New full-substituted cyclopropanes derived from the one-pot reaction of Meldrum’s acid with aldehydes and BrCN in the presence of Et₃N

1 Introduction

Numerous Meldrum’s acid derivatives are a highly interesting class of compounds, and research directed to their biological and pharmaceutical properties is continuously attracting great interest in the scientific community (Emtenäs et al., 2000; Snider et al., 2001; Dudinov et al., 2009; Lipson et al., 2008; Song et al., 2003). 5-Arylidene and/or 5-alkylidene derivatives of Meldrum’s acid are useful intermediates for cycloaddition reaction and for the synthesis of heterocyclic compounds with potential pharmaceutical activity (Pita et al., 2000).

They are well-documented reactions (Mudhar and Witty, 2010) and are useful reactive intermediates, such as 1,4-addition, (Wilsily and Fillion, 2009; Knöpfel et al., 2005; Ziegler et al., 1980) acting as activated dienophiles in Diels–Alder reactions (Pałasz et al., 2007; Borah et al., 2005) and for the preparation of heterocyclic molecules such as benzofurans, indoles (Baxter et al., 1974) and coumarins (Mahulikar and Mane, 2006).

First synthesis of 3-substituted cyclopropane has been described by Mariella and Roth (1957). The methods for cyclopropane synthesis have been divided into two main groups: intramolecular cyclization and interaction of alkenes and carbenes (Faust, 2001; Donaldson, 2001). On the other hand, Michael Initiated Ring Closer (MIRC) is an important synthesis method for cyclization (Caine, 2001). Reaction of halogenated acid anion with the activated alkene followed by cyclization with elimination of halogen has generated tetramethyl 3,3-dialkylcyclopropane-1,1,2,2-tetracarboxylates (McCoy, 1964).

The cyclopropanation of Meldrum’s acid has been reported by the reaction of Meldrum’s acid with an aldehyde and thiophenol in the presence of catalytic amount of piperidinium acetate (Eberle and Lawton, 1988). Cyclopropanation of Meldrum’s acid has also been reported by treatment of bismuthonium ylides with aldehydes (Ogawa et al., 1988). 1,1,2,2-Cyclopropanetetracarboxylate and its derivatives have been prepared by treating the sodium salt of 5-alkylidene Meldrum’s acid with iodine or bromine (Hedge et al., 1961).

As part of our research program concerning the use of cyanogen bromide (BrCN) and triethylamine (Et₃N), we have investigated the one-pot condensation reaction of Meldrum’s acid, aldehydes and BrCN in the presence of Et₃N for the synthesis of full substituted spiro cyclopropanes based on Meldrum’s acid at room temperature.

2 Experimental

The drawing and nomenclature of compounds were done by ChemBioDraw Ultra 12.0 and 8.0 versions software. Melting points were measured with a digital melting point apparatus (Electrothermal) and were uncorrected. IR spectra were determined in the region 4000–400 cm⁻¹ on a NEXUS 670 FT IR spectrometer by preparing KBr pellets. The ¹H and ¹³C NMR spectra were recorded on Bruker 300 FT-NMR at 300 and 75 MHz, respectively (Urmia University, Urmia, Iran). ¹H and ¹³C NMR spectra were obtained on solution in DMSO-d₆ or in CDCl₃ as solvents 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). All reactions were monitored by TLC with silica gel-coated plates (EtOAc: n-hexane/8:10/v:v). The mass analysis was performed using mass spectrometer (Agilent Technology (HP) type, MS Model: 5973 network Mass selective detector Electron Impact (EI) 70 eV), ion source temperature was 230 °C (Tehran University, Tehran, Iran). Cyanogen bromide was synthesized based on reported references (Hartman and Dreger, 1943). Compounds 1, 2a–u, triethylamine and used solvents were purchased from Merck and Aldrich without further purification.

3 Results and discussion

This paper describes the one-pot new reaction of Meldrum’s acid (1) with various aldehydes and BrCN in the presence of Et₃N that afforded new full-substituted cyclopropanes containing Meldrum’s acid ring moieties (3) and new salt of triethylammonium 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ide (4) in moderate to good yield at room temperature (Scheme 1, path A and Table 1). The reaction between 1 and 2 afforded the corresponding 5,5′-(alkyl- or arylmethylene)bis(2,2-dimethyl-1,3-dioxane-4,6-dione) (5) in the presence of Et₃N and absence of BrCN (Scheme 1, path B). No 2,2,8,8-tetramethyl-5-alkyl and/or aryl-4H-pyrano[2,3-d:6,5-d’]bis([1,3]dioxine)-4,6(5H)-dione (6) was obtained from 5 under present condition (path B). Expectedly, no corresponding 5′-alkyl- or 5′-aryl-2,2,2′,2′-tetramethyl-spiro[[1,3]dioxane-5,6′-furo[2,3-d][1,3]dioxine]-4,4′,6(5′H)-trione (7) was also observed (Scheme 1, path C).

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Scheme 1

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Table 1 One-pot reaction of Meldrum’s acid 1 with various aldehydes (2a–u) mediated by BrCN in the presence of Et₃N.

Entry	R	Product	mp (°C)	Yield (%)
1	H (2a)	3a	217–218	45
2	CH3 (2b)	3b	216–218	55
3	CH3CH2 (2c)	3c	212–214	60
4	CH3CH2CH2 (2d)	3d	204–205	50
5	p-NO2-C6H4 (2f)	3f	202–203	60
6	m-NO2-C6H4 (2g)	3g	192–194	51
7	o-NO2-C6H4 (2h)	3h	198–199	75
8	4-CN-C6H4 (2i)	3i	204–205	50
9	p-Br-C6H4 (2j)	3j	192–193	52
10	2,4-di-Chloro-C6H3 (2k)	3k	178–180	60
11	p-Cl-C6H4 (2l)	3l	178–179	55
12	o-CH3O-C6H4 (2o)	3o	178–180	55
13	(2p)	3p	198–200	46
14	p-CH3O-C6H4 (2r)	8ra	126–128b	50
15	p-(CH3)2N-C6H4 (2s)	8s	175–177	85c
16	(2t)	8t	182–184	65d
17	(2u)	8u	194–196	90e

A Exclusively Knoevenagel adduct was obtained.

b Lit.: 161–162 °C (Zeng, 2011).

c Yield refers to 8s.

d Yield refers to 8t.

e Yield refers to 8u.

Based on this concept, expectedly, we have investigated the one-pot condensation of Meldrum’s acid 1 with aldehydes and BrCN in the presence of Et₃N under the same condition. In this reaction, new full-substituted cyclopropanes 3 and the new salt of 4 were obtained in good yield. The residue of unreacted starting materials (1 and 2) was also recovered.

According to the mechanism of the bromination of 1-alkyl imidazoles by BrCN (McCallum et al., 1999) and the mechanism of the formation of 11–13 (Jalilzadeh et al., 2011; Hosseini et al., 2011), and 14 (Noroozi Pesyan et al., 2013) the mechanism of the formation of 4 is shown in Scheme 2. It was assumed that the enolic form of Meldrum’s acid 1a reacted with BrCN and formed the intermediate 9. Intramolecular rearrangement of 9 afforded 5-bromo-2,2-dimethyl-1,3-dioxane-4,6-dione (10) followed by the loss of HCN. Triethylamine as a base captured the acidic methylene proton of 10 formed salt 4 (Scheme 2, path a). The salt of 4 was isolated from reaction mixture (about 20% yield) and this compound is needed for the synthesis of 3 (see later). The salt of triethylammonium hydrobromide was also formed and filtered off. Unfortunately, all attempts failed to separate or characterize 9 and 10. In this reaction, no 2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonitrile (15) was observed (Scheme 2, path b). We performed the reaction of 1 with BrCN and Et₃N in the absence of aldehydes under the same condition as model reaction. Obviously, 4 was obtained and isolated in moderate yield.

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Scheme 2

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The structure of 4 was characterized by IR, ¹H and ¹³C NMR spectroscopy. The ¹H NMR spectrum of 4 consists of a triplet at δ 1.27, a quartet at δ 3.09 and a broad singlet at δ 10.10 ppm corresponding to methyl, methylene and NH proton in triethyl ammonium salt moiety, respectively. A singlet at δ 1.54 ppm corresponds to the two equivalent methyl groups on Meldrum’s acid ring moiety. The ¹³C NMR spectrum of 4 consists of six distinct peaks (Fig. 1 and see experimental). The IR spectrum of this compound shows a broad absorption peak at the frequency of 3448 cm⁻¹ for OH group of enolic form and/or NH group of triethylammonium salt moiety and carbonyl frequency at 1752 cm⁻¹. Other evidence for the formation of 4 (the existence of bromine atom in this molecule) was performed by the Beilstein test and the wet silver nitrate test (Schriner et al., 1980) (Precipitate of pale yellow silver bromide). These data confirm and have good agreement together for the proposed structure of 4.

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Figure 1 ¹H (a) and ¹³C NMR spectra of 4 (b).

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The proposed mechanism of the formation of 3 is shown in Scheme 3. First, the Knoevenagel condensation of 1 (Bigi et al., 2001) with equimolar of aldehydes 2 afforded the corresponding 5-alkylidene- or 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (8). The Michael addition of compound 4 (as a nucleophile) with 8 as a key intermediate gave the intermediate (16). In this reaction, compound 4 plays either nucleophile or electrophile character. Finally, an intramolecular condensation of 16 (C-attack to the carbon atom as an electrophile containing bromine) with the removal of bromide ion afforded 3 in moderate yield. In intermediate 16, no O-attack occurred for the formation of 7. Two geminal oxygen atoms on carbon atom in 16 intermediate have inductive effect to each other. For this reason, the geminal oxygen atom prevents the O-attacking of oxygen anion to the electrophile for the formation of 7. Therefore, the C-attack was favored (Scheme 3). Unfortunately, all attempts failed to separate or characterize 16.

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Scheme 3

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Representatively, in ¹H NMR spectrum of 3a, two geminal methyl groups show two singlets at δ 1.84 and 1.91 ppm and methylene protons show a singlet at δ 2.92 ppm, respectively (Fig. 2a). ¹³C NMR spectrum of this compound shows six distinct peaks (Fig. 2b). In ¹³C NMR spectrum of 3a, the carbonyl groups of C4, C6, C2″ and C4″ (Assigned as Cf in Fig. 2b) show a peak at δ 160.33 ppm and indicated that these carbonyl groups have equivalent chemical shifts due to two plane of symmetry in this molecule (Fig. 3). In contrast, in model molecule of 6a, carbon atoms of C4 and C6 have equivalent chemical shifts and the carbon atoms of C10 and C11 have the same case. On the other hand, C6 and C10 have different chemical shifts and also C4 and C11 have the same. Other cyclopropane derivatives 3b–3q (with exception 3a) show two distinct peaks for carbonyl groups because of a plane of symmetry (Fig. 3 and see experimental). These observations are the best evidence for supporting the cyclopropanation and the structure of 3a as representative. Other evidence for the cyclopropanation is the chemical shift value of cyclopropane CH proton that appeared in high field (a singlet at δ 2.92 ppm for 3a and a quartet at δ 3.33 ppm for 3b as representative).

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Figure 2 Representatively, the ¹H (a) and ¹³C NMR spectra of 3a (b).

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Figure 3 Two planes of symmetry in 3a and hypothetical molecule 6a and equivalency of four carbonyl groups in 3a and a plane of symmetry in 3b as representative.

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The different reactivity of variously substituted aldehydes in the reaction with β-dicarbonyl compounds could be rationalized taking into account that the reaction occurs in two steps, i.e. the nucleophilic attack and the dehydration (Bigi et al., 2001). Electron-withdrawing substituents facilitate the first step, meanwhile electron donating substituents facilitate the loss of water giving conjugated stabilized α,β-unsaturated carbonyl compounds. In contrast, aldehydes possessing electron-withdrawing substituents facilitate the formation of bis adduct, 5 in the reaction with 1 in the absence of BrCN (Schemes 1 and 4). No corresponding 5-alkyl and/or aryl-2,2,8,8-tetramethyl-4H-pyrano[2,3-d:6,5-d′]bis([1,3]dioxine)-4,6(5H)-dione (6) was observed from 5 via intramolecular condensation (Schemes 1 and 4).

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Scheme 4

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Previously, it has been reported that aldehyde possessing strong electron-donor substituents in the reaction with barbituric acids, only Knoevenagel condensation was occurred (Adamson et al., 1999). In the reaction of aldehydes 2s–2u with 1 in the presence of BrCN and Et₃N, the Knoevenagel adducts (8s–8u) were obtained (Table 1). Interestingly, in 5-(4-(dimethylamino)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8s) the two carbon atoms of carbonyl groups have equivalent chemical shift at δ 165.21 ppm. This phenomenon has arisen from the low rotational barrier around α,β-unsaturated double bond in 8s because of the easy resonance of nitrogen lone pair with carbonyl groups (Fig. 4A). In 5-((1H-pyrrol-2-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8t), the two carbonyl groups have slightly different chemical shift (at δ 164.35 and 164.24 ppm, respectively). It seems that the NH group of the pyrrole ring moiety has intramolecular H-bond with one of carbonyl bonds and prevents the rotation around α,β-unsaturated double bond in 8t (Fig. 4B). The peak of NH proton on pyrrole ring moiety appeared at δ 12.69 ppm and confirms the intramolecular H-bond in 8t. In 5-(anthracen-9-ylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8u), the chemical shifts of two nonequivalent carbonyl groups appeared at δ 161.87 and 157.84 ppm. This nonequivalency corresponds to restricted rotational barrier around α,β-unsaturated double bond in 8u due to the hindrance effect of bulky anthranyl ring moiety (Fig. 4C).

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Figure 4 ¹³C NMR spectra of 8s (A), 8t (B) and 8u (C) at carbonyl region.

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4 Conclusion

In summary, we have presented and developed a versatile one-pot new reaction of Meldrum’s acid with aldehydes and cyanogen bromide to selectively afford novel full-substituted cyclopropanes based on Meldrum’s acid in the presence of triethylamine at room temperature in moderate yields. The experimental results indicated that the aromatic aldehydes are more reactive than that of aliphatics. The aromatic aldehydes possessing electron-withdrawing substituent are more reactive than that of electron-donating substituent. The aromatic aldehydes possessing strong electron-donating substituent gave exclusively Knoevenagel adducts.