Aliphatic thioacetate deprotection using catalytic tetrabutylammonium cyanide

Article abstract of DOI:10.1016/j.tet.2005.09.092

A series of thiol-functionalized organic compounds were selected to analyze the scope and efficiency of a new thioacetate deprotection method using catalytic tetrabutylammonium cyanide (TBACN) to effect the transformation of a thioacetate group to a free thiol in the presence of a protic solvent. Particularly attractive are the mild reaction and workup conditions, reduced byproduct formation typically seen using literature methods and yields of greater than 80% for the free aliphatic thiols. This method is effective on aliphatic thiols with trityl, benzyl, p-halo-benzyl, phenethyl, phenoxyethyl, and cyclohexylethyl structural moieties, but it is not effective with thiophenols.

Full text of DOI:10.1016/j.tet.2005.09.092

Tetrahedron 61 (2005) 12339–12342
Aliphatic thioacetate deprotection using catalytic
tetrabutylammonium cyanide
*
Brian T. Holmes and Arthur W. Snow
Department of Chemistry, Naval Research Laboratory, Washington, DC 20375, USA
Received 23 August 2005; revised 21 September 2005; accepted 21 September 2005
Available online 11 October 2005
Abstract—A series of thiol-functionalized organic compounds were selected to analyze the scope and efficiency of a new thioacetate
deprotection method using catalytic tetrabutylammonium cyanide (TBACN) to effect the transformation of a thioacetate group to a free thiol
in the presence of a protic solvent. Particularly attractive are the mild reaction and workup conditions, reduced byproduct formation typically
seen using literature methods and yields of greater than 80% for the free aliphatic thiols. This method is effective on aliphatic thiols with
trityl, benzyl, p-halo-benzyl, phenethyl, phenoxyethyl, and cyclohexylethyl structural moieties, but it is not effective with thiophenols.
Published by Elsevier Ltd.
1. Introduction
multifunctional thioacetate moieties and often result in poor
yields and mixtures. Deprotecting reagents such as
ammonium hydroxide, potassium hydroxide, sulfuric acid,
hydrogen cyanide, hydrochloric acid, sodium thiometh-
oxide, potassium carbonate, and lithium aluminum hydride
are employed with variable results.17–23 These methods
typically produce better results when the S-acetyl is attached
to a lengthy methylene chain segment ((CH2)n; nR6).24
Herein, we describe the development of a general, effective
and mild method practicable in organic solvents for the
deprotection of thioacetate protected molecules.
The synthesis of thiol protected molecules and their
deprotection are increasingly important prerequisites in
the development of chemical self-assembly methods. Many
applications are dependent on this chemistry. These include
the fabrication of nano and molecular electronic struc-
tures,1–4 soft lithography,5 contact printing,6 fabrication of
nanoparticulate composites,7,8 vapor and condensed phase
sensors,9 surface immobilization of biomolecular10 and
synthetic dye11 functionalities, corrosion resistance treat-
ments,12 adhesion promotion,13 biomolecular surface
passivation14 and electrode modification.15
2. Results and discussion
A particularly important issue in employing the thiol group
for these purposes is its shelf life prior to use. The thiol
group is sensitive to slow oxidation to a disulfide or
sulfoxide under ambient conditions. As such, derivatization
with a protecting group provides for long term stability.16
Acylation to a thioacetate is the most frequently employed
protective chemistry. Deprotection of this thioacetate group
back to the thiol is a necessary step for practical use thiol
agents. Although numerous deprotection methods for this
transformation of the thioacetate to the free thiol have been
developed, many involve harsh conditions and are
accompanied by significant formation of unwanted side-
products including disulfides. Reported conditions include
strong acids or bases, which can be particularly adverse to
This new method centers on the use of tetrabutylammonium
cyanide salt (TBACN) to catalyze the transformation of a
thioacetate functional group to a free thiol at room
temperature. Initial work was based on the O-deacylation
of polyacylated sugars using catalytic potassium cyanide in
methanol.25 Compared to more standard methods, initial
studies of catalyst and solvent mixtures were promising on
several model thioacetate compounds. Using potassium
cyanide, the mild conditions and workup reduced side
product formation and the thioacetates were all converted to
thiols to some degree, but it was deduced that an organo-
cyanide salt was ideal for solubility issues that probably
hampered potassium cyanide catalysis and resulted in only
partial conversion to the free thiol. We have adapted this
cyanide-catalyzed methanolysis of acylated sugars to an
organic medium cyanide-catalyzed deprotection of thio-
acetates by using a tetrabutylammonium counter ion in
Keywords: Thioacetate; Deprotection; Tetrabutylammonium cyanide;
Thiol.
*
Corresponding author. Tel.: C1 202 404 8893; fax: C1 202 767 0594;
e-mail: bholmes@ccs.nrl.navy.mil
0040–4020/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.09.092

12340
B. T. Holmes, A. W. Snow / Tetrahedron 61 (2005) 12339–12342
place of the potassium ion. It is reasonable to believe that
the catalytic thioacetate deprotection pathway, shown
below, is similar in mechanism to the solvolytic O-deacyl-
ation initially reported.
Deacylation is readily accomplished upon stirring for 3 h a
solution of an aliphatic thioacetate in methanol and a
cosolvent in the presence of a catalytic amount
(0.5 mol equiv per thioacetate) of TBACN. The reaction
typically proceeds in high yields (O80%) at room
temperature and under an oxygen-free atmosphere (see
Fig. 1). Catalytic residue can be removed during workup, by
column chromatography or distillation. Experiments reveal
that the free thiols can be obtained without significant
isolation/purification difficulties commonly caused by side
product formation. Reactions incorporating chloroform as
the cosolvent are ideal, although dichloromethane has been
adequate. This deprotect reaction is sensitive to selection of
solvent as well as the presence of oxygen. It has been
observed that the use of tetrahydrofuran as a cosolvent can
result in the formation of disulfides. Additionally, disulfide
formation has been observed if the reaction is not performed
in an inert, oxygen-free atmosphere.
A protic solvent is required for this method. Reactions
incorporating methanol are ideal, denoted by higher yields
and absence of side product formation in comparison to
ethanol and halogen-substituted alcohols. Acidic solvents
(pKa!15) or certain functional groups such as amines,
haloaliphatics, and fluoroaromatics hinder the catalytic
process. In difunctional aliphatic systems that include
thioacetate and acetate functional groups, it has been
observed that the cyanide can chemoselectively deprotect
the thioacetate, maintaining the unhindered acetate (Fig. 2).
A similar effect was originally explored with the use of
HCN buffered by H2O for ethyl benzoate and ethyl-p-
nitrobenzoate, which were unaffected, whereas ethyl
thiolacetate was deprotected.26
Figure 1. Catalytic deprotection yields of a series of available or readily
synthesized aliphatic thioacetates 1–10. Reactions were performed in a 1:1
chloroform/MeOH solvent mixture under nitrogen using 0.5 equiv of
TBACN for 3 h. Note: conditions were not optimized.
The efficiency of the method is denoted by the amount of
tetrabutylammonium cyanide required for conversion of the
thioacetate to the free thiol. Standard literature procedures
employ an excess (O1 mol equiv) of the deprotecting agent
per thioacetate group, whereas catalytic amounts of
tetrabutylammonium cyanide sufficiently convert the thio-
acetate to the free thiol product, ultimately lowering the
quantity of material needed for each reaction. Several
experiments implemented a variety of reaction times and
TBACN quantities (0.1–0.7 mol equiv) to determine the
effective limits of the catalytic process. Longer reaction
times (R5 h) were generally required for catalytic amounts
lower than 0.5 equiv and for greater than 60% conversion to
the free thiol. Higher amounts of catalyst usually fully
converted the thioacetates to the free thiol in a shorter
Figure 2. Selective deprotection of difunctional thioacetates 11 and 12.
Although a mixture of products was observed for 12, a higher ratio of
thioacetate was deprotected than acetate (w65/35).

B. T. Holmes, A. W. Snow / Tetrahedron 61 (2005) 12339–12342
12341
3. Summary
A series of aliphatic thioacetates were efficiently depro-
tected in high yield and with minimal side product
formation using catalytic tetrabutylammonium cyanide in
the presence of a protic solvent. The combination of
methanol and chloroform is ideal at room temperature under
an inert atmosphere. Experiments revealed that aliphatic
thioacetates are selectively deprotected in the presence of
acetates whereas phenylacetates react competitively. This
deprotection method appears to be ineffective with aromatic
thiols and is adversely affected by fluorinated moieties.
Figure 3. Deprotection of dithioacetate 13 revealed some side product
formation and generally lower yields than for the monothioacetates.
amount of time (!3 h), but revealed a higher tendency for
side products to form.
Initially a series of both aliphatic (compounds 1–13) and
aromatic thiol and thioacetate functionalized compounds
were chosen for deprotection studies. The thiols were
converted to their respective thioacetates by reaction with
acetic anhydride in a pyridine–dichloromethane mixture in
high yield.27 Proton and carbon NMR spectra of reacted
thioacetates were compared to the commercial materials and
analyzed for side products, conversion and yields.
4. Experimental
4.1. General
All synthetic procedures were performed under an inert
nitrogen atmosphere with oven dried glassware. Solvents
were dried by passage through activated alumina columns
and degassed with nitrogen prior to use. All reagents and
catalysts were purchased from Aldrich and used as received
except for compounds 10 and 11, which were synthesized
previously in our lab (**Note: without proper storage in a
dry box or dessicator, it has been observed that tetra-
butylammonium cyanide can lose effectiveness over time).
1H and 13C NMR were recorded on a Bruker Avance-300
instrument. Chemical shifts are reported in parts per million
(ppm) and referenced to the residual chloroform peak at
7.28 and 77.0 ppm, respectively.
The aliphatic thiol series includes normal alkane, trityl,
ethyl-cyclohexyl, phenethyl, phenoxyethyl, benzyl, and
p-halobenzyl moieties. With the exception of the p-fluoro-
benzyl thioacetate, all yields were R80%. The effect of the
fluorine substitution or even a fluorocarbon presence in the
reaction medium is not understood at this time. In the case
for compound 9 there was no evidence of ring substitution
by the cyanide at the fluorine position.28 As a control
experiment a small amount of a,a,a-trifluorotoluene was
added to the deprotect reaction of compound 4. This resulted
in a large amount of complex byproduct formation and only
traces of thiol observed.
4.2. General deprotection procedure for
monothioacetates 1–10
Under an atmosphere of nitrogen, tetrabutylammonium
cyanide (0.5 mol equiv) was added to chloroform (2 mL),
methanol (2 mL), and monothioacetate reagent (0.1 g).
After stirring for 3 h at room temperature under nitrogen,
distilled water (10 mL) and chloroform (10 mL) were
added, the organic layer was separated and the aqueous
layer was extracted with chloroform (10 mL). The organic
layers were combined, washed with ammonium chloride
(aq) (10 mL), dried with MgSO4, filtered, and concentrated
in vacuo. After purification by column chromatography on
silica gel (hexane), the product was obtained and dried in
vacuo. The spectral data for 1–9 are analogous to those
obtained for a commercial sample. The synthesis, boiling
point, and elemental data for compound 10 has previously
been reported and are analogous to our product.29
Difunctional a-thiol-u-alcohol and a-thiol-u-phenol
were acylated to the corresponding acetates (compounds
11 and 12, respectively) and competitive deprotection
reaction undertaken. Compound 11 displayed a sequen-
tial cleavage wherein the thioacetate was converted to
the thiol prior to any conversion of the acetate. Similar
deprotection conditions for compound 1232 resulted in
concurrent cleavage of both the thioacetate and
phenylacetate functionalities.
The bifunctional o-xylylene dithiol (compound 13) was
acylated and then deprotected using TBACN (Fig. 3). The
yield was 63% with some byproduct formation, probably
disulfide.
4.2.1. Cyclohexylethanethiol (10). 1H NMR (300 MHz,
CDCl3): d 2.56 (q, 2H, JZ6.3 Hz), 1.64–1.73 (m, 5H), 1.53
(q, 2H, JZ7.8 Hz), 1.17–1.41 (m, 5H), 0.83–1.0 (m, 2H).
13C NMR (75 MHz, CDCl3): d 41.8, 36.5, 32.9, 26.6, 26.2,
22.2.
The effectiveness of TBACN does not apparently include
aromatic thiol deprotections. Experiments with thiophenyl
acetate were unsuccessful. Only starting reagent and
disulfide were isolated. We speculate that the thiophenolate
anion is insufficiently basic to abstract a proton from
methanol. More acidic alcohols were added to counter this
effect, but this approach was not successful. Apparently, the
cyanide ion is protonated by the more acidic alcohols and
the initial reaction does not occur. WARNING: it should be
noted that the reactivity of cyanide salts with acids to
generate HCN gas can be potentially dangerous and fatal if
improperly supervised or inhaled.
4.3. General selective deprotection procedure for
diacetate 11
Analogous procedure for reactions 1–10 except
0.1 mol equiv of tetrabutylammonium cyanide was used
and the reaction was stirred for 16 h. The synthesis and

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B. T. Holmes, A. W. Snow / Tetrahedron 61 (2005) 12339–12342
10. McGovern, M. E.; Thompson, M. Can. J. Chem. Revue
Canadienne de Chemie 1999, 77, 1678.
11. Haas, U.; Thalacker, C.; Adams, J.; Fuhrmann, J.; Riethmu¨ller,
elemental data for compound 11 has previously been
reported and are analogous to our product.30,31
4.3.1. 7-Mercaptoheptylacetate (11). 1H NMR (300 MHz,
CDCl3): d 4.06 (t, 2H, JZ6.6 Hz), 2.53 (q, 2H, JZ7.2 Hz),
2.06 (s, 3H), 1.56–1.65 (m, 5H), 1.26–1.45 (m, 6H). 13C
NMR (75 MHz, CDCl3): d 171.2, 64.5, 33.9, 28.7, 28.5,
28.2, 25.8, 24.5, 21.0.
¨
S.; Beginn, U.; Ziener, U.; Moller, M.; Dobrawa, R.;
Wu¨rthner, F. J. Mater. Chem. 2003, 13, 767.
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4.4. General deprotection procedure for dithioacetate 13
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Analogous procedure for reactions 1–10 except
1.0 mol equiv of tetrabutylammonium cyanide was used
and the reaction was stirred for 16 h. The spectral data are
analogous to those obtained for a commercial sample.
¨
¨
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