2024年2月17日发(作者：那曼)
7072
J.
Org. Chem. 1995,60,
7072-7074
A
Simple One-Step Conversion
of
Carboxylic
Acids
to Esters Using
EEDQt
Boulos Zacharie,* Timothy
P.
Connolly, and
Christopher
L.
Penney
Department
of
Medicinal Chemistry,
BioChem Therapeutic Inc.,
275 Armand-Frappier Blvd.,
Laval, QuCbec, Canada
H7V
4A7
Received April
7,
1995
Scheme
1.
Directed Esterification
of
Carboxylic
Acids with Alcohols Using
EEDQ
1
1
CH3CH20
1
The esterification of carboxylic acids is a commonly
2
encountered reaction in organic chemistry.
A
large
number of ester protecting groups have been described
in the 1iterature.l Although a variety of conditions for
ester formation have already been developed,2 they are
not always satisfactory in yield andor simplicity of
operation. Most require either the presence of strong
acids, bases, or other catalysts or the application of heat.
Simple processes that allow esterification under mild
conditions are very desirable. These procedures are of
considerable interest, especially in the manipulation of
many peptides, macrolides, and natural products. Our
goal, therefore, was to develop a general and simple one-
step procedure for the preparation of esters, under
neutral conditions, from their parent acids.
Several methods are reported for the activation of
carboxylic acids and subsequent conversion to esters and
other derivatives. The most common are ~arbodiimides,~
N-acyl derivatives of imida~ole,~ acyl
(carbonyldioxy)dibenzotriazoles,6
chlorotrimethyl~ilane,~~~~
carbonate^,^^^^
1,l’-
several organophosphorus reagents,S sulfonyl chlorides,2e
sulfuryl chloride fl~oride,~ and
nyl)-1,2-dihydroquinoline
(EEDQ,1°
2-ethoxy-l-(ethoxycarbo-
1).
The latter re-
agent is a well-known coupling agent for the formation
of peptide It allows the coupling of protected
amino acids with amino acid esters in a single operation
and with little or no racemization.
c=o
OC2H5
I
1
lumbus, OH, June
+Presented at the Fourteenth American Peptide Symposium (Co-
Synthesis;
(1)
(a) Greene, T.
18-23).
W.;
Wuts,
P.
G. M.
Protective Groups in Organic
Pearson,
York,
D.
John Wiley
E.
Survey
&
Sons: New York, (b) Buchler,
of
Organic Synthesis;
Wiley-Interscience: New
1991.
C.
A.;
Synthesis
(2)
For
1970.
(c)
51,
Shono, T1983,
selected examples, see: (a) Brook, M. A.; Chan, T.
.; Ishige,
201.
0.;
(b) Ramaiah, M.
H.
Uyama,
H.;
Kashimura,
J.
Org. Chem.
S.
J.
O1985,
rg. Chem.
50,
4991.
1986,
P.; Lecolier,
546.
(d) Jouin, P.; Castro, B.; Zeggaf,
C.;
Pantaloni, A.; Senet, J.
Jaszay,
K.;
M.; Petnehlzy,
S.;
Sennyey, G.
I.;
Toke, L.
Tetrahedron Lett.
Synthesis
1987,
28,
1661.
(e)
H.; Harigaya, Y.
Akiyama,
Z.
H.;
Nakamura,
H.;
Takizawa,
1989,745.
(0 Takeda,
1978,
(3)
Gorecka,
A,;
Synthesis
Leplawy, M.; Zabrocki, J.; Zwierzak, A.
1994, 1063.
S.;
Mizuno, Y.; Takayangi,
Synthesis
(4)
Paul, R.; Anderson, G. W.
475.
charest)
a) Voinescu,
J.
Am. Chem. SOC.
1960,
82,
V.;
Herman, M.; Ramontian,
E.
4596.
(5)
(24,
1968,19,678.
(b) Kim, Y. C.; Lee, J.
I. Tetrahedron
Rev.
Chim. (Bu-
Lett.
1983,
(6)
3365.
(7)
Ueda, M.; Oikawa, H.; Teshirogi, T.
Nakao, R.; Oka,
K.;
Fukomoto, T.
Synthesis
1983, 908.
34,
-,
Bull. Chem. SOC. Jpn.
1981,
IZbl.
1960-7072$09.0010
i
jR”H2
I
x1
f
+
-+
R-C-OR‘
+
COO
R-CONHR‘ COP
3
CHBCH~OH
+
CH3CH20H
Another advantage of EEDQ is that hydroxylic amino
acids do not require side-chain protection since under
conditions encountered during peptide synthesis
carboxy-
lic
esters do
not
form.
The coupling reaction is expected
to moceed bv reaction of the mixed anhvdride intermedi-
ate
2
with imines to give amide derivatives (Scheme 1,
path i). We hypothesized that the reaction of an excess
of alcohol with the active anhydride
2
would form the
corresponding esters (Scheme 1, path
ii).
Indeed, treat-
ment of a mixture of reactant carboxvlic acid with EEDQ
in the presence of excess alcohol
at
room temperature
overnight or by heating at reflux for
a
few hours gave
the corresponding ester in high yield. Two minor varia-
tions were developed. In those reactions where the
alcohol has
may be used
a
low boiling point andor
as the reaction solvent. In those reactions
is
inexpensive,
it
where the alcohol has a high boiling point and/or the cost
prohibits its use
as solvent,
5-6
equiv of alcohol is added
to an inert solvent such as chloroform. Excess alcohol is
necessary because, as shown in Scheme 1, activation of
the carboxylic acid with EEDQ generates the mixed
anhydride
react with intermediate
2
with ethanol as byproduct. Ethanol could
not present, to give the corresponding ethyl ester.12
2,
if a competing nucleophile is
Indeed, this was observed by us during some difficult
peptide coupling reactions. To avoid this reaction, an
excess of alcohol is therefore employed as reactant.
Our results are summarized in Table
1.
A
variety of
acids are converted efficiently to their alkyl and benzyl
esters. The method is general and applicable to
a$-
unsaturated (entry lo), aromatic (entry 141, and aliphatic
acids. The reaction conditions are very mild, and as a
result, different functionalities (entries 9,11,12, and 14)
as well as acid sensitive (entries
sensitive (entry
23)
groups are unaffected.
7 and
8)
andor base
J.;
1976,
(8)
(a) Hendrickson,
277.
(b) Mestres, R.; Palomo, C.
J.
B.; Shwartzman,
Synthesis
S.
M.
1982,
Tetrahedron Lett.
288.
(c)
Cabre,
(9)
Palomo, A.
Olah, G. A,;
L.
Synthesis
Narang,
S.
1984, 413.
N. L.; Perron, Y. G.
(10)
(a) Belleau,
B;
C.; Garcia-Luna, A.
Synthesis
1981,790.
Malek, G.
J.
MAartel, R.; Lacasse, G.; MBnard, M.; Weinberg,
m. Chem. SOC.
1978, 90, 823.
(b) Belleau,
B.;
Approach to Enzyme Action;
(11)
Dugas,
J.
Am. Chem. SOC.
H.;
Penney, C.
1968,
90, 1651.
ester, was calculated by
(12)
The amount
of
ethyl ester byproduct, relative
Springer-Verlag: New York,
Bioorganic Chemistry;
A
to
the desired
1981.
Chemical
up to
less than
10%
of
lH
NMR. Although the byproduct could form
2%
the total yield at room temperature, typically it constituted
of the reaction under refluxing conditions.
0
1995 American Chemical Society
Notes
J.
Org. Chem.,
Vol.
60,
No.
21,
1995
7073
Table
1.
Esterification
of
RCOOH
with
R'OH using
EEDQ
reaction conditionsa
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
RCOOH
Z-Gly-OH
Z-Ala-OH
Z-Gly-OH
Z-Ala-OH
Z-Pro-OH
stearic acid
Boc-Phe-OH
Di-Boc-diaminopropionic acid
4-chlorophenylacetic acid
trans-cinnamic acid
6-bromohexanoic acid
3-(4-hydroxyphenyl)propionic
acid
R'OH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
equiv of ROH
solvent
solvent
solvent
solvent
solvent
solvent
6
6
solvent
solvent
solvent
solvent
solvent
time
O/N
O/N
O/N
O/N
5h
O/N
O/N
O/N
5h
temp
rt
yield
(%)b,c
94
80
95
80
88
84
79
70
94
80
75
84
91
rt
rt
rt
reflux
rt
rt
rt
O/N
O/N
5h
&LCOOH
p-anisic acid
Z-Gly-OH
Z-Gly-OH
Z-Gly-OH
Z-Ala-OH
Z-Ala-OH
Z-Gly-OH
Z-Phe-OH
Z-Phe-OH
Fmoc-Ala-OH
O/N
reflux
rt
rt
reflux
rt
14
15
16
17
18
19
20
21
22
23
EtOH
cyclohexanol
HO(CHd21
i-PrOH
i-PrOH
t-BuOH
t-BuOH
PhCHzOH
allyl alcohol
EtOH
solvent
12
6
solvent
solvent
solvent
solvent
6
solvent
solvent
5h
O/N
O/N
5h
5h
5h
5h
O/N
reflux
rt
rt
reflux
reflux
reflux
reflux
rt
5h
O/N
reflux
reflux
56
76
66
92
77
70
65
92
87
88
a
1.2
equiv of EEDQ. Isolated yield. All products had spectroscopic characteristics consistant with the assigned structures.
Sterically hindered acids (entry 13) as well as protected
amino acids (entries 1-5, 7, 8, and 15-23) were also
converted
to
their corresponding esters in high yield. "he
procedure is not limited to primary and secondary
alcohols (entries 17 and 18) since tert-butyl alcohol
reacted under similar conditions
to
give tert-butyl esters
(entries 19 and 20) in reasonable yield. Additionally,
esterification
of
t'posine with a nonprotected phenolic
hydroxyl (entry 12) was also successful. Finally, this
method is applicable
to
esters which are difficult
to
prepare by traditional methods (entries 15, 16, and 22).
No
evidence
of
racemization was observed in the
preparation
of
the dipeptide ester Z-Val-Ala-OCH3 from
the parent acid. Comparison of the
lH
NMR
and optical
rotation with an authentic sample demonstrated the
absence
of
diastereoisomers.
EEDQ is a stable, readily available reagent which
offers a number
of
advantages over the use
of
other
commonly used esterification reagents and procedures.
One set
of
reaction conditions is suitable for a variety
of
esters, the manipulation
of
EEDQ does not require
strictly anhydrous conditions or an inert atmosphere, and
the purification
of
product is uniquely simple. The ester
products are conveniently isolated by aqueous acid wash
of
the crude residue to remove quinoline. The synthesis
is therefore amenable
to
scale-up. Further, EEDQ is
easier
to
handle than carbodiimides such as N,N-dicy-
clohexylcarbodiimide (DCC), which can elicit contact
dermatitis. Urea byproducts generated from carbodiim-
ide
reactions are more difficult
to
remove than quinoline.
Another disadvantage
of
DCC
arises when used with
DMAF':
the procedure is inappropriate for compounds
with base-labile f~nctiona1ities.l~ More recently a new
esterification methodology was reported which employs
BOP reagent.14 This procedure is limited
to
primary and
secondary alcohols and the workup is tedious. Further-
(13)
Campbell,
D.
A.
unpublished data,
see
ref
13.
(14)
Kim,
M. H.;
Patel,
D.
V.
Tertrahedron
Lett.
1994,
5603.
more, no data was provided regarding racemization
during esterification.
In concl,usion, we have discovered a new use for a well-
known
peptide coupling agent, EEDQ. Depending upon
reagent concentrations and reaction conditions, EEDQ
may be used
to affect efficient esterification of carboxylic
acids.
Experimental Section
Melting points were measured on a Fisher-Johns melting
point apparatus and are uncorrected. lH NMR spectra were
obtained on a Bruker DRX-400
or
on
a
Varian
VXR
300
spectrometer. Mass spectra were recorded on
a
Kratos MS-50
TA instrument. EEDQ was obtained from Aldrich (Milwaukee,
WI),
and all amino acids wre obtained from Bachem Bioscience
(King of Prussia, PA).
General Procedure
for
the
Preparation
of
Ester.
EEDQ
(1.2
mmol) was added to a solution of the acid
(1
mmol) dissolved
mL)
or
in chloroform
(20
mL) containing excess in alcohol
(20
h
at room alcohol (6 mmol). The reaction was stirred for
12
temperature
or
at
reflux for
5
h,
and the solvent was evaporated
under reduced pressure. The residue was dissolved in ethyl
mL), washed with 5% hydrochloric acid, and dried acetate
(20
with anhydrous sodium sulfate. Ethyl acetate was evaporated
under reduced pressure to afford the crude product which was
purified by short column flash silica gel chromatography. In
the case of acid-labile compounds, the acid wash was omitted
and the crude product chromatographed directly after removal
of the reaction solvent.
Acknowledgment.
We appreciate the thoughtful
reading
of
this manuscript by Drs.
S.
Abbott and
J.
Gillard. We also thank Ms.
L.
Marcil and Ms. N. Pilote
for secretarial and technical assistance.
Registry
numbers (supplied
by
author):
N4Ben-
zyloxycarbony1)glycine methyl ester, 1212-53-9; N-(ben-
zyloxcarbony1)alanine methyl ester, 28819-05-8; N-(ben-
zyloxycarbony1)glycine ethyl ester, 1145-81-9; D-Alanine,
N-[(phenylmethoxy)carbonyl]-,
ethyl ester, 157774-53-3;
1,2-pyrrolidinedicarboxylic
acid, 2-ethyl 1-(phenylmethyl)
ester,
(S),
51207-69-3; ethyl stearate, 111-61-5; N-(tert-
7074
J.
Org. Chem.,
Vol.
60,
No.
21,
1995
Additions and Corrections
bonyl)glycinate, 3612495-5;
N4benzyloxcarbonyl)alanine
isopropyl ester, 121616-33-9;
N-(benzyloxycarbony1)ala-
nine tert-butyl ester, 50300-96-4; N4benzyloxycarbonyl)
glycine tert-butyl ester, 16881-32-6; L-phenylalanine,
N-[(phenylmethoxy)carbonyl]-,
phenylmethyl ester, 60379-
01-3; L-phenylalanine,
N-[(phenylmethoxy)carbonyll-,
2-propenyl ester, 64286-85-7; L-alanine, N-[(SH-fluoren-
9-ylmethoxy)carbonyl]-, ethyl ester, 117402-82-1.
509506645
butoxycarbony1)phenylalanine
ethyl ester, 53588-99-1;
alanine,
N-[
(l,l-dimethylethoxy)carbonyl]-3-[
[(
1,
l-di-
methylethoxy)carbonyl]amino]-,
ethyl ester, 109461-78-
1; ethyl
(4-~hlorophenyl)acetate,
14062-24-9; ethyl cin-
namate, 103-36-6; ethyl 6-bromohexanoate, 25542-62-5;
23795-02-0; ethyl
ethyl
3-(4-hydroxyphenyl)propionate,
1-adamantanecarboxylate, 2094-73-7; ethyl 4-methoxy-
benzoate, 94-30-4; glycine, N-carboxy-N-benzyl cyclohexyl
N-[(phenylmethoxy)carbonyll-
ester, 108977-05-5; glycine,
,240doethyl ester, 156539-07-0; isopropyl (benzyloxycar-
Additions and Corrections
Vol. 59, 1994
William
Adcock,*
Jason
Cotton, and Neil
A
Trout.
Elec-
trostatic
us
Hyperconjugative Effects
as
Stereoinductive Factors
in the Adamantane Ring System.
Page 1872, Table
3,
entry for
S
=
H in CHzClz should
be 31
(%E)
69 (%Z). Table 4, footnote 2,
@FS
should be
-1.021.
Page 1873, Table
5,
footnote 2,
@FS
should be -1.635.
Table 6, footnote
2,
@FS
should be 2.502.
509540209
Vol. 60, 1995
A
S. C. Chan,* T. T. Huang,
J.
H.
Wagenknecht, and
R. E.
Miller.
A
Novel Synthesis
of
2-Aryllactic Acids via
Electrocarboxylation
of
Methyl Aryl Ketones
.
Page 742. In refs 9-15 we failed to include the work
by Silvestri and co-workers on
the
use of a sacrificial
aluminum anode for the electrocarboxylation of various
aryl methyl ketones including the 6-methoxynaphthyl
and p-isobutylphenyl precursors to naproxen and ibu-
profen. The representative articles are as follows:
(1)
Silvestri, G.; Gambino,
S.;
Filardo,
G.
Tetrahedron Lett.
1986,27,
U.S.
3429. (2) Silvestri, G.; Gambino,
S.;
Filardo,
G. Pat.
4,708,780, 1987.
50954016X
Nina
E.
Heard* and
JoLyn
Turner.
Synthesis
of
a
Novel
N-Hydroxypyrrole via Lithium Perchlorate Accelerated Diels-
Alder Methodology.
Page 4302, paragraph 4, line
2
should read N-siloxy-
pyrrole
12l.
Page 4302, paragraph 2, line
3
should read
reaction .5...and line 4 should read diethyl etherL6. 4.
Footnote 7 should be added
to
the experimental synthesis
of compound
k7
13
as follows:
...-
ene-2-carbonitrile
(13).
Method
Siloxypyrrole
....
Page 4303, Table
1.
Column head for column
8
should
read yield
13d.
Entry 9 in column 8 should read
0733.
J0954017P
2024年2月17日发(作者：那曼)
7072
J.
Org. Chem. 1995,60,
7072-7074
A
Simple One-Step Conversion
of
Carboxylic
Acids
to Esters Using
EEDQt
Boulos Zacharie,* Timothy
P.
Connolly, and
Christopher
L.
Penney
Department
of
Medicinal Chemistry,
BioChem Therapeutic Inc.,
275 Armand-Frappier Blvd.,
Laval, QuCbec, Canada
H7V
4A7
Received April
7,
1995
Scheme
1.
Directed Esterification
of
Carboxylic
Acids with Alcohols Using
EEDQ
1
1
CH3CH20
1
The esterification of carboxylic acids is a commonly
2
encountered reaction in organic chemistry.
A
large
number of ester protecting groups have been described
in the 1iterature.l Although a variety of conditions for
ester formation have already been developed,2 they are
not always satisfactory in yield andor simplicity of
operation. Most require either the presence of strong
acids, bases, or other catalysts or the application of heat.
Simple processes that allow esterification under mild
conditions are very desirable. These procedures are of
considerable interest, especially in the manipulation of
many peptides, macrolides, and natural products. Our
goal, therefore, was to develop a general and simple one-
step procedure for the preparation of esters, under
neutral conditions, from their parent acids.
Several methods are reported for the activation of
carboxylic acids and subsequent conversion to esters and
other derivatives. The most common are ~arbodiimides,~
N-acyl derivatives of imida~ole,~ acyl
(carbonyldioxy)dibenzotriazoles,6
chlorotrimethyl~ilane,~~~~
carbonate^,^^^^
1,l’-
several organophosphorus reagents,S sulfonyl chlorides,2e
sulfuryl chloride fl~oride,~ and
nyl)-1,2-dihydroquinoline
(EEDQ,1°
2-ethoxy-l-(ethoxycarbo-
1).
The latter re-
agent is a well-known coupling agent for the formation
of peptide It allows the coupling of protected
amino acids with amino acid esters in a single operation
and with little or no racemization.
c=o
OC2H5
I
1
lumbus, OH, June
+Presented at the Fourteenth American Peptide Symposium (Co-
Synthesis;
(1)
(a) Greene, T.
18-23).
W.;
Wuts,
P.
G. M.
Protective Groups in Organic
Pearson,
York,
D.
John Wiley
E.
Survey
&
Sons: New York, (b) Buchler,
of
Organic Synthesis;
Wiley-Interscience: New
1991.
C.
A.;
Synthesis
(2)
For
1970.
(c)
51,
Shono, T1983,
selected examples, see: (a) Brook, M. A.; Chan, T.
.; Ishige,
201.
0.;
(b) Ramaiah, M.
H.
Uyama,
H.;
Kashimura,
J.
Org. Chem.
S.
J.
O1985,
rg. Chem.
50,
4991.
1986,
P.; Lecolier,
546.
(d) Jouin, P.; Castro, B.; Zeggaf,
C.;
Pantaloni, A.; Senet, J.
Jaszay,
K.;
M.; Petnehlzy,
S.;
Sennyey, G.
I.;
Toke, L.
Tetrahedron Lett.
Synthesis
1987,
28,
1661.
(e)
H.; Harigaya, Y.
Akiyama,
Z.
H.;
Nakamura,
H.;
Takizawa,
1989,745.
(0 Takeda,
1978,
(3)
Gorecka,
A,;
Synthesis
Leplawy, M.; Zabrocki, J.; Zwierzak, A.
1994, 1063.
S.;
Mizuno, Y.; Takayangi,
Synthesis
(4)
Paul, R.; Anderson, G. W.
475.
charest)
a) Voinescu,
J.
Am. Chem. SOC.
1960,
82,
V.;
Herman, M.; Ramontian,
E.
4596.
(5)
(24,
1968,19,678.
(b) Kim, Y. C.; Lee, J.
I. Tetrahedron
Rev.
Chim. (Bu-
Lett.
1983,
(6)
3365.
(7)
Ueda, M.; Oikawa, H.; Teshirogi, T.
Nakao, R.; Oka,
K.;
Fukomoto, T.
Synthesis
1983, 908.
34,
-,
Bull. Chem. SOC. Jpn.
1981,
IZbl.
1960-7072$09.0010
i
jR”H2
I
x1
f
+
-+
R-C-OR‘
+
COO
R-CONHR‘ COP
3
CHBCH~OH
+
CH3CH20H
Another advantage of EEDQ is that hydroxylic amino
acids do not require side-chain protection since under
conditions encountered during peptide synthesis
carboxy-
lic
esters do
not
form.
The coupling reaction is expected
to moceed bv reaction of the mixed anhvdride intermedi-
ate
2
with imines to give amide derivatives (Scheme 1,
path i). We hypothesized that the reaction of an excess
of alcohol with the active anhydride
2
would form the
corresponding esters (Scheme 1, path
ii).
Indeed, treat-
ment of a mixture of reactant carboxvlic acid with EEDQ
in the presence of excess alcohol
at
room temperature
overnight or by heating at reflux for
a
few hours gave
the corresponding ester in high yield. Two minor varia-
tions were developed. In those reactions where the
alcohol has
may be used
a
low boiling point andor
as the reaction solvent. In those reactions
is
inexpensive,
it
where the alcohol has a high boiling point and/or the cost
prohibits its use
as solvent,
5-6
equiv of alcohol is added
to an inert solvent such as chloroform. Excess alcohol is
necessary because, as shown in Scheme 1, activation of
the carboxylic acid with EEDQ generates the mixed
anhydride
react with intermediate
2
with ethanol as byproduct. Ethanol could
not present, to give the corresponding ethyl ester.12
2,
if a competing nucleophile is
Indeed, this was observed by us during some difficult
peptide coupling reactions. To avoid this reaction, an
excess of alcohol is therefore employed as reactant.
Our results are summarized in Table
1.
A
variety of
acids are converted efficiently to their alkyl and benzyl
esters. The method is general and applicable to
a$-
unsaturated (entry lo), aromatic (entry 141, and aliphatic
acids. The reaction conditions are very mild, and as a
result, different functionalities (entries 9,11,12, and 14)
as well as acid sensitive (entries
sensitive (entry
23)
groups are unaffected.
7 and
8)
andor base
J.;
1976,
(8)
(a) Hendrickson,
277.
(b) Mestres, R.; Palomo, C.
J.
B.; Shwartzman,
Synthesis
S.
M.
1982,
Tetrahedron Lett.
288.
(c)
Cabre,
(9)
Palomo, A.
Olah, G. A,;
L.
Synthesis
Narang,
S.
1984, 413.
N. L.; Perron, Y. G.
(10)
(a) Belleau,
B;
C.; Garcia-Luna, A.
Synthesis
1981,790.
Malek, G.
J.
MAartel, R.; Lacasse, G.; MBnard, M.; Weinberg,
m. Chem. SOC.
1978, 90, 823.
(b) Belleau,
B.;
Approach to Enzyme Action;
(11)
Dugas,
J.
Am. Chem. SOC.
H.;
Penney, C.
1968,
90, 1651.
ester, was calculated by
(12)
The amount
of
ethyl ester byproduct, relative
Springer-Verlag: New York,
Bioorganic Chemistry;
A
to
the desired
1981.
Chemical
up to
less than
10%
of
lH
NMR. Although the byproduct could form
2%
the total yield at room temperature, typically it constituted
of the reaction under refluxing conditions.
0
1995 American Chemical Society
Notes
J.
Org. Chem.,
Vol.
60,
No.
21,
1995
7073
Table
1.
Esterification
of
RCOOH
with
R'OH using
EEDQ
reaction conditionsa
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
RCOOH
Z-Gly-OH
Z-Ala-OH
Z-Gly-OH
Z-Ala-OH
Z-Pro-OH
stearic acid
Boc-Phe-OH
Di-Boc-diaminopropionic acid
4-chlorophenylacetic acid
trans-cinnamic acid
6-bromohexanoic acid
3-(4-hydroxyphenyl)propionic
acid
R'OH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
equiv of ROH
solvent
solvent
solvent
solvent
solvent
solvent
6
6
solvent
solvent
solvent
solvent
solvent
time
O/N
O/N
O/N
O/N
5h
O/N
O/N
O/N
5h
temp
rt
yield
(%)b,c
94
80
95
80
88
84
79
70
94
80
75
84
91
rt
rt
rt
reflux
rt
rt
rt
O/N
O/N
5h
&LCOOH
p-anisic acid
Z-Gly-OH
Z-Gly-OH
Z-Gly-OH
Z-Ala-OH
Z-Ala-OH
Z-Gly-OH
Z-Phe-OH
Z-Phe-OH
Fmoc-Ala-OH
O/N
reflux
rt
rt
reflux
rt
14
15
16
17
18
19
20
21
22
23
EtOH
cyclohexanol
HO(CHd21
i-PrOH
i-PrOH
t-BuOH
t-BuOH
PhCHzOH
allyl alcohol
EtOH
solvent
12
6
solvent
solvent
solvent
solvent
6
solvent
solvent
5h
O/N
O/N
5h
5h
5h
5h
O/N
reflux
rt
rt
reflux
reflux
reflux
reflux
rt
5h
O/N
reflux
reflux
56
76
66
92
77
70
65
92
87
88
a
1.2
equiv of EEDQ. Isolated yield. All products had spectroscopic characteristics consistant with the assigned structures.
Sterically hindered acids (entry 13) as well as protected
amino acids (entries 1-5, 7, 8, and 15-23) were also
converted
to
their corresponding esters in high yield. "he
procedure is not limited to primary and secondary
alcohols (entries 17 and 18) since tert-butyl alcohol
reacted under similar conditions
to
give tert-butyl esters
(entries 19 and 20) in reasonable yield. Additionally,
esterification
of
t'posine with a nonprotected phenolic
hydroxyl (entry 12) was also successful. Finally, this
method is applicable
to
esters which are difficult
to
prepare by traditional methods (entries 15, 16, and 22).
No
evidence
of
racemization was observed in the
preparation
of
the dipeptide ester Z-Val-Ala-OCH3 from
the parent acid. Comparison of the
lH
NMR
and optical
rotation with an authentic sample demonstrated the
absence
of
diastereoisomers.
EEDQ is a stable, readily available reagent which
offers a number
of
advantages over the use
of
other
commonly used esterification reagents and procedures.
One set
of
reaction conditions is suitable for a variety
of
esters, the manipulation
of
EEDQ does not require
strictly anhydrous conditions or an inert atmosphere, and
the purification
of
product is uniquely simple. The ester
products are conveniently isolated by aqueous acid wash
of
the crude residue to remove quinoline. The synthesis
is therefore amenable
to
scale-up. Further, EEDQ is
easier
to
handle than carbodiimides such as N,N-dicy-
clohexylcarbodiimide (DCC), which can elicit contact
dermatitis. Urea byproducts generated from carbodiim-
ide
reactions are more difficult
to
remove than quinoline.
Another disadvantage
of
DCC
arises when used with
DMAF':
the procedure is inappropriate for compounds
with base-labile f~nctiona1ities.l~ More recently a new
esterification methodology was reported which employs
BOP reagent.14 This procedure is limited
to
primary and
secondary alcohols and the workup is tedious. Further-
(13)
Campbell,
D.
A.
unpublished data,
see
ref
13.
(14)
Kim,
M. H.;
Patel,
D.
V.
Tertrahedron
Lett.
1994,
5603.
more, no data was provided regarding racemization
during esterification.
In concl,usion, we have discovered a new use for a well-
known
peptide coupling agent, EEDQ. Depending upon
reagent concentrations and reaction conditions, EEDQ
may be used
to affect efficient esterification of carboxylic
acids.
Experimental Section
Melting points were measured on a Fisher-Johns melting
point apparatus and are uncorrected. lH NMR spectra were
obtained on a Bruker DRX-400
or
on
a
Varian
VXR
300
spectrometer. Mass spectra were recorded on
a
Kratos MS-50
TA instrument. EEDQ was obtained from Aldrich (Milwaukee,
WI),
and all amino acids wre obtained from Bachem Bioscience
(King of Prussia, PA).
General Procedure
for
the
Preparation
of
Ester.
EEDQ
(1.2
mmol) was added to a solution of the acid
(1
mmol) dissolved
mL)
or
in chloroform
(20
mL) containing excess in alcohol
(20
h
at room alcohol (6 mmol). The reaction was stirred for
12
temperature
or
at
reflux for
5
h,
and the solvent was evaporated
under reduced pressure. The residue was dissolved in ethyl
mL), washed with 5% hydrochloric acid, and dried acetate
(20
with anhydrous sodium sulfate. Ethyl acetate was evaporated
under reduced pressure to afford the crude product which was
purified by short column flash silica gel chromatography. In
the case of acid-labile compounds, the acid wash was omitted
and the crude product chromatographed directly after removal
of the reaction solvent.
Acknowledgment.
We appreciate the thoughtful
reading
of
this manuscript by Drs.
S.
Abbott and
J.
Gillard. We also thank Ms.
L.
Marcil and Ms. N. Pilote
for secretarial and technical assistance.
Registry
numbers (supplied
by
author):
N4Ben-
zyloxycarbony1)glycine methyl ester, 1212-53-9; N-(ben-
zyloxcarbony1)alanine methyl ester, 28819-05-8; N-(ben-
zyloxycarbony1)glycine ethyl ester, 1145-81-9; D-Alanine,
N-[(phenylmethoxy)carbonyl]-,
ethyl ester, 157774-53-3;
1,2-pyrrolidinedicarboxylic
acid, 2-ethyl 1-(phenylmethyl)
ester,
(S),
51207-69-3; ethyl stearate, 111-61-5; N-(tert-
7074
J.
Org. Chem.,
Vol.
60,
No.
21,
1995
Additions and Corrections
bonyl)glycinate, 3612495-5;
N4benzyloxcarbonyl)alanine
isopropyl ester, 121616-33-9;
N-(benzyloxycarbony1)ala-
nine tert-butyl ester, 50300-96-4; N4benzyloxycarbonyl)
glycine tert-butyl ester, 16881-32-6; L-phenylalanine,
N-[(phenylmethoxy)carbonyl]-,
phenylmethyl ester, 60379-
01-3; L-phenylalanine,
N-[(phenylmethoxy)carbonyll-,
2-propenyl ester, 64286-85-7; L-alanine, N-[(SH-fluoren-
9-ylmethoxy)carbonyl]-, ethyl ester, 117402-82-1.
509506645
butoxycarbony1)phenylalanine
ethyl ester, 53588-99-1;
alanine,
N-[
(l,l-dimethylethoxy)carbonyl]-3-[
[(
1,
l-di-
methylethoxy)carbonyl]amino]-,
ethyl ester, 109461-78-
1; ethyl
(4-~hlorophenyl)acetate,
14062-24-9; ethyl cin-
namate, 103-36-6; ethyl 6-bromohexanoate, 25542-62-5;
23795-02-0; ethyl
ethyl
3-(4-hydroxyphenyl)propionate,
1-adamantanecarboxylate, 2094-73-7; ethyl 4-methoxy-
benzoate, 94-30-4; glycine, N-carboxy-N-benzyl cyclohexyl
N-[(phenylmethoxy)carbonyll-
ester, 108977-05-5; glycine,
,240doethyl ester, 156539-07-0; isopropyl (benzyloxycar-
Additions and Corrections
Vol. 59, 1994
William
Adcock,*
Jason
Cotton, and Neil
A
Trout.
Elec-
trostatic
us
Hyperconjugative Effects
as
Stereoinductive Factors
in the Adamantane Ring System.
Page 1872, Table
3,
entry for
S
=
H in CHzClz should
be 31
(%E)
69 (%Z). Table 4, footnote 2,
@FS
should be
-1.021.
Page 1873, Table
5,
footnote 2,
@FS
should be -1.635.
Table 6, footnote
2,
@FS
should be 2.502.
509540209
Vol. 60, 1995
A
S. C. Chan,* T. T. Huang,
J.
H.
Wagenknecht, and
R. E.
Miller.
A
Novel Synthesis
of
2-Aryllactic Acids via
Electrocarboxylation
of
Methyl Aryl Ketones
.
Page 742. In refs 9-15 we failed to include the work
by Silvestri and co-workers on
the
use of a sacrificial
aluminum anode for the electrocarboxylation of various
aryl methyl ketones including the 6-methoxynaphthyl
and p-isobutylphenyl precursors to naproxen and ibu-
profen. The representative articles are as follows:
(1)
Silvestri, G.; Gambino,
S.;
Filardo,
G.
Tetrahedron Lett.
1986,27,
U.S.
3429. (2) Silvestri, G.; Gambino,
S.;
Filardo,
G. Pat.
4,708,780, 1987.
50954016X
Nina
E.
Heard* and
JoLyn
Turner.
Synthesis
of
a
Novel
N-Hydroxypyrrole via Lithium Perchlorate Accelerated Diels-
Alder Methodology.
Page 4302, paragraph 4, line
2
should read N-siloxy-
pyrrole
12l.
Page 4302, paragraph 2, line
3
should read
reaction .5...and line 4 should read diethyl etherL6. 4.
Footnote 7 should be added
to
the experimental synthesis
of compound
k7
13
as follows:
...-
ene-2-carbonitrile
(13).
Method
Siloxypyrrole
....
Page 4303, Table
1.
Column head for column
8
should
read yield
13d.
Entry 9 in column 8 should read
0733.
J0954017P