Journal of the American Chemical Society
Communication
material. Extension of the reaction time to 8 h then afforded
the desired product in 75% yield with no trace of reduced
product, α- or dicarboxylation being detected by GC-MS
analysis. This protocol proved to be applicable to an initial
range of α,β,β-substituted alkenes 1w−1ab all affording the all
carbon quaternary center acid in good to excellent yield (Table
4). Extension to the biologically relevant unprotected α,α,β,β-
Table 4. Unprecedented Hydrocarboxylation of β,β-
a c
−
Substituted Alkenes
Figure 1. Cyclic voltammograms representing (a) the blank cycle
highlighting the electrochemical window of DMF containing 0.1 M
LiBF4, (b) the redox behavior of 4-(trifluoromethyl)styrene 1e under
the same conditions, and (c) the redox behavior of 1e after saturation
with CO2.
dominates (K ≈ 6.1 × 104 s−1 vs 5.4 × 106 s−1).17a,b However,
when the phenyl substituted cyclopropane 1u was subjected to
the reaction conditions, ring opening of the cyclopropane was
observed to afford the carboxylic acid 2u (5:1 ratio with
cyclopropane 2u′). Repeating the reaction in the absence of
CO2 also resulted in the reduced compound 6′ from ring
opening of the cyclopropane along with some further reduction
of the resultant alkene (16:1 ratio of ring opened 6′ vs
cyclopropane 6). In this case, the ring opening of the
cyclopropane is irreversible and the rate of ring opening (K
≈ 2 × 108 s−1) is significantly greater than that for substrates
1k and 1o.17b
Attempts to trap the TEMPO adduct, such as that reported
by Lin et al.in their diazidation of alkenes,18 through treatment
with the radical trap TEMPO were unsuccessful and no
carboxylation or reduction of 1a was observed.19 Deuterium
labeling studies of styrene 1a employing D2O resulted in
formation of [D]2a with >95% incorporation of deuterium at
the benzylic position. GC-MS analysis revealed approximately
10% of deuterated ethylbenzene (Table 3, entry 3).
a
b
As in Table 1 (entry 1) but ran for 8 h. Isolated yield; in all cases,
1
only β-carboxylation was observed by H NMR spectroscopy or GC-
MS. Yield of 2ac after 8 h.
c
This leads us to propose the mechanism highlighted [Table
3, entry 1, route (b)] in which the alkene is adsorbed to the
surface of the cathode and electron transfer proceeds to form
the adsorbed radical anion of the alkene; subsequent
carboxylation and further electron transfer results in disasso-
ciation from the electrode and protonation from water to
afford the final monocarboxylated product. However, because
the reactions occur at such a biased potential, it is impossible
to rule out direct reduction of CO2 [Table 3, entry 1, route
(a)].
The propensity for the carboxylation process to enable
selective hydrocarboxylation on substrates that are typically
unreactive in photochemical carboxylation routes prompted
the exploration of β,β-substituted alkenes, particularly as these
have been reported to be a significant challenge for the
corresponding alkoxycarbonylation process. Successful carbox-
ylation would lead to the formation of an all carbon quaternary
center. The formation of all carbon quaternary centers is itself
an area of intense interest.
tetrasubstituted oxindole substrate 1ac initially afforded only
the reduced product 2ac′ after 8 h; however, when we tracked
the reaction by GC-MS (Table S7), we observed good yield of
the carboxylated product 2ac after 90 min. Isolation of 2ac and
resubmission to the reaction conditions for 6 h afforded solely
the decarboxylated product 2ac′ (Table 4).
In summary, a highly regioselective hydrocarboxylation
process that enables the direct formation of carboxylic acids
from aryl-alkenes giving access to β-carboxylation products has
been reported. A wide variety of substrates have been tolerated
under these electrosynthetic conditions, exemplified by the
selective direct monocarboxylation of challenging di-and
trisubstituted alkenes. Thus, this approach is complementary
to the wide range of metal catalyzed approaches and the
recently reported photochemical systems. The current process
goes beyond these state-of-the-art systems, enabling the
selective monocarboxylation of β,β-substituted alkenes to
afford all carbon quaternary centers.
Utilizing the optimized conditions from Table 1, β,β-
dimethylstyrene 1v was selectively monocarboxylated to 2v in
30% yield along with significant amounts of unreacted starting
D
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX