Heterocyclization reactions using malononitrile dimer (2-aminopropene-1,1,3-tricarbonitrile)

In this work, we provide the first generalized and critical analysis of data on the chemistry of malononitrile dimer (2-aminopropene-1,1,3-tricarbonitrile) – a multifunctional reagent that is widely used for the preparation of diverse heterocyclic systems. The majority of references are from the last 20–25 years.

Malononitrile derivatives are known as highly reactive compounds offering rich synthetic possibilities and are actively used for the preparation of various carbo- and heterocyclic products. Of particular significance among malononitrile derivatives is its dimer (2-aminopropene-1,1,3-tricarbonitrile), which was first obtained^1,2 in the middle of 1950s and serves as an important reagent in the synthesis of dyes, biologically active pyridine derivatives, and other compounds. Some chemical properties of malononitrile dimer have been described in a series of review articles,^3,4,5 mostly in the context of the reactivity of other compounds. A most detailed discussion on the chemistry of malononitrile dimer is available in a dedicated chapter of monograph by Sharanin, Promonenkov, and Litvinov,⁶ devoted to the reactions of malononitrile derivatives. A review article on the chemistry of crotononitrile was published in 1998, where some aspects of 2-aminopropene-1,1,3-tricarbonitrile reactivity were briefly discussed.⁷ Substantial advances in the chemistry of malononitrile dimer were made over the following two decades, thus we considered it necessary to provide a comprehensive overview of this field in the current work.

The aim of this review is to demonstrate the synthetic potential of malononitrile dimer as a convenient and multifunctional reagent for assembling a wide range of heterocyclic systems. We organize the available references according to the type and size of the target heterocycle.

1. Synthesis, structure, and properties of malononitrile dimer

Malononitrile dimer (1) is a beige crystalline compound that is soluble in EtOH or water upon heating, stable during storage, safe in handling, and commercially available. The most common approach to the preparation of dimer 1 relies on the dimerization of malononitrile in the presence of various catalysts; some of the early methods for its synthesis are considered in review articles.^4,6 Currently, the preparative procedure proposed by Mittelbach⁸ can be considered as the most convenient option providing access to this compound.

Synthesis of 2-aminopropene-1,1,3-tricarbonitrile (1) (Scheme 1).⁸ Malononitrile (33 g, 0.5 mol) was added to a cooled solution of KОН (0.25 mol) in anhydrous EtOH (100 ml). The temperature of the stirred reaction mixture was slowly raised to reflux. Potassium salt of dimer 1 precipitated after 5–10 min. After heating for 30 min, the mixture was cooled, the potassium salt was filtered off, washed with cold EtOH, and dried. The salt was dissolved in a small amount of water and acidified with concentrated HCl to рН 4. The precipitated product was filtered off and recrystallized from water, giving dimer 1 in the form of colorless needles, mp 172°С, yield 87%. Replacement of anhydrous EtOH with 96% EtOH decreased the yield to 83%.

Scheme 1

Recently proposed methods for the preparation of dimer 1 rely on the dimerization of malononitrile by the action of sodium powder in THF–ether mixture (61% yield)⁹ or sodium ethoxide in anhydrous EtOH (87% yield of compound 1 in the form of sodium salt)¹⁰ and are essentially based on previously published procedures.^2,11 The spectral characteristics of dimer 1 have been described in several original studies,^{11,12,13,14,15} as well as discussed in review articles.^4,6 The crystal structure features of compound 1 were studied by X-ray structural analysis.¹⁶ The tautomeric transformations of dimer 1, the details of the dimerization process, and the structures of the intermediates were studied by quantum-chemical calculations using MNDO method.¹⁷

2. Synthesis of three–five-membered heterocycles

As a compound containing an activated methylene group, dimer 1 readily reacts under the conditions of basic catalysis (piperidine,^18,19 piperidinium acetate^20,21,22) with aromatic aldehydes, resulting in the formation of 4-arylbuta-1,3-diene-1,1,3-tricarbonitriles 2 (Scheme 2). The latter were treated with peroxyacetic acid giving 81–95% yields of oxiranes 3,^23,24,25 which were easily recyclized in the presence of alkali thio(seleno)cyanates into derivatives of furo[3,2-c]isothiazole²⁶ and -selenazole 4.²⁷

Scheme 2

As an active 1,3-С,N-dinucleophile, malononitrile dimer (1) reacted in the presence of bases with 1,2-dicarbonyl compounds and analogous dielectrophilic substrates, resulting in the cyclization of five-membered pyrrole ring. The possibilities for the synthesis of substituted pyrroles according to the given scheme were initially demonstrated with the reaction between dimer 1 and diethyl oxalate.² Disodium derivative 5 that was thus obtained has found applications in the synthesis of push-pull chromophores 6 of pyrroline series^10,28 (Scheme 3).

Scheme 3

The interaction of dimer 1 with 1,2-diketones has been studied in considerable detail.^29,30 At the same time, it should be noted that the previously published^31,32 acyclic structures of condensation products 7 were incorrect and the products formed in reactions of dimer 1 with diketones actually had the structure of pyrrolines 8^30,33 (Scheme 4). Recently, it has been demonstrated that the reaction of 1-arylpropane-1,2-diones with dimer 1 proceeded regioselectively and gave pyrroles 9 in 53–61% yields.³⁴ The selective formation of regioisomers 9 was explained by the deactivation of acetyl group resulting from the enolization in basic medium.

Scheme 4

The preparation of new chromophoric pyrrolines 10 starting by the reaction of ethyl pyruvate with dimer 1 and followed by the condensation of the obtained cyclic product with 4-(dialkylamino)benzaldehydes has been described in the literature (Scheme 5).^9,35,36

Scheme 5

Functionalized pyrrole derivatives 11 were isolated in moderate yields after the treatment of monobromination product obtained from dimer 1 with anilines (Scheme 6).³⁷ Derivatives of anthranilic acid under the given conditions underwent a cascade reaction, resulting in the formation of pyrrolo[1,2-a]quinazolines, for example, compound 12.

Scheme 6

Pyrroline derivative 13 was obtained by reaction of dimer 1 with diethyl acetylenedicarboxylate in the presence of a base (Scheme 7).³⁸ The reaction apparently was not widely applicable: for example, the reactions of dimer 1 with other highly electrophilic acetylenes gave carbocyclization products 14.³⁹

Scheme 7

A publication appeared in 2011 where the products obtained by alkylation of malononitrile dimer (1) with α-bromo ketones were assigned the structure of spiro-dipyrrolines 15 (Scheme 8).⁴⁰ However, subsequent characterization by X-ray structural analysis showed that the reaction products in fact were pyrroles 16.⁴¹

Scheme 8

Butadienetricarbonitriles 2 were found to be convenient reagents for the assembly of five-membered heterocyclic systems. Thus, dienes 2 participated in a reaction with α-bromonitriles, resulting in cyclopropane ring closure and further intramolecular 5-exo-dig cyclization, leading to bicyclic products 17 (Scheme 9).^{22,24,25,42,43} It was noted that the reaction proceeded regio- and stereoselectively with the formation of diаstereomers featuring trans relationship of the pyrroline moiety and the aryl substituent. As a result of an analogous reaction between dienes 2 and 2-bromo-1,3-dicarbonyl compounds^22,44 pyrrolidine derivatives 18 and 19 were formed. At the same time, it was established that in the case of 5-bromobarbituric acid the reaction stopped at the stage of spirocyclopropanes 20.²²

Scheme 9

An alternative to the use of malononitrile dimer (1) in the synthesis of substituted pyrrolines (for example, from 1,2-diketones²⁹) is the rearrangement of compounds 21 – Michael adducts obtained from tetracyanoethylene and cyclohexanones. This rearrangement is catalyzed by D-glucose (Scheme 10),⁴⁵ the role of which, according to the proposed mechanism, is to transfer the malononitrile fragment through the formation of addition product at the aldehyde group. In the absence of glucose the product yield decreased to 19–28%.

Scheme 10

Compounds 2, as well as 1-azabutadienes 22 obtained by Ehrlich–Sachs condensation reacted quite readily at the amino group with anhydrides of succinic, citraconic, and phthalic acids with the formation of push-pull dyes 23 (Scheme 11).^46,47,48,49 It was noted that such modification led to a bathochromic shift of the absorption maximum.

Scheme 11

The purple-colored polymethine dyes 24 were obtained as a result of an unusual carbocyclization reaction, which occurred in parallel with the formation of cyanines 25 through a reaction sequence involving the condensation of malononitrile dimer (1) with ω-(2-thienyl)polyenals 26 followed by a reaction with phthalic anhydride (Scheme 12).⁵⁰ Longer refluxing of the mixture facilitated complete conversion of compound 25 to compound 24. It was noted that the cyclization was facilitated by the unusually high dipole moment (˃20 D) of molecules 25, resulting from intramolecular charge transfer. The cyclization was promoted by bases. The reaction occurred with polymethines 25 having n ˃ 1, which could be explained by the increased flexibility of longer polyene chains.

Scheme 12

It has been reported in the literature⁵¹ that 2-aminopropene-1,1,3-tricarbonitrile (1) underwent Clauson–Kaas reaction, resulting in the formation of pyrrole 27 (Scheme 13), but we consider that these observations need additional experimental verification.

Scheme 13

Indolizine derivatives 28 were formed as a result of reaction between Kröhnke–Mukaiyama salts 29 and dimer 1 under mild conditions (Scheme 14).⁵² Indolizines 28 showed an interesting dual reactivity: brief heating in alcohols resulted in the loss of a malononitrile molecule and produced indolizines 30, while treatment with KOH in DMF medium led to tricyclic structures 31. N-Allyl-2-halopyridinium salts under analogous conditions reacted with dimer 1, providing only the linear product that was cyclized to indolizine 32 upon heating.

Scheme 14

A recent publication⁵³ described an example where furan derivatives were prepared using dimer 1. Thus, electrochemical oxidation of hydroquinones in the presence of malononitrile dimer (1) led to the formation of benzofuro[2,3-b]pyridines 33. It was proposed that the reaction proceeded via cascade cyclization of Michael adducts 34 involving the formation of non-isolated benzofuran derivatives (Scheme 15).

Scheme 15

The intermediate product arising from bromination of malononitrile dimer reacted with NaHS with the formation of functionalized thiophene derivative 35.⁵⁴ It should be noted that thiophene 35 was obtained earlier⁵⁵ in a better yield by direct thiolation of dimer 1 with elemental sulfur in the presence of diethylamine (Scheme 16).

Scheme 16

Several publications^56,57,58,59 describe the synthesis of thiophene derivatives from malononitrile dimer (1) using the Gewald reaction. The product from condensation of dimer 1 with carbonyl compounds reacted with elemental sulfur in the presence of amines upon heating (Scheme 17). The products of this reaction were assigned the structure of 2-aminothiophenes 36. At the same time, an earlier study by Junek and coworkers used a series of analogous examples⁶⁰ to show that the reaction proceeded further even under mild conditions, resulting in the formation of thieno[2,3-b]pyridines 37. Obviously, additional research in this direction is needed.

Scheme 17

The preparation of functionalized thiophene derivatives 38 in good yields has been also described. The procedure involved treatment of malononitrile dimer 1 with alkylating agents and carbon disulfide in the presence of alkali (Scheme 18).⁶¹

Scheme 18

In the case of an analogous reaction using isothiocyanates instead of CS₂, further cyclization of the thiophene intermediates was observed, leading to the formation of thieno[2,3-b]pyridines 39 (Scheme 19).⁶²

Scheme 19

So far only isolated examples have been published where the synthesis of 1,3-dithiol derivatives was accomplished starting from malononitrile dimer (1) (Scheme 20). Thus, dithiolium iodide 40 upon treatment with malononitrile dimer (1) gave a low yield of 1,4-dithiafulvene derivative 41.⁶³ The reaction of polyenals containing a dithiol moiety or the respective iminium salts 42 with dimer 1 enabled the preparation of new merocyanine dyes 43.⁶⁴

Scheme 20

The reaction of dimer 1 with isothiocyanates in the presence of elemental sulfur provides an accessible route for the preparation of substituted thiazoles 44 (Scheme 21).⁶⁵ Another approach to the assembly of thiazole ring on the basis of malononitrile dimer (1) involves the interaction with thioglycolic acid at elevated temperature. It was demonstrated that this transformation affects the unconjugated nitrile group (Scheme 21).⁶⁶

Scheme 21

The most general method for the preparation of pyrazole derivatives from malononitrile dimer (1) is based on the reaction with hydrazines RNHNH₂ where dimer 1 acts in the role of β-enaminonitrile substrate. The possibility for obtaining 3-amino-5-(cyanomethyl)-1H-pyrazole-4-carbonitriles by this route was first demonstrated in late 1950s.^2,11,67 Since that time, this approach has been used without substantial changes for the preparation of N-substituted 3-aminopyrazoles 45,^{68,69,70,71,72} which have found applications in the synthesis of various polyheterocyclic compounds^{67,68,69,70,71,72,73,74,75,76,77,78,79} – for example, azaheterocycles 46–49 (Scheme 22).

Scheme 22

3-Aminomethylidene derivative of dimer 1 reacted with hydrazines by a different route – with a sequential closure of pyrazole and pyridine rings and the formation of compound 50 (Scheme 23).⁸⁰ It was shown that hydrazones 51 in the presence of hydrazines were converted to pyrazoles 52,^81,82 with further cyclization in the molecule of pyrazolo[3,4-b]pyridine 53 occurring upon the treatment with a strong base (EtONa).⁸¹ The products arising from the condensation of malononitrile dimer (1) with ketones also reacted with hydrazines with the formation of pyrazole derivatives: thus, the heating of compounds 54 in the presence of PhNHNH₂ gave pyrazolines 55.^57,58 However, it must be noted that insufficient structural characterization of the obtained compounds is available from the literature.^57,58,81,82 The provided spectral data are inconclusive and do not exclude the possibility of alternative structures (for example, tautomers or even regioisomers) for the products of hydrazinolysis. Therefore we consider it necessary to obtain additional experimental data about such products.

Scheme 23

An isoxazole derivative was obtained in a reaction of compound 54 with hydroxylamine (Scheme 24).⁵⁸

Scheme 24

Malononitrile dimer (1) readily participated in the Dimroth reaction with azides, resulting in the formation of 1,2,3-triazoles. Thus, 9-azidoacridine reacted with dimer 1 in darkness at room temperature in the presence of MeONa, giving triazole 56 in a moderate yield (Scheme 25). Thermolysis of the latter was performed according to the Graebe–Ullmann method, resulting in substituted pyrido[4,3,2-kl]acridine 57.⁸³ It has been recently demonstrated^84a that the reaction of dimer 1 with aryl azides in refluxing methanol did not stop at the stage of 4-amino-1,2,3-triazole formation and proceeded as a cascade process leading to either triazolo[4,5-b]pyridines 58 in up to 98% yields or, in the case of ethers or nitriles derived from о-azidoarylcarboxylic acids – to [1,2,3]triazolo[1,5-a]pyrimidine derivatives 59.^84b Taking into account these results, it must be noted that the spectral dataset for pyridoacridine 57 available in the literature⁸³ does not in principle exclude the possibility for the formation of isomeric naphthyridino[4,3,2-kl]acridine structure 60 during the thermolysis process.

Scheme 25

3. Synthesis of pyridine, quinoline, and naphthyridine derivatives

3.1. Malononitrile dimer as С₅–N-synthon in the synthesis of pyridines

In late 1950s, it was established^2,85 that malononitrile dimer (1) readily undergoes intramolecular 6-exo-dig cyclization in the presence of hydrogen halides in anhydrous THF. Later it was proved that the 2,4-diamino-6-halopyridine-3-carbonitrile structure initially proposed in the aforementioned literature sources^2,85 for the cyclization products was incorrect. In fact, isomeric 4,6-diamino-2-halopyridine-3-carbonitriles were formed.⁸⁶ A modified variant of this approach was recently proposed for the synthesis of 4,6-diamino-2-bromopyridine-3-carbonitrile, which has been found to be a convenient precursor for the preparation of hybrid nucleobases 61 (Scheme 26).⁸⁷

Scheme 26

Butadienes 2 reacted with HCl or HBr in the presence of various oxidants (Br₂, SeO₂, O₂, and others) with the formation of 2-halopyridines 62 (Scheme 27).⁸⁸ Ammonolysis products, pyridines 63 showed fluorescence with emission peak at λ 400–460 nm.⁸⁹

Scheme 27

Regarding the cyclization of malononitrile dimer (1) in the presence of hydrogen sulfide, there are few literature sources containing contradictory data and additional research is needed in this direction. Thus, according to one publication,⁹⁰ bubbling H₂S gas through a solution of sodium salt of dimer 1 in anhydrous EtOH gave a product that was assigned the structure of pyridine-2(1Н)-thione 64 (Scheme 28). According to other data,⁹¹ the products of reaction between dimer 1 and H₂S or H₂Sе in the presence of N-methylmorpholine (NMM) were pyridines 65. The latter interpretation was confirmed by a recent study:⁵⁴ an intermediate product was isolated when the reaction was performed under mild conditions and was identified as acyclic thioamide 66, which was cyclized upon heating to pyridine 65 (X = S).

Scheme 28

Mercaptans reacted with dimer 1 in a less predictable manner. For example, the formation of pyridine 67 from 4-methoxythiophenol has been described, although no spectral data or experimental procedures were revealed (Scheme 29).⁹² On the other hand, according to the data of another work,⁹³ 2-aminothiophenol reacted with dimer 1 at the non-conjugated cyano group with the formation of compound 68. It should be added that thioglycolic acid derivatives in reactions with dimer 1 gave thiazole derivatives⁶⁶ instead of pyridine derivatives (Scheme 21).

Scheme 29

A recently described reaction of butadienetricarbonitriles 2 with elemental sulfur in benzonitrile led to the formation of pyridine-2(1Н)-thiones 69 with a wide range of yields (34–70%).⁹⁴ An alternative route to thiones 69 was based on nucleophilic substitution of bromine atom in 2-bromopyridines 62 (Scheme 30).⁹⁴

Scheme 30

С-Alkyl derivative of malononitrile dimer 70 reacted with methoxide ion at the conjugated nitrile group with the formation of 2-methoxypyridine 71 (Scheme 31).⁹⁵ It should be noted that, according to the data from the same research group,^96,97 analogous reactions with 2-heptyl derivative 72 proceeded nonselectively and produced a mixture of the regioisomeric pyridines 73 and 74 as a result of competing attacks at the conjugated and non-conjugated CN groups, which is in agreement with the results obtained by Junek and coworkers.⁹⁸ 4-Arylbuta-1,3-diene-1,1,3-tricarbonitriles 2 containing electron-donating substituents in the ring underwent attack by methoxide ion at the С-1 atom, followed by cyclization and oxidation of the intermediate, forming the respective 2-methoxypyridines. ^21,22

Scheme 31

3.2. Malononitrile dimer as С₄-synthon in the synthesis of pyridines

As a compound containing an activated methylene group, dimer 1 can react with various С=N- or С≡N- electrophiles followed by cyclization into pyridine derivatives. The examples of reactions between dimer 1 and amidines, cyanates, iminoesters, and other types of compounds described in оlder literature sources (before 1990) have been considered in detail in a review article.⁶

Nucleophilic substitution of methylsulfanyl group in compound 75 by anion of dimer 1 was accompanied by spontaneous cyclization forming a derivative of a new heterocyclic system – benzo[cd]pyrido[1,2-a]indole 76 (Scheme 32).⁹⁹

Scheme 32

The reaction of dimer 1 with isothiuronium salt allowed to isolate an intermediate with linear structure that was cyclized in acidic medium with the formation of triaminopyridine-3,5-dicarbonitrile 77 (Scheme 33).¹⁰⁰

Scheme 33

The literature sources from recent years contain contradictory data about the reactions of malononitrile dimer (1) with isothiocyanates. According to one study,¹⁰¹ the reaction with PhNCS in refluxing pyridine resulted in the formation of substituted pyrimidine 78 (Scheme 34). At the same time, the results of other studies^54,62a,102 supported conclusions that cyclization leads to the formation of pyridine ring. Thus, the preparation of thioxopyridine 79 was accomplished in a high yield as a result of a reaction between dimer 1 and PhNCS in refluxing DMF in the presence of a base.⁵⁴ It is interesting to note that triethylammonium dithiocarbamates reacted¹⁰³ with malononitrile dimer not as S-nucleophiles, but rather in similar fashion to isothiocyanates; the reaction products analogous to compounds 79 were found to exist as 4-imino-2-mercapto tautomers 80.

Scheme 34

It is known from the literature that malononitrile dimer (1) readily participates in Thorpe reaction with activated nitriles in the presence of bases, followed by cyclization of the linear intermediates and formation of substituted pyridines.⁶ Another example of a similar transformation can be found in a recent publication¹⁰⁴ describing the synthesis of α-(2-pyridyl)acetamides 81 (Scheme 35). However, according to other sources,¹⁰⁵ dimer 1 reacted with cyanoacetamides in the presence of a base as enaminodinitrile with the formation of pyridylacetonitriles 82.

Scheme 35

3.3. Malononitrile dimer as С₃–N-synthon in the synthesis of pyridines

Very few examples are known where pyridine ring was constructed using dimer 1 as a source of C₃–N fragment. It was shown¹⁰⁶ that dimer 1 reacted with N-sulfonylketenimines (generated in situ from terminal acetylenes and sulfonyl azides) with the formation of substituted pyridines 83 in good yields (Scheme 36). Contrary to expectations, ethyl benzoylacetate reacted with dimer 1 not as a 1,3-dielectrophile, but rather as a reagent containing activated methylene group, with the formation of pyridine 84 (Scheme 37).¹⁰⁷ Analogous reactivity was also observed in the case of (isoxazol-5-yl)acetonitrile 85.¹⁰⁸ However, taking into account other data about the reactivity of β-dicarbonyl compounds and nitriles containing activated methylene groups in reactions with dimer 1 (chapters 3.2., 3.4.1.), the obtained results must be further refined.

Scheme 36

Scheme 37

When attempting to obtain pyridines 86 by a reaction of dimer 1 with β-nitrostyrenes, only carbocyclization products 87 were isolated (Scheme 38).¹⁰⁹

Scheme 38

3.4. Malononitrile dimer as С–C–N-synthon in the synthesis of pyridines

Malononitrile dimer (1) participates in reactions with various 1,3-dielectrophilic reagents – β-diketones, keto esters, and activated alkenes – with the formation of functionalized pyridine derivatives. The material presented below has been arranged according to the types of reagents used.

3.4.1. The reactions of malononitrile dimer with 1,3-dicarbonyl compounds. α-Formyl ketone enolate sodium salts 88 easily reacted with malononitrile dimer (1), forming after acidification (3-cyanopyridin-2(1H)-ylidene)malononitriles 89 in high yields (Scheme 39).¹¹⁰ As shown by the results of X-ray structural analysis,¹¹¹ the reaction occurred selectively, with the formation of a single regioisomer – the product arising from initial condensation at the more active aldehyde group.

Scheme 39

The reaction of 1,3-diketones with dimer 1 was first reported in 1964 by Junek¹¹² and has been explored by several other researchers since then.^{113,114,115,116,117,118} This variant of Guareschi–Thorpe synthesis has been performed with different catalysts – aqueous 10% NaOH solution,^112,116 piperidine,^112,114,115 Et₃N,¹¹⁷ EtONa.^112,118 The best yields of pyridines 90 (Scheme 40) – up to quantitative conversion – ere obtained by performing the reaction in aqueous alkali solutions.

Scheme 40

It should be pointed out that in the majority of studies concerning the reaction of dimer 1 with unsymmetrical β-diketones it was assumed that a single regioisomer was formed with the least sterically hindered substituent at position 4 of the pyridine ring. Nevertheless, there are contradictory assertions in the literature about this issue. Thus, it has been claimed¹¹⁷ that the condensation product obtained in reaction of dimer 1 with benzoylacetone was pyridine derivative 91, while other authors reported¹¹⁸ the isomeric product 92 (Scheme 41). It is known¹¹² that the reaction of dimer 1 with 2-acetylcyclohexanone leads to quinoline derivative 93, but a recent publication¹¹⁹ showed that β-cycloketoles 94 initially reacted at the endocyclic С=О group and were further cyclized into isoquinolines 95. A series of analogous Guareschi–Thorpe cyclization reactions have been used¹²⁰ to show that the reaction in the case of 2-acetylcycloalkanones can proceed nonselectively and lead to the formation of mixtures containing regioisomeric products with very similar spectral characteristics. Taking into account the insufficiently strong proof (in our opinion) for the selectivity of the described processes,^{112,117,118,119} the obtained results must be viewed with caution.

Scheme 41

3.4.2. Reactions of malononitrile dimer with α,β-unsaturated carbonyl compounds. According to several studies,^49,50,121 malononitrile dimer (1) undergoes Knoevenagel condensation with α,β-unsaturated aldehydes in refluxing EtOH with the formation of hexatriene-1,1,3-tricarbonitriles 96 (Scheme 42).

Scheme 42

However, there are data indicating that the reaction of dimer 1 with cinnamic aldehyde in pyridine gives the cyclization product for which the structure of 4-phenylpyridine 97 was proposed on the basis of ¹H NMR spectroscopy (Scheme 43).¹²²

Scheme 43

In contrast to aldehydes, the reaction of α,β-unsaturated ketones with malononitrile dimer (1) in the majority of cases proceeded as Michael addition followed by cyclization into (pyridin-2(1H)-ylidene)malononitriles 98 (Scheme 44).^116,118,123 There are also isolated reports on the preparation of stable Michael adducts¹²⁴ and partially hydrogenated pyridine analogs 98 in this reaction.^116,123,125

Scheme 44

Malononitrile reacts with 1-(hetaryl)-3-(2-hydroxyphenyl)-2-propen-1-ones in the presence of alcoholic alkali solutions, forming a mixture of benzopyranо[3,4-c]pyridines 99 and pyridines 100 (Scheme 45).¹²⁶ The formation of products 100 was explained by the authors of the cited publication by alcoholysis of the starting chalcones and dimerization of malononitrile under the conditions of the synthesis.

Scheme 45

Mesityl oxide participated in a reaction with malononitrile in the presence of piperidine¹²⁷ or In(OTf₃)–Et₃N¹²⁸ with the formation of azabicyclo[2.2.2]octene 101. According to the proposed mechanism,¹²⁷ H₂C(CN)₂ was dimerized at the initial step, which was confirmed by the synthesis of product 101 in a higher yield from dimer 1 (Scheme 46). Isoquinuclidines 102 were obtained in a reaction of dibenzalacetones with sodium salt of dimer 1 (formed in situ from H₂C(CN)₂ and NaOH).¹²⁹

Scheme 46

Mannich bases obtained by aminomethylation of ketones can serve as precursors of unsaturated ketones in reactions with malononitrile dimer (1). However, there are contradictory data in the literature on the regioselectivity of such reactions and the structures of the products. Thus, it has been reported¹³⁰ that the reaction of β-amino ketone hydrochlorides with dimer 1 proceeds as a tandem process involving Knoevenagel condensation and cyclization, leading to pyridines 103 or isoquinolines 104 (Scheme 47). The opposite regioselectivity was described in an earlier study¹²² where the product arising from reaction of Mannich base salt 105 with dimer 1 was assigned the structure of pyridine derivative 106.

Scheme 47

An alternative method for the synthesis of (pyridin-2(1H)-ylidene)malononitriles was based on the reaction of dimer 1 with a compound containing activated methylene group and aldehyde. The α,β-unsaturated ketone in this case was generated during the reaction; the components containing activated methylene groups can be selected from α-cyano ketones,¹³¹N-(phenacyl)pyridinium salts,^123,132 and others. In a recent example¹³³ demonstrating the feasibility of such approach dimer 1 was used in a reaction with ArCHO and deoxybenzoin. The target pyridines 107 were obtained after treating the crude product with tetracyanoethylene (TCNE) as oxidant. Tetrahydropyridines 108 could be isolated in the absence of an oxidant (Scheme 48).

Scheme 48

The condensation of malononitrile dimer (1) with aldehydes and Meldrum's acid in the presence of Et₃N proceeded via the formation of arylidene derivatives 109 and Michael adducts 110; the products of this process were salts 111; lactams 112 were isolated after acidification (Scheme 49).¹³⁴

Scheme 49

The opposite approach was also successful, starting from the condensation of dimer 1 with aldehydes and using the obtained butadienes 2 in reactions with various carbonyl compounds (Scheme 50).¹³⁵ By varying the starting reagents and reaction conditions, it was possible to perform the syntheses of a series of pyridine derivatives.

Scheme 50

Scheme 51

3.4.3. Reactions of malononitrile dimer with α,β-unsaturated nitriles. Acrylonitrile reacted with dimer 1, producing the С,С-dicyanoethylation product, which was cyclized in the presence of metallic sodium, producing a low yield of quinoline derivative 113 (Scheme 51).¹²²

Unsaturated nitrile 114 (R = Ph) reacted with dimer 1, forming tetrahydropyridine 115 that could be oxidized with dichlorodicyanoquinone (DDQ) (Scheme 52).¹³⁶ At the same time, hetero analog 114 (R = benzimidazol-2-yl) gave directly aromatic product 116.¹³⁷

Scheme 52

The base-catalyzed reactions of dimer 1 with arylmethylidenemalononitriles have been studied in considerable detail. Generally, the reaction products are 2-(dicyanomethylene) pyridines 117, 1,4-dihydropyridines 118, or their mixtures (Scheme 53).^80,138,139 The direction of the reaction substantially depends on the type of the aromatic substituent Ar, as well as on the reaction conditions. Products with partially saturated ring structures were favored in the cases of heterocyclic substituents Ar, as well as phenyl substituents bearing ortho-substituents (even under relatively harsh reaction conditions), while aromatization occurred quite readily in the case of Ar = Ph, 4-RC₆H₄. Performing the process under mild conditions (0°С) also favored the preservation of the 1,4-dihydropyridine system.^138a,b 1,4-Dihydropyridines 118 can be easily oxidized to pyridines 117 with DDQ.^138b The formation of carbocyclic product 119 in a high yield has been described⁸⁰ when the reaction was performed in АсОН in the presence of AcONH₄. The earlier reports¹⁴⁰ on the isolation of pyrimidines 120 from reactions of dimer 1 with arylmethylenemalononitriles have not been confirmed and are apparently erroneous.

Scheme 53

Unsaturated dinitrile 121 reacted with malononitrile dimer (1) with the formation of the expected product 122 (Scheme 54).¹⁴¹ It was established that 2-cyanothioacrylamides under analogous conditions were cyclized with the participation of thioamide group instead of the nitrile group, giving pyridines 122 or 123 as a result.^141,142

Scheme 54

A convenient modification of the approaches described above is the three-component cyclocondensation of aldehydes with nitriles containing an activated methylene group and malononitrile dimer (1). In this case, the unsaturated nitrile was generated in situ, giving pyridine derivatives 124 as products (Scheme 55). Aldehydes suitable for this reaction include formaldehyde^143,144 and aliphatic^131,145 aldehydes. It is interesting to note that an analogous reaction between benzaldehyde, malononitrile, and its dimer in the presence of cyclic secondary amines¹⁴⁶ resulted in the formation of naphthyridines 125, apparently as a result of cascade transformation of the =С(СN)₂ group in the presence of amines.

Scheme 55

Contradictory data are found in the literature about the reactions of 2-cyanoacrylates with malononitrile dimer (1). Thus, it has been reported¹⁴⁷ that cyanoacrylates react with dimer 1 with the formation of products 126 that are structurally related to Guareschi imides. However, earlier studies indicated that 2-aminonicotinates 127 were formed in the reactions of dimer 1 with 2-cyanoacrylates (or cyanoacetic ester and formaldehyde) under analogous conditions (base catalysis, heating) (Scheme 56).^138b,148 Besides that, the preparation of ester 128 in a reaction of acetaldehyde with dimer 1 and cyanoacetic ester has been described.¹³¹ It can be concluded that additional detailed studies will be needed for complete understanding of the regioselectivity in the reactions of dimer 1 with 2-cyanoacrylates.

Scheme 56

3.4.4. Reactions of malononitrile dimer with push-pull alkenes. The reaction of malononitrile dimer (1) with β-enaminoketones can be illustrated with the following overall scheme (Scheme 57).

Scheme 57

The reaction proceeds as a vinyl substitution at the activated multiple bond and selectively leads to pyridines 129, as confirmed by a large number of syntheses.^{38,149,150,151,152,153,154,155,156,157} Nevertheless, the work by Junek¹⁵⁷ and later publications¹⁵⁸ describe examples using the opposite sequence of steps (condensation at С=О group → S_NVin) leading to isomeric products. Thus, depending on the reaction conditions, regioisomeric condensation products were formed from enaminodiketone 130 and dimer 1 (Scheme 58).¹⁵⁸

Scheme 58

When 2-aminomethylidene derivatives of unsymmetrical 1,3-dicarbonyl compounds or their analogs are used, the cyclization reaction, as a rule, proceeds at the more reactive group (Scheme 59).¹⁵⁹

Scheme 59

In the case of the simplest enaminoketones 131 products 129 were often obtained in mediocre yields. This was explained by the possibility of a competing process leading to the formation of substituted ketones 132 in parallel with the closure of the pyridine ring.^80,160,161 Optimization of the reaction conditions allowed to direct the process toward either hetero- or carbocyclization route (Scheme 60).⁸⁰

Scheme 60

In several cases it was noted that the reaction proceeded further. For example, the reaction of enaminoketone 133 with malononitrile dimer (1) unexpectedly resulted in the formation of 1,8-naphthyridine derivative (Scheme 61).¹⁶² According to the data from another study,³⁸ enaminoketones 131 under conditions similar to those proposed for the synthesis of benzophenones 132 were converted to 1,6-naphthyridines 134, while 2:1 reagent ratio resulted in pyranо[4,3,2-de][1,6]naphthyridines 135.³⁸ The reaction of benzodiazepinone aminomethylidene derivative 136 with dimer 1 produced polycyclic product 137 (Scheme 61).¹⁶³

Scheme 61

Dithioacetals of α-oxoketenes reacted with the sodium salt of malononitrile dimer according to the S_NVin → cyclization scheme, forming 4-(alkylsulfanyl)pyridines 138 (Scheme 62).¹⁶⁴

Scheme 62

The reaction of malononitrile dimer (1) with push-pull alkenes 139 produced the expected pyridine derivatives 140 (Scheme 63).¹³⁶ At the same time, the product from the reaction of dimer 1 with ester 141 was assigned the structure of 4-aminopyridine 142,¹⁶⁵ which was later revised on the basis of X-ray structural analysis results to the isomeric structure 143.¹³⁶

Scheme 63

3.4.5. Synthesis of pyridines from malononitrile dimer and other 1,3-dielectrophilic reagents. It was shown that solvent-free fusion of malononitrile dimer (1) with α-ketohydrazone 144 in the presence of a base led to the formation of dihydropyridine 145 in a practically quantitative yield (Scheme 64).¹⁶⁶

Scheme 64

3.5. Some reactions of (3-cyanopyridin-2(1H)-ylidene)malononitriles

(3-Cyanopyridin-2(1H)-ylidene)malononitriles are readily prepared in a reaction of dimer 1 with 1,3-dielectrophilic reagents or by other methods suitable for the construction of 2-amino-1,1,3-tricyanopropene motif in the molecule (see the review articles^6,167). Due to the presence of closely arranged cyano groups, these compounds present rich possibilities for performing various heterocyclization reactions. The most important approaches to the transformation of these derivatives of malononitrile dimer (1) are described below.

It has been demonstrated^149,150 that (3-cyanopyridin-2(1H)-ylidene)malononitriles in alkaline media are selectively alkylated at the middle carbon atom of the malononitrile moiety. Furthermore, depending on the structure of the alkylating agent and the reaction conditions, the isolated products may arise exclusively from С-alkylation or polycyclic structures 146 may be obtained by spontaneous further cyclization (Scheme 65).

Scheme 65

The thiolysis of tetrahydropyridines 147 by reaction with mercaptans occurred selectively at one of the cyano groups of the dicyanomethylidene moiety. The resulting spontaneous cyclization produced 1,6-naphthyridines 148 in 38–95% yields.^168,169 It was noted that the reaction was equally successful with both aliphatic mercaptans and thiophenols. In the case of reaction between 2-(dicyanomethylidene)piperidines 112 and α-mercaptoacetanilide, depending on the reaction conditions either [1,6]naphthyridines or products of further Thorpe–Ziegler cyclization – thieno[2,3-h][1,6]naphthyridines 149 were obtained¹³⁴ (Scheme 66).

Scheme 66

There are contradictory data in the literature regarding the interaction of (3-cyanopyridin-2(1H)-ylidene)malononitriles with О-nucleophiles. For example, pyridines 147 in the presence of bases reacted selectively with phenols¹⁶⁸ or alcohols¹⁶⁹ with the formation of 7-(alk/aryloxy)-1,6-naphthyridines 150. When the reaction was performed in the presence of a strong base (NaOH), 7-hydroxy-substituted analogs were also isolated.¹⁶⁸ At the same time, the reactions of compounds 90 with sodium methoxide in methanol showed different regioselectivity of the initial attack by methoxide ion, which eventually led to the formation of 5-methoxynaphthyridines 151 (Scheme 67).¹¹⁶ However, in the case of compounds 152, the treatment with sodium methoxide produced a mixture of regioisomeric solvolysis products.¹⁷⁰ On the other hand, hydrolysis with aqueous alkali solution¹⁷⁰ or in acidic medium³⁸ led to 6-oxonaphthyridines (for example, forming the structure of compounds 153).

Scheme 67

Thus, the regioselective direction of reactions between (3-cyanopyridin-2(1H)-ylidene)malononitriles and О-nucleophiles substantially depended both on the structure of the substrate and the activity of the reagent.

The reaction of (3-cyanopyridin-2(1H)-ylidene)malononitriles with N-nucleophiles has been studied in considerable details. The reaction of pyridines 147 with trimethylsilyl azide led to the formation of tetrazoles 154 in moderate to good yields (Scheme 68).¹⁷¹

Scheme 68

The reactions of (3-cyanopyridin-2(1H)-ylidene)malononitriles with primary and secondary amines occurred mostly regioselectively as nucleophilic addition at one of the nitrile groups in the =С(СN)₂ moiety and was followed by spontaneous cyclization leading to 7-amino-1,6-naphthyridines (Scheme 69).^172,173,174 Detailed investigation of the reaction mechanism¹⁷⁴ showed that the solvent polarity, type of amine, and steric hindrance in the pyridine substrate had a crucial effect on the selectivity of the reaction and the content of the minor 5-amino-1,6-naphthyridine isomer (less polar reaction medium promoted the exclusive formation of 7-amino isomer). Another side reaction during this process was oxidative decyanation¹⁷⁴ that produced noticeable yields (up to 35%) of picolinamides 155 or pyrrolo[3,4-b]pyridines 156. This direction of the reaction can be completely suppressed by performing the reaction under argon atmosphere.

Scheme 69

It has been demonstrated^158,175,176 that the hydrazinolysis of (3-cyanopyridin-2(1H)-ylidene)malononitriles reliably produces pyrazolo[3,4-h][1,6]naphthyridine derivatives. For example, refluxing compounds 147 with hydrazines in alcohol solution produced products 157 in good yields¹⁷⁶ (Scheme 70). The results of earlier studies^114,115 pointed to the formation of azoles 158 as a result of reactions between (3-cyanopyridin-2(1H)-ylidene)malononitriles and hydrazines or hydroxylamine under similar conditions, but it appears that these experimental observations need additional verification.

Scheme 70

The reaction of (3-cyanopyridin-2(1H)-ylidene)malononitriles with ammonia leads to various products depending on the reaction conditions and the molecular structure of the substrate. Thus, compounds 147 gave good yields of 5,7-diamino-1,6-naphthyridines 159 when irradiated with microwaves in aqueous ammonia solution, but naphthyridines 160 were obtained under analogous conditions in the presence of carboxylic acids (Scheme 71).¹⁷⁷ It should be also noted that earlier studies involving the treatment of related substrates with aqueous ammonia¹¹⁴ or NH₄OAc in АсОН³⁸ led only to hydrolysis or gave products of further transformations.

Scheme 71

As vinylogs of malononitrile dimer, pyridines 147 participate in azo coupling reactions with diazonium salts (Scheme 72).¹⁷⁶

Scheme 72

According to publications by various authors, the cyclization of (3-cyanopyridin-2(1H)-ylidene)malononitriles by the action of HBr or HCl can give 7-amino-5-halo-1,6-naphthyridines^113,170,178 or their isomers – 5-amino-7-halonaphthyridines¹¹⁶ (Scheme 73). This topic was studied in detail. It was established that the regioselectivity of the reaction was substantially affected by several factors, namely, solvent polarity affecting the tautomeric equilibrium between the dicyanomethylene and dicyanomethyl forms of the substrate, planar configuration of the reactive site, reaction temperature, the relative basicity of the cyano groups, and the presence of a substituent at position 4 of the pyridine ring.¹¹⁸ Careful attention to the reaction conditions and the selection of suitable substrates in the majority of the cases allowed to achieve high regioselectivity or even regiospecificity in the given reaction.

Scheme 73

It has been reported¹⁶⁴ that refluxing of 4-(methylsulfanyl)pyridine 138 (X = Ac) in an HCl solution in АсОН resulted in nucleophilic substitution of the methylthio group with chlorine atom and cyclization to naphthyridine 161 (Scheme 74).

Scheme 74

The oxidation of dicyanomethylene moiety can be considered to be a promising but so far insufficiently explored area in the chemistry of (3-cyanopyridin-2(1H)-ylidene)malononitriles. Thus, the photooxidation of dicyanomethylenepyridines 117 with air oxygen in the presence of rose bengal as sensitizer produced good yields of picolinates 162 (Scheme 75).¹⁷⁹ However, it should be noted that for partially hydrogenated analogs of compounds 117 the main direction of oxidation was merely aromatization of the di- or tetrahydropyridine ring.^136,138b,142 For example, the treatment of dicyanomethylide 123 with acetic acid under air atmosphere led to the formation of oxidation product 117 in 66% yield.¹⁴²

Scheme 75

3.6. Synthesis of 1,8-naphthyridine derivatives from malononitrile dimer

Besides the methods considered in chapter 3.5. for the preparation of 1,6-naphthyridine derivatives by cyclization of 1,5-dinitriles belonging to pyridine series, several examples are known for the construction of 1,8-naphthyridine system starting from malononitrile dimer (1). This approach is generally applicable and involves a cascade reaction of enaminocarbonyl compound (or related push-pull alkene) with a carbonyl compound and dimer 1 (or product of their condensation). The initial 1,4-dihydropyridine intermediate 163 formed by a Hantzsch-type condensation contained a δ-aminopentadienonitrile moiety, which was transformed by spontaneous cyclization into the second pyridine ring (Scheme 76). The reaction occurred upon heating in basic medium and, as a rule, gave high yields of 1,8-naphthyridines.

Scheme 76

The given approach allowed to obtain a large number of fused 1,8-naphthyridine derivatives by starting from various enaminoketones, enaminoesters^{180,181,182,183,184} or ketenaminals.^185,186,187 Among examples illustrating the possibilities offered by this method, we should mention the synthesis of furo[3,4-b]naphthyridines 164¹⁸¹ or the preparation of compounds with insecticidal activity against the Aphis craccivora Koch aphid – imidazo[1,2-a][1,8]naphthyridines 165¹⁸⁷ (Scheme 77). It should be noted that the synthesis of fused 1,8-naphthyridines 166 can be achieved within the framework of a four-component domino process by generating ketenaminals in situ.¹⁸⁶

Scheme 77

The reaction of aldehydes with 2 equiv of malononitrile dimer (1) in the presence of a base followed a similar route.¹⁸⁸ The intermediates were apparently 4-arylbuta-1,3-diene-1,1,3-tricarbonitriles 2, which underwent a Michael addition of a second equivalent of dimer 1 and after a chain of cascade transformations formed dicyanomethylides 167 in good yields (Scheme 78).

Scheme 78

Among the few limitations of the strategy outlined above we should note the unsuccessful attempt to obtain naphthyridines from N-unsubstituted enamine dimedone 168: in that case the competing process predominated with the elimination of malononitrile and formation of quinoline 169 (Scheme 79).¹⁸²

Scheme 79

Another strategically important approach to the assembly of 1,8-naphthyridine system is based on the interaction of 1,4-aminocarbonyl compounds with dimer 1 according to the Friedländer reaction mechanism followed by 6-exo-dig cyclization of the δ-iminonitrile moiety (Scheme 80).

Scheme 80

The first example of such transformations was described by Junek already in 1963.¹⁸ A one-pot method was recently reported for the preparation of chromeno[2,3-b][1,8]naphthyridine 170 from 2-amino-4-oxochromene-3-carbaldehyde 171 (Scheme 81).¹⁸⁹ Another example of a tandem process on the basis of the Friedländer reaction and subsequent cyclization was used in the synthesis of benzonaphthyridine 172.¹⁹⁰

Scheme 81

A method is known for the preparation of 1,8-naphthyridines using the reaction of dimer 1 with β-oxothioanilide anions generated in situ from compounds with activated methylene groups and isothiocyanate (Scheme 82).^191,192

Scheme 82

An unusual condensation of 3-cyanoquinolin-2-one 173 and dimer 1 has been described that occurred under relatively mild conditions and led to the formation of naphthyridine 174 (Scheme 83).¹⁹³ However, taking into account the reaction conditions and the absence of essential analytical data on product 174 and the known types of reactivity of the starting compounds, we strongly believe that the aforementioned interpretations should be in doubt. The reported synthesis of naphthyridine 175, described in an earlier work, also seems to be in question.¹⁹⁴

Scheme 83

An original method was proposed for the preparation of functionalized naphthyridines 176 on the basis of a reaction between 4-arylbuta-1,3-diene-1,1,3-tricarbonitriles 2 with dimedone in the presence of sodium methoxide (Scheme 84).²¹

Scheme 84

4. Synthesis of diazine derivatives

4.1. Synthesis of pyridazine derivatives

It was observed in the early 1980s that the azo coupling reaction in the case of malononitrile dimer (1) led to hydrazones 51, which were readily cyclized upon heating or treatment with alcoholic alkali solutions, leading to the formation of pyridazines 177 (Scheme 85).^138е,194

Scheme 85

This approach has been successfully used in recent years for the preparation of functionalized pyridazines.^{195,196,197,198} In the cases when the diazo component contains functional groups, further processes of cascade heterocyclization become possible. Thus, hydrazone 178 was converted to pyridazine 179 by refluxing in an alcoholic alkali solution,⁸² however, according to other sources⁸¹ the reaction under the same conditions proceeded further with the formation of tetracyclic product 180 (Scheme 86).

Scheme 86

The products arising from malononitrile dimer condensation with ketones reacted with diazonium salts at the activated methylene group.^58,199 The azo coupling product that was thus obtained underwent cyclization in the presence of a strong base. Thus, refluxing of compound 181 in alcohol solution of EtONa gave cinnoline 182 (Scheme 87). It was noted that the attempts to achieve further cyclization led only to hydrolysis at the imino group.¹⁹⁹

Scheme 87

The bromination product obtained from malononitrile dimer reacted with hydrazine with the formation of a compound that was identified as pyridazine 183 (Scheme 88).³⁷

Scheme 88

Another important approach to the preparation of pyridazine derivatives is based on the interaction of dimer 1 with azo coupling products obtained from compounds containing activated methylene groups. The possibilities from using such an approach were first demonstrated already in 1986, with the example of reaction between dimer 1 and arylazomalononitriles (Scheme 89).²⁰⁰

Scheme 89

As a rule, the reaction did not stop at the stage of pyridazine ring formation and subsequent cascade processes led to fused ring structures. In the case of unsymmetrically substituted arylhydrazones ArNHN=C(X)Y, the nucleophilic attack by anion of dimer 1 in the majority of cases proceeded selectively and was directed at only one of the substituents Х or Y. On the basis of dataset obtained from reactions of malononitrile dimer (1) with arylazo derivatives of acetylacetone and acetoacetic ester,^166,201 α-formyl ketones,^202,203,204 cyanoacetic ester,²⁰⁵ α-cyano ketones,^166,205,206 and cyanothioacetamide,^207,208 substituents can be arranged in the following order according to decreasing susceptibility toward nucleophilic attack: CHO > RC(O) > C≡N > CO₂Et / C(S)NH₂.

Thus, the reactions of hydrazones 184 with dimer 1 led to the formation of pyrido[2,3-c]pyridazines 185, while the presence of an ester group at the ortho position of the aryl substituent allowed to change the direction of the reaction toward the formation of tricyclic products 186 (Scheme 90).^202,203,204

Scheme 90

In some cases the reaction gave peculiar results. For example, the reaction of dimer 1 with arylazoacetoacetic ester gave mixtures of pyridines 187 with the expected pyridopyridazines 188 in approximately equal amounts (Scheme 91).²⁰¹ Changing the conditions of cyclocondensation reactions led to a major change in the regioselective direction of the process and formation of 1,6-naphthyridine 189.¹⁶⁶

Scheme 91

2-Arylhydrazonylidene-3-oxobutyronitriles 144 also react in unusual manner, resulting in the formation of 2-(dicyanomethylidene)pyridines 145 (Scheme 64),¹⁶⁶ although other α-ketohydrazones under the same conditions formed the expected pyridopyridazines 190 (Scheme 92). ^{166,201,205,206}

Scheme 92

4.2. Synthesis of pyrimidine derivatives

Malononitrile dimer (1) can act as enaminonitrile in reactions with amidines 191, leading to vinyl substitution of amino group followed by cyclization step producing pyrimidines 192.²⁰⁹ It should be noted that the reaction is not universally applicable. Thus, it has been demonstrated earlier by Junek and coworkers that the reactions of dimer 1 with formamidine and acetamidine produce pyridine derivatives.²¹⁰ In the case of N,N'-disubstituted amidines, as demonstrated in a recent work,²¹¹ pyrimidine derivatives 193 were formed (Scheme 93).

Scheme 93

It has been reported²¹² that S-substituted thioamidine 194 under the conditions of basic catalysis participates in a reaction with dimer 1, producing dihydropyrimidine in 69% yield (Scheme 94). However, it should be pointed out that dimer 1 reacted differently with isothiuronium salts in the presence of bases¹⁰⁰ (Scheme 33).

Scheme 94

Synthesis of tricyclic product 195via cascade reaction of 3-amino-4-phenyl-1H-pyrazole with dimer 1 has been reported (Scheme 95).²¹³ At the same time, according to literature data, isomeric 5-phenylpyrazole 196 reacted differently – with the formation of pyrazolo[1,5-a]pyrimidine 197.²¹⁴ Obviously, the details of aminoazole reactions with malononitrile dimer (1) should be studied in greater detail.

Scheme 95

It has been reported that the product obtained by treatment of malononitrile dimer (1) with 2 equiv of dimethylformamide dimethyl acetal, compound 198, participated in reactions with primary amines, and depending on the ratio of the starting reagents the products were either pyrimidine 199 or the condensation product 200 (Scheme 96).¹⁹⁵ It should be noted here that the given reaction has been previously studied in detail by Mittelbach and Junek,²¹⁵ who showed that the reaction of compound 198 with amines actually led to the formation of pyridopyrimidines 201.

Scheme 96

2-Aminobutadiene-1,1,3-tricarbonitrile (2) reacted with dimethylformamide dimethyl acetal at the amino group⁷⁸ and the condensation product was further treated with ammonium acetate in refluxing acetic acid, producing a good yield of pyrimidine 202 (Scheme 97).

Scheme 97

4.3. Synthesis of pyrazine derivatives

The only found example for the preparation of pyrazine derivatives was based on the treatment of dimer 1 with tosylate 203 in the presence of a base (Scheme 98).²¹⁶

Scheme 98

5. Synthesis of oxygen- and sulfur-containing heterocycles

5.1. Synthesis of chromenopyridine derivatives

A significant number of studies in recent years have been devoted to the chemistry of chromeno[2,3-b]pyridine. The interest toward this heterocyclic system is motivated by recent discoveries of its broad spectrum of biological activity, allowing to consider these structures as examples of the so-called privileged scaffolds. Thus, compounds 204 (R = ArS, R¹ = H) have shown good activity against hepatitis C virus and liver fibrosis,^217,218 as well as moderate anticancer activity.⁹² Chromeno[2,3-b]pyridines 204 (R = H, HC(CN)₂, R¹ = H, alkyl) act as inhibitors of mitogen-activated protein kinases MK-2.^190,219 The standard synthetic approach for the construction of tricyclic system 204 is the reaction of salicylic aldehydes with dimer 1 in the presence of a reducing agent (Et₃SiH)^190,219 or mercaptans⁹² (Scheme 99).

Scheme 99

A successful modification of this synthesis was discovered by using 2 equiv of malononitrile instead of dimer 1 (Scheme 100).²²⁰ The reaction between 2-hydroxybenzaldehydes, malononitrile, and mercaptans proceeded in the presence of Et3N, therefore it was logical to assume that malononitrile dimer (1) in this case was generated in situ, although alternative mechanisms for this synthesis cannot be completely excluded. Despite the high yields of products 204 in the proposed variant, which in some cases reached 85–90%,^92,220,221 some additional improved procedures have been recently published, providing practically quantitative yields and relying on the application of such exotic catalysts as Fe₃O₄@SiO₂–NH₂ nanocomposite,²²² ZrP₂O₇ nanoparticles,²²³ chitosan functionalized with citric acid,²²⁴ SnO nanoparicles,²²⁵ and others. In our opinion, the justification of such modifications for solving real synthetic challenges is doubtful. It was also established⁹² that using microwave irradiation allowed to obtain the target products 204 with yields not exceeding 45%.

Scheme 100

Mercaptans in the reaction with dimer 1 and 2-hydroxybenzaldehydes could be successfully replaced with other nucleophiles (Scheme 101), such as secondary amines²²⁶ and 3-phenylisoxazol-5(4H)-one.²²⁷

Scheme 101

An alternative approach to the synthesis of structures 204 was based on the interaction of о-quinone methides 205 with dimer 1^190a or 2 equiv of malononitrile^228,229 (Scheme 102). In the latter case, malononitrile dimer (1) was likely formed during the reaction in the presence of base.

Scheme 102

The structure of products arising from the reactions of malononitrile dimer (1) with salicylic aldehyde and its analogs in the absence of nucleophilic agents (mercaptans, amines etc.) has been the matter of discussions for a long time. A publication by Junek²³⁰ and several later studies²³¹ have shown that the condensation process generally stopped at the stage of 2-iminochromenes 206 (Scheme 103) and, contrary to expectations, did not lead to the formation of chromenopyridine derivatives. At the same time, some data point to the formation of dihydropyridine 207 under the conditions of this reaction.^115,232

Scheme 103

Malononitrile dimer (1) is capable of addition to coumarins at the С-4 atom, with the formation of either Michael adducts or chromenopyridine derivatives. Thus, a reaction of nitro-substituted 3-ethoxycarbonylcoumarin 208 with in situ generated dimer 1 led to the formation of compound 209 (Scheme 104).²³³ At the same time, a method is known from the literature for the preparation of chromenopyridine 210 from dimer 1 and an unsubstituted coumarin analog 208 (Scheme 104).²³⁴ 3-Cyanocoumarin reacted with dimer 1 in the expected way,²³⁵via Michael addition followed by cyclization to chromenopyridine 211. However, 3-carbamoylcoumarin reacted by a different mechanism – with recyclization step leading to the formation of chromeno[4,3,2-de][1,6]naphthyridine 212.²³⁶

Scheme 104

Treatment of iminochromene 213 with malononitrile dimer (1) produced chromenonaphthyridine 214 (Scheme 105).²³⁷ In this case, the nucleophilic attack by anion of dimer 1 was directed at the cyano group of chromene, instead of the С-4 position, which probably can be explained by steric hindrance.

Scheme 105

3-Cyanochromone 215 reacted with malononitrile dimer (1) in the presence of diazabicycloundecene (DBU), leading to recyclization and the formation of chromeno[4,3-b]pyridine 216 in a moderate yield (Scheme 106).¹⁸⁹ Another example of a similar recyclization can be found in the recently described synthesis of chromenopyridine 217 from vinylogous nitrile 215.²³⁸

Scheme 106

The reaction of 4-chloro-3-formylcoumarin 218 with dimer 1 proceeded as a tandem Knoevenagel condensation – nucleophilic substitution process and led to the formation of chromenopyridine 219 that was characterized as a fluorescent dye (Scheme 107).²³⁹

Scheme 107

An important method for the preparation of chromeno[2,3-b]pyridines is the reaction of aldehydes, malononitrile dimer (1) (or products of their condensation) with reagents serving as sources of С–С–О fragment: activated phenols, enols of carbonyl compounds, and others. The reaction was catalyzed by bases: alkali metal alkoxides or amines (Scheme 108). Suitable sources of the С–С–О fragment include dimedone,^{21,240,241,242,243} activated phenols^{92,244,245,246} and α-naphthol,²⁴⁷ 1,3-cyclohexanedione,²⁴⁰ 4-hydroxyquinolin-2(1Н)-one,²⁴⁰ kojic acid,²⁴⁰ and 3-methyl-1Н-pyrazol-5(4Н)-one.²⁴⁸

Scheme 108

As a rule, the synthesis of chromeno[2,3-b]pyridines according to the given scheme proceeded without complications and gave high yields. One of the relevant publications reported an unusual change in the direction of the reaction between malononitrile dimer (1), dimedone, and aromatic dialdehydes depending on the length and position of the linker Z in the starting dialdehydes, leading to selective formation of either compounds 220 or the partial hydrolysis products 221 (Scheme 109).²⁴¹ The formation of the latter compounds occurred in the case if the linker was quite short (no longer than 2-3 methylene groups) and connected the ortho positions of aromatic rings in the dialdehydes.

Scheme 109

Compound 222 showing strong fungicidal activity against the pathogens Helminthosporium oryzae and Pyricularia oryzae was synthesized in 71% yield from dimer 1 and 4-arylidene-2-phenylthiazolin-5-one (Scheme 110).²⁴⁹

Scheme 110

Among the most interesting transformations of chromeno[2,3-b]pyridines we should note the recently discovered recyclization of compounds 223 to 1,6-naphthyridine derivatives by the action of alkali in alcohol solutions (Scheme 111).²⁵⁰ The reaction presumably occurred by an ANRORC mechanism, giving high yields of the products.

Scheme 111

5.2. Synthesis of thiopyran and thiochromene derivatives

The product obtained by bromination of malononitrile dimer reacted with thioglycolic acid by a mechanism involving steps of alkylation and Thorpe–Ziegler cyclization, with the formation of 4Н-thiopyran 224 (Scheme 112).⁵⁴

Scheme 112

2-Mercaptobenzaldehydes reacted with dimer 1 analogously to salicylic aldehyde, forming the thio analogs of compounds 204 – thiochromeno[2,3-b]pyridines 225 (Scheme 113).¹⁹⁰

Scheme 113

Prolonged refluxing (10–25 h) of 3-cyanopyridine-2-thiolates with malononitrile dimer (1) in alcohol led to the formation of cascade heterocyclization products, pyrido[2',3':2,3]thiopyranо[4,5-b]pyridines 226 in moderate yields (Scheme 114).^251,252,253 Compounds 226 were found to be convenient precursors for the synthesis of polycyclic systems 227.²⁵³

Scheme 114

The possibility of effectively obtaining thiopyranо[2,3-b]pyridine derivatives by recyclization of 1,2-dithiol-3-thiones in the presence of dimer 1 was demonstrated by the synthesis of compound 228 (Scheme 115).²⁵⁴

Scheme 115

An alternative approach to the assembly of thiopyranо[2,3-b]pyridine system was based on the interaction of active methylene compounds with carbon disulfide followed by the reaction of the obtained ethene-1,1-dithiolates with dimer 1.^59,191 Thus, a reaction of malononitrile with carbon disulfide and then with malononitrile dimer (1) allowed to obtain heterocyclic compound 229 in 77% yield (Scheme 116).¹⁹¹

Scheme 116

5.3. Synthesis of oxazine and thiazine derivatives

1,2-Oxazine derivative 230 was obtained in 62% yield by treatment of 2-amino-3-bromo-1,1,3-tricyanopropene with hydroxylamine (Scheme 117).³⁷

Scheme 117

1,2-Oxazines can be obtained by condensation of malononitrile dimer with α-isonitroso ketones. For example, solvent-free fusion of benzil monooxime with dimer 1 gave oxazine 231 (Scheme 118).²⁵⁵ It should be noted that this approach is not universal and the reaction is apparently sensitive to the structure of the nitroso/isonitroso component. Thus, malononitrile dimer (1) participated in the Ehrlich–Sachs reaction with 4-isonitrosopyrazol-5-one and, as a result of further intramolecular cyclization, representatives of a relatively rare heterocyclic system – pyrazolo[3,4-b][1,4]oxazines 232 were formed.²⁵⁶

Scheme 118

The possibility of assembling 1,3-thiazine ring can be illustrated by the synthesis of compound 233 through recyclization of 1,2-dithiolium bromide in the presence of dimer 1, as described in a study by Barsy²⁵⁷ (Scheme 119).

Scheme 119

6. Miscellaneous syntheses

In this chapter we consider the syntheses of heterocycles containing three and more heteroatoms, as well as the syntheses of polycyclic systems.

Two studies by Wardakhan^81,82 describe a series of transformations starting from hydrazone 178, leading to the formation of polyazacyclic systems. An illustrative example would be the formation of 1,2,4-triazine 234 (Scheme 120).

Scheme 120

Several examples for the preparation of polycyclic systems on the basis of azo coupling products have been presented in the literature.^{166,206,258,259} Thus, for instance, the azo coupling reactions of malononitrile dimer (1) with azolyldiazonium salts led to tricyclic products 235²⁵⁸ and 236²⁵⁹ (Scheme 121).

Scheme 121

Synthesis of polyazaheterocycle 237 was accomplished using a cascade process including the steps of nucleophilic substitution (S_NAr) and two Thorpe cyclization reactions, starting from sodium salt of dimer 1 and 4-amino-1,2,4-triazine 238 (Scheme 122).²⁶⁰

Scheme 122

5-Amino-4-nitrosopyrazole 239 underwent Ehrlich–Sachs condensation with dimer 1, resulting in the formation of tricyclic product 240 as a result of subsequent cascade processes (Scheme 123).²⁶¹

Scheme 123

Contrary to the expectations, malononitrile dimer (1) did not give Michael addition products with azalactones 241: the reaction occurred along recyclization mechanism and led to the formation of pyrrolo[2,3-b]pyridines 242 (Scheme 124).²⁶²

Scheme 124

Pyrazolo[3,4-b]pyridine derivative 243 can be obtained by the Friedländer reaction from 3-aminopyrazole-4-carbaldehyde (Scheme 125).²⁶³ The reaction proceeded with elimination of ammonia.

Scheme 125

According to Aly and coworkers,²⁶⁴ thiocarbohydrazones 244 reacted with malononitrile dimer (1) with the formation of 1,3,4-thiadiazines 245 upon refluxing in DMF medium in the presence of piperidine (10–25% yields) or under the conditions of microwave irradiation (yields 60–80%) (Scheme 126). It should be noted that, according to another source,²⁶⁵ the reaction of 4-phenylthiosemicarbazide with dimer 1 proceeded along a different route and led to pyrazolopyridine 246. Clearly, the mechanism and direction of the reactions between dimer 1 and carbothiohydrazides must be studied in greater detail.

Scheme 126

An original diаstereoselective synthesis of 2,3-dihydrofuro[2,3-b]pyridines 247, using the recyclization of pyrroles 8 under reducing conditions (Scheme 127) has been described in a recent work.²⁶⁶

Scheme 127

7. Practical applications of malononitrile dimer and its derivatives

The biological activity of malononitrile dimer (1) was observed already in the early 1960s, when it was found that the presence of dimer 1 caused the increase of nucleoproteins in cells upon treatment with aqueous solutions of malononitrile.²⁶⁷ At the same time, the antithyroid effect of dimer 1 was observed during in vivo experiments on rats and humans.²⁶⁸ Subsequent studies showed that malononitrile dimer (1) in general has pronounced nootropic properties – it serves as a mimetic of nerve growth factor and promotes the regeneration of neural tissues,²⁶⁹ upregulates the synthesis of RNA in neurons and neural tissues,²⁷⁰ promotes the biosynthesis of neuromediator acetylcholine,²⁷¹ reduces the amnesia after electric shock,²⁷² stimulates the processes of learning and memory.²⁷³ However, subsequent studies of the nootropic effects in vivo produced inconclusive results.²⁷⁴ Thus, it has been noted in one study^274b that the nootropic properties of malononitrile dimer were offset by the antithyroid effect.

Dimer 1 was proposed as a specific reagent for fluorimetric determination of copper at low levels.²⁷⁵ Recently it was found²⁷⁶ that compounds 51 serve as effective corrosion inhibitors for copper in the presence of HNO₃. Push-pull polyenes (for example, compound 248, Scheme 128) obtained by condensation reactions of various polyenals^{50,63,64,277,278,279,280} or nitrosoarenes^46,47,48,49 with dimer 1 are of interest as dyes and chromophores for the design of systems with nonlinear optical properties. A recently proposed method provides access to potentially useful fluorescent dyes – 4-arylbuta-1,3-diene-1,1,3-tricarbonitriles (for example, compounds 249, Scheme 128), on the basis of reactions between dimer 1 and aldehydes in aqueous media in the presence of non-ionic surfactants as catalysts (62–92% yields).²⁸¹

Scheme 128

A reaction of malononitrile dimer (1) and azacrown ethers containing nitrosyl or aldehyde functional groups was used for the synthesis of original chromoionophores suitable for analytical chemistry applications and in medical diаgnostics.²⁸² The effectiveness of both the chromophoric and ionophoric parts of molecule 250 (Fig. 1) was achieved by their separation using a linker consisting of several methylene groups.

Figure 1.

Chromoionophores on the basis of malononitrile dimer.

Malononitrile dimer has found its role as active and multifunctional reagent with considerable synthetic potential, useful for solving a wide range of problems in heterocyclic chemistry. Our presented analysis of literature data, as well as another brief review focused on the chemistry of malononitrile dimer,²⁸³ which was published during the preparation of this article reveal an abundance of synthetic applications for this reagent. Compared to the closest structural analogs – malononitrile,^3,4,5,6 cyanoacetamide,²⁸⁴ cyanothioacetamide,²⁸⁵ and cyanoselenoacetamide,²⁸⁶ – the molecule of 2-aminopropene-1,1,3-tricarbonitrile has several unique features that enable directed synthesis of original molecular structures with finely tuned functionality. At the same time, some of the early experimental data suffer from contradictions that should be eliminated through careful further studies, which can be recognized as an important task in this area of synthetic organic chemistry. In general, considering the analysis of all available data, we can predict further development of productive research regarding the chemistry of malononitrile dimer.