Mild Ti-mediated transformation of t-butyl thio-ethers into thio-acetates

Article abstract of DOI:10.1039/c4ob02120g

We report a straightforward method for the rapid conversion of thio-ethers to thio-acetates using TiCl₄, in good to excellent yields. The reaction conditions tolerate a variety of functional groups, including halide, nitro, ether, thiophene and acetylene functionalities. A catalytic variant of this reaction is also described. This journal is

Full text of DOI:10.1039/c4ob02120g

Organic &
Biomolecular Chemistry
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Mild Ti-mediated transformation of t-butyl
thio-ethers into thio-acetates†
Cite this: Org. Biomol. Chem., 2015,
3, 265
1
a
b
a,b
a,b
Thomas C. Pijper,‡ Jort Robertus,‡ Wesley R. Browne and Ben L. Feringa*
Received 4th October 2014,
Accepted 3rd November 2014
We report a straightforward method for the rapid conversion of thio-ethers to thio-acetates using TiCl4,
in good to excellent yields. The reaction conditions tolerate a variety of functional groups, including
halide, nitro, ether, thiophene and acetylene functionalities. A catalytic variant of this reaction is also
described.
DOI: 10.1039/c4ob02120g
www.rsc.org/obc
thio-ethers can be synthesised with relative ease, either from
the free thiol using t-butyl chloride or t-butanol, or from
Numerous nanoscale materials and devices are based on self- halides (R-X) using t-butyl thiol. Once the synthetic steps
incompatible with the thio-acetate have been performed,
Thiols have proven to be versatile anchoring groups for immo- exchange of the protecting groups can be achieved by deprotec-
Introduction
1
2
assembled monolayers (SAMs) of thiols on gold substrates.
3
4
bilising functional units for photoswitching, molecular elec- tion of the t-butyl thio-ether by BBr followed by quenching
3
5
6
7
13
tronics, control of surface wettability, cell adhesion, to with acetyl chloride at room temperature.
name but a few examples. Although thiol chemistry is often Although S-t-butyl to S-acetyl exchange procedures have
3
13
8
16
used in SAM formation, the introduction of a thiol group in a been reported (using BBr3, but also Br2 or AlCl3 ), several
8
compound frequently presents synthetic challenges because important functionalities do not tolerate these conditions,
the R–S–H group can be deprotonated, is nucleophilic, and is examples being vinyl, TBDMSO, acetylene, aldehyde, and nitro
2
8,13
prone to oxidation. Hence, protected thiols such as thio-acet- functionalities.
This prompted us to identify more versatile
ates are frequently used. Indeed, acetyl and trityl protected Lewis acids, with which the exchange reaction can be per-
thiols can be deprotected readily in situ during self-assembly formed under mild conditions while tolerating a wider variety
2
on gold surfaces. In particular acetyl protected thiol substi- of functionalities. One such candidate is TiCl , as there have
4
tuted arenes are convenient in their use as these can typically been several examples of TiCl /n-Bu NI-mediated deprotection
4
4
1
7
be cleaved in situ without requiring an exogenous base to form of ethers (R–O–R). Furthermore, TiCl
4
has been used in the
stable monolayers equivalent to those formed starting from deprotection of silyl ether protected alcohols. The results of
9
–11
free thiols.
Tanabe and co-workers, who successfully deprotected aryl and
However, the thio-acetate group is often unstable under aliphatic TBDMS-ethers in excellent yields (91–99%) using
aqueous reaction conditions, while the thio-trityl group is TiCl -Lewis base (AcOEt, CH NO ) complexes, are particularly
4
3
2
1
8
unstable under various other reaction conditions, such as encouraging. Finally, TiCl was used with great efficacy as a
4
1
2
those employed in Suzuki–Miyaura cross-coupling reactions.
deprotection reagent in the hydrolysis of t-butyl esters in
These drawbacks can be overcome through a method develo- β-lactam chemistry, whereas the use of AlCl , BF , and FeCl
3
3
3
9
1
ped by Stuhr–Hansen in which the thiol is initially protected resulted in degradation of the starting material or poor yields.
by a t-butyl protecting group and later exchanged for the
Herein, we present a robust method for the conversion of
desired acetyl protecting group by treatment with BBr3. The t-butyl thio-ethers to thio-acetates using TiCl instead of BBr .
1
3
4
3
t-butyl thio-ether is beneficial as it is typically stable under We have found that TiCl is tolerant towards a wider variety of
4
1
4
15
3
both acidic and basic conditions. Furthermore, t-butyl functional groups and performs consistently better than BBr ,
providing the desired thio-acetates in high yields and in
shorter reaction times (Scheme 1).
a
Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4,
747 Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl
9
b
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
Results and discussion
9
†
747 Groningen, The Netherlands
Electronic supplementary information (ESI) available: Experimental pro-
1
4
2 substrates were examined to explore the utility of TiCl for
cedures, characterization and spectroscopic data. See DOI: 10.1039/c4ob02120g
Both authors contributed equally.
‡
the conversion of thio-ethers (a) to thio-acetates (b) (Table 1).
This journal is © The Royal Society of Chemistry 2015
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thio-acetate within a few seconds (2a, 4a, and 6a as well as 8a
and 10a). In addition, improved yields were observed for
several substrates when TiCl
version of 7a–10a using BBr
4
was used (1a, 3a, and 5a). Con-
was found to result in decompo-
3
sition only. In sharp contrast, 7a and 8a were converted to their
corresponding thio-acetates in high yield when TiCl was used.
4
Aldehyde and pyrid-2-yl functionalized thioethers were
examined to explore functional group limitations. Treatment
of aldehyde 9a under these reaction conditions still resulted in
decomposition. Analysis of the product revealed that with BBr
3
Scheme 1 Rapid and clean conversion of thiotertbutyl ethers to acetyl
the t-butyl group was cleaved while with TiCl the t-butyl group
4
4
protected thiols with stoichiometric and catalytic TiCl .
remained intact. In neither case, however, was thio-acetate 9b
4
obtained. For thio-ether 10a, the TiCl -mediated reaction did
t-Butyl thio-ethers 1–6a were converted to the corresponding not provide the desired product either with full conversion to
2
0,21
thio-acetates 1–6b in good to excellent isolated yields using an unidentified compound instead.
It was also attempted
TiCl or BBr . However, whereas the reactions using BBr
4
3
3
were to use the above reaction conditions for the conversion of a
complete after 2.5 to 7 h, the use of TiCl allowed for substan- methyl thio-ether group to the corresponding thio-acetate
4
tially shorter reaction times, in several cases providing the group. The methyl thio-ether group of 12a was found to be
3 4
Table 1 Thio-ether to thio-acetate exchange: comparison of BBr and TiCl
Reaction
time BBr
Isolated
yield
Reaction
time TiCl
4
Isolated
yield
Substrate
3
1a
2a
3a
5 h
6 h
5 h
81%
96%
76%
<1 h
5 s
93%
94%
88%
<1 h
4a
7 h
>99%
5 s
>99%
5
6
a
a
3 h
4 h
92%
65%
1 h
5 s
>99%
89%
7
a
a
—
—
Dec.
<1 h
5 s
88%
83%
a
8
—
9
a
—
Dec.
—
Dec.
b
1
0a
1a
7 h
n/a
Dec.
n/a
5 s
1
2 h
87%
c
12a
7 h
No conv.
3 h
a
b
c
Forms multiple products. Full conversion to an unidentified product with an R
f
2
= 0.19 on SiO . The Friedel–Crafts acylation product p-
2
2
3 6 4 3
CH (CvO)C H SCH was isolated in 94% yield. Dec. = decomposition of the starting material.
266 | Org. Biomol. Chem., 2015, 13, 265–268
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Friedel–Crafts acylation product obtained with compound 12a.
The acylium ion undergoes nucleophilic attack from the
sulphur of the thio-ether. Expulsion of the 2-methylpropan-
2-ylium carbocation subsequently results in product for-
mation. Conversion of the anionic Ti species is achieved by
dissociation of a chloride and the subsequent capture of the
chloride ion by the carbocation resulting in the formation of
2
-chloro-2-methylpropane and TiCl , thus completing the cata-
4
lytic cycle for the exchange of the t-Bu thio-ether to the
thio-acetate. In d -dichloromethane, the formation of iso-
-chloro-2-methylpropane was observed, whereas the for-
2
2
mation of isobutene was not, which supports the proposed
pathway (see ESI†).
The reaction mechanism proposed furthermore implies that
TiCl
4
might be used catalytically. Indeed, it was found that treat-
(10 mol%) resulted
ment of 4a with a catalytic amount of TiCl
4
Scheme 2 Stability of (i) the OTBDMS protecting group and (ii) terminal
alkenes and THP ethers under reaction conditions with 1.09 eq. of TiCl
4
.
in full conversion to the thio-acetate in 3 h with isolated yields
of ca. 86% (Scheme 4). These results therefore support the pro-
4
posed mechanism and further establish the potential of TiCl to
stable to both BBr and TiCl . However, treatment of 12a with
3
4
mediate the S-t-Bu to S-acetyl exchange reaction. The conversion
from 4a to 4b under stoichiometric conditions was completed
within 5 s, whereas under catalytic conditions the reaction
was finished within 3 h. It should be noted that under these
catalytic conditions the catalytic reaction still proceeds faster
with TiCl then when a stoichiometric quantity of BBr is used.
4 3
In summary, the method reported herein provides a versa-
tile, mild and selective method compared to existing thio-ether
TiCl for 3 h resulted in the aromatic Friedel–Crafts acylation
4
product.
The stability of the OTBDMS protecting group, alkenes and
THP ethers under reaction conditions was examined
(Scheme 2). p-Br-phenyl TBDMS ether was found to be stable
under reaction conditions (see ESI, Fig. S2†), however, both
the THP and alkene of 2-(dec-9-en-1-yloxy)tetrahydro-2H-pyran
were found to react. It should be noted, however, that more
complex structures such as 11a are stable under reaction con-
ditions (vide infra).
to thio-acetate exchange methods. The use of TiCl
4
is more
atom economic then the use of BBr given that the former can
3
be employed catalytically. Furthermore, conditions using TiCl
4
A possible mechanism by which the reaction may proceed
for the exchange tolerate a wider range of functional groups
is that addition of TiCl to acetyl chloride results in the for-
4
than BBr -mediated methods, including acetylene groups,
3
2
3
mation of the acylium ion (Scheme 3), as is supported by the
2
which is in contrast to conditions using Br that provide only
8
moderate conversion to the thio-acetate. The exchange of the
t-butyl protecting group for a thio-acetate group in aliphatic
thio-ether 11a provides 11b in high yield (Table 1), even
though 11a contains a dithienyl ethene photochromic switch-
ing unit. The high reaction rate at room temperature implies
that the exchange reaction is also able to proceed at low tem-
perature. Indeed, the reaction was found to proceed with full
conversion of 4a to 4b within 30 min at −78 °C. Performing
the exchange at low temperature opens opportunities to avoid
undesirable side-reactions of sensitive substituents.
Conclusions
In conclusion, the conversion from thio-ether to thio-acetate
using TiCl represents a highly versatile and fast method for a
4
Scheme 3 Proposed cycle for the conversion of thio-ethers to thio-
acetates using TiCl
4
as a catalyst.
4
Scheme 4 Thio-ether to thio-acetate conversion as catalysed by TiCl .
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