Convenient Formation of Diphenylmethyl Esters Using Diphenylmethyl Trichloroacetimidate

Article abstract of DOI:10.1055/s-0033-1340293

Diphenylmethyl trichloroacetimidate is a useful reagent for the protection of carboxylic acids as their corresponding diphenylmethyl esters. These esterifications proceed rapidly without the need for an added catalyst or promoter. A variety of carboxylic

Full text of DOI:10.1055/s-0033-1340293

LETTER
▌283
lCettoernvenient Formation of Diphenylmethyl Esters Using Diphenylmethyl Tri-
chloroacetimidate
Formation of Diphenylmethyl Esters
Arijit A. Adhikari, Jigisha P. Shah, Kyle T. Howard, Christopher M. Russo, Daniel R. Wallach, Matthew R. Linaburg,
John D. Chisholm*
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244, USA
Fax +1(315)4434070; E-mail: jdchisho@syr.edu
Received: 14.10.2013; Accepted after revision: 24.10.2013
proved convenience, practicality and safety are desirable.
Abstract: Diphenylmethyl trichloroacetimidate is a useful reagent
Ideally, any new reagent for the generation of diphenyl-
for the protection of carboxylic acids as their corresponding diphe-
methyl esters would: 1) form the ester under mild condi-
tions at room temperature, 2) not require stoichiometric
nylmethyl esters. These esterifications proceed rapidly without the
need for an added catalyst or promoter. A variety of carboxylic acid
substrates undergo esterification in excellent yields with the trichlo- amounts of toxic metal salts or powerful oxidizing agents,
roacetimidate reagent, including substrates possessing acid- or
base-sensitive functionality. Protection of a carboxylic acid with a
3) react selectively with the carboxylic acid without dis-
turbing other functionality in the molecule, and 4) be rel-
highly enolizable α-stereocenter using diphenylmethyl imidate was
atively stable with a long shelf-life.
also accomplished without racemization.
Recently, we began to evaluate alternatives for the forma-
Key words: esters, protecting groups, C–O bond formation, che-
tion of diphenylmethyl esters under mild conditions from
the corresponding trichloroacetimidate. Trichloroacetimi-
dates are excellent alkylating agents under acidic condi-
tions, as the alkylation is driven by the loss of the imidate
and the formation of trichloroacetamide. This process pro-
vides a substantial thermodynamic driving force, facilitat-
ing the alkylation reactions. Most trichloroacetimidates
require an acid catalyst to react with carboxylic acids and
form esters,9 however, there have been reports of sponta-
neous esterification with glycosyl imidates,10 4-methoxy-
benzyl trichloroacetimidate,11 and 2-phenylisopropyl
trichloroacetimidate.12 In the spontaneous cases the imi-
date appears to act as a precursor to a stabilized carboca-
tion. As the diphenylmethyl imidate can provide a similar
stabilized carbocation, we hypothesized that the diphenyl-
methyl imidate may also function as an effective esterifi-
cation reagent. The diphenylmethyl imidate is also a
white solid, which should provide a greater shelf-life than
4-methoxybenzyl trichloroacetimidate and 2-phenyliso-
propyl trichloroacetimidate, which are both oils that un-
dergo hydrolysis under ambient conditions.
moselectivity, esterification
Esters are common protecting groups for carboxylic acids
and are often utilized in multistep organic synthesis. A
popular choice is the diphenylmethyl (DPM) ester, as it
can be removed using aqueous base, by hydrogenation, or
under acidic conditions.1 This flexibility is advantageous,
as the different conditions provide options should incom-
patibilities with other functional groups be encountered
during removal. Diphenylmethyl esters are also popular
because they do not introduce new stereogenic centers or
overly complicate NMR spectra. For these reasons, the di-
phenylmethyl protecting group has been used extensively
in the synthesis of peptides,2 β-lactam antibiotics3 and
complex natural products.4
Formation of diphenylmethyl esters with simple sub-
strates is typically effected using acid catalysis with di-
phenylmethanol,5 however, these conditions do not
tolerate complex substrates with delicate functionality.
With sensitive substrates, diphenylmethyl esters are typi-
cally prepared by exposing the carboxylic acid to diphe-
nyldiazomethane.6 The unstable and toxic nature of this
reagent7 has led to a number of surrogate reactions based
on the in situ formation of diphenyldiazomethane from di-
phenylmethyl hydrazone. Unfortunately, these proce-
dures typically depend on strong oxidizing reagents or
environmentally hazardous metal salts.3b,7a,8 The scope of
these esterifications is also restricted due to the powerful
oxidizing conditions required to form the diphenyldiazo-
methane. Given the limitations associated with known
methods, especially with carboxylic acids possessing sen-
sitive functionality, esterification reagents that show im-
To test these hypotheses, diphenylmethyl trichloroaceti-
midate (2) was prepared according to the procedure of
Schmidt.13 This reagent has been previously utilized in
Lewis acid catalyzed etherification reactions to protect al-
cohols. Treatment of the commercially available and inex-
pensive diphenylmethanol (1) with trichloroacetonitrile
and catalytic 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
afforded imidate 2 in 92% yield (Scheme 1). Purification
of imidate 2 was performed using silica gel chromatogra-
phy with 1% triethylamine as a co-solvent, as silica gel
was acidic enough to facilitate decomposition of the imi-
date.
Initial studies on esterification with imidate 2 employed
lauric acid (3) (Scheme 1). Simply mixing imidate 2 with
lauric acid (3) in anhydrous dichloromethane provided the
corresponding diphenylmethyl ester 4 in high conversion.
SYNLETT 2014, 25, 0283–0287
Advanced online publication: 03.12.2013
DOI: 10.1055/s-0033-1340293; Art ID: ST-2013-S0967-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

284
A. A. Adhikari et al.
LETTER
to play a role with carboxylic acids bearing α-quaternary
carbon centers (Table 1, entries 5 and 6), providing more
moderate yields. Unsaturated carboxylic acids and aro-
matic acids also proved to be excellent substrates, afford-
ing the corresponding diphenylmethyl esters in high
yields.
NH
OH
O
CCl3
Cl3CCN
DBU (1 mol%)
CH2Cl2
92%
2
1
O
Table 1 Esterification Reactions with Diphenylmethyl Imidate 2
HO
10
3
CH2Cl2
84%
NH
Ph
O
O
Ph
Cl3C
O
O
O
2 (1.3 equiv)
O
10
CH2Cl2
18 h, r.t.
Ph
R
OH
R
ODPM
O
Ph
HN
CCl3
Ph
Ph
Ph
Ph
6
Entry
1
Ester
Yield (%)
84
4
5
Scheme 1 Esterification of lauric acid (3) with imidate 2
CO2DPM
9
While the ester could be easily separated from trichloro-
acetamide, two other side products were also detected af-
ter purification, acetamide 5 and ether 6. These
compounds co-eluted with the ester product, which made
purification significantly more difficult. The formation of
ether 6 and acetamide 5 were traced to the use of an aque-
ous work-up and application of the reaction residue con-
taining unreacted imidate 2 to silica gel without using
triethylamine to buffer the purification medium. To facil-
itate isolation of the ester and to avoid the side products
related to unreacted 2, the aqueous work-up was omitted
and the reaction mixture was purified directly by silica gel
chromatography in the presence of triethylamine. This
procedure provided pure ester 4 in 84% isolated yield
without generating 5 and 6.
4
CO2DPM
2
3
92
89
7
CO2DPM
8
Ph
CO2DPM
4
5
6
76
59
59
Ph
9
CO2DPM
The stability of pure diphenylmethyl trichloroacetimidate
(2) as a solid is quite notable. Unlike 4-methoxybenzyl tri-
chloroacetimidate and 2-phenylisopropyl trichloroaceti-
midate, which are oils that are prone to hydrolysis,
imidate 2 is stable for at least several months when stored
as a solid below 0 °C. During our work described herein,
we did note that improper storage at room temperature
over several weeks led to contamination of a sample of
imidate 2 with acetamide 5, which evidently forms from a
thermally driven process. Experimentation showed that
the rearrangement between imidate 2 and acetamide 5 was
quite facile, with complete rearrangement being observed
by simply heating imidate 2 in refluxing toluene for 24
hours without the addition of a catalyst. Still, with proper
storage at low temperature, imidate 2 is stable for long pe-
riods making it a useful precursor to diphenylmethyl es-
ters.
10
MeO CF3
Ph
CO2DPM
11
CO2DPM
7
8
79
93
12
CO2DPM
CO2DPM
Ph
13
9
85
79
Ph
14
CO2DPM
7
10
11
15
The scope of the esterification reaction was then investi-
gated with a number of simple carboxylic acids (Table 1).
These reactions were carried out by stirring the acids with
1.3 equivalents of imidate 2 in anhydrous dichlorometh-
ane at room temperature for 18 hours. Esterification of
CO2DPM
88
99
16
PhCO2DPM
most substrates occurred in good to excellent yields. Sim- 12
ple alkyl acids reacted with 2 cleanly, to give the corre-
sponding esters in 76–92% yields. Steric factors seemed
17
Synlett 2014, 25, 283–287
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formation of Diphenylmethyl Esters
285
Table 1 Esterification Reactions with Diphenylmethyl Imidate 2
(continued)
Table 2 Esterification Reactions Using Imidate 2 with Complex
Substrates
NH
Ph
NH
Ph
Cl3C
O
Ph
Ph
Cl3C
O
O
O
O
O
2 (1.3 equiv)
2 (1.3 equiv)
CH2Cl2
18 h, r.t.
R
OH
R
ODPM
CH2Cl2
18 h, r.t.
R
OH
R
ODPM
Entry
13
Ester
Yield (%)
97
Entry
1
Ester
Yield (%)
76
CO2DPM
CO2DPM
Br
20
CO2DPM
18
19
7
CO2DPM
OMe
2
3
83
63
Br
21
14
74
H
N
H
S
PhO
O
N
O
In order to evaluate the utility of this new method in the
presence of substrates possessing more sensitive function-
alities, several complex carboxylic acids were explored
(Table 2). Esterification of vinyl acetic acid provided ester
20 with only a trace amount of the product resulting from
isomerization of the alkene into conjugation with the ester
CO2DPM
CO2DPM
22
MeO
4
5
89
90
1
(~3% by H NMR). Esterification was successful in the
presence of both the α-bromide of 21 and the sensitive β-
lactam ring of 22, although the yield for 22 was moderate,
likely due to steric considerations. No epimerization of
the ester or opening of the β-lactam ring were detected for
ester 22, clearly demonstrating the esterification in a high-
ly complex substrate. (S)-6-Methoxy-α-methyl-2-naph-
thaleneacetic acid (Table 2, entry 4) was chosen as a
substrate, due to the highly enolizable stereogenic center
adjacent to the carboxylic acid. No racemization was ob-
served by chiral HPLC analysis after isolation of the cor-
responding diphenylmethyl ester 23.
23
CO2DPM
OAc
24
Ph
CO2DPM
6
7
8
92
79
76
OH
25
OH
CO2DPM
Ph
Other base-sensitive functionality such as the acetate ester
of a phenol (as in ester 24) was also stable to the reaction
conditions. Esterification reactions with diphenylmethyl
imidate 2 in the presence of protic functionality were also
evaluated. Esterification of mandelic acid (Table 2, entry
6) showed that the presence of an unprotected alcohol was
well tolerated. In addition, β-hydroxy ester 26 was formed
in 79% yield without competing β-elimination or retroal-
dol reactions being observed. tert-Butoxycarbonyl-pro-
tected D-alanine was also esterified in good yield (Table
2, entry 8) using these reaction conditions. Again, no ra-
cemization of the adjacent stereogenic center was detect-
ed in ester 27 by chiral HPLC analysis. Attempts to
esterify unprotected alanine were unsuccessful due to a
lack of solubility of the zwitterion in dichloromethane,
with no reaction being observed in more polar solvents
such as N,N-dimethylformamide or acetonitrile.
26
CO2DPM
NHBoc
27
28
CO2DPM
N
9
71
75
OBn
CO2DPM
10
S
29
Esterification of salicylic acid (30) under these conditions
led to a mixture of products (Scheme 2). These included
the ester 31, the bis-protected salicylate 32 and a trace of
the protected phenol 33. The greater reactivity of the phe-
nol evidently leads to some alkylation with the imidate,
which was not observed with alcohols (e.g., 25 and 26,
Table 2).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 283–287

286
A. A. Adhikari et al.
LETTER
Cleavage of the highly enolizable ester 23 back to the acid
without racemization was also briefly investigated. Hy-
drogenation was chosen for this deprotection, as removal
of diphenylmethyl esters via this process has been report-
ed to proceed at accelerated rates compared to other func-
tionalized benzyl esters.1b Submitting naproxen ester 23 to
standard hydrogenation conditions with palladium on car-
bon led to the formation of the free carboxylic acid 34 in
93% yield without racemization of the α-stereocenter
(Scheme 4).
O
OH
OH
30
NH
Ph
Cl3C
O
Ph
2 (1.3 equiv)
CH2Cl2, 18 h, r.t.
O
O
O
MeO
ODPM
+
ODPM
+
OH
ODPM
CO2DPM
OH
ODPM
23
31
32
33
77%
15%
3%
H
2 (1 atm)
Pd/C (10 mol%)
THF–MeOH
93%
Scheme 2 Reaction of salicylic acid (30) with imidate 2
MeO
Work in our laboratory and by others10–12 has indicated
that the spontaneous reaction of trichloroacetimidates
with carboxylic acids occurs only when the imidates are
precursors to stabilized carbocations. This observation
suggests that these esterification reactions proceed
through an SN1 mechanism where the carboxylic acid is
sufficiently acidic to initiate the reaction by protonation of
CO2H
34
Scheme 4 Deprotection of diphenylmethyl ester 23 without racemi-
zation
diphenylmethyl imidate 2 (Scheme 3). Loss of trichloro- In summary, a convenient method for the protection of
acetamide then provides the diphenylmethyl cation, carboxylic acids as their diphenylmethyl esters has been
which is trapped by the carboxylate leading to the ob- reported.14,15 The use of the diphenylmethyl imidate 2 al-
served ester product. Support for this mechanism comes lows for formation of diphenylmethyl esters without rely-
from the attempted esterification of trans-cinnamic acid ing on toxic and energetic diazo reagents. In addition, no
in the presence of two equivalents of triethylamine. No es- strong oxidizing agents or toxic metal salts are needed for
terification was observed under these conditions; instead this new esterification. The required imidate reagent is
the carboxylic acid was obtained unchanged. This sug- easily prepared from inexpensive starting materials and
gests that the free carboxylic acid is acidic enough to pro- can be used to esterify efficiently a variety of carboxylic
mote the transformation and that the necessary pKa of the acid substrates. These esterifications are operationally
initiating acid must lie below that of triethylammonium simple and proceed without the requirement of any Brøn-
(10.75). The maximum pKa of the initiating acid must also sted or Lewis acid. The conditions for the esterification
be higher than the pKa of the pyridinium salt of 2-picolinic are quite mild, and do not disturb stereogenic centers ad-
acid (5.39), as this ester was readily formed without an jacent to the reacting carboxylic acid or other sensitive
added acid (Table 2, entry 9), which would be impossible functional groups. In addition, this esterification is toler-
unless the pyridinium salt can protonate the imidate and ant of unprotected alcohols, carbamates and nitrogen het-
initiate the reaction.
erocycles. Imidate 2 also displayed a long shelf-life when
stored at low temperature. Given the continuing need for
convenient, safe, inexpensive and tolerant esterification
reagents,16 diphenylmethyl imidate 2 should find applica-
tion for the protection of complex carboxylic acids where
mild reaction conditions are essential.
O
H
H
R
O
+
H
O
H
N
N
O
CCl3
CCl3
Ph
Ph
Ph
Ph
Acknowledgment
O
Acknowledgement is made to Syracuse University for support of
this research.
H2N
CCl3
O
O
O
R
Supporting Information for this article is available online at
–O
R
+
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Ph
Ph
Ph
Ph
Scheme 3 Proposed mechanism of the esterification
Synlett 2014, 25, 283–287
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formation of Diphenylmethyl Esters
287
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trichloroacetimidate (2) (0.580 g, 1.76 mmol) were added to
a flame-dried round-bottom flask. Anhydrous CH2Cl2 (5.4
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 283–287

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