Synthesis and screening of quinolone antibiotic isosteres

Article abstract of DOI:10.3184/030823408X389372

Condensation of either 4-(benzothiazol-2-yl)phenylamine 1 or 4-amino-2-(benzothiazol-2-yl)-phenol 2 with ethyl cyanoethoxyacrylate or diethyl ethoxymethylenemalonate (EMME) followed by intra molecular thermal cyclisation results in substituted quinolones

Full text of DOI:10.3184/030823408X389372

JOURNAL OF CHEMICAL RESEARCH 2008
DECEMBER, 715-718
RESEARCH PAPER 715
Synthesis and screening of quinolone antibiotic isosteres
Mohamed. A. Shabana, Ossama M. AI Badryb, Aliaa M. Kamala* and
Mohamd Abd el Wahap Abd EI-Gawadc
aDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr EI-Aini 11562, Cairo, Egypt
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, AI-Ahram Canadian University, Cairo, Egypt
CDepartment of Organic Chemistry, Faculty of Pharmacy, Beni-swef University, Beni-swef, Egypt
Condensation of either 4-(benzothiazol-2-yl)phenylamine
cyanoethoxyacrylate or diethyl ethoxymethylenemalonate
1 or 4-amino-2-(benzothiazol-2-yl)-phenol
(EMME) followed by intra molecular thermal cyclisation
2 with ethyl
results in substituted quinolones which upon alkylation then base-hydrolysis yielded the target compounds
6-(benzoth iazol-2-yl )-1-aIkyl-4-oxo-1 ,4-d ihyd roq uinol ine-3-ca rboxyl ic acid (3a,b); 7-(benzothi azol-2-yl )-1-alkyl-4-oxo-
1,4-dihydro-6-alkoxyquinoline-3-carboxylic
acid (4a,b). Meanwhile diazotisation of 4-(benzothiazol-2-yl)phenylamine
(1) followed
by reaction with malononitrile
then intra molecular Friedel-Crafts acylation gave 4-amino-6-
(benzothiazol-2-yl)cinnoline-3-carbonitrlie
5. The antimicrobial activity of some of the target compounds using gram-
positive microbes (Staphylococcus aureus and Bacillus subtilis) and gram-negative bacteria (Escherichia coli and
Pseudomonas aeruginosa) is carried out and 6-(benzothiazol-2-yl)-1-alkyl-4-oxo-1,4-dihydro
acid (3a,b) and 7-(benzothiazol-2-yl)-1-alkyl-4-oxo-1,4-dihydro-6-alkoxyquinoline-3-carboxylic
promising activity.
quinoline-3-carboxylic
acid (4a,b) showed
Keywords: quino10nes, benzothiazo1es, isosteres, pyridinone carboxylic acid, antibiotics
Quino10nes are very promising class of antibiotics since they
have been proved to exhibit broad spectrum, potent activity
and good pharmacokinetics properties. Many clinically
important antibacterial agents having a quino10ne moiety
and collectively known as quino10nes have been discovered.
Modification ofthe groups which occupy the N-1, C-7 and C-8
positions has been successful in yielding potent antibacterial
agents Fig. 1.1,2
Results and discussion
Synthesis of the target compounds 3-5 is illustrated in
Scheme 1. This shows preparation of the aminophenyl-
benzothiazoles 1 and 2 is via cyclodehydration reaction
between 2-aminothiophenol and either 4-aminobenzoic
acid (PABA) or 5-aminosalicylic acid sequentially using
polyphosphoric acid (PPA) as a dehydrating agent. Several
dehydrating agents have been reported, however, PPA is
the reagent of choice since it documented that it gave good
yield4-11 and this is the procedure that was adapted
herein.l l Reaction of compounds 1 and 2 with either ethyl
cyanoethoxyacrylate or diethyl ethoxymethylenemalonate
in refluxing ethanol is through Michael addition followed
by elimination of ethanop2-14to give rise to two geometrical
isomers (ZE) in nearly equimolar amounts, so there is no
significant steric effect between the two isomers.
eooH
The structure-activity relationship studies concluded that, for
optimal antimicrobial activity of any quino10ne antibiotics
position 1 should have either a methyl or an ethyl group or
its bioisosteres such as fluoroethy1, methy1amino, methoxy
etc. while position 2 requires a hydrogen atom for maximum
antimicrobial potency. Positions 3 and 4 are a link between
the carboxylic acid group and the keto group, and are
generally considered necessary for binding of quino10nes
to DNA gyrase.I,3 Classical studies have produced no
active quino10nes with a significant modification of the C-3
carboxylic acid group. For position 4, it has been extensively
explored, and replacement of the 4-keto group with other
groups so far has led to inactive compounds. Of the various
C-6 substituents (H, F, C1, Br, CH3, SCH3, COCH3, CN and
N02), the addition of a fluorine atom resulted in a dramatic
increase in antibacterial potency. 1The "medium size" concept
concerning the 7-substituents is no longer valid. Numerous
potent quino10nes with a large group at position 7 have been
discovered. A certain amount of free rotation in the position
7-substituents appears to emerge as an important factor which
influences the activity of the compounds.2 The objective of
this work is to synthesise compounds that are a combination
between quino10ne nucleus and another higWy antimicrobial
nucleus, e.g. benzothiazo1e moiety, to evaluate the activity
and whether a synergistic effect will occur or there is no
pronounced change in the activity.
The IR spectra of compounds 6b and 7b showed two
values of the carbonyl of the two ester groups and this may be
attributed to the formation of intra molecular hydrogen bond
as shown in Fig. 2.
( }-<{:::'
H----O
Examination of IH NMR spectrum of compounds 6a and
7a suggested the presence of two geometrical isomers (ZE)
Fig. 3. This was indicated by the appearance of two single
peaks each equal to 0.5 proton and do not disappear after D20
addition at 8 8.42 and 8.62 ppm (2 s, O.5H,CH=C). In the case
of compounds 6b and 7b there is a doublet signal at 8 8.48
ppm for CH=C. This is due to the exchange of the NH proton
which was coupled with CH=C.
~R71
~R71
::,.. ~COOC2H5
~s
::,..
~s
I
I
,N
H~
_
CN
-COOC2H5
I
I
,N _
::,..
N
::,..
N
H
~
H
CN
(E)
(Z)
R= H, OH
Compounds 6a,b and 7a,b were exposed to intra molecular
cycloacylation reaction in a high boiling point solvent-
diphenyl ether- to yield the unalkylated 4-quinolones 8a,b and
* Correspondent. E-mail: K_aliaa2@hotmail.com

716 JOURNAL OF CHEMICAL RESEARCH 2008
R
0
R
0
W
: I I COOH 0XrYCOOC;!-l5
NaOH
? '
I
I
S,
N
- 1
£
- - -
S
::,...
N
&N
k
cYN
R
(4 a,b)
(11a,b)
CDOG,H5
;t)HO"c,,.O...J.
CCSH
I ~
. #
5-aminosalicylic aci:
s" ~
~
~~'I
~N
~
NH2
R1=0<
NH2 PPA
CCXlC,f-l,
(2)
(9a,b)
(7a,b)
Scheme
1
9a,b according to the basic Gould-Jacob reaction.3 Alkylation
of the latter compounds was achieved using different alkylating
agents in DMF to allow SN2reaction to take place and afford
the alkylated ester derivatives of the 4-quinolone 10a-d and
lla,b. Alkylation of9a resulted in the dialkyl derivative since
both N- and 0 - were alkylated and this was confirmed using
IH NMR and mass spectrometry.
The base hydrolysis of compounds 10a-d and lla,b to give
the target compounds 3a,b and 4a,b was carried out in THF
rather than water to overcome the poor solubility of these
compounds in water and to avoid the ease of decarboxylation
of ~-keto acids upon boiling with aqueous sodium hydroxide. 15
Diazotisation of compound 1 followed by coupling of the
diazonium salt with either diethyl malonate or malononitrile
in basic medium gave compounds 12 and 13 respectively.
The basic medium of this reaction was achieved by using one
equivalent of sodium acetate to convert either diethyl malonate
or malononitrile into the mono-sodio derivative as a result of
removal of one a-proton to yield an ambident anion.16 This
conjugated base will be stabilised by resonance and will react
with the diazonium salt to yield compounds 12 and 13.
Once again the IR spectrum of compound 12 showed
two values of the two carbonyl of the two ester groups and
this can be attributed to the formation of intra molecular
hydrogen bond.
Several attempts were made to prepare 4-oxo-l,4-dihydro-
cinnoline-3-carboxylic acid using compound 12 but all trials
were unsuccessful.
Heating compound 12 with diphenyl ether for 1 hour
(cf. quinolone synthesis) resulted in a compound which
Table 1 Anti-infective activity
Compound
Ps. aeruginosa
St. aureus
E. coli
B. subtilis
3a
3b
4a
<100
<200
<25
>400
<200
<25
<400
<400
>400
<400
<400
<25
4b
<25
<25
>400
>25
5
<400
< 12.50
<200
< 12.50
>400
< 12.50
>400
<12.50
Ciproflexacin

JOURNAL OF CHEMICAL RESEARCH 2008 717
(0.02 mol) in ethanol (60 ml) was refluxed for 4 h, the reaction
mixture was evaporated under reduced pressure and the separated
solid was crystallised from ethanol.
6a (A=CN): Yield 80%; m.p. 174-178°C; IR (KBr): 3421 (NH),
2981-2930 (CH aliphatic) and 2212 (CN) em-I; IH NMR (300 MHz,
DMSO-d6): /) 1.26(t, 3H, CH2CH3), 4.21 (q, 2H,CH2CH3), 7.42-8.13
(m, 8H, ArH), 8.42, 8.62 (2 s, O.5H, CH=C) and 10.85, 11.00 (2 s,
0.5 H, HN, D20 exchangeable) ppm; ElMS: m/z 349 (M+) (100%);
Anal.Calcd for CI9HISN302S: C, 65.31; H, 4.33; N, 12.03. Found;
C, 65.80; H, 4.02; N, 12.03%.
6b (A =COOC2Hs): Yield 75%; m.p. 135-137°C; IR (KBr):
3421 (NH), 2981-2930 (CH aliphatic) and 1676-1671 (C=O) em-I;
IH NMR (300 MHz,DMSO-d6): /) 1.26(m, 6H, 2CH2CH3), 4.22
(m, 4H, 2CH2CH3), 7.42-8.13 (m, 8H, ArH), 8.48 (d, lH, CH=C)
and 10.87 (d, 1 H, HN, D20 exchangeable) ppm; Anal.Calcd for
C2IH2oN204S: C, 63.62; H, 5.08; N, 7.07. Found: C, 63.38; H, 4.86;
N,7.23%.
7a (A =CN): Yield 60%; m.p. 199-204 °C; IR (KBr): 3446-3271
(NH and OH), 2984-2927 (CH aliphatic), 2210 (CN) and 1671 (C=O)
em-I; IH NMR (300 MHz, DMSO-d6): /) 124 (t, 3H, CH2CH3), 4.19
(q, 2H, CH2CH3), 7.06-8.29 (m, 7H, ArH), 8.38, 8.42 (2 s, O.5H,
CH=C), 10.75, 10.80 (2 s, 0.5 H, HN, D20 exchangeable) and 11.00
(s, 1 H, OH, D20 exchangeable) ppm; ElMS: m/z 365 (M+) (100%);
Anal.Calcd for CI9HISN303S: C, 62.45; H, 4.14; N, 11.50. Found; C,
62.40; H, 4.40; N, 11.35%.
spectral data indicated is neither compound 12 nor ethyl 4-
oxo-l,4-dihydrocinnoline-3-carboxylate.
According to both physical constant (m.p. 322-324°C) and
spectral data, it was found that the given compound was 2-[4-
(benzothiazol-2-yl)phenylhydrazono) acetic acid.12-14The IR
spectrum showed band s at 3325-3266 (NH) cm-1, 1690 (CO)
cm-1and the disappearance of band sat 1657 (CO) cm-1and
2983-2930 (CH) aliphatic cm-1which indicated the hydrolysis
and decarboxylation of one ofthe carboxylic groups. The mass
spectrum of the unexpected compound is m/z 297(13.19%).
Another trial took place when heating compound 12 with
either PPA for 3 hours or with A1C13/cWorobenzene for
6 hours (tracing both reactions with TLC) afforded a compound
which was not compound 12 or cinnolone derivative. Upon
examining the spectral data besides its melting point it was
found that the resulting compound was N-4-(benzothiazol-2-
yl)phenyl-N'-methylene hydrazine.16-17IR spectrum revealed
the disappearance of band s at 2983-2930 cm-1 and band
s at 1690 and 1657 cm-1 and this indicated that surprisingly
hydrolysis and decarboxylation of both carboxylic groups
occured. This may be due to the more drustic conditions of
both reactions and this was confirmed by 1H NMR (DMSO-
d6): 84.16 (s, lH, HN-N=C, D20 exchangeable), 6.95 (s, 2H,
N=CH2) and 7.34-8.05 (m, 8H, ArH) ppm.
7b (A =COOC2Hs): Yield 80%; m.p. 154-156°C; IR (KBr):
3446-3271 (NH and OH),2981-2930 (CH aliphatic), 1705 (C=O)
and 1648 (C=O) em-I; IH NMR(300 MHz, DMSO-d6): d 1.26(t,
6H,2 CH2CH3), 4.19 (q, 4H, 2CH2CH3), 7.10-8.16 (m, 7H, ArH),
8.34-8.39 (d, lH, CH=C), 10.74 (d, 1 H, HN, D20 exchangeable)
and (100%); Anal.Calcd for C2IH2oN20SS: C, 61.15; H, 4.89; N,
6.79.Found; C, 61.06; H, 4.73; N, 6.70%.
From the previously mentioned attempts it was concluded
that hydrolysis and decarboxylation of either one or the two
carboxylic moieties (according to the reaction time) is faster
than intra molecular cyclisation. Cyclisation of compound
13 adopting Friedel-Crafts intra molecular acylation method
using A1C13/chlorobenzene16-17 resulted in 4-amino-3-
cyanocinnoline 5.
6-(Benzothiazol- 2-yl)-4-oxo-l, 4-dihydroquinoline- 3-carbo-nitrile(8a);
ethyl 6-(benzothiazol-2-yl)-4-oxo-I,4-dihydro-quinoline-3-carboxylate
(8b); 7-(Benzothiazol-2-yl)-4-oxo-l, 4-dihydro-6-hydroxy-quinoline-3-
carbonitrile (9a) and Ethyl 7-(Benzothiazol-2-yl)-4-oxo-I,4-dihydro-
6-hydroxyquinoline-3-carboxylate (9b)
Conclusions
A solution of compound 6a, 6b, 7a or 7b, (0.01 mol) in diphenyl
ether (30 ml) was refluxed for 1 h, cooled, diluted with ether
(100 ml) then filtered. The formed precipitate was washed with pet
ether (40-60), dried and crystallised from DMF.
Since quinolone anti-infective agents have broad spectrum
activity, the tested compounds were evaluated against
different microorganisms including gram-positive microbes
(Staphylococcus aureus and Bacillus subtilis) and gram-
negative bacteria (Escherichia coli and Pseudomonas
aeruginosa) using the agar-dilution method according to
the National Committee for Clinical Laboratory Standards
(NCCLS). The results were expressed as MIC using
ciprofloxacin as reference stand ard. Compounds 4a and 4b
show strong and moderate antibacterial activity while 3a and
3b, showed a moderate activity since they lack the C-6 high
electronegative atom that can form hydrogen bonding and
there is no substituent at C-7 and compound 5 revealed weak
activity since it only has about 30% of the criteria that should
be present in any structure to show the perfect quinolone
antibiotics-like anti-infective activity (Table 1).
8a (A=CN): Yield 70%; m.p. >300°C; IR (KBr): 3446 (NH) and
2216 (CN) em-I; IH NMR (300 MHz, DMSO-d6): /)7.46-8.74 (m,
7H, ArH), 8.80(s, lH, CH=C) and 13.00 (s, 1 H, HN,exchangeable)
ppm; ElMS: m/z 303 (M+) (100%); Anal.Calcd for C17H~30S:C,
67.31; H, 2.99; N, 13.85. Found; C, 67.06; H, 3.50; N, 13.62%.
8b (A =COOC2Hs): Yield 75%; m.p. >300°C; IR (KEr): 3421
(NH), and 1631 (C=O) em-I; IH NMR (300 MHz, DMSO-d6): /) 129
(t, 3H, CH2CH3), 4.24 (q, 2H, CH2CH3), 7.46-8.74 (m, 7H, ArH),
8.80(s, lH, CH=C) and 12.60 (s, 1 H, HN, D20 exchangeable) ppm;
Anal.Calcd for CI~I4N203S: C, 65.13; H, 4.03; N, 7.99. Found: C,
65.11; H, 3.80; N, 7.85%.
9a (A=CN): Yield 60%; m.p. >300°C; IR (KBr): 3446-3231 (NH
and OH), 2211(CN), and 1671 (C=O)cm-I; IH NMR (300 MHz,
DMSO-d6): /) 6.92-8.72 (m, 6H, ArH), 8.78 (s, lH, CH=C) and
12.00-12.10 (br s, 2 H, HN and OH, D20 exchangeable) ppm; ElMS:
m/z 319 (M+) (19.8%); Anal.Calcd forr C17H~302S: C, 63.94; H,
2.84; N, 13.16.Found; C, 63.80; H, 2.80; N, 12.94%.
Experimental
9b (A =COOC2Hs): Yield 65%; m.p. >300°C; IR (KBr): 3446-
3231 (NH and OH), 2211(CN), 1703 (C=O) and 1652 (C=O) em-I;
IH NMR (300 MHz, DMSO-d6): /) 1.27 (t, 3H, CH2CH3), 4.20
(q, 2H, CH2CH3), 6.98-8.66 (m, 6H, ArH), 8.78 (s, lH, CH=C) and
11.55-11.65 (s, 2 H, HN and OH, D20 exchangeable) ppm; ElMS:
m/z 366 (M+) (33%); Anal.Calcd for CI~I4N204S: C, 62.29; H, 3.85;
N, 7.65.Found; C,62.30; H,3.70; N, 7.68%.
Melting points were determined in capillary tubes using Griffin
apparatus and are uncorrected. Chemical analyses were carried out
at the Microanalytical Centre, Cairo University, Giza, Egypt. Infrared
spectra were measured on a Schimadzu IR 435 spectrometer. Proton
magnetic resonances (lH NMR) were measured at 300 MHz on
Varian Gemini spectrophotomer using tetramethylsilane as internal
standard (chemical shifts are reported in /) ppm). Mass spectra were
obtained on Hewlett Packard 5988 spectrometer.
6-(B enzothiazol-2 -yl)-I-alkyl-4-oxo-l,
4-dihydroquinoline-3-
The following compounds were prepared according to the same
carbonitrile (IOa,b); Ethyl 6-(Benzothiazol-2-yl)-I-alkyl-4-oxo-I,4-
dihydroquinoline-3-carboxylate (IOe,d) and ethyl 7-(benzothiazol-
reported procedure:
4-benzothiazol-2-yl-phenylarnine(I)I8
and
amino-2-(benzothiazol-2-yl)phenol (2).19
2-yl)-I-alkyl-4-oxo-l,
4-dihydro-6-alkoxyquinoline-3
-carboxylate
(lla,b).
Ethyl 3-[(4-Benzothiazol-2-yl)phenylaminoj-2-cyanoacrylate
(6a);
A mixture of compound 8a, 8b or 9b (0.01 mol), anhydrous potassium
carbonate (0.025 mol) and the appropriate alkyl halide (0.05 mol)
in DMF (50 ml) was heated at 80-90°C for 18-36 h. The reaction
mixture was evaporated to dryness and the residue was extracted
with ethyl acetate (50 ml). The organic layer was dried (Na2S04)'
evaporated to dryness then the residue was crystallised from DMF.
Diethyl 2-[(4-benzothiazol-2-yl)phenylamino jmethylenej malonate
(6b); ethyl 3-[(3-Benzothiazol-2-yl)-4-hydroxyphenylamino j -2-cyano-
acrylate (7a) and diethyl 2-[-(4-Benzothiazol-2-yl)-4-hydroxyphenyl-
aminojmethylenejmalonate (7b).
Equimolar amounts of either compound I or 2 (0.02 mol) with either
ethyl 2-cyano-3-ethoxyacrylate or diethyl ethoxymethylenemalonate

718 JOURNAL OF CHEMICAL RESEARCH 2008
10a-d: lR (KEr): 2966-2877 (CH aliphatic), 2222-2207 (CN),
1717-1709 (C=O) and 1631-1627 (C=O) em-I.
(s, 1 H, OH, D20 exchangeable) ppm; ElMS: m/z 350 (M+) (12.3%);
Anal. Calcd for CI~I~203S:
65.52; H, 3.96; N, 7.76%.
C, 65.13; H, 4.03; N, 7.99. Found: C,
10a(R =CH3,A=CN): Yield45%;m.p.>300°C; IHNMR(300MHz,
DMSO-d6): /)3.90 (s, 3H, CH3), 7.46-8.74 (m, 7H, ArH) and 8.81
(s, lH, CH=C) ppm; ElMS: m/z 317(M+) (100%); Anal.Calcd for
CIsHllN30S: C, 68.12; H, 3.49; N, 13.24.Found; C, 68.04; H,3.56;
N,13.20%.
lOb (R=C2Hs,A=CN): Yield 50%; m.p.> 300°C; ElMS:
m/z 331(M+) (100%); Anal.Calcd for CI9H13N30S: C, 68.86; H, 3.95;
N, 12.68. Found: C, 68.70; H, 4.00; N, 12.72%.
10e (R =CH3, A =COOC2Hs): Yield 47%; m.p. > 300°C; IH NMR
(300 MHz, DMSO-d6): /) 1.29 (t, 3H, CH2CH3), 3.90 (s, 3H, CH3),
4.23 (q, 2H, CH2CH3), 7.48-8.78 (m, m,ArH) and 8.84 (s, lH, CH=C)
ppm; EIMS: m/z 364 (M+) (1.6%); Anal.Calcd for C2oHI~203S: C,
65.92; H,4.43; N, 7.69. Found: C, 65.80; H, 4.50; N,7.67%.
10d (R =C2Hs, A =COOC2Hs): Yield 43%; m.p. > 300°C; IH NMR
(300 MHz, DMSO-d6): /) 1.1871.36 (m, 6H, 2CH2CH3), 4.18-4.46
(m, 4H, 2CH2CH3), 7.00-8.71 (m, 7H, ArH) and 8.83 (s, lH, CH=C)
ppm; Anal.Calcd for C2IHIsN203S:C, 66.65; H,4.79; N, 7.40. Found:
C, 66.52; H,4.64; N, 7.85%.
4a,b: lR (KEr): 3500-3000 (OH), 2961 (CH aliphatic), 1672, 1652
(C=O) and 1621, 1611 (C=O) em-I.
4a (R =CH3): Yield 70%; m.p. >300°C; IH NMR (300 MHz,
DMSO-d6): /) 4.39 (s, 6H, NCH3 and 0 CH3), 7.45-8.84 (m, 6H,
ArH), 8.92 (s, lH, CH=C) and 12.00 (s, 1 H, OH, D20 exchangeable)
ppm; ElMS: m/z 366 (M+) (18%); Anal.Calcd for CI9HI~204S: C,
62.28; H, 3.85; N, 7.65. Found: C, 62.50; H, 3.56; N, 7.67%.
4b (R = C2Hs): Yield 50%; m.p. >300°C; IH NMR (300 MHz,
DMSO-d6): /) 1.52 (t, 3H, NCH2CH3), 1.59(t, 3H, OCH2CH3), 4.42-
4.46 (q, 2H, NCH2CH3),
4.65 (q, 2H, OCH2CH3), 7.49-8.15 (m, 5H,
ArH), 8.87(s, lH, Ar H, 9.02 (s, lH, CH=C) and 15.09 (s, 1 H, OH,
D20 exchangeable)ppm; ElMS: m/z 395 (M++ 1) (28%); Anal.Calcd
for C2IHIsN204S: C, 63.94; H, 4.60; N, 7.10. Found: C, 64.12; H,
4.54; N, 7.14%
4-Amino-6-(benzothiazol-2-yl)cinnoline-3-carbonitrlie
(5): A mixture
of compound 12 (0.01 mol), anhydrous aluminum chloride
(0.04 mol) and chlorobenzene (30 ml) was refluxed for 6 h,
hydrochloric acid (2N,20 ml) was then added portionwise under
ice cooling to the reaction mixture which was then heated at 90°C
for 10 min, cooled and set aside. The separated solid was filtered,
washed with absolute ethanol. The salt was neutralised with saturated
solution of sodium carbonate. The solid product was collected and
crystallised fromDMF to give 1.51 gm of5 (50%); m.p. 253-255°C;
lR (KEr): 3382-3219 (NH2), 2223 (CN) em-I; IH NMR (300 MHz,
DMSO-d6): /)5.86 (s, 2H, NH2, D20 exchangeable) and 6.64-8.12
(m, 7H, ArH) ppm; Anal.Calcd for CI6H9NsS: C, 63.35; H, 2.99; N,
23.09. Found: C, 63.92; H, 3.11; N, 23.09%.
11a, b: lR (KEr): 2966-2877 (CH aliphatic), 1704 (C=O) and
1610 (C=O) em-I.
11a (R =CH3,A =COOC2Hs): Yield 50%; m.p. > 300°C; IH NMR
(300 MHz, DMSO-d6): /) 1.19 (t, 3H, CH2CH3), 3.82-4.15 (m, 8H,
CH2CH3, NCH3 and OCH3) 7.05-8.21 (m, 6H, ArH) and 8.56 (s,
lH, CH=C) ppm; Anal.Calcd for C2IHIsN204S: C, 63.94; H, 4.60;
N, 7.10. Found: C, 63.70; H, 4.41; N, 7.15%.
11b (R =C2Hs,A=COOC2Hs):Yield 50%; m.p.> 300°C; IH NMR
(300 MHz, DMSO-d6):d 1.05-1.54 (m, 9H, CH2CH3), 4.42-4.46
(m, 6H, CH2CH3), 6.99-8.11 (m, 6H, ArH) and 8.17 (s, lH, CH=C)
ppm; ElMS: m/z 422 (M+) (38.7%), Anal.Calcd for C23H22N204S:
C, 65.39; H, 5.25; N, 6.63. Found: C, 65.26; H, 5.28; N, 7.10%.
This research was presented in 10th Ibn Sina International
Conference on Pure and Applied Heterocyclic Chemistry in
Luxor 17-20 February 2007.
DiethyI2-[ 4-(benzothiazol-2-yl)phenyl
Benzothiazol-2yl)phenylhydrazonojmalononitrile
hydrazono jmalonate (12), 2-[(4-
(13)
To an ice-cold solution of 1 (0.01 mol) in hydrochloric acid (2.5 ml)
and distilled water (5 ml), a solution of sodium nitrite (0.013 mol)
in distilled water (5 ml) was added portionwise. This solution
was added portionwise to a well-stirred cooled solution of either
diethyl malonate (0.01 mol) or malononitrile (0.01 mol) in aqueous
ethanol (10 ml, 50%) containing sodium acetate (0.011 mol).
After completion of addition, the reaction mixture was kept in ice
for 2 h and then filtered. The product was dried and then crystallised
from the appropriate solvent(s).
Received 16August 2008; accepted 9 October 2008
Paper 08/0108 doi: 10.3184/030823408X389372
Published online: 17 December 2008
Reference
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12: Yield 75% (ethanol); m.p. 93-95°C; lR (KEr): 3400-3100
(NH), 2950 (CH aliphatic), 1699 (C=O), 1657(C=0) em-I; IH NMR
(300 MHz, DMSO-d6): 1.32 (t, 6H, 2CH3), 4.35(q, 4H, 2CH2), 7.52-
8.13 (m, 8H, ArH) and 11.97(s, lH, HN-N=C, D20 exchangeable)
ppm; ElMS: m/z 397(M +.) (62.74%). Anal.Calcd for C2oHI~304S:
C, 60.44; H, 4.82; N, 10.57. Found: C, 60.63; H 5.01; N, 10.27%.
l3:Yield 85% (DMF/MeOH); m.p. 299-300°C; IR (KEr): 3500-
3200 (NH), 2200 (CN) em-I; IH NMR (300 MHz, DMSO-d6):
/)3.32 (s, 1 H, HN-N=C, D20 exchangeable) and 7.4-8.1 (m, 8H,
ArH) ppm; ElMS: m/z 303 (M+) (100%). Anal.Calcd for Cl(,H~sS:
C, 63.35; H, 2.99; N, 23.09. Found: C, 63.60; H, 3.00; N, 23.09%.
5
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6-(Benzothiazol-2
oxylicacid (3a,b); 7-(Benzothiazol-2-yl)-I-alkyl-4-oxo-l,
6-alkoxyquinoline-3-carboxylic acid (4a,b).
A mixture of compound lOa, lOb, 10e, 10d, 11a or 11b (0.01 mol)
and sodium hydroxide (2N, 10.5 ml) in tetrahydrofuran (60 ml) was
heated under reflux for 24 h. THF was evaporated to dryness, water
was added to the residue and the mixture was filtered. The filtrate was
acidified with hydrochloric acid (6N) and then the formed precipitate
was filtered, dried and crystallised from DMF.
3a,b: lR (KEr): 3500-3000 (OH), 2974 (CH aliphatic), 1717-1715
(C=O) and 1631-1627 (C=O) em-I.
3a (R = CH3): Yield 50%; m.p. >300°C; ElMS: m/z 336 (M+)
(11.3%); Anal.Calcd for CISH12N203S: C, 64.27; H, 3.60; N, 8.33.
Found: C, 63.90; H, 3.67; N, 8.27%.
-yl)-I-alkyl-4-oxo-l,
4-dihydroquinoline-3-carb-
4-dihydro-
3b (R = C2Hs): Yield 50%; m.p. >300°C; IH NMR (300 MHz,
DMSO-d6):
d 1.44-1.48 (t, 3H, NCH2CH3), 4.59-4.68 (q, 2H,
19 M.F.G. Stevens, D.F. Shi and A. Castro, J. Chern., Soc., Perkin Trans.
1995,1,83.
NCH2CH3), 7.47-8.95 (m, m, ArH), 8.91 (s, lH, CH=C) and 14.85