A new strategy for chemoselective O-acylation of β-mercapto alcohols via alkylsilyl and stannyl protection

Article abstract of DOI:10.1016/j.tetlet.2008.11.047

Chemoselective preparation of O-acylated derivatives from bis-protected mercapto alcohols was described. Trialkylsilyl and trialkylstannyl chloride are used to generate an intermediate with O- and S-protection. The intermediates from β-mercapto alcohols a

Full text of DOI:10.1016/j.tetlet.2008.11.047

Tetrahedron Letters 50 (2009) 480–483
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new strategy for chemoselective O-acylation of b-mercapto
alcohols via alkylsilyl and stannyl protection
Muchchintala Maheswara a, Mirae Kim a, Sun-Ju Yun a, Jung Jin Ju b, Jung Yun Do a,
*
a Department of Advanced Materials for Information and Display, Pusan National University, Busan 609-735, Republic of Korea
b Convergence Components and Materials Research Lab, ETRI, Daejeon 305-700, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoselective preparation of O-acylated derivatives from bis-protected mercapto alcohols was
described. Trialkylsilyl and trialkylstannyl chloride are used to generate an intermediate with O- and
S-protection. The intermediates from b-mercapto alcohols are reactive toward acylating agents and selec-
tive to provide O-acylated derivatives. The present preparation involves the direct conversion of alcohol
to the corresponding O-acylated compounds without deprotection.
Received 8 October 2008
Revised 10 November 2008
Accepted 13 November 2008
Available online 18 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Mercapto alcohol
O-Acrylation
Alkoxy tin
Chemoselective acrylation
1. Introduction
tively occurred depending on carboxylic acids.4e,f Lipase-catalyzed
acylations of b-mercapto alcohols also reported.4g,h The chemose-
Protection of functional groups is one of the most important and
widely carried out synthetic transformations in preparative organ-
ic chemistry.1 We sought to prepare functional methacrylate and
acrylate polymers used in a large number of applications2a includ-
ing attachable of metal or semiconductors nanoparticle.2b,c Mole-
cules bearing free-SH are considered important protectors
against radiation-induced damage to DNA3a by gamma3b and fast
neutron radiation.3c If tumor cells absorb fewer drugs than the nor-
mal ones, thiol compounds can be used in cancer radiotherapy.3d
Moreover, these compounds are also employed in cosmetic
preparations to reduce actinic damage to human skin due to
over-exposure to sunlight.3e The thiol group can involve in a radi-
cal reaction so that chemical protection is often required during ac-
rylic polymerization.3f The selective O- or S-acylation of mercapto
alcohols is synthetically important but there are few examples in
the literature.4a–m The typical example of selective O-acylation in-
volves acid-catalyzed esterifications of alcohols with thiolcarboxy-
lic acids.4a,b Selective O-acylation of mercaptoethanol with
moderate yield was achieved with acetic acid in the presence of yt-
tria-zirconia-based Lewis acid as a heterogeneous catalyst.4c In
general, proton and Lewis acid-catalyzed thioesterifications are
disfavored by lower equilibrium constants between carboxylic
acids and thioesters as well as a higher energy transition state.4d
Sometimes, S- or O-acylation via carbodiimide couplings selec-
lectivity of these reactions is probably enzyme-specific as lipase-
catalyzed esterifications and transesterifications have been
successfully in the selective acylation of various kinds of polyfunc-
tional compounds such as sugars and aminoalcohols.4i–m However,
many of these selective methods present low yields depending on
alcohols, poor regioselectivity, and harsh catalytic conditions.
Therefore, the development of convenient, mild, and high yielding
approaches to the selective O-acylation was still desirable and
much in demand.
2. Results and discussion
In this Letter, we wish to report a new strategy and simple pro-
cedure for chemoselective O-acylation of mercaptoethanol and
mercaptophenol using protective groups such as trialkyl/triphenyl
silyl and stannyl groups. To begin with, we studied b-mercap-
toethanol that was simply treated with one equivalent of
acrylating agents in the presence of Et3N and it was found that
S-acrylation preferentially occurred (Scheme 1). The acrylation pro-
ceeded inefficiently to afford low isolating yields and it was partly
due to further thiol reaction such as olefinic addition. The similar
reaction of acetic anhydride with b-mercaptoethanol exhibited
O-acetylation in major with minor S-acetylation. While opposite
selectivity of b-mercaptoethanol was resulted according to acylating
agents, the selectivity was not high as shown in Scheme 1.5
Alkylsilyl protection groups of alcohols are stable under
conventional basic reaction conditions. Recently, we observed
* Corresponding author. Tel.: +82 51 510 3598.
E-mail address: jydo@pusan.ac.kr (J. Y. Do).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.047

M. Maheswara et al. / Tetrahedron Letters 50 (2009) 480–483
481
O
O
O
O
O
O
SH
OH
S
O
S
O
+
+
+
1 eq
O
O
O
O
10.5%
O
3 h
1.2%
SH
45.5%
OH
O
S
S
O
O
S
Et3N
Cl
1 eq
OH
+
+
HS
O
O
O
O
2 h
CH2Cl2, r.t.
12.9%
O
5.6%
SH
47.1%
OH
O
O
O
S
1 eq
3 h
+
6.6%
O
44.4%
0%
Scheme 1.
that protected b-mercaptoethanols were found to be reactive and
selectively converted into O-acylated products. When triphenylsi-
lyl protected mercaptoethanol was treated with methacrylic
anhydride, it converted to O-acrylated product in high yield.
S-acrylation product was not detected. Similar selective results were
found with methacrylic chloride and acetic anhydride with quanti-
tative yields. The reaction presumably involves nucleophilic attack
of protected alkoxy groups. Thus, our attention shifts to stannyl
protection which increases the attacking reactivity of alkoxy group.
We prepared bis-(O,S-triphenylstannyl)-2-mercaptoethanol (3b)
from b-mercaptoethanol (2a) and triphenylstannyl chloride in
the presence of Et3N with 99% conversion within 1 h. The resultant
compound 3b was in situ O-acylated with methacrylic anhydride
(4a), methacrylic chloride (4b), and acetic anhydride (4c) with
excellent yields at room temperature as shown in Table 1 (entries
4–6). This method involves the direct conversion to corresponding
O-acylated compounds without deprotection. High selectivity and
conversions are summarized in Table 1.
To study the applicability of this new method, we have pre-
pared several bis-protected b-mercaptoethanol including tributyl-
Table 1
Selective O-acylation of several b-mercapto alcohols with acylating agents
Entry
Mercapto alcohols
Intermediate
Acylating agenta
Product
Time (h)
3
Yieldb (%)
97
OH
HS
OSiPh3
1
4a
Ph3SiS
O
O
3a
2a
Ph3SiS
O
O
5a
5b
2
3
2a
2a
3a
3a
4b
4c
5a
1
2
99
98
Ph3SiS
OSnPh3
O
4
5
6
2a
2a
2a
4a
4b
4c
3
1
2
99
98
97
Ph3SnS
Ph3SnS
5c
3b
5c
O
3b
3b
O
Ph3SnS
5d
O
OSn(n-Bu)3
O
(n-Bu)3SnS
7
8
2a
2a
4a
4b
3
1
90
93
(n-Bu)3SnS
3c
5e
O
3c
3c
5e
O
O
(n-Bu)3SnS
9
10
11
2a
2a
2a
4c
4d
4a
4
97
97
16
5f
O
O
Ph
(n-Bu)3SnS
3c
3
5g
OSiMe3
O
12
Me3SiS
Me3SiS
3d
5h
O
12
2a
3d
4b
5h
6
18
(continued on next page)

482
M. Maheswara et al. / Tetrahedron Letters 50 (2009) 480–483
Table 1 (continued)
Entry
Mercapto alcohols
Intermediate
Acylating agenta
Product
Time (h)
12
Yieldb (%)
21
O
Me3SiS
13
2a
3d
4c
5i
O
SSiMe3
O
SSiMe3
OSiMe3
SH
OH
14
15
16
4a
4b
4c
8
6
8
27 (35)
30 (30)
32 (30)
O
2b
3e
5j
2b
3e
3e
5j
SSiMe3
O
2b
O
5k
OSnPh3
O
Ph
6
OH
Ph3SnS
Me3SiS
HS
O
S
17
18
4c
4a
2
6
45 (36)
34 (40)
Ph
3f
Ph
2c
O
OSiMe3
O
Me3SiS
2c
Ph
3g
Ph
5l
O
19
20
2c
2c
3g
3g
4b
4c
5l
5
6
38 (30)
35 (33)
O
Me3SiS
Ph
O
5m
The structures of the products were determined from spectral (IR and 1H NMR) data.
a
Compounds 4a, 4b, 4c, and 4d represent methacrylic anhydride, methacrylic chloride, acetic anhydride, and benzoyl chloride, respectively.
Isolated yield after purification by flash column chromatography. The parentheses contain recovered intermediate yield.
b
stannyl (3c) and trimethylsilyl (3d) groups. By treating with 4a, 4b,
phenacyl bromide in Scheme 3. Mercaptoethanol (2c) was easily
converted to bis-triphenylstannyl (3f) and bis-trimethylsilyl deriv-
atives (3g). The reaction of stannyl derivative (3f) in situ with ace-
tic anhydride resulted in the formation of diacetylated product (6)
as shown in Table 1 (entry 17) with no expected O-acetylated
product. This was overcome with trimethylsilyl chloride (entries
18–20). In spite of low product yields, mono-S-acylation derivative
was not found.
Finally, we studied the selective reaction with aromatic mer-
capto alcohol. o-Mercapto phenol (9) was prepared from the reac-
tion of a diazotization product of o-aminophenol and potassium
ethylxanthate.7 Triphenylstannyl derivative 10 formed a diacety-
lated product (12) with acetic anhydride, while trimethylsilyl
derivative (11) underwent selective O-acylation. Deprotection
and 4c they generated only O-acylated products (Scheme 2).
Tributylstannyl chloride produced quantitatively O-acylation
products, but trimethylsilyl chloride afforded low yields of O-acyl-
ated products even in prolonged reaction times in Table 1 (entries
11–13). The reaction of benzoyl chloride with 3c also yielded
O-benzoyl compound 5g (entry 10). Furthermore, trans-1-merca-
ptocyclohexane-2-ol (2b), prepared from cyclohexene oxide and
sulfurated sodium borohydride,6 underwent selective O-acylation
via corresponding bis-trimethylsilyl derivative 3e, which was
recovered to give low conversion yield after acylation.
In continuation, we have prepared a substituted mercap-
toethanol, 2-mercapto-1-phenylethanol (2c) prepared through
LiAlH4 reduction of thioacetyl acetophenone (8) derived from
2
2
2
R
R
R
3
1
4
R
Et N
1
3
O-G(R )
4
O
R
3
1
1
(R ) GCl
3
HS
+
(R ) G-S
(R ) G-S
3
3
CH Cl , r.t.
2
2
3
3
OH
R
R
O
1
2
3
5
1
4
4a =(CH C(CH )CO) O
R
= Ph, n-Butyl, CH ; G = Sn, Si (1)
R
= CH C(CH )
2
3
2
3
2
3
2
3
2
3
4b =
4c =
4d =
R = R = H (2a); R , R = -(CH ) - (2b)
CH C(CH )COCl
= Ph
2 4
2
3
2
3
(CH CO) O
R
= H, R = Ph (2c)
3
2
= CH
3
PhCOCl
Scheme 2.

M. Maheswara et al. / Tetrahedron Letters 50 (2009) 480–483
483
O
O
OH
Br
S
O
SH
a
b
7
8
2c
Scheme 3. Reagents and conditions: (a) thioacetic acid, DMF, K2CO3, rt, 2 h, 71%; (b) LiAlH4, Ether, rt, 1 h, 62%.
O
O
d or
OSnPh3
SSnPh3
OAc
SAc
OH
SH
OSiMe3
SSiMe3
e
a
b
c
SH
13
14
OAc
f
12
10
9
11
SH
Scheme 4. Reagents and conditions:8 (a) Ph3SnCl, CH2Cl2, Et3N, rt, 1 h, 95%; (b) 4c, 3 h, 30%; (c) Me3SiCl, CH2Cl2, Et3N, rt,1 h, 95%; (d) 4a, 5 h, 40%; (e) 4b, 4 h, 50%; (f) 4c, 6 h,
46%.
Synthesis 2006, 2841; (g) Baldessari, A.; Iglesias, L. E.; Gros, E. G. J. Chem. Res. (S)
1992, 204; (h) Baldessari, A.; Iglesias, L. E.; Gros, E. G. Biotechnol. Lett. 1994, 16,
479; (i) Wang, Y. F.; Wong, C. H. J. Org. Chem. 1988, 53, 3127; (j) Colombo, D.;
Ronchetti, F.; Scala, A.; Toma, L. J. Carbohydr. Chem. 1992, 11, 89; (k) Panza, L.;
Luisetti, M.; Crociati, E.; Riva, S. J. Carbohydr. Chem. 1993, 12, 125; (l) Kanerva, L.;
Rahiala, K.; Vanttinen, E. J. Chem. Soc. Perkin Trans. 1 1992, 1759; (m) Izumi, T.;
Fuyaka, K. Bull. Chem. Soc. Jpn. 1993, 66, 1216.
occurred during isolation to give free –SH of O-acylated products
(13 and 14) with moderate yields (Scheme 4). Unreacted interme-
diate (11) was recovered with 30–40%.
The acylation of triphenylsilyl alcohol was unique for b-mer-
capto alcohol and did not occur with 6-mercaptohexyl alcohol or
4-mercaptomethylbenzyl alcohol of remote functionalities. Thus,
the exceptional reactivity and selectivity of b-mercapto alcohol
seem to be due to the assistance of a neighboring sulfur.
5. The reason of the opposite selectivity is not clear. The possibility of
intramolecular acyl rearrangement was excluded because isolated two
products of O-acetyl and S-acetyl did not interconvert in methylene chloride
containing triethylamine.
6. Lalancette, J. M.; Freche, A. Can. J. Chem. 1971, 49, 4047.
7. Djerassi, C.; Gorman, M.; Markley, F. X.; Oldenburg, E. B. J. Am. Chem. Soc. 1955,
77, 568.
3. Conclusion
8. General procedure for the preparation of O-acylation derivatives: To a solution of a
mercapto alcohol (2, 9) (1.0 mmol) in CH2Cl2 (3.0 mL), triphenylsilyl chloride
(2.2 mmol) and Et3N (2.1 mmol) were added and stirred for appropriate time at
room temperature. After complete disappearance of starting material as
indicated by TLC, a solution of acylating agent (4) (1.0 mmol) was added. The
progress of the reaction was monitored by TLC, and upon completion the
reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2. The
organic portion was dried over MgSO4 and concentrated. The residue was
subjected to column chromatography to give the corresponding O-acylated
product in moderate to high yields. The spectral (IR and 1H NMR) data of some of
the representative compounds are given below.
We have developed a simple and efficient method for the
chemoselective O-acylation of several mercapto alcohols via bis-
protective derivatives using alkyl/arylsilyl and stannyl groups.
The reaction underwent only with b-mercapto alcohols to give O-
acrylated or O-acetylated products. One-step synthesis, high con-
version, and impressive chemoselectivity are the noteworthy
advantages of present protocol.
Compound 5a: 1H NMR (CDCl3, 300 MHz): d 1.97 (s, 3H), 3.19 (t, 2H, J = 6.3 Hz),
3.94 (t, 2H, J = 7.2 Hz), 5.59 (s, 1H), 6.08 (s, 1H), 7.38–7.49 (m, 10H), 7.63–7.67
(m, 5H). Compound 5b: 1H NMR (CDCl3, 300 MHz): d 2.30 (s, 3H), 3.12 (t, 2H,
J = 6.3 Hz), 3.92 (t, 2H, J = 6.3 Hz), 7.38–7.49 (m, 10H), 7.62–7.66 (m, d 5H).
Compound 5c: 1H NMR (CDCl3, 300 MHz): 1.96 (s, 3H), 2.84 (t, 2H, J = 6.9 Hz),
4.14 (t, 2H, J = 7.2 Hz), 5.53 (s, 1H), 6.05 (s, 1H), 7.42–7.48 (m, 10H), 7.65–7.69
(m, 5H). Compound 5d: 1H NMR (CDCl3, 300 MHz): d 1.85 (s, 3H), 2.81 (t, 2H,
J = 6.9 Hz), 4.08 (t, 2H, J = 6.9 Hz), 7.44–7.47 (m, 10H), 7.64–7.69 (m, 5H).
Compound 5e: 1H NMR (CDCl3, 300 MHz): d 0.89 (t, 9H, J = 7.2 Hz), 1.16 (t, 6H,
J = 8.1 Hz), 1.34 (q, 7H, J = 7.5 Hz), 1.51–1.59 (m, 5H), 1.94 (s, 3H), 2.77 (t, 2H,
J = 7.5 Hz), 4.17 (t, 2H, J = 7.5 Hz), 5.55 (s, 1H), 6.11 (m, 1H). Compound 5f: 1H
NMR (CDCl3, 300 MHz): d 0.90 (t, 9H, J = 7.2 Hz), 1.15 (t, 6H, J = 8.1 Hz), 1.34 (q,
7H, J = 7.2 Hz), 1.51–1.59 (m, 5H), 2.05 (s, 3H), 2.74 (t, 2H, J = 7.2 Hz), 4.10 (t, 2H,
J = 7.2 Hz). Compound 5g: 1H NMR (CDCl3, 300 MHz): d 0.92 (t, 9H, J = 7.2 Hz),
1.19 (t, 6H, J = 6.6 Hz), 1.33 (q, 6H, J = 7.5 Hz), 1.53–1.65 (m, 6H), 2.89 (t, 2H,
J = 7.2 Hz), 4.37 (t, 2H, J = 7.8 Hz), 7.41–7.47 (m, 2H), 7.53–7.59 (m, 1H), 8.04–
8.08 (m, 2H). Compound 5h: 1H NMR (CDCl3, 300 MHz): d 0.07 (s, 9H), 1.98 (s,
3H), 3.10 (t, 2H, J = 6.6 Hz), 3.73 (t, 2H, J = 6.6 Hz), 5.59 (s, 1H), 6.09 (s, 1H).
Compound 5k: 1H NMR (CDCl3, 300 MHz): d 0.09 (s, 9H), 1.34–1.49 (m, 4H),
1.81–1.89 (m, 4H), 2.08–2.12 (m, 1H), 2.31 (s, 3H), 3.42–3.49 (m, 1H). Compound
5m: 1H NMR (CDCl3, 300 MHz): d 0.08 (s, 9H), 2.34 (s, 3H), 3.01–3.19 (m, 2H),
4.71–4.78 (m, 1H), 7.33–7.36 (m, 5H). Compound 13: IR (KBr): mmax 2925, 2854,
Acknowledgments
This work was supported for two years by the Pusan National
University, Research Grant and by the IT R&D program (2006-S-
073-02) of the MKE/IITA, Korea.
References and notes
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R. K.; Bodas, M. S.; Dagade, S. P.; Dongare, M. K.; Ramaswamy, A. V. J. Mol. Catal.
A: Chem. 2002, 181, 207; (d) Bruice, T. C.. In Organic Sulfur Compounds; Kharasch,
N., Ed.; Springer: London, 1961; Vol. 1, p 421; (e) Shelkov, R.; Nahmany, M.;
Melman, A. Org. Biomol. Chem. 2004, 2, 397; (f) Nahmany, M.; Melman, A.
2361, 1741, 1434, 1377, 1201, 946 cmÀ1 1H NMR (CDCl3, 300 MHz): d 2.09 (s,
;
3H), 2.99 (s, 1H), 5.57 (s, 1H), 6.40 (s, 1H), 7.15–7.24 (m, 2H), 7.29 (d, 1H,
J = 8.7 Hz), 7.60 (dd, 1H, J = 8.1 Hz). Compound 14: IR (KBr): mmax 2924, 2855,
2361, 1769, 1464, 1368, 1186, 1058, 952 cmÀ1 1H NMR (CDCl3, 300 MHz): d
;
2.33 (s, 3H), 7.15–7.24 (m, 2H), 7.30 (d, 1H, J = 7.8 Hz), 7.59 (dd, 1H, J = 7.8 Hz).