Selective removal of 2,2,2-trichloroethyl- and 2,2,2- trichloroethoxycarbonyl protecting groups with Zn-N-methylimidazole in the presence of reducible and acid-sensitive functionalities

Article abstract of DOI:10.1016/j.tetlet.2004.10.026

Activated zinc dust in the presence of N-methylimidazole in ethyl acetate or acetone at reflux or room temperature removes 2,2,2-trichloroethyl- and 2,2,2-trichloroethoxycarbonyl protecting groups while azido-, nitro-, chloro-, phenacyl-, and tert-butyl ester functionalities as well as double bonds remain intact.

Full text of DOI:10.1016/j.tetlet.2004.10.026

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9095–9097
Selective removal of 2,2,2-trichloroethyl- and
2,2,2-trichloroethoxycarbonyl protecting groups with
Zn–N-methylimidazole in the presence of reducible and
acid-sensitive functionalities
*
Laszlo Somsak, Katalin Czifrak and Edit Veres
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Department of Organic Chemistry, University of Debrecen, H-4010, POB 20, Debrecen, Hungary
Received 25 August 2004; revised 27 September 2004; accepted 5 October 2004
Abstract—Activated zinc dust in the presence of N-methylimidazole in ethyl acetate or acetone at reflux or room temperature
removes 2,2,2-trichloroethyl- and 2,2,2-trichloroethoxycarbonyl protecting groups while azido-, nitro-, chloro-, phenacyl-, and
tert-butyl ester functionalities as well as double bonds remain intact.
Ó 2004 Elsevier Ltd. All rights reserved.
Removal of 2,2,2-trichloroethyl- (TCE) and 2,2,2-tri-
chloroethoxycarbonyl (Troc) protecting groups is based
on a reductive elimination process.1 This feature makes
this kind of protection orthogonal to several other pro-
tecting groups.1b Originally, TCE and Troc were
removed by Zn in 90% aqueous AcOH,2 but several
modifications such as the use of Zn in MeOH, Zn in buff-
ered THF–H2O, Zn–Cu or Zn–Ag couples in MeOH,
Zn–Pb in THF have been reported.1 These procedures
are carried out under protic (in some cases acidic) condi-
tions. In one specific case, for the cleavage of bis-trichlo-
roethyl-acetals, Zn was reported to be effective in EtOAc
or THF without any additional reagent.3 For eliciting the
reductive elimination many other reagent systems have
been applied: Li in liquid NH3, SmI2 in THF, Na–Hg
in THF–MeOH, Cd in AcOH–DMF, Cd–Pb in AcOH,
or electrolysis.1 Some of these methods are performed
under aprotic conditions, however, even those cannot
be used with molecules having functional groups prone
to reduction under the given circumstances.4 Thus, the
known deprotection conditions do not allow easily reduc-
ible or acid-sensitive groups to be retained in substrates.
Zn–AcOH conditions gave a-amino acid 25 as expected.
Applying Zn in EtOAc brought about no change. When
Zn in the presence of N-methylimidazole6 (NMI) in
refluxing EtOAc was tried, an a-azido carboxylic acid
derivative 3 was isolated as indicated by the 2130and
3000–3500cmÀ1 absorptions for the N3 and the COOH
groups, respectively, in the IR spectrum. This finding
prompted us to test if these conditions could be applied
with other substrates.
In trichloroethyl carbamate 47 the azide was easier to
reduce with Zn–AcOH than to remove the Troc protec-
tion as shown by the formation of glycosylamine 5. The
Zn–NMI system left the azide untouched and 68 was
formed accompanied by 7 which could be the result of
an O/N-acetyl migration.
Further experiments were carried out with aromatic
model compounds. The nitro group of TCE ester 8
and Troc derivatives 11 and 14 was reduced with Zn–
AcOH to give 9, 12, and 15, respectively, but survived
with Zn–NMI as indicated by the deprotected products
10, 13, and 16, respectively. Neither conditions removed
the aromatic chloride of 17 as shown by the formation
of 18 in both reactions.
In the course of a project to elaborate synthetic methodo-
logy to obtain anomeric a-amino acid derivatives, TCE
ester 15 (Table 1) needed to be deprotected. The classic
The double bond in 19 was partially reduced by zinc in
90% acetic acid to give a mixture of 20 and 21. On the
other hand removal of the TCE ester gave only 21 both
under Zn–glacial acetic acid and Zn–NMI conditions.
*
Corresponding author. Tel.: +36 525129002348; fax: +36
52453836; e-mail: somsak@tigris.unideb.hu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.026

Table 1. Removal of 2,2,2-trichloroethyl- or 2,2,2-trichloroethoxycarbonyl groups with zinca
Starting material
Products (yield) under the specified reaction conditions
A: Zn, 90% aq AcOH, 0°C B: Zn, glacial AcOH, rt
Cb: Zn–N-methylimidazole (NMI)
Solvent, temp, eq NMI, reaction
time
OAc
AcO
OAc
O
OAc
O
AcO
AcO
AcO
AcO
EtOAc, reflux, 3 NMI, 8h
O
NH2
CO2H
N3
N3
AcO
1
4
2 B: 2h (45%)
5 B: 2h (68%)
3 (59%)
AcO
AcO
AcO
CO2CH2CCl3
CO2H
OAc
O
OAc
O
OAc
O
OAc
O
AcO
AcO
AcO
AcO
AcO
AcO
6 (43%) + AcO
7 (25%) EtOAc, reflux, 3 NMI, 6h
NH2
N3
N3
N3
HO
NHCO2CH2CCl3
CO2CH2CCl3
NHCOOCH2CCl3
NH2
CO2H
NHAc
CO2H
8
9 A: 1h (49%) B: 2h (66%)
10 (61%)
13 (59%)
16 (80%)
18 (60%)
21 (62%)
24 (54%)
Acetone, rt, 3 NMI, 5d
O2N
O2N
O2N
Cl
H2N
H2N
H2N
Cl
O2N
O2N
O2N
Cl
OH
OCO2CH2CCl3
N(CO2CH2CCl3)2
N(CO2CH2CCl3)2
OH
11
14
17
19
22
12 A: 18h (63%) B: 2h (45% 12 + 13 5:1)
EtOAc, reflux, 3 NMI, 3.5h
EtOAc, reflux, 1 NMI, 20h
EtOAc, reflux, 3 NMI, 1h
Acetone, reflux, 3 NMI, 5h
EtOAc, rt, 3 NMI, 27h
NH2
NH2
15 A: 0.5h (95%)
NH2
NH2
18 B: 0.5h (81%)
CO2CH2CCl3
CO2H
CO2H
A: 24h (65% 20 + 21 1:10) B: 1h (80 %21)
CO2CH2CCl3
CO2H
CO2H
CO2H
23 A: 5h (83%)
CO2CH2C(=O)Ph
CO2CH2C(=O)Ph
Cl3CCH2OCONHCH2CO2t-Bu 25
H2NCH2CO2t-Bu 26 (57%)
EtOAc, reflux, 3 NMI, 6h
a Without any additive, activated Zn in EtOAc at reflux temperature caused no change in the starting materials.
b Typical reaction conditions: the starting material (0.5mmol) was dissolved in dry solvent (3–5ml), Zn dust (5mmol, activated by washing with 2M HCl, water, acetone, ether, then dried) and NMI were
added and the mixture was vigorously stirred (for solvent, NMI equivalents, reaction temperature and time see Table 1). Workup: filtration through Celite, (in the case of products of acidic character,
1
acidification by dilute HCl), washing with water, drying, evaporation of the solvent, followed by crystallization or column chromatography. Products 3 and 5–7 were characterized by IR, H and 13C
NMR spectra (see electronic supplementary information). Products from reactions with model compounds were identified by comparing their 1H NMR spectra with those of authentic samples.

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L. Somsak et al. / Tetrahedron Letters 45 (2004) 9095–9097
9097
ski, P. Protecting Groups; Thieme: Stuttgart, New York,
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2. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;
Phenacyl groups are used for the protection of carboxy-
lic acids and phenols, and their removal can also be
effected by Zn–AcOH.1 Trichloroethyl-phenacyl phtha-
late 22 was cleaved to phthalic acid 23 by zinc in 90%
aq. AcOH as expected. The use of the Zn–NMI system,
however, left the phenacyl moiety intact and removed
the TCE protection only resulting in 24.
Oppolzer, W.; Ramage, R.; Rangamathan, S.; Vorbruggen,
¨
H. J. Am. Chem. Soc. 1966, 88, 852–853.
3. Isidor, J. L.; Carlson, R. M. J. Org. Chem. 1973, 38, 554–
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4. For example, –N3 and –NO2 can be reduced by Zn (Pathak,
D.; Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Chem. Lett.
2000, 816–817; Lin, W. Q.; Zhang, X. M.; Ze, H.; Yi, J.;
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2003, 5, 25; Schro¨ter, R. Reduktion von Nitroverbindungen
zu Aminen—Reduktion mit Zink. In Methoden der Organis-
Troc-N-Gly-Ot-Bu 25 was also deprotected by Zn–NMI
to give glycine tert-butyl ester 26 demonstrating the sur-
vival of an acid sensitive group under the new conditions.
In summary, Zn–N-methylimidazole in an aprotic sol-
vent represents a new reagent system for the selective
removal of TCE and Troc protecting groups in the
presence of azido-, nitro-, chloro-, phenacyl-, and tert-
butyl ester functionalities as well as double bonds.
chen Chemie (Houben-Weyl); Muller, E., Ed.; Thieme:
¨
Stuttgart 1957; Vol. XI/1, pp 463–469); or SmI2 (Benati, L.;
Montevecchi, P. C.; Nanni, D.; Spagnolo, P.; Volta, M.
Tetrahedron Lett. 1995, 36, 7313–7314; Goulaouic-Dubois,
C.; Hesse, M. Tetrahedron Lett. 1995, 36, 7427–7430;
Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1991, 32,
1699–1702; Zhong, W. H.; Zhang, Y. M.; Chen, X. Y. J.
Chem. Res. (S) 2000, 532–534); double bonds by Zn
(Marchand, A. P.; Reddy, G. M. Synthesis 1991, 198–
200).
Acknowledgements
This work was supported by the Hungarian Scientific
Research Fund (Grant: OTKA T46081).
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´
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5. Czifrak, K.; Szilagyi, P.; Somsak, L. Tetrahedron: Asym-
metry, Carbohydrate Special Issue, submitted for
publication.
6. Up to now the only use of this reagent system was described
in the carbohydrate field for the preparation of glycals:
Supplementary data
´
Somsak, L. Carbohydr. Res. 1989, 195, C1–C2; Somsak, L.;
Nemeth, I. J. Carbohydr. Chem. 1993, 12, 679–684; for a
´
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.10.026.
´
´
review see: Somsak, L. Chem. Rev. 2001, 101, 81–135. For
reactivity enhancement of alkylzinc reagents in the presence
of NMI see as leading references: Inoue, S.; Yokoo, Y. J.
Organomet. Chem. 1972, 39, 11–16; Zhou, J. R.; Fu, G. C.
J. Am. Chem. Soc. 2003, 125, 12527–12530.
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1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
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8. Bertho, A.; Revesz, A. Liebigs Ann. Chem. 1953, 581, 161–
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