A simple and selective method for the O-AcCl removal using sodium borohydride

Article abstract of DOI:10.1016/j.tetlet.2010.02.057

A deprotection of chloroacetylated alcohols using NaBH₄ is reported. The free alcohols are obtained in excellent yields. The reaction was performed on primary, secondary, alkyl, allyl, benzylic alcohols and phenols. The compatibility of the method with other sensitive or protective groups is demonstrated.

Full text of DOI:10.1016/j.tetlet.2010.02.057

Tetrahedron Letters 51 (2010) 2115–2118
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A simple and selective method for the O-AcCl removal using
sodium borohydride
*
Emmanuelle Villedieu, Chrystel Lopin-Bon, Sabine Berteina-Raboin
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005, BP 6759, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A deprotection of chloroacetylated alcohols using NaBH4 is reported. The free alcohols are obtained in
excellent yields. The reaction was performed on primary, secondary, alkyl, allyl, benzylic alcohols and
phenols. The compatibility of the method with other sensitive or protective groups is demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 December 2009
Revised 5 February 2010
Accepted 10 February 2010
Available online 18 February 2010
1. Introduction
NaBH4 (1equiv), EtOH
0°C
ROAcCl
The chloroacetyl (AcCl) is an important group for the synthesis
of various compounds and is commonly used in carbohydrate
chemistry. This protecting group is used for the temporary protec-
tion of hydroxyl groups, as it is a very base-sensitive group due to
the inductive effect of the chlorine substituent and can be selec-
tively removed in the presence of other acyl functions by a number
of methods,1 mainly using a nucleophilic attack. In addition to
aqueous ammonia,2 hydrazine acetate,3 hydrazine dithiocarbonate
(HDTC)4, or 1-selenocarbamoylpiperidine5 for example, the most
widely used deprotection reagent is thiourea.6 Deprotections using
tertiary amine as a base were reported too.7 The latter reactions al-
low the presence of other protecting groups but require either rel-
atively long reaction times and/or high temperature, or
preparation of the reagent just before use,8 or large excess of re-
agents which cannot be compatible to sensitive compounds.
ROH
Scheme 1. General scheme for the NaBH4 cleavage of O-AcCl protective groups.
the corresponding deprotected alcohols in excellent 71–95% yield.
Sensitive compounds such as epoxides or sugars were deprotected
in the same way, in very good yields.
The orthogonality of the deprotection was then examinated
(Table 2) and structures bearing other protective groups such as
acyl groups (entries 1, 2 and 3), silylethers (entries 4 and 5) or
other kinds (entries 6 and 7) were treated. It appeared that no
other groups were affected.
Continuing this investigation, it was noticed that an equimolar
amount of hydride (0.25 equiv of NaBH4) allowed the deprotection
of 1 to 1a in 73% yield (Scheme 2).
It is noteworthy to mention that the selectivity of the O-AcCl
deprotection by NaBH4 was also studied using compound 7 which
bears both aromatic and alkyl O-AcCl protection. The reaction was
performed with 0.25 equiv of NaBH4 in EtOH at 0 °C. Under these
conditions, only the cleavage of the protected phenol was ob-
served in 84% yields (Scheme 3). The structure of 7b was estab-
lished by the comparison between 1H NMR, 13C NMR of 7, 7a
and 7b (see analytical data of 7, 7a and 7b).10–12 Particularly,
we observed in 1H NMR spectrum of 7b, recorded in CDCl3, the
disappearance of a singlet at 4.29 ppm (corresponding to the
chloromethyl–CH2Cl) and the appearance of a broad signal at
5.93 ppm corresponding to the OH, the shifts of CH2 groups did
not change.
2. Results and discussion
In addition to the existing methods for deprotecting the O-AcCl
group, we propose an alternative to deprotect AcCl under soft con-
ditions. Sodium borohydride (NaBH4) turned out to be selective,
fast and easy to handle (Scheme 1). The reaction provides the cor-
responding alcohol in very good yields and can be performed at
low temperatures.
The O-AcCl deprotection was performed using chloroacetylger-
aniol as a typical example.9
The scope and limitation of the method were investigated on
various primary, secondary, alkyl, allyl, benzylic alcohols and phe-
nols (Table 1). In most cases, the treatment of O-AcCl-protected
alcohols with 1 equiv NaBH4 in EtOH at low temperature gave
As we observed the selectivity of deprotection of phenolic over
alkyl O-AcCl, we decided to study it for other combinations
(Schemes 4 and 5).
It appeared that the selective cleavage of phenolic esters over
homobenzyl (Scheme 3) or benzyl esters (Scheme 4) was possible.
* Corresponding author. Tel.: +33 2 38 49 48 56; fax: +33 2 38 41 72 81.
E-mail address: sabine.berteina-raboin@univ-orleans.fr (S. Berteina-Raboin).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.057

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E. Villedieu et al. / Tetrahedron Letters 51 (2010) 2115–2118
Table 1
Cleavage of the O-AcCl-protected compounds with NaBH4
Entry
1
Substrate
Product
Yielda (%)
80
OAcCl
OH
OH
1a
1
OAcCl
2
79
O
O
2a
2
OAcCl
OH
3
4
95
95
3
3a
OAcCl
OH
4
4a
Br
Br
OAcCl
OH
5
6
96
96
5
5a
OAcCl
OH
O
O
6a
6
ClAcO
HO
7
8
81
86
OH
OAcCl
7a
OH
7
OAcCl
O
O
OMP
OMP
HO
HO
BzO
BzO
OBz
OBz
8
8a
a
Yields are given in isolated products after short column chromatography, all compounds were either compared with known data in the literature or if new, fully
characterized by IR, 1H NMR, 13C NMR and MS.
0,25 equiv NaBH4
EtOH
OAcCl
OH
1
1a
NaBH4 (1equiv.)
80%
NaBH4 (0,25 equiv.) 73%
Scheme 2. Results of NaBH4 cleavage of 1.
HO
ClAcO
0.25 equiv. NaBH4
EtOH, 0°C
OAcCl
OAcCl
84%
7b
7
Scheme 3. Result of NaBH4 selective cleavage of 7.
Unfortunately, no selectivity was observed for the cleavage of pri-
mary over secondary protected alcohols.
In order to conclude on the investigations on this new method
of O-AcCl cleavage, we intended to deprotect compounds bearing
both protected alcohol and carbonyl group. The treatment of
compound 18 with 0.25 equiv of NaBH4 did not lead to any
selectivity, but to a mixture of deprotection and/or reduction
(Scheme 6).

E. Villedieu et al. / Tetrahedron Letters 51 (2010) 2115–2118
2117
Table 2
Studies on the orthogonality of the cleavage of the O-AcCl-protected compounds with NaBH4
Entry
Substrate
Product
Yield (%)
ClAcO
HO
1
OBz
75
93
80
OBz
9
9a
AcO
AcO
OAcCl
2
3
OH
10a
10
11
PivO
PivO
OAcCl
OH
11a
TBDMSO
TBDMSO
OAcCl
OH
4
78
O
O
12
12a
TESO
SEMO
TESO
SEMO
5
6
91
81
OH
OAcCl
13a
14a
13
OH
OAcCl
14
OAcCl
OH
O
O
OMP
OMP
HO
7
ClAcO
71
BzO
BzO
OBz
OBz
15a
15
3. Conclusion
OAcCl
OAcCl
To conclude, we found a simple and selective method for the
cleavage of AcCl-protected alcohols using NaBH4. The reaction con-
ditions are compatible with other protective and sensitive groups.
Moreover, the protected group was removed at low temperature,
in short time, and was compatible with sensitive starting materials
and the procedure was easy to perform. The method was used to
deprotect aromatic and phenolic O-AcCl over alkyl ones. No selec-
tivity was observed for primary over secondary protected alcohols.
0.25 equiv. NaBH4
EtOH, 0°C
OH
16a
OAcCl
16
71%
Scheme 4. Result of NaBH4 selective cleavage of 16.
0.25 equiv. NaBH4
EtOH, 0°C
OAcCl
OAcCl
OH
2
+
OAcCl
OAcCl
OH
17b
90%
17a
17
:
1
Scheme 5. Result of NaBH4 non-selective cleavage of 17.
R
0.25 equiv. NaBH4
OAcCl
EtOH, 0°C
90%
R'
O
R = OAcCl, OH
R' = O, OH
18
Scheme 6. Result of NaBH4 non-selective cleavage of 18.

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E. Villedieu et al. / Tetrahedron Letters 51 (2010) 2115–2118
dried over MgSO4 and concentrated in vacuo. The residue was purified by flash
Unfortunately, it was not possible to cleave AcCl in the presence
chromatography on silica gel to afford expected geraniol in 80% yield.
10. Typical experiment protocol of chloroacetylation: Chloroacetic anhydride
(1 equiv/OH) was added to a stirred solution of commercially available 4-
hydroxyphenethyl alcohol in a mixture of pyridine/CH2Cl2 (1:3) (4 mL/mmol)
under argon at room temperature. After 2 h, addition of ice water followed by
three extractions with CH2Cl2 gave an organic solution which was washed with
brine, dried over MgSO4 and concentrated in vacuo. The residue was subjected
to a short column chromatography on silica gel to afford the corresponding
protected compound 7 in 76% yields. Analytical data for 7 are as follows. 4-[2-
(2-chloroacetyl)oxyethyl]phenyl-2-chloroacetate. 1H NMR (250 MHz, CDCl3): d
7.25 (2H, d, J = 8.5 Hz, ArH), 7.08 (2H, d, J = 8.5 Hz, ArH), 4.39 (2H, t, J = 7.0 Hz,
CH2O), 4.29, 4.05 (2 Â 2H, 2s, 2CH2Cl), 2.98 (2H, t, J = 7.0 Hz, PhCH2). 13C NMR
(62.5 MHz, CDCl3): d 167.4 (CO), 166.1 (CO), 149.3 (C), 135.6 (C), 130.2 (CH),
121.4 (CH), 66.5 (CH2O), 41.1 (CH2Cl), 41.0 (CH2Cl), 34.6 (PhCH2). IR (diamand
ATR): 2958, 1744, 1131 (cmÀ1). MS (IS) 308, 310, 313, 315 (M+18)+.
11. Compound 7a is obtained from 7 as described for 1a using 1 equiv of NaBH4.
Analytical data for 7a were in agreement with the literature: The Aldrich
Library of 13C and 1H NMR Spectra, 1st ed., Vol II; Aldrich, 1993.
12. Compound 7b is obtained from 7 as described for 1a using 0.25 equiv of NaBH4.
Analytical data for 7b are as follows. 2-(4-Hydroxyphenyl)ethyl-2-
chloroacetate. RMN 1H (250 MHz, CDCl3): d 6.98 (2H, d, J = 8.5 Hz, ArH), 6.70
(2H, d, J = 8.5 Hz, ArH), 5.93 (1H, br s, OH), 4.27 (2H, t, J = 7.0 Hz, CH2O), 3.97
(2H, s, CH2Cl), 2.81 (2H, t, J = 7.0 Hz, PhCH2). RMN 13C (62.5 MHz, CDCl3): d
167.4 (CO), 154.4 (C), 130.0 (CH), 129.5 (C), 115.4 (CH), 66.8 (CH2O), 40.8
(CH2Cl), 34.0 (PhCH2). IR (diamand ATR): 2965, 1745, 1129 (cmÀ1). MS (IS) 237,
239 (M+23)+.
of a carbonyl group without leading to the reduction.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley
& Sons, 1999. and references cited therein; Goering, B. K. Ph.D.
Dissertation, Cornell University, 1995.
2. Reese, C. B.; Stewart, J. C. M.; Van Boom, J. H.; de Leeuw, H. P. M.; Nagel, L.; de
Rooy, J. F. M. J. Chem. Soc., Perkin Trans. 1 1975, 934–942; Buchanan, J. G.; Sable,
H. Z.. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley: New
York, 1972; Vol. 2, pp 1–95.
3. Udodong, U. E.; Rao, C. S.; Fraser-Reid, B. Tetrahedron 1992, 48, 4713–4724.
4. Van Boeckel, C. A. A.; Beetz, T. Tetrahedron Lett. 1983, 24, 3775–3778.
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6. Blatter, G.; Jacquinet, J. C. Carbohydr. Res. 1996, 288, 109–125.
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Kamerling, J. P.; Vliegenthart, J. F. G. Org. Lett. 2000, 2, 701–703.
8. Smith, A. B., III; Hale, K. J.; Vaccaro, H. A.; Rivero, R. A. J. Am. Chem. Soc. 1991,
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9. NaBH4 (1 equiv) was added to
a stirred solution of chloroacetylgeraniol
(1 equiv) in EtOH under argon at 0 °C and the reaction mixture was stirred at
room temperature for 30 min. Addition of iced water followed by three
extractions with CH2Cl2 gave an organic layer which was washed with brine,