Introduction

Barbiturates and spirobarbiturates have attracted intense interest due to their useful biological and pharmacological properties, such as being anticonvulsant, antiepileptic, hypnotic, anti-invasive, antiangiogenic, and anticancer agents [1, 2]. 5-Benzylbarbituric acid derivatives have potential usefulness in the therapy of cancer and AIDS, as well as other pathological and physiological disorders [3].

Scheme 1
scheme 1

Structures of TBBDA, PBBS, TCBDA, and PCBS

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Spirobarbiturate compounds also play an important role as a basic skeleton for the design of a number of central nervous system (CNS) depressant agents, dihydroorotate dehydrogenase (DHODase), and matrix metalloproteinases (MMPs) inhibitors and the construction of modified oligonucleotides [4, 5].

A number of synthetic approaches to spirocyclopropanes and cyclopropanes have been reported, which include transition metal-catalyzed cyclopropanation of alkenes with diazo compounds, domino aldol/Horner–Wadsworth–Emmons reaction, 1,3-dipolar cycloaddition, Diels–Alder, Simmons–Smith reaction, reaction of alkenes with free carbenes, carbenoids, or ylides, for example, phosphorus, sulfur, arsenic, and henyliodonium ylides [6–10].

Table 1 Optimization of the cyclopropanation of benzylidenemalononitrile 1g with barbituric acid 2 using N-halosulfonamides and basic additives
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Table 2 Solvent effects on the cyclopropanation of benzylidenemalononitrile 1g with barbituric acid 2 using N-halosulfonamides
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Table 3 Synthesis of spirocyclopropylbarbiturates 3a–o using N-halosulfonamides
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Michael-initiated ring closure (MIRC) is one of the most important strategies for the construction of cyclopropane rings [11]. Several methods have been developed for the synthesis of spirodicyanocyclopropyl barbiturates involving the reaction of electron-deficient alkenes with dibromomethylene compounds activated by cyano and ester groups in the presence of LiI or tetrabutylammonium bromide in DMF [12], the reaction of benzylidenemalononitriles with \({ N,N}^{\prime }\)-dialkylbarbituric acids in the presence of bromine and sodium ethoxide in ethanol [13], the combined electrolysis of benzylidenemalononitriles or benzylidenecyanoacetates and barbituric acids in methanol in the presence of sodium bromide [14], and the electrolysis of aldehydes, malononitrile, and barbituric acids in alcohol in the presence of sodium bromide [15].

The methods for 3-substituted-1,1,2,2-tetracyanocyclopropane synthesis have been divided into four main groups: the interaction of 2,2-dibromomalononitrile with carbonyl compounds, the reaction of alkylidenemalononitriles or arylidenemalononitriles with bromomalononitrile, the action of free halogen or active halogen-containing compounds on benzylidenemalononitriles and malononitrile, and the direct transformation of carbonyl compounds and malononitrile for the preparation of 3-substituted-1,1,2,2-tetracyanocyclopropanes by the action of free halogen or active halogen-containing compounds [16–24].

As halogenated organic compounds are particularly significant from the standpoint of biological activity provided a specific site of an organic molecule is substituted with a halogen atom(s), many attempts have been made to develop new methods and reagents for selective halogenation. In this regard, a large number of compounds called N-halo reagents have been widely used in organic transformations and in the chemistry of natural compounds [25]. Some halogenating agents require special equipment and techniques because of their explosive, toxic, unstable, and hygroscopic qualities but N-halo sulfonamides are easy to handle and only half of their halogens are consumed, as in the case of elemental halogen [26].

Results and discussion

Based on the above facts and in continuation of our previous studies on the application of N-halo reagents in organic synthesis [27–30], we now report convenient methods for the cyclopropanation of 2-arylidenemalononitriles 1 with barbituric acids 2 and cyclopropanation of carbonyl compounds 6 with malononitrile 5 using \(N{,}N{,}N^\prime {,}N^\prime \)-tetrabromobenzene-1,3-disulfonamide [TBBDA], poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS], \(N{,}N{,}N^\prime {,}N^\prime \)-tetrachlorobenzene-1,3-disulfonamide [TCBDA], and poly(N-chloro-N-ethyl-benzene-1,3-disulfonamide) [PCBS] (Scheme 1).

The reaction of benzylidenemalononitrile 1g as a model compound with barbituric acid 2 was examined under various reaction conditions (Table 1). First, the effect of various bases was investigated (Table 1, entries 1–7). The best yield of cyclopropane 3g was achieved using NaOAc (Table 1, entry 7). We also found that 1.0 mmol of NaOAc, and 0.25 mmol of TBBDA were sufficient and no improvement in the reaction rate was observed by increasing the amount of them (Table 1, entries 8 and 9). Other halogen sources such as PBBS, TCBDA, and PCBS, were also screened. All of them gave the final product in good to high yields (Table 1, entries 10–12).

Next, solvent effects on the cyclopropanation of benzylidenemalononitrile 1g with barbituric acid 2 were examined by applying the optimized conditions (Table 1, entry 7). In this context, \(\hbox {H}_{2}\hbox {O/EtOH}\) (1:3) is the preferred choice as a solvent system (Table 2, entry 6). When the reaction was carried out at higher temperature (\(50\,^{\circ }\hbox {C}\) or refluxing the entire reaction mixture for 10 min) gave the same results as the room-temperature reaction in \(\hbox {H}_{2}\hbox {O/EtOH}\) (1:3) (Table 2, entries 7 and 8). Therefore, this reaction was most efficient when using benzylidenemalononitrile 1g (1.0 mmol), barbituric acid 2 (1.0 mmol), TBBDA (0.14 g, 0.25 mmol), and NaOAc (1.0 mmol) in \(\hbox {H}_{2}\hbox {O/EtOH}\) (1:3) (2 mL) at room temperature (Table 2, entry 6).

After optimization of the reaction conditions, in order to study the generality of the procedure, various 2-arylidenemalononitriles 1 and barbituric acid or 1,3-dimethylbarbituric acid 2 were submitted to these reaction conditions and provide corresponding spirocyclopropylbarbiturate derivatives 3a–o in good to high yields (Table 3).

Scheme 2
scheme 2

Cyclopropanation of 5-arylidenebarbituric acids 4 with malononitrile 5 using N-halosulfonamides

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Scheme 3
scheme 3

Proposed mechanism for the synthesis of spirocyclopropylbarbiturates

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Table 4 Performance comparison of various methods for the preparation of 2-(2-chlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3h
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Replacing barbituric acid 2 (\(\hbox {R} = \hbox {H}\)) with 1,3-dimethylbarbituric acid 2 (\(\hbox {R} = \hbox {Me}\)) produced the corresponding dimethyl derivatives in a shorter time (Table 3). The reason for longer time in producing the desired products with barbituric acid 2 is probably due to N–H hydrogen atoms which are acidic. The acidity results from the ability of the N to lose hydrogen and the stabilization of the resulting anionic charge of the conjugate base by resonance delocalization [31].

On the other hand, we explored the formation of spirocyclopropylbarbiturates 3 from 5-arylidenebarbituric acids 4 and malononitrile 5 under these reaction conditions (Scheme 2). In our protocol, benzaldehyde and barbituric acid 2 were stirred in water and heated at reflux until the reaction was completed (reaction progress monitored by TLC) [32]. Then, the reaction of 5-benzylidenebarbituric acids 4 with malononitrile 5 under the optimal reaction conditions produced corresponding spirocyclopropylbarbiturates 3 in good to high yields (85–97 %) similar to the results of the reaction between 2-arylidenemalononitriles 1 and barbituric acid 2 under the optimized conditions (Scheme 2).

Table 5 Cascade one-pot transformation of carbonyl compounds 6a–p and malononitrile 5 into 3-substituted-1,1,2,2-tetracyanocyclopropanes 7a–p
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Since the procedure for the preparation of 2-arylidenemalononitriles 1 has several advantages such as short reaction times, easy work-up, high yields, and pure products compared to the preparation of 5-arylidenebarbituric acids 4, we preferred to carry out synthesis of spirocyclopropylbarbiturates 3 using of 2-arylidenemalononitriles 1 and barbituric acids 2 under the optimized conditions.

Based on these results, a plausible reaction pathway for the cyclopropanation 2-arylidenemalononitriles 1 with barbituric acids 2 using N-halosulfonamides is shown in Scheme 3. First, deprotonation of barbituric acid 2 with the use of an acetate anion in aqueous ethanol gives the barbiturate anion A. Michael addition of the barbiturate anion A to the \(\beta \)-carbon position of 2-arylidenemalononitrile 1 as an \(\alpha ,\beta \)-unsaturated compound afforded intermediate B. The intermediate B should exist in equilibrium with intermediate C by the proton migration possible under the conditions studied. Then, halogenation of the intermediate C with the use of N-halosulfonamides as sources for electrophilic halogens occurs to give the intermediate D. In the presence of base, deprotonation of intermediate D takes place leading to the formation of intermediate E. Intramolecular C-attack of carbanion E to carbon atom containing bromine atom as an electrophile produces spirocyclopropylbarbiturates 3 [14, 33].

To demonstrate the efficiency of the described method in comparison with formerly reported procedures in the literature, we compared the results obtained in the preparation of 2-(2-chlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3h with those of other methods (Table 4). The results clearly indicate that the use of TBBDA is an efficient method for the synthesis of spirocyclopropylbarbiturates. We observed significant decrease of reaction time, product purity, and thus cost efficiency.

In the next stage of our investigation, we decided to test the multicomponent transformation of benzaldehyde, malononitrile 5, and barbituric acid 2 into 4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3g. When the reaction was carried out under these conditions, a complex mixture of compounds was found in the end of the reaction (reaction progress was monitored by TLC) and the major product was 3-phenylcyclopropane-1,1,2,2-tetracarbonitrile 7c (49 %). Undoubtedly, the nucleophilic attack of the second molecule of malononitrile 5 to the benzylidenemalononitrile 1 takes place faster than the nucleophilic attack of barbituric acid 2 under the given reaction conditions. Herein, we report an effective and simple domino procedure for cyclopropanation of carbonyl compounds 6 with malononitrile 5 using N-halosulfonamides and sodium acetate in \(\hbox {H}_{2}\hbox {O/EtOH}\) at room temperature (Table 5).

It was shown that the aromatic aldehydes reacted faster than the ketone compounds (Table 5, entries 1–6). Moreover, in most cases, when a carbonyl group conjugated with an aromatic ring or a double bond, the corresponding 3-substituted-1,1,2,2-tetracyanocyclopropanes were achieved in a longer time (Table 5, entries 8, 10–13 and 16). Because of that extra stability, it might not be surprising that conjugated carbonyls are often a little slower to react than regular carbonyls.

Scheme 4
scheme 4

Proposed mechanism for the synthesis of 3-substituted-1,1,2,2-tetracyanocyclopropanes

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A possible mechanism for the cyclopropanation of carbonyl compounds 6 with malononitrile 5 using N-halosulfonamides is shown in Scheme 4. First, the Knoevenagel condensation of the carbonyl compound 6 with malononitrile 5 leads to the formation of alkylidenemalononitrile A. On the other hand, deprotonation of the second molecule of malononitrile 5 occurs to give dicyanocarbanion B in aqueous ethanol with the use of base. Michael addition of dicyanocarbanion B to the \(\beta \)-carbon position of alkylidenemalononitrile A as an \(\alpha \),\(\beta \)-unsaturated compound afforded intermediate C. Thereupon, halogenation of the intermediate C with the use of N-halosulfonamides as sources for electrophilic halogens occurs to give the intermediate D. In the presence of base, deprotonation of intermediate D takes place leading to the formation of intermediate E. Intramolecular C-attack of carbanion E to carbon atom containing bromine atom as an electrophile produces 3-substituted-1,1,2,2-tetracyanocyclopropanes F (Scheme 4, path a). Under these reaction conditions, cyclobutanation of carbonyl compounds 6 with the C-attack of carbanion E to nitrile group did not occur (Scheme 4, path b) [10, 23].

Conclusions

In conclusion, simple and highly efficient methods for the synthesis of spirocyclopropylbarbiturates by cyclopropanation of 2-arylidenemalononitriles 1 with barbituric acids 2 and synthesis of substituted-1,1,2,2-tetracyanocyclopropanes by cyclopropanation of carbonyl compounds 6 with malononitrile 5 using \(N{,}N{,}N^\prime {,}N^\prime \)-tetrabromobenzene-1,3-disulfonamide [TBBDA], poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS], \(N{,}N{,}N^\prime {,}N^\prime \)-tetrachlorobenzene-1,3-disulfonamide [TCBDA], and poly(N-chloro-N-ethyl-benzene-1,3-disulfonamide) [PCBS] were developed. These methods offer several significant advantages, such as being inexpensive reagents, high yield, high atom economy, ease of product isolation, environmental friendliness (non-corrosive reagents) which make them useful, and attractive processes for the rapid synthesis of 4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles, 5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles and 3-substituted-1,1,2,2-tetracyanocyclopropane derivatives.

Experimental

Melting points were measured with a digital melting point apparatus (Electrothermal) and are uncorrected. Mass spectra were recorded on a Shimadzu QP 1100 BX Mass Spectrometer (University of Tehran, Iran). \(^{1}\hbox {H}\) and \(^{13}\hbox {C}\)-NMR spectra were recorded on Bruker Advance 400 FT NMR spectrometers (undertaken at University of Isfahan, Iran) at 400 and 100 MHz spectrometer in DMSO-\(d_{6}\), respectively. Chemical shift values are reported in parts per million relative to the internal standard of tetramethylsilane (TMS); s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sep (septet), m (multiplet); J in Hertz (Hz). Infrared (IR) spectroscopy was performed on a Perkin Elmer GX FT-IR spectrometer in KBr pellets. All starting materials were obtained from commercial sources and used without purification.

General procedure for preparation of 4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile and 5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile derivatives 3a–o using N-halosulfonamides

A mixture of 2-arylidenemalononitriles 1 (1 mmol), barbituric acid (0.128 g, 1 mmol) or 1,3-dimethylbarbituric acid 2 (0.156 g, 1 mmol), sodium acetate (0.08 g, 1 mmol), TBBDA (0.14 g, 0.25 mmol) or PBBS (0.2 g) or TCBDA (0.1 g, 0.25 mmol) or PCBS (0.15 g) in \(\hbox {H}_{2}\hbox {O/EtOH}\) (2 mL) (1:3) was placed in a test tube. The mixture was stirred at room temperature for the appropriate time specified in Table 3. After completion of the reaction [monitored by TLC (5:2, n-hexane/acetone)], the precipitate was filtered off, washed with ethanol (\(2 \times 1\) mL), and dried under reduced pressure to isolate pure spirocyclopropylbarbiturates. The filtrate was evaporated, washed with hot water, \(\hbox {CH}_{2}\hbox {Cl}_{2}\) (3 mL) was added, and the precipitated sulfonamide was removed by filtration. The sulfonamide was rehalogenated and used for several times.

General procedure for preparation of 3-substituted-1,1,2,2-tetracyanocyclopropanes 7a–p using N-halosulfonamides

A mixture of carbonyl compound 6 (1 mmol), malononitrile 5 (0.13 g, 2 mmol), sodium acetate (0.08 g, 1 mmol), TBBDA (0.14 g, 0.25 mmol) or PBBS (0.2 g) or TCBDA (0.1 g, 0.25 mmol) or PCBS (0.15 g) in \(\hbox {H}_{2}\hbox {O/EtOH}\) (1 mL) (1:3) was placed in a test tube. The mixture was stirred at room temperature for the appropriate time in Table 5. After completion of the reaction [monitored by TLC (5:3, n-hexane/acetone)], the precipitate was filtered off, washed with ethanol (\(2 \times 1\) mL), and dried under reduced pressure to isolate pure 3-substituted-1,1,2,2-tetracyanocyclopropanes 7. The filtrate was evaporated and washed with hot water, \(\hbox {CH}_{2}\hbox {Cl}_{2}\) (3 mL) was added, and the precipitated sulfonamide was removed by filtration. The sulfonamide was rehalogenated and used for several times.

General procedure for preparation of 2-arylidenemalononitriles 1 using aromatic aldehyde and malononitrile 5

To a 5 mL ethanol solution of aromatic aldehyde (2 mmol) and malononitrile 5 (0.15 g, 2.2 mmol) in a 25-mL round-bottomed flask, 0.5 mL of saturated solution of sodium bicarbonate in water was added. The mixture was magnetically stirred at room temperature for appropriate time (5 min–1 h) monitored by TLC (5:1, n-hexane/acetone). After completion of the reaction, the precipitate was filtered off washed with cold ethanol, and dried to isolate pure 2-arylidenemalononitriles 1 in 75–97 % yields.

Spectral data analysis for compounds

2-(4-Nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3a). White solid; Yield: 97 %; M.p: 247–248 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3253, 3125, 2263, 1762, 1723, 1706, 1519, 1398, 1354, 1281, 789, 521 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.42 (s, 1H, CH), 7.85 (d, \( J = 8.4\) Hz, 2H, ArH), 8.21 (d, \(J = 8.4\) Hz, 2H, ArH), 11.78 (s, 1H, NH), 11.97 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.7, 40.6, 41.3, 110.5, 112.0, 122.9, 131.0, 136.6, 147.2, 149.9, 161.8, 163.7; MS: \(m/z = 325\) (\(\mathrm{M}^+\), 19 %), 282 (24 %), 244 (60 %), 214 (38 %), 193 (17 %), 165 (55 %), 133 (41 %), 89 (95 %), 69 (37 %), 45 (100 %)

2-(4-Chlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3b). White solid; Yield: 95 %; M.p: 286–289 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3267, 3227, 2262, 1759, 1731, 1711, 1497, 1420, 1360, 1090, 769, 511 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.23 (s, 1H, CH), 7.44 (d, \( J = 8.4\) Hz, 2H, ArH), 7.54 (d, \(J = 8.4\) Hz, 2H, ArH), 11.71 (s, 1H, NH), 11.91 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.6, 40.4, 41.8, 110.7, 112.2, 127.8, 128.0, 131.3, 132.9, 150.1, 161.8, 164.0; MS: \(m/z = 314\) (\(\hbox {M}^{+}\), 31  %), 313 (98 %), 270 (22 %), 249 (27 %), 227 (38 %), 199 (100 %), 165 (48 %), 123 (29 %), 99 (39 %), 69 (50  %), 43 (91  %).

2-(Naphthalen-2-yl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3c). White solid; Yield: 92 %; M.p: 258–260 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3279, 3241, 2260, 1761, 1735, 1708, 1522, 1418, 1364, 1196, 768, 504 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.43 (s, 1H, CH), 7.56 (m, 2H, ArH), 7.89 (m, 4H, ArH), 8.07 (s, 1H, ArH), 11.74 (s, 1H, NH), 11.97 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.6, 40.5, 42.9, 110.9, 112.4, 126.3, 126.5, 126.9, 127.4, 12.7.5, 127.7, 128.4, 132.4, 149.9, 161.8, 164.1; MS: \(m/z = 330\) (\(\hbox {M}^{+}\), 7  %), 294 (19 %), 266 (23 %), 204 (100 %), 180 (79 %), 153 (24 %), 126 (39 %), 89 (13 %), 69 (20 %), 42 (25 %).

2-(2,4-Dichlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3d). White solid; Yield: 85 %; M.p: 285–287 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3257, 3229, 2262, 1760, 1735, 1716, 1481, 1433, 1355, 1102, 813, 515 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.19 (s, 1H, CH), 7.51 (dd, \( J = 8.4\), 2 Hz, 1H, ArH), 7.65 (d, \(J = 8.4\) Hz, 1H, ArH), 7.72 (d, \( J = 2\) Hz, 1H, ArH), 11.90 (s, 1H, NH), 12.12 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 23.3, 40.4, 40.7, 110.4, 111.9, 125.9, 127.1, 128.7, 132.8, 134.1, 134.5, 149.8, 161.7, 163.6; MS: \(m/z = 348\) (\(\hbox {M}^{+}\), 18  %), 313 (100 %), 262 (20  %), 250 (34  %), 239 (44 %), 199 (100 %), 165 (23 %), 123 (16 %), 99 (19 %), 70 (18 %).

2-(4-Bromophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3e). White solid; Yield: 89 %; M.p: 270–272 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3273, 3232, 2262, 1759, 1732, 1712, 1491, 1420, 1359, 1012, 768, 510 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.21 (s, 1H, CH), 7.47 (d, \( J = 8.4\) Hz, 2H, ArH), 7.56 (d, \(J = 8.4\) Hz, 2H, ArH), 11.72 (s, 1H, NH), 11.92 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.5, 40.4, 41.9, 110.7, 112.2, 121.6, 128.2, 130.9, 131.6, 149.9, 161.7, 163.9; MS: \(m/z = 358\) (\(\hbox {M}^{+}\), 44 %), 357 (100   %), 325 (26   %), 290 (36  %), 262 (40   %), 228 (20   %), 192 (17 %), 164 (97 %), 133 (33 %), 91 (49 %).

2-(3-Nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3f). White solid; Yield: 94 %; M.p: 271–273 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3420, 3262, 2255, 1758, 1732, 1715, 1540, 1416, 1357, 1034, 821, 511 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 4.37 (s, 1H, CH), 7.69 (t, \( J = 8\) Hz, 1H, ArH), 8.01 (d, \(J = 7.6\) Hz, 1H, ArH), 8.19 (d, \(J = 8.4\) Hz, 1H, ArH), 8.58 (s, 1H, ArH), 11.76 (s, 1H, NH), 11.95 (s, 1H, NH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.9, 40.5, 40.8, 110.6, 112.1, 123.0, 124.9, 129.5, 131.2, 136.2, 147.3, 150.0, 161.9, 163.7; MS: \(m/z = 325\) (\(\hbox {M}^{+}\), 5 %), 320 (22 %), 273 (100 %), 239 (60 %), 199 (98 %), 165 (72 %), 152 (72 %), 126 (44 %), 91 (38 %), 56 (64 %).

2-(2,4-Dichlorophenyl)-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3i). White solid; Yield: 93 %; M.p: 268–270 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)2998, 2251, 1698, 1681, 1592, 1457, 1384, 1301, 1112, 788, 752 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 3.15 (s, 3H, \(\hbox {CH}_{3})\), 3.30 (s, 3H, \(\hbox {CH}_{3})\), 4.34 (s, 1H, CH), 7.52 (dd, \(J = 8.4\), 2 Hz, 1H, ArH), 7.61 (d, \(J = 8.4\) Hz, 1H, ArH), 7.74 (d, \(J = 2\) Hz, 1H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 24.6, 28.6, 29.1, 41.1, 41.6, 110.4, 111.8, 125.7, 127.1, 128.8, 133.0, 134.2, 134.5, 150.5, 160.5, 162.4; MS: \(m/z = 376\) (\(\hbox {M}^{+}\), 6 %), 341 (100 %), 285 (17 %), 262 (19 %), 227 (35 %), 199 (90 %), 187 (27 %), 172 (14 %), 117 (15 %), 56 (30 %).

5,7-Dimethyl-2-(3-nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3j). White solid; Yield: 84 %; M.p: 255–257 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3034, 2251, 1750, 1700, 1685, 1536, 1433, 1382, 1343, 1145, 733, 621 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 3.12 (s, 3H, \(\hbox {CH}_{3})\), 3.29 (s, 3H, \(\hbox {CH}_{3})\), 4.51 (s, 1H, CH), 7.70 (t, \(J = 8\) Hz, 1H, ArH), 8.01 (d, \(J = 7.6\) Hz, 1H, ArH), 8.21 (d, \(J = 8\) Hz, 1H, ArH), 8.53 (s, 1H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 23.9, 28.5, 29.0, 41.3, 41.8, 110.5, 112.0, 123.1, 124.6, 129.6, 131.1, 136.0, 147.4, 150.9, 160.7, 162.6; MS: \(m/z = 353\) (\(\hbox {M}^{+}\), 32 %), 326 (14 %), 239 (100 %), 205 (37 %), 187 (63 %), 178 (77 %), 165 (94 %), 140 (39 %), 103 (40 %), 77 (46 %).

5,7-Dimethyl-2-(naphthalen-1-yl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3k). White solid; Yield: 87 %; M.p: 283–285 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)2989, 2246, 1752, 1702, 1678, 1509, 1459, 1390, 1297, 1118, 774, 455 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 3.03 (s, 3H, \(\hbox {CH}_{3})\), 3.36 (s, 3H, \(\hbox {CH}_{3})\), 4.76 (s, 1H, CH), 7.65 (m, 5H, ArH), 8.00 (m, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 24.0, 28.5, 29.2, 41.3, 42.8, 110.9, 112.4, 122.5, 124.0, 124.9, 126.1, 127.0, 128.2, 128.9, 129.2, 130.7, 133.1, 150.6, 160.4, 162.7; MS: \(m/z = 358\) (\(\hbox {M}^{+}\), 46 %), 331 (45 %), 293 (45 %), 244 (50 %), 230 (47 %), 215 (74 %), 189 (65 %), 151 (39 %), 69 (100 %), 43 (98 %).

5,7-Dimethyl-4,6,8-trioxo-2-(m-tolyl)-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3l). White solid; Yield: 89 %; M.p: 264–266 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3000, 2249, 1702, 1677, 1459, 1424, 1392, 1299, 1141, 753, 497 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 2.29 (s, 3H, \(\hbox {CH}_{3})\), 3.12 (s, 3H, \(\hbox {CH}_{3})\), 3.27 (s, 3H, \(\hbox {CH}_{3})\), 4.31 (s, 1H, CH), 7.16 (m, 1H, ArH), 7.24 (m, 3H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 20.8, 23.3, 28.5, 28.9, 41.2, 43.9, 110.8, 112.3, 126.1, 128.0, 128.4, 128.8, 129.5, 137.3, 150.8, 160.4, 162.9; MS: \(m/z = 322\) (\(\hbox {M}^{+}\), 26 %), 295 (26 %), 265 (43 %), 238 (18 %), 208 (100 %), 180 (98 %), 166 (57 %), 153 (40  %), 115 (37 %), 56 (24 %).

2-(4-Chloro-3-nitrophenyl)-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile ( 3m). White solid; Yield: 95 %; M.p: 268–270 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3021, 2249, 1702, 1678, 1531, 1460, 1427, 1393, 1300, 1142, 822, 494 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 3.12 (s, 3H, \(\hbox {CH}_{3})\), 3.29 (s, 3H, \(\hbox {CH}_{3})\), 4.49 (s, 1H, CH), 7.85 (d, \(J = 8.4\) Hz, 1H, ArH), 7.91 (d, \(J = 8\) Hz, 1H, ArH), 8.38 (s, 1H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 24.0, 28.5, 29.0, 41.1, 41.2, 110.3, 111.8, 124.8, 126.8, 130.2, 131.3, 134.9, 146.9, 150.8, 160.7, 162.4; MS: \(m/z = 387\) (\(\hbox {M}^{+}\), 40 %), 360 (28 %), 330 (109 %), 273 (100 %), 245 (68 %), 199 (82 %), 165 (45 %), 117 (37 %), 91 (45 %), 56 (59 %).

3-(Thiophen-2-yl)cyclopropane-1,1,2,2-tetracarbonitrile ( 7a). White solid; Yield: 96 %; M.p: 155–157 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3310, 3032, 2260, 2232, 1573, 1429, 1362, 1257, 1147, 1058, 728, 636 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 5.42 (s, 1H, CH), 7.15 (t, \(J = 4\) Hz, 1H, ArH), 7.54 (s, 1H, ArH), 7.70 (d, \(J = 4.4\) Hz, 1H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 24.5, 38.6, 109.9, 111.1, 127.7, 130.4, 130.9; MS: \(m/z = 224\) (\(\hbox {M}^{+}\), 100 %), 197 (92 %), 171 (25 %), 160 (58 %), 147 (9 %), 133 (24 %), 109 (23 %), 96 (95 %), 69 (30 %), 45 (86 %).

3-([1, \(1^{\prime }\) -Biphenyl]-4-yl)cyclopropane-1,1,2,2-tetracar bonitrile ( 7b). White solid; Yield: 98 %; M.p: 224–225 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3063, 3013, 2925, 2263, 1582, 1490, 1406, 1133, 1045, 852, 762, 700 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 5.35 (s, 1H, CH), 7.41 (t, \(J = 3.2\) Hz, 1H, ArH), 7.49 (t, \(J = 7.6\) Hz, 2H, ArH), 7.74 (d, \(J = 7.2\) Hz, 2H, ArH), 7.82 (d, \(J = 8.8\) Hz, 2H, ArH), 7.92 (d, \(J = 8\) Hz, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 23.2, 41.5, 109.5, 111.0, 125.9, 126.8, 127.0, 128.0, 129.0, 130.1, 138.8, 141.5; MS: \(m/z = 294\) (\(\hbox {M}^{+}\), 48 %), 267 (19 %), 230 (44 %), 178 (17 %), 155 (21 %), 133 (11 %), 115 (21 %), 91 (100 %), 65 (28 %), 43 (78 %).

3-Isobutylcyclopropane-1,1,2,2-tetracarbonitrile ( 7d). White solid; Yield: 87 %; M.p: 125–127 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3042, 2964, 2934, 2875, 2265, 1643, 1470, 1390, 1171, 984, 727, 461 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 0.98 (d, \( J = 6.8\) Hz, 6H, 2\(\hbox {CH}_{3})\), 1.66 (t, \(J = 6.8\) Hz, 2H, \(\hbox {CH}_{2}\)), 1.93 (sep, \(J = 2.8\) Hz, 1H, CH), 3.93 (t, \( J = 6.8\) Hz, 1H, CH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 21.8, 22.1, 26.1, 34.9, 38.0, 109.5, 110.7; MS: \(m/z = 198\) (\(\hbox {M}^{+}\), 20 %), 181 (100 %), 167 (35 %), 149 (23 %), 124 (21 %), 105 (33 %), 93 (63 %), 80 (60 %), 69 (72 %), 43 (92 %).

3-Hexylcyclopropane-1,1,2,2-tetracarbonitrile ( 7e). White solid; Yield: 84 %; M.p: 110–112 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)3052, 2956, 2932, 2857, 2261, 1719, 1467, 1379, 1124, 992, 726, 463 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 0.88 (t, \( J = 6.8\) Hz, 3H, \(\hbox {CH}_{3})\), 1.29 (m, 6H, 3\(\hbox {CH}_{2}\)), 1.55 (quin, \(J = 8\) Hz, 2H, \(\hbox {CH}_{2}\)), 1.74 (dd, \(J = 7.2\), 8 Hz, 2H, \(\hbox {CH}_{2}\)), 3.87 (t, \(J = 6.8\) Hz, 1H, CH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 13.8, 21.8, 22.2, 25.7, 26.7, 27.8, 30.7, 39.2, 109.4, 110.8; MS: \(m/z = 226\) (\(\hbox {M}^{+}\), 5 %), 201 (95 %), 198 (74 %), 186 (41 %), 183 (95 %), 152 (53 %), 133 (8 %), 105 (10 %), 77 (100 %), 51 (59 %).

3-Phenethylcyclopropane-1,1,2,2-tetracarbonitrile ( 7f). White solid; Yield: 95 %; M.p: 168–169 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3038, 2961, 2259, 1603, 1496, 1455, 1213, 1130, 998, 753, 701, 489 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 2.00 (t, \(J = 5.6\) Hz, 2H, \(\hbox {CH}_{2}\)), 2.89 (t, \(J = 5.6\) Hz, 2H, \(\hbox {CH}_{2}\)), 3.89 (s, 1H, CH), 7.25 (m, 3H, ArH), 7.27 (m, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.6, 29.3, 32.3, 40.2, 109.7, 111.2, 127.1, 129.0, 129.1, 139.7; MS: \(m/z = 246\) (\(\hbox {M}^{+}\), 8 %), 219 (9 %), 192 (6 %), 156 (28 %), 128 (21 %), 107 (5 %), 91 (100 %), 65 (22 %), 50 (9 %).

3-Methyl-3-phenethylcyclopropane-1,1,2,2-tetracarbonitrile ( 7g). White solid; Yield: 94 %; M.p: 146–147 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3067, 3025, 2970, 2255, 1603, 1496, 1458, 1395, 1059, 977, 753, 698, 492 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.65 (s, 3H, \(\hbox {CH}_{3})\), 2.02 (dd, \(J = 6.8\), 10 Hz, 2H, \(\hbox {CH}_{2}\)), 2.90 (dd, \(J = 6.8\), 10 Hz, 2H, \(\hbox {CH}_{2}\)), 7.22 (m, 3H, ArH), 7.3 (m, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 16.9, 28.0, 30.7, 35.9, 43.7, 110.4, 110.5, 126.9, 128.6, 129.1, 140.4; MS: \(m/z = 260\) (\(\hbox {M}^{+}\), 49 %), 232 (33 %), 205 (29 %), 178 (52 %), 155 (34 %), 117 (28 %), 112 (39 %), 91 (100 %), 65 (86 %), 41 (29 %).

3-(4-Chlorophenyl)-3-ethylcyclopropane-1,1,2,2-tetracarbonitrile ( 7h). White solid; Yield: 92 %; M.p: 154–156 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3091, 3038, 2980, 2936, 2262, 1595, 1492, 1400, 1095, 1014, 822, 730 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 0.91 (t, \(J = 6.4\) Hz, 3H, \(\hbox {CH}_{3})\), 2.04 (q, \( J = 6.4\) Hz, 2H, \(\hbox {CH}_{2}\)), 7.59 (d, \(J = 6\) Hz, 2H, ArH), 7.98 (d, \(J = 6\) Hz, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 9.4, 28.4, 29.7, 51.1, 110.5, 129.2, 129.3, 132.8, 135.5; MS: \(m/z = 280\) (\(\hbox {M}^{+}\), 19 %), 245 (38 %), 218 (100 %), 191 (21 %), 174 (7 %), 152 (41 %), 117 (92 %), 99 (8 %), 75 (24 %), 50 (16 %).

3-(2-Methoxybenzyl)-3-methylcyclopropane-1,1,2,2-tetracarbonitrile ( 7i). White solid; Yield: 89 %; M.p: 153–154 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3069, 2993, 2944, 2839, 2254, 1603, 1589, 1497, 1249, 1120, 1025, 761 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.22 (s, 3H, \(\hbox {CH}_{3})\), 3.16 (s, 2H, \(\hbox {CH}_{2}\)), 3.86 (s, 3H, O\(\hbox {CH}_{3})\), 6.97 (t, \(J = 7.6\) Hz, 1H, ArH), 7.08 (d, \(J = 7.6\) Hz, 1H, ArH), 7.19 (d, \(J = 7.6\) Hz, 1H, ArH), 7.35 (t, \(J = 7.6\) Hz, 1H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 17.5, 28.6, 34.9, 42.5, 55.7, 110.4, 110.5, 111.5, 121.3, 122.3, 130.0, 131.8, 157.8; MS: \(m/z = 276\) (\(\hbox {M}^{+}\), 60 %), 234 (5 %), 197 (10 %), 171 (22 %), 148 (18 %), 132 (24 %), 121 (100 %), 91 (88 %), 78 (29 %), 65 (28 %).

3-Methyl-3-(4-nitrophenyl)cyclopropane-1,1,2,2-tetracarbonitrile ( 7k). White solid; Yield: 84 %; M.p: 238–240 \(^{\circ }\)C; IR (KBr): \(\upsilon \)2924, 2854, 2260, 1604, 1521, 1455, 1354, 1074, 860, 699 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.87 (s, 3H, \(\hbox {CH}_{3})\), 8.39 (dd, \(J = 2.8\), 9.2 Hz, 4H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 22.7, 28.0, 46.5, 109.9, 110.0, 124.0, 131.2, 139.3, 148.2; MS: \(m/z = 277\) (\(\hbox {M}^{+}\), 31 %), 250 (59 %), 231 (70 %), 204 (100 %), 177 (47 %), 140 (49 %), 119 (26 %), 102 (43 %), 77 (87 %), 50 (68 %).

3-(4-Fluorophenyl)-3-methylcyclopropane-1,1,2,2-tetracarbonitrile ( 7l). White solid; Yield: 79 %; M.p: 256–257 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3067, 2260, 1602, 1498, 1448, 1389, 1317, 1071, 1054, 983, 761, 699, 565 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.84 (s, 3H, \(\hbox {CH}_{3}\)), 7.49 (d, \(J = 7.6\) Hz, 2H, ArH), 7.97 (d, \(J = 7.6\) Hz, 2H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 23.3, 27.9, 47.5, 109.9, 110.2, 128.9, 129.3, 129.7, 132.6; MS: \(m/z = 250\) (\(\hbox {M}^{+}\), 5 %), 243 (94 %), 224 (4 %), 205 (3 %), 186 (100 %), 168 (4 %), 153 (4 %), 130 (6 %), 109 (44 %), 80 (19 %).

Spiro[2.5]oct-4-ene-1,1,2,2-tetracarbonitrile ( 7m). White solid; Yield: 76 %; M.p: 205–207 \(^{\circ }\)C (dec.); IR (KBr): \(\upsilon \)2958, 2926, 2867, 2257, 1621, 1605, 1451, 1301, 1186, 989, 872, 730 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.28 (dd, \(J = 9.2\), 12.8 Hz, 1H, CH), 1.55 (d, \(J = 13.6\) Hz, 1H, CH), 1.75 (d, \(J = 12.8\) Hz, 1H, CH), 1.97 (d, \(J = 11.6\) Hz, 1H, CH), 2.25 (quin, \( J = 11.6\) Hz, 1H, CH), 2.63 (t, \(J = 12.8\) Hz, 1H, CH), 5.21 (s, 1H, CH vinyl), 5.23 (s, 1H, CH vinyl); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 21.0, 27.5, 28.3, 31.4, 34.9, 43.8, 109.4, 109.6, 112.6, 112.7; MS: \(m/z = 208\) (\(\hbox {M}^{+}\), 10 %), 199 (21 %), 181 (63 %), 167 (16 %), 145 (29 %), 130 (23 %), 118 (26 %), 104 (32 %), 80 (100 %), 66 (52 %).

6-Benzyl-6-azaspiro[2.5]octane-1,1,2,2-tetracarbonitrile ( 7n). White solid; Yield: 71 %; M.p: 163–164 \(^{\circ }\)C; IR (KBr): \(\upsilon \)3028, 2962, 2805, 2254, 1598, 1493, 1453, 1346, 1314, 1140, 996, 746 \(\hbox {cm}^{-1}\); \(^{1}\hbox {H}\) NMR (400 MHz, DMSO-\(d_{6})\): \(\delta \) 1.98 (m, 2H, \(\hbox {CH}_{2}\)), 2.61 (m, 2H, \(\hbox {CH}_{2}\)), 3.58 (s, 2H, \(\hbox {CH}_{2}\)), 7.33 (s, 5H, ArH); \(^{13}\hbox {C}\) NMR (100 MHz, DMSO-\(d_{6})\): \(\delta \) 26.5, 28.8, 44.5, 49.6, 60.9, 109.5, 127.1, 128.2, 128.8, 137.7; MS: \(m/z = 301\) (\(\hbox {M}^{+}\), 50 %), 236 (7 %), 224 (15 %), 209 (10 %), 172 (34 %), 145 (5 %), 118 (8 %), 91 (100 %), 65 (72 %), 42 (48 %).