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Chemical Science
Page 6 of 6
ARTICLE
Journal Name
Conclusions
DOI: 10.1039/C9SC02528F
7. (a) D. K. Romney, F. H. Arnold, B. H. Lipshutz and C. J. Li, J. Org.
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In summary, a new palladacycle has been uncovered that mediates
Suzuki-Miyaura couplings in water at the 300 ppm level of precious
metal. Key to this methodology is placement of an isopropyl group
on each aromatic ring of the biaryl skeleton making up the
palladacycle, a substitution pattern that could not have been
predicted given the lack of precedent for such pre-catalysts.
Likewise, screening of several monophosphines, including some of
ther most commonly used for such Pd-catalyzed cross-couplings,
ultimately identifying HandaPhos as the preferred ligand (i.e., P7),
requires further study to rationalize the effectiveness of this novel
ligand/palladacycle precursor combination. Applications to various
targets within the pharma, agro, and materials domains have been
demonstrated, along with the potential for large scale use, recycling
of the aqueous reaction medium, and tandem 1-pot processes. The
nature of the nanomicelles involved has been determined via cryo-
TEM measurements, both initially as well as after use in the presence
of added co-solvent. Residual levels of Pd in the products formed
have been shown to be well within governmental limits for safety,
further enhancing the attractiveness of this technology. The
prognosis for use of the same pre-catalyst for other types of Pd-
catalyzed cross-couplings (e.g., Stille, Sonogashira, and Heck
couplings) looks encouraging, with the results from these ongoing
studies to be reported in due course.
11. S. Handa, M. P. Andersson, F. Gallou, J. Reilly and B. H. Lipshutz,
Angew. Chem., Int. Ed., 2016, 55, 4914.
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13. The lower yield in the reaction leading to product 19, isolated in
60% yield, was due to incomplete conversion. This may be due to
some complexation of the Pd by the bi-heteroaromatic being
formed. Alternatively, an increase in temperature to 55 °C might
help further drive it towards completion.
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16. C. M. Gabriel, N. R. Lee, F. Bigorne, P. Klumphu, M. Parmentier, F.
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17. J. Najib, Clin Ther., 2002, 24, 2022.
18. E.-H. Pommer, N. Goetz, B. Zeeh and B. Giergensohn, U.S. Patent
4,001,416, January 4, 1977.
19. N. R. Lee, A. A. Bikovtseva, M. Cortes-Clerget, F. Gallou and B. H.
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Conflicts of interest
There are no conflicts to declare.
20. The biaryl portions of these drugs are prepared using high catalyst
loadings and harsh reaction conditions in organic solvents, see: (a)
C. Chung, G. Humphrey, P. E. Maligres and T. J. Wright, WO
2013/066768, May 10, 2013; (b) J. Bradner, M. Erba and J. Qi, WO
2016/196879 A1, December 8, 2016; (c) I. Rukhman, B. -Z. Dolitzky
and E. Flyaks, U.S. Patent 7,199,144 B2, April 3, 2007.
21. (a) D. J. Hwang, J. Wang, W. Li and D. D. Miller, ACS Med. Chem.
Lett., 2015, 6, 993; (b) M. -J. Lai, H. -Y. Lee, L. -H. Chuang, A. -C.
Tsai, M. -C. Chen, H. L. Huang, Y. -W. Wu, C. -M. Teng, S. L. Pan, Y.
-M. Liu, S. Mehndiratta and J. -P. Liou, J. Med. Chem., 2015, 58,
6549; (c) A. Döbber, A. F. Phoa, R. H. Abbassi, B. W. Stringer, B. W.
Day, T. G. Johns, M. Abadleh, C. Peifer and L. Munoz, ACS Med.
Chem. Lett., 2017, 8, 395.
Acknowledgements
Financial support provided by Novartis and PHT International
(postdoctoral fellowship to B.S.T.) is warmly acknowledged with
thanks.
Notes and references
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Chem., Int. Ed., 2013, 52, 10911.
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Endangered
Elements,
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6 | J. Name., 2012, 00, 1-3
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