A mild and chemoselective method for deprotection of aryl acetates and benzoates under non-hydrolytic condition

Article abstract of DOI:10.1016/S0040-4020(01)00922-X

Chemoselective deprotection of aryl acetates and benzoates can be achieved under non-hydrolytic condition by treatment with K₂CO₃ in N-methyl-2-pyrrolidone (NMP) at 100°C. Selective cleavage of aryl acetates and benzoates take place in the presence of alkyl carboxylates during intramolecular competitions.

Full text of DOI:10.1016/S0040-4020(01)00922-X

TETRAHEDRON
Pergamon
Tetrahedron 57 ꢀ2001) 9343±9346
A mild and chemoselective method for deprotection of aryl
acetates and benzoates under non-hydrolytic condition
p
Asit K. Chakraborti, Lalima Sharma and Upasana Sharma
²
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research ꢀNIPER), Sector 67,
S.A.S. Nagar 160 062, India
Received 14 June 2001; revised 14 August 2001; accepted 6 September 2001
AbstractÐChemoselective deprotection of aryl acetates and benzoates can be achieved under non-hydrolytic condition by treatment with
K CO in N-methyl-2-pyrrolidone ꢀNMP) at 1008C. Selective cleavage of aryl acetates and benzoates take place in the presence of alkyl
2 3
carboxylates during intramolecular competitions. q 2001 Elsevier Science Ltd. All rights reserved.
1
17
Protection/deprotection of functional groups is one of the
most inevitable synthetic transformations. In the synthesis
of multifunctional targets the necessity of deprotection of
a particular functionality in the presence of others is
frequently desired. Amongst the many functional groups
requiring synthetic manipulation involving deprotection,
one often encounters the phenolic hydroxyl group, due to
its presence in a variety of biologically active compounds.
Thus, the masking of phenolic hydroxyl function is a
frequently desirable process in organic synthesis and
considering the ease of preparation and the availability of
starting materials, phenols are protected as acetates and
benzoates. The various methods available for deprotection
of aryl acetates/benzoates include the treatment with
alkyl ether and alkyl ester through in situ generation of
thiolate anion in a `demand based' fashion. Although
excellent selectivity was achieved, dealing with thiols is
alarming because of their radical generating ability. The
susceptibility of thiols for areal oxidation ꢀto form the corre-
1
8
sponding disul®des ) is also a potential problem with the
use of thiols. Thus we felt the need to develop a method for
ef®cient chemoselective deprotection of aryl esters using
cheap and easy to handle reagents.
As the carboxyl carbon of an ester is a hard centre, appli-
cation of the `Hard Soft Acid Base ꢀHSAB)' principle
suggests that hard nucleophiles should preferably react at
this site. Hydrolytic deprotections of the ester are amongst
the simplest and most common of all laboratory reactions
and are normally accomplished by heating the ester in either
1
9
2
3
activated zinc in MeOH, NaHTe in re¯uxing EtOH,
2-bromo-1,3,2-benzodioxaborole in DCM, BuNH in ben-
2
zene, guanidine in EtOH±DCM, N-methyl-2-dimethyl-
4
n
5
6
20
aqueous acid or base ꢀhard±hard interaction). However, in
aminoacetohydroxamic acid in THF/aqueous phosphate
buffer, p-TsOH on SiO in toluene saturated with water at
most of these cases, the harsh treatment required for these
hydrolytic cleavages are not compatible with multi-
functional substrates ꢀparticularly those with acid or alkali
labile groups).
7
2
8
n
9
8
wave irradiation, PPl/CCL in organic solvent, antibody
08C, ꢀ Bu Sn) O in re¯uxing toluene, Al O under micro-
3 2 2 3
1
0
11
1
2
13
17E8), cyclodextrine in aqueous DMSO, BiꢀIII)-
ꢀ
mandelate in DMSO at 80±1258C, YbꢀOTf)3, and
1
4
15
Carbonate anion is a hard nucleophile and we were attracted
by a recent report wherein the intermittently formed
1
6
21
natural kaolinitic clay. However, most of these methods
are applicable only to acetates, lack the selectivity between
aryl and alkyl esters, and require stringent conditions, longer
reaction times, special reagents and apparatus.
monoalkyl carbonate anion has been exploited as a nucleo-
phile for the preparation of mixed alkyl carbonates.
Although potassium carbonate in aqueous methanol has
been utilised for the deprotection of alkoxymethyl carbo-
2
2
The most strategic approach for the deprotection of aryl
esters seems to be the nucleophilic attack on the carboxyl
group. Recently we have developed an ef®cient procedure
for selective deprotection of aryl ester in the presence of aryl
nate and alkali metal carbonates/bicarbonates have been
employed for peptidic methyl, ethyl and benzyl ester depro-
2
3
tection, however, in these cases it is not certain whether
carbonate anion is the effective nucleophile as the reactions
are carried out in presence of water and the question of
maintenance of chemoselectivity between aryl and alkyl
esters remains unaddressed. The sole report available in
the literature depicting the use of alkali metal carbonates
for cleavage of aryl esters under non-aqueous medium is
Keywords: deprotection; arylacetate; benzoate; non-hydrolytic condition.
Corresponding author. Tel.: 191-0-172-214682; fax: 191-0-172-
p
214692; e-mail: niper@chd.nic.in
Project trainee from the Department of Chemistry, Lucknow University.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020ꢀ01)00922-X

9344
A.K.Chakraborti et al./ Tetrahedron 57 ꢀ2001) 9343±9346
Scheme 1.
Table 1. Reaction of 2-naphthyl benzoate with K
2
CO
3
under various conditions
a
3
b,c
Entry
1
K
2
CO
Solvent
100
Re¯ux
NMP
NMP
NMP
DMPU
DMEU
Sulfolane
DMF
Temperature ꢀ8C)
Time ꢀh)
Isolated yield ꢀ%)
1.2NMP
3
44
69
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1.2NMP
Re¯ux
1
72
1.2NMP
1.6
1.6
0.5
100
100
Re¯ux
100
100
100
100
100
3
3
0.5
3
3
3
97
90
d
1.6
1.6
1.6
1.6
1.6
1.6
100
60
55.5
83
90
33
0
1
21.6
3
4
5
3
3
DMSO
MeCN
Re¯ux
3
14
1.6
1.6
1.6
THF
THP
DME
Re¯ux
Re¯ux
Re¯ux
3
3
3
3
30
22
a
b
c
d
Equivalent amount used with respect to 2-naphthyl benzoate.
Yield of 2-naphthol.
On each occasion the unreacted starting material could be recovered.
Reaction with 2-naphthyl acetate.
2
4
from Zaugg wherein phenanthrene diacetate and resorci-
nol dibenzoate undergo selective cleavage to the corre-
sponding monoacetate or monobenzoate in the presence of
a 10% excess of Cs CO in either boiling THF ꢀ21 h) or
greater solubility in the employed solvents compared to that
of the corresponding potassium salt. As the key step of the
reaction is the nucleophilic attack at the carboxyl carbon by
the carbonate anion, we felt that activation of the ester
carbonyl through co-ordination may facilitate the formation
of the tetrahedral intermediate ꢀScheme 1). Considering the
2
3
boiling DME ꢀ10±24 h). The serious drawbacks of this
deprotection methodology are the use of costly Cs CO
and long reaction time. Therefore, we planned to modify
the deacetylation/debenzoylation procedure with an aim to
carry out the reaction with cheaper reagent and shorter
periods.
2
3
2
5
co-ordinating capability of the lithium ion we thought of
using Li CO . The poor solubility of Li CO in THF was
expected to be overcome by the use of tetrahydropyran
2
3
2
3
2
6
ꢀTHP). However, when 4-nitrophenyl benzoate and
-naphthyl acetate were treated with Li CO in THP under
2
2
3
The reason for using Cs CO in the above example was its
2
re¯ux for 6 and 16 h, respectively, no appreciable amount of
debenzoylation or deacetylation was observed. Reaction of
3
2
-naphthyl acetate with Li CO in THF in the presence of a
2 3
Table 2. Reaction of 2-naphthyl benzoate with various metal carbonates
stoichiometric amount of TMEDA or 5 mol% of 12-C-4 or
TBAI under re¯ux for 16 h did not result in any deprotec-
tion. Use of K CO in THF in the presence of 5 mol% sepa-
rately of TBAI, 18-C-6, PEG 8000 or PEG 4600 under
re¯ux for 16 h also failed to produce any desirable result.
a,b
Entry
Carbonate
Yield ꢀ%)
2
3
c
1
K
2
CO
CO
3
97 ꢀ6)
83 ꢀ2)
99
14
7
c,d
2
3
4
5
6
7
8
9
1
1
1
1
Cs
2
3
Rb
Na
Li
CaCO
MgCO
BaCO
SrCO
ZnCO
Bi
2
2
CO
CO
3
3
2
CO
3
We planned to use dipolar aprotic solvents as these should
speci®cally solvate the cation generating the `naked' car-
bonate anion and enhance the rate of the nucleophilic
attack. In order to determine the best operative conditions,
2-naphthyl benzoate was treated with K CO under various
conditions and the results are summarised in Table 1.
Amongst the various dipolar aprotic solvents employed,
excellent results are obtained with NMP, DMF and sul-
folane whereas DMEU and DMPU provided only moderate
yields. Weakly polar ethereal solvents were ineffective. The
debenzoylation is best carried out with 1.6 equiv. of K CO
3
7
7
3
3
Nil
Nil
32
Nil
Nil
Nil
27
3
0
1
2La
3
3
2 3
2
ꢀCO
ꢀCO
ꢀCO
3
)
)
3
2
3
3
´xH
2
O
Y
2
3
)
3
´xH
2
O
Reactions were carried out by treatment of the ester with 1.6 equiv. of the
carbonate in NMP at 1008C for 3 h.
a
Isolated yield of 2-naphthol.
The unreacted 2-naphthyl benzoate could be recovered on each occasion.
The ®gures in parenthesis are the yields of the product using the corre-
sponding bicarbonate.
No appreciable amount of deprotecion was observed in carrying out the
reaction at room temperature for 4 h.
2
3
b
in NMP either at 1008C for 3 h or under re¯ux ꢀ,2008C) for
0 min.
c
3
d
Various metal carbonates were used in the reaction with

A.K.Chakraborti et al./ Tetrahedron 57 ꢀ2001) 9343±9346
Table 3. Reaction of 2-naphthyl benzoate with various salts of potassium
9345
a,b
Entry
K-salt
Yield ꢀ%)
5
1
2 2 8
K S O
2
3
4
5
6
7
8
9
KSCN
17
KNO
3
9
K
K
K
3
2
3
PO
HPO
PO
4
Nil
Nil
7
Nil
Nil
Nil
4
4
KH
2
PO
4
K
K
2
2
SO
4
2
S O
3
2
´xH O
Reactions were carried out by the treatment of the ester with 1.6 equiv. of
the K-salt in NMP at 1008C for 3 h.
a
Isolated yield of 2-naphthol.
The unreacted 2-naphthyl benzoate could be recovered on each occasion.
Scheme 2.
b
bearing both aryl and alkyl ester functionalities during
intramolecular competition ꢀScheme 2). Excellent level
of selectivity was observed in that aryl acetates and aryl
benzoates are deprotected selectively in preference to
2
-naphthyl benzoate in NMP at 1008C for 3 h and the results
are summarised in Table 2. Although Rb CO and Cs CO
3
2
3
2
provided comparable results, others such as Na CO ,
2
Li CO , MgCO , CaCO , SrCO , ZnCO , Bi ꢀCO ) ,
3 3
3
3
0
alkyl benzoates.
2
3
3
3
3
3
2
La ꢀCO ) and Y ꢀCO ) were ineffective. No signi®cant
2
3 3
2
3 3
amount of debenzoylation could be observed with KHCO
In conclusion, we have developed an improved and ef®cient
method for selective deprotection of aryl esters under non-
hydrolytic conditions using a cheap and easy to handle
reagent.
3
2
4
or CsHCO3. The inef®ciency of the bicarbonates may be
explained as a result of decrease of nucleophilicity due to
hydrogen bonding.
To evaluate the effect of counter anion, other potassium
salts, e.g. persulfate, thiocyanate, nitrate, hydrogen
phosphates, etc. were also employed and found to be
ineffective ꢀTable 3).
1. Experimental
The esters were either available commercially or prepared
following standard procedure. The solvents were distilled
1
Various aryl benzoates were treated with K CO
2
before use. K
and KSCN were procured from S.d. Fine Chemicals, India.
Li CO , Na CO , CaCO , KHCO , K HPO , KH PO , and
SO were procured from Loba Chemie, India. ZnCO was
purchased from CDH, India. Rb CO , Cs CO , CsHCO
´xH O, KNO PO ꢀCO ´xH and
ꢀCO ´xH O were procured from Aldrich, USA.
ꢀCO was procured from Titan Biotech, India.
2 3 3 3 3 2 2 8 3
CO , BaCO , MgCO , SrCO , K S O , KNO ,
3
ꢀ
1.6 equiv.) in NMP at 1008C under nitrogen and the results
are summarised in Table 4. Chemoselectivity was observed
by the fact that methyl ethers do not experience any nucleo-
2
3
2
3
3
3
2
4
2
4
K
2
4
3
2
8
philic cleavage ꢀentries 1, 8), no competitive aromatic
nucleophilic substitution takes place for substrates bearing
2
3
2
3
,
3
K
S
2
O
3
,
K
3
,
Y
)
3
O
2
2
2
3
4
2
3
2
9
halogen atoms ꢀentries 2, 3), and ketone, aldehyde and
nitrile functionalities remain unaffected. The chemo-
selectivity of the process was further tested for substrates
La
Bi
2
3
)
)
3 3
3
2
2
1
1
.1. General procedure for the deprotection
2 3
Table 4. Deprotection of various aryl benzoates with K CO in NMP
.1.1. Representative procedure for deprotection of aryl
a,b
Entry
Aryl benzoate
Yieldꢀ%)
ester. A mixture of 2-naphthyl benzoate ꢀ0.62 g, 2.5 mmol)
and K CO ꢀ0.55 g, 4 mmol) in NMP ꢀ2.5 ml) were heated
2
3
at 1008C for 3 h under N . The cold reaction mixture was
2
diluted with 5% aqueous NaOH ꢀ10 ml) and extracted with
Et O ꢀ3£20 ml) to separate any neutral component. The
2
1
2
c
1
2
3
4
5
6
7
8
7
8
R ˆH; R ˆOMe
57 ꢀ67)
93
90
aqueous layer was acidi®ed with ice-cooling ꢀ6 M HCl)
and extracted with Et O ꢀ3£20 ml). The combined ethereal
1
2
R ˆH; R ˆCl
2
1
2
R ˆMe; R ˆCl
1
2
d
extracts were washed with saturated aqueous NaHCO
ꢀ2£20 ml) to separate the liberated benzoic acid, brine
3
R ˆH; R ˆOCOPh
86
66
1
2
d
R ˆOCOPh; R ˆH
1
2
R ˆH; R ˆCOMe
73
72
ꢀ20 ml), dried ꢀNa SO ) and concentrated to afford
2
4
1
2
R ˆH; R ˆNO
2
2-naphthol ꢀmpˆ1228C, yieldˆ97%, 350 mg, GC-MS
31
sample.
1
2
R ˆH; R ˆCHO
75
c
38 ꢀ80)
66
1
purityˆ100%), identical ꢀ H NMR, FTIR) with an authentic
1
2
R ˆH; R ˆCN
1
2
R ˆOMe; R ˆCHO
Reactions were carried out by treatment of the ester with 1.6 equiv. of
K
GC-MS ꢀm/z): 144 ꢀM, 100), 115 ꢀM2CHO, 91), 89 ꢀ115-
C H , 19), 63 ꢀ89-C H , 20).
2 3
CO in NMP at 1008C for 3 h.
2
2
2
2
a
Isolated yield of the corresponding phenol.
The unreacted starting material could be recovered on each occasion.
The ®gures in parenthesis are the corresponding yields under re¯ux for
b
c
1.1.2. Representative procedure for deprotection of aryl
ester in the presence of alkyl ester. A mixture of methyl
4-acetoxy benzoate ꢀ0.48 g, 2.5 mmol) and K CO ꢀ0.55 g,
20 min.
The product was isolated through freeze drying.
d
2
3

9346
A.K.Chakraborti et al./ Tetrahedron 57 ꢀ2001) 9343±9346
4 mmol) in NMP ꢀ2.5 ml) were heated at 1008C for 3 h
under N . The cold reaction mixture was diluted with 2%
10. Ley, S. V.; Mynett, D. M. Synlett 1993, 793.
11. Parmar, V. S.; Prasad, A. K.; Sharma, N. K.; Bisht, K. S.; Pati,
H. N.; Taneja, P. Bioorg.Med.Chem.Lett. 1993, 3, 585.
12. Guo, J.; Huang, W.; Scanlan, T. S. J.Am.Chem.Soc. 1994,
116, 6062.
2
aqueous NaOH ꢀ10 ml) and extracted with Et O ꢀ3£20 ml)
2
to separate any neutral component. The aqueous layer was
acidi®ed with ice-cooling ꢀ6 M HCl) and extracted with
Et O ꢀ3£20 ml). The combined ethereal extracts were
13. Tee, O. S.; Mazza, C.; Lozano-Hemmer, R.; Giorgi, J. B.
J.Org.Chem. 1994, 59, 7602.
2
dried ꢀMgSO ) and concentrated under vacuo to afford
4
methyl 4-hydroxy benzoate ꢀmpˆ1268C, yieldˆ92%,
14. Boisselier, V. L.; Postel, M.; Du nÄ ach, E. Tetrahedron Lett.
1997, 38, 2981.
15. Sharma, G. V. M.; Ilangovan, A. Synlett 1999, 12, 1963.
1
3
FTIR) with an authentic sample.
50 mg, GC-MS purityˆ100%) identical ꢀ H NMR,
3
1
1
6. Bandgar, B. P.; Uppalla, L. S.; Sagar, A. D.; Sadavarte, V. S.
Tetrahedron Lett. 2001, 42, 1163.
GC-MS ꢀm/z): 152ꢀM, 33), 1 12 ꢀM 2OCH , 100), 93
3
ꢀ
M2CO CH , 37), 65 ꢀ93-CO, 59).
2
17. Chakraborti, A. K.; Nayak, M. K.; Sharma, L. J.Org.Chem.
999, 64, 8027.
3
1
These generalised methods were followed for the remaining
substrates and in each occasion the product was found to be
identical ꢀ H NMR, FTIR and GCMS) with an authentic
sample. In most of the cases the product was isolated
in pure form and whenever required puri®cation was
accomplished through crystallisation ꢀEtOAc/hexane) or
chromatography ꢀsilica gel, eluent 15% EtOAc/hexane).
18. Sainte-Marie, L.; Guib e -Jampel, E.; Therisod, M. Tetrahedron
Lett. 1998, 39, 9661.
1
19. Pearson, R. G. J.Am.Chem.Soc. 1963, 85, 3533. Pearson,
R. G. Acc.Chem.Res. 1993, 26, 250.
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21. Kim, S.-I.; Chu, F.; Duenco, E. E.; Jung, K. W. J.Org.Chem.
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Tetrahedron Lett. 1999, 40, 1847.
2
2. Teranishi, K.; Nakao, H.; Komoda, A.; Hisamatsu, M.;
Yamada, T. Synthesis 1995, 176.
Acknowledgements
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Tetrahedron Lett. 1991, 32, 327.
24. Zaugg, H. E. J.Org.Chem. 1976, 41, 3419.
L. S. thanks CSIR, New Delhi for award of senior research
fellowship.
2
5. Chakraborti, A. K.; Basak ꢀn e e Nandi), A.; Grover, V. J.Org.
Chem. 1999, 64, 8014. Basak ꢀn e e Nandi), A.; Nayak, M. K.;
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