Tris(2-hydroxyethyl)ammonium 4-halo-2-methylphenoxyacetates (halocresacins)

Article abstract of DOI:10.1134/S1070428014120082

Convenient and efficient procedures have been developed for the synthesis of tris(2-hydroxyethyl)-ammonium 4-halo-2-methylphenoxyacetates (halocresacins). 4-Chloro-2-methylphenoxyacetic acid necessary for the preparation of chlorocresacin has been obtained by chlorination of 2-methylphenoxyacetic acid with sulfuryl chloride in the presence of aluminum powder. Bromocresacin has been synthesized by reaction of triethanolamine with 4-bromo-2-methylphenoxyacetic acid prepared by bromination of 2-methylphenoxyacetic acid with molecular bromine. Fluoro- and iodocresacins have been synthesized by exchange reaction of chlorocresacin with potassium fluoride and sodium iodide, respectively.

Full text of DOI:10.1134/S1070428014120082

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 12, pp. 1763–1766. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © M.G. Voronkov, L.I. Belousova, O.Yu. Grigor’eva, N.N. Vlasova, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 12, pp. 1782–1785.
Tris(2-hydroxyethyl)ammonium 4-Halo-2-methylphenoxyacetates
(Halocresacins)
M. G. Voronkov†, L. I. Belousova, O. Yu. Grigor’eva, and N. N. Vlasova
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: grigoreva_o@irioch.irk.ru
Received June 17, 2014
Abstract—Convenient and efficient procedures have been developed for the synthesis of tris(2-hydroxyethyl)-
ammonium 4-halo-2-methylphenoxyacetates (halocresacins). 4-Chloro-2-methylphenoxyacetic acid necessary
for the preparation of chlorocresacin has been obtained by chlorination of 2-methylphenoxyacetic acid with
sulfuryl chloride in the presence of aluminum powder. Bromocresacin has been synthesized by reaction of
triethanolamine with 4-bromo-2-methylphenoxyacetic acid prepared by bromination of 2-methylphenoxyacetic
acid with molecular bromine. Fluoro- and iodocresacins have been synthesized by exchange reaction of
chlorocresacin with potassium fluoride and sodium iodide, respectively.
DOI: 10.1134/S1070428014120082
Tris(2-hydroxyethyl)ammonium 2-methylphenoxy-
acetate (also known as cresacin or trecresan) is
an original synthetic biologically active compound
which was designed under the guidance of
M.G. Voronkov (Full Member of the Russian Academy
of Sciences) [1]. It exhibited unique physiological
properties, in particular efficient adaptogenic and im-
munostimulatory effects, which opened wide prospects
for its application in medicine, microbiology, and agri-
culture [1, 2]. Cresacin was synthesized by reaction of
triethanolamine with 2-methylphenoxyacetic acid
which was prepared by O-alkylation of methylphenol
with chloroacetic acid [3] (Scheme 1).
efficient as physiologically active substance. It exhibit-
ed pronounced antitumor activity [4]. Furthermore, it
can act as both immunosuppressant and immuno-
stimulant [5] and accelerate the growth of embryo cells
by a factor of 2 to 3 [6]. Chlorocresacin was synthe-
sized by analogy with cresacin, and the synthesis addi-
tionally included chlorination of 2-methyl-phenol or
2-methylphenoxyacetic acid with gaseous chlorine [7].
Thus, the procedure for the synthesis of chlorocresa-
cine is even more laborious and time-consuming;
moreover, the use of gaseous chlorine is unsafe and
therefore undesirable.
Scheme 1.
We have developed a more convenient and efficient
synthesis of chlorocresacin. Initial 4-chloro-2-methyl-
phenoxyacetic acid was prepared by treatment of
2-methylphenoxyacetic acid with sulfuryl chloride in
diethyl ether in the presence of aluminum powder [8]
(Scheme 2). Howard and Sidwell [9] previously pro-
posed to carry out the reaction in the presence of finely
dispersed elemental sulfur, which complicated purifi-
cation of the target product, so that its purity did not
exceed 94%. Our procedure is free from this drawback
A chloro-substituted analog of cresacin, tris(2-hy-
droxyethyl)ammonium 4-chloro-2-methylphenoxy-
acetate (chlorocresacin) turned out to be even more
†
Deceased.
1763

VORONKOV et al.
1764
Scheme 2.
since the catalyst can be removed completely by hot
filtration of the reaction mixture.
acetic acid was obtained by replacement of the
chlorine atom in 2-chloro-2-methylphenoxyacetic acid
by iodine via reaction with sodium iodide in boiling
acetone (reaction time 7–10 h; Scheme 4). However,
unlike chloro- and bromo-substituted analogs, the reac-
tion of 4-iodo-2-methylphenoxyacetic acid with tri-
ethanolamine afforded no expected iodocresacine but
was accompanied by exchange process leading to the
formation of 4-hydroxy-2-methylphenoxyacetic acid
and N,N′-bis(2-hydroxyethyl)-2-iodoethanamine
(Scheme 5).
Tris(2-hydroxyethyl)ammonium 4-bromophenoxy-
acetate (bromophenacin) is a highly efficient phytohor-
mone [10] which stimulates crop germination [11].
Tris(2-hydroxyethyl)ammonium 4-bromo-2-methyl-
phenoxyacetate (bromocresacin) was also expected to
exhibit analogous biological activity. It was synthe-
sized by analogy with chlorocresacin from 4-bromo-2-
methylphenoxyacetic acid which was prepared in turn
by bromination of 2-methylphenoxyacetic acid with
molecular bromine in the presence of aluminum
powder or mercury acetate in glacial acetic acid [8]
(Scheme 3).
Scheme 5.
Me
O
COOH
+
N(CH2CH2OH)3
Scheme 3.
I
Me
O
COOH
Me2CO
+ ICH2CH2NH(CH2CH2OH)2
HO
It is known that the iodine atom in iodoarenes is
readily involved in exchange reactions. For example,
replacement of iodine by hydrogen in the reaction of
iodoarenes with mineral acids was reported [12]. The
observed reaction (Scheme 5) is an example of unusual
behavior of both iodine atom in an aromatic ring and
4-iodo-2-methylphenoxyacetic acid itself.
Me
O
COO–
EtOH
· HN(CH2CH2OH)3
Br
We succeeded in obtaining iodocresacine only by
exchange reaction of chlorocresacin with sodium
iodide in boiling acetone (Scheme 6). We failed to
introduce a fluorine atom into the benzene ring of
2-methylphenoxyacetic acid by numerous known
procedures for fluorination of organic compounds [13].
Therefore, tris(2-hydroxyethyl)ammonium 4-fluoro-2-
methylphenoxyacetate (fluorocresacin) was synthe-
sized in a way similar to iodocresacin, by reaction of
chlorocresacin with potassium fluoride in boiling
acetone (Scheme 7).
We also synthesized such potentially biologically
active compounds as tris(2-hydroxyethyl)ammonium
4-fluoro- and 4-iodo-2-methylphenoxyacetates (fluoro-
and iodocresacins). Initial 4-iodo-2-methylphenoxy-
Scheme 4.
Me
Me
O
O
NaI, Me2CO
–NaCl
COOH
COOH
Cl
I
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 12 2014

TRIS(2-HYDROXYETHYL)AMMONIUM 4-HALO-2-METHYLPHENOXYACETATES
1765
Scheme 6.
Me
Me
O
O
COO–
O
O
COO–
NaI, Me2CO
–NaCl
· HN(CH2CH2OH)3
· HN(CH2CH2OH)3
Cl
Cl
I
Scheme 7.
Me
Me
COO–
COO–
KF, Me2CO
–KCl
· HN(CH2CH2OH)3
· HN(CH2CH2OH)3
F
Tris(2-hydroxyethyl)ammonium 4-bromo-2-
EXPERIMENTAL
methylphenoxyacetate (bromocresacin). Triethanol-
amine, 0.45 g (3 mmol), was added under stirring to
a solution of 0.73 g (3 mmol) of 4-bromo-2-methyl-
phenoxyacetic acid in 10 mL of ethanol, and the
mixture was stirred for 30 min. The mixture was then
cooled to 0–5°C, 10 mL of diethyl ether was added,
and the crystalline product was filtered off, washed
with diethyl ether, and dried under reduced pressure.
Yield 1.0 g (94%), mp 86–87°C. IR spectrum, ν, cm–1:
3355 (O–H), 2969 (N+–H), 1602 (CO2–, asym.), 1489
(CO2–, sym.), 1243 (δ O–H). Found, %: C 45.62;
H 6.01; Br 20.59; N 3.51. C15H24BrNO6. Calculated,
%: C 45.69; H 6.09; Br 20.30; N 3.55.
4-Iodo-2-methylphenoxyacetic acid. A mixture of
4.0 g (20 mmol) of 4-chloro-2-methylphenoxyacetic
acid and 3.0 g (20 mmol) of sodium iodide in 35 mL of
anhydrous acetone was heated for 10 h at 56–57°C
under stirring. The mixture was cooled and filtered
from sodium chloride, and the filtrate was evaporated.
Yield 5.6 g (96%), mp 130–132°C. IR spectrum, ν,
cm–1: 3500 (O–H), 1739 (C=O), 441 (C–I). Found, %:
C 37.19; H 3.56; I 43.95. C9H9IO3. Calculated, %:
C 37.01; H 3.11; I 43.45.
The IR spectra were recorded on a UR-20 spec-
trometer from thin films.
4-Chloro-2-methylphenoxyacetic acid. Sulfuryl
chloride, 1.35 g (10 mmol), was added under stirring to
a solution of 1.66 g (10 mmol) of 2-methylphenoxy-
acetic acid in 10 mL of diethyl ether containing 0.01 g
of aluminum powder. The mixture was heated for 4 h
under reflux and filtered while hot, the filtrate was
cooled to 0−5°C, and the white crystalline solid was
filtered off, washed with diethyl ether, and dried under
reduced pressure. Yield 2.9 g (98%), mp 111–112°C;
published data [7]: mp 114–116°C. Found, %: C 53.23;
H 4.31; Cl 17.72. C9H9ClO3. Calculated, %: C 53.86;
H 4.49; Cl 17.71.
Tris(2-hydroxyethyl)ammonium 4-chloro-2-
methylphenoxyacetate (chlorocresacin). Triethanol-
amine, 3.0 g (20 mmol), was added under stirring to
a solution of 4.0 g (20 mmol) of 4-chloro-2-methyl-
phenoxyacetic acid in 10 mL of acetone, and the mix-
ture was stirred for 30 min. The precipitate was filtered
off, washed with diethyl ether, and dried under reduced
pressure. Yield 6.8 g (98%), mp 87–88°C; published
data [4]: mp 91–92°C. Found, %: C 51.43; H 6.87;
Cl 10.10; N 4.20. C15H24ClNO6. Calculated, %:
C 51.50; H 6.90; Cl 10.16; N 4.01.
4-Bromo-2-methylphenoxyacetic acid. Molecular
bromine, 0.8 g (10 mmol), was added under stirring to
a solution of 1.66 g (10 mmol) of 2-methylphenoxy-
acetic acid in 7 mL of glacial acetic acid containing
0.01 g of aluminum powder. The mixture was heated
for 5 h at 45–50°C and filtered, and the solvent was
distilled off from the filtrate under reduced pressure
(100 mm). The crystalline product was washed with
small portions of cold water and dried in a vacuum
desiccator. Yield 2.1 g (86%), mp 124–125°C. Found,
%: C 43.44; H 4.04; Br 32.37. C9H9BrO3. Calculated,
%: C 44.08; H 3.67; Br 32.65.
Reaction of 4-iodo-2-methylphenoxyacetic acid
with triethanolamine. Freshly distilled triethanol-
amine was added to 5.84 g (20 mmol) of 4-iodo-2-
methylphenoxyacetic acid in 35 mL of anhydrous
acetone, and the mixture was heated for 5–6 h under
reflux. The mixture was cooled, and the precipitate
was filtered off and washed with diethyl ether.
2-Iodoethyl(bis-2-hydroxyethyl)amine. Yield
3.92 g (76%), colorless crystals, mp 157°C. IR spec-
trum, ν, cm–1: 3354 (O–H), 1338 (δO–H), 1229, 1126
(C–N), 1051 (C–O), 439 (C–I). Found, %: C 27.38;
H 5.56; I 48.93; N 5.43. C6H14INO2. Calculated, %:
C 27.82; H 5.45; I 48.98; N 5.40.
4-Hydroxy-2-methylphenoxyacetic acid was iso-
lated by removal of the solvent from the filtrate. Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 12 2014

VORONKOV et al.
1766
2. Vil’ken, A.E., Khabriev, R.U., Fisenko, V.P.,
Krylov, Yu.F., and Rudakov, A.G., Registr lekarstven-
nykh sredstv Rossii (Register of Medicines of Russia),
Moscow: Informkhim, 1995, p. 512.
3. Voronkov, M.G., D’yakov, V.M., Semenova, N.V., Ste-
tsenko, N.A., and Prokhoda, E.F., USSR Inventor’s
Certificate no. 515742, 1973; Byull. Izobret., 1976,
no. 20.
4. Cof’ina, Z.P., Voronkov, M.G., D’yakov, V.M., Seme-
nova, N.V., Platonova, G.N., Peretolchina, N.M.,
Lesnaya, N.A., and Smetankina, O.Z., Pharm. Chem. J.,
1978, vol. 12, no. 4, p. 489.
5. Kolesnikova, O.P., Mirskova, A.N., Adamovich, S.N.,
Mirskov, R.G., Kudaeva, O.T., and Voronkov, M.G.,
Dokl. Biol. Sci., 2009, vol. 425, p. 107.
3.51 g (96%), viscous grease-like material. IR spec-
trum, ν, cm–1: 3353 (O–H), 3108 (O–H), 1774 (C=O),
1229 (δ O–H), 1051 (C–O). Found, %: C 58.53;
H 5.52. C9H11O4. Calculated, %: C 59.33; H 5.53.
Tris(2-hydroxyethyl)ammonium 4-iodo-2-
methylphenoxyacetate (iodocresacin). A mixture of
3.83 g (11 mmol) of chlorocresacin and 1.64 g
(11 mmol) of NaI in 30 mL of anhydrous acetone was
heated for 10 h at 56–57°C. The mixture was cooled
and filtered, and the filtrate was evaporated. Yield
4.8 g (99%), colorless water-soluble crystals, mp 90–
91°C. IR spectrum, ν, cm–1: 3391 (O–H), 3137 (O–H),
2923 (N+–H), 1734 (C=O), 1618 (CO2–, asym.), 1409
(CO2–, sym.), 1241 (δO–H), 495 (C–I). Found, %:
C 40.80; H 5.60; I 28.60; N 3.02. C15H24INO6. Calcu-
lated, %: C 40.80; H 5.48; I 28.76; N 3.17.
6. Kassin, V.Yu., Nikolaev, M.P., Mironova, L.L.,
Rolik, I.S., Konyushko, O.I., Mirskova, A.N., and
Voronkov, M.G., Ross. Otorinol., 2004, no. 12, p. 85.
Tris(2-hydroxyethyl)ammonium 4-fluoro-2-
methylphenoxyacetate (fluorocresacin). A mixture of
5.42 g (15 mmol) of chlorocresacin and 0.90 g
(15 mmol) of KF in 30 mL of anhydrous acetone was
heated for 30 h at 56–57°C under stirring. The mixture
was cooled and filtered, the filtrate was evaporated,
and the crystalline residue was washed with diethyl
ether. Yield 4.9 g (95%), mp 93–94°C. IR spectrum, ν,
cm–1: 3353 (O–H), 3151 (O–H), 2931 (N+–H), 1605
(CO2–, asym.), 1402 (CO–2, sym.), 1290 (δO–H). Found,
%: C 53.61; H 7.30; F 4.75; N 4.39. C15H24FNO6. Cal-
culated, %: C 54.05; H 7.26; F 5.70; N 4.20.
7. Simonov, V.D., Poluektova, Z.M., Ikrina, M.A.,
Ivanov, V.I., Reznikova, L.I., Chaikina, T.D., Shagie-
va, L.K., and Shipanov, L.P., USSR Inventor’s
Certificate no. 256750, 1967; Byull. Izobret., 1969,
no. 35.
8. Voronkov, M.G., Grigor’eva, O.Yu., and Vlasova, N.N.,
RF Patent no. 2427568, 2009; Byull. Izobret., 2011,
no. 24.
9. Howard, K.J. and Sidwell, A.E., US Patent
no. 4345097, 1982.
10. Voronkov, M.G., Semenova, N.V., Tseitlina, V.R., and
Yakovleva, Z.M., Dokl. Akad. Nauk, 1994, vol. 335,
p. 390.
This study was financially supported by the
President of the Russian Federation (program for
support of leading scientific schools, project no. NSh-
3649.2014.3).
11. Svarinskaya, R.A., Platonova, R.N., Semenova, N.V.,
Lyubimtseva, I.V., and Voronkov, M.G., Dokl. Akad.
Nauk SSSR, 1980, vol. 250, p. 508.
12. Filimonov, V.D., Krasnokutskaya, E.A., and Lesi-
na, Yu.A., Russ. J. Org. Chem., 2003, vol. 39, p. 875.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 12 2014