Angewandte
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Chemie
unmitigated. Thus, thermally driven and operationally simple
means of Barton decarboxylation and decarboxylative Giese
reactions remain highly desirable.
cially on large scale).[9] Densely functionalized natural
products were decarboxylated in high yields;[17] indole (13),
hydroxy (15, 18a, and 19a), ketones (17 and 19a), and olefins
(18a and 19a) were left unscathed. The alternative route to 15
involves dissolving metal reduction of the corresponding
nitrile.[18] Although 19a can be furnished in good yields
through PET-mediated decarboxylation, long reaction times
(24 h), an expensive solvent (TFE), and Fukuzumiꢀs photo-
sensitizer (more expensive than the starting carboxylic acid)
are required.[5d] Barton decarboxylation has been applied
numerous times to access pyrroloindoline alkaloids from
tryptophan derivatives.[19] Substrate 14, though not natural
product-derived per se, showcases the viability of this
methodology to synthesize these alkaloids in a highly prac-
tical fashion.
Similarly, the conjugate addition exhibited broad scope
with respect to both reaction partners. Michael acceptors
bearing assorted electron-withdrawing groups (EWGs) such
as esters, ketones, sulfones, and nitriles were all shown to react
in good yields. These functional groups open up many
opportunities for product diversification. It is also of note
that the addition is unencumbered by a or b substitutions on
the Michael acceptor (26–27, 28–29). Whereas similar con-
jugate additions with Barton esters oftentimes require large
excesses of Michael acceptors, two equivalents of these
activated olefins was deemed sufficient in the nickel catalyzed
reaction.[20]
Efforts in our laboratory beginning in 2015 led to the
realization that Barton esters (1) are redox-active species that
readily accept electrons from metal complexes through
a purely thermal single electron transfer (SET) process.[11–14]
This property is shared by various activated carboxylates
commonly employed in amide coupling. Collectively termed
redox-active esters (RAEs), these compounds (exemplified
by NHPI ester 4) undergo facile SET reduction with
inexpensive nickel[11–13] or iron catalysts.[14] The ensuing
radical anion fragments to afford alkyl radicals under thermal
conditions. Combination of the alkyl radical with a metal
center by virtue of the persistent radical effect (PRE) enables
cross-coupling of various modalities. Herein, reductive decar-
boxylation (4 to 2) and Giese reaction (4 to 3) of NHPI RAEs
are disclosed, exhibiting broad substrate scope, chemoselec-
tivity, and scalability while obviating the need for toxic
reductants and photochemical irradiation. The bench stability
of 4 offers another advantage although as shown below its
discreet isolation is not necessary.
Though conceptually straightforward, both transforma-
tions were only realized after considerable experimentation.
Figure 1B provides the optimal reaction parameters along
with a simplified picture of the optimization process on
piperidine derivative 5.
Zinc (0.5 equiv) (entry 1, Figure 1B1) was necessary to
reduce the NiII species in the decarboxylation reaction, while
PhSiH3 was found to be the most effective source of hydrogen
(entries 3, 10, and 14). The ternary mixture comprising THF,
DMF, and iPrOH delivers the highest yield whereby iPrOH is
believed to provide activation of the silane.[15] A 1:2 mixture
of NiCl2·6H2O and L1 provided the best catalyst system.
Addition of tBuSH or LiCl as additives had deleterious
effects on the yield (entries 13 and 14).
Meanwhile, LiCl was identified as an essential additive in
the conjugate addition (Figure 1B2, entry 3). In the absence
of a terminal silane reductant, zinc was required in stoichio-
metric quantities. Ni(ClO4)2·6H2O ($120molÀ1) performed
the best for this reaction; addition of Lewis acids, bipyridine
ligands, or the use of other metal salts all led to diminished
yields. In both transformations, the choice of RAE was
critical; while NHPI esters reacted efficiently, use of TCNHPI
esters led to lower yields. Zinc (ca. $5molÀ1) could be used
straight out of the bottle, as the use of activated zinc had
minimal impact in either reaction. Overall, decarboxylation
was complete within 1 h at 408C, while the conjugate addition
proceeded smoothly at ambient temperature.
As with the decarboxylation, RAEs of primary, secondary
and tertiary acids, bearing multiple functional groups, can be
used in this Giese-type reaction (32–44).[21] Good levels of
stereocontrol were observed on several substrates (36, 40–42).
Many substrates represent derivatives of natural products
which are difficult to access through alternative routes. For
example, a previous synthesis of the acid corresponding to 42
requires a laborious six-step sequence from the same starting
material.[22] Moreover, attempts to make 35 and structural
analogs of 40 through the decarboxylative conjugate addition
of Barton esters were reportedly complicated by the compet-
ing coupling of the 2-thiopyridone byproduct with the
intermediate b radical, requiring a separate step of thiopyridyl
removal.[20] To this end, the use of an NHPI redox-active ester
circumvents this lingering problem in classical Barton
chemistry.
Across the many substrates examined, both reactions
were found to be impervious to moisture and required
minimal precautions. This robustness, in combination with the
inexpensive reagents employed bode well for large-scale
reactions. Indeed, gram-scale decarboxylation and Giese
addition using 5 delivered 6 and 7 in high yields.
RAEs derived from primary (10, 13, 15, and 17),
secondary (6, 12, and 14), and tertiary (8, 9, 11, 16, 18, and
19a) carboxylic acids are all competent substrates in the
decarboxylation reaction (Scheme 1). Though 10 and 12 are
also accessible from the corresponding Barton esters, the
classical conditions enlist stoichiometric amounts of pungent
tBuSH.[16] Conversely, 8 can be made in comparable yield
using Tsanaktsidis and Williamsꢀs modified protocol with
chloroform as the hydrogen donor; the need for photo-
irradiation, however, still presents an inconvenience (espe-
While RAEs employed in these transformations are
readily diversifiable building blocks which can be conven-
iently purified and stored without special precautions, further
experimentations revealed that isolation of the RAEs was not
necessary: decarboxylation and conjugate addition can be
performed on RAEs generated in situ. For example, a simple
activation of acid 45, followed by the decarboxylation or
conjugate addition protocols, furnished 6 and 7 in comparable
yields (Scheme 2A). Owing to the ubiquity and availability of
carboxylic acids, such one-pot procedures may have a tangible
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 7
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