and 7.26À7.32 (5H, 2 Â m). 13C NMR
(CDCl3): δ À5.42 (CH3); À5.37 (CH3); 18.2 (C); 20.1 (CH3); 21.8
(CH3); 25.9 (CH3); 32.7 (CH2); 44.6 (CH); 54.3 (CH); 59.7 (CH2);
79.7 (CH); 115.6 (CH); 122.0 (CH); 129.5 (CH); 157.8 (C); 165.5
(C). IR (cmÀ1): νCdO = 1754. MS: m/z (%): 364 (M+ + 1, 100). Anal.
Calcd for C20H33NO3Si: C 66.07; H 9.15; N 3.85. Found: C 65.87; H
9.37; N 4.18.
cis-3-Benzyloxy-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-
isopropylazetidin-2-one 6b. (35%) Yellow oil. Rf = 0.10 (hexane/
EtOAc 6/1). 1H NMR (CDCl3): δ À0.07 and À0.06 (2 Â 3H, 2 Â s);
0.87 (9H, s); 1.20 and 1.24 (2 Â 3H, 2 Â d, J = 6.6 Hz); 1.91À1.97 (2H,
8370
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
m); 3.58À3.81 (3H, m); 3.88 (1H, ddd, J = 8.8, 4.7, 4.4 Hz); 4.52 (1H, d,
J = 4.7 Hz); 4.65 and 4.87 (2 Â 1H, 2 Â d, J = 11.9 Hz); 7.23À7.35 (5H,
m). 13C NMR (CDCl3): δ À5.4 (CH3); À5.3 (CH3); 18.3 (C); 20.1
(CH3); 21.8 (CH3); 25.9 (CH3); 32.6 (CH2); 44.2 (CH); 53.9 (CH);
59.9 (CH2); 72.6 (CH2); 80.6 (CH); 127.8 (CH); 128.1 (CH); 128.4
(CH); 137.5 (C); 167.3 (C). IR (cmÀ1): νCdO = 1747. MS: m/z (%):
378 (M+ + 1, 100). HRMS (ESI) calcd for C21H36NO3Si 378.2464
[M + H]+, found 378.2463.
7.28À7.37 (5H, m). 13C NMR (ref = CDCl3): δ 20.2 (CH3); 21.1
(CH3); 32.5 (CH2); 56.3 (CH2); 57.6 (CH); 60.8 (CH2); 67.0 (CH);
70.5 (CH); 70.9 (CH2); 127.8 (CH); 128.4 (CH); 128.4 (CH); 137.7
(C). IR (cmÀ1): νOH = 3380. MS: m/z (%): 250 (M+ + 1, 100). Anal.
Calcd for C15H23NO2: C 72.25; H 9.30; N 5.62. Found: C 72.17; H
9.44; N 5.61.
cis-3-Benzyloxy-1-cyclohexyl-2-(2-hydroxyethyl)azetidine
11c. (50%) White crystals. Mp = 93.3 °C. Recrystallization from hexane/
EtOAc (1/25). 1H NMR(CDCl3): δ 0.88À1.28 and 1.61À1.80 (5H and
6H, 2 Â m); 2.05À2.15 (1H, m); 2.17À2.26 (1H, m); 3.02 (1H, dd, J =
9.5, 6.5Hz); 3.55 (1H, dd, J = 9.5, 2.8 Hz);3.57À3.59 (1H, m); 3.71 (1H,
ddd, J = 10.3, 5.1, 5.1 Hz); 3.92 (1H, ddd, J = 10.3, 10.2, 3.1 Hz); 4.26
(1H, ddd, J = 6.6, 6.5, 2.8 Hz); 4.38 and 4.58 (2 Â 1H, 2 Â d, J = 11.9 Hz);
7.28À7.37 (5H, m). 13C NMR (ref = CDCl3): δ 24.7 (CH2); 24.8
(CH2); 25.9 (CH2); 30.4 (CH2); 31.5 (CH2); 32.7 (CH2); 56.1 (CH2);
61.0 (CH2); 66.3 (CH); 66.9 (CH); 71.0 (CH2); 71.1 (CH); 127.8
(CH); 128.5 (CH); 128.5 (CH); 137.8 (C). IR (cmÀ1): νOH = 3147.
MS: m/z (%): 290 (M+ + 1, 100). Anal. Calcd for C18H27NO2: C 74.70;
H 9.40; N 4.84. Found: C 74.52; H 9.54; N 4.84.
Synthesis of cis-1-Alkyl-2-(2-mesyloxyethyl)azetidines 5.
As a representative example, the synthesis of cis-1-isopropyl-2-(2-
mesyloxyethyl)-3-phenoxyazetidine 5a is described here. To an ice-
cooled solution of cis-2-(2-hydroxyethyl)-1-isopropyl-3-phenoxyazeti-
dine 11a (1 mmol) in CH2Cl2 (15 mL) were added 4-(dimethy-
lamino)pyridine (0.1 mmol, 0.1 equiv), Et3N (1.1 mmol, 1.1 equiv),
and mesyl chloride (1.05 mmol, 1.05 equiv), after which the mixture was
stirred for 3 h at 0 °C. Afterward, the reaction mixture was washed with
brine (2 Â 15 mL) and a saturated NaHCO3 solution (2 Â 15 mL). The
aqueous phase was washed with CH2Cl2 (2 Â 20 mL). Drying
(MgSO4), filtration of the drying agent, and removal of the solvent in
vacuo afforded cis-1-isopropyl-2-(2-mesyloxyethyl)-3-phenoxyazetidine
5a. Due to the high intrinsic reactivity of azetidines 5, no accurate HRMS
data could be obtained.
cis-3-Benzyloxy-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-
cyclohexylazetidin-2-one 6c. (55%) Colorless oil. Rf = 0.11
1
(hexane/EtOAc 9/1). H NMR (CDCl3): δ 0.00 and 0.01 (2 Â 3H,
2 Â s); 0.86 (9H, s); 1.04À1.30, 1.34À1.47, 1.52À1.60 and 1.69À2.02
(12H, 4 Â m); 3.32À3.42 (1H, m); 3.58À3.83 (2H, m); 3.87 (1H, ddd,
J = 8.7, 4.5, 4.0 Hz); 4.52 (1H, d, J = 4.5 Hz); 4.65 and 4.87 (2 Â 1H, 2 Â
d, J = 11.9 Hz); 7.26À7.32 (5H, m). 13C NMR (CDCl3): δ À5.4 (CH3);
À5.3 (CH3); 18.3 (C); 25.2 (CH2); 25.3 (CH2); 25.3 (CH2); 25.9
(CH3); 30.5 (CH2); 31.9 (CH2); 32.6 (CH2); 52.1 (CH); 54.1 (CH);
59.8 (CH2); 72.6 (CH2); 80.6 (CH); 127.8 (CH); 128.4 (CH); 128.4
(CH); 137.5 (C); 167.3 (C). IR (cmÀ1): νCdO = 1746. MS: m/z (%):
418 (M+ + 1, 100). HRMS (ESI) calcd for C24H40NO3Si 418.2777
[M + H]+, found 418.2788.
Synthesis of cis-1-Alkyl-2-(2-hydroxyethyl)azetidines 11.
As a representative example, the synthesis of cis-2-(2-hydroxyethyl)-1-
isopropyl-3-phenoxyazetidine 11a is described here. To a solution of
aluminum(III) chloride (8 mmol, 1 equiv) in dry Et2O (30 mL) was
added carefully lithium aluminum hydride (24 mmol, 3 equiv) at 0 °C.
The reaction mixture was stirred at room temperature for 1 h. Subse-
quently, a solution of cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-iso-
propyl-3-phenoxyazetidin-2-one 6a (8 mmol) in dry Et2O (15 mL) was
added slowly, and after the addition was complete, the reaction mixture
was stirred for 2 h at 0 °C, after which water (10 mL) was added
cautiously at 0 °C in order to neutralize the excess of LiAlH4. Afterward,
the reaction mixture was filtered and extracted with Et2O (3 Â 25 mL).
Drying (MgSO4), filtration of the drying agent, and removal of the
solvent afforded a mixture of cis-2-[2-(tert-butyldimethylsilyloxy)ethyl]-
1-isopropyl-3-phenoxyazetidine and cis-2-(2-hydroxyethyl)-1-isopro-
pyl-3-phenoxyazetidine 11a. In the next step, TBAF (8.8 mmol, 1.1
equiv) was added to an ice-cooled solution of the latter reaction mixture
in THF (30 mL), and the resulting solution was stirred at room
temperature for 5 h. Subsequently, the reaction mixture was poured
into brine and extracted with CH2Cl2 (3 Â 25 mL), after which the
organic fraction was dried (MgSO4), followed by removal of the drying
agent and evaporation of the solvent in vacuo. Purification by means of
column chromatography on silica gel (CH2Cl2/MeOH 95/5) afforded
pure cis-2-(2-hydroxyethyl)-1-isopropyl-3-phenoxyazetidine 11a.
cis-2-(2-Hydroxyethyl)-1-isopropyl-3-phenoxyazetidine
11a. (48%) White crystals. Mp = 70.2 °C. Rf = 0.10 (CH2Cl2/MeOH
95/5). 1H NMR (CDCl3): δ 0.96 and 1.07 (2 Â 3H, 2 Â d, J = 6.2 Hz);
1.83À1.92 (1H, m); 2.18À2.35 (1H, m); 2.56 (1H, septet, J = 6.2 Hz);
3.28 (1H, dd, J = 9.9, 7.7 Hz); 3.62 (1H, ddd, J = 9.9, 2.9, 1.1 Hz);
3.70À3.79 (2H, m); 4.07 (1H, ddd, J = 11.7, 8.1, 2.9 Hz); 4.91 (1H,
ddd, J = 7.7, 7.7, 2.9 Hz); 6.76À6.79, 6.93À6.98 and 7.23À7.29 (5H, 3
 m). 13C NMR (CDCl3): δ 20.1 (CH3); 21.0 (CH3); 32.2 (CH2);
56.7 (CH2); 57.7 (CH); 60.8 (CH2); 66.0 (CH); 68.8 (CH); 114.9
(CH); 121.1 (CH); 129.5 (CH); 157.2 (C). IR (cmÀ1): νOH = 3360.
MS: m/z (%): 236 (M+ + 1, 100). Anal. Calcd for C14H21NO2: C
71.46; H 8.99; N 5.95. Found: C 71.72; H 9.31; N 5.88.
cis-1-Isopropyl-2-(2-mesyloxyethyl)-3-phenoxyazetidine
5a. (90%) Colorless oil. 1H NMR (CDCl3): δ 0.93 and 1.03 (2 Â 3H, 2
 d, J = 6.1 Hz); 2.01À2.12 (1H, m); 2.44À2.65 (2H, m); 2.96 (3H, s);
3.19 (1H, dd, J = 9.4, 6.1 Hz); 3.50 (1H, ddd, J = 9.4, 1.9, 1.1 Hz); 3.63
(1H, ddd, J = 10.1, 6.3, 3.4 Hz); 4.25À4.40 (2H, m); 4.83 (1H, ddd, J =
6.3, 6.1, 1.9 Hz); 6.76À6.79, 6.88À7.03 and 7.23À7.34 (5H, 3 Â m).
13C NMR (ref = CDCl3): δ 20.0 (CH3); 21.1 (CH3); 30.2 (CH2); 37.3
(CH3); 56.8 (CH2); 57.9 (CH); 64.0 (CH); 67.8 (CH2); 68.0 (CH);
115.1 (CH); 121.3 (CH); 129.7 (CH); 157.1 (C). IR (cmÀ1): νmax
=
2966, 2939, 2872, 1492, 1352, 1234, 1171, 967, 930, 754, 692. MS: m/z
(%) 314 (M+ + 1, 100).
cis-3-Benzyloxy-1-isopropyl-2-(2-mesyloxyethyl)azetidine
5b. (88%) Colorless oil. 1H NMR (CDCl3): δ 0.93 and 0.98 (2 Â 3H, 2
 d, J = 6.3 Hz); 1.90À2.01 (1H, m); 2.38À2.53 (2H, m); 2.91 (3H, s);
2.93À3.01 (1H, m); 3.35À3.55 (2H, m); 4.15 (1H, ddd, J = 6.0, 6.0, 1.7
Hz); 4.21À4.35 (2H, m); 4.36 and 4.61 (2 Â 1H, 2 Â d, J = 12.1 Hz);
7.28À7.37 (5H, m). 13C NMR (ref = CDCl3): δ 20.1 (CH3); 21.2
(CH3); 30.1 (CH2); 37.1 (CH3); 56.5 (CH2); 57.9 (CH); 64.4 (CH);
68.3 (CH2); 69.6 (CH); 70.8 (CH2); 127.8 (CH); 127.8 (CH); 128.4
(CH); 138.0 (C). IR (cmÀ1): νmax = 2964, 2931, 2855, 1352, 1172, 960,
925, 813, 735, 698. MS: m/z (%) 328 (M+ + 1, 100).
cis-3-Benzyloxy-1-cyclohexyl-2-(2-mesyloxyethyl)azetidine
5c. (85%) Yellow oil. 1H NMR (CDCl3): δ 0.99À1.25 and 1.59À1.74
(6H and 4H, 2 Â m); 1.90À2.01 and 2.03À2.13 (2 Â 1H, 2 Â m);
2.41À2.53 (1H, m); 2.90 (3H, s); 2.94À2.98 (1H, m); 3.44À3.51 (2H,
m); 4.16 (1H, ddd, J = 6.1, 6.1, 1.1 Hz); 4.21À4.35 (2H, m); 4.36 and 4.61
(2 Â 1H, 2 Â d, J = 11.9 Hz); 7.28À7.39 (5H, m). 13C NMR (ref =
CDCl3): δ 24.6 (CH2); 24.7 (CH2); 25.8 (CH2); 30.1 (CH2); 30.2
(CH2); 31.4 (CH2); 37.1 (CH3); 56.2 (CH2); 64.3 (CH2); 66.4 (CH);
68.4, 70.0, 70.9 (CH, CH, CH2); 127.8 (CH); 127.9 (CH); 128.4 (CH);
cis-3-Benzyloxy-2-(2-hydroxyethyl)-1-isopropylazetidine
11b. (49%) White crystals. Mp = 76.3 °C. Rf = 0.10 (CH2Cl2/MeOH
95/5). 1H NMR (CDCl3): δ 0.93 and 1.01 (2 Â 3H, 2 Â d, J = 6.2 Hz);
1.76À1.85 (1H, m); 2.15À2.27 (1H, m); 2.47 (1H, septet, J = 6.2 Hz);
3.04 (1H, dd, J = 9.4, 6.6 Hz); 3.49À3.63 (2H, m); 3.72 (1H, ddd, J =
10.4, 5.1, 4.3 Hz); 3.91 (1H, ddd, J = 10.4, 10.2, 3.0 Hz); 4.25 (1H, ddd,
J = 6.6, 6.6, 2.8 Hz); 4.39 and 4.58 (2 Â 1H, 2 Â d, J = 11.8 Hz);
8371
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
138.0 (C). IR (cmÀ1): νmax = 3029, 2927, 2853, 1350, 1172, 969, 921, 812,
734, 699. MS: m/z (%) 368 (M+ + 1, 100).
d, J = 6.4 Hz); 2.16À2.21 (2H, m); 2.60 (2H, ∼t, J = 5.8 Hz); 2.82 (1H,
septet, J=6.4Hz);3.17(2H, s(broad));4.91À4.94 (1H, m); 7.03À7.10 and
7.29À7.34 (5H, 2 Â m). 13C NMR (ref = CDCl3): δ 18.6 (CH3); 24.4
(CH2); 45.9 (CH2); 48.9 (CH2); 54.0 (CH); 102.7 (CH); 119.5 (CH);
123.3 (CH); 129.6 (CH); 152.1 (C); 155.9 (C). IR (cmÀ1): νCdC = 1685.
MS: m/z (%): 218 (M+ + 1, 100). HRMS (ESI) calcd for C14H20NO
218.1545 [M + H]+, found 218.1548.
Synthesis of cis-1-Alkyl-4-bromopiperidines 15. As a repre-
sentative example, the synthesis of cis-4-bromo-1-isopropyl-3-phenox-
ypiperidine 15a is described here. To a solution of cis-1-isopropyl-2-(2-
mesyloxyethyl)-3-phenoxyazetidine 5a (5.5 mmol) in acetonitrile
(30 mL) was added LiBr (11 mmol, 2 equiv) at room temperature.
After a period of 15 h, the solvent was removed in vacuo, and the residue
was extracted with CH2Cl2 (1 Â 30 mL) and water (2 Â 30 mL). The
aqueous phase was washed with CH2Cl2 (2 Â 25 mL). Drying
(MgSO4), filtration of the drying agent, and removal of the solvent in
vacuo afforded cis-4-bromo-1-isopropyl-3-phenoxypiperidine 15a, which
was further purified by column chromatography on silica gel (hexane/
EtOAc 9/1).
cis-4-Bromo-1-isopropyl-3-phenoxypiperidine 15a. (47%)
Light-yellow oil. Rf = 0.10 (hexane/EtOAc 9/1). 1H NMR (CDCl3): δ
1.06 (6H, d, J = 6.6 Hz); 2.17À2.23 (2H, m); 2.60 (1H, d  t, J = 11.4,
4.0 Hz); 2.70À2.89 (4H, m); 4.31 (1H, ddd, J = 8.5, 4.0, 3.7 Hz); 4.64
(1H, d(broad), J = 3.7 Hz); 6.96À7.01 and 7.28À7.33 (5H, 2 Â m). 13C
NMR (CDCl3): δ 18.1 (CH3); 18.3 (CH3); 32.8 (CH2); 43.9 (CH2);
48.1 (CH2); 53.5 (CH); 54.5 (CH); 74.8 (CH); 117.0 (CH); 121.9
(CH); 129.6 (CH); 156.9 (C). IR (cmÀ1): νmax = 2964, 2828, 2360,
1587, 1492, 1237, 1168, 1059, 752, 690. MS: m/z (%): 298/300 (M+ + 1,
100). HRMS (ESI) calcd for C14H21BrNO 298.0807 [M + H]+, found
298.0797.
3-Benzyloxy-1-isopropyl-1,2,5,6-tetrahydropyridine 16b.
(60%) Light-brown oil. Rf = 0.04 (hexane/EtOAc 2/1). 1H NMR
(CDCl3): δ 1.08 and 1.09 (2 Â 3H, 2 Â d, J = 6.5 Hz); 2.16À2.23
(2H, m); 2.56 (2H, ∼t, J = 5.5 Hz); 2.77 (1H, septet, J = 6.5 Hz); 3.08
(2H, s(broad)); 4.74 (2H, s); 4.77 (1H, t, J = 3.3 Hz); 7.27À7.39 (5H,
m, C6H5). 13C NMR (ref = CDCl3): δ 18.7 (CH3); 24.5 (CH2); 46.4
(CH2); 49.9 (CH2); 54.0 (CH); 69.0 (CH2); 92.6 (CH); 127.7 (CH);
127.9 (CH); 128.5 (CH); 137.4 (C); 153.2 (C). IR (cmÀ1): νCdC
=
1677. MS: m/z (%): 232 (M+ + 1, 100). HRMS (ESI) calcd for
C15H22NO 232.1701 [M + H]+, found 232.1700.
Synthesis of cis-4-Acetoxy-1-alkylpiperidines 18. As a re-
presentative example, the synthesis of cis-4-acetoxy-1-isopropyl-3-phe-
noxypiperidine 18a is described here. To a solution of cis-1-isopropyl-
2-(2-mesyloxyethyl)-3-phenoxyazetidine 5a (10 mmol) in acetonitrile
(50 mL) was added NaOAc (20 mmol, 2 equiv) at room temperature.
After a reflux period of 15 h, the solvent was removed in vacuo and the
residue was extracted with CH2Cl2 (1 Â 30 mL) and water (2 Â 30 mL).
The aqueous phase was washed with CH2Cl2 (2 Â 25 mL). Drying
(MgSO4), filtration of the drying agent, and removal of the solvent in
vacuo afforded cis-4-acetoxy-1-isopropyl-3-phenoxypiperidine 18a,
which was further purified by column chromatography on silica gel
(hexane/EtOAc 2/1).
cis-4-Acetoxy-1-isopropyl-3-phenoxypiperidine 18a. (63%)
Colorless oil. Rf = 0.09 (hexane/EtOAc 2/1). 1H NMR (CDCl3): δ 1.04
(6H, d, J = 6.1 Hz); 1.76À1.86 (1H, m); 2.06 (3H, s); 1.98À2.14 (1H, m);
2.51À2.64 (2H, m); 2.77À2.89 (3H, m); 4.49 (1H, ddd, J = 5.9, 5.9, 2.9
Hz); 5.18À5.20 (1H, m); 6.91À6.98 and 7.23À7.29 (5H, 2 Â m). 13C
NMR (CDCl3): δ 17.8 (CH3); 18.6 (CH3); 21.2 (CH3); 28.4 (CH2); 44.5
(CH2); 48.1 (CH2); 54.3 (CH); 69.5 (CH); 74.2 (CH); 116.6 (CH); 121.4
(CH); 129.5 (CH); 157.8 (C); 170.5 (C). IR (cmÀ1): νCdO = 1736. MS:
m/z (%): 278 (M+ + 1, 100). HRMS (ESI) calcd for C16H24NO3 278.1756
[M + H]+, found 278.1755.
cis-4-Acetoxy-3-benzyloxy-1-isopropylpiperidine 18b. (55%)
Light-yellow oil. Rf = 0.05 (hexane/EtOAc 2/1). 1H NMR (CDCl3): δ 1.03
and 1.04 (2 Â 3H, 2 Â d, J = 6.3 Hz); 1.66À1.77 and 1.91À2.00 (2 Â 1H,
2 Â m); 2.10 (3H, s); 2.44À2.53 (2H, m); 2.57À2.66 (2H, m); 2.77 (1H,
septet, J = 6.3 Hz); 3.61 (1H, ddd, J = 8.1, 3.9, 3.9 Hz); 4.52 and 4.65 (2 Â
1H, 2 Â d, J = 12.1 Hz); 5.26 (1H, s(broad)); 7.28À7.39 (5H, m). 13C
NMR (ref = CDCl3): δ 18.0 (CH3); 18.6 (CH3); 21.4 (CH3); 28.6 (CH2);
44.1 (CH2); 48.7 (CH2); 54.5 (CH); 68.5 (CH); 71.0 (CH2); 74.9 (CH);
127.7 (CH); 127.9 (CH); 128.5 (CH); 138.4 (C); 170.7 (C). IR (cmÀ1):
νCdO = 1735. MS: m/z (%): 292 (M+ + 1, 100). HRMS (ESI) calcd for
C17H26NO3 292.1913 [M + H]+, found 292.1916.
cis-3-Benzyloxy-4-bromo-1-isopropylpiperidine 15b. (62%)
1
White crystals. Mp = 79.9 °C. Recrystallization from absolute EtOH. H
NMR (CDCl3): δ 1.03 and 1.04 (2 Â 3H, 2 Â d, J = 6.6 Hz); 2.02À2.21
(2H, m); 2.52À2.69 (4H, m); 2.76 (1H, septet, J = 6.6 Hz); 3.47 (1H, ddd,
J = 8.3, 3.9, 3.9 Hz); 4.52 (1H, d, J = 11.9 Hz); 4.62 (1H, s(broad)); 4.69
(1H, d, J = 11.9 Hz); 7.28À7.40 (5H, m). 13C NMR (ref = CDCl3): δ 18.2
(CH3); 18.4 (CH3); 32.7 (CH2); 44.0 (CH2); 48.6 (CH2); 54.5 (CH);
54.7 (CH); 70.4 (CH2); 75.2 (CH); 127.9 (CH); 128.0 (CH); 128.5
(CH); 138.0 (C). IR (cmÀ1): νmax = 3400, 3028, 2962, 2824, 1165, 1134,
1116, 1094, 1023, 1004, 750, 697. MS: m/z (%): 312/314 (M+ + 1, 100).
Anal. Calcd for C15H22BrNO: C 57.70; H 7.10; N 4.49. Found: C 58.10; H
7.34; N 4.48.
cis-3-Benzyloxy-4-bromo-1-cyclohexylpiperidine 15c. (65%)
White crystals. Mp = 76.6 °C. Rf = 0.06 (hexane/EtOAc 4/1). 1H NMR
(CDCl3): δ 1.05À1.25, 1.60À1.65 and 1.78À1.80 (10H, 3 Â m);
2.01À2.20 (2H, m); 2.27À2.37 (1H, m); 2.54À2.62 (1H, m);
2.66À2.78 (3H, m); 3.46 (1H, ddd, J = 8.3, 3.9, 3.6 Hz); 4.53 (1H, d, J =
12.1 Hz); 4.62 (1H, d(broad), J = 3.6 Hz); 4.68 (1H, d, J = 12.1 Hz);
7.28À7.39 (5H, m). 13C NMR (ref = CDCl3): δ 26.1 (CH2); 26.4 (CH2);
28.7 (CH2); 29.0 (CH2); 32.9 (CH2); 44.4 (CH2); 49.1 (CH2); 54.8
(CH); 63.8 (CH); 70.3 (CH2); 75.3 (CH); 127.8 (CH); 128.0 (CH);
128.5 (CH); 138.1 (C). IR (cmÀ1): νmax = 3062, 3030, 2926, 2852, 1451,
1202, 1116, 1099, 1026, 948, 734, 696. MS: m/z (%): 352/354 (M+ + 1,
100). Anal. Calcd for C18H26BrNO: C 61.36; H 7.44; N 3.98. Found: C
61.57; H 7.77; N 4.10.
cis-4-Acetoxy-3-benzyloxy-1-cyclohexylpiperidine 18c.
Attempts to purify this compound failed. Spectral data are based on
1H NMR and 13C NMR of the crude reaction mixture (purity of 18c:
∼85%), and no HRMS analysis was performed. (66%) Colorless oil.
1H NMR (CDCl3): δ 1.05À1.33, 1.57À1.65 and 1.70À1.84 (4H, 1H
and 6H, 3 Â m); 1.88À1.99 (1H, m); 2.10 (3H, s); 2.29À2.38 (1H,
m); 2.53À2.57 (2H, m); 2.64À2.73 (2H, m); 3.60 (1H, ddd, J = 8.4,
4.0, 4.0 Hz); 4.52 and 4.64 (2 Â 1H, 2 Â d, J = 12.1 Hz); 5.25 (1H,
s(broad)); 7.23À7.36 (5H, m). 13C NMR (ref = CDCl3): δ 21.4
(CH3); 22.7 (CH2); 26.1 (CH2); 26.4 (CH2); 28.6 (CH2); 29.0
(CH2); 31.7 (CH2); 44.4 (CH2); 49.1 (CH2); 63.7 (CH); 68.5
(CH); 70.9 (CH2); 74.9 (CH); 127.7 (CH); 127.9 (CH); 128.4
(CH); 138.4 (C); 170.7 (C). IR (cmÀ1): νCdO = 1737. MS: m/z
(%): 332 (M+ + 1, 100).
Synthesis of 1-Alkyl-1,2,5,6-tetrahydropyridines 16. As a
representative example, the synthesis of 1-isopropyl-3-phenoxy-1,2,5,6-
tetrahydropyridine 16a is described here. To a solution of cis-4-bromo-1-
isopropyl-3-phenoxypiperidine 15a (4.2 mmol) in DMSO (40 mL) was
added NaH (16.8 mmol, 4 equiv, 60% dispersion in mineral oil), after
which the resulting suspension was stirred for 15 h at 150 °C. Subse-
quently, the reaction mixture was poured into water (40 mL) and
extracted with Et2O (3 Â 25 mL). Afterward, the organic phase was
washed intensively with brine (4 Â 30 mL). Drying (MgSO4), filtration
of the drying agent, and removal of the solvent in vacuo afforded
1-isopropyl-3-phenoxy-1,2,5,6-tetrahydropyridine 16a, which was further
purified by column chromatography on silica gel (hexane/EtOAc 2/1).
1-Isopropyl-3-phenoxy-1,2,5,6-tetrahydropyridine 16a. (56%)
Yellow oil. Rf = 0.08 (hexane/EtOAc 2/1). 1H NMR (CDCl3): δ 1.11 (6H,
8372
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
Synthesis of cis-1-Alkyl-4-hydroxypiperidines 19. As a
representative example, the synthesis of cis-4-hydroxy-1-isopropyl-3-
phenoxypiperidine 19a is described here. To a solution of cis-4-acetoxy-
1-isopropyl-3-phenoxypiperidine 18a (6 mmol) in methanol (40 mL)
was added K2CO3 (12 mmol, 2 equiv). After a reflux period of 1 h, the
solvent was removed in vacuo, and the residue was extracted with Et2O
(1 Â 30 mL) and water (2 Â 30 mL). The aqueous phase was washed
with Et2O (2 Â 25 mL). Drying (MgSO4), filtration of the drying agent,
and removal of the solvent in vacuo afforded cis-4-hydroxy-1-isopropyl-
3-phenoxypiperidine 19a, which was further purified by column chro-
matography on silica gel (hexane/EtOAc 1/2).
cis-3-Benzyloxy-4-formyloxy-1-isopropylpiperidine 21b.
(68%) Colorless oil. Rf = 0.06 (hexane/EtOAc 1/2). 1H NMR
(CDCl3): δ 1.03 and 1.04 (2 Â 3H, 2 Â d, J = 6.3 Hz); 1.71À1.82
(1H, m); 1.94À2.02 (1H, m); 2.45À2.63 (3H, m); 2.68À2.72 (1H, m);
2.79 (1H, septet, J = 6.3 Hz); 3.64 (1H, ddd, J = 9.1, 4.1, 4.1 Hz); 4.54
and 4.66 (2 Â 1H, 2 Â d, J = 11.9 Hz); 5.38 (1H, s(broad)); 7.24À7.39
(5H, m); 8.15 (1H, s). 13C NMR (ref = CDCl3): δ 18.0 (CH3); 18.5
(CH3); 28.8 (CH2); 43.6 (CH2); 48.4 (CH2); 54.5 (CH); 68.4 (CH);
71.1 (CH2); 74.8 (CH); 127.9 (CH); 128.0 (CH); 128.5 (CH); 138.1
(C); 160.7 (CH). IR (cmÀ1): νCdO = 1720. MS: m/z (%): 278 (M+ + 1,
100). HRMS (ESI) calcd for C16H24NO3 278.1756 [M + H]+, found
278.1770.
cis-4-Hydroxy-1-isopropyl-3-phenoxypiperidine 19a. (56%)
Colorless oil. Rf = 0.05 (hexane/EtOAc 1/2). 1H NMR (CDCl3): δ 1.04
(6H, d, J= 6.6 Hz); 1.77À1.88 and 1.94À2.03 (2 Â 1H, 2 Â m); 2.48À2.70
(4H, m); 2.75À2.85 (2H, m); 4.11À4.15 (1H, m); 4.43 (1H, ddd, J = 9.0,
4.4, 3.1 Hz); 6.95À7.00 and 7.26À7.33 (5H, 2 Â m). 13C NMR (ref =
CDCl3): δ18.0 (CH3); 18.5 (CH3); 30.6 (CH2);43.2 (CH2); 46.6 (CH2);
54.5 (CH); 66.4 (CH); 76.1 (CH); 116.3 (CH); 121.6 (CH); 129.7 (CH);
157.2 (C). IR (cmÀ1): νOH = 3406. MS: m/z (%): 236 (M+ + 1, 100).
HRMS (ESI) calcd for C14H22NO2 236.1651 [M + H]+, found 236.1653.
cis-3-Benzyloxy-4-hydroxy-1-isopropylpiperidine 19b. (70%)
Colorless oil. Rf = 0.03 (hexane/EtOAc 1/3). 1HNMR(CDCl3):δ1.02 and
1.04 (2 Â 3H, 2 Â d, J = 6.7 Hz); 1.63À1.74 and 1.86À1.95 (2 Â 1H, 2 Â
m); 2.34 (1H, s(broad)); 2.39À2.45 (1H, m); 2.49À2.64 (3H, m); 2.76
(1H, septet, J = 6.7 Hz); 3.58 (1H, ddd, J = 8.5, 4.1, 4.1 Hz); 3.98 (1H,
s(broad)); 4.58 and 4.63 (2 Â 1H, 2 Â d, J = 12.1 Hz); 7.28À7.38 (5H, m).
13C NMR (ref = CDCl3): δ 18.0 (CH3); 18.6 (CH3); 30.5 (CH2); 43.3
(CH2); 47.4 (CH2); 54.5 (CH); 66.1 (CH); 70.8 (CH2); 76.9 (CH); 127.9
(CH); 127.9 (CH); 128.6 (CH); 138.3 (C). IR (cmÀ1): νOH = 3445. MS:
m/z (%): 250 (M+ + 1, 100). HRMS (ESI) calcd for C15H24NO2 250.1807
[M + H]+, found 250.1812.
cis-3-Benzyloxy-1-cyclohexyl-4-formyloxypiperidine 21c.
(70%) Colorless oil. Rf = 0.06 (hexane/EtOAc 4/1). 1H NMR (CDCl3):
δ 1.05À1.28, 1.59À1.66 and 1.73À1.83 (6H, 1H and 4H, 3 Â m);
1.92À2.01 (1H, m); 2.29À2.38 (1H, m); 2.54À2.60 (2H, m);
2.63À2.78 (2H, m); 3.62 (1H, ddd, J = 9.0, 3.9, 3.9 Hz); 4.54 and
4.64 (2 Â 1H, 2 Â d, J = 11.6 Hz); 5.36 (1H, s(broad)); 7.28À7.36 (5H,
m); 8.14 (1H, s). 13C NMR (ref = CDCl3): δ 26.1 (CH2); 26.1 (CH2);
26.4 (CH2); 28.6 (CH2); 28.9 (CH2); 29.1 (CH2); 44.0 (CH2); 48.9
(CH2); 63.8 (CH); 68.6 (CH); 71.0 (CH2); 74.9 (CH); 127.8 (CH);
127.9 (CH); 128.5 (CH); 138.2 (C); 160.8 (CH). IR (cmÀ1): νCdO
=
1724. MS: m/z (%): 318 (M+ + 1, 100). HRMS (ESI) calcd for
C19H28NO3 318.2069 [M + H]+, found 318.2077.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra of compounds 10a,b, 6aÀc, 11aÀc, 5aÀc, 15aÀc, 16a,b,
18aÀc, 19aÀc, and 21aÀc. Cartesian coordinates and energies
of the optimized geometries (B3LYP/6-31++G(d,p)) of ground
states; Cartesian coordinates, energies, imaginary and low fre-
quencies of the optimized geometries (B3LYP/6-31++G**) of
transition states. This material is available free of charge via the
Internet at http://pubs.acs.org.
cis-3-Benzyloxy-1-cyclohexyl-4-hydroxypiperidine 19c. At-
1
tempts to purify this compound failed. Spectral data are based on H
NMR and 13C NMR of the crude reaction mixture (purity of 19c: ∼80%),
1
and no HRMS analysis was performed. (60%) Colorless oil. H NMR
(CDCl3): δ 1.05À1.29, 1.53À1.73 and 1.74À1.92 (5H, 1H and 6H, 3 Â
m); 2.28À2.38 (1H, m); 2.44À2.51 (1H, m); 2.56À2.71 (3H, m); 3.58
(1H, ddd, J = 8.5, 4.1, 4.1 Hz); 3.97 (1H, s(broad)); 4.57 and 4.62 (2 Â 1H,
2 Â d, J = 11.8 Hz); 7.25À7.35 (5H, m). 13C NMR (ref = CDCl3): δ 26.1
(CH2); 26.2 (CH2); 26.4 (CH2); 28.5 (CH2); 29.1 (CH2); 30.6 (CH2);
43.7 (CH2); 47.7 (CH2); 63.9 (CH); 66.1 (CH); 70.8 (CH2); 76.8 (CH);
127.8 (CH); 127.9 (CH); 128.6 (CH); 138.3 (C). IR (cmÀ1): νOH = 3428.
MS: m/z (%): 290 (M+ + 1, 100).
Synthesis of cis-1-Alkyl-4-formyloxypiperidines 21. As a
representative example, the synthesis of cis-4-formyloxy-1-isopropyl-3-
phenoxypiperidine 21a is described here. A solution of cis-1-isopropyl-
2-(2-mesyloxyethyl)-3-phenoxyazetidine 5a (1 mmol) in DMF (15 mL)
was heated at 80 °C for 3 h. Subsequently, the reaction mixture was
poured into water (15 mL) and extracted with Et2O (3 Â 15 mL).
Afterward, the organic phase was washed intensively with brine (4 Â
20 mL). Drying (MgSO4), filtration of the drying agent, and removal of
the solvent in vacuo afforded cis-4-formyloxy-1-isopropyl-3-phenoxypi-
peridine 21a, which was further purified by column chromatography on
silica gel (hexane/EtOAc 2/1).
cis-4-Formyloxy-1-isopropyl-3-phenoxypiperidine 21a. (53%)
Colorless oil. Rf = 0.07 (hexane/EtOAc 2/1). 1H NMR (CDCl3): δ 1.04
(6H, d, J = 6.1 Hz); 1.82À1.93 and 2.04À2.13 (2 Â 1H, 2 Â m); 2.57À2.60
(2H, m);2.70À2.87 (3H, m); 4.49 (1H, ddd, J=8.4, 4.0, 4.0Hz);5.34À5.36
(1H, m); 6.90À6.99 and 7.24À7.31 (5H, 2 Â m); 8.14 (1H, s). 13C NMR
(CDCl3): δ 17.9 (CH3); 18.4 (CH3); 28.7 (CH2); 43.8 (CH2); 47.7
(CH2); 54.4 (CH); 69.2 (CH); 74.0 (CH); 116.3 (CH); 121.6 (CH); 129.6
(CH);157.3(C);160.5(CH).IR(cmÀ1):νCdO = 1721. MS: m/z(%):264
(M+ + 1, 100). HRMS (ESI) calcd for C15H22NO3 264.1600 [M + H]+,
found 264.1602.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: veronique.vanspeybroeck@UGent.be; matthias.dhooghe@
UGent.be; norbert.dekimpe@UGent.be.
Notes
§Aspirant of the Research Foundation À Flanders (FWO-
Vlaanderen).
’ ACKNOWLEDGMENT
The authors are indebted to Ghent University (GOA) and the
Research Foundation À Flanders (FWO-Vlaanderen) for finan-
cial support. The computational resources used in this work were
provided by Stevin Supercomputer Infrastructure Ghent Uni-
versity (Belgium), the Hercules Foundation, and the Flemish
Government - department EWI.
’ REFERENCES
(1) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(2) For reviews on the synthesis of piperidines, see: (a) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693. (c) Weintraub, Ph. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953. (d) Laschat, S.; Dickner,
T. Synthesis 2000, 1781. (e) Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun 1998, 633.
8373
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
(3) (a) Couty, F.; Durrat, F.; Evano, G. Targets Heterocycl. Syst. 2005,
9, 186. (b) Bott, T. M.; Vanecko, J. A.; West, F. G. J. Org. Chem. 2009,
74, 2832. (c) Van Brabandt, W.; Dejaegher, Y.; Van Landeghem, R.; De
Kimpe, N. Org. Lett. 2006, 8, 1101. (d) Vanecko, J. A.; West, F. G. Org.
Lett. 2005, 7, 2949. (e) Couty, F.; Durrat, F.; Evano, G.; Marrot, J. Eur.
J. Org. Chem. 2006, 4214. (f) Singh, G. S.; D’hooghe, M.; De Kimpe, N.
Compr. Heterocycl. Chem. III 2008, 2, 1.
(f) D’hooghe, M.; Baele, J.; Contreras, J.; Boelens, M.; De Kimpe, N.
Tetrahedron Lett. 2008, 49, 6039.
(17) (a) Vanderhaeghe, H.; Janssen, G.; Compernolle, F. Tetra-
hedron Lett. 1971, 12, 2687. (b) Aiello, A.; Fattorusso, E.; Giordano, A.;
Menna, M.; M€uller, W. E. G.; Perovic-Ottstadt, S.; Schr€oder, H. C.
Bioorg. Med. Chem. 2007, 15, 5877. (c) Ho, B.; Zabriskie, T. M. Bioorg.
Med. Chem. Lett. 1998, 8, 739.
(4) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003,
44, 5209. (b) Couty, F.; Kletskii, M. J. Mol. Struct. 2009, 908, 26. (c)
Dekeukeleire, S.; D’hooghe, M.; T€ornroos, K. W.; De Kimpe, N. J. Org.
Chem. 2010, 75, 5934. (d) Van Brabandt, W.; Van Landeghem, R.; De
Kimpe, N. Org. Lett. 2006, 8, 1105. (e) Krow, G. R.; Lin, G.; Moore,
K. P.; Thomas, A. M.; DeBrosse, C.; Ross, C. W.; Ramjit, H. G. Org. Lett.
2004, 6, 1669. (f) Outurquin, F.; Pannecoucke, X.; Berthe, B.; Paulmier,
C. Eur. J. Org. Chem. 2002, 1007.
(5) (a) Mollet, K.; Broekcx, L.; D’hooghe, M.; De Kimpe, N.
Heterocycles 2012, 84, in press (DOI: 10.3987/COM-11-S(P)3). (b)
Durrat, F.; Sanchez, M. V.; Couty, F.; Evano, G.; Marrot, J. Eur. J. Org.
Chem. 2008, 3286.
(6) (a) DeVita, R. J.; Parikh, M.; Jiang, J.; Fair, J. A.; Young, J. R.;
Walsh, T. F.; Goulet, M. T.; Lo, J.-L.; Ren, N.; Yudkovitz, J. B.; Cui, J.;
Yang, Y. T.; Cheng, K.; Rohrer, S. P.; Wyvratt, M. J. Bioorg. Med. Chem.
Lett. 2004, 14, 5599. (b) DeVita, R. J.; Hollings, D. D.; Goulet, M. T.;
Wyvratt, M. J.; Fisher, M. H., Jr.; Lo, J.; Yang, Y. T.; Cheng, K.; Smith,
R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2615.
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
€
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
(19) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(7) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3390.
(20) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
56, 2257. (b) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650.
(21) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363.(b) Hratchian, H. P.;
Schlegel, H. B.; Clifford, E. D.; Gernot, F.; Kwang, S. K.; Gustavo, E. S. In
Theory and Applications of Computational Chemistry; Elsevier: Amster-
dam, 2005; p 195.
(8) Pearson, W. H.; Kropf, J. E.; Choy, A. L.; Lee, I. Y.; Kampf, J. W.
J. Org. Chem. 2007, 72, 4135.
(9) (a) Barrow, K. D.; Spotswood, T. M. Tetrahedron Lett. 1965,
6, 3325. (b) Decazes, J.; Luche, J. L.; Kagan, H. B. Tetrahedron Lett. 1970,
11, 3361.
(10) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007,
107, 4437. (b) D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe,
N. Pure Appl. Chem. 2010, 82, 1749. (c) Singh, G. S. Tetrahedron 2003,
59, 7631.
(11) (a) Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem.
2002, 67, 2075. (b) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J. Org.
Chem. 1991, 56, 5263. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C.;
Salgado, N. R. J. Org. Chem. 1999, 64, 9596.
(22) Boese, A. D.; Jan, M. L. M. J. Chem. Phys. 2004, 121, 3405.
(23) (a) Hermosilla, L.; Catak, S.; Van Speybroeck, V.; Waroquier,
M.; Vandenbergh, J.; Motmans, F.; Adriaensens, P.; Lutsen, L.; Cleij, T.;
Vanderzande, D. Macromolecules 2010, 43, 7424. (b) Hemelsoet, K.;
Van Durme, F.; Van Speybroeck, V.; Reyniers, M.-F.; Waroquier, M.
J. Phys. Chem. A 2010, 114, 2864.
(24) (a) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215. (b)
Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(12) (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008,
108, 3988. (b) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Compr.
Heterocycl. Chem. III 2008, 2, 1.
(25) For recent applications of the M06-2X functional in organic
reactions, see: (a) Catak, S.; D’hooghe, M.; De Kimpe, N.; Waroquier,
M.; Van Speybroeck, V. J. Org. Chem. 2010, 75, 885. (b) Liu, L.;
Malhotra, D.; Paton, R. S.; Houk, K. N.; Hammond, G. B. Angew. Chem.,
Int. Ed. 2010, 49, 9132. (c) Cantillo, D.; Kappe, C. O. J. Org. Chem. 2010,
75, 8615. (d) Catak, S.; Hemelsoet, K.; Hermosilla, L.; Waroquier, M.;
Van Speybroeck, V. Chem.—Eur. J. 2011, in press. (e) Winne, J. M.;
Catak, S.; Waroquier, M.; Van Speybroeck, V. Angew. Chem., Int. Ed.
2011, DOI: 10.1002/anie.201104930.
(26) Yanai, T.; Tew, D.; Handy, N. Chem. Phys. Lett. 2004, 393, 51.
(27) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008,
10, 6615.
(28) Goerigk, L; Grimme, S. Phys. Chem. Chem. Phys. 2011, 13, 6670.
(29) Thanthiriwatte, K. S.; Hohenstein, E. G.; Burns, L. A.; Sherrill,
D. J. Chem. Theory Comput. 2011, 7, 88.
(13) For selected recent reports on bioactive compounds containing
the azetidine ring, see: (a) Evans, G. B.; Fumeaux, R. H.; Greatrex, B.;
Murkin, A. S.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948.
(b) Honcharenko, D.; Barman, J.; Varghese, O. P.; Chattopadhyaya, J.
Biochemistry 2007, 46, 5635. (c) Ikee, Y.; Hashimoto, K.; Nakashima,
M.; Hayashi, K.; Sano, S.; Shiro, M.; Nagao, Y. Bioorg. Med. Chem. Lett.
2007, 17, 942. (d) Provins, L.; Christophe, B.; Danhaive, P.; Dulieu, J.;
Gillard, M.; Quere, L.; Stebbins, K. Bioorg. Med. Chem. Lett. 2007,
17, 3077. (e) Kolocouris, N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.;
Prathalingham, S. R.; Kelly, J. M.; Naesens, L.; De Clercq, E. Bioorg. Med.
Chem. Lett. 2007, 17, 4358. (f) Yeh, C. H.; Wu, S. J.; Tsai, Y. F.; Chen,
H. Y.; Lin, C. Y. Plant Sci. 2007, 172, 1124.
(14) (a) Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C.
Tetrahedron 1997, 53, 245. (b) Bartali, L.; Casini, A.; Guarna, A.;
Occhiato, E. G.; Scarpi, D. Eur. J. Org. Chem. 2010, 5831.
(15) Balsamo, A.; Lapucci, A.; Macchia, B.; Macchia, F. Eur. J. Med.
Chem. 1981, 16, 163.
(16) (a) Dang, Z.; Yang, Y.; Ji, R.; Zhang, S. Bioorg. Med. Chem. Lett.
2007, 17, 4523. (b) Koech, P. K.; Krische, M. J. Tetrahedron 2006,
62, 10594. (c) Smith, N. D.; Hayashida, J.; Rawal, V. H. Org. Lett. 2005,
7, 4309. (d) Ashton, W. T.; Sisco, R. M.; Dong, H.; Lyons, K. A.; He, H.;
Doss, G. A.; Leiting, B.; Patel, R. A.; Wu, J. K.; Marsilio, F.; Thornberry,
N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2005, 15, 2253. (e) Emmett,
G. C.; Cain, G. A.; Estrella, M. J.; Holler, E. R.; Piecara, J. S.; Blum,
A. M.; Mical, A. J.; Teleha, C. A.; Wacker, D. A. Synthesis 2005, 92.
(30) Cramer, C. J.; Truhlar, D. G. Solvent Effects and Chemical
Reactivity; Kluwer: Dordrecht, 1996.
(31) For recent reports on microsolvation and selected applica-
tions of mixed explicit/implicit solvent models, see: (a) Pliego, J. R.;
Riveros, J. M. J. Phys. Chem. A 2001, 105, 7241. (b) Kelly, C. P.;
Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. A 2006, 110, 2493. (c) da
Silva, E. F.; Svendsen, H. F.; Merz, K. M. J. Phys. Chem. A 2009,
113, 6404. (d) D’hooghe, M.; Catak, S.; Stankovic, S.; Waroquier, M.;
Kim, Y.; Ha, H. J.; Van Speybroeck, V.; De Kimpe, N. Eur. J. Org.
Chem. 2010, 4920. (e) Stankoviꢀc, S.; Catak, S.; D’hooghe, M.;
Goossens, H.; Tehrani, K. A.; Bogaert, P.; Waroquier, M.; Van
Speybroeck, V.; De Kimpe, N. J. Org. Chem. 2011, 76, 2157. (f)
Catak, S.; D’hooghe, M.; Verstraelen, T.; Hemelsoet, K.; Van
8374
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375

The Journal of Organic Chemistry
ARTICLE
Nieuwenhove, A.; Ha, H.-J.; Waroquier, M.; De Kimpe, N.; Van
Speybroeck, V. J. Org. Chem. 2010, 75, 4530.
(32) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999.
(33) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995. (b)
Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003,
24, 669.
(34) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378.
8375
dx.doi.org/10.1021/jo201556t |J. Org. Chem. 2011, 76, 8364–8375