Organic Letters
Letter
was previously obtained in six steps starting from 4-
methylpyridine, wherein only two of those steps contribute
to building skeletal bonds (C−C and C−N). Interestingly, the
key C−N bond-forming step relies on a single-electron
Mukaiyama-type reaction between an olefin and DTAD.
Because carboxylic acid 2 is commercial, a far more direct
path to 1 would involve direct a decarboxylative union with
pyrazole 3 (via a two-electron pathway this time). In its
optimized manifestation, this N-alkylation afforded compound
1 in 52% isolated yield. An extensive optimization was
conducted on this and other substrates (see the SI) to arrive
at this final set of conditions, some of which is summarized in
Scheme 1B. Notably, both the procedure we reported for
etherification and the closest electrochemical precedent
afforded only a low yield in this transformation (entries 1
and 2). A key departure from etherification occurred when
switching the cathode material from graphite (34% yield, entry
4) to nickel. The addition of molecular sieves and collidine was
essential relative to the prior electrochemical alkylation
approach (entries 5 and 6). The use of dichloromethane
(DCM), as with etherification, was also essential for the
reaction (entry 7). Although lowering the amount of carboxylic
acid to one or two equivalents is detrimental to the reaction
(entries 8 and 9), the excess acid can be recovered, if desired,
for valuable substrates. Finally, a screen of bases revealed that
collidine was optimum (e.g., 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) afforded lower yield, entry 10). Variables such as
the electrolyte and the concentration are further discussed in
the SI but had only a negligible effect on the reaction.
Scheme 3. (A) Applications and (B) Mechanistic
Investigation
With an optimized set of conditions in hand, the scope of
this transformation was explored, as illustrated in Scheme 2. In
addition to the ester moiety, a variety of functional groups
were tolerated such as those sensitive to hydrolytic (cyano, 43,
and 46), oxidative (BPin, 9 and 51), reductive (nitro, 48), and
acidic conditions (acetal, Boc-protected amines, 1, 30, 31, 33,
35, 36, and 38). Aryl halides (F, Cl, Br, and I, 10, 13, 17, 27,
49, and 50) and fluoroalkyl substituents (11, 25, 47, and 67)
were also unharmed in this reaction. To our knowledge, this
represents the first use of nonstabilized/nonbridged tertiary
acids in a direct decarboxylative N-alkylation process (4, 6, and
7). With regards to the scope of the heterocycles, aside from
pyrazoles, (benzo)triazoles (40 and 41), tetrazoles (42),
imidazoles (43), 1,2,4-triazoles (53 and 54), indazoles (56
and 57), xanthones (58), oxazolidinones (59 and 64), γ-
lactams (60), succinimides (61), pyridones (62), 2-amino-
pyrimidines (63), and oxindoles (65) could all be employed.
The operationally simple protocol (setup in ca. 5−10 min)
could be conducted on a commercial potentiostat without the
exclusion of air and was amenable to scale up (8, 69% yield on
1 mmol scale) without a significant diminishment in yield. In
cases where the reaction only proceeds to a modest extent (for
example, cyclobutane 22 and 23), the remaining pyrazole
substrate (limiting reagent) can be recovered.
diazirines as radical traps.5 Recent developments (Figure 1)
include the use of intermediary N-hydroxyphthalimide
(NHPI)-based redox-active esters or I(III)-based esters in
concert with Cu-based photochemical systems (with or
without additional photocatalysts) to achieve amine and
heterocycle alkylations with a broad scope.6 Nonactivated
approaches that do not traverse through activated esters are
less common.7 For example, decarboxylative methods to
convert stabilized acids to N-alkylated products were reported
in 2019,7a,b and earlier this year, a photochemical N-alkylation
of DTAD (di-tert-butyl azodicarboxylate) was reported; such
adducts could be converted to pyrazoles after deprotection/
condensation.7c In 2019 our group reported a simple means to
prepare hindered ethers through an electrochemical decarbox-
ylative approach wherein an electrogenerated carbocation
could be intercepted with an alcohol.8 It was hypothesized
that similar conditions might also be amenable to capture N-
heterocycles. In this Letter, we report our findings and
demonstrate that a simple electrochemically driven approach
analogous to ether synthesis can be employed to generate N-
alkylated heterocycles. The reaction exhibits a broad substrate
scope with regards to the heterocyclic substrate, employs a
simple and scalable procedure, and can be used to simplify
prior routes to such targets.
Aside from the highlighted application in Scheme 1A
(pyrazole 1), a small selection of additional known compounds
were targeted, such as pyrazoles 70−72 (Scheme 3A).10−12
Hemiaminals 70 and 71 could be accessed in high yields in one
simple step versus the multistep procedures used in the past.
Finally, the tert-butylated pyrazole 72 could be accessed in a
single step (although in low yield due to an extended reaction
time needed with pivalic acid).
At the outset, optimization was conducted on a medicinally
relevant substrate that was employed in the synthesis of a
Cereblon binder, pyrazole 1 (Scheme 1A).9 This compound
Mechanistically we hypothesize that a cationic intermediate
is formed after decarboxylation, analogous to etherification
C
Org. Lett. XXXX, XXX, XXX−XXX
Baran, Phil. S.
