7072 J . Org. Chem.

1995,60,7072-7074

A Simple One-Step Conversion of Scheme 1. Directed Esterification of Carboxylic

Carboxylic Acids to Esters Using EEDQt Acids with Alcohols Using EEDQ

Boulos Zacharie,* Timothy P. Connolly, and

Christopher L. Penney
Department of Medicinal Chemistry,
BioChem Therapeutic Inc., 275 Armand-Frappier Blvd., 1 1 CH3CH20
1
Laval, QuCbec, Canada H7V 4A7

Received April 7, 1995

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
i R”H2
I
j 1
x
ester formation have already been developed,2they are f
R-C-OR‘ + COO
not always satisfactory in yield andor simplicity of
operation. Most require either the presence of strong R-CONHR‘ -+ COP 3
acids, bases, or other catalysts or the application of heat. + CHBCH~OH + CH3CH20H
Simple processes that allow esterification under mild
Another advantage of EEDQ is that hydroxylic amino
conditions are very desirable. These procedures are of
acids do not require side-chain protection since under
considerable interest, especially in the manipulation of
conditions encountered during peptide synthesis carboxy-
many peptides, macrolides, and natural products. Our
lic esters do not form. The coupling reaction is expected
goal, therefore, was to develop a general and simple one- to moceed bv reaction of the mixed anhvdride intermedi-
step procedure for the preparation of esters, under ate 2 with imines to give amide derivatives (Scheme 1,
neutral conditions, from their parent acids. path i). We hypothesized that the reaction of an excess
Several methods are reported for the activation of of alcohol with the active anhydride 2 would form the
carboxylic acids and subsequent conversion to esters and corresponding esters (Scheme 1, path ii). Indeed, treat-
other derivatives. The most common are ~arbodiimides,~ ment of a mixture of reactant carboxvlic acid with EEDQ
N-acyl derivatives of i m i d a ~ o l eacyl , ~ carbonate^,^^^^ 1,l’- in the presence of excess alcohol at room temperature
(carbonyldioxy)dibenzotriazoles,6chlorotrimethyl~ilane,~~~~overnight or by heating at reflux for a few hours gave
several organophosphorus reagents,S sulfonyl chlorides,2e the corresponding ester in high yield. Two minor varia-
sulfuryl chloride f l ~ o r i d eand , ~ 2-ethoxy-l-(ethoxycarbo- tions were developed. In those reactions where the
nyl)-1,2-dihydroquinoline(EEDQ,1° 1). The latter re- alcohol has a low boiling point andor is inexpensive, it
agent is a well-known coupling agent for the formation may be used as the reaction solvent. In those reactions
of peptide bonds.ll It allows the coupling of protected where the alcohol has a high boiling point and/or the cost
amino acids with amino acid esters in a single operation prohibits its use as solvent, 5-6 equiv of alcohol is added
and with little or no racemization. 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 2 with ethanol as byproduct. Ethanol could
react with intermediate 2, if a competing nucleophile is
c=o not present, to give the corresponding ethyl ester.12
I Indeed, this was observed by us during some difficult
OC2H5 peptide coupling reactions. To avoid this reaction, an
1 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
+Presented at the Fourteenth American Peptide Symposium (Co-
lumbus, OH, June 18-23). esters. The method is general and applicable to a$-
(1)(a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic unsaturated (entry lo), aromatic (entry 141, and aliphatic
Synthesis; John Wiley & Sons: New York, 1991.(b) Buchler, C. A.; acids. The reaction conditions are very mild, and as a
Pearson, D. E. Survey of Organic Synthesis; Wiley-Interscience: New
York, 1970. result, different functionalities (entries 9,11,12, and 14)
(2)For selected examples, see: (a) Brook, M. A.; Chan, T. H. as well as acid sensitive (entries 7 and 8 ) andor base
Synthesis 1983,201.(b) Ramaiah, M. J. Org. Chem. 1985,50,4991. sensitive (entry 23) groups are unaffected.
( c ) Shono, T.; Ishige, 0.;Uyama, H.; Kashimura, S. J. Org. Chem. 1986,
51, 546. (d) Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J .
P.; Lecolier, S.; Sennyey, G. Tetrahedron Lett. 1987,28, 1661. (e) (8) (a) Hendrickson, J. B.; Shwartzman, S. M. Tetrahedron Lett.
Jaszay, Z.M.; Petnehlzy, I.; Toke, L. Synthesis 1989,745.(0 Takeda, 1976,277.(b) Mestres, R.; Palomo, C. Synthesis 1982,288.( c ) Cabre,
K.;Akiyama, H.; Nakamura, H.; Takizawa, S.; Mizuno, Y.; Takayangi, J.; Palomo, A. L. Synthesis 1984,413.
H.; Harigaya, Y. Synthesis 1994,1063. (9)Olah, G. A,; Narang, S. C.; Garcia-Luna, A. Synthesis 1981,790.
(3)Gorecka, A,; Leplawy, M.; Zabrocki, J.; Zwierzak, A. Synthesis (10)(a) Belleau, B;Martel, R.; Lacasse, G.; MBnard, M.; Weinberg,
1978,475. N. L.; Perron, Y. G. J. Am. Chem. SOC.1978,90,823.(b) Belleau, B.;
(4)Paul, R.; Anderson, G. W. J.Am. Chem. SOC.1960,82, 4596. Malek, G. J.Am. Chem. SOC.1968,90,1651.
(5) (a) Voinescu, V.; Herman, M.; Ramontian, E. Rev. Chim. (Bu- (11)Dugas, H.;Penney, C. Bioorganic Chemistry; A Chemical
charest) 1968,19,678. (b) Kim, Y. C.; Lee, J . I. Tetrahedron Lett. 1983, Approach to Enzyme Action; Springer-Verlag: New York, 1981.
24, 3365. (12)The amount of ethyl ester byproduct, relative to the desired
(6)Ueda, M.; Oikawa, H.; Teshirogi, T. Synthesis 1983,908. ester, was calculated by lH NMR. Although the byproduct could form
-,
(7)Nakao, R.; Oka, K.; Fukomoto, T. Bull. Chem. SOC.Jpn. 1981, up to 10% of the total yield at room temperature, typically it constituted
34, I Z b l . less than 2% of the reaction under refluxing conditions.
0022-326319511960-7072$09.0010 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 RCOOH R'OH equiv of R O H time temp yield (%)b,c
1 Z-Gly-OH MeOH solvent O/N rt 94
2 Z-Ala-OH MeOH solvent O/N rt 80
3 Z-Gly-OH EtOH solvent O/N rt 95
4 Z-Ala-OH EtOH solvent O/N rt 80
5 Z-Pro-OH EtOH solvent 5h reflux 88
6 stearic acid EtOH solvent O/N rt 84
7 Boc-Phe-OH EtOH 6 O/N rt 79
8 Di-Boc-diaminopropionic acid EtOH 6 O/N rt 70
9 4-chlorophenylacetic acid EtOH solvent 5h reflux 94
10 trans-cinnamic acid EtOH solvent O/N rt 80
11 6-bromohexanoic acid EtOH solvent O/N rt 75
12 3-(4-hydroxyphenyl)propionicacid EtOH solvent 5h reflux 84
13 EtOH solvent O/N rt 91
&LCOOH
14 p-anisic acid EtOH solvent 5h reflux 56
15 Z-Gly-OH cyclohexanol 12 O/N rt 76
16 Z-Gly-OH HO(CHd21 6 O/N rt 66
17 Z-Gly-OH i-PrOH solvent 5h reflux 92
18 Z-Ala-OH i-PrOH solvent 5h reflux 77
19 Z-Ala-OH t-BuOH solvent 5h reflux 70
20 Z-Gly-OH t-BuOH solvent 5h reflux 65
21 Z-Phe-OH PhCHzOH 6 O/N rt 92
22 Z-Phe-OH allyl alcohol solvent 5h reflux 87
23 Fmoc-Ala-OH EtOH solvent O/N reflux 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 more, no data was provided regarding racemization
amino acids (entries 1-5, 7, 8, and 15-23) were also during esterification.
converted to their corresponding esters in high yield. "he In concl,usion,we have discovered a new use for a well-
procedure is not limited to primary and secondary known peptide coupling agent, EEDQ. Depending upon
alcohols (entries 17 and 18) since tert-butyl alcohol reagent concentrations and reaction conditions, EEDQ
reacted under similar conditions to give tert-butyl esters may be used to affect efficient esterification of carboxylic
(entries 19 and 20) in reasonable yield. Additionally, acids.
esterification of t'posine with a nonprotected phenolic
hydroxyl (entry 12) was also successful. Finally, this Experimental Section
method is applicable to esters which are difficult to
prepare by traditional methods (entries 15, 16, and 22). Melting points were measured on a Fisher-Johns melting
point apparatus and are uncorrected. lH NMR spectra were
No evidence of racemization was observed in the obtained on a Bruker DRX-400 or on a Varian VXR 300
preparation of the dipeptide ester Z-Val-Ala-OCH3from spectrometer. Mass spectra were recorded on a Kratos MS-50
the parent acid. Comparison of the lH NMR and optical TA instrument. EEDQ was obtained from Aldrich (Milwaukee,
rotation with an authentic sample demonstrated the WI), and all amino acids wre obtained from Bachem Bioscience
absence of diastereoisomers. (King of Prussia, PA).
General Procedure for the Preparation of Ester. EEDQ
EEDQ is a stable, readily available reagent which (1.2mmol) was added to a solution of the acid (1mmol) dissolved
offers a number of advantages over the use of other in alcohol (20 mL) or in chloroform (20 mL) containing excess
commonly used esterification reagents and procedures. alcohol (6 mmol). The reaction was stirred for 12 h a t room
One set of reaction conditions is suitable for a variety of temperature or at reflux for 5 h, and the solvent was evaporated
esters, the manipulation of EEDQ does not require under reduced pressure. The residue was dissolved in ethyl
acetate (20 mL), washed with 5% hydrochloric acid, and dried
strictly anhydrous conditions or an inert atmosphere, and with anhydrous sodium sulfate. Ethyl acetate was evaporated
the purification of product is uniquely simple. The ester under reduced pressure to afford the crude product which was
products are conveniently isolated by aqueous acid wash purified by short column flash silica gel chromatography. In
of the crude residue to remove quinoline. The synthesis the case of acid-labile compounds, the acid wash was omitted
is therefore amenable to scale-up. Further, EEDQ is and the crude product chromatographed directly after removal
easier to handle than carbodiimides such as N,N-dicy- of the reaction solvent.
clohexylcarbodiimide (DCC), which can elicit contact
dermatitis. Urea byproducts generated from carbodiim- Acknowledgment. We appreciate the thoughtful
ide reactions are more difficult to remove than quinoline. reading of this manuscript by Drs. S. Abbott and J.
Gillard. We also thank Ms. L. Marcil and Ms. N. Pilote
Another disadvantage of DCC arises when used with for secretarial and technical assistance.
DMAF': the procedure is inappropriate for compounds
with base-labile f~nctiona1ities.l~More recently a new Registry numbers (supplied by author): N4Ben-
esterification methodology was reported which employs zyloxycarbony1)glycinemethyl ester, 1212-53-9;N-(ben-
BOP reagent.14 This procedure is limited to primary and zyloxcarbony1)alanine methyl ester, 28819-05-8; N-(ben-
secondary alcohols and the workup is tedious. Further- zyloxycarbony1)glycine ethyl ester, 1145-81-9; D-Alanine,
N-[(phenylmethoxy)carbonyl]-, ethyl ester, 157774-53-3;
(13)Campbell, D. A. unpublished data, see ref 13. 1,2-pyrrolidinedicarboxylicacid, 2-ethyl 1-(phenylmethyl)
(14)Kim, M. H.; Patel, D. V. Tertrahedron Lett. 1994, 5603. ester, (S),
51207-69-3; ethyl stearate, 111-61-5; N-(tert-
7074 J. Org. Chem., Vol. 60, No. 21, 1995 Additions and Corrections

butoxycarbony1)phenylalanine ethyl ester, 53588-99-1; bonyl)glycinate,3612495-5; N4benzyloxcarbonyl)alanine

alanine, N-[(l,l-dimethylethoxy)carbonyl]-3-[ [(1,l-di- isopropyl ester, 121616-33-9; N-(benzyloxycarbony1)ala-
methylethoxy)carbonyl]amino]-, ethyl ester, 109461-78- nine tert-butyl ester, 50300-96-4; N4benzyloxycarbonyl)
1; ethyl (4-~hlorophenyl)acetate, 14062-24-9; ethyl cin- glycine tert-butyl ester, 16881-32-6; L-phenylalanine,
namate, 103-36-6; ethyl 6-bromohexanoate, 25542-62-5; N-[(phenylmethoxy)carbonyl]-,phenylmethyl ester, 60379-
ethyl 3-(4-hydroxyphenyl)propionate, 23795-02-0; ethyl 01-3; L-phenylalanine, N-[(phenylmethoxy)carbonyll-,
1-adamantanecarboxylate, 2094-73-7; ethyl 4-methoxy- 2-propenyl ester, 64286-85-7; L-alanine, N-[(SH-fluoren-
benzoate, 94-30-4; glycine,N-carboxy-N-benzyl cyclohexyl 9-ylmethoxy)carbonyl]-, ethyl ester, 117402-82-1.
ester, 108977-05-5;glycine,N-[(phenylmethoxy)carbonyll-
,240doethyl ester, 156539-07-0; isopropyl (benzyloxycar- 509506645

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, 3429. (2) Silvestri, G.; Gambino, S.; Filardo,
G. U.S.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 13 as follows: ...-ene-2-carbonitrile (13).
Method k7Siloxypyrrole....
Page 4303, Table 1. Column head for column 8 should
read yield 13d. Entry 9 in column 8 should read 0733.
J0954017P