Base-mediated one-pot synthesis of 3,4,5,6-tetrahydro-4-substituted benzo[h]quinazoline-2(1H)-thione derivatives and evaluation of their antioxidant activity

Article abstract of DOI:10.1080/00397911.2017.1393688

One-pot three-component Beginelli-like reactions of a ketone 1, an aryl aldehyde 2, and thiourea 3 in the presence of sodium hydroxide are described. In this reaction, 3,4,5,6-tertrahydro-4-substituted quinazoline-2(1H)-thione derivatives 4a–h were obtain

Full text of DOI:10.1080/00397911.2017.1393688

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Base-mediated one-pot synthesis
of 3,4,5,6-tetrahydro-4-substituted
benzo[h]quinazoline-2(1H)-thione derivatives and
evaluation of their antioxidant activity
Matam Sivakumar, Kaliyan Prabakaran & Muthu Seenivasa Perumal
To cite this article: Matam Sivakumar, Kaliyan Prabakaran & Muthu Seenivasa Perumal (2017):
Base-mediated one-pot synthesis of 3,4,5,6-tetrahydro-4-substituted benzo[h]quinazoline-2(1H)-
thione derivatives and evaluation of their antioxidant activity, Synthetic Communications, DOI:
10.1080/00397911.2017.1393688
To link to this article: https://doi.org/10.1080/00397911.2017.1393688
View supplementary material
Published online: 26 Dec 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [RMIT University Library]
Date: 27 December 2017, At: 01:36

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1393688
Base-mediated one-pot synthesis of 3,4,5,6-tetrahydro-4-
substituted benzo[h]quinazoline-2(1H)-thione derivatives
and evaluation of their antioxidant activity
Matam Sivakumar, Kaliyan Prabakaran, and Muthu Seenivasa Perumal
Department of Chemistry, Gandhigram Rural Institute-Deemed University, Gandhigram, Dindigul,
Tamilnadu, India
ABSTRACT
ARTICLE HISTORY
Received 14 August 2017
One-pot three-component Beginelli-like reactions of a ketone 1, an
aryl aldehyde 2, and thiourea 3 in the presence of sodium hydroxide
are described. In this reaction, 3,4,5,6-tertrahydro-4-substituted
quinazoline-2(1H)-thione derivatives 4a–h were obtained in good
yields (73–85%). The compound 4a has been characterized by single
crystal X-ray analysis. All the synthesized compounds 4a–h and 5a–b
were screened for their in vitro antioxidant activity. Compounds 4c,
4e, and 4h have exhibited an excellent than the standard ascorbic
acid. Compounds 4d, 4f, and 4g have also shown good activity.
Remaining compounds show moderate antioxidant activity.
KEYWORDS
α-Tetralone; aldehyde;
antioxidant activity;
IC50 value; quinazoline-2
(1H)-thione; thiourea
GRAPHICAL ABSTRACT
Introduction
The compound-containing quinazoline-2(1H)-thione moieties are important classes of
bioactive molecules that can show a wide variety of properties such as antibacterial,
antiviral, and anti-inflammatory activities.[1] Also, these compounds act as antihyperten-
sives, anticancer agents, calcium-channel blockers, and neuropeptide γ antagonists.[2]
One of the well-established synthetic procedures available for quinazoline-2(1H)-thione
scaffold is the Biginelli reaction, which combines an aromatic aldehyde 2, thiourea 3,
and carbonyl compound 1 under acidic conditions in ethanol, gives a 3,4,5,6-tetrahydro
4-substituted benzo[h]quinazoline-2(1H)-thione 4. It has seen widespread use for generat-
ing large collections of molecules in combinatorial synthesis (Fig. 1).[3]
CONTACT Muthu Seenivasa Perumal
mspchem99@gmail.com; M.seenivasaperumal@ruraluniv.ac.in
Department of
Chemistry, Gandhigram Rural Institute-Deemed University, Gandhigram, Dindigul district, Tamilnadu 624 302, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data (full experimental detail, IR, 1H-NMR, 13C-NMR, mass spectra, and microanalysis) can be accessed on
the publisher’s website.
© 2017 Taylor & Francis

2
M. SIVAKUMAR ET AL.
Figure 1. Some examples of biologically active dihydropyrimidinthiones.
Over past few years, many Biginelli-like scaffolds have been reported, and substantial
efforts have been made to build up new methods for the synthesis of such compounds
because of their therapeutic and pharmacological properties.[2c,4] There are several reports
on the synthesis of derivatives containing quinazoline-2(1H)-thione moieties using protic
acids,[5] Lewis acids,[6] triflates,[7] microwave irradiation,[8] ionic liquids,[9] ultra sound,[10]
metallic/ammonium salts,[11] Dowex-50 W,[12] and dodecyl hydrogen sulfate.[13a] Unfortu-
nately, many of these methods have used expensive or toxic reagents and strong acidic con-
ditions. Therefore, the development of a less expensive, high-yielding protocol for the
synthesis of compounds containing a quinazoline-2(1H)-thione 4 moiety remains of great
attention and stand for a considerable challenge. However, despite of extensive studies on
the Biginelli-like reactions reported in the literature[13b], to best of our knowledge, there are
few reports focusing on the development of base-mediated one-pot Biginelli-like
reactions.[3c]
Results and discussion
To pursue our interest in the synthesis and antioxidant activity of quinazoline-2(1H)-
thione, 4 We report herein the sodium hydroxide mediated, one-pot synthesis of 3,4,5,
6-tertrahydro-4-substituted quinazoline-2(1H)-thione 4 derivatives through three-compo-
nent condensation of ketone 1, an aromatic aldehydes 2 and thiourea 3. The reaction
proceeded smoothly in the presence of NaOH (1 eq) to afford 3,4,5,6-tertrahydro-4-
substituted quinazoline-2(1H)-thione 4 derivatives in good yields (Scheme 1). The pure
products 4 were obtained without any additional column chromatography. In addition,
through a detailed mechanistic study, (E)-2-benzylidene-3,4-dihydronaphthalen-1(2H)-
one 6 was suggested as reaction intermediate.
Scheme 1. General scheme for synthesis of 3,4,5,6-tetrahydro-4-substituted benzo[h]quinazoline-2
(1H)-thione derivatives.

SYNTHETIC COMMUNICATIONS®
3
Very recently,[14] it has been reported that the cyclocondensation of 2-arylidene-1-
tetralonene with thiosemicarbazide under alkaline medium through two step (chalcone
preparation followed by cyclocondensation). We have examined the reaction of α-tetralone
1, anisaldehyde 2a with thiourea 3 in the presence of NaOH at reflux temperature,
gives 85% yield. To optimize the reaction conditions, the reaction was examined with
various bases (Table 1). It was found that using of α-tetralone 1 (1 mmol), anisaldehyde
2a (1 mmol) with thiourea 3 (1 mmol), and NaOH (1 mmol) in 5 mL of in ethanol
at 70 °C for 1.5 h, the quinazoline 2 (1H)-thione 4a was obtained in 85% yield (Table 1,
Entry 1).
Table 1. Optimization of reaction conditions using various bases.
Entrya
Baseb
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
9
NaOH
KOH
LiOH
1.5
1.5
2.5
7
7
24
7
85d
82d
80d
NaOEt
NatOBu
K2CO3
Pyridine
Et3N
76e
61e
Trace
64e
24
7
Trace
11e
DABCO
aUnless otherwise mentioned, the reactions were performed using α-tetralone 1 (1 mmol), anisaldehyde 2a (1 mmol) with
thiourea 3 (1 mmol), and base (1 mmol) in 5 mL of ethanol at 70 °C.
bAll these cases, 1 mmol of base is used.
cYields are of isolated product.
dThe products are thrown out from the reaction mixture.
eThe products are purified using column chromatography.
The reaction of the α-tetralone 1 (1 mmol), anisaldehyde 2a (1 mmol), and thiourea 3
(1 mmol) with KOH or LiOH in 5 mL of in ethanol, at 70 °C for 1.5 or 2.5 h, gave the
quinazoline 2 (1H)-thione 4a in 82 and 80% yields, respectively (Table 1, Entries 2, 3).
We have performed the reaction in identical conditions except time 7 h, where the bases
NaOEt or NatOBu were used, the quinazoline 2 (1H)-thione 4a was obtained in 76 and
61% yields, respectively (Table 1, Entries 4, 5). The reaction of the α-tetralone 1 (1 mmol),
anisaldehyde 2a (1 mmol) with thiourea 3 (1 mmol) and organic bases such as pyridine
or DABCO in 5 mL of ethanol, at 70 °C for 7 h gave the quinazoline 2 (1H)-thione 4a
in 64 and 11% yields, respectively (Table 1, Entries 7, 9), whereas, under the same
conditions, the weak bases such as K2CO3, Et3N gave only traces of yield even after 24 h
(Table 1, Entries 6, 8).
Furthermore, efforts were undertaken to optimize solvent, and the results are summar-
ized (Table 2). We have chosen alcoholic solvent such as methanol, ethanol, isopropanol,
THF, ACN, DMF, and DMSO for our study.

4
M. SIVAKUMAR ET AL.
Table 2. Optimization study of solvent for reaction condition.
Entry
Solvent
Time (h)
Yield (%)c
1a
2a
3a
4b
5b
6b
7b
Methanol
Ethanol
IPA
1.5
1.5
1.5
14
75
85
73
43
19
60
72
THF
ACN
DMF
DMSO
14
14
14
aThe reactions were performed using α-tetralone 1 (1 mmol), anisaldehyde 2a (1 mmol) with thiourea 3 (1 mmol), and NaOH
(1 mmol) in 5 mL of respective solvent at 70 °C for 1.5 h.
bThe reactions were performed using α-tetralone 1 (1 mmol), anisaldehyde 2a (1 mmol) with thiourea 3 (1 mmol), and NaOH
(1 mmol) in 5 mL of respective solvent at 70 °C for 14 h.
cYields are of isolated product and are thrown out from the reaction mixture.
The reaction of the α-tetralone 1 (1 mmol) and anisaldehyde 2a (1 mmol) with thiourea
3 (1 mmol) in 5 mL of alcoholic solvents such as MeOH, EtOH, and IPA in the presence of
NaOH (1 mmol), under reflux conditions for 1.5 h gave the quinazoline 2 (1H)-thione 4a
in 75, 85, and 73% yields, respectively (Table 2, Entries 1–3). When we examined the
reaction with the same condition, the solvents such as THF, ACN, DMF, and DMSO, gave
the quinazoline 2 (1H)-thione 4a in 43, 19, 60, and 72% yields, respectively (Table 2,
Entries 4–7). It was found that the reaction proceeds better in protic solvents than in apro-
tic solvent. With the optimized condition in hand, this transformation (Scheme 1) was
examined using ketone 1, 1a aldehyde 2a–h, and thiourea 3 in the presence of NaOH.
As shown in Table 3, the NaOH mediated one-pot condensation of substituted aromatic
aldehydes 2, cyclic ketone 1, and thiourea 3 proceeded smoothly to furnish the correspond-
ing quinazoline 2 (1H)-thione 4 in good yields. It is noted that the methodology worked
well even for heterocyclic aldehyde 2 h (Table 3, Entry 8).
Table 3. Synthesis of quinazoline-2(1H)-thione 4a–4h.
Entrya
Ketone 1
Aldehyde 2
Productb
4
Time (h)
1.5
Yield (%)c
85
1
(Continued)

SYNTHETIC COMMUNICATIONS®
5
Table 3. Continued.
Entrya
Ketone 1
Aldehyde 2
Productb
4
Time (h)
1.5
Yield (%)c
2
82
3
1.5
73
4
5
2.0
1.5
80
81
6
7
1.5
1.5
83
79
8
2.0
77
aThe reactions were performed using α-tetralone 1 (3 mmol), aldehyde 2a–h (3 mmol) with thiourea 3 (3 mmol), and NaOH
(3 mmol) in 5 mL of EtOH at 70 °C.
bThe products are characterized by Mass, IR, 1H NMR, and 13C NMR spectroscopy.
cYields are of isolated product and are thrown out from the reaction mixture.

6
M. SIVAKUMAR ET AL.
The versatility of the reaction was investigated with a variety of aldehyde derivatives.
According to Table 3, the aldehydes 2a–h containing both electron-releasing and
electron-withdrawing substituents proved to be suitable substrate for this reaction
(Table 3, Entries 1–8).
Recently,[15] the two step preparation of quinazoline-2(1H)-thione 5a and 5b has been
reported through the cyclocondensation of bis(arylmethylene)cyclohexanone with thiourea
in the presence of sodium methoxide and gave 50–70% yield. It was of our interest to
examine the reaction in one pot in the presence of sodium hydroxide as a base. Accord-
ingly, we have performed the reaction of cyclohexanone 1a (3 mmol), aldehyde 2a, 2f
(6 mmol), and thiourea 3 (3 mmol) in 5 mL ethanol in the presence of NaOH (3 mmol)
at 70 °C for 6 h gave the quinazoline-2(1H)-thione 5a and 5b in 58 and 66% yields, respect-
ively (Table 4, Entries 1, 2). All the structures 4a–h and 5a–b were characterized by physi-
cal and spectroscopic techniques such as mp, Mass, IR, 1H NMR, and 13C NMR.
1
Compound 4a H NMR spectrum, as an example, revealed the presence of two singlet sig-
nals delta 9.00 and 9.69 due to two –NH group of quinozoline-2(1H)-thione scaffold. The
two singlet signals delta 3.73 (3H) and 4.87 (1H) correspond to –OCH3 and asymmetric
benzylic proton. The doublet at 6.91, multiplet at 7.41, and triplet at 7.66 correspond to
aromatic protons. The multiplet at 1.70–2.80 corresponds to aliphatic protons. Structure
of compound 4a was further confirmed by single crystal X-ray analysis. The single crystal
X-ray structure of compound 4a is shown in Fig. 2.
Table 4. Preparation of quinazoline-2(1H)-thione 5a–5b.
Entrya
1
Ketone 1
Aldehyde 2
Productb
4
Time (h)
6
Yield (%)c
58
2
6
66
aThe reactions were performed using cyclohexanone 1 (3 mmol), aldehyde 2a or 2f (6 mmol) with thiourea 3 (3 mmol), and
NaOH (3 mmol) in 5 mL of EtOH at 70 °C.
bThe products are characterized by Mass, IR, 1H NMR, and 13C NMR spectroscopy.
cYields are of isolated product and are thrown out from the reaction mixture.

SYNTHETIC COMMUNICATIONS®
7
Figure 2. Single crystal X-ray structure of compound 4a (CCDC No. 1472495).
Previously, Kappe et al.[16] proposed that Lewis acid or protic acid promoted Biginelli
reaction proceeded through the formation of an iminium ion (acid catalyzed condensation
of aldehyde with urea) as a key intermediate rather than the carbenium ion intermediate
(acid catalyzed Knoevenagel reaction of aldehyde and ethyl acetoacetate). The current
methodology and the basic condition using NaOH, we visualized that the reaction proceed
through Knoevenagel followed by aza-Michel reaction.
To probe the mechanism, we have examined the reaction of α-tetralone 1 with p-chlor-
obenzaldehyde 2f in ethanol in the presence of 4N NaOH, the formed (E)-2-(4-chloroben-
zylidene)-3,4-dihydronaphthalen-1(2H)-one 6[17] was isolated and characterized by NMR.
Then the 6 was treated with thiourea in the presence of NaOH at 70 °C for 5 h (Scheme 2)
to afford 4f in 80% yield. Also, we have investigated the reaction of three-component, one-
pot base-mediated reaction of α-tetralone 1, p-chlorobenzaldehyde 2f with thiourea 3 in
ethanol in the presence of NaOH. It was observed that after 15 min of addition of the
reagent, it formed a yellow precipitate which was characterized by 1H NMR and confirmed
as (E)-2-(4-chlorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one 6. Furthermore, the
yellow precipitate slowly dissolved in another 15 min formed as white precipitate which
1
was filtered and characterized by H NMR and confirmed as quinazoline-2(1H)-thione
4f, it was clearly seen that the reaction intermediate formed in the one-pot reaction is
(E)-2-(4-chlorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one 6.
Scheme 2. Preparation of 3,4,5,6-tetrahydro-4-Substituted benzo[h]quinazoline-2(1H)-thiones through
the intermediate 6.

8
M. SIVAKUMAR ET AL.
According to above observations, the plausible reaction mechanism was proposed.
As shown in Fig. 3, the reaction using thiourea is initiated through base-mediated
Knoevenagel condensation of aldehyde 2 with α-tetralone 1 to give the intermediate 6. Sub-
sequently, base-mediated aza-Michel addition of thiourea 3 to (E)-2-(4-chlorobenzyli-
dene)-3,4-dihydronaphthalen-1(2H)-one 6 leads to the formation of Michel adduct 7.
Finally, amino group of intermediate 7 attacked on the carbonyl group in an intramolecu-
lar fashion gave the intermediate 9, followed by elimination of the hydroxyl group gave the
desired product 4.
Figure 3. Proposed mechanism.
Antioxidant activity
The DPPH radicals react with suitable reducing agents as a result of which the electrons
become paired off forming the corresponding hydrazine. The solution, therefore, loses
color stoichiometrically depending on the number of electrons taken up. Substances cap-
able of donating electrons/hydrogen atoms are able to convert DPPH (purple) into their
nonradical form 1,1-diphenyl-2-picrylhydrazine (Yellow), a reaction which can be followed
spectrophotometrically.[18]
In the DPPH Free radical scavenging activity, compounds 4a–4h and 5a, 5b were eval-
uated for their free radical scavenging activity with ascorbic acid as standard compound.
The IC50 value was calculated for each compound as well as ascorbic acid are summarized
in Table 5 and shown in figures (see supplementary material). The scavenging effect
increased with the increasing concentrations of test compounds. The IC50 values for com-
pounds 4c, 4e, 4h were 1.77 � 10−4 M, 1.73 � 10−4 M, and 1.55 � 10−4 M, respectively,
which are comparatively lower than the IC50 value (1.80 � 10−4 M) of ascorbic acid. The
compounds 4d, 4f, and 4g were comparable IC50 value with ascorbic acid. The IC50 value
of compounds 4a, 5a, and 5b were slightly higher than the standard (Table 5). DPPH is rela-
tively stable nitrogen-centered free radical that easily accepts an electron or hydrogen radical
to become a stable diamagnetic molecule. Free radical scavenging activity of the quinazo-
line-2(1H)-thione derivatives are concentration dependent, as the concentration of the test
compounds increases, the radical scavenging activity increases and lower IC50 value reflects
better protective action. From results, it may be postulated that compounds 4c, 4e, 4h
were able to reduce the stable free radical DPPH to the yellow-colored
diphenylpicrylhydrazine exhibiting better free radical scavenging activity than the standard
antioxidant ascorbic acid.

SYNTHETIC COMMUNICATIONS®
9
Table 5. IC50 Values for compounds 4a–h and 5a–b.
Entry
Product
IC50 Value (� 10−4)M
1
2
4a
2.47
3.14
1.77
1.87
1.73
1.85
1.85
1.55
2.01
1.99
1.80
4b
3
4c
4
4d
5
4e
6
4f
7
4g
8
4h
9
5a
5b
10
11
Ascorbic acid
Among the synthesized compounds, the kinetic study were performed for the most
potent compound 4h to verify the complete quenching time for DPPH radicals as shown
in Fig. 4. As time increases, the intensity at 517 nm decreases, and at 54 min, the DPPH
radicals were quenched completely.
Figure 4. Kinetic study for DPPH Vs 4h.
Conclusions
In this study, we have developed the sodium hydroxide-mediated one-pot synthesis of
3,4,5,6-tertrahydro-4-substituted quinazoline-2(1H)-thione derivatives 4a–h, and the
compound 4a has been characterized by single crystal X-ray analysis. This method provides
several advantages such as inexpensive reagents, short reaction times, easy synthetic
procedure, good yields, simple workup procedure, and easy isolation. It is expected to
be useful synthetic procedure for the synthesis of wide variety of drug-like molecules con-
tains quinazoline-2(1H)-thione 4 moiety. All the synthesized compounds 4a–h and 5a–b
were screened for antioxidant activity. Among the synthesized compound, 4h exhibits
an excellent antioxidant activity.

10
M. SIVAKUMAR ET AL.
General procedure for synthesis of 3,4,5,6-tetrahydro-4-substituted benzo[h]
quinazoline-2(1H)-thione derivatives
To a stirred solution of ketone 1 (3 mmol) in EtOH (5 mL), aryl aldehyde 2 (3 mmol), thio-
urea 3 (3 mmol), and NaOH (3 mmol) were added and were heated at 70 °C for respective
time (Table 3). After 15 min, yellow solid was thrown out from the reaction mixture. The
heating was continued, the yellow solid was slowly dissolved, and a white solid was
precipitated from the reaction mixture. The white solid was filtered and washed twice with
cold ethanol (10 mL) to afford 3,4,5,6-tetrahydro-4-substituted benzo[h]quinazoline-2
(1H)-thione 4 in 73–85% yields.
3,4,5,6-tetrahydro-4-(4-methoxyphenyl)benzo[h]quina-zoline-2(1H)-thione (4a)[8f]
Yield: 0.82 g, (85%); White solid; mp 219–221 °C.[8f] IR (KBr): 3436, 3209, 2927, 2860,
1
1619, 1572, 1477, 1176, 1032 cm−1; H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.00
(s, 1H), 7.66 (m, 1H), 7.41 (m, 5H), 6.91 (d, 2H, J ¼ 8.40 Hz), 4.87 (s, 1H), 3.73 (s, 3H),
2.70 (m, 1H), 2.57 (m, 1H), 2.11 (m, 1H), 1.81 (m, 1H); 13C NMR (100 MHz, DMSO-
d6): δ 174.4, 159.4, 135.8, 135.4, 128.7, 128.2, 128.0, 126.9, 122.0, 114.4, 111.9, 58.3, 55.5,
27.8, 24.0; MS (EI): m/z ¼ 323 [M þ 1].
Acknowledgments
We are thankful to the DST-SERB, UGC-BSR New Delhi for a research grant. K. Prabhakaran thanks
DST-SERB, New Delhi for financial support. We are also grateful to DST New Delhi for support
under “DST-FIST” program.
Funding
This work was supported by the Department of Science and Technology, New Delhi [Grant Number
SB/FT/CS-004/2012, dated 24/05/2013]
References
[1] (a) Klutchko, S. R.; Zhou, H.; Winters, R. T.; Tran, T. P.; Bridges, A. J.; Althaus, I. W.; Amato,
D. M.; Elliott, W. L.; Ellis, P. A.; Meade, M. A.; Roberts, B. J.; Fry, D. W.; Gonazales, A. J.;
Harvey, P. J.; Nelson, J. M.; Sherwood, V.; Han, H. K.; Pace, G.; Smaill, J. B.; Denny, W. A.;
Showalter, H. D. H. J. Med. Chem. 2006, 49, 1475; (b) Snider, B. B.; Shi, Z. J. Org. Chem.
1993, 58, 3828; (c) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc.
1995, 117, 2657; (d) Amr, A. E.; Ashraf, M. M.; Salwa, F. M.; Nagla, A. A.; Hammam, A. G.
Bioorg. Med. Chem. 2006, 14, 5481 (e) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
[2] (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E. D.; Floyd, M.; Moreland, S.; Hodberg, A.; O’Reilly,
B. C. J. Med. Chem. 1991, 34, 806; (b) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.;
Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med.
Chem. 1990, 33, 2629 (c) Kidwai, M.; Bhatnagar, D.; Kumar, R.; Luthra, P. M. Chem. Pharm.
Bull. 2010, 58, 1320.
[3] (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (b) Al-Omary, F. A. M.; Hassan, G. S. S.;
Messery, M. E.; E. Subbagh, H. I. Eur. J. Med. Chem. 2012, 47, 65; (c) Shen, Z. L.; Xu, X. P.;
Ji, S. J. J. Org. Chem. 2010, 75, 1162.
[4] (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Abelman, M. M.; Smith, S. C.; James, D. R.
Tetrahedron Lett. 2003, 44, 4559; (c) Lin, H.; Zhao, Q.; Xu, B.; Wang, X. J. Mol. Catal. A Chem.
2007, 268, 221; (d) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.; Klimesova, V.;
Kaustova, J. Farmaco 2001, 56, 803; (e) Baruah, B.; Dasu, K.; Vaitilingam, B.; Mamnoor, P.;

SYNTHETIC COMMUNICATIONS®
11
Venkata, P.; Rajagopal, S.; Yeleswarapu, K. R. Bioorg. Med. Chem. 2004, 12, 1991; (f) Gali, R.;
Banothu, J.; Porika, M.; Velpula, R.; Hnamte, S.; Bavantula, R.; Abbagani, S.; Busi, S. Bioorg.
Med. Chem. Lett. 2014, 24, 4239; (g) Sosnicki, G. J.; Maciejewska, G.; Struk, L.; Kurzawski,
M.; Drozdzik, M.; Peruzynska, M. Org. Biomol. Chem. 2014, 12, 3427.
[5] (a) Bussolari, J. C.; McDonnell, P. A. J. Org. Chem. 2000, 65, 6777; (b) Atwal, K. S.; O’Reilly,
B. C.; Gougoutas, J. Z.; Malley, M. F. Heterocycles 1987, 26, 1189.
[6] (a) Tu, S.; Fang, F.; Zhu, S.; Li, T.; Zhang, X.; Zhang, Q. Synlett 2004, 3, 537; (b) Gohain, M.;
Prajapati, D.; Sandhu, J. S. Synlett 2004, 2, 235; (c) Sabita, G.; Reddy, G. S. K. K.; Reddy, K. B.;
Yadav, J. S. Tetrahedron Lett. 2003, 44, 6497; (d) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H.
Tetrahedron 2000, 41, 907; (e) Reddy, V.; Mahesh, C.; Raju, M.; Ramesh Babu, T.; Reddy, N.
V. V. Tetrahedron Lett. 2002, 43, 2657.
[7] (a) Ma, Y.; Qian, C. T.; Wang, L. M.; Yang, M. J. Org. Chem. 2000, 65, 386; (b) Adapa, S. R.;
Alam, M. M.; Varala, R. Synlett 2003, 1, 67–70.
[8] (a) Kaur, N. Synth Commun. 2015, 45, 1145; (b) Kaur, N. Synth. Commun. 2015, 45, 300;
(c) Kaur, N. Synth. Commun. 2015, 45, 149; (d) Mirza-Aghayan, M.; Bolourtchian, M.;
Hosseini, M. Synth. Commun. 2004, 34, 3335 (e) Legeay, J. C.; Eynde, J. J. V.; Bazureau, J.
P. Tetrahedron 2005, 61, 12386; (f) Kaur, B.; Kaur, R. Arkivoc 2007, xv, 315; (g) Ivanova, A.
L.; Chesnokov, D. V.; Mazhukina, O. A.; Fedotova O. V. Izv. Saratov Univ. (N. S.), Ser. Chem.
Biol. Ecol. 2017, 17, 5.
[9] (a) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917; (b) Gupta, R.; Chaudhary, R. P. J. Chem.
Res. 2012, 36, 718.
[10] Dutta, M.; Gogoi, J.; Shekarrao, K.; Goswami, J.; Gogoi, S.; Boruah, R. C. Synthesis 2012, 44,
2614.
[11] (a) Velpula, R.; Banothu, J.; Gali, R.; Deshineni, R.; Bavantula, R. Chin. Chem. Lett. 2015, 26,
309; (b) Liu, C.; Wang, J.; Li, Y. J. Mol. Catal. A Chem. 2006, 258, 367; (c) Surya, K.; Gibbs, A.
Synthesis 2005, 11, 1748; (d) Liang, B.; Wang, X.; Wang, J. X.; Du, Z. Tetrahedron 2007, 63,
1981; (e) Bose, S.; Sudharshan, D. M.; Chavhan, S. W. Arkivoc 2005, iii, 228; (f) Shabaani,
A.; Bazgir, A.; Teimouri, F. Tetrahedron 2003, 44, 857; (g) Kiyani, H.; Ghiasi, M. Chin. Chem.
Lett. 2014, 25, 313; (h) Kiyani, H.; Ghiasi, M. Res. Chem. Intermed. 2015, 41, 5177; (i) Velpula,
R.; Banothu, J.; Gali, R.; Sargam, Y.; Bavantula, R. Turk. J. Chem. 2015, 39, 620.
[12] Singh, K.; Arora, D.; Singh, S. Tetrahedron Lett. 2006, 47, 4205.
[13] (a) Palaniappan, S.; John, A. J. Mol. Catal. A Chem. 2005, 233, 9; (b) Wahab, B. F. A.; Farahat,
A. A.; Bekheit, M. S. Phosphorus Sulfur Silicon Relat. Elem. 2017, 192, 1.
[14] (a) Gautam, D.; Chaudhary, R. P. Spectrochim. Acta Part A 2015, 135, 219; (b) Gupta, R.;
Chaudhary, R. P. J. Mol. Struct. 2013, 1049, 189.
[15] Pal, R.; Tapas, K. M.; Ashok, K. M. J. Indian Chem. Soc. 2009, 86, 402.
[16] (a) Kappe, C. O. J. Org. Chem. 1997, 62, 7201; (b) De Souza, R. O. M. A.; da Penha, E. T.;
Milagre, H. M. S.; Garden, S. J.; Esteves, P. M.; Eberlin, M. N.; Antunes, O. A. C. Chem.
Eur. J. 2009, 15, 9799.
[17] (a) Feng, F.; Ding, X.; Chen, T.; Chen, L.; Liu, F.; Jia, X.; Luo, X.; Shen, X.; Chen, K.; Jiang, H.;
Wang, H.; Liu, H.; Liu, D. J. Med. Chem. 2010, 53, 3465.
[18] Gul, M. Z.; Ahmad, F.; Kondapi, A. K.; Qureshi, I. A.; Ghazi, I. A. BMC Complementary Altern.
Med. 2013, 13, 1.