Pyrano[4,3-b]quinolines library generation via iodocyclization and palladium-catalyzed coupling reactions

Article abstract of DOI:10.1021/co200100z

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to

Full text of DOI:10.1021/co200100z

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Pyrano[4,3-b]quinolines Library Generation via Iodocyclization and
Palladium-Catalyzed Coupling Reactions
Trapti Aggarwal,† Maryam Imam,†,‡ Naveen K. Kaushik,‡ Virander S. Chauhan,‡ and Akhilesh K. Verma*,†
†Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
‡International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India
S Supporting Information
b
ABSTRACT: Synthesis of a 80-member library of novel pyrano-
[4,3-b]quinolines in solution-phase is reported. The key inter-
mediate, 4-iodopyrano[4,3-b]quinolines were synthesized by
the electrophilic iodocyclization of corresponding ortho-alkynyl
aldehydes in good to excellent yields under mild reaction
conditions. Subsequently a diverse set of libraries was generated
by employing palladium-catalyzed SuzukiÀMiyaura, Heck,
and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]-
quinolines. In this way, a series of structurally different and
biologically interesting molecules were obtained. Some of the
selected compounds were screened against 3D7 strains of
Plasmodium falciparum for antimalarial activity. Suzuki coupling
products 6{3} and 6{21} and Heck coupling product 8{12}
exhibit promising antimalarial activity.
KEYWORDS: iodocyclization, cross-coupling, pyranoquinoline, rutaceae, Plasmodium falciparum
’ INTRODUCTION
The development of efficient synthesis of pyranoquinolines
has been the focus of much research for several decades
and continues to be an active and rewarding research area.
However, most of the existing methods suffer from limited
scope or availability of starting materials, or require multistep
procedures.8,9 Iodine mediated and Pd(II)-catalyzed coupling
reactions with aryl iodides have been extensively used for
the preparation of numerous biologically active molecules.10
These coupling reactions have been used as a facile method
for the synthesis of substituted aryl compounds from aryl
halides.11
In continuation of our efforts to adapt heterocyclization chem-
istry to a high-throughput format,12 we herein report the library
synthesis of pyrano[4,3-b]quinolineusingalkynecyclizationchem-
istry as the key step. Pyrano[4,3-b]quinoline moiety has not
been much explored and due to its presence in synthetic and
natural biologically active compounds,13 a libraryonpyrano[4,3-b]-
quinoline has been synthesized.
In recent years combinatorial chemistry and high-throughput
screening (HTS) has emerged as a powerful tool in the drug
discovery process. Heterocyclic systems containing nitrogen
atoms often play important roles as the scaffolds of bioactive
substances. Quinoline is one of the most popular N-heteroaro-
matics incorporated into the structure of many pharmaceuticals.
It is known that many quinoline-containing compounds exhibit a
wide spectrum of pharmacological activities such as antiasth-
matic, anti-inflammatory, and antimalarial activities.1 The plant
family Rutaceae is known2 to be a prolific source of pyranoquino-
line and furoquinoline alkaloids. These alkaloids have been re-
ported3 to be associated with interesting pharmacological as well
as biological properties and have been synthesized by several
methods.
Different families of nitrogen-containing heterocycles are
currently used in cancer chemotherapy. For instance, the quina-
zolines4 gefitinib, erlotinib, and canertinib are EGFR tyrosine
kinase inhibitors indicated for the treatment of colorectal, renal,
gynecologic, and prostate cancer. Quinolines5 are structural ana-
logues of quinazolines that are being explored for cancer chemo-
therapy with a number of compounds (EKB-569, HKI-272, and
SNS-595) in different phases of clinical trials. Cikotiene et al.
screened the pyranoquinoline compounds against the Gram-
positive and the Gram-negative strains.6 Magedov et al. reported
the antiproliferative and antitubulin activities of pyrano[3,2-c]-
pyridones and pyrano[3,2-c]quinolones.7
’ RESULT AND DISCUSSION
The key intermediate 4-iodopyranoquinolines (4) required
for this library synthesis were prepared by using our alkyne iodo-
cyclization chemistry14 (Scheme 1). Subsequent diversification
Received: June 2, 2011
Revised:
July 19, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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RESEARCH ARTICLE
Scheme 1. Synthesis of 4-Iodopyrano[4,3-b]quinolines
Boronic acids 5{5} and 5{6} containing sulfur and nitrogen
heteroatoms were used to enhance the biological properties of
coupling products. It was found that boronic acid 5{3} having
benzodioxane group and 5{9} having isopropoxy group reacted
well but afforded the desired product in comparatively lower
yield as compared to other boronic acids.
A brief examination of the reaction conditions suggested that
heating at 80 °C for 2 h in presence of Pd(PPh3)2Cl2 catalyst and
base in DMF/H2O was sufficient for obtaining desired products
in good yields, no high temperature heating was required. How-
ever in some cases coupling products were obtained in low yields
due to deiodonation of iodopyranoquinoline (4) in presence of
Pd(II)-catalyst and base.
Figure 1. Terminals alkynes 2{1À7} used for the Sonogashira reaction.
The formation of products 6{1À40} were confirmed by the
1H NMR, 13C NMR, and X-ray crystallographic data of com-
pound16 6{7} (Figure 4).
by various palladium-catalyzed cross-coupling reactions should
afford a diverse set of pyrano[4,3-b]quinolines.
The starting material 2-alkynylquinoline-3-carbaldehydes
(3) were prepared by Sonogashira coupling of 2-chloroquino-
line-3-carbaldehydes (1) with various terminal alkynes (2)14b
(Scheme 1). Accordingly a set of 4-iodopyranoquinoline
4{1À15} were synthesized from (3) by electrophilic iodocycli-
zation reaction. We have chosen 2-chloro-6-methoxy-3-quinoli-
necarbaldehyde and 2,6-dichloro-3-quinolinecarbaldehyde as the
starting material. The methoxy and chloro group present in the
starting substrate should enhance the biological activity of final
compounds.
The terminal alkynes 2{1À7} used for Sonogashira reaction,
were chosen on the basis of commercially available acetylenes.
Heteroatoms were included in the acetylenes to impart drug-like,
hydrogen bond donor or acceptor properties to pyranoquino-
lines (Figure 1). Sulfur atom present in acetylene 2{4} increases
the probability of molecules to act like drugs.
According to our designed strategy, the 4-iodopyranoquino-
lines 4{1À15} were synthesized by iodocyclization reaction of
ortho-alkynylaldehyde (3) at room temperature in good yields
(Figure 2).
These iodocyclized products (4) are the key components for
library generation and subsequently elaborated by palladium-
catalyzed cross-coupling reactions and afford a diverse set of
pyranoquinolines (Scheme 2).
We obtained aryl substituted pyranoquinolines 6{1À40} by
the palladium-catalyzed Suzuki-Miyaura reaction15 of the iodo-
pyranoquinoline intermediates 4{1À15} with various boronic
acids (Table 1). The boronic acids were chosen on the basis of
their commercial availability and their ability to provide the indis-
pensable diversity and drug-like properties to the cross-coupled
pyranoquinolineproducts. For instance, the methoxyÀcontaining
boronic acids 5{2} and 5{7} increases the polarity and yield of
the pyranoquinolines (Figure 3). The fluorine-containing boro-
nic acid 5{8} was chosen with a view toward its importance of
fluorine in medicinal chemistry and this boronic acid afforded
good yields of coupled product.
The pyranoquinoline 8{1À20} have been prepared by the
Heck reaction17 using acrylates (Table 2). A small acrylate sub
library (Figure 5) for the Heck reaction was chosen. By allowing
the compound to react under Heck reaction condition in the
presence of the acrylates 7{1À5}, we obtained the acryl sub-
stituted pyranoquinoline products 8{1À20}.
For instance, the acryl substrate 7{1À5} were chosen with
a view toward increasing the biological activity of pyrano-
quinolines. Acrylonitrile 7{5} reacted well but the yield
obtained was comparatively lower than other acrylates. N,
N-dimethylacrylate 7{3} was highly reactive and afforded the
desired product in appreciable yields. The reaction condi-
tions for Heck reaction suggested that heating at 120 °C for
2 h in presence of 10 mol % Pd(II)-catalyst and 2.5 equiv of
base in DMF was sufficient for obtaining desired products in
good yields.
By using acrylates for Heck reaction we have prepared a
small library of ester substituted pyranoquinolines. The presence
of ester group will impart biological significance to these com-
pounds.
Next, we employed the Sonogashira coupling reaction of
4-iodopyranoquinoline 4{1} with terminal alkynes to produce
another set of pyranoquinolines 9{1À5}14b (Table 3).
In vitro antimalarial activity of some selected substituted
pyranoquinoline scaffolds was determined against 3D7 strains
of Plasmodium falciparum using SYBR green based florescence
assay (Table 4). It is evident from Table 4 that presence
of substituents at 1, 4, and 8 position of the pyranoquinoline
scaffolds plays an important role for the activity. Suzuki coup-
ling products 6{3} and 6{21} with methoxy group at 1 position
of the scaffold showed good antimalarial activity with IC50
values ranging from 1.9 to 2.1 μM (entries 1 and 3). However,
increase in chain length at 1 position of the scaffolds drastically
decreased the antimalarial activity with IC50 value >100 μg/mL
(entry 2). Heck coupling product 8{12}, with ethyl acrylate
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RESEARCH ARTICLE
Figure 2. Key intermediate 4-pyrano[4,3-b]quinoline 4{1À15}.
Scheme 2. Library generation of Pyrano[4,3-b]quinolines from the 4-Iodopyranoquinolines
substitution at 4 position of the scaffold having electron-
donating thiophene ring and methoxy group at 3 and 8
position, respectively, showed good antimalarial activity
(entry 5); however, compound 8{15} with acrylonitrile sub-
stitution at 4 position and electron-donating thiophene ring
and methoxy group at 3 and 8 position showed moderate
activity (entry 7). Compounds 8{1} and 8{20} with acryloni-
trile substitution at 4 position and compound 8{13} with
amide functionality at 4 position were found ineffective
(entries 4, 6, and 8). Compounds which showed IC50 less than
10 μg/mL were further analyzed for toxicity to mammalian HeLa
cell line and they were found nontoxic up to a concentration of
50 μg/mL (Table 4).
’ CONCLUSION
In summary, we have designed a novel pyrano[4,3-b]quinoline
library in solution phase which has been rapidly constructed
utilizing iodocyclization and palladium catalyzed cross-coupling
reactions. Diversely substituted pyranoquinolines have been
achieved because of the high efficiency, good substrate genera-
lity, mild conditions and commercially available building blocks.
Some of the selected Suzuki and Heck coupling products
were screened against 3D7 strains of Plasmodium falciparum for
antimalarial activity. Suzuki coupling products 6{3}, 6{21} and
Heck coupling product 8{12} exhibit promising antimalarial activity.
Further studies on the biological mechanism of action of pyrano-
[4,3-b]quinoline are in progress and will be reported in due course.
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Table 1. Library Data of Compounds 6{1À40} Synthesized
mixture was then quenched with saturated aq Na2S2O3 and
water. The resulting solution was extracted using ethyl acetate.
The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated under vacuum. The crude pro-
duct was purified by flash column chromatography (Silica
gel 100À200 mesh, hexane/EtOAc) to afford pure com-
pounds.
via Suzuki Reactiona
entry
iodo pyranoquinoline
boronic acid
product
yieldb%
1
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
4{3}
4{3}
4{4}
4{4}
4{4}
4{5}
4{5}
4{6}
4{6}
4{6}
4{7}
4{8}
4{8}
4{8}
4{8}
4{9}
4{9}
4{9}
4{10}
4{10}
4{11}
4{11}
4{11}
4{12}
4{12}
4{13}
4{13}
4{13}
4{13}
4{13}
4{14}
4{15}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{8}
5{4}
5{4}
5{2}
5{1}
5{5}
5{8}
5{4}
5{5}
5{1}
5{2}
5{4}
5{2}
5{1}
5{2}
5{3}
5{7}
5{4}
5{6}
5{7}
5{3}
5{4}
5{5}
5{8}
5{9}
5{8}
5{9}
5{4}
5{5}
5{6}
5{8}
5{9}
5{4}
5{9}
6{1}
81
82
70
80
82
78
80
74
80
78
79
80
78
79
82
84
78
80
79
80
79
77
68
72
80
68
70
79
81
77
65
76
68
80
82
78
76
68
80
70
2
6{2}
3
6{3}
4-Iodo-1-methoxy-3-(thiophen-3-yl)-1H-pyrano[4,3-b]quino-
4
6{4}
line 4{6}. The product was obtained as yellow solid. mp:
5
6{5}
1
146À148 °C. Yield: 86%. H NMR (300 MHz, CDCl3) δ:
6
6{6}
8.21À8.14 (m, 2H), 7.95 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H),
7.76À7.72 (m, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.38À7.37 (m,
1H), 6.21 (s, 1H), 3.70 (s, 3H). 13C NMR (75 MHz, CDCl3):
152.4, 148.9, 148.1, 137.1, 132.8, 130.2, 129.5, 129.4, 128.8,
127.5, 126.4, 124.7, 122.1, 100.2, 77.5, 56.3. HRMS (ESI):
calcd for [C17H12INO2S]+ requires m/z 420.9633, found
420.9640.
7
6{7}
8
6{8}
9
6{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
6{10}
6{11}
6{12}
6{13}
6{14}
6{15}
6{16}
6{17}
6{18}
6{19}
6{20}
6{21}
6{22}
6{23}
6{24}
6{25}
6{26}
6{27}
6{28}
6{29}
6{30}
6{31}
6{32}
6{33}
6{34}
6{35}
6{36}
6{37}
6{38}
6{39}
6{40}
General Procedure for the Synthesis of Compounds
6{1À40}. To a vial was added the 4-iodopyranoquinoline 4
(0.25 mmol), the boronic acid 6 (1.2 equiv), 10 mol %
Pd(PPh3)2Cl2, K2CO3 (2.5 equiv), and DMF/H2O (4:1).
The solution was flushed with nitrogen and then heated
to 80 °C until TLC revealed complete conversion of the
starting material. The solution was allowed to cool and diluted
with H2O and then extracted with EtOAc. The combined
organic layers were dried over MgSO4, concentrated, and
purified by column chromatography to afford the correspond-
ing product.
4-(1-Methoxy-3-phenyl-1H-pyrano[4,3-b]quinolin-4-yl)-N,N-
dimethylaniline 6{5}. The product was obtained as yellow solid.
mp: 156À158 °C. 1H NMR (300 MHz, CDCl3) δ: 8.04 (s, 1H),
7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.2
Hz, 1H), 7.44À7.39 (m, 3H), 7.29À7.20 (m, 5H), 6.71 (d, J =
8.7 Hz, 2H), 6.28 (s, 1H), 3.73 (s, 3H), 2.96 (s, 6H). 13C NMR
(75 MHz, CDCl3): 152.6, 150.4, 149.5, 148.9, 135.8, 132.9,
132.6, 130.0, 129.5, 128.6, 128.2, 127.6, 127.4, 126.7, 125.5,
123.1, 122.8, 117.5, 112.2, 100.0, 56.0, 40.6. HRMS (ESI):
calcd for [C27H24N2O2]+ requires m/z 408.1838, found
408.1836.
General Procedure for the Synthesis of Compounds
8{1À20}. To a vial was added the 4-iodopyranoquinoline
4 (0.25 mmol), the acrylates 7 (1.2 equiv), 10 mol % Pd-
(PPh3)2Cl2, K2CO3 (2.5 equiv), and DMF (2.0 mL). The
solution was flushed with nitrogen, and then heated to 120 °C
until TLC revealed complete conversion of the starting
material. The solution was allowed to cool and diluted
with H2O and then extracted with EtOAc. The combined
organic layers were dried over MgSO4, concentrated, and
purified by column chromatography to afford the correspond-
ing product.
(E)-Methyl 3-(1-methoxy-3-p-tolyl-1H-pyrano[4,3-b]quinolin-
4-yl)acrylate 8{1}. The product was obtained as yellow solid.
mp: 174À176 °C. 1H NMR (400 MHz, CDCl3) δ: 8.24 (d, J =
8.8 Hz, 1H), 8.09 (s, 1H), 7.82À7.79 (m, 3H), 7.73 (t, J = 7.3 Hz,
1H), 7.54À7.51 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 6.21 (s, 1H),
3.77 (s, 3H), 3.74 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3): 169.0, 162.6, 148.9, 148.2, 141.1, 139.5, 132.9, 130.8,
130.5, 130.2, 129.4, 129.2, 127.6, 126.5, 126.3, 122.7, 119.2,
111.0, 100.7, 56.7, 51.3, 21.5. HRMS (ESI): calcd for
[C24H21NO4]+ requires m/z 387.1471, found 387.1475.
General Procedure for the Synthesis of Compounds
9{1À5}. To a vial was added the 4-iodopyranoquinoline
a The reactions were performed using iodo pyranoquinolines 4 (0.25
mmol), 1.2 equiv of the boronic acids 5, 2.5 equiv of K2CO3, 10 mol %
Pd(PPh3)2Cl2 in 2.0 mL of DMF/H2O (4:1) under nitrogen condition
at 80 °C for 2 h. b Yield of isolated product
’ EXPERIMENTAL PROCEDURES
General Procedure for the Synthesis of 4-Iodo-1H-
pyrano[4,3-b]quinolines 4{1À15}. Into a solution of the 2--
(alkynyl)quinoline-3-carbaldehyde 3 (1.0 mmol), K2CO3 (2.5
equiv), and I2 (2.5 equiv) in CH2Cl2 (2.0 mL), the nucleo-
phile (1.2 equiv) was added, and the solution was stirred
at room temperature until the total disappearance of the
starting material as determined by TLC analysis. The reaction
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Figure 3. Boronic acids 5{1À9} used for Suzuki reaction.
Figure 4. ORTEP plot of single crystal structure of compound 6{7}.
4 (0.25 mmol), the alkynes 2 (1.2 equiv), 10 mol % Pd-
(PPh3)2Cl2, and Et3N (2.5 equiv) in CH3CN (2.0 mL).
The solution was flushed with nitrogen, and then heated
to 65 °C until TLC revealed complete conversion of the
starting material. The solution was allowed to cool and diluted
with H2O and then extracted with EtOAc. The combined
organic layers were dried over MgSO4, concentrated, and
purified by column chromatography to afford the correspond-
ing product.
malaria parasites were grown in vitro.18 Chloroquine sensi-
tive 3D7 strain of P. falciparum was used in culture. The
parasite was cultured in RPMI 1640 supplemented with
HEPES, sodium bicarbonate, gentamycin, 10% human serum
or albumax, and human erythrocytes. The parasite was grown
in plates incubated at 370C in carbon dioxide incubator.
The parasitemia was monitored by microscopic examination
of blood smears after staining with Giemsa stain. For vari-
ous studies the parasite cultures would be prepared after
synchronization.
1-Methoxy-3-phenyl-4-(p-tolylethynyl)-1H-pyrano[4,3-b]quino-
1
line 9{2}. The product was obtained as yellow oil. H NMR
In vitro drug susceptibility testing in P. falciparum will be
determined by a SYBR Green I-based fluorescence method
described previously by Smilkstein and Riscoe.19 Stock solutions
of each test drug were prepared in DMSO/sterile distilled water.
The 50% inhibitory concentration (IC50) was determined by
analysis of doseÀresponse curves.
(400 MHz, CDCl3) δ: 8.27À8.21 (m, 3H), 8.07 (s, 1H),
7.82À7.80 (d, J = 8.4 Hz, 1H), 7.72 (td, J = 7.3 and 1.4 Hz,
1H), 7.47À7.43 (m, 6H), 7.13 (d, J = 8.8 Hz, 2H), 6.32
(s, 1H), 3.75 (s, 3H), 2.35 (s, 3H). 13C NMR (100 MHz,
CDCl3): 159.5, 149.1, 149.0, 137.8, 134.2, 132.9, 131.3,
130.2, 130.0, 129.8, 129.0, 128.9, 127.9, 127.6, 127.1, 126.1,
122.0, 121.1, 101.0, 100.4, 95.9, 84.1, 56.4, 20.7. HRMS
(ESI): calcd for [C28H21NO2]+ requires m/z 403.4718, found
403.4711.
Procedure for Antimalarial Screening. Compounds were
screened for antimalarial activity using SYBR Green fluorescence
based assay of P. falciparum growth in microtiter plate wells in
vitro. To check parasite growth inhibition by the above extracts,
Determination of Therapeutic Potential of Purified Anti-
plasmodial Molecules. Therapeutic index is a ratio of toxic
concentration (TC50) for host to inhibitory concentration
(IC50) for the pathogen. Therapeutic indices will be determined
by measuring the cytotoxicity of test molecules on mammalian
cells. Animal cell line Hela was used to determine drug toxicity by
using MTT assay for mammalian cell viability as described by
Mosmann in 1983.20
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Table 2. Library Data of Compounds 8{1À20} Synthesized
Table 4. Antimalarial Activity of Pyranoquinolines against
via Heck Reactiona
3D7 Strains of Plasmodium falciparuma
entry
iodo pyranoquinoline
reactant
product
yieldb%
entry
compounds
IC50 Pf3D7 (μg/mL)
TC50 HeLa (μg/mL)
1
2
3
4
5
6
7
8
4{4}
4{4}
4{4}
4{5}
4{5}
4{5}
4{6}
4{6}
7{1}
7{3}
7{4}
7{1}
7{2}
7{4}
7{1}
7{3}
7{1}
7{4}
7{1}
7{2}
7{3}
7{4}
7{5}
7{1}
7{2}
7{1}
7{3}
7{5}
8{1}
8{2}
8{3}
8{4}
8{5}
8{6}
8{7}
8{8}
80
75
70
78
75
68
79
78
80
72
79
75
78
71
65
77
75
78
76
66
1
2
6{3}
1.9
>100
2.1
>50
6{10}
3
6{21}
>50
>50
>50
4
8{1}
28
5
8{12}
2
6
8{13}
>100
9
7
8{15}
9
4{9}
4{9}
8{9}
8
8{20}
>100
0.021
0.0045
10
11
12
13
14
15
16
17
18
19
20
8{10}
8{11}
8{12}
8{13}
8{14}
8{15}
8{16}
8{17}
8{18}
8{19}
8{20}
9
chloroquine
4{10}
4{10}
4{10}
4{10}
4{10}
4{11}
4{11}
4{12}
4{12}
4{12}
10
artemisnin
a Experiment was performed in triplicate.
’ ASSOCIATED CONTENT
S
Supporting Information. X-ray crystallographic data of
b
compound 6{7} and copies of H and 13C NMR spectra are
reported for all the compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
a Reactions were performed using 4-iodopyranoquinolines 4 (0.25
mmol), 1.2 equiv of the acrylates 7, 2.5 equiv of K2CO3, 10 mol %
Pd(PPh3)2Cl2 in 2.0 mL of DMF under nitrogen condition at 120 °C
for 2 h. b Yield of the isolated product
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: averma@acbr.du.ac.in, Phone: 91-11-27666646 (Ext.
175).
Funding Sources
We gratefully acknowledge the University of Delhi for the
financial support and USIC for providing instrumentation facil-
ities. T. A. thanks CSIR and N.K. thanks ICMR for their
fellowships.
’ ACKNOWLEDGMENT
Our sincere thanks to Ms. Shruti Khanna for her kind help in
solving X-ray crystallographic data.
Figure 5. Acrylates used for Heck reaction 7{1À5}.
’ REFERENCES
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iodo pyranoquinoline
reactant
product
yieldb%
1
2
3
4
5
4{1}
4{1}
4{1}
4{1}
4{1}
2{2}
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70
75
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68
65
a Reactions were performed using 4-iodopyranoquinolines 4 (0.25 mmol),
1.2 equiv of the alkynes, 2.5 equiv of Et3N, 10 mol % Pd(PPh3)2Cl2 in
2.0 mL of CH3CN under nitrogen condition at 70 °C for 4 h. b Yield of
the isolated product
535
dx.doi.org/10.1021/co200100z |ACS Comb. Sci. 2011, 13, 530–536

ACS Combinatorial Science
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