Biginelli and Hantzsch-type reactions leading to highly functionalized dihydropyrimidinone, thiocoumarin, and pyridopyrimidinone frameworks via ring annulation with β-oxodithioesters

Article abstract of DOI:10.1021/jo101572c

An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unreported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocondensation of aromatic aldehydes, β-oxodithioesters, and urea/6-amino-1,3-dim

Full text of DOI:10.1021/jo101572c

pubs.acs.org/joc
Biginelli and Hantzsch-Type Reactions Leading to Highly Functionalized
Dihydropyrimidinone, Thiocoumarin, and Pyridopyrimidinone
Frameworks via Ring Annulation with β-Oxodithioesters
Ganesh Chandra Nandi, Subhasis Samai, and Maya Shankar Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
mssinghbhu@yahoo.co.in
Received August 13, 2010
An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unre-
ported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocon-
densation of aromatic aldehydes, β-oxodithioesters, and urea/6-amino-1,3-dimethyluracil in the
presence of recyclable SiO2-H2SO4. On the other hand, salicylaldehyde, β-oxodithioester, and urea
reacted under similar conditions to afford the 3-aroyl/heteroaroyl-2H-chromen-2-thiones in high
yields instead of Biginelli product. The attractive feature of this approach is the synthesis of three
important bioactive heterocyclic frameworks from the same β-oxodithioester under the similar
reaction conditions, making this new strategy highly useful in diversity-oriented synthesis (DOS).
Introduction
total synthesis of complex natural products, the Biginelli
MCR2,3 has been adapted successfully to the needs
and expectations of modern synthetic organic chemistry.
The interesting and multifaceted biological profiles of
dihydropyrimidinones4,5 have been explored through the
generation of libraries of compounds. In the past decades,
a broad range of biological effects6 including antiviral,
antitumor, antibacterial, analgesic, and anti-inflammatory
activities have been ascribed to Biginelli compounds. More-
over, appropriately functionalized DHPMs (Chart 1) exhibit
The Biginelli dihydropyrimidinone MCR has come a long
way since its discovery 117 years ago in 1893 by Italian
chemist Pietro Biginelli.1 From the preparation of simple
pyrimidine heterocycles in the late 19th century to the
generation of targeted compound libraries of biofunctional
dihydropyrimidinones (DHPMs) and the enantioselective
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DOI: 10.1021/jo101572c
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Published on Web 10/27/2010
J. Org. Chem. 2010, 75, 7785–7795 7785
2010 American Chemical Society

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JOCArticle
CHART 1. Examples of Biologically Active Heterocyclic Fra-
meworks
mitotic kinesin Eg5 inhibitor (monastrol, 4), and anticancer
(5, MAL3-101).9 Furthermore, apart from synthetic DHPM
derivatives, several marine natural products containing DHPM
skeleton such as batzelladine B (6), ptilomycalines, and
crambescidines with interesting biological activities4d,5e,f
have recently been isolated. Similarly, thiocoumarins display
a remarkable array of biochemical and pharmacological
actions10 such as 7 is used as blocker10e of the lymphocyte
potassium channel Kv1.3. Another heterocyclic core unit
dihydropyridopyrimidinones, which is structurally similar
with the DHPM also display the promising pharmacological
activity such as adenosine kinase inhibitor,11a AbI kinase
inhibitor,11b tyrosine phosphatase inhibitor,11c antiviral,11d
in treatment of diarrhea,11e and as a Ca2þ channel modu-
lator. The diverse range of biological activities of these
moieties has stimulated considerable interest to synthesize
these units via a new and efficient route.
In the 1970s and 1980s, interest slowly increased, and the
scope of the original cyclocondensation reaction shown in
Scheme 1 was gradually extended by variation of all the three
building blocks allowing access to a large number of attrac-
tive multifunctionalized DHPMs. A plethora of useful meth-
odologies involving various types of homogeneous and
heterogeneous catalysts12,13 have been elaborated in order
to keep the simplicity and to improve the efficiency of the
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its undesirable features. Asymmetric14 and chemo/regiose-
lective synthesis15 of Biginelli products using organocata-
lysts have been developed. Ammonium chloride,16a ammo-
nium and tetrabutylammonium bromides,16b,c copper nitrate,17
SiO2-HClO4,18a CaF2,18b Al2O3-MeSO3H,18c polymer-
supported aminoformoyl diphenylammonium triflate,18d metal
triflate/triflimide,19 piperidinium triflate,19k sodium chloride,20a
thiamine hydrochloride,20b chlorotrimethylsilane,20c aluminum-
planted mesoporous silica,21a graphite supported lanthanum
chloride,21b hexaaquaaluminium(III) tetrafluoroborate21c and
pyrazolidine dihydrochloride22 have also been utilized as efficient
catalysts for the Biginelli reaction. Recently, a base-catalyzed23
and modified syntheses of DHPMs in aqueous media have also
been carried out.20b,24 The use of the common open-chain
β-dicarbonyl compounds in Biginelli reactions has been extended
SCHEME 1. Biginelli Dihydropyrimidinone Synthesis
to the use of cyclic β-diketones,25 β-ketolactones,26 cyclic
β-diesters27 or β-diamides,27,28 benzocyclic ketones,29 R-keto
acids,29 diketenes,30 and 3-amino-1,2,4-triazole as urea
component.31
Despite the plethora of different catalysts ranging over
diverse methods published so far also suffer from drawbacks,
such as limitation of applicable β-ketoesters, the need for
strong acids, toxic organic solvents and catalysts, cumbersome
experimental procedures, and lacking generality. Therefore,
more general, efficient and viable routes employing recyclable
catalysts in Biginelli synthesis are very much desirable in view
of their broad array of biological activity and would be of great
relevance to both synthetic and medicinal chemists. The use of
solid supported catalysts has become highly desirable in recent
years to meet the environmental considerations.32 It is well-
known that silica-sulfuric acid is a cheap, nontoxic, and stable
acidic reagent,33 which has been extensively utilized in various
synthetic transformations34 due to its several advantages such
as operational simplicity, reusability, low price, and air toler-
ance. In continuation of our recent work35 on the synthesis
of heterocycles by the development of new methodology, in
this paper, we report for the first time silica-sulfuric acid
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Tolmachev, A. A. Synthesis 2007, 417–427.
(21) (a) Murata, H.; Ishitani, H.; Iwamoto, M. Org. Biomol. Chem. 2010,
8, 1202–1211. (b) Khabazzadeh, H.; Saidi, K.; Sheibani, H. Bioorg. Med.
Chem. Lett. 2008, 18, 278–280. (c) Litvic, M.; Vecenaj, I.; Ladisic, Z. M.;
Lovric, M.; Vinkovic, V.; Litvic, M. F. Tetrahedron 2010, 66, 3463–3471.
(22) Suzuki, I.; Iwata, Y.; Taketa, K. Tetrahedron Lett. 2008, 49, 3238–
3241.
(23) Debache, A.; Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B.
Tetrahedron Lett. 2008, 49, 6119–6121.
J. Org. Chem. Vol. 75, No. 22, 2010 7787

Nandi et al.
JOCArticle
TABLE 1. Synthesis of β-Oxodithioesters 9
SCHEME 2. Synthesis of β-Oxodithioesters 9
entry
Ar1
dithioester
yielda (%)
1
2
3
4
5
C6H5
4-Cl C6H4
9a
9b
9c
9d
9e
72
75
73
80
70
3
4-MeO C6H4
3
2-thienyl
2-furyl
SCHEME 3. Synthesis of 5-Methylmercaptothiocarbonyl-4,6-
diaryl-1,2,3,4-tetrahydropyrimidin-5-ones 12a-v
aIsolated yields.
promoted Biginelli- and Hantzsch-type reactions that allowed
the formation of a diverse range of new heterocyclic frame-
worksvia ringannulationofβ-oxodithioesters by aldehydes. A
continuing exciting future for the Biginelli and Hantzsch-type
reactions in the 21st century is therefore secured.
Results and Discussion
Our literature survey at this stage revealed that Singh and
Devi12h utilized β-oxodithioesters for the first time as a
β-dicarbonyl component in Biginelli reaction catalyzed by
SnCl2, which is applicable for only limited aldehydes and
β-oxodithioesters. Moreover, the catalyst used cannot be
recycled and the temperature is also high (100 °C). Further-
more, there was no report of synthesis of DHPMs from 9,
thus warranting a more elaborate investigation. We there-
fore became interested in devising more general synthetic
strategy utilizing 3-aryl/heteroaryl-β-oxodithioesters 9 as the
versatile templates for the construction of DHPMs 12
(Scheme 3) and other bioactive heterocyclic frameworks 14
and 17 in the presence of recyclable SiO2-H2SO4 (Schemes 5
and 7). Access to a diverse collection of starting materials
is critical to render any method as practical. While many
β-dicarbonyl compounds are commercially available, the
same cannot be said for β-oxodithioesters. The desired
β-oxodithioesters36 9a-e (Table 1) were synthesized in good
yields (70-80%) by stirring ketones 8 with (S,S)-dimethyl
trithiocarbonate in the presence of NaH in DMF-hexane
(1:4) mixture at room temperature (Scheme 2). The synthesis
of DHPMs 12 (Scheme 3) was first undertaken. Thus, in
a typical general procedure, 4-nitrobenzaldehyde 10a (1.1
mmol), urea 11 (1.2 mmol), and 3-oxo-3-(2-furyl)dithio-
propionic acid methyl ester 9e (1.0 mmol) were mixed in
minimum amount of dry ethanol to get a paste like mixture.
SiO2-H2SO4 was added to pasty mixture and was heated at
80 °C to afford DHPM 12u in 85% yield (Table 3, entry 21).
The new methodology allows facile introduction of substit-
uents at 4-, 5-, and 6-positions of the DHPM skeleton and
flexibility for the construction of novel pyridopyrimidinone
and thiocoumarin ring systems.
TABLE 2. Optimization of the Catalyst on Model Reactiona
entry
catalyst
timeb (h)
yieldc (%)
1
2
p-TSA
oxalic acid
4
5
51
53
40
35
15
55
60
80
85
70
50
3
4
camphorsulfonic acid
L-proline
5
5
5
6
7
8
9
10
11
cyanuric chloride
HClO4-SiO2
PPA-SiO2
BF3.OEt2
H2SO4-SiO2
HCl
4
4
4
3.5
2.5
3.5
5
HCl-SiO2
aReaction of 4-nitrobenzaldehyde (1.1 mmol), 3-oxo-3-(2-furyl)-
dithiopropionic acid methyl ester (1.0 mmol), and urea (1.2 mmol).
bTime required. cIsolated yields.
and BF3 OEt2 facilitated DHPMs formation in good yields
3
(Table 2). H2SO4-SiO2 is a versatile stable acidic reagent
uniquely suited for this one-pot transformation, acting as both
a Lewis acid and a mild dehydrating reagent. The relatively
mild nature of this reagent achieved a high degree of functional
group tolerance. Even extremely electron-rich aromatic
β-oxodithioesters such as 9d and 9e (Table 1) proceeded
smoothly. SiO2-H2SO4 was easily recycled and used over
three times without loss of activity, when 4-nitrobenzaldehyde
10a, 3-oxo-3-phenyldithiopropionic acid methyl ester 9a, and
urea were condensed in Biginelli reaction to give 12a (Table 3,
entry 1). This feature provides a significant benefit (environ-
mental and cost) over traditional catalysts.
Initially, a variety of alternate catalysts such as p-TSA,
oxalic acid, camphorsulfonic acid, L-proline, cyanuric
Confident that the method would tolerate structural di-
versity, focus then shifted to optimization. A control experi-
ment in the absence of the catalyst provided no desired
product. Moreover, we also carried out this experiment
under solvent-free conditions, but the desired product was
not obtained. We then carried out the reaction in different
solvents. The observations revealed that in aprotic solvents
such as THF, DMF, and acetonitrile the product yield was
found to be low, but in the case of protic solvents such as
EtOH and MeOH the reaction rate as well as the product
yield were found to be improved comparatively. After
screening for different solvents, EtOH was found to be the
chloride, BF3 OEt2, HClO4-SiO2, PPA-SiO2, HCl, HCl-
SiO2, and H2SO4-SiO2 were screened to identify a suitable
activator for this transformation, but only H2SO4-SiO2
3
(35) (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh., M. S. Tetrahedron
2009, 65, 7129–7134. (b) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S.
Tetrahedron Lett. 2009, 50, 7220–7222. (c) Samai, S.; Nandi, G. C.; Kumar,
R.; Singh, M. S. Tetrahedron Lett. 2009, 50, 7096–7098. (d) Samai, S.; Nandi,
G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65, 10155–10161. (e) Kumar,
R.; Nandi, G. C.; Verma, R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51, 442–
445. (f) Nandi, G. C.; Samai, S.; Singh, M. S. Synlett 2010, 1133–1137.
(36) Samuel, R.; Asokan, C. V.; Suma, S.; Chandran, P.; Retnamma, S.;
Anabha, E. R. Tetrahedron Lett. 2007, 48, 8376–8378, and references
therein.
7788 J. Org. Chem. Vol. 75, No. 22, 2010

Nandi et al.
JOCArticle
SCHEME 4. Plausible Mechanism for the Synthesis of
DHPMs 12
TABLE 3. Scope Exploration: Variation of Ar1 and Ar2
entry
Ar1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Ar2
product time (h) yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-NO2 C6H4
3
12a
12b
12c
12d
12e
12f
12g
12h
12i
3
3
3
3.5
3
3
3
3
3.5
3
76
72
70
68
73
65
78
73
69
76
67
80
73
76
77
75
76
70
69
82
85
80
4-Br C6H4
3
C6H5
4- MeO C6H4
3
4-Cl C6H4
3
2-thienyl
4-MeO C6H4 4-Br C6H4
3
3
4-MeO C6H4 4-MeO C6H4
3
3
4-MeO C6H4 2-Cl C6H4
3
3
4-MeO C6H4 C6H5
3
12j
SCHEME 5. Synthesis of 2H-Chromene-2-thiones 14
4-MeO C6H4 2-thienyl
3
12k
12l
3.5
3
4-Cl C6H4
4-Cl C6H4
4-Cl C6H4
3-NO2 C6H4
4-MeO C6H4
3
3
12m
12n
12o
12p
12q
12r
12s
12t
12u
12v
3
2.5
3
3
3
3
3
2.5
2.5
2.5
3
3
4-Cl C6H4
3
3
2-thienyl
2-thienyl
2-thienyl
2-thienyl
2-thienyl
2-furyl
4-Cl C6H4
3
4-Br C6H4
3
3-NO2 C6H4
3
C6H5
2-MeO C6H4
3
3-NO2 C6H4
3
2-furyl
2-furyl
4-NO2 C6H4
3
4-Br C6H4
3
aIsolated yields.
medium of choice, which afforded the products not only in
good yield but also with higher reaction rates. In addition, we
studied the influence of temperature on the reaction time and
percentage yield. Increasing the temperature above 80 °C
neither improved the yield nor reduced the reaction time
whereas; lowering the temperature is detrimental to the
reaction resulting in lower yields. Following the optimized
reaction conditions, we extended our study using various
aromatic aldehydes containing electron-withdrawing or elec-
tron-releasing substituents at the ortho-, meta- or para-posi-
tions. Generally, the yields are moderate to high irrespective
of the steric and electronic nature of the substituents. No-
tably, the heteroaromatic aldehydes also afforded good
yields (Table 3, entries 6 and 11). However, unfortunately,
when some aliphatic aldehydes such as acetaldehyde, pro-
pionaldehyde and isobutyraldehyde were utilized the desired
product was observed only in trace amount, which could not
be isolated. The diversity of this protocol with respect to
β-oxodithioesters 9a-e (Table 1) was also investigated, and
the results are indicated in Table 3. The structures of all the
newly synthesized compounds were deduced from their
satisfactory elemental and spectral (IR, 1H, 13C NMR, and
MS) studies. Importantly, the crystallinity of DHPM 12t
allowed for structural verification by X-ray crystallo-
graphy41a and, thus, unambiguous regiochemical confirma-
tion showing S-configuration at chiral carbon.
rate-determining step, acts as an electrophile for the nucleo-
philic addition of the dithioester enol 9. The ketone carbonyl
of the resulting open-chain ureide adduct C undergoes
intramolecular cyclocondensation with the urea NH2 fol-
lowed by dehydration (facilitated by SiO2-H2SO4) to give
the cyclized product 12.
To further add diversity to the DHPM framework, the
β-oxodithioesters 9 were next subjected to cyclocondensa-
tion with salicylaldehyde 13 in the presence of urea. To our
surprise, we could not trace any corresponding Biginelli
product 15, and only the thiocoumarin derivatives 14 were
obtained in 73-87% yields (Scheme 5) in contrast to the
literature data.4b,5a,37 The structures of all the thiocoumarins
14a-h were confirmed with the help of spectral (IR, 1H, 13
C
NMR, and MS) and analytical data. This result suggested
nonparticipation of urea in the cyclocondensation. Thus, to
ascertain the role of urea, the above cyclocondensation was
carried out in the absence of urea under similar reaction
condition, but this tactic resulted the same thiocoumarins
14a-h in lower yields (43-55%). Thus, a more concise
approach was exploited by carrying out the reaction in
presence of urea (1 equiv), which provided 14a-h in excellent
yields (Table 4). Though the role of urea in these transforma-
tions is not clear, higher yields of thiocoumarins were
Although we have not established the mechanism of
reaction experimentally, a possible explanation is proposed
in Scheme 4, on the basis of the literature and substrate
trends. The first step in the mechanism is believed to be the
condensation between the aldehyde 10 and urea 11, with
some similarities to the Mannich condensation to generate
A. The iminium intermediate B generated, which is the key
(37) (a) Wang, M.; Jiang, H.; Gong, H. Prep. Biochem. Biotechnol. 2009,
39, 372–379. (b) Gui, J.; Liu, D.; Wang, C.; Lu, F.; Lian, J.; Jiang, H.; Sun, Z.
Synth. Commun. 2009, 39, 3436–3443.
J. Org. Chem. Vol. 75, No. 22, 2010 7789

Nandi et al.
SCHEME 6. Plausible Mechanism for the Synthesis of
2H-Chromene-2-thiones 14
JOCArticle
TABLE 4. Scope Exploration for the Synthesis of 14a
entry
Ar1
R
product
timeb (h)
yieldc (%)
1
2
3
4
5
6
7
8
Ph
Ph
H
3-OMe
5-Br
5-NO2
3-OMe
5-Br
3-OEt
5-Br
14a
14b
14c
14d
14e
14f
14g
14h
3.5
2.5
3
3.5
2.5
3
76
85
82
73
83
82
87
83
4-MeO C6H4
3
4-MeO C6H4
3
2-thienyl
2-thienyl
2-furyl
2.5
3
2-furyl
aReaction of β-oxodithioester (1 mmol), salicylaldehyde (1 mmol),
and urea (1 mmol). bTime required. cIsolated yields.
obtained in the presence of urea in analogy with the previous
report.12h For optimization of the reaction, 3-oxo-3-phenyl-
dithiopropionic acid methyl ester 9a (1 mmol), 2-hydroxy-3-
methoxybenzaldehyde 13b (1 mmol), and urea (1 mmol) were
heated at 85 °C in the presence of H2SO4-SiO2 (60 mg, 5
mmol/g) under solvent-free conditions to afford 14b in 85%
yield (Table 4, entry 2). Structural varieties of salicylalde-
hydes 13 and β-oxodithioesters 9 have been successfully
utilized for this transformation (Table 4).
SCHEME 7. Synthesis of Dihydropyridopyrimidinones 17
Coumarins are among the best known oxygen hetero-
cycles and are present as a structural motif in numerous
natural products including edible vegetables and fruits.38
Interest in their chemistry continues unabated because they
possess a broad range of biological activities39 such as
antiHIV,40a-d anticoagulation,40e antibiotic,40f-i anticancer,40j,k
antiinflammatory,40l,m antioxidant,40n-p antitumor,40q-s anti-
viral,40t antihypertensive, and antimicrobial activity.
In view of the above results obtained, a plausible mecha-
nism for the synthesis of thiocoumarin 14 is presented in
Scheme 6. First, the elimination of MeSH occurs via the
reaction of salicylaldehyde and β-oxodithioester to give the
condensation product D, which undergoes enolization to
its enol form E that participates in subsequent intramolecu-
lar aldol condensation to provide 2H-chromene-2-thiones 14
via F.
Many unique structures can be attained when three or
more reactants were combined in a single step to afford new
compounds possessing the combined features of the building
blocks. Encouraged by the successful application of β-oxo-
dithioesters 9 in the Biginelli reaction, the scope of this
methodology was further expanded through the synthesis
of highly functionalized dihydropyridopyrimidinones 17
using Hantzsch-type reaction (Scheme 7). These compounds
contain reactive functionalities for further elaboration of
new molecular system, and they will likely be useful for the
synthesis of biologically active molecules.
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Nandi et al.
JOCArticle
of all the newly synthesized compounds were confirmed from
TABLE 5. Synthesis of Dihydropyridopyrimidinones 17
1
their satisfactory elemental and spectral (IR, H, 13C NMR,
entry
Ar1
C6H5
C6H5
Ar2
product time (h) yielda (%)
and MS) studies. Furthermore, the structure of 17a has been
confirmed by single-crystal X-ray data.41b
1
2
3
4
5
6
7
8
3-NO2 C6H4
3
17a
17b
17c
17d
17e
17f
17g
17h
6
7
7
6
6
6
6
6
66
61
62
61
55
64
62
65
3-Cl C6H4
3
4-MeO C6H4 4-Br C6H4
3
A plausible mechanism is portrayed in Scheme 8. The
reaction was found to proceed via aldol product G of
aldehyde 10 and the β-oxodithioester 9. Subsequent addition
of the uracil to the aldol product followed by intramolecular
cyclization and dehydration produced the dihydropyrido-
pyrimidinone 17. Both electron-withdrawing and electron-
donating substituents on the aldehyde reactant are well
tolerated in the reaction without significant impact on the
yields of the products 17.
3
4-MeO C6H4 3-NO2 C6H4
3-NO2 C6H4
3
3
2-thienyl
4-Cl C6H4
3
3-NO2 C6H4
3-NO2 C6H4
4-NO2 C6H4
3
3
2-furyl
2-furyl
3
3
aIsolated yields.
SCHEME 8. Proposed Mechanism for the Formation of 17
Conclusion
In summary, β-oxodithioesters as 1,3-dicarbonyl compo-
nents for the Biginelli reaction have been identified, and a
diverse set of 5-methylmercaptothiocarbonyl-substituted
3,4-dihydropyrimidin-2(1H)-ones has been synthesized in
high yields at ambient temperature. Our literature survey
shows that this is the first example promoted by silica-
sulfuric acid in which β-oxodithioesters as an activated
β-dicarbonyl synthon is used in a Biginelli reaction. The
DHPM formation is accomplished through the ability of
silica-sulfuric acid to function dually as a Lewis acid and
dehydrating agent in the same transformation. The metho-
dology has been further elaborated to the corresponding
6-amino-1,3-dimethyluracil, the cyclic analogue of urea leading
to pyridopyrimidinones, thus providing a further point of
diversity in the newly synthesized heterocyclic framework.
Further, the facile access to 3-aroyl/heteroaroyl-2H-chromen-
2-thiones demonstrates the versatility of the annulation proto-
col via β-oxodithioesters in generating novel biologically
important thiocoumarins, as some of them cannot be synthe-
sized easily by traditional classical methods. The tolerance to
acid-sensitive reactants such as thienyl and furyl carbaldehydes,
applicability to sterically hindered β-oxodithioesters, and sim-
ple recyclability without losing catalytic activity make this
catalyst a good alternative to literature methods.
The synthesis commenced with commercially available
6-amino-1,3-dimethyluracil 16, which upon treatment with
9 and 10 resulted in dihydropyridopyrimidinones 17 in
55-66% yields (Scheme 7). In this case, the reaction of
3-nitrobenzaldehyde, 6-amino-1,3-dimethyluracil 16, and
β-oxodithioester 9a was taken as a model reaction and per-
formed in the presence of SiO2-H2SO4 in refluxing ethanol to
afford 17a in 66% yield (Table 5, entry 1). To check the real
effect of the catalyst, the reaction was performed without cata-
lyst, which gave the expected product 17a in low yield (25%). To
increase the yield of the desired product, catalysts such as
Experimental Section
BF3 OEt2 and InCl3 were also tried that furnished the desired
3
General Methods. All starting materials were commercially
available and used as received without further purification.
Silica-sulfuric acid was prepared according to the protocol
described in literature.33b β-Oxodithioesters 9a-e were pre-
pared following the known procedure36 displayed in Scheme 2.
Thin-layer chromatography (TLC) was performed using silica
gel 60 F254 precoated plates. Infrared (IR) spectra are measured
products but in lower yields (40-45%). Further, we carried out
the above reaction under solvent-free condition also, which
shows several close spots on TLC, and the desired product could
not be isolated. In order to find the optimum solvent, the
reaction was performed in various solvents, such as EtOH,
MeOH, acetonitrile, THF, DMF, and CCl4 at 80 °C, and it
was found that EtOH provided the best result. To evaluate the
scope of the reaction, various substituted aldehydes 10 and
structurally varied β-oxodithioesters 9 were used, and in all
cases, moderate yields were obtained (Table 5). However, when
some aliphatic aldehydes such as acetaldehyde, propionalde-
hyde, and isobutyraldehyde were used, it led to a number of very
close spots on TLC, which could not be isolated. The structures
in KBr, and wavelengths (ν) are reported in cm-1. 1H and 13
C
NMR spectra were recorded on NMR spectrometers operating
at 300 and 75.5 MHz, respectively. Chemical shifts (δ) are given
in parts per million (ppm) using the residue solvent peaks as
reference relative to TMS. J values are given in Hz. Mass spectra
were recorded using electrospray ionization (ESI) mass spectro-
metry. The C, H, and N analyses were performed from micro-
analytical laboratory. The melting points are uncorrected.
General Procedure for Synthesis of Dihydropyrimidin-2(1H)-
ones (12a-v). The β-oxodithioester (1.0 mmol), aldehyde (1.1
mmol), and urea (1.2 mmol) were mixed in a minimum amount
of dry ethanol to get a paste like mixture. SiO2-H2SO4 (60 mg)
was added to the pasty mixture, which was then heated at 80 °C
for the stipulated period of time. After completion of the
reaction (monitored by TLC), EtOAc (10 mL) was added to
(41) (a) Crystallographic data for compound 12t have been deposited
with the Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC 784530. These data can be obtained free of charge at
www.ccdc.cam.ac.uk; (b) Crystallographic data for compound 17a have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 783933. These data can be obtained free of
charge at www.ccdc.cam.ac.uk.
J. Org. Chem. Vol. 75, No. 22, 2010 7791

Nandi et al.
JOCArticle
the reaction mixture and the catalyst was filtered off. Then water
(20 mL) was added to the reaction mixture to remove any
unreacted urea and the mixture extracted with ethyl acetate
(2 ꢀ 10 mL). The combined organic layers were dried over
anhyd Na2SO4 and then evaporated in vacuo. The crude residue
was purified by column chromatography over silica gel using
acetone/dichloromethane (1:99) as eluent to afford pure dihy-
dropyrimidin-2(1H)-ones.
General Procedure for the Synthesis of 2H-Chromene-2-
thiones (14a-h). The β-oxodithioester (1.0 mmol), salicylalde-
hyde (1.2 mmol), urea (1.0 mmol), and SiO2-H2SO4 (60 mg)
were mixed and heated at 85 °C for the stipulated period of time.
After completion of the reaction (monitored by TLC), ethyl
acetate (10 mL) was added to the reaction mixture, and the
catalyst was filtered off. Water (20 mL) was then added to the
reaction mixture and the mixture extracted with ethyl acetate
(2 ꢀ 10 mL). The combined organic layers were dried over
anhyd Na2SO4 and then evaporated in vacuo. The crude residue
was purified by column chromatography over silica gel using
increasing amounts of ethyl acetate in n-hexane as eluent to
afford 2H-chromene-2-thiones.
General Procedure for the Synthesis of Pyridopyrimidinones
(17a-h). Toanethanolic solutionof β-oxodithioester (1.0mmol),
aldehyde (1.0 mmol), and 6-amino-1,3-dimethyluracil (1.2 mmol)
was added SiO2-H2SO4 (60 mg) and the mixture refluxed for the
stipulated period of time. After completion of the reaction
(monitored by TLC), the catalyst was filtered out. Ethanol was
evaporated; water (20 mL) was added and the mixture extracted
by ethyl acetate (2 ꢀ 10 mL). The combined organic layers were
dried over anhyd Na2SO4 and then evaporated in vacuo. The
crude residue was purified by column chromatography over silica
gel using increasing amounts of ethyl acetate in n-hexane as eluent
to afford pyridopyrimidinones.
134.6, 133.9, 129.8, 128.7, 128.4, 128.1, 119.6, 113.9, 60.4, 55.2,
20.4; IR (KBr, νmax, cm-1): 3214, 3078, 1695, 1457; MS m/z =
370 (Mþ). Anal. Calcd for C19H18N2O2S2: C, 61.60; H, 4.90; N,
7.56. Found: C, 61.42; H, 5.26; N, 7.76.
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-phenyl-
3,4-dihydropyrimidin-2(1H)-one (12e): bright yellow powder;
1
mp 250-251 °C; H NMR (300 MHz, CDCl3, δ ppm) 7.45-
7.25 (m, 9H), 6.38 (s, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.38 (s, 1H),
2.29 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm)
224.3, 151.4, 140.5, 140.2, 133.3, 131.5, 128.6, 127.7, 127.4,
127.2, 127.1, 117.3, 57.6, 19.3; IR (KBr, νmax, cm-1) 3196, 3080,
1696, 1457; MS m/z = 374 (Mþ). Anal. Calcd for C18H15ClN2-
OS2: C, 56.67; H, 4.03; N, 7.47. Found: C, 56.82; H, 4.30; N,
7.28.
5-Methylmercaptothiocarbonyl-4-thienyl-6-phenyl-3,4-dihy-
dropyrimidin-2(1H)-one (12f): bright yellow powder; mp 201-
1
202 °C; H NMR (300 MHz, CDCl3, δ ppm) 7.44-7.41 (m,
5H), 7.03-6.91 (m, 3H), 6.34 (s, 1H), 6.24 (d, J=2.7 Hz, 1H),
5.45 (s, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm)
225.1, 152.4, 145.6, 138.1, 134.5, 130.2, 128.9, 128.4, 126.7,
125.5, 125.2, 119.6, 56.0, 20.7; IR (KBr, νmax, cm-1) 3196,
3085, 1695, 1523; MS m/z=346 (Mþ). Anal. Calcd for C16H14-
N2OS3: C, 55.46; H, 4.07; N, 8.08. Found: C, 55.23; H, 4.26; N,
8.30.
5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-(4-meth-
oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12g): bright yellow
powder; mp 194-195 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.44-7.34 (m, 4H), 7.26-7.23 (m, 2H), 7.11 (s, 1H), 6.89 (d, J =
8.7 Hz, 2H), 6.03 (s, 1H), 5.85 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H),
2.32 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 226.7, 160.9,
152.8, 140.9, 137.6, 131.7, 129.8, 128.8, 126.4, 122.0, 118.3,
114.1, 60.1, 55.3, 20.5; IR (KBr, νmax, cm-1) 3212, 3091, 1697,
1454; MS m/z = 448 (Mþ). Anal. Calcd for C19H17BrN2O2S2: C,
50.78; H, 3.81; N, 6.23. Found: C, 50.54; H, 3.67; N, 6.41.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-6-(4-meth-
oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12h): bright yellow
Characterization Data of the Isolated Compounds. 5-Methyl-
mercaptothiocarbonyl-4-(4-nitrophenyl)-6-phenyl-3,4-dihydro-
pyrimidin-2(1H)-one (12a): bright yellow powder; mp 214-
1
1
215 °C; H NMR (300 MHz, CDCl3, δ ppm) 8.20 (d, J = 8.7
powder; mp 203-204 °C; H NMR (300 MHz, CDCl3, δ ppm)
Hz, 2H), 7.57-7.41 (m, 7H), 7.16 (s, 1H), 6.33 (s, 1H), 6.04 (d, J =
2.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm)
226.1, 153.1, 148.5, 147.5, 137.9, 133.9, 130.2, 128.8, 128.2, 128.0,
123.9, 118.0, 59.8, 20.5; IR (KBr, νmax, cm-1) 3215, 3076, 1697,
1530; MS m/z = 385 (Mþ). Anal. Calcd for C18H15N3O3S2: C,
56.09; H, 3.92; N, 10.90. Found: C, 56.18; H, 3.78; N, 11.01.
5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-phenyl-
3,4-dihydropyrimidin-2(1H)-one (12b): bright yellow powder;
7.39-7.36 (m, 2H), 7.30-7.25 (m, 2H), 6.89-6.82 (m, 4H), 6.32 (s,
1H), 5.86 (d, J = 2.1 Hz, 1H), 5.29 (s, 1H), 3.82 (s, 3H), 3.78 (s,
3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ
ppm) 227.3, 160.8, 159.3, 152.4, 136.3, 134.0, 129.6, 128.4, 126.8,
119.2, 114.1, 113.9, 60.5, 55.3, 55.2, 20.4; IR (KBr, νmax, cm-1
)
3196, 3096, 1699, 1639; MS m/z = 400 (Mþ). Anal. Calcd for
C20H20N2O3S2: C, 59.98; H, 5.03; N, 6.99. Found: C, 60.18; H,
5.29; N, 7.26.
1
mp 239-240 °C; H NMR (300 MHz, CDCl3, δ ppm) 7.46-
5-Methylmercaptothiocarbonyl-4-(2-chlorophenyl)-6-(4-meth-
oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12i): bright yellow
powder; mp 239-241 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.48-7.38 (m, 4H), 7.26-7.23 (m, 2H), 6.95-6.88 (m, 3H), 6.18
7.37 (m, 8H), 7.27-7.24 (m, 1H), 6.46 (s, 1H), 5.93 (d, J = 2.7
Hz, 1H), 5.45 (s, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3þ
DMSO-d6, δ ppm) 224.3, 151.5, 141.0, 140.2, 133.3, 130.1,
128.7, 127.8, 127.3, 119.9, 117.3, 57.8, 19.3; IR (KBr, νmax
,
(d, J = 3.0 Hz, 1H), 5.74 (s, 1H), 3.86 (s, 3H), 2.36 (s, 3H); 13
C
cm-1) 3197, 3081, 1697, 1636; MS m/z=418 (Mþ). Anal. Calcd
for C18H15BrN2OS2: C, 51.55; H, 3.61; N, 6.68. Found: C,
51.36; H, 3.77; N, 6.41.
NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm) 224.7, 160.3,
151.9, 141.2, 138.2, 132.1, 129.7, 129.1, 128.4, 127.8, 126.5,
125.6, 115.6, 113.3, 56.3, 54.5, 19.6; IR (KBr, νmax, cm-1
)
5-Methylmercaptothiocarbonyl-4,6-diphenyl-3,4-dihydropyri-
midin-2(1H)-one (12c): bright yellow powder; mp 196-198 °C;
1H NMR (300 MHz, CDCl3, δ ppm) 7.45-7.29 (m, 10H), 6.97
(s, 1H), 5.91 (s, 1H), 5.81 (s, 1H), 2.28 (s, 3H); 13C NMR (75
MHz, CDCl3, δ ppm) 227.0, 152.5, 141.6, 136.3, 134.5, 129.8,
3205, 3067, 1703, 1635; MS m/z = 404 (Mþ). Anal. Calcd for
C19H17ClN2O2S2: C, 56.36; H, 4.23; N, 6.92. Found: C, 56.13;
H, 4.19; N, 7.25.
5-Methylmercaptothiocarbonyl-4-phenyl-6-(4-methoxyphenyl)-
3,4-dihydropyrimidin-2(1H)-one (12j): bright yellow powder; Mp
199-200 °C; 1H NMR (300 MHz, CDCl3, δ ppm): 7.39-7.25 (m,
7H), 6.89 (d, J = 8.7 Hz, 2H), 6.77 (s, 1H), 5.90 (d, J=1.8 Hz,
1H), 5.63 (s, 1H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3, δ
ppm) 227.0, 160.8, 141.9, 137.4, 129.8, 129.3, 128.6, 127.9, 127.1,
128.7, 128.6, 128.1, 127.1, 119.3, 60.9, 20.4; IR (KBr, νmax
,
cm-1) 3214, 3085, 1698, 1637; MS m/z = 340 (Mþ). Anal. Calcd
for C18H16N2OS2: C, 63.50; H, 4.74; N, 8.23. Found: C, 63.33;
H, 4.93; N, 8.39.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-6-phenyl-
3,4-dihydropyrimidin-2(1H)-one (12d): bright yellow powder; mp
188-190 °C; 1H NMR (75 MHz, CDCl3, δ ppm) 7.46-7.37 (m,
5H), 7.31-7.26 (m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H),
5.89 (d, J = 1.5 Hz, 1H), 5.29 (s, 1H), 3.78 (s, 3H), 2.28 (s, 3H);
13C NMR (300 MHz, CDCl3, δ ppm) 227.2, 159.3, 152.5, 136.1,
126.7, 126.5, 118.7, 114.0, 60.6, 55.2, 20.4; IR (KBr, νmax, cm-1
)
3206, 3088, 2193, 1695; MS m/z = 370 (Mþ). Anal. Calcd for
C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56. Found: C, 61.88; H,
5.18; N, 7.32.
5-Methylmercaptothiocarbonyl-4-thienyl-6-(4-methoxyphenyl)-
3,4-dihydropyrimidin-2(1H)-one (12k): bright yellow powder; mp
7792 J. Org. Chem. Vol. 75, No. 22, 2010

Nandi et al.
JOCArticle
176-177 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.39 (d, J = 8.4
Hz, 2H), 7.25-7.21 (m, 1H), 7.03 (d, J = 3.3 Hz, 1H), 6.94-6.88
(m,3H), 6.65 (s, 1H), 6.20 (d, J =3.3Hz, 1H), 5.76 (s,1H), 3.83(s,
3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 224.9,
161.2, 152.7, 145.9, 139.1, 130.0, 126.6, 126.4, 125.3, 125.0, 119.1,
114.3, 55.9, 55.3, 20.7; IR (KBr, νmax, cm-1) 3218, 3065, 1701,
1645; MS m/z = 376 (Mþ). Anal. Calcd for C17H16N2O2S3: C,
54.23; H, 4.28; N, 7.44. Found: C, 54.10; H, 4.42; N, 7.21.
5-Methylmercaptothiocarbonyl-4-(3-nitrophenyl)-6-(4-chloro-
phenyl)-3,4-dihydropyrimidin-2(1H)-one (12l): bright yellow
powder; mp 226-227 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
8.23 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H),
7.54-7.36 (m, 5H), 6.90 (s, 1H), 6.02 (d, J = 2.4 Hz, 1H), 5.81 (s,
1H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ
ppm) 224.6, 152.4, 147.6, 144.2, 139.5, 135.5, 132.9, 132.2, 129.9,
128.9, 128.7, 128.3, 127.9, 122.1, 121.6, 117.5, 58.5, 20.0; IR
(KBr, νmax, cm-1) 3215, 3078, 1693, 1643; MS m/z = 419 (Mþ).
Anal. Calcd for C18H14ClN3O3S2: C, 51.49; H, 3.36; N, 10.01.
Found: C, 51.63; H, 3.56, N, 10.22.
(Mþ). Anal. Calcd for C16H13N3O3S3: C, 49.09; H, 3.35; N, 10.73.
Found: C, 49.35; H, 3.60; N, 10.51.
5-Methylmercaptothiocarbonyl-4-phenyl-6-thienyl-3,4-dihydro-
pyrimidin-2(1H)-one (12r): bright yellow powder; mp 178-179
°C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.40-7.23 (m, 7H), 7.02
(t, J = 3.6 Hz, 1H), 6.81 (s, 1H), 5.77 (d, J = 1.5 Hz, 1H), 5.60 (s,
1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 227.6,
153.0, 141.2, 134.7, 129.2, 129.0, 128.6, 128.3, 128.2, 127.3, 127.2,
119.9, 61.0, 20.6; IR (KBr, νmax, cm-1) 3214, 3096, 1696, 1638;
MS m/z = 346 (Mþ). Anal. Calcd for C16H14N2OS3: C, 55.46; H,
4.07; N, 8.08. Found: C, 55.28; H, 4.28; N, 8.30.
5-Methylmercaptothiocarbonyl-4-(2-methoxyphenyl)-6-thienyl-
3,4-dihydropyrimidin-2(1H)-one (12s): bright yellow powder; mp
180-181 °C;1H NMR(300 MHz, CDCl3, δ ppm) 7.48 (d, J = 5.4
Hz, 1H), 7.35-7.33 (m, 2H), 7.08-6.89 (m, 4H), 6.40 (s, 1H), 5.91
(s, 1H), 5.73 (s, 1H), 3.88 (s, 3H), 2.43(s,3H);13CNMR (75MHz,
CDCl3 þ DMSO-d6, δ ppm) 225.9, 156.1, 134.3, 133.1, 128.8,
128.5, 128.0, 127.9, 126.9, 126.7, 119.6, 117.2, 110.0, 54.7, 54.4,
19.8; IR (KBr, νmax, cm-1) 3083, 2905, 1697, 1634; MS m/z = 376
(Mþ). Anal. Calcd for C17H16N2O2S3: C, 54.23; H, 4.28; N, 7.44.
Found: C, 54.41; H, 4.50; N, 7.28.
5-Methylmercaptothiocarbonyl-4-(3-nitrophenyl)-6-furyl-3,4-
dihydropyrimidin-2(1H)-one (12t): yellow crystals; mp 219-
220 °C; H NMR (300 MHz, CDCl3, δ ppm) 8.20-8.14 (m,
2H), 7.74 (d, J = 7.5 Hz, 1H), 7.54-7.49 (m, 2H), 7.05 (s, 1H),
6.61 (d, J = 3.6 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 5.73 (d, J =
2.1 Hz, 1H), 5.68 (s, 1H), 2.48 (s, 3H); 13C NMR (75 MHz,
CDCl3 þ DMSO-d6, δ ppm) 224.6, 151.7, 146.8, 144.4, 143.6,
143.0, 132.4, 130.2, 128.2, 121.3, 121.0, 115.6, 112.7, 111.0, 57.3,
19.1; IR (KBr, νmax, cm-1) 3100, 2914, 1698, 1435; MS m/z =
375 (Mþ). Anal. Calcd for C16H13N3O4S2: C, 51.19; H, 3.49; N,
11.19. Found: C, 51.06; H, 3.64; N, 11.40.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-6-(4-chloro-
phenyl)-3,4-dihydropyrimidin-2(1H)-one (12m): bright yellow pow-
der; mp 197-198 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.40-7.31 (m, 4H), 7.28 (s, 1H), 6.84-6.81 (m, 4H), 5.84 (s, 1H),
5.51 (s, 1H), 3.78 (s, 3H), 2.30 (s, 3H); 13CNMR(75MHz,CDCl3 þ
DMSO-d6, δ ppm) 226.6, 158.9, 152.9, 135.8, 135.3, 134.0, 132.7,
1
129.7, 128.5, 128.1, 119.6, 113.6, 59.7, 54.9, 20.2; IR (KBr, νmax
,
cm-1) 3197, 3078, 1699, 1640; MS m/z =404 (Mþ). Anal. Calcdfor
C19H17ClN2O2S2: C, 56.36; H, 4.23; N, 6.92. Found: C, 56.18; H,
4.46; N, 6.73.
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-(4-chloro-
phenyl)-3,4-dihydropyrimidin-2(1H)-one (12n): bright yellow
powder; mp 226-227 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.37-7.36 (m, 4H), 7.29-7.25 (m, 4H), 6.53 (s, 1H), 5.90 (d, J =
2.1 Hz, 1H), 5.43 (s, 1H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3, δ ppm) 226.5, 152.6, 139.9, 136.0, 135.2, 134.0, 132.6,
5-Methylmercaptothiocarbonyl-4-(4-nitrophenyl)-6-furyl-3,4-
dihydropyrimidin-2(1H)-one (12u): bright yellow powder; mp
209-210 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 8.20 (d,
J = 8.4 Hz, 2H), 7.55-7.49 (m, 3H), 6.99 (s, 1H), 6.60 (d, J =
3.0 Hz, 1H), 6.46 (s, 1H), 5.74 (d, J = 1.5 Hz, 1H), 5.60 (s, 1H),
2.48 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm)
226.2, 152.4, 148.8, 146.8, 144.8, 143.3, 128.6, 127.8, 123.1, 116.4,
112.9, 111.7, 58.8, 19.9; IR (KBr, νmax, cm-1) 3097, 2911, 1697,
1641; MS m/z = 375 (Mþ). Anal. Calcd for C16H13N3O4S2: C,
51.19; H, 3.49; N, 11.19. Found: C, 51.33; H, 3.23; N, 11.34.
5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-furyl-3,4-
dihydropyrimidin-2(1H)-one (12v): bright yellow powder; mp
129.5, 129.0, 128.9, 128.5, 119.2, 60.3, 20.4; IR (KBr, νmax, cm-1
)
3214, 3085, 2914, 1697; MS m/z = 408 (Mþ). Anal. Calcd for
C18H14Cl2N2OS2: C, 52.81, H, 3.45; N, 6.84. Found: C, 52.66; H,
3.59; N, 6.98.
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-thienyl-
3,4-dihydropyrimidin-2(1H)-one (12o): bright yellow powder;
mp 226-227 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.41 (d,
J = 4.5 Hz, 1H), 7.29-7.25 (m, 5H), 7.03 (t, J = 4.2 Hz, 1H),
6.59 (s, 1H), 5.78 (d, J = 2.1 Hz, 1H), 5.48 (s, 1H), 2.37 (s, 3H);
13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm) 226.2, 152.0,
140.3, 134.0, 132.5, 131.5, 128.8, 128.0, 127.9, 127.7, 126.5,
118.7, 58.7, 19.8; IR (KBr, νmax, cm-1) 3076, 1689, 1543; MS m/
z = 380 (Mþ). Anal. Calcd for C16H13ClN2OS3: C, 50.45; H,
3.44; N, 7.35. Found: C, 50.67; H, 3.68; N, 7.10.
1
205-206 °C; H NMR (300 MHz, CDCl3, δ ppm) 7.45-7.42
(m, 3H), 7.26-7.21 (m, 3H), 6.59 (d, J = 3.6 Hz, 1H), 6.44 (s,
1H), 5.78 (s, 1H), 5.59 (d, J = 2.1 Hz, 1H), 2.47 (s, 3H); 13C NMR
(75 MHz, CDCl3, δ ppm) 228.0, 152.9, 144.8, 143.3, 140.1, 131.7,
129.1, 125.2, 122.3, 117.5, 112.7, 112.1, 60.4, 20.4; IR (KBr, νmax
,
cm-1) 3212, 3089, 1697, 1637; MS m/z = 408 (Mþ). Anal. Calcd
for C16H13BrN2O2S2: C, 46.95; H, 3.20; N, 6.84. Found: C, 46.77;
H, 3.36; N, 6.60.
5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-thienyl-
3,4-dihydropyrimidin-2(1H)-one (12p): bright yellow powder;
mp 216-217 °C; H NMR (300 MHz, CDCl3, δ ppm) 7.46-
1
7.41 (m, 3H), 7.26-7.22 (m, 3H), 7.03 (t, J = 4.8 Hz, 1H), 6.56
(s, 1H), 5.76 (s, 1H), 5.45 (s, 1H), 2.37 (s, 3H); 13C NMR (75
MHz, CDCl3, δ ppm) 227.3, 151.8, 140.1, 134.6, 131.8, 129.1,
129.0, 128.9, 128.5, 127.4, 122.4, 119.5, 60.6, 20.6; IR (KBr,
3-Benzoyl-2H-chromene-2-thione (14a): yellow solid; mp
171-172 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.93 (d, J =
7.8 Hz, 2H), 7.67-7.35 (m, 8H); 13C NMR (75 MHz, CDCl3, δ
ppm) 193.5, 192.2, 157.0, 139.2, 135.6, 133.9, 133.5, 133.2, 129.6,
128.7, 128.5, 125.8, 119.9, 116.7; IR (KBr, νmax, cm-1) 3060, 2996,
1673, 1603, 1230; MS m/z = 266 (Mþ). Anal. Calcd for
C16H10O2S: C, 72.16; H, 3.78. Found: 72.30; H, 3.95.
ν
max, cm-1) 3196, 3089, 1697, 1635; MS m/z = 424 (Mþ). Anal.
Calcd for C16H13BrN2OS3: C, 45.18; H, 3.08; N, 6.59. Found:
C, 45.33; H, 3.30; N, 6.32.
5-Methylmercaptothiocarbonyl-4-(3-nitrophenyl)-6-thienyl-3,4-
dihydropyrimidin-2(1H)-one (12q): bright yellow powder; mp
203-205 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 8.22 (s, 1H),
8.17 (d, J=8.1 Hz, 1H), 7.74 (d, J =7.5 Hz, 1H), 7.54-7.44 (m,
2H), 7.29-7.25 (m, 1H), 7.05 (t, J=4.8 Hz, 1H), 6.79 (s, 1H), 5.89
(d, J = 2.1Hz, 1H), 5.82 (s, 1H), 2.37 (s, 3H); 13C NMR(75MHz,
CDCl3 þ DMSO-d6, δ ppm) 225.3, 151.8, 147.3, 143.9, 133.8,
133.5, 132.8, 129.2, 128.6, 128.3, 126.6, 121.7, 121.4, 117.7, 58.1,
19.8; IR (KBr, νmax, cm-1) 3216, 3086, 1696, 1646; MS m/z = 391
3-Benzoyl-8-methoxy-2H-chromene-2-thione (14b): yellow so-
lid; mp 141-143 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.94
(d, J = 7.5 Hz, 2H), 7.61-7.58 (m, 2H), 7.48 (t, J = 7.8 Hz, 2H),
7.32 (t, J = 7.8 Hz, 1H), 7.19-7.12 (m, 2H), 4.01 (s, 3H); 13C
NMR (75 MHz, CDCl3, δ ppm) 192.8, 192.3, 147.0, 146.7,
139.4, 135.6, 133.8, 133.6, 129.6, 128.7, 125.7, 120.6, 119.5,
114.5, 56.3; IR (KBr, νmax, cm-1) 3085, 3029, 1662, 1601,
1229; MS m/z = 296 (Mþ). Anal. Calcd for C17H12O3S: C,
68.90; H, 4.08. Found: 68.72; H, 4.25.
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JOCArticle
3-(4-Methoxybenzoyl)-6-bromo-2H-chromene-2-thione (14c):
yellow solid; mp 206-207 °C; H NMR (300 MHz, CDCl3, δ
146.3, 143.1, 135.1, 134.1, 133.0, 129.9, 129.4, 129.0, 128.2, 127.9,
1
127.0, 126.5, 124.1, 89.9, 44.3, 28.7, 28.1, 20.5; IR (KBr, νmax,
ppm) 7.91 (d, J = 9.0 Hz, 2H), 7.74-7.69 (m, 2H), 7.45 (s, 1H),
7.40 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H);
13C NMR (75 MHz, CDCl3, δ ppm) 192.9, 190.2, 164.4, 155.6,
140.3, 135.6, 132.1, 131.2, 130.5, 128.3, 121.5, 118.4, 118.2,
114.1, 55.5; IR (KBr, νmax, cm-1) 3076, 3031, 1656, 1607,
1235; MS m/z = 374 (Mþ). Anal. Calcd for C17H11BrO3S: C,
54.41; H, 2.95. Found: C, 54.22; H, 3.15.
3-(4-Methoxybenzoyl)-6-nitro-2H-chromene-2-thione (14d): yel-
low solid; mp 208-209 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
8.46 (m, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.63-7.58 (m, 2H), 6.95 (d,
J = 8.7 Hz, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm)
192.2, 189.6, 164.6, 159.3, 132.1, 130.7, 127.9, 127.3, 123.9, 120.1,
117.6, 114.2, 55.6; IR (KBr, νmax, cm-1) 3051, 1643, 1593, 1236;
MS m/z = 341 (Mþ). Anal. Calcd for C17H11NO5S: C, 59.82; H,
3.25; N, 4.10. Found: C, 59.98; H, 3.06; N, 4.38.
cm-1) 3447, 2954, 1709, 1499; MS m/z = 469 (Mþ). Anal. Calcd
for C23H20ClN3O2S2: C, 58.77; H, 4.29; N, 8.94. Found: C, 58.52;
H, 4.43; N, 8.72.
6-Methylmercaptothiocarbonyl-5-(4-bromophenyl)-7-(4-methoxy-
phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-
d]pyrimidine (17c): reddish powder; mp 205-206 °C; 1H NMR
(300 MHz, CDCl3, δ ppm) 7.42-7.36 (m, 4H), 7.30-7.25 (m,
2H), 6.91 (d, J = 8.7 Hz, 2H), 5.86 (s, 1H), 5.36 (s, 1H), 3.83 (s,
3H), 3.48 (s, 3H), 3.28 (s, 3H), 2.33 (s, 3H); 13C NMR (75 MHz,
CDCl3, δ ppm) 229.9, 160.9, 160.8, 150.9, 143.5, 143.0, 133.3,
131.3, 129.7, 129.6, 127.2, 123.6, 120.7, 114.4, 90.2, 55.3, 44.0,
28.7, 28.1, 20.5; IR (KBr, νmax, cm-1) 3451, 2934, 1707, 1506;
MS m/z = 543 (Mþ). Anal. Calcd for C24H22BrN3O3S2: C,
52.94; H, 4.07; N, 7.72. Found: C, 52.68; H, 4.23; N, 7.50.
6-Methylmercaptothiocarbonyl-7-(4-methoxyphenyl)-1,3-dimeth-
yl-5-(3-nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
pyrimidine (17d): reddish powder; mp 240-241 °C; 1H NMR (300
MHz, CDCl3, δ ppm) 8.24 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.79
(d, J = 7.5 Hz, 1H), 7.45-7.41 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H),
5.99 (s, 1H), 5.51 (s, 1H), 3.84 (s, 3H), 3.51 (s, 3H), 3.28 (s, 3H),
2.31 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 229.2, 161.0,
150.8, 148.4, 146.7, 143.2, 134.8, 134.4, 129.7, 128.9, 126.9, 122.5,
3-(2-Acetylthiophene)-8-methoxy-2H-chromene-2-thione (14e):
1
yellow solid; mp 174-175 °C; H NMR (300 MHz, CDCl3, δ
ppm) 7.75 (d, J = 4.2 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.57 (s,
1H), 7.32-7.26 (m, 1H), 7.18-7.11 (m, 3H), 4.01 (s, 3H); 13C
NMR (75 MHz, CDCl3, δ ppm) 192.2, 184.3, 146.7, 142.8, 139.0,
135.5, 135.0, 133.0, 128.3, 125.7, 120.4, 119.5, 114.6, 56.3; IR
(KBr, νmax, cm-1) 3059, 2985, 1671, 1602, 1230; MS m/z = 302
(Mþ). Anal. Calcd for C15H10O3S2: C, 59.58; H, 3.33. Found: C,
59.73; H, 3.52.
121.8, 114.5, 89.7, 55.4, 44.2, 28.8, 28.1, 20.5; IR (KBr, νmax
,
cm-1) 3449, 2934, 1701, 1512; MS m/z = 510 (Mþ). Anal. Calcd
for C24H22N4O5S2: C, 56.46; H, 4.34; N, 10.97. Found: C, 56.67;
H, 4.59; N, 10.71.
3-(2-Acetylthiophene)-6-bromo-2H-chromene-2-thione (14f):
1
yellow solid; mp 166-167 °C; H NMR (300 MHz, CDCl3, δ
ppm) 7.78-7.64 (m, 4H), 7.50 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H),
7.15-7.11 (t, J = 4.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, δ
ppm) 192.4, 183.7, 155.7, 142.5, 139.6, 135.9, 135.1, 131.2, 130.6,
128.4, 121.2, 118.5, 118.2; IR (KBr, νmax, cm-1) 3054, 1676, 1610;
MS m/z = 350 (Mþ). Anal. Calcd for C14H7BrO2S2: C, 47.87; H,
2.01. Found: C, 47.66; H, 2.21.
3-(2-Acetylfuran)-8-ethoxy-2H-chromene-2-thione (14g): yel-
low solid; mp 175-176 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.61-7.58 (m, 2H), 7.29-7.23 (m, 2H), 7.17-7.10 (m, 2H), 6.57
(d, J = 1.8 Hz, 1H), 4.28 (q, J = 6.9 Hz, 2H), 1.55-1.53 (m, 3H);
13C NMR (75 MHz, CDCl3, δ ppm) 192.7, 179.6, 151.7, 147.4,
146.0, 138.2, 133.8, 125.7, 120.5, 120.1, 119.6, 116.0, 112.7, 65.1,
14.6; IR (KBr, νmax, cm-1) 3085, 3033, 1677, 1600, 1225; MS
m/z = 300 (Mþ). Anal. Calcd for C16H12O4S: C, 63.99; H, 4.03.
Found: C, 64.05; 4.32.
3-(2-Acetylfuran)-6-bromo-2H-chromene-2-thione (14h): yel-
low solid; mp 198-199 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
7.74-7.62 (m, 2H), 7.51 (s, 1H), 7.39-7.25 (m, 3H), 6.59 (s, 1H);
13C NMR (75 MHz, CDCl3, δ ppm) 192.5, 179.0, 155.7, 147.6,
138.9, 136.0, 131.7, 130.7, 121.3, 120.2, 118.5, 118.2, 112.9; IR
(KBr, νmax, cm-1) 3076, 3023, 1667, 1606, 1223; MS m/z = 334
(Mþ). Anal. Calcd for C14H7BrO3S: C, 50.17; H, 2.11. Found:
C, 50.01; H, 2.28.
6-Methylmercaptothiocarbonyl-1,3-dimethyl-5-(3-nitrophenyl)-
2,4-dioxo-7-thiophen-2-yl-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
pyrimidine (17e): reddish powder; mp 235-236 °C; 1H NMR
(300 MHz, CDCl3, δ ppm) 8.23 (s, 1H), 8.06 (d, J=8.1 Hz,
1H), 7.75 (d, J=7.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.29-7.28
(m, 1H), 7.06-7.03 (m, 1H), 6.07 (s, 1H), 5.39 (s, 1H), 3.57 (s,
3H), 3.27 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3, δ
ppm) 222.8, 160.9, 146.2, 143.1, 134.8, 129.3, 128.9, 128.4,
127.8, 123.0, 122.7, 122.0, 112.8, 112.6, 89.4, 44.4, 28.7, 28.2,
20.5; IR (KBr, νmax, cm-1) 3441, 2945, 1700, 1503; MS m/z =
486 (Mþ). Anal. Calcd for C21H18N4O4S2: C, 51.84; 3.73; N,
11.51. Found: C, 51.99; H, 3.98; N, 11.27.
6-Methylmercaptothiocarbonyl-7-(4-chlorophenyl)-1,3-dimeth-
yl-5-(3-nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
pyrimidine (17f): reddish powder; mp 257-258 °C; 1H NMR (300
MHz, CDCl3, δ ppm) 8.23 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.76
(d, J = 7.5 Hz, 1H), 7.46-7.37 (m, 5H), 5.89 (s, 1H), 5.51 (s, 1H),
3.51(s,3H),3.27(s,3H),2.30(s,3H);13CNMR(75MHz, CDCl3 þ
DMSO-d6, δ ppm) 228.1, 160.6, 150.5, 147.7, 147.1, 143.7, 136.5,
135.2, 134.1, 132.9, 130.5, 128.5, 128.1, 121.7, 121.5, 121.0, 90.0, 42.9,
29.7, 27.5, 19.9; IR (KBr, νmax, cm-1) 3451, 2961, 1703, 1509; MS m/
z = 514 (Mþ). Anal. Calcd for C23H19ClN4O4S2: C, 53.64; H, 3.72;
N, 10.88. Found: C, 53.89; H, 3.91, N, 10.68.
6-Methylmercaptothiocarbonyl-1,3-dimethyl-5-(3-nitrophenyl)-
2,4-dioxo-7-phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine
(17a): red crystals; mp 222-223 °C; 1H NMR (300 MHz, CDCl3,
δ ppm) 8.26 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 6.9 Hz,
1H), 7.50-7.43 (m, 6H), 5.99 (s, 1H), 5.54 (s, 1H), 3.51 (s, 3H),
3.28 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm)
229.0, 160.9, 150.8, 148.4, 146.5, 143.3, 134.8, 134.0, 130.1, 129.0,
128.9, 128.3, 123.2, 122.6, 121.9, 89.4, 44.3, 28.9, 28.1, 20.4; IR
(KBr, νmax, cm-1) 3453, 2961, 1705, 1510; MS m/z=480 (Mþ).
Anal. Calcd for C23H20N4O4S2: C, 57.48; H, 4.19; N, 11.66.
Found: C, 57.61; H, 4.35; N, 11.42.
6-Methylmercaptothiocarbonyl-7-furan-2-yl-1,3-dimethyl-5-(3-
nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine
(17g): reddish powder; mp 238-239 °C; H NMR (300 MHz,
1
CDCl3, δppm) 8.20 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.5
Hz, 1H), 7.51-7.38 (m, 2H), 6.73 (s, 1H), 6.57 (d, J = 3.3 Hz,
1H), 6.46 (s, 1H), 5.20 (s, 1H), 3.61 (s, 3H), 3.27 (s, 3H), 2.51 (s,
3H); 13C NMR (75 MHz, CDCl3, δ ppm) 230.2, 160.9, 150.8,
148.4, 146.1, 144.5, 143.3, 142.8, 134.7, 128.9, 122.9, 122.6, 122.1,
112.7, 112.6, 88.6, 44.5, 28.6, 28.1, 20.5; IR (KBr, νmax, cm-1) 3447,
2953, 1705, 1505; MS m/z= 470 (Mþ). Anal. Calcd for C21H18-
N4O5S2: C, 53.61; H, 3.86; N, 11.91. Found: C, 53.46; H, 3.98; N,
11.72.
6-Methylmercaptothiocarbonyl-5-(3-chlorophenyl)-1,3-dimeth-
yl-2,4-dioxo-7-phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine
6-Methylmercaptothiocarbonyl-7-furan-2-yl-1,3-dimethyl-5-(4-
nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyri-
midine (17h): reddish powder; mp 235-236 °C; 1H NMR (300
MHz, CDCl3, δ ppm) 8.12 (d, J = 8.4 Hz, 2H), 7.55-7.51 (m,
3H), 6.71 (s, 1H), 6.57 (d, J = 3.3 Hz, 1H), 6.48 (t, J = 1.5 Hz,
1
(17b). Reddish powder; Mp 233-234 °C; H NMR (300 MHz,
CDCl3, δ ppm) 7.50-7.37 (m, 6H), 7.32-7.29 (m, 1H), 7.18-7.16
(m, 2H), 5.91 (s, 1H), 5.40 (s, 1H), 3.49 (s, 3H), 3.29 (s, 3H), 2.31 (s,
3H). 13C NMR (75 MHz, CDCl3, δ ppm) 229.6, 160.9, 150.9,
7794 J. Org. Chem. Vol. 75, No. 22, 2010

Nandi et al.
JOCArticle
1H), 5.18 (s, 1H), 3.60 (s, 3H), 3.27 (s, 3H), 2.52 (s, 3H); 13C
NMR (75 MHz, CDCl3, δ ppm) 230.1, 160.8, 151.2, 150.8,
146.8, 144.5, 143.3, 142.8, 129.0, 123.6, 122.7, 122.0, 112.7,
112.6, 88.5, 44.6, 28.6, 28.1, 20.5; IR (KBr, νmax, cm-1) 3431,
2951, 1707, 1510; MS m/z = 470 (Mþ). Anal. Calcd for
Research (Grant No. 01(2260)/08/EMR-II) and Department
of Science and Technology (Grant No. SR/S1/OC-66/2009),
New Delhi. G.C.N. and S.S are thankful to CSIR, New Delhi,
for senior research fellowship.
C21H18N4O5S2: C, 53.61; H, 3.86; N, 11.91. Found: C, 53.85;
H, 3.98; N, 11.63.
Supporting Information Available: Full experimental de-
1
tails; analytical and spectroscopic data (copies of H and 13C
NMR for compounds 12, 14, and 17); X-ray data for com-
pounds 12t and 17a (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We great fully acknowledge the gener-
ous financial support from Council of Scientific and Industrial
J. Org. Chem. Vol. 75, No. 22, 2010 7795