A convenient procedure for parallel ester hydrolysis

Article abstract of DOI:10.1055/s-2004-832828

The treatment of alkyl esters with barium hydroxide octahydrate in methanol followed by protonation with anhydrous hydrogen chloride affords carboxylic acids. The procedure does not require aqueous workup and is particularly suitable for parallel synthesis applications.

Full text of DOI:10.1055/s-2004-832828

LETTER
2391
A Convenient Procedure for Parallel Ester Hydrolysis
C
onvenient Procedur
e
a
for
P
arallel
r
Ester
H
c
ydrolysis O. Anderson,a Jamie Moser,a John Sherrill,a R. Kiplin Guy*a,b
a
Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94143-2280, USA
b
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94142-2280, USA
Fax +1(415)5140689; E-mail: rguy@cgl.ucsf.edu
Received 15 July 2004
Table 1 Examples of Ester Hydrolysis Using Barium Hydroxide
Octahydrate Followed by Non-Aqueous Workup (Bz = benzoyl;
Ns = 2-nitrobenzenesulfonyl)
Abstract: The treatment of alkyl esters with barium hydroxide
octahydrate in methanol followed by protonation with anhydrous
hydrogen chloride affords carboxylic acids. The procedure does not
require aqueous workup and is particularly suitable for parallel
synthesis applications.
Entry Substrate
Isolated
Conditions
yield (%)
Key words: ester hydrolysis, deprotection, parallel synthesis,
barium hydroxide octahydrate, 9-chloroacridine
1
85
98
87
2 h, r.t.
2 h, r.t.
15 h, r.t.
MeO
CO(CH2)2CO2Me
2
MeO
(CH2)3-CO2Me
OH
Esters are commonly used protecting groups in multi-step
organic synthesis. Deprotection is often carried out using
acidic or basic hydrolysis conditions in various aqueous
solvent systems (e.g. THF–MeOH–H2O). Conventional
methods almost always include an aqueous workup step,
which is difficult to implement in the parallel synthesis of
libraries. Non-hydrolytic methods of ester-cleavage have
been reported, including BCl3,1 BBr3,2 and NaI/pyridine.3
However, these conditions are often non-selective, caus-
ing reaction with non-ester functional groups (e.g. aryl
alkoxides). To provide a general and selective method for
hydrolysis of esters that is useful in parallel synthesis, we
examined non-aqueous conditions of hydroxide-mediated
ester cleavage. Barium hydroxide octahydrate, which is
soluble in methanol, has been previously used to deprotect
simple alkyl esters.4 A non-aqueous workup was devised
for the reagent where the products are concentrated, pro-
tonated using anhydrous hydrogen chloride, dried over
MgSO4, and isolated by filtration (Equation 1). These op-
erations are easily implemented in parallel.
3
OEt
Bz-HN
O
4
5
93
15 h, r.t.
CO2Me
N-Ns
HO
100
4 h, 80 °C,
MeOH–
THF (6:1)
CO2Me
CO2Me
6
7
80
97
2 h, 80 °C
2 h, 80 °C
O
O
CO2Me
OPh
8
9
100
87
2 h, 80 °C
2 h, 80 °C
CO2Et
CO2Et
OH
1) Ba(OH)2·8H2O
CH3OH
R-CO2R
R-CO2H
2) anhydrous HCl
10
11
100
94
2 h, 80 °C
2 h, 80 °C
CO2Me
Equation 1 Ester hydrolysis followed by non-aqueous protonation
with anhydrous hydrogen chloride
F
OH
CO2Me
To explore the generality of the method, several model re-
actions were conducted (Table 1). Entries 1–4 proceeded
in varying times at room temperature, while entries 5–11
required heating. Entry 5 required a small amount of THF
as a co-solvent. In all cases, product was obtained in good
to quantitative yield.
MeO
OH
The procedure was also utilized in a typical parallel syn-
thesis route: a solution-phase, three-step, one-pot route to
9-chloroacridines without purification of intermediates
(Equation 2). Thus aryl triflates (1), readily available from
the corresponding salicylic acids, were coupled with
anilines (2) using Buchwald’s conditions.5 The crude ester
product was then hydrolyzed with barium hydroxide
octahydrate in methanol, followed by treatment with
phosphorous oxychloride6 to yield 9-chloroacridines (3).
SYNLETT 2004, No. 13, pp 2391–2393
0
3
.1
1
.2
0
0
4
Advanced online publication: 28.09.2004
DOI: 10.1055/s-2004-832828; Art ID: S06904ST
© Georg Thieme Verlag Stuttgart · New York

2392
M. O. Anderson et al.
LETTER
In this case the crude barium carboxylate salts were uti- applications where such workups are impractical. The
lized directly in the cyclization step, omitting an explicit method appears to be fairly general allowing hydrolysis of
protonation step. The 9-chloroacridine products were pu- both alkyl and aryl esters.
rified automatically by SiO2 chromatography using the
CombiFlash® system (Iscotm). The sequence was evaluat-
ed for a series of substrates (Table 2). Entries 1–7 show
1) Pd(OAc)2
BINAP
2) Ba(OH)2
CH3OH
2 h, 80 °C
Cl
CO2Me
H2N
the generation of purified products in reasonable yields
and excellent purity. In the case of entry 8, the coupling
reaction was successful, but ester hydrolysis did not pro-
ceed to completion, even after several days in refluxing
methanol. This may be due to deactivation caused by the
two electron-donating groups in the molecule. However,
the method is reliable with a single strong electron-donat-
ing group (entries 1–5).
OTf
R'
3) POCl3
N
R
R'
R
1
2
3
Equation 2 Three-step synthesis of 9-chloroacridines avoiding
aqueous workup
Acknowledgment
In summary, a method has been described for performing
ester hydrolysis reactions which avoids aqueous workup.7
The reaction is particularly useful in parallel synthesis
This work has been supported by grants from the NIH (AG21601)
and the Sandler Research Foundation.
Table 2 Examples of Parallel 9-Chloroacridine Synthesis
Entry
1
Salicyl triflate
Aniline
Product
1H NMR (400 MHz, CDCl3)
Isolated yield,
% (purity, %)a
d = 4.01 (s, 3 H), 7.34 (dd, 1 H, J = 2.2, 9.5
Hz), 7.43 (s, 1 H), 7.64 (d, 1 H, J = 9.5 Hz),
8.17–8.20 (m, 2 H), 8.29 (d, 1 H, J = 9.2 Hz)
50 (99)
CO2Me
Cl
OCF3
OCF3
CF3
MeO
MeO
OTf
H2N
H2N
MeO
MeO
N
2
3
4
5
d = 4.04 (s, 3 H), 7.37 (dd, 1 H, J = 2.6, 9.5
Hz), 7.45 (d, 1 H, J = 2.6 Hz), 7.92 (dd, 1 H,
J = 1.8, 9.2 Hz), 8.25 (d, 1 H, J = 9.2 Hz), 8.34
(d, 1 H, J = 9.5 Hz), 8.73 (s, 1 H)
45 (99)
Cl
CF3
CO2Me
OTf
N
d = 4.02 (s, 3 H), 7.33 (dd, 1 H, J = 2.6, 9.5
Hz), 7.42 (d, 1 H, J = 2.6 Hz), 7.71 (dd, 1 H,
J = 2.6, 9.2 Hz), 8.08 (d, 1 H, J = 9.2 Hz), 8.29
(d, 1 H, J = 9.2 Hz), 8.38 (d, 1 H, J = 2.2 Hz)
47 (98)
CO2Me
OTf
Cl
Cl
Cl
Me
F
MeO
MeO
MeO
H2N
H2N
H2N
MeO
MeO
MeO
N
d = 2.62 (s, 3 H), 4.01 (s, 3 H), 7.30 (dd, 1 H, 40 (100)
J = 2.6, 9.5 Hz), 7.43 (d, 1 H, J = 2.6 Hz), 7.63
(dd, 1 H, J = 1.8, 8.8 Hz), 8.05 (d, 1 H, J = 8.8
Hz), 8.14 (s, 1 H), 8.30 (d, 1 H, J = 9.2 Hz)
Me
Cl
CO2Me
OTf
N
d = 4.01 (s, 3 H), 7.32 (dd, 1 H, J = 2.6, 9.5
Hz), 7.41 (d, 1 H, J = 2.2 Hz), 7.58 (t, 1 H,
J = 9.5 Hz), 7.99 (dd, 1 H, J = 2.6, 9.5 Hz),
8.14 (dd, 1 H, J = 5.5, 9.5 Hz), 8.27 (d, 1 H,
J = 9.5 Hz)
44 (100)
Cl
CO2Me
OTf
F
N
6
7
d = 4.04 (s, 3 H), 7.50–7.52 (mult, 2 H), 7.55 48 (99)
(d, 1 H, J = 9.2), 8.08 (d, 1 H, J = 10), 8.19 (s,
1 H), 8.33 (d, 1 H, J = 9.2)
CO2Me
OTf
OMe
Cl
Cl
OMe
Cl
H2N
H2N
Cl
N
d = 2.78 (s, 3 H), 7.22 (t, 1 H, J = 7.8 Hz), 7.32 33 (95)
(d, 1 H, J = 7.8 Hz), 7.68 (dd, 1 H, J = 3.0, 8.8
Hz), 7.86–7.90 (m, 2 H), 8.27 (d, 1 H, J = 2.9
Hz)
CO2Me
OTf
Cl
N
Cl
Me
Me
8
n/a
No reaction
during ester
hydrolysis
OMe
Cl
N
CO2Me
OTf
OMe
H2N
MeO
MeO
a Purity gauged by RP-HPLC analysis (UV detection at 254 nm).
Synlett 2004, No. 13, 2391–2393 © Thieme Stuttgart · New York

LETTER
Convenient Procedure for Parallel Ester Hydrolysis
2393
(6) (a) Maxime, R.; Faure, R.; Perichaud, A.; Galy, J.-P. Synth.
Commun. 2002, 32, 981. (b) Lormier, A. T.; Boyer, G.;
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(c) Cain, B. F.; Atwell, G. J. J. Med. Chem. 1976, 19, 1408.
(d) Acheson, R. M.; Harvey, C. W. C. J. Chem. Soc., Perkin
Trans. 1 1976, 465.
(7) Typical Procedure: A solution of ethyl salicylate (0.161 g,
0.968 mmol) in MeOH (10 mL) was treated with
BaOH·8H2O (0.458 g, 1.45 mmol, 1.5 equiv) and heated to
80 °C for 2 h. Solvent was removed in vacuo, followed by
the addition of HCl (1 M in Et2O) (10 mL) and MgSO4, and
the mixture was filtered, and concentrated to afford salicylic
acid (0.115 g, 87%).
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Synlett 2004, No. 13, 2391–2393 © Thieme Stuttgart · New York