Solvent- and base-free dicyclohexylcarbodiimide-promoted esterifications

Article abstract of DOI:10.1055/s-2001-14605

N,N'-Dicyclohexylcarbodiimide/base-promoted esterification of carboxylic acids containing α-halogen atom(s) gave low yields of products when performed in a solvent. This failure was found to be due to the low stability of appropriate intermediates under t

Full text of DOI:10.1055/s-2001-14605

LETTER
809
Solvent- and Base-Free Dicyclohexylcarbodiimide-Promoted Esterifications
Ludvík Streinz,* Bohumír Koutek, David Šaman
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, CZ-166 10, Czech Republic
E-mail: streinz@uochb.cas.cz; koutek@uochb.cas.cz; saman@uochb.cas.cz
Received 13 March 2001
the DCC method in its classical form certainly provides a
Abstract: N,N’-Dicyclohexylcarbodiimide/base-promoted esterifi-
versatile approach for the synthesis of numerous esters,
we have found that the conditions are incompatible with
cation of carboxylic acids containing -halogen atom(s) gave low
yields of products when performed in a solvent. This failure was
found to be due to the low stability of appropriate intermediates un- the presence of -halogen functionality. Similar failures
der the reaction conditions. On the other hand, high yields of esters have also been previously observed.6 When applied to
,8
were obtained, when the same esterification was performed without
the -halogen substituted acids, the method suffers from
both the solvent and base. Carboxylic acids without -halogen at-
low ester yields while producing an unacceptably large
om(s) also undergo the esterification under solvent- and base-free
amount of side-products such as N-acyl and N,N´-diacyl
conditions giving products in medium yield.
derivatives. This limitation prompted us to develop a new
Key words: esterification, ester, carbodiimide, dicyclohexylcarbo-
diimide, green chemistry
esterification route to the -halogen framework employ-
29
ing a solvent- as well as base-free reaction medium.
Such a methodology offers an additional advantage since
it is in line with the green chemistry (eco-friendly technol-
ogies) concept.
The N,N-dialkyldiimides in general and dicyclohexylcar-
bodiimide (DCC) in particular, have broadly been used as
dehydrating condensing agents.1-4 There are many exam-
ples of their versatile utilization described in the literature
30
5
-7
including esterification of carboxylic acids, fatty ac-
8
,9
10-12
ids, peptides
and acids with sensitive functionality
9
,13,14
in the molecule.
Besides this, N,N-dialkyldiimides
were also found useful for reduction of carboxylic acids
1
5
16
with lithiumborohydride, olefin epoxidation, intramo-
lecular dehydration of -hydroxyalkyl phosphonic ac-
1
7
18,19
ids, kinetic resolution of racemic carboxylic acids,
2
0
non-classical acetalation of pyranoses and of others. Table Prepared (1R,2S,5R)-( )-Menthyl Esters (see text for details)
However, in spite of this rather broad applicability range,
the most common use of N,N-dialkyldiimides remains in
their mediation of reactions between alcohols and organic
acids.
It has been well documented1,3,7,21-25 that diimide-promot-
ed esterifications include the formation of O-acyldialkyl
1
,3,21-24
urea (O-acyl-DCU)
and/or the corresponding anhy-
dride which may originate from the first species by a nu-
7,25
cleophilic attack of the second molecule of the acid. In
6
addition to these base-catalyzed reactions, the reaction
milieu may cause an intramolecular rearrangement of
2
6,27
O-acyl-DCU to the corresponding N-acyl derivative.
2
8
The independent kinetic experiments by Balcom support
the view that the DCC-promoted esterification is a rather Here we report our results indicating the success of this
complex process affected by interaction between all par- new strategy when used for the esterification of -halogen
ticipating components, including solvents. In other words, substituted acetic acids with (1R, 2S, 5R)-(-)-menthol as a
the yields of products depend on the stability of reaction model alcohol. The menthyl esters prepared in this work
intermediates under the reaction conditions used.
are listed in the Table. Mosher and palmitic acids (entry 7,
) were also included as non-halogen atom containing car-
boxylic acids.
8
As a part of our ongoing work, we recently required ac-
cess to a series of carboxylic esters containing -halogen
atom(s) in the molecule for the synthesis of biologically The Table lists the results of the DCC mediated esterifica-
interesting targets. Intrigued by the possibility that the tions performed without the presence of any base and sol-
DCC-promoted esterification would lead to the desired vent with equimolar amounts of reagents (A) as well as
esters, we investigated this reaction in more details. While with two-fold excess of an acid (B). In order to compare
Synlett 2001 No. 6, 809–811 ISSN 0936-5214 © Thieme Stuttgart · New York

8
10
L. Streinz et al.
LETTER
Scheme 1
the new method with those broadly used today, esterifica-
tions of particular acids were also done in a solvent under
the base catalysis according to Hassner (C, equimolar
7
amounts of all ingredients), Wiener (D, two-fold excess
8
of an alcohol) or Svatoš (E, three-folds excess of DCC
2
4
and acid, resp.). In addition, all reagents in equimolar
quantities were mixed and the base (DMAP) was added as
the last (F).
Scheme 2
The data obtained revealed that the DCC solvent- and
base-free esterifications afford high to medium yields of
esters with structurally different carboxylic acids while
the yields of reactions performed in the solvent are signif-
icantly structure-dependent affording a broad spectrum of
yields that range from 20% (entry 1) to more than 90%
In conclusion, the method reported here offers a useful al-
ternative to the broadly used DCC promoted esterifica-
tions giving satisfactory results with structurally different
substrates. It simplifies the reaction because dry solvents
as well as base are no more needed. The reaction design
suppresses the formation of reaction side-products so high
yields can be expected. Reproducibility as well as isola-
tion procedures are high and easy, respectively.
(
entry 6). It appears that these yields approximately corre-
late with the electronegativity of the acid. Two-fold ex-
cess of an acid which is needed when the acid anhydride
is assumed to be present as reaction intermediate appar-
ently decreases the yield probably due to acid-catalyzed
Acknowledgement
3
1
side-reactions (B).
The authors wish to thank to the Grant Agency of the Czech Repu-
The relatively high temperature used during the reaction blic (grants Nos. 203/98/0462 and 203/01/0116) for financial sup-
affects the conversion positively even when the tempera- port.
ture-sensitive acids were subjected to the esterification
(
entry 7). Comparing all the solvent-based methods
References and Notes
considered, the best results are obtained either with three-
fold excess of reagents to the alcohol used (E) or with
equimolar quantities of all chemicals when the base is
added as the last component which minimizes the neutral-
ization process by excess of an acid (F).
(
(
(
(
(
1) Haslam, E. Tetrahedron 1980, 36, 2409.
2) Mathias, L.J. Synthesis 1979, 561.
3) Khorana, H. G. Chem. Rev. 1953, 53, 145.
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5) Kunstler, T., Schollmeyer, D., Singer, H., Siegerwald, M.
Tetrahedron: Asymmetry 1993, 4, 1645.
A general comparison of all solvent-based models with
our solvent- and base-free method indicates that the sol-
vent- and/or base-mediated consecutive reaction of the
rather unstable O-acyl-DCU (9) into the undesired
N-acylderivatives (10 and 11) is eliminated. Consequent-
(
(
(
(
6) Ziegler, F. E., Berger, G. D. Synth. Commun. 1979, 9, 539.
7) Hassner, A., Alexanian, V. Tetrahedron Lett.1978, 46, 4475.
8) Wiener, H. Gilon, Ch. J. Mol. Catal. 1986, 37, 45.
9) Jie, M. S., Mustafa, J., Pasha, M. K. Chem. Phys. Lipids 1999,
100, 165.
ly, only the ester products and DCU (12) are present in the (10) Wasserman, H. H., Lu, T-J. Tetrahedron Lett. 1982, 23, 3831.
reaction mixture. The fact that optimum results are ob- (11) McCarthy, D. G., Hagarthy, A. F., Hathaway, B. J. Chem.
Soc., Perkin Trans. 2 1977, 224.
tained using equimolar amounts of all chemicals led us to
(
12) Izdebski, J., Orlowska, A., Anulewicz, R., Witkowska, E.,
Fiertek, D. Int. J. Pept. Protein Res. 1994, 43, 184.
13) Woydowski, K., Liebsher, J. Tetrahedron 1999, 55, 9205.
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15) Herbert, J. M., Hewson, A. T., Peace, J. E. Synth. Commun.
1998, 28, 823.
believe that the anhydride does not participate in the reac-
tion. This assumption was additionally proved by spectral
data (neither NMR or IR spectra of the reaction mixture
showed the presence of anhydride-related bands). Thus,
compared to the general mechanism of DCC-promoted
(
(
(
1
,7,8
esterification
the simplified picture shown in the (16) Murray, R.W., Iyanar, K. J. Org. Chem. 1998, 63, 1730.
(
17) Kawashima, T., Nakamura, M., Nakajo, A., Inamoto, N.
Scheme 2 seems to be the most consistent with experi-
mental evidence given above for solvent- and base-free
conditions.
Chem. Lett. 1994, 8, 1483.
Synlett 2001, No. 6, 809–811 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Solvent- and Base-Free Dicyclohexylcarbodiimide-Promoted Esterifications
811
(
(
(
(
(
18) Mazon, A., Najera, C., Yus, M., Heumann, A. Tetrahedron:
Representative analyses:
4: Anal. Cald for C H O FCl: C 57.48, H 8.48; Found: C
Asymmetry 1992, 3, 1455.
19) Chinchilla, R., Najera, C., Yus, M., Heumann, A.
Tetrahedron: Asymmetry. 1991, 2, 101.
20) Anderson, G. W., Zimmerman J. E.,Callahan, F. M. J. Am.
Chem. Soc. 1964, 86, 1839.
21) DeTar, D. L. F. Silverstein, R. J. Am. Chem. Soc. 1966, 88,
1
2
20
2
1
57.29, H 8.41; H NMR (500 MHz, CDCl /TMS): 6.24 and
3
6.25 d, 1H (JHF = 50.6) (H-12), 4.82 and 4.83 dt, 1H (J = 4.5,
2
11.0) (H-1), 2.03 and 2.02 dddd, 1H (J = 2.0, 3.5, 4.5,
12.0) (H-6e), 1.91 and 1.89 m, 1H (J = 2.8, 6 7.0) (H-7),
1.68-1.74 m, 2H (H-4e, H-3e), 1.46-1.50 m, 2H (H-5, H-2a),
1.02-1.13 m, 2H (H-3a, H-6a), 0.93 d, 3H (J = 6.5) (H-10),
0.91 d, 3H (J = 7.0) (H-8), 0.89 ddt, 1H (J = 3.5, 2 12.0,
13.0) (H-4a), 0.78 and 0.79 d, 3H (J = 7.0) (H-9);
1
013.
22) Ibrahim, I. T., Williams, A. J. Chem. Soc., Perkin Trans. 2
982, 1459.
1
1
3
(
(
23) Doleschall, G., Lempert, K. Tetrahedron Lett. 1963, 18, 1195.
24) Svatoš, A., Valterová, I., Šaman, D., Vrko , J. Collect. Czech
Chem. Commun. 1990, 55, 485.
C NMR (125.7 MHz, CDCl ): 163.6 (J = 4.6) and 163.8
3 CF
(JCF = 4.9) (C-11), 90.3 (JCF = 10.0) and 92.4 (JCF = 10.7) (C-
12), 77.8 (C-1), 46.9 (C-2), 40.2 and 40.3 (C-6), 34.0 (C-4),
31.4 (C-5), 26.1 and 26.3 (C-8), 23.4 and 23.5 (C-3), 21.9 (C-
7), 20.6 (C-10), 16.1 and 16.2 (C-9); MS (EI, m/z,%): 249(4),
192(2), 138(67), 123(48), 109(8), 95(100), 81(94), 67(33); IR
(
25) Smith, M., Moffat, J.,G., Khorana, H.G. J. Am. Chem. Soc.
1958, 80, 6204.
(26) Slebioda, M. Pol. J. Chem. 1994, 68, 957.
(
27) Hegarthy, A. F., McCormack, M. T., Brady, K., Ferguson, G.,
Roberts, P. J. J. Chem. Soc., Perkin Trans. 2 1980, 867.
28) Balcom, B. J. Petersen, N. O. J. Org. Chem. 1989, 54, 1922.
29) Tanaka, K., Toda, F. Chem. Rev. 2000, 100, 1025.
30) Tundo, P., Anastas, P., Black, D.S., Breen, J., Collins, T.,
Memoli, S., Miyamoto J., Polyakoff, M., Tumas, W. Pure
Appl. Chem. 2000, 72, 1207.
(CCl ): 1774, 1755, 1719, 1389, 1372, 1302, 1241, 1230,
1140, 1124, 1086 cm ;
4
-
1
(
(
(
6: Anal. Cald for C H O Br: C 52.00, H 7.64; Found: C
1
2
21
2
1
51.86, H 7.38; H NMR: 4.73 dt, 1H (J = 4.5, 2 11.0) (H-1),
3.82 d, 1H (J = 11.9) (H-12a),3.79 d, 1H (J = 11.9) (H-12b),
2.01 dddd, 1H (J = 2.0, 3.5, 4.5, 12.0) (H-6e), 1.91 m, 1H
(J = 2.8, 6 7.0) (H-7), 1.70 ddq, 1H (J = 2.0, 3 3.5, 13.0)
(H-4e), 1.69 dq, 1H (J = 3 3.4, 14.0) (H-3e), 1.50 m, 1H
(J = 2 3.5, 3 6.5, 11.0, 12.0) (H-5), 1.43 dddd, 1H
(J = 2.8, 3.7, 11.0, 12.4) (H-2a), 1.07 ddt, 1H (J = 3.5,
(
31) Nakao, K., Hamada, Y., Shiory, T. Chem. Pharm. Bull. 1989,
37, 930
®
(
32) Representative procedure: A 4 mL Reacti-Vial equipped
with a Teflon-stirrer bar and containing 0.25g (1.2 mmol)
DCC was supplied with 0.16g (1.0 mmol) of (–)-menthol. As
soon as the mixture solidified, the organic acid was added (1.2
mmol) at once and the vial sealed with a septum cap. The
reaction mixture was warmed up to 100 C and the heating was
maintained for three hours under stirring. After being cooled,
the crude reaction mixture was diluted with 1.5 mL of diethyl-
ether, 3 g of silicagel was added and the solvent evaporated
under vacuum. The solid was chromatographed on a silicagel
column (10 g) with light-petroleum as eluent.
2
12.2, 14.0) (H-3a), 1.02 dt, 1H (J = 2 11.0, 12.0) (H-6a),
0.92 d, 3H (J = 6.5) (H-10), 0.90 d, 3H (J = 7.0) (H-8), 0.89
ddt, 1H (J = 3.5, 2 12.0, 13.0) (H-4a), 0.77 d, 3H (J = 7.0)
1
3
(H-9); C NMR: 166.9 (C-11), 76.5 (C-1), 47.0 (C-2),
40.5(C-6), 34.1 (C-4), 31.4 (C-5), 26.2 (C-8), 26.2 (C-12),
23.4 (C-3), 21.9 (C-7), 20.7 (C-10), 16.2 (C-9); MS (EI, m/
z,%): 138(100), 123(36), 109(9), 95(94), 81(67), 69(14); IR
(CCl ): 1757, 1732, 1423, 1389, 1371, 1287, 1277, 1166,
4
-
1
1108, 1208, 562 cm .
Article Identifier:
437-2096,E;2001,0,06,0809,0811,ftx,en;G04401ST.pdf
1
Synlett 2001, No. 6, 809–811 ISSN 0936-5214 © Thieme Stuttgart · New York