Facile diversity-oriented synthesis and antitubercular evaluation of novel aryl and heteroaryl tethered pyridines and dihydro-6H-quinolin-5-ones derived via variants of the Bohlmann-Rahtz reaction

Article abstract of DOI:10.1021/co2000604

The diversity oriented synthesis of substituted pyridines and dihydro-6H-quinolin-5-ones tethered with aryls and heteroaryls was achieved in very good yields through CeCl₃?7H₂O-NaI catalyst via variants of the Bohlmann-Rahtz reaction

Full text of DOI:10.1021/co2000604

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Facile Diversity-Oriented Synthesis and Antitubercular Evaluation
of Novel Aryl and Heteroaryl Tethered Pyridines and
Dihydro-6H-quinolin-5-ones Derived via Variants of the
BohlmannꢀRahtz Reaction
Srinivas Kantevari,*,† Santhosh Reddy Patpi,† Dinesh Addla,† Siddamal Reddy Putapatri,†
Balasubramanian Sridhar,‡ Perumal Yogeeswari,§ and Dharmarajan Sriram§
†Organic Chemistry Division-II and ‡Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology,
Hyderabad 500007, India
§Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani,
Hyderabad Campus, Jawahar Nagar, Hyderabad-500078, India
S Supporting Information
b
ABSTRACT: The diversity oriented synthesis of substituted
pyridines and dihydro-6H-quinolin-5-ones tethered with aryls
and heteroaryls was achieved in very good yields through
CeCl3 7H2O-NaI catalyst via variants of the BohlmannꢀRahtz
3
reaction. β-Enaminones derived from various aryl and hetero-
aryl methyl ketones were regioselectively reacted with ethyl
acetoacetate or 5,5-dimethylcyclohexane-1,3-dione or 4,4-di-
methylcyclohexane-1,3-dione and ammonium acetate refluxing
in 2-propanol. Applicability of nontoxic cerium catalyst, high
reactivity with wide range of aryl and heteroaryl β-enaminones
leading to diverse analogues, operational simplicity, and shorter
reaction time at comparatively low temperatures are prominent
features of the developed protocol. These synthesized substituted pyridines and dihydro-6H-quinolin-5-one analogues have been
evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method.
Among the 48 compounds screened, six compounds 2-(5-chlorothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
4{13,2}, 2-(5-bromothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{14,2}, 2-(5-chloro thiophen-2-yl)-6,6-dimethyl-
7,8-dihydroquinolin-5(6H)-one 4{13,3}, and 2-(5-bromothiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{14,3},
7,7-dimethyl-2-(naphthalen-2-yl)-7,8-dihydroquinoline-5(6H)-one 4{6,2}, 6,6-dimethyl-2-(naphthalen-2-yl)-7,8-di hydroquinolin-5(6H)-
one 4{6,3} resulted as the most promising antitubercular agents.
KEYWORDS: enaminones, cerium(III) chloride, pyridines, regioselectivity, BohlmannꢀRahtz reaction, dihydroquinolinones
’ INTRODUCTION
numerous synthetic strategies for the preparation of these scaffolds
have been developed. Among them, one-pot creation of 2,3,6-
trisubstituted pyridines through the reaction of alkynones with
1,3-dicarbonyls under modified BohlmannꢀRahtz conditions
is prominent one (Figure 2A).4 Here, the functionalized alky-
nones and 1,3-dicarbonyls were custom synthesized and used as
starting materials to annelate the trisubstituted pyridine system.5
β-Enaminones, because of the presence of ambident nucleophilic
character of enamine moiety and the ambident elctrophilic char-
acter of enone moiety, turned out to be simple synthetic inter-
mediates6 for the subject of the present synthesis (Figure 2B).
Taking advantage of their electronic properties, we envisioned to
use aryl and heteroaryl embodied β-enaminones as polarized
In the current era of chemical genomics, the rapid identifica-
tion of small molecules having efficacy to perturb the functions
of enzymes and receptors is a major challenge for understanding
the complex biological events and hence diseases.1 Research in
this direction has shown a dramatic shift of focus from natural
products to the combinatorial chemistry and diversity oriented
synthesis (DOS).2 In this contest, polysubstituted pyridines and
dihydro-6H-quinolin-5-ones have gained considerable atten-
tion in recent years because of their broad spectrum biological
activity. Notable among them are thiopeptide antibiotics, Strep-
tonigrin, Lavendamycin (anti cancer), and MRZ-8676 (mGluR5
modulator) having substituted pyridine as central core unit
(Figure 1).3 With the exponential increase in potential ther-
apeutic targets, a series of skeletal and stereochemical analogues
have to be generated by using synthesis to meet demand on
access to novel and diverse chemical libraries.1,2 Therefore,
Received: March 28, 2011
Revised:
June 8, 2011
Published: June 14, 2011
r
2011 American Chemical Society
427
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|

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RESEARCH ARTICLE
Figure 1. Representative bioactive quinolinone analogues.
1{1ꢀ16} (here after called as enaminones) derived from the
respective commercially available aryl and heteroaryl methyl
ketones; with readily available ethyl acetoacetate 2{1} or cyclic
1,3-dicarbonyls 2{2ꢀ3} and ammonium acetate in the presence
of catalytic amount of CeCl3 7H2O-NaI resulted title com-
3
pounds with high regioselectivity at 2,3,6-positions. Furthermore
the current method allows facile preparation of a library of novel
substituted dihydroquinolin-5-ones for screening their biological
activity. Among all the new compounds tested for in vitro
antimycobacterial activity against Mycobacterium tuberculosis
H37Rv (MTB), four compounds 4{13,2}, 4{14,2}, 4{13, 3},
and 4{14, 3} (MIC 3.13 μg/mL) and two compounds 4{6,2}
and 4{6, 3} (MIC 1.56 μg/mL) resulted as the most active
antitubercular agents.
Figure 2. Approaches for the preparation of 2, 3, 6-trisubstituted
pyridines.
’ RESULTS AND DISCUSSION
variants of acetylenic ketones in the synthesis of 2,3,6-trisubsti-
tuted pyridines and quinolin-5-ones with three points of
diversity.7
β-Enaminones 1{1ꢀ16} (Figure 3) are generally prepared by
the condensation of respective aryl and heteroaryl methyl
ketones with dimethylformamide dimethylacetal (DMF-DMA)
in refluxing xylene.11
Synthesis of these substituted pyridines are reported by the
reaction of β-enaminones with β-dicarbonyls in the presence of
ammonium acetate in refluxing acetic acid, or by using Mont-
morillonite K10 in 2-propanol.8 However, these methods suffer
from low yields and exhibit limited substrate tolerance and
reactivity. Recently, among the lanthanide catalysts, Cerium(III)
chloride has emerged as a very cheap and efficient green reagent
(in fact, it shows the same toxicity level as sodium chloride) and is
able to catalyze various selective CꢀC bond forming reactions
and cyclizations.9 In most cases, the reactivity of CeCl3 can be
increased in combination with NaI.9 The successful utility of
Cerium(III) in reactions originated from 1,3-dicarbonyls10
prompted us to investigate its applicability in oneꢀpot conden-
sation of various β-enaminones derived from aryl and heteroaryl
methyl ketones with 1,3-dicarbonyls and ammonium acetate.
On the basis of our progressive endeavors in exploring
Although the method is readily adopted, there is no synthetic
protocol for the preparation of several β-enaminones used in this
work. Literature described11 β-enaminones were synthesized by
a protocol standardized in our laboratory.7 Extending it to other
heteroaryl β-enaminones, (E)-1-(Dibenzo[b,d] thiophene-2-yl)-
3-(dimethylamino)-2-propenone 1{7}, (E)-3-Dimethyl amino-
1-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]propenone 1{10},
(E)-1-(5-Chlorothiophen-2-yl)-3-dimethylaminopropenone 1{13},
(E)-6-(3-Dimethylaminoacryloyl-3-methyl-3H-benzothiazol-
2-one 1{15}, and (E)-6-(3-Dimethylamino acryloyl)-4-methyl-
4H-benzo[1,4]xazin-3-one 1{16} were synthesized in excellent
yields. In case of 1{15} and 1{16}, methylation occurred at
nitrogen prior to enaminone formation, and excess of DMF-
DMA (4 equiv) was required to complete the conversion. All
new as well as known enaminones 1{1ꢀ16} were fully char-
acterized by 1H, 13C NMR and mass spectral analysis. Further,
the structure of enaminone 1{9} was confirmed by single crystal
X-ray analysis (Figure 4).
novel one-pot reactions,7 we herein report an efficient CeCl3
3
7H2O-NaI catalyzed regioselective conversion of β-enaminones
1{1ꢀ16} to novel substituted pyridines 3 {(1ꢀ16),1} and
dihydro-6H-quinolin-5-ones 4{(1ꢀ16),(2ꢀ3)} having appended
aryl and heteroaryl groups through Michael addition, cyclodehydra-
tion and elimination sequence. One-pot reaction of substituted
(E)-aryl and (E)-heteroaryl 3-(dimethylamino)-3-prop-2-enone
To affect the desired conversion of β-enaminones (polarized
variant of BohlmannꢀRahtz substrate, alkynones) to substi-
tuted pyridines, we examined the three component reaction of
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RESEARCH ARTICLE
Figure 3. Diversity of reagents.
Figure 4. ORTEP diagrams of β-enaminone 1{9} with thermal displacement ellipsoids drawn at the 30% probability level.
(E)-1-(thiophene-2-yl)-3-(dimethylamino)-2-propenone 1{12},
ethyl acetoacetate 2{1}, and ammonium acetate in the presence
of different catalysts and reaction conditions. The results ob-
tained are outlined in Table 1. The reaction was facile when
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RESEARCH ARTICLE
Table 1. Evaluation of Potential Catalystsa
CeCl3 7H2O-NaI in 2-propanol at reflux temperature gave
3
exclusively 2-(5-chlorothiophen-2-yl)-6,6-dimethyl-7,8-dihydro-
quinolin-5(6H)-one 4 {13,3} in 65% yield. The formation of the
other possible regioisomer 5 was not observed in all these
reactions. The compound 4 {13, 3} was fully characterized by
1H and 13C NMR, IR, mass (ESI and HRMS) spectral data, and
single crystal X-ray diffraction studies. The methylene protons of
C7 and C8 in dihydroquinolinone moiety appeared as two
triplets at δ 2.02 and 3.12, respectively. The regioselectivity of
the gem dimethyl substituents at C6 position in dihydroquinolin-
5(6H)-one 4 {13, 3} was unambiguously confirmed by single
crystal X-ray studies (Figure 6).
entry
catalyst
mol %
time (h)
yield (%)b
1
2
AcOH
24
24
6
15.0
12
montmorilonite-K10
30
30
20
20
20
20
20
20
20
3
K5CoW12O40 3H2O
48.0
18.0
32.0
8.0
3
Similarly, the regioselectivity in 6,6-dimethyl-2-p-tolyl-7,8-
dihydroquinolin-5(6H)-one 4{2,3} was also confirmed by single
crystal X-ray analysis (Figure 7). The structures of all other 6,6-
dimethyl-7,8-dihydroquinolin-5(6H)-ones 4{(1ꢀ16),3} were
4
Co(OAc)2 4H2O
24
24
24
24
24
4.0
24
3
5
CeCl3 7H2O
3
6
SnCl2 2H2O
3
1
also assigned using their H and 13C NMR, IR, mass (ESI and
7
Mg(ClO4)2
13.0
∼3.0
84.0
8
CeCl3 (Anhyd)
HRMS) spectral data. The observed regioselectivity for dihy-
droquinolin-5(6H)-ones 4{(1ꢀ16), 3} is due to their initial
selective formation of 3-amino-6,6-dimethylcyclohex-2-enone 6
rather than 3-amino-4,4-dimethylcyclohex-2-enone 7 (Figure 8).
A probable reason for the selectivity could be a steric effect. The
conversion of carbonyl group to enamine would be through the
formation of quaternary aminol 6A and 7A. The formation of 7A,
is less likely because the carbonyl adjacent to another quaternary
carbon, the gem dimethyl, would be having significantly higher
transition state energy trying to quaternize prior to dehydration.
Such transition state energy might favors 6A rather than 7A.
All the synthesized substituted pyridines 3{(1ꢀ16), 1} and
dihydro-6H-quinolin-5-one analogues 4{(1ꢀ16), (2ꢀ3)} have
been evaluated for their in vitro antimycobacterial activity against
M. tuberculosis H37Rv (MTB) by the agar dilution method. The
minimum inhibitory concentration (MIC) is defined as the
minimum concentration of the compound required to comple-
tely inhibit the bacterial growth. The determination of MIC
values was performed in triplicate at pH 7.40. The MICs of the
synthesized compounds 3{(1ꢀ16), 1}, 4{(1ꢀ16), (2ꢀ3)}
along with the standard drugs for comparison are depicted in
Table 2 and 3. The LogP/CLogP values were calculated using
Chembiodraw ultra 12.0.
All the 48 compounds screened have shown in vitro activity
against MTB with MIC ranging from 1.56ꢀ25.0 μg/mL. When
compared to one of the first line anti-TB drug ethambutol (MIC
3.13 μg/mL), four compounds 4{13,2}, 4{14,2}, 4{13, 3}, and
4{14, 3} (MIC 3.13 μg/mL) are found to be equally active as
ethambutol, and two compounds 4{6,2} and 4{6, 3} (MIC
1.56 μg/mL) were found to be more potent than ethambutol.
When compared to pyrazinamide (MIC 50.8 μg/mL), all the
48 compounds were found to be more potent, though all the
compounds were less potent than the other anti-TB drugs
isoniazid and Rifampicin (Table 2 and 3). Structural correlations
of all the new compounds with respect to their antitubercular
activity reveal that aryl and heteroaryl tethered 7,8-dihydroqui-
nolin-5(6H)-ones 4{(1ꢀ16),(2ꢀ3)} have shown better in vitro
activity against MTB than the corresponding aryl and heteroaryl
tethered pyridine derivatives 3{(1ꢀ16), 1}. All these results
reveal that liphophilic nature along with halo substituents are
needed for aryl and heteroaryl tethered 7,8-dihydroquinolin-
5(6H)-ones 4{(1ꢀ16), (2ꢀ3)} to become active against
M. tuberculosis H37Rv (MTB). Among all the compounds
evaluated, two compounds 4{6,2} and 4{6,3} (MIC 1.56 μg/mL)
in which 7,8-dihydroquinolin-5(6H)-one tethered with naphthalene
9
CeCl3 7H2O-NaI
3
10
NaI
a All the reactions were performed with 1{12} (1.0 mmol), 2{1} (1.2 mmol),
and NH4OAc (2.0 mmol) in the presence of catalyst, and the progress of the
reaction was monitored by tlc. b Isolated yield.
CeCl3 7H2O in combination with NaI was used, and no reaction
3
took place with NaI alone. With CeCl3 7H2O alone, the reaction
3
requires 24 h to give 3{12, 1} in 32% yield. Examining various
solvents (DMF, methanol, 2-propanol, acetonitrile, water, and
neat) resulted in optimum yield (84%) of target product 3{12, 1}
in 2-propanol at reflux temperature.
With optimal reaction conditions in hand, the generality of the
protocol was explored (Table 2). A variety of structurally diverse
β-enaminones 1{1ꢀ16}, embodied with aryls and heteroaryls,
were reacted with ethyl acetoacetate 2{1} and ammonium
acetate in the presence of CeCl3 7H2O-NaI in 2-propanol at
3
reflux temperature. As illustrated in Table 2, all the β-enami-
nones 1{1ꢀ16} were well tolerated to the reaction conditions
and participated in the clean reactions with in 3.0 to 6.0 h, giving
rise to the desired products 3{1ꢀ16,1} in the yields ranging from 66%
to 85%. All these substituted pyridine analogues 3{1ꢀ16,1} were fully
characterized by 1H and 13C NMR, IR and mass (ESI and HRMS)
spectral data. Further, the structure of 3{9, 1} was unambiguously
confirmed by single crystal X-ray diffraction data (Figure 5).
To further examine the scope of this three component
reaction, and to obtain more structurally diverse dihydro-6H-
quinolin-5-ones, two readily available cyclic1,3-diones such as
5,5-dimethylcyclohexane-1,3-dione 2{2} and 4,4-dimethylcyclo-
hexane-1,3-dione 2{3} were employed to react with all the aryl
and heteroaryls embodied β-enaminones 1 {1ꢀ16} (Scheme 1,
Table 3). As anticipated, the reaction of 5,5-dimethylcyclo-
hexane-1,3-dione 2{2} with all the β-enaminones 1 {1ꢀ16}
and ammonium acetate were successful under the similar reaction
conditions to give 2-substituted-7,7-dimethyl-7,8-dihydro-6H-quino-
lin-5-ones 4{(1ꢀ16),2} in high yields (68% to 85%; Table 3).
β-Enaminones 1{1ꢀ16} were also reacted regioselectively with 4,4-
dimethyl cyclohexane-1,3-dione 2{3} and ammonium acetate under
the similar reaction conditions to give 6,6-dimethyl-7,8-dihydro-
quinolin-5(6H)-ones 4{(1ꢀ16),3} in very good yields (Table 3).
For example, the reaction of (E)-1-(5-Chlorothiophen-2-yl)-
3-dimethylaminopropenone 1{13}, 4,4-dimethylcyclohexane-
1,3-dione 2{3}, and ammonium acetate in the presence of
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RESEARCH ARTICLE
Table 2. Synthesis, Physical Data, and Antitubercular Evaluation of 3{1-16, 1} against M. tuberculosis H37RV
entry
enaminone 1{1ꢀ16}
react time (h)
product 3
yield (%)a
m.p (°C)
LogP/CLogPb
MIC (μg/mL)
1
1{1}
4.0
4.0
4.5
3.0
4.5
4.0
6.0
4.0
4.5
4.5
6.0
4.0
4.5
4.0
6.0
6.0
3{1,1}
3{2,1}
3{3,1}
3{4,1}
3{5,1}
3{6,1}
3{7,1}
3{8,1}
3{9,1}
3{10,1}
3{11,1}
3{12,1}
3{13,1}
3{14,1}
3{15,1}
3{16,1}
84
80
75
86
74
85
68
82
80
76
66
84
76
78
72
69
44
54
75
73
142
98
86
96
60
102
55
58
67
79
91
92
3.66/3.89
4.15/4.39
4.22/4.61
4.49/4.76
2.96/3.64
4.66/5.06
5.69/6.30
4.32/5.06
3.99/4.78
5.19/6.21
2.20/2. 86
3.64/3.78
4.01/4.51
4.35/4.66
3.58/3.75
2.25/3.00
>25.0
>25.0
>25.0
25.0
25.0
6.25
25.0
25.0
6.25
25.0
25.0
12.5
6.25
6.25
12.5
12.5
0.1
2
1{2}
3
1{3}
4
1{4}
5
1{5}
6
1{6}
7
1{7}
8
1{8}
9
1{9}
10
11
12
13
14
15
16
17
18
19
20
1{10}
1{11}
1{12}
1{13}
1{14}
1{15}
1{16}
Isoniazid
Ethambutol
Pyrazinamide
Rifampicin
3.13
50.8
0.2
a Isolated yields. b Calculated using Chemdraw Ultra 12.0.
ambident nucleophilic character of the enamine moiety and
the ambident elctrophilic character of the enone moiety, β-
enaminones derived from various aryl and heteroaryl methyl
ketones were efficiently used as polarized substrates in the
reaction with ethyl acetoacetate or 5,5-dimethylcyclohexane-
1,3-dione or 4,4-dimethylcyclohexane-1,3-dione and ammo-
nium acetate refluxing in 2-propanol. The regioselectivity of
dihydro-6H-quinolin-5-ones 4{2,3} and 4{13,3} accom-
plished in the reaction of β-enaminones with 4,4-dimethyl-
cyclohexane-1,3-dione and ammonium acetate in the
presence of CeCl3 7H2O-NaI was assessed by single crystal
3
X-ray crystallographic data. Applicability of nontoxic cerium
catalyst, high reactivity with wide range of aryl and heteroaryl
β-enaminones, operational simplicity, and shorter reaction
time at comparatively low temperatures are prominent
features of the developed protocol. Evaluation of the 48
compounds for their in vitro antimycobacterial activity
against M. tuberculosis H37Rv (MTB) resulted in four com-
pounds 4{13,2}, 4{14,2}, 4{13, 3}, and 4{14, 3} (MIC 3.13
μg/mL) and two compounds 4{6,2} and 4{6,3} (MIC 1.56
μg/mL) as most promising antitubercular agents.
Figure 5. ORTEP diagrams of 3{9,1} with thermal displacement
ellipsoids drawn at the 30% probability level.
resulted as the most active antitubercular agents against
M. tuberculosis H37Rv (MTB).
’ CONCLUSION
In summary, we have accomplished a facile, diversity oriented
synthesis of substituted pyridines 3{1ꢀ16,1} and dihydro-6H-
quinolin-5-ones 4{(1ꢀ16), (2ꢀ3)} tethered with aryls and
’ EXPERIMENTAL SECTION
heteroaryls through CeCl3 7H2O-NaI catalyst via variants
General Procedure for the Preparation of β-Enaminones 1
{1ꢀ16}. To a solution of 6-acetyl-2H-1,4-benzoxazin-3(4H)-one
3
of the BohlmannꢀRahtz reaction. Because of the presence of
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Scheme 1. Synthesis of Substituted Dihydroquinolin-5-ones 4{(1ꢀ16), (2ꢀ3)}
Table 3. Synthesis, Physical Data, And Antitubercular Evaluation of 4{1(1-16), 2(2-3)} against M. tuberculosis H37RV
entry
enaminone 1{1ꢀ16}
dione2{2ꢀ3}
reaction time (h)
product 4
yield (%)a
m.p (°C)
LogP/CLogPb
MIC (μg/mL)
1
1{1}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
4.0
4.0
4.5
3.0
4.5
4.0
6.0
4.0
4.5
4.5
4.0
6.0
4.5
4.0
6.0
6.0
4.5
4.0
4.5
3.5
4.5
4.0
5.0
4.0
4.0
4.5
4.0
6.0
4.0
4.0
6.0
6.0
4{1, 2}
4{2, 2}
4{3, 2}
4{4, 2}
4{5, 2}
4{6, 2}
4{7, 2}
4{8, 2}
4{9, 2}
4{10, 2}
4{11, 2}
4{12, 2}
4{13, 2}
4{14, 2}
4{15, 2}
4{16, 2}
4{1, 3}
4{2, 3}
4{3, 3}
4{4, 3}
4{5, 3}
4{6, 3}
4{7, 3}
4{8, 3}
4{9, 3}
4{10, 3}
4{11, 3}
4{12, 3}
4{13, 3}
4{14, 3}
4{15, 3}
4{16, 3}
78
72
82
85
76
85
68
82
76
76
84
68
76
78
72
69
86
84
72
81
70
73
65
76
72
70
70
72
65
68
66
60
67
3.84/4.16
4.32/4.65
4.39/4.88
4.67/5.03
3.41/3.91
4.83/5.33
5.87/6.57
4.49/5.33
4.16/5.05
5.37/6.48
2.38/3.12
3.82/4.05
4.19/4.78
4.53/4.93
3.76/4.02
2.43/3.27
4.31/4.16
4.80/4.65
4.87/4.88
5.14/5.03
3.41/3.91
5.31/5.33
6.34/6.57
4.97/5.33
4.64/5.05
5.84/6.48
2.85/3.12
4.29/4.05
4.66/4.78
5.00/4.93
4.23/4.02
2.90/3.27
>25.0
>25.0
12.5
12.5
>25.0
1.56
12.5
6.25
6.25
25.0
12.5
6.25
3.13
3.13
6.25
6.25
>25.0
>25.0
12.5
12.5
>25.0
1.56
12.5
12.5
6.25
>25
2
1{2}
120
105
132
182
97
3
1{3}
4
1{4}
5
1{5}
6
1{6}
7
1{7}
132
105
101
143
65
8
1{8}
9
1{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
1{10}
1{11}
1{12}
1{13}
1{14}
1{15}
1{16}
1{1}
75
96
110
152
155
90
1{2}
104
90
1{3}
1{4}
116
120
80
1{5}
1{6}
1{7}
142
97
1{8}
1{9}
106
132
72
1{10}
1{11}
1{12}
1{13}
1{14}
1{15}
1{16}
Isoniazid
Ethambutol
Pyrazinamide
Rifampicin
25.0
6.25
3.13
3.13
6.25
6.25
0.1
55
114
122
146
138
3.13
50.8
0.2
a Isolated yields. b Calculated using Chemdraw Ultra 12.0.
(1.0 g, 5.23 mmol) in xylene (15 mL) was added N,N-dimethyl-
formamide dimethylacetal (2.91 mL, 20.92 mmol) and refluxed
for 7 h (monitored by TLC). Xylene was then removed by
distillation; crude residue was triturated with hexane. Solid
residue thus formed was filtered to give (E)-6-(3-Dimethyl-
aminoacryloyl)-4-methyl-4H-benzo[1,4]oxazin-3-one 1{16} as
a pure white solid (1.17 g, 86%). 1H NMR (CDCl3, 300 MHz) δ
7.74 (d, J = 12.2 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.48 (dd, J =
1.8 Hz and 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.64 (d, J =
12.2 Hz, 1H), 4.62 (s, 2H), 3.44 (s, 3H), 3.08 (d, br, 6H).
432
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RESEARCH ARTICLE
13C NMR (CDCl3, 75 MHz) δ 186.6, 164.0, 154.2, 147.3, 135.3,
129.2, 123.2, 120.1, 115.9, 114.5, 91.3, 67.4, 28.1. IR(KBr) 2919,
1685, 1635, 1545, 1355, 1238, 1121, 892, 766. MS(ESI) m/z 261
(M+H)+; HRMS (ESI) Calcd for C14H16N2O3 (M+H)+:
261.1239, found: 261.1230.
Synthesis of 6-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-
quinolin-2-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one
(4{16,2}) As a Representative Example. To a mixture of (E)-
6-(3-Dimethylaminoacryloyl)-4-methyl-4H-benzo[1,4]oxazin-
3-one 1{16} (0.27 g, 1.0 mmol), 1,3-cyclohexanedione 2(2ꢀ3)
(0.16 g, 1.2 mmol), ammonium acetate (0.15 g, 2.0 mmol)
crude residue obtained was subjected to column chromatography
(silica gel; hexane:ethyl acetate, 9:1) to obtain 6-(7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydroquinolin-2-yl)-4-methyl-2H-benzo[b][1,4]-
oxazin-3(4H)-one 4{16,2} (0.24 g, 69%) as pale yellow solid.
mp 155 °C; 1H NMR (CDCl3, 500 MHz) δ 8.26 (d, J = 8.3
Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.68ꢀ7.59 (m, 2H), 7.03
(d, J = 8.3 Hz, 1H), 4.65 (s, 2H), 3.49 (s, 3H), 3.08 (s, 2H),
2.54 (s, 2H), 1.17 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ
197.7, 164.1, 162.4, 159.8, 137.8, 135.4, 133.2, 129.9, 125.4,
123.0, 118.2, 117.0, 114.1, 67.5, 52.0, 46.7, 32.9, 29.6, 28.3,
28.1. IR(KBr) 2925, 2854, 1687, 1579, 1445, 1367, 1279,
1044, 831, 727 cmꢀ1. MS(ESI) m/z 337(M+H)+ ; HRMS
(ESI) Calcd for C20H21 N2O3 (M+H)+: 337.1552, found:
337.1569.
General Procedure for in Vitro Antimycobacterial Eva-
luation of 3{(1ꢀ16), 1} and 4{(1ꢀ16), (2ꢀ3)} Against M.
tuberculosis H37Rv (MTB). Ten-fold serial dilutions of each
test compound/drug were prepared and incorporated into
Middle brook 7H11 agar medium with OADC Growth Supple-
ment. Inoculum of M. tuberculosis H37Rv ATCC 27294 (MTB)
was prepared from fresh Middle brook 7H11 agar slants with
OADC growth supplement adjusted to 1 mg/mL (wet weight)
in Tween 80 (0.05%) saline diluted to 10ꢀ2 to give a concen-
tration approximately 107 cfu/mL. A 5 μL amount of bacterial
suspension was spotted into 7H11 agar tubes containing 10-
fold serial dilutions of drugs per mL. The tubes were incubated
at 37 °C, and final readings were recorded after 28 days. The
minimum inhibitory concentration (MIC) is defined as the
minimum concentration of test compound required to give
complete inhibition of bacterial growth. This method is similar
to that recommended by the National Committee for Clinical
Laboratory Standards for the determination of MIC in
triplicate.
in 2-propanol (5 mL) were added CeCl3 7H2O (75 mg,
3
0.2 mmol), NaI (30 mg, 0.2 mmol) and refluxed for 4 h
(monitored by TLC). The reaction mixture was cooled to room
temperature; a solid precipitate was filtered and washed with cold
2-propanol. The combined solvent was evaporated, and the
Figure 6. ORTEP diagram of 2-(5-chlorothiophen-2-yl)-6,6-dimethyl-
7,8-dihydroquinolin-5(6H)-one 4 {13, 3} with thermal displacement
ellipsoids drawn at the 30% probability level.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures for the synthesis of starting materials β-enaminones
1{1ꢀ16}, Representative procedure for synthesis of pyridine
derivatives 3{(1ꢀ16,1}, dihydroquinolin-5-ones 4 {(1ꢀ16),
(2ꢀ3)}; characterization data for all the products and copies
of H, 13C NMR and mass (HRMS) spectra of all the new
1
compounds; Single crystal X-ray diffraction data (cif files) for
1{9}, 3{(9,1}, 4 {2,3}, and 4 {13,3}. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 7. ORTEP diagram of 6,6-dimethyl-2-p-tolyl-7,8-dihydroquino-
lin-5(6H)-one 4{2,3} with thermal displacement ellipsoids drawn at the
30% probability level.
Figure 8. Regioselective formation of 6,6-dimethyl-7,8-dihydroquinolin-5(6H)-ones 4{(1ꢀ16), 3}.
433
dx.doi.org/10.1021/co2000604 |ACS Comb. Sci. 2011, 13, 427–435

ACS Combinatorial Science
RESEARCH ARTICLE
’ AUTHOR INFORMATION
954–958. (c) Bohlmann, F.; Rahtz, D. Uber eine neue Pyridinsynthese.
Chem. Ber. 1957, 90, 2265–2272.
Corresponding Author
*E-mail: kantevari@yahoo.com, kantevari@gmail.com. Phone:
+91-4027191437. Fax: +91-4027198933.
(5) (a) Bagley, M. C.; Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J.
One-Pot Multistep BohlmannꢀRahtz Heteroannulation Reactions:
Synthesis of Dimethyl Sulfomycinamate. J. Org. Chem. 2005, 70, 1389–
1399. (b) Bagley, M. C.; Xiong, X. Stereoselective Synthesis of the
γ-Lactam Hydrolysate of the Thiopeptide Cyclothiazomycin. Org. Lett.
2004, 6, 3401–3404. (c) Bagley, M. C.; Dale, J. W.; Xiong, X.; Bower, J.
Synthesis of Dimethyl Sulfomycinamate. Org. Lett. 2003, 5, 4421–4424.
(d) Bagley, M. C.; Dale, J. W.; Ohnesorge, M.; Xiong, X.; Bower, J. A
Facile Solution Phase Combinatorial Synthesis of Tetrasubstituted
Pyridines Using the Bohlmann-Rahtz Heteroannulation Reaction.
J. Comb. Chem. 2003, 5, 41–44.
Author Contributions
S.K., S.R.P., D.A., and S.R.P. conceived, performed the experi-
ments, and characterized the compounds with spectral data. B.S.
performed single crystal X-ray analysis. P.Y. and D.S. evaluated
compounds for antitubercular activity. S.K. and S.R.P. cowrote
the manuscript and the Supporting Information.
(6) (a) Wan, J.-P.; Pan, Y.-J. Chemo-/regioselective synthesis of
6-unsubstituted dihydropyrimidinones, 1,3-thiazines and chromones via
novel variants of Biginelli reaction. Chem. Commun. 2009, 2768–2770.
(b) Lieby-Muller, F.; Allais, C.; Constantieux, T. Rodriguez. Metal-free
Michael addition initiated multicomponent oxidative cyclodehydration
route to polysubstituted pyridines from 1,3-dicarbonyls. J. Chem. Com-
mun. 2008, 4207–4209. (c) Senaiar, R. S.; Young, D. D.; Deiters, A.
Pyridines via solid-supported [2 + 2 + 2] cyclotrimerization. Chem.
Commun. 2006, 1313–1315. (d) Davis, J. M.; Truong, A.; Hamilton,
A. D. Synthesis of a 2,30;60,300-Terpyridine Scaffold as an R-Helix
Mimetic. Org. Lett. 2005, 7, 5405–5408. (e) Al-Saleh, B.; Abdelkhalik,
M. M.; Eltoukhy, A. M.; Elnagdi, M. H. Enaminones in heterocyclic
synthesis: A new regioselective synthesis of 2,3,6-trisubstituted pyri-
dines, 6-substituted-3-aroylpyridines and 1,3,5-triaroylbenzenes. J. Het-
erocycl. Chem. 2002, 39, 1035–1038. (f) Omran, F. A.; Awadi, N. A.;
Khair, A. A. E.; Elnagdi, M. H. Org. Prep. Proced. Int. 1997, 29, 285–289.
(7) (a) Kantevari, S.; Patpi, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram,
D. Synthesis and antitubercular evaluation of novel substituted aryl and
thiophenyl tethered dihydro-6H-quinolin-5-ones. Bioorg. Med. Chem.
Lett. 2011, 21, 1214–1217. (b) Kantevari, S.; Putapatri., S. R. A Facile
synthesis of novel acyclo-C-nucleoside analogues from L-Rhamnose via
variants of Bohlmann-Rahtz reaction. Synlett 2010, 2251–2256.
(c) Kantevari, S.; Addla, D.; Sridhar, B. Cerium (III)-catalyzed facile
synthesis of dihydrobenzofuran-tethered pyridines and dihydroquino-
lin-5(6H)-ones from β-enaminones. Synthesis 2010, 3745–3754.
(d) Kantevari, S.; Chary, M. V.; Vuppalapati, S. V. N. A highly efficient
regioselective one-pot synthesis of 2,3,6-trisubstituted pyridines and
2,7,7-trisubstituted tetrahydroquinolin-5-ones using K5CoW12O40.
3H2O as a heterogeneous recyclable catalyst. Tetrahedron 2007, 63,
13024–13031. (e) Kantevari, S.; Chary, M. V.; Vuppalapati, S. V. N.;
Lingaiah, N. Microwave assisted regioselective one-pot synthesis of
trisubstituted pyridine scaffolds using K5CoW12O40.3H2O under sol-
vent free conditions. J. Heterocycl. Chem. 2008, 1099–1102.
’ ACKNOWLEDGMENT
The authors are thankful to Dr. J. S. Yadav, Director, IICT, and
Dr. V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad, for their constant support, encouragement, and
financial assistance from MLP projects. S.R.P., D.A., and S.R.P.
are thankful to CSIR for senior research fellowships.
’ REFERENCES
(1) (a) Galloway, W. R. J. D.; Spring, D. R. Better leads come from
diversity. Nature 2011, 470, 43. (b) Galloway, W. R. J. D.; Isidro-Llobet,
A.; Spring, D. R. Diversity-oriented synthesis as a tool for the discovery
of novel biologically active small molecules. Nat. Commun. 2010, 1, 80.
(c) Bender, A. Diversity oriented synthesis: A challenge for synthetic
chemists. In Chemical Genomics: Small Molecule Probes to Study Cellular
Function; Jaroch, S., Weinmann, H., Eds.; Springer-Verlag: Berlin,
Germany, 2006; pp 47ꢀ60.
(2) (a) Schreiber, S. L. Organic Chemistry Molecular diversity by
design. Nature 2009, 457, 153–154. (b) Tan, D. S. Diversity-oriented
synthesis: exploring the intersections between chemistry and biology.
Nat. Chem Biol. 2005, 1, 74–84. (c) Kennedy, J. P. Application of
combinatorial chemistry science on modern drug discovery. J. Comb.
Chem. 2008, 10, 345–354. (d) Burke, M. D.; Schreiber, S. L. A Planning
Strategy for Diversity-Oriented Synthesis. Angew. Chem., Int. Ed. 2004,
43, 46–58. (e) Henry, G. D. De novo synthesis of substituted pyridines.
Tetrahedron 2004, 60, 6043–6061.
(3) (a) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X.
Thiopeptide antibiotics. Chem. Rev. 2005, 105, 685–714. (b) Harding,
M. M.; Long, G. V.; Brown, C. L. Solution conformation of the
antitumor drug Streptonigrin. J. Med. Chem. 1993, 36, 3056–3060.
(c) Hassani, M.; Cai, W.; Holley, D. C.; Lineswala, J. P.; Maharjan,
B. R.; Ebrahimian, G. R.; Seradj, H.; Stocksdale, M. G.; Mohammadi, F.;
Marvin, C. C.; Gerdes, J. M.; Beall, H. D.; Behforouz, M. Novel
Lavendamycin Analogues as Antitumor Agents: Synthesis, in Vitro
Cytotoxicity, StructureꢀMetabolism, and Computational Molecular
Modeling Studies with NAD(P)H:Quinone Oxidoreductase 1. J. Med.
Chem. 2005, 48, 7733–7749. (d) Rocher, J.-P.; Bonnet, B.; Bolea, C.;
Lutjens, R.; Le Poul, E.; Poli, S.; Epping-Jordan, M.; Bessis, A.-S.;
Ludwig, B.; Mutel, V. mGluR5 Negative Allosteric Modulators Over-
view: A Medicinal Chemistry Approach Towards a Series of Novel
Therapeutic Agents. Curr. Topics. Med. Chem. 2011, 11, 680–695.
(e) Rodriguez, A. L.; Grier, M. D.; Jones, C. K.; Herman, E. J.; Kane,
A. S.; Smith, R. L.; Williams, R.; Zhou, Y.; Marlo, J. E.; Days, E. L.; Blatt,
T. N.; Jadhav, S.; Menon, U. N.; Vinson, P. N.; Rook, J. M.; Stauffer,
S. R.; Niswender, C. M.; Lindsley, C. W.; Weaver, C. D.; Conn, P. J.
Discovery of Novel Allosteric Modulators of Metabotropic Glutamate
Receptor Subtype 5 Reveals Chemical and Functional Diversity and
In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsy-
chotic Activity. Mol. Pharmacol. 2010, 78, 1105–1123.
(8) (a) Al-Saleh, B.; Abdelkhalik, M. M.; Eltoukhy, A. M.; Elnagdi,
M. H. Enaminones in hetero cyclic synthesis: A new regioselective
synthesis of 2,3,6-trisubstituted pyridines, 6-substituted-3-aroylpyri-
dines and 1,3,5-triaroylbenzenes. J. Heterocycl. Chem. 2002, 39, 1035–
1038. (b) Reddy, G. J.; Latha, D.; Thirupathaiah, C.; Rao, K. S. A facile
synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using
montmorillonite K10 as solid acid support. Tetrahedron Lett. 2005,
46, 301–302.
(9) (a) Bartoli, G.; Marcantoni, E.; Sambri, L. The CeCl3 nH2O/
3
NaI System in Organic Synthesis: An Efficient Water Tolerant
Lewis Acid Promoter. SynLett 2003, 2101–2116. (b) Bartoli, G.;
Fernꢀandez-Bolan~os, J. G.; Antonio, G. D.; Foglia, G.; Giuli, S.; Gunnella,
R.; Mancinelli, M.; Marcantoni, E.; Paoletti, M. SiO2-Supported CeCl3
3
7H2O-NaI Lewis Acid Promoter: Investigation into the Garcia Gonzalez
Reaction in Solvent-Free Conditions. J. Org. Chem. 2007, 72, 6029–
6036. (c) Christofeers, J.; Kauf, T.; Werner, T.; Rossle, M. Cerium-
Catalyzed R-Hydroxylation Reactions of R-Cyclopropyl β-Dicarbonyl-
Compounds with Molecular Oxygen. Eur. J. Org. Chem. 2006,
2601–2608. (d) Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy,
N. M.; Yadav, J. S. A New, Efficient and Environmentally Benign
Protocol for the Synthesis of 1,5-Benzodiazepines using Cerium(III)
Chloride/Sodium Iodide Supported on Silica Gel. Adv. Synth. Catal.
(4) (a) Bagley, M. C.; Glover, G.; Merritt, E. A. The Bohlmann-Rahtz
pyridine synthesis: From discovery to applications. Synlett 2007,
2459–2482. (b) Merritt, E. A.; Bagley, M. C. Convergent Synthesis of
the Central Heterocyclic Domain of Micrococcin P1. Synlett 2007,
434
dx.doi.org/10.1021/co2000604 |ACS Comb. Sci. 2011, 13, 427–435

ACS Combinatorial Science
RESEARCH ARTICLE
2004, 346, 921–923. (e) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya,
R.; Yadav, J. S. Cerium(III) Chloride Promoted Highly Regioselective
Ring Opening of Epoxides and Aziridines Using NaN3 in Acetonitrile: A
Facile Synthesis of 1,2-Azidoalcohols and 1,2-Azidoamines. Org. Lett.
2002, 4, 343–345.
(10) Khodaei, M. H.; Khosropour, A. R.; Kookhazadeh, M. Enam-
ination of β-Dicarbonyl Compounds Catalyzed by CeCl3 7H2O at
3
Ambient Conditions: Ionic Liquid and Solvent-Free Media. Synlett
2004, 1980–1984.
(11) (a) Al-Omran, F.; Al-Awadhi, N.; Khalik, M. M. A.; Kaul, K.;
EL-Khair, A. A.; Elnagdi, M. H. 1-Substituted 3-Dimethyl aminoprop-
2-en-1-ones as Building Blocks in Heterocyclic Synthesis: Routes to
6-Aryl and 6-Heteroaryl-2H-pyran-2-ones and 6- and 4-Aryl-pyridin-
2(1H)-ones. J. Chem. Res. 1997, 3, 601–615. (b) Ioachim, E.; Medlycott,
E. A.; Polson, M. I. J.; Hanan, G. S. Synthesis of a Novel Series of 6,6-
Disubstituted 4,4-Bipyrimidines by Radical Anion Coupling: New π-
Accepting Ligands for Coordination Chemistry. Eur. J. Org. Chem. 2005,
17, 3775–3780.
435
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