New reactions of benzocaine

Article abstract of DOI:10.1134/S1070363216110074

Reaction of benzocaine with indane-1,3-dione-2-carbaldehyde afforded the corresponding azomethine. Ethoxymethylenemalonate reacted with benzocaine to form ethyl 4-{[2-(ethoxycarbonyl)-4-methoxy-3-oxobuten-1-yl]amino}benzoate, which was converted to the co

Full text of DOI:10.1134/S1070363216110074

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 11, pp. 2442–2445. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © Yu.A. Azev, O.S. Ermakova, V.S. Berseneva, V.A. Bakulev, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 11,
pp. 1799–1802.
New Reactions of Benzocaine
Yu. A. Azev*, O. S. Ermakova, V. S. Berseneva, and V. A. Bakulev
B.N. Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
*e-mail: azural@yandex.ru
Received April 14, 2016
Abstract—Reaction of benzocaine with indane-1,3-dione-2-carbaldehyde afforded the corresponding
azomethine. Ethoxymethylenemalonate reacted with benzocaine to form ethyl 4-{[2-(ethoxycarbonyl)-4-
methoxy-3-oxobuten-1-yl]amino}benzoate, which was converted to the corresponding quinolone when heated
to 185–190°C. Reactions of benzocaine with aliphatic aldehydes furnished 2,3-alkyl-substituted quinolines.
Keywords: aromatic amines, benzocaine, quinolones, 2,3-substituted quinolines
DOI: 10.1134/S1070363216110074
Aromatic amine derivatives are suitable starting
materials for the synthesis of various biologically
active derivatives of quinoline. A number of 8-
hydroxyquinoline derivatives possess antibacterial,
antiparasitic and antifungal activity [1]. Gould–Jacobs
reaction, Combes and Skraup quinoline syntheses are
general methods of preparation of substituted
quinolines starting from aromatic amines. 6,7-Difluoro-
substituted quinolones (precursors in the synthesis of
fluoroquinolone antibiotics) are known to be produced
by reacting 3,4-difluoroaniline with ethoxymethylene-
malonate [2]. 2,3-Alkyl-substituted quinolines can be
obtained by reacting aliphatic aldehydes with aniline in
the presence of LnCl3·6H2O [3]. Benzocaine (ethyl p-
aminobenzoate), which is an active local anesthetic
agent, is prepared by reducing ethyl p-nitrobenzoate.
Previously, we have suggested an efficient method of
catalytic reduction of ethyl p-nitrobenzoate [4]. In turn,
benzocaine is the starting material for the synthesis of
β-diethylaminoethyl p-aminobenzoate hydrochloride
(Procaine drug) [5].
in the formation of ethyl 4-{[(1,3-dioxo-2,3-dihydro-
1H-inden-2-yl)methylene]amino}benzoate 3 (Scheme 1).
1
In the H NMR spectrum of compound 3 a spin-
spin coupling between of the signals of methine
protons and amino group is registered that indicates the
existence of an enamine tautomer 3a (Scheme 2).
The reaction of benzocaine 1 with ethoxymethylene-
malonate 4 proceeded smoothly in a formic acid solu-
tion at 50–55°C to give ethyl 4-{[2- (ethoxycarbonyl)-
4-methoxy-3-oxobuten-1-yl]amino}benzoate 5. Accord-
ing to NMR data, in dimethylsulfoxide solution com-
pound 5 is an enamine isomer.
Upon heating at 185–190°C in dodecane, benzoate
5 underwent cyclization to form quinoline 6 (Scheme 1),
which is capable of keto-enol tautomerism. The lack of
spin-spin interactions between the protons of adjacent
1
NH and CH groups of heterocycle in the H NMR
spectrum of compound 6 indicates the existence of
enol isomer in dimethylsulfoxide solution.
Reactions of aromatic amines with ethoxymethylene-
malonic acid esters leading to the formation of sub-
stituted 4-oxyquinolines (quinolones) are known as the
Gould–Jacobs reaction [6]. We have performed such
conversion of 3,4-difluoroanilines earlier in the
synthesis of intermediates for fluoroquinolone anti-
biotics [2].
Since benzocaine is an industrial product, it was
appropriate to use this available aromatic amine deri-
vative as a starting material for a synthesis of new
compounds with potential biological activity. In this
regard, the aim of the present work was to develop
new synthetic approaches and to use the known
methods for obtaining new p-aminobenzoic acid
derivatives and fused benzopyridines (quinolines).
We discovered unusual transformations when reacting
benzocaine 1 with aliphatic aldehydes 7a and 7b in
formic acid. The reaction afforded the corresponding
We found that the reaction of benzocaine 1 with
indane-1,3-dione-2-carbaldehyde 2 in ethanol resulted
2442

2443
NEW REACTIONS OF BENZOCAINE
Scheme 1.
O
O
O
O
C2H5O
CO2C2H5
CO2C2H5
O
2
4
O
NH2
O
1
O
O
O
O
N
H
N
O
O
O
R
H
O
5
7a, 7b
O
3
O
O
O
O
OH
N
O
R
R
R
R
HO
O
O
NaOH
N
N
6
8a, 8b
9a, 9b
R = Et (a), Pr (b).
Scheme 2.
H
O
O
O
O
O
O
N
N
O
O
3
3a
2,3-substituted quinoline derivatives 8a and 8b
(Scheme 1). The structure of the compounds obtained
was confirmed by mass spectrometry and NMR spec-
troscopy data.
Hence, we have found a new type of transforma-
tions in which benzocaine reacts with two molecules of
the starting aldehyde that get cross-linked with each
other and acting as a 1,3-dicarbonyl reagent. As a
result, it makes possible to obtain 2,3-alkyl-substituted
quinolines in one step in the reaction of benzocaine
with aliphatic monocarbonyl compounds.
Obviously, the formation of quinolines 8 occurs as
a result of the reaction between 1 mol of benzocaine
with 2 mol of the corresponding aldehyde. Apparently,
the initially formed azomethine A adds the second
aldehyde molecule; and the resulting intermediate B
undergoes ring closure to form quinoline 8 (Scheme 3).
Brief heating of esters 8 in an aqueous alcohol alkali
solution led to the formation of the corresponding
acids 9.
In conclusion, it should be noted that the obtained
new quinoline and benzocaine derivatives are not only
of interest as potentially active compounds, but may
also be used as synthons, which may be modified due
to the presence of carboethoxy moiety in an aromatic
or heterocyclic core.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 11 2016

2444
AZEV et al.
Scheme 3.
O
HN
N
H
[O]
O
7b
7b
8b
1
−H2O
O
O
O
O
A
B
EXPERIMENTAL
d (2H, CH2Ar, J = 8.4 Hz), 8.45 d (1H, CH, J = 13.2 Hz),
10.86 d (1H, NH, J = 13.2 Hz). Mass spectrum, m/z
(Irel, %): 335 (90) [M]+. Found, %: C 60.65; H 6.52; N
4.05. C17H21NO6. Calculated, %: C 60.89; H 6.31; N 4.18.
1H and 13C NMR spectra were recorded on a Bruker
DRX-400 spectrometer. Electron impact mass
spectrometry was performed on a GCMS-QP2010
Ultra Shimadzu instrument (Japan) at 75 eV and 200°C.
Diethyl 4-oxyquinoline-3,6-dicarboxylate (6). A
solution of 0.335 g (1.0 mmol) of 5 in 5 mL of
dodecane was heated at 185–190°C for 1 h. The
precipitate was filtered off, washed with 2.0 mL of
ethanol, and dried. Yield 0.2 g (70.0%), mp >250°C
(aq. DMF). 1H NMR spectrum (CDCl3), δ, ppm: 1.36 t
(3H, CH3, J = 6.8 Hz), 1.43 t (3H, CH3, J = 6.8 Hz),
4.27 q (2H, CH2, J = 6.8 Hz), 4.39 q (2H, CH2, J =
6.8 Hz), 7.66 d (1H, CHAr, J = 8.8 Hz), 8.15 d. d (1H,
CHAr, J = 8.8, J = 2.0 Hz), 8.52 s (1H, CHAr), 8.76 d
(1H, CHAr, J = 2.0 Hz), 12.36 s (1H, OH). Mass
spectrum, m/z (Irel, %): 289 (88) [M]+. Found, %: C
62.52; H 5.34; N 4.69. C15H15NO5. Calculated, %: C
62.28; H 5.23; N 4.84.
Ethyl 4-{[(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-
methylene]amino}benzoate (3). To a solution of
0.082 g (0.5 mmol) of benzocaine 1 in 5.0 mL of
ethanol 0.087 g (0.5 mmol) of aldehyde 2 was added.
The mixture was stirred for 10–15 min. After cooling
the precipitate was filtered off, washed with water and
2.0–3.0 mL of ethanol, and then dried. Yield 0.106 g
1
(66.0%), mp 234–235°C (DMF). H NMR spectrum
(CDCl3), δ, ppm: 1.43 t (3H, CH3, J = 7.2 Hz), 4.40 q
(2H, CH2, J = 7.2 Hz), 7.28 d (2H, CHAr, J = 5.6 Hz),
7.30–7.75 m (2H, CHAr), 7.82–7.88 m (2H, CHAr),
8.12 d (2H, CHAr, J = 5.6 Hz), 8.26 d (1H, N=CH, J =
13.6 Hz), 10.98 d (1H, NH, J = 13.6 Hz). Mass
spectrum, m/z (Irel, %): 321 (100) [M]+. Found, %: C
71.13; H 4.65; N 4.53. C19H15NO4. Calculated, %: C
71.02; H 4.71; N 4.36.
Ethyl 2-propyl-3-ethylquinoline-6-carboxylate (8a).
A mixture of 0.5 g (3.0 mmol) of benzocaine 1 and
1.0 g (13.9 mmol) of butanal in 5.0 mL of formic acid
was stirred at 50–55°C for 5 h. After the solvent was
removed the residue was treated with 5.0 mL of
ethanol. The precipitate was filtered off and
recrystallized from ethanol. Yield 0.300 g (36.0%), mp
91–92°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.05
t (3H, CH3, J = 7.2 Hz), 1.36 t (3H, CH3, J = 7.6 Hz),
1.44 t (3H, CH3, J = 7.2 Hz), 1.82–1.93 m (2H, CH2),
2.85 q (2H, CH2, J = 7.6 Hz), 2.94 t (2H, CH2, J =
7.6 Hz), 4.39 q (2H, CH2, J = 7.2 Hz), 7.93 d (1H,
CHAr, J = 8.8 Hz), 8.10 s (1H, CH), 8.11 d. d (1H,
CHAr, J = 8.0, J = 2.0 Hz), 8.51 d (1H, CHAr, J = 2.0 Hz).
Mass spectrum, m/z (Irel, %): 271 (20) [M]+. Found, %:
C 75.62; H 7.98; N 5.03. C17H21NO2. Calculated, %: C
75.25; H 7.80; N 5.16.
Ethyl 4-{[(2-(ethoxycarbonyl)-4-methoxy-3-oxo-
buten-1-yl]amino}benzoate (5). A mixture of 0.25 g
(1.5 mmol) of benzocaine 1, 1.0 g (4.5 mol) of
ethoxymethylenemalonate 4, and 5.0 mL of formic
acid was stirred at 50–55°C for 5–6 h. The solvent was
removed, and the precipitate was treated with 3.0–
5.0 mL of ethanol. Next, the precipitate was filtered off
and dried. Yield 0.240 g (50.0%), mp 72–73°C
(ethanol). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.31
t (3H, CH3, J = 7.2 Hz), 1.34 t (3H, CH3, J = 6.8 Hz),
1.38 t (3H, CH3, J = 7.2 Hz), 4.17 q (2H, CH2, J =
6.8 Hz), 4.25 q (2H, CH2, J = 7.2 Hz), 4.32 q (2H,
CH2, J = 7.2 Hz), 7.39 d (2H, CH2Ar, J = 8.8 Hz), 7.97
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 11 2016

2445
NEW REACTIONS OF BENZOCAINE
Ethyl 2-butyl-3-propylquinoline-6-carboxylate (8b)
was prepared similarly from 0.5 g (3.0 mmol) of
benzocaine 1 and 1.0 g (11.6 mmol) of pentanal. Yield
1H NMR spectrum (CDCl3), δ, ppm: 1.01 t (3H, CH3,
J = 7.6 Hz), 1.06 t (3H, CH3, J = 7.6 Hz), 1.46–1.51 m
(2H, CH2), 1.69–1.84 m (4H, CH2), 2.79 t (2H, CH2,
J = 7.6 Hz), 2.95 t (2H, CH2, J = 7.6 Hz), 7.91 d (1H,
CHAr, J = 8.8 Hz), 8.07–8.11 m (2H, CHAr), 8.47 d
(1H, CHAr, J = 1.6 Hz), 12.77 br.s (1H, OH). Mass
spectrum, m/z (Irel, %): 271 (10) [M]+. Found, %: C
75.36; H 7.82; N 5.34. C17H21NO2. Calculated, %: C
75.25; H 7.80; N 5.16.
1
0.35 g (38.0%), mp 77–78°C. H NMR spectrum
(CDCl3), δ, ppm: 1.01 t (3H, CH3, J = 7.2 Hz), 1.08 t
(3H, CH3, J = 7.2 Hz), 1.46 t (3H, CH3, J = 7.2 Hz),
1.52–1.56 m (2H, CH2), 1.70–1.90 m (4H, CH2), 2.81 t
(2H, CH2, J = 8.0 Hz), 3.02 t (2H, CH2, J = 8.0 Hz),
4.45 q (2H, CH2, J = 7.2 Hz), 7.95 s (1H, CH), 8.05 d
(1H, CHAr, J = 8.8 Hz), 8.22 d. d (1H, CHAr, J = 8.8,
J = 1.6 Hz), 8.51 d (1H, CHAr, J = 1.6 Hz). Mass
spectrum, m/z (Irel, %): 299 (10) [M]+. Found, %: C
76.53; H 8.60; N 4.51. C19H25NO2. Calculated, %: C
76.22; H 8.42; N 4.68.
ACKNOWLEDGMENTS
This work was supported by the Russian Foundation
for Basic Research (grant no. 14-03-01033) and
Ministry of Education and Science of the Russian
Federation (project 4.1626.2014/К).
2-Propyl-3-ethylquinoline-6-carboxylic acid (9a).
A mixture of 0.13 g (0.53 mmol) of 8a, 0.130 g
(3.2 mmol) of NaOH and 10 mL of 50% ethanol was
refluxed for 25–30 min, and then treated with 15%
HCl (рH 3–4). The precipitate was filtered off and
recrystallized from aqueous ethanol. Yield 0.090 g
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Meditsyna, 1993.
1
(77.0%), mp 180–181°C. H NMR spectrum (CDCl3),
2. RF Patent 2052454, 1996.
δ, ppm: 1.05 t (3H, CH3, J = 7.6 Hz), 1.34 t (3H, CH3,
J = 7.6 Hz), 1.81–1.90 m (2H, CH2, J = 8.0 Hz), 2.81–
2.95 m (4H, CH2), 7.90 d (1H, CHAr, J = 8.4 Hz), 8.10–
8.07 m (2H, CHAr), 8.49 d (1H, CHAr, J = 2.0 Hz),
12.82 br.s (1H, OH). Mass spectrum, m/z (Irel, %): 243
(35) [M]+. Found, %: C 74.36; H 7.23; N 5.99.
C15H17NO2. Calculated, %: C 74.05; H 7.04; N 5.76.
3. Bulgakov, R.G., Kuleshov, S.P., Makhmutov, A.R., and
Dzhemilev, U.M., Russ. J. Org. Chem., 2006, vol. 42,
no. 10, p. 1573. doi 10.1134/S1070428006100307
4. RF Patent 2505526, 2012.
5. Abdullaev, M.G., Pharm. Chem. J., 2001, vol. 35,
no. 10, p. 556. doi 10.1023/A:1014762419378
6. Vatsuro, K.V. and Mishchenko, G.L., Imennye reaktsii v
organicheskoi khimii (Name Reactions in Organic
Chemistry), Moscow: Khimiya, 1976.
2-Butyl-3-propylquinoline-6-carboxylic acid (9b)
was prepared similarly. Yield 65.0%, mp 131–132°C.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 11 2016