Cascade palladium-catalyzed alkenyl aminocarbonylation/ Intramolecular aryl amidation: An annulative synthesis of 2-quinolones

Article abstract of DOI:10.1021/ol802624e

(Chemical Equation Presented) Palladium-catalyzed intermolecular aminocarbonylation/intramolecular amidation cascade sequences can be used to convert a range of 2-(2-haloalkenyl)aryl halide substrates efficiently and selectively to the corresponding 2-qui

Full text of DOI:10.1021/ol802624e

ORGANIC
LETTERS
2009
Vol. 11, No. 3
583-586
Cascade Palladium-Catalyzed Alkenyl
Aminocarbonylation/ Intramolecular Aryl
Amidation: An Annulative Synthesis of
2-Quinolones
Andrew C. Tadd, Ai Matsuno, Mark R. Fielding, and Michael C. Willis*
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K., and AstraZeneca Process Research and
DeVelopment, Silk Road Business Park, Macclesfield SK10 2NA, U.K.
michael.willis@chem.ox.ac.uk
Received November 13, 2008
ABSTRACT
Palladium-catalyzed intermolecular aminocarbonylation/intramolecular amidation cascade sequences can be used to convert a range of 2-(2-
haloalkenyl)aryl halide substrates efficiently and selectively to the corresponding 2-quinolones. Delaying the introduction of the CO atmosphere
allows an amination/carbonylation sequence and the preparation of an isoquinolone.
The development of efficient palladium-1 and, more recently,
copper-catalyzed2 methods for the amination of aryl halides
has revolutionized the synthesis of aromatic C-N bonds.
These reactions have been exploited in the synthesis in a
number of heterocyclic systems,1-3 most often when com-
bined with a second transformation.4 Less common are
processes in which a catalytic amination reaction is combined
with a second metal-catalyzed step to construct the hetero-
cycle core.5 Given the variety of C-C and C-X bond
forming reactions that are catalyzed by palladium,6 such
approaches have the potential to deliver powerful new routes
to heteocyclic structures.
We recently demonstrated that 2-(2-haloalkenyl)aryl ha-
lides can undergo two sequential palladium-catalyzed ami-
nation reactions, the first intermolecular, the second intramo-
lecular, to provide efficient routes to
a range of
N-functionalized indoles (1 f 2, Scheme 1).7 We reasoned
that if a catalyst capable of promoting both amination and
(4) Selected examples: (a) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani,
M.; Larsen, R. D.; Faul, M. M. Org. Lett. 2008, 10, 2609. (b) Minatti, A.;
Buchwald, S. L. Org. Lett. 2008, 10, 2721. (c) Zheng, N.; Buchwald, S. L.
Org. Lett. 2007, 9, 4749. (d) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9,
4291. (e) Martín, R.; Rodríguez Rivero, M.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 7079. (f) Willis, M. C.; Snell, R. H.; Fletcher, A. J.;
Woodward, R. L. Org. Lett. 2006, 8, 5089. (g) Scott, J. P. Synlett 2006,
2083. (h) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433.
(5) Selected examples: (a) Viirre, R. D.; Evindar, G.; Batey, R. A. J.
Org. Chem. 2008, 73, 3452. (b) Jensen, T.; Pedersen, H.; Bang-Andersen,
B.; Madsen, R.; Jørgensen, M. Angew. Chem., Int. Ed. 2008, 47, 888. (c)
Battistuzzi, G.; Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G. AdV. Synth.
Catal. 2007, 349, 297. (d) Thansandote, P.; Raemy, M.; Rudolph, A.;
Lautens, M. Org. Lett. 2007, 9, 5255. (e) Loones, K. T. J.; Maes, B. U. W.;
Meyers, C.; Deruytter, J. J. Org. Chem. 2006, 71, 260. (f) Fang, Y.-Q.;
Lautens, M. Org. Lett. 2005, 7, 3549.
(1) Reviews: (a) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E. I., Ed.; Wiley-Interscience:
New York, 2002; Vol. 1, p 1051. (b) Jiang, L.; Buchwald, S. L. In Metal-
Catalysed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004; p 699.
(2) Reviews: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008,
47, 3096. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400.
(3) Selected recent examples: (a) Nodwell, M.; Riffell, J. L.; Roberge,
M.; Andersen, R. J. Org. Lett. 2008, 10, 1051. (b) McLaughlin, M.; Palucki,
M.; Davies, I. W. Org. Lett. 2006, 8, 3311. (c) Venkatesh, C.; Sundaram,
G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71, 1280. (d) Wrona,
I. E.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127,
15026. (e) van den Hoogenband, A.; den Hartog, J. A. J.; Lange, J. H. M.;
(6) (a) Tsuji, J. Palladium Reagents and Catalysts: New PerspectiVes
for the 21st Century, 2nd ed.; Wiley: Chichester, 2004. (b) Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E. I., Ed.;
Wiley-Interscience: New York, 2002.
Terpstra, J. W. Tetrahedron Lett. 2004, 45, 8535
.
10.1021/ol802624e CCC: $40.75
Published on Web 01/06/2009
2009 American Chemical Society

Scheme 1
.
Pd-Catalyzed Indole, Quinolone, and Isoquinolone
Synthesis
Table 1. Reaction Evaluation for the Formation of Quinolone 6a
entry
base
ligand
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
14e
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
7
8
9
48
62
61
53
77
22
74
47
66
<5
<5
0
10
11
12
13
14
15
13
13
13
13
13
carbonylation processes could be identified, then combination
of the same precursors with an N-nucleophile under an
atmosphere of carbon monoxide should allow access to the
corresponding quinolone or isoquinolone derivatives (1 f
3 or 4, Scheme 1).8 In this paper, we detail the realization
of this goal, with an efficient and selective synthesis of
2-quinolones from 2-(2-haloalkenyl)aryl halides. We also
show that using modified reaction conditions allows the same
substrates to deliver an isoquinolone.
Both quinolones and isoquinolones are important hetero-
cycles, featuring in a number of natural products and
designed medicinal agents, and also serve as useful precur-
sors to the corresponding quinoline and isoquinolines,
respectively.9 The ability to access both systems from a single
precursor was an attractive prospect. However, for synthetic
utility, it was important that reactions selective for the specific
isomers be achieved. Which isomer was obtained would be
dependent on the site of initial reactionsaryl halide versus
alkenyl halidesand on which of the two catalytic reactions
occurred firstsamination or carbonylation. Based on our own
earlier studies on indole synthesis using the same class of
substrates,7 and on related literature examples,10 we expected
the alkenyl halide to be the site of first reaction. Literature
precedent suggested that carbonylation should be the faster
of the two processes.6b,11 These two predictions would lead
to the formation of 2-quinolones from the 2-(2-haloalkeny-
NaOtBu
Cs2CO3
Cs2CO3
12d
14d
a Reaction conditions: dibromide (1.0 equiv), octylamine (2.0 equiv),
Pd2(dba)3 (3 mol %), ligand (6 mol %), base (3.0 equiv), CO (balloon
pressure), toluene, 100 °C, 16 h. Alkene used as a 12.1 mixture of Z/E
isomers. b Isolated yields. c Dioxane used as solvent. d Conversion, deter-
mined by 1H NMR spectroscopy. e Reaction performed at 80 °C.
l)aryl halide substrates. To test this hypothesis, we explored
the coupling of dibromo styrene 5 and octylamine under a
balloon pressure of carbon monoxide (Table 1). Guided by
recent aminocarbonylation examples, we evaluated a variety
of phosphines in combination with Pd2(dba)3 using Cs2CO3
as base.11
Pleasingly, a number of structurally varied ligands deliv-
ered reasonable yields of the expected quinolone product 6
(entries 1-9). For example, the iPr-phosphine derivative of
MOP (11), the simple diphosphine dppp (13), and the bulky
electron-rich monodentate phosphine PtBu3 (15) all delivered
>65% yields of N-octylquinolone. Formation of the corre-
sponding isoquinolone was not observed. Use of the alterna-
tive bases Na2CO3, K3PO4, or NaOtBu, in combination with
the ligand dppp (13), resulted in inefficient reactions (entries
10-12). Finally, exchanging the solvent to dioxane (from
toluene), or performing the reactions at 80 °C instead of
100 °C, also resulted in poor yields of product (entries 13
and 14).
(7) (a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int.
Ed. 2005, 44, 403. (b) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes,
I. P. AdV. Synth. Catal. 2006, 348, 851. (c) Fletcher, A. J.; Bax, M. N.;
Willis, M. C. Chem. Commun. 2007, 4764.
(8) For examples of carbonylation used in combination with alternative
palladium-catalyzed reactions, see: (a) Worlikar, S. A.; Larock, R. C. J.
Org. Chem. 2008, 73, 7175. (b) Chouhan, G.; Alper, H. Org. Lett. 2008,
10, 4987. (c) Zheng, H.; Alper, H. Org. Lett. 2008, 10, 4903. (d) Tang, S.;
Yu, Q.-F.; Peng, P.; Li, J.-H.; Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9,
3413. (e) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772.
(f) Kaliinin, V. N.; Shostakovsky, M. V.; Poonomaryov, A. B. Tetrahedron
Lett. 1992, 33, 373. (g) Mori, M.; Chiba, K.; Ohta, N.; Ban, Y. Heterocycles
1979, 13, 329.
(9) (a) Gonza´lez, M. C.; Zafia-Polo, M. C.; Bla´zquez, M. A.; Serrano,
A.; Cortes, D. J. Nat. Prod. 1997, 60, 108. (b) Chen, C.-Y.; Chang, F.-R.;
Pan, W.-B.; Wu, Y.-C. Phytochemistry 2001, 56, 753. (c) Ruchelman, A. L.;
Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem.
2005, 48, 792. (d) Nagarajan, M.; Moreell, A.; Fort, B. C.; Rae Meckley,
M.; Anthony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem.
2004, 47, 5651. (e) Wang, S.-W.; Pan, S.-L.; Huang, Y.-C.; Guh, J.-H.;
Chiang, P.-C.; Hunag, D.-Y.; Kuo, S.-C.; Lee, K.-H.; Teng, C.-M. Mol.
Cancer Ther. 2008, 7, 350.
(11) Examples of palladium catalyzed aminocarbonylation: (a) Deagos-
tino, A.; Larini, P.; Occhiato, E. G.; Pizzuto, L.; Prandi, C.; Venturello, P.
J. Org. Chem. 2008, 73, 1941. (b) Doi, T.; Kamioka, S.; Shimazu, S.;
Takahashi, T. Org. Lett. 2008, 10, 817. (c) Martinelli, J. R.; Clark, T. P.;
Watson, D. A.; Munday, R. H.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 8460. (d) Martinelli, J. R.; Freckmann, D. M. M.; Buchwald,
S. L. Org. Lett. 2006, 8, 4843. (e) Trost, B. M.; Ameriks, M. A. Org. Lett.
2004, 6, 1745.
(10) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.sEur.
J. 2004, 10, 494.
584
Org. Lett., Vol. 11, No. 3, 2009

Table 2. Variation of the N-Nucleophilea
Table 3. Variation of Dibromide Alkenylarenesa
a Reaction conditions: dibromide (1.0 equiv), N-nucleophile (2.0 equiv),
Pd2(dba)3 (3 mol %), ligand (6 mol %), Cs2CO3 (3.0 equiv), CO (balloon
pressure), toluene, 100 °C, 16 h. Alkene used as a 12.1 mixture of Z:E
isomers. b Isolated yields. c 3.0 equiv of amine used. Heated at 50 °C for
2 h and then 100 °C for 16 h. d CO balloon removed after 3 h, purged with
N2, and heated at 100 °C for a further 16 h. e Reaction performed in two
stages with isolation of amide intermediate. See main text and the Supporting
Information for further details.
We next explored the variety of N-nucleophiles that could
be incorporated in the process. In all examples, Cs2CO3 was
used as base, along with Pd2(dba)3 as the Pd source.
However, some variation of the ligand was used to achieve
optimum yields. The three simple alkyl amines, together with
p-methoxybenzylamine, used in Table 2, entries 1-4, all
delivered the expected quinolones in good yield. The same
procedure allowed access to a cyclopropylmethyl-substituted
quinolone by simply employing cyclopropylmethylamine as
the nucleophile (entry 5). Despite its volatility, allylamine
could also be successfully introduced; the reaction was
performed at the lower temperature of 50 °C for 2 h before
heating at 100 °C (entry 6). The use of O-phenylethanolamine
initially proved problematic, with only low yields of product
being obtained with a variety of ligands. A convenient
solution was to start the reaction using the standard condi-
tions and then remove the CO atmosphere after 3 h had
elapsed. Using this protocol, the expected quinolone was
isolated in 77% yield (entry 7). p-Anisidine was also a
problematic substrate; reactions under the standard condi-
tions, using Xantphos as ligand, delivered only 33% of the
N-arylquinolone (entry 8). Closer inspection of the products
of these reactions showed that efficient conversion to the
intermediate amide was being achieved; however, the final
ring closure to deliver the quinolone was extremely sluggish.
Removing the CO atmosphere at an intermediate time, as
used in entry 6, failed to improve the process. Access to the
N-aryl product could be achieved. However, it required a
a Reaction conditions: (i) dibromide (1.0 equiv), octylamine (2.0 equiv),
Pd2(dba)3 (3 mol %), ligand (6 mol %), Cs2CO3 (3.0 equiv), CO (balloon
pressure), toluene, 100 °C, 3 h; (ii) purge with N2, 100 °C, 16 h. b Isolated
yields.
discrete two-step process involving isolation of the interme-
diate N-arylamide, and then resubjection of the amide to ring-
closure conditions. Xantphos was employed as the ligand
for both steps of the process and allowed the quinolone to
be isolated in 65% yield for the two steps (entry 9).12 The
final entry demonstrates that carbamate nucleophiles could
not be successfully employed.
Table 3 presents the scope of the process with respect to
variation of the dihalide substrates; N-octylamine was used
as the coupling partner in all cases and to achieve the most
coherent results the reactions were all performed with the
CO atmosphere being removed after 3 h. Entries 1-3
establish that a range of electron-donating substituents can
be tolerated on the aryl ring, while entries 4 and 5
demonstrate that both inductive and resonance electron-
withdrawing groups can also be introduced. Entries 6 and 7
establish the successful incorporation of alkenyl substitution.
The final entry illustrates the use of a pyridyl substrate to
generate the corresponding azaquinolone product in good
yield.
Having established that a variety of 2-(2-haloalkenyl)aryl
halides can be selectively and efficiently converted to
(12) See the Supporting Information for further details.
Org. Lett., Vol. 11, No. 3, 2009
585

sterically demanding N-nucleophile, as the use of less
hindered coupling partners results in competitive indole
formation.14
Scheme 2. Pd-Catalyzed Isoquinolone Synthesis
In summary, we have demonstrated that a number of Pd
catalysts can be used to promote intermolecular aminocar-
bonylation/intramolecular amidation cascade sequences to
convert 2-(2-haloalkenyl)aryl halide substrates efficiently and
selectively to the corresponding 2-quinolones. Significant
variation of both the N-nucleophile and the styryl-backbone
is possible, allowing access to a range of structurally varied
quinolones, including an azaquinolone. We have also estab-
lished that when starting from the same initial substrate, an
amination/carbonylation sequence, achieved by delaying the
introduction of the carbon monoxide atmosphere, allows a
corresponding isoquinolone derivative to be prepared. The
conversion of 2-(2-haloalkenyl)aryl halides to quinolone and
isoquinolone systems, together with their earlier use in the
preparation of indoles, begins to establish this group of
substrates as a general class of precursors for heterocycle
syntheses;15 further applications in this direction are under-
way in our laboratory.
quinolones, we turned our attention to transforming the same
substrates into the corresponding isoquinolones. Although
it was not possible to access isoquinolones in a cascade
sequence analogous to the quinolone synthesis, variation of
the order of reagent addition provided a successful route.
For example, N-arylisoquinolone 16 could be prepared using
the two-step one-pot procedure shown in Scheme 2. Dibromo
styrene 5 and o-Me-aniline (17) were combined using a
Xantphos-derived catalyst and NaOtBu as base at 55 °C under
an N2 atmosphere to generate the corresponding N-arylena-
mine.13 After 30 min reaction time, the vessel was opened
to a CO atmosphere and the temperature increased to 100
°C, triggering carbonylation of the aryl bromide, followed
by ring closure, to deliver the isoquinolone in 68% yield. A
limitation of this approach is the requirement to employ a
Acknowledgment. We thank the EPSRC and AstraZeneca
for their support of this study.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802624E
(13) (a) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43, 9085.
(b) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem. Commun.
2002, 2362. (c) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P.
Org. Lett. 2003, 5, 4759. (d) Klapers, A.; Campos, K. R.; Chen, C.-y.;
Volante, R. P. Org. Lett. 2005, 7, 1185. (e) Willis, M. C.; Chauhan, J.;
Whittingham, W. G. Org. Biomol. Chem. 2005, 3094. (f) Willis, M. C.;
Brace, G. N.; Holmes, I. P. Synthesis 2005, 3229.
(14) For example, reaction of styrene 5 with p-anisidine results in the
formation of 58% of the expected isoquinolone, together with 17% of the
corresponding indole.
(15) For an example of the related alkenyl triflate-aryl halide substrates
used in benzofuran synthesis, see: Tadd, A. C.; Fielding, M. R.; Willis,
M. C. Tetrahedron Lett. 2007, 48, 7578.
586
Org. Lett., Vol. 11, No. 3, 2009