Selenochromanes via tandem homolytic addition/substitution chemistry

Article abstract of DOI:10.1039/b919415k

Selenochromanes and analogues are conveniently prepared through a tandem homolytic addition/substitution sequence involving suitably substituted olefins.

Full text of DOI:10.1039/b919415k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Selenochromanes via tandem homolytic addition/substitution chemistryw
Maree K. Staplesab and Carl H. Schiesser*ab
Received (in Cambridge, UK) 17th September 2009, Accepted 20th November 2009
First published as an Advance Article on the web 10th December 2009
DOI: 10.1039/b919415k
Selenochromanes and analogues are conveniently prepared
through a tandem homolytic addition/substitution sequence
involving suitably substituted olefins.
As part of an ongoing interest in the synthesis of selenium-
containing heterocycles of biological relevance,1 we required
Scheme 2
methodology for the preparation of the selenochromane
scaffold 1, such as found in the analogue 2 of selenotocopherol
knowledge this had not been attempted for the construction
of six-membered selenium-containing rings.
3. Having developed free radical homolytic substitution
methods for the construction of selenium-containing rings,2
our initial work focused on the preparation of suitable
precursors to achieve that aim. For example, 2 was prepared
by thermolysis of the pyridinethioneoxycarbonyl (PTOC) ester
precursor 4, presumably via an intramolecular homolytic
substitution reaction involving the tertiary carbon-centred
radical 5 (Scheme 1).3
Xanthates (dithiocarbonates) are versatile radical precursors
that have found application in the contruction of small
molecules as well as polymers and can be used in the presence
or absence of chain-carrying reagents such as tributyltin
hydride.4,5 We chose to explore the utility of benzylic
xanthates such as 6 in the tandem chemistry described above;
6 was conveniently prepared from 2-(benzylseleno)benzaldehyde6
by simple borohydride reduction followed by mesylation and
reaction with potassium ethyl xanthate (Scheme 2).
Despite the success of the route depicted in Scheme 1,
preparation of the precursor 4 is somewhat laborious, largely
because of chain homologation steps necessary for the
construction of the six-membered ring from commercially-
available starting materials such as 3-hydroxybenzoic acid.
We reasoned that compounds such as 1 should be available
through a one-pot sequence involving intermolecular homolytic
addition (double chain homologation) followed by intramolecular
homolytic substitution at selenium. To the best of our
With xanthate 6 in hand, we turned our attention to
developing a protocol for the formation of selenochromanes
such as 1. Initial experiments involved the reaction of 6 with
methyl acrylate 7, in toluene, under thermolysis or photolysis
conditions, with and without the addition of dilauryl peroxide
as initiator. In the absence of photolysis, none of the reactions
attempted afforded anything other than partially polymerized
methyl acrylate as a thick jelly, even at temperatures up to
200 1C (sealed tube). Under photolysis conditions, dilauryl
peroxide proved to be unnecessary.
To our delight, when a solution of 6 (0.35 M) and 3
equivalents of 7 (R = CO2Me) in toluene was irradiated with
a low-pressure mercury lamp at 200 1C for 4 h, methyl 3,4-
dihydro-2H-1-benzoselenin-2-carboxylate 1 (R = CO2Me)
was obtained in 33% yield and was isolated as a colourless
oil after flash chromatography (Scheme 3).z As expected,
reduction in temperature required longer reaction times to
achieve similar yields; optimum conditions appeared to be
about 12 h at 80 1C (Scheme 3, entry 3), with further increases
in time providing no increase in the yield of 1 (R = CO2Me).y
This is an excellent outcome as it affords an important ring
system, functionalized at a key position,z from readily
available starting materials in yields that exceed those from
the multi-step sequence described above.3
Scheme 1
Under the optimum reaction conditions described above
1-heptene and styrene failed to react, while methyl meth-
acrylate 8 and N-benzyl maleimide 9 afforded the corresponding
selenochromanes 10,z 11z in 25% and quantitative8 yield
respectively, while benzyl acrylate and maleic anhydride 12
afforded 13 in 22% isolated yield, and 14** in high conver-
sion (Scheme 4). These results highlight the importance of
a School of Chemistry, The University of Melbourne, Victoria 3010,
Australia. E-mail: carlhs@unimelb.edu.au; Fax: +61 3 9347 8189;
Tel: +61 3 8344 2432
b Bio21 Molecular Science and Biotechnology Institute,
The University of Melbourne, Victoria 3010, Australia
w Electronic supplementary information (ESI) available: Characterisa-
tion data for all new compounds reported. See DOI: 10.1039/b919415k
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 565–567 | 565

View Article Online
Scheme 3
Scheme 5
(chromatography),y while the corresponding reaction with
maleic anhydride afforded an insoluble solid that was converted
to the corresponding diester 17z in 43% overall yield by
treatment with acidic methanol followed by chromatography.
The remaining xanthates 15, 16 afforded the corresponding
selenochromanes 18,z 19z in 40–70% yield (Scheme 5), while
none of the xanthates reacted with methyl acrylate 7 under
these conditions. It is interesting to note that diminished yields
seem to correspond with the less reactive radicals such as that
derived from 16.
Scheme 4
We are currently exploring the scope and utility of this novel
chemistry, together with its application to key targets, and will
report the outcome of this work, in full, in due course.
Generous support by the Australian Research Council
through the Centres of Excellence Scheme is gratefully
acknowledged.
electron-withdrawing groups in the initial addition step
involving the weakly nucleophilic benzyl radical. It should
be noted that the addition of benzyl radical to 9 has been
reported previously.7
To briefly explore the general versatility of this chemistry,
the preparation of selenochromane analogues requiring
benzylic radicals with differing electron demand was next
explored. To that end, xanthates 15, 16 were prepared
from ethyl 2-(benzylseleno)-5-nitrobenzoate8,z and ethyl
2-(benzylseleno)nicotinate9 respectively by reduction, mesylation
and reaction with potassium ethyl xanthate. At the same time
we explored more convenient methods for the initiation of
these radicals and eventually turned to the low-temperature
borane methods originally developed by Brown.10
Notes and references
z This is a new compound. Analytical data are provided in the
Electronic Supporting Information.
y Experimental procedure for the preparation of 1 (R = CO2Me):
O-ethyl-S-(2-(benzylseleno)benzyl) dithiocarbonate (209 mg, 0.55 mmol)
and methyl acrylate (76 mL, 0.82 mmol) were dissolved in toluene
(1.5 mL) in a Pyrex tube after ‘‘degassing’’ by bubbling a steady stream
of nitrogen through the solvent. The reaction vessel was sealed and
irradiated for 12 h with a 125 W medium pressure mercury lamp at a
distance of 15 cm while maintaining the temperature at 80 1C.
(Temperature control was made possible by placing the sealed tube
in a preheated silicone oil bath during irradiation.) The product was
purified by flash chromatography (5% ethyl acetate/petroleum spirits)
to give a colourless oil (0.22 mmol, 40%); 1H NMR (400 MHz,
CDCl3) d 7.36–7.24 (m, 1H), 7.20–7.04 (m, 3H), 4.24–4.18 (m, 1H),
To our delight, xanthates 6, 15, 16 reacted smoothly with 9,
as well as maleic anhydride 12 at 0 1C, in dichloromethane,
initiated with Et3B/O2 under standard conditions.11 In the case
of 6, the product 11 was isolated after 30 min in 71% yield
ꢀc
This journal is The Royal Society of Chemistry 2010
566 | Chem. Commun., 2010, 46, 565–567

View Article Online
3.74 (s, 3H), 2.96–2.87 (m, 1H), 2.74–2.64 (m, 1H), 2.20–2.12 (m, 2H);
13C NMR (500 MHz, CDCl3) d 173.13, 138.24, 129.26, 128.77, 128.40,
127.06, 125.83, 52.55, 35.43, 31.32, 25.69; 77Se NMR (CDCl3) d
305.168; IR (neat) cmꢁ1: 2949.1, 1731.0, 1433.6, 1307.4, 1234.7,
1157.6; MS (EI) m/z (relative intensity) 256 (66), 195 (31), 169 (23),
115.1 (100), 89.1 (18); HRMS calcd for C11H12O2Se [M + Ag]
362.90480, found 362.90491.
8 By 1H NMR assessment; isolated in 71% yield after chromatography.
** This is a highly insoluble compound in most organic solvents.
Conversion estimated from the 1H NMR spectrum of the crude
reaction mixture.
1 C. H. Schiesser, Chem. Commun., 2006, 4055; K. M. Aumann,
P. J. Scammells, J. M. White and C. H. Schiesser, Org. Biomol.
Chem., 2007, 5, 1276; T. D. Ashton, K. M. Aumann, S. P. Baker,
C. H. Schiesser and P. J. Scammells, Bioorg. Med. Chem. Lett.,
2007, 17, 6779; R. L. Grange, J. Ziogas, A. J. North, J. A. Angus
and C. H. Schiesser, Bioorg. Med. Chem. Lett., 2008, 18, 1241.
2 L. J. Benjamin, C. H. Schiesser and K. Sutej, Tetrahedron, 1993,
49, 2557; J. E. Lyons, C. H. Schiesser and K. Sutej, J. Org. Chem.,
1993, 58, 5632; M. C. Fong and C. H. Schiesser, J. Org. Chem.,
1997, 62, 3103.
3 N. Al-Maharik, L. Engman, J. Malmstrom and C. H. Schiesser,
¨
J. Org. Chem., 2001, 66, 6286.
4 N. Charrier, D. Gravestock and S. Z. Zard, Angew. Chem., Int.
Ed., 2006, 45, 6520.
5 G. Moad, E. Rizzardo and S. H. Thang, Acc. Chem. Res., 2008, 41,
1133.
6 M. C. Fong, M. J. Laws and C. H. Schiesser, Aust. J. Chem., 1995,
48, 1221.
Experimental procedure for the preparation of 11: Ethyl-S-
(2-(benzylseleno)benzyl) dithiocarbonate (52 mg, 0.14 mmol) and
N-benzyl maleimide (51 mg, 0.27 mmol) were dissolved in
dichoromethane (300 mL). Triethylborane in cyclohexane (1 M,
1.1 equivalents) was added via syringe (with the needle under the
surface of the solution), followed by an equivalent volume of air. The
reaction mixture was stirred for 30 min and then diluted with
dichloromethane (1 mL), washed with water (1 mL) and brine
(1 mL). The solution was dried (MgSO4) and the solvent removed
in vacuo. The desired product was isolated as colourless needles
(34 mg, 71%) after flash chromatography (10% ethyl acetate/
petroleum spirits, increasing to 20%). Mp 193 1C; 1H NMR
(500 MHz, CDCl3) d 7.45–7.40 (m, 1H), 7.28–7.05 (m, 6H), 6.71
(d, J = 7.3, 2H), 4.49 (q, J = 14.6, 2H), 4.27 (d, J = 9.5, 1H), 3.60
(dt, J = 4.6, 9.4, 1H), 3.39 (dd, J = 4.2, 13.9, 1H), 2.93 (dd, J = 5.0,
13.9, 1H); 13C NMR (CDCl3) d 176.81, 176.68, 137.00, 134.86, 131.90,
129.65, 128.47, 128.42, 128.38, 128.18, 127.36, 127.25, 43.28, 42.48,
36.91, 35.20; 77Se NMR (CDCl3) d 320.312; IR (neat) cmꢁ1: 1773.9,
1698.8, 1426.6, 1395.3, 1339.8, 1168.2; MS (EI) m/z (relative intensity)
357.1 (94), 276.1 (12), 195 (75), 186 (30), 168.9 (30), 115 (100), 106.1
(29), 91.1 (100), 89 (24), 65 (21); Anal. Calc. for C18H15NO2Se: C 60.68,
H 4.24; found C 60.79, H 4.01%.
7 P. Delduc, C. Tailhan and S. Z. Zard, J. Chem. Soc., Chem.
Commun., 1988, 308.
8 Prepared by the reaction of ethyl 2-fluoro-5-nitrobenzoate with
sodium benzylselenoate following the general procedure in ref. 9.
9 T. Fenner, J. M. White and C. H. Schiesser, Org. Biomol. Chem.,
2006, 4, 466.
z Selenochromanes bearing functionality, as opposed to alkyl or aryl
substitution, at the 2-position are novel.
10 H. C. Brown, Angew. Chem., Int. Ed. Engl., 1972, 11, 692.
11 C. Ollivier and P. Renaud, Chem. Rev., 2001, 101, 3415.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 565–567 | 567