A catalytic fluoride-rebound mechanism for C(sp3)-CF3 bond formation

Article abstract of DOI:10.1126/science.aan1411

The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp³)-CF₃ reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the fluoride-rebound mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF₃-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography.

Full text of DOI:10.1126/science.aan1411

RESEARCH
bearing bromide and a,a-difluoroethyl substitu-
ents, as a mixture of two coordination isomers
(Fig. 2B). Treatment of 4 with AgF leads to the
gradual formation of MeCF3 and 3 (Fig. 2C). Taken
together, these results implicate an overall mech-
anism (Fig. 2D) in which fluoride abstraction
(i) from a CF3 moiety of 1 by the borane 2 results
in an intermediate difluorocarbenoid (or alter-
natively the carbenium resonance form, shown)
that undergoes migratory insertion (ii) of the alkyl
fragment, followed by formal C-F reductive elim-
ination (iii) to afford trifluoroethane. Additional
experiments in support of this proposal include the
formation of 1,1-difluoroethyl triflate (MeCF2OTf)
when stoichiometric trimethylsilane triflate is
used in place of 2 (fig. S5) and the observation of
an intermediate aquo complex of the migratory
insertion product during low-temperature kinet-
ics in wet CD2Cl2 (figs. S12 to S15) (24).
To various extents, these elementary steps have
been observed previously at gold centers; in par-
ticular, our earlier work on C-F reductive elimi-
nation suggests that an outer-sphere mechanism
with considerable carbocationic character is oper-
ative (25, 26). Although migratory insertion at
Au(III) is comparatively rarer, density functional
theory (DFT) calculations suggest that a-insertion
to the difluorocarbene occurs readily (enthalpy
of activation, DH‡ < 4 kcal/mol; see fig. S32 and
table S24 for details) (27). Such a low barrier
likely explains why competitive hydrolysis of the
difluorocarbene, common in metal halocarbene
complexes, was not observed here even in wet
solvent (28). Regardless, this mechanism is un-
usual because it represents a formal C(sp3)-CF3
reductive elimination—itself rarely if ever observed—
by a catalytic process involving iterative disassem-
bly and reassembly of the CF3 moiety (29–31).
It became clear to us that interception of the
rebounding fluoride and introduction of a radio-
labeled surrogate could hold promise for the syn-
thesis of PET traces, provided that more complex
organic substituents could be used than the par-
ent methyl in 1. Diversification of the organic
fragment beyond the simple methyl analog was
accomplished by means of a variety of synthetic
manipulations (including hydroboration, cross-
metathesis, hydrogenation, and aluminum hydride
reduction) of h1-allyl 6, allowing the preparation of
more functionally diverse complexes (32). Reduc-
tive elimination from these elaborated derivatives
was likewise triggered with 2, ultimately affording
reductive elimination products such as 8 and 11
(Fig. 3A). Similar diversity was seen in the chem-
istry of arylgold complex 12 (remarkably includ-
ing aromatic nitration without rupture of the
gold-carbon bond), enabling the synthesis of
Leflunomide via C-CF3 reductive elimination from
an advanced intermediate (Fig. 3B) (33).
CHEMISTRY
A catalytic fluoride-rebound
mechanism for C(sp3)-CF3
bond formation
Mark D. Levin,1,2 Tiffany Q. Chen,1 Megan E. Neubig,1 Cynthia M. Hong,1,2
Cyril A. Theulier,1 Ilia J. Kobylianskii,1 Mustafa Janabi,3
James P. O’Neil,3* F. Dean Toste1,2
*
The biological properties of trifluoromethyl compounds have led to their ubiquity in
pharmaceuticals, yet their chemical properties have made their preparation a substantial
challenge, necessitating innovative chemical solutions. We report the serendipitous
discovery of a borane-catalyzed formal C(sp3)-CF3 reductive elimination from Au(III) that
accesses these compounds by a distinct mechanism proceeding via fluoride abstraction,
migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction.
The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic
protocols, enabling the synthesis of complex organic derivatives without cleavage of the
Au-C bond. This feature, combined with the “fluoride-rebound” mechanism, was translated
into a protocol for the synthesis of 18F-radiolabeled aliphatic CF3-containing compounds,
enabling the preparation of potential tracers for use in positron emission tomography.
he trifluoromethyl (CF3) functional group
is both a crucial pharmaceutical moiety
and a synthetic frustration. This dual na-
ture stems from a common cause: Strong,
noninteracting C-F bonds lend metabolic
tion (i.e., SN2 or SNAr) chemistry, which is used
for the majority of organic fluoride radiosyn-
thesis, is generally incompatible with the stereo-
electronic demands of the CF3 unit (10). Rather,
in the most successful technology, a “CF2” pre-
cursor is reacted with radiofluoride to generate
the relevant CF3 unit prior to incorporation into
the tracer via an organocopper intermediate
(Fig. 1A) (11–13).
An isolable yet reactive difluoroalkyl metal
substituent that affords the corresponding CF3
unit upon treatment with radiofluoride would
represent an alternative retrosynthetic approach
by which to access these important tracer com-
pounds (14–19). We report the serendipitous dis-
covery of a class of Au(III) complexes that exactly
match this profile of reactivity, simultaneously
providing synthetic access to the requisite precur-
sors while enabling their implementation for radio-
fluorination (Fig. 1B). The successful development
of this advance depended on mechanistic inves-
tigation of an unexpected trifluoromethylated
compound observed upon treatment of complex
1a with B(C6F5)3 (2) (Fig. 2A), namely the for-
mal product of C(sp3)-CF3 reductive elimina-
tion from the gold center (20, 21).
Our investigation into the mechanism com-
menced with 19F nuclear magnetic resonance
(NMR) monitoring of the formal reductive elim-
ination of Me-CF3 from 1a in the presence of
stoichiometric 2 at –15°C. The reaction showed
clean first-order kinetics (fig. S11), consistent with
catalytic action of 2 (22). At catalytic loadings of 2,
complete conversion was observed in less than
5 min at room temperature, affording IPr-Au-CF3
(3a) as the major Au-containing product. The
same reactivity was observed with the related
phosphine complex 1b (23). Addition of 10 equiv-
alents of Me3SiBr to the 2-catalyzed reductive eli-
mination formed an isolable Au(III) complex (4),
T
stability while simultaneously limiting the ability
of chemical transformations to forge the relevant
linkages and install the CF3 unit. Generally speak-
ing, nucleophilic (i.e., the Ruppert-Prakash reagent),
electrophilic (Umemoto’s or Togni’s reagents), or
metal-mediated (e.g., CuCF3) chemistry is used to
deliver a preformed CF3 unit to an organic sub-
strate, although the latter class of chemistries is
often plagued by the slow direct reductive elim-
ination of fluoroalkyl ligands (1–6). Nonetheless,
these modern protocols have aided the contin-
uing proliferation of trifluoromethyl-containing
compounds in medicinal chemistry, including
several high-profile drugs.
When these same synthetic considerations are
extended toward the synthesis of trifluoromethyl-
ated positron emission tomography (PET) tracers,
the situation becomes more complex (7–9). The
biomedical applications of PET rely on the avail-
ability of these tracers—radiolabeled compounds
in which a positron-emitting isotope, usually
18F (half-life, t1/2 ~ 110 min), is incorporated into a
molecule of biological importance. These com-
pounds can be used for high-resolution real-time
imaging of tissue-level phenomena, enabling di-
rect interrogation of disease states and mechanisms
of bioactivity. However, nucleophilic substitu-
To further demonstrate the utility and func-
tional group tolerance of this method, we pre-
pared the Bayer lead compound BAY 59-3074 via
straightforward elaboration of 6 (Fig. 3C) (34). In
addition to the depicted transformations, we also
found the complexes to be tolerant of Simmons-
Smith cyclopropanation, osmium-catalyzed dihy-
droxylation, periodate-mediated diol cleavage, and
1Department of Chemistry, University of California, Berkeley,
CA 94720, USA. 2Chemical Sciences Division, Lawrence
Berkeley National Laboratory, Berkeley, CA 94720, USA.
3Biomedical Isotope Laboratory, Lawrence Berkeley National
Laboratory, Berkeley, CA 94720, USA.
*Corresponding author. Email: jponeil@lbl.gov (J.P.O.); fdtoste@
berkeley.edu (F.D.T.)
Levin et al., Science 356, 1272–1276 (2017)
23 June 2017
1 of 4

RESEARCH
| REPORT
palladium-catalyzed cross-coupling. Initial Au-C
bond construction was also achieved with dialkyl
zinc or copper acetylide reagents, further ex-
panding the diversity of accessible structures.
Cleavage of the Au-C bond was observed only
in the presence of exceptionally strong acids
(CF3SO3H) and elemental halogens (e.g., Br2).
All of the intermediate gold complexes exhibited
complete air and water tolerance and were uni-
versally amenable to purification by silica gel
column chromatography. As such, we have be-
gun to regard the Au moiety as a triggerable but
otherwise inert functional group, enabling rou-
tine chemical synthesis akin to typical organic
substrates. Although synthetically tolerant metal
complexes have previously been reported, such
broad compatibility is rare, especially for Au(III),
which tends to be highly sensitive toward reduc-
tive decomposition (35–39).
For the radiochemical protocol, we initially
envisioned introduction of fluoride to complexes
analogous to 4. However, the silver-mediated re-
ductive elimination (Fig. 2C) was deemed too slug-
gish for these purposes, requiring the development
of a modified strategy. Although complexes with
several other counterions (such as triflate and
tosylate) rapidly eliminated alkyl-CF2X, the cor-
responding acetate complex exhibited an appro-
priate blend of stability and reactivity to enable
nucleophilic reductive elimination when treated
with 2 and a suitable fluoride source (Fig. 4A)
(40). Borane 2 was required for rapid reductive
elimination to occur; in its absence, the inter-
mediate [Au(III)]-F persisted for long enough to be
observed by 19F NMR spectroscopy, and side re-
actions arising from base-mediated decompo-
sition or glass-etching occurred alongside slow
reductive elimination, consistent with an outer-
sphere mechanism for C-F bond formation assisted
by 2 (41–43). The combined protocol was directly
translated to a radiological analog, affording the
corresponding radiolabeled reductive elimina-
tion products starting from KF and Kryptofix
[2.2.2], as shown in Fig. 4B (44).
Several features of this protocol merit addi-
tional comment. First, aromatic complexes remain
inaccessible for radiochemical functionalization
by this method because of the rapid reductive
elimination of the benzylic difluoroalkyl moiety;
treatment of phenyl complex 12 with Me3SiBr
and 2 results in PhCF2Br rather than an isolable
Au(III) complex. As such, the scope of this pro-
tocol remains fully complementary to the cor-
responding Cu-mediated analog via CuCF3 (11–13).
Second, isolation of [18F]BAY 59-3074 by prepara-
tive high-performance liquid chromatography
(HPLC) afforded an isolated radiochemical yield
of 6% and a specific activity of 8 mCi/mmol starting
from 71 mCi of [18F]fluoride. Such a specific
Fig. 1. Retrosynthetic analysis for CF3 radiosynthesis. (A) Pregeneration of a metal CF3 unit and
transfer to an organic substrate, Y = CO2Me, H; X = Cl, I, S(aryl)2 (Me, methyl). (B) By virtue of
the CF3 activation mechanism reported herein, Au(III) enables synthetic elaboration of the organometallic
species prior to activation for implementation for radiochemistry.
+
Fig. 2. Discovery of formal C(sp3)-CF3 reductive elimination from Au(III). (A) Borane-catalyzed reductive elimination of trifluoroethane. (B) Trapping
of a rearranged intermediate by bromotrimethylsilane. (C) Outer-sphere C-F reductive elimination from a difluoroalkyl Au(III) complex. (D) Proposed
mechanism of catalysis by tris(pentafluorophenylborane). IPr, 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene; Cy, cyclohexyl; TS, transition state.
Levin et al., Science 356, 1272–1276 (2017)
23 June 2017
2 of 4

RESEARCH
| REPORT
Fig. 3. Synthetic versatility of bis(trifluoromethyl) gold complexes. (A) Elaboration of allyl gold complex via multistep synthesis. (B) Synthesis of
Leflunomide. (C) Synthesis of BAY 59-3074. Isolated yields are listed for all reactions (see supplementary materials for details). Grubbs II, Grubbs’
second-generation metathesis catalyst; EtOAc, ethyl acetate; MeOH, methanol; DIBAL-H, diisobutylaluminum hydride; DIAD, diisopropyl azodicarbox-
ylate; Tol, toluene; TFAA, trifluoroacetic anhydride; Et3N, trimethylamine; 9-BBN-H, 9-borabicyclononane; NCS, N-chlorosuccinimide; Ph, phenyl; KSAc,
potassium thioacetate; Ar, aryl (aromatic substituent).
activity is on par with that of many CuCF3-based
protocols, although values ranging from 2.7 to
860 mCi/mmol have been obtained depending
on the preparative method. [These values are
all much lower than those achieved with classi-
cal nucleophilic substitution methodologies for
alkyl fluoride synthesis (typically in excess of
1000 mCi/mmol), highlighting an important di-
rection for the future development of radio-
trifluoromethylation (11–13).] Finally, the cost
associated with the use of stoichiometric organo-
gold reagents, although substantial by the metrics
of process-scale pharmaceutical preparation, are
relatively small in this context given the low con-
centrations required, the cost of 18F production,
and the costs of the associated medical imaging
technology (45).
The protocol established here represents an
important proof of concept in the radiosynthesis
of organic trifluoromethyl groups by a retrosyn-
thetic paradigm involving C-F reductive elimina-
tion and should prove a fruitful area for further
exploration. The broader mechanistic framework
consisting of fluoride-rebound reductive elimina-
tion upon which this radiochemical reaction is
built also has implications for the understanding
of transition metal catalysis, as it seems possible
that such a mechanism is in fact operative in the
related copper-mediated protocols currently in
use (in both radiochemical and nonradiochem-
ical contexts) (46–48). Furthermore, this work
suggests a promising direction for the develop-
ment of organometallic reagents via catalytically
Levin et al., Science 356, 1272–1276 (2017)
23 June 2017
3 of 4

RESEARCH
| REPORT
Fig. 4. Radiosynthesis via C-F reductive elimination from Au(III). (A) Synthesis
of an Au(III) acetate precursor and validation of its reductive elimination chemistry with 19F
NMR spectroscopy. (B) Radiosynthesis of aliphatic trifluoromethyl groups via Au(III). Yields
given are radiochemical conversions determined by radio–thin-layer chromatography.
triggered reductive elimination of functionally
tolerant complexes.
22. E. Y.-X. Chen, T. J. Marks, Chem. Rev. 100, 1391–1434 (2000).
43. R. Kumar, A. Linden, C. Nevado, Angew. Chem. Int. Ed. 54,
14287–14290 (2015).
23. No thermally induced reductive elimination is observed with
1a or 1b upon heating at 100°C in toluene solution for 24 hours.
24. Fluoride abstraction by 2 from 3a and 3b is supported by the
observation that addition of superstoichiometric 2 results in the
formation of LAuC6F5 as the major Au-containing product.
Addition of tetramethylethylene as a scavenger in these
reactions results in the formation of the corresponding
difluorocyclopropane. See figs. S3, S4, and S8 for details.
25. S. Martínez-Salvador, J. Forniés, A. Martín, B. Menjón,
Angew. Chem. Int. Ed. 50, 6571–6574 (2011).
26. N. P. Mankad, F. D. Toste, Chem. Sci. 3, 72–76 (2012).
27. F. Rekhroukh, R. Brousses, A. Amgoune, D. Bourissou,
Angew. Chem. Int. Ed. 54, 1266–1269 (2015).
28. P. J. Brothers, W. R. Roper, Chem. Rev. 88, 1293–1326
(1988).
29. J. R. Bour et al., J. Am. Chem. Soc. 138, 16105–16111
(2016).
30. M. C. Leclerc et al., J. Am. Chem. Soc. 137, 16064–16073
(2015).
31. J. Choi et al., Science 332, 1545–1548 (2011).
32. S. Martínez-Salvador, L. R. Falvello, A. Martín, B. Menjón,
Chem. Eur. J. 19, 14540–14552 (2013).
33. R. R. Bartlett et al., Agents Actions 32, 10–21 (1991).
34. J. De Vry et al., J. Pharmacol. Exp. Ther. 310, 620–632
(2004).
44. This protocol is unoptimized with respect to solvent choice,
temperature, or reagent stoichiometries.
45. A. K. Buck et al., J. Nucl. Med. 51, 401–412 (2010).
46. D. M. Wiemers, D. J. Burton, J. Am. Chem. Soc. 108, 832–834
(1986).
47. O. A. Tomashenko, V. V. Grushin, Chem. Rev. 111, 4475–4521
(2011).
48. A. I. Konovalov, A. Lishchynskyi, V. V. Grushin, J. Am. Chem.
Soc. 136, 13410–13425 (2014).
REFERENCES AND NOTES
1. G. K. S. Prakash, A. K. Yudin, Chem. Rev. 97, 757–786 (1997).
2. S. Barata-Vallejo, B. Lantaño, A. Postigo, Chem. Eur. J. 20,
16806–16829 (2014).
3. M. A. García-Monforte, S. Martínez-Salvador, B. Menjón,
Eur. J. Inorg. Chem. 2012, 4945–4966 (2012).
4. A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz,
V. V. Grushin, J. Am. Chem. Soc. 133, 20901–20913 (2011).
5. E. J. Cho et al., Science 328, 1679–1681 (2010).
6. N. D. Ball, J. W. Kampf, M. S. Sanford, J. Am. Chem. Soc. 132,
2878–2879 (2010).
7. S. Preshlock, M. Tredwell, V. Gouverneur, Chem. Rev. 116,
719–766 (2016).
8. A. F. Brooks, J. J. Topczewski, N. Ichiishi, M. S. Sanford,
P. J. H. Scott, Chem. Sci. 5, 4545–4553 (2014).
9. M. G. Campbell et al., Nat. Chem. 9, 1–3 (2016).
10. V. T. Lien, P. J. Riss, BioMed Res. Int. 2014, 380124 (2014).
11. M. Huiban et al., Nat. Chem. 5, 941–944 (2013).
12. D. van der Born et al., Angew. Chem. Int. Ed. 53, 11046–11050
(2014).
13. P. Ivashkin et al., Chem. Eur. J. 20, 9514–9518 (2014).
14. S. H. Liang, N. Vasdev, Aust. J. Chem. 68, 1319–1328 (2015).
15. E. Lee et al., Science 334, 639–642 (2011).
16. H. Teare et al., Angew. Chem. Int. Ed. 49, 6821–6824 (2010).
17. T. J. A. Graham, R. F. Lambert, K. Ploessl, H. F. Kung,
A. G. Doyle, J. Am. Chem. Soc. 136, 5291–5294 (2014).
18. X. Huang et al., J. Am. Chem. Soc. 136, 6842–6845 (2014).
19. E. Lee, J. M. Hooker, T. Ritter, J. Am. Chem. Soc. 134,
17456–17458 (2012).
20. J. Gil-Rubio, J. Vicente, Dalton Trans. 44, 19432–19442 (2015).
21. The mechanism elucidated here indicates that the reaction
is not a true C-C reductive elimination, occurring instead by an
alternate series of three steps terminating with C-F reductive
elimination, and is thus rather a formal C-C reductive
elimination. However, for the sake of brevity we have used the
phrase “reductive elimination” throughout, with the intention
that it be understood as a reference to the overall
transformation and not to its microscopic mechanism.
ACKNOWLEDGMENTS
Supported by NSF grant DGE 1106400 and an ARCS Foundation
graduate research fellowship (M.D.L.), a Swiss National Science
Foundation postdoctoral fellowship (I.J.K.), and National Institute of
General Medical Sciences grant R35 GM118190. DFT studies were
conducted at the Molecular Graphics and Computation Facility,
funded by NSF grant CHE-0840505. We thank H. Celik, W. Wolf, and
L. Sofen for technical assistance; R. Bergman, D. Kaphan, R. Thornbury,
M. Winston, Y. Wang, and A. Zhukhovitskiy for helpful discussions;
and B. Cwick for facilitating the collaboration that prompted the
radiochemical applications of this work. Metrical parameters for the
structures of compounds 1a, 1b, 4, 5, 6, 7, 18, S2, and S8 are available
free of charge from the Cambridge Crystallographic Data Centre under
reference numbers CCDC 1537030 to 1537038, respectively, with
all other data available in the supplement. M.D.L., J.P.O., and F.D.T.
are listed as inventors on a patent application describing Au(III)
reagents for radiofluorination, Provisional Application 62/268,842 filed
22 May 2017.
35. M. Rosillo, G. Domínguez, J. Pérez-Castells, Chem. Soc. Rev.
36, 1589–1604 (2007).
36. K. M. Nicholas, R. Pettit, Tetrahedron Lett. 12, 3475–3478
(1971).
37. W. D. Harman, Chem. Rev. 97, 1953–1978 (1997).
38. A. S. K. Hashmi, M. C. Blanco, D. Fischer, J. W. Bats, Eur. J. Org.
Chem. 2006, 1387–1389 (2006).
39. W. J. Wolf, M. S. Winston, F. D. Toste, Nat. Chem. 6, 159–164
(2014).
40. Both isomers of the [Au(III)]-OAc complexes are consumed in
these reactions.
41. M. S. Winston, W. J. Wolf, F. D. Toste, J. Am. Chem. Soc. 137,
7921–7928 (2015).
42. D. S. Laitar, P. Müller, T. G. Gray, J. P. Sadighi, Organometallics
24, 4503–4505 (2005).
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/356/6344/1272/suppl/DC1
Materials and Methods
Figs. S1 to S32
Tables S1 to S24
References (49, 50)
9 March 2017; accepted 31 May 2017
10.1126/science.aan1411
Levin et al., Science 356, 1272–1276 (2017)
23 June 2017
4 of 4

A catalytic fluoride-rebound mechanism for C(sp3)-CF3 bond formation
Mark D. Levin, Tiffany Q. Chen, Megan E. Neubig, Cynthia M. Hong, Cyril A. Theulier, Ilia J. Kobylianskii, Mustafa Janabi,
James P. O'Neil and F. Dean Toste
Science 356 (6344), 1272-1276.
DOI: 10.1126/science.aan1411
Trifluoromethylation via broken C-F bonds
Trifluoromethyl substituents are widely used in pharmaceutical research to tune the properties of drug candidates.
Generally, they are introduced intact through the formation of carbon-carbon bonds. Levin et al. discovered an unusual
alternative mechanism, in which borane abstracts fluoride from the CF 3 group in a gold complex. The activated CF2
fragment can then bond to a wide variety of other carbon substituents added to the same gold center. Return of the
fluoride liberates a trifluoromethylated compound from the metal. This mechanism could be useful for the introduction of
radioactive fluoride substituents for positron emission tomography applications.
Science, this issue p. 1272
ARTICLE TOOLS
http://science.sciencemag.org/content/356/6344/1272
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.