Copper-Catalyzed C-H Fluorination/Functionalization Sequence Enabling Benzylic C-H Cross Coupling with Diverse Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.0c02238

Site-selective transformation of benzylic C-H bonds into diverse functional groups is achieved via Cu-catalyzed C-H fluorination with N-fluorobenzenesulfonimide (NFSI), followed by substitution of the resulting fluoride with various nucleophiles. The benzyl fluorides generated in these reactions are reactive electrophiles in the presence of hydrogen-bond donors or Lewis acids, allowing them to be used without isolation in C-O, C-N, and C-C coupling reactions.

Full text of DOI:10.1021/acs.orglett.0c02238

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed C−H Fluorination/Functionalization Sequence
Enabling Benzylic C−H Cross Coupling with Diverse Nucleophiles
Aristidis Vasilopoulos, Dung L. Golden, Joshua A. Buss, and Shannon S. Stahl*
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ABSTRACT: Site-selective transformation of benzylic C−H
bonds into diverse functional groups is achieved via Cu-catalyzed
C−H fluorination with N-fluorobenzenesulfonimide (NFSI),
followed by substitution of the resulting fluoride with various
nucleophiles. The benzyl fluorides generated in these reactions are
reactive electrophiles in the presence of hydrogen-bond donors or
Lewis acids, allowing them to be used without isolation in C−O,
C−N, and C−C coupling reactions.
Scheme 1. C−H Cross-Coupling via a Benzyl Fluoride
Medicinal chemistry and drug discovery efforts greatly benefit
from synthetic coupling reactions that facilitate access to
analogues of pharmaceutical building blocks and core
structures. Functional groups that participate in efficient
coupling, such as carboxylic acids, aryl halides, and boronic
acids, provide the foundation for these methods.1 Expansion of
latent functionalities that participate in coupling could greatly
increase the scope of synthetic diversity.2 Benzylic C−H bonds
are an appealing target in this context as they are prevalent in
druglike molecules and are susceptible to site-selective
activation owing to their enhanced reactivity (e.g., reduced
bond strength, higher acidity). Recent studies demonstrate that
benzylic C−H substrates may be used as the limiting reagent in
cross-coupling reactions with a number of different reaction
partners, including alcohols,3 amides,4 and arylboronic acids.5
Cu catalysts in combination with N-fluorobenzenesulfonimide
(NFSI) are particularly effective in these reactions as they
exhibit unique selectivity for benzylic C−H bonds and
promote a radical relay mechanism that enables coupling
with diverse reaction partners (Scheme 1).3a,4b,5a,6 We recently
discovered that a Cu/NFSI-based catalyst system switches
selectivity, from C−N to C−F bond formation, when the
reaction is conducted with MeB(OH)2 as a redox buffer and
Li2CO3 as a Brønsted base.7 These observations provide the
foundation for the present study in which we demonstrate a
C−H fluorination/substitution sequence that enables benzylic
C−H cross-coupling with diverse oxygen, nitrogen, and carbon
nucleophiles (Scheme 1). This strategy, which takes advantage
of the intrinsic lability of benzyl monofluorides,8,9 contrasts the
many C−H fluorination efforts motivated by the inertness of
the C−F bond.10,11 This approach allows for successful
benzylic C−H cross coupling with reaction partners that are
oxidatively sensitive or otherwise incompatible with direct Cu/
NFSI-catalyzed methods, thereby greatly expanding the
synthetic scope and versatility of benzylic C−H cross coupling.
The present study began by testing the previously optimized
fluorination conditions7 with a variety of benzylic C−H
substrates (Scheme 2). p-Bromoethylbenzene proceeds
effectively in 81% yield to the corresponding benzyl fluoride
product 1 (Scheme 2). Use of o-bromoethylbenzene resulted
in low conversion of the starting material (<20%), presumably
reflecting the deleterious steric or σ-electron-withdrawing
effect of the o-halogen on hydrogen atom transfer. Empirical
Received: July 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02238
© XXXX American Chemical Society
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and even when stored in glass vessels. These observations belie
the frequent incorporation of fluorine in organic molecules to
inhibit reactivity at specific sites, for example, to slow drug
metabolism.10 Separately, benzylic monofluorides have been
shown to undergo nucleophilic substitution in the presence of
acids or hydrogen-bond donors.8,9 These insights suggest that
monofluorination of benzylic C−H bonds is not a compelling
end goal for many substrates. On the other hand, they suggest
that benzyl fluorides could serve as strategic intermediates in a
sequential approach to benzylic C−H functionalization.
Efforts to explore sequential C−H fluorination/functional-
ization were initiated by testing hexafluoroisopropanol (HFIP,
10 equiv) as a hydrogen bond donor to activate the benzyl
fluoride (Scheme 3).9f Initial results demonstrated conversion
of benzyl fluorides to benzyl alcohols by including water as a
nucleophile in the reaction mixture (25−27). Formation of 25
shows that hydrogen-bond activation supports displacement of
the fluoride, even in the presence of a primary alkyl bromide.
This fluorination/water-substitution sequence to access
benzylic alcohols is noteworthy because C−H oxygenation
strategies will typically proceed directly to ketones, reflecting
the higher reactivity of alcohols relative to C−H bonds.13
Analogous efforts were effective for the formation of benzylic
ethers and esters (28−36). For less nucleophilic alcohols, like
tert-butyl alcohol, more forcing conditions were needed to
form the product, using BF3·OEt2 as a Lewis acid catalyst (28
and 33).9i This approach also enabled reactivity with alcohols
bearing Boc-pyrrolidine or pyridine substituents (31 and 32).
These results expand the scope of accessible products relative
to the recently reported method for direct Cu/NFSI-catalyzed
benzylic etherification,3a which shows limited compatibility
with basic heterocycles, such as pyridines, and Boc-protected
pyrrolidines. Carboxylic acids were also effective coupling
partners (34−36). These substrates have innate acidity, but
the reactions were more effective with HFIP or BF3 additives.
The presence of allylic and benzylic C−H bonds in the
carboxylic acids used to prepare 34 and 36 would likely
complicate direct C−H carboxylation methods with these
partners.
Scheme 2. Cu/NFSI Fluorination of Benzylic C−H Bonds
a
b
1H or 19F NMR yields, CH2Br2 or PhCF3 as internal standard. 35
c
°C, 0.5 equiv of MeB(OH)2. 55 °C, 1 mol % of Cu/1.2 mol % of
BPhen, 4 equiv of NFSI, 1 equiv of B2pin2 instead of MeB(OH)2. 75
d
°C, 1 mol % of Cu/1.2 mol % of BPhen, 4 equiv of NFSI, 1 equiv of
e
B2pin2 instead of MeB(OH)2. Acetone solvent.
We then targeted C−N coupling reactions. Direct C−H
amidation reactions typically feature primary sulfonamides or
other stabilized ammonia surrogates capable of generating
nitrenoid intermediates.14 Few precedents exist for oxidative
coupling of C−H bonds with carbamates or secondary
sulfonamides.4b,15 tert-Butyl carbamate itself proved to be an
effective coupling partner when using BF3·Et2O to activate the
benzyl fluoride (37). Then a range of secondary sulfonamides
were shown to undergo effective displacement of the benzyl
fluoride, with BF3·Et2O as an activator (38−43). The good
reactivity with less nucleophilic, but more readily deprotected,
nosylamides is noteworthy. Competitive Friedel−Crafts
reactivity with chlorobenzene was observed in some of these
reactions, but this complication was resolved by using
dichloromethane as the solvent for the fluorination step
(40−43).
The observation of Friedel−Crafts reactivity highlights
opportunities for coupling with electron-rich arenes and
other carbon nucleophiles that would not be compatible with
a direct Cu/NFSI-catalyzed C−H coupling reaction. Such
reactivity was demonstrated with phenols (44−46), N-sulfonyl
indole (47, 48), and a silyl enol ether and allyl silane (49, 50).
Each of the reactions highlighted above proceeds via a
straightforward two-step protocol, without isolation of the
modification of the conditions, including use of 4 equiv of
NFSI, replacement of MeB(OH)2 with B2pin2 as the reductant,
and operating at 55 °C, led to a 50% yield of the desired
product 2. The modified conditions, either at 55 or 75 °C, also
proved effective with other electron-deficient substrates (2, 4,
5, 6, 9, 13, 17, and 19), while the original conditions were
favored for more reactive substrates (3, 7, 8, 10, 11, 12, and
14). The latter group also includes celestolide, which
underwent fluorination in 86% yield (18), and substrates
with tertiary C−H bonds, leading to 23 and 24 in 92% and
84% yields. Overoxidation to ketone- or styrene-derived side
products was observed with more activated C−H substrates,
necessitating the identification of milder conditions (35 °C, 0.5
equiv of MeB(OH)2). These conditions allowed several benzyl
fluorides to be obtained in good yield (15, 16, and 20),
including a bromochroman derivative. Methylarenes appear to
favor C−H sulfonimidation rather than fluorination, as
observed by the formation of 21 and 22. A collection of
other less successful substrates is provided in Table S9 of the
Supporting Information, but overall, these results show that the
catalytic conditions may be tuned to access good fluorination
reactivity for a broad range of benzylic C−H substrates.12
Complications were encountered during product isolation.
Many of the products decomposed in the presence of silica gel,
B
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Scheme 3. Benzylic C−H Cross-Coupling to C−O, C−N, and C−C Bonds via a Benzyl Fluoride
a
Reaction uses 10 equiv of HFIP as a H-bond donor. Isolated yields calculated with respect to the 1H NMR yield of the benzyl fluoride (or the C−
b
c
d
H substrate, in parentheses). 10 mol % BF3·Et2O used instead of HFIP. 50 mol % BF3·Et2O used instead of HFIP. Both HFIP and BF3·Et2O
e
f
g
were used. 2.5 equiv of MsOH added to the nucleophile. Used dichloromethane as the fluorination reaction solvent. 1.5 equiv of BF3·Et2O used
instead of HFIP. Isolated as the amine.
benzyl fluoride intermediate. Following the fluorination step,
sodium dithionite is added to quench any unreacted NFSI.
The slurry is then diluted with dichloromethane and filtered.
Subsequent addition of the nucleophile and HFIP/BF3
promoter initiates the displacement reaction. As conveyed in
several instances above, this two-step C−H cross-coupling
sequence greatly expands the scope of useful reaction partners.
Many of the electron-rich substrates and nucleophiles bearing
oxidatively sensitive substituents would decompose or undergo
deleterious side reactions with NFSI in a direct oxidative
coupling reaction.11c,16
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02238.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
In summary, the results described above introduce a new
strategy to achieve selective benzylic C−H cross-coupling with
diverse reaction partners. The use of Cu/NFSI conditions that
may be tuned to accommodate different substrate electronic
properties allowed the formation of benzyl fluorides that may
be used without isolation as coupling partners to access
products with new C(sp3)−O, −N, and −C bonds. This
method joins a number of emerging strategies for C(sp3)−H
cross-coupling that involve formation of strategic intermedi-
ates, such as xanthate esters, isocyanates, lactones, and
alkylboronates,17 that allow rapid access to diversified
products.
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
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
C
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(9) For leading primary references, see: (a) Bernstein, J.; Roth, J. S.;
Miller, W. T., Jr. The Preparation and Properties of Some Substituted
Benzyl Fluorides. J. Am. Chem. Soc. 1948, 70, 2310−2314. (b) Swain,
C. G.; Spalding, R. E. T., III. Mechanism of Acid Catalysis of the
Hydrolysis of Benzyl Fluoride. J. Am. Chem. Soc. 1960, 82, 6104−
6107. (c) Toteva, M. M.; Richard, J. P. Hydrogen Bonding and
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Brown, J. M.; Gouverneur, V. Palladium-Catalyzed Substitution and
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Joshua A. Buss − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3347-8583
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02238
Notes
The authors declare no competing financial interest.
́
2757. (e) Champagne, P. A.; Pomarole, J.; Therien, M.-E.;
ACKNOWLEDGMENTS
Benhassine, Y.; Beaulieu, S.; Legault, C. Y.; Paquin, J.-F. Enabling
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O.; Perrin, D. M. Synthesis and Activation of Bench-Stable 3a-
Fluoropyrroloindolines as Latent Electrophiles for the Synthesis of C-
2-Thiol-Substituted Tryptophans and C-3a-Substituted Pyrroloindo-
■
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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