Acylation of amino acids with furancarboxylic acid chlorides

Article abstract of DOI:10.1023/A:1013926624228

Acylation of aromatic amino acids with furancarboxylic acid chlorides effectively proceeds in water-acetone medium at pH 8-9. Aliphatic amino acids are acylated at higher pH values, but under these conditions hydrolysis of acid chlorides becomes the main

Full text of DOI:10.1023/A:1013926624228

Russian Journal of General Chemistry, Vol. 71, No. 9, 2001, pp. 1479 1483. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 9, 2001,
pp. 1561 1566.
Original Russian Text Copyright
2001 by Lapina, Pevzner.
Acylation of Amino Acids with Furancarboxylic Acid Chlorides
I. M. Lapina and L. M. Pevzner
St. Petersburg Institute of Technology, St. Petersburg, Russia
Received June 6, 2000
Abstract Acylation of aromatic amino acids with furancarboxylic acid chlorides effectively proceeds in
water-acetone medium at pH 8 9. Aliphatic amino acids are acylated at higher pH values, but under these
conditions hydrolysis of acid chlorides becomes the main process. Acylation of chlorohydrates of methyl
esters of aliphatic amino acids proceeds smoothly in chloroform in the presence of triethylamine. Alkaline
hydrolysis of obtained products leads to N-acylated amino acids containing furan heteroring in the acyl radical.
N-Acylated amino acids containing the furan frag-
ment present interest in the field of searching of bio-
logically active compounds because the substances of
analogous structure may be formed in the course of the
simultaneous destruction of carbohydrates and peptides,
for example while cooking. The aim of the present
tion of aliphatic and aromatic amino acids with furan-
carboxylic acid chlorides and to study the dependence
of reaction conditions on the nature of reagents.
Acid chlorides I VI were the acylating agents,
and amino acids VII XV were chosen as the objects
work is to develop synthetic procedure for the acyla- of acylation.
COCl
CH3
CH3
COCl
CH3
COCl
CH3
CH3
COCl
H 3 C
COCl
O
O
O
O
O
I
II
III
IV
V
COCl
CH3
NH2
CH2COOH
NH2
COOH
NH2
NH2
(CH3)3C
O
COOH
VIII
CH=CH COOH
VI
VII
IX
X
HN
NH2CH(CH2)2SCH3 (CH3)2CH CH NH2
CH2 CH NH2 HOOC (CH2)2CH NH2
COOH
COOH
COOH
COOH
XIII
COOH
XI
XII
XIV
XV
It is known that amino acids exist in the equilib-
rium with their internal salts. Amino group of the
latter is protonated and can not undergo acylation. In
the case of -amino acids the internal salts are additio-
nally stabilized by formation of five-membered ring,
what complifies the process of acylation. That is why
As the basicity of nitrogen in alphatic and especially
in aromatic amino acids is much less than in aliphatic
amines, we tried to carry out acylation of free amino
acids in nonaqueous solvents (acetonitrile, acetone)
in the presence of an excess of triethylamine by
the procedure similar to that for p-nitrobenzoyl-
for the proceeding of the reaction the presence of base, chloride [1]. But no formation of the target products
permitting to create free amine in sufficient concentra-
tion and accepting hydrogen chloride is required.
was observed. Evidently in aprotic solvents the
studied amino acids exist mainly in a form of internal
1070-3632/01/7109-1479$25.00 2001 MAIK Nauka/Interperiodica

1480
LAPINA, PEVZNER
salts, which can not be deprotonated with triethyl-
amine.
ethanolic solution of potassium hydroxide at room
temperature for 2 3 h. Depending on the easiness of
crystallization, the reaction products were isolated as
free acids or their sodium salts. It occurred, that this
procedure permits to obtain N-furoyl amides of all the
native -amino acids under study. The yields of all
obtained compounds, their melting points and 1H
NMR spectral parameters are listed in Table 1.
The next procedure, used by us, was the acylation
in the water-organic medium at controlled pH. Ac-
cording to this procedure an amino acid was dissolved
in water-acetone mixture by the addition of water solu-
tion of alkali, and at 0 5 C the acetone solution of
an acid chloride was added to the reaction mixture.
The established pH value was maintained by the
addition of alkali solution (Schotten-Baumann acyla-
tion). Under these conditions hydrolysis of acid
chloride takes place together with acylation. Its rate
increases with the increase of pH. Therefore the
possibility of formation of acyl derivatives depends
on the ratio of the reactions rates of acid chloride with
amine and hydroxide anion.
EXPERIMENTAL
1H NMR spectra of obtained products were re-
corded on a Bruker WM-250 (250.13 MHz) spectro-
meter in DMSO-d6 with internal HMDS.
Acylation of aromatic amino acids (general
procedure). A sample of amino acid was suspended
in water, and 15% solution of potassium hydroxide
was added at 0 C until clear solution formed. Then
reaction mixture was twice diluted with acetone and
equivalent amount of 10 15% acetone solution of acid
chloride was added dropwise with stirring at 0 C. The
reaction mixture was maintained in the range pH 8 9
by the addition of 15% solution of potassium hydr-
oxide. After the complete addition of acid chloride
the reaction mixture was kept at 0 C until pH re-
mained unchanged. Its value was maintained no less
than 8.0 for 40 60 min by means of potassium hyd-
roxide solution. After that acetone was removed at
reduced pressure if necessary, reaction mixture was
diluted by 1.5 2 volumes of water and acidified with
diluted (1:1) hydrochloric acid to pH 3. Obtained
crystals were filtered off, washed with small amount
of water and dried at 40 50 C.
We found that aromatic amino acids VII X are
smoothly acylated with acid chlorides I VI at pH 8 9.
The yelds of corresponding amides are 89 95%.
Acylation of aliphatic amino acids proceeds at higher
pH values (9 10) because at milder conditions the
substrates can not be dissolved, and in heterogeneous
system reaction does not take place. It occured, that
in such highly basic medium hydrolysis of acid chlo-
rides becomes the main process, and in the majority
of cases the mixtures of acylamino acid and furan-
carboxylic acid were isolated. The only exclusions
were the compounds XVI, XVI which were prepared
on the basis of the most reactive acid chlorides I
and IV in the yields 36% and 50.7% respectively.
CON
COOH
H3C
O
N-Acyl derivatives of aliphatic amino acids
(general procedure). A sample of amino acid methyl
ester hydrochloride was suspended in 6 7-fold amount
of chloroform, cooled to 2 C, and 2 equivalents of
triethylamine was added. The obtained mixture was
stirred for 10 20 C. Then one equivalent of 10 15%
solution of furancarboxylic acid chloride was added
dropwise with stirring at 0 C. Resulting mixture was
stirred for 2 h and left overnight. On the next day
water was added with vigorous stirring until the dis-
solution of triethylamine hydrochloride. Water layer
was removed, and the organic layer was twice washed
with water. Chloroform was removed at reduced
pressure, and 2 equivalents (4 equivalents in the case
of dicarboxylic amino acid) of 20% water ethanolic
(1:1) solution of potassium hydroxide was added.
Resulting mixture was stirred for 2 3 h at room
XVI
CH3
CONH CH (CH2)2SCH3
O
XVII
From that it follows that furancarboxylic acid chlo-
rides are more easily hydrolized as compared to sub-
stituted benzoyl chlorides, because for example 4-me-
thylbenzoyl chloride under the analogous conditions
acylates valine with 98% yield.
Due to failed direct acylation of aliphatic -amino
acids we performed acylation of of their methyl esters
hydrochlorides with the subsequent hydrolysis of
obtained acylamino ester analogously to the typical
procedure [2]. Reaction was carried out in chloroform temperature. After that ethanol was removed at
at 0 5 C, and after removing of triethylamine hydro-
chloride crude aminoester was isolated. Without
further purification it was hydrolized with water
reduced pressure, the residue was diluted in 2 3 times
with water and acidified with diluted hydrochloric
acid (1:1) to pH 3. Obtained crystals were filtered
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 9 2001

ACYLATION OF AMINO ACIDS WITH FURANCARBOXYLIC ACID CHLORIDES
1481
N-Furoyl amino acids, their yields, melting points, and 1H NMR spectral parameters
Yield,
%
mp,
C
Compound
1H NMR spectrum, , ppm
4-N-(5-Methyl-2-furoyl)amino-
benzoic acid
3-N-(5-Methyl-2-furoyl)amino-
benzoic acid
89
90
250 2.42 s (3H, CH3-furan), 6.22 s (1H, H4-furan), 7.20 s (1H,
H3-furan), 7.84 7.89 m (4H, arom.), 10.02 s (1H, NH)
112 2.43 s (3H, CH3-furan), 6.24 s (1H, H4-furan), 7.20 s (1H,
H3-furan), 7.40 t (1H, Hm-phenyl), 7.60 d (1H, Hp-phenyl),
8.04 d (1H, Ho-phenyl), 8.32 s (1H, Ho-phenyl), 10.0 s (1H, NH)
156 2.42 s (3H, CH3-furan), 6.23 s (1H, H4-furan), 6.38 d (1H, CH ),
7.15 s (1H, H3-furan), 7.30 m (2H, Hm + Hp-phenyl), 7.80 d (1H,
Ho-phenyl), 8.00 s (1H, Ho-phenyl), 9.90 s (1H, NH)
137 1.40 m (2H, CH42-piperidine), 1.70 m (4H, CH23 + CH25-piperidine),
2.20 d (1H, N CHeq-piperidine), 2.50 s (3H, CH3-furan), 4.28 d
(1H, N CHax-piperidine), 5.10 br.s (1H, NCH COO-piperidine),
6.22 s (1H, H4-furan), 6.85 s (1H, H3-furan)
N-(5-Methyl-2-furoyl)-m-aminocin-
amic acid
88
36
N-(5-Methyl-2-furoyl)pipecolino acid
N-(5-Methyl-2-furoyl)methionin
74
58
85
170 2.10 m (5H, CH3S + CH2 CH), 2.40 s (3H, CH3-furan), 2.55 m
(2H, CH2 S), 4.50 m (1H, CH-aliph.), 6.17 s (1H, H4-furan),
7.00 s (1H, H3-furan), 8.00 br.s (1H, NH), 12.50 s (1H, COOH)
217 2.00 m (2H, CH2), 2.29 m (2H, CH2), 2.38 s (3H, CH3-furan),
4.38 m (1H, CH), 6.12 br.s (1H, H4-furan), 7.00 br.s (1H,
H3-furan), 8.07 br.s (1H, NH), 12.14 br.s (2H, COOH)
228 2.68 s (3H, CH3-furan), 7.20 7.40 m (5H, phenyl), 7.65 m [3H,
(Hp + Hm)-phenyl + H4-furan], 8.10 d (1H, Ho, phenyl), 8.34 s
(1H, Ho, phenyl), 9.81 s (1H, NH)
N-(5-Methyl-2-furoyl)glutaminic acid
N-(5-Phenyl-2-methyl-3-furoyl)-3-
aminobenzoic acid
N-(5-Phenyl-2-methyl-3-furoyl)-3-
aminocynnamic acid
88
82
267 2.60 s (3H, CH3-furan), 6.37 d (1H, =CH ), 7.30 7.61 m (5H,
H-phenyl + H4-furan + =CH ), 77.7 m (Ho-phenyl), 8.00 m (Ho-
phenyl), 9.64 s (1H, NH), 12.30 s (1H, COOH)
217 2.68 s (3H, CH3-furan), 3.50 s (2H, CH2 COOH), 7.20 d (2H, Ho,
phenyl), 7.30 t (1H, Hp-phenyl at furan), 7.45 m [3H, (Hm-phenyl
at furan) + H4-furan], 7.68 m [4H, (Ho-phenyl at furan) + Hm-
phenyl]
N-(5-Phenyl-2-methyl-3-furoyl)-p-
aminophenylacetic acid
N-(5-Phenyl-2-methyl-3-furoyl)-
methionin
62
73
47
75
149 2.10 m (5H, CH3S + CH2 CH), 2.55 m (2H, CH2 S), 2.60 s (3H,
CH3-furan), 4.50 m (1H, CH-aliph.), 7.27 m (1H, Hp, phenyl),
7.30 s (1H, H4-furan), 7.40 m (2H, Hm, phenyl), 7.61 d (2H, Ho,
phenyl), 8.04 d (1H, NH), 12.45 s (1H, COOH)
202 2.49 s (3H, CH3-furan), 3.00 m (2H, CH2), 4.57 m (1H, CH),
7.20 m (7H, phenyl + H4-furan, overlapping), 7.43 s (2H,
Hm, phenyl in furan fragment), 7.57 d (2H, Ho, phenyl in furan
fragment), 8.10 d (1H, NH), 12.60 s (1H, COOH)
N-(5-Phenyl-2-methyl-3-furoyl)-
phenylalanine
N-(5-Phenyl-2-methyl-3-furoyl)
163 0.90 d (6H, CH3-alkyl), 2.20 m (1H, CH-alkyl), 2.61 s (3H, CH3-
furan), 4.06 m (1H, CH COONa), 7.14 s (1H, H5-furan), 7.20 m
(1H, Hp, phenyl), 7.37 m (2H, Hm, phenyl), 7.60 m (2H, Ho,
phenyl)
N-(2-Methyl-3-furoyl)-m-
aminocynnamic acid
166 2.55 s (3H, CH3-furan), 6.37 d (1H, =CH ), 7.06 s (1H, H4-furan),
7.35 br.s (2H, H5-furan + Hp-phenyl), 7.50 d (2H, Hm-phenyl +
+ =CH ), 7.77 m (1H, Ho, phenyl), 8.00 s (1H, Ho, phenyl),
9.65 s (1H, NH), 12.25 s (1H, COOH)
N-(2-Methyl-3-furoyl)-p-amino-
phenylacetic acid
69
206 2.58 s (3H, CH3-furan), 3.50 s (2H, CH2 COOH), 7.03 s (1H,
H4-furan), 7.20 d (2H, Ho, phenyl), 7.43 s (1H, H5-furan), 7.65 d
(2P, Hm, phenyl), 9.50 s (1H, NH), 12.0 br.s (1H, COOH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 9 2001

1482
LAPINA, PEVZNER
Table (Contd.)
Yield,
%
mp,
C
Compound
1H NMR spectrum, , ppm
N-(2-Methyl-3-furoyl)phenyl-
alaninefuran
52
67
51
95
125
2.408 s (3H, CH3-furan), 3.05 m (2H, CH2-phenyl), 4.52 m (1H,
CH), 6.79 s (1H, H4-furan), 7.19 m (5H, H-phenyl), 7.45 s (1H,
H5-furan), 8.00 m (1H, NH), 12.5 br.s (1H, COOH)
2.00 m (2H, CH2), 2.24 m (2H, CH2), 2.50 s (3H, CH3-furan),
4.34 m (1H, CH), 6.91 s (1H, H4-furan), 7.41 s (1H, H5-furan),
8.00 m (1H, NH), 12.17 s (2H, COOH)
N-(2-Methyl-3-furoyl)glutaminic
acid
153
117
242
N-(3-Methyl-2-furoyl)methionin
2.10 m (5H, CH3S + CH2 CH), 2.31 s (3H, CH3-furan), 2.52 m
(2H, CH2S), 4.50 q (CH COOH), 6.42 s (1H, H4-furan), 7.57 s
(1H, H5-furan), 7.93 s (1H, NH)
N-(2,5-Dimethyl-3-furoyl)-m-
aminobenzoic acid
2.28 s (3H, CH53-furan), 2.50 s (3H, CH23-furan), 6.63 s (1H,
(decomp.) H4-furan), 7.38 t (1H, Hm), 7.62 d (1H, Hp), 8.08 d (1H, Ho),
8.30 s (1H, Ho betwen substituents), 9.57 s (1H, NH), 12.50 s
(1H, COOH)
N-(2,5-Dimethyl-3-furoyl)-m-
aminocynnamic acid
89
183
2.28 s (3H, CH53-furan), 2.50 s (3H, CH23-furan), 6.36 d (1H, CH ),
6.60 s (1H, H4-furan), 7.25 m (2H, Hm + Hp, phenyl), 7.52 d (1H,
CH ), 7.74 d (1H, Ho, phenyl), 8.00 s (1H, Ho, phenyl), 9.47 s
(1H, NH)
N-(2,5-Dimethyl-3-furoyl)-4-amino-
phenylacetic acid
98
68
62
95
94
92
89
146
135
181
260
2.28 s (3H, CH53-furan), 2.52 s (3H, CH32-furan), 3.48 s (2H, CH2
COOH), 6.60 s (1H, H4-furan), 7.15 d (2H, Ho, phenyl), 7.62 d
(2H, Hm, phenyl), 9.38 s (1H, NH)
N-(2,5-Dimethyl-3-furoyl)
glutaminic acide
2.00 m (2H, CH2), 2.19 s (3H, CH53-furan), 2.36 m (2H, CH2),
2.43 s (3H, CH23-furan), 4.29 m (1H, CH), 6.50 s (1H, H4-furan),
7.84 br.s (1H, NH), 12.5 s (2H, COOH)
N-(2,5-Dimethyl-3-furoyl)phenyl-
alanine
2.17 s (3H, CH53-furan), 2.43 s (3H, CH23-furan), 3.00 m (2H,
CH2), 4.50 br.s (1H, CH), 6.41 s (1H, H4-furan), 7.19 br.s
(5H, phenyl), 7.89 d (1H, NH), 12.5 s (1H, COOH)
2.28 s (3H, CH53-furan), 2.50 s (3H, CH23-furan), 6.63 s (1H,
N-(2,5-Dimethyl-3-furoyl)-4-amino-
benzoic acid
(decomp.) H4-furan), 7.88 m (4H, H-arom.), 9.64 m (1H, NH), 12.30 br.s
(1H, COOH)
N-(5-tert-Butyl-2-methyl-3-furoyl)-
4-aminobenzoic acid
243
264
236
1.30 s [9H, (CH3)3C], 2.58 s (3H, CH3-furan), 6.65 s (1H, H4-
furan), 7.77 dis.t (4H, H-arom.), 9.62 s (1H, NH), 12.3 s (1H,
COOH)
N-(5-tert-Butyl-2-methyl-3-furoyl)-
3-aminobenzoic acid
1.30 s [9H, (CH3)3C], 2.58 s (3H, CH3-furan), 6.70 s (1H, H4-
furan), 7.38 t (1H, Hm),7.62 d (1H, Hp), 8.08 d (1H, Ho), 8.30 s
(1H, Ho between substituents), 9.57 s (1H, NH)
N-(5-tert-Butyl-2-methyl-3-furoyl)-
m-aminocynnamic acid
1.30 s [9H, (CH3)3C], 2.60 s (3H, CH3-furan), 6.37 d (1H, =CH ),
6.64 s (1H, H-furan), 7.30 br.s (2H, Ho + Hp), 7.51 d (1H, =CH ),
7.80 d (1H, CH-arom. at olephine), 8.0 s (1H, CH-arom. between
substituents), 9.46 s (1H, NH)
N-(5-tert-Butyl-2-methyl-3-furoyl)-
p-aminophenylacetic acid
90
61
70
79
163
139
186
120
1.30 s [9H, (CH3)3C], 2.54 s (3H, CH3-furan), 3.48 s (2H,
Ph CH2 COOH), 6.63 s (1H, H4-furan), 7.17 d (2H, Ho-phenyl),
7.63 d (2H, Hm-phenyl), 9.35 s (1H, NH), 12.0 s (1H, COOH)
1.24 s [9H, (CH3)3C], 2.06 s (3H, S CH3), 2.50 m (6H, CH3 S +
+ CH3-furan), 3.20 br.s (4H, CH2 S + CH2), 4.47 m (1H, CH),
6.50 s (1H, H4-furan), 7.98 d (1H, NH), 12.25 s (1H, COOH)
1.22 s [9H, (CH3)3C], 2.38 s (3H, CH3-furan), 3.00 m (2H, CH2),
4.44 br.s (1H, CH), 6.43 s (1H, H4-furan), 7.69 br.s (5H,
phenyl), 7.91 br.s (1H, NH), 12.5 s (1H, COOH)
1.24 s [9H, (CH3)3C], 2.00 m (2H, CH2), 2.29 m (2H, CH2),
4.41 m (1H, CH), 6.50 s (1H, H4-furan), 7.86 d (1H, NH),
12.25 s (2H, COOH)
N-(5-tert-Butyl-2-methyl-3-furoyl)-
methionin
N-(5-tert-Butyl-2-methyl-3-furoyl)-
phenylalanine
N-(5-tert-Butyl-2-methyl-3-furoyl)-
glutaminic acid
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 9 2001

ACYLATION OF AMINO ACIDS WITH FURANCARBOXYLIC ACID CHLORIDES
1483
off and washed with small amount of water and dried
at 40 50 C. Some acylated aliphatic amino acids,
formed) until the formation of a viscous syrup. Reac-
tion mixture was triturated with ethyl acetate until the
especially dicarboxylic acids, are well soluble in water, formation of the shaped crystals, obtained mixture
and their washing must be carried out with care and
sometimes rejected. If the crystalline acylamino acid
could not be isolated the product was extracted with
chloroform, extract was evaporated in a vacuum
(10 mm), the residue was dissolved in butanol, 10
15% of water was added, and obtained mixture was
alkalified with 15% solution of sodium hydroxide to
pH 9 9.5. Obtained solution was evaporated atreduced
pressure (10 mm). After removing of water-butanol
azeotrope a small amount of inorganic salts was fil-
tered off, and the filtrate was concentrated until the
beginning of crystallization or (if no crystals were
was kept for 2 3 h to complete crystallization, the
precipitate was filtered off, washed with ethyl acetate
and dried at 30 40 C.
REFERENCES
1. Kuhn, R., Moller, E.F., Wendt, G., and Beinert, K.,
Chem. Ber., 1942, vol. 75, no. 3, pp. 717 722.
2. Greenstein, J.P. and Winitz, M., Chemistry of Amino
Acids, New York: Wiley, 1961.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 9 2001