Journal of the American Chemical Society
Communication
reduction51,52 erode the functional group tolerance in
electrochemical strategies.
Table 1. Variation of Hydrocarboxylation Reaction
Conditions
a
In contrast to CO2-reduction strategies, formate enters the
reaction in the appropriate oxidation state for alkene
hydrocarboxylation without the need for a sacrificial electron
donor. We suspected that redox-neutral hydrocarboxylation by
the delivery of formate across alkenes would not only improve
the atom economy relative to net-reductive strategies but
would also provide an appealing chemoselectivity profile by
circumventing the need for strong reductants.53 Our group54
and others55,56 recently introduced a collection of photo-
redox57−65 strategies to generate CO2•− in situ via the cleavage
of the formate C(sp2)−H bond. In these prior studies, the
66
•−
nascent CO2 was primarily employed as a SET reductant.
We hypothesized that our catalytic system could be repurposed
as a general and functional-group-tolerant strategy to access
•−
CO2 for C−C bond-forming reactions. Overall, this would
introduce a mechanistically distinct approach to promote
hydrocarboxylation reactions via either a mild oxidation event
−
(Eox(CHO2 ) = +1.25 V vs SCE) or hydrogen atom
abstraction (BDE = 86 kcal/mol)20 instead of the difficult
SET reduction of CO2. Herein, we report a redox-neutral
approach to hydrocarboxylation via the addition of formate
across alkene substrates (Figure 1, bottom).
We selected styrene as a model substrate, as diverse analogs
are commercially available and 3-aryl propionic acids are well-
represented in bioactive molecules.14,15 Of note, the
anticipated linear selectivity will complement the CO2-based
transition-metal-catalyzed processes that furnish branched
a
Reactions were conducted under air on a 1 mmol scale with 1.1
equiv of KCHO2. The yield of 3 was determined by 1H NMR analysis.
run for 24 h with 1 mol % Ir-1.
b
products from alkenylarenes,35,37,38,40,42,44,45 with one recent
40
̈
exception from Konig and co-workers. Accordingly, we
•−
evaluated our previously developed conditions for CO2
generation from formate54 in the presence of styrene. These
conditions fully converted styrene in 20 h and provided a 25%
yield of the linear carboxylate 3 alongside a 37% yield of
ethylbenzene. Reaction optimization, including adjusting the
irradiation wavelengths away from those that excite reduced
4DPAIPN,67 resulted in improved conditions that furnished
nearly quantitative yield of 3 without observable ethylbenzene.
Furthermore, these reaction conditions provided complete
conversion in 2 h with low loadings of the photoredox and
thiol catalysts (Table 1, entry 1). Control experiments
confirmed that no conversion of styrene was observed in the
absence of the photoredox catalyst (Table 1, entry 2).68
The structure of the thiol hydrogen atom transfer (HAT)
catalyst was identified as a key parameter. Omission of the thiol
from the reaction resulted in a diminished rate and,
consequently, a reduced chemical yield (Table 1, entry 3).
The alkyl thiol we employed in related formate-based
hydroarylation processes,54 CySH, was similarly ineffective
(Table 1, entry 4). While several thiolphenols and electron-
deficient thiols performed comparably to T1 (see Table S1),
when T1 was substituted for an electron-rich analog, T2, the
yield was substantially diminished and reverted to nearly that
of the reaction performed without thiol (Table 1, entry 5).
Overall, these data cannot be rationalized using thermody-
namic parameters such as BDEs69,70 but are fully consistent
with substantial polar effects on the HAT transition
structures.71
accelerates the rate (Table 1, entry 7; see Table S6 for details
regarding rate changes). We attribute this effect to the
differential solubility of the formate salts in DMSO. Potassium
formate was selected for further study, as it furnishes nearly
quantitative product in only 2 h and is inexpensive.72
The photoredox catalyst identified (4DPAIPN) was
particularly effective; however, a variety of other photocatalysts
promote the reaction. For example, iridium-based photo-
catalysts could be used in place of 4DPAIPN, albeit with
extended reaction times (Table 1, entry 8).73 We found that
the generation of these carboxylic acid products is robust; no
precautions to exclude air or moisture are necessary, and the
process tolerates the deliberate addition of water (Table 1,
entry 9).
We next examined the scope of this new alkene hydro-
carboxylation reaction. These simple conditions promote the
delivery of formate across a wide range of alkenylarene
substrates with exquisite functional group tolerance (Table 2).
Diverse electron-donating and electron-withdrawing substitu-
ents could be introduced on the arene (3−8) without a
substantial impact on reaction efficiency. Since the reaction
conditions are only mildly basic, protic substrates were well-
tolerated. Alkenylarenes bearing carbamates (5), carboxylic
acids (7 and 14),74 and unprotected alcohols (9 and 13) each
underwent the hydrocarboxylation in high yields. Furthermore,
a substrate containing a synthetically versatile but Lewis acidic
boronic acid pinacol ester (8) was efficiently converted into
the linear carboxylic acid. This redox-neutral process also
tolerates reductively sensitive functional groups, such as aryl
chlorides (6). This substrate was of particular interest because
we have previously engaged aryl chlorides in reductive radical
The formate counterion also had an impact on the reaction.
The substitution of potassium for sodium slows the reaction
and results in a lower yield (Table 1, entry 6). Replacing
potassium with cesium delivers a similar yield and modestly
13023
J. Am. Chem. Soc. 2021, 143, 13022−13028