Mild and selective sodium azide mediated cleavage of p-nitrobenzoic esters.

Article abstract of DOI:10.1021/ol016104b

[reaction: see text] A mild and selective cleavage of p-nitrobenzoic esters by sodium azide in methanol is reported. This new methodology is mild enough for use with acid- or base-sensitive compounds. No elimination byproducts are formed. Fmoc- and trifluoroacetyl-amino protecting groups, benzyl esters, and ethyl esters remain unaffected. Less reactive compounds are discussed in terms of steric factors, and yields are increased by altering the azide solvation.

Full text of DOI:10.1021/ol016104b

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2477-2479
Mild and Selective Sodium Azide
Mediated Cleavage of p-Nitrobenzoic
Esters
Jose´ A. Go´mez-Vidal, Michael T. Forrester, and Richard B. Silverman*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60201-3113
agman@chem.northwestern.edu
Received May 11, 2001
ABSTRACT
A mild and selective cleavage of p-nitrobenzoic esters by sodium azide in methanol is reported. This new methodology is mild enough for use
with acid- or base-sensitive compounds. No elimination byproducts are formed. Fmoc- and trifluoroacetyl-amino protecting groups, benzyl
esters, and ethyl esters remain unaffected. Less reactive compounds are discussed in terms of steric factors, and yields are increased by
altering the azide solvation.
The Mitsunobu reaction has been extensively reported for
the inversion of hydroxy-bearing stereocenters.1 The use of
p-nitrobenzoic acid was reported to increase the efficiency
of this methodology in hindered secondary alcohols,2 and
this acid has become a standard when inverting the config-
uration of chiral alcohols.3 A potential drawback of this
methodology occurs when the formed ester is â to a carbonyl
group: hydrolysis of this intermediate under basic conditions
proceeds with elimination, affording the conjugated enone
as the major product (Scheme 1).
reported as a catalyst for the hydrolysis of aryl acetates.5
Scandium trifluoromethanesulfonate was developed for the
selective cleavage of acetates in the presence of a coordi-
native group.6 Nucleophilic dealkylation or nucleophilic
attack on the ester carbonyl group using alkali metal salts
were described at high temperature to obtain the free acid
under neutral conditions.7 Alkali azide and alkali iodine in
DMF at 100 °C were used for cleavage of phosphonic acid
diesters to monoesters.8 Potassium cyanide was reported as
a catalyst for ester exchange in refluxing ethanol9 or the
O-deacylation of polyacylated sugars.10
Different conditions have been described to cleave esters
under mild conditions.4 For example, Bi(III)-mandelate was
(1) For reviews, see: (a) Dodge, J. A.; Jones, S. A. Res. DeVel. Org.
Chem. 1997, 1, 273-283. (b) Hughes, D. L. Org. Prep. Proc. Int. 1996,
28, 127-164. (c) Hughes, D. L. Org. React. 1992, 42, 335-656. (d)
Misunobu, O. Synthesis 1981, 1-28.
(2) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-
3020. (b) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59,
234-236.
Scheme 1
(3) Hughes, D. L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967-2971.
(4) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999; Chapter 5.
(5) Boisselier, V. L.; Postel, M.; Dun˜ach, E. Tetrahedron Lett. 1997,
38, 2981-2984.
(6) (a) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Tetrahedron Lett.
1999, 40, 1689-1692. (b) Kajiro, H.; Shuichi, M.; Mori, A.; Hiyama, T.
Bull. Chem. Soc. Jpn. 1999, 72, 1553-1560.
(7) Gilligan, P. J.; Krenitsky, P. J. Tetrahedron Lett. 1994, 35, 3441-
3444.
(8) Holy, A. Synthesis 1998, 381-385.
10.1021/ol016104b CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/17/2001

zoate cleavage in the presence of two protecting groups
sensitive to nucleophiles or basic conditions. These condi-
tions were applied to a number of substrates to determine
the scope and limitations of this reaction (Table 1).
The two amino acids 1a and 2a were cleaved in high yield
using an excess of sodium azide (Table 1). This clearly shows
that these conditions do not affect base- or nucleophile-labile
functionalities such as an Fmoc protecting group. No
elimination products were observed under these conditions.
These conditions also are selective for p-nitrobenzoic
esters. Other esters were less prone to hydrolysis, as shown
for compound 3a.13 Methyl 4-hydroxybenzoate was not
detected. Compounds that had bulky substituents or that were
highly substituted in the R position showed less reactivity
(6a, 7a, and 8a in Table 1) or no reactivity (compare 4 in
Table 1 with 9 in Figure 1), presumably because of steric
hindrance.
Table 1. Conditions and Results for p-Nitrobenzoic Ester
Cleavage
NaN3
temp
(°C)
reaction
time (h)
yieldb
(%)
ester
(equiv)
solventa
1a
2a
3a
3a
4a
5a
5a
5a
5a
6a
6a
7a
8a
5
5
3
0.1
3
3
3
3
6
6
6
3
1.1
MeOH
MeOH
MeOH
A
35
35
40
40
40
40
50
75
50
50
50
40
40
14
24
6
5 days
6
24
24
24
24
24
60
6
95
100
100
80
94
54
74
74
96
52
Figure 1. Compounds that were stable toward sodium azide in
methanol under various temperature and time conditions. R )
p-nitrobenzoyl.
B
MeOH
C
C
C
C
C
It was necessary to carry out the reaction using a cosolvent
when the reactivity of the compound was compromised using
methanol as solvent. It has been reported that solvation has
a role in the manifestation of the R effect in nucleophiles
such as sodium azide.14
Ethyl esters such as 10 were not transesterified (Figure
1). This accounts for the necessity of an activated carbonyl
group for cleavage under these conditions. Activated amides
such as 10 and 11 were stable under these conditions.
Trifluoroacetyl is an amino protecting group that has been
reported as one of the more easily cleaved amides.4 Lac-
tones13 and good leaving groups, however, are functional
groups that are affected under these conditions.
An intermediate in this reaction (12) is proposed in Scheme
2. Nucleophilic attack of azide on the activated carbonyl
group gives tetrahedral intermediate 12, which presumably
collapses to acyl azide 13 and gives methyl p-nitrobenzoate
14 and the free alcohol in the presence of methanol.
The proper balance of the carbonyl reactivity and the
special reactivity of sodium azide that exhibits the R effect
explains the selectivity already shown. Byproduct 14 was
isolated and is formed in a 1:1 ratio with the free alcohol.
This reaction is catalytic, as shown when it was carried out
with only 0.1 equiv of sodium azide (Table 1). The use of
81
79
49
MeOH
MeOH
24
a A, MeOH/DMF (3/1); B, MeOH/DME (1/3); C, MeOH/ACN (6/1);
DMF, N,N-dimethylformamide; DME, 1,2-dimethoxyethane; ACN, aceto-
nitrile. b Isolated hydroxy compounds (R ) H).
Recently, picolinic acid has been reported as a new partner
for the Mitsunobu reaction.11 Hydrolysis of the picolinic
esters with copper acetate in methanol affords the alcohol
with no elimination byproduct. However, these conditions
do not cleave a p-nitrobenzoic ester.
Herein we report a new procedure for the methanolysis
of p-nitrobenzoic esters in the presence of sodium azide under
very mild conditions.12
N-Fmoc-O-(p-nitrobenzoyl)-L-serine methyl ester was
chosen to investigate the best conditions for the p-nitroben-
(9) Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M. Synthesis 1973,
790-791.
(10) Herzig, J.; Nudelman, A.; Gottlieb, H.; Fischer, B. J. Org. Chem.
1986, 51, 727-730.
(11) Sammakia, T.; Jacobs, J. S. Tetrahedron Lett. 1999, 40, 2685-
2688.
(12) The present work has been introduced in part: Forrester, M. T.;
Go´mez-Vidal, J. A.; Silverman, R. B. Abstract of Papers, 221th National
Meeting of the American Chemical Society, San Diego, CA; American
Chemical Society: Washington, DC, 2001; CHED-275.
(13) See also: Go´mez-Vidal, J. A.; Silverman, R. B. Org. Lett. 2001, 3,
2481.
(14) Colthurst, M. J.; Kanagasooriam, A. J. S. S.; Wong, M. S. O.;
Contini, C.; Williams, A. Can. J. Chem. 1998, 76, 678-685.
2478
Org. Lett., Vol. 3, No. 16, 2001

compound was recovered unaffected, when the reaction was
not carried out to completion.
Scheme 2
In summary, a new method for the cleavage of p-
nitrobenzoates under mild conditions has been developed.
The use of sodium azide in methanol with or without a
cosolvent to cleave these esters will further extend the
applicability of p-nitrobenzoic acid in the Mitsunobu reaction.
Furthermore, these conditions open the scope of p-nitroben-
zoyl as a selective protecting group for alcohols.
Acknowledgment. The award of the grants from NATO
and the Spanish Ministry of Science and Technology to
J.A.G.V. and from the National Institutes of Health
(GM49725) to R.B.S. is acknowledged.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
an excess of sodium azide to reduce the reaction time was
not inconvenient because it was easily separated from the
reaction by aqueous workup. Moreover, the unreacted
OL016104B
Org. Lett., Vol. 3, No. 16, 2001
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