One-Pot Reactions of Triethyl Orthoformate with Amines

Abstract

One-pot reactions offer advantages like easy automation, higher product yields, minimal waste generation, operational simplicity, and thus reduced cost, time and energy. This review presents a comprehensive overview of one-pot reactions including triethyl orthoformate and amines as valuable and efficient reagents for carrying out two-, three- or four-component organic reactions.

1. Introduction

In organic chemistry, the one-pot reaction is a relevant and common topic due to its immense advantages as a simple operation, with high mass efficiency, low cost, a lesser amount of waste disposal, short reaction time, and simplification of practical aspects. The reaction is also clean; it is possible to combine several catalytic procedures in the same reaction vessel and provides high regioselectivity, atom efficiency and does not involve workup and isolation of many intermediates [1]. One-pot multi-component synthesis has great importance in organic synthesis and has increased in prevalence in recent years, particularly in heterocyclic chemistry, which involves the simultaneous construction of multiple new C−C and C−heteroatom bonds [2]. There are several terminologies to describe one-pot synthesis, including “cascade or tandem or domino reaction”, “multicomponent reaction” or “one-pot step-by-step synthesis” [3]. The definition of one-pot reactions, Figure 1, based on a single-operation reaction involving one reagent (intramolecular) or two reagents (intermolecular) with sequential chemical transformations should be called a cascade reaction instead of a multi-step reaction; a one-operation reaction with three or more reagents should be called a multicomponent reaction (MCR) instead of a one-pot reaction, although they belong to this category. These are reactions that converge to form a product containing substantial elements from all or most of the atoms of the reagents; a one-pot reaction with multiple steps, with three or more reagents of operation, should be called one-pot stepwise synthesis (OPSS) rather than a cascade reaction because this OPSS is carried out step by step using different reaction conditions for different steps [4,5,6].

In the last decade, several one-pot syntheses have been reported to construct various molecular scaffolds of biological interest. Synthetic methods are very valuable because they avoid various reaction steps as well as purification of intermediate products [7]. Orthoesters have occupied a significant place in the synthesis of heterocycles since the beginning of the 20th century. Orthoformates are a very valuable group of reagents that are storage-stable and very reactive. As alkylating agents, they transfer the associated alkyl group; on the other hand, as formylation reagents, they are reactive in acidic as well as basic conditions [8]. The reaction of amines with orthoesters is a suitable and commonly used synthetic approach to obtain imidates, amidines, triazachrysenes, and quinazolines [9,10]. Triethyl orthoformate (TEOF), an organic compound with the formula CH(OEt)₃, also called diethoxymethoxyethane, ethyl orthoformate and triethoxymethane, is a colorless volatile liquid, orthoester of formic acid and is commercially available (C₇H₁₆O₃, MW = 148.23 g/mol, bp = 146 °C, mp = −76 °C and d = 0.891 g/mL), which also being soluble in many organic solvents (water, alcohol, ether, etc.).

This review summarizes some procedures of triethyl orthoformate reactions in the one-pot synthesis of heterocyclic compounds.

2. Synthesis by Two-Component Reaction

Benzimidazole, benzoxazole, benzothiazole and their derivatives are essential classes of heterocyclic compounds in medicinal chemistry, presenting considerable biological activities [11]. In the past, various synthetic methods have been described in the literature via the condensation reactions of triethyl orthoformate (TEOF) 1 with substituted amino aromatics 2 (Scheme 1), such as o-phenylenediamine, o-aminophenol, and o-aminobenzenethiol, by the presence or absence of catalytic amounts under solvent-free conditions [8,12,13,14].

Numerous other methods for using TEOF with hydrazino reagents have also been documented in the literature [8]. Al-Majidi, in 2014, obtained 1,2,4-triazolo[3,4-b]benzothiazole 5 (65%) via treatment of TEOF 1 with 2-hydrazinobenzothiazole 4, under the reflux of methanol and in the presence of acetic acid (a few drops) for 3 h (Scheme 1) [15].

Wang et al. [16] combined TEOF 1 and 2-amino-N-(1-arylethylidene)benzohydrazide 6 catalyzed by 10 mol % iodine (I₂) in ionic liquid gave pyrazolo[5,1-b]quinazoline moiety 7 (Scheme 1). In the presence of K₂S₂O₈, it can be oxidized and produce aromatized products 8 with excellent yields (75–86%).

Proença et al. [9] described the formation of triazachrysenes 10 through the dimerization of 2-aminobenzonitrile 9 by a cascade reaction (Scheme 2). The sequence involved the reaction of TEOF 1 with 2-aminobenzonitrile 9 using a protic acid as catalyst (H₂SO₄/HNO₃/CH₃COOH) ranging from 41 to 83% under different optimization conditions. When water was used as a solvent, one of the dimerization conditions, a new product (11), was obtained, with only a yield of 26–33%. The proposed mechanism involves the attack of 2-aminobenzonitrile 9 on the imidate formed by another molecule 9 with TEOF. The nucleophilic attack of the amine on the cyanide group followed by hydrolysis gave rise to the formation of compound 11, while the additional attack of the imine formed in the earlier step to the nitrile functionality gives the formation of the triazachyrsenes 10, always isolated like a salt.

In 2015, Szczepankiewicz and Kuznik [17] reported a one-step reaction for the synthesis of 3-arylquinazolin-4(3H)imines 13 by heating TEOF 1 with 2-amino-N′-arylbenzamidines 12, without solvent (Scheme 3).

Bunce et al. [18], published the path for the synthesis of quinazolin-4(3H)-ones 15 (Scheme 3), from TEOF 1 with 2-aminobenzamide 14, promoted by acetic acid, in one step.

Formamidines are one of the vital intermediates for the synthesis of heterocyclic and functional group changes. Generally, this synthesis includes the reaction between TEOF and amine derivatives, and can occur in the presence or absence of an acidic catalyst.

F. Shirini et al. [14], described a green and efficient procedure for the synthesis of N,N′-diarylformamidines 17, using nanoporous TiO₂ containing an ionic liquid bridge (Scheme 3). The methods provided products with very good yields, short reaction times under solvent-free conditions and catalyst reuse.

3. Synthesis by Three-Component Reaction

The three-component reaction between TEOF 1, amines 18 and diethyl phosphite 19 is the most used method for the synthesis of N-substituted aminomethylenebisphosphonic acids 20, Scheme 4. Some of these review approaches were reported in 2016 by Haji [19].

Between 2017 and 2020, Chmielewska et al. studied in some detail the three-component reaction with benzylamines [20], 3-amino-1,2,4-triazole [21], and diamines (like benzenes, cyclohexanes, cyclohexenes and piperazines) [22], which usually mainly resulted in the introduction of mono-substituted products or the formation of bisphosphonates 20, aminophosphonates 21 or mixtures of the two compounds in the molecule in addition to aminomethylenebisphosphonic acid 22. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This reaction often results in product mixtures that are difficult to separate. Cirandur et al. [23] developed the formation of aminomethylene bisphosphonates 23 via the one-pot reaction of various aryl/heteroaryl amines under microwave irradiation and solvent-free conditions, using CuO nanoparticles as catalyst.

Amira et al. [24] describe a simplified eco-friendly method for the synthesis of sulfamide-containing bisphosphonate derivatives 25 (Scheme 5) involving one-pot three-component reactions of TEOF 1, substituted aromatic sulfamides 24 and diethyl phosphite 19 under microwave irradiation (500 W, 150 °C).

Tetrazoles are a class of nitrogen-containing heterocyclic compounds, which do not exist in nature but are of certain importance. They have received a lot of attention in recent years due to their wide spectrum of applications in the field of biology and medicine, such as anti-allergic, antibiotic, anticancer, anticonvulsants, anti-HIV, antihypertensive and antiviral applications. Tetrazole is a pharmacophore fragment, which is metabolically more stable, and acts as a bioisosteric analogue for several functional groups like carboxylic acids, clamidine and furan ring [1,25,26].

Darvish and Khazraee [27] developed an efficient and facile one-pot multi-component approach for the synthesis of 1-aryl 1H-tetrazole derivatives 27 from TEOF 1, aromatic amine 16 and trimethylsilyl azide (TMSA) 26 with FeCl₃ as an environmentally benign catalyst (Scheme 6).

Tetrazole compound 27 has also been reported to be produced from sodium azide 28 instead of TMSA. In 2014, Naeimi and Mohamadabadi [28] reported that Fe₃O₄@silica sulfonic acid can be an efficient and reusable catalyst for the one-pot synthesis of 1-substituted 1H-tetrazoles 27. A wide diversity of aromatic amines containing electron-donating and electron-withdrawing groups, like acetyl, methyl, bromine and chlorine, have undergone condensation in shorter reaction times with very good yields. The catalyst can be effortlessly recovered from the reaction by a magnet and reused six times without weakening the catalytic activity. In 2015, Naeimi and Kiani [29] synthesized 1-substituted-1H-tetrazole derivatives 27 using zinc sulphide nanoparticles as a new heterogeneous catalyst at room temperature under ultrasonic irradiation (50 W), in DMF as a solvent. The same research group [30] described, in 2018, the synthesis of 27 by microwave irradiation (600 W, 60 °C), with excellent yields (73–88%) and shorter reaction time (20 min). This method has advantages over other techniques, such as the more environmentally friendly process, the recyclable solid catalyst and solvent-free conditions. These authors also found that the catalyst can be recovered and used seven times with minimal loss of its action.

Similarly, Khan et al. [31] explore a series of 1-aryl 1H-tetrazole derivatives 27, as antibacterial agents, using silver oxide as a reusable catalyst. The synthesized compounds were obtained with high yields between 85 and 93% in a short time of 30–50 min. Another approach for the synthesis of 1-aryl 1H-tetrazole derivatives 27 using Fe₃O₄/HT-NH₂-Cu^II as a new heterogeneous catalyst was reported by Salimi and Zamanpour [32]. The corresponding products were isolated in good yields in water as solvent. The catalytic activity of Fe₃O₄@SiO₂-Im[Br]-SB-Cu (II) was investigated, by Mashhoori and Sandaroos [33], in the synthesis of 1-aryl 1H-tetrazole derivatives 27. As proposed by the authors, the mechanism proceeds with TEOF 1 activated by the N₃-coordinated Cu(II)Nano-catalyst followed by the attack of amine 16 on TEOF, which results in the formation of an amide acetal intermediate. Nucleophilic attack of the azide anion on the acetal amide followed by cyclization leads to tetrazole 27.

A similar approach was described by Sarg et al. [34], using the combination of TEOF 1 with 3-amino-thiophene-2-carboxylates 29 in the presence of sodium azide 28 afforded the 3-tetrazolylthienopyridine-2-carboxylate derivative 30 (Scheme 7). Also, treatment with 2-amino-thiophene-3-carboxylates 31 in acetic acid afforded 2-(1H-tetrazol-1-yl)thiophenes derivatives 32, in good yields (Scheme 7) [35].

Muralidharan et al. [36], also synthesized tetrazole derivatives such as 2-(1H-tetrazol-1-yl)-1H-imidazole-4,5-dicarbonitrile 34, 1-(1H-1,2,4-triazol-3-yl)-1H-tetrazole 36, and 5-(1H-tetrazol-1-yl)-1H-1,2,4-triazol-3-amine 3 via the reaction of TEOF 1 and NaN₃ 28 with imidazole 33, and triazole 35 and 37, respectively (Scheme 7).

The reaction between substituted thiazolylamine or oxazolylamine in DMSO and tributylmethylammonium chloride (TBMAC) as catalyst gives 1-substituted 1H-1,2,3,4-tetrazole, isolated in excellent yields (Scheme 8) [37].

Substituted quinazolines or quinazolinone analogs, bicyclic heterocyclic compounds obtained from the combination of two six-membered aromatic rings of benzene and pyrimidine, are a class of nitrogen-containing heterocyclic compounds which have attracted widespread attention in medicinal chemistry for the design and development of new drugs due to their numerous biological properties that depend on the position and nature of the substituent in their skeleton and include, among others, antibacterial, anticancer, anti-inflammatory, antifungal, antihypertensive, antimicrobial and antiviral properties. Conventional heating methods are generally applied, as well as other strategies that include the use of efficient and more environmentally friendly catalysts, or microwave irradiation. The synthesis of quinazoline derivatives has also attracted great attention in recent years, and numerous synthetic procedures for their formation have been developed [38,39,40,41,42,43]. It is currently in numerous accepted drugs and biologically active compounds, like erlotinib, gefitinib, prazosin, rutaecarpine and many others, as well as in clinical candidates and biologically active molecules [44,45,46]. Pyrimidines and their derivatives are an important class of heteroaromatic systems found in natural products, used as key intermediates in medicinal chemistry to generate new chemical structures with a diverse range of pharmacological activities, and are gaining attention due to their structural similarity to the purines [47].

Compounds 46 were prepared in yields of 79–85%, via the one-pot reaction between TEOF 1, with the 2-amino-thiophene-3-carboxylates 45 and the appropriate amine 18 (Scheme 9) [48].

An efficient procedure for the synthesis of 4(3H)-quinazolinones 48, (Scheme 10) by one-pot reaction of TEOF 1, amines 18 and anthranilic acid 47 was also reported in the literature, using Zn(ClO₄)₂ [49], silica-supported boron trifluoride (BF₃–SiO₂) [50], CoCl₂ [51], thiamine hydrochloride (vitamin B₁) [52], and I₂ [53] as the organocatalyst. The different quinazolinone 48 were obtained in yields of 67–98% within 15 min to 8 h, at reflux or room temperature.

Venkateswarlu et al. [54] describe a facile, three-component, one-pot synthesis of 8H-quinazolino[4,3-b]quinazolin-8-ones 49 from TEOF 1, 2-aminobenzonitriles 9 and anthranilic acid derivatives 47, with good yields, Scheme 11.

Different types of 3-acetyl-4-hydroxiquinoline derivatives 51 (Scheme 12) were synthesized by a highly efficient multi-component microwave irradiation (MW) with reduced reaction times and good yields using TEOF 1, and aromatic amines 16 with ethyl acetoacetate 50 [55]. Huang et al. [56] reported two effective, sustainable and clear approaches for the formation of quinolone derivatives based on a branched/linear domino procedure under ecological conditions. The position of the substituent significantly affected the reaction yield. Groups like halogen, methyl, methoxy, nitro, and trifluoromethyl at the para position of anilines reacted easily with TEOF 1 and dicarbonyl compound 50 provided the corresponding products 52 with good yields (Scheme 12). If the methyl or methoxy group is situated in the meta or ortho position, this may result in moderate yields. The reactions of dicarbonyl compounds substituted by phenyl, t-butyl and cyclopropyl were carried out under ideal reaction conditions and produced products with moderate to excellent yields. When diethyl malonate was used in the reaction, the product yield was reduced.

Rad-Moghadam et al. [57] reported a microwave-promoted one-pot method for the synthesis of 4-aminoquinazoline 54 (Scheme 13). The possible mechanism of the reaction mainly includes the formation of the amidine intermediate from the reaction of TEOF 1 with 2-aminobenzonitrile 9 and NH₄OAc 53. This is followed by the nucleophilic attack of the amino group on the carbon atom of the nitrile group which gives the formation of the 4(3H)-iminoquinazoline intermediate, tautomerizes and results in product 54.

The formation of quinazolin-4(3H)-imines from TEOF 1, 2-aminobenzonitrile 9 and variously substituted aniline 18 using ammonium chloride as promoter, assisted by microwave irradiation, has also been reported (Scheme 14) [58]. Using substituted aniline, the reaction gave an excellent yield of the resulting products, regardless of the electron-donating or electron-withdrawing substituent positioned on the aniline ring.

Zhang et al. [59] described a palladium(II)-catalyzed cascade reaction of TEOF 1 with 2-aminobenzonitriles 9 and boronic acids 55 that produces 4-arylquinazolines 56, in good yields (Scheme 15). The pathway involves the coupling of the sp-sp2 carbon bond followed by the formation of the intramolecular carbon-nitrogen bond.

Rao et al. [60] described the cyclocondensation of TEOF 1 with ethyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate 57, which, in the presence of a few drops of acetic acid as a catalyst and substituted aniline 16, gave ethyl (halo substituted phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate derivatives 58 in good yield (Scheme 16).

A simple, one-pot synthesis by a three-component coupling reaction of TEOF 1, ammonium acetate 53 and ketones 59 or 61 is also reported, as shown in Scheme 17. Konakahara et al. [61] use the multicomponent coupling reaction catalyzed by zinc chloride (ZnCl₂) for the synthesis of the 4,5-disubstituted pyrimidine derivative using ketone 59, in a single step. Soheilizad et al. [62] report the synthesis of pyrimidine derivatives 60 in the presence of boron sulfuric acid as a recyclable and effective catalyst under solvent-free conditions. This procedure has some advantages, such as catalyst reuse, shorter reaction time (2 h) and good yields (70–86%). Trivedi et al. [63], presented an efficient and ecofriendly method for the synthesis of 4-disubstituted quinazolines 62, under solvent and catalyst-free conditions at 100 °C, from 2-aminoaryl ketones 61. This method provides high yields (88–94%) in a moderate reaction time (90–120 min).

Dolzhenko et al. explored a one-pot reaction using TEOF 1, and cyanamide 63 with different amines under microwave irradiation (MW), at 150 °C (Scheme 18). This three-component reaction produced a variety of amino substituents, making it perfect for generating compound libraries for drug discovery processes. In general, this multicomponent reaction does not require any catalyst, resulting in the formation of product with high purity and similar yields. These authors confirm that the method is reproducible in diverse microwave reactors and under microwave-like heating. The synthesis of substituted 5-aza-adenines 65 [64,65] or 5-aza-7-deaza-adenines 67 [66] or 5-aza-9-deaza-adenines 69 [67,68] from 5-amino-1,2,4-triazoles 64 or 2-amino-4-phenylimidazole 66 or 5-aminopyrazoles 68 was performed using methanol or ethyl acetate as solvent. In these cases, higher yields were obtained with very short reaction times. Together with the previous components, TEOF 1 and cyanamide 63, 3-amino-substituted 5-aminopyrazole-4-carbonitriles 70 were used to carry out the synthesis of the new 7-aminosubstituted pyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles 71 without catalysis [69] or in the presence of DIPEA [70], both in methanol.

A three-component, microwave-assisted reaction of TEOF 1 with a series of cyclic secondary amines 72 and 5-aminopyrazoles 70, was also developed by Dolzhenko et al. [71] for the synthesis of the new N-pyrazolylformamidines 73 (Scheme 19).

The efficient three-component reaction of TEOF 1 with cyanoamide 63 and primary aromatic amines 16 at reflux in toluene provides N′-aryl-N-cyanoformamidines 74 in high yields (Scheme 20). It is reported that the reaction occurred in toluene as the selected solvent as it forms an azeotrope with the ethanol that can be eliminated from the system by distillation, permitting a fast and broad exchange of reagents [72].

In 2023, Kalinin et al. [73], reported the synthesis of formamidines 75, Scheme 21, by a three-component, one-pot method, as key intermediates for the further synthesis of 5-azapurines derivatives.

Hua et al. [74] described the one-pot synthesis of TEOF 1 and primary amines like benzylamine 77, aniline 79 and adenine 81 with pyridinone 76 under similar reaction conditions (DMF and AcOH). Monocyclic pyridinones 78–82, were formed in yields of 68%, 61% and 50%, respectively (Scheme 22).

The synthesis of a novel class of enaminone derivatives 84 with TEOF 1, aryl/heteroaryl amines 18 and lawsone 83, in guanidinium chloride as organocatalyst under solvent-free condition at 90 °C was reported by Olyaei et al. in excellent yields (75–87%) (Scheme 23) [75].

In 2015, Sadek et al. [76] reported a one-pot reaction for the synthesis of pyrazolo[1,5-a]pyrimdines-7(4H)-ones 87 through the reaction of TEOF 1, 5-aminopyrazoles 18 and Meldrum’s acid 85, under dioxane reflux (Scheme 24). A series of five 5-arylidene Meldrum’s acid derivatives 86 were synthesized in 13–68% yield via Knoevenagel condensation from aryl amine 18, by Pungot et al. [77]. More recently, other derivatives of 5-aminomethylene Meldrum’s acid 86 have also been successfully synthesized by Al-Messri [78] with different aromatic amines 18, TEOF 1 and Meldrum’s acid 85. The reaction proceeded through a Knoevenagel condensation of TEOF 1 with Meldrum’s acid 85 to produce an intermediate such as Michael’s acceptor, followed by the regioselective addition of Michael’s with the exocyclic amino moiety of the amino compound 18 to obtain the corresponding acyclic adducts 86. After intramolecular cyclization, elimination of acetone and CO_2, it yielded 87.

Vandyshev et al. [79,80] explored the cascade heterocyclization reactions of TEOF 1, 1,2-diamino-4H-phenylimidazole 88 with cyclohexanedione 89 or ethyl acetoacetate 50 (Scheme 25). High yields of imidazo[1,5-b]pyridazines 90 and 91 were obtained when a mixture of dimethylformamide (DMF), isopropyl alcohol (i-PrOH) and acetic acid, in catalytic amounts, were used as solvents.

A novel series of hetarylaminomethylidene derivatives 93 was reported by Tikhomolova et al. [81], and this author used furan-2(3H)-ones 92 by a three-component reaction (Scheme 26). As proposed by the authors, the mechanism can proceed in two ways (Scheme 27). In pathway A, the reaction continues through the formation of intermediate imine 94 in situ by the nucleophilic addition of amine 18 to TEOF 1, which loses two ethanol molecules. Then, furan-2(3H)-one 93 reacts with imine 94 to form intermediate 95, yielding 93, after which another ethanol molecule is eliminated. On the other hand, in pathway B, the initial reaction is that of furan-2(3H)-one molecule 92 with 1 to form ethoxymethylene derivatives 96, which are converted into intermediate compounds 95, by reaction with amine 18. Product 93 is obtained after eliminating another ethanol molecule.

More recently, Berrichi et al. [82] synthesized the 2-imino-2H-pyrano[3,2-c]pyridin-5(6H)-ones derivatives 98 (Scheme 28) between TEOF 1, primary amines 18 and 2H-iminopyranes 97. The reaction takes place at 80 °C for 5 h, in the presence of acetic anhydride. Various primary amines such as aromatic, cyclic and aliphatic were used to explore the versatility of this approach in synthesizing new compounds.

4. Synthesis by Four-Component Reaction

Wu et al. [83] reported a palladium-catalyzed four-component carbonylative coupling system for the formation of 3-aryl-4(3H)-quinazolinones 48 in a one-pot approach. A combined mixture of TEOF 1, 2-bromoanilines 99, amine 16 and carbon monoxide (CO) 100 with a palladium acetate/di(1-adamantyl)-n-butylphosphine [Pd(OAc₂)/(BuPAd₂)] complex at 100 °C gives 3-aryl-4(3H)-quinazolinones 48 with good yields (Scheme 29).

Heterocycles containing a pyridone core have a diversity of biological properties, such as anticancer, antiulcer, ACE-inhibiting, anti-inflammatory, antifungal, anti-HIV, antiviral and cardiotonic activities [84].

Huang et al. [2] described, for the first time, a new four-component synthesis of a substituted 2-piridone derivative 102 (Scheme 30) by branched domino reaction between TEOF 1 as a building block C1, aromatic amines 16 and two categories of dicarbonyl compounds, such as 1,3-acyclic diketones 50 and diethyl malonate 101, under microwave irradiation (120 °C). The same research group also evaluated the scope and limitations of the reaction with various alkylamines or other amines, and products were obtained in yields of 50 to 78%.

5. Conclusions

One-pot reactions allow many reactions to be combined so that synthetic efficacy can be initiated to match that of nature, but important tasks remain before this promising method will be able to meet the demands of pharmaceutical chemistry and materials. In summary, we have reviewed recent developments in the one-pot reactions of triethyl orthoformate with different amines and numerous new reaction sequences have been developed in the last decade. The reaction method allows combining several catalytic procedures in the same reaction vessel and provides high regioselectivity, atomic efficiency and does not involve workup and isolation of many intermediates.