Hydrogenation of fluoroarenes: Direct access to all-cis-(multi)fluorinated cycloalkanes

Article abstract of DOI:10.1126/science.aao0270

All-cis-multifluorinated cycloalkanes exhibit intriguing electronic properties. In particular, they display extremely high dipole moments perpendicular to the aliphatic ring, making them highly desired motifs in material science. Very few such motifs have been prepared, as their syntheses require multistep sequences from diastereoselectively prefunctionalized precursors. Herein we report a synthetic strategy to access these valuable materials via the rhodium-cyclic (alkyl)(amino)carbene (CAAC)-catalyzed hydrogenation of readily available fluorinated arenes in hexane. This route enables the scalable single-step preparation of an abundance of multisubstituted and multifluorinated cycloalkanes, including all-cis-1, 2, 3, 4, 5, 6-hexafluorocyclohexane as well as cis-configured fluorinated aliphatic heterocycles.

Full text of DOI:10.1126/science.aao0270

REPORTS
Cite as: M. P. Wiesenfeldt et al.,
Science 10.1126/science.aao0270
(2017).
Hydrogenation of fluoroarenes: Direct access to all-cis-
(multi)fluorinated cycloalkanes
Mario P. Wiesenfeldt, Zackaria Nairoukh, Wei Li, Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms–Universität Münster, Corrensstraße 40, 48149 Münster, Germany.
*Corresponding author. Email: glorius@uni-muenster.de
All-cis-multifluorinated cycloalkanes exhibit intriguing electronic properties. In particular they display
extremely high dipole moments perpendicular to the aliphatic ring, making them highly desired motifs in
material science. Only very few such motifs have been prepared, with their syntheses requiring multistep
sequences from diastereoselectively prefunctionalized precursors. Herein, we report a synthetic strategy
to access these valuable materials via the rhodium-cyclic (alkyl)(amino)carbene (CAAC)-catalyzed
hydrogenation of readily available fluorinated arenes in hexane. This route enables the scalable single-
step preparation of a plethora of multisubstituted and multifluorinated cycloalkanes, including all-cis-
1,2,3,4,5,6-hexafluorocyclohexane as well as cis-configured fluorinated aliphatic heterocycles.
Fluorine is the most electronegative element in the periodic
Based on our experience with stereoselective (het-
table. As a result, the carbon–fluorine bond has substantial ero)arene hydrogenation using ruthenium-N-heterocyclic
electrostatic character, making it the most polarized carbon carbene (NHC) complexes (14–16), we envisioned that such
single-bond in organic chemistry. The strong dipole moment multistep processes could be obviated by the design of a
introduced by the C–F bond, the high bond strength, and protocol for the catalytic hydrogenation of the inexpensive
the relatively small steric demand are widely exploited in and readily available fluoroarenes, as hydrogenation of
agrochemical and pharmaceutical science to fine-tune the arenes is usually highly cis-selective (17, 18). However, all
polarity, pKa-value, conformation, and metabolic stability previously reported attempts to hydrogenate fluoroarenes
of test compounds (1–4). Moreover, control of the relative were hampered by a competing hydrodefluorination path-
orientation of several C–F bonds allows for the design way (Figs. 1C and 2) (19–21). Hence, a synthetically useful
of highly polar compounds that are applied in material sci- protocol for the hydrogenation of fluorinated arenes re-
ence for example as dielectric materials in liquid crystals mained elusive. Several mechanistic pathways are known to
(5, 6). In that regard, it has recently been demonstrated lead to a net hydrodefluorination (Fig. 2) (22), and synthetic
that achieving a cis-alignment-, in particular for 1,3-diaxial protocols for the selective substitution of fluorine with hy-
C–F bonds, is required for the synthesis of facially polarized drogen following seminal work by Milstein have been de-
fluorinated cycloalkanes (7–9), with all-cis-1,2,3,4,5,6- signed (23).
hexafluorocyclohexane (1) being among the most polar or-
Herein, we describe a protocol for the highly selective
ganic molecules known (9). Syntheses of mono-fluorinated hydrogenation of a broad scope of (multi)fluorinated arenes
(substituted) cyclohexanes from unfunctionalized precursors and heteroarenes, offering convenient access to
(10–12) or with complete site-selectivity from alkylcarboxylic cis-diastereoselectively (multi)fluorinated building blocks,
acids (13) have been reported recently. The trans-isomer is highly polar all-cis-(multi)fluorocycloalkanes, and fluorinat-
usually the major diastereomer, and is often obtained in low ed aliphatic heterocycles. Studies toward the chemo- (and
selectivity, as the fluorination proceeds via an alkyl radical enantio-) selective hydrogenation of simple fluorine-
intermediate. Selectively multifluorinated cycloalkanes, substituted alkenes, have resulted in a limited number of
however, remained out of reach. The desired cis-selectivity successful examples employing ruthenium (24), rhodium
can be obtained by nucleophilic substitution, for example (25), and iridium complexes (26). However, in contrast to
via ring-opening of epoxides, substitution of leaving groups the hydrogenation of alkenes, the hydrogenation of stabi-
and deoxyfluorination, thus requiring the use of diastereose- lized arenes is dominated by heterogeneous catalysis (27).
lectively pre-decorated substrates (Fig. 1, A and B). As a re- Hence, the hydrogenation of the relatively non-volatile tert-
sult, multisubstituted cyclohexanes require multistep butyl (4-fluorophenoxy)dimethyl silane (3a) was attempted
sequences as exemplified by O’Hagan’s prominent 12-step with a variety of standard heterogeneous catalysts, known
synthesis of all-cis-1,2,3,4,5,6-hexafluorocyclohexane (Fig. 1B, to be capable of arene hydrogenation (28). However, these
1) (9).
reactions yielded multiple products, with the hydrodefluori-
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release) 1

nated cycloalkane 6a as the major identified product (table agrochemicals. In a similar fashion, TBS-protected diol
S1). When employing a combination of rhodium with a products (7n, o) could be useful for the incorporation of
strongly electron-donating cyclic alkyl amino carbene fluorine into polymers.
(CAAC) ligand (29), which was first reported for an arene
A series of all-cis-(multi)fluorinated cyclohexane deriva-
hydrogenation reaction by X. Zheng (30), these decomposi- tives was also synthesized with this methodology.
tion pathways were significantly diminished, though the Three members of this family, namely all-cis-
hydrodefluorinated cycloalkane 6a remained as the major tetrafluorocyclohexanes 8e,
f
and all-cis-1,2,3,4,5,6-
product (52% yield, 1:2.1 ratio of hydrogenation vs hydro- hexafluorocyclohexane (8h) have previously been synthe-
defluorination, table S2, entry 3) under the described condi- sized via nucleophilic substitution in 2, 8 and 12 steps re-
tions. Exchange of the trifluoroethanol solvent with the less spectively (7–9). Our methodology gives access to these
polar hexane resulted in a highly selective reaction (25:1) in highly polar compounds, as well as to several previously
which the desired product 7a was formed in 95% yield (ta- unknown analogs, with complete diastereoselectivity in a
ble S2, entry 10). The catalyst loading could be lowered to single synthetic step. Convenient access to these all-cis-
0.1 mol% with conserved complete conversion and improved multifluorinated cycloalkanes in larger quantities will allow
selectivity (53:1) (table S3, entry 6). The hydrogenation reac- further investigation into their unique properties in the fu-
tion proceeded smoothly at pressures as low as 10 bar, alt- ture. The highly diastereoselectively enriched all-cis-4,4'-
hough a decrease in selectivity (13:1) was observed (table S4, difluoro-1,1'-bi(cyclohexane) (8k) was also isolated in high
entry 1).
yields; however it was found to contain a mixture of two
Subsequently, the scope of the reaction was studied un- stable conformers.
der the optimized conditions. The ready availability of fluor-
To further explore the limits of the reaction, the scope
inated arenes, either from commercial suppliers or in a was extended to aliphatic heterocycles (9a–d) including
single step following literature methods, allowed us to per- piperidine analog 9d. In addition, a fluorinated estrone de-
form the reaction on a synthetically useful 1 mmol scale. rivative could be hydrogenated smoothly with complete
Gram-scale reactions were carried out for three representa- preservation of the easily reducible keto-group (Fig. 4) (31).
tive examples (Fig. 3B). The high selectivity made product
Diastereoselectively fluorinated analogs to the promi-
isolation straightforward. Likewise, isolation of the major nent ICy ligand (precursor, 10) and the commercial anti-
diastereomer by standard column chromatography or re- cancer drug lomustine (11), as well as the mucolytic agent
crystallization was often possible, especially for multisubsti- bromhexine (12), were synthesized from tert-butyl (cis-4-
tuted products. In the case of less reactive, highly sterically fluorocyclohexyl)carbamate (7f), which could be accessed as
hindered or electron-poor substrates, dilution, substitution a single diastereomer following recrystallization. A depro-
of molecular sieves with silica gel, and an increase of the tection of 7f with trifluoroacetic acid and formation of the
catalyst loading to 0.5 or 1 mol% improved the yields. The ammonium chloride, followed by imidazolium synthesis,
observed cis-selectivity could be confirmed by NOE (Nuclear
NHC ligand precursor 10. The
gave fluorinated ICy∙HBF4
Overhauser Effect) experiments (fig. S1). Furthermore, a electron-withdrawing fluorine could influence the catalytic
molecular structure for all-cis-1,2,4,5-tetrafluorocyclohexane activity of an NHC-metal complex. Furthermore, incorpora-
(8e) was determined by single crystal x-ray diffraction (fig. tion of the NMR-active fluorine offers an opportunity for
S2) and matched that of the previous report (7). Many useful spectroscopic mechanistic investigations, analogous to the
functional
groups
were
well-tolerated,
including established use of 31P NMR analysis. The ammonium chlo-
tert-butyl(dimethyl)silyl (TBS)-protected-(7a, b) and free ride could also be transferred to the lomustine analog 11 by
(phenolic) alcohol (7p), pinacol boronic ester (7c–e), condensation of the in-situ formed primary amine with an
tert-butyloxycarbonyl (BOC)-protected amine (7f, g, j) and isocyanate and subsequent nitrosylation. After methylation,
ester (7i), thus demonstrating that the fluorinated cycloal- and analogous deprotection, the methylated crude ammoni-
kanes could be further functionalized. Despite the simplicity um chloride could be condensed with in-situ formed benzyl
and preparative versatility of these products, tert-butyl (cis- chloride,
derived
from
commercial
2-amino-3,5-
4-fluorocyclohexyl)carbamate (7f) is the only member of the dibromobenzaldehyde, to yield the desired bromhexine ana-
formerly mentioned cis-fluorocyclohexyl-building blocks log 12. In pharmaceuticals, the introduction of fluorine is
that is known in the literature. Multifluorinated arenes recognized to often improve the bioavailability. Moreover,
bearing additional functional groups such as a pinacol bo- structural analogs to known liquid crystalline materials, in
ronic ester (7k) or a TBS-protected alcohol (7l–o) also un- which our building blocks replace the previously employed
derwent the hydrogenation reaction. We envision that these polar head groups, were prepared from all-cis-tert-
readily accessible all-cis-(multi)fluorinated building blocks butyldimethyl((3,4,5-trifluorocyclohexyl)oxy)silane (7l). Af-
will be useful for the fine-tuning of pharmaceuticals and ter recrystallization and deprotection, the diastereomerically
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
2

16. W. Li, M. P. Wiesenfeldt, F. Glorius, Ruthenium-NHC-diamine catalyzed
enantioselective hydrogenation of isocoumarins. J. Am. Chem. Soc. 139, 2585–
2588 (2017). doi:10.1021/jacs.6b13124 Medline
17. The trans isomer can be formed if a π-face exchange, e.g., via a catalyst-
substrate dissociation and recoordination step, precedes the further
hydrogenation of a highly reactive dearomatized intermediate (18).
pure
alcohol
could
be
converted
via
N,N'-
dicyclohexylcarbodiimide (DCC)-mediated coupling to ester
13, or via Mitsunobu etherification and subsequent Suzuki
coupling with an in situ formed alkylborane to ether 14.
We undertook preliminary mechanistic experiments to
understand the observed increase in selectivity for the hy-
drogenated product compared to the hydrodefluorinated
side products when moving from polar solvents, such as
methanol (1:9) or trifluoroethanol (1:2) to less polar solvents
such as dichloromethane (5:1) and eventually hexane (25:1)
(table S2). Our results suggest that the observed defluorina-
tion in methanol and dichloromethane occur via different
mechanistic pathways (see SM). The influence of different
solvents on the catalyst, and consequently the mechanism of
defluorination are the subject of ongoing mechanistic stud-
ies.
18. M. M. Stalzer, C. P. Nicholas, A. Bhattacharyya, A. Motta, M. Delferro, T. J. Marks,
Single-face/all-cis arene hydrogenation by
a
supported single-site d0
organozirconium catalyst. Angew. Chem. Int. Ed. 55, 5263–5267 (2016).
doi:10.1002/anie.201600345 Medline
19. F. Fache, S. Lehuede, M. Lemaire, A catalytic stereo- and chemo-selective
method for the reduction of substituted aromatics. Tetrahedron Lett. 36, 885–
888 (1995). doi:10.1016/0040-4039(94)02386-P
20. H. Yang, H. Gao, R. J. Angelici, Hydrodefluorination of fluorobenzene and 1,2-
difluorobenzene under mild conditions over rhodium pyridylphosphine and
bipyridyl complexes tethered on
a silica-supported palladium catalyst.
Organometallics 18, 2285–2287 (1999). doi:10.1021/om990151e
21. G. Haufe, S. Pietz, D. Wölker, R. Fröhlich, Synthesis of fluorinated cycloalkyl N-
phenylcarbamates and their microbial defluorination/oxygenation by Beauveria
bassiana.
Eur.
J.
Org.
Chem.
2003,
2166–2175
(2003).
doi:10.1002/ejoc.200200648
REFERENCES AND NOTES
22. M. K. Whittlesey, E. Peris, Catalytic hydrodefluorination with late transition metal
complexes. ACS Catal. 4, 3152–3159 (2014). doi:10.1021/cs500887p
23. M. Aizenberg, D. Milstein, Catalytic activation of carbon-fluorine bonds by a
soluble transition metal complex. Science 265, 359–361 (1994).
doi:10.1126/science.265.5170.359 Medline
24. M. Saburi, L. Shao, T. Sakurai, Y. Uchida, Asymmetric hydrogenation of 2-fluoro-
2-alkenoic acids catalyzed by Ru-binap complexes: A convenient access to
optically active 2-fluoroalkanoic acids. Tetrahedron Lett. 33, 7877–7880 (1992).
doi:10.1016/S0040-4039(00)74767-8
1. D. O’Hagan, Understanding organofluorine chemistry. An introduction to the C–F
bond. Chem. Soc. Rev. 37, 308–319 (2008). doi:10.1039/B711844A Medline
2. B. E. Smart, Fluorine substituent effects (on bioactivity). J. Fluor. Chem. 109, 3–11
(2001). doi:10.1016/S0022-1139(01)00375-X
3. K. Müller, C. Faeh, F. Diederich, Fluorine in pharmaceuticals: Looking beyond
intuition. Science 317, 1881–1886 (2007). doi:10.1126/science.1131943 Medline
4. S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Fluorine in medicinal chemistry.
Chem. Soc. Rev. 37, 320–330 (2008). doi:10.1039/B610213C Medline
5. M. Hird, Fluorinated liquid crystals—Properties and applications. Chem. Soc. Rev.
36, 2070–2095 (2007). doi:10.1039/b610738a Medline
25. T. D. Nelson, M. H. Kress, S. W. Krska, J. V. Mitten, Y. Sun, Patent WO
2006069287 A1 (2006).
6. P. Kirsch, M. Bremer, Nematic liquid crystals for active matrix displays: Molecular
design and synthesis. Angew. Chem. Int. Ed. 39, 4216–4235 (2000).
doi:10.1002/1521-3773(20001201)39:23<4216:AID-ANIE4216>3.0.CO;2-K
7. A. J. Durie, A. M. Z. Slawin, T. Lebl, P. Kirsch, D. O’Hagan, Fluorocyclohexanes:
Synthesis and structure of all-syn-1,2,4,5-tetrafluorocyclohexane. Chem.
Commun. (Camb.) 48, 9643–9645 (2012). doi:10.1039/c2cc34679f Medline
8. A. J. Durie, A. M. Z. Slawin, T. Lebl, P. Kirsch, D. O’Hagan, Synthesis and structure
of all-syn-1,2,3,4-tetrafluorocyclohexane. Chem. Commun. (Camb.) 47, 8265–
8267 (2011). doi:10.1039/c1cc13016a Medline
9. N. S. Keddie, A. M. Z. Slawin, T. Lebl, D. Philp, D. O’Hagan, All-cis 1,2,3,4,5,6-
hexafluorocyclohexane is a facially polarized cyclohexane. Nat. Chem. 7, 483–
488 (2015). doi:10.1038/nchem.2232 Medline
10. W. Liu, X. Huang, M.-J. Cheng, R. J. Nielsen, W. A. Goddard III, J. T. Groves,
Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese
porphyrin. Science 337, 1322–1325 (2012). doi:10.1126/science.1222327
Medline
11. S. Bloom, C. R. Pitts, D. C. Miller, N. Haselton, M. G. Holl, E. Urheim, T. Lectka, A
polycomponent metal-catalyzed aliphatic, allylic, and benzylic fluorination.
Angew. Chem. Int. Ed. 51, 10580–10583 (2012). doi:10.1002/anie.201203642
Medline
12. C. R. Pitts, D. D. Bume, S. A. Harry, M. A. Siegler, T. Lectka, Multiple enone-
directed reactivity modes lead to the selective photochemical fluorination of
polycyclic terpenoid derivatives. J. Am. Chem. Soc. 139, 2208–2211 (2017).
doi:10.1021/jacs.7b00335 Medline
13. S. Ventre, F. R. Petronijevic, D. W. C. MacMillan, Decarboxylative fluorination of
aliphatic carboxylic acids via photoredox catalysis. J. Am. Chem. Soc. 137, 5654–
5657 (2015). doi:10.1021/jacs.5b02244 Medline
14. S. Urban, N. Ortega, F. Glorius, Ligand-controlled highly regioselective and
asymmetric hydrogenation of quinoxalines catalyzed by ruthenium N-
heterocyclic carbene complexes. Angew. Chem. Int. Ed. 50, 3803–3806 (2011).
doi:10.1002/anie.201100008 Medline
26. M. Engman, J. S. Diesen, A. Paptchikhine, P. G. Andersson, Iridium-catalyzed
asymmetric hydrogenation of fluorinated olefins using N,P-ligands: A struggle
with hydrogenolysis and selectivity. J. Am. Chem. Soc. 129, 4536–4537 (2007).
doi:10.1021/ja0686763 Medline
27. P. J. Dyson, Arene hydrogenation by homogeneous catalysts: Fact or fiction?
Dalton Trans. 0 2964–2974 (2003). doi:10.1039/b303250g
28. R. L. Augustine, Heterogeneous Catalysis for the Synthetic Chemist (M. Dekker,
New York, 1996), pp. 403–437.
29. M. Soleilhavoup, G. Bertrand, Cyclic (alkyl)(amino)carbenes (CAACs): Stable
carbenes on the rise. Acc. Chem. Res. 48, 256–266 (2015).
doi:10.1021/ar5003494 Medline
30. Y. Wei, B. Rao, X. Cong, X. Zeng, Highly selective hydrogenation of aromatic
ketones and phenols enabled by cyclic (amino)(alkyl)carbene rhodium
complexes.
doi:10.1021/jacs.5b05868 Medline
31. Several isomers were detected in the 19F NMR spectrum. The two major ones are
believed to exhibit cis substitution at the ring and result from the
J.
Am.
Chem.
Soc.
137,
9250–9253
(2015).
A
hydrogenation of the different faces of the molecule. The presented structure
was confirmed by single-crystal x-ray analysis (fig. S3) and by multiplicity
analysis of the signal in the 1H NMR spectrum.
32. Bruker AXS, Inc., APEX3 (Madison, WI, 2016).
33. Bruker AXS, Inc., SAINT (Madison, WI, 2015).
34. Bruker AXS, Inc., SADABS (Madison, WI, 2015).
35. G. M. Sheldrick, SHELXT
determination. Acta
doi:10.1107/S2053273314026370 Medline
-
Integrated space-group and crystal-structure
Crystallogr. 71, 3–8 (2015).
A
36. Bruker AXS, Inc., XP–Interactive molecular graphics, version 5.1, (Madison, WI,
1998).
37. M. S. Baker, S. T. Phillips, A two-component small molecule system for activity-
based detection and signal amplification: Application to the visual detection of
threshold levels of Pd(II). J. Am. Chem. Soc. 133, 5170–5173 (2011).
doi:10.1021/ja108347d Medline
15. N. Ortega, S. Urban, B. Beiring, F. Glorius, Ruthenium NHC catalyzed highly
asymmetric hydrogenation of benzofurans. Angew. Chem. Int. Ed. 51, 1710–1713
(2012). doi:10.1002/anie.201107811
38. E. Arkoudis, I. N. Lykakis, C. Gryparis, M. Stratakis, Biomimetic synthesis of
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
3

dimeric metabolite acremine G via a highly regioselective and stereoselective
Diels-Alder reaction. Org. Lett. 11, 2988–2991 (2009). doi:10.1021/ol901004e
Medline
39. G. Özüduru, T. Schubach, M. M. K. Boysen, Enantioselective cyclopropanation of
indoles: Construction of all-carbon quaternary stereocenters. Org. Lett. 14,
4990–4993 (2012). doi:10.1021/ol302388t Medline
40. T. Fujimoto, T. Ritter, PhenoFluorMix: Practical chemoselective
deoxyfluorination of phenols. Org. Lett. 17, 544–547 (2015).
doi:10.1021/ol5035518 Medline
41. V. Ramella, Z. He, C. G. Daniliuc, A. Studer, Palladium-catalyzed dearomatizing
difunctionalization of indoles and benzofurans. Eur. J. Org. Chem. 2016, 2268–
2273 (2016). doi:10.1002/ejoc.201600194
42. I. M. Smallwood, Handbook of Organic Solvent Properties (Arnold, London, 1996).
43. M. Hans, J. Wouters, A. Demonceau, L. Delaude, Probing the diastereoselectivity
of staudinger reactions catalyzed by N-heterocyclic carbenes. Chem. Eur. J. 21,
10870–10877 (2015). doi:10.1002/chem.201501060 Medline
44. J. W. Lown, S. M. S. Chauhan, Synthesis of specifically nitrogen-15- and carbon-
13-labeled antitumor (2-haloethyl)nitrosoureas. The study of their
conformations in solution by nitrogen-15 and carbon-13 nuclear magnetic
resonance electronic control in their aqueous decomposition. J. Org. Chem. 46,
5309–5321 (1981). doi:10.1021/jo00339a010
45. A. J. Kennedy, T. P. Mathews, Y. Kharel, S. D. Field, M. L. Moyer, J. E. East, J. D.
Houck, K. R. Lynch, T. L. Macdonald, Development of amidine-based sphingosine
kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in
human leukemia cells. J. Med. Chem. 54, 3524–3548 (2011).
doi:10.1021/jm2001053 Medline
ACKNOWLEDGMENTS
We gratefully acknowledge the Studienstiftung des Deutschen Volkes (M.P.W.), the
Hans-Jensen-Minerva Foundation (Z.N.), the Alexander von Humboldt
foundation (W.L.) and the Deutsche Forschungsgemeinschaft (F.G.) for
generous financial support. We thank C. Schlepphorst, Dr. L. Candish, Dr. M. van
Gemmeren and Dr. R. Honeker for helpful discussions. We thank Dr. K.
Bergander for NMR measurements and helpful discussions, and Dr. C. G.
Daniliuc for x-ray crystallographic analysis. Crystallographic data for 8e and 9e
are available free of charge from the Cambridge Crystallographic Data Centre
under CCDC-1561951 and CCDC-155388, respectively. Additional data are
available in the supplementary materials. M. P. W., Z. N. and F. G. are inventors
on German patent application 10 2017 106 467.2 held/submitted by WWU
Muenster that covers a method for the synthesis of fluorinated cyclic aliphatic
compounds.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/cgi/content/full/science.aao0270/DC1
Materials and Methods
Figs. S1 to S3
Tables S1 to S4
References (32–45)
NMR Spectra
Crystallography Reports
6 June 2017; accepted 28 July 2017
Published online 10 August 2017
10.1126/science.aao0270
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
4

Fig. 1. Cis-selective synthesis of (multi)fluorinated cycloalkanes by arene hydrogenation.
(A) Previously described methodologies for the preparation of fluorinated cycloalkanes. The
cis-selective synthesis of fluorinated cycloalkanes requires diastereoselectively
prefunctionalized substrates. (B) Synthetic route to the facially polarized all-cis-1,2,3,4,5,6-
hexafluorocyclohexane (1). (C) The competing hydrodefluorination side reactions that have
previously precluded development of a protocol for hydrogenation of fluorinated arenes to
fluorinated cycloalkanes. (D) The method reported herein to access stereodefined
(multi)fluorinated building blocks and highly polar multifluorinated cycloalkanes.
Fig. 2. Mechanistic pathways for the undesired hydrodefluorination
side reaction. The hydrodefluorination reaction can take place via
oxidative addition or nucleophilic aromatic substitution at the aryl halide 3,
via β-Fluorine elimination from alkyl-metal complex 4 or via Lewis acid
(LA) or Brønsted acid or base catalyzed HF-elimination from the alkyl
halide product 7.
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
5

Fig. 3. Scope of the hydrogenation of fluorinated arenes. (A) Synthesis of fluorinated building blocks and
all-cis-(multi)fluorinated cyclohexanes. Dipp, 2,6-diisopropylphenyl; BPin, pinacolboron; Me, methyl. All data
are reported as isolated yields unless otherwise stated. For details concerning concentration and catalyst
loading see SM;. Diastereomeric ratio (d.r.) values of the major isomer relative to all other isomers were
determined by 19F NMR or GC analysis prior to purification. *The major isomer could be isolated by standard
column chromatography using pentane/diethylether = 99:1. †The major isomer could be isolated via
‡
§
recrystallization in pentane/diethyl ether. The d.r. values of crude and isolated product were identical. The
yield was determined by 19F NMR spectroscopy with hexafluorobenzene as internal standard. The yield was
||
determined via GC-FID with mesitylene as internal standard.¶A 10:1 mixture of enol and alcohol was obtained.
(B) Scale-up to gram scale. MS, molecular sieves.
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
6

First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
7

Fig. 4. Applications of the developed method for the hydrogenation of fluorinated arenes.
(A) Synthesis of biologically relevant compounds. All data are reported as isolated yields unless
otherwise stated. For details concerning concentration and catalyst loading see SM. d.r. values of
the major isomer relative to all other isomers were determined by 19F NMR or GC analysis prior to
purification. *The d.r. values of crude and isolated product were identical. (B) Use of fluorinated
Boc-protected amine 7f as cis-fluorinated building block for the synthesis of ICy∙HBF4 derivative 10
and fluorinated analogs 11, 12 of the commercial pharmaceuticals lomustine and bromhexine.
ICy∙HBF4, 1,3-dicyclohexyl-imidazolium tetrafluoroborate. TFA, trifluoracetic acid (C) Use of 3,4,5-
trifluorinated TBS-protected cyclohexanol as building block for the synthesis of structural analogs
13, 14 of known liquid crystalline materials. TBAF, tetra-n-butylammonium fluoride,
THF, tetrahydrofuran, n-Pent, n-pentyl, DMAP, 4-dimethylaminopyridine, DIAD, diisopropyl
azodicarboxylate, 9-BBN, 9-borabicylco(3.3.1)nonane, dppf, 1,1'-bis(diphenylphosphino)ferrocene,
DMF, dimethylformamide.
First release: 10 August 2017
www.sciencemag.org
(Page numbers not final at time of first release)
8

Hydrogenation of fluoroarenes: Direct access to all-cis-(multi)fluorinated cycloalkanes
Mario P. Wiesenfeldt, Zackaria Nairoukh, Wei Li and Frank Glorius
published online August 10, 2017
ARTICLE TOOLS
http://science.sciencemag.org/content/early/2017/08/09/science.aao0270
SUPPLEMENTARY
MATERIALS
http://science.sciencemag.org/content/suppl/2017/08/09/science.aao0270.DC1
REFERENCES
This article cites 36 articles, 3 of which you can access for free
http://science.sciencemag.org/content/early/2017/08/09/science.aao0270#BIBL
PERMISSIONS
http://www.sciencemag.org/help/reprints-and-permissions
Use of this article is subject to the Terms of Service
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee
American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a
registered trademark of AAAS.