The first compound of the homolog row of nitriles, the nitrile of formic acid, hydrogen cyanide was first synthesized by C.W. Scheele in 1782 [1]. In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid. The nitrile of benzoic acids was first prepared by Friedrich Wohler and Justus von Liebig, but due to minimal yield of the synthesis neither physical nor chemical properties were determined or a structure suggested. Théophile-Jules Pelouze synthesized propionitrile in 1834 suggesting it to be ether of propionic alcohol and hydrocyanic acid [2]. The synthesis of benzonitrile by Hermann Fehling in 1844, by heating ammonium benzoate, was the first method yielding enough of the substance for chemical research. He determined the structure by comparing it to the already known synthesis of hydrogen cyanide by heating ammonium formate to his results. He coined the name nitrile for the newfound substance, which became the name for the compound group [3].

Nitriles occur naturally in a diverse set of plant and animal sources with over 120 naturally occurring nitriles being isolated from terrestrial and marine sources. Nitriles are most commonly encountered in fruit pits, especially almonds, and during cooking of Brassica crops (such as cabbage, brussel sprouts, and cauliflower) which lead to nitriles being released through hydrolysis. Mandelonitrile, a cyanohydrin produced by ingesting almonds or some fruit pits, releases cyanide as the main degradation pathway and is responsible for the toxicity of cyanogenic glycosides [4].

Historically over 30 nitrile-containing pharmaceuticals are currently marketed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. The nitrile group is quite robust and, in most cases, is not readily metabolized but passes through the body unchanged. The types of pharmaceuticals containing nitriles are diverse, from Vildagliptin a recently released antidiabetic drug to Anastrazole which is the gold standard in treating breast cancer. In many instances the nitrile mimics functionality present in the natural enzyme substrate while in other cases the nitrile increases water solubility or decreases susceptibility to oxidative metabolism in the liver [5].

Alkenyl nitrile is one of the most versatile reagents in Organic Chemistry. It has been used as a precursor for producing nucleotides and for synthesising a wide variety of heterocyclic compounds [6] including purines [7,8], pyrimidines [9], pyrazines [10] (some which are widely employed in the fluorescent dye industry [11]), imidazoles [12], biphenylenes [13], porphyrazines (which have great potential in optical sensor technology) [14] and diimines that are used as catalysts [15]. This review highlights the alkenyl nitrile chemistry with the focus on the utility of heterocyclic compounds. The synthesis and chemistry of the highly strained aryl nitrile is also briefly reviewed [16].

Heterocycles are ubiquitous in all kind of compounds of interest, and among all the possible synthetic methods of achieving their introduction into an structure, probably the use of a alkenyl nitrile analogue is the most direct one. The present review deals with the generation and synthetic uses of alkenyl nitriles and aryl nitriles formed in heterocyclic synthesis, and can be considered as an update of our revision published in 2007 on this topical [17]. Therefore, only references published from the second quarter of 2003 until the third quarter of 2010 are included, and the same restrictions to the literature coverage applied. Thus, only heterocycles compounds which are found applicability are considered. As previously, the present review is organized by the type of ring members and subdivided by the type of heterocycles fused compounds, including methods for their preparation and their synthetic uses. New developments in the utilities of some alkenyl nitriles in heterocyclic synthesis are reviewed. General synthetic routes based on the utilization of alkenyl nitriles of active imines are discussed. The major methods and modifications are analyzed [18-21].

In this review, which covers the literature up to date, we describe the new and improved methods for the construction of the skeletons, with a particular emphasis on the four, five and six membered ring of heterocyclic compounds. Some of these procedures have clear technical advantages over older methods in terms of yield and versatility, but do not employ new chemistry in the construction of the ring systems. The use of combinatorial synthesis, microwave enhanced processes and new catalytic methodologies in the preparation of these heterocycles is a clear indication that significant advancement has been made in recent years. The syntheses of both on the four, five and six membered ring of fused and polyheterocyclic compounds will be classified into the following five categories, based on the substitution patterns of the ring system: New approaches for synthesis of different mono and polyheterocyclic derivatives arranged by increasing ring size and the heteroatoms utilizing activated nitriles are surveyed. Activated nitriles are very important in organic synthesis since they can be used as effective species for efficient construction of rather complex structures from relatively simple starting materials. The scope and limitation of the most important of these approaches are demonstrated.

Industrially, the main methods for producing nitriles 2 are ammoxidation and hydrocyanation. Both routes are green in the sense that they do not generate stoichiometric amounts of salts. In ammonoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile, as shown below [22].

An example of hydrocyanation is the production of adiponitrile 4 from 1,3-butadiene 3, as outlined below.

Scheme 1

Usually for more specialty applications in organic synthesis, nitriles can be prepared by a wide variety of other methods: Dehydration of primary amides. Many reagents are available, the combination of ethyl dichlorophosphate and DBU just one of them in this conversion of benzamide to benzonitrile [23]. Two intermediates in this reaction are amide tautomer A and their phosphate adducts B, as summarized diagrammatically in Scheme 1.

In one study an aromatic or aliphatic aldehyde is reacted with hydroxylamine and anhydrous sodium sulfate in a dry media reaction for a very small amount of time under microwave irradiation through an intermediate aldoxime [24], as shwon in Scheme 2. A commercial source for the cyanide group is diethylaluminum cyanide Et2AlCN [25], which can be prepared from triethylaluminium and HCN, it has been used as nucleophilic addition into ketones [26].

Scheme 2

For an example of its use Kuwajima Taxol total synthesis of cyanide ions facilitate the coupling of dibromides. Reaction of α,αβ-dibromo adipic acid with sodium cyanide in ethanol yields the cyano cyclobutane [27], as shown in Scheme 3.

Scheme 3

In the so-called Franchimont Reaction (A. P. N. Franchimont, 1872) α-bromocarboxylic acid is dimerized after hydrolysis of the cyan group and decarboxylation. Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl₃)=NH) in the Houben-Fischer synthesis [28-31]. In reductive decyanation the nitrile group is replaced by a proton [32]. An effective decyanation is by a dissolving metal reduction with HMPA and potassium metal in tert-butanol. α-Amino nitriles can be decyanated with lithium aluminium hydride. Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition. In organometallic chemistry nitriles are known to add to alkynes in carbocyanation, as summarized diagrammatically in Scheme 4 [33].

Scheme 4

Four membered rings

Organic cyano compounds are versatile reagents, which have been extensively utilized in heterocyclic synthesis. Alkenyl nitriles behaves as a typical stable organic molecule, the stability of alkenyl nitriles and aryl nitriles arises from the fact that it has an aromatic delocalized π-electron system. Enormous number of reports [34-43], on the utility of these compounds in synthesis of heterocycles has been reported. It is our intention in this review, therefore, to fill the gaps and report on the utilities of α-β-unsaturated nitriles. Such as arylidene malononitrile 13 which successfully used to prepare 4-Aryl-2-iminothietane-3-carbonitrile 14 in a moderate yield via the reaction [44] of with ammonium benzyl dithio-carbamate 15, as outlined in Scheme 5.

Scheme 5

Five membered rings

Five membered ring with one heteroatom:

Synthesis of thiophene and fused thiophene derivatives: The α-β-unsaturated nitriles with active methylene group at β-carbon 16 could react with elemental sulphur to yield an intermediate mercapto derivative 17, which cyclizes into the most isolable stable aminothiophene derivative 18, as outlined in sheme 6 [45-49].

Scheme 6

α-β-unsaturated nitriles were thiolated into thiophene derivatives. For example, the arylidene derivative of cyclohexanone 19 was converted into the enaminothiophene derivative 20 on treatment with elemental sulphur [45]. The enamines can also be formed on heating mixtures of the ketone, the activated nitrile and elemental sulphur in the presence of a basic catalyst.

Scheme 7

Formation of thiophenes 22 from the reaction of α-β-unsaturated nitriles with thioglycollic acid has been reported [50-53].

Scheme 8

Tetracyanoethylene 23 has been reported to react with hydrogen sulphide [54,55] to produce the thiophene derivative 24 in moderate yields 68%.

Scheme 9

Another similar synthesis that affords thiophene derivatives 26 utilizing thioanilides of the type as starting component is the reaction of 25 with active methylene reagents [56].

Scheme 10

Formation of thiophenes via the reaction of arylidene derivatives of 3-oxoalkanenitriles has been reported by El-Nagdy et al. [51,52,56-58]. For example, the thiophene derivatives 28 were formed from the reaction of 27 with ethyl thioglycollate. On the other hand, the thiophene derivative 29 was isolated on using thioglycollic acid together with Michael adduct 30, as outlined in Scheme 11.

Scheme 11

Synthesis of furan derivatives: To be considered as an update of our revision published in 1998 on this topic such as photochemical transformations of 2(5H) furanones [59]. In the last decade, it was reported by Aran and Soto [60] for the formation of furan derivatives 31 by heating 2-benzoyl-3-phenyl-acrylonitrile 27 with cyanide ion.

Scheme 12

Synthesis of pyrrole and condensed pyrrole derivatives: Several synthesis of pyrrole derivatives utilizing organic cyano compounds as starting components were reported [60-68]. The most interesting results of that are demonstrated in Scheme 13 [68-73].

Scheme 13

Hydrazinolysis of Z or E-2-methyl-3-cyano-4-pentenoate 38 afforded the pyrrole derivatives shown below 39, 40 [74-76].

Scheme 14

Nucleosides pyrrole derivatives have also been synthesized utilizing α-β-unsaturated nitriles [77], an interesting example is depicted in Scheme 15.

Scheme 15

Several indole syntheses have been reported [78-82]. For example, heating o-azidocinnamonitrile 47 in DMSO at 140°C afforded 2-cyanoindole 49 [83] in good yield. The latter could also be obtained on heating o-nitrocinnamonitrile 48 in triethylorthophosphate at 160°C [84].

Scheme 16

The 5-Amino-26-diethylcarboxy-3-substituted-4-(4 chlorophenyl)- 6-iminothieno[3,2-5,6], thiopyrano[2,3-b]pyrrols 51 were synthesized in a one-pot procedure via the reaction of β-substituted arylidene malononitrile 50 with CS₂ and ethylchloroacetate in 1:1:2 molar ratio under PTC conditions (dioxane/K₂CO₃/tetrabutylammonium bromide TBAB) in good yield [85].

Scheme 17

Heating pyrrole-2-carbodithionates 52 with anions of C-H acids generated from malononitrile or cyanoacetamide in KOH/DMSO (room temperature, 0.5 h). Interaction of the resulting enethiolates 53 with haloacetylenes 54 afforded the pyrrolothiazolidines 55, as outlined in Scheme 18 [86-91].

Scheme 18

Five membered rings with two heteroatoms:

Synthesis of 1,2-oxazole derivatives: The α-β-Unsaturated nitriles are extensively utilized for the syntheses of 1,2-oxazoles [92-95]. For example, the dimer of ethyl cyanoacetate 56 reacted with hydroxylamine hydrochloride to yield 57.

Scheme 19

Other examples for the syntheses of amino-1,2-oxazole are shown in Scheme 20 [96-98].

Scheme 20

Compound 27a was examined against hydroxylamine hydrochloride to yield a mixture of the aldoxime 61 and the aminoisoxazole derivatives 62 [99].

Scheme 21

In contrast to the previously reported behaviour of 2-pyrazolin-5- one [100], 2-thiazoline-4-one [101], and 2-thiohydantion derivatives [102], towards the action of arylidenemalononitrile, 3-phenyl-2- isoxazolin-5-one 64 reacted with the cinnamonitrile derivative 63 to yield only the arylidene derivative 65 [103], as shown in Scheme 22.

Scheme 22

3-Oxime-4-phenyl-1(H)-1,5-benzodiazepin-2-one 66 was allowed to react with different arylidenenitriles in the presence of triethylamine and yielded spirobenzodia-zepine isoxazole derivatives 67 and 68, as outlined in Scheme 23 [104].

Scheme 23

Synthesis of isothiazole derivatives: The chemistry of isothiazoles has been reviewed by one of us [105] and the isothiazole derivatives 72 was produced by treatment of the dimercaptomethylenemalononitrile salt 69 with elemental sulfur in refluxing methanol, in a good yield. The existence of intermediates 70 and 71 has been envisioned. The former arises from nucleophilic attack by mercaptide anion on sulfur, whereas the latter involves a second nucleophilic attack on the nitrile with expulsion of the sulfur moiety by the nitrogen. Another example of this reaction involving the mononitrile derivative 73 has been described, which presumably proceeds through the same path, leading to the isothiazole derivative 74 [106], as outlined in Scheme 24.

Scheme 24

Synthesis of thiazole derivatives: An investigation was undertaken to explore the potential utility of the reaction of some activated nitriles with mercaptoacetic acid as a route for the synthesis of thiazoles, thus, cinnamonitriles 35 react with mercaptoacetic acid to give the thiazole derivatives 75 [107,108], as outlined in Scheme 25.

Scheme 25

Synthesis of pyrazole and fused pyrazole derivatives: Scission of the double bond in the arylidene derivatives of 3-oxoalkanenitriles 27 was reported to take place by the action of hydrazines in basic media, whereas the formation of 3,5-diaryl-3-pyrazolines 76 was reported to take place in acidic media [109-111]. The intermediate phenylhydrazone derivative 77 was isolated together with 78 on reaction of 27 (Ar = p-O₂N-C₆H₄-) with phenylhydrazine. El-Nagdy et al. [112-114] have reported that 27 (Ar = p-Me₂N-C₆H₄-) reacts with β-cyano-ethylhydrazine to yield the hydrazone 79, which was cyclized to yield either 80 or 81 depending on the applied reaction conditions as shown in Scheme 26.

Scheme 26

Cusmano and Sprio [109,110,115,116] have shown that the double bond in compound 27 functions as a ylidenic bond even toward the action of semicarbazide hydrochloride, thus heating benzylidene- ω-cyanoacetophenone 27 with semicarbazide hydrochloride in an ethanolic solution of sodium carbonate results in the formation of benzaldehyde semicarbazone and ω-cyanoacetophenone. However, when the reaction mixture was left for several days, compound 82 (formulated by Cusmano and Sprio as 83 (R1 = H, R2 = Ph, R3 = CONH₂) was formed in addition to benzaldehyde phenylhydrazono, as described in Scheme 27.

Scheme 27

It has been shown that ethyl β-trichloromethyl-β- aminomethylenecyanoacetate (84, X = CCl₃) reacts with hydrazine hydrate to afford the aminopyrazole derivative 86 via intermediate formation of the amidrazone 85 which could be isolated [116,117-119]. This is in contrast to the reported formation of 3-amino-4-cyano- 5-trifluoromethylpyrazole 87 on treatment of β-trifluoromethyl-β-aminomethylene-malononitrile (84, X = CF₃) with hydrazine hydrate [120]. Synthesis of pyrazoles via similar routes has been reported [107,121], as outlined in Scheme 28.

Scheme 28

Ethoxymethylenemalononitrile 88 reacted with hydrazine hydrate to yield the pyrazole derivatives 89 and 90 [122], as outlined in Scheme 29.

Scheme 29

In an attempt to synthesize 3-amino-4-ethoxycarbonyl-pyrazole 92 via reacting 91 with hydrazine hydrate in a manner similar to that reported for its reaction with phenyl hydrazine which is established to afford pyrazole derivatives, Midorikawa et al. [123,124] have obtained, instead of the expected pyrazole derivative 92, the pyrazolo[1,5-a]pyrimidine derivative 94. The formation of this product is expected to proceed via intermediate formation of 93, as outlined in Scheme 30.

Scheme 30

4-(4-Phenyl-3-pyrazolyl)-4H-1,2,4-triazole 97 was recently prepared by the action of formylhydrazine 96 on α-phenyl-α- cyanoacetaldehyde 95 [125], as depicted in Scheme 31.

Scheme 31

β-Dimethylamino- α-(2-ribosyl) acrylonitrile 98 reacted with hydrazine hydrate to yield the aminopyrazole derivative 99. This reaction opened a new route for the synthesis of formycone and formycine analogues [126], as shown in Scheme 32.

Scheme 32

A variety of new pyrazole derivatives 101-104 have been synthesized utilizing the same idea of reacting α-β-unsaturated nitriles 100a-c with hydrazine or acylated hydrazines [99,127-149]. Examples for the most interesting of these syntheses are shown in Scheme 33.

Scheme 33

3,4-Dicyano-5-aminopyrazoles have been synthesized by taking the advantage of the tetracyanoethylene 23 for Michael addition. Thus, aryl and alkyl hydrazones as well as hydrazides, semicarbazides and thiosemicarbazides have been reported to react with tetracyanoethylene to afford 1-substituted-4,5-dicyano-3-aminopyrazoles [145]. The structure assigned for the reaction product of 23 with methylhydrazine was reinvestigated by Hecht et al. [145] and Earl et al. [146] in two separate contributions. It has been shown by Hecht et al. [145] that consideration of the mechanistic routes suggested in literature for this reaction illustrates the source of structural ambiguity in the formation of these products from methylhydrazine and 23. Thus, one might for example, envision formation of the 1-methyl-4,5-dicyano-3-aminopyrazole 105 by conjugate addition of the more nucleophilic substituted hydrazine nitrogen of the hydrazine to the cyano group, affording the observed product is depicted in scheme 34.

Scheme 34

Alternatively, as has been previously suggested, addition of the substituted nitrogen of methylhydrazine to the cyano group might occur first to give 106 and the reaction then proceeds are depected in
Scheme 35.

Scheme 35

Both authors on reconducting the above reaction have shown that it affords a mixture of two isomeric pyrazoles (53% and 27%) [146], (47% and 8%) [147]. These author have shown on the basis of chemical evidences as well as spectroscopic data that the major product for which the 3-amino-4,5-dicyano-1-methylpyrazole structure was formally assigned is really 1-methyl-3,4-dicyano-5-aminopyrazole. El-Nagdy et al. [113] reported that the reaction of arylhydrazono derivatives of 2,3-dioxo-3-phenylpropionitrile 107 reacted with ethyl hydrazinoacetate 108 to yield the imidazo[1,2-b]pyrazole derivatives which can be formulated as 109 or 110. Structure 110 was considered most likely for these products based on spectroscopic data. The formation of 110 in this reaction may be assumed to proceed via the sequence demonstrated in Scheme 36 and attempted to isolate intermediates for this reaction were unsuccessful.

Scheme 36

Furthermore, compound 108 reacted with the dimer of malononitrile 111 to afford 112 in excellent yield. Attempted cyclization of 111 by action of 3% NaOH has afforded the carboxylic acid derivatives 113. On the other hand the hydrochloride 114 was obtained on attempted cyclization of 112 by the action of conc. HCl [113], as shown in Scheme 37.

Scheme 37

Similar to the behaviour of 77, phenyl hydrazonomalononitrile 115 reacted with 108 to yield the imidazo[1,2-b]pyrazole derivative 116 is depicted in Scheme 38.

Scheme 38

The behaviour of the ethoxymethylene derivatives of cyanoacetic acid 117 has also been investigated [113]. It has been found that 117 react with 108 to yield the aminopyrazole derivatives 118 are depicted in Scheme 39.

Scheme 39

The nitrile 119 reacted with 4-bromo-3-methylpyrazol-5-one 120 in ethanol in the presence of catalytic amount of triethylamine to give the corresponding pyrano[2,3-c]pyrazole derivatives 121 [150] are depicted in Scheme 40.

Scheme 40

Treatment of activated nitrile 122 under the above conditions gave the acyclic pyrazolone derivative 123 which could not be cyclized under the applied conditions in contrast to the previous case [150], the product is depicted in Scheme 41.

Scheme 41

The arylidene malononitrile 124a-c has been reacted with 3-methyl- 2-pyrazolin-5-one 125a to yield the pyranopyrazoles 126a-c, which were also obtained from the reaction of arylidene pyrazolones 127a-c with malononitrile [100] and this reaction proved to be a general one. Thus, pyranopyrazoles 126d-i were formed from 125a and 124d-i in yield (66-99%) [151-156] and the products are depicted in Scheme 42.

Scheme 42

However, attempts to extend this approach in order to enable synthesis of 128 failed. Abdo et al. [100] reinvestigated reaction of 125 with 124a,b and obtained a product the structure of which was assigned as 129 since they proved that 128a,b were obtained via addition of malononitrile to 100a,b [100,140] as depiected in Scheme 43.

Scheme 43

The structure of the products of the reaction of 124 with 125b has been recently shown [157] to be 133 formed most likely via decomposition of the initially formed Michael adduct 131 into 132 and addition of one molecule of 125b to this decomposition product affording arylidene-bis-pyrazolones that react with piperidine present in the reaction mixture to yield 133, as depicted in Scheme 44 [158].

Scheme 44

Girgis et al. [150] have reported that compound 129g,h were formed via reacting 124g,h with 125b. However, Abdelrazik et al. [151] have later reported that the product of the reaction of 125b with 124g is 129. Similar to the behaviour of 125a, compound 125c reacted with 124a to yield 134 [159]. Similar results were obtained with 125d, as depicted in Scheme 45 [160-162].

Scheme 45

El-Torgoman et al. [162] reported the formation of 137 from 125 and p-anisylidene thiocyanoacetamide 135 via elimination of hydrogen sulphide from the intermediate Michael adduct 136, as shown Scheme 46.

Scheme 46

Mahmoud et al. [163] reported that equimolar amounts of 1-phenyl-3-methylpyrazolin-5-one 125 and α-cyano-3,4,5- trimethoxycinnamonitrile 138 were refluxed in absolute ethanol in the presence of piperidine as a catalytic base. After 15 minutes an insoluble fraction was isolated as colorless crystals (13%) and detected to be the oxinobispyrazole 139 and the reaction was completed for 3h. Removal of most of the solvent and acidification with dilute acetic acid afforded the 1:1 adduct 140a or 140b as pale yellow crystals (44% and 46% yield, respectively), as outlined in Scheme 47.

Scheme 47

Spiropyranopyrazoles 142 have been obtained through reacting substituted cyanomethylideneindolidinones 141 with 125a,b. It is of value to report that these products were earlier believed to be the quinoline derivatives 143. ¹³C-NMR spectra have been utilized to discriminate between the two structures (Scheme 48) [159,164].

Scheme 48

Pyranopyrazoles 145 were formed via reacting 144a,b with 125a [100]. However, the reaction of 144c with 125a led to the formation of 126 [151]. Similar results have been reported on treatment of 125 derivatives with 144, as depiected in Scheme 49 [160].

Scheme 49

The reaction of chalcones 146a with 125a yields the corresponding Michael adducts 147 [165-168]. These could be cyclized by the action of polyphosphoric acid into 148. The reaction of α-cyanochalcone 146b with 125a resulted in the direct formation of 148b (X = CN), as outlined in Scheme 50.

Scheme 50

Excellent yield of pyranopyrazole derivatives 149 were obtained upon treatment of nitrile 27 with 125 [169], and is depicted in Scheme 51.

Scheme 51

1-Phenyl-pyrazolin-3,5-dione 150 reacts with activated nitrile derivatives to yield several pyrano[2,3-c]pyrazoles [161] 151, 152. Similarly 1,3-diphenylthio-hydantoin, thiazolidinethiones and isorhodanine reacts with cinnamonitriles to yield the corresponding pyranoazole derivatives, however in some cases, ylidene group exchange took place and the compound is depicted in Scheme 52 [161].

Scheme 52

During the course of our investigations on the use of DAMN in heterocyclic synthesis, we designed new approaches to 4-cyano-1,3- dihydro-2oxo-2H-imidazole-5-(N1-tosyl)carboxamide as a reactive precursor thiopurine [170]. In some of these cases, new DAMN derivatives, N-({[(Z)-2-amino-1,2-dicyanovinyl]amino}carbonyl)-4- methylbenzenesulfonamide, were used as the key intermediates. Since until now the preparation and characterization of the above stated sulfonamides have been mentioned only briefly, we give herein a report on these compounds in more detail [170]. Tetracyanoethylene 23 reacted with 123 to yield product of condensation by the elimination of hydrogen cyanide, which is formulated as 124 depicted in Scheme 53 [171].

Scheme 53

Madkour et al. [171] has reported that hydrazinolysis of 3-(4-methoxyphenyl) and 3-(2′-thienyl)-2-cyano-2-propenoyl chlorides 155a [172-176] and 155b at 0°C afforded the pyrazolone derivatives 156, bishydrazine 157 and anisylideneazine 158, while, treatment of 155a with benzoylhydrazine afforded the pyrazolone 159, as outlined in Scheme 54.

Scheme 54

Furthermore, the electrophilicity of the lactonic carbonyl functionality of benzoxazinone 160 has been investigated [172] via its reaction with some nitrogen and oxygen nucleophiles. Thus, stirring 160 with hydrazine hydrate at 0°C in dioxane gave the pyrazolo[5,1-b]- (1H) quinazolinone 161 in moderate yield. On the other hand, addition of hydrazine hydrate to 160 in n-butanol followed by stirring at room temperature or at reflux afforded a mixture of 2-aminopyrazolo [5,1-b] quinazolinone 162 besides the Schiff ′s base 163 and the azine 158, as outlined in Scheme 55.

Scheme 55

4-Arylidene-1-phenyl-3,5-pyrazolinediones 164 [177] reacted with activated nitriles 165 (N, S-acetals) [178] to give pyrazolino-1,3- oxazine derivatives 166, as outlined in Scheme 56.

Scheme 56

On refluxing compound 167 with cycloalkylidenecyanoacetamide 168 in dioxane in the presence of triethylamine, the corresponding pyrrazolopyridinethione derivatives 169 were obtained [179], as outlined in Scheme 57.

Scheme 57

Treatment of 170 [179] with benzylidenemalononitrile furnished the corresponding spiropyrazolopyridine derivatives 171 and are depicted in Scheme 58 [180].

Scheme 58

The synthesis of various pyrazolo[1,5-a]pyrimidines as unique phophodiesterase inhibitors from easily available starting materials has been the subject of several publication [181-183]. In spite of enormous literature reported for the synthesis of pyrazolo[1,5-a]pyrimidines using 5-aminopyrazoles as educts, very few reports have appeared describing the utility of diaminopyrazoles as starting components for the synthesis of condensed pyrazoles. In conjuction to previous work, compound 172 was reacted with cinnamonitrile derivative to yield the pyrazolo[1,5-a] pyrimidine derivatives 173 is depicted in Scheme 59 [184].

Scheme 59

New spiro heterocyclic systems attached by coumarin nucleus were synthesized by the reaction of 2-coumarylidene malononitrile 174 with some active methylene or bidentates such as hydrazine hydrate to afford 175 and 176, respectively [179], as outlined in Scheme 60.

Scheme 60

Synthesis of midazole and condensed imidazole derivatives: A New Synthesis of 4-Cyano-1,3-dihydro-2-oxo-2H-imidazole-5-(N1- tosyl) carboxamide: A Reactive Precursor for ThioPurine Analogs Hamad et al. [169]. 2,3-Diaminodinitrile 177 has been recently utilized for the synthesis of imidazole derivatives. Thus, 177 reacted with formamidine to yield 2,3-diaminofumaronitrile 178 which could be cyclized under different conditions to yield different imidazole derivatives 179-182, and the product is depicted in Scheme 61 [149,185-188].

Scheme 61

Aziz et al. [102] found that the activated nitriles 184 react with 3-phenyl-2-thiohydantoin 185 to yield 1:1 adducts 186 together with the 5-benzylidene-2-thiohydantoin derivatives 187. The same products were obtained when 187 were treated with malononitrile, as shown in
Scheme 62.

Scheme 62

In contrast to the behaviour of compound 185a towards 184a-d, the 2-thiohydantoin derivatives 185b,c reacted with 184a,b to yield 5-arylidene derivative 187ab, 187bb and 187ac, respectively, as the sole isolable products and were recovered almost unaffected after treatment with 184c under the same experimental conditions, as outlined in
Scheme 63.

Scheme 63

Treatment of compound 187ab and 187bb with malononitrile afforded the pyrano[2,3-d]imidazole derivatives 188ab and 188bb, respectively, whereas treatment of 187ac with malononitrile afforded the pyrrolo[1,2-c]imidazole derivative 189ac, as outlined in Scheme 52. Compound 184e reacted with 185a to yield the pyrrolo[1,2-c] imidazole derivative 190. On the other hand, the pyrano[2,3-d] imidazole derivative 188eb was formed from the reaction of 184e and 185b, as outlined in Scheme 64.

Scheme 64

In contrast to the behaviour of compound 184a-c toward 185, ethylbenzylidene cyanoacetate 152f reacted with imidazolidines 185a-c to give the benzylidene derivatives 187aa, 187ab and 155ac, respectively. The reaction of thiohydantoin 185b with 27 has been, however, shown to yield either pyrano[2,3-d]imidazoles 191 or pyrrolo[1,2-c]imidazoles 192 depending on the nature of substituents on the thiohydantoin and is depicted in Scheme 65 [102].

Scheme 65

Synthesis of five membered rings with three heteroatoms

The synthetic potentialities of 2-arylhydrazinonitriles have recently been reviewed [189]. El-Mousawi et al. have reported that 2-phenylhydrazono-3-oxo-butanenitrile 193 reacted with hydroxylamine hydrochloride in ethanolic sodium acetate to yield amidoxime 194 that cyclized readily into 4-acetyl-2-phenyl-1,2,3-triazol-5-amine 195 upon reflux in DMF in presence of piperidine [190], as outlined in Scheme 66.

Scheme 66

¹³C-NMR of the reaction product indicated that this is not the case, as it indicated the absence of the carbonyl carbon in the range δ = 180-200 ppm. Therefore, the formation of isomeric oxazole II was considered as the correct structure which can take place only via intermediacy of the initial product of condensation of the ketocarbonyl of 193 with hydroxylamine yielding inetrmediate I that could cyclize to isomeric oxazole II. Intermediate isomeric oxazole II when heated in DMF in the presence of piperidine it rearranged readily to 195 [191], as outlined in Scheme 67.

Scheme 67

Tetracyanoethylene 23 reacts with ethyldiazoacetate to yield 1,2,3-triazoles 196 is depicted in Scheme 68 [186,192]

Scheme 68

Cyanamide derivatives 197 have been extensively utilized for the synthesis of 1,2,4-triazoles [193-195]. The one interesting example for the utility of these reactions in synthesis of triazole derivatives 198 and 199 is shown below in the following Scheme 69.

Scheme 69

Cyanamide derivatives have been utilized for the synthesis of oxadiazoles [196]. For example, benzoyldicyandiamide 200 afforded a mixture of the urido-1,2,4-oxadiazole derivatives 201 and 202 on treatment with hydroxylamine, the first was predominating, as the product depicted in Scheme 70 [194,196].

Scheme 70

Similarly, the iminoether 203 afforded the amino-oxadiazole derivative 204 on reaction with hydroxylamine and the product depicted in Scheme 71 [197].

Scheme 71

Also, the cyanamide 205 reacted with hydroxylamine to yield 1,2,4-oxadiazole derivative 206 is depicted in Scheme 72 [198].

Scheme 72

1-Substituted-3-cyano-isothioureas 207, gave mixture of the 5-amino-3-substituted-amino-1,2,4-oxadiazoles 208 and the isomeric 3-amino-5-substituted-amino-1,2,4-oxadiazoles 209 on reaction with hydroxylamine, the compound 208 usually predominated and is depicted in Scheme 73 [199].

Scheme 73

Six-membered heterocycles

Six membered heterocycles with one heteroatom

Synthesis of pyridine and condensed pyridine derivatives: Several pyridine syntheses, utilizing nitriles as starting components have been reported [37-41]. Although a number of papers have been published concerning the synthesis of 2-oxopyridine derivatives [200-212] no preparations using 2-cyano acrylates, cycloalkanones and ammonium acetate as starting materials have been reported. Some 2-oxopyridine derivatives such as 4-aryl-3-cyano-2-oxo-7- (substituted benzylidene)-2,5,6,7-tetrahydro-1H-pyridines (38- 57% yield) 212 were synthesized from ethyl 2-cyanoacrylates 210, cycloalkanones 211 and ammonium acetate in refluxing ethanol [213], as shown in Scheme 74.

Scheme 74

An analoguous reaction between ethyl 2-cyanoacrylates (R = Me, Et) 213, cyclopentanone and ammonium acetate gave, as products, ethyl-2-cyclopentylidene-2-cyanoacetate (major product) and the 4-alkyl-3-cyano-2-oxo-2,5,6,7-tetrahydro-1H-1-pyridines 214 instead of the expected 7-alkylidene derivatives and the product depicted in
Scheme 75.

Scheme 75

The reaction of 210a-d with 215b gave the 4-aryl-3-cyano-2- oxo-1,2,3,4,5,6,7, 8-(or 1,2,3,4,4a,5,6,7-)octahydroquinolines 216 and/ or the 4-aryl-3-cyano-2-oxo-1,2, 5,6,7,8-hexahydroquinoline 217, the product depicted in Scheme 76.

Scheme 76

The 2-iminopyridine derivatives 220 obtained in fairly good yield from the condensation of arylidene malononitrile 218 with alkyl ketones 219 in the presence of excess ammonium acetate with boiling benzene and the product depicted in Scheme 77 [214].

Scheme 77

The reaction of β-alkylarylidenemalononitrile 50 with phenylisocyanate or phenylisothiocyanate under PTC conditions (MeCN/K₂CO₃/TBAB) yielded pyridinone and pyridine-2-thione derivatives 221 [105,215], as shown in Scheme 78.

Scheme 78

However, treatment of arylidene malononitrile with some reactive halo compounds under PTC afforded the N-aminopyridine derivative 222, [105,215]. Where with hydrazine hydrate yielded the pyridine derivatives 223 and 224 in moderate to good yields, as shown in
Scheme 79.

Scheme 79

The cinnamonitriles 63 react with cyanoacetic acid hydrazide 226 to afford N-aminopyridones. Soto et al. [215] reported the direct formation of 226 as sole reaction product on heating 63 with 225 for 5 min. However, El-Moghayar et al. [216] have reported that the product previously identified as 226 is really 227 which rearranged on refluxing in aqueous ethanolic triethylamine solutions into 228, as shown in Scheme 80. Evidence afforded on this problem are not conclusive and further investigation seem to be mandatory.

Scheme 80

The reaction of the dimers 111 and 56 with cinnamonitriles in ethanolic triethylamine solutions afforded the pyridine derivatives 229, 230 are depicted in Scheme 81 [217-219].

Scheme 81

Recently, this approach has been explored for the synthesis of several pyridine derivatives 231-236, as outlined in Scheme 82 [220-223].

Scheme 82

Daboun et al. [223] have found that a solution of equimolar amounts of 2-amino-1,1,3-tricyanoprop-1-ene 111 and acetylacetone in ethanol was refluxed for 2 hr in the presence of piperidine as a catalyst to yield a product of molecular formula C11H8N4. Two possible structures, 3-cyano-2-dicyanomethylene-4,6-dimethyl-1,2-dihydropyridine 237 and the isomeric 238, were considered. Structure 237 was established by the results of IR and ¹H-NMR spectra. The obtained products beer several functional substituents and appear promising for further chemical transformations, as outlined in Scheme 83.

Scheme 83

The activated nitrile 240 and 241 was synthesized by El-Nagdy et al. [224] through the reaction of phenacylthiocyanate 239 with malononitrile. as outlined in Scheme 84

Scheme 84

The structure 241 was ruled out on the basis of IR and ¹H-NMR spectra. Reaction of trichloroacetonitrile with 240 in refluxing toluene in the presence of a catalytic amount of piperidine yield a 1:1 gave adduct 241 wich cyclized into produce 243 which was suggested based on spectroscopies. The compound 240 also might be gave 242 and then cyclized to give 244, as outlined in Scheme 85.

Scheme 85

Conflicting results have been reported for the reaction of cinnamonitrile 63 with cyanothioacetamide 215. Thus, Daboun and Riad [225] reported that the dihydropyridines 246a,b were isolated from the reaction of 63 with 245. On the other hand, Sato et al. [226] reported that the pyridines 246a,b were the isolable products from the reaction of 63 and 245 [227,228]. Recently, it has been shown that the thiopyrans 247 are the products of the kinetically controlled reactions of 63 with 245 (via chemical routes and inspection of the high resolution ¹H-NMR and ¹³C-NMR). These products rearrange on heating in aqueous ethanol into the thermodynamically stable dihydropyridines 248. Observed [100,101,151] dependency of the products of reactions of active methylene reagents with cinnamonitrile derivatives on the nature of reactants and reaction conditions has been reported [134,226-236], as outlined in Scheme 86.

Scheme 86

Pyridine derivatives 250, 251, 252, 253 and 255 were successfully synthesized via condensation of cyanothioacetamide 245 with the cinnamonitrile derivatives 249 or the acrylonitrile derivatives 253, as outlined in Scheme 87 [237].

Scheme 87

Gewald et al. [237] have shown that the product of reaction of 56 and 111 with trichloroacetonitrile are really the pyridine derivatives 256 and 257, respectively. Convincing evidence from ¹³C-NMR for the proposed structures were reported, as outlined in Scheme 88.

Scheme 88

A route for the synthesis of 6-[5-amino-pyrrol-4-yl]pyridines 253 and their conversion into 3-[pyridine-6-yl]pyrazolo[1,5-a]pyrimidine 263 has been reported [238]. Thus, 1-phenylethylidene malononitrile 258 was refluxed in pyridine solution with enaminonitriles 253ac to yield products via chloroform elimination. Structure 230 or its cyclized product 231 seemed possible as 253a-c were assumed to add 258 affording the intermediate Michael adducts 229 which then lost chloroform to 230. 230 may undergo cyclization into 261 under the reaction conditions. Compound 261 reacted with hydrazine hydrate affording 261, which condensed readily with acetylacetone affording the required pyrazolo[1,5-a]pyrimidines 263, as outlined in Scheme 89.

Scheme 89

El-Nagdy et al. [239] reported that 3-amino-2-cyano-4- ethoxycarbonyl crotononitrile 234 reacted with trichloroacetonitrile in refluxing ethanol in presence of triethylamine to give 235 which resemble the formation of pyridine derivative from the reaction of 2-amino-1,1,3-tricyanopropene with trichloroacetonitrile. Compound 235 reacted with hydrazine hydrate to yield hydrazine derivatives 236 which successfully cyclized into 237, as outlined in Scheme 90.

Scheme 90

It was reported that when indan-1,3-dione or 1-phenyliminoindan- 3-one 268a,b were heated with arylidenecyanothioacetamide in refluxed ethanol in the presence of a catalytic amount of piperidine, 4-aryl-3-cyano-5-oxo- or (phenylimino)-indeno[1,2-b]pyridine-2[1H] thiones [240] 269a-c were obtaine, as outlined in Scheme 91.

Scheme 91

When 269 was subjected to react with NaN₃ in DMF in the presence of NH₄Cl to synthesize mercaptotetrazolylindeno pyridine 271 as reported [241,242] the aminoindenopyridine derivative 270 was obtained instead of 271, as depicted in Scheme 92.

Scheme 92

1-Dicyanomethylene-3-indanone 272 was prepared by the reaction of indandione and malononitrile in ethanolic sodium ethoxide solution [243,244]. Compound 272 reacted with carbon disulphide to give the dithiocarboxylic acid derivative 273, which in turn was alkylated with methyl iodide and ethyl chloroacetate to give 274 and 275. Indeno[2,1-c] pyridines 276 were prepared through the reaction of 272 with phenyl (benzoyl) isothiocyanate. Compound 272 with malononitrile and aromatic aldehyde afforded 277, which reacted with acetic acid to give 278. Bromination of 272 with N-bromosuccinimide afforded 2-bromo derivative 279 which reacted with aniline, methylthioglycolate, and ethylglycinate to give indeno[2,1-b]pyrroles 280, 281 [245], indeno[2,1-b]thiopyrane 282, 283 and 284, as outlined in Scheme 93.

Scheme 93

Piperidylidene malononitrile 285 reacts with benzaldehyde to give 286, which underwent an addition reaction with malononitrile to give 287, which was also obtained by reacting 288 with one mole of benzaldehyde and two moles of malononitrile [246], as outlined in
Scheme 94.

Scheme 94 & 95

Synthesis of novel 1,4,5,6,7,8-hexahydroquinoline 291 bearing amino and cyano groups on C₂ and C₃ has been carried out by refluxing equimolar amounts of the corresponding arylidene malononitrile 289, dimedone 290 and excess of ammonium acetate in acetic acid as solvent in a similar way to that reported for other related structures [247,248]. Compounds 291 are obtained as crystalline solids in 55-75% yields, as outlined in Scheme 96.

Scheme 96

A route for the synthesis of thiazolo[2,3-a]pyridine 293 from the reaction of 2-functionally substituted 2-thiazoline-4-one 292 with cinnamonitrile has been reported simultaneously and independently by El-Nagdy et al. [101] and Kambe et al. [249]. Better yields were obtained using a 2:1 molar ratio of cinnamonitrile derivative and 292, as outlined in Scheme 97.

Scheme 97

In our laboratories [250] it has been found that the reaction of 292 with cinnamonitrile 294a,b in absolute ethanol in presence of piperidine afforded a semisolid product from which 6-substituted- 7H-2,3-dihydro-5-amino-8-cyano-3-oxo-7-(3,4,5-trimethoxyphenyl)- thiazolo[3,2-a] pyridines 295a,b (ethanol soluble fraction, major yield) and 6-substituted-7H-2,3-dihydro-5-amino-8-cyano-3-oxo-2-(3,4,6- trimethoxybenzylidene)-7-(3,4,5-trimethoxyphenyl)-thiazolo [3,2-a] pyridines 296a,b (ethanol-insoluble fraction, minor yield) can be isolated, as depicted in Scheme 98.

Scheme 98

E-Z-assignement of compounds containing exocyclic C=C double bonds throughout the present work were elucidated and proven by ¹H-NMR calculations [251]. Unexpectedly, it has been found that the product 299 from the reaction of 292 with 2-oxo-3-dicyanomethylidene-2,3-dihydroindole 297a, 2-oxo-3-cyanoethoxy carbonylmethylidene-2,3-dihydroindole 297b and with isatin under the same experimental conditions was one and the same product 298 [252], as outlined in Scheme 99.

Scheme 99

It was believed that the reaction product was found via additions of 292 to the activated double bond in 297a,b to form the corresponding intermediate Michael adducts, which then loses either malononitrile or ethyl cyanoacetate to yield the final isolable product 298. Junek [253] has reported that salicylaldehyde 299 reacts with 2-amino-1,1,3- tricyano prop-1-ene 111 to yield the benzopyrano[3,4-c]pyridine 300 is depicted in Scheme 100.

Scheme 100

Midorikawa et al. [249] have shown that the reaction of substituted amines with ylidenemalononitriles affords pyridine derivatives 301 and 302, as outlined in Scheme 101.

Scheme 101

Conversion of 4-acetyloxazoles 303 into pyridine derivatives 306 via reaction with malononitrile has been reported. The reaction proceeds via formation of the ylidenemalononitrile derivative 304 and then cyclized into 305 [254], as outlined in Scheme 102.

Scheme 102

Several other pyridine syntheses from activated α,β-unsaturated nitriles are already available in literature; a very old example is the reaction of two fold of 2-amino crotononitrile with aromatic aldehyde 307 to yield a pyridine derivative 308 is depicted in
Scheme 103 [255].

Scheme 103

Other interesting examples, 2-amino-1,1,3-tricyano-prop-1- ene 111 has been reported to react with benzalmalononitrile to yield pyridine derivative [256] 309. Similarly, diethyl-3-amino-2-cyanopent- 2-ene-1,5-dicarboxylate 56 has been reported to yield pyridines 310 utilizing almost the same idea [218], as outlined in Scheme 104.

Scheme 104

2-Amino-1,1,3-tricyano-prop-1-ene 111 has been reported to condense with β-diketones 311 and β-aminoenones 312 to yield pyridine derivatives 313, 314 respectively [40,257], as outlined in
Scheme 105.

Scheme 105

The reaction of 3-aminoacrylonitriles derivative 315 with ethoxymethylene malononitrile in chloroform or dichloromethane at temperature below 0°C and 5°C for 24 hours, leads to dienaminonitriles 316 in good yields [257]. These adducts 316 are transformed into the pyridine derivatives 317 in almost quantitative yields. The reaction of compound 317 with formamide lead to pyrido[2,3-d]pyrimidine derivatives 318 in 65-98% yields as outlined in Scheme 106.

Scheme 106

The synthesis of pyridine derivatives 320 is best accomplished by cyclization of the new dienaminoester 319 in refluxing DMSO and as depicted in Scheme 107 [258].

Scheme 107

5.3.1.2. Synthesis of quinoline and fused quinolone derivatives: The ylidene 321 could be cyclized by heating with ethylphosphite at 160-170°C into the corresponding quinoline derivatives 322 is depicted in Scheme 108 [259].

Scheme 108

Several pyrano[3,2-c]quinolines 324 were prepared [231,260] from 4-hydroxy-2(1H)quinolinones 323 and ylidene nitriles is depicted in
Scheme 109.

Scheme 109

Khallh et al. [261] reported that 8-quinolinol 325 reacts with cinnamonitrile derivatives in an ethanolic solution in the presence of piperidine to afford 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3- carbonitriles 326 or ethyl 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline- 3-carboxylates 326 in moderate yield, as depicted in Scheme 110.

Scheme 110

Mahmoud et al. [262] reported that the same results obtained when α-cyano-3,4,5-trimethoxyphenyl cinnamonitrile 327a and/or ethyl α-cyano-3,4,5-trimethoxy phenylcinnamate 327b been reacted with 325. Thus, 2-amino-3-cyano-4-(3,4,5-trimethoxyphenyl)-4Hpyrano[ 3,2-h]quinoline 328a and ethyl 2-amino-3-cyano-4-(3,4,5- trimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carboxylate 328b were synthesized from 325 and 327a,b, as depicted in Scheme 111.

Scheme 111

The reaction of acetyl and benzoylmethyl pyridine 329 with ethoxymethylene malononitrile in DMSO in the presence of potassium carbonate gave acylcyanoimino quinolines 330 with yields 70-96%, respectively, as depicted in Scheme 112 [263].

Scheme 112

Ortho-itrobenzaldehyde 307 reacted with 2-amino-1,1,3-tricyanoprop- 1-ene 111 to yield the condensation product 331 which could be readily cyclized into 332 is depicted in Scheme 113 [254].

Scheme 113

High yielding syntheses of polyfunctional benzo[a]quinolizines are well-documented [264]. Abdallah et al. [265] reported a new and general one-step route affording polyfunctional substituted benzo[a] quinolizines in good yield from readily available inexpensive starting materials using isoquinoline derivatives. Thus, treatment of 1-methyl isoquinoline 334 with arylidenesulfonylacetonitriles 333 in boiling acetonitrile in the presence of an equimolar amount of piperidine leads, in each case, to the formation of only one product 337 and 338, as indicated by TLC and ¹H-NMR analysis. The formation of 337 may be explained by cyclization of the initially formed Michael adduct 335 to the unisolated product 336, subsequent autoxidation of the latter leads to the final product 337. When the reaction of 334 with 333 was carried out in the presence of excess piperidine (2 moles) then the product 338 were formed directly, as outlined in Scheme 114.

Scheme 114

Similarly, isoquinoline-1-yl acetonitrile 339 reacted with 333 to give 341 and 342 through the cyclization and dehydrogenation of 340, as outlined in Scheme 115.

Scheme 115

Synthesis of pyran, coumarin and condensed pyran derivatives: Pyrans were readily obtained in good yields on treatment of ylidene derivatives of α-cyanochalcones with active methylene nitriles and active methylene ketones. Thus, benzylidene derivatives, aminomethylene and mercaptomethylene derivatives has been reported [170,235,236] to react with active methylene reagents to yield pyran derivatives [266-272].

The formation of pyrans in these reactions is assumed to proceed via additions of the reagent to the activated double bond and subsequent cyclization to the pyrane derivative, as demonstrated by the formation of 345 from the reaction of cinnamonitrile derivative 343 with active methylene reagents and as depicted in Scheme 116.

Scheme 116

The development of new method [273] for asymmetric synthesis of highly functionalized 2-amino-4-aryl-4H-pyrans 347 was achieved via Michael addition reaction of β-ketoesters 346 to arylidene malononitriles 218, as depicted in Scheme 117 in the presence of piperidine as a base.

Scheme 117

4-Alkyl-2-amino-4H-pyran 349 was synthesized via Michael addition reaction of benzoyl acetonitrile to α-cyanoacrylates 348 is depicted in (Scheme 118) using piperidine as a catalyst [274].

Scheme 118

Asymmetric Michael addition of cyanoacetates 45 to α-benzoylcinnamonitrile 27 in the presence of piperidine as catalyst has been studied, the resulting 3-alkoxy carbonyl-2-amino-5-cyano- 4,6-diphenyl-4H-pyrans 350 have been obtained in good yield, , as depicted in Scheme 119 [275].

Scheme 119

The reaction of arylidene malononitrile 63 with some reactive halo compounds under phase transfer conditions (PTC) afforded the pyran derivative 351, as depicted in Scheme 120.

Scheme 120

Several new benzo[b]pyrans 352, naphtho[1,2-b : 6,5-b]dipyrans 353, naphtho [1,2-b]pyrans 354 and naphtho[2,1-b]pyrans 355 have been prepared by the reaction of cinnamonitriles 63 with resorcinol, 1,5-naphthalenediol, 1-naphthol and 2-naphthol, respectively [276,277], as outlined in Scheme 121.

Scheme 121

It was reported [254] that salicylaldehyde reacted with diethyl 3-amino-2-cyano-pent-2-ene-1,5-dicarboxylate 111 to yield the coumarin derivative 356. The same compound has been claimed to be obtained directly from the reaction of salicylaldehyde with ethylcyanoacetate [278], as shown in Scheme 122.

Scheme 122

Similarly, substituted salicyaldehyde have been reported [254] to afford the iminocoumarin derivative 357 when reacted with 2-amino- 1,1,3-tricyanoprop-1-ene, as depicted in Scheme 123.

Scheme 123

3-Phenyl-7-hydroxy-3,4-dihydrocoumarin 358 [279,280] has been reported from the reaction of resorcinol with activated nitrile in catalytic amount of zinc chloride, as depicted in Scheme 124.

Scheme 124

Cycloaddition of substituted phenols with the nitriles derivative gave the 3-cyanocoumarin derivatives 359 is depicted in Scheme 125 [281,282].

Scheme 125

Condensation of 4-hydroxycoumarin 358 has also been successful with unsaturated nitriles 210 using pyridine [283] and yielded the pyrano[3,2-c]coumarin derivatives 360 is depicted in Scheme 126.

Scheme 126

4-Phenylcoumarin-3,4-dihydro-α-pyrone 362 (m.p. 183-4°C) was obtained by condensation of 4-hydroxy coumarin 358 with benzylidene malononitriles 63b in pyridine and the resulting intermediate 361 was subsequently hydrolyzed with HCl/AcOH and finally cyclized with Ac₂O [284], as outlined in Scheme 127.

Scheme 127

Recently [285], it was reported that annulations reactions of 4-hydroxycoumarin 358 with p-anisylidene ethylcyanoacetate or p-anisylidene malononitrile 210 yielded the corresponding 2-amino- 3-carbomethoxy(cyano)-4-(4′-methoxyphenyl)-5H-1-benzo pyrano- [4,3-b]-pyran-5-ones 363a,b, as depicted in Scheme 128.

Scheme 128

It was reported that [286] thermal Michael addition reaction takes place when 6,7-dimethoxy isochromanone 334 was treated with benzylidene malononitrile 21 at 190°C to afford 264 which underwent elimination of malononitrile producing 365, as shown in Scheme 129.

Scheme 129

New spiro pyran systems attached to coumarin nucleus 366 and 367 were synthesized by the reaction of 2-coumarylidenemalononitriles with some active methylene compounds in the presence of triethylamine [189], as shown in Scheme 130.

Scheme 130

Six membered rings with two heteroatoms

Synthesis of pyridazine and condensed pyridazine derivatives: An interesting approach for synthesis of pyridazines 368 has been achieved by cyclization of the intermediated of the reaction of cinnamonitrile derivatives 63 with aryldiazonium chloride [287]. This synthetic approach is summarized below in the following Scheme 131.

Scheme 131

El-Nagdy et al. [239] reported that 3-amino-2-cyano-4- ethoxycarbonyl but-2-enonitrile coupled with aromatic diazonium chlorides to yield 369 which converted to 370 on refluxing in acetic acid / HCl mixture, as outlined in Scheme 132.

Scheme 132

Coupling of 2-amino-1,1,3-tricyanoprop-1-ene with aryldiazonium salts and subsequent cyclization of the coupling products yielded the pyridazine derivative 349. The same pyridazine derivatives 373 could be alternatively synthesized via treatment of arylhydrazonomethylenemalononitrile derivatives 371 with malononitrile, a reaction that proceeds almost certainly via the intermediacy of the hydrazone 372 [288], as outlined in Scheme 133.

Scheme 133

Similar synthesis of pyridazine derivatives utilizing diethyl 3-amino-2-cyano-pent-2-ene-1,5-dicarboxylate has been reported [287]. Acenaphthenoquinones readily condense with malononitrile to yield the corresponding yildenemalononitrile 374, which reacts readily with hydrazine hydrate to yield aminopyridazine derivatives 375 [41], as depicted in Scheme 134

Scheme 134

Cinnoline derivatives were also reported utilizing α-hydrazononitrile as starting components. Thus, heating phenylhydrazonomalononitrile 371 with anhydrous aluminum chloride affords 4-amino-3- cyanocinnoline 376 is depicted in Scheme 135 [289].

Scheme 135

Synthesis of pyrimidine and fused pyrimidine derivatives: α,β-Unsaturated nitriles have been extensively utilized for the synthesis of pyrimidines. Tylor et al. [290,291] have summarized all literature in this area in more than one reference. One of the interesting examples of the utility of α,β-unsaturated nitriles for pyrimidine synthesis is the reported reaction of 2-aminomethylene malononitrile 377 with acetamidine 378 to yield pyrimidines 379 and 380 and cyclized into fused pyrimidine derivative 381, as outlined in Scheme 136 [291].

Scheme 136

Cyanoethylation [292] of cyanoguanidine in presence of lithium hydride has been reported to yield pyrimidines 382-385 in good to moderate yields, as outlined in Scheme 137.

Scheme 137

4-Oxo-2-thioxopyrimidine derivative 386 [293] was obtained by the reaction of ethyl α-cyano-β-methoxy-cinnamate with thiourea in the presence of potassium carbonate, as depicted in Scheme 138.

Scheme 138

The reaction of ethoxymethylene derivatives 388 with urea derivatives 387 were shown to yield carbethoxy pyrimidines [294-296]. The behaviour of 363 with thiourea [297] was demonstrated and gave the pyrimidine derivatives 389-393, as outlined in Scheme 139.

Scheme 139

A direct one-step synthesis of pyrimidines has been reported utilizing 3-oxoalkanenitriles as starting materials, thus, 2-aryl-3- oxoalkanenitriles 394 reacts with formamide and phosphoryl chloride to yield pyrimidines 395, as depicted in Scheme 140 [297].

Scheme 140

The isolation of several other side products, depending on the nature of the oxoalkanenitrile, has been reported [298-301]. Several other synthetic approaches for pyrimidines utilizing 3-oxoalkanenitriles as starting material have been reported and surveyed [301,302]. Compound 396 reacted with either phenylisothiocyanate or benzoylisothio-cyanate in refluxing dioxane to yield the pyrimidine derivative 397 is depicted in Scheme 141 [240].

Scheme 141

The reaction of barbituric acid, thiobarbituric acid and 4-bromo- 3-methyl pyrazolin-5-one with acrylonitriles 398 was reported by Abdel-Latif [303], thus, the compound 399a reacted with 398a-c to give the pyrano[3,2-d]pyrimidines 400a-c. The alternative structure 401 was excluded on the basis of spectral data. Similarly, the acid 399b reacted with 398a,d to give the corresponding pyrano[3,2-d] pyrimidines 400de. On the contrary, attempts to bring about addition of 399b to 398b,c (Ar = 2-furyl, 2-thienyl) failed and the reactions were recovered unchanged after being refluxed in ethanolic triethylamine. Thus, it can be concluded that the introductions of a π-deficient heterocycles at β-position of the acrylonitrile increases the reactivity of the double bond towards Michael type addition reaction and the introduction of a π-excessive heterocycle decrease its reactivity. In contrast to the behaviour of 398a-d towards 399a,b attempts to bring about addition of 373f-h to 399a,b resulted in the formation of ylidene derivatives 402a-d, which assumed to be formed via elimination of a malononitrile molecule from the Michael adduct intermediate. Similar ylidene formation by the addition of α,β-unsaturated nitriles to active methylene reagents has been observed earlier in several reactions [101,250], as shown in Scheme 142.

Scheme 142

Mahmoud et al. [163] found that when compound 374a,b was submitted to react with the cinnamonitrile derivatives 63 in refluxing pyridine afforded the arylidene derivative 378 as the sole product, as depicted in Scheme 143.

Scheme 143

A variety of pyrimidine synthesis, utilizing nitriles as starting components has been reported [291,292,304-308]. Enaminonitriles 403 and 404 react with trichloro-acetonitrile to yield the corresponding pyrimidine derivatives 405 and 406, respectively [106,229,309], as shown in Scheme 144.

Scheme 144

Another reported pyrimidine synthesis is summarized below as depicted in Scheme 145 [310].

Scheme 145

Fawzy et al. [310] reported that hydrazopyrimidine 407 was reacted with cinnamonitriles afforded the corresponding arylhydrazopyrimidine 408 is depicted in Scheme 146

Scheme 146

Geies [311] has been reported that 6-aminouracil and 6-aminothiouracil 409 were reacted with benzylidenemalononitrile in ethanol in the presence of piperidine to afford 410a,b, respectively. The reaction was assumed to proceed via Michael addition of the pyrimidine nucleus to the α,β-unsaturated nitriles and subsequent cyclization through nucleophilic addition of the amino group to one of the two cyano groups [312], as shown in Scheme 147.

Scheme 147

The structure of compound 410a,b was established as pyridopyrimidine rather than pyranopyrimidine 411 on the basis of ¹H-NMR and IR spectra. On the other hand, the reaction of 409a,b with benzylideneethylcyanoacetate under the same conditions results in a mixture of compound 412a,b and/or 413a,b, respectively. Aminopyrazole and aminoisoxazole derivatives have also been reported to react with acrylonitrile to yield either fused pyrimidines or ring N-cyanoethylated products, which readily cyclized to fused pyrimidines 414-416 [46,111,309,313-324], as outlined in Scheme 148.

Scheme 148

A recent interesting pyrimidine synthesis has been reported and is summarized in Scheme 149. The utility of the resulting cyanopyrimidines for building up fused heterocycles has also been reported [106].

Scheme 149

The enaminonitrile 31 was utilized for synthesis of several new fused pyrimidine derivatives 422-427, as described in Scheme 150.

Scheme 150

Synthesis of several new ring system derived from pyrazolo[1,5-a] pyrimidines 429 and 1,2,4-triazolo[3,4-a]pyrimidines 430 has been recently reported via the reaction of enaminonitrile 428 with cyclic amidines. The mechanism of the reaction involved was discussed, as deicted in Scheme 151 [320].

Scheme 151

Other syntheses of fused pyrimidines 431-433 from enaminonitriles are shown below [320-324], as outlined in Scheme 152.

Scheme 152

Synthesis of pyrazine derivatives: Only few examples for synthesis of pyrazines 434, 435 utilizing nitriles as starting materials have been reported. A demonstrated example for this synthesis approach is shown below [325,326], as outlined in Scheme 153.

Scheme 153

Synthesis of thiazine derivatives: Several new pyrolidino[1,2-a]- 3,1-thiazine-5,6-dione derivative 436 was synthesized via the reaction of 4-cyano-2,3-dioxo-5-thienopyrolidine 437 with a variety of activated nitriles, as depicted in Scheme 154 [327].

Scheme 154

Treatment of coumarinylmalononitrile 438 with bidentates, namely, guanidine hydrochloride, thiourea, thiosemicarbazide, thioacetamide and phenyl isothiocyanate in the presence of acetylacetone under phase transfer conditions gave the corresponding spiro coumarinyl-1,3- thiazine 439 and 440 [178], as outlined in Scheme 155.

Scheme 155

Six-membered rings with three heteroatoms: Several triazine syntheses starting from α,β-unsaturated nitriles have appeared in some literature [41,287,288]. An interesting example of these syntheses is shown in Scheme 156 [328,329].

Scheme 156

The recent wide applications of 2-propenoylamides, esters and 2-propenoyl chlorides in the synthesis of biologically and pharmacologically active compounds [330-340] and beside their uses in the synthesis of industriasl products make them worthy to be synthesized to obtain new structures of anticipated enhanced potency. Madkour et al. reported the reaction and uses of 3-(4′-methoxyphenyl) and 3-(2′-thienyl)-2-cyano-2-propenoyl chloride in heterocyclic synthesis, as described in Scheme 157.

Scheme 157

les have proved to be a rich source of various heterocyclic compounds, and the discovery of potential biologically active heterocyclic compounds has become increasingly probable. Starting from alkenyl nitriles, our current work is focussed on synthesising novel heterocycles with or without sulphur that have biological activities against different diseases. The search for cheaper and simpler methods to synthesis such new compounds are continuing.

This review has summarised some of the achievements in the field of heterocyclic compounds derived from alkenyl nitriles. Our knowledge of the chemistry and reactions of alkenyl nitriles remains shallow, however, and this field needs to be explored in more detail. Further studies and investigations by us or other workers should continue to provide a strong background in the chemistry and reactions of alkenyl nitriles.