Journal of the American Chemical Society
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Copies of H NMR and 13C NMR spectra for all coupling prod-
ucts, as well as details on experimental procedures. This material
(9) Nielsen, D. U.; Korsager, S.; Lindhardt, A. T.; Skrydstrup, T. Adv.
Synth. Catal. 2014, 356, 3519.
(10) Lian, Z.; Friis, S. D.; Skrydstrup, T. Chem. Commun. 2015, 51,
3600.
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(12) Jusseau, X.; Yin, H.; Lindhardt, A. T. Skrydstrup, T. Chem. Eur.
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AUTHOR INFORMATION
Corresponding Author
(13) For some recent reviews on Pd-catalyzed carbonylations, see: (a)
Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 131, 1. (b) Wu,
X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986. (c)
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(14) (a) Fritz, G, Int. J. Oncol. 2005, 27, 1401. (b) Maron, D. J.;
Fazio, S.; Linton, M. F. Circulation 2000, 101, 207. (c) Demierre, M.-
F.; Higgins, P. D. R.; Gruber, S. B.; Hawk, E.; Lippman, S. M. Nat.
Rev. Cancer 2005, 5, 930. (d) Istvan, E. S.; Deisenhofer, J. Science
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*E-mail: lindhardt@eng.au.dk ts@chem.au.dk
Notes
The authors declare the following competing financial interest(s):
Anders T. Lindhardt and Troels Skrydstrup are co-owners of
SyTracks a/s, which commercializes the two-chamber technology.
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ACKNOWLEDGMENT
We are deeply appreciative of generous financial support of this
work from the Danish National Research Foundation, (grant no.
DNRF118), the Villum Foundation, the Danish Council for Inde-
pendent Research: Technology and Production Sciences, the
Lundbeck Foundation, and Aarhus University.
(15) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J.
Am. Chem. Soc. 2011, 133, 18114.
(16) A reagent ratio of 4-iodoanisole:2:NaHMDS of 1:2:4 proved to
be the best ratio for obtaining the reported yield of compound 3.
(17) The γ-selective alkylation and chlorination of the dienolate of
2,2,6-trimethyl-4H-1,3-dioxin-4-one is known. For example see: (a)
Smith III, A. B.; Scarborough Jr., R. M. Tetrahedron Lett. 1978, 19,
4193. (b) Boeckman Jr., R. K.; Perni, R. B.; Macdonald, J. E.; Thomas,
A. J. Org. Synth. 1988, 66, 194.
(18) We have earlier shown that LiHMDS is not an effective base for
the Pd-catalyzed carbonylative α-arylation of simple ketones, whereas
NaHMDS is (see ref. 7 a). We are currently examining the role of the
counterion in carbonylation reactions with other enolates in order to
understand this effect.
(19) Despite extensive screening of palladium sources, ligands, sol-
vents and bases, no conversion was observed for the corresponding aryl
bromides. On the other hand, compound 24 could be obtained from the
vinyl bromide equivalent, although at best with an NMR yield of ap-
prox. 50%.
(20) (a) Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe, E. J.;
Deana, A. A.; Gilfillan, J. L.; Hirshfield, J.; Holtz, W. J.; Hoffman, W.
F.; Huff, J. W.; Lee, T. J.; Novello, F. C.; Prugh, J. D.; Rooney, C. S.;
Smith, R. L.; Willard, A. K. J. Med. Chem. 1986, 29, 170. b) Naskar,
D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699. c) Naskar,
D.; Roy, S. Tetrahedron 2000, 56, 1369.
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(23) The 2.2 equivalents of 2,2,6-trimethyl-4H-1,3-dioxin-4-one and
2.2 equivalents of LiHMDS were pre-mixed at 0 °C prior to the addi-
tion to the reaction mixture. See Supporting Information for the de-
tailed procedure. The addition of 2.2 equivalents of LiHMDS to the re-
action mixture at room temperature did not afford dioxinone 35, proba-
bly because of the acidity of the cyclopropylic proton at the 2-position
of the quinoline.
(24) The low yield is explained by the competitive 1,6-addition of the
hydride compare to the 1,4-addition during the reduction step, leading
to a 2/1 mixture of alkene and alkane, which are difficult to separate.
(8) Korsager, S.; Nielsen, D. U.; Taaning, R. H.; Skrydstrup, T. An-
gew. Chem. Int. Ed. 2013, 52, 9763.
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