A new aspect of the Pfitzinger reaction: Microwave-assisted synthesis of the new heterocyclic ring system 6-Arylbenzo[4,5]imidazolo[2,1-b]quino[4,3-e]-1, 3-thiazin-14-one

Article abstract of DOI:10.1515/znb-2009-0709

We report herein on the utility of the Pfitzinger reaction in a facile two-step synthesis of the new heterocyclic ring system 6-arylbenzo[4,5] imidazolo[2,1-b]quino[4,3-e]-1,3-thiazin-14-one using microwave irradiation (MWI) and/or conventional heating. M

Full text of DOI:10.1515/znb-2009-0709

A New Aspect of the Pfitzinger Reaction:
Microwave-assisted Synthesis of the New Heterocyclic Ring System
6-Arylbenzo[4,5]imidazolo[2,1-b]quino[4,3-e]-1,3-thiazin-14-one
Hatem A. Abdel-Aziza and Sobhi M. Gomhab
a Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt
b Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Reprint requests to Dr. Hatem A. Abdel-Aziz. E-mail: hatem 741@yahoo.com
Z. Naturforsch. 2009, 64b, 826 – 830; received March 30, 2009
We report herein on the utility of the Pfitzinger reaction in a facile two-step synthesis of the new
heterocyclic ring system 6-arylbenzo[4,5]imidazolo[2,1-b]quino[4,3-e]-1,3-thiazin-14-one using mi-
crowave irradiation (MWI) and/or conventional heating. Microwave irradiation was used for a rapid
and efficient synthesis of quinoline-4-carboxylic acids 6a – d from the reaction of isatin with 2-(1H-
benzimidazol-2-ylthio)-1-arylethanones 3a – d. Cyclization of cinchoninic acids 6a – d afforded the
fused title compounds 7a – d.
Key words: Quinolines, Antibiotics, Cyclization, Pfitzinger Reaction, Microwave Irradiation (MWI)
Introduction
Pfitzinger [17] and is known in organic chemistry as
the Pfitzinger reaction.
Quinolines are an important class of heterocycles
found in numerous natural products [1, 2] and medici-
nal structures [3, 4] such as ciprofloxacin, norfloxacin
and pefloxacin [5], which are amongst the most effec-
tive broad-spectrum agents developed to date as po-
tent antibiotics. They are now frequently the drugs
of choice for treating infections of the urinary and
genital tracts. On the other hand, quinoline-contain-
ing compounds, such as quinine, chloroquine and
mefloquine [6 – 9] have long been used for treat-
ment of malaria, one of the most devastating in-
fectious diseases in the world. In addition, quino-
line is the backbone of the antiarrythmic drug quini-
dine [2, 10] and the antiulcer agent rebamipide [11].
Furthermore, quinoline-4-carboxylic acids and their
analogs have interesting antiviral, analgesic, tran-
quillizer, antitumor, and antitubercular activities
[12 – 15].
Consequently, the efficient construction of quino-
lines has received significant attention [16]. One of
the powerful methods for the synthesis of these com-
pounds involves the Pfitzinger reaction. The formation
of 4-quinolinecarboxylic(cinchoninic) acid derivatives
as a result of the reaction of isatin or its derivatives with
ketones containing the –CH2CO– group in the pres-
ence of sodium hydroxide or potassium hydroxide was
first discovered at the end of the nineteenth century by
The first successful use of keto ethers or keto
thioethers in the Pfitzinger reaction was made by Cal-
away et al. in the middle of the last century [18 – 21].
Recently, the first attempt to use microwave irradia-
tion (MWI) for performing the Pfitzinger reaction has
been reported by El Ashry [22]. Although many strate-
gies for the construction of substituted quinolines or
their fused systems have been explored depending on
the Pfitzinger reaction [16], a convergent synthesis of
fused quinolines from Pfitzinger reaction products with
a thioether substituent at C3 has not yet emerged.
In the course of our research efforts towards the
preparation of new biologically active heterocyles
[23 – 30], we report herein on the utility of keto thio-
ethers in the Pfitzinger reaction in a facile two-step
synthesis of the title compounds using microwave ir-
radiation (MWI) and/or conventional heating. The lat-
ter two-component Pfitzinger reaction was utilized as a
convenient method to generate the quinolines that un-
dergo subsequent cyclization to afford the title com-
pounds with expected interesting biological activity.
Results and Discussion
Microwave irradiation has been used for a rapid
and efficient synthesis of quinoline-4-carboxylic acids
6a – d from the reaction of isatin with 2-(1H-benz-
c
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H. A. Abdel-Aziz – S. M. Gomha · A New Aspect of the Pfitzinger Reaction
827
Scheme 1.
imidazol-2-ylthio)-1-arylethanones 3a – d in aqueous
potassium hydroxide solution (Scheme 1). Thus, un-
der conventional heating, the reaction required reflux-
ing for 12 h to afford 63 – 68 % yield, but MWI acceler-
ated the condensation of isatin with compounds 3a – d
where the reaction time was dramatically reduced to
9 min, and slightly higher yields (77 – 85 %) were ob-
served.
The structures of 6a – d were elucidated on the ba-
sis of their spectra (1H NMR, 13C NMR, IR, and MS)
1
and microanalyses. For example, the H NMR spec-
tra of the latter compounds showed a D2O-exchange-
able NH proton signal at δ = 6.23 – 6.9 ppm in addi-
tion to the D2O-exchangeable signal of the OH proton
Scheme 2.
at δ = 10.45– 10.62 ppm. The mass spectra of 6a – d
were also consistent with their assigned structures. In
addition to the molecular ion peak, they revealed peaks
at m/z corresponding to [M–18]+.
of the Pfitzinger reaction have melting points lower
than the acids from which they are derived [18, 19].
In our case, the cyclized compounds 7a – d have melt-
ing points higher than their correspondingacyclic com-
pounds 6a – d.
Surprisingly, upon attempts to decarboxylation of
cinchoninic acids 6a – d to afford compounds 8a – d,
cyclization of the latter acids occurred to afford the
fused compounds 7a – d via loss of a water molecule
(Scheme 2). Thus, during solvent-free heating of the
solid acids 6a – d under MWI, the material melted and
solidified within 1 min to afford compounds 7a – d.
The conventional heating of acids 6a – d in DMSO for
5 min gave the same results and approximately, in each
case, the same yield. Furthermore, acids 6a – d were
also cyclized upon solvent-free conventional heating
Although all attempts to get crystals of 7a – d for
X-ray diffraction analysis failed, the spectra of 7a – d
(1H NMR, 13C NMR, IR, and MS) and their micro-
analyses were sufficient to establish, beyond doubt, the
1
assigned structures. The IR and H NMR spectra of
7a – d were lacking the NH and OH signals, which
were characteristic of the starting substrates 6a – d.
The mass spectra of 7a – d showed, in each case, a peak
corresponding to their molecular ions.
In summary, a rapid and efficient synthesis of a
for 5 min. Generally, the decarboxylated quinolines new ring system, 6-arylbenzo[4,5]imidazolo[2,1-b]-
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H. A. Abdel-Aziz – S. M. Gomha · A New Aspect of the Pfitzinger Reaction
quino[4,3-e]-1,3-thiazin-14-one,with expected biolog- 128.9, 129.4, 131.8, 139.4, 147.3, 148.3, 149.4, 161.9, 165.3,
166.8. – MS (EI, 70 eV): m/z (%) = 398 (21.5) [M+1]+, 397
ical activity was described.
(43.6) [M]+, 379 (12.2), 235 (28.4), 134 (27.8), 89 (29.7), 77
(50.8), 51 (100.0). – C23H15N3O2S: calcd. C 69.50, H 3.80,
N 10.57, S 8.07; found C 69.32, H 3.77, N 10.52, S 8.12.
Experimental Section
Melting points were taken on an Electrothermal IA 9000
series digital melting point apparatus. Elemental analyses
were obtained from the microanalytical unit, Cairo Univer-
sity, Cairo, Egypt. The results were found to be in good
3-(1H-Benzimidazol-2-ylthio)-2-(4-tolyl)quinoline-4-carb-
oxylic acid (6b)
Pale-yellow powder; yield (%/method): 84/A, 63/B. –
M. p. 218 – 219 ◦C. – IR (KBr): ν = 3389 (NH), 2737 (OH),
1612 (C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 2.42 (s, 3H, CH3), 6.25 (s, D2O-exchangeable, 1H,
NH), 7.11 – 7.27 (m, 5H, Ar-H), 7.53 – 8.18 (m, 3H, Ar-H),
8.26 (d, J = 8.0 Hz, 2H, Ar-H), 8.31 (d, J = 7.4 Hz, 1H,
Ar-H), 9.12 (d, J = 6.8 Hz, 1H, Ar-H), 10.27 (s, D2O-
exchangeable, 1H, OH). – 13C NMR (75 MHz, [D6]DMSO):
δ = 20.8, 113.9, 116.4, 121.3, 122.9, 125.1, 127.3, 128.1,
128.3, 128.9, 129.4, 131.7, 139.3, 147.3, 148.3, 149.3, 161.9,
165.4, 166.8. – MS (EI, 70 eV): m/z (%) = 412 (21.6)
[M+1]+, 411 (100.0) [M]+, 393 (19.5), 321 (46.3), 249
(32.7), 77 (71.6). – C24H17N3O2S: calcd. C 70.05, H 4.16,
N 10.21, S 7.79; found C 70.15, H 4.03, N 10.01, S 7.68.
agreement with the calculated values. The IR spectra (KBr)
were recorded on a Shimadzu CVT-04 spectrophotometer.
The NMR spectra were recorded on a Varian Mercury VX-
300 NMR spectrometer. 1H Spectra were run at 300 MHz
in deuterated dimethylsulfoxide, [D6]DMSO. Mass spectra
were measured on a Varian MAT CH-5 spectrometer (70 eV).
Irradiation was achieved using a domestic microwave oven
(800 W output power). 1-Aryl-2-(1H-benzimidazol-2-ylthio)
ethanones 3a – d were synthesized according to the reported
method [31].
General procedure for the synthesis of 2-aryl-3-(1H-benz-
imidazol-2-ylthio)quinoline-4-carboxylic acids 6a – d
Method A: To a solution of isatin (1.47 g, 10.0 mmol) in
33 % aqueous potassium hydroxide solution (15 mL), the ap-
propriate 1-aryl-2-(1H-benzimidazol-2-ylthio)ethanone 3a –
d (10.0 mmol) was added, and the mixture was irradiated
by MWI for 9 min. The resulting dark solution was filtered.
The clarified solution was poured into an ice-water mixture
(100 mL) and acidified with acetic acid. The pale-yellow
solid which separated was filtered, washed with water, and
dried to afford compounds 6a – d in 77 – 85 % yield. The lat-
ter compounds were used directly in the next reaction with-
out further purification.
Method B: To a solution of isatin (1.47 g, 10.0 mmol) in
33 % aqueous potassium hydroxide solution (15 mL), the ap-
propriate 1-aryl-2-(1H-benzimidazol-2-ylthio)ethanone 3a –
d (10.0 mmol) was added, and the mixture was heated under
reflux for 12 h. The treatment of the resulting solution was
carried out as mentioned above in method A to afford com-
pounds 6a – d in 63 – 68 % yield.
3-(1H-Benzimidazol-2-ylthio)-2-(4-chlorophenyl)quinoline-
4-carboxylic acid (6c)
Pale-yellow powder; yield (%/method): 84/A, 68/B. –
M. p. 228 – 229 ◦C. – IR (KBr): ν = 3418 (NH), 2767 (OH),
1625 (C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 6.90 (s, D2O-exchangeable, 1H, NH), 7.42 – 7.20 (m,
7H, Ar-H), 8.46 (d, J = 8.4 Hz, 2H, Ar-H), 8.75 (d, 1H, J =
8.2 Hz, Ar-H), 9.47 (d, J = 8.3 Hz, 1H, Ar-H), 10.62 (s, D2O-
exchangeable, 1H, OH). – 13C NMR (75 MHz, [D6]DMSO):
δ = 114.1, 116.6, 121.3, 122.9, 125.2, 127.3, 128.3, 128.5,
129.1, 129.6, 131.8, 139.3, 147.6, 148.5, 149.4, 161.0, 165.5,
166.9. – MS (EI, 70 eV): m/z (%) = 433 (13.5) [M+2]+,
432 (37.3) [M+1]+, 431 (72.2) [M]+, 413 (24.3), 385 (24.3),
269 (38.1), 102 (27.0), 64 (100.0). – C23H14ClN3O2S: calcd.
C 63.96, H 3.27, N 9.73, S 7.42; found C 63.92, H 3.12,
N 9.58, S 7.40.
3-(1H-Benzimidazol-2-ylthio)-2-(4-bromophenyl)quinoline-
3-(1H-Benzimidazol-2-ylthio)-2-phenylquinoline-4-carb-
4-carboxylic acid (6d)
oxylic acid (6a)
Pale-yellow powder; yield (%/method): 85/A, 68/B. –
Pale-yellow powder; yield (%/method): 77/A, 65/B. –
M. p. 205 – 207 ◦C. – IR (KBr): ν = 3417 (NH), 2745 (OH), M. p. 237 – 239 ◦C. – IR (KBr): ν = 3418 (NH), 3752 (OH),
1623 (C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO): 1632 (C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 6.23 (s, D2O-exchangeable, 1H, NH), 7.05 – 7.08 (m, δ = 6.35 (s, D2O-exchangeable, 1H, NH), 7.21 – 7.63
2H, Ar-H), 7.26 – 7.33 (m, 5H, Ar-H), 7.55 – 7.58 (m, 2H, (m, 6H, Ar-H), 8.01 (d, 1H, Ar-H), 8.12 (d, J = 8.3,
Ar-H), 7.80 (dd, J = 6.6, 1.2 Hz, 1H, Ar-H), 7.89 – 7.97 (m, 2H, Ar-H), 8.36 (d, J = 7.7, 1H, Ar-H), 9.11 (d, J =
2H, Ar-H), 8.20 (d, J = 8.4 Hz, 1H, Ar-H), 10.52 (s, D2O- 8.4 Hz, 1H, Ar-H), 10.45 (s, D2O-exchangeable, 1H, OH). –
exchangeable, 1H, OH). – 13C NMR (75 MHz, [D6]DMSO): 13C NMR (75 MHz, [D6]DMSO): δ = 113.9, 116.5, 121.3,
δ = 113.9, 116.5, 121.5, 122.9, 125.2, 127.3, 128.2, 128.3, 122.8, 125.2, 127.3, 128.3, 128.4, 129.1, 129.5, 131.7,
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H. A. Abdel-Aziz – S. M. Gomha · A New Aspect of the Pfitzinger Reaction
829
139.2, 147.6, 148.5, 149.2, 161.1, 165.4, 166.8. – MS (EI, H 3.45, N 11.07, S 8.45; found C 72.83, H 3.42, N 10.87,
70 eV): m/z (%) = 478 (9.7) [M+2]+, 477 (14.7) [M+1]+, S 8.34.
476 (34.2) [M]+, 458 (22.7), 234 (22.7), 123 (18.2), 89
(36.4), 62 (100.0). – C23H14BrN3O2S: calcd. C 57.99,
H 2.96, N 8.82, S 6.73; found C 57.83, H 3.03, N 8.73,
S 6.66.
6-(4-Tolyl)benzo[4,5]imidazolo[2,1-b]quino[4,3-e]-1,3-
thiazin-14-one (7b)
Pale-yellow powder; yield (%/method): 85/A, 87/B,
85/C. – M. p. 337 – 339 ◦C. – IR (KBr): ν = 1692
(C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 2.45
(s, 3H, CH3), 7.42 – 8.21 (m, 8H, Ar-H), 8.28 (d, J = 8.3 Hz,
2H, Ar-H), 8.42 (d, J = 6.4 Hz, 1H, Ar-H), 8.98 (d, J =
6.6 Hz, 1H, Ar-H). – 13C NMR (75 MHz, [D6]DMSO): δ =
20.7, 113.7, 116.5, 121.3, 122.7, 125.2, 127.3, 128.0, 128.3,
129.1, 129.3, 131.6, 139.4, 147.4, 147.8, 149.0, 161.7, 165.3,
176.0. – MS (EI, 70 eV): m/z (%) = 394 (37.5) [M+1]+, 393
(70.3) [M]+, 293 (100.0), 248 (26.1), 204 (13.5), 124 (16.2),
63 (21.6). – C24H15N3OS: calcd. C 73.26, H 3.84, N 10.68,
S 8.15; found C 73.11, H 3.81, N 10.64, S 8.01.
General procedure for the synthesis of 6-arylbenzo[4,5]-
imidazolo[2,1-b]quino[4,3-e]-1,3-thiazin-14-ones 7a – d
Method A: On heating of the appropriate compound 6a – d
(1.0 mmol) in a microwave oven for 1 min the solid material
melted and solidified. It was then left to cool, taken up in
ethanol, filtered off, washed with ethanol, dried, and crystal-
lized from DMSO to afford compounds 7a – d, respectively.
Method B: A solution of the appropriate compound 6a – d
(1.0 mmol) in DMSO (10 mL) was refluxed for 5 min and
then left to cool. The solid which separated was filtered off,
washed with ethanol, dried, and crystallized from DMSO to
afford compounds 7a – d, respectively.
6-(4-Chlorophenyl)benzo[4,5]imidazolo[2,1-b]quino-
[4,3-e]-1,3-thiazin-14-one (7c)
Method C: On heating of the appropriate compound 6a – d
(1.0 mmol) in a sand bath for 5 min at a temperature, in each
◦
Pale-yellow fine needles; yield (%/method): 92/A, 90/B,
92/C. – M. p. 322 – 324 ◦C. – IR (KBr): ν = 1694
(C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.53 – 8.74 (m, 7H, Ar-H), 8.21 (d, J = 8.0 Hz, 2H, Ar-H),
8.53 – 8.65 (m, 2H, Ar-H), 9.74 (d, J = 6.6 Hz, 1H, Ar-H). –
MS (EI, 70 eV): m/z (%) = 415 (16.2) [M+2]+, 414 (43.2)
[M+1]+, 413 (78.4) [M]+, 385 (24.3), 269 (27.0), 176 (27.0),
102 (27.0), 64 (100.0), 51 (91.9). – C23H12ClN3OS: calcd.
C 66.75, H 2.92, N 10.15, S 7.75; found C 66.67, H 2.90,
N 10.00, S 7.72.
case, over the melting point by 10 C, the solid substance
melted and solidified within 1 – 3 min. It was then left to cool,
taken up in ethanol, filtered off, washed with ethanol, dried,
and crystallized from DMSO to afford compounds 7a – d, re-
spectively.
Due to the limited solubility of products 7c and 7d in com-
mon 13C NMR solvents, the 13C NMR spectra were recorded
for 7a and 7b only as representative examples of the series
prepared.
6-Phenylbenzo[4,5]imidazolo[2,1-b]quino[4,3-e]-1,3-
thiazin-14-one (7a)
6-(4-Bromophenyl)benzo[4,5]imidazolo[2,1-b]quino-
[4,3-e]-1,3-thiazin-14-one (7d)
Greenish-yellow fine needles; yield (%/method): 92/A,
94/B, 90/C. – M. p. 296 – 298 ◦C. – IR (KBr): ν = 1692
(C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.52 – 7.82 (m, 9H, Ar-H), 8.21 (dd, J = 6.3, 3.1 Hz,
1H, Ar-H), 8.63 (dd, J = 6.6, 3.0 Hz, 1H, Ar-H), 9.74
(dd, J = 6.6, 3.6 Hz, 1H, Ar-H). – 13C NMR (75 MHz,
[D6]DMSO): δ = 113.8, 116.5, 121.5, 122.8, 125.2, 127.2,
128.2, 128.3, 128.9, 129.3, 131.8, 139.7, 147.3, 148.1, 149.3,
161.8, 165.3, 176.2. – MS (EI, 70 eV): m/z (%) = 380 (31.0)
[M+1]+, 379 (100.0) [M]+, 350 (51.2), 235 (15.5), 189
(21.4), 64 (9.3), 51 (7.9). – C23H13N3OS: calcd. C 72.80,
Pale-yellow fi◦bers; yield (%/method): 86/A, 84/B, 86/C. –
M. p. 334 – 336 C. – IR (KBr): ν = 1693(C=O) cm−1. –
1H NMR (300 MHz, [D6]DMSO): δ = 7.40 – 8.26 (m, 8H,
Ar-H), 8.31 (d, J = 8.2 Hz, 2H, Ar-H), 8.61 (d, J = 6.3 Hz,
1H, Ar-H), 9.28 (d, J = 6.6 Hz, 1H, Ar-H). – MS (EI, 70 eV):
m/z (%) = 460 (12.3) [M+2]+, 459 (32.5) [M+1]+, 458
(38.2) [M]+, 359 (79.4), 312 (29.4), 233 (41.2), 188 (47.1),
93 (100.0), 64 (26.5), 51 (50.0). – C23H12BrN3OS: calcd.
C 60.27, H 2.64, N 9.17, S 7.00; found C 60.18, H 2.57,
N 9.01, S 6.88.
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