Spontaneous formation of PMB esters using 4-methoxybenzyl-2,2,2- trichloroacetimidate

Article abstract of DOI:10.1016/j.tetlet.2014.01.097

Carboxylic acids are converted to the corresponding 4-methoxybenzyl (PMB) esters with 4-methoxybenzyl-2,2,2-trichloroacetimidate in the absence of an acid catalyst. This operationally simple procedure is a highly effective method for the formation of PMB esters. The reaction is promoted by the carboxylic acids themselves in excellent yields (72-99%). Sterically hindered carboxylic acids, which provide lower yields with other imidates, are esterified in higher yield with the more reactive PMB imidate. No racemization is observed in the case of carboxylic acids bearing an α-stereocenter, and no isomerization is observed with Z-α,β-unsaturated acids. This method may therefore find use in the esterification of complex or sensitive substrates where more common techniques lead to decomposition.

Full text of DOI:10.1016/j.tetlet.2014.01.097

Tetrahedron Letters 55 (2014) 1740–1742
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Spontaneous formation of PMB esters using 4-methoxybenzyl-2,2,
2-trichloroacetimidate
⇑
Jigisha P. Shah, Christopher M. Russo, Kyle T. Howard, John D. Chisholm
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Carboxylic acids are converted to the corresponding 4-methoxybenzyl (PMB) esters with 4-methoxyben-
zyl-2,2,2-trichloroacetimidate in the absence of an acid catalyst. This operationally simple procedure is a
highly effective method for the formation of PMB esters. The reaction is promoted by the carboxylic acids
themselves in excellent yields (72–99%). Sterically hindered carboxylic acids, which provide lower yields
with other imidates, are esterified in higher yield with the more reactive PMB imidate. No racemization is
Received 18 January 2014
Accepted 23 January 2014
Available online 31 January 2014
Keywords:
Esterification
PMB ester
Trichloroacetimidate
Carboxylic acid
Protecting groups
observed in the case of carboxylic acids bearing an
Z- ,b-unsaturated acids. This method may therefore find use in the esterification of complex or sensitive
substrates where more common techniques lead to decomposition.
a-stereocenter, and no isomerization is observed with
a
Ó 2014 Elsevier Ltd. All rights reserved.
4-Methoxybenzyl (PMB) esters are common protecting groups
for carboxylic acids,1,2 as their ability to be removed by treatment
with Brønsted acids,3,4 Lewis acids5–7 or hydrogenation8,9 nicely
complements other esters, which are typically removed via basic
hydrolysis. The ease of removal of PMB esters explains their
increasingly common role in numerous synthetic studies.10–15
While the formation of 4-methoxybenzyl esters in simple mole-
cules can typically be addressed by alkylation reactions with the
benzyl halide, these conditions often employ a strong base or
acylation catalysts such as DMAP, which can limit the scope of
these esterifications as these conditions are often not tolerant of
sensitive functionality. To broaden the scope of the esterification
to base sensitive substrates some alternative methods have been
developed,16,17 but there remains a need for new methods of
PMB ester formation that occur under mild conditions, are compat-
ible with polyfunctional complex molecules, and can be accessed
from simple, inexpensive starting materials. Recently a single
example using 4-methoxybenzyl-2,2,2-trichloroacetimidate (1) to
form a PMB ester without the need for a catalyst was reported
by Hayashi.3,4 This interesting reaction seemed to indicate that 4-
Initially we adopted the conditions of Hayashi,3,4 where dichlo-
romethane was used as the solvent at 0 °C with two equivalents of
the trichloroacetimidate. No advantage was found in performing
the reaction at low temperature, so the use of an ice bath was
abandoned. Some of the esterifications were sluggish, so a reaction
time of 24 h was adopted to ensure complete conversion of the
starting material. Under these conditions benzoic acid was esteri-
fied in 89% yield after purification by silica column chromatogra-
phy (Table 1, entry 1). Other benzoic acids possessing electron
poor and electron rich substituents were also esterified in good
yield under these conditions. Alkenes and alkynes were well toler-
ated (Table 1, entries 5 and 6) under these reaction conditions.
Alkyl substituted carboxylic acids also proved to be excellent sub-
strates for the esterification reaction. The yield of the esterification
showed some dependence on the steric bulk of the group next to
the carboxylic acid (Table 1, entries 8, 9, and 10), with the yield
decreasing slightly with increasing branching next to the carbox-
ylic acid. In one particularly hindered case (entry 9) the reaction
also required 48 h to proceed to high conversion. Still, the hindered
ester 10 was formed in a synthetically useful 82% yield. The yields
with hindered carboxylic acids were significantly higher than those
obtained with more hindered imidates like the diphenylmethyl tri-
chloroacetimidate,19 likely for steric reasons. Some efforts were
also made to investigate the functional group tolerance of the reac-
tion. Highly electrophilic groups (like the bromide in 12) were
quite compatible, providing the ester products in excellent yields.
Esterification of vinylacetic acid provided ester 13 in 83% yield un-
der the mild reaction conditions, with no detectable isomerization
methoxybenzyl-2,2,2-trichloroacetimidate
1 may be especially
well suited for the formation of PMB esters. This reagent could
serve as an excellent protecting group precursor since it is com-
mercially available or easily synthesized.18 An investigation into
the generality of this ester formation was therefore initiated.
⇑
Corresponding author. Tel.: +1 315 443 6894; fax: +1 315 443 4070.
E-mail address: jdchisho@syr.edu (J.D. Chisholm).
of the b,c-unsaturated alkene to the more stable a,b position as
http://dx.doi.org/10.1016/j.tetlet.2014.01.097
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. P. Shah et al. / Tetrahedron Letters 55 (2014) 1740–1742
1741
Table 1
PMB imidate 1 should be used in similar systems where isomeriza-
tion is undesired.
Esterification reactions using 4-methoxybenzyl-2,2,2-trichloroacetimidate (1)
CCl3
O
The presence of a free alcohol and a carbamate NAH bond was
also well tolerated, as shown in entries 13 and 14. With the success
of the esterification of N-Boc phenylalanine attempts were made to
esterify unprotected phenylalanine, but this returned only the
starting amino acid and unreacted imidate, likely due to the lim-
ited solubility of the zwitterionic amino acid in dichloromethane.
2-Picolinic acid also formed the PMB ester (Table 1, entry 15),
demonstrating that heterocycles with basic functionality also par-
ticipate in the esterification reaction.
MeO
NH
1
RCO2H
RCO2PMB
CH2Cl2, rt, 24 h
Entry
1
Ester product
Yield (%)
89
O
2
Ph
OPMB
A search of the literature revealed that in most cases esterifica-
tion reactions with trichloroacetimidates require the presence of a
Brønsted or Lewis acid.20,21 Only in the case of the 2-phenylisopro-
pyl trichloroacetimidate,22,23 glycosyl imidates24,25 and the
diphenylmethyl imidate19 did ester formation occur spontane-
ously. Schmidt also observed similar reactivity with glycosyl
trichloroacetimidates and phosphoric acids leading to the corre-
sponding phosphate esters.26,27 These results indicate that, at least
in cases where the corresponding cation is highly stabilized, imi-
dates can be employed to form esters without the need for a cata-
lyst or promoter under mild reaction conditions. Given that ester
formation only occurs in cases where the corresponding cation is
especially stabilized, an SN1 type reaction pathway is implicated
in the formation of these esters. The carboxylic acid itself may
act as a promoter in this esterification by protonating the basic
imidate nitrogen. This would explain the unreactive nature of
phenylalanine, as the amino acid exists as a zwitterion with a sig-
nificantly higher pKa than a typical carboxylic acid. To test the
hypothesis of self-promotion, the esterification reaction was at-
tempted with benzoic acid in the presence of two equivalents of
triethylamine. No ester formation was observed, leading to the
conclusion that activation of the imidate by protonation with the
carboxylic acid appears to be a necessary component of the reac-
tion. The successful esterification with 2-picolinic acid in Table 1
(entry 15) can be rationalized by the greater acidity of the pyridi-
nium as opposed to the ammonium formed with triethylamine.
In order to investigate the effectiveness of these esterification
conditions on sensitive substrates some further studies were
undertaken (Scheme 1). First the esterification was performed with
O
3
OPMB
2
3
4
85
80
92
F3C
O
4
OPMB
OAc
O
5
OPMB
MeO
Ph
O
O
6
5
6
94
99
OPMB
7
OPMB
Ph
O
8
7
8
89
86
OPMB
8
O
9
Ph
Ph
OPMB
O
10
9
82a
78
OPMB
11
CO2PMB
the 92:8 cis:trans mixture of a,b-unsaturated ester 17, which was
10
produced by Lindlar reduction of the corresponding alkyne.28 Sim-
ilar systems are highly prone to isomerization under basic condi-
tions or with common esterification catalysts such as DMAP.29–31
Treatment of acid 17 with two equivalents of imidate 1 gave the
corresponding ester in 72% yield after chromatography. No isomer-
ization to the more stable trans isomer was detected in the 1H NMR
of the purified product, which showed an unchanged 92:8 ratio of
products. This is the first example of the use of an imidate to alkyl-
O
12
OPMB
11
12
13
93
83
79
8
Br
O
13
OPMB
O
14
ate a Z-a,b-unsaturated carboxylic acid as a substrate, presenting a
straightforward route to access these structures from the corre-
sponding carboxylic acid without isomerization. Next, a chiral car-
Ph
Ph
OPMB
OH
O
boxylic acid bearing an
a-stereocenter was esterified with imidate
15
1. Chiral naproxen 19 was chosen as a challenging substrate for
14
15
91
83
OPMB
NHBoc
O
Ph
O
Ph
O
16
OPMB
imidate 1
CH2Cl2
rt, 24 h
OH
OPMB
72% 18
N
17
a
Reaction was allowed to proceed for 48 h.
MeO
MeO
imidate 1
CH2Cl2
rt, 24 h
determined by the analysis of the crude 1H NMR of the reaction
mixture. Other imidate esterifications have shown trace amounts
of isomerization in this system,19 and while the reason for the lack
of isomerization with imidate 1 is unclear, this result indicates that
80% 20
19
CO2H
CO2PMB
Scheme 1.

1742
J. P. Shah et al. / Tetrahedron Letters 55 (2014) 1740–1742
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Supplementary data
Supplementary data (detailed experimental procedures, NMR
data (1H and 13C spectra) and chiral HPLC traces) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.01.097.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th Ed.; John
Wiley & Sons: Hoboken, NJ, 2006; pp 610–611.