Journal of the American Chemical Society
Article
Primary amine nucleophiles possessing a variety of func-
tional groups (41−45) were amenable to the reaction
conditions in fair to good yields. Enantiomerically pure
phenylethylamine (46) did not racemize under the reaction
conditions nor did amino esters (47 and 48), thus preserving
the configuration of the starting nucleophile. The free base of
rimantadine, an antiviral drug, also gave the desired product 49
in moderate yield. Alkyl carboxylic acid 50 and gabapentin
phthalimide 51 were also compatible with the reaction
conditions, demonstrating the method is not restricted to
benzoic acid derivatives. Although detailed mechanistic work
has not been undertaken, we envision our defluorination
reaction proceeding in an analogous manner to our previously
reported CRA-SNAr transformations.20,21
Product Inhibition. It is worth noting the products of
these reactions can also be oxidized by the excited photo-
catlyst. Product inhibition is likely responsible for the poor
yields obtained in some cases. A case study was performed
using fluoroarene 20 and the corresponding SNAr products.
Cyclic voltammetry demonstrated that the products 20A−C
are preferentially oxidized over the starting fluoroarene 20 on a
thermodynamic basis (Figure 2). As a result, competitive
oxidation of the substitution products by the excited state
photoredox catalyst occurs more at higher levels of conversion,
rendering the desired substitution process less efficient as the
reaction proceeds. Experimentally, we tested this hypothesis
via competition experiments performed with equimolar
amounts of starting material and product. In this case, a 50%
yield represents no further formation of product (complete
product inhibition), whereas a yield of 100% demonstrates full
conversion of the starting fluoroarene to the desired
substitution product (no product inhibition). The reactions
using aniline products 20A or 20B demonstrate little to no
product formation under otherwise normal reaction con-
ditions, highlighting the severity of product inhibition present
when synthesizing anilines using this methodology. Interest-
ingly, product inhibition was less significant using benzoic acid
as a nucleophile (20C). This is somewhat surprising given that
these reactions tend to have lower yields than those of the
amination products. While oxidation of these oxygenation
products occurs, it is possible that the lower yields observed
are the result of reduced nucleophilicity. The negative charge
of a carboxylate is delocalized across two oxygen atoms,
meaning it is less nucleophilic than amines. This is likely a
significant factor in the lower yields obtained using carboxylic
acids as nucleophiles. Taken together, competitive oxidation of
the desired substitution products (especially anilines) and the
poor nucleophilicity of carboxylate anions account for the poor
yields obtained in some cases.
Rationale for Regioselectivity. A major concern in this
methodology was selective functionalization of C−F bonds in
alkoxy-substituted fluoroarenes. In all cases, save for one
example, the desired C−F substitution product was isolated as
a single regioisomer without additives. . This triggered a brief
of the alkoxy-substituted fluoroarenes and their corresponding
cation radicals using natural population analysis (NPA). In all
cases, the greatest degree of positive charge was found to reside on
the fluorine-bearing carbon of both the ground state and the cation
radicals of the fluoroarenes studied. The decreased electron
density at the C−F carbon in arene cation radicals allows for
highly selective nucleophilic substitution to occur with a range
of substrates (Figure 3). Previous computational models
Figure 2. Competition experiments using equimolar amounts of
fluoroarene and products. All potentials are reported vs SCE in
MeCN.
Figure 3. Computational model for selective C−F regiocontrol.
selectivity (29C) with disubstitution occurring as a minor
product (not observed for amine nucleophiles).
Substrates with applications toward liquid crystals (30) or
biology (31) gave good yields of the desired amination
products while demonstrating limited oxygenation. Hetero-
cyclic substrates were also tolerated, including protected
indolinone, indazole, quinazolinone, and benzothiophene
motifs in modest yields (32−35). Benzisoxazole 36 is uniquely
interesting as this aromatic core is found in a family of
antipsychotics, including risperidone and iloperidone.38 Some
benzenoids did not demonstrate reactivity across all
nucleophile classes. For example, benzaldehyde derivative 37
was only reactive toward ammonia. Similarly, only oxygenation
was observed with a protected benzylic alcohol (38). The
inability of amine nucleophiles to tolerate a benzylic
functionality in this case is likely the result of an increased
acidity of benzylic protons upon arene oxidation.39 The
presence of these sites leads to deprotonation instead of
nucleophilic addition in the presence of amines. Finally, late-
stage functionalization of pharmaceuticals was demonstrated
with flurbiprofen methyl ester 39 (oxygenation) as well as
diflunisal acetonide 40 (amination and oxygenation), albeit in
low yields.
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX