Synthesis of some new o-substituted arylcarbamates and related compounds

Article abstract of DOI:10.1006/bioo.1996.1053

Seven new 2-substituted-5-N',N'-dimethylaminophenyl N,N- dimethylcarbamates and three other compounds of similar structures have been synthesized aiming at obtaining potent anti-ChE agents. It has been found that the 2-substituents, regardless of their character, decrease the biological activity of the carbamates.

Full text of DOI:10.1006/bioo.1996.1053

BIOORGANIC CHEMISTRY 25, 37–41 (1997)
ARTICLE NO. BH961053
Synthesis of Some New o-Substituted Arylcarbamates and
Related Compounds
J
OSE E. BARBARINI,* ROBERTO RITTNER,* NELCI F. HOEHR,†
´
¨
AND
J
ERZY
SUWINSKI
‡
*Chemistry Institute and †Faculty of Medical Sciences, UNICAMP, 13083-970, Campinas, SP, Brazil;
and ‡Faculty of Chemistry, The Silesian Technical University, 44-101 Gliwice, Poland
Received October 21, 1996
Seven new 2-substituted-5-NЈ, NЈ-dimethylaminophenyl N,N-dimethylcarbamates and three
other compounds of similar structures have been synthesized aiming at obtaining potent anti-
ChE agents. It has been found that the 2-substituents, regardless of their character, decrease
the biological activity of the carbamates.
1997 Academic Press
Many efforts had been made in the past to synthesize anticholinesterase agents
(anti-ChE), e.g., carbamates, and to study the structure–activity relationship. Until
1945 most of the work had been directed toward the development of toxic agents.
Later on, some compounds of that class, e.g., arylcarbamates, had found therapeutic
applications, including the treatment of several serious diseases (1). Structure–
activity studies indicated the importance of the presence of two alkyl groups at the
carbamate nitrogen atom and a substituted amino group at the other part of the
molecule (2–4). Effects of additional substituents, e.g., at the benzene ring in phenyl
carbamates, had not yet been fully recognized.
Therefore, the main goal of this work was to synthesize the new 2-substituted-
5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamates, 2b–8b, and some other
compounds 9b–11b, with allosteric substitution in the known 3-NЈ,NЈ-dimethylami-
nophenyl N,N-dimethylcarbamate 1b (Scheme 1), to search for more satisfactory
anti-ChE agents. Actually, compound 5b has already been described (5) as a by-
product from the neostigmine bromide degradation. It had been assumed by us
that a substituent in the 2 position (ortho to the carbamate oxygen atom) would
affect activity of the compounds to a greater extent. This assumption can be sup-
ported by the observation that, in a number of cases, anomalously enhanced trans-
missibility of electronic effects from substituents at the benzene ring to the carbamyl
moiety had been observed (so called ‘‘the positive bridge effect’’). In addition, effects
of 2-substituents, in contrast to 3- or 4-substituents (6), due to steric interactions, are
rather unpredictable. Therefore, a synthetic work seemed to be necessary.
RESULTS AND DISCUSSION
Compounds 2b–8b were obtained in a reaction of N,N-dimethylcarbamyl chloride
with appropriately 2-substituted-5-N,N-dimethylaminophenols in the presence of
bases. All attempts to use triethylamine in the reaction have failed. Even at elevated
37
0045-2068/97 $25.00
Copyright 1997 by Academic Press
All rights of reproduction in any form reserved.

38
BARBARINI ET AL.
S
CHEME 1
temperature (120ЊC) starting aminophenols have been recovered. The use of sodium
salts, prepared from the dimethylaminophenols 1a–8a by treating them with sodium
hydroxide, led to the formation of the desired aryl carbamates, however, in low
yields. Good results (yields 58–83%) were obtained when the sodium salts, prepared
in situ by means of sodium hydride (6), were treated with dimethylcarbamyl chloride
in anhydrous dimethylformamide at 110ЊC for ca. 3 h.
Products 1b–5b and 7b, separated from postreaction mixtures by extraction off
unreacted dimethylaminophenols and residue distillation under reduced pressure,
were practially pure. The iodo-derivative 6b required column chromatography puri-
fication and the nitroderivative 8b was precipitated by dilution of the postreaction
solution with aqueous potassium hydroxide.
NЈ-(3-dimethylaminophenyl)-N,N-dimethylurea 9b, allosteric with 1a, was pre-
pared by carbamylation of the corresponding amine 9a according to the method
of Michler and Escherich (7) known for a synthesis of, e.g., NЈ-phenyl-N,N-dimethy-
lurea. The reaction of 1a (formerly treated with sodium hydride) with N,N-dimethyl-
thiocarbamyl chloride yielded a crude product which required troublesome purifica-
tion to obtain the expected 10b in 33%. Thermal rearrangement of 10b gave known
11b, though in a lower yield than reported earlier (7).
Structures of all new compounds were proved by elemental analyses, IR and 1H
NMR spectra. Elemental analysis data were in accordance with calculated ones
within a range of 0.1% for C, 0.2% for H, and 0.1% for N. Basic physical constants
1
and yields of the synthesized compounds are given in the experimental part. H
NMR data are disclosed in Table 1.
We have undertaken several attempts to correlate the protons chemical shifts

SYNTHESIS OF NEW o-SUBSTITUTED ARYLCARBAMATES
39
TABLE 1
1H NMR Chemical Shifts and Coupling Constants of 2-Substituted-NЈ,NЈ-dimethylaminophenyl
N,N-Dimethylcarbamates and Related Compounds
ͳ/ppm
5-NMe2
Ji,ka/Hz
Compound
X
2-X
3-H
4-H
6-H
s-Meb
a-Meb
J3,4
J4,6
1bc
2b
3b
4b
5b
6b
7b
8b
H
Me
MeO
Cl
Br
I
MeCO
NO2
H
H
H
6.46
2.09
3.77
—
—
—
2.47
—
6.42
6.28
6.61
7.18
7.03
6.87
7.19
7.34
7.51
7.76
8.08
7.11
7.09
7.10
6.55
6.52
6.55
6.48
6.44
6.34
6.49
6.46
6.59
6.46
6.71
2.93
2.89
2.85
2.91
2.92
2.92
3.02
3.08
2.93
2.94
2.90
6.44
6.44
6.54
6.52
6.54
6.54
6.31
6.35
7.01
6.26
6.72
3.00
3.02
3.00
3.02
3.03
3.03
3.03
3.03
3.00
3.31d
2.90
3.08
3.11
3.11
3.14
3.15
3.17
3.15
3.15
3.00
3.37d
2.95
8.6
8.4
9.2
8.8
8.9
8.8
8.9
9.5
8.1
8.0
7.9
2.3
2.5
3.0
2.9
2.9
2.9
2.6
2.8
2.1
2.0
2.4
9bc
10bc
11bc
a All coupling constants between para protons were not readable: J2,4 Ȃ J2,6 Ȃ J4,6 in the spectra of 1b
and 9b–11b.
b s and a refer to the syn and anti position of the carbamate methyl group relative to the carbonyl oxygen.
c Numbering of benzene positions like in 2-substituted phenyl carbamates.
d CSNMe groups.
with substituents parameters. Neither mono- nor dual parameter correlations could
be achieved.
Additionally, toxicity of four compounds (1b, 3b, 4b, and 8b) was tested in mice,
measuring LD50 (8). Both electron withdrawing (NO2 , Cl) and electron releasing
substituents (MeO) at the position 2, of the tested arylcarbamates, substantially
decreased toxicity of the compounds in comparison to the parent one (X ϭ H; 1b).
These very preliminary results of biological screening of 2-substituted-5-NЈ,NЈ-
dimethylaminophenyl N,N-dimethylcarbamates unfortunately indicated that, in
contrast to our expectation, substituents at the position 2 regardless their character
decrease the biological activity of arylcarbamates. Therefore further planned screen-
ing has been abandoned.
CONCLUSIONS
2-substituted-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamates can be
prepared in moderate to high yields by treating sodium 2-substituted 5-N,N-dimeth-
ylaminophenolates with N,N-dimethylcarbamylchloride in DMF at an elevated tem-
perature. 2-Substituted compounds are less toxic to mice than the unsubstituted
one. High anti-ChE activity of the compounds is not to be expected. Effects of 2-
substituents on the protons chemical shifts do not correlate well with substituent pa-
rameters.

40
BARBARINI ET AL.
EXPERIMENTAL
Melting points were determined on a MQAPF-301 apparatus without correction.
Boiling points were read by distillation under reduced pressure. IR spectra were
1
recorded on a Perkin–Elmer 1430 or FTIR 1600, H NMR spectra were taken on
Varian Gemini-300 or Bruker AC 300/P spectrometers in CDCl3-TMS.
Aryl N,N-dimethylcarbamates (1b–8b): A General Procedure
A solution of appropriately substituted 5-N,N-dimethylaminophenol 1a–8a (32.5
mmol) in DMF (20 ml) was added dropwise at 0–5ЊC to a slurry of sodium hydride
(36 mmol) stirred under nitrogen in DMF (10 ml). When hydrogen evolution ceased,
N,N-dimethylcarbamyl chloride (41.5 mmol) in DMF (10 ml) was dropped in at
10ЊC. The resulting solution was heated slowly to 110ЊC (ca. 45 min) and maintained
in these conditions for an additional 2 h. The mixture was cooled and then poured
into 1% aqueous potassium hydroxide (100 ml) and extracted with a benzene-
diethyl ether (4 : 1 v/v) mixture (4 ϫ 50 ml). The organic extract was washed with
water (3 ϫ 25 ml), dried (Na2SO4), filtered, condensed, and distilled under low
pressure to yield 1b–7b. Compound 6b required further purification by column
chromatography. The nitroderivative 8b precipitated straight after addition of an
aqueous potassium hydroxide solution. It was collected and rinsed with water.
Yields and some properties of the parent (1b) and of the new compounds (2b–8b)
are given below. NMR data are listed in the Table 1.
3-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (1b). Oil, b.p. 175–176ЊC/
1
9 mmHg [lit. (9) 195ЊC/20 mmHg]; yield 67%; IR ␯ (film), 1720 cmϪ .
CO
2-Methyl-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (2b). Oil, b.p.
1
140ЊC/1 mmHg; yield 77%; IR ␯ (film), 1720 cmϪ .
CO
2-Methoxy-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (3b). Oil, b.p.
1
158–160ЊC/0.75 mmHg; yield 73%; IR ␯ (film), 1720 cmϪ .
CO
2-Chloro-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (4b). Oil, b.p.
1
178ЊC/2 mmHg; yield 83%; IR ␯ (film), 1732 cmϪ .
CO
2-Bromo-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (5b). Oil; b.p.
1
161ЊC/1.2 mmHg; yield 65%; IR ␯ (film), 1725 cmϪ .
CO
2-Iodo-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (6b). Oil, yield
1
77%; IR ␯ (film), 1725 cmϪ .
CO
2-Acetyl-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (7b). Solid, m.p.
1
86–88ЊC; yield 74%: IR ␯ (in KBr), 1719 cmϪ .
CO
2-Nitro-5-NЈ,NЈ-dimethylaminophenyl N,N-dimethylcarbamate (8b). Solid, m.p.
1
122–123ЊC; yield 58%; IR ␯ (in KBr), 1720 cmϪ .
CO
NЈ-(3-NЉ,NЉ-Dimethylaminophenyl)-N,N-dimethylurea (9b)
To a cold (2ЊC) stirred solution of N,N-dimethyl-1,3-phenylenediamine (5.2
mmol) in benzene (10 ml), a solution of N,N-dimethylcarbamyl chloride (6.4 mmol)
in benzene (5 ml) was added all at once. Ten minutes later the temperature was
raised up to 25ЊC and the solution was stirred for 2 h. The resulting mixture was
washed with 5% aqueous potassium hydroxide (3 ϫ 10 ml) and water (3 ϫ 10 ml),

SYNTHESIS OF NEW o-SUBSTITUTED ARYLCARBAMATES
41
dried (Na2SO4), filtered, and condensed under low pressure. The residual oil was
subjected to column chromatography with n-hexane-diethyl ether-methanol mixture
to yield the desired product—Solid, m.p. 120–121ЊC; yield 66%; IR ␯ (in KBr),
CO
1
1648 cmϪ .
O-3-NЈ,NЈ-Dimethylaminophenyl N,N-dimethylthiocarbamate 10b and S-3-NЈ,NЈ-
Dimethylaminophenyl N,N-dimethylthiocarbamate 11b
N,N-Dimethylthiocarbamyl chloride and 1a were condensend according to the
procedure given for 1b–8b preparation. A crude product was chromatographed
like 9b to yield 10b—Solid, m.p. 72ЊC; yield 33%; IR ␯
(in KBr), 1380, 1275,
max
1
1225 cmϪ .
Compound 10b was converted to 11b by thermal rearrangement according to the
known procedure (10), followed by distillation under low pressure and column
1
chromatography—Oil, b.p. 180ЊC 1.5 mmHg; yield 60%; IR ␯ (film), 1715 cmϪ .
CO
ACKNOWLEDGMENTS
The authors are indebted to FAPESP and CNPq for financial support.
REFERENCES
1. TAYLOR, P. (1985) in Goodman and Gilman’s The Pharmacological Basis of Therapeutics (Gilman,
A. G., Goodman, L. S., Rall, T. W., and Murad, F., Eds.), 7th ed., pp. 110–129, Macmillan, New York.
2. AESCHLIMANN, J. A., AND
3. MILLNER, O. E., STANLEY, J. W., AND
4. HETNARSKI, B., AND O’BRIEN, R. D. (1975) J. Agric. Food Chem. 23, 709–713.
5. PORST, H., AND YN, L. (1985) Pharmazie 40, 325–328.
6. PERJESSY, A., JONES, R. G., M LAIR, S. L., AND ILKINS, J. M. (1983) J. Org. Chem. 48, 1266–1271.
7. MICHLER, W., AND SCHERICH, C. (1879) Ber 12, 1162–1164.
8. HOEHR, N. F., (1993) Ph.D. thesis, Universidade Estadual de Campinas, 266 pp.
R
EINERT, M. (1931) J. Pharmacol. Exp. Ther. 43, 413–444.
P
URCELL, W. P. (1974) J. Med. Chem. 17, 13–18.
K
CC
W
E
¨
9. BOBRANSKII, B. R., AND
EKER, I. M., (1941) J. Appl. Chem. USSR (Engl. Transl.) 14, 524–527.
10. NEWMAN, M. S., AND ARNES, H. A. (1966) J. Org. Chem. 31, 3980–3984.
K