Preparation of 2,3-dihydroselenolo[2,3-b]pyridines and related compounds by free-radical means

Article abstract of DOI:10.1039/b515385a

Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-(benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2-carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process presumably involving intramolecular homolytic substitution by a tertiary alkyl radical at selenium with loss of a benzyl radical. Alternatively, rearrangement of O-(ω-haloalkyl)esters 34 of 2-carboethoxy-N-hydroxypyridine-2-selone affords azonianaphthalenium halides 37 in 79% yield. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b515385a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Preparation of 2,3-dihydroselenolo[2,3-b]pyridines and related compounds
by free-radical means†
Tahli Fenner,a Jonathan M. Whitea,b and Carl H. Schiesser*‡a,b
Received 21st October 2005, Accepted 28th November 2005
First published as an Advance Article on the web 21st December 2005
DOI: 10.1039/b515385a
Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-(benzylseleno)pyridin-
3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2-carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine
(22) in 89% yield in a process presumably involving intramolecular homolytic substitution by a tertiary
alkyl radical at selenium with loss of a benzyl radical. Alternatively, rearrangement of
O-(x-haloalkyl)esters 34 of 2-carboethoxy-N-hydroxypyridine-2-selone affords azonianaphthalenium
halides 37 in 79% yield.
while lipid peroxidation has been implicated in diseases such as
atherosclerosis.6a,8 Reactive oxygen species do have some positive
Introduction
roles in biology, such as providing defense against infection,6a,9
however, excessive concentrations of ROS can lead to oxidative
stress.6a,9 Nature has evolved clever methods for controlling
ROS. Preventative antioxidant enzymes such as glutathione per-
oxidase remove ROS through redox cycling,5 while chain breaking
antioxidants such as vitamin E, interrupt the chain reactions
responsible for the formation of radical species.10 It should be
noted that vitamin E refers to a family of related compounds
known as tocopherols of which a-tocopherol 4 is most potent.10b
Interest in selenium-containing therapeutics has grown over the
last thirty years.1 Simple organoselenium compounds have been
prepared, such as selenazolopyrimidone (1), that show antitumor
activity against mouse leukemia.2 (Aminoethyl)phenylselenide (2)
shows excellent antihypertensive activity and selenazine deriva-
tives, such as 3, show both antibacterial and antitumor activity.3
Despite this, the major therapeutic benefit that selenium currently
offers appears to be in the form of dietary supplements.4 Selenium
is an essential trace element and dietary deficiency can lead to
ailments including gum disease, as well as debilitating conditions
such as Keshan’s disease.4e The biochemistry and pharmacology of
selenium is of intense current interest. Selenium is now known to be
intimately involved in the activity of enzymes such as glutathione
peroxidase and thioredoxin reductase, that catalyse chemistry
essential to the protection of biomolecules against oxidative stress
and free radical damage.5
Reactive oxygen species (ROS) are a byproduct of normal
aerobic metabolism.6 Superoxide is formed when electrons leak
from the electron transport chain and react with molecular
oxygen, and is also the product of some enzymatic processes.6b,7
Superoxide dismutase converts superoxide to hydrogen peroxide,
which can, in turn, lead to the formation of hydroxyl and lipid
peroxyl radicals.6b,7 Hydroxyl radicals are extremely reactive and
can cause damage to important biomolecules that include DNA,
In recent years there has been much interest in developing new,
more potent antioxidants such as ebselen (5), that also acts as a
glutathione peroxidase mimic and is due to be released for human
use as a non-steroidal anti-inflammatory.11 Water-soluble vitamin
E analogues that have been prepared include Trolox (6),12 while our
group has used intramolecular homolytic substitution chemistry
to prepare a selenium containing analogue 7 of vitamin E that
possesses dual mode of action.13
aSchool of Chemistry, The University of Melbourne, Victoria, Australia 3010
bBio21 Molecular Science and Biotechnology Institute, The University
of Melbourne, Victoria, Australia 3010. E-mail: carlhs@unimelb.edu.au;
Fax: +61 3 9347 8189; Tel: +61 3 8344 2432
† Electronic supplementary information (ESI) available: B3LYP/6-
311G** optimised geometries of 28a, 28b, 29a and 29b as Gaussian archive
entries. See DOI: 10.1039/b515385a
‡ Parts of this work have been published in preliminary form: T. Fenner
and C. H. Schiesser, Molecules, 2004, 9, 472.
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Work in our laboratories has also been directed at the devel-
opment of water-soluble, dual acting, tocopherol/ebselen hybrids
such as 8 and to pyridine-fused tocopherol systems such as 9.
the generation of carbon-centered radicals from tertiary alcohols.
To our surprise, reaction of 17 with oxalyl chloride, followed by
R
sodium omadineꢀ, afforded none of the desired cyclized product
10, despite the reaction being carried out under a number of
different conditions. 1H NMR spectroscopy of the only identified
product suggested strongly that elimination has occurred to afford
a mixture of isomeric alkenes (Scheme 2).
Results and discussion
Free radical ring closure approaches to the
2,3-dihydroselenolo[2,3-b]pyridine core structure
Preliminary investigations began with the attempted preparation
of model compound 10 that contained many of the salient feature
of structures 8 and 9. To that end, ethyl 2-chloronicotinate (11)
was reacted with sodium benzylselenoate, generated in situ by
reduction of dibenzyl diselenide with sodium borohydride, to give
ethyl 2-(benzylseleno)nicotinate (12) in 64% yield (Scheme 1).
Scheme 2
Given the problems associated with the methodology described
above, it became apparent that an alternative method for the
generation of the required radical was needed. Following a
modification of the procedure described in Scheme 1, chloride
14 was reacted with t-butyl ethyl malonate to afford selenide
18 in moderate (54%) yield (Scheme 3). Further treatment with
sodium hydride and 1-bromododecane provided diester 19 in 72%
yield, which was selectively deprotected by the action of trifluo-
roacetic acid to afford 2-carboethoxy-2-(2-(benzylseleno)pyridin-
3-yl)tridecylcarboxylic acid (20), suitable for conversion into a
radical precursor.
Scheme 1
Further reduction with lithium aluminium hydride afforded
alcohol 13 in 91% yield. It is interesting to note that the alternative
sequence of reactions, namely reduction of the ester 11 followed
by treatment with sodium benzylselenoate, proceeded only very
poorly. We attribute this observation to the electrophilicity of
the pyridine ring in the various substrates, specifically that the
electron-withdrawing ester substituent is able to increase ring
reactivity in a manner that the alcohol cannot. The alcohol 13
was further reacted with methanesulfonyl chloride to give the
chloride 14 in 92% yield, which was subsequently reacted with t-
butyl acetoacetate and base to give the ketoester 15 following the
procedure developed by Engman and Malmstro¨m.13 Treatment
of 15 with concentrated hydrochloric acid afforded the required
ketone 16 in excellent overall yield. Finally, reaction of 16 with
n-butylmagnesium bromide gave the desired tertiary alcohol 17 in
86% yield (Scheme 1).
Scheme 3
Kim recently described a new method for generating carbon-
centered radicals from thiohydroximate esters of carboxylic acids
and we have generally found this precursor to be superior to
those described by Barton and coworkers14 for reasons including
stability, especially in tertiary systems.15 Therefore, 20 was con-
verted into precursor 21 by the action of N-methylhydroxydithio-
carbamate and dicyclohexylcarbodiimide (DCC); 21 was isolated
Following our previously published work, we expected that
alcohol 17 could be converted into the PTOC oxalate ester,
originally described by Barton and Crich as a suitable precursor for
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as a yellow oil after column chromatography. Photolysis of 21 in
heptane afforded the target 2-dodecyl-2-carboethoxy-2,3-dihydro-
selenolo[2,3-b]pyridine (22) in 89% yield. The dihydroselenolo[2,3-
b]pyridine 22 displayed a 77Se NMR signal at d 547.6 characteristic
of structurally related selenium heterocycles.16
Having successfully demonstrated that tertiary carbon-centered
radicals, such as 23 are capable of undergoing intramolecular
homolytic substitution to afford dihydroselenolo[2,3-b]pyridines
such as 22, we next turned our attention to the preparation of a
precursor for the synthesis of a six-membered ring such as that
found in the initial target compound 10.
Scheme 4
To that end, 2-chloronicotinaldehyde (25) was added to a
solution of ethyl propiolate and lithium bis(trimethylsilyl)amide
in THF at −78 ◦C. After stirring at −78 ◦C for 4 h, the reaction was
quenched using saturated ammonium chloride solution to give the
acetylinic alcohol 26 in 73% yield after purification. It is important
that the reaction mixture is quenched at low temperature, as signi-
ficantly lower yields were obtained when the mixture was allowed
to warm before addition of the ammonium chloride solution.
Hydrogenolysis of alcohol 26 followed by PCC oxidation
afforded ketone 27 in poor (36%) yield. Significant amounts
of by-product appeared to accompany this transformation. De-
spite this, ketone 27 was further reacted with sodium benzylse-
lenoate, generated as described above, to afford ethyl 3-oxo-3-(2-
(benzylseleno)pyridin-3-yl)butyrate (28) in acceptable yield.
With 28 in hand, the next task was the removal of the
ketone functional group. We envisaged that Wolff–Kischner or
Clemenson techniques would result in the required compound.
Unfortunately, the action of zinc-mercury amalgam (Clemensen
reduction) returned only 28, while reaction with alkaline hydrazine
(Wolff–Kischner reduction) afforded a single product that was
assigned to be pyradizinone 29 that was isolated in 63% yield. The
formation of 29 can be rationalized by the nucleophilic capture of
the initial ketone–hydrazine adduct by the proximate ester moiety,
with subsequent dehydration (Scheme 4).
Fig. 1 Perspective diagram of 28.
by us recently.17 The Se–O1 interaction might possibly involve
donation of electron density into the Se1–C12 r* orbital, however
the C1–C2 bond distance of 1.403(4) A, the ketone carbonyl C6–
˚
˚
O1 bond distance of 1.219(3) A, the C2–C6 bond distance of
˚
˚
1.4629(4) A and the C1–Se1 distance of 1.917(3) A are all similar
to bond distances for similar fragments which were extracted
from the Cambridge Crystallographic Database18 and thus do not
provide any further structural evidence for contributions from
resonance form 31.
Ketone 28 proved to surprisingly difficult to reduce using
standard techniques. Treatment with a large excess of sodium
borohydride at room temperature resulted in no reduction,
however in refluxing ethanol, clean conversion to the diol 30 was
observed after several hours. Single crystal X-ray analysis of 28
provided interesting structural information that may help in our
understanding of the relative inertness of the ketone moiety in 28
to reduction.
A second, weaker interaction exists between O1, and the ester
carbonyl C9, this interaction is characterised by the O1 · · · C9
˚
distance of 2.791(3) A which is shorter than the sum of the van
˚
der Waals radii of oxygen and carbon (3.25 A), furthermore the
ester carbonyl carbon (C9) deviates by 0.019 A from the plane
˚
A perspective diagram of 28 is presented in Fig. 1. There appears
to be a remarkably short selenium–oxygen separation in 28, which
at 2.679(3) A is well below the sum of the van der Waals radii
defined by O4, O4 and C8 towards O1, this interaction may also
stabilise the gauche conformation of the side chain substituent
[C6–C7–C8–C9-65.9(4)] (Fig. 1).
˚
˚
of the two atoms involved (3.4 A) and is suggestive of significant
The contribution of 31 to the overall structure of 28 is
further supported by computational studies. B3LYP/6-311G**
calculations19 (Fig. 2) predict that in the closely-related methylse-
lenides, conformation 28a is preferred over 28b by 17.6 kJ mol−1.
Conformer 28a displays similar interations to those observed in the
contribution of resonance structure 31 to the overall bonding in 28.
Indeed, the Se–O1 separation in 28 is, to the best of our knowledge,
the shortest selenium–carbonyl oxygen interaction reported, being
˚
˚
some 0.04 A shorter than the previous “record” of 2.72 A reported
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Fig. 2 B3LYP/6-311G** optimised structures for 28a (left) and 28b (right). Mulliken bond populations in parentheses.
Fig. 3 B3LYP/6-311G** optimised structures for 29a (left) and 29b (right). Mulliken bond populations in parentheses.
˚
X-ray structure of ketone 28 with a short (2.72 A) N–Se separation.
rangement to form 2-(alkylseleno)pyridines (Scheme 5) through a
mechanism that is likely to involve a radical cage mechanism.20
In addition, the N–Se Mulliken bond populations and remaining
bond lengths in 28a when compared with 28b are supportive of
the bonding interaction depicted in 31, with the N–Se population
of 0.027 corresponding to about a “10% bond”.
Similar reasoning can be used to explain the formation of
29 during the attempted Wolff–Kischner reduction; resonance
structure 32 would be expected to contribute strongly to the
stabilization of 29. This hypothesis is once again supported by
computational studies; B3LYP/6-311G** calculations (Fig. 3)
predict that in the closely-related methylselenides, conformation
29a is preferred over 29b by 9.2 kJ mol−1, with 29a displaying
similar interations to those observed in the X-ray structure of
Scheme 5
With the initial intention that cyclized structures such as 33
could be prepared from haloalkylselenides such as 34, we chose
to explore the use of the selone chemistry described above for the
preparation of 34.
˚
ketone28 andthecalculated structure 28a, with a short (2.78 A) N–
Se separation. Once again, N–Se Mulliken bond populations and
bond lengths are supportive of the bonding interaction depicted
in 32, with the N–Se population of 0.018 corresponding to about
a “5% bond”.
Ethyl 2-chloronicotinate 11 was oxidised using hydrogen per-
oxide in trifluoroacetic acid. The resultant N-oxide 35 was
treated with selenium powder and sodium borohydride following
Barton’s protocol20 to give 2-carboethoxy-N-hydroxypyridine-2-
selone (36) as a yellow oil. As expected, selone 36 proved to
be unstable and was immediately reacted with 4-bromobutanoyl
chloride. After 30 min in benzene at reflux, the precipitate was
collected and was shown to be the azonianaphthalenium halide
37 by HRMS. The filtrate was subjected to flash chromatography
Free radical rearrangements of carboxylic esters of
2-selenopyridine-N-oxide
Some twenty years ago, Barton described the preparation of O-
esters of 2-selenopyridine-N-oxide and their decarboxylative rear-
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affording the halopropylselenides 34 (X = Br/Cl) as an inseparable
mixture. Clearly, the initially rearranged selenide 34 (X = Br)
has undergone further nucleophilic attack by both chloride ion
(intermolecularly), as well as the nucleophilic nitrogen in 34 to
produce the observed products. When the reaction was repeated
with overnight reflux, the azonianaphthalenium halide 37 was
isolated in 79% yield, with no intermediate 34 present in the
reaction mixture (Scheme 6).
the residual peak of CHCl3 was used as the internal reference
(7.26 ppm) while the central peak of CDCl3 (77.0 ppm) was used
as the reference for carbon spectra. 77Se NMR chemical shifts are
given in ppm relative to externally referenced diphenyl diselenide
(d 464). EI mass spectra were recorded at 70 eV. M+ ions are given
for 80Se. Tetrahydrofuran and diethyl ether were distilled under
nitrogen from sodium–benzophenone. Benzene and pyridine were
distilled under nitrogen from calcium hydride. Elemental analyses
were performed by Chemical and Micro Analytical services Pty.
Ltd, Geelong, Victoria, Australia.
Ethyl 2-(benzylseleno)nicotinate (12)
Sodium borohydride was added in portions to a suspension
of dibenzyl diselenide (5.00 g, 14.7 mmol) in degassed ethanol
(100 mL) under a flow of nitrogen until a colourless solution
formed. Ethyl 2-chloronicotinate21 (11) (5.47 g, 29.4 mmol) in
ethanol (20 ml) was added and the reaction mixture refluxed for
3 h. Water (70 mL) was added and the volume of solvent reduced
under vacuum. The residue was extracted with ether (3 × 70 mL)
and the combined extracts dried (MgSO4) and separated by flash
chromatography (5% EtOAc–hexane followed by 20% EtOAc–
hexane after residual dibenzyl diselenide had eluted). The title
compound was obtained as pale yellow crystals (71%). Mp 52–
53 C. H NMR d 1.36 (t, 3H, J = 7.2), 4.35 (q, 2H, J = 7.2),
4.41 (s, 2H), 7.09–7.26 (m, 4H), 7.38 (d, 2H, J = 8.1), 8.20 (dd,
1H, J = 1.8, 7.8) 8.59 (dd, 1H, J = 1.8, 4.6). 13C NMR d 14.3,
29.2, 61.6, 119.0, 124.7, 126.5, 128.3, 129.3, 138.6, 139.2, 152.3,
160.7, 165.5. 77Se NMR d 469.8. IR 2918, 1701. MS m/z (M + H)+
322.3. (HRMS Found: 322.0346. C15H16NO2Se requires 322.0343).
(Found: C, 56.14 H, 4.79 N, 4.36. C15H15NO2Se requires C, 56.26
H, 4.72 N, 4.37%).
Scheme 6
The preparation of the azonianaphthalenium halide 37 fits
well with the original aim of preparing water-soluble selenium-
containing antioxidants. With this in mind, we attempted to
prepare the related compound 38. Treatment of selone 36 with
3-bromopropanoyl chloride resulted in the rapid evolution of gas,
presumably CO2, and a complex mixture of products from which
diselenide 39 was isolated as the only identifiable product. We
speculate that the first-formed ester 40 decomposes through a b-
cleavage machanism to afford radical 41 that dimerises to give the
observed product (Scheme 7).
◦
1
[2-(Benzylseleno)pyridin-3-yl]methanol (13)
A solution of ethyl 2-(benzylseleno)nicotinate (12) (2.63 g,
8.23 mmol) in ether (50 mL) was added by a dropping funnel
to an ice cooled suspension of lithium aluminiumhydride (0.34 g,
9.0 mmol) in ether (15 mL). After stirring at room temperature
for 1.5 h under N2, the reaction was quenched with water. After
stirring for 30 min, the reaction mixture was washed with water
(2 × 70 mL), sat. NaCl (40 mL) and the organic phase dried
(MgSO4). Flash chromatography (50% EtOAc–hexane) gave the
Scheme 7
Conclusion
1
title compound as a very pale oil (97%). H NMR d 4.52 (s, 2H,
J77Se = 10.2), 4.58 (s, 2H), 7.08 (dd, 1H, J = 4.9, 7.6), 7.18–7.27
(m, 3H), 7.35 (d, 2H, J = 8.3), 7.60 (dd, 1H, J = 1.2, 7.6), 8.43
(dd, 1H, J = 1.2, 4.9). 13C NMR d 29.2, 62.5, 120.5, 126.8, 128.4,
129.0, 134.3, 136.2, 139.1, 148.5, 154.2.; 77Se NMR d 384.8; IR
3331 (br). MS m/z (M + H)+ 280.2. (Found: C, 56.13 H, 4.71 N,
5.05. C13H13NOSe requires C, 56.12 H, 4.71 N, 5.03%).
We have presented work toward the preparation of novel pyridine-
fused, selenium-containing antioxidants and have demonstrated
that, intramolecular homolytic substitution as well as free-radical
rearrangements of O-esters of 2-selenopyridine-N-oxide are effec-
tive methods for the preparation of model ring systems. The reac-
tivity of ethyl 3-oxo-3-(2-(benzylseleno)pyridin-3-yl)butyrate (28)
and 6-[2-(benzylseleno)pyridin-3-yl]-4,5-dihydro-2H-pyridazin-3-
one (29) is attributed to strong non-bonded O–Se interactions that
are supported by X-ray as well as computational analysis.
2-(Benzylseleno)-3-(chloromethyl)pyridine (14)
A solution of [2-(Benzylseleno)pyridin-3-yl]methanol (13) 4.40 g,
15.8 mmol) and triethylamine (4.4 mL, 32 mmol) in THF
(30 mL) was cooled to 0◦C and methanesulfonyl chloride (2.5 mL,
32 mmol) was slowly added under N2. The mixture was allowed
to warm to room temperature and then heated at reflux for 1 h.
The reaction was quenched with water and extracted with ether
Experimental
Melting points are uncorrected. Unless otherwise stated, 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded in
CDCl3 on a Varian unity 400 spectrometer. For proton spectra
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1
(3 × 70 mL), the combined extracts dried (MgSO4) and separated
by flash chromatography (10% EtOAc–hexane) to afford the title
compound as a colourless oil (96%). 1H NMR d 4.53 (s, 2H), 4.55
(s, 2H), 7.09 (dd, 1H, J = 4.8, 7.8), 7.18–7.28 (m, 3H), 7.38 (d, 2H,
J = 7.8), 7.57 (1H, dd, J = 1.5, 7.8), 8.46 (1H, dd, J = 1.5, 4.8).
13C NMR d 29.6, 44.0, 120.4, 126.9, 128.4, 129.1, 132.8, 136.4,
138.9, 149.3, 156.2. 77Se NMR d 390.5. MS m/z (M + H)+ 298.2.
(HRMS found 319.9716. C13ClH12NNaSe requires 319.9721).
pale yellow oil (86%). H NMR d 0.91 (t, 3H, J = 6.8), 1.21 (s,
3H), 1.29–1.35 (m, 4H) 1.48 (m, 2H), 1.67 (m, 2H) 2.63 (m, 2H),
4.51 (s, 2H, J77Se = 10.2) 7.01 (dd, 1H, J = 4.6, 7.6) 7.19–7.40 (m,
6H), 8.36 (dd, 1H, J = 1.9, 4.6). 13C NMR d 14.1, 23.2, 26.1, 26.7,
28.2, 29.1, 41.4, 41.7, 72.5, 121.0, 126.7, 128.4, 129.1, 135.4, 137.7,
139.4, 147.2, 155.4. 77Se NMR d 383.8. IR 3420 (br). MS m/z
(M + H)+ 378.4. (Found: C, 63.63; H, 7.20; N, 3.81. C20H27NOSe
requires C, 63.82; H, 7.23; N, 3.72%).
tert-Butyl 2-[(2-(benzylseleno)pyridin-3-yl)methyl]-3-oxobutyrate
tert-Butyl ethyl 2-[2-(benzylseleno)pyridin-3-ylmethyl]malonate
(15)
(18)
tert-Butyl acetoacetate (0.95 mL, 5.67 mmol) was added to a
suspension of sodium hydride (0.17 g of 60% in mineral oil,
5.66 mmol) in dry THF (2 mL) cooled to 0 ◦C under N2. The
mixture was stirred at room temperature for 45 min after which 2-
(benzylseleno)-3-(chloromethyl)pyridine (14) (0.573 g, 1.93 mmol)
was added and the reaction mixture refluxed for 18 h before
quenching with water. The resultant mixture was extracted with
diethyl ether (3 × 15 mL) washed with sat. NaCl (15 mL), dried
(MgSO4) and the solvent evaporated to afford the title ester as a
tert-Butyl ethyl malonate (0.92 mL, 4.87 mmol) was added to
a suspension of sodium hydride (200 mg of a 60% suspension
in oil, 4.87 mmol) in THF (5 mL) at 0 ◦C under N2. After
stirring at room temperature for 30 min, 2-(benzylseleno)-3-
(chloromethyl)pyridine (14) (1.11 g, 3.75 mmol) was added and the
reaction heated at reflux for 18 h, at which time water was added
carefully to the cooled reaction mixture. After extraction with
ether (3 × 30 mL), the combined extracts were dried (MgSO4) and
concentrated to dryness under vacuum. The residue was separated
by flash chromatography (10% EtOAc–hexane) to give the title
compound as a colourless oil (54%). 1H NMR d 1.21 (t, 3H, J =
7.1), 1.39 (s, 9H), 3.13 (d, 2H J = 7.8), 3.71 (t, 1H J = 7.8), 4.11–
4.17 (m, 2H), 4.53 (s, 2H), 6.99 (dd, 1H, J = 4.7, 7.2), 7.19–7.21
(m, 1H), 7.25–7.29 (m, 2H), 7.38–7.40 (m, 3H), 8.38 (dd, 1H, J =
1.5, 4.7). 13C NMR d 14.0, 27.8, 29.3, 32.5, 51.6, 61.3, 82.1, 120.1,
126.8, 128.4, 129.1, 133.3, 136.9, 139.0, 148.0, 155.9, 167.5, 168.8;
77Se NMR d 385.1. IR 1730. (Found: C, 58.88; H, 5.93; N, 3.09.
C22H27NO4Se requires C, 58.93; H, 6.07; N, 3.12%).
1
colourless oil and of sufficient purity for further use (84%). H
NMR d 1.39 (s, 9H), 2.18 (s, 3H), 3.05 (dd, 2H, J = 1.8, 6.9), 3.81
(t, 1H, J = 6.9) 4.53 (s, 2H, J77Se 10.0), 6.99 (dd, 1H, J = 4.5, 7.2),
7.20–7.29 (m, 3H), 7.38 (d, 3H, J = 7.8), 8.38 (dd, 1H, J = 1.9,
4.6). 13C NMR d 27.9, 29.5, 29.6, 31.7, 59.0, 82.3, 120.2, 126.8,
128.5, 129.1, 133.8, 137.3, 139.2, 148.0, 167.8, 202.3. 77Se NMR d
385.5. IR 1715. MS m/z (M + H)+ 420.4. (HRMS found 420.1066.
C21H26NO3Se requires 420.1078).
4-[2-(Benzylseleno)pyridin-3-yl]butan-2-one (16)
tert-Butyl ethyl 2-[2-(benzylseleno)pyridin-3-ylmethyl]-2-
dodecylmalonate (19)
A mixture of tert-butyl 2-[(2-(benzylseleno)pyridin-3-yl)methyl]-
3-oxobutyrate (15) (4.96 g, 11.9 mmol) and conc. HCl (60 mL)
was stirred at room temperature for 18 h. The reaction mixture
was basified to pH 8.5 with 10% NaOH and extracted with ether
(3 × 100 mL). The combined organics were dried (MgSO4) and
concentrated under vacuum. The residue was separated by flash
chromatography (10% EtOAc–h◦exane) to give the title ketone as
white crystals (86%). Mp 54–55 C. 1H NMR d 2.11 (s, 3H), 2.72
(m, 2H), 2.83 (m, 2H) 4.51 (s, 2H, J77Se = 20.4) 7.01 (dd, 1H, J =
4.9, 7.6) 7.20–7.29 (m, 3H) 7.35–7.39 (m, 3H), 8.36 (dd, 1H, J =
1.7, 4.9). 13C NMR d 27.5, 29.2, 29.9, 42.5, 120.7, 126.8, 128.4,
129.1, 136.1, 139.3, 147.6, 155.4, 207.2. 77Se NMR d 385.8. IR
1713. MS m/z (M + H)+ 320.3. (Found: C, 60.47; H, 5.33; N, 4.41.
C16H17NOSe requires C, 60.38; H, 5.38; N, 4.40%).
A
solution of tert-butyl ethyl 2-[2-(benzylseleno)pyridin-3-
ylmethyl]malonate (18) (920 mg, 2.02 mmol) and sodium hydride
(100 mg of a 60% suspension in mineral oil) in THF (5 mL) was
stirred at 0 ◦C for 30 min under N2. 1-Bromododecane (1. 5 mL,
6.25 mmol) was added and the mixture heated under reflux for 5 h
and partitioned between water and ether. The aqueous phase was
further extracted with ether (2 × 20 mL) and the combined ether
extracts dried (MgSO4). The solvent was removed in vacuo and the
residue separated by flash chromatography (5% EtOAc–hexane)
to give the title compound as a viscous oil (74%). 1H NMR d 0.87
( (t, 3H, J = 6.9), 1.16 (t, 3H, J = 7.1), 1.22–1.25 (m, 20H), 1.37
(s, 9H), 1.80 (m, 2H), 3.18 (s, 2H), 4.05–4.16 (m, 2H), 4.46 (s, 2H),
6.93–6.96 (dd, 1H, J = 4.9, 7.5), 7.16 (d, 1H, J = 7.2), 7.20–7.25
(m, 2H), 7.33–7.40 (m, 3H), 8.34 (dd, 1H, J = 1.3, 4.6). 13C NMR
d 13.9, 14.0, 22.6, 24.2, 27.7, 27.6, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7,
29.9, 31.8, 33.4, 35.6, 58.7, 61.0, 81.7, 119.8, 126.6, 128.6, 129.0,
133.1, 136.5, 139.2, 147.6, 157.0, 170.0, 171.4. 77Se NMR d 392.1.
IR 1732. (Found: C, 66.30; H, 8.28; N, 2.25. C34H51NO4Se requires
C, 66.21; H, 8.34; N, 2.27%).
1-[2-(Benzylseleno)pyridin-3-yl]-3-methylheptan-3-ol (17)
4-[2-(Benzylseleno)pyridin-3-yl]butan-2-one (16) (1.13 g,
3.57 mmol) in dry ether (15 mL) was added carefully, under
N2, to a cooled (0 ◦C) stirred solution of butylmagnesium
bromide [prepared from 1-bromobutane (0.50 mL, 4.70 mmol)
and magnesium (128 mg, 5.27 mmol) in dry ether (16 mL)]. The
mixture was stirred for 1 h. Sat. NH4Cl was added carefully and
the reaction mixture was partioned between water and ether.
The aqueous phase was extracted with ether (3 × 20 mL), the
combined organics dried (MgSO4), and the solvent removed in
vacuo. The residue was separated by flash chromatography (20%
EtOAc–petroleum spirit 60–80 ◦C) to give the title alcohol as a
2-(Ethoxycarbonyl)-2-[2-(benzylseleno)pyridin-3-
ylmethyl]tetradecanoic acid (20)
tert-Butyl ethyl 2-(2-benzylselenopyridin-3-ylmethyl)-2-dodecyl
malonate (20) (90.1 mg, 1.45 mmol) and trifluoroacetic acid
(4 mL) were stirred at 0 ◦C in dichloromethane (4 mL). After
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1 h, sat. NaHCO3 was added carefully and the resultant mixture
extracted with dichloromethane (3 × 20 mL). The combined
extracts were dried (MgSO4) and the solvent removed in vacuo.
Flash chromatography (20% EtOAc–hexane) afforded the title
ture was stirred for 15 min after which 2-chloronicotinaldehyde21
(25) (5.1 g, 36.2 mmol) in THF (5 mL) was added slowly. The
reaction was monitored by TLC and after stirring for 5 h at −78 ◦C,
sat. NH4Cl was added dropwise and the reaction allowed to
warm to room temperature. The reaction mixture was partitioned
between water and ether and the aqueous phase extracted with
ether (3 × 50 mL). The combined ethereal layers were dried
(MgSO4) and the solvent removed in vacuo. The residue was
separated by flash chromatography (10% to 50% EtOAc–hexane)
to give the tit◦le compound as a pale yellow crystalline solid (92%).
1
compound as a colorless oil (67%). H NMR d 0.87 (t, 3H, J =
6.3), 1.14 (t, 3H, J = 6.1), 1.22–1.29 (m, 20H), 1.94 (m, 2H), 3.21
(d, 1H, J = 14.8), 3.32 (d, 1H, J = 14.9), 4.06–4.20 (m, 2H),
4.40 (d, 1H, J = 11.7), 4.46 (d, 1H, J = 11.6), 7.00 (dd, 1H, J =
4.9, 7.5), 7.17–7.39 (m, 6H), 8.40 (d, 1H, J = 4.5). 13C NMR d
13.7, 14.1, 22.6, 24.7, 24.8, 29.2, 29.3, 29.4, 29.5, 29.5, 29.7, 30.3,
31.9, 35.8, 38.2, 58.1, 62.0, 120.4, 126.8, 128.4, 129.0, 132.8, 136.5,
138.9, 148.0, 156.5, 173.6, 174.2; 77Se NMR d 391.8. IR 1740, 1713.
(HRMS found 562.2448. C30H44NO4Se requires: 562.2448).
1
Mp 68–69.5 C. H NMR d 1.32 (t, 3H, J = 7.2), 2.70 (bs, 1H),
4.26 (q, 2H, J = 7.2), 5.90 (s, 1H), 7.35 (dd, 1H, J = 4.8, 7.6), 8.08
(dd, 1H, J = 2.0, 7.6), 8.42 (dd, 1H, J = 2.0, 4.8). 13C NMR d
13.9, 60.7, 62.4, 74.4, 84.0, 123.0, 133.3, 137.2, 149.3, 149.5, 153.0.
IR 3155 (br), 2230, 1719. MS m/z 240.1 (M + H)+. (Found: C,
55.18; H, 4.21; N, 5.90. C11H10ClNO3 requires: C, 55.13; H, 4.21;
N, 5.84%).
N-[2-(Ethoxycarbonyl)-2-[2-(benzylseleno)pyridin-3-
ylmethyl]tetradecanoyloxy]-N,S-dimethyldithiocarbamate (21)
N,S-dimethyl-N-hydroxydithiocarbamate22 (70 mg, 0.56 mmol)
was added to a solution of 2-(ethoxycarbonyl)-2-[2-(benzyl-
seleno)pyridin-3-ylmethyl]tetradecanoic acid (20) (244 mg,
0.435 mmol), dicyclocarbodiimide (90 mg, 0.44 mmol) and DMAP
(catalytic) in dichloromethane (4 mL). The reaction mixture was
stirred for 18 h before being filtered through a plug of celite. The
fitrate was washed with sat. NaHCO3 and the dried (MgSO4).
Separation of the residue by flash chromatography (gradient: 5–
50% EtOAc–hexane) afforded the title compound as a yellow oil
(70%). 1H NMR d 0.87 (t, 3H, J = 6.9), 1.15 (m, 3H), 1.20–1.29
(m, 20H), 2.03 (t, 2H, J = 8.4), 2.52 (s, 3H), 3.28 (d, 1H, J =
15.3), 3.42 (d, 1H, J = 15.3), 3.66 (s, 3H), 4.08–4.17 (m, 2H),
4.48 (s, 2H), 6.98–7.02 (m, 1H), 7.18–7.26 (m, 3H), 7.35 (d, 1H,
J = 8.1), 7.44 (d, 1H, J = 7.6), 8.39 (m, 1H). 13C NMR d 13.8,
14.1, 18.6, 22.6, 24.3, 29.22, 29.3, 29.4, 29.5, 29.6, 30.1, 31.9, 33.6,
35.9, 42.3, 42.3, 57.7, 61.7, 62.2, 119.9, 126.8, 128.4, 129.0, 131.7,
136.9, 139.0, 148.2, 157.2, 167.9, 169.3, 197.6. 77Se NMR d 394.8.
(HRMS found 681.2291 C33H49N2O4S2Se requires: 681.2298).
Ethyl 4-(2-chloropyridin-3-yl)-4-hydroxybutyrate
Ethyl 4-(2-chloropyridin-3-yl)-4-hydroxybut-2-ynoate (1.57 g,
6.56 mmol) and 10% Pd/C (catalytic) in methanol (30 mL) was
reacted with hydrogen gas at atmospheric pressure for 5 h, at
which time approximately 430 mL of H2 had been consumed.
The reaction mixture was passed through a plug of Celite and
the solvent removed under vacuum. The residue was separated
by flash chromatography (20 to 50% EtOAc–hexane) to give the
title compound as a pale yellow oil (48% yield) together with ethyl
4-(pyridin-3-yl)butyrate (15%).
Ethyl 4-(2-chloropyridin-3-yl)-4-hydroxybutyrate. 1H NMR d
1.17 (t, 3H, J = 7.2), 1.88 (ddt, 1H, J = 7.2, 8.1, 14.5), 2.06 (ddt,
1H, J = 3.5, 7.2, 14.5), 2.42 (t, 2H, J = 7.2), 3.67 (bs, 1H), 4.04
(q, 2H, J = 7.2), 5.01 (dd, 1H, J = 3.5, 8.1), 7.19 (dd, 1H, J =
4.7, 7.6), 7.90 (dd, 1H, J = 1.8, 7.6), 8.15 (dd, 1H, J = 1.8, 4.7).
13C NMR d 14.0, 30.6, 31.8, 60.7, 69.0, 122.8, 136.4, 138.6, 147.9,
148.4, 174.0. IR 3363 (br) 1788, 1715. MS m/z 244.1 (M + H)+.
(Found C, 54.24; H, 5.70; N, 5.76. C11H15ClNO3 requires: C, 54.22;
H, 5.79; N, 5.75%).
2-Dodecyl-2-ethoxycarbonyl-2,3-dihydroselenolo[2,3-b]pyridine
(22)
N-[2-(Ethoxycarbonyl)-2-[2-(benzylseleno)pyridin-3-ylmethyl]-
tetradecanoyloxy]-N,S-dimethyldithiocarbamate (21) (0.100 g,
0.157 mmol) and AIBN (approx. 4 mg) in heptane (20 mL) was
irradiated with a low-pressure mercury lamp for 4 h. The solvent
was removed in vacuo and the residue was separated by flash
chromatography (gradient: 10% EtOAc–hexane to 20% EtOAc–
Ethyl 4-(pyridin-3-yl)butyrate. 1H NMR d 1.25 (t, 3H, J =
9.2), 1.95 (m, 2H), 2.33 (m, 2H), 2.66 (m, 2H), 4.11 (q, 2H, J =
9.2), 7.21 (m, 1H), 7.49 (m, 1H), 8.4.2 (m, 2H). 13C NMR d 14.1,
26.1, 32.1, 33.3, 60.3, 123.3, 136.0, 136.7, 147.3, 149.6, 173.0. IR
1732. MS m/z 194.1 (M + H)+ (Found: C, 68.41; H, 7.80; N, 7.19.
C11H15NO2 requires: C, 68.37; H, 7.82; N, 7.25%).
1
hexane) to give the title compound as a colourless oil (89%) H
NMR d 0.86 (t, 3H, J = 6.5), 1.12–1.38 (m, 23H), 2.05–2.24 (m,
2H), 3.18 (d, 1H, J = 16.2), 3.79 (d, 1H, J = 16.2), 4.20 (m, 2H),
6.96 (dd, 1H, J = 4.8, J = 7.2), 7.34 (d, 1H, J = 7.2), 8.22 (d,
1H, J = 0.6). 13C NMR d 14.0, 14.1, 22.6, 26.2, 29.3, 29.3, 29.4,
29.5, 29.5, 29.6, 29.6, 31.9, 39.7, 42.5, 59.0, 61.7, 120.0, 128.3,
129.0, 131.7, 148.4, 173.7. 77Se NMR d 547.6. IR 1732. (Found: C,
62.16; H, 8.35; N, 3.28. C22H35NO2Se requires C, 62.25; H, 8.31;
N, 3.30%.)
Ethyl 4-(2-chloropyridin-3-yl)-4-oxobutyrate (27)
Ethyl 4-(2-chloropyridin-3-yl)-4-hydroxybutyrate (0.753 g,
3.08 mmol) and pyridinium chlorochromate (1.6 g) were stirred
in dichloromethane (10 mL) at room temperature for 6 h. The
solid was washed with ether (4 × 15 mL) and the combined
washings reduced in vacuo. Purification was effected by flash
chromatography (50% EtOAc–hexane) to give the title compound
Ethyl 4-(2-chloropyridin-3-yl)-4-hydroxybut-2-ynoate (26)
1
as a colourless oil (67%). H NMR d 1.27 (t, 3H, J = 7.2), 2.80
Lithium bis(trimethylsilyl)amide (40 mL of a 1 M in THF,
40.0 mmol) was added to a solution of ethyl propiolate (4.1 mL,
40.4 mmol) in THF (80 mL) at −78 ◦C under N2. The reaction mix-
(t, 2H, J = 6.4), 3.29 (t, 2H, J = 6.4), 4.14 (q, 2H, J = 7.2), 7.33
(dd, 1H, J = 4.6, 7.6), 7.90 (d, 1H, J = 7.6), 8.47 (d, 1H, J =
4.6). 13C NMR d 14.2, 28.6, 37.5, 60.9, 122.5, 135.3, 138.4, 147.3,
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151.3, 172.4, 200.0. IR 1724, 1676. (HRMS found: 242.0585.
C11H13ClNO3 requires 242.0584).
29.0, 29.6, 34.9, 62.5, 70.8, 120.7, 126.8, 128.4, 129.0, 133.1, 139.1,
140.5, 148.3, 153.0. 77Se NMR d 380.8; IR 3265 (br). MS m/z 338.1
(M + H)+. (Found: C, 56.33; H, 5.39; N, 3.71. C16H19NO2Se + 33%
methanol requires: C, 56.54; H, 5.91; N, 4.04%).
Ethyl 4-[2-(benzylseleno)pyridin-3-yl]-4-oxobutyrate (28)
Sodium borohydride was added in portions to a suspension
of dibenzyl diselenide (2.00 g, 5.87 mmol) in degassed ethanol
(30 mL) under a flow of N2 until a colourless solution formed. Ben-
zophenone (2 g) was added to quench excess sodium borohydride
and the reaction mixture stirred for 20 min after which time ethyl
4-(2-chloropyridin-3-yl)-4-oxobutyrate (27) (1.52 g, 6.30 mmol)
was added. The reaction mixture was refluxed under nitrogen for
12 h before being worked up as described for 12. Purification was
effected by flash chromatography (10% EtOAc–hexane) and the
product recrystallised (chloroform) to◦give the title compound as
a crystalline solid (75%). Mp 70–71.5 C. 1H NMR d 1.25 (t, 3H,
J = 7.2), 2.76 (t, 2H, J = 6.8), 3.25 (t, 2H, J = 6.8), 4.14 (q, 2H,
J = 7.2), 4.41 (s, 2H), 7.16–7.19 (m, 2H), 7.23–7.26 (m, 2H, 7.39
(d, 2H, J = 7.6), 8.18 (dd, 1H, J = 1.6, 7.6), 8.64 (dd, 1H, J = 1.6,
4.8). 13C NMR d 14.1, 28.0, 29.1. 33.5, 60.7, 118.8, 126.4, 128.3,
129.3, 129.8, 137.7, 139.2, 152.2, 161.1, 172.6, 197.5. 77Se NMR
d 492.6. IR 1728, 1661. MS m/z 378.1 (M + H)+. (Found: C,
57.53; H, 5.10; N, 3.61. C18H19NO3Se requires: C, 57.45; H, 5.09;
N, 3.72%).
Ethyl 2-chloronicotinate-N-oxide23 (35)
Ethyl 2-chloronicotinate (11) (4.102 g, 22.0 mmol) and 30%
aqueous hydrogen peroxide (4 mL) were heated to 60 ◦C for 36 h
in trifluoroacetic acid (40 mL). The solution was concentrated in
vacuo and the residue neutralised with sat. NaHCO3. The mixture
was extracted with dichloromethane (3 × 45 mL), the combined
organics dried (MgSO4) and the solvent removed. The residue was
purified by flash chromatography (100% EtOAc) to give the title
compound as a pale solid (48%). Mp 39–40 ◦C. 1H NMR d 1.43
(t, 3H, J = 7.2), 4.45 (q, 2H, J = 7.2), 7.33 (dd, 1H, J = 6.4, 7.8),
7.69 (dd, 1H, J = 1.2, 7.8), 8.49 (dd, 1H, J = 1.2, 6.4). 13C NMR
d 13.9, 62.6, 122.7, 126.7, 130.6, 142.0, 162.6; MS m/z (M + H)+
201.8.
3-Carboethoxy-N-hydroxypyridine-2-selone (36)
Sodium borohydride (0.57 g, 15 mmol) was added to a suspension
of selenium powder (0.57 g, 7.2 mmol) in ethanol (6 mL) under a
flow of nitrogen. After 45 min, ethyl 2-chloronicotinate-N-oxide
(33) (0.997 g, 4.94 mmol) in ethanol (2 mL) and NaHCO3 (140 mg)
were added to the colourless solution. A bright yellow precipitate
formed immediately. The mixture was heated at reflux for 1 h
under nitrogen at which time glacial acetic acid was added and
the solvent removed in vacuo. The residue was mixed with benzene
(15 mL) and the solvent removed. The residue was extracted with
chloroform (4 × 30 mL) and THF (4 × 30 mL). The combined
extracts were dried (MgSO4) and the solvent removed to give the
title compound as an unstable yellow oil (93%) that was used
immediately and without further purification. 1H NMR d 1.42 (t,
3H, J = 7.2), 4.44 (q, 2H, J = 7.2), 7.03 (m, 1H), 7.75 (d, 1H, J =
7.2) 8.39 (d, 1H, J = 6.8). 77Se NMR d 380.3.
6-[2-(Benzylseleno)pyridin-3-yl]-4,5-dihydro-2H-pyridazin-3-one
(29)
Ethyl 4-(2-benzylseleno-pyridin-3-yl)-4-oxobutyrate (28) (207 mg,
0.549 mmol), potassium hydroxide (0.2 g, 3.56 mmol) and
hydrazine monohydrate (2 mL, 41.2 mmol) were heated at reflux
for 5 h in digol (2 mL). The reaction mixture was diluted with water
(20 mL) and acidified to pH 8–9 with 10% hydrochloric acid. The
aqueous solution was extracted with toluene (3 × 20 mL) and the
combined organics dried (MgSO4). Flash chromatography (50%
EtOAc–hexane) gav◦ e the title compound as colourless crystals
(61%) mp 151–152 C (toluene). 1H NMR d 2.62 (t, 2H, J = 7.8),
2.93 (t, 2H, J = 7.8), 4.41 (s, 2H), 7.14–7.19 (m, 2H), 7.27 (m,
2H), 7.37 (m, 2H), 7.61 (dd, 1H, J = 1.8, 7.8), 8.52 (dd, 1H, J =
1.8, 4.7), 8.61 (bs, 1H). 13C NMR d 23.5, 26.3, 30.6, 119.3, 126.5,
128.4, 129.2, 131.2, 134.6, 139.2, 149.2 (2C), 156.5, 166.6; 77Se
NMR d 456.7; IR 3198, 1678. MS m/z 346.1 (M + H)+ (40%),
336.1 (100%). HRMS found: 346.0457. C16H16N3OSe requires:
346.0459).
2-Carboethoxy-3,4,-dihydro-2H-1-seleno-4a-azonianaphthalenium
halide (37)
A solution of 4-bromobutanoyl chloride (0.19 mL, 1.95 mmol)
in benzene (15 mL) was added slowly to a refluxing solution of
freshly prepared 3-carboethoxy-N-hydroxypyridine-2-selone (36)
(0.48 g, 1.95 mmol), DMAP (spatula tip) and pyridine (0.2 mL) in
benzene (20 mL) and under nitrogen. The bright orange solution
was heated at reflux overnight and the yellow precipitate collected
by filtration and identified as the title compound (79%). Mp 175–
177.5 ◦C 1H NMR (d6-DMSO) d 1.37 (m, 3H), 2.38 (m, 2H), 3.26
(t, 2H, J = 6.3), 4.41 (m, 2H), 4.62 (m, 2H), 7.85 (m, 1H), 8.74 (d,
1H, J = 6.1), 9.07 (d, 1H, J = 7.6). 13C NMR (d6-DMSO) d 14.0,
22.2, 24.1, 60.4, 63.0, 122.0, 130.6, 144.2, 151.0, 158.4, 163.1. MS
m/z (M)+ 271.9 (100%);. (HRMS found: 272.0177. C11H14NO2Se
requires 272.0190).
1-[2-(Benzylseleno)pyridin-3-yl]-butane-1,4-diol (30)
A large excess of sodium borohydride and ethyl 4-(2-benzyl-
selenopyridin-3-yl)-4-oxobutyrate (28) (150 mg, 0.399 mmol) in
methanol (6 mL) were heated at reflux for 4 h, at which time TLC
analysis showed the absence of starting material. The reaction
mixture was partitioned between water and dichloromethane and
the aqueous phase extracted with dichloromethane (4 × 15 mL).
After evaporation of the solvent, the residue was separated by flash
chromatography (50% EtOAc–hexane) to give the title compound
as a colourless oil (95%). 1H NMR d 1.60–1.66 (m, 3H), 1.76 (m,
1H), 3.54 (dt, 1H, J = 5.8, 10.1), 3.60 (dt, 1H, J = 5.8, 10.1), 4.45
(d, 1H, J = 12), 4.49 (d, 1H, J = 12), 4.75 (dd, 1H, J = 3.6, 8.0),
7.04 (dd, 1H, J = 4.7, 7.6), 7.16–7.23 (m, 3H), 7.32 (m, 2H), 7.65
(dd, 1H, J = 1.8, 7.6), 8.36 (dd, 1H, J = 1.8, 4.7). 13C NMR d
Bis(2-carboethoxypyridine-2-selenide) (39)
3-Bromopropionic acid (0.340 g, 2.22 mmol) and DMF (3 drops)
was heated at reflux in thionyl chloride (5 mL) for 2 h. The
excess thionyl chloride was removed in vacuo and the residue
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dissolved in benzene (3 mL) and reacted with freshly prepared 3-
carboethoxy-N-hydroxypyridine-2-selone (36) (0.46 g, 1.87 mmol)
in accordance with the procedure described above. After the
vigorous evolution of gas had ceased, the reaction mixture was
worked-up as described above and the residue separated by flash
chromatography (hexane) to afford the title compound (8%) as
the only isolable compound. Mp 204–206 C. H NMR d 1.45
(t, 3H, J = 7.2), 4.46 (q, 2H, J = 7.2), 7.15 (dd, 1H, J = 4.7,
7.8), 8.23 (dd, 1H, J = 1.7, 7.6), 8.50 (dd, 1H, J = 1.8, 4.8). MS
m/z (M + H)+ 461.0; (HRMS found: 460.9513. C16H17N2O4Se2
requires 460.9519).
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Chem., 2002, 277, 2687.
Crystallography
Intensity data were collected with a Bruker SMART Apex CCD
detector using Mo Ka radiation (graphite crystal monochromator
k = 0.71073). Data were reduced using the program SAINT.24
The structure was solved by direct methods and difference Fourier
synthesis using the SHELX suite of programs25 as implemented
with the WINGX software.26
12 (a) V. F. Sagach, M. Scrosati, J. Fielding, G. Rossoni, C. Galli and F.
Visioli, Pharmacol. Res., 2002, 45, 435; (b) V. Forrest, Y. Kang, D. E.
McCain, D. H. Robinson and N. Ramakrisgnan, Free Radical Biol.
Med., 1994, 675.
13 N. Al-Maharik, L. Engman, J. Malmstro¨m and C. H. Schiesser, J. Org.
Chem., 2001, 66, 6286.
14 D. H. R. Barton, D. Crich and W. B. Motherwell, Tetrahedron, 1985,
41, 3901.
15 S. Kim, C. Lim, S. Song and H. Kang, Chem. Commun., 2001, 1410.
16 H. Duddeck, Prog. Nucl. Magn. Reson. Spectrosc., 1995, 27, 1.
17 M. W. Carland, C. H. Schiesser and J. M. White, Aust. J. Chem., 2004,
57, 97; See also: R. W. Gable, M. J. Laws and C. H. Schiesser, Acta
Crystallogr., 1997, 53, 641.
Crystal data for 28§. C18H19NO3Se, M = 376.30, T = 295(2)
K, k = 0.71069, orthorhombic, space group P212121, a = 4.8305(8),
3
˚
˚
b = 13.532(2), c = 26.210(4), A, V = 1713.3(5) A , Z = 4, Dc =
1.459 mg M−3 l(Mo Ka) 2.205 mm−1, F(000) = 768, crystal
size 0.35 × 0.15 × 0.10 mm. 10646 reflections measured, 3892
independent reflections (Rint = 0.10) the final R was 0.0408 [I >
2r(I)] and wR(F2) was 0.0791 (all data).
Computational chemistry
18 F. H. Allen, S. Bellard, M. D. Brice, B. A. Cartwright, A. Doubleday, H.
Higgs, T. Hummelink, B. G. Hummelink-Peters, O. Kennard, W. D. S.
Motherwell, J. R. Rogers and D. G. Watson, Acta Crystallogr., Sect. B,
1979, 35, 2331.
Ab initio molecular orbital calculations were carried out using the
Gaussian 03 program.19 Geometry optimisations were performed
using standard gradient techniques at the B3LYP/6-311G** level
of theory.
19 Gaussian 03, Revision B.04, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J.
Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A.
Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.
Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
W. Chen, M. W. Wong, and C. Gonzalez, and J. A. Pople, Gaussian,
Inc., Pittsburgh PA, 2003.
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged.
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