Chemoselective alkylation of 3- and 4-(5-amino-4-hetaryl-2,3-dihydro-3- oxopyrrol-1-yl)benzoic acids

Article abstract of DOI:10.1023/B:RUJO.0000034973.29561.7c

Alkylation of 3- and 4-(5-amino-4-hetaryl-2,3-dihydro-3-oxopyrrol-1-yl) benzoic acids with phenacyl bromides or chloroacetanilides in DMF in the presence of triethylamine occurs at the carboxy group with high selectivity and yields the corresponding phenacyl and arylcarbamoylmethyl esters. The initial pyrrolylbenzoic acids were synthesized by reaction of 3- and 4-aminobenzoic acids with 4-chloro-2-hetaryl-3-oxo-butyronitriles.

Full text of DOI:10.1023/B:RUJO.0000034973.29561.7c

Russian Journal of Organic Chemistry, Vol. 40, No. 3, 2004, pp. 368–371. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 3, 2004,
pp. 398–401.
Original Russian Text Copyright © 2004 by Resnyanskaya, Tverdokhlebov, Volovenko, Shokol.
Chemoselective Alkylation of 3- and 4-(5-Amino-4-hetaryl-
2,3-dihydro-3-oxopyrrol-1-yl)benzoic Acids
E. V. Resnyanskaya, A. V. Tverdokhlebov, Yu. M. Volovenko, and T. V. Shokol
Taras Shevchenko Kiev National University, ul. Vladimirskaya 62, Kiev, 01033 Ukraine
e-mail: atver@mail.univ.kiev.ua
Received January 17, 2003
Abstract—Alkylation of 3- and 4-(5-amino-4-hetaryl-2,3-dihydro-3-oxopyrrol-1-yl)benzoic acids with phen-
acyl bromides or chloroacetanilides in DMF in the presence of triethylamine occurs at the carboxy group with
high selectivity and yields the corresponding phenacyl and arylcarbamoylmethyl esters. The initial pyrrolyl-
benzoic acids were synthesized by reaction of 3- and 4-aminobenzoic acids with 4-chloro-2-hetaryl-3-oxo-
butyronitriles.
In 1990s, a number of compounds exhibiting a high
antitumor activity have been found among derivatives
of 3- and 4-(2-aminopyrrol-1-yl)benzoic acid [10–12].
Therefore, we selected carboxy group as a func-
tionality to be introduced into the substituent R.
Following the procedure developed previously [3–6],
reactions of 3- and 4-aminobenzoic acids with
2-(2-thiazolyl)- and 2-(2-benzothiazolyl)-4-chloro-3-
oxobutyronitriles II and III [3, 13] afforded 70–80%
of 3- and 4-(5-amino-4-hetaryl-3-oxo-2,3-dihydro-
pyrrol-1-yl)benzoic acids IV–VII (Scheme 1). The
structure of compounds IV–VII was confirmed by the
data of elemental analysis and IR and 1H NMR
We previously developed various procedures for
the synthesis of 5-amino-4-hetaryl-2,3-dihydropyrrol-
3-ones I [1–6]. Further studies of the chemical
properties of compounds I revealed low reactivity of
the 5-amino group [7], which was explained by
conjugation between the amino and carbonyl groups
in molecule I. Therefore, these compounds can be
regarded as vinylogous to amides. The existence of
such conjugation was proved by the X-ray diffraction
data which showed considerable deviations of the
corresponding bond lengths in the β-enaminoketone
fragment [7] from the standard values, as well as by
comparison of the spectral data of pyrrolones I and
model compounds [8] specially synthesized for that
purpose. An analogous conjugation in structurally
related systems was also observed by other authors [9].
1
spectroscopy. The H NMR spectra were consistent
with the known data for (benzo)thiazolyl-substituted
derivatives of I [3, 4, 6].
The carboxy group in pyrrolylbenzoic acids IV–
VII was modified via the known reaction [14] of the
corresponding salts with phenacyl halides. Alkylation
of IV–VII with 4-chlorophenacyl bromide (VIIIa) in
DMF in the presence of an equimolar amount of
triethylamine occurred selectively at the carboxy group
to give 4-chlorophenacyl 3- and 4-(5-amino-4-hetaryl-
3-oxo-2,3-dihydropyrrol-1-yl)benzoates IXa, XIa, and
XIIa. With the use of structural analogs of phenacyl
halides, chloroacetanilides VIIIb–VIIIf, as alkylating
agents we obtained arylcarbamoylmethyl esters IXb,
IXc, Xc, Xd, XIf, XIIb, and XIIe. The yields of esters
IX–XII ranged from 70 to 90%, and no alkylation
products at the amino group were detected.
Ht
O
H2N
N
R
I
R = Alk, Ar.
Taking into account the low reactivity of the
amino group in compounds I, we made an attempt to
introduce a functional group into the R substituent
and modify it by the action of electrophilic reagents
without protection of the amino group. The present
communication reports on the results of this study.
The structure of compounds IX–XII was deter-
mined on the basis of the IR and 1H NMR spectra. The
1070-4280/04/4003-0368 © 2004 MAIK “Nauka/Interperiodica”

CHEMOSELECTIVE ALKYLATION OF 3- AND 4-(5-AMINO-4-HETARYL-...
369
Scheme 1.
R1
O
NH2
N
N
O
R1
R2
N
COOH
+
S
Cl
S
NH2
R2
COOH
NC
II, III
IV–VII
O
XCH2C(O)R3 (VIIIa–VIIIf), Et3N
N
R1
C(O)OCH2C(O)R3
N
NH2
IXa–IXc, Xc, Xd, XIa, XIf, XIIa, XIIb, XIIe
S
R2
II, IV, V, IX, X, R1R2 = benzo; III, VI, VII, XI, XII, R1 = 4-ClC6H4, R2 = H; IV, VI, IX, XI, 4-COOH or 4-COOCH2COR3;
V, VII, X, XII, 3-COOH or 3-COOCH2COR3; VIIIa, X = Br; VIIIb–VIIIf, X = Cl; R3 = 4-ClC6H4 (a), 3-MeOC6H4NH (b),
3,4-Cl2C6H3NH (c), 4-(F2CHS)C6H4NH (d), 4-EtOC6H4NH (e), 4-Me2NC6H4NH (f).
1H NMR spectra of IX–XII in DMSO-d6 lacked signal
from the COOH proton, which was present in the
spectra of initial acids IV–VII at δ 12.9–13.2 ppm.
The spectra of both IX–XII and IV–VII contained
a two-proton singlet at 4.3–4.5 ppm from the
methylene protons in the dihydropyrrole ring and two
broadened one-proton singlets at δ 8.0–9.0 ppm due to
protons of the amino group; magnetic nonequivalence
of the latter results from restricted rotation about the
C–N bond [7, 8]. In addition, compounds IX–XII
showed in the spectra a two-proton singlet from the
methylene group in the ester fragment at δ 5.7–
5.8 ppm for phenacyl esters IXa, XIa, and XIIa or at
δ 4.9–5.0 ppm for arylcarbamoylmethyl esters IXb,
IXc, Xc, Xd, XIe, XIIb, and XIIe. Resonance signals
from protons in the substituents R1, R2, and R3, as well
as in the aminobenzoic acid moiety were located in the
expected regions.
Table 1. Yields, melting points, and elemental analyses of 3- and 4-(5-amino-4-hetaryl-3-oxo-2,3-dihydropyrrol-1-yl)benzoic
acids IV–VII and esters IX–XII
Found, %
Calculated, %
Comp. Yield,
mp, °C
Formula
no.
%
C
H
N
S
C
H
N
S
74
76
80
76
86
79
75
81
76
84
82
89
75
76
>300
>300
>300
>300
>300
>300
>300
>233
>300
>300
>300
>300
>293
>300
61.59
61.52
58.29
58.30
61.92
62.98
56.49
56.42
57.20
59.55
61.22
59.61
60.62
61.13
3.80
3.75
3.49
3.41
3.57
4.36
3.22
3.31
3.51
3.42
4.45
3.46
3.98
4.31
12.02
11.99
10.18
10.23
08.33
10.95
10.05
10.09
09.94
07.49
11.98
07.38
09.71
09.56
9.06
9.11
7.86
7.82
6.42
6.29
5.81
5.71
C18H13N3O3S
C18H13N3O3S
C20H14ClN3O3S
C20H14ClN3O3S
C26H18ClN3O4S
C27H22N4O5S
61.53
61.53
58.32
58.32
61.97
63.02
3.73
3.73
3.43
3.43
3.60
4.31
3.28
3.28
3.56
3.39
4.46
3.39
4.03
4.28
11.96
11.96
10.20
10.20
08.34
10.89
10.12
10.12
09.89
07.44
11.91
07.44
09.74
09.51
9.12
9.12
7.78
7.78
6.36
6.23
5.79
5.79
11.320
5.68
5.45
5.68
5.58
5.44
IV
V
VI
VII
IXa
IXb
IXc
Xc
C26H18Cl2N4O4S 56.43
C26H18Cl2N4O4S 56.43
11.280 C27H20F2N4O4S2
57.24
C28H19Cl2N3O4S 59.58
C30H26ClN5O4S 61.27
C28H19Cl2N3O4S 59.58
Xd
5.74
5.39
5.69
5.54
5.39
XIa
XIf
XIIa
XIIb
XIIe
C29H23ClN4O5S
C30H25ClN4O5S
60.57
61.17
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

RESNYANSKAYA et al.
370
1
Table 2. H NMR spectra of 3- and 4-(5-amino-4-hetaryl-3-oxo-2,3-dihydropyrrol-1-yl)benzoic acids IV–VII and esters
IX–XII
Comp.
no.
Chemical shifts δ,a ppm (J, Hz)
4.42 s (2H, NCH2CO), 7.26 t (1H, R1R2, J = 7.8), 7.41 t (1H, R1R2, J = 7.8), 7.61 d (2H, Ha, J = 8.4), 7.81 d (1H,
IV
RR1, J = 7.8), 7.97 d (1H, R1R2, J = 7.8), 8.05 d (2H, Ha, J = 8.4), 8.53 s (1H, NH2), 8.98 s (1H, NH2), 12.94 s
(1H, COOH)
4.38 s (2H, NCH2CO), 7.25 t (1H, R1R2, J = 7.8), 7.40 t (1H, R1R2, J = 7.8), 7.65 t (1H, Ha, J = 7.5), 7.78 m (2H,
V
Ha), 7.91 d (1H, R1R2, J = 7.8), 7.96 d (1H, R1R2, J = 7.8), 8.03 s (1H, Ha), 8.40 s (1H, NH2), 8.83 s (1H, NH2),
13.01 s (1H, COOH)
4.41 s (2H, NCH2CO), 7.51 d (2H, R1, J = 8.4), 7.61 d (2H, Ha, J = 8.8), 7.82 s (1H, R2), 7.99 d (2H, R, J = 8.4),
VI
8.04 d (2H, Ha, J = 8.8), 8.46 s (1H, NH2), 8.78 s (1H, NH2), 13.10 s (1H, COOH)
4.37 s (2H, NCH2CO), 7.49 d (2H, R1, J = 8.8), 7.63 t (1H, Ha, J = 7.6), 7.74 d (1H, Ha, J = 7.6), 7.79 s (1H, R2),
VII
7.88 d (1H, Ha, J = 7.6), 7.99 d (2H, R1, J = 8.8), 8.02 s (1H, Ha), 8.30 s (1H, NH2), 8.60 s (1H, NH2), 13.19 s
(1H, COOH)
4.50 s (2H, NCH2CO), 5.60 s (2H, OCH2CO), 7.30 t (1H, R1R2, J = 8.0), 7.46 t (1H, R1R2, J = 8.0), 7.71 m (4H,
IXa
Ha, R3), 7.86 d (1H, R1R2, J = 8.0), 8.01 d (1H, R1R2, J = 8.0), 8.07 d (2H, Ha, J = 8.4), 8.19 d (2H, R3, J = 8.4),
8.67 s (1H, NH2), 9.07 s (1H, NH2)
3.72 s (3H, OCH3), 4.45 s (2H, NCH2CO), 4.96 s (2H, OCH2CO), 6.66 d (1H, 4-H in R3, J = 9.2), 7.12 d (1H,
IXb
6-H in R3, J = 9.2), 7.23 t (1H, R1R2, J = 8.0), 7.27 m (2H, 2-H, 5-H in R3), 7.41 t (1H, R1R2, J = 8.0), 7.67 d
(2H, Ha, J = 8.8), 7.82 d (1H, R1R2, J = 8.0), 7.98 d (1H, R1R2, J = 8.0), 8.13 d (2H, Ha, J = 8.8), 8.61 s (1H,
NH2), 9.04 s (1H, NH2), 10.20 s (1H, CONH)
4.49 s (2H, NCH2CO), 5.00 s (2H, OCH2CO), 7.30 t (1H, R1R2, J = 8.0), 7.45 t (1H, R1R2, J = 8.0), 7.53 d.d (1H,
IXc
6-H in R3, J = 9.2, 2.4), 7.63 d (1H, 5-H in R3, J = 9.2), 7.71 d (2H, Ha, J = 8.8), 7.86 d (1H, R1R2, J = 8.0),
8.00 m (2H, R1R2, 2-H in R3), 8.17 d (2H, Ha, J = 8.8), 8.66 s (1H, NH2), 9.08 s (1H, NH2), 10.60 s (1H, CONH)
4.41 s (2H, NCH2CO), 5.00 s (2H, OCH2CO), 7.24 t (1H, R1R2, J = 7.2), 7.41 t (1H, R1R2, J = 7.2), 7.49 d.d (1H,
Xc
6-H in R3, J = 8.8, 2.0), 7.60 d (1H, 5-H in R3, J = 8.8), 7.72 t (1H, Ha, J = 8.0), 7.82 m (2H, Ha), 7.98 m (3H,
R1R2, 2-H in R3), 8.13 s (1H, Ha), 8.51 s (1H, NH2), 8.88 s (1H, NH2), 10.56 s (1H, CONH)
4.40 s (2H, NCH2CO), 5.01 s (2H, OCH2CO), 7.25 t (1H, R1R2, J = 7.6), 7.41 t (1H, R1R2, J = 7.6), 7.42 t (1H,
Xd
CHF2, J = 54.8), 7.55 d (2H, R3, J = 8.0), 7.68 m (3H, R3, Ha,), 7.81 d (1H, Ha, J = 8.0), 7.84 d (1H, Ha, J = 8.0),
7.97 d (1H, R1R2, J = 7.6), 8.00 d (1H, R1R2, J = 7.6), 8.13 s (1H, Ha), 8.50 s (1H, NH2), 8.88 s (1H, NH2),
10.49 s (1H, CONH)
4.45 s (2H, NCH2CO), 5.55 s (2H, OCH2CO), 7.51 d (2H, R1, J = 8.4), 7.67 m (4H, Ha, R3), 7.83 s (1H, R2), 8.00 d
XIa
(2H, R1, J = 8.4), 8.05 d (2H, Ha, J = 8.4), 8.12 d (2H, R3, J = 8.8), 8.62 s (1H, NH2), 8.78 s (1H, NH2)
2.87 s (6H, NMe2), 4.44 s (2H, NCH2CO), 4.90 s (2H, OCH2CO), 6.74 d (2H, R3, J = 8.3), 7.44 d (2H, R3, J =
XIf
8.3), 7.55 d (2H, R1, J = 8.4), 7.76 d (2H, Ha, J = 8.8), 7.87 s (1H, R2), 8.00 d (2H, R1, J = 8.4), 8.13 d (2H, Ha,
J = 8.8), 8.55 s (1H, NH2), 8.79 s (1H, NH2), 9.96 s (1H, CONH)
4.39 s (2H, NCH2CO), 5.79 s (2H, OCH2CO), 7.49 d (2H, R1, J = 8.4), 7.68 d (2H, R3, J = 8.4), 7.71 t (1H, Ha,
XIIa
J = 8.0), 7.79 s (1H, R2), 7.83 d (1H, Ha, J = 8.0), 7.99 m (3H, R1, Ha), 8.05 d (2H, R3, J = 8.4), 8.11 s (1H, Ha),
8.40 s (1H, NH2), 8.60 s (1H, NH2)
3.73 s (3H, OCH3), 4.39 s (2H, NCH2CO), 4.96 s (2H, OCH2CO), 6.66 d.d (1H, 4-H in R3, J = 8.2, 2.4), 7.11 d.d
XIIb
(1H, 6-H in R3, J = 8.2, 2.4), 7.23 t (1H, 5-H in R3, J = 8.2), 7.30 t (1H, 2-H in R3, J = 2.4), 7.49 d (2H, R1,
J = 8.8), 7.70 t (1H, Ha, J = 7.8), 7.79 s (1H, R2), 7.82 d (1H, Ha, J = 7.8), 7.98 m (3H, R1, Ha), 8.12 s (1H, Ha),
8.38 s (1H, NH2), 8.62 s (1H, NH2), 10.24 s (1H, CONH)
1.31 t (3H, Et, J = 5.8), 3.98 q (2H, Et, J = 5.8), 4.38 s (2H, NCH2CO), 4.93 s (2H, OCH2CO), 6.87 d (2H, R3,
XIIe
J = 8.0), 7.48 m (4H, R3, R1), 7.69 t (1H, Ha, J = 6.8), 7.82 m (2H, Ha, R2), 7.98 m (3H, R1, Ha), 8.12 s (1H, Ha),
8.43 s (1H, NH2), 8.55 s (1H, NH2), 10.04 s (1H, CONH)
a
The notation Ha refers to aromatic protons of the aminobenzoic acid moiety.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

CHEMOSELECTIVE ALKYLATION OF 3- AND 4-(5-AMINO-4-HETARYL-...
371
In the IR spectra of IX–XII we observed a strong
band at 1700–1740 cm–1, belonging to stretching
vibrations of the ester carbonyl group, and two bands
at 3150 and 3300 cm–1 due to stretching vibrations of
the primary amino group. A strong carbonyl absorption
band of the COR3 fragment was located at 1680–
1700 cm–1 for 4-chlorophenacyl esters IXa, XIa, and
XIIa and at 1660–1670 cm–1 for carbamoyl derivatives
IXb, IXc, Xc, Xd, XIe, XIIb, and XIIe. The above
spectral data are in full agreement with the proposed
structures of compounds IX–XII; their elemental
compositions were also consistent with the calculated
values.
Thus, due to reduced reactivity of the amino group
in the dihydropyrrole fragment, the alkylation of
3- and 4-(5-amino-4-hetaryl-3-oxo-2,3-dihydropyrrol-
1-yl)benzoic acids IV–VII involves the carboxy group
with high selectivity. This reaction may be regarded as
a convenient preparative route to phenacyl and arylcar-
bamoylmethyl aminopyrrolylbenzoates IX–XII which
are structural analogs of known antitumor agents.
4-chlorophenacyl bromide (VIIIa) or 2 mmol of
chloroacetanilide VIIIb–VIIIf, and the mixture was
heated for 3 h at 110–120°C. It was then cooled and
poured into 10 ml of water, and the precipitate was
filtered off and recrystallized from DMF (IXa, XIa,
XIIa) or acetic acid (IXb, IXc, Xc, Xd, XIe, XIIb,
and XIIe). The yields and analytical and spectral data
of esters IX–XII are given in Tables 1 and 2.
This study was performed under financial support
by NVP Enamin Ltd.
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are given in Table 1, and their spectral data are
collected in Table 2.
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3- and 4-(5-amino-4-hetaryl-3-oxo-2,3-dihydropyr-
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of acid IV–VII and 0.3 ml (2.2 mmol) of triethylamine
in 5 ml of DMF we added 0.47 g (2 mmol) of
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004