A mild deprotection of trichloroethyl carbamates using indium metal

Article abstract of DOI:10.1055/s-2002-31919

The trichloroethoxycarbonyl moiety was efficiently removed from carbamates to furnish the corresponding amines using indium metal in good to excellent yields.

Full text of DOI:10.1055/s-2002-31919

LETTER
883
A Mild Deprotection of Trichloroethyl Carbamates Using Indium Metal
M
ild Deprotecti
o
on of Trichl
m
oroethyl Carbamate
s
a
b
c
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA
Department of Chemistry, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA
National Center for Natural Products Research, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA
Fax +1(662)9155638; E-mail: mavery@olemiss.edu
Received 20 March 2002
indium was increased to 5 equiv, the reaction proceeded
to afford 84% of the desired 4-aminobenzonitrile
(Table 1, entry 2). Unfortunately, unsatisfactory results
were obtained with other substrates under the identical re-
action conditions (Table 1, entries 3 and 4), prompting us
to search for more suitable reaction conditions. The reac-
tion was improved when the solvent was changed from
MeOH–H2O (5:1) to EtOH–H2O (3:2), presumably due to
the higher boiling point of EtOH (bp 78 °C) compared to
MeOH (bp 65 °C). The most efficient deprotection of a
Troc moiety was observed in the case of Troc-protected 4-
aminobenzonitrile, requiring only 2 equiv of indium metal
and 3 equiv of NH4Cl (Table 1, entry 5).
Abstract: The trichloroethoxycarbonyl moiety was efficiently re-
moved from carbamates to furnish the corresponding amines using
indium metal in good to excellent yields.
Key words: indium, deprotection, amines, 2,2,2-trichloroethyl car-
bamates, chemoselectivity
Protection strategies using the 2,2,2-trichloroethoxycar-
bonyl (Troc) group for the masking of hydroxy and amino
groups, and the 2,2,2-trichloroethoxy group for carboxyl-
ic acids1,2 have been exceedingly useful in total synthe-
sis.3–6 Furthermore, several methods exist for the cleavage
of the Troc protecting group from carbamates. The Troc
unit can be removed by reduction with Zn metal,1,7 elec-
trolysis,8,9 Zn–Pb couple,10 Cd dust,11 Cd–Pb couple,12 co-
balt(I)-phthalocyanine anion,13 and telluride reagents.14 In
recent years, indium-mediated reduction and deprotection
reactions have received considerable attention as a conve-
nient method for effecting various organic transforma-
tions.15
Table 1 Optimization of Reaction Conditionsa
O
NH2
HN
O
CCl3
R2
R2
R1
R1
We have recently reported that deprotection of Troc- and
trichloroacetyl-protected alcohols can be carried out
chemoselectively with indium metal under mild condi-
tions.16 In an ongoing effort to develop indium-mediated
chemistry, we have found that carbamates can also be
cleaved chemoselectively under mild conditions, into the
corresponding amines using indium metal. Herein, we
wish to report the details of our studies on the release of
amines from their trichloroethyl carbamates (Scheme).
Entry R1
R2
Solvent
In
NH4Cl Yieldb
(equiv) (equiv) (%)
1 c
2
CN
H
MeOH–H2O (5:1)
MeOH–H2O (5:1)
MeOH–H2O (5:1)
MeOH–H2O (5:1)
EtOH–H2O (3:2)
2
5
5
5
2
5
10
10
10
3
49
84
22
68
98
CN
Ac
H
H
3
H
4
Ac
H
5
CN
O
a All reactions were performed at reflux.
b Isolated yields.
In, aq. NH4Cl
R
Cl
Cl
R
NH2
N
O
EtOH/H2O
reflux
c Starting material (33%) was also recovered.
H
Cl
R = aryl, alkyl
Having improved the deprotection conditions, various ar-
omatic and aliphatic carbamates were prepared by known
methods17 and subjected to the above deprotection condi-
tions. Table 2 shows that the reaction proceeded smoothly
to furnish the corresponding amines in good to excellent
yields. Deprotection of halogenated aromatic carbamates
was carried out without dehalogenation (Table 2, entries
3, 11, and 12). Under these reaction conditions, neither
ketones nor nitriles underwent reduction in spite of the re-
ductive property of indium metal (Table 2, entries 1, 7,
and 8). The reaction also led to the desired amines without
affecting methoxy groups (Table 2, entries 2, 4, 5, and 9).
Scheme
Applying the reaction conditions from our previous
work,16 deprotection of Troc-protected 4-aminobenzoni-
trile gave poor results even after 5 h of reflux, using 2
equiv of indium (Table 1, entry 1). When the amount of
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

884
T. Mineno et al.
LETTER
The release of 1-adamantylamine (Table 2, entry 6) and 2- equiv (Table 3, entry 3), the deprotection was improved
aminobiphenyl (Table 2, entry 10) required extended re- to 68% yield. The by-product in the deprotection of the
action times for completion, presumably due to steric hin- Troc group from the ortho-TBDMS derivative is from
drance.
loss of the silyl group, which does not occur with the
para-TBDMS derivative (Table 3, entry 4). Thus, entry 3
may give lower yields as a result of the contribution of
steric decompression to the enhancement of the TBDMS
group’s acid catalyzed hydrolysis rate. While acid sensi-
tive protecting groups generally tolerate the indium con-
dition, in certain instances, cleavage of the TBDMS
(Table 3, entry 7) or ketal (Table 2, entry 13) groups can
occur within short times in spite of the resistance of
TBDMS group itself for relatively long times under indi-
um condition (Table 3, entry 8). Overall, these results
demonstrate chemoselectivity in the deprotection of Troc-
protected amines with indium metal, further expanding
the array of multifunctional protecting strategies for
amines in the presence of alcohols.
To determine the selectivity of the reaction conditions,
we introduced triisopropylsilyl (TIPS), methoxyethoxy-
methyl (MEM), and t-butyldimethylsilyl (TBDMS)
groups into Troc-protected compounds and performed the
deprotection of the Troc group under the same reaction
conditions. Both TIPS- and MEM-protected alcohols
were resistant to these reaction conditions while only the
Troc group was removed in excellent yields (Table 3, en-
tries 1 and 2). When the Troc-protected aromatic amine
moiety was placed para to a more acid sensitive t-bu-
tyldimethylsilyloxy moiety (Table 3, entry 4), deprotec-
tion of the Troc group nevertheless proceeded smoothly
and in satisfactory yield. In contrast, when these two sub-
stituents were ortho to each other, the deprotecting reac-
tion of the Troc group led initially to an unacceptably low
yield. Upon increasing the amount of indium metal to 5
Table 2 Deprotection of Troc Groups Using Indiuma
Entry
1
Starting Material
Product
Time (h)
3
Yieldb (%)
98
Troc
NH
NC
NH2
NC
2
3
76
H3CO
H3CO
NH2
H
H3CO
H3CO
N
Troc
3
4
3
4
88
83
H
NH2
N
Troc
Br
Br
Troc
NH2
HN
OCH3
H3CO
OCH3
5
6
4
6
76
91
Troc
NH2
HN
H3CO
HN
Troc
NH2
7
8
3
3
93
84
Troc
NH2
HN
O
CH3
O
CH3
Troc
NH2
HN
CH3
CH3
O
O
Synlett 2002, No. 6, 883–886 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Mild Deprotection of Trichloroethyl Carbamates
885
Table 2 Deprotection of Troc Groups Using Indiuma (continued)
Entry
9
Starting Material
Product
Time (h)
3.5
Yieldb (%)
66
Troc
HN
NH2
H3CO
NH2
OCH3
OCH3
H3CO
OCH3
OCH3
10
11
6
80
86
Troc
HN
HN
2.5
Troc
NH2
Cl
Cl
12
13
2.5
2.5
86
91
NH2
Troc
HN
Br
Br
Troc
O
NH2
HN
CH3
CH3
O
O
a All reactions were performed at reflux.
b Isolated yields.
We compared our method to other N-Troc deprotecting higher yielding. Further applications of these methods are
conditions for chemoselectivity. The common method for in progress.
Troc deprotection is the use of zinc metal in acetic acid,
which is not typically used in the presence of acid-sensi-
General experimental procedure: The Troc protected amine (1
tive protecting groups.1,7 Using excess zinc in acetic acid
deprotected both Troc and TBDMS groups of the para-
TBDMS derivative leading to mixtures of products
(Table 3, entry 5). On the other hand, the silyl group of the
TBDMS protected aryl ethanol (Table 3, entry 6) was
more stable than the former silylphenoxide (Table 3, entry
5). Another mild cleavage method of Troc-carbamates to
amines using zinc and NH4OAc–THF deprotected both
protecting groups as well as required relatively longer re-
action times and large excess zinc to complete the reaction
(Table 3, entry 9).7 The other disadvantage of zinc meth-
ods is the development of a slurry during the reaction.
Overall, zinc condition not only gave lower yields be-
cause of cleavage of the silyl group but also required long-
er reaction times (Table 3, entries 5, 6, and 9).
mmol) was combined with indium powder18 (2 mmol), NH4Cl (3
mmol), and EtOH–H2O, 3:2 (5 mL). The mixture was refluxed and
monitored for completion by TLC. Indium was filtered off, and the
solvent was removed by rotary evaporation under vacuum. The res-
idue was combined with aqueous NaOH solution (1 M, 10 mL) and
extracted with ethyl acetate (3 15 mL). The combined organic lay-
ers were washed with brine and dried over anhydrous Na2SO4. The
mixture was filtered and concentrated by rotary evaporation. The
resulting residue was purified by silica gel flash column chromatog-
raphy to afford the desired amines. All products were consistent
with their required physical and spectral data.
References
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Synlett 2002, No. 6, 883–886 ISSN 0936-5214 © Thieme Stuttgart · New York

886
T. Mineno et al.
LETTER
Table 3 Chemoselective Deprotection of Troc Group
Entry
1
Starting Material
Product
Condition
Time (h)
2
Yield (%)
2 equiv In
aq. NH4Cl
91
Troc
HN
NH2
OMEM
OMEM
2
3
4
2 equiv In
aq. NH4Cl
1.5
3
92
68
93
Troc
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OTIPS
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aq. NH4Cl
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OTBDMS
OTBDMS
5
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in AcOH
24
–
Troc
HN
OTBDMS
NH
6b
7
6 equiv Zn
in AcOH
24
61
78
NH2
Troc
OTBDMS
OTBDMS
OH
2 equiv In
aq. NH4Cl
1.5
NH
Troc
NH2
OH
OTBDMS
8
9
2 equiv In
aq. NH4Cl
12
48
60
–
OTBDMS
mixturec
10 equiv Zn
NH4OAc–THF
NH
Troc
OTBDMS
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Synlett 2002, No. 6, 883–886 ISSN 0936-5214 © Thieme Stuttgart · New York