The tert-butyl moiety - A base resistent thiol protecting group smoothly replaced by the labile acetyl moiety

Article abstract of DOI:10.1081/SCC-120015820

Aryl t-butyl sulfides underwent quantitative tert-butyl/acetyl exchange reactions affording thioacetic acid S-aryl esters when treated with acetyl chloride and boron tribromide.

Full text of DOI:10.1081/SCC-120015820

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The tert -Butyl Moiety—A Base Resistent Thiol
Protecting Group Smoothly Replaced by the Labile
Acetyl Moiety
Nicolai Stuhr-Hansen a
a Nano Science Center , Department of Chemistry , University of Copenhagen , Copenhagen
Ø, Denmark
Published online: 16 Aug 2006.
To cite this article: Nicolai Stuhr-Hansen (2003) The tert -Butyl Moiety—A Base Resistent Thiol Protecting Group Smoothly
Replaced by the Labile Acetyl Moiety, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:4, 641-646, DOI: 10.1081/SCC-120015820
To link to this article: http://dx.doi.org/10.1081/SCC-120015820
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 641–646, 2003
The tert-Butyl Moiety—A Base Resistent Thiol
Protecting Group Smoothly Replaced
by the Labile Acetyl Moiety
Nicolai Stuhr-Hansen*
Nano Science Center, Department of Chemistry,
University of Copenhagen, Copenhagen Ø, Denmark
ABSTRACT
Aryl t-butyl sulfides underwent quantitative tert-butyl/acetyl
exchange reactions affording thioacetic acid S-aryl esters when
treated with acetyl chloride and boron tribromide.
The t-butyl group is widely used as a thiol protective group[1] in
organic synthesis since it is stable towards bases. In contrast to the
n-alkyl and isopropyl groups itcan be cleaved off wiht Lewis acids
under relatively mild conditions. Reported reagents for the cleavage of
*Correspondence: Nicolai Stuhr-Hansen, Nano Science Center, Department of
Chemistry, University of Copenhagen, Universitetsparken 5, DK 2100
Copenhagen Ø, Denmark; E-mail: nsh@symbion.ki.ku.dk.
641
DOI: 10.1081/SCC-120015820
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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642
Stuhr-Hansen
the t-butyl/S bond include mercury(II) acetate in TFA/anisole followed
by treatment with hydrogen sulfide,[2] hydrogen fluoride in anisole,[3] and
2-nitrobenzenesulfenyl chloride followed by reduction of the unsymme-
trical disulfide with sodium borohydride.[4] Ithas been reporetd htat
thioacetic acid S-aryl esters form upon treatment of aryl t-butyl sulfides
with acetyl chloride/aluminum chloride,[5] whereas the thiols form in
absence of acetyl chloride by toluene scavenge.[6] We have studied the
clean reaction between aryl t-butyl sulfides and acetyl chloride/boron
tribromide and found a high-yielding alternative to the AcCl/AlCl3
couple.
The reaction between t-butyl aryl sulfides and boron tribromide in
dichloromethane/toluene gave thiols after quenching in water.
Irreversible scavenging of the t-butyl group by means of toluene pulled
the reaction in direction of thiol resulting in quantitative GC-MS yields
of thiols and t-butyltoluene after two days reaction at room temperature.
For synthetic applications thiols needed to be trapped effectively in
order to speed up the deprotection of the thiol moiety. Acetyl chloride
and boron tribromide in dichloromethane/toluene quantitatively
converted the aryl t-butyl sulfides 1a–c into thioacetic acid S-aryl
esters 2a–c. Thioesters may easily be further hydrolyzed into thiols[7]
under mild acidic or mild basic conditions.
Extreme base stability of t-butylthio structural unit was shown by a
new facile synthesis of 4-(t-butylthio)benzaldehyde (3) via 4-(t-butylthio)-
lithiobenzene in search for building blocks for preparation of stilbenes
carrying mercapto termini (Sch. 1).
Aryl t-butyl sulfides, in contrast to thioesters, were found tolerable
towards McMurry conditions. 3 was smoothly coupled with low valent
titanium in THF forming solely trans-4,40-bis(t-butylthio)stilbene (4).
Upon treatment of with boron tribromide and acetyl chloride under
standard conditions the new protected stilbenedithiol formed as an
Scheme 1. Reagents and conditions: (i) Boron tribromide (1.0 M in dichloro-
methane, 1.1 equiv.)/acetyl chloride/toluene, r.t., 2 h, 2a: 96%, 2b: 93%, 2c:
89%; (ii) Butyllithium (2.5 M solution in hexanes)/THF, À78ꢀC, 15 min; (iii)
DMF, r.t., 15 min, 3: 83%.

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tert-Butyl Moiety Replaced by Acetyl
643
Scheme 2. Reagents and conditions: (i) Zn (2.4 equiv.)/TiCl4 (1.2 equiv.)/THF,
reflux, 2 h, 4: 67%; (ii) Boron tribromide (1.0 M in dichloromethane, 1.1 equiv.)/
acetyl chloride/toluene, r.t., 2 h; (iii) I2 (cat.) in toluene, 5: 89%.
isomerized cis/trans mixture. Upon treatment with iodine in boiling
toluene pure trans-4,40-bis(S-acetyl)stilbenedithiol (5) was isolated in
high yield (Sch. 2).
The presented method for deprotection and reprotection of a thiol
group by converting the base stable t-butyl sulfide into the base labile and
readily cleavable acetyl sulfide may be of broad scope. The technique can
be incorporated in synthetic sequences as an excellent alternative to trityl
protection.
EXPERIMENTAL
t-Butyl phenyl sulfide[8] (1a) and t-butyl 4-tolyl sulfide[9] (1b) were
prepared according to literature.
4-Bromophenyl t-butyl sulfide[10] (1c): To a slurry of 4-bromothiophe-
nol (100 g, 0.53 mol) in t-butylchloride (400 mL) was added aluminum
chloride (3.5 g, 0.03 mol) in small portions. The reaction became
vigorously foaming and evolved HCl was lead through solid sodium
hydroxide. Stirring at room temperature was maintained at room for
30 min and the orange reaction mixture was poured into water
(700 mL) and extracted with pentane (3 Â 150 mL). The pooled extracts
were washed with water (40 mL), then dried with magnesium sulfate and
filtered. After evaporation the residual oil was purified by distillation
affording the t-butyl sulfide 1c (113.2 g, 87%) as a colorless liquid; b.p.
93–95ꢀC/12 Pa. Purity >98% (GC-MS). MS: EI (m/z, relative intensity):
246 (Mþ, 10), 190 (100), 108 (45). 1H NMR (400 MHz, CHCl3-d ):
ꢀ ¼ 1.27 (s, 9H), 7.38 (d, 2H, J ¼ 8.6), 7.45 (d, 2H, J ¼ 8.6).
4-(t-Butylthio)benzaldehyde[11] (3): 1c (12.26 g, 50 mmol) was added
dropwise under a nitrogen atmosphere to a mixture of butyllithium
(2.5 M in hexanes, 20 mL, 50 mmol) and THF (50 mL) cooled in a dry
ice/acetone bath. The reaction mixture was stirred at ꢁ78ꢀC for 15 min,
then DMF (10 mL) was added in one portion and stirring was maintained

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644
Stuhr-Hansen
at room temperature for 30 min. The clear reaction mixture was poured
into water (200 mL) and extracted with heptane (3 Â 50 mL). The pooled
extracts were washed with water (40 mL), then dried with magnesium
sulfate, and concentrated. The residual oil was purified by kugelrohr
distillation (air-bath 130ꢀC, 100 Pa) affording the protected 4-
mercaptobenzaldehyde 3 (8.11 g, 83%) as a colorless liquid. Purity
>98% (GC-MS). MS: EI (m/z, relative intensity): 194 (Mþ, 13), 179
(3), 138 (100), 109 (29). 1H NMR (250 MHz, CHCl3-d ): ꢀ ¼ 1.31 (s,
9H), 7.65 (d, 2H, J ¼ 6.4), 7.80 (d, 2H, J ¼ 6.4), 10.00 (s, 1H).
trans-4,40-bis(t-Butylthio)stilbene (4): Titanium(IV) chloride (2.6 mL,
24 mmol) was added dropwise to a slurry of zinc dust (3.14 g, 48 mmol) in
THF (100 mL). 3 (3.89 g, 20 mmol) was added. The reaction mixture was
refluxed for 2 h, poured into water (200 mL) and extracted with dichloro-
methane–heptane (1:2, 3 Â 50 mL). The pooled extracts were washed with
water (40 mL), then dried with magnesium sulfate, and concentrated to
give a crystalline residue. Recrystallization from heptane gave the stilbene
4 (2.38 g, 67%) as white plates; m.p. 159–160ꢀC. H NMR (250 MHz,
1
CHCl3-d ): ꢀ ¼ 1.31 (s, 18H), 7.13 (s, 2H), 7.46 (d, 4H, J ¼ 8.5), 7.53 (d,
4H, J ¼ 8.5). 13C NMR (250 MHz, CHCl3-d ): ꢀ ¼ 30.9, 46.1, 126.4, 128.7,
132.2, 137.4, 137.6. MS: EI (m/z, relative intensity): 356 (Mþ, 17), 300 (4),
244 (100), 210 (9). Anal. calcd. for C22H28S2: C 74.10, H 7.91, S 17.98;
Found: C 73.77, H 7.96, S 17.90.
Thioacetic Acid S-Aryl Esters 2 and 5; General Procedure
To a mixture of t-butylthiobenzenes (1, 10 mmol; or 4, 5 mmol),
acetyl chloride (5 mL), and toluene (20 mL) was added boron tribromide
(1.0 M solution in dichloromethane, 11 mL, 11 mmol). Stirring for 2 h at
room temperature. The dark reaction mixture was poured into ice (100 g),
then the phases were separated and the water phase was further extracted
with ether:heptane (1:2, 2 Â 20 mL). The pooled extracts were washed
with water (40 mL), then dried with magnesium sulfate, and
concentrated. The residual materials were (except from 5) purified by
kugelrohr distillation (air-bath 160ꢀC, 100 Pa).
Thioacetic acid S-phenyl ester[12] (2a): Colorless liquid; 1.46 g (96%).
MS: EI (m/z, relative intensity): 152 (Mþ, 13), 110 (100), 84 (7), 65 (19).
Thioacetic acid S-4-tolyl ester[13] (2b): Colorless liquid; 1.54 g (93%).
MS: EI (m/z, relative intensity): 166 (Mþ, 10), 124 (100), 108 (5), 91 (64).
Thioacetic acid S-4-bromophenyl ester[14] (2c): Colorless liquid; 2.05 g
(89%); crystallizes into white crystals at room temperature; m.p. 51–52ꢀC

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tert-Butyl Moiety Replaced by Acetyl
645
(lit.[15] m.p. 51.5–52ꢀC). MS: EI (m/z, relative intensity): 232 (Mþ, 4), 188
(36), 143 (2), 109 (27), 82 (7), 69 (12), 43 (100).
trans-4,40-bis(S-Acetyl)stilbenedithiol (5): The white crystalline mate-
rial was boiled in toluene (30 mL containing 0.01 M iodine) for 12 h. After
evaporation of toluene in vacuo recrystallization from heptane gave the
protected stilbenedithiol 5 (1.46 g, 89%) as white needles; m.p.
165–166ꢀC. H NMR (250 MHz, CDCl3): ꢀ ¼ 2.43 (s, 6H), 7.14 (s, 2H),
1
7.41 (d, 4H, J ¼ 8.4 Hz), 7.55 (d, 4H, J ¼ 8.4 Hz). MS: EI (m/z, relative
intensity): 328 (Mþ, 66), 286 (33), 244 (100), 210 (8). Anal. calcd.
for C18H16O2S2: C 65.83, H 4.91, S 19.52; Found: C 65.53, H 4.83, S
19.51.
ACKNOWLEDGMENT
Financial support from the European Union under the IST program
‘NANOMOL’ is greatfully acknowledged.
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Received in the UK December 3, 2001