Esterification of amino acids and mono acids using triphosgene

Article abstract of DOI:10.1081/SCC-100104468

Alkyl esters of several amino acids and acids were prepared using triphosgene [trichloromethyl carbonate, TPA (2)].

Full text of DOI:10.1081/SCC-100104468

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ESTERIFICATION OF AMINO ACIDS AND MONO ACIDS
USING TRIPHOSGENE
I. A. Rivero a , S. Heredia a & A. Ochoa a
a Centro de Graduados e Investigación del Instituto Tecnológico de Tijuana , Apdo. Postal
1166, Tijuana, B.C., 22000, Mexico
Published online: 09 Nov 2006.
To cite this article: I. A. Rivero , S. Heredia & A. Ochoa (2001) ESTERIFICATION OF AMINO ACIDS AND MONO ACIDS USING
TRIPHOSGENE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:14, 2169-2175, DOI: 10.1081/SCC-100104468
To link to this article: http://dx.doi.org/10.1081/SCC-100104468
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SYNTHETIC COMMUNICATIONS, 31(14), 2169–2175 (2001)
ESTERIFICATION OF AMINO ACIDS AND
MONO ACIDS USING TRIPHOSGENE
I. A. Rivero,* S. Heredia, and A. Ochoa
Centro de Graduados e Investigacion del Instituto
Tecnologico de Tijuana, Apdo. Postal 1166,
22000, Tijuana, B.C., Mexico
ABSTRACT
Alkyl esters of several amino acids and acids were prepared
using triphosgene [t richloromethyl carbonate, TPA (2)].
We have described the synthesis of quinazolinedione-dipeptides
(1a–e),1 as a part of a preliminary study of anti-hypertensive effects. In that
study, we focused on modifying the aminoacids (AA) side chain in order to
examine the resulting anti-hypertensive properties of 1a–e. However, it was
necessary to pre-protect the amino acids in the form of esters.
Specifically, we needed a method to convert the amino acids to their
alkyl esters without racemization. Several esterification methods known in
the literature involve acid catalysts: HCl,2 H2SO4,3 TsCl-Pyr,4 DCC-
DMAP,5 SOCl2,6 etc., but all of these methods exhibit some loss of chirality.
Suppression of racemization has been an important goal in the development
of coupling methods, and many techniques have been introduced, including
the use of activated esters plays a prominent role.7a–c
Herein we describe a new preparation of an active ester, using triphos-
gene (TPA) (2); earlier this substitute for phosgene was used in cyclization,8
* Corresponding author.
2169
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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RIVERO, HEREDIA, AND OCHOA
soft oxidation,9 and chlorination10 in this laboratory. Reaction of the amino
acids (3) with TPA yielded the Leuch’s anhyride11 (4) (Figure 1). Reaction of
(4) with the added methanol gave (5). No racemization of the aminoacid in
(5) was apparent, based on 1H-NMR using the chiral shift reagent Eu(tfc)3.
The amino acid esterification method was broadened to include esteri-
fication of typical carboxylic acids with simple alcohols (Figure 2). An
equivalent amount of TPA in dichloromethane was added at ꢀ5ꢁC to the
Figure 1. Esterification of aminoacids.
Figure 2. Esterification of acids.

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ESTERIFICATION OF AMINO ACIDS AND MONO ACIDS
2171
acid dissolved in an eight-fold excess of alcohol followed by warming to
40ꢁC for two hours. Isolation of the intermediate (7) (Figure 2) was not
necessary. Isolated yields of the esters were 95–97%.
EXPERIMENTAL
Melting points were obtained on an Electrothermal 88629 apparatus
and are uncorrected. Infrared (IR) spectra were recorded on
a
PerkinElmerFT-IR1600spectrophotometer. Nuclearmagneticresonance 1H
spectra and 13C spectra (50.289 Hz in CDCl3) were recorded on a Varian
Gemini 200 Spectrometer with TMS as internal standard, the chiral resolution
was obtained with Eu(tfc)3. Mass spectra were obtained on a Hewlett-
Packard 5989 by El at 70 eV using direct insertion. Purity was obtained on
a High Pressure Liquid Chromatography 1090 series II, column HP C-18.
Automatic Polarimeter, Rudolph Research, Flanders, New Jersey.
Esterification of Amino Acids
General Method
5a) D-Phenylalanine methyl ester: To a stirred solution of D-phenyl-
alanine hydrochloride (15.02 g, 18 mmol) and TEA (10.86 g, 18 mmol) in
anhydrous THF (50 mL) was added slowly a solution of TPA (20.01 g,
123 mmol) in THF (50 mL). After complete addition, the mixture was
warmed to 55–60ꢁC to allow complete dissolution, then methanol (10 mL)
was added and the mixture was stirred for an additional half-hour. Excess
solvent was evaporated in vacuo to give a white residue. This was neutralized
(pH ꢂ 7) with a NaOH (0.5%) solution; the mixture was extracted with
ethyl acetate (2 ꢃ 50 mL). The organic layer was dried (sodium sulfate) and
removal of solvent under reduced pressure gave white solid. 12.67 g, 95%.
20
D
20
D
Mp 158–162ꢁC. ½aŠ ¼ ꢀ25.8 (c ¼ 1 in EtOH), (lit,12a ½aŠ ¼ ꢀ26.0, c ¼ 2.2 in

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RIVERO, HEREDIA, AND OCHOA
EtOH). IR(KBr): 3374, 3028, 2952, 1732, 1538, 1263 cm–1. 1H RMN(CDCl3):
d 7.42–7.30(m, 5H, Ar-H), 4.80–4.60(t, 1H, J ¼ 7.0 Hz, CH), 3.83(s,
3H, OCH3), 3.33–3.23(dd, 2H, J1 ¼ J2 ¼ 5.12 Hz, CH2) ppm. 13C
RMN(CDCl3): d 169, 133, 129, 128, 127, 58, 54, 36 ppm. MS(m/e): 179,
120(100), 103, 91.
5b) L-Phenylalanine methyl ester: White solid, 12.67 g, 95%. Mp
20
20
D
158–162ꢁC. ½aŠ ¼ þ32 (c ¼ 1 in EtOH), (lit,12b ½aŠ ¼ þ32.4, c ¼ 2 in
D
EtOH). IR(KBr): 3374, 3028, 2952, 1732, 1538, 1263 cm–1. 1H RM N
(CDCl3): d 7.42–7.30(m, 5H, Ar-H), 4.80–4.60(t, 1H, J ¼ 7.0 Hz, CH),
3.83(s, 3H, OCH3), 3.33–3.23(dd, 2H, J1 ¼ J2 ¼ 5.12 Hz, CH2) ppm.
13C RMN(CDCl3): d 169, 133, 129, 128, 127, 58, 54, 36 ppm. MS(m/e):
179, 120(100), 103, 91.
5c) L-Tryptophan methyl ester: White solid, 76%. Mp 218–220ꢁC.
20
D
20
D
½aŠ ¼ þ18.0 (c ¼ 1 in CH3OH). (lit,12b, ½aŠ ¼ þ18.0, c ¼ 5 in CH3OH),
IR(KBr): 3400, 3056, 2952, 1732, 1518, 1218 cm–1. H RMN (CDCl3): d
11.49(sa, 1H, NH), 7.53–7.04(m, 5H, Ar-H), 4.21–4.15(t, 1H, J ¼ 5.9 Hz,
CH), 3.76(s, 3H, OCH3), 3.54–3.49(dd, 2H, J1 ¼ 3.3 Hz, J2 ¼ 4.8 Hz,
CH2) ppm. 13C RMN(CDCl3): d 127, 124, 121, 119, 113 ppm. MS(m/e):
218, 130(100).
1
5d) Glycine methyl ester: White solid, 82%. Mp 174–176ꢁC. (lit12b
Mp 175ꢁC). IR(KBr): 3477, 2975, 1746, 1553, 1455, 1249, 1094 cm–1. H
1
RMN(CDCl3): d 4.79(s, 2H, CH2), 3.82(S, 3H, OCH3) ppm. 13C RM N
(CDCl3): d 172, 55, 32 ppm.
5e) L-Alanine methyl ester: White solid, 91%. Mp 108–110ꢁC.
20
D
20
D
½aŠ ¼ þ7.0 (c ¼ 1 in CH3OH), (lit,12b ½aŠ ¼ þ7.0, c ¼ 1.6 in CH3OH).
IR(KBr): 3407, 2923, 1745, 1621, 1521, 1461, 1250, 1117, 754 cm–1.
1H RMN(CDCl3): d 4.48–4.22(dc, 1H, J1 ¼ J2 ¼ 7.3 Hz, CH), 3.66(s, 1H,
OCH3), 1.34–1.30(d, 3H, J ¼ 7.2 Hz, CH3) ppm. 13C RMN(CDCl3): d 169,
52, 48, 15 ppm. MS(m/e): 103, 88, 44(100).
5f) L-Proline methyl ester: Light yellow solid, 87%. Mp 69–71ꢁC.
20
D
20
D
½aŠ ¼ ꢀ31.0 (c ¼ 1 in H2O), (lit,12b ½aŠ ¼ ꢀ31.0 (c ¼ 0.5 H2O)). IR(KBr):
3446, 2960, 1729, 1455, 1196, 1092, 773 cm–1. H RMN(CDCl3): d 4.51(m,
1H, CH), 3.68(s, 3H, OCH3), 3.53(m, 2H, CH2N), 2.24(m, 2H, CH2-CH-N),
1.92(m, 2H, CH2-CH2-N) ppm. 13C RMN(CDCl3): d 60, 45, 28, 27, 23 ppm.
MS(m/e): 129, 70(100).
1
5g) D-Phenylalanine ethyl ester: White solid, 76%. Mp 143–144ꢁC.
20
D
21
D
½aŠ ¼ ꢀ36.3 (c ¼ 1 in EtOH), (lit,12a ½aŠ ¼ ꢀ36.5, c ¼ 2.2 in
EtOH). IR(KBr): 3395, 3030, 2934, 1742, 1498, 1292, 1238, 749, 701 cm–1.
1H RMN(CDCl3): d 7.32–7.10 (m, 5H, Ar-H), 4.10(t, 2H, J ¼ 7.1 Hz,
O-CH2), 3.74(m, 1H, CH2-N), 3.10(dd, 2H, J1 ¼ J2 ¼ 5.0 Hz, Ar-CH2),
1.25(t, 3H, J ¼ 7.1 Hz, CH3) ppm. 13C RMN(CDCl3): d 169, 129, 128, 126,
61, 54, 37, 14 ppm. MS(m/e): 193, 120(100), 102, 91.

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2173
5h) L-Phenylalanine ethyl ester: White solid, 76%. Mp 143–144ꢁC.
20
D
20
½aŠ ¼ ꢀ7.7 (c ¼ 1 in H2O), (lit,12b ½aŠ ¼ ꢀ7.8, c ¼ 2 in H2O). IR(KBr):
D
3395, 3030, 2934, 1742, 1498, 1292, 1238, 749, 701 cm–1. 1H RM N
(CDCl3): d 7.32–7.10(m, 5H, Ar-H), 4.10(t, 2H, J ¼ 7.1 Hz, O-CH2),
3.74(m, 1H, CH2-N), 3.10(dd, 2H, J1 ¼ J2 ¼ 5.0 Hz, Ar-CH2), 1.25(t, 3H,
J ¼ 7.1 Hz, CH3) ppm. 13C RMN(CDCl3): d 169, 129, 128, 126, 61, 54, 37,
14 ppm. MS(m/e): 193, 120(100), 102, 91.
Esterification of Acids
TPA
R0COOH ÀÀÀÀÀÀÀÀ! R0COOR000
R000-OH
General Method
8a) Methyl 3,5-dimethoxybenzoate: A mixture of 3,5-dimethoxyben-
zoic acid (3.32 g, 18.22 mmol) and methanol (5.90 mL, 145.8 mmol), was
cooled to ꢀ5ꢁC a ꢀ10ꢁC in an ice-salt bath. A solution of TPA
(1.98 g, 20.00 mmol) in DCM(5 mL) was added dropwise to the mixture.
The mixture was warmed to 40ꢁC and stirred for two hours. Excess
solvent was the removed in vacuo leaving a white residue. The solid
was neutralized with NaOH (5%) solution, and the two-phase system
was extracted with ethyl acetate (2 ꢃ 50 mL). The combined organic
phases were dried (sodium sulfate) and removal of solvent under reduced
pressure gave the product. The crude solid consists only of the pure ester; no
further purification was made. White solid, 3.43 g, 95%. (purity >97%).
Mp 42–44ꢁC, (lit12b mp 42–43ꢁC). IR(KBr): 3004, 2948, 1719, 1235 cm–1. 1H
RMN(CDCl3): d 7.27(s, 2H, Ar-H), 6.65(s, 1H, Ar-H), 3.90(s, 6H, O-CH3),
3.82(s, 3H, O-CH3) ppm. 13C RMN(CDCl3): d 167, 160, 132, 107, 106, 56,
52 ppm. MS(m/e): 196(100), 165.
8b) Methyl 3-Phenylpropanoate: Yellow oil, 97%. (purity >98%).
Bp 237–239ꢁC, (lit,12a bp 238–239ꢁC). IR(KBr): 3025, 2954, 1739, 1600,
1
1497, 1292, 1200, 1071 cm–1. H RMN(CDCl3): d 7.30–7.10(m, 5H, Ar-
H), 3.66(s, 3H, O-CH3), 2.99–2.91(t, 2H, J ¼ 7.4 Hz, CH2), 2.66–2.59(t,
2H, J ¼ 8.1 Hz, CH2) ppm. 13C RMN(CDCl3): d 129, 128, 126, 52, 36,
31 ppm. MS(m/e): 164, 104(100), 91.
8c) Methyl trans-3-phenyl-2-propenoate: Yellow oil, 96%. (purity
>97%) Cryst (EtOH). Mp 35–37ꢁC, (lit,12a mp 36ꢁC). IR(KBr): 3060, 2950,

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RIVERO, HEREDIA, AND OCHOA
1
1716, 1636, 1578, 1495, 11201, 1072 cm–1. H RMN(CDCl3): d 7.72–7.64(d,
1H, J ¼ 16.0 Hz, CH), 7.50–7.30(m, 5H, Ar-H), 6.46–6.38(d, 1H,
J ¼ 16.1 Hz, CH), 3.79(s, 3H, O-CH3) ppm. 13C RMN(CDCl3): d 145, 134,
130, 129, 128, 118, 67, 52 ppm. MS(m/e): 162, 131(100), 103.
8d) Methyl 3-chlorobenzoate: Yellow oil, 96%. (purity >96%). Bp
98–100ꢁC/12 mm, (lit,12b bp 99–101ꢁ/12 mm) IR(KBr): 3072, 3002, 2953,
1726, 1575, 1435, 1287, 1126, 1086. 1H RMN(CDCl3): d 8.02(s, 1H,
Ar-H2), 7.92(d, 1H, J ¼ 7.6 Hz, Ar-H6), 7.55–7.50(d, 1H, J ¼ 8.1, Ar-H4),
7.42–7.34(dd, 1H, J1 ¼ J2 ¼ 7.8 Hz, Ar-H5), 3.93(s, 3H, O-CH3) ppm.
13C RMN(CDCl3): d 133, 130, 127, 52 ppm. MS(m/e): 170, 139(100).
8e) Methyl 9H-fluoren-9-ylideneacetate: White solid, 97%. (purity
>95%). Mp 59–62ꢁC, (lit,12a mp 62ꢁC). IR(KBr): 3062, 1733, 1446, 1267,
1
1200, 1154, 1010 cm–1. H RMN(CDCl3): d 7.76(d, 1H, J ¼ 7.7 Hz, Ar-H4),
7.66(d, 1H, J ¼ 7.4 Hz, Ar-H), 7.43–7.33(m, 2H, Ar-H3), 6.42(s, 1H, ¼ CH),
3.74(s, 3H, O-CH3) ppm. 13C RMN(CDCl3): d 128 127 125 120, 53, 52 ppm.
MS(m/e): 165(100), 224.
ACKNOWLEDGMENT
We gratefully acknowledge support for this project by Consejo
Nacional de Ciencia y Tecnologia (CONACyT, GRANT No. 28488-E)
and Consejo Nacional de Educacion Tecnologica (COSNET, GRANT
No. 623.97-P). S. Heredia thanks CONACyT and A. Ochoa thanks
COSNET for fellowships. The authors are indebted to R. Somanathan
and L. H. Hellberg for encouragement.
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2175
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Received in the USA October 19, 2000

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