Formate-Mediated Cross-Electrophile Reductive Coupling of Aryl Iodides and Bromopyridines

Article abstract of DOI:10.1002/ijch.202000069

Two catalytic systems for the formate-mediated cross-electrophile reductive coupling of aryl iodides with 6-bromopyridines are described. Using homogenous rhodium or heterogeneous palladium catalysts, the products of reductive biaryl cross-coupling could

Full text of DOI:10.1002/ijch.202000069

Communication
DOI: 10.1002/ijch.202000069
Formate-Mediated Cross-Electrophile Reductive Coupling of
Aryl Iodides and Bromopyridines
Leyah A. Schwartz,[a] Kim Spielmann,[a] Robert A. Swyka,[a] Ming Xiang,[a] and Michael J. Krische*[a]
Dedicated to Professor Barry M. Trost on the occasion of his 80th birthday.
Abstract: Two catalytic systems for the formate-mediated or heterogeneous palladium catalysts, the products of
cross-electrophile reductive coupling of aryl iodides with 6- reductive biaryl cross-coupling could be formed in moderate
bromopyridines are described. Using homogenous rhodium yield with excellent levels of chemoselectivity.
Keywords: cross-electrophile coupling · reductive coupling · rhodium · palladium · formate
Metal-catalyzed cross-couplings have opened vast volumes of
chemical space.[1] Nevertheless, a major liability associated
with their use is the requirement of premetalated nucleophiles,
which are often prepared through multi-step protocols involv-
ing numerous sacrificial reagents. Metal-catalyzed cross-
electrophile reductive coupling[2,3] avoids the use of premeta-
lated reagents, however, such processes typically utilize
elemental zinc or manganese as reductants, which generates
stoichiometric quantities of metallic byproducts. Additionally,
the activated surface of such zero-valent metals poses serious
safety issues, which is not ideal for large volume
applications.[4] Clearly, metallic reductants are as problematic
as the premetalated reagents they are intended to replace.
Use of safe, abundant, low molecular weight reductants
such as elemental hydrogen, 2-propanol or sodium formate in
metal-catalyzed cross-electrophile reductive coupling would
enable process-relevant transformations of this type. Precedent
can be found in palladium-catalyzed reductive biaryl homo-
couplings that employ elemental hydrogen,[5] 2-propanol,[6]
ascorbic acid[7] and formate[8a–d,f] as terminal reductants. A
rhodium-catalyzed reductive biaryl homo-coupling mediated
by formate also has been disclosed.[8c] Studies on the use of
organic reductants in metal-catalyzed cross-electrophile reduc-
tive coupling are also few in number, and include the use of
tetrakis(dimethylamino)ethylene (TDAE),[9,10] which is rela-
tively expensive, poly(ethylene glycol),[11] hydrazine,[12]
strained 1,2-diols (via retro-pinacol reaction)[13] and diisopro-
pylethylamine (via photoredox catalysis).[14]
4-iodoansiole with 6-bromo-2-picoline based on rhodium and
palladium (Figure 1).
Utilizing conditions previously developed in our laboratory
for rhodium-catalyzed transfer hydrogenative aryl-aldehyde
couplings,[16a] 4-iodoanisole 1a and 6-bromo-2-picoline 2a
In connection with the discovery and development of
reductive CÀ C couplings promoted by hydrogenation, transfer
hydrogenation and hydrogen auto-transfer,[15] we recently
described a series of formate-mediated carbonyl reductive
couplings of aryl iodide,[16a] vinyl bromide[16b] and vinyl
triflate[16c] pronucleophiles. The ability to promote reductive
couplings of aryl halide partners prompted an investigation
into related formate-mediated cross-electrophile reductive
couplings. Here, we report two promising catalytic systems for
the formate-mediated cross-electrophile reductive coupling of
Figure 1. Construction of new carbon-carbon bonds via various
methods of cross coupling.
[a] L. A. Schwartz, Dr. K. Spielmann, R. A. Swyka, M. Xiang,
Prof. M. J. Krische
Department of Chemistry, University of Texas at Austin
Welch Hall, 105 E 24th St., Austin, TX 78712, USA
E-mail: mkrische@cm.utexas.edu
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.202000069
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Table 1. Selected optimization experiments in the formate-mediated
cross-electrophile coupling of 4-iodoanisole 1a and 6-bromo-2-
picoline 2a catalyzed by rhodium.[a]
Table 2. Rhodium-catalyzed formate-mediated cross-electrophile
coupling of aryl iodides 1a–1d and bromopyridines 2a–2c.[a]
[a]
Yields are of material isolated by silica gel chromatography. The
loading of dimeric rhodium precatalysts was 2.5 mol%.
[a]
Yields are of material isolated by silica gel chromatography. See
supporting information for further experimental details.
undergo cross-electrophile reductive coupling to form biaryl
3a in 25% yield (Table 1, Entry 1). Only trace amounts (<
5%) of the homo-coupling products were detected. The major
side product of the reaction is dehalogenation of the starting
materials 1a and 2a to give anisole and 2-picoline,
respectively. Other commercially available rhodium precata-
lysts were evaluated, and it was found that complexes lacking
carbonyl ligands delivered only trace amounts of the cross-
coupling product 3a along with dehalogenated starting
materials. Evaluation of other organic reductants, such as 2-
propanol, hydroquinone, and formic acid, failed to deliver
significant quantities of hetero-coupling product. Other for-
mate salts provided the product, however in slightly decreased
yields (Table 1, Entries 4–7). Lewis basic and acidic additives
failed to increase the yield, although upon introduction of
tetrabutylammonium iodide (10 mol%) the cross-coupling
product 3a could be obtained in 40% yield (Table 1, Entry 8).
Other iodide salts (e.g. KI, NaI, etc.) did not have the same
favorable effect. Additionally, a wide variety of mono- and bi-
dentate phosphine and NHC ligands were evaluated under
these conditions, however similar or worse levels of con-
version were observed. Variation of base also failed to increase
yield. Lower reaction temperatures decreased conversion,
while elevated reaction temperatures proved to be of little
benefit. Evaluation of other aryl iodides and bromopyridines
under these conditions selectively furnished the cross-coupling
products in modest yields due to competing dehalogenation of
the starting materials (Table 2).
utilizing palladium black (Table 3, Entry 1). Encouraged by
the effect of additives in the rhodium-based catalyst system,
diverse additives were screened. Again, tetrabutylammonium
iodide was found to increase the yield of 3a, although super-
stoichiometric quantities were required (Table 3, Entry 2). As
with the rhodium-based catalyst system, only trace amounts of
the homo-coupling products were observed and dehalogena-
tion of the starting materials 1a and 2a accounted for the
remainder of the mass balance. Control experiments revealed
that triethylamine, and not hydrogen, served as the reducing
agent (Table 3, Entries 3 and 4). This led to the evaluation of
other organic reductants. While reactions conducted using 2-
Table 3. Selected optimization experiments in the formate-mediated
cross-electrophile coupling of 4-iodoanisole and 6-bromo-2-picoline
catalyzed by Pd black.[a]
Inspired by a report from Sasson and co-workers[5] in
which palladium on carbon was utilized in the presence of
hydrogen gas to affect aryl halide homo-coupling, palladium-
catalyzed cross-electrophile reductive couplings were ex-
plored. Initial screening utilizing palladium on carbon in
combination with hydrogen gas (1 atm) as reductant and
triethylamine (200 mol%) as base provided the cross-coupling
product in low yields. Similar results were observed when
[a]
1
Yields were determined by H NMR of crude reaction mixtures
using trimethoxybenzene as an internal standard. Select experi-
ments were duplicated and NMR yields were in close alignment with
yields of material isolated by silica gel chromatography.
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propanol were less efficient (Table 3, Entry 5), a 45% yield of
the cross-coupling product 3a was obtained using sodium
formate (Table 3, Entry 6). Subsequent optimization experi-
ments focused on sodium formate due to its tractability and
low cost. Increasing the loading of formate salt, the cross-
coupling product 3a could be obtained in 52% yield (Table 3,
Entry 7). Interestingly, decreased loadings of tetrabutylammo-
nium iodide resulted in lower yields of 3a (Table 3, Entry 8).
Finally, it was observed that the loading of palladium black
could be decreased without compromising the yield of 3a. In
fact, similar yields could be observed at catalyst loadings as
low as 1 mol% (Table 3, Entries 9 and 10). Additionally, use
of 2-bromoquinoline in place of 6-bromo-2-picoline resulted
in formation of the cross-coupling product in 53% yield (see
Supporting Information).
The requirement of TBAI in these reactions suggested its
potential role in creating a new active catalyst when combined
with the palladium(0) source. Hence, a series of anionic
palladium complexes [PdX3(DMSO)][NBu4] (X=Cl, Br) were
prepared[17] and evaluated as catalysts in the cross-electrophile
reductive coupling of 4-iodianisole 1a with 6-bromo-2-pico-
line 2a (Eq 1). The cross-coupling product 3a was formed in
moderate yields. Utilizing a slight excess of 4-iodoanisole
under otherwise identical conditions gives the cross-coupling
product 3a in 55% yield (Eq 2). In both cases the primary side
products result from dehalogation of 1a and 3a to form
anisole and 2-picoline, respectively, and not biaryl homo-
coupling. These data corroborate intervention of anionic
palladium complexes as catalysts. Such anionic palladium
species are known to participate in aryl halide oxidative
addition with enhanced rates in comparison to corresponding
neutral palladium(0) species.[18]
Scheme 1. Proposed catalytic mechanism for the rhodium- or
anionic palladium-catalyzed cross-electrophile coupling.
products. A second aryl halide oxidative addition can then
occur to give the bis(aryl) rhodium(III) or anionic palladium
(II) intermediate VI. Reductive elimination releases the cross-
coupling product and regenerates complex I to close the
catalytic cycle. The bis(aryl) species VI might also form
through alternate mechanism involving reversible transmetala-
tion between complementary arylmetal intermediates IVa and
IVb. In this case, elimination of diatomic hydrogen from
intermediate VII would be required to close the catalytic
cycle. Reductive elimination from complexes containing one
electron-rich aryl group and electron-poor aryl group is
kinetically preferred,[19] which may account for the preferential
formation of cross-coupling (vs homo-coupling) products.
In summary, we have demonstrated the potential of two
distinct catalytic systems for formate-mediated cross-electro-
phile reductive coupling of 4-iodianisole 1a and 6-bromo-2-
picoline 2a. Our current set of conditions provide the desired
cross-coupling product 3a in up to 55% yield accompanied by
only trace quantities of homo-coupling product. Studies
toward improved catalytic systems for formate-mediated
cross-electrophile reductive coupling are currently underway.
Acknowledgements
The indicated general catalytic mechanism is one of
several that could be proposed based on the collective data
(Scheme 1). Aryl halide oxidative addition to either rhodium
(I) or anionic palladium(0) I followed by ligand exchange with
formate gives intermediate III. β-Hydride elimination releases
carbon dioxide and forms the hydride complex IVa, which
engages in HX reductive elimination to generate either
arylrhodium(I) or anionic arylpalladium(0) complexes V.
Alternatively, carbon-hydrogen reductive elimination from
intermediate IVa generates the observed dehalogenation side-
We thank the Robert A. Welch Foundation (F-0038) and the
NIH-NIGMS (RO1-GM069445) for generous support of our
research.
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Manuscript received: August 11, 2020
Revised manuscript received: September 11, 2020
Version of record online: ■■■, ■■■■
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L. A. Schwartz, Dr. K. Spielmann,
R. A. Swyka, M. Xiang, Prof. M. J.
Krische*
1 – 5
Formate-Mediated Cross-Electro-
phile Reductive Coupling of Aryl
Iodides and Bromopyridines