Open-Shell Fluorination of Alkyl Bromides: Unexpected Selectivity in a Silyl Radical-Mediated Chain Process

Article abstract of DOI:10.1021/jacs.9b11434

We disclose a novel radical strategy for the fluorination of alkyl bromides via the merger of silyl radical-mediated halogen-atom abstraction and benzophenone photosensitization. Selectivity for halogen-atom abstraction from alkyl bromides is observed in the presence of an electrophilic fluorinating reagent containing a weak N-F bond despite the predicted favorability for Si-F bond formation. To probe this surprising selectivity, preliminary mechanistic and computational studies were conducted, revealing that a radical chain mechanism is operative in which kinetic selectivity for Si-Br abstraction dominates due to a combination of polar effects and halogen-atom polarizability in the transition state. This transition-metal-free fluorination protocol tolerates a broad range of functional groups, including alcohols, ketones, and aldehydes, which demonstrates the complementary nature of this strategy to existing fluorination technologies. This system has been extended to the generation of gem-difluorinated motifs which are commonly found in medicinal agents and agrochemicals.

Full text of DOI:10.1021/jacs.9b11434

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Communication
Open-Shell Fluorination of Alkyl Bromides: Unexpected
Selectivity in a Silyl Radical-Mediated Chain Process
Gabrielle H. Lovett, Shuming Chen, Xiao-Song Xue, K. N. Houk, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11434 • Publication Date (Web): 27 Nov 2019
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Journal of the American Chemical Society
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Open-Shell Fluorination of Alkyl Bromides: Unexpected Selectivity
in a Silyl Radical-Mediated Chain Process
Gabrielle H. Lovett, † Shuming Chen, ‡ Xiao-Song Xue,‡ K. N. Houk,*‡ and David W. C. MacMillan*†
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†
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California, 90095, United States
Supporting Information Placeholder
ABSTRACT: We disclose a novel radical strategy for the
fluorination of alkyl bromides via the merger of silyl radical-
mediated halogen-atom abstraction and benzophenone
photosensitization. Selectivity for halogen-atom abstraction
from alkyl bromides is observed in the presence of an
electrophilic fluorinating reagent containing a weak N–F bond
despite the predicted favorability for Si–F bond formation. To
probe this surprising selectivity, preliminary mechanistic and
computational studies were conducted, revealing that a radical
chain mechanism is operative in which kinetic selectivity for
Si–Br abstraction dominates due to a combination of polar
effects and halogen atom polarizability in the transition state.
This transition metal-free fluorination protocol tolerates a broad
range of functional groups, including alcohols, ketones, and
aldehydes, which demonstrates the complementary nature of
this strategy to existing fluorination technologies. This system
has been extended to the generation of gem-difluorinated
motifs, which are commonly found in medicinal agents and
agrochemicals.
This Work: Silyl Radical-Mediated Conversion of C(sp3)–Br to C(sp3)–F
F
Br
R
R
photocatalyst, visible light
silyl radical source
N
F
R
R
R
R
F
N
Si
R
Overcoming Highly Exothermic Undesired Pathway
N–F BDE: ~ 63 kcal/mol
PhO2S SO2Ph
PhO2S
PhO2S
∆G =
R3Si
F
N
N
δ+
– 65 kcal/mol
F
R
strong Si–F bond
δ-
~ 130 kcal/mol
Si
R
R
Br
R
∆G =
δ+
R'
R3Si Br
– 18 kcal/mol
observed pathway
R
R'
weaker Si–Br bond
The properties of alkyl fluorides, and their unique impact on
organic molecules, have been exploited in the areas of
pharmaceutical, agrochemical, and material sciences.1–3 The
increasing demand for novel mechanisms that allow C–F bond
installation to be broadly applicable, operationally simple, and
amenable to early or late stage implementation has greatly
driven the community’s interest in expanding the fluorination
toolbox. Established protocols for the generation of C(sp3)–F
bonds include deoxyfluorination of alcohols, hydrofluorination
of alkenes, decarboxylative fluorination of acids, and radical C–
H fluorination.4 Given that these valuable technologies convert
common organic functional groups to fluorine substituents, it is
remarkable to consider that a general protocol for the
transformation of a broad range of alkyl bromides into alkyl
fluorides remains elusive.5–7
Silicon-centered radicals have long been known to serve as
potent halogen-atom abstraction agents, forming alkyl radicals
from the corresponding bromides at near-diffusion-limited
reaction rates.8 Recently, our laboratory has introduced the
concept of photocatalytically-generated silyl radicals for the
formation of alkyl and aryl radicals from their corresponding
bromides using visible light. This open-shell halide activation
mechanism has subsequently been incorporated into a variety
of metallaphotoredox reaction designs including nickel- and
copper-catalyzed cross-couplings of value to the medicinal
chemistry sector.9 With these technologies in mind, and given
C–Br BDE: ~ 72 kcal/mol
~ 90 kcal/mol
strong thermodynamic driving force for undesired abstraction from N–F bond
Kinetic Factors in Halogen Atom Transfer
halogen atom
vs.
C
Br
Si
N
F
Si
polarizability
radical character better stabilized by more polarizable Br atom
favors desired abstraction for C–Br bond
δ–
δ+
δ–
δ+
Si
charge transfer
character in TS
vs.
C
Br
Si
N
F
negative charged better stabilized by more electron-deficient N atom
favors undesired abstraction for N–F bond
can we exploit polarizability to overcome a strong thermodynamic bias?
Figure 1. Silyl radical-mediated fluorination of alkyl bromides
the widespread availability of alkyl bromides, we hypothesized
that silyl radical activation in combination with radicophilic
fluorine sources might allow ambient temperature access to
C(sp3)–F bonds in a generic fashion using a photocatalyst,
visible light, and a mild fluorinating agent. Notably, an open-
shell fluorination strategy should provide complementary scope
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1
Table 1. Optimization of silyl radical-mediated fluorination
Scheme 1. Proposed radical chain initiation and propagation
2
Radical Initiation
3
4
*
O
O
R
(TMS)3SiOH
RO Si
5
R
SET or HAT
Ph
Ph
Ph
Ph
6
1
2
7
Radical Propagation
8
9
Br
PhO
2S
SO2Ph
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N
H
BzN
R
RO Si
R
alkyl bromide
3
XAT
SET
Radical
Chain
(TMS)3SiOH
Br–SiR3
supersilanol
Propagation
PhO2S
N
SO2Ph
BzN
5
4
F atom transfer
F
PhO
2S
SO2Ph
N
>
ϕ
1000
BzN
fluorinated product
F
NFSI
a
b
c
1.5 equiv. 1.75 equiv. 2.5 mol%
(HTE) in an effort to uncover which combination of fluorination
sources, solvent polarity, and abstraction agents might deliver
proof of concept, chemoselectivity, and, thereafter, broad
scope. Because the mechanism for silyl radical generation9 and
fluorine atom transfer14,15 should be similar to those previously
proposed by our laboratory, we began our investigation by
exposing 1-benzoyl-4-bromopiperidine to visible light
to classical substitution methods. While an open-shell
fluorination strategy has been developed for tertiary alkyl
bromides,7 a silyl radical-mediated protocol should allow for a
broad range of alkyl bromides to be converted to their
corresponding alkyl fluorides.
From the outset, we recognized a significant challenge to
achieving the desired selectivity for C–F bond formation using
a silyl radical/bromine abstraction approach. Specifically, the
required chemoselectivity of silyl radical abstraction from an
alkyl bromide in the presence of an electrophilic fluorinating
reagent (e.g., Selectfluor) appeared to be intrinsically
problematic. First, there is large thermodynamic driving force
for the formation of a strong Si–F bond via silyl radical
abstraction from a weak N–F bond (63 kcal/mol for NFSI)10
versus formation of the weaker Si–Br bond via desired
abstraction from the alkyl bromide C–Br bond (~70 kcal/mol).11
Second, polar effects in the transition state should favor
abstraction from the electrophilic fluorinating reagent over the
alkyl bromide, as the partial negative charge buildup in the
transition state during abstraction by a nucleophilic silicon-
centered radical12 can be better stabilized by the electron-
deficient nitrogen atom of an electrophilic fluorinating reagent
than the carbon atom of the alkyl bromide (Figure 1). While
these factors both favor the undesired abstraction, we were
aware that the rates of silyl radical abstraction from C–X bonds
are often dependent on the degree of atom polarizability of the
halogen atom,13 an aspect that should favor abstraction of the
more polarizable bromine atom in lieu of a fluorine atom, thus
leading to the desired selectivity.
irradiation (40
W
blue LEDs) in the presence of
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (PC-1), tris(trimethylsilyl)silane
[(TMS)3SiH] as the silyl radical agent, Selectfluor as the
fluorine source, along with Na2HPO4 in MeCN/H2O. Despite
the potential challenges of this approach, we observed 1% of
the desired fluoroalkyl adduct (Table 1, entry 1), presumably
due to photocatalytic reduction (E red[IrIII/IrII] = –1.37 V vs.
½
SCE in MeCN)9 of the electrophilic fluorine source
(Selectfluor, Epc = +0.33 V vs. SCE in MeCN)15 being the
dominant pathway.
Using a high-throughput evaluation protocol, we next
evaluated a broad range of photocatalysts and electrophilic
fluorine sources, and quickly determined that the desired 4-
fluoro-piperidinyl adduct 1 could be obtained in 46% yield
using N-fluorobenzenesulfonimide (NFSI) (Epc = –0.78 V vs.
SCE)14 in combination with the photocatalyst PC-2,
[Ir(dF(CF3)ppy)2((5,5'-CF3)bpy)]PF6 (E red[IrIV/IrIII] = –0.42 V
½
vs. SCE in MeCN)16 (entries 2 and 3). This outcome supports
the mechanistic hypothesis that a less reducing photocatalyst
and a less oxidizing electrophilic fluorine source could
circumvent the deleterious chemoselectivity observed in our
initial experiment. Moreover, replacing the (TMS)3SiH with
supersilanol [(TMS)3SiOH] and employing K3PO4 as base
improved the overall efficiency for alkyl fluoride production to
87% yield (entry 5). Control experiments revealed that the
reaction requires light and supersilanol (see SI for details);
Given the difficulties in predicting a priori which factors
would impact the kinetic selectivity between these pathways,
we chose to incorporate high throughput experimentation
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however, removal of the photocatalyst did not fully suppress
to alkyl radicals14 are known and well-precedented. The
nitrogen-centered radical 5 formed can then undergo single
electron transfer (SET) from supersilanol (or the corresponding
silanolate), followed by a radical Brook rearrangement18 to
furnish a silyl radical species; alternatively, 5 can abstract a
hydrogen-atom from the silanol O–H bond (see SI for details)
to generate a silyl radical species following rearrangement.
To further explore the plausibility of our proposed radical
chain pathway and to probe the unique selectivity observed, we
performed a series of density functional theory (DFT)
calculations (Figure 2). These computational studies using the
supersilyl radical 619 revealed that the formation of the strong
C–F and Si–O bonds provides a powerful thermodynamic
driving force. Remarkably, the supersilyl radical exhibits
excellent kinetic selectivity for the C–Br bond of the alkyl
bromide over the weaker N–F bond of NFSI. While both of
these steps are substantially exergonic (–17.6 kcal/mol and –
64.8 kcal/mol, respectively), the N–F abstraction step proceeds
with a less favorable activation free energy of 13.1 kcal/mol,
which is 1.9 kcal/mol higher than that of the corresponding C–
Br abstraction. Importantly, computational analysis reveals that
this kinetic discrepancy is due to a sharper increase in the
energy required to distort the less polarizable NFSI into its
transition state geometry as compared to the alkyl bromide (see
SI for details), in line with our initial theoretical considerations.
Importantly, fluorine atom transfer from NFSI will lead to the
corresponding nitrogen-centered radical (5) which is polarity
matched to abstract a hydrogen atom from the hydridic silane 7,
thereby propagating this mechanism via a supersilyl radical
species. Details of this computational study, including DFT
calculations for a variety of alternative or competing reaction
pathways, are provided in the Supporting Information.
1
2
3
4
5
6
7
8
product formation (entry 7, 22% yield), an unexpected finding
that led us to question our initial mechanistic hypothesis.
Intriguingly, further studies to evaluate an array of
photocatalysts and photosensitizers (see SI for details)
demonstrated that 2.5 mol% benzophenone provided the
desired alkyl fluoride adduct in 86% yield (entry 8).
Given the success of benzophenone as a suitable replacement
for the Ir photocatalyst, we next sought to examine the
mechanistic aspects of this novel fluorination protocol. More
specifically, we began to question if a photoinitiation-radical
chain propagation pathway was operating. Such a mechanism
would be consistent with the negligible absorbance of
benzophenone within the range of visible light employed (see
SI for details). Indeed, experiments to determine the quantum
yield for this process revealed a value significantly higher than
unity (φ >1000), indicating that a radical propagation step is
involved (see SI for details).
On the basis of the results above, a revised mechanistic
description for the relevant fluorine atom transfer is presented
in Scheme 1. Numerous radical initiation events may be
operative in this system. The reaction proceeds, albeit in lower
efficiency, in the absence of benzophenone (table 1, entry 7);
thus, plausible initiation events may include the bond homolysis
of a minute concentration of the weaker bonds in the system
(e.g., C–Br and N–F). In the presence of benzophenone (1),
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irradiation with visible light should lead to
a small
concentration of the corresponding aryl ketone triplet excited
state (2), which is known to serve as a potent hydrogen atom
abstractor as well as
a
strong oxidant.17 The excited
benzophenone may engage the supersilanol in either a SET or
HAT event to deliver a silyl radical (3) (see SI for details).
Further investigations into the exact nature of this interaction
are ongoing. Both silyl radical abstraction of alkyl bromides9
(Scheme 1, XAT) as well as fluorine atom transfer from NFSI
We next sought to investigate the generality of the kinetic
selectivity by exploring the scope of this novel C(sp3)–F bond-
Figure 2. DFT free energy profile (in kcals/mol) and calculated transition state structures for the proposed radical chain at the M06-
2X/6-311++G(d,p)//M06-2X/6-31G(d) level of theory. Hydrogen atoms are omitted for clarity. Interatomic distances are in Ångströms.
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Table 2. Scope for the transition metal-free, silyl radical-mediated protocol for the fluorination of secondary alkyl bromidesa
1
2
3
4
2.5–5 mol% benzophenone
PS
O
Br
F
PhO2S
SO2Ph
(TMS)3SiOH, base
N
F
Ph
Ph
5
6
1:1 MeCN/H2O (0.1 M)
blue LEDs, 1–8 h
alkyl bromide
F+ reagent
alkyl fluoride
benzophenone
7
8
secondary bromides
9
Br
O
10
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Br
Br
Br
N
N
BzN
CbzN
O
N
Boc
F3C
Br
F3C
N
F
O
N
F
F
F
F
N
O
BzN
CbzN
N
Boc
F3C
F3C
N
8, 84% yield
9, 89% yield
10, 86% yield
11, 80% yield
(±) 12, 75% yield
3:1 d.r.
O
Br
OH
Br
Br
Me
O
Me
Br
Br
BzHN
HO
O
F
OH
F
F
Me
O
Me
F
F
BzHN
HO
13, 41% yieldc
14, 99% yieldb
15, 62% yieldd
(±) 16, 80% yield
(±) 17, 72% yieldb
1.2:1 d.r.
4:1 d.r.
O
O
Br
O
Br
AcO
Me
BzO
O
N
N
Me
BocHN
AcO
AcO
OAc
Br
BzO
F
O
Br
OAc
AcO
OAc
O
O
F
O
AcO
AcO
F
Me
O
N
N
Me
BocHN
BzO
AcO
OAc
F
O
F
BzO
F
OAc
AcO
OAc
(±) 18, 83% yield
19, 86% yield
20, 90% yield
> 20:1 d.r.
21, 85% yield
5:1 d.r.
1:1 d.r.
aYields of isolated products unless otherwise indicated. Performed with benzophenone (2.5 or 5 mol%), alkyl bromide (0.5 mmol), NFSI (3 equiv.),
(TMS)3SiOH (1.75 equiv.), and base (K3PO4 or Na2HPO4, 2 equiv.) in 1:1 MeCN/H2O for 1–8 h. See supporting information for experimental details.
bYields determined by 19F NMR analysis (average of two runs). cStarting material d.r. = 8:1. dConcentration of 0.08 M.
forming reaction. As demonstrated in Table 2, a broad range of
cyclic and acyclic secondary alkyl bromides are readily
transformed to the corresponding alkyl fluorides in good to
excellent yields. Specifically, a variety of ring sizes from 4- to
7-membered rings were well tolerated (8–14, 41–99% yield),
including an array of saturated and unsaturated heterocycles.
Notably, functionalities that are typically sensitive to
nucleophilic fluorination conditions (e.g., DAST for
deoxyfluorination), including benzylic alcohols and phenols, as
well as substrates prone to elimination, were fully compatible
with this open-shell mechanism (15–18, 62–83% yield). As one
notable example, b-fluoroamine 18, a motif found in numerous
medicinal agents,1b was readily generated from the
corresponding b-bromoamine (83% yield). To further illustrate
the orthogonal nature of this transformation compared to
closed-shell ionic mechanisms, we were delighted to find that
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Table 3. Further scope of fluorination of alkyl bromidesa
As a further demonstration of the utility of this new
1
2
3
4
5
6
7
8
fluorination technology, we next examined the capacity to form
geminal difluoroalkanes, a motif increasingly incorporated into
medicinal agents. As shown in Table 3, the desired difluoride
moiety was formed in excellent yield from the corresponding
Br
Si•
PS
F
F
gem-dibromide
using
an
iterative
halogen-atom
alkyl bromide
alkyl fluoride
abstraction/radical capture mechanism (30, 72% yield). Given
the accessibility of C(sp3)–geminal dibromo systems,21 we
expect this dual-fluorination variant will find significant
implementation in both academic and industrial settings.
3
°
fluorides
F
F
Me Et
9
Supporting Information
F
10
11
12
13
14
15
16
17
18
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The Supporting Information is available free of charge on
the ACS Publications website at DOI: (link to DOI)
Experimental procedures, spectral data, and details of the
computational study
O
22, 61% yieldb
(±) 24, 86% yield
23, 55% yield
O
Me Me
O
Me Me
AUTHOR INFORMATION
Corresponding Author
O
F
O
F
H
X
O
25, 82% yield
*houk@chem.ucla.edu
*dmacmill@princeton.edu
Notes
X= Cl
X= Br
27, 82% yieldb
26, 63% yieldb
The authors declare no competing financial interests.
benzylic fluoride
1
°
fluoride
F
ACKNOWLEDGMENT
F
Me
Financial support was provided by the Office of Naval
Research (ONR) (N00014-18-1-2178) and kind gifts from
Merck, Abbvie, Pfizer, Celgene, Genentech, and Janssen. G.
H. Lovett thanks Y. Liang and R. T. Smith for their assistance
in preparing the manuscript.
MeO2C
28, 24% yieldb
(±) 29, 27% yield
gem-difluorination
Br Br
F
F
REFERENCES
Me
Me
(1) (a) Meanwell, N. A.; Donnelly, D. J.; Hill, M. D.; Eastman, K. J.;
Gillis, E. P. Applications of Fluorine in Medicinal Chemistry. J. Med.
Chem. 2015, 58, 8315. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev.
2008, 37, 320.
gem-dibromide
30, 72% yieldb
aYields of isolated products unless otherwise indicated. Performed with
benzophenone (2.5 or 5 mol%), alkyl bromide (0.5 mmol), NFSI (3
equiv.), (TMS)3SiOH (1.75 equiv.), and base (K3PO4 or Na2HPO4, 2
equiv.) in 1:1 MeCN/H2O for 1–8 h. See supporting information for
experimental details. bYields determined by 19F NMR analysis (average
of two runs).
(2) (a) Fujiwara, T.; O’Hagan, D. Successful Fluorine-containing
Herbicide Agrochemicals. J. Fluor. Chem. 2014, 167, 16. (b) Jeschke,
P. The Unique Role of Fluorine in the Design of Active Ingredients for
Modern Crop Protection. ChemBioChem 2004, 5, 570.
(3) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J.
Organic Fluorine Compounds: A Great Opportunity for Enhanced
Material Properties. Chem. Soc. Rev. 2011, 40, 3496.
(4) For selected reviews, see: (a) Champagne, P. A.; Desroches, J.;
Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Monofluorination of
Organic Compounds: 10 Years of Innovation. Chem. Rev, 2015, 115,
9073. (b) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of Fluorine
and Fluorine-Containing Functional Groups. Angew. Chem. Int. Ed.
2013, 52, 8214.
(5) The poor nucleophilicity and high basicity of fluoride has limited
its application in classic SN2 chemistry to primary and simple
secondary substrates. Recently, novel two-electron pathways have been
developed to accomplish this transformation, though these often
require moisture-sensitive fluoride salts or harmful HF reagents, or
stoichiometric transition metal-complexes at elevated reaction
temperatures. For selected examples, see: (a) Sun, H.; DiMango, S. G.
Anhydrous Tetrabutylammonium Fluoride. J. Am. Chem. Soc. 2005,
127, 2050. (b) Murray, C. B.; Sandford, G.; Korn, S. R.; Yufit, D. D.;
Howard, A. K. New Fluoride Ion Reagent from Pentafluoropyridine. J
Fluor. Chem. 2005, 126, 569. (c) Kim, D. W.; Jeong, H.-J.; Lim, S. T.;
Sohn, M.-H.; Chi, D. Y. Facile Nucleophilic Fluorination by
Synergistic Effect Between Polymer-supported Ionic Liquid Catalyst
and tert-alcohol Reaction Media System. Tetrahedron, 2008, 64, 4209.
(d) Kim, D.W.; Jeong, H.-J.; Lim, S.T.; Sohn, M.-H. Facile
an array of monosaccharides and nucleosides could be readily
transformed to their a-fluoro analogs without the requirement
of accessing high-energy b-acetoxy- or b-fluoro-oxocarbenium
ions (19–21, 85–90% yield).
Cyclic and acyclic tertiary fluorides, typically difficult to
access using traditional bromide substitution mechanisms, were
also successfully generated using this open-shell fluorination
protocol (22–29, 55–86% yield). Importantly, aryl bromides
and chlorides are comparatively unreactive towards abstraction,
thereby enabling chemoselective fluorination of the attendant
tertiary bromides (25 and 26, 82% and 63% yield, respectively).
Moreover, the utility of this technology in comparison to
nucleophilic deoxygenation mechanisms was further
highlighted in that a range of carbonyl moieties were readily
tolerated, including aldehydes, ketones, and esters (27, 22–23,
55–82% yield). In addition, primary and benzylic bromides
could be converted to their corresponding fluorides, albeit in
lower yields (28 and 29, 24% and 27% yield, respectively).20
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Nucleophilic Fluorination of Primary Alkyl Halides using
(16) Zhu, Q.; Graff, D. E.; Knowles, R. R. Intermolecular Anti-
Markovnikov Hydroamination of Unactivated Alkenes with
Sulfonamides Enabled by Proton-Coupled Electron Transfer. J. Am.
Chem. Soc. 2018, 140, 741.
Tetrabutylammonium Fluoride in a tert-alcohol Medium. Tetrahedron
Lett. 2010, 51, 432. (e) Zhao, H.; Gabbai, G. Nucleophilic Fluorination
Reactions Starting from Aqueous Fluoride Ion Solutions. Org. Lett.
2011, 13, 1444. (h) Liu, Y.; Chen, C.; Li, H.; Huang, K.-W.; Tan, J.;
Weng, Z. Efficient SN2 Fluorination of Primary and Secondary Alkyl
Bromides by Copper(I) Fluoride Complexes. Organometallics, 2013,
32, 6587. (i) Bouvet, S.; Pegot, J.; Marrot, E.; Magnier, E. Solvent Free
Nucleophilic Introduction of Fluorine with [bmim][F]. Tetrahedron
Lett. 2014, 55, 826.
(6) Fluorination of 3º alkyl bromides is primarily limited to fluorination
of alkyl carbocation intermediates, which routinely suffer from
undesired elimination or rearrangement. For selected examples, see: (a)
Yoneda, N.; Kukuhara, T.; Nagata, S.; Suzuki, A. Halogen-exchange
Fluorination of Cyclo and Tertiary Alkyl Halides using Cu2O-HF-
Organic Base Solutions. Chem. Lett. 1985, 14, 1693. (b) Olah, G. A.;
Shih, J. G.; Singh, B. P.; Gupta, B. G. B. Fluorination of 1-
1
2
3
4
5
6
7
8
(17) (a) Nocera, G.; Young, A.; Palumbo F.; Emery, K. J.; Coulthard,
G.; McGuire, T.; Tuttle, T.; Murphy, J. A. Electron Transfer Reactions:
KOtBu (but not NaOtBu) Photoreduces Benzophenone under
Activation by Visible Light. J. Am. Chem. Soc. 2018, 140, 9751. (b) Li,
H.; Zhang, M.-T. Tuning Excited-State Reactivity by Proton-Coupled
Electron Transfer. Angew. Chem. 2016, 128, 13326. The calculated
value for the excited state reduction potential for benzophenone, which
has a ground state reduction potential of –1.69 V vs. Fc+/Fc0 and a
triplet energy of 69 kcal/mol, is 1.75 V vs. SCE in MeCN. This should
9
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•
be sufficient to oxidize super silanol [Ep (SiOH+ /SiOH)] = + 1.54 V
vs. SCE in MeCN, see ref. 7b).
(18) Paredes, M. D.; Alonso, R. On the Radical Brook Rearrangement.
Reactivity of a-Silyl Alcohols, a-Silyl Alcohol Nitrite Esters, and b-
Haloacylsilanes under Radical-Forming Conditions. J. Org. Chem.
2000, 65, 2292.
(19) Supersilyl radical was used in this computational model as this
radical is well-characterized and studied for bromide atom transfer
reactions (see refs. 2 and 3). The exact silyl radical species that
performs the halogen atom abstraction using supersilanol is currently
under investigation. Both supersilane and supersilanol are competent
silane sources in this reaction (Table 1).
Haloadamantanes
and
–diamantane
with
Nitronium
Tetrafluoroborate/Pyridine Polyhydrogen Fluoride or Sodium
Nitrate/Pyridine Polyhydrogen Fluoride. Synthesis, 1983, 713. (c)
Olah, G. A.; Bollinger, J. M. Halonium Ion Formation via Neighboring
Halogen Participation. Trimethyl- and 1,1-Dimethylethylenehalonium
Ions. J. Am. Chem. Soc. 1968, 90, 947.
(7) For a recent example using a radical strategy to fluorinate tertiary
alkyl bromides, see: Chen, H.; Liu, Z.; Lv, Y.; Tan, X.; Shen, H.; Yu,
H.-Z.; Li, C. Selective Radical Fluorination of Tertiary Alkyl Halides
at Room Temperature. Angew. Chem. Int. Ed. 2017, 56, 15411.
(8) (a) Chatgilialoglu, C. Organosilanes in Radical Chemistry; Wiley:
Chichester, U.K., 2004. (b) Chatgilialoglu, C. Organosilanes as
Radical-based Reducing Agents. Acc. Chem. Res. 1992, 25, 188. (c)
Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese, B.;
Kopping, B. Tris(trimethylsilyl)silane as a Radical-based Reducing
Agent in Synthesis. J. Org. Chem. 1991, 56, 678.
(20) Under standard conditions, 3-bromocyclohexene failed to give the
desired allylic fluoride.
(21) (a) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. A
Mild Synthesis of Vinyl Halides and gem-Dihalides using Triphenyl
Phosphite-Halogen-Based Reagents. J. Org. Chem. 2007, 72, 2216. (b)
Takeda, T.; Sasaki, R.; Yamauchi, S.; Fujiwara, T. Transformation of
Ketones and Aldehydes to gem-Dihalides via Hydrazones Using
Copper(II) Halides. Tetrahedron 1997, 53, 557.
(9) (a) Zhang, P.; Le, C. C.; MacMillan, D. W. C. Silyl Radical
Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique
Pathway for Cross-Electrophile Coupling. J. Am. Chem. Soc. 2016,
138, 8084. (b) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan,
D.W.C. A Radical Approach to the Copper Oxidative Addition
Problem: Trifluoromethylation of Bromoarenes. Science 2018, 360,
1010. (c) Smith, R. T.; Zhang, X.; Rincón, J. A.; Agejas, J.; Mateos,
C.; Barberis, M.; García-Cerrada, S.; de Frutos, O.; MacMillan, D. W.
C. Metallaphotoredox-Catalyzed Cross-Electrophile Csp3–Csp3
Coupling of Aliphatic Bromides. J. Am. Chem. Soc. 2018, 140, 17433.
(d) Kornfilt, D. J. P.; MacMillan, D. W. C. Copper-Catalyzed
Trifluoromethylation of Alkyl Bromides. J. Am. Chem. Soc. 2019, 141,
6853.
(10) Yang, J.-D.; Wang, Y.; Xue, X.-S.; Cheng, J.-P. A Systematic
Evaluation of the N–F Bond Strength of Electrophilic N–F Reagents:
Hints for Atomic Fluorine Donating Ability. J. Org. Chem. 2017, 82,
4129.
(11) Gordon, A. J.; Ford, R. A. The Chemist’s Companion: A
Handbook of Practical Data, Techniques, and References; Wiley: New
York, 1972.
(12) Jiang, X.-K.; Ding, W. F.-X.; Zhang, Y.-H. The Nucleophilic Silyl
Radical: Dual-parameter Correlation Analysis of the Relative Rates of
Bromine-atom Abstraction Reactions as Measured by a Rigorous
Methodology. Tetrahedron, 1997, 53, 8479.
(13) Krech, R. H.; McFadden, D. L. An Empirical Correlation in
Activation Energy with Molecular Polarizability for Atom Abstraction
Reactions. J. Am. Chem. Soc. 1977, 99, 8402.
(14) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu,
T.; Kennepohl, P. Paquin, J.-F.; Sammis, G. M. Fluorine Transfer to
Alkyl Radicals. J. Am. Chem. Soc. 2012, 134, 4026.
(15) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C.
Decarboxylative Fluorination of Aliphatic Carboxylic Acids via
Photoredox Catalysis. J. Am. Chem. Soc. 2015, 137, 5654.
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Graphical TOC
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unexpected kinetic selectivity for contra-thermodynamic pathway
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