Thienopyridone antibacterials V [1]. Synthesis of some N(7)-azacyclohexyl- 4-oxothieno[2,3-b]pyridine-5-carboxylic acids and related congeners

Article abstract of DOI:10.1515/znb-2009-11-1249

A series of N(7)-azacyclohexyl-4-oxo-4,7-dihydrothieno[2,3-b]-pyridine-5- carboxylic acids 9a - c, related congeners 9d - g and their methyl esters 8a - g were prepared by cyclization of the respective 2-[(2,5-dichlorothien-3-yl) carbonyl]-3-[(N(7)-azacyc

Full text of DOI:10.1515/znb-2009-11-1249

Thienopyridone Antibacterials V [1]. Synthesis of Some
N(7)-Azacyclohexyl-4-oxothieno[2,3-b]pyridine-5-carboxylic
Acids and Related Congeners
Hala I. Al-Jabera, Mustafa M. El-Abadelaha, Salim S. Sabrib, Taleb H. Al-Telb,
and Wolfgang Voelterc
a Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan
b University of Sharjah, Sharjah, P. O. Box 27272, UAE
c Interfakulta¨res Institut fu¨r Biochemie, Universita¨t Tu¨bingen, Hoppe-Seyler-Straße 4,
72076 Tu¨bingen, Germany
Reprint requests to Prof. Dr. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de or
Prof. Dr. M. M. El-Abadelah. E-mail: mustelab@ju.edu.jo
Z. Naturforsch. 2009, 64b, 1625 – 1632; received August 21, 2009
Dedicated to Professor Hubert Schmidbaur on the occasion of his 75th birthday
A series of N(7)-azacyclohexyl-4-oxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carboxylic acids 9a –
c, related congeners 9d – g and their methyl esters 8a – g were prepared by cyclization of the respec-
tive 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-[(N(7)-azacyclyl/acyclic)amino]acrylates 7a – g. The lat-
ter intermediates are accessible from methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-ethoxyacrylate
(6). Of the present series, the 7-(N,N-dimethylamino) derivative 9d exhibited good activity, espe-
cially against Klebsiella pneumoniae and Salmonella paratyphi A (MIC = 0.5 and 1.0 µg mL−1
respectively).
,
Key words: 4-Oxothieno[2,3-b]pyridines, 7-(N,N-Dimethylamino), 7-Azacyclohexyl Derivatives,
7-Chiral Alaninol / Phenylethylamine Moieties, Antibacterial Activity
Introduction
sis and the antibacterial activity of a new series of 2-
chloro-4-oxothieno[2,3-b]pyridine-5-carboxylic esters
8a – c and acids 9a – c having selected azacyclohexyl
appendages and related congeners at the N(7) locus
(Scheme 1). Herein, the choice is confined to piper-
azino, morpholino, piperidino, N,N-dimethylamino,
chiral alaninol and related biophoric amino entities.
Several 4-oxothieno[2,3-b]pyridine-5-carboxylic
acids, potential bioisosteres of quinolone antibacter-
ials, e. g. norfloxacin (1a) [3], ciprofloxacin (1b) [4]
and ofloxacin (2) [5] (Fig. 1), were prepared and
biotested [2, 6 – 13]. Substitution at the N(7)-position
of thienopyridones has been reported for alkyl groups,
e. g. compounds 3a [6] and 3b [7, 8] (Fig. 1) which
exhibited a good level of activity against Gram-
negative bacteria. N(7)-Aryl substitution has also
been achieved, exemplified by compounds 4a, b [2],
which exhibited a good level of activity against Gram-
negative and Gram-positive bacterial strains. Quite
recently, N(7)-heteroaryl substitution, exemplified by
compound 4c [1], has also been investigated.
Results and Discussion
Chemistry
The preparation of the new thieno[2,3-b]pyridines
9a – g is achieved by utilizing 3-(2,5-dichlorothien-3-
yl)-3-oxopropanoate (5) as starting material (acces-
sible from 3-acetyl-2,5-dichlorothiophene) [14], and
However, incorporation of saturated N(7)-aza- constructing the pyridone nucleus thereupon through
heterocyclyl substituents has not been described in the a series of conversions, as illustrated in Scheme 1.
literature for the thieno[2,3-b]pyridine class. Accord- Thus, treatment of the β-keto ester 5 with triethyl or-
ingly, and as a continuation of our research project thoformate in acetic anhydride gave the correspond-
directed toward structure-activity relationship (SAR) ing methyl 3-ethoxyacrylate derivative 6 [7] which
studies, we report in the present work on the synthe- serves as the common intermediate for the synthe-
c
0932–0776 / 09 / 1100–1625 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
Fig. 1. Structures of some fluoroqui-
nolones (1a, b / 2) and thieno[2,3-b]pyri-
dones (3a, b / 4a – c).
sis of the target compounds 9a – g. Herein, conden- enamino-keto esters 7a – g, is displayed as two sets of
sation of the enol ether 6 with the appropriate amino resonances with unequal peak areas; this feature is in
compound resulted in smooth production of the re- accordance with the existence of Z/E diastereomeric
spective 3-substituted aminoacrylates 7a – g. Cycliza- forms in solution. Likewise, 13C-signal doubling, aris-
tion of deprotonated 7a – g (using NaH in tetrahydro- ing from Z/E diastereomers, is also observed for a
furan) yielded the respective methyl 4-oxothieno[2,3- number of carbons such as C-4, C-5, C-4ꢀ, C-2ꢀꢀ, C-3ꢀꢀ
b]pyridine-5-carboxylates 8a – g. This intramolecular and ester-CH3. Such a phenomenon is well-known and
nucleophilic heteroaromatic substitution (SN-Ar) reac- has been previously documented for related systems
tion is presumably facilitated by the presence of the [2, 7].
vicinal electron-withdrawing keto group at C-3ꢀꢀ and
neighboring chlorine atom at C-5ꢀꢀ. Saponification of
esters 8a – g furnished the desired N-(7)-substituted-4-
Antibacterial activity
oxothieno[2,3-b]pyridine-5-carboxylic acids 9a – g.
The new compounds 7 – 9 were characterized by el-
emental analyses, MS and NMR spectral data. These
data, detailed in the Experimental Section, are con-
sistent with the suggested structures. Thus, their MS
spectra displayed the correct molecular ions [M]+ for
which the m/z values are in agreement with those cal-
culated from the respective molecular formulas.
Compounds 9a – g were tested in vitro as sodium
salts in aqueous solution against eight different bacte-
rial species (listed in Table 1) using ofloxacin (2, OFL)
as reference. The antibacterial activity was evaluated
by the minimal inhibitory concentration (MIC) tech-
nique.
Compound 9d exhibits a moderate to low level of
antibacterial activity against the test organisms except
1H and 13C signal assignments to the different pro- for St. Faecalis and P. aeruginosa where it is inactive at
tons and carbons in the NMR spectra of the new com- ≥ 128 µg mL−1. Compounds 9b – g did not show any
pounds followed from DEPT and 2D (COSY, HMQC, significant antibacterial activity.
HMBC) experiments which showed correlations that
In conclusion, the 7-(N,N-dimethylamino) deriva-
helped in the full assignments. Each of the 1H signals, tive 9d might be envisaged as a lead compound for
belonging to the different hydrogens in the acyclic further manipulations. In particular, fluorination of va-
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
1627
Table 1. In vitro antibacterial activity (MIC values in µg mL−1) of 9d and ofloxacin (OFL) as reference agent.
Strain
OFL
0.125
4
9d
32
> 128
8
1
4
Strain
OFL
≤ 0.06
≤ 0.06
2
< 0.06
0.25
9d
0.5
4
> 128
8
4
Staphylococcus aureus ATCC 9144
Streptococcus faecalis ATCC 11700
Escherichia coli ATCC 10536
Salmonella paratyphi A
Shigella sonnei
Klebsiella pneumoniae ATCC 10031
Proteus mirabilis
Pseudomonas aeruginosa ATCC 27853
Salmonella paratyphi C
Providencia rettgeri
≤ 0.06
0.06
< 0.06
◦
◦
Scheme 1. (i) Ac2O, (EtO)3CH / 130 C, 3 – 4 h; (ii) R-NH2, CH2Cl2; (iii) NaH, THF / 24 C, 30 min, then 60 ◦C; (iv) 1 %
ethanolic NaOH / r. t., 1 – 2 h, then 10 % aq. HCl.
cant CH-thiophene sites in 9d might produce drugable reference to TMS as internal standard. Mass spectra were
obtained using a Finnigan MAT 731 spectrometer at 70 eV.
Elemental analyses were preformed at M. H. W Laboratories,
Arizona, USA.
fluorothieno[2,3-b]pyridonescomparable in potency to
marketed fluoroquinolone antibacterials.
Experimental Section
Antibacterial tests
3-Acetyl-2,5-dichlorothiophene was purchased from Flu-
The MICs were determined by the conventional agar dilu-
orochem (England), (R)-alaninol, (S)-alaninol, 1-amino-4- tion procedures according to the method of Mueller-Hinton
methylpiperazine and N-aminomorpholine were purchased at pH = 7.4. Aqueous stock solutions (1000 µg mL−1) of the
from Acros. 1-Aminopiperidine was a product from Aldrich. test compounds were prepared with 0.1 N NaOH. Serial di-
Sodium hydride (80 % dispersion in mineral oil) was ob- lutions were then made to obtain test concentrations in the
tained from Fluka. Tetrahydrofuran (THF) and dimethyl car- range 128 – 0.06 µg mL−1. The agar plates were inoculated
bonate were dried before use. Melting points were deter- with approximately 105 CFU per spot. The agar plates were
◦
mined on an electrothermal melting temperature apparatus. then incubated at 37 C for 18 h. The MICs were taken as
1H and 13C NMR spectra were measured on a Bruker DPX- the lowest concentration of the test compounds that inhibits
300 instrument. Chemical shifts are expressed in ppm with visible growth.
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
Synthesis of compounds 5 and 6
(300 MHz, CDCl3): δ = 2.94 (m, 4H, 3ꢀ-H2 + 5ꢀ-H2), 3.80
(m, 4H, 2ꢀ-H2 + 6ꢀ-H2), 3.65, 3.67 (2s, 3H, OCH3, Z/E),
6.79, 6.92 (2s,1H, 4ꢀꢀ-H, Z/E), 8.35, 8.16 (2d, 1H, J = 11.4,
11.4 Hz, 3-H, Z/E), 11.09, 9.69 (2d, 1H, J = 11.4, 11.4 Hz,
NH). – 13C NMR (75 MHz, CDCl3): δ = 51.4 (OCH3), 57.0
(C-3ꢀ + C-5ꢀ), 66.1 (C-2ꢀ + C-6ꢀ), 99.9 (C-2), 125.9 (C-3ꢀꢀ),
126.2 (C-4ꢀꢀ), 127.2 (C-5ꢀꢀ), 139.5 (C-2ꢀꢀ), 159.0 (C-3), 166.6,
169.0 (C-1, Z/E), 187.0, 183.9 (C-4, Z/E). – MS (EI, 70 eV):
m/z (%) = 364 (81) [M]+, 329 (63), 297 (55), 269 (2),
179 (51), 144 (48), 116 (8), 86 (41). – C13H14N2O4SCl2
(365.24): calcd. C 42.75, H 3.86, N 7.67; found C 42.69,
H 3.92, N 7.63.
Methyl 3-(2,5-dichlorothien-3-yl)-3-oxopropanoate (5)
This compound was prepared from 3-acetyl-2,5-dichloro-
thiophene and dimethyl carbonate, following a recently re-
ported procedure [7, 14].
Methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-ethoxyacryl-
ate (6)
A stirred mixture of compound 5 (5.3 g, 21 mmol), tri-
ethyl orthoformate (4.6 g, 32 mmol) and acetic anhydride
(9.2 g, 90 mmol) was heated at 135 – 140 ◦C for 3 – 4 h.
The resulting solution was concentrated in vacuo to give 6
as a brown viscous oil in nearly quantitative yield (∼ 6.4 g),
which was used as such in the next step without further pu-
rification [7, 14].
Methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-[(piperidin-
1-yl)amino]acrylate (7c)
The obtained solid product was recrystalllized from
chloroform/diethyl ether. Yield: 4.5 g (62 %), m. p. 108 –
Preparation of methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-
3-(N-substituted amino)acrylates 7a – g
◦
110 C. – 1H NMR (300 MHz, CDCl3): δ = 1.45 (m, 2H,
4ꢀ-H2), 1.71 (m, 4H, 3ꢀ-H2 + 5ꢀ-H2), 2.85 (m, 4H, 2ꢀ-H2 +
6ꢀ-H2), 3.64, 3.67 (2s, 3H, OCH3, Z/E), 6.80, 6.90 (2s, 1H,
4ꢀꢀ-H, Z/E), 8.34, 8.11 (2d, 1H, J = 11.7, 11.7 Hz, 3-H, Z/E),
11.12, 9.70 (2d, 1H, J = 11.7, 11.7 Hz, NH). – 13C NMR
(75 MHz, CDCl3): δ = 22.8 (C-4ꢀ), 25.2 (C-3ꢀ + C-5ꢀ), 51.3
(OCH3), 58.1 (C-2ꢀ + C-6ꢀ), 99.3, 98.9 (C-2, Z/E), 125.7,
124.9 (C-3ꢀꢀ, Z/E), 126.3, 127.2 (C-4ꢀꢀ, Z/E), 127.3 (C-5ꢀꢀ),
139.7 (C-2ꢀꢀ), 158.8, 159.0 (C-3, Z/E), 166.7, 169.0 (C-1,
Z/E), 186.8, 183.9 (C-4, Z/E). – MS (EI, 70 eV): m/z (%) =
362 (17) [M]+, 327 (46), 295 (100), 267 (3), 179 (30), 144
(2), 116 (2), 84 (34). – C14H16N2O3SCl2 (363.27): calcd.
C 46.29, H 4.44, N 7.71; found C 46.30, H 4.39, N 7.65.
General procedure
To a stirred solution of methyl 2-[(2,5-dichlorothien-
3-yl)carbonyl]-3-ethoxyacrylate (6) (6.16 g, 20 mmol) in
dichloromethane (50 mL) was added the particular amino
compound (22 mmol) at 2 – 4 ◦C. The resulting reaction was
then stirred at 20 ◦C for 24 h. In the case of compound 7a, the
particular amine (1-amino-4-methylpiperazine) was added at
r. t.,◦and the resulting reaction mixture was stirred at 40 –
45 C for 24 h. The solvent was then evaporated and the
residue recrystallized from the appropriate solvent. Yields
were in the range 60 – 91 %.
Methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-[(4-methyl-
piperazin-1-yl)amino]acrylate (7a)
Methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-N-(2,2-di-
methylhydrazino)acrylate (7d)
The compound was obtained as an off-white solid that was
recrystallized from chloroform / petroleum ether (b. p. 40 –
The solid product was recrystallized from chloro-
form/diethyl ether. Yield: 3.3 g (51 %), m. p. 93 – 95 C. –
◦
60 C). Yield: 4.9 g (65 %), m. p. 99 – 100 C. – 1H NMR
(300 MHz, CDCl3): δ = 2.32 (s, 3H, NCH3), 2.57 (m, 4H,
3ꢀ-H2 + 5ꢀ-H2), 2.97 (m, 4H, 2ꢀ-H2 + 6ꢀ-H2), 3.65, 3.67 (2s,
3H, OCH3, Z/E), 6.79, 6.91 (2s, 1H, H-4ꢀꢀ, Z/E), 8.33, 8.10
(2d, 1H, J = 11.6, 11.6 Hz, 3-H, Z/E), 11.08, 9.67 (2d, 1H,
J = 11.6, 11.6 Hz, NH, Z/E). – 13C NMR (75 MHz, CDCl3):
δ = 45.6 (NCH3), 51.4 (OCH3), 54.1 (C-3ꢀ + C-5ꢀ), 56.5
(C-2ꢀ + C-6ꢀ), 99.7 (C-2), 125.8 (C-3ꢀꢀ), 126.3 (C-4ꢀꢀ), 127.2
(C-5ꢀꢀ), 139.6 (C-2ꢀꢀ), 159.0 (C-3), 166.7 (C-1), 186.9, 183.9
(C-4, Z/E). – MS (EI, 70 eV): m/z (%) = 377 (23) [M]+, 342
(31), 310 (61), 282 (2), 179 (14), 144 (1), 116 (2), 99 (97). –
C14H17N3O3SCl2 (378.28): calcd. C 44.45, H 4.53, N 11.11;
found C 44.64, H 4.59, N 10.89.
◦
◦
1H NMR (300 MHz, CDCl3): δ = 2.70, 2.67 (2s, 6H,
N(CH3)2, Z/E), 3.65, 3.68 (2s, 3H, OCH3, Z/E), 6.79, 6.91
(2s, 1H, 4ꢀꢀ-H, Z/E), 8.33, 8.10 (2d, 1H, J = 11.6, 11.6 Hz,
3-H, Z/E), 11.08, 9.63 (2d, 1H, J = 11.6, 11.6 Hz, NH). –
13C NMR (75 MHz, CDCl3): δ = 48.7 (N(CH3)2), 51.4
(OCH3), 99.3, 100.3 (C-2, Z/E), 125.0 (C-3ꢀꢀ), 125.8 (C-5ꢀꢀ),
126.3, 127.2 (C-4ꢀꢀ, Z/E), 139.6 (C-2ꢀꢀ), 158.8, 159.1 (C-3,
Z/E), 166.7, 169.0 (C-1, Z/E), 186.8, 183.9 (C-4, Z/E). – MS
(EI, 70 eV): m/z (%) = 322 (67) [M]+, 287 (65), 255 (100),
227 (13), 179 (41), 116 (9), 44 (19). – C11H12N2O3SCl2
(323.20): calcd. C 40.88, H 3.74, N 8.67; found C 40.66,
H 3.89, N 8.88.
Methyl (R)-2-[(2,5-dichlorothien-3-yl)carbonyl]-3-N-(2-
hydroxy-1-methylethylamino)acrylate (7e)
Methyl 2-[(2,5-dichlorothien-3-yl)carbonyl]-3-[(morpholin-
4-yl)amino]acrylate (7b)
The solid product was recrystallized from methanol.
The compound was obtained as an oil. Yield: 5.8 g
1
Yield: 5.9 g (81 %), m. p. 118 – 119 ◦C. – 1H NMR (86 %). – H NMR (300 MHz, CDCl3): δ = 1.32, 1.30 (2d,
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
1629
3H, J = 6.4, 6.4 Hz, CHCH3, Z/E), 3.56 (m, 3H, CH2OH + then stirred at r. t.◦for 30 min. The temperature was allowed
CHMe), 3.63, 3.64 (2s, 3H, OCH3, Z/E), 4.20 (br s, 1H, to rise to 60 – 62 C and maintained at that temperature for
CH2OH), 6.78, 6.89 (2s, 1H, 4ꢀꢀ-H, Z/E), 8.17, 7.99 (2d, 2 – 3 h. The solvent was then evaporated, and the residue was
1H, J = 14.4, 14.4 Hz, 3-H, Z/E), 10.83, 9.42 (2dd, 1H, J = washed with water. The solid product was purified by crys-
14.4, 6.4 Hz / 14.4, 6.4 Hz, NH, Z/E). – 13C NMR (75 MHz, tallization from the appropriate solvent.
CDCl3): δ = 17.0 (CHCH3), 51.4, 51.2 (OCH3, Z/E), 57.9,
57.5 (CHMe, Z/E), 65.9, 66.1 (CH2OH, Z/E), 100.7, 100.4
(C-2, Z/E), 124.6 (C-3ꢀꢀ), 126.0 (C-5ꢀꢀ), 126.3, 126.1 (C-4ꢀꢀ,
Z/E), 139.9 (C-2ꢀꢀ), 159.9, 159.7 (C-3, Z/E), 167.5, 169.1
(C-1, Z/E), 186.8 (C-4). – MS (EI, 70 eV): m/z (%) = 337
(2) [M]+, 302 (100), 270 (4), 242 (1), 179 (62), 144 (2),
116 (2), 59 (9). – C12H13NO4SCl2 (338.21): calcd. C 42.62,
H 3.87, N 4.14; found C 42.53, H 3.78, N 4.06.
Methyl 2-chloro-7-(4-methylpiperazin-1-yl)-4-oxo-4,7-di-
hydrothieno[2,3-b]pyridine-5-carboxylate (8a)
The obtained solid was recrystallized from chloro-
◦
form/methanol. Yield: 4.5 g (82 %), m. p. 210 – 211 C. –
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3H, NCH3), 2.42
(br t, 2H, J = 10.5, 3ꢀ-H + 5ꢀ-H), 2.96 (br d, 2H, J = 10.2 Hz,
3ꢀ-H + 5ꢀ-H), 3.30 (br t, 2H, J = 10.2 Hz, 2ꢀ-H + 6ꢀ-H),
3.19 (br d, 2H, J = 10.5 Hz, 2ꢀ-H + 6ꢀ-H), 3.91 (s, 3H,
OCH3), 7.40 (s, 1H, 3-H), 8.58 (s, 1H, 6-H). – 13C NMR
(75 MHz, CDCl3): δ = 45.5 (NCH3), 52.4 (OCH3), 53.9
(C-3ꢀ + C-5ꢀ), 54.6 (C-2ꢀ + C-6ꢀ), 115.7 (C-5), 123.4 (C-3),
126.1 (C-4a), 131.5 (C-2), 139.2 (C-6), 149.2 (C-7a), 165.6
(CO2Me), 169.6 (C-4). – MS (EI, 70 eV): m/z (%) = 341
(74) [M]+, 242 (26), 211 (87), 183 (3), 99 (100), 56 (39),
53 (6). – C14H16N3O3SCl (341.82): calcd. C 49.19, H 4.72,
N 12.29; found C 48.99, H 4.69, N 11.99.
Methyl (S)-2-[(2,5-dichlorothien-3-yl)carbonyl]-3-N-(2-
hydroxy-1-methylethyl)acrylate (7f)
This compound was obtained as an oil. Yield: 5.7 g
(84 %). – C12H13NO4SCl2 (338.21): calcd. C 42.62, H 3.87,
N 4.14; found C 42.45, H 3.82, N 4.11. The spectral data
for this compound are in complete match with those of its
(R)-enantiomer.
Methyl (R)-2-[(2,5-dichlorothien-3-yl)carbonyl]-3-N-(2-
phenylethylamino)acrylate (7g)
Methyl 2-chloro-7-(morpholin-4-yl)-4-oxo-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylate (8b)
The compound was recrystallized from benzene/
petroleum ether. Yield: 6.5 g (85 %), m. p. 93 – 94 ◦C. –
1H NMR (300 MHz, CDCl3): δ = 1.67, 1.65 (2d, 3H, J =
6.9, 6.9 Hz, CHCH3), 3.60, 3.64 (2s, 3H, OCH3, Z/E), 4.65,
4.06 (2m, 1H, CHMe), 6.80, 6.87 (2s, 1H, 4ꢀꢀ-H, Z/E), 7.37,
7.29 (2m, 5H, Ph), 8.13, 7.93 (2d, 1H, J = 14.3, 14.2 Hz,
3-H, Z/E), 11.20, 9.70 (2dd, 1H, J = 14.3, 6.9 Hz / 14.3,
6.9 Hz, NH). – 13C NMR (75 MHz, CDCl3): δ = 23.0
(CHCH3), 51.3, 51.2 (OCH3, Z/E), 59.3, 58.9 (CHMe, Z/E),
101.0, 100.8 (C-2, Z/E), 125.7 (C-3ꢀꢀ), 126.0 (C-3ꢀ + C-5ꢀ),
126.3, 125.9 (C-4ꢀꢀ, Z/E), 127.1 (C-5ꢀꢀ), 128.3 (C-4ꢀ), 129.1
(C-2ꢀ + C-6ꢀ), 139.9 (C-2ꢀꢀ), 141.1, 141.2 (C-1ꢀ, Z/E), 158.8,
159.1 (C-3, Z/E), 166.7, 169.0 (C-1, Z/E), 186.8, 183.9 (C-4,
Z/E). – MS (EI, 70 eV): m/z (%) = 383 (2) [M]+, 348 (51),
316 (1), 288 (2), 179 (11), 151 (2), 116 (1), 105 (100). –
C17H15NO3SCl2 (384.28): calcd. C 53.14, H 3.93, N 3.64;
found C 53.3, H 4.16, N 3.56.
The solid obtained was recrystallized from chloro-
form/petroleum ether. Yield: 4.8 g (91 %), m. p. 200 – 202 ◦C
(dec.). – 1H NMR (300 MHz, CDCl3): δ = 3.17 (br d, 2H, J =
10.3 Hz, 3ꢀ-H + 5ꢀ-H), 3.31 (dt, 2H, J = 10.2, J = 3.0, 3ꢀ-H +
5ꢀ-H), 3.81 (dt, 2H, J = 10.3, J = 3.0 Hz, 2ꢀ-H + 6ꢀ-H), 4.07
(br d, 2H, J = 10.3 Hz, 2ꢀ-H + 6ꢀ-H), 3.93 (s, 3H, OCH3),
7.40 (s, 1H, 3-H), 8.55 (s, 1H, 6-H). – 13C NMR (75 MHz,
CDCl3): δ = 52.5 (OCH3), 54.5 (C-3ꢀ + C-5ꢀ) , 66.8 (C-2ꢀ +
C-6ꢀ), 115.9 (C-5), 123.4 (C-3), 126.1 (C-4a), 131.6 (C-2),
138.9 (C-6), 148.9 (C-7a), 165.7 (CO2Me), 169.4 (C-4). –
MS (EI, 70 eV): m/z (%) = 328 (43) [M]+, 242 (3), 211
(14), 183 (5), 86 (35), 56 (100), 53 (11). – C13H13N2O4SCl
(328.78): calcd. C 47.49, H 3.99, N 8.52; found C 47.46,
H 3.69, N 8.48.
Methyl 2-chloro-4-oxo-7-(piperidin-1-yl)-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylate (8c)
Preparation of methyl 7-(N-substituted amino)- and
7-alkyl-2-chloro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-
carboxylates 8a – g
The obtained solid was recrystallized from a mixture of
chloroform/diethyl ether. Yield: 4.6 g (88 %), m. p. 160 –
◦
162 C. – 1H NMR (300 MHz, CDCl3): δ = 1.84 (m, 6H,
General procedure
3ꢀ-H2 + 4ꢀ-H2 + 5ꢀ-H2), 3.01 (dt, 2H, J = 10.2, 2.1 Hz,
To a stirred solution of the particular methyl 3-(N- 2ꢀ-H + 6ꢀ-H), 3.28 (br d, 2H, J = 9.3 Hz, 2ꢀ-H + 6ꢀ-H),
substituted amino)- or methyl 3-(N-alkylamino)-2-[(2,5- 3.92 (s, 3H, OCH3), 7.40 (s, 1H, 3-H), 8.54 (s, 1H, 6-H). –
dichlorothien-3-yl)carbonyl]acrylate 7a – g (16 mmol) in dry 13C NMR (75 MHz, CDCl3): δ = 22.8 (C-4ꢀ), 26.1 (C-3ꢀ +
THF (70 mL) was added sodium hydride (80 % dispersion C-5ꢀ), 52.4 (OCH3), 55.7 (C-2ꢀ + C-6ꢀ), 115.6 (C-5), 123.3
in mineral oil; 0.5 g, 20 mmol). The reaction mixture was (C-3), 126.1 (C-4a), 131.5 (C-2), 139.2 (C-6), 149.4 (C-7a),
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
166.0 (CO2Me), 169.6 (C-4). – MS (EI, 70 eV): m/z (%) = 8.47 (s, 1H, 6-H). – 13C NMR (75 MHz, CDCl3): δ = 20.4
326 (5) [M]+, 242 (1), 211 (5), 183 (3), 84 (18), 53 (4), 50 (CHCH3), 52.5 (OCH3), 65.1 (CHMe), 115.2 (C-5), 123.0
(100). – C14H15N2O3SCl (326.80): calcd. C 51.45, H 4.63, (C-3), 125.5 (C-4a), 126.5 (C-3ꢀ + C-5ꢀ), 129.4 (C-4ꢀ), 129.5
N 8.57; found C 51.48, H 4.64, N 8.59.
(C-2ꢀ + C-6ꢀ), 133.3 (C-2), 137.1 (C-1ꢀ), 142.4 (C-6), 147.0
(C-7a), 166.2 (CO2Me), 169.8 (C-4). – MS (EI, 70 eV): m/z
(%) = 347 (45) [M]+, 289 (5), 243 (97), 211 (93), 185 (2),
183 (1), 105 (100), 53 (2). – C17H14NO3SCl (347.82): calcd.
C 58.71, H 4.06, N 4.03; found C 58.49, H 3.90, N 3.83.
Methyl 2-chloro-7-(dimethylamino)-4-oxo-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylate (8d)
The obtained solid was recrystallized from methanol.
Yield: 1.6 g (35 %), m. p. 203 – 204 ◦C. – 1H NMR
(300 MHz, CDCl3): δ = 2.96 (s, 6H, N(CH3)2), 3.93 (s, 3H,
OCH3), 7.40 (s, 1H, 3-H), 8.56 (s, 1H, 6-H). – 13C NMR
(75 MHz, CDCl3): δ = 46.2 (NCH3), 52.5 (OCH3), 115.9
(C-5), 123.3 (C-3), 126.2 (C-4a), 131.5 (C-2), 138.6 (C-6),
149.2 (C-7a), 166.0 (CO2Me), 169.6 (C-4). – MS (EI,
70 eV): m/z (%) = 286 (96) [M]+, 255 (10), 228 (100), 211
(49), 185 (39), 183 (17), 53 (23), 44 (16). – C11H11N2O3SCl
(286.74): calcd. C 46.08, H 3.87, N 9.77; found C 45.98,
H 3.69, N 9.55.
Preparation of methyl 7-(N-substituted amino)- and methyl
7-alkyl-2-chloro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-
carboxylic acids 9a – g; general procedure
The appropriate methyl 7-(N-substituted amino)- or
methyl 7-alkyl-2-chloro-4-oxo-4,7-dihydro[2,3-b]pyridine-
5-carboxylate 8a – g (5.0 mmol) was added to an ethanolic
solution of sodium hydroxide (40 mL, 2 M). The resulting
solution was stirred for 1 – 2 h, filtered, diluted with H2O
(40 mL) and then acidified with 8 % aqueous hydrochloric
acid. The precipitated product was collected by suction fil-
tration, washed with water, dried and recrystallized from the
appropriate solvent.
Methyl (R)-2-chloro-7-[N-(2-hydroxy-1-methylethyl)]-4-
oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (8e)
The obtained solid was recrystallized from chloro-
form/diethyl ether. Yield: 3.0 g (62 %), m. p. 180 – 181 C
◦
2-Chloro-7-(4-methylpiperazin-1-yl)-4-oxo-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylic acid (9a)
(dec.). – 1H NMR (300 MHz, [D6]DMSO): δ = 1.65 (d,
3H, J = 6.9 Hz, CHCH3), 3.65 (m, 2H, CH2OH), 3.85
(s, 3H, OCH3), 4.16 (m, 1H, CHMe), 7.40 (s, 1H, 3-H),
8.58 (s, 1H, 6-H). – 13C NMR (75 MHz, [D6]DMSO): δ =
15.7 (CHCH3), 52.5 (OCH3), 62.6 (CH2OH), 64.8 (CHMe),
115.9 (C-5), 122.0 (C-3), 125.5 (C-4a), 131.9 (C-2), 142.8
(C-6), 148.5 (C-7a), 165.1 (CO2Me), 169.7 (C-4). – MS (EI,
70 eV): m/z (%) = 301 (24) [M]+, 266 (11), 242 (26), 211
(23), 207 (67), 183 (20), 59 (94), 53 (100). – C12H12NO4SCl
(301.75): calcd. C 47.77, H 4.01, N 4.64; found C 47.81,
H 3.99, N 4.63.
The solid product was recrystallized from chloro-
form/diethyl ether. Yield: 1.36 g (83 %), m. p. 235 – 236 ◦C. –
1H NMR (300 MHz, [D4]CH3OH): δ = 3.00 (s, 3H, NCH3),
3.63 (m, 8H, 2ꢀ-H2 + 3ꢀ-H2 + 5ꢀ-H2 + 6ꢀ-H2)), 7.51 (s,
1H, 3-H), 9.13 (s, 1H, 6-H). – 13C NMR (75 MHz, D2O +
NaOD): δ = 45.5 (NCH3 ), 50.8 (C-3ꢀ + C-5ꢀ) , 53.3 (C-2ꢀ +
C-6ꢀ), 112.9 (C-5), 121.7 (C-3), 128.6 (C-4a), 129.0 (C-2),
141.4 (C-6), 151.0 (C-7a), 166.2 (CO2H), 173.4 (C-4). – MS
(EI, 70 eV): m/z (%) = 327 (17) [M]+, 283 (51), 229 (28),
211 (99), 185 (100), 157 (5). – C13H14N3O3SCl (327.79):
calcd. C 47.64, H 4.31, N 12.82; found C 47.57, H 4.29,
N 11.69.
Methyl (S)-2-chloro-7-[N-(2-hydroxy-1-methylethyl)]-4-
oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (8f)
2-Chloro-7-(morpholin-4-yl)-4-oxo-4,7-dihydrothieno[2,3-
b]pyridine-5-carboxylic acid (9b)
The obtained solid was recrystallized from chloro-
form/diethyl ether. Yield: 2.9 g (60 %), m. p. 180 – 181 C
◦
(dec.). – C12H12NO4SCl (301.75): calcd. C 47.77, H 4.01,
N 4.64; found C 47.72, H 3.89, N 4.61. The spectral data
for this compound are in complete match with those of its
(R)-enantiomer (compound 8e).
The solid compound was obtained by recrystallization
from chloroform/petroleum ether. Yield: 1.37 g (87 %), m. p.
◦
245 – 246 C (dec.). – 1H NMR (300 MHz, CDCl3): δ =
3.20 (br d, 2H, J = 10.0 Hz, 3ꢀ-H + 5ꢀ-H), 3.37 (dt, 2H,
J = 10.3, J = 2.2 Hz, 3ꢀ-H + 5ꢀ-H), 3.82 (dt, 2H, J = 10.3,
J = 2.2 Hz, 2ꢀ-H + 6ꢀ-H), 4.07 (br d, 2H, J = 10.0 Hz,
2ꢀ-H + 6ꢀ-H), 7.46 (s, 1H, 3-H), 8.86 (s, 1H, 6-H), 15.05
Methyl (R)-2-chloro-7-[N-(2-phenylethyl)]-4-oxo-4,7-di-
hydrothieno[2,3-b]-pyridine-5-carboxylate (8g)
The obtained solid was purified by recrystallization from (s, 1H, CO2H). – 13C NMR (75 MHz, CDCl3): δ = 54.8
chloroform/diethyl ether. Yield: 4.7 g (85 %), m. p. 178 – (C-3ꢀ + C-5ꢀ) , 66.7 (C-2ꢀ + C-6ꢀ), 113.8 (C-5), 122.2 (C-3),
◦
180 C. – 1H NMR (300 MHz, CDCl3): δ = 1.99 (d, 3H, 128.6 (C-4a), 129.3 (C-2), 138.4 (C-6), 151.2 (C-7a), 166.0
J = 7.0 Hz, CHCH3), 3.90 (s, 3H, OCH3), 5.30 (q, 1H, (CO2H), 173.2 (C-4). – MS (EI, 70 eV): m/z (%) = 314
J = 7.0 Hz, CHMe), 7.40 (m, 5H, Ph), 7.42 (s, 1H, 3-H), (19) [M]+, 270 (100), 229 (2), 211 (7), 185 (30), 157 (4), 86
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H. I. Al-Jaber et al. · Thienopyridone Antibacterials
1631
(36). – C12H11N2O4SCl (314.75): calcd. C 45.79, H 3.52, (75 MHz, [D6]DMSO): δ = 15.4 (CHCH3), 62.6 (CH2OH),
N 8.90; found C 45.83, H 3.60, N 8.66.
65.8 (CHMe), 111.8 (C-5), 121.5 (C-3), 126.0 (C-4a), 129.0
(C-2), 142.3 (C-6), 150.7 (C-7a), 165.7 (CO2H), 172.7
(C-4). – MS (EI, 70 eV): m/z (%) = 287 (19) [M]+, 269 (11),
243 (100), 211 (15), 185 (51), 183 (3), 157 (7), 59 (7). –
C11H10NO4SCl (287.72): calcd. C 45.92, H 3.50, N 4.87;
found C 45.89, H 3.60, N 4.88.
2-Chloro-4-oxo-7-(piperidin-1-yl)-4,7-dihydrothieno-
[2,3-b]pyridine-5-carboxylic acid (9c)
The pure compound was obtained by recrystallization
from chloroform/petroleum ether. Yield: 1.25 g (80 %), m. p.
250 – 251 ◦C. – 1H NMR (300 MHz, [D6]DMSO): δ = 1.30
(m, 6H, 3ꢀ-H2 + 4ꢀ-H2 + 5ꢀ-H2), 1.66 (br t, 2H, J = 13.0 Hz,
2ꢀ-H + 6ꢀ-H), 1.83 (br d, 2H, J = 12.0 Hz, 2ꢀ-H + 6ꢀ-H),
7.60 (s, 1H, 3-H), 9.22 (s, 1H, 6-H), 15.38 (s, 1H, CO2H). –
13C NMR (75 MHz, [D6]DMSO): δ = 22.5 (C-4ꢀ), 26.4
(C-3ꢀ + C-5ꢀ), 54.8 (C-2ꢀ + C-6ꢀ), 112.9 (C-5), 121.9 (C-3),
127.1 (C-4a), 127.8 (C-2), 140.6 (C-6), 152.3 (C-7a), 165.2
(CO2H), 172.6 (C-4). – MS (EI, 70 eV): m/z (%) = 312
(21) [M]+, 268 (93), 229 (1), 211 (4), 185 (21), 183 (1), 157
(4), 84 (100). – C13H13N2O3SCl (312.78): calcd. C 49.92,
H 4.19, N 8.96; found C 49.91, H 4.18, N 8.94.
(S)-2-Chloro-7-[N-(2-hydroxy-1-methylethyl)]-4-oxo-4,7-
dihydrothieno[2,3-b]pyridine-5-carboxylic acid (9f)
The pure compound was obtained by recrystallization
from chloroform/diethyl ether. Yield: 1.15 g (80 %), m. p.
◦
249 – 250 C. – C11H10NO4SCl (287.72): calcd. C 45.92,
H 3.50, N 4.87; found C 45.89, H 3.60, N 4.88. The spec-
tral data for this compound are identical to those obtained
for its (R)-enantiomer (compound 9e).
(R)-2-Chloro-7-N-(2-phenylethyl)-4-oxo-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylic acid (9g)
2-Chloro-7-( N,N-dimethylamino)-4-oxo-4,7-dihydro-
thieno[2,3-b]pyridine-5-carboxylic acid (9d)
The pure compound was obtained after recrystallization
from chloroform/petroleum ether. Yield: 1.47 g (88 %), m. p.
192 – 193 ◦C. – 1H NMR (300 MHz, CDCl3): δ = 2.04
(d, 3H, J = 6.9 Hz, CHCH3), 5.43 (q, 1H, J = 6.9 Hz,
CHMe), 7.44 (m, 5H, Ph), 7.46 (s, 1H, 3-H), 8.78 (s, 1H,
6-H), 15.12 (s, 1H, CO2H). – 13C NMR (75 MHz, CDCl3):
δ = 20.6 (CHCH3), 66.3 (CHMe), 112.9 (C-5), 121.6 (C-3),
126.5 (C-3ꢀ + C-5ꢀ), 127.9 (C-4a), 129.7 (C-2ꢀ + C-6ꢀ), 129.8
(C-4ꢀ), 130.6 (C-2), 136.2 (C-1ꢀ), 141.6 (C-6), 149.0 (C-7a),
166.6 (CO2H), 173.4 (C-4). – MS (EI, 70 eV): m/z (%) =
333 (32) [M]+, 289 (72), 229 (99), 211 (15), 185 (23),
183 (5), 157 (3), 105 (100). – C16H12NO3SCl (333.80):
calcd. C 57.57, H 3.62, N 4.20; found C 57.32, H 3.48,
N 4.14.
The compound was recrystallized from chloroform/
petroleum ether. Yield: 0.90 g (66 %), m. p. 210 – 211 ◦C
(dec.). – 1H NMR (300 MHz, CDCl3): δ = 3.01 (s, 6H,
N(CH3)2), 7.43 (s, 1H, 3-H), 8.87 (s, 1H, 6-H), 15.17 (s, 1H,
CO2H). – 13C NMR (75 MHz, CDCl3): δ = 46.5 (N(CH3)2),
113.9 (C-5), 122.0 (C-3), 128.7 (C-4a), 129.1 (C-2), 138.0
(C-6), 151.4 (C-7a), 166.2 (CO2H), 173.1 (C-4). – MS (EI,
70 eV): m/z (%) = 272 (46) [M]+, 228 (100), 210 (25), 185
(99), 182 (3), 157 (8), 44 (28). – C10H9N2O3SCl (272.71):
calcd. C 44.04, H 3.33, N 10.27; found C 43.81, H 3.42,
N 10.07.
(R)-2-Chloro-7-[N-(2-hydroxy-1-methylethyl)]-4-oxo-4,7-
dihydrothieno[2,3-b]pyridine-5-carboxylic acid (9e)
Acknowledgements
We thank the Deanship of Scientific Research, The Uni-
versity of Jordan (Amman, Jordan), the Deanship of Grad-
uate Studies and Research of Sharjah University (Sharja,
UAE), and the DFG and DMBF (Bonn, Germany) for finan-
cial support. We are grateful to Prof. Miche`le Calas (Univer-
site´ de Montpellier, France) for obtaining the antibacterial
testing data.
The pure compound was obtained by recrystallization
from chloroform/diethyl ether. Yield: 1.18 g (82 %), m. p.
249 – 250 ◦C. – 1H NMR (300 MHz, [D6]DMSO): δ = 1.65
(d, 3H, J = 6.8 Hz, CHCH3), 3.82 (m, 2H, CH2OH), 4.46 (m,
1H, CHMe), 5.35 (t, 1H, J = 5.4 Hz, CH2OH), 7.66 (s, 1H,
3-H), 8.80 (s, 1H, 6-H), 15.48 (s, 1H, CO2H). – 13C NMR
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