Reactions of aminobenzoic acids with α,β-acetylenic γ-hydroxy nitriles: synthesis of functionalized amino acids and unusually facile esterification and acetylene hydration

Article abstract of DOI:10.1016/j.tet.2009.01.073

2-Aminobenzoic acid 1 reacts with α,β-acetylenic γ-hydroxy nitriles 4 and 5 to afford 2-[(5-iminio-2,2-dialkyl-2,5-dihydro-3-furanyl)amino]benzenecarboxylates 7 and 8 (yield 73-74%), a new class of unnatural amino acids in a peculiar zwitterionic form, ha

Full text of DOI:10.1016/j.tet.2009.01.073

Tetrahedron 65 (2009) 2472–2477
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactions of aminobenzoic acids with a,b-acetylenic g-hydroxy
nitriles: synthesis of functionalized amino acids and unusually facile
esterification and acetylene hydration
,
a
a
a
Boris A. Trofimov a , Anastasiya G. Mal’kina , Olesya A. Shemyakina , Valentina V. Nosyreva ,
Angela P. Borisova a, Alexander I. Albanov a, Olga N. Kazheva b, Grigorii G. Alexandrovc,
Anatolii N. Chekhlov b, Oleg A. Dyachenko b
*
a A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Academician N.N. Semenov Str., 142432 Chernogolovka, Russian Federation
c N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninskii Prosp., 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Aminobenzoic acid 1 reacts with a,b-acetylenic g-hydroxy nitriles 4 and 5 to afford 2-[(5-iminio-2,2-
Received 6 November 2008
Received in revised form 23 December 2008
Accepted 15 January 2009
dialkyl-2,5-dihydro-3-furanyl)amino]benzenecarboxylates 7 and 8 (yield 73–74%), a new class of un-
natural amino acids in a peculiar zwitterionic form, having the positive charge transferred to the remote
imino group of the dihydrofuranyl substituent. 3- and 4-Aminobenzoic acids 2 and 3 with
a,b-acetylenic
Available online 21 January 2009
g
-hydroxy nitriles 4–6 undergo entirely different transformations to deliver the esters of cyanome-
thylhydroxyalkyl ketones 9–12, which result from the unusually facile esterification of the hydroxyl
function and simultaneous hydration of the triple bond. 4-Aminobenzoic acid 3 is found to be an active
Keywords:
Aminobenzoic acids
a,b-Acetylenic g-hydroxy nitriles
2-[(5-Iminio-2,2-dialkyl-2,5-dihydro-3-
furanyl)amino]benzenecarboxylate
Esterification
organic catalyst for the one-pot conversion of
a,
b
-acetylenic
g
-hydroxy nitrile 4 to 5-amino-2,2-di-
methyl-3(2H)-furanone 13, in 80% yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Cyanomethylhydroxyalkyl ketones
1. Introduction
with a,b-acetylenic g-hydroxy nitriles 4–6, which prove to be both
worthwhile and available reagents.8
The ever-growing demand for biological ligands to provide
a clear understanding of their function at a molecular level and to
pave shorter routes to therapeutic agents puts a special emphasis
on the availability of unusual amino acids and their derivatives.1
Among aromatic amino acids, 2-, 3-, and 4-aminobenzoic acids
occupy an important place as intermediates in the synthesis of
pharmaceutical products,2 dyes,3 and flavors.4 Aminobenzoic acids
are employed as building blocks for the preparation of molecules
with targeted biological activity,5 compounds capable of selectively
absorbing harmful solar radiation6 and materials with luminescent
properties.7 Thus, new and original approaches to the synthesis of
unknown classes of unnatural amino acids represent an area
of paramount interest for wide circles of diverse specialists. The aim
of this work is to develop a new general synthetic methodology of
structural modification of aminobenzoic acids 1–3 by the reactions
2. Results and discussion
Experiments have shown that 2-aminobenzoic acid 1, on one
hand, and 3- and 4-aminobenzoic acids 2 and 3, on the other hand,
react with a,b-acetylenic g-hydroxy nitriles 4–6 in completely dif-
ferent ways, depending on the mutual disposition of the amino and
carboxylic functions in the benzene ring. Thus, the reaction be-
tween 2-aminobenzoic acid 1 and acetylenes 4 and 5 gives exclu-
sively amino acids with dihydrofuranyl substituents as the
O
OH
_
R2
O
MeCN
70-75 °C, 60 h
O
R1
CN
+
NH
R2
R1
NH2
OH
4, 5
H
H
+
1
N
O
4, 7: R1 = R2 = Me
5, 8: R1 = Me, R2 = Et
7, 8
* Corresponding author. Fax: þ7 3952 41 9346.
Scheme 1.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.073

B.A. Trofimov et al. / Tetrahedron 65 (2009) 2472–2477
2473
O
OH
O
CN
O
O
70-75 °C, 15-55 h, MeCN
(or rt, 100 h, Et3N, MeCN)
R1
R2
R2
+
CN
HO
R1
4-6
NH2
NH2
2, 3
9-12
2: 3-NH2C6H4COOH
3: 4-NH2C6H4COOH
4: R1 = R2 = Me
9: R1 = R2 = Me, 3-NH2C6H4COOH
10: R1 = R2 = Me, 4-NH2C6H4COOH
11: R1 = Me, R2 = Et, 4-NH2C6H4COOH
12: R1 - R2 = (CH2)5, 4-NH2C6H4COOH
5: R1 = Me, R2 = Et
6: R1 - R2 = (CH2)5
Scheme 2.
zwitterions 7 and 8 (in 73–74% yield, 70–75 ꢀC, 60 h, no catalyst,
MeCN) (Scheme 1).
On the contrary, 3- and 4-aminobenzoic acids 2 and 3 on re-
action with acetylenes 4–6 also furnish chemo- and regiospecifi-
cally, esters of cyanomethylhydroxyalkyl ketones 9–12 (in 14–93%
yield, 70–75 ꢀC, 15–55 h, no catalyst, MeCN or in 48–95% yield, rt,
100 h, Et3N, MeCN) (Scheme 2).
The zwitterion structure of amino acid 7 (and apparently that of
8) was determined by X-ray analysis of its single crystal (Fig. 1). The
benzene and furan cycles are almost planar: maximal deviations of
the atoms from the average planes are 0.02 and 0.01 Å, respectively,
for C(7) and O(12). The dihedral angle between the planes equals
157.5ꢀ. The dihedral angle between the benzene plane and that
formed by C(1)O(1)O(2) is 172.4ꢀ. The deviation of the N(1) atom
out of furan cycle plane is 0.02 Å. In the molecule, the
intramolecular H-bond O(2)/H(8)–N(8) is realized, its parameters
being O(2)/N(8)d2.558(2) Å, O(2)/H(8)d1.69(2) Å, N(8)–
H(8)d0.96(2) Å, O(2) /H(8)–N(8)d148(2)ꢀ.
The zwitterionic character of the molecule 7 explicitly follows
from the equivalency of the carboxylic oxygen atoms O(1) and O(2),
the absence of the O–H covalent bond in the carboxylic moiety, and
the practically equal N–H bonds in the ]NþH2 group. Noteworthy
is that the positive charge is transferred to the remote imino group
of the dihydrofuran cycle, which is not typical for common amino
acids. For the first time such an unusual zwitterionic structure has
The close-to-plane structure of amino acid 7, its high polarity,
and polarizability should provide for through-conjugation and
hence easy electron-transfer along the whole system including its
supramolecular architectures in solution and crystal state. Conse-
quently, amino acids 7 and 8 are assumed to be highly responsive
toward any physical and chemical changes of the surrounding that
secure their applications as optoelectronic materials and sensors.
Besides, the iminodihydrofuran substituents considerably extend
their chemical and pharmaceutical potentials, since the dihy-
drofuran moiety is known to be a key motif in a number of bio-
logically active compounds and pharmaceutical important
molecules.9
X-ray analysis of single crystal of ester 10 (Fig. 2) shows that
maximal atom deviation out of the benzene ring is 0.01 Å [atom
C(4)]. Deviations of the N(1), C(8), O(9), and O(10) atoms out of the
benzene ring plane equal to 0.02, 0.09, 0.30, and 0.10 Å, re-
spectively. The dihedral angle between benzene ring and the
C(8)O(9)O(10) fragment is 169.5ꢀ and the angle between the ben-
zene ring and the C(11)C(13)O(16) fragment is 71.6ꢀ. The torsion
angles C(11)O(10)C(8)C(5) and C(11)O(10)C(8)O(9) are 161.3(1)ꢀ
and 18.7(2)ꢀ, respectively.
In the crystal structure of ester 10, the molecules are likely
bound in the chain by bifurcate H-bonds between CN and NH2
groups (the contacts H/N are shorten and the N/N distances are
close to the sums of Van der Waals radii).10
recently been fixed for the adducts of aliphatic amino acids to
a
,
b
-
NMR (1H, 13C, HMBC) and IR spectra as well as MS spectra of
esters 9–12 are in agreement with their structure (see Experi-
mental). In the 13C NMR spectrum (DMSO-d6) of ester 9, doubling of
all the signals except CN and CH2 groups is observed, maybe due to
hindered rotation of the ester carbonyl group, and its different
orientation relative to the amino function. Upon chromatography
acetylenic g
-hydroxy nitriles.8f
NMR (1H and 13C) and IR spectra of amino acids 7 and 8 corre-
spond to their structure (see Experimental).
Figure 1. The conformation and designation of atoms in the molecule of 2-[(5-iminio-
2,2-dimethyl-2,5-dihydro-3-furanyl)amino]benzenecarboxylate 7.
Figure 2. Designation of atoms in the molecule of ester 10.

2474
B.A. Trofimov et al. / Tetrahedron 65 (2009) 2472–2477
(250 ꢀC) a small peak (10–12% [M]þ 228) appears, seemingly a re-
sult of water elimination from ester 9:
Unlike 2-aminobenzoic acid 1, 3- and 4-aminobenzoic acids 2
and 3 do not add to acetylenes 4–6 by the amino group. Instead, the
amazingly easy esterification of the hydroxyl function of acetylenes
4–6 is accompanied by unusually facile hydration of the triple bond.
It is noteworthy that propargyl alcohol was reported11 to react with
carboxylic acids, including protected amino acids, in the presence
of special ruthenium complexes, e.g., RuCl2(PMe)3(arene), to give in
the first step the adducts across the triple bond, neither esterifi-
cation nor hydration of the acetylenic moiety being occurred.
The easy esterification and the triple bond hydration in the
substituted propargyl alcohols 4–6 are assumed to be strictly con-
certed: the molecule of water released from the esterification is
scavenged by the triple bond to form enol C, which further tauto-
merizes to the ketone moiety (Scheme 4).
Consequently, it is the combination of carboxylic and amino
functions in the 3- and 4-position of the benzene ring that allows
the two above classical reactions (esterification and acetylene hy-
dration) to proceed so easily. Apparently, we face here a novel ex-
ample of organic catalysis. It is known that the presence of
carboxylic and amino functions in a molecule is a key prerequisite
of organic catalysis.12
The mechanism of the catalytic action of 3- and 4-aminobenzoic
acids on the tandem esterification–hydration process of acetylenes
4–6 is not yet fully understood and deserves to be specially scruti-
nized. Tentatively, the carboxylic function of amino acids 2 and 3
protonates the hydroxyl of acetylenes 4–6, thus making it a better
leaving group, while the remaining propargyl type carbcationic
moiety is stabilized by the amino function of the second molecule of
the amino acid, until it is quenched with released water (Scheme 5).
Therefore, in this case, 3- and 4-aminobenzoic acids 2 and 3
behave both as reactant and catalyst. Indeed, the experiments
show, under the same conditions with benzoic acid, that the above
transformation of acetylenes 4–6 does not take place. Corre-
spondingly, the methyl ester of 4-aminobenzoic acid proves to be
inactive toward acetylene 4 (70–75 ꢀC, 43 h, MeCN). In aqueous
media, 4-aminobenzoic acid 3 does not react with acetylene 4,
although it actively catalyzes its hydration, cyclization, and isom-
erization of the intermediate enol D to yield 5-amino-2,2-dimethyl-
3(2H)-furanone 13 (Scheme 6, Table 1).
OH
Me
Me
CN
O
O
O
O
CN
Me
Me
250 °C
- H2O
9
NH2
NH2
Zwitterions 7 and 8 obviously result from the initial nucleophilic
addition of 2-aminobenzoic acid 1 to the triple bond of acetylenes 4
and 5. The intermediate adducts A then undergo the ring closure (in
the E-configuration) to give iminodihydrofurans B, which are fi-
nally transformed to their zwitterionic isomers 7 and 8 via the
hydrogen transfer from the carboxyl function to the imino group as
most basic center (Scheme 3).
O
OH
O
OH
NH
1
+
4, 5
7, 8
NH
R2
R1
CN
R2
R1
NH
OH
O
B
A
4, 7: R1 = R2 = Me
5, 8: R1 = Me, R2 = Et
Scheme 3.
R2
R1
OH
R2
O
R1
CN
O
O
CN
H2O
O
9-12
2, 3 + 4-6
-H2O
NH2
NH2
C
Scheme 4.
O
Me
HO
Me
HO
Me
It should be emphasized that a similar reaction of aliphatic
3
4
NH2
CN
NH
amino acids with
a,b-acetylenic g-hydroxy nitriles requires an
H2O
Me
O
O
OH
Me
entirely different set of condition (rt, NaOH, H2O)8f owing to the
considerable differences in basicity and acidity of their functions as
well as the low solubility of 2-aminobenzoic acid 1 in water (<1%).
Me
D
13
Scheme 6.
O
OH
C6H4
H2N
..
R2
R1
-
R2
+
O
O
H
H2N
H4C6
CN
+
H2O
O
CN
.
.
C6H4
.
R1
H2N
O
O
H
O
OH
C6H4
H2N
R2
R1 OH
O
OH
C6H4
CN
H2N
O
O
+
C6H4
H2N
9-12
Scheme 5.

B.A. Trofimov et al. / Tetrahedron 65 (2009) 2472–2477
2475
Table 1
4-Aminobenzoic acid
dihydrofuranone 13
prospective candidates in the design of optoelectronic devices,
sensors, and pharmaceuticals.
With 3- and 4-aminobenzoic acids, unusually facile esterifica-
tion and hydration of a,b-acetylenic g-hydroxy nitriles occur to give
aromatic amino esters having nitrile and ketone moieties, a novel
family of potent building blocks for organic synthesis.
4 as catalyst of the acetylene hydration to amino-
Mol ratio
of 3/4
Solvent
Temperature (ꢀC)
Time (h)
Yield of 13 (%)
1:1
1:9
1:9
1:1
H2O
H2O
H2O
50–60
50–60
50–60
20–25
18
7.5
30
4 months
63
56
80
12
The4-aminobenzoicacid isshowntobe an activeorganic catalyst
for one-pot conversion of
a,b-acetylenic g-hydroxy nitriles in
H2O–dioxane (4:1)
aqueous media to aminodihydrofuranones (still inaccessible, so
useful as synthetically and pharmaceutically intermediates) and the
reaction sequence includes hydration of the acetylenic moieties,
intramolecular addition of the hydroxyl to the cyano group, and
prototropic rearrangements. The results significantly contribute to
basic and preparative chemistry of amino acids and acetylenes.
Table 1 shows, with a catalytic amount of 4-aminobenzoic acid 3
(mol ratio 3/4¼1:9), that the yield of aminodihydrofuranone 13
reaches 80%. Without aminobenzoic acid 3 the reaction is not ob-
served (50–60 ꢀC, 20 h). Further attempts to hydrate acetylene 4
under various conditions gave much lower yields of amino-
dihydrofuranone 13: 32% (reflux, 1 h, Et3N, H2O),13 27% (rt, 6 h,
LiOH, H2O),14 and 17% (rt, 4 h, KCN, H2O–dioxane).15
4. Experimental
4.1. General
As far as 2-aminobenzoic acid 1 is concerned, its inability to
form esters like 9–12 can be explained in terms of formation of the
strong intramolecular H-bond between its amino and carboxyl
functions:
IR spectra were measured on a Bruker IFS-25 in KBr pellets. 1H
(400.13 MHz) and 13C (100.62 MHz) spectra were recorded on
a Bruker DPX-400 spectrometer in (CD3)2CO, CDCl3, and DMSO-d6.
Mass spectra were recorded on a GC–MS-QP5050A spectrometer
made by Shimadzu Company. Chromatographic column parame-
ters were as follows: SPBÔ-5, length 60 m, internal diameter
OH
0.25 mm, thickness of stationary phase film 0.25 mm; injector
N
O
temperature 250 8C, gas carrier helium, flow rate 0.7 mL minꢁ1
;
H
H
detector temperature 250 ꢀC; mass analyzer: quadrupole, electron
ionization, electron energy 70 eV, ion source temperature 200 ꢀC;
mass range 34–650 Da.
The influence of the reaction condition and the reactant struc-
ture on the yield of esters 9–12 is illustrated in Table 2.
The reaction was controlled by thin-layer chromatography on
neutral Al2O3 (chloroform–benzene–ethanol, 20:4:1 as eluent). 2-,
3-, and 4-Aminobenzoic acids 1–3 are commercial reagents
It is notable that Et3N (6–11 mass %) exhibits a remarkable cat-
alytic effect on the reaction. Under comparable conditions amino-
benzoic acid 3 with acetylenes 4 and 5 gave practically the same
yield of the corresponding esters. A more noticeable structural ef-
fect, mostly of steric character, is displayed by hydroxyalkyl sub-
stituents in acetylenes 4–6. Thus, in the case of hydroxycyclohexyl
substituent (acetylene 6) the yield of the corresponding ester 12
drops sharply: from 79 to 14% or from 83 to 48% (under different
conditions) as compared to that for acetylene 4 (Table 2).
(‘Merck’).
a,b-Acetylenic g-hydroxy nitriles 4–6 were prepared
according to a published method.16
4.2. X-ray diffraction
X-ray diffraction studies of 7 and 10 were carried out with an
Enraf Nonius CAD-4 diffractometer at room temperature (
u/2q-
3. Conclusion
scan mode, Mo for 7 or Cu for 10 K radiation, graphite mono-
a
chromator). Crystalline structure was solved by direct methods
followed by Fourier synthesis using SHELXS 97.17a The structure
was refined using anisotropic full-matrix approximation for all
non-hydrogen atoms with SHELXL 97.17b Coordinates of hydrogen
atoms were defined experimentally and refined isotropically. These
data are available via www.ccdc.cam.uk/contsretrieving.html (or
from CCDC, 12 Union CambrigeCB2 1EZ, UK, fax: þ44(0)1223 336
033; or e-mail: deposit@ccdc.cam.ac.uk). Any request to the CCDC
for data should quote the full literature citation and CCDC reference
The reaction of 2-aminobenzoic acid with accessible
a,b-acety-
lenic -hydroxy nitriles leads to a new type of amino acid having
g
dihydrofuran moieties and existing in a uncommon zwitterionic
form with a positive charge located on the remote imino group. X-
ray analysis reveals the almost planar structure of the amino acids
that secures the through-conjugation between the anionic and
cationic centers, and thus making these molecules potentially re-
sponsive to chemical and physical surrounding and hence
Table 2
Synthesis of esters 9–12 (1:1 mol ratio 2,3/4–6, MeCN)
Aminobenzoic acid
Acetylene
Temperature (ꢀ C)
Time (h)
Et3Na (mass %)
Product
Yield (%)
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
5
5
5
6
6
70–75
70–75
20–25
70–75
20–25
70–75
70–75
20–25
70–75
20–25
15
30
60 days
40
100
44
55
100
40
None
None
None
None
6
None
None
11
9
9
75
85
68
79
83
70
93
95
14
48
10
10
10
11
11
11
12
12
None
7
100
a
Relative to the reactant mass.

2476
B.A. Trofimov et al. / Tetrahedron 65 (2009) 2472–2477
numbers 705263 and 705262 (for amino acids
respectively).
7
and 10,
4.4.1. 3-Cyano-1,1-dimethyl-2-oxopropyl 3-
aminobenzenecarboxylate 9
Yield 75%; yellow powder; mp 150–153 ꢀC; IR (KBr) 3456, 3373,
4.2.1. Crystallographic data for 7
3236 (NH2), 2261 (CN),1711,1625 (C]O),1607 (C]C) cmꢁ1; 1H NMR
C13H14N2O3, M¼246.26, monoclinic, P21/c, a¼7.809(3) Å,
(400.13 MHz, CDCl3)
d
7.38 (d, J¼7.6 Hz,1H), 7.30 (s,1H), 7.21 (dd,1H),
b¼13.985(4) Å, c¼11.554(3) Å,
b
¼97.52(3)ꢀ, U¼1250.9(7) Å3, Z¼4,
6.89 (d, J¼7.4 Hz,1H), 4.11 (br s, 2H), 3.59 (s, 2H),1.56 (s, 6H); 13C NMR
Dcalcd¼1.31 g cmꢁ3
,
m
¼0.094 mmꢁ1
,
reflection observed/in-
(100.62 MHz, DMSO-d6) d 200.2,166.0,149.7,130.1,127.5,120.7,115.7,
dependent 2350/2184, 220 parameters refined, R¼0.045 for 1275
114.4, 113.3, 82.6, 23.1, 22.5; MS m/z (%) (EI): 246 (15), 137 (12), 120
(100), 92 (36), 65 (28), 41 (10), 39 (15). Anal. Calcd for C13H14N2O3: C,
63.40; H, 5.73; N, 11.38. Found: C, 63.53; H, 5.85; N, 11.18.
reflections with [F0>4s(F0)].
4.2.2. Crystallographic data for 10
4.5. The reaction of 4-aminobenzoic acid 3 with
acetylenic -hydroxy nitriles 4–6
a,b-
C13H14N2O3, M¼246.26, monoclinic, P21/c, a¼10.627(2) Å,
¼102.53(3)ꢀ, U¼1297.4(4) Å3, Z¼4,
g
b¼11.717(2) Å, c¼10.674(2) Å,
b
Dcalcd¼1.26 g cmꢁ3
,
m
¼0.751 mmꢁ1
,
reflection observed/in-
Method A. To a solution of 4-aminobenzoic acid 3 (247 mg,
1.8 mmol) in acetonitrile (4 mL), a solution of the appropriate
acetylenes 4–6 (1.0 mmol) in acetonitrile (2 mL) was added at room
temperature. The reaction mixture was stirred at 70–75 ꢀC for 40–
55 h (Table 2). The solvent was removed in vacuo, the residue was
treated with diethyl ether, and dried in vacuo to give compounds
10–12.
dependent 2670/2414, 220 parameters refined, R¼0.046 for 1974
reflections with [F0>4
s(F0)], (2
q
)
¼139.9 Å.
max
4.3. The reaction of 2-aminobenzoic acid 1 with
acetylenic -hydroxy nitriles 4 and 5
a,b-
g
Method B. To a solution of 4-aminobenzoic acid 3 (137 mg,
1.0 mmol) and the appropriate acetylenes 4–6 (1.0 mmol) in ace-
tonitrile (4 mL), Et3N (6–11 mass %) was added (Table 2). The re-
action mixture was stirred at room temperature for 100 h. The
solvent was removed in vacuo, the residue was treated with diethyl
ether, and dried in vacuo to give compounds 10–12.
General method. To
a solution of 2-aminobenzoic acid 1
(247 mg, 1.8 mmol) in acetonitrile (4 mL), the appropriate acety-
lenes 4 or 5 (1.8 mmol) in acetonitrile (2 mL) was added at room
temperature. The reaction mixture was stirred at 70–75 ꢀC for
60 h. The solvent was removed in vacuo, and the residue was
treated with diethyl ether and dried in vacuo to give compounds 7
and 8.
4.5.1. 3-Cyano-1,1-dimethyl-2-oxopropyl 4-
aminobenzenecarboxylate 10
4.3.1. 2-[(5-Iminio-2,2-dimethyl-2,5-dihydro-3-
Method A: yield 83%; method B: 79%; yellow crystals; mp 157–
158 ꢀC (acetonitrile); IR (KBr) 3460, 3360, 3230 (NH2), 2255 (CN),
furanyl)amino]benzenecarboxylate 7
Yield 74%; beige crystals; mp 288–290 ꢀC; IR (KBr) 3500–2500
1720, 1665 (C]O), 1605 (C]C) cmꢁ1
;
1H NMR [400.13 MHz,
(NH, ]NþH2, C]CH, CH), 1671 (C]O), 1607 (C]C) cmꢁ1; 1H NMR
(CD3)2O]
d
7.73 (d, J¼8.8 Hz, 2H), 6.68 (d, J¼8.8 Hz, 2H), 5.56 (s, 2H),
(400.13 MHz, DMSO-d6)
1H), 7.28 (d, J¼8.0 Hz, 1H), 7.08 (t, J¼7.3 Hz, 1H), 5.64 (s, 1H), 1.64 (s,
6H); 13C NMR (100.62 MHz, DMSO-d6)
176.4, 169.9, 168.6, 142.4,
d
8.03 (d, J¼7.6 Hz, 1H), 7.44 (t, J¼7.4 Hz,
3.95 (s, 2H), 1.57 (s, 6H); 13C NMR [100.62 MHz, (CD3)2O]
d
198.7,
165.5, 154.2, 131.7, 115.5, 114.4, 112.6, 81.5, 27.4, 22.9; MS m/z (%)
(EI): 246 (6), 137 (6), 120 (100), 92 (16), 65 (23), 41 (11), 39 (14).
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.49; H, 5.87; N, 11.17.
d
131.3, 131.0, 125.3, 122.6, 116.5, 91.6, 78.4, 24.9. Anal. Calcd for
C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.59; H, 5.95; N,
11.46.
4.5.2. 3-Cyano-1-ethyl-1-methyl-2-oxopropyl 4-
aminobenzenecarboxylate 11
4.3.2. 2-[(2-Ethyl-5-iminio-2-methyl-2,5-dihydro-3-
furanyl)amino]benzenecarboxylate 8
Yield 73%; beige crystals; mp 290–292 ꢀC; IR (KBr) 3500–2500
Method A: yield 93%; method B: 95%; yellow powder; mp 142–
144 ꢀC; IR (KBr) 3477, 3377, 3230 (NH2), 2259 (CN),1736,1681 (C]O),
(NH, ]NþH2, C]CH, CH), 1681 (C]O), 1624 (C]C) cmꢁ1; 1H NMR
1601 (C]C) cmꢁ1 1H NMR [400.13 MHz, (CD3)2O]
; d 7.78–7.74 (m,
(400.13 MHz, DMSO-d6)
d
8.00 (d, J¼8.0 Hz, 1H), 7.41 (t, J¼7.0 Hz,
2H), 6.70–6.65 (m, 2H), 5.52 (s, 2H), 3.92 (q, 2JAB¼19.6 Hz, 2H), 2.06,
1H), 7.27 (d, J¼7.6 Hz, 1H), 7.07 (t, J¼7.4 Hz, 1H), 5.70 (s, 1H), 2.05,
1.85 (dq, 2J¼11.0 Hz, 3J¼7.6 Hz, 2H),1.44 (s, 3H),1.00 (t, J¼7.6 Hz, 3H);
1.94 (dq, 2J¼15.6 Hz, 3J¼7.0 Hz, 2H), 1.59 (s, 3H), 0.75 (t, J¼7.0 Hz,
13C NMR (100.62 MHz, CDCl3)
d 197.2, 166.2, 152.1, 132.3, 117.6, 114.1,
3H); 13C NMR (100.62 MHz, DMSO-d6)
d 177.2, 169.0, 168.7, 142.2,
113.9, 85.7, 29.4, 26.9,19.6, 7.7. Anal. Calcd for C14H16N2O3: C, 64.60; H,
6.20; N, 10.76. Found: C, 64.49; H, 5.97; N, 10.57.
131.4, 131.2, 125.4, 122.9, 116.6, 94.5, 79.7, 30.6, 23.8, 7.0. Anal. Calcd
for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.66; H, 6.44;
N, 10.48.
4.5.3. 1-(2-Cyanoacetyl)cyclohexyl 4-aminobenzenecarboxylate 12
Method A: yield 14%; method B: 48%; yellow powder; mp 146–
148 ꢀC; IR (KBr) 3487, 3385 (NH2), 2256 (CN), 1726, 1680 (C]O),
4.4. The reaction of 3-aminobenzoic acid 2 with
acetylenic -hydroxy nitrile 4
a,b-
1600 (C]C) cmꢁ1
; d 7.82 (d,
1H NMR [400.13 MHz, (CD3)2O]
g
J¼8.8 Hz, 2H), 6.73 (d, J¼8.8 Hz, 2H), 5.61 (s, 2H), 3.93 (s, 2H), 2.20–
2.17 (m, 2H), 1.81–1.60 and 1.37–1.33 (m, 8H); 13C NMR
To a solution of 3-aminobenzoic acid 2 (247 mg, 1.8 mmol) in
acetonitrile (4 mL), acetylene 4 (196 mg, 1.8 mmol) in acetonitrile
(2 mL) was added at room temperature. The reaction mixture was
stirred at 70–75 ꢀC for 15 h. The solvent was removed in vacuo
and the residue was treated with diethyl ether. The filtered resi-
due was dried in vacuo to give 50 mg of 3-aminobenzoic acid 2.
The solvent was removed from diethyl ether fraction, the residue
(390 mg, purity 84%, by 1H NMR spectroscopy) was washed by
small portions of diethyl ether, and dried in vacuo to give 328 mg
ester 9.
[100.62 MHz, (CD3)2O] d 198.2, 165.9, 154.2,132.3, 116.3,114.7, 113.2,
83.6, 30.8, 26.5, 24.5, 21.3. Anal. Calcd for C16H18N2O3: C, 67.12; H,
6.34; N, 9.78. Found: C, 67.34; H, 6.18; N, 9.71.
4.6. 5-Amino-2,2-dimethyl-3(2H)-furanone 13
To a solution of 4-aminobenzoic acid 3 (29 mg, 0.2 mmol) in
water (4 mL), acetylene 4 (196 mg, 1.8 mmol) was added at room

B.A. Trofimov et al. / Tetrahedron 65 (2009) 2472–2477
2477
temperature. The reaction mixture was stirred at 50–60 ꢀC for 30 h.
Water was removed and the residue was washed with diethyl ether
(4ꢂ5 mL) to result in 183 mg (80%) 5-aminodihydrofuranone 13;
mp 228–230 ꢀC. MS, IR, 1H, and 13C NMR spectra correspond to
literature data.12–14
A. I.; Klyba, L. V.; Zhanchipova, E. R.; Trofimov, B. A. Synthesis 2006, 637–640;
(e) Trofimov, B. A.; Andriyankova, L. V.; Mal’kina, A. G.; Belyaeva, K. V.; Nikitina,
L. P.; Dyachenko, O. A.; Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Afonin, A.
V.; Ushakov, I. A.; Baikalova, L. V. Eur. J. Org. Chem. 2007, 1018–1025; (f) Trofi-
mov, B. A.; Mal’kina, A. G.; Shemyakina, O. A.; Borisova, A. P.; Nosyreva, V. V.;
Dyachenko, O. A.; Kazheva, O. N.; Alexandrov, G. G. Synthesis 2007, 2641–2646;
(h) Trofimov, B. A.; Mal’kina, A. G.; Borisova, A. P.; Nosyreva, V. V.; Shemyakina,
O. A.; Kazheva, O. N.; Shilov, G. V.; Dyachenko, O. A. Tetrahedron Lett. 2008,
3104–3107.
Acknowledgements
9. (a) Mangnus, E. M.; Stommen, P. L. A.; Zwanenburg, B. J. Plant Growth Regul
1992, 11, 91–98; (b) Gao, W. Y.; Agbaria, R.; Driscoll, J. S.; Mitsuya, H. J. Biol.
Chem. 1994, 269, 12633–12638; (c) Gunasekera, S. P.; McCarthy, P. J.; Kelly-
Borges, M. J. Am. Chem. Soc. 1996, 118, 8759–8760; (d) Corey, E. J.; Roberts, B.
E. J. Am. Chem. Soc. 1997, 119, 12425–12431; (e) Meier, C. Synlett 1998, 233–
242; (f) Effenberger, F.; Syed, J. Tetrahedron: Asymmetry 1998, 9, 817–825; (g)
Saboulard, D.; Naesens, L.; Cahard, D.; Salgado, A.; Pathirana, R.; Velazquez, S.;
Mcguigan, Ch.; De Clercq, E.; Balzarini, J. Mol. Pharmacol. 1999, 56, 693–704;
(h) Tahir, H.; Hindsgaul, O. J. Org. Chem. 2000, 65, 911–913; (i) Soriente, A.;
Crispino, A.; De Rosa, M.; De Rosa, S.; Scettri, A.; Scognamiglio, G.; Villano, R.;
Sodano, G. Eur. J. Org. Chem. 2000, 947–954; (j) Takahashi, M.; Dodo, K.; Su-
gimoto, Y.; Aoyagi, Y.; Yamada, Y.; Hasimoto, Y.; Shirai, R. Bioorg. Med. Chem.
Lett. 2000, 10, 2571–2574; (k) Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y.
J. Org. Chem. 2001, 66, 1429–1435; (l) Brohm, D.; Philippe, N.; Metzger, S.;
Bhargava, A.; Muller, O.; Lieb, F.; Waldmann, H. J. Am. Chem. Soc. 2002, 124,
13171–13178; (m) Shenoy, G.; Kim, P.; Goodwin, M.; Nguyen, Q.-A.; Barry,
C. E.; Dowd, C. S. Heterocycles 2004, 63, 519–527; (n) Lichtenthaler, F. W.;
Cuny, E.; Sakanaka, O. Angew. Chem., Int. Ed. 2005, 44, 4944–4948; (o) Brad-
shaw, P. C.; Li, J.; Samuels, D. C. Biochem. J. 2005, 392, 363–373; (p) Kuad, P.;
Borkovec, M.; Murr, M. D.-E.; Le Gall, T.; Mioskowski, Ch.; Spiess, B. J. Am.
Chem. Soc. 2005, 127, 1323–1333; (r) Basabe, P.; Delgado, S.; Marcos, I. S.; Diez,
D.; Diego, A.; De Roman, M.; Urones, J. G. J. Org. Chem. 2005, 70, 9480–9485;
(s) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8, 2019–2021; (t) Zografos, A. I.;
Georgiadis, D. Synthesis 2006, 3157–3188.
This work was supported by the Russian Foundation for Basic
Research (Grant No. 08-03-00156), Presidium of RAS (Program 18),
Presidium of Department of Chemical Sciences and Materials RAS
(Grant No. 5.1.8.), and Integration Project No.54.
References and notes
1. (a) North, M. Contemp. Org. Synth. 1995, 2, 269–287; (b) Trost, B. M.; Dake, G. R.
J. Am. Chem. Soc. 1997, 119, 7595–7596.
2. (a) Mashkovskii, M. D. Drugs; Novaya Volna: Moscow, 2003; (In Russian); (b)
Madrakian, T.; Afkhami, A.; Khalafi, L.; Mohammadnejad, M. J. Braz. Chem. Soc.
2006, 17, 1259–1265.
3. (a) Etzbach, K.-H.; Freund, T.; Tresh, R. German Patent 6,048,968, 2000; (b)
Bindra, A. P. U.S. Patent WO 01/56541 A1, 2001.
4. (a) Smets, J.; Trujillo, R.; Fredj, A.; White, D. J., Jr.; Boswell, R. W., Jr.; Ridley, G.
Patent PCT Int. Appl. WO 02/092746, 2002; (b) Vlad, F. J.; Mounier, R.; Wong, K.;
Daugeron, A.; Herd, T. U.S. Patent 0,084,589, 2006; (c) Birkbeck, A. A.; Moulin,
O.; Nagel, C.; Perring, K. D.; Sell, C. S., Tuck, K. M. U.S. Patent 7,129,204 B2, 2006.
5. (a) Lehmann, T.; Albers, M.; Ro¨lle, T.; Mu¨ller, G.; Hebler, G.; Tajimi, M.; Zie-
gelbauer, K.; Okigami, H. Patent PCT Int. Appl. WO 03/030889 A1, 2003; (b) Abd
El Wahed, M. G.; Abd El Wanees, S.; El Gamel, M.; Abd El Haleem, S. J. Serb.
Chem. Soc. 2004, 69, 255–264; (c) Varnavas, A.; Lassiani, L.; Valenta, V.; Men-
nuni, L.; Makovec, F.; Hadjipavlou-Litina, D. Eur. J. Med. Chem. 2005, 40, 563–
581; (d) Correa-Basurto, J.; Va´zquez Alca´ntara, I.; Espinoza-Fonseca, L. M.;
Trujillo-Ferrara, J. G. Eur. J. Med. Chem. 2005, 40, 732–735; (e) Shen, H. C.; Ding,
F.-X.; Luell, S.; Forrest, M. J.; Carbollo-Jane, E.; Wu, K. K.; Wu, T.-J.; Cheng, K.;
Wilsie, L. C.; Krsmanovic, M. L.; Taggart, A. K.; Ren, N.; Cai, T.-Q.; Deng, Q.; Chen,
Q.; Wang, J.; Wolff, M. S.; Tonq, X.; Holt, T. G.; Waters, M. G.; Hammond, M. L.;
Tata, J. R.; Colleti, S. L. J. Med. Chem. 2007, 50, 6303–6306.
6. Dominique, R.; Louis, J. U.S. Patent 5,298,647, 1994.
7. (a) Ito, A. S.; de Souza, E. S.; Barbosa, S. R.; Nakaie, C. R. Biophys. J. 2001, 81, 1180–
1189; (b) Wang, Q.; Yan, B. J. Mater. Chem. 2004, 14, 2450–2454.
8. (a) Hopf, H.; Witulski, B. Functionalized Acetylenes in Organic SynthesisdThe
Case of the 1-Cyano- and 1-Halogenoacetylenes. In Modern Acetylene Chemis-
try; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, New-York, Basel, Cambridge,
Tokyo, 1995; pp 33–67; (b) Trofimov, B. A.; Mal’kina, A. G. Heterocycles 1999, 51,
2485–2523; (c) Andriyankova, L. V.; Mal’kina, A. G.; Nikitina, L. P.; Belyaeva, K.
V.; Ushakov, I. A.; Afonin, A. V.; Nikitin, M. V.; Trofimov, B. A. Tetrahedron 2005,
61, 8031–8034; (d) Mal’kina, A. G.; Shemyakina, O. A.; Nosyreva, V. V.; Albanov,
10. Batsanov, S. S. Zh. Neorg. Khim. 1991, 36, 3015–3037.
11. (a) Devanne, D.; Ruppin, C.; Dixneuf, P. H. J. Org. Chem. 1988, 53, 925–926; (b)
Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1997, 507–512; (c) Darcel, C.; Bru-
neau, C.; Dixneuf, P. H.; Roberts, S. M. Tetrahedron 1997, 53, 9241–9252; (d)
Doucet, H.; Derrien, N.; Kabouche, Z.; Bruneau, C.; Dixneuf, P. H. J. Organometal.
Chem. 1997, 551, 151–157.
12. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
13. Abramova, N. D.; Andriyankova, L. V.; Mal’kina, A. G.; Bel’ski, V. K.; Kositsyna, E.
I.; Skvortsov, Yu, M. Izv. Acad. Nauk SSSR. Ser. Khim. 1989, 2344–2346.
14. Andriyankova, L. V.; Abramova, N. D.; Mal’kina, A. G.; Skvortsov, Yu. M. Izv. Acad.
Nauk SSSR. Ser. Khim. 1989, 1421–1422.
15. Mal’kina, A. G.; Shemyakina, O. A.; Nosyreva, V. V.; Albanov, A. I.; Klyba, L. V.;
Zhanchipova, E. R.; Trofimov, B. A. Mendeleev Commun. 2006, 4, 228–230.
16. Landor, S. R.; Demetriou, B.; Grzeskowiak, R.; Pavey, D. J. Organometal. Chem.
1975, 93, 129–132.
17. (a) Sheldrick, G. M. SHELXS 97: Program for crystal structure determination;
University of Gottingen: Gottingen, Germany, 1997; (b) Sheldrick, G. M. SHELXL
97: Program for the refinement of crystal structures; University of Gottingen:
Gottingen, Germany, 1997.