Use of ultrasound in the synthesis of 2-(alkylamino)benzoic acids in water

Article abstract of DOI:10.1055/s-2005-869834

The synthesis of substituted 2-(alkylamino)benzoic acids using the Ullmann condensation with water as the solvent and utilizing ultrasound irradiation was achieved with high yields in a short reaction time. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869834

1606
LETTER
Use of Ultrasound in the Synthesis of 2-(Alkylamino)benzoic Acids in Water
U
se of
U
ltrasound
o
in the Synt
l
hesis
o
a
2-(Alkyla
n
mino)benzoic
d
Acids in
W
o
ater F. Pellón,*a Ana Estévez-Braun,b Maite L. Docampo,a Ana Martín,a Angel G. Ravelob
a
Center of Pharmaceutical Chemistry, P.O. Box 16042 Havana, Cuba
Instituto Universitario de Bio-Orgánica Antonio González, Universidad de la Laguna, Avda. Astrofisico F. Sanchez 2, 38206 La Laguna,
b
Tenerife, España
Fax +53(7)2736471; E-mail: rolando.pellon@infomed.sld.cu
Received 25 January 2005
Excess amine has been also used as the solvent in the con-
densation, but the yields are not usually as good as when
amyl alcohol is employed.7 The dry method, developed by
Ullmann8 is commonly used when the solvents do not
bring about good results.
Abstract: The synthesis of substituted 2-(alkylamino)benzoic acids
using the Ullmann condensation with water as the solvent and
utilizing ultrasound irradiation was achieved with high yields in a
short reaction time.
Key words: Ullmann condensation, copper, catalysis, ultrasound,
2-(alkylamino)benzoic acids
Different theories have appeared in the scientific literature
about the role of water in this reaction.9–11 It has been re-
ported that sometimes it is advantageous to remove most
of the water formed during the neutralization by distilling
off part of the solvent before or during the reaction. How-
ever, the use of water at temperatures up to 130 °C has
given good results in certain cases.7
There is high demand for new methods to facilitate
syntheses using the classical copper-mediated Ullmann
condensation of aryl derivatives, which are present as
structural motifs in a wide range of molecules with nu-
merous and important applications. However, the harsh
reaction conditions needed to effect these transforma-
tions, usually only in moderate yields, led to severe limi-
tations in the general use of this reaction, especially on a
large scale.1 Some advances in the use of ultrasounds,2
and microwave3 enhancing reaction rates have been re-
ported, however, these have not resulted in widespread
popularity or use. Recently, several reviews on synthetic
methods for copper-mediated C(aryl)–O, C(aryl)–N,
C(aryl)–S bond formations have been published.1,4,5
We found when the reaction between 2-chlorobenzoic
acid and aniline was carried out in water, with one equiv-
alent of potassium carbonate, the reaction took place sat-
isfactorily, and N-phenylanthranilic acid was obtained in
good yield and high purity.12a In these conditions, the re-
action is conducted essentially between the potassium 2-
chlorobenzoate and the amine, with a pH of seven main-
tained during the course of the reaction.
As a continuation of our previous studies on the Ullmann
condensation,12 in this paper we describe the synthesis of
2-(alkylamino)benzoic acids using water as a solvent with
or without the presence of ultrasound irradiation
(Scheme 2). This is the first example of Ullmann conden-
sation conditions using aliphatic amines instead of aro-
matic amines in the presence of water as solvent.
The reaction of 2-halogen benzoic acids with phenols and
aromatic amines using copper salts or metal as catalyst is
known as the Ullmann condensation (Scheme 1).6 Several
alcohols have been satisfactorily used as solvents in this
reaction of which the most commonly used is isoamyl al-
cohol. Other alcohols of higher boiling points are usually
employed when high temperatures are required.
Scheme 2
It is well known that 2-(alkylamino)benzoic acids are in-
teresting compounds because of their hypolipidemic
properties useful in counteracting the consequences of
hyperlipidemia.13 A condition involving elevated choles-
terol, phospholipid and/or triglyceride levels in the blood,
and of hyperlipoproteinemia, involving an imbalance of
the lipoproteins. The most serious condition associated
with hyperlipidemia and hyperlipoproteinemia is athero-
sclerosis, the most common cause of coronary artery
disease.
Scheme 1
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Advanced online publication: 10.05.2005
DOI: 10.1055/s-2005-869834; Art ID: S01005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Use of Ultrasound in the Synthesis of 2-(Alkylamino)benzoic Acids in Water
1607
We analyzed the influence of some parameters on the con- The beneficial effects (i.e., shorter reaction times at lower
densation of 2-chlorobenzoic acid and substituted primary temperatures, higher yields, and narrower product distri-
alkylamines to obtain the corresponding 2-(alkylami- bution) of ultrasonic waves on a broad spectrum of chem-
no)benzoic acids. Thus, we studied the reaction time and ical reactions have been reported by several research
the quantities of potassium carbonate, taking as a model groups.16 Prominent among these successes are those
the condensation of 2-chlorobenzoic acid and propyl- reactions involving metals. Presumably, the mechanism is
amine in water as solvent.
simple: the cavity produced by the passage of ultrasonic
waves through the solvent gives rise to sufficiently high
temperatures and pressures to clean the surface of the
metal of hindering impurities formed before and during
the reaction.6,17
It was observed, as in the synthesis of N-phenylanthranilic
acids,12a that when we used 3% (by weight) of copper and
two equivalents of alkylamine per mole of 2-chlorobenzo-
ic acid with one equivalent of potassium carbonate, the re-
action took place satisfactorily within 7.5 hours and the 2- In homogeneous systems, bond-breaking often initiates
(propylamino)benzoic acid was obtained in 56% yield. the sonochemical reaction. In heterogeneous systems
The use of smaller or larger quantities of potassium car- there is the additional benefit that ultrasound is a very
bonate (0.5 or 2 equiv) led to decreased yields (18% or efficient tool for increasing mass transport.18
23%, respectively).
To establish the minimum time necessary for the reaction,
To establish the minimum time necessary for the reaction, we scanned various reaction times (10 to 30 min). 2-(Pro-
some experiments were performed. Experimental results pylamino)benzoic acid was obtained in 76% yield after
demonstrated that the best yield was obtained with a reac- only 20 minutes. It is noteworthy that with longer ultra-
tion time of five hours. When the reaction was left more sonic irradiation times the yield of the acid remains con-
than five hours the yield remained constant. Using this stant. With an irradiation time of less than 20 minutes the
method (K2CO3, 1 equiv; Cu, 3%; alkylamine, 2 equiv; 5 reaction yield is reduced, and with a reaction time of 15
h) several 2-(alkylamino)benzoic acid derivatives were minutes a yield of only 55% results.
synthesized; Table 1 shows the yields obtained in each
Once the time required for the reaction was established, a
case. Yields were superior to those reported in the litera-
series of 2-(alkylamino)benzoic acids were synthesized
ture using other procedures.13,18–20
employing the above conditions (Table 1; K2CO3, 1
When we used secondary amines the reaction did not take equiv; Cu, 3%; amine, 2 equiv; ultrasonic irradiation; 20
place satisfactorily, but with cyclic amines we obtained min).
salicylic acid.
In conclusion, we have demonstrated the advantage of
It is well known that the substitution of chlorine atom onto using ultrasound and water as solvent in the synthesis of
a benzene ring does not take place easily, but 2-halogen- 2-(alkylamino)benzoic acids, resulting in an environmen-
carboxylic acids in the presence of copper permit the for- tally friendly alternative to the classical procedures.
mation of an intermediary copper chelate, which
facilitates nucleophilic substitution.14 This copper chelate
is destroyed in a basic media and then it is not possible to
Table 1 Results of the Synthesis of Substituted 2-Carboxyalkyl-
aminesa
obtain salicylic acid, but we demonstrated that if pyridine
No
R
Yield (%)
is present, there is competition between the nucleophilic
agent and the hydroxide group. We studied the effect of
pyridine on the Ullmann Condensation and demonstrated
that pyridine acts as a co-catalyst and results in reduced
reaction times.12b–d These results suggest that pyridine sta-
bilizes the intermediate copper complex;12c perhaps the
cyclic amines have the same effect as pyridine.
Classical heatingb Ultrasonic irradiationc
1
2
3
4
5
6
7
8
9
Methyl19
Ethyl19
52
54
56
59
57
58
71
74
82
78
74
76
81
80
78
88
89
87
Propyl19
Butyl19
In order to reduce the reaction time and improve the yields
we examined the effect of ultrasound irradiation on the
synthesis of 2-(propylamino)benzoic acid, using the con-
ditions previously mentioned.
Isobutyl13
Pentyl20
Octyl13
In previous work, conditions were optimized for the use of
the Ullmann condensation on the synthesis of 2-fenoxi-
benzoic acids,15a N-phenylanthranilic acids,15b and sali-
cylic acid15c in the presence of water as solvent using
ultrasound irradiation.
Dodecyl13
Glycyl21
a All the products were characterized by analytical and spectroscopic
data.
b Yield of isolated and recrystallized products after 5 h reflux.
c Yield of isolated and recrystallized products 20 min of ultrasonic
irradiation.
Synlett 2005, No. 10, 1606–1608 © Thieme Stuttgart · New York

1608
R. F. Pellón et al.
LETTER
(3) Lange, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.;
2-(Propylamino)benzoic Acid; Typical Procedure (Water as
Solvent)
Osnabrug, S. J. M.; Verver, P. C.; Kruse, C. G.; Feenstra, R.
A mixture of 2-chlorobenzoic acid (0.04 mol, 6.26 g), i-PrNH2 (0.08
mol, 5.6 mL), anhyd K2CO3 (0.02 mol, 2.8 g), and Cu powder
(0.003 mol, 0.2 g) was refluxed in H2O (25 mL) for 5 h. The reaction
mixture was cooled and acidified with dilute HCl (1:1). The solid
was filtered off, washed with H2O and dissolved in aq NaOH solu-
tion (10%). The basic solution was acidified with AcOH–H2O (1:3)
to pH 5. The 2-(propylamino)benzoic acid crystallized and was fil-
tered off, then washed with H2O and recrystallized from EtOH–H2O
(1:1).
W. Tetrahedron Lett. 2002, 1101.
(4) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(5) Kuns, K.; Schulz, U.; Ganzer, D. Synlett 2003, 2428.
(6) Ullmann, F. Berichte 1904, 37, 2001.
(7) Acheson, R. M.; Orgel, L. E. In The Chemistry of
Heterocyclic Compounds, Vol.9; Interscience Inc.: New
York, 1956, 176.
(8) Price, C.; Roberts, R. J. Org. Chem. 1946, 11, 463.
(9) Goldberg, A. A.; Walker, H. J. Chem. Soc. 1953, 1348.
(10) Giral, F.; Calderon, L. Ciencia (Mexico City) 1945, 6, 369.
(11) Wilkinaon, J.; Finar, L. J. Chem. Soc. 1947, 759.
(12) (a) Pellon, R. F.; Carrasco, R.; Rodés, L. Synth. Commun.
1993, 23, 1447. (b) Pellon, R. F.; Carrasco, R.; Milian, V.;
Rodés, L. Synth. Commun. 1995, 25, 1007. (c)Pellon, R. F.;
Carrasco, R.; Rodés, L. Synth. Commun. 1996, 26, 3869.
(d) Pellon, R. F.; Mamposo, T.; Carrasco, R.; Rodés, L.
Synth. Commun. 1996, 26, 3877.
2-(Propylamino)benzoic Acid; Typical Procedure (Ultrasonic
Irradiation)
A mixture of 2-chlorobenzoic acid (0.04 mol, 6.26 g), i-PrNH2 (0.08
mol, 5.6 mL), anhyd K2CO3 (0.02 mol, 2.8 g), Cu powder, (0.003
mol, 0.2 g), and H2O (25 mL) was irradiated for 20 min with a sonic
horn at 20 kHz. The reaction mixture was acidified with dilute HCl
(1:1). The solid was filtered off, washed with H2O, and dissolved in
aq NaOH solution (10%). The basic solution was acidified with
AcOH–H2O (1:3) to pH 5. The 2-(propylamino)benzoic acid crys-
tallized and was filtered off, then washed with H2O and recrystal-
lized from EtOH–H2O (1:1).
(13) Gordon, R. GB Pat. 2061914, 1981.
(14) Goldberg, A. A. J. Chem. Soc. 1952, 4368.
(15) (a) Pellon, R. F.; Docampo, M. L. Synth. Commun. 2002, 33,
921. (b) Docampo, M. L.; Pellon, R. F. Synth. Commun.
2003, 33, 1771. (c) Docampo, M. L.; Pellon, R. F. Synth.
Commun. 2003, 33, 1783.
(16) (a) Chanon, M.; Luche, J.-L. Synth. Org. Sonochem. 1998,
377 . (b) Mason, T. J.; De Meulenaer, E. C. Synth. Org.
Sonochem. 1998, 301. (c) Jean-LouisLuche, J.-L.; Cintas, P.
Adv. Sonochem. 1999, 5, 147.
All experiments performed in this work were repeated five times.
The yield reported represents an average of the values obtained for
each reaction. The identity of the products was checked by elemen-
tal analyses, 1H NMR spectra, mass spectra, and by comparison of
TLC15 with authentic samples. Melting points were compared with
those reported in the literature
(17) Lickiss, P. D. New Chem. 2000, 76.
(18) (a) Abdulla, R. F. Aldrichimica Acta 1988, 21, 31.
(b) Goldberg, Y.; Sturkovich, R.; Lukevics, E. Heterocycles
1989, 29, 597.
(19) Petyonin, P. A. Zh. Priklad. Khim. 1960, 33, 1428.
(20) Dunsmuir, J. H. Brit Pat. 754845, 1956.
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Synlett 2005, No. 10, 1606–1608 © Thieme Stuttgart · New York