Scholarly article on topic 'Synthesis of azafluorenones and related compounds using deprotocupration–aroylation followed by intramolecular direct arylation'

Synthesis of azafluorenones and related compounds using deprotocupration–aroylation followed by intramolecular direct arylation Academic research paper on "Chemical sciences"

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Abstract of research paper on Chemical sciences, author of scientific article — Nada Marquise, Philip J. Harford, Floris Chevallier, Thierry Roisnel, Vincent Dorcet, et al.

Abstract 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.

Academic research paper on topic "Synthesis of azafluorenones and related compounds using deprotocupration–aroylation followed by intramolecular direct arylation"

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Tetrahedron

journal homepage: www.elsevier.com/locate/tet

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

Nada Marquise a, Philip J. Harford b, Floris Chevalliera, Thierry Roisnelc,

Vincent Dorcetc, Anne-Laure Gagez e, Sophie Sablé e, Laurent Picote, Valerie Thiéry6,*,

Andrew E. H. Wheatley^ *, Philippe C. Grosd, Florence Mongin3,*

a Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 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, Bâtiment 10B, Case 1003, Campus de Beaulieu, 35042 Rennes, France

d HECRIN, SRSMC, Université de Lorraine-CNRS, Boulevard des Aiguillettes, 54506 Vandoeuvre-Lès-Nancy, France e LIENSs UMR 7266, Universite de La Rochelle, Avenue Crepeau, 17042 La Rochelle, France

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ARTICLE INFO

Article history: Received 18 July 2013

Received in revised form 5 September 2013 Accepted 9 September 2013 Available online 17 September 2013

Keywords:

Deprotometalation

Copper

Lithium

Heterocycle

Palladium

ABSTRACT

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.

© 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

1. Introduction

Due to the biological interest of azafluorenones, for example, in relation to their antifungal,1 antimicrobial,2 antimalarial,213,3 and cytotoxic213,4 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,y can be cited. In 2010, Kraus and Kempema developed an approach using 2-bromoaryl 3-pyridyl ketones, prepared by reaction of 3-pyridyllithiums with 2-bromobenzaldehydes followed by oxidation, in intramolecular Heck cyclization reactions.2c Facile oxidation

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: +33 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).

of the corresponding a-aryl-a-(2-bromo-3-pyridyl)methanols led Ray and co-workers to successfully perform, within one step, both 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. Applied to the synthesis of 2-chloro diaryl ketones, this method could be combined with direct arylation through C—H bond activation by intramolecular transition metal-catalysis,11 to afford azafluorenones and related compounds. We have recently demonstrated the feasibility of this two-step access to such tricyclic heterocycles;12 herein, the details of our investigations, including the testing of a large range of substrates, and the unexpected outcomes observed for the cycli-zation reactions are described.

0040-4020/$ — see front matter © 2013 The Authors. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.09.030

2. Results and discussion

Before embarking on a study aimed at using the depro-tocupration—aroylation 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 (X=F, Cl, Br, I) and LiTMP (2 equiv) at 0 °C in THF containing TMEDA (1 equiv, TMEDA=N,N,N',N'-tetramethylethylenediamine).10c

Prior work on the deprotometalation—iodination of benzox-azole involved the use of a (TMP)2Zn—TMPLi 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 corresponding 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 isostructural 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 chloride starting material.

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 8—15. All these

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 tricycles (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,613,15 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 protocol 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-

Table 1

Deprotocupration of 2-chloropyridine using in situ prepared (TMP)2CuLi $ LiCl (A) or (TMP)2CuLi $ LiBr (B) followed by benzoylation

2 LiTMP

1) (TMP)2CuLi LiX (1 equiv) TMEDA (1 equiv)

N Cl THF, rt, 2 h 2) CiCOAr

N Cl 1-3

ClCOAr

CuX (base)

Product

Yielda (%)

ClCOPh

CuCl (A)

CuBr(B) CuCl (A)

CuBr (B)

CuCl (A)

CuBr (B)

N Cl O

N Cl O

78-90b,1°

60-70b 60-80b

56-80b 55-61b

a Yield after purification by column chromatography. The rest is starting material. b Reaction performed at least twice.

Table 2

Synthesis of the diaryl ketones 1—15 by deprotocupration followed by aroylation

1) (TMP)2CuLiLiCl (1 equiv) TMEDA (1 equiv) Ar—H -

THF, rt, 2 h 2) ClCOAr' Ar'

ClCOAr'

R and/or X

Product

Yielda (%)

N' "Cl

ClCOPh

4-OMe, CH 4-Cl, CH 3-OMe, CH 2-Cl, CH 2-Cl, N

T— R

COPh N' "Cl

80 80 66 59 65

"OMe H

MeO' "N' "OMe

MeO N OMe

O R Cl C

Cl, CH

Br, CH Cl, N

MeO N OMe O Cl

MeO N OMe O Cl

35, 57b

a Yield after purification by column chromatography. The rest is starting material. b Trapping step performed at 60 °C instead of rt.

rich and bulky trialkyl phosphine, and K2CO3 as a base. Different transition metal—ligand ratios were screened by using Cy3P (Cy=cyclohexyl) 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 1—4). 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 conditions, 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 ketone (8), for which two cyclization products are possible, the reaction proved regioselective,18 the C—H 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 confirmed 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 corresponding chloro cyclized product. Indeed, 4-azafluorenone (16) was again the sole identifiable product obtained using Cy3P or fBu3P (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

Table 3

Synthesis of the azafluorenones 16—19 by intramolecular arylation

2 Pd(OAc)2 (x mol%)

>X3 L HBF4 (y mol%)

-j—R -»-

K2CO3 (2 equiv) f,' DMF, 130 °C, 24 h ^

Substrate

Product

Yielda (%)

5 10 20

Cy3P (10)

Cy3P (15) Cy3P (10) Cy3P (10)

82 81 64b

2 (R=OMe)

3 (R=Cl)

,COPh "N' "Cl

Cy3P (10)

Cy3P (10) £B^P (10)

Cy3P (10)

Cy3P (10)

Cy3P (10)

£Bu3P (10)

Cy3P (10)

a After purification by column chromatography. b Only organic product present in the crude. c Compound 2 was also recovered in 10% yield.

d 8-Chloro-5H-indeno[1,2-b]pyridin-5-one was not obtained but 16 was isolated in 19% yield. e 8-Chloro-5H-indeno[1,2-b]pyridin-5-one was not obtained but 16 was isolated in 8% yield.

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[3',4':4,5]cyclopenta[1,2-b]pyridin-5-one was not obtained but 5H-pyrano[2,3-b:6,5-b']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-b']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 arylation of the ketones prepared from methoxypyridines (Table 4). The diaryl ketone 11, in which the chloro group is connected to the phenyl component, led to the corresponding azafluorenone, but did so less

Pd(OAc)2 (5 mol%) Cy3PHBF4 (10 mol%)

K2CO3 (2 equiv) DMF, 130 °C, 24 h

70% yield

Scheme 1. Synthesis of 5H-pyrano[2,3-b:6,5-b']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,l-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 toluene or DMA as solvent led to lower conversions. It is worth noting 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

OMe O X

R-HN(N

Pd(OAc)2 (5 mol%) MeO L HBF4 (10 mol%)

K2CO3 (2 equiv) DMF, 130 °C, 24 h

Substrate

Product

Yielda (%)

11 (X=Cl)

12 (X=Br)

Cy3P Cy3P

48b,c,d

40,Dt61t

MeO N OMe

MeO N OMe

MeO N OMe

a After purification by column chromatography. b Reaction performed in the presence of Pr4NCl (2 equiv). c Lower conversion without Pr4NCl. d Only organic product present in the crude.

e 1-Methoxy-9H-indeno[2,1-c]pyridin-9-one (21) was not obtained (see Scheme 2). f The rest is starting material.

g 6-Methoxy-5H-pyrido[3',4':4,5]cyclopenta[1,2-b]pyridin-5-one was not obtained, see Scheme 3. h Compound 5 (34%) was recovered; an unidentified product also formed. 1 4-Methoxy-5H-indeno[1,2-b]pyridin-5-one was not obtained, see Scheme 5. j 2,4-Dimethoxy-5H-indeno[1,2-d]pyrimidin-5-one was not obtained, see Scheme 6.

Pd(OAc)2 (5 mol%) 'Bu3PHBF4 (10 mol%)

K2CO3 (2 equiv) DMF, 130 °C, 24 h

22: 14% yield

Scheme 2. Synthesis of 5H-benzopyrano[2,3-b]pyridin-5-one (22) from 11.

N "OMe 23: 12% yield

The disappointing results obtained using 11 led us to also consider the diaryl ketone 12, which bears a bromo group instead of a chloro one. Its cyclization in the presence of Pr4NCl using either Cy3P or tBu3P 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 considered to explain the presence of oxygen in the product) and 13 through a common intermediate can be explained by the mechanism depicted in Scheme 4.

O Cl O

Pd(OAc)2 (5 mol%) Cy3P HBF4 (10 mol%)

K2CO3 (2 equiv) DMF, 130 °C, 24 h

79% yield

Scheme 3. Synthesis of 5H-pyrano[2,3-b:6,5-b']dipyridin-5-one (20) from 13.

substitution and oxidative addition

Toxidative addition 13

O—Pd

reductive I elimination j

Scheme 4. Mechanism proposed to explain the formation of 5H-pyrano[2,3-b:6,5-b'] 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 cyclization conditions using Cy3P, no azafluorenone was obtained, but 10H-benzopyrano[3,2-c]pyridin-10-one (25) formed instead in 31%

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.

8H-lndeno[2,1-b]thiophen-8-one (27) has previously been efficiently synthesized by Campo and Larock from 3-(2-bromophenyl) thiophene using palladium-catalyzed cyclocarbonylation.19 Starting 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).

3. Biological evaluation

A preliminary study has been carried out to investigate the cytotoxic 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 melanoma cells. MCF-7 is an invasive differentiated mammary epithelial 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 similarity 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 antibacterial activity against a panel of Gram-positive and Gram-negative reference strain bacteria (Escherichia coli ATCC25922, Salmonella enterica serovar Typhimurium C1P5858, Pseudomonas aeruginosa ATCC27853, Staphylococcus aureus ATCC25923, Bacillus subtilis C1P52.62), and for their antifungal activity against pathogenic strain

OMe O Cl

Pd(OAc)2 (5 mol%) Cy3P HBF4 (10 mol%)

K2CO3 (2 equiv) Pr4NCl (2 equiv) DMF, 130 °C, 24 h

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.

Cl O OMe

Pd(OAc)2 (10 mol%) Cy3P HBF4 (20 mol%)

K2CO3 (2 equiv) Pr4NCl (2 equiv) DMF, 130 °C, 24 h

NHMe O

17% yield

Scheme 6. Degradation of 7 under palladium catalysis and ORTEP diagram (50% probability) of compound 26.

^-"-AOO /--N

*Cl Me^

\ f \ Me

-A A^n© O Pd-O Me e„, (ii) C|

(II^nN^0

Pd O Me

.J^NMe

1 J!%O

Pd O Me

\(ii) Pd—N

reductive élimination

hydrolysis

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

14 or 15

Pd(OAc)2 (5 mol%) L HBF4 (10 mol%)

K2CO3 (2 equiv) DMF, 130 °C, 24 h

Entry Substrate L Yielda (%)

1 14 O Cl /VS Cy3P 90

2 vJ r u 'B^P b

3 15 O Cy3P c

4 O Cu Cl d

a After purification by column chromatography.

b The rest corresponds to recovered 14 but also to the formation of an unidentified product. c The formation of 2-benzoylthiophene was also noted.

d The rest corresponds to recovered 15 but also to the formation of unidentified products.

(Candida glabrata DSM6425). However, no antimicrobial activity was detected against bacteria or yeast.

4. Conclusion

In summary, different heterocyclic diaryl ketones have been synthesized by sequential deprotocupration—aroylation. 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 adjacent 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 methoxy group led to lower yields of fluorenones, with unexpected 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.

5. Experimental section

5.1. General

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 (63—200 mm). Nuclear magnetic resonance spectra were acquired using Bruker AC-300 spectrometer (300 MHz and 75 MHz for 1H and 13C, respectively). 1H chemical shifts (5) are given in parts per million (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.

X-ray crystallography. The samples 16,19, 20 and 24—26 were studied with graphite monochromatized Mo-Ka radiation (1=0.71073 A). X-ray diffraction data were collected at T=150(2) K 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 idealized geometry employed for the refinement of H atoms.

5.2. General procedure 1: deprotonation using the lithium—copper base prepared from CuCl (1 equiv) and LiTMP (2 equiv) before trapping with an aroyl chloride

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 substrate (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 (2x20 mL). After washing the organic phase with an aqueous saturated solution of NH4Cl (10 mL) and drying over anhydrous Na2SO4, the

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).

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 NMR (300 MHz, CDCl3) 5 7.38 (dd, 1H,J=7.5 and 4.9 Hz), 7.42-7.50 (m, 2H), 7.61 (tt, 1H, J=7.4 and 1.3 Hz), 7.72 (dd, 1H, J=7.5 and 2.0 Hz), 7.75-7.81 (m, 2H), 8.52 ppm (dd, 1H, J=4.9 and 2.0 Hz). 13C NMR (75 MHz, CDCl3) 5 122.3 (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), 193.3 ppm (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) 5 3.89 (s, 3H), 6.96 (d, 2H, J=9.0 Hz), 7.38 (dd, 1H, J=7.5 and 4.8 Hz), 7.72 (dd, 1H, J=7.5 and 1.9 Hz), 7.78 (d, 2H, J=4.8 Hz), 8.54 ppm (s, 1H); 13C NMR (75 MHz, CDCl3) 5 55.8 (CH3), 114.3 (2CH), 122.4 (CH), 128.9 (C), 132.7 (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

5.2.3. 4-Chlorophenyl 2-chloro-3-pyridyl ketone (3). Compound 3 was prepared from 2-chloropyridine (using 4-chlorobenzoyl chloride) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 80%): mp 56 °C; 1H NMR (300 MHz, CDCl3) 5 7.40 (dd, 1H, J=7.5 and 4.8 Hz), 7.44-7.48 (m, 2H), 7.71-7.76 (m, 3H), 8.57 (dd, 1H, J=4.8 and 1.9 Hz); 13C NMR (75 MHz, CDCl3) 5 122.5 (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

5.2.4. 2-Chloro-3-benzoylquinoline (4).10c Compound 4 was prepared from 2-chloroquinoline (using benzoyl chloride) and was isolated (eluent: 7:3 heptane/AcOEt) as a beige powder(yield: 44%): mp 98 °C; 1H NMR(300 MHz, CDCl3) 5 7.43-7.48 (m, 2H), 7.55-7.61 (m, 2H), 7.77-7.84 (m, 4H), 8.05 (d, 1H, J=8.5 Hz), 8.18 ppm (s, 1H); 13C NMR (75 MHz, CDCl3) 5 126.0 (C), 127.9 (CH), 128.1 (CH), 128.5 (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) 5 3.81 (s, 3H), 3.98 (s, 3H), 6.37 (d, 1H, J=8.4 Hz), 7.31 -7.37 (m, 4H), 7.98 ppm (d, 1H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) 5 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), 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 (300 MHz, C6D6) 5 3.76 (s, 3H), 6.95-7.05 (m, 1H), 7.31-7.43 (m, 3H), 7.45-7.49 (m, 1H), 8.42-9.76 (br m, 2H); 13C NMR (75 MHz, C6D6) 5 55.0 (CH3), 108.8 (C), 126.7 (CH), 128.3 (CH), 130.1 (CH), 130.1 (CH), 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/

AcOEt) as an orange powder (yield: 58%): mp 74 °C; 1H NMR (300 MHz, CDCl3) 5 3.91 (s, 3H), 4.06 (s, 3H), 7.31-7.44 (m, 4H), 8.62 ppm (br s, 1H); 13C NMR (75 MHz, CDCl3) 5 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).

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 orange powder (yield: 66%): mp 62 °C; 1H NMR (300 MHz, CDCl3) 5 3.72 (s, 3H), 7.05 (ddd, 1H, J=8.1, 2.6 and 1.0 Hz), 7.13 (ddd, 1H, J=7.6, 2.6 and 1.3 Hz), 7.22-7.30 (m, 3H), 7.63 (dd, 1H, J=7.5 and 1.9 Hz), 8.41 (d, 1H, J=4.6 Hz); 13C NMR (75 MHz, CDCl3) 5 55.6 (CH3), 113.6 (CH), 120.9 (CH), 122.3 (CH), 123.3 (CH), 129.9 (CH),

135.0 (C), 137.2 (CH), 137.9 (C), 147.8 (C), 150.9 (CH), 160.1 (C),

193.2 ppm (C=O); HRMS (ESI): m/z calcd for C13H3§ClNaNO2 [(M+Na)+-j 270.0298, found 270.0298.

5.2.9. 2-Chlorophenyl 2-chloro-3-pyridyl ketone (9).12 Compound 9 was prepared from 2-chloropyridine (using 2-chlorobenzoyl chloride) and was isolated (eluent: 9:1 heptane/AcOEt) as an orange oil (yield: 59%): 1H NMR (300 MHz, CDCl3) 5 7.35-7.51 (m, 4H), 7.57 (dd, 1H, J=7.6 and 1.7 Hz), 7.88 (dd, 1H, J=7.6 and 2.0 Hz), 8.52 ppm (dd, 1H, J=4.8 and 2.0 Hz); 13C NMR (75 MHz, CDCl3) 5 122.7 (CH),

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 C12H75Cl2NNaO [(M+Na)+-j 273.9802, found 273.9805.

5.2.10. Bis(2-chloro-3-pyridyl) ketone (10). Compound 10 was prepared from 2-chloropyridine (using 2-chloronicotinoyl chloride) and was isolated (eluent: 7:3 heptane/AcOEt) as a yellow powder (yield: 65%): mp 109 °C; 1H NMR (300 MHz, CDCl3) 5 7.43 (dd, 2H, J=7.5 and 4.8 Hz), 7.98 (dd, 2H, J=7.5 and 1.8 Hz), 8.59 ppm (br s, 2H); 13C NMR (75 MHz, CDCl3) 5 122.8 (2CH), 134.1 (2C), 139.8 (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) 5 3.81 (s, 3H), 7.01 (dd, 1H, J=7.5 and 4.9 Hz), 7.31 -7.41 (m, 3H), 7.44-7.47 (m, 1H), 7.99 (dd, 1H,J=7.5 and 2.0 Hz), 8.34 ppm (dd, 1H, J=4.9 and 2.0 Hz); 13C NMR (75 MHz, CDCl3) 5 53.9 (CH3), 117.1 (CH), 121.8 (C), 126.9 (CH), 129.7 (CH), 129.9 (CH), 131.5 (CH), 131.6 (C), 139.7 (C), 140.6 (CH), 151.3 (CH), 162.2 (C), 193.7 ppm (C=O); HRMS (ESI): m/z calcd for C13H35ClNO2 [(M+H)+-j and C13H3oClNNaO2 [(M+Na)+-j 248.0478 and 270.0298, found 248.0483 and 270.0298, respectively.

5.2.12. 2-Bromophenyl 2-methoxy-3-pyridyl ketone (12). 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 (300 MHz, CDCl3) 5 3.82 (s, 3H), 6.94 (dd, 1H, J=7.5 and 4.9 Hz), 7.28-7.35 (m, 1H), 7.38-7.40 (m, 2H), 7.62 (dd, 1H, J=7.5 and 0.9 Hz), 8.03 (dd, 1H, J=7.5 and 2.0 Hz), 8.38 ppm (dd, 1H, J=4.9 and 2.0 Hz); 13C NMR(75 MHz, CDG3) 5 53.9 (CH3), 117.1 (CH), 119.6 (C),

121.2 (C), 127.4 (CH), 129.5 (CH), 131.5 (CH), 133.1 (CH), 140.9 (CH), 141.7 (C), 151.5 (CH), 162.2 (C), 194.3 ppm (C=O); HRMS (ESI): m/z calcd for C13H7§BrNNaO2 [(M+Na)+-j 313.9793, found 313.9795.

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

heptane/AcOEt) as a yellow powder (yield: 39%): mp 87 °C; 1H NMR (300 MHz, CDCl3) 5 3.79 (s, 3H), 7.08 (dd, 1H, J=7.5 and 4.9 Hz), 7.38 (br m, 1H), 7.82 (dd, 1H, J=7.5 and 1.4 Hz), 8.14 (dd, 1H, J=7.5 and 2.0 Hz), 8.40 (dd, 1H, J=4.9 and 2.0 Hz), 8.52 ppm (br m, 1H); 13C NMR (75 MHz, CDG3) 5 54.1 (CH3), 117.5 (CH), 120.9 (C), 122.5 (CH), 136.6 (C), 138.2 (CH), 140.7 (CH), 147.7 (C),

150.7 (CH), 152.1 (CH), 162.1 (C), 192.0 ppm (C=O); HRMS (ESI): m/z calcd for C12H35ClN2NaO2 [(M+Na)+-j 271.0250, found 271.0251.

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 orange oil (yield: 57%): 1H NMR (300 MHz, CDCl3) 5 7.12 (dd, 1H, J=4.9 and 3.8 Hz), 7.33-7.49 (m, 5H), 7.76 ppm (dd, 1H, J=4.9 and 1.2 Hz); 13C NMR (75 MHz, CDCl3) 5 126.7 (CH), 128.4 (CH), 128.0 (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

5.2.15. 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 a yellow viscous oil (yield: 85%): 1H NMR (300 MHz, CDCl3) 5 6.99 (d, 1H, J=5.2 Hz), 7.43-7.46 (m, 2H), 7.54-7.60 (m, 2H), 7.81-7.83 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) 5 128.4 (2Ch), 129.6 (2CH), 130.1 (CH), 130.7 (CH), 133.0 (CH), 134.3 (C), 137.8 (C),

187.8 ppm (C=O), one C not seen; HRMS (ESI): m/z calcd for C11H35ClOS [(M+H)+-j and C11H75ClNaOS [(M+Na)+-j 222.9984 and 244.9804, found 222.9999 and 244.9803, respectively.

5.3. General procedure used for the cyclization step

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 (3x10 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).

5.3.1. 5H-Indeno[1,2-b]pyridin-5-one (16). Compound 16 was obtained from 1 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and Cy3PHBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 87%): mp 138 °C (lit.29 137-138 °C); 1H NMR (300 MHz, CDCl3) 5 7.21 (1H, dd, J=7.4 and 5.1 Hz), 7.44 (1H, td, J=7.5 and 0.9 Hz), 7.61 (1H, td, J=7.5 and 1.1 Hz), 7.73 (1H, ddd, J=7.5,1.1 and 0.9 Hz), 7.86 (1H, dt, J=7.5 and 0.9 Hz), 7.90 (1H, dd, J=7.4 and 1.6 Hz), 8.61 ppm (1H, dd, J=5.1 and 1.6 Hz); 13C NMR (75 MHz, CDCl3) 5 121.0 (CH), 123.4 (CH), 124.3 (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 analogous to those described previously.30

X-ray data for compound 16: C12H7NO, M=181.19, monoclinic, P21/c, a=12.068(3), b=5.1986(15), c=14.465(3) A, (3=108.686(13)°, V=859.7(4) Ä3, Z=4, pc=1.4 g cm"3, m=0.090 mm"1. A final refinement on F2 with 1964 unique intensities and 128 parameters converged at wR(F2)=0.0996 (R(F)=0.0452) for 1460 observed reflections with I>2s(I). CCDC 944094.

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 mmol, 11 mg) and Cy3PHBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 69%): mp

113 °C; 1H NMR (300 MHz, CDCh) 5 3.96 (s, 3H), 6.92 (dd, 1H, J=8.3 and 2.3 Hz), 7.24 (dd, 1H, J=7.4 and 5.1 Hz), 7.41 (d, 1H, J=2.3 Hz), 7.7 (d, 1H, J=8.3 Hz), 7.89 (dd, 1H, J=7.4 and 1.6 Hz), 8.62 ppm (dd, 1H, J=5.1 and 1.6 Hz); 13C NMR (75 MHz, CDCl3) 5 56.1 (CH3), 106.4 (CH), 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 [(M+Na)+-j 234.0531, found 234.0534.

5.3.3. 11H-Indeno[1,2-b]quinolin-11-one (18). Compound 18 was obtained from 4 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and Cy3PHBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 63%): mp 173 °C (lit.29 176 °C); 1H NMR (300 MHz, CDCl3) 5 7.49—7.56 (2H, m), 7.69 (1H, td,J=7.5 and 1.1 Hz), 7.82 (1H, td, J=7.0 and 1.4 Hz), 7.84 (1H, dt, J=7.5 and 0.7 Hz), 7.88 (1H, dd, J=8.2 and 1.2 Hz), 8.11—8.16 (2H, m), 8.4 (s, 1H); 13C NMR (75 MHz, CDCl3) 5 121.9 (CH), 124.2 (CH), 127.1 (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 described previously.31

5.3.4. 7-Methoxy-5H-indeno[1,2-b]pyridin-5-one (19). Compound 19 was prepared from 8 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and Cy3PHBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as an orange powder (yield: 60%): mp 190 °C; 1H NMR (300 MHz, CDCh) 5 3.82 (s, 3H), 7.07—7.15 (m, 2H), 7.18 (d, 1H, J=2.4 Hz), 7.79 (d, 1H, J=8.2 Hz), 7.84 (dd, 1H, J=7.4 and 1.6 Hz), 8.53 (dd, 1H, J=5.2 and 1.4 Hz); 13C NMR (75 MHz, CDCl3) 5 55.9 (CH3), 109.4 (CH), 120.9 (CH), 122.3 (CH), 122.5 (CH), 128.6 (CH), 131.4 (CH), 135.9 (C), 136.8 (C), 153.8 (CH), 162.5 (C), 165.5 (C), 191.7 (C=O); HRMS (ESI): m/z calcd for C13H9NNaO2 [(M+Na)+-] 234.0531, found 234.0531.

X-ray data for compound 19: C13H9NO2, M=211.21, monoclinic, P21/a, a=15.323(3), b=3.8645(7), c=17.224(3) A, 0=112.183(6)°, V=944.4(3) A3, Z=4, pc=1.485 g cm"3, m=0.102 mm"1. A final refinement on F2 with 2082 unique intensities and 147 parameters converged at wR(F2)=0.1524 (R(F)=0.0569) for 1532 observed reflections with I>2s(I). CCDC 944095.

5.3.5. 5H-Pyrano[2,3-b:6,5-b']dipyridin-5-one (20). Compound 20 was prepared from 10 or 13 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and Cy3PHBF4 (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 2 40 °C); 1H NMR (300 MHz, CDCl3) 5 7.50 (dd, 2H, J=7.8 and 4.6 Hz), 8.70 (dd, 2H, J=7.8 and 2.1 Hz), 8.83 ppm (dd, 2H, J=4.6 and 2.1 Hz); 13C NMR (75 MHz, CDCl3) 5 116.7 (2C), 121.8 (2CH), 137.4 (2CH), 155.1 (2CH), 160.3 (2C), 178.0 ppm (C=O). The 1H NMR data are analogous to those described previously.27

X-ray data for compound 20: 2(C11H6N2O2), M=396.36, mono-clinic, Pc, a=3.7934(8), b=20.911(4), c=10.908(2) A, 0=97.678(10)°, V=857.5(3) A3, Z=2, pc=1.535 g cm"3, m=0.109 mm"1. A final refinement on F2 with 2910 unique intensities and 271 parameters converged at wR(F2)=0.0876 (R(F)=0.0416) for 2263 observed reflections with I>2s(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 mmol, 11 mg) and tBu3P HBF4 (10 mol %, 0.10 mmol, 29 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 81%): mp 160 °C; 1H NMR (300 MHz, CDCl3) 5 4.13 (s, 3H), 7.15 (d, 1H, J=5.0 Hz), 7.44 (td, 1H, J=7.2 and 1.6 Hz), 7.49—7.60 (m, 2H), 7.71 (ddd, 1H, J=7.2, 1.1 and 0.8 Hz), 8.37 (d, 1H, J=5.0 Hz); 13C NMR (75 MHz, CDCl3) 5 54.4 (CH3), 109.8 (CH), 113.4 (C), 121.5 (CH), 124.3 (CH), 131.5 (CH), 134.1 (C), 134.2 (CH), 141.1 (C), 155.0 (CH), 156.4 (C),

161.0 (C), 191.5 (C=O); HRMS (ESI): m/z calcd for C13H9NNaO2 [(M+Na)+-] 234.0531, found 234.0532.

5.3.7. 5H-Benzopyrano[2,3-b]pyridin-5-one (22). Compound 22 was prepared from 11 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and tBu3P 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.32 178—179 °C); 1H NMR (300 MHz, CDQ3) 5 7.45—7.57 (m, 2H), 7.62 (dd, 1H, J=8.4 and 0.6 Hz), 7.79 (ddd, 1H, J=8.4, 6.9 and 1.5 Hz), 8.32 (dd, 1H, J=8.1 and 1.8 Hz), 8.72 (dd, 1H, J=7.8 and 1.8 Hz), 8.75 (br s, 1H); 13C NMR (75 MHz, CDCl3) 5 116.9 (C), 118.7 (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

5.3.8. 2-Methoxy-3-pyridyl phenyl ketone (23). Compound 23 was prepared from 11 (usingPd(OAc)2(5mol%,50mmol, 11 mg)and tBu3P$ 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-Dimethoxy-9H-indeno[2,1-c]pyridin-9-one (24). Compound 24 was prepared from 5 (using Pd(OAc)2 (5 mol %, 50 mmol, 11 mg) and Cy3P HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 8:2 heptane/AcOEt) as a yellow powder (yield: 30%): mp 166 °C; 1H NMR (300 MHz, CDQ3) 5 4.02 (s, 3H), 4.1 (s, 3H), 6.52 (s, 1H), 7.36—7.51 (m, 3H), 7.70 (d, 1H,J=7.1 Hz); 13C NMR (75 MHz, CDCl3) 5 54.2 (CH3), 54.6 (CH3), 96.1 (CH), 106.8 (C), 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 C14H11NNaO3 [(M+Na)+-] 264.0637, found 264.0635.

X-ray data for compound 24: C14H11NO3, M=241.24, monoclinic, P21/n, a=5.2623(4), b=17.1350(9), c=12.1808(9) A, 0=93.170(3)°, V=1096.66(13) A3, Z=4, pc=1.461 g cm"3, m=0.104 mm"1. A final refinement on F2 with 2506 unique intensities and 166 parameters converged at wR(F2)=0.0962 (R(F)=0.0397) for 2049 observed reflections with I>2s(I). CCDC 944097.

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 mmol, 11 mg) and Cy3P HBF4 (10 mol %, 0.10 mmol, 37 mg)) and was isolated (eluent: 1:1 heptane/AcOEt) as a white powder (yield: 51%): mp185 °C(lit.33 184 °C); 1H NMR(300 MHz, CDCl3) 5 7.40—7.54 (m, 3H), 7.79 (dt, 1H, J=7.2 and 1.7 Hz), 8.34 (dd, 1H, J=7.8 and 1.7 Hz), 8.82 (d, 1H, J=5.2 Hz), 9.52 (s, 1H). These data are in accordance with the literature.33 13C NMR (75 MHz, CDCl3) 5 112.8 (CH), 118.3 (CH), 123.1 (C),

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).

X-ray data for compound 25: C12H7NO2, M=197.19, orthorhom-bic, Pc21b, a=5.1389(5), b=8.3386(7), c=20.173(2) A, V=864.44(14) A3, Z=4, pc=1.515 g cm"3, m=0.105 mm"1. A final refinement on F2 with 1664 unique intensities and 136 parameters converged at wR(F2)=0.1816 (R(F)=0.0645) for 1509 observed reflections with I>2s(I). CCDC 944098.

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)).

X-ray data for compound 26: C12H12N2O2, M=216.24, monoclinic, P21/n, a=4.7522(4), b=13.1688(12), c=16.4679(14) A, 0=96.766(4)°, V=1023.40(15) A3, Z=4, pc=1.403 g cm"3, m=0.098 mm"1. A final refinement on F2 with 2305 unique intensities and 147 parameters converged at wR(F2)=0.1047 (R(F)=0.0372) for 1962 observed reflections with I>2s(I). CCDC 944099.

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 mmol, 11 mg) and

Cy3PHBF4 (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.34 107-109 °C); 1H NMR (300 MHz, CDCh) 5 7.11 -7.19 (m, 3H), 7.31 -7.36 (m, 1H), 7.46-7.49 (m, 1H), 7.73 ppm (d, 1H, J=4.7 Hz); 13C NMR(75 MHz, CDCl3) 5 119.7 (CH), 120.3 (CH), 124.2 (CH), 128.3 (CH), 133.8 (CH), 137.2 (C), 138.0 (C), 139.4 (CH), 139.8 (C), 158.9 (C), 185.7 ppm (C=O).

Acknowledgements

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 France and Rennes Metropole, and P.J.H. the UK EPSRC. V.T. thanks CPER Poitou-Charentes and the Comité 17 de la Ligue contre le Cancer for financial support.

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.

References and notes

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