D
K. L. Wilson et al.
Letter
Synlett
Chromatographic purification is less feasible at larger
scales; however, the addition of a medium polarity solvent
mixture (40% EtOAc in petroleum ether) facilitates the pre-
cipitation of 1a, which can then be removed via filtration,
while aqueous washing allows removal of residual Cyrene
and enables extraction of the product. For example, in the
case of 4w above (Scheme 3), the product was isolated ana-
lytically pure using this precipitation/washing method
without the requirement of chromatography. In the context
of waste generation/disposal, the formation of 1a precludes
recovery and reuse of Cyrene and so this must be disposed
of; safety information regarding 1a is not currently avail-
able.
In summary, we have developed a mild method for the
SM reaction, which employs Cyrene as a direct alternative
to conventional solvents (DMF, THF, 1,4-dioxane).64 The
conditions developed demonstrate excellent generality and
functional group tolerance with high yields obtained on
both small and larger scale synthesis. Physical and chemical
properties affecting recovery and disposal of Cyrene raise
concerns over the impact on environmental criteria. Not-
withstanding these issues, the bio-derived nature of Cyrene
in addition to its innocuous attributes are attractive with
respect to sustainability and safety guidelines when com-
pared to solvents such as DMF, and should not be over-
looked as a potential alternative.
(9) Clark, J. H.; Tavener, S. J. Org. Process Res. Dev. 2007, 11, 149.
(10) Welton, T. Proc. R. Soc. A 2015, 471, 1.
(11) Dunn, P. J. Chem. Soc. Rev. 2012, 41, 1452.
(12) Roschangar, F.; Colberg, J.; Dunn, P. J.; Gallou, F.; Hayler, J. D.;
Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Mergelsberg, I.; Tucker,
J. L.; Sheldon, R. A.; Senanayake, C. H. Green Chem. 2016, 19, 281.
(13) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(14) Tobiszewski, M.; Namieśnik, J.; Pena-Pereira, F. Green Chem.
2017, 19, 1034.
(15) Alder, C. M.; Hayler, J. D.; Henderson, R. K.; Redman, A. M.;
Shukla, L.; Shuster, L. E.; Sneddon, H. F. Green Chem. 2016, 18,
3879.
(16) Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H. M.; Clark, J. H.;
Farmer, T. J.; Hunt, A. J.; McElroy, C. R.; Sherwood, J. Sustainable
Chem. Processes 2016, 4, 7.
(17) Diorazio, L. J.; Hose, D. R. J.; Adlington, N. K. Org. Process Res.
Dev. 2016, 20, 760.
(18) Eastman, H. E.; Jamieson, C.; Watson, A. J. B. Aldrichimica Acta
2015, 48, 51.
(19) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H. F.; McElroy, C. R.;
Abou-Shehada, S.; Dunn, P. J. Green Chem. 2015, 18, 288.
(20) Skowerski, K.; Białecki, J.; Tracz, A.; Olszewski, T. K. Green Chem.
2014, 16, 1125.
tal/substancesearch/page.action?pageID=0; accessed October
2017.
(22) Candidate List of substances of very high concern for Authori-
sation
accessed October 2017.
(23) Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15,
3950.
Funding Information
(24) Franzén, R.; Xu, Y. Can. J. Chem. 2005, 83, 266.
(25) Ghorbani-Choghamarani, A.; Norouzi, M. New J. Chem. 2016, 40,
6299.
We thank the University of Strathclyde for a PhD studentship (KLW)
and Merck KGaA for financial and material support.
)(
(26) Hie, L.; Garg, N. K. Org. Synth. 2016, 93, 306.
(27) Stibingerova, I.; Voltrova, S.; Kocova, S.; Lindale, M.; Srogl, J. Org.
Lett. 2016, 18, 312.
Acknowledgment
(28) Azua, A.; Mata, J. A.; Heymes, P.; Peris, E.; Lamaty, F.; Martinez,
J.; Colacino, E. Adv. Synth. Catal. 2013, 355, 1107.
(29) Wan, J.-P.; Wang, C.; Zhou, R.; Liu, Y. RSC Adv. 2012, 2, 8789.
(30) Horváth, I. T. Green Chem. 2008, 10, 1024.
(31) Spear, S. K.; Griffin, S. T.; Granger, K. S.; Huddleston, J. G.;
Rogers, R. D. Green Chem. 2007, 9, 1008.
We thank Circa for provision of Cyrene, and the EPSRC UK National
Mass Spectrometry Facility at Swansea University for analyses.
Supporting Information
(32) Gu, Y.; Jérôme, F. Green Chem. 2010, 12, 1127.
(33) Pace, V.; Hoyos, P.; Castoldi, L.; Dominguez de Maria, P.;
Alecantara, A. R. ChemSusChem. 2012, 5, 1369.
(34) Lomba, L.; Giner, B.; Bandrés, I.; Lafuente, C.; Pino, R. Green
Chem. 2011, 13, 2062.
(35) Pereira, C. S. M.; Silva, V. M. T. M.; Rodrigues, A. E. Green Chem.
2011, 13, 2658.
(36) Alonso, D. M.; Wettstein, S. G.; Dumesic, J. A. Green Chem. 2013,
15, 584.
(37) Byrne, F.; Forier, B.; Bossaert, G.; Hoebers, C.; Farmer, T. J.; Clark,
J. H.; Hunt, A. J. Green Chem. 2017, 19, 3671.
(38) Ilgen, F.; König, B. Green Chem. 2009, 11, 848.
(39) Imperato, G.; Vasold, R.; König, B. Adv. Synth. Catal. 2006, 348,
2243.
(40) Pongrácz, P.; Kollár, L.; Mika, L. T. Green Chem. 2016, 18, 842.
(41) Ismalaj, E.; Strappaveccia, G.; Ballerini, E.; Elisei, F.; Piermatti,
O.; Gelman, D.; Vaccaro, L. ACS Sustainable Chem. Eng. 2014, 2,
2461.
Supporting information for this article is available online at
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References and Notes
(1) King, A. O.; Yasuda, N. Palladium-Catalyzed Cross-Coupling
Reactions in the Synthesis of Pharmaceuticals; Springer: Heidel-
berg, 2004.
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4442.
(3) Roughley, S. D.; Vernalis, A. M. J. J. Med. Chem. 2011, 54, 3451.
(4) Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.
(5) Ohe, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Hall, D. Boronic Acids: Preparation, Application in Organic Syn-
thesis and Medicine; John Wiley and Sons: Weinheim, 2006.
(8) Jessop, P. G. Green Chem. 2011, 13, 1391.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E