Novel chiral bridged azepanes: Stereoselective ring expansion of 2-azanorbornan-3-yl methanols

Article abstract of DOI:10.1016/j.tet.2012.07.028

The reaction of 2-azanorbornan-3-yl methanols under Mitsunobu or mesylation conditions with various nucleophiles led to a series of chiral-bridged azepanes with configuration at C-4 dependent on the configuration of the starting alcohol. High yielding, st

Full text of DOI:10.1016/j.tet.2012.07.028

Tetrahedron 68 (2012) 7848e7854
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Novel chiral bridged azepanes: stereoselective ring expansion of 2-azanorbornan-
3-yl methanols
a
,
b
a
*
_
ꢀ
_
Elzbieta Wojaczynska , Ilona Turowska-Tyrk , Jacek Skarzewski
a
_
ꢀ
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
Institute of Physical and Theoretical Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
b
_
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2012
Received in revised form 17 June 2012
Accepted 10 July 2012
Available online 20 July 2012
The reaction of 2-azanorbornan-3-yl methanols under Mitsunobu or mesylation conditions with various
nucleophiles led to a series of chiral-bridged azepanes with configuration at C-4 dependent on the
configuration of the starting alcohol. High yielding, stereoselective ring expansion to novel 2-azabicyclo
[3.2.1]octane system occurred via aziridinium intermediates, which were specifically opened by nucle-
ophilic attack at the more substituted carbon.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Azanorbornane
Ring expansion
2-Azabicyclo[3.2.1]octane
Azepane
Stereoselectivity
1. Introduction
has been described earlier by Hongo et al.3b Here we report the
results of our current experiments that proved that the structures
Configurationally stable, rigid bicyclic systems with properly
placed donor centers are molecular motifs in many effective chiral
ligands.1 Among them, natural products can be found, e.g., spar-
teine and Cinchona alkaloids, as well as synthetic compounds, such
as 2-azanorbornyl (2-azabicyclo[2.2.1]heptane) derivatives.2 The
respective exo-(1S,3R,4R)-1 and minor endo-(1S,3S,4R)-1 esters are
easily obtained in the cycloaddition of cyclopentadiene to an imi-
nium ion formed in situ from ethyl glyoxylate and (S)-1-
phenylethylamine (Scheme 1). Compound 1 and the product of
its reduction, 2-azanorbornan-3-yl methanol (2), turned out to be
attractive precursors of different chiral ligands, which were used in
various stereoselective processes.3
Recently, we have reported the preparation of this type of li-
gand bearing additional chalcogen (S, Se) and nitrogen donors.4,5
These derivatives were obtained from N-(1-phenylethyl)-2-
azanorbornane-3-carboxaldehyde (Scheme 2) and these com-
pounds were highly effective in the TrosteTsuji reaction giving up
to 95% ee.4 However, we have also described less effective ligands
3 prepared by the direct nucleophilic substitution of the activated
hydroxy group in exo-2 (Scheme 3).4,5 It is noteworthy that
a similar synthetic approach to 2-azanorbornylmethanethiol (3c)
of 3 must be revised.
The key evidence that led to verification of the previously
assigned structures of the ligands 3 was an unexpected single
crystal X-ray structure of the N-proline amide of supposed N-[(S)-1-
phenylethyl]-2-azanorbornyl-3-methylamine obtained from 3d.5
2. Results and discussion
In our preparation of (N,N)-donating ligands based on 2-
azanorbornyl framework, exo-2 was treated with Ph3P, DEAD, and
HN3.5 Physicochemical characteristics (HRMS, 1D NMR, IR) of the
only reaction product formed were in general agreement with the
structure of 3. Its structure seemed analogous to exo-2 and the
product apparently resulted from a simple nucleophilic sub-
stitution. However, in the course of the present investigation we
came to a conclusion that the Mitsunobu reaction of alcohol exo-2
with an azide ion must proceed in a different manner. Thus, a bi-
cyclic structure 4d containing a seven-membered ring has been
selectively formed. Reduction of the azide 4d with triphenylphos-
phine yielded amine 5, which was converted by the DCC method6
into the (S)-proline derivative 6 in 54% yield (Scheme 4).
The X-ray structure of 6 shown in Fig. 1 unambiguously proves
the presence of an extended bicyclic system. Five stereogenic car-
bon atoms are present in the molecule, three of them in the
2-azabicyclo[3.2.1]octane fragment have (1S,4S,5R) configuration.
* Corresponding author. Tel.: þ48 713202410; fax: þ48 713202427; e-mail
ꢀ
address: elzbieta.wojaczynska@pwr.wroc.pl (E. Wojaczynska).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.028

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E. Wojaczynska et al. / Tetrahedron 68 (2012) 7848e7854
7849
Scheme 1.
Careful examination of the 2D NMR spectra of 5 and 6 led to
a conclusion on the structure consistent with the crystallographic
data. In particular, the analysis of NOESY and 1H,13C HMBC maps
revealed couplings possible only if an additional CH2 group (3-CH2)
is present in the ring (Fig. 2).
The structural evidence showed that under the Mitsunobu re-
action7 conditions (Ph3P, DEAD, and HN3)8 exo-2 underwent
transformation to the seven-membered ring system. The reaction is
highly regio- and stereoselective since no other isomer of the
product could be detected. An identical product 4d was also
obtained when, instead of a Mitsunobu protocol, a DPPA/DBU
combination9 was applied.
Scheme 2.
In order to additionally confirm the rearrangement of exo-2
under the Mitsunobu reaction conditions, we separately reacted it
with p-nitrobenzoic acid (PNBA)/Ph3P/DEAD and with PNBA-
chloride. As expected, two different isomeric PNBA-esters were
obtained. The Mitsunobu reaction gave the rearranged product 4e,
while the acid chloride clearly gave PNBA-ester of exo-2.
The observed rearrangement with ring expansion clearly results
from the formation of the three-membered aziridinium ring fol-
lowed by its stereoselective opening by a nucleophile (Scheme 5).
Generally, this type of reactivity of
b-aminoalcohols requires an
activation of the hydroxy group followed by the addition of a nu-
cleophile.10 It is also documented that the Mitsunobu reaction of
chiral aminoalcohols can give optically pure aziridines,11 which can
be in turn easily opened by nucleophiles. Recently, ring expansion
of aza-heterocycles through aziridines and aziridinium in-
termediates has been developed into an attractive synthetic
Scheme 3.
Scheme 4.

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E. Wojaczynska et al. / Tetrahedron 68 (2012) 7848e7854
7850
from exo-2 via the nucleophilic substitutions using the Hata22
((PhS)2/Bu3P) and Grieco23 (PhSeCN/Bu3P) protocols. Furthermore,
the respective thioacetate 3c has been reported3b as a product of the
nucleophilic substitution on the mesylate of exo-2 with sodium thi-
oacetateand werepeated its synthesis. Therecorded correlationNMR
experiments (COSY, NOESY, HSQC/HMQC, HMBC) for the obtained
products allowed complete resonance assignments (see
Supplementary data), which are in full agreement with the presence
of a rearranged skeleton. The DFT calculations for the respective
three-membered ring intermediates further support the proposed
reaction pathway.24 The structures of the aziridinium ions determine
the observed direction of nucleophilic attack (Schemes 5 and 6). In
the three-membered ring of the intermediate, the NeC bond, which
is eventually broken is slightly longer than the preserved one, and the
attack of nucleophile on more substituted carbon atom is expected
with an inversion of configuration. The determined mechanism is in
an agreement with the general pathway of aziridinium ring opening
by nucleophiles studied previously.25
An additional proof for the regio- and stereochemical outcome
of the observed rearrangement is an X-ray structure of the sulfoxide
obtained from the previously supposed 3a, which was in fact 4a
(Fig. 3). Thus, the 2-azabicyclo[3.2.1]octane fragment has (1S,4S,5R)
configuration.
Moreover, when endo-2 was subjected to the Mitsunobu reaction
with hydrazoic acid, we also observed the rearranged azide product,
but this time of the (1S,4R,5R) configuration. As previously, the
Staudinger reduction furnished the respective amino-derivative.
Also here, the direction of nucleophilic attack is in agreement with
the calculated structure of the intermediate24 (Scheme 6), which
accounts for the observed regio- and stereoselectivity.
Fig. 1. Molecular structure of 6. Displacement ellipsoids are drawn at the 30% proba-
bility level.
Interestingly, we observed that the reaction of exo-2 with mesyl
chloride in the presence of Et3N at 0 ꢀC did not produce the
expected mesylate of exo-2 but gave directly the bridged azepane
chloride 4f in 83% yield. A similar chloride formation in the reaction
of piperidine-derived diol with tosyl chloride has already been
described in the literature.17 The stereochemistry at the newly
created center (as suggested by the observed NOE correlations) is
the same as that of the previous compounds ((1S,4S,5R)-4aee, 5, 6).
The chloride derivative 4f underwent nucleophilic substitution
with sodium thiophenolate giving the corresponding sulfide 7
20
([a
]
ꢁ83.0 (dichloromethane)), which clearly differs from
D
20
(1S,4S,5R)-4a ([
the configuration ascribed to the C-4 center of 4f.
a]
ꢁ5.1 (CH2Cl2)). This result corroborates with
D
Fig. 2. Selected NOESY (left) and HMBC connectivities (right), crucial for the
determination of the molecular structure for 6 (R¼(S)-prolyl) and 5, respectively.
However, when the mesylate of exo-2 was reacted in situ with
the nucleophiles stronger than the chloride anion, the respective
nucleophilic substitution products 4 of (1S,4S,5R) configuration
were smoothly obtained (Scheme 7).
In summary, we have presented the diastereospecific ring ex-
pansion of bicyclic 2-azanorbornyl skeleton upon the reactions of
exo- and endo-2-azanorbornan-3-yl methanols leading exclusively
to 2-azabicyclo[3.2.1]octane (instead of the previously described 2-
azabicyclo[2.2.1]heptane)3b,4,5 derivatives. The stereochemical
outcome of the reaction was unambiguously proved by the X-ray
structures and the observed NOE correlations. A stereoselective
method.12e16 Also compounds bearing an azepane backbone have
been prepared through the ring expansion of piperidines.17,18 In
spite of the abundance of chiral azepane rings in various natural
products,19 their stereoselective synthesis still remains a chal-
lenge.17 Rearrangements involving bicyclic and tricyclic amines
have been explored,20 although the ring expansion of
2-azanorbornyl derivatives has not been observed before.21
All these led us to reexamine our earlier reported structures of
sulfurand selenium analogues (3a and 3b), which were also prepared
Scheme 5.

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E. Wojaczynska et al. / Tetrahedron 68 (2012) 7848e7854
7851
Scheme 6.
incorporation of an additional carbon atom into bicyclic skeleton
opens up a new route to the synthesis of bridged azepane de-
rivatives of potential biological activity.
3. Experimental section
3.1. General
IR spectra were recorded on a Perkin Elmer System 2000 FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were measured
on a Bruker Avance DRX 300 (1H, 300 MHz) or a Bruker Avance 600
(1H, 600 MHz) spectrometer using TMS as an internal standard or
solvent residual peak as a reference. The reported J values are those
observed from the splitting patterns in the spectrum and may not
reflect the true coupling constant values. Optical rotations were
measured using an Optical Activity Ltd. Model AA-5 automatic
polarimeter. High-resolution mass spectra were recorded using
a microTOF-Q and WATERS LCT Premier XE instruments utilizing
electrospray ionization mode. Separations of products by chroma-
tography were performed on silica gel 60 (70e230 mesh) pur-
chased from Merck. Thin layer chromatography was carried out
using silica gel 60 precoated plates (Merck).
X-ray data were collected at 100 K (compound 6) and 299 K (4a)
using a KM4CCD diffractometer. Crystallographic data for the
structures in this paper have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publications nos.
CCDC 830423 and CCDC 874403, respectively.
For DFTcalculations, a hybrid functional M062X in 6-311þ(2d,2p)
basis set was used.24
3.2. Preparations
Fig. 3. Molecular structure of (1S,4S,5R)-2-[(S)-1-phenylethyl]-4-[(S)-phenylsulfinyl]-
2-azabicyclo[3.2.1]octane. Displacement ellipsoids are drawn at the 25% probability
level.
Syntheses of DielseAlder cycloadducts exo-(1S,3R,4R)-1, endo-
(1S,3S,4R)-1, and respective alcohols exo-(1S,3R,4R)-2, endo-
(1S,3S,4R)-2 were performed as described in the literature.2c,4
Though the procedure for preparation of sulfide 4a, selenide 4b,
azide 4d, amine 5, and their diastereomers was given in our
Scheme 7.

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E. Wojaczynska et al. / Tetrahedron 68 (2012) 7848e7854
7852
previous work,4,5 the structures proposed for these compounds
were incorrect. For this reason, the relevant experimental data for
these compounds are also reported below.
or a solution of KOH in ethanol led to derivatives 4g and 4h, re-
spectively. These compounds were purified by column chroma-
tography with diethyl ether as eluent.
Attempted isolation of mesylate from the reaction mixture
obtained by treatment of 2 with MsCl/Et3N led to chloride de-
rivative 4f. The crude product was chromatographed on silica gel
column with n-hexane/ethyl acetate (5:1 v/v).
3.2.1. Preparation of azides.5 Alcohol exo-(1S,3R,4R)-2 (0.46 g,
2 mmol) and triphenylphosphine (0.68 g, 2.6 mmol, 1.3 equiv) were
dissolved in 15 mL of dry toluene and cooled in an ice bath. A 1 M
solution of HN3 in benzene (2.6 mL, 2.6 mmol, 1.3 equiv) was then
added in one portion under inert atmosphere, followed by a 40%
solution of DEAD in toluene (1.37 mL, 3 mmol, 1.5 equiv), which
was added dropwise. The reaction mixture was stirred overnight
under argon. After evaporation of solvent, the residue was chro-
matographed on a silica column using n-hexane/ethyl acetate (6:1
v/v), yielding a fraction containing azide (1S,4S,5R)-4d (0.45 g, 88%).
(1S,4R,5R)-Isomer was prepared in a similar manner starting
from endo-(1S,3S,4R)-2.
3.2.2.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-acetylthiomethyl-2-
20
azabicyclo[3.2.1]octane (4c). Yellow oil.,
[
a
]
ꢁ78.7 (c 0.89,
D
CH2Cl2). 1H NMR (CDCl3):
d
¼1.31 (d, 3H, J¼6.3 Hz), 1.36e1.45 (m,
2H), 1.50e1.53 (m, 1H), 1.75e1.82 (m, 2H), 1.96 (br d, 1H,
J¼11.6 Hz), 2.29 (s, 3H), 2.32e2.35 (m, 1H), 2.51 (d, 1H, J¼13.6 Hz),
2.60e2.64 (m, 1H), 3.38e3.42 (m, 1H), 3.50 (br s, 1H), 3.59 (br s,
1H), 7.23 (t, 1H, J¼6.6 Hz), 7.28e7.33 (m, 4H) ppm. 13C NMR
(CDCl3):
d
¼21.4, 22.7, 29.3, 30.7, 36.6, 39.8, 45.2, 49.9, 56.3, 62.3,
Alternatively, azide 4d was prepared by the use of diphenyl-
phosphorylazide/DBU.
126.7, 127.3, 128.3, 145.5, 196.1 ppm. MS (ESI): m/z¼290.1580
(calculated for C17H24NOSþ ([MþH]þ) m/z¼290.1573). IR (film):
638, 701, 769, 955, 1112, 1135, 1351, 1453, 1491, 1686, 2793, 2864,
DBU (0.92 g, 0.92 mL, 6 mmol) and (PhO)2P(O)N3 (1.66 g,
1.30 mL, 6 mmol) were added to a stirred solution of alcohol exo-
(1S,3R,4R)-2 (0.92 g, 4 mmol) in 20 mL of dry toluene at 0 ꢀC under
inert atmosphere. After stirring for 2 h at 0 ꢀC and 24 h at room
temperature, water (10 mL) and 5% HCl (10 mL) were added to the
reaction mixture. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (2ꢂ15 mL). The combined organic
extracts were dried (Na2SO4) and evaporated. The residue was
purified by chromatography (n-hexane/ethyl acetate, 9:1 v/v) giv-
ing 4d as yellow oil (0.78 g, 76%).
2951, 3024, 3060 cmꢁ1
.
3.2.2.2. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-chloro-2-azabicyclo
20
[3.2.1]octane (4f). Yellow oil, yield 83%.
[
a
]
ꢁ37.8 (c 1.64,
D
CH2Cl2). 1H NMR (CDCl3):
d
¼1.28e1.48 (m, 3H), 1.33 (d, 3H,
J¼6.6 Hz), 1.68e1.82 (m, 2H), 2.39e2.55 (m, 3H), 2.75 (ABq, 1H,
J¼13.8 Hz), 3.43 (q, 1H, J¼6.6 Hz), 3.59 (t, 1H, J¼5.0 Hz),
3.87e3.92 (m, 1H), 7.20e7.36 (m, 5H, ArH) ppm. 13C NMR
(CDCl3):
d
¼21.6, 22.2, 28.4, 33.7, 42.4, 51.4, 56.0, 61.2, 62.0, 126.8,
127.3, 128.3, 145.4 ppm. MS (ESI): m/z¼250.1379 (calculated for
C15H21NClþ ([MþH]þ) m/z¼250.1357). IR (film): 546, 681, 702,
769, 957, 1137, 1261, 1452, 1491, 1686, 2098, 2795, 2806, 2952,
3.2.1.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-azide-2-azabicyclo
20
[3.2.1]octane (4d). [
d
a
]
ꢁ71.3 (c 0.60, CH2Cl2). 1H NMR (CDCl3):
D
¼1.28e1.48 (m, 3H), 1.33 (d, 3H, J¼6.6 Hz), 1.68e1.82 (m, 2H), 2.12
3025, 3061, 3082 cmꢁ1
.
(d, 1H, J¼11.7 Hz), 2.24 (ABqX, 1H, J1¼13.2 Hz, J2¼3.6 Hz), 2.30e2.38
(m, 1H), 2.56 (ABq, 1H, J¼13.2 Hz), 3.23e3.29 (m, 1H), 3.36 (q, 1H,
J¼6.6 Hz), 3.58e3.63 (m, 1H), 7.20e7.38 (m, 5H, ArH) ppm. 13C NMR
3.2.2.3. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-methoxy-2-azabicyclo
[3.2.1]octane (4g). Yellow oil, yield 39%. [
a
]
20 ꢁ33.0 (c 0.18, CH2Cl2).
D
(CDCl3):
d
¼21.5, 21.9, 27.2, 34.2, 38.9, 47.8, 56.0, 60.7, 62.5, 127.0,
1H NMR (CDCl3):
d
¼1.23e1.29 (m, 2H), 1.28 (d, 3H, J¼6.4 Hz),
127.5, 128.4, 145.2 ppm. HRMS (ESI) 257.1678 ([MþH]þ); for
(C15H21N4)þ M¼257.1766. IR (film): 701, 770, 1264, 1453, 1749, 2097
1.33e1.37 (m, 1H), 1.66e1.72 (m, 1H), 1.72e1.79 (m, 1H), 2.02 (ABq,
1H, J¼12.6 Hz), 2.14 (d, 1H, J¼11.4 Hz), 2.39e2.42 (m, 1H), 2.62 (ABq,
1H, J¼12.6 Hz), 2.97 (br s, 1H), 3.21 (s, 3H), 3.34e3.37 (m, 1H), 3.57
(t, 1H, J¼4.9 Hz), 7.20 (t, 1H, J¼7.3 Hz), 7.27 (t, 2H, J¼7.5 Hz), 7.31 (d,
(N3), 2953, 3026 cmꢁ1
.
3.2.1.2. (1S,4R,5R)-2-[(S)-1-Phenylethyl]-4-azide-2-azabicyclo
2H, J¼7.3 Hz) ppm. 13C NMR (CDCl3):
¼21.5, 21.7, 26.5, 33.1, 37.6,
d
20
[3.2.1]octane. Yield 85%. [
(CDCl3):
a
]
D
þ34.5 (c 0.58, CH2Cl2). 1H NMR
47.5, 56.0, 56.1, 62.6, 79.3, 126.7, 127.5, 128.3, 145.7 ppm. MS (ESI):
m/z¼246.1852 (calculated for C16H24NOþ ([MþH]þ) m/z¼246.1852).
IR (film): 701, 770, 1103, 1118, 1452, 1677, 1735, 2817, 2865, 2970,
d
¼1.15e1.50 (m, 3H), 1.23 (d, 3H, J¼6.6 Hz), 1.52e2.10 (m,
4H), 2.36 (s, 1H), 2.40e2.52 (m, 1H), 2.98e3.12 (m, 2H), 3.40 (br s,
1H), 7.17e7.45 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d
¼21.9, 22.0,
3025, 3060 cmꢁ1
.
27.0, 33.6, 38.8, 47.1, 570, 60.6, 62.0, 126.9, 127.6, 128.3, 145.2 ppm.
HRMS (ESI): 257.1757 ([MþH]þ); for (C15H21N4)þ m/z¼257.1766. IR
(film): 548, 702, 767, 955, 1029, 1046, 1160, 1263, 1453, 1492, 1748,
3.2.2.4. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-ethoxy-2-azabicyclo
20
[3.2.1]octane (4h). Yellow oil, yield 88%. [
a
]
ꢁ29.7 (c 0.74,
D
2096 (N3), 2810, 2871, 2972, 3026 cmꢁ1
.
CH2Cl2). 1H NMR (CDCl3):
d
¼1.17 (t, 3H, J¼7.0 Hz), 1.25e1.39 (m,
3H), 1.35 (d, 3H, J¼6.6 Hz), 1.66e1.78 (m, 2H), 2.04 (dd, 1H,
J1¼13.3 Hz, J2¼3.4 Hz), 2.22 (ABq, 1H, J¼11.4 Hz), 2.37e2.41 (m,
1H), 2.64 (ABq, 1H, J¼13.3 Hz), 3.08e3.10 (m, 1H), 3.33e3.39 (m,
2H), 3.40 (q, 1H, J¼6.6 Hz), 3.55e3.61 (m, 1H), 7.23 (t, 1H,
J¼7.3 Hz), 7.31 (t, 2H, J¼7.4 Hz), 7.36 (d, 2H, J¼7.1 Hz) ppm. 13C
3.2.2. Synthesis of chloride 4f, thioacetate 4c, and ethers 4g and
4h Mesylation of alcohol exo-(1S,3R,4R)-2 followed by the reaction
with nucleophiles gave ring-expanded derivatives 4c, 4fe4h. To a so-
lution of 2 (0.25 g, 1.08 mmol) in CH2Cl2 (5 mL) were added triethyl-
amine (0.15 mL, 1.17 mmol) and mesyl chloride (0.15 g, 1.30 mmol) at
0 ꢀC, and the reaction mixture was stirred for 5 h at 0 ꢀC.
After evaporation of solvent, ethanol (15 mL) and potassium
thioacetate (0.37 g, 3.25 mmol) were added and the solution was
stirred for 24 h under inert atmosphere. Solvent was removed in
vacuo, and the residue was dissolved in ethyl ether (10 mL). After
washing with water (3ꢂ5 mL), the organic layer was dried with
MgSO4 and evaporated. The solid residue was chromatographed on
a silicagel column with ethyl ether, yielding compound 4c (0.28 g,
90%).
NMR (CDCl3):
d
¼15.6, 21.7, 21.9, 26.6, 33.2, 38.4, 47.8, 56.2, 62.4,
63.6, 77.5, 126.6, 127.5, 128.2, 146.0 ppm. MS (ESI): m/z¼260.1705
(calculated for C17H26NOþ ([MþH]þ) m/z¼260.2009). IR (film):
701, 769, 956, 1106, 1371, 1452, 1491, 1599, 2792, 2948, 2971, 3024,
3061 cmꢁ1
.
3.2.3. Preparation of PNBA derivatives Alcohol exo-(1S,3R,4R)-2
(0.23 g, 1 mmol), triphenylphosphine (0.34 g, 1.46 mmol), and 4-
nitrobenzoic acid (0.18 g, 1.08 mmol) were dissolved in dry THF
(10 mL) at 0 ꢀC under inert atmosphere and DEAD (0.17 mL,
1.08 mmol) was added dropwise to the reaction mixture, which
was then stirred for 24 h at room temperature. After removal of
A similar mesylation procedure followed by the addition of so-
dium methanolate (prepared by dissolving of sodium in methanol)

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7853
solvent, the crude product was chromatographed on silica column
3.2.5. Preparation of amide 6 Amine 5 (0.23 g, 1 mmol), N-Boc-L-
using ethyl acetate as eluent, yielding ring-expanded compound 4e
as yellow oil (0.19 g, 50%).
proline (0.22 g, 1.11 mmol), potassium carbonate (0.28 g,
2.02 mmol), and N,N0-dicyclohexylcarbodiimide (DCC, 0.21 g,
1.0 mmol) were dissolved in 15 mL of acetonitrile and stirred for
24 h at room temperature. The precipitated (dicyclohexylurea)
was filtered off, and the filtrate was evaporated to dryness. The
solid residue was chromatographed on a silica column with CHCl3/
methanol (9:1 v/v) as eluent. The resulting amide was deprotected
by dissolving in 3 mL of TFA/CH2Cl2 (1:4), and stirring for 2 h at
room temperature. The reaction mixture was neutralized with
concentrated aqueous ammonia and extracted with dichloro-
methane. Evaporation of solvent yielded compound 6 as a color-
less solid (0.20 g, 60%). A single crystal of 6 suitable for X-ray
3.2.3.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-(4-nitrobenzoyloxy)-
2-azabicyclo[3.2.1]octane (4e). [
(CDCl3):
a
]
20 þ43.8 (c 3.40, CH2Cl2). 1H NMR
D
d
¼1.36 (d, 3H, J¼6.6 Hz), 1.38e1.44 (m, 1H), 1.47e1.53 (m,
2H), 1.78e1.85 (m, 2H), 2.27 (d, 1H, J¼11.5 Hz), 2.41 (ABqX, 1H,
J1¼13.9 Hz, J2¼3.2 Hz), 2.56e2.60 (m, 1H), 2.72 (ABq, 1H, J¼13.8 Hz),
3.45 (q, 1H, J¼6.6 Hz), 3.71 (t, 1H, J¼4.7 Hz), 4.86 (br s, 1H), 7.21 (t,
1H, J¼7.3 Hz), 7.27 (t, 2H, J¼7.3 Hz), 7.36 (d, 2H, J¼7.1 Hz), 8.27 (d,
2H, J¼8.9 Hz), 8.35 (d, 2H, J¼8.9 Hz) ppm. 13C NMR (CDCl3):
¼21.7,
d
21.8, 26.4, 33.9, 38.1, 48.6, 55.7, 62.3, 74.3, 123.6, 126.8, 127.2, 128.3,
130.7, 136.4, 145.6, 150.5, 164.2 ppm. MS (ESI): m/z¼381.1792 (cal-
measurement was obtained by
dichloromethane.
a slow crystallization from
þ
culated for C22H25N2O4 ([MþH]þ) m/z¼381.1809). IR (film): 702,
720, 1015, 1061, 1104, 1119, 1277, 1302, 1346, 1529, 1607, 1722, 2870,
2973, 3056 cmꢁ1
.
3.2.5.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-[(S)-prolylamine]-2-
20
Direct esterification of alcohol exo-(1S,3R,4R)-2 with 4-
nitrobenzoic chloride in the presence of Et3N gave (1S,3R,4R)-2-
[(S)-1-Phenylethyl]-3-(4-nitrobenzoyloxy)methyl-2-azabicyclo[2.2.1]
azabicyclo[3.2.1]octane (6). Mp¼148e149 ꢀC. [
a
]
þ10.0 (c 0.39,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
¼1.26e1.42 (m, 6H), 1.67e1.80
(m, 4H), 1.82e1.91 (m, 2H), 2.11e2.17 (m, 1H), 2.28e2.38 (m, 3H),
2.50 (s, 1H, NH), 3.02e3.08 (m, 2H), 3.36e3.38 (m, 1H), 3.57e3.68
(m, 3H), 7.20e7.38 (m, 5H, ArH), 8.20 (d, 1H, J¼7.2 Hz, NH) ppm. 13C
heptane. Yellow oil, yield 63%. [
a
]
20 ꢁ49.6 (c 0.49, CH2Cl2). 1H NMR
D
(CDCl3):
d
¼1.32e1.39 (m, 2H), 1.37 (d, 3H, J¼6.4 Hz), 1.43e1.49 (m,
1H), 1.66e1.74 (m, 1H), 1.84 (br d, 1H, J¼9.7 Hz) 2.03e2.09 (m, 1H),
2.27e2.28 (m, 1H), 2.41 (dd, 1H, J1¼9.6 Hz, J2¼3.4 Hz), 3.18 (dd, 1H,
J1¼10.8 Hz, J2¼3.6 Hz), 3.56 (q, 1H, J¼6.4 Hz), 3.65 (t, 1H, J¼10.3 Hz),
3.70 (br s, 1H), 7.27 (t, 1H, J¼7.4 Hz), 7.33 (t, 2H, J¼7.5 Hz), 7.40 (d,
2H, J¼7.4 Hz), 8.08 (d, 2H, J¼9.3 Hz), 8.25 (d, 2H, J¼9.3 Hz) ppm. 13C
NMR (75 MHz, CDCl3):
d
¼21.3, 22.0, 26.2, 27.4, 30.9, 34.6, 38.4, 47.4,
47.9, 49.4, 56.2, 60.7, 62.5, 126.9, 127.3, 128.4, 151.0, 174.9 ppm.
HRMS (ESI): m/z¼328.2386; calculated for (C20H30N3O)þ ([MþH]þ)
m/z¼328.2383. IR (KBr): 747, 1294, 1370, 1670, 2858, 2935, 2978,
3195 cmꢁ1
.
NMR (CDCl3):
d
¼22.7, 22.8, 28.7, 35.1, 39.8, 58.7, 61.1, 66.9, 67.4,
123.4, 127.5, 128.1, 128.4, 130.6, 135.8, 146.0, 150.4þ, 164.1 ppm. MS
(ESI): m/z¼381.1803 (calculated for C22H25N2O4 ([MþH]þ) m/
z¼381.1809). IR (film): 702, 720, 1104, 1116, 1275, 1295, 1347, 1455,
3.2.6. Preparation of sulfide 4a.4 Tributylphosphine (1.62 g,
1.97 mL, 8 mmol) was added by a syringe to the solution of alcohol
exo-(1S,3R,4R)-2 (0.46 g, 2 mmol) and diphenyldisulfide (1.31 g,
6 mmol) in dry toluene (6 mL). The mixture was transferred to the
ampoule, filled with argon, and sealed. This reaction mixture was
kept at the oil bath at 80 ꢀC for 3 days. Diethyl ether (20 mL) was
added to the cooled solution, the organic layer was washed with
10% aqueous NaOH, water and brine, and dried over anhydrous
Na2SO4. The solvent was evaporated and product 4a was purified by
column chromatography using hexane/ethyl acetate (9:1 v/v) as
eluent (0.26 g, 40%).
1527, 1606, 1641, 1727, 2872, 2972, 3029 cmꢁ1
.
3.2.4. Reduction of azides.5 Azide 4d (0.42 g, 1.6 mmol) was dis-
solved in 20 mL of methanol. Triphenylphosphine (0.63 g, 2.4 mmol,
1.5 equiv) was added and the reaction mixture was heated overnight
under reflux. The solvent was evaporated, and the residue was
chromatographed on silica column. Elution with chloroform yielded
the unreacted phosphine and phosphine oxide, while a chloroform/
methanol mixture (90:10 v/v) eluted the desired product 5 as yellow
oil (0.34 g, 92%).
3.2.6.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-phenylsulfanyl-2-
20
azabicyclo[3.2.1]octane (4a). Yellow oil. [
a
]
ꢁ5.1 (c 1.47, CH2Cl2).
D
3.2.4.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-amine-2-azabicyclo
1H NMR (CDCl3, 500 MHz):
d
¼1.23e1.32 (m, 6H), 1.60e1.66 (m,
20
[3.2.1]octane (5). [
d
a
]
ꢁ17.5 (c 0.40, CH2Cl2). 1H NMR (CDCl3):
1H), 1.75e1.77 (m, 1H), 1.93e1.98 (m, 1H), 2.11e2.14 (m, 1H),
2.20e2.28 (m, 2H), 2.43e2.48 (m, 1H), 3.45 (q, 1H, J¼6.42 Hz), 3.64
(br s, 1H), 6.62e6.63 (m, 2H, ArH), 7.04e7.06 (m, 3H, ArH),
D
¼1.25e1.37 (m, 3H), 1.31 (d, 3H, J¼6.6 Hz), 1.60e1.70 (m, 2H), 1.87
(br s, 2H), 2.03 (d, 1H, J¼10.2 Hz), 2.10e2.20 (m, 1H), 2.24 (d, 2H,
J¼2.7 Hz), 2.54e2.62 (m, 1H), 3.34 (q, 1H, J¼6.6 Hz), 3.56 (t, 1H,
7.28e7.36 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d
¼22.9, 23.8, 29.1,
J¼2.4 Hz), 7.20e7.30 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d¼21.3,
35.3, 37.7, 40.7, 59.9, 61.6, 68.9, 125.4, 127.8, 128.4, 128.7, 128.7,
129.0, 132.4, 136.9 ppm. HRMS (ESI): 324.1653 ([MþH]þ); for
(C21H26NS)þ M¼324.1786. IR (film) 737, 761, 1163, 1304, 1452,
21.4, 28.0, 33.4, 41.5, 50.9, 52.2, 56.4, 62.6, 126.8, 127.4, 128.3,
145.6 ppm. HRMS (ESI): 231.1846 ([MþH]þ); for (C15H23N2)þ m/
z¼231.1861. IR (film): 549, 701, 771, 952, 1134, 1453, 1491, 1599,
1480, 1583, 2870, 2969, 3059 cmꢁ1
.
2812, 2864, 2947, 3025, 3365 cmꢁ1
.
(1S,4R,5R)-Isomer was prepared analogously using (1S,4R,5R)-
azide in place of its diastereomer 4d.
3.2.7. Preparation of sulfide 7 Chloride derivative 4f (0.10 g,
0.4 mmol) was added to a solution of sodium thiophenolate
(0.4 mmol) in 4 mL of ethanol. The solution was stirred for 24 h at
room temperature. After evaporation of solvent, diethyl ether
(5 mL) was added, and the organic layer was washed with 10%
aqueous NaOH, water, and brine, and dried over anhydrous Na2SO4.
The solvent was evaporated and product 7 was purified by column
chromatography using hexane/ethyl acetate (9:1 v/v) as eluent
(0.032 g, 25%).
3.2.4.2. (1S,4R,5R)-2-[(S)-1-Phenylethyl]-4-amine-2-azabicyclo
[3.2.1]octane. Yellow oil, yield 56%. [
NMR (CDCl3):
a
]
20 ꢁ19.8 (c 0.61, CH2Cl2). 1H
D
d
¼1.10e1.40 (m, 4H), 1.23 (d, 3H, J¼6.6 Hz),
1.70e1.80 (m, 1H), 1.85e1.95 (m, 1H), 2.10e2.20 (m, 1H), 2.29 (br
s, 2H), 2.38e2.49 (m, 2H), 2.71e2.80 (m, 1H), 2.92e3.10 (m, 1H),
3.35 (q, 1H, J¼6.6 Hz), 7.21e7.35 (m, 5H, ArH) ppm. 13C NMR
(CDCl3):
d
¼21.0, 22.1, 27.9, 33.0, 41.6, 50.6, 51.1, 57.6, 61.9, 126.7,
127.5, 128.3, 146.0 ppm. HRMS (ESI): 231.1882 ([MþH]þ); for
(C15H23N2)þ m/z¼231.1861. IR (film): 543, 703, 772, 967, 1050,
1180, 1305, 1370, 1453, 1492, 1602, 1741, 2790, 2820, 2873, 2971,
3.2.7.1. (1S,4R,5R)-2-[(S)-1-Phenylethyl]-4-phenylsulfanyl-2-
azabicyclo[3.2.1]octane (7). Yellow oil. [
a
]
20 ꢁ83.3 (c 0.42, CH2Cl2).
D
1H NMR (CDCl3):
d
¼1.27e1.44 (m, 3H), 1.33 (d, 3H, J¼6.5 Hz),
3468 cmꢁ1
.
1.73e1.79 (m, 2H), 2.35 (br d, 1H, J¼11.7 Hz), 2.40e2.46 (m, 2H),

ꢀ
E. Wojaczynska et al. / Tetrahedron 68 (2012) 7848e7854
7854
2.64 (ABq, 1H, J¼12.3 Hz), 3.04 (br s, 1H), 3.40 (q, 1H, J¼6.6 Hz),
3.62 (t, 1H, J¼4.8 Hz), 7.15e7.38 (m, 10H) ppm. 13C NMR (CDCl3):
(C21H26NSe)þ M¼372.1232. IR (film) 692, 738, 1437, 1452, 1476,
1578, 2946, 3057 cmꢁ1
.
d
¼21.6, 22.7, 29.7, 34.9, 39.3, 48.9, 51.5, 56.5, 62.4, 126.6, 126.7,
127.4, 128.2, 128.8, 132.0, 136.5, 145.7 ppm. MS (ESI): m/
z¼324.1791 (calculated for C21H26NSþ ([MþH]þ) m/z¼324.1780).
IR (film): 701, 756, 1025, 1135, 1285, 1453, 1479, 1584, 1686, 2791,
Acknowledgements
The work was financed by a statutory activity subsidy from the
Polish Ministry of Science and Higher Education for the Faculty of
Chemistry of Wroc1aw University of Technology.
2862, 2948, 3024 cmꢁ1
.
3.2.8. Oxidation of (1S,4S,5R)-2-[(S)-1-phenylethyl]-4-phenylsulfanyl-
2-azabicyclo[3.2.1]octane (sulfide 4a) Vanadyl acetylacetonate
(5.2 mg, 0.02 mmol) and (S)-(ꢁ)-N-(3-phenyl-5-nitrosalicylidene)
valinol (0.03 mmol) were dissolved in a test tube in dichloro-
methane (4 mL), and the solution was stirred for 5 min at 25 ꢀC.
After the addition of sulfide 4a (0.65 g, 2 mmol) the solution was
cooled to 0 ꢀC and 30% H2O2 (0.26 mL, 2.3 mmol) was added
dropwise within 10 min. The mixture was stirred for 20 h at 0 ꢀC
and extracted with CH2Cl2 (2ꢂ5 mL). The combined organic
extracts were washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product was sub-
mitted to chromatography on silica (t-BuOMe/CHCl3/n-hexane
3:2:4) and the major diastereomer was recrystallized from meth-
ylene chloride/n-hexane, yielding sulfoxide 6 as a white powder
(0.41 g, 60%). A single crystal of 6 suitable for X-ray measurement
was obtained by a slow crystallization from n-hexane/dichloro-
methane mixture.
Supplementary data
Tables showing spectral assignments for 2-azabicyclo[3.2.1]oc-
tane derivatives together with an example of analysis of 2D NMR
spectra and DFT optimized structures. Supplementary data associ-
ated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2012.07.028.
References and notes
1. Privileged Chiral Ligands and Catalysts; Zhou, Q., Ed.; Wiley-VCH Verlag GmbH &
Co. KgaA: Weinheim, 2011.
2. (a) Bailey, P. D.; Wilson, R. D.; Brown, G. R. Tetrahedron Lett. 1989, 30,
6781e6784; (b) Nakano, H.; Kumagai, N.; Kabuto, C.; Matsuzaki, H.; Hongo, H.
Tetrahedron: Asymmetry 1995, 6, 1233e1236; (c) Ekegren, J. K.; Modin, S. A.;
Alonso, D. A.; Andersson, P. G. Tetrahedron: Asymmetry 2002, 13, 447e449.
3. (a) Brandt, P.; Andersson, P. G. Synlett 2000,1092e1106; (b) Nakano, H.;Kumagai, N.;
Matsuzaki, H.;Kabuto, C.;Hongo, H. Tetrahedron: Asymmetry 1997, 8,1391e1401; (c)
Lu, J.; Xu, Y.-H.; Liu, F.; Loh, T.-P. Tetrahedron Lett. 2008, 49, 6007e6008.
ꢀ
ꢀ
_
4. Wojaczynska, E.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19, 2252e2257.
3.2.8.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-[(S)-phenylsulfinyl]-2-
5. Wojaczynska, E. Tetrahedron: Asymmetry 2011, 21, 161e166.
20
azabicyclo[3.2.1]octane. De 70%. [
a
]
ꢁ168.0 (0.50, CH2Cl2). 1H
ꢀ
D
6. Pedrosa, R.; Andres, J. M.; Manzano, R.; Rodríguez, P. Eur. J. Org. Chem. 2010,
5310e5319.
NMR (CDCl3):
d
¼1.27e1.45 (m, 3H),1.40 (d, 3H, J¼6.6 Hz),1.58e1.70
7. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380e2382; (b)
Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P.
Chem. Rev. 2009, 109, 2551e2651.
(m, 2H), 1.83 (br s, 1H), 2.16 (d, 1H, J¼11.4 Hz), 2.37 (br s, 1H), 2.54
(dd, 1H, J1¼13.8 Hz, J2¼3.9 Hz), 3.45 (d, 1H, J¼13.8 Hz), 3.58e3.61
(m, 2H), 7.20e7.40 (m, 5H), 7.47e7.52 (m, 3H), 7.65e7.75 (m, 2H)
8. Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100e2113.
9. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E.
J. J. J. Org. Chem. 1993, 58, 5886e5888.
ppm. 13C NMR (CDCl3):
d
¼20.5, 23.6, 29.5, 34.8, 35.7, 42.4, 56.8,
62.5, 70.2, 125.4, 127.0, 127.5, 128.4, 129.2, 131.3, 144.0, 144.4 ppm.
MS (ESI): m/z¼340.1725 (calculated for C21H26NOSþ ([MþH]þ)
m/z¼340.1730). IR (KBr): 699, 749, 1021, 1037, 1287, 1442, 1489,
ꢀ
10. Metro,T.-X.; Duthion, B.;GomezPardo, D.; Cossy, J.Chem.Soc. Rev. 2010, 39, 89e102.
11. (a) Pfister, J. R. Synthesis 1984, 969e970; (b) Wipf, P.; Miller, C. P. Tetrahedron
Lett. 1992, 33, 6267e6270.
12. Tymoshenko, D. O. Arkivoc 2011, i, 329e345.
2951, 3440 cmꢁ1
.
13. Mena, M.; Bonjoch, J.; Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2006, 71, 5930e5935.
14. Cochi, A.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2011, 13, 4442e4445.
15. Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830e3833.
16. (a) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11, 1935e1938;
(b) Oxenford, S. J.; Moore, S. P.; Carbone, G.; Barker, G.; O’Brien, P.; Shipton, M.
R.; Gilday, J.; Campos, K. R. Tetrahedron: Asymmetry 2010, 21, 1563e1568.
17. Chong, H.; Ganguly, B.; Broker, G. A.; Rogers, R. D.; Brechbiel, M. W. J. Chem. Soc.,
Perkin Trans. 1 2002, 2080e2086.
3.2.9. Preparation of selenide.4 PhSeCN (0.15 mL, 1.2 mmol) was
added by a syringe to the solution of alcohol exo-(1S,3R,4R)-2
(0.23 g, 1 mmol) in dry toluene (15 mL) under argon atmosphere.
The mixture was cooled to 0 ꢀC in an ice bath, and tribu-
tylphosphine (0.74 mL, 3 mmol) was injected to the stirred solu-
tion. The mixture was kept at room temperature for 20 h. After
evaporation of solvent, chloroform (10 mL) was added to the re-
action mixture, and it was washed with 10% aqueous NaOH, water
and brine. The organic layer was dried over anhydrous Na2SO4. The
solvent was evaporated and product (4b) was purified by column
chromatography with hexane/ethyl acetate (9:1 v/v) as eluent
(0.089 g, 24%).
18. Cutri, S.; Bonin, M.; Micouin, L.; Husson, H.-P.; Chiaroni, A. J. Org. Chem. 2003,
68, 2645e2651.
19. O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637e651.
20. (a) Wilken, J.; Kossenjans, M.; Saak, W.; Haase, D.; Pohl, S.; Martens, J. Liebigs
€
Ann./Recl. 1997, 12, 573e579; (b) Roper, S.; Frackenpohl, J.; Schrake, O.;
Wartchow, R.; Hoffmann, H. M. R. Org. Lett. 2000, 2, 1661e1664; (c) Ogier, L.;
Turpin, F.; Baldwin, R. M.; Riche, F.; Law, H.; Innis, R. B.; Tamagnan, G. J. Org.
Chem. 2002, 67, 3637e3642; (d) Timen, A. S.; Fischer, A.; Somfai, P. Chem.
Commun. 2003, 1150e1151; (e) Timen, A. S.; Somfai, P. J. Org. Chem. 2003, 68,
9958e9963; (f) Verhelst, S. H. L.; Paez Martinez, B.; Timmer, M. S. M.; Lodder,
G.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. J. Org. Chem. 2003, 68,
9598e9603; (g) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Smith,
A. D. Synlett 2004, 901e903; (h) Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H.
Tetrahedron 2005, 61, 2075e2104.
ꢀ
ꢁ
ꢀ
ꢁ
ꢀ
3.2.9.1. (1S,4S,5R)-2-[(S)-1-Phenylethyl]-4-phenylselenalyl-2-
azabicyclo[3.2.1]octane (4b). Yellow oil. [
a
]
20 ꢁ80.3 (c 0.66, CH2Cl2).
D
1H NMR (CDCl3, 300 MHz):
d¼1.29e1.32 (d, 3H, J¼6.64 Hz),
21. Gayet, A.; Andersson, P. G. Adv. Synth. Catal. 2005, 347, 1242e1246.
22. Hata, T.; Sekine, M. Chem. Lett. 1974, 837e838.
1.34e1.43 (m, 3H), 1.54e1.58 (m, 1H), 1.70e1.78 (m, 2H), 2.19e2.24
(m, 1H), 2.49e2.54 (m, 1H), 2.67e2.72 (m, 1H), 3.08e3.11 (m, 1H),
3.37 (q, 1H, J¼6.65 Hz), 3.60 (t, 1H, J¼4.78 Hz) 7.15e7.61 (m, 10H,
23. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485e1486.
24. Dr. Robert Wieczorek is gratefully acknowledged for performing DFT calcula-
tions. All optimized structures are shown in Supplementary data.
25. (a) O’Brien, P.; Towers, T. D. J. Org. Chem. 2002, 67, 304e307; (b) Silva, M. A.;
Goodman, J. M. Tetrahedron Lett. 2005, 46, 2067e2069; (c) D’hooghe, M.; Catak,
ArH) ppm. 13C NMR (CDCl3):
d
¼21.6, 22.6, 30.1, 36.3, 40.3, 48.4, 50.1,
56.4, 62.4, 126.7, 127.1, 127.4, 128.3, 128.8, 131.6, 132.8, 134.4 ppm.
ꢀ
S.; Stankovic, S.; Waroquier, M.; Kim, Y.; Ha, H.; Van Speybroeck, V.; De Kimpe,
77Se NMR:
d
¼382.7 ppm. HRMS (ESI): 372.1195 ([MþH]þ); for
N. Eur. J. Org. Chem. 2010, 4920e4931.