Synthesis of a selenium-substituted diselenide

Article abstract of DOI:10.1080/10426500590907282

A wide range of diselenides as precursors for selenium electrophiles is already known, but the development of reagents with higher selectivity is still ongoing. Herein we report the first synthesis of selenium-stabilized diselenides together with some pre

Full text of DOI:10.1080/10426500590907282

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Phosphorus, Sulfur, and Silicon
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Synthesis of a Selenium-
Substituted Diselenide
Thomas Wirth a & Matthew Cox a
a Department of Chemistry, Cardiff University,
Cardiff, United Kingdom
Version of record first published: 01 Feb 2007.
To cite this article: Thomas Wirth & Matthew Cox (2005): Synthesis of a Selenium-
Substituted Diselenide, Phosphorus, Sulfur, and Silicon and the Related Elements,
180:3-4, 659-666
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Phosphorus, Sulfur, and Silicon, 180:659–666, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590907282
Synthesis of a Selenium-Substituted Diselenide
Matthew Cox
Thomas Wirth
Department of Chemistry, Cardiff University, Cardiff, United Kingdom
A wide range of diselenides as precursors for selenium electrophiles is already
known, but the development of reagents with higher selectivity is still ongoing.
Herein we report the first synthesis of selenium-stabilized diselenides together
with some preliminary reactions of these reagents in stereoselective selenenylation
reactions.
Keywords Diselenides; selenium electrophiles; stereoselective synthesis
INTRODUCTION
For several decades now, selenium reagents have attracted growing in-
terest for their application in organic synthesis.1,2 In particular, the
oxidative functionalization of nonactivated or only slightly activated
carbon carbon double bonds with selenium-based reagents and the cy-
clization of unsaturated alcohols, amines and carbonyl derivates offer
a wide range of applications. Selenium electrophiles are highly potent
for such transformations because of their high anti-Markovnikov selec-
tivity, their mild reaction conditions as well as their ability to undergo
a wide range of further reactions leading to even higher functionalized
compounds.3–5
The introduction of a large number of chiral, non-racemic selenium
electrophiles for stereoselective variants of the aforementioned trans-
formation has led to much interest in organoselenium chemistry. We
have developed a series of differentially substituted chiral diselenides
1 as versatile precursors for selenium electrophiles 2 (Scheme 1). A
nonbonded interaction between the lone pair of the heteroatom X and
Received January 6, 2004; in final form September 29, 2004.
We are thankful for the high-resolution mass spectrometric data obtained from the
EPSRC National Mass Spectrometry Service Centre, Swansea, UK. We like to thank
EPSRC for support (M.C.).
Address correspondence to Thomas Wirth, Cardiff University, Department of Chem-
istry, PO Box 912, Cardiff, Wales CF10 3TB, United Kingdom. E-mail: wirth@cf.ac.uk
659

660
M. Cox and T. Wirth
SCHEME 1 Heteroatom-interaction with selenium electrophiles.
the σ∗-orbital of the selenium cation stabilizes the electrophilic species.
Furthermore, this interaction brings the chiral benzylic carbon atom
close to the electrophilic selenium atom. The coordination of the lone
pair of an oxygen-heteroatom (X = O) to the electrophile was already
subject of calculations showing that a rotation of the oxygen-atom out
of the aromatic plane by approximately 30◦ as shown in 3 is resulting
in conformations having lowest energies.6
Strong evidence for such an oxygen–selenium interaction has been
also found by NMR spectroscopy.7 Other heteroatoms like nitrogen in
similar position have been investigated previously, recently other re-
search groups have reported on fluorine heteroatoms8 and on sulfur
heteroatoms.9
The strength of the heteroatom–selenium coordination is reflected in
different properties of these reagents. One indication is the 77Se NMR
shift of the corresponding diselenides 1. Some of those values are sum-
marized in Table I.5,7–11 A better coordination of the heteroatom is in-
dicated by higher 77Se NMR shift values of 1.
The interaction of the heteroatom X with the selenium electrophile
has obviously also an influence on the selectivities in addition reactions.
Some of the highest selectivities of a range of selenenylations of alkenes
observed to date have been achieved using ortho-methoxy substituted
TABLE I 77Se NMR Values of Diselenides 1
Diselenide
X
R
Rꢀ
77Se [ppm] Reference
1a
1b
1c
1d
1e
1f
1g
1h
1i
OH
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
OMe
OMe
445.9
427.5
424.8
430.2
454.1
439.1
437.3
365.6
365.7
[7]
[7]
[7]
[8]
[9]
[9]
[5]
[10]
[11]
OMe
OEt
SEt
NMe2
NEt2
F
OH
SMe
Me
Me

Synthesis of a Selenium-Substituted Diselenide
661
TABLE II Methoxyselenenylation of Styrene-Derivatives
(R = Me)
Diselenide
X
Rꢀ
Rꢀꢀ
4 yield
4 (de)
Reference
1b
1j
1h
1i
1h
1i
OMe
SMe
OMe
SMe
OMe
SMe
H
H
OMe
OMe
OMe
OMe
H
H
H
H
Me
Me
67%
80%
55%
72%
50%
75%
83%
92%
96%
96%
85%
96%
[10]
[6a]
[7]
[11]
[7]
[11]
electrophiles (Rꢀ = OMe) derived from diselenides 1g and 1h. Although
having similar 77Se NMR shifts, the selectivities obtained with sele-
nium electrophiles stabilized by a sulfur-atom in the chiral side chain
are in some cases higher than with the corresponding oxygen analogues
as shown in Table II.
We are interested in extending this concept to selenium-stabilized
selenium electrophiles.12–14 To access the corresponding diselenides,
we followed the procedure published by Tiecco for the synthesis of the
sulfur-containing diselenides.15 The selenium containing aryl bromide
7 were prepared (Scheme 2) by reduction of 2-bromoacetophenone 5
with (+)-chloro diisopinocampheyl borane [(+)-(ipc)2BCl] to give the al-
cohol 6 in 89% yield and 96% ee. The alcohol 6 was then converted into
the corresponding tosylate by treatment with potassium hydroxide and
tosyl chloride. The selenium nucleophile required to displace the tosy-
late was generated in situ from dimethyl diselenide and sodium borohy-
dride in ethanol. The tosylate was not isolated but immediately treated
with the methylselenolate complex to give the selenide 7 in 38% yield.
SCHEME 2 Synthesis of selenium-containing precursor molecules.

662
M. Cox and T. Wirth
SCHEME 3 Synthesis of diselenide 1k.
Attempts to introduce the selenium via a bromine–lithium exchange
followed by treatment with elemental selenium caused a range of side
reaction to occur. Foremost among these side reactions was the forma-
tion of the novel diselenide 8 (Scheme 3). This cyclic diselenide formed
in yields up to 57% though optically inactive. The formation of this
diselenide appears to involve the exchange of both the bromine on the
aromatic ring and the selenium on the side chain with lithium. The
dilithiated species can react with elemental selenium followed by an
oxidative workup to give 8. By varying the reaction conditions, a small
amount of the diselenide 1k was finally obtained. The preparation of
a Grignard-reagent from the precursor 7 failed as well under various
reaction conditions.
In an alternative approach towards the synthesis of 1k, the ini-
tial introduction of the aromatic selenium atom was successful using
bis(methoxymethyl)diselenide.16 The subsequent introduction of the
side-chain selenium moiety, however, was again unsuccessful as shown
in Scheme 4. Also the selenolate derived from diphenyl diselenide did
show no reaction.
SCHEME 4 Attempted synthesis of compound 11.
Using diselenide 1k for the generation of the corresponding selenium
electrophile 2k, we perfomed the methoxyselenenylation of styrene. The
addition product 4k was obtained in reasonable yield of 73%, although
the diastereomeric excess as determined by NMR was found to be only
81% and lower as the diastereoselectivities observed for the correspond-
ing addition products 4 using oxygen-containing electrophile 2b (4b:
83% de) and the sulfur-containing electrophile 2j (4j: 92% de) as shown
in Table II.

Synthesis of a Selenium-Substituted Diselenide
663
In conclusion, we were able to synthesize a selenium-stabilized dis-
elenide. The selenium electrophile generated did, however, not show
higher selectivities in the methoxyselenenylation of styrene.
EXPERIMENTAL
1
General: H and 13C NMR experiments were carried out on a Bruker
400-DPX spectrometer. IR measurements were taken using a Perkin-
Elmer 1600FTIR spectrometer as a liquid film. Low resolution mass
spectrometry was carried out using a Varian Saturn 2 GC-MS. Flash
chromatography was carried out using Fisher Silica Gel (35–70 mesh).
Preparative thin layer chromatography was carried out using Merck
silica gel 60 F254 on glass plates. All solvents used were dried and
purified by standard methods. Reactions requiring the exclusion of air
were carried out under an atmosphere of argon in oven dried glassware.
(1R)-1-(2-Bromophenyl)ethanol) 6
Prepared according to ref. 13.
(S)-1-Bromo-2-(1-methylselanyl-ethyl)-benzene 7
Enantiomerically pure (1R)-1-(2-bromophenyl)ethanol) 6 (1.005 g,
5 mmol) was dissolved in ethanol (15 mL) and cooled to −20◦C. The
solution was treated with potassium hydroxide (560 mg, 10 mmol) and
tosyl chloride (980 mg, 5 mmol) and stirred for 24 h. In a separate
flask, dimethyl diselenide (470 mg, 2.5 mmol) was dissolved in ethanol
(10 mL), cooled to 0◦C and treated with sodium borohydride (190 mg,
5 mmol). This solution was added to the tosylate and slowly warmed to
room temperature. After stirring for 18 h, water and diethyl ether were
added and organic layer dried over magnesium sulfate. The solvent was
removed and the product was purified by flash chromatography (eluent
9:1 petroleum ether:diethyl ether) to give 7 as a red oil. (526 mg, 38%
yield, 94% ee).
[α]D = +118.4 (c 0.5 in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.64
(3 H, d, J = 7.1, CH ), 1.83 (3 H, s, SeCH ), 4.57 (1 H, q, J = 7.1, CH),
3
3
6.99 (1 H, dt, J = 8.0, J = 1.5, Ar-H), 7.24 (1 H, t, J = 7.7, Ar-H), 7.41
(1 H, dd, J = 7.8, J = 1.5, Ar-H), 7.46 (1 H, d, J = 8.0, Ar-H); 13C NMR
(100.6 MHz, CDCl3): δ = 4.2 (SeCH3), 22.0 (CHCH3), 36.1 (CH), 124.3
(Ar), 128.2 (Ar), 128.4 (Ar), 128.6 (Ar), 133.7 (Ar), 143.6 (Ar); IR (NaCl):
ν = 2963, 2922, 2863, 1588, 1563, 1468, 1437, 1374, 1272, 1175, 1052,
1021, 899, 755, 723, 661 cm−1; m/z (int.): 279 (7%) [M+], 185 (84%), 183

664
M. Cox and T. Wirth
(85%), 104 (100%), 77 (32%), 51 (18%); HRMS for C9H11BrSe: calcd.
277.9204, found 277.9202.
Bis-[2-(1-Methylselanyl-ethyl]diselenide 1k
Rac-7 (277 mg, 1 mmol) was dissolved in hexane (5 mL), cooled to –
78◦C and treated with t-BuLi (1.5 mmol, 1.6 M in hexane). The solution
was allowed to warm to room temperature and stirred for 30 min then
recooled to −78◦C and treated with THF (5 mL). The solution was al-
lowed to warm to room temperature and stirred for a further 30 min
before cooling to −78◦C. Elemental selenium (86 mg, 1.1 mmol) was
added and the solution warmed slowly to room temperature. After stir-
ring for 4 h, HCl (1 M, 10 mL) was added, followed by diethyl ether
and water. The organic layer was separated, washed with water and
brine, and dried over magnesium sulfate. The solvent was removed and
the product purified by flash chromatography (eluent 9:1 petroleum
ether:diethyl ether) to give diselenide 1k as a red oil. (40 mg, 16% yield).
1H NMR (400 MHz, CDCl3): δ = 1.62 (3 H, d, J = 6.8, CHCH ), 1.69 (3 H,
3
d, J = 7.1, CHCH ), 1.81 (3 H, s, SeCH ) 1.83 (3 H, s, SeCH ), 4.48 (1 H,
3
3
3
q, J = 7.1, CH), 4.52 (1 H, q, J = 6.8, CHSe), 6.95 (2 H, m, Ar-H), 7.14
(2 H, m, Ar-H), 7.23 (2 H, m, Ar-H), 7.65 (1 H, d, J = 7.7, Ar-H), 7.73
(1 H, d, J = 7.9, Ar-H).
3-Methyl-3H-benzo[1,2]-diselenacyclopentane 8
Synthesized and purified as above but using enantiomerically pure se-
lenide. (147 mg, 56% yield); 1H NMR (400 MHz, CDCl3): δ = 1.78 (3 H,
d, J = 6.8, CH ), 4.87 (1 H, q, J = 6.8, CH), 6.96–7.08 (3 H, m, Ar-H),
3
7.24 (1 H, dd, J = 6.9, J = 1.7, Ar-H); 13C NMR (100.6 MHz, CDCl3):
δ = 23.3 (CH3), 49.7 (CH), 125.9 (Ar), 126.2 (Ar), 127.1 (Ar), 127.7 (Ar),
137.1 (Ar), 148.2 (Ar); 77Se NMR (95 MHz CDCl3): δ = 366.7, 509.8;
IR (NaCl): ν = 2955, 2363, 2338, 1548, 1463, 1433, 1363, 1252, 1157,
1056, 1021, 750 cm−1; m/z (int.): 266 (28%), 264 (100%) [M+], 262 (88%),
261 (36%), 260 (55%), 249 (65%), 247 (57%), 245 (31%), 183 (94%), 181
(46%), 103 (40%), 102 (57%), 78 (28%), 77 (36%), 63 (25%), 51 (39%);
HRMS for C8H8Se2: calcd 263.8951, found 263.8952.
1-(2-{[(2-Methoxy-2-phenyl)ethyl]seleno}phenyl)
ethylmethylselenide 4k
The diselenide 1k (40 mg, 0.07 mmol) was dissolved in diethyl ether
(2 mL), cooled to 0◦C, and treated with bromine (0.07 mmol, 1M solu-
tion in CCl4). After stirring for 5 min the solution was cooled to −78◦C

Synthesis of a Selenium-Substituted Diselenide
665
and treated with silver triflate (50 mg, 0.19 mmol as a solution in 2 mL
of methanol). The solution was stirred for a further 5 min, then treated
with styrene (15 mg, 0.14 mmol). The reaction mixture was stirred at
−78◦C for 4 h and then allowed to warm slowly to room temperature
before quenching with sym-collidine (0.1 mL). Water and diethyl ether
were then added and the organic layer separated and dried over mag-
nesium sulfate. Purification by preparative TLC (eluent 20:1 petroleum
ether:diethyl ether) gave 4k as a clear oil (41 mg, 72% yield, 82% de).
1
Major isomer: H NMR (400 MHz, CDCl3): δ = 1.67 (3 H, d, J = 7.0,
CHCH ), 1.81 (3 H, s, SeCH ), 3.03 (1 H, dd, J = 12.2, J = 4.9, SeCHH),
3
3
3.17 (3 H, s, OCH ), 3.21 (1 H, dd, J = 12.3, J = 8.7, SeCHH), 4.26 (1 H,
dd, J = 8.8, J = 34.7, CHOCH3), 4.69 (1 H, q, J = 7.0, CHCH3), 7.01
(1 H, dt, J = 7.7, J = 1.0, Ar-H), 7.14–7.33 (7 H, m, Ar-H), 7.42 (1 H,
d, J = 7.7, Ar-H); 13C NMR (100.6 MHz, CDCl3): δ = 4.2 (SeCH3), 22.3,
(CHCH3), 36.2 (SeCH2), 36.7 (OCH3) 57.4 (OCH3), 83.4 (PhCHOCH3);
m/z (int.) 414 (38%) [M+], 399 (49%), 319 (4%), 287 (55%), 279 (95%),
206 (3%), 183 (79%), 135 (53%), 121 (52%), 103 (100%), 91 (85%), 77
(42%), 59 (15%), 51 (33%), 43 (39%).
(R)-1-(2-Methoxymethylselanylbenzene)ethanol 10
Enantiomerically pure (1R)-1-(2-bromophenyl)ethanol 6 (201 mg,
1 mmol) was dissolved in THF (10 mL), cooled to −78◦C and treated
with t-butyllithium (1.5 mmol of a 1.5M solution in hexane). Af-
ter warming up to room temperature and stirring for 30 min,
bis(methoxymethyl)diselenide (271 mg, 1.1 mmol) was added at 0◦C.
The reaction was stirred for a further 6 h, treated with aq. HCl (1M,
10 mL) and extracted with diethyl ether (3 × 20 mL). The organic layer
was washed with water, dried over magnesium sulfate, then treated
with powdered potassium hydroxide (50 mg). The solvent was removed
and the crude mixture purified by flash chromatography (eluent 4:1
petroleum ether:diethyl ether) gave 10 as a yellow oil (164 mg, 67%
1
yield). [α]D = −29.2 (c = 1.0 in CHCl3). H NMR (400 MHz, CDCl3):
δ = 1.41 (3 H, d, J = 6.8, CHCH ), 2.60 (1 H, br, OH), 3.33 (3 H, s,
3
OCH ), 5.08 (2 H, s, CH ), 5.23 (1 H, q, J = 6.8, CH), 7.12 (1 H, dt,
3
2
J = 6.4, J = 1.2, Ar-H), 7.25 (1 H, dt, J = 8.0, J = 1.2, Ar-H), 7.46 (1 H,
dd, J = 7.6, J = 1.2, Ar-H), 7.61 (1 H, dd, J = 7.6, J = 1.2, Ar-H);13C
NMR (100.6 MHz, CDCl3): δ = 23.6 (CH3), 57.6 (OCH3), 69.3 (CH), 75.4
(CH2), 126.0 (1 C), 128.6 (1 C), 128.7 (1 C), 129.8 (1 C), 135.0 (1 C), 147.7
(1 C); 77Se NMR (95 MHz CDCl3) δ = 285.6; IR (NaCl): ν = 2920, 1448,
1273, 1180, 1085, 926, 877, 757 cm−1; m/z (intensity) 246 (100%) [M+],
229 (63%), 214 (10), 199 (7%), 184 (14%), 122 (12%), 104 (5%); HRMS
for C10H14O2Se calcd: 246.0154, found 246.0156.

666
M. Cox and T. Wirth
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