A convenient method for regeneration of free thiol from a tert-butyl thioether

Article abstract of DOI:10.1055/s-2007-991091

When dimethylmethylthiosulfonium triflate (DMTST) is added to a tert-butyl-protected thiol (RSt-Bu), the unsymmetrical disulfide RSSMe is formed. At this point the free thiol (RSH) can be obtained by the addition of trimethylphosphine and water. Most byproducts are small organic molecules that are easily removed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991091

LETTER
2851
A Convenient Method for Regeneration of Free Thiol from a tert-Butyl
Thioether
R
egeneration of
l
Free
T
i
hiol fr
j
om
a
te
a
rt-Butyl Th
h
ioether J. Kragulj, Jeffery L. Gustafson, Douglas B. Grotjahn*
Department of Chemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, USA
Fax +1(619)5944634; E-mail: grotjahn@sciences.sdsu.edu
Received 23 May 2007
also unfortunately limit the number of deprotection
methods.
Abstract: When dimethylmethylthiosulfonium triflate (DMTST) is
added to a tert-butyl-protected thiol (RSt-Bu), the unsymmetrical
disulfide RSSMe is formed. At this point the free thiol (RSH) can
be obtained by the addition of trimethylphosphine and water. Most
byproducts are small organic molecules that are easily removed.
In an effort to overcome this problem, we have focused on
improving the conversion of RSt-Bu to unsymmetrical
disulfide RSSR¢, followed by reduction of the disulfide.
The one literature method2 for deprotection of thioethers
in this manner uses 2-nitrobenzenesulfenyl chloride
(R¢ = 2-nitrophenyl) to form a 2-nitrophenyl disulfide,
which is reduced with sodium borohydride to give the de-
sired thiol (RSH). The workup and purification steps must
deal with the presence of boron-containing byproducts
and 2-nitrothiophenol, which are not always easy to re-
move. Therefore, our goal was to use organic disulfide-
forming and disulfide-cleaving reagents with small alkyl
groups (ideally methyl) to aid in removing byproducts
formed. In our improved procedure (Scheme 1), the
majority of side products can be removed either by
vacuum or by precipitation.
Key words: thiol, deprotection, tert-butyl, trimethyl phosphine,
thioether
In organic synthesis it is often necessary to protect a free
thiol in order to prevent disulfide bond formation by oxi-
dation.1 The synthesis of large polypeptides with multiple
intermolecular or intramolecular disulfide bonds requires
many different thiol protecting groups and methods for
deprotection in order to form them selectively. Outside of
peptide chemistry, polyfunctional thiols are important
synthetic targets because the thiol function can be used to
attach molecules to gold surfaces. Among methods for the
protection of thiols of cysteine and other organic com-
pounds2 use of the tert-butyl group is attractive because it
is relatively inert, and its size hinders undesired reactions
at sulfur.
MeSH
2a) PMe3, H2O
R
S
1a) DMTST, THF
N
RSH
S
Me
+
Me3PO
Contrary to what one might expect, there are few uni-
versal methods for deprotection of tert-butyl thioethers.
Several classes of reagents of limited scope have been
described for deprotection thus far. Strong acids such as
HF,3 HCl,4 and HBF45 have all been employed with sub-
strates tolerant of such conditions. The combinations of
TMSiSO3CF3/TFA6 and H2S/strong acid ion-exchange
resin7 have found use as well. For certain specialized
aromatic substrates ArSt-Bu, the potent Lewis acid
AlCl3,8 or highly reducing sodium metal9 can remove the
tert-butyl group. When milder conditions have been
required heavy metals such as mercury and thallium10
have been used, but in some cases10b the thiol is first
liberated as the corresponding disulfide, which must then
be reduced.
+
+
*
*
N
H
DMTST:
S
S
R
t-Bu
+ Me2S
OTf
S
OTf
MeSH
RSH
1b) DMTST,
THF–HOAc
2a) PMe3, H2O
R
S
S
Me
Me3PO
+ t-BuOAc*
+ Me2S
+ HOTf *
* these products were not conclusively identified
Scheme 1
To date the most effective method for this transformation
has been found to be sequential treatment with 2-nitro-
benzenesulfenyl chloride and borohydride.11 In short, the
robust nature of tert-butyl thioethers makes them valuable
as secure, stable thiol protecting groups, but these features
HO
(CH2)15SR
RS
SR
(CH2)13SR
O
1
2
3
O
OMe
SR
O
H
Boc
N
a R = t-Bu
b R = H
Boc
N
H
OMe
SR
N
H
4
5
O
SYNLETT 2007, No. 18, pp 2851–2854
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991091; Art ID: S03807ST
Figure 1
© Georg Thieme Verlag Stuttgart · New York

2852
E. J. Kragulj et al.
LETTER
Table 1 Methods and Results of Deprotection
ferred to the solution and the mixture was allowed to warm to r.t. be-
fore it was heated for 23 h at 45 °C. Then, Et2O (75 mL) was added,
and the reaction mixture was transferred to a separatory funnel with
H2O (125 mL). The organic phase was separated and the aqueous
phase was extracted with Et2O (2 × 25 mL). The combined organic
extracts were washed with brine (125 mL), and the aqueous phase
was again extracted with Et2O (2 × 25 mL). After concentration 1a
(2.26 g, 8.00 mmol, 98% yield) was obtained as yellow crystals (mp
32.6–35.4 °C). IR (NaCl): 2959, 2924, 2859, 1605, 1588, 1470,
Compd Scale
(mmol)
DMTST Lutidine PMe3
Yield
(%)
(equiv)
(equiv)
(equiv)
1
2
3
4
5
0.50
4.0
4.1
5.0
85
100
64
0.50
0.50
0.10
0.50
2.5
0
4.0
3.0
2.6
4.0
1
1456, 1390, 1363, 1212, 1161, 1082 cm–1. H NMR (500 MHz,
2.5
2.6
4.0
77
CDCl3): d = 1.36 (s, 18 H), 3.76 (s, 4 H), 7.22–7.23 (m, 3 H), 7.34
(s, 1 H). 13C NMR (125 MHz, CDCl3): d = 30.93, 33.33, 42.86,
127.46, 128.57, 129.57, 138.76. Anal. Calcd for C16H26S2 (282.5):
C, 68.02; H, 9.28. Found: C, 68.19; H, 8.65.
2.5
2.6
4.0
85
Methylsulfenyl chloride has been known for decades12 but
is a somewhat unstable liquid, difficult to handle. Follow-
ing the reports of Zoller13 and Chmielewski14 we were en-
couraged to use crystalline DMTST15 to convert tert-butyl
thioether to the corresponding methyl disulfide. Depend-
ing on the nature of the substrate, either 1:1 acetic acid–
THF or 2,6-lutidine in THF can be used. Under acidic
conditions the disulfide-forming step is much slower, tak-
ing 28 hours compared to 3 hours under basic conditions.
After the first step is complete, a small amount of water is
added to the reaction mixture, and trimethylphosphine16 is
Preparation of 2a
16-Bromohexadecanoic acid (5.07 g, 15.1 mmol) in THF (100 mL)
was transferred to thiolate solution prepared as above from 2-meth-
ylpropane-2-thiol (7.13 mL, 63 mmol) and n-BuLi (1.6 M, 39 mL,
62 mmol) and the mixture was allowed to warm to r.t. overnight.
The reaction was quenched with HCl (250 mL, 1 M), and then ex-
tracted with EtOAc (3 × 300 mL). The organic layers were com-
bined and washed with H2O (300 mL) and brine (300 mL). These
organic extracts were then dried with MgSO4 and concentrated to
yield a solid, which was dissolved in hexanes and cooled to –39 °C.
The resulting white crystals were determined to be 3a (2.90 g 55%
yield). IR (KBr): 2917, 2849, 1696, 1471 cm–1. 1H NMR (500 MHz,
added dropwise. On a small scale, it is acceptable to run CDCl3): d = 1.24–1.32 (m, 18 H), 1.33 (br s, 9 H), 1.36–1.42 (m, 4
H), 1.57 (q, J = 7.5 Hz, 2 H), 1.64 (q, J = 7.7 Hz, 2 H), 2.35 (t,
this reaction at room temperature; however, on a large
scale it would be advisable to cool the exothermic reac-
tion. This second step typically is complete after 2 hours.
J = 7.5 Hz, 2 H), 2.52 (t, J = 7.5 Hz, 2 H). 13C NMR (125 MHz,
CDCl3): d = 24.91, 28.57, 29.29, 29.45, 29.53, 29.64, 29.74, 29.80,
29.81, 29.85, 30.12, 31.23, 34.18, 41.96, 179.68. Anal. Calcd for
As for product purification, the trimethylphosphine oxide
that forms can be removed by either precipitation with
nonpolar solvent or can be washed away with water. Thus,
most of the impurities from this sequence can be removed
with minimal effort, however, to achieve analytical purity,
remaining traces of impurities were removed by recrystal-
lization or column chromatography. The lipophilicity of 3
C20H40O2S (344.60): C, 69.71; H, 11.70. Found: C, 69.35; H, 11.38.
Preparation of 3a
Pentadec-14-ynyl methanesulfonate (15.03 g, 52.60 mmol) was
prepared according to ref.17 and it was added to thiolate solution
prepared as above from 2-methylpropane-2-thiol (10.40 g, 115.2
mmol) and n-BuLi (1.6 M, 65.5 mL, 103.1 mmol). The resulting
mixture was heated in a 55 °C oil bath and allowed to stir for 12 h.
made column chromatography difficult and resulted in The reaction was then quenched with NH4Cl (300 mL, 1 M) and ex-
tracted with Et2O (3 × 300 mL). The combined organic extracts
were then washed with H2O (1 L) and extracted with Et2O (3 × 1 L).
These extracts were washed with brine (1 L), and then dried over
MgSO4. After filtration and concentration the crude oil was distilled
(Kugelrohr) to yield 2a (14.52 g, 97% yield). IR (NaCl): 3313,
lower isolated yield. No identifiable substrate-derived
side products were formed (<5%) in either step of the
transformation for all substrates tested including the fully
protected cysteine or dipeptide.
1
2925, 2854, 1459, 1364 cm–1. H NMR (500 MHz, CDCl3): d =
In summary, we have developed an efficient means of
deprotection of thioethers, under mildly acidic and mildly
basic conditions compatible with N-Boc protection while
maintaining existing chirality.
1.24–1.32 (m, 12 H), 1.33 (br s, 9 H), 1.34–1.42 (q, 4 H), 1.54 (ob-
scured q, J = 7.8 Hz), 1.57 (obscured q, J = 7.3 Hz), 1.94 (t, J = 2.8
Hz, 1 H), 2.18 (dt, J = 7.0, 2.5 Hz, 2 H), 2.52 (t, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 18.62, 28.57, 28.73, 28.99, 29.32,
29.52, 29.71, 29.73, 29.80, 29.82, 30.12, 31.23, 41.95, 68.22, 85.02.
Anal. Calcd for C18H34S (282.2): C, 76.95; H, 12.24; Found: C,
77.38; H, 12.38.
General Procedure
All reactions were carried out under positive pressure from dry
nitrogen. Tetrahydrofuran was distilled from sodium and benzo-
phenone; DMTST was stored in a glove-box freezer at –42 °C.
Preparation of 4a
H-Cys(t-Bu)-OH hydrochloride2 (0.625 g, 2.90 mmol) was dis-
solved in MeOH (20 mL) and SOCl2 (2.13 mL). After 25.1 h the re-
action was concentrated to yield H-Cys(t-Bu)-OMe hydrochloride
(0.650 g, 98%). Then, THF (12 mL) was added to some of this ma-
terial (0.12 g, 0.50 mmol) and Boc-Val (0.11 g, 0.50 mmol), HOBT
(0.07 mL, 0.5 mmol), and 4-methylmorpholine (0.069 g, 0.50
mmol) were added sequentially to this solution. After the flask was
allowed to cool in an ice bath DCC was added (0.11 g, 0.50 mmol).
After 1 h the ice bath was removed and the reaction was stirred
overnight; 12 h later the THF was removed under vacuum and
EtOAc was added. The remaining white precipitate was removed by
Preparation of DMTST
This reagent was prepared according to ref. 15.
Preparation of 1a
Dry and deoxygenated THF (50 mL) was added to 2-methylpro-
pane-2-thiol (4.51 g, 50.0 mmol, 6.40 equiv) under nitrogen. The
flask was then cooled in an ice bath. At this point n-BuLi (1.6 M, 30
mL, 48.8 mmol, 6.0 equiv) was added dropwise. After 1.4 h, a,a¢-
dibromo-m-xylene (2.15 g, 8.10 mmol) in THF (30 mL) was trans-
Synlett 2007, No. 18, 2851–2854 © Thieme Stuttgart · New York

LETTER
Regeneration of Free Thiol from a tert-Butyl Thioether
2853
filtration. The filtrate was washed with concentrated NaHCO3 (30
mL), citric acid (75 mL, 10%), concentrated NaHCO3 (75 mL), and
H2O(150 mL). Each time the aqueous layer was extracted three
times with an equal amount of EtOAc. A crude solid (0.47 g) was
obtained, and purified by column chromatography [EtOAc–hex-
anes (1:3), Rf = 0.33]. The white crystals that were obtained after
concentration were determined to be 4a (0.13 g, 0.32 mmol, 65%
yield). IR (NaCl): 2930, 1745, 1729, 1710, 1688, 1679, 1513, 1502,
Pentadec-14-yne-1-thiol (2b)
Compound 2b was purified by column chromatography (hexanes,
Rf = 0.3). IR (NaCl): 3305, 2927, 2855, 1465, 1250 cm–1. 1H NMR
(500 MHz, CDCl3): d = 1.28 (br s, 12 H), 1.33 (obscured t, 1 H,
J = 7.7), 1.35–1.41 (m, 4 H), 1.54 (q, J = 7.6 Hz, 2 H), 1.62 (q,
J = 7.5 Hz, 2 H), 1.94 (t, J = 2.7 Hz, 1 H), 2.19 (t d, J = 2.7, 4.4 Hz,
2 H), 2.53 (q, J = 7.2 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d =
24.67, 28.40, 28.53, 28.78, 29.09, 29.12, 29.5, 29.51, 29.53, 29.58,
29.59, 29.61, 34.07, 68.03, 84.82. Anal. Calcd for C14H26S
(226.42): C, 74.93; H, 11.74. Found: C, 75.25; H, 10.83.
1
1493, 1485, 1462, 1367, 1231, 1208, 1172 cm–1. H NMR (500
MHz, CDCl3): d = 0.94 (d, 3 H, J = 6.8 Hz), 0.99 (d, 3 H, J = 6.8
Hz), 1.31 (s, 9 H), 1.46 (s, 9 H), 3.01 (d, 2 H, J = 5.1 Hz), 3.77 (s, 3
H), 4.00 (br s, 1 H), 4.84 (t d, 1 H, J = 5.0, 2.6 Hz), 5.04 (br s, 1 H),
6.60 (br s, 1 H). 13C NMR (125 MHz, CDCl3): d = 17.79, 19.39,
28.54, 30.57, 31.03, 31.12, 31.28, 42.91, 52.11, 52.81, 60.01,
155.89, 171.02, 171.52. Anal. Calcd for C18H33N2O5S (389.53): C,
55.50; H, 8.54; N, 7.19. Found: C, 54.89; H, 8.75; N, 7.26.
16-Mercaptohexadecanoic Acid (3b)
Compound 3b was purified by recrystallization in hexanes. NMR
and IR data were consistent with published literature on this com-
pound.19
Boc-Val-Cys-OMe (4b)
Preparation of 5a
Compound 4b was purified by column chromatography [EtOAc–
hexanes (2:3), Rf = 0.5]. NMR and IR data were consistent with
published literature on this compound.20
H-Cys(t-Bu)-OMe hydrochloride (0.42 g, 1.9 mmol), as prepared
previously, was dissolved in a solution of H2O (40 mL) and THF
(100 mL). Sodium bicarbonate (0.46 g, 5.7 mmol) was then added
to this solution. Finally, (Boc)2O (0.40 g, 1.9 mmol) was added in
THF (30 mL). After 17 h the reaction was quenched with sat. ice-
cold NaHSO4 (75 mL). After extracting the aqueous phase with
EtOAc (3 × 75 mL) the combined organics were dried with Na2SO4
and concentrated under vacuum. Column chromatography [EtOAc–
hexanes (1:4), Rf = 0.4] allowed for 5a to be isolated (0.39 g, 77%).
IR (NaCl): 3369, 2927, 1716, 1505, 1392 cm–1. 1H NMR (500 MHz,
CDCl3): d = 1.31 (s, 9 H), 1.45 (s, 9 H), 2.98 (br s, 2 H), 3.77 (s, 3
H), 4.58 (br s, 1 H), 5.32 (br s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 171.47, 155.17, 80.06, 53.23, 52.51, 42.61, 30.85, 30.35, 28.32.
Anal. Calcd for C13H25NO4S (291.4): C, 53.58; H, 8.65; N, 4.81.
Found: C, 53.54; H, 8.65; N, 6.33.
Boc-Cys-OMe (5b)
Compound 5b was purified by adding pentanes and separating the
precipitate from the supernatant. Concentration of the supernatant
yielded 5b. NMR and IR data were consistent with published liter-
ature on this compound.21
References
(1) Olsen, R. K.; Currie, J. O. In The Chemistry of the
Functional Groups, Part 2; Patai, S., Ed.; John Wiley and
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General Procedure for Deprotection in THF–Lutidine (Figure
1, Table 1)
The substrate was placed into a vial and brought into the glove box
(these procedures could be done under normal air-free conditions in
flasks but in our labs, a glove box was readily available). Tetrahy-
drofuran (5 mL) was added to the substrate, followed by 2,6-luti-
dine. Then, DMTST was added to the resulting solution and it was
stirred for 3 h. Water (250 mL) and PMe3 were added successively,
and after another 3 h the vial was taken out of the glove box. After
concentration under reduced pressure EtOAc was added and this so-
lution was washed with H2O. The aqueous layer was extracted three
times with an equal amount of EtOAc. When a solid was obtained
after concentration, recrystallization was used. When the product
obtained was an oil, column chromatography was needed in some
cases.
(7) Arretz, E. FR 2627184, 1989.
(8) Olesen, P.; Kappe, T.; Becher, J. J. Heterocycl. Chem. 1988,
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General Procedure for Deprotection in THF–AcOH
The tert-butyl-protected thioether was placed in a vial and brought
into the glove box. A 1:1 mixture of THF–AcOH (5 mL) was added
to the substrate. Then, DMTST was added to the substrate. The
reaction was then left to stir overnight for 26 h. At this point the
procedure followed is that previously described.
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1951, 84, 911.
a,a¢-m-Xylene-dithiol (1b)
Compound 1b was purified by column chromatography [EtOAc–
hexanes (1:20), Rf = 0.4]. 1H NMR data were consistent with pub-
lished literature on this compound.18
(13) Zoller, T.; Ducep, J. B.; Chouaib, T.; Marcel, H.
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(14) Bishop, P.; Jones, C.; Chmielewski, J. Tetrahedron Lett.
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Synlett 2007, No. 18, 2851–2854 © Thieme Stuttgart · New York

2854
E. J. Kragulj et al.
LETTER
(15) (a) Okuma, K.; Koike, T.; Yamamoto, S.; Takeuchi, H.;
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(17) Menger, F. M.; Brocchini, S.; Chen, X. Angew. Chem., Int.
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