Copper-Catalyzed Functionalization of Benzylic C-H Bonds with N-Fluorobenzenesulfonimide: Switch from C-N to C-F Bond Formation Promoted by a Redox Buffer and Br?nsted Base

Article abstract of DOI:10.1021/acs.orglett.0c02239

A copper catalyst in combination with N-fluorobenzenesulfonimide (NFSI) has been reported to functionalize benzylic C-H bonds to the corresponding benzylic sulfonimides via C-N coupling. Here, we reported a closely related Cu-catalyzed method with NFSI that instead leads to C-F coupling. This switch in selectivity arises from changes to the reaction conditions (Cu/ligand ratio, temperature, addition of base) and further benefits from inclusion of MeB(OH)2 in the reaction. MeB(OH)2 is shown to serve as a "redox buffer"in the reaction, responsible for rescuing inactive Cu(II) for continued promotion of fluorination reactivity.

Full text of DOI:10.1021/acs.orglett.0c02239

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Letter
Copper-Catalyzed Functionalization of Benzylic C−H Bonds with
N‑Fluorobenzenesulfonimide: Switch from C−N to C−F Bond
Formation Promoted by a Redox Buffer and Brønsted Base
Joshua A. Buss, Aristidis Vasilopoulos, Dung L. Golden, and Shannon S. Stahl*
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ABSTRACT: A copper catalyst in combination with N-fluoro-
benzenesulfonimide (NFSI) has been reported to functionalize
benzylic C−H bonds to the corresponding benzylic sulfonimides
via C−N coupling. Here, we reported a closely related Cu-
catalyzed method with NFSI that instead leads to C−F coupling.
This switch in selectivity arises from changes to the reaction
conditions (Cu/ligand ratio, temperature, addition of base) and
further benefits from inclusion of MeB(OH)2 in the reaction.
MeB(OH)2 is shown to serve as a “redox buffer” in the reaction,
responsible for rescuing inactive Cu(II) for continued promotion of fluorination reactivity.
Scheme 1. C−N to C−F Bond Formation when Using NFSI
in C(sp2) and C(sp3) C−H Functionalization
N-Fluorobenzenesulfonimide (NFSI) is a widely used reagent
in organic synthesis. It is commonly used as a terminal oxidant
in transition-metal-catalyzed oxidations1 and as a group-
transfer reagent for sulfonylation, fluorination, and sulfonimi-
dation of organic molecules.2,3 The majority of these methods
take advantage of the reactive N−F bond. For example, NFSI
is commonly featured in electrophilic and radical fluorination
of carbanions, carbon-centered radicals, and acidic C−H
bonds,4 while complementary methods and mechanisms have
been identified for C−N bond formation with the sulfonimide
group.5 This bifurcation in reactivity between C−F and C−N
bond formation is well documented in C(sp2)−H functional-
ization of (hetero)arenes with NFSI (Scheme 1A).3 We and
others have recently been exploring Cu-catalyzed methods for
site-selective functionalization of benzylic C(sp3)−H bonds.6,7
These reactions employ NFSI in a radical-relay mechanism
that enables oxidative C−H coupling with diverse nucleophilic
partners, including cyanide, azide, trifluoromethyl, alcohols,
and arylboronic acids (Scheme 1B). The earliest example of
this reactivity featured direct transfer of the sulfonimide group
from NFSI to the benzylic position (Scheme 1C, top).6 Here,
we show that variation of the Cu/NFSI C−H sulfonimidation
reaction conditions leads to C−F rather than C−N bond
formation, complementing other benzylic C−H fluorination
methods in the literature.8 Mechanistic studies provide insights
into the origin of this switch in selectivity, highlighting the role
of MeB(OH)2 as a “redox buffer” and Li2CO3 as a Brønsted
base in the reaction. Additional studies reveal the intrinsic
lability of secondary benzylic fluorides, making them
susceptible to nucleophilic substitution. The latter reactivity
is noted here but provides the basis for a complementary effort,
leading to a versatile new class of benzylic C−H cross-coupling
reactions.9
Received: July 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02239
© XXXX American Chemical Society
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A

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Table 1. Fluorination Reaction Optimizations
a
entry
[Cu] (mol %)
BPhen (mol %)
MeB(OH)2 (equiv)
Li2CO3 (equiv)
conv (%)
C−N (%)
C−F (CF2) (%)
b c
,
1
2
3
4
5
6
7
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (2)
see Scheme 1A for conditions
nd
24
100
100
100
86
76
19
42
44
25
4
nd
4
c
c
c
5
5
5
5
1
2
2
2
2
3
3
3
3
21 (4)
40 (6)
74 (4)
81 (11)
CuOAc (2)
2.4
2
100
a
b
c
0.3 mmol scale. 1H NMR yields int std = CH2Br2. Reported results with ethylbenzene (ref 6). 1,2-Dichloroethane (DCE) used as the solvent.
The present study was initiated by investigating the original
The impact of MeB(OH)2 on the catalytic reaction is clearly
evident in Figure 1B. Virtually no reaction is observed in the
absence of MeB(OH)2. In contrast, full substrate conversion
occurs in the presence of 2 equiv of MeB(OH)2, leading to an
84% yield of the benzyl fluoride. This behavior is rationalized
by the ability of MeB(OH)2 to serve as a “redox buffer” for the
Cu catalyst, slowly reducing CuII during the reaction. A
mechanistic framework for these observations is illustrated in
Figure 1C. CuI is oxidized rapidly to CuII by NFSI at the
beginning of the reaction, but slow reduction of CuII by
MeB(OH)2 (dashed arrow, Figure 1C) generates small
amounts of CuI that can react with additional NFSI.
Cu/NFSI-catalyzed sulfonimidation reaction (Scheme 1C).6
This reaction takes place at much higher temperatures than
more recent Cu/NFSI reactions, which often proceed near
room temperature.7 Attempting the sulfonimidation of p-
bromoethylbenzene at lower temperature led to low
conversion, with a preference for C−N over C−F bond
formation (Table 1, entry 2). The formation of a C−F bond
could arise from reaction of an intermediate benzylic radical
with a CuII−F species10 or via a Cu-promoted radical-chain
process involving NFSI.8g,11 Addition of MeB(OH)2 as an in
situ reductant for the Cu catalyst7e (see further discussion
below) led to complete substrate conversion, but only
moderate yield of the C−N product was observed, with no
C−F product (Table 1, entry 3). Further variation of the
conditions, however, including addition of Li2CO3 as a base,
using PhCl as the solvent, and lowering the catalyst loading,
led to C−H fluorination in good yield (81%, Table 1, entry 7),
with no C−N product formation (see additional screening data
in the Supporting Information). Difluorination of the benzylic
position is the primary side reaction.
•
Generation of NSI at this stage can lead to hydrogen atom
transfer (HAT) from the benzylic C−H with only limited
•
competitive quenching of NSI by CuI, due to the low CuI
concentration.
The synthetic scope of this reactivity is the focus of a
separate study;9 however, testing of representative substrates
showed that isolation of benzyl monofluorides can be rather
challenging, with poor mass balance and the appearance of new
byproducts (see the Supporting Information, section V).
Similar challenges are evident from previous C−H fluorination
methods,8 and other studies show that benzyl monofluorides
undergo facile displacement in the presence of Brønsted and
Lewis acids or hydrogen-bond donors.14 The latter insights
prompted us to assess the role of Li2CO3 in the reaction, which
was also used in a previous benzylic C−H fluorination
method.8g A time course for the optimized reaction conditions
in Figure 1B (right) may be compared to the time course
obtained without added Li2CO3 (Scheme 2A). The rate of
substrate conversion is virtually identical in the presence and
absence of Li2CO3; however, very little C−F product is
observed after the first few hours of the reaction without
Li2CO3, and the major products arise from C−O and C−N
bond formation. NHSI is a strong acid and will build up as the
fluorination reaction proceeds, and it could promote acidolysis
of the benzyl fluoride.15 In a control experiment, 1 equiv of
NHSI was added to a solution of benzyl fluoride obtained from
the catalytic reaction, following filtration through a silica plug
to remove the Li2CO3. This reaction results in rapid formation
of 1-phenylethanol (Scheme 2B). The hydroxy group
presumably originates from adventitious water from the solvent
or reagents present in the original reaction mixture. The net
C−H fluorination/hydrolysis sequence resembles the recently
reported C−H mesylation/hydrolysis strategy to achieve C−H
hydroxylation, reported by Ritter and co-workers.16
Several fundamental studies were undertaken to gain insight
into the observed reactivity and the role of MeB(OH)2 and
other reaction components. Copper(I) is proposed to react
with NFSI, forming a CuII−F species and an imidyl radical,
•NSI (Scheme 1B). The imidyl radical can promote hydrogen
atom transfer from the benzylic C−H bond, but it can react
even more rapidly with another CuI center,7e,12 generating a
second equivalent of CuII and halting catalysis. To probe Cu/
NFSI reactivity, NFSI was titrated into a solution of
BPhenCuI(OAc) in PhCl (Bphen = bathophenanthroline).
Nearly isosbestic behavior was observed by UV−vis spectros-
copy, corresponding to oxidation of CuI to CuII species by
NFSI (Figure 1A, step 1). Complete consumption of CuI was
observed upon addition of 0.5 equiv of oxidant. This oxidation
is rapid at room temperature, occurring on the time scale of
mixing. Addition of NFSI beyond 0.5 equiv has no effect on
the UV−vis spectrum, suggesting that CuII does not react
further with NFSI.
The CuII species generated by NFSI is reduced by
MeB(OH)2. Addition of 5 equiv of MeB(OH)2 to a solution
of CuII generated from a combination of BPhenCuI(OAc) and
0.5 equiv of NFSI in PhCl slowly regenerates CuI over
approximately 1 h (Figure 1A, step 2). This process generates
Me−N(SO2Ph)2 as a byproduct of the reaction, resembling the
previously reported Chan−Lam amidation of alkylboronic
acids13 (see Figure S2).
B
https://dx.doi.org/10.1021/acs.orglett.0c02239
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Scheme 2. Li2CO3 Effect on Benzyl Fluoride Lability
reaction. Li2CO3 serves as a Brønsted base that prevents acid-
promoted displacement of the fluoride during the reaction.
While the observed substitutional lability of the products
undermines the accessibility and practical utility of isolated
benzyl monofluorides, this property introduces the possibility
of using benzyl fluorides as strategic intermediates in a C−H
fluorination/substitution sequence. Development and elabo-
ration of the latter C−H cross-coupling strategy is the focus of
a parallel report.9
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02239.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 1. Fundamental insights into Cu/NFSI-catalyzed fluorination
reactions. (A) Spectroscopic analysis of stoichiometric oxidation of
CuI by NFSI and reduction of CuII by MeB(OH)2. (B) Reaction time
course data demonstrating the effect of MeB(OH)2 redox buffering in
the catalytic fluorination reaction. (C) Mechanism depicting the
redox buffering role of MeB(OH)2 in benzylic fluorination.
Conditions: (A) Step 1: 0.33 mM BPhenCuIOAc + 0.1 equiv of
NFSI (×8) in PhCl. Step 2: [CuII] (from 0.33 mM BPhenCuI(OAc)
+ 0.5 equiv of NFSI) + 5 equiv of MeB(OH)2, 15 equiv of Li2CO3 in
PhCl. (B) See Table 1, entry 7.
Shannon S. Stahl − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-9000-7665; Email: stahl@
chem.wisc.edu
Authors
Joshua A. Buss − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3347-8583
Aristidis Vasilopoulos − Department of Chemistry, University
of WisconsinMadison, Madison, Wisconsin 53706, United
States
Dung L. Golden − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States
The results presented herein reveal an unusual switch in
selectivity, from C−N to C−F bond formation, in Cu/NFSI-
promoted oxidative functionalization of benzylic C−H bonds.
Mechanistic studies show how two new reaction additives
contribute to formation of the fluorination product. MeB-
(OH)2 serves as a redox buffer7e that promotes steady-state
reduction of CuII to the active CuI species during the catalytic
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02239
C
https://dx.doi.org/10.1021/acs.orglett.0c02239
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Scott McCann and Si-Jie Chen (UW
Madison) for valuable discussions leading to the development
of redox buffering in Cu/NFSI systems. This work was
supported by the NIH (R01 GM126832, R35 GM134929),
including a Ruth L. Kirschstein NRSA fellowship (F32
GM129909, to J.A.B.). Spectroscopic instrumentation was
partially supported by the NIH (1S10 OD020022-1) and the
NSF (CHE-1048642).
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