SCHEME 1. Prior Synthesis of DMA Esters from
Carboxylic Acids1
An Improved Method for the Protection of
Carboxylic Acids as 1,1-Dimethylallyl Esters
Minoo Sedighi, Selc¸uk C¸ alimsiz, and Mark A. Lipton*
Department of Chemistry and Cancer Center, Purdue
UniVersity, 560 OVal DriVe, West Lafayette, Indiana
47907-2084
SCHEME 2. Catalyzed and Uncatalyzed Reactions of
Allylic Sulfonium Ions with Benzoate2,3
ReceiVed June 12, 2006
SCHEME 3. Synthesis of 1
1,1-Dimethylallyl (DMA) esters of various N-protected
amino acids have been synthesized using prenyldimethyl-
sulfonium tetrafluroborate, a reagent that can be readily made
and stored, in conjunction with catalytic CuBr. These
reactions were complete within several hours and afforded
DMA esters in high yields. As has been previously shown
in our group, DMA esters represent a palladium-labile
proctecting group for carboxylic acids that resists nucleo-
philic attack as a tert-butyl ester would.
preferential nucleophilic attack at its most substituted end.4,5
Although the replacement of potassium benzoate with other
nucleophiles was explored, the use of this reaction with other
carboxylate salts was not explored. We therefore decided to re-
examine this reaction with our previously reported substrates
for DMA protection to assay this reaction for both generality
and convenience of use. Herein are reported the results of our
study.
Prompted by Julia’s findings, we sought to explore the
generality of this reaction using a variety of carboxylic acids.
Prenyldimethylsulfonium tetrafluoroborate (1) was prepared by
reaction of dimethyl sulfide with prenyl alcohol in the presence
of tetrafluoroboric acid (Scheme 3). Although 1 was stable for
several months at -20 °C as judged by NMR, it was found
that freshly prepared material afforded the best yields in
reactions with carboxylic acids.
In an earlier publication, we reported a general approach for
the protection of carboxylic acids as their 1,1-dimethylallyl
(DMA) esters (Scheme 1),1 which can serve as an alternative
to tert-butyl esters for the protection of acid-sensitive substrates
when resistance to nucleophilic attack on the ester carbonyl is
needed. In our previous work, the synthesis of DMA esters was
performed in two steps: formation of 1,1-dimethylpropargyl
ester intermediates and subsequent partial hydrogenation to
afford the desired DMA esters.
In pursuit of a one-pot method for synthesizing this potentially
useful protecting group, we turned to the earlier work of Julia
and co-workers (Scheme 2), who had reported that the alkylation
of potassium benzoate with allylic sulfonium salts could be
catalyzed by copper(I) salts to afford a reversed regioselectivity
of addition.2,3
Julia found that, whereas the uncatalyzed reaction took place
essentially without significant allylic rearrangement, copper(I)
catalysis dramatically changes the regioselectivity as shown in
Scheme 2.2,4,5 Julia explained this remarkable reversal of
regioselectivity by the formation of a reactive π-allyl or rapidly
equilibrating σ-allyl copper intermediate that would undergo
With 1 in hand, we first esterified benzoic acid to verify the
ability of 1 and catalytic CuBr to regioselectively alkylate
carboxylic acids. When benzoic acid was reacted with 1 in the
presence of potassium carbonate and catalytic copper bromide
in dichloromethane at ambient temperature, it furnished the
corresponding 1,1-dimethylallyl ester (4) in quantitative yield
with no need for purification. The high yield and excellent
regioselectivity encouraged us to study the generality of this
reaction by investigating the reaction of several different
N-protected amino acids (Table 1) used in our previous study.1
It was found that 1 reacts in high yield and regioselectively
with the amino acids studied regardless of the functionality
present. Generally, the reactions were completed within 8-16
h, and in most cases good yields were obtained. Of all the cases
examined, the lowest yield obtained was with Fmoc-glycine (7i),
which most likely results from loss of material during workup
and isolation. When the Fmoc derivatives of Cys, His, and Arg
(7k-m), which have highly nucleophilic sidechains, were
subjected to the reaction conditions, it was found that 4 equiv
of 1 was required to obtain a high yield of DMA ester. In most
* To whom correspondence should be addressed. Tel: +765-494-0132.
Fax: +765-494-0239.
(1) Sedighi, M.; Lipton, M. A. Org. Lett. 2005, 7, 1473.
(2) Badet, B.; Julia, M.; Ramirez-Munoz, M.; Sarrazin, A. Tetrahedron
1983, 39, 3111.
(3) Julia, M.; Mestdagh, H.; Rolando, C. Tetrahedron 1986, 42, 3841.
(4) Gauchet, F.; Julia, M.; Mestdagh, H.; Rolando, C. Bull. Soc. Chim.
Fr. 1987, 1036.
(5) Gauchet, F.; Julia, M.; Mestdagh, H.; Rolando, C. Bull. Soc. Chim.
Fr. 1990, 127, 268.
1
cases, H NMR analysis of the crude product after workup
showed essentially pure DMA ester, indicating near-quantitative
10.1021/jo061207z CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/08/2006
J. Org. Chem. 2006, 71, 9517-9518
9517