New synthetic protocol for stereoselective synthesis of diethyl 1,2-dicyano-3-alkyl-(aryl)cyclopropane-1,2-dicarboxylate

Abstract

A new, fast and straightforward method for the one-pot reaction of aromatic and aliphatic aldehydes and dialdehydes with ethyl cyanoacetate and cyanogen bromide was developed to afford stereoselectively diethyl 1,2-dicyano-3-alkyl/arylcyclopropane-1,2-dicarboxylate in excellent yields and short reaction time (about 5 s). The structures were characterized by IR, ¹H NMR and ¹³C NMR spectroscopy. The reaction mechanism was discussed.

Introduction

The cyclopropyl group is an important structural motif in many herbal compounds, displaying antibacterial, antiviral and some enzyme inhibition activities [1–7]. The first synthesis of 1,1,2,2,3-pentasubstituted cyclopropane was described by Mariella and Roth [8]. In this reaction, at first the simple condensation reaction of aldehyde and malononitrile affords alkylidenemalononitriles; then, reaction with the second malononitrile affords the Michael adduct. Subsequently, bromination of this product with bromine and finally intramolecular nucleophilic attack of a C-atom to the C-atom containing the Br-atom produces pentasubstituted cyclopropane.

The use of alkylidenemalononitriles is common in organic synthesis. Direct transformation of benzylidenemalononitriles and malononitrile into 3-aryl-1,1,2,2-tetracyanocyclopropanes in basic alcohol solution has been described by Elinson et al. [9]. On the other hand, a one-pot cascade assembling of 3-substituted tetracyanocyclopropanes from alkylidenemalononitriles and malononitrile by the only bromine direct reaction has also been reported by the same group [10, 11]. Previously, Kawai et al. [12] reported the cyclopropanation mediated by lithium iodide of electron-deficient alkenes with activated dibromomethylene compounds. Recently, we have developed the one-pot synthesis of 3-substituted tetracyanocyclopropanes in the reaction of various aldehydes, malononitrile [13] and di-spiro cyclopropanation of Meldrum’s acids [14] with cyanogen bromide (BrCN) in the presence of Et₃N.

A search in the literature found no report about cyclopropanation of ethyl cyanoacetate via the chemical reaction route. The only report is the electrochemical cyclopropanation of this compound reported by Elinson et al. [15]. The electrochemical transformation of malononitrile and various ketones to 3,3-dialkyl tetracyanocyclopropanes have also been reported by the same author(s) [16].

Owing to these concepts, in this research, we have developed the chemical synthetic stereoselective cyclopropanation of ethyl cyanoacetate in the reaction with various aldehydes and BrCN under alkali condition.

Experimental

General

The drawing and nomenclature of compounds were done by ChemDraw Ultra 8.0 version software. Melting points were measured with a digital melting point apparatus (Electrothermal) and were uncorrected. IR spectra were determined in the region 4,000–400 cm⁻¹ on a NEXUS 670 FT IR spectrometer by KBr pellets. The ¹H and ¹³C NMR spectra were recorded on Bruker 400 FT-NMR at 400 and 100 MHz, respectively (Isfahan University, Isfahan, Iran). ¹H and ¹³C NMR spectra were obtained on solution in DMSO-d ₆ and/or CDCl₃ as solvent using TMS as internal standard. The data are reported as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, bs = broad singlet, coupling constant(s) in Hz, integration. The ¹H and ¹³C NMR spectra were opened and analyzed via MestReC software from original spectra files. Cyanogen bromide was synthesized based on reported references [17]. Aliphatic and aromatic (di)aldehydes, Et₃N and solvents were purchased from Merck and Aldrich without further purification.

General procedure for the synthesis of diethyl 1,2-dicyano-3-alkyl-(aryl)cyclopropane-1,2-dicarboxylate

In a 10 mL Teflon-faced screw cap tube equipped with a magnetic stirrer and an ice bath, dissolved formaldehyde (1.0 mmol), ethyl cyanoacetate (2.0 mmol) in 5 ml EtOH added the appropriate base (1.33 mmol, see Table 1), and then (1.2 mmol) cyanogen bromide was added to the solution at 0 °C to r.t. The Teflon-faced screw cap tube prevents the evaporation of cyanogen bromide. A cream color solid was precipitated immediately after 5 s, after about 2 min it was filtered off, washed with cool EtOH (3 × 3 ml), recrystallized in minimum hot EtOH, filtered off and dried as a colorless crystalline solid (0.236 g, 100 % yield).

Table 1 The structure of aldehydes 1, products 3, used base and reaction time and yields

Triethylammonium 1-bromo-1-cyano-2-ethoxy-2-oxoethan-1-ide (4a′)

Colorless crystalline powder; mp 280–282 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.36 (s, 1H, NH), 4.22–4.25 (m, 8H, –NCH ₂–CH₃ and –O CH ₂–CH₃), 1.25–1.30 (m, 12H, –NCH₂–CH ₃ and –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 14.1, 14.4, 59.3, 61.4, 117.5, 128.8, 141.2; IR (KBr, cm⁻¹): 3,739, 3,425, 2,983, 2,212, 1,680, 1,506, 1,256, 1,138, 1,025, 685, 571, 444.

Diethyl 1,2-dicyanocyclopropane-1,2-dicarboxylate (3a)

Colorless crystalline solid; mp 78.5–79.5 °C. ¹H NMR (400 MHz, CDCl₃) δ: 5.29 (s, 2H, cyclopropane-H), 4.36 (qd, J = 7.2, J = 2 Hz, 4H, diastereotopic –OCH ₂–CH₃), 1.34 (t, J = 7.2 Hz, 6H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 14.0, 25.3, 29.7, 65.1, 112.2, 161.4; IR (KBr, cm⁻¹): 3,138, 3,047, 2,984, 2,940, 2,256, 1,737, 1,416, 1,375, 1,325, 1,271, 1,190, 1,160, 1,100, 995, 918, 859, 818, 859, 825, 747, 604, 557, 471, 438.

Diethyl 1,2-dicyano-3-phenylcyclopropane-1,2-dicarboxylate (3c)

Colorless crystalline solid; mp 94–95 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.39 (m, 5H, Ar–H), 4.25–4.33 (m, 4H, –OCH ₂–CH₃), 3.87 (s, 1H, cyclopropane-H), 1.30 (t, J = 7.2 Hz, 6H, –OCH₂–CH ₃),¹³C NMR (100 MHz, CDCl₃) δ: 13.9, 34.2, 39.0, 64.7, 111.7, 127.8, 129.0, 129.3, 129.8, 161.2; IR (KBr, cm⁻¹): 3,062, 3,014, 2,983, 2,937, 2,250, 1,758, 1,652, 1,503, 1,452, 1,394, 1,265, 1,202, 1,081, 1,006, 859, 751, 702, 655, 511.

Diethyl 1,2-dicyano-3-(2-nitrophenyl)cyclopropane-1,2-dicarboxylate (3d)

Colorless crystalline solid; mp 100 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J = 8.4 Hz, 1H, Ar–H), 7.69 (t, J = 7.6 Hz, 1H, Ar–H), 7.57 (t, J = 9.2 Hz, 2H, Ar–H), 4.44 (qd, J = 7.2, 5.6 Hz, 2H, diastereotopic –OCH ₂–CH₃), 4.32 (s, 1H, cyclopropane-H), 4.14 (qd, J = 7.2, 5.6 Hz, 2H, diastereotopic –OCH ₂–CH₃), 1.41 (t, J = 7.2 Hz, 3H, –OCH₂–CH ₃), 1.18 (t, J = 7.2 Hz, 3H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 13.7, 14.0, 39.3, 64.9, 65.6, 110.8, 112.4, 124.0, 125.7, 130.5, 131.3, 134.2, 161.4; IR (KBr, cm⁻¹): 2,992, 2,931, 2,258, 1,749, 1,639, 1,579, 1,526, 1,462, 1,346, 1,300, 1,248, 1,209, 1,181, 1,098, 1,041, 985, 855, 793, 725, 661, 610.

Diethyl 1,2-dicyano-3-(3-nitrophenyl)cyclopropane-1,2-dicarboxylate (3e)

Colorless crystalline solid; mp 133–134 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.64 (s, 1H, Ar–H), 8.34 (t, J = 7.2 Hz, 1H, Ar–H), 8.25 (s, 1H, Ar–H), 7.68 (t, J = 8 Hz, 1H, Ar–H), 4.35 (q, J = 7.2 Hz, 4H, –OCH ₂–CH₃), 1.35 (t, J = 7.2 Hz, 6H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 14.1, 63.3, 106.6, 114.6, 125.9, 127.1, 130.6, 132.9, 135.2, 148.6, 151.9, 161.5; IR (KBr, cm⁻¹): 3,097, 3,031, 2,989, 2,949, 2,906, 2,869, 2,225, 1,721, 1,606, 1,572, 1,528, 1,474, 1,355, 1,315, 1,267, 1,203, 1,094, 1,015, 971, 807, 763, 668, 587, 524.

Diethyl 3-(4-nitrophenyl)-1,2-dicyanocyclopropane-1,2-dicarboxylate (3f)

Colorless crystalline solid; mp 135–136 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.22 (d, J = 8.8 Hz, 2H, Ar–H), 7.52 (d, J = 8.8 Hz, 2H, Ar–H), 4.39–4.52 (m, 2H, diastereotopic –OCH ₂–CH₃), 4.16–4.24 (m, 2H, diastereotopic –OCH ₂–CH₃), 4.10 (s, 1H, cyclopropane-H), 1.41 (t, J = 7.2 Hz, 3H, –OCH₂–CH ₃), 1.19 (t, J = 7.2 Hz, 3H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 13.8, 14.0, 31.6, 32.4, 39.3, 65.0, 65.8, 110.5, 112.3, 124.2, 129.9, 134.5, 148.3, 159.3, 161.4,; IR (KBr, cm⁻¹): 3,489, 3,113, 3,082, 2,989, 2,940, 2,742, 2,678, 2,491, 2,258, 2,218, 1,753, 1,604, 1,522, 1,471, 1,352, 1,297, 1,243, 1,179, 1,105, 1,043, 993, 856, 758, 725, 697, 641, 593, 509, 471, 413.

Diethyl 3-(2,4-dichlorophenyl)-1,2-dicyanocyclopropane-1,2-dicarboxylate (3g)

Colorless crystalline solid; mp 95–96.5 °C. ¹H NMR (400 MHz. CDCl₃) δ: 7.50 (dd, J = 8.4, 1.2 Hz, 1H, Ar–H), 7.41 (s, 1H, Ar–H), 7.42 (dd, J = 8.4, 1.2 Hz, 1H, Ar–H), 7.33 (dd, J = 8.4, 2 Hz, 0.06H, Ar–H), 7.28 (dd, J = 8.4, 2 Hz, 1H, Ar–H), 4.37–4.49 (m, 2H, diastereotopic –OCH ₂–CH₃), 4.32 (q, J = 7.2 Hz, 0.33H, diastereotopic –OCH ₂–CH₃), 4.15–4.24 (m, 2H, diastereotopic –OCH ₂–CH₃), 3.84 (s, 1H, cyclopropane-H), 3.80 (s, 0.07H, cyclopropane-H), 1.31 (t, J = 7.2 Hz, 0.5H, –OCH₂–CH ₃), 1.26 (t, J = 7.2 Hz, 0.25H, –OCH₂–CH ₃), 1.19 (t, J = 7.2 Hz, 3H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 13.7, 13.96, 14.04, 32.5, 32.9, 37.0, 38.4, 64.6, 64.9, 65.6, 110.8, 112.5, 124.9, 127.8, 128.0, 129.7, 130.4, 130.6, 130.8, 135.4, 136.1, 159.6, 161.4 (Mixtures of three stereoisomers); IR (KBr, cm⁻¹): 3,482, 3,093, 2,988, 2,258, 1,752, 1,590, 1,559, 1,474, 1,375, 1,301, 1,249, 1,211, 1,182, 1,100, 1,044, 981, 909, 855, 822, 779, 754, 677, 602, 569, 454.

Diethyl 1,2-dicyano-3-(3,4,5-trimethoxyphenyl)cyclopropane-1,2-dicarboxylate (3h)

Colorless crystalline solid; mp. 151–152 °C. ¹H NMR (400 MHz, CDCl₃) δ: 6.65 (s, 2H, Ar–H), 3.87 (s, 6H–OCH ₃), 3.83 (s, 3H, –OCH ₃), 3.80 (q, J = 7.2 Hz, 4H, –OCH ₂–CH₃), 3.79 (s, 1H, cyclopropane-H), 1.2 (t, J = 7.2 Hz, 6H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 29.7, 31.9, 39.7, 55.0, 56.3, 60.9, 106.0, 111.7, 122.6, 139.2, 153.7, 161.7; IR (KBr, cm⁻¹): 3,087, 3,061, 3,005, 2,264, 1,622, 1,590, 1,492, 1,401, 1,072, 1,014, 844, 785, 732, 491.

Diethyl 1,2-dicyano-3-(furan-2-yl)cyclopropane-1,2-dicarboxylate (3l)

Colorless crystalline solid; mp 94–95 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (s, 1H, Ar–H), 7.69 (s, 1H, Ar–H); 7.32 (d, J = 3.6 Hz, 1H, Ar–H), 6.60 (d, J = 3.6 Hz, 1H, Ar–H), 4.29 (qd, J = 7.2, 0.8 Hz, 4H, –OCH ₂–CH₃), 1.31 (td, J = 7.2, 0.8 Hz, 6H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 14.2, 62.6, 98.6, 113.9, 115.4, 121.8, 139.5, 148.3, 148.7, 162.6; IR (KBr, cm⁻¹): 3,417, 3,129, 3,041, 2,988, 2,938, 2,221, 1,915, 1,717, 1,620, 1,532, 1,463, 1,390, 1,366, 1,263, 1,210, 1,090, 1,019, 965, 932, 877, 843, 760, 701, 587.

Tetraethyl 3,3′-(1,4-phenylene)bis(1,2-dicyanocyclopropane-1,2-dicarboxylate) (9c′′)

Colorless crystalline solid; mp 230–231 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.57 (s, 4H, Ar–H), 4.36 (qd, J = 6.8, 2.8 Hz, 8H, –OCH ₂–CH₃), 3.89 (s, 2H, cyclopropane-H), 1.32 (t, J = 7.2 Hz, 12H, –OCH₂–CH ₃), ¹³C NMR (100 MHz, CDCl₃) δ: 13.9, 29.7, 38.4, 64.9, 111.5, 129.7, 130.0, 160.9; IR (KBr, cm⁻¹): 3,050, 2,996, 2,900, 2,249, 1,760, 1,473, 1,389, 1,266, 1,201, 1,081, 1,009, 860, 625.

Results and discussion

This paper describes a new one-pot reaction of aldehydes (1a–1n) with ethyl cyanoacetate (2) and BrCN to afford diethyl 1,2-dicyano-3-alkyl- (aryl)cyclopropane-1,2-dicarboxylate (3a–3n) under alkali condition in excellent yields with short reaction time (5 s) (Scheme 1).

Scheme 1

Synthesis of diethyl 1,2-dicyano-3-alkyl-(aryl)cyclopropane-1,2-dicarboxylate (3) in the reaction of aldehydes (1) with ethyl cyanoacetate (2) in the presence of BrCN under alkali condition

As described in Scheme 2, in these reactions, the salt 4 plays an essential role for the synthesis of 3. The structures of salts 4a′–4c′ are shown in Fig. 1. According to our previous reported mechanisms for the formation of the salts 10 [13] and 11 [14, 18–24], a representative proposed reaction mechanism for the formation of triethylammonium 1-bromo-1-cyano-2-ethoxy-2-oxoethan-1-ide (4a′) is shown in Scheme 2.

Scheme 2

Representative proposed mechanism for the synthesis of 4a′

Fig. 1

Formula structure of salts 4a′–4c′ (this work), 10 [13] and 11 [14, 18–24]

On the basis of the well-established chemistry of some β-dicarbonyl compounds such as malononitrile [13], Meldrum’s acid [14], barbituric acids [18–23] and dimedone [24] in the reaction with BrCN in the presence of Et₃N and also the mechanism of the bromination of imidazoles by cyanogen bromide [25], it is reasonable to assume that compound 2 reacts directly with BrCN to form ethyl 3-bromo-2-cyano-3-iminopropanoate (5) intermediate through path a. Intramolecular rearrangement of 5 produces ethyl 2-bromo-2-cyanoacetate (6) as a new intermediate. Finally, Et₃N as a base captures the acidic proton to afford 4a′ (Scheme 2). Ethyl cyanoacetate (2) directly reacts with Et₃N to form the salt of 7a′ in the absence of BrCN (path b). We performed the reaction of 2 with BrCN in the presence of Et₃N and in the absence of aldehydes 1, so that salt 4a′ was isolated in excellent yield. These experiments confirm the major role of 4 in the synthesis of 3.

According to our search, there is no report about compounds 4 in the literature. Salts 4 were isolated and characterized by spectroscopic techniques. Representatively, the IR spectrum of 4a′ shows the frequency of NH+ stretching at the broad range of 2,731–3,739 cm⁻¹ and the frequencies of C≡N, C=O and C–Br stretching at 2,212, 1,680 and 571 cm⁻¹, respectively. The ¹H-NMR spectrum of this compound shows (integration in parenthesis) a multiplet at δ 1.25–1.30 (12H) and a multiplet (a quartet approximately) at δ 4.22–4.25 ppm (8H) for Me and CH₂ groups in Et₃NH⁺ and ethyl 2-bromocyanoacetate moieties, respectively. A singlet at δ 8.36 ppm (1H) corresponds to NH⁺. ¹³C-NMR spectrum of this salt shows seven distinct peaks that confirm the structure of 4a′ (Fig. 1, “Experimental” and supplementary data). Unfortunately, all attempts failed to separate or characterize intermediates 5 and 6. Other evidence for the formation and confirmation of 4 (the existence of bromine atom in this salt structure) was performed by Beilstein test and the wet silver nitrate test (precipitate of pale yellow silver bromide).

Fig. 2

A representation of plane of symmetry in 3 and a C ₂ axis in 3a(C)

Representatively, the reaction mechanism for the formation of 3c is shown in Scheme 3. First, the reaction of benzaldehyde 1c with ethyl cyanoacetate 2 afforded mixtures of two geometrical isomers, (E)- and (Z)-ethyl 2-cyano-3-phenylacrylate (12c); then the nucleophilic attack of 4a′ on the C-atom of 12c as an α,β-unsaturated C=O compound afforded intermediate triethylammonium 4-bromo-2,4-dicyano-1,5-diethoxy-1,5-dioxo-3-phenylpentan-2-ide (13c). Intramolecular C-attack of the carbanion on carbon atom containing bromine atom (path a) as an electrophile (pushing the bromide ion out) resulted in diethyl 1,2-dicyano-3-phenylcyclopropane-1,2-dicarboxylate (3c). All attempts to separate and characterize the intermediates 12c and 13c failed. No 15c was observed through intermediate 14c (path b). This observation indicated that the C-attack of carbanion on nitrile group did not occur (Scheme 3).

Scheme 3

Representatively, proposed mechanism for the synthesis of 3c (path a) and no paths b–f were occurred

As mentioned above, from the reaction of 1c and 2, mixtures of two geometrical (E)- and (Z)-isomers 12c were exclusively also obtained in the presence of triethylamine and absence of BrCN. It has been shown that the salt 4 plays a major role in these reactions. First, it is a nucleophile in the reaction with 12c; then it has an electrophilic character (carbon atom containing a bromine atom) in the intermediate 13c to form 3c (Scheme 3). On the other hand, the probable compounds ethyl 1,3-dicyano-2-oxo-4-phenylcyclobutanecarboxylate (17c), ethyl 2,4-dicyano-5-ethoxy-3-phenyl-2,3-dihydrofuran-2-carboxylate (18c) and 3-bromo-6-ethoxy-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-3,5-dicarbonitrile (20c) were not formed through paths c, d and f, respectively (Scheme 3). The reaction condition, time and yields are outlined in Table 1.

Representatively, IR spectrum of 3c shows stretching frequencies at 2,250 and 1,758 cm⁻¹ for the C≡N and C=O groups, respectively. By comparison of the C≡N and C=O stretching frequencies of 4a′ with 3a, it is obvious that the resonance of the negative charge with C≡N and C=O groups in 4a′ caused the stretching frequencies of these functional groups to shift to low frequency (). ¹H NMR spectrum of 3c shows a triplet at δ 1.31 ppm for methyl groups and a multiplet at δ 4.25–4.33 ppm for methylene groups (two H-atoms of CH₂ groups are diastereotopic due to the neighbor being a chiral center). A singlet at δ 3.87 ppm corresponds to cyclopropyl proton and a multiplet at δ 7.30–7.43 ppm to phenyl group. The ¹³C NMR spectrum of this compound shows ten distinct peaks and confirms the assigned structure (see “Experimental” and also supplementary data). Compound 3c was found to be stereoselectively cis form (3cA and/or 3cB forms), due to having a triplet at δ 1.31 ppm and also a distinct carbonyl peak at δ 161.2 ppm in ¹H and ¹³C NMR spectroscopies, respectively (Fig. 2; Table 2).

Table 2 Stereoisomers of obtained 3 and 9

One of the interesting situations in these compounds is the stereostructure of these compounds (Fig. 2). Many of these compounds (3A and 3B forms) have a plane of symmetry (σ), so that the two ethyl groups are equivalent in chemical shift (Fig. 2). The structure of 3C form (with exception of the products derived from formaldehyde (3a)) has neither plane of symmetry nor C ₂ axis. For instance, the structure of 3aA has a plane of symmetry (σ) and so does the meso form; however, 3aC has a C ₂ axis and is a chiral form. The ¹H NMR spectrum of 3a shows a triplet for methyl groups at δ 1.34 ppm, a quartet–doublet at δ 4.35 ppm (J = 7.2 Hz, J = 5.2 Hz) for diastereotopic methylene protons and a singlet at δ 2.52 ppm for cyclopropane methylene protons. On the other hand, in 3aA form, H^a and H^b protons are diastereotopic, while these protons in 3aC are homotopic. According to the ¹H NMR data for 3a, and the equivalency of two protons on the cyclopropane ring moiety (a singlet at δ 2.52 ppm), we conclude that this compound was formed as 3aC (trans form). The ¹³C NMR spectrum of this compound shows six distinct peaks at δ 161.4 (for C=O), 112.2 (for CN), 65.1 (for CO–CH₂–CH₃), 29.7 (cyclopropane-CH₂), 25.3 (cyclopropane-C–CO) and 14.0 ppm (for CO–CH₂–CH₃). These observations confirm the formation of distinct 3aC form (see also “Experimental” and supplementary data). All these spectroscopic explanation results for stereostructures of 3 are summarized in Table 2.

For instance, the ¹H NMR spectrum of compound 3g shows three stereoisomers (Table 2; Fig. 3). The main stereoisomer (3gC) is trans form (88.9 % yield, obtained from ¹H NMR spectrum). Owing to the two different chemical shifts for Me groups (also two multiplets for methylene groups), the 3gC isomer was found to be a major product. This isomer (3gC) has neither plane of symmetry nor a C ₂ axis. In contrast, the cis isomers (3gA and 3gB) have a plane of symmetry and are meso forms. According to ¹H NMR spectrum of 3g, there are two main distinct triplets for methyl groups of 3gC. The two meso forms were obtained in 7.4 and 3.7 % yields (Fig. 3).

Table 3 The structure of dialdehydes 8 and products (9a″–c″ and 9d″), and reaction time and yields

Fig. 3

Representative ¹H NMR spectrum of the mixtures of stereoisomers of 3g at aliphatic regions [Me (a) and CH₂ (b) regions; for more information see supplementary data]

The reaction of bulky aldehyde such as 9-anthracene carbaldehyde (1o) and aldehydes containing exchangeable protons (1p–1t) with 2 and BrCN afforded a mixture of E- and Z- Knoevenagel adducts (12p–12t) under the same condition and did not yield cyclopropanes (3p–3t). Presumably, the hindrance effect in 1o led to the formation of 12o (mixture of E- and Z- isomers). Instead, the existence of acidic OH group upon 12p–12t caused 4 as nucleophile to be able to capture acidic proton on the OH group (path a) prior to Michael addition to β-carbon position of Knoevenagel adducts 12p–12t (path b) (Scheme 4). Therefore, the path a is more favored than path b. It seems that the existence of exchangeable proton having acidic nature on Knoevenagel adducts prevented the Michael addition of 4 and made the path a more favorable to form 21p (Scheme 4). Another possible pathway can be path c. For instance, triethylamine as a base can attack acidic proton on phenol derivative (4-hydroxy benzaldehyde 1p as representative) to form triethylammonium 4-formylphenolate 22p (Scheme 4, path c). Our attempt to separate and characterize 12p, 21p and 22p failed. These results demonstrated the reason for the unsuccessful cyclopropanation of aromatic aldehydes possessing exchangeable proton.

Scheme 4

The proposed mechanism for the favored path a and unfavored path b

We also performed the reaction of glutaraldehyde (8a″), isophthalaldehyde (8b″), terphthalaldehyde (8c″) and phthalaldehyde (8d″) with 2 in the presence of BrCN under the same conditions (Scheme 5). In these reactions, the reaction of 8a″ was crucial, while those of 8b″–8c″ were easy. The reaction of 8d″ with 2 and BrCN under alkali condition afforded diethyl 1,2-dicyano-3-(2-formylphenyl)cyclopropane-1,2-dicarboxylate (9d″) due to ortho formyl hindrance effect. In contrast, with 8a″–8c″, both aldehyde groups in each compound reacted with 2 and tetraethyl 3,3′-(propane-1,3-diyl)bis(1,2-dicyanocyclopropane-1,2-dicarboxylate) (9a″), tetraethyl 3,3′-(1,3-phenylene)bis(1,2-dicyanocyclopropane-1,2-dicarboxylate) (9b″) and tetraethyl 3,3′-(1,4-phenylene)bis(1,2-dicyanocyclopropane-1,2-dicarboxylate) (9c″) were obtained, respectively (Scheme 5; Table 3).

Scheme 5

Stereoselective synthesis of tetraethyl bis(1,2-dicyanocyclopropane-1,2-dicarboxylate) (9) in the reaction of dialdehydes (8) with 2 in the presence of BrCN and in alkali condition

Representatively, ¹H NMR spectrum of 9c″ shows a triplet and a multiplet for four equivalent Me and diastereotopic methylene protons at δ 1.30 and 4.31 ppm, respectively. This compound also shows two singlets for Ph and cyclopropyl protons at δ 7.57 and 3.89 ppm, respectively. The ¹³C NMR spectrum of 9c″ shows eight distinct peaks. Peaks at δ 160.9 (C=O), 130.0, 129.7 (Ph ring), 111.5 (CN), 64.9 (–O–CH₂–), 38.4 (cyclopr.–C–C=O), 29.4 (cyclopr.–C–H) and 13.9 (Me) confirm the assigned structure (Figs. 4, 5). Both structures of 9c″A (cis–cis) and 9c″B (trans–trans) confirms the ¹H and ¹³C NMR spectral data. The 9c″A[I] form has a plane of symmetry (σ), C ₂ axis and a center of symmetry (C _i ). The rotamer of 9c″A[I] is the 9c″A[II] form, due to the free rotation about single bonds between phenyl and both cyclopropyl rings. In fact, the 9c″A[II] form has two perpendicular σ and a C ₂ axis. On the other hand, the 9c″B[I] form has a σ and can convert to the rotamer of 9c″B[II] that consists of a C _i symmetry. No unfavored form of 9c″C (trans–cis) was observed (Figs. 4, 5).

Fig. 4

Possibly favored forms 9c′′A and 9c′′B and unfavored form 9c′′C. A plane of symmetry, a C ₂ axis and C _i in 9c′′A[I] equal two planes of symmetry and C ₂ axis in 9c′′A[II], and a plane of symmetry in 9c′′B[I] also equals a C _i symmetry in 9c′′B[II] [C _i is assigned a blue dot]

Fig. 5

¹H NMR (a) and ¹³C NMR spectra of 9c′′ (b) in CDCl₃

Conclusions

In summary, the reaction of various mono- and di-aldehydes with ethyl cyanoacetate and cyanogen bromide in basic media afforded stereoselectively diethyl 1,2-dicyano-3-alkyl-(aryl)cyclopropane-1,2-dicarboxylate in excellent yields and short reaction times. Some aldehydes gave the cis and some others gave the trans cyclopropane stereoisomer. These observations were found in the results of ¹H and ¹³C NMR spectroscopy analysis in detail.