Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

Multicomponent reactions (MCRs) are one of the most important processes for the preparation of highly functionalized organic compounds in modern synthetic chemistry. As shown in this review, they play an important role in organophosphorus chemistry where phosphorus reagents are used as substrates for the synthesis of a wide range of phosphorylated heterocycles. In this article, an overview about multicomponent reactions used for the synthesis of heterocyclic compounds bearing a phosphonate group on the ring is given.


Introduction
Heterocyclic rings are found in many naturally occurring compounds and they compose the core structures of many biologically active scaffolds as well as some industrial compounds [1][2][3]. On the other hand, phosphonic acid and its related derivatives are considered as potential bioisosters of the corresponding carboxylic acids [4]. Thus, the incorporation of phosphonyl groups into the heterocyclic systems has led to an important class of organophosphorus compounds that has attracted the attention of both industrial and medicinal chemists [5][6][7][8][9][10][11][12]. Many efforts have been made to prepare these bioactive compounds over the last 60 years [13]. There are two general approaches to the synthesis of heterocyclic phosphonates: (a) the direct electrophilic or nucleophilic phosphorylation of the heterocyclic systems and (b) the ring closure of phosphoryl-functionalized substrates through cyclization or cycloaddition reactions [14][15][16][17][18][19].
Multicomponent reactions (MCRs) constitute one of the most efficient tools in modern synthetic organic chemistry, since they have all features that contribute to an ideal synthesis: high atom efficiency, quick and simple implementation, time and energy saving, environment-friendly and they offer a target and diversity-oriented synthesis [20]. Therefore, the development of new multicomponent reactions towards biomedical and industrial scaffolds is inevitable at the present time. Furthermore, the combination of established multicomponent reactions with postreaction transformations opens the way towards a vast number of diverse and complex products. Some of these post-MCR Scheme 2: The Biginelli reaction of β-ketophosphonates catalyzed by ytterbium triflate.
Up to now, two review articles have been reported on azaheterocyclic phosphonates [22,23], but no overview article about the multicomponent synthesis of phosphono-substituted heterocycles has been reported so far. This review focuses on general multicomponent reactions as well as on modified MCR towards heterocyclic phosphonates. It is organized by the reaction types and covers literature published up to September 2015.

Idris Essid and Soufiane
Touil showed that the Biginelli condensation of β-ketophosphonates was highly sensitive to the nature of solvents, acid catalysts and reactants [28]. They found that the use of inorganic acids including HCl and H 2 SO 4 or Lewis acids such as SnCl 2 , FeCl 3 and VCl 3 , as well as heterogeneous catalysts including silica gel supported sulfuric acid and sodium hydrogen sulfate did not affect this reaction. Also, the reaction in the presence of p-toluenesulfonic acid (TsOH), in aprotic solvents proceeded with much better yields than in protic solvents. When diethyl (2-oxopropyl)phosphonate and 4-nitrobenzaldehyde were treated in the presence of 50 mol % TsOH in acetonitrile, 5-phosphonato-3,4-dihydropyrimidin-2one 18 was obtained in excellent yield (Scheme 5).
Due to their wide range of biological activities, α-aminophosphonates have been extensively investigated and several reviews about their syntheses through the Kabachnik-Fields reaction have been reported [31][32][33]. However, an important feature of this reaction is that it provides an efficient route to phosphonylated heterocycles. The different applications of the Kabachnik-Fields reaction in the preparation of phosphonylated heterocycles can be classified into two major categories: a) phosphonylation of heterocyclic ketones through a classic Kabachnik-Fields reaction and b) synthesis of heterocyclic phosphonates through modification of the products obtained by the Kabachnik-Fields reaction.
The reaction of isatin (27) with diethyl phosphite and benzylamine under similar conditions gave the corresponding α-aminophosphonate 28 in 90% yield together with small amounts of α-hydroxyphosphonate 29 as a side product (Scheme 8).
The one-pot reaction of substituted isatins 30 with aniline (32) and dimethyl-or diethyl phosphite under solvent-free conditions in the presence of magnetic Fe 3 O 4 nanoparticle-supported phosphotungstic acid as a recyclable catalyst at 80 °C furnished α-aminophosphonates 33 in yields from 80% to 98% depending on the reaction time and the structure of the dialkyl phosphite and isatin (Scheme 9) [35].
In this way a one-pot three-component reaction between 1-tosylpiperidine-4-one (34), aromatic amines 35 and diethyl phosphonate in the presence of magnesium perchlorate as a catalyst, under neat conditions at 80 °C afforded α-aminophosphonates 36 in good yields (Scheme 10). Some of the resulting α-aminophosphonates showed insecticidal activity against Plutella xylostella [36].
The same research group found a useful method for the synthesis of isoindolin-1-one-3-phosphonates from aromatic amines [41]. The one-pot reaction of aniline 59 with formylbenzoic acid (55) and dimethyl phosphonate (31) under the abovementioned conditions at 90 °C afforded the desired isoindolin-1-one-3-phosphonates 60 in only 14% yields after five days. Noteworthy, the treatment of the same reaction mixture under microwave irradiation at 90 °C gave the expected product 60 in 77% yields after several minutes. Subsequently, the isoindolin-1-one-3-phosphonates 60 were dephosphorylated by treatment with lithium aluminum hydride to give isoindolin-1-ones 61 (Scheme 15). Recently, an efficient method was developed for the synthesis of ethyl (2-alkyl-and 2-aryl-3-oxoisoindolin-1-yl)phosphonates 71 from 2-formylbenzoic acid (55), triethyl phosphite and amines 70 using OSU-6, a novel MCM-41-type hexagonal mesoporous silica, as a catalyst (Scheme 17) [44]. The important advantages of this methodology is that the (3-oxoisoindolin-1-yl)phosphonates 71 are obtained in high yields from benzylic, aliphatic and aromatic amines possessing both, electron-donating and electron-withdrawing groups, in shorter reaction times with minimum purification requirements. Also, the catalyst can be used for up to four reaction cycles without significant loss of activity.

Pyrazolyl-and oxazolylphosphonates:
A series of modified Kabachnik-Fields condensations based on the reaction of 6-methyl-3-formylchromone (75) with some 1,2-, 1,3-and 1,4bi-nucleophiles and diethyl phosphonate under solvent-free conditions have been developed by E. Ali et al. [46]. The resulting α-aminophosphonate intermediates 77 and 80 were nonisolable and interconverted to the corresponding heterocyclic phosphonates via ring opening through an intramolecular nucleophilic attack at the 2-position of the pyrone. Thus, the three-component reaction of 75 with hydrazine derivatives 76 or hydroxylamine 79 in the presence of diethyl phosphonate led to pyrazolylphosphonate 78 and oxazolylphosphonate 81, respectively (Scheme 19).
A more detailed investigation on the catalytic cyclization during Kabachnik-Fields reactions of acetylenic aldehydes with aromatic amines and dialkyl phosphonates has been reported by Čikotienė et al. [50]. They found that the cyclization type during these three-component reactions strongly depends on the nature of the acetylenic aldehydes 102. The Kabachnik-Fields adducts of various carbocyclic acetylenic aldehydes 104 and 105 in the presence of AuBr 3 , PdCl 2 , AgOTf, AgNO 3 or I + underwent a 5-exo-dig cyclization to give dialkyl 1H-pyrrol-2ylphosphonates 106. However, iodine-mediated cyclizations lead to pyrrol-1-ylphosphonates bearing a carbonyl (107) or 1-iodoalkenyl substituent (108) depending on the substituent R. In contrast, electron-deficient heterocycles 113 and 114 in the presence of CuI reacted through a tandem imine formation-6endo-dig cyclization to give the corresponding 1,2-dihydropyridin-2-ylphosphonates 115. However, electron-rich heterocyclic Kabachnik-Fields adducts were found to be unreactive towards Lewis acid catalyzed cyclization processes. On the other hand, benzene derivatives 109 can participate in both cyclization modes depending on the catalyst's nature. They either can cyclize to give the corresponding 1,2-dihydropyridin-2-ylphosphonates 111 in the presence of CF 3 [54]. The authors observed that the presence of molecular sieves (4 Å) had a beneficial effect on the yield of the reaction due to trapping of water resulting from the imine formation reaction. The generality of the reaction has been investigated by the use of structurally diverse diamines, ketones and phosphonates. While the reaction proceeded well with different amines and phosphonates, only the use of acetone as the ketone component afforded the corresponding benzodiazepinylphosphonates. With other ketones only ketimine intermediates were obtained which were sterically too crowded for attacking the phosphorus atom of the phosphonates. The use of unsymmetrically substituted diamines led to the corresponding syn-regioisomers as the major product and the anti-regioisomer as the minor product. Some of the synthesized 1,5-benzodiazepin-2ylphosphonates showed cysteine protease inhibition activities.

Heterocyclic bisphosphonates: A modified
Kabachnik-Fields reaction of the substituted amine 135 with triethyl orthoformate followed by reaction with sodium diethylphosphite afforded bisphosphonate intermediate 136 that was converted to the heterocyclic bisphosphonate 137 through an intramolecular cyclization (Scheme 29) [55]. The sequenced reaction of the amine with triethyl orthoformate followed by the addition of sodium diethylphosphite dissolved in toluene considerably increased the yields of bisphosphonates.

Knoevenagel-induced domino reactions
An efficient method into phosphorylated heterocycles is the condensation of an activated methylene component with a carbonyl compound followed by subsequent transformations such as intramolecular cyclization, Michael-type addition and hetero-Diels-Alder cycloaddition.

Domino Knoevenagel/phospha-Michael process
A convenient one-pot ZnO nanorods-catalyzed reaction of isatin derivatives 144 with malononitrile (145) and dialkyl or diphenyl phosphonates 146 has been performed to give 2-oxindolin-3ylphosphonates 147 (Scheme 31) [56]. The products were ob- tained in good to excellent yields using 10 mol % of the catalyst under solvent-free conditions at room temperature. However, when using ethyl cyanomalonate instead of malononitrile, the reaction in water led to the corresponding 2-oxoindolin-3ylphosphonate in good yield. Further, the investigations showed that the recovered ZnO nanorods could be reused up to five times.

Three-component synthesis of (2-amino-3cyano-4H-chromen-4-yl)phosphonates
Because of the widespread biological activities related to 2-amino-4H-chromene derivatives, the synthesis of (2-amino-3cyano-4H-chromen-4-yl)phosphonates has attracted much attention from organic chemists. The best procedure for the preparation of these compounds involves a one-pot three-component reaction between salicylaldehydes 157, malononitrile (145) and trialkyl phosphite that was first reported by Perumal In recent years, several methods using different catalysts have been developed to prepare 2-amino-3-cyano-4H-chromen-4ylphosphonates. These methods and other aspects of reaction conditions are summarized in Table 1.

Domino Knoevenagel/hetero-Diels-Alder process
The one-pot synthesis of dihydropyrans via a three-component reaction between an activated methylene compound, an aldehyde and an electron-rich alkene was firstly reported by Tietze et al. [72]. Collignon et al. applied this protocol for the prepara-tion of phosphonodihydropyrans 163 or 164 starting from phosphonopyruvate 159 or phosphonopyruvamide 160, p-nitrobenzaldehyde (161) and ethyl vinyl ether (162) in a reactor equipped with a Dean-Stark separator (Scheme 35) [73]. The yields of the resulting cycloadducts 163 and 164 were 87% and 91%, respectively and were much higher than the overall yields of the  A CuI-catalyzed four-component reaction through a methyleneaziridine ring-opening process has been developed for the synthesis of α-aminophosphonates [76]. Thus, the one-pot reaction between methyleneaziridines 173, Grignard reagents 174, alkyl halides 175 and dialkyl phosphonates in the presence of CuI afforded acyclic α-aminophosphonates 176. However, using difunctionalized electrophiles such as 1,3-diiodopropane 178 resulted in piperidinylphosphonates 179 with moderate yields (Scheme 38). This one-pot transformation involves an aziridine ring opening, C-alkylation, and hydrophosphorylation of the formed imine to create three intermolecular bonds.

Isocyanide-based multicomponent reactions
Although isocyanide-based multicomponent reactions (IMCRs) are one of the most important routes into heterocyclic compounds, there are only a few publications related to the isocyanide-based multicomponent synthesis of heterocyclic phosphonates in the literature. However, three different isocyanide-based multicomponent reactions for the synthesis of heterocyclic phosphonates are described here.
A one-pot three-component reaction between the acylphosphonates 192 formed by treatment of triethyl phosphite and acyl chlorides 191, isocyanides 193 and dialkyl acetylenedicarboxyl-ates 194 to afford 2-phosphonofuran derivatives 196 has been reported by our group (Scheme 41) [79]. The desired furanylphosphonates were isolated in 52-67% yield at rt in CH 2 Cl 2 . In this transformation the zwitterionic intermediate 195, resulting from reaction of isocyanide with dialkyl acetylenedicarboxylate, added to the carbonyl group of the acylphosphonate followed by an intramolecular cyclization.
Yavari et al. described the synthesis of phosphorylated 2,6dioxohexahydropyrimidines 311 via a three-component reaction [102]. This method involved the one-pot reaction of N,N'dimethylurea (310) and dialkyl acetylenedicarboxylates 309 in the presence of trialkyl phosphites 308 at room temperature (Scheme 64). The desired products were obtained in high yields between 84 and 94%.

Conclusion
In this article the use of different multicomponent reactions (MCRs) for the synthesis of heterocyclic phosphonates has been reviewed. This review demonstrates the synthetic potential of multicomponent reactions for the construction of phosphonosubstituted heterocyclic rings. The Kabachnik-Fields reaction can be considered the starting point of multicomponent synthesis of this class of compounds. However, the major advancements in this interesting field have been achieved in recent years. More than 75% of the cited literature in this review has been published within the last six years, of which more than three quarters dealt with the synthesis of new heterocyclic phosphonates from non-heterocyclic phosphorus reagents. The remaining works reported the phosphorylation of parent heterocyclic systems. It is worth mentioning, that most of the cited publications focused on the synthesis of five and six-membered rings and only four articles described the synthesis of three and seven-membered heterocycles. Additionally, the majority of the reported syntheses were devoted to the development of new methodologies including the use of advanced catalytic systems, alternative solvents and microwave irradiation. Thus, the development of novel MCR based on phosphorous reagents would allow the synthesis of macrocyclic and medium or large-sized heterocyclic systems, substances which are currently underrepresented in the literature. Further, the design of new biocompatible scaffolds such as β-lactams and peptidomimetics possessing phosphonate groups by MCR-based strategies would significantly extend the synthetic potential of MCRs towards heterocyclic phosphonates.