Synthesis of azafluorenones and related compounds using deprotocupration-aroylation followed by intramolecular direct arylation

Article abstract of DOI:10.1016/j.tet.2013.09.030

The efficiency of the deprotocupration-aroylation of 2-chloropyridine using lithiocuprates prepared from CuX (X=Cl, Br) and LiTMP (TMP=2,2,6,6- tetramethylpiperidido, 2 equiv) was investigated. CuCl was identified as a more suitable copper source than CuBr for this purpose. Different diaryl ketones bearing a halogen at the 2 position of one of the aryl groups were synthesized in this way from azines and thiophenes. These were then involved in palladium-catalyzed ring closure: substrates underwent expected CH-activation-type arylation to afford fluorenone-type compounds, and were also subjected to cyclization reactions leading to xanthones, notably in the presence of oxygen-containing substituents or reagents.

Full text of DOI:10.1016/j.tet.2013.09.030

Tetrahedron 69 (2013) 10123e10133
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of azafluorenones and related compounds using
deprotocuprationearoylation followed by intramolecular direct
arylationq
Nada Marquise a, Philip J. Harford b, Floris Chevallier a, Thierry Roisnel c,
c
e
e
e,
*
ꢀ e
ꢀ
ꢀ
Vincent Dorcet , Anne-Laure Gagez , Sophie Sable , Laurent Picot , Valerie Thiery
,
,
d
a,
*
Andrew E. H. Wheatley b , Philippe C. Gros , Florence Mongin
*
a
ꢀ
ꢀ
^
Chimie et Photonique Moleculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Universite de Rennes 1, Batiment 10A,
Case 1003, Campus de Beaulieu, 35042 Rennes, France
b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
c
ꢀ
ꢀ
^
Centre de Diffractometrie X, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Universite de Rennes 1, Batiment 10B, Case 1003,
Campus de Beaulieu, 35042 Rennes, France
d
ꢀ
ꢁ
HECRIN, SRSMC, Universite de Lorraine-CNRS, Boulevard des Aiguillettes, 54506 Vandoeuvre-Les-Nancy, France
e
ꢀ
ꢀ
LIENSs UMR 7266, Universite de La Rochelle, Avenue Crepeau, 17042 La Rochelle, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2013
Received in revised form 5 September 2013
Accepted 9 September 2013
Available online 17 September 2013
The efficiency of the deprotocuprationearoylation of 2-chloropyridine using lithiocuprates prepared
from CuX (X¼Cl, Br) and LiTMP (TMP¼2,2,6,6-tetramethylpiperidido, 2 equiv) was investigated. CuCl was
identified as a more suitable copper source than CuBr for this purpose. Different diaryl ketones bearing
a halogen at the 2 position of one of the aryl groups were synthesized in this way from azines and
thiophenes. These were then involved in palladium-catalyzed ring closure: substrates underwent ex-
pected CH-activation-type arylation to afford fluorenone-type compounds, and were also subjected to
cyclization reactions leading to xanthones, notably in the presence of oxygen-containing substituents or
reagents.
Keywords:
Deprotometalation
Copper
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Lithium
Heterocycle
Palladium
1. Introduction
of the corresponding a-aryl-a-(2-bromo-3-pyridyl)methanols led
Ray and co-workers to successfully perform, within one step, both
Due to the biological interest of azafluorenones, for example, in
relation to their antifungal,1 antimicrobial,2 antimalarial,2b,3 and
cytotoxic2b,4 properties, or else for their role in the treatment of
neurodegenerative disorders,5 many studies have been devoted to
their synthesis. Among modern synthetic methods by which to
access them, lithiations6 and multicomponent reactions2d,4a,7 can
be cited. In 2010, Kraus and Kempema developed an approach us-
ing 2-bromoaryl 3-pyridyl ketones, prepared by reaction of 3-
pyridyllithiums with 2-bromobenzaldehydes followed by oxida-
tion, in intramolecular Heck cyclization reactions.2c Facile oxidation
oxidation and cyclization reactions.8
In the course of the development of lithium 2,2,6,6-
tetramethylpiperidido (LiTMP) bases for the deprotonative metal-
lation of aromatic compounds,9 we have developed the use of the
lithiocuprates prepared in situ from CuCl and LiTMP (2 equiv).10
Besides its possible use at rt, one main advantage of using the
resulting bimetallic base is the possible trapping of the formed
arylmetal species by aroyl chlorides to directly afford ketones. Ap-
plied to the synthesis of 2-chloro diaryl ketones, this method could
be combined with direct arylation through CeH bond activation by
intramolecular transition metal-catalysis,11 to afford azafluorenones
and related compounds. We have recently demonstrated the feasi-
bility of this two-step access to such tricyclic heterocycles;12 herein,
the details of our investigations, including the testingof a largerange
of substrates, and the unexpected outcomes observed for the cycli-
zation reactions are described.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
* Corresponding authors. Fax: þ33 2 2323 6955; e-mail addresses: valerie.thiery@
ꢀ
univ-lr.fr (V. Thiery), aehw2@cam.ac.uk (A.E.H. Wheatley), florence.mongin@
univ-rennes1.fr (F. Mongin).
0040-4020/$ e see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.030

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N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
2. Results and discussion
Before embarking on a study aimed at using the depro-
tocuprationearoylation sequence as the main step in the synthesis
of azafluorenones and related compounds, we sought to investigate
what the best source of lithiocuprate base might be. This could
conceivably involve preparation of the cuprate in situ from CuX
(X¼F, Cl, Br, I) and LiTMP (2 equiv) at 0 ꢀC in THF containing TMEDA
(1 equiv, TMEDA¼N,N,N0,N0-tetramethylethylenediamine).10c
Prior work on the deprotometalationeiodination of benzox-
azole involved the use of a (TMP)2ZneTMPLi mixture and afforded
only a 2% difference in yield between the quenched products when
the base was prepared from ZnBr2 (58% yield) or ZnCl2 (60% yield).13
In a similar way, the putative base (TMP)3FeLi gave approximately
equivalent yields (80% using FeCl2 vs 86% with FeBr2),14 suggesting
essentially equivalent reactivities for these two halides. In contrast,
prior work with FeI2 clearly gave a lower yield (62%) and it proved
substantially worse with FeF2 (27%).14 On the back of these data we
tested both CuCl and CuBr as potential substrates in the present
study; 2-chloropyridine was reacted with bases generated using
either copper(I) halide at rt for 2 h before interception of the cor-
responding arylmetal reagents with different benzoyl chlorides. In
line with expectation, lithiocuprates generated using CuBr and CuCl
achieved essentially similar yields (Table 1). However, it was noted
that, reproducibly, chloride reagents performed slightly better and
these were therefore selected for more detailed study (vide infra).
This notwithstanding, the isolation and full characterization of
Lipshutz-type (TMP)2CuLi$LiBr (B) (Fig. 1) suggests that it is iso-
structural with the known chloride12 analogue, so that the nominal
differences observed in product yield are unlikely to be attributable
to lithiocuprate structure based on the choice of bromide or chlo-
ride starting material.
Fig. 1. ORTEP diagram (50% probability, H atoms omitted) of the dimer of (TMP)2Cu-
Li$LiBr (B).
compounds, gathered in Table 2, could lead to heterocyclic tri-
cycles (or tetracycle in the case of 4) through cyclizing arylation.
It is worth noting that the trapping step was improved in the
thiophene series by raising the reaction temperature to 60 ꢀC
(entry 14).
We subsequently turned our attention to the cyclization of the
halogeno diaryl ketones, using them to yield azafluorenones and
related compounds through palladium-catalyzed intramolecular
arylation. The synthesis of 4-azafluorenone (16) has previously
been the subject of several studies,6b,15 and harsh conditions are
known to sometimes be required for its formation. For example,
Stauffer and co-workers prepared it by heating 2-phenylnicotinic
acid (obtained in two steps from 2-chloro-3-cyanopyridine) at
190 ꢀC in polyphosphoric acid.16 To attempt the conversion of 3-
benzoyl-2-chloropyridine (1) to the tricycle 16, we used a pro-
tocol previously described for the cyclization of 2-chloro diaryl
aniline to carbazole as a basis for this.17 The reactions were carried
out in the presence of catalytic amounts of Pd(OAc)2, an electron-
Based on the prior work with CuF and CuI, and on the data in
Table 1, CuCl was selected for preparing the lithiocuprate for use
in subsequent deprotocupration-aroylation work. The technique
to be used has previously been applied to the synthesis of the
heterocyclic ketones 1,10b 4,10c 5,10b 610b and 7,10b and has been
successfully used to reach the diaryl ketones 8e15. All these
Table 1
Deprotocupration of 2-chloropyridine using in situ prepared (TMP)2CuLi$LiCl (A) or (TMP)2CuLi$LiBr (B) followed by benzoylation
2 LiTMP
CuX
1) (TMP)2CuLi·LiX (1 equiv)
COAr
TMEDA (1 equiv)
THF, rt, 2 h
2) ClCOAr
N
Cl
N
Cl
1-3
Entry
1
ClCOAr
ClCOPh
CuX (base)
Product
Yielda (%)
CuCl (A)
1
78e90b,10
COPh
Cl
60e70b
60e80b
N
2
3
CuBr (B)
CuCl (A)
O
O
2
3
Cl
4
5
CuBr (B)
CuCl (A)
CuBr (B)
49
OMe
Cl
N
Cl
OMe
Cl
56e80b
55e61b
O
O
Cl
6
N
Cl
a
Yield after purification by column chromatography. The rest is starting material.
Reaction performed at least twice.
b

N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
10125
Table 2
Synthesis of the diaryl ketones 1e15 by deprotocupration followed by aroylation
1) (TMP)2CuLi·LiCl (1 equiv)
TMEDA (1 equiv)
O
Ar
H
Ar
1-3
THF, rt, 2 h 2) ClCOAr'
Ar'
Entry
1
AreH
ClCOAr0
R and/or X
H, CH
Product
Yielda (%)
1
9010b
O
O
H
2
2
2
3
4
5
6
4-OMe, CH
4-Cl, CH
3-OMe, CH
2-Cl, CH
2
3
8
9
80
80
66
59
65
X3
Cl
X3
R
R
N
Cl
4
4
N
Cl
2-Cl, N
10
H
COPh
Cl
7
8
ClCOPh
4
4410c
N
Cl
N
O
R
X
Cl, CH
11
56
O
R
H
Cl
Cl
Cl
Cl
X
9
10
Br, CH
Cl, N
12
13
43
39
N
OMe
N
OMe
O
Cl
O
O
O
Cl
Cl
Cl
Cl
H
11
12
13
14
5
6
7
9110b
5710b
5810b
MeO
N
N
OMe
MeO
N
OMe
Cl
O
H
N
OMe
H
OMe
O
Cl
N
N
MeO
N
OMe
MeO
N
OMe
Cl
O
O
O
H
S
35, 57b
S
14
15
Cl
Cl
O
H
S
85b
S
15
Cl
Cl
a
Yield after purification by column chromatography. The rest is starting material.
Trapping step performed at 60 ꢀC instead of rt.
b
rich and bulky trialkyl phosphine, and K2CO3 as a base. Different
transition metaleligand ratios were screened by using Cy3P
(Cy¼cyclohexyl) in DMF at 130 ꢀC, and the best result was observed
using 5 mol % of Pd(OAc)2 and 10 mol % of phosphine (incomplete
conversion was noted using 20 mol % of Pd(OAc)2 and 10 mol % of
phosphine) (Table 3, entries 1e4). Using DMA or dioxane as solvent
or even a tetraalkylammonium chloride, as recommended by Kraus
and Kempema for the cyclization of bromo diaryl ketones,2c proved
less suitable.
These optimized conditions in hand, the ketones 2 and 3 were
involved in the reaction. Whereas the former led to the expected
methoxy-substituted azafluorenone 17 in 69% yield (entry 5), only
4-azafluorenone (16, 19%) was isolated alongside unidentified side
products using the latter (entry 6). Cyclization of 3-benzoyl-2-
chloroquinoline (4) was achieved under the same reaction condi-
tions, affording 11H-indeno[1,2-b]quinolin-11-one (18) in 63% yield
(entry 8). In the case of 2-chloro-3-pyridyl 3-methoxyphenyl ke-
tone (8), for which two cyclization products are possible, the re-
action proved regioselective,18 the CeH bond activation occurring
para to the methoxy group in the course of the formation of the
tricycle 19 (entry 9). The structures of both 16 and 19 were con-
firmed unambiguously by X-ray diffraction (Fig. 2). As was observed
of its isomer 3, the reagent 9, expected to allow further coupling
thanks to the presence of a chloro group, did not afford the corre-
sponding chloro cyclized product. Indeed, 4-azafluorenone (16)
was again the sole identifiable product obtained using Cy3P or tBu3P
(entries 10 and 11). The use of 10, in which the 2-chlorophenyl is
replaced by a 2-chloro-3-pyridyl, also failed to lead to the isolation

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N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
Table 3
Synthesis of the azafluorenones 16e19 by intramolecular arylation
O
O
2
Pd(OAc)2 (x mol%)
L·HBF4 (y mol%)
X3
4
R
4
K2CO3 (2 equiv)
DMF, 130 °C, 24 h
R
N
Cl
3
N
X
Entry
1
Substrate
x
L (y)
Product
Yielda (%)
87
1
5
5
Cy3P (10)
16
O
O
2
3
4
Cy3P (15)
Cy3P (10)
Cy3P (10)
82
10
20
81
N
Cl
64b
N
O
O
5
2 (R¼OMe)
3 (R¼Cl)
5
Cy3P (10)
17
69c
6
7
5
5
Cy3P (10)
tBu3P (10)
d
d
dd
de
N
N
Cl
R
R
O
COPh
Cl
8
9
4
8
9
5
5
Cy3P (10)
Cy3P (10)
18
19
63b
N
N
O
O
OMe
60b
OMe
N
Cl
N
O
O
Cl
Cl
df
df
Cl
10
11
5
5
Cy3P (10)
tBu3P (10)
d
d
N
N
Cl
O
N
N
O
Cl
12
10
5
Cy3P (10)
d
dg
N
N
Cl
a
After purification by column chromatography.
Only organic product present in the crude.
Compound 2 was also recovered in 10% yield.
8-Chloro-5H-indeno[1,2-b]pyridin-5-one was not obtained but 16 was isolated in 19% yield.
8-Chloro-5H-indeno[1,2-b]pyridin-5-one was not obtained but 16 was isolated in 8% yield.
b
c
d
e
f
6-Chloro-5H-indeno[1,2-b]pyridin-5-one was not obtained but 16 and 3-benzoylpyridine were isolated in 18 and 13% yields, respectively, among unidentified products.
g
6-Chloro-5H-pyrido[30,40:4,5]cyclopenta[1,2-b]pyridin-5-one was not obtained but 5H-pyrano[2,3-b:6,5-b0]dipyridin-5-one 20 was isolated in 70% yield (only organic
product present in the crude), see Scheme 1.
Fig. 2. ORTEP diagrams (50% probability) of compounds 16 and 19.
of an azafluorenone (entry 12). Surprisingly, 5H-pyrano[2,3-b:6,5-
b0]dipyridin-5-one (20) was isolated instead in 70% yield
(Scheme 1), a result that could be attributed to the presence of
a carbonate reagent (vide infra).
We next turned to the cyclization through intramolecular aryla-
tion of the ketones prepared from methoxypyridines (Table 4). The
diaryl ketone 11, inwhich the chloro group is connected tothe phenyl
component, led to the corresponding azafluorenone, but did so less

N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
10127
O
Cl
O
Pd(OAc)2 (5 mol%)
Cy3P·HBF4 (10 mol%)
N
K2CO3 (2 equiv)
DMF, 130 °C, 24 h
N
Cl
O
N
N
10
20
70% yield
Scheme 1. Synthesis of 5H-pyrano[2,3-b:6,5-b0]dipyridin-5-one (20) from 10 and ORTEP diagram (50% probability) of compound 20.
efficiently than either 1, 2, 4 or 8 (Table 3). Using a tetraalkylammo-
nium chloride, as recommended by Kraus and Kempema for the
cyclization of bromo diaryl ketones,2c we were able to isolate the
expected methoxy-substituted 9H-indeno[2,1-c]pyridin-9-one 21 in
48% yield (Table 4, entry 1). Various attempts to increase the yield by
recourse to cesium carbonate or sodium tert-butoxide as base or to
tolueneorDMAas solventledto lowerconversions. It is worthnoting
that using tBu3P in this case did not lead to an azafluorenone but only
to the cyclized demethylated azaxanthone 22 together with the non-
cyclized dechlorinated product 23 (entry 2, Scheme 2).
Table 4
Synthesis of the azafluorenones 21 and 24 by intramolecular arylation
O
Pd(OAc)2 (5 mol%)
OMe
N(N)
O
X
MeO
N(N)
L·HBF4 (10 mol%)
(N)
R
(N)
K2CO3 (2 equiv)
DMF, 130 °C, 24 h
R
Entry
1
Substrate
L
Product
Yielda (%)
48b,c,d
11 (X¼Cl)
12 (X¼Br)
Cy3P
21
O
X
2
3
4
tBu3P
Cy3P
tBu3P
O
de
40,b,f 61f
N
OMe
O
81b
N
OMe
Cl
N
5
13
Cy3P
d
dg
N
O
N
OMe
N
OMe
O
Cl
6
7
5
Cy3P
24
30h
21
O
tBu3P
MeO
N
OMe
Cl
MeO
N
OMe
O
OMe O
N
MeO
8
6
7
Cy3P
d
di
N
O
Cl
9
Cy3P
d
dj
N
N
O
N
MeO
OMe
MeO
N
OMe
a
After purification by column chromatography.
Reaction performed in the presence of Pr4NCl (2 equiv).
Lower conversion without Pr4NCl.
Only organic product present in the crude.
1-Methoxy-9H-indeno[2,1-c]pyridin-9-one (21) was not obtained (see Scheme 2).
The rest is starting material.
6-Methoxy-5H-pyrido[30,40:4,5]cyclopenta[1,2-b]pyridin-5-one was not obtained, see Scheme 3.
Compound 5 (34%) was recovered; an unidentified product also formed.
4-Methoxy-5H-indeno[1,2-b]pyridin-5-one was not obtained, see Scheme 5.
2,4-Dimethoxy-5H-indeno[1,2-d]pyrimidin-5-one was not obtained, see Scheme 6.
b
c
d
e
f
g
h
i
j

10128
N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
O
O
Ph
Pd(OAc)2 (5 mol%)
t
Bu3P·HBF4 (10 mol%)
O
11
+
K2CO3 (2 equiv)
DMF, 130 °C, 24 h
N
N
OMe
22: 14% yield
23: 12% yield
Scheme 2. Synthesis of 5H-benzopyrano[2,3-b]pyridin-5-one (22) from 11.
The disappointing results obtained using 11 led us to also con-
sider the diaryl ketone 12, which bears a bromo group instead of
a chloro one. Its cyclization in the presence of Pr4NCl using either
t
Cy3P or Bu3P afforded the methoxy-substituted azafluorenone 21
in 40 and 81% yields, respectively. It transpired that Pr4NCl was not
actually required since 21 could still be isolated in 61% yield using
Cy3P without this ammonium salt (entries 3 and 4). Replacing
K2CO3 by Cs2CO3 also allowed us to isolate 21 using toluene as
solvent (110 ꢀC), but in a low 20% yield.
We next turned to the cyclization of the diaryl ketone 13, which
differs from 11 in that the 2-chlorophenyl ring is replaced by a 2-
chloro-3-pyridyl one. As noted using 10, no azafluorenone was
obtained, but instead the same azaxanthone 20 was isolated in 79%
yield (the crude also contained recovered 13 and unidentified
products, entry 5, Scheme 3). The formation of 20 from both 10 (in
this case, the substitution of a chloro group by a carbonate is con-
sidered to explain the presence of oxygen in the product) and 13
through a common intermediate can be explained by the mecha-
nism depicted in Scheme 4.
Fig. 3. ORTEP diagram (50% probability) of compound 24.
yield. The presence of Pr4NCl improved this yield to 51% (25 was the
only organic product present in the crude, entry 8, Table 4,
Scheme 5).
From the pyrimidyl ketone 7, neither an azafluorenone nor an
azaxanthone was formed, but a complex mixture resulted instead.
Doubling the amount of catalyst led to a complete degradation of
the substrate. Crystals suitable for X-ray diffraction were isolated in
this case and therefore allowed the pyrimidine ring-opening
product shown in Scheme 6 to be evidenced. To rationalize the
unexpected formation of 26, the plausible mechanistic sequence
depicted in Scheme 7 was proposed.
O
Cl
O
Pd(OAc)2 (5 mol%)
Cy3P·HBF4 (10 mol%)
N
8H-Indeno[2,1-b]thiophen-8-one (27) has previously been effi-
ciently synthesized by Campo and Larock from 3-(2-bromophenyl)
thiophene using palladium-catalyzed cyclocarbonylation.19 Start-
ing from 14, which bears the chloro group on the phenyl ring, both
Cy3P and tBu3P were tested as ligand in DMF at 130 ꢀC, affording 27
in 90 and 38% yields, respectively. Lower 35 and 17% yields were,
respectively, obtained from 15, for which the chloro group is
present on the thiophene ring (Table 5).
K2CO3 (2 equiv)
N
OMe
O
N
N
DMF, 130 °C, 24 h
13
20
79% yield
Scheme 3. Synthesis of 5H-pyrano[2,3-b:6,5-b0]dipyridin-5-one (20) from 13.
10
substitution and
oxidative addition
R = CO2K: - CO2
- KCl
O
O
3. Biological evaluation
A preliminary study has been carried out to investigate the cy-
totoxic potential of the fluorenone derivatives 16, 17, 18, 21, 27 and
the azaxanthones 20 and 25. The anti-proliferative activity of the
derivatives was determined using breast cancer cell lines: MCF-7,
A549 human lung adenocarcinoma cells, and A2058 human mel-
anoma cells. MCF-7 is an invasive differentiated mammary epi-
thelial breast cancer cell line; A549 is an adenocarcinomic alveolar
epithelial cell line, and A2058 is a highly invasive and tumorigenic
epithelial melanoma cell line. These three cell lines are used
worldwide to screen and compare the anti-proliferative activity of
new molecules vs standard anticancer compounds. The molecules
tested fell short of exhibiting moderate-to-strong activity at 10 mM
with the selected cell lines, with none of the molecules causing
more than a 10% inhibition of growth. Because of structural simi-
larity with natural azafluorenone antimicrobial agents such as
Onychine,2b the synthesized compounds 16, 17, 18, 21, and the
thiofluorenone analogue 27 were then screened for their antibac-
terial activity against a panel of Gram-positive and Gram-negative
reference strain bacteria (Escherichia coli ATCC25922, Salmonella
enterica serovar Typhimurium CIP5858, Pseudomonas aeruginosa
ATCC27853, Staphylococcus aureus ATCC25923, Bacillus subtilis
CIP52.62), and for their antifungal activity against pathogenic strain
(II)
Pd
N
N
N
N
O
R
O
Pd
R = Me: - MeCl
(II)
Cl
reductive
elimination
oxidative addition
13
Scheme 4. Mechanism proposed to explain the formation of 5H-pyrano[2,3-b:6,5-b0]
20
dipyridin-5-one (20) from 10 and 13 through
a common intermediate (ligands
omitted).
As observed for 11, the cyclization of the dimethoxy ketone 5
furnished the expected 9H-indeno[2,1-c]pyridin-9-one 24 (Fig. 3).
However, the yield proved to be lower in the case of 24 since it was
isolated in 30 and 21% yields, respectively, using Cy3P and tBu3P as
ligand. The presence of a second electron-donating methoxy group
on the substrate 5 could be responsible for the reduced reactivity
observed; indeed, the ketone 5 was recovered in 34% yield using
Cy3P as ligand (entries 6 and 7).
Compared with 11, the ketone 6, for which the methoxy group
was moved from the 2- to the 4-position of the pyridine ring, gave
a different result. Indeed, when treated under the general cycliza-
tion conditions using Cy3P, no azafluorenone was obtained, but
10H-benzopyrano[3,2-c]pyridin-10-one (25) formed instead in 31%

N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
10129
Pd(OAc)2 (5 mol%)
Cy3P·HBF4 (10 mol%)
OMe
N
O
Cl
O
K2CO3 (2 equiv)
Pr4NCl (2 equiv)
DMF, 130 °C, 24 h
O
6
25
N
51% yield
Scheme 5. Synthesis of 10H-benzopyrano[3,2-c]pyridin-10-one (25) from 6 and ORTEP diagram (50% probability) of compound 25.
O
NHMe
O
Cl
O
OMe
N
Pd(OAc)2 (10 mol%)
Cy3P·HBF4 (20 mol%)
K2CO3 (2 equiv)
Pr4NCl (2 equiv)
DMF, 130 °C, 24 h
N
N
OMe
Me
7
26
17% yield
Scheme 6. Degradation of 7 under palladium catalysis and ORTEP diagram (50% probability) of compound 26.
7
oxidative addition
O
O
O
N
N
NMe
Me
OMe
(II)
Pd
N
O
O
P(dII)
O
N
N
O
Me
Pd
O
Me
Me
Cl
Cl
(II)
Cl
reductive
O
O
O
CO
NMe
N
elimination
26
Me
O
(II)
Pd O
hydrolysis
P(dII)
N
N
Me
Cl
Me
Cl
Scheme 7. Mechanistic sequence proposed for the formation of 26.
Table 5
Synthesis of 8H-indeno[2,1-b]thiophen-8-one (27) by intramolecular arylation
O
Pd(OAc)2 (5 mol%)
L·HBF4 (10 mol%)
S
14 or 15
K2CO3 (2 equiv)
DMF, 130 °C, 24 h
27
Entry
1
Substrate
L
Yielda (%)
O
Cl
14
15
Cy3P
90
S
S
2
3
tBu3P
Cy3P
38b
35c
O
4
tBu3P
17d
Cl
a
After purification by column chromatography.
The rest corresponds to recovered 14 but also to the formation of an unidentified product.
The formation of 2-benzoylthiophene was also noted.
b
c
d
The rest corresponds to recovered 15 but also to the formation of unidentified products.

10130
N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
(Candida glabrata DSM6425). However, no antimicrobial activity
was detected against bacteria or yeast.
solvent was evaporated under reduced pressure, and the product
was isolated after purification by flash chromatography on silica gel
(the eluent is given in the product description).
4. Conclusion
5.2.1. 2-Chloro-3-pyridyl phenyl ketone (1).10b Compound 1 was
prepared from 2-chloropyridine (using benzoyl chloride) and was
isolated (eluent: 9:1 heptane/AcOEt) as a yellow oil (yield: 90%): 1H
In summary, different heterocyclic diaryl ketones have been
synthesized by sequential deprotocuprationearoylation. For diaryl
ketone reagents bearing a halogen at the 2-position of one of the aryl
groups cyclization under palladium catalysis was considered. In the
absence of a methoxy or a second chloro group at the position ad-
jacent to the ketone function, fluorenones were obtained. The
presence of a second chloro group was not tolerated, and resulted in
mixtures containing dechlorinated products. The presence of
a methoxygroup led to lower yields of fluorenones, withunexpected
xanthones being obtained in some cases. In the case of the dime-
thoxylated pyrimidyl ketone 7, ring-opening of the pyrimidine ring
was established. Lastly, efficient thiofluorenone formation was
demonstrated, though the efficiency of this reaction proved to be
strongly dependent on the location of the chloro-substituent.
NMR (300 MHz, CDCl3)
d
7.38 (dd,1H, J¼7.5and4.9 Hz), 7.42e7.50 (m,
2H), 7.61 (tt, 1H, J¼7.4 and 1.3 Hz), 7.72 (dd, 1H, J¼7.5 and 2.0 Hz),
7.75e7.81 (m, 2H), 8.52 ppm (dd, 1H, J¼4.9 and 2.0 Hz). 13C NMR
(75 MHz, CDCl3)
d 122.3 (CH), 128.9 (2CH), 130.0 (2CH), 134.3 (CH),
134.9(C),135.7 (C),138.0(CH),147.7(C),150.9(CH),193.3ppm (C]O).
5.2.2. 2-Chloro-3-pyridyl 4-methoxyphenyl ketone (2). Compound 2
was prepared from 2-chloropyridine (using 4-methoxybenzoyl
chloride) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow
powder (yield: 80%): mp 79 ꢀC; 1H NMR (300 MHz, CDCl3)
d 3.89 (s,
3H), 6.96(d, 2H, J¼9.0 Hz), 7.38 (dd,1H, J¼7.5and 4.8 Hz), 7.72 (dd,1H,
J¼7.5 and 1.9 Hz), 7.78 (d, 2H, J¼4.8 Hz), 8.54 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3) d 55.8 (CH3),114.3 (2CH),122.4 (CH),128.9 (C),132.7
5. Experimental section
5.1. General
(2CH),135.5 (C),137.8 (CH),147.8 (C),150.7 (CH),164.6 (C),192.0 ppm
(C]O). These NMR data are analogous to those described
previously.25
All reactions were performed in Schlenk tubes under an argon
atmosphere. THF was distilled over sodium/benzophenone. DMF
was dried over CaH2 and distilled before use. Liquid chromatography
separations were achieved on silica gel Merck-Geduran Si 60
5.2.3. 4-Chlorophenyl 2-chloro-3-pyridyl ketone (3). Compound 3
was prepared from 2-chloropyridine (using 4-chlorobenzoyl chlo-
ride) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow
powder (yield: 80%): mp 56 ꢀC; 1H NMR (300 MHz, CDCl3)
d 7.40
(63e200
m
m). Nuclear magnetic resonance spectra were acquired
(dd, 1H, J¼7.5 and 4.8 Hz), 7.44e7.48 (m, 2H), 7.71e7.76 (m, 3H),
using Bruker AC-300 spectrometer (300 MHz and 75 MHz for 1H and
8.57 (dd, 1H, J¼4.8 and 1.9 Hz); 13C NMR (75 MHz, CDCl3)
d 122.5
13C, respectively).1H chemical shifts (
d
) are given in parts per million
(CH), 129.4 (2CH), 131.4 (2CH), 134.2 (C), 134.6 (C), 138.1 (CH), 141.0
(C), 147.8 (C), 151.2 (CH), 192.3 ppm (C]O). These NMR data are
analogous to those described previously.26
(ppm) relative to the residual solvent peak, and 13C chemical shifts
relative to the central peak of the solvent signal. High-resolution
mass spectrometry measurements were performed at the Centre
Regional de Mesures Physiques de l’Ouest (CRMPO) in Rennes.
5.2.4. 2-Chloro-3-benzoylquinoline (4).10c Compound 4 was pre-
pared from 2-chloroquinoline (using benzoyl chloride) and was
isolated (eluent: 7:3 heptane/AcOEt) as a beige powder (yield: 44%):
ꢀ
X-ray crystallography. The samples 16, 19, 20 and 24e26 were
studied with graphite monochromatized Mo-K
a
radiation
(l¼0.71073 A). X-ray diffraction data were collected at T¼150(2) K
mp 98 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.43e7.48 (m, 2H), 7.55e7.61
(m, 2H), 7.77e7.84 (m, 4H), 8.05 (d, 1H, J¼8.5 Hz), 8.18 ppm (s, 1H);
13C NMR (75 MHz, CDCl3)
126.0 (C), 127.9 (CH), 128.1 (CH), 128.5
ꢂ
using APEXII, Bruker-AXS diffractometer. All structures were solved
by direct methods using the SIR97 program,20 and then refined
with full-matrix least-square methods based on F2 (SHELX-97)21
with the aid of the WINGX program.22 All non-hydrogen atoms
were refined with anisotropic atomic displacement parameters. H
atoms were finally included in their calculated positions. Molecular
diagrams were generated by ORTEP-3 (version 2.02).22 For B
a Nonius Kappa-CCD and an Oxford Cryostream low-temperature
device were used. Structure solution used direct methods,23 with
full-matrix least-squares refinement based on F2.24 Non-hydrogen
atoms were refined anisotropically and a riding model with ideal-
ized geometry employed for the refinement of H atoms.
d
(CH),128.8 (2CH),130.1 (2CH),131.9 (CH),132.4 (C),134.1 (CH),136.2
(C), 138.5 (CH), 146.5 (C), 147.9 (C), 193.3 ppm (C]O).
5.2.5. 2-Chlorophenyl 2,6-dimethoxy-3-pyridyl ketone (5).10b
Compound 5 was prepared from 2,6-dimethoxypyridine (using 2-
chlorobenzoyl chloride) and was isolated (eluent: 9:1 heptane/
AcOEt) as a yellow powder (yield: 91%): mp 55 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
3.81 (s, 3H), 3.98 (s, 3H), 6.37 (d, 1H, J¼8.4 Hz),
7.31e7.37 (m, 4H), 7.98 ppm (d, 1H, J¼8.4 Hz); 13C NMR (75 MHz,
CDCl3)
d 54.0 (CH3), 54.2 (CH3), 102.7 (CH), 113.1 (C), 126.8 (CH),
128.7 (CH), 129.6 (CH), 130.6 (CH), 130.9 (C), 141.1 (C), 144.1 (CH),
5.2. General procedure 1: deprotonation using the lith-
iumecopper base prepared from CuCl (1 equiv) and LiTMP
(2 equiv) before trapping with an aroyl chloride
163.0 (C), 166.3 (C), 192.1 ppm (C]O).
5.2.6. 2-Chlorophenyl
4-methoxy-3-pyridyl
ketone
(6).10b
Compound 6 was prepared from 4-methoxypyridine (using 2-
chlorobenzoyl chloride) and was isolated (eluent: 2:8 heptane/
AcOEt) as a yellow powder (yield: 57%): mp 107 ꢀC; 1H NMR
A stirred cooled (0 ꢀC) solution of LiTMP prepared at 0 ꢀC in THF
(6 mL) from 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and
BuLi (1.6 M hexanes solution, 10 mmol) was treated with TMEDA
(0.77 mL, 5.0 mmol) and CuCl (495 mg, 5.0 mmol). The mixture was
stirred for 15 min at 0 ꢀC before introduction of the required sub-
strate (5 mmol). After 2 h at rt, a solution of the required aroyl
chloride (10 mmol) in THF (3 mL) was added. The mixture was
stirred at rt or 60 ꢀC overnight before addition of a 1 M aqueous
solution of NaOH (20 mL) and extraction with Et2O (2ꢁ20 mL).
After washing the organic phase with an aqueous saturated solu-
tion of NH4Cl (10 mL) and drying over anhydrous Na2SO4, the
(300 MHz, C6D6)
7.45e7.49 (m, 1H), 8.42e9.76 (br m, 2H); 13C NMR (75 MHz, C6D6)
55.0 (CH3), 108.8 (C), 126.7 (CH), 128.3 (CH), 130.1 (CH), 130.1 (CH),
d 3.76 (s, 3H), 6.95e7.05 (m,1H), 7.31e7.43 (m, 3H),
d
131.3 (CH), 132.1 (C), 140.8 (C), 152.7 (CH), 154.5 (CH), 164.1 (C),
192.3 ppm (C]O).
5.2.7. 2-Chlorophenyl 2,4-dimethoxypyrimidin-5-yl ketone (7).10b
Compound 7 was prepared from 2,4-dimethoxypyrimidine (using
2-chlorobenzoyl chloride) and was isolated (eluent: 8:2 heptane/

N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
10131
AcOEt) as an orange powder (yield: 58%): mp 74 ꢀC; 1H NMR
(300 MHz, CDCl3) 3.91 (s, 3H), 4.06 (s, 3H), 7.31e7.44 (m, 4H),
8.62 ppm (br s, 1H); 13C NMR (75 MHz, CDCl3)
54.7 (CH3), 55.7
(CH3), 114.1 (C), 127.0 (CH), 129.4 (CH), 129.9 (CH), 131.3 (C), 131.6
(CH), 139.4 (C), 163.4 (CH), 167.0 (C), 169.6 (C), 190.8 ppm (C]O).
heptane/AcOEt) as a yellow powder (yield: 39%): mp 87 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
d
3.79 (s, 3H), 7.08 (dd, 1H, J¼7.5 and
d
4.9 Hz), 7.38 (br m, 1H), 7.82 (dd, 1H, J¼7.5 and 1.4 Hz), 8.14 (dd,
1H, J¼7.5 and 2.0 Hz), 8.40 (dd, 1H, J¼4.9 and 2.0 Hz), 8.52 ppm
(br m, 1H); 13C NMR (75 MHz, CDCl3)
d 54.1 (CH3), 117.5 (CH),
120.9 (C), 122.5 (CH), 136.6 (C), 138.2 (CH), 140.7 (CH), 147.7 (C),
5.2.8. 2-Chloro-3-pyridyl 3-methoxyphenyl ketone (8). Compound 8
was prepared from 2-chloropyridine (using 3-methoxybenzoyl
chloride) and was isolated (eluent: 8:2 heptane/AcOEt) as an or-
ange powder (yield: 66%): mp 62 ꢀC; 1H NMR (300 MHz, CDCl3)
150.7 (CH), 152.1 (CH), 162.1 (C), 192.0 ppm (C]O); HRMS (ESI):
35
ClN2NaO2 [(MþNa)þ
] 271.0250, found
ꢂ
m/z calcd for
C
H
12
9
271.0251.
d
3.72 (s, 3H), 7.05 (ddd, 1H, J¼8.1, 2.6 and 1.0 Hz), 7.13 (ddd, 1H,
5.2.14. 2-Chlorophenyl 2-thienyl ketone (14). Compound 14 was
prepared from thiophene (using 2-chlorobenzoyl chloride, trapping
step at 60 ꢀC) and was isolated (eluent: 97:3 heptane/AcOEt) as an
J¼7.6, 2.6 and 1.3 Hz), 7.22e7.30 (m, 3H), 7.63 (dd, 1H, J¼7.5 and
1.9 Hz), 8.41 (d, 1H, J¼4.6 Hz); 13C NMR (75 MHz, CDCl3)
d 55.6
(CH3), 113.6 (CH), 120.9 (CH), 122.3 (CH), 123.3 (CH), 129.9 (CH),
orange oil (yield: 57%): 1H NMR (300 MHz, CDCl3)
d
7.12 (dd, 1H,
J¼4.9 and 3.8 Hz), 7.33e7.49 (m, 5H), 7.76 ppm (dd, 1H, J¼4.9 and
1.2 Hz); 13C NMR (75 MHz, CDCl3)
126.7 (CH), 128.4 (CH), 128.0
135.0 (C), 137.2 (CH), 137.9 (C), 147.8 (C), 150.9 (CH), 160.1 (C),
35
193.2 ppm (C]O); HRMS (ESI): m/z calcd for C
H
ClNaNO2
d
13 10
[(MþNa)þꢂ] 270.0298, found 270.0298.
(CH), 130.4 (CH), 131.3 (C), 131.4 (CH), 135.8 (CH), 136.1 (CH), 138.5
(C), 143.8 (C), 187.2 ppm (C]O). These NMR data are analogous to
those described previously.28
5.2.9. 2-Chlorophenyl 2-chloro-3-pyridyl ketone (9).12 Compound 9
was prepared from 2-chloropyridine (using 2-chlorobenzoyl chlo-
ride) and was isolated (eluent: 9:1 heptane/AcOEt) as an orange oil
5.2.15. 3-Chloro-2-thienyl phenyl ketone (15).12 Compound 15 was
prepared from 3-chlorothiophene (using benzoyl chloride, trapping
step at 60 ꢀC) and was isolated (eluent: 9:1 heptane/AcOEt) as
(yield: 59%): 1H NMR (300 MHz, CDCl3)
d 7.35e7.51 (m, 4H), 7.57
(dd, 1H, J¼7.6 and 1.7 Hz), 7.88 (dd, 1H, J¼7.6 and 2.0 Hz), 8.52 ppm
(dd, 1H, J¼4.8 and 2.0 Hz); 13C NMR (75 MHz, CDCl3)
d
122.7 (CH),
a yellow viscous oil (yield: 85%): 1H NMR (300 MHz, CDCl3)
d
6.99
(d, 1H, J¼5.2 Hz), 7.43e7.46 (m, 2H), 7.54e7.60 (m, 2H),
7.81e7.83 ppm (m, 2H); 13C NMR (75 MHz, CDCl3)
128.4 (2CH),
127.3 (CH), 130.9 (CH), 131.2 (CH), 132.8 (C), 133.3 (CH), 134.9 (C),
137.1 (C), 139.5 (CH), 148.6 (C), 151.8 (CH), 193.1 ppm (C]O); HRMS
(ESI): m/z calcd for C
273.9805.
d
35
H
Cl2NNaO [(MþNa)þꢂ] 273.9802, found
129.6 (2CH), 130.1 (CH), 130.7 (CH), 133.0 (CH), 134.3 (C), 137.8 (C),
12
7
187.8 ppm (C]O), one C not seen; HRMS (ESI): m/z calcd for
35
C
11
H
8
ClOS [(MþH)þꢂ] and C11H375ClNaOS [(MþNa)þꢂ] 222.9984 and
5.2.10. Bis(2-chloro-3-pyridyl) ketone (10). Compound 10 was pre-
pared from 2-chloropyridine (using 2-chloronicotinoyl chloride)
and was isolated (eluent: 7:3 heptane/AcOEt) as a yellow powder
244.9804, found 222.9999 and 244.9803, respectively.
5.3. General procedure used for the cyclization step
(yield: 65%): mp 109 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.43 (dd, 2H,
J¼7.5 and 4.8 Hz), 7.98 (dd, 2H, J¼7.5 and 1.8 Hz), 8.59 ppm (br s,
2H); 13C NMR (75 MHz, CDCl3)
122.8 (2CH), 134.1 (2C), 139.8
A degassed mixture of K2CO3 (0.28 g, 2.0 mmol), Pd(OAc)2 (the
amount is given in the product description), the ligand (its nature
and the amount is given in the product description), the required
ketone (1.0 mmol), and in some cases Pr4NCl (0.44 g, 2 mmol), in
DMF (4 mL) was heated at 130 ꢀC for 24 h. After filtration over
a Celite pad, washing using CH2Cl2 (3ꢁ10 mL), and removal of the
solvent under reduced pressure, the product was isolated after
purification by flash chromatography on silica gel (the eluent is
given in the product description).
d
(2CH), 148.5 (2C), 152.3 (2CH), 192.2 ppm (C]O). These NMR data
are analogous to those described previously.27
5.2.11. 2-Chlorophenyl
2-methoxy-3-pyridyl
ketone
(11).12
Compound 11 was prepared from 2-methoxypyridine (using 2-
chlorobenzoyl chloride) and was isolated (eluent: 9:1 heptane/
AcOEt) as a yellow powder (yield: 56%): mp 65 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
3.81 (s, 3H), 7.01 (dd, 1H, J¼7.5 and 4.9 Hz),
7.31e7.41 (m, 3H), 7.44e7.47 (m,1H), 7.99 (dd,1H, J¼7.5 and 2.0 Hz),
5.3.1. 5H-Indeno[1,2-b]pyridin-5-one (16). Compound 16 was ob-
8.34 ppm (dd, 1H, J¼4.9 and 2.0 Hz); 13C NMR (75 MHz, CDCl3)
tained from 1 (using Pd(OAc)2 (5 mol %, 50
mmol, 11 mg) and
d
53.9 (CH3), 117.1 (CH), 121.8 (C), 126.9 (CH), 129.7 (CH), 129.9 (CH),
Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent:
131.5 (CH), 131.6 (C), 139.7 (C), 140.6 (CH), 151.3 (CH), 162.2 (C),
8:2 heptane/AcOEt) as a yellow powder (yield: 87%): mp 138 ꢀC
35
193.7 ppm (C]O); HRMS (ESI): m/z calcd for
C
H
13 11
ClNO2
(lit.29 137e138 ꢀC); 1H NMR (300 MHz, CDCl3)
d
7.21 (1H, dd, J¼7.4
35
[(MþH)þꢂ] and C13
H
10
ClNNaO2 [(MþNa)þꢂ] 248.0478 and 270.0298,
and 5.1 Hz), 7.44 (1H, td, J¼7.5 and 0.9 Hz), 7.61 (1H, td, J¼7.5 and
1.1 Hz), 7.73 (1H, ddd, J¼7.5, 1.1 and 0.9 Hz), 7.86 (1H, dt, J¼7.5 and
0.9 Hz), 7.90 (1H, dd, J¼7.4 and 1.6 Hz), 8.61 ppm (1H, dd, J¼5.1 and
found 248.0483 and 270.0298, respectively.
5.2.12. 2-Bromophenyl
2-methoxy-3-pyridyl
ketone
(12).
1.6 Hz); 13C NMR (75 MHz, CDCl3)
d 121.0 (CH), 123.4 (CH), 124.3
Compound 12 was prepared from 2-methoxypyridine (using 2-
bromobenzoyl chloride) and was isolated (eluent: 9:1 heptane/
AcOEt) as a yellow powder (yield: 43%): mp 80 ꢀC; 1H NMR
(CH),128.5 (C),131.1 (CH),131.4 (CH), 134.8 (C), 135.4 (CH),143.6 (C),
154.0 (CH), 165.1 (C), 191.8 ppm (C]O). These NMR data are anal-
ogous to those described previously.30
(300 MHz, CDCl3)
d
3.82 (s, 3H), 6.94 (dd, 1H, J¼7.5 and 4.9 Hz),
X-ray data for compound 16: C12H7NO, M¼181.19, monoclinic,
¼108.686(13)ꢀ,
ꢂ
7.28e7.35 (m, 1H), 7.38e7.40 (m, 2H), 7.62 (dd, 1H, J¼7.5 and
0.9 Hz), 8.03 (dd, 1H, J¼7.5 and 2.0 Hz), 8.38 ppm (dd, 1H, J¼4.9 and
P21/c, a¼12.068(3), b¼5.1986(15), c¼14.465(3) A,
b
3
V¼859.7(4) A , Z¼4, rc¼1.4 g cmꢃ3
,
m
¼0.090 mmꢃ1. A final re-
ꢂ
2.0 Hz); 13C NMR (75 MHz, CDCl3)
d
53.9 (CH3), 117.1 (CH), 119.6 (C),
finement on F2 with 1964 unique intensities and 128 parameters
121.2 (C), 127.4 (CH), 129.5 (CH), 131.5 (CH), 133.1 (CH), 140.9 (CH),
converged at
u
R(F2)¼0.0996 (R(F)¼0.0452) for 1460 observed re-
141.7 (C), 151.5 (CH), 162.2 (C), 194.3 ppm (C]O); HRMS (ESI): m/z
flections with I>2s(I). CCDC 944094.
79
calcd for C
H
BrNNaO2 [(MþNa)þꢂ] 313.9793, found 313.9795.
13 10
5.3.2. 8-Methoxy-5H-indeno[1,2-b]pyridin-5-one (17).12 Compound
17 was prepared from 2 (using Pd(OAc)2 (5 mol %, 50 mol, 11 mg)
5.2.13. 2-Chloro-3-pyridyl 2-methoxy-3-pyridyl ketone (13).
Compound 13 was prepared from 2-methoxypyridine (using 2-
chloronicotinoyl chloride) and was isolated (eluent: 8:2
m
and Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated
(eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 69%): mp

10132
N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
113 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.96 (s, 3H), 6.92 (dd, 1H, J¼8.3
161.0 (C), 191.5 (C]O); HRMS (ESI): m/z calcd for C13H9NNaO2
[(MþNa)þꢂ] 234.0531, found 234.0532.
and 2.3 Hz), 7.24 (dd,1H, J¼7.4 and 5.1 Hz), 7.41 (d,1H, J¼2.3 Hz), 7.7
(d, 1H, J¼8.3 Hz), 7.89 (dd, 1H, J¼7.4 and 1.6 Hz), 8.62 ppm (dd, 1H,
J¼5.1 and 1.6 Hz); 13C NMR (75 MHz, CDCl3)
d
56.1 (CH3), 106.4 (CH),
5.3.7. 5H-Benzopyrano[2,3-b]pyridin-5-one (22). Compound 22
116.7 (CH), 123.7 (CH), 126.4 (CH), 127.8 (C), 129.8 (C), 131.2 (CH),
146.5 (C), 153.4 (CH), 164.2 (C), 166.1 (C), 190.3 ppm (C]O); HRMS
(ESI): m/z calcd for C13H9NNaO2 [(MþNa)þꢂ] 234.0531, found
234.0534.
was prepared from 11 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg)
t
and Bu3P$HBF4 (10 mol %, 0.10 mmol, 29 mg)) and was isolated
(eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 14%): mp
180 ꢀC (lit.32 178e179 ꢀC); 1H NMR (300 MHz, CDCl3)
d 7.45e7.57
(m, 2H), 7.62 (dd, 1H, J¼8.4 and 0.6 Hz), 7.79 (ddd, 1H, J¼8.4, 6.9 and
5.3.3. 11H-Indeno[1,2-b]quinolin-11-one (18). Compound 18 was
1.5 Hz), 8.32 (dd, 1H, J¼8.1 and 1.8 Hz), 8.72 (dd, 1H, J¼7.8 and
obtained from 4 (using Pd(OAc)2 (5 mol %, 50
m
mol, 11 mg) and
1.8 Hz), 8.75 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 116.9 (C), 118.7
Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent:
(CH), 121.3 (CH), 121.7 (C), 124.8 (CH), 126.8 (CH), 135.8 (CH), 137.5
(CH), 154.3 (CH), 155.9 (C), 160.5 (C), 177.8 (C). These NMR data are
analogous to those described previously.32
8:2 heptane/AcOEt) as a yellow powder (yield: 63%): mp 173 ꢀC
(lit.29 176 ꢀC); 1H NMR (300 MHz, CDCl3)
d 7.49e7.56 (2H, m), 7.69
(1H, td, J¼7.5 and 1.1 Hz), 7.82 (1H, td, J¼7.0 and 1.4 Hz), 7.84 (1H, dt,
J¼7.5 and 0.7 Hz), 7.88 (1H, dd, J¼8.2 and 1.2 Hz), 8.11e8.16 (2H, m),
5.3.8. 2-Methoxy-3-pyridyl phenyl ketone (23). Compound 23 was
8.4 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
121.9 (CH), 124.2 (CH), 127.1
prepared from 11 (usingPd(OAc)2 (5 mol %, 50m
mol,11 mg) and tBu3P$
(C), 127.3 (CH), 127.7 (C), 129.9 (CH), 130.6 (CH), 131.6 (CH), 132.1
(CH), 132.5 (CH), 135.6 (CH), 137.5 (C), 143.9 (C), 150.7 (C), 162.1 (C),
190.9 ppm (C]O). The 1H NMR data are analogous to those de-
scribed previously.31
HBF4 (10 mol %, 0.10 mmol, 29 mg)) and was similarly isolated (yield:
12%). The analyses are analogous to those described previously.10b
5. 3. 9 . 1, 3 - Di me t ho xy-9H- i n de no[ 2,1 - c ]py r id i n-9-on e
(24). Compound 24 was prepared from 5 (using Pd(OAc)2 (5 mol %,
5.3.4. 7-Methoxy-5H-indeno[1,2-b]pyridin-5-one (19). Compound
50
mmol, 11 mg) and Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and
19 was prepared from 8 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg)
and Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated
was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder
(yield: 30%): mp 166 ꢀC; 1H NMR (300 MHz, CDCl3)
d 4.02 (s, 3H),
(eluent: 8:2 heptane/AcOEt) as an orange powder (yield: 60%): mp
4.1 (s, 3H), 6.52 (s, 1H), 7.36e7.51 (m, 3H), 7.70 (d, 1H, J¼7.1 Hz); 13
C
190 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.82 (s, 3H), 7.07e7.15 (m, 2H),
NMR (75 MHz, CDCl3) d 54.2 (CH3), 54.6 (CH3), 96.1 (CH), 106.8 (C),
7.18 (d, 1H, J¼2.4 Hz), 7.79 (d, 1H, J¼8.2 Hz), 7.84 (dd, 1H, J¼7.4 and
121.3 (CH), 123.7 (CH), 131.1 (CH), 133.4 (CH), 136.3 (C), 140.3 (C),
158 (C), 160.5 (C), 168.3 (C), 189.3 (C]O); HRMS (ESI): m/z calcd for
1.6 Hz), 8.53 (dd, 1H, J¼5.2 and 1.4 Hz); 13C NMR (75 MHz, CDCl3)
d
55.9 (CH3), 109.4 (CH), 120.9 (CH), 122.3 (CH), 122.5 (CH), 128.6
C
14H11NNaO3 [(MþNa)þꢂ] 264.0637, found 264.0635.
(CH), 131.4 (CH), 135.9 (C), 136.8 (C), 153.8 (CH), 162.5 (C), 165.5 (C),
X-ray data for compound 24: C14H11NO3, M¼241.24, monoclinic,
191.7 (C]O); HRMS (ESI): m/z calcd for C13H9NNaO2 [(MþNa)þ
]
P21/n, a¼5.2623(4), b¼17.1350(9), c¼12.1808(9) A,
b
¼93.170(3)ꢀ,
ꢂ
ꢂ
3
ꢂ
234.0531, found 234.0531.
V¼1096.66(13) A , Z¼4, rc¼1.461 g cmꢃ3
, m
¼0.104 mmꢃ1. A final
X-ray data for compound 19: C13H9NO2, M¼211.21, monoclinic,
refinement on F2 with 2506 unique intensities and 166 parameters
ꢂ
P21/a, a¼15.323(3), b¼3.8645(7), c¼17.224(3) A,
b
¼112.183(6)ꢀ,
converged at
flections with I>2s(I). CCDC 944097.
u
R(F2)¼0.0962 (R(F)¼0.0397) for 2049 observed re-
V¼944.4(3) A , Z¼4, rc¼1.485 g cmꢃ3
,
m
¼0.102 mmꢃ1. A final re-
3
ꢂ
finement on F2 with 2082 unique intensities and 147 parameters
converged at
u
R(F2)¼0.1524 (R(F)¼0.0569) for 1532 observed re-
5.3.10. 10H-Benzopyrano[3,2-c]pyridin-10-one (25). Compound 25
was prepared from 6 (using Pd(OAc)2 (5 mol %, 50 mol, 11 mg) and
flections with I>2
s
(I). CCDC 944095.
m
Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent:
5.3.5. 5H-Pyrano[2,3-b:6,5-b0]dipyridin-5-one (20). Compound 20
was prepared from 10 or 13 (using Pd(OAc)2 (5 mol %, 50 mol,
1:1 heptane/AcOEt) as a white powder (yield: 51%): mp 185 ꢀC (lit.33
m
184 ꢀC); 1H NMR (300 MHz, CDCl3)
d 7.40e7.54 (m, 3H), 7.79 (dt, 1H,
11 mg) and Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was
isolated (eluent: 7:3 heptane/AcOEt) as a yellow powder (yield: 70
or 79%, respectively): mp 240 ꢀC (lit.27 240 ꢀC); 1H NMR (300 MHz,
J¼7.2 and 1.7 Hz), 8.34 (dd, 1H, J¼7.8 and 1.7 Hz), 8.82 (d, 1H,
J¼5.2 Hz), 9.52 (s, 1H). These data are in accordance with the liter-
ature.33 13C NMR (75 MHz, CDCl3)
d 112.8 (CH), 118.3 (CH), 123.1 (C),
CDCl3)
d
7.50 (dd, 2H, J¼7.8 and 4.6 Hz), 8.70 (dd, 2H, J¼7.8 and
125.2 (CH), 126.9 (CH), 135.8 (CH), 150.6 (CH), 153.8 (CH), 156.0 (C),
161.3 (C), 176.3 (C), 191.3 ppm (C]O).
2.1 Hz), 8.83 ppm (dd, 2H, J¼4.6 and 2.1 Hz); 13C NMR (75 MHz,
CDCl3)
d
116.7 (2C), 121.8 (2CH), 137.4 (2CH), 155.1 (2CH), 160.3 (2C),
X-ray data for compound 25: C12H7NO2, M¼197.19, orthorhom-
178.0 ppm (C]O). The 1H NMR data are analogous to those de-
bic,
Pc21b,
a¼5.1389(5),
b¼8.3386(7),
c¼20.173(2)
A,
ꢂ
scribed previously.27
V¼864.44(14) A , Z¼4, rc¼1.515 g cmꢃ3
,
m
¼0.105 mmꢃ1. A final
3
ꢂ
X-ray data for compound 20: 2(C11H6N2O2), M¼396.36, mono-
refinement on F2 with 1664 unique intensities and 136 parameters
clinic, Pc, a¼3.7934(8), b¼20.911(4), c¼10.908(2) A,
b
¼97.678(10)ꢀ,
converged at
flections with I>2s(I). CCDC 944098.
u
R(F2)¼0.1816 (R(F)¼0.0645) for 1509 observed re-
ꢂ
V¼857.5(3) A , Z¼2, rc¼1.535 g cmꢃ3
,
m
¼0.109 mmꢃ1. A final re-
3
ꢂ
finement on F2 with 2910 unique intensities and 271 parameters
converged at
flections with I>2
u
R(F2)¼0.0876 (R(F)¼0.0416) for 2263 observed re-
5.3.11. 1,4-Dihydro-N,1-dimethyl-4-oxo-3-quinolinecarboxamide
(26). Compound 26 was obtained from 7 (using Pd(OAc)2 (10 mol %,
0.1 mmol, 22 mg) and Cy3P$HBF4 (20 mol %, 0.20 mmol, 74 mg)).
s
(I). CCDC 944096.
5.3.6. 1-Methoxy-9H-indeno[2,1-c]pyridin-9-one (21).12 Compound
21 was prepared from 12 (using Pd(OAc)2 (5 mol %, 50 mol, 11 mg)
X-ray data for compound 26: C12H12N2O2, M¼216.24, monoclinic,
¼96.766(4)ꢀ,
ꢂ
m
P21/n, a¼4.7522(4), b¼13.1688(12), c¼16.4679(14) A,
b
t
3
V¼1023.40(15) A , Z¼4, rc¼1.403 g cmꢃ3
, m
¼0.098 mmꢃ1. A final
ꢂ
and Bu3P$HBF4 (10 mol %, 0.10 mmol, 29 mg)) and was isolated
(eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 81%): mp
refinement on F2 with 2305 unique intensities and 147 parameters
160 ꢀC; 1H NMR (300 MHz, CDCl3)
d
4.13 (s, 3H), 7.15 (d, 1H,
converged at
u
R(F2)¼0.1047 (R(F)¼0.0372) for 1962 observed re-
J¼5.0 Hz), 7.44 (td, 1H, J¼7.2 and 1.6 Hz), 7.49e7.60 (m, 2H), 7.71
flections with I>2s(I). CCDC 944099.
(ddd, 1H, J¼7.2, 1.1 and 0.8 Hz), 8.37 (d, 1H, J¼5.0 Hz); 13C NMR
(75 MHz, CDCl3)
d
54.4 (CH3), 109.8 (CH), 113.4 (C), 121.5 (CH), 124.3
5.3.12. 8H-Indeno[2,1-b]thiophen-8-one (27).12 Compound 27 was
prepared from 14 (using Pd(OAc)2 (5 mol %, 50 mol, 11 mg) and
(CH), 131.5 (CH), 134.1 (C), 134.2 (CH), 141.1 (C), 155.0 (CH), 156.4 (C),
m

N. Marquise et al. / Tetrahedron 69 (2013) 10123e10133
10133
9. (a) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed.
2007, 46, 3802e3824; (b) Mulvey, R. E. Acc. Chem. Res. 2009, 42, 743e755; (c)
Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew. Chem., Int. Ed.
2011, 50, 9794e9824; (d) Mongin, F.; Uchiyama, M. Curr. Org. Chem. 2011, 15,
2340e2361; (e) Mongin, F.; Harrison-Marchand, A. Chem. Rev. 2013, http://dx.
doi.org/10.1021/cr3002966
Cy3P$HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent:
8:2 heptane/AcOEt) as an orange powder (yield: 38%): mp 106 ꢀC
(lit.34 107e109 ꢀC); 1H NMR (300 MHz, CDCl3)
d 7.11e7.19 (m, 3H),
7.31e7.36 (m, 1H), 7.46e7.49 (m, 1H), 7.73 ppm (d, 1H, J¼4.7 Hz); 13
C
NMR (75 MHz, CDCl3) d 119.7 (CH),120.3 (CH),124.2 (CH),128.3 (CH),
10. (a) Nguyen, T. T.; Chevallier, F.; Jouikov, V.; Mongin, F. Tetrahedron Lett. 2009, 50,
6787e6790; (b) Nguyen, T. T.; Marquise, N.; Chevallier, F.; Mongin, F. Chem.
133.8 (CH), 137.2 (C), 138.0 (C), 139.4 (CH), 139.8 (C), 158.9 (C),
185.7 ppm (C]O).
ꢀ
dEur. J. 2011, 17, 10405e10416; (c) Snegaroff, K.; Nguyen, T. T.; Marquise, N.;
Halauko, Y. S.; Harford, P. J.; Roisnel, T.; Matulis, V. E.; Ivashkevich, O. A.;
Chevallier, F.; Wheatley, A. E. H.; Gros, P. C.; Mongin, F. Chem.dEur. J. 2011, 17,
13284e13297.
Acknowledgements
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N.M., P.J.H., F.C., A.E.H.W., P.C.G. and F.M. gratefully acknowledge
the financial support of the Agence Nationale de la Recherche
(ACTIVATE program). F.M. also thanks the Institut Universitaire de
13. L’Helgoual’ch, J. M.; Seggio, A.; Chevallier, F.; Yonehara, M.; Jeanneau, E.;
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France and Rennes Metropole, and P.J.H. the UK EPSRC. V.T. thanks
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.09.030.
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