Solvent-Free Approaches for the Synthesis of Lophine Derivatives

Abstract

Solvent-free synthesis comes with many advantages such as cost reduction, waste reduction, ease of operation, sustainability, environmentally benign operations, etc. These benefits have prompted many chemists to develop new protocols for solvent-free synthesis of various interesting chemical compounds. One such class of compounds is 2,4,5-triarylimidazoles, commonly known as lophines due to their applications in materials science, chemo- and bio-sensors, and pharmacology. This article focuses on solvent-free synthesis of lophine derivatives via different protocols, including the use of inorganic-, organic-, and biocatalysts; solid-supported catalysts; microwave-mediated heating; and grinding.

Keywords

Lophine - Triaryl imidazoles - Imidazoles - Solvent-free - Neat - Sustainable chemistry - Green chemistry - Multicomponent reactions

Significance

Lophines, also known as 2,4,5-triaryl imidazoles, have demonstrated numerous applications as fluorescent, chemiluminescent, and biologically interesting scaffolds. Thousands of research articles have been published, including the synthesis and applications of this fascinating class of heterocyclic compounds. A few of these reports have focused on solvent-free approaches for the synthesis of lophines, including catalysis, microwave radiation, grinding, and visible light-mediated synthesis. This review will serve as first-hand information about these sustainable and green approaches for the synthesis of lophines.

Introduction

Green chemistry also called sustainable or environmentally benign chemistry is a recent and continuously developing approach for designing nature-friendly synthetic procedures. The 12 well-known principles of green chemistry were introduced by Dr. Paul Anastas and Dr. John Warner in 1998 [1]. Over the last three decades, the focus has shifted toward the development of approaches that follow the principles of green chemistry [2].

Organic solvents are extensively used in the chemical science field, including in academic and industrial research, for the mass production of countless products [3]. This results in an increasing rate of health and safety issues as well as having environmental and economic impacts [4]. Eliminating or significantly reducing the use of solvents can provide cost efficiency in synthesis likewise handling skills and managing special storage conditions can be minimized as well. The syntheses carried out without the use of solvents are known as solvent-free synthesis also known as neat synthesis [5]. Solvent-free synthesis adheres to more than one principle of green chemistry and adopting this in a sustainable manner is the duty of scientists to protect the environment and society from destructive consequences.

2,4,5-Triaryl-1H-imidazole (TAI), also called lophine, was first synthesized more than a century ago and has achieved remarkable relevance as a result of its extensive use in synthetic chemistry [6]. Lophine derivatives exhibit a wide range of characteristics and demonstrate applications in medicine, luminous materials, etc [7]. Many interesting studies on TAI and its derivatives have already been carried out and applications were explored, which include dye-sensitized solar cells [8], fluorescent probes [9], photo-responsive materials [10], chemiluminescent molecules [11], temperature probes [12], colorimetric sensors [13], nanowires [14], etc. TAIs have the potential to address the shortcomings associated with the other relevant molecules and thus might be employed as new building blocks to generate effective functional molecules.

Lophine derivatives can be synthesized using the multicomponent reaction of benzil, amine source, and various substituted benzaldehyde [15]. There are several methods reported for the synthesis of lophine derivatives using solvent-free conditions, under microwave irradiation, grinding, catalysis, etc. These methods are environmentally friendly as well as less toxic than the methods that generally use a solvent.

Catalysis

Catalysis enhances the efficiency, selectivity, and sustainability of chemical reactions while minimizing energy and time consumption. There are various types of catalysts developed according to the requirements of the organic reactions. The versatility in the use of catalysts is presented in [Table 1].

Table 1 Solvent-free synthesis of Lophine derivatives using various catalysts.

Entry	Catalystsa	Quantity (mol %) or (mg) or (equiv)	Reaction conditions		Examples	Yield (%)	Reference
			Temperature (°C)/room temperature (RT)	Time (min)
aAll the reactions are carried out under solvent-free conditions. bExamples and yields of 1,2,4,5-tetrasubstituted imidazoles. cExamples and yields for the synthesis using benzoin.
[A]	Inorganic catalysts
1	Sodium dihydrogen phosphate (NaH2PO4)	33 mol %	120	25–45	3, 11b	98–99, 80–92b	[16]
2	Dendrimer-PWA n nanocatalyst	35 mol %	90	10–100	15, 30b	78–96, 82–96b	[17]
3	NiO nanoparticles	10 mg	120	60	8	81–-98	[18]
[B]	Organic catalysts
4	N-acetyl glycine (NAG)	1 equiv	150	120	8	62–85	[19]
5	Pyridine-2-carboxylic acid	50 mol %	120	120–180	13	74–96	[20]
6	Mandelic acid	20 mol %	120	30	10	80–91	[21]
[C]	Biocatalysts
7	Graphene oxide–chitosan bio nanocomposite	12 mol %	120	8–35, 18–40c	15	80–96	[22]
8	Extract of Pomelo	50 mol %	RT	240–360	6	88–98	[23]
[D]	Organometallic catalysts
9	ZrO2 supported-β-cyclodextrin (ZrO2-β-CD) nanocatalyst	40 mol %	100	20–35	14	80–98	[24]
10	NiFe2O4@SiO2@amino glucose nanoparticles	5 mol %	RT	10–18	13	90–99	[25]
11	MIL-101 (chromium(III) benzene-1,4-dicarboxylate)	5 mol %	120	7–25	14	85–95	[26]
[E]	Lewis acid catalysts
12	(Ce(SO4)2·4H2O)	3 mol %	120	10–20	14, 14b	78–97, 85–93b	[27]
[F]	Solid-supported catalysts
(a)	Solid-supported Brønsted acid catalysts
13	Silica-bonded S-sulfonic acid (SBSSA)	0.068 mol %	130	30	23	84–95	[28]
14	MCM-41-SO3H	40 mg	100	9–15	9	70–95	[29]
15	MCM-41-nPr-NHSO3H	100 mg	130	20–150	13	53–98	[30]
16	(Carboxy-3-oxopropylamino)-3-propylsilylcellulose (COPAPSC)	200 mg	110	240–360	11, 12b	75–88, 75–87b	[31]
17	Silica-bonded propyl-N-sulfamic acid nanocatalyst (NHSO3H-KIT-5)	50 mg	120	10–25	12	83–92	[32]
(b)	Solid-supported Lewis acid catalysts
18	Silica-supported tin oxide (SiO2:SnO2)	50 mol %	80	15–30	8, 8b	90–94, 92–94b	[33]
19	Ferric(III) nitrate supported on Kieselguhr (Fe(NO3)3-Kie)	1.6 mol %	120	60–90	10	80–91	[34]
20	KSF-supported 10-molybdo-2-vanadophosphoric acid (H5PMo10V2O40/KSF)	100 mg	110	25–50	13	83–96	[35]
21	NiFe2O4@SiO2–H3PMo12O40	20 mg	120	10–30	9, 9c, 10b 10,c	75–96, 86–94c, 78–90b, 75–90b,c	[36]
22	Zeolite ZSM-11	50 mg	110	30–40	10	78–90	[37]
23	Nanoclinoptilolite with titanium dioxide (NCP@SiO3PrNHPRSiO3TiO2)	7 mg	60	4–14	11	93–98	[38]
24	Silica-supported lanthanum trifluoroacetate and trichloroacetate	40 mg	70	40	12	90–96	[39]
[G]	Ionic liquid catalysts
25	(4-Sulfobutyl) tris(4-sulfophenyl) phosphonium hydrogen sulfate (4-SB)T(4-SPh)PHSO4	15 mol %	120	10–15	20	89–98, 87–96c	[40]

Inorganic Catalysts

Jaberi and Barekat synthesized lophine derivatives by reaction of benzil, substituted benzaldehyde, and ammonium acetate using 33 mol % of sodium dihydrogen phosphate (NaH₂PO₄) under solvent-free conditions and got 98–99% yield in 25–45 min at 120 °C ([Table 1], entry 1) [16]. The authors applied the same protocol for the synthesis of 1,2,4,5-tetrasubstituted imidazoles as well and got 80–92% yields.

Esmaeilpour et al. used dendrimer-PWA ⁿ (dendrimer-H₃PMo₁₂O₄ nanoparticles) nanocatalyst for efficient synthesis of lophine derivatives ([Table 1], entry 2) [17]. The authors developed two reaction conditions, one having conventional heating under a solvent-free system while in the other they used ultrasound and ethanol solvent. In terms of yields, a better output with heating under solvent-free conditions was observed. The protocol was successfully applied in the synthesis of 1,2,4,5-tetrasubstituted imidazoles as well.

Bhanage prepared NiO nanoparticles using different cyclodextrins as capping agents under ultrasound conditions. The prepared nanocatalyst was then used in the synthesis of various lophine derivatives under solvent-free conditions. In the one-pot reaction [18], benzil (1 mmol), aryl aldehydes (1 mmol), ammonium acetate (2.5 mmol), and the nanocatalyst (10 mg) were heated together at 120 °C to obtain the desired lophine derivatives in good to excellent yields ([Table 1], entry 3).

The proposed mechanism depicted that NiO nanoparticle (Np) coordination increases the electrophilicity of aryl benzaldehyde and diketone. This facilitates the coupling, condensation, and insertion of two ammonia molecules to produce the diamine intermediate. Further, it attacks electrophilic diketone and rearranges to give the desired lophine derivative ([Scheme 1]).

Scheme 1 Mechanism of NiO nanoparticle catalyzed synthesis of lophine derivatives.

In comparison of cost, simplicity, and yields, the use of sodium dihydrogen phosphate as an inorganic catalyst seems better than the other two inorganic catalysts discussed above. A reduction in the amount of inorganic catalysts used is indeed desirable in the future.

Organic Catalysts

Yar et al. used N-acetyl glycine (NAG) as an organic catalyst for the synthesis of lophine derivatives without using any solvent [19]. The reaction of benzil with various aromatic aldehydes and ammonium acetate in the presence of NAG catalyst at 150 °C in 2 h furnished the desired 2,4,5-triarylimidazoles in good to excellent yields ([Table 1], entry 4). All final compounds were subjected to in vitro α-glucosidase inhibitory activity, which revealed that compounds bearing a hydroxyl group on the C2-phenyl possessed significantly higher activity compared to those that did not have a hydroxyl group.

Khan et al. investigated the catalytic performance of several organic molecules having a carboxylic acid functionality in the synthesis of lophine derivative and found that pyridine-2-carboxylic acid has a good catalytic potential [20]. Under solvent-free conditions at 120 °C and 50 mol % of the catalyst provided the triarylimidazoles in 2–3 h with good to excellent yields ([Table 1], entry 5).

An efficient mandelic acid (20 mol %)-catalyzed solvent-free synthesis of lophine derivatives was developed by Ghogare and Ramesh ([Table 1], entry 6) [21]. Interestingly, the authors observed diminished yields when solvent was used compared to solvent-free conditions.

Clearly, the mandelic acid catalyst is better than the NAG and pyridine-2-carboxylic acid catalysts as the previous is effective at 20 mol % and the reaction time is shorter.

Biocatalysts

Maleki and Paydar utilized graphene oxide–chitosan bionanocomposite as a nanocatalyst for the synthesis of lophine derivatives [22]. The reactions were carried out under solvent-free conditions at 120 °C for 10–35 min and achieved 80–96% yields according to the substitution of benzaldehydes ([Table 1], entry 7). The authors demonstrated that benzil and benzoin both could be employed in this reaction and both provided good to excellent yields however a bit longer reaction time was required in the case of benzoin compared to benzil. The graphene oxide–chitosan bionanocomposite was successfully reused up to six times with little loss of yield. In the proposed mechanism, the aldehyde is activated by the catalyst to allow for the formation of a diamine intermediate. This diamine intermediate further reacts with the catalyst-activated benzil to form the cyclized intermediate which upon dehydration and [1,5] hydrogen shift forms the substituted lophine ([Scheme 2]).

Scheme 2 Mechanism of synthesis using a graphene oxide–chitosan bionanocomposite as a biocatalyst.

Bordoloi and coworkers developed a novel route of citrus fruit extract promoting efficient, inexpensive, and solvent-free synthesis of lophine derivatives [23]. The fresh citrus fruit Pomelo karp part was extracted with water followed by lyophilization yielding the solid WEP (extract of Pomelo). Benzil (1 eq.), various aldehydes (1 eq.), and ammonium acetate (2 eq.) in the presence of 100 mg of WEP under solvent-free and ambient conditions furnished the triaryl imidazoles in excellent yields of 88–98% ([Table 1], entry 8). The biocatalyst was successfully employed in the Biginelli reaction as well to demonstrate the versatility of the protocol. The authors also successfully used other citrus fruits like lemon and star fruit extracts in the developed protocol for the synthesis of triaryl imidazoles.

The reaction occurs at ambient conditions when Pomelo extract is used as a catalyst compared to 120 °C in the case of graphene oxide–chitosan bionanocomposite. The previous is cost-effective for being cheaper and requires ambient conditions and thus is a better biocatalyst. In the future, exploration of more natural citrous sources and expansion of substrate scope is desirable.

Organometallic Catalysts

Rangappa and Shashikanth prepared ZrO₂ supported-β-cyclodextrin (ZrO₂-β-CD) nanocatalyst by coprecipitation method and used in the solvent-free synthesis of various lophine derivatives [24]. Benzil (1 eq.), aromatic aldehyde (1 eq.), and ammonium acetate (2 eq.) were reacted in the presence of ZrO₂-β-CD heterogeneous catalyst (40 mol %) at 100 °C under neat conditions for 20–35 min reaction time ([Table 1], entry 9). Interestingly, the authors observed lower yields in reactions where solvent was used. The optimized protocol was successfully applied for the synthesis of benzimidazoles as well, albeit with doubled reaction time.

Fekri et al. synthesized a magnetically separable heterogeneous catalyst, NiFe₂O₄@SiO₂@amino glucose nanoparticles for the solvent-free synthesis of lophine derivatives ([Table 1], entry 10) [25]. Benzil or benzoin (1 eq.) reacted with substituted benzaldehyde (1 eq.) and ammonium acetate (1 eq.) in the presence of 5 mol % of the heterogenous catalyst at room temperature without solvent. The catalyst efficiency is visible in terms of short reaction time (10–18 min) and high yield (90–99%) of the desired triaryl imidazoles. The magnetically separable heterogeneous catalyst could be reused up to five times without loss of any yield. The authors also applied the optimized protocol for the synthesis of benzimidazoles and benzoxazoles.

The proposed mechanism involves the activation of aldehyde by the catalyst followed by an attack of ammonia from the ammonium acetate to form the corresponding imine. Similarly, benzil via activation forms a bisimine intermediate. Catalyst-activated imine attacks the bisimine carbon followed by subsequent cyclization and loss of ammonia forming the desired triaryl imidazole ([Scheme 3]).

Scheme 3 Mechanism of synthesis using NiFe₂O₄@SiO₂@amino glucose nanoparticles.

Tehrani and Manteghi used a chromium-containing metal-organic framework (MOF), MIL-101 (Chromium(III) benzene-1,4-dicarboxylate) for the synthesis of lophine derivatives under solvent-free conditions [26]. Benzil or benzoin (1 mmol), substituted benzaldehyde (1 mmol), and ammonium acetate (2.5 mmol) in the presence of 5 mg of MIL-101 under neat conditions at 120 °C temperature produced the triarylimidazoles in excellent yields ([Table 1], entry 11). It is noteworthy that benzil required less time (7–20 min) compared to benzoin (14–25 min) while yields were slightly better with the previous compared to the latter in all cases. The reusability was demonstrated by reusing the catalyst up to six times with 95% yield in the first run compared to 80% in the sixth.

Among all three organometallic catalysts, the NiFe₂O₄@SiO₂@amino glucose nanoparticles outperform the other two, as only 5 mol % of this catalyst under ambient reaction conditions gives excellent yields. More organometallic catalysts should be tested in the future to find new cost-effective organometallic catalyst systems.

Lewis Acid Catalysts

Li et al. used the Lewis acid catalyst (Ce(SO₄)₂·4H₂O) for the efficient synthesis of lophine derivatives under solvent-free conditions [27]. Benzil or benzoin (1 eq.) reacted with substituted benzaldehyde (1 eq.) and ammonium acetate (3 eq.) in the presence of 3 mol % of the Ce(SO₄)₂,4H₂O catalyst at 120 °C without solvent to furnish the 2,4,5-triaryl imidazoles in excellent yields within 10–25 min ([Table 1], entry 12). The synthesis of 1,2,4,5-tetrasubstituted imidazoles (14 examples, 85–93% yields) was carried out as well using the optimized conditions. The Lewis acid (Ce^IV) enhanced the formation of diamine intermediate (a) and activated the benzil or benzoin molecule by increasing the electrophilicity of the carbonyl group of the aryl aldehyde and diketone respectively. Intermediate (a) condenses with activated benzil or benzoin molecule and form intermediate (b) or (c). Intermediate (b) gets rearranged to form the desired lophine derivatives via a [1,5] hydrogen shift, while intermediate (c) oxidizes in the presence of air and forms the desired lophine derivatives ([Scheme 4]). The high efficiency of this Lewis acid suggests that there is a lot of scope for testing other Lewis acid catalysts to further improve the cost efficiency and simplicity of this reaction.

Scheme 4 Mechanism of solvent-free synthesis of lophine derivatives using the Ce(SO₄)₂,4H₂O catalyst.

Solid Support Catalysts

Solid-supported catalysts are well known due to the ease of recovery after the completion of reactions, thus adding value in terms of recoverability and reusability. According to its catalytic activity, it can be further classified into two parts, which are as follows.

Solid-Supported Brønsted Acid Catalysts

Khodabakhsh et al. prepared silica-bonded S-sulfonic acid (SBSSA) as a solid support catalyst for the synthesis of various lophine derivatives and achieved 84–95% yield at 130 °C and solvent-free conditions ([Table 1], entry 13) [28].

Mahdavinia et al. prepared MCM-41-SO₃H (Mobil Composition of Matter No. 41 – SO₃H), which was used as a solid-supported nanocatalyst in the synthesis of lophine derivatives ([Table 1], entry 14) [29]. The solvent-free reaction of benzil, aldehyde, and ammonium acetate in the presence of MCM-41-SO₃H at 100 °C temperature in a few minutes gives good to excellent yields of triarylimidazoles. The sulfonic acid part of the reported nanocatalyst activates the carbonyl group of substituted aromatic aldehydes and benzil. The attack of ammonia on the imine intermediate gives diamine intermediate (a), which attacks benzil, followed by cyclocondentation, forming imidazol-5-ol intermediate (c). Finally, the elimination of water molecule results in the desired lophine derivatives ([Scheme 5]). The recyclability and reusability of the solid-supported nanocatalyst were proved by reusing the catalyst for up to four reactions with yields of 92, 92, 85, and 83%, respectively.

Scheme 5 Mechanism for the synthesis of lophine derivatives using MCM-41-SO₃H.

Choghamarani et al. synthesized MCM-41-nPr-NHSO₃H and used it as an efficient heterogeneous catalyst for the one-pot synthesis of lophine derivatives under solvent-free conditions ([Table 1], entry 17) [30]. Benzil (1 mmol), aromatic aldehyde (1 mmol), and ammonium acetate (2.5 mmol) under the influence of MCM-41-nPr-NHSO₃H (0.1 g) were heated neat in an oil bath at 130 °C to obtain the desired lophine derivatives in average to excellent yields. The catalyst could be recycled by simple filtration after completion of the reaction and reused up to five times without any appreciable loss of yield.

Salimi and coworkers prepared (carboxy-3-oxopropylamino)-3-propylsilylcellulose (COPAPSC) as a biodegradable solid-supported organic catalyst for the solvent-free synthesis of lophine derivatives ([Table 1], entry 18) [31]. The consecutive surface functionalization of cellulose involved the reaction of cellulose with 3-aminopropyltriethoxysilane, followed by the condensation of the surface –NH₂ groups with succinic anhydride. This allowed the synthesis of –COOH group functionalized cellulose (COPAPSC). An amount of 0.2 g of this catalyst (equal to 0.05 mmol H⁺) was enough to drive the reaction to completion within 4–6 h at 110 °C. The reusability of the solid-supported catalyst was also demonstrated for up to five cycles with little loss of yield. The optimized protocol was successfully applied toward the synthesis of 1,2,4,5-tetrasubstituted imidazoles as well.

Heravi and coworkers developed a silica-bonded propyl-N-sulfamic acid nanocatalyst (NHSO₃H-KIT-5) and performed the catalytic synthesis of various lophine derivatives [32]. In this one-pot reaction of benzil (1 mmol), aromatic aldehyde (1 mmol), and ammonium acetate (2 mmol) were reacted together with 0.05 g of the nanocatalyst NHSO₃H-KIT-5 at 120 °C under neat conditions to furnish the desired lophine derivatives ([Table 1], entry 21). The catalyst could be easily recycled and reused for up to 5 cycles without significant loss of catalytic activity.

The MCM-41-SO₃H solid-supported Brønsted acid catalyst requires a short reaction time of 9–15 min only, and at 100 °C, it furnished good to excellent yields. Thus, it trumps the other solid-supported Brønsted acid catalysts as per our understanding. In future scope, recyclability and reusability of other solid-supported Brønsted acid catalysts should be tested and reaction temperature could be lowered to further improve monetary benefits.

Solid-Supported Lewis Acid Catalysts

Borhade et al. developed silica-supported tin oxide (SiO₂:SnO₂) as a nanocatalyst and successfully used it for the synthesis of lophine derivatives [33]. Under the optimized conditions benzil (1 mmol), aromatic aldehyde (1.2 mmol), and ammonium acetate (1 mmol) were stirred at 80 °C for a stipulated time in the presence of 50 mol % of the catalyst to produce the triaryl imidazoles in good to excellent yields ([Table 1], entry 15). The authors also applied the developed protocol for the synthesis of 1,2,4,5-tetrasubstituted imidazoles.

The solvent-free procedure for the synthesis of lophine derivatives using a catalytic amount of ferric(III) nitrate supported on Kieselguhr (Fe(NO₃)₃-Kie) as a Lewis acid catalyst was developed by Xu and Li [34]. Benzil (1 mmol), aromatic aldehyde (1 mmol), and ammonium acetate (2 mmol) were reacted in the presence of the Fe(NO₃)₃-Kie (1.6 mol %) at 120 °C neat until completion. The desired 2,4,5-triarylimidazoles were obtained in good to excellent yields ([Table 1], entry 16). The authors observed longer reaction times and diminished yields when a solvent was used instead of neat conditions.

Shankarwar and Chavan synthesized a variety of lophine derivatives under thermal solvent-free conditions in the presence of a KSF (Montmorillonite KSF clay) supported 10-molybdo-2-vanadophosphoric acid catalyst [35]. The reaction of benzil (1 mmol), aromatic aldehyde (1 mmol), and ammonium acetate (2 mmol) in the presence of the 20% H₅PMo₁₀V₂O₄₀/KSF (0.1 g) under solvent-free conditions at 110 °C furnished excellent yields of the 2,4,5-triarylimidazoles ([Table 1], entry 19). The catalyst could be recycled and reused for up to three reactions with little loss of yield.

Maleki and group developed NiFe₂O₄@SiO₂–H₃PMo₁₂O₄₀ as a magnetically recoverable nanocatalyst, which was further used in the synthesis of lophine derivatives under solvent-free conditions ([Table 1], entry 20) [36]. Here, both benzil and benzoin were employed as reactants, and yields from both were compared under the optimized reaction conditions of 120 °C and 10–30 min reaction time. After completion of the reaction, the catalyst was removed using an external magnetic field, while the addition of 1 mL of ethanol followed by pouring the reaction mixture into crushed ice afforded the crude product, which was further purified by recrystallization. The protocol was also applied in the synthesis of 1,2,4,5-tetrasubstituted imidazoles.

Gaikwad et al. developed a ZSM-11 (Zeolite Socony Mobil 11) catalyst for the efficient synthesis of lophine derivatives under solvent-free conditions ([Table 1], entry 22) [37]. Suspension of benzaldehyde (1 mmol), benzil (1 mmol), and ammonium acetate (3 mmol) were heated in an oil bath at 110 °C in the presence of 0.05 g of the heterogeneous catalyst ZSM-11 until reaction completion. Efficient recyclability and reusability were also demonstrated for up to five reaction cycles. The proposed mechanism involves the activation of the aldehyde as well as benzil by catalyst coordination with carbonyl oxygen. An attack of in situ-generated ammonia on aldehyde and benzil could generate the imines I and II. A nucleophilic attack of the intermediate I on the II followed by cyclization could form the desired lophines ([Scheme 6]).

Scheme 6 Mechanism of the synthesis of lophine derivatives using Zeolite ZSM-11 as a solid-supported catalyst.

Rabiei et al. synthesized functionalized nanoclinoptilolite with titanium dioxide (NCP@SiO₃PrNHPRSiO₃TiO₂), which was used as a nanocatalyst for the solvent-free synthesis of lophine derivatives and achieved more than 90% yields ([Table 1], entry 23) [38]. It is noteworthy that full conversion is observed within a few minutes under solvent-free conditions.

Lande and group prepared silica-supported lanthanum trifluoroacetate and trichloroacetate green Lewis acid catalysts and utilized them in the solvent-free synthesis of various lophine derivatives ([Table 1], entry 24) [39]. Both lanthanum trifluoroacetate and trichloroacetate catalysts were successfully employed separately in the reaction of benzil (1 mmol), substituted benzaldehyde (1 mmol), and ammonium acetate (3 mmol) under neat conditions at 70 °C in reaction times of 14–16 and 17–20 min respectively. The authors also demonstrated the reusability of the catalysts up to five times with little loss of yields.

Considering the cost and amount of catalyst, the ferric(III) nitrate supported on Kieselguhr (Fe(NO₃)₃-Kie) Lewis acid catalyst is better compared to other catalysts of the same category as only 1.6 mol % of this catalyst gives the desired lophines in good to excellent yields. Lowering the reaction temperature and increasing the substrate scope is desirable in the future scope.

Ionic Liquid Catalyst

Bavantula used Brønsted acidic ionic liquid, (4-sulfobutyl) tris(4-sulfophenyl) phosphonium hydrogen sulfate (4-SB)T(4-SPh)PHSO₄, as a catalyst for the solvent-free synthesis of the series of lophine derivatives ([Table 1], entry 25) [40]. In the optimized reaction conditions, the benzil or benzoin (1 mmol), aryl aldehydes (1 mmol), ammonium acetate (3 mmol), and the catalyst (15 mol %) were heated together at 120 °C neat to obtain the desired 2,4,5-trisubstituted imidazoles. The reaction times were slightly lower and yields were slightly higher for benzil compared to benzoin.

Authors proposed the mechanism for the role of given Brønsted acidic ionic liquid catalyst in which protonation of aldehyde allowed ammonia attack to form the diamine intermediate ([Scheme 7]). This diamine intermediate attacked the activated benzil followed by dehydration and rearrangement giving 2,4,5-trisubstitutedimidazoles. More ionic liquid catalysts should be tested in the future to get further insight into the benefits of this catalytic system.

Scheme 7 Mechanism of Brønsted acidic ionic liquid (4-SB)T(4-SPh)PHSO₄ catalyzed synthesis of lophine derivatives using solvent-free approach.

Visible Light-Mediated Synthesis

Banerjee reported a visible light and heat-promoted synthetic method for a series of lophine derivatives without any catalyst or solvent [41]. The reaction was carried out under white LED (10 W) at 100 °C for 30 min and about 92–98% yields were achieved ([Scheme 8]). Control experiments revealed that in the absence of light or heat, no desired product was formed, while in the presence of radical quencher TEMPO or under argon atmosphere, diminished yield was observed. This observation indicated the light-mediated formation of superoxide from oxygen and amine radicals from ammonia ([Scheme 9]). The amine-centered radical could attack the imine to form diamine species b, followed by cyclocondensation with benzil to give the lophine derivatives. Here there is a lot of scope for testing different sensitizers as photocatalysts and lowering reaction temperature.

Scheme 8 LED-mediated synthesis of derivatives under neat conditions.

Scheme 9 Mechanism of LED-mediated synthesis of lophine derivatives.

Microwave-Assisted Synthesis

Zhou et al. used catalyst-free, solvent-free, and heat-promoted microwave-assisted synthesis of a variety of lophine derivatives and achieved good yields in short reaction time ([Table 2], entry 1) [42]. Benzil (1 mmol), aryl aldehydes (1 mmol), and ammonium acetate (3 mmol) were charged in a vial and sealed with a septum-containing cap. The reaction mixture was irradiated at 150 W at 120 °C for 3–5 min.

Table 2 Microwave-assisted synthesis of lophine derivatives in heat.

Entry	Reaction conditions			Example	Yields	Reference
	Catalyst (mg)	Watts (W)	Time (min)
aAll the reactions are carried out under solvent-free conditions. bExamples and yields of 1,2,4,5-tetrasubstituted imidazoles.
1	–	150	3–5	14	80–99	42
2	Fe3O4@SiO2-Imid-PMA n	100	50–180	14, 19b	80–97, 81–97b	43
3	Fe3O4@SiO2·HM·SO3H		7–8	14	76–93	44
4	Pumice@SO3H	280	11–15	11	80–92	45

The group of Esmaeilpour prepared Fe₃O₄@SiO₂-Imid-PMA ⁿ as a magnetic nanocatalyst and used it in the synthesis of various lophine derivatives under microwave heating ([Table 2], entry 2) [43]. Benzil (1 mmol), aryl aldehyde (1 mmol), and ammonium acetate (3 mmol) were heated neat under microwave irradiation in the presence of the nanocatalyst at 110 °C to afford the desired lophine derivatives. The authors compared microwave and conventional heating conditions to find that the latter required around 8–10 times longer reaction time in general. The catalyst could also be recycled and reused for up to six cycles without loss of significant yield.

Naeimi and Aghaseyedkarimi developed an ionic liquid-coated nanomagnetite catalyst and used it as a reusable nanocatalyst in the solvent-free synthesis of lophine derivatives under microwave irradiation [44]. Under the optimized conditions benzil (1 mmol), aryl aldehyde (1 mmol), and ammonium acetate (3 mmol) were heated neat under microwave irradiation in the presence of 30 mg of the nanocatalyst Fe₃O₄@SiO₂·HM·SO₃H ([Table 2], entry 3). In just 7–8 min reaction time, the desired substituted lophines were obtained in good to excellent yields. The catalyst recyclability and reusability were found to be excellent, as after six runs, the yield only dropped to 85 from 93%.

Shirole and coworkers studied the catalytic performance of pumice@SO₃H for the synthesis of 2,4,5-triaryl imidazoles under solvent-free microwave irradiation [45]. Benzil (1 mmol), aryl aldehyde (1 mmol), and ammonium acetate (3 mmol) were heated neat under microwave irradiation in the presence of the pumice@SO₃H catalyst (100 mg) to afford the 2,4,5-triaryl imidazoles in excellent yields ([Table 2], entry 3). The catalyst was found to be reusable successfully for up to four cycles without loss of significant yield. The optimized protocol was also applied in the synthesis of acridine-1,8-diones to demonstrate the versatility of the catalyst. The mechanism starts with the pumice@SO₃H catalyzed activation of benzaldehydes and the benzil molecules by which imine intermediates of both molecules are produced (I and II). Cyclocondensation followed by rearrangement gives desired lophine derivatives ([Scheme 10]).

Scheme 10 Mechanism of the microwave-assisted synthesis in the presence of pumice@SO₃H catalyst.

Clearly in comparison, the first method ([Table 2], entry 1), which is catalyst-free under microwave irradiation, is the best, as it produced the desired lophines in excellent yields in a dramatically short reaction time of 3–5 min. All conventionally heated reactions discussed earlier could be tested under microwave irradiation for comparison and thus hold a lot of value for future scope.

Synthesis by Grinding

Patil et al. synthesized lophine derivatives under solvent-free conditions by grinding reaction components together in the presence of I₂ or NaH₂PO₄ or SnCl₂·2H₂O as catalyst ([Scheme 11]) [46]. The catalytic activity was observed in the order of SnCl₂·2H₂O, NaH₂PO_4, and I₂ accordingly with the Lewis acid character of individual catalysts.

Scheme 11 Solvent-free synthesis of lophine derivatives using the grinding method in the presence of I₂ or NaH₂PO₄ or SnCl₂·2H₂O as a catalyst.

Nanda and coworkers reported a solvent-free synthesis of various lophine derivatives using mechanical grinding and heating methods ([Scheme 12]) [47]. Due to the high polarizability of carbonyl bonds, the extremely weak dipole of carbonyls can generate polarization in bulk, which ultimately increases the electrophilicity of carbonyls and makes the synthesis of lophine derivatives easy due to self-catalysis. Benzil (1 mmol), aryl aldehyde (1 mmol), and ammonium acetate (10 mmol) were taken in an agate mortar and thoroughly ground. The reaction mixture was then transferred to a test tube and heated to 150–160 °C for 4–5 min.

Scheme 12 Synthesis of lophine derivatives using grinding and heating methods without using solvents.

Miscellaneous

Wang reported a solvent-free microwave synthesis for various lophine derivatives for which hexamethyldisilazane (HMDS) was used as a nitrogen source and trifuoromethane sulfonate (TMSOTf) as a Lewis acid catalyst ([Scheme 13]) [48]. They used both electron-rich and electron-deficient groups attached to the aldehydes and got average to excellent yields.

Scheme 13 Neat synthesis of lophine derivatives using HMDS as a nitrogen source and TMSOTf as a Lewis acid catalyst.

In the mechanism, TMSOTf first activates the carbonyl oxygen of the aldehyde (a) as well as one of the diketone molecules (b). The reaction between intermediate (a) and (b) forms imine (c), which is further activated by TMSOTf to allow the attack of the HMDS nitrogen. Elimination of TMSOH and intramolecular cyclization gives the five-membered ring intermediate (d) followed by [1,5] H-shift furnishes the desired 2,4,5-triarylimidazoles ([Scheme 14]).

Scheme 14 Mechanism of synthesis using HMDS as a nitrogen source and TMSOTf as a Lewis acid catalyst.

Recently, a unique approach was reported for the synthesis of lophine by the group of Dandela [49]. They used cis-stilbene instead of diketone as a starting material and the reaction was carried out with 2 mole equiv of benzylamine in the presence of an I₂-DMSO catalyst at 60 °C for 8 h followed by debenzylation to produce lophine ([Scheme 15]). cis-Stilbene first converted to 2-iodo-1,2-diphenylethan-1-one (a) in the presence of iodine-DMSO which facilitates Kornblum oxidation. The resulting intermediate undertakes a condensation reaction with the first benzylamine to give the iodinated imine intermediate (b). Afterward, intermediate (b) is coupled with another molecule of benzylamine and gives intermediate (c). Then intermediate (c) loses one electron and gets oxidized to nitrogen-centered radical cation intermediate (d). Intramolecular cyclization gives intermediate (f) and subsequent oxidation forms tetrasubstituted dihydro imidazole. Debenzylation was carried out using the standard conditions of Pd/C and hydrogen gas to form lophine ([Scheme 16]).

Scheme 15 Synthesis of lophine from cis-stilbene as a starting material.

Scheme 16 Mechanism of the synthesis of lophine using cis-stilbene as a precursor.

Conclusions and Outlooks

In conclusion, we have demonstrated the solvent-free synthesis of lophine derivatives via different protocols, including inorganic-, organic-, bio-, solid-supported, Lewis acid, and ionic liquid catalysts, as well as microwave-mediated synthesis, grinding methods, and visible light-mediated synthesis. Due to the neat reaction conditions, all of these protocols inherently possess cost-effectiveness and have minimum impact on the environment, biodiversity, and human health. The ease of operation is demonstrated by almost all examples, while recyclability and reusability are demonstrated particularly by the solid-supported catalyst systems. In the future, new catalyst systems that work under neat conditions should be tested and recyclability as well as reusability should be explored further to improve the benefits of the neat lophine synthesis. We hope that this review will be of great interest to the chemistry community and will further promote research and development in the fascinating field of solvent-free synthesis.

Shiv R. Desai

Shiv R. Desai received his Bachelor’s degree in chemistry (2018) and master’s degree in organic chemistry (2020) from the Veer Narmad South Gujarat University, Surat, Gujarat, India. Subsequently, he worked as a chemist in the Research and Development section of the pharmaceutical industry for over a year. Since 2021, he has been pursuing doctoral research under the guidance of Dr. Sachin G. Modha at Uka Tarsadia University, Bardoli, Surat, Gujarat, India. His doctoral research focuses on synthetic organic chemistry, where he designs and establishes new protocols to synthesize chemical compounds containing nitrogen heterocycles, create efficient synthetic processes using multicomponent reactions and microwave irradiation, and perform analytical evaluations, structural characterizations, and photophysical properties of synthesized molecules.

Dr. Sachin G. Modha

Dr. Sachin G. Modha received his master’s degree in organic chemistry (2006) from Saurashtra University, Rajkot, India, under the guidance of Prof. Anamik Shah. He completed his Ph.D. in organic chemistry (2012) under the supervision of Prof. Erik Van der Eycken at the University of Leuven (KU Leuven), Belgium. He then moved on to carry out post-doctoral research at the University of Manchester, United Kingdom, with Prof. Michael F. Greaney (2013–2015) and at the Technical University of Munich, Germany, with Prof. Thorsten Bach as Alexander von Humboldt fellow (2016–2018) and one-year extended stay as a post-doctoral research associate (2018–2019). He was appointed as an assistant professor at Uka Tarsadia University in 2019. His research interests include multicomponent reactions, photochemistry, transition metal catalysis, microwave-assisted organic synthesis, tandem approaches, alkyne activation, post-multi-component transformations, and research in the field of solvatochromic and halochromic compounds.

Contributors’ Statement

Data collection: S. R. Desai, S. G. Modha; Analysis and interpretation of the data: S. R. Desai, S. G. Modha; Drafting the manuscript: S. R. Desai, S. G. Modha; critical revision of the manuscript: S. G. Modha.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

SRD is thankful to the Government of Gujarat for financial support under the SHODH fellowship (File No. KCG/SHODH/2023-24/2022017310).

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Publication History

Received: 18 July 2024

Accepted after revision: 20 September 2024

Accepted Manuscript online:
27 September 2024

Article published online:
11 November 2024