Silver-Catalyzed Domino Hydroarylation/Cycloisomerization Reactions of 2-Alkynylquinoline-3-carbaldehydes: Access to (Hetero)arylpyranoquinolines

Article abstract of DOI:10.1055/s-0035-1562234

A silver trifluoromethanesulfonate catalyzed efficient access to the indolylpyranoquinoline scaffold is reported. Starting from 2-alkynylquinoline-3-carbaldehyde units with various substitution patterns on the quinoline and alkynyl parts, the use of silver trifluoromethanesulfonate (10 mol%) in 1,2-dichloroethane allowed a domino hydroarylation/cycloisomerization reaction, generating (hetero)aryl-functionalized pyranoquinolines. The heteroarenes that were used are N-methylindole (18 compounds, 67-100%), indole, and 2-methylindole (4 compounds, 36-89%), and the reaction was also compatible to a lesser extent with arenes such as pyrroles (5 compounds, 43-90%), 1,3,5-trimethoxybenzene, and 3-methylbenzofuran.

Full text of DOI:10.1055/s-0035-1562234

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2015, 47, A–M
A
feature
Synthesis
A. Bontemps et al.
Feature
Silver-Catalyzed Domino Hydroarylation/Cycloisomerization
Reactions of 2-Alkynylquinoline-3-carbaldehydes: Access to
(
Hetero)arylpyranoquinolines
Alexis Bontempsa
Gaëlle Mariaulea,b
Stéphanie Desbène-Fincka
Philippe Helisseya
Sylviane Giorgi-Renaulta
Véronique Michelet*c
Philippe Belmont*a,b
other nucleophiles (12 compounds)
NH
nucleophile
N
N
R
R1
O
AgOTf
(10 mol%)
R = H, Me
N
R
N
+
OMe
R2
DCE (0.2 M)
reflux, 1–48 h
O
R1
(43–55%)
3
equiv
(36–89%)
O
N
R2
R1 = H, OMe, Cl
R2 = aryl, alkyl
N
MeO
OMe
(36–54%)
18 compounds
67% to quant.)
(
(23%)
(66–90%)
a
Université Sorbonne Paris Cité and Université Paris Des-
cartes, Faculté de Pharmacie de Paris, UMR CNRS 8638, 4
avenue de l’Observatoire, 75006 Paris, France
Institut Curie, UMR CNRS 176, 26 rue d’Ulm, 75005 Paris, France
b
philippe.belmont@parisdescartes.fr
c
PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 11 rue P. et M. Curie, 75005 Paris, France
veronique.michelet@chimie-paristech.fr
nes,14 hydride,15 and aromatics ). Particularly, we recently
focused on nucleophiles such as aromatics, since they still
remain underexplored (Scheme 1, a).1 Indeed, domino hy-
droarylation/cycloisomerization reactions have attracted
our attention and we recently reported the reactivity of
aromatics as nucleophiles on o-alkynylbenzaldehydes to
form 1-aryl-1H-isochromenes (Scheme 1, a). Among these,
one example with N-methylindole as a nucleophile trig-
gered our interest to form indolylquinoline derivatives,
since we already reported the formation of furo- and pyra-
noquinoline under silver or gold catalysis with alcohol
groups as nucleophiles (Scheme 1, b).8 Therefore, we in-
tended to develop this chemistry on 2-alkynylquinoline-3-
carbaldehydes to access mixed indole/quinoline moieties,
using as a link a dihydropyran unit, providing the original
indolylpyranoquinoline scaffold (Scheme 1, c) via a selec-
tive 6-endo-dig cyclization process.8a
16
Received: 18.04.2016
Accepted: 21.04.2016
Published online: 07.06.2016
DOI: 10.1055/s-0035-1562234; Art ID: ss-2016-z0264-fa
6d
Abstract A silver trifluoromethanesulfonate catalyzed efficient access
to the indolylpyranoquinoline scaffold is reported. Starting from 2-
alkynylquinoline-3-carbaldehyde units with various substitution pat-
terns on the quinoline and alkynyl parts, the use of silver trifluorometh-
anesulfonate (10 mol%) in 1,2-dichloroethane allowed a domino hy-
droarylation/cycloisomerization reaction, generating (hetero)aryl-
functionalized pyranoquinolines. The heteroarenes that were used are
N-methylindole (18 compounds, 67–100%), indole, and 2-methylindole
(
4 compounds, 36–89%), and the reaction was also compatible to a
lesser extent with arenes such as pyrroles (5 compounds, 43–90%),
,3,5-trimethoxybenzene, and 3-methylbenzofuran.
1
Key words, hydroarylation, silver, cycloisomerization, indolylpyrano-
quinolines, domino reaction, cyclofunctionalization
Quinolines and indoles are ubiquitous heterocycles ex-
hibiting a large array of biological properties. In order to
develop new pharmacophores according to a diversity-
oriented synthesis (DOS) strategy, some efforts have been
1
First of all, to reach the desired 2-alkynyl(benzo)quino-
line-3-carbaldehyde precursors (Scheme 2), we used the
2
17
classical Meth-Cohn quinoline synthesis methodology to
oriented towards the formation of mixed indolylquinoline
moieties, with various linking features, allowing the discov-
ery of new bioactive derivatives. Among all the strategies
obtain a wide array of 2-chloro(benzo)quinoline-3-carb-
aldehydes, which underwent Sonogashira coupling reac-
tions to yield known (1a–c, 1k, 1l) or new (1d–j, 1m–r)
3
8a
to reach indolylquinoline derivatives, we chose to focus on
straightforward and atom-economical metal-catalyzed cy-
cloisomerization reactions, due to our continuing interest
functionalized derivatives. For the Sonogashira reaction we
needed to choose between four methods including a
chloro–iodo exchange (see experimental part).18 We also
synthesized four alkynyl derivatives bearing aromatic sub-
stitutions (1b, 1h, 1l, 1p, 76–91%) and focused on alkynyl
derivatives bearing aliphatic substitutions (46–84% yield),
which are less known in comparison with their aromatic
counterparts (Scheme 2).
4
5
6
in enyne, aniline-yne, alkynylsilylenol ether, enamine-
7
8
yne, and carbonyl-yne cycloisomerization and domino re-
actions. We and others investigated cyclofunctionalization
reactions on carbonyl-yne units with various nucleophilic
8
,9
10
11
species (alcohols, terminal alkynes, phosphites, nitro-
1
2
13
gen derivatives, activated methylenes, allyl trialkylsila-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

B
Synthesis
A. Bontemps et al.
Feature
OMe
DMF, POCl3
O
a)
OMe
R1
NHAc
Meth-Cohn
R1
N
Cl
O
AgOTf
R1
R2
quinoline synthesis
R2
(
10 mol%)
MeO
OMe
R2
R3
+
anilides
quinolines
Sonogashira
R2 MeO
OMe DMF (0.5 M)
O
R1 = H, OMe, Cl or R –R = fused aryl
1
2
R1
r.t. to 80 °C
nucleophile
R1 = H, OMe, F, CF3
R2 = H, TMS, aryl, alkyl
O
O
1H,1-arylisochromenes
OR2
N
Cl
N
R3
R3
R3
R3
=
=
O
CH2OMe 73% 1a
C6H5 85% 1b
c-Pr 84% 1c
n-Pr 46% 1d
i-Bu 80% 1e
CH2OMe 81% 1g
C6H5 79% 1h
n-Pr 47% 1i
N
b)
R1
furoquinolines
n-Hex 76% 1j
[
M] (5 mol%)
I
I
M = AuPPh3SbF6
or AgOTf...
M = Ag , Au
O
n-Hex 72% 1f
2
OR2
R OH (0.05 M)
or in DCE, r.t.
or
N
O
O
R1
O
1
N
R
R
= aryl, alkyl
O
N
2
R3
= alkyl, benzyl
R1
R3
N
R3
R3
=
=
pyranoquinolines
CH2OMe 58% 1k
C6H5 91% 1l
n-Pr 62% 1m
n-Hex 80% 1n
CH2OMe 65% 1o
C6H5 76% 1p
n-Pr 82% 1q
M = Ag2O...
c) this work:
N
n-Hex 83% 1r
AgOTf
(10 mol%)
O
R1
N
Scheme 2 Synthesis of precursors
+
O
N
R1
DCE (0.2 M)
reflux, 1–24 h
R2
R2
N
R1 = H, OMe, Cl
R2 = aryl, alkyl
With these polycyclic precursors in hand, and based on
our previous optimized reaction conditions (Scheme 1, a),
we investigated the addition of N-methylindole and also
other nucleophiles (Scheme 3), for the tandem hydroaryla-
nucleophile
other nucleophiles = 1H-indoles, pyrroles, benzofuran,1,3,5-trimethoxybenzene
Scheme 1 Previous work from our group (a, b), and this work (c)
Biographical Sketches
Véronique Michelet com-
pleted her graduate studies at
the Ecole Nationale Supérieure
de Chimie de Paris (ChimieParis-
Tech, France) in 1993 and re-
ceived her PhD degree in 1996
from the University P. et M.
Curie in the group of Prof. J.-P.
Genêt. After two years of post-
doctoral research in the groups
of Prof. J. D. Winkler (University
of Pennsylvania, USA) and Prof.
A. G. M. Barrett (Imperial Col-
lege, UK), she was appointed at
ChimieParisTech as CNRS Asso-
ciate Researcher in 1998 and
promoted to Director of
Research in 2007. Her research
interests combine basic and ap-
plied aspects of catalysis for the
development of new synthetic
methodologies for carbon–car-
bon and carbon–heteroatom
bond formation. This involves
asymmetric catalysis, metallo-
organocatalysis, and the devel-
opment of novel catalytic sys-
tems for atom- and step-
economical reactions such as
cycloisomerization
reactions
and domino processes. The syn-
thesis of fluorescent complex-
ing agents is also developed in
her group for the detection of
polluting metal ions.
Philippe Belmont was born in
Paris in 1970, grew up in the
French Caribbean, and in 1990
moved to Grenoble (France) to
study at the University Joseph
Fourier, where, in 1996, he ob-
tained his PhD degree in organic
chemistry under the guidance
of Dr. M. Demeunynck and Prof.
J. Lhomme. He then moved for
three years of post-doctoral re-
search to Case Western Reserve
University (Prof. A. J. Pearson,
Cleveland, USA) and to the
Collège de France (Prof. J.-M.
Lehn and Dr. J.-P. Vigneron,
Paris, France). In 2000 he joined
the group of Prof. M. A. Ciufolini
(University of Lyon, France) as a
researcher for the CNRS. In
2004 he obtained his habilita-
tion diploma and since then has
chemistry (Rh, Au, Ag, Co) for
the synthesis of nitrogen- and
oxygen-containing heterocyclic
compounds, with an interest in
their biological properties. In
2009 he arrived at the Institut
Curie in Paris (2009–2014) and
since 2011 has been a Full Pro-
fessor of Organic Chemistry at
the School of Pharmacy (Univer-
sity Paris Descartes).
managed
a
research group
organometallic
investigating
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

C
Synthesis
A. Bontemps et al.
Feature
Nu
Table 1 Reaction Conditions Optimization with N-Methylindole as the
Nucleophile
O
AgOTf (10 mol%)
solvent (0.5 M)
O
nucleophile
3 equiv)
Nu)
(
N
(
N
R
N
R
N
AgOTf (10 mol%)
solvent
O
1
a (R = CH2OMe), 1b (R = C6H5)
+
N
O
OMe
OMe
O
1a
O
DMF (50, 80 or 110 °C)
or dioxane (80 °C)
N
3a
MeO
N
OMe or DCE (reflux)
–5 h
MeO
OMe
DMF (50 °C)
1
Entry
Solvent
Temp
Conc Nuequiv
n
Time (h)
Yield(%)
1
3
5 h
6%, 2b
O
traces only, 2a
O
a
(
°C)
O
(M)
N
R'
1
DMF
DMF
DMF
50
0.5
0.5
0.2
0.1
0.2
0.4
0.2
0.2
0.2
0.2
0.2
0.2
3
2
24
2
2
1
1
1
1
1
2
1
1
64
–
DMF (50 °C), 2 h
R' = Me, R'' = H
N
2b
r.t.
3
N
DMF (50 °C)
R''
6
4%, 3a
R' = H, R'' = Me
2%, 7a
3
4
5
6
7
8
9
80
3
68
73
76
75
80
77
86
75
83
80
2
h
46%, 5a
O
O
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
50
3
3
O
O
50
3
N
N
50
3
Scheme 3 First optimization
80
3
80
1.5
10
3
tion/cycloisomerization reaction. Of note, we chose a model
substrate bearing an alkyl side chain (CH OMe) on the
80
2
10
50
alkynyl unit, most of all because alkyl-substituted alkynes
are more challenging and less studied substrates due to
their instability and lower reactivity compared to the aryl-
substituted ones.
Using 1,3,5-trimethoxybenzene as a nucleophile on
substrate 1a was inefficient, regardless of the reaction sol-
vent (DMF, dioxane, DCE) or temperature (50–110 °C) cho-
sen, and only traces of 2a were detected (Scheme 3). This
was in sharp contrast with our previous optimized condi-
tions to construct isochromenes.1 Using the phenylal-
kynyl-functionalized quinoline substrate 1b with 1,3,5-tri-
methoxybenzene as a nucleophile led to a low yield (36%) of
the desired pyranoquinoline product 2b.
Therefore, other nucleophiles were tested on 1a. The
use of N-methylindole gave the best results, with (N-me-
thylindolyl)pyranoquinoline 3a (Scheme 3) obtained in 64%
yield in only two hours, but the temperature had to be
lowered to 50 °C to control the amount of side products
formed. Finally, the results with the unsubstituted indole as
a nucleophile on substrate 1a was disappointing (7a, 32%,
Scheme 3) and N-methylpyrrole gave fair results (5a, 46%,
Scheme 3).
Overall, the first optimization attempts (Scheme 3)
showed that, for the choice of the nucleophile, the reactivi-
ty of N-methylindole was superior to the other tested nu-
cleophiles, although limited (3a, 64%). Therefore, we as-
sumed that the presence of the nitrogen-containing quino-
line could have an impact on the previously optimized
1
1
DCE
reflux
reflux
3
12
DCE
10
a
C = concentration of the reaction mixture.
Partial conversion.
b
Thus, we decided to have a look at the reactivity of N-
methylindole as a heteroaromatic nucleophile under or-
ganometallic catalysis, since only few papers described
some reactivity with gold,
Using our optimized reaction conditions for obtaining iso-
chromenes (Table 1, entry 1),1 we saw that performing the
reaction at room temperature was ineffective even after 24
h (entry 2) and that indolylpyranoquinoline 3a could be ob-
tained, but only in 68% yield at 80 °C (entry 3), with a con-
centration of 0.2 M to avoid side-product formation.
Changing DMF for dioxane was slightly better, since the
yields increased steadily from 73% to 86% (entries 4–9). In-
creasing the reaction medium concentration (entries 4 and
5, 0.1 to 0.2 M), did not have a major effect on the yields,
but it permitted a reduction in the reaction time (1 h in-
stead of 2 h). A higher concentration of the reaction medi-
um did not give better results (entry 6, 0.4 M, 75%), but the
factors influencing the yield improvement were the in-
crease of the reaction temperature, from 50 to 80 °C, giving
80% of the desired derivative 3a (entry 7), and also the
amount of nucleophile used (from 3 to 10 equiv, entry 9)
producing 86% of 3a, whereas decreasing the amount (1.5
equiv, entry 8) had almost no effect (77%) compared with
entry 7 (80%). Switching to DCE as the solvent (entries 10–
12) was also promising, since with three equivalents of N-
methylindole, at reflux for one hour at 0.2 M (entry 11), 3a
6d
16a
16b
16c,d
palladium,
or silver.
6d
16d
reaction conditions, and we decided to further adjust the
reaction conditions with N-methylindole as the nucleophile
(
Table 1).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

D
Synthesis
A. Bontemps et al.
Feature
was produced efficiently (83%). This last result was about
the same as for entry 7 performed in dioxane, but DCE was
preferred due to easier reaction media treatment and better
substrate solubilization, and was therefore chosen for the
scope and limitations studies.
Then we examined the reactivity of various nucleo-
philes (NuH) with alkynylquinolines 1a, 1b, and 1p (Scheme
5). Overall, the domino hydroarylation/cycloisomerization
reactions were less efficient compared to when N-meth-
ylindole was used as the nucleophile, since the isolated
yields were modest to good. Nevertheless, a large variation
of the nucleophile was possible, as outlined in Scheme 5,
leading to the 6-endo-dig cyclization products.
Therefore, starting from alkynylquinolines 1a–f
(
Scheme 2), indolylpyranoquinolines 3a–f (Scheme 4) were
obtained efficiently, bearing a phenyl group substituent
3b, quant) or, more interestingly, a variety of alkyl chains:
(
Nu
functionalized (3a, 83%), cyclic (3c, 89%), and possessing a
linear or branched alkyl chain (3d–f, 80–94%). Then, the
methodology was extended to indolylpyranoquinolines
substituted on the quinoline core with an electron-with-
drawing chloro atom (3g–j) or an electron-donating meth-
oxy group (3k–n). The results were compared on the basis
of the formation of four derivatives, in each case bearing a
phenyl or alkyl substituent. We could observe that the pres-
ence of an electron-withdrawing chloro atom had a favor-
able impact on the reaction, since all the indolylpyrano-
quinolines were efficiently formed, whatever the substitu-
tion on the alkynyl unit (3g–j, 93–100%), whereas the pres-
ence of the electron-donating methoxy group (3k–n)
caused a noticeable decrease in the product yields of 15–
AgOTf
O
(10 mol%)
O
N
+
Nu-H
R1
(3 equiv) DCE (0.2 M)
R1
N
R1 = CH OMe (1a)
reflux, 1–24 h
2
C6H5 (1b, 1p)
NH
R = H, 63% 4a
R = Me, 36% 7aa
R
Nu
O
Nu =
N
8a
O
N
66%
N
R = H, 48%
5ab
R
6
a
a series
R = Me, 55%
NH
4b
R = H, 89%
Nu
R
R = Me, 62% 7b
2
9%, the overall yields ranging from 67% to 79%. Finally, in-
O
OMe
Nu =
2ba
dolylpyranobenzoquinolines 3o–r were successfully pre-
pared when containing a CH OMe group (3o, 74%) and a
hexyl chain (3r, 75%), and even more successfully prepared
when containing a phenyl (3p, 90%) or a propyl group (3q,
N
N
9
0%
36%
2
b series
MeO
OMe
6
b
94%).
5
pa
3%
N
Nu
4
N
O
AgOTf
O
OMe
O
N
Nu =
R1
(10 mol%)
2pa
N
23%
+
N
54%
9pa
DCE (0.2 M)
reflux, 1–24 h
R2
R1
O
(
3 equiv)
MeO
OMe
p series
N
R2
R1 = H, OMe, Cl
R2 = aryl, alkyl
Scheme 5 Variation of the nucleophilic species. a Reaction performed
b
in DMF. 5-exo-dig product observed.
N
N
N
Interestingly, the reaction of indole or 1,2,5-trimeth-
ylpyrrole with compound 1a yielded 4a (63%) and 6a (66%),
respectively (Scheme 5). Using the more hindered 2-meth-
ylindole produced compound 7a in lower yield (36%). In
comparison with 1,2,5-trimethylpyrrole, the use of less nu-
cleophilic pyrrole or N-methylpyrrole19 respectively gave
moderate yields of compounds 8a (48%), accompanied with
uncharacterized side products, and 5a (55%) with some 5-
exo-dig product. Gratifyingly, the reactions of alkynylquino-
line 1b, bearing a phenyl substituent on the alkynyl group,
gave much better results with various nucleophiles such as
indole (4b, 89%), 2-methylindole (7b, 62%), and 1,2,5-
trimethylpyrrole (6b, 90%). Using the less nucleophilic
O
O
O
N
R2 Cl
N
R2
O
N
R2
R2
=
R2
=
R2
=
CH2OMe 83% 3a
C6H5 quant 3b
c-Pr 89% 3c
CH2OMe 93% 3g
C6H5 quant. 3h
n-Pr 95% 3i
CH2OMe 67% 3k
C6H5 71% 3l
n-Pr 79% 3m
n-Hex 76% 3n
n-Pr 94% 3d
i-Bu 80% 3e
n-Hex 93% 3j
N
n-Hex 92% 3f
R2
=
CH2OMe 74% 3o
C6H5 90% 3p
O
n-Pr 94% 3q
R2 n-Hex 75% 3r
N
1,3,5-trimethoxybenzene generated arylpyranoquinoline
2
b in a modest 36% yield. Finally, the reactivity of alkynyl-
Scheme 4 Scope and limitations with N-methylindole as the nucleophile
benzoquinoline 1p followed a mixed nucleophilic/hin-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

E
Synthesis
A. Bontemps et al.
Feature
drance scale, with the yields depending on the nature of the
nucleophile, increasing as follows: 3-methylbenzofuran (9p,
Method C: Anhydrous THF (15 mL) and Et N (0.21 mL, 1.50 mmol, 1.5
equiv), previously degassed with bubbling argon for 10 min, were
added to a flask containing the appropriate chlorinated quinoline
3
23%), N-methylpyrrole (5p, 43%), and 1,3,5-trimethoxy-
(
1.00 mmol, 1 equiv), [PdCl (PPh ) ] (49.1 mg, 0.070 mmol, 0.07
2 3 2
benzene (2p, 54%).
equiv), and CuI (57.1 mg, 0.300 mmol, 0.3 equiv) under an argon at-
mosphere. Finally, the alkyne derivative (1.20 mmol, 1.2 equiv) was
added dropwise to the mixture, which was then stirred overnight at
r.t. After completion of the reaction (attested by TLC analysis), the
mixture was filtered through a short pad of silica and Celite and elut-
ed with EtOAc. The crude was concentrated under reduced pressure
and purified by column chromatography (silica gel, various solvent
mixtures).
In conclusion, we have developed an efficient and versa-
tile silver-catalyzed domino hydroarylation/cycloisomeri-
zation reaction of 2-alkynylquinoline-3-carbaldehyde scaf-
folds exhibiting a large variety of substitution on the
alkynyl part (particularly the less studied aliphatic ones),
on the quinoline core, or on the nucleophilic unit. Thanks to
this straightforward AgOTf-catalyzed reaction, numerous
aryl and heteroaryl substituents could be placed on the
pyranoquinoline unit, efficiently generating 22 different in-
dolylpyranoquinolines and 8 more compounds with a pyra-
noquinoline core bearing a pyrrole, a benzofuran, or a 1,3,5-
trimethoxybenzene unit. This simple and efficient proce-
dure opens new perspectives for the generation of key
building blocks in medicinal chemistry.
Method D: Anhydrous THF (12 mL) and Et N (7.0 mL, 12.0 mmol, 3
3
equiv), previously degassed with bubbling argon for 10 min, were
added to a sealed tube containing the appropriate chlorinated quino-
line (4.00 mmol, 1 equiv), [PdCl (PPh ) ] (140 mg, 0.200 mmol, 0.05
2
3 2
equiv), and CuI (38.1 mg, 0.200 mmol, 0.05 equiv) under an argon at-
mosphere. Finally, the alkyne derivative (6.00 mmol, 1.5 equiv) was
added dropwise to the mixture, which was then heated at 60 °C for 3
h under microwave irradiation. After completion of the reaction (at-
tested by TLC analysis), the mixture was filtered through a short pad
of basic alumina and Celite and eluted with CH Cl . The crude was
2
2
concentrated under reduced pressure and purified by column chro-
matography (silica gel, various solvent mixtures).
All reactions were conducted under an inert atmosphere. Compounds
8a
1a, 1b, 1c, 1k, and 1l are known derivatives. Flash chromatography
was performed by using 40–63 μm silica. Analytical TLC was carried
out on Merck pre-coated GF 254 silica gel plates. Melting points were
measured on a Stuart SMP3 melting point apparatus and are uncor-
2
-(Pent-1-ynyl)quinoline-3-carbaldehyde (1d)
The crude product obtained by method A was purified by column
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
:2); this afforded a light yellow solid; yield: 88 mg (46%); mp 54–
6 °C.
1
13
3
rected. H and C NMR spectra were recorded on a Bruker AC 300 or
8
5
AC 400 spectrometer by using CDCl or DMSO-d as both solvent and
3
6
internal standard. Coupling constants (J) are given in Hz. IR spectra
were obtained on a Perkin-Elmer 1600 spectrophotometer. HRMS
was performed on a Q-TOF Waters spectrometer (UMR-8638, Paris,
France) and on an ESI-MicrOTOFQ-II Bruker spectrometer (UMR-
IR (neat): 3057, 2958, 2850, 2215, 1688, 1583, 1551, 1489, 1454,
1370, 1155, 1111, 917, 786, 754, 710 cm
–1
.
1
H NMR (400 MHz, CDCl ): δ = 10.70 (s, 1 H), 8.70 (s, 1 H), 8.12 (d,
3
5246, Lyon, France).
J = 8.5 Hz, 1 H), 7.94 (d, J = 8.1 Hz, 1 H), 7.84 (ddd, J = 8.5, 6.9, 1.5 Hz, 1
H), 7.60 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 H), 2.57 (t, J = 7.1 Hz, 2 H), 1.75
(sext, J = 7.3 Hz, 2 H), 1.11 (t, J = 7.4 Hz, 3 H).
13
2-Alkynylquinoline-3-carbaldehydes 1 by Sonogashira Coupling;
General Procedures
C NMR (100 MHz, CDCl ): δ = 191.4 (CH), 150.3 (C), 144.6 (C), 136.9
3
Method A: Anhydrous DMF (1 mL) and Et N (0.56 mL, 4.00 mmol, 4
3
(CH), 133.0 (CH), 129.7 (CH), 129.4 (CH), 128.9 (C), 128.1 (CH), 126.4
equiv), previously degassed with bubbling argon for 10 min, were
added to a flask containing the appropriate chlorinated quinoline
(C), 98.1 (C), 77.8 (C), 21.9 (CH ), 21.8 (CH ), 13.9 (CH ).
2 2 3
HRMS (ESI): m/z [M + H]+ calcd for C15H14NO: 224.1075; found:
(
1.00 mmol, 1 equiv), [PdCl (PPh ) ] (35.1 mg, 0.050 mmol, 0.05
2 3 2
224.1076.
equiv), and CuI (9.5 mg, 0.050 mmol, 0.05 equiv) under an argon at-
mosphere. Finally, the appropriate alkyne derivative (1.20 mmol, 1.2
equiv) was added dropwise to the mixture, which was then stirred
overnight at r.t. After completion of the reaction (attested by TLC
analysis), the mixture was filtered through a short pad of silica and
Celite and eluted with EtOAc. The crude was concentrated under re-
duced pressure and purified by column chromatography (silica gel,
various solvent mixtures).
2-(4-Methylpent-1-ynyl)quinoline-3-carbaldehyde (1e)
The crude product obtained by method A was purified by column
chromatography (silica gel, cyclohexane–EtOAc, 9:1); this afforded a
brown solid; yield: 189 mg (80%); mp 120–125 °C.
IR (neat): 3054, 2957, 2929, 2849, 2220, 1693, 1654, 1612, 1581,
1550, 1489, 1453, 1383, 1369, 1153, 1112, 915, 786, 760, 753, 712
–1
Method B: Anhydrous THF (15 mL) and Et N (0.21 mL, 1.50 mmol, 1.5
cm
1
.
3
equiv), previously degassed with bubbling argon for 10 min, were
added to a flask containing the appropriate iodinated quinoline (1.00
H NMR (300 MHz, CDCl ): δ = 10.70 (s, 1 H), 8.69 (s, 1 H), 8.12 (d,
3
J = 8.6 Hz, 1 H), 7.93 (d, J = 7.9 Hz, 1 H), 7.83 (ddd, J = 8.6, 6.9, 1.2 Hz, 1
H), 7.59 (ddd, J = 7.9, 6.9, 0.7 Hz, 1 H), 2.49 (d, J = 6.6 Hz, 2 H), 2.12–
mmol, 1 equiv), [PdCl (PPh ) ] (49.1 mg, 0.070 mmol, 0.07 equiv), and
2
3 2
CuI (57.1 mg, 0.300 mmol, 0.3 equiv) under an argon atmosphere. Fi-
nally, the alkyne derivative (1.20 mmol, 1.2 equiv) was added drop-
wise to the mixture, which was then stirred overnight at r.t. After
completion of the reaction (attested by TLC analysis), the mixture was
filtered through a short pad of silica and Celite and eluted with EtOAc.
The crude was concentrated under reduced pressure and purified by
column chromatography (silica gel, various solvent mixtures).
1
.98 (m, 1 H), 1.10 (d, J = 6.7 Hz, 6 H).
13
C NMR (75 MHz, CDCl ): δ = 191.4 (CH), 150.2 (C), 144.6 (C), 137.0
3
(
(
CH), 133.0 (CH), 129.7 (CH), 129.3 (CH), 128.9 (C), 128.1 (CH), 126.4
C), 97.3 (C), 78.5 (C), 29.0 (CH ), 28.1 (CH), 22.4 (2 × CH ).
2
3
HRMS (CI): m/z [M + H]+ calcd for C16H16NO: 238.1226; found:
38.1236.
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

F
Synthesis
A. Bontemps et al.
Feature
2
-(Oct-1-ynyl)quinoline-3-carbaldehyde (1f)
IR (neat): 3050, 2965, 2860, 2216, 1686, 1608, 1583, 1547, 1482,
–1
1467, 1368, 1066, 871, 845, 807, 754 cm .
The crude product obtained by method A was purified by column
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
1
3
H NMR (400 MHz, CDCl ): δ = 10.65 (s, 1 H), 8.65 (s, 1 H), 8.10 (s, 1
3
6
5
:4); this afforded a light yellow solid; yield: 164 mg (72%); mp 50–
2 °C.
H), 7.86 (d, J = 8.7 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 2.57 (t, J = 7.1 Hz, 2
H), 1.75 (sext, J = 7.2 Hz, 2 H), 1.10 (t, J = 7.4 Hz, 3 H).
1
3
IR (neat): 3073, 2930, 2854, 2234, 1691, 1584, 1552, 1491, 1469,
C NMR (100 MHz, CDCl ): δ = 190.9 (CH), 150.41 (C), 145.6 (C),
3
–1
1452, 1372, 1157, 1112, 960, 915, 783, 745, 711 cm
.
139.3 (C), 136.7 (CH), 130.8 (CH), 129.2 (CH), 129.0 (C), 128.3 (CH),
124.8 (C), 99.2 (C), 77.38 (C), 21.8 (CH ), 21.8 (CH ), 13.9 (CH ).
1
H NMR (400 MHz, CDCl ): δ = 10.69 (s, 1 H), 8.69 (s, 1 H), 8.11 (d,
2
2
3
3
+
J = 8.5 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.83 (ddd, J = 8.5, 7.0, 1.5 Hz, 1
H), 7.59 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 H), 2.58 (t, J = 7.2 Hz, 2 H), 1.71
HRMS (ESI): m/z [M + Na] calcd for C15H12ClNONa: 280.0505; found:
280.0509.
(quin, J = 7.3 Hz, 2 H), 1.55–1.45 (m, 2 H), 1.38–1.29 (m, 4 H), 0.90 (t,
J = 6.8 Hz, 3 H).
7
-Chloro-2-(oct-1-ynyl)quinoline-3-carbaldehyde (1j)
13
C NMR (100 MHz, CDCl ): δ = 191.4 (CH), 150.3 (C), 144.7 (C), 136.9
3
The crude product obtained by method A was purified by column
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
95:5); this afforded a pale yellow solid; yield: 226 mg (76%); mp 77–
79 °C.
(CH), 133.0 (CH), 129.7 (CH), 129.3 (CH), 128.9 (C), 128.0 (CH), 126.4
3
(C), 98.4 (C), 77.6 (C), 31.5 (CH ), 28.9 (CH ), 28.3 (CH ), 22.7 (CH ),
2
2
2
2
1
9.8 (CH ), 14.2 (CH ).
2
3
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NONa: 288.1364; found:
IR (neat): 3046, 2929, 2857, 2229, 1686, 1606, 1582, 1547, 1471,
288.1363.
–1
1368, 1065, 932, 875, 847, 810, 756, 708 cm
.
1
H NMR (400 MHz, CDCl ): δ = 10.66 (s, 1 H), 8.66 (s, 1 H), 8.10 (s, 1
3
7
-Chloro-2-(3-methoxyprop-1-ynyl)quinoline-3-carbaldehyde
H), 7.87 (d, J = 8.7 Hz, 1 H), 7.54 (dd, J = 8.8, 2.1 Hz, 1 H), 2.59 (t, J = 7.1
Hz, 2 H), 1.72 (quin, J = 7.1 Hz, 2 H), 1.57–1.45 (m, 2 H), 1.41–1.29 (m,
(1g)
The crude product obtained by method A was purified by column
4 H), 1.00–0.85 (m, 3 H).
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
13
3
C NMR (100 MHz, CDCl ): δ = 191.0 (CH), 150.5 (C), 145.7 (C), 139.3
3
6:4); this afforded a beige solid; yield: 207 mg (81%); mp 127–129 °C.
(C), 136.7 (CH), 130.9 (CH), 129.2 (CH), 129.0 (C), 128.3 (CH), 124.8
IR (neat): 3049, 2949, 2853, 2233, 1693, 1608, 1583, 1548, 1479,
(C), 99.4 (C), 77.4 (C), 31.4 (CH ), 28.9 (CH ), 28.3 (CH ), 22.7 (CH ),
19.9 (CH ), 14.2 (CH ).
2 3
2
2
2
2
–1
1365, 1095, 1069, 897, 846, 756 cm
.
1
+
H NMR (400 MHz, CDCl ): δ = 10.66 (s, 1 H), 8.70 (s, 1 H), 8.13 (s, 1
HRMS (ESI): m/z [M + Na] calcd for C18H18ClNONa: 322.0975; found:
3
H), 7.90 (d, J = 8.7 Hz, 1 H), 7.59 (dd, J = 8.7, 1.9 Hz, 1 H), 4.48 (s, 2 H),
322.0977.
3.53 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 190.1 (CH), 150.2 (C), 144.2 (C), 139.4
7-Methoxy-2-(pent-1-ynyl)quinoline-3-carbaldehyde (1m)
3
(
C), 136.9 (CH), 130.7 (CH), 129.5 (CH), 128.9 (C), 128.3 (CH), 124.9
The crude product obtained by method B was purified by column
(C), 92.4 (C), 82.3 (C), 60.3 (CH ), 58.3 (CH ).
2
3
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
3
+
HRMS (ESI): m/z [M + Na] calcd for C14H10ClNO Na: 282.0298; found:
2
75:25); this afforded a yellow solid; yield: 89 mg (62%); mp 104–
106 °C.
2
82.0293.
IR (neat): 3016, 2960, 2860, 2231, 1685, 1614, 1585, 1496, 1446,
7-Chloro-2-(phenylethynyl)quinoline-3-carbaldehyde (1h)
1388, 1374, 1310, 1219, 1134, 1021, 917, 839, 827, 762, 706 cm–1
.
1
The crude product obtained by method C was purified by column
H NMR (400 MHz, CDCl ): δ = 10.63 (s, 1 H), 8.59 (s, 1 H), 7.79 (d,
3
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
J = 9.0 Hz, 1 H), 7.41 (d, 1 H), 7.22 (dd, J = 9.0, 2.3 Hz, 1 H), 3.96 (s, 3
H), 2.55 (t, J = 7.1 Hz, 2 H), 1.74 (sext, J = 7.3 Hz, 2 H), 1.10 (t, J = 7.4 Hz,
3
9:1); this afforded a white solid; yield: 232 mg (79%); mp 178–180 °C.
3
13
H).
IR (neat): 3049, 2860, 2207, 1692, 1609, 1585, 1545, 1480, 1382,
–1
1370, 1289, 1146, 1065, 933, 881, 867, 806, 753, 744, 681 cm
.
C NMR (100 MHz, CDCl ): δ = 191.24 (CH), 163.7 (C), 152.4 (C),
3
1
145.3 (C), 136.2 (CH), 130.8 (CH), 127.4 (C), 121.8 (C), 121.7 (CH),
07.1 (CH), 97.8 (C), 77.8 (C), 55.9 (CH ), 21.9 (CH ), 21.8 (CH ), 13.9
H NMR (400 MHz, CDCl ): δ = 10.78 (s, 1 H), 8.72 (s, 1 H), 8.16 (s, 1
3
1
H), 7.90 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 7.4 Hz, 2 H), 7.58 (d, J = 8.7 Hz,
1
3
2
2
(
CH3).
H), 7.52–7.38 (m, 3 H).
+
13
HRMS (ESI): m/z [M + Na] calcd for C16H15NO Na: 276.1000; found:
2
C NMR (100 MHz, CDCl ): δ = 190.5 (CH), 150.6 (C), 145.1 (C), 139.5
3
276.0990.
(C), 137.0 (CH), 132.5 (2 × CH), 130.9 (CH), 130.2 (CH), 129.5 (CH),
1
8
29.1 (C), 128.8 (2 × CH), 128.5 (CH), 124.9 (C), 121.3 (C), 96.5 (C),
5.4 (C).
7-Methoxy-2-(oct-1-ynyl)quinoline-3-carbaldehyde (1n)
HRMS (ESI): m/z [M + H]+ calcd for C18H11ClNO: 292.0524; found:
The crude product obtained by method B was purified by column
2
92.0523.
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et
:2); this afforded an ochre solid; yield: 135 mg (80%); mp 61–63 °C.
IR (neat): 2933, 2855, 2225, 1689, 1620, 1582, 1495, 1445, 1388,
3
N), 1:0 to
8
7
-Chloro-2-(pent-1-ynyl)quinoline-3-carbaldehyde (1i)
–
1
1375, 1309, 1227, 1134, 1014, 875, 842, 814, 763, 708 cm .
The crude product obtained by method A was purified by column
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
1
3
H NMR (400 MHz, CDCl ): δ = 10.63 (s, 1 H), 8.60 (s, 1 H), 7.80 (d,
3
8
1
:2); this afforded a pale yellow solid; yield: 120 mg (47%); mp 109–
10 °C.
J = 9.0 Hz, 1 H), 7.42 (s, 1 H), 7.23 (d, J = 8.9 Hz, 1 H), 3.96 (s, 3 H), 2.57
(t, J = 7.1 Hz, 2 H), 1.71 (quin, J = 7.1 Hz, 2 H), 1.55–1.44 (m, 2 H),
1.39–1.29 (m, 4 H), 0.97–0.87 (m, 3 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

G
Synthesis
A. Bontemps et al.
Feature
13
C NMR (100 MHz, CDCl ): δ = 191.3 (CH), 163.7 (C), 152.5 (C), 145.4
2-(Oct-1-ynyl)benzo[h]quinoline-3-carbaldehyde (1r)
3
(
C), 136.2 (CH), 130.8 (CH), 127.5 (C), 121.8 (C), 121.7 (CH), 107.2
The crude product obtained by method A was purified by column
(CH), 98.1 (C), 77.7 (C), 55.9 (CH ), 31.5 (CH ), 28.9 (CH ), 28.4 (CH ),
3
2
2
2
chromatography (silica gel, cyclohexane–EtOAc (0.5% Et N), 1:0 to
3
2
2.7 (CH ), 19.8 (CH ), 14.2 (CH ).
2 2 3
95:5); this afforded a beige solid; yield: 171 mg (83%); mp 72–74 °C.
+
HRMS (ESI): m/z [M + Na] calcd for C19H NO Na: 318.1470; found:
3
21
2
IR (neat): 3051, 2930, 2849, 2227, 1687, 1579, 1558, 1486, 1402,
18.1465.
–1
1377, 1327, 1137, 993, 935, 823, 800, 749, 715 cm
.
1
H NMR (400 MHz, CDCl ): δ = 10.74 (s, 1 H), 9.39–9.30 (m, 1 H), 8.65
3
2-(3-Methoxyprop-1-ynyl)benzo[h]quinoline-3-carbaldehyde (1o)
(s, 1 H), 7.93–7.87 (m, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.79–7.70 (m, 3
The crude product obtained by method D was purified by column
chromatography on basic alumina gel (CH Cl –MeOH, 1:0 to 9:1); this
H), 2.63 (t, J = 7.1 Hz, 2 H), 1.75 (quin, J = 7.2 Hz, 2 H), 1.63–1.49 (m, 2
H), 1.37 (s, 4 H), 0.98–0.90 (m, 3 H).
2
2
afforded a light yellow solid; yield: 720 mg (65%); mp 147–149 °C.
13
C NMR (100 MHz, CDCl ): δ = 191.7 (CH), 149.7 (C), 144.0 (C), 135.5
3
IR (neat): 3056, 2930, 2823, 2223, 1687, 1578, 1558, 1488, 1442,
(CH), 135.0 (C), 130.6 (C), 130.0 (CH), 129.7 (C), 129.4 (CH), 128.1
(CH), 127.7 (CH), 126.0 (CH), 125.7 (CH), 125.0 (C), 98.1 (C), 78.0 (C),
–1
1402, 1382, 1363, 1328, 1132, 1096, 917, 897, 817, 803, 748 cm .
1
31.5 (CH ), 29.0 (CH ), 28.5 (CH ), 22.7 (CH ), 20.0 (CH ), 14.2 (CH ).
HRMS (ESI): m/z [M + Na]+ calcd for C22H21NONa: 338.1521; found:
H NMR (400 MHz, CDCl ): δ = 10.74 (s, 1 H), 9.40–9.29 (m, 1 H), 8.68
2 2 2 2 2 3
3
(s, 1 H), 7.96–7.89 (m, 1 H), 7.87 (d, J = 8.9 Hz, 1 H), 7.83–7.71 (m, 3
H), 4.53 (s, 2 H), 3.57 (s, 3 H).
338.1515.
13
C NMR (100 MHz, CDCl ): δ = 190.9 (CH), 149.6 (C), 142.55 (C),
3
1
1
8
35.7 (CH), 135.01 (C), 130.5 (C), 130.1 (CH), 129.9 (CH), 129.7 (C),
28.1 (CH), 127.9 (CH), 126.0 (CH), 125.6 (CH), 125.4 (C), 91.4 (C),
Silver-Catalyzed Domino Hydroarylation–Cycloisomerization;
General Procedure
3.2 (C), 60.6 (CH ), 58.4 (CH ).
2
3
The nucleophilic moiety NuH (3 equiv) and AgOTf (10 mol%) were
added to a 0.2 M solution or suspension of the appropriate ortho-
alkynylquinolinecarbaldehyde (1 equiv) in anhyd distilled DCE (1 mL)
under argon. The mixture was stirred at reflux temperature and the
reaction was monitored by TLC analysis until completion (1–24 h).
Then, the reaction mixture was filtered through a short pad of silica
and Celite and eluted with a CH Cl –MeOH mixture (90:10). The
+
HRMS (ESI): m/z [M + Na] calcd for C18H13NO Na: 298.0844; found:
2
298.0830.
2
-(Phenylethynyl)benzo[h]quinoline-3-carbaldehyde (1p)
The crude product obtained by method D was purified by column
chromatography (silica gel, cyclohexane–EtOAc (1% Et N), 95:5 to
2
2
3
crude was concentrated under reduced pressure and purified by col-
umn chromatography (silica gel, various solvent mixtures).
8
1
:2); this afforded a light yellow solid; yield: 940 mg (76%); mp 121–
23 °C.
IR (neat): 3056, 2850, 2209, 1686, 1578, 1556, 1493, 1443, 1381,
3
-Phenyl-1-(2,4,6-trimethoxyphenyl)-1H-pyrano[4,3-b]quinoline
–1
1334, 1168, 995, 925, 817, 802, 743, 680 cm .
(2b)
1
H NMR (400 MHz, CDCl ): δ = 10.84 (s, 1 H), 9.43–9.35 (m, 1 H), 8.69
3
The reaction was carried out at 50 °C in DMF instead of DCE. The
crude product was purified by column chromatography (silica gel, cy-
clohexane–EtOAc, 1:0 to 8:2); this afforded a yellow solid; yield: 31
mg (36%); mp 191–193 °C.
(s, 1 H), 7.94–7.89 (m, 1 H), 7.86 (d, J = 8.9 Hz, 1 H), 7.82–7.69 (m, 5
H), 7.51–7.39 (m, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 191.2 (CH), 149.7 (C), 143.3 (C), 135.7
3
(
1
CH), 135.0 (C), 132.4 (2 × CH), 130.6 (C), 130.1 (CH), 129.9 (CH),
29.8 (CH), 129.7 (C), 128.8 (2 × CH), 128.1 (CH), 127.9 (CH), 126.1
IR (neat): 2970, 2899, 1608, 1417, 1226, 1123 cm–1
.
1
H NMR (300 MHz, CDCl ): δ = 7.96 (d, J = 8.0 Hz, 1 H), 7.83–7.78 (m, 2
3
CH), 125.7 (CH), 125.2 (C), 121.8 (C), 95.4 (C), 86.2 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C22H13NONa: 330.0895; found:
3
H), 7.61–7.51 (m, 2 H), 7.40–7.26 (m, 5 H), 7.10 (s, 1 H), 6.74 (s, 1 H),
6.25 (s, 2 H), 3.89 (s, 3 H), 3.71 (s, 6 H).
30.0889.
13
C NMR (75 MHz, CDCl ): δ = 162.1 (C), 160.7 (C), 160.4 (2 × C), 152.5
3
(
C), 147.8 (C), 134.4 (C), 129.6 (CH), 129.2 (CH), 128.9 (CH), 128.3 (2 ×
2
-(Pent-1-ynyl)benzo[h]quinoline-3-carbaldehyde (1q)
CH), 128.2 (CH), 127.9 (C), 127.7 (C), 127.4 (CH), 125.8 (2 × CH), 124.8
CH), 107.8 (C), 101.0 (CH), 91.2 (2 × CH), 72.9 (CH), 56.0 (2 × CH3),
The crude product obtained by method A was purified by column
chromatography (silica gel, CH Cl –PE (0.5% Et N), 3:7 to 6:4); this af-
forded a beige solid; yield: 146 mg (82%); mp 105–107 °C.
(
2
2
3
55.4 (CH3).
HRMS (CI): m/z [M + H]+ calcd for C27H24NO : 426.1700; found:
4
4
IR (neat): 3051, 2960, 2847, 2230, 1686, 1580, 1558, 1499, 1486,
26.1689.
–1
1402, 1377, 1327, 1136, 984, 934, 823, 800, 749, 739, 714 cm .
1
H NMR (400 MHz, CDCl ): δ = 10.74 (s, 1 H), 9.39–9.30 (m, 1 H), 8.64
10-Phenyl-8-(2,4,6-trimethoxyphenyl)-8H-benzo[h]pyrano[4,3-
b]quinoline (2p)
3
(s, 1 H), 7.92–7.86 (m, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.79–7.69 (m, 3
H), 2.61 (t, J = 7.0 Hz, 2 H), 1.79 (sext, J = 7.2, 6.6 Hz, 2 H), 1.14 (t,
J = 7.3 Hz, 3 H).
The reaction was carried out at 80 °C in DMF instead of DCE, and at
0.5 M reaction media concentration. The crude product was purified
13
C NMR (100 MHz, CDCl ): δ = 191.6 (CH), 149.6 (C), 144.0 (C), 135.5
by column chromatography (silica gel, cyclohexane–EtOAc, 1:0 to
1:1); this afforded an orange solid; yield: 128 mg (54%); mp 227–
229 °C.
3
(
(
CH), 135.0 (C), 130.6 (C), 130.0 (CH), 129.7 (C), 129.4 (CH), 128.0
CH), 127.7 (CH), 126.0 (CH), 125.7 (CH), 125.0 (C), 97.8 (C), 78.2 (C),
2
2.0 (CH ), 21.9 (CH ), 13.9 (CH ).
2 2 3
IR (neat): 3048, 2940, 2841, 1592, 1490, 1451, 1419, 1407, 1215,
HRMS (ESI): m/z [M + H]+ calcd for C19H16NO: 274.1232; found:
74.1224.
1201, 1156, 1150, 1121, 1040, 1025, 810, 767, 746, 687 cm
–1
.
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

H
Synthesis
A. Bontemps et al.
Feature
1
1
H NMR (400 MHz, DMSO-d ): δ = 9.17 (d, J = 8.0 Hz, 1 H), 7.97 (d,
H NMR (400 MHz, CDCl ): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 7.9
6
3
J = 7.2 Hz, 1 H), 7.85–7.77 (m, 2 H), 7.78–7.65 (m, 4 H), 7.49–7.40 (m,
Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.51 (s, 1 H),
7.34 (t, J = 6.2 Hz, 2 H), 7.31–7.26 (m, 1 H), 7.14 (t, J = 7.3 Hz, 1 H),
6.78 (s, 1 H), 6.60 (s, 1 H), 6.18 (s, 1 H), 3.73 (s, 3 H), 1.68–1.57 (m, 1
H), 1.01–0.91 (m, 1 H), 0.81–0.70 (m, 2 H), 0.70–0.59 (m, 1 H).
4
H), 7.06 (s, 1 H), 6.90 (s, 1 H), 6.41 (s, 2 H), 3.87 (s, 3 H), 3.69 (s, 6 H).
13
C NMR (100 MHz, DMSO-d ): δ = 162.1 (C), 160.0 (C), 159.1 (2 × C),
6
150.5 (C), 144.7 (C), 133.6 (C), 133.3 (C), 130.5 (C), 129.8 (CH), 129.3
13
(
1
(
CH), 128.6 (2 × CH), 127.9 (CH), 127.8 (CH), 127.3 (C), 126.6 (CH),
25.8 (CH), 125.7 (CH), 125.3 (2 × CH), 124.7 (C), 123.8 (CH), 106.4
C), 101.3 (CH), 91.7 (2 × CH), 72.5 (CH), 56.0 (2 × CH ), 55.4 (CH ).
C NMR (100 MHz, CDCl ): δ = 165.8 (C), 152.3 (C), 148.3 (C), 137.6
3
(C), 131.4 (CH), 129.5 (2 × CH), 128.4 (CH), 127.8 (CH), 127.2 (C),
126.7 (C), 125.6 (C), 124.8 (CH), 122.4 (CH), 120.2 (CH), 120.0 (CH),
3
3
HRMS (ESI): m/z [M + H]+ calcd for C31H26NO : 476.1862; found:
112.9 (C), 109.7 (CH), 101.2 (CH), 74.7 (CH), 33.0 (CH
3
), 14.8 (CH), 6.5
4
(
2 × CH2).
476.1855.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N O: 353.1654; found:
2
353.1642.
3-(Methoxymethyl)-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-
b]quinoline (3a)
1
-(1-Methyl-1H-indol-3-yl)-3-propyl-1H-pyrano[4,3-b]quinoline (3d)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 8:2 to 6:4); this afforded an orange solid;
yield: 59 mg (83%); mp 81–83 °C.
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 7:3); this afforded an orange oil; yield:
6
7 mg (94%).
IR (neat): 3051, 2932, 2823, 1638, 1615, 1559, 1476, 1463, 1424,
–1
1303, 1197, 1107, 993, 968, 818, 754, 736 cm .
IR (neat): 3058, 2961, 2931, 2873, 1612, 1557, 1465, 1424, 1371,
1152, 976, 907, 727 cm .
–
1
1
H NMR (400 MHz, DMSO-d ): δ = 7.90 (d, J = 8.5 Hz, 1 H), 7.75 (d,
6
1
J = 8.1 Hz, 1 H), 7.70 (s, 1 H), 7.65 (tt, J = 8.2, 1.5 Hz, 1 H), 7.51 (d,
J = 8.0 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.40 (tt, J = 8.2, 1.4 Hz, 1 H),
H NMR (400 MHz, CDCl ): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.0
3
Hz, 1 H), 7.61 (ddd, J = 8.4, 6.8, 1.5 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H),
7.51 (s, 1 H), 7.38–7.27 (m, 3 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.92 (s, 1 H),
6.64 (s, 1 H), 6.11 (s, 1 H), 3.77 (s, 3 H), 2.24 (t, J = 7.5 Hz, 2 H), 1.64–
1.50 (m, 7.1 Hz, 2 H), 0.87 (t, J = 7.4 Hz, 3 H).
7
.25 (s, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 6.85 (s, 1
H), 6.22 (s, 1 H), 3.99 (d, J = 14.1 Hz, 1 H), 3.92 (d, J = 14.1 Hz, 1 H),
3
.77 (s, 3 H), 3.24 (s, 3 H).
13
13
C NMR (100 MHz, DMSO-d ): δ = 160.5 (C), 150.6 (C), 147.5 (C),
C NMR (100 MHz, CDCl ): δ = 167.7 (C), 151.7 (C), 146.3 (C), 137.7
6
3
1
1
1
5
37.1 (C), 131.3 (CH), 130.3 (CH), 129.5 (CH), 128.0 (CH), 127.9 (CH),
27.0 (C), 125.9 (C), 125.8 (C), 125.3 (CH), 121.6 (CH), 119.7 (CH),
19.3 (CH), 111.8 (C), 110.2 (CH), 103.2 (CH), 74.3 (CH), 70.7 (CH2),
7.8 (CH ), 32.5 (CH ).
(C), 132.7 (CH), 130.2 (CH), 129.6 (CH), 127.8 (CH), 127.2 (CH), 127.1
(C) 126.6 (C), 125.7 (C), 125.5 (CH), 122.5 (CH), 120.4 (CH), 120.1
(CH), 112.4 (C), 109.8 (CH), 101.7 (CH), 74.9 (CH), 36.7 (CH ), 33.1
2
(CH ), 20.1 (CH ), 13.7 (CH ).
3
3
3
2
3
+
HRMS (ESI): m/z [M + H]+ calcd for C24H23N O: 355.1810; found:
HRMS (ESI): m/z [M + Na] calcd for C23H20N O Na: 379.1422; found:
2
2
2
379.1430.
355.1809.
1-(1-Methyl-1H-indol-3-yl)-3-phenyl-1H-pyrano[4,3-b]quinoline
3-Isobutyl-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-b]quino-
(3b)
line (3e)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 9:1 to 6:4); this afforded an orange oil (78
mg, quant).
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 6:4); this afforded a yellow oil; yield:
59 mg (80%).
IR (neat): 3057, 2932, 1675, 1609, 1576, 1553, 1492, 1468, 1448,
IR (neat): 3052, 2955, 2927, 2868, 1632, 1615, 1558, 1495, 1463,
–1
–1
1364, 1235, 1221, 1047, 907, 729, 690 cm
.
1422, 1304, 1152, 980, 907, 852, 816, 803, 752, 739, 729 cm
.
1
1
H NMR (300 MHz, CDCl ): δ = 8.07 (d, J = 8.4 Hz, 1 H), 7.83–7.74 (m, 3
H NMR (300 MHz, CDCl ): δ = 8.00 (d, J = 8.2 Hz, 1 H), 7.69–7.48 (m, 4
3
3
H), 7.70–7.56 (m, 3 H), 7.42–7.26 (m, 6 H), 7.17 (t, J = 7.6 Hz, 1 H), 6.93
H), 7.40–7.27 (m, 3 H), 7.12 (t, J = 7.4 Hz, 1 H), 6.93 (s, 1 H), 6.63 (s, 1
H), 6.12 (s, 1 H), 3.77 (s, 3 H), 2.23–2.07 (m, 2 H), 2.00–1.85 (m, 1 H),
0.93 (d, J = 6.6 Hz, 3 H), 0.80 (d, J = 6.6 Hz, 3 H).
(
s, 1 H), 6.89 (s, 1 H), 6.85 (s, 1 H), 3.74 (s, 3 H).
13
C NMR (75 MHz, CDCl ): δ = 159.9 (C), 152.2 (C), 148.1 (C), 137.6 (C),
3
13
134.1 (C), 131.8 (CH), 130.0 (CH), 129.8 (CH), 129.8 (CH), 128.5 (2 ×
C NMR (75 MHz, CDCl ): δ = 165.1 (C), 152.3 (C), 148.1 (C), 137.6 (C),
3
CH), 128.3 (CH), 127.9 (CH), 127.5 (C), 126.7 (C), 126.2 (C), 126.1 (2 ×
CH), 125.4 (CH), 122.4 (CH), 120.3 (CH), 120.0 (CH), 112.5 (C), 109.8
131.7 (CH), 129.6 (CH), 129.5 (CH), 128.3 (CH), 127.8 (CH), 127.4 (C),
126.6 (C), 125.7 (C), 125.0 (CH), 122.3 (CH), 120.5 (CH), 120.0 (CH),
112.6 (C), 109.7 (CH), 103.9 (CH), 74.8 (CH), 44.0 (CH ), 33.0 (CH ),
(
CH), 102.1 (CH), 74.9 (CH), 33.0 (CH3).
2
3
HRMS (ESI): m/z [M + H]+ calcd for C27H21N O: 389.1654; found:
26.5 (CH), 22.6 (CH
HRMS (ESI): m/z [M + H]+ calcd for C25H25N O: 369.1967; found:
3
), 22.3 (CH ).
3
2
389.1667.
2
369.1961.
3-Cyclopropyl-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-b]quin-
oline (3c)
3-Hexyl-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-b]quinoline
3f)
(
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 7:3); this afforded a pale yellow solid;
yield: 62 mg (89%); mp 189–190 °C.
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 6:4); this afforded a brownish oil;
yield: 73 mg (92%).
IR (neat): 3047, 2923, 2851, 1611, 1603, 1557, 1493, 1477, 1418,
–1
1304, 1286, 1053, 1028, 965, 949, 809, 798, 752, 740 cm
.
IR (neat): 3059, 2954, 2926, 2856, 1611, 1466, 1371, 1152, 1093, 980,
–1
9
08, 730 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

I
Synthesis
A. Bontemps et al.
Feature
1
1
H NMR (400 MHz, CDCl ): δ = 8.01 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 7.9
H NMR (400 MHz, CDCl ): δ = 8.03 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H),
3
3
Hz, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 7.57–7.52 (m, 2 H), 7.35 (t, J = 7.9 Hz,
7.48 (s, 1 H), 7.45 (d, J = 8.7 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 1 H), 7.31–7.27
2
(
H), 7.29 (d, J = 7.3 Hz, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 6.86 (s, 1 H), 6.65
s, 1 H), 6.14 (s, 1 H), 3.75 (s, 3 H), 2.33–2.19 (m, 2 H), 1.50 (quin,
J = 7.2 Hz, 2 H), 1.29–1.04 (m, 6 H), 0.82 (t, J = 6.8 Hz, 3 H).
(m, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.96 (s, 1 H), 6.61 (s, 1 H), 6.18 (s, 1
H), 3.79 (s, 3 H), 2.27 (t, J = 7.5 Hz, 2 H), 1.58 (sext, J = 7.1 Hz, 2 H), 0.88
(t, J = 7.4 Hz, 3 H).
13
13
C NMR (100 MHz, CDCl ): δ = 166.3 (C), 152.1 (C), 147.7 (C), 137.7
C NMR (100 MHz, CDCl ): δ = 168.3 (C), 152.6 (C), 146.9 (C), 137.7
3
3
(
(
(
(
C), 131.9 (CH), 129.7 (CH), 129.6 (CH), 128.1 (CH), 127.8 (CH), 127.3
C), 126.6 (C), 125.7 (C), 125.1 (CH), 122.4 (CH), 120.5 (CH), 120.0
(C), 136.0 (C), 132.4 (CH), 129.7 (CH), 129.0 (CH), 126.4 (C), 126.3 (2 ×
CH), 125.9 (C), 125.5 (C), 122.5 (CH), 120.4 (CH), 120.1 (CH), 112.0 (C),
109.8 (CH), 101.6 (CH), 75.0 (CH), 36.7 (CH ), 33.1 (CH ), 20.1 (CH ),
CH), 112.8 (C), 109.7 (CH), 102.6 (CH), 74.8 (CH), 34.6 (CH ), 33.0
2
2
3
2
CH ), 31.6 (CH ), 28.8 (CH ), 26.6 (CH ), 22.7 (CH ), 14.2 (CH ).
13.7 (CH3).
3
2
2
2
2
3
HRMS (ESI): m/z [M + H]+ calcd for C27H29N O: 397.2280; found:
HRMS (ESI): m/z [M + H]+ calcd for C24H22ClN O: 389.1415; found:
2
2
397.2272.
389.1409.
7
-Chloro-3-(methoxymethyl)-1-(1-methyl-1H-indol-3-yl)-1H-
7-Chloro-3-hexyl-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-
b]quinoline (3j)
pyrano[4,3-b]quinoline (3g)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 75:25); this afforded a brownish oil;
yield: 73 mg (93%).
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 9:1); this afforded a white solid; yield:
80 mg (93%); mp 116–118 °C.
IR (neat): 3057, 2915, 2805, 1641, 1610, 1596, 1558, 1479, 1466,
IR (neat): 3052, 2949, 2927, 2860, 1615, 1596, 1545, 1464, 1442,
–1
–1
1374, 1107, 1067, 983, 927, 922, 807, 750, 738, 720 cm
.
1413, 1369, 1334, 1234, 1069, 1000, 987, 929, 893, 805, 772, 735 cm
.
1
1
H NMR (400 MHz CDCl ): δ = 8.18 (s, 1 H), 7.64–7.54 (m, 2 H), 7.50
H NMR (400 MHz, CDCl ): δ = 7.94 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H),
3
3
(
d, J = 8.6 Hz, 1 H), 7.36 (t, J = 9.9 Hz, 2 H), 7.32–7.27 (m, 1 H), 7.12 (t,
7.45–7.39 (m, 2 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 2 H),
7.09 (t, J = 7.5 Hz, 1 H), 6.85 (s, 1 H), 6.58 (s, 1 H), 6.05 (s, 1 H), 3.73 (s,
3 H), 2.30–2.16 (m, 2 H), 1.47 (quin, J = 7.1 Hz, 2 H), 1.27–1.08 (m, 6
H), 0.79 (t, J = 6.7 Hz, 3 H).
J = 7.5 Hz, 1 H), 7.00 (s, 1 H), 6.71 (s, 1 H), 6.56 (s, 1 H), 4.08 (d, J = 14.6
Hz, 1 H), 3.98 (d, J = 14.5 Hz, 1 H), 3.79 (s, 3 H), 3.37 (s, 3 H).
1
3
C NMR (100 MHz, CDCl ): δ = 165.2 (C), 151.3 (C), 145.3 (C), 137.7
3
13
(
(
(
(
C), 137.0 (C), 133.8 (CH), 130.1 (CH), 129.1 (CH), 127.2 (CH), 126.2
C), 126.0 (C), 125.6 (CH), 125.4 (C), 122.7 (CH), 120.3 (CH), 120.3
CH), 111.2 (C), 109.9 (CH), 101.1 (CH), 75.4 (CH), 71.5 (CH ), 59.1
CH ), 33.2 (CH ).
C NMR (101 MHz, CDCl ): δ = 166.9 (C), 153.2 (C), 148.5 (C), 137.7
3
(C), 135.3 (C), 131.4 (CH), 129.5 (CH), 128.9 (CH), 127.4 (CH), 126.6
(C), 125.9 (CH), 125.9 (C), 125.7 (C), 122.5 (CH), 120.4 (CH), 120.0
2
(CH), 112.6 (C), 109.7 (CH), 102.6 (CH), 74.8 (CH), 34.7 (CH ), 33.0
3
3
2
HRMS (ESI): m/z [M + H]+ calcd for C23H20ClN O : 391.1208; found:
(CH
3
), 31.6 (CH ), 28.8 (CH ), 26.6 (CH ), 22.6 (CH ), 14.1 (CH ).
2 2 2 2 3
2
2
391.1198.
HRMS (ESI): m/z [M + H]+ calcd for C27H28ClN O: 431.1885; found:
2
431.1872.
7-Chloro-1-(1-methyl-1H-indol-3-yl)-3-phenyl-1H-pyrano[4,3-
b]quinoline (3h)
7-Methoxy-3-(methoxymethyl)-1-(1-methyl-1H-indol-3-yl)-1H-
pyrano[4,3-b]quinoline (3k)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 85:15); this afforded an orange oil (83
mg, quant).
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 8:2 to 4:6); this afforded a light yellow solid;
yield: 81 mg (67%); mp 68–70 °C.
IR (neat): 3056, 2933, 1607, 1595, 1574, 1489, 1475, 1450, 1416,
–1
1216, 1067, 1044, 1025, 942, 739, 688 cm
.
IR (neat): 3075, 2932, 2826, 1645, 1615, 1553, 1504, 1476, 1445,
1364, 1235, 1218, 1193, 1130, 1111, 1027, 840, 811, 744, 721 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 8.08 (s, 1 H), 7.79–7.75 (m, 2 H), 7.74
3
1
(d, J = 8.0 Hz, 1 H), 7.57 (s, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 7.41–7.27 (m,
H NMR (400 MHz, CDCl ): δ = 7.65 (d, J = 7.9 Hz, 1 H), 7.46 (s, 1 H),
3
6
H), 7.16 (t, J = 7.4 Hz, 1 H), 6.94 (s, 2 H), 6.81 (s, 1 H), 3.75 (s, 3 H).
7.44–7.36 (m, 2 H), 7.33 (d, J = 8.2 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.10 (t,
J = 7.4 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H), 6.89 (s, 1 H), 6.66 (s, 1 H), 6.35
13
C NMR (100 MHz, CDCl ): δ = 161.2 (C), 152.9 (C), 147.7 (C), 137.6
3
(
(
1
s, 1 H), 4.05 (d, J = 14.2 Hz, 1 H), 3.99–3.88 (m, 4 H), 3.72 (s, 3 H), 3.36
s, 3 H).
(
(
C), 135.8 (C), 133.7 (C), 132.0 (CH), 130.4 (CH), 129.8 (CH), 129.0
CH), 128.6 (2 × CH), 126.8 (CH), 126.6 (C), 126.4 (C), 126.4 (CH),
3
1
(
26.3 (2 × CH), 125.7 (C), 122.5 (CH), 120.2 (CH), 120.2 (CH), 112.0
C), 109.8 (CH), 101.2 (CH), 75.0 (CH), 33.0 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C27H20ClN O: 423.1259; found:
C NMR (100 MHz, CDCl ): δ = 160.9 (C), 160.5 (C), 151.5 (C), 149.7
3
(C), 137.6 (C), 131.6 (CH), 129.7 (CH), 128.7 (CH), 126.5 (C), 123.5 (C),
122.5 (C), 122.3 (CH), 120.4 (CH), 119.9 (CH), 118.1 (CH), 112.5 (C),
2
1
09.6 (CH), 107.0 (CH), 103.9 (CH), 75.2 (CH), 71.7 (CH ), 58.7 (CH ),
423.1241.
2
3
5
5.5 (CH ), 32.9 (CH ).
3
3
HRMS (ESI): m/z [M + H]+ calcd for C24H23N O : 387.1703; found:
7
-Chloro-1-(1-methyl-1H-indol-3-yl)-3-propyl-1H-pyrano[4,3-
2
3
387.1697.
b]quinoline (3i)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 9:1); this afforded a yellow solid;
yield: 70 mg (95%); mp 164–166 °C.
7
-Methoxy-1-(1-methyl-1H-indol-3-yl)-3-phenyl-1H-pyrano[4,3-
b]quinoline (3l)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 9:1 to 1:1); this afforded an orange oil; yield:
IR (neat): 3048, 2959, 2929, 2869, 1630, 1614, 1596, 1557, 1478,
–1
1464, 1336, 1066, 970, 919, 891, 809, 741, 720 cm .
60 mg (71%).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

J
Synthesis
A. Bontemps et al.
Feature
IR (neat): 3057, 2929, 2850, 1605, 1575, 1542, 1501, 1447, 1421,
IR (neat): 3073, 2929, 2850, 1652, 1600, 1560, 1476, 1446, 1399,
377, 1344, 1234, 1207, 1152, 1130, 1044, 1024, 811, 739, 691 cm–1
.
1388, 1202, 1115, 997, 818, 804, 753, 741 cm
–1
.
1
1
1
H NMR (400 MHz, CDCl ): δ = 7.83–7.71 (m, 3 H), 7.60 (s, 1 H), 7.54
H NMR (400 MHz, DMSO-d ): δ = 9.18 (d, J = 7.5 Hz, 1 H), 7.97 (d,
3
6
(
1
s, 1 H), 7.49 (d, J = 8.9 Hz, 1 H), 7.41–7.27 (m, 5 H), 7.16 (t, J = 7.4 Hz,
H), 7.06 (dd, J = 8.9, 2.4 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 1 H), 6.84 (s, 1
J = 7.2 Hz, 1 H), 7.81–7.64 (m, 5 H), 7.56 (d, J = 7.9 Hz, 1 H), 7.46 (d,
J = 8.2 Hz, 1 H), 7.23 (s, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.03 (t, J = 7.5 Hz,
1 H), 6.92 (s, 1 H), 6.37 (s, 1 H), 4.01 (d, J = 14.1 Hz, 1 H), 3.95 (d,
J = 14.1 Hz, 1 H), 3.75 (s, 3 H), 3.25 (s, 3 H).
H), 3.97 (s, 3 H), 3.76 (s, 3 H).
1
3
C NMR (100 MHz, CDCl ): δ = 161.1 (C), 159.6 (C), 152.4 (C), 149.9
3
13
(
(
1
1
C), 137.6 (C), 134.3 (C), 131.5 (CH), 129.8 (CH), 129.7 (CH), 128.8
CH), 128.5 (2 × CH), 126.9 (C), 126.1 (2 × CH), 123.9 (C), 122.5 (C),
C NMR (100 MHz, DMSO-d ): δ = 159.8 (C), 149.4 (C), 145.0 (C),
6
137.1 (C), 133.3 (C), 131.6 (CH), 130.5 (C), 130.2 (CH), 127.9 (CH),
127.8 (CH), 126.6 (CH), 125.9 (CH), 125.9 (C), 125.7 (C), 125.5 (CH),
124.7 (C), 123.8 (CH), 121.6 (CH), 119.6 (CH), 119.3 (CH), 112.1 (C),
22.4 (CH), 120.3 (CH), 120.0 (CH), 118.2 (CH), 113.0 (C), 109.7 (CH),
07.0 (CH), 102.2 (CH), 75.0 (CH), 55.6 (CH ), 33.0 (CH ).
3
3
HRMS (ESI): m/z [M + H]+ calcd for C28H23N O : 419.1754; found:
110.0 (CH), 103.4 (CH), 74.1 (CH), 70.7 (CH
HRMS (ESI): m/z [M + H]+ calcd for C27H23N O : 407.1754; found:
2
), 57.8 (CH ), 32.4 (CH ).
3
3
2
2
419.1739.
2
2
407.1740.
7-Methoxy-1-(1-methyl-1H-indol-3-yl)-3-propyl-1H-pyrano[4,3-
b]quinoline (3m)
8-(1-Methyl-1H-indol-3-yl)-10-phenyl-8H-benzo[h]pyrano[4,3-
b]quinoline (3p)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 6:4); this afforded an orange oil; yield:
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 9:1); this afforded a light brown solid;
yield: 79 mg (90%); mp 118–120 °C.
61 mg (79%).
IR (neat): 3055, 3006, 2960, 2932, 2872, 2831, 1611, 1558, 1503,
–1
1465, 1447, 1237, 1218, 1140, 1028, 983, 810, 739 cm
.
IR (neat): 3049, 2930, 1615, 1598, 1575, 1490, 1450, 1427, 1392,
–1
1
1334, 1258, 1045, 1025, 813, 766, 739, 688 cm .
H NMR (400 MHz, CDCl ): δ = 7.66 (d, J = 7.9 Hz, 1 H), 7.42–7.30 (m, 4
3
1
H), 7.29–7.22 (m, 1 H), 7.11 (t, J = 7.4 Hz, 1 H), 6.98 (dd, J = 8.8, 1.9 Hz,
H NMR (400 MHz, DMSO-d ): δ = 9.24 (d, J = 7.8 Hz, 1 H), 8.01 (d,
6
1
2
H), 6.87 (s, 1 H), 6.58 (s, 1 H), 6.11 (s, 1 H), 3.92 (s, 3 H), 3.70 (s, 3 H),
.25 (t, J = 7.5 Hz, 2 H), 1.66–1.49 (m, 2 H), 0.88 (t, J = 7.4 Hz, 3 H).
J = 7.6 Hz, 1 H), 7.95 (s, 1 H), 7.85–7.71 (m, 7 H), 7.46 (d, J = 8.2 Hz, 1
H), 7.43–7.36 (m, 3 H), 7.20 (t, J = 7.7 Hz, 1 H), 7.16 (s, 1 H), 7.12–7.07
(m, 2 H), 7.05 (s, 1 H), 3.72 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 165.5 (C), 160.8 (C), 152.3 (C), 149.6
3
13
(C), 137.5 (C), 131.3 (CH), 129.4 (CH), 128.6 (CH), 126.5 (C), 123.2 (C),
C NMR (100 MHz, DMSO-d ): δ = 157.4 (C), 150.1 (C), 145.4 (C),
6
1
1
1
22.2 (CH), 120.4 (CH), 119.7 (CH), 117.5 (CH), 112.7 (C), 109.5 (CH),
137.1 (C), 133.6 (C), 133.4 (C), 131.7 (CH), 130.5 (C), 130.3 (CH), 129.8
(CH), 128.5 (2 × CH), 128.1 (CH), 127.9 (CH), 126.8 (CH), 126.1 (C),
126.1 (CH), 125.8 (C), 125.7 (CH), 125.4 (2 × CH), 124.8 (C), 123.9
(CH), 121.7 (CH), 119.5 (CH), 119.5 (CH), 112.4 (C), 110.2 (CH), 102.2
06.8 (CH), 102.6 (CH), 74.8 (CH), 55.4 (CH ), 36.4 (CH ), 32.8 (CH ),
3
2
3
9.9 (CH ), 13.6 (CH ).
2
3
HRMS (ESI): m/z [M + H]+ calcd for C25H25N O : 385.1911; found:
2
2
(
CH), 73.8 (CH), 32.4 (CH3).
385.1896.
HRMS (ESI): m/z [M + H]+ calcd for C31H23N O: 439.1810; found:
2
439.1794.
3-Hexyl-7-methoxy-1-(1-methyl-1H-indol-3-yl)-1H-pyrano[4,3-
b]quinoline (3n)
8
-(1-Methyl-1H-indol-3-yl)-10-propyl-8H-benzo[h]pyrano[4,3-
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 7:3); this afforded an orange oil; yield:
b]quinoline (3q)
6
5 mg (76%).
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 95:5); this afforded an orange solid;
yield: 76 mg (94%); mp 138–140 °C.
IR (neat): 3059, 3007, 2953, 2928, 2856, 1612, 1557, 1504, 1465,
–1
1446, 1235, 1216, 1140, 1027, 810, 738 cm .
IR (neat): 3056, 2957, 2928, 2871, 1638, 1603, 1557, 1478, 1464,
1
2
6
3
H NMR (400 MHz, CDCl ): δ = 7.67 (d, J = 7.9 Hz, 1 H), 7.50–7.40 (m,
3
1
cm
1
446, 1393, 1374, 1335, 1301, 1141, 1067, 975, 816, 804, 753, 741
H), 7.41–7.31 (m, 2 H), 7.32–7.23 (m, 1 H), 7.11 (t, J = 7.4 Hz, 1 H),
.99 (d, J = 8.8 Hz, 1 H), 6.84 (s, 1 H), 6.61 (s, 1 H), 6.08 (s, 1 H), 3.92 (s,
H), 3.73 (s, 3 H), 2.25 (sept, J = 7.3 Hz, 2 H), 1.49 (quin, J = 7.3 Hz, 2
–1
.
H NMR (300 MHz, CDCl ): δ = 9.31 (d, J = 7.7 Hz, 1 H), 7.86 (d, J = 7.3
3
H), 1.33–1.01 (m, 6 H), 0.82 (t, J = 6.4 Hz, 3 H).
Hz, 1 H), 7.75–7.60 (m, 4 H), 7.56 (s, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 7.36
(
d, J = 8.2 Hz, 1 H), 7.32–7.26 (m, 1 H), 7.13 (ddd, J = 8.0, 6.9, 1.2 Hz, 1
1
3C NMR (100 MHz, CDCl ): δ = 165.9 (C), 160.9 (C), 152.3 (C), 149.5
3
H), 6.90 (s, 1 H), 6.72 (s, 1 H), 6.24 (s, 1 H), 3.76 (s, 3 H), 2.26 (dd,
J = 8.4, 6.6 Hz, 2 H), 1.65–1.51 (m, 2 H), 0.87 (t, J = 7.3 Hz, 3 H).
(C), 137.6 (C), 131.5 (CH), 129.5 (CH), 128.7 (CH), 126.6 (C), 123.1 (C),
1
1
3
22.3 (CH), 122.2 (C), 120.5 (CH), 119.9 (CH), 117.7 (CH), 113.0 (C),
09.6 (CH), 106.7 (CH), 102.5 (CH), 74.7 (CH), 55.6 (CH ), 34.6 (CH ),
2.9 (CH ), 31.6 (CH ), 28.8 (CH ), 26.6 (CH ), 22.6 (CH ), 14.1 (CH ).
1
3
C NMR (100 MHz, CDCl ): δ = 164.7 (C), 151.0 (C), 146.1 (C), 137.7
3
2
3
(C), 134.0 (C), 131.7 (CH), 129.7 (C+CH), 127.9 (2 × CH), 126.9 (CH),
126.6 (C), 126.1 (CH), 125.4 (C+CH), 124.9 (C), 124.7 (CH), 122.4 (CH),
1
3
3
2
2
2
2
3
HRMS (ESI): m/z [M + H]+ calcd for C28H31N O : 427.2380; found:
2
2
20.5 (CH), 120.0 (CH), 112.9 (C), 109.7 (CH), 103.3 (CH), 74.7 (CH),
6.6 (CH ), 33.0 (CH ), 20.1 (CH ), 13.7 (CH ).
427.2368.
2
3
2
3
HRMS (ESI): m/z [M + H]+ calcd for C28H25N O: 405.1961; found:
1
0-(Methoxymethyl)-8-(1-methyl-1H-indol-3-yl)-8H-ben-
2
405.1949.
zo[h]pyrano[4,3-b]quinoline (3o)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 8:2); this afforded a light yellow solid;
yield: 60 mg (74%); mp 170–172 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

K
Synthesis
A. Bontemps et al.
Feature
10-Hexyl-8-(1-methyl-1H-indol-3-yl)-8H-benzo[h]pyrano[4,3-
HRMS (ESI): m/z [M + H]+ calcd for C26H19N O: 375.1497; found:
2
b]quinoline (3r)
375.1501.
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 98:2); this afforded a light yellow sol-
id; yield: 67 mg (75%); mp 134–136 °C.
3-(Methoxymethyl)-1-(1-methyl-1H-pyrrol-2-yl)-1H-pyrano[4,3-
b]quinoline (5a)
IR (neat): 3047, 2954, 2924, 2889, 2855, 1634, 1600, 1543, 1476,
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 75:25); this afforded a beige solid;
yield: 67 mg (55%); mp 101–103 °C.
1
7
1
446, 1424, 1388, 1375, 1334, 1237, 1153, 978, 959, 899, 813, 786,
–1
47, 678 cm
.
H NMR (300 MHz, CDCl ): δ = 9.32 (d, J = 7.9 Hz, 1 H), 7.86 (dd,
IR (neat): 3037, 3000, 2933, 2878, 2812, 1648, 1637, 1620, 1611,
1494, 1401, 1293, 1204, 1115, 1016, 1003, 944, 902, 848, 818, 751,
3
J = 7.8, 1.2 Hz, 1 H), 7.76–7.61 (m, 4 H), 7.57 (s, 1 H), 7.47 (d, J = 8.8 Hz,
–
1
1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.31–7.26 (m, 1 H), 7.14 (ddd, J = 8.0, 6.9,
1.2 Hz, 1 H), 6.83 (s, 1 H), 6.74 (s, 1 H), 6.23 (s, 1 H), 3.74 (s, 3 H), 2.39–
2.17 (m, 2 H), 1.51 (quin, J = 7.2 Hz, 2 H), 1.25–1.00 (m, 6 H), 0.83 (t,
723 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.00 (d, J = 8.7 Hz, 1 H), 7.68–7.60 (m, 2
3
H), 7.51 (s, 1 H), 7.40 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 6.72 (dd, J = 2.6,
J = 6.9 Hz, 3 H).
1.8 Hz, 1 H), 6.51 (s, 1 H), 6.32 (s, 1 H), 6.05 (dd, J = 3.7, 2.6 Hz, 1 H),
13
C NMR (75 MHz, CDCl ): δ = 164.7 (C), 151.1 (C), 146.2 (C), 137.7 (C),
5.91 (dd, J = 3.7, 1.8 Hz, 1 H), 4.04 (d, J = 13.9 Hz, 1 H), 3.99 (d, J = 13.9
3
1
1
1
1
2
33.9 (C), 131.7 (CH), 131.4 (C), 129.6 (CH), 127.9 (CH), 127.8 (CH),
26.8 (CH), 126.7 (C), 125.9 (CH), 125.6 (CH), 125.2 (C), 124.9 (C),
24.6 (CH), 122.3 (CH), 120.5 (CH), 119.9 (CH), 113.3 (C), 109.6 (CH),
Hz, 1 H), 3.69 (s, 3 H), 3.28 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 159.2 (C), 150.9 (C), 148.3 (C), 131.8
3
(CH), 129.8 (CH), 128.7 (CH), 128.6 (C), 127.8 (CH), 127.5 (C), 125.7
03.3 (CH), 74.6 (CH), 34.6 (CH ), 33.0 (CH ), 31.7 (CH ), 28.9 (CH ),
2
3
2
2
(CH), 125.0 (CH), 124.8 (C), 112.3 (CH), 106.9 (CH), 105.0 (CH), 74.1
(CH), 71.7 (CH ), 58.3 (CH ), 35.0 (CH ).
6.7 (CH ), 22.7 (CH ), 14.2 (CH ).
2
2
3
2
3
3
HRMS (ESI): m/z [M + H]+ calcd for C31H31N O: 447.2431; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H19N O : 307.1441; found:
2
2 2
447.2413.
307.1429.
1
-(1H-Indol-3-yl)-3-(methoxymethyl)-1H-pyrano[4,3-b]quinoline
8
-(1-Methyl-1H-pyrrol-2-yl)-10-phenyl-8H-benzo[h]pyrano[4,3-
(4a)
b]quinoline (5p)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 8:2 to 6:4); this afforded an orange solid;
yield: 43 mg (63%); mp 117–119 °C.
The reaction was carried out at 80 °C in DMF instead of DCE, and at
0.5 M reaction media concentration. The crude product was purified
by column chromatography (silica gel, cyclohexane–EtOAc, 1:0 to
9:1); this afforded an ochre solid; yield: 83 mg (43%); mp 209–211 °C.
IR (neat): 3145, 3060, 2920, 2850, 1644, 1614, 1550, 1496, 1457,
–1
1
426, 1354, 1199, 1108, 973, 901, 824, 743 cm .
IR (neat): 3095, 2923, 2854, 1618, 1597, 1575, 1489, 1450, 1442,
1428, 1409, 1394, 1318, 1255, 1055, 1050, 998, 816, 770, 757, 731,
1
H NMR (400 MHz, DMSO-d ): δ = 11.32 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1
6
–
1
H), 7.79 (d, J = 8.1 Hz, 1 H), 7.75 (s, 1 H), 7.70 (ddd, J = 8.5, 6.9, 1.5 Hz,
689 cm .
1
1
H), 7.48–7.41 (m, 3 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.12 (ddd, J = 8.3, 7.0,
.2 Hz, 1 H), 6.97 (t, J = 7.6 Hz, 1 H), 6.88 (s, 1 H), 6.30 (s, 1 H), 4.05 (d,
1
H NMR (400 MHz, DMSO-d ): δ = 9.23 (dd, J = 7.3, 2.1 Hz, 1 H), 8.02
6
(dd, J = 7.6, 1.7 Hz, 1 H), 7.98 (s, 1 H), 7.85 (dd, J = 8.2, 2.3 Hz, 3 H),
J = 14.7 Hz, 1 H), 3.96 (d, J = 14.5 Hz, 1 H), 3.27 (s, 3 H).
7
.82–7.71 (m, 3 H), 7.49–7.42 (m, 3 H), 7.05 (s, 1 H), 7.03 (s, 1 H), 6.86
13
C NMR (100 MHz, DMSO-d ): δ = 162.6 (C), 150.0 (C), 145.4 (C),
(t, J = 2.2 Hz, 1 H), 5.86 (t, J = 3.1 Hz, 1 H), 5.55 (dd, J = 3.7, 1.8 Hz, 1 H),
6
136.7 (C), 132.6 (CH), 130.1 (CH), 128.0 (CH), 126.9 (C), 126.3 (2 ×
3.86 (s, 3 H).
CH), 125.9 (C), 125.6 (CH), 125.4 (C), 121.5 (CH), 119.4 (CH), 119.1
13
C NMR (100 MHz, DMSO-d ): δ = 156.2 (C), 149.9 (C), 145.5 (C),
6
(
CH), 112.1 (C), 111.8 (CH), 101.3 (CH), 74.7 (CH), 70.6 (CH ), 57.9
2
133.5 (2 × C), 132.0 (CH), 130.6 (C), 130.0 (CH), 129.5 (C), 128.8 (2 ×
CH), 128.3 (CH), 128.1 (CH), 126.9 (CH), 126.3 (CH), 125.7 (CH), 125.2
(2 × CH), 124.8 (C), 124.7 (CH), 124.6 (C), 123.9 (CH), 111.2 (CH),
(
CH3).
+
HRMS (ESI): m/z [M + Na] calcd for C22H18N O Na: 365.1266; found:
2
2
365.1265.
106.4 (CH), 102.4 (CH), 71.9 (CH), 34.2 (CH ).
3
HRMS (ESI): m/z [M + H]+ calcd for C27H21N O: 389.1654; found:
2
1-(1H-Indol-3-yl)-3-phenyl-1H-pyrano[4,3-b]quinoline (4b)
389.1646.
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 7:3); this afforded a light yellow solid;
yield: 67 mg (89%); mp 200–202 °C.
3-(Methoxymethyl)-1-(1,2,5-trimethyl-1H-pyrrol-3-yl)-1H-pyra-
no[4,3-b]quinoline (6a)
IR (neat): 3134, 3057, 2981, 2918, 2855, 1606, 1577, 1553, 1493,
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 8:2 to 5:5); this afforded a light yellow solid;
yield: 59 mg (66%); mp 48–50 °C.
–1
1457, 1445, 1420, 1340, 1319, 1250, 1052, 906, 739, 683 cm .
1
H NMR (400 MHz, DMSO-d ): δ = 11.26 (s, 1 H), 7.95 (d, J = 8.3 Hz, 1
6
H), 7.84–7.74 (m, 4 H), 7.71–7.61 (m, 2 H), 7.47–7.35 (m, 5 H), 7.21 (s,
IR (neat): 3057, 2916, 2818, 1642, 1616, 1495, 1427, 1398, 1382,
–1
1
H), 7.13 (t, J = 7.6 Hz, 1 H), 7.06–6.98 (m, 2 H), 6.97 (s, 1 H).
1311, 1115, 1096, 986, 823, 745, 716, 661 cm
.
13
1H NMR (300 MHz, CDCl
C NMR (100 MHz, DMSO-d ): δ = 158.3 (C), 151.4 (C), 147.7 (C),
3
): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.66–7.53 (m, 3
6
1
36.7 (C), 133.6 (C), 131.2 (CH), 129.9 (CH), 129.5 (CH), 128.5 (2 ×
H), 7.36 (t, J = 7.5 Hz, 1 H), 6.33 (s, 1 H), 6.28 (s, 1 H), 5.83 (s, 1 H), 4.12
(d, J = 14.3 Hz, 1 H), 3.98 (d, J = 14.3 Hz, 1 H), 3.44 (s, 3 H), 3.43 (s, 3
H), 2.24 (s, 3 H), 2.21 (s, 3 H).
CH), 128.0 (CH), 128.0 (CH), 127.0 (C), 126.3 (CH), 126.1 (C), 125.7 (C),
25.5 (2 × CH), 125.3 (CH), 121.6 (CH), 119.5 (CH), 119.3 (CH), 112.8
C), 112.0 (CH), 101.9 (CH), 74.5 (CH).
1
(
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

L
Synthesis
A. Bontemps et al.
Feature
13
13
C NMR (75 MHz, CDCl ): δ = 161.5 (C), 151.9 (C), 147.9 (C), 132.0
C NMR (75 MHz, DMSO-d ): δ = 159.7 (C), 152.1 (C), 147.6 (C), 136.2
3
6
(
(
7
CH), 129.4 (CH), 128.5 (CH), 128.2 (C), 127.8 (CH), 127.7 (C), 127.6
C), 127.3 (C), 125.2 (CH), 115.1 (C), 105.6 (CH), 103.6 (CH), 75.9 (CH),
(C), 135.7 (C), 133.5 (C), 131.0 (CH), 130.0 (CH), 129.5 (CH), 128.6 (2 ×
CH), 128.0 (CH), 127.9 (CH), 127.2 (C), 126.9 (C), 126.7 (C), 125.5 (2 ×
CH), 125.3 (CH), 120.6 (CH), 119.0 (2 × CH), 111.0 (CH), 107.3 (C),
1.7 (CH ), 58.9 (CH ), 30.4 (CH ), 12.7 (CH ), 10.8 (CH ).
2 3 3 3 3
HRMS (ESI): m/z [M + H]+ calcd for C21H23N O : 335.1754; found:
101.9 (CH), 74.8 (CH), 11.7 (CH
HRMS (ESI): m/z [M + H]+ calcd for C27H21N O: 389.1648; found:
3
).
2
2
335.1751.
2
389.1636.
3-Phenyl-1-(1,2,5-trimethyl-1H-pyrrol-3-yl)-1H-pyrano[4,3-
b]quinoline (6b)
3-(Methoxymethyl)-1-(1H-pyrrol-2-yl)-1H-pyrano[4,3-b]quino-
line (8a)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 9:1 to 85:15); this afforded an ochre solid;
yield: 66 mg (90%); mp 122–124 °C.
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 1:9); this afforded a white solid; yield:
2
8 mg (48%); mp 180–182 °C.
IR (neat): 3055, 2912, 2851, 1606, 1575, 1536, 1492, 1415, 1396,
–1
1312, 1042, 1024, 929, 903, 755, 725, 717, 689 cm
.
IR (neat): 3174, 3131, 3090, 2997, 2924, 2871, 2815, 1654, 1614,
1604, 1564, 1497, 1429, 1400, 1311, 1286, 1207, 1154, 1117, 1095,
1
H NMR (400 MHz, CDCl ): δ = 8.02 (d, J = 8.3 Hz, 1 H), 7.88–7.79 (m, 2
3
–1
1015, 941, 813, 756, 718 cm .
H), 7.68–7.58 (m, 3 H), 7.43–7.34 (m, 4 H), 6.88 (s, 1 H), 6.42 (s, 1 H),
1
5
.83 (s, 1 H), 3.46 (s, 3 H), 2.31 (s, 3 H), 2.21 (s, 3 H).
H NMR (300 MHz, CDCl ): δ = 8.79 (s, 1 H), 7.98 (d, J = 8.2 Hz, 1 H),
3
1
3
7.71–7.56 (m, 3 H), 7.42 (td, J = 7.3, 1.2 Hz, 1 H), 6.87 (td, J = 2.6, 1.4
Hz, 1 H), 6.47 (s, 1 H), 6.28 (s, 1 H), 6.18 (q, J = 2.9 Hz, 1 H), 6.07 (s, 1
H), 4.04 (d, J = 13.7 Hz, 1 H), 3.98 (d, J = 13.7 Hz, 1 H), 3.35 (s, 3 H).
C NMR (100 MHz, CDCl ): δ = 160.5 (C), 152.7 (C), 147.9 (C), 134.2
3
(C), 131.9 (CH), 129.9 (CH), 129.5 (CH), 128.5 (2 × CH), 128.2 (CH),
1
27.9 (C+CH), 127.7 (C), 127.6 (C), 127.4 (C), 126.1 (2 × CH), 125.2
13
(CH), 115.4 (C), 105.9 (CH), 102.1 (CH), 75.9 (CH), 30.4 (CH ), 12.7
C NMR (100 MHz, CDCl ): δ = 159.4 (C), 150.4 (C), 148.2 (C), 132.0
3
3
(
CH ), 10.8 (CH ).
(CH), 129.9 (CH), 128.8 (C), 128.6 (CH), 127.9 (CH), 127.5 (C), 125.8
(CH), 125.1 (C), 119.5 (CH), 109.8 (CH), 108.5 (CH), 104.9 (CH), 74.9
3
3
HRMS (CI): m/z [M + H]+ calcd for C25H23N O: 367.1810; found:
3
2
(
CH), 71.8 (CH ), 58.7 (CH ).
67.1805.
2
3
+
HRMS (ESI): m/z [M + Na] calcd for C18H16N O Na: 315.1109; found:
2
2
315.1103.
3-(Methoxymethyl)-1-(2-methyl-1H-indol-3-yl)-1H-pyrano[4,3-
b]quinoline (7a)
8
-(3-Methylbenzofuran-2-yl)-10-phenyl-8H-benzo[h]pyrano[4,3-
The reaction was carried out at 50 °C in DMF instead of DCE. The
crude product was purified by column chromatography (silica gel, cy-
clohexane–EtOAc, 8:2 to 1:1); this afforded a light yellow solid; yield:
b]quinoline (9p)
The reaction was carried out at 80 °C in DMF instead of DCE, and at
0.5 M reaction media concentration. The crude product was purified
by column chromatography (silica gel, cyclohexane–EtOAc, 1:0 to
9:1); this afforded a yellow solid; yield: 51 mg (23%); mp 227–229 °C.
85 mg (36%); mp 226–228 °C.
IR (neat): 3142, 3034, 2920, 2841, 2759, 1645, 1617, 1566, 1496,
–1
1
464, 1426, 1397, 1311, 1198, 1105, 1010, 904, 816, 753, 740 cm .
1
IR (neat): 3061, 2920, 1618, 1599, 1574, 1492, 1450, 1318, 1257,
H NMR (400 MHz, DMSO-d ): δ = 11.29 (s, 1 H), 7.89 (d, J = 8.4 Hz, 1
6
–1
1196, 1051, 1005, 911, 811, 765, 748, 689 cm .
H), 7.66 (d, J = 8.1 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.40 (s, 1 H), 7.38–
7
1
.32 (m, 2 H), 7.15 (d, J = 7.9 Hz, 1 H), 7.02 (t, J = 7.4 Hz, 1 H), 6.84 (t,
H NMR (400 MHz, DMSO-d ): δ = 9.23 (d, J = 7.7 Hz, 1 H), 8.00 (d,
6
J = 7.4 Hz, 1 H), 6.76 (s, 1 H), 6.26 (s, 1 H), 4.09 (d, J = 14.1 Hz, 1 H),
J = 7.4 Hz, 1 H), 7.93–7.71 (m, 7 H), 7.68 (d, J = 7.5 Hz, 1 H), 7.50 (d,
J = 7.9 Hz, 1 H), 7.48–7.43 (m, 3 H), 7.36–7.27 (m, 2 H), 7.26 (s, 1 H),
7.10 (s, 1 H), 2.35 (s, 3 H).
3.98 (d, J = 14.1 Hz, 1 H), 3.34 (s, 3 H), 2.44 (s, 3 H).
13
C NMR (100 MHz, DMSO-d ): δ = 161.7 (C), 151.2 (C), 147.4 (C),
6
13
1
1
1
5
36.0 (C), 135.6 (C), 131.1 (CH), 129.4 (CH), 127.9 (CH), 127.9 (CH),
27.1 (C), 126.7 (C), 126.4 (C), 125.2 (CH), 120.5 (CH), 118.9 (CH),
18.9 (CH), 110.9 (CH), 107.4 (C), 103.0 (CH), 74.6 (CH), 70.7 (CH2),
7.9 (CH ), 11.6 (CH ).
C NMR (100 MHz, DMSO-d ): δ = 157.6 (C), 153.7 (C), 149.7 (C),
6
148.8 (C), 145.5 (C), 133.5 (C), 133.1 (C), 131.8 (CH), 130.3 (C), 130.0
(CH), 128.9 (C), 128.6 (2 × CH), 128.2 (CH), 127.9 (CH), 126.8 (CH),
126.4 (CH), 125.5 (CH), 125.4 (2 × CH), 125.4 (CH), 124.9 (C), 123.9
(CH), 123.3 (C), 122.7 (CH), 120.2 (CH), 115.6 (C), 111.3 (CH), 102.3
3
3
HRMS (ESI): m/z [M + H]+ calcd for C23H21N O : 357.1598; found:
2
2
(
CH), 71.9 (CH), 7.6 (CH3).
357.1589.
HRMS (ESI): m/z [M + H]+ calcd for C31H22NO : 440.1651; found:
2
440.1644.
1-(2-Methyl-1H-indol-3-yl)-3-phenyl-1H-pyrano[4,3-b]quinoline
(7b)
The crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 1:0 to 0:1) and then washed with EtOAc; this
afforded a yellow solid; yield: 42 mg (62%); mp 246–248 °C.
Acknowledgment
This work was supported by the CNRS, ATIP CNRS-INCa, and Institut
Curie. A. B. and G. M. are respectively grateful to the French Ministry
of Research and the Fondation Pierre-Gilles de Gennes for financial
support. We thank A. Berlioz-Barbier and C. Duchamp, from the Cen-
tre Commun de Spectrométrie de Masse (CCSM) of Université Lyon 1,
for the assistance and access to the mass spectrometry facility.
IR (neat): 3143, 3056, 2920, 2843, 2758, 1607, 1576, 1494, 1460,
–1
1
444, 1419, 1339, 1049, 1028, 904, 753, 741, 685 cm .
1
H NMR (300 MHz, DMSO-d ): δ = 11.33 (s, 1 H), 7.92 (d, J = 8.3 Hz, 1
6
H), 7.84–7.77 (m, 2 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.64 (t, J = 7.3 Hz, 1 H),
7
2
.47 (s, 1 H), 7.46–7.32 (m, 5 H), 7.17 (d, J = 7.9 Hz, 1 H), 7.05–6.96 (m,
H), 6.91 (s, 1 H), 6.82 (t, J = 7.5 Hz, 1 H), 2.46 (s, 3 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M

M
Synthesis
A. Bontemps et al.
Feature
Supporting Information
(d) Parker, E.; Leconte, N.; Godet, T.; Belmont, P. Chem. Commun.
2
011, 47, 343. (e) Bantreil, X.; Vaxelaire, C.; Godet, T.; Parker, E.;
Sauer, C.; Belmont, P. Org. Biomol. Chem. 2011, 9, 4831.
f) Belmont, P. In Silver in Organic Chemistry; Harmata, M., Ed.;
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562234.
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p
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Wiley: Hoboken, 2010.
(
9) (a) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E. Synthesis
References
2010, 2367. (b) Dell’Acqua, M.; Castano, B.; Cecchini, C.;
Pedrazzini, T.; Pirovano, V.; Rossi, E.; Caselli, A.; Abbiati, G. J.
Org. Chem. 2014, 79, 3494. (c) Kotera, A.; Uenishi, J. I.; Uemura,
M. Tetrahedron Lett. 2010, 51, 1166. (d) Liu, L.-P.; Hammond, G.
B. Org. Lett. 2010, 12, 4640. (e) Bacchi, A.; Costa, M.; Della Ca’,
N.; Fabbricatore, M.; Fazio, A.; Gabriele, B.; Nasi, C.; Salerno, G.
Eur. J. Org. Chem. 2004, 574. (f) Obika, S.; Kono, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462. (g) Asao,
N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc.
(
1) (a) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015,
89, 421. (b) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem.
2010, 47, 491. (c) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar,
N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
d) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. (e) Abdel-Wahab,
B. F.; Khidre, R. E.; Farahat, A.-A. S.; El-Ahl, A.-A. ARKIVOC 2012,
i), 211. (f) Mukherjee, S.; Pal, M. Curr. Med. Chem. 2013, 20,
386. (g) Pati, B.; Banerjee, S. J. PharmaSciTech 2014, 3, 59.
h) Kumar, S.; Bawa, S.; Gupta, H. Mini-Rev. Med. Chem. 2009, 9,
648.
2) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43,
6. (b) Diversity-Oriented Synthesis: Basics and Applications in
(
(
4
(
1
2002, 124, 764. (h) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004,
69, 5139. (i) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J.
Org. Chem. 2003, 68, 9496. (j) Wei, L.-L.; Wei, L.-M.; Pan, W.-B.;
Wu, M.-J. Synlett 2004, 1497. (k) Gulias, M.; Rodriguez, J. R.;
Castedo, L.; Mascareñas, J. L. Org. Lett. 2003, 5, 1975. (l) Jha, R.
R.; Aggarwal, T.; Verma, A. K. Tetrahedron Lett. 2014, 55, 2603.
(
4
Organic Synthesis, Drug Discovery, and Chemical Biology;
Trabocchi, A., Ed.; Wiley: New York, 2013.
(m) For an enantioselective version, see: Handa, S.; Slaughter, L.
(
3) (a) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
Zilbersteint, A. J. Med. Chem. 1994, 37, 2129. (b) Oliva, B.; Miller,
K.; Caggiano, N.; O’Neill, A. J.; Cuny, G. D.; Hoemann, M. Z.;
Hauske, J. R.; Chopra, I. Antimicrob. Agents Chemother. 2003, 47,
M. Angew. Chem. Int. Ed. 2012, 51, 2912. (n) Nanayakkara, Y. S.;
Woods, R. M.; Breitbach, Z. S.; Handa, S.; Slaughter, L. M.;
Armstrong, D. W. J. Chromatogr. A 2013, 1305, 94. For selected
work using nonmetallic electrophiles or non-transition metals,
see: (o) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.;
Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028. (p) Yue, D.;
Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6, 1581. (q) Dell’Acqua,
M.; Facoetti, D.; Abbiati, G.; Rossi, E.; Alfonsi, M.; Arcadi, A. Eur.
J. Org. Chem. 2009, 2852.
458. (c) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I.
W.; Hughes, D. L. J. Org. Chem. 2005, 70, 2555. (d) Payack, J. F.;
Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. A. J. Org. Chem.
2
005, 70, 175. (e) Bhowal, S. K.; Lala, S.; Hazra, A.; Paira, P.;
Banerjee, S.; Mondal, N. B.; Chakraborty, S. Contraception 2008,
7, 214. (f) Liu, C. Y.; Wu, P. T.; Wang, J. P.; Fan, P. W.; Hsieh, C.
H.; Su, C. L.; Chiu, C. C.; Yao, C. F.; Fang, K. Apoptosis 2015, 20,
471.
7
(
(
10) Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953.
11) Yu, X.; Ding, Q.; Wang, W.; Wu, J. Tetrahedron Lett. 2008, 49,
1
4390.
(
4) (a) Chao, C.-M.; Beltrami, D.; Toullec, P. Y.; Michelet, V. Chem.
Commun. 2009, 6988. (b) Pradal, A.; Chao, C.-M.; Beltrami, D.;
Toullec, P. Y.; Michelet, V. Beilstein J. Org. Chem. 2011, 7, 1021.
(
12) Domaradzki, M. E.; Long, Y.; She, Z.; Liu, X.; Zhang, G.; Chen, Y.
J. Org. Chem. 2015, 80, 11360.
(
13) (a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A. Jr. J. Am. Chem.
Soc. 2007, 129, 1413. (b) Leng, B.; Chichetti, S.; Su, S.; Beeler, A.
B.; Porco, J. A. Jr. Beilstein J. Org. Chem. 2012, 8, 1338.
14) (a) Asao, N.; Chan, C. S.; Takahashi, K.; Yamamoto, Y. Tetrahe-
dron 2005, 61, 11322. (b) Bhunia, S.; Wang, K.-C.; Liu, R.-S.
Angew. Chem. Int. Ed. 2008, 47, 5063.
15) Tomas-Mendivil, E.; Starck, J.; Ortuno, J.-C.; Michelet, V. Org.
Lett. 2015, 17, 6126.
16) (a) Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem. Int.
Ed. 2003, 42, 4399. (b) Tang, R.-Y.; Li, J.-H. Chem. Eur. J. 2010, 16,
(c) Pradal, A.; Chen, Q.; Faudot dit Bel, P.; Toullec, P. Y.; Michelet,
V. Synlett 2012, 23, 74. (d) Chao, C.-M.; Toullec, P. Y.; Michelet,
V. Tetrahedron Lett. 2009, 50, 3719. (e) Toullec, P. Y.; Blarre, T.;
Michelet, V. Org. Lett. 2009, 11, 2888. (f) Chao, C.-M.; Vitale, M.
R.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. Chem. Eur. J. 2009, 15,
(
1319. (g) Leseurre, L.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. Org.
(
Lett. 2007, 9, 4049.
(
5) (a) Arcadi, A.; Chiarini, M.; Del Vecchio, L.; Marinelli, F.;
Michelet, V. Chem. Commun. 2016, 52, 1458. (b) Arcadi, A.;
Pietropaolo, E.; Alvino, A.; Michelet, V. Org. Lett. 2013, 15, 2766.
6) (a) Carrër, A.; Péan, C.; Perron-Sierra, F.; Mirguet, O.; Michelet,
V. Adv. Synth. Catal. 2016, 358, 1540. (b) Belmont, P.; Andrez,
J.-C.; Allan, C. S. M. Tetrahedron Lett. 2004, 45, 2783. (c) Godet,
T.; Belmont, P. Synlett 2008, 2513.
(
4733. (c) Ouyang, B.; Yuan, J.; Yang, Q.; Ding, Q.; Peng, Y.; Wu, J.
(
Heterocycles 2011, 82, 1239. (d) Mariaule, G.; Newsome, G.;
Toullec, P. Y.; Belmont, P.; Michelet, V. Org. Lett. 2014, 16, 4570.
17) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J. Chem. Soc., Perkin
Trans. 1 1981, 1520.
18) Meth-Cohn, O.; Narine, B.; Tarnowski, B.; Hayes, R.; Keyzad, A.;
Rhouati, S.; Robinson, A. J. Chem. Soc., Perkin Trans. 1 1981,
(
(
(7) (a) Tiano, M.; Belmont, P. J. Org. Chem. 2008, 73, 4101.
(b) Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793.
(
8) (a) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P.
Chem. Eur. J. 2007, 13, 5632. (b) Michel, C.; Godet, T.; Dheu-
Andries, M.-L.; Belmont, P.; Milet, A. J. Mol. Struct. 2007, 811,
2509.
(
19) Mayr, H. Tetrahedron 2015, 71, 5095.
175. (c) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–M