Perfluoroalkylation of aliphatic thiols in the presence of sodium hydroxymethanesulfinate

Article abstract of DOI:10.1016/S0022-1139(00)00286-4

Direct perfluoroalkylation of aliphatic thiols was performed in the presence of sodium hydroxymethanesulfinate (Rongalite). Reaction of mercaptoalkanoic esters with trifluoromethyl bromide gave the corresponding trifluoromethylthio ethers. Condensation of

Full text of DOI:10.1016/S0022-1139(00)00286-4

Journal of Fluorine Chemistry 105 (2000) 41±44
Per¯uoroalkylation of aliphatic thiols in the presence of sodium
hydroxymethanesul®nate
*
Elsa Anselmi, Jean-Claude Blazejewski, Marc Tordeux, Claude Wakselman
SIRCOB, ESA CNRS 8086, Universit e de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles, France
Received 18 February 2000; accepted 16 March 2000
Abstract
Direct per¯uoroalkylation of aliphatic thiols was performed in the presence of sodium hydroxymethanesul®nate (Rongalite). Reaction of
mercaptoalkanoic esters with tri¯uoromethyl bromide gave the corresponding tri¯uoromethylthio ethers. Condensation of alkane dithiols
with per¯uoroalkyl iodides led mainly to ¯uorinated dithioethers. These alkylation reactions are interpreted as occurring via in situ
formation of dialkyldisul®des. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Per¯uoroalkyl sul®des; Thiols; Tri¯uoromethyl bromide; Disul®des; Hydroxymethanesul®nate
1
. Introduction
the results of the per¯uoroalkylation reaction of mercap-
toalkanoic esters and alkanedithiols.
Owing to its high lipophilicity and its electron-withdraw-
ing ability, the tri¯uoromethylthio group has long attracted
the interest of chemists [1±3]. Numerous methods are now
available for the synthesis of tri¯uoromethylthioaromatic
2. Results and discussion
1
compounds [3,4]. The introduction of this group in the
The condensation of thiolates with per¯uoroalkyl halides
may be envisaged as occurring by either of the two compe-
titive processes: an halogenophilic mechanism (S 2 attack
aliphatic series, however, is more problematic because the
spontaneous condensation of alkyl thiolates with per¯uor-
oalkyl halides can produce a notable quantity of disul®de
N
on the larger halogen followed by an anionic chain process)
and a radical-anion chain mechanism initiated by a single
electron transfer process [9,10]. Moreover, formation of
disul®des can compete with both of these mechanisms
(Scheme 1 and Scheme 2), and is often the major pathway.
With aliphatic thiolates, disul®de formation often limits
the yield of these spontaneous per¯uoroalkylation reactions
[5]. Disul®des can themselves be per¯uoroalkylated in
the presence of sulfoxylate radical anion precursors, such
as sodium hydroxymethanesul®nate (Rongalite) [7,8]
(Scheme 3).
[
5]. The occurrence of this secondary reaction was reported
to be reduced when the per¯uoroalkylation of thiols by
per¯uoroalkyl iodides was performed in the presence of
triethylamine [6]. In our hands, an attempt to use this
procedure for the condensation of tri¯uoromethyl bromide
with ethyl mercaptoacetate gave in fact the corresponding
disul®de (see Section 3).
On the other hand, disul®des themselves can be trans-
formed to per¯uoroalkylthioethers by the action of per¯uor-
oalkyl halides in the presence of sulfoxylate radical anion
precursors [7,8]. It appeared that a combination of the two
transformations (in situ formation of the disul®de from the
thiol and its alkylation) should be useful when the disul®de
is not easily available or is thermally fragile. We report here
In principle, combination of these two successive con-
densations, that is, in situ disul®de formation and subsequent
reduction with SO radical anion, should lead to aliphatic
2
per¯uoroalkylthioethers (Scheme 4). Consequently, a direct
per¯uoroalkylation of aliphatic thiols was attempted in the
presence of sodium hydroxymethanesul®nate (Rongalite) in
aqueous DMF. Sodium phosphate was placed in the medium
in order to transform the thiol to its corresponding thiolate
and, after, to neutralize the sulfur dioxide formed in the
reaction.
*
Corresponding author. Tel.: ‡33-01-39-25-44-11;
fax: ‡33-01-39-25-44-52.
1
For references on the recent methods of preparation of trifluoromethyl
sulfides in the aliphatic or aromatic series, see [4].
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 8 6 - 4

4
2
E. Anselmi et al. / Journal of Fluorine Chemistry 105 (2000) 41±44
Scheme 1.
Scheme 4.
Scheme 2.
Scheme 5.
Scheme 3.
Scheme 6.
Mercaptoalkanoic esters were chosen as substrates owing
iodide (53%), per¯uorohexyl-1-hydride (21%), 1,3-bis-(tri-
deca¯uorohexylthio)propane (11%), 1,8-(trideca¯uoro-
hexythio)-4,5-dithiaoctane (2%) and an unknown product
of higher molecular weight.
2
to the thermal fragility of their corresponding disul®des.
The per¯uoroalkylation was performed with tri¯uoromethyl
bromide (1) because tri¯uoromethylthioacetic esters (3) are
interesting synthons [11,12]. The desired derivatives were
indeed obtained in 33±52% isolated yields (Scheme 5).
Some tri¯uoromethanesul®nate has also been detected on
the NMR spectra of the crude products. Formation of this
product can be explained as shown on Scheme 4. This salt
can also arise from the direct transformation of tri¯uoro-
methyl bromide by Rongalite [13].
3. Experimental
3.1. General
NMR spectra were recorded as CDCl solutions, on a
3
The reactivity of alkanedithiols (5) has also been studied.
Cyclic disul®des or oligomeric disul®des can be produced in
situ from these substrates. Whatever their structure may be,
they can react following the process written on Scheme 4.
Bis-per¯uoroalkylation can occur as shown by the isolation
of the ¯uorinated dithioethers (6) in 30±45% isolated yields
Bruker AC-300 spectrometer. Reported coupling constants
and chemicals shifts were based on a ®rst order analysis.
Internal reference was the residual peak of CHCl
1
(7.27 ppm) for H (300 MHz), central peak of CDCl
3
3
3
13
(77 ppm) for C (75 MHz) spectra and internal CFCl
19
(0 ppm) for F (282 MHz) NMR spectra. IR spectra were
recorded as CCl solutions on an Impact 400D Nicolet
(
Scheme 6). Detection of compound 8 is in agreement with
the in situ formation of disul®de (Scheme 4).
4
spectrophotometer. GCMS were performed with Chrom-
pack CP Sil 19 CB chromatography column, length 30 m,
diameter 0.25 mm, ®lm thickness 0.25 mm, initial tempera-
ture 508C over 2 min, gradient 108C/min, ®nal temperature
2508C on a HP 5989B quadrupolar mass spectrometer.
High resolution mass spectra were performed with a Finni-
gan MAT 95S spectrometer. Boiling points were determined
by the Siwoloboff method on a Buchi melting point
apparatus.
The yield was not increased by addition of an excess of
per¯uoroalkyl iodide or of a greater excess of sodium
hydroxymethanesul®nate.
The reaction of per¯uorohexyl iodide with ethanedithiol
in the presence of two equivalents of triethylamine in
dimethylformamide did not give the ¯uorinated sul®de.
With propanedithiol, we obtained a mixture of the starting
2
Sodium hydroxymethanesul®nate (Rongalite) was pur-
chased from Aldrich.
We have observed that distillation of these disulfides often result in the
loss of product and the formation of high boiling materials.

E. Anselmi et al. / Journal of Fluorine Chemistry 105 (2000) 41±44
43
3
.2. Preparation of trifluoromethyl sulfides 3a-c
duced into a Parr apparatus. The ¯ask was evacuated (5 mm
Hg) before being connected to a bromotri¯uoromethane
pressure cylinder. Pressure was maintained at 4.5 bar over
Methyl [(tri¯uoromethyl)thio]acetate (3a). A mixture of
19
methyl mercaptoacetate (5 g, 47 mmol) and sodium phos-
phate (7.72 g, 47 mmol) in DMF (100 ml) was magnetically
stirred for 15 min in a heavy walled glass ¯ask (Parr
apparatus). Water (4.5 ml) and Rongalite (10.9 g, 70 mmol)
were then quickly introduced. The ¯ask was immediately
evacuated (5 mm Hg) before being connected to a bromo-
tri¯uoromethane pressure cylinder. The pressure was main-
tain at 4.5 bar, with constant shaking, during the absorption
process which takes ca. 8 h. The apparatus was vented, the
supernatant liquor was removed and diluted with 50 ml of
water. The remaining salts were taken up in diethyl ether
17 h, with constant shaking. F NMR analysis of the crude
mixture did not show the presence of SCF compounds. The
3
resulting liquor was removed and diluted with 50 ml of
water. After extraction with diethyl ether (3Â50 ml), the
organic phase was washed with water (5Â30 ml) and brine
(100 ml). After drying (MgSO ), the solvents were removed
4
under reduced pressure. Column chromatography of the
residue (SiO , CH Cl ) afforded 0.52 g (27%) of diethyl
(2,3-dithiabutane)-1,4-dicarboxylate which had: bp 275±
2
2
2
1
2808C dec. (lit. [15] 1228C/0.5 mm Hg); H NMR 1.27
(6H, t, Jˆ7.1 Hz, CH ), 3.55 (4H, s, CH S) and 4.18 (4H, q,
3
2
13
(50 ml), ®ltered, and washed with 100 ml of diethyl ether.
Combined liquid phases were washed with water
Jˆ7.2 Hz, CH O) ppm. C NMR 14.0 (CH ), 41.3 (CH S),
2
3
2
‡
61.6 (CH O) and 169.2 (CO) ppm; EI (m/z): 238 (M , 23),
2
(
5Â100 ml) and brine (100 ml). After drying (MgSO ),
192 (37), 165 (22), 119 (49), 59 (100%).
4
the solvents were removed under reduced pressure. Short
path distillation of the residue (15 mm Hg) afforded sul®de
3.4. Condensation of dithiols with iodoperfluoroalkanes
3
a (3.9 g, 48%) which had: HRMS (found: 173.9960
C H O F S needs 173.9962); bp 120±1228C (lit. [14]
3.4.1. Condensation of ethane-1,2-dithiol (4a) with 1-iodo-
tridecafluorohexane (5a)
4
5 2 3
1
5
08C/15 mm Hg); H NMR 3.66 (2H, s, CH S) and 3.76
2
19 13
(
3H, s, CH O) ppm; F NMR � 42.9 (s, CF ) ppm;
C
A mixture of ethane-1,2-dithiol (4a) (0.94 g, 0.01 mol)
and sodium phosphate (3.3 g, 0.02 mol) in DMF (20 ml) was
stirred at room temperature for a quarter of an hour. Then
sodium hydroxymethanesul®nate (4.65 g, 0.03 mol) and
water (1 ml) were introduced followed by 1-iodo-trideca-
¯uorohexane (5a) (9 g, 0.02 mol). The mixture was stirred
over 17 h, then poured into water (150 ml) and extracted
three times with diethyl ether. The organic phase was
washed three times with 1 N hydrochloric acid, 10% sodium
carbonate and water, dried over magnesium sulfate and
evacuated under vacuum. GCMS of the mixture (3.9 g)
showed the presence of 2-(trideca¯uorohexylthio)etha-
nethiol (7a), 1,2-bis-(trideca¯uorohexylthio) ethane (6a)
and 1,6-(trideca¯uorohexylthio)-3,4-dithiahexane (8a)
(9.6, 10.9, 20.2 min) in the ratio 0.06/0.74/0.20. Individual
samples of these compounds were obtained by preparative
thin layer chromatography on silica gel, using pentane as
eluant. The dithioether migrated with the front of the
solvent. The rf of the sul®de-thiol 7a was 0.9 and the rf
of the 6a disul®de 8a 0.3.
3
3
3
NMR 31.5 (q, J ˆ2.6 Hz, CH S), 53.0 (CH O), 130.0 (q,
CF
2
3
1
J ˆ307 Hz, CF ) and 168.0 (CO) ppm; n
(CCl ) 1095,
4
CF
3
max
�
1
‡
1
6
154, 1448, 1764, 2850 and 2962 cm , EI (m/z) 174 (M ,
5), 114 (100) and 69 (40%).
Compounds prepared in the same way were
Ethyl [(tri¯uoromethyl)thio]acetate (3b), (52%) which
1
had: bp 142±1448C (lit. [14] 688C/35 mm Hg); H NMR
1
.28 (3H, t, JHHˆ7.1 Hz, CH ), 3.65 (2H, s, CH S) and 4.23
3
2
19
(
2H, q, J ˆ7.1 Hz, CH O) ppm; F NMR � 42.8 (s, CF )
3
3 2
CF
HH 2 3
1
3
3
ppm; C NMR 13.7 (CH ), 31.7 (q, J ˆ2.6 Hz, CH S),
1
6
2.2 (CH O), 130.1 (q, J ˆ306 Hz, CF ) and 167.5 (CO)
2
CF
3
ppm; n
2
and 69 (41%).
(CCl ) 1037, 1304, 1143, 1748, 1755 and
4
1
989 cm ; EI (m/z) 188 (M , 20), 143 (14), 115 (100)
max
�
‡
Ethyl 2-[tri¯uoromethyl)thio]propanoate (3c), (33%)
1
which had: bp 140±1428C (lit. [14] 448C/8 mm Hg); H
NMR 1.29 (3H, t, JHHˆ7.1 Hz, CH CH ), 1.59 (3H, d,
3
2
JHHˆ7.2 Hz, CH CH), 3.92 (1H, q, J ˆ7.2 Hz, CH)
3
HH
and 4.22 (2H, apparent dq: AB part of an ABX spin system,
3
1
9
JHHˆ7.1 and 4.4 Hz, CH O) ppm; F NMR � 41.1 (s, CF )
The ¯uoro chemical shifts of the three corresponding
19
2
3
1
ppm; C NMR 13.9 (CH CH ), 18.3 (CH CH), 41.6 (q,
3
compounds are exactly the same:
� 87.3, � 120.0, � 121.9, � 123.2 and � 126.7 ppm. 1,2-Bis-
F NMR � 81.3,
3
2
3
3
1
JCFˆ2.3 Hz, CH), 62.1 (CH O), 130.1 (q, JCFˆ307 Hz,
2
CF ) and 171.1 (CO) ppm; n
1
(CCl ) 1090, 1154, 1448,
4
(trideca¯uorohexylthio)ethane (6a), yield 30%, had: HRMS
3
max
�
1
764, 2946 and 2994 cm , EI (m/z) 202 (M , 16), 129
‡
1
(found: 729.9364 C H F S needs 729.9380); H NMR
1
4 4 26 2
‡
(
100) and 69 (11%).
3.22 (s) ppm; EI (m/z): 730 (M , 14), 411 (32), 379 (100)
and 319 (14%). 2-(trideca¯uorohexylthio)ethanethiol (7a)
1
3.3. Condensation of methyl mercaptoacetate with
bromotrifluoromethane in the presence of triethylamine
(3% yield) had: H NMR 3.24 (1H, t, Jˆ7.1 Hz, SH), 2.85
(2H, q, Jˆ7.1 Hz, CH SH) and 1.45 (2H, t, Jˆ7.1 Hz,
2
R SCH ); GCMS mˆ412; EI (m/z): 412 (M‡, 100), 379
F
2
A mixture of methyl mercaptoacetate (2 g, 17 mmol) and
triethylamine (2.4 g, 24 mmol) in DMF (25 ml) was intro-
(21), 365 (19) and 319 (11%). 1,6-(Trideca¯uorohexylthio)-
1
3,4-dithiahexane (8a), yield 8%, had: H NMR 3.28 (2H, t,
Jˆ7.1 Hz) and 3.03 (2H, t, Jˆ7.1 Hz); GCMS mˆ822; EI
3
We must point out this differs from the reported value of 7.8 Hz [14].
(m/z): 504 (2), 445 (13), 379 (100), 265 (7) and 319 (6%).

4
4
E. Anselmi et al. / Journal of Fluorine Chemistry 105 (2000) 41±44
3.4.2. Condensation of propane-1,3-dithiol (4b) with 1-
iodo-nonafluorobutane (5b)
xymethanesul®nate or of other sulfoxylate radical anion
precursors (sodium dithionite, combination of sulfur dioxide
with a reductant such as zinc or sodium formate . . .). This
method appears useful when the intermediate disul®de is
fragile or not easily available.
Using the same experimental conditions as for Section
.4.1 with propane-1,3-dithiol (4b) (1.08 g) and 1-iodo-
3
nona¯uorobutane (5b) (7 g), we isolated a mixture (3.4 g)
of ¯uorinated products shown by GCMS to be composed of
3
-(nona¯uorobutylthio)propanethiol (7b), 1,3-bis-(nona-
uorobutylthio)propane (6b) and 1,8-(nona¯uorobu-
¯
Acknowledgements
tylthio)-4,5-dithiaoctane (7.45, 8.85, 18.54 min) in the
ratio 22/70/8. This residue was chromatographed on silica
gel plates, using pentane as eluant. The dithioether 6b
migrated with the solvent front. The rf of the sul®de-thiol
This work enters in the frame of the European TMR
programme ERB FMRX-CT970120, entitled `Fluorine As a
Unique Tool for Engineering Molecular Properties'. We
thank Atochem for the generous gifts of per¯uoroalkyl
halides.
7
b was 0.9 and the rf of the disul®de 8b 0.3. The ¯uorine
chemical shifts of the three corresponding compounds are
1
9
exactly the same: F NMR � 81.3, � 87.3, � 121.4 and
126.2 ppm. 1,3-Bis-(nona¯uorobutylthio)ethane (6b),
yield 45%, had: HRMS (found: 543.9609 C H F S needs
�
1
1 6 18 2
References
1
5
43.9624); H NMR 3.09 (4H, t, Jˆ7.1 Hz, CH S) and 2.14
2
(
3
2H, quint, Jˆ7.1 Hz, CH CH CH ) ppm; EI (m/z) 325 (45),
2 2 2
[1] C. Hansch, A. Leo, R.W. Taft, Chem. Rev. 91 (1991) 165.
[2] L.M. Yagupolskii, Yu.L. Yagupolskii, J. Fluorine Chem. 72 (1995)
24 (39), 293 (14), 265 (23), 106 (100) and 105 (49%); CI
225.
(
m/z) 545 (2.3), 544 (11), 543 (6), 325 (51) and 106 (100%).
-(Nona¯uorobutylthio)propanethiol (7b), yield 14%, had:
[
[
3] J.H. Clark, D. Wails, T.W. Bastock, Aromatic Fluorination, CRC
Press, Boca Raton, 1996, p. 119.
3
1
H NMR 3.09 (1H, t, Jˆ7.1 Hz, SH), 2.09 (2H, quint,
4] T. Billard, N. Roques, B.R. Langlois, J. Org. Chem. 64 (1999) 3813.
Jˆ7.1 Hz, CH CH CH ), 2.67 (2H, q, Jˆ7.1 Hz, CH SH)
[5] C. Wakselman, in: M. Hudlicky, A.E. Pavlath (Eds.), Chemistry of
Organic Fluorine Compounds. II. A Critical Review, ACS Mono-
graph 187, Washington, DC, 1995, pp. 459.
2
2
2
2
and 1.45 (2H, t, Jˆ7.1 Hz, R SCH ) ppm; EI (m/z) 327
F
2
‡
(
(
(
0.7), 326 (M , 2.4), 325 (1.7), 131 (4.5), 119 (2.4), 107
100) and 106 (51.4%); CI (m/z) 325 (94), 324 (47), 107
100) and 106 (59%). 1,8-(Nona¯uorobutylthio)-4,5-
[
[
6] V.N. Boiko, G.M. Schchupak, J. Fluorine Chem. 69 (1994) 207.
7] C. Wakselman, M. Tordeux, J.L. Clavel, B. Langlois, J. Chem. Soc.,
Chem. Commun. (1991) 993.
1
dithiaoctane (8b), yield 5%, had: H NMR 3.09 (4H, t,
Jˆ7.1 Hz, CH S), 2.09 (4H, quint, Jˆ7.1 Hz, CH CH CH )
[8] J.L. Clavel, B. Langlois, R. Nantermet, M. Tordeux, C. Wakselman,
J. Chem. Soc., Perkin Trans. 1 (1992) 3371.
2
2
2
2
[
9] C. Wakselman, C. Kaziz, J. Fluorine Chem. 33 (1986) 347.
and 2.82 (4H, t, Jˆ7.1 Hz, R SCH ) ppm; EI (m/z) 651 (3),
F
2
[
10] C. Wakselman, A. Lantz, in: R.E. Banks (Ed.), Organofluorine
Chemistry: Principles and Commercial Applications, Plenum Press,
New York, 1994, p. 177.
6
(
49 (6), 325 (53), 293 (11), 265 (16.5), 107 (57) and 106
100%); CI (m/z) 651 (57), 650 (71), 649 (71), 325 (100) and
1
06 (66%).
[11] R.M. DeMarinis, W.M. Bryan, J. Org. Chem. 42 (1977) 2024.
[
[
[
12] G.S. Ponticello, R.D. Hartman, W.C. Lumma Jr., J.J. Baldwin, J. Org.
Chem. 44 (1979) 3080.
13] M. Tordeux, B. Langlois, C. Wakselman, J. Org. Chem. 54 (1989)
4
. Conclusion
2452.
14] W.L. Mendelson, J.-H. Liu, L.B. Killmer Jr., S.H. Levinson, J. Org.
Chem. 48 (1983) 298.
Direct per¯uoroalkylation of aliphatic thiols and poly-
thiols can be performed in the presence of sodium hydro-
[15] R.G. Hiskey, A.J. Dennis, J. Org. Chem. 33 (1968) 563.