Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

Review

Introduction

Electron-deficient alkenes form an important class of organic compounds, which are of key importance in organic synthesis. The best known representative of this class is tetracyanoethylene (TCNE) with numerous applications [1-3], and its role in cycloaddition reactions is of special interest. Dialkyl dicyanofumarates E-1 and dicyanomaleates Z-1 ((E)- and (Z)-butenedioates 1, Figure 1) are less known, but the availability of both stereoisomers is of great advantage for the exploration in mechanistic studies of their reactions. Similar to TCNE, these compounds are also attractive Michael acceptors with numerous applications for multistep reactions leading to heterocyclic products.

The chemistry of E-1 and Z-1 has not been reviewed, and the goal of the present survey is to summarize the methods of their preparation and their applications in organic syntheses. In addition, mechanistic studies of cycloaddition reactions performed with E- and Z-1 will be discussed.

Synthesis of dialkyl dicyanofumarates and maleates

Numerous methods for the synthesis of E-1 have been reported and cyanoacetates as well as their bromo and dibromo derivatives are the most important starting materials. The first described method comprised the treatment of ethyl cyanoacetate (2a) with SeO₂ at 120–125 °C, leading to E-1a in ca. 10% yield [4] (Scheme 1). More efficient syntheses of diverse dialkyl esters E-1 were achieved in reactions of alkyl cyanoacetates 2 with SOCl₂ in tetrahydrofuran (THF) at reflux temperature [5-8]. Unexpectedly, the attempted preparation of the di(tert-butyl) derivative was unsuccessful. The highest yield (90%) was obtained for E-1a when 2a was oxidized with I₂ in the presence of Al₂O₃·KF in acetonitrile at room temperature (rt) [9].

Another efficient method for the preparation of dialkyl esters E-1 relies on the usage of alkyl bromo(cyano)acetates 3, which upon treatment with potassium thiocyanate in aqueous acetonitrile at room temperature are converted into the corresponding E-1 [10] (Scheme 2).

Alternatively, the same transformation can be performed with 3 and thiourea derivative 4 in a two-step reaction through intermediate 5 [11] (Scheme 2). The latter, upon treatment with Et₃N, generates a carbene [:C(CN)CO₂Et], which dimerizes to give E-1a albeit in low yield.

The dimerization of the same carbene leading to a mixture of E- and Z-1a was observed when ethyl dibromocyanoacetate was treated with equimolar amounts of LiI in DMF at room temperature with the highest reported yield of 83% [12]. The dimethyl ester E-1b was also obtained selectively by treatment of dimethyl 2,3-bis(hydroxyiminomethyl)fumarate with (CF₃CO)₂O in dioxane in the presence of pyridine at 0–10 °C [13]. The starting material was prepared in a multistep reaction from methyl β-nitropropanoate.

An efficient method for the preparation of E-1b comprises the multistep reaction of dialkylselenonium (cyano)(methoxycarbonyl)methanide with episulfides [14] or thioamides [15]. Also, methyl cyanoacetate was reported to undergo both chemical (using (NH₄)₂Ce(NO₃)₆ = CAN in methanol) or electrochemical oxidation (Ce(NO₃)₃, HNO₃ in acetonitrile) yielding selectively E-1b in 68 and 77% yield, respectively [16].

However, the most efficient method for the synthesis of dialkyl dicyanomaleates Z-1 is the photochemical isomerization of the corresponding E-isomers. The reaction is performed in dichloromethane [17] and in the presence of benzophenone [18,19] or 1,4-dicyanobenzene [20] as photosensitizer.

The comparison of the methods for the synthesis of E- and Z-1 shows that the most convenient protocol is the treatment of the corresponding alkyl cyanoacetate with SOCl₂ and subsequent photoisomerization of the obtained E-1 into the Z-isomer.

Applications in organic synthesis

Reactions with carbenes; cyclopropanations

Dimethoxycarbene (6), generated in situ by thermal decomposition of 2,2-dimethoxy-2,5-dihydro-1,3,4-oxadiazole 7, reacts with E-1b yielding a mixture of the trans-configured tetramethoxycyclobutane 8 and 2,3-dihydrofuran 9 [21,22] (Scheme 3). The latter reacts further with dimethoxycarbene and converts into the orthoester 10 via insertion into the C–O bond. The reaction mechanism for the formation of 8 and 9 comprises the initial attack of the nucleophilic carbene onto the electron-deficient C atom of E-1b to give an intermediate zwitterion 11. The latter undergoes two competitive reactions. The first one is the ring closure leading to 9, and the second one involves the addition of a second carbene followed by ring closure to yield 8.

The reaction with Z-1b led to the same set of products with trans-orientation of the substituents in 8 indicating the appearance of an intermediate zwitterion 11. In contrast to the nucleophilic dimethoxycarbene, the formal transfer of the bis(carbomethoxy)carbene from the sulfur ylide 12 to E-1a leads to the cyclopropane derivative 13 [23] (Scheme 4). The reaction was proposed to occur stepwise via the zwiterrionic intermediate 14.

Another example of a similar transfer of a carbene unit was presented to explain the formation of cyclopropanes 15 in the reaction of E- and Z-1b with the in situ generated thiocarbonyl S-isopropanide 16a. The latter is formed through a thermal N₂ elimination from 2,5-dihydro-1,3,4-thiadiazole 17a [24,25] (Scheme 5). The mechanistic explanation of this cyclopropanation reaction is based on the assumption that the intermediate zwitterion 18a undergoes either a 1,3- or 1,5-electrocyclization leading to 15 or thiolanes 19a. The experiments with both isomers of 1b showed that the reactions proceeded non-stereospecifically and mixtures of isomeric cyclopropanes were obtained in each case.

The trans and cis-isomers of cyclopropane 15 were also obtained in reactions of 2-diazopropane with E-1b and Z-1b, respectively [25]. In that case, the formation of the cyclopropanes was stereospecific.

The formation of mixtures of thiolanes of type 19 and cyclopropanes of type 15 in which Me₂C is replaced by H₂C was observed when the sterically hindered S-methanide derived from 2,2,6,6-tetramethylcyclohexanethione was reacted with E- or Z-1b [26], whereas in the cases of 2,2,5,5-tetramethylcyclopentanethione and 1,1,3,3-tetramethylindane-2-thione, respectively, only cis/trans-thiolanes were formed [27].

In contrast, the reactions of E- and Z-1b with di(tert-butyl)thiocarbonyl S-methanide gave ca. 1:1 mixtures of cis/trans-cyclopropanes as products of the CH₂-transfer to the C=C bond in 82% yield [28]. The same products are formed in reactions with diazomethane albeit in very low yields [29].

[2 + 2]-Cycloadditions

The electron-deficient dicyanofumarates E-1 react with electron-rich ethenes, yielding cyclobutane derivatives as product of [2 + 2]-cycloadditions. Depending on the reaction conditions and on the type of the electron-rich ethene, the reaction occurs stereoselectively or with loss of the stereochemical arrangement of substituents. For example, 4-methoxystyrene (20) reacts with E-1b in 2,5-dimethyltetrahydrofuran in the presence of ZnCl₂ with complete stereoselectivity and the cyclobutane derivative 21 is formed as the sole product [30] (Scheme 6). The analogous reaction with phenyl vinyl sulfide (22) gave the expected cyclobutane 23 exclusively. However, in the absence of ZnCl₂, a mixture of 23 and 3,4-dihydro-2H-pyran 24 was obtained, with the latter compound formed through a competitive hetero-Diels–Alder reaction [30].

The competitive formation of cyclobutane and pyran derivatives was also observed in reactions of E-1b or Z-1b with ethyl prop-1-enyl ether performed in CDCl₃ at room temperature [31].

The reaction of N-vinylcarbazole (25) with E-1b or Z-1b in boiling benzene gave mixtures of four diastereoisomers of cyclobutanes 26 [20] (Scheme 7). The ratio of the isomers was the same irrespective of the configuration of 1b, indicating a stepwise reaction mechanism.

Non-concerted [2 + 2]-cycloadditions were reported to occur between E- and Z-1b and bicyclo[2.1.0]pentene (27) [32]. Whereas in the case of E-1b two cycloadducts 28 were identified in the mixture, the reaction with Z-1b afforded four diastereoisomers of type 28 (Scheme 8).

The observed stereochemical outcome was explained by a diradical mechanism with isomerization of the intermediate 29 taking place only in the reaction with Z-1b. As side products isomeric homo-Diels–Alder adducts were found in the mixture.

[3 + 2]-Cycloadditions (1,3-dipolar cycloadditions)

Electron-rich 1,3-dipoles such as thiocarbonyl S-methanides and azomethine ylides react with dipolarophiles E-1 and Z-1 to give five-membered cycloadducts through stepwise zwitterionic reaction mechanisms. The in situ generated sterically crowded thiocarbonyl S-methanide 16b in dry THF undergoes a [3 + 2]-cycloaddition with both E- and Z-1b forming mixtures of diastereoisomeric thiolanes 19b [19] (Scheme 9). However, in all studied cases, the configuration of the starting dipolarophile was preserved in the major cycloadduct. A non-concerted course of the reaction via the stabilized zwitterion 18b was proposed to rationalize this unexpected result. In an additional experiment performed in wet THF, mixtures of diastereoisomeric, spirocyclic seven-membered lactams 30b were isolated side by side with thiolanes 19b. Their formation proves the appearance of the labile seven-membered ketenimine 31b, which exists in equilibrium with zwitterion 18b. Ketenimine 31b is efficiently trapped with water to give 30b.

Analogous results were obtained with different thiocarbonyl S-methanides 16, generated from the corresponding precursors 17 with methyl, ethyl and isopropyl esters of type E- and Z-1 [19,33-36]. Remarkably, the reactions of (E)- and (Z)-1b with thiocarbonyl S-methanides 16b-e, in contrast to the corresponding S-isopropanide 16a (Scheme 5), occurred without formation of cyclopropane derivatives.

The treatment of methyl 3-methyl-2-oxodithiobutanoate with diazomethane at −80 °C in hexane/CH₂Cl₂ afforded the expected 2-sulfanyl-2-isobutanoyl-2,5-dihydro-1,3,4-thiadiazole. After the addition of E-1a and warming of the mixture to room temperature, the corresponding thiolane as the [2 + 3]-cycloadduct of the intermediate thiocarbonyl S-methanide onto the C=C bond was obtained. The reaction was reported to occur with complete stereoselectivity [37].

Thermally generated azomethine ylides 32, from 1,2,3-trisubstituted aziridines 33, were tested in [3 + 2]-cycloadditions with E- and Z-1b, and depending on the substitution pattern of the aziridine ring, the formation of the pyrrolidine derivative 34 occurred either with complete stereoselectivity or mixtures of isomeric products were obtained. The [3 + 2]-cycloaddition of the azomethine ylide E,Z-32a, formed via conrotatory ring opening of aziridine cis-33a, with E-1b yielded cycloadduct 34a exclusively through a concerted mechanism [38] (Scheme 10). In contrast, a more complex reaction of cis-1-methyl-2,3-diphenylaziridine (cis-33b) with both E- and Z-1b led to a mixture of stereoisomeric cycloadducts 34b. The same mixture of products was obtained starting from trans-33b. The formation of these isomeric products suggests that in the course of the reaction, isomerizations of both the intermediate azomethine ylide of type 32 as well as of the electron-deficient dipolarophiles E- and Z-1b, occur. The observed experimental results were rationalized by a computational study performed at the DFT B3LYP/6-31G(d) level of theory with the PCM solvation model [39].

The thermal [3 + 2]-cycloadditions of azomethine ylides derived from diethyl cis- and trans-1-(4-methoxyphenyl)aziridine-2,3-dicarboxylates with E-1b led to isomeric pyrrolidines with preserved configuration in the fragment of the former dipolarophile [39]. Furthermore, the configuration of the ester groups at C2 and C5 corresponded with the structure of the intermediate azomethine ylide predicted for thermal ring opening of the starting aziridine. Also in this series the experimental results were confirmed by computational methods.

In the reaction of diazomethane with E-1b in THF at room temperature 4,5-dihydro-3H-pyrazole 35 was detected as the initial [3 + 2]-cycloadduct by ¹H NMR spectroscopy [29] (Scheme 11). Fast tautomerization led to the corresponding 1H-pyrazole 36. The cycloaddition occurred with preservation of the configuration of the dipolarophile. In the presence of excess diazomethane the five-membered cycloadducts 35 and 36 were converted into a complex mixture of products.

In a very recent study, we demonstrated that the reactions of both E-1b and Z-1b with 9-diazofluorene at room temperature lead to mixtures of two isomeric cyclopropanes in each case. The major product obtained in the reaction with E-1b was identified as the corresponding trans-1,2-dicyanocyclopropane-1,2-dicarboxylate, the structure of which was established by an X-ray single crystal analysis. On the other hand, the major product isolated after the reaction with Z-1b was identified as cis-1,2-dicyanocyclopropane-1,2-dicarboxylate based on spectroscopic data [40]. This result suggests that the reactions follow a non-concerted pathway.

The presented studies on [3 + 2]-cycloadditions with dialkyl dicyanofumarates E-1 and maleates Z-1 are important from the point of view of the interpretation of reaction mechanisms of cycloadditions. The results obtained with electron-rich thiocarbonyl S-methanides 16 demonstrate that the classical concerted mechanism changes to non-concerted stepwise processes, which can involve zwitterionic or diradical intermediates.

[4 + 2]-Cycloadditions (Diels–Alder reactions)

In analogy to reactions with tetracyanoethene (TCNE), the first [4 + 2]-cycloadditions (Diels–Alder reactions) of E-1a were performed using typical 1,3-dienes such a buta-1,3-diene, isoprene, cyclopentadiene and anthracene. In all cases the reaction occurred at elevated temperature and afforded the expected cycloadducts in good to excellent yields [41]. The problem of the configuration of the substituents has not been discussed, but it seems likely that the homogeneous products are trans-configured. This assumption is supported by the results obtained with cyclopentadiene and both E- and Z-1b [32]. Whereas the reaction with E-1b led to only one stereoisomer, in the case of Z-1b, exo- and endo-isomers with preserved cis-orientation of the CN and CO₂Me substituents were formed.

Polycyclic products 35 were prepared through a concerted [4 + 2]-cycloaddition of E-1a with thiophene-functionalized fulvenes 36 [42] (Scheme 12). These cycloadducts are reported to undergo reversible intramolecular photocyclization to give products of type 37.

The formation of the thermolabile [4 + 2]-cycloadducts 38 was observed in reactions of some dialkyl dicyanofumarates E-1 with anthracene (39a) and 9,10-dimethylanthracene (39b) [8,43] (Scheme 13). In an experiment with 38b and tert-butyl tricyanoacrylate (40) in CDCl₃ at 25 °C an exchange of the dipolarophile leading to 41 was observed by ¹H NMR spectroscopy [8]. Similar systems were prepared on solid phase and used as a new molecular recognition system [44].

The [4 + 2]-cycloaddition reactions of E- and Z-1b with electron-rich 1,3-dienes have been studied extensively by Sustmann and collaborators. Thus, 1-methoxybuta-1,3-diene reacted with both dienophiles in a stereospecific manner, and in both cases mixtures of two stereoisomeric cyclohexenes with preserved stereochemistry in the dienophile fragment were obtained [45]. On the other hand, reactions with 1,1-dimethoxybuta-1,3-diene (42) led, in both cases, to similar mixtures of cycloadducts 43, however, with loss of stereochemistry of the used dienophiles (Scheme 14). These results were explained by a stepwise reaction mechanism proceeding through zwitterion 44 as an intermediate. This hypothesis was confirmed by a trapping experiment with MeOH, which afforded 1,1,1-trimethoxy derivative 45.

In analogy to 1-methoxybuta-1,3-diene, 1-(dimethylamino)buta-1,3-diene was reacted with E- and Z-1b in CH₂Cl₂ at −50 °C yielding a single cycloadduct, which exists in equilibrium of two conformers as characterized by ¹H NMR spectroscopy [46]. In the case of Z-1b, the initial isomerization to E-1b, induced by the basic nature of the Me₂N group, is a likely explanation for the observed result.

In extension of the study with amino-substituted electron-rich 1,3-dienes, reactions were also performed with 1,4-bis(dimethylamino)buta-1,3-diene. These required low temperature (ca. −50 °C) to avoid the formation of complex product mixtures. Based on the ¹H NMR analysis, only one product, identical in reactions with E- and with Z-1b, was formed [47]. Also bis(dimethylamino)-substituted 1,3-dienes including bicyclic representatives were used for reactions with E- and Z-1b [48,49]. Herewith the formation of the [4 + 2]-cycloadducts occurred non-stereospecifically and mixtures of stereoisomeric products resulting from a stepwise mechanism were obtained. In order to find proofs for the postulated reaction pathways, supporting kinetic, spectroscopic and computational studies were carried out [45,48,50,51].

A stepwise reaction has also been suggested for the formal [4 + 2]-cycloaddition of E- and Z-1b with ethyl prop-1-enyl ether leading to a mixture of the corresponding 3,4-dihydro-2H-pyran and cyclobutane derivatives in a non-stereospecific manner [31].

A mechanism with the radical intermediate 46 governs the formal [4 + 2]-cycloaddition reaction of E-1b with 3,4-di(α-styryl)furan (47, Scheme 15). The photoinduced reaction occurs via an electron-transfer (PET) process and led to the formation of the polycyclic product 48 in a stereospecific manner [52]. Similar products were obtained as well with less electron-deficient dienophiles such as dimethyl fumarate and maleic anhydride.

Michael-type reactions

Enolizable ketones 49 react with E-1 in ethanolic solution in the presence of HCl to yield, after heating for 5 h, the corresponding Michael adduct 50 in 68–76% yield [53] (Scheme 16). These reactions were performed using both acyclic and cyclic ketones. In the case of dimedone, the reaction was carried out in ethanol at room temperature overnight [54].

Remarkably, N,N-dialkylanilines in DMF solution at 50–60 °C also react with E-1a as Michael donors to give diethyl 2-(4-dialkylaminophenyl)-2,3-dicyanosuccinates [55]. Heating these adducts with aqueous Na₂CO₃ solution results in elimination of HCN leading to the corresponding ethene derivatives.

The electron-deficient dialkyl dicyanofumarates E-1 undergo smooth reactions with N-nucleophiles, such as ammonia, primary and secondary amines, hydrazine, and carbohydrazides. In some of these reactions, the initially formed adducts, after subsequent elimination of HCN, undergo heterocyclization (see chapter Heterocyclization reactions). The reaction of E-1a with either aqueous ammonia or gaseous NH₃ in acetonitrile leads to the enamines 51 [56] (Scheme 17). Further reaction with excess NH₃ gives rise to the corresponding monoamide 52. Analogous reactions with differently substituted anilines and β-naphthylamine, respectively, afforded the corresponding enamines of type 51, when the amine was used in excess.

On the other hand, the reactions of E-1a and an aromatic amine in a ratio of 2:1 led, unexpectedly, to the formation of another enamine with two cyano and one ester group. Notably, in the case of 4-nitroaniline, no reaction was observed. However, in another publication, the formation of an enamine of type 51 was described when E-1a was treated with the 4-nitroaniline anion in DMSO [57].

Diverse primary and secondary amines were reacted with dialkyl dicyanofumarates E-1 in CH₂Cl₂ at room temperature (molar ratio ca. 1:1), and enamines containing two ester and one cyano group were formed as exclusive products in good to high yields. The X-ray analysis showed that products 53 obtained with primary amines are Z-configured whereas those derived from secondary amines, 54, display E-configuration [58] (Scheme 18). The observed different configurations demonstrate the importance of the intramolecular hydrogen-bond between the NH and ester groups.

The reactions of E-1 with morpholine performed in the presence of equimolar amounts of strained 1-azabicyclo[1.1.0]butanes 55 afforded enamines 56 containing both amine units [58] (Scheme 19). Their structures evidence that the first reaction step is the Michael-type reaction of 55 leading to a zwitterionic intermediate 57, which is trapped by morpholine to give the adduct 58. The latter eliminates HCN and converts to enamine 56. The postulated pathway was supported by a similar experiment, in which methanol replaced morpholine as a trapping reagent [58,59]. An interesting observation was made when less nucleophilic anilines were used as trapping agents. The formation of adducts of type 56 proceeds in competition with the trapping reaction by a second molecule of 55 leading to the homologue enamine 59 [60].

Finally, reactions performed with 55 in the absence of any trapping reagent yielded 1-azabicyclo[2.1.1]hexanes 60 as products of an intramolecular cyclization of the intermediate zwitterion 57. In all cases, these products were obtained as mixtures of cis-and trans-stereoisomers in favor of the trans-isomer [59,61].

Another class of nucleophilic reagents used for reactions with E-1b is hydrazine and its derivatives. The parent hydrazine used as the hydrate reacts with E-1 in ethanol at room temperature, and in the case of diisopropyl dicyanofumarate (E-1c), the crystalline enehydrazine was isolated in 82% yield [62]. In addition, the N-benzyl-protected (S)-proline hydrazide took part in the reaction in CH₂Cl₂ solution at room temperature, and after the addition–elimination sequence, the corresponding enehydrazide, analogous to enamines 53/54, was obtained in 56% yield [63]. The configuration of this enehydrazide has not been proved, but the course of its heterocyclization suggests the E-configuration (see following chapter).

Heterocyclization reactions

Due to the presence of six electrophilic centers, dialkyl dicyanofumarates E-1 are useful starting materials for reactions with dinucleophilic reagents, which in one-pot procedures lead to diverse heterocyclic products (tandem reactions). These reactions occur through an initial formation of the Michael-type adduct followed by a heterocyclization step upon involvement of either a cyano or an ester group as a second electrophilic center.

Hydrazine is a powerful dinucleophile and reacts easily with E-1 in ethanol at room temperature yielding, after spontaneous elimination of HCN, the corresponding enehydrazine derivatives 61 [62] (Scheme 20). In case of the sterically less crowded E-1a,b these products immediately undergo a heterocylization through a selective attack of the NH–NH₂ group onto the vicinal Z-oriented ester group. The only products obtained are 1,2-dihydropyrazole-3-carboxylates 62 in good yield.

Interestingly, reactions with arylhydrazines afforded, in the presence of ammonium or sodium acetate, 5-aminopyrazole-3,4-dicarboxylates 63 [64] (Scheme 20). Apparently, in these cases, the intermediate enehydrazines 61 undergo an alternative heterocyclization involving the cyano group. This result suggests that the E-configuration should be attributed to these enehydrazines 61 (R¹ = Ar).

Carbohydrazides were widely applied for reactions with E-1. The enehydrazide 64, derived from N-benzylproline hydrazide, in the presence of ethanol, undergoes a cyclization reaction yielding the aminopyrazole 65 in 44% yield [63] (Scheme 21). The explanation of the reaction course is based on the assumption that under the reaction conditions ethanolysis of the carbohydrazide occurs and the formed enehydrazine 61 (R¹ = H) converts into product 65. The analogous reaction sequence was observed when E-1b was treated with hydrazide 66 in ethanolic solution at room temperature. These results show that enehydrazides of type 64, very likely, exist as E-isomers, because the enehydrazine formed after ethanolysis has to be E-configured to enable cyclization with the CN group.

An analogous reaction pathway was also described for the formation of 5-amino-1-carbamoylpyrazole-3,4-dicarboxylates from dialkyl dicyanofumarates E-1 and semicarbazide hydrochloride in boiling ethanol solution in the presence of sodium acetate [64]. The yields of the products are in the range of 57–72%.

A different type of heterocyclization was reported in the reactions of carbohydrazides 67 derived from benzoic acid and some hetarylcarboxylic acids with E-1a [65,66]. In these cases, the formation of mixtures of two products is described, and in both cases pyrazol-3-ones 68 were obtained in ca. 35% yield (Scheme 22). The heterocyclization leading to 68 occurs in the intermediate enehydrazide 69 through the nucleophilic attack of the N-atom onto the ester group. The second product was postulated either as a 2,3-dihydro-1,3,4-oxadiazole-2-carboxylate 70 [65] or 2-(6-oxo-4H-1,3,4-oxadiazin-5(6H)-ylidene)acetate 71 [66].

The reaction of E-1a with 1-benzyl-1-phenyl or 1-allyl-2,5-dithiobiurea in THF at 20 °C is reported to produce, via multistep conversions, mixtures of 6H-1,3,4-thiadiazine derivatives containing only half of the starting fumarate [67].

Differently substituted piperazin-2-ones can be efficiently prepared by reacting dialkyl dicyanofumarates E-1 with alkane or cycloalkane-1,2-diamines. For example, the reaction with trans-cyclohexane-1,2-diamine (72) performed in acetonitrile at room temperature for 30 min gave the bicyclic piperazine (quinoxaline) derivative 73 in 61% yield [68] (Scheme 23). The analogous reaction with [(S)-pyrrolidin-2-yl]methylamine ((S)-prolinamine) with E-1a–c occurred smoothly in CH₂Cl₂ at room temperature yielding optically active (4-oxohexahydropyrrolo[1,2-a]pyrazin-3-ylidene)-2-cyanoacetates as single stereoisomers (79% yield) [63].

The same reaction pathway was observed in reactions with aromatic 1,2-diamines. For example, starting with benzene-1,2-diamine, the corresponding 2-oxo-1,2,3,4-tetrahydroquinoxaline derivatives, analogous to 73, were obtained in high yields as Z-isomers exclusively [69]. In the case of the isomeric 2,3- and 3,4-diaminopyridines, the initial addition reaction occurred via the attack of the more nucleophilic NH₂ group at the 3-position [69].

Less nucleophilic 1,2-diamines, such as 5,6-diaminouracil and -thiouracil or 1,2-diaminobenzimidazole, react with E-1 in a different way, and 7-aminopteridin-6-carboxylates are formed. For example, 5,6-diaminouracil (74, R¹ = H) and E-1a react in boiling ethanol within 1 h to give the heterocyclic product 75 (R¹ = H) in 65% yield [70] (Scheme 24). The mechanistic interpretation of this conversion comprises the elimination of cyanoacetate instead of HCN from the primary adduct 76. The subsequent heterocyclization of 77 occurs via nucleophilic attack of the NH₂ group onto the CN group, and H-migration then leads to the products 75.

Another class of dinucleophilic reagents rarely used in reactions with E-1 is that of β-aminoalcohols. The different nucleophilicity of the NH₂ and OH groups determines the sequence of the reaction steps. In the reported cases, the initially formed N-(β-hydroxyalkyl)enamines 79 undergo spontaneous lactonization with the geminal alkoxycarbonyl group leading to the six-membered morpholin-2-one derivatives 80 as the only products [62] (Scheme 25). In one case, the stereochemical structure of the product was established by X-ray determination.

An interesting reaction course was observed in the reaction of E-1 with 3-amino-5-arylpyrazoles 81, which are known to react as N or C nucleophiles. The type of the products obtained depended on the reaction conditions. Whereas heating in 1,2-dichloroethane (85 °C) or stirring in DMF at room temperature afforded mixtures of hetero-bicyclic products 82 and 83 in favor of 82, reactions performed in DMF at 100 °C led to 82 as the sole product [6] (Scheme 26). The formation of the products is initiated by the nucleophilic attack of either C4 or NH₂ of 81 onto E-1, followed, in both cases, by elimination of HCN to give intermediates 84 and 85, respectively. The heterocyclization leading to 82 is a lactamization, whereas a ring closure via N attack onto the terminal cyano group in 85 results in the formation of the minor product 83.

Another example of a heterocyclization, which occurs with participation of an N- and a C-nucleophile was reported for the reaction of E-1a and thiosemicarbazone 86, derived from furfural. This reaction, performed in ethyl acetate at room temperature, led to a mixture of pyrazolone 87 and pyridazine 88 in favor of the former compound (54%) [71] (Scheme 27).

Heating equimolar amounts of E-1a and dimedone (89) in ethanol at reflux for 8 h afforded 4H-pyran 90 as the heterocyclization product of the initially formed succinate 91 (see chapter Michael type reactions) [54] (Scheme 28). In this case, the reaction pathway comprises the ring closure through the attack of the O-nucleophile onto the terminal cyano group. The analogous reaction was reported for the enolizable indane-1,3-dione.

Redox reactions

The replacement of β-aminoalcohols by β-aminothiols in reactions with dialkyl dicyanofumarates E-1 led, unexpectedly, to products containing a disulfide group together with enamine units. For example, the reaction with cysteamine (92) with E-1a in CH₂Cl₂ at room temperature gave the disulfide 93 in 42% yield [72] (Scheme 29).

Similar reactions performed with β-mercaptoalcohols, e.g., 1-mercaptopropan-2-ol (94), took place smoothly at room temperature, and the corresponding dihydroxydisulfides (e.g., 95) were formed side-by-side with diethyl 2,3-dicyanosuccinates (96, Scheme 30). Finally, when 1,2-dithiols of type 97 were subjected to reactions with E-1a under the same reaction conditions, cyclic disulfides 98 were obtained as products of a redox reaction [72].

The analogous reaction course was observed with selenols, which were converted into the corresponding diselenides in good yields.

The formation of disulfides and diselenides is explained as a redox process through a single-electron transfer (SET) mechanism with E-1a as the oxidizing reagent, which converted into a mixture of diastereoisomeric diethyl dicyanosuccinates 96 [72]. Very likely, an analogous SET mechanism governs also the reaction of E-1 with diethyl phosphite in boiling 1,2-dichloroethane leading to the dialkyl dicyanosuccinates 96 [7].

Charge-transfer (CT) complexes

Dialkyl dicyanofumarates E-1, similar to tetracyanoethylene (TCNE), are well-known as one-electron acceptors. They react with metallocenes 99, such as manganocenes [73,74] and chromocenes [75], to form one-to-one charge-transfer salts 100 (Scheme 31), which are molecular magnets. Their physical properties depend on the size of the alkyl groups of the ester function [73]. Some chromocene complexes with E-1a,b were studied by means of X-ray crystallography [74,76].

Dialkyl dicyanofumarates E-1 form also CT complexes with electron-rich non-conjugated dienes such as hexamethyl Dewar benzene [77,78], as well as indene and acenaphthylene [79]. These complexes were used for photochemical studies, e.g., the photoisomerization of Dewar benzenes into the corresponding aromatic systems.

Miscellaneous reactions

The oxidation of E-1a with H₂O₂ in acetonitrile gave oxirane 101, which subsequently was used for reactions with diverse nucleophiles [80] (Scheme 32). Upon treatment with diheptyl sulfide, 101 was transformed into ethoxalyl cyanide (102) [81].

The aziridination of E-1b through the addition of in situ generated aminonitrene leading to aziridine 103 bearing the phthalimido residue at the N-atom was also reported [82] (Scheme 33).

Conclusion

Dialkyl dicyanofumarates and dicyanomaleates, which belong to the group of strongly electron-deficient alkenes, are versatile building blocks for the synthesis of diverse carbo- and heterocycles through [2 + 2], [3 + 2] and [4 + 2]-cycloaddition reactions, functionalized with ester and cyano groups. The high ability for stabilization of radical and carbanionic centers leads, in many instances, to the violation of the classical concerted cycloaddition mechanisms. The accessibility of both stereoisomers offers a unique opportunity to prove mechanistic pathways experimentally. Furthermore, dialkyl dicyanofumarates are good Michael acceptors and easily react with N- and C-nucleophiles. Their reactions with dinucleophiles, such as 1,2-diamines and β-aminoalcohols are of special importance as they offer access to a variety of heterocycles through an addition–elimination–heterocyclization sequence. Their ability to act as single-electron acceptors, demonstrated in the reaction with thiols and selenols, allows their application as oxidizing reagents. In addition, this property allows the preparation of charge-transfer salts with manganocenes and chromocenes, which are of interest as molecular magnets.