Synthesis of α- and β-pyran naphthoquinones as a new class of antitubercular agents

Article abstract of DOI:10.1002/ardp.200900162

A series of α- and β-pyran naphthoquinones (lapachones) have been synthesized and evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar-Blue susceptibility test; the activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL. The synthetic methodology consisted of the formation of methylene and aryl o-quinone methides (o-QMs) generated by Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with formaldehyde and arylaldehydes. These o-QMs then undergo facile hetero Diels-Alder reactions with dienophiles in aqueous ethanol media. Some naphthoquinones exhibited inhibition with MIC values of 1.25 μg/mL, similar to that of pharmaceutical concentrations currently used in tuberculosis treatment. These results justify further research into the value of these quinones as part of an original treatment for tuberculosis.

Full text of DOI:10.1002/ardp.200900162

Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
S. B. Ferreira et al.
81
Full Paper
Synthesis of a- and b-Pyran Naphthoquinones as a New Class
of Antitubercular Agents
Sabrina B. Ferreira1,2, Fernando de Carvalho da Silva1,2, Flꢀvio A. F. M. Bezerra3,
Maria C. S. Lourenꢁo3, Carlos R. Kaiser1, Angelo C. Pinto1, and Vitor F. Ferreira2
1 Universidade Federal do Rio de Janeiro, Instituto de Quꢀmica, LABRMN, Rio de Janeiro, Brazil
2 Universidade Federal Fluminense, Instituto de Quꢀmica, Departamento de Quꢀmica Orgꢁnica, Campus do
Valonguinho, CEG, Niterꢂi, Brazil
3 Fundaꢃ¼o Oswaldo Cruz, Instituto de Pesquisa Clꢀnica Evandro Chagas – IPEC, Laboratꢂrio de
Bacteriologia e Bioensaios em Micobactꢄrias, Rio de Janeiro, Brazil
A series of a- and b-pyran naphthoquinones (lapachones) have been synthesized and evaluated
for their in-vitro antibacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC
27294) using the Alamar-Blue susceptibility test; the activity was expressed as the minimum
inhibitory concentration (MIC) in lg/mL. The synthetic methodology consisted of the formation
of methylene and aryl o-quinone methides (o-QMs) generated by Knoevenagel condensation of 2-
hydroxy-1,4-naphthoquinone with formaldehyde and arylaldehydes. These o-QMs then undergo
facile hetero Diels–Alder reactions with dienophiles in aqueous ethanol media. Some naphtho-
quinones exhibited inhibition with MIC values of 1.25 lg/mL, similar to that of pharmaceutical
concentrations currently used in tuberculosis treatment. These results justify further research
into the value of these quinones as part of an original treatment for tuberculosis.
Keywords: Lapachones / Naphthoquinones / Synthesis / Tuberculostatics /
Received: July 12, 2009; accepted: September 27, 2009
DOI 10.1002/ardp.200900162
Introduction
Naphthoquinones are an important class of quinones
found in many synthetic and natural products with a
wide range of pharmacological activities, such as trypa-
nocidal [1], anticancer [2], antibacterial [3], antifungal [4],
leishmanicidal [5], and antimicrobial [6]. Despite the
large number of compounds described in the literature,
few studies have been described measuring the efficacy
of naphthoquinones against tuberculosis [7].
Figure 1. Structures of a- (1), b-lapachone 2 and lapachol 3.
chol 3 (Fig. 1). b-Lapachone, one of the most important
derivatives of lapachol [8], presents biological activities
against various pathogens and, most significantly, also
exhibits anticancer activity [9, 10] and trypanocidal prop-
erties [11–13]. In view of the importance and variety of
biological activities of b-lapachone 2 against various
pathogens, it may be an excellent model compound for
the development of more selective and more active
agents. Perhaps this is why b-lapachone has been one of
the most studied naphthoquinones in recent years [14–
20].
The a- (1) and b-lapachones 2 are described in the litera-
ture as important naphthoquinones derived from lapa-
Correspondence: Vitor F. Ferreira, Universidade Federal Fluminense,
Instituto de Quꢀmica, Departamento de Quꢀmica Orgꢁnica, CEG, Campus
do Valonguinho, 24020-141 Niterꢂi – RJ- Brazil.
E-mail: cegvito@vm.uff.br
Fax: +55 21 262-923-62
Abbreviations: multiple drug resistent tuberculosis (MDR-TB); o-quinone
methides (o-QMs); tuberculosis (TB)
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Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
Figure 2. Structures of isoniazid 4, rifampicin 5, pyrazinamide 6, ethambutol 7, thioacetazone 8, cycloserine 9,
clofazimine 10, terizidone 11, canamicine 12, and amicacine 13.
Numerous biological activities of b-lapachone 2 are (WHO) declared TB a global emergency in an attempt to
linked to its ability to generate intracellular reactive oxy- increase public awareness of the disease and political
gen species [21, 22]. For instance, 2 is a potent cytotoxic will to combat it [33]. Two new factors have contributed
agent, alone or in combination with other compounds, to the spread of tuberculosis: the Human Immunodefi-
against several cancer cell lines [23, 24]. The pharmaco- ciency Virus (HIV) and the emergence of strains of M.
logical mechanism of action remains unclear, despite tuberculosis resistant to one or more drugs (multiple drug
intense research. Understanding this mechanism resistent – MDR-TB) [34]. It is estimated that one third of
requires the recognition that the compound acts on mul- the 42 million individuals infected with HIV are co-
tiple biological targets. In this regard, the trypanocidal, infected with M. tuberculosis, and most people infected
antibacterial, and cytotoxic activities are attributed to with HIV develop TB as the first manifestation of AIDS. As
the mechanism of formation of reactive oxygen species HIV progressively destroys the immune system, there is a
that cause cellular damage, particularly to DNA [25, 26]. greater chance of people infected with the virus develop-
The b-lapachone was semi-synthesized from lapachol 3 ing tuberculosis. The relationship between the two dis-
by Hooker in 1892. Since then, several other preparations eases is particularly concentrated in poor countries. In
of 2 and analogues have been reported [27–30].
sub-Saharan Africa, for example, about 50% of people
Currently, tuberculosis (TB) is a serious worldwide pub- with HIV develop TB, and one in three dies as a result of
lic health problem. In the past, TB was considered a the disease. Furthermore, the increased number of cases
neglected disease because it did not receive significant of MDR-TB has caused great concern, as it increases the
investment from international pharmaceutical compa- proportion of deaths from TB, and is frequently associ-
nies for the development of new drugs [31]. While it ated with HIV infection [35]. The presence of multiresist-
might be expected that this disease, which was consid- ant strains reflects deficiencies in the control of TB,
ered a scourge of the 19th and early 20th centuries by which complicates the treatment and prevention of the
developed nations, would have already been eradicated, disease, contributing to its spread. Although MDR-TB is
statistics suggest that one-third of the world's population treatable, it requires a longer course of chemotherapy,
is currently infected with the TB bacillus, and each year with approximately two years of treatment. This entails a
eight million people worldwide develop active TB, of high cost, 100 times greater than the treatment of drug-
whom about 1.7 million die [32]. Due to the seriousness sensitive TB strains (typically conducted in six to nine
of the situation, in 1993 the World Health Organization months) and exposes the patient to increased risk of tox-
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Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
a- and b-Pyran Naphthoquinones as Antitubercular Agents
83
Scheme 1. Synthesis of a- and b-pyran naphthoquinones 14a–j and 15a–j.
Table 1. Synthesized a-pyran naphthoquinones.
icity. TB-Chemotherapy regimens developed in the 1940s
classify available treatments as drugs of first or second
choice. The drugs of first choice are isoniazid 4, rifampi-
cin 5, pyrazinamide 6, and ethambutol 7. The second
choice drugs are used when first choices fail, and include
thioacetazone 8, cycloserine 9, clofazimine 10, terizidone
11, canamicine 12, and amicacine 13 ([36], Fig. 2). How-
ever, the emergence of MDR-TB and the indifference on
the part of governments, which have invested little in
prevention campaigns, in combating the illness, or in
the development of new treatments, have precipitated
an urgent need for new antitubercular drugs. In light of
this goal, our research group has focused on the search
for new antitubercular candidates [37].
Entry
R1
R2
R3
Time (h) Yield (%)
14a
14b
14c
14d
14e
14f
14g
14h
14i
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
6
6
6
4
4
4
6
5
8
8
75
75
80
73
74
58
70
29
19
27
CH3
CH3
Cl
F
Br
OCH3
CH3
CH3
4-NO2Ph
Ph
2-thiophene CH3
14j
H
Table 2. Synthesized b-pyran naphthoquinones.
Entry
R1
R2
R3
Time (h) Yield (%)
In this paper, we report our findings on the prepara-
tion of a- and b-lapachone derivatives via methylene and
aryl o-quinone methides (o-QMs) generated in situ by
Knoevenagel condensation of 2-hydroxy-1,4-naphthoqui-
none with formaldehyde or arylaldehydes, followed by
hetero Diels–Alder reaction with substituted styrenes in
aqueous ethanol media. We also report results from tests
of inhibition of the growth of M. tuberculosis strain H37Rv
(ATCC 27294).
15a
15b
15c
15d
15e
15f
15g
15h
15i
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
6
6
6
4
4
4
6
5
8
8
23
20
17
25
26
19
17
24
33
33
CH3
CH3
Cl
F
Br
OCH3
CH3
CH3
4-NO2Ph
Ph
2-thiophene CH3
15j
H
water mixture (Scheme 1). The naphthoquinones were
obtained in a high degree of purity and in good chemical
yields with respect to the quantity of aldehydes used. The
separations of a- and b-pyran naphthoquinones were car-
ried out via silica gel column chromatography (Tables 1
and 2).
Results and discussion
Chemistry
The preparations of a- and b-pyran naphthoquinones
14a–j and 15a–j were carried out in one step by an
improved synthetic protocol recently reported by the cur-
rent authors [38]. Briefly, the Knoevenagel condensation
of lawsone 16 with commercially available aldehydes
17a–d, forming the intermediate 18, followed by an
intermolecular hetero Diels–Alder cycloaddition with
styrene derivatives 19a–g was performed in an ethanol/
All compounds were identified by IR spectral data, 1-D
and 2-D NMR techniques, and by ESI-TOF mass spectrome-
1
try. In general, the H-NMR spectra mainly showed the
signal for the hydrogen presented in the ortho-carbon of
the chromogenic ring, which appeared as a double of
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S. B. Ferreira et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
Table 3. The in-vitro activity of compounds 14a–j in lg/mL
(lmol/L) against M. tuberculosis H37Rv strain (ATCC 27294)
and clogP.
Table 4. The in-vitro activity of compounds 15a–j in lg/mL
(lmol/L) against M. tuberculosis H37Rv strain (ATCC 27294)
and clogP measurements.
Compound
MICc), lg/mL (lmol/L)
cLogP
Compound
MIC lg/mL (lmol/L)
cLogP
14a
14b
14c
14d
14e
14f
14g
14h (syn)
14h (anti)
14i
14j (syn)
14j (anti)
A100.0 (A344.46)a)
A100.0 (A328.58)a)
A100.0 (A314.09)a)
A100.0 (A307.91)a)
A100.0 (A324.36)a)
A100.0 (A270.84)a)
A100.0 (A312.17)a)
A100.0 (A235.06)a)
A100.0 (A235.06)a)
Ndb)
3.42
3.74
4.05
4.03
3.48
4.12
3.32
5.15
5.15
5.24
5.08
5.08
15a
15b
15c
15d
15e
15f
15g
15h
15i
2.5 (8.6)
3.36
3.68
4.00
3.98
3.42
4.06
3.26
4.36
5.18
5.03
1.25 (4.10)
3.12 ( 9.80)
2.5 (7.69)
2.5 (8.10)
3.12 (8.45)
6.25 (19.51)
2.5 (5.87)
3.12 (8.20)
6.25 (16.17)
15j
A100.0 (A258.75)a)
A100.0 (A258.75)a)
a)
microplate Alamar-Blue1 assay (MABA) [40], with rifampi-
cin as a positive control (MIC = 1.0 lg/mL). This method
consisted of a microdilution in microplates using Alamar
Blue as an indicator of cell growth. Alamar Blue is a fluo-
rescent/colorimetric redox indicator that is present in a
MIC A 100.0 lg/mL indicates that the strain is resistant to the
tested substance.
Nd = Not detected.
b)
c)
Riphampicin control (MIC = 1.0 lg/mL).
doublet signals between 4.99 to 5.35 ppm for the a com- blue (non-fluorescent) oxidized form in the absence of
pounds, and between 5.07 to 5.35 ppm for the b-com- bacterial growth, while the pink (fluorescent) reduced
pounds. The differentiation into derivatives a and b is form indicates the proliferation of bacteria. Compounds
given mainly by the aromatic region in the 1H-NMR spec- showing 90% inhibition in the primary screening were
trum: in b-pyran naphthoquinones, the aromatic hydro- considered active, and were then re-tested at a lower con-
gens are differentiated into four signals, while in the a- centration against M. tuberculosis (ATCC 27294 H37Rv) in
pyran naphthoquinones there are only two signals order to determine the actual MIC. The MIC was defined
because of the symmetry of this type of compound.
The stereoisomers formation in the Diels–Alder cyclo- change from blue (no growth) to pink (growth).
addition leading to each group of products 14a–j and
In order to study the hydrophobic properties of these
as the lowest drug concentration that prevented a color
15a–j are in complete agreement with a [4+2]-cycloaddi- compounds, we calculated values for the log of the octa-
tion of the o-QM with the styrene in asynchronous fash- nol/water partition coefficient (cLogP) using the Osiris
ion by a zwitterion-like transition state.
Property Explorer (www.organic-chemistry.org). These
For reactions that produced disubstituted naphthoqui- results showed good correlation and proportionality
nones 14h–j and 15h–j, a mixture of a- and b-isomers are with BACTEC radiometric methods [39]; they are shown
composed by syn- and anti-diastereoisomers. In most in Table 3 and Table 4.
cases, the amounts of the anti-isomers were higher than
Some of the novel naphthoquinones tested showed
the syn-isomers. Only in the cases of 14h and 14j it was high inhibitory activity in vitro against M. tuberculosis
possible to separate the syn- and anti-diastereoisomers by H37Rv (ATCC 27294). While the a-pyran naphthoquinone
flash column chromatography. The other compounds series 14a–j, (Table 3) was inactive, the b-pyran naphtho-
were used as diastereoisomeric mixtures.
quinone series 15a–j, (Table 4) were highly active, with
In general, the 13C-NMR spectra of naphthoquinones MICs in the range of 1.25 to 6.25 lg/mL. The results pre-
14a–j and 15a–j were easily distinguished by the signals sented in Table 4 show that compounds 15a, 15b, 15d,
between 75.0 to 79.9 ppm and 76.6 to 80.4 ppm, respec- 15e, and 15h, all of which contain a phenyl group, dem-
tively, due to differences at carbon-1 of the chromogenic onstrated high inhibitory activities, suggesting that the
ring.
phenyl group is important for in-vitro activity.
In order to evaluate this observation, we tested b-lapa-
chone, which has only two methyl groups at the same
Pharmacology
The microplate Alamar-Blue Assay was performed as position of the pyran ring present in the naphthoqui-
described by Reis et al. [39]. The antimycobacterial tests none series. The MIC value obtained for this compound
against M. tuberculosis ATTC 27294 of the derivatives was 12.5 lg/mL, well above the values obtained for com-
14a–j and 15a–j were performed using the colorimetric pounds in the b-pyran naphthoquinone series. These
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Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
a- and b-Pyran Naphthoquinones as Antitubercular Agents
85
results suggest that the presence of a bulky group in posi- General procedure for the preparation of 14a–j and
tion-2 of the pyran ring, such as a phenyl group, is impor- 15a–j
In a round-bottom flask equipped with a magnetic stirring bar,
lawsone 16 was dissolved (1 mmol) with water (10 mL) and etha-
nol (10 mL). Then, the appropriate aldehyde (8 mmol for the
formaldehyde and 3 mmol for arylaldehydes) was added. Substi-
tuted styrenes (3 mmol) were added dropwise and the reaction
mixture was stirred under reflux until total consumption of the
starting material. Ethanol was removed under reduced pressure,
ethyl acetate was added to the residue and the mixture was
washed with a saturated aqueous solution of sodium bicarbon-
ate. The combined organic extracts were washed with water,
dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The residual crude product was purified via silica-gel
column chromatography, using a gradient mixture of hexane-
ethyl acetate.
tant for antimicrobial activity. Another important obser-
vation is that the various substituents of the aromatic
rings had similar levels of activity. However, the methyl
group in compound 15b showed the most significant
level of inhibition, while an aromatic ring at position-4
of the pyran ring was found to decrease activity.
It is important to remark that lipophilicity was not an
important parameter for predicting the activity of a- and
b-pyran naphthoquinones. Calculated lipophilicity
(cLogP) indicated insignificant differences between the
two series, despite marked differences in antimicrobial
activity.
2-Phenyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione
14a
Conclusions
Yellow solid, m.p.: 168–1708C; IR (KBr, cm– 1) m: 1679, 1649,
1617, 1260, 1202, 1063, 958, 910, 721; 1H-NMR (CDCl3, 300 MHz)
d: 2.15 (1H, dddd, J = 2.6, 3.2, 5.7, and 14.0 Hz, H-3a), 2.30 (1H,
dddd, J = 2.2, 6.2, 6.5, and 14.0 Hz, H-3b), 2.63 (1H, ddd, J = 3.2,
6.2, and 13.7 Hz, H-4a), 2.77 (1H, ddd, J = 2.2, 5.7, and 13.7 Hz, H-
4b), 5.22 (1H, dd, J = 2.6 and 6.5 Hz, H-2), 7.32–7.40 (5H, m, 2-phe-
nyl), 7.68 (2H, dddd, J = 2.0, 7.5, 9.2, and 11.0 Hz, H-8 and H-7),
8.10 (2H, dddd, J =2.0, 7.5, 9.2, and 11.0 Hz, H-9 and H-6);13C-NMR
(CDCl3, 75 MHz) d: 18.3 (C-4), 27.6 (C-3), 78.8 (C-2), 121.4 (C-4a),
125.6 (C-49-phenyl), 125.8 (C-6), 126.1 (C-9), 128.1 (C-29-phenyl),
128.4 (C-39-phenyl), 130.8 (C-9a), 131.7 (C-5a), 132.9 (C-7, C-8), 133.7
(C-H-ar), 139.1 (C-19), 152.2 (C-10a), 184.0 (C-5 and C-10). HRMS
(ESI) calcd. for C19H14O3: 290.0943. Found: 290.0936.
Few naphthoquinones are described in the literature as
having antitubercular activity. The MICs found for the
compounds synthesized in this work are below the 6.25
lg/mL value postulated by the Global Program for the
Discovery of New Antituberculosis Drugs as an upper
threshold in the evaluation of new candidates for inhibit-
ing M. tuberculosis. Therefore, our results indicate that
analogues of b-lapachone bearing a bulky moiety in the
pyran ring are promising anti-TB agents, and that this
activity should be thoroughly investigated.
2-(p-Tolyl)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione
14b
Experimental
Yellow solid, m.p.: 135–1378C; IR (KBr, cm– 1) m: 1677, 1645,
1617, 1595, 1341, 1300, 1258, 1200, 1065, 958, 910, 816, 720; 1H-
NMR (CDCl3, 300 MHz) d: 2.06 (1H, dddd, J = 2.6, 3.4, 6.0, and 13.0
Hz, H-3a), 2.31 (1H, dddd, J = 2.3, 6.4, 6.3, and 13.0 Hz, H-3b), 2.36
(1H, s, CH3), 2.64 (1H, ddd, J = 3.4, 6.4, and 12.7 Hz, H-4a), 2.75
(1H, ddd, J = 2.3, 6.0, and 12.7 Hz, H-4b), 5.18 (1H, dd, J = 2.6 and
6.3 Hz, H-2), 7.1 (2H, dd, J = 7.7 Hz, H-meta tolyl), 7.27 (2H, dd, J =
7.7 Hz, H-ortho tolyl), 7.69 (2H, dddd, J = 1.0, 7.3, 9.0, and 10.7 Hz,
H-8 and H-7), 8.09 (2H, dddd, J = 1.0, 7.3, 9.0, and 10.7 Hz, H-9 and
H-6); 13C-NMR (CDCl3, 75 MHz) d: 18.8 (C-4), 21.4 (CH3), 28.0 (C-3),
79.2 (C-2), 121.8 (C-4a), 126.1 (C-6), 126.2 (C-9), 126.5 (C-29), 129.5
(C-39), 131.3 (C-9a), 133.7 (C-49), 134.1 (C-19), 136.3 (C-5a), 138.3 (C-
19), 155.8 (C-10a), 179.6 and 184.0 (C-5 and C-10). HRMS (ESI) calcd.
for C20H16O3: 304.1099. Found: 304.1261.
Chemistry
Reagents were purchased from Aldrich (Sigma-Aldrich, Ger-
many) or Acros Chemical Co. (Geel, Belgium), and were used
without further purification. Column chromatography was per-
formed with silica gel 60 (Merck 70-230 mesh; Merck, Germany).
Analytical thin-layer chromatography was performed with silica
gel plates (Merck, TLC silica gel 60 F254), and the plots were
visualized using UV light or aqueous solutions of sodium sulfate.
Yields refer to chromatographically and spectroscopically homo-
geneous materials. Melting points were obtained on a Fischer-
Johns apparatus (Fischer-Scientific, Pittsburgh, PA, USA), and are
uncorrected. Infrared spectra were measured using KBr pellets
on a Perkin-Elmer model 1420 FT-IR Spectrophotometer (Perkin-
Elmer, Norwalk, CT, USA), calibrated relative to the 1601.8 cm– 1
absorbance of polystyrene. NMR spectra were recorded on a Var-
ian Unity Plus VXR (300 MHz) instrument (Varian Inc., Palo Alto,
CA, USA) in DMSO-d6 and CDCl3 solutions. The chemical shift
data were reported in units of d (ppm) downfield from tetrame-
thylsilane, which was used as an internal standard; coupling
constants (J) are reported in Hertz, and refer to apparent peak
multiplicities. High resolution mass spectra (HRMS) were
recorded on MICROMASS Q-TOF Micro Mass spectrometer (Micro-
mass, Manchester, UK) using ESI-TOF (electrospray ionization-
time of flight).
2-(2,4-Dimethylphenyl)-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione 14c
Yellow solid, m.p.: 148–1528C; IR (KBr, cm– 1) m: 1673, 1646,
1617, 1590, 1261,1204, 1199, 1063, 961, 825, 718, 676; 1H-NMR
(CDCl3, 300 MHz) d: 1.99 (1H, dddd, J = 2.4, 3.4, 5.9, and 13.2 Hz,
H-3a), 2.25 (1H, dddd, J = 2.4, 6.4, 7.8, and 13.2 Hz, H-3b), 2.32 (3H,
s, CH3), 2.34 (3H, s, CH3), 2.64 (1H, ddd, J = 3.4, 6.4, and 13.0 Hz, H-
4a), 2.85 (1H, m, ddd, J = 2.4, 5.9, and 13.0 Hz, H-4b), 5.25 (1H, dd,
J = 2.4 and 7.8 Hz, H-2), 7.01 (1H, s, H-meta tolyl), 7.06 (1H, d, J =
7.8 Hz, H-ortho tolyl), 7.30 (1H, d, J = 7.8 Hz, H-meta tolyl), 7.69
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S. B. Ferreira et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
(2H, dddd, J = 2.0, 7.8, 9.2 and 10.7 Hz, H-8 and H-7), 8.10 (2H,
dddd, J = 2.0, 7.6, 9.2, and 10.7 Hz, H-9 and H-6); 13C-NMR (CDCl3,
75 MHz) d: 19.2 (CH3), 19.6 (C-4), 21.3 (CH3), 27.2 (C-3), 77.0 (C-2),
121.6 (C-4a), 125.9 (C-59 ortho tolyl), 126.2 and 126.5 (C-6 and C-9),
127.3 (C-69), 131.6 (C-39 ortho tolyl), 131.3 (C-9a), 132.2 (C-5a), 133.3
and 134.1 (C-7 and C-8), 134.7 and 134.9 (C-29 and C-49), 138.1 (C-
19), 156.2 (C-10a), 179.6 and 184.0 (C-5 and C-10). HRMS (ESI) calcd.
for C21H18O3: 318.1256. Found: 318.1196.
2-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione 14g
Yellow solid, m.p.: 165–1668C; IR (KBr, cm– 1) m: 1681, 1645,
1612, 1245, 1194, 1062, 1021, 953, 720; 1H-NMR (CDCl3, 300
MHz) d: 2.10 (1H, dddd, J = 2.6, 3.5, 6.4, and 13.0 Hz, H-3a), 2.28
(1H, dddd, J = 2.0, 6.1, 6.3, and 13.0 Hz, H-3b), 2.59 (1H, ddd, J =
3.5, 6.1, and 12.2 Hz, H-4a), 2.76 (1H, ddd, J = 2.0, 6.4, and 12.2 Hz,
H-4b), 5.14 (1H, dd, J = 2.6 and 6.3 Hz, H-2), 6.89 (2H, d, J = 8.3 Hz,
ArH), 7.30 (2H, d, J = 8.3 Hz, ArH), 7.69 (2H, dddd, J = 1.5, 7.5, 9.0,
11.0 Hz, H-8 and H-7), 8.09 (2H, dddd, J = 1.5, 7.5, 9.0, 10.9 Hz, H-9
and H-6); 13C NMR (CDCl3, 75 MHz) d: 19.0 (C-4), 28.0 (C-3), 55.5
(OCH3), 79.1 (C-2), 114.3 (C-4a), 126.2 (C-6), 126.5 (C-9), 133.5 (C-7),
134.1 (C-8), 131.3 (C-9a), 131.7 (C-5a), 155.8 (C-10a), 159.9 (C-49),
179.7 and 184.5 (C-5 and C-10). HRMS (ESI) calcd. for C21H18O3:
320.1049. Found: 320.3606.
2-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione 14d
Yellow solid, m.p.: 130–1328C; IR (KBr, cm– 1) m: 1677, 1650,
1620, 1597, 1260, 1202, 1095, 1065, 958, 911, 720; 1H-NMR
(CDCl3, 300 MHz) d: 2.03 (1H, dddd, J = 2.3, 3.2, 6.2, and 12.9 Hz,
H-3a), 2.30 (1H, dddd, J = 2.1, 6.3, 6.8, and 12.9 Hz, H-3b), 2.63 (1H,
ddd, J = 3.2, 6.3, and 12.4 Hz, H-4a), 2.76 (1H, ddd, J = 2.1, 6.2, and
12.4 Hz, H-4b), 5.17 (1H, dd, J = 2.3 and 6.8 Hz, H-2), 7.29–7.39
(4H, m, ArH), 7.70 (2H, dddd, J = 2.0, 7.8, 9.2, and 10.9 Hz, H-8 and
H-7), 8.10 (2H, dddd, J = 2.0, 7.8, 9.2 and 10.9 Hz, H-9 and H-6);13C-
NMR (CDCl3, 75 MHz) d: 18.8 (C-4), 28.1 (C-3), 78.5 (C-2), 121.8 (C-
4a), 126.3 (C-6), 126.6 (C-9), 127.5 (C-7), 129.1 (C-8), 133.4 (C-29),
134.2 (C-39), 131.2 (C-9a), 132.1 (C-49), 134.4 (C-5a), 138.1 (C-19);
155.4 (C-10a), 179.5 and 184.4 (C-5 and C-10). HRMS (ESI) calcd.
for C21H18O3: 324.0553. Found: 324.0175.
4-(4-Nitrophenyl)-2-p-tolyl-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione, syn-isomer 14h
Yellow solid, m.p.: 205–2078C; IR (KBr, cm– 1) m: 1677, 1649,
1612, 1516, 1344, 1305, 1266, 1209, 1106, 968, 900, 856, 818,
725; 1H-NMR (CDCl3, 300 MHz) d: 2.25 (1H, dt, J = 2.4 and 14.3 Hz,
H-3a), 2.35 (3H, s, CH3), 2.44 (1H, ddd, J = 5.7, 11.9, and 14.3 Hz, H-
3b), 4.52 (1H, dd, J = 1.5 and 5.7 Hz, H-4), 4.99 (1H, dd, J = 2.4 and
11.9 Hz, H-2), 7.17 (1H, d, J = 8.5 Hz, H-meta p-tolyl), 7.22 (1H, d, J =
8.5 Hz, H-ortho p-tolyl), 7.46 (1H, d, J = 8.6 Hz, H-ortho 4-nitro-
phenyl), 7.71–7.77 (1H, m, H-7), 7.71–7.77 (1H, m, H-8), 8.00–
8.06 (1H, m, H-9), 8.17–8.22 (1H, m, H-6), 8.22 (1H, d, J = 8.6 Hz, H-
meta 4-nitrophenyl); 13C-NMR (CDCl3, 75 MHz) d: 21.0 (CH3), 35.2
(C-4), 36.5 (C-3), 75.0 (C-2), 120.2 (C-4a), 124.0 (C-39 4-nitrophenyl),
126.0 (C-9), 126.3 (C-29 4-nitrophenyl), 126.5 (C-7), 128.5 (C-39 p-
tolyl), 129.3 (C-29 p-tolyl), 131.0 (C-9a), 131.7 (C-5a), 133.3 (C-6),
134.2 (C-8), 135.0 (C-49 p-tolyl), 138.5 (C-19 p-tolyl), 146.8 (C-49 4-
nitrophenyl), 151.0 (C-19 4-nitrophenyl), 156.6 (C-10a), 179.0 (C-
10), 183.1 (C-5).
2-(4-Fluorophenyl)-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione 14e
Yellow solid, m.p.: 171–1738C; IR (KBr, cm– 1) m: 1678, 1647,
1618, 1513, 1260, 1201, 1065, 958, 835, 720; 1H-NMR (CDCl3, 300
MHz) d: 2.15 (1H, dddd, J = 2.4, 3.3, 6.5, and 13.0 Hz, H-3a), 2.30
(1H, dddd, J = 2.1, 6.2, 7.0, and 13.0 Hz, H-3b), 2.75 (1H, ddd, J =
3.3, 6.2, and 12.5 Hz, H-4a), 2.80 (1H, ddd, J = 2.1, 6.5, and 12.5 Hz,
H-4b), 5.16 (1H, dd, J = 2.4 and 7.0 Hz, H-2), 7.08 (2H, t, J = 8.7, 2CH-
ar-F), 7.36–7.41 (2H, m, 2ArH), 7.70 (2H, dddd, J = 1.5, 7.5, 9.2,
and 11.0 Hz, H-8 and H-7), 8.10 (2H, dddd, J = 1.5, 7.5, 9.2, and
10.9 Hz, H-9 and H-6); 13C-NMR (CDCl3, 75 MHz) d: 18.5 (C-4), 27.8
(C-3), 78.3 (C-2), 115.3 and 115.6 (d, J = 21.4 Hz, 2CH-ar-F), 121.4 (C-
4a), 125.9 (C-6), 126.2 (C-9), 127.5 (C-7), 127.6 (C-8), 133.0 (C-29),
133.8 (C-39), 130.8 (C-9a), 131.8 (C-5a), 135.0 (C-49), 155.1 (C-10a),
179.1 and 184.0 (C-5 and C-10). HRMS (ESI) calcd. for C21H18O3:
308.0849. Found: 308.3238.
4-(4-nitrophenyl)-2-p-tolyl-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione, anti-isomer 14h
Yellow solid, m.p.: 231–2348C; IR (KBr, cm– 1) m: 1677, 1650,
1607, 1511, 1345, 1301, 1266, 1258, 1199, 961, 724; 1H-NMR
(CDCl3, 300 MHz) d: 2.25 (1H, dt, J = 2.4 and 14.3 Hz, H-3a), 2.35
(3H, s, CH3), 2.62 (1H, ddd, J = 2.2, 7.1, and 14.4 Hz, H-3b), 4.40
(1H, dd, J = 7.1 and 10.7 Hz, H-4), 5.20 (1H, dd, J = 2.0 and 11.0 Hz,
H-2), 7.18 (1H, d, J = 8.1 Hz, H-meta p-tolyl), 7.30 (1H, d, J = 8.1 Hz,
H-ortho p-tolyl), 7.35 (1H, d, J = 8.8 Hz, H-ortho 4-nitrophenyl),
7.67–7.74 (1H, m, H-7), 7.67–7.74 (1H, m, H-8), 7.90–7.93 (1H, m,
H-9), 8.11–8.17 (1H, m, H-6), 8.13 (1H, d, J = 8.8 Hz, H-meta 4-nitro-
phenyl); 13C-NMR (CDCl3, 75 MHz) d: 21.0 (CH3), 29.6 (C-3), 38.6 (C-
3), 79.2 (C-2), 122.8 (C-4a), 123.9 (C-39 4-nitrophenyl), 125.9 (C-9),
126.2 (C-29 4-nitrophenyl), 126.4 (C-7), 127.6 (C-39 p-tolyl), 129.3 (C-
29 p-tolyl), 130.8 (C-9a), 131.8 (C-5a), 133.3 (C-6), 134.2 (C-8), 134.8
(C-49 p-tolyl), 138.6 (C-19 p-tolyl), 146.4 (C-49 4-nitrophenyl), 151.2
(C-19 4-nitrophenyl), 157.4 (C-10a), 183.2 (C-10), 186.8 (C-5).
2-(4-Bromophenyl)-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione 14f
Yellow solid, m.p.: 167–1688C; IR (KBr, cm– 1) m: 1674, 1648,
1619, 1260, 1204, 1067, 909, 720; 1H-NMR (CDCl3, 300 MHz) d:
2.11 (1H, dddd, J = 2.4, 3.4, 6.5, and 12.7 Hz, H-3a), 2.27 (1H, dddd,
J = 2.3, 6.4, 7.0, and 12.7 Hz, H-3b), 2.62 (1H, ddd, J = 3.4, 6.4, and
12.6 Hz, H-4a), 2.76 (1H, ddd, J = 2.3, 6.5, and 12.6 Hz, H-4b), 5.15
(1H, dd, J = 2.4 and 7.0 Hz, H-2), 7.08 (2H, m, 2CH-ar-Br), 7.37–
7.40 (2H, m, 2ArH), 7.71 (2H, dddd, J = 1.5, 7.5, 9.2, and 11.0 Hz, H-
8 and H-7), 8.09 (2H, dddd, J = 1.5, 7.5, 9.2, and 11.0 Hz, H-9 and H-
6); 13C-NMR (CDCl3, 75 MHz) d: 18.3 (C-4), 27.7 (C-3), 78.1 (C-2),
121.4 (C-4a), 125.9 (C-6), 126.2 (C-9), 127.4 (C-7), 131.3 (C-8), 131.7
(C-29), 133.0 (C-39), 133.8 (C-49), 130.8 (C-9a), 122.1 (C-5a), 138.2 (C-
19), 155.0 (C-10a), 180.0 and 183.9 (C5 and C-10). HRMS (ESI) calcd.
for C21H18O3: 368.0048. Found: 367.9784.
4-Phenyl-2-p-tolyl-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione 14i
Yellow solid, m.p.: 203–2058C; IR (KBr, cm– 1) m: 1678, 1647,
1615, 1365, 1336, 1302, 1257, 1194, 1068, 1043, 960, 894, 812,
760, 725, 702; 1H-NMR (300 MHz, CDCl3) d: 2.13–2.32 (1H, m, H-
3a), 2.34 and 2.35 (3H, s, CH3), 2.44 (1H, ddd, J = 2.0, 7.3 and 14.4
Hz, H-3b), 4.29 (1H, dd, J = 7.3 and 11.0 Hz, H-4 anti isomer), 4.46
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
a- and b-Pyran Naphthoquinones as Antitubercular Agents
87
(1H, dd, J = 1.5 and 5.7 Hz, H-4 syn isomer), 5.06 (1H, dd, J = 3.2
and 11.0 Hz, H-2 syn isomer) and 5.12 (1H, dd, J = 1.2 and 11.0 Hz,
H-2 anti isomer), 7.14–7.34 (4H, m, p-tolyl), 7.14–7.34 (5H, m,
Ph), 7.63–7.72 (1H, m, H-7), 7.63–7.72 (1H, m, H-8), 7.91–7.94
(1H, m, H-9 anti isomer) and 8.02–8.05 (1H, m, H-9 syn isomer),
8.11–8.18 (1H, m, H-6); 13C-NMR (75 MHz, CDCl3) d: 21.4 (CH3),
35.6 and 39.3 (C-4), 37.3 and 41.2 (C-3), 75.5 and 79.9 (C-2), 125.0
(C-4a), 126.5 and 126.6 (C-9), 126.7 (C-7), 126.8 (C-29 Ph), 127.1 (C-39
Ph), 128.0 (C-39 p-tolyl), 128.9 and 129.1 (C-49 Ph), 129.5 and 129.6
(C-29 p-tolyl), 131.2 (C-9a), 132.5 (C-5a), 133.3 and 133.4 (C-6), 134.3
and 134.4 (C-8), 135.8 (C-49 p-tolyl), 138.6 (C-19 p-tolyl), 143.9 (C-49
Ph), 157.5 (C-10a), 179.9 (C-10), 183.4 (C-5).
Hz, H-3a), 2.33 (1H, dddd, J = 3.4, 6.3, 7.4, and 13.8 Hz, H-3b), 2.60
(1H, ddd, J = 3.2, 6.3 and 8.8 Hz, H-4a), 2.76 (1H, ddd, J = 3.4, 5.6
and 8.8 Hz, H-4b), 5.27 (1H, dd, J = 2.7 and 7.4 Hz, H-2), 7.39–7.46
(5H, m, 2-phenyl), 7.53 (1H, ddd, J = 1.0, 7.4, and 8.6 Hz, H-8), 7.64
(1H, ddd, J = 1.4, 7.6, and 9.1 Hz, H-9), 7.83 (1H, dd, J = 1.0 and 7.6
Hz, H-10), 8.01 (1H, dd, J = 1.4 and 7.6 Hz, H-7);13C-NMR (CDCl3, 75
MHz) d: 18.2 (C-4), 28.2 (C-3), 79.9 (C-2), 113.8 (C-4a), 123.9 (C-10),
125.6 (C-7), 125.7 (C-49-phenyl), 128.4 (C-8), 128.5 (C-29-phenyl),
128.6 (C-39-phenyl), 129.8 (C-6a), 130.6 (C-9), 131.9 (C-19-phenyl),
139.2 (C-10a), 162.7 (C-10b), 178.7 and 179.0 (C-5 and C-6). HRMS
(ESI) calcd. for C19H14O3: 290.0943. Found: 290.0944.
2-p-Tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione
4-(Thiophen-2-yl)-2-p-tolyl-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione, syn-isomer 14j
15b
Orange solid, m.p.: 165–1678C; IR (KBr, cm– 1) m: 1697, 1647,
Yellow solid, m.p.: 123–1258C; IR (KBr, cm– 1) m: 1680, 1650,
1614, 1338, 1299, 1261, 1205, 1063, 959, 896, 815, 721; 1H-NMR
(CDCl3, 300 MHz) d: 2.22–2.39 (2H, m, H-3), 2.36 (3H, s, CH3), 4.70
(1H, ddd, J = 0.7, 1.9 and 4.9 Hz, H-4), 5.23 (1H, dd, J = 2.9 and 11.2
Hz, H-2), 6.92 (1H, dt, J = 1.0 and 3.4 Hz, H-39 thiophen-2-yl), 6.96
(1H, dd, J = 3.7 and 5.1 Hz, H-49 thiophen-2-yl), 7.20 (1H, dd, J = 1.2
and 5.1 Hz, H-59 thiophen-2-yl), 7.20 (1H, d, J = 8.0 Hz, H-meta),
7.28 (1H, d, J = 8.0 Hz, H-ortho), 7.67–7.76 (1H, m, H-7), 7.67–7.76
(1H, m, H-8), 8.06–8.09 (1H, m, H-9), 8.13–8.16 (1H, m, H-6); 13C-
NMR (CDCl3, 75 MHz) d: 21.5 (CH3), 30.9 (C-4), 37.4 (C-3), 76.0 (C-2),
122.0 (C-4a), 124.5 (C-59 thiophen-2-yl), 125.5 (C-9), 126.5 (C-7),
126.7 (C-49 thiophen-2-yl), 127.3 (C-39 p-tolyl), 129.6 (C-29 p-tolyl),
131.4 (C-49 p-tolyl), 132.3 (C-6), 133.5 (C-8), 134.4 (C-39 thiophen-2-
yl), 136.0 (C-19 p-tolyl), 138.6 (C-29 thiophen-2-yl), 147.2 (C-11),
176.5 (C-10), 183.6 (C-5).
1605, 1590, 1572, 1393, 1301, 1280, 1158, 1076, 922, 771; H-
1
NMR (CDCl3, 300 MHz) d: 2.06 (1H, dddd, J = 2.4, 3.6, 5.6, and 12.7
Hz, H-3a), 2.31 (1H, dddd, J = 3.1, 6.2, 7.8, and 12.7 Hz, H-3b), 2.40
(3H, s, CH3), 2.59 (1H, ddd, J = 3.6, 6.2 and 8.7 Hz, H-4a), 2.77 (1H,
ddd, J = 3.1, 5.6, and 8.7 Hz, H-4b), 5.24 (1H, dd, J = 2.4 and 7.8 Hz,
H-2), 7.25 (2H, d, J = 7.7 Hz, H-meta tolyl), 7.32 (2H, d, J = 7.7 Hz, H-
ortho tolyl), 7.51 (1H, ddd, J = 1.4, 7.5, and 8.7 Hz, H-8), 7.62 (1H,
ddd, J = 1.4, 7.5, and 9.0 Hz, H-9), 7.81 (1H, dd, J = 1.2 and 7.8 Hz,
H-10), 8.01 (1H, dd, J = 1.4 and 7.5 Hz, H-7); 13C-NMR (CDCl3, 75
MHz) d: 18.7 (C-4), 21.4 (CH3), 28.6 (C-3), 80.4 (C-2), 114.3 (C-4a),
124.3 (C-10), 126.1 (C-7), 128.9 (C-8), 129.7 (C-29-phenyl), 130.2 (C-
6a), 131.0 (C-39-phenyl), 132.4 (C-99), 135.1 (C-19-phenyl), 136.7 (C-
49-phenyl), 138.7 (C-10a), 163.2 (C-10b), 178.8 and 179.8 (C-5 and
C-6). HRMS (ESI) calcd. for C20H16O3: 304.1099. Found: 304.1012.
2-(2,4-Dimethylphenyl)-3,4-dihydro-2H-
4-(Thiophen-2-yl)-2-p-tolyl-3,4-dihydro-2H-
benzo[h]chromene-5,6-dione 15c
Orange solid, m.p.: 164–1678C; IR (KBr, cm– 1) m: 1694, 1646,
benzo[g]chromene-5,10-dione, anti-isomer 14j
Yellow solid, m.p.: 172–1758C; IR (KBr, cm– 1) m: 1678, 1649,
1611, 1363, 1333, 1300, 1256, 1192, 1041, 954, 892, 847, 814,
1603, 1574, 1394, 1283, 1231, 1034, 998, 775; H-NMR (CDCl3,
1
300 MHz) d: 1.99 (1H, dddd, J = 2.4, 3.0, 5.3, and 12.2 Hz, H-3a),
2.26 (1H, dddd, J = 2.4, 6.6, 7.8, and 12.2 Hz, H-3b), 2.36 (3H, s,
CH3); 2.38 (3H, s, CH3), 2.59 (1H, ddd, J = 3.0, 6.6, and 8.7 Hz, H-4a),
2.85 (1H, ddd, J = 2.4, 5.3, and 8.7 Hz, H-4b), 5.35 (1H, dd, J = 2.4
and 7.8 Hz, H-2), 7.10 (2H, d, J = 7.8 Hz, H-ortho and meta tolyl),
7.33 (1H, d, J = 7.8 Hz, H-meta tolyl), 7.51 (1H, ddd, J = 1.2, 7.5, and
8.7 Hz, H-8), 7.61 (1H, ddd, J = 1.4, 7.5, and 9.0 Hz, H-9), 7.71 (1H,
dd, J = 0.9 and 7.8 Hz, H-10), 8.06 (1H, dd, J = 1.4 and 7.5 Hz, H-7);
13C-NMR (CDCl3, 75 MHz) d: 19.2 (CH3), 19.2 (C-4), 21.2 (CH3), 27.5
(C-3), 77.9 (C-2), 114.2 (C-4a), 124.3 (C-59 ortho tolyl), 125.8 (C-6 and
C-9), 127.3 (C-69), 128.9 (C-39 ortho tolyl), 130.9 (C-9a), 131.8 (C-5a),
134.6 (C-19),130.2 (C-6a), 132.4 (C-10a), 135.1 and 138.5 (C-29 and C-
49), 163.5 (C-10b), 178.7 and 179.8 (C-5 and C-10). HRMS (ESI)
calcd. for C21H18O3: 318.1256. Found: 318.1892.
1
721; H-NMR (CDCl3, 300 MH) d: 2.28–2.43 (1H, m, H-3a), 2.40
(3H, s, CH3), 2.68 (1H, ddd, 2.1, 7.1 and 14.4 Hz, H-3b), 4.57 (1H,
dd, J = 7.1 and 11.0 Hz) and 4.65 (1H, dd, J = 1.0 and 3.2 Hz, H-4
conformers), 5.23 (1H, dd, J = 1.9 and 11.5 Hz) and 5.35 (1H, dd, J
= 4.4 and 10.0 Hz, H-2 conformers), 6.89 and 6.90 (1H, dd, J = 1.0
and 3.4 Hz, H-39 thiophen-2-yl conformers), 6.86 and 6.95 (1H, dd,
J = 3.7 and 5.1 Hz, H-49 thiophen-2-yl conformers), 7.06 and 7.18
(1H, dd, J = 1.2 and 5.1 Hz, H-59 thiophen-2-yl conformers), 7.24
and 7.25 (1H, d, J = 8.0 Hz, H-meta conformers), 7.30 and 7.36 (1H,
d, J = 8.0 Hz, H-ortho conformers), 7.54 and 7.57 (1H, td, J = 1.2
and 7.6 Hz, H-8 conformers), 7.63 and 7.65 (1H, dt, J = 1.2 and 7.6
Hz, H-7 conformers), 7.89 (1H, d, J = 7.6 Hz, H-9), 8.09 and 8.13
(1H, dd, J = 1.5 and 7.6 Hz, H-6 conformers); 13C-NMR (CDCl3, 75
MHz) d: 21.4 (CH3), 30.9 (C-4), 41.5 (C-3), 79.9 (C-2), 124.4 (C-4a),
124.6 (C-59 thiophen-2-yl), 126.4 (C-9), 126.5 (C-7), 126.6 (C-49 thio-
phen-2-yl), 127.0 (C-39 p-tolyl), 129.6 (C-29 p-tolyl), 131.2 (C-49 p-
tolyl), 132.5 (C-6), 133.4 (C-8), 134.4 (C-39 thiophen-2-yl), 135.5 (C-
19 p-tolyl), 138.7 (C-29 thiophen-2-yl), 146.6 (C-11), 179.8 (C-10),
183.7 (C-5).
2-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione 15d
Orange solid, m.p.: 143–1458C; IR (KBr, cm– 1) m: 1697, 1647,
1574, 1607, 1393, 1291, 1092, 923, 774, 725; 1H-NMR (CDCl3, 300
MHz) d: 2.01 (1H, dddd, J = 2.4, 3.5, 5.8, and 12.9 Hz, H-3a), 2.32
(1H, dddd, J = 3.3, 6.5, 7.8, and 12.9 Hz, H-3b), 2.63 (1H, ddd, J =
3.5, 6.5, and 8.9 Hz, H-4a); 2.74 (1H, ddd, J = 3.3, 5.8, and 8.8 Hz, H-
4b); 5.24 (1H, dd, J = 2.4 and 7.8 Hz, H-2), 7.36–7.45 (4H, m, H-ar),
7.53 (1H, ddd, J = 1.2, 7.5, and 8.5 Hz, H-8), 7.64 (1H, ddd, J = 1.4,
7.5, and 9.0 Hz, H-9), 7.83 (1H, dd, J = 1.2 and 7.8 Hz, H-10), 8.01
(1H, dd, J = 1.9 and 8.0 Hz, H-7); 13C-NMR (CDCl3, 75 MHz) d: 18.2
2-Phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione
15a
Orange solid, m.p.: 161–1638C; IR (KBr, cm– 1) m: 1696, 1647,
1
1605, 1573, 1397, 1300, 1280, 1232, 1158, 1093, 922, 700; H-
NMR (CDCl3, 300 MHz) d: 2.08 (1H, dddd, J = 2.7, 3.2, 5.6, and 13.8
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88
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(C-4), 28.2 (C-3), 79.2 (C-2), 113.8 (C-4a), 123.8 (C-10), 127.1 (C-7),
128.6 (C-8), 128.8 (C-29), 129.8 (C-6a), 130.7 (C-39), 131.9 (C-99), 134.2
(C-49), 134.8 (C-19), 137.7 (C-10a), 162.5 (10b), 178.3 and 179.2 (C-5
and C-6); HRMS (ESI) calcd. for C21H18O3: 324.0553 Found:
324.8102.
4-(4-Nitrophenyl)-2-p-tolyl-3,4-dihydro-2H-
benzo[h]chromene-5,6-dione 15h
Orange solid, m.p.: 232–2358C; IR (KBr, cm– 1) m: 1696, 1645,
1600, 1570, 1513, 1344, 1287, 1233, 1168, 1091, 912, 736, 702;
1H-NMR (300 MHz, CDCl3) d: 2.19 (1H, dt, J = 2.4 and 14.4 Hz, H-3a
syn isomer) and 2.27 (1H, dt, J = 11.2 and 14.4 Hz, H-3a anti iso-
mer), 2.38 and 2.39 (3H, s, CH3), 2.55 (1H, ddd, J = 5.9, 12.0 and
14.4 Hz, H-3b syn isomer) and 2.61 (1H, ddd, J = 2.2, 7.1 and 14.4
Hz, H-3b anti isomer), 4.31 (1H, dd, J = 7.1 and 11.0 Hz, H-4 anti
isomer) and 4.48 (1H, dd, J = 2.4 and 5.9 Hz, H-4 syn isomer), 5.07
(1H, dd, J = 2.4 and 12.0 Hz, H-2 syn isomer) and 5.31 (1H, dd, J =
2.2 and 11.2 Hz, H-2 anti isomer), 7.25 (1H, d, J = 8.1 Hz, H-meta p-
tolyl), 7.35 (1H, d, J = 8.1 Hz, H-ortho p-tolyl), 7.38 and 7.47 (1H, d, J
= 8.8 Hz, H-ortho 4-nitrophenyl), 7.56–7.94 (1H, m, H-7), 7.56–
7.94 (1H, m, H-8), 8.11 (1H, d, J = 8.8 Hz, H-meta 4-nitrophenyl),
8.09–8.23 (1H, m, H-9), 8.09–8.23 (1H, m, H-6);13C-NMR (75 MHz,
CDCl3) d: 21.1 (CH3), 34.9 and 38.4 (C-4), 36.7 and 39.8 (C-3), 80.0
(C-2), 115.9 (C-4a), 123.8 and 123.9 (C-39 4-nitrophenyl), 124.0 (C-29
4-nitrophenyl), 125.9 and 126.0 (C-39 p-tolyl), 127.7 (C-8), 128.6 (C-
7), 128.8 and 129.0 (C-29 p-tolyl), 129.5 (C-10), 130.3 (C-6a), 130.4
(C-19 p-tolyl), 131.3 (C-9), 131.7 (C-49 p-tolyl), 135.0 (C-10a), 138.9 (C-
49 4-nitrophenyl), 151.1 (C-19 4-nitrophenyl), 164.9 (C-10b), 177.6
(C-5), 178.7 (C-6). HRMS (ESI) calcd. for C26H19NO5H+: 426.1336.
Found: 426.4483.
2-(4-Fluorophenyl)-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione 15e
Orange solid, m.p.: 142–1478C; IR (KBr, cm– 1) m: 1573, 1607,
1513, 1394, 1280, 1229, 1156, 922; 1H-NMR (CDCl3, 300 MHz) d:
2.07 (1H, dddd, J = 2.4, 3.2, 5.6, and 12.8 Hz, H-3a), 2.34 (1H, dddd,
J = 3.1, 6.5, 7.8, and 12.8 Hz, H-3b), 2.61 (1H, ddd, J = 3.2, 6.5, and
8.7 Hz, H-4a), 2.75 (1H, ddd, J = 3.1, 5.6, and 8.7 Hz, H-4b), 5.24
(1H, dd, J = 2.4 and 7.8 Hz, H-2), 7.15 (2H, t, J = 8.5 Hz, 2CH-ar-F),
7.39–7.44 (2H, m, H-ar), 7.53 (1H, ddd, J = 1.2, 7.2 and 8.7 Hz, H-
8), 7.64 (1H, ddd, J = 1.4, 7.8, and 9.2 Hz, H-9), 7.83 (1H, dd, J = 1.1
and 6.5 Hz, H-10), 8.01 (1H, dd, J = 1.1 and 6.3 Hz, H-7); 13C-NMR
(CDCl3, 75 MHz) d: 18.3 (C-4), 28.3 (C-3), 79.4 (C-2), 113.8 (C-4a),
115.4 and 115.7 (d, J = 21.4 Hz, C-39), 123.8 (C-10), 127.5 (C-7),
127.6 (C-8), 128.6 (C-19), 129.8 (C-6a), 130.7 (C-39), 131.8 (C-29), 134.7
(C-99), 135.7 (C-49), 137.7 (C-10a), 162.6 (C-10b), 178.4 and 179.2
(C-5 and C-6). HRMS (ESI) calcd. for C21H18O3: 308.0849. Found:
308.3243.
4-Phenyl-2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione 15i
Orange solid, m.p.: 92–958C; IR (KBr, cm– 1) m: 1696, 1653, 1600,
1568, 1382, 1284, 1231, 1164, 1086, 909, 767, 699; 1H-NMR (300
MHz, CDCl3) d: 2.13–2.37 (1H, m, H-3a), 2.38 and 2.39 (3H, s, CH3),
2.59 (1H, ddd, J = 2.0, 7.3 and 14.4 Hz, H-3b), 4.20 (1H, dd, J = 7.1
and 11.2 Hz, H-4 anti isomer) and 4.42 (1H, dd, J = 1.7 and 5.4 Hz,
H-4 syn isomer), 5.15 (1H, dd, J = 2.7 and 12.0 Hz, H-2 syn isomer)
and 5.24 (1H, dd, J = 1.7 and 12.0 Hz, H-2 anti isomer), 7.13–7.38
(4H, m, p-tolyl), 7.13–7.38 (5H, m, Ph), 7.52–7.60 (1H, m, H-7),
7.64–7.70 (1H, m, H-8), 7.88–7.92 (1H, m, H-9), 8.07–8.10 (1H, m,
H-6 anti isomer) and 8.12–8.15 (1H, m, H-6 syn isomer); 13C-NMR
(75 MHz, CDCl3) d: 21.1 (CH3), 34.6 and 38.5 (C-4), 40.6 (C-3), 80.1
(C-2), 117.5 (C-4a), 124.5 (C-39 Ph), 126.0 and 126.1 (C-39 p-tolyl),
126.3 (C-29 Ph), 126.7 and 126.8 (C-49 Ph), 128.4 (C-8), 128.5 and
128.6 (C-7), 129.2 and 129.3 (C-29 p-tolyl), 130.2 (C-6a), 130.8 (C-
10), 132.1 (C-19 p-tolyl), 134.8 (C-9), 135.6 (C-49 p-tolyl), 138.6 (C-
10a), 143.3 (C49Ph), 164.1 (C-10b), 178.0 (C-5), 179.1 (C-6). HRMS
(ESI) calcd. for C26H20O3H+: 381.1485. Found: 381.4503.
2-(4-Bromophenyl)-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione 15f
Orange solid, m.p.: 169–1708C; IR (KBr, cm– 1) m: 1726, 1648,
1
1604, 1390, 1283, 1073, 922, 775; H-NMR (CDCl3, 300 MHz) d:
2.05 (1H, dddd, J = 2.4, 3.7, 5.6, and 12.9 Hz, H-3a), 2.32 (1H, dddd,
J = 3.3, 6.5, 7.8, and 12.9 Hz, H-3b), 2.55 (1H, ddd, J = 3.7, 6.5, and
8.8 Hz, H-4a), 2.75 (1H, ddd, J = 3.3, 5.6, and 8.8 Hz, H-4b), 5.23
(1H, dd, J = 2.4 and 7.8 Hz, H-2), 7.29–7.33 (2H, m, H-ar), 7.51–
7.72 (5H, m, H-8, H-9 and 2H-ar), 7.80 (1H, dd, J = 1.1 and 7.8 Hz,
H-10), 8.01 (1H, dd, J = 1,1 and 7.5 Hz, H-7); 13C-NMR (CDCl3, 75
MHz) d: 18.2 (C-4), 28.2 (C-3), 79.3 (C-2), 113.8 (C-4a), 123.8 (C-10),
127.4 (C-7), 127.6 (C-8), 128.7 (C-29), 129.8 (C-6a), 130.7 (C-39), 131.8
(C-99), 134.8 (C-19), 132.8 (C-49), 138.2 (C-10a), 162.4 (C-10b), 178.4
and 178.2 (C5 and C-6). HRMS (ESI) calcd. for C21H18O3: 368.0048.
Found: 367.9640.
2-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[h]chromene-
4-(Thiophen-2-yl)-2-p-tolyl-3,4-dihydro-2H-
5,6-dione 15g
benzo[h]chromene-5,6-dione 15j
Orange solid, m.p.: 155–1578C; IR (KBr, cm– 1) m: 1605, 1572,
Orange solid, m.p.: 83–878C; IR (KBr, cm– 1) m: 1696, 1652, 1599,
1568, 1383, 1284, 1231, 1170, 1086, 907, 818, 722, 697; 1H-NMR
(300 MHz, CDCl3) d: 2.28–2.43 (1H, m, H-3a), 2.40 (3H, s, CH3),
2.68 (1H, ddd, 2.1, 7.1 and 14.4 Hz, H-3b), 4.57 (1H, dd, J = 7.1 and
11.0 Hz) and 4.65 (1H, dd, J = 1.0 and 3.2 Hz, H-4 conformers),
5.23 (1H, dd, J = 1.9 and 11.5 Hz) and 5.35 (1H, dd, J = 4.4 and 10.0
Hz, H-2 conformers), 6.89 and 6.90 (1H, dd, J = 1.0 and 3.4 Hz, H-39
thiophen-2-yl conformers), 6.86 and 6.95 (1H, dd, J = 3.7 and 5.1
Hz, H-49 thiophen-2-yl conformers), 7.06 and 7.18 (1H, dd, J = 1.2
and 5.1 Hz, H-59 thiophen-2-yl conformers), 7.24 and 7.25 (1H, d, J
= 8.0 Hz, H-meta conformers), 7.30 and 7.36 (1H, d, J = 8.0 Hz, H-
ortho conformers), 7.54 and 7.57 (1H, td, J = 1.2 and 7.6 Hz, H-8
conformers), 7.65 and 7.67 (1H, dt, J = 1.2 and 7.6 Hz, H-9 con-
formers), 7.90 (1H, d, J = 7.6 Hz, H-10), 8.09 and 8.13 (1H, dd, J =
1
1525, 1280, 1249, 1170, 921, 774; H-NMR (CDCl3, 300 MHz) d:
2.11 (1H, dddd, J = 2.4, 3.6, 5.7, and 13.0 Hz, H-3a), 2.31 (1H, dddd,
J = 3.2, 6.2, 7.8, and 13.0 Hz, H-3b), 2.61 (1H, ddd, J = 3.6, 6.2, and
8.7 Hz, H-4a), 2.76 (1H, ddd, J = 3.2, 5.7, and 8.7 Hz, H-4b), 3.85
(3H, s, OCH3), 5.20 (1H, dd, J = 2.4 and 7.8 Hz, C-2), 6.96–6.99 (2H,
m, H-ar), 7.34–7.37 (2H, m, H-ar), 7.51 (1H, ddd, J = 1.4, 7.5 and
8.7 Hz, H-8), 7.60 (1H, ddd, J = 1.4, 7.5, and 9.0 Hz, H-9), 7.80 (1H,
dd, J = 1.2 and 7.8 Hz, H-10), 8.08 (1H, dd, J = 1.4 and 7.5 Hz, H-7);
13C-NMR (CDCl3, 75 MHz) d: 18.4 (C-4), 28.0 (C-3), 55.2 (OCH3), 79.9
(C-2), 113.8 (C-4a), 114.0 (C-10), 123.9 (C-7), 127.2 (C-8), 128.5 (C-29),
129.8 (C-6a), 130.6 (C-39), 131.2 (C-99), 132.0 (C-10a), 134.7 (C-19),
159,6 (C-49), 162.9 (C-10b), 178.4 and 179.4 (C-5 and C-6). HRMS
(ESI) calcd. for C21H18O3: 320.1049. Found: 320.3596.
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Arch. Pharm. Chem. Life Sci. 2010, 343, 81–90
a- and b-Pyran Naphthoquinones as Antitubercular Agents
89
1.5 and 7.6 Hz, H-7 conformers); 13C-NMR (75 MHz, CDCl3) d: 21.0
(CH3), 30.1 and 33.4 (C-4), 37.1 and 40.9 (C-3), 76.6 and 80.0 (C-2),
115.2 and 117.2 (C-4a), 122.7 and 123.9 (C-59 thiophen-2-yl), 124.5
and 124.6 (C-39 p-tolyl), 125.0 (C-8), 126.0 and 126.1 (C-29 p-tolyl),
126.4 and 126.9 (C-10), 128.6 and 128.7 (C-7), 129.3 (C-49 thio-
phen-2-yl), 130.2 and 130.3 (C-6a), 130.9 and 131.0 (C-9), 131.7
and 131.9 (C-19 p-tolyl), 134.7 and 134.8 (C-39 thiophen-2-yl), 135.3
and 135.7 (C-49 p-tolyl), 138.5 and 138.6 (C-10a), 146.2 and 146.7
(C-29 thiophen-2-yl), 163.0 and 163.4 (C-10b), 177.7 and 178.0 (C-
5), 179.0 (C-6). HRMS (ESI) calcd. for C24H18O3SH+: 387.1049.
Found: 387.4789.
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