A new base mediated method for the cleavage of tert-butyl esters

Article abstract of DOI:10.1055/s-2002-32583

A new method for the cleavage of tert-butyl esters with NaH in DMF is described.

Full text of DOI:10.1055/s-2002-32583

LETTER
1107
A New Base Mediated Method for the Cleavage of tert-Butyl Esters
B
ase Mediate
d
o
Methodfor
u
the Cleavag
m
of tert-Butyl
E
ster
e
s
ndu Paul, Richard R. Schmidt*
Fakultät für Chemie M 725, Universität Konstanz, 78457 Konstanz, Germany
Fax +49(7531)883135; E-mail: richard.schmidt@uni-konstanz.de
Received 28 April 2002
Table Transformation of tert-Butyl Esters into the Corresponding
Acids with NaH in DMF
Abstract: A new method for the cleavage of tert-butyl esters with
NaH in DMF is described.
Key words: tert-butyl esters, sodium hydride, DMF, sodium dime-
thylamide
En- R
try
T
(h)
Eluent Yield
ratioa (%)
1
6
7:1
7:1
4:1
9:1
2:3
74
76
70
87
78
In one of our projects, we were interested in protecting a
hydroxy group with tert-butyl 3-bromomethyl-6-methyl-
benzoate (1, Scheme).1 The reaction was performed under
standard conditions (NaH, DMF). To our surprise, the re-
action proceeded with the concomitant cleavage of the
tert-butyl ester group to provide benzoic acid derivative 2.
The novelty of the above mentioned reaction which to the
best of our knowledge has not been reported, and the lack
of suitable methods for the base mediated cleavage of tert-
butyl esters,2 motivated us to extend the above reaction to
other substrates (Table), in order to establish the follow-
ing general reaction:
2b,c
3b,c
4
4
16
2
5
3
6
7
2
1:1
3:1
74
66
Scheme
In a typical reaction procedure, the tert-butyl ester sub-
strate (1.00 mmol)3 was dissolved in DMF (10–20 mL) to
which NaH (8.00 mmol) was added and the reaction was
stirred at room temperature (or at 70–80 °C in some cases)
till completion of the reaction. Next, the solvent was re-
moved in vacuo and the residue was dissolved in water.
The aqueous solution was acidified to give a precipitate,
which was then extracted with ethyl acetate. The organic
extract was further washed with water, brine, dried over
Na2SO4 and evaporated to yield the product, which was
purified by chromatography on silica gel.4 It is worth
mentioning that the reactions failed to proceed in THF un-
der both room temperature and reflux conditions.
24
(80 °C)
8
9
20
(70 °C)
4:1
1:1
65
60
20
The reaction worked well with differently substituted ben-
zoate esters (entries 1 and 2); even the presence of an
ortho-nitro group or bromomethyl group (entries 3 and 4)
a Silica gel chromatography with petroleum ether–ethyl acetate as elu-
ent.
b Use of KH as base under the same conditions led practically to the
same yield, whereas LiH as base furnished a lower yield; elevated re-
action temperature led to a yield increase.
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1107,1108,ftx,en;G05802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
c DBU or CsF as base gave no reaction

1108
S. Paul, R. R. Schmidt
LETTER
was tolerated. Also the reactions of the substrates in en-
tries 5 and 6 gave good results, however they required
careful monitoring, as longer reaction times lead to the
cleavage of the methoxycarbonyl and the levulinoyl
groups, respectively. At this point, it was also of interest
to investigate alkanecarboxylate tert-butyl esters having
functional groups (entries 7 and 8); they could be also suc-
cessfully transformed into the acids. In order to compare
the stabilities of the N-tert-butoxycarbonyl (Boc) groups
with the O-tert-butyl esters under the given conditions,
the tert-butyl ester of N-Boc-L-tryptophan (entry 9) was
prepared, and subjected to the same reaction conditions.
Figure
ylamide anion seems to be decisive and not metal ion che-
lation to the carboxylate group.
In conclusion, we have presented a facile and versatile
base mediated method for the cleavage of tert-butyl esters
The reaction afforded optically active N-Boc-L-tryp- which is compatible with various functional groups.
tophan in good yield. The difference in the reactivities of
the O-ester and N-Boc groups can be explained on the ba-
sis of the mechanism of the reaction as discussed below.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
Considering the fact that the reaction failed to proceed
when THF was used as a solvent, and that DMF under-
goes fragmentation in the presence of bases at room tem-
perature,5,6 it is expected that the reactive base is not
sodium hydride but sodium dimethylamide formed by the
reaction of sodium hydride and dimethylamine (formed
by fragmentation of DMF):
References
(1) Paul, S.; Schmidt, R. R., manuscript under preparation.
(2) (a) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
(b) Fisher, J. W.; Trinkle, K. L. Tetrahedron Lett. 1994, 35,
2505. (c) Trzeciak, A.; Bannwarth, W. Synthesis 1996,
1433. (d) Jung, M. E.; Lyster, M. J. Am. Chem. Soc. 1977,
99, 968.
(3) Armstrong, A..; Brackenbridge, I.; Jackson, R. F. W.; Kirk,
J. M. Tetrahedron Lett. 1988, 29, 2483.
(4) All products were identical with the material used for tert-
butyl ester formation.
DMF + NaH NaNMe2 + CO + H2
This hypothesis was confirmed by the fact that reaction of
the compound in entry 4 (Table) with dimethylamine and
NaH afforded the same product as was obtained with so-
dium hydride in DMF.
Mechanistically, the reaction is expected to proceed
through a concerted fragmentation (Figure) which trans-
forms the tert-butyl ester into isobutene and sodium car-
boxylate. Because KH is as effective as base as NaH but
not LiH (see Table), the presence of highly basic dimeth-
(5) Comins, D. L.; Joseph, S. P.In Encyclopedia of Reagents for
Organic Synthesis, Paquette L. A, Vol. 3; Wiley
InterScience: New York, 1995, 2072.
(6) Bredereck, H.; Effenberger, F.; Gleiter, R. Angew. Chem.
Int. Ed. Engl 1965, 4, 951; Angew. Chem. 1965, 77, 964.
Synlett 2002, No. 7, 1107–1108 ISSN 0936-5214 © Thieme Stuttgart · New York