Redox-Neutral Decarbonylative Cross-Couplings Coming of Age

Article abstract of DOI:10.1002/cssc.201900408

Major progress has recently been made in the challenging redox-neutral decarbonylative cross-coupling of carboxylic acids. For example, the use of acid fluorides as effective cross-coupling partners has been found to enable control of the decarbonylation selectivity and facilitates challenging Pd⁰-catalyzed nucleophilic trifluoromethylation and exogenous base-free Suzuki cross-coupling reactions. In another recent advance, the use of acid chlorides in room temperature difluoromethylation and direct decarbonylative cross-coupling of carboxylic acids allows these classical substrates to be used as aryl electrophiles in cross-coupling reactions. Further challenges that are yet to be addressed in redox-neutral decarbonylative cross-couplings are also briefly summarized.

Full text of DOI:10.1002/cssc.201900408

Accepted Article
Title: Redox-Neutral Decarbonylative Cross-Couplings Coming of Age
Authors: Qun Zhao and Michal Szostak
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ChemSusChem
10.1002/cssc.201900408
HIGHLIGHT
Redox-Neutral Decarbonylative Cross-Couplings Coming of Age
Qun Zhao and Michal Szostak*
Carboxylic acids represent quintessential substrates for organic
synthesis.[1] Diverse electrophilic and nucleophilic reactions of
carboxylic acids form the foundation of daily research by
practicing organic chemists[2] and feature as the pillar of all
undergraduate organic chemistry textbooks.[3] The steadily
increasing demand for efficient and sustainable carbon-carbon
bond forming protocols has given rise to the exponential growth
of transition-metal-catalyzed cross-coupling reactions as firmly
manifested by the 2010 Nobel Prize in Chemistry.[4] Following
the inspiring breakthrough reported by Gooßen in 2006,[5]
traditionally, the cross-coupling of carboxylic acids is addressed
via decarboxylation.[6] Typically, this involves generation of
arenecarboxylate and extrusion of carbon dioxide, which
converts carboxylic acids into aryl nucleophiles.[7] This approach
has proven extremely valuable as it allows to exploit carboxylic
acids as ubiquitous, orthogonal and readily accessible cross-
coupling partners in paradigms under decarboxylative regimen.
However, despite the profound impact on chemical synthesis,
decarboxylative cross-couplings have been a challenge due to
high energy required for the decarboxylation step,[5] which often
requires stoichiometric metal additives, substrates that favor
decarboxylation and typically demand high temperature.[6]
Recently, significant progress has been made in the
development of cross-coupling reactions of carboxylic acids via
redox-neutral decarbonylative pathway (Figure 1). In this
approach, carboxylic acid is first converted to an activated
easily-accessible acyl carboxylic acid derivative, followed by
metal insertion, transmetallation/ decarbonylation and reductive
elimination, thus mimicking the classical M(0)/(II) (M = metal)
cross-coupling mechanism under redox-neutral conditions
The developed decarbonylative strategies are important from
the sustainability standpoint because they open up new avenues
for utilization of carboxylic acids in the cross-coupling strategies
of paramount significance in chemical synthesis. Because
carboxylic acids are produced at much lower cost than aryl
halides, efficient cross-coupling of these alternative substrates
offers new ways of reducing energy, cost and time required for
chemical processes. Another potentially intriguing aspect
involves circumventing the release of carbon dioxide, which at
present is considered as the major greenhouse gas.
Recent breakthroughs in novel decarbonylative cross-
couplings can be classified into three main categories. In 2018,
Schoenebeck and co-workers reported
catalyzed decarbonylative trifluoromethylation
fluorides.[14] Subsequently, Sanford and co-workers described a
Ni(0)/PPh Me-catalyzed Suzuki-Miyaura cross-coupling of the
a
Pd(0)/Xantphos-
of acid
2
same class of substrates.[15] Ritter and co-workers have
independently accomplished extraordinary mild, Pd(0)/RuPhos-
catalyzed difluoromethylation of acid chlorides.[16] Our group
together with Hong and co-workers reported a Pd(0)/dppb-
2
catalyzed direct borylation of carboxylic acids using in situ piv O
activation.[17] These methods combine the advantages of using
carboxylic acids together with facile decarbonylation, thus
establishing new general tactics in organic synthesis that can be
incorporated into complex substrates and synthetic sequences.
(
Figure 2). Altogether, this provides a powerful alternative
approach to the decarboxylative cross-coupling of carboxylic
acids[6] as well as the traditional cross-coupling of aryl halides.[4]
Surely, decarbonylative cross-couplings are not new.[4] One
of the first efficient examples of a decarbonylative cross-coupling
was reported by de Vries and colleagues in 1998 and involved
Figure 1. New vistas in decarbonylative cross-coupling of carboxylic acids.
2
the use of symmetrical anhydrides in a PdCl /LiCl-co-catalyzed
decarbonylative Heck cross-coupling.[8,9] Subsequently, this
approach was refined by Gooßen and colleagues who utilized
aromatic esters and vinylic esters thus minimizing generation of
toxic halide waste.[10] The idea of forming aryl electrophiles from
carboxylic acids by decarbonylation laid dormant until 2012
when Itami et al. found that relatively unactivated phenolic esters
can be induced to undergo selective decarbonylation/C–C cross-
coupling with acidic heterocycles utilizing Ni(cod)
2
and dcype as
a
key bidentate ligand.[11] In 2015, our group introduced
Figure 2. Catalytic cycles for classical and decarbonylative cross-coupling.
decarbonylative cross-coupling of amides by selective N–C
activation using Pd, and later Rh and Ni,[12] and this approach
was elegantly expanded by Rueping and colleagues.[13]
The benefits of these strategies include: (1) advantageous
use of carboxylic acids as much more available, cheaper and
less toxic substrates than the current state-of-the-art aryl halides
or designer amides and esters; (2) access to unconventional
downstream disconnections enabled by the inherent ubiquitous
presence of carboxylic acids in natural products, functional
materials, and most importantly, plethora of pharmaceuticals; (3)
[*]
Dr. Q. Zhao, Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (United States)
E-mail: michal.szostak@rutgers.edu
Website: https://szostakgroup.com
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ChemSusChem
10.1002/cssc.201900408
HIGHLIGHT
[
20]
capacity for orthogonal cross-coupling strategies in the presence
of aryl halides; (4) novel approaches to biomass valorization.
The strategy by Schoenebeck has provided the first example
of a Pd(0)-catalyzed decarbonylative cross-coupling of acid
fluorides (Scheme 1).[14] This process establishes a rare protocol
for a Pd(0)/Pd(II) trifluoromethylation, introducing the biorelevant
comparatively activated C(O)–X bonds.
In all cases, the
elementary oxidative addition initiating the cross-coupling occurs
readily at mild, room temperature conditions, highlighting the
crucial role of rate-limiting decarbonylation or transmetallation.
Third, acid halides and certainly carboxylic acids are readily
available and over the years have become a classic group of
substrates in the repertoire of organic chemists.[
1–3]
CF
3
motif with broad generality and very promising reaction
Since the
scope. It is particularly noteworthy that (1) the method avoids the
use of external fluoride additives, and (2) the process operates
effectively with general Xantphos as a supporting ligand. As
redox neutral decarbonylative cross-coupling manifold offers
evident advantages to chemists and exploits well-familiar
substrates, which differ in their stability, ease of decarbonylation
and transmetallation, thus allowing for control and fine-tuning of
elementary reactions, the research is now perfectly poised for
widespread adoption by the synthetic community pending the
establishment of general cross-coupling methods.
–
expected, the leaving F group serves as internal fluoride source,
activating the trifluoromethylating agent. This in turn allows to
limit the concentration of CF
3
anions, thus avoiding facile
displacement of the phosphines from Pd.[18] On the basis of DFT
studies, the authors proposed that the transmetallation step
In this vein, following the pioneering work on
trifluoromethylation,[14] Sanford el al. reported the Suzuki-
Miyaura cross-coupling of acid fluorides (Scheme 2).[15]
Impressive levels of selectivity for the synthesis of valuable
biaryls[21] were achieved using an exogenous base-free protocol.
Mechanistically, the authors showed that both oxidative addition
of benzoyl fluoride and decarbonylation of the PhCO-
ǂ
-1
ǂ
precedes decarbonylation (ꢀG = 17.4 kcal mol vs. ꢀG = 27.3
-1
kcal mol from PhCO-[Pd]-CF
Furthermore, studies correlated the reaction selectivity (Ar–CF
vs. ArCO–CF with temperature, with high temperatures
3
vs. PhCO-[Pd]-F, respectively).
3
3
)
favoring decarbonylation. As this protocol provides rapid entry to
trifluoromethylated arenes, this method may find broad
application in synthesis, agrochemistry and drug discovery.
3 2
[Pd(PCy ) ]-F intermediate occur readily at room temperature.
Most crucially, they showed that the fluoride delivered by the
acid electrophile is vital for the transmetallation step with aryl
boronic acids, whereby the use of analogous acid chloride and
3 2
bromide intermediates, PhCO-[Ni(PCy ) ]-X (X = Cl, Br), was
unproductive. This is consistent with a “fluoride effect” to
promote transmetallation,[ thus switching to “transmetallation
active” [Ar–M–X] intermediates in a selective manner enabled by
21]
–
an internal transfer of the F anion. The remarkable net result is
that Suzuki cross-coupling operates under base-free regimen,
which limits off-cycle side-reactions promoted by the base. This
concept provides a highly attractive alternative for realizing the
Suzuki cross-coupling of aryl halides and pseudohalides.
Scheme 1. Selected examples of the Pd/Xantphos-catalyzed decarbonylative
trifluoromethylation of acid fluorides. Inset shows TS for decarbonylation.
More generally, the reactivity of carboxylic acid halides
should be benchmarked against the reactivity of other carboxylic
acid derivatives. First, acid fluorides are more stable than the
more commonly used in synthesis acid chlorides.[19] This is
evidenced by the C–X bond lengths (MeC(O)–F: 1.37 Å,
MeC(O)–Cl: 1.82 Å MeC(O)–Br: 2.00 Å), consistent with a
decreasing n → ꢁ*CO conjugation in the series, while the C=O
X
bond lengths are in the range of approx. 1.16 Å, which is shorter
than in esters and signifies a more C=O double bond character.
Second, recent studies make it quite clear that oxidative addition
of C(O)–X bonds is relatively easy and cannot be considered a
rate-determining step in these cross-couplings. The resonance
Scheme 2. Selected examples of the Ni/PPh
2
Me-catalyzed decarbonylative
Suzuki cross-coupling of acid fluorides. Inset shows (PhCO)Ni(F)(PEt ) .
3 2
-1
energy (RE) of acid fluorides (PhC(O)–F = 14.0 kcal mol ), acid
-1
chlorides (PhC(O)–Cl = 5.1 kcal mol ) and acid bromides
Recently,
a
pioneering example of Pd(0)-catalyzed
-
1
(
PhC(O)–Br = 3.5 kcal mol ) is in the range of activated amides
decarbonylative cross-coupling of acid chlorides at room
temperature was reported by Ritter and co-workers (Scheme
3).[16] They have shown that Pd(dba)2 in combination with a
bulky monodentate phosphine RuPhos and (DMPU) Zn(CF H)
-1
(
PhC(O)–N(glutarimide) = –1.4 kcal mol ; PhC(O)–NPh/Me =
3.5 kcal mol ) and esters (barrier to rotation, PhC(O)–OPh, 9.3
kcal mol ; PhC(O)–OMe, 12.8 kcal mol ) indicating
-1
1
-1
-1
2
2
2
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ChemSusChem
10.1002/cssc.201900408
HIGHLIGHT
as
a nucleophilic difluoromethylating agent promotes the
decarbonylative cross-coupling within 5 min at room temperature.
This remarkably facile process was explained by the mechanism
involving (i) oxidative addition; (ii) rate-limiting transmetallation;
(
iii) decarbonylation promoted by the coordinatively unsaturated
-coordinate Ar–Pd(RuPhos)–CF H complex; and (iv) reductive
3
2
elimination. Furthermore, the authors clearly established that the
rate and selectivity of the reductive elimination step is closely
connected to electronic properties of the ligands on Pd, whereby
(
i) Ar–Pd(PR
Pd(PR )–CF
ArC(O)/CF H reductive elimination. Thus, this elegant protocol
3
)–Cl leads to slower reductive elimination than Ar–
H; (ii) electron-rich arenes lead to a competing
3
2
2
provides not only
underrepresented CF
a
highly practical entry to the
2
H motif, but also furnishes many key
insights into the future development of decarbonylative cross-
couplings of the traditionally unstable acid chlorides.
Scheme 4. Selected examples of the Pd/dppb-catalyzed decarbonylative
borylation of carboxylic acids. Inset shows (Ph)Pd(OPiv)(dppb).
of acid chlorides is more facile than that of aryl iodides; (ii)
Xantphos ligands are the privileged class of ligands for the
selective oxidative addition of unstable acyl electrophiles.
In conclusion, major progress has recently been made in the
challenging redox-neutral decarbonylative cross-coupling of
carboxylic acids. For the first time, acid fluorides have been
proved to be effective cross-coupling partners in the
decarbonylative manifold allowing for the exquisite control of the
decarbonylation selectivity, such that the challenging Pd(0)-
catalyzed nucleophilic trifluoromethylation and exogenous base-
free Suzuki cross-coupling have been achieved. Another
significant advance is the use of acid chlorides in the room
temperature difluoromethylation and the direct decarbonylative
cross-coupling of carboxylic acids which open the door to the
use of these classical substrates as aryl electrophiles in cross-
coupling manifolds. Finally a comment should be made that
despite the undeniable breakthroughs, several challenges still
need to be addressed. Acid fluorides have emerged as the
preferred acid derivatives for the cross-coupling; however, the
synthesis of acyl fluorides is still not straightforward using cost-
effective reagents. Second, thus far all but one protocol involve
a separate preparation step. It would take us closer to the ideal
cross-coupling paradigm if all reactions could be performed in a
one-pot fashion. Third, the generality of the platform must be
established so that different disconnections become available to
Scheme 3. Selected examples of the Pd/RuPhos-catalyzed decarbonylative
difluoromethylation of acid chlorides. Inset shows (ArCO)Pd(Cl)(RuPhos).
In addition, our group together with Hong and co-workers
successfully developed a Pd(0)-catalyzed direct decarbonylative
borylation of carboxylic acids (Scheme 4).[17] In contrast to other
reports, this redox-neutral approach directly engages carboxylic
acids by combining all reaction components in one-pot without
the need for separate activation steps. The user-friendly catalyst
system provides an efficient gateway to highly functionalized
aryl–boron bonds, including a broad range of sensitive functional
groups, direct functionalization of APIs and bioactive natural
products. Detailed DFT studies indicated that the substituent at
the carboxylic acid anhydride controls the selectivity of the C–O
bond activation by sterics with the ArC(O)– vs. t-BuC(O)–
activation favored by 4.7 kcal mol-1 and transmetallation as the
rate-limiting step. Since the activation of acid anhydrides (RE of
practicing organic chemists for the efficient functionalization of
carboxylic acids. Further developments in this important area[23]
using general catalyst systems are certainly expected and will
offer new sustainable tactics for organic synthesis.
-1
5
.1 kcal mol ) is facile, the anhydride is stable under the cross- Acknowledgements
coupling conditions and the reaction follows well-defined
Pd(0)/(II) cycle, this approach could potentially enable a wide
variety of cross-coupling protocols using directly ubiquitous
carboxylic acid electrophiles.
We thank Rutgers University, the NSF (CAREER CHE-1650766)
and the ACS PRF (DNI-55549) for generous financial support.
Keywords: decarbonylation • carboxylic acids • cross-coupling •
homogeneous catalysis • arenes
In the context of decarbonylative cross-couplings of acid
halides it is also important to mention two recent breakthroughs
on functional group ꢂ-bond metathesis of acid chlorides and aryl
iodides reported independently by Morandi and Arndtsen.[22]
These reports clearly foreshadow that (i) the oxidative addition
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ChemSusChem
10.1002/cssc.201900408
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