Modified Yamaguchi reagent: Convenient and efficient esterification

Article abstract of DOI:10.1080/00397911.2014.919659

A convenient and efficient esterification method that used a modified Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride-4-dimethylaminopyridine) and avoided use not only of intractable acid chloride but also of acid anhydrides was proposed. The reaction mechanism was described by Fourier transform infrared spectroscopy and supported by a density functional theory calculation.

Full text of DOI:10.1080/00397911.2014.919659

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Modified Yamaguchi Reagent: Convenient and Efficient
Esterification
Yoshinori Okuno a , Shigeki Isomura a , Akihiro Nishibayashi a , Aiko Hosoi a , Kei Fukuyama a ,
Masashi Ohba a & Kazuyoshi Takeda a
a Yokohama College of Pharmacy
Accepted author version posted online: 22 May 2014.
To cite this article: Yoshinori Okuno , Shigeki Isomura , Akihiro Nishibayashi , Aiko Hosoi , Kei Fukuyama , Masashi Ohba &
Kazuyoshi Takeda (2014): Modified Yamaguchi Reagent: Convenient and Efficient Esterification, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.919659
To link to this article: http://dx.doi.org/10.1080/00397911.2014.919659
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Modified Yamaguchi Reagent: Convenient and Efficient Esterification
Yoshinori Okuno1, Shigeki Isomura1, Akihiro Nishibayashi1, Aiko Hosoi1, Kei
Fukuyama1, Masashi Ohba1, Kazuyoshi Takeda1
1Yokohama College of Pharmacy
Corresponding Author: Email: y.okuno@hamayaku.ac.jp
Abstract
A convenient and efficient esterification method that used a modified Yamaguchi reagent
(TCB-DMAP) and avoided to use not only intractable acid chloride but also acid
anhydrides was proposed. The reaction mechanism was described by FT-IR spectroscopy
and supported by a density functional theory calculation.
KEYWORDS: DMAP, acylation, esterification, condensation, acylpyridinium salt.
INTRODUCTION
The effectiveness of 4-dimethylaminopyridine (DMAP) as a highly nucleophilic base
catalyst has been reported by both Steglich and Höfle–Litvinenko–Kirichenko.[1] Because
DMAP can be utilized in a variety of group-transfer reactions, such as the acylation of
alcohols and amines, it has been studied widely.[2] Notably, Yamaguchi and co-workers
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have reported a convenient method for the preparation of carboxylic esters and lactones
in the presence of triethylamine and DMAP using 2,4,6-trichlorobenzoyl chloride as a
bulky acid moiety for the formation of the intermediary mixed anhydride.[3] Recently, a
regioselective version of the Yamaguchi esterification method was reported by
SantaLucia and Dhimitruka.[4] In addition, Shiina and co-workers developed an effective
esterification method using 2-methyl-6-nitrobenzoic anhydride, a reagent similar to the
Yamaguchi reagent.[5] It is estimated that these esterification methods proceed via
intermediates including a mixed anhydride and an N-acylpyridinium salt with an
activated acyl group.[6] Generally, acid chlorides and acid anhydrides are intractable in
condensation reactions, such as peptide bond formation and esterification, because acid
chlorides react with both carboxylates and nucleophiles, such as alcohols and amines.
We demonstrate a convenient and practical protocol for these esterification methods via
mixed anhydride and an N-acylpyridinium salt with an activated acyl group. For this
purpose, we prepared the modified Yamaguchi reagent 2′,4′,6′-trichlorobenzoyl-4-
dimethylaminopyridinium chloride (TCB-DMAP) (1), which is a stable crystal in
atmosphere and hence handled easily. In addition, we report the development of an
effective method for monitoring esterification by IR spectroscopy and density functional
theory (DFT) calculation[7], and we apply the results to clarify the esterification
mechanism in the presence of TCB–DMAP.
RESULTS AND DISCUSSION
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First, we prepared TCB-DMAP by the following method. To a solution of DMAP (5.5
mmol) in 20 mL of dry THF was added 2,4,6-trichlorobenzoylchloride (5mmol), and the
mixture was stirred for 24 h. The precipitate was collected by suction filtration, washed
with THF, and recrystallized from THF-CH2Cl2 mixed solvent to give TCB-DMAP (90%
yield). This reagent is very stable crystal avoiding humidity. It has been stored in the
desiccator for several years, and the activity is no change at all.
A typical procedure for esterification is as follows. TCB-DMAP (0.26 mmol) was added
to a solution of carboxylic acid (0.20 mmol) and N′,N′-diisopropylethylamine (DIPEA)
(0.26 mmol) in anhydrous toluene (2 mL) and stirred for a minute. l-menthol (0.20 mmol)
was added to the mixture over a period of 1 min and then stirred for 24 h at room
temperature. In every case, this reaction proceeded at room temperature to give the
corresponding carboxylic esters in high yields from equimolar amounts of carboxylic
acids and alcohols, such as the benzyl, allyl, and secondary aliphatic alcohols (Table 1).
This method is also applicable to various carboxylic acids including , -unsaturated and
aromatic carboxylic acids, with alcohols (benzyl, allyl and secondary aliphatic alcohols)
using TCB-DMAP to obtain the corresponding carboxylic esters. Therefore, various
carboxylic esters can be obtained in good to high yields under mild reaction conditions.
In addition, this method was applied to the synthesis of 3R-[3R-(3R-
hydroxybutyryloxy)butyryloxy] butyric acid (23), a pheromone of Linyphia triangularis8,
which was obtained in an overall good yield (Scheme 1).
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The DMAP-supported reaction pathway in the esterification reaction using TCB-DMAP
was then studied by evaluating the time-dependent changes in the FT-IR spectrum.
Specifically, the absorption bands associated with C=O bond stretching were observed
(Figure 1). TCB-DMAP in acetonitrile displays a stretching vibration at 1751.2 cm−1
corresponding to the C=O bond stretching of the N-acylpyridinium salt. The FT-IR
spectrum of a mixture of phenylpropionic acid, TCB-DMAP, and DIPEA in acetonitrile
showed the presence of the mixed anhydride, 2,4,6-trichlorobenzoic phenylpropionic
anhydride (II) (1818.3 cm−1), and the acylpyridinium salt, 4-dimethylamino-1-(3-
phenylpropionyl)pyridinium salt (III) (1767.7 cm−1). The IR spectral changes that
occurred upon addition of l-menthol to the mixture are shown in Figure 1. The increase in
the new absorbance corresponding to a stretching band at 1724.4 cm−1 is due to the
accumulation of the product (−)-menthyl 3-phenylpropionate (IV) in the reaction
mixture. Concurrently, the intensity of the bands for (II) and (III) decreased
dramatically. These spectral changes were associated with the absorption bands of the
alternatively synthesized mixed anhydride (2,4,6-trichlorobenzoic phenylpropionic
anhydride) and N-acylpyridinium salt (4-dimethylamino-1-(3-
phenylpropionyl)pyridinium chloride) and their conversion to the product ester (IV). In
this way, the carboxylate anion attacks the carbonyl group of TCB-DMAP, which is the
most activated site at the beginning of the reaction. These results suggest that the
esterification mechanism with TCB-DMAP favors the formation of a mixed anhydride
derived from the carboxylic acid and the 2,4,6-trichlorobenzoyl group that is released
from TCB-DMAP, followed by subsequent reacylation of DMAP to form the N-
acylpyridinium salt.
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Further, we have discussed for absorption of IR spectrum by use of quantum calculation.
Molecular orbital calculations for mixed anhydride (II), DMAP, and l-menthol were also
performed using DFT, as implemented in the DMol3 package from Accelrys Inc (Figure
2). The delocalized lowest unoccupied molecular orbital (LUMO) was observed near the
C1, and 2,4,6-trichlorophenyl groups. The localized LUMO orbital was observed on C15.
Therefore, nucleophiles such as DMAP or alcohols are more likely to attack the localized
carbonyl carbon C15 than the delocalized C1 (Figure 2). In addition, the energy levels of
the highest occupied molecular orbital (HOMO) of DMAP and l-menthol were also
calculated. The energy levels of the HOMO for DMAP and the HOMO for l-menthol
were −5.7 and −7.0 eV, respectively. Thus, the nucleophilicity of the N-atom of the
pyridine ring of DMAP with respect to C15 is greater than that of the hydroxyl group of
l-menthol. Therefore, in this DMAP-catalyzed esterification, nucleophilic alcohol does
not react to C15 of the mixed anhydride. The released DMAP attacks C15 and gives N-
acylpyridinium salt.
CONCLUSIONS
In conclusion, we demonstrated a modified Yamaguchi esterification method using TCB-
DMAP which avoided the use of acid chlorides and acid anhydrides. Due to the crystal
stability of TCB-DMAP, this protocol provides a convenient one-pot procedure that is
easily handled. Furthermore, we elucidated the mechanism of this esterification reaction
using the modified Yamaguchi reagent by time-dependent FT-IR spectroscopy and DFT
calculations. This esterification proceeds via a mixed anhydride and an acylpyridinium
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salt. These results support the catalytic mechanism for DMAP that has been proposed on
the basis of other studies completed to date.9
EXPERIMENTAL
1H NMR spectra were recorded on a 500 NMR spectrometer operating at JAOL ECA500,
respectively in CDCl3 unless otherwise noted. Coupling constant (J) values are reported
in Hertz. Mass Spectra (MS) were performed at JAOL JMS-700 MStation at the
University of Kitasato using chemical ionization or electron impact techniques. HPLC
experiments were performed on a LC solution ( = 254 nm) system using a wakosil-II
3C18 HG (3.0 mm φ x 75 mm) column. Assay yields calculated by HPLC using an
internal standard method under 40 ºC, 0.8 mL/min. The calibration curve was prepared
from various concentrations of each esters. Infrared (IR) spectra were obtained on a
Perkin Elmer Spectrum 100 FT-IR spectrometer. Compounds were visualized located by
UV (254 nm) and spraying the TLC plate with a solution of phosphomolybdic acid
followed by heating until color developed. Optimized geometry and molecular orbital
were calculated by DFT method using the Materials Studio DMol3 package of Accelrys
Inc. First, optimized geometry was obtained using the Perdew-Wong GGA functional
(PWC) and double numerical puls d-functional (DND) basis set. Second, the optimized
geometry obtained were further calculated for molecular orbital using the Becke
exchange puls Lee-Young-Parr correlation (B3LYP) and the double numerical plus
polarization (DNP) basis set.
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General Method
To a solution of carboxylic acid (0.20 mmol) and DIPEA (0.26 mmol) in 2 mL of
anhydrous toluene was added TCB-DMAP (1) (0.26 mmol) and stirred for 1 min. The
mixture was added alcohol (0.20 mmol) over 1 min and stirred for 24 h at room
temperature. The portion (50 L) of the mixture was added coumarin as internal standard
substance, and diluted with 2 mL of acetonitrile / H2O (5 : 1). The solution was analyzed
by HPLC using an internal method of coumarin.
Synthesis Of (R)-(−)-2-{(R)-(−)-2-Carboxy-1-Methylethoxy Carbonyl}-1-Methylethyl
(R)-(−)-3-Hydroxybutyrate (23)
(22) (0.418 mmol) was dissolved in 10 mL of EtOH. To the solution was added Pd/C
(5%) (10 mg), and stirred under H2 for 24 h. The residue was filtrated and concentrated in
vacuo to give colorless oil (23) (>99% yield).
1H NMR (500 MHz, CDCl3) δ : 1.25 (d, 3H, J=6.9 Hz), 1.30 (m, 6H), 2.41-2.64 (m, 6H),
4.29 (m, 1H), 5.37 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 173.5, 171.9, 170.0, 68.1,
67.8, 64.9, 43.1, 41.2, 40.8, 22.4, 20.2, 20.1; HRMS [M+H]+ calcd for C12H21O7
277.1287, found 277.1291; [ ]D24 = -23.8 (c 1.0, CHCl3)
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher's website.
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ACKNOWLEDGMENTS
The authors would like to thank Professor Y. Mazaki and Dr. M. Hasegawa of the School
of Science, Kitasato University and Dr. K. Nagai from the School of Pharmaceutical
Sciences, Kitasato University.
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Table 1 Synthesis of various esters by TCB-DMAP
entry R1COOH
R2OH
Product A (%)a
1
Ph(CH2)2COOH
(-)-Menthyl-OH
BnOH
2
3
99
94
88
93
95
88b
88
77
>99
91
90
84
2
Ph(CH2)2COOH
Ph(CH2)2COOH
Ph(CH2)2COOH
PhCOOH
3
1-Phenylethyl-OH 4
(E)-Cinnamyl-OH 5
4
5
(-)-Menthyl-OH
BnOH
6
7
6
PhCOOH
7
PhCOOH
1-Phenylethyl-OH 8
(E)-Cinnamyl-OH 9
8
PhCOOH
9
(E)-PhCH=CHCOOH (-)-Menthyl-OH
(E)-PhCH=CHCOOH BnOH
10
11
10
11
12
(E)-PhCH=CHCOOH 1-Phenylethyl-OH 12
(E)-PhCH=CHCOOH (E)-Cinnamyl-OH 13
aAssay yields calculated by HPLC using an internal standard method of coumarin
bIsolated yield
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Scheme 1 Synthesis of a Linyphia triangularis pheromone
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Scheme 2 Detailed proposed mechanism esterification using TCB-DMAP
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Figure 1 IR spectra of the intermediates generated in esterification using TCB-DMAP.
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Figure 2 Delocalized LUMO+1 of the mixed anhydride (II). Method : B3LYP/DNP(6-
31G*)//B3LYP/DNP(6-31G*)
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