Efficient and selective removal of chloroacetyl group promoted with tetra-n-butylammonium fluoride (TBAF)

Article abstract of DOI:10.1016/j.carres.2011.09.033

A practical method for the efficient and selective cleavage of chloroacetyl protecting group using tetra-n-butylammonium fluoride (TBAF) in THF solution at rt was disclosed.

Full text of DOI:10.1016/j.carres.2011.09.033

Carbohydrate Research 346 (2011) 2801–2804
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Efficient and selective removal of chloroacetyl group promoted
with tetra-n-butylammonium fluoride (TBAF)
a
b,
Guofeng Gu a, , Min Fang , Yuguo Du
⇑
⇑
a National Glycoengineering Research Center, Shandong University, Jinan 250100, PR China
b Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, PO Box 2871, Beijing 100085, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 August 2011
Received in revised form 26 September 2011
Accepted 29 September 2011
Available online 5 October 2011
A practical method for the efficient and selective cleavage of chloroacetyl protecting group using tetra-n-
butylammonium fluoride (TBAF) in THF solution at rt was disclosed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chloroacetyl group
Tetra-n-butylammonium fluoride
Chemoselective deprotection
The chloroacetyl (ClAc) group was widely used as temporary
protecting group in carbohydrate chemistry. It could be orthogo-
nally compatible with other acyl protecting groups, such as acetyl,
benzoyl, pivaloyl, and levulinoyl.1 The frequently-used regent for
cleaving chloroacetyl group is thiourea.2 Other highly selective
and efficacious dechloroacetylation regents, such as hydrazine
dithiocarbonate (HDTC),3 diazabicyclo[2.2.2]octane (DABCO),4 1-
selenocarbamoylpiperidine,5 and sodium borohydride (NaBH4)6
were increasingly developed in recent years. Nevertheless, these
regents have their own deficiencies which potentially impede its
broad application in the dechloroacetylation reaction. For instance,
thiourea-promoted cleavage of ClAc group demands relatively
harsh reflux conditions and long reaction time, and occasionally
gives rise to acyl group migration.7 The poor chemical stability of
HDTC requires its usage immediately after fresh preparation. The
application of DABCO was limited by the reaction media which
was solely confined to alcoholic solvents. The recently reported
1-selenocarbamoylpiperidine exhibited high chemoselectivity
and broad tolerance of reaction solvents in dechloroacetylation,
but it is also subject to the laborious preparation of selenourea
intermediate and high reaction temperature. The reductive ability
of sodium borohydride would potentially hinder its application in
carbohydrate chemistry. Thus, mild and easily handling method for
highly chemoselective cleavage of chloroacetyl group deserves fur-
ther exploitation.
Tetra-n-butylammonium fluoride (TBAF) has been widely used
in organic synthesis8–11 as an activator for O-acylation and N-alkyl-
ation,12,13 nitro-aldol formation,14 Dieckmann-type cyclization,15
and palladium-catalyzed Sonogashira reaction.16,17 More impor-
tantly, it served as a specific regent for the efficient cleavage of var-
ious silyl protecting groups, including tert-butyldimethylsilyl
(TBDMS),18 tert-butyldiphenylsilyl (TBDPS),19 and triisopropylsilyl
(TIPS)20 groups. TBAF-promoted unusual cleavage of carbamate
and benzoyl in THF or DMF solution has also been observed.21–24
In this study, we present a novel application of TBAF for the effi-
cient and selective cleavage of chloroacetyl protecting group from
various organic substrates.
In an attempt to selectively remove TBDMS protecting group
from
isopropyl
4-O-benzoyl-3-O-tert-butyldimethylsilyl-2-O-
chloroacetyl-1-thio-
a
-L
-rhamnopyranoside (1)25 with commer-
cially available 1 M TBAF solution in THF at rt, we surprisingly
found that the ClAc group on C-2 was also efficiently cleaved and
the corresponding 2,3-diol 2 was obtained in 90% isolated yield (Ta-
ble 1, entry 1). This finding encouraged us to investigate the appli-
cation and scope of TBAF-promoted dechloroacetylation by
utilizing a diverse range of substrates which have ClAc protecting
group in different chemical environments (Table 1). The experi-
mental results demonstrated that this new method was effective
to most of the substrates and the reaction finished in 2 h. Protecting
groups, such as acetyl, benzoyl, benzyl, benzylidene, isopropyli-
dene, and trityl group, were compatible under cleavage reaction
conditions; whereas, as previously reported,18,23 the silyl ether
and base-labile fluorenylmethyloxycarbonyl (Fmoc) group were
simultaneously removed with ClAc group (entries 1 and 6).
⇑
Corresponding authors. Tel.: +86 531 88362809; fax: +86 531 88363002 (G.G.).
E-mail addresses: guofenggu@sdu.edu.cn (G. Gu), duyuguo@rcees.ac.cn (Y. Du).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.09.033

2802
G. Gu et al. / Carbohydrate Research 346 (2011) 2801–2804
Table 1
TBAF-promoted cleavage of chloroacetyl protection group in THF
Entry
Substratea
Product
Time (h)
1.0
Yieldb (%)
1
90
2
3
2.0
2.0
93
92
4
5
1.0
2.0
94
87
6
1.5
90
7
8
1.0
2.0
84
91
9
2.5
1.0
83
78
10
11
12
4.0
50c
38
12
a
b
c
MP: 4-methoxyphenyl; Tr: triphenylmethyl.
Isolation yield.
Decomposition with prolonged reaction time.
Moreover, subjection of the protected sugar derivatives 1, 3, 5, 7,
9,26 11, 13, and 15 to this method afforded the products 2, 4,27
6,28 8,29 10,30 12,31 14,32 and 16,33,34 respectively, in high yields
and excellent selectivities (entries 1–8). Furthermore, the different
cleavage efficiencies were also observed for the non-carbohydrate
derivatives. Dechloroacetylation of gibberellin derivative 17 and

G. Gu et al. / Carbohydrate Research 346 (2011) 2801–2804
2803
hexaethylene glycol azide derivative 19 afforded the desired prod-
1.4.2. Isopropyl 4-O-chloroacetyl-2,3-O-isopropylidene-1-thio-
uct 1835 and 2036 in the good yields of 83% and 78%, respectively
(entries 9 and 10). The 3-O-chloroacetyl ursolic acid benzyl ester
21 furnished the product 2237 in moderate yield (entry 11), while
the chloroacetylated 6-azido-1-hexanol 23 produced 2438,39 only
in the yield of 38% with prolonged reaction time over 12 h (entry
12). We ascribed this efficiency differences to the substrate solubil-
ity effect40 and/or the inductive electron-attractive effect41,42 from
oxygen atoms in the substrates, and it could be triggered by a nucle-
ophilic attacking of fluoride anion to the carboxyl group.21
a-L-rhamnopyranoside (3)
Yield: 96%; [
a]
À49 (c 4.0, CHCl3); 1H NMR (600 MHz): d 5.60
D
(s, 1H, H-1), 4.96 (dd, 1H, J 10.0, 7.8 Hz, H-4), 4.20 (d, 1H, J
5.2 Hz, H-2), 4.19–4.14 (m, 2H, H-3, H-5), 4.12, 4.09 (2d, 2 Â 1H,
ClCH2CO), 3.09–3.03 (m, 1H, CH(CH3)2), 1.58, 1.34 (2s, 2 Â 3H,
C(CH3)2), 1.35, 1.30 (2d, 2 Â 3H, J 6.8 Hz, CH(CH3)2), 1.18 (d, 3H, J
6.3 Hz, H-6); 13C NMR (150 MHz): d 166.6, 109.9, 79.3, 77.1, 77.0,
75.2, 64.2, 40.8, 34.9, 27.7, 26.5, 23.4, 23.2, 16.8; Anal. Calcd for
C14H23ClO5S: C, 49.62; H, 6.84. Found: C, 49.87; H, 6.75.
In summary, a highly efficient method for dechloroacetylation
of various sugar substrates with TBAF has been developed. The
mild reaction conditions, experimental simplicities, and excellent
yields are major advantages of this new method. We believe that
this method has potential applications in orthogonal protection–
deprotection manipulation for oligosaccharide synthesis.
1.4.3. 3-O-Chloroacetyl-1,2;5,6-di-O-isopropylidene-a-D-
glucofuranose (5)
Yield: 93%; [
a]
À24 (c 10, CHCl3); 1H NMR (600 MHz): d 5.88
D
(d, 1H, J 3.6 Hz, H-3), 5.32 (d, 1H, J 1.9 Hz, H-1), 4.52 (d, 1H, J
3.6 Hz, H-4), 4.22–4.18 (m, 2H), 4.12–4.06 (m, 3H), 4.00–3.97 (m,
1H), 1.51, 1.39, 1.30 (3s, 4 Â 3H, 2C(CH3)2); 13C NMR (150 MHz):
d 166.0, 112.4, 109.4, 105.0, 83.1, 79.7, 77.6, 72.2, 67.3, 40.6,
26.8, 26.6, 26.2, 25.2; Anal. Calcd for C14H21ClO7: C, 49.93; H,
6.29. Found: C, 49.81; H, 6.44.
1. Experimental
1.1. General methods
1.4.4. 3-O-Chloroacetyl-1,2-O-isopropylidene-5-O-trityl-a-D-
Optical rotations were determined at 25 °C with a WZZ-2S auto-
matic polarimeter. 1H NMR and 13C NMR spectra were recorded
with Bruker 400 and 600 spectrometers for solutions in CDCl3.
Chemical shifts are given in ppm downfield from internal Me4Si.
Thin-layer chromatography (TLC) was performed on silica gel
HF254 with detection by charring with 30% (v/v) H2SO4 in MeOH
or in some cases by a UV detector.
xylofuranose (7)
Yield: 88%; [
a]
D À16 (c 10, CHCl3); 1H NMR (600 MHz): d 7.44–
7.27 (m, 15H, Ph), 5.91 (d, 1H, J 3.6 Hz, H-3), 5.48 (d, 1H, J 2.8 Hz, H-
1), 4.56 (m, 1H, H-4), 4.53 (d, 1H, J 3.6 Hz, H-2), 3.80, 3.66 (2d,
2 Â 1H, J 14.4 Hz, ClCH2CO), 3.55 (dd, 1H, J 9.0, 5.2 Hz, H-5a),
3.21 (t, 1H, J 9.0 Hz, H-5b), 1.60, 1.35 (2s, 2 Â 3H, C(CH3)2); 13C
NMR (150 MHz): d 165.9, 143.4, 128.6, 127.8, 127.2, 112.3, 104.7,
86.9, 83.1, 77.8, 77.4, 59.9, 40.3, 26.7, 26.2; Anal. Calcd for
1.2. General procedure for TBAF-promoted dechloroacetylation
C29H29ClO6: C, 68.43; H, 5.74. Found: C, 68.57; H, 5.91.
To a solution of the chloroacetylated substrate (0.1 mmol) in
THF (4 mL) was added 1 M TBAF solution in THF (2.0 equiv per ClAc)
at rt. The reaction mixture was stirred at conditions mentioned in
Table 1, and then concentrated under reduced pressure. The corre-
sponding residue was diluted with EtOAc (15 mL), washed by H2O
and brine. The organic phase was dried over Na2SO4, concentrated,
and the resulting residue was purified on column chromatography
to yield the desired product (see Table 1).
1.4.5. Isopropyl 4,6-O-benzylidene-2-O-chloroacetyl-3-O-
fluorenylmethyloxycarbonyl-1-thio-b- -galactopyranoside (11)
Yield: 90%; [
D +33 (c 6.0, CHCl3); 1H NMR (400 MHz): d 7.74–
D
a]
7.20 (m, 13H, Ph), 5.55 (t, 1H, J 9.9 Hz, H-2), 5.49 (s, 1H, PhCH), 4.89
(dd, 1H, J 9.9, 3.5 Hz, H-3), 4.56 (d, 1H, J 9.9 Hz, H-1), 4.47 (d, 1H, J
3.5 Hz, H-4), 4.34–4.28 (m, 3H, H-6a, CH2 of Fmoc), 4.24 (t, 1H, J
7.4 Hz, CH of Fmoc), 4.03 (s, 2H, ClCH2CO), 3.99 (d, 1H, J 12.5 Hz,
H-6b), 3.50 (s, 1H, H-5), 3.31–3.27 (m, 1H, CH(CH3)2), 1.38, 1.27
(2d, 2 Â 3H, J 6.6 Hz, C(CH3)2); 13C NMR (100 MHz): d 165.9,
154.3, 143.1, 141.3, 137.4, 129.2, 128.2, 127.9, 127.3, 127.2,
126.4, 125.3, 125.2, 120.1, 101.1, 82.8, 76.4, 73.4, 70.4, 69.7, 69.0,
68.8, 65.6, 46.6, 40.7, 34.9, 24.8, 23.6; Anal. Calcd for C33H33ClO8S:
C, 63.40; H, 5.32. Found: C, 63.67; H, 5.03.
1.3. General procedure for preparation of the chloroacetylated
substrates
To a solution of the corresponding hydroxyl group of various
substrates (0.2 mmol) in pyridine/CH2Cl2 (v/v 1:1, 6 mL) at 0 °C
was added chloroacetic anhydride (1.2 equiv). The reaction mix-
ture was stirred under these conditions until TLC indicated the
completion of the reaction. The reaction mixture was diluted with
CH2Cl2 (20 mL), and then washed by 1 M HCl, saturated aqueous
NaHCO3 and brine, respectively. The organic phase was dried over
Na2SO4, concentrated and purified by column chromatography
using ethyl acetate–petroleum ether as the eluents to furnish the
chloroacetylated product in high yield.
1.4.6. 1,2,4-Tri-O-acetyl-3-O-choroacetyl-
Yield: 95%; [
+21 (c 5.0, CHCl3); 1H NMR (400 MHz): d 6.27
(d, 0.5H, J 3.6 Hz, H-1
0.5H, J 9.9 Hz, H-3 ), 5.27 (t, 0.5H, J 8.5 Hz, H-3b), 5.11–4.99 (m,
2H, H-2, 4), 4.16 (dd, 0.5H, J 12.0, 5.1 Hz, H-5a ), 4.02 (s, 2H,
ClCH2CO), 3.95 (dd, 0.5H, J 11.2, 6.0 Hz, H-5ab), 3.72 (t, 0.5H, J
D-xylopyranose (13)
a
]
D
a
), 5.72 (d, 0.5H, J 7.1 Hz, H-1b), 5.51 (t,
a
a
11.2 Hz, H-5bb), 3.54 (dd, 0.5H, J 12.0, 8.7 Hz, H-5ba), 2.19, 2.11,
2.07, 2.06, 2.05, 2.03 (6s, 6 Â 1.5H, 3Ac); 13C NMR (100 MHz): d
169.7, 169.6, 169.3, 169.0, 168.9, 168.8, 166.8, 166.5, 92.0, 89.1,
73.1, 71.4, 69.4, 69.1, 68.4, 68.1, 62.8, 60.5, 40.4, 20.8, 20.7, 20.6,
20.5, 20.4, 20.3; Anal. Calcd for C13H17ClO9: C, 44.27; H, 4.86.
Found: C, 44.11; H, 5.04.
1.4. Characteristic data of new compounds
1.4.1. Isopropyl 4-O-benzoyl-1-thio-a-L-rhamnopyranoside (2)
Yield: 90%; [
a
]
À135 (c 1.5, CHCl3); 1H NMR (400 MHz): d
1.4.7. 4-Methoxyphenyl 2,3,6-tri-O-benzyl-4-O-chloroacetyl-b-D-
glucopyranoside (15)
D
8.08–7.45 (m, 5H, Ph), 5.41 (d, 1H, J 1.0 Hz, H-1), 5.04 (t, 1H, J
9.4 Hz, H-4), 4.42–4.36 (m, 1H, H-5), 4.11–4.07 (m, 1H, H-2),
4.02–3.96 (m, 1H, H-3), 3.27 (d, 1H, J 5.4 Hz, –OH), 3.13–3.07 (m,
1H, CH(CH3)2), 2.76 (d, 1H, J 3.6 Hz, –OH), 1.36, 1.35 (2d, 2 Â 3H,
J 6.8 Hz, CH(CH3)2), 1.30 (d, 3H, J 6.2 Hz, H-6); Anal. Calcd for
Yield: 84%; [
a
]
À13 (c 9, CHCl3); 1H NMR (600 MHz): d 7.41–
D
7.27 (m, 15H, Ph), 7.08, 6.86 (2d, 2 Â 2H, J 9.0 Hz, Ph), 5.12 (t, 1H,
J 9.6 Hz, H-4), 5.07, 4.87 (2d, 2 Â 1H, J 10.9 Hz, CH2Ph), 4.93 (d,
1H, J 7.8 Hz, H-1), 4.90, 4.67 (2d, 2 Â 1H, J 11.6 Hz, CH2Ph), 4.53,
4.50 (2d, 2 Â 1H, J 11.9 Hz, CH2Ph), 3.81–3.78 (m, 4H), 3.71 (t,
C
16H22O5S: C, 58.87; H, 6.79. Found: C, 58.95; H, 6.58.

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G. Gu et al. / Carbohydrate Research 346 (2011) 2801–2804
1H, J 9.0 Hz), 3.69–3.63 (m, 2H), 3.62–3.58 (m, 3H); 13C NMR
(150 MHz): d 166.2, 155.5, 151.3, 118.5, 114.6, 102.7, 81.9, 75.3,
75.2, 73.7, 73.0, 72.5, 69.6, 65.5, 55.6; Anal. Calcd for C36H37ClO8:
C, 68.29; H, 5.89. Found: C, 68.06; H, 5.73.
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1.4.8. Compound 17
Yield: 87%; [a]
+8 (c 5.0, CHCl3); 1H NMR (400 MHz): d 7.36–
D
7.33 (m, 5H, Ph), 5.16, 5.12 (2d, 2 Â 1H, J 12.2 Hz, CH2Ph), 5.02
(br s, 1H), 4.96 (s, 1H), 4.80 (s, 1H), 4.08, 4.04 (2d, 2 Â 1H, J
14.4 Hz, ClCH2CO), 3.15 (d, 1H, J 10.8 Hz), 2.72 (d, 1H, J 10.8 Hz),
2.62 (br t, 1H, J 6.4 Hz), 1.02 (s, 3H, CH3); 13C NMR (100 MHz): d
176.4, 172.1, 166.6, 156.5, 135.4, 128.6, 128.5, 107.5, 93.5, 73.6,
66.8, 53.7, 53.2, 51.9, 51.6, 51.5, 44.3, 40.8, 38.8, 36.7, 31.3, 27.6,
25.4, 16.1, 14.6; Anal. Calcd for C28H31ClO6: C, 67.40; H, 6.26.
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1.4.9. 17-Azido-3,6,9,12,15-pentaoxaheptadecyl 2-chloroacetate
(19)
Yield: 93%; 1H NMR (600 MHz): d 4.31 (t, 2H, J 5.0 Hz), 4.08 (s,
2H, ClCH2CO), 3.70 (t, 2H, J 4.6 Hz), 3.66–3.54 (m, 18H), 3.35 (t,
2H, J 5.0 Hz); 13C NMR (150 MHz): d 167.3, 70.6 (5C), 70.5 (3C),
70.0, 68.7, 65.1, 50.6, 40.8; Anal. Calcd for C14H26ClN3O7: C,
43.81; H, 6.83; N, 10.95. Found: C, 43.68; H, 6.98; N, 10.70.
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7.32 (m, 5H, Ph), 5.28 (t, 1H, J 3.6 Hz), 5.10, 5.05 (2d, 2 Â 1H, J
12.6 Hz, CH2Ph), 4.57 (t, 1H, J 6.5 Hz, H-3), 4.07, 4.03 (2d, 2 Â 1H,
J 14.6 Hz, ClCH2CO), 2.90 (dd, 1H, J 13.9, 4.1 Hz), 1.14, 0.92, 0.91,
0.89, 0.88, 0.87, 0.84, 0.61 (7s, 7 Â 3H, 7CH3); 13C NMR
(100 MHz): d 177.4, 167.1, 143.7, 136.4, 128.4, 128.0, 127.9, 12.3,
65.9, 55.3, 47.5, 46.7, 45.8, 41.7, 41.4, 41.2, 39.3, 38.0, 37.9, 36.9,
33.9, 33.1, 32.6, 32.4, 30.7, 28.0, 27.6, 25.8, 23.6, 23.4, 23.0, 18.2,
16.9, 16.6, 15.3; Anal. Calcd for C39H55ClO4: C, 75.15; H, 8.89.
Found: C, 75.38; H, 8.71.
1.4.11. 6-Azidohexyl 2-chloroacetate (23)
Yield: 90%; 1H NMR (600 MHz): d 4.16 (t, 2H, J 6.6 Hz), 4.04 (s,
2H, ClCH2CO), 3.24 (t, 2H, J 6.9 Hz), 1.68–1.62 (m, 2H), 1.60–1.55
(m, 2H), 1.42–1.36 (m, 4H); 13C NMR (150 MHz): d 167.3, 66.0,
51.3, 40.8, 28.6, 28.3, 26.2, 25.3; Anal. Calcd for C8H14ClN3O2: C,
43.74; H, 6.42; N, 19.13. Found: C, 43.88; H, 6.57; N, 18.85.
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Acknowledgments
This work was supported by NNSF of China (Projects 21002060
and 20872172) and Specialized Research Fund for the Doctoral
Program of Higher Education (No. 200804221020).