2
Suzuki–Miyaura Cross-Coupling
The transition-metal-catalyzed Suzuki–Miyaura (SM) cross-coupling of aryl chlorides
with arylboronic acids/esters has emerged as a powerful tool for constructing biaryl
compounds (Scheme [1]).[1] The SM cross-coupling is highly valuable because many arylboronic acids used as
reactants are commercially available, inexpensive, and non-hazardous. Additionally,
arylboronic acids are stable under heat, air, and moisture. Although arylboronic acids
S1 and their esters S2 are typical coupling partners in the SM cross-coupling of aryl chlorides, many other
boron sources are also listed in the literature, such as arylborinates S3, triarylboranes S4, and diarylborinic acids S5 (Figure [1]).
Scheme 1 General representation of the Suzuki–Miyaura cross-coupling of aryl chlorides
Figure 1 Commonly used boron sources for SM reactions
SM cross-coupling involves three mechanistic steps: (i) oxidative addition, (ii) transmetalation,
and (iii) reductive elimination (Scheme [2]). Owing to the low reactivity of aryl chlorides [bond-dissociation energy (BDE):
330 kJ/mol], the oxidative process becomes difficult; thus, oxidative addition typically
becomes the rate-limiting step. To overcome the low reactivity of aryl chlorides,
researchers have developed highly active transition-metal catalysts using bulky ligands.
The addition of additives such as TBAB or NaI to the reaction mixture is another way
to solve the issue of the low reactivity of aryl chlorides. TBAB can act as a phase-transfer
catalyst, and it can stabilize transition-metal nanoparticles by avoiding aggregation.[3] The addition of NaI is reported to facilitate the reaction of aryl chlorides via
halide exchange.[4] Additionally, the ligand design might also assist in overcoming the low reactivity
issue; for example, electron-rich ligands usually perform better in the oxidative
addition of aryl chlorides than electron-deficient ligands.[5] The presence of a suitable base makes the transmetalation step more accessible.
Similarly, the presence of bulky ligands usually favors reductive elimination. In
Section 2, recent examples of SM cross-couplings of aryl chlorides using homogeneous
(2.1 and 2.3) and heterogeneous (2.2 and 2.4) palladium (2.1 and 2.2) and nickel (2.3
and 2.4) catalysts are presented.
Scheme 2 General catalytic cycle for the SM cross-coupling
2.1
Homogeneous Palladium Catalysis
In 2013, Nechaev et al. developed a diaminocarbene palladium complex C1 (Figure [2]) for the SM reaction.[6] They performed the reaction of 2-chloropyridine and arylboronic acids in the presence
of 0.5 mol% of C1. The addition of TBAB was essential for this transformation and the coupling products
were obtained in up to 99% yield. In 2014, the group of Balcells, Hazari, and Tilset
developed Pd(IPr)(η
3-cinnamyl)Cl complex C2.[7] The SM coupling of tolyl chloride with phenylboronic acid proceeded in >99% yield
within 30 minutes at 30 °C using 1 mol% of the palladium complex C2. During their mechanistic studies, they observed Pd(I)-dimeric complex 10, which originated from the comproportionation reaction of Pd(II) and Pd(0) complexes
(Scheme [3]). This Pd(I)-μ-allyl dimer 10 was less reactive and provided only a 4% yield of the biaryl product under the same
conditions using C2.
Figure 2 Homogeneous Pd complexes and ligands used for the SM reactions
Scheme 3 A plausible pathway for the generation of a PdI dimer
In 2015, Ayogu et al. prepared antimicrobial compounds via SM cross-couplings using
Pd2(dba)3 (1 mol%) and SPhos (2 mol%), and the corresponding products 13a or 13b were both obtained in 43% yield (Scheme [4]).[8] Li, Zhong and co-workers reported the SM cross-couplings of aryl chlorides with
trialkyl- and triaryl-borane derivatives S4.[9] They used Pd(OAc)2 (2.5 mol%) as the metal source and RuPhos (5 mol%) as the ligand. They prepared the
trialkylboranes from the corresponding olefin and BF3·Et2O, and used them in the SM cross-couplings in one-pot. In this one-pot process, the
products were obtained in up to 86% yield. Das and co-workers applied the hydrophilic
salen-Pd(II) complex C3 (1 mol%) to the cross-couplings of aryl chlorides and arylboronic acids in water
at 100 °C.[10] The reaction of an electron-rich 4-chloroanisole with phenylboronic acid afforded
4-methoxybiphenyl in 93% yield, whereas the reaction of electron-deficient 4-chloronitrobenzene
and phenylboronic acid gave only a 45% yield of 4-nitrobiphenyl. This was improved
by adding a phase-transfer catalyst, cetyltrimethylammonium bromide (CTAB), leading
to the desired product in 96% yield. Zou, Tang and co-workers used O,N-chelate-stabilized diarylborinates S3 (Figure [1]) as reactants for SM coupling reactions. They used a mixture of Pd(OAc)2/IPr/P(OPh)3 in a 1:1:5 ratio as a catalyst precursor (Pd: 0.1 mol%).[11] The reactions of electron-rich or electron-deficient aryl chlorides and diarylborinates
afforded the corresponding products in 70–99% yield, indicating that the reaction
was less sensitive to electronic variation on the benzene rings. Unfortunately, the
chemical yield decreased because of steric hindrance in the substrates. For example,
the reactions of 2-chlorotoluene and 2,6-dimethylchlorobenzene with diphenylborinate
afforded biaryl compounds in 72 and 42% yields, respectively, with 1 mol% of the catalyst.
Yu et al. reported SM couplings by using Pd(OAc)2 (0.02 mol%) and ligand L1 (0.04 mol%) in toluene/i-PrOH/H2O.[12] Heterocyclic aryl chlorides such as 2-chloropyridine, 3-chloropyridine, and 2-chloropyrazine
were converted into the desired products in yields of 84–95%. The intermediate 16 for the synthesis of boscalid was produced in 91% yield via a SM reaction, and the
TON of the catalyst reached 4550 (Scheme [5]). Ren, Young, and Lang used N-diphenylphosphanyl-2-aminopyridine (L2) as a ligand and PdCl2 (1.5 mol%) for the palladium-catalyzed SM cross-couplings of aryl chlorides.[13] This reaction was applied to electron-deficient aryl chlorides only, while the products
were obtained in up to 98% yield. Reddy et al. developed a zwitterionic Pd(II) complex
C4 (0.5 mol%) and utilized it for SM couplings of aryl or heteroaryl chlorides,[14] where triphenylphosphine (PPh3) (2 mol%) was used as an additional ligand. The reactions of multiple heterocyclic
aryl chlorides, including pyridine, pyrazine, quinoline, isoquinoline, and thiophene,
afforded cross-coupling products 17–24 in yields of 80–95% (Scheme [6]).
Scheme 4 Synthesis of antimicrobial compounds
Scheme 5 Synthesis of an intermediate for the preparation of boscalid
Scheme 6 SM couplings of heteroaryl chlorides
The SM coupling of chlorobenzene and phenylboronic acid using a pyridylformidine-based
Pd(II)-complex C5 proceeded quantitatively in water at 100 °C.[15] The addition of TBAB was essential for facilitating this reaction. The reactions
of chlorobenzene, 4-chlorophenol, and 4-chloroaniline afforded the corresponding products
in quantitative yields (three examples). Ji et al. reported the one-pot Miyaura borylation
and SM coupling at room temperature.[16] They used XPhos-Pd-G2 (C6) (0.5 mol%) and XPhos (0.5 mol%) as the metal source and the ligand, respectively.
The reactions of electron-rich and electron-deficient aryl chlorides with arylboronic
acids produced the coupled products in 56–96% yield. Heteroaryl chlorides and heteroarylboronic
acids were tolerated in the reaction. Similarly, Ma et al. reported another one-pot
Miyaura borylation and SM coupling using Pd(OAc)2/Gorlos-Phos, with product yields of up to 95%.[17] Liu, Huang, Wang and co-workers reported the diamine-based palladium complex C7.[18] The use of 0.05 mol% of C7 led to yields of up to 96% in SM reactions. Unfortunately, the reactions of heteroaryl
chlorides and sterically hindered aryl chlorides failed to produce the coupling products.
The authors detected Pd0, PdII, and PdIV species using XPS. Thus, they proposed two simultaneous reaction pathways: conventional
Pd0/PdII and PdII/PdIV catalysis (Scheme [7]). In addition, they confirmed the possibility of a PdII/PdIV catalytic pathway using DFT studies, which suggested that transmetalation was the
rate-determining step in this catalytic cycle. Schmidt et al. reported that the oxidative
addition of aryl chlorides to ligand-free Pd species was a reversible process.[19] Thus, under ligand-free conditions, oxidative addition was not the rate-determining
step. In 2020, Zeng and Liu reported the NHC-Pd(II)-azole complex C8 as a pre-catalyst for the SM reaction.[20] The reaction using sterically hindered 2,6-dimethylchlorobenzene with different
arylboronic acids afforded the corresponding products in 78–98% yield. This reaction
tolerated steric hindrance but did not tolerate heteroaryl chlorides. The monophosphine
ligand WK-phos was reported by Kwong et al.[21] Using this WK-phos ligand and Pd(OAc)2, the palladium loading was reduced to 10 mol ppm without dropping the reaction yield
(>99%), with a TON of up to 100,000. Electron-rich and electron-deficient aryl chlorides
were tolerated under these conditions. Yet et al. prepared 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligand L3 and utilized it with Pd(OAc)2 (2.5 mol%) for SM reactions.[22] They obtained yields of up to 92% of the desired biaryl derivatives.
Scheme 7 A PdII/PdIV catalytic cycle for SM reactions
Niwa and Uetake have reported a Lewis acid assisted SM coupling under base-free conditions.[23] In the conventional SM coupling, a base facilitates the transmetalation step. Thus,
a base-free SM coupling of aryl chlorides is unique.[24] The base-free SM coupling is mainly reported with a cationic organopalladium(II)
intermediate, which is thermally unstable and limits the applications.[25] The role of the Lewis acid is to mask and stabilize the cationic intermediate. Zinc
complex 29, which is used as a Lewis acid, interacts with palladium complex 28 to produce 28′ (Scheme [8]). The palladium intermediate 28′ underwent transmetalation with borates. Although the authors mainly focused on the
reactivity of aryl bromides, they also showed that the reaction of aryl chlorides
afforded the corresponding products in up to 86% yield.
Scheme 8 Activation of a Pd species for base-free Lewis acid mediated SM reactions
The N-hydroxyethylpyrrolidone (HEP) (31) promoted reduction of a Pd(II) complex was reported by Fanatoni and Carbi.[26] The proposed mechanism for HEP-promoted Pd0 formation from PdII is shown in Scheme [9]. This Pd0 species efficiently catalyzed the SM coupling to produce products in yields of up
to 95%. In this study, PdCl2(MeCN)2 (0.05 mol%) and sSPhos (0.15 mol%) were used as the metal and the ligand, respectively.
Leyva-Peréz et al. introduced an indomuscone-based sterically encumbered phosphine
ligand L4 for the Pd-catalyzed SM reaction.[27] The use of Pd(OAc)2 (2.5 mol%) and L4 (5 mol%) provided biaryl derivatives in up to 80% yield. In 2021, Schaub et al. reported
a Pd(OAc)2 (50 ppm)-catalyzed SM coupling of aryl chlorides and arylboronic acids in water.[28] As the ligand, they used P(tBu)Cy2 (0.02 mol%), and the corresponding products were obtained in up to quantitative yield.
Additionally, they synthesized several industrially important fungicides, such as
boscalid, fluxapyroxad, and bixafen. In this reaction, they achieved a TON of up to
20,000 and a TOF of 2,000 h–1. Denmark et al. reported that the transmetalation of arylboronic esters was faster
than that of arylboronic acids.[29a] They reported the SM coupling of arylboronic esters with aryl halides in the presence
of C9 (2 mol%). They used potassium trimethylsilanolate (TMSOK) as the base, and the reaction
was performed at 23 °C. The reactions of aryl chlorides with aryl neopentyl esters
afforded the products in up to 91% yield. The same group also reported a pre-transmetalation
Pd–O–B intermediate 38, which they called a missing link.[29b] This intermediate was formed before the transmetalation step, as shown in Scheme
[10].
Scheme 9 HEP-promoted reduction of a Pd(II) complex
Scheme 10 A pre-transmetalation Pd–O–B intermediate: a missing link
A microwave-assisted regioselective SM coupling of 1,4-dihydropyridines and aryl/heteroarylboronic
acids using Pd(PPh3)4 (0.5 mol%) was reported by Sova et al.[30] The reaction was completed within 15 minutes under microwave irradiation conditions
at 100 °C. This reaction afforded C4-substituted pyrimidines. The products 43 and 44 were obtained with a selectivity of 9:1 and an overall yield of 72% (Scheme [11]). McIntosh and Mansell reported the SM cross-couplings of aryl chlorides and arylboronic
acids at room temperature using the Pd(II) complex C10 (1 mol%) and monoanionic [N,O] ligands.[31] The authors observed that the rate of the reaction increased significantly on increasing
the reaction temperature. They proposed that the decomposition of C10 at higher temperatures resulted in the generation of active Pd nanoparticles, which
accelerated the reaction rate.
Scheme 11 C4-selective SM reactions
Lee et al. developed a xylyl-linked bis-benzimidazolium-based palladium complex C11.[32] Using 1 mol% of C11, biaryl derivatives were obtained in up to 97% yield. While the reaction was mainly
limited to electron-deficient aryl chlorides, 2-methylchlorobenzene and phenylboronic
acid afforded 2-methylbiphenyl in 95% yield, whereas 3- and 4-chlorobenzene afforded
27% and 17% yields, respectively.
In summary, significant progress has been made during the last decades, which includes
base-free SM couplings and the discovery of pre-transmetalation intermediates. Additionally,
researchers have shown that the choice of ligand (electron-rich) and base (to prevent
substrate decomposition) are crucial for SM reactions of aryl/heteroaryl chlorides.
2.2
Heterogeneous Palladium Catalysis
Sureshbabu et al. reported SM couplings catalyzed by poly(vinyl chloride) (PVC)-supported
palladium nanoparticles at room temperature.[33] They obtained biaryls in up to 99% yield using 1 mol% of Pd. The catalyst was recycled
four times in the reaction, and the yield decreased from 99% to 90% during the fourth
reuse. ICP-OES analysis suggested that the Pd loading decreased during recycling.
The Pd loading after the fourth reuse was 11.81%, whereas the original loading (fresh
catalyst) was 13%. Mohammadpoor-Baltork and Mirkhani developed a nano-silica triazine
dendritic polymer (nSTDP) supported palladium complex (Pd-nSTDP) (Figure [3]).[34] Using this Pd-nSTDP complex (60 mol ppm), up to 96% coupling yields were obtained
under microwave irradiation. Although the authors mainly focused on the reactions
of aryl bromides and iodides, they found that the reactions of chlorobenzene, 4-chloroacetophenone,
and 4-chlorobenzaldehyde with phenylboronic acid proceeded in up to 94% yield. The
recyclability of the catalyst was investigated in a reaction using an aryl bromide
as the substrate. During catalyst recycling, 2% Pd leaching was observed.
Figure 3 Pd complexes and ligands used for heterogeneous palladium-catalyzed SM reactions
Metin and Sun prepared bimetallic Ni/Pd core/shell nanoparticles supported on graphene
(G-Ni/Pd).[35] They performed SM cross-couplings of aryl chlorides and heteroaryl chlorides with
phenylboronic acid to afford the desired products in up to 96% yield by using 0.91
mol% of Pd. A catalyst reusability test was performed for the reaction of an aryl
iodide, revealing no loss of catalytic activity after the fifth reuse. TEM observations
showed that there were no changes in the nanoparticle morphology, and ICP-AES analysis
indicated no change in the Ni/Pd composition after the SM coupling reaction. Firouzabadi
et al. have reported phosphinite-functionalized clay-composite-stabilized Pd nanoparticles.[36] In their studies, the cross-coupling of chlorobenzene and phenylboronic acid proceeded
with 720 mol ppm of Pd (from the clay composite) in water to give an 88% yield of
biphenyl at 80 °C. The SM couplings of 4-chloronitrobenzene and 4-chlorotoluene with
phenylboronic acid also proceeded successfully. Inductively coupled plasma (ICP) analysis
suggested a 7% loss of Pd in the recovered catalyst.
Sawamura et al. developed a silica-supported triptycene-type phosphine (Silica-TRIP)
(L5) (Figure [3]).[37] The authors used this Silica-TRIP as a ligand (0.5 mol%) for the SM coupling of
aryl chlorides using PdCl2(py)2 as a metal source (0.5 mol%). While the reaction using in situ generated PdCl2(py)2/L5 provided a 5% yield of the biaryl product, pre-complexed PdCl2(py)2/L5 gave a 56% yield. The yield further improved to 93% when the metal source was changed
from PdCl2(py)2 to Pd(OAc)2. The recovered Pd(OAc)2/L5 catalytic system afforded the product in 28% yield on the second run and in 3% yield
on the third run. The authors proposed that Pd leaching occurred because of the moderate
coordination ability of the phosphine center of L5. In 2015, an interesting discovery by Lipshutz et al. was reported, where they found
that FeCl3, which contained Pd as a contaminating metal species, promotes SM reactions.[38] They used FeCl3 (5 mol%, 97% purity), in which 300–350 ppm of Pd contamination was detected by ICP
analysis. Grignard reagents (MeMgCl) (10 mol%) were added to prepare the Pd nanoparticles
(Fe-ppm-Pd). Without the Grignard treatment, SM coupling did not proceed. In addition,
Fe is essential for this transformation. The choice of the ligand was also crucial,
as SPhos or XPhos were the only ligands that promoted this reaction. The reactions
of aryl chlorides with the commercially available surfactant TPGS-750-M in water afforded
the corresponding products in 85% yield. A reusability test was performed with a more
reactive aryl bromide; however, a loss in reactivity was observed: the yield dropped
to 87% in the fourth run while the yield was 95% in the first run using fresh catalyst.
Andrés and Flores developed the silica-supported bis-(NHC) complex C16 containing palladium (Figure [3]).[39] This palladium catalyst was immobilized on γ-Fe2O3 and provided an 89% yield of the product in the reaction of 4-chlorotoluene and phenylboronic
acid using 0.024 mol% of Pd. The catalyst was magnetically recovered after the reaction.
However, the catalyst exhibited a gradual decrease in yield, and Pd leaching from
the catalyst was observed. ICP-MS analysis showed 10 ppm of Pd contamination in the
product. Li and Chen reported a Pd and Co bimetallic hybrid nanocrystal (Pd-Co3[Co(CN)6]2) with a Pd/Co ratio of 3:1.[40] This nanocrystal (0.45 mol% Pd) afforded biphenyl in 86% yield. The catalyst was
recovered and reused eight times. The Pd content of the solution after the first and
fifth cycles was less than 100 ppb, whilst the Pd-to-Co ratio remained unchanged after
the reaction.
Friedrich et al. prepared PdCuCeO by substituting Pd2+ and Cu2+ in the CeO2 lattice.[41] PdCuCeO as a catalyst promoted the SM reaction in the presence of tetrapropylammonium
bromide (TPAB). SM coupling of electron-deficient aryl chlorides using 2.3 mol% Pd
proceeded to provide the products in quantitative yields. However, this catalyst failed
to cross-couple arylboronic acids with electron-rich aryl chlorides. Sajiki et al.
developed an anatase-type TiO2-supported Pd catalyst, Pd/TiO2.[42] The SM coupling of an electron-deficient aryl chloride proceeded with the Pd/TiO2 (5 mol%) catalyst to give the product in 98% yield. Electron-rich aryl chlorides
were not tolerated under these conditions. The products and reaction mixture showed
traces of Pd contamination, and the catalyst was not reusable. The authors suggested
that this was likely due to catalyst deactivation. SM coupling of aryl chlorides using
glass-supported palladium nanoparticles (SGIPd) (0.35 mol%) under microwave irradiation
was reported by Arisawa et al.[43] In this reaction, the TON reached 28,571, and the TOF reached 1,120 h–1. The catalyst was used 10 times, and the yield dropped to 90% on the tenth use from
98% on its first use. Electron-rich, electron-deficient, and heteroaryl chlorides
reacted to yield the corresponding products in up to 98% yield.
Motokura et al. observed the unexpected formation of triphenylborane (Ph3B) during a palladium-catalyzed SM coupling reaction using a mesoporous silica-supported
Pd complex catalyst Pd/MS.[44] Ph3B is an active intermediate in the SM coupling of aryl chlorides and phenylboronic
acids. Meanwhile, Bai et al. reported an effective photothermal dual-responsive Pd1Cu4/CexOy catalyst (1 mg/mmol substrate).[45] The SM reactions of aryl chlorides and arylboronic acids with this catalyst proceeded
under thermal heating at 70 °C. Additionally, SM cross-coupling proceeded under visible-light
irradiation at room temperature to afford biaryls in up to 99% yield. The catalyst
was reused five times with a gradual loss of catalytic activity. Phan and Zhang have
reported graphene oxide supported palladium-nanoparticle-catalyzed (Pd/rGO-60) (0.5
mol%) SM coupling in water under microwave irradiation.[46] The reactions of electron-rich and electron-deficient aryl chlorides afforded the
products in up to 95% yield. Microwave irradiation reduced the reaction time from
20 hours to 2.5 hours, and the presence of tetrabutylammonium bromide (TBAB) was essential
in this reaction. Abdellah and Huc developed a palladium PEPPSI-IPr complex supported
on calix[8]arene C13 (0.2 mol% to 1 mol%) (Figure [3]).[47] The cross-coupling reactions of electron-rich and electron-deficient aryl chlorides
and heteroaryl chlorides proceeded to give the products in up to 98% yield. ICP-MS
analysis of the reaction solution showed trace amounts of Pd contamination, indicating
the heterogeneous nature of the catalyst.
We developed a convoluted poly(4-vinylpyridine)-supported palladium catalyst, P4VP-Pd
(C17) (Figure [3]),[48a] using our molecular convolution method.[48] P4VP-Pd showed high catalytic activity (up to 99% yield), even at a 40 ppm level,
toward the SM coupling of aryl chlorides and arylboronic acids in water. Electron-rich
and electron-deficient heteroaryl chlorides were tolerated by this P4VP-Pd catalyst.
Interestingly, the non-steroidal anti-inflammatory drug fenbufen (46) was directly synthesized using P4VP-Pd catalysis (Scheme [12]). The catalyst was recovered and reused without a significant loss of catalytic
activity, with a 92% yield on the first use and a 91% yield on the fourth use. No
Pd contamination was observed in the reaction mixture during ICP-MS analysis. We also
developed a convoluted poly(meta-phenylene oxide) palladium catalyst, Pd@poly(mPO)n (C18),[48e] with a 400 ppb Pd loading, which enabled SM coupling in water. The TON and TOF reached
1,900,000 and 95,000 h–1, respectively.
Scheme 12 Synthesis of the anti-inflammatory drug fenbufen
Farinola et al. utilized a silk-fibroin-supported palladium catalyst (Pd/SF) for the
SM coupling of aryl chlorides.[49a] The reaction of chlorobenzene and 4-methoxybenzoic acid took place in the presence
of Pd/SF with 3.8 mol% Pd over 3 hours in aqueous ethanol to give the product quantitatively.
The authors reused the catalyst 25 times in the reaction of an aryl iodide.[49b] After the twenty-fifth reuse, the biaryl product was obtained in 42% yield. The
authors proposed that palladium cluster formation segregates catalytically active
metal atoms. In 2022, Wang and Liu reported SM coupling reactions using a Pd-PEPPSI-embedded
conjugated microporous polymer-supported complex, Pd-PEPPSI-CMP (C12) (Figure [3]).[50] A catalyst reusability test showed a gradual catalytic activity loss until the third
reuse (the yield changed from 96% to 91%), followed by a sudden decrease to 56% during
the fourth reuse. Wu and Chen reported flow-through SM coupling using a Pd-loaded
functionalized ceramic membrane C14 (1.9 mol% Pd).[51] The catalyst showed no significant loss of catalytic activity until the fifth reuse.
Nakajima et al. reported SM couplings using a Pd catalyst supported on phosphine periodic
mesoporous organosilica L6.[52] They used Pd(dba)2 (2.5 mol% Pd) as the transition-metal source. Under these conditions, the SM reaction
using 4-chlorophenol and 4-(mercapto)chlorobenzene as substrates did not proceed.
Dai and Sun reported a porous supramolecular-assembled palladium catalyst that was
utilized for SM reactions of aryl chlorides.[53] Irrespective of the steric and electronic nature of the aryl chloride, the reactions
provided quantitative yields of products by utilizing 0.5 mol% of Pd. ICP-MS analysis
showed that the reaction mixture contained less than 0.1 ppb Pd, which indicated that
the Pd catalyst is stable and that leaching of Pd does not occur. The catalyst was
reused five times, affording the product in 95% yield on the fifth reuse. Lee and
Joung reported an ordered mesoporous polymeric phosphine (Meso-PPh2)-supported palladium catalyst C15 (Figure [3]).[54] The reaction of electron-deficient aryl chlorides using 4 mol% of C15 afforded the products in up to 93% yield. The reactions of electron-rich aryl chlorides
produced biaryls in 19–43% yield. Catalyst C15 was not reusable, and inactive palladium black formation was observed in the recovered
catalyst by TEM. In addition, Pd leaching was observed.
In summary, there are multiple reports of heterogeneous palladium-catalyzed SM reactions
of aryl chlorides. However, in most of these reports, either palladium leaching or
deactivation of the palladium catalyst was observed. A convoluted polymer-supported
palladium catalyst might be helpful for this purpose.
2.3
Homogeneous Nickel Catalysis
Since the Suzuki–Miyaura coupling is the reaction of organic halides (and their equivalents)
with organic boronic acids (and their equivalents) using Pd catalysts, the reaction
using Ni catalysts should be described as a Suzuki–Miyaura-type reaction (coupling).
To simplify the description, we also use the term ‘SM reaction (SM coupling)’ for
the Ni-catalyzed reactions described herein.
In 2013, Garg et al. reported nickel-catalyzed SM couplings in t-amyl alcohol or 2-Me-THF as green solvents.[55] The SM coupling of 3-chloropyridine and phenylboronic acid proceeded quantitatively
using NiCl2(PCy3)2 (1–5 mol%). Several heteroarylboronic acids were converted into the corresponding
products in 81–98% yield (Scheme [13]). In the same year, Lei et al. reported the SM reaction of aryl chlorides using
the Ni(II) σ-aryl complex C20 (Figure [4]).[56] The SM coupling proceeded with 5 mol% of C20 and 10 mol% of PPh3. Although the reactions of electron-rich 4-chlorotoluene and 4-chloroanisole with
phenylboronic acid gave the corresponding products in 97% and 86% yields, respectively,
those of electron-deficient 4-chloronitrobenzene and phenylboronic acid did not proceed
at all. Additionally, electron-deficient arylboronic acids or heteroarylboronic acids
were not suitable for this reaction (trace to 8% yields).
Scheme 13 Nickel-catalyzed SM reactions of heteroaryl chlorides and heteroarylboronic acids
in green solvents. a 5 mol% NiCl2(PCy3)2.
Figure 4 Nickel complexes and surfactants used in heterogeneous nickel-catalyzed SM reactions
In 2014, Zou et al. reported the SM coupling of aryl chlorides with diarylborinic
acids S5 using NiCl2[(4-MeOC6H4)3P]2 (5 mol%).[57] Interestingly, in this reaction, a chloride moiety selectively underwent the SM
coupling with the diarylborinic acid in the presence of a tosylate (Scheme [14]). Additionally, the same authors synthesized 2-cyanobiphenyl (55), a key intermediate for the synthesis of a sartan (a medicine for hypertension),
on a scale of ca. 24 g (Scheme [15]).
Scheme 14 Aryl chloride selective nickel-catalyzed SM reactions
Scheme 15 Synthesis of a biphenyl sartan on gram scale
In 2021, Nelson et al. reported the SM coupling of 3- and 4-chloropyridines using
Ni(cod)(dppf).[58] They also found that 2-chloropyridine underwent dimerization (Scheme [16]). A similar dimerization proceeded in the reaction of α-halo-N-heterocycles (2-chloropyridine, 2-chloroquinoline). Dimeric nickel complex 57 was inactive in the SM reactions. Meanwhile, Kumar et al. reported the SM coupling
reaction of aryl halides using NiBr2 (8 mol%) as the catalyst.[59] Although their method provided yields of up to 92% with aryl bromides and iodides,
it only provided yields of up to 42% with aryl chlorides. Doyle et al. have reported
comparison studies of monophosphine and bisphosphine ligands for the Ni-catalyzed
SM reactions of aryl chlorides (Scheme [17]).[60] Although bisphosphine-type ligands are typically used for nickel-catalyzed SM reactions,
the results suggested that monomeric phosphine ligands (e.g., CyTyrannoPhos) might
outperform bisphosphine ligands depending on the nature of the substrates. They proposed
that monophosphine ligands enabled challenging oxidative addition and transmetalation
steps, whereas bisphosphine ligands prevented off-cycle reactivity and catalyst deactivation.
Scheme 16 Dimeric nickel-complex formation, which inhibits the SM coupling of 2-chloropyridine
Scheme 17 Comparison of the reactivity of monophosphine and bisphosphine ligands
In summary, electron-rich and sterically hindered ligands are suitable for SM couplings
of aryl chlorides under homogeneous nickel catalysis.
2.4
Heterogeneous Nickel Catalysis
In 2015, Lipshutz et al. reported a nickel-nanoparticle-catalyzed SM reaction in water.[61] They used complex C19 (3 mol%) as the nickel source and performed SM coupling reactions in the presence
of TPGS-750-M as a surfactant (Figure [4]). They prepared Ni nanoparticles in situ by adding MeMgBr (3 mol%). ICP-MS analysis
of the isolated products revealed nickel contamination of less than or equal to 5
ppm. The authors mainly focused on aryl iodides, bromides, and triflates, but also
provided a few examples of aryl chlorides. Electron-rich, electron-deficient, and
heteroaryl chlorides provided the SM coupling products in up to 93% yield.
Scheme 18 Generation of a B–N ate complex
In 2017, Hajipour and Abolfathi developed chitosan-supported nickel nanoparticles
C22 (Figure [4]).[62] The SM couplings of electron-rich and electron-deficient aryl chlorides proceeded
well with 0.2 mol% of the catalyst and afforded the products in up to 87% yield. Catalyst
reusability tests were performed using aryl bromide substrates. A gradual decrease
in the yield of the SM reaction products was observed, and the reaction solution showed
only 0.04 ppm of nickel contamination. Cai et al. have developed a recyclable and
efficient NiCl2(dppp)/PEG-400 catalytic system for the SM reactions of aryl chlorides and arylboronic
acids.[63] Using a catalyst loading of 2 mol%, they obtained yields of up to 95% from electron-rich,
electron-deficient, and heteroaryl chlorides. The NiCl2(dppp)/PEG-400 system was recovered and reused 6 times. The yield of biaryl formation
was 92% on the sixth use, whereas the fresh catalytic reaction provided a 95% yield.
A nickel contamination test using ICP-MS showed only 0.8 ppm of nickel contamination
in the products. In 2020, we developed activator-promoted aryl-halide-dependent C–C
and C–N bond-forming reactions, where aryl chlorides led to C–C bond formation and
aryl iodides favored C–N bond formation.[64] This chemoselective reaction was catalyzed by NiI2 (0.5 mol%). The presence of an aryl amine as an activator was essential for SM coupling
between aryl chlorides and arylboronic acids, whilst the Ni species were stabilized
on the surface of the base (K3PO4). The SM couplings using this K3PO4-supported heterogeneous nickel species provided yields of up to 99%. 15N and 11B NMR studies suggested that a B–N ate complex was formed (Scheme [18]), which further underwent transmetalation to produce a C–C bond. Hot-filtration
tests revealed the heterogeneous nature of the catalyst, which was recovered and reused.
The yield of the SM coupling dropped to 89% when the recovered catalyst was used,
whereas the yield was 98% for the fresh catalyst. Y. Dong and Y.-B. Dong reported
a diimine-based nickel complex, C21,[65] which was utilized in the SM cross-coupling between chlorobenzene and phenylboronic
acid to provide biphenyl in 26% yield.
On utilizing these reported (2013–2024) heterogeneous nickel catalysts, leaching was
observed. Thus, further development of new, more stable, and reusable heterogeneous
nickel catalysts is still in demand for SM couplings of aryl chlorides.
3
Buchwald–Hartwig Amination Reactions
Since 1995,[66] the Buchwald–Hartwig amination (BHA) of aryl halides and pseudohalides has become
a fundamental tool for forming C–N bonds (Scheme [19]). Several natural products, pharmaceuticals, and agrochemicals containing nitrogen
heterocycles can be synthesized using BHA reactions.[2] Mechanistically, the BHA follows three significant steps: (i) oxidative addition,
(ii) ligand exchange or transmetalation, and (iii) reductive elimination (Scheme [20]). The rate-determining step usually varies among these three steps depending on
the reaction conditions, which include the transition metal, ligand, base, and additive.
Scheme 19 General scheme for the BHA reaction
Scheme 20 General catalytic cycle for the BHA reaction
3.1
Homogeneous Palladium Catalysis
In 2013, Buchwald et al. developed a new palladium complex, Xphos-Pd-G3 (C23) (Figure [5]), and applied it in SM and BHA reactions.[67a] In BHA reactions of aryl chlorides, 0.01–0.5 mol% of C23 was used, and product yields of up to 97% were observed. Electronic and steric variations
on the aryl chlorides had minimal effects on these reactions. In 2020, Buchwald developed
another Pd catalyst, GPhos-Pd-G6 (C24) for the BHA reaction.[67b] This Pd catalyst has unique features, such as the tBuO group improving the catalyst stability, the OMe group increasing the reaction
rate, and the free p-position of the diisopropyl-substituted benzene ring expanding the substrate scope.
Using this Pd complex (0.2–0.5 mol%), the authors performed the BHA reactions of base-sensitive
amines,[67c] electron-deficient amines, and electron-rich amines at room temperature. In 2017,
Yu et al. reported a Pd(dba)2/L8 catalyzed BHA reaction under solvent-free conditions. The reaction also proceeded
in an aqueous medium.[68] Under solvent-free conditions, several diarylamines were obtained in up to 89% yield
using Pd(dba)2 (1 mol%). Although the authors used L8 as the ligand, control experiments showed that XPhos and RuPhos produced similar
results. Li et al. synthesized a series of 3-arylbenzofuran-2-ylphosphines (e.g.,
L9) and applied them as ligands in BHA reactions.[69] The BHA reactions of aryl chlorides and primary, secondary, and aromatic amines
proceeded in the presence of Pd(OAc)2 (2.5 mol%) and L9 (7.5 mol%) to produce the C–N coupling products in yields of up to 90%. In 2021,
Hartwig et al. reported the BHA reactions of aryl chlorides and hydrazine using 800
mol ppm of Pd[P(o-tolyl)3]2 and CyPF-tBu (800 mol ppm) in the presence of KOH as the base.[70a] However, reactions using base-sensitive functional groups, such as ester- or amide-bearing
aryl chlorides, provided yields of only 45% and 56%, respectively. Hydrazine deprotonation
is the rate-determining step in this reaction. Furthermore, the same group reported
the BHA reactions of aryl chlorides and ammonium salts using the same catalytic system.[70b]
Figure 5 Pd complexes and ligands used for C–N bond-forming BHA reactions under homogeneous
palladium catalysis
Xu et al. have reported a dianisole-containing Pd-NHC complex, Pd-PEPPSI-IPrOMe (C25) (Figure [5]), for BHA reactions.[71] Although the BHA reactions of electron-rich aryl chlorides and primary, secondary,
and aryl amines using C25 (0.1 mol%) proceeded to provide yields of 54–98%, the same reaction with electron-deficient
aryl chlorides did not occur. Gevorgyan et al. performed BHA reactions in lipids and
lipid impurities under XPhos-Pd-G3 (C23) (2 mol%) catalysis and obtained diarylamines from aryl chlorides in up to 99% yield.[72] Qiu and co-workers have reported a solvent-free BHA reaction using an NHC-Pd complex
[(SIPr)Ph2Pd(cin)Cl (C26)] at room temperature.[73] The presence of two phenyl rings on the backbone of the NHC ligand is thought to
be essential, according to the reported control experiments. The authors proposed
that the electron-donating ability and steric hindrance created by these phenyl groups
increases the catalytic activity. Several sterically challenging diaryl amines were
obtained under these solvent-free conditions using a Pd loading of 0.05–3 mol% (Scheme
[21]). They also synthesized the commercial pharmaceutical piribedil (69) directly from a heteroaryl chloride (Scheme [22]).
Scheme 21 Synthesis of sterically and electronically challenging aryl amines
Scheme 22 Synthesis of the commercial pharmaceutical piribedil under solvent-free conditions
Recently, Yet et al. reported a BHA reaction using Pd(OAc)2 (2.5 mol%) and JagPhos II (L11) (5 mol%).[74] The reaction using aryl amines and secondary amines with aryl chlorides provided
BHA products in 7–98% yields, but in general, primary and benzylic amines provided
poor yields (2–27%). A super bulky mesoionic carbene (S-iMIC, ‘i’ represents the 1,3-imidazole
unit) (Figure [5]) was reported by the Ghadwal et al.[75] They utilized this super bulky mesoionic carbene in BHA-type reactions between tolyl
chlorides and morpholines in the presence of Pd(OAc)2 (2.5 mol%). Reactions using the S-iMIC ligand produced C–N coupling products in up
to 99% yield, whereas reactions using IPr or iMIC as ligands produced yields of only
7% and 9%, respectively.
In summary, the use of bulky ligands in homogeneous palladium catalysis appears beneficial
for the C–N bond-forming BHA reactions of aryl chlorides.
3.2
Heterogeneous Palladium Catalysis
In 2021, Sobhani et al. reported a Pd-Co bimetallic alloy encapsulated in a melamine-based
dendrimer supported on magnetically active γ-Fe2O3 that was named γ-Fe2O3@MBD/Pd-Co.[76] ICP-MS analysis suggested that the bimetallic alloy contains 0.75 and 3.15 mmol
of Pd and Co, respectively, per kg of the catalyst. The Pd:Co molar ratio was 1:4.2.
Using this bimetallic alloy as the catalyst (500 mol ppm Pd) for the BHA reaction
between chlorobenzenes and aryl amines, biaryl amines were obtained in up to 91% yield.
The authors also applied this bimetallic catalyst to the Mizoroki–Heck reaction and
examined the catalyst reusability for that reaction only. In 2024, Lipshutz et al.
reported a BippyPhos-ligand-assisted Pd-catalyzed BHA reaction of aryl chlorides and
aliphatic amines under micellar conditions.[77] They used [Pd(crotyl)Cl]2 as the metal source with a 0.25 mol% Pd loading. In addition, the BippyPhos ligand
(L10) (2 mol%) (see Figure [5]) was used along with 2 wt% Savie/water (0.5 M) to generate micelles. BHA reactions
using primary, secondary, and benzylic amines produced products containing newly formed
C–N bonds in 55–99% yields. The catalyst was recovered and recycled three times. The
yield of the BHA decreased from 98% to 90% on the third reuse. ICP-MS analysis of
the BHA product showed only 0.78 ppm of Pd contamination.
In summary, only a few reports on this topic have been published within the time frame
(2013–2024) of this short review. Thus, there is still a demand for highly active
and reusable heterogeneous palladium catalysts for the BHA reactions of aryl chlorides.
3.3
Homogeneous Nickel Catalysis
In 1997, Buchwald et al. reported a nickel-catalyzed BHA reaction of aryl chlorides
and amines where they used Ni(COD)2 as a transition-metal source.[78a] In continuation of previous work, in 2014, Buchwald prepared a new air-stable nickel
catalyst named (dppf)Ni(o-tolyl)Cl (C31) (Figure [6]).[78b] They used this nickel complex (5 mol%) for the BHA reaction of aryl chlorides at
100 °C. The aminations of aliphatic secondary amines and aryl amines afforded products
in up to 98% yield. Amination using a secondary aryl amine required an increased catalyst
loading (10 mol%) and an increased reaction temperature (130 °C). In 2015, Stradiotto
et al. reported a nickel-catalyzed monoarylation of ammonia using Ni(COD)2/JosiPhos.[79] Hartwig et al. reported a (BINAP)Ni(η
2-NCPh) catalyst (C30) for the BHA reactions of primary amines and aryl chlorides.[80a] The use of this BINAP-supported nickel catalyst (1 mol%) provided yields of up to
96% and was highly selective for primary amines. If the substrate contained both primary
and secondary amines, then only the primary amines reacted, leaving the secondary
amines intact. The same group also reported the BHA reaction of ammonia.[80b] They prepared the new nickel complex C29 by combining Ni(COD)2, JosiPhos, and benzonitrile (PhCN), which they used with 2–4 mol% loading for the
coupling of ammonia or ammonium sulfate with aryl chlorides to produce primary aryl
amines in yields of up to 58–84%. In general, ammonia performed better than (NH4)2SO4. In addition, ammonia, methylamine hydrochloride (MeNH3Cl), and ethylamine hydrochloride (EtNH3Cl) were reacted with aryl chlorides, resulting in the production of secondary aryl
amines in yields of 52–99%.
Figure 6 Ligands and nickel complexes used for homogeneous nickel-catalyzed BHA reactions
In 2015, Monfette and Magano prepared the tetramethylethylenediamine (TMEDA)-ligated
nickel complex C27 (Figure [6]).[81] This complex was not air- or moisture-sensitive and was easily prepared on multigram
scale. Using nickel complex C27 (5 mol%), the cross-coupling of morpholine and electron-deficient aryl chlorides
afforded the desired amination products in up to 91% yield. In the same year, Doyle
et al. prepared the same catalyst independently and applied it to SM and BHA reactions.[82] Unlike Monfette who used Ni(cod)2 for the synthesis of C27, Doyle used Ni(acac)2 and Al(OEt)Me2. In the field of nickel-catalyzed BHA reactions, the Stradiotto group has made major
contributions over recent decades.[83] They developed a series of DalPhos ligands, including Pad-DalPhos,[83b] NHP-DalPhos,[83c] PhPAd-DalPhos,[83g] PAd2-DalPhos,[83e] and Phen-DalPhos,[83f] for nickel-catalyzed BHA reactions (Figure [6]). They also compared the reactivities of Ni(I) (PAd-NiI) and Ni(II) (PAd-NiII) complexes for the BHA reactions of aryl chlorides.[83a] Using their DalPhos-type ligand, the Ni(II) complex generally performs better than
the Ni(I) complex. A computational study suggested that reductive elimination was
the rate-limiting step in the Ni(0)/Ni(II) catalytic cycle. Meanwhile, oxidative addition
is the rate-limiting step in the Ni(I)/Ni(III) catalytic system. The same authors
also reported ligand-enabled site-selective reactions (Scheme [23]). The reaction using Phen-DalPhos as the ligand promoted the amination of indoles
to provide products 72, whereas that using PAd2-DalPhos promoted the amination of anilines to produce compounds
73. Interestingly, Baran et al. have reported BHA reactions using electrochemistry.[84] This electrochemical reaction utilized an RVC anode and a nickel foam cathode, with
LiBr (4 mol equiv) being used as the electrolyte. They used NiBr2·glyme complex (10 mol%) as the nickel source. Although they mainly focused on aryl
bromides, they also showed that electron-deficient aryl chlorides were tolerated (up
to 73% yield) in BHA reactions under these conditions.
Scheme 23 Ligand-enabled site-selective BHA reactions
In 2020, Engle et al. reported an air-stable 18-electron nickel(0)-olefin complex
named Ni(cod)(dq) that catalyzed BHA and SM reactions.[85] This catalyst was prepared on an 8 g scale in 79% yield. This Ni(cod)(dq) complex
was initially reported by Schrauzer in 1962.[86] Engle et al. applied Ni(cod)(dq) in cross-coupling reactions and compared its reactivity
with that of Ni(cod)2. The Ni(cod)(dq) complex (5 mol%) showed improved reactivity toward aryl chlorides
(BHA reaction); however, in the case of heteroaryl chlorides, Ni(cod)2 performed better. In the same year, Cornella and Nattmann reported a 16-electron-nickel(0)-olefin
complex (C28) derived from trans-stilbene (Figure [6]).[87] The tBu substituent increased the thermal stability of this complex. The authors claimed
that complex C28 could be stored open to air at room temperature for at least 1 month. The BHA reactions
of aryl chlorides and amines using this nickel complex provided the amination products
in up to 90% yield, whereas Ni(cod)2 provided the products in up to 96% yield. In 2021, we used a machine-learning approach
to find suitable reaction conditions for the BHA reactions of tolyl chloride and toluidine
under nickel(II) catalysis.[88] This approach suggested that a combination of Ni(acac)2 and XPhos would provide the maximum yield (35%), and laboratory experiments showed
this to be the case with a 33% yield being obtained under the proposed conditions.
A C–N bond-forming amination via kinetic resolution enabled by flexible and bulky
chiral ligands was reported by Hong and Shi (Scheme [24]).[89] As a chiral ligand, they used (R,R,R,R)-ANIPE (1.5 mol%) in the presence of Ni(cod)2 (1.5 mol%). Multiple sterically hindered α-branched amines successfully underwent
amination with ee values of up to 99.5%. Computational studies suggested that the
oxidative addition had an energy barrier of 8.9 kcal/mol, whereas the reductive elimination
had an energy barrier of 14.7 kcal/mol. The transmetalation had an energy barrier
of 14.0 kcal/mol. Thus, reductive elimination is the rate-determining step as well
as the enantioselectivity-determining step. Computational studies also suggested that
the Ni(I)/Ni(III) catalytic cycle is unlikely to occur because of the high energy
barrier. Hernandez, Garlets, and Frantz used a dual-base approach for BHA reactions
to overcome functional group compatibility issues in the presence of strong alkoxide-type
bases.[90] Alkoxide bases are poorly soluble and challenging to utilize in large-scale reactions.
The authors collaborated with industry and academia to develop a general method that
could be applied to heteroaryl chlorides and amines (both aliphatic and aromatic).
They found that the reaction using a combination of NaOTf (1.5 mol equiv) and BTMG
(1.5 mol equiv) enabled the amination of several heteroaryl and aryl chlorides in
up to 99% yield (Scheme [25]). They also performed a 20-gram-scale reaction of amine 79, which is found in the TYK2 inhibitor deucravacitinib, to obtain coupling product
81 in 99% yield (Scheme [25]). Ananikov et al. have developed NiCl2Py2 (10 mol%)- and IPr (20 mol%)-catalyzed BHA reactions of aryl chlorides and amines
to obtain N-arylation products in yields of 14–95%.[91] Meanwhile, Xue et al. utilized purple LED light (390–395 nm) for nickel-catalyzed
BHA reactions.[92] They used Ni(OAc)2 (10 mol%) and dMeppy (10 mol%) for C–N bond-forming cross-couplings of aryl chlorides
with ammonium bromide (NH4Br),[92a] aliphatic amines,[92b] and hydrazine.[92c] Recently, Xue used the Warner salt ([Ni(NH3)6]Cl2) as a catalyst for the BHA reactions of aqueous ammonia.[92d] Irradiation with purple LED light generates a Ni(I)-OAc complex via the formation
of an acetate radical, and the reaction subsequently follows a Ni(I)/Ni(III) catalytic
pathway (Scheme [26]). These visible-light-promoted photocatalyst-free nickel-catalyzed reactions are
limited to ammonia and primary and secondary amines. Lin et al. reported nickel-catalyzed
C–N cross-couplings of aryl chlorides and aryl amines promoted by sodium iodide under
visible-light irradiation (455 nm).[4] The light irradiation generated a Ni(I) species via the formation of aryl radicals,
with halogen exchange being a critical step in this reaction (Scheme [27]). Control experiments suggested that the addition of NaI was essential. Although
the reaction provided yields of up to 99%, it was limited to electron-deficient aryl
chlorides. Furthermore, this reaction followed the Ni(I)/Ni(III) catalytic pathway.
Xue et al. also found that the addition of KI was beneficial for the BHA reactions
of aryl chlorides.[92b]
Scheme 24 Formation of C–N bonds via kinetic resolution
Scheme 25 Demonstration of the BHA reaction using a dual-base approach
Scheme 26 Mechanism of the purple-light-mediated nickel-catalyzed BHA reaction
Scheme 27 A plausible catalytic pathway for NaI-promoted nickel-catalyzed BHA reactions
MacMillan et al. have reported a ligand-free nickel-iridium dual-catalyzed BHA reaction
of aryl bromides.[93] They used NiCl2·glyme (5 mol%) and the iridium photocatalyst PC1 (Figure [7]). The main role of the Ir photocatalyst was to destabilize the nickel-amido intermediate
via single-electron transfer (SET) and facilitate reductive elimination (Scheme [28]). Additionally, the photocatalyst assisted in the in situ generation of the Ni(0)
species. Unfortunately, the BHA reaction of aryl chlorides did not proceed under these
reaction conditions due to the formation of catalytically inactive nickel black during
the reaction. Pieber et al. have reported nickel-catalyzed BHA reactions of aryl chlorides
by using CN-OA-m as a photocatalyst.[94] NiBr2·3H2O (5 mol%) was used as a nickel source. Using this NiBr2/CN-OA-m system, the BHA reactions of electron-deficient aryl chlorides were performed.
However, electron-rich aryl chlorides, such as the chloride of 4-methoxyanisole, coupled
with pyrrolidine in only 2% yield, even after 168 hours.
Figure 7 Photocatalysts used for BHA reactions
Scheme 28 Plausible mechanistic pathway for Ni/Ir dual catalyzed BHA reactions
Buchwald et al. reported a BHA reaction using nickel/ruthenium dual catalysis in flow
in the presence of photocatalyst PC2.[95] They obtained yields of 65–93% using electron-deficient aryl chlorides, whereas
the coupling between chlorobenzene and pyrrolidine provided only a 22% yield. In 2023,
Yasuran and Zhang reported nickel-catalyzed BHA reactions in the presence of an acetylene-based
hydrazone-linked covalent organic framework (AC-COF-1) (Figure [6]) and blue LED (440 nm) irradiation.[96] Like Peiber, they also used NiBr2·3H2O (7.5 mol%) as the nickel source. Using this Ni/AC-COF-1 dual-catalytic system, the
authors performed BHA reactions of electron-deficient and electron-rich aryl chlorides
and obtained product yields of up to 99%. In this study, pyrrolidine was used as the
only amine source.
In summary, the utilization of dual nickel-photocatalyst systems has proven to be
effective for BHA reactions of aryl chlorides. The use of electron-rich ligands in
nickel catalysis under photoredox-free conditions would represent an alternative pathway.
3.4
Heterogeneous Nickel Catalysis
Sawamura et al. reported a polystyrene-cross-linking bisphosphine (PS-DPPBz) (Figure
[8]) as a ligand for nickel-catalyzed amination reactions.[97] As a nickel source, they used Ni(cod)2 (1 mol%). The in situ generated polymer-supported nickel complex catalyzed the BHA
reactions of electron-deficient and electron-rich aryl chlorides and primary aliphatic
amines to produce the corresponding products in up to 97% yield. Hot-filtration and
mercury-poisoning experiments confirmed the heterogeneous nature of the catalysts.
The PS-DPPBz-Ni catalyst was recovered and reused. The catalytic activity decreased
to 73% in the third run compared to 90% in the first run, with ICP-AES analysis of
the reaction mixture confirming the leaching of Ni. There are a few reports on light-assisted
heterogeneous nickel-catalyzed BHA reactions of aryl halides.[98] Unfortunately, these reactions were restricted to aryl iodides and bromides. We
recently prepared the linear polymeric iridium photocatalyst PC3 (Figure [7]).[99] This newly developed polymeric iridium photocatalyst was used for the nickel-iridium
dual-catalyzed BHA reactions of aryl chlorides. As the nickel catalyst, we used poly(4-vinylpyridine)
(P4VP-NiCl2) (0.2 mol%), a convoluted polymeric nickel complex (Figure [8]). In this reaction, dual irradiation with visible light (430 nm) and microwaves
was essential. The addition of TBAB was also necessary for this reaction. Several
electron-rich and electron-deficient aryl chlorides (96–102) were used in this reaction to produce high to quantitative yields of the products
(Scheme [29]). Cyclic primary amines, cyclic secondary amines, linear primary amines, branched
primary amines, and aryl amines produced BHA reaction products 103–106 in yields of 43–91%. Molecules with antimalarial (107), anticancer, anti-HIV (108), and antiviral (109) properties were synthesized under these conditions. The polymer-supported Ni and
Ir catalysts could be recovered and reused at least five times without any loss of
the catalytic activity (Table [1]).
Figure 8 A ligand and nickel catalyst used for heterogeneous nickel-catalyzed BHA reactions
Scheme 29 BHA reactions under visible light and microwave dual irradiation using polymeric
Ir and Ni catalysts
Table 1 A Catalyst Reusability Study on the Dual Nickel/Iridium Catalysis
|
|
Entry
|
Catalytic run
|
Yield of 101 (%)
|
|
1
|
1st
|
>99
|
|
2
|
2nd
|
99
|
|
3
|
3rd
|
99
|
|
4
|
4th
|
99
|
|
5
|
5th
|
99
|
|
6
|
6th
|
99
|
In summary, a reusable nickel-photocatalyst dual catalytic system serves as a promising
catalytic system for the BHA reactions of aryl chlorides.
