An improved "one-pot" procedure for synthesis of fluorinated DL-phenylalanines

Article abstract of DOI:10.1081/SCC-120002709

DL-arylalanines were synthesized from corresponding aromatic aldehydes by an efficient "one-pot" procedure involving Erlenmeyer reaction and subsequent reduction of the resulting oxazolones (without prior isolation) using P/HI.

Full text of DOI:10.1081/SCC-120002709

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
AN IMPROVED “ONE-POT” PROCEDURE FOR
SYNTHESIS OF FLUORINATED DL-PHENYLALANINES
Alexander V. Samet , Daniel J. Coughlin , A. C. Buchanan III & Andrei A. Gakh
To cite this article: Alexander V. Samet , Daniel J. Coughlin , A. C. Buchanan III & Andrei A.
Gakh (2002) AN IMPROVED “ONE-POT” PROCEDURE FOR SYNTHESIS OF FLUORINATED DL-
PHENYLALANINES, Synthetic Communications, 32:6, 941-946, DOI: 10.1081/SCC-120002709
To link to this article: http://dx.doi.org/10.1081/SCC-120002709
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Date: 30 September 2015, At: 23:46

SYNTHETIC COMMUNICATIONS, 32(6), 941–946 (2002)
AN IMPROVED ‘‘ONE-POT’’
PROCEDURE FOR SYNTHESIS OF
FLUORINATED DL-PHENYLALANINES
Alexander V. Samet,1, Daniel J. Coughlin,2
*
A. C. Buchanan III,1 and Andrei A. Gakh1,
*
1Chemical and Analytical Sciences Division, Oak Ridge
National Laboratory, Oak Ridge, TN 37831-6197, USA
2American Cyanamid Co., P.O. Box 400, Princeton,
NJ 08543, USA
ABSTRACT
DL-arylalanines were synthesized from corresponding aro-
matic aldehydes by an efficient ‘‘one-pot’’ procedure involving
Erlenmeyer reaction and subsequent reduction of the resulting
oxazolones (without prior isolation) using P/HI.
INTRODUCTION
Fluoro-containing a-amino acids are of significant interest for protein
chemistry because fluorinated analogs often possess unique biological prop-
erties.1a,b Also, the presence of fluorine atom facilitates structural investiga-
tions of peptide molecules.2a–e Therefore, a search for new synthetic
*Corresponding authors.
941
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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SAMET ET AL.
approaches to fluoro-containing a-amino acids, and an improvement of the
existing ones2f are important, especially for parallel high throughput syn-
thesis applications.2g
Erlenmeyer azlactone synthesis is a well-known and important
approach for preparation of DL-a-amino acids from carbonyl compounds.3
Optically active amino acids can also be prepared using this procedure.4,5
However, the synthesis has always been performed as a multi-step pro-
cedure, with inevitable losses during isolation and purification of intermedi-
ate products. The first step (Erlenmeyer reaction) is a three-component
condensation between a carbonyl compound (in most cases, an aromatic
aldehyde), N-acetyl- or N-benzoylglycine, and excess acetic anhydride in the
presence of a basic catalyst (usually, NaOAc). The resulting oxazolone 1
(‘‘azlactone’’) undergoes a reductive ring cleavage (Na/Hg, P/HI or catalytic
hydrogenation) to yield the target DL-a-amino acid 3. This transformation is
performed either directly or as a two-step sequence, involving hydrolysis of
the azlactone to form a corresponding unsaturated a-acylamino acid 2 and a
subsequent reduction of the latter (Scheme).6 Of the above mentioned redu-
cing agents, red phosphorus in hydroiodic acid is considered to be one of the
most versatile.7 The reaction normally is carried out in acetic anhydride.
Scheme.
RESULTS AND DISCUSSION
During the preparation of fluoro-containing DL-phenylalanines
using the P/HI system, we realized that the azlactone did not need to be
isolated from the reaction mixture before the reduction. Indeed, yields of
azlactones from aromatic aldehydes in Erlenmeyer reaction are usually high,
so the only compound present in the mixture in significant amounts by

FLUORINATED DL-PHENYLALANINES
943
the end of the reaction (besides azlactone itself ) is Ac2O, which serves
both as a solvent and as a dehydrating agent. Thus, no other compounds
are present to interfere with the subsequent reduction. Moreover, as men-
tioned above, the reduction is usually performed in Ac2O as a reaction
medium.
This approach proved to be quite successful. Thus, DL-phenylalanine
3a was obtained from benzaldehyde in 48% isolated yield starting from
N-acetylglycine and in 51% isolated yield starting from hippuric acid
(N-benzoylglycine) compared to 39–43% total yield described previously5
for a 2-step sequence (starting from hippuric acid). The results for fluori-
nated DL-phenylalanines are summarized in table.
Both N-acetyl- and N-benzoylglycines could be successfully used in the
reaction. However, in some cases yields with hippuric acid are markedly
lower. This difference is probably due to a higher stability of phenyl-
substituted azlactones towards acidic hydrolysis compared to the methyl-
substituted ones.2,6 Indeed, ether extracts from the reaction work-up (see
Experimental) contained largely unreacted azlactones; their amounts being
higher for the reactions with hippuric acid. Therefore, we used N-acetyl-
glycine as a starting compound in most cases.
In summary, we have developed an efficient one-pot procedure for
the preparation of fluorinated DL-phenylalanines. The yields for known
compounds are comparable or higher than those achieved by known multi-
step procedures involving the Erlenmeyer reaction. We expect that this
method could also be successfully employed for the synthesis of other
substituted DL-phenylalanines.
Table. Yields and M.P. of Fluorinated Phenylalanines 3b–i
Compound
Ar
Yield (%)a
3bb
3cc
3dd
3e
2-FC6H4
4-CF3C6H4
42 (B)
32 (A)
44 (A)
52 (A), 20 (B)
44 (A), 23 (B)
62 (A)
4-CF3OC6H4
3-CF3OC6H4
2-F-4-CF3C6H3
3-F-4-ClC6H3
2-F-4-BrC6H3
2-F-5-BrC6H3
3f
3g
3h
3i
43 (A)
36 (A)
aA—starting from N-acetylglycine; B—starting from hippuric acid.
bLiterature yield 21% (3-step procedure, starting from hippuric acid).8
cLiterature yield 20% (4-step procedure, starting from N-acetylglycine).9
dReported in 1990,10 no details presented.

944
SAMET ET AL.
EXPERIMENTAL
General procedure. A mixture of hippuric acid (0.90 g, 5 mmol) or
N-acetylglycine (0.60 g, 5 mmol), aromatic aldehyde (10% molar excess),
and NaOAc (0.3 g) in Ac2O (1.5 ml) was heated for 30 min at 110–115ꢀC.
Red phosphorus (0.4 g) and more Ac2O (1 ml) were added to the reaction
mixture, followed by a dropwise addition of 47% HI (2.5 ml). The resulting
suspension was refluxed for 3.5 h with stirring, then filtered (still hot), and
the precipitate washed on the filter with AcOH (1 ml). The filtrate was
evaporated to dryness in vacuo, and the residue was taken into a mixture
of water (7ml) and ether (5 ml). The water layer was separated, extracted
once more with ether (5 ml) and evaporated to dryness again. The residue
was dissolved in 1–2 ml of water, and pH was adjusted to 5–6 with aqueous
NH3. The resulting white precipitate of amino acid was filtered off, washed
with 1 ml of an ice-cold water, and dried.
1H NMR spectra (400 MHz, DMSO-d6) and m.p. of DL-phenyl-
alanines 3b-i.
DL-2-Fluorophenylalanine 3b. M.p. 254–256ꢀC (decomp.) (lit.11 m.p.
258.5–259ꢀC (decomp.). 1H NMR: d 2.77 (dd, J ¼ 13.5 Hz, J ¼ 8.8 Hz,
1H); 3.21 (br.d, J ¼ 13.5 Hz, 1H); 3.39 (br.s, 1H); 7.1–7.2 (m, 2H); 7.25
(m, 1H), 7.34 (m, 1H).
DL-4-(Trifluoromethyl)phenylalanine 3c. M.p. 228–231ꢀC (decomp.)
(lit.12 m.p. 222ꢀC (decomp.). H NMR: d 2.94 (dd, J ¼ 14.0 Hz, J ¼ 8.5 Hz,
1
1H); 3.17(dd, J ¼ 14.4 Hz, J ¼ 5.0 Hz, 1H); 3.44 (dd, J ¼ 8.5 Hz, J ¼ 5.0 Hz,
1H) ; 7.46 (d, J ¼ 7.8 Hz, 2H); 7.62 (d, J ¼ 7.8 Hz, 2H).
DL-4-(Trifluoromethoxy)phenylalanine 3d. M.p. 257–259ꢀC (decomp.).
1H NMR: d 2.90 (dd, J ¼ 14.2 Hz, J ¼ 7.9 Hz, 1H); 3.13 (dd, J ¼ 14.2 Hz,
J ¼ 4.4 Hz, 1H); 3.42 (dd, J ¼ 7.9 Hz, J ¼ 4.4 Hz, 1H); 7.246 (d, J ¼ 8.3 Hz,
2H); 7.37 (d, J ¼ 8.3 Hz, 2H).
DL-3-(Trifluoromethoxy)phenylalanine 3e. M.p. 241–244ꢀC (decomp.).
Calculated for C10H10F3NO3, %: H, 4.04; N, 5.62. Found, %: H, 3.76;
N, 5.22. 1H NMR: d 3.04 (dd, J ¼ 14.2 Hz, J ¼ 8.6 Hz, 1H); 3.21 (dd,
J ¼ 14.2 Hz, J ¼ 4.8 Hz, 1H); 3.75 (m, 1H); 7.37 (m, 3H); 7.44 (t,
J ¼ 8.1 Hz, 1H).
DL-2-Fluoro-4-(trifluoromethyl)phenylalanine 3f. M.p. 260–262ꢀC
(decomp.). Calculated for C10H9F4NO2, %: H, 3.61; N, 5.58. Found, %:
H, 3.63; N, 5.56. 1H NMR: d 2.90 (dd, J ¼ 13.9 Hz, J ¼ 8.1 Hz, 1H); 3.35 (dd,
J ¼ 13.9 Hz, J ¼ 5.3 Hz, 1H); 3.46 (dd, J ¼ 8.1 Hz, J ¼ 5.3 Hz, 1H); 7.50–7.65
(m, 3H).
DL-4-Chloro-3-fluorophenylalanine 3g. M.p. 243–245ꢀC (decomp.).
Calculated for C9H9ClFNO2, %: H, 4.17; N, 6.44. Found, %: H, 4.00;
N, 6.42. 1H NMR: d 2.80 (dd, J ¼ 14.0 Hz, J ¼ 8.2 Hz, 1H); 3.16 (br.d,

FLUORINATED DL-PHENYLALANINES
945
J ¼ 14.0 Hz, 1H); 3.43 (br.d, J ¼ 8.5 Hz, 1H); 7.13 (d, J ¼ 8.3 Hz, 1H); 7.32
(d, J ¼ 10.3 Hz, 1H); 7.50 (m, 1H).
DL-4-Bromo-2-fluorophenylalanine 3h. M.p. 265–267ꢀC (decomp.).
Calculated for C9H9BrFNO2, %: H, 3.46; N, 5.34. Found, %: H, 3.78;
N, 5.15. 1H NMR: d 2.78 (dd, J ¼ 14.2 Hz, J ¼ 8.5 Hz, 1H); 3.20 (dd,
J ¼ 14.2 Hz, J ¼ 4.0 Hz, 1H); 3.44 (dd, J ¼ 8.5 Hz, J ¼ 4.0 Hz, 1H); 7.34 (m,
2H); 7.48 (d, J ¼ 9.1 Hz, 1H).
DL-5-Bromo-2-fluorophenylalanine 3i. M.p. 261–264ꢀC (decomp.).
Calculated for C9H9BrFNO2, %: H, 3.46; N, 5.34. Found, %: H, 3.48;
N, 5.28. 1H NMR: d 2.77 (dd, J ¼ 14.3 Hz, J ¼ 8.8 Hz, 1H); 3.25 (dd,
J ¼ 14.3 Hz, J ¼ 5.2 Hz, 1H); 3.39 (dd, J ¼ 8.8 Hz, J ¼ 5.2 Hz, 1H); 7.14
(t, J ¼ 9.2 Hz, 1H); 7.47 (m, 1H); 7.56 (dd, J ¼ 6.3 Hz, J ¼ 2.2 Hz, 1H).
ACKNOWLEDGMENT
The research was sponsored by the IPP program, U.S. Department of
Energy, under contract DE-AC05-00OR22725 with Oak Ridge National
Laboratory, managed and operated by UT-Battelle, LLC.
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Received in the USA April 5, 2001