Synthesis of hexylselenol and hexylselenides from hexylthiol involving hexylthiolanium salts

Article abstract of DOI:10.1055/s-2006-951470

Selenium nucleophiles react regioselectively at the endocyclic or exocyclic carbon of hexylthiolanium salts depending upon the nature of the salt. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951470

LETTER
2601
Synthesis of Hexylselenol and Hexylselenides from Hexylthiol Involving
Hexylthiolanium Salts
Synthesis of
Hexy
l
lselenol
a
a
nd Hexyl
i
selenid
n
es from
H
exylthio
K
rief,*a Willy Dumont,a Michael Roberta,b
a
Laboratoire de Chimie Organique de Synthèse, Facultés Universitaires N.-D. de la Paix, 61 rue de Bruxelles, Namur, 5000, Belgium
Fax +32(81)724536; E-mail: alain.krief@fundp.ac.be
b
Fonds pour la Formation à la Recherche dans l’Industrie et l’Agriculture, 5 rue d’Egmont, Bruxelles 1000, Belgium
Received 5 July 2006
To Professor Atta-ur-Rahman, HEJ International Chemical Research Institute, University of Karachi, Karachi, Pakistan, on the occasion
of its 65th birthday for his contribution to the development of chemical knowledge in third world countries.
Effectively S-1-hexylthiolanium bromide (3b) has been
Abstract: Selenium nucleophiles react regioselectively at the endo-
successfully synthesised2a,b from hexylthiol (1) and 1.5
cyclic or exocyclic carbon of hexylthiolanium salts depending upon
equivalents of 1,4-dibromobutane in the presence of
the nature of the salt.
potassium carbonate in ethanol (20 °C, 5 h; 86% yield).
Key words : halides , S-alkylations, selenium, nucleophiles
Under these conditions the second alkylation is so fast that
it precludes isolation of the 4-bromobutyl hexylsulfide
intermediate (2b; Scheme 3). In order to avoid competing
substitution by the bromide ion we have performed, in our
preliminary experiments, the reaction of selenium nucleo-
philes with the corresponding fluoroborate 3c. The later
We recently reported that hexylthiol (1) can be trans-
formed to hexylselenol (4) and related selenides 5 in a
multistep process, which involves hexyl diphenyl sulfo-
nium salts 3a as intermediates (Scheme 1).1
has been produced almost quantitatively by the reaction of
3b with silver tetrafluoroborate (CH2Cl2, 20 °C, 24 h,
95% yield).
Ph
Hex-SeR1
Hex-S-Ph
Hex-SH
Hex
3a
S
X
Ph
4 R = H
2a
1
5 R = Alkyl, aryl
6 R = CN
Br
K2CO3,
EtOH,
Br
Hex-SH + 1.5 Br(CH2)4Br
Hex S
Scheme 1 Synthesis of hexylselenol and the corresponding seleni-
des from hexylthiol involving hexyl diphenyl sulfonium salts as inter-
mediates.
Hex-S
2b
20 °C, 5 h
86%
1
3b
Scheme 3 Synthesis of hexylthiolanium bromide (3b).
The diphenyl sulfonium moiety has been chosen over the
dialkyl sulfonium moiety not only because it was expect-
ed to possess a better leaving group but also because it
allows selective substitution on the hexyl chain. There-
fore, arylation of hexylphenyl sulfide required harsh
conditions (diphenyliodonium salts, toluene, 110 °C, 1 h).
The selective substitution by selenium nucleophiles at the
exocyclic carbon of 3c was our next goal, although it
appeared to be far from obvious. It has been reported that
sodium azide3 and sodium methylthiolate in water3 as well
as potassium benzoate in benzene4 react at the endocyclic
carbon of S-methylthiolanium iodide (mainly)3 and S-1-
hexylthiolanium tetrafluoroborate (exclusively).4 Effec-
tively, sodium phenylselenolate reacts very efficiently
with 3c but produces in almost quantitative yield 1-hexyl
1-(4-phenylseleno)butyl sulfide (7a; Scheme 4, Table 1);
this product results from ring cleavage of 3c (endocyclic
attack).
Activation of hexylthiols as S-1-hexylthiolanium salts
should offer the advantage of easy alkylation with 1,4-di-
halogenoalkanes. The intermediates d-halogenosulfides
should easily undergo an intramolecular reaction to pro-
vide the desired heterocycle (Scheme 2).
X
Hex-SeR1
Hex-S
Hex-SH
Hex
S
X,
SeR
BF4
Hex
3c
+ Hex-SeR
3
b X = Br
c X = BF4
d X = SeCN
2
1
4 R = H
5 R = Alkyl, aryl,
6 R = CN
Hex-S
+ RSeNa
S
– NaBF4
7
5
Scheme 2 Retrosynthesis of hexylselenol and selenides from
hexylthiol involving thiolanium salts as intermediates.
Scheme 4 Reaction of selenolates with S-1-hexylthiolanium tetra-
fluoroborate (3c).
Performing the reaction in another solvent did not change
the endocyclic/exocyclic ratio significantly. Product 7a
was formed in 90% yield in ethanol, while aprotic sol-
vents DMF, acetone and DMSO gave yields of 88%, 79%,
SYNLETT 2006, No. 16, pp 2601–2604
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951470; Art ID: G22306ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6

2602
A. Krief et al.
LETTER
Table 1 Reaction of Selenolates with Hexylthiolanium Tetrafluoroborate
Product
7a
RSeM
Temp (°C)
Time (h)
Yield of 7/5 (EtOH) Yield of 7/5 (DMF)
PhSeNa
20
20
20
20
1
1
1
1
90:0
80:4
81:0
73:14
88:0
73:8
87:0
92:0
7b
MeSeNa
7c
PhCH2SeNa
o-NO2PhSeNa
7d
87%, respectively. Other selenolates behave similarly and – The IR spectra of aged 8 (3 years, 20 °C; 2150 and 2060
mainly produce the corresponding hexyl 1-(alkyl- cm–1) is substantially different from that of a freshly
seleno)butyl sulfide (7) resulting from endocyclic attack prepared sample (2150 cm–1) suggesting the formation of
on 3c, especially if the reaction is carried out in DMF 3d from 8 and the presence of an equilibrium between 3
(Table 1, 7b–d).
and 8 on the way to 6 (Scheme 6).5
Potassium selenocyanate also reacts at room temperature The results reported above led us to suspect that 1-hexyl
with S-1-hexylthiolanium tetrafluoroborate (3c). Appar- 1-(4-selenocyanato)butyl sulfide (8) is the kinetic product
ently the exchange of the counter ion on the sulfonium whereas 6 is generated under thermodynamic control. We
salt, leading to S-1-hexylthiolanium selenocyanate (3d), have proved that this is effectively the case by producing
takes place rapidly but the substitution reaction leading to 1-hexylselenocyanate (6; 78% yield) on heating 1-hexyl
1-hexyl 1-(4-selenocyanato)butyl sulfide (8) is quite slow 1-(4-selenocyanato)butyl sulfide (8) at 80 °C in DMF for
at that temperature.5 The reaction is faster at 60 °C espe- 8 hours (Scheme 6).
cially when performed in DMF and affords 1-hexyl 1-(4-
selenocyanato)butyl sulfide (8) as well as small amounts
of the desired hexylselenocyanate (6; Scheme 5, Table 2,
entries 1–3).
DMF,
80 °C
SeCN
Hex-SeCN
SeCN
Hex-S
Hex-S
78%
8 h
8
3d
6
Scheme 6 Synthesis of 1-hexylselenocyanate (6) from 4-hexyl 1-
(4-selenocyanato)butyl sulfide (8).
BF4
SeCN
Hex-SeCN
+
+ KSeCN
Hex-S
Hex
3c
S
– KBF4
6
8
Therefore, the synthesis of 1-hexylselenocyanate (6) from
4-hexyl 1-(4-selenocyanato)butyl sulfide (8) involves se-
quential intramolecular and intermolecular substitution
reactions in which the selenocyanato group plays the role
of a leaving group and that of a nucleophile alternatively.
We have planned an even more convergent approach to
hexylselenocyanate (6) from sodium hexylthiolate and 4-
bromo-butylselenocyanate (10;6 20 °C, 1 h then 80 °C, 24
h, Scheme 7). Although the desired product 6 is formed in
this process, its yield is extremely poor (10%) compared
to that of 1-hexylthiocyanate (11), which is formed in-
stead (90% yield, Scheme 7). Apparently the thiolate
reacts at the carbon of the cyano group of 10, leading to 1-
hexylthiocyanate (11) and tetrahydroselenophene (12),
rather than at the carbon atom of the methylene bromide
to produce sequentially 8 then 6 and tetrahydothiophene
(9). Even 4-iodo-selenocyanate behaves similarly.
Scheme 5 Reaction of potassium selenocyanate with S-1-hexyl-
thiolanium tetrafluoroborate (3c).
The course of the reaction changes when carried out at
higher temperature for an extended period (Table 2, entry
4). 1-Hexylselenocyanate (6) is produced in up to 68%
yield in DMF along with tetrahydrothiophene (9, 65%),
which results from the substitution reaction (Table 2,
entry 4).
We have also observed the following in two separate ex-
periments:
– 1-Hexylselenocyanate does not react with tetra-
hydrothiophene (9), even after heating at 80 °C in DMF
for several hours. This strongly suggests that the trans-
formation of 3c to 6 is not reversible.
Table 2 Synthesis of 1-Hexyl 1-(4-Selenocyanato)butyl Sulfide
Entry
Temp (°C)
Time (h)
Yield of 8/6 (EtOH) Yield of 8/6 (DMF)
Yield of 8/6 (MeOH)
1
2
3
4
60
60
60
80
2
4
12:0
54:8
20:trace
15:36
48
24
41:17
0:73
0:68
Synlett 2006, No. 16, 2601–2604 © Thieme Stuttgart · New York

LETTER
Synthesis of Hexylselenol and Hexylselenides from Hexylthiol
2603
DMF, 20 °C, 1 h
80 °C, 24 h
equiv, EtOH, 20 °C, 1 h). Its acid hydrolysis produces
hexylselenol (4; Table 3, entry 1,) whereas its alkylation
with benzyl bromide or methyl iodide leads to the related
benzyl and methyl selenides 5a and 5b (Table 3, entries 2
and 3) in high yield. We also found that the hexylseleno-
late prepared from sodium borohydride in butanol can be
in situ phenylated using phenyl iodide and a Pd(0) catalyst
to produce 5c in a one-pot process (Table 3, entry 4);
heating the reaction to 110 °C is required. Hexylphenyl
selenide (5c) has been more conveniently prepared at
room temperature and without the need for a palladium
catalyst by employing diphenyliodonium triflate (Table 3,
entry 5).9 This reaction must be performed in DMF and
not in ethanol in order to avoid arylation of the latter.
Finally as expected the synthesis of hexyl o-nitrophen-
ylselenide (5d) was very easily achieved from o-nitro-
fluorobenzene taking advantage of the well known
electrophilic substitution reaction (addition–elimination
process, Table 3, entry 6).10
Se-CN
Hexyl-S-Na +
Br
10
b
a
Se-CN
Hexyl-S-Na +
Route a
Br
a
b
Route b
(90%)
Hex-S-CN 11
Hex-Se-CN (10%) 6
SeCN
Tetrahydro-
selenophene 12
Tetrahydro-
thiophene
Hex-S
9
8
Scheme 7 Reactivity of sodium hexylthiolate towards 4-bromo-bu-
tylselenocyanate (10).
For synthetic purposes, we have produced 1-hexylseleno-
cyanate (6)7b from hexylthiol (1) in two high-yielding
steps (86%, 68%, Scheme 8, Table 3) involving the inter-
mediate formation of S-1-hexylthiolanium bromide
(3b).7a
Therefore, we have achieved the goal to smoothly pro-
duce primary alkyl selenols and selenides from primary
alkyl thiols. Work is in progress to extend this reaction to
thiolanium salts derived from secondary or tertiary alkyl
thiols and to homologous thialium salts.
1.5 Br(CH2)4Br,
Br
K2CO3
KSeCN, DMF,
Hex-SH
Hex
3b
S
Hex-SeCN
EtOH, 20 °C,
5 h, 86%
80 °C, 24 h
68%
6
1
References and Notes
Scheme 8 Synthesis of hexylselenol, and alkyl and aryl hexyl-
selenides from hexylthiol (1).
(1) (a) Krief, A.; Dumont, W.; Robert, M. Synlett 2006, 484.
(b) Krief, A.; Dumont, W.; Robert, M. Chem. Commun.
2005, 2167.
(2) (a) Anklam, E. Synthesis 1987, 841. (b) It is necessary to
employ 1.5 equivalents of 1,4-dibromo-butane to avoid
competing formation of 1,4-di(hexylthio)butane; the latter is
produced in up to 16% yield along with 3b (75%) if a
stoichiometric amount of the substrate is used. (c) 1-
Bromo-4-chloro-butane behaves similarly to 1,4-dibromo-
butane.
1-Hexylselenocyanate (6) proved in turn to be a valuable
precursor of hexylselenol (4; Scheme 8, Table 3, entry
1)7c as well as of related alkyl hexyl selenides (Table 3,
entries 2 and 3) and aryl hexyl selenides (Table 3, entries
4–6).
All these reactions rely on the easy reduction of seleno-
cyanate by sodium borohydride8 leading to sodium hexyl-
selenolate probably complexed to a boron derivative (1.25
(3) Eliel, E.; Hutchins, R. O.; Mebane, R.; Willer, R. L. J. Org.
Chem. 1976, 41, 1052.
Table 3 Synthesis of Hexylselenol, Alkyl Hexyl Selenides and Aryl Hexyl Selenides from Selenocyanate 6
Entry
1
Reagents
Product
Yield
75%
(i) NaBH4 (1.25 equiv), EtOH, 20 °C, 0.25 h;
(ii) H3O+
HexSeH (4)
2
3
4
5
(i) NaBH4 (1.25 equiv), EtOH, 20 °C, 1 h;
(ii) PhCH2Br, 20 °C, 1 h
HexSeCH2Ph (5a)
HexSeMe (5b)
HexSePh (5c)
HexSePh (5c)
87%
71%
76%
85%
(i) NaBH4 (1.25 equiv), EtOH, 20 °C, 1 h;
(ii) MeI, 20 °C, 1 h
(i) NaBH4 (1.25 equiv), BuOH, 1 h;
(ii) PhI, Pd(PPh3)4, 110 °C, 4 h
(i) EtOH (8 equiv), 20 °C, DMF;
(ii) NaBH4 (1.25 equiv);
(iii) Ph2I+TfO–, 20 °C, 1 h
6
(i) NaBH4 (1.25 equiv), EtOH, 20 °C, 1 h;
HexSe-o-NO2C6H4 (5d)
89%
(ii) o-NO2C6H4F, 20 °C, 1 h
Synlett 2006, No. 16, 2601–2604 © Thieme Stuttgart · New York

2604
A. Krief et al.
LETTER
(4) (a) Badet, B.; Jacob, L.; Julia, M. Tetrahedron 1981, 37,
887. (b) Badet, B.; Julia, M.; Ramirez-Mundoz, M.;
Sarrazin, C. A. Tetrahedron 1983, 39, 3111.
(1 mL) was added at r.t. to a stirred solution of KSeCN (143
mg, 1 mmol) in DMF (1 mL). The resulting solution was
stirred at 80 °C for 24 h, cooled to r.t., then washed with H2O
(5 mL) and extracted with Et2O (3 × 5 mL). The organic
layer was washed with H2O (2 × 5 mL) and dried over
MgSO4. After filtration, the solvent was evaporated under
vacuum (10 mm Hg). Purification of the resulting liquid by
preparative TLC (silica gel; pentane–Et2O, 9:1) leads to 1-
hexylselenocyanate (6; 130 mg, 68% yield).
(5) We have also performed this reaction successfully in
acetone. On mixing a solution of KSeCN (1 mmol) in
acetone (3 mL) at r.t. with a solution of the tetrafluoroborate
3c (1 mmol) in the same solvent (1 mL), a red-brown solid
precipitates almost instantaneously. This solid mainly
contains potassium tetrafluoroborate and some KSeCN,
which co-precipitates. The resulting solution [IR (neat):
2060 cm–1 (s), attributed to the selenocyanate anion] slowly
delivers 1-hexyl 1-(4-selenocyanato)butyl sulfide (8; 20 °C,
72 h, 3c/8: 39:61). Evaporation of acetone and distillation of
the residue (short-path distillation, 150 °C, 200 mmHg)
leads to 6 in 68% yield; IR(neat): 2150 cm–1 (s), attributed to
the selenocyanato group attached to an alkyl chain.
(6) Prepared from potassium selenocyanate and 1,4-dibromo-
butane. IR and NMR spectra support this assignment rather
than that of its cyclic isomer.
(c) Hexylselenol: NaBH4 (190 mg, 5 mmol) was added at
r.t., in small portions, to a stirred solution of hexylseleno-
cyanate (950 mg, 5 mmol) in EtOH (5 mL). After 0.2 h, aq
HCl (10%) was added. The resulting solution was extracted
with Et2O (3 × 20 mL), the organic layer was washed with
H2O (2 × 5 mL) and then dried over MgSO4. After filtration
and evaporation of the solvent the residue was distilled to
give hexylselenol (82 °C, 20 mm Hg, 638 mg, 75% yield).
(8) Krief, A.; Delmotte, C.; Dumont, W. Tetrahedron 1997, 53,
12147.
(7) (a) S-1-Hexylthiolanium Bromide: A mixture of hexane-
thiol (590 mg, 5.0 mmol), 1,4-dibromobutane (1.6 g, 1.5
equiv, 7.5 mmol), and K2CO3 (690 mg, 1.5 equiv, 5.0 mmol)
in EtOH (10 mL) was stirred at r.t. for 5 h under argon. EtOH
was then removed, the residue was suspended in CHCl3, and
KBr was removed by filtration. CHCl3 was removed under
vacuum, the resulting oil was first triturated with anhyd
Et2O and then dried under vacuum to produce 1.1 g of the
oily S-1-hexylthiolanium bromide (86% yield of crude
product). (b) 1-Hexylselenocyanate: A solution of S-1-
hexylthiolanium bromide (254 mg, 1 mmol) in DMF
(9) (a) For a synthesis of selenides from aryl iodides and
stannylselenides using a palladium catalyst: Beletskaya, I.
P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V. J.
Organomet. Chem. 2000, 605, 96. (b) For a related reaction
recently performed on thiolates see ref. 1a.
(10) (a) Carey, F. A.; Sundberg, R. J. In Advanced Organic
Chemistry, Part A: Structure and Mechanisms; Kluwer
Academic/Plenum Publishers: New York, 2000. (b) Carey,
F. A.; Sundberg, R. J. In Advanced Organic Chemistry, Part
B: Reactions and Synthesis; Kluwer Academic/Plenum
Publishers: New York, 2000.
Synlett 2006, No. 16, 2601–2604 © Thieme Stuttgart · New York