Alkaline-Earth-Catalyzed sp3 C-H Functionalization of Methyl Azaarenes and Its Use in a One-Pot Four-Component Synthesis of Azaarenyl Benzylpyrazolones

Article abstract of DOI:10.1055/s-0035-1560385

The sp³ C-H functionalization of methyl azaarenes by using calcium triflate as the catalyst is described, together with its use in the first synthesis of azaarenyl benzylpyrazolones by a one-pot four-component reaction.

Full text of DOI:10.1055/s-0035-1560385

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–G
letter
A
S. Yaragorla et al.
Letter
Synlett
Alkaline-Earth-Catalyzed sp3 C–H Functionalization of Methyl
Azaarenes and Its Use in a One-Pot Four-Component Synthesis of
Azaarenyl Benzylpyrazolones
Srinivasarao Yaragorla*
Ravikrishna Dada
Garima Singh
H
O
O
N
R2
N
R2
OEt
N
H2O, reflux
R1
O
Ca2+
R1CHO
H
N
5 h, 67–83%
Department of Chemistry, Central University of Rajasthan,
Bandarsindri, NH-8, Ajmer District, Rajasthan, 305817, India
srinivasarao@curaj.ac.in
H
H
NHNH2
first synthesis
broad substrate scope
one-pot, four-component reaction
green solvent
R1 = aryl, alkyl
2 = H, NO2
ysriict@gmail.com
R
23 compounds
Received: 03.10.2015
Accepted: 23.10.2015
Published online: 23.12.2015
DOI: 10.1055/s-0035-1560385; Art ID: st-2015-d0790-l
Me
Me
Me
N
N
N
N
N
N
N
N
O
O
O
O
Abstract The sp3 C–H functionalization of methyl azaarenes by using
calcium triflate as the catalyst is described, together with its use in the
first synthesis of azaarenyl benzylpyrazolones by a one-pot four-com-
ponent reaction.
NH2
phenazone
propyphenazone
ampyrone
edarvone
Figure 1 Representative examples of biologically active pyrazolones
Key words nitrogen heterocycles, azaarenes, sp3 C–H functionaliza-
tion, multicomponent reactions, pyrazolones
sition-metal- and lanthanide-based catalysts, because of its
greater abundance, non-toxicity, and stability towards
moisture and air.13,14 Our group has demonstrated that cal-
cium triflate is an efficient catalyst for the Ritter reaction,14c
and in the syntheses of pyranocoumarins,14b benzopy-
rans,14b benzylpyrazolyl coumarins,14a styryl azaarenes, and
2-aryl 1,3-bisazaarenes.14
Owing to the biological significance of both azaarene
and pyrazolone derivatives, we considered that it might be
useful to develop a method for the synthesis of a new class
of azaarene–pyrazolone derivatives by using a one-pot
multicomponent approach. In continuation of our research
aimed towards the synthesis of biologically important mol-
ecules,14 we report a straightforward method for the syn-
thesis of methyl azaarene derivatives through benzylic C–H
functionalization in a one-pot four-component approach
with water as the solvent.
We first studied the reaction of quinaldine (1a; 2-meth-
ylquinoline), benzaldehyde, ethyl acetoacetate, and phenyl-
hydrazine in the presence of 5 mol% calcium triflate and 5
mol% tetrabutylammonium hexafluorophosphate in reflux-
ing water at 100 °C (Table 1). After five hours, the reaction
was found to be complete and the desired product 5a was
isolated in 74% yield after column chromatography (Table 1,
entry 3) together with 10% of the benzylbispyrazolone 6.
Product 5a was characterized by means of 1H and 13C NMR
The sp3 C–H functionalization of methyl azaarenes is an
important method for constructing biologically important
N-heterocyclic compounds.1 Methyl azaarene derivatives
are known to possess important biological activities;2 for
example, FZ41 and KHD161 act as promising HIV integrase
inhibitors through a previously unknown mechanism,3 and
montelukast sodium is used as a potent antiasthma drug.4
Chimanine B,5 VUF 5017,6 L-660,711,7 and LY1901548 are
other biologically important azaarene derivatives. Methyl
azaarenes are also key building blocks for the synthesis of
2-alkyl heterocyclic compounds.9.
Pyrazolone derivatives have proved to be potent struc-
tural motifs in drug candidates. For example phenazone,
propyphenazone, and ampyrone (Figure 1) are well-known
antipyretic and antianalgesic drugs. Pyrazolone derivatives
are also known to show antifungal, antimycobacterial, anti-
bacterial, antiinflammatory, antitumor, antidepressant, and
antitubercular activities.10
One-pot multicomponent reactions have a key role in
the synthesis of heterocycles, generating molecular com-
plexity in a single reaction vessel with concomitant atom
and step economies.11 The use of water as the reaction me-
dium is always advantageous where possible.12 Recently,
calcium triflate has been explored as an alternative to tran-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

B
S. Yaragorla et al.
Letter
Synlett
spectroscopy and mass spectrometry. Encouraged by this
result, we attempted to optimize the reaction conditions by
examining the roles of the catalyst, additive, and water.
When the reaction was performed without the catalyst and
solvent at 100 °C, no change was observed by TLC (entry 1),
but when the reactants were heated to reflux in water un-
der catalyst-free conditions, 35% of the desired product was
formed, along with 25% of benzylbispyrazolone 6 (entry 2).
Increasing the temperature to 120 °C (entry 4) did not im-
prove the yield. We therefore increased the catalyst loading
from 5 mol% to 10 mol%, and we observed an increase in
yield to 80% (entry 5). When the amount of additive was
also increased to 10 mol%, the same yield was obtained (en-
try 6). This suggested that the additive has little influence
on the reaction; to confirm this, we heated the reactants to
reflux in water in the presence of 10 mol% of calcium tri-
flate, and we still obtained an 80% yield of the desired prod-
uct 5a, along with 9% of bispyrazolone 6 (entry 7). There-
fore, these conditions were identified as optimal for the sp3
C–H functionalization and for the one-pot four-component
synthesis of methyl azaarene derivatives.
Having established the optimal conditions, we then in-
vestigated the substrate scope of the method (Table 2). Qui-
naldine (1a) reacted with 4-nitrobenzaldehyde and phenyl-
hydrazine to give the azaarene derivative 5b in 83% yield,
along with 6% of the corresponding dimeric pyrazolone (Ta-
ble 2, entry 2). Similarly, quinaldine (1a) reacted with 4-
chloro-, 4-bromo-, or 4-fluorobenzaldehyde to give the cor-
responding azaarenyl pyrazolyl derivatives 5c, 5d, and 5e in
83, 78 and 75% yield, respectively (entries 3–5). In the case
of aldehydes with electron-releasing groups, 4-methoxy-
benzaldehyde and 4-methylbenzaldehyde gave the corre-
sponding products 5f and 5g in 80 and 75% yields, respec-
tively, whereas 3-hydroxybenzaldehyde gave 5h in 81%
yield. The hetaryl aldehydes pyridine-3-carbaldehyde and
furfural also reacted at similar rates (5.5 hours) to give the
corresponding products 5i and 5j in 80 and 69% yield, re-
spectively. Having explored the scope of the substituted ar-
omatic aldehydes in the method, we then examined the re-
actions of 7-chloroquinaldine (1b; 7-chloro-2-methylquin-
oline). When benzaldehyde was used with 1b under the
optimized reaction conditions, 5l was obtained in 79% yield
along with 8% of the corresponding bispyrazolone. We
therefore examined the reactions of this substrate with a
range of aromatic aldehydes to give products 5m–r in good
yields (entries 13–18). Hetaryl aldehydes also reacted with
1b to give products 5s and 5t in 75 and 67% yield, respec-
tively (entries 19 and 20). To examine the scope with re-
spect to the phenylhydrazine derivative, we treated 4-nitro-
phenylhydrazine with 1b and benzaldehyde under the
same reaction conditions and obtained 75% of product 5u.
Finally, we examined the participation of aliphatic alde-
hydes (Scheme 1). When quinaldine (1a) was treated with
2-methylpropanal, phenylhydrazine, and ethyl acetoacetate
under the same catalytic conditions, product 5v was ob-
tained in 58% yield after six hours. Similarly, 7-chloroqui-
naldine (1b) with 2-methylpropanal gave product 5w in
62% yield. Further exploration of the reactions of various al-
iphatic aldehydes and compounds with active methylene
groups is ongoing.
Table 1 Optimization Studies for the Four-Component Synthesis of Azaarenyl Pyrazolone Derivative 5aa
NH
PhCHO
N
Ph
+
+
PhNHNH2
+
N
conditions
+
HN
Ph
NH
Ph
N
O
MeCOCH2COOEt
N
N
O
O
6
5a
Entry
Ca(OTf)2 (mol%)
Bu4NPF6 (mol%)
Solvent
Temp (°C)
Time (h)
Yieldb (%) of 5a (6)
1
2
3
4
5
6
7
8
0
0
0
0
–
100
100
100
120
100
100
100
100
20
15
5
nr
H2O
H2O
H2O
H2O
H2O
H2O
H2O
35 (25)
74 (10)
74 (12)
80 (10)
80 (10)
80 (9)
35 (28)
5
5
5
5
5
10
10
10
0
5
5
10
0
5
5
5
15
a All reactants were used stoichiometric amounts.
b Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

C
S. Yaragorla et al.
Letter
Synlett
Table 2 One-Pot Four-Component Synthesis of Pyrazolone Derivatives 5 by Calcium-Catalyzed sp3 C–H Functionalization of Methyl Azaarenesa
NHNH2
O
NH
N
Ar
OEt
N
R
+
Ca(OTf)2 (10 mol%)
H2O, 100 °C, 5 h
H
H
+
+
N
CHO
O
O
Ar
H
R
1
2
3
4
5
Entry
1
Azaarene
Ar
R
Product 5
Yieldb (%)
Mp (°C)
67–68
NH
N
N
Ph
H
H
80
O
N
1a
1a
5a
NH
N
N
O
2
3
4-O2NC6H4
83
83
104–105
5b
NO2
NH
N
N
O
1a
1a
4-ClC6H4
H
H
79–80
Cl
5c
NH
N
N
O
4
5
6
4-BrC6H4
78
75
80
86–88
74–75
67–68
5d
Br
NH
N
N
1a
1a
4-FC6H4
H
H
O
5e
F
NH
N
N
O
4-MeOC6H4
5f
OMe
NH
N
N
O
7
1a
4-MeC6H4
H
75
86–87
5g
Me
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

D
S. Yaragorla et al.
Letter
Synlett
Table 2 (continued)
Entry
Azaarene
Ar
R
Product 5
Yieldb (%)
Mp (°C)
NH
N
N
8
1a
3-HOC6H4
H
81
183–184
O
5h
N
OH
NH
N
9
1a
1a
3-pyridyl
2-furyl
H
H
80
69
60–61
73–75
O
N
5i
NH
N
N
10
O
O
5j
NH
N
N
NO2
11
12
1a
Ph
Ph
NO2
79
79
104–105
133–134
O
5k
NH
N
Cl
N
H
O
Cl
N
1b
5l
NH
N
Cl
N
O
13
1b
4-O2NC6H4
H
78
105–106
5m
NO2
NH
N
Cl
N
O
14
1b
4-ClC6H4
H
77
82–83
5n
Cl
NH
N
Cl
N
O
15
16
1b
1b
4-BrC6H4
H
H
74
78
90–91
82–83
5o
Br
NH
N
Cl
N
O
4-FC6H4
5p
F
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

E
S. Yaragorla et al.
Letter
Synlett
Table 2 (continued)
Entry
17
Azaarene
Ar
R
Product 5
Yieldb (%)
Mp (°C)
77–78
NH
N
Cl
N
O
1b
4-MeOC6H4
H
74
5q
OMe
NH
N
Cl
N
18
19
1b
1b
4-MeC6H4
H
H
73
75
106–107
O
5r
OH
NH
N
Cl
N
3-HOC6H4
62–64
O
5s
N
NH
N
Cl
Cl
N
20
21
1b
1b
3-pyridyl
H
67
75
74–75
O
O
5t
NH
N
N
NO2
Ph
NO2
176–177
O
5u
a All substrates were present in stoichiometric amounts except for ethyl acetoacetate (1.2 equiv); the mixture was refluxed in H2O for 5 h with 10 mol% of
catalyst.15
b Isolated yields after column chromatography.
A plausible mechanism for this one-pot four-compo-
nent process is outlined in Scheme 2. Initially a pyrazolone
is formed by condensation of the aryl hydrazine and ethyl
acetoacetate; this undergoes Knoevenagel condensation
with the aldehyde to give adduct IA. Adduct IA undergoes
1,4-conjugate addition with the calcium triflate activated
methyl azaarene to give IB, which tautomerizes to the final
product 5a. Alternatively, adduct IA can undergo condensa-
tion with another molecule of the pyrazolone to give the
bispyrazolone adduct 6 as byproduct.
In summary, an alkaline-earth-catalyzed benzylic C–H
functionalization of azaarenes in a multicomponent syn-
thesis of pyrazolone derivatives has been described for the
first time. The use of water as the solvent and calcium tri-
flate as the catalyst, the simple procedure, and the wide
substrate scope are features of this protocol, leading to the
first synthesis of this type of molecule.
NH
N
O
NHNH2
N
Ca(OTf)2 (10 mol%)
+
+
OEt
+
CHO
H2O, 100 °C
6 h
R
N
O
R
O
1a: R = H
1b: R–Cl
5v: R = H, 58%
5w;R = Cl, 62%
Scheme 1 Reaction of 2-methylpropanal with quinaldines 1a and 1b in the calcium-promoted, one-pot, four-component synthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

F
S. Yaragorla et al.
Letter
Synlett
Ph
O
N
O
N
Ph
H
OEt
H2O
N
H2N
Ar
HO
pyrazole formation
O
Knoevenagel
condensation
H2O
OH
OH
Ph
Ph
conjugate addition/
dimerization
N
N
Ph
Ph
OTf
N
N
Ca
N
O
N
OH
N
Ca(OTf)2
+Ca
Ph
N
R
IC
N
N
sp3 C–H
IA
functionalization
Ca(II)-promoted
1,4-conjugate addition
Ph
O
O
Ph
OH
Ph
Ph
N
N
N
Ph
HN
NH
N
N
IB
6
Ph
O
N
Ph
N
NH
5a
Scheme 2 Plausible mechanism for the calcium(II)-catalyzed sp3 C–H functionalization and four-component synthesis
Acknowledgment
3056. (s) Blocker, M.; Immaneni, S.; Shaikh, A. Tetrahedron Lett.
2014, 55, 5572. (t) Kumar, N. S.; Rao, L. C.; JagadeeshBabu, N.;
Kumar, V. D.; Murthy, U. S. N.; Meshram, H. M. Synlett 2015, 26,
1808. (u) Jamal, Z.; Teo, Y.-C. RSC Adv. 2015, 5, 26949. (v) Hao,
S.-H.; Zhang, X.-Y.; Dong, D.-Q.; Wang, Z.-L. Chin. Chem. Lett.
2015, 26, 599. (w) Kumar, A.; Shukla, R. D. Green Chem. 2015,
17, 848. (x) Obora, Y.; Ogawa, S.; Yamamoto, N. J. Org. Chem.
2012, 77, 9429. (y) Xu, L.; Shao, Z.; Wang, L.; Zhao, H.; Xiao, J.
Tetrahedron Lett. 2012, 55, 6856. (z) Jamal, Z.; Teo, Y.-C. Synlett
2014, 25, 2049. (aa) Li, V. M.; Gavrishova, T. N.; Budyka, M. F.
Russ. J. Org. Chem. 2012, 48, 823.
S.Y. acknowledges financial support from DST-India. R.D. and G.S.
thank the CSIR and the Central University of Rajasthan, respectively,
for their fellowships.
References
(1) For syntheses of methyl azaarenyl derivatives, see: (a) Komai,
H.; Yoshino, T.; Matsunaga, S.; Kanai, M. Org. Lett. 2011, 13,
1706. (b) Rueping, M.; Tolstoluzhsky, N. Org. Lett. 2011, 13,
1095. (c) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2010, 132, 3650. (d) Qian, B.; Xie, P.;
Xie, Y.; Huang, H. Org. Lett. 2011, 13, 2580. (e) Yan, Y.; Xu, K.;
Fang, Y.; Wang, Z. J. Org. Chem. 2011, 76, 6849. (f) Niu, R.; Yang,
S.; Xiao, J.; Liang, T.; Li, X. Cuihua Xuebao 2012, 33, 1636. (g) Niu,
R.; Xiao, J.; Liang, T.; Li, X. Org. Lett. 2012, 14, 676. (h) Lou, S.-J.;
Xu, D.-Q.; Shen, D.-F.; Wang, Y.-F.; Liu, Y.-K.; Xu, Z.-Y. Chem.
Commun. 2012, 48, 11993. (i) Jin, J.-J.; Niu, H.-Y.; Qu, G.-R.; Guo,
H.-M.; Fossey, J. S. RSC Adv. 2012, 2, 5968. (j) Meshram, H. M.;
Rao, N. N.; Rao, L. C.; Kumar, S. N. Tetrahedron Lett. 2012, 53,
3963. (k) Mulla, S. A. R.; Pathan, M. Y.; Chavan, S. S. RSC Adv.
2013, 3, 20281. (l) Graves, V. B.; Shaikh, A. Tetrahedron Lett.
2013, 54, 695. (m) Jin, J.; Wang, D.-C.; Niu, H.-Y.; Wu, S.; Qu, G.-
R.; Zhang, Z.; Guo, H. Tetrahedron 2013, 69, 6579. (n) Rao, N. N.;
Meshram, H. M. Tetrahedron Lett. 2013, 54, 5087. (o) Pi, D.;
Jiang, K.; Zhou, H.; Sui, Y.; Uozumi, Y.; Zou, K. RSC Adv. 2014, 4,
57875. (p) Shao, Z.; Wang, L.; Xu, L.; Zhao, H.; Xiao, J. RSC Adv.
2014, 4, 53188. (q) Chatterjee, S.; Bhattacharjee, P.; Temburu, J.;
Nandi, D.; Jaisankar, P. Tetrahedron Lett. 2014, 55, 6680.
(r) Jiang, K.; Pi, D.; Zhou, H.; Liu, S.; Zou, K. Tetrahedron 2014, 70,
(2) (a) Mekouar, K.; Mouscadet, J. F.; Desmaële, D.; Subra, F.; Leh,
H.; Savouré, D.; Auclair, C.; Angelo, J. J. Med. Chem. 1998, 41,
2846. (b) Fournet, A.; Mahieux, R.; Fakhfakh, M. A.; Franck, X.;
Hocquemiller, R.; Figadère, B. Bioorg. Med. Chem. Lett. 2003, 13,
891. (c) Fakhfakh, M. A.; Fournet, A.; Prina, E.; Mouscadet, J.-F.;
Franck, X.; Hocquemiller, R.; Figadère, B. Bioorg. Med. Chem.
2003, 11, 5013.
(3) (a) Bayle, M. N.; Bénard, C.; Zouhiri, F.; Mouscadet, J.-F.; Leh, H.;
Thomas, C.-M.; Mbemba, G.; Desmaële, D.; d’Angelo, J. Bioorg.
Med. Chem. Lett. 2005, 15, 4019. (b) Bénard, C.; Zouhiri, F.;
Normand-Bayle, M.; Danet, M.; Desmaële, D.; Leh, H.;
Mouscadet, J.-F.; Mbemba, G.; Thomas, C.-M.; Bonnenfant, S.; Le
Bret, M.; d’Angelo, J. Bioorg. Med. Chem. 2004, 14, 2473.
(4) (a) Harrington, P. J. Pharmaceutical Process Chemistry for Syn-
thesis: Rethinking the Routes to Scale-Up; Wiley: Oxford, 2011,
Chap. 6, 164. (b) Young, R. N. In Case Studies in Modern Drug Dis-
covery and Development; Huang, X.; Aslanian, R. G., Eds.; Wiley:
Hoboken, 2012, Chap. 8, 154.
(5) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

G
S. Yaragorla et al.
Letter
Synlett
(6) Zwaagstra, M. E.; Schoenmakers, S. H. H. F.; Nederkoorn, P. H. J.;
Gelens, E.; Timmerman, H.; Zhang, M.-Q. J. Med. Chem. 1998, 41,
1439.
(12) (a) Simon, M.-O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415.
(b) Jessop, P. G. Green Chem. 2011, 13, 1391.
(13) (a) Forkel, N. V.; Henderson, D. A.; Fuchter, M. J. Green Chem.
2012, 14, 2129. (b) Arrowsmith, M.; Shepherd, W. M. S.; Hill, M.
S.; Kociok-Köhn, G. Chem. Commun. 2014, 50, 12676.
(c) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005,
127, 2042. (d) Begouin, J.; Niggemann, M. Chem. Eur. J. 2013, 19,
8030. (e) Niggemann, M.; Meel, M. J. Angew. Chem. Int. Ed. 2010,
49, 3684.
(14) (a) Yaragorla, S.; Pareek, A.; Dada, R. Tetrahedron Lett. 2015, 56,
4770. (b) Yaragorla, S.; Saini, P. L.; Singh, G. Tetrahedron Lett.
2015, 56, 1649. (c) Yaragorla, S.; Singh, G.; Saini, P.; Reddy, M. K.
Tetrahedron Lett. 2014, 55, 4657. (d) Yaragorla, S.; Sudhakar, A.;
Kiranmai, N. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2014, 53, 1471. (e) Yaragorla, S.; Kumar, G. S. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 2015, 54, 240.
(7) (a) Zamboni, R.; Belley, M.; Champion, E.; Charette, L.; DeHaven,
R.; Frenette, R.; Gauthier, J. Y.; Jones, T. R.; Leger, S.; Masson, P.;
McFarlane, C. S.; Metters, K.; Pong, S. S.; Piechuta, H.; Rokach, J.;
Thérien, M.; Williams, H. W. R.; Young, R. N. J. Med. Chem. 1992,
35, 3832. (b) King, A.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J.; Xiang, Y. B.; Belley, M.; Leblanc, Y.
J. Org. Chem. 1993, 58, 3731. (c) McNamara, J. M.; Leazer, J. L.;
Bhupathy, M.; Amato, J. S.; Reamer, R. A.; Reider, P. J.;
Grabowski, E. J. J. J. Org. Chem. 1989, 54, 3718.
(8) Merschaert, A.; Boquel, P.; Van Hoeck, J.-P.; Gorissen, H.;
Borghese, A.; Bonnier, B.; Mockel, A.; Napora, F. Org. Process Res.
Dev. 2006, 10, 776.
(9) (a) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693.
(b) Carey, J. S.; Laffan, L.; Thompson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337.
(15) 2-Aryl-4-(1-Aryl-2-hetarylethyl)-5-methyl-1,2-dihydro-3H-
pyrazol-3-ones 5a–u; General Procedure
(10) (a) Himly, M.; Jahn-Schmid, B.; Pittertschatscher, K.; Bohle, B.;
Grubmayr, K.; Ferreira, F.; Ebner, H.; Ebner, C. J. Allergy Clin.
Immunol. 2003, 111, 882. (b) Watanabe, T.; Yuki, S.; Egawa, M.;
Nishi, H. J. Pharmacol. Exp. Ther. 1994, 268, 1597. (c) Kawai, H.;
Nakai, H.; Suga, M.; Yuki, S.; Watanabe, T.; Saito, K. I. J. Pharma-
col. Exp. Ther. 1997, 281, 921. (d) Wu, T. W.; Zeng, L. H.; Wu, J.;
Fung, K. P. Life Sci. 2002, 71, 2249. (e) Al-Haiza, M. A.; El-Assiery,
S. A.; Sayed, G. H. Acta Pharm. (Zagreb, Croatia) 2001, 51, 251.
(f) Castagnolo, D.; Manetti, F.; Radi, M.; Bechi, B.; Pagano, M.; De
Logu, A.; Meleddu, R.; Saddi, M.; Botta, M. Bioorg. Med. Chem.
2009, 17, 5716. (g) Radi, M.; Bernardo, V.; Bechi, B.; Castagnolo,
D.; Pagano, M.; Botta, M. Tetrahedron Lett. 2009, 50, 6572.
(h) Moreau, F.; Desroy, N.; Genevard, J. M.; Vongsouthi, V.;
Gerusz, V.; Le Fralliec, G.; Oliveira, C.; Floquet, S.; Denis, A.;
Escaich, S.; Wolf, K.; Busemann, M.; Aschenbsenner, A. Bioorg.
Med. Chem. Lett. 2008, 18, 4022. (i) Badawey, E. A. M.; El-Ash-
mawey, I. M. Eur. J. Med. Chem. 1998, 33, 349. (j) Pasha, F. A.;
Muddassar, M.; Neaz, M. M.; Cho, S. J. J. Mol. Graphics Modell.
2009, 28, 54. (k) Rosiere, C. E.; Grossman, M. I. Science 1951, 113,
651. (l) Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman, E. R.;
Pearl, J.; Defelice, A. F.; Feigenson, M. E. J. Med. Chem. 1985, 28,
256. (m) Chauhan, P. M. S.; Singh, S.; Chatterjee, R. K. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1993, 32, 858.
(n) Gunasekaran, P.; Perumal, S.; Yogeeswari, P.; Sriram, D. Eur.
J. Med. Chem. 2011, 46, 4530.
Ca(OTf)2 (10 mol%) was added to a stirred solution of MeCO-
CO2Et (1.13 mmol), arylhydrazine 3 (0.942 mmol), aryl alde-
hyde 2 (0.934 mmol), and 2-methylazarene 1 (0.942 mmol) in
H2O (3 mL), and the mixture was heated to 100 °C. When the
reaction was complete (TLC; ~5 h), the mixture was extracted
with EtOAc (3 × 5 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated to give a crude solid that
was purified by column chromatography.
5-Methyl-2-phenyl-4-(1-phenyl-2-quinolin-2-ylethyl)-1,2-
dihydro-3H-pyrazol-3-one (5a)
Pink solid; yield: 227.9 mg (80%); mp 67–68 °C. 1H NMR (500
MHz, CDCl3): δ = 7.97 (t, J = 9 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 2 H),
7.69–7.62 (m, 2 H), 7.63 (t, J = 7 Hz, 1 H), 7.44 (t, J = 7 Hz, 2 H),
7.17–7.02 (m, 7 H), 4.32 (d, J = 9 Hz, 1 H), 3.77 (dd, J = 2, 13.5 Hz,
1 H), 3.76 (t, J = 13.5 Hz, 1 H), 1.72 (s, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 160.3, 148.5, 144.8, 144.3, 139.6, 138.3, 132.7, 130.6,
129.1 (2C), 128.6 (2C), 128.4, 127.8, 127.7 (2C), 126.8, 126.4,
126.2, 125.1, 122.9, 121.8 (2C), 100.8, 42.7, 42.1, 13.4.
4-[2-(7-Chloroquinolin-2-yl)-1-(4-nitrophenyl)ethyl]-5-
methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (5m)
Brown solid; yield: 222.7 mg (78%); mp 105–106 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.01–7.95 (m, 4 H), 7.8 (d, J = 7.5 Hz, 2 H),
7.66 (d, J = 8.5 Hz, 1 H), 7.45–7.38 (m, 3 H), 7.26 (d, J = 7.5 Hz, 2
H), 7.21–7.18 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 4.48 (d, J = 9.5
Hz, 1 H), 3.77 (t, J = 13.5 Hz, 1 H), 3.66 (dd, J = 2.5, 14.0 Hz, 1 H),
1.74 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 160.3, 151.5, 150.7,
147.9, 146.5, 145.3, 139.2, 138.5, 137.2, 129.0, 128.8, 128.6,
128.4, 125.6, 125.5, 125.2, 123.7, 122.9, 122.0, 99.4, 42.0, 41.4,
13.3.
(11) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(b) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev.
2014, 114, 8323.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G