One-step tethering of ω-mercaptoalkyl function to alcohols

Article abstract of DOI:10.1055/s-2006-942516

A new method of attachment of ω-mercaptoalkyl function to primary, secondary, and tertiary hydroxy groups based on ω-mercaptoalkyl monomalonates is reported. The attachment process proceeds in one stage and does not require a deprotection step thus directly providing high yields of unsymmetric malonates possessing a terminal thiol functionality. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942516

PAPER
2841
One-Step Tethering of w-Mercaptoalkyl Function to Alcohols
O
ne-Ste
p
T
ethering of
o
w
-Mercapto
s
alkyl Func
h
tionto
A
lc
o
e
hols Nahmany, Artem Melman*
Department of Organic Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel
Fax +972(2)6585279; E-mail: amelman@chem.ch.huji.ac.il
Received 21 March 2006; revised 25 April 2006
higher reaction rates than do those with alcohols.19 How-
ever, the chemoselectivity of carbodiimide couplings is
radically different for carboxylic acids possessing strong
electron-withdrawing groups in the alpha position. These
Abstract: A new method of attachment of w-mercaptoalkyl func-
tion to primary, secondary, and tertiary hydroxy groups based on w-
mercaptoalkyl monomalonates is reported. The attachment process
proceeds in one stage and does not require a deprotection step thus
directly providing high yields of unsymmetric malonates possess- acids, upon treatment with carbodiimides as well as other
coupling reagents, form ketene intermediates20 that are ca-
ing a terminal thiol functionality.
pable of efficient acylation of even highly sterically hin-
dered alcohols. Rates of acylation of alcohols with
electron-withdrawing group substituted ketenes are ex-
tremely high,21 thus enabling their selective acylation in
the presence of other functionalities such as phenols.19
Key words: thiols, acylations, chemoselectivity, esters, self-assem-
bly
Fabrication of well-ordered Self-Assembled Monolayers
(SAM) of thiols on a gold surface has emerged as the most
commonly used method for the preparation of functional-
ized surfaces.1 It has found numerous applications in
nanofabrication,2 molecular electronics,3 bioanalytics,4
and sensors.5 Other important applications of SAM such
as protective coatings,6 lubricants,7 and templates for
crystal nucleation8 have also been reported. Growing ap-
plications of SAM necessitated preparation of tailor made
monolayers using functionalized thiols. Since terminal
alkylthiols form very stable SAM, the derivatization of or-
ganic molecules with a w-mercaptoalkyl functionality is a
highly efficient approach toward functionalized monolay-
ers.
Our synthetic approach was based on w-mercaptoalkyl
monoesters of malonic acid as common precursors for the
derivatization of model alcohols. w-Mercaptoalkyl mo-
noesters of type 2 were prepared (Scheme 1) by a reaction
of mono tert-butyl malonate 1 with corresponding w-mer-
capto alcohols and DCC. In contrast to previously report-
ed S-acylation19 this reaction proceeded with complete O-
selectivity providing malonates of type 2 in essentially
quantitative yields. No traces of S-acylation products
were observed in the reaction mixture.
O
O
HO(CH2)nSH,
DCC
O
O
t-BuO
OH
t-BuO
O(CH2)nSH
w-Mercaptoalkyl functions can be attached to organic
molecules by alkylation,9 acylation,10 free-radical addi-
tion,11 and other methods.12 The high reactivity of thiol
groups to electrophiles usually necessitates its protection
as disulfides,13 thioesters14 and dithiocarbonates,15 tert-
butyl16 or trityl17 thioesters, and other protecting groups,18
with final deprotection stage releasing the thiol function.
The expansion of SAM to bioanalytical applications re-
quires derivatization of polyfunctional biopolymers thus
introducing a stricter requirement for chemoselectivity in
reactions involving the introduction and deprotection of
w-mercaptoalkyl function.
1
2a–c
n = 2, 3, 4
HCl
95–97%
EtOAc
O
O
HO
O(CH2)nSH
3a–c
Scheme 1 Preparation of w-mercaptoalkyl malonates.
Deprotection of w-mercaptoalkyl tert-butyl malonates of
type 2a–c with TFA provided a very low yield of mono-
Here we report a new method of attachment of a w-mer- malonates 3. This can be expected since the thiol function
captoalkyl function to primary, secondary, and tertiary is very reactive toward carbocations22 and lower thiols are
hydroxy groups. In contrast to existing approaches the at- commonly used for trapping tert-butyl cations.23 Howev-
tachment process involves one stage and does not require er, replacement of TFA with 2 M HCl in ethyl acetate
a deprotection step thus directly providing high yields of
the corresponding thiols.
eliminated undesired reactions of the thiol group and pro-
vided monomalonates 3a–c in quantitative yields.
We have previously reported that carbodiimide couplings Carbodiimide couplings of monomalonates 3a–c with
of most carboxylic acid with thiols proceed with much model alcohols (Scheme 2) proceeded smoothly provid-
ing the corresponding malonates 4a–i. Primary and sec-
ondary alcohols provided equally high yields. No traces of
either inter- or intramolecular S-acylation products were
SYNTHESIS 2006, No. 17, pp 2841–2844
Advanced online publication: 25.07.2006
x
x.
x
x
.
2
0
0
6
DOI: 10.1055/s-2006-942516; Art ID: P03706SS
© Georg Thieme Verlag Stuttgart · New York

2842
M. Nahmany, A. Melman
PAPER
IR (CDCl3): 2980, 2550, 1728, 1332, 1144, 757, 667 cm–1.
1H NMR (300 MHz): d = 1.28 (t, J = 9 Hz, 1 H), 1.29 (s, 9 H), 1.78
(quin, J = 6.7 Hz, 2 H), 2.44 (q, J = 7 Hz, 2 H), 3.11 (s, 2 H), 4.08
(t, J = 6 Hz, 2 H).
O
O
O
O
ROH,
DCC
HO
O(CH2)nSH
RO
O(CH2)nSH
3a–c
4a–i
13C NMR (75 MHz): d = 20.69, 27.68, 32.45, 42.60, 62.91, 81.66,
t-BuOH,
DCC
165.37, 166.55.
95%
Anal. Calcd for C10H18O4S: C, 51.26; H, 7.74. Found: C, 51.46; H,
7.70.
2a–c
4a,b,c n = 2, 3, 4
Isolated yields
tert-Butyl 4-Mercaptobutyl Malonate (2c)
Colorless oil; yield: 95%.
R = 1-pyrenylmethyl
R = cholesteryl
80–85%
92–95%
4d,e,f
n = 2, 3, 4
IR (CDCl3): 2978, 2550, 1728, 1333, 1144, 757, 666 cm–1.
4g,h,i
n = 2, 3, 4
R =
75–80%
O
O
O
O
1H NMR (300 MHz): d = 1.28 (t, J = 9 Hz, 1 H), 1.38 (s, 9 H), 1.57–
1.73 (m, 4 H), 2.48 (q, J = 7 Hz, 2 H), 3.20 (s, 2 H), 4.07 (t, J = 6
Hz, 2 H).
13C NMR (75 MHz): d = 23.88, 26.97, 27.68, 30.01, 42.65, 64.41,
81.72, 165.44, 166.70.
O
Scheme
function to model alcohols.
2
Attachment of malonyl-tethered w-mercaptoalkyl
Anal. Calcd for C11H20O4S: C, 53.20; H, 8.12. Found: C, 53.24; H,
8.06.
observed. Similar reactions with tert-butanol provided
compounds 2a–c.
In conclusion, we report a one-step synthetic method that
attaches a w-mercaptoalkyl function to primary, second-
ary, and tertiary alcohols in high yields. Very high
chemoselectivity of acylation through ketene intermedi-
ates allows the O-acylation of mercaptoalchols without
protecting the thiol functionality.
Preparation of w-Mercaptoalkyl Monomalonates 3a–c; General
Procedure
To a 1 M solution of a tert-butyl w-mercaptoalkyl malonates 3a–c
(1 mL) in CH2Cl2 was added under stirring at 25 °C a 2 M solution
of HCl in EtOAc (5.0 mL). The reaction mixture was stirred for 2 h,
evaporated, and purified by flash chromatography (CHCl3–MeOH,
0–50%) to afford the title compounds in quantitative yields.
2-Mercaptoethyl Monomalonate (3a)
Colorless oil.
IR (CDCl3): 3019, 2399, 1748, 1508, 1215, 928, 757, 669 cm–1.
Unless otherwise stated, all reagents used are commercially avail-
able. Solvents for reactions were purified by standard procedures.
Reactions were conducted under a nitrogen atmosphere. The H
1
NMR spectra were acquired on Bruker AMX-300 and DRX-400 in-
struments in CDCl3 using the residual solvent peaks for calibration.
IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrome-
ter in thin films. Microanalyses were performed at the Microanaly-
sis Laboratory of the Hebrew University of Jerusalem. Flash
chromatography was performed on Merck Si 60 silica gel (230–400
mesh) using chloroform alone or a mixture with methanol as the
eluent. Reactions were monitored by analytical TLC, which was
performed on Merck silica gel 60 F254 covered aluminum sheets.
1H NMR (300 MHz): d = 1.53 (t, J = 9 Hz, 1 H), 2.76 (q, J = 7 Hz,
2 H), 3.45 (s, 2 H), 4.28 (t, J = 6 Hz, 2 H), 8.49 (br s, 1 H, OH).
13C NMR (75 MHz): d = 22.89, 40.79, 66.85, 166.25, 171.27.
Anal. Calcd for C5H8O4S: C, 36.58; H, 4.91. Found: C, 36.36; H,
4.78.
3-Mercaptopropyl Monomalonate (3b)
Colorless oil.
IR (CDCl3): 3019, 1717, 1508, 1418, 1215, 757, 669 cm–1.
Preparation of tert-Butyl Mercaptoalkyl Malonates 2a–c;
General Procedure
To a mixture of mono tert-butyl malonate (1 mL; 1 M solution in
anhyd CH2Cl2) and w-mercaptoalkanol (1.1 mmol) stirring at 25 °C
was added DCC (1.1 mL, 1 M solution in anhyd CH2Cl2). The reac-
tion mixture was stirred for 45 min, filtered, evaporated, and puri-
fied by flash chromatography using CHCl3 as eluent.
1H NMR (300 MHz): d = 1.39 (t, J = 9 Hz, 1 H), 1.93 (quin J = 6.7
Hz, 2 H), 2.57 (q, J = 7 Hz, 2 H), 3.41 (s, 2 H), 4.26 (t, J = 6 Hz, 2
H), 9.24 (br s, 1 H, OH).
13C NMR (75 MHz): d = 20.73, 32.30, 40.83, 63.68, 166.53, 171.34.
Anal. Calcd for C6H10O4S: C, 40.44; H, 5.66. Found: C, 40.36; H,
5.64.
tert-Butyl 2-Mercaptoethyl Malonate (2a)
Colorless oil; yield: 95%.
4-Mercaptobutyl Monomalonate (3c)
Colorless oil.
IR (CDCl3): 3019, 1732, 1507, 1215, 757, 669 cm–1.
1H NMR (300 MHz): d = 1.47 (s, 9 H), 1.54 (t, J = 9 Hz, 1 H), 2.77
(q, J = 7 Hz, 2 H), 3.31 (s, 2 H), 4.26 (t, J = 6 Hz, 2 H).
IR (CDCl3): 3020, 1718, 1508, 1418, 1215, 757, 668 cm–1.
1H NMR (300 MHz): d = 1.33 (t, J = 9 Hz, 1 H), 1.61–1.79 (m, 4
H), 2.53 (q, J = 7 Hz, 2 H), 3.41 (s, 2 H), 4.15 (t, J = 6 Hz, 2 H), 9.89
(br s, 1 H, OH).
13C NMR (75 MHz): d = 23.97, 26.95, 30.02, 40.84, 65.17, 166.56,
171.52.
13C NMR (75 MHz): d = 22.5, 27.3, 42.1, 65.9, 81.4, 164.9, 166.0.
Anal. Calcd for C9H16O4S: C, 49.07; H, 7.32. Found: C, 49.28; H,
7.20.
Anal. Calcd for C7H12O4S: C, 43.74; H, 6.29. Found: C, 43.86; H,
6.24.
tert-Butyl 3-Mercaptopropyl Malonate (2b)
Colorless oil; yield: 97%.
Synthesis 2006, No. 17, 2841–2844 © Thieme Stuttgart · New York

PAPER
One-Step Tethering of w-Mercaptoalkyl Function to Alcohols
Cholesteryl 3-Mercaptopropyl Malonate (4e)
2843
Acylation of Alcohols with w-Mercaptoalkyl Monomalonates
4a–i; General Procedure
Prepared from 3b and cholesterol; pale yellow oil; yield: 94%.
To a mixture of a 1 M solution of w-mercaptoalkyl monomalonates
3a–c (1 mL) in anhyd CH2Cl2, molecular sieves (4 Å), and the ap-
propriate alcohol (1.15 mmol) stirring at 25 °C was added a 1 M so-
lution of DCC in CH2Cl2 (1.1 mL). The reaction mixture was stirred
for 45 min, filtered, evaporated, and purified by flash chromatogra-
phy (100% CHCl3) to afford the title compounds.
IR (CDCl3): 3019, 2951, 2400, 2253, 1732, 1473, 1215, 908, 759,
735, 669 cm–1.
1H NMR (300 MHz): d = 0.66 (s, 3 H), 0.84 (s, 3 H), 0.87 (s, 3 H),
0.91 (s, 3 H), 1.00 (s, 3 H), 1.10–2.10 (m, 27 H, SH, cholesterol),
1.95 (quin, J = 6.7 Hz, 2 H), 2.34 (d, J = 7.7 Hz, 2 H), 2.61 (q, J =
7 Hz, 2 H), 3.35 (s, 2 H), 4.27 (t, J = 6 Hz, 2 H), 4.60–4.72 (m, 1 H),
5.38 (d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz): d = 11.81, 18.67, 19.26, 20.23, 20.92, 22.52,
22.77, 23.78, 24.23, 27.56, 27.96, 28.17, 31.79, 32.59, 35.74, 36.14,
36.52, 37.85, 39.47, 39.67, 41.86, 42.26, 43.79, 49.95, 56.08, 56.62,
63.29, 75.34, 122.94, 139.24, 165.84, 166.58.
Pyren-1-ylmethyl 2-Mercaptoethyl Malonate (4a)
Prepared from 3a and 1-pyrene methanol; greenish amorphous
mass; yield: 85%.
IR (CDCl3): 2926, 2253, 1733, 1147, 908, 847, 733 cm–1.
1H NMR (300 MHz): d = 1.34 (t, J = 9 Hz, 1 H), 2.56 (q, J = 7 Hz,
2 H), 3.47 (s, 2 H), 4.15 (t, J = 6 Hz, 2 H), 5.90 (s, 2 H), 8.03–8.24
(m, 9 H).
13C NMR (75 MHz): d = 22.74, 41.40, 65.74, 66.53, 122.64, 124.45,
124.49, 124.71, 125.45, 125.54, 126.05, 127.20, 127.85, 127.86,
127.89, 128.25, 129.48, 130.51, 131.06, 131.82, 165.95, 166.25.
Cholesteryl 4-Mercaptobutyl Malonate (4f)
Prepared from 3c and cholesterol; pale yellow oil; yield: 95%.
IR (CDCl3): 3019, 2950, 2868, 2360, 2341, 1727, 1467, 1215, 926,
757, 668 cm–1.
1H NMR (300 MHz): d = 0.67 (s, 3 H), 0.85 (s, 3 H), 0.86 (s, 3 H),
0.90 (s, 3 H), 1.00 (s, 3 H), 1.10–2.04 (m, 31 H, cholesterol, SH,
HSCH2CH2CH2), 2.34 (d, J = 7 Hz, 2 H), 2.56 (q, J = 7 Hz, 2 H),
3.34 (s, 2 H), 4.16 (t, J = 6 Hz, 2 H), 4.63–4.71 (m, 1 H), 5.38 (d,
J = 5 Hz, 1 H).
13C NMR (75 MHz): d = 11.81, 18.67, 19.27, 20.98, 22.52, 22.78,
23.78, 24.13, 24.24, 27.18, 27.57, 28.18, 30.22, 31.80, 31.85, 35.75,
36.14, 36.53, 37.86, 39.47, 39.67, 41.90, 42.27, 43.70, 49.95, 56.08,
56.63, 64.80, 75.30, 122.92, 139.28, 165.91, 166.68.
Anal. Calcd for C22H18O4S: C, 69.82; H, 4.79. Found: C, 69.43; H,
4.98.
Pyren-1-ylmethyl 3-Mercaptopropyl Malonate (4b)
Prepared from 3b and 1-pyrene methanol, greenish amorphous
mass; yield: 83%.
IR (CDCl3): 3019, 2927, 2359, 2341, 1732, 1215, 848, 756 cm–1.
1H NMR (300 MHz): d = 1.20 (t, J = 8 Hz, 1 H), 1.73 (quin, J = 6.7
Hz, 2 H), 2.36 (q, J = 7 Hz, 2 H), 3.45 (s, 2 H), 4.15 (t, J = 6 Hz, 2
H), 5.90 (s, 2 H), 8.00–8.28 (m, 9 H).
13C NMR (75 MHz): d = 20.70, 32.32, 41.57, 63.43, 65.75, 122.74,
124.54, 124.58, 124.60, 124.81, 125.51, 125.60, 126.12, 127.29,
127.96, 127.98, 128.32, 129.59, 130.59, 131.13, 131.91, 166.27,
166.39.
Anal. Calcd for C34H56O4S: C, 72.81; H, 10.06. Found: C, 72.45; H,
10.23.
Tetrahydro-2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)fu-
ro[2,3-d][1,3]dioxol-6-yl 2-Mercaptoethyl Malonate (4g)
Prepared from 3a and diisopropylidene glucose; white amorphous
mass; yield: 75%.
Anal. Calcd for C23H20O4S: C, 70.39; H, 5.14. Found: C, 70.54; H,
5.70.
IR (CDCl3): 2988, 2554, 1380, 1260, 1216, 1148, 1077, 1024, 733,
649 cm–1.
Pyren-1-ylmethyl 4-Mercaptobutyl Malonate (4c)
Prepared from 3c and 1-pyrene methanol; greenish amorphous
mass; yield: 80%.
IR (CDCl3): 3019, 2927, 2855, 2360, 2342, 1731, 1215, 756 cm–1.
1H NMR (300 MHz): d = 1.30 (s, 3 H), 1.31 (s, 3 H), 1.40 (s, 3 H),
1.51 (s, 3 H), 1.53 (t, J = 9 Hz, 1 H), 2.77 (q, J = 7 Hz, 2 H), 3.45 (s,
2 H), 3.98–4.10 (m, 5 H), 4.26 (t, J = 6 Hz, 2 H), 4.56 (d, J = 3.6 Hz,
1 H), 5.87 (d, J = 3.6 Hz, 1 H).
1H NMR (300 MHz): d = 1.17 (t, J = 8 Hz, 1 H), 1.38–1.53 (m, 4
H), 2.29 (q, J = 7 Hz, 2 H), 3.44 (s, 2 H), 4.02 (t, J = 6 Hz, 2 H), 5.91
(s, 2 H), 8.01–8.29 (m, 9 H).
13C NMR (75 MHz): d = 22.91, 25.15, 26.10, 26.58, 26.80, 41.11,
66.71, 67.71, 72.13, 76.66, 79.45, 82.96, 104.93, 109.36, 112.29,
164.95, 165.69.
13C NMR (75 MHz): d = 23.94, 26.91, 29.66, 29.99, 41.65, 64.91,
65.75, 122.83, 124.58, 124.83, 125.52, 125.62, 126.15, 127.31,
127.93, 127.98, 128.03, 128.06, 128.30, 129.63, 130.62, 131.15,
131.91, 166.34, 166.44.
Tetrahydro-2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)fu-
ro[2,3-d][1,3]dioxol-6-yl 3-Mercaptopropyl Malonate (4h)
Prepared from 3b and diisopropylidene glucose; white amorphous
mass; yield: 75%.
Cholesteryl 2-Mercaptoethyl Malonate (4d)
IR (CDCl3): 3019, 1215, 908, 757, 668 cm–1.
Prepared from 3a and cholesterol; pale yellow oil; yield: 92%.
1H NMR (300 MHz): d = 1.30 (s, 3 H), 1.32 (s, 3 H), 1.41 (s, 3 H),
1.51 (t, 1 H and s, 3 H), 1.96 (quin, J = 6.7 Hz, 2 H), 2.60 (q, J = 7
Hz, 2 H), 3.43 (s, 2 H), 3.98–4.20 (m, 5 H), 4.27 (t, J = 6 Hz, 2 H),
4.55 (d, J = 3.6 Hz, 1 H), 5.87 (d, J = 3.6 Hz, 1 H).
13C NMR (75 MHz): d = 20.85, 25.23, 26.17, 26.65, 26.87, 30.89,
41.25, 63.63, 67.24, 68.40, 72.21, 79.54, 83.04, 105.00, 109.44,
112.39, 165.13, 166.05.
IR (CDCl3): 2949, 2254, 1730, 1466, 1380, 1331, 1151, 1006, 908,
733, 649 cm–1.
1H NMR (300 MHz): d = 0.67 (s, 3 H), 0.85 (s, 3 H), 0.87 (s, 3 H),
0.91 (s, 3 H), 1.00 (s, 3 H), 1.10–2.10 (m, 27 H, cholesterol, SH),
2.34 (d, J = 7.7 Hz, 2 H), 2.77 (q, J = 7 Hz, 2 H), 3.38 (s, 2 H), 4.27
(t, J = 6 Hz, 2 H), 4.60–4.72 (m, 1 H), 5.38 (d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz): d = 11.78, 18.65, 19.22, 20.95, 22.49, 22,75,
23.01, 23.76, 24.20, 27.93, 28.15, 31.76, 31.81, 35.71, 36.11,
36.48, 36.82, 39.44, 39.63, 41.70, 42.17, 42.23, 49.92, 56.06, 56.59,
66.51, 75.37, 122.90, 139.19, 165.70, 166.28.
Tetrahydro-2,2-dimethyl-5-(2,2-dimethyl-1,3-dioxolan-4-yl)fu-
ro[2,3-d][1,3]dioxol-6-yl 4-Mercaptobutyl Malonate (4i)
Prepared from 3c and diisopropylidene glucose; white amorphous
mass; yield: 80%.
Anal. Calcd for C32H52O4S: C, 72.13; H, 9.84. Found: C, 72.34; H,
10.10.
IR (CDCl3): 3019, 2360, 1261, 908, 756, 669 cm–1.
Synthesis 2006, No. 17, 2841–2844 © Thieme Stuttgart · New York

2844
M. Nahmany, A. Melman
PAPER
(10) (a) Camarero, J. A.; Kwon, Y.; Coleman, M. A. J. Am.
1H NMR (300 MHz): d = 1.21 (s, 3 H), 1.25 (s, 3 H), 1.27 (t, J = 8
Hz, 1 H), 1.33 (s, 3 H), 1.39 (s, 3 H), 1.57–1.67 (m, 4 H), 2.45 (q,
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2 H), 4.41 (d, J = 3.6 Hz, 1 H), 5.81 (d, J = 3.6 Hz, 1 H).
13C NMR (75 MHz): d = 23.90, 25.32, 26.19, 26.65, 26.75, 27.00,
29.98, 41.65, 64.30, 65.60, 73.30, 74.90, 76.70, 81.50, 104.93,
109.13, 111.43, 165.48, 166.73.
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Prepared from 3a–c and tert-BuOH according to the general proce-
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95%, all data as above.
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