The Chemistry of Alkenyl Nitriles and its Utility in Heterocyclic Synthesis

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].


Introduction
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] 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.

Preparation of Alkenyl Nitrile and Aryl Nitrile Derivatives
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. 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.

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 Et 2 AlCN [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. 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(CCl 3 )=NH) in the Houben-Fischer synthesis [28][29][30][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 tertbutanol. 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]. 11 toluene 50 o C, 16 hrs 0.01 eq. Ni(cod) 2 0.02 eq. PPhMe 2 0.04 eq. Me 2 AlCl

Synthesis 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][35][36][37][38][39][40][41][42][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-3carbonitrile 14 in a moderate yield via the reaction [44] of with ammonium benzyl dithio-carbamate 15, as outlined in Scheme 5.

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 Scheme 7 Formation of thiophenes 22 from the reaction of α−β-unsaturated nitriles with thioglycollic acid has been reported [50][51][52][53]. Tetracyanoethylene 23 has been reported to react with hydrogen sulphide [54,55] to produce the thiophene derivative 24 in moderate yields 68%. 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]. 25 S

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][57][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 20
Compound 27a was examined against hydroxylamine hydrochloride to yield a mixture of the aldoxime 61 and the aminoisoxazole derivatives 62 [99].

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][110][111]. The intermediate phenylhydrazone derivative 77 was isolated together with 78 on reaction of 27 (Ar = p-O 2 N-C 6 H 4 -) with phenylhydrazine. El-Nagdy et al. [112][113][114] have reported that 27 (Ar = p-Me 2 N-C 6 H 4 -) 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 benzylideneω-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 (R 1 = H, R 2 = Ph, R 3 = CONH 2 ) was formed in addition to benzaldehyde phenylhydrazono, as described in Scheme 27.

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]

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,. Examples for the most interesting of these syntheses are shown in 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. 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 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. under the applied conditions in contrast to the previous case [150], the product is depicted in Scheme 41. 122 123

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. 128 129

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][161][162].

Scheme 46
Mahmoud et al. [163] reported that equimolar amounts of 1-phenyl-3-methylpyrazolin-5-one 125 and α-cyano-3,4,5trimethoxycinnamonitrile 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. 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. 13 C-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  [151]. Similar results have been reported on treatment of 125 derivatives with 144, as depiected in Scheme 49 [160].
Excellent yield of pyranopyrazole derivatives 149 were obtained upon treatment of nitrile 27 with 125 [169], and is depicted in Scheme 51. 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]. During the course of our investigations on the use of DAMN in heterocyclic synthesis, we designed new approaches to 4-cyano-1,3dihydro-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)-4methylbenzenesulfonamide, 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 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 0ºC in dioxane gave the pyrazolo [  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. 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][182][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 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.

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.   13 C-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 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/K 2 CO 3 /TBAB) yielded pyridinone and pyridine-2-thione derivatives 221 [105,215], as shown in 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. 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 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 C 11 H 8 N 4 . 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 1 H-NMR spectra. The obtained products beer several functional substituents and appear promising for further chemical transformations, as outlined in Scheme 83.

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 1 H-NMR and 13 C-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][227][228][229][230][231][232][233][234][235][236], as outlined in Scheme 86.  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.  El-Nagdy et al. [239] reported that 3-amino-2-cyano-4ethoxycarbonyl 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 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 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

Scheme 105
The reaction of 3-aminoacrylonitriles derivative 315 with ethoxymethylene malononitrile in chloroform or dichloromethane at temperature below 0ºC and 5ºC 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-

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]. 319
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 124
Cycloaddition of substituted phenols with the nitriles derivative gave the 3-cyanocoumarin derivatives 359 is depicted in Scheme 125 [281,282].

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 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]. The isolation of several other side products, depending on the nature of the oxoalkanenitrile, has been reported [298][299][300][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]. 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. 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. 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. 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][314][315][316][317][318][319][320][321][322][323][324]

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 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].

Conclusion
Alkenyl nitriles 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.