Efficient domino strategy for the synthesis of polyfunctionalized benzofuran-4(5 H)-ones and cinnoline-4-carboxamides

Article abstract of DOI:10.1021/co5000097

An efficient, three-component strategy for the improved synthesis of multifunctionalized 6,7-dihydrobenzofuran-4(5H)-ones under microwave irradiation in ethyl alcohol within short periods has been established. The synthesized benzofuran-4(5H)-ones have been readily converted into polyfunctionalized cinnoline-4-carboxamides by treating with hydrazine hydratein in the same solvent through a regioselective ring-opening of the furan. Tedious workup procedures can be avoided because of the direct precipitation of products from the reaction solution by water addition, thus rendering the two-steps process ecofriendly.

Full text of DOI:10.1021/co5000097

Research Article
pubs.acs.org/acscombsci
Efficient Domino Strategy for the Synthesis of Polyfunctionalized
Benzofuran-4(5H)‑ones and Cinnoline-4-carboxamides
Guan-Hua Ma, Xing-Jun Tu, Yi Ning, Bo Jiang,* and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R. China
S
* Supporting Information
ABSTRACT: An efficient, three-component strategy for the improved
synthesis of multifunctionalized 6,7-dihydrobenzofuran-4(5H)-ones under
microwave irradiation in ethyl alcohol within short periods has been
established. The synthesized benzofuran-4(5H)-ones have been readily
converted into polyfunctionalized cinnoline-4-carboxamides by treating
with hydrazine hydratein in the same solvent through a regioselective ring-
opening of the furan. Tedious workup procedures can be avoided because
of the direct precipitation of products from the reaction solution by water
addition, thus rendering the two-steps process ecofriendly.
KEYWORDS: domino reaction, benzofuran-4(5H)-ones, cinnoline-4-carboxamides, microwave irradiation, isocyanides
reactions leading to useful functionalized heterocycles of
chemical and pharmaceutical interest.14 In a continuation of
our efforts, herein, we would like to report a new and efficient
domino strategy for rapid, regioselective synthesis of highly
functionalized cinnoline derivatives. The reaction can be
conducted by using readily available and inexpensive substrates,
such as cyclic-1,3-diones (Figure 1), isocyanides (Figure 2), and
INTRODUCTION
■
The structural range and biological importance of functional
cinnolines and their derivatives have made them striking targets
in research over many years.1 A variety of synthetic cinnoline
derivatives have shown a wide range of biological activities
including antibacterial, antitumor, anti-inflammatory, antifungal,
anticancer, and phosphodiesterase inhibitors in the pharma-
ceutical industry.2 Cinnolines were also widely used as
agrochemicals and pharmaceuticals,3 including as micro-
biocides, pollen suppressants, fungicides and herbicides.4 In
addition, some of these compounds show interesting physical
characteristics, such as electrochemical, luminescent, and
nonlinear optical properties.5 Therefore, the synthesis of
functional cinnolines occupied a key place in the area of
synthetic organic chemistry because of their important chemical
and physical properties. Many methodologies for synthesizing
these compounds have been developed;6 most of them
involved arenediazonium salts,7 arylhydrazones,8 arylhydra-
zines,9 and nitriles,10 as well as aryl phenylallylidene hydrazone
as the starting materials.11 However, these synthetic procedures
suffered from limitations involving poor yields, multiple steps,
or metal catalysts. These undesirable conditions encouraged us
to develop a new methodology for their syntheses.
Figure 1. Diversity of cyclic-1,3-diones 1.
arylglyoxals (Figure 3) under microwave irradiation for short
short periods, providing a series of benzofuran-4(5H)-ones
with good to excellent yields. The resulting benzofuran-4(5H)-
ones have been readily converted into cinnoline derivatives by
treating with hydrazine hydrate (80% in aqueous solution)
Domino reactions for total synthesis of natural products or
natural-like structures have become a challenging topic in
modern organic chemistry.12 These reactions have attracted
special attention because of their simplicity, efficiency,
selectivity, convergence, and atom-economy.13 They have
been powerful tools for the synthesis of numerous complex
molecules. Therefore, the development of a selective domino
strategy for the efficient synthesis of cinnoline derivatives is
highly desired. Recently, we have accomplished various domino
Figure 2. Diversity of isocyanides 2.
Received: January 16, 2014
Revised: February 25, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Table 1. Three-Component Domino Synthesis of
Compounds 4
a
b
entry
product 4
yield (%)
Figure 3. Diversity of arylglyoxals 3.
1
4{1,1,1}
4{1,1,3}
4{2,1,4}
4{2,1,5}
4{1,2,3}
4{1,2,4}
4{1,2,7}
4{2,2,3}
4{2,2,4}
4{2,2,6}
4{1,3,3}
4{1,3,4}
4{1,3,6}
4{2,3,3}
4{2,3,7}
4{1,4,1}
4{1,4,2}
4{1,4,5}
4{2,4,3}
4{2,4,7}
72
89
71
72
89
73
77
73
82
77
80
75
72
77
80
85
92
90
71
78
2
3
under microwave irradiation through a regioselective ring-
opening of the furan (Scheme 1). A tedious workup procedure
is avoided because of the direct precipitation of products from
the reaction solution.
4
5
6
7
It is well-known that the benzofuran subunit plays a
prominent role in organic and medicinal chemistry, and they
exist in a wide variety of naturally occurring compounds and
rationally designed pharmaceutical agents.15 Benzofurans are
integral to a large number of drug substances with activities
including anticoagulant, insecticide, anthelminthic, hypnotic,
antifungal, and HIV protease inhibition properties.16 Some
benzofurans serve as versatile synthetic intermediates that can
synthesize various useful compounds.17 Therefore, their
syntheses have been attractive considerable attention. Recently,
Anary-Abbasinejad and co-workers reported the synthesis of
benzofuran-4(5H)-ones via a three-component reaction of 5,5-
dimethyl-1,3-cyclohexandione with arylglyoxals and alkyl
isocyanides.18 However, this method suffered from long
reaction times (5 h), and the preparation of products only
reserved in milligram level. These facts limited the application
of benzofuran-4(5H)-ones. Since benzofuran-4(5H)-ones can
serve as an important intermediate to prepare cinnoline
derivatives, we attempted to improve the synthesis of
benzofuran-4(5H)-ones.
8
9
10
11
12
13
14
15
16
17
18
19
20
a
Reactions were performed on a 10-mmol scale, and 1, 2, and 3 was in
1:1:1 ratio. Isolated yields.
b
good yields. In the initial experiment, the reaction between
benzofuranes 4{1,1,3} and hydrazine hydrate 5 was run with a
1:1 mol ratio at 60 °C under microwave heating using EtOH as
a solvent. The expected hexahydrocinnoline-4-carboxamides
6{1,1,3,(5)} was isolated in 46% yield. The yield of product
6{1,1,3,(5)} was increased from 46 to 83% as the mol ratio of 4
and 5 varied from 1:1 to 1:3. Further increase of mol ratio failed
to improve the yield of product 6{1,1,3,(5)}. The solvent effect
was then investigated. The reaction scarcely proceeded in
toluene or DCM even at an enhanced temperature of boiling
point under MW irradiation (entries 5−6). The polar solvent,
DMF, resulted in low yield of product 6{1,1,3,(5)} (entry 7).
Other two polar solvents, acetonitrile and methanol gave
slightly lower yields than that in EtOH. A lower yield of
product was obtained when the reaction was performed in
EtOH at lower (40 °C) or higher (80 °C) reaction temperature
(entries 10−11). Next, the three-component reaction of 1{1}
with 2{1} and 3{3} was carried out for 25 min under
microwave heating. Without isolation, hydrazine hydrate 5 was
then added into this mixture system. The two-step, one-pot
reaction led to much lower chemical yield of 6{1,1,3,(5)}
RESULTS AND DISCUSSION
■
The similar three-component reaction was performed in EtOH
under microwave heating for 25 min. Good yields (71%-92%)
of benzofuran-4(5H)-ones were obtained on a multigram scale.
Various isocyanides 2 and arylglyoxals 3 were explored to
establish the applicability of this protocol. The results are listed
in Table 1. A variety of arylglyoxal monohydrates 3 bearing
either electron-withdrawing or electron-donating groups can
react with above cyclic-1,3-diones 1 and isocyanides 2 to give
corresponding benzofuran-4(5H)-one products 4{1,1,1}-
4{2,4,7}. Cyclohexyl-, t-butyl-, n-butyl-, and benzyl-substituted
isocyanides all worked efficiently in this reaction.
After we accomplished the above three-component reaction,
we then subjected the resulting benzofuran-4(5H)-ones 4 to
the reaction with hydrazine hydrate 5 (80% in aqueous
solution) under similar conditions. The expected hexahydro-
cinnoline-4-carboxamides 6 were regioselectively afforded in
Scheme 1. Two-Step Domino Synthesis of Cinnoline Derivatives
B
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
(entry 12). Four-component one-pot reaction of 1{1}, 2{1},
3{3}, and 5 did not give the expected product 6{1,1,3,(5)}
under similar conditions (entry 13).
Table 3. Domino Synthesis of Cinnoline-4-carbonxamides 6
Table 2. Optimization for the Synthesis of 6{1,1,3,(5)}
a
entry
product
yield (%)
1
6{1,1,1,(5)}
6{1,1,3,(5)}
6{2,1,4,(5)}
6{2,1,5,(5)}
6{1,2,3,(5)}
6{1,2,4,(5)}
6{1,2,7,(5)}
6{2,2,3,(5)}
6{2,2,4,(5)}
6{2,2,6,(5)}
6{1,3,3,(5)}
6{1,3,4,(5)}
6{1,3,6,(5)}
6{2,3,3,(5)}
6{2,3,7,(5)}
6{1,4,1,(5)}
6{1,4,2,(5)}
6{1,4,5,(5)}
6{2,4,3,(5)}
6{2,4,7,(5)}
75
83
73
80
81
79
73
82
70
74
72
79
74
81
73
80
71
73
78
83
2
3
4
a
b
entry
solvent
temp (°C) mol ratio
time (min) yield (%)
5
1
EtOH
EtOH
EtOH
EtOH
toluene
CH2Cl2
DMF
60
60
60
60
60
60
60
60
60
40
80
60
60
1:1
1:2
1:3
1:4
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
30
30
30
30
50
50
50
30
30
30
30
30
30
46
69
6
2
7
3
83
8
4
72
9
5
trace
trace
21
10
11
12
13
14
15
16
17
18
19
20
6
7
8
MeOH
CH3CN
EtOH
EtOH
EtOH
EtOH
65
9
67
10
11
12
13
55
81
c
28
d
ND
a
b
Reactions were performed on a 1.0-mmol scale. Isolated yields.
c
Two-step one-pot reaction of 1{1}, 2{1}, 3{3}, and hydrazine
d
a
hydrate. Four-component one-pot reaction of 1{1}, 2{1}, 3{3}, and
Isolated yields.
hydrazine hydrate.
HRMS spectra. Furthermore, the structure of compound
6{1,2,7,(5)}was unequivocally confirmed by X-ray analysis
(Figure 4).
With the optimal conditions in hand, we next examined the
reaction scope by using benzofuran-4(5H)-ones 4 generated
from above three-component transformation. A range of
hydrocinnoline derivatives were prepared from 6,7-dihydro-
benzofuran-4(5H)-one 4 and hydrazine hydrate 5. As shown in
Table 3, the substituents on 6,7-dihydrobenzofuran-4(5H)-one
ring did not hamper the domino reaction process. Reactions of
dihydrobenzofurans 4, derived from dimedone or cyclohexane-
1,3-dione, with 5 all worked well in this transformation to
afford the desired products in moderate to good yields. The
substituent variation at dihydrobenzofuran C2 position,
including cyclohexylamino, t-butylamino, n-butylamino, and
benzylamino groups, were smoothly transformed into corre-
sponding cinnoline-4-carbonxamides 6{1,1,1,(5)}−6{2,4,7,(5)}
within 30 min (Table 3, entries 1−20), which provides a
valuable asset for further catalytic functionalization chemistry. It
was also found that phenyl groups bearing either electron-
withdrawing or electron-donating groups on the benzofuran
ring were tolerated under the reaction conditions, leading to
the desired cinnoline derivatives in satisfactory yields (up to
83%). It is worth mentioning that it affords a new example for a
heterocyclization involving ring-opening of furan ring in an
economical and atom-efficient fashion, providing a unique
pathway to discover new bioactive compounds.
Figure 4. X-ray structure of 6{1,2,7,(5)}.
Although the detailed mechanism of this reaction remains to
be fully clarified, the formation of products 6 could be
explained by the reaction sequence in Scheme 2. First, the
Knoevenagel condensation between cyclic-1,3-diones 1 and
arylglyoxals 3 occurs, leading to intermediate A, which
undergoes a Michael addition and intramolecular cyclization
with isocyanides 2 to afford an imine intermediate C.
Intermediate C undergoes a [1,3]-H shift to yield benzofur-
an-4(5H)-ones 4, which is attacked by hydrazine hydrate 5
through intermolecular Michael addition to give intermediate
D. The final products 6 are obtained through a ring-opening of
Similar to our previous domino processes, the present new
reactions showed the following attractive characteristics: the
reaction occurred rapidly in all cases allowing energy and
manpower to be saved in potential industrial production. In
most cases, the products precipitated from the reaction mixture
when poured into cold water. The structures of products 4 and
1
6 were characterized using their IR, HNMR, 13CNMR, and
C
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Scheme 2. Proposed Mechanisms for Forming Compounds 4 and 6
furan (D to E), intramolecular addition (E to F), and
dehydration (F to 6) sequence.
CH2), 1.29−1.31 (m, 1H, CH2), 1.14 (s, 6H, CH3). HRMS
(ESI) m/z calcd for C23H26FNNaO3 406.1794 [M + Na]+;
found 406.1777.
In conclusion, a convenient, rapid three-component reaction
of cyclic-1,3-diones, isocyanides, and arylglyoxals has been
improved for efficient synthesis of polysubstituted benzofuran-
4(5H)-ones, which was trapped by hydrazine hydrate to
regioselectively form cinnoline-4-carboxamides through domi-
no ring-opening of furan process. Undoubtedly, this domino
strategy provides a straightforward and facile pathway to
construct the target molecules in an atom-economic fashion,
avoiding the use of strong acid or base and transition metal
catalysts. Other features of this tactic include convenient
operation, short reaction times, high bond-forming efficiency,
and excellent regioselectivity.
Typically, 2-(cyclohexylamino)-3-(4-fluorobenzoyl)-6,6-di-
methyl-6,7-dihydrobenzofuran-4(5H)-one (1 mmol) was in-
troduced in a 10-mL initiator reaction vial, hydrazine hydrate
(80% in aqueous solution, 3.75 mmol), as well as ethanol (1.5
mL), were then successively added. Subsequently, the reaction
vial was closed and then prestirred for 10 s. The mixture was
irradiated (time = 30 min, temperature = 60 °C; absorption
level = high; fixed hold time) until TLC (petroleum ether (60−
90 °C)/ethyl acetate 1:1) revealed that the conversion of the
starting material 4-fluorophenylglyoxal monohydrate was
complete. The reaction mixture was then cooled to room
temperature and diluted with cold water (20 mL). The solid
EXPERIMENTAL PROCEDURES
product was collected by Buchner filtration and was purified by
̈
■
recrystallization from petroleum ether (60−90 °C)/diethyl
General Procedure for the Synthesis of Compounds 4
and 6. Typically, 5,5-dimethylcyclohexane-1,3-dione (10
mmol) was introduced in a 25-mL initiator reaction vial,
isocyanocyclohexane(10 mmol), and 4-fluorophenylglyoxal
monohydrate (10 mmol), as well as ethanol (6 mL), were
then successively added. Subsequently, the reaction vial was
closed and then prestirred 10 s. The mixture was irradiated
(time = 25 min, temperature = 60 °C;absorption level: high;
fixed hold time) until TLC (petroleum ether (60−90 °C)/ethyl
acetate 3:1) revealed that the conversion of the starting material
4-fluorophenylglyoxal monohydrate was complete. The reac-
tion mixture was then cooled to room temperature and diluted
with cold water (150 mL). The solid product was collected by
ether 4:1 to afford the desired pure 6{1,1,1,(5)}.
N-Cyclohexyl-3-(4-fluorophenyl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydrocinnoline-4-carboxamide 6{1,1,1,
(5)}: White solid, mp (291−293 °C); IR (KBr, v, cm−1)
3258, 3199, 3076, 2927, 1656, 1596, 1498, 1393, 1333, 1250,
1
1153, 838, 566; H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H,
NH), 7.76−7.73 (m, 2H, ArH), 7.13 (d, J = 8.4 Hz, 1H, NH),
7.06 (t, J = 8.6 Hz, 2H, ArH), 4.91 (s, 1H, CH), 3.78−3.67 (m,
1H, CH), 2.35−2.13 (m, 4H, CH2), 1.91 (d, J = 10.0 Hz, 1H),
1.84−1.56 (m, 4H, CH2), 1.41−1.33 (m, 3H, CH2), 1.11−1.16
(m, 2H, CH2), 1.00 (s, 3H, CH3), 0.96 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 195.9, 170.8, 163.6 (1JCF
=
̈
248.5), 149.8, 143.4, 132.3 (4JCF = 3.1), 128.1 (3JCF = 8.3),
115.4 (2JCF = 21.6), 98.3, 50.6, 48.2, 38.3, 37.3, 32.5, 29.8, 26.2,
25.5; HRMS (ESI) m/z calcd for C23H27FN3O2 396.2088 [M −
H]−; found 396.2077.
Buchner filtration and was purified by recrystallization from
95% EtOH to afford the desired pure 4{1,1,1}.
2-(Cyclohexylamino)-3-(4-fluorobenzoyl)-6,6-dimeth-
yl-6,7-dihydrobenzofuran-4(5H)-one 4{1,1,1}: Yellow solid
(mp 129 °C); IR (KBr, v, cm−1) 2940, 2856, 1643, 1602, 1541,
1
1468, 1222, 1151, 1068, 770; H NMR (400 MHz, CDCl3) δ
ASSOCIATED CONTENT
■
8.43 (d, J = 8.0 Hz, 1H, NH), 7.62−7.44 (m, 2H, ArH), 7.09−
6.96 (m, 2H, ArH), 3.79−3.67 (m, 1H, CH), 2.71 (s, 2H,
CH2), 2.30 (s, 2H, CH2), 2.09−1.98 (m, 2H, CH2), 1.80−1.78
(m, 2H, CH2), 1.65−1.62 (m, 1H, CH2), 1.46−1.35 (m, 4H,
S
* Supporting Information
1H NMR spectra of all pure products. This material is available
free of charge via the Internet at http://pubs.acs.org.
D
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
selective synthesis of tetracyclic cinnolino[5,4,3-cde]cinnolines. Org.
Biomol. Chem. 2009, 7, 1171−1175.
AUTHOR INFORMATION
■
Corresponding Authors
*Fax: 86-516-83500065. E-mail: jiangchem@jsnu.edu.cn.
*E-mail: laotu@jsnu.edu.cn.
(7) (a) Vasilevsky, S. F.; Tretyakov, E. V.; Verkruijsse, H. D. A
convenient synthesis of 4-chloro- and 4-bromocinnolines from o-
aminophenylacetylenes. Synth. Commun. 1994, 24, 1733−1736.
(b) Kanner, C. B.; Pandit, U. K. Functionalized enamines. Part
XXXI. Base-catalyzed transformations of iminium phenylhydrazones:
A new convenient synthesis of imidazo[1,2a]azacycloalkanes. Tetrahe-
dron 1981, 37, 3519−3523.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(8) (a) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul, K.;
Kumar, A. Effcient synthesis of 3-aroylcinnolines from aryl methyl
ketones. Tetrahedron 2001, 57, 1609−1614. (b) Gomaa, M.-A. M. An
efficient and facile synthesis of substituted cinnoline and benzo[h]-
cinnoline derivatives. Tetrahedron Lett. 2003, 44, 3493−3496.
(9) Alford, E. J.; Schofield, K. Peptides III. Selective degradation from
the carboxyl end. The use of carbodimides. J. Chem. Soc. 1952, 2081−
2088.
■
We are grateful for the financial support from the NSFC (Nos.
21232004, 21272095, and 21102124), PAPD of Jiangsu Higher
Education Institutions, Jiangsu Science and Technology
Support Program (No. BE2011045), the Qing Lan Project
(12QLG006), Graduate Education Innovation Project of
Jiangsu Province (No. CXZZ13_0975).
(10) Chen, D.; Yang, C.; Xie, Y.; Ding, J. Novel process to 4,4-
dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines via Grignard reac-
tion. Heterocycles 2009, 77, 273−277.
(11) Prasanta, G.; Sandhya, R. G.; Namita, D.; Pranjit, B. Aluminium
chloride catalyzed synthesis of 4-benzyl cinnolines from aryl
hydrazones. Synth. Commun. 2013, DOI: 10.1080/
00397911.2013.853799.
(12) (a) Hussain, M. M.; Walsh, P. J. Tandem reactions for
streamlining synthesis: Enantio- and diastereoselective one-pot
generation of functionalized epoxy alcohols. Acc. Chem. Res. 2008,
41, 883−893. (b) Tietze, L. F.; Brasche, G.; Gerike, K. Domino
Reactions in Organic Chemistry; Wiley-VCH: Weinheim, Germany,
2006. (c) Pellissier, H. Stereocontrolled domino reactions. Chem. Rev.
2013, 113, 442−524.
(13) (a) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, Germany, 2004. (b) Anastas, P. T.; Warner, J. C.
Green Chemistry Theory and Practice; Oxford University Press: New
York, 1998. (c) Indumathi, S.; Menendez, J. C.; Perumal, S. L-Proline
catalyzed domino reactions for the synthesis of heterocycles. Curr. Org.
Chem. 2013, 17, 2038−2064.
(14) (a) Jiang, B.; Wang, X.; Xu, H. W.; Tu, M. S.; Tu, S. J.; Li, G. G.
Highly selective domino multicyclizations for forming polycyclic fused
acridines and azaheterocyclic skeletons. Org. Lett. 2013, 7, 1540−1543.
(b) Tu, M. S.; Li, Y.; Wang, X.; Jiang, B.; Wang, S. L.; Tu, S. J.
Regioselective [5 + 1] rearrangement-annulation: A new and efficient
domino route to highly functionalized [1,6]naphthyridines. RSC Adv.
2013, 3, 3877−3880. (c) Jiang, B.; Feng, B. M.; Wang, S. L.; Tu, S. J.;
Li, G. G. Domino constructions of pentacyclic indeno[2,1-c]quinolines
and pyrano[4,3-b]oxepines by [4 + 1]/[3 + 2+1]/[5 + 1] and [4 + 3]
multiple cyclizations. Chem.Eur. J. 2012, 18, 9823−9826.
(15) (a) Simonetti, S. O.; Larghi, E. L.; Braccaa, A. B. J.; Kaufman, T.
S. Angular tricyclic benzofurans and related natural products of fungal
origin. Isolation, biological activity and synthesis. Nat. Prod. Rep. 2013,
30, 941−969. (b) Liu, T.; Somarajan J. Nair, S. J.; Lescarbeau, A.;
Belani, J.; Stephane Peluso, S.; Conley, J.; Tillotson, B.; O’Hearn, P.;
Smith, S.; Slocum, K.; West, K.; Helble, J.; Douglas, M.; Bahadoor, A.;
Ali, J.; McGovern, K.; Fritz, C.; Palombella, V. J.; Wylie, A.; Castro, A.
C.; Tremblay, M. R. Synthetic silvestrol analogues as potent and
selective protein synthesis inhibitors. J. Med. Chem. 2012, 55, 8859−
8878. (c) Bang, H. B.; Han, S. Y.; Choi, D. H.; Yang, D. M.; Hwang, J.
W.; Lee, H. S.; Jun, J.-G. Facile total synthesis of benzo[b]furan natural
product XH-14. Synth. Commun. 2009, 39, 506−515.
(16) (a) Deana, A. A.; Stokker, G. E.; Schultz, E. M.; Smith, R. L.;
Cragoe, E. J.; Russo, H. F.; Watson, L. S. 2-(Aminomethyl)phenols, a
new class of saluretic agents. 5. Fused-ring analogues. J. Med. Chem.
1983, 26, 580−585. (b) E. Wenkert, E.; Buckwalter, B. L. Carbon-13
nuclear magnetic resonance spectroscopy of naturally occurring
substances. X. Pimaradienes. J. Am. Chem. Soc. 1972, 94, 4367−4369.
(17) (a) Petronijevic, F. R.; Wipf, P. Total synthesis of ( )-cyclo-
clavine and ( )-5-epi-cycloclavine. J. Am. Chem. Soc. 2011, 133, 7704−
7707. (b) Boonsompat, J.; Padwa, A. J. Org. Chem. 2011, 76, 2753−
2761. (c) Kiren, S.; Hong, X.; Leverett, C. A.; Padwa, A. Org. Lett.
REFERENCES
■
(1) Li, B.;Lv, L.; Liang, B.; Liang, S. J.; Song, Y. Q.; Gu, X. L.; Guan,
A. Y.; Zhu, D. Q. Preparation of cinnoline ring-containing ether
compounds as insecticides. CN 102952081 A 20130306, 2013.
(2) (a) Hennequin, L. F.; Thomas, A. P.; Johnstone, C.; Stokes, E. S.;
Ple, P. A.; Lohman, J.-J.; Oqilve, D. J.; Dukes, M.; Wedge, S. R.;
Curwen, J. O. Design and structure–activity relationship of a new class
of potent VEGF receptor tyrosine kinase inhibitors. J. Med. Chem.
1999, 42, 5369−5389. (b) Yu, Y.; Singh, S. K.; Liu, A.; Li, T.-K.; Liu,
L. F.; LaVoie, E. J. Substituted dibenzo[c,h]cinnolines: Topoisomerase
I-targeting anticancer agents. Bioorg. Med. Chem. 2003, 11, 1475−
1491. (c) Hu, E.; Kunz, R. K.; Rumfelt, S.; Chen, N.; Burli, R.; Li, C.;
̈
Andrews, K. L.; Zhang, J.; Chmait, S.; Kogan, J.; Lindstrom, M.;
Hitchcock, S. A.; Treanor, J. Discovery of potent, selective, and
metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodies-
terase 10A (PDE10A) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22,
2262−2265. (d) Chapdelaine,M. J.; Ohnmacht, C. J.; Becker, C.;
Chang, H. F.; Dembofsky, B. T. Strandboard molding having holes at
angles of 20 degrees to vertical or more. US0142328 A1 20070621,
2007.
(3) Tonk, R. K.; Bawa, S.; Chawla, G.; Deora, G. S.; Kumar, S.;
Rathore, V.; Mulakayala, N.; Rajaram, A.; Kalle, A. M.; Afzal, O.
Synthesis and pharmacological evaluation of pyrazolo[4,3-c]cinnoline
derivatives as potential anti-inflammatory and antibacterial agents. Eur.
J. Med. Chem. 2012, 57, 176−184.
(4) (a) Labovitz, J.; Guilford, W.; Liang, Y.; Fang, L.; Patterson, T.
Pollen suppressant comprising a 5-oxy- or amino-substituted cinnoline.
EP0363236 A1 900411, 1990. (b) Mizutani, M.; Shiroshita, M.;
Okuda, H.; Mito, N.; Sakaki, M. Plant male sterilant. EP0320782 A2
890621, 1989. (c) Mizutani, M.; Shiroshita, M.; Sakaki, M.; Mito, N.;
Okuda, H. Cinnoline derivative, Process for preparing the same and
herbicidal composition containing the same. EP0320793 A2 890621,
1989. (d) Munro, D.; Bit, R. A. Heterocyclic phenyl ether compounds.
GB2189238 A1 871021, 1987.
(5) (a) Chen, J. C.; Wu, H. C.; Chiang, C. J.; Peng, L. C.; Chen, T.;
Xing, L.; Liu, S. W. Investigations on the electrochemical properties of
new conjugated polymers containing benzo[c]cinnoline and oxadia-
zole moieties. Polymer 2011, 52, 6011−6019. (b) Dietrich, M.; Heinze,
J.; Krieger, C.; Neugebauer, F. A. Electrochemical oxidation and
structural changes of 5,6-dihydrobenzo[c]cinnolines. J. Am. Chem. Soc.
1996, 118, 5020−5030. (c) Mitsumori, T.; Bendikov, M.; Sedo, J.;
Wudl, F. Synthesis and properties of novel highly fluorescent
pyrrolopyridazine derivatives. Chem. Mater. 2003, 15, 3759−3768.
́
(d) Chapoulaud, V. G.; Ple, N.; Turck, A.; Queguiner, G. Synthesis of
4,8-diarylcinnolines and quinazolines with potential applications in
nonlinear optics diazines. Tetrahedron 2000, 56, 5499−5507.
(6) (a) Alajarin, M.; Bonillo, B.; Marin-Luna, M.; Vidal, A.; Orenes,
R.-A. [4 + 2] Cycloaddition reaction of C-aryl ketenimines with PTAD
as a synthetic equivalent of dinitrogen: Synthesis of triazolocinnolines
and cinnolines. J. Org. Chem. 2009, 74, 3558−3561. (b) Jiang, B.; Hao,
W. J.; Zhang, J. P.; Tu, S. J.; Shi, F. New domino reaction for the
E
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
2009, 11, 1233−1235. (d) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.;
Fong, K. C.; Choi, H. S. J. Am. Chem. Soc. 2002, 124, 2190−2201.
(18) Mohammad, H. M.; Mohammad, A. A.; Abbas, F. N.; Samaneh,
B.; Hossein, A. A. Synthesis of furan annulated heterocycles via a one-
pot three-component reaction. J. Chem. Res. 2009, 10, 599−601.
F
dx.doi.org/10.1021/co5000097 | ACS Comb. Sci. XXXX, XXX, XXX−XXX