Conversion of α-amino acids into nitriles by oxidative decarboxylation with trichloroisocyanuric acid

Article abstract of DOI:10.1081/SCC-200030958

Trichloroisocyanuric acid oxidation of α-amino acids in water or methanol in the presence of pyridine produces nitriles with one less carbon in good yields and of high purity.

Full text of DOI:10.1081/SCC-200030958

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Conversion of α‐Amino Acids
into Nitriles by Oxidative
Decarboxylation with
Trichloroisocyanuric Acid
Gene A. Hiegel a , Justin C. Lewis a & Jason W.
Bae a
a Department of Chemistry and Biochemistry ,
California State University , Fullerton, California,
92834, USA
Published online: 10 Jan 2011.
To cite this article: Gene A. Hiegel , Justin C. Lewis & Jason W. Bae (2004)
Conversion of α‐Amino Acids into Nitriles by Oxidative Decarboxylation with
Trichloroisocyanuric Acid, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:19, 3449-3453, DOI:
10.1081/SCC-200030958
To link to this article: http://dx.doi.org/10.1081/SCC-200030958
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3449–3453, 2004
Conversion of a-Amino Acids into Nitriles
by Oxidative Decarboxylation with
Trichloroisocyanuric Acid
*
Gene A. Hiegel, Justin C. Lewis, and Jason W. Bae
Department of Chemistry and Biochemistry, California State University,
Fullerton, California, USA
ABSTRACT
Trichloroisocyanuric acid oxidation of a-amino acids in water or
methanol in the presence of pyridine produces nitriles with one less
carbon in good yields and of high purity.
Key Words: a-Amino acids; Nitriles; Oxidative decarboxylation; Oxidation;
Decarboxylation; Preparation; Synthesis; Trichloroisocyanuric acid.
Amino acid oxidations have been carried out with a variety of oxidizing
agents to produce a variety of products. Silver oxide oxidation produces car-
*
Correspondence: Gene A. Hiegel, Department of Chemistry and Biochemistry,
California State University, Fullerton, CA 92834, USA; E-mail: ghiegel@fullerton.
edu.
3449
DOI: 10.1081/SCC-200030958
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3450
Hiegel, Lewis, and Bae
boxylic acids with one less carbon.[1] Electrochemical oxidation in the presence
of triphenylphosphine gives a-amino aldehydes.[2] Silver catalyzed oxidation by
persulfate generates aldehydes with one less carbon.[3] The reaction with chlor-
ine produces a mixture of aldehydes and nitriles with one less carbon.[4]
A
search of the literature did not reveal any synthetic procedures for the conver-
sion of a-amino acids effectively into nitriles. We wish to report that a-amino
acids are converted cleanly and efficiently into nitriles by means of an oxidative
decarboxylation reaction carried out with trichloroisocyanuric acid [TCICA;
1,3,5-trichloro-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; C3Cl3N3O3] in water or
methanol in the presence of pyridine Eq. (1). The reaction is exothermic, and
therefore, TCICA is added slowly while using a dry-ice condenser for the
lower molecular weight products. Yields of the more volatile nitriles were con-
siderably lower without the dry-ice condenser. The results are shown in Table 1.
L-Isoleucine [(2S,3S)-(þ)-2-amino-3-methylpentanoic acid] was
converted into (S)-(þ)-2-methylbutyronitrile with a specific rotation of
þ37.468 for the purest fraction. This nitrile has also been prepared from the
corresponding aldehyde, from the oxime of the aldehyde, and from the corres-
ponding carboxylic acid.[5] The highest observed specific rotation was þ32.78,
although the estimated maximum specific rotation was 36.38. Oxidation of
isoleucine with TCICA appears to be the best method for the synthesis of
(S)-(þ)-2-methylbutyronitrile considering the simplicity of the reaction,
the availability of isoleucine, and the high optical purity obtained.
EXPERIMENTAL
All reagents were used as received. Valine, leucine, isoleucine, norleu-
cine, phenylalanine, phenylglycine, glutaric acid, isobutyronitrile, isovalero-
nitrile, 2-methylbutyronitrile, valeronitrile, benzonitrile, and methanol were
obtained from Aldrich. Pyridine and phenylacetonitrile were obtained from
J. T. Baker. The TCICA (99%) was obtained from Chem Lab Products. All
products except for methyl 3-cyanopropanoate were compared with authentic
1
samples by means of H FT-NMR and Fourier-transform infrared (FT-IR)
spectra and GC retention time. 3-Cyanopropanoic acid was converted into
methyl 3-cyanopropanoate before isolation and characterized by means of
the IR spectrum and boiling point.

Conversion of a-Amino Acids into Nitriles by Oxidative Decarboxylation 3451
Table 1. Conversion of a-amino acids into nitriles.
Amino acid
Nitrile
Yield
Boiling point
GC purity
99.1%
58.4%a
102.7–103.08C
79.3%a
88.0%a
84.2%a
66.1%a
128.0–128.58C
124.0–125.08C
139.5–140.08C
190.08C
97.9%
97.4%
98.9%
99.3%
c
77.0%b
61.4%b
—
99.9%
96.5%
104.0–105.28C
(13.4–14.2 torr)d
aReaction run in water.
bReaction run in methanol.
cPurified by flash chromatography.
dConverted to the methyl ester before isolation.
1H FT-NMR spectra were recorded in CDCl3 using an Anasazi-modified
Varian EFT 90 MHz spectrometer. The FT-IR spectra were recorded using a
Perkin Elmer 1650 spectrometer. GC analyses were carried out with a
Hewlett-Packard 5890 Series II on a 6 ft ꢀ 1/8 in 10% Carbowax 20-M
column. Optical rotations were recorded using a Rudolph Instruments
Model 51 polarimeter equipped with a sodium vapor lamp.
Conversion of L-Isoleucine into (S)-(1)-2-Methylbutyronitrile
L-isoleucine, 15.300 g (0.1166 mol), 120 mL water, 29.05 g (0.3673 mol)
pyridine, and a magnet were placed in a 300-mL three-neck round bottom

3452
Hiegel, Lewis, and Bae
flask fitted with a dry-ice condenser, a stopper, and a solid addition funnel
containing 23.362 g (0.1000 mol, 0.3000 eq) TCICA. While stirring, TCICA
was added over a period of 30 min. The reaction was exothermic. After 3 hr
additional stirring at room temperature, solid NaHSO3 was added in order
to destroy excess TCICA until a negative test with iodide-starch paper was
obtained. After filtration to remove the cyanuric acid that formed and
washing the solid with ether, the mixture was acidified with HCl and the
aqueous phase was saturated with NaCl. The mixture was extracted with
ether (4 ꢀ 50 mL), dried over MgSO4, and filtered. The ether was removed
by distillation through a concentric tube column and the amine distilled to
give several fractions of (S)-(þ)-2-methylbutyronitrile, bp 124.0–125.08C.
Fractions 3–6, 8.532 g (88.0%), had a purity of 97.4% by GC. Fractions
4–6, 7.618 g (78.6%) had a purity of 99.2% by GC. Fraction 5, 4.904 g
(50.6%), had a purity of 99.5% by GC: [a]2D0 þ 37.468 (neat). The FT-IR,
1H FT-NMR, and GC retention time were identical to an authentic sample.
Conversion of L-Glutaric Acid into Methyl
3-Cyanopropanoic Acid
Glutaric acid, 15.655 g (0.1064 mol), 75 mL methanol, 17.67 g.
(0.2233 mol) pyridine, and a magnet were placed in a 300-mL three-neck
round bottom flask fitted with a dry-ice condenser, a stopper, and a solid
addition funnel containing 21.098 g (0.09077 mol, 0.2723 eq) TCICA. While
stirring, TCICA was added over a period of 45 min. The reaction was exothermic.
After 1 hr 50 min additional stirring at room temperature, solid NaHSO3 was
added in order to destroy excess TCICA until a negative test with iodide-
starch paper was obtained. After filtration to remove the cyanuric acid that
formed and washing the solid with methanol, 7 mL conc H2SO4 was added
to the filtrate and the solution was refluxed for 3 hr in order to form the
methyl ester. The methanol was removed using a rotary evaporator and
25 mL of water was added, and the mixture was extracted with ether
(3 ꢀ 100 mL). The ether solution was dried over MgSO4, and after filtration,
the ether was removed using a rotary evaporator and the residue distilled using
a concentric tube column to give 7.338 g. (61.4%) [bp 104.0–105.28C (13.4–
14.2 torr)] methyl 3-cyanopropanoate with a purity by GC of 96.5% [reported
bp 95–978C (8 torr)];[6] FT-IR (film) 2252 (CN), 1739 (CO), 1293, 1254,
1209, 1179, 1058, 1023, 1001, 981, 946, 878, 838, 784, 705 cm21 [reported
(film) 2246, 1735, 1286, 1247, 1202, 1172, 1052, 1017, 996, 975, 940, 871,
833, 778, 697 cm21];[7] 1H FT-NMR (CDCl3) d 3.76 (s, 3, OCH3), 2.70
(s, 4, CH2CH2).

Conversion of a-Amino Acids into Nitriles by Oxidative Decarboxylation 3453
ACKNOWLEDGMENT
This research was supported in part by a grant from the CSU Special Fund
for Research, Scholarship, and Creative Activity to G. A. H. and funds from
the Southern California Academy of Sciences Research Training Program
to J. W. B.
REFERENCES
1. Clarke, T.G.; Hampson, N.A.; Lee, J.B.; Morley, J.R.; Scanlon, B. Argentic
oxide oxidations of organic compounds. Tetrahedron Lett. 1968, (54),
5685–5688.
2. Maeda, H.; Maki, T.; Ohmori, H. One-step transformation of a-amino
acids to a-amino aldehydes effected by electrochemical oxidation of
Ph3P. Tetrahedron Lett. 1992, 33 (10), 1347–1350.
3. Bacon, R.G.R.; Hanna, W.J.W.; Stewart, D. Oxidation by persulfate. Part
V. Silver-catalyzed oxidation of secondary aliphatic amines and a-amino
acids. J. Chem. Soc. (C) 1966, 1388–1389.
4. Ishikawa, S.; Fujino, H.; Yasuda, K.; Shigemori, N. Products at the reaction
of amino acids in aqueous solution with chlorine. Suishitsu Odaku Kenkyu
1986, 9 (12), 786–792.
5. Botteghi, C.; Chelucci, G.; Marchetti, M. Synthesis of optically active ali-
phatic nitriles from aldehydes and acids. Synth. Commun. 1982, 12 (1),
25–33.
6. McElvain, S.M.; Schroeder, J.P. Orthoesters and related compounds from
malono- and succinonitriles. J. Am. Chem. Soc. 1949, 71, 40–46.
7. Simons, W.W. Ed. The Sadtler Handbook of Infrared Spectra; Sadtler
Research Laboratories, Inc.: Philadelphia, PA, 1978; spectrum no. 2737.
Received in the USA May 27, 2004