2. C–H Activation Reactions
In 2017, Punzi and coworkers reported, for the first time, the use of DESs in C–H activation reactions to prepare thiophene−aryl derivatives 3 
. Hydrophobic DESs worked better than hydrophilic ones, but they decided to choose the hydrophilic DES composed of choline chloride (ChCl) and urea, in a molar ratio of (1:2), as it had a simpler work-up process. In the presence of Pd2
(5 mol%) as the catalyst, P(o-MeOPh)3
as the ligand, Cs2
as the base and pivalic acid (PivOH) (1 equiv.) as additive, the diarylation of 5-octylthieno [3,4-c]pyrrole-4,6-dione (TPD) 1
with aryl iodides 2
successfully occurred, providing high yield of the desired product 3
(Scheme 1). No reaction took place in the absence of the ligand. Electron rich aryl iodides were more reactive than electron poor ones, yielding moderate to good yields. Bromobenzene exhibited less reactivity as a coupling partner, resulting in low yields. The optimized reaction conditions were used to prepare aromatic molecules for push-pull molecular and polymeric semiconductors.
Scheme 1. Thiophene−aryl coupling reaction via C–H bond activation in DES.
Heydari and co-workers described an environmentally safe approach for the arylation of imidazoles with aryl bromides in DESs 
. Authors synthesized a palladium-based magnetic reduced graphene oxide (MRGO@DAP-AO-Pd(ll)) as a reusable catalyst for C-5 arylation of 1,2-dimethyl-1H-imidazole 4
with 4-bromobenzaldehyde 5
. Various types of choline chloride based DESs were studied. The best solvent for the reaction system was K2
:glycerol (1:5) (Scheme 2). DES can also offer several advantages for this reaction. The high basicity of the solvent can promote the deprotonation of the imidazole compound, which can enhance its reactivity towards the palladium catalyst 
Scheme 2. The arylation of imidazoles via C–H bond activation.
Various electron rich and electron deficient aryl halides were used to investigate the limitations of the optimized conditions for the C5-arylation of 1,2-dimethyl-1H-imidazole. C5-arylated products 6 were obtained in good yields using 1-methyl-1H-imidazole with several (hetero)aryl bromides. C5 position of imidazole is more reactive than C2 and C4 position for monoarylation, with only traces of the C2-arylated product detected. The catalyst could be used for seven subsequent runs with a broad substrate scope without significant loss in activity within this protocol.
Recently, Tran and Hang have described DES-catalyzed arylation of benzoxazoles 7
with aromatic aldehydes 8
(Scheme 3) 
. When using ZnCl2
:ethylene glycol (1:4) as both the catalyst and solvent, benzoxazoles can be combined with benzaldehyde derivatives to form C2-arylation products 9
. Without exclusion of air, benzoxazoles and aromatic aldehydes, either with electron donating or electron withdrawing groups, yielded the desired products in high to excellent yields. High to excellent yields of the desired products were obtained at 120–140 °C for 4–6 h. In addition, benzothiazole and benzimidazole were compatible with aromatic aldehydes affording good yields of the desired products 9
. Extraction with diethyl ether was performed once the reaction finished. As an interesting side note, DES ZnCl2
:ethylene glycol (1:4) can be reused up to five times without significant loss in activity. Benzoxazoles arylation has been reported frequently in different solvents. These solvents include H2
, PhCl 
, DMF 
, pivalonitrile 
, and p-xylene 
Scheme 3. DES–catalyzed arylation of benzoxazoles with aromatic aldehydes.
In a recent report, D’Amico et al. demonstrated the use of DES as a sustainable and benign solvent to directly arylate a series of 3,4-disubstituted thiophenes. These thiophenes are well-known for their wide range of applications in optoelectronics, from photovoltaics to semiconductors and electrochromes 
. ChCl:glycerol (1:2) was chosen as the DES for its high biocompatibility and biodegradability 
(Scheme 4). A catalytic system consisting of Pd(Cl)2
(x = 1–5 mol%), P(2-MeOPh)3
(2x mol%) as the ligand, PivOH (30 mol%) as additive, and K2
(2.5 equiv.) as the base at 110 °C for 24 h could effectively diarylate 3,4-ethylenedioxythiophene 10
with aryl and heteroaryl bromides 11
in moderate-to-high yield of the target product 12
. Air can promote the oxidation of Pd(0) to Pd(II) after the catalytic cycle of C–H activation reaction 
. This allows palladium to be reused in subsequent cycles of the transformation. As a result of undertaking the reaction under air, there is no need to use inert gas atmospheres and the setup becomes much simpler. This can also reduce the environmental impact of the reaction by eliminating the need to purge the inert gas.
Scheme 4. Pd–catalyzed direct arylation of thienyl derivatives with (hetero)aromatic bromides in DESs.
In this strategy, electron poor bromides provided excellent yield even with low catalyst loading (1.0 mol%), while electron rich bromides needed more of the catalyst (5.0 mol%) for a good yield. Ortho-substituted bromides did not affect the reaction negatively, and heteroaromatic bromides, such as 2-bromopyridine, were moderately reactive. Note that simple recrystallization with EtOH or EtOAc is often sufficient for purification.
Very recently, Vitale and colleagues reported a new strategy for synthesizing 1-arylpropan-2-ones in DESs under aerobic conditions (Scheme 5) 
. These compounds are known for their pharmacological activity 
. The group began their study by optimizing the conditions for preparing the enolate intermediate. They achieved this by subjecting 1-phenylpropan-2-one 13
to t-BuOK as the optimum base and ChCl:urea (1:2) as the eutectic mixture at room temperature for 1 h. Alkyls and alkenes 14
with different electronic natures were compatible and generated the desired α-substituted products 15
in high to excellent yields. A series of arylpropan-2-ones with fluorine or CF3
-, or para
- position of aryl ring afforded moderate to high yields.
Scheme 5. Synthesis of 1-arylpropan-2-ones in DES.
The authors arylated 1-phenylpropan-2-one 13
at room temperature for 1 h with t-BuOK (3 equiv.) as the base, and ChCl:urea (1:2) as the solvent. Then, they added iodoaryls or bromoaryls 14
(1.1 equiv.) and Pd[P(t-Bu)3
(5–10 mol%) to the mixtures and heated it at 45–70 °C for 2–12 h. The yield of the products ranged from moderate to excellent, with iodoaryls more reactive than aryl bromides. DESs have shown great potential in activating carbonyl-containing substrates for alpha-arylation. The activation process involves the formation of a hydrogen bond between the carbonyl group of the substrate and the HBD moiety of the DES. This interaction enhances the electrophilicity of the carbonyl group, facilitating the formation of the desired α-substituted product 
Nawaz Khan et al. developed a novel approach for sp3
-CH functionalization of acetophenones 16
with benzyl alcohols 17
using DES 
. The optimized conditions include Pd(PPh3
/xantphos as the catalyst/ligand combination and KOtBu (1.5 equiv.) as the base. Among the DESs used, ChCl:malonic acid (1:1) was found to be the most effective solvent, producing high yields of the α,β-saturated ketones 18
(Scheme 6). The use of ChCl−oxalic acid (1:1) as the DES mixture also led to the desired product in good yields. A variety of electron donating and electron withdrawing groups were tolerated on acetophenone and benzyl alcohol to isolate the desired α,β-saturated ketones in good to high yields. By using the ChCl-based DESs as alternatives to toluene, the acidic pH of the DESs neutralized the reaction medium from strongly basic to slightly basic. This adjustment reduced the likelihood of ketone reduction into alcohols and the formation of side products. The mechanism of DES involves hydrogen bonding, activating benzyl alcohol before dehydrogenation catalyzed by the palladium complex. The DES medium enhances electrophilicity by interacting with the oxygen atom of the ketone group, promoting the nucleophilic attack to form an α-alkylated saturated ketone 18
Scheme 6. Palladium-catalyzed sp3 C–H functionalization of methyl ketones.
The Friedländer reaction between ketone 19
and acetylacetone 20
suggests that DES acted as both the solvent and catalyst. The DES formed hydrogen bonds with the reagents, facilitating the reaction, and the formation of a chalcone intermediate was observed 
. The reaction involved an N-heterocyclic ketone that was 4-α-alkylated with benzyl alcohols 21
, resulting in a good yield of the desired product 22
. Various substituents on benzyl alcohol were compatible and steric hindrance had no effect on the reaction yield (Scheme 7). DES was reused for five consecutive cycles, with no observable detrimental effects on yields.
Scheme 7. Friedländer reaction and palladium-catalyzed, sp3 C–H functionalization of methyl ketones.
Marset recently described a strategy for the free-silver-mediated Csp3
–H functionalization of unactivated 8-aminoquinoline amides using palladium catalysts in a DES 
. He established the conditions for functionalizing the amide derived from 8-aminoquinoline 23
with aryl iodides 24
. The conditions involved Pd(OAc)2
(10 mol%) as the catalyst, NaHCO3
(1.5 equiv.) as the base, and 2-pyridone (40 mol%) as the ligand. The reaction was carried out in betaine (choline derivative):hexafluoroisopropanol (HFIP) (1:2) as the solvent at 110 °C for 2.5 h, resulting in a good to high yields of the desired products 25
. Additionally, ChCl:acetamide (1:2) also proved effective among the various DESs evaluated, providing the desired products in good yields (Scheme 8).
Scheme 8. Arylation of amide derived from 8-aminoquinoline.
The protocol was efficient with aryl iodides that had both electron withdrawing and electron donating groups in betaine:HFIP (1:2) and ChCl:acetamide (1:2) DESs, resulting in good to excellent yields. Betaine:HFIP provided higher yields. However, ortho-substituted aryl iodides had drastic results due to steric hindrance. In ChCl:acetamide (1:2), shorter alkyl-chain lengths resulted in marginal yields, while full conversions were obtained in betaine:HFIP (1:2). Furthermore, a one-pot directing group removal was presented by quenching the reaction with 40% aqueous sulfuric acid 
and heating the mixture at 110 °C for 24 h, affording 28
in a good yield (Scheme 9). Although the reusability of DESs with the catalyst may be limited to no more than two cycles, DESs can facilitate the recycling of transition-metal catalysts in multiple reaction processes. This can result in a substantial enhancement of the overall turnover number of reactions 
Scheme 9. One-pot directing group removal.
Recently, in 2022, a research team led by González–Gallardo published a study on a highly effective method for C–H activation using a ruthenium catalyst in DESs 
. The optimized conditions for the reaction involved 3 mol% [RuCl2
as the catalyst, and 20 mol% NaOAc as an additive, at 70 °C for 16 h. After examining various DESs, ChCl:ethylene glycol (1:2) was the most effective solvent. Choline chloride-based DESs are highly polar solvents that can increase reaction rates and stabilize reactive intermediates, making them effective for polar reactions 
. Electron withdrawing substituents on the para
position of N-methoxybenzamide 29
reacted with internal alkynes with aromatic substituents 30
and favored the desired isoquinolones with high yields 31
(Scheme 10). The DES can be reused for up to three times without any significant loss in yield. Isoquinolone derivatives have displayed various pharmacological and biological effects, including antitumor 
, anti-inflammatory 
, and antihypertensive activities 
Scheme 10. C–H activation reaction using disubstituted alkynes and electron poor olefins.
The C–H activation reaction with N-methoxybenzamide 29 proved effective for electron poor olefins 32 under identical conditions. High yields were achieved when utilizing olefins containing electron withdrawing groups. Interestingly, exceptional Michael acceptor reagents, such as vinyl ketone and phenyl–vinyl, sulfone-generated cyclic products 33, or a mixture of acyclic and cyclic products 33 and 34, had excellent yields (Scheme 10).
To assess the flexibility of this approach, Cu(OAc)2
(10 mol%) was used instead of NaOAC, and betaine:HFIP (1:2) was chosen as the solvent among various DESs tested. A variety of olefins 36,
containing electron withdrawing groups, reacted with benzoic acid 35
, leading to high yields of the products 37
. Electron withdrawing substituents at the para position in the carboxylic acid 35
favored the reaction, while electron donating groups showed lower reactivity. Experiments were conducted using various disubstituted alkynes 39
to create isocoumarin derivatives 40
. Isocoumarin scaffolds are a group of natural products that are biologically, structurally, pharmacologically fascinating, and commonly used in drug discovery, pharmaceutical and medical chemistry 
. Good yields were obtained when carboxylic acids were subjected to internal alkynes with aromatic, aryl–alkyl, and alkyl–alkyl substituents 39
Scheme 11. C–H activation reaction using electron poor olefins and disubstituted alkynes with benzoic acid derivatives.
Successful synthesis of heterocycles commonly found in drug candidates 
was achieved by reacting 2-thiophenecarboxylic acid 41
with various olefins 42
containing electron withdrawing groups. Every reaction produced moderate to good yields of exclusively acyclic derivatives 43
. To demonstrate the method’s applicability, the reaction was scaled up to the gram level, resulting in excellent yield of the desired product through precipitation with a small amount of water (Scheme 12). The reaction was conducted under air conditions, air can act as an oxidant to make the reaction more cost-effective and safer than other commonly used oxidants, such as peroxides or molecular oxygen.
Scheme 12. C–H activation reaction using electron poor olefins with 2-thiophenecarboxylic acid.
Under the previously mentioned conditions, and to broaden the range of substrates for this transformation, several aryl pyrazole derivatives 44
and electron poor olefins 45
were tested, resulting in moderate to good yields. Interestingly, the use of methyl–vinyl ketone as a substrate, led to the production of both saturated 46
and unsaturated compounds 47
in similar proportions. Additionally, in some instances, a double addition product to 1-phenylpyrazole 48
was observed (Scheme 13). Certain arylpyrazoles have exhibited noteworthy pharmacological activities 
Scheme 13. C–H activation reaction using electron poor olefins with 1-arylpyrazole derivatives.