Selective deprotection of isopropyl esters, carbamates and carbonates with aluminum chloride

Article abstract of DOI:10.1055/s-2001-17466

The O-isopropyl bond of isopropyl esters, carbamates, and carbonates has been effectively and selectively cleaved by treatment with AlCl₃ in nitromethane at 0-50 °C to give carboxylic acids, amines, and alcohols, respectively, in good to excell

Full text of DOI:10.1055/s-2001-17466

LETTER
1593
Selective Deprotection of Isopropyl Esters, Carbamates and Carbonates with
Aluminum Chloride
D
eprotection of Iso
a
propyl Est
i
ers,
C
a
k
rbamates
a
nd
-
Carbon
L
ates ean Chee*
Crompton Co./Cie, Research Laboratories, P.O.Box 1120, 120 Huron Street, Guelph, Ontario, N1H 6N3, Canada
Fax +1(519)8211956; E-mail: gaik-lean_chee@cromptoncorp.com
Received 9 August 2001
Abstract: The O-isopropyl bond of isopropyl esters, carbamates,
and carbonates has been effectively and selectively cleaved by treat-
ment with AlCl3 in nitromethane at 0–50 °C to give carboxylic ac-
ids, amines, and alcohols, respectively, in good to excellent yields.
Key words: isopropoxycarbonyls, selective deprotection, alumi-
num chloride, nitromethane, carbocations
Scheme
Carboxylic acids, amines, and alcohols are frequently pro-
tected when forming the corresponding simple alkyl es-
a sulfide,4c or sodium iodide.4d The selectivity of these
ters, carbamates, and carbonates.1 The alkyl groups used
are usually the methyl, ethyl, t-butyl, and benzyl groups.
Commonly employed deprotection methods for these
functionalities have been conventional acid- or base-hy-
drolysis and SN2-type dealkylation of methoxy- and
ethoxycarbonyls,2 acid treatment of t-butyloxycarbonyls,
and hydrogenation of benzyloxycarbonyls. Although iso-
propoxycarbonyls are as easily prepared and inexpensive
as the above described protecting groups, they have been
used infrequently as protecting groups because their ad-
vantages have not been widely realized.
non-saponification dealkylation reactions was either poor
or not reported. For the reactions that proceeded with poor
selectivity, both primary and secondary O-alkyl bonds of
esters were cleaved during the reactions. Anhydrous hy-
drogen fluoride gas has been employed to selectively
cleave alkoxycarbonyls capable of liberating stable car-
bocations such as the t-butyl, isopropyl, and benzyl cat-
ions.5 However, the requirement of a special experimental
setup with non-glass apparatus for this reaction, due to the
caustic nature of the gas, has limited the usefulness of this
procedure.5a
This paper describes the use of isopropoxycarbonyls as
protecting groups by presenting a method that selectively
cleaves the O-isopropyl bond of isopropyl esters, carbam-
ates, and carbonates in the presence of other alkoxycarbo-
nyl groups. Our method involved the treatment of
isopropoxycarbonyl compounds with AlCl3 in ni-
tromethane as shown in the Scheme. The cleavage of the
O-isopropyl bond occurs presumably via the formation of
a stable isopropyl cation. Other alkoxycarbonyl groups
that are incapable of giving rise to stable alkyl cations are
not affected during the reaction. While isopropoxycarbo-
nyls can be selectively cleaved using our new method, un-
like t-butyloxycarbonyls and benzyloxycarbonyls they are
much less sensitive towards acidic conditions. In addition,
isopropoxycarbonyls are also unaffected during the hy-
drogenation of benzyloxycarbonyls.
Our present procedure6 not only allows selective depro-
tection of isopropoxycarbonyl groups, but it is also easy to
handle. The reaction can be carried out in an air atmo-
sphere using non-anhydrous solvents and AlCl3. Howev-
er, at least 4 equivalent of AlCl3 must be used in the
reaction. Other Lewis acids such as BF3 OEt2, ZnCl2,
SnCl4, FeCl3, and ZrCl4 failed to catalyze the deprotection
reactions as well as AlCl3. The reactions did not proceed
when ethyl acetate, acetonitrile, diethyl ether, and tetrahy-
drofuran were used as solvents. While other solvents such
as methylene chloride and toluene worked well in a few
cases (Table, entries 2, 3, 5 and 6), nitromethane is the
universal solvent suitable for all the deprotection reac-
tions shown in the Table. However, reactions in ni-
tromethane proceeded much more slowly than those in
methylene chloride or toluene (Table, entries 1, 2, 3, 5 and
6).
The use of Lewis acids in the dealkylation of esters to give
carboxylic acids have been reported.3,4 However, the
study has not been extended to carbonate and carbamate
systems.1 The dealkylation reactions often involved the
use of boron halides3 or aluminum halides in the absence
or presence of a nucleophile such as an anisole,4a a thiol,4b
The selectivity of the cleavage of the O-isopropyl bond
can be influenced by careful choice of the reaction tem-
perature and solvent (Table). For instance, the O-isopro-
pyl bond of di-isopropoxycarbonyl 1a can be selectively
cleaved in nitromethane (10 °C for 24 h) at the ester moi-
ety to give the carboxylic acid 2a in excellent yield (Ta-
ble, entry 1). On the other hand, when the reaction was
conducted at 50 °C for 5 h, both the ester and the carbam-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1593,1595,ftx,en;S05201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1594
G.-L. Chee
LETTER
Table The Deprotection of Isopropyl Esters, Carbamates, and Carbonates using Aluminum Chloride.6
Entry
1
Substrate
Producta
Solvent
Temp. (°C) Time (h)
Yieldb (%)
92
CH3NO2
10
24
2
3
CH3Ph
5
1
91
CH3NO2
CH2Cl2
50
5
5
1
88
85
4
5
CH3NO2
5
1
89
CH3NO2
CH2Cl2
25
5
5
1
90
85
6
CH3NO2
CH2Cl2
50
25
5
1
85
85
7
8
CH3NO2
CH3NO2
25
50
24
5
78
90
9
CH3NO2
50
5
92
10
11
CH3(CH2)7OCO2i-Pr (1h)
CH3(CH2)7OH (3h)
CH3NO2
CH3NO2
25
25
3
3
90
86
EtO2CCH2CH2 CH2OCO2i-Pr (1i) EtO2CCH2CH2 CH2OH (3i)
a The products were identified by comparison of their physical data with the authentic samples.
b Isolated yields after purification.
ate moieties underwent a deprotection reaction to afford The present method has allowed the selective deprotec-
exclusively the aminobenzoic acid 3a’ (Table, entry 3). tion of isopropoxycarbonyl groups in the presence of pri-
This di-cleavage reaction can be facilitated at a much low- mary alkoxycarbonyl groups such as O- and N-methoxy-
er temperature and in a shorter time using dichlo- and ethoxycarbonyls, as well as methyl and ethyl esters
romethane as solvent (Table, entry 3). It was surprising to (Table, entries 5–7). Other functional groups that re-
observe that when toluene was used as solvent and the re- mained unaffected during the reaction were: amide, ph-
action was conducted at ~5 ºC, the less reactive carbamate thalamide, benzoyl, nitro, nitrile, alkene, aliphatic and
group of (1a) was selectively deprotected, leaving the es- deactivated aromatic ethers,7 and aromatic halogens. The
ter moiety unaffected to give the amino ester 3a (Table, functional groups that were sensitive to the reaction
entry 2).
conditions described in this report were the secondary
and tertiary alkoxycarbonyls, and benzyloxycarbonyls
Synlett 2001, No. 10, 1593–1595 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Deprotection of Isopropyl Esters, Carbamates and Carbonates
(2) (a) Chen, J.; Zhou, X. J. Synthesis 1987, 586. (b) Mc
1595
presumably due to the ability of these groups to liberate
the corresponding stable alkyl cations. The reactivity of
these groups was found to be in the order of t-butyl > ben-
zyl > isopropyl >>> methyl or ethyl. In addition, phenyl
rings lacking electron-withdrawing substituent(s) were
found to cause undesirable side reactions, leading to the
formation of intractable products as has been observed in
hydrogen fluoride gas catalyzed deprotection reactions.5a
A Friedel–Crafts addition of isopropyl cation(s) to the
phenyl ring has been suggested to be the side reaction re-
sponsible. Despite these drawbacks, the present method
has allowed the selective cleavage of the O-isopropyl
bond of aliphatic and deactivated aromatic isopropyl es-
ters, carbamates, and carbonates in good to excellent
yields.
Murry, J. Org. React. 1976, 24, 187. (c) Kong, F.; Chen, J.;
Zhou, X. Synth. Commun. 1988, 18, 801. (d) Liotta, D.;
Sunay, U.; Santiesteban, H.; Markiewicz, W. J. Org. Chem.
1981, 46, 2605. (e) Sheehan, J. C.; Daves, G. D. Jr. J. Org.
Chem. 1964, 29, 2006.
(3) Felix, A. M. J. Org. Chem. 1974, 39, 1427.
(4) (a) Tsuji, T.; Kataoka, T.; Yoshioka, M.; Sendo, Y.;
Nishitani, Y.; Hirai, S.; Maeda, T.; Nagata, W. Tetrahedron
Lett. 1979, 2793. (b) Node, M.; Nishide, K.; Sai, M.; Fujita,
E. Tetrahedron Lett. 1978, 5211. (c) Node, M.; Nishide, K.;
Sai, M.; Fuji, K.; Fujita, E. J. Org. Chem. 1981, 46, 1991.
(d) Bhatt, M. V.; Setty, K. S. S. Indian J. Chem. 1987, 26B,
467.
(5) (a) Sakakibara, S.; Shimonishi, Y.; Kishida, Y.; Okada, M.;
Sugihara, H. Bull. Chem. Soc. Jpn. 1967, 40, 2164.
(b) Tam, J. P.; Wong, T.; Riemen, M. W.; Tjoeng, F.;
Merrifield, R. B. Tetrahedron Lett. 1979, 4033.
(6) Aluminum chloride (4 mmol) was added to a cold solution
of solvent described in the table (i.e. nitromethane, toluene
or methylene chloride) (2 mL) at 0 °C, and then was added
the substrate (1 mmol) dropwise (if liquid) or portionwise (if
solid). The mixture was then stirred at the temperature and
time as given in the table. The reaction mixture was poured
into ice-water (ca. 10 mL). If a solid formed, the mixture was
filtered and the solid washed with more water and dried
under vacuum. If no solid was resulted, the mixture was
extracted with EtOAc (3 4 mL). The organic phase was
washed with water (3 4 mL), dried (MgSO4), and
concentrated under vacuum to give the desired product.
(7) The cleavage of activated aryl isopropyl ethers by AlCl3
have been reported: Banwell, M. G.; Flynn, B. L.; Stewart,
S. G. J. Org. Chem. 1998, 63, 9139.
Acknowledgement
The author gratefully acknowledges Dr. David Brewer for helpful
discussions.
References and Notes
(1) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; Wiley Interscience: New York,
1999, Chap. 1, 5, 7, and references cited therein.
Synlett 2001, No. 10, 1593–1595 ISSN 0936-5214 © Thieme Stuttgart · New York