Applications of alkyl orthoesters as valuable substrates in organic transformations, focusing on reaction media

Abstract

In this review we focus on applications of alkyl orthoesters as valuable and efficient substrates to perform various classes of two-component and multi-component organic reactions. The article has classified them according to two aspects, which are: (i) a focus on the reaction medium (solvent-free conditions, aqueous media, and organic solvents); and (ii) an examination of product structures. Reaction accomplishment under solvent-free conditions is an eco-friendly process with the absence of volatile toxic solvents, which puts it in line with green chemistry goals. Water is an interesting choice in organic transformations due to its inexpensiveness and safety. The authors hope their assessment will help chemists to attain new approaches for utilizing alkyl orthoesters in various organic synthetic methods. The review covers the corresponding literature up to the beginning of 2020.

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1. Introduction

Orthoester (1,1,1-triorganyloxyalkane) (1) is the general name for a functional group containing three alkoxy groups attached to one central carbon atom, with the general formula RC(OR')₃. In fact they are the esters of orthoacids which do not exist in a free state.^1,2 Orthoesters were first synthesized via nucleophilic the substitution reaction of chloroform (2) with alkoxides (3) by Williamson and Kay in 1854 (Scheme 1).³ There are several examples of acyclic alkylorthoesters such as:⁴

Scheme 1 The Pinner reaction for orthoester synthesis.

(a) Trimethyl orthoformate (TMOF) is the simplest orthoester in organic chemistry, which is also called trimethoxymethane, 2-methoxyacetaldehyde dimethyl acetal, methoxymethylal, and methyl orthoformate. This colorless liquid with a pungent odor is soluble in ethanol and ether ((CH(OMe)₃, 4), bp = 100.6 °C, and d = 0.9676 g mL⁻¹).

(b) Triethyl orthoformate (TEOF, CH(OEt)₃, 5), also called diethoxymethoxyethane, triethoxymethane, and ethyl orthoformate a colorless volatile liquid with bp = 146 °C and d = 0.891 g mL⁻¹, is the orthoester of formic acid.

(c) Triethyl orthoacetate (TEOAc, CH₃C(OEt)₃, 6) 1,1,1-triethoxyethane, (bp = 142 °C, d = 0.885 g mL⁻¹), is an oily yellow to colorless liquid with a pungent odor.

(d) Triethyl orthopropionate (CH₃CH₂C(OEt)₃, 7), also called 1,1,1-triethoxypropane and orthopropionic acid triethyl ester, is a clear colorless liquid (bp = 155–169 °C, d = 0.886 g mL⁻¹) which is soluble in alcohol, chloroform, ethyl acetate, and ether and hydrolyzes slowly in water.

(e) 3,3,3-Triethoxy-1-propyne (HCC(OEt)₃, 8).

Orthoesters may be considered to be products of the exhaustive alkylation of unstable orthocarboxylic acids and it is from these that the name “orthoester” is derived. Orthoesters are highly reactive owing to the electron-deficient central carbon atom caused by the –I effect of the electronegative groups OR.¹ Among the ortheosters introduced above, TEOF involved maximal exploitation in the reactions based on our literature survey (109 reports) followed by TMOF (54 reports), TEOAc (21 cases), TMOAc (4 items), and triethyl orthopropionate (2 cases), and other kinds of alkyl orthoesters (1 case) (Fig. 1a). Several orthoesters were applied in various domains as dehydrating agents,^5–18 alkylating agents,^19–24 dialkoxymethylation agents,²⁵ esterification agents,²⁶ methoxy sources,²⁷ additives,^28–30 solvents,^31–33 and protecting groups.^34–36 This functional group is also necessary for some conversions such as the Johnson–Claisen rearrangement.³⁷ Fig. 1b demonstrates the assorted applications mentioned vs. the type of orthoester. As specified, TMOF and TEOF are the most commonly used in different processes, except for the case of rearrangements where TMOAc is the most abundant.

Fig. 1 The abundances of different orthoesters as substrates in organic transformations (a), assorted applications of different kinds of orthoesters in some processes (b), and the classification of their utilization in various domains of science and technology (c).

Different kind of orthoesters also have many applications in several branches of science, such as polymers,^38–43 liquid-crystalline compounds,⁴⁴ biochemistry,^45–49 medicine^50–56 and medicinal organic chemistry,^57–60 inorganic chemistry,^61,62 organometallic chemistry,⁶³ dynamic covalent chemistry,⁶⁴ supramolecular chemistry,^65–68 and crystal structure analysis.⁶⁹ Orthoesters have also been used in the synthesis of natural products, e.g. loganin is a monoterpene glucoside occupying a central position in the generation of secoiridoids and alkaloids, obtained from orthoesters biosynthetically. Because of this, in 1973, Buechi and co-workers described the total synthesis of loganin. It should be noted that trimethyl orthoformate was employed in some of the steps in the preparation of loganin,⁷⁰ and the total synthesis of (−)-monomorine,⁷¹ and (±)-vernolepin.⁷² It has been reported that TEOF is exploited in the total synthesis of palytoxin, as a marine natural product.⁷³ In 1976, Greenlee and Woodward reported the total synthesis of marasmic acid, one of the many fungal metabolites obtained from the Basidiomycetes, in which trialkyl orthoformates were applied in some of the syntheses.⁷⁴ Chan and Koide utilized orthoesters for the first total synthesis of the stresgenin B scaffold as a heat shock protein expression inhibitor.⁷⁵ The application of orthoesters in the synthesis of condensed carbon-cage organics was investigated in the preparation of twistane as a cycloalkane and also the simplest diamondoid. In 1967, Gauthier and Deslongchamps obtained twistane via a multi-step process started by TEOF as one of the substrates.⁷⁶ The diagram in Fig. 1c illustrates the vast range of applications of different kinds of orthoesters in various sciences. The results indicate the comprehensive use of orthoesters in many domains of science and technology.

In addition to the Williamson and Kay method, there are various procedures for the preparation of orthoesters. The Pinner reaction of nitriles (9) with alcohols (10) in the presence of strong acids generated orthoesters (Scheme 1).⁷⁷ Electrochemical approaches^78–81 are also employed for the synthesis of these compounds, e.g., new highly fluorinated orthoesters (14) were synthesized through the functionalization of 1,3-benzodioxoles (11) in the 2 position with diverse fluorinated alcohols (such as 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP, 12) or 2,2,2-trifluoroethanol (TFE, 13)) in an undivided cell and in the presence of N,N-diisopropylethylamine or 1,8-diazabicyclo-[5.4.0]undec-7-ene (DIPEA/DBU) as basic electrolytes by boron-doped diamond (BDD) electrodes under a constant current density of 7.2 mA cm⁻² until a catalytic quantity of 3.0 F mol⁻¹ of electricity has passed (Scheme 2).⁸²

Scheme 2 The electrochemical synthesis of highly fluorinated orthoesters.

Secondary and tertiary amides (15) were reacted with triflic anhydride (16) by pyridine in CH₂Cl₂ at low temperatures to form imino and iminium triflates within 4 h, which on treatment with 2,2-bishydroxymethyl-1-propanol (17) utilizing pyridine buffered solution attained 2,6,7-trioxabicyclo[2.2.2]octane orthoesters (18) (Scheme 3).⁸³

Scheme 3 A synthetic approach to 2,6,7-trioxabicyclo[2.2.2]octane orthoesters.

2,4-Di-O-benzoyl-myo-inositol 1,3,5-orthoformate (20), a cyclic alkyl orthoester, was obtained from successive treatment of myo-inositol (19) with TEOF (5) and benzoyl chloride by Shashidhar and Praveen in 2001 (Scheme 4).⁸⁴

Scheme 4 The preparation of 2,4-di-O-benzoyl-myo-inositol 1,3,5-orthoformate.

The reaction of epoxides (21) and lactones (22) in the presence of a cationic indium catalyst under heating with benzene resulted in spiro orthoesters (23) (Scheme 5).⁸⁵

Scheme 5 The synthesis of spiro orthoesters.

Tetrahydropyranyl acetals containing a phenyl diazoketone substituent (24) underwent Rh(II)-catalyzed C–H insertion through an unusual C–O bond generation to give spirocyclic orthoesters (25) (Scheme 6).⁸⁶

Scheme 6 The Rh(II)-catalyzed synthesis of spirocyclic orthoesters.

3,4,6-Tri-O-acetyl-1,2-O-(1-tocopheroxyethylidene)-α-D-glucopyranose (vitamin E sugar 1,2-orthoester) (33–36) with exo-type stereoselectivity were synthesized through the reaction of sugar halides (26–29) with various phenols, such as α-tocopherol (30), chroman-6-ol (31), and 2,6-dimethylphenol (32) by N,N-diisopropylethylamine (DIPEA) and tetrabutylammonium iodide (TBAI) or tetraethylammonium bromide (TEABr) in refluxing CH₂Cl₂ for 4–24 h. The obtained peracetylated orthoesters (33–36) were deprotected by utilizing aminolysis (NH₃/MeOH) or by reduction in the presence of DIBAL-H (Scheme 7).⁸⁷

Scheme 7 Synthetic procedure for peracetylated orthoester.

Palladium on carbon (Pd/C) catalyzed the straightforward methoxylation of the benzylic positions of cyclic acetals (37) by i-Pr₂NEt in refluxing methanol under atmospheric oxygen as a green oxidant to obtain orthoesters (38) (Scheme 8).⁸⁸

Scheme 8 The synthesis of orthoesters via the methoxylation of cyclic acetals.

The Koenigs–Knorr glycosylation reaction of glucopyranoside (39) with rhamnosyl chloride (40) as a glycosyl donor was accomplished using a catalytic amount of 2-aminoethyl diphenylborinate (2-APB, 5 mol%)⁸⁹ and silver(I) oxide (Ag₂O) in acetonitrile at 60 °C to obtain the mixture of 3- and 2-orthoesters (41) and (42) in 55% and 36% yields, respectively within 3 h (Scheme 9).⁹⁰

Scheme 9 The preparation of orthoesters via the Koenigs–Knorr glycosylation reaction.

Zhao et al. prepared sugar 1,2-orthoesters (45) via the reaction of peracetylated mannopyranosyl bromides (43) with alcohol derivatives (44) and anhydrous sodium acetate (NaOAc) as a base in acetonitrile at room temperature under ultrasound irradiation (40 KHz and 600 W) (method A), and the traditional reaction under high-speed magnetic stirring (method B). The results confirmed that an ultrasound-assisted reaction proceeded much better than the traditional method (70–91% yields, 3–6 h) (Scheme 10).⁹¹

Scheme 10 The synthetic route to sugar 1,2-orthoesters.

The reaction of dilactone (46) with ethylene glycol (47) by p-toluenesulfonic acid (p-TSA) in the presence of magnesium sulfate in refluxing benzene obtained the crystalline ethylene orthoester (48) in 66% yield within 4.5 h, which underwent a reduction reaction with diisobutylaluminum hydride as a reducing agent in combined dimethoxyethane/toluene (1 : 2) media at −76 °C to room temperature to afford the hydroxy aldehyde (49) in 94% yield (Scheme 11).⁹²

Scheme 11 The preparation of a crystalline ethylene orthoester possessing an aldehydic moiety.

Hexachlorobuta-1,3-diene (50) was refluxed with sodium methoxide in methanol for 12 h to obtain a mixture of 4,4-dimethoxy-2-oxobut-3-enoic acid (51) and (Z)-2,4,4-trichloro-1,1,1,3-tetramethoxybut-2-ene (52) in 39% and 54% yields, respectively in which for easy identification, compound (51) was reacted with diazomethane (CH₂N₂) in methanol at room temperature to produce methyl (Z)-4,4-dimethoxy-2-oxobut-3-enoate (53) in moderate yield (56%), while orthoester Z-52 was converted into methyl (Z)-2,4,4-trichloro-3-methoxybut-2-enoate (Z-54) in good yield (70%) via acid hydrolysis in THF at 50 °C for 2 h (Scheme 12).⁹³

Scheme 12 The synthesis of some Z-orthoester structures.

In 2018, a review entitled “Synthesis and biological activity of oxazolopyrimidines” was published. In some parts of it, orthoesters were used to prepare oxazolo[4,5-d]pyrimidines and 7-aminooxazolo[5,4-d]pyrimidines.⁹⁴

Perillo et al. presented a review article entitled “Synthesis and properties of seven- to nine-membered ring nitrogen heterocycles. Cyclic amidines and cyclic amidinium salts” which pointed to the application of orthoesters in synthetic methods.⁹⁵ In 2011, Lavigne's research group published a review article about the route yield from N-heterocyclic carbene precursors. They introduced trialkylorthoesters as the precarbenic unit.⁹⁶ In 2013, A. Elassar and co-workers published a review article about diaminomaleonitrile (DAMN) in which the mentioned synthon reacted with various orthoesters to prepare different kinds of biologically active heterocycles.⁹⁷

Numerous review papers have reported on different applications of orthoesters;^98,99 for example, a 1986 review article entitled “Alkyl orthoesters and their applications in organic synthesis”, by Pavlova and co-workers, focused on a systematic account of data describing the chemical properties of alkyl esters of orthocarboxylic acids. The proposed reaction mechanisms were discussed and the scope of utility of the orthoesters in the solution of diverse problems in organic synthesis was shown.¹⁰⁰ Moreover, a 1988 article entitled “Carbon–carbon bond formation and annulation reactions using trimethyl and triethyl orthoformates”, by Ghosh and Ghatak, focused on the annulation reactions by orthoformates and also the introduction of a formylation–cyclization method for the production of functionalized polycyclic bridged-bicyclo[3.3.1]nonanes, cyclopentenones, and other isolated products to develop the synthetic potential of carbon–carbon bond formation reaction via orthoformates.⁹⁸ In 2007, a review of “Recent studies on reaction pathways and applications of sugar orthoesters in synthesis of oligosaccharides”, was published by Kong.¹⁰¹ In 2009, Liao and co-workers presented a focused literature survey on plant orthoesters.¹⁰² In 2014, a review article with the title “The orthoester Johnson–Claisen rearrangement in the synthesis of bioactive molecules, natural products, and synthetic intermediates-recent advances”, was published with 211 ref. 103. In 2016, another review was also published with the title “Recent development in the orthoester Johnson–Claisen rearrangement and application”, by the Alam group.⁹⁹ In 2009, a spotlight titled “Alkyl orthoformate: a versatile reagent in organic synthesis”, was compiled by Frizzo.¹⁰⁴ It should be noted that, during the preparation of this review article, a paper was published entitled “Orthoesters: multiple role players in organic synthesis”, by Nazarian and Dabiri.¹⁰⁵

Due to the central role of orthoesters and their comprehensive applications, the authors considered the literature reports of usage of orthoesters according to several classes of organic transformations. The initial classification is based on the reaction media: solvent-free conditions, aqueous medium and organic solvents. Each part is also subdivided according to the structures of the achieved products. This dual classification demonstrates the importance of the reaction media in progressing the preparation of each class of organics, because the nature of the solvent and its interaction with the reaction components and reagents (orthoesters and other participants) affect the route of the process and may change it seriously. The authors hope the review will highlight the significant role of orthoesters in organic and pharmaceutical chemistry as well as in biosciences and be a proper guide to designing new procedures and approaches to obtain new organics to reach a better life.

2. Orthoester reactions under solvent-free conditions

Performing organic reactions under solvent-free conditions has been notable recently for chemists due to its individual eco-environmental and economical features. In fact, in the absence of solvents the substrates are closer, allowing the right effectual contacts to let the reaction happen. This process, that elevates the reactivity of the substrates, diminishes the reaction time and energy usage, and performs the procedures more selectively in a safe and clean manner. In addition, the absence of hazardous solvents is in line with the rules of green chemistry, turning the transformation into an eco-friendly process. So, because of the importance of the reaction being accomplished under solvent-free conditions, below we focus on reports of utilizing orthoesters in various classes of organic synthesis. The presence of about 150 references in this area confirmed the significance of this method.

2.1. Synthesis of ethoxymethylenes

In 2004, Lamphon et al. synthesized 3-ethoxy-2-[5-(4-(morpholin-4-yl)benzylidenyl)-4-oxo-4,5-dihydro-thiaol-2-yl]acrylonitrile containing an ethoxymethylene moiety (56) in 74% yield via the condensation of TEOF (5) with 2-cyanomethyl-5-[4-(morpholin-4-yl)benzylidenyl]-4,5-dihydro-4-thiazolinones (55) under reflux conditions within 3 h (Scheme 13).¹⁰⁶

Scheme 13 The synthesis of 3-ethoxy-2-[5-(4-(morpholin-4-yl)benzylidenyl)-4-oxo-4,5-dihydro-thiaol-2-yl]acrylonitrile by TEOF.

2.2. Synthesis of ethoxymethylene amino derivatives

In 2001, Mekheimer presented a novel technique for the synthesis of ethoxymethyleneamino derivative (58)^107–110 in high yield (73%) via the condensation of a 1,8-naphthyridin-2-one ring system (57) with TEOF under reflux conditions within 8 h.¹⁰⁹ Condensation of TEOF¹¹¹ with 3-amino-5-bromo-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile¹¹² also generated a Schiff base (Scheme 14).¹¹³

Scheme 14 The synthesis of ethoxymethyleneamino derivatives.

2.3. Synthesis of acetamides

In 2015, Grandi et al. presented an efficacious, fast and high-yielding method for the conversion of amine hydrochloride salts (61) to acetamides (63). Initially, the reaction between equimolar amounts of the primary and secondary amines (59) with ammonium chloride (60) under heating in ethanol obtained amine hydrochloride salts (61) in a 2 h period with excellent yields (>90%)¹¹⁴ which were transformed into their corresponding acetamides (63) via the acetylation reaction with trimethyl orthoacetate (62)^115,116 by two different pathways: (a) using microwave irradiation (Biotage Initiator™ Sixty EXP) at 135 °C in methanol, and (b) under conventional heating conditions through refluxing. The results demonstrated that MW-assisted reaction promotion with shorter reaction times (15 min) than conventional heating (1–4 h) (Scheme 15).¹¹⁶

Scheme 15 The synthesis of acetamides from amine hydrochloride salts and trimethyl orthoacetate.

In 2010, Khan et al. presented a simple methodology for the synthesis of unsymmetrical N,N′-disubstituted acetamidines (67).^117,118 In this paper, ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)ethanimidoate (65) was first prepared via the condensation reaction of 3-amino-2-phenyl-4(3H)-quinazolinone (64) with TEOAc (6) using acetic acid under reflux conditions. After completion of the reaction, the mixture was poured into ice-cold water. The resultant precipitation was filtered, washed with water and recrystallized from ethanol to produce (65) as a white crystalline solid in 83% yield within 5 h.¹¹⁹ In the next step, N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines (67) were obtained through the condensation reaction of (65) with substituted aromatic amines (66) by glacial acetic acid at reflux condition in moderate to excellent yields (46–95%) for 4–5 h (Scheme 16). It was found that electron-donating aromatic amines gave the corresponding acetamidines in good yields while the reaction failed with electron-withdrawing aromatic amines. The reaction proceeded selectively with just primary aromatic amines, including electron-donating substituents.¹¹⁸ On the other hand, symmetrical N,N′-disubstituted acetamidines were produced by a microwave-assisted (850 W) condensation reaction of triethyl orthoacetate with the anilines in acetic acid within very short reaction times (5–7 min). High yields and high purity of the product were obtained by the removal of ethanol as a by-product, via placing a receiver between the round-bottom flask and the condenser under heating by microwave irradiation at 850 W for 2–3 min.¹²⁰

Scheme 16 The preparation of N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines begins by forming amino quinazolinone and TEOAc.

2.4. Synthesis of imines

In 2012, Olyaei et al. synthesized novel anil-like products (70)^121,122 via the one-pot three-component condensation reaction of naphthols (68), TEOF (5), and heteroaryl amines (69) by formic acid as catalyst under solvent-free conditions at 80 °C in high yields (79–90%) within 1.5–2.5 h (Scheme 17). Investigation of ¹H NMR and FT-IR exhibited that the products are in tautomeric equilibrium between the enol–imine and keto–enamine forms. Moreover, intramolecular hydrogen bonds were observed in the synthesized Schiff bases. In this research, 14-(2-hydroxynaphthyl)-14H-dibenzo[a,j]xanthene was also prepared through the treatment of 2-naphthol with TEOF in the absence of heteroaryl amines under solvent-free conditions at 80 °C.¹²²

Scheme 17 Anil-like product formation utilizing TEOF.

2.5. Synthesis of imidates

In 2018, Verrier et al. reported metal and solvent-free microwave-assistance for the convenient preparation of N-sulfonyl and N-sulfinyl imidate derivatives by a leaky septum filled up with 4 Å MS which was placed 3 cm above the top of the microwave-tube. The treatment of trimethylorthoesters (71) with 4-methylbenzenesulfonamide (72) under solvent-free conditions at 180 °C afforded N-sulfonylimidates (73) within 10–30 min. Replacing (72) with tert-butanesulfinamide (74) in the presence of pyridinium p-toluenesulfonate (PPTS) (10 mol%) at 80 °C yielded N-sulfinyl imidates (75) within 30–60 min (Scheme 18). The design of an efficient apparatus with the ability to use molecular sieves to trap methanol, short reaction times, easy purification and isolation of the compounds, and excellent conversion and yields are some advantages of this strategy.¹²³

Scheme 18 Imidate synthetic procedure to form trimethyl orthoesters.

2.6. Synthesis of enamines

Majee et al. developed an improved method of the Miyashita protocol¹²⁴ for the synthesis of enamine derivatives (78)^125,126 by the three-component condensation reaction of 1,3-dicarbonyls (76), N-methylurea (77) and TMOF (4) using zinc triflate [Zn(OTf)₂, (5 mol%)] under solvent-free conditions at room temperature within 7–9 h in good yields (56–85%) (Scheme 19).¹²⁶

Scheme 19 Enamine synthesis by TMOF.

2.7. Synthesis of formamidines

Mazloumi et al. originated and characterized TiO₂-[bip]-NH₂⁺HSO₄⁻ as an effective and eco-friendly catalyst through the modification of nanoporous TiO₂ with bis-3-(trimethoxysilylpropyl)-ammonium hydrogen sulfate and then its catalytic activity was investigated for the generation of N,N′-diarylformamidines (80)^127,128 via the N-formylation reaction of anilines (79) with TEOF (5) under solvent-free conditions at 60 °C in very short reaction times (3–40 min) in high to excellent yields (83–100%) (Scheme 20). In this research, the formation of the unsymmetrical diarylformamidines or aliphatic formamidines was unsuccessful.¹²⁸

Scheme 20 The generation of N,N′-diarylformamidines with TEOF.

2.8. Synthesis of lactones

The condensation reaction of trans-2-alkene-1,4-diols (81) with triethyl orthoesters (6, 7) in 1 : 2 molar ratio was accomplished by utilizing catalytic amounts of hydroquinone or phenol under solvent-free conditions at 140–150 °C to give γ-lactones containing a vinylic substituent on the β-position (82) in 52–91% yields within 24 h (Scheme 21).¹²⁹

Scheme 21 The preparation of some classes of γ-lactones.

2.9. Synthesis of aminomethylene bisphosphonates

In 2011, Reddy et al. designed an easy, efficient, and green procedure for the synthesis of amino methylene bisphosphonates (85)^130–135 via the one-pot three-component condensation reaction of amines (83), TEOF (5), and dimethyl phosphite (84) using an alumina solid support (Al₂O₃) by microwave irradiation (490 W) in excellent yield (82–90%) for 12 min in two intervals. In addition to the microwave irradiation manner, the reaction was also performed under conventional thermal heating (90 °C, 3–4 h, 30–58%) (Scheme 22). The results revealed shorter reaction times and higher yields using microwave-assistance.¹³⁵ A similar transformation occurred via the treatment of primary amines, diethyl phosphite, and TEOF using amberlyst-15 under solvent-free conditions at room temperature within 90 min in good to excellent yields (70–95%). All compounds were screened for in vitro antioxidant (by nitric oxide, DPPH radical scavenging, H₂O₂ methods),^136–139 and antimicrobial activities.¹⁴⁰

Scheme 22 A three-component route to obtain amino methylene bisphosphonates.

2.10. Synthesis of aminomethylenebisphosphonic acids

In 2017, some aminomethylenebisphosphonic acids (88) were prepared by Miszczyk et al. through the reaction of 3-amino-1,2,4-triazole (86) with diethyl phosphite (87) and TEOF (5), in a 1 : 2 : 4 molar ratio (Scheme 23). The products are powerful inhibitors of the activity of J774E cells. So they can be used in antiosteolytic therapy, and are equipotent to the popular drug zoledronate and exhibit higher activity than the drug incadronate.^141,142

Scheme 23 The synthesis procedure for biologically active aminomethylenebisphosphonic acid.

2.11. Synthesis of indole derivatives

Zirconium(IV) chloride (ZrCl₄, 5 mol%) catalyzed the electrophilic substitution reaction of indole (89) with TEOF (5) in a 3 : 1 molar ratio under solvent-free conditions at 50 °C to obtain tris(indolyl)methane (90)¹⁴³ in a short reaction time (22 min) in excellent yield (95%) (Scheme 24).¹⁴⁴

Scheme 24 Tris(indolyl)methane synthesis.

The regioselective reaction of carbazole (91) with TEOF (5) using p-TSA under solvent-free conditions at 80 °C gave 9-(diethoxymethyl)carbazole (92) in 65% yield in 48 h. On the other hand, 4-methoxycarbazole (93) was regioselectively functionalized at the C₁ position via reaction with (5) in the presence of trichloroacetic acid in dichloromethane at room temperature to furnish various carbazole derivatives, such as 4-methoxycarbazole-1-carboxaldehyde (94), bis[4-methoxycarbazol-1-yl]methylium trichloroacetate (95), tricarbazolylrnethane (96) according to the reaction conditions (Scheme 25).¹⁴⁵

Scheme 25 The preparation of various heterocycles containing an indole moiety using TEOF.

2.12. Synthesis of triaroyl methanes

Boron trifluoride etherate liquid (BF₃·OEt₂, 0.05 mol) catalyzed the condensation reaction of aryl ketones (97) with TEOF (5) under microwave irradiation to obtain triaroyl methanes (98) in 55–85% yields for 8–10 min. It was found that a substrate containing a bulky group such as (99) afforded a fused cyclopentenone ring product (100) in 79% yield within 8 min (Scheme 26).¹⁴⁶

Scheme 26 The triaroyl methane synthetic procedure.

2.13. Synthesis of 5,15-diphenyl-10,20-dimethyl porphyrins

In 2003, the reaction of 5-phenyldipyrromethanes (101) with orthoesters (102) was presented for the generation of 5,15-diphenyl-10,20-dimethyl porphyrins (DPPs) (103) by trichloroacetic acid (TCA) (Scheme 27). Notably, trimethyl orthobenzoates as the bulky orthoesters produced scrambled products. Also, the 5-phenyldipyrromethane, including strong electron-withdrawing substituents on the phenyl ring, improved the scrambled products.¹⁴⁷

Scheme 27 Obtaining 5,15-diphenyl-10,20-dimethyl porphyrins (DPPs).

2.14. Synthesis of allyl alcohol

In 2019, Wormann and Maier presented an integrated procedure for the conversion of glycerol (104) to the cyclic orthoester (105) in high yield through the reaction with TMOF (4) by a catalytic amount of PPTS at room temperature for 2 h, which was converted into allyl alcohol (107) under pyrolysis conditions at 270 °C using PPTS under solvent-free conditions. This reaction progressed via the disintegration of the orthoester (105) into carbene (106) and recoverable methanol, which was followed by decarboxylation to produce the mentioned product (107) in high yield (76%) within 1.5 h (Scheme 28).¹⁴⁸

Scheme 28 Allyl alcohol preparation from glycerol and TMOF.

2.15. Orthoester exchange reaction

Calmanti et al. investigated the reactivity of glycerol (104) with TMOF (4) with the purpose of developing a credible synthetic strategy for glycerol valorization. It was found that the treatment of glycerol with TMOF under various conditions provided a mixture of compounds (105), (108), (109). Hence, in order to synthesize 4-(dimethoxymethoxy)methyl)-2-methoxy-1,3-dioxolane (109), different parameters, such as different molar ratios of TMOF, temperature, and the absence or presence of various catalysts, were examined. Significantly among different amounts of glycerol and TMOF, the best result was obtained in a molar ratio of 1 : 10 at 90 °C. Moreover, product (109) was selectively synthesized in the presence of a catalyst as well as in catalyst-free conditions, taking advantage of the thermodynamically controlled equilibrium between intermediates. To probe the effect of a catalyst, various catalysts, such as basic catalysts (K₂CO₃, ([P₁₈₈₈]CH₃OCO₂⁻) or Brønsted and Lewis acid catalysts were employed in which both Brønsted and Lewis acid catalysts progressed this reaction, and specifically Brønsted acidic ionic liquids (BSMImHSO₄ and BSMImBr) were the most efficient catalysts (Scheme 29).¹⁴⁹

Scheme 29 The synthesis of 4-(dimethoxymethoxy)methyl-2-methoxy-1,3-dioxolane.

In 2012, the one-pot fusion reaction of bis(enaminone)derivative (110) with TEOF (5) under solvent-free conditions was reported to obtain 1,1′-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(4,4,4-triethoxybut-2-en-1-one) (111) as pale red crystals in relatively high yield (57%) (Scheme 30).¹⁵⁰

Scheme 30 Preparing 1,1′-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(4,4,4-triethoxybut-2-en-1-one).

2.16. Synthesis of 1,2-dimethyltetramethoxydisilane

The reaction of methyldichlorosilane with TMOF at room temperature afforded dimethoxymethylsilane overnight^151,152 in 61% yield. Then, photolysis of dimethoxymethylsilane in the presence of a drop of mercury in the gas phase resulted in 1,2-dimethyltetramethoxydisilane in 81% yield within 8 h.¹⁵³

2.17. Synthesis of chromanes, chromenes, and thiochromene

In 2002, Yadav et al. interpreted the highly diastereoselective synthesis of 2,4-dimethoxy-2-methyl-2H-1-benzopyrans (114) via the three-component reaction of o-hydroxybenzaldehydes (112), acetone (113), and trimethyl orthoformate (4) utilizing a catalytic amount of ferric chloride hexahydrate (FeCl₃·6H₂O, 0.5 mmol) at room temperature in excellent yields (87–92%) for 20–60 min. The only diastereomer bore a trans-relationship between two methoxy groups at the 2- and 4-positions (Scheme 31). Mild reaction conditions, experimental simplicity, easily available substrates, short reaction times, and excellent yields are some of the advantages of this process.¹⁵⁴

Scheme 31 The synthesis of 2,4-dimethoxy-2-methyl-2H-1-benzopyrans.

In 2012, Ahmad and Silva Jr investigated the oxidation of different oxygen-containing benzo-fused cycloalkenes with various trialkyl orthoformates (4, 5) in the presence of hypervalent iodine reagent [[hydroxy(tosyloxy)iodo]benzene, HTIB] under solvent-free conditions. It was found that 2H-chromenes (115) generated alkoxy-substituted 4H-chromenes (116) as the main product, along with the trans-addition product (117). On the other hand, 2H-thiochromene (118) and 4-methyl-2H-chromene (120) obtained 4H-thiochromene (119) and cis-3,4-dialkoxy-4-methyl-3,4-dihydro-2H chromenes (121), respectively (Scheme 32).¹⁵⁵

Scheme 32 The synthesis of different chromenes using trialkyl orthoformates.

2.18. Synthesis of coumarin derivatives

Kulkarni and Sun's research group investigated a three-step sequence, as an array to obtain angularly fused polycyclic heterocycles with coumarin, benzofuran and pyridine rings (125). They started from 4-bromomethylcoumarins (122) and salicylonitrile (123) followed by the addition of TEOF (5) (Scheme 33). Several of these exhibited promising inflammation-inhibiting and anti-microbial properties.¹⁵⁶

Scheme 33 The synthesis of fused polycyclic heterocycles utilizing TEOF.

2.19. Etherification and esterification reaction, and Johnson–Claisen rearrangement

In 1997, Liu and co-workers described a simple and efficient process for the preparation of alkyl squarates (131) through the reaction of squaric acid (126), orthoformates (4, 5, 127–129), and appropriate alcohols (130) under reflux conditions in 77–97% yields (Scheme 34).¹⁵⁷

Scheme 34 Preparation method of alkyl squarates.

Furfuryl ethers (135) as bio-renewable fuel could be synthesized via two pathways: (a) a sequential reaction method was used in which the appropriate orthoester (5, 128, 133) was synthesized upon treatment with TMOF (4) and an alcohol (132) in the presence of ZSM-5 zeolite (Si/Al ratio = 30 : 1, ZSM-5-(30)) catalyst (40 mg) at 60–40 °C, followed by the addition of furfuryl alcohol (134) to obtain furfuryl ether (135) bio-fuels. (b) The mentioned products were synthesized through a tandem etherification condensation reaction of (4), an excess amount of alcohol (132), and furfuryl alcohol (134) at 40 °C by ZSM-5-(30) (40 mg) in good yield and good to high selectivity (Scheme 35). It must be mentioned that the low temperature applied improved selectivity by decreasing the production of hydrolysis products, and the competing polymerization reactions resulting in humin by-products.¹⁵⁸

Scheme 35 The synthesis of furfuryl alcohols.

In 2015, Zhang et al. utilized ZrO₂ supported Pd(OH)₂ (Pd(OH)₂/ZrO₂) as a new catalytic system for the synthesis of aryl ethers (137) via the reaction of substituted cyclohexanones (136) with orthoesters (4, 5, 127) as both dehydrating and nucleophilic reagents under an atmospheric pressure of oxygen (0.5 MPa) at 140 °C for 6 h (Scheme 36). It was found that in the presence of TMOF (4) reagent, the corresponding aryl ethers were obtained in moderate to good yields. Additionally, replacing other orthoester reagents, such as TEOF (5) and triisopropyl orthoformate (127) with (4) furnished the relevant products in low yields. Comparatively, the weak yields of the products compared to their high conversion were because of the generation of phenols as by-products. Due to the lower reactivity of TIPOF (127) to attain the related product than TMOF (4) or TEOF (5), this orthoester was employed as a dehydrating reagent in the reaction of cyclohexanones with alcohols to provide aryl ethers without forming isopropoxybenzene.¹⁵⁹

Scheme 36 The synthesis of aryl ethers.

In 1998, Varma and Kumar developed an applicable oxidative method for the synthesis of 4-alkoxy-2-arylquinolines (139) through the reaction of readily available 2-aryl-l,2,3,4-tetrahydro-4-quinolones (138) with orthoformates (4, 5) using the hypervalent iodine oxidative reagent, HTIB, in the presence of a few drops of perchloric acid under solvent-free conditions at reflux to room temperature within 1.5 h in good yields (75–88%) (Scheme 37).¹⁶⁰

Scheme 37 The synthesis of 4-alkoxy-2-arylquinolines.

Unsymmetrical ethers (141) were obtained via the reaction of allylic and benzylic alcohols (140) with orthoesters (5, 6, 62, 133) using acidic catalysts such as montmorillonite KSF and K10, BF₃·Et₂O, SiO₂, amberlyst-15 at room temperature under an N₂ atmosphere. It is noteworthy that the change in the catalyst was accompanied by an important change in the yields and the type of products obtained, such as dimerized ethers (142) and O-acetylated (143) via competitive reactions (Scheme 38). This reaction was general due to the presence of varied orthoesters, but selective with regard to different allylic and benzylic alcohols. On the other hand, Johnson–Claisen orthoester rearrangement^161–164 of allylic alcohols (144) with TEOAc (6) by MMKSF, MMK10, and SiO₂ under reflux conditions and N₂ atmosphere produced a mixture of Claisen ester (145), acetylated product (146), ethyl ether (147), unsymmetrical terminal ether (148), and dimeric ether (149) in which O-acetylation and O-alkylations were significant side reactions (Scheme 39).¹⁶⁴

Scheme 38 The reaction of allylic and benzylic alcohols with orthoesters.

Scheme 39 The Johnson–Claisen orthoester rearrangement of allylic alcohols.

Tamura and co-workers prepared 2-arylalkanoates (151, 152) via oxidative 1,2-aryl migration of alkyl aryl ketones (150) with diacetoxyphenyliodine, as oxidizing reagent, in TMOF (4) under acidic conditions at room temperature or 60 °C in high yields (74–88%) (Scheme 40).¹⁶⁵

Scheme 40 2-Arylalkanoate preparation.

In 2004, Yoshino and Togo introduced a green, easy, inexpensive, and highly efficient system for the esterification of carboxylic acids (153) with TEOAc (6) by a typical room-temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆), at 80–100 °C under neutral and solvent-free conditions in good yields (Scheme 41). The proposed method greatly facilitated the formation of the desired ethyl esters (154), especially for less acidic carboxylic acids, and it could also be used for sterically hindered carboxylic acids, like 2,4,6-triisopropylbenzoic acid or 2,2,2-triphenylacetic acid, and for amino acid without any racemization. Notably, replacement of trimethyl orthoacetate with TEOAc exhibited similar reactivity. On the other hand, the utilization of [bmim]BF₄ instead of [bmim]PF₆, as an ionic liquid, revealed the same results.¹⁶⁶

Scheme 41 The esterification of carboxylic acids with TEOAc.

The cross-coupling reaction of aryl iodides (155) with 3,3,3-triethoxy-1-propyne (156) using dichlorobis(triphenylphosphine) palladium [(PPh₃)₂PdCl₂] and cuprous iodide (CuI) in triethylamine (Et₃N) at room temperature led to the production of 3,3,3-triethoxy-1-aryl-1-propyne within 1–4 h, which after isolation was subsequently reacted with a catalytic amount of p-TSA in benzene at room temperature for 12 h to yield the ethyl arylpropiolates (157) (Scheme 42).¹⁶⁷

Scheme 42 The synthesis of ethyl arylpropiolate.

Padmapriya and co-workers reported the alkylation of sulfonic acids (158) by trialkyl orthoformates (4, 5) to generate the alkyl sulfonates (159) under solvent-free conditions at room temperature for 14 h or under reflux conditions in a 30 min period in 43–99% yields (Scheme 43).¹⁶⁸

Scheme 43 The alkylation of sulfonic acids by trialkyl orthoformates.

In 2009, Borths et al. synthesized O-ethyl thioformate (161) via the condensation reaction of TEOF (5) with hydrogen sulfide gas (H₂S) (160) at 2.1 bar in the presence of sulfuric acid (H₂SO₄, 98%, 1 mol%) as a Brønsted acid catalyst under solvent-free conditions. The 46 wt% ethanolic O-ethyl thioformate solution was obtained in 95% assay yield and could be purified initially by washing with basic aqueous sodium hydrogen carbonate (NaHCO₃) to eliminate the sulfuric acid and ethanol and then by distillation at atmospheric pressure to remove the residual ethanol to provide 97 wt% of O-ethyl thioformate as a yellow oil in 83% yield, which could be utilized as a thioformylating agent for amines (Scheme 44).¹⁶⁹

Scheme 44 The condensation of TEOF with H₂S to obtain O-ethyl thioformate.

In 2016, Malmedy and Wirth developed a stereoselective reaction to access 2-aryl alkanoates (165) in good enantioselectivity via the rearrangement reaction of 1-(naphthalen-1-yl)propan-1-one (162) with orthoesters (4, 5, 127) by iodine(III) reagent (163, 164) and triflic acid (TfOH) at −20 to 40 °C, yielding the corresponding alkyl 2-(naphthalen-1-yl)propanoate (165) (Scheme 45). In this reaction the effect of different parameters, such as the type of catalyst, catalytic amounts of Lewis acid, the nature of the orthoester, and temperature were investigated. It was found that a reaction with too high a bulkiness of the triisopropyl orthoformate (127) did not result in any rearranged compound. Also, acceptable results were obtained in the presence of 2 equivalents of TfOH. A plausible mechanism for the rearrangement is shown in Scheme 46.¹⁷⁰ The reaction was promoted through the reaction of the enolic form (167) of ketone (166) with the iodine(III) moiety to produce the intermediate (168), which provided the ketal (169) by TMOF (4). The elimination of aryliodide was accompanied with 1,2-aryl migration to form the intermediate (170); which was followed by hydrolysis in water to afford the rearranged product (171).¹⁷¹

Scheme 45 The preparation of alkyl 2-(naphthalen-1-yl)propanoates.

Scheme 46 Reaction mechanism for the reaction of ketones with TMOF.

The linear diester diethyl adipate (175) was synthesized by the merger of Johnson–Claisen rearrangement and alkoxycarbonylation via a one-pot procedure. This reaction proceeded through Johnson–Claisen rearrangement (JCR) of allyl alcohol (107) with TEOAc (6, 2 equiv.) to afford ethyl 4-pentenoate (172), which was followed by quenching the excess of (6) by the addition of formic acid (173) to obtain ethyl formate (174). Then, the alkoxycarbonylation of ethyl 4-pentenoate (172) with ethyl formate (174) using the palladium catalytic system such as palladium(II)acetylacetonate (Pd(acac)₂, 0.5 mol%) and 1,2-bis((di-tert-butylphosphino)methyl)benzene (2 mol% 1,2-DTBPMB) and methanesulfonic acid (MSA, 8 mol%) produced the linear diester diethyl adipate (175) in good yield (89%) (Scheme 47).¹⁷²

Scheme 47 The synthesis of linear diester diethyl adipate by the Johnson–Claisen rearrangement and alkoxycarbonylation.

2.20. Alkylation reactions

In 2008, the one-pot chemoselective S-alkylation and N-acylation reaction of 2-thiohydantoins (176) utilizing alkyl orthoformates (4, 5) and acetic anhydride (177) was presented for the synthesis of the products (178) by zinc chloride (ZnCl₂, 1.2 mmol) at 100 °C within 4–18 h in 40–90% yields (Scheme 48).¹⁷³

Scheme 48 S-Alkylation and N-acylation of 2-thiohydantoins.

In 1980, Swaringen et al. discovered that the reaction of N-alkylanilines (179) and ortho formats (4, 5), in a 2 : 1 molar ratio, gave high yields of N-alkylformanilides (180) and N,N-dialkylanilines (181) in the presence of p-TSA (Scheme 49). In addition, aliphatic cyclic amines (such as morpholine or piperidine) and orthoformates gave the corresponding orthoamides.¹⁷⁴

Scheme 49 The synthesis of N-alkylformanilides and N,N-dialkylanilines.

2.21. Acetalization reaction

In 2017, Ugarte and Hudnall presented a highly selective, environmentally friendly, rapid, and solvent-free procedure for the protection of carbonyls to acetals (184)^175–182 via the reaction of aldehydes (182) with TEOF (5) in equimolar amounts using the tetraarylstibonium salt, 1-diphenylphosphinonaphthyl-8-triphenylstibonium triflate ([183][OTf], 0.1 mol%), at room temperature (Scheme 50). Notably, the rate of the reactions increased in the presence of aliphatic aldehydes. This catalyst was recycled and reused for up to 6 runs without losing activity. Furthermore, the tetraarylstibonium salt could catalyze the deprotection of the acetals into their corresponding aldehydes in aqueous media.¹⁸²

Scheme 50 Acetalization with TEOF in the presence of tetraarylstibonium salt.

In 2009, Kharkongor and Myrboh presented a convenient and efficient one-pot method for the synthesis of α-ketoacetals (186) from substituted acetophenones (185) and TEOF (5) by selenous acid (H₂SeO₃, 0.7 equiv.) and BF₃·Et₂O (1.5 mL) as a catalyst under solvent-free conditions at room temperature in moderate to excellent yields (55–90%) within 8–14 h (Scheme 51).¹⁸³ Acetals could be also synthesized via the reaction of various acidic methines such as cyanoesters and 3,4,5-trimethoxybenzylmalononitrile with orthoformates under heating and solvent-free conditions. The reaction has been shown to be useful for the production of protected aldehydes and 2,4-diamino-5-benzylpyrimidines.¹⁸⁴

Scheme 51 Acetalization with TEOF in the presence of selenous acid.

Aromatic aldehyde acetals (189)^185,186 were synthesized via double debromoalkoxylation of dibromomethylarenes (187) with trialkyl orthoformate (4, 5) using ZnCl₂ (10 mol%) under solvent-free conditions at 80 °C (Scheme 52). This reaction was promoted by the reaction of dibromomethylarenes (187) with an excess of (4, 5) to form α-brominated ether intermediates (188) which underwent a second debromoalkoxylation in the presence of an excess of (4, 5) to provide acetal (189) and the removal of 2 moles of alkyl bromide and 3 moles of formate ester.¹⁸⁶

Scheme 52 Acetalization via the double debromoalkoxylation of dibromomethylarenes.

In 2006, Gazizov et al. investigated the reaction of TEOF with 1,1,2,2-tetrabromoethane with different molar ratios at 180 °C under solvent-free conditions within 10 h. It was found that dehydrobromination reaction took place via the reaction of triethyl orthoformate with 1,1,2,2-tetrabromoethane in 1 : 2 molar ratios to obtain tribromoethylene, ethyl formate, ethyl bromide, and ethanol as the main products along with low amounts of ethyl acetate and dibromoethylene. On the other hand, the debromination reaction was accomplished via the reaction of substrates in a 2 : 1 molar ratio to give ethyl formate, ethyl bromide, dibromoethylene, ethyl hypobromite, and acetal.¹⁸⁷

2.22. Synthesis of α-iodo ketones and α-iodo dimethyl ketals

In 2008, Yadav et al. presented a new, effective, and simple protocol for the synthesis of α-iodo ketones (191) and α-iodo dimethyl ketals (192) via the reaction of substituted acetophenones (190), TMOF (4) and iodine at room temperature under solvent-free conditions (Scheme 53). It must be mentioned that the selectivity of the obtained products from acetophenones was attributed to the workup procedures. It was found that, after completion of the reaction, if the reaction mixture was quenched in the presence of aqueous saturated Na₂S₂O₃ and then extracted by dichloromethane, the α-iodinated dimethoxy ketal was obtained as the main product, but when the reaction mixture was stirred in the presence of water before washing with aqueous saturated Na₂S₂O₃, the α-iodo ketones were afforded as the main products. In this conversion, the ring-directed iodination or α,α-diiodination products were never obtained. It is significant that this transformation in the presence of cyclohexanones (193) as a starting material resulted in the α-iodo ketos (194) as the only product, but 1,3-cyclohexadione (195) and substituted 1,3-cyclohexadione such as dimedone (197) yielded the α-iodinated products (196, 198) and the aromatized compound (199)¹⁸⁸ in good yields.¹⁸⁹

Scheme 53 The synthesis of iodo ketones and iodo dimethyl ketals.

2.23. Ring-contraction reactions

In 2007, Kumar et al. described a stereoselective method for the synthesis of trans-methyl N-acetyl-2-aryl-2,3-dihydroindol-3-carboxylates (201) via the ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones (200) with TMOF (4) by HTIB as oxidizing agent in the presence of a few drops of either HClO₄ or H₂SO₄ at room temperature in high yields (65–73%) for appropriate times (75–90 min) (Scheme 54). This reaction was accompanied by the formation of methyl p-toluenesulfonate (202) as a by-product in small quantity. The proposed mechanism, shown in Scheme 55, was begun through the ketalisation of (200) with (4) using either HClO₄ or H₂SO₄ to form intermediate enol ether (203). Then the electrophilic attack of HTIB on the double bond of enol ether (203) led to the iodine(III) complex (204), from which the elimination of iodobenzene from (204) with concurrent migration of aryl residue from the C₄ to the C₃ position gave intermediate carbocation (205), which on hydrolysis obtained the ring-contracted product (201) together with (202). To accomplish greater stability of the resultant carbocation, the migration of aryl residue was preferred over the C₂ position aryl ring. Eventually, (201) was afforded by ring contraction of compound (200), and meanwhile by-product (202) was produced, probably through the in situ condensation of methanol with p-TSA.¹⁹⁰

Scheme 54 The ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones with TMOF.

Scheme 55 A mechanistic approach for the ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones with TMOF.

Flavanones (206),^191–193 through the oxidative reaction with TMOF (4) using lead tetraacetate (Pb(OAc)₄, 0.0011 mol) and 70% perchloric acid under solvent-free conditions at room temperature, were converted into cis-methyl-2,3-dihydro-2-arylbenzofuran-3-carboxylates (207) in high yields (70–86%) within 1–2 h. Subsequent alkaline hydrolysis of the product (207) by aqueous NaOH solution under reflux conditions obtained the corresponding acids (208) within 5–6 h in 70% yields (Scheme 56).¹⁹³

Scheme 56 The oxidative reaction of flavanones with TMOF using Pb(OAc)₄.

Thallium(III) trinitrate [Tl(NO₃)₃·3H₂O] catalyzed the oxidation of various olefins¹⁹⁴ such as 1,2-dihydronaphthalenes (209) with TMOF (4) at 0 °C to obtain indans (210) in good yields (82–92%) within a very short 1 min period (Scheme 57).¹⁹⁵ It was found that 1,2-dihydronaphthalenes (209) without an alkyl substituent at the double bond produced mainly the ring-contraction products (210) in high yields,^194–204 while the substrates containing an alkyl group because of their lower reactivity gave the addition products (211) in the presence of methanol,^197,198,205 although there are some exceptions.^200,206

Scheme 57 The reaction of 1,2-dihydronaphthalenes with TMOF.

2.24. Synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and oxazolo[4,5-b]pyridines

In 2007, the Mohammadpoor-Baltork group presented a green and efficient protocol for the preparation of a new library of benzimidazoles (213), benzoxazoles (215),^207,208 benzothiazoles (217),^128,209 and oxazolo[4,5-b]pyridines (219)^210–212 via the condensation reactions of orthoesters (5, 6, 7) with o-substituted aminoaromatics such as o-phenylenediamine (212), o-aminophenol (214), o-aminothiophenol (216), and 2-amino-3-hydroxypyridine (218), respectively, by catalytic amounts of ZrOCl₂·8H₂O under solvent-free conditions at room temperature or 85 °C for short reaction times (4–12 min) and moderate to excellent yields (83–97%) (Scheme 58).²¹²

Scheme 58 The synthesis of benzimidazoles through the condensation of trialkyl orthoformates with diamines.

In 2018, ZrOCl₂·8H₂O@nano SiO₂ as a new catalyst was originated and characterized and subsequently its catalytic activity (0.01 g) has been investigated for the preparation of benzimidazoles^213,214 via the condensation reaction of trialkyl orthoformates with diamines under solvent-free condition at 60 °C within reaction times of 1.5–5.5 h and 70–90% yields. High yields (70–90%), recyclability, and reusability of the synthesized catalyst are some of the main advantages of this method.²¹⁴ Nano-Ni(II)/Y zeolite, as a non-toxic heterogeneous catalyst, at 60 °C under solvent-free conditions also accelerated this transformation within 46–122 min in good to excellent 79–99% yields.²¹⁵

In 2013, Wang and co-workers developed a simple and efficacious process for the synthesis of benzimidazole-based N-heterocyclic carbenes (222) via the cyclization of N,N′-diarylaryldiamines (221), arising from aryldiamines (220), with TMOF (4) using concentrated HCl and formic acid at 80 °C for 2 h in 88–97% yields (Scheme 59). Notably, the reaction was unsuccessful with diamines containing strong electron-withdrawing substitutions.²¹⁶

Scheme 59 The synthesis of benzimidazole-based N-heterocyclic carbenes.

2.25. Synthesis of oxadiazoles and thiadiazoles

In 2016, Kaboudin et al. investigated iron(III) chloride/L-proline as an efficient catalytic system for the synthesis of 3-substituted 1,2,4-oxadiazoles (224) from amidoximes (223) and TEOF (5) (Scheme 60).²¹⁷

Scheme 60 The preparation of 3-substituted 1,2,4-oxadiazoles.

Polshettiwar and Varma performed the solvent-free synthesis of 1,3,4-oxadiazoles (226)^218–223 and 1,3,4-thiadiazoles (227) by the condensation of acid hydrazide (225) and triethyl orthoalkanates (5) under microwave irradiation (40–140 W). According to Scheme 61, the condensation of hydrazide and TEOF were successfully undertaken in two catalytic systems which were solid supported Nafion® NR50 and P₄S₁₀/Al₂O₃.²²³

Scheme 61 The microwave-assisted synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles.

The double [4 + 1] cyclocondensation reaction of 6-hydrazinonicotinic acid hydrazide hydrate (228) containing two dinucleophilic centers²²⁴ with TEOAc (6) obtained oxadiazolyltriazolopyridine (229) in 82% yield within 16 h under reflux conditions (Scheme 62). In this transformation, the hydrazine and the hydrazide moieties exhibited similar reactivity, whereas in the presence of aldehyde as one other carbon donor moiety the hydrazine and the hydrazide groups were treated chemoselectively and regioselectivly.²²⁵

Scheme 62 Double [4 + 1] cyclocondensation of 6-hydrazinonicotinic acid hydrazide hydrate with TEOAc.

2.26. Synthesis of quinolones

In 2012, Yadav et al. developed a simple and green method for the synthesis of 4(1H)-quinolones via a two-step reaction. At first, the one-pot three-component condensation reaction of arylamines (230), Meldrum's acid (231), and TMOF (4) by 1-butyl-3-methylimidazolium bromide [bmim]Br as ionic liquid catalyst at 40 ± 2 °C obtained arylaminomethylene-1,3-dioxane-4,6-dione (232) in 68–94% yield in 2 h. After purifying, the resulting products underwent a cyclization reaction along with the elimination of acetone and CO₂ using [bmim]BF₄ or [bmim]OTf at 80 ± 2 °C in a 2 h period to afford 4(1H)-quinolones (233) (Scheme 63). The results revealed the better utility of [bmim]OTf in comparison with [bmim]BF₄.²²⁶

Scheme 63 The synthesis of 4(1H)-quinolones.

In 2018, Kanaani and Nasr-Esfahani prepared and characterized maleic anhydride coated magnetite nanoparticles (Fe₃O₄@APTES-MAH NPs) and nanorod vanadatesulfuric acid (VSA NRs) as Brønsted acid nanocatalysts. Subsequently, their catalytic activity was examined for the synthesis of new 4-iminoquinolines (236) via the one-pot three-component reaction of equimolar amounts of 2-aminobenzonitrile (234), orthoesters (4, 5), and active methylenes (235) under solvent-free conditions at 80 °C. In this reaction the influence of different parameters, such as the type of catalyst and orthoesters, was examined. It was found that both VSA NRs and Fe₃O₄@APTES-MAH NPs catalysts yielded the corresponding 4-iminoquinolines (236) in good to excellent yields. VSA NRs in comparison with Fe₃O₄@APTES-MAH NPs slightly improved the reaction times and yields (Scheme 64). They discovered that, among different orthoesters, TEOF was more effective. Short reaction times, high yields, simple purification of the products, the inexpensiveness, stability, recyclability and reusability of the catalysts are some of the advantages of this method.²²⁷

Scheme 64 The synthesis of new 4-iminoquinolines.

2.27. Synthesis of isoquinoline derivatives

1,2,3,4-Tetrahydro-10-oxopyrimido[4′,5′:4,5]thieno[2,3-c][1,2,4]triazolo[3,4-a]isoquinoline (239, 68%) and 5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (241, 72%) were synthesized via the ring closure of triazolo and pyrazolothienotetrahydroisoquinoline (238, 240), derived from key precursors beginning from 4-cyano-1-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-3(2H)thione (237), with TEOF (5) using a few drops of glacial acetic acid under reflux conditions for 1–2 h (Scheme 65). The synthesized products were examined and evaluated as antimicrobial agents.²²⁸

Scheme 65 The synthesis of isoquinolines with the aid of TEOF.

2.28. Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles

Indium triflate [In(OTf)₃, 5 mol%] as a highly efficient Lewis acid catalyst, catalyzed the one-pot three-component condensation reaction of amines (242), TMOF (4), and sodium azide (243) under solvent-free conditions at 100 °C to furnish 1-substituted-1H-1,2,3,4-tetrazoles (244)^229–245 in good to excellent yields (70–92%) within 1.5–3.5 h. Both electron-donating and electron-withdrawing anilines yielded the products in high yields. The catalytic system also proceeded well with heterocyclic amine and aliphatic amines (Scheme 66).²⁴⁵ On the other hand, the reaction of substituted anilines, TEOF, and trimethylsilyl azide^209,246 also afforded 244 using FeCl₃ (20 mmol%) under solvent-free conditions at 70 °C within 5–7 h in 87–95% yields.²⁴⁶

Scheme 66 The preparation of substituted-1H-1,2,3,4-tetrazoles.

2.29. Synthesis of selenoureas

Selenoureas (247) were obtained by a novel three-component condensation reaction from primary or secondary amines (245), TEOF (5) and metallic selenium (246) (Scheme 67).²⁴⁷

Scheme 67 Selenourea synthesis by the condensation of amines, TEOF, and Se.

2.30. Synthesis of piperazinyl pyridines

In 2000, Rao et al. described a new simple method for the synthesis of 2-amino-3-cyano-5-N-substitued piperazinyl pyridines (250) via the condensation reaction of TEOAc (6), malononitrile (248), and N-substituted piperazine (249) in a 2 : 1 : 1 molar ratio in the presence of excess of ammonium acetate (5 moles) under reflux conditions at 90–92 °C for 2 h in moderate yields (50–68%) (Scheme 68). The products were obtained by a simple filtration and recrystallization from ethylacetate/n-hexane. Elemental and spectral data (FT-IR, PMR) confirmed the structures of the isolated compounds.²⁴⁸

Scheme 68 Synthetic route to substituted piperazinyl pyridines.

2.31. Synthesis of pyrimidine derivatives

In 2010, Nagarajan and Reddy prepared substituted pyrimidine derivatives (253) via the one-pot three-component condensation reaction of acetylenedicarboxylates (251), amines (252), and orthoformates (4, 5) with a molar ratio of 1 : 2 : 1 in the presence of ZnCl₂ (0.5 mol%) under solvent-free conditions at room temperature in 27–80% yields within 1–3 h (Scheme 69).²⁴⁹

Scheme 69 The synthesis of substituted pyrimidine derivatives.

In 2006, Toche et al. presented a two-step procedure for the synthesis of 4-amino-5-(4-bromobenzoyl)-3-ethyl-2(1H)-pyrimidone (257). First, the domino three-component condensation reaction of 4-bromobenzoylacetonitrile (254), mono-alkylated ureas (77, 255), and TEOF (5) at 65–70 °C yielded enamine intermediates (256). Subsequently, the resultant precipitate (which dissolved in EtOH/NaOEt under reflux conditions) underwent an intramolecular cyclization reaction and dissolved in refluxing ethanol to produce 257 in 56–64% yield (Scheme 70). The compounds were evaluated for their insect repellent activity against Sitophilus oryzae (Coleoptera, Curculeonidae).²⁵⁰

Scheme 70 The domino synthesis of 4-amino-5-(4-bromobenzoyl)-3-ethyl-2(1H)-pyrimidones.

1,2-Oxazolo[5,4-d]pyrimidin-4(5H)-ones (259) were obtained in 46–74% yields via the ring-closure reaction of 1,2-oxazole-4-carbohydrazides (258) with boiling orthoesters (5, 6) under solvent-free conditions within 1–5 h (Scheme 71). The in vitro mycobacterial and cytotoxicity activities of the products were screened against Mycobacterium fortuitum in an MABA test, and lung (A549) and fibroblasts (L929) cell lines, respectively.²⁵¹

Scheme 71 Ring closure of 1,2-oxazole-4-carbohydrazides with orthoesters.

Ethyl-substituted 2-(4-bromo-phenyl)amino-3-aminopyrazolo[3,4-d]pyrimidin-4-one (260) was refluxed in the presence of TEOF (5) and p-TSA, as catalyst, in order to obtain 2-ethyl-8-(4-bromophenyl)-pyrazolo[3,4-d][1,2,4]8H-triazolo[2,3-a]4H-pyrimidin-4-one (261) in 95% yield (Scheme 72).²⁵² The products have previously been reported as potential anti-inflammatory–analgesic agents.²⁵³

Scheme 72 The synthesis of 2-ethyl-8-(4-bromophenyl)-pyrazolo[3,4-d][1,2,4]8H-triazolo[2,3-a]4H-pyrimidin-4-ones.

Due to the key role of fluorine-containing heterocyclic products in biological and pharmacological activities,^254–256 and also the development of new functional groups,^257–263 in 2008, 5-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidines (264), 6-thienoyl-7-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrimidine (266) and 6-thienoyl-7-(trifluoromethyl)benzimidazo[1,2-a]pyrimidine (268) were synthesized via the condensation reaction of 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione (262), TEOF (5) and the appropriate heterocyclic amines, such as aminopyrazoles (263), 3-amino-l,2,4-triazole (265), and 2-aminobenzimidazole (267), respectively, by pressurized microwave irradiation (300 W, 17.2 bar) at 100 °C under solvent-free conditions for 5 min (Scheme 73).²⁶⁴

Scheme 73 The preparation of some fluorinated pyrimidines.

In 2000, 2-amino-4,5-di-(2-furyl)furan-3-carbonitrile (269)²⁶⁵ was utilized as a key starting material for the synthesis of furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (273). At first, the condensation of (269) with TEOAc (6) under reflux conditions for 5 h obtained the corresponding 2-ethoxyimine (270) in good yield (65%) which upon treatment with hydrazine hydrate (271) was converted into (272). Eventually, the cyclocondensation of (272) with TEOF (5) under reflux conditions for 8 h achieved (273) in 73% yield (Scheme 74). The products were purified by simple filtration and crystallization and were finally characterized by their correct analyses and spectroscopic data (IR and ¹H NMR).²⁶⁶

Scheme 74 Preparation procedure of furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines.

In 2000, Dave and Shah synthesized 7H-1,2,4-triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (277) via the domino multicomponent reaction of 1,4-disubstituted 2-amino-3-cyanopyrroles (274),²⁶⁷ TEOF (5), and hydrazine hydrate (271) under reflux conditions. This reaction proceeded through the condensation of 274 with 5 under reflux conditions to generate 1,4-disubstituted N-ethoxymethylene-2-amino-3-cyanopyrroles (275) in 3–4 h in good yields (70–88%) which led to 5,7-disubstituted 3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidines (276) (60–88%) on hydrazinolysis with 271 within 3.5–4 h. Finally, the cyclocondensation reaction of 276 with one carbon donor moiety, such as 5, afforded product (277)^268,269 in 6–7 h in weak to high yields (42–70%) (method A). On the other hand, the similar reaction of 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidines (278)²⁷⁰ with 5 and 271 (method B) obtained the [4,3-c] isomers (279), which using formic acid were isomerized to the thermodynamically more stable [1,5-c] isomers (277) through Dimroth rearrangement (Scheme 75). Notably, the latter procedure was faster and more efficient.²⁶⁹

Scheme 75 The synthesis of 7H-1,2,4-triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines.

In 2005, Rashad et al. prepared several derivatives containing thieno[2,3-d]pyrimidine systems with potent anti-inflammatory properties: e.g. 11-hydrazino-5,6-dihydronaphtho[1′,2′:4,5]-thieno[2,3-d]pyrimidines were refluxed with triethyl orthoesters for 10 h to obtain 8,9-dihydronaphtho[1′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines^271,272 in 72–86% yields; which were isomerized to the thermodynamically more stable triazolo[1,5-c]pyrimidines under heating in either acid or basic media.²⁷² Thieno[2,3-b]-pyridine-2-carbohydrazide (280) was refluxed with TEOF (5) for 4 h to form 3-aminopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines (281) in 73% yield (Scheme 76).²⁷³

Scheme 76 Formation of 3-aminopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines.

2,4-Dimethyl-7-benzyledineamino-8-oxopyrimido[4′,5′:4,5]-seleno[2,3-b]pyridine (283) was synthesized upon cyclocondensation of benzylidene carbohydrazone (282) with TEOF (5) by a few drops of acetic acid under reflux conditions for 1 h in 51% yield (Scheme 77).²⁷⁴

Scheme 77 Synthetic approach for 2,4-dimethyl-7-benzyledineamino-8-oxopyrimido[4′,5′:4,5]-seleno[2,3-b]pyridine.

In 2004, three pathways were presented for the synthesis of pyrido[2,3-d]pyrimidines (286) through the one-pot three-component condensation reaction of equimolar amounts of 6-aminouracils (284), alkyl nitriles (285), and TEOF (5) in (a) solvent-free conditions, (b) using ethanol as a solvent under heating thermal conditions, and (c) under microwave irradiation with 360 W power at 75 °C utilizing acetic anhydride (Scheme 78), for which the third method had a great effect on decreasing the time and increasing the yield.²⁷⁵ Some compounds have different pharmacological activities, such as antibacterial,²⁷⁶ antitumor,²⁷⁷ cardiotonic, hepatoprotective, and antihypertensive,²⁷⁸ and antibronchitic effects.²⁷⁹

Scheme 78 Pyrido[2,3-d]pyrimidine synthetic routes under three sets of conditions.

2,3,5,7-Substituted-pyrido[2,3-d]pyrimidin-4(3H)-ones (288) were synthesized in good to excellent yields (75–96%) from the cyclocondensation reaction of 2-amino-N,6-substituted phenyl-4-substituted nicotinamides (287) with orthoesters (6, 7) by catalytic amounts of glacial acetic acid at 90 °C for 7 h (Scheme 79). All the resultant compounds (288) were examined for antibacterial activity against Gram +ve and Gram −ve bacteria.²⁸⁰

Scheme 79 The formation of substituted-pyrido[2,3-d]pyrimidin-4(3H)-ones.

The cyclization of compounds (289) with excess amounts of trialkyl orthoformates (4, 5) resulted in products (290) using catalytic amounts of p-TSA under reflux conditions or in DMSO as solvent at 95–115 °C in 5–41% yields within 18–24 h (Scheme 80).²⁸¹

Scheme 80 Cyclization by TEOF to obtain N-containing heterocycles.

Acid-mediated cyclocondensation of ethyl 5-amino-4-(substituted amino)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylates (291) with TEOF (5) resulted in ethyl 5-substituted 7-(methylthio)-5H-1-thia-3,5,6,8-azaacenaphthylene-2-carboxylates (292) in 60–97% yields within 15–60 min (Scheme 81).²⁸²

Scheme 81 The preparation of 7-(methylthio)-5H-1-thia-3,5,6,8-azaacenaphthylene-2-carboxylates.

In 2016, Castillo and co-workers developed pyrazolo[5,1-b]purines (294) by a microwave-assisted (300 W) cyclocondensation of pyrazolo[1,5-a]pyrimidine-6,7-diamines (293) with orthoesters (4, 6, 7) at 110–120 °C under solvent-free conditions in good to excellent yields (81–96%) within 5–10 min (Scheme 82).²⁸³

Scheme 82 The microwave-assisted synthesis of pyrazolo[5,1-b]purines.

2.32. Synthesis of triazin derivatives

In 2012, Sachdeva and co-workers synthesized 2-amino-4-methylpyrimido[1,2-a][1,3,5]triazin-6-ones (297) and 4-amino-2-methylpyrimido[1,2-a][1,3,5]triazin-6-ones (299) utilizing 1-(6-oxo-1,6-dihydropyrimidin-2-yl)guanidines (295) as starting materials. Firstly, the guanidines (295) were condensed with triethylorthoacetate (6) in glacial acetic acid under reflux conditions to form an iminium ion intermediate (296). Subsequent intramolecular cyclization along with the elimination of ethanol yielded product (297); which was followed by thermal rearrangement for unsubstituted (NH₂), alkyl-substituted (NHCH₃), and aralkyl guanidines (NHCH₂Ph(R)) via ring opening of pyrimidine at the amide moiety to produce the ring-open triazine carbenone (298). Finally, intramolecular nucleophilic attack of the N-1 nitrogen of 1,3,5-triazine on the carbonyl functional group and annulation, respectively, achieved product (299) (Scheme 83). It is noteworthy that the guanidines (295) containing a tertiary amino group such as –N(CH₃)₂, –N(CH₂CH₂)₂O, indolino and or aryl secondary amino substituent groups, e.g. –NHPh, NHPh(3-Br), NHPh(3-Cl), NHPh(4-OMe) produced mainly the corresponding product 297.²⁸⁴

Scheme 83 The synthesis of 4-amino-2-methylpyrimido[1,2-a][1,3,5]triazin-6-ones.

In 2002, Světlík and Liptaj synthesized new heterocyclic ring systems including a pyrazole moiety, such as N-[(5E)-1,12-b-dihydro-substituted-5H-pyrazolo[1,5-e][1,3,5]-benzoxadiazocin-5-ylidene]guanidine (303) or 2-amino-4-[4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine (308). The products (303) were obtained via the re-esterification of TEOF (5) with phenolic hydroxys of two equivalents of 4,5-dihydro-3-methyl-5-(2-hydroxyphenyl)-1H-pyrazole-1-carboximidamide (300) to produce orthoester (301) which underwent a cyclization reaction with the vicinal amidine moiety to form an oxadiazocine system (302). Then, the nucleophilic attack of the adjoining exocyclic imine nitrogen on the carbon atom of the other amidine group enabled C1-transfer, which was followed by loss of the disubstituted pyrazoline component to obtain (303) (Scheme 84). On the other hand, the condensation reaction of 4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-carboximidamide acetate (305) with 5 under reflux conditions gave intermediate (306) which was followed by a cyclization reaction to get (307). The reaction was completed by the formation of 2-amino-4-[4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine (308) for 1 h in 65% yield through the elimination of the disubstituted pyrazoline component (Scheme 85).²⁸⁵

Scheme 84 The synthesis of dihydro-pyrazolo benzoxadiazocin-5-ylidene guanidines.

Scheme 85 Formation procedure for 2-amino-4-[4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine.

2.33. Synthesis of quinazoline derivatives

In 2010, Wu et al. prepared 4(3H)-quinazolinones (311) in excellent yields (84–96%) and very short reaction times (15–20 min) via the one-pot three-component condensation reaction of anthranilic acid (309),^286–293 TEOF (5) and primary amines (310) under solvent-free conditions at room temperature by silica-supported boron trifluoride (BF₃–SiO₂, 100 mg) as a green, recyclable and reusable heterogeneous catalyst (Scheme 86).²⁹³ Microwaves (210 W) accelerated the formation of 4(3H)-quinazolinones in the absence of solvent via the one-pot three-component condensation reaction of anthranilic acid, orthoesters, and ammonium acetate using a catalytic amount of antimony(III) chloride (SbCl₃, 1 mol%) in excellent yields (89–93%) within 5 min. According to the results, both aliphatic and aromatic substituents on orthoesters indicated no significant effect on the reaction times and the yields, but generally, the presence of a substituent on orthoesters prolonged the reaction times.²⁹⁴ Quinazolin-4(3H)-ones could also be obtained from the condensation of anthranilic amide with orthoesters using ionic liquids under ultrasound irradiation in 20–25 min in 82–91% yields.²⁰⁹

Scheme 86 The preparation of 4(3H)-quinazolinones.

The catalyst/solvent-free one-pot three-component reaction of isatoic anhydrides (312), TEOAc (6), and various amines (313) in equimolar amounts obtained 4(3H)-quinazolinones (311) through two different pathways: (a) utilizing microwave irradiation (150 W) at 140 °C, and (b) under conventional heating at 120 °C. This method developed through the Knoevenagel condensation reaction of 4(3H)-quinazolinones with aromatic aldehydes (314) by a tandem four-component condensation reaction to achieve (E)-3-substituted-2-styrylquinazolin-4(3H)-ones (315).^295,296 The results affirmed that MW assisted the reaction progression much better than conventional heating (Scheme 87).²⁹⁶

Scheme 87 Tandem preparation route for (E)-3-substituted-2-styrylquinazolin-4(3H)-ones.

In 2006, three pathways were presented for the synthesis of 2-substituted 4-aminoquinazolines (319) via the uncatalyzed one-pot three-component condensation reaction of 2-aminobenzonitrile (234), orthoesters (5, 6, 7, 316, 317), and ammonium acetate (318) in (a) ethanol as solvent under heating conditions, (b) under reflux conditions without a solvent, and (c) microwave irradiation in the absence of a solvent. The results showed that, in comparison with the two premier routes, microwave irradiation has an important influence on decreasing the reaction time (5–7 min) (Scheme 88).²⁹⁷

Scheme 88 The synthesis of 2-substituted 4-aminoquinazolines.

In 2015, a catalyst and solvent-free one-step method was reported for the synthesis of 3-arylquinazolin-4(3H)imines (321) by heating 2-amino-N′-arylbenzamidines (320) with TEOF (5) (Scheme 89).²⁹⁸

Scheme 89 The synthesis of 3-arylquinazolin-4(3H)imines.

In 2015, Bhat and co-workers, presented an efficient and eco-friendly method for the synthesis of 2,4-disubstituted quinazolines (324) in high yields (76–94%) via the catalyst/solvent-free one-pot three-component reaction of 2-aminoaryl ketones (322), trialkyl orthoesters (5, 6, 7, 102, 323), and ammonium acetate (318) in a 1 : 1.5 : 1.5 molar ratio at 110 °C within 1.5–2.5 h (Scheme 90). In this study, in order to investigate the scope and limitations of the presented procedure, the reaction was carried out by diverse substituted 2-aminoaryl ketones and trialkyl orthoesters. The reaction was performed by 2-aminobenzophenones and 2′-aminoacetophenones. It was found that the transformation with 2′-aminoacetophenones proceeded faster, which may be ascribed to the steric effect resulting from the aryl substitution, which decreases the reactivity of the carbonyl group. Remarkably, 2-aminobenzophenones containing both electron-withdrawing and electron-donating groups on the aniline ring provided good results. However, 2′-aminoacetophenones including a strong electron-donating substituent on the aniline ring obtained poor yield. It was also found that the reactivity of aliphatic orthoesters was better than orthobenzoate as an aromatic orthoester, which could probably be attributed to the steric effect of different substituents on the orthoester functional group. It was found that the chain length of the orthoalkylates did not have a significant influence on the reaction results.²⁹⁹

Scheme 90 The synthesis of 2,4-disubstituted quinazolines.

In 1970, Potts and Brugel synthesized 3-substituted-triazolo[4,3-c]quinazolines (326) in good yields (70–90%) via the cyclization reaction of 4-quinazolylhydrazine (325) with orthoesters (5, 6, 7) using potassium carbonate under reflux conditions for 30 min (Scheme 91).³⁰⁰

Scheme 91 Formation procedure of 3-substituted-triazolo[4,3-c]quinazolines.

2.34. Synthesis of macrocycles

The three-component cyclocondensation of N,N′-dimesityl-propane-1,3-diamine (327), TEOF (5), and ammonium tetrafluoroborate (328) was accomplished to produce the main product macrocycle (329) under solvent-free conditions (Scheme 92) and 1,3-dimesityl-3,4,5,6-tetrahydropyrimidin-1-ium tetrafluoroborate in the presence of ethanol as solvent.³⁰¹

Scheme 92 N-Bearing macrocycle synthesis.

3. Orthoester reactions in aqueous media

One of the most interesting challenges to chemists is the reaction performance in water media as a cheap, readily available, safe, and non-toxic solvent. This effective and completely green medium causes the ready hydrolysis of some substrates and/or products, such as orthoesters. In fact, reports of the transformation of orthoesters in aqueous media are very rare (8 references) that are discussed below.

3.1. Synthesis of formamidines

In 2013, a simple, eco-friendly, and catalyst-free methodology was reported for the N-formylation of amines by TEOF under ultrasound irradiation in water.³⁰² Symmetric formamidines could be also prepared via the N-formylation reaction of amines with TMOF using tin(II) chloride–choline chloride (ChCl/SnCl₂, 30 mol%), as catalyst and reaction media, in water at 70 °C for 20–160 min in 30–80% yields.¹²⁷

3.2. Alkylation reactions

The treatment of anilines (330) with TMOF (4) utilizing sulfuric acid at 115–120 °C resulted in the formation of an N-methylformanilide intermediate; which without isolation was hydrolyzed by aqueous hydrochloric acid (10%) at 170–175 °C to obtain N-methylated anilines (331) in weak to good yields (20–85%) and in some cases along with dimethylated derivatives (332) in minor yields (3–13%) as by-products (Scheme 93).³⁰³

Scheme 93 The aqueous alkylation of amines.

3.3. Synthesis of N-arylureas

In 2014, a facile and green procedure was presented for the preparation of N-arylureas (334) through the hydration of various aromatic cyanamides (333) with TEOF (5) in refluxing water in 64–73% yields within 6–11 h (Scheme 94). It should be noted that the cyanamides including electron-withdrawing groups prolonged reaction times.³⁰⁴

Scheme 94 The water-mediated synthesis of N-arylureas.

3.4. Synthesis of homoisoflavones

In 2008, Rao et al. described a process for the preparation of homoisoflavones (336)³⁰⁵ in good yields (78–88%) via the ring closure of TEOF (5) with 1-(2-hydroxyphenyl)-3-phenylpropane-1-ones (335) in the presence of 70% perchloric acid, which was followed by aqueous hydrolysis of the intermediate perchlorates (Scheme 95). The in vitro antioxidant and antifungal activities of the products were examined using the superoxide (NBT) and agar cup methods, respectively.³⁰⁶

Scheme 95 The preparation of homoisoflavones.

3.5. Synthesis of benzoxazoles

Maleki et al. synthesized and characterized Ag (1.5%)@TiO₂ (0.1 mL) as a heterogeneous, hazardless, eco-friendly, and reusability nanocatalyst. Then its catalytic activity was examined for the preparation of benzoxazole^214,307 via the condensation reaction of orthoesters with 2-amino phenol in water at room temperature within very short reaction times (4–10 min) and at excellent yields (82–93%).³⁰⁷

3.6. Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles

In 2018, Sharghi et al. synthesized iron-doped acidic multi-walled carbon nanotubes (Fe@acidic-MWCNs). The characterization by inductively coupled plasma (ICP), X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman, and FT-IR analysis confirmed that the iron nanoparticles were supported on the acidic multi-walled carbon nanotubes (MWCNs). Subsequently their catalytic activity was probed for the preparation of 1-substituted-1H-tetrazoles via the one-pot three-component reaction of substituted anilines, TEOf, and sodium azide in water at 50 °C within 1–3.5 h with excellent yields (80–95%). This reaction was carried out faster in the presence of electron-donating anilines than with electron-withdrawing analogs.³⁰⁸ Copper(II) nanoparticles loaded on magnetic core (Fe₃O₄@SiO₂/aza-crown ether–Cu(II)) as a new and highly effective magnetic nanocomposite catalyst in water at 100 °C also facilitated this transformation within 40–70 min in excellent yields (87–98%).³⁰⁹

4. Orthoester reactions in organic solvents

Organic solvents, as carbon-based liquids, are conventional common media to accomplish organic transformations. There are too many organic liquids categorized as solvents. The subdivision of the vast list of solvents could be based on polarity, melting point range, volatility, chemical inertness towards substrates and reagents, or solubility of the existing components in the reaction. In addition to the solvent characteristics, the chemical and physical nature of each reaction member, and the effective relationship between components and solvents determines the choice of reaction media. According to the detailed data below, most solvents utilized in orthoester-participating transformations are alcohols that dissolve many organic compounds as well as most orthoesters (20 reports). The subsequent grades belong to CH₂Cl₂ (16 cases), acetic anhydride (15 items), benzene and its halogen and alkyl substituted analogs (such as chlorobenzene, xylenes, and toluene, 11 cases), acetic acid (10 items), CH₃CN (8 cases), THF (5 points), ether and DMF (each with 3 cases), and dioxane (2 items). The other solvents reported in the literature survey are DMSO, pyridine, CCl₄, and ionic liquid that each appeared in just one study.

4.1. Synthesis of ethoxymethylenes

In 2000, Elkholy et al. reported the synthesis of 1-benzoyl-1-phenylsulfonyl-2-ethoxyethene containing an ethoxymethylene group (338),^310–315 as yellow crystals, by the reaction of 1-phenyl-2-(phenylsulfonyl)ethanone (337) with TEOF (5) in refluxing acetic anhydride. In this reaction 2 moles of ethanol were removed (Scheme 96).³¹⁵

Scheme 96 The synthesis of ethoxymethylenes.

4.2. Synthesis of ethoxymethylene amino derivatives

In 2002, 2-(4-fluorophenyl)methylidene-7-(4-fluorophenyl)-2,3-dihydro-5-ethoxymethyleneamino-7H-3-oxo-thiazolo[3,2-a]-pyrimidin-6,8-dicarbonitrile containing an ethoxymethylene amino motif (340)^316–328 was synthesized via the condensation of 5-amino-2-(4-fluorophenyl)methylidene-7-aryl-6,8-dicyano-3-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyridine (339) with TEOF (5) in refluxing acetic anhydride (10 mL) (as catalyst and solvent) (Scheme 97). Pure (340) was obtained from recrystallization from cold water in 78% yield. Compound (340) exhibited highly antimicrobial activity against Staphylococcus aureus (NCTC-7447).³²⁸

Scheme 97 The synthesis of an anti-Staphylococcus aureus heterocycle.

4.3. Synthesis of acetamides

The three-component Ugi reaction of 2-aminophenols (341), cyclohexyl isocyanide (342), and TEOF (5) in equimolar amounts was accomplished using ZnCl₂ (10 mol%) in methanol at room temperature to construct N-cyclohexyl-2-(2-hydroxyphenylamino)-2-ethoxyacetamides (343) for 12 h in high yields (80–82%) (Scheme 98).³²⁹

Scheme 98 The Ugi reaction to obtain acetamides.

4.4. Synthesis of enamines

In 2006, Komkov et al. investigated the reaction of cyclohexane-1,3-diones (195, 197) and orthoesters (6, 7) with various amines (344, 346). It was found that the one-pot three-component condensation reaction of cyclohexane-1,3-dione (195) and orthoesters with 5-acetyl-4-aminopyrimidines (344) under reflux in p-xylene obtained a novel series of 7-(1,3-dioxocyclohex-2-ylidene)-7,8-dihydropyrido[2,3-d]pyrimidines (345) in 32–61% yields in 2.5–5 h, while the condensation of dimedone (197) and orthoesters with p-toluidine (346) progressed to generate enamine derivatives (347)^330–335 under reflux conditions within 8 h in 44–58% yields (Scheme 99).³³⁶

Scheme 99 The synthesis of enamine-bearing heterocycles.

4.5. Synthesis of formamidines

Lim et al. designed the catalyst-free one-pot three-component condensation reaction of polysubstituted 5-aminopyrazoles (348), TEOF (5),³³⁷ and cyclic secondary amines (349)³³⁸ under microwave irradiation (150 W) at 150 °C in methanol in order to prepare novel N-pyrazolylformamidines (350) in 20 min in 64–93% yields (Scheme 100). Some of the synthesized products were found to inhibit interleukin-17 secretion in phenotypic in vitro evaluations.³³⁹

Scheme 100 Preparing novel N-pyrazolylformamidines.

1,3-Bis-arylcarbamylformamidines were prepared via the reaction of N-arylureas with TEOF in boiling acetic anhydride in 85–90% yields.³⁴⁰

4.6. Synthesis of substituted 2-dialkyliminio-1,3-dithietane tetrafluoroborates

In 2015, a facile and straightforward methodology was presented for the synthesis of 4-(N,N-dialkyldithiocarbamato)-2-dialkyliminio-1,3-dithietane tetrafluoroborates (354) in 30–42% yields. In this paper, the condensation reaction of secondary aliphatic amines (351) with carbon disulfide (352) in CHCl₃ at room temperature first afforded dithiocarbamic acid salt (353) which upon treatment with TMOF (4) using BF₃·OEt₂ as catalyst in CHCl₃ at room temperature furnished (354) (Scheme 101). This reaction failed with some orthoesters, such as orthovalerate and trimethyl orthobenzoate.³⁴¹

Scheme 101 Dithiocarbamic acid salt synthetic approach.

4.7. Synthesis of lactones

In 2015, Wang and co-workers described the asymmetric total synthesis of (+)-isoiresin (363) and (−)-isoiresin (364) from (3S,5aR,7aS,8R,9R,11aR,11bR)-8-(hydroxymethyl)-3,8,11a-trimethyldecahydro-1H-3,5a-epoxynaphtho[1,2-e][1,3]dioxepin-9-ol (356) derived from readily available aldehyde (355). This transformation occurred via acidic hydrolysis (HCl, 6 N) of the orthoester (356) in THF at 23 °C for 30 min to form a mixture of monoacetate compounds (357a and 357b) which underwent acetylation to produce the tetrakis-acetate (358). Subsequent regioselective dehydration of (358) by various dehydrating agents and then deacetylation resulted in (359) and (360) in different molar ratios, which upon the regioselective oxidative lactonization reaction using Fétizon reagent obtained (361 and 362). Finally, the reduction of the aldehyde functional group by NaBH₄ at 0 °C in methanol yielded (363) and (364) (Scheme 102).³⁴²

Scheme 102 The asymmetric total synthesis of (+)-iresin and (−)-isoiresin.

4.8. Synthesis of aminomethylene bisphosphonates

In 2012, Reddy et al. presented an effective, rapid and green method for the synthesis of aminomethylene bisphosphonates via the one-pot three-component reaction of amines, diethyl phosphite and TEOF in a 1 : 2 : 1 molar ratio using Yb(PFO)₃ (10 mol%) in the presence of ionic liquid [bmim][Cl] at 100 °C for 15–25 min in good to excellent yields (70–93%).³⁴³

4.9. Synthesis of 4-dialkylarylamino-1-naphthaldehyderivatives

The reaction of N,N-dialkylarylamines (365) with TMOF (4) was accomplished using TiCl₄ (10 mmol) in CH₂Cl₂ at 0–25 °C to obtain the corresponding formyl derivatives (366) in 75–89% yields (Scheme 103).³⁴⁴

Scheme 103 The formylation of N,N-dialkylarylamines by TMOF.

4.10. Synthesis of pyrrolidines and piperidines

Boron trifluoride diethyl etherate (BF₃·OEt₂, 0.050 mmol) catalyzed the cyclodehydration of N-carbamate-protected amino alcohols (367) with trimethyl orthobenzoate (102) in CH₂Cl₂ at room temperature to get azaheterocycles such as pyrrolidines and piperidines within 2–7 h, in high yields (62–87%) (368). Replacing (367) with N-carbamate-protected amino vicinal diols (369) in refluxing CH₂Cl₂ yielded regio- and stereoselective prolinol derivatives (370) in excellent yields (87–94%) (Scheme 104).³⁴⁵

Scheme 104 The synthesis of pyrrolidines and piperidines.

4.11. Synthesis of pyrrole derivatives

In 1998, Tardieux and co-workers presented a simple and mild one-step route for the synthesis of 3,4-disubstituted pyrrole-2,5-dicarbaldehydes (372) via the diformylation^346,347 reaction of β-substituted pyrrole-2-carboxylic acids (371) with TEOF (5) in trifluoroacetic acid, in a dual role of catalyst and solvent, at room temperature for 1 h in 22–65% yields (Scheme 105).³⁴⁷

Scheme 105 The preparation of disubstituted pyrrole-2,5-dicarbaldehydes.

Tri-(pyrrol-2-yl)alkanes (374) could be synthesized via the reaction of pyrrole (373) with orthoesters (5, 7, 62, 102) using chloroacetic acid (45 mmol) in CH₂Cl₂ at 0 °C within 30 min, in 34–38% yields (Scheme 106). 5-Phenyl-4,6-dipyrrin has also been prepared in comparatively good yield (51%) through the reaction of pyrrole with trimethyl orthobenzoate by dichloroacetic acid (38 mmol) under similar conditions.³⁴⁸

Scheme 106 Synthetic procedure for tri-(pyrrol-2-yl)alkanes.

4.12. Synthesis of indole derivatives

In 1990, indole-3-carbaldehyde (376) as pale yellow crystals was synthesized upon treatment of 4-methoxyindole (375) with TEOF (5) using trichloroacetic acid in CH₂Cl₂ at room temperature within 20 min in 36% yield. On the other hand, bis-benzo-annellated pentamethine cyanines such as bis(4-methoxyindol-3-yl)methyliumtrichloroacetate (377a) and bis(4-methoxyindol-3-yl)methyliumtetrafluoroborate (377b) were also synthesized in 51 and 76% yields under similar conditions using trichloroacetic acid and tetrafluoroboric acid diethyl ether (HBF₄·OEt₂), respectively (Scheme 107).³⁴⁹

Scheme 107 The synthesis of bis(indolyl)methane salts.

In 2012, Khaksar and co-workers prepared symmetrical tris(indolyl)methanes^349,350 via a catalyst-free reaction of indoles with orthoesters in the presence of hexafluoro-2-propanol (HFIP) at room temperature within 15–60 min in excellent yields (88–98%).³⁵⁰

6-Monosubstituted and 6,12-disubstituted 5,11-dihydroindolo[3,2-b]carbazoles (381) were synthesized in 20–50% yields via the one-pot three-stage condensation reaction of indole (89) and aldehydes (378) using a catalytic amount of iodine; which underwent an acid-mediated intramolecular ring-closure reaction by orthoesters (5, 6, 7, 380) in methanol at room temperature for 14 h (Scheme 108).³⁵¹

Scheme 108 The synthesis of substituted dihydroindolo[3,2-b]carbazoles.

4.13. Synthesis of pyrazole derivatives

In 2003, Hassen et al. described that N-(2′,2′,2′-trifluoroethyl) phosphonyl β-hydrazones (382) on cyclization with TEOF (5) in the presence of acetic acid in refluxing xylene resulted in novel 1-fluorinated-4-phosphopyrazoles (383) in 46 h, in moderate to excellent yields (60–94%) (Scheme 109).³⁵²

Scheme 109 The formation of novel 1-fluorinated-4-phosphopyrazoles.

1-Substituted 5-aminopyrazole-4-carbonitriles (385) could be prepared via two pathways: (a) The products were produced through the one-pot three-component reaction of 1-substituted hydrazines (384), malononitrile (248), and TEOF (5), in refluxing ethanol within 2 h in low to moderate yields (17–58%). (b) The reaction of malononitrile (248) with TEOF (5) in acetic anhydride at 100 °C which got ethoxymethylenemalononitrile (386) in 93% yield within 4 h. After completion of the reaction, 1-substituted hydrazines (384) were added under similar conditions to afford the desired product (385) in 42–78% within 1 h (Scheme 110).³⁵³

Scheme 110 The formation of substituted 5-aminopyrazole-4-carbonitriles.

In 2002, an effective, useful, and versatile synthetic approach was introduced for the regiospecific synthesis of 3,4-fused-cycloalkyl-1-arylpyrazoles (395) in 48–64% yields via two pathways A and B. In pathway A, BF₃-progressed alkylation of symmetric ketones (387) with TMOF (4) in dichloromethane by Hunig's base formed an α-(dimethoxymethyl)ketone intermediate (388), and after isolation, the cyclocondensation of intermediate (388) with arylhydrazine (389) under acidic conditions in refluxing benzene produced product (390) (Scheme 111). In pathway B, the kinetic enolates were first regiospecifically obtained via the condensation of α,β-unsaturated cycloalkanones (391) with organolithium/Grignard reagents (392) by a copper(I) bromide dimethyl sulfide complex (CuBr·Me₂S) which was followed by trapping of the above-mentioned enolate utilizing chlorotrimethylsilane (393) as silyl enol–ethers (394). Then, the reaction of the crude enol–ethers (394) with TMOF (4) utilizing catalytic amounts of iodotrimethylsilane (TMSI) in CH₂Cl₂ at −78 °C for 1 h achieved intermediate (395) regiospecifically, which on cyclocondensation with arylhydrazine (389) resulted in the product (390) (Scheme 112).³⁵⁴

Scheme 111 The regiospecific synthesis of 3,4-fused-cycloalkyl-1-arylpyrazoles (method A).

Scheme 112 The regiospecific synthesis of 3,4-fused-cycloalkyl-1-arylpyrazoles (method B).

4.14. Synthesis of methoxyfurans, furanones, and furans

In 2018, Croisetière and Spino devised a rapid and effective sequence of reactions to synthesize O-heterocycles, containing methoxyfurans, furanones, and furans. Initially, the [4 + 1]-annulation reaction of dimethoxycarbene (397),³⁵⁵ arising from Warkentin's oxadiazoline (396), with readily available α,β-unsaturated carbonyls (398) gave cyclic orthoesters (399) (Scheme 113), which were applied as key precursors for the synthesis of methoxyfurans (400), furanones (401), and furans (402). The synthetic methoxyfurans in this report were classified in four parts: first, by a catalytic amount of camphorsulfonic acid in CHCl₃; secondly, trimethylaluminum in CH₂Cl₂ at −40 °C; third, using a weaker Lewis acid aluminum tris(tert-butoxide) in toluene at 140 °C; finally, in the presence of n-BuLi in THF at −78 °C. Furanone (401) could be prepared from the acid hydrolysis of orthoester by concentrated HCl in CHCl₃ (method A). Also, utilizing a mild Lewis acid such as TMSCl/TMSI in the presence of NaI iodide in CH₃CN furnished furanones (method B). Furan (402) was achieved from the reduction of the resultant furanone by DIBAL-H at −40 °C in THF³⁵⁶ (Scheme 114).³⁵⁷

Scheme 113 Synthesizing O-heterocycles containing methoxyfurans, furanones, and furans.

Scheme 114 The synthesis of some novel methoxyfurans and furans.

4.15. Synthesis of dihydropyran-4-ones

In 2015, Clarke et al. utilized a novel modification Maitland–Japp cyclization reaction for the synthesis of highly functionalized dihydropyran-4-ones (404) via the reaction of δ-hydroxy-β-ketoesters (403) with two easily available orthoesters (62, 323) in the presence of acetic anhydride as a dehydrating agent in dry toluene under heating conditions through refluxing and microwave irradiation. It was found that replacing conventional heating with microwave irradiation reduced the large excess amount of orthoesters from 10 equivalents to only 2 equivalents and also the reaction progressed in a few minutes (Scheme 115).³⁵⁸

Scheme 115 The synthesis of highly functionalized dihydropyran-4-ones.

4.16. Synthesis of pyrano[2,3-c]pyrazoles

3-Substituted pyrazolin-5-ones (405) were condensed with TEOF (5) in refluxing acetic anhydride to give the intermediate (406) which was then cyclized via Michael addition with hippuric acids (407) together with ethanol elimination and acetylation of the ring nitrogen to achieve pyrano[2,3-c]pyrazoles (408) for 10–30 min in good to excellent yields (75–94%) (Scheme 116).³⁵⁹

Scheme 116 Pyrano[2,3-c]pyrazoles achievement route.

4.17. Synthesis of chromane derivatives

Scandium triflate [Sc(OTf)₃, 3 mol%] catalyzed the diastereoselective reaction of o-hydroxybenzaldehydes (409), glycals (410), and TMOF (4) in dichloromethane at room temperature to furnish cis-fused pyranobenzopyrans (411) within 0.5–1.5 h in good yields (74–83%) with high diastereoselectivity (Scheme 117).³⁶⁰ This transformation was also accomplished with various other alkenes, such as indene, styrene and allyltrimethylsilane under similar conditions to give substituted benzopyrans within 2–6 h in 78–90% yields with high selectivity.³⁶¹

Scheme 117 The formation of cis-fused pyranobenzopyrans.

In 1999, Miyazaki et al. reported a novel, effective, and stereoselective procedure for the synthesis of trans-tetrahydropyrano[3,2-c]benzopyrans (414) in 8–96% yields in 1–24 h via the one-pot three-component reaction of o-hydroxybenzaldehydes (412), TMOF (4), and unsaturated alcohols (413) utilizing a catalytic amount of p-TSA (0.2 mmol) in benzene at room temperature (Scheme 118).³⁶²

Scheme 118 The stereoselective synthesis of trans-tetrahydropyrano[3,2-c]benzopyrans.

In 2003, the one-pot three-component reaction of 4-hydroxy coumarins (415),^363,364 carbamates (416), and TEOF (5) was presented for the synthesis of 2-[(substituted 2,4-dioxochromane-3-ylidene)methyl]amino acetic acids (417)³⁶⁵ in refluxing 2-propanol within 2 h in moderate yields (40.5–55%) (Scheme 119). All the products were screened for their biological activity but only a few molecules were active against B. subtilis, S. aureus, E. coli and P. aeruginosa at minimum inhibitory concentrations (MIC) of 100, 300, 500 μg mL⁻¹ compared to streptomycin (CAS 57-92-1) and kanamycin (CAS 59-01-8).³⁶⁶

Scheme 119 The synthesis of 2-[(substituted-2,4-dioxochromane-3-ylidene)methyl]amino acetic acids.

Pd(II) catalyzed the one-pot cascade three-component coupling reaction of o-hydroxybenzaldehydes (418), 4-pentyn-1-ols (419), and orthoesters (4, 5) in CH₃CN at −30 °C to room temperature achieved a direct diastereoselective synthetic method for chromane spiroacetals (420).^367–369 It was found that replacing 4-pentyn-1-ols (419) with the 5α- and 5β-epimers of 4,5-secocholestan-5-ol (421a, b) yielded the corresponding steroid chroman spiroketals (422a, b and 423a, b) (Scheme 120).³⁶⁸

Scheme 120 A synthetic method for chromane spiroacetals.

4.18. Synthesis of chromene derivatives

Various 2,2-dimethyl-2H-chromenes (426)^370–374 could be prepared in 42–67% yields through a two-step Yb(OTf)₃-catalyzed reaction of o-hydroxybenzaldehydes (424), TMOF (4), and 2-methylpropene (425) in CH₂Cl₂ at room temperature for 60 h, which was followed by refluxing toluene in the presence of a catalytic amount of p-TSA (0.03 g) for 1 h to eliminate the methanol from the reaction mixture (Scheme 121). Notably, the reaction failed with salicylaldehydes containing methoxy substituents at the 2- and 4-positions. On the other hand, aldehydes including hydroxyl functional groups at the 3- and 5-positions could not be fully isolated because other unidentified compounds were formed with similar polarity that prevented a complete purification.³⁷⁴

Scheme 121 A synthetic approach to various 2,2-dimethyl-2H-chromenes.

4.19. Synthesis of coumarin derivatives

The synthesis of substituted 3-benzoylamino-5-oxo-5,6,7,8-tetrahydrocoumarins (427) from 1,3-cyclohexanediones (195, 197), hippuric acid (407), and TEOF (5) (or other one-carbon synthetic equivalents, such as diethoxymethyl acetate or N,N-dimethylformamide dimethyl acetal) in acetic anhydride has been described (Scheme 122).³⁷⁵

Scheme 122 The synthesis of substituted 3-benzoylamino-5-oxo-5,6,7,8-tetrahydrocoumarins.

In 2003, 8-amino-7-(p-bromophenyl)-10-hydroxypyridino[3′,2′-6,5]4H-pyrano[3,2-c][1]benzopyran-6-one (429) was prepared via the cyclocondensation of 2-amino-4-(4′-bromophenyl)-3-cyano-4H,5H-pyrano[3,2-c][1]benzopyran-5-one (428) with TEOF (5) in refluxing acetic anhydride within 2 h in 55% yield (Scheme 123). The resultant product exhibited antibacterial and antifungal activities.³⁷⁶

Scheme 123 The formation of amino-7-(p-bromophenyl)-10-hydroxypyridino[3′,2′-6,5]4H-pyrano[3,2-c][1]benzopyran-6-ones.

In 2000, the El-Agrody group synthesized 14-methyl-13,14H-[1]benzopyrano[3′,4′:5,6]-pyrano[3,2-e][1,2,4]triazolo[1,5-c]-pyrimidine-13-one as colorless crystals in 87% yield via the ring-closure reaction of 9-amino-8,9-dihydro-8-imino-7-methyl-6H,7H-[1]benzopyrano[3′,4′:5,6]-pyrano[2,3-d]-pyrimidine-6-one with TEOF in refluxing benzene within 3 h.³⁷⁷ In 2001, they also reported the preparation of antibacterial and antifungal active 11-bromo-14-(p-methoxyphenyl)-14H-naphtho[1′,2′:5,6]pyrano[3,2-e][1,2,4]triazolo[2,3-c] pyrimidine through the cyclocondensation of 10-amino-3 -bromo-12-(p-methoxyphenyl)-11-imino-10,11-dihydro-12H-naphtho[1′,2′:5,6]-pyrano[2,3-d]pyrimidine with TEOF under similar condition for 6 h in 79% yield.³²⁶

4.20. Etherification and esterification reactions

Bakos et al. reported that a single frustrated Lewis pair catalyst B(C₆Cl₃H₂)(C₆F₄H)₂ could progress the tandem reductive etherification reaction of aldehydes/ketones (430) with trialkyl orthoformate (4, 5), as alkylating agent, to produce ethers (431) under 20 bar H₂ pressure in THF at 55–100 °C, for 16–84 h with high selectivity (98–99%) and weak to good yields (35–92%) (Scheme 124).³⁷⁸

Scheme 124 Tandem reductive etherification reaction of aldehydes/ketones.

In 2016, estrone 3-secondary ethers (435) were made through the eco-friendly etherification/aromatization reaction of readily accessible dienone (432) with trialkyl orthoformates (127, 433, 434), as alkylating agent, in a 1 : 5 molar ratio by triflic acid (TfOH, 0.5 mmol) in the corresponding alcohol (5 mL) at 100 °C for 2 h in 80–87% yields (Scheme 125). The above-mentioned procedure was applied for the generation of three marketed 3-etherified estrogen drugs, quinestrol, quinestradol, and nilestriol, utilizing 19-hydroxyandrost-4-ene-3,17-dione as a commercially available precursor.³⁷⁹

Scheme 125 Etherification/aromatization reaction of dienone.

Scandium triflate [Sc(OTf)₃, 10 mol%] catalyzed the one-pot three-component condensation of aldehydes, allylsilane and TMOF in dichloromethane to produce homoallyl ethers^380,381 at room temperature. Mild reaction conditions, good yields (70–90%), high selectivity, recyclability, and reusability of the catalyst are some important advantages of this procedure.³⁸¹ On the other hand, the reaction of equimolar amounts of homoallyl alcohol (436) with TMOF (4) using Lewis acids such as InCl₃ (3 mmol) in CH₂Cl₂ at room temperature obtained homoallyl ethers (437) and homoallyl chlorides (439) in good yields. Notably, homoallyl alcohols with aryl moieties with electron-donating substituents furnished exclusively homoallyl ethers (437) in 84–92% yields. Homoallyl alcohol including halogen atoms as the substituents resulted in homoallyl ethers (437, 61–72%) along with bishomoallyl ethers (438) (9–14%) as by-products. The homoallyl alcohols containing several halogen atoms or an electron-withdrawing substituent produced only the homoallyl chlorides (439) in 67–88% yields (Scheme 126). Similarly, this transformation was accomplished using BiCl₃ at room temperature and BF₃·OEt₂ at −78 °C, while treatment utilizing TiCl₄ at −78 °C afforded exclusively the homoallyl chloride (439) in 92% yield. Hence, the type of product could be controlled through the selection of the desired Lewis acid.³⁸²

Scheme 126 The preparation of some homoallylic compounds.

Maulide and Markó synthesized spirocyclic ethers (442) in 35–63% yields via the Mukaiyama aldol reaction of the silylated acyloins (440) with functionalized orthoesters (441) by ZnCl₂ in dichloromethane at room temperature, which was followed by desilylation of the resultant adducts using TBAF in THF, and finally annulation in the presence of t-BuOK (Scheme 127).³⁸³

Scheme 127 Mukaiyama aldol reaction of silylated acyloins.

In 2013, Lee and Kraus presented a new technique for the synthesis of substituted benzoates (446) in 72–94% yields via the one-step one-pot inverse electron-demand Diels–Alder reaction of methyl coumalate (443) with orthoesters (62, 444, 445) as an electron-rich dienophile in toluene at 200 °C for 16 h (Scheme 128).³⁸⁴

Scheme 128 The synthesis of substituted benzoates.

In 1998, Fletcher co-workers reported a facile and inexpensive process for the formation of alkoxy/aryloxycyclopropanes (448) with preference for the generation of the more hindered cis-isomers through the reaction of TMOF (4) with alkenes (447) in the presence of zinc amalgam and Me₃SiCl in refluxing diethyl ether for 24 h (Scheme 129).³⁸⁵

Scheme 129 The formation of alkoxy/aryloxycyclopropanes.

In 2018, Bunse et al. synthesized ethoxycarbonyl-substituted 1-alkylidenephthalanes (451) from the reaction of orthoester (449) arising from triethyl orthopropanoate (7). This reaction was prompted via halogen–metal exchange of the orthoester (449) with n-butyllithium (n-BuLi) in THF at −78 °C for 15 min which was followed by the nucleophilic addition reaction with diverse carbonyl compounds (450) along with regioselective 5-exo-dig cyclization of the corresponding intermediate lithium alcoholate and eventually hydrolysis to produce the products (451) as mixtures of (Z)- and (E)-configured diastereomers with an approximate range of 90 : 10 to 95 : 5 (Scheme 130). Notably, the aromatic aldehyde benzaldehyde was unsuccessful in getting the phenyl-substituted derivative.³⁸⁶

Scheme 130 The preparation of ethoxycarbonyl-substituted 1-alkylidenephthalanes.

In 2018, Sempere and Carreira prepared β-substituted γ,δ-unsaturated esters (453) via an iridium-catalyzed enantioselective allylic alkylation reaction of trimethyl orthoacetate (62), as an acetate enolate source, with racemic allylic carbonates (452), utilizing ZnBr₂ as an additive in 1,4-dioxane at room temperature (Scheme 131). Significantly, halogenated and electron-rich substrates yielded the relative products with high yields and excellent enantioselectivity. Notably, the meroterpenoid (+)-conicol has been synthesized through employment of this new procedure in a formal enantioselective synthesis.³⁸⁷

Scheme 131 The preparation of β-substituted γ,δ-unsaturated esters.

Brodzka and co-workers probed the enzymatic kinetic resolution (EKR) of Novozym 435 as a biocatalyst for the synthesis of enantiomerically pure carboxylic acid esters (456) via the esterification of racemic 3-phenyl-4-pentenoic acid (454) with trialkyl orthoesters (4, 5, 6, 62, 102, 323, 380, 444, 455) as alkoxy group donors in toluene at 40 °C (Scheme 132). Based on the resulting data, trialkyl orthoesters including bulky alkyl groups, such as trialkyl orthobenzoate, obtained excellent results for both yield and enantioselectivity (50% yield, >99% ee). It was found that the enantioselectivity of EKR is highly dependent on the structure of an alkoxy group donor.³⁸⁸

Scheme 132 The synthesis of enantiomerically pure carboxylic acid esters.

In 2015, Koszelewski et al. described a novel method of kinetic resolution based on irreversible enzymatic esterification of rac-3-hydroxy-3-(aryl)propanoic acids (457) with triethyl orthobenzoate (380) using Novozym 435 tandem metal-enzyme dynamic kinetic resolution (DKR) in toluene at 40 °C to access enantiomerically active β-hydroxy ester (458) with low enantioselectivities in low yields (<1–45%) for 48 h (Scheme 133).³⁸⁹

Scheme 133 The synthesis of enantiomerically active β-hydroxy ester.

In 1993, Trujillo and Gopalan used triethylorthoacetate as an ideal reagent for the transformation of sulfonic acids into their ethyl esters under a catalyst-free mode in dichloromethane (CH₂Cl₂) at room temperature in high to excellent yields (69–97%) for 30 min. The uncatalyzed esterification reaction of carboxylic acids using this reagent was also conveniently performed in refluxing toluene within 24 h in high yields (81–92%). Replacing trimethylorthoacetate with triethylorthoacetate resulted in the desired methyl esters. According to the resulting data, the utilization of TEOF instead of triethylorthoacetate was unsuccessful.³⁹⁰

In 1996, Schwabacher and Stefanescu designed a useful and convenient method for the generation of methyl phosphinate (460) together with the elimination of methyl formate and methanol via the reaction of phosphinic acid (459) with TMOF (4) in a combined dry THF/toluene (1 : 1) medium at 5 °C to room temperature. This reaction was accompanied by the formation of a by-product (461), which was assumed to form through the attack of the dimethoxymethyl cation on the phosphorus(III) tautomer of (459) or (460) (Scheme 134).³⁹¹

Scheme 134 The generation of methyl phosphinate.

In 1994, King introduced a convenient method for the formation of ester–ethers (463) in 61–95% yields via the reaction of lactones (462) with orthoformates (4, 5, 133) using sulfuric acid in the desired alcohol as solvent at 50 °C within 3–8 h (Scheme 135).³⁹²

Scheme 135 The formation of ester–ethers from lactones and orthoformates.

4.21. Johnson–Claisen rearrangement

In 2001, Takao et al. showed that the Claisen rearrangement of the substrate (464)^393,394 derived from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, with triethyl orthopropionate (7) by a catalytic amount of propanoic acid in DMF at 130 °C for 4 h obtained an inseparable mixture of the rearrangement products (465, 466, and 467) as a 1 : 2.5 : 10 diastereomeric mixture in a combined yield of 87% (Scheme 136). Under similar conditions, the reaction of (464) with trimethyl orthobutyrate (455) by powdered molecular sieves 4A (MS-4 Å) afforded an inseparable mixture of the rearrangement products (468 and 469) as a 1 : 3 diastereomeric mixture in a combined yield of 46% (Scheme 137). In both reactions, the σ-bond formation progressed prevalently from the β-side. This resultant stereochemical was opposite to the observed rearrangement of (464) with TEOAc.³⁹⁵

Scheme 136 The Claisen rearrangement of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose with triethyl orthopropionate.

Scheme 137 The Claisen rearrangement of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose with trimethyl orthobutyrate.

4.22. Acetalization reaction

In 2003, Ma et al. presented an efficient and chemoselective method for the preparation of diethyl acetals in good to excellent yields (63–96%) via the acetalization^{178,396–408} of aldehydes/ketones with TEOF using TiO₂/SO₄²⁻ in refluxing ethanol for 25 min to 3 h. It was found that, in competitive reactions, aldehydes and cyclic aliphatic ketones revealed excellent chemoselectivity.⁴⁰⁸ The reaction of enamines (470) with trialkyl orthoformates (4, 5) was also accomplished in the presence of BF₃·OEt₂ in CH₂Cl₂ to give α-dialkoxymethyl carbonyl compounds (471), after hydrolysis, in 61–85% yields within 1 h (Scheme 138).⁴⁰⁹

Scheme 138 The chemoselective preparation of diethyl acetals.

In 1999, Martins et al. reported the regioselective reaction of 2-acylcycloalkanones (472) with TMOF (4) using p-TSA (0.78 mmol) in methanol at room temperature to afford the corresponding acetals within 24 h (Scheme 139). It was found that the reverse Claisen condensation of electron-donating substituted 2-acylcyclohexanones, where R was Me, Et or CH₂Ph with TMOF led to 7,7-dimethoxyalkanoate methyl esters (473) in 80–93% yields. On the other hand, 2-acyl cyclohexanone dimethyl acetal derivatives (474) in 80–85% yields were produced when R was Ph, CF₃ or OMe. Similar to the products (474), 2-acetylcyclooctanone derivative (R = Me) resulted in acetal (475) in 86% yield. Finally, 2-acetylcyclopentanone (R = Me) and 2-acetyl cycloheptanone (R = Me) gave rise to acetals (476) and (477) in 75 and 74% yields, respectively.⁴¹⁰

Scheme 139 The regioselective reaction of 2-acylcycloalkanones with TMOF.

In 1991, the highly enantioselective hydroformylation of vinyl aromatics (478) was reported by the Hegedus group in the presence of TEOF (5). They discovered that TEOF plays a special role in stereoselectivity. As can be seen in Scheme 140, the reaction proceeded with (Pt^IIBPPM)/SnCl₂ (Pt^IIBPPM: l-(tert-butoxycarbonyl)-(2S,4S)-4-(dibenzophospholyl)-2-[(dibenzophospholyl)methyl]pyrrolidine) in o-dichlorobenzene as solvent.⁴¹¹

Scheme 140 The enantioselective hydroformylation of vinyl aromatics.

In 2015, Pospech and co-workers introduced an intermolecular one-step methoxylation/acetalization reaction of donor–acceptor substituted diazo compounds (480) with TMOF (4) utilizing Rh₂(S-pttl)₄ (1.0 mol%) in CH₂Cl₂ at room temperature to synthesize functionalized tertiary α-alkoxy-β-oxo-esters (481) in 1 h in 40–91% yields (Scheme 141). The concurrent C–O/C–C bond generation produces products with exclusive quaternary carbon centers containing substituent groups with various oxidation levels, such as esters, protected aldehydes and alkoxidse.⁴¹²

Scheme 141 Methoxylation/acetalization of diazo compounds with TMOF.

In 2015, the cyanation of orthoesters (5, 102, 317, 380),⁴¹³ with sterically congested α-cyanoamines, like dicyclohexylcyanoamine (482), as effective cyanating reagents, was described for the formation of cyanoacetals (483) by trichlorosilyl triflate (SiCl₃OTf) in CH₂Cl₂ at 0 °C within 0.5 h, in excellent yields (73–97%) (Scheme 142).⁴¹⁴

Scheme 142 The cyanation of orthoesters.

Casiraghi and co-workers prepared 2-hydroxyaryl-1-carboxyaldehyde diethylacetals (485) via the reaction of special phenol salts like magnesium halides (484) with TEOF (5) in benzene or diethylether at 20–80 °C (Scheme 143). This reaction was promoted by a C-regiospecific attack at the ortho positron of the phenoxy moiety.⁴¹⁵

Scheme 143 The regioselective preparation of 2-hydroxyaryl-1-carboxyaldehyde diethylacetals.

In 1993, Byun and Bittman synthesized (−)-dimethyl 2,3-O-benzylidene-L-tartrate and its enantiomer (488) in 83–91% yields via the reaction of L-tartaric acid (486), benzaldehyde (487), and TMOF (4) by p-TSA (10 mmol) in methanol at room temperature (Scheme 144).⁴¹⁶

Scheme 144 The formation of (−)-dimethyl 2,3-O-benzylidene-L-tartrate.

In 2013, Geng et al. prepared 4,6-O-arylidenated derivatives (493) and orthoesters (494), regioselectively via the protected/unprotected sugars (489), benzaldehydes (487, 490), and TEOF (5) by organocatalysts such as thiourea (491)/squaramide derivatives (492) in anhydrous CH₃CN at room temperature (Scheme 145). In this procedure the influence of various parameters, such as the amount and type of aldehyde, catalyst and orthoester, was investigated on the time and yield of reaction. It was found that a strong acid-catalyst like p-TSA has a great effect in reducing the reaction time.⁴¹⁷

Scheme 145 The regioselective preparation of 4,6-O-arylidenated derivatives of sugars.

5-Substituted 5,5-dialkoxy-2-penten-4-olides (496) were made through the reaction of 2-(trimethylsiloxy)furan (495) with orthoesters (4, 5, 6, 7, 380) in the presence of a few drops of tin(IV)chloride (SnCl₄) in CH₂Cl₂ at −40 to 10 °C in 48–91% yields in a 2 h period (Scheme 146).⁴¹⁸

Scheme 146 The synthesis of 5-substituted 5,5-dialkoxy-2-penten-4-olides.

The vicinal diequatorial diols reaction of 2,2,3,3-tetramethoxybutane (497) with TMOF (4) using camphorsulfonic acid in refluxing methanol for 12–18 h yielded butane 2,3-bisacetal (498) in moderate to excellent yields (54–91%) to protect trans-1,2-diols (Scheme 147).⁴¹⁹

Scheme 147 The reaction of 2,2,3,3-tetramethoxybutane with TMOF.

In 1991, Hoffman and Salvador described a one-pot conversion of cyclic ketones to N-methyl lactams. The reaction of ketones (499) with TEOF (5) by p-TSA in ethanol gave acetal (500) which was treated in situ with N-(((p-nitrobenzene)sulfonyl)oxy)methylamine (501) to furnish the N-methyl group of the imidate salt (502). Finally, dealkylation of the resulting O-ethyl imidate with sodium iodide in refluxing acetonitrile achieved lactams (503) in moderate to high yields (Scheme 148).⁴²⁰

Scheme 148 The conversion of cyclic ketones to N-methyl lactams with TEOF.

DeMong and Williams suggested an asymmetric synthesis of 2-amino-3,3-dimethoxypropanoic acid (−)-506. The key step is the quenching of a chiral glycine (504) titanium enolate with TMOF (4) in CH₂Cl₂ at −78 °C to form the appropriate α-dimethylacetal^421,422 (+)-505 in 94% yield. The (−)-506 was obtained in 98% yield through the hydrogenolysis of the lactone moiety by 20 mol% of Pd(OH)₂ in a combined THF/MeOH (3 : 1) medium; followed by utilizing trituration with ether to eliminate the dibenzyl by-product (Scheme 149).⁴²²

Scheme 149 The asymmetric synthesis of 2-amino-3,3-dimethoxypropanoic acid.

The reaction of chalcones (507) with TMOF (4) was accomplished using thallium(III) trinitrate (TTN) in acidic methanol to afford a 50 : 50 mixture of 3,3-dimethoxy-1,2-diphenylpropan-1-one (508, Ar = Ar₁ = C₆H₅) and methyl 2,3-diphenyl-3-methoxypropanoate (512, Ar = Ar₁ = C₆H₅). The keto acetal (508)⁴²³ was obtained through normal Ar ring migration, while the ester (512) was obviously achieved by migration of the Ar₁ ring. As shown in Scheme 150, owing to the low rate of the treatment of chalcone with TTN and also the faster reaction of aldehydes and ketones with TMOF by TTN to form acetals and ketals,⁴²⁴ the ketalization reaction of chalcone apparently competes with oxidative rearrangement. Hence, the oxidative rearrangement resulted in product (508) and the ketalization reaction formed intermediate (510) which upon treatment with TTN was converted into intermediate (511). Finally, the 1,2-migration of the Ar₁ group and the respective elimination of TTN furnished product (512) (Scheme 150).⁴²⁵

Scheme 150 The reaction of chalcones with TMOF.

2-Dimethoxymethyl-4,4-dimethoxycyclohexa-2,5-dienone (514) could be prepared via oxidation of 2-formyl-4-methoxyphenol (513) with TMOF (4), utilizing thallium trinitrate^426,427 in methanol at −20 °C while the oxidation of 2-methoxycarbonyl-4-methoxyphenol furnished 2-methoxycarbonyl-3,4,4-trimethoxycyclohexa-2,5-dienone (Scheme 151).⁴²⁷

Scheme 151 The oxidation of 2-formyl-4-methoxyphenol with TMOF.

In 2007, Graham and Smith demonstrated that alcohols could be transformed directly into either acyclic or cyclic acetals in both tandem and sequential oxidation/acetalization processes using manganese dioxide, trialkyl orthoformates and an indium triflate catalyst in dichloromethane at ambient temperature.⁴²⁸ In 2015, Manojveer and Balamurugan developed a convenient method for the synthesis of naphthalenes (517) via a domino three-component condensation reaction of o-alkynylbenzaldehydes (515), ketones (516), and TMOF (4) in the presence of TfOH (20 mol%) in acetonitrile at room temperature (Scheme 152). This transformation was initiated via the condensation of o-alkynylbenzaldehyde (515) with TMOF (4) by TfOH to obtain the in situ formed acetal (518), which was condensed with enol ether (519), arising from the reaction of ketones with TMOF, to form chalcone (520) which underwent intramolecular cyclization reaction to afford naphthyl ketones (517).⁴²⁹

Scheme 152 The synthesis of naphthalenes via domino three-component condensation.

Manojveer and Balamurugan presented a facile and efficient process to get substituted benzo[a]fluorenes (524), with regioselectivity via a domino three-component reaction of o-alkynylbenzaldehydes, alkynes, and TMOF by TfOH (20 mol%) in CH₃CN or CH₂Cl₂ at room temperature. This reaction proceeded through the reaction of aldehydes (515) with TMOF (4) by TfOH to obtain the in situ formed acetal (521). Subsequent [2 + 2] cycloaddition between acetal (521) and alkynes (522) generated the cis-isomer (523) which on intramolecular annulation reaction achieved substituted benzo[a]fluorenes (524) in 45–98% yields in 0.5–24 h (Scheme 153).⁴³⁰

Scheme 153 The regioselective synthesis of substituted benzo[a]fluorenes.

TfOH catalyzed the one-pot three-component reaction of ketones, such as acetophenones and ethyl phenyl ketones (525), chalcones (526), and TMOF (4) in carbon tetrachloride (CCl₄) at room temperature to obtain a series of symmetrical and unsymmetrical 1,5-diketones (527) within 6–8 h. This reaction progressed through the in situ formation of acetals (528) from the reaction of ketones with TMOF which set up an equilibrium with the enol ether (529), as an Michael acceptor, which was followed by Michael addition with the activated chalcones by an acidic catalyst (530) to afford 1,5-diketones (527). Replacing acetophenones with ethyl phenyl ketones yielded a mixture of diastereomeric 1,5-diketones (where the syn diastereomers were the major product) in 55–95% yields (Scheme 154).⁴³¹

Scheme 154 The preparation of 1,5-diketones.

4.23. Synthesis of benzoxazoles, benzothiazoles, benzimidazoles, oxazoles, oxadiazoles, and imidazoles

In 2009, Lee et al. reported a simple and effective procedure for the generation of benzoxazoles and oxazoles via the one-pot reduction-triggered heterocyclization reaction. Indium/acetic acid promoted the reaction of 2-nitrophenols with trimethyl orthoesters in refluxing benzene to produce benzoxazoles^432–434 in 50–98% yields in a 1 h period. In a similar manner, 1-aryl-2-nitroethanones upon treatment with trimethyl orthobenzoate using In/AcOH in refluxing acetonitrile afforded oxazoles in 1 h in 46–72% yields.⁴³⁴ In 2014, Gnanasekaran and co-workers reported arylhydrazides (531) on reaction with orthoesters (5, 6, 7, 380) by NH₄Cl (30 mol%) as catalyst in a polar solvent like ethanol under reflux conditions yielding 2-substituted and 2,5-disubstituted 1,3,4-oxadiazoles (532)^435–437 within 0.5–10 h, in 22–98% yields (Scheme 155). The reaction was successful with electron-releasing and electron-withdrawing groups on the arylhydrazide precursor and progressed gently for both non-aromatic and aromatic orthoesters.⁴³⁸

Scheme 155 Synthetic approach for substituted 1,3,4-oxadiazoles.

In 2014, Al-Majidi obtained 1,2,4-triazolo[3,4-b]benzothiazole (534) as pale yellow crystals on treatment of 2-hydrazinobenzothiazole (533) with TEOF (5) in the presence of a few drops of acetic acid in refluxing methanol for 3 h in 65% yield (Scheme 156). The synthesized compound showed moderate antimicrobial activity against Serratia but was inactive against Staphylococcus aureus.⁴³⁹

Scheme 156 The formation of 1,2,4-triazolo[3,4-b]benzothiazole.

2-Oxo-2H-pyrimido[2,1-b]benzothiazole-3-carbonitriles were prepared through the cyclocondensation of cyanoacetamides with TEOF in nitrobenzene at 190–200 °C in 77–79% yields within 3 h.⁴⁴⁰ In 2010, the Jeffries-EL group prepared some classes of synthetically useful 2,6-disubstituted benzobisthiazoles (539) based on the Lewis acid-catalyzed ring-closing reaction between diamino benzene dithiol (535) and substituted orthoesters (5, 6, 536, 537, 538) in dimethylacetamide (DMA) as organic solvent (Scheme 157). These products are of interest for the development of new organic semiconductors.⁴⁴¹

Scheme 157 The formation of disubstituted benzobisthiazoles.

Wang et al. developed a mild and facile two-step one-pot method for the synthesis of benzo and heteroaromatic fused imidazoles.^442–445 In first step, ortho-nitroanilines were converted into ortho-diamines by the reduction of the nitro group using iron powder. In the next step, cyclization occurred between ortho-diamines and TEOF by catalytic amounts of ytterbium triflate (0.005 equiv.) in acetic acid (1.0 M) at 75 °C to obtain the corresponding imidazoles within 3 h.⁴⁴⁵ Benzimidazoles^308,446,447 were also prepared by Zhang et al. from o-phenylenediamines with orthoesters using sulfamic acid (0.05 mmol) in methanol at room temperature in 0.5–5 h in excellent yields (85–98%).⁴⁴⁷ ZrCl₄ in ethanol at room temperature also accelerated this transformation within 0.8–6 h in excellent yields (81–95%).⁴⁴⁸ In 2004, the one-pot three-component reaction of 2-cyanobenzimidazole (540), TEOF (5), and hippuric acid (407) was presented for the synthesis of pyrido[1,2-a]benzimidazole derivatives (541)^359,449 in refluxing acetic anhydride within 10 min, in excellent yields (84–91%) (Scheme 158).³⁵⁹

Scheme 158 The synthesis of pyrido[1,2-a]benzimidazole derivatives.

Due to the noteworthy biological activities of the natural nucleoside antibiotic, bredinin, such as antiviral and antihepatitis C effects, and its versatile biological activities, Nair and Zhang synthesized a new carbocyclic analog of bredinin (545) using (3aS,4R,6R,6aR)-6-((methoxymethoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (542) as a key precursor. In the first step, (542) was converted into the malondiamide intermediate (543) via side-chain functional group conversions. Subsequently, (543) on reaction with TEOF (5) by acetic acid as catalyst under heating in ethanol at 90 °C underwent cyclization to afford the appropriate 4-carbamoyl-imidazolium-5-olate ring (544) within 1.5 h in moderate yield (55%). In the final step, the deprotection reaction of the recent compound (544) resulted in (545) (Scheme 159). The resultant product displayed antiviral activity, although it was low, against a number of RNA viruses. More biological properties are under investigation.⁴⁵⁰

Scheme 159 Synthesizing a carbocyclic analog of bredinin.

The cyclodehydration of urea derivatives (546) with TMOF (4) was accomplished in the presence of boronic acid (10–20 mol%) under refluxing toluene to attain compounds (547) in 75–95% yields in 12–24 h which as key intermediates were converted into a 1H-imidazo[1,2-a]imidazol-2-one LFA-1 antagonist (548) (Scheme 160).⁴⁵¹

Scheme 160 The cyclodehydration of ureas with TMOF.

4.24. Synthesis of thiadiazoles, triazoles, and 1H-tetrazoles

2-Alkylamino-1,3,4-thiadiazoles have been synthesized via the ethanol-mediated reaction of 4-alkylthiosemicarbazide and TEOF, in a 1 : 2 molar ratio, through the accelerated role of concentrated hydrochloric acid by Tomalia and Pmge in 1973.⁴⁵² In 2015, Aouali et al. prepared 5-amino-1-phenyl-1,2,4-triazole derivatives (552) through the one-pot three-component reaction of orthoester (6, 7, 549), phenylhydrazine (550) and cyanamide (551) by acetic acid (5 mol%) in methanol through two different pathways: (a) utilizing microwave irradiation (200 W) at 80 °C, and (b) under classical heating conditions. The results indicated shorter reaction times and higher yields by the microwave method (87–95%, 40 min) (Scheme 161).⁴⁵³

Scheme 161 The synthesis of 5-amino-1-phenyl-1,2,4-triazoles.

Kerr and co-workers synthesized various chiral and achiral 1,2,4-triazolium salts as key precursors for the generation of N-heterocyclic carbine. In this paper, various 1,2,4-triazolium salts were obtained under different conditions, e.g. pentafluorophenyl triazolium salt (555) as a light tan solid was produced through the reaction of hydrazinium tetrafluoroborate (554), arising from morpholinone derivative (553), with TEOF (5) in chlorobenzene at 110 °C in 24 h in 66% yield (Scheme 162).⁴⁵⁴

Scheme 162 The preparation of pentafluorophenyl triazolium salt.

Chuprun et al. synthesized tetrazoles via the enantioselective reaction of α-amino acids with sodium azide and TEOF in the presence of glacial acetic acid both as catalyst and solvent at 55 °C within 4 h in weak to good yields (23–83%). The product structure was characterized by ¹H and ¹³C NMR and mass spectra, and their stereoisomeric excess amounts were assigned by chiral HPLC (20–100%).⁴⁵⁵ 1-(6,7,9,10,17,18,20,21-Octahydrodibenzo[b,k]-[1,4,7,10,13,16]hexaoxacyclooctadecen-2-yl)-1H-tetrazole (2) could be synthesized via the domino three-component reaction of an arylamino derivative of dibenzo-18-crown-6 (1), TEOF, and sodium azide under heating in glacial acetic acid at 105 °C for 3 h in 73% yield.⁴⁵⁶ Yb(OTf)₃ also promoted the reaction of amines, TEOF, and sodium azide in 2-methoxyethanol at 100 °C to prepare the 1-susbstituted 1H-1,2,3,4-tetrazoles^457–462 in 6–9 h in 71–91% yields. Some of the products revealed phytocidal activity.⁴⁶² Muralidharan et al. also synthesized a library of nitrogen-rich heterocycles, such as 2-(1H-tetrazol-1-yl)-1H-imidazole-4,5-dicarbonitrile (557), 1-(1H-1,2,4-triazol-3-yl)-1H-tetrazole (559), and 5-(1H-tetrazol-1-yl)-1H-1,2,4-triazol-3-amine (561) via the critical role of TEOF. As could be seen, the above-mentioned compounds were obtained via the reaction of TEOF and also NaN₃ (243) with 2-amino-1H-imidazole-4,5-dicarbonitrile (556), 1H-1,2,4-triazol-3-amine (558), and 1H-1,2,4-triazole-3,5-diamine (560), as starting materials, respectively (Scheme 163).⁴⁶³

Scheme 163 Synthesizing a library of nitrogen-rich heterocycles.

4.25. Synthesis of pyridines

5-Nitropyridines (564) were obtained by Sagitullina et al. via the cyclocondensation of nitroacetone (562), TEOF (5) and enamines (563) in acetic acid media (Scheme 164).⁴⁶⁴

Scheme 164 The cyclocondensation of nitroacetone, TEOF, and enamines.

4.26. Synthesis of pyridazine derivatives

6-Methyl-3,4-diphenylpyrimido[4′,5′:4,5]selenolo[2,3-c]pyridazine-8(7H)-one was synthesized via the cyclocondensation reaction of 5-amino-3,4-diphenyl-6-substitutedselenolo[2,3-c]pyridazine with TEOF in acetic anhydride under reflux conditions within 8 h in 72% yield.⁴⁶⁵ In 2015, Arghiani and co-workers reported a simple procedure for the synthesis of new [1,2,4]triazolo[4,3-b]pyridazines (567) on treatment of 6-choloro-5-(4-substituted phenyl)-3-pyridazinyl hydrazines (565) with orthoesters (5, 6, 7, 566) in refluxing acetic acid for 5 h (Scheme 165). The products were filtered off and crystallized from methanol.⁴⁶⁶

Scheme 165 The synthesis of some new [1,2,4]triazolo[4,3-b]pyridazines.

4.27. Synthesis of tetrahydropyrimidinium salts

The cyclization of N,N′-dialkyl or diaryl ethane-1,2-diamines or propane-1,3-diamines (568) with inorganic ammonium salts (328) and TEOF (5) proceeds under microwave irradiation to afford the corresponding imidazolinium or tetrahydropyrimidinium salts (569). As can be seen in the Scheme 166, the microwave-assisted preparation of some 1,3-diaryl-3,4,5,6-tetrahydropyrimidium tetrafluoroborates was performed in ethanolic media. The TEOF is in 2–6 excess to the other substrates.⁴⁶⁷

Scheme 166 The cyclization of N,N′-dialkyl ethane-1,2-diamines with ammonium salts and TEOF.

4.28. Synthesis of pyrimidine derivatives

In the synthetic route to obtain 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives (571), the first step was reported via the reaction of 5-amino-4-cyano-3-methylthiophene-2-carboxylate (570) with TEOF, in refluxing toluene through the catalytic activity of acetic acid (Scheme 167).⁴⁶⁸

Scheme 167 Obtaining 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives.

In 2003, Abdel-Rahman and coworkers have reported that pyridine-2-carboxamide derivatives (572) were reacted with TEOF in refluxing acetic anhydride to furnish white crystals of 9-aryl-7-(2′-thienyl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4(3H)-ones (573) (Scheme 168).^469–471

Scheme 168 The formation of 9-aryl-7-(2′-thienyl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4(3H)-ones.

The cyclocondensation of 5-acetyl-3-amino-4-aryl-2-(N-aryl)carbamoyl-6-methyl-thieno[2,3-b]pyridines (574) with TEOF was accomplished in refluxing acetic anhydride, in a dual role of catalyst and solvent, to achieve 8-acetyl-3,9-diaryl-7-methylpyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine-4(3H)-ones (575)^325,472 in excellent yields (87–94%) in 2 h (Scheme 169).³²⁵

Scheme 169 The preparation of 8-acetyl-3,9-diaryl-7-methylpyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine-4(3H)-ones.

Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines (577) were produced via the cyclocondensation reaction of pyrazolo[3,4-d]pyrimidine (576) with triethyl orthoesters (5, 6, 7) in a 1 : 2 molar ratio in acetic acid, in a dual role of solvent and catalyst, under reflux conditions within 3 h in 63–83% yields (Scheme 170).⁴⁷³

Scheme 170 Obtaining pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines.

Pyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-6(7H)-ones (579) were made through cyclocondensation of 7-hydrazinyl-substituted pyrimido[4,5-d]pyrimidin-4(3H)-ones (578) with triethyl orthoesters (5, 6, 7) in equimolar amounts in refluxing AcOH in a 6 h period in 40–90% yields (Scheme 171). The products showed fluorescent and photophysical properties.⁴⁷⁴

Scheme 171 The formation of pyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-6(7H)-ones.

In 2016, 2,4-dichloro-5-amino-6-methylpyrimidine (580) was applied as a starting material for the synthesis of 5-hydrazinyl-7-methyl[1,3]thiazolo[5,4-d]pyrimidines (581) via a multi-step reaction which, on a cyclization reaction with orthoesters (5, 6) in refluxing acetonitrile using catalytic amounts of acetic acid along with the elimination of 3 moles of ethanol, furnished novel thiazolo[5,4-d][1,2,4]triazolo[4,3-a]pyrimidines (582) for 2–4 h in high yields (62–89%) (Scheme 172).⁴⁷⁵

Scheme 172 A novel thiazolo[5,4-d][1,2,4]triazolo[4,3-a]pyrimidine preparation approach.

Benzo[4,5]imidazo[1,2-c]-[1,2,5]oxadiazolo[3,4-e]pyrimidine (584) was obtained via the cyclocondensation of 3-amino-4-(1H-benzo[d]imidazol-2-yl)-1,2,5-oxadiazole (583) with TEOF in boiling acetic anhydride for 12 h, in 60% yield (Scheme 173).⁴⁷⁶

Scheme 173 The synthesis of benzo[4,5]imidazo[1,2-c]-[1,2,5]oxadiazolo[3,4-e]pyrimidine.

6-{[(5-Nitrothiophen-2-yl)methylene]amino}-3-phenyl-2-thioxo-2,3-dihydrothiazolo-[4,5-d]-pyrimidin-7(6H)-one (587)^477,478 as a brown compound was prepared via the cyclocondensation of thiazoline derivative (586), arising from 5-nitro-2-thiophenecarboxaldehyde (585), with TEOF in the presence of acetic anhydride under reflux conditions within 3 h in 61% yield (Scheme 174). The product (587) revealed good anti-inflammatory activity.⁴⁷⁸

Scheme 174 The synthesis of 6-{[(5-nitrothiophen-2-yl)methylene]amino}-3-phenyl-2-thioxo-2,3-dihydrothiazolo-[4,5-d]-pyrimidin-7(6H)-one.

Due to the growing biological importance of fused thiazoles, in 2007, Bondock et al. employed 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde (588) as a key precursor for the formation of thiazoline derivative (589) via a multi-step reaction. Subsequent cyclization with TEOF in acetic anhydride under reflux conditions yielded the thiazolo[5,4-d]pyrimidine derivative (590) in 60% yield in 3 h (Scheme 175). The compounds were screened and evaluated as antimicrobial agents.⁴⁷⁹

Scheme 175 Achieving thiazoline derivatives.

In 1998, Porcari and Townsend developed a fast and efficient method for the preparation of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine (594) from 2-amino-5-bromo-3,4-dicyanopyrrole (591), TEOF (5), and ethanolic ammonia (593). In the first step the reaction of 2-amino-5-bromo-3,4-dicyanopyrrole (591) with triethylorthoformate (5) in dry acetonitrile at reflux temperature, for 1 h formed 2-bromo-5-(ethoxymethylene)iminopyrrole-3,4-dicarbonitrile (592) which was used without further purification. Ring annulation to obtain 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine (594) was accomplished by dissolving the unpurified intermediate (592) in saturated ethanolic ammonia and heating this mixture at 105 °C in a sealed steel reaction vessel for 6 h (Scheme 176).⁴⁸⁰

Scheme 176 The preparation of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine.

In 2015, Abdel Hameed et al. demonstrated a regioselective procedure for the synthesis of pyrazolo[1,5-a]pyrimdines-7(4H)-ones (598) via the reaction of 5-amino pyrazoles (595), Meldrum's acid (231), and TEOF (5) in dioxane at room temperature. This transformation took place via a Knoevenagel condensation of Meldrum's acid (231) with TEOF (5) to produce intermediate (596), as a Michael acceptor, followed by the regioselective Michael addition with the exocyclic amino moiety of 5-amino pyrazoles (595) to obtain the corresponding acyclic adducts (597) in dioxane at room temperature; which after isolation underwent an intramolecular cyclization and then the elimination of acetone and CO₂ to get pyrazolo[1,5-a]pyrimdines-7(4H)-ones (598) in refluxing dioxane for 12 h. The compound (598) could also be directly obtained at once via the one-step condensation reaction of substrates in refluxing dioxane for 15 h (Scheme 177).⁴⁸¹

Scheme 177 The regioselective synthesis of pyrazolo[1,5-a]pyrimdines-7(4H)-ones.

In 2008, a facile and high-yielding process was developed for the synthesis of pyrazolo[3,4-d]pyrimidin-4-ones (601) in excellent yields (82–92%). First, aminopyrazoles (599) were condensed with TEOF (5) in glacial acetic acid under reflux conditions for 3 h to form the intermediate (600) which was then followed by cyclization and removal of an equivalent ethanol to achieve (601) (Scheme 178).⁴⁸²

Scheme 178 The synthesis of pyrazolo[3,4-d]pyrimidin-4-ones.

In 2015, 6-amino-3-methyl-4-fluorophenyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (602) was employed as a starting material for the preparation of 4-(4-fluorophenyl)-5-imino-3-methyl-1,4-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidin-6(5H)-amine (603)^483,484 as yellow powder. Hence, in the first step, (602) was condensed with TEOF (5) in refluxing acetic anhydride for 5 h; which was followed by the reaction of the isolated solid with hydrazine hydrate (271) in ethanol under reflux conditions for 2 h to produce (603) in 60% yield (Scheme 179). The product was screened for antibacterial and antifungal activities compared with norfloxacin and fluconazole as standard drugs.⁴⁸⁴

Scheme 179 The preparation of 4-(4-fluorophenyl)-5-imino-3-methyl-1,4-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidin-6(5H)-amine.

4.29. Synthesis of triazine derivatives

Montazeri et al. established a simple and catalyst-free method for the preparation of new bis[1,2,4]triazolo[4,3-b:1′,5′-d][1,2,4]triazines (606). This reaction progressed through the nucleophilic substitution reaction of 8-methyl-5-methylthio-2-aryl-6H-[1,2,4]triazolo[1,5-d][1,2,4]triazines (604) with hydrazine hydrate (271) in refluxing ethanol for 3 h to generate 5-hydrazino compounds (605); which was followed a cyclocondensation by triethyl orthoesters (5, 6) under refluxing in ethanol for 8 h to produce products (606) in 51–67% yields (Scheme 180).⁴⁸⁵

Scheme 180 The preparation of new bis[1,2,4]triazolo[4,3-b:1′,5′-d][1,2,4]triazines.

In 2017, the Zemanová group reported that 4H-furo[3,2-b]pyrrole-5-carbohydrazide (607) on reaction with orthoesters (5, 6, 536) in a polar solvent like DMF under reflux conditions yielded furo[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones (608) within 3.5–24 h, in high yields (69–75%) (Scheme 181). The products were screened for their antibacterial activity on Gram-negative bacterial species Escherichia coli CCM 7929, Pseudomonas syringae CCM 2114 and Gram-positive bacterial species Micrococcus luteus CCM 732, Bacillus pumilus CCM 2218 and it was found to have good activity.⁴⁸⁶

Scheme 181 The synthesis of furo[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones.

In 1989, some new 8-substituted-10-methyl-l,2-dihydro-1-oxo-l,2,4-triazino[4,5-a]indoles (610) were prepared in 70–78% yields from the reaction of various 3-methylindole-2-carbohydrazides (609) with TEOF (5) in refluxing dimethylformamide within 8 h (Scheme 182). These derivatives were evaluated for their antimicrobial activity. Most of the compounds showed good activity against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. Chloro-substituted derivatives showed the highest activity against all of the organisms tested.⁴⁸⁷

Scheme 182 The formation of new 8-substituted-10-methyl-l,2-dihydro-1-oxo-l,2,4-triazino[4,5-a]indoles.

In 2018, Lim and et al. described a chemo- and regioselective procedure for the synthesis of new 2-alkyl substituted 4-aminoimidazo[1,2-a][1,3,5]triazines (612) in weak to good yields (11–61%) via the catalyst-free one-pot three-component reaction of 2-aminoimidazoles (611), trialkylorthoesters (6, 7, 316, 317), and cyanamide (551) under microwave irradiation (Discover SP CEM) at 160 °C in ethyl acetate for 35 min (Scheme 183). It was found that a growth in length of the alkyl chain group on compound (612) resulted in a reduction in isolated yields. For example, the products originating from TEOAc (6) and triethyl orthopropionate, (7) obtained higher isolated yields than triethyl orthobutyrate (316) or trimethyl orthovalerate (317), which could be ascribed to the proportionately lower reactivity of long-chain orthoesters for the preparation of compounds (612). Molecular and crystal building blocks of resultant molecules were examined using X-ray crystallography.⁴⁸⁸

Scheme 183 The synthesis of new 2-alkyl substituted 4-aminoimidazo[1,2-a][1,3,5]triazines.

4.30. Synthesis of tetrazine derivatives

Preyssler heteropolyacid (H₁₄[NaP₅W₃₀O₁₁₀], 0.1 mmol) catalyzed the green one-pot reaction of 4-amino-3-hydrazino-6-methyl-1,2,4-triazin-5(2H)-one with orthoesters in acetic acid under reflux conditions to produce [1,2,4]triazino[4,3-b][1,2,4,5]tetrazines within 1–6 h in excellent yields (79–95%).⁴⁸⁹ [1,2,4]Triazino[4,5-b][1,2,4,5]tetrazines were also prepared from the reaction of 6-methyl-4-amino-5-hydrazino-1,2,4-triazin-3-one with orthoesters.⁴⁹⁰ [1,2,4]Triazino[3,4-b][1,2,4,5]-tetrazine-6-thiones (614) were synthesized in 58–78% yields upon treatment of 4-amino-6-methyl-3-hydrazino-4,5-dihydro-1,2,4-triazine-5-thione (613) with excess amounts of triethyl orthoesters (5, 6) in refluxing ethanol for 1 h (Scheme 184).⁴⁹¹

Scheme 184 The preparation of [1,2,4]triazino[3,4-b][1,2,4,5]-tetrazine-6-thiones.

4.31. Synthesis of cinnoline derivative

The cyclocondensation of 10-amino-7-(p-tolyl)pyrimido[4′′,5′′:4′,5]thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline-11-imine (615) with TEOF (5) was accomplished in refluxing acetic acid for 5 h to give 7-(p-tolyl)-1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido[4′′,5′′:4′,5′]thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline (616) in 70% yield (Scheme 185).⁴⁹²

Scheme 185 The synthesis of 7-(p-tolyl)-1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido[4′′,5′′:4′,5′]thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline.

4.32. Synthesis of quinazoline derivatives

Cobalt(II) chloride (CoCl₂, 10 mol%) catalyzed the one-pot three-component reaction of anthranilic acid, TEOF, and anilines in CH₃CN at 70 °C to obtain 3-substituted-quinazolin-4(3H)-ones.^493–495 Both electron-donating and electron-withdrawing anilines provided the products in good yields (75–95%).⁴⁹⁵ Quinazolin-4(3H)-ones (618) could also be obtained in good yields via the novel reductive cyclization of o-nitrobenzamides (617) and TEOF (5), promoted by TiCl₄/Zn in refluxing THF (Scheme 186).⁴⁹⁶

Scheme 186 The synthesis of quinazolin-4(3H)-ones.

The cyclocondensation of 6-hydrazino-substituted benzimidazo[1,2-c]quinazolines (619) with orthoesters (5, 6, 7) was accomplished in refluxing ethanol to obtain new benzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazolines (620) fin 1 h in high yields (70–81%) (Scheme 187).⁴⁹⁷

Scheme 187 Obtaining new benzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazolines.

Bis(quinazolinon-4(1H)-one) derivatives (622) were also synthesized via the regioselective one-pot pseudo five-component cyclocondensation reaction of isatoic anhydride (312), orthoesters (5, 6, 7, 102, 323, 455), and diamines (621) using KAl(SO₄)₂·12H₂O (alum, 20 mol%) as an inexpensive, eco-friendly, readily available, easily separable, and recyclable catalyst in refluxing DMF within 30–50 min in good to excellent yields (79–90%) (Scheme 188).⁴⁹⁸ 4-Arylaminoquinazolines⁴⁹⁹ were synthesized in excellent yields (84–96%) within 2 h via the one-pot three-component condensation reaction of 2-aminobenzamide, anilines, and orthoesters by a catalytic amount of Keggin-type heteropolyacid (H₆[PMo₉V₃O₄₀], 0.03 mmol) in refluxing CH₃CN. Significantly, anilines containing electron-donating groups were obtained in slightly better yield. In this reaction, 3-quinazolin-4-one (2) was formed as a by-product in low yield.⁵⁰⁰ Preyssler heteropolyacid H₁₄ [NaP₅W₃₀O₁₁₀] also progressed this transformation in refluxing CH₃CN within 2 h.⁵⁰¹

Scheme 188 The formation of bis(quinazolinon-4(1H)-one) derivatives.

4.33. Synthesis of quinoxalines

Novel 3-substitued [1,2,4]triazolo[3′,4′;2,3][1,3]triazolo[4,5-b]quinoxaline derivatives (624) were achieved through the cyclocondensation of [1,3]thiazolo[4,5-b]quinoxaline-2(3H)-one hydrazone (623) with orthoesters (4, 6) in acetic acid under reflux conditions within 4–8 h (Scheme 189).⁵⁰²

Scheme 189 The synthesis of novel 3-substitued [1,2,4]triazolo[3′,4′;2,3][1,3]triazolo[4,5-b]quinoxalines.

4.34. Glycosidation, glycosylation, and oligomerization reactions

In 2015, Rao et al. employed propargyl 1,2-orthoesters (625) as key synthons and glycosyl donors for the synthesis of thiosaccharides and 1-thiotrehaloses (627) in a 1,2-trans diastereoselective form only via the glycosidation reaction^503–509 with glycosyl mercaptans (626), as glycosyl acceptor, using gold(III) bromide (AuBr₃, 7 mol%) as catalyst in CH₂Cl₂ at room temperature under argon atmosphere in excellent yields (83–94%) within 6 h (Scheme 190).⁵⁰⁹

Scheme 190 The synthesis of thiosaccharides and 1-thiotrehaloses.

In 2015, Vadhadiya and Ramana reported the first total synthesis of sinenside A. In this survey, the glycosidation reaction of orthoester (628)⁵¹⁰ with allylic alcohol (629), as a glycosyl acceptor, by BF₃·Et₂O (0.15 equiv.) as catalyst in dichloromethane at 0 °C in the presence of 4 Å molecular sieves obtained β-glucoside (630) in good yield (76%) in a 1 h period, which was employed as a key precursor for the synthesis of sinenside A (631) via a multi-step reaction (Scheme 191).⁵¹¹

Scheme 191 The total synthesis of sinenside A.

The stereoselective O-glycosylation of glycals (632) and glycosylbromides (634) by orthoformates (4, 5, 127) in the presence of InCl₃ in corresponding solvents (CH₃CN and CH₂Cl₂) yielded O-glycopyranosides (633, 635) at room temperature (Scheme 192). It must be mentioned that both perbenzyl and peracetyl glycals resulted in 2,3-unsaturated-O-glycosides with major α-selectivity while glycosylbromides furnished alkoxy glycosides with high β-selectivity in most cases.⁵¹²

Scheme 192 The formation of O-glycopyranosides.

SnCl₄ catalyzed the oligomerization reaction of 3-O-benzoyl-β-D-arabinofuranose 1,2,5-orthobenzoate (636)^513,514 with 4-(2-chloroethoxy) phenol (637a) or (4-(2-chloroethoxy)phenoxy)trimethylsilane (CEP-OTMS, 637b) as a terminating agent in CH₂Cl₂ at −25 °C to form selectively α(1 → 5) linked arabinofuranose oligomers, including 4-(2-chloroethoxy)phenyl (CEP) aglycon with a deprotected 5-OH group at the non-reducing end (638) (Scheme 193).⁵¹⁵ The resultant glycosyl acceptor (638) could be used in glycosylation reactions.^514,516

Scheme 193 Glycosyl acceptor synthetic procedure.

4.35. Synthesis of (±)-1,2-O-ethylidene-myo-inositol

The reaction of myo-inositol (639) with TEOF (5) using p-TSA (2g) under heating in dimethyl sulfoxide at 100 °C has been used to obtain myo-inositol monoorthoformate (640) and (±)-1,2-O-ethylidene-myo-inositol (641) within a 24 h period in 42% and 33% yields, respectively (Scheme 194). It was found that the presence of the chiral carbon of ethylidene in the compound (641) formed a mixtures of the four diastereomers which were not isolated by silica gel column chromatography but were characterized by NMR spectra.⁵¹⁷

Scheme 194 The synthesis of myo-inositol monoorthoformate and (±)-1,2-O-ethylidene-myo-inositol.

4.36. α-Arylation and alkylation of protected pyruvate esters

In 2017, Esteves et al. interpreted a novel process for the enolate arylation and alkylation of protected pyruvate esters. Hence, in the first step, the orthoester-masked pyruvate equivalent (oxabicyclo[2.2.2]octyl orthoester, OBO)^518–521 was prepared through the reaction of pyruvic acid (642) with oxalyl chloride (643) to form pyruvoyl chloride (644) which underwent an esterification reaction with 3-methyl-3-oxetanemethanol (645) in the presence of pyridine to afford the ester (646) via a two-step reaction which on reaction with BF₃·OEt₂ in CH₂Cl₂ at 0 °C yielded the OBO orthoester (647) (Scheme 195). Then, the mono α-arylation (649) reaction was accomplished via the reaction of (647) with aryl bromide (648) by Pd(dtbpf)Cl₂ (5 mol%), utilizing at least two equivalents of base in THF at 50 °C for 24 h. Due to the greater acidity of the product than the starting material,⁵²² the resultant aryl ketone was deprotonated in situ by the extra base. Subsequent alkylation by different equivalents of electrophile at 50–80 °C obtained α-arylation and alkylation products (Scheme 196). In the final step, the OBO protective group was conveniently removed using acidic conditions such as p-TSA in ethanol at 90 °C for 3–8 h. The method also enabled mono- and diarylation reactions to happen on a readily available OBO-protected precursor.⁵²¹

Scheme 195 The preparation of OBO orthoester.

Scheme 196 The mono α-arylation of OBO orthoester.

5. Conclusions

In this review, several types of orthoesters have been reported as applicable substrates in classified organic transformations. These treatments have been subdivided according to the reaction medium. This focus is because of the significance of economical and green reactions in organic syntheses. Based on the overall results, the reaction could happen in solvent-free media, in the presence of aqueous conditions, or in organic solvents. Detailed investigations in the form of a literature survey affirmed that the processes containing orthoesters progressed well in the absence of solvents. This important attainment has let researchers design new procedures to achieve compounds with multi-functionalized motifs in the absence of hazardous solvents, utilizing the greater activity potential of substrates and reagents, as they could come into contact effectively within short periods. The aqua-mediated reactions were not extensive, which may be due to the hydrolysis affinity of orthoesters in water. Traditional organic solvents were also mentioned a great deal in reports. The greatest usage involved alcohols, dichloromethane, acetic anhydride, acetonitrile, acetic acid, benzene and its derivatives, and THF. Other common solvents used in lower abundance were DMF, ether, DMSO, dioxane, and CCl₄. Some transformations were done under heating conditions and some others required microwave or ultrasound assistance for promotion. Based on the many mentions, TEOF was the most commonly used alkyl orthoester in a vast range of reactions. The authors hope that this article will guide general readers to gain an intense interest in using orthoesters, as versatile and easily-handled synthons, in a great range of reactions with a focus on the environment.

Conflicts of interest

There are no conflicts to declare.

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