Organic Letters
Letter
indicated by the yield of 1-OR after 1 or 24 h at 80 °C) among
the alcohol adducts examined. Further optimization of the
reaction time (moving from 1 to 24 h) and equivalents of
Me4NF·t-AmylOH (changing from 1.0 to 1.5 equiv) resulted in
a quantitative yield of 1-F.35 Under these conditions, the
reaction was highly reproducible (yields varied by 5% over 12
runs). Furthermore, the yield showed minimal variance with
different batches of DMSO or with changes in the ambient
humidity.36
We next explored the scope of SNAr fluorination with Me4NF·
t-AmylOH for various commercially available halo- and nitro-
(hetero)arene electrophiles. As summarized in Scheme 3, good
to excellent yields were obtained for >50 different quinoline,
pyridine, electron-deficient arene, diazine, and fused hetero-
cyclic substrates.37 Importantly, all of these transformations
were conducted on the benchtop at 80 °C, without drying or
purification of the electrophile substrates or DMSO solvent.
These reactions provided comparable yields on scales ranging
from 40 mg to 1 g (for instance 1-F was obtained in 73% and
92% isolated yield, respectively, on these scales). Some other key
trends and observations from these studies are summarized
below.
mitigate competing SNAr of the alcohol. Me4NF·t-AmylOH was
ultimately identified as the optimal fluoride reagent. It can be
synthesized, stored, and utilized on the benchtop without the
rigorous exclusion of air/moisture. Furthermore, Me4NF·t-
AmylOH proved effective for the SNAr fluorination of a wide
range of aryl and heteroaryl electrophiles under mild and
convenient conditions (80 °C in DMSO, without drying of
solvent or reagents). Overall, we anticipate that this reagent will
find widespread application in the construction of C(sp2)−F
bonds.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures, characterization data, and
FAIR data, including the primary NMR FID files, for
compounds 1, 4, 5−7, 9−16, 28−32, 36−38, 40−58,
Me4NF·EtOH, Me4NF·iPrOH, Me4NF·MeOH, Me4NF·
t-AmylOH, and Me4NF·t-BuOH (ZIP)
(1) Functional group compatibility. Arene substituents includ-
ing halogen (F, Cl, Br, I), nitrile (21−23,33−35), ether
(9), ester (16, 31, 32), trifluoromethyl (17), nitro (20,
25), tertiary nitrogen (45), and N-Boc protecting groups
(48) are all compatible with Me4NF·t-AmylOH SNAr
reactions. Many of these are valuable handles for
downstream functionalization. In addition, various
heterocycles found in biologically relevant scaffolds are
tolerated (e.g., imidazole, pyrazole, indole, pyrrolidine,
piperazine, benzimidazole).
AUTHOR INFORMATION
■
Corresponding Author
Melanie S. Sanford − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
(2) Inherent reactivity. In a series of isomeric chloroquinoline
electrophiles, the 2-Cl derivative affords the highest yield
(99% of 1-F) followed by the 4-Cl (74% of 2), and then
the 3-Cl (0% of 3). A similar trend was observed in the
nitro benzonitrile series (33 in 81% yield; 34 in 53% yield;
35 in 0% yield) and the bromo benzonitrile series (33 in
52% yield; 34 in 39% yield; 35 in 0% yield). This reactivity
reflects well-documented trends in SNAr reactions.38
(3) Site selectivity of substitution. In substrates containing
multiple possible leaving groups, SNAr fluorination with
Me4NF·t-AmylOH reliably favors substitution at the
more activated site, independent of the nature of the
leaving group. This is exemplified by 4−7 and 24−27, as
well as 18 versus 20.
(4) Effect of leaving group. The impact of the leaving group on
reaction yield was examined in three different classes of
substrates (that form products 27, 33, and 34).39 In all
cases, the yields trend as follows: NO2 > Cl ∼ Br > I. This
is generally consistent with observations in other SNAr
fluorination systems.12
(5) Biologically relevant scaffolds. Substrate 16-Cl, which
forms the core of quinazoline based antibiotics, under-
went SNAr fluorination to afford 16 in 76% isolated yield.
In addition, 5-fluoropicolinate 32 was obtained using this
method. This structural motif appears in numerous
agrochemical candidates.40
Authors
María T. Morales-Colón − Department of Chemistry,
University of Michigan, Ann Arbor, Michigan 48109, United
Yi Yang See − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
So Jeong Lee − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States
Peter J. H. Scott − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States;
Douglas C. Bland − Process Sciences & Technology, Corteva
Agriscience, Indianapolis, Indiana 46268, United States
Complete contact information is available at:
Author Contributions
‡M.T.M.-C. and Y.Y.S. contributed equally. The manuscript was
written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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In summary, this Letter describes the development of Me4NF·
ROH adducts as reactive and practical reagents for SNAr
fluorination. We show that the alcohol substituent (R) can be
tuned to enhance the nucleophilicity of fluoride as well as to
Corteva Agriscience and the National Institutes of Health
(R01EB021155) are acknowledged for supporting this work.
M.T.M.-C. acknowledges support from the National Science
Foundation’s Graduate Research Fellowship Program (GRFP).
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Org. Lett. 2021, 23, 4493−4498